Methyl 2-phenyl-2-(piperidin-2-yl)acetate (Methylphenidate; MPH; MPD; Ritalin) [C14H19NO2]

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189 reactions in Reaxys

2018-06-01 05h:21m:11s (UTC)

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Search as: Product, As drawn, No mixtures ))

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Rx-ID: 5484997 View in Reaxys 1/189 Yield

Conditions & References Patent; Rhone-Poulenc; US2928835; (1960); ; vol. 55; nb. 2694c; (1961) View in Reaxys Patent; Richter et al.; HU148659; (1959); ; vol. 58; nb. 10180b; (1963) View in Reaxys NAITO; DOHMORI; KOTAKE; Chemical and pharmaceutical bulletin; vol. 12; (1964); p. 588 - 590 View in Reaxys Earle et al.; Journal of the Chemical Society [Section] C: Organic; (1969); p. 2093,2096 View in Reaxys 6.a : EXAMPLE 6 a) preparation of dibenzoyl-D-tartrate salt enriched with the d-threo isomer of methylphenidate To a 500 ml, 4-necked, round-bottomed flask, equipped with a mechanical stirrer, digital thermometer, nitrogen inlet-outlet, heating-cooling bath and addition funnel, is added 12.95 g (48 mmol) of d-l-threo methylphenidate hydrochloride and 22.05 g (48 mmol) of the salt of Example 5. To the resultant mixture is added 62 ml of methanol and the suspension is heated to a temperature between 45° and 50° C. To the resultant clear solution is then added 31 ml of water and ~5 mg of pure dibenzoyl-D-tartrate salt seeds enriched with the d-threo isomer of methylphenidate (obtained essentially as described earlier in the specification, and the mixture is then cooled to a temperature between 20° and 25° C., over a period of 1 hour, and then maintained at this temperature for another hour with stirring. The mixture is then cooled to a temperature between 0° and 5° C. over a period of 15 minutes and then maintained at this temperature for another 2 hours with stirring. The mixture is then filtered and the residue is washed with 21 ml of a pre-cooled (0° to 5° C.) mixture of methanol and water (in a 2:1 v/v ratio) in 3 equal portions of 7 ml each and then dried at a temperature between 50° and 55° C. (100 mmHg) to obtain the desired tartrate salt as a white solid. Patent; Novartris AG; US6100401; (2000); (A) English View in Reaxys 14. and at least one number selected from the group consisting of Pentylenetetrazole Methylphenidate Bunamidine Pyrvinium pamoate Meprobamate Phenacemide Dipyridamol Indomethacin Nicotinamide ... Patent; The Regents of the University of Michigan; US4034087; (1977); (A) English View in Reaxys

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Rx-ID: 5085362 View in Reaxys 2/189 Yield

Conditions & References

97.2 %

9; 10 : Example 10; Dexmethylphenidate hydrochloride; Scheme 9 [0120] Gaseous hydrogen chloride was passed through a boiling solution of (R,R)-N-Boc-ritalinic acid (95.4 g, 299 mmol) in methanol (1.5 L). The mixture was stirred for 12 hours under reflux conditions and concentrated to the volume of 250 mL. Toluene (750 mL) was added to the stirred residue, then methanol lo was removed from boiling suspension under normal pressure. The obtained mixture was stirred overnight at 0-5 C. The precipitated solids were filtered off, washed on the filter with toluene (350 mL) and dried under reduced pressure to give 78.4 g (97.2percent yield) of dexmethylphenidate hydrochloride as white crystals with mp 222-224 C. and [α]D25 87.0 (c=1, MeOH). With hydrogenchloride, Time= 12h, Heating / reflux Patent; ISP INVESTMENTS INC.; US2004/180928; (2004); (A1) English View in Reaxys

82 %

1.9 Synthesis of (R, R), (R, S), (S, S) and (S, R) methyl 2-piperidin-2-yl-phenylacetate hydrochloride (1a, 1b, 1c and 1d) General procedure: Compound 8a, 8b, 8c or 8d (400 mg, 1.3 mmol) was dissolved into methanol solution (15 mL), and then thionyl chloride (1 mL) was added drop-wise. The reaction mixture was stirred for 12 hours and concentrated in vacuum; a white solid was precipitated and filtered to afford the final product. (1a. 0.28 g, 82percent yield; 1b. 0.30 g, 84percent yield; 1c. 0.31 g, 85percent yield; 1d. 0.30 g, 84percent yield). With thionyl chloride, Time= 12h Li, Chunzheng; Ji, Yuanbo; Cao, Qing; Li, Jianqi; Li, Bonan; Synthetic Communications; vol. 47; nb. 14; (2017); p. 1301 1306 View in Reaxys

70 %

With hydrogenchloride, Time= 15h, T= 50 °C Prashad, Mahavir; Kim, Hong-Yong; Lu, Yansong; Liu, Yugang; Har, Denis; Repic, Oljan; Blacklock, Thomas J.; Giannousis, Peter; Journal of Organic Chemistry; vol. 64; nb. 5; (1999); p. 1750 - 1753 View in Reaxys

70 %

With hydrogenchloride, T= 50 °C Krishna, Palakodety Radha; Lopinti, Krishnarao; Synlett; nb. 11; (2007); p. 1742 - 1744 View in Reaxys

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Rx-ID: 11695311 View in Reaxys 3/189

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Yield

Conditions & References Reaction Steps: 3 1: Dess-Martin periodinane; NaHCO3 / CH2Cl2 / 0 °C 2: sodium chlorite; NaH2PO4*2H2O; 2-methyl-2-butene / 2-methyl-propan-2-ol / 12 h / 0 - 20 °C 3: 70 percent / HCl / 50 °C With hydrogenchloride, sodium chlorite, sodium dihydrogenphosphate, 2-methyl-but-2-ene, sodium hydrogencarbonate, DessMartin periodane in dichloromethane, tert-butyl alcohol Krishna, Palakodety Radha; Lopinti, Krishnarao; Synlett; nb. 11; (2007); p. 1742 - 1744 View in Reaxys Reaction Steps: 2 1: 80 percent / NaIO4, RuCl3*H2O / H2O; acetonitrile; CCl4 / 2 h / 22 °C 2: 70 percent / HCl / 15 h / 50 °C With hydrogenchloride, ruthenium trichloride, sodium periodate in tetrachloromethane, water, acetonitrile Prashad, Mahavir; Kim, Hong-Yong; Lu, Yansong; Liu, Yugang; Har, Denis; Repic, Oljan; Blacklock, Thomas J.; Giannousis, Peter; Journal of Organic Chemistry; vol. 64; nb. 5; (1999); p. 1750 - 1753 View in Reaxys Reaction Steps: 3 1: PDC / dimethylformamide / 17 h 2: diethyl ether 3: HCl / methanol / Ambient temperature With hydrogenchloride, dipyridinium dichromate in methanol, diethyl ether, N,N-dimethyl-formamide Thai, Dung L.; Sapko, Michael T.; Reiter, Clara T.; Bierer, Donald E.; Perel, James M.; Journal of Medicinal Chemistry; vol. 41; nb. 4; (1998); p. 591 - 601 View in Reaxys Reaction Steps: 2 1: dipyridinium dichromate / N,N-dimethyl-formamide / 12 h 2: thionyl chloride / 12 h With dipyridinium dichromate, thionyl chloride in N,N-dimethyl-formamide Li, Chunzheng; Ji, Yuanbo; Cao, Qing; Li, Jianqi; Li, Bonan; Synthetic Communications; vol. 47; nb. 14; (2017); p. 1301 1306 View in Reaxys O

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Rx-ID: 23583053 View in Reaxys 4/189 Yield 95 %

Conditions & References 2 :Examples 2-6These examples illustrate various aspects of the synthesis of threo-methylphenidate by the process of the present invention as described below and summarized in Table 1.Example 2 illustrates the process performed as in Example 1 except that the threo-methylphenidate was isolated from isopropyl alcohol after solvent exchange.Example 3 illustrates the reaction in which the trimethyl orthoacetate was added at the start of the reaction.Examples 4, 5 and 6 illustrate the reaction in absence of the water sequestrant, trimethyl orthoacetate, in which isolation was from methanol (Examples 4 and 5) or from isopropyl alcohol after solvent exchange (Example 6). Stage 1: With hydrogenchloride, T= 69.4 °C Stage 2: With Trimethyl orthoacetate, T= 60 - 63 °C , Product distribution / selectivity Patent; Mallinckrodt Inc.; US2010/179327; (2010); (A1) English View in Reaxys

93.9 %

7 :Example 7; Synthesis of dl-threo methylphenidate hydrochloride with hydrogen chloride, trimethyl orthoformate, and isopropanol as anti-solvent at 19-20 °C:Dry methanol (250 mL) was charged with hydrogen chloride gas (33.85 g) at 20-25 °C. The

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solution was diluted with methanol (50 mL) and charged with dl- threo ritalinic acid (50.88 g, 4 eq). After stirring 5 days at 19-20 °C, conversion as determined by HPLC was 99.86percent. Trimethyl orthoformate (76 mL, 3 eq) was added and the reaction was heated 2 hours at 40 °C. Vacuum distillation was carried out at 19.9-26.7 kPa (150-200 torr), with a pot temperature of 38-42 °C. The distillate was collected in three fractions, charging 100 mL of dry isopropanol between each fraction. The reaction mixture was cooled to 20 °C, filtered, and washed with isopropanol (2 x 100 mL). The resulting white solid was dried in a vacuum drying oven at room temperature overnight to afford dl-threo methylphenidate hydrochloride as a white crystalline solid (58.77 g, 93.9percent yield, 99.98percent HPLC purity). Stage 1: With hydrogenchloride, Time= 120h, T= 19 - 25 °C Stage 2: With trimethyl orthoformate in methanol, Time= 2h, T= 40 °C , Product distribution / selectivity Patent; RHODES TECHNOLOGIES; HUNTLEY, C., Frederick, M.; KATAISTO, Erick, Wayne; LA LUMIERE, Knicholaus, Dudley; REISCH, Helge, Alfred; WO2012/80834; (2012); (A1) English View in Reaxys 10 : EXAMPLE 10 About 10.9 grams of dl-ritalinic acid in about 40 mL of methanol saturated with hydrogen chloride gas were reacted. The reaction mixture was refluxed for about 4 hours. The hot reaction mixture was then filtered and the filtrate taken to dryness in vacuo to give about 4.9 grams of dl-threo-methylphenidateHCl. In certain embodiments, the dl-threo-methylphenidateHCl obtained in step 275 was recrystallized from methanol prior to use in step 210. With hydrogenchloride, Time= 4h, Heating / reflux Patent; Krsek, George R.; Durazo, Enrique E.; US2005/171155; (2005); (A1) English View in Reaxys

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Rx-ID: 23669021 View in Reaxys 5/189 Yield 89.88 %

Conditions & References 2 : Example 2: Example 2: α-Phenyl-α-pipyridyl-2-methyl acetate In a reaction vessel, a mixture of 100 gm α-phenyl-α-pyridyl-2- methyl acetate, 100 ml of 0.1 N perchloric acid in acetic acid in presence of 10 gm 5percent Pd/C (50percent wet) and 1000 ml methanol were heated to 45-50°C under 12-15 Kg/cm2 hydrogen pressure for 15 to 18 hrs. The catalyst was removed by filtration. Filtrate was concentrated under reduced pressure and the concentrated mass was diluted with water and basified with aqueous sodium hydroxide solution to get the product α-phenyl-α-pipyridyl-2-methyl acetate. Yield of product = 92 gm (89.88percent). Stage 1: With perchloric acid, hydrogen, acetic acid, Johnson & Matthey type 440 in methanol, water, Time= 15 - 18h, T= 45 50 °C , p= 8826.87 - 11033.6Torr Stage 2: With sodium hydroxide in water Patent; IPCA Laboratories Limited; EP1607388; (2005); (A1) English View in Reaxys

89.88 %

2 :In a reaction vessel, a mixture of 100 gm .proportional.-phenyl-.proportional.-pyridyl-2-methyl acetate, 100 ml of 0.1 N perchioric acid in acetic acid in presence of 10 gm 5percent Pd/C (50percent wet) and 1000 ml methanol were heated to 45-50° C. under 12-15 Kg/cm2 hydrogen pressure for 15 to 18 hrs. The catalyst was rem by filtration. Filtrate was concentrated under reduced pressure and the concentrated mass was diluted with water and basified with aqueous sodium hydroxide solution to get the product .proportional.-phenyl-.proportional.-pipyridyl-2-methyl acetate. Yield of product=92 gm (89.88percent). Stage 1: With perchloric acid, hydrogen, Johnson & Matthey type 440 in methanol, acetic acid Stage 2: With sodium hydroxide in water

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Patent; Kumar, Ashok; Singh, Dharmendra; Patil, Swapnali Hemant; Mahale, Ganesh Devidas; Sawant, Uttamrao Arjunrao; US2005/277667; (2005); (A1) English View in Reaxys With hydrogen, platinum Li, Yahui; Wang, Zechao; Wu, Xiao-Feng; ACS Catalysis; vol. 8; nb. 1; (2018); p. 738 - 741 View in Reaxys

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Rx-ID: 36657604 View in Reaxys 6/189 Yield

Conditions & References With sodium chloride, sodium hydroxide in Isopropyl acetate, water, Time= 0.5h, T= 20 - 25 °C Prashad, Mahavir; Hu, Bin; Repic, Oljan; Blacklock, Thomas J.; Giannousis, Peter; Organic Process Research and Development; vol. 4; nb. 1; (2000); p. 55 - 59 View in Reaxys 1 : Example 1 Example 1 Preparation of Methylphenidate (free base) 1 Methylphenidate hydrochloride (2g, 7.41mmol) was dissolved in water (50ml) and sodium bicarbonate was added until the pH was 9-10. The resulting mixture was stirred at room temperature for one hour. The reaction mixture was extracted several times with dichloromethane, the combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo to give methylphenidate free base 1 (1.7g) as a light yellow oil. With sodium hydrogencarbonate in water Patent; Randox Laboratories Ltd.; Benchikh, Elouard; Fitzgerald, Peter; Lowry, Philip; McConnell, Ivan; EP2769994; (2014); (A2) English View in Reaxys 3 : Preparation of dl-threo methylphenidate free base from dlthreomethylPhenidate hydrochloride dI-threomethylphenidate hydrochloride (25.0 gm) was added to 250 ml ethyl acetate at ambient temperature and pH is adjusted with 20percent sodium hydroxide solution at 0-SeC. The mixture is then stirred at 20-25eC for about 1-2 hours. Deionized water was added. The organic layer was separated and washed with 10percent Sodium Chloride solution followed by drying over sodium sulphate and concentration under vacuum to obtain the desired free base With sodium hydroxide in ethyl acetate, T= 0 - 25 °C , Solvent, Temperature Patent; HARMAN FINOCHEM LIMITED; KADAM, Vijay Trimbak; SARANAPU, Nareesh; CHAVAN, Santosh Uttamrao; MINHAS, Harpreet Singh; MINHAS, Gurpreet Singh; (18 pag.); WO2018/15971; (2018); (A1) English View in Reaxys

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Rx-ID: 4924468 View in Reaxys 7/189

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Yield

Conditions & References

94.7 %

15 :Example 15; Synthesis of d-threo methylphenidate hydrochloride with hydrogen chloride, trimethyl orthoformate, and isopropanol as anti-solvent:Dry methanol (200 mL) was charged with hydrogen chloride (13.6 g, 373 mmol, 2.2 eq) at 20-25 °C over 15 minutes. To this solution was added d-threo ritalinic acid hydrochloride (43.2 g, 169 mmol, 1.0 eq) in one portion, followed by additional methanol (23 mL, 6 volumes total methanol based on free base). The reaction was heated at 35 °C for 27 hours, at which time the conversion by HPLC was 98.81percent. After 28 h, trimethyl orthoformate (40.7 mL, 372 mmol, 2.2 eq) was added and the reaction was allowed to stir 1 hour at 40 °C. The reaction mixture was distilled in vacuo (119 mL distillate collected) and isopropanol (100 mL) was added. The reaction mixture was distilled further (65 mL distillate collected), and isopropanol (95 mL) was added. The reaction mixture was distilled further (25 mL distillate collected), and cooled to room temperature. After stirring at room temperature for 3 days, the slurry was cooled to 2 °C, filtered, washed with cold (<10 °C), isopropanol (2 x 100 mL), and dried to afford enantiopure d-threo methyphenidate HC1 as a white solid (43.19 g, 94.7percent yield, 99.73percent HPLC purity).Example 7; Synthesis of dl-threo methylphenidate hydrochloride with hydrogen chloride, trimethyl orthoformate, and isopropanol as anti-solvent at 19-20 °C:Dry methanol (250 mL) was charged with hydrogen chloride gas (33.85 g) at 20-25 °C. The solution was diluted with methanol (50 mL) and charged with dl- threo ritalinic acid (50.88 g, 4 eq). After stirring 5 days at 19-20 °C, conversion as determined by HPLC was 99.86percent. Trimethyl orthoformate (76 mL, 3 eq) was added and the reaction was heated 2 hours at 40 °C. Vacuum distillation was carried out at 19.9-26.7 kPa (150-200 torr), with a pot temperature of 38-42 °C. The distillate was collected in three fractions, charging 100 mL of dry isopropanol between each fraction. The reaction mixture was cooled to 20 °C, filtered, and washed with isopropanol (2 x 100 mL). The resulting white solid was dried in a vacuum drying oven at room temperature overnight to afford dl-threo methylphenidate hydrochloride as a white crystalline solid (58.77 g, 93.9percent yield, 99.98percent HPLC purity). Stage 1: With hydrogenchloride, Time= 28h, T= 20 - 35 °C Stage 2: With trimethyl orthoformate in methanol, Time= 1h, T= 40 °C Patent; RHODES TECHNOLOGIES; HUNTLEY, C., Frederick, M.; KATAISTO, Erick, Wayne; LA LUMIERE, Knicholaus, Dudley; REISCH, Helge, Alfred; WO2012/80834; (2012); (A1) English View in Reaxys

16 %

With hydrogenchloride, Time= 16h, T= 45 - 50 °C Prashad, Mahavir; Har, Denis; Repic, Oljan; Blacklock, Thomas J.; Giannousis, Peter; Tetrahedron Asymmetry; vol. 9; nb. 12; (1998); p. 2133 - 2136 View in Reaxys

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Rx-ID: 9352074 View in Reaxys 8/189 Yield

Conditions & References With sodium tetrahydroborate, acetic acid in acetonitrile, T= 20 °C , Product distribution, Further Variations: Reagents, Solvents Russowsky, Dennis; Da Silveira Neto, Brenno Amaro; Tetrahedron Letters; vol. 44; nb. 14; (2003); p. 2923 - 2926 View in Reaxys With platinum(IV) oxide, perchloric acid, hydrogen in methanol, water, Time= 24h, p= 3800.26Torr , optical yield given as percent de, stereoselective reaction Neto, Brenno A.D.; Lapis, Alexandre A.M.; Bernd, Alinne B.; Russowsky, Dennis; Tetrahedron; vol. 65; nb. 12; (2009); p. 2484 - 2496 View in Reaxys

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N O

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Rx-ID: 14212538 View in Reaxys 9/189 Yield

Conditions & References Reaction Steps: 2 1: Rh2(S-DOSP)4 / hexane / -50 - 23 °C 2: TFA / CH2Cl2 / 1 h / 23 °C With Rh2[(N-(4-dodecylphenyl)sulfonyl)-(S)-prolinate]4, trifluoroacetic acid in hexane, dichloromethane Davies, Huw M. L.; Venkataramani, Chandrasekar; Hansen, Tore; Hopper, Darrin W.; Journal of the American Chemical Society; vol. 125; nb. 21; (2003); p. 6462 - 6468 View in Reaxys Reaction Steps: 3 1: Rh2(S-DOSP)4 / various solvent(s) / 0.5 h 2: TFA / CH2Cl2 / 2 h 3: 124 mg / H2 / 10 percent Pd/C / tetrahydrofuran With Rh2[(N-(4-dodecylphenyl)sulfonyl)-(S)-prolinate]4, hydrogen, trifluoroacetic acid, 10 wt. % palladium on activated carbon in tetrahydrofuran, dichloromethane Davies, Huw M. L.; Venkataramani, Chandrasekar; Hansen, Tore; Hopper, Darrin W.; Journal of the American Chemical Society; vol. 125; nb. 21; (2003); p. 6462 - 6468 View in Reaxys Reaction Steps: 2 1: Rh2(S-biDOSP)2 2: TFA With Rh2(S-biDOSP)2, trifluoroacetic acid Davies, Huw M. L.; Hansen, Tore; Hopper, Darrin W.; Panaro, Stephen A.; Journal of the American Chemical Society; vol. 121; nb. 27; (1999); p. 6509 - 6510 View in Reaxys Reaction Steps: 2 1: Rh2(S-DOSP)4 / various solvent(s) / 25 °C 2: TFA With Rh2[(N-(4-dodecylphenyl)sulfonyl)-(S)-prolinate]4, trifluoroacetic acid in various solvent(s) Davies, Huw M. L.; Hansen, Tore; Hopper, Darrin W.; Panaro, Stephen A.; Journal of the American Chemical Society; vol. 121; nb. 27; (1999); p. 6509 - 6510 View in Reaxys

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Rx-ID: 14214464 View in Reaxys 10/189 Yield

Conditions & References Reaction Steps: 2 1: Rh2(S-DOSP)4 / hexane / -50 - 23 °C

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2: TFA / CH2Cl2 / 1 h / 23 °C With Rh2[(N-(4-dodecylphenyl)sulfonyl)-(S)-prolinate]4, trifluoroacetic acid in hexane, dichloromethane Davies, Huw M. L.; Venkataramani, Chandrasekar; Hansen, Tore; Hopper, Darrin W.; Journal of the American Chemical Society; vol. 125; nb. 21; (2003); p. 6462 - 6468 View in Reaxys Reaction Steps: 2 1: Rh2(S-biDOSP)2 2: TFA With Rh2(S-biDOSP)2, trifluoroacetic acid Davies, Huw M. L.; Hansen, Tore; Hopper, Darrin W.; Panaro, Stephen A.; Journal of the American Chemical Society; vol. 121; nb. 27; (1999); p. 6509 - 6510 View in Reaxys Reaction Steps: 2 1: Rh2(S-DOSP)4 / various solvent(s) / 25 °C 2: TFA With Rh2[(N-(4-dodecylphenyl)sulfonyl)-(S)-prolinate]4, trifluoroacetic acid in various solvent(s) Davies, Huw M. L.; Hansen, Tore; Hopper, Darrin W.; Panaro, Stephen A.; Journal of the American Chemical Society; vol. 121; nb. 27; (1999); p. 6509 - 6510 View in Reaxys

O O

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Rx-ID: 16947543 View in Reaxys 11/189 Yield

Conditions & References Reaction Steps: 4 1: 1.) BH3*THF, 2.) aq. H2O2, NaOH / 1.) THF, RT, 4 h, 2.) THF, RT 2: PDC / dimethylformamide / 17 h 3: diethyl ether 4: HCl / methanol / Ambient temperature With hydrogenchloride, sodium hydroxide, dipyridinium dichromate, borane-THF, dihydrogen peroxide in methanol, diethyl ether, N,N-dimethyl-formamide Thai, Dung L.; Sapko, Michael T.; Reiter, Clara T.; Bierer, Donald E.; Perel, James M.; Journal of Medicinal Chemistry; vol. 41; nb. 4; (1998); p. 591 - 601 View in Reaxys Reaction Steps: 3 1: dimethylsulfide borane complex / tetrahydrofuran / 5 h 2: dipyridinium dichromate / N,N-dimethyl-formamide / 12 h 3: thionyl chloride / 12 h With dipyridinium dichromate, thionyl chloride, dimethylsulfide borane complex in tetrahydrofuran, N,N-dimethyl-formamide Li, Chunzheng; Ji, Yuanbo; Cao, Qing; Li, Jianqi; Li, Bonan; Synthetic Communications; vol. 47; nb. 14; (2017); p. 1301 1306 View in Reaxys

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O O

O

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H Cl N

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HN

Rx-ID: 16947548 View in Reaxys 12/189 Yield

Conditions & References Reaction Steps: 4 1: 1.) BH3*THF, 2.) aq. H2O2, NaOH / 1.) THF, RT, 4 h, 2.) THF, RT 2: PDC / dimethylformamide / 17 h 3: diethyl ether 4: HCl / methanol / Ambient temperature With hydrogenchloride, sodium hydroxide, dipyridinium dichromate, borane-THF, dihydrogen peroxide in methanol, diethyl ether, N,N-dimethyl-formamide Thai, Dung L.; Sapko, Michael T.; Reiter, Clara T.; Bierer, Donald E.; Perel, James M.; Journal of Medicinal Chemistry; vol. 41; nb. 4; (1998); p. 591 - 601 View in Reaxys Reaction Steps: 3 1: dimethylsulfide borane complex / tetrahydrofuran / 5 h 2: dipyridinium dichromate / N,N-dimethyl-formamide / 12 h 3: thionyl chloride / 12 h With dipyridinium dichromate, thionyl chloride, dimethylsulfide borane complex in tetrahydrofuran, N,N-dimethyl-formamide Li, Chunzheng; Ji, Yuanbo; Cao, Qing; Li, Jianqi; Li, Bonan; Synthetic Communications; vol. 47; nb. 14; (2017); p. 1301 1306 View in Reaxys

