Michael_Addition_Acrylate_Glycine_Equiv by Asch

Query 1. Query

Query

Results

Date

(filtered by |TRBIN

78 reactions in Reaxys

2017-11-14 05h:52m:06s (EST)

78 reactions in Reaxys

2017-11-14 05h:51m:03s (EST)

2. Query

O O

Search as: Product, As drawn

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N H

O O

Rx-ID: 179084 View in Reaxys 1/78 Yield

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

H N

N O

Rx-ID: 651963 View in Reaxys 2/78 Yield

Conditions & References With potassium carbonate Patent; Robins Co.; US2878264; (1957) View in Reaxys O H N

N O

Rx-ID: 651965 View in Reaxys 3/78 Yield

Conditions & References With potassium carbonate Leonard et al.; Journal of the American Chemical Society; vol. 73; (1951); p. 2371 View in Reaxys O H N

N O

Rx-ID: 1239602 View in Reaxys 4/78 Yield

Conditions & References With potassium carbonate 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

H N

O O

Rx-ID: 1243338 View in Reaxys 5/78 Yield

Conditions & References Davies,W.A.M. et al.; Journal of the Chemical Society; (1960); p. 3504 - 3512 View in Reaxys

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H N

O Br

Rx-ID: 2907959 View in Reaxys 6/78 Yield

Conditions & References

71 %

With sodium carbonate, Time= 5h, T= 120 °C McHugh, Michael; Proctor, George R.; Journal of Chemical Research, Miniprint; nb. 8; (1984); p. 2230 - 2253 View in Reaxys O O

H N

O O

Rx-ID: 2922432 View in Reaxys 7/78 Yield

Conditions & References

83 %

With potassium carbonate in N,N-dimethyl-formamide, Time= 2h, T= 60 °C Su; Watanabe; Journal of Organic Chemistry; vol. 54; nb. 1; (1989); p. 220 - 224 View in Reaxys O

O H 2N

H N

Rx-ID: 3352180 View in Reaxys 8/78 Yield

Conditions & References

91 %

in methanol, Time= 48h Mauger, Anthony B.; Stuart, Oswald A.; Katz, Edward; Journal of Medicinal Chemistry; vol. 34; nb. 4; (1991); p. 1297 - 1301 View in Reaxys O

O H 2N

H N

O O

Rx-ID: 3790777 View in Reaxys 9/78 Yield

Conditions & References

95 %

in ethanol McDowell, Robert S.; Blackburn, Brent K.; Gadek, Thomas R.; McGee, Lawrence R.; Rawson, Thomas; Reynolds, Mark E.; Robarge, Kirk D.; Somers, Todd C.; Thorsett, Eugene D.; Tischler, Maureen; Webb II, Robert R.; Venuti, Michael C.; Journal of the American Chemical Society; vol. 116; nb. 12; (1994); p. 5077 - 5083 View in Reaxys O

H 2N

Cl O

H O

O O

N H

Rx-ID: 3790945 View in Reaxys 10/78 Yield 78%

Conditions & References With triethylamine in ethanol, Time= 48h, T= 20 °C , Michael Addition Dong, Shuai; Indukuri, Kiran; Clive, Derrick L. J.; Gao, Jin-Ming; Chemical Communications; vol. 52; nb. 53; (2016); p. 8271 - 8274 View in Reaxys

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76 %

With triethylamine in ethanol, T= 20 °C Williams, Robert M.; Cao, Jianhua; Tsujishima, Hidekazu; Cox, Rhona J.; Journal of the American Chemical Society; vol. 125; nb. 40; (2003); p. 12172 - 12178 View in Reaxys

70 %

With sodium hydroxide, Time= 19h, T= 0 - 20 °C , Michael addition 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

68 %

With sodium hydroxide, Time= 19h, Ambient temperature Roglans; Marquet; Moreno-Manas; Synthetic Communications; vol. 22; nb. 9; (1992); p. 1249 - 1258 View in Reaxys

67 %

1 :[Reference Example 1] Synthesis of ethyl 3-(ethoxycarbonylmethylamino)propionate; [Show Image] [Show Image] 150 g of glycine ethyl ester hydrochloride (1.07 mol) was mixed with 1.200 L of ethanol. To this mixture, 110 mL of ethyl acrylate (1.02 mol) was added at an internal temperature of 2 to 25°C. 150 mL of triethylamine (1.08 mol) was then added dropwise at an internal temperature of 20 to 21°C over 5 minutes. Subsequently, the mixture was stirred at an internal temperature of 23 to 27°C for 8.5 hours and was allowed to stand overnight. The insoluble material was separated by filtration and the filtrate was evaporated under reduced pressure. 300 mL of ethyl acetate was added to the resulting residue and the insoluble material was separated by filtration and washed with 50 mL of ethyl acetate. The filtrate and the wash were combined and concentrated under reduced pressure. The resulting residue was distilled under reduced pressure (533 Pa, 130°C) to give 138 g of the title compound as a colorless oil (67percent yield). 1H-NMR (CDCl3, 400 Mz) δ: 1.27 (3H, t, J = 7.1 Hz), 1.28 (3H, t, J = 7.3 Hz), 2.51 (2H, t, J = 6.6 Hz), 2.90 (2H, t, J = 6.6 Hz), 3.42 (2H, s), 4.15 (2H, q, J = 7.1 Hz), 4.19 (2H, q, J = 7.1 Hz). FAB-MS (positive): 204 [M+H] +

With triethylamine in ethanol, T= 2 - 27 °C Patent; Kyorin Pharmaceutical Co., Ltd.; EP1992613; (2008); (A1) English View in Reaxys 65 %

With triethylamine in ethanol, Time= 144h Rosowsky, Andre; Bader, Henry; Forsch, Ronald A.; Moran, Richard G.; Freisheim, James H.; Journal of Medicinal Chemistry; vol. 31; nb. 4; (1988); p. 763 - 768 View in Reaxys

61 %

A 4.7 M aqueous solution of sodium hydroxide (50 mL) was added into a stirred, ice-cooled solution of ethyl glycinate hydrochloride (32.19 g, 0.23 mole) in water (50 mL). Then, ethyl acrylate (23.1 g, 0.23 mole) was added and the mixture was stirred at room temperature until the completion of reaction was ascertained by TLC (19 h). After 19 h which it was partitioned with dichloromethane (3 x 100 mL). The organic layer was dried with anhydrous sodium sulfate, filtered and evaporated. The residue was distilled to affordAA(28.8 g, 61percent). With sodium hydroxide in water, Time= 19h, T= 0 - 20 °C Patent; ALNYLAM PHARMACEUTICALS, INC.; WO2006/36916; (2006); (A2) English View in Reaxys

61 %

2 :A 4.7 M aqueous solution of sodium hydroxide (50 mL) was added into a stirred, ice- cooled solution of ethyl glycinate hydrochloride (32.19 g, 0.23 mole) in water (50 mL). Then, ethyl acrylate (23.1 g, 0.23 mole) was added and the mixture was stirred at room temperature until the completion of reaction was ascertained by TLC (19 h). After 19 h which it was partitioned with dichloromethane (3 x 100 mL). The organic layer was dried with anhydrous sodium sulfate, filtered and evaporated. The residue was distilled to afford AA (28.8 g, 61percent). With sodium hydroxide in water, Time= 19h, T= 20 °C Patent; ALNYLAM PHARMACEUTICALS, INC.; WO2006/81192; (2006); (A2) English View in Reaxys

61 %

Diethyl-2-azabutane-1,4-dicarboxylate AA

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Diethyl-2-azabutane-1,4-dicarboxylate AA A 4.7 M aqueous solution of sodium hydroxide (50 mL) was added into a stirred, ice-cooled solution of ethyl glycinate hydrochloride (32.19 g, 0.23 mole) in water (50 mL). Then, ethyl acrylate (23.1 g, 0.23 mole) was added and the mixture was stirred at room temperature until completion of the reaction was ascertained by TLC. After 19 h the solution was partitioned with dichloromethane (3*100 mL). The organic layer was dried with anhydrous sodium sulfate, filtered and evaporated. The residue was distilled to afford AA (28.8 g, 61percent). With sodium hydroxide in water, Time= 19h, T= 20 °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 61 %

2 : Diethyl-2-azabutane-1,4-dicarboxylate AA Diethyl-2-azabutane-1,4-dicarboxylate AA A 4.7 M aqueous solution of sodium hydroxide (50 mL) was added into a stirred, ice-cooled solution of ethyl glycinate hydrochloride (32.19 g, 0.23 mole) in water (50 mL). Then, ethyl acrylate (23.1 g, 0.23 mole) was added and the mixture was stirred at room temperature until completion of the reaction was ascertained by TLC. After 19 h the solution was partitioned with dichloromethane (3*100 mL). The organic layer was dried with anhydrous sodium sulfate, filtered and evaporated. The residue was distilled to afford AA (28.8 g, 61percent). With sodium hydroxide in water, Time= 19h, T= 0 - 20 °C 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

61 %

1 :Example 1: Diethyl2-azabutane-1.4-dicarboxvlateAA O ~ H AAA 4.7M aqueous solution of sodium hydroxide (50 niL) was added into a stirred, ice- cooled solution of ethyl glycinate hydrochloride (32.19 g, 0.23 mole) in water (50 mL). Then, ethyl acrylate (23.1 g, 0.23 mole) was added and the mixture was stirred at room temperature until the completion of reaction was ascertained by TLC (19 h). After 19 h which it was partitioned with dichloromethane (3 x 100 mL). The organic layer was dried with anhydrous sodium sulfate, filtered and evaporated. The residue was distilled to afford AA (28.8 g, 61percent). With sodium hydroxide in water, Time= 19h, T= 0 - 20 °C Patent; ALNYLAM PHARMACEUTICALS, INC.; WO2006/20768; (2006); (A2) English View in Reaxys

61 %

A 4.7 M aqueous solution of sodium hydroxide (50 mL) was added into a stirred, ice-cooled solution of ehtyl glycinate hydrochloride (32.19 g, 0.23 mole) in water (50 mL). Then, ethyl acrylate (23.1 g, 0.23 mole) was added and the mixture was stirred at room temperature until completion of the reaction was ascertained by TLC. After 19 h the solution was partitioned with dichloromethane (3.x.100 mL). The organic layer was dried with anhydrous sodium sulfate, filtered and evaporated. The residue was distilled to afford AA (28.8 g, 61percent). With sodium hydroxide in water, Time= 19h, T= 0 °C Patent; Bumcrot, David; Tan, Pamela; Vornlocher, Hans-Peter; Geick, Anke; US2007/281899; (2007); (A1) English View in Reaxys

61 %

A 4.7 M aqueous solution of sodium hydroxide (50 mL) was added into a stirred, ice- cooled solution of ethyl glycinate hydrochloride (32.19 g, 0.23 mole) in water (50 mL). Then, ethyl acrylate (23.1 g, 0.23 mole) was added and the mixture was stirred at room temperature until completion of the reaction was ascertained by TLC. After 19 h the solution was partitioned with dichloromethane (3 x 100 mL). The organic layer was dried with anhydrous sodium sulfate, filtered and evaporated. The residue was distilled to afford AA (28.8 g, 61percent). With sodium hydroxide in water, Time= 19h, T= 0 - 20 °C Patent; ALNYLAM PHARMACEUTICALS, INC.; THE SCRIPPS RESEARCH INSTITUTE; WO2007/137156; (2007); (A2) English View in Reaxys

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61 %

A 4.7 M aqueous solution of sodium hydroxide (50 mL) was added into a stirred, ice-cooled solution of ethyl glycinate hydrochloride (32.19 g, 0.23 mole) in water (50 mL). Then, ethyl acrylate (23.1 g, 0.23 mole) was added and the mixture was stirred at room temperature until completion of the reaction was ascertained by TLC. After 19 h the solution was partitioned with dichloromethane (3 x 100 mL). The organic layer was dried with anhydrous sodium sulfate, filtered and evaporated. The residue was distilled to afford AA (28.8 g, 61percent). With sodium hydroxide in water, Time= 19h, T= 0 - 20 °C Patent; ALNYLAM PHARMACEUTICALS, INC.; THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER AT DALLAS; WO2008/36638; (2008); (A2) English View in Reaxys

