Process for the preparation of donepezil
View Patent ↗The invention provides a process for the preparation of a compound of the formula 6 comprising the hydrolysis and decarboxylation of a compound of the formula 5 according to the reaction: wherein R and R 2 independently a C 1 -C 4 alkyl group or an aralkyl group.
1. A process for the preparation of a compound of the formula 6 comprising hydrolyzing and decarboxylating a compound of the formula 5 according to the reaction:
wherein R and R 2 are independently a C 1 -C 4 alkyl group or an aralkyl group.
2. A process for the preparation of compound 6 as described in claim 1 , further comprising preparing compound 5 by the alkylation or aralkylation of compound 4 according to the reaction:
wherein R and R 2 are as defined in claim 1 and Y is a leaving group.
3. A process for the preparation of compound 6 according to claim 2 , further comprising preparing compound 4 by the removal of the N-protecting group of compound 3 according to the reaction:
wherein R is as defined in claim 2 , and R 1 is N-protecting group.
4. A process for the preparation of compound 6 according to claim 3 , further comprising preparing compound 3 by the coupling of compounds 1 and 2 according to the reaction:
wherein R and R 1 are as defined in claim 3 , and X is a leaving group.
5. A process according to claim 1 wherein the hydrolysis and decarboxylation are carried out in a solution, at elevated temperature and in the presence of a base.
6. A process according to claim 5 wherein the temperature is in the range of 60-100° C.
7. A process according to claim 5 wherein the base is a hydroxide or a carbonate of an alkali metal.
8. A process according to claim 7 wherein the base is potassium hydroxide.
9. A process according to claim 5 wherein the reaction is carried out in a mixture of a C 1 -C 6 alcohol and water.
10. A process according to claim 9 wherein the reaction is carried out in the presence of ethanol and water.
11. A process according to claim 2 wherein the alkylation or aralkylation reaction is carried out in a solution, in the presence of an organic or an inorganic base.
12. A process according to claim 11 wherein the solvent is toluene, methylene chloride, chloroform, tetrahydrofuran (THF).
13. A process according to claim 11 wherein the solvent is methylene chloride.
14. A process according to claim 11 wherein the base is an alkali metal hydroxide, an alkali metal carbonate or an amine.
15. A process according to claim 11 wherein the base is triethylamine.
16. A process according to claim 3 wherein R 1 is benzyloxycarbonyl (CBZ).
17. A process according to claim 16 wherein the deprotection reaction is carried out in the presence of solvent, at elevated temperature using acid as catalyst.
18. A process according to claim 17 wherein the solvent is methylene chloride, toluene, chloroform or THF.
19. A process according to claim 18 wherein the solvent is toluene.
20. A process according to claim 17 wherein the acid is 30% solution of HBr in acetic acid.
21. A process according to claim 16 wherein the deprotection reaction is carried out in a solvent by hydrogenolysis in the presence of a precious metal catalyst.
22. A process according to claim 21 wherein the solvent is a C 1 -C 6 alcohol.
23. A process according to claim 22 wherein the solvent is ethanol.
24. A process according to claim 21 wherein the catalyst is a supported palladium or platinum catalyst.
25. A process according to claim 24 wherein the catalyst is palladium on charcoal.
26. A process according to claim 3 wherein R 1 is t-butoxycarbonyl (t-BOC).
27. A process according to claim 26 wherein the deprotection is carried out in solution in a the presence of an acid.
28. A process according to claim 27 wherein the solvent is selected from the group consisting of methylene chloride, toluene, chloroform and THF.
29. A process according to claim 28 wherein the solvent is methylene chloride.
30. A process according to claim 28 wherein the acid is trifluoroacetic acid.
31. A process according to claim 4 wherein the coupling reaction is carried out in a solution, at elevated temperature and in the presence of a base.
32. A process according to claim 31 wherein the solvent is selected from the group consisting of dimethylformamide (DMF), dimethylsulfoxide (DMSO), ethanol and methanol.
33. A process according to claim 32 wherein the solvent is dimethylformamide.
34. A process according to claim 31 wherein the base is an alkali metal carbonate, alkali metal hydroxide, alkali metal hydride or alkali metal alkoxide.
35. A process according to claim 34 wherein the base is potassium carbonate.
36. A process according to claim 31 wherein the reaction is carried out within a temperature range of 30-70° C.
37. A process for the preparation of Donepezil comprising:
a. coupling a compound of general formula 1 with a compound of general formula 2 wherein R is a C 1 -C 4 alkyl group or an aralkyl group, R 1 is an N-protecting group, and X is a leaving group;
b. deprotecting a compound of general formula 3, wherein R is a C 1 -C 4 alkyl group or an aralkyl group, and R 1 is an N-protecting group;
c. benzylating a compound of general formula 4 with a compound of formula PhCH 2 Y, wherein Y is a leaving group; and
d. hydrolyzing and decarboxylating a compound of general formula 5, wherein R is a C 1 -C 4 alkyl group or an aralkyl group, and R 2 is benzyl.
38. A process according to claim 37 wherein step c is carried out with a benzylhalide.
39. Donepezil or salts thereof produced according to claim 37 .
40. Compounds of general formula 3 wherein R and R, are as defined in claim 4 .
41. Compounds as claimed in claim 40 wherein R is methyl or ethyl group and R 1 is CBZ or t-BOC group.
42. Compounds of general formula 4 or salts thereof wherein R is as defined in claim 3 .
43. Compounds as claimed in claim 42 wherein R is methyl or ethyl group.
44. Compounds of general formula 5 or salts thereof wherein R and R 2 are as defined in claim 2 .
45. Compounds as claimed in claim 44 wherein R 2 is benzyl group and R is ethyl or methyl group.