O

O

H

O

H

O Cl

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H

Rx-ID: 16947549 View in Reaxys 13/189 Yield

Conditions & References Reaction Steps: 4 1: 1.) BH3*THF, 2.) aq. H2O2, NaOH / 1.) THF, RT, 4 h, 2.) THF, RT 2: PDC / dimethylformamide / 17 h 3: diethyl ether 4: HCl / methanol / Ambient temperature With hydrogenchloride, sodium hydroxide, dipyridinium dichromate, borane-THF, dihydrogen peroxide in methanol, diethyl ether, N,N-dimethyl-formamide Thai, Dung L.; Sapko, Michael T.; Reiter, Clara T.; Bierer, Donald E.; Perel, James M.; Journal of Medicinal Chemistry; vol. 41; nb. 4; (1998); p. 591 - 601 View in Reaxys Reaction Steps: 3 1: dimethylsulfide borane complex / tetrahydrofuran / 5 h 2: dipyridinium dichromate / N,N-dimethyl-formamide / 12 h 3: thionyl chloride / 12 h

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With dipyridinium dichromate, thionyl chloride, dimethylsulfide borane complex in tetrahydrofuran, N,N-dimethyl-formamide Li, Chunzheng; Ji, Yuanbo; Cao, Qing; Li, Jianqi; Li, Bonan; Synthetic Communications; vol. 47; nb. 14; (2017); p. 1301 1306 View in Reaxys

O O

O

O

H Cl N

H

HN

Rx-ID: 16947554 View in Reaxys 14/189 Yield

Conditions & References Reaction Steps: 4 1: 1.) BH3*THF, 2.) aq. H2O2, NaOH / 1.) THF, RT, 4 h, 2.) THF, RT 2: PDC / dimethylformamide / 17 h 3: diethyl ether 4: HCl / methanol / Ambient temperature With hydrogenchloride, sodium hydroxide, dipyridinium dichromate, borane-THF, dihydrogen peroxide in methanol, diethyl ether, N,N-dimethyl-formamide Thai, Dung L.; Sapko, Michael T.; Reiter, Clara T.; Bierer, Donald E.; Perel, James M.; Journal of Medicinal Chemistry; vol. 41; nb. 4; (1998); p. 591 - 601 View in Reaxys Reaction Steps: 3 1: dimethylsulfide borane complex / tetrahydrofuran / 5 h 2: dipyridinium dichromate / N,N-dimethyl-formamide / 12 h 3: thionyl chloride / 12 h With dipyridinium dichromate, thionyl chloride, dimethylsulfide borane complex in tetrahydrofuran, N,N-dimethyl-formamide Li, Chunzheng; Ji, Yuanbo; Cao, Qing; Li, Jianqi; Li, Bonan; Synthetic Communications; vol. 47; nb. 14; (2017); p. 1301 1306 View in Reaxys

O

O

O H

N

O

H Cl

OH

H

HN

Rx-ID: 16947579 View in Reaxys 15/189 Yield

Conditions & References Reaction Steps: 3 1: PDC / dimethylformamide / 17 h 2: diethyl ether 3: HCl / methanol / Ambient temperature With hydrogenchloride, dipyridinium dichromate in methanol, diethyl ether, N,N-dimethyl-formamide Thai, Dung L.; Sapko, Michael T.; Reiter, Clara T.; Bierer, Donald E.; Perel, James M.; Journal of Medicinal Chemistry; vol. 41; nb. 4; (1998); p. 591 - 601

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View in Reaxys Reaction Steps: 2 1: dipyridinium dichromate / N,N-dimethyl-formamide / 12 h 2: thionyl chloride / 12 h With dipyridinium dichromate, thionyl chloride in N,N-dimethyl-formamide Li, Chunzheng; Ji, Yuanbo; Cao, Qing; Li, Jianqi; Li, Bonan; Synthetic Communications; vol. 47; nb. 14; (2017); p. 1301 1306 View in Reaxys

O

O

O H

N

O

H Cl

OH

H

HN

Rx-ID: 16947581 View in Reaxys 16/189 Yield

Conditions & References Reaction Steps: 3 1: PDC / dimethylformamide / 17 h 2: diethyl ether 3: HCl / methanol / Ambient temperature With hydrogenchloride, dipyridinium dichromate in methanol, diethyl ether, N,N-dimethyl-formamide Thai, Dung L.; Sapko, Michael T.; Reiter, Clara T.; Bierer, Donald E.; Perel, James M.; Journal of Medicinal Chemistry; vol. 41; nb. 4; (1998); p. 591 - 601 View in Reaxys Reaction Steps: 2 1: dipyridinium dichromate / N,N-dimethyl-formamide / 12 h 2: thionyl chloride / 12 h With dipyridinium dichromate, thionyl chloride in N,N-dimethyl-formamide Li, Chunzheng; Ji, Yuanbo; Cao, Qing; Li, Jianqi; Li, Bonan; Synthetic Communications; vol. 47; nb. 14; (2017); p. 1301 1306 View in Reaxys

O

O

O H H

H N

OH

O

HN

Cl

H

Rx-ID: 16947582 View in Reaxys 17/189 Yield

Conditions & References Reaction Steps: 3 1: PDC / dimethylformamide / 17 h 2: diethyl ether 3: HCl / methanol / Ambient temperature With hydrogenchloride, dipyridinium dichromate in methanol, diethyl ether, N,N-dimethyl-formamide

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Thai, Dung L.; Sapko, Michael T.; Reiter, Clara T.; Bierer, Donald E.; Perel, James M.; Journal of Medicinal Chemistry; vol. 41; nb. 4; (1998); p. 591 - 601 View in Reaxys Reaction Steps: 2 1: dipyridinium dichromate / N,N-dimethyl-formamide / 12 h 2: thionyl chloride / 12 h With dipyridinium dichromate, thionyl chloride in N,N-dimethyl-formamide Li, Chunzheng; Ji, Yuanbo; Cao, Qing; Li, Jianqi; Li, Bonan; Synthetic Communications; vol. 47; nb. 14; (2017); p. 1301 1306 View in Reaxys

O H H

H

O

HO

Cl

HN

N H

O

H

NH 2

Rx-ID: 22866811 View in Reaxys 18/189 Yield

Conditions & References

100 g

Stage 1: With sulfuric acid, Time= 48h, Heating / reflux Stage 2: With sodium hydroxide in diethyl ether, water, pH= 12 Stage 3: With hydrogenchloride in diethyl ether Patent; Celgene Corporation; US6359139; (2002); (B1) English View in Reaxys 4 : Example 4; d-ThreoMethyl α-Piperid-2-ylphenylacetate Hydrochloride A mixture of 27.83 g (128 mmol) of d-threoα-piperid-2-ylphenylacetamide and 33.4 mL of concentrated sulfuric acid in 300 mL of methanol was heated at reflux for 60 hours. The reaction mixture was cooled to ambient temperature, and concentrated in vacuo. The residue was added to 300 g of crushed ice and the pH was adjusted to 13 with 10 M sodium hydroxide. The mixture was extracted twice with 200 mL of ether and these extracts were dried over magnesium sulfate. Hydrogen chloride gas was passed through the solution and the solid was collected by filtration under suction and washed with ether to give 33.07 g of product which was recrystallized from methanol to give 26.2 g of d-threo methyl α-piperid-2-ylphenylacetate hydrochloride as a white solid. [α]D = +85.4°, (methanol, c = 1.0). Stage 1: With sulfuric acid, Time= 60h, Heating / reflux Stage 2: With sodium hydroxide in water, pH= 13 Stage 3: With hydrogenchloride in diethyl ether Patent; CELGENE CORPORATION; EP1082307; (2005); (B1) English View in Reaxys

O

O

H N

O

O

H N

Cl

H

Rx-ID: 23670120 View in Reaxys 19/189 Yield 78 %

Conditions & References 3 : Example 3: Example 3: Methylphenidate hydrochloride In a reaction vessel, 100 gm methylphenidate, 1000 ml isopropyl alcohol were mixed at 30 to 35 °C, cool the mixture to 10 to 15°C.

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To this mixture Isopropanol hydrochloride solution (18-20percent HCl (dry) in isopropyl alcohol) was added by maintaining the reaction mass below 15 °C. This was maintained for about 5 hours at 30 °C, cooled to 10 °C and filtered to isolate methylphenidate hydrochloride. The precipitate was washed with isopropyl alcohol and dried at 60 to 70 °C. Yield was 88 gm (78percent) M. P. =224 - 226°C. With hydrogenchloride in isopropyl alcohol, Time= 5h, T= 10 - 35 °C Patent; IPCA Laboratories Limited; EP1607388; (2005); (A1) English View in Reaxys 78 %

3 :In a reaction vessel, 100 gm methylphenidate, 1000 ml isopropyl alcohol were mixed at 30 to 35° C., cool the mixture to 10 to 15° C. To this mixture Isopropanol hydrochloride solution (18-20percent HCl (dry) in isopropyl alcohol) was added by maintaining the reaction mass below 15° C. This was maintained for about 5 hours at 30° C., cooled to 10° C. and filtered to isolate methylphenidate hydrochloride. The precipitate was washed with isopropyl alcohol and dried at 60 to 70° C. Yield was 88 gm (78percent) M. P.=224-226° C With hydrogenchloride in isopropyl alcohol, Time= 5h, T= 10 - 30 °C Patent; Kumar, Ashok; Singh, Dharmendra; Patil, Swapnali Hemant; Mahale, Ganesh Devidas; Sawant, Uttamrao Arjunrao; US2005/277667; (2005); (A1) English View in Reaxys

H N

H

H

O

O

H H

O

O

HN

Cl

H

Rx-ID: 27821937 View in Reaxys 20/189 Yield

Conditions & References 13 :Example 13Dexmethylphenidate Free Base and Hydrochloride Salt FormationD-Threo-methylphenidate-di-p-toluoyl-D-tartrate (0.47 Kg, 0.758 mol, ee 98.9percent) was charged to a suitable reactor followed by water (1.2 Kg) and isopropyl acetate (0.7 Kg). The formed slurry was cooled to about 15° C. and was treated with sodium hydroxide (25percent, 0.3 Kg) at less than 25° C., followed by 30 minutes aging. The lower aqueous layer was separated and the organic layer was washed with process water (3.x.0.4 Kg)The organic layer was dewatered by azeotropic distillation under vacuum and was concentrated in vacuum to give D-threo-methylphenidate free base as an oil, which was used directly in hydrochloride salt formation. The solution of Dthreo-methylphenidate free base in isopropanol (0.29 Kg) was charged to a jacketed vessel, cooled to 5-10° C. and treated with a solution of 37percent HCl (78 g) in a mixture of isopropanol (40 g) and methanol (63 g) at less than 20° C. The formed slurry was cooled to 0 to 5° C., aged for 2 hours and filtered. The wet cake was washed with isopropanol (0.32 Kg total) in two portions and dried under vacuum at 45° C. for 16 hours to give Dexmethylphenidate hydrochloride (0.175 Kg, 0.649 mol, 86percent yield) as a off-white solid; mp 206.4° C., ee 99.7percent, 25 α D +83° (c 1 wt percent, MeOH). With hydrogenchloride in methanol, isopropyl alcohol, Time= 2h, T= 0 - 20 °C Patent; Kalinin, Alexei; Qiu, Guofang; Marren, Thomas J.; Aldred, James E.; Ji, Yu; US2008/167470; (2008); (A1) English View in Reaxys

98.3 g

With hydrogenchloride in water, Time= 2h Xing, Long-Xuan; Shen, Cheng-Wu; Sun, Yuan-Yuan; Huang, Lei; Zheng, Yong-Yong; Li, Jian-Qi; Journal of Heterocyclic Chemistry; vol. 54; nb. 2; (2017); p. 1298 - 1303 View in Reaxys

Copyright © 2018 Reed Elsevier Properties SA. All rights reserved. Authorized use only. Reaxys® and the Reaxys® trademark are owned and protected by Reed Elsevier Properties SA and used under license.

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O H H

O O H N

P

HN

O

O Cl

H

OH O

H O

Rx-ID: 36657609 View in Reaxys 21/189 Yield

Conditions & References

93.2 %

6 : Preparation of dexmethylphenidate hydrochloride: 100mL three-necked flask, A solution of 5.00 g (8.61 mmol) of the organic salt of (R) -binaphthol phosphate of dexmethylphenidate in 25 mL of acetonitrile, Warming to 35 ° C clear, 1.4 mL (17.22 mmol) of 37percent hydrochloric acid was added dropwise and reacted at 50 ° C for 1 h. After the reaction was cooled to 25 ° C, Add 100mL ether and stir for 2h. Filtered to give a white solid 2.33g, yield 93.2percent No ester hydrolysis impurities and transesterification impurities were detected With hydrogenchloride in water, acetonitrile, Time= 1h, T= 35 - 50 °C Patent; Shanghai Pharmaceutical Industry Institute; China Pharmaceutical Industry Zongyuan; Zhang Fuli; Zhang Jie; Yang Zhezhou; Zhang Lin; Chen Lingling; Wang Zhengwen; Gao Shenghua; (8 pag.); CN107325039; (2017); (A) Chinese View in Reaxys

31.4 %

Stage 1: With sodium hydroxide in Isopropyl acetate, water, Time= 0.5h, T= 20 - 25 °C Stage 2: With hydrogenchloride in water, Time= 0.75h, T= 0 - 25 °C , enantioselective reaction Prashad, Mahavir; Hu, Bin; Repic, Oljan; Blacklock, Thomas J.; Giannousis, Peter; Organic Process Research and Development; vol. 4; nb. 1; (2000); p. 55 - 59 View in Reaxys

O

OH

O H N

O

H N

HO

Rx-ID: 3830206 View in Reaxys 22/189 Yield

Conditions & References With sulfuric acid, Time= 0.25h, T= 85 °C Nakajima; Kotaki; Saitoh; Nakagawa; Chemical and Pharmaceutical Bulletin; vol. 34; nb. 4; (1986); p. 1701 - 1708 View in Reaxys

H 11 C 3

11CH

O O

O

O

3

O

O

N

H N

S N

Rx-ID: 4017538 View in Reaxys 23/189 Yield

Conditions & References With hydrogenchloride, mercaptoacetic acid in diethyl ether, N,N-dimethyl-formamide, Time= 0.05h, Ambient temperature Ding; Sugano; Fowler; Salata; Journal of Labelled Compounds and Radiopharmaceuticals; vol. 34; nb. 10; (1994); p. 989 997 View in Reaxys

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H 11 3 C

11CH

O

3

O

O

O

O

O

N

H N

S N

Rx-ID: 4017539 View in Reaxys 24/189 Yield

Conditions & References With hydrogenchloride, mercaptoacetic acid in diethyl ether, N,N-dimethyl-formamide, Time= 0.05h, Ambient temperature Ding; Sugano; Fowler; Salata; Journal of Labelled Compounds and Radiopharmaceuticals; vol. 34; nb. 10; (1994); p. 989 997 View in Reaxys

H 11 3 C

11CH

O

3

O

O

O

O

O

N

H N

S N

Rx-ID: 4017540 View in Reaxys 25/189 Yield

Conditions & References With hydrogenchloride, mercaptoacetic acid in diethyl ether, N,N-dimethyl-formamide, Time= 0.05h, Ambient temperature Ding; Sugano; Fowler; Salata; Journal of Labelled Compounds and Radiopharmaceuticals; vol. 34; nb. 10; (1994); p. 989 997 View in Reaxys

O

OH

H N

H

H

O

O H H

H N

O

O

HO

HN

Rx-ID: 4504689 View in Reaxys 26/189 Yield

Conditions & References With thionyl chloride, Time= 24h, Ambient temperature, Yield given. Yields of byproduct given Deutsch, Howard M.; Shi, Qing; Gruszecka-Kowalik, Ewa; Schwer, Margaret M.; Journal of Medicinal Chemistry; vol. 39; nb. 6; (1996); p. 1201 - 1209 View in Reaxys

Copyright © 2018 Reed Elsevier Properties SA. All rights reserved. Authorized use only. Reaxys® and the Reaxys® trademark are owned and protected by Reed Elsevier Properties SA and used under license.

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O

O

O

O

O H

H

N

Cl

O

H

HN

Rx-ID: 4916932 View in Reaxys 27/189 Yield

Conditions & References With hydrogenchloride in methanol, Ambient temperature, Yield given Thai, Dung L.; Sapko, Michael T.; Reiter, Clara T.; Bierer, Donald E.; Perel, James M.; Journal of Medicinal Chemistry; vol. 41; nb. 4; (1998); p. 591 - 601 View in Reaxys

O

O

O H

O

H

O

H N

O

Cl

HN

H

Rx-ID: 4916933 View in Reaxys 28/189 Yield

Conditions & References With hydrogenchloride in methanol, Ambient temperature, Yield given Thai, Dung L.; Sapko, Michael T.; Reiter, Clara T.; Bierer, Donald E.; Perel, James M.; Journal of Medicinal Chemistry; vol. 41; nb. 4; (1998); p. 591 - 601 View in Reaxys

O

O

O H

O

H

H N

O

HN

O Cl

H

Rx-ID: 4916934 View in Reaxys 29/189 Yield

Conditions & References With hydrogenchloride in methanol, Ambient temperature, Yield given Thai, Dung L.; Sapko, Michael T.; Reiter, Clara T.; Bierer, Donald E.; Perel, James M.; Journal of Medicinal Chemistry; vol. 41; nb. 4; (1998); p. 591 - 601 View in Reaxys

Copyright © 2018 Reed Elsevier Properties SA. All rights reserved. Authorized use only. Reaxys® and the Reaxys® trademark are owned and protected by Reed Elsevier Properties SA and used under license.

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O

O

O

O

O H

H

N

Cl

O

H

HN

Rx-ID: 4916935 View in Reaxys 30/189 Yield

Conditions & References With hydrogenchloride in methanol, Ambient temperature, Yield given Thai, Dung L.; Sapko, Michael T.; Reiter, Clara T.; Bierer, Donald E.; Perel, James M.; Journal of Medicinal Chemistry; vol. 41; nb. 4; (1998); p. 591 - 601 View in Reaxys

H N

H

H

O

O H H

O

Cl

O

H

Cl

HN

H

Rx-ID: 4951207 View in Reaxys 31/189 Yield

Conditions & References Prashad, Mahavir; Har, Denis; Repic, Oljan; Blacklock, Thomas J.; Giannousis, Peter; Tetrahedron Asymmetry; vol. 9; nb. 12; (1998); p. 2133 - 2136 View in Reaxys

O

O

H N

H N

H

H

O

H N

H

H

O

O H N

O

H

O

O

O

H

O HN

Rx-ID: 4992029 View in Reaxys 32/189 Yield

Conditions & References Title compound not separated from byproducts Schleuder; Duerrbeck; Jira; Pharmazie; vol. 53; nb. 6; (1998); p. 381 - 386 View in Reaxys

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O H H

H

HO

O Cl

HN

H

N O

Rx-ID: 5085409 View in Reaxys 33/189 Yield

Conditions & References

100 %

With hydrogenchloride Axten, Jeffrey M.; Krim, Lori; Kung, Hank F.; Winkler, Jeffrey D.; Journal of Organic Chemistry; vol. 63; nb. 26; (1998); p. 9628 - 9629 View in Reaxys

H N

N O

N

H

H

H

O

H O

Cl

H

HN

N

O

O

O

O Cl

H

O

Rx-ID: 5199700 View in Reaxys 34/189 Yield

Conditions & References With Rh2(5R-MEPY)4, 1.) 50 deg C, Multistep reaction. Title compound not separated from byproducts Axten, Jeffrey M.; Ivy, Robert; Krim, Lori; Winkler, Jeffrey D.; Journal of the American Chemical Society; vol. 121; nb. 27; (1999); p. 6511 - 6512 View in Reaxys

O

O

O

O

O H N

H O

HN

Rx-ID: 5222492 View in Reaxys 35/189 Yield

Conditions & References With trifluoroacetic acid Davies, Huw M. L.; Hansen, Tore; Hopper, Darrin W.; Panaro, Stephen A.; Journal of the American Chemical Society; vol. 121; nb. 27; (1999); p. 6509 - 6510 View in Reaxys

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O O

O

H

O

H

O

H N

O

HN

Rx-ID: 5222493 View in Reaxys 36/189 Yield

Conditions & References With trifluoroacetic acid Davies, Huw M. L.; Hansen, Tore; Hopper, Darrin W.; Panaro, Stephen A.; Journal of the American Chemical Society; vol. 121; nb. 27; (1999); p. 6509 - 6510 View in Reaxys

O

O

O

O

O H

H

N

O

HN

Rx-ID: 5222494 View in Reaxys 37/189 Yield

Conditions & References With trifluoroacetic acid Davies, Huw M. L.; Hansen, Tore; Hopper, Darrin W.; Panaro, Stephen A.; Journal of the American Chemical Society; vol. 121; nb. 27; (1999); p. 6509 - 6510 View in Reaxys 11CH

O

O H N H 11 3 C

3

OH

I

O

H N

Rx-ID: 5245804 View in Reaxys 38/189 Yield

Conditions & References With aluminum oxide, potassium fluoride in acetonitrile, Time= 0.0833333h, T= 85 °C , Methylation Adam; Jivan; Huser; Lu; Journal of Labelled Compounds and Radiopharmaceuticals; vol. 42; nb. SUPPL. 1; (1999); p. S445S447 View in Reaxys

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HN H

O O

O

O

HO

H

N

HN

O

Rx-ID: 5256977 View in Reaxys 39/189 Yield

Conditions & References

85 %

With LnI3 in tetrahydrofuran, Time= 16h, T= 20 °C , methanolysis Prashad, Mahavir; Liu, Yugang; Kim, Hong-Yong; Repic, Oljan; Blacklock, Thomas J.; Tetrahedron Asymmetry; vol. 10; nb. 18; (1999); p. 3479 - 3482 View in Reaxys

H N

H

H

O

O

H H O

Cl

O

H

HN

Rx-ID: 5284725 View in Reaxys 40/189 Yield

Conditions & References salt with O,O'-dibenzoyl-L-(-)-tartaric acid in the presence of 4-methylmorpholine, enantioselective resolution Prashad, Mahavir; Har, Denis; Repic, Oljan; Blacklock, Thomas J.; Giannousis, Peter; Tetrahedron Asymmetry; vol. 10; nb. 16; (1999); p. 3111 - 3116 View in Reaxys

H N

H

H

O

O

H H O

Cl

O

H

HN

Rx-ID: 5284726 View in Reaxys 41/189 Yield

Conditions & References salt with O,O'-dibenzoyl-D-(+)-tartaric acid in the presence of 4-methylmorpholine, enantioselective resolution Prashad, Mahavir; Har, Denis; Repic, Oljan; Blacklock, Thomas J.; Giannousis, Peter; Tetrahedron Asymmetry; vol. 10; nb. 16; (1999); p. 3111 - 3116 View in Reaxys

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O H H

(+)(R)-phenyl-<(S)-<2>piperidyl>-acetic acid amide

O Cl

HN

H

Rx-ID: 8477849 View in Reaxys 42/189 Yield

Conditions & References With potassium hydroxide, Erwaermen des Reaktionsprodukts mit wss. HCl und anschliessend mit methanol. HCl Patent; CIBA; US2838519; (1954) View in Reaxys

O H H

(S)-phenyl-<(R)-<2>piperidyl>-acetic acid amide

O Cl

HN

H

Rx-ID: 8477850 View in Reaxys 43/189 Yield

Conditions & References With potassium hydroxide, Erwaermen des Reaktionsprodukts mit wss. HCl und anschliessend mit methanol. HCl Patent; CIBA; US2838519; (1954) View in Reaxys

O H H

(+)(R)-phenyl-<(R)-<2>piperidyl>-acetic acid

O Cl

HN

H

Rx-ID: 8477851 View in Reaxys 44/189 Yield

Conditions & References With hydrogenchloride Patent; CIBA; US2838519; (1954) View in Reaxys

O H H

(+)(S)-phenyl-<(S)-<2>piperidyl>-acetic acid

O Cl

HN

H

Rx-ID: 8477852 View in Reaxys 45/189 Yield

Conditions & References With hydrogenchloride Patent; CIBA; US2838519; (1954) View in Reaxys

Copyright © 2018 Reed Elsevier Properties SA. All rights reserved. Authorized use only. Reaxys® and the Reaxys® trademark are owned and protected by Reed Elsevier Properties SA and used under license.