61 %

A 4.7 M aqueous solution of sodium hydroxide (50 mL) was added into a stirred, ice- cooled solution of ethyl glycinate hydrochloride (32.19 g, 0.23 mole) in water (50 mL). Then, ethyl acrylate (23.1 g, 0.23 mole) was added and the mixture was stirred at room temperature until completion of the reaction was ascertained by TLC. After 19 h the solution was partitioned with dichloromethane (3 x 100 mL). The organic layer was dried with anhydrous sodium sulfate, filtered and evaporated. The residue was distilled to afford AA (28.8 g, 61percent). With sodium hydroxide in water, Time= 19h, T= 0 - 20 °C Patent; NOVARTIS AG; WO2008/116860; (2008); (A2) English View in Reaxys

61 %

1 : Diethyl-2-azabutane-1,4-dicarboxylate AA Diethyl-2-azabutane-1,4-dicarboxylate AA A 4.7 M aqueous solution of sodium hydroxide (50 mL) was added into a stirred, ice-cooled solution of ethyl glycinate hydrochloride (32.19 g, 0.23 mole) in water (50 mL). Then, ethyl acrylate (23.1 g, 0.23 mole) was added and the mixture was stirred at room temperature until completion of the reaction was ascertained by TLC. After 19 h the solution was partitioned with dichloromethane (3*100 mL). The organic layer was dried with anhydrous sodium sulfate, filtered and evaporated. The residue was distilled to afford AA (28.8 g, 61percent). With sodium hydroxide in water, Time= 19h, T= 0 - 20 °C Patent; ALNYLAM PHARMACEUTICALS, INC.; GOVERNMENT OF THE UNITED STATES; US2009/143323; (2009); (A1) English View in Reaxys

61 %

1.2.1 :A 4.7 M aqueous solution of sodium hydroxide (50 mL) was added into a stirred, ice- cooled solution of ethyl glycinate hydrochloride (32.19 g, 0.23 mole) in water (50 mL). Then, ethyl acrylate (23.1 g, 0.23 mole) was added and the mixture was stirred at room temperature until completion of the reaction was ascertained by TLC. After 19 h the solution was partitioned with dichloromethane (3 x 100 mL). The organic layer was dried with anhydrous sodium sulfate, filtered and evaporated. The residue was distilled to afford AA (28.8 g, 61 percent). With sodium hydroxide in water, Time= 19h, T= 0 - 20 °C Patent; ALNYLAM PHARMACEUTICALS, INC.; WO2005/115481; (2005); (A2) English View in Reaxys

61 %

Diethyl-2-azabutane-1,4-dicarboxylate AA Diethyl-2-azabutane-1,4-dicarboxylate AA A 4.7 M aqueous solution of sodium hydroxide (50 mL) was added into a stirred, ice-cooled solution of ethyl glycinate hydrochloride (32.19 g, 0.23 mole) in water (50 mL). Then, ethyl acrylate (23.1 g, 0.23 mole) was added and the mixture was stirred at room temperature until completion of the reaction was ascertained by TLC. After 19 h the solution was partitioned with dichloromethane (3*100 mL). The organic layer was dried with anhydrous sodium sulfate, filtered and evaporated. The residue was distilled to afford AA (28.8 g, 61percent). With sodium hydroxide in water, T= 20 °C , Cooling with ice Patent; Alnylam Pharmaceuticals, Inc.; US7605251; (2009); (B2) English View in Reaxys

61 %

Diethyl-2-azabutane-l,4-dicarboxylate AAOH OAAA 4.7 M aqueous solution of sodium hydroxide (50 mL) was added into a stirred, ice- cooled solution of ethyl glycinate hydrochloride (32.19 g, 0.23 mole) in water (50 mL). Then, ethyl

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acrylate (23.1 g, 0.23 mole) was added and the mixture was stirred at room temperature until completion of the reaction was ascertained by TLC. After 19 h the solution was partitioned with dichloromethane (3 x 100 mL). The organic layer was dried with anhydrous sodium sulfate, filtered and evaporated. The residue was distilled to afford AA (28.8 g, 61percent). With sodium hydroxide in water, Time= 19h, T= 0 - 20 °C Patent; ALNYLAM PHARMACEUTICALS, INC.; IMPERIAL INNOVATIONS LTD; WO2007/137220; (2007); (A2) English View in Reaxys 61 %

1 : Diethyl-2-azabutane-1,4-dicarboxylate AA Diethyl-2-azabutane-1,4-dicarboxylate AA A 4.7 M aqueous solution of sodium hydroxide (50 mL) was added into a stirred, ice-cooled solution of ethyl glycinate hydrochloride (32.19 g, 0.23 mole) in water (50 mL). Then, ethyl acrylate (23.1 g, 0.23 mole) was added and the mixture was stirred at room temperature until completion of the reaction was ascertained by TLC. After 19 h the solution was partitioned with dichloromethane (3*100 mL). The organic layer was dried with anhydrous sodium sulfate, filtered and evaporated. The residue was distilled to afford AA (28.8 g, 61percent). With sodium hydroxide in water, Time= 19h, T= 20 °C , Cooling with ice Patent; Alnylam Pharmaceuticals, Inc.; Sah, Dinah Wen-Yee; US9101643; (2015); (B2) English View in Reaxys

61 %

1 : Diethyl-2-azabutane-1,4-dicarboxylate AA A 4.7 M aqueous solution of sodium hydroxide (50 mL) was added into a stirred, ice-cooled solution of ethyl glycinatc hydrochloride (32.19 g, 0.23 mole) in water (50 mL). Then, ethyl acrylate (23.1 g, 0.23 mole) was added and the mixture was stirred at room temperature until completion of the reaction was ascertained by TLC. After 19 h the solution was partitioned with dichloromethane (3 x 100 mL). The organic layer was dried with anhydrous sodium sulfate, filtered and evaporated. The residue was distilled to afford AA (28.8 g, 61percent). With sodium hydroxide in water, Time= 19h, T= 20 °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

61 %

1 : Diethyl-2-azabutane-1,4-dicarboxylate AA Diethyl-2-azabutane-1,4-dicarboxylate AA A 4.7 M aqueous solution of sodium hydroxide (50 mL) was added into a stirred, ice-cooled solution of ethyl glycinate hydrochloride (32.19 g, 0.23 mole) in water (50 mL). Then, ethyl acrylate (23.1 g, 0.23 mole) was added and the mixture was stirred at room temperature until completion of the reaction was ascertained by TLC. After 19 h the solution was partitioned with dichloromethane (3*100 mL). The organic layer was dried with anhydrous sodium sulfate, filtered and evaporated. The residue was distilled to afford AA (28.8 g, 61percent). With sodium hydroxide in water, Time= 19h, T= 20 °C , Cooling with ice Patent; Alnylam Pharmaceuticals, Inc.; Sah, Dinah Wen-Yee; Chen, Qingmin; US9200282; (2015); (B2) English

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View in Reaxys 61%

1 : Diethyl-2-azabutane-1,4-dicarboxylate AA Diethyl-2-azabutane-1,4-dicarboxylate AA A 4.7 M aqueous solution of sodium hydroxide (50 mL) can be added into a stirred, ice-cooled solution of ethyl glycinate hydrochloride (32.19 g, 0.23 mole) in water (50 mL). Then, ethyl acrylate (23.1 g, 0.23 mole) can be added and the mixture can be stirred at room temperature until completion of the reaction can be ascertained by TLC. After 19 h the solution can be partitioned with dichloromethane (3*100 mL). The organic layer can be dried with anhydrous sodium sulfate, filtered and evaporated. The residue can be distilled to afford AA (28.8 g, 61percent). With sodium hydroxide in water, Time= 19h, T= 20 °C Patent; Alnylam Pharmaceuticals, Inc.; Sah, Dinah Wen-Yee; Hinkle, Gregory; (240 pag.); US2016/24497; (2016); (A1) English View in Reaxys

61 %

1 : Diethyl-2-azabutane-1,4-dicarboxylate AA Diethyl-2-azabutane-1,4-dicarboxylate AA A 4.7 M aqueous solution of sodium hydroxide (50 mL) was added into a stirred, ice-cooled solution of ethyl glycinate hydrochloride (32.19 g, 0.23 mole) in water (50 mL). Then, ethyl acrylate (23.1 g, 0.23 mole) was added and the mixture was stirred at room temperature until completion of the reaction was ascertained by TLC. After 19 h the solution was partitioned with dichloromethane (3*100 mL). The organic layer was dried with anhydrous sodium sulfate, filtered and evaporated. The residue was distilled to afford AA (28.8 g, 61percent). With sodium hydroxide in water, Time= 19h, T= 20 °C , Cooling with ice Patent; Alnylam Pharmaceuticals, Inc.; de Fougerolles, Antonin; Borodovsky, Anna; Novobrantseva, Tatiana; US2015/353934; (2015); (A1) English View in Reaxys

61 %

5 : Diethyl-2-azabutane-1,4-dicarboxylate AA Diethyl-2-azabutane-1,4-dicarboxylate AA A 4.7 M aqueous solution of sodium hydroxide (50 mL) is added into a stirred, ice-cooled solution of ethyl glycinate hydrochloride (32.19 g, 0.23 mole) in water (50 mL). Then, ethyl acrylate (23.1 g, 0.23 mole) is added and the mixture is stirred at room temperature until completion of the reaction is ascertained by TLC. After 19 h the solution is partitioned with dichloromethane (3*100 mL). The organic layer is dried with anhydrous sodium sulfate, filtered and evaporated. The residue is distilled to afford AA (28.8 g, 61percent). With sodium hydroxide in water, Time= 19h, T= 20 °C , Cooling with ice Patent; Alnylam Pharmaceuticals, Inc.; de Fougerolles, Antonin; Novobrantseva, Tatiana; Akinc, Akin; (87 pag.); US2016/17336; (2016); (A1) English View in Reaxys

61 %

1 : diethyl-2-azabutane-1,4-dicarboxylate AA

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A 4.7 M aqueous solution of sodium hydroxide (50 mL) was added into a stirred, ice-cooled solution of ethyl glycinate hydrochloride (32.19 g, 0.23 mole) in water (50 mL). Then, ethyl acrylate (23.1 g, 0.23 mole) was added and the mixture was stirred at room temperature until completion of the reaction was ascertained by TLC. After 19 h the solution was partitioned with dichloromethane (3×100 mL). The organic layer was dried with anhydrous sodium sulfate, filtered and evaporated. The residue was distilled to afford AA (28.8 g, 61percent). With sodium hydroxide in dichloromethane, water, Time= 19h, T= 20 °C , Cooling with ice Patent; Alnylam Pharmaceuticals, Inc.; Bumcrot, David; Sah, Dinah Wen-Yee; Toudjarska, Ivanka; (103 pag.); US2016/819; (2016); (A1) English View in Reaxys 61 %

1 : Diethyl-2-azabutane-1,4-dicarboxylate AA Diethyl-2-azabutane-1,4-dicarboxylate AA A 4.7 M aqueous solution of sodium hydroxide (50 mL) is added into a stirred, ice-cooled solution of ethyl glycinate hydrochloride (32.19 g, 0.23 mole) in water (50 mL). Then, ethyl acrylate (23.1 g, 0.23 mole) is added and the mixture is stirred at room temperature until completion of the reaction is ascertained by TLC. After 19 h the solution is partitioned with dichloromethane (3*100 mL). The organic layer is dried with anhydrous sodium sulfate, filtered and evaporated. The residue is distilled to afford AA (28.8 g, 61percent). With sodium hydroxide in water, Time= 19h, T= 20 °C , Cooling with ice Patent; Alnylam Pharmaceuticals, Inc.; Gollob, Jared; Hinkle, Gregory; Toudjarska, Ivanka; Bumcrot, David; (73 pag.); US9566295; (2017); (B2) English View in Reaxys 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 With triethylamine 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 62 :Reference Example 62 Ethyl 3-[N-benzyloxycarbonyl-N-(ethoxycarbonyl methyl)amino]propionate To a suspension of glycine ethyl ester hydrochloride (41.9 g, 0.3 mol) in ethanol (300 mL) was added triethylamine (41.8 mL, 0.3 mol) and ethyl acrylate (10.8 mL, 0.1 mol) in an ice bath, and the mixture was stirred at 80° C. for 1 hour. The reaction mixture was concentrated under reduced pressure, and water (400 mL) was added to the residue, and the mixture was extracted with ethyl acetate (200 mL*3). The extract was washed with water (200 mL*2) and saturated aqueous solution of sodium chloride (200 mL) in this order, an the dried with anhydrous sodium sulfate. After the filtration, the filtrate was concentrated under reduced pressure, and the residue was dissolved in acetone (150 mL). To this solution were added aqueous solution of sodium carbonate (11.5 g, 108 mmol) (50 mL) and a solution of benzyloxycarbonyl chloride (18.4 g, 108 mmol) in acetone (50 mL) in an ice bath, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and water (400 mL) was added to the residue. The mixture was extracted with ethyl acetate (200 mL*3), and the extract was washed with saturated aqueous solution of sodium chloride (200 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, 5:1) to obtain 31.1 g (92percent) of the title compound as a colorless oily product. 1H-NMR (400 MHz, CDCl )δ ppm: 1.16-1.29 (6H, m), 2.58-2.70 (2H, m), 3.59-3.66 (2H, m), 4.04-4.22 (6H, m), 3 5.10-5.18 (2H, m), 7.26-7.38 (5H, m). MS (ESI) m/z: 338 (M+H)+. With triethylamine in ethanol, Time= 1h, T= 0 - 80 °C

