15_page_3-Pyrrolidinone_Dieckmann_1 by Asch

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176 reactions in Reaxys

2017-11-14 06h:00m:13s (EST)

O N GH

Search as: Product, As drawn )

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O O

N O

O O

Rx-ID: 9522023 View in Reaxys 1/176 Yield 72 %

Conditions & References 63 :Reference Example 63 Ethyl 1-benzyloxycarbonyl-4-oxopyrrolidine-3-carboxylate To a solution of ethyl 3-[N-benzyloxycarbonyl-N-(ethoxycarbonyl methyl)amino]ethylpropionate (26.8 g, 79.5 mmol) in ethanol (200 mL), sodium ethoxide (20percent solution in ethanol, 40.6 mL, 119.3 mmol) was added, and the mixture was heated under reflux for 2 hours. After concentrating the reaction mixture under reduced pressure, the residue was dissolved in water (100 mL). Concentrated hydrochloric acid was added to this solution in an ice bath for acidification, and the solution was extracted with chloroform (100 mL*3). The extract was washed with saturated aqueous solution of sodium chloride (100 mL), and dried with anhydrous sodium sulfate. After the filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate, 2:1) to obtain 16.7 g (72percent) of the title compound as a pale brown oily product. 1H-NMR (400 MHz, CDCl )δ ppm: 1.25-1.33 (3H, m), 3.87-4.37 (7H, m), 5.16-5.22 (2H, m), 7.23-7.41 (5H, m). 3 MS (ESI) m/z: 314 (M+Na)+. Stage 1: With sodium ethanolate in ethanol, Time= 2h, Heating / reflux Stage 2: With hydrogenchloride, water, T= 0 °C Patent; DAIICHI PHARMACEUTICAL CO., LTD.; US2006/264428; (2006); (A1) English View in Reaxys

72 %

63 With sodium ethanolate in ethanol, Time= 2h, Heating / reflux Patent; DAIICHI PHARMACEUTICAL CO., LTD.; WO2006/123792; (2006); (A1) Japanese View in Reaxys With potassium tert-butylate Choi, Dong Rack; Shin, Jung Han; Yang, Jin; Yoon, Sue Hye; Jung, Yong Ho; Bioorganic and Medicinal Chemistry Letters; vol. 14; nb. 5; (2004); p. 1273 - 1277 View in Reaxys 3 :[Reference Example 3] Synthesis of 1-benzyl 3-ethyl 4-oxopyrrolidine-1,3-dicarboxylate [Show Image]; 0.35 kg of sodium ethoxide (5.15 mol) was suspended in 9.47 L of tetrahydrofuran. While this suspension was stirred, 3.16 L of a tetrahydrofuran solution containing 1. 64 kg of the crude product of ethyl 3-benzyloxycarbonyl-3-(ethoxycarbonylmethylamino)propionate (equivalent to 4.68 mol) was added dropwise at an internal temperature of 25 to 32°C. The mixture was then stirred at an internal temperature of 25 to 32°C for 2 hours. While the reaction mixture was stirred, 5.15 L of 1 mol/L hydrochloric acid (pH 4.78) was added at an internal temperature of 27 to 28°C and the mixture was stirred for 10 minutes (pH changed from 4.78 to 4.76). Subsequently, tetrahydrofuran (approx. 12 L) was evaporated under reduced pressure. To the resulting residue, 7.89 L of ethyl acetate was added and the mixture was stirred for 5 minutes. The reaction mixture was then allowed to stand and the organic layer (top layer) was collected. To this layer, 3.95 L of water was added and the mixture was stirred for 5 minutes. The mixture was allowed to stand again and the organic layer (top layer) was collected. To this layer, 3.95 L of 28percent brine was added and the mixture was stirred for 5 minutes. The mixture was allowed to stand again and the organic layer (top layer) was collected. To this layer, 0.39 kg of anhydrous sodium sulfate was added and the mixture was stirred for 1 hour. The resulting solid was separated by filtration and washed with 1.58 L of ethyl acetate. The filtrate and the wash were combined and concentrated under reduced pressure. This product was then dried under reduced pressure at an external temperature of 40°C for 30 minutes. The resulting pale brown oil (1.52 kg) was dissolved in 9.47 L of diisopropyl ether and the solution was stirred at an internal temperature of 25°C. Once the formation of crystals was observed (internal temperature of 25°C), the solution was further stirred for 15 minutes at an internal temperature of 25

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to 28°C. Subsequently, the solution was cooled in an ice bath under stirring and was kept stirred for 30 minutes at an internal temperature of 10°C or below. The crystals were then collected by filtration at an internal temperature of 7 °C and washed with a chilled, 4: mixtures of diisopropyl ether/hexane (3.95 L, internal temperature of 3°C). The washed crystals were drained for 15 minutes and air-dried overnight. Subsequently, the product was dried under reduced pressure at 40°C for 9 hours. This gave 1.03 kg of the title compound as a faintly yellowish white powder (75percent yield in the two steps). Melting Point: 56.6-59.7°C EI-MS : m/z 91 (base peak), 291 (M) + With sodium ethanolate in tetrahydrofuran, Time= 2h, T= 25 - 32 °C Patent; Kyorin Pharmaceutical Co., Ltd.; EP1992613; (2008); (A1) English View in Reaxys With potassium tert-butylate in toluene, Dieckmann reaction Jung, Myung-Ho; Joon, Hee Hong; Cho, Jung-Hyuck; Oh, Chang-Hyun; Archiv der Pharmazie; vol. 341; nb. 12; (2008); p. 780 - 786 View in Reaxys

N O

O N

Rx-ID: 4476577 View in Reaxys 2/176 Yield 98 %

Conditions & References 1.3 : 3) Synthesis of compound (d) The crude 1127.324 g compound (c) is dissolved in 2.5 L toluene without water, 243.028g tert potassium butanolate is added gradually under ice bath, stirred for 2h, TLC was carried out to detect the completion of the reaction, 4M HCl in ice bath was added, PH in acidic was adjusted to PH=8 using saturated sodium bicarbonate, extracted with ethyl acetate, dried using anhydrous Na2SO4, filtered, and spin-dried to obtain 376.7g pink solid compound (d), yield 98percent. With potassium tert-butylate in toluene, Time= 2h, Cooling with ice Patent; Allist Pharmaceuticals, Inc; Luo, HuiBing; Guo, JianHui; (20 pag.); CN102584828; (2016); (B) Chinese View in Reaxys

78 %

2 :Above-prepared ethyl 3-[N-benzyl-N-(ethoxycarbonylmethyl)amino]propionate (14.0 g, 0.0479 mol) was dissolved in toluene (100 mL), and the solution was mixed with potassium tert-butoxide (5.9 g, 0.0525 mol) gradually added under ice-cooling, followed by stirring under ice-cooling for two hours. The reaction mixture was mixed with diluted hydrochloric acid (about 1 mol/L, 100 mL) under ice-cooling, followed by shaking and separation, to yield an aqueous layer. Saturated aqueous sodium bicarbonate solution (300 mL) was added dropwise to the aqueous layer, and ethyl acetate (400 mL) was further added thereto, followed by shaking and separation. After drying the organic layer over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, to thereby yield ethyl 1benzyl-4-oxopyrrolidine-3-carboxylate (9.23 g, in a yield of 78percent). With potassium tert-butylate in toluene, Time= 2h, T= 0 °C Patent; KYOWA HAKKO KOGYO CO., LTD.; EP1552842; (2005); (A1) English View in Reaxys With titanium tetrachloride, triethylamine, 1) CH2Cl2, -10 deg C, 0.5 h; 2) CH2Cl2, -10 deg C, 2 h, Yield given. Multistep reaction Deshmukh; Gangakhedkar; Sampath Kumar; Synthetic Communications; vol. 26; nb. 9; (1996); p. 1657 - 1661 View in Reaxys

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H N

N O

O O

HN O

O N O

Rx-ID: 23767459 View in Reaxys 3/176 Yield 39 %

Conditions & References Potassium t-butoxide (1.1 g, 9.8 mmol) was slurried in 30 mL of dry toluene. The mixture was cooled to 0°C on ice and 5 g (6.6 mmol) of diester AD was added slowly with stirring within 20 mins. The temperature was kept below 5°C during the addition. The stirring was continued for 30 mins at 0°C and 1 mL of glacial acetic acid was added, immediately followed by 4 g of NaH2PO4-H2O in 40 mL of water The resultant mixture was extracted twice with 100 mL of dichloromethane each and the combined organic extracts were washed twice with 10 mL of phosphate buffer each, dried, and evaporated to dryness. The residue was dissolved in 60 mL of toluene, cooled to 0°C and extracted with three 50 mL portions of cold pH 9.5 carbonate buffer. The aqueous extracts were adjusted to pH 3 with phosphoric acid, and extracted with five 40 mL portions of chloroform which were combined, dried and evaporated to a residue. The residue was purified by column chromatography using 25percent ethylacetate/hexane to afford 1.9 g of b- ketoester (39percent). EPO <DP n="61"/> With potassium tert-butylate, acetic acid in toluene, Time= 0.833333h, T= 0 - 5 °C Patent; ALNYLAM PHARMACEUTICALS, INC.; WO2006/36916; (2006); (A2) English View in Reaxys

39 %

Potassium t-butoxide (1.1 g, 9.8 mmol) was slurried in 30 mL of dry toluene. The mixture was cooled to 0° C. on ice and 5 g (6.6 mmol) of diester AD was added slowly with stirring within 20 mins. The temperature was kept below 5° C. during the addition. The stirring was continued for 30 mins at 0° C. and 1 mL of glacial acetic acid was added, immediately followed by 4 g of NaH2PO4.H2O in 40 mL of water The resultant mixture was extracted twice with 100 mL of dichloromethane each and the combined organic extracts were washed twice with 10 mL of phosphate buffer each, dried, and evaporated to dryness. The residue was dissolved in 60 mL of toluene, cooled to 0° C. and extracted with three 50 mL portions of cold pH 9.5 carbonate buffer. The aqueous extracts were adjusted to pH 3 with phosphoric acid, and extracted with five 40 mL portions of chloroform which were combined, dried and evaporated to dryness. The residue was, purified by column chromatography using 25percent ethylacetate/hexane to afford 1.9 g of b-ketoester (39percent). With potassium tert-butylate in toluene, Time= 0.833333h, T= 0 - 5 °C Patent; Sah, Dinah Wen-Yee; Hadwiger, Philipp; Roehl, Ingo; Bramlage, Birgit; Tan, Pamela; Vornlocher, Hans-Peter; Bumcrot, David; US2007/99860; (2007); (A1) English View in Reaxys

39 %

Potassium t-butoxide (1.1 g, 9.8 mmol) was slurried in 30 rnL of dry toluene. The mixture was cooled to 0 0C on ice and 5 g (6.6 mmol) of diester AD was added slowly with stirring within 20 mins. The temperature was kept below 5°C during the addition. The stirring was continued for 30 mins at 00C and 1 mL of glacial acetic acid was added, immediately followed by 4 g of NaH2PO4-H2O in 40 mL of water The resultant mixture was extracted twice with 100 mL of dichloromethane each and the combined organic extracts were washed twice with 10 mL of phosphate buffer each, dried, and evaporated to dryness. The residue was dissolved in 60 mL of toluene, cooled to 0 0C and extracted with three 50 mL portions of cold pH 9.5 carbonate buffer. The aqueous extracts were adjusted to pH 3 with phosphoric acid, and extracted with five 40 mL portions of chloroform which were combined, dried and evaporated to dryness.

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The residue was purified by column chromatography using 25percent ethylacetate/hexane to afford 1.9 g of b-ketoester (39percent). Stage 1: With potassium tert-butylate in toluene, Time= 0.833333h, T= 0 - 5 °C Stage 2: With sodium dihydrogenphosphate, acetic acid in water, toluene Patent; ALNYLAM PHARMACEUTICALS, INC.; THE SCRIPPS RESEARCH INSTITUTE; WO2007/137156; (2007); (A2) English View in Reaxys 39%

1-{6-[17-(1,5-Dimethyl-hexyl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a] phenanthren-3-yloxycarbonylamino]hexanoyl}-4-oxo-pyrrolidine-3-carboxylic acid ethyl ester AE 1-{6-[17-(1,5-Dimethyl-hexyl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a] phenanthren-3-yloxycarbonylamino]hexanoyl}-4-oxo-pyrrolidine-3-carboxylic acid ethyl ester AE Potassium t-butoxide (1.1 g, 9.8 mmol) was slurried in 30 mL of dry toluene. The mixture was cooled to 0° C. on ice and 5 g (6.6 mmol) of diester AD was added slowly with stirring within 20 mins. The temperature was kept below 5° C. during the addition. The stirring was continued for 30 mins at 0° C. and 1 mL of glacial acetic acid was added, immediately followed by 4 g of NaH2PO4.H2O in 40 mL of water. The resultant mixture was extracted twice with 100 mL of dichloromethane each and the combined organic extracts were washed twice with 10 mL of phosphate buffer each, dried, and evaporated to dryness. The residue was dissolved in 60 mL of toluene, cooled to 0° C. and extracted with three 50 mL portions of cold phi 9.5 carbonate buffer. The aqueous extracts were adjusted to pH 3 with phosphoric acid, and extracted with five 40 mL portions of chloroform which were combined, dried and evaporated to dryness. The residue was purified by column chromatography using 25percent ethylacetate/hexane to afford 1.9 g of b-ketoester (39percent). Stage 1: With potassium tert-butylate in toluene, Time= 0.833333h, T= 0 - 5 °C Stage 2: With sodium dihydrogen phosphate monohydrate, acetic acid in water, toluene Patent; Alnylam Pharmaceuticals, Inc.; US7605251; (2009); (B2) English View in Reaxys

39 %

Potassium t-butoxide (1.1 g, 9.8 mmol) was slurried in 30 mL of dry toluene. The mixture was cooled to 0 0C on ice and 5 g (6.6 mmol) of diester AD was added slowly with stirring within 20 mins. The temperature was kept below 5°C during the addition. The stirring was continued for 30 mins at 00C and 1 mL of glacial acetic acid was added, immediately followed by 4 g OfNaH2PO4-H2O in 40 mL of water The resultant mixture was extracted twice with 100 mL of dichloromethane each and the combined organic extracts were washed twice with- 10 mL of phosphate buffer each, dried, and evaporated to dryness. The residue was dissolved in 60 mL of toluene, cooled to 0 0C and extracted with three 50 mL portions of cold pH 9.5 carbonate buffer. The aqueous extracts were adjusted to pH 3 with phosphoric acid, and extracted with five 40 mL portions of chloroform which were combined, dried and <n="53"/>Attorney Docket No. 14174-128WO1/ALNE-030PCevaporated to dryness. The residue was purified by column chromatography using 25percent ethylacetate/hexane to afford 1.9 g of b-ketoester (39percent). With potassium tert-butylate, acetic acid, sodium salt of phosphorous acid in water, toluene, Time= 0.833333h, T= 0 - 5 °C Patent; ALNYLAM PHARMACEUTICALS, INC.; WO2007/56331; (2007); (A2) English View in Reaxys

H N

O H

N O

H H

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H H

H O O

HN O

N O

Rx-ID: 24291070 View in Reaxys 4/176 Yield 39 %

Conditions & References 2 :Potassium t-butoxide (1.1 g, 9.8 mmol) was slurried in 30 niL of dry toluene. The mixture was cooled to 0°C on ice and 5 g (6.6 mmol) of diester AD was added slowly with stirring within 20 mins. The temperature was kept below 5°C during the addition. The stirring was continued for 30 mins at 0°C and 1 mL of glacial acetic acid was added, immediately followed by 4 g of NaH2PO4-H2O in 40 mL of water The resultant mixture was extracted twice with 100 mL of dichloromethane each and the combined organic extracts were washed twice with 10 mL of phosphate buffer each, dried, and evaporated to dryness. The residue was dissolved in 60 mL of toluene, cooled to O°C and extracted with three 50 mL portions of cold pH 9.5 carbonate buffer. The aqueous extracts were adjusted to pH 3 with phosphoric acid, and extracted with five 40 mL portions of chloroform which were combined, dried and evaporated to a residue. The residue was purified by column chromatography using 25percent ethylacetate/hexane to afford 1.9 g of b-ketoester (39percent). With potassium tert-butylate in toluene, Time= 0.833333h, T= 0 - 5 °C Patent; ALNYLAM PHARMACEUTICALS, INC.; WO2006/81192; (2006); (A2) English View in Reaxys

39 %

2 : [6-(3-Hydroxy-4-hydroxymethyl-pyrrolidin-1-yl)-6-oxo-hexyl]-carbamic acid 17-(1,5-dimethyl-hexyl)-10,13dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl ester AF Potassium t-butoxide (1.1 g, 9.8 mmol) was slurried in 30 mL of dry toluene. The mixture was cooled to 0° C. on ice and 5 g (6.6 mmol) of diester AD was added slowly with stirring within 20 mins. The temperature was kept below 5° C. during the addition. The stirring was continued for 30 mins at 0° C. and 1 mL of glacial acetic acid was added, immediately followed by 4 g of NaH2PO4.H2O in 40 mL of water The resultant mixture was extracted twice with 100 mL of dichloromethane each and the combined organic extracts were washed twice with 10 mL of phosphate buffer each, dried, and evaporated to dryness. The residue was dissolved in 60 mL of toluene, cooled to 0° C. and extracted with three 50 mL portions of cold pH 9.5 carbonate buffer. The aqueous extracts were adjusted to pH 3 with phosphoric acid, and extracted with five 40 mL portions of chloroform which were combined, dried and evaporated to dryness. The residue was purified by column chromatography using 25percent ethylacetate/hexane to afford 1.9 g of b-ketoester (39percent). Stage 1: With potassium tert-butylate in toluene, Time= 0.833333h, T= 0 - 5 °C Stage 2: With acetic acid in toluene Patent; Sah, Dinah; Frank-Kamenetsky, Maria; Geick, Anke; Hadwiger, Philipp; Roehl, Ingo; Tan, Pamela; Vornlocher, Hans-Peter; US2007/105806; (2007); (A1) English View in Reaxys

39 %

5 :Example 5: l-{6-[17-(l,5-Dimethyl-hexyl)-10,13-dimethyl-2,3,4,7,8,9,10,ll,12,13,14,15,16,17- tetradecahydro-lH-cyclopenta[a] phenanthren-3-yloxycarbonylamino]-hexanoyl}-4-oxo- pyrrolidine-3-carboxylic acid ethyl ester AEAEPotassium t-butoxide (1.1 g, 9.8 mmol) was slurried in 30 mL of dry toluene. The mixture was cooled to 0 0C and 5 g (6.6 mmol) of diester was added slowly with stirring within 20 mins. The temperature was kept below 5 0C during the addition. The stirring was continued for 30 mins at 0 0C and 1 mL of glacial acetic acid was added, immediately followed by 4 g of NaH2PO4-H2O in 40 mL of water The resultant mixture was extracted with two 100 mL of dichloromethane and the combined organic extracts were washed twice with 10 mL of phosphate buffer, dried, and evaporated to dryness. The residue was dissolved in 60 mL of toluene, cooled to 0 0C and extracted with three 50 mL portions of cold pH 9.5 carbonate buffer. The aqueous extracts were converted to pH 3 with phosphoric acid, and extracted with five 40 mL portions of chloroform which were combined, dried and evaporated to a residue. The residue was purified by column chromatography using 25percent ethylacetate/hexanes to afford 1.9 g of β-ketoester was obtained (39 percent). Stage 1: With potassium tert-butylate in toluene, Time= 0.833333h, T= 0 - 5 °C Stage 2: With sodium dihydrogenphosphate, acetic acid in water, toluene Patent; ALNYLAM PHARMACEUTICALS, INC.; WO2006/20768; (2006); (A2) English

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View in Reaxys 39 %

Potassium t-butoxide (1.1 g, 9.8 mmol) was slurried in 30 mL of dry toluene.The mixture was cooled to 0°C on ice and 5 g (6.6 mmol) of diester AD was added slowly with stirring within 20 mins. The temperature was kept below 5°C during the addition. The stirring was continued for 30 mins at 0°C and 1 mL of glacial acetic acid was added, immediately followed by 4 g of NaH2PO4.H2O in 40 mL of water The resultant mixture was extracted twice with 100 mL of dichloromethane each and the combined organic extracts were washed twice with 10 mL of phosphate buffer each, dried, and evaporated to dryness. The residue was dissolved in 60 mL of toluene, cooled to 0°C and extracted with three 50 mL portions of cold pH 9.5 <n="66"/>carbonate buffer. The aqueous extracts were adjusted to pH 3 with phosphoric acid, and extracted with five 40 mL portions of chloroform which were combined, dried and evaporated to dryness. The residue was purified by column chromatography using 25percent ethylacetate/hexane to afford 1.9 g of b-ketoester (39percent). Stage 1: With potassium tert-butylate in toluene, Time= 0.833333h, T= 0 - 5 °C Stage 2: With sodium dihydrogenphosphate, acetic acid in water, toluene Patent; ALNYLAM PHARMACEUTICALS, INC.; THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER AT DALLAS; WO2008/36638; (2008); (A2) English View in Reaxys

39%

1 : 1-{6-[17-(1,5-Dimethyl-hexyl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yloxycarbonylamino]-hexanoyl}-4-oxo-pyrrolidine-3-carboxylic Acid Ethyl Ester AE 1-{6-[17-(1,5-Dimethyl-hexyl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yloxycarbonylamino]-hexanoyl}-4-oxo-pyrrolidine-3-carboxylic Acid Ethyl Ester AE Potassium t-butoxide (1.1 g, 9.8 mmol) was slurried in 30 mL of dry toluene. The mixture was cooled to 0° C. on ice and 5 g (6.6 mmol) of diester AD was added slowly with stirring within 20 mins. The temperature was kept below 5° C. during the addition. The stirring was continued for 30 mins at 0° C. and 1 mL of glacial acetic acid was added, immediately followed by 4 g of NaH2PO4.H2O in 40 mL of water The resultant mixture was extracted twice with 100 mL of dichloromethane each and the combined organic extracts were washed twice with 10 mL of phosphate buffer each, dried, and evaporated to dryness. The residue was dissolved in 60 mL of toluene, cooled to 0° C. and extracted with three 50 mL portions of cold pH 9.5 carbonate buffer. The aqueous extracts were adjusted to pH 3 with phosphoric acid, and extracted with five 40 mL portions of chloroform which were combined, dried and evaporated to dryness. The residue was purified by column chromatography using 25percent ethylacetate/hexane to afford 1.9 g of b-ketoester (39percent). Stage 1: With potassium tert-butylate in toluene, Time= 0.833333h, T= 0 - 5 °C Stage 2: With sodium dihydrogenphosphate, acetic acid in water, toluene Patent; ALNYLAM PHARMACEUTICALS, INC.; GOVERNMENT OF THE UNITED STATES; US2009/143323; (2009); (A1) English View in Reaxys