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O H H

(RS)-phenyl-<(RS)-<2>piperidyl>-acetic acid

O Cl

HN

H

Rx-ID: 8477853 View in Reaxys 46/189 Yield

Conditions & References With hydrogenchloride Patent; CIBA; US2838519; (1954) View in Reaxys O H H

(RS)-phenyl-<(SR)-<2>piperidyl>-acetic acid

O Cl

HN

H

Rx-ID: 8477854 View in Reaxys 47/189 Yield

Conditions & References With hydrogenchloride Patent; CIBA; US2838519; (1954) View in Reaxys

(+-)-phenyl-<2>pyridyl-acetic acid methyl ester O H H

O Cl

HN

H

(RS)-phenyl-<(RS)-<2>piperidyl>-acetic acid methyl ester

Rx-ID: 8493805 View in Reaxys 48/189 Yield

Conditions & References With acetic acid, platinum, Hydration Panizzon; Helvetica Chimica Acta; vol. 27; (1944); p. 1748,1753 View in Reaxys

(+-)-phenyl-<2>pyridyl-acetic acid methyl ester O H H HN

O Cl

H

(RS)-phenyl-<(SR)-<2>piperidyl>-acetic acid methyl ester

Rx-ID: 8493806 View in Reaxys 49/189 Yield

Conditions & References With acetic acid, platinum, Hydration Panizzon; Helvetica Chimica Acta; vol. 27; (1944); p. 1748,1753 View in Reaxys

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O

H

H N

H

O

O H H

O O

O

O HN

O

N

Rx-ID: 8592084 View in Reaxys 50/189 Yield

Conditions & References

61 %, 22 %

With hydrogen, palladium dihydroxide in methanol, Time= 0.5h, Hydrogenolysis Dias, Luiz C.; De Piloto Fernandes, Anna Maria A.; Synthetic Communications; vol. 30; nb. 7; (2000); p. 1311 - 1318 View in Reaxys

O

O O O

H Cl N

O

O

H

HN

Rx-ID: 8647136 View in Reaxys 51/189 Yield

Conditions & References Stage 1: With trimethylsilyl iodide in dichloromethane, Time= 12h, T= 20 °C , Decarboxylation Stage 2: With hydrogenchloride in methanol, salt formation Matsumura, Yoshihiro; Kanda, Yasuhisa; Shirai, Kimihiro; Onomura, Osamu; Maki, Toshihide; Tetrahedron; vol. 56; nb. 38; (2000); p. 7411 - 7422 View in Reaxys

O

O

H H O O

O Cl

H

HN O

N

Rx-ID: 8647137 View in Reaxys 52/189 Yield 60 %

Conditions & References Stage 1: With trimethylsilyl iodide in dichloromethane, Time= 12h, T= 20 °C , Decarboxylation Stage 2: With hydrogenchloride in methanol, salt formation Matsumura, Yoshihiro; Kanda, Yasuhisa; Shirai, Kimihiro; Onomura, Osamu; Maki, Toshihide; Tetrahedron; vol. 56; nb. 38; (2000); p. 7411 - 7422 View in Reaxys

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18O

18OH

18O

H N N

18O

H N

N

Rx-ID: 8664566 View in Reaxys 53/189 Yield

Conditions & References in methanol, diethyl ether, Methylation Leis, Hans Jrg; Fauler, Gnter; Raspotnig, Gnther; Windischhofer, Werner; Journal of Mass Spectrometry; vol. 35; nb. 9; (2000); p. 1100 - 1104 View in Reaxys H

H N

N

H N

H

O

O H

N

H

O

O HN

O O

Rx-ID: 8799653 View in Reaxys 54/189 Yield

Conditions & References With Rh2[(N-(4-dodecylphenyl)sulfonyl)-(S)-prolinate]4 Davies, Huw M.L; Ren, Pingda; Tetrahedron Letters; vol. 42; nb. 18; (2001); p. 3149 - 3151 View in Reaxys

O

O

H 2N

H N

H

H

O

O H H

O

O

HO

HN

O S O O

Rx-ID: 8864722 View in Reaxys 55/189 Yield 65 %

Conditions & References Stage 1: With hydrogenchloride, bromocresol green, sodium cyanoborohydride in methanol, pH= 6 Stage 2: With potassium hydroxide, Heating Stage 3: With thionyl chloride Deutsch, Howard M; Ye, Xiaocong; Shi, Qing; Liu, Zhanzhu; Schweri, Margaret M; European Journal of Medicinal Chemistry; vol. 36; nb. 4; (2001); p. 303 - 311 View in Reaxys

Copyright © 2018 Reed Elsevier Properties SA. All rights reserved. Authorized use only. Reaxys® and the Reaxys® trademark are owned and protected by Reed Elsevier Properties SA and used under license.

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O

O

H

H N

H 2N

H

O

O H H

O

O HN

O S O O

Rx-ID: 8911098 View in Reaxys 56/189 Yield

Conditions & References With hydrogenchloride, bromocresol green, sodium cyanoborohydride in methanol, pH= 6, Title compound not separated from byproducts Deutsch, Howard M; Ye, Xiaocong; Shi, Qing; Liu, Zhanzhu; Schweri, Margaret M; European Journal of Medicinal Chemistry; vol. 36; nb. 4; (2001); p. 303 - 311 View in Reaxys

H N

N O

N

H

H

O

O

H

O

H

O

O

HN

N

O O

Rx-ID: 9315260 View in Reaxys 57/189 Yield

Conditions & References Stage 1: With Rh2(bi-TISP)2 in hexane, T= -50 - 23 °C Stage 2: With trifluoroacetic acid in dichloromethane, Title compound not separated from byproducts Davies, Huw M. L.; Venkataramani, Chandrasekar; Hansen, Tore; Hopper, Darrin W.; Journal of the American Chemical Society; vol. 125; nb. 21; (2003); p. 6462 - 6468 View in Reaxys

O

O

O

O

H

H N HN

Rx-ID: 9350071 View in Reaxys 58/189 Yield 124 mg

Conditions & References With hydrogen, 10 wt. % palladium on activated carbon in tetrahydrofuran Davies, Huw M. L.; Venkataramani, Chandrasekar; Hansen, Tore; Hopper, Darrin W.; Journal of the American Chemical Society; vol. 125; nb. 21; (2003); p. 6462 - 6468 View in Reaxys

Copyright © 2018 Reed Elsevier Properties SA. All rights reserved. Authorized use only. Reaxys® and the Reaxys® trademark are owned and protected by Reed Elsevier Properties SA and used under license.

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H

H N O O

H

O O

O

O

O

H

O N

HN

Rx-ID: 9355984 View in Reaxys 59/189 Yield

Conditions & References With trifluoroacetic acid in dichloromethane, Time= 1h, T= 23 °C Davies, Huw M. L.; Venkataramani, Chandrasekar; Hansen, Tore; Hopper, Darrin W.; Journal of the American Chemical Society; vol. 125; nb. 21; (2003); p. 6462 - 6468 View in Reaxys

N O

N

O

N

O O

H

H N

H

H

H N

O

H

O

O H N

O

H

O

O

O

H

O HN

Rx-ID: 9590771 View in Reaxys 60/189 Yield

Conditions & References Stage 1: With Rh2[(N-(4-dodecylphenyl)sulfonyl)-(S)-prolinate]4, T= -50 °C Stage 2: With trifluoroacetic acid, Title compound not separated from byproducts Davies, Huw M. L.; Hopper, Darrin W.; Hansen, Tore; Liu, Quixu; Childers, Steven R.; Bioorganic and Medicinal Chemistry Letters; vol. 14; nb. 7; (2004); p. 1799 - 1802 View in Reaxys

H N

N O

N

H

H

O

O H

O

H

O

O HN

N

O O

Rx-ID: 9590772 View in Reaxys 61/189 Yield

Conditions & References Stage 1: With rhodium (II) octanoate dimer, Heating Stage 2: With trifluoroacetic acid Davies, Huw M. L.; Hopper, Darrin W.; Hansen, Tore; Liu, Quixu; Childers, Steven R.; Bioorganic and Medicinal Chemistry Letters; vol. 14; nb. 7; (2004); p. 1799 - 1802

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View in Reaxys

11CH

O–

O O

O

11CH

3

O

O

3

O

O

N

H 11 3 C

Na + S

H N

I

H N

N

Rx-ID: 10193936 View in Reaxys 62/189 Yield

Conditions & References Stage 1: With tetrabutyl ammonium fluoride in acetonitrile, Time= 0.0833333h, T= 80 °C Stage 2: With L-Cysteine, sulfuric acid in acetonitrile, Time= 0.05h, T= 20 °C Studenov, Andrei R.; Jivan; Lu; Adam; Jensen; O'Neil; Ding; Journal of Labelled Compounds and Radiopharmaceuticals; vol. 49; nb. 5; (2006); p. 455 - 458 View in Reaxys

O O

O

H

O

H

O

H N

OH

Cl

HN

H

Rx-ID: 11004840 View in Reaxys 63/189 Yield

Conditions & References Reaction Steps: 2 1: diethyl ether 2: HCl / methanol / Ambient temperature With hydrogenchloride in methanol, diethyl ether Thai, Dung L.; Sapko, Michael T.; Reiter, Clara T.; Bierer, Donald E.; Perel, James M.; Journal of Medicinal Chemistry; vol. 41; nb. 4; (1998); p. 591 - 601 View in Reaxys

O O H

H H

O

N

O

HN O

O

Rx-ID: 11148522 View in Reaxys 64/189 Yield 75 %

Conditions & References With trimethylsilyl iodide in dichloromethane, Time= 12h, T= 20 °C Matsumura, Yoshihiro; Kanda, Yasuhisa; Shirai, Kimihiro; Onomura, Osamu; Maki, Toshihide; Organic Letters; vol. 1; nb. 2; (1999); p. 175 - 178 View in Reaxys

Copyright © 2018 Reed Elsevier Properties SA. All rights reserved. Authorized use only. Reaxys® and the Reaxys® trademark are owned and protected by Reed Elsevier Properties SA and used under license.

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O

O

H H

O

O O

HN N

O

Rx-ID: 11148523 View in Reaxys 65/189 Yield

Conditions & References With trimethylsilyl iodide in dichloromethane, Time= 12h, T= 20 °C Matsumura, Yoshihiro; Kanda, Yasuhisa; Shirai, Kimihiro; Onomura, Osamu; Maki, Toshihide; Organic Letters; vol. 1; nb. 2; (1999); p. 175 - 178 View in Reaxys

O

O

O

O

N

HN O

O

Rx-ID: 11148524 View in Reaxys 66/189 Yield

Conditions & References With trimethylsilyl iodide in dichloromethane, Time= 12h, T= 20 °C Matsumura, Yoshihiro; Kanda, Yasuhisa; Shirai, Kimihiro; Onomura, Osamu; Maki, Toshihide; Organic Letters; vol. 1; nb. 2; (1999); p. 175 - 178 View in Reaxys

O

O

S

Si O

H H

O

O

O Cl

H

HN

Rx-ID: 11657304 View in Reaxys 67/189 Yield

Conditions & References Reaction Steps: 10 1.1: 73 percent / NaN3 / dimethylformamide / 80 °C 2.1: PPh3; methanol / 20 °C 2.2: 62 percent / Et3N; DMAP / CH2Cl2; methanol / 0 - 20 °C 3.1: 75 percent / Grubbs' first-generation catalyst / CH2Cl2 / Heating 4.1: 86 percent / H2 / Pd/C / 20 °C 5.1: BH3*DMS / tetrahydrofuran / 0 - 20 °C 5.2: 82 percent / ethanol / Heating 6.1: 85 percent / Et3N / tetrahydrofuran / 0 - 20 °C 7.1: 80 percent / HF*Py / tetrahydrofuran / 20 °C

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8.1: Dess-Martin periodinane; NaHCO3 / CH2Cl2 / 0 °C 9.1: sodium chlorite; NaH2PO4*2H2O; 2-methyl-2-butene / 2-methyl-propan-2-ol / 12 h / 0 - 20 °C 10.1: 70 percent / HCl / 50 °C With hydrogenchloride, methanol, sodium chlorite, sodium dihydrogenphosphate, sodium azide, 2-methyl-but-2-ene, dimethylsulfide borane complex, hydrogen, sodium hydrogencarbonate, Dess-Martin periodane, pyridine hydrogenfluoride, triethylamine, triphenylphosphine, 10 wt. % palladium on activated carbon, bis(tricyclohexylphosphine)benzylidene ruthenium(IV) dichloride in tetrahydrofuran, dichloromethane, N,N-dimethyl-formamide, tert-butyl alcohol, 2.1: Staudinger reaction Krishna, Palakodety Radha; Lopinti, Krishnarao; Synlett; nb. 11; (2007); p. 1742 - 1744 View in Reaxys

O

N N

Si N

H H

O

O Cl

H

HN

Rx-ID: 11657312 View in Reaxys 68/189 Yield

Conditions & References Reaction Steps: 9 1.1: PPh3; methanol / 20 °C 1.2: 62 percent / Et3N; DMAP / CH2Cl2; methanol / 0 - 20 °C 2.1: 75 percent / Grubbs' first-generation catalyst / CH2Cl2 / Heating 3.1: 86 percent / H2 / Pd/C / 20 °C 4.1: BH3*DMS / tetrahydrofuran / 0 - 20 °C 4.2: 82 percent / ethanol / Heating 5.1: 85 percent / Et3N / tetrahydrofuran / 0 - 20 °C 6.1: 80 percent / HF*Py / tetrahydrofuran / 20 °C 7.1: Dess-Martin periodinane; NaHCO3 / CH2Cl2 / 0 °C 8.1: sodium chlorite; NaH2PO4*2H2O; 2-methyl-2-butene / 2-methyl-propan-2-ol / 12 h / 0 - 20 °C 9.1: 70 percent / HCl / 50 °C With hydrogenchloride, methanol, sodium chlorite, sodium dihydrogenphosphate, 2-methyl-but-2-ene, dimethylsulfide borane complex, hydrogen, sodium hydrogencarbonate, Dess-Martin periodane, pyridine hydrogenfluoride, triethylamine, triphenylphosphine, 10 wt. % palladium on activated carbon, bis(tricyclohexylphosphine)benzylidene ruthenium(IV) dichloride in tetrahydrofuran, dichloromethane, tert-butyl alcohol, 1.1: Staudinger reaction Krishna, Palakodety Radha; Lopinti, Krishnarao; Synlett; nb. 11; (2007); p. 1742 - 1744 View in Reaxys

O

O

Si NH

H H

O

O Cl

H

HN

Rx-ID: 11657319 View in Reaxys 69/189

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Yield

Conditions & References Reaction Steps: 8 1.1: 75 percent / Grubbs' first-generation catalyst / CH2Cl2 / Heating 2.1: 86 percent / H2 / Pd/C / 20 °C 3.1: BH3*DMS / tetrahydrofuran / 0 - 20 °C 3.2: 82 percent / ethanol / Heating 4.1: 85 percent / Et3N / tetrahydrofuran / 0 - 20 °C 5.1: 80 percent / HF*Py / tetrahydrofuran / 20 °C 6.1: Dess-Martin periodinane; NaHCO3 / CH2Cl2 / 0 °C 7.1: sodium chlorite; NaH2PO4*2H2O; 2-methyl-2-butene / 2-methyl-propan-2-ol / 12 h / 0 - 20 °C 8.1: 70 percent / HCl / 50 °C With hydrogenchloride, sodium chlorite, sodium dihydrogenphosphate, 2-methyl-but-2-ene, dimethylsulfide borane complex, hydrogen, sodium hydrogencarbonate, Dess-Martin periodane, pyridine hydrogenfluoride, triethylamine, 10 wt. % palladium on activated carbon, bis(tricyclohexylphosphine)benzylidene ruthenium(IV) dichloride in tetrahydrofuran, dichloromethane, tertbutyl alcohol Krishna, Palakodety Radha; Lopinti, Krishnarao; Synlett; nb. 11; (2007); p. 1742 - 1744 View in Reaxys

O

O

Si NH

H H

O

O Cl

H

HN

Rx-ID: 11657325 View in Reaxys 70/189 Yield

Conditions & References Reaction Steps: 7 1.1: 86 percent / H2 / Pd/C / 20 °C 2.1: BH3*DMS / tetrahydrofuran / 0 - 20 °C 2.2: 82 percent / ethanol / Heating 3.1: 85 percent / Et3N / tetrahydrofuran / 0 - 20 °C 4.1: 80 percent / HF*Py / tetrahydrofuran / 20 °C 5.1: Dess-Martin periodinane; NaHCO3 / CH2Cl2 / 0 °C 6.1: sodium chlorite; NaH2PO4*2H2O; 2-methyl-2-butene / 2-methyl-propan-2-ol / 12 h / 0 - 20 °C 7.1: 70 percent / HCl / 50 °C With hydrogenchloride, sodium chlorite, sodium dihydrogenphosphate, 2-methyl-but-2-ene, dimethylsulfide borane complex, hydrogen, sodium hydrogencarbonate, Dess-Martin periodane, pyridine hydrogenfluoride, triethylamine, 10 wt. % palladium on activated carbon in tetrahydrofuran, dichloromethane, tert-butyl alcohol Krishna, Palakodety Radha; Lopinti, Krishnarao; Synlett; nb. 11; (2007); p. 1742 - 1744 View in Reaxys

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O

O

Si NH

H H

O

O Cl

H

HN

Rx-ID: 11657330 View in Reaxys 71/189 Yield

Conditions & References Reaction Steps: 6 1.1: BH3*DMS / tetrahydrofuran / 0 - 20 °C 1.2: 82 percent / ethanol / Heating 2.1: 85 percent / Et3N / tetrahydrofuran / 0 - 20 °C 3.1: 80 percent / HF*Py / tetrahydrofuran / 20 °C 4.1: Dess-Martin periodinane; NaHCO3 / CH2Cl2 / 0 °C 5.1: sodium chlorite; NaH2PO4*2H2O; 2-methyl-2-butene / 2-methyl-propan-2-ol / 12 h / 0 - 20 °C 6.1: 70 percent / HCl / 50 °C With hydrogenchloride, sodium chlorite, sodium dihydrogenphosphate, 2-methyl-but-2-ene, dimethylsulfide borane complex, sodium hydrogencarbonate, Dess-Martin periodane, pyridine hydrogenfluoride, triethylamine in tetrahydrofuran, dichloromethane, tert-butyl alcohol Krishna, Palakodety Radha; Lopinti, Krishnarao; Synlett; nb. 11; (2007); p. 1742 - 1744 View in Reaxys

O

Si NH

H H

O

O Cl

H

HN

Rx-ID: 11657334 View in Reaxys 72/189 Yield

Conditions & References Reaction Steps: 5 1: 85 percent / Et3N / tetrahydrofuran / 0 - 20 °C 2: 80 percent / HF*Py / tetrahydrofuran / 20 °C 3: Dess-Martin periodinane; NaHCO3 / CH2Cl2 / 0 °C 4: sodium chlorite; NaH2PO4*2H2O; 2-methyl-2-butene / 2-methyl-propan-2-ol / 12 h / 0 - 20 °C 5: 70 percent / HCl / 50 °C With hydrogenchloride, sodium chlorite, sodium dihydrogenphosphate, 2-methyl-but-2-ene, sodium hydrogencarbonate, DessMartin periodane, pyridine hydrogenfluoride, triethylamine in tetrahydrofuran, dichloromethane, tert-butyl alcohol Krishna, Palakodety Radha; Lopinti, Krishnarao; Synlett; nb. 11; (2007); p. 1742 - 1744 View in Reaxys

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O O H

O

N

H

O

Si

Cl

HN

H

O

Rx-ID: 11657338 View in Reaxys 73/189 Yield

Conditions & References Reaction Steps: 4 1: 80 percent / HF*Py / tetrahydrofuran / 20 °C 2: Dess-Martin periodinane; NaHCO3 / CH2Cl2 / 0 °C 3: sodium chlorite; NaH2PO4*2H2O; 2-methyl-2-butene / 2-methyl-propan-2-ol / 12 h / 0 - 20 °C 4: 70 percent / HCl / 50 °C With hydrogenchloride, sodium chlorite, sodium dihydrogenphosphate, 2-methyl-but-2-ene, sodium hydrogencarbonate, DessMartin periodane, pyridine hydrogenfluoride in tetrahydrofuran, dichloromethane, tert-butyl alcohol Krishna, Palakodety Radha; Lopinti, Krishnarao; Synlett; nb. 11; (2007); p. 1742 - 1744 View in Reaxys

O O

N

H

O

H

O Cl

HN

O

H

Rx-ID: 11657340 View in Reaxys 74/189 Yield

Conditions & References Reaction Steps: 2 1: sodium chlorite; NaH2PO4*2H2O; 2-methyl-2-butene / 2-methyl-propan-2-ol / 12 h / 0 - 20 °C 2: 70 percent / HCl / 50 °C With hydrogenchloride, sodium chlorite, sodium dihydrogenphosphate, 2-methyl-but-2-ene in tert-butyl alcohol Krishna, Palakodety Radha; Lopinti, Krishnarao; Synlett; nb. 11; (2007); p. 1742 - 1744 View in Reaxys

O H

OH

H

O

HO

HN

Cl

H

Rx-ID: 11657349 View in Reaxys 75/189 Yield

Conditions & References Reaction Steps: 12 1.1: 95 percent / imidazole / CH2Cl2 / 20 °C 2.1: 87 percent / Et3N / CH2Cl2 / 0 - 20 °C

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3.1: 73 percent / NaN3 / dimethylformamide / 80 °C 4.1: PPh3; methanol / 20 °C 4.2: 62 percent / Et3N; DMAP / CH2Cl2; methanol / 0 - 20 °C 5.1: 75 percent / Grubbs' first-generation catalyst / CH2Cl2 / Heating 6.1: 86 percent / H2 / Pd/C / 20 °C 7.1: BH3*DMS / tetrahydrofuran / 0 - 20 °C 7.2: 82 percent / ethanol / Heating 8.1: 85 percent / Et3N / tetrahydrofuran / 0 - 20 °C 9.1: 80 percent / HF*Py / tetrahydrofuran / 20 °C 10.1: Dess-Martin periodinane; NaHCO3 / CH2Cl2 / 0 °C 11.1: sodium chlorite; NaH2PO4*2H2O; 2-methyl-2-butene / 2-methyl-propan-2-ol / 12 h / 0 - 20 °C 12.1: 70 percent / HCl / 50 °C With 1H-imidazole, hydrogenchloride, methanol, sodium chlorite, sodium dihydrogenphosphate, sodium azide, 2-methyl-but-2ene, dimethylsulfide borane complex, hydrogen, sodium hydrogencarbonate, Dess-Martin periodane, pyridine hydrogenfluoride, triethylamine, triphenylphosphine, 10 wt. % palladium on activated carbon, bis(tricyclohexylphosphine)benzylidene ruthenium(IV) dichloride in tetrahydrofuran, dichloromethane, N,N-dimethyl-formamide, tert-butyl alcohol, 4.1: Staudinger reaction Krishna, Palakodety Radha; Lopinti, Krishnarao; Synlett; nb. 11; (2007); p. 1742 - 1744 View in Reaxys

O

Si OH

H H

O

O Cl

H

HN

Rx-ID: 11657359 View in Reaxys 76/189 Yield

Conditions & References Reaction Steps: 11 1.1: 87 percent / Et3N / CH2Cl2 / 0 - 20 °C 2.1: 73 percent / NaN3 / dimethylformamide / 80 °C 3.1: PPh3; methanol / 20 °C 3.2: 62 percent / Et3N; DMAP / CH2Cl2; methanol / 0 - 20 °C 4.1: 75 percent / Grubbs' first-generation catalyst / CH2Cl2 / Heating 5.1: 86 percent / H2 / Pd/C / 20 °C 6.1: BH3*DMS / tetrahydrofuran / 0 - 20 °C 6.2: 82 percent / ethanol / Heating 7.1: 85 percent / Et3N / tetrahydrofuran / 0 - 20 °C 8.1: 80 percent / HF*Py / tetrahydrofuran / 20 °C 9.1: Dess-Martin periodinane; NaHCO3 / CH2Cl2 / 0 °C 10.1: sodium chlorite; NaH2PO4*2H2O; 2-methyl-2-butene / 2-methyl-propan-2-ol / 12 h / 0 - 20 °C 11.1: 70 percent / HCl / 50 °C With hydrogenchloride, methanol, sodium chlorite, sodium dihydrogenphosphate, sodium azide, 2-methyl-but-2-ene, dimethylsulfide borane complex, hydrogen, sodium hydrogencarbonate, Dess-Martin periodane, pyridine hydrogenfluoride, triethylamine, triphenylphosphine, 10 wt. % palladium on activated carbon, bis(tricyclohexylphosphine)benzylidene ruthenium(IV) dichloride in tetrahydrofuran, dichloromethane, N,N-dimethyl-formamide, tert-butyl alcohol, 3.1: Staudinger reaction Krishna, Palakodety Radha; Lopinti, Krishnarao; Synlett; nb. 11; (2007); p. 1742 - 1744 View in Reaxys

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O

N

H

N

H

O

HN

O O

Rx-ID: 14212537 View in Reaxys 77/189 Yield

Conditions & References Reaction Steps: 2 1: Rh2(S-DOSP)4 / hexane / -50 - 23 °C 2: TFA / CH2Cl2 / 1 h / 23 °C With Rh2[(N-(4-dodecylphenyl)sulfonyl)-(S)-prolinate]4, trifluoroacetic acid in hexane, dichloromethane Davies, Huw M. L.; Venkataramani, Chandrasekar; Hansen, Tore; Hopper, Darrin W.; Journal of the American Chemical Society; vol. 125; nb. 21; (2003); p. 6462 - 6468 View in Reaxys

O O

H

O

H

O

HN

N

Rx-ID: 14214463 View in Reaxys 78/189 Yield

Conditions & References Reaction Steps: 2 1: Rh2(S-DOSP)4 / hexane / -50 - 23 °C 2: TFA / CH2Cl2 / 1 h / 23 °C With Rh2[(N-(4-dodecylphenyl)sulfonyl)-(S)-prolinate]4, trifluoroacetic acid in hexane, dichloromethane Davies, Huw M. L.; Venkataramani, Chandrasekar; Hansen, Tore; Hopper, Darrin W.; Journal of the American Chemical Society; vol. 125; nb. 21; (2003); p. 6462 - 6468 View in Reaxys

O O

O

O

H N

HN

Rx-ID: 14218788 View in Reaxys 79/189 Yield

Conditions & References Reaction Steps: 3 1: Rh2(S-DOSP)4 / various solvent(s) / 0.5 h 2: TFA / CH2Cl2 / 2 h 3: 124 mg / H2 / 10 percent Pd/C / tetrahydrofuran With Rh2[(N-(4-dodecylphenyl)sulfonyl)-(S)-prolinate]4, hydrogen, trifluoroacetic acid, 10 wt. % palladium on activated carbon in tetrahydrofuran, dichloromethane Davies, Huw M. L.; Venkataramani, Chandrasekar; Hansen, Tore; Hopper, Darrin W.; Journal of the American Chemical Society; vol. 125; nb. 21; (2003); p. 6462 - 6468