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Patent; DAIICHI PHARMACEUTICAL CO., LTD.; US2006/264428; (2006); (A1) English View in Reaxys Diethyl-2-azabutane-1,4-dicarboxylate AA Diethyl-2-azabutane-1,4-dicarboxylate AA A 4.7 M aqueous solution of sodium hydroxide (50 mL) was added into a stirred, ice-cooled solution of ethyl glycinate hydrochloride (32.19 g, 0.23 mole) in water (50 mL). Then, ethyl acrylate (23.1 g, 0.23 mole) was added and the mixture was stirred at room temperature until completion of the reaction was ascertained by TLC. After 19 h the solution was partitioned with dichloromethane (3*100 mL). The organic layer was dried with anhydrous sodium sulfate, filtered and evaporated. The residue was distilled to afford AA (28.8 g, 61percent). With sodium hydroxide in dichloromethane, water Patent; Benson, John; Bramlage, Birgit; Fitzgerald, Kevin; Tan, Pamela; Vornlocher, Hans-Peter; US2009/247607; (2009); (A1) English View in Reaxys 1 : Diethyl-2-azabutane-1,4-dicarboxylate Diethyl-2-azabutane-1,4-dicarboxylate A 4.7 M aqueous solution of sodium hydroxide (50 mL) is added into a stirred, ice-cooled solution of ethyl glycinate hydrochloride (32.19 g, 0.23 mole) in water (50 mL). Then, ethyl acrylate (23.1 g, 0.23 mole) is added and the mixture stirred at room temperature until completion of the reaction is ascertained by TLC. After 19 h the solution is partitioned with dichloromethane (3*100 mL). The organic layer is dried with anhydrous sodium sulfate, filtered and evaporated. The residue is distilled to afford AA (28.8 g, 61percent). With sodium hydroxide in dichloromethane, water Patent; Fitzgerald, Kevin; Hinkle, Gregory; US2009/275638; (2009); (A1) English View in Reaxys 1.A :To ethyl glycinate hydrochloride (12.9 g, 92 mmol) in water (20 mL) at 0 0C was added cold aqueous NaOH (19.5 mL, 93 mmol, 4.75 M) followed by ethyl acrylate (9.18 g, 92 mmol). The reaction stirred about 18 hours and warmed to room temperature. The mixture was extracted with CH2Cl2 four times and the solution was dried (Na2SO4). The material was distilled at about 110 0C ( 1.8 torr) to afford the product, 1 -a With sodium hydroxide in water, Time= 18h, T= 0 °C Patent; MERCK and CO., INC.; WO2009/108499; (2009); (A1) English View in Reaxys 1 : Diethyl-2-azabutane-1,4-dicarboxylate AA Diethyl-2-azabutane-1,4-dicarboxylate AA A 4.7 M aqueous solution of sodium hydroxide (50 mL) is added into a stirred, ice-cooled solution of ethyl glycinate hydrochloride (32.19 g, 0.23 mole) in water (50 mL). Then, ethyl acrylate (23.1 g, 0.23 mole) is added and the mixture is stirred at room temperature until completion of the reaction is ascertained by TLC. After 19 h the solution is partitioned with dichloromethane (3*100 mL). The organic layer is dried with anhydrous sodium sulfate, filtered and evaporated. The residue is distilled to afford AA (28.8 g, 61percent). With sodium hydroxide in dichloromethane, water Patent; Gollob, Jared; Hinkle, Gregory; Toudjarska, Ivanka; Bumcrot, David; US2010/168206; (2010); (A1) English View in Reaxys 1 : Diethyl-2-azabutane-1,4-dicarboxylate AA Diethyl-2-azabutane-1,4-dicarboxylate AA A 4.7 M aqueous solution of sodium hydroxide (50 mL) was added into a stirred, ice-cooled solution of ethyl glycinate hydrochloride (32.19 g, 0.23 mole) in water (50 mL). Then, ethyl acrylate (23.1 g, 0.23 mole) was added and the mixture was stirred at room temperature until completion of the reaction was ascertained by TLC. After 19 h the solution was partitioned with dichloromethane (3*100 mL). The organic layer was dried with anhydrous sodium sulfate, filtered and evaporated.

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The residue was distilled to afford AA (28.8 g, 61N. With sodium hydroxide in dichloromethane, water Patent; NOVARTIS AG; US2010/183704; (2010); (A1) English View in Reaxys 1 : Diethyl-2-azabutane-1,4-dicarboxylate AA Diethyl-2-azabutane-1,4-dicarboxylate AA A 4.7 M aqueous solution of sodium hydroxide (50 mL) was added into a stirred, ice-cooled solution of ethyl glycinate hydrochloride (32.19 g, 0.23 mole) in water (50 mL). Then, ethyl acrylate (23.1 g, 0.23 mole) was added and the mixture was stirred at room temperature until completion of the reaction was ascertained by TLC. After 19 h the solution was partitioned with dichloromethane (3*100 mL). The organic layer was dried with anhydrous sodium sulfate, filtered and evaporated. The residue was distilled to afford AA (28.8 g, 61percent). With sodium hydroxide in dichloromethane, water Patent; Sah, Dinah Wen-Yee; Hinkle, Gregory; Alvarez, Rene; Milstein, Stuart; Chen, Qingmin; US2010/120893; (2010); (A1) English View in Reaxys Patent; Labow, Mark Aron; Gaither, Larry Alexander; Borawski, Jason; US2010/184823; (2010); (A1) English View in Reaxys 6 : Diethyl-2-azabutane-1,4-dicarboxylate AA Diethyl-2-azabutane-1,4-dicarboxylate AA A 4.7 M aqueous solution of sodium hydroxide (50 mL) is added into a stirred, ice-cooled solution of ethyl glycinate hydrochloride (32.19 g, 0.23 mole) in water (50 mL). Then, ethyl acrylate (23.1 g, 0.23 mole) is added and the mixture is stirred at room temperature until completion of the reaction is ascertained by TLC. After 19 h the solution is partitioned with dichloromethane (3*100 mL). The organic layer is dried with anhydrous sodium sulfate, filtered and evaporated. The residue is distilled to afford AA (28.8 g, 61percent). With sodium hydroxide in dichloromethane, water Patent; De Fougerolles, Antonin; Tan, Pamela; Borodovsky, Anna; Novobrantseva, Tatiana; Bavari, Sina; Warfield, Kelly Lyn; US2011/34537; (2011); (A1) English View in Reaxys 1 : Diethyl-2-azabutane-1,4-dicarboxylate AA Diethyl-2-azabutane-1,4-dicarboxylate AA A 4.7 M aqueous solution of sodium hydroxide (50 mL) can be added into a stirred, ice-cooled solution of ethyl glycinate hydrochloride (32.19 g, 0.23 mole) in water (50 mL). Then, ethyl acrylate (23.1 g, 0.23 mole) can be added and the mixture can be stirred at room temperature until completion of the reaction can be ascertained by TLC. After 19 h the solution can be partitioned with dichloromethane (3*100 mL). The organic layer can be dried with anhydrous sodium sulfate, filtered and evaporated. The residue can be distilled to afford AA (28.8 g, 61percent). With sodium hydroxide in dichloromethane, water Patent; Sah, Dinah Wen-Yee; Sah, Dinah; Hinkle, Gregory; US2011/184046; (2011); (A1) English View in Reaxys Diethyl-2-azabutane-1,4-dicarboxylate AA Diethyl-2-azabutane-1,4-dicarboxylate AA A 4.7 M aqueous solution of sodium hydroxide (50 mL) was added into a stirred, ice-cooled solution of ethyl glycinate hydrochloride (32.19 g, 0.23 mole) in water (50 mL). Then, ethyl acrylate (23.1 g, 0.23 mole) was added and the mixture was stirred at room temperature until completion of the reaction was ascertained by TLC. After 19 h the solution was partitioned with dichloromethane (3*100 mL). The organic layer was dried with anhydrous sodium sulfate, filtered and evaporated. The residue was distilled to afford AA (28.8 g, 61percent). With sodium hydroxide in dichloromethane, water

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Patent; Alnylam Pharmaceuticals ,Inc. a corporation; US2012/16006; (2012); (A1) English View in Reaxys 1 : Diethyl-2-azabutane-1,4-dicarboxylate AA Diethyl-2-azabutane-1,4-dicarboxylate AA A 4.7 M aqueous solution of sodium hydroxide (50 mL) is added into a stirred, ice-cooled solution of ethyl glycinate hydrochloride (32.19 g, 0.23 mole) in water (50 mL). Then, ethyl acrylate (23.1 g, 0.23 mole) is added and the mixture is stirred at room temperature until completion of the reaction is ascertained by TLC. After 19 h the solution is partitioned with dichloromethane (3*100 mL). The organic layer is dried with anhydrous sodium sulfate, filtered and evaporated. The residue is distilled to afford AA (28.8 g, 61percent). With sodium hydroxide in dichloromethane, water Patent; ALNYLAM PHARMACEUTICALS, INC.; US2011/263684; (2011); (A1) English View in Reaxys Patent; Sah, Dinah; Tan, Pamela; Cavenee, Webster; Furnari, Frank; Perez, Maria del Mar Inda; Bonavia, Rudy; US2012/22132; (2012); (A1) English View in Reaxys Patent; Fitzgerald, Kevin; Hinkle, Gregory; US2012/41051; (2012); (A1) English View in Reaxys 38 :Ethyl acrylaie ( 11.5 g, 0.115 mol ) was added to a solution of glycine ethyl ester hydrochloride (187) (20 g, 0.144 mol). and triethy famine (17.6 mL, 0.127 mol) in ethariol (134 mL) and the mixture heated to 35-4 °C for 3.5 hrs. The mixture was concentrated and partitioned between water (100 mL) and ethyl acetate (I χ 300mL). The orgaatcs were washed wit 1 x 100 mL half saturated sodium bicarbonate, I 50 mL saturated sodium chloride, and dried over N stSO . The dried organics were evaporated to 20.94 g of clear colorless oil that .bul.was used in the next step without further purification. MS (ESI) m z 204 [M+Hf With triethylamine in ethanol, Time= 3.5h, T= 35 - 40 °C Patent; MITHRIDION, INC.; ABRAHAM, Brent, D.; COPP, Richard, R.; FARNHAM, James, G.; HANSON, Seth, A.; HENDRICKSON, Michael, L.; OCKULY, Jeffrey, C.; TWOSE, Trevor, M.; VERDONE, Melinda, L.; WO2012/33956; (2012); (A1) English View in Reaxys 4.1.17. Ethyl 3-((tert-butoxycarbonyl)(2-ethoxy-2-oxoethyl)amino)propanoate (30) To a suspension of ethyl glycinate hydrochloride 29 (7.0 g, 50.1 mmol) in 95percent ethanol (115 mL) was added ethyl acrylate(6.0 mL, 55.1 mmol) and Et3N (7.0 mL, 50.1 mmol). The reaction mixture was allowed to stir at room temperature for 48 h. The reaction was concentrated and water was added. The aqueous phase was extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4 and evaporated. The crude product, isolated as a yellow oil, was dissolved in CHCl3 (80 mL), and Boc2O (15.3 g, 70.1 mmol) was added at 0 C, followed by 5percent aqueous NaOH (80 mL). The reaction was stirred at 0 C for 1 h, and then at room temperature for 72 h. The mixture was extracted with CHCl3 and the organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by automated flash chromatography (pet. ether/ EtOAc 4:1, Rf 0.56), to afford 30 as a yellow oil (11.78 g, 77percent yield over two step). 1H NMR (CDCl3, 200 MHz) major rotamer: d 4.16 (q, J = 7.1 Hz, 2H), 4.11 (qd, J = 3.6, 7.1 Hz, 2H), 4.00 and 3.94 (s, 2H), 3.55 and 3.51 (t, J = 6.6 Hz, 2H), 2.62 and 2.59 (t, J = 6.6 Hz, 2H), 1.46 and 1.40 (s, 9H), 1.25 (m, 6H). Anal. C14H25NO6 (C, H, N). With triethylamine in ethanol, Time= 48h, T= 20 °C Calugi, Chiara; Trabocchi, Andrea; Lalli, Claudia; Guarna, Antonio; European Journal of Medicinal Chemistry; vol. 56; (2012); p. 96 - 107 View in Reaxys 17.8 g