39 %

1.2.5 :Potassium t-butoxide (1.1 g, 9.8 mmol) was slurried in 30 mL of dry toluene. The mixture was cooled to 0°C on ice and 5 g (6.6 mmol) of diester AD was added slowly with stirring within 20 mins. The temperature was kept below 5°C during the addition. The stirring was continued for 30 mins at 0°C and 1 mL of glacial acetic acid was added, immediately followed by 4 g of NaH2PO4No.H2O in 40 mL of water The resultant mixture was extracted twice with 100 mL of dichloromethane each and the combined organic extracts were washed twice with 10 mL of phosphate buffer each, dried, and evaporated to dryness. The residue was dissolved in 60 mL of toluene, cooled to 0°C and extracted with three 50 mL portions of cold pH 9.5 carbonate buffer. The aqueous extracts were adjusted to pH 3 with phosphoric acid, and extracted with five 40 mL portions of chloroform which were combined, dried and evaporated to dryness. The residue was purified by column chromatography using 25percent ethylacetate/hexane to afford 1.9 g of b-ketoester (39percent). Stage 1: With potassium tert-butylate in toluene, Time= 0.833333h, T= 0 - 5 °C Stage 2: With sodium dihydrogenphosphate, acetic acid in water, toluene Patent; ALNYLAM PHARMACEUTICALS, INC.; WO2005/115481; (2005); (A2) English View in Reaxys

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39 %

1 : 1-{6-[17-(1,5-Dimethyl-hexyl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yloxycarbonylamino]-hexanoyl}-4-oxo-pyrrolidine-3-carboxylic acid ethyl ester AE Potassium t-butoxide (1.1 g, 9.8 mmol) was slurried in 30 mL of dry toluene. The mixture was cooled to 0°C on ice and 5 g (6.6 mmol) of diester AD was added slowly with stirring within 20 mins. The temperature was kept below 5°C during the addition. The stirring was continued for 30 mins at 0°C and 1 mL of glacial acetic acid was added, immediately followed by 4 g of NaH2PO4·H2O in 40 mL of water The resultant mixture was extracted twice with 100 mL of dichloromethane each and the combined organic extracts were washed twice with 10 mL of phosphate buffer each, dried, and evaporated to dryness. The residue was dissolved in 60 mL of toluene, cooled to 0°C and extracted with three 50 mL portions of cold pH 9.5 carbonate buffer. The aqueous extracts were adjusted to pH 3 with phosphoric acid, and extracted with five 40 mL portions of chloroform which were combined, dried and evaporated to dryness. The residue was purified by column chromatography using 25percent ethylacetate/hexane to afford 1.9 g of b-ketoester (39percent). With potassium tert-butylate in toluene, Time= 0.833333h, T= 0 - 5 °C , Cooling with ice Patent; Alnylam Pharmaceuticals, Inc.; Sah, Dinah Wen-yee; Hinkle, Gregory; Alvarez, Rene; Milstein, Stuart; Chen, Qingmin; EP2937418; (2015); (A1) English View in Reaxys

39 %

1 : 1-{6-[17-(1,5-Dimethyl-hexyl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yloxycarbonylamino]-hexanoyl}-4-oxo-pyrrolidine-3-carboxylic acid ethyl ester AE 1-{6-[17-(1,5-Dimethyl-hexyl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yloxycarbonylamino]-hexanoyl}-4-oxo-pyrrolidine-3-carboxylic acid ethyl ester AE Potassium t-butoxide (1.1 g, 9.8 mmol) was slurried in 30 mL of dry toluene. The mixture was cooled to 0° C. on ice and 5 g (6.6 mmol) of diester AD was added slowly with stirring within 20 mins. The temperature was kept below 5° C. during the addition. The stirring was continued for 30 mins at 0° C. and 1 mL of glacial acetic acid was added, immediately followed by 4 g of NaH2PO4.H2O in 40 mL of water. The resultant mixture was extracted twice with 100 mL of dichloromethane each and the combined organic extracts were washed twice with 10 mL of phosphate buffer each, dried, and evaporated to dryness. The residue was dissolved in 60 mL of toluene, cooled to 0° C. and extracted with three 50 mL portions of cold pH 9.5 carbonate buffer. The aqueous extracts were adjusted to pH 3 with phosphoric acid, and extracted with five 40 mL portions of chloroform which were combined, dried and evaporated to dryness. The residue was purified by column chromatography using 25percent ethylacetate/hexane to afford 1.9 g of b-ketoester (39percent). Stage 1: With potassium tert-butylate in toluene, Time= 0.833333h, T= 0 - 5 °C Stage 2: With sodium dihydrogen phosphate monohydrate, acetic acid in water, toluene Patent; Alnylam Pharmaceuticals, Inc.; Sah, Dinah Wen-Yee; Chen, Qingmin; US9200282; (2015); (B2) English View in Reaxys

39%

1 : 1-{6-[17-(1,5-Dimethyl-hexyl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yloxycarbonylamino]-hexanoy}-4-oxo-pyrrolidine-3-carboxylic acid ethyl ester AE 1-{6-[17-(1,5-Dimethyl-hexyl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yloxycarbonylamino]-hexanoy}-4-oxo-pyrrolidine-3-carboxylic acid ethyl ester AE Potassium t-butoxide (1.1 g, 9.8 mmol) can be slurried in 30 mL of dry toluene. The mixture can be cooled to 0° C. on ice and 5 g (6.6 mmol) of diester AD can be added slowly with stirring within 20 mins. The temperature can be kept below 5° C. during the addition. The stirring can be continued for 30 mins at 0° C. and 1 mL of glacial acetic acid can be added, immediately followed by 4 g of NaH2PO4.H2O in 40 mL of water. The resultant mixture can be extracted twice with 100 mL of dichloromethane each and the combined organic extracts can be washed twice with 10 mL of phosphate buffer each, dried, and evaporated to dryness. The residue can be dissolved in 60 mL of toluene, cooled to 0° C. and extracted with three 50 mL portions of cold pH 9.5 carbonate buffer. The aqueous extracts can be adjusted to pH 3 with phosphoric acid, and extracted with five 40 mL portions of chloroform which can be combined, dried and evaporated to dryness. The residue can be purified by column chromatography using 25percent ethylacetate/hexane to afford 1.9 g of bketoester (39percent).

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Stage 1: With potassium tert-butylate in toluene, Time= 0.833333h, T= 0 - 5 °C Stage 2: With sodium dihydrogen phosphate monohydrate, acetic acid in water Patent; Alnylam Pharmaceuticals, Inc.; Sah, Dinah Wen-Yee; Hinkle, Gregory; (240 pag.); US2016/24497; (2016); (A1) English View in Reaxys 39 %

5 : 1-{6-[17-(1,5-Dimethyl-hexyl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yloxycarbonylamino]-hexanoyl}-4-oxo-pyrrolidine-3-carboxylic acid ethyl ester AE 1-{6-[17-(1,5-Dimethyl-hexyl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yloxycarbonylamino]-hexanoyl}-4-oxo-pyrrolidine-3-carboxylic acid ethyl ester AE Potassium t-butoxide (1.1 g, 9.8 mmol) is slurried in 30 mL of dry toluene. The mixture is cooled to 0° C. on ice and 5 g (6.6 mmol) of diester AD is added slowly with stirring within 20 mins. The temperature is kept below 5° C. during the addition. The stirring is continued for 30 mins at 0° C. and 1 mL of glacial acetic acid is added, immediately followed by 4 g of NaH2PO4.H2O in 40 mL of water. The resultant mixture is extracted twice with 100 mL of dichloromethane each and the combined organic extracts are ished twice with 10 mL of phosphate buffer each, dried, and evaporated to dryness. The residue is dissolved in 60 mL of toluene, cooled to 0° C. and extracted with three 50 mL portions of cold pH 9.5 carbonate buffer. The aqueous extracts are adjusted to pH 3 with phosphoric acid, and extracted with five 40 mL portions of chloroform which are combined, dried and evaporated to dryness. The residue is purified by column chromatography using 25percent ethylacetate/hexane to afford 1.9 g of b-ketoester (39percent). Stage 1: With potassium tert-butylate in toluene, Time= 0.833333h, T= 0 - 5 °C Stage 2: With sodium dihydrogen phosphate monohydrate, acetic acid in toluene Patent; Alnylam Pharmaceuticals, Inc.; de Fougerolles, Antonin; Novobrantseva, Tatiana; Akinc, Akin; (87 pag.); US2016/17336; (2016); (A1) English View in Reaxys

39 %

1 : 1-{6-[17-(1,5-Dimethyl-hexyl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yloxycarbonylamino]-hexanoyl}-4-oxo-pyrrolidine-3-carboxylic acid ethyl ester AE 1-{6-[17-(1,5-Dimethyl-hexyl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yloxycarbonylamino]-hexanoyl}-4-oxo-pyrrolidine-3-carboxylic acid ethyl ester AE Potassium t-butoxide (1.1 g, 9.8 mmol) was slurried in 30 mL of dry toluene. The mixture was cooled to 0° C. on ice and 5 g (6.6 mmol) of diester AD was added slowly with stirring within 20 mins. The temperature was kept below 5° C. during the addition. The stirring was continued for 30 mins at 0° C. and 1 mL of glacial acetic acid was added, immediately followed by 4 g of NaH2PO4.H2O in 40 mL of water The resultant mixture was extracted twice with 100 mL of dichloromethane each and the combined organic extracts were washed twice with 10 mL of phosphate buffer each, dried, and evaporated to dryness. The residue was dissolved in 60 mL of toluene, cooled to 0° C. and extracted with three 50 mL portions of cold pH 9.5 carbonate buffer. The aqueous extracts were adjusted to pH 3 with phosphoric acid, and extracted with five 40 mL portions of chloroform which were combined, dried and evaporated to dryness. The residue was purified by column chromatography using 25percent ethylacetate/hexane to afford 1.9 g of b-ketoester (39percent). With potassium tert-butylate in toluene, Time= 0.833333h, T= 0 °C Patent; Ando, Yukio; Jono, Hirofumi; Alvarez, Rene; Sah, Dinah Wen-Yee; (417 pag.); US2016/76029; (2016); (A1) English View in Reaxys

39 %

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the combined organic extracts are washed twice with 10 mL of phosphate buffer each, dried, and evaporated to dryness. The residue is dissolved in 60 mL of toluene, cooled to 0° C. and extracted with three 50 mL portions of cold pH 9.5 carbonate buffer. The aqueous extracts are adjusted to pH 3 with phosphoric acid, and extracted with five 40 mL portions of chloroform which are combined, dried and evaporated to dryness. The residue is purified by column chromatography using 25percent ethylacetate/hexane to afford 1.9 g of b-ketoester (39percent). With potassium tert-butylate in toluene, Time= 0.833333h, T= 0 - 5 °C Patent; Alnylam Pharmaceuticals, Inc.; Gollob, Jared; Hinkle, Gregory; Toudjarska, Ivanka; Bumcrot, David; (73 pag.); US9566295; (2017); (B2) English View in Reaxys

O O

N H

O O

H H

O H H

HN O

O N O

Rx-ID: 10746471 View in Reaxys 5/176 Yield 39 %

Conditions & References l-l-IlT-tl^-Dimethyl-hexyO-lOaS-dimethyl-Z.S^J.S^.lO.l l.n.π.H.lS.l,.?- tetradecahydro-lH-cyclopenta[a] ρhenanthren-3yloxycarbonylaminoJ-hexanoyl}-4-oxo- pyrrolidine-3-carboxylic acid ethyl ester AEAEPotassium t-butoxide (1.1 g, 9.8 mmol) was slurried in 30 mLof dry toluene. The mixture was cooled to O0C on ice and 5 g (6.6 mmol) of diester AD was added slowly with stirring within 20 mins. The temperature was kept below 50C during the addition. The stirring was continued for 30 mins at O0C and 1 mL of glacial acetic acid was added, immediately followed by 4 g of NaH2PO4 H2O in 40 mL of water The resultant mixture was extracted twice with 100 mL of dichloromethane each and the combined organic extracts were washed twice with 10 mL of phosphate buffer each, dried, and evaporated to dryness. The residue was dissolved in 60 mL of toluene, cooled to 00C and extracted with three 50 mL portions of cold pH 9.5 carbonate buffer. The aqueous extracts were adjusted to pH 3 with phosphoric acid, and extracted with five 40 mL portions of chloroform which were combined, dried and evaporated to dryness. The residue was purified by column chromatography using 25percent ethylacetate/hexane to afford 1.9 g of b-ketoester (39percent). Stage 1: With potassium tert-butylate in toluene, Time= 0.833333h, T= 0 - 5 °C Stage 2: With acetic acid in toluene Patent; ALNYLAM PHARMACEUTICALS, INC.; IMPERIAL INNOVATIONS LTD; WO2007/137220; (2007); (A2) English View in Reaxys

39 %

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each and the combined organic extracts were washed twice with 10 mL of phosphate buffer each, dried, and evaporated to dryness. The residue was dissolved in 60 mL of toluene, cooled to 0° C. and extracted with three 50 mL portions of cold pH 9.5 carbonate buffer. The aqueous extracts were adjusted to pH 3 with phosphoric acid, and extracted with five 40 mL portions of chloroform which were combined, dried and evaporated to dryness. The residue was purified by column chromatography using 25percent ethylacetate/hexane to afford 1.9 g of b-ketoester (39percent). With potassium tert-butylate in toluene, Time= 0.833333h, T= 0 °C , Cooling with ice Patent; Alnylam Pharmaceuticals, Inc.; Sah, Dinah Wen-Yee; US9101643; (2015); (B2) English View in Reaxys 39 %

1 : 1-{6-[17-(1,5-Dimethyl-hexyl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yloxycarbonylamino]-hexanoyl}-4-oxo-pyrrolidine-3-carboxylic acid ethyl ester AE 1-{6-[17-(1,5-Dimethyl-hexyl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yloxycarbonylamino]-hexanoyl}-4-oxo-pyrrolidine-3-carboxylic acid ethyl ester AE Potassium t-butoxide (1.1 g, 9.8 mmol) was slurried in 30 mL of dry toluene. The mixture is cooled to 0° C. on ice and 5 g (6.6 mmol) of diester AD is added slowly with stirring within 20 mins. The temperature is kept below 5° C. during the addition. The stirring is continued for 30 mins at 0° C. and 1 mL of glacial acetic acid is added, immediately followed by 4 g of NaH2PO4.H2O in 40 mL of water The resultant mixture is extracted twice with 100 mL of dichloromethane each and the combined organic extracts are washed twice with 10 mL of phosphate buffer each, dried, and evaporated to dryness. The residue is dissolved in 60 mL of toluene, cooled to 0° C. and extracted with three 50 mL portions of cold pH 9.5 carbonate buffer. The aqueous extracts are adjusted to pH 3 with phosphoric acid, and extracted with five 40 mL portions of chloroform which are combined, dried and evaporated to dryness. The residue is purified by column chromatography using 25percent ethylacetate/hexane to afford 1.9 g of b-ketoester (39percent). With potassium tert-butylate in toluene, Time= 0.833333h, T= 0 - 5 °C Patent; Alnylam Pharmaceuticals, Inc.; de Fougerolles, Antonin; Novobrantseva, Tatiana; Hinkle, Gregory; US9206421; (2015); (B2) English View in Reaxys O

O Cl

O O

N O

O N

O O

Rx-ID: 46077353 View in Reaxys 6/176 Yield 85 %

Conditions & References 1 : preparation of intermediate 1 1000ml four-necked flask by adding Boc-pyrrolidone 120g, DMF 600ml, Stirring down to 0-5 , Sodium hydride was added to 26 g, 70.5 g of ethyl chloroformate was slowly added dropwise with stirring, 40min drop finished. 0-5 reaction 2h, TLC detection reaction is completed, Slowly add 3L ice water, With dilute hydrochloric acid to adjust the pH = 7 after ethyl acetate extraction, dry, Concentrated to give intermediate 1. Yield 85percent. With sodium hydride in N,N-dimethyl-formamide, Time= 2.66667h, T= 0 - 5 °C , Reagent/catalyst, Solvent, Temperature Patent; Jinan Tonglu Pharmaceutical Co., Ltd.; Yu Lun; Wang Haibo; Li Jiayuan; Liu Ge; Liu Jing; Qin Jingyan; Wang Ruifeng; (7 pag.); CN106905325; (2017); (A) Chinese View in Reaxys

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O HO

N H

O N

O O

Rx-ID: 33104329 View in Reaxys 7/176 Yield 63 %

Conditions & References 8.1 :Example 8 : Preparation of (3R,4S)-3-amino-4-(3-boronopropyl)pyrrolidine-3- carboxylic acidStep 1, Method A: tert-butyl 3-allyl-4-oxopyrrolidine-l-carboxylate[0179] An ice-cooled (3 °C) stirred solution of N-boc-glycine, allyl ester (6.46 g, 30 mmol) in anhydrous tetrahydrofuran (60 mL) under nitrogen was treated with IN lithiumbis(trimethylsilylamide)/tetrahydrofuran (33 mL, 33 mmol) at a rate to keep pot temperature below 10 °C, then stirred at 3 °C for 15 min and cooled (-40 °C). A solution of allyl acrylate (4.45 mL, 35 mmol) in anhydrous tetrahydrofuran (25 mL) was added dropwise, and the mixture allowed to reach room temperature, stirred 1 h, and refluxed for 2 h. The mixture was cooled to room temperature, quenched with glacial acetic acid (2.5 mL), andconcentrated. The residual oil was dissolved in methylene chloride (300 mL) and the solution washed with water and saturated sodium bicarbonate (150 mL each), dried (Na2S04), and concentrated. The residue was dissolved in minimum methylene chloride and loaded onto a silica gel column (350 mL volume) and eluted with 55:30: 15 heptane/methylene chloride/ethyl acetate to afford 3-allyl 1-tert-butyl 4-oxopyrrolidine-l,3-dicarboxylate (5.07g, 63percent) as a colorless oil. NMR (CDC1 3): δ 5.85 - 6.00 (m, 1 H), 5.20 - 5.40 (m, 2 H), 4.60 - 4.75 (m, 2 H), 4.20 (m, 1 H), 3.95 - 4.10 (m, 1 H), 3.87 (dJ= 6.5 Hz, 1 H), 3.62 (t, J = 8 Hz, 1 H), 1.48 (s, 9 H). MS (m + 1): 270.4; MS (m - bu + 1): 214.2. Stage 1: With lithium hexamethyldisilazane in tetrahydrofuran, Time= 0.25h, T= -40 - 10 °C , Inert atmosphere, Dieckmann Reaction Stage 2: in tetrahydrofuran, Time= 3h, Reflux Patent; MARS INCORPORATED; VAN ZANDT, Michael; JAGDMANN, JR., Gunnar Erik; WO2012/58065; (2012); (A1) English View in Reaxys

O N

O O H

N H O

O O

O H H

H H

Rx-ID: 10684477 View in Reaxys 8/176 Yield 39 %

Conditions & References Potassium t-butoxide (1.1 g, 9.8 mmol) was slurried in 30 mL of dry toluene. The mixture was cooed to 0° C. on ice and 5 g (6.6 mmol) of diester AD was added slowly with stirring within 20 mins. The temperature was kept below 5° C. during the addition. The stirring was continued for 30 mins at 0° C. and 1 mL of glacial acetic acid was added, immediately followed by 4 g of NaH2PO4-H2O in 40 mL of water. The resultant mixture was extracted twice with 100 mL of dichloromethane each and the combined organic extracts were washed twice with 10 mL of phosphate buffer each, dried, and evaporated to dryness. The residue was dissolved in 60 mL of toluene, cooled to 0° C. and extracted with three 50 mL portions of cold pH 9.5 carbonate buffer. The aqueous extracts were adjusted to pH 3 with phosphoric acid, and extracted with five 40 mL portions of chloroform which were combined, dried and evaporated to dryness. The residue was purified by column chromatography using 25percent ethylacetate/hexane to afford 1.9 g of b-detoester (39percent). With sodium dihydrogenphosphate, potassium tert-butylate, acetic acid in toluene, Time= 0.833333h, T= 0 - 5 °C

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Patent; Bumcrot, David; Tan, Pamela; Vornlocher, Hans-Peter; Geick, Anke; US2007/281899; (2007); (A1) English View in Reaxys

O O

N O

H N

O N

O O

Rx-ID: 27728659 View in Reaxys 9/176 Yield 39 %

Conditions & References Potassium t-butoxide (1.1 g, 9.8 mmol) was slurried in 30 mL of dry toluene. The mixture was cooled to O 0C on ice and 5 g (6.6 mmol) of diester AD was added slowly with stirring within 20 mins. The temperature was kept below 5°C during the addition. The stirring was continued for 30 mins at 00C and 1 mL of glacial acetic acid was added, immediately followed by 4 g of NaH2PO4-H2O in 40 mL of water The resultant mixture was extracted twice with 100 mL of dichloromethane each and the combined organic extracts were washed twice with 10 mL of phosphate buffer each, dried, and evaporated to dryness. The residue was dissolved in 60 mL of toluene, cooled to 0 0C and extracted with three 50 mL portions of cold pH 9.5 carbonate buffer. The aqueous extracts were adjusted to pH 3 with phosphoric acid, and extracted with five 40 mL portions of chloroform which were combined, dried and evaporated to dryness. The residue was purified by column chromatography using 25percent ethylacetate/hexane to afford 1.9 g of b-ketoester (39percent). Stage 1: With potassium tert-butylate in toluene, Time= 0.833333h, T= 0 - 5 °C Stage 2: With sodium dihydrogenphosphate, acetic acid in water, toluene Patent; NOVARTIS AG; WO2008/116860; (2008); (A2) English View in Reaxys

13/81

2017-11-14 06:00:59

O N O

H N

O H

N O

O O

H H

H H H

Rx-ID: 41732518 View in Reaxys 10/176 Yield 39 %

Conditions & References 1 : 1-{6-[17-(1,5-Dimethyl-hexyl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yloxycarbonylamino]-hexanoyl}-4-oxo-pyrrolidine-3-carboxylic acid ethyl ester AE Potassium t-butoxide (1.1 g, 9.8 mmol) is slurried in 30 mL of dry toluene. The mixture is cooled to 0° C. on ice and 5 g (6.6 mmol) of diester AD is added slowly with stirring within 20 mins. The temperature is kept below 5° C. during the addition. The stirring is continued for 30 mins at 0° C. and 1 mL of glacial acetic acid is added, immediately followed by 4 g of NaH2PO4.H2O in 40 mL of water. The resultant mixture is extracted twice with 100 mL of dichloromethane each and the combined organic extracts are washed twice with 10 mL of phosphate buffer each, dried, and evaporated to dryness. The residue is dissolved in 60 mL of toluene, cooled to 0° C. and extracted with three 50 mL portions of cold pH 9.5 carbonate buffer. The aqueous extracts are adjusted to pH 3 with phosphoric acid, and extracted with five 40 mL portions of chloroform which are combined, dried and evaporated to dryness. The residue is purified by column chromatography using 25percent ethylacetate/hexane to afford 1.9 g of b-ketoester (39percent). Stage 1: With potassium tert-butylate in toluene, Time= 0.833333h, T= 0 °C Stage 2: With sodium dihydrogen phosphate monohydrate, acetic acid in water, toluene, Time= 0.5h, T= 0 - 5 °C Patent; Alnylam Pharmaceuticals, Inc.; Ludwig Institute for Cancer Research Ltd.; Sah, Dinah; Tan, Pamela; Cavenee, Webster; Furnari, Frank; Perez, Maria del Mar Inda; Bonavia, Rudy; US9212364; (2015); (B2) English View in Reaxys