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View in Reaxys

O O

O

O

O

O

H N

HN

Rx-ID: 14233319 View in Reaxys 80/189 Yield

Conditions & References Reaction Steps: 2 1: TFA / CH2Cl2 / 2 h 2: 124 mg / H2 / 10 percent Pd/C / tetrahydrofuran With hydrogen, trifluoroacetic acid, 10 wt. % palladium on activated carbon in tetrahydrofuran, dichloromethane Davies, Huw M. L.; Venkataramani, Chandrasekar; Hansen, Tore; Hopper, Darrin W.; Journal of the American Chemical Society; vol. 125; nb. 21; (2003); p. 6462 - 6468 View in Reaxys O H H

O

OH

HN N

Rx-ID: 15255929 View in Reaxys 81/189 Yield

Conditions & References Reaction Steps: 3 1.1: Et3N / CH2Cl2 2.1: zinc / tetrahydrofuran / Heating 2.2: 79 percent / tetrahydrofuran / Heating 3.1: NaBH3CN; HCl; bromocresol green / methanol / pH 6 3.2: aq. KOH / Heating 3.3: 65 percent / SOCl2 With hydrogenchloride, bromocresol green, sodium cyanoborohydride, triethylamine, zinc in tetrahydrofuran, methanol, dichloromethane, 2.1: modified Blaise reaction Deutsch, Howard M; Ye, Xiaocong; Shi, Qing; Liu, Zhanzhu; Schweri, Margaret M; European Journal of Medicinal Chemistry; vol. 36; nb. 4; (2001); p. 303 - 311 View in Reaxys Reaction Steps: 3 1.1: Et3N / CH2Cl2 2.1: zinc / tetrahydrofuran / Heating 2.2: 79 percent / tetrahydrofuran / Heating 3.1: NaBH3CN; HCl; bromocresol green / methanol / pH 6 With hydrogenchloride, bromocresol green, sodium cyanoborohydride, triethylamine, zinc in tetrahydrofuran, methanol, dichloromethane, 2.1: modified Blaise reaction Deutsch, Howard M; Ye, Xiaocong; Shi, Qing; Liu, Zhanzhu; Schweri, Margaret M; European Journal of Medicinal Chemistry; vol. 36; nb. 4; (2001); p. 303 - 311 View in Reaxys

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O H H

O

OH HN N

Rx-ID: 15255930 View in Reaxys 82/189 Yield

Conditions & References Reaction Steps: 3 1.1: Et3N / CH2Cl2 2.1: zinc / tetrahydrofuran / Heating 2.2: 79 percent / tetrahydrofuran / Heating 3.1: NaBH3CN; HCl; bromocresol green / methanol / pH 6 3.2: aq. KOH / Heating 3.3: SOCl2 With hydrogenchloride, bromocresol green, sodium cyanoborohydride, triethylamine, zinc in tetrahydrofuran, methanol, dichloromethane, 2.1: modified Blaise reaction Deutsch, Howard M; Ye, Xiaocong; Shi, Qing; Liu, Zhanzhu; Schweri, Margaret M; European Journal of Medicinal Chemistry; vol. 36; nb. 4; (2001); p. 303 - 311 View in Reaxys Reaction Steps: 3 1.1: Et3N / CH2Cl2 2.1: zinc / tetrahydrofuran / Heating 2.2: 79 percent / tetrahydrofuran / Heating 3.1: NaBH3CN; HCl; bromocresol green / methanol / pH 6 With hydrogenchloride, bromocresol green, sodium cyanoborohydride, triethylamine, zinc in tetrahydrofuran, methanol, dichloromethane, 2.1: modified Blaise reaction Deutsch, Howard M; Ye, Xiaocong; Shi, Qing; Liu, Zhanzhu; Schweri, Margaret M; European Journal of Medicinal Chemistry; vol. 36; nb. 4; (2001); p. 303 - 311 View in Reaxys O H

O

H

O

S N

O

O

HN

Rx-ID: 15274962 View in Reaxys 83/189 Yield

Conditions & References Reaction Steps: 2 1.1: zinc / tetrahydrofuran / Heating 1.2: 79 percent / tetrahydrofuran / Heating 2.1: NaBH3CN; HCl; bromocresol green / methanol / pH 6 2.2: aq. KOH / Heating 2.3: 65 percent / SOCl2 With hydrogenchloride, bromocresol green, sodium cyanoborohydride, zinc in tetrahydrofuran, methanol, 1.1: modified Blaise reaction Deutsch, Howard M; Ye, Xiaocong; Shi, Qing; Liu, Zhanzhu; Schweri, Margaret M; European Journal of Medicinal Chemistry; vol. 36; nb. 4; (2001); p. 303 - 311 View in Reaxys Reaction Steps: 2 1.1: zinc / tetrahydrofuran / Heating 1.2: 79 percent / tetrahydrofuran / Heating 2.1: NaBH3CN; HCl; bromocresol green / methanol / pH 6

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With hydrogenchloride, bromocresol green, sodium cyanoborohydride, zinc in tetrahydrofuran, methanol, 1.1: modified Blaise reaction Deutsch, Howard M; Ye, Xiaocong; Shi, Qing; Liu, Zhanzhu; Schweri, Margaret M; European Journal of Medicinal Chemistry; vol. 36; nb. 4; (2001); p. 303 - 311 View in Reaxys O H

O

H

O

S N

O

O

HN

Rx-ID: 15274963 View in Reaxys 84/189 Yield

Conditions & References Reaction Steps: 2 1.1: zinc / tetrahydrofuran / Heating 1.2: 79 percent / tetrahydrofuran / Heating 2.1: NaBH3CN; HCl; bromocresol green / methanol / pH 6 2.2: aq. KOH / Heating 2.3: SOCl2 With hydrogenchloride, bromocresol green, sodium cyanoborohydride, zinc in tetrahydrofuran, methanol, 1.1: modified Blaise reaction Deutsch, Howard M; Ye, Xiaocong; Shi, Qing; Liu, Zhanzhu; Schweri, Margaret M; European Journal of Medicinal Chemistry; vol. 36; nb. 4; (2001); p. 303 - 311 View in Reaxys Reaction Steps: 2 1.1: zinc / tetrahydrofuran / Heating 1.2: 79 percent / tetrahydrofuran / Heating 2.1: NaBH3CN; HCl; bromocresol green / methanol / pH 6 With hydrogenchloride, bromocresol green, sodium cyanoborohydride, zinc in tetrahydrofuran, methanol, 1.1: modified Blaise reaction Deutsch, Howard M; Ye, Xiaocong; Shi, Qing; Liu, Zhanzhu; Schweri, Margaret M; European Journal of Medicinal Chemistry; vol. 36; nb. 4; (2001); p. 303 - 311 View in Reaxys

O H H

2-alkoxy-2-phenyl-1,3-dioxalane

O

HN

O Si O

Rx-ID: 15872497 View in Reaxys 85/189 Yield

Conditions & References Reaction Steps: 2 1: 90 percent / TESOTf / CH2Cl2 / 1.5 h / 0 - 20 °C 2: 61 percent / H2 / Pd(OH)2/C / methanol / 0.5 h With hydrogen, triethylsilyl trifluoromethyl sulfonate, palladium dihydroxide in methanol, dichloromethane, 1: Condensation / 2: Hydrogenolysis Dias, Luiz C.; De Piloto Fernandes, Anna Maria A.; Synthetic Communications; vol. 30; nb. 7; (2000); p. 1311 - 1318 View in Reaxys

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O H H

2-alkoxy-2-phenyl-1,3-dioxalane

O

HN

O Si O

Rx-ID: 15872498 View in Reaxys 86/189 Yield

Conditions & References Reaction Steps: 2 1: 90 percent / TESOTf / CH2Cl2 / 1.5 h / 0 - 20 °C 2: 22 percent / H2 / Pd(OH)2/C / methanol / 0.5 h With hydrogen, triethylsilyl trifluoromethyl sulfonate, palladium dihydroxide in methanol, dichloromethane, 1: Condensation / 2: Hydrogenolysis Dias, Luiz C.; De Piloto Fernandes, Anna Maria A.; Synthetic Communications; vol. 30; nb. 7; (2000); p. 1311 - 1318 View in Reaxys

O H H O

O

O

HN N

O

Rx-ID: 15882110 View in Reaxys 87/189 Yield

Conditions & References Reaction Steps: 2 1: 90 percent / TESOTf / CH2Cl2 / 1.5 h / 0 - 20 °C 2: 61 percent / H2 / Pd(OH)2/C / methanol / 0.5 h With hydrogen, triethylsilyl trifluoromethyl sulfonate, palladium dihydroxide in methanol, dichloromethane, 1: Condensation / 2: Hydrogenolysis Dias, Luiz C.; De Piloto Fernandes, Anna Maria A.; Synthetic Communications; vol. 30; nb. 7; (2000); p. 1311 - 1318 View in Reaxys

O H H O

O

O

HN N

O

Rx-ID: 15882111 View in Reaxys 88/189 Yield

Conditions & References Reaction Steps: 2 1: 90 percent / TESOTf / CH2Cl2 / 1.5 h / 0 - 20 °C 2: 22 percent / H2 / Pd(OH)2/C / methanol / 0.5 h With hydrogen, triethylsilyl trifluoromethyl sulfonate, palladium dihydroxide in methanol, dichloromethane, 1: Condensation / 2: Hydrogenolysis

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Dias, Luiz C.; De Piloto Fernandes, Anna Maria A.; Synthetic Communications; vol. 30; nb. 7; (2000); p. 1311 - 1318 View in Reaxys

O

HO

H

N-BOC-(L)-3,4-dimethoxyphenylalanine on Merrifield resin

O

O

HN

Rx-ID: 16077004 View in Reaxys 89/189 Yield

Conditions & References Reaction Steps: 6 1: 85 percent / t-BuCOCl; Et3N / toluene / 12 h / 80 °C 2: LiHMDS / tetrahydrofuran / 1 h / 0 °C 3: trifluoroacetic acid / CH2Cl2 / 4 h / 0 - 20 °C 4: aq. NaHCO3 5: H2; 10 percent Pd/C / ethyl acetate / 24 h / 20 °C 6: 85 percent / LnI3 / tetrahydrofuran / 16 h / 20 °C With 10 wt. % palladium on activated carbon, hydrogen, pivaloyl chloride, sodium hydrogencarbonate, triethylamine, trifluoroacetic acid, lithium hexamethyldisilazane in tetrahydrofuran, dichloromethane, ethyl acetate, toluene, 1: Acylation / 2: Acylation / 3: deprotection / 4: Cyclization / 5: Hydrogenation / 6: methanolysis Prashad, Mahavir; Liu, Yugang; Kim, Hong-Yong; Repic, Oljan; Blacklock, Thomas J.; Tetrahedron Asymmetry; vol. 10; nb. 18; (1999); p. 3479 - 3482 View in Reaxys

O

O O

O

H N H

O

HO

HN

Rx-ID: 16082117 View in Reaxys 90/189 Yield

Conditions & References Reaction Steps: 6 1: 100 percent / Et3N / toluene / 4 h / 20 °C 2: LiHMDS / tetrahydrofuran / 1 h / 0 °C 3: trifluoroacetic acid / CH2Cl2 / 4 h / 0 - 20 °C 4: aq. NaHCO3 5: H2; 10 percent Pd/C / ethyl acetate / 24 h / 20 °C 6: 85 percent / LnI3 / tetrahydrofuran / 16 h / 20 °C With 10 wt. % palladium on activated carbon, hydrogen, sodium hydrogencarbonate, triethylamine, trifluoroacetic acid, lithium hexamethyldisilazane in tetrahydrofuran, dichloromethane, ethyl acetate, toluene, 1: Acylation / 2: Acylation / 3: deprotection / 4: Cyclization / 5: Hydrogenation / 6: methanolysis Prashad, Mahavir; Liu, Yugang; Kim, Hong-Yong; Repic, Oljan; Blacklock, Thomas J.; Tetrahedron Asymmetry; vol. 10; nb. 18; (1999); p. 3479 - 3482 View in Reaxys

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O

O

H

O

HN

N O O

Rx-ID: 16086493 View in Reaxys 91/189 Yield

Conditions & References Reaction Steps: 5 1: LiHMDS / tetrahydrofuran / 1 h / 0 °C 2: trifluoroacetic acid / CH2Cl2 / 4 h / 0 - 20 °C 3: aq. NaHCO3 4: H2; 10 percent Pd/C / ethyl acetate / 24 h / 20 °C 5: 85 percent / LnI3 / tetrahydrofuran / 16 h / 20 °C With 10 wt. % palladium on activated carbon, hydrogen, sodium hydrogencarbonate, trifluoroacetic acid, lithium hexamethyldisilazane in tetrahydrofuran, dichloromethane, ethyl acetate, 1: Acylation / 2: deprotection / 3: Cyclization / 4: Hydrogenation / 5: methanolysis Prashad, Mahavir; Liu, Yugang; Kim, Hong-Yong; Repic, Oljan; Blacklock, Thomas J.; Tetrahedron Asymmetry; vol. 10; nb. 18; (1999); p. 3479 - 3482 View in Reaxys

O

O

O H N

O

H O

O

HN

O

Rx-ID: 16093230 View in Reaxys 92/189 Yield

Conditions & References Reaction Steps: 5 1: LiHMDS / tetrahydrofuran / 1 h / 0 °C 2: trifluoroacetic acid / CH2Cl2 / 4 h / 0 - 20 °C 3: aq. NaHCO3 4: H2; 10 percent Pd/C / ethyl acetate / 24 h / 20 °C 5: 85 percent / LnI3 / tetrahydrofuran / 16 h / 20 °C With 10 wt. % palladium on activated carbon, hydrogen, sodium hydrogencarbonate, trifluoroacetic acid, lithium hexamethyldisilazane in tetrahydrofuran, dichloromethane, ethyl acetate, 1: Acylation / 2: deprotection / 3: Cyclization / 4: Hydrogenation / 5: methanolysis Prashad, Mahavir; Liu, Yugang; Kim, Hong-Yong; Repic, Oljan; Blacklock, Thomas J.; Tetrahedron Asymmetry; vol. 10; nb. 18; (1999); p. 3479 - 3482 View in Reaxys

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O

O N

O

H

O O

HN

O

NH 2

Rx-ID: 16112633 View in Reaxys 93/189 Yield

Conditions & References Reaction Steps: 3 1: aq. NaHCO3 2: H2; 10 percent Pd/C / ethyl acetate / 24 h / 20 °C 3: 85 percent / LnI3 / tetrahydrofuran / 16 h / 20 °C With 10 wt. % palladium on activated carbon, hydrogen, sodium hydrogencarbonate in tetrahydrofuran, ethyl acetate, 1: Cyclization / 2: Hydrogenation / 3: methanolysis Prashad, Mahavir; Liu, Yugang; Kim, Hong-Yong; Repic, Oljan; Blacklock, Thomas J.; Tetrahedron Asymmetry; vol. 10; nb. 18; (1999); p. 3479 - 3482 View in Reaxys

N OH

O

N

O

O

H

O HN

Rx-ID: 16113117 View in Reaxys 94/189 Yield

Conditions & References Reaction Steps: 2 1: H2; 10 percent Pd/C / ethyl acetate / 24 h / 20 °C 2: 85 percent / LnI3 / tetrahydrofuran / 16 h / 20 °C With 10 wt. % palladium on activated carbon, hydrogen in tetrahydrofuran, ethyl acetate, 1: Hydrogenation / 2: methanolysis Prashad, Mahavir; Liu, Yugang; Kim, Hong-Yong; Repic, Oljan; Blacklock, Thomas J.; Tetrahedron Asymmetry; vol. 10; nb. 18; (1999); p. 3479 - 3482 View in Reaxys

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O

NH

O

O

O

H O O

HN N

O

O

Rx-ID: 16115387 View in Reaxys 95/189 Yield

Conditions & References Reaction Steps: 4 1: trifluoroacetic acid / CH2Cl2 / 4 h / 0 - 20 °C 2: aq. NaHCO3 3: H2; 10 percent Pd/C / ethyl acetate / 24 h / 20 °C 4: 85 percent / LnI3 / tetrahydrofuran / 16 h / 20 °C With 10 wt. % palladium on activated carbon, hydrogen, sodium hydrogencarbonate, trifluoroacetic acid in tetrahydrofuran, dichloromethane, ethyl acetate, 1: deprotection / 2: Cyclization / 3: Hydrogenation / 4: methanolysis Prashad, Mahavir; Liu, Yugang; Kim, Hong-Yong; Repic, Oljan; Blacklock, Thomas J.; Tetrahedron Asymmetry; vol. 10; nb. 18; (1999); p. 3479 - 3482 View in Reaxys

O

N

H

N

H

O

HN

O O

Rx-ID: 16217571 View in Reaxys 96/189 Yield

Conditions & References Reaction Steps: 2 1: Rh2(S-biDOSP)2 2: TFA With Rh2(S-biDOSP)2, trifluoroacetic acid Davies, Huw M. L.; Hansen, Tore; Hopper, Darrin W.; Panaro, Stephen A.; Journal of the American Chemical Society; vol. 121; nb. 27; (1999); p. 6509 - 6510 View in Reaxys

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N O

O

N H

O

HN

O

Rx-ID: 16217572 View in Reaxys 97/189 Yield

Conditions & References Reaction Steps: 2 1: Rh2(S-biDOSP)2 2: TFA With Rh2(S-biDOSP)2, trifluoroacetic acid Davies, Huw M. L.; Hansen, Tore; Hopper, Darrin W.; Panaro, Stephen A.; Journal of the American Chemical Society; vol. 121; nb. 27; (1999); p. 6509 - 6510 View in Reaxys Reaction Steps: 2 1: Rh2(S-DOSP)4 / various solvent(s) / 25 °C 2: TFA With Rh2[(N-(4-dodecylphenyl)sulfonyl)-(S)-prolinate]4, trifluoroacetic acid in various solvent(s) Davies, Huw M. L.; Hansen, Tore; Hopper, Darrin W.; Panaro, Stephen A.; Journal of the American Chemical Society; vol. 121; nb. 27; (1999); p. 6509 - 6510 View in Reaxys

O O

H

O

H

O

HN

N

Rx-ID: 16219479 View in Reaxys 98/189 Yield

Conditions & References Reaction Steps: 2 1: Rh2(S-biDOSP)2 2: TFA With Rh2(S-biDOSP)2, trifluoroacetic acid Davies, Huw M. L.; Hansen, Tore; Hopper, Darrin W.; Panaro, Stephen A.; Journal of the American Chemical Society; vol. 121; nb. 27; (1999); p. 6509 - 6510 View in Reaxys

O O

O

O

H N

HN

Rx-ID: 16219480 View in Reaxys 99/189 Yield

Conditions & References Reaction Steps: 2

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1: Rh2(S-biDOSP)2 2: TFA With Rh2(S-biDOSP)2, trifluoroacetic acid Davies, Huw M. L.; Hansen, Tore; Hopper, Darrin W.; Panaro, Stephen A.; Journal of the American Chemical Society; vol. 121; nb. 27; (1999); p. 6509 - 6510 View in Reaxys Reaction Steps: 2 1: Rh2(S-DOSP)4 / various solvent(s) / 25 °C 2: TFA With Rh2[(N-(4-dodecylphenyl)sulfonyl)-(S)-prolinate]4, trifluoroacetic acid in various solvent(s) Davies, Huw M. L.; Hansen, Tore; Hopper, Darrin W.; Panaro, Stephen A.; Journal of the American Chemical Society; vol. 121; nb. 27; (1999); p. 6509 - 6510 View in Reaxys

O HO

H H

O

N-BOC-(L)-3,4-dimethoxyphenylalanine on Merrifield resin

HN

O Cl

H

Rx-ID: 16469393 View in Reaxys 100/189 Yield

Conditions & References Reaction Steps: 9 1: 78 percent / pivaloyl chloride, triethylamine / toluene 3: 93 percent / triethylamine / toluene / 2 h / 0 °C 4: 91 percent / NaBH4 / tetrahydrofuran; H2O / 0 - 22 °C 5: 60 percent / 3 h / 85 °C 6: hydrogen / Pd/C / ethanol / 4 h / 2585.74 Torr / Ambient temperature 7: 160 mg / triethylamine / tetrahydrofuran / 19 h / 22 °C 8: 80 percent / NaIO4, RuCl3*H2O / H2O; acetonitrile; CCl4 / 2 h / 22 °C 9: 70 percent / HCl / 15 h / 50 °C With hydrogenchloride, ruthenium trichloride, sodium tetrahydroborate, sodium periodate, hydrogen, pivaloyl chloride, triethylamine, 10 wt. % palladium on activated carbon in tetrahydrofuran, tetrachloromethane, ethanol, water, toluene, acetonitrile Prashad, Mahavir; Kim, Hong-Yong; Lu, Yansong; Liu, Yugang; Har, Denis; Repic, Oljan; Blacklock, Thomas J.; Giannousis, Peter; Journal of Organic Chemistry; vol. 64; nb. 5; (1999); p. 1750 - 1753 View in Reaxys Reaction Steps: 9 1: 78 percent / pivaloyl chloride, triethylamine / toluene 3: 92 percent / pyridine / CH2Cl2 / 3 h / 0 °C 4: 91 percent / NaBH4 / tetrahydrofuran; H2O / 0 - 22 °C 5: 60 percent / 3 h / 85 °C 6: hydrogen / Pd/C / ethanol / 4 h / 2585.74 Torr / Ambient temperature 7: 160 mg / triethylamine / tetrahydrofuran / 19 h / 22 °C 8: 80 percent / NaIO4, RuCl3*H2O / H2O; acetonitrile; CCl4 / 2 h / 22 °C 9: 70 percent / HCl / 15 h / 50 °C With pyridine, hydrogenchloride, ruthenium trichloride, sodium tetrahydroborate, sodium periodate, hydrogen, pivaloyl chloride, triethylamine, 10 wt. % palladium on activated carbon in tetrahydrofuran, tetrachloromethane, ethanol, dichloromethane, water, toluene, acetonitrile Prashad, Mahavir; Kim, Hong-Yong; Lu, Yansong; Liu, Yugang; Har, Denis; Repic, Oljan; Blacklock, Thomas J.; Giannousis, Peter; Journal of Organic Chemistry; vol. 64; nb. 5; (1999); p. 1750 - 1753 View in Reaxys

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O H

O

H

O

N O

Cl

HN

H

O

Rx-ID: 16486974 View in Reaxys 101/189 Yield

Conditions & References Reaction Steps: 8 2: 93 percent / triethylamine / toluene / 2 h / 0 °C 3: 91 percent / NaBH4 / tetrahydrofuran; H2O / 0 - 22 °C 4: 60 percent / 3 h / 85 °C 5: hydrogen / Pd/C / ethanol / 4 h / 2585.74 Torr / Ambient temperature 6: 160 mg / triethylamine / tetrahydrofuran / 19 h / 22 °C 7: 80 percent / NaIO4, RuCl3*H2O / H2O; acetonitrile; CCl4 / 2 h / 22 °C 8: 70 percent / HCl / 15 h / 50 °C With hydrogenchloride, ruthenium trichloride, sodium tetrahydroborate, sodium periodate, hydrogen, triethylamine, 10 wt. % palladium on activated carbon in tetrahydrofuran, tetrachloromethane, ethanol, water, toluene, acetonitrile Prashad, Mahavir; Kim, Hong-Yong; Lu, Yansong; Liu, Yugang; Har, Denis; Repic, Oljan; Blacklock, Thomas J.; Giannousis, Peter; Journal of Organic Chemistry; vol. 64; nb. 5; (1999); p. 1750 - 1753 View in Reaxys Reaction Steps: 8 2: 92 percent / pyridine / CH2Cl2 / 3 h / 0 °C 3: 91 percent / NaBH4 / tetrahydrofuran; H2O / 0 - 22 °C 4: 60 percent / 3 h / 85 °C 5: hydrogen / Pd/C / ethanol / 4 h / 2585.74 Torr / Ambient temperature 6: 160 mg / triethylamine / tetrahydrofuran / 19 h / 22 °C 7: 80 percent / NaIO4, RuCl3*H2O / H2O; acetonitrile; CCl4 / 2 h / 22 °C 8: 70 percent / HCl / 15 h / 50 °C With pyridine, hydrogenchloride, ruthenium trichloride, sodium tetrahydroborate, sodium periodate, hydrogen, triethylamine, 10 wt. % palladium on activated carbon in tetrahydrofuran, tetrachloromethane, ethanol, dichloromethane, water, acetonitrile Prashad, Mahavir; Kim, Hong-Yong; Lu, Yansong; Liu, Yugang; Har, Denis; Repic, Oljan; Blacklock, Thomas J.; Giannousis, Peter; Journal of Organic Chemistry; vol. 64; nb. 5; (1999); p. 1750 - 1753 View in Reaxys

H N

O

H OH

H H

O

HN

Cl

H

Rx-ID: 16494943 View in Reaxys 102/189 Yield

Conditions & References Reaction Steps: 3 1: 160 mg / triethylamine / tetrahydrofuran / 19 h / 22 °C 2: 80 percent / NaIO4, RuCl3*H2O / H2O; acetonitrile; CCl4 / 2 h / 22 °C 3: 70 percent / HCl / 15 h / 50 °C With hydrogenchloride, ruthenium trichloride, sodium periodate, triethylamine in tetrahydrofuran, tetrachloromethane, water, acetonitrile

