Patent EA-001207-B1 (EA)
Title: PROCESS FOR THE PREPARATION OF R-a-PROPYL-PIPERONYL AMINE AND ITS ANALOGS, INTERMEDIATE PRODUCTS USED IN SAID PROCESS
Inventor: LI HUI-YIN
IPC: A61K31/496
Filed: 1997-03-17
Abstract: 1. A process for the synthesis of a compound of formula I:   or stereoisomer or salt form thereof, comprising:  (a) contacting a compound of formula II:   with a chiral methylbenzylamine to form a compound of formula III:   or stereoisomer thereof, wherein R is selected from H, OH and. OCH3; (b) hydrogenating a compound of formula III of stereoisomer or salt form thereof in the presence of Ra-Ni to form a compound of formula IV:   or diastereomer or salt form thereof, wherein the hydrogenation is performed under conditions selected from: (bi) about 0.0007-0.703 kg/cm<2> (0.01-10 psi) of hydrogen at one temperature of from 0-100 degree C for about 2-30 hours or 10-3000 psi at one temperature of from 60 to 80 degree C for about 2-30 hours; or 0.703-210.9 kg/cm<2> (10-300 psi) at one temperature of from 60-80 degree C for about 2-30 hours; or (bii) about 0.0007-210.9 kg/cm<2> (0.01-3000 psi) of hydrogen at a first temperature for about 2-8 hours and a second temperature for about 2-24 hours, the first temperature being from 0-35 degree C and the second temperature being from 50-100 degree C; and,  (c) hydrogenating a compound of formula IV or stereoisomer or salt form thereof in the presence of palladium on carbon and a solvent selected from an alcohol, a carboxylic acid, a dicarboxylic acid, an aromatic carboxylic acid and mixtures thereof to form a compound of formula I or stereoisomer or salt form thereof; provided that the compound of formula IV hydrogenated in step (c) is not a hydrogen bromide salt.  2. A process according to claim 1, wherein in step (a), the chiral methylbenzylamine is R-.alpha.-methylbenzylamine, in step (b) R is H, and in step (c) R is H and the solvent is selected from a C1-3 alcohol, a C2-4 carboxylic acid, and mixtures thereof. 3. A process according to claim 2, wherein hydrogenation step (b) is performed under conditions (bi) under 0.0007-o.703 kg/cm<2> (0.01-10 psi) of hydrogen; and, hydrogenation step (c) is performed in a mixture of a C1-3 alcohol and a C2-4 acid, wherein the alcohol and acid are present in a ratio of from 30:1 to 1:10. 4. A process according to claim 3, wherein hydrogenation step (bi) is performed under 0.0007-0.141 kg/cm<2> (0.01-2 psi) of hydrogen at a temperature of from 20 to 60 degree C for from 3-24 hours; and, in hydrogenation step (c), the alcohol is selected from methanol and ethanol, the acid is acetic acid, and the ratio of alcohol to acid is from 30:1 to 1:1. 5. A process according to claim 4, wherein hydrogenation step (bi) is performed under 0.0007-0.070 kg/cm<2> (0.01-1 psi) of hydrogen at a temperature selected from ambient temperature or 50 to 60 degree C for from 3-12 hours; and, hydrogenation step (c) is performed in ethanol and acetic acid in a ratio of from 20:1 to 8:1. 6. A process according to claim 4, wherein hydrogenation step (bi) is performed under 0.0007-0.070 kg/cm<2> (0.01-1 psi) of hydrogen at a temperature selected from ambient temperature or 50 to 60 degree C for from 3-12 hours; and hydrogenation step (c) is performed in methanol and acetic acid in a ratio of from 20:1 to 8:1. 7. A process according to claim 3, wherein in step (c) from 1 to 4 equivalents of acid based on the amount of IV are present. 8. A process according to claim 3, wherein in step (c) about 2 equivalents of acid based on the amount of IV are present. 9. A process according to claim 2, wherein hydrogenation step (b) is performed under conditions (bi) under 0.703-70.3 kg/cm<2> (10-1000 psi) hydrogen at a temperature of from 60 to 80 degree C for from 3-24 hours. 10. A process according to claim 9, wherein hydrogenation step (bi) is performed under 3.515-35.15 kg/cm<2> (50-500 psi) hydrogen. 11. A process according to claim 1, wherein hydrogenation step (b) is performed under conditions (bii); and, hydrogenation step (c) is performed in a mixture of a C1-3 alcohol and a C2-4 acid, wherein the alcohol and acid are present in a ratio of from 30:1 to 1:10. 