O O

N O O H

NH O

H H H

14/81

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H H

O O

HN O

N O

Rx-ID: 42153523 View in Reaxys 11/176 Yield

Conditions & References

39 %

1 : 1-{6-[17-(1,5-Dimethyl-hexyl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yloxycarbonylamino]-hexanoyl}-4-oxo-pyrrolidine-3-carboxylic acid ethyl ester AE 1-{6-[17-(1,5-Dimethyl-hexyl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yloxycarbonylamino]-hexanoyl}-4-oxo-pyrrolidine-3-carboxylic acid ethyl ester AE Potassium t-butoxide (1.1 g, 9.8 mmol) was slurried in 30 mL of dry toluene. The mixture was cooled to 0° C. on ice and 5 g (6.6 mmol) of diester AD was added slowly with stirring within 20 mins. The temperature was kept below 5° C. during the addition. The stirring was continued for 30 mins at 0° C. and 1 mL of glacial acetic acid was added, immediately followed by 4 g of NaH2PO4.H2O in 40 mL of water The resultant mixture was extracted twice with 100 mL of dichloromethane each and the combined organic extracts were washed twice with 10 mL of phosphate buffer each, dried, and evaporated to dryness. The residue was dissolved in 60 mL of toluene, cooled to 0° C. and extracted with three 50 mL portions of cold pH 9.5 carbonate buffer. The aqueous extracts were adjusted to pH 3 with phosphoric acid, and extracted with five 40 mL portions of chloroform which were combined, dried and evaporated to dryness. The residue was purified by column chromatography using 25percent ethylacetate/hexane to afford 1.9 g of b-ketoester (39percent). Stage 1: With potassium tert-butylate in toluene, Time= 0.833333h, T= 0 - 5 °C Stage 2: With sodium dihydrogen phosphate monohydrate, acetic acid in water, toluene Patent; Alnylam Pharmaceuticals, Inc.; de Fougerolles, Antonin; Borodovsky, Anna; Novobrantseva, Tatiana; US2015/353934; (2015); (A1) English View in Reaxys

H N

N O

H H

H O O

HN O

O N O

Rx-ID: 42401273 View in Reaxys 12/176 Yield 39 %

Conditions & References 1 : 1-{6-[17-(1,5-dimethyl-hexyl)10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yloxycarbonylamino]hexanoyl}4-oxo-pyrrolidine-3-carboxylic acid ethyl ester AE Potassium t-butoxide (1.1 g, 9.8 mmol) was slurried in 30 mL of dry toluene. The mixture was cooled to 0° C. on ice and 5 g (6.6 mmol) of diester AD was added slowly with stirring within 20 mins. The temperature was kept below 5° C. during the addition. The stirring was continued for 30 mins at 0° C. and 1 mL of glacial acetic acid was added, immediately followed by 4 g of NaH2PO4.H2O in 40 mL of water The resultant mixture was extracted twice with 100

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mL of dichloromethane each and the combined organic extracts were washed twice with 10 mL of phosphate buffer each, dried, and evaporated to dryness. The residue was dissolved in 60 mL of toluene, cooled to 0° C. and extracted with three 50 mL portions of cold pH 9.5 carbonate buffer. The aqueous extracts were adjusted to pH 3 with phosphoric acid, and extracted with five 40 mL portions of chloroform which were combined, dried and evaporated to dryness. The residue was purified by column chromatography using 25percent ethylacetate/hexane to afford 1.9 g of b-ketoester (39percent). With potassium tert-butylate in toluene, Time= 0.5h, T= 0 °C Patent; Alnylam Pharmaceuticals, Inc.; Bumcrot, David; Sah, Dinah Wen-Yee; Toudjarska, Ivanka; (103 pag.); US2016/819; (2016); (A1) English View in Reaxys

O O

Rx-ID: 186852 View in Reaxys 13/176 Yield

Conditions & References With sodium, xylene Miyamoto; Yakugaku Zasshi; vol. 77; (1957); p. 568; ; (1957); p. 16422 View in Reaxys 3 :Step 3. diethyl 4-oxopyrrolidine-1,3-dicarboxylate (f) Intermediate (e) (18.Og, 65.2 mmol) was added to an ice bath cooled solution of NaOEt (32.6 mL) (21percent by weight in EtOH) in absolute EtOH (41.7 mL) under a nitrogen atmosphere.The ice bath was removed and the mixture was heated at 800C for about 12h until the condensation was complete as observed by TLC. The mixture was poured onto ice/water and extracted into EtOAc. The solvent was dried with Na2SO4, filtered, and evaporated to afford crude intermediate (f) as an off white solid (14.05g) which was carried on without purification. With ethanol, sodium ethanolate, Time= 12h, T= 80 °C Patent; PFIZER INC.; WO2008/96218; (2008); (A1) English View in Reaxys 1.3 :Intermediate (e) (18.0 g, 65.2 mmol) was added to an ice bath cooled solution of NaOEt (32.6 mL) (21percent by weight in EtOH) in absolute EtOH (41.7 mL) under a nitrogen atmosphere. The ice bath was removed and the mixture was heated at 80° C. for about 12 h until the condensation was complete as observed by TLC. The mixture was poured onto ice/water and extracted into EtOAc. The solvent was dried with Na2SO4, filtered, and evaporated to afford crude intermediate (f) as an off white solid (14.05 g) which was carried on without purification. With sodium ethanolate in ethanol, T= 80 °C , Inert atmosphere, Cooling with ice Patent; Pfizer Inc; US2010/41681; (2010); (A1) English View in Reaxys

N O

Rx-ID: 33104307 View in Reaxys 14/176 Yield 90 %

Conditions & References 8.1 :Step 1, Method B: tert-butyl 3-aUyl-4-oxopyrrolidine-l-carboxylate[0181] A solution of 1-tert-butyl 3-methyl 4-oxopyrrolidine-l,3-dicarboxylate (48.65 g, 0.20 mol), allyl alcohol (300 mL), and dibutyltin oxide (5.0 g, 20 mmol) in anhydrous toluene (800 mL) was refluxed for 20 h under a Dean-Stark trap with portionwise removal of solvent (total of

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2017-11-14 06:00:59

200 mL) over the first 6 hours, followed by addition of more allyl alcohol (75 mL) at the end of the first 6 hours. The reaction mixture was concentrated, dissolved in minimal methylene chloride, and loaded onto a silica gel column (700 mL volume) and eluted with methylene chloride, 10percent, then 15percent, then 20percent ethyl acetate/methylene chloride to afford 3- allyl 1-tert-butyl 4-oxopyrrolidine-l,3-dicarboxylate (48.6 g, 90percent) as a pale pink oil (NMR and MS as above). This compound (48.47g, 0.18 mol) was dissolved in anhydrous tetrahydrofuran (200 mL) and added to a stirred solution of Pd(PPh3)4 (4.16 g, 3.6 mmol) in anhydrous tetrahydrofuran (400 mL) under nitrogen, stirred for 4 h, and concentrated. The residue was dissolved in heptane and loaded onto a silica gel column (1000 mL volume) and eluted with 60:35:5 heptane/methylene chloride/ethyl acetate to afford tert-butyl 3-allyl-4- oxopyrrolidine-l-carboxylate (27.93, 69percent) as a pale yellow oil (NMR and MS as above). With di(n-butyl)tin oxide in toluene, Time= 20h, Reflux Patent; MARS INCORPORATED; VAN ZANDT, Michael; JAGDMANN, JR., Gunnar Erik; WO2012/58065; (2012); (A1) English View in Reaxys

O O

N H

N O

Rx-ID: 10441939 View in Reaxys 15/176 Yield

Conditions & References

62 %

Stage 1: With sodium hydride in toluene, Time= 1h, T= 20 °C Stage 2: in toluene, Time= 4.5h, T= 0 °C Simpson, Graham L.; Gordon, Andrew H.; Lindsay, David M.; Promsawan, Netnepa; Crump, Matthew P.; Mulholland, Keith; Hayter, Barry R.; Gallagher, Timothy; Journal of the American Chemical Society; vol. 128; nb. 33; (2006); p. 10638 - 10639 View in Reaxys

72.6 g

Stage 1: With sodium hydride in toluene, Time= 5h, T= 4 °C Stage 2: in toluene, Time= 2h, T= 20 °C , Further stages. Kim, Sung-Gon; Lee, Sang Ho; Park, Tae-Ho; Tetrahedron Letters; vol. 48; nb. 29; (2007); p. 5023 - 5026 View in Reaxys

N H

N O

Rx-ID: 28954209 View in Reaxys 16/176 Yield

Conditions & References

85 %

With potassium tert-butylate in tetrahydrofuran, T= 0 - 20 °C Smith, Alexander M.R.; Billen, Denis; Hii, King Kuok; Chemical Communications; nb. 26; (2009); p. 3925 - 3927 View in Reaxys

O O

O N

O O

Rx-ID: 2592251 View in Reaxys 17/176 Yield 64 %

Conditions & References With sodium ethanolate in ethanol, benzene, Time= 0.5h, Heating

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Su; Watanabe; Journal of Organic Chemistry; vol. 54; nb. 1; (1989); p. 220 - 224 View in Reaxys 64%

3 : EXAMPLE 3 EXAMPLE 3 A solution of ethyl N-(b-ethoxycarbonylethyl)-N-(4-methoxyphenyl)glycinate (106.7 g, 0.345 mol) in dry benzene (400 mL) is added to a mixture of ethanolic sodium ethoxide in benzene (prepared by dissolving 13.1 g of sodium metal in 300 mL of ethanol and then the ethanolic sodium ethoxide solution is diluted with 500 mL of benzene) at room temperature over a period of 90 minutes. The mixture is heated at reflux for 30 minutes and then is cooled to room temperature. The solid is collected by filtration, and then is suspended in an ice-water mixture (1 L). The mixture, after being neutralized with 1 N hydrochloric acid, is extracted with diethyl ether (3*500 mL). The combined extracts are washed with water, dried over sodium sulfate, concentrated, and the residue is crystallized from n-hexane-diethyl ether to afford 1-(4-methoxyphenyl)-4-ethoxycarbonylpyrrolidine-3-one (87.4 g, 64percent), mp 58°-60° C. 1 H NMR (CDCl3) d 1.34 (3H, dt, CH2 Me), 3.76 (3H, s, OMe), 3.75 (2H, dq, CH2 Me), 4.14 (2H, s, 2-CH2), 4.12-4.39 (3H, m, H-4 and 5-CH2), 6.46 and 6.86 (each 2H, m, Ph). Microanalyses Calculated for C12 H17 NO4: C, 63.86, H, 6.51, N, 5.32percent. Found: C, 63.78, H, 6.56, N, 5.41percent. in ice-water, ethanol, benzene Patent; Sloan-Kettering Institute for Cancer Research; US4925939; (1990); (A1) English View in Reaxys O O

N O

Rx-ID: 9475306 View in Reaxys 18/176 Yield

Conditions & References With sodium ethanolate in ethanol, Time= 3h, Heating, Dieckmann reaction Lee, Ji Hoon; Lee, Kyung Seok; Kang, Yong Koo; Yoo, Kyung Ho; Shin, Kye Jung; Kim, Dong Chan; Kong, Jae Yang; Lee, Yeonhee; Lee, Sook Ja; Kim, Dong Jin; Bioorganic and Medicinal Chemistry Letters; vol. 13; nb. 24; (2003); p. 4399 - 4403 View in Reaxys 5 : The Preparation of Compound 14D: The Preparation of Compound 14D: Sodium (27.6 g, 0.765 mol) was added stepwise to absolute ethanol (1.5 L). When the solid completely disappeared, compound 14C (300 g, 1.04 mol) was added to the solution. The reaction mixture was refluxed overnight, monitored with TCL (PE/EA=4:1), until the starting material was completely consumed. The reaction mixture was evaporated to remove most of the solvent. The residue was dissolved in water (1 L) and acidified with citric acid to pH 6. The mixture was extracted with EA (1 L×3). The extract liquors were combined, washed with brine (1 L×3), dried with anhydrous Na2SO4 and evaporated, to obtain compound 14D (169 g, 63.4percent) as a brown oily substance. The crude product was used directly in the next step without a further purification. With ethanol, sodium, Reflux Patent; GUANGZHOU HUI BO RUI BIOLOGICAL PHARMACEUTICAL TECHNOLOGY CO., LTD.; ZHONGSHAN OPHTHALMIC CENTER, SUN YAT-SEN UNIVERSITY; Hou, Rui; Zhang, Kang; (25 pag.); US2016/75708; (2016); (A1) English View in Reaxys 5 : Preparation of Compound 14D: Sodium ethoxide (27.6 g, 0.765 mol) was added stepwise to absolute ethanol (1.5 L). When the solid completely disappeared, compound 14C (300 g, 1.04 mol) was added to the solution. The reaction mixture was refluxed overnight, monitored with TCL (PE/EA=4:1), until the starting material was completely consumed. The reaction mixture was evaporated to remove most of the solvent. The residue was dissolved in water (1 L) and acidified with citric acid to pH 6. The mixture was extracted with EA (1 L×3). The extract liquors were combined, washed with brine (1 L×3),

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dried with anhydrous Na2SO4 and evaporated, to obtain compound 14D (169 g, 63.4percent) as a brown oily substance. The crude product was used directly in the next step without a further purification. With sodium ethanolate in ethanol, Reflux Patent; Hui Guangzhou Borui Biological pharmaceutical technology co.Ltd; zhongshan ophthalmic center sun yat-sen university; Ho, Wo Louie; Jang, Khang; (31 pag.); KR2015/139962; (2015); (A) Korean View in Reaxys O

O O

N H

N O

Rx-ID: 29066665 View in Reaxys 19/176 Yield

Conditions & References 1.A :To a solution of BOC glycine methyl ester (J. Med. Chem. 2001, 44, 8, 1192-1201) (19.2 g, 101.5 mmol) in THF at 0° C. was added dropwise ethyl acrylate (11 mL, 101.5 mmol) over 10 minutes. The solution was stirred for 20 minutes, then KOtBu (111.65 mL, 111.65 mmol) was added over 45 minutes. The solution was allowed to warm to 25° C. overnight. The resulting solution concentrated in vacuo and portioned between ethyl acetate and water containing 5 mL of acetic acid. The ethyl acetate layer was removed and aqueous layer extracted with 2*200 mL of ethyl acetate. The combined ethyl acetate layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to afford an oil. MS (DCI/NH4) m/z=258 (M+H)+, 275 (M+NH4)+. Stage 1: in tetrahydrofuran, T= 0 °C Stage 2: With potassium tert-butylate in tetrahydrofuran, T= 0 - 25 °C Patent; Abbott Laboratories; US2010/29686; (2010); (A1) English View in Reaxys O

O O O

NH 2

Rx-ID: 32203992 View in Reaxys 20/176 Yield

Conditions & References

99.5 %

6 :A solution of 6.45 g of 3-dimethylaminopropylamine (63.2 mmol) in 50 ml of ethanol was added dropwise to a solution of 8.90 ml of dimethyl itaconate (63.2 mmol) in 200 ml of ethanol, and, after addition, the reaction medium was stirred for 24 hours. The solvents were then evaporated off under reduced pressure to obtain 14.3 g of the expected product in the form of a pale yellow oil, in a yield of 99.5percent.The 1 H and 13C NMR spectra are in accordance with the structure of the compound of formula 1 . in ethanol, Time= 24h Patent; L'OREAL; BLAISE, Christian; WO2011/154457; (2011); (A1) English View in Reaxys

O O

N H O

N O

O O

Rx-ID: 30642743 View in Reaxys 21/176 Yield 90 %

Conditions & References With potassium tert-butylate in tetrahydrofuran, Time= 16h, T= 23 °C , Inert atmosphere, Cooling with ice

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Christoffers, Jens; Sluiter, Jonas; Schmidt, Jan; Synthesis; nb. 6; (2011); p. 895 - 900; Art.No: T21410SS View in Reaxys 90 %

With potassium tert-butylate in tetrahydrofuran, Time= 16h, T= 23 °C , Dieckmann reaction Penning, Miriam; Christoffers, Jens; European Journal of Organic Chemistry; nb. 9; (2012); p. 1809 - 1818 View in Reaxys

O H N

N O

O O

Rx-ID: 3351995 View in Reaxys 22/176 Yield

Conditions & References

75 %

Stage 1: With sodium hydride in toluene, Time= 24h, T= 20 °C Stage 2: With sodium hydride in toluene, Time= 5h, T= 20 °C , Further stages. Akue-Gedu, Rufine; Gautret, Philippe; Lelieur, Jean-Pierre; Rigo, Benoit; Synthesis; nb. 21; (2007); p. 3319 3322; Art.No: P08507SS View in Reaxys With sodium, 1) toluene, xylene, 80 deg C (1/4 h), room temperature (overnight); 2) toluene, xylene, reflux, 3.5 h, Yield given. Multistep reaction Thorbek; Hjeds; Schaumburg; Acta Chemica Scandinavica, Series B: Organic Chemistry and Biochemistry; vol. 35; nb. 7 B; (1981); p. 473 - 479 View in Reaxys

O O

O O O

N H

N O

O O

Rx-ID: 3790834 View in Reaxys 23/176 Yield 83 %

Conditions & References With sodium in toluene Jones, Keith; Wilkinson, James; Journal of the Chemical Society, Chemical Communications; nb. 24; (1992); p. 1767 - 1769 View in Reaxys R.1 : 1-Benzyloxycarbonyl-4-ethoxycarbonyl-3-oxopyrrolidine REFERENCE EXAMPLE 1 1-Benzyloxycarbonyl-4-ethoxycarbonyl-3-oxopyrrolidine Ethyl acrylate (65.01 ml, 600.0 mmol) was added to a toluene (1,200 ml) solution containing N-benzyloxycarbonylglycine ethyl ester (156.3 g, 600.0 mmol) and then, under ice-cooling, sodium hydride (60percent oil; 26.40 g, 660.0 mmol) was added thereto. After 10 minutes of stirring at the same temperature, the ice bath was taken off, and the mixture was stirred at room temperature for 20 minutes and then at 50° C. for 3 hours. After completion of the reaction, and under ice-cooling, the reaction solution was adjusted to about pH 3 by adding 10percent citric acid aqueous solution and mixed with ethyl acetate, and the mixture was shaken and then subjected to separation of layers. The organic layer was separated and washed with saturated brine, and the water layer was further extracted with ethyl acetate. The organic layers were dried over anhydrous sodium sulfate and then filtered, and the solvent was evaporated under a reduced pressure to obtain 196.7 g (600.0 mmol, quantitative) of the title compound. 1H-NMR (400 MHz, CDCl ) δ (ppm): 1.22-1.32 (3 H, m), 3.93-4.05 (1 H, m), 4.05-4.31 (5 H, m), 5.13-5.23 (2 H, m), 3 7.28-7.40 (5 H, m).

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With citric acid in ethyl acetate, toluene Patent; Daiichi Pharmaceutical Co., Ltd.; US6423843; (2002); (B1) English View in Reaxys

O O

H N

O O

Rx-ID: 8520179 View in Reaxys 24/176 Yield

Conditions & References

85 %

Stage 1: With sodium hydride in benzene, Time= 12h, T= 20 - 100 °C , Metallation Stage 2: in benzene, Time= 2h, Heating, Cyclization Yadav; Sarkar, Sanjita; Chandrasekhar; Tetrahedron; vol. 55; nb. 17; (1999); p. 5449 - 5456 View in Reaxys

O O O

N O

O O

Rx-ID: 9161170 View in Reaxys 25/176 Yield

Conditions & References

83 %

With sodium hydride in N,N-dimethyl-formamide, toluene, T= 20 - 100 °C , Dieckmann condensation Sunagawa, Makoto; Itoh, Masanori; Kubota, Kubota; Sasaki, Akira; Ueda, Yutaka; Angehrn, Peter; Bourson, Anne; Goetschi, Erwin; Hebeisen, Paul; Then, Rudolf L.; Journal of Antibiotics; vol. 55; nb. 8; (2002); p. 722 757 View in Reaxys

O O

N O O

Rx-ID: 11418365 View in Reaxys 26/176 Yield

Conditions & References Reaction Steps: 2 1.1: triethylamine / methanol / 4 h / 20 °C 2.1: sodium hydride / toluene / 5 h / 4 °C 2.2: 72.6 g / toluene / 2 h / 20 °C With sodium hydride, triethylamine in methanol, toluene Kim, Sung-Gon; Lee, Sang Ho; Park, Tae-Ho; Tetrahedron Letters; vol. 48; nb. 29; (2007); p. 5023 - 5026 View in Reaxys Reaction Steps: 2 1.1: 99 percent / NaHCO3 / acetonitrile / 16 h / 20 °C 2.1: NaH / toluene / 1 h / 20 °C 2.2: 62 percent / toluene / 4.5 h / 0 °C With sodium hydride, sodium hydrogencarbonate in toluene, acetonitrile Simpson, Graham L.; Gordon, Andrew H.; Lindsay, David M.; Promsawan, Netnepa; Crump, Matthew P.; Mulholland, Keith; Hayter, Barry R.; Gallagher, Timothy; Journal of the American Chemical Society; vol. 128; nb. 33; (2006); p. 10638 - 10639 View in Reaxys Reaction Steps: 2

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1: CH2Cl2 / 1 h / 20 °C 2: NaOEt / ethanol / 3 h / Heating With sodium ethanolate in ethanol, dichloromethane, 2: Dieckmann reaction Lee, Ji Hoon; Lee, Kyung Seok; Kang, Yong Koo; Yoo, Kyung Ho; Shin, Kye Jung; Kim, Dong Chan; Kong, Jae Yang; Lee, Yeonhee; Lee, Sook Ja; Kim, Dong Jin; Bioorganic and Medicinal Chemistry Letters; vol. 13; nb. 24; (2003); p. 4399 - 4403 View in Reaxys Reaction Steps: 2 1: 98 percent / Et3N / CH2Cl2 / 2 h / Ambient temperature 2: 43 percent / t-BuOK / toluene / 0.5 h / 0 °C With potassium tert-butylate, triethylamine in dichloromethane, toluene Cooper, Jeremy; Gallagher, Peter T.; Knight, David W.; Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999); nb. 12; (1993); p. 1313 - 1318 View in Reaxys

O O

N H

N O O

Rx-ID: 28954208 View in Reaxys 27/176 Yield

Conditions & References

51 %

With potassium tert-butylate in tetrahydrofuran, T= 0 - 20 °C Smith, Alexander M.R.; Billen, Denis; Hii, King Kuok; Chemical Communications; nb. 26; (2009); p. 3925 - 3927 View in Reaxys

O O O O

O O

N O

Rx-ID: 23765249 View in Reaxys 28/176 Yield

Conditions & References 1.4 :Step 4. 4-Oxo-pyrrolidine-1,3-dicarboxylic acid 1-benzyl ester 3-ethyl ester (4) t-BuOK 9.6 g (86 mmol) is added to a mixture of 3 (12.0 g, 36 mmol) in THF (300 ml). The reaction mixture is stirred for 2 hr, satu rated aq NH4Cl (50 ml) is then added. The THF is removed in vacuo. The residue is extracted with (2*150 mL) CHCl3/H2O and the organic layer washed with water (50 mL) and brine (50 mL), dried (Na2SO4), and the CHCl3 is removed in vacuo. The residue is purified by flash chromatography (EtOAc) to afford 4 as a white solid. LCMS (API) m/z calcd for C15H17NO5 291 ([M+]); found 292 ([M+H]+). 1H

NMR (300 MHz, CDCl3): δ 1.25-1.34 (m, 3H), 3.93-4.32 (m, 7H), 5.18 (s, 2H), 7.34-7.40 (m, 5H).