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Prashad, Mahavir; Kim, Hong-Yong; Lu, Yansong; Liu, Yugang; Har, Denis; Repic, Oljan; Blacklock, Thomas J.; Giannousis, Peter; Journal of Organic Chemistry; vol. 64; nb. 5; (1999); p. 1750 - 1753 View in Reaxys

O O

O S

O

OH

H H

O Cl

HN

H

Cl

Rx-ID: 16498247 View in Reaxys 103/189 Yield

Conditions & References Reaction Steps: 5 1: 60 percent / 3 h / 85 °C 2: hydrogen / Pd/C / ethanol / 4 h / 2585.74 Torr / Ambient temperature 3: 160 mg / triethylamine / tetrahydrofuran / 19 h / 22 °C 4: 80 percent / NaIO4, RuCl3*H2O / H2O; acetonitrile; CCl4 / 2 h / 22 °C 5: 70 percent / HCl / 15 h / 50 °C With hydrogenchloride, ruthenium trichloride, sodium periodate, hydrogen, triethylamine, 10 wt. % palladium on activated carbon in tetrahydrofuran, tetrachloromethane, ethanol, water, acetonitrile Prashad, Mahavir; Kim, Hong-Yong; Lu, Yansong; Liu, Yugang; Har, Denis; Repic, Oljan; Blacklock, Thomas J.; Giannousis, Peter; Journal of Organic Chemistry; vol. 64; nb. 5; (1999); p. 1750 - 1753 View in Reaxys

O H H

H N

OH

HN

O Cl

H

Rx-ID: 16500098 View in Reaxys 104/189 Yield

Conditions & References Reaction Steps: 4 1: hydrogen / Pd/C / ethanol / 4 h / 2585.74 Torr / Ambient temperature 2: 160 mg / triethylamine / tetrahydrofuran / 19 h / 22 °C 3: 80 percent / NaIO4, RuCl3*H2O / H2O; acetonitrile; CCl4 / 2 h / 22 °C 4: 70 percent / HCl / 15 h / 50 °C With hydrogenchloride, ruthenium trichloride, sodium periodate, hydrogen, triethylamine, 10 wt. % palladium on activated carbon in tetrahydrofuran, tetrachloromethane, ethanol, water, acetonitrile Prashad, Mahavir; Kim, Hong-Yong; Lu, Yansong; Liu, Yugang; Har, Denis; Repic, Oljan; Blacklock, Thomas J.; Giannousis, Peter; Journal of Organic Chemistry; vol. 64; nb. 5; (1999); p. 1750 - 1753 View in Reaxys

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O

O

H

N

H

O

O Cl

O HO

H

HN

Cl

Rx-ID: 16503978 View in Reaxys 105/189 Yield

Conditions & References Reaction Steps: 7 1: 93 percent / triethylamine / toluene / 2 h / 0 °C 2: 91 percent / NaBH4 / tetrahydrofuran; H2O / 0 - 22 °C 3: 60 percent / 3 h / 85 °C 4: hydrogen / Pd/C / ethanol / 4 h / 2585.74 Torr / Ambient temperature 5: 160 mg / triethylamine / tetrahydrofuran / 19 h / 22 °C 6: 80 percent / NaIO4, RuCl3*H2O / H2O; acetonitrile; CCl4 / 2 h / 22 °C 7: 70 percent / HCl / 15 h / 50 °C With hydrogenchloride, ruthenium trichloride, sodium tetrahydroborate, sodium periodate, hydrogen, triethylamine, 10 wt. % palladium on activated carbon in tetrahydrofuran, tetrachloromethane, ethanol, water, toluene, acetonitrile Prashad, Mahavir; Kim, Hong-Yong; Lu, Yansong; Liu, Yugang; Har, Denis; Repic, Oljan; Blacklock, Thomas J.; Giannousis, Peter; Journal of Organic Chemistry; vol. 64; nb. 5; (1999); p. 1750 - 1753 View in Reaxys Reaction Steps: 7 1: 92 percent / pyridine / CH2Cl2 / 3 h / 0 °C 2: 91 percent / NaBH4 / tetrahydrofuran; H2O / 0 - 22 °C 3: 60 percent / 3 h / 85 °C 4: hydrogen / Pd/C / ethanol / 4 h / 2585.74 Torr / Ambient temperature 5: 160 mg / triethylamine / tetrahydrofuran / 19 h / 22 °C 6: 80 percent / NaIO4, RuCl3*H2O / H2O; acetonitrile; CCl4 / 2 h / 22 °C 7: 70 percent / HCl / 15 h / 50 °C With pyridine, hydrogenchloride, ruthenium trichloride, sodium tetrahydroborate, sodium periodate, hydrogen, triethylamine, 10 wt. % palladium on activated carbon in tetrahydrofuran, tetrachloromethane, ethanol, dichloromethane, water, acetonitrile Prashad, Mahavir; Kim, Hong-Yong; Lu, Yansong; Liu, Yugang; Har, Denis; Repic, Oljan; Blacklock, Thomas J.; Giannousis, Peter; Journal of Organic Chemistry; vol. 64; nb. 5; (1999); p. 1750 - 1753 View in Reaxys

O S O O

O

Cl

H H

O

N

O

O Cl

HN

H

O

Rx-ID: 16505471 View in Reaxys 106/189

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Yield

Conditions & References Reaction Steps: 6 1: 91 percent / NaBH4 / tetrahydrofuran; H2O / 0 - 22 °C 2: 60 percent / 3 h / 85 °C 3: hydrogen / Pd/C / ethanol / 4 h / 2585.74 Torr / Ambient temperature 4: 160 mg / triethylamine / tetrahydrofuran / 19 h / 22 °C 5: 80 percent / NaIO4, RuCl3*H2O / H2O; acetonitrile; CCl4 / 2 h / 22 °C 6: 70 percent / HCl / 15 h / 50 °C With hydrogenchloride, ruthenium trichloride, sodium tetrahydroborate, sodium periodate, hydrogen, triethylamine, 10 wt. % palladium on activated carbon in tetrahydrofuran, tetrachloromethane, ethanol, water, acetonitrile Prashad, Mahavir; Kim, Hong-Yong; Lu, Yansong; Liu, Yugang; Har, Denis; Repic, Oljan; Blacklock, Thomas J.; Giannousis, Peter; Journal of Organic Chemistry; vol. 64; nb. 5; (1999); p. 1750 - 1753 View in Reaxys

H

H N

H

O

O

H H O

Cl

O

H

Cl

HN

H

Rx-ID: 16793109 View in Reaxys 107/189 Yield

Conditions & References Reaction Steps: 2 1: α-Chymotrypsin, 1 N NaOH, phosphate buffer / 48 h / Ambient temperature 2: 16 percent / HCl (gas) / 16 h / 45 - 50 °C With hydrogenchloride, sodium hydroxide, phosphate buffer, α-chymotrypsin Prashad, Mahavir; Har, Denis; Repic, Oljan; Blacklock, Thomas J.; Giannousis, Peter; Tetrahedron Asymmetry; vol. 9; nb. 12; (1998); p. 2133 - 2136 View in Reaxys

O

O

H

O

H

O Cl

HN

N

H

Br

Rx-ID: 16947529 View in Reaxys 108/189 Yield

Conditions & References Reaction Steps: 4 1: 1.) BH3*THF, 2.) aq. H2O2, NaOH / 1.) THF, RT, 4 h, 2.) THF, RT 2: PDC / dimethylformamide / 17 h 3: diethyl ether 4: HCl / methanol / Ambient temperature With hydrogenchloride, sodium hydroxide, dipyridinium dichromate, borane-THF, dihydrogen peroxide in methanol, diethyl ether, N,N-dimethyl-formamide Thai, Dung L.; Sapko, Michael T.; Reiter, Clara T.; Bierer, Donald E.; Perel, James M.; Journal of Medicinal Chemistry; vol. 41; nb. 4; (1998); p. 591 - 601 View in Reaxys

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O

O

H

O

H

O Cl

HN

N

H

Br

Rx-ID: 16947535 View in Reaxys 109/189 Yield

Conditions & References Reaction Steps: 4 1: 1.) BH3*THF, 2.) aq. H2O2, NaOH / 1.) THF, RT, 4 h, 2.) THF, RT 2: PDC / dimethylformamide / 17 h 3: diethyl ether 4: HCl / methanol / Ambient temperature With hydrogenchloride, sodium hydroxide, dipyridinium dichromate, borane-THF, dihydrogen peroxide in methanol, diethyl ether, N,N-dimethyl-formamide Thai, Dung L.; Sapko, Michael T.; Reiter, Clara T.; Bierer, Donald E.; Perel, James M.; Journal of Medicinal Chemistry; vol. 41; nb. 4; (1998); p. 591 - 601 View in Reaxys

O

O

O

H H

N

O Cl

HN

H

O

Rx-ID: 16947644 View in Reaxys 110/189 Yield

Conditions & References Reaction Steps: 4 1: 1.) BH3*THF, 2.) aq. H2O2, NaOH / 1.) THF, RT, 4 h, 2.) THF, RT 2: PDC / dimethylformamide / 17 h 3: diethyl ether 4: HCl / methanol / Ambient temperature With hydrogenchloride, sodium hydroxide, dipyridinium dichromate, borane-THF, dihydrogen peroxide in methanol, diethyl ether, N,N-dimethyl-formamide Thai, Dung L.; Sapko, Michael T.; Reiter, Clara T.; Bierer, Donald E.; Perel, James M.; Journal of Medicinal Chemistry; vol. 41; nb. 4; (1998); p. 591 - 601 View in Reaxys

O

O

O

H H

N

O Cl

HN

H

O

Rx-ID: 16947650 View in Reaxys 111/189

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Yield

Conditions & References Reaction Steps: 4 1: 1.) BH3*THF, 2.) aq. H2O2, NaOH / 1.) THF, RT, 4 h, 2.) THF, RT 2: PDC / dimethylformamide / 17 h 3: diethyl ether 4: HCl / methanol / Ambient temperature With hydrogenchloride, sodium hydroxide, dipyridinium dichromate, borane-THF, dihydrogen peroxide in methanol, diethyl ether, N,N-dimethyl-formamide Thai, Dung L.; Sapko, Michael T.; Reiter, Clara T.; Bierer, Donald E.; Perel, James M.; Journal of Medicinal Chemistry; vol. 41; nb. 4; (1998); p. 591 - 601 View in Reaxys

O

O

O

O

O H

H

N

Cl

OH

H

HN

Rx-ID: 16947955 View in Reaxys 112/189 Yield

Conditions & References Reaction Steps: 2 1: diethyl ether 2: HCl / methanol / Ambient temperature With hydrogenchloride in methanol, diethyl ether Thai, Dung L.; Sapko, Michael T.; Reiter, Clara T.; Bierer, Donald E.; Perel, James M.; Journal of Medicinal Chemistry; vol. 41; nb. 4; (1998); p. 591 - 601 View in Reaxys

O O

O

H

O

H

H N

OH

O

HN

Cl

H

Rx-ID: 16947956 View in Reaxys 113/189 Yield

Conditions & References Reaction Steps: 2 1: diethyl ether 2: HCl / methanol / Ambient temperature With hydrogenchloride in methanol, diethyl ether Thai, Dung L.; Sapko, Michael T.; Reiter, Clara T.; Bierer, Donald E.; Perel, James M.; Journal of Medicinal Chemistry; vol. 41; nb. 4; (1998); p. 591 - 601 View in Reaxys

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O

O

O

O

O H

H

N

Cl

OH

H

HN

Rx-ID: 16947957 View in Reaxys 114/189 Yield

Conditions & References Reaction Steps: 2 1: diethyl ether 2: HCl / methanol / Ambient temperature With hydrogenchloride in methanol, diethyl ether Thai, Dung L.; Sapko, Michael T.; Reiter, Clara T.; Bierer, Donald E.; Perel, James M.; Journal of Medicinal Chemistry; vol. 41; nb. 4; (1998); p. 591 - 601 View in Reaxys

H 2N

O

O

H H

O

N

HN

Rx-ID: 17749971 View in Reaxys 115/189 Yield

Conditions & References Reaction Steps: 3 1: H2 / 5percent Pt/C / acetic acid / 10 h / 1551.4 - 2068.6 Torr 2: 1.) 6N HCl, 2.) 50percent KOH / 1.) reflux, 6 h, 2.) reflux, 4 d 3: SOCl2 / 24 h / Ambient temperature With hydrogenchloride, potassium hydroxide, thionyl chloride, hydrogen, 10% platinum on carbon in acetic acid Deutsch, Howard M.; Shi, Qing; Gruszecka-Kowalik, Ewa; Schwer, Margaret M.; Journal of Medicinal Chemistry; vol. 39; nb. 6; (1996); p. 1201 - 1209 View in Reaxys H 2N

O

O H H

N

O

HN

Rx-ID: 17749972 View in Reaxys 116/189 Yield

Conditions & References Reaction Steps: 3 1: H2 / 5percent Pt/C / acetic acid / 10 h / 1551.4 - 2068.6 Torr 2: 1.) 6N HCl, 2.) 50percent KOH / 1.) reflux, 6 h, 2.) reflux, 4 d 3: SOCl2 / 24 h / Ambient temperature With hydrogenchloride, potassium hydroxide, thionyl chloride, hydrogen, 10% platinum on carbon in acetic acid Deutsch, Howard M.; Shi, Qing; Gruszecka-Kowalik, Ewa; Schwer, Margaret M.; Journal of Medicinal Chemistry; vol. 39; nb. 6; (1996); p. 1201 - 1209 View in Reaxys

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O

N

H H

O

N

HN

Rx-ID: 17749980 View in Reaxys 117/189 Yield

Conditions & References Reaction Steps: 4 1: 12 N HCl / 15 h / Ambient temperature 2: H2 / 5percent Pt/C / acetic acid / 10 h / 1551.4 - 2068.6 Torr 3: 1.) 6N HCl, 2.) 50percent KOH / 1.) reflux, 6 h, 2.) reflux, 4 d 4: SOCl2 / 24 h / Ambient temperature With hydrogenchloride, potassium hydroxide, thionyl chloride, hydrogen, 10% platinum on carbon in acetic acid Deutsch, Howard M.; Shi, Qing; Gruszecka-Kowalik, Ewa; Schwer, Margaret M.; Journal of Medicinal Chemistry; vol. 39; nb. 6; (1996); p. 1201 - 1209 View in Reaxys N

O H H

O

N HN

Rx-ID: 17749981 View in Reaxys 118/189 Yield

Conditions & References Reaction Steps: 4 1: 12 N HCl / 15 h / Ambient temperature 2: H2 / 5percent Pt/C / acetic acid / 10 h / 1551.4 - 2068.6 Torr 3: 1.) 6N HCl, 2.) 50percent KOH / 1.) reflux, 6 h, 2.) reflux, 4 d 4: SOCl2 / 24 h / Ambient temperature With hydrogenchloride, potassium hydroxide, thionyl chloride, hydrogen, 10% platinum on carbon in acetic acid Deutsch, Howard M.; Shi, Qing; Gruszecka-Kowalik, Ewa; Schwer, Margaret M.; Journal of Medicinal Chemistry; vol. 39; nb. 6; (1996); p. 1201 - 1209 View in Reaxys

H 2N

O

O

H H

H N

O

HN

Rx-ID: 17753649 View in Reaxys 119/189 Yield

Conditions & References Reaction Steps: 2 1: 1.) 6N HCl, 2.) 50percent KOH / 1.) reflux, 6 h, 2.) reflux, 4 d 2: SOCl2 / 24 h / Ambient temperature With hydrogenchloride, potassium hydroxide, thionyl chloride Deutsch, Howard M.; Shi, Qing; Gruszecka-Kowalik, Ewa; Schwer, Margaret M.; Journal of Medicinal Chemistry; vol. 39; nb. 6; (1996); p. 1201 - 1209 View in Reaxys

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H 2N

O

O H H

H N

O

HN

Rx-ID: 17753650 View in Reaxys 120/189 Yield

Conditions & References Reaction Steps: 2 1: 1.) 6N HCl, 2.) 50percent KOH / 1.) reflux, 6 h, 2.) reflux, 4 d 2: SOCl2 / 24 h / Ambient temperature With hydrogenchloride, potassium hydroxide, thionyl chloride Deutsch, Howard M.; Shi, Qing; Gruszecka-Kowalik, Ewa; Schwer, Margaret M.; Journal of Medicinal Chemistry; vol. 39; nb. 6; (1996); p. 1201 - 1209 View in Reaxys

O H H

H

O

HO

Cl

HN

N H

O

H

NH 2

Rx-ID: 22866817 View in Reaxys 121/189 Yield

Conditions & References Stage 1: With sulfuric acid, Time= 48h, Heating / reflux Stage 2: With sodium hydroxide in diethyl ether, water, pH= 12 Stage 3: With hydrogenchloride in diethyl ether Patent; Celgene Corporation; US6359139; (2002); (B1) English View in Reaxys O

O

N

HO

H N

H

H

N

O

O H H

O

O HN

Rx-ID: 23074843 View in Reaxys 122/189 Yield

Conditions & References 4; 10 : Example 4; Methylphenidate; Scheme 10 Hydrogen chloride (gas) was passed through a stirred solution of 7-phenyl-1-azabicyclo[4.2.0]octan-8-one with R*R*/S*R* 3.3:1 by GC (2.61 Kg, 13.0 mol) in methanol (13 L) under reflux conditions for 60 hour until TLC indicated that all starting material had been consumed.The mixture was evaporated under reduced pressure.The residue was treated with hot water (8 L) for 0.5 h.The hot mixture was filtered, cooled to 50° C., washed with toluene (2*1.2 L), cooled to the room temperature, basified with sodium carbonate to PH 10-11 and extracted with dichloromethane (3*2.5 L).The combined organic extracts were dried over sodium sulfate, filtered and evaporated under reduced pressure to give 2.33 Kg (76.9percent) of methylphenidate with threolerythro 3.5:1 by GC. With hydrogenchloride in methanol, Time= 60h, Heating / reflux Patent; ISP INVESTMENTS INC.; US2004/180928; (2004); (A1) English

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View in Reaxys H N

H

H

O

H

H N

H

O

O

H H

O

O

O

HN

Cl

H

Rx-ID: 23237401 View in Reaxys 123/189 Yield

Conditions & References

58.2 %

5 : Example 5; threo-Methylphenidate Hydrochloride Acetyl chloride (15.7 g, 0.2 mol, 1.0 eq) was added dropwise to a stirred methanol solution (150 mL) at 0-10° C. to form HCl in situ. The solution of methylphenidate, threo/erythro 3.5:1 by GC (46.7 g, 0.2 mol, 1.0 eq) in methanol (150 mL) was added dropwise to the obtained acidic solution at 0° C. The obtained solution was stirred under reflux conditions for 10 min. Methyl tert-butyl ether (MTBE) (300 mL) was added to the stirred solution at 50-60° C. The mixture was stirred for 2 hours at 20-30° C. and for 2 hours at -5-10° C. The precipitated solids were filtered off, washed on the filter with cold MTBE (400 mL) and dried under reduced pressure to give 31.1 g (58.2percent) of threo-methylphenidate hydrochloride with 98.8percent purity by GC (0.8percent of erythro-isomer). With hydrogenchloride in methanol, Time= 0.166667h, T= 0 °C , Heating / reflux Patent; ISP INVESTMENTS INC.; US2004/176412; (2004); (A1) English View in Reaxys

O H

N

HO

N

H O

H N

H

H

O

O H H

O

O HN

Rx-ID: 23249142 View in Reaxys 124/189 Yield

Conditions & References 4 :Hydrogen chloride (gas) was passed through a stirred solution of 7-phenyl-1-azabicyclo[4.2.0]octan-8-one with R*R*/S*R* 3.3:1 by GC (2.61 Kg, 13.0 mol) in methanol (13 L) under reflux conditions for 60 hour until TLC indicated that all starting material has been consumed. The mixture was evaporated under reduced pressure. The residue was treated with hot water (8 L) for 0.5 h. The hot mixture was filtered, cooled to the room temperature, washed with toluene (2.x.1.2 L), basified with sodium carbonate to pH 10-11 and extracted with dichloromethane (2.x.2.5 L). The combined organic extracts were dried over sodium sulfate, filtered and evaporated under reduced pressure to give is 2.33 Kg (76.9percent) of methylphenidate with threo/erythro 3.5:1 by GC With hydrogenchloride, Time= 60h, Heating / reflux Patent; ISP INVESTMENTS INC.; US2004/176412; (2004); (A1) English View in Reaxys

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H

H N

H

O

O

H H

O

O

l-threo-methylphenidate - d-threo-methylphenidate

HN

Rx-ID: 23589288 View in Reaxys 125/189 Yield

Conditions & References 3 : EXAMPLE 3 The methanol/water mother liquors from step 225 were treated with about 300 mL of water to precipitate most of the d-isomer, and those solids were collected and dried. The water fraction was concentrated to in vacuo by removing all of the methanol. The 4-methylmorpholine HCl remained in the water layer and the remaining d-isomer precipitated. The solid d-isomer was collected and dried. The water layer was discarded. The combined d-isomer fraction was treated with a total of about 400 mL of isopropyl acetate and about 70 mL of an aqueous saturated sodium carbonate solution. The ethyl acetate layer was separated and evaporated to dryness in vacuo to give about 13 grams of solids. An assay of those solids showed about 95 percent d-threo-methylphenidate and about 5 percent l-threo-methylphenidate. Stage 1: in methanol, water Stage 2: With sodium carbonate in Isopropyl acetate, water Patent; Krsek, George R.; Durazo, Enrique E.; US2005/171155; (2005); (A1) English View in Reaxys

O H H

H

conc. H2 SO4

N H

O

HN

O Cl

H

NH 2

Rx-ID: 24282511 View in Reaxys 126/189 Yield

Conditions & References

100 g (80%) Procedure: Procedure: A solution of d-threo-α-phenyl-α-piperidyl-(2)-acetamide (from Example 1.E) and conc. H2 SO4 in methanol was heated to reflux and stirred for 2 days. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. Water (0.81 L) and ether (1.0 L) were added to the residue. NaOH was added to a pH of 12, and the layers ere separated. The aqueous layer was extracted with ether (1.0 L). MgSO4 was added to he combined ether layers, filtered, and washed with ether (1.0 L). HCl gas was passed through the filtrate with stirring, whereby white crystals of d-threo-methylphcnidate hydrochloride precipitated out. The crystals were filtered, washed with ether (1.0 L), and dried to give 100 g (80percent) of d-threo-methylphenidate hydrochloride. The overall yield for Example 1 was 14.7percent. With sodium hydroxide, magnesium sulfate in methanol, water Patent; Celgene Corporation; US5936091; (1999); (A) English View in Reaxys 100 g (80%) Procedure: Procedure: A solution of d-threo-α-phenyl-α-piperidyl-(2)- acetamide (from Example 2.E) and conc. H2 SO4 in methanol was heated to reflux and stirred for 2 days. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. Water (0.81 L) and ether (1.0 L) were added to the residue. The NaOH was added to a pH of 12, and the layers were separated.