Stage 1: With sodium hydroxide in water, Time= 0.166667h, T= 0 °C , Inert atmosphere Stage 2: in water, T= 0 - 20 °C , Inert atmosphere Allmendinger, Thomas; Bixel, Dominique; Clarke, Adrian; Di Geronimo, Laura; Fredy, Jean-Wilfried; Manz, Marco; Gavioli, Elena; Wicky, Regine; Schneider, Martin; Stauffert, Fabien J.; Tibi, Markus; Valentekovic, Darko; Organic Process Research and Development; vol. 16; nb. 11; (2012); p. 1754 - 1769 View in Reaxys

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5 :Compound 14A (100 g, 0.716 mol) and ethanol (1.0 L) were loaded into a 3 L flask equipped with a mechanical stirrer and a calcium chloride tube. The mixture was stirred for 20 min, and then triethylamine (TEA, 72.5 g, 0.716 mol) was dropped. The resulted mixture was stirred for 10 min, and then ethyl acrylate (61.6 g, 0.716 mol) was added to the above mixture. The reaction mixture was stirred at room temperature for 17 hours. (Boc) 2O (234.5 g, 1.08 mol) was added dropwise at room temperature. Then the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated to remove most of ethanol. The residue was dissolved in water (3 L), and extracted with Et2O (1 L×3), then washed with water, ammonium chloride (500 mL×3) solution and brine (500 mL×3), dried with anhydrous Na2SO4 and concentrated, to obtain a crude compound 14C (300 g, 92percent) as a yellow oily substance, which was used directly in the next step without a further purification. Stage 1: With triethylamine in ethanol, Time= 0.166667h Stage 2: in ethanol, Time= 17h, T= 20 °C 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 :Compound 14A (100 g, 0.716 mol) and ethanol (1.0 L) were loaded into a 3 L flask equipped with a mechanical stirrer and a calcium chloride tube. The mixture was stirred for 20 min, and then triethylamine (TEA, 72.5 g, 0.716 mol) was dropped. The resulted mixture was stirred for 10 min, and then ethyl acrylate (61.6 g, 0.716 mol) was added to the above mixture. The reaction mixture was stirred at room temperature for 17 hours. (Boc) 2O (234.5 g, 1.08 mol) was added dropwise at room temperature. Then the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated to remove most of ethanol. The residue was dissolved in water (3 L), and extracted with Et2O (1 L×3), then washed with water, ammonium chloride (500 mL×3) solution and brine (500 mL×3), dried with anhydrous Na2SO4 and concentrated, to obtain a crude compound 14C (300 g, 92percent) as a yellow oily substance, which was used directly in the next step without a further purification. With triethylamine in ethanol, Time= 17.5h, T= 20 °C 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 513.1 g

1.1 : 1) Synthesis of compound (b) Under an ice bath, 300 g glycine ethyl ester hydrochloride dissolved in 450 ml water was added 4.7M NaOH (aq) 457 ml, 227 ml ethyl acrylate was added, and the mixture was stirred at room temperature overnight. After TLC detection reaction end, the reaction solution was extracted with DCM, the organic phase was separated, dried with anhydrous Na2SO4, filtered, and spin-dried to obtain crude yellow oily liquid compound (b) 513.1 g. With sodium hydroxide in water, T= 20 °C , Cooling with ice Patent; Allist Pharmaceuticals, Inc; Luo, HuiBing; Guo, JianHui; (20 pag.); CN102584828; (2016); (B) Chinese View in Reaxys

O O

N H

N O

Rx-ID: 4090880 View in Reaxys 11/78 Yield

Conditions & References Denmark, Scott E.; Forbes, David C.; Hays, David S.; DePue, Jeffrey S.; Wilde, Richard G.; Journal of Organic Chemistry; vol. 60; nb. 5; (1995); p. 1391 - 1407 View in Reaxys

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N H

O O

N O

Rx-ID: 4813044 View in Reaxys 12/78 Yield

Conditions & References

91.1 %

With N-ethyl-N,N-diisopropylamine in N,N-dimethyl-formamide, 1.) 0 deg C, 30 min, 2.) room temperature, 3 h Muller, Dan; Zeltser, Irena; Bitan, Gal; Gilon, Chaim; Journal of Organic Chemistry; vol. 62; nb. 2; (1997); p. 411 416 View in Reaxys O O

H 2N

N H

N O

O O

Rx-ID: 4949264 View in Reaxys 13/78 Yield

Conditions & References With indium(III) chloride in water, 1.) r.t., 10 min, 2.) r.t., 18 h, Yield given. Yields of byproduct given. Title compound not separated from byproducts Loh, Teck-Peng; Wei, Lin-Li; Synlett; nb. 9; (1998); p. 975 - 976 View in Reaxys

O O

N O

N H

Rx-ID: 8748814 View in Reaxys 14/78 Yield

Conditions & References

83 %

With sodium carbonate in tetrahydrofuran, Time= 14h, Heating 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

N H

N O

Rx-ID: 8764476 View in Reaxys 15/78 Yield 86 %

Conditions & References With sodium carbonate in tetrahydrofuran, Time= 14h, Heating Pinto, Americo C.; Abdala, Rodrigo V.; Costa, Paulo R.R.; Tetrahedron Asymmetry; vol. 11; nb. 21; (2000); p. 4239 - 4243 View in Reaxys

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O O

Rx-ID: 11460885 View in Reaxys 16/78 Yield

Conditions & References Reaction Steps: 2 1: DIPEA 2: DIPEA / toluene / 96 h / 75 °C With N-ethyl-N,N-diisopropylamine in toluene Busnel, Olivier; Baudy-Floc'h, Michele; Tetrahedron Letters; vol. 48; nb. 33; (2007); p. 5767 - 5770 View in Reaxys

H 2N

Rx-ID: 11460886 View in Reaxys 17/78 Yield

Conditions & References Reaction Steps: 3 1: DIPEA 2: DIPEA / toluene / 96 h / 75 °C 3: H2 / Pd/C / methanol / 12 h With hydrogen, N-ethyl-N,N-diisopropylamine, palladium on activated charcoal in methanol, toluene Busnel, Olivier; Baudy-Floc'h, Michele; Tetrahedron Letters; vol. 48; nb. 33; (2007); p. 5767 - 5770 View in Reaxys

O O

N O

O O

Rx-ID: 13042985 View in Reaxys 18/78 Yield

Conditions & References Reaction Steps: 2 1: 26 percent / NaOH / H2O / 0.42 h / Heating 2: 80 percent / K2CO3 / dimethylformamide / 20 °C With sodium hydroxide, potassium carbonate in water, N,N-dimethyl-formamide Jaszberenyi, Zoltan; Sour, Angelique; Toth, Eva; Benmelouka, Meriem; Merbach, Andre E.; Dalton Transactions; nb. 16; (2005); p. 2713 - 2719 View in Reaxys O

Cl O

H N

O Cl

O O

Rx-ID: 13995169 View in Reaxys 19/78

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Yield

Conditions & References Reaction Steps: 2 1: 90 percent / DEAD; PPh3 / CH2Cl2 2: 81 percent / PhSH; K2CO3 / dimethylformamide / 25 °C With potassium carbonate, thiophenol, triphenylphosphine, diethylazodicarboxylate in dichloromethane, N,N-dimethyl-formamide, 1: Mitsunobu reaction Sato, Koji; Hada, Noriyasu; Takeda, Tadahiro; Tetrahedron Letters; vol. 44; nb. 52; (2003); p. 9331 - 9335 View in Reaxys Cl Cl Cl

O O

Rx-ID: 13995170 View in Reaxys 20/78 Yield

Conditions & References Reaction Steps: 3 1: 90 percent / DEAD; PPh3 / CH2Cl2 2: 81 percent / PhSH; K2CO3 / dimethylformamide / 25 °C 3: 94 percent / Et3N / CH2Cl2 With potassium carbonate, thiophenol, triethylamine, triphenylphosphine, diethylazodicarboxylate in dichloromethane, N,N-dimethyl-formamide, 1: Mitsunobu reaction Sato, Koji; Hada, Noriyasu; Takeda, Tadahiro; Tetrahedron Letters; vol. 44; nb. 52; (2003); p. 9331 - 9335 View in Reaxys

O O

(CO)5W=C(OMe)Ph

O O

Rx-ID: 15354826 View in Reaxys 21/78 Yield

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

O Br

O O

Rx-ID: 17194916 View in Reaxys 22/78 Yield

Conditions & References Reaction Steps: 2 1: 79 percent / DIPEA / acetonitrile / 0.25 h / 0 °C 2: 98 percent / DCC / CH2Cl2 / 5 h / Ambient temperature

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With N-ethyl-N,N-diisopropylamine, dicyclohexyl-carbodiimide in dichloromethane, acetonitrile Kim, Jin Mi; Roy, Rene; Carbohydrate Research; vol. 298; nb. 3; (1997); p. 173 - 179 View in Reaxys

silver-salt of phosphoric acid-<2-benzyloxycarbonylamino-ethyl ester>-phenyl ester

Rx-ID: 18052193 View in Reaxys 23/78 Yield

Conditions & References Reaction Steps: 2 Denmark, Scott E.; Forbes, David C.; Hays, David S.; DePue, Jeffrey S.; Wilde, Richard G.; Journal of Organic Chemistry; vol. 60; nb. 5; (1995); p. 1391 - 1407 View in Reaxys

(+-)-<5,6,7,8-tetrahydro-<1,3>dioxolo<4,5-g>isoquinolin-5yl>-acetic acid ethyl ester

O O

O NH 2 N

N H 2N

N O

Rx-ID: 19102190 View in Reaxys 24/78 Yield

Conditions & References Reaction Steps: 2 1: 65 percent / Et3N / ethanol / 144 h 2: 53 percent / Et3N, diethyl phosphorocyanidate / dimethylformamide / 96 h / Ambient temperature With diethyl cyanophosphonate, triethylamine in ethanol, N,N-dimethyl-formamide Rosowsky, Andre; Bader, Henry; Forsch, Ronald A.; Moran, Richard G.; Freisheim, James H.; Journal of Medicinal Chemistry; vol. 31; nb. 4; (1988); p. 763 - 768 View in Reaxys O O

O O

Rx-ID: 21273115 View in Reaxys 25/78 Yield

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

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O O

Rx-ID: 22034086 View in Reaxys 26/78 Yield

Conditions & References Reaction Steps: 3 1: 80 °C 3: concentrated sulfuric acid With sulfuric acid de Mouilpied; Journal of the Chemical Society; vol. 87; (1905); p. 438 View in Reaxys

O O

N O

Rx-ID: 22205568 View in Reaxys 27/78 Yield

Conditions & References Reaction Steps: 2 2: K2CO3 With potassium carbonate Patent; Robins Co.; US2878264; (1957) View in Reaxys O O

N O

Rx-ID: 22205569 View in Reaxys 28/78 Yield

Conditions & References Reaction Steps: 2 1: ethanol 2: K2CO3 With ethanol, potassium carbonate Leonard et al.; Journal of the American Chemical Society; vol. 73; (1951); p. 2371 View in Reaxys

O O O

Rx-ID: 22216932 View in Reaxys 29/78 Yield

Conditions & References Reaction Steps: 2 1: alcohol 2: benzene With ethanol, benzene Ruzicka; Seidel; Helvetica Chimica Acta; vol. 5; (1922); p. 717