With potassium tert-butylate in tetrahydrofuran, Time= 2h Patent; Bradbury, Barton J.; Deshpande, Milind; Pucci, Michael J.; Wang, Qiuping; Wiles, Jason Allan; Song, Yongsheng; Hashimoto, Akihiro; Lucien, Edlaine; US2006/100215; (2006); (A1) English View in Reaxys

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O O

Rx-ID: 29010995 View in Reaxys 29/176 Yield

Conditions & References 1.C :To the product of Step B, 1-b, (7.06 g, 24.7 mmol) in EtOH (40 mL) was added NaOEt (20.3 mL, 54.4 mmol, 21 wt percent in EtOH). The reaction was heated to reflux for 3 h and then cooled before the addition of aq HCl (28 mL, 2 M) followed by dilution with EtOAc and brine. The solution was extracted three times with EtOAc and dried (Na2SO4) to afford the title compound, 1-1, which was used without further purification to prepare Intermediate 4. HPLC/MS: 240.1(M+l); Rt = 2.22 min Stage 1: With sodium ethanolate in ethanol, Time= 3h, Reflux Stage 2: With hydrogenchloride in ethanol, water Patent; MERCK and CO., INC.; WO2009/108499; (2009); (A1) English View in Reaxys

N O

Rx-ID: 8780671 View in Reaxys 30/176 Yield

Conditions & References

74 %, 13 %

With potassium tert-butylate in tetrahydrofuran, Time= 3h, T= -78 °C , Dieckmann cyclization Pinto, Americo C.; Abdala, Rodrigo V.; Costa, Paulo R.R.; Tetrahedron Asymmetry; vol. 11; nb. 21; (2000); p. 4239 - 4243 View in Reaxys

O O

Rx-ID: 8781314 View in Reaxys 31/176 Yield

Conditions & References

69 %, 9 %

O O

N H

N O O

Rx-ID: 28954210 View in Reaxys 32/176 Yield 33 %

Conditions & References With potassium tert-butylate in tetrahydrofuran, T= 0 - 20 °C Smith, Alexander M.R.; Billen, Denis; Hii, King Kuok; Chemical Communications; nb. 26; (2009); p. 3925 - 3927

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View in Reaxys O

O O O

N H

O O

Rx-ID: 34669326 View in Reaxys 33/176 Yield

Conditions & References

68 %

With potassium tert-butylate in tetrahydrofuran, Time= 72h, T= 0 - 23 °C , Dieckmann Condensation Penning, Miriam; Christoffers, Jens; European Journal of Organic Chemistry; nb. 2; (2013); p. 389 - 400 View in Reaxys O

O O

Rx-ID: 4699152 View in Reaxys 34/176 Yield

Conditions & References

60 %

With potassium tert-butylate in toluene, Time= 0.5h, T= 0 °C , Yields of byproduct given Knight, David W.; Sibley, A. William; Journal of the Chemical Society - Perkin Transactions 1; nb. 15; (1997); p. 2179 - 2187 View in Reaxys

60 %

With potassium tert-butylate in toluene, Time= 0.5h, T= 0 °C , Yield given Knight, David W.; Sibley, A. William; Journal of the Chemical Society - Perkin Transactions 1; nb. 15; (1997); p. 2179 - 2187 View in Reaxys

O O

Rx-ID: 8848898 View in Reaxys 35/176 Yield

Conditions & References

61.5 %

With 4 A molecular sieve, sodium ethanolate in toluene, Time= 5h, T= 20 °C Gangjee; Mavandadi; Queener; Journal of Heterocyclic Chemistry; vol. 38; nb. 1; (2001); p. 213 - 220 View in Reaxys

O O

Rx-ID: 3457709 View in Reaxys 36/176

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Yield

Conditions & References

43 %, 45 %

With potassium tert-butylate in toluene, Time= 0.5h, T= 0 °C Cooper, Jeremy; Gallagher, Peter T.; Knight, David W.; Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999); nb. 12; (1993); p. 1313 - 1318 View in Reaxys

S N

O O

Rx-ID: 10356117 View in Reaxys 37/176 Yield 2.1 g

Conditions & References With triethylamine in dichloromethane, Time= 0.5h, T= 20 °C Jeon; Kim; Hong; Cho; Oh; European Journal of Medicinal Chemistry; vol. 41; nb. 10; (2006); p. 1201 - 1209 View in Reaxys

H H

O O

H H

HN O

O O

Rx-ID: 41391876 View in Reaxys 38/176 Yield

Conditions & References Reaction Steps: 2 1: N-ethyl-N,N-diisopropylamine / dichloromethane / 0 °C / |Cooling with ice 2: potassium tert-butylate / toluene / 0.83 h / 0 - 5 °C / |Cooling with ice With potassium tert-butylate, N-ethyl-N,N-diisopropylamine in dichloromethane, toluene Patent; Alnylam Pharmaceuticals, Inc.; Sah, Dinah Wen-yee; Hinkle, Gregory; Alvarez, Rene; Milstein, Stuart; Chen, Qingmin; EP2937418; (2015); (A1) English View in Reaxys Reaction Steps: 2 1: N-ethyl-N,N-diisopropylamine / dichloromethane / 0 °C 2: potassium tert-butylate / toluene / 0.83 h / 0 - 5 °C With potassium tert-butylate, N-ethyl-N,N-diisopropylamine in dichloromethane, toluene Patent; Alnylam Pharmaceuticals, Inc.; Sah, Dinah Wen-Yee; Hinkle, Gregory; (240 pag.); US2016/24497; (2016); (A1) English View in Reaxys Reaction Steps: 2 1: N-ethyl-N,N-diisopropylamine / dichloromethane / 0 °C 2: potassium tert-butylate / toluene / 0.83 h / 0 - 5 °C With potassium tert-butylate, N-ethyl-N,N-diisopropylamine in dichloromethane, toluene Patent; Alnylam Pharmaceuticals, Inc.; de Fougerolles, Antonin; Novobrantseva, Tatiana; Hinkle, Gregory; US9206421; (2015); (B2) English View in Reaxys Reaction Steps: 2

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1: N-ethyl-N,N-diisopropylamine / dichloromethane / 0 °C 2: potassium tert-butylate / toluene / 0.83 h / 0 - 5 °C With potassium tert-butylate, N-ethyl-N,N-diisopropylamine in dichloromethane, toluene Patent; Alnylam Pharmaceuticals, Inc.; de Fougerolles, Antonin; Novobrantseva, Tatiana; Akinc, Akin; (87 pag.); US2016/17336; (2016); (A1) English View in Reaxys Reaction Steps: 2 1: N-ethyl-N,N-diisopropylamine / dichloromethane / 0 °C 2: potassium tert-butylate / toluene / 0.5 h / 0 °C With potassium tert-butylate, N-ethyl-N,N-diisopropylamine in dichloromethane, toluene Patent; Alnylam Pharmaceuticals, Inc.; Bumcrot, David; Sah, Dinah Wen-Yee; Toudjarska, Ivanka; (103 pag.); US2016/819; (2016); (A1) English View in Reaxys

O H 2N

O O

N O

O HCl

HN O

O N O

Rx-ID: 41391872 View in Reaxys 39/176 Yield

Conditions & References Reaction Steps: 2 1: N-ethyl-N,N-diisopropylamine / dichloromethane / 0 °C / |Cooling with ice 2: potassium tert-butylate / toluene / 0.83 h / 0 - 5 °C / |Cooling with ice With potassium tert-butylate, N-ethyl-N,N-diisopropylamine in dichloromethane, toluene Patent; Alnylam Pharmaceuticals, Inc.; Sah, Dinah Wen-yee; Hinkle, Gregory; Alvarez, Rene; Milstein, Stuart; Chen, Qingmin; EP2937418; (2015); (A1) English View in Reaxys Reaction Steps: 2 1: N-ethyl-N,N-diisopropylamine / dichloromethane / 0 °C 2: potassium tert-butylate / toluene / 0.83 h / 0 - 5 °C With potassium tert-butylate, N-ethyl-N,N-diisopropylamine in dichloromethane, toluene Patent; Alnylam Pharmaceuticals, Inc.; Sah, Dinah Wen-Yee; Hinkle, Gregory; (240 pag.); US2016/24497; (2016); (A1) English View in Reaxys Reaction Steps: 2 1: N-ethyl-N,N-diisopropylamine / dichloromethane / 0 °C 2: potassium tert-butylate / toluene / 0.83 h / 0 - 5 °C With potassium tert-butylate, N-ethyl-N,N-diisopropylamine in dichloromethane, toluene Patent; Alnylam Pharmaceuticals, Inc.; de Fougerolles, Antonin; Borodovsky, Anna; Novobrantseva, Tatiana; US2015/353934; (2015); (A1) English View in Reaxys Reaction Steps: 2 1: N-ethyl-N,N-diisopropylamine / dichloromethane / 0 °C 2: potassium tert-butylate / toluene / 0.83 h / 0 - 5 °C With potassium tert-butylate, N-ethyl-N,N-diisopropylamine in dichloromethane, toluene Patent; Alnylam Pharmaceuticals, Inc.; de Fougerolles, Antonin; Novobrantseva, Tatiana; Akinc, Akin; (87 pag.); US2016/17336; (2016); (A1) English View in Reaxys

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Patent; Alnylam Pharmaceuticals, Inc.; Gollob, Jared; Hinkle, Gregory; Toudjarska, Ivanka; Bumcrot, David; (73 pag.); US9566295; (2017); (B2) English View in Reaxys O

H N

O O

Rx-ID: 3790709 View in Reaxys 40/176 Yield

Conditions & References

63 %

With sodium hydride, oil in toluene, Time= 3h, Heating McHugh, Michael; Proctor, George R.; Journal of Chemical Research, Miniprint; nb. 8; (1984); p. 2230 - 2253 View in Reaxys

N H

N O

Rx-ID: 29583363 View in Reaxys 41/176 Yield

Conditions & References With potassium tert-butylate in tetrahydrofuran, Time= 18h, T= 20 °C , Michael addition Wallace, Michael B.; Adams, Mark E.; Kanouni, Toufike; Mol, Clifford D.; Dougan, Douglas R.; Feher, Victoria A.; O'Connell, Shawn M.; Shi, Lihong; Halkowycz, Petro; Dong, Qing; Bioorganic and Medicinal Chemistry Letters; vol. 20; nb. 14; (2010); p. 4156 - 4158 View in Reaxys

H H

O O

HN O

O O N O

Rx-ID: 42104914 View in Reaxys 42/176 Yield

Conditions & References Reaction Steps: 5 1: sodium hydroxide / water / 19 h / 20 °C / |Cooling with ice 2: dmap; diisopropyl-carbodiimide / dichloromethane / 6 h / 0 - 20 °C 3: piperidine / N,N-dimethyl-formamide / 1 h / 0 °C 4: N-ethyl-N,N-diisopropylamine / dichloromethane / 0 °C 5: potassium tert-butylate / toluene / 0.83 h / 0 - 5 °C With piperidine, dmap, potassium tert-butylate, N-ethyl-N,N-diisopropylamine, sodium hydroxide, diisopropyl-carbodiimide in dichloromethane, water, N,N-dimethyl-formamide, toluene Patent; Alnylam Pharmaceuticals, Inc.; Sah, Dinah Wen-Yee; Chen, Qingmin; US9200282; (2015); (B2) English View in Reaxys Reaction Steps: 5 1: sodium hydroxide / water / 19 h / 20 °C / |Cooling with ice 2: diisopropyl-carbodiimide / dichloromethane / 6 h / 0 - 20 °C 3: piperidine / N,N-dimethyl-formamide / 1 h / 0 °C 4: N-ethyl-N,N-diisopropylamine / dichloromethane / 0 °C 5: potassium tert-butylate / toluene / 0.83 h / 0 - 5 °C With piperidine, potassium tert-butylate, N-ethyl-N,N-diisopropylamine, sodium hydroxide, diisopropyl-carbodiimide in dichloromethane, water, N,N-dimethyl-formamide, toluene

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Patent; Alnylam Pharmaceuticals, Inc.; de Fougerolles, Antonin; Borodovsky, Anna; Novobrantseva, Tatiana; US2015/353934; (2015); (A1) English View in Reaxys Reaction Steps: 5 1: sodium hydroxide / water / 19 h / 20 °C / |Cooling with ice 2: dmap; diisopropyl-carbodiimide / dichloromethane; ethyl acetate / 6 h / 0 - 20 °C 3: piperidine / N,N-dimethyl-formamide / 1 h / 0 °C 4: N-ethyl-N,N-diisopropylamine / dichloromethane / 0 °C 5: potassium tert-butylate / toluene / 0.83 h / 0 °C With piperidine, dmap, potassium tert-butylate, N-ethyl-N,N-diisopropylamine, sodium hydroxide, diisopropyl-carbodiimide in dichloromethane, water, ethyl acetate, N,N-dimethyl-formamide, toluene Patent; Ando, Yukio; Jono, Hirofumi; Alvarez, Rene; Sah, Dinah Wen-Yee; (417 pag.); US2016/76029; (2016); (A1) English View in Reaxys Reaction Steps: 5 1: sodium hydroxide / water / 19 h / 20 °C / |Cooling with ice 2: diisopropyl-carbodiimide; dmap / dichloromethane / 6 h / 0 - 20 °C 3: piperidine / N,N-dimethyl-formamide / 1 h / 0 °C 4: N-ethyl-N,N-diisopropylamine / dichloromethane / 0 °C 5: potassium tert-butylate / toluene / 0.83 h / 0 - 5 °C With piperidine, dmap, potassium tert-butylate, N-ethyl-N,N-diisopropylamine, sodium hydroxide, diisopropyl-carbodiimide in dichloromethane, water, N,N-dimethyl-formamide, toluene Patent; Alnylam Pharmaceuticals, Inc.; Gollob, Jared; Hinkle, Gregory; Toudjarska, Ivanka; Bumcrot, David; (73 pag.); US9566295; (2017); (B2) English View in Reaxys

H H

H O O O O

H N

N O

HN O

O N O

Rx-ID: 42104916 View in Reaxys 43/176 Yield

Conditions & References Reaction Steps: 3 1: piperidine / N,N-dimethyl-formamide / 1 h / 0 °C 2: N-ethyl-N,N-diisopropylamine / dichloromethane / 0 °C 3: potassium tert-butylate / toluene / 0.83 h / 0 - 5 °C With piperidine, potassium tert-butylate, N-ethyl-N,N-diisopropylamine in dichloromethane, N,N-dimethyl-formamide, toluene Patent; Alnylam Pharmaceuticals, Inc.; Sah, Dinah Wen-Yee; Chen, Qingmin; US9200282; (2015); (B2) English View in Reaxys Reaction Steps: 3 1: piperidine / N,N-dimethyl-formamide / 1 h / 0 °C 2: N-ethyl-N,N-diisopropylamine / dichloromethane / 0 °C 3: potassium tert-butylate / toluene / 0.83 h / 0 - 5 °C With piperidine, potassium tert-butylate, N-ethyl-N,N-diisopropylamine in dichloromethane, N,N-dimethyl-formamide, toluene Patent; Alnylam Pharmaceuticals, Inc.; de Fougerolles, Antonin; Borodovsky, Anna; Novobrantseva, Tatiana; US2015/353934; (2015); (A1) English View in Reaxys Reaction Steps: 3 1: piperidine / N,N-dimethyl-formamide / 1 h / 0 °C

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2: N-ethyl-N,N-diisopropylamine / dichloromethane / 0 °C 3: potassium tert-butylate / toluene / 0.83 h / 0 °C With piperidine, potassium tert-butylate, N-ethyl-N,N-diisopropylamine in dichloromethane, N,N-dimethyl-formamide, toluene Patent; Ando, Yukio; Jono, Hirofumi; Alvarez, Rene; Sah, Dinah Wen-Yee; (417 pag.); US2016/76029; (2016); (A1) English View in Reaxys Reaction Steps: 3 1: piperidine / N,N-dimethyl-formamide / 1 h / 0 °C 2: N-ethyl-N,N-diisopropylamine / dichloromethane / 0 °C 3: potassium tert-butylate / toluene / 0.83 h / 0 - 5 °C With piperidine, potassium tert-butylate, N-ethyl-N,N-diisopropylamine in dichloromethane, N,N-dimethyl-formamide, toluene Patent; Alnylam Pharmaceuticals, Inc.; Gollob, Jared; Hinkle, Gregory; Toudjarska, Ivanka; Bumcrot, David; (73 pag.); US9566295; (2017); (B2) English View in Reaxys

H H

O O O

N H

O O

HN O

N O

Rx-ID: 42104930 View in Reaxys 44/176 Yield

Conditions & References Reaction Steps: 4 1: dmap; diisopropyl-carbodiimide / dichloromethane / 6 h / 0 - 20 °C 2: piperidine / N,N-dimethyl-formamide / 1 h / 0 °C 3: N-ethyl-N,N-diisopropylamine / dichloromethane / 0 °C 4: potassium tert-butylate / toluene / 0.83 h / 0 - 5 °C With piperidine, dmap, potassium tert-butylate, N-ethyl-N,N-diisopropylamine, diisopropyl-carbodiimide in dichloromethane, N,N-dimethyl-formamide, toluene Patent; Alnylam Pharmaceuticals, Inc.; Sah, Dinah Wen-Yee; Chen, Qingmin; US9200282; (2015); (B2) English View in Reaxys Reaction Steps: 4 1: diisopropyl-carbodiimide / dichloromethane / 6 h / 0 - 20 °C 2: piperidine / N,N-dimethyl-formamide / 1 h / 0 °C 3: N-ethyl-N,N-diisopropylamine / dichloromethane / 0 °C 4: potassium tert-butylate / toluene / 0.83 h / 0 - 5 °C With piperidine, potassium tert-butylate, N-ethyl-N,N-diisopropylamine, diisopropyl-carbodiimide in dichloromethane, N,N-dimethyl-formamide, toluene Patent; Alnylam Pharmaceuticals, Inc.; de Fougerolles, Antonin; Borodovsky, Anna; Novobrantseva, Tatiana; US2015/353934; (2015); (A1) English View in Reaxys Reaction Steps: 4 1: dmap; diisopropyl-carbodiimide / dichloromethane; ethyl acetate / 6 h / 0 - 20 °C 2: piperidine / N,N-dimethyl-formamide / 1 h / 0 °C 3: N-ethyl-N,N-diisopropylamine / dichloromethane / 0 °C 4: potassium tert-butylate / toluene / 0.83 h / 0 °C With piperidine, dmap, potassium tert-butylate, N-ethyl-N,N-diisopropylamine, diisopropyl-carbodiimide in dichloromethane, ethyl acetate, N,N-dimethyl-formamide, toluene Patent; Ando, Yukio; Jono, Hirofumi; Alvarez, Rene; Sah, Dinah Wen-Yee; (417 pag.); US2016/76029; (2016); (A1) English

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View in Reaxys Reaction Steps: 4 1: diisopropyl-carbodiimide; dmap / dichloromethane / 6 h / 0 - 20 °C 2: piperidine / N,N-dimethyl-formamide / 1 h / 0 °C 3: N-ethyl-N,N-diisopropylamine / dichloromethane / 0 °C 4: potassium tert-butylate / toluene / 0.83 h / 0 - 5 °C With piperidine, dmap, potassium tert-butylate, N-ethyl-N,N-diisopropylamine, diisopropyl-carbodiimide in dichloromethane, N,N-dimethyl-formamide, toluene Patent; Alnylam Pharmaceuticals, Inc.; Gollob, Jared; Hinkle, Gregory; Toudjarska, Ivanka; Bumcrot, David; (73 pag.); US9566295; (2017); (B2) English View in Reaxys

O O

O– Na +

O N

Rx-ID: 185254 View in Reaxys 45/176 Yield

Conditions & References With benzene Prill, E. A.; McElvain, S. M.; Journal of the American Chemical Society; vol. 55; (1933); p. 1233 - 1241 View in Reaxys

O K+

O O

–O

O O

Rx-ID: 186851 View in Reaxys 46/176 Yield

Conditions & References With toluene Uchibayashi; Yakugaku Zasshi; vol. 78; (1958); p. 845,848; ; (1959); p. 331 View in Reaxys Blake et al.; Journal of the American Chemical Society; vol. 86; (1964); p. 5293,5298 View in Reaxys

O O

S N

N S

O O

Rx-ID: 12159501 View in Reaxys 47/176 Yield

Conditions & References Reaction Steps: 2 1: oxalyl chloride / CH2Cl2 / 2 h / 20 °C 2: 2.1 g / triethylamine / CH2Cl2 / 0.5 h / 20 °C With oxalyl dichloride, triethylamine in dichloromethane Jeon; Kim; Hong; Cho; Oh; European Journal of Medicinal Chemistry; vol. 41; nb. 10; (2006); p. 1201 - 1209

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View in Reaxys O

H N

O N

O O

Rx-ID: 21245988 View in Reaxys 48/176 Yield

Conditions & References Reaction Steps: 2 1: 83 percent / K2CO3 / dimethylformamide / 2 h / 60 °C 2: 64 percent / NaOEt / benzene; ethanol / 0.5 h / Heating With sodium ethanolate, potassium carbonate in ethanol, N,N-dimethyl-formamide, benzene Su; Watanabe; Journal of Organic Chemistry; vol. 54; nb. 1; (1989); p. 220 - 224 View in Reaxys O