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The aqueous layer was extracted with ether (1.0 L). MgSO4 was added to the combined ether layers, filtered, and washed with ether (1.0 L). HCl gas was passed through the filtrate with stirring, whereby white crystals of d-threo-methylphenidate hydrochloride precipitated out. The crystals were filtered, washed with ether (1.0 L), and dried to give 100 g (80percent) of d-threo-methylphenidate hydrochloride. In contrast to Example 1, the overall yield for Example 2 was 24.5percent, an increase of over 66percent. With sodium hydroxide, magnesium sulfate in methanol, water Patent; Celgene Corporation; US5936091; (1999); (A) English View in Reaxys

O

O

H N

Cl

H

Rx-ID: 24393865 View in Reaxys 127/189 Yield

Conditions & References 1.e : c) e) Preparation of the Title Compound in a Higher Optical Purity To a 250 ml, 4-necked, round-bottomed flask, equipped with a mechanical stirrer, digital thermometer, nitrogen inlet-outlet, heating mantle, condenser and addition funnel, is added 29 g of deionized water which is then heated to a temperature of between 74° and 75° C. To the heated water is then added 24.62 g of the hydrochloride salt obtained in d) above, and the mixture is heated to a temperature between 80° and 82° C. The resultant clear solution is then cooled to a temperature of between 20° and 22° C., over a period of 45 minutes. To the resultant heterogeneous mixture is then added 9.0 g of concentrated hydrochloric acid (37percent), over a period of 10 minutes, while the temperature is maintained at less than 25° C. The mixture is then cooled to a temperature between 0° and 5° C., over a period of 15 minutes, and then stirred at this temperature for an additional 30 minutes. The mixture is then filtered and the resultant solid is washed with 8 ml of pre-cooled water (between 0° and 5° C.) in 2 equal portions of 4 ml each, and dried at a temperature between 50° and 55° C. (100 mmHg) to obtain the desired title compound as a white crystalline solid (2R,2'R:2S,2'S ratio is 100:0, i.e., the 2S,2'S enantiomer was undetectable). Patent; Novartis AG; US6162919; (2000); (A) English View in Reaxys

H

13C

H 13C

N

13

O

13

C

N

O

13CH

CH

H N

13C

N

O O

O

H

13CH

H 13C

HO

HCl

13C 13C

H

H

H

13CH 13C

H

Rx-ID: 24788614 View in Reaxys 128/189 Yield

Conditions & References 5 :A portion (180 mg) of the crude oil 1-31 is treated with excess diazomethane in ether (10 mL). The solution is evaporated to a light yellow oil which is stirred in 3 N methanolic HCl (10 mL) at room temperature overnight. Evaporation under reduced pressure provides a crude off-white solid which is recrystallized from EtOH/EtoO to give 125 mg of (2R,2'R)-5 as a white solid (67percent yield from (1R,2R)-I-3O). With hydrogenchloride in methanol, diethyl ether, T= 20 °C Patent; DR PHARMA NOVA, LLC; WO2006/91885; (2006); (A2) English

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View in Reaxys

O O

OH O

O

H

H

O

O

O

H N

Cl

H

OH O

O

O

O

O

O

O O

O

OH

OH

H N

H O

OH

OH

O NH

O

H

O

O

O

O

O

Rx-ID: 27821935 View in Reaxys 129/189 Yield

Conditions & References

69.5 %

C Ex 2 :Examples 1 and 2 and Comparative Examples 1 and 2Effect of Tertiary Amine Base and Resolving Agent Equivalents on Yield and Enantiomeric Purity of D-threo-Methylphenidate/Chiral Acid SaltThreo-methylphenidate hydrochloride (10.0 g, 0.037 mol) was suspended in methanol (36 g) and di-p-toluoyl-d-tartaric acid (D-TA) was charged (see Table 1 for charge quantities) and the formed mixture was heated to 45° C. to provide a clear solution. The mixture was treated with diisopropylethylamine (DIPEA, see Table 1 for charge quantities) while an internal temperature below 45° C. was maintained. Deionized water was added to the mixture at about 45° C. until a cloudy point was achieved. The resulting slurry was cooled to 20° C. over 1 hour, aged for 2 hours, cooled to 0° C. and aged for 1 hour. The formed precipitate of D-threo-Methylphenidate/Chiral Acid Salt (Dex-TA) was filtered and washed sequentially with 20 ml of cold (0-5° C.) MeOH/water (2:1 w/w) mixture, 40 ml of deionized water and 40 ml acetone. The Dex-TA wet cake was dried at 50° C. in vacuum overnight. A reference sample of Dex-TA exhibits mp 161.8° C. and 25 α D +121.8° (c 1 wt percent, MeOH). TABLE 1 D-TA DIPEA Dex-TA Equiv g Equiv g Water g g Yield, percent EE, percent Ex 1 0.5 7.2 0.5 2.4 25 9.3 40.4 99.2 C 0.5 7.2 1.0 4.8 123 n/a* n/a n/a Ex 1 Ex 2 1.0 14.3 0.5 2.4 24 9.2 40.0 99.5 C 1.0 14.3 1.0 4.8 21 16.0 69.5 45.5 Ex 2 *No crystallization took place With N-ethyl-N,N-diisopropylamine in methanol, water, Time= 3h, T= 0 - 45 °C , Product distribution / selectivity Patent; Kalinin, Alexei; Qiu, Guofang; Marren, Thomas J.; Aldred, James E.; Ji, Yu; US2008/167470; (2008); (A1) English View in Reaxys

O

O

O

H O

H OH

H O

O

HN

OH O

NH

O

O O

Rx-ID: 27821938 View in Reaxys 130/189

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Yield

Conditions & References 13 :Example 13Dexmethylphenidate Free Base and Hydrochloride Salt FormationD-Threo-methylphenidate-di-p-toluoyl-D-tartrate (0.47 Kg, 0.758 mol, ee 98.9percent) was charged to a suitable reactor followed by water (1.2 Kg) and isopropyl acetate (0.7 Kg). The formed slurry was cooled to about 15° C. and was treated with sodium hydroxide (25percent, 0.3 Kg) at less than 25° C., followed by 30 minutes aging. The lower aqueous layer was separated and the organic layer was washed with process water (3.x.0.4 Kg)The organic layer was dewatered by azeotropic distillation under vacuum and was concentrated in vacuum to give D-threo-methylphenidate free base as an oil, which was used directly in hydrochloride salt formation. The solution of Dthreo-methylphenidate free base in isopropanol (0.29 Kg) was charged to a jacketed vessel, cooled to 5-10° C. and treated with a solution of 37percent HCl (78 g) in a mixture of isopropanol (40 g) and methanol (63 g) at less than 20° C. The formed slurry was cooled to 0 to 5° C., aged for 2 hours and filtered. The wet cake was washed with isopropanol (0.32 Kg total) in two portions and dried under vacuum at 45° C. for 16 hours to give Dexmethylphenidate hydrochloride (0.175 Kg, 0.649 mol, 86percent yield) as a off-white solid; mp 206.4° C., ee 99.7percent, 25 α D +83° (c 1 wt percent, MeOH). With sodium hydroxide in Isopropyl acetate, water, Time= 0.5h, T= 15 - 25 °C Patent; Kalinin, Alexei; Qiu, Guofang; Marren, Thomas J.; Aldred, James E.; Ji, Yu; US2008/167470; (2008); (A1) English View in Reaxys

O

O

O

H H

H N

O

HN

Rx-ID: 28524506 View in Reaxys 131/189 Yield 90 %

Conditions & References With hydrogenchloride, sodium cyanoborohydride in methanol, acetonitrile, Time= 0.5h, T= 20 °C , optical yield given as percent de, stereoselective reaction Neto, Brenno A.D.; Lapis, Alexandre A.M.; Bernd, Alinne B.; Russowsky, Dennis; Tetrahedron; vol. 65; nb. 12; (2009); p. 2484 - 2496 View in Reaxys

O

O

O O S

O

O

O

N N H

H N

H

O

HN

Rx-ID: 30455496 View in Reaxys 132/189 Yield

Conditions & References Reaction Steps: 3 1.1: C15H24ClNO2Si / dichloromethane / 0.17 h / Inert atmosphere 1.2: 1.5 h / 0 °C / Inert atmosphere 2.1: basic alumina / ethyl acetate / Inert atmosphere 3.1: methanol; samarium diiodide / tetrahydrofuran / 0.17 h / 23 °C / Inert atmosphere With methanol, samarium diiodide, C15H24ClNO2Si in tetrahydrofuran, dichloromethane, ethyl acetate, 1.1: Mannich reaction / 1.2: Mannich reaction Notte, Gregory T.; Baxter Vu, Jenny M.; Leighton, James L.; Organic Letters; vol. 13; nb. 4; (2011); p. 816 - 818 View in Reaxys

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O

O

O

O

NH N

O

H N

O

H HN

O

Rx-ID: 30455499 View in Reaxys 133/189 Yield 46 %

Conditions & References With methanol, samarium diiodide in tetrahydrofuran, Time= 0.166667h, T= 23 °C , Inert atmosphere Notte, Gregory T.; Baxter Vu, Jenny M.; Leighton, James L.; Organic Letters; vol. 13; nb. 4; (2011); p. 816 - 818 View in Reaxys

O

O

O

O

O

O

S

H N

O

H HN

O

Rx-ID: 30455514 View in Reaxys 134/189 Yield

Conditions & References Reaction Steps: 4 1.1: titanium(IV) isopropylate / tetrahydrofuran / 14 h / Inert atmosphere 2.1: C15H24ClNO2Si / dichloromethane / 0.17 h / Inert atmosphere 2.2: 1.5 h / 0 °C / Inert atmosphere 3.1: basic alumina / ethyl acetate / Inert atmosphere 4.1: methanol; samarium diiodide / tetrahydrofuran / 0.17 h / 23 °C / Inert atmosphere With titanium(IV) isopropylate, methanol, samarium diiodide, C15H24ClNO2Si in tetrahydrofuran, dichloromethane, ethyl acetate, 2.1: Mannich reaction / 2.2: Mannich reaction Notte, Gregory T.; Baxter Vu, Jenny M.; Leighton, James L.; Organic Letters; vol. 13; nb. 4; (2011); p. 816 - 818 View in Reaxys

O O

HO

O

H N

HO

Cl

H

NH

Rx-ID: 30993676 View in Reaxys 135/189 Yield 89 %

Conditions & References II :To a solution of threo-a-phenyl-a-pipyridyl-2-acetic acid (75 g) (From example 1 ) and methanol (750 ml) was added thionyl chloride (83 g) maintaining the temperature below 10°C.The reaction mass was kept under stirring over night at room temperature. Excess methanol was then distilled off under reduced pressure and the reaction mass was further cooled to 10°C. Purified water (900ml) was then charged maintaining the temperature between 0-10°C followed by addition of ethyl acetate (375ml) under constant stirring. pH of the mixture was made alkaline using dilute caustic solution, with stirring followed by separation of the layers. The separated aqueous layer was once again extracted with ethyl acetate (225ml).The combined ethyl acetate layers were then washed with water and the solvent was distilled off completely. To the residue was charged Isopropyl alcohol (225 ml) and cooled to 0-5°C .The reaction mass was then acidified by adding hydrochloric acid (25percent solution in isopropanol) at 0-

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10°C. The temperature was raised to 25°C, stirred at this temperature for 2-4 hrs, cooled the reaction mass again to 0-10°C and stirred for 2 hrs. The precipitated solid was filtered off, washed with chilled isopropyl alcohol and air dried to get 82.2g (89percent) of methyl phenidate hydrochloride.(Chromatographic purity by HPLC > 99.5percent) Stage 1: With thionyl chloride in water, ethyl acetate, T= 0 - 20 °C Stage 2: With hydrogenchloride in isopropyl alcohol, Time= 4 - 6h, T= 0 - 25 °C Patent; HARMAN FINOCHEM LIMITED; JAIN, Kirti, Prakash; APAR, Shrikrishna, Motiram; MINHAS, Harpreet, Singh; WO2011/67783; (2011); (A1) English View in Reaxys

11CH

HO

3

O O

H

H N

F

Cl

O

O S

11CH

H

O F

O

H N

3

F

H

Rx-ID: 31581796 View in Reaxys 136/189 Yield

Conditions & References in butanone, Time= 0.5h, pH= 7.4, aq. phosphate buffer Moran, Matthew D.; Wilson, Alan A.; Stableford, Winston T.; Wong, Min; Garcia, Armando; Houle, Sylvain; Vasdev, Neil; Journal of Labelled Compounds and Radiopharmaceuticals; vol. 54; nb. 3; (2011); p. 168 - 170 View in Reaxys OH

H

H N

O

H

O OH OH

O

O

OH

OH 2

H N

O

OH OH

O

H O OH

O

Rx-ID: 32483479 View in Reaxys 137/189 Yield 92 %

Conditions & References 3 :To a 100 mL one neck round bottom flask equipped with a magnetic stir bar, thermowell and nitrogen inlet was charged 2.20 g (9.43 mmol) racemic-methylphenidate. As solvent, 17 mL dimethylformamide (DMF) was then added which produced a clear colorless solution. Pamoic acid (1.83 g; 4.71 mmol; 0.36percent moisture) was subsequently added over thirty seconds which produced a clear yellow solution. The solution was stirred under nitrogen for 3 hours at ambient temperature followed by filtration through a medium fritted glass filter to remove any particulates. The filtrate was transferred to a 250 mL one-neck round bottom flask and 54 g isopropanol was added over one minute. The solution was concentrated under reduced pressure at 100° C. to yield 4.2 g of a residue which was subsequently triturated in 24 g isopropanol and the yellow solids collected by filtration

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(medium fritted glass filter). The product was dried overnight under vacuum at ambient temperature to provide 3.7 g (92percent) of a yellow solid (0.36percent water) which was analyzed by DSC, FTIR (FIG. 5), and PXRD (FIG. 6). An HPLC analysis indicated a 1.8/1 ratio of methylphenidate/pamoate which was corroborated by NMR. The PXRD analysis indicated the drug substance salt was crystalline. The DSC is provided in FIG. 4 wherein an endotherm of at least 75 J/gram is illustrated above 200° C. in N,N-dimethyl-formamide, Time= 3h, T= 20 °C , Inert atmosphere Patent; King, Clifford Riley; D'Ambrosio, Stephen G.; Bristol, David W.; US2012/28960; (2012); (A1) English View in Reaxys

H N

H

H

O O

H H O

Cl

O

H

HN

Rx-ID: 32483481 View in Reaxys 138/189 Yield

Conditions & References

98 %

5 :To a 200 mL beaker was charged 10.0 g (37.1 mmol) racemic-methylphenidate hydrochloride and 135 mL water. Ammonium hydroxide (3.40 g; 96.8 mmol) was then added to bring the pH to approximately 9 upon which an oily semi-solid formed. The product was extracted with three 100 mL portions of ethyl acetate, the combined organic layers were dried over sodium sulfate, filtered and concentrated under reduce pressure at 40° C. to provide 8.5 g of a clear, colorless viscous oil (98percent yield). The free base was characterized by FTIR and found to be consistent with the anticipated structure With ammonium hydroxide in water, pH= ~ 9 Patent; King, Clifford Riley; D'Ambrosio, Stephen G.; Bristol, David W.; US2012/28960; (2012); (A1) English View in Reaxys 2

O

Na +

O– H N

OH OH

O

H

H

O

O

Cl

H

O

O

2

O

OH

H OH OH

O

NH OH

O

Rx-ID: 32483482 View in Reaxys 139/189 Yield 89 %

Conditions & References 7 :To a 100 mL round bottom flask equipped with a magnetic stir bar, thermowell and nitrogen inlet was charged 0.41 g (0.925 mmol) disodium pamoate (3.16percent moisture) and 10 mL water. A solution of 0.5 g (1.85 mmol) d-methylphenidate hydro-

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chloride in 10 mL water was prepared and added to the above disodium pamoate solution over a thirty minute period under a nitrogen atmosphere. The solution was then heated from ambient temperature to 95° C. and held on temperature for 5 hours under nitrogen upon which the solids turned to a yellow gum. Heating was ceased and the mixture allowed to slowly cool back to ambient temperature overnight and continuously under a nitrogen atmosphere. The solids were collected by filtration (medium fritted glass filter) and dried overnight under vacuum at ambient temperature to provide 0.7 g (89percent) of a yellow solid (0.51percent water) which was analyzed by DSC, HPLC, FTIR (FIG. 14), and PXRD (FIG. 15). PXRD showed the product to be crystalline. HPLC showed a 1.7/1 ratio of d-methylphenidate/pamoate. The DSC is provided in FIG. 13 wherein an endothermic phase change of at least 35 J/gram is observed at greater than 185° C. in water, Time= 5.5h, T= 20 - 95 °C , Inert atmosphere, Product distribution / selectivity Patent; King, Clifford Riley; D'Ambrosio, Stephen G.; Bristol, David W.; US2012/28960; (2012); (A1) English View in Reaxys Rx-ID: 32483486 View in Reaxys 140/189 Yield 84 %

Conditions & References 13 :To a 100 mL round-bottom flask equipped with a magnetic stir bar and addition funnel was charged 0.8 g (0.936 mmol) methylphenidate pamoate, (2:1) salt and 20 g toluene to form a suspension. A solution of 252.3 mg (0.936 mmol) octadecylamine in 20 g toluene was prepared and added dropwise to the above suspension over 30 minutes. The suspension was stirred overnight and the solids collected by filtration through a medium fritted filter. The product was dried under vacuum to provide 700 mg (84percent) of an off-white solid (2.0percent water) which was characterized by DSC, FTIR (FIG. 47), PXRD (FIG. 48), 1H NMR (FIG. 49), and HPLC. The PXRD diffractogram indicated the drug substance to be crystalline. The relative ratio of methylphenidate/pamoate was determined to be 0.9/1 by HPLC and the structure corroborated by 1H NMR with the relative ratio of stearylamine/pamoate as 1/1. The filtrate from the above work-up was concentrated at reduced pressure and dried under vacuum to give 220 mg of a yellow residue which was by FTIR consistent with authentic methylphenidate free base. The DSC scan is provided in FIG. 46 wherein illustrated is an endothermic phase change of at least 15 J/g at a temperature above 50° C.; an endothermic phase change of at least 10 J/g at a temperature of above 90° C.; an endothermic phase change of at least 2 J/g at a temperature above 105° C.; an endothermic phase change of at least 4 J/g at above 155° C. and an endothermic phase change of at least 20 J/g above 180° C. in toluene Patent; King, Clifford Riley; D'Ambrosio, Stephen G.; Bristol, David W.; US2012/28960; (2012); (A1) English View in Reaxys 2

O

Na +

O– H N

OH OH

H

H

O

O– O

Cl

H

O

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H N

H 2N

O H O

OH

OH OH

O

OH

O

Rx-ID: 32483490 View in Reaxys 141/189 Yield

Conditions & References Reaction Steps: 2 1: sodium hydroxide / water / 1.55 h / 20 °C / pH 9 - 9.5 2: toluene With sodium hydroxide in water, toluene Patent; King, Clifford Riley; D'Ambrosio, Stephen G.; Bristol, David W.; US2012/28960; (2012); (A1) English View in Reaxys 2

O

Na +

O– H N

OH OH

H

H

O

O– O

Cl

H

O

OH 2

H N

O

OH OH

O

H O OH

O

Rx-ID: 32483491 View in Reaxys 142/189 Yield 89 %

Conditions & References 2 :To a 100 mL round bottom flask equipped with a magnetic stir bar, thermowell and nitrogen inlet was charged about 1.65 g (3.7 mmol) disodium pamoate (3.2percent moisture) and 25 mL water. The pH was adjusted to 9-9.5 (pH paper) using 0.1 N sodium hydroxide. A solution of 2.0 g (7.4 mmol) racemic-methylphenidate hydrochloride in 37 mL water was prepared (pH 4-4.5 (pH paper)) and added to the above disodium pamoate solution over three minutes. As the resulting solution became a

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thick slurry; 20 mL more water was added and stirred at ambient temperature for 1.5 hours. The solids were collected by filtration (medium fritted glass filter) and dried under vacuum overnight at ambient temperature to provide 2.81 g (89percent) of an off-white solid (1.42percent water) which was analyzed by DSC, FTIR (FIG. 2), and PXRD (FIG. 3). PXRD analysis indicated the drug substance to be amorphous and HPLC analysis indicated a 1.8/1 ratio of methylphenidate/pamoate. The NMR results were consistent with the assigned structure. The DSC is provided in FIG. 1 wherein an endothermic phase change of at least 70 J/gram is observed at greater than 200° C. With sodium hydroxide in water, Time= 1.55h, T= 20 °C , pH= 9 - 9.5 Patent; King, Clifford Riley; D'Ambrosio, Stephen G.; Bristol, David W.; US2012/28960; (2012); (A1) English View in Reaxys H

H N

H

O

O

H N

H 2N

O H O

OH

OH OH

O

OH

O

Rx-ID: 32483493 View in Reaxys 143/189 Yield

Conditions & References Reaction Steps: 2 1: N,N-dimethyl-formamide / 3 h / 20 °C / Inert atmosphere 2: toluene in N,N-dimethyl-formamide, toluene Patent; King, Clifford Riley; D'Ambrosio, Stephen G.; Bristol, David W.; US2012/28960; (2012); (A1) English View in Reaxys

H N

H

O H

O

H H O

Cl

O

H

HN

Rx-ID: 32483495 View in Reaxys 144/189 Yield 95 %

Conditions & References 1 :To a 200 mL beaker was charged 10.0 g (37.1 mmol) racemic-methylphenidate hydrochloride and 135 mL water. About 3.39 g (96.8 mmol) ammonium hydroxide was then added to bring the pH to approximately 9 upon which an oily semi-solid formed.

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The product was extracted with three 100 mL portions of ethyl acetate, the combined organic layers dried over sodium sulfate, filtered and concentrated under reduced pressure at about 40° C. to provide 8.2 g of a clear, colorless viscous oil (95percent yield). The IR spectrum of the oil was consistent with the intended product. With ammonium hydroxide in water, pH= ~ 9 Patent; King, Clifford Riley; D'Ambrosio, Stephen G.; Bristol, David W.; US2012/28960; (2012); (A1) English View in Reaxys H

H N

H

O

O

Cl

H N

H

H 2N

O H O

OH

OH OH

O

OH

O

Rx-ID: 32483497 View in Reaxys 145/189 Yield

Conditions & References Reaction Steps: 3 1: ammonium hydroxide / water / pH ~ 9 2: N,N-dimethyl-formamide / 3 h / 20 °C / Inert atmosphere 3: toluene With ammonium hydroxide in water, N,N-dimethyl-formamide, toluene Patent; King, Clifford Riley; D'Ambrosio, Stephen G.; Bristol, David W.; US2012/28960; (2012); (A1) English View in Reaxys

H N

H

H

O

OH O

Cl

H

2

H N

O

OH OH

O

H O OH

O

Rx-ID: 32483498 View in Reaxys 146/189

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Yield

Conditions & References Reaction Steps: 2 1: ammonium hydroxide / water / pH ~ 9 2: N,N-dimethyl-formamide / 3 h / 20 °C / Inert atmosphere With ammonium hydroxide in water, N,N-dimethyl-formamide Patent; King, Clifford Riley; D'Ambrosio, Stephen G.; Bristol, David W.; US2012/28960; (2012); (A1) English View in Reaxys

O

O

O

O O

H N

Cl

H

O

H P

OH O NH

Rx-ID: 36657602 View in Reaxys 147/189 Yield

Conditions & References Reaction Steps: 2 1: sodium chloride; sodium hydroxide / water; Isopropyl acetate / 0.5 h / 20 - 25 °C 2: methanol; Isopropyl acetate / 6.25 h / 0 - 65 °C / Resolution of racemate With sodium chloride, sodium hydroxide in methanol, Isopropyl acetate, water Prashad, Mahavir; Hu, Bin; Repic, Oljan; Blacklock, Thomas J.; Giannousis, Peter; Organic Process Research and Development; vol. 4; nb. 1; (2000); p. 55 - 59 View in Reaxys

O

O

H N

Cl

H

O

O

O

O O

H N

O

H

P O

P OH

OH

O

O

H

NH

O

Rx-ID: 36657603 View in Reaxys 148/189 Yield

Conditions & References Reaction Steps: 2 1: sodium chloride; sodium hydroxide / water; Isopropyl acetate / 0.5 h / 20 - 25 °C 2: methanol; Isopropyl acetate / 16 h / 20 °C / Resolution of racemate With sodium chloride, sodium hydroxide in methanol, Isopropyl acetate, water Prashad, Mahavir; Hu, Bin; Repic, Oljan; Blacklock, Thomas J.; Giannousis, Peter; Organic Process Research and Development; vol. 4; nb. 1; (2000); p. 55 - 59 View in Reaxys

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O O

O

H H

O

H N

Cl

HN

H

Rx-ID: 36657610 View in Reaxys 149/189 Yield

Conditions & References Reaction Steps: 2 1.1: methanol; Isopropyl acetate / 16 h / 20 °C / Resolution of racemate 2.1: sodium hydroxide / water; Isopropyl acetate / 0.5 h / 20 - 25 °C 2.2: 0.75 h / 0 - 25 °C With sodium hydroxide in methanol, Isopropyl acetate, water Prashad, Mahavir; Hu, Bin; Repic, Oljan; Blacklock, Thomas J.; Giannousis, Peter; Organic Process Research and Development; vol. 4; nb. 1; (2000); p. 55 - 59 View in Reaxys Reaction Steps: 2 1.1: methanol; Isopropyl acetate / 6.25 h / 0 - 65 °C / Resolution of racemate 2.1: sodium hydroxide / water; Isopropyl acetate / 0.5 h / 20 - 25 °C 2.2: 0.75 h / 0 - 25 °C With sodium hydroxide in methanol, Isopropyl acetate, water Prashad, Mahavir; Hu, Bin; Repic, Oljan; Blacklock, Thomas J.; Giannousis, Peter; Organic Process Research and Development; vol. 4; nb. 1; (2000); p. 55 - 59 View in Reaxys

HO

H

HO

O

O H

H N

H

Cl

H HN

O Cl

H

Rx-ID: 37183450 View in Reaxys 150/189 Yield 88 %

Conditions & References 2 : Example 2: Preparation of Dexmethylphenidate hydrochloride of formula (A): To a solution of d-threo ritalinic acid hydrochloride of formula (III) (40 gm, 0. 1564 mole) in methanol (200 ml, 5v/w), thionyl chloride (40 gm, 0.3362 mole) was added within 1 hr by maintaining the temperature 0- 10°C. subsequently, the reaction mass was heated to reflux at 65-70°C for 4 hr. Excess methanol and low boilers were then distilled off under reduced pressure; water (80 ml, 2v/w) was added and degassed traces of methanol below 50°C. Resulting mass was then cooled to 20-25°C and added water (400 ml, 10v/w), further cooled to 0- 10°C. Dexmethylphenidate free base of formula (IV) was extracted in methylene dichloride (200 ml, 5v/w) at a pH 10- 13 using 10percent aqueous solution of NaOH below 10°C. Second extraction of methylene dichloride ( 120 ml, 3v/w) was applied, then combined both organic mass and followed by water wash (240 ml, 6v/w) below 10°C. Separated organic layer was distilled off completely at 40-45°C under reduced pressure. The obtained oily mass is free base of Dexmethylphenidate was dissolved in isopropyl alcohol (160 ml, 4v/w) and cooled to 0-10°C. Hydrochloric acid 23.64percent solution in isopropyl alcohol (36.4 gm, 0.2357 mole) was added in the reaction mass slowly within 1 hr by maintaining temperature 0-10°C. After addition completed, temperature raised to 20-25°C and allowed it to stir for 2-3 hr subsequently maintained to 0- 10°C for 1 hr. The precipitated solid was then filtered off under suction and washed with chilled isopropyl alcohol (40 ml, lv/w, 10- 15°C) of 10- 15°C, dried at 50-60°C to get 37 gm of desired pure Dexrnethylphenidate hydrochloride of formula (A) . Results: percentYield: 88percent Melting Point: 206-212°C SOR [a] D2o: +88.0° (C= 1.0percent w/v in methanol) Purity by HPLC: >99.50percent Chiral purity: >99.5percent With thionyl chloride, Time= 5h, T= 0 - 70 °C Patent; ZCL CHEMICALS LIMITED; AGARWAL, Nand Lal; BHAVSAR, Rahul Arunbhai; PATHAK, Kunal Kamleshbai; WO2014/24203; (2014); (A1) English View in Reaxys

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O

OH

O H

H N

H

O Cl

HN

H

Rx-ID: 37183451 View in Reaxys 151/189 Yield

Conditions & References Reaction Steps: 3 1: methanol; water / 20 - 80 °C / Resolution of racemate 2: hydrogenchloride / methanol; water; toluene / 60 - 70 °C 3: thionyl chloride / 5 h / 0 - 70 °C With hydrogenchloride, thionyl chloride in methanol, water, toluene Patent; ZCL CHEMICALS LIMITED; AGARWAL, Nand Lal; BHAVSAR, Rahul Arunbhai; PATHAK, Kunal Kamleshbai; WO2014/24203; (2014); (A1) English View in Reaxys

O O

O

O

H N

Cl

H

NH

Rx-ID: 40034236 View in Reaxys 152/189 Yield 78.9 %

Conditions & References 4 : Example 4 Preparation and Crystallization of Dex-Methylphenidate Hydrochloride Example 4 Preparation and Crystallization of Dex-Methylphenidate Hydrochloride [0344] Dex-Methylphenidate in an isopropyl acetate solution was prepared from dex-ritalinic acid HCl (25 g scale), as previously described herein. [0346] To a mixture of HCl (4.57) in isopropanol (50.0 g) was added water (10.0 g), and the resulting solution was heated to 40° C. The dex-methylphenidate in isopropyl acetate solution was added over 60 minutes. The resulting solution was held at 40° C. for 30 minutes, cooled to 15° C. over 30 minutes and then held at that temperature for 30 minutes. The resulting solids were filtered and washed with isopropyl acetate to yield dex-methylphenidate hydrochloride as a white crystalline solid (24.3 g, 78.9percent yield). [0347] The impurity level of the isolated solid was 0.05 area percent from in situ HPLC measurement of 0.19 area percent (before the recrystallization). With hydrogenchloride in water, isopropyl alcohol, Time= 1.5h, T= 40 °C Patent; Barr, Charla; Dobish, Mark C.; Smith, Brian J.; Stefanick, Stephen M.; US2015/133667; (2015); (A1) English View in Reaxys

O

O

O

OH

HO

O

HO

S

O

NH

OH NH

Rx-ID: 40034237 View in Reaxys 153/189 Yield

Conditions & References 2 : Synthesis of Di-Threo-Methylphenidate Sulfate Salt Synthesis of Di-Threo-Methylphenidate Sulfate Salt Di-threo-methylphenidate was prepared according to the process(es) of the present invention, varying reaction parameters including amount of DMC, amount of sulfuric acid, amount of MeOH, reaction time, reaction temperature, etc., and measuring percent unreacted di-threo-ritalinic acid, as detailed in Table 1 below. [0338] One skilled in the art will recognize that percent unreacted di-threo-ritalinic acid as listed in Table 1 below, provides an indirect measure of the product yield. One skilled in the art will further recognize that for any given example, the calculation of 100percent-(percent unreacted di-threo-ritalinic acid) provides a maximum theoretical yield for the desired di-threo-methylphenidate.