12. A process according to claim 11, wherein hydrogenation step (bii) is performed under from 3.515-35.15 kg/cm<2> (50-500 psi) of hydrogen at a first temperature of from 20-30 degree C for about 3-6 hours and a second temperature of from 60-80 degree C for about 6-18 hours; and, in hydrogenation step (c), the alcohol is selected from methanol and ethanol, the acid is acetic acid, and the ratio of alcohol to acid is from 30:1 to 1:1. 13. A process according to claim 12, wherein hydrogenation step (bii) is performed under from 3.515-35.15 kg/cm<2> (50-500 psi) of hydrogen at a first temperature of from 20-30 degree C for about 3-6 hours and a second temperature of from 60-80 degree C for about 10-15 hours; and  in hydrogenation step (c), the alcohol is selected from methanol and ethanol, the acid is acetic acid, and the ratio of alcohol to acid is from 30:1 to 1:1. 14. A process according to claim 13, wherein hydrogenation step (bii) is performed under from 7.03-21.09 kg/cm<2> (100-300 psi) of hydrogen at a first temperature which is about ambient temperature for about 3, 4, 5, or 6 hours and a second temperature of from 65-75 degree C for about 10, 11, 12, 13, 14, or 15 hours; and  hydrogenation step (c) is performed in ethanol and acetic acid in a ratio of from 20:1 to 8:1. 15. A process according to claim 13, wherein hydrogenation step (bii) is performed under from 7.03-21.09 kg/cm<2> (100-300 psi) of hydrogen at a first temperature which is about ambient temperature for about 3, 4, 5, or 6 hours and a second temperature of from 65-75 degree C for about 10, 11, 12, 13, 14, or 15 hours; and hydrogenation step (c) is performed in methanol and acetic acid in a ratio of from 20:1 to 8:1. 16. A process according to claim 11, wherein in step (c) about 1 to 4 equivalents of acid based on the amount of IV are present. 17. A process according to claim 11, wherein in step (c) about 2 equivalents of acid based on the amount of IV are present. 18. A process for the synthesis of a compound of formula I:   or stereoisomer or salt thereof, comprising:  (d) contacting a compound of formula V:   with a chiral methylbenzylamine to form a compound of formula VI:   or stereoisomer or salt form thereof, wherein R is H, OH, or OCH3;  (e) contacting the compound of formula VI or stereoisomer or salt form thereof with allylmagnesium bromide to form a compound of formula VII:   or diastereoisomer or salt form thereof, wherein R is H, OH, or OCH3 and the diastereomeric excess obtained is at least 75%; and, (f) hydrogenating a compound of formula VII or diastereomer or salt form thereof in the presence of palladium on carbon in a C1-3 alcohol and a C2-4 carboxylic acid to form a compound of Formula I or stereoisomer or salt form thereof; provided that a cerium reagent is not present in step (e). 19. A process according to claim 18, wherein the chiral methylbenzylamine in step (d) is S-phenyl glycinol and R is OH in steps (e) and (f). 20. A process according to claim 19, wherein in step (e) the diastereomeric excess obtained is at least 85%; and in step (f) the alcohol is selected from methanol and ethanol and the acid is acetic acid and the ratio of alcohol to acid is from 10:1 to 1:10. 21. A process according to claim 20, wherein in step (e) the diastereomeric excess obtained is at least 90%; and, in step (f) the alcohol is ethanol and the ratio of alcohol to acid is from 10:1 to 1:1. 22. A process according to claim 20, wherein in step (e) the diastereomeric excess obtained is at least 90%; and in step (f) the alcohol is methanol and the ratio of alcohol to acid is from 10:1 to 1:1. 23. A process according to claim 19, wherein tetrahydrofuran is used as solvent in step (e). 24. A compound of formula IV:   wherein R is selected from H, OH, and OCH3, or stereoisomers or salt forms thereof. 25. A compound according to claim 24, wherein R is H. 26. A compound according to claim 25, wherein the compound of formula IV is in the mandelic acid salt form. 27. A compound of formula VII:   wherein R is selected from H, OH, and OCH3, or stereoisomers or salt forms thereof. 28. A compound according to claim 27, wherein R is OH. 29. A compound according to claim 28, wherein the compound of formula VII is in the tartaric acid salt form.