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View in Reaxys

O O O

N O

N H

Rx-ID: 23916220 View in Reaxys 30/78 Yield

Conditions & References

29 g (76%) 4 : Preparation of 3-(Benzyl-ethoxycarbonylmethylamino) Propionic Acid Ethyl Ester (I-4a): Example 4 Preparation of 3-(Benzyl-ethoxycarbonylmethylamino) Propionic Acid Ethyl Ester (I-4a): Ethyl N-benzylglycinate (0.1295 mol, 1 eq), ethyl acrylate (0.142 mol, 1.1 eq) and 155 μL of Triton.(TM). B (available from Sigma-Aldrich, St. Louis, Mo.) were combined at room temperature under N2. The mixture was then heated to reflux overnight. An aliquot was removed and NMR spectrum was taken of the crude material. The product was present plus both starting materials. The excess of the ethyl acrylate was removed under vacuum at 10 mmHg (60° C. water bath). The crude amber oil that resulted was dissolved in 50 mL of CH2Cl2 and was charge onto a Biotage.(TM). 75L cartridge and eluted with the following gradient 0.5percent by volume acetone in hexanes, 1percent (1200 mL), 1.5percent (1200 mL) and 2.5percent (3600 mL). The fractions containing the desired product were combined and concentrated to a colorless oil which was dried under high vacuum for 2 hours to afford 29 g (76percent) of product (I-4a). 1H NMR spectrum (CDCl ) and LC/MS (294) were consistent with the compound I-4a. 3 in dichloromethane, acetone Patent; Colon-Cruz, Roberto; Didiuk, Mary T.; Duffy, Erin M.; Garigipati, Ravi; Lau, Wan F.; McDonald, Wayne S.; US2003/8893; (2003); (A1) English View in Reaxys O

O Br

NH 2 Cl

H N

Rx-ID: 24129418 View in Reaxys 31/78 Yield 14%

Conditions & References 4.1 : Step 1: Step 1: 3-(tert-Butoxycarbonylmethyl-amino)-propionic acid methyl ester Triethylamine (7 mL, 50 mmol) was added to a solution of β-alanine methyl ester hydrochloride (5.25 g, 37.5 mmol) in methylene chloride (100 mL). The solution was cooled to 0° C. and t-butyl bromoacetate (4.88 g, 25 mmol) in methylene chloride (100 mL) was then added. The reaction mixture was warmed to room temperature and stirred overnight. The solvent was removed in vacuo and the residue was taken up in ethyl acetate. The ethyl acetate was washed with saturated NaHCO3, brine, dried over MgSO4, filtered and concentrated in vacuo; 0.80 g (14percent yield). With triethylamine in dichloromethane, ethyl acetate Patent; Warner-Lambert Company; US6369034; (2002); (B1) English View in Reaxys 1.a : (a) (a) N-(2-(1,1-Dimethylethoxy)-2-oxoethyl)-β-alanine methyl ester 1,1-Dimethylethyl bromoacetate (7.0g, 36mmoles) was added dropwise to a stirred suspension at 0° of β-alanine methyl ester hydrochloride (5.0g, 36mmoles) and triethylamine (7.5g, 74mmoles) in acetonitrile (50ml).

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After 24 hours, the solvent was evaporated and the residue dissolved in dichloromethane and saturated sodium bicarbonate. The organic layer was separated, dried (Na2SO4) and the solvent was evaporated. Chromatography on silica eluding with ethylacetate/petroleum ether (60-80°) mixtures gave the title compound (5.0g). nmr δ(CDCl3) 1.47 (9H,s), 3.31 (2H,s) 3.69 (3H,s). With triethylamine in dichloromethane, acetonitrile Patent; FISONS plc; EP384636; (1990); (A1) English View in Reaxys O

H 2N

N H

Rx-ID: 27891366 View in Reaxys 32/78 Yield

Conditions & References 1 :Step 1. ethyl /V-(ethoxycarbonyl)-/?-alaninate (c)Ethyl acrylate (a) (50 mL, 460 mmol, 1.1eq), glycine ethyl ester hydrochloride (b) (58.4 g, 418 mmol, 1eq), and triethylamine (58.3 mL, 418 mmol, 1eq) in absolute EtOH (960 mL) was stirred at ambient temperature for approximately 72h. After reaction was complete, volatile components were removed under vacuum and the crude intermediate (c) was carried on directly. With triethylamine in ethanol, Time= 72h, T= 20 °C Patent; PFIZER INC.; WO2008/96218; (2008); (A1) English View in Reaxys With triethylamine in ethanol 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

O O

N H

N O

O O

Rx-ID: 27920635 View in Reaxys 33/78 Yield

Conditions & References

99 %

2 :Commercially available ethyl 3-benzylaminopropionate(10.0 g, 0.0482 mol) was dissolved in 2-butanone (100 mL), and the solution was mixed with potassium carbonate (10.0 g, 0.0724 mol) and sodium iodide (10.9 g, 0.0724 mol). Ethyl bromoacetate (8.47 g, 0.0507 mol) was added dropwise to the resulting suspension, and the suspension was stirred under reflux over night. After filtrating the reaction mixture, the filtrate was mixed with water (200 mL) and chloroform (100 mL), followed by shaking and separation. After drying the organic layer over magnesium sulfate, the solvent was distilled off under reduced pressure, to thereby yield ethyl 3-[N-benzyl-N-(ethoxycarbonylmethyl)amino]propionate (14.0 g, in a yield of 99percent). With potassium carbonate, sodium iodide in butanone, Heating / reflux Patent; KYOWA HAKKO KOGYO CO., LTD.; EP1552842; (2005); (A1) English View in Reaxys O

H 2N

O Cl

H N

O O

Rx-ID: 28089113 View in Reaxys 34/78

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Yield

Conditions & References 94.1 :To an acetonitrile solution (650 mL) of bromoacetic acid benzyl ester (10.7 mL), β-alanine ethyl ester hydrochloride (25.0 g) and DIEA (55.3 mL) were added, and the mixture was stirred overnight at 80°C. The reaction mixture was left to stand to cool to room temperature and concentrated under reduced pressure. Saturated aqueous sodium bicarbonate solution was added to the residue, followed by extraction thrice, each with ethyl acetate. The extracts were combined and washed with saturated brine, followed by drying over sodium sulfate anhydrate. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (Yamazen Hi-Flash column 4L), whereby the title compound (16.9 g) was yielded. 1H-NMR (CDCl3) δ: 1.26(3H,t,J=7.2Hz),2.50(2H,t,J=6.6Hz),2.91(2H,t,J=6.6Hz),3.47 (2H,s),4.15(2H,q,J=7.2Hz), 5.17(2H,s),7.32-7.37(5H,m). MS (ESI) m/z:266 (M+H)+. With N-ethyl-N,N-diisopropylamine in acetonitrile, T= 80 °C Patent; Daiichi Sankyo Company, Limited; EP2017263; (2009); (A1) English View in Reaxys Cl F

N O

Rx-ID: 30716147 View in Reaxys 35/78 Yield

Conditions & References Reaction Steps: 2 1: 2,6-dimethylpyridine / toluene / 48 h / Reflux 2: 2,6-dimethylpyridine / 14 h / 60 °C With 2,6-dimethylpyridine in toluene Patent; F. HOFFMANN-LA ROCHE AG; AEBI, Johannes; BINGGELI, Alfred; GREEN, Luke; HARTMANN, Guido; MAERKI, Hans P.; MATTEI, Patrizio; WO2011/48032; (2011); (A1) English View in Reaxys Reaction Steps: 2 1: 2,6-dimethylpyridine / toluene / 48 h / Reflux 2: 2,6-dimethylpyridine / 14 h / 60 °C / Neat (no solvent) With 2,6-dimethylpyridine in toluene Patent; Aebi, Johannes; Binggeli, Alfred; Green, Luke; Hartmann, Guido; Maerki, Hans P.; Mattei, Patrizio; US2011/92698; (2011); (A1) English View in Reaxys

O 2

H N

O 2H

Rx-ID: 32840875 View in Reaxys 36/78 Yield

Conditions & References Reaction Steps: 5 1.1: triethylamine / ethanol / 3.5 h / 35 - 40 °C 2.1: triethylamine / dichloromethane / 4.08 h / 0 - 20 °C 3.1: EtOD; 1,8-diazabicyclo[5.4.0]undec-7-ene / 94 h / 20 °C / Reflux 4.1: trifluoroacetic acid / dichloromethane / 3.5 h / 0 - 35 °C 4.2: pH 8 5.1: potassium carbonate / acetonitrile / 18.5 h / 5 - 40 °C With EtOD, potassium carbonate, 1,8-diazabicyclo[5.4.0]undec-7-ene, triethylamine, trifluoroacetic acid in ethanol, dichloromethane, acetonitrile

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Patent; MITHRIDION, INC.; ABRAHAM, Brent, D.; COPP, Richard, R.; FARNHAM, James, G.; HANSON, Seth, A.; HENDRICKSON, Michael, L.; OCKULY, Jeffrey, C.; TWOSE, Trevor, M.; VERDONE, Melinda, L.; WO2012/33956; (2012); (A1) English View in Reaxys

O O O

N H

N 2H

O 2H

Rx-ID: 32840900 View in Reaxys 37/78 Yield

Conditions & References Reaction Steps: 4 1.1: triethylamine / dichloromethane / 4.08 h / 0 - 20 °C 2.1: EtOD; 1,8-diazabicyclo[5.4.0]undec-7-ene / 94 h / 20 °C / Reflux 3.1: trifluoroacetic acid / dichloromethane / 3.5 h / 0 - 35 °C 3.2: pH 8 4.1: potassium carbonate / acetonitrile / 18.5 h / 5 - 40 °C With EtOD, potassium carbonate, 1,8-diazabicyclo[5.4.0]undec-7-ene, triethylamine, trifluoroacetic acid in dichloromethane, acetonitrile Patent; MITHRIDION, INC.; ABRAHAM, Brent, D.; COPP, Richard, R.; FARNHAM, James, G.; HANSON, Seth, A.; HENDRICKSON, Michael, L.; OCKULY, Jeffrey, C.; TWOSE, Trevor, M.; VERDONE, Melinda, L.; WO2012/33956; (2012); (A1) English View in Reaxys

O O

O Br

O E

N S

Rx-ID: 34076257 View in Reaxys 38/78 Yield

Conditions & References Reaction Steps: 2 1.1: triethylamine / dichloromethane / 2 h 2.1: N,N-dimethyl-formamide; oxalyl dichloride / dichloromethane / 0.17 h 2.2: 2 h With oxalyl dichloride, triethylamine, N,N-dimethyl-formamide in dichloromethane Patent; AJINOMOTO CO., INC.; EP2511271; (2012); (A1) English View in Reaxys O O O

O Br

O E N

O O

Rx-ID: 34328628 View in Reaxys 39/78 Yield

Conditions & References Reaction Steps: 2 1: triethylamine / dichloromethane / 2 h 2: triethylamine / dichloromethane / 0.5 h With triethylamine in dichloromethane

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Patent; AJINOMOTO CO., INC.; EP2511271; (2012); (A1) English View in Reaxys O O

N O

O O

Rx-ID: 34328630 View in Reaxys 40/78 Yield

Conditions & References Reaction Steps: 3 1.1: triethylamine / dichloromethane / 2 h 2.1: N,N-dimethyl-formamide; oxalyl dichloride / dichloromethane / 0.17 h 2.2: 2 h 3.1: hydrogen / palladium(II) oxide hydrate / chloroform; methanol / 20 °C With oxalyl dichloride, hydrogen, triethylamine, N,N-dimethyl-formamide, palladium(II) oxide hydrate in methanol, dichloromethane, chloroform Patent; AJINOMOTO CO., INC.; EP2511271; (2012); (A1) English View in Reaxys O

O O

O Br

O O

O O NH

H 2N

Rx-ID: 34328635 View in Reaxys 41/78 Yield

Conditions & References Reaction Steps: 4 1: triethylamine / dichloromethane / 2 h 2: triethylamine / dichloromethane / 0.5 h 3: hydrogen / palladium 10 on activated carbon / ethanol / 1 h / 20 °C 4: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / pyridine / 20 °C With hydrogen, 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride, triethylamine, palladium 10 on activated carbon in pyridine, ethanol, dichloromethane Patent; AJINOMOTO CO., INC.; EP2511271; (2012); (A1) English View in Reaxys