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[0339] In each experiment listed in Table 1 below, was performed essentially in accordance with the procedure outlined in Example 1 and where the order of addition was as follows: (1) di-threo-ritalinic acid, (2) dimethylcarbonate, (3) methanol, (4) sulfuric acid; followed by work-up with an inorganic base and reaction with HCl. With sulfuric acid, Time= 20h Patent; Barr, Charla; Dobish, Mark C.; Smith, Brian J.; Stefanick, Stephen M.; US2015/133667; (2015); (A1) English View in Reaxys

O

O

HO

O

NH

HO NH

O

O

O

Rx-ID: 40034238 View in Reaxys 154/189 Yield 94.2 %

Conditions & References 1 :Example 1 Synthesis of Di-Threo-Methylphenidate Hydrochloride A reactor was charged with di-threo-ritalinic acid (25.0 g, 0.114 mol, 1.0 eq.), dimethylcarbonate (43.75 g, 0.486 mol, 4.26 eq.), and methanol (4.38 g, 0.137 mol, 1.20 mol eq.). To the resulting suspension was then added sulfuric acid (16.77 g, 0.171 mol, 1.44 eq.) at 22° C. The system was allowed to naturally exotherm to ˜60° C. during the addition. The suspension was then heated to and maintained reflux temperature for 18 h 40 min. The suspension quickly turned to a pale yellow homogenous solution upon heating. Upon reaction completion the solution was cooled to room temperature (˜22° C.) and isopropyl acetate (50.0 g, 0.490 mol, 4.30 eq.) was charged to the solution. 18percent Sodium hydroxide was then added to adjust the pH of the mixture to pHα9, while maintaining an internal reaction temperature of 20° C. The internal reaction temperature was then adjusted to ˜22° C. and the mixture stirred for about 10 minutes. Agitation was ceased and the resulting biphasic mixture was allowed to separate over 20 minutes. The aqueous layer was removed and discarded. Water (37.5 g, 2.08 mol, 18.25 eq.) was added to the organic layer and the resulting mixture was stirred for 20 minutes. Agitation was ceased and the resulting biphasic mixture was allowed to settle for 20 minutes. The aqueous layer was removed and discarded to yield the organic layer (containing di-threo-methylphenidate base). In a separate reactor IPA (50.0 g, 0.832 mol, 7.30 eq.) was cooled to α20° C. and HCl(g) (4.16 g, 0.114 mol, 1.0 eq.) was slowly added to the IPA slowly while maintaining an internal temperature of α20° C. The IPA/HCl solution was then warmed to room temperature and the organic phase (containing di-threo-methylphenidate base) was added to the IPA/HCl solution via addition funnel. Isopropyl Acetate (6.25 g, 0.061 mol, 0.54 eq.) was used to rinse the addition funnel into the mixture. The mixture was stirred for 30 minutes at room temperature, then cooled to 0° C. and stirred for 17.5 h. The resulting mixture was filtered and washed with isopropanol (25 g, 0.416 mol, 3.65 eq.). The resulting solids were dried under vacuum at 40° C. to a constant weight to yield di-threo-methylphenidate hydrochloride as a white crystalline solid. (28.86 g, 94.2percent yield) Stage 1: With sulfuric acid, Time= 18.67h, T= 60 °C , Reflux Stage 2: With hydrogenchloride in Isopropyl acetate, isopropyl alcohol, Time= 0.5h, T= 20 °C , Temperature Patent; Barr, Charla; Dobish, Mark C.; Smith, Brian J.; Stefanick, Stephen M.; US2015/133667; (2015); (A1) English View in Reaxys

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O

O

O

HO

O

OH

O O

HO NH

S

O

O

OH NH

Rx-ID: 40034239 View in Reaxys 155/189 Yield

Conditions & References 2 : Synthesis of Di-Threo-Methylphenidate Sulfate Salt Synthesis of Di-Threo-Methylphenidate Sulfate Salt Di-threo-methylphenidate was prepared according to the process(es) of the present invention, varying reaction parameters including amount of DMC, amount of sulfuric acid, amount of MeOH, reaction time, reaction temperature, etc., and measuring percent unreacted di-threo-ritalinic acid, as detailed in Table 1 below. [0338] One skilled in the art will recognize that percent unreacted di-threo-ritalinic acid as listed in Table 1 below, provides an indirect measure of the product yield. One skilled in the art will further recognize that for any given example, the calculation of 100percent-(percent unreacted di-threo-ritalinic acid) provides a maximum theoretical yield for the desired di-threo-methylphenidate. [0339] In each experiment listed in Table 1 below, was performed essentially in accordance with the procedure outlined in Example 1 and where the order of addition was as follows: (1) di-threo-ritalinic acid, (2) dimethylcarbonate, (3) methanol, (4) sulfuric acid; followed by work-up with an inorganic base and reaction with HCl. With sulfuric acid, Time= 21h Patent; Barr, Charla; Dobish, Mark C.; Smith, Brian J.; Stefanick, Stephen M.; US2015/133667; (2015); (A1) English View in Reaxys

O

O

O

HO

O

OH

O O

NH

O

S

O

OH NH

Rx-ID: 40034240 View in Reaxys 156/189 Yield

Conditions & References 2 : Synthesis of Di-Threo-Methylphenidate Sulfate Salt Synthesis of Di-Threo-Methylphenidate Sulfate Salt Di-threo-methylphenidate was prepared according to the process(es) of the present invention, varying reaction parameters including amount of DMC, amount of sulfuric acid, amount of MeOH, reaction time, reaction temperature, etc., and measuring percent unreacted di-threo-ritalinic acid, as detailed in Table 1 below. [0338] One skilled in the art will recognize that percent unreacted di-threo-ritalinic acid as listed in Table 1 below, provides an indirect measure of the product yield. One skilled in the art will further recognize that for any given example, the calculation of 100percent-(percent unreacted di-threo-ritalinic acid) provides a maximum theoretical yield for the desired di-threo-methylphenidate. [0339] In each experiment listed in Table 1 below, was performed essentially in accordance with the procedure outlined in Example 1 and where the order of addition was as follows: (1) di-threo-ritalinic acid, (2) dimethylcarbonate, (3) methanol, (4) sulfuric acid; followed by work-up with an inorganic base and reaction with HCl. With sulfuric acid, Time= 22h Patent; Barr, Charla; Dobish, Mark C.; Smith, Brian J.; Stefanick, Stephen M.; US2015/133667; (2015); (A1) English View in Reaxys O HO

O H

O

N H N

H

N Cl

H

H

O S

HN

O Cl

H

O

Rx-ID: 41119578 View in Reaxys 157/189

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Yield

Conditions & References

85.7 %

1 : Preparation of d-Threo-MethylphenidateHydrochloride from d-Threo-Ritalinic AcidHydrochloride Using Diazomethane d-threo-ritalinic acid hydrochloride (10 g, 0.04 mol, iS) was added to the receiver portion of a reaction cell, followed by the addition of ethyl acetate (180 g, 18 5). The solution containing d-threo-ritalinic acid hydrochloride was then cooled to —20 C. In the generator portion of the reaction cell, 45percent potassium hydroxide solution (30 g, 3S), diethylene glycol monoethyl ether (59 g, 5.9 5) and diethyl ether (5 g, 0.5 5) were charged and heated to a temperature that was maintained between to 48° C. to 53° C.10108] Separately, a diazald solution in ether was prepared (approx 26 wt percent, 140 g, 14 5). The diazald solution was then fed into the generator, with the temperature maintained at a range of 48° C. to 53° C. The distillate was collected in the receiver, with the temperature of the receiver maintained at—15° C. to —22° C. during collection of the distillate.j0109] After collection of the distillate was complete, the receiver was heated to 10° C. and post-stirred for 12 hours. The reaction was quenched by adding 60percent acetic acid (4 g) to the receiver, maintaining the temperature at 10° C. (.-80percent conversion was observed in process). The quenched reaction solution was vacuum distilled at ambient temperature to remove diethyl ether until approximately 110 g (11 5) of solution remained. The mother liquor was filtered to remove unreacted d-threo-ritalinic acid hydrochloride (approximately 2 g wet, 0.2 5). The filtrate was cooled down to between 0-5° C., and charged with 37percent aqueous hydrochloric acid (2.70 g, 0.27 5) to precipitate solids. The precipitated solids were filtered and washed with a mixture of iProAc (5 g, 0.5 5) and acetone (27 g, 2.7 5) until an in process sample contained no less than 99.5percent of d-threo-methylphenidate hydrochloride and not more than any unknown of 0.10percent. The product was dried under vacuum at 45° C. until a constant weight was achieved (approximately 12 h). Expected yield 76percent; HPLC Purity 99.7percent area. Actual yield 85.7percent yield; HPLC purity 99.92percent area. Stage 1: With potassium hydroxide in diethyl ether, T= 48 - 53 °C Stage 2: in ethyl acetate, Time= 12h, T= -20 - 10 °C Patent; AMPAC FINE CHEMICALS LLC; MALIK, Aslam; HEMPENSTALL, Francis; DUDA, Nicholas; SULEMAN, Ali; US2015/259289; (2015); (A1) English View in Reaxys

O H

H

H N H

H 2N

O

HN

O

Rx-ID: 44983577 View in Reaxys 158/189 Yield

Conditions & References Reaction Steps: 2 1.1: O,O'-dibenzoyl-D-tartaric acid / isopropyl alcohol / 12 h / 60 °C / Cooling; Resolution of racemate 2.1: sulfuric acid / 40 h / 65 °C 2.2: pH 12 With sulfuric acid, O,O'-dibenzoyl-D-tartaric acid in isopropyl alcohol Xing, Long-Xuan; Shen, Cheng-Wu; Sun, Yuan-Yuan; Huang, Lei; Zheng, Yong-Yong; Li, Jian-Qi; Journal of Heterocyclic Chemistry; vol. 54; nb. 2; (2017); p. 1298 - 1303 View in Reaxys

O H

H

H N H

H 2N

O

HN

Cl

H

O

Rx-ID: 44983578 View in Reaxys 159/189 Yield

Conditions & References Reaction Steps: 3 1.1: O,O'-dibenzoyl-D-tartaric acid / isopropyl alcohol / 12 h / 60 °C / Cooling; Resolution of racemate 2.1: sulfuric acid / 40 h / 65 °C

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2.2: pH 12 3.1: hydrogenchloride / water / 2 h With hydrogenchloride, sulfuric acid, O,O'-dibenzoyl-D-tartaric acid in water, isopropyl alcohol Xing, Long-Xuan; Shen, Cheng-Wu; Sun, Yuan-Yuan; Huang, Lei; Zheng, Yong-Yong; Li, Jian-Qi; Journal of Heterocyclic Chemistry; vol. 54; nb. 2; (2017); p. 1298 - 1303 View in Reaxys

O H H

H

O

HO

HN

N H

O

NH 2

Rx-ID: 44983579 View in Reaxys 160/189 Yield

Conditions & References Stage 1: With sulfuric acid, Time= 40h, T= 65 °C Stage 2: With sodium hydroxide in water, pH= 12 Xing, Long-Xuan; Shen, Cheng-Wu; Sun, Yuan-Yuan; Huang, Lei; Zheng, Yong-Yong; Li, Jian-Qi; Journal of Heterocyclic Chemistry; vol. 54; nb. 2; (2017); p. 1298 - 1303 View in Reaxys

O H H

O

N

HN

Rx-ID: 44983582 View in Reaxys 161/189 Yield

Conditions & References Reaction Steps: 5 1.1: sodium amide / toluene / 2 h / 20 °C / Inert atmosphere 2.1: sulfuric acid / 12 h / 10 - 20 °C 2.2: 10 °C / pH 12 3.1: 10% palladium on activated carbon; Degussa type; hydrogen / acetic acid / 10 h / 70 °C / 15001.5 Torr / Autoclave 4.1: O,O'-dibenzoyl-D-tartaric acid / isopropyl alcohol / 12 h / 60 °C / Cooling; Resolution of racemate 5.1: sulfuric acid / 40 h / 65 °C 5.2: pH 12 With sulfuric acid, 10% palladium on activated carbon; Degussa type, O,O'-dibenzoyl-D-tartaric acid, hydrogen, sodium amide in acetic acid, isopropyl alcohol, toluene Xing, Long-Xuan; Shen, Cheng-Wu; Sun, Yuan-Yuan; Huang, Lei; Zheng, Yong-Yong; Li, Jian-Qi; Journal of Heterocyclic Chemistry; vol. 54; nb. 2; (2017); p. 1298 - 1303 View in Reaxys Reaction Steps: 5 1.1: sodium amide / toluene / 20 °C 2.1: sulfuric acid / 12 h / 10 - 20 °C 2.2: 10 °C / pH 12 3.1: 10% palladium on activated carbon; Degussa type; hydrogen / acetic acid / 10 h / 70 °C / 15001.5 Torr / Autoclave 4.1: O,O'-dibenzoyl-D-tartaric acid / isopropyl alcohol / 12 h / 60 °C / Cooling; Resolution of racemate 5.1: sulfuric acid / 40 h / 65 °C 5.2: pH 12 With sulfuric acid, 10% palladium on activated carbon; Degussa type, O,O'-dibenzoyl-D-tartaric acid, hydrogen, sodium amide in acetic acid, isopropyl alcohol, toluene

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Xing, Long-Xuan; Shen, Cheng-Wu; Sun, Yuan-Yuan; Huang, Lei; Zheng, Yong-Yong; Li, Jian-Qi; Journal of Heterocyclic Chemistry; vol. 54; nb. 2; (2017); p. 1298 - 1303 View in Reaxys

O H H

O

N

Cl

HN

H

Rx-ID: 44983583 View in Reaxys 162/189 Yield

Conditions & References Reaction Steps: 6 1.1: sodium amide / toluene / 2 h / 20 °C / Inert atmosphere 2.1: sulfuric acid / 12 h / 10 - 20 °C 2.2: 10 °C / pH 12 3.1: 10% palladium on activated carbon; Degussa type; hydrogen / acetic acid / 10 h / 70 °C / 15001.5 Torr / Autoclave 4.1: O,O'-dibenzoyl-D-tartaric acid / isopropyl alcohol / 12 h / 60 °C / Cooling; Resolution of racemate 5.1: sulfuric acid / 40 h / 65 °C 5.2: pH 12 6.1: hydrogenchloride / water / 2 h With hydrogenchloride, sulfuric acid, 10% palladium on activated carbon; Degussa type, O,O'-dibenzoyl-D-tartaric acid, hydrogen, sodium amide in water, acetic acid, isopropyl alcohol, toluene Xing, Long-Xuan; Shen, Cheng-Wu; Sun, Yuan-Yuan; Huang, Lei; Zheng, Yong-Yong; Li, Jian-Qi; Journal of Heterocyclic Chemistry; vol. 54; nb. 2; (2017); p. 1298 - 1303 View in Reaxys Reaction Steps: 6 1.1: sodium amide / toluene / 20 °C 2.1: sulfuric acid / 12 h / 10 - 20 °C 2.2: 10 °C / pH 12 3.1: 10% palladium on activated carbon; Degussa type; hydrogen / acetic acid / 10 h / 70 °C / 15001.5 Torr / Autoclave 4.1: O,O'-dibenzoyl-D-tartaric acid / isopropyl alcohol / 12 h / 60 °C / Cooling; Resolution of racemate 5.1: sulfuric acid / 40 h / 65 °C 5.2: pH 12 6.1: hydrogenchloride / water / 2 h With hydrogenchloride, sulfuric acid, 10% palladium on activated carbon; Degussa type, O,O'-dibenzoyl-D-tartaric acid, hydrogen, sodium amide in water, acetic acid, isopropyl alcohol, toluene Xing, Long-Xuan; Shen, Cheng-Wu; Sun, Yuan-Yuan; Huang, Lei; Zheng, Yong-Yong; Li, Jian-Qi; Journal of Heterocyclic Chemistry; vol. 54; nb. 2; (2017); p. 1298 - 1303 View in Reaxys

O N

Cl

H H

O

HN

Rx-ID: 44983587 View in Reaxys 163/189 Yield

Conditions & References Reaction Steps: 5 1.1: sodium amide / toluene / 2 h / 20 °C / Inert atmosphere 2.1: sulfuric acid / 12 h / 10 - 20 °C 2.2: 10 °C / pH 12 3.1: 10% palladium on activated carbon; Degussa type; hydrogen / acetic acid / 10 h / 70 °C / 15001.5 Torr / Autoclave 4.1: O,O'-dibenzoyl-D-tartaric acid / isopropyl alcohol / 12 h / 60 °C / Cooling; Resolution of racemate

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5.1: sulfuric acid / 40 h / 65 °C 5.2: pH 12 With sulfuric acid, 10% palladium on activated carbon; Degussa type, O,O'-dibenzoyl-D-tartaric acid, hydrogen, sodium amide in acetic acid, isopropyl alcohol, toluene Xing, Long-Xuan; Shen, Cheng-Wu; Sun, Yuan-Yuan; Huang, Lei; Zheng, Yong-Yong; Li, Jian-Qi; Journal of Heterocyclic Chemistry; vol. 54; nb. 2; (2017); p. 1298 - 1303 View in Reaxys Reaction Steps: 5 1.1: sodium amide / toluene / 20 °C 2.1: sulfuric acid / 12 h / 10 - 20 °C 2.2: 10 °C / pH 12 3.1: 10% palladium on activated carbon; Degussa type; hydrogen / acetic acid / 10 h / 70 °C / 15001.5 Torr / Autoclave 4.1: O,O'-dibenzoyl-D-tartaric acid / isopropyl alcohol / 12 h / 60 °C / Cooling; Resolution of racemate 5.1: sulfuric acid / 40 h / 65 °C 5.2: pH 12 With sulfuric acid, 10% palladium on activated carbon; Degussa type, O,O'-dibenzoyl-D-tartaric acid, hydrogen, sodium amide in acetic acid, isopropyl alcohol, toluene Xing, Long-Xuan; Shen, Cheng-Wu; Sun, Yuan-Yuan; Huang, Lei; Zheng, Yong-Yong; Li, Jian-Qi; Journal of Heterocyclic Chemistry; vol. 54; nb. 2; (2017); p. 1298 - 1303 View in Reaxys

O N

Cl

H H HN

O Cl

H

Rx-ID: 44983588 View in Reaxys 164/189 Yield

Conditions & References Reaction Steps: 6 1.1: sodium amide / toluene / 2 h / 20 °C / Inert atmosphere 2.1: sulfuric acid / 12 h / 10 - 20 °C 2.2: 10 °C / pH 12 3.1: 10% palladium on activated carbon; Degussa type; hydrogen / acetic acid / 10 h / 70 °C / 15001.5 Torr / Autoclave 4.1: O,O'-dibenzoyl-D-tartaric acid / isopropyl alcohol / 12 h / 60 °C / Cooling; Resolution of racemate 5.1: sulfuric acid / 40 h / 65 °C 5.2: pH 12 6.1: hydrogenchloride / water / 2 h With hydrogenchloride, sulfuric acid, 10% palladium on activated carbon; Degussa type, O,O'-dibenzoyl-D-tartaric acid, hydrogen, sodium amide in water, acetic acid, isopropyl alcohol, toluene Xing, Long-Xuan; Shen, Cheng-Wu; Sun, Yuan-Yuan; Huang, Lei; Zheng, Yong-Yong; Li, Jian-Qi; Journal of Heterocyclic Chemistry; vol. 54; nb. 2; (2017); p. 1298 - 1303 View in Reaxys Reaction Steps: 6 1.1: sodium amide / toluene / 20 °C 2.1: sulfuric acid / 12 h / 10 - 20 °C 2.2: 10 °C / pH 12 3.1: 10% palladium on activated carbon; Degussa type; hydrogen / acetic acid / 10 h / 70 °C / 15001.5 Torr / Autoclave 4.1: O,O'-dibenzoyl-D-tartaric acid / isopropyl alcohol / 12 h / 60 °C / Cooling; Resolution of racemate 5.1: sulfuric acid / 40 h / 65 °C 5.2: pH 12 6.1: hydrogenchloride / water / 2 h With hydrogenchloride, sulfuric acid, 10% palladium on activated carbon; Degussa type, O,O'-dibenzoyl-D-tartaric acid, hydrogen, sodium amide in water, acetic acid, isopropyl alcohol, toluene

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Xing, Long-Xuan; Shen, Cheng-Wu; Sun, Yuan-Yuan; Huang, Lei; Zheng, Yong-Yong; Li, Jian-Qi; Journal of Heterocyclic Chemistry; vol. 54; nb. 2; (2017); p. 1298 - 1303 View in Reaxys

N

O H H

O

N

HN

Rx-ID: 44983591 View in Reaxys 165/189 Yield

Conditions & References Reaction Steps: 4 1.1: sulfuric acid / 12 h / 10 - 20 °C 1.2: 10 °C / pH 12 2.1: 10% palladium on activated carbon; Degussa type; hydrogen / acetic acid / 10 h / 70 °C / 15001.5 Torr / Autoclave 3.1: O,O'-dibenzoyl-D-tartaric acid / isopropyl alcohol / 12 h / 60 °C / Cooling; Resolution of racemate 4.1: sulfuric acid / 40 h / 65 °C 4.2: pH 12 With sulfuric acid, 10% palladium on activated carbon; Degussa type, O,O'-dibenzoyl-D-tartaric acid, hydrogen in acetic acid, isopropyl alcohol Xing, Long-Xuan; Shen, Cheng-Wu; Sun, Yuan-Yuan; Huang, Lei; Zheng, Yong-Yong; Li, Jian-Qi; Journal of Heterocyclic Chemistry; vol. 54; nb. 2; (2017); p. 1298 - 1303 View in Reaxys N