O O

NH 2

Rx-ID: 21268776 View in Reaxys 49/176 Yield

Conditions & References Reaction Steps: 3 1: 86 percent / ethanol / 72 h / Heating 2: 83 percent / K2CO3 / dimethylformamide / 2 h / 60 °C 3: 64 percent / NaOEt / benzene; ethanol / 0.5 h / Heating With sodium ethanolate, potassium carbonate in ethanol, N,N-dimethyl-formamide, benzene Su; Watanabe; Journal of Organic Chemistry; vol. 54; nb. 1; (1989); p. 220 - 224 View in Reaxys

H H

H O

O H -1Cl

O O

HN O

N O

NH 2

N O

Rx-ID: 42104920 View in Reaxys 50/176 Yield

Conditions & References Reaction Steps: 2 1: N-ethyl-N,N-diisopropylamine / dichloromethane / 0 °C 2: potassium tert-butylate / toluene / 0.83 h / 0 - 5 °C With potassium tert-butylate, N-ethyl-N,N-diisopropylamine in dichloromethane, toluene Patent; Alnylam Pharmaceuticals, Inc.; Sah, Dinah Wen-Yee; Chen, Qingmin; US9200282; (2015); (B2) English View in Reaxys Reaction Steps: 2 1: N-ethyl-N,N-diisopropylamine / dichloromethane / 0 °C 2: potassium tert-butylate / toluene / 0.83 h / 0 - 5 °C With potassium tert-butylate, N-ethyl-N,N-diisopropylamine in dichloromethane, toluene

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Patent; Alnylam Pharmaceuticals, Inc.; de Fougerolles, Antonin; Novobrantseva, Tatiana; Hinkle, Gregory; US9206421; (2015); (B2) English View in Reaxys Reaction Steps: 2 1: N-ethyl-N,N-diisopropylamine / dichloromethane / 0 °C 2: potassium tert-butylate / toluene / 0.83 h / 0 °C With potassium tert-butylate, N-ethyl-N,N-diisopropylamine in dichloromethane, toluene Patent; Ando, Yukio; Jono, Hirofumi; Alvarez, Rene; Sah, Dinah Wen-Yee; (417 pag.); US2016/76029; (2016); (A1) English View in Reaxys

O O

N H

Rx-ID: 15426144 View in Reaxys 51/176 Yield

Conditions & References Reaction Steps: 2 1: 83 percent / aq. Na2CO3 / tetrahydrofuran / 14 h / Heating 2: 69 percent / t-BuOK / tetrahydrofuran / 3 h / -78 °C With potassium tert-butylate, sodium carbonate in tetrahydrofuran, 2: Dieckmann cyclization Pinto, Americo C.; Abdala, Rodrigo V.; Costa, Paulo R.R.; Tetrahedron Asymmetry; vol. 11; nb. 21; (2000); p. 4239 - 4243 View in Reaxys Reaction Steps: 2 1: 86 percent / aq. Na2CO3 / tetrahydrofuran / 14 h / Heating 2: 74 percent / t-BuOK / tetrahydrofuran / 3 h / -78 °C With potassium tert-butylate, sodium carbonate in tetrahydrofuran, 2: Dieckmann cyclization Pinto, Americo C.; Abdala, Rodrigo V.; Costa, Paulo R.R.; Tetrahedron Asymmetry; vol. 11; nb. 21; (2000); p. 4239 - 4243 View in Reaxys

H 2N

4-[4,4-di(allyloxycarbonyl)-3-phenylbutanoyl]benzoyl-Rink resin

Rx-ID: 15433045 View in Reaxys 52/176 Yield

Conditions & References Reaction Steps: 3 1: 90 percent / 48 h / -30 °C 2: 83 percent / aq. Na2CO3 / tetrahydrofuran / 14 h / Heating 3: 69 percent / t-BuOK / tetrahydrofuran / 3 h / -78 °C With potassium tert-butylate, sodium carbonate in tetrahydrofuran, 3: Dieckmann cyclization Pinto, Americo C.; Abdala, Rodrigo V.; Costa, Paulo R.R.; Tetrahedron Asymmetry; vol. 11; nb. 21; (2000); p. 4239 - 4243 View in Reaxys Reaction Steps: 3 1: 90 percent / 48 h / -30 °C 2: 86 percent / aq. Na2CO3 / tetrahydrofuran / 14 h / Heating 3: 74 percent / t-BuOK / tetrahydrofuran / 3 h / -78 °C With potassium tert-butylate, sodium carbonate in tetrahydrofuran, 3: Dieckmann cyclization

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Pinto, Americo C.; Abdala, Rodrigo V.; Costa, Paulo R.R.; Tetrahedron Asymmetry; vol. 11; nb. 21; (2000); p. 4239 - 4243 View in Reaxys

N O

O O

Rx-ID: 42285996 View in Reaxys 53/176 Yield

Conditions & References Reaction Steps: 3 1.1: triethylamine / ethanol / 0.17 h 1.2: 17 h / 20 °C 2.1: triethylamine / ethanol / 20 °C 3.1: sodium; ethanol / |Reflux With ethanol, sodium, triethylamine in ethanol Patent; GUANGZHOU HUI BO RUI BIOLOGICAL PHARMACEUTICAL TECHNOLOGY CO., LTD.; ZHONGSHAN OPHTHALMIC CENTER, SUN YAT-SEN UNIVERSITY; Hou, Rui; Zhang, Kang; (25 pag.); US2016/75708; (2016); (A1) English View in Reaxys Reaction Steps: 3 1: triethylamine / ethanol / 17.5 h / 20 °C 2: ethanol / 20 °C 3: sodium ethanolate / ethanol / |Reflux With sodium ethanolate, triethylamine in ethanol Patent; Hui Guangzhou Borui Biological pharmaceutical technology co.Ltd; zhongshan ophthalmic center sun yat-sen university; Ho, Wo Louie; Jang, Khang; (31 pag.); KR2015/139962; (2015); (A) Korean View in Reaxys

O O

N H

N O O

Rx-ID: 42285997 View in Reaxys 54/176 Yield

Conditions & References Reaction Steps: 2 1: triethylamine / ethanol / 20 °C 2: sodium; ethanol / |Reflux With ethanol, sodium, triethylamine in ethanol Patent; GUANGZHOU HUI BO RUI BIOLOGICAL PHARMACEUTICAL TECHNOLOGY CO., LTD.; ZHONGSHAN OPHTHALMIC CENTER, SUN YAT-SEN UNIVERSITY; Hou, Rui; Zhang, Kang; (25 pag.); US2016/75708; (2016); (A1) English View in Reaxys Reaction Steps: 2 1: ethanol / 20 °C 2: sodium ethanolate / ethanol / |Reflux With sodium ethanolate in ethanol Patent; Hui Guangzhou Borui Biological pharmaceutical technology co.Ltd; zhongshan ophthalmic center sun yat-sen university; Ho, Wo Louie; Jang, Khang; (31 pag.); KR2015/139962; (2015); (A) Korean View in Reaxys

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O O

Rx-ID: 3614319 View in Reaxys 55/176 Yield

Conditions & References

49 %

With methanol, sodium, Time= 16h, Heating McHugh, Michael; Proctor, George R.; Journal of Chemical Research, Miniprint; nb. 8; (1984); p. 2230 - 2253 View in Reaxys O

O +

–

Rx-ID: 411912 View in Reaxys 56/176 Yield

Conditions & References With benzene Bauer; Safir; Journal of Medicinal Chemistry; vol. 15; (1972); p. 440 View in Reaxys

O O N

NH 2 O

Rx-ID: 15336236 View in Reaxys 57/176 Yield

Conditions & References Reaction Steps: 3 1: 59 percent / tetrahydrofuran / 48 h / 20 °C 2: 90 percent / K2CO3 / dimethylformamide / 5 h / 60 °C 3: 61.5 percent / NaOEt; molecular sieves 4A / toluene / 5 h / 20 °C With 4 A molecular sieve, sodium ethanolate, potassium carbonate in tetrahydrofuran, N,N-dimethyl-formamide, toluene Gangjee; Mavandadi; Queener; Journal of Heterocyclic Chemistry; vol. 38; nb. 1; (2001); p. 213 - 220 View in Reaxys

O O

N H

O N

O O

Rx-ID: 15343889 View in Reaxys 58/176 Yield

Conditions & References Reaction Steps: 2 1: 90 percent / K2CO3 / dimethylformamide / 5 h / 60 °C 2: 61.5 percent / NaOEt; molecular sieves 4A / toluene / 5 h / 20 °C With 4 A molecular sieve, sodium ethanolate, potassium carbonate in N,N-dimethyl-formamide, toluene Gangjee; Mavandadi; Queener; Journal of Heterocyclic Chemistry; vol. 38; nb. 1; (2001); p. 213 - 220

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View in Reaxys

O O

(CO)5W=C(OMe)Ph

O O

Rx-ID: 15354825 View in Reaxys 59/176 Yield

NH 2

Rx-ID: 18873592 View in Reaxys 60/176 Yield

Conditions & References Reaction Steps: 3 1: 59 percent / SnCl4 / benzene / 40 h / Heating 2: 71 percent / Na2CO3 / 5 h / 120 °C 3: 49 percent / Na/CH3OH / 16 h / Heating With methanol, sodium, tin(IV) chloride, sodium carbonate in benzene McHugh, Michael; Proctor, George R.; Journal of Chemical Research, Miniprint; nb. 8; (1984); p. 2230 - 2253 View in Reaxys

Rx-ID: 43995053 View in Reaxys 61/176 Yield

Conditions & References Reaction Steps: 3 1: sodium hydroxide / water / 20 °C / |Cooling with ice 2: potassium carbonate; sodium iodide / ethanol / |Inert atmosphere; |Reflux; |Large scale 3: potassium tert-butylate / toluene / 2 h / |Cooling with ice With potassium tert-butylate, potassium carbonate, sodium iodide, sodium hydroxide in ethanol, water, toluene Patent; Allist Pharmaceuticals, Inc; Luo, HuiBing; Guo, JianHui; (20 pag.); CN102584828; (2016); (B) Chinese View in Reaxys

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O N

N H

Rx-ID: 43995062 View in Reaxys 62/176 Yield

Conditions & References Reaction Steps: 2 1: potassium carbonate; sodium iodide / ethanol / |Inert atmosphere; |Reflux; |Large scale 2: potassium tert-butylate / toluene / 2 h / |Cooling with ice With potassium tert-butylate, potassium carbonate, sodium iodide in ethanol, toluene Patent; Allist Pharmaceuticals, Inc; Luo, HuiBing; Guo, JianHui; (20 pag.); CN102584828; (2016); (B) Chinese View in Reaxys

N H

N O

Rx-ID: 10393915 View in Reaxys 63/176 Yield

Conditions & References With potassium tert-butylate Kati; Montgomery; Maring; Stoll; Giranda; Chen; Laver; Kohlbrenner; Norbeck; Antimicrobial Agents and Chemotherapy; vol. 45; nb. 9; (2001); p. 2563 - 2570 View in Reaxys O

O O

Rx-ID: 411913 View in Reaxys 64/176 Yield

Conditions & References With sodium ethanolate, benzene de Mouilpied; Journal of the Chemical Society; vol. 87; (1905); p. 438 View in Reaxys Reaction Steps: 2 1: sodium ethylate; benzene 2: alcoholic-aqueous KOH-solution With potassium hydroxide, sodium ethanolate, benzene de Mouilpied; Journal of the Chemical Society; vol. 87; (1905); p. 438 View in Reaxys O O

N O

O N

Rx-ID: 4489698 View in Reaxys 65/176 Yield

Conditions & References With titanium tetrachloride, triethylamine, 1) CH2Cl2, -10 deg C, 0.5 h; 2) CH2Cl2, -10 deg C, 2 h, Yield given. Multistep reaction

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Deshmukh; Gangakhedkar; Sampath Kumar; Synthetic Communications; vol. 26; nb. 9; (1996); p. 1657 - 1661 View in Reaxys O

O O

Rx-ID: 4490024 View in Reaxys 66/176 Yield

Conditions & References With titanium tetrachloride, triethylamine, 1) CH2Cl2, -10 deg C, 0.5 h; 2) CH2Cl2, -10 deg C, 2 h, Yield given. Multistep reaction Deshmukh; Gangakhedkar; Sampath Kumar; Synthetic Communications; vol. 26; nb. 9; (1996); p. 1657 - 1661 View in Reaxys

O O

Rx-ID: 4490230 View in Reaxys 67/176 Yield

O O

O H N

Rx-ID: 22031432 View in Reaxys 68/176 Yield

Conditions & References Reaction Steps: 3 1: 90 °C 2: concentrated sulfuric acid 3: sodium ethylate; benzene With sulfuric acid, sodium ethanolate, benzene de Mouilpied; Journal of the Chemical Society; vol. 87; (1905); p. 438 View in Reaxys Reaction Steps: 4 1: 90 °C 2: concentrated sulfuric acid 3: sodium ethylate; benzene 4: alcoholic-aqueous KOH-solution With potassium hydroxide, sulfuric acid, sodium ethanolate, benzene de Mouilpied; Journal of the Chemical Society; vol. 87; (1905); p. 438 View in Reaxys

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O H N

Rx-ID: 22041210 View in Reaxys 69/176 Yield

Conditions & References Reaction Steps: 3 2: concentrated sulfuric acid 3: sodium ethylate; benzene With sulfuric acid, sodium ethanolate, benzene de Mouilpied; Journal of the Chemical Society; vol. 87; (1905); p. 438 View in Reaxys Reaction Steps: 4 2: concentrated sulfuric acid 3: sodium ethylate; benzene 4: alcoholic-aqueous KOH-solution With potassium hydroxide, sulfuric acid, sodium ethanolate, benzene de Mouilpied; Journal of the Chemical Society; vol. 87; (1905); p. 438 View in Reaxys O

HO O

Rx-ID: 22050584 View in Reaxys 70/176 Yield

Conditions & References Reaction Steps: 2 1: concentrated sulfuric acid 2: sodium ethylate; benzene With sulfuric acid, sodium ethanolate, benzene de Mouilpied; Journal of the Chemical Society; vol. 87; (1905); p. 438 View in Reaxys Reaction Steps: 3 1: concentrated sulfuric acid 2: sodium ethylate; benzene 3: alcoholic-aqueous KOH-solution With potassium hydroxide, sulfuric acid, sodium ethanolate, benzene de Mouilpied; Journal of the Chemical Society; vol. 87; (1905); p. 438 View in Reaxys OH

O O

Rx-ID: 22056234 View in Reaxys 71/176 Yield

Conditions & References Reaction Steps: 2 1: concentrated sulfuric acid 2: sodium ethylate; benzene With sulfuric acid, sodium ethanolate, benzene

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de Mouilpied; Journal of the Chemical Society; vol. 87; (1905); p. 438 View in Reaxys Reaction Steps: 3 1: concentrated sulfuric acid 2: sodium ethylate; benzene 3: alcoholic-aqueous KOH-solution With potassium hydroxide, sulfuric acid, sodium ethanolate, benzene de Mouilpied; Journal of the Chemical Society; vol. 87; (1905); p. 438 View in Reaxys

O HO

H 2N

Rx-ID: 22065595 View in Reaxys 72/176 Yield

Conditions & References Reaction Steps: 4 1: 80 °C 3: concentrated sulfuric acid 4: sodium ethylate; benzene With sulfuric acid, sodium ethanolate, benzene de Mouilpied; Journal of the Chemical Society; vol. 87; (1905); p. 438 View in Reaxys Reaction Steps: 5 1: 80 °C 3: concentrated sulfuric acid 4: sodium ethylate; benzene 5: alcoholic-aqueous KOH-solution With potassium hydroxide, sulfuric acid, sodium ethanolate, benzene de Mouilpied; Journal of the Chemical Society; vol. 87; (1905); p. 438 View in Reaxys

H N

O O

N O

O O

Rx-ID: 260280 View in Reaxys 73/176 Yield

Conditions & References With sodium, benzene, anschliessendes Behandeln mit Acrylsaeure-aethylester Kuhn; Osswald; Chemische Berichte; vol. 89; (1956); p. 1423,1436 View in Reaxys

O N

O O

Rx-ID: 331146 View in Reaxys 74/176 Yield

Conditions & References With potassium hydroxide de Mouilpied; Journal of the Chemical Society; vol. 87; (1905); p. 438

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View in Reaxys O

O O

Rx-ID: 411914 View in Reaxys 75/176 Yield

Conditions & References With sodium ethanolate, benzene de Mouilpied; Journal of the Chemical Society; vol. 87; (1905); p. 438 View in Reaxys

O O

N H

O O

Rx-ID: 3790694 View in Reaxys 76/176 Yield

Conditions & References With sodium hydride, 1.) C6H6, Yield given. Multistep reaction Roglans; Marquet; Moreno-Manas; Synthetic Communications; vol. 22; nb. 9; (1992); p. 1249 - 1258 View in Reaxys O

O H N

Rx-ID: 18871711 View in Reaxys 77/176 Yield

Conditions & References Reaction Steps: 2 1: 71 percent / Na2CO3 / 5 h / 120 °C 2: 49 percent / Na/CH3OH / 16 h / Heating With methanol, sodium, sodium carbonate McHugh, Michael; Proctor, George R.; Journal of Chemical Research, Miniprint; nb. 8; (1984); p. 2230 - 2253 View in Reaxys

O O

O H N

Rx-ID: 22031433 View in Reaxys 78/176 Yield

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Rx-ID: 22034085 View in Reaxys 79/176 Yield

H N

Rx-ID: 22041211 View in Reaxys 80/176 Yield

HO O

Rx-ID: 22050585 View in Reaxys 81/176 Yield

O O

Rx-ID: 22056235 View in Reaxys 82/176 Yield

Conditions & References Reaction Steps: 2 1: concentrated sulfuric acid 2: sodium ethylate; benzene With sulfuric acid, sodium ethanolate, benzene

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de Mouilpied; Journal of the Chemical Society; vol. 87; (1905); p. 438 View in Reaxys

O O

H 2N

Rx-ID: 22065633 View in Reaxys 83/176 Yield

O N O

NH O O

Rx-ID: 28426783 View in Reaxys 84/176 Yield 39%

Conditions & References 1-{6-[17-(1,5-Dimethyl-hexyl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yloxycarbonylamino]-hexanoyl}-4-oxo-pyrrolidine-3-carboxylic acid ethyl ester AE 1-{6-[17-(1,5-Dimethyl-hexyl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yloxycarbonylamino]-hexanoyl}-4-oxo-pyrrolidine-3-carboxylic acid ethyl ester AE Potassium t-butoxide (1.1 g, 9.8 mmol) was slurried in 30 mL of dry toluene. The mixture was cooled to 0° C. on ice and 5 g (6.6 mmol) of diester AD was added slowly with stirring within 20 mins. The temperature was kept below 5° C. during the addition. The stirring was continued for 30 mins at 0° C. and 1 mL of glacial acetic acid was added, immediately followed by 4 g of NaH2PO4.H2O in 40 mL of water The resultant mixture was extracted twice with 100 mL of dichloromethane each and the combined organic extracts were washed twice with 10 mL of phosphate buffer each, dried, and evaporated to dryness. The residue was dissolved in 60 mL of toluene, cooled to 0° C. and extracted with three 50 mL portions of cold pH 9.5 carbonate buffer. The aqueous extracts were adjusted to pH 3 with phosphoric acid, and extracted with five 40 mL portions of chloroform which were combined, dried and evaporated to dryness. The residue was purified by column chromatography using 25percent ethylacetate/hexane to afford 1.9 g of b-ketoester (39percent).

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Patent; Benson, John; Bramlage, Birgit; Fitzgerald, Kevin; Tan, Pamela; Vornlocher, Hans-Peter; US2009/247607; (2009); (A1) English View in Reaxys 39%

5 : 1-{6-[17-(1,5-Dimethyl-hexyl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yloxycarbonylamino]-hexanoyl}-4-oxo-pyrrolidine-3-carboxylic acid ethyl ester AE 1-{6-[17-(1,5-Dimethyl-hexyl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yloxycarbonylamino]-hexanoyl}-4-oxo-pyrrolidine-3-carboxylic acid ethyl ester AE Potassium t-butoxide (1.1 g, 9.8 mmol) is slurried in 30 mL of dry toluene. The mixture is cooled to 0° C. on ice and 5 g (6.6 mmol) of diester AD is added slowly with stirring within 20 mins. The temperature is kept below 5° C. during the addition. The stirring is continued for 30 mins at 0° C. and 1 mL of glacial acetic acid is added, immediately followed by 4 g of NaH2PO4.H2O in 40 mL of water The resultant mixture is extracted twice with 100 mL of dichloromethane each and the combined organic extracts are ished twice with 10 mL of phosphate buffer each, dried, and evaporated to dryness. The residue is dissolved in 60 mL of toluene, cooled to 0° C. and extracted with three 50 mL portions of cold pH 9.5 carbonate buffer. The aqueous extracts are adjusted to pH 3 with phosphoric acid, and extracted with five 40 mL portions of chloroform which are combined, dried and evaporated to dryness. The residue is purified by column chromatography using 25percent ethylacetate/hexane to afford 1.9 g of b-ketoester (39percent). Patent; ALNYLAM PHARMACEUTICALS, INC.; US2009/264511; (2009); (A1) English View in Reaxys

39%

1 : 1-{6-[17-(1,5-Dimethyl-hexyl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yloxycarbonylamino]-hexanoyl}-4-oxo-pyrrolidine-3-carboxylic Acid Ethyl Ester AE 1-{6-[17-(1,5-Dimethyl-hexyl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yloxycarbonylamino]-hexanoyl}-4-oxo-pyrrolidine-3-carboxylic Acid Ethyl Ester AE Potassium t-butoxide (1.1 g, 9.8 mmol) was slurried in 30 mL of dry toluene. The mixture was cooled to 0° C. on ice and 5 g (6.6 mmol) of diester AD was added slowly with stirring within 20 mins. The temperature was kept below 5° C. during the addition. The stirring was continued for 30 mins at 0° C. and 1 mL of glacial acetic acid was added, immediately followed by 4 g of NaH2PO4.H2O in 40 mL of water The resultant mixture was extracted twice with 100 mL of dichloromethane each and the combined organic extracts were washed twice with 10 mL of phosphate buffer each, dried, and evaporated to dryness. The residue was dissolved in 60 mL of toluene, cooled to 0° C. and extracted with three 50 mL portions of cold pH 9.5 carbonate buffer. The aqueous extracts were adjusted to pH 3 with phosphoric acid, and extracted with five 40 mL portions of chloroform which were combined, dried and evaporated to dryness. The residue was purified by column chromatography using 25percent ethylacetate/hexane to afford 1.9 g of b-ketoester (39percent). Patent; Sah, Dinah Wen-Yee; Hinkle, Gregory; Alvarez, Rene; Milstein, Stuart; Chen, Qingmin; US2010/120893; (2010); (A1) English View in Reaxys