O Br

H 2N

HCl

Rx-ID: 34328637 View in Reaxys 42/78 Yield

Conditions & References 42.1 :β-Alanine tert-butyl ester hydrochloride (1.0 g, 5.5 mmol) was dissolved in dichloromethane (10 mL), triethylamine (1.52 mL, 11.1 mmol) and bromoacetic acid tert-butyl ester (0.57 g, 2.9 mmol) were added, and the mixture was stirred for 2 hr. The solvent was evaporated and the residue was purified by high performance liquid chromatography. To the fraction containing the object product was added 0.1N hydrochloric acid (30 mL), and the mixture was freezedried to give the title compound (0.52 g). 1H-NMR(400MHz, CDCl ) δ 3.75(2H, s), 3.29(2H, t, J=6.4Hz), 2.94(2H, d, J=6.4Hz), 1.51(9H, s), 1.47(9H, s). 3 MS(ESI) m/z 246(M+H)+ Stage 1: With triethylamine in dichloromethane, Time= 2h

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Stage 2: With hydrogenchloride in water Patent; AJINOMOTO CO., INC.; EP2511271; (2012); (A1) English View in Reaxys

N O

O O

Rx-ID: 34556317 View in Reaxys 43/78 Yield

Conditions & References Reaction Steps: 2 1.1: sodium hydroxide / water / 0.17 h / 0 °C / |Inert atmosphere 1.2: 0 - 20 °C / |Inert atmosphere 2.1: sodium hydrogencarbonate / acetonitrile / 18 h / 20 °C / |Inert atmosphere With sodium hydrogencarbonate, sodium hydroxide in water, acetonitrile Allmendinger, Thomas; Bixel, Dominique; Clarke, Adrian; Di Geronimo, Laura; Fredy, Jean-Wilfried; Manz, Marco; Gavioli, Elena; Wicky, Regine; Schneider, Martin; Stauffert, Fabien J.; Tibi, Markus; Valentekovic, Darko; Organic Process Research and Development; vol. 16; nb. 11; (2012); p. 1754 - 1769 View in Reaxys Reaction Steps: 2 1: sodium hydroxide / water / 20 °C / |Cooling with ice 2: potassium carbonate; sodium iodide / ethanol / |Inert atmosphere; |Reflux; |Large scale With potassium carbonate, sodium iodide, sodium hydroxide in ethanol, water Patent; Allist Pharmaceuticals, Inc; Luo, HuiBing; Guo, JianHui; (20 pag.); CN102584828; (2016); (B) Chinese View in Reaxys

O O O

N H

N O

Rx-ID: 34556319 View in Reaxys 44/78 Yield

Conditions & References

3.1 g

With sodium hydrogencarbonate in acetonitrile, Time= 18h, T= 20 °C , Inert atmosphere Allmendinger, Thomas; Bixel, Dominique; Clarke, Adrian; Di Geronimo, Laura; Fredy, Jean-Wilfried; Manz, Marco; Gavioli, Elena; Wicky, Regine; Schneider, Martin; Stauffert, Fabien J.; Tibi, Markus; Valentekovic, Darko; Organic Process Research and Development; vol. 16; nb. 11; (2012); p. 1754 - 1769 View in Reaxys

O O O

H 2N

O O

Rx-ID: 36026186 View in Reaxys 45/78 Yield

Conditions & References 1 : Reference Example 1 tert-Butyl 3-{N-benzyloxycarbonyl-N-(ethoxycarbonylmethyl)amino}propionate Reference Example 1 tert-Butyl 3-{N-benzyloxycarbonyl-N-(ethoxycarbonylmethyl)amino}propionate [0165] To glycine ethyl ester hydrochloride (163 g, 1.17 mol) were put a 3:1 mixed solvent of 2-propanol and water (600 mL), followed by warming the mixture and triethylamine (174 mL, 1.25 mol) was added thereto at an internal temperature of 59° C. To the mixed liquid was added dropwise tert-butyl acrylate (50.0 g, 0.390 mol) at an internal temperature of from 60° C. to 62° C., followed by stirring at an internal temperature of from 60° C. to 62° C. for 2 hours. Further-

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more, to the mixed liquid was added dropwise tert-butyl acrylate (50.0 g, 0.390 mol) at an internal temperature of from 62° C. to 63° C., followed by stirring at an internal temperature of from 60° C. to 62° C. for 5 hours. [0166] The reaction mixture was cooled to room temperature and was allowed to stand overnight. The reaction mixture was diluted by the addition of ethyl acetate (1 L), and extracted by the addition of 3percent sodium hydrogen carbonate (1 L). The organic layer was collected by separation to obtain a solution of tert-butyl 3-(ethoxycarbonylmethylamino)propionate in ethyl acetate. The product was partially concentrated and 1H NMR was measured. [0167] 1H NMR (400 MHz, CDCl3) δ: 1.28 (3H, t, J=7.2 Hz), 1.45 (9H, s), 2.44 (2H, t, J=6.6 Hz), 2.87 (2H, t, J=6.6 Hz), 3.41 (2H, s), 4.20 (2H, q, J=7.1 Hz). [0168] To the total amount of the solution of tert-butyl 3-(ethoxycarbonylmethylamino)propionate in ethyl acetate was added a sodium hydrogen carbonate solution (72.1 g (0.860 mol) of sodium hydrogen carbonate was dissolved in 1.3 L of water) at approximately room temperature, and benzyl chloroformate (133 g, 0.780 mol) was added dropwise at an internal temperature of from 26° C. to 33° C., followed by stirring at an internal temperature of from 28° C. to 33° C. for 2 hours. [0169] The reaction mixture was cooled to room temperature and allowed to stand overnight and then extracted. The organic layer was collected by separation, and the organic layer was sequentially washed with 0.5 mol/L hydrochloric acid (0.5 L) and 5percent brine (0.5 L), and dried over anhydrous sodium sulfate. The insoluble materials were separated by filtration and the filtrate was concentrated under reduced pressure to obtain 265 g of a title compound as yellow oil. [0170] 1H NMR (400 MHz, CDCl3) δ: 1.23 (3H, dt, J=29.3, 7.3 Hz), 1.43 (9H, s), 2.56 (2H, dt, J=22.5, 6.4 Hz), 3.56-3.64 (2H, m), 4.05-4.21 (4H, m), 5.11-5.17 (2H, m), 7.29-7.38 (5H, m). With triethylamine in water, isopropyl alcohol, Time= 7h, T= 59 - 63 °C Patent; KYORIN PHARMACEUTICAL CO., LTD.; Araya, Ichiro; Kiyota, Koichi; Nagao, Muneki; US2013/217893; (2013); (A1) English View in Reaxys

N O

O O

Rx-ID: 36026187 View in Reaxys 46/78 Yield

Conditions & References Reaction Steps: 2 1: triethylamine / water; isopropyl alcohol / 7 h / 59 - 63 °C 2: sodium hydrogencarbonate / water; ethyl acetate / 2 h / 20 - 33 °C With sodium hydrogencarbonate, triethylamine in water, ethyl acetate, isopropyl alcohol Patent; KYORIN PHARMACEUTICAL CO., LTD.; Araya, Ichiro; Kiyota, Koichi; Nagao, Muneki; US2013/217893; (2013); (A1) English View in Reaxys

Br O

H 2N

O O

Rx-ID: 37217759 View in Reaxys 47/78 Yield

Conditions & References With N-ethyl-N,N-diisopropylamine in N,N-dimethyl-formamide, Time= 18h, T= 20 °C De Cola, Chiara; Fiorillo, Gaetano; Meli, Alessandra; Aime, Silvio; Gianolio, Eliana; Izzo, Irene; De Riccardis, Francesco; Organic and Biomolecular Chemistry; vol. 12; nb. 3; (2014); p. 424 - 431 View in Reaxys

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O O O

N H

N O

O O

Rx-ID: 37909726 View in Reaxys 48/78 Yield

Conditions & References

53 %

3 With triethylamine in dichloromethane Patent; THE SCRIPPS RESEARCH INSTITUTE; CARROLL, Kate, S.; WO2014/89546; (2014); (A1) English View in Reaxys

O O

H 2N

O O

Rx-ID: 38431595 View in Reaxys 49/78 Yield

Conditions & References

2.88 g

Synthesis of 8 A solution of H-β-Ala-O-Bzl*TosOH (2.5 g, 7.1 mmol), tert-butyl bromoacetate (3.86 mL, 28.4 mmol), and DIEA (6 mL, 35.5 mmol) in dry DMF (8 mL) was stirred overnight at 60 °C. After dilution with water, the reaction mixture was extracted with AcOEt (x2). The extracts were washed with sat. NaHCO3 aq. and brine followed by drying over Na2SO4. After removal of the solvent in vacuo, the residue was purified by column chromatography on SiO2 (hexane : AcOEt= 3:1) to give 8 (2.88 g, 99percent) as a pale brown oil. With N-ethyl-N,N-diisopropylamine in N,N-dimethyl-formamide, T= 60 °C Takahira, Ikuko; Fuchida, Hirokazu; Tabata, Shigekazu; Shindo, Naoya; Uchinomiya, Shohei; Hamachi, Itaru; Ojida, Akio; Bioorganic and Medicinal Chemistry Letters; vol. 24; nb. 13; (2014); p. 2855 - 2858 View in Reaxys

O Br

N H

O O N O

Rx-ID: 39481733 View in Reaxys 50/78 Yield

Conditions & References To a stirred solution of benzylamino-acetic acid methyl ester (222 mg, 1.03 mmol) in acetone (10 mL) were added tert-butyl 3-bromopropionate (3*834 μL, 3*5 mmol), K2CO3 (3*290 mg, 3*2.09 mmol) and KI (174 mg, 1.04 mmol) and the mixture was refluxed overnight. The solvent was evaporated and the residue was solubilized in ethyle acetate. The organic layer was washed with water and brine then dried over MgSO4 and concentrated under reduced pressure to give a white powder, directly used in the next step. tR ,LCMS = 4.76 min; Purity 99percent; MS (ESI+): m/z = 308 (M + H)+. With potassium carbonate, potassium iodide in acetone, Reflux Charton, Julie; Gauriot, Marion; Totobenazara, Jane; Hennuyer, Nathalie; Dumont, Julie; Bosc, Damien; Marechal, Xavier; Elbakali, Jamal; Herledan, Adrien; Wen, Xiaoan; Ronco, Cyril; Gras-Masse, Helene; Heninot, Antoine; Pottiez, Virginie; Landry, Valerie; Staels, Bart; Liang, Wenguang G.; Leroux, Florence; Tang, Wei-Jen; Deprez, Benoit; Deprez-Poulain, Rebecca; European Journal of Medicinal Chemistry; vol. 90; (2015); p. 547 - 567 View in Reaxys

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H N

Rx-ID: 39694105 View in Reaxys 51/78 Yield

Conditions & References

70 %

in benzyl alcohol, Time= 16h, T= 23 °C Noda, Hidetoshi; Bode, Jeffrey W.; Journal of the American Chemical Society; vol. 137; nb. 11; (2015); p. 3958 3966 View in Reaxys

H 2N

H N

O O

Rx-ID: 40239832 View in Reaxys 52/78 Yield

Conditions & References

10 %

22.1 : Synthesis of ethyl 3-((2-methoxy-2-oxoethyl)amino)propanoate (2) To a stirred solution of methyl glycinate.HCl (5.0 g, 39.8 mmol) in 2-propanol:H2O (3: 1, 40 mL) was added Et3N (5.69 mL, 42.2 mmol) at 60 °C under inert atmosphere. To this, ethyl acrylate (2.8 mL, 26.2 mmol) was added in two portions with an interval of 2 h and stirred for 5 h; then stirred at RT for 16 h. The reaction mixture was diluted with 3percent aq. NaHCO3 (30 mL) and extracted with EtOAc (2 x 30 mL). The combined organic extracts were washed with brine (20 mL), dried over Na2S04, filtered and dried in vacuo to obtain the crude. The crude was purified (silica gel chromatography; 30-50percent EtOAc/hexanes) to afford compound 2 (720 mg, 10percent) as a colorless liquid. 1H NMR (500 MHz, DMSO-d6): δ 4.05 (q, J= 7.0 Hz, 2H), 3.62 (s, 3H), 3.33-3.32 (m, 2H), 2.74 (t, J= 6.5 Hz, 2H), 2.40 (t, J= 6.5 Hz, 2H), 2.09 (br s, 1H), 1.18 (t, J= 7.0 Hz, 3H). With triethylamine in water, isopropyl alcohol, Time= 21h, T= 20 - 60 °C , Inert atmosphere Patent; PHARMAKEA, INC.; HUTCHINSON, John, Howard; LONERGAN, David; ROWBOTTOM, Martin; LAI, Andiliy, Gokching; WO2015/77502; (2015); (A1) English View in Reaxys