O H H N

O

HN

Cl

H

Rx-ID: 44983592 View in Reaxys 166/189 Yield

Conditions & References Reaction Steps: 5 1.1: sulfuric acid / 12 h / 10 - 20 °C 1.2: 10 °C / pH 12 2.1: 10% palladium on activated carbon; Degussa type; hydrogen / acetic acid / 10 h / 70 °C / 15001.5 Torr / Autoclave 3.1: O,O'-dibenzoyl-D-tartaric acid / isopropyl alcohol / 12 h / 60 °C / Cooling; Resolution of racemate 4.1: sulfuric acid / 40 h / 65 °C 4.2: pH 12 5.1: hydrogenchloride / water / 2 h With hydrogenchloride, sulfuric acid, 10% palladium on activated carbon; Degussa type, O,O'-dibenzoyl-D-tartaric acid, hydrogen in water, acetic acid, isopropyl alcohol Xing, Long-Xuan; Shen, Cheng-Wu; Sun, Yuan-Yuan; Huang, Lei; Zheng, Yong-Yong; Li, Jian-Qi; Journal of Heterocyclic Chemistry; vol. 54; nb. 2; (2017); p. 1298 - 1303 View in Reaxys

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H 2N

O

O

H H

N

O

HN

Rx-ID: 44983594 View in Reaxys 167/189 Yield

Conditions & References Reaction Steps: 3 1.1: 10% palladium on activated carbon; Degussa type; hydrogen / acetic acid / 10 h / 70 °C / 15001.5 Torr / Autoclave 2.1: O,O'-dibenzoyl-D-tartaric acid / isopropyl alcohol / 12 h / 60 °C / Cooling; Resolution of racemate 3.1: sulfuric acid / 40 h / 65 °C 3.2: pH 12 With sulfuric acid, 10% palladium on activated carbon; Degussa type, O,O'-dibenzoyl-D-tartaric acid, hydrogen in acetic acid, isopropyl alcohol Xing, Long-Xuan; Shen, Cheng-Wu; Sun, Yuan-Yuan; Huang, Lei; Zheng, Yong-Yong; Li, Jian-Qi; Journal of Heterocyclic Chemistry; vol. 54; nb. 2; (2017); p. 1298 - 1303 View in Reaxys

H 2N

O

O H H

N

O Cl

HN

H

Rx-ID: 44983595 View in Reaxys 168/189 Yield

Conditions & References Reaction Steps: 4 1.1: 10% palladium on activated carbon; Degussa type; hydrogen / acetic acid / 10 h / 70 °C / 15001.5 Torr / Autoclave 2.1: O,O'-dibenzoyl-D-tartaric acid / isopropyl alcohol / 12 h / 60 °C / Cooling; Resolution of racemate 3.1: sulfuric acid / 40 h / 65 °C 3.2: pH 12 4.1: hydrogenchloride / water / 2 h With hydrogenchloride, sulfuric acid, 10% palladium on activated carbon; Degussa type, O,O'-dibenzoyl-D-tartaric acid, hydrogen in water, acetic acid, isopropyl alcohol Xing, Long-Xuan; Shen, Cheng-Wu; Sun, Yuan-Yuan; Huang, Lei; Zheng, Yong-Yong; Li, Jian-Qi; Journal of Heterocyclic Chemistry; vol. 54; nb. 2; (2017); p. 1298 - 1303 View in Reaxys

H 2N

O

O

H

H N

H

O

HN

Rx-ID: 44983597 View in Reaxys 169/189 Yield

Conditions & References Reaction Steps: 3 1.1: potassium tert-butylate / toluene / 6 h / 70 °C / Inert atmosphere 2.1: O,O'-dibenzoyl-D-tartaric acid / isopropyl alcohol / 12 h / 60 °C / Cooling; Resolution of racemate 3.1: sulfuric acid / 40 h / 65 °C 3.2: pH 12 With sulfuric acid, O,O'-dibenzoyl-D-tartaric acid, potassium tert-butylate in isopropyl alcohol, toluene

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Xing, Long-Xuan; Shen, Cheng-Wu; Sun, Yuan-Yuan; Huang, Lei; Zheng, Yong-Yong; Li, Jian-Qi; Journal of Heterocyclic Chemistry; vol. 54; nb. 2; (2017); p. 1298 - 1303 View in Reaxys

H 2N

O

O H

H N

H

O Cl

HN

H

Rx-ID: 44983598 View in Reaxys 170/189 Yield

Conditions & References Reaction Steps: 4 1.1: potassium tert-butylate / toluene / 6 h / 70 °C / Inert atmosphere 2.1: O,O'-dibenzoyl-D-tartaric acid / isopropyl alcohol / 12 h / 60 °C / Cooling; Resolution of racemate 3.1: sulfuric acid / 40 h / 65 °C 3.2: pH 12 4.1: hydrogenchloride / water / 2 h With hydrogenchloride, sulfuric acid, O,O'-dibenzoyl-D-tartaric acid, potassium tert-butylate in water, isopropyl alcohol, toluene Xing, Long-Xuan; Shen, Cheng-Wu; Sun, Yuan-Yuan; Huang, Lei; Zheng, Yong-Yong; Li, Jian-Qi; Journal of Heterocyclic Chemistry; vol. 54; nb. 2; (2017); p. 1298 - 1303 View in Reaxys

O

O

O

O

O

HO

H N

H Cl

OH

H

HN

Rx-ID: 45725581 View in Reaxys 171/189 Yield 84 %

Conditions & References 1.9 Synthesis of (R, R), (R, S), (S, S) and (S, R) methyl 2-piperidin-2-yl-phenylacetate hydrochloride (1a, 1b, 1c and 1d) General procedure: Compound 8a, 8b, 8c or 8d (400 mg, 1.3 mmol) was dissolved into methanol solution (15 mL), and then thionyl chloride (1 mL) was added drop-wise. The reaction mixture was stirred for 12 hours and concentrated in vacuum; a white solid was precipitated and filtered to afford the final product. (1a. 0.28 g, 82percent yield; 1b. 0.30 g, 84percent yield; 1c. 0.31 g, 85percent yield; 1d. 0.30 g, 84percent yield). With thionyl chloride, Time= 12h Li, Chunzheng; Ji, Yuanbo; Cao, Qing; Li, Jianqi; Li, Bonan; Synthetic Communications; vol. 47; nb. 14; (2017); p. 1301 1306 View in Reaxys

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O

O

O H

O

H

O

H

HO

N

OH

Cl

HN

H

Rx-ID: 45725582 View in Reaxys 172/189 Yield

Conditions & References

85 %

1.9 Synthesis of (R, R), (R, S), (S, S) and (S, R) methyl 2-piperidin-2-yl-phenylacetate hydrochloride (1a, 1b, 1c and 1d) General procedure: Compound 8a, 8b, 8c or 8d (400 mg, 1.3 mmol) was dissolved into methanol solution (15 mL), and then thionyl chloride (1 mL) was added drop-wise. The reaction mixture was stirred for 12 hours and concentrated in vacuum; a white solid was precipitated and filtered to afford the final product. (1a. 0.28 g, 82percent yield; 1b. 0.30 g, 84percent yield; 1c. 0.31 g, 85percent yield; 1d. 0.30 g, 84percent yield). With thionyl chloride, Time= 12h Li, Chunzheng; Ji, Yuanbo; Cao, Qing; Li, Jianqi; Li, Bonan; Synthetic Communications; vol. 47; nb. 14; (2017); p. 1301 1306 View in Reaxys

O

O

O

O

O H

HO

N

H Cl

OH

H

HN

Rx-ID: 45725583 View in Reaxys 173/189 Yield

Conditions & References

84 %

1.9 Synthesis of (R, R), (R, S), (S, S) and (S, R) methyl 2-piperidin-2-yl-phenylacetate hydrochloride (1a, 1b, 1c and 1d) General procedure: Compound 8a, 8b, 8c or 8d (400 mg, 1.3 mmol) was dissolved into methanol solution (15 mL), and then thionyl chloride (1 mL) was added drop-wise. The reaction mixture was stirred for 12 hours and concentrated in vacuum; a white solid was precipitated and filtered to afford the final product. (1a. 0.28 g, 82percent yield; 1b. 0.30 g, 84percent yield; 1c. 0.31 g, 85percent yield; 1d. 0.30 g, 84percent yield). With thionyl chloride, Time= 12h Li, Chunzheng; Ji, Yuanbo; Cao, Qing; Li, Jianqi; Li, Bonan; Synthetic Communications; vol. 47; nb. 14; (2017); p. 1301 1306 View in Reaxys

O

OH

O

O

H H O

O H

HN

O Cl

H

NH

Rx-ID: 46851562 View in Reaxys 174/189

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Yield

Conditions & References

96 %

5 : Preparation of dexmethylphenidate hydrochloride 100mL three-necked flask, 5.00 g (11.17 mmol) of organic salt of (-) - menthoxyacetic acid of dexmethylphenidate, 25 mL of methanol, Warming to 40 deg C clear, 5.5 mL (17.88 mmol) of 10percent hydrochloric acid was added dropwise and reacted at 40 ° C for 0.5 h. After the reaction was cooled to 25 ° C, 150 mL of ether was added and stirred for 1 h. Filtration gave 2.40 g of an off-white solid in 96percent yield, with no detectable ester hydrolysis impurities and transesterification impurities With hydrogenchloride in methanol, water, Time= 0.5h, T= 40 °C Patent; Shanghai Pharmaceutical Industry Institute; China Pharmaceutical Industry Zongyuan; Zhang Fuli; Zhang Jie; Yang Zhezhou; Zhang Lin; Chen Lingling; Wang Zhengwen; Gao Shenghua; (8 pag.); CN107325039; (2017); (A) Chinese View in Reaxys

O

OH O

O H

H N

O

O

H

H

O

H

O Cl

HN

O

H

O O

OH

Rx-ID: 46851563 View in Reaxys 175/189 Yield

Conditions & References

96.5 %

1 : Preparation of dexmethylphenidate hydrochloride A 100 mL three-necked flask was charged with 3.50 g (5.92 mmol) dexmethylphenidate of D-DBTA organic salt and 20 mL of isopropanol. The mixture was warmed to 50 ° C. and then added dropwise to 0.8 mL 6.67 mmol) 37percent hydrochloric acid, at 50 ° C under reaction lh. After the reaction was cooled to 25 ° C, 40mL isopropyl ether was added and stirred lh. Filtration yielded an white solid 1.54 g, 96.5percent yield, with no ester hydrolysis impurities and transesterification impurities detected. With hydrogenchloride in water, isopropyl alcohol, Time= 1h, T= 50 °C Patent; Shanghai Pharmaceutical Industry Institute; China Pharmaceutical Industry Zongyuan; Zhang Fuli; Zhang Jie; Yang Zhezhou; Zhang Lin; Chen Lingling; Wang Zhengwen; Gao Shenghua; (8 pag.); CN107325039; (2017); (A) Chinese View in Reaxys

O O

O H

O

H OH

H O

HN

OH

O Cl

H

O NH

O

O O

Rx-ID: 46851564 View in Reaxys 176/189 Yield 97 %

Conditions & References 2 : Preparation of dexmethylphenidate hydrochloride 100mL three-necked flask, 5.00 g (8.87 mmol) dexmethylphenidate of D-DTTA organic salt , 25mL isopropanol, warmed to 50 ° C clear, 1.1 mL (13.30 mmol) of 37percent hydrochloric acid was added dropwise, The reaction was carried out at 50 ° C for 1 hour. After the reaction was cooled to 25 ° C, Add 50mL ether and stir for 1h. filter, Obtained as an off-white solid 2.32g, yield 97.0percent No ester hydrolysis impurities and transesterification impurities were detected With hydrogenchloride in water, isopropyl alcohol, Time= 1h, T= 50 °C , Temperature, Solvent, Reagent/catalyst

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Patent; Shanghai Pharmaceutical Industry Institute; China Pharmaceutical Industry Zongyuan; Zhang Fuli; Zhang Jie; Yang Zhezhou; Zhang Lin; Chen Lingling; Wang Zhengwen; Gao Shenghua; (8 pag.); CN107325039; (2017); (A) Chinese View in Reaxys

O

O O

OH

H H

HO

H OH

O

O

OH

Cl

HN

H

NH

O

Rx-ID: 46851565 View in Reaxys 177/189 Yield

Conditions & References

97.5 %

3 : Preparation of dexmethylphenidate hydrochloride 100mL three-necked flask, 5.00 g (8.87 mmol) of the dexmethylphenidate of D-tartaric acid organic salt , 25 mL isopropanol, Warming to 45° C clear, Add 1.1 drops mL (13.30 mmol) 37percent hydrochloric acid, The reaction was carried out at 50 ° C for 1 hour. After the reaction was cooled to 25 ° C, Add 55 mL ether and stir for 1 h. filter, Obtained white white solid 3.42g, yield 97.5percent, and not seized Ester hydrolysis impurities and transesterification impurities were measured With hydrogenchloride in water, isopropyl alcohol, Time= 1h, T= 45 - 50 °C Patent; Shanghai Pharmaceutical Industry Institute; China Pharmaceutical Industry Zongyuan; Zhang Fuli; Zhang Jie; Yang Zhezhou; Zhang Lin; Chen Lingling; Wang Zhengwen; Gao Shenghua; (8 pag.); CN107325039; (2017); (A) Chinese View in Reaxys

OH

O

O

OH

H H

O

O

O H

Cl

HN

H

NH

Rx-ID: 46851566 View in Reaxys 178/189 Yield 94.4 %

Conditions & References 4 : Preparation of dexmethylphenidate hydrochloride 100mL three-necked flask, 5.00 g (12.98 mmol) of the organic salt dexmethylphenidate of D-mandelic acid, 50mL ethanol, dissolved at 20 deg C, 2.4 mL (14.28 mmol) of 20percent hydrochloric acid was added dropwise, The reaction was carried out at 20 ° C for 1 hour. After the reaction was completed, 20 mL of diethyl ether was added at 20 ° C and stirred for 1 h. filter, Obtained as an off-white solid 2.36g, yield 94.4percent No ester hydrolysis impurities and transesterification impurities were detected. With hydrogenchloride in ethanol, water, Time= 1h, T= 20 °C Patent; Shanghai Pharmaceutical Industry Institute; China Pharmaceutical Industry Zongyuan; Zhang Fuli; Zhang Jie; Yang Zhezhou; Zhang Lin; Chen Lingling; Wang Zhengwen; Gao Shenghua; (8 pag.); CN107325039; (2017); (A) Chinese View in Reaxys

O

OH O

H N

HO

O

H N

Cl

H

Rx-ID: 47313854 View in Reaxys 179/189

Copyright © 2018 Reed Elsevier Properties SA. All rights reserved. Authorized use only. Reaxys® and the Reaxys® trademark are owned and protected by Reed Elsevier Properties SA and used under license.

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Yield

Conditions & References

89 %

2 : Preparation of di-threomethyl phenidate hydrochloride To a solution of threo -phenyl- -pipyridyl-2-acetic acid (75 g) and methanol (750m1) was added thi onyl chloride (83g) mai ntai ni ng the temperature below 1 OC. The reaction mass was kept under stirring overnight at room temperature. Excess methanol was then distilled off under reduced pressure and the reaction mass was further cooled to lOC. Purified water (900 ml) was then charged maintaining the temperature between 0-1 OC followed by addition of ethyl acetate (375 ml) under constant stirring. pH of the mixture was made alkaline using dilute caustic solution, with sti rn ng followed by separation of the layers. The separated aqueous layer was once again extracted with ethyl acetate (225 ml). The combined ethyl acetate layers were then washed with water and ethyl acetate distilled off completely. To the residue was charged i sopropyl alcohol (225 ml) and cooled to 0-SeC. The reaction mass as then acidified by adding hydrochloric acid (25percent solution in isopropanol) at 0-1 OC. The temperature was raised to 25C, stirred at this temperature for 2-4 hrs, cooled the reaction mass again to 0-lOC and stirred for 2 hrs. The precipitated solid was filtered off, washed with chilled isopropyl alcohol and air dried to get 82.2 g (89.0percent) of dlthreo methyl phenidate hydrochloride.(Chromatographic purity by H PLC: > 99.5percent) Stage 1: With thionyl chloride, T= 10 - 20 °C Stage 2: With hydrogenchloride in isopropyl alcohol, T= 0 - 25 °C Patent; HARMAN FINOCHEM LIMITED; KADAM, Vijay Trimbak; SARANAPU, Nareesh; CHAVAN, Santosh Uttamrao; MINHAS, Harpreet Singh; MINHAS, Gurpreet Singh; (18 pag.); WO2018/15971; (2018); (A1) English View in Reaxys

O

NH 2 O

O

H Cl

HN

H

HN

Rx-ID: 47313855 View in Reaxys 180/189 Yield

Conditions & References Reaction Steps: 5 1.1: water; hydrogenchloride / Reflux 2.1: thionyl chloride / 10 - 20 °C 2.2: 0 - 25 °C 3.1: sodium hydroxide / ethyl acetate / 0 - 25 °C 4.1: acetone / 2 h / 20 °C 5.1: sodium hydroxide / water; dichloromethane / pH Ca. 11 With hydrogenchloride, thionyl chloride, water, sodium hydroxide in dichloromethane, water, ethyl acetate, acetone Patent; HARMAN FINOCHEM LIMITED; KADAM, Vijay Trimbak; SARANAPU, Nareesh; CHAVAN, Santosh Uttamrao; MINHAS, Harpreet Singh; MINHAS, Gurpreet Singh; (18 pag.); WO2018/15971; (2018); (A1) English View in Reaxys

O

NH 2 O

O

H N

Cl

H

HN

Rx-ID: 47313857 View in Reaxys 181/189 Yield

Conditions & References Reaction Steps: 2 1.1: water; hydrogenchloride / Reflux 2.1: thionyl chloride / 10 - 20 °C 2.2: 0 - 25 °C With hydrogenchloride, thionyl chloride, water

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Patent; HARMAN FINOCHEM LIMITED; KADAM, Vijay Trimbak; SARANAPU, Nareesh; CHAVAN, Santosh Uttamrao; MINHAS, Harpreet Singh; MINHAS, Gurpreet Singh; (18 pag.); WO2018/15971; (2018); (A1) English View in Reaxys

O

NH 2

O

O

H N HN

Rx-ID: 47313858 View in Reaxys 182/189 Yield

Conditions & References Reaction Steps: 3 1.1: water; hydrogenchloride / Reflux 2.1: thionyl chloride / 10 - 20 °C 2.2: 0 - 25 °C 3.1: sodium hydroxide / ethyl acetate / 0 - 25 °C With hydrogenchloride, thionyl chloride, water, sodium hydroxide in ethyl acetate Patent; HARMAN FINOCHEM LIMITED; KADAM, Vijay Trimbak; SARANAPU, Nareesh; CHAVAN, Santosh Uttamrao; MINHAS, Harpreet Singh; MINHAS, Gurpreet Singh; (18 pag.); WO2018/15971; (2018); (A1) English View in Reaxys

O

NH 2

O

O

H N O

O

HN

O

S

H NH

HO O

HO

Rx-ID: 47313859 View in Reaxys 183/189 Yield

Conditions & References Reaction Steps: 4 1.1: water; hydrogenchloride / Reflux 2.1: thionyl chloride / 10 - 20 °C 2.2: 0 - 25 °C 3.1: sodium hydroxide / ethyl acetate / 0 - 25 °C 4.1: acetone / 2 h / 20 °C With hydrogenchloride, thionyl chloride, water, sodium hydroxide in ethyl acetate, acetone Patent; HARMAN FINOCHEM LIMITED; KADAM, Vijay Trimbak; SARANAPU, Nareesh; CHAVAN, Santosh Uttamrao; MINHAS, Harpreet Singh; MINHAS, Gurpreet Singh; (18 pag.); WO2018/15971; (2018); (A1) English View in Reaxys

O

OH O

H N

O

H Cl

H

HN

Rx-ID: 47313860 View in Reaxys 184/189

Copyright © 2018 Reed Elsevier Properties SA. All rights reserved. Authorized use only. Reaxys® and the Reaxys® trademark are owned and protected by Reed Elsevier Properties SA and used under license.

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Yield

Conditions & References Reaction Steps: 4 1.1: thionyl chloride / 10 - 20 °C 1.2: 0 - 25 °C 2.1: sodium hydroxide / ethyl acetate / 0 - 25 °C 3.1: acetone / 2 h / 20 °C 4.1: sodium hydroxide / water; dichloromethane / pH Ca. 11 With thionyl chloride, sodium hydroxide in dichloromethane, water, ethyl acetate, acetone Patent; HARMAN FINOCHEM LIMITED; KADAM, Vijay Trimbak; SARANAPU, Nareesh; CHAVAN, Santosh Uttamrao; MINHAS, Harpreet Singh; MINHAS, Gurpreet Singh; (18 pag.); WO2018/15971; (2018); (A1) English View in Reaxys

O

OH

O H N

O

H N

Rx-ID: 47313861 View in Reaxys 185/189 Yield

Conditions & References Reaction Steps: 2 1.1: thionyl chloride / 10 - 20 °C 1.2: 0 - 25 °C 2.1: sodium hydroxide / ethyl acetate / 0 - 25 °C With thionyl chloride, sodium hydroxide in ethyl acetate Patent; HARMAN FINOCHEM LIMITED; KADAM, Vijay Trimbak; SARANAPU, Nareesh; CHAVAN, Santosh Uttamrao; MINHAS, Harpreet Singh; MINHAS, Gurpreet Singh; (18 pag.); WO2018/15971; (2018); (A1) English View in Reaxys

O

OH O

H N

O

H N O

O

O

S

H NH

HO

HO

O

Rx-ID: 47313862 View in Reaxys 186/189 Yield

Conditions & References Reaction Steps: 3 1.1: thionyl chloride / 10 - 20 °C 1.2: 0 - 25 °C 2.1: sodium hydroxide / ethyl acetate / 0 - 25 °C 3.1: acetone / 2 h / 20 °C With thionyl chloride, sodium hydroxide in ethyl acetate, acetone Patent; HARMAN FINOCHEM LIMITED; KADAM, Vijay Trimbak; SARANAPU, Nareesh; CHAVAN, Santosh Uttamrao; MINHAS, Harpreet Singh; MINHAS, Gurpreet Singh; (18 pag.); WO2018/15971; (2018); (A1) English View in Reaxys

Copyright © 2018 Reed Elsevier Properties SA. All rights reserved. Authorized use only. Reaxys® and the Reaxys® trademark are owned and protected by Reed Elsevier Properties SA and used under license.

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O

O

O

H N

Cl

O

H N

H

O

O

O

S

H NH

HO

HO

O

Rx-ID: 47313864 View in Reaxys 187/189 Yield

Conditions & References Reaction Steps: 2 1: sodium hydroxide / ethyl acetate / 0 - 25 °C 2: acetone / 2 h / 20 °C With sodium hydroxide in ethyl acetate, acetone Patent; HARMAN FINOCHEM LIMITED; KADAM, Vijay Trimbak; SARANAPU, Nareesh; CHAVAN, Santosh Uttamrao; MINHAS, Harpreet Singh; MINHAS, Gurpreet Singh; (18 pag.); WO2018/15971; (2018); (A1) English View in Reaxys

O

O

HO

O

O

O O

H N

O

H N

S NH

O

O

H

O

S

H NH

HO

O

HO

HO

O

Rx-ID: 47313865 View in Reaxys 188/189 Yield 79.2 g

Conditions & References 8 : Preparation of L -tosylglutamate Salt of Dexmethylphenidate A mixture of 60.9 gm L-tosyl glutamic acid and 76 gmdl-threo methylphenidate in acetone is stirred for 2 hours at ambient temperature. T he slurry was filtered and washed with 50 ml acetone. Dried the material to obtain glutamate salt of L-tosyl Dexmethylphenidate as a white solid (79.2 gm) in acetone, Time= 2h, T= 20 °C , Temperature Patent; HARMAN FINOCHEM LIMITED; KADAM, Vijay Trimbak; SARANAPU, Nareesh; CHAVAN, Santosh Uttamrao; MINHAS, Harpreet Singh; MINHAS, Gurpreet Singh; (18 pag.); WO2018/15971; (2018); (A1) English View in Reaxys

O

O

H

H O

O

O

S

Cl

N H

H

HN

NH O

O

HO

HO

O

Rx-ID: 47313866 View in Reaxys 189/189

Copyright © 2018 Reed Elsevier Properties SA. All rights reserved. Authorized use only. Reaxys® and the Reaxys® trademark are owned and protected by Reed Elsevier Properties SA and used under license.

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Yield 6.13 g

Conditions & References 11 : Preparation of pure Dexmethylphenidate Hydrochloride To a mixture of N-tosyl glutamate salt of dexmethylphenidate (12.46gm), water (150 ml) and MDC (150 ml), added 2NNaOH solution to adjust the pH to —11.0. Separated the layers, MDC layer was washed with water and the aqueous layer was extracted with MDC. Combined both M DC layers, dried over sodium sulphate and concentrated under reduced pressure to yield crude dexmethyl pheni date. The crude dex methyl pheni date was taken in i sopropyl alcohol and heated to get clear solution. Cooled to room temperature and stirred for 1 hour, to which slowly added IPA . H Cl solution to obtain a white crystalline solid. Filtered the solid and washed with isopropyl alcohol. Dried the product under vacuum below 7OC to obtain pure dexmethylphenidate hydrochloride (6.13gm) having an optical purity of 99.9percent Stage 1: With sodium hydroxide in dichloromethane, water, pH= Ca. 11 Stage 2: With hydrogenchloride in isopropyl alcohol, pH-value, Solvent Patent; HARMAN FINOCHEM LIMITED; KADAM, Vijay Trimbak; SARANAPU, Nareesh; CHAVAN, Santosh Uttamrao; MINHAS, Harpreet Singh; MINHAS, Gurpreet Singh; (18 pag.); WO2018/15971; (2018); (A1) English View in Reaxys

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