39%

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The aqueous extracts were adjusted to pH 3 with phosphoric acid, and extracted with five 40 mL portions of chloroform which were combined, dried and evaporated to dryness. The residue was purified by column chromatography using 25percent ethylacetate/hexane to afford 1.9 g of b-ketoester (39percent). Patent; NOVARTIS AG; US2010/183704; (2010); (A1) English View in Reaxys 39%

6 : 1-{6-[17-(1,5-Dimethyl-hexyl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yloxycarbonylamino]hexanoyl}-4-oxo-pyrrolidine-3-carboxylic acid ethyl ester AE 1-{6-[17-(1,5-Dimethyl-hexyl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yloxycarbonylamino]hexanoyl}-4-oxo-pyrrolidine-3-carboxylic acid ethyl ester AE Potassium t-butoxide (1.1 g, 9.8 mmol) is slurried in 30 mL of dry toluene. The mixture is cooled to 0° C. on ice and 5 g (6.6 mmol) of diester AD is added slowly with stirring within 20 mins. The temperature is kept below 5° C. during the addition. The stirring is continued for 30 mins at 0° C. and 1 mL of glacial acetic acid is added, immediately followed by 4 g of NaH2PO4.H2O in 40 mL of water The resultant mixture is extracted twice with 100 mL of dichloromethane each and the combined organic extracts are washed twice with 10 mL of phosphate buffer each, dried, and evaporated to dryness. The residue is dissolved in 60 mL of toluene, cooled to 0° C. and extracted with three 50 mL portions of cold pH 9.5 carbonate buffer. The aqueous extracts are adjusted to pH 3 with phosphoric acid, and extracted with five 40 mL portions of chloroform which are combined, dried and evaporated to dryness. The residue is purified by column chromatography using 25percent ethylacetate/hexane to afford 1.9 g of b-ketoester (39percent). Patent; De Fougerolles, Antonin; Tan, Pamela; Borodovsky, Anna; Novobrantseva, Tatiana; Bavari, Sina; Warfield, Kelly Lyn; US2011/34537; (2011); (A1) English View in Reaxys

39%

1 : 1-{6-[17-(1,5-Dimethyl-hexyl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a] phenanthren-3-yloxycarbonylamino]-hexanoyl}-4-oxo-pyrrolidine-3-carboxylic acid ethyl ester AE 1-{6-[17-(1,5-Dimethyl-hexyl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a] phenanthren-3-yloxycarbonylamino]-hexanoyl}-4-oxo-pyrrolidine-3-carboxylic acid ethyl ester AE Potassium t-butoxide (1.1 g, 9.8 mmol) was slurried in 30 mL of dry toluene. The mixture is cooled to 0° C. on ice and 5 g (6.6 mmol) of diester AD is added slowly with stirring within 20 mins. The temperature is kept below 5° C. during the addition. The stirring is continued for 30 mins at 0° C. and 1 mL of glacial acetic acid is added, immediately followed by 4 g of NaH2PO4.H2O in 40 mL of water The resultant mixture is extracted twice with 100 mL of dichloromethane each and the combined organic extracts are washed twice with 10 mL of phosphate buffer each, dried, and evaporated to dryness. The residue is dissolved in 60 mL of toluene, cooled to 0° C. and extracted with three 50 mL portions of cold pH 9.5 carbonate buffer. The aqueous extracts are adjusted to pH 3 with phosphoric acid, and extracted with five 40 mL portions of chloroform which are combined, dried and evaporated to dryness. The residue is purified by column chromatography using 25percent ethylacetate/hexane to afford 1.9 g of b-ketoester (39percent). Patent; ALNYLAM PHARMACEUTICALS, INC.; US2011/263684; (2011); (A1) English View in Reaxys

39%

1-{6-[17-(1,5-Dimethyl-hexyl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yloxycarbonylamino]-hexanoyl}-4-oxo-pyrrolidine-3-carboxylic acid ethyl ester AE 1-{6-[17-(1,5-Dimethyl-hexyl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yloxycarbonylamino]-hexanoyl}-4-oxo-pyrrolidine-3-carboxylic acid ethyl ester AE Potassium t-butoxide (1.1 g, 9.8 mmol) was slurried in 30 mL of dry toluene. The mixture was cooled to 0° C. on ice and 5 g (6.6 mmol) of diester AD was added slowly with stirring within 20 mins. The temperature was kept below 5° C. during the addition. The stirring was continued for 30 mins at 0° C. and 1 mL of glacial acetic acid was added, immediately followed by 4 g of NaH2PO4.H2O in 40 mL of water The resultant mixture was extracted twice with 100 mL of dichloromethane each and the combined organic extracts were washed twice with 10 mL of phosphate buffer each, dried, and evaporated to dryness.

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The residue was dissolved in 60 mL of toluene, cooled to 0° C. and extracted with three 50 mL portions of cold pH 9.5 carbonate buffer. The aqueous extracts were adjusted to pH 3 with phosphoric acid, and extracted with five 40 mL portions of chloroform which were combined, dried and evaporated to dryness. The residue was purified by column chromatography using 25percent ethylacetate/hexane to afford 1.9 g of b-ketoester (39percent). Patent; Alnylam Pharmaceuticals ,Inc. a corporation; US2012/16006; (2012); (A1) English View in Reaxys 39%

1 : 1-{6-[17-(1,5-Dimethyl-hexyl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yloxycarbonylamino]-hexanoyl}-4-oxo-pyrrolidine-3-carboxylic acid ethyl ester AE 1-{6-[17-(1,5-Dimethyl-hexyl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yloxycarbonylamino]-hexanoyl}-4-oxo-pyrrolidine-3-carboxylic acid ethyl ester AE Potassium t-butoxide (1.1 g, 9.8 mmol) is slurried in 30 mL of dry toluene. The mixture is cooled to 0° C. on ice and 5 g (6.6 mmol) of diester AD is added slowly with stirring within 20 mins. The temperature is kept below 5° C. during the addition. The stirring is continued for 30 mins at 0° C. and 1 mL of glacial acetic acid is added, immediately followed by 4 g of NaH2PO4.H2O in 40 mL of water The resultant mixture is extracted twice with 100 mL of dichloromethane each and the combined organic extracts are washed twice with 10 mL of phosphate buffer each, dried, and evaporated to dryness. The residue is dissolved in 60 mL of toluene, cooled to 0° C. and extracted with three 50 mL portions of cold pH 9.5 carbonate buffer. The aqueous extracts are adjusted to pH 3 with phosphoric acid, and extracted with five 40 mL portions of chloroform which are combined, dried and evaporated to dryness. The residue is purified by column chromatography using 25percent ethylacetate/hexane to afford 1.9 g of b-ketoester (39percent). Patent; Sah, Dinah; Tan, Pamela; Cavenee, Webster; Furnari, Frank; Perez, Maria del Mar Inda; Bonavia, Rudy; US2012/22132; (2012); (A1) English View in Reaxys

39%

1 : 1-{6-[17-(1,5-Dimethyl-hexyl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yloxycarbonylamino]-hexanoyl}-4-oxo-pyrrolidine-3-carboxylic acid ethyl ester AE 1-{6-[17-(1,5-Dimethyl-hexyl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yloxycarbonylamino]-hexanoyl}-4-oxo-pyrrolidine-3-carboxylic acid ethyl ester AE Potassium t-but oxide (1.1 g, 9.8 mmol) is slurred in 30 mL of dry toluene. The mixture is cooled to 0° C. on ice and 5 g (6.6 mmol) of diester AD is added slowly with stirring within 20 mins. The temperature is kept below 5° C. during the addition. The stirring is continued for 30 mins at 0° C. and 1 mL of glacial acetic acid is added, immediately followed by 4 g of NaH2PO4.H2O in 40 mL of water The resultant mixture is extracted twice with 100 mL of dichloromethane each and the combined organic extracts are washed twice with 10 mL of phosphate buffer each, dried, and evaporated to dryness. The residue is dissolved in 60 mL of toluene, cooled to 0° C. and extracted with three 50 mL portions of cold pH 9.5 carbonate buffer. The aqueous extracts are adjusted to pH 3 with phosphoric acid, and extracted with five 40 mL portions of chloroform which are combined, dried and evaporated to dryness. The residue is purified by column chromatography using 25percent ethylacetate/hexane to afford 1.9 g of b-ketoester (39percent). Patent; Fitzgerald, Kevin; Hinkle, Gregory; US2012/41051; (2012); (A1) English View in Reaxys

O N

Rx-ID: 5829529 View in Reaxys 85/176

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Yield

Conditions & References vgl. Cavalla et al., C.A. 55, 23488h Patent; Dr.Karl Thomae, GmbH; GB1037640; (1963); ; vol. 65; nb. 20146a; (1966) View in Reaxys /BRN= 418861/, K-tert.-Butylat Patent; Arthur D.Little Inc.; DE2035363; (1971); ; vol. 74; nb. 100014 View in Reaxys Diethylbenzylazaadipat Patent; Little; US3994922; (1976); ; vol. 86; nb. 106556 View in Reaxys Ethyl-N-benzyl-N-(2-carbethoxy-ethyl)-glycinat, K-tert.-Butylat, Toluol (unterhalb 10grad, 3h) Jaeger; Biel; Journal of Organic Chemistry; vol. 30; (1965); p. 740,743 View in Reaxys (yield)57.5percent Jaeger; Biel; Journal of Organic Chemistry; vol. 30; (1965); p. 740,743 View in Reaxys By following the same procedure but using the corresponding ethyl N,N-disubstituted-glycinates the following 1-substituted 4-ethoxycarbonylpyrrolidine-3-ones are synthesised. ... 4-ethoxycarbonyl-1-(3,4,5-trichlorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,4,6-tribromophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,4,5-tribromophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,4,5-tribromophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-benzylpyrrolidine-3-one, 4-ethoxycarbonyl-1-(2-methoxybenzyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3-methoxybenzyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(4-methoxybenzyl)pyrrolidine-3-one, ... Patent; Sloan-Kettering Institute for Cancer Research; US4925939; (1990); (A1) English View in Reaxys

O O

Rx-ID: 5496717 View in Reaxys 86/176 Yield

Conditions & References N-(Carboxymethyl)N-phenyl-β-alanin-diethylester, K-t.-Butylat, Bzl. (Δ) Bauer; Safir; Journal of Medicinal Chemistry; vol. 15; (1972); p. 440 View in Reaxys 3-Anilino-propionsaeure-ethylester, Bromessigsaeure-ethylester, A., Na-Acetat Southwick et al.; Journal of Heterocyclic Chemistry; vol. 6; (1969); p. 507,510, 514 View in Reaxys By following the same procedure but using the corresponding ethyl N,N-disubstituted-glycinates the following 1-substituted 4-ethoxycarbonylpyrrolidine-3-ones are synthesised. ... 4-ethoxycarbonyl-1-cyclopropylpyrrolidine-3-one, 4-ethoxycarbonyl-1-cycopentylpyrrolidine-3-one,

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4-ethoxycarbonyl-1-cyclohexylpyrrolidine-3-one, 4-ethoxycarbonyl-1-cyclohexylmethylpyrrolidine-3-one, 4-ethoxycarbonyl-1-phenylpyrrolidine-3-one, 4-ethoxycarbonyl-1-(2-methoxyphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3-methoxyphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,3-dimethoxyphenyl)pyrrolidine-3-one, ... Patent; Sloan-Kettering Institute for Cancer Research; US4925939; (1990); (A1) English View in Reaxys

O N

Rx-ID: 25217680 View in Reaxys 87/176 Yield 40%

Conditions & References 1.A : A. A. 2-Benzyl-4-oxo-9-hydroxy-7-(3-methyl-2-octyl)-1,2,3,4tetrahydro[ 1]benzopyrano[ 3,4-c]pyrrole This first intermediate was prepared by the following reaction: SPC5 The ethyl 1-benzyl-4-pyrrolidone-3-carboxylate was prepared in 40percent yield (5 g) from 14.7 g of diethyl 13. benzyl.3.azaadipate and 5.6 g of potassium t-butoxide according to the procedure of E. Jaeger and J. H. Beal, J. Org. Chem. 30, 742 (1965). It was a colorless, slightly cloudy oil with nD 25 1.5147 (lit. nD 25 1.5264). The infrared spectrum was the same as the published value. The 5-(3-methyl-2-octyl) resorcinol was prepared by the method of Adams, MacKenzie and Loewe, JACS 70, 664-8 (1948). Patent; Arthur D. Little, Inc.; US3994922; (1976); (A1) English View in Reaxys

O N O O

Rx-ID: 5499771 View in Reaxys 88/176 Yield

Conditions & References N-Ethoxycarbonyl-glycinethylester, 1) Na, Bzl., 2) 1 Aequiv. Acrylsaeure-ethylester Rapoport; Willson; Journal of the American Chemical Society; vol. 84; (1962); p. 630,633 View in Reaxys N-Ethoxycarbonyl-glycin-ethylester, 1) NaH, Bzl. (ca. 1/2h, Siedetemp.), 2) Acrylsaeureethylester (3h, Siedetemp.) Wu,Y.-H. et al.; Journal of Medicinal and Pharmaceutical Chemistry; vol. 5; (1962); p. 752 - 762 View in Reaxys (yield)78percent Wu,Y.-H. et al.; Journal of Medicinal and Pharmaceutical Chemistry; vol. 5; (1962); p. 752 - 762 View in Reaxys N-Ethoxycarbonyl-glycin-ethylester, 1) Bzl., Na, 2) Acrylsaeure-ethylester Patent; BASF; DE1024966; (1956); ; nb. 7735; (1960) View in Reaxys Triester der β-NH2-Propionsaeure, NaOEt, Benzol

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Dyke,S.F. et al.; Tetrahedron; vol. 29; (1973); p. 213 - 220 View in Reaxys N-Carbethoxy-glycinethylester, Acrylsaeureethylester, Na Hultsch et al.; Arzneimittel Forschung; vol. 21; (1971); p. 1979,1980 View in Reaxys Wu; Feldkamp; Journal of Organic Chemistry; vol. 26; (1961); p. 1519 View in Reaxys Patent; Johnson; US3083208; (1961); ; vol. 59; nb. 8709b; (1963) View in Reaxys N-Ethoxycarbonyl-glycin-ethylester, 1) K-tert.-butylat, tert.-BuOH, Bzl., 2) Acrylsaeure-ethylester (60grad) Patent; BASF; DE1024966; (1956); ; nb. 7735; (1960) View in Reaxys N-Ethoxycarbonyl-glycin-ethylester, Acrylsaeure-ethylester, ethanol. K-Ethylat, Bzl. Patent; BASF; DE1024966; (1956); ; nb. 7735; (1960) View in Reaxys

O N

Rx-ID: 5436080 View in Reaxys 89/176 Yield

Conditions & References N-Ethoxycarbonylmethyl-2-methylaminopropionsaeureethylester, NaH Mattocks,A.R.; Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999); (1978); p. 896 - 905 View in Reaxys By following the same procedure but using the corresponding ethyl N,N-disubstituted-glycinates the following 1-substituted 4-ethoxycarbonylpyrrolidine-3-ones are synthesised. 4-ethoxycarbonyl-1-methylpyrrolidine-3-one, 4-ethoxycarbonyl-1-ethylpyrrolidine-3-one, 4-ethoxycarbonyl-1-(n-propyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(n-butyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-cyclopropylpyrrolidine-3-one, 4-ethoxycarbonyl-1-cycopentylpyrrolidine-3-one, 4-ethoxycarbonyl-1-cyclohexylpyrrolidine-3-one, 4-ethoxycarbonyl-1-cyclohexylmethylpyrrolidine-3-one, 4-ethoxycarbonyl-1-phenylpyrrolidine-3-one, ... Patent; Sloan-Kettering Institute for Cancer Research; US4925939; (1990); (A1) English View in Reaxys

O N O O

Rx-ID: 24105945 View in Reaxys 90/176 Yield 10.92 g (71%)

Conditions & References 1.a : a) a) 4-Oxo-pyrrolidine-1,3-dicarboxylic acid 1-tert. butylester 3-ethylester (J. Cooper et al. J. Chem.Soc.Perkin Trans. 1, 1993, 1313-1318)

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To a refluxing suspension of 1.58 g (66 mmol) sodium hydride in 100 ml THF was added dropwise a solution of 12.79 g (60 mmol) N-tert-butyloxycarbonyl-glycine ethyl ester and 7.15 g (66 mmol) ethyl acrylate in 100 ml THF. After the addition was complete the mixture was heated to reflux for additional 2 h. The clear solution was cooled to room temperature, poured on 100 ml ether/100 ml water and acidified under vigorous stirring with 1N hydrochloric acid against methyl orange. The layers were separated and the aqueous layer was extracted three times with ether. The combined organic layers were washed with sat. sodium bicarbonate and brine, dried over MgSO 4 and evaporated. Short-path distillation of the residue gave 10.92 g (71percent) 4-oxo-pyrrolidine-1,3-dicarboxylic acid 1-tert. butylester 3-ethylester as a colorless oil, b.p. 119-122° C. (0.2 mbar), which solidified on prolonged standing in the freezer. GC/MS (HP 5890 II/HP 5972; column: HP 5, 30 m*25 mm*0.25 μm film thickness, carrier gas: helium; temperature gradient: 50° C., 3 min, then with 20° C./min to 250° C.) tR=9.68 min m/z [percent]=185 (2), 130 (10), 112 (18), 85 (6), 57 (100). Patent; Roche Diagnostics GmbH; US6429288; (2002); (B1) English View in Reaxys

O N

Rx-ID: 24827549 View in Reaxys 91/176 Yield

Conditions & References By following the same procedure but using the corresponding ethyl N,N-disubstituted-glycinates the following 1-substituted 4-ethoxycarbonylpyrrolidine-3-ones are synthesised. 4-ethoxycarbonyl-1-methylpyrrolidine-3-one, 4-ethoxycarbonyl-1-ethylpyrrolidine-3-one, 4-ethoxycarbonyl-1-(n-propyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(n-butyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-cyclopropylpyrrolidine-3-one, 4-ethoxycarbonyl-1-cycopentylpyrrolidine-3-one, 4-ethoxycarbonyl-1-cyclohexylpyrrolidine-3-one, 4-ethoxycarbonyl-1-cyclohexylmethylpyrrolidine-3-one, 4-ethoxycarbonyl-1-phenylpyrrolidine-3-one, ... Patent; Sloan-Kettering Institute for Cancer Research; US4925939; (1990); (A1) English View in Reaxys

O N

Rx-ID: 24827550 View in Reaxys 92/176 Yield

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View in Reaxys

O N

Rx-ID: 24827551 View in Reaxys 93/176 Yield

Rx-ID: 24827552 View in Reaxys 94/176 Yield

O N

Rx-ID: 24827553 View in Reaxys 95/176 Yield

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4-ethoxycarbonyl-1-cyclopropylpyrrolidine-3-one, 4-ethoxycarbonyl-1-cycopentylpyrrolidine-3-one, 4-ethoxycarbonyl-1-cyclohexylpyrrolidine-3-one, 4-ethoxycarbonyl-1-cyclohexylmethylpyrrolidine-3-one, 4-ethoxycarbonyl-1-phenylpyrrolidine-3-one, 4-ethoxycarbonyl-1-(2-methoxyphenyl)pyrrolidine-3-one, ... Patent; Sloan-Kettering Institute for Cancer Research; US4925939; (1990); (A1) English View in Reaxys

Rx-ID: 24827554 View in Reaxys 96/176 Yield

Conditions & References By following the same procedure but using the corresponding ethyl N,N-disubstituted-glycinates the following 1-substituted 4-ethoxycarbonylpyrrolidine-3-ones are synthesised. ... 4-ethoxycarbonyl-1-(n-butyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-cyclopropylpyrrolidine-3-one, 4-ethoxycarbonyl-1-cycopentylpyrrolidine-3-one, 4-ethoxycarbonyl-1-cyclohexylpyrrolidine-3-one, 4-ethoxycarbonyl-1-cyclohexylmethylpyrrolidine-3-one, 4-ethoxycarbonyl-1-phenylpyrrolidine-3-one, 4-ethoxycarbonyl-1-(2-methoxyphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3-methoxyphenyl)pyrrolidine-3-one, ... Patent; Sloan-Kettering Institute for Cancer Research; US4925939; (1990); (A1) English View in Reaxys

O N

Rx-ID: 24827555 View in Reaxys 97/176 Yield

Conditions & References By following the same procedure but using the corresponding ethyl N,N-disubstituted-glycinates the following 1-substituted 4-ethoxycarbonylpyrrolidine-3-ones are synthesised. ... 4-ethoxycarbonyl-1-cycopentylpyrrolidine-3-one, 4-ethoxycarbonyl-1-cyclohexylpyrrolidine-3-one, 4-ethoxycarbonyl-1-cyclohexylmethylpyrrolidine-3-one, 4-ethoxycarbonyl-1-phenylpyrrolidine-3-one, 4-ethoxycarbonyl-1-(2-methoxyphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3-methoxyphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,3-dimethoxyphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,4-dimethoxyphenyl)pyrrolidine-3-one, ... Patent; Sloan-Kettering Institute for Cancer Research; US4925939; (1990); (A1) English View in Reaxys

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O N O

Rx-ID: 24827556 View in Reaxys 98/176 Yield

Conditions & References By following the same procedure but using the corresponding ethyl N,N-disubstituted-glycinates the following 1-substituted 4-ethoxycarbonylpyrrolidine-3-ones are synthesised. ... 4-ethoxycarbonyl-1-cyclohexylpyrrolidine-3-one, 4-ethoxycarbonyl-1-cyclohexylmethylpyrrolidine-3-one, 4-ethoxycarbonyl-1-phenylpyrrolidine-3-one, 4-ethoxycarbonyl-1-(2-methoxyphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3-methoxyphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,3-dimethoxyphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,4-dimethoxyphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,5-dimethoxyphenyl)pyrrolidine-3-one, ... Patent; Sloan-Kettering Institute for Cancer Research; US4925939; (1990); (A1) English View in Reaxys

O N

O O

Rx-ID: 24827557 View in Reaxys 99/176 Yield

Conditions & References By following the same procedure but using the corresponding ethyl N,N-disubstituted-glycinates the following 1-substituted 4-ethoxycarbonylpyrrolidine-3-ones are synthesised. ... 4-ethoxycarbonyl-1-cyclohexylmethylpyrrolidine-3-one, 4-ethoxycarbonyl-1-phenylpyrrolidine-3-one, 4-ethoxycarbonyl-1-(2-methoxyphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3-methoxyphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,3-dimethoxyphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,4-dimethoxyphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,5-dimethoxyphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,4-dimethoxyphenyl)pyrrolidine-3-one, ... Patent; Sloan-Kettering Institute for Cancer Research; US4925939; (1990); (A1) English View in Reaxys

O O

Rx-ID: 24827558 View in Reaxys 100/176 Yield

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4-ethoxycarbonyl-1-(2-methoxyphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3-methoxyphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,3-dimethoxyphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,4-dimethoxyphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,5-dimethoxyphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,4-dimethoxyphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,5-dimethoxyphenyl)pyrrolidine-3-one, ... Patent; Sloan-Kettering Institute for Cancer Research; US4925939; (1990); (A1) English View in Reaxys