O N O

O N

O O

Rx-ID: 40239834 View in Reaxys 53/78 Yield

Conditions & References Reaction Steps: 2 1.1: triethylamine / water; isopropyl alcohol / 21 h / 20 - 60 °C / |Inert atmosphere 2.1: N-ethyl-N,N-diisopropylamine; benzotriazol-1-ol; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 0.25 h / |Inert atmosphere 2.2: 16 h / |Inert atmosphere With benzotriazol-1-ol, triethylamine, N-ethyl-N,N-diisopropylamine, N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate in water, N,N-dimethyl-formamide, isopropyl alcohol Patent; PHARMAKEA, INC.; HUTCHINSON, John, Howard; LONERGAN, David; ROWBOTTOM, Martin; LAI, Andiliy, Gokching; WO2015/77502; (2015); (A1) English View in Reaxys

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O N O

O NH

O N

Rx-ID: 40239835 View in Reaxys 54/78 Yield

Conditions & References Reaction Steps: 3 1.1: triethylamine / water; isopropyl alcohol / 21 h / 20 - 60 °C / |Inert atmosphere 2.1: N-ethyl-N,N-diisopropylamine; benzotriazol-1-ol; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 0.25 h / |Inert atmosphere 2.2: 16 h / |Inert atmosphere 3.1: trifluoroacetic acid / dichloromethane / 4 h / |Inert atmosphere With benzotriazol-1-ol, triethylamine, N-ethyl-N,N-diisopropylamine, trifluoroacetic acid, N-[(dimethylamino)-3oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate in dichloromethane, water, N,N-dimethyl-formamide, isopropyl alcohol Patent; PHARMAKEA, INC.; HUTCHINSON, John, Howard; LONERGAN, David; ROWBOTTOM, Martin; LAI, Andiliy, Gokching; WO2015/77502; (2015); (A1) English View in Reaxys O

O O

O H 2N

N O

Rx-ID: 41391883 View in Reaxys 55/78 Yield

Conditions & References Reaction Steps: 3 1: sodium hydroxide / water / 19 h / 20 °C / |Cooling with ice 2: diisopropyl-carbodiimide; 2-(Dimethylamino)pyridine / dichloromethane / 6 h / 0 - 20 °C / |Cooling with ice 3: piperidine / N,N-dimethyl-formamide / 1 h / 0 °C With piperidine, 2-(Dimethylamino)pyridine, sodium hydroxide, diisopropyl-carbodiimide in dichloromethane, water, N,N-dimethyl-formamide 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: 3 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 With piperidine, dmap, sodium hydroxide, diisopropyl-carbodiimide in dichloromethane, water, N,N-dimethyl-formamide 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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H N

N O

Rx-ID: 41391884 View in Reaxys 56/78 Yield

Conditions & References Reaction Steps: 2 1: sodium hydroxide / water / 19 h / 20 °C / |Cooling with ice 2: diisopropyl-carbodiimide; 2-(Dimethylamino)pyridine / dichloromethane / 6 h / 0 - 20 °C / |Cooling with ice With 2-(Dimethylamino)pyridine, sodium hydroxide, diisopropyl-carbodiimide in dichloromethane, water 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: sodium hydroxide / water / 19 h / 20 °C / |Cooling with ice 2: dmap; diisopropyl-carbodiimide / dichloromethane / 6 h / 0 - 20 °C With dmap, sodium hydroxide, diisopropyl-carbodiimide in dichloromethane, water Patent; Alnylam Pharmaceuticals, Inc.; de Fougerolles, Antonin; Novobrantseva, Tatiana; Akinc, Akin; (87 pag.); US2016/17336; (2016); (A1) English View in Reaxys

H -1Cl

N O

NH 2 O

Rx-ID: 42104912 View in Reaxys 57/78 Yield

Conditions & References Reaction Steps: 3 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 With piperidine, dmap, sodium hydroxide, diisopropyl-carbodiimide in dichloromethane, water, N,N-dimethyl-formamide Patent; Alnylam Pharmaceuticals, Inc.; Sah, Dinah Wen-Yee; Chen, Qingmin; US9200282; (2015); (B2) English View in Reaxys Reaction Steps: 3 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 With piperidine, dmap, sodium hydroxide, diisopropyl-carbodiimide in dichloromethane, water, ethyl acetate, N,N-dimethyl-formamide Patent; Ando, Yukio; Jono, Hirofumi; Alvarez, Rene; Sah, Dinah Wen-Yee; (417 pag.); US2016/76029; (2016); (A1) English View in Reaxys

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H N

O H

N O

Rx-ID: 42104913 View in Reaxys 58/78 Yield

Conditions & References Reaction Steps: 4 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 With piperidine, dmap, N-ethyl-N,N-diisopropylamine, sodium hydroxide, diisopropyl-carbodiimide in dichloromethane, water, N,N-dimethyl-formamide Patent; Alnylam Pharmaceuticals, Inc.; Sah, Dinah Wen-Yee; Chen, Qingmin; US9200282; (2015); (B2) English View in Reaxys Reaction Steps: 4 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 With piperidine, dmap, N-ethyl-N,N-diisopropylamine, sodium hydroxide, diisopropyl-carbodiimide in dichloromethane, water, ethyl acetate, N,N-dimethyl-formamide Patent; Ando, Yukio; Jono, Hirofumi; Alvarez, Rene; Sah, Dinah Wen-Yee; (417 pag.); US2016/76029; (2016); (A1) English View in Reaxys Reaction Steps: 4 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 With piperidine, dmap, N-ethyl-N,N-diisopropylamine, sodium hydroxide, diisopropyl-carbodiimide in dichloromethane, water, N,N-dimethyl-formamide Patent; Alnylam Pharmaceuticals, Inc.; Gollob, Jared; Hinkle, Gregory; Toudjarska, Ivanka; Bumcrot, David; (73 pag.); US9566295; (2017); (B2) English View in Reaxys O

O O

O H 2N

N O

HCl

Rx-ID: 42153518 View in Reaxys 59/78 Yield

Conditions & References Reaction Steps: 3 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 With piperidine, sodium hydroxide, diisopropyl-carbodiimide in dichloromethane, water, N,N-dimethyl-formamide Patent; Alnylam Pharmaceuticals, Inc.; de Fougerolles, Antonin; Borodovsky, Anna; Novobrantseva, Tatiana; US2015/353934; (2015); (A1) English

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View in Reaxys Reaction Steps: 3 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 With piperidine, dmap, sodium hydroxide, diisopropyl-carbodiimide in dichloromethane, water, N,N-dimethyl-formamide Patent; Alnylam Pharmaceuticals, Inc.; Gollob, Jared; Hinkle, Gregory; Toudjarska, Ivanka; Bumcrot, David; (73 pag.); US9566295; (2017); (B2) English View in Reaxys

O O

N O

O O

NH O

H H H

Rx-ID: 42153519 View in Reaxys 60/78 Yield

Conditions & References Reaction Steps: 4 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 With piperidine, N-ethyl-N,N-diisopropylamine, sodium hydroxide, diisopropyl-carbodiimide in dichloromethane, water, N,N-dimethyl-formamide Patent; Alnylam Pharmaceuticals, Inc.; de Fougerolles, Antonin; Borodovsky, Anna; Novobrantseva, Tatiana; US2015/353934; (2015); (A1) English View in Reaxys -1 NHHCl 2

O O

N H

Rx-ID: 42416097 View in Reaxys 61/78 Yield 61 %

Conditions & References 1 : Diethyl-2-azabutane-1,4-dicarboxylate AA Diethyl-2-azabutane-1,4-dicarboxylate AA A 4.7M aqueous solution of sodium hydroxide (50 mL) was added into a stirred, ice-cooled solution of ethyl glycinate hydrochloride (32.19 g, 0.23 mole) in water (50 mL). Then, ethyl acrylate (23.1 g, 0.23 mole) was added and the mixture was stirred at room temperature until completion of the reaction was ascertained by TLC. After 19 h the solution was partitioned with dichloromethane (3×100 mL). The organic layer was dried with anhydrous sodium sulfate, filtered and evaporated. The residue was distilled to afford AA (28.8 g, 61percent). With sodium hydroxide in water, Time= 19h, T= 20 °C , Cooling with ice Patent; Ando, Yukio; Jono, Hirofumi; Alvarez, Rene; Sah, Dinah Wen-Yee; (417 pag.); US2016/76029; (2016); (A1) English View in Reaxys

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O O O

N H

N O

Rx-ID: 43995051 View in Reaxys 62/78 Yield

Conditions & References

1127.324 g 1.2 : 2) Synthesis of compound (c) 513.1g compound (b), 392 g benzyl chloride, 432 g K2CO3, 3.78gNaI dissolved in 1L EtOH, were refluxed overnight under N2 protection. After completion of the reaction by TLC detection, the reaction mixture was cooled to room temperature, filtered, the filtrate was dried and dissolved in ethyl acetate, washed, organic phase was retained, washed with 2N HCl, washed with saturated sodium bicarbonate solution to adjust PH=8, extracted with ethyl acetate, dried using anhydrous NaSO4, filtered, and evaporated to obtain crude compound (c) 1127.324 g. With potassium carbonate, sodium iodide in ethanol, Inert atmosphere, Reflux, Large scale Patent; Allist Pharmaceuticals, Inc; Luo, HuiBing; Guo, JianHui; (20 pag.); CN102584828; (2016); (B) Chinese View in Reaxys

H N

O O

N O

O O

Rx-ID: 44544369 View in Reaxys 63/78 Yield

Conditions & References 11; 12 : Monomer A To the solution of amine 1 (10 mmol) in THF/MeOH (1:1, 200 mL) was added K2C03 (20 mmol) at room temp. Bromo compound (10 mmol) was then added to the suspension and the mixture was stirred for 2h. H20 was added and the mixture was extracted with EtOAc, washed with brine and dried with Na2SO4. Removingthe solvent under vacuum afforded crude secondary amine, which was used for next step without purification. To this solution of crude secondary amine (10 mmol) in THF was added tert-Butyl bromoacetate (11 mmol). The mixture was stirred for 4 h and the solvent was removed under vacuum. The residual was purified with flash column (MeOH: CH2C12 1: 10) to give monomer A (70percent for 2 steps).‘H NMR (400 IVIFlz, CDC13) 1.44 (s, 9H), 2.44 (t, J= 7.9 Hz, 4H), 2.96 ((t, J7.9 Hz, 4H), 3.28 (s, 2H), 3.65 (s, 6H). in tetrahydrofuran, Time= 4h Patent; UNIVERSITY OF WASHINGTON; JIANG, Shaoyi; BAI, Tao; ELLA-MENYE, Jean-Rene; HUNG, HsiangChieh; JAIN, Priyesh; SINCLAIR, Andrew; SUNDARAM, Harihara Subramanian; LI, Yang; ZHANG, Peng; (98 pag.); WO2017/3639; (2017); (A2) English View in Reaxys O

O O

NH S O O O

Br N

O O N

S O O

Rx-ID: 45086826 View in Reaxys 64/78 Yield 5g

Conditions & References 7.b :A suspension of 4-((3-methoxy-3-oxopropyl)amino)-3-nitrobenzenesulfonic acid (4.30 g) , tert-butyl 2-bromoacetate (2.10 mL) , and cesium carbonate (9.30 g) in acetonitrile (100 mL) was stirred at room temperature for 10 hours. The reaction solution was diluted with water, and then extracted with ethyl acetate twice. After the resulting organic layer was dried over anhydrous sodium sulfate, it was filtered off and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate = 1:0-1:2) to yield 4((2-(tert-butoxy)-2-oxoethyl)(3-methoxy-3-oxopropyl)amino)-3-nitrobenzenesulfonic acid (5.00 g) .

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With caesium carbonate in acetonitrile, Time= 10h, T= 20 °C Patent; Boston Biomedical, INC (US); Sumitomo Dainippon Pharma Co., LTD (JP); BAN, HITOSHI; KAMIOKA, SEIJI; SAWAYAMA, YUSUKE; LI, CHIANGJIA; (239 pag.); TW2016/39824; (2016); (A) Chinese View in Reaxys

O O

N H

N O

O O

Rx-ID: 8826117 View in Reaxys 65/78 Yield

Conditions & References

90 %

With potassium carbonate in N,N-dimethyl-formamide, Time= 5h, T= 60 °C Gangjee; Mavandadi; Queener; Journal of Heterocyclic Chemistry; vol. 38; nb. 1; (2001); p. 213 - 220 View in Reaxys

O O

O H N

O O

N H

Rx-ID: 11122567 View in Reaxys 66/78 Yield

Conditions & References With N-ethyl-N,N-diisopropylamine in toluene, Time= 96h, T= 75 °C Busnel, Olivier; Baudy-Floc'h, Michele; Tetrahedron Letters; vol. 48; nb. 33; (2007); p. 5767 - 5770 View in Reaxys

O HO

O O

O Br

F N HO

O F N

O O

OH OH

O O

Rx-ID: 23749177 View in Reaxys 67/78 Yield

Conditions & References Compound 10 (200 mg; 0,2 mmol) was dissolved in THF (10 ml). In the solution methylbromoacetate (46 μl; 0,5 mmol) and potassium carbonate (55 mg; 0,4 mmol) were added. The reaction mixture was stirred at room temperature for 20 hours. The solvent was evaporated under vacuum and crude product was purified on silica gel column in the solvent system CH2Cl2 :MeOH:NH4OH 90:8: 1. 148 mg of the compound 23 was obtained. MS(ES) m/z: [MH]+ 1013,5 With potassium carbonate in tetrahydrofuran, Time= 20h, T= 20 °C Patent; PLIVA-ISTRAZIVACKI INSTITUT D.O.O.; WO2006/46123; (2006); (A2) English View in Reaxys

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Cl Cl

H N

O O

Rx-ID: 29103148 View in Reaxys 68/78 Yield

Conditions & References

71 %

1.B :B) 3-[(3,4-Dichloro-phenyl)-methoxycarbonylmethyl-amino]-propionic Acid tert-butyl ester; A neat solution of 8.82 g (30.39 mmol) of 3-(3,4-dichloro-phenylamino)-propionic acid tert-butyl ester, 13.97 ml (151.97 mmol) of methyl bromoacetate and 17.64 ml (151.97 mmol) of 2,6-lutidine was stirred 14 h at 60° C., diluted with 20 ml of CH 3CN and heated at 115° C. for 6 h. The reaction was then partitioned between aq. 10percent KHSO 4 solution and EtOAc (3.x.). The organic phases were washed with aq. 10percent NaCl solution, dried over Na2SO4 evaporated and purified by flash silica gel column (n-heptane:EtOAc 95:5 to 9:1) to yield 7.86 g (71percent) of the title compound as an yellow oil. MS: 362.0 (MH+, 2Cl). With 2,6-dimethylpyridine in acetonitrile, Time= 20h, T= 60 - 115 °C Patent; Adam, Jean-Michel; Aebi, Johannes; Binggeli, Alfred; Green, Luke; Hartmann, Guido; Maerki, Hans P.; Mattei, Patrizio; Ricklin, Fabienne; Roche, Olivier; US2010/22518; (2010); (A1) English View in Reaxys Cl

O F

N O

Rx-ID: 30716164 View in Reaxys 69/78 Yield 64 %

Conditions & References B :A neat solution of 8.50 g (22.5 mmol) of 3-(3-chloro-4-trifluoromethoxy- phenylamino)-propionic acid tert-butyl ester, 10.71 ml (112.6 mmol) of methyl bromoacetate and 13.07 ml (1 12.6 mmol) of 2,6-lutidine was stirred 14 h at 60 °C, diluted with 30 ml of CH3CN and heated at 115 °C for 20 h. The reaction was then partitioned between aqueous 10percent) KHSO4 solution and EtOAc (3x). The organic phases were washed with aqueous 10percent> NaCl, dried over Na2S04 evaporated and purified by flash silica gel column (n- heptane:EtOAc 95:5 to 85:1) to yield 5.94 g (64percent>) of the title compound as light yellow oil. MS: 412.11 (MH+, CI). With 2,6-dimethylpyridine, Time= 14h, T= 60 °C Patent; F. HOFFMANN-LA ROCHE AG; AEBI, Johannes; BINGGELI, Alfred; GREEN, Luke; HARTMANN, Guido; MAERKI, Hans P.; MATTEI, Patrizio; WO2011/48032; (2011); (A1) English View in Reaxys

64 %

40.B :B) 3-[(3-Chloro-4-trifluoromethoxy-phenyl)-methoxycarbonylmethyl-amino]-propionic acid tert-butyl ester A neat solution of 8.50 g (22.5 mmol) of 3-(3-chloro-4-trifluoromethoxy-phenylamino)-propionic acid tert-butyl ester, 10.71 ml (112.6 mmol) of methyl bromoacetate and 13.07 ml (112.6 mmol) of 2,6-lutidine was stirred 14 h at 60° C., diluted with 30 ml of CH3CN and heated at 115° C. for 20 h. The reaction was then partitioned between aqueous 10percent KHSO4 solution and EtOAc (3*). The organic phases were washed with aqueous 10percent NaCl, dried over Na2SO4 evaporated and purified by flash silica gel column (n-heptane:EtOAc 95:5 to 85:1) to yield 5.94 g (64percent) of the title compound as light yellow oil. MS: 412.11 (MH+, Cl). With 2,6-dimethylpyridine, Time= 14h, T= 60 °C , Neat (no solvent) Patent; Aebi, Johannes; Binggeli, Alfred; Green, Luke; Hartmann, Guido; Maerki, Hans P.; Mattei, Patrizio; US2011/92698; (2011); (A1) English View in Reaxys

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H N

O 2H

Rx-ID: 32840860 View in Reaxys 70/78 Yield

Conditions & References 38 :th l 3 2-ethoxy-2-oxoethyIamuio)propanoaie ~d4 (11 ..) (11.3 gs 0.055 mol) was dissolved in 120 mL acetoniirile. Potassium carbonate (9.12 mL, 0.066 mol) and benzyl bromide (7.14 mL, 0.060 mol) were added and the mixture was stirred for 1 hour at room temperature and stored at 5°C for .16 hrs. The mixture was heated to 40°C for 1.5 hours. The reaction mixture was- concentrated and partitioned between water (200 mL) and C3/4C3/4 (1 χ 100 mL). The aqueous layer was back extracted with CH2CI2 (2 x. .50 m.L) and the combined organics were dried over NaaSO^ The dried organics were evaporated to an oil -andchromatographed over 1 0 g silica gel with 5-10percent ethyl acelate hexanes, to obtain 14.03 g of clear, colorless oil MS (ESI) m/z 298 [ +H]\\ lll M (CDCh) 6 1.23-1.28 (m, 6 H), 3.04 (s, 2 H), 3.82 (s, 2 H), 4.1 1 -4, 17 (m, 4 H), 7.23-7.30 (m, 5 H). With potassium carbonate in acetonitrile, Time= 18.5h, T= 5 - 40 °C Patent; MITHRIDION, INC.; ABRAHAM, Brent, D.; COPP, Richard, R.; FARNHAM, James, G.; HANSON, Seth, A.; HENDRICKSON, Michael, L.; OCKULY, Jeffrey, C.; TWOSE, Trevor, M.; VERDONE, Melinda, L.; WO2012/33956; (2012); (A1) English View in Reaxys 2

H 2H

H N H

O O

H 2H

O O

N 2H

Rx-ID: 32841011 View in Reaxys 71/78 Yield

Conditions & References 39 :Methyl bromoaeetaie-2,2-d2 (2.1 mL, 0,022 mol) was added to a suspension of N-Benzyl beta almiu e~2,2,3,3~d4 ethyl ester (1.24) (4.61 g, 0.02.2 mol) and sodium carbonate (2.5 g. 0.024 -mol) in tetrahydrofuran (50 mL) and I3/40 (2.5 mL). The mixture was heated to 35~40°C for 7 hrs. The mixture was concentrated and partitioned between water (25 mL) and ethyl acetate (1 * 150 mL). The organies were washed with water (25 mL) and saturated sodium chloride (25 mL) The aqueous layer was extracted with ethyl acetate (50 mL) and the combined organies were dried over NajSCU, and concentrated to a oil The residue was chromatographed over 50 g silica gel with 1 -15percent ethyl aceiaie/hexanes to obtain 4.46 g of 125 as clear colorless oih MS (ESI) m/z 286 [M+Hf . lE NMR (CDCI3) 8 1.23-1.26 ( 3. H), 3.68 (s, 3 H), 3,81 (s, 2 H), 4.12-4.14 (q, 2), 7.23-7.30 (m s.5 II). With sodium carbonate in tetrahydrofuran, water-d2, Time= 7h, T= 35 - 40 °C Patent; MITHRIDION, INC.; ABRAHAM, Brent, D.; COPP, Richard, R.; FARNHAM, James, G.; HANSON, Seth, A.; HENDRICKSON, Michael, L.; OCKULY, Jeffrey, C.; TWOSE, Trevor, M.; VERDONE, Melinda, L.; WO2012/33956; (2012); (A1) English View in Reaxys

O Br

S O

O O

O N H

O O

O O O

Rx-ID: 41345927 View in Reaxys 72/78 Yield

Conditions & References Stage 1: With potassium carbonate in N,N-dimethyl-formamide, Time= 0.25h, Inert atmosphere Stage 2: in N,N-dimethyl-formamide, Time= 3h, T= 20 °C , Inert atmosphere

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Jobin, Steve; Vézina-Dawod, Simon; Herby, Claire; Derson, Antoine; Biron, Eric; Organic Letters; vol. 17; nb. 22; (2015); p. 5626 - 5629 View in Reaxys

O O

O S O

N H

O O

Rx-ID: 41345962 View in Reaxys 73/78 Yield

Conditions & References

98 %

Stage 1: With potassium carbonate in N,N-dimethyl-formamide, Time= 0.25h, Inert atmosphere Stage 2: in N,N-dimethyl-formamide, Time= 3h, T= 20 °C , Inert atmosphere Jobin, Steve; Vézina-Dawod, Simon; Herby, Claire; Derson, Antoine; Biron, Eric; Organic Letters; vol. 17; nb. 22; (2015); p. 5626 - 5629 View in Reaxys O

O HN

O Br

Rx-ID: 43801918 View in Reaxys 74/78 Yield

Conditions & References

51 %

With caesium carbonate in N,N-dimethyl-formamide, Inert atmosphere Sharma, Bhavya; Bugga, Pradeep; Madison, Lindsey R.; Henry, Anne-Isabelle; Blaber, Martin G.; Greeneltch, Nathan G.; Chiang, Naihao; Mrksich, Milan; Schatz, George C.; Van Duyne, Richard P.; Journal of the American Chemical Society; vol. 138; nb. 42; (2016); p. 13952 - 13959 View in Reaxys O

H 2N

N H

Rx-ID: 3790971 View in Reaxys 75/78 Yield

Conditions & References

95 %

With triethylamine in ethanol, Time= 12h, Ambient temperature Bureau; Mortier; Joucla; Tetrahedron; vol. 48; nb. 41; (1992); p. 8947 - 8952 View in Reaxys

F F

H 2N

O O O

N H

O O

O N

O O

Rx-ID: 4250204 View in Reaxys 76/78

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Yield

Conditions & References With sodium hydride, triethylamine in tetrahydrofuran, Time= 5h, T= 0 - 5 °C , Yield given. Yields of byproduct given Sunagawa; Matsumura; Sumita; Nouda; Journal of Antibiotics; vol. 48; nb. 5; (1995); p. 408 - 416 View in Reaxys O O

Cl Cl

O N

Cl Cl

Rx-ID: 9459514 View in Reaxys 77/78 Yield

Conditions & References

90 %

With triphenylphosphine, diethylazodicarboxylate in dichloromethane, Mitsunobu reaction Sato, Koji; Hada, Noriyasu; Takeda, Tadahiro; Tetrahedron Letters; vol. 44; nb. 52; (2003); p. 9331 - 9335 View in Reaxys

O O

N H

HN O

Rx-ID: 35999195 View in Reaxys 78/78 Yield 71 %

Conditions & References With sodium hydride in N,N-dimethyl-formamide, T= 40 °C Sim, Neil; Gottschalk, Sven; Pal, Robert; Engelmann, Joern; Parker, David; Mishra, Anurag; Chemical Science; vol. 4; nb. 8; (2013); p. 3148 - 3153 View in Reaxys

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