Rx-ID: 24827559 View in Reaxys 101/176 Yield

Conditions & References By following the same procedure but using the corresponding ethyl N,N-disubstituted-glycinates the following 1-substituted 4-ethoxycarbonylpyrrolidine-3-ones are synthesised. ... 4-ethoxycarbonyl-1-(2-methoxyphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3-methoxyphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,3-dimethoxyphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,4-dimethoxyphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,5-dimethoxyphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,4-dimethoxyphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,5-dimethoxyphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,4,5-trimethoxyphenyl)pyrrolidine-3-one, ... Patent; Sloan-Kettering Institute for Cancer Research; US4925939; (1990); (A1) English View in Reaxys

O O

N O O

Rx-ID: 24827560 View in Reaxys 102/176 Yield

Conditions & References By following the same procedure but using the corresponding ethyl N,N-disubstituted-glycinates the following 1-substituted 4-ethoxycarbonylpyrrolidine-3-ones are synthesised. ... 4-ethoxycarbonyl-1-(3-methoxyphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,3-dimethoxyphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,4-dimethoxyphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,5-dimethoxyphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,4-dimethoxyphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,5-dimethoxyphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,4,5-trimethoxyphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2-methylphenyl)pyrrolidine-3-one, ... Patent; Sloan-Kettering Institute for Cancer Research; US4925939; (1990); (A1) English

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View in Reaxys

N O

Rx-ID: 24827561 View in Reaxys 103/176 Yield

Conditions & References By following the same procedure but using the corresponding ethyl N,N-disubstituted-glycinates the following 1-substituted 4-ethoxycarbonylpyrrolidine-3-ones are synthesised. ... 4-ethoxycarbonyl-1-(2,3-dimethoxyphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,4-dimethoxyphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,5-dimethoxyphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,4-dimethoxyphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,5-dimethoxyphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,4,5-trimethoxyphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2-methylphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3-methylphenyl)pyrrolidine-3-one, ... Patent; Sloan-Kettering Institute for Cancer Research; US4925939; (1990); (A1) English View in Reaxys

N O

Rx-ID: 24827562 View in Reaxys 104/176 Yield

Conditions & References By following the same procedure but using the corresponding ethyl N,N-disubstituted-glycinates the following 1-substituted 4-ethoxycarbonylpyrrolidine-3-ones are synthesised. ... 4-ethoxycarbonyl-1-(2,4-dimethoxyphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,5-dimethoxyphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,4-dimethoxyphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,5-dimethoxyphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,4,5-trimethoxyphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2-methylphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3-methylphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(4-methylphenyl)pyrrolidine-3-one, ... Patent; Sloan-Kettering Institute for Cancer Research; US4925939; (1990); (A1) English View in Reaxys

O N

Rx-ID: 24827563 View in Reaxys 105/176

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Yield

Conditions & References By following the same procedure but using the corresponding ethyl N,N-disubstituted-glycinates the following 1-substituted 4-ethoxycarbonylpyrrolidine-3-ones are synthesised. ... 4-ethoxycarbonyl-1-(2,5-dimethoxyphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,4-dimethoxyphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,5-dimethoxyphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,4,5-trimethoxyphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2-methylphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3-methylphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(4-methylphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,3-dimethylphenyl)pyrrolidine-3-one, ... Patent; Sloan-Kettering Institute for Cancer Research; US4925939; (1990); (A1) English View in Reaxys

O N

Rx-ID: 24827564 View in Reaxys 106/176 Yield

Conditions & References By following the same procedure but using the corresponding ethyl N,N-disubstituted-glycinates the following 1-substituted 4-ethoxycarbonylpyrrolidine-3-ones are synthesised. ... 4-ethoxycarbonyl-1-(3,4-dimethoxyphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,5-dimethoxyphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,4,5-trimethoxyphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2-methylphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3-methylphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(4-methylphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,3-dimethylphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,4-dimethylphenyl)pyrrolidine-3-one, ... Patent; Sloan-Kettering Institute for Cancer Research; US4925939; (1990); (A1) English View in Reaxys

O O

Rx-ID: 24827565 View in Reaxys 107/176 Yield

Conditions & References By following the same procedure but using the corresponding ethyl N,N-disubstituted-glycinates the following 1-substituted 4-ethoxycarbonylpyrrolidine-3-ones are synthesised. ... 4-ethoxycarbonyl-1-(3,5-dimethoxyphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,4,5-trimethoxyphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2-methylphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3-methylphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(4-methylphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,3-dimethylphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,4-dimethylphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,5-dimethylphenyl)pyrrolidine-3-one, ...

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Patent; Sloan-Kettering Institute for Cancer Research; US4925939; (1990); (A1) English View in Reaxys

O N

Rx-ID: 24827566 View in Reaxys 108/176 Yield

Conditions & References By following the same procedure but using the corresponding ethyl N,N-disubstituted-glycinates the following 1-substituted 4-ethoxycarbonylpyrrolidine-3-ones are synthesised. ... 4-ethoxycarbonyl-1-(3,4,5-trimethoxyphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2-methylphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3-methylphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(4-methylphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,3-dimethylphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,4-dimethylphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,5-dimethylphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,4-dimethylphenyl)pyrrolidine-3-one, ... Patent; Sloan-Kettering Institute for Cancer Research; US4925939; (1990); (A1) English View in Reaxys

Rx-ID: 24827567 View in Reaxys 109/176 Yield

Conditions & References By following the same procedure but using the corresponding ethyl N,N-disubstituted-glycinates the following 1-substituted 4-ethoxycarbonylpyrrolidine-3-ones are synthesised. ... 4-ethoxycarbonyl-1-(2-methylphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3-methylphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(4-methylphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,3-dimethylphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,4-dimethylphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,5-dimethylphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,4-dimethylphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,5-dimethylphenyl)pyrrolidine-3-one, ... Patent; Sloan-Kettering Institute for Cancer Research; US4925939; (1990); (A1) English View in Reaxys

O O

Rx-ID: 24827568 View in Reaxys 110/176

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Yield

Conditions & References By following the same procedure but using the corresponding ethyl N,N-disubstituted-glycinates the following 1-substituted 4-ethoxycarbonylpyrrolidine-3-ones are synthesised. ... 4-ethoxycarbonyl-1-(3-methylphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(4-methylphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,3-dimethylphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,4-dimethylphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,5-dimethylphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,4-dimethylphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,5-dimethylphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,4,5-trimethylphenyl)pyrrolidine-3-one, ... Patent; Sloan-Kettering Institute for Cancer Research; US4925939; (1990); (A1) English View in Reaxys

Rx-ID: 24827569 View in Reaxys 111/176 Yield

Conditions & References By following the same procedure but using the corresponding ethyl N,N-disubstituted-glycinates the following 1-substituted 4-ethoxycarbonylpyrrolidine-3-ones are synthesised. ... 4-ethoxycarbonyl-1-(4-methylphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,3-dimethylphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,4-dimethylphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,5-dimethylphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,4-dimethylphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,5-dimethylphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,4,5-trimethylphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2-fluorophenyl)pyrrolidine-3-one, ... Patent; Sloan-Kettering Institute for Cancer Research; US4925939; (1990); (A1) English View in Reaxys

O O

Rx-ID: 24827570 View in Reaxys 112/176 Yield

Conditions & References By following the same procedure but using the corresponding ethyl N,N-disubstituted-glycinates the following 1-substituted 4-ethoxycarbonylpyrrolidine-3-ones are synthesised. ... 4-ethoxycarbonyl-1-(2,3-dimethylphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,4-dimethylphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,5-dimethylphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,4-dimethylphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,5-dimethylphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,4,5-trimethylphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2-fluorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3-fluorophenyl)pyrrolidine-3-one,

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... Patent; Sloan-Kettering Institute for Cancer Research; US4925939; (1990); (A1) English View in Reaxys

Rx-ID: 24827571 View in Reaxys 113/176 Yield

Conditions & References By following the same procedure but using the corresponding ethyl N,N-disubstituted-glycinates the following 1-substituted 4-ethoxycarbonylpyrrolidine-3-ones are synthesised. ... 4-ethoxycarbonyl-1-(2,4-dimethylphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,5-dimethylphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,4-dimethylphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,5-dimethylphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,4,5-trimethylphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2-fluorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3-fluorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(4-fluorophenyl)pyrrolidine-3-one, ... Patent; Sloan-Kettering Institute for Cancer Research; US4925939; (1990); (A1) English View in Reaxys

O N

Rx-ID: 24827572 View in Reaxys 114/176 Yield

Conditions & References By following the same procedure but using the corresponding ethyl N,N-disubstituted-glycinates the following 1-substituted 4-ethoxycarbonylpyrrolidine-3-ones are synthesised. ... 4-ethoxycarbonyl-1-(2,5-dimethylphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,4-dimethylphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,5-dimethylphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,4,5-trimethylphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2-fluorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3-fluorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(4-fluorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2-chlorophenyl)pyrrolidine-3-one, ... Patent; Sloan-Kettering Institute for Cancer Research; US4925939; (1990); (A1) English View in Reaxys

O N F

Rx-ID: 24827573 View in Reaxys 115/176

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Yield

Conditions & References By following the same procedure but using the corresponding ethyl N,N-disubstituted-glycinates the following 1-substituted 4-ethoxycarbonylpyrrolidine-3-ones are synthesised. ... 4-ethoxycarbonyl-1-(3,4-dimethylphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,5-dimethylphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,4,5-trimethylphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2-fluorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3-fluorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(4-fluorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2-chlorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3-chlorophenyl)pyrrolidine-3-one, ... Patent; Sloan-Kettering Institute for Cancer Research; US4925939; (1990); (A1) English View in Reaxys

Rx-ID: 24827574 View in Reaxys 116/176 Yield

Conditions & References By following the same procedure but using the corresponding ethyl N,N-disubstituted-glycinates the following 1-substituted 4-ethoxycarbonylpyrrolidine-3-ones are synthesised. ... 4-ethoxycarbonyl-1-(3,5-dimethylphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,4,5-trimethylphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2-fluorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3-fluorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(4-fluorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2-chlorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3-chlorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(4-chlorophenyl)pyrrolidine-3-one, ... Patent; Sloan-Kettering Institute for Cancer Research; US4925939; (1990); (A1) English View in Reaxys

O N

Rx-ID: 24827575 View in Reaxys 117/176 Yield

Conditions & References By following the same procedure but using the corresponding ethyl N,N-disubstituted-glycinates the following 1-substituted 4-ethoxycarbonylpyrrolidine-3-ones are synthesised. ... 4-ethoxycarbonyl-1-(3,4,5-trimethylphenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2-fluorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3-fluorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(4-fluorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2-chlorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3-chlorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(4-chlorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2-bromophenyl)pyrrolidine-3-one, ...

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Patent; Sloan-Kettering Institute for Cancer Research; US4925939; (1990); (A1) English View in Reaxys

O N Cl

Rx-ID: 24827576 View in Reaxys 118/176 Yield

Conditions & References By following the same procedure but using the corresponding ethyl N,N-disubstituted-glycinates the following 1-substituted 4-ethoxycarbonylpyrrolidine-3-ones are synthesised. ... 4-ethoxycarbonyl-1-(2-fluorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3-fluorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(4-fluorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2-chlorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3-chlorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(4-chlorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2-bromophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3-bromophenyl)pyrrolidine-3-one, ... Patent; Sloan-Kettering Institute for Cancer Research; US4925939; (1990); (A1) English View in Reaxys

Rx-ID: 24827577 View in Reaxys 119/176 Yield

Conditions & References By following the same procedure but using the corresponding ethyl N,N-disubstituted-glycinates the following 1-substituted 4-ethoxycarbonylpyrrolidine-3-ones are synthesised. ... 4-ethoxycarbonyl-1-(3-fluorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(4-fluorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2-chlorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3-chlorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(4-chlorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2-bromophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3-bromophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(4-bromophenyl)pyrrolidine-3-one, ... Patent; Sloan-Kettering Institute for Cancer Research; US4925939; (1990); (A1) English View in Reaxys

O N

Rx-ID: 24827578 View in Reaxys 120/176 Yield

Conditions & References By following the same procedure but using the corresponding ethyl N,N-disubstituted-glycinates the following 1-substituted 4-ethoxycarbonylpyrrolidine-3-ones are synthesised.

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... 4-ethoxycarbonyl-1-(4-fluorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2-chlorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3-chlorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(4-chlorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2-bromophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3-bromophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(4-bromophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,3-difluorophenyl)pyrrolidine-3-one, ... Patent; Sloan-Kettering Institute for Cancer Research; US4925939; (1990); (A1) English View in Reaxys

O N Br

Rx-ID: 24827579 View in Reaxys 121/176 Yield

Conditions & References By following the same procedure but using the corresponding ethyl N,N-disubstituted-glycinates the following 1-substituted 4-ethoxycarbonylpyrrolidine-3-ones are synthesised. ... 4-ethoxycarbonyl-1-(2-chlorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3-chlorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(4-chlorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2-bromophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3-bromophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(4-bromophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,3-difluorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,4-difluorophenyl)pyrrolidine-3-one, ... Patent; Sloan-Kettering Institute for Cancer Research; US4925939; (1990); (A1) English View in Reaxys

O O

Rx-ID: 24827580 View in Reaxys 122/176 Yield

Conditions & References By following the same procedure but using the corresponding ethyl N,N-disubstituted-glycinates the following 1-substituted 4-ethoxycarbonylpyrrolidine-3-ones are synthesised. ... 4-ethoxycarbonyl-1-(3-chlorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(4-chlorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2-bromophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3-bromophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(4-bromophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,3-difluorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,4-difluorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,5-difluorophenyl)pyrrolidine-3-one, ... Patent; Sloan-Kettering Institute for Cancer Research; US4925939; (1990); (A1) English View in Reaxys

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Rx-ID: 24827581 View in Reaxys 123/176 Yield

Conditions & References By following the same procedure but using the corresponding ethyl N,N-disubstituted-glycinates the following 1-substituted 4-ethoxycarbonylpyrrolidine-3-ones are synthesised. ... 4-ethoxycarbonyl-1-(4-chlorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2-bromophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3-bromophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(4-bromophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,3-difluorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,4-difluorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,5-difluorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,4-difluorophenyl)pyrrolidine-3-one, ... Patent; Sloan-Kettering Institute for Cancer Research; US4925939; (1990); (A1) English View in Reaxys

Rx-ID: 24827582 View in Reaxys 124/176 Yield

Conditions & References By following the same procedure but using the corresponding ethyl N,N-disubstituted-glycinates the following 1-substituted 4-ethoxycarbonylpyrrolidine-3-ones are synthesised. ... 4-ethoxycarbonyl-1-(2-bromophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3-bromophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(4-bromophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,3-difluorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,4-difluorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,5-difluorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,4-difluorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,5-difluorophenyl)pyrrolidine-3-one, ... Patent; Sloan-Kettering Institute for Cancer Research; US4925939; (1990); (A1) English View in Reaxys

O O

Rx-ID: 24827583 View in Reaxys 125/176 Yield

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4-ethoxycarbonyl-1-(4-bromophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,3-difluorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,4-difluorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,5-difluorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,4-difluorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,5-difluorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,3-dichlorophenyl)pyrrolidine-3-one, ... Patent; Sloan-Kettering Institute for Cancer Research; US4925939; (1990); (A1) English View in Reaxys

N F F

Rx-ID: 24827584 View in Reaxys 126/176 Yield

Conditions & References By following the same procedure but using the corresponding ethyl N,N-disubstituted-glycinates the following 1-substituted 4-ethoxycarbonylpyrrolidine-3-ones are synthesised. ... 4-ethoxycarbonyl-1-(4-bromophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,3-difluorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,4-difluorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,5-difluorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,4-difluorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,5-difluorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,3-dichlorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,4-dichlorophenyl)pyrrolidine-3-one, ... Patent; Sloan-Kettering Institute for Cancer Research; US4925939; (1990); (A1) English View in Reaxys

O O

N F

Rx-ID: 24827585 View in Reaxys 127/176 Yield

Conditions & References By following the same procedure but using the corresponding ethyl N,N-disubstituted-glycinates the following 1-substituted 4-ethoxycarbonylpyrrolidine-3-ones are synthesised. ... 4-ethoxycarbonyl-1-(2,3-difluorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,4-difluorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,5-difluorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,4-difluorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,5-difluorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,3-dichlorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,4-dichlorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,5-dichlorophenyl)pyrrolidine-3-one, ... Patent; Sloan-Kettering Institute for Cancer Research; US4925939; (1990); (A1) English View in Reaxys

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O N

Cl Cl

Rx-ID: 24827586 View in Reaxys 128/176 Yield

Conditions & References By following the same procedure but using the corresponding ethyl N,N-disubstituted-glycinates the following 1-substituted 4-ethoxycarbonylpyrrolidine-3-ones are synthesised. ... 4-ethoxycarbonyl-1-(2,4-difluorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,5-difluorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,4-difluorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,5-difluorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,3-dichlorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,4-dichlorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,5-dichlorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,4-dichlorophenyl)pyrrolidine-3-one, ... Patent; Sloan-Kettering Institute for Cancer Research; US4925939; (1990); (A1) English View in Reaxys

Rx-ID: 24827587 View in Reaxys 129/176 Yield

Conditions & References By following the same procedure but using the corresponding ethyl N,N-disubstituted-glycinates the following 1-substituted 4-ethoxycarbonylpyrrolidine-3-ones are synthesised. ... 4-ethoxycarbonyl-1-(2,5-difluorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,4-difluorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,5-difluorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,3-dichlorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,4-dichlorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,5-dichlorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,4-dichlorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,5-dichlorophenyl)pyrrolidine-3-one, ... Patent; Sloan-Kettering Institute for Cancer Research; US4925939; (1990); (A1) English View in Reaxys

O O

Rx-ID: 24827588 View in Reaxys 130/176 Yield

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4-ethoxycarbonyl-1-(3,5-difluorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,3-dichlorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,4-dichlorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,5-dichlorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,4-dichlorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,5-dichlorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,3-dibromophenyl)pyrrolidine-3-one, ... Patent; Sloan-Kettering Institute for Cancer Research; US4925939; (1990); (A1) English View in Reaxys

N Cl Cl

Rx-ID: 24827589 View in Reaxys 131/176 Yield

Conditions & References By following the same procedure but using the corresponding ethyl N,N-disubstituted-glycinates the following 1-substituted 4-ethoxycarbonylpyrrolidine-3-ones are synthesised. ... 4-ethoxycarbonyl-1-(3,5-difluorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,3-dichlorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,4-dichlorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,5-dichlorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,4-dichlorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,5-dichlorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,3-dibromophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,4-dibromophenyl)pyrrolidine-3-one, ... Patent; Sloan-Kettering Institute for Cancer Research; US4925939; (1990); (A1) English View in Reaxys

O O

N Cl

Rx-ID: 24827590 View in Reaxys 132/176 Yield

Conditions & References By following the same procedure but using the corresponding ethyl N,N-disubstituted-glycinates the following 1-substituted 4-ethoxycarbonylpyrrolidine-3-ones are synthesised. ... 4-ethoxycarbonyl-1-(2,3-dichlorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,4-dichlorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,5-dichlorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,4-dichlorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,5-dichlorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,3-dibromophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,4-dibromophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,5-dibromophenyl)pyrrolidine-3-one, ... Patent; Sloan-Kettering Institute for Cancer Research; US4925939; (1990); (A1) English View in Reaxys

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O N

Br Br

Rx-ID: 24827591 View in Reaxys 133/176 Yield

Conditions & References By following the same procedure but using the corresponding ethyl N,N-disubstituted-glycinates the following 1-substituted 4-ethoxycarbonylpyrrolidine-3-ones are synthesised. ... 4-ethoxycarbonyl-1-(2,4-dichlorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,5-dichlorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,4-dichlorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,5-dichlorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,3-dibromophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,4-dibromophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,5-dibromophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,4-dibromophenyl)pyrrolidine-3-one, ... Patent; Sloan-Kettering Institute for Cancer Research; US4925939; (1990); (A1) English View in Reaxys

Rx-ID: 24827592 View in Reaxys 134/176 Yield

Conditions & References By following the same procedure but using the corresponding ethyl N,N-disubstituted-glycinates the following 1-substituted 4-ethoxycarbonylpyrrolidine-3-ones are synthesised. ... 4-ethoxycarbonyl-1-(2,5-dichlorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,4-dichlorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,5-dichlorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,3-dibromophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,4-dibromophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,5-dibromophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,4-dibromophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,5-dibromophenyl)pyrrolidine-3-one, ... Patent; Sloan-Kettering Institute for Cancer Research; US4925939; (1990); (A1) English View in Reaxys

O O

Rx-ID: 24827593 View in Reaxys 135/176 Yield

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4-ethoxycarbonyl-1-(3,5-dichlorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,3-dibromophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,4-dibromophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,5-dibromophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,4-dibromophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,5-dibromophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,4,6-trifluorophenyl)pyrrolidine-3-one, ... Patent; Sloan-Kettering Institute for Cancer Research; US4925939; (1990); (A1) English View in Reaxys

N Br Br

Rx-ID: 24827594 View in Reaxys 136/176 Yield

Conditions & References By following the same procedure but using the corresponding ethyl N,N-disubstituted-glycinates the following 1-substituted 4-ethoxycarbonylpyrrolidine-3-ones are synthesised. ... 4-ethoxycarbonyl-1-(3,5-dichlorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,3-dibromophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,4-dibromophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,5-dibromophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,4-dibromophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,5-dibromophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,4,6-trifluorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,4,5-trifluorophenyl)pyrrolidine-3-one, ... Patent; Sloan-Kettering Institute for Cancer Research; US4925939; (1990); (A1) English View in Reaxys

O O

N Br

Rx-ID: 24827595 View in Reaxys 137/176 Yield

Conditions & References By following the same procedure but using the corresponding ethyl N,N-disubstituted-glycinates the following 1-substituted 4-ethoxycarbonylpyrrolidine-3-ones are synthesised. ... 4-ethoxycarbonyl-1-(2,3-dibromophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,4-dibromophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,5-dibromophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,4-dibromophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,5-dibromophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,4,6-trifluorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,4,5-trifluorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,4,5-trifluorophenyl)pyrrolidine-3-one, ... Patent; Sloan-Kettering Institute for Cancer Research; US4925939; (1990); (A1) English View in Reaxys

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Rx-ID: 24827596 View in Reaxys 138/176 Yield

Conditions & References By following the same procedure but using the corresponding ethyl N,N-disubstituted-glycinates the following 1-substituted 4-ethoxycarbonylpyrrolidine-3-ones are synthesised. ... 4-ethoxycarbonyl-1-(2,5-dibromophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,4-dibromophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,5-dibromophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,4,6-trifluorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,4,5-trifluorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,4,5-trifluorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,4,6-trifluorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,4,5-trifluorophenyl)pyrrolidine-3-one, ... Patent; Sloan-Kettering Institute for Cancer Research; US4925939; (1990); (A1) English View in Reaxys

Cl Cl

Rx-ID: 24827597 View in Reaxys 139/176 Yield

Conditions & References By following the same procedure but using the corresponding ethyl N,N-disubstituted-glycinates the following 1-substituted 4-ethoxycarbonylpyrrolidine-3-ones are synthesised. ... 4-ethoxycarbonyl-1-(2,4,5-trifluorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,4,5-trifluorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,4,6-trifluorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,4,5-trifluorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,4,6-trichlorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,4,5-trichlorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,4,5-trichlorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,4,6-tribromophenyl)pyrrolidine-3-one, ... Patent; Sloan-Kettering Institute for Cancer Research; US4925939; (1990); (A1) English View in Reaxys

O O

Rx-ID: 24827598 View in Reaxys 140/176 Yield

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4-ethoxycarbonyl-1-(3,4,5-trifluorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,4,6-trifluorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,4,5-trifluorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,4,6-trichlorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,4,5-trichlorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,4,5-trichlorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,4,6-tribromophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,4,5-tribromophenyl)pyrrolidine-3-one, ... Patent; Sloan-Kettering Institute for Cancer Research; US4925939; (1990); (A1) English View in Reaxys

N Cl

Rx-ID: 24827599 View in Reaxys 141/176 Yield

Conditions & References By following the same procedure but using the corresponding ethyl N,N-disubstituted-glycinates the following 1-substituted 4-ethoxycarbonylpyrrolidine-3-ones are synthesised. ... 4-ethoxycarbonyl-1-(2,4,6-trifluorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,4,5-trifluorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,4,6-trichlorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,4,5-trichlorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,4,5-trichlorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,4,6-tribromophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,4,5-tribromophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,4,5-tribromophenyl)pyrrolidine-3-one, ... Patent; Sloan-Kettering Institute for Cancer Research; US4925939; (1990); (A1) English View in Reaxys

Br Br

Rx-ID: 24827600 View in Reaxys 142/176 Yield

Conditions & References By following the same procedure but using the corresponding ethyl N,N-disubstituted-glycinates the following 1-substituted 4-ethoxycarbonylpyrrolidine-3-ones are synthesised. ... 4-ethoxycarbonyl-1-(3,4,5-trifluorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,4,6-trichlorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,4,5-trichlorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,4,5-trichlorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,4,6-tribromophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,4,5-tribromophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,4,5-tribromophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-benzylpyrrolidine-3-one, ... Patent; Sloan-Kettering Institute for Cancer Research; US4925939; (1990); (A1) English View in Reaxys

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Rx-ID: 24827601 View in Reaxys 143/176 Yield

Conditions & References By following the same procedure but using the corresponding ethyl N,N-disubstituted-glycinates the following 1-substituted 4-ethoxycarbonylpyrrolidine-3-ones are synthesised. ... 4-ethoxycarbonyl-1-(2,4,6-trichlorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,4,5-trichlorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,4,5-trichlorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,4,6-tribromophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,4,5-tribromophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,4,5-tribromophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-benzylpyrrolidine-3-one, 4-ethoxycarbonyl-1-(2-methoxybenzyl)pyrrolidine-3-one, ... Patent; Sloan-Kettering Institute for Cancer Research; US4925939; (1990); (A1) English View in Reaxys

N Br Br

Rx-ID: 24827602 View in Reaxys 144/176 Yield

Conditions & References By following the same procedure but using the corresponding ethyl N,N-disubstituted-glycinates the following 1-substituted 4-ethoxycarbonylpyrrolidine-3-ones are synthesised. ... 4-ethoxycarbonyl-1-(2,4,5-trichlorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,4,5-trichlorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,4,6-tribromophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,4,5-tribromophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,4,5-tribromophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-benzylpyrrolidine-3-one, 4-ethoxycarbonyl-1-(2-methoxybenzyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3-methoxybenzyl)pyrrolidine-3-one, ... Patent; Sloan-Kettering Institute for Cancer Research; US4925939; (1990); (A1) English View in Reaxys

O O

Rx-ID: 24827603 View in Reaxys 145/176 Yield

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4-ethoxycarbonyl-1-(2,4,6-tribromophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,4,5-tribromophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,4,5-tribromophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-benzylpyrrolidine-3-one, 4-ethoxycarbonyl-1-(2-methoxybenzyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3-methoxybenzyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(4-methoxybenzyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,4-dimethoxybenzyl)pyrrolidine-3-one, ... Patent; Sloan-Kettering Institute for Cancer Research; US4925939; (1990); (A1) English View in Reaxys O

O O

Rx-ID: 24827604 View in Reaxys 146/176 Yield

Conditions & References By following the same procedure but using the corresponding ethyl N,N-disubstituted-glycinates the following 1-substituted 4-ethoxycarbonylpyrrolidine-3-ones are synthesised. ... 4-ethoxycarbonyl-1-(2,4,5-tribromophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,4,5-tribromophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-benzylpyrrolidine-3-one, 4-ethoxycarbonyl-1-(2-methoxybenzyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3-methoxybenzyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(4-methoxybenzyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,4-dimethoxybenzyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,5-dimethoxybenzyl)pyrrolidine-3-one, ... Patent; Sloan-Kettering Institute for Cancer Research; US4925939; (1990); (A1) English View in Reaxys O

O O

Rx-ID: 24827605 View in Reaxys 147/176 Yield

Conditions & References By following the same procedure but using the corresponding ethyl N,N-disubstituted-glycinates the following 1-substituted 4-ethoxycarbonylpyrrolidine-3-ones are synthesised. ... 4-ethoxycarbonyl-1-(3,4,5-tribromophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-benzylpyrrolidine-3-one, 4-ethoxycarbonyl-1-(2-methoxybenzyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3-methoxybenzyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(4-methoxybenzyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,4-dimethoxybenzyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,5-dimethoxybenzyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,4-dimethoxybenzyl)pyrrolidine-3-one, ...

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Patent; Sloan-Kettering Institute for Cancer Research; US4925939; (1990); (A1) English View in Reaxys O

O O

Rx-ID: 24827606 View in Reaxys 148/176 Yield

Conditions & References By following the same procedure but using the corresponding ethyl N,N-disubstituted-glycinates the following 1-substituted 4-ethoxycarbonylpyrrolidine-3-ones are synthesised. ... 4-ethoxycarbonyl-1-benzylpyrrolidine-3-one, 4-ethoxycarbonyl-1-(2-methoxybenzyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3-methoxybenzyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(4-methoxybenzyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,4-dimethoxybenzyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,5-dimethoxybenzyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,4-dimethoxybenzyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,5-dimethoxybenzyl)pyrrolidine-3-one, ... Patent; Sloan-Kettering Institute for Cancer Research; US4925939; (1990); (A1) English View in Reaxys

O O

Rx-ID: 24827607 View in Reaxys 149/176 Yield

Conditions & References By following the same procedure but using the corresponding ethyl N,N-disubstituted-glycinates the following 1-substituted 4-ethoxycarbonylpyrrolidine-3-ones are synthesised. ... 4-ethoxycarbonyl-1-(2-methoxybenzyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3-methoxybenzyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(4-methoxybenzyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,4-dimethoxybenzyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,5-dimethoxybenzyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,4-dimethoxybenzyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,5-dimethoxybenzyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,4,5-trimethoxybenzyl)pyrrolidine-3-one, ... Patent; Sloan-Kettering Institute for Cancer Research; US4925939; (1990); (A1) English View in Reaxys

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O O

Rx-ID: 24827608 View in Reaxys 150/176 Yield

Conditions & References By following the same procedure but using the corresponding ethyl N,N-disubstituted-glycinates the following 1-substituted 4-ethoxycarbonylpyrrolidine-3-ones are synthesised. ... 4-ethoxycarbonyl-1-(3-methoxybenzyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(4-methoxybenzyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,4-dimethoxybenzyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,5-dimethoxybenzyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,4-dimethoxybenzyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,5-dimethoxybenzyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,4,5-trimethoxybenzyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,4,5-trimethoxybenzyl)pyrrolidine-3-one, ... Patent; Sloan-Kettering Institute for Cancer Research; US4925939; (1990); (A1) English View in Reaxys O

O O

Rx-ID: 24827609 View in Reaxys 151/176 Yield

Conditions & References By following the same procedure but using the corresponding ethyl N,N-disubstituted-glycinates the following 1-substituted 4-ethoxycarbonylpyrrolidine-3-ones are synthesised. ... 4-ethoxycarbonyl-1-(4-methoxybenzyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,4-dimethoxybenzyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,5-dimethoxybenzyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,4-dimethoxybenzyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,5-dimethoxybenzyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,4,5-trimethoxybenzyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,4,5-trimethoxybenzyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2-methylbenzyl)pyrrolidine-3-one, ... Patent; Sloan-Kettering Institute for Cancer Research; US4925939; (1990); (A1) English View in Reaxys O

O O

Rx-ID: 24827610 View in Reaxys 152/176

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Yield

Conditions & References By following the same procedure but using the corresponding ethyl N,N-disubstituted-glycinates the following 1-substituted 4-ethoxycarbonylpyrrolidine-3-ones are synthesised. ... 4-ethoxycarbonyl-1-(2,4-dimethoxybenzyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,5-dimethoxybenzyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,4-dimethoxybenzyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,5-dimethoxybenzyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,4,5-trimethoxybenzyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,4,5-trimethoxybenzyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2-methylbenzyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3-methylbenzyl)pyrrolidine-3-one, ... Patent; Sloan-Kettering Institute for Cancer Research; US4925939; (1990); (A1) English View in Reaxys

O O

O N

O O

Rx-ID: 24827611 View in Reaxys 153/176 Yield

Conditions & References By following the same procedure but using the corresponding ethyl N,N-disubstituted-glycinates the following 1-substituted 4-ethoxycarbonylpyrrolidine-3-ones are synthesised. ... 4-ethoxycarbonyl-1-(2,5-dimethoxybenzyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,4-dimethoxybenzyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,5-dimethoxybenzyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,4,5-trimethoxybenzyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,4,5-trimethoxybenzyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2-methylbenzyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3-methylbenzyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(4-methylbenzyl)pyrrolidine-3-one, ... Patent; Sloan-Kettering Institute for Cancer Research; US4925939; (1990); (A1) English View in Reaxys

O O

Rx-ID: 24827612 View in Reaxys 154/176 Yield

Conditions & References By following the same procedure but using the corresponding ethyl N,N-disubstituted-glycinates the following 1-substituted 4-ethoxycarbonylpyrrolidine-3-ones are synthesised. ... 4-ethoxycarbonyl-1-(3,4-dimethoxybenzyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,5-dimethoxybenzyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,4,5-trimethoxybenzyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,4,5-trimethoxybenzyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2-methylbenzyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3-methylbenzyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(4-methylbenzyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,5-dimethylbenzyl)pyrrolidine-3-one.

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Patent; Sloan-Kettering Institute for Cancer Research; US4925939; (1990); (A1) English View in Reaxys

Rx-ID: 24827613 View in Reaxys 155/176 Yield

Conditions & References By following the same procedure but using the corresponding ethyl N,N-disubstituted-glycinates the following 1-substituted 4-ethoxycarbonylpyrrolidine-3-ones are synthesised. ... 4-ethoxycarbonyl-1-(3,5-dimethoxybenzyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,4,5-trimethoxybenzyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,4,5-trimethoxybenzyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2-methylbenzyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3-methylbenzyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(4-methylbenzyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,5-dimethylbenzyl)pyrrolidine-3-one. Patent; Sloan-Kettering Institute for Cancer Research; US4925939; (1990); (A1) English View in Reaxys

Rx-ID: 24827614 View in Reaxys 156/176 Yield

Conditions & References By following the same procedure but using the corresponding ethyl N,N-disubstituted-glycinates the following 1-substituted 4-ethoxycarbonylpyrrolidine-3-ones are synthesised. ... 4-ethoxycarbonyl-1-(2,4,5-trimethoxybenzyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,4,5-trimethoxybenzyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2-methylbenzyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3-methylbenzyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(4-methylbenzyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,5-dimethylbenzyl)pyrrolidine-3-one. Patent; Sloan-Kettering Institute for Cancer Research; US4925939; (1990); (A1) English View in Reaxys

O O

Rx-ID: 24827615 View in Reaxys 157/176 Yield

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4-ethoxycarbonyl-1-(3,4,5-trimethoxybenzyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2-methylbenzyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3-methylbenzyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(4-methylbenzyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,5-dimethylbenzyl)pyrrolidine-3-one. Patent; Sloan-Kettering Institute for Cancer Research; US4925939; (1990); (A1) English View in Reaxys

N F

Rx-ID: 24860339 View in Reaxys 158/176 Yield

Conditions & References By following the same procedure but using the corresponding ethyl N,N-disubstituted-glycinates the following 1-substituted 4-ethoxycarbonylpyrrolidine-3-ones are synthesised. ... 4-ethoxycarbonyl-1-(3,5-dibromophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,4,6-trifluorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,4,5-trifluorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,4,5-trifluorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,4,6-trifluorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,4,5-trifluorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,4,6-trichlorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,4,5-trichlorophenyl)pyrrolidine-3-one, ... Patent; Sloan-Kettering Institute for Cancer Research; US4925939; (1990); (A1) English View in Reaxys

O O

N F

Rx-ID: 24860340 View in Reaxys 159/176 Yield

Conditions & References By following the same procedure but using the corresponding ethyl N,N-disubstituted-glycinates the following 1-substituted 4-ethoxycarbonylpyrrolidine-3-ones are synthesised. ... 4-ethoxycarbonyl-1-(2,4,6-trifluorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,4,5-trifluorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,4,5-trifluorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,4,6-trifluorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,4,5-trifluorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,4,6-trichlorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(2,4,5-trichlorophenyl)pyrrolidine-3-one, 4-ethoxycarbonyl-1-(3,4,5-trichlorophenyl)pyrrolidine-3-one, ... Patent; Sloan-Kettering Institute for Cancer Research; US4925939; (1990); (A1) English View in Reaxys

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O 14

O N O O

Rx-ID: 5837224 View in Reaxys 160/176 Yield

Conditions & References N-Ethoxycarbonyl-N-(2-ethoxycarbonylethyl)-(1-14C)glycin-ethylester, K-tert.-butanolat, Toluol (0grad; neben 1Ethoxycarbonyl-3-oxo-2-(14C)carbonsaeure-ethylester) Blake et al.; Journal of the American Chemical Society; vol. 86; (1964); p. 5293,5298 View in Reaxys N-Ethoxycarbonyl-glycin-(1-14C)-ethylester, 1) Na-Ethylat, A. 2) Acrylsaeure-ethylester Rapoport; Willson; Journal of the American Chemical Society; vol. 84; (1962); p. 630,633 View in Reaxys N-Ethoxycarbonyl-N-(2-ethoxycarbonylethyl)-glycin-1-14C-ethylester, Na-Ethylat, A. Rapoport; Willson; Journal of the American Chemical Society; vol. 84; (1962); p. 630,633 View in Reaxys

O 14

O N O O

Rx-ID: 5636216 View in Reaxys 161/176 Yield

Conditions & References N-Ethoxycarbonyl-N-(2-tert.-butoxycarbonylethyl)-(1-14C)glycin-tert.-butylester, K-tert.-butanolat, Toluol (0grad) Blake et al.; Journal of the American Chemical Society; vol. 86; (1964); p. 5293,5298 View in Reaxys

O N O

Rx-ID: 5827565 View in Reaxys 162/176 Yield

Conditions & References N-(2-Ethoxycarbonyl-ethyl)-N-ethoxycarbonylmethyl-acetamid, Bzl., ethanol. Na-Ethylat-Lsg. (N2-Atm., Siedetemp., 3h) Carelli; Morlacchi; Annali di Chimica (Rome, Italy); vol. 54; (1964); p. 1291,1299; View in Reaxys N-Acetylglycin Et ester, 1) NaH, Bzl., 2) Ethylacrylat Patent; Mead Johnson and Co.; GB873303; (1961); US; ; vol. 57; nb. 16566a; (1962) View in Reaxys N-Acetylglycinethylester, NaH, Ethylacrylat Patent; Sandoz-Wander Inc.; US3687973; (1969); ; vol. 77; nb. 151889 View in Reaxys Patent; Johnson; US3083208; (1961); ; vol. 59; nb. 8709b; (1963) View in Reaxys

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O N O O

Rx-ID: 5830661 View in Reaxys 163/176 Yield

Conditions & References N-Methoxycarbonyl-glycinethylester, 1) NaH, Bzl. (ca. 1/2h, Siedtemp.), 2) Acrylsaeureethylester (3h, Siedetemp.) Wu,Y.-H. et al.; Journal of Medicinal and Pharmaceutical Chemistry; vol. 5; (1962); p. 752 - 762 View in Reaxys (yield)53percent Wu,Y.-H. et al.; Journal of Medicinal and Pharmaceutical Chemistry; vol. 5; (1962); p. 752 - 762 View in Reaxys N-Acetyl-glycin-ethylester, 1) NaH, Bzl. (Siedetemp.; ca. 1/2d, R.T.), 2) CH2=CH-CO2Et (ca. 1 1/4 h, R.T.; 2h, Siedetemp.) Wu et al.; Journal of Medicinal and Pharmaceutical Chemistry; vol. 5; (1962); p. 762,766,768 View in Reaxys (yield)57.3percent Wu et al.; Journal of Medicinal and Pharmaceutical Chemistry; vol. 5; (1962); p. 762,766,768 View in Reaxys N-Carbomethoxyglycin Etester, 1) NaH, Bzl., 2) Et acrylat (reflux), 3) HCl (aq.) Patent; Mead Johnson and Co.; GB873303; (1961); US; ; vol. 57; nb. 16566a; (1962) View in Reaxys

O N O O

Rx-ID: 5833983 View in Reaxys 164/176 Yield

Conditions & References N-Isobutyloxycarbonyl-glycinethylester, 1) NaH, Bzl. (ca. 1/2h, Siedtemp.), 2) Acrylsaeureethylester (3h, Siedetemp.) Wu,Y.-H. et al.; Journal of Medicinal and Pharmaceutical Chemistry; vol. 5; (1962); p. 752 - 762 View in Reaxys (yield)65percent Wu,Y.-H. et al.; Journal of Medicinal and Pharmaceutical Chemistry; vol. 5; (1962); p. 752 - 762 View in Reaxys N-Carboisobutoxyglycin Etester, 1) NaH, Bzl., 2) Et acrylat (reflux), 3) HCl (aq.) Patent; Mead Johnson and Co.; GB873303; (1961); US; ; vol. 57; nb. 16566a; (1962) View in Reaxys Patent; Johnson; US3083208; (1961); ; vol. 59; nb. 8709b; (1963) View in Reaxys

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O O

N O O

Rx-ID: 5638154 View in Reaxys 165/176 Yield

Conditions & References Glycinester 2, K-tert.-butylat Feil,P.D.; Vercellotti,J.R.; Carbohydrate Research; vol. 31; (1973); p. 311 - 322 View in Reaxys O

O O

Rx-ID: 5595340 View in Reaxys 166/176 Yield

Conditions & References Butylamin-Verb. (VIII), NaOCH3 Arbuzov,B.A. et al.; Chemistry of Heterocyclic Compounds (New York, NY, United States); vol. 5; (1969); p. 730 736; Khimiya Geterotsiklicheskikh Soedinenii; vol. 5; (1969); p. 978 - 985 View in Reaxys O

O O

N N

Rx-ID: 5596886 View in Reaxys 167/176 Yield

Conditions & References Patent; Mead Johnson; US3184462; (1961); ; vol. 63; nb. 7020d; (1965) View in Reaxys

O N

Rx-ID: 5601939 View in Reaxys 168/176 Yield

Conditions & References vgl. Cavalla et al., C.A. 55 23488h Patent; Dr.Karl Thomae, GmbH; GB1037640; (1963); ; vol. 65; nb. 20146a; (1966) View in Reaxys

O O

Rx-ID: 5615821 View in Reaxys 169/176 Yield

Conditions & References vgl. Cavalla et al., C.A. 55 23488h

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Patent; Dr.Karl Thomae, GmbH; GB1037640; (1963); ; vol. 65; nb. 20146a; (1966) View in Reaxys

Rx-ID: 5619167 View in Reaxys 170/176 Yield

Conditions & References vgl. Cavalla et al., C.A. 55 23488h Patent; Dr.Karl Thomae, GmbH; GB1037640; (1963); ; vol. 65; nb. 20146a; (1966) View in Reaxys

N O

Rx-ID: 5623633 View in Reaxys 171/176 Yield

Conditions & References N-(2-Ethoxycarbonyl-ethyl)-aminoessigsaeure-ethylester, in Py.(10grad), 1) Benzoylchlorid (10grad, dann 20grad, 12h), 2) Na-Ethylat, abs. A. (Siedetemp., 2h) Sheradsky; Southwick; Journal of Heterocyclic Chemistry; vol. 4; (1967); p. 1,6 View in Reaxys

O N

Rx-ID: 5636571 View in Reaxys 172/176 Yield

Conditions & References XXIIb, K-tert.-Butylat McCaustland,D.J. et al.; Journal of Heterocyclic Chemistry; vol. 8; (1971); p. 89 - 97 View in Reaxys

O N O

Rx-ID: 5826260 View in Reaxys 173/176 Yield

Conditions & References N-Formyl-N-ethoxycarbonylmethyl-β-alanin-ethylester, Na-Ethylat, Bzl. (Siedetemp., 1h) Coburn,M.D.; Ungnade,H.E.; Journal of Heterocyclic Chemistry; vol. 2; (1965); p. 308 - 309 View in Reaxys

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Rx-ID: 5827288 View in Reaxys 174/176 Yield

Conditions & References 3-Anilino-propionsaeure-methylester, 1) Bromessigsaeure-ethylester, 2) Me., Na-Methylat-Lsg. Southwick et al.; Journal of Heterocyclic Chemistry; vol. 6; (1969); p. 507,510, 514 View in Reaxys

Rx-ID: 5831303 View in Reaxys 175/176 Yield

Conditions & References 3-(4-Chlor-anilino)-propionsaeure-methylester, 1) Bromessigsaeure-ethylester, 2) Me., Na-Methylat-Lsg. Southwick et al.; Journal of Heterocyclic Chemistry; vol. 6; (1969); p. 507,510, 514 View in Reaxys

O O

Rx-ID: 5837984 View in Reaxys 176/176 Yield

Conditions & References 3-(4-Methoxycarbonyl-anilino)-propionsaeure-methylester, Bromessigsaeure-ethylester, A., Na-Acetat Southwick et al.; Journal of Heterocyclic Chemistry; vol. 6; (1969); p. 507,510, 514 View in Reaxys

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