Enzymatic process for the preparation of (S)-5-(4-fluoro-phenyl)-5-hydroxy-1morpholin-4-yl-pentan-1-one, an intermediate of Ezetimibe and further conversion to Ezetimibe
The present invention provides an enzymatic process for the preparation of (S)-5-(4-Fluoro-phenyl)-5-hydroxy-1morpholin-4-yl-pentan-1-one by the reduction of 1-(4-Fluoro-phenyl)-5-morpholin-4-yl-pentane-1,5-dione by using a suitable enzyme or by the resolution of (R,S)-5-(4-Fluoro-phenyl)-5-hydroxy-1morpholin-4-yl-pentan-1-one by using an enzyme. The present invention also provides process for the preparation of Ezetimibe comprising the steps of a) protecting the compound (S)-5-(4-Fluoro-phenyl)-5-hydroxy-1morpholin-4-yl-pentan-1-one with hydroxy protecting group b) hydrolyzing the obtained compound c) condensing with a chiral auxiliary d) reacting with an protected imine compound e) converting to alkyl ester f) cyclizing and g) deprotecting to obtain Ezetimibe.
1. A process for preparing (S)-5-(4-fluoro-phenyl)-5-hydroxy-1morpholin -4-yl-pentan-1-one having the formula
comprising:
resolving 5-(4-fluorophenyl)-5-hydroxy-1-morpholin-4-yl-pentane-1-one of the following formula
using a lipase enzyme of Candida antartica lipase (CAL-A) in the presence of a suitable solvent and an acylating agent.
2. The process of claim 1 , wherein in acylating agent is selected from the group consisting of vinyl acetate, vinyl propionate, isopropenyl acetate, succinic anhydride, and acetic anhydride.
3. A process for the preparation of Ezetimibe comprising the steps of:
a) protecting the compound formula 3 with a suitable protecting group to obtain a compound of formula 3(a)
wherein P 1 is a hydroxyl protecting group;
b) hydrolyzing the compound of formula 3(a) to obtain a compound of formula 4;
c) reacting the compound of formula 4 with pivaloyl chloride and acylating the product with a chiral auxiliary of formula 5 wherein R is C 1 -C 6 alkyl, phenyl, naphthyl, substituted phenyl, substituted naphthyl, C 1 -C 6 alkoxycarbonyl, or benzyl, in the presence of a base to obtain a compound of formula 6;
d) reacting the compound of formula 6 with a protected imine compound of formula 7 in a suitable solvent in the presence of an organic amine base and a Lewis acid to obtain a compound of formula 8
wherein P 1 and P 2 are hydroxy protecting groups with the proviso that one of the hydroxy protecting group is a benzyl protecting group;
e) reacting the compound of formula 8, with an alkalimetal alkoxide or aryloxide in a suitable solvent to obtain an alkyl or aryl ester compound of formula 9
wherein R 1 is C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, aryl or substituted aryl;
f) cyclizing the compound of formula 9 in the presence of a non-nucleophilic base to obtain an azetidinone compound of formula 10;
g) removing the hydroxy protecting groups; and
h) isolating the ezetimibe;
wherein the compound of formula 3 is prepared by resolving 5-(4-fluorophenyl)-5-hydroxy-1-morpholin-4-yl-pentane-1-one of the following formula
using a lipase enzyme of Candida antarctica lipase (CAL-A) in the presence of a suitable solvent and an acylating agent.
4. The process according to claim 3 , wherein in step (a), the hydroxy protecting group is a benzyl or silyl protecting group.
5. The process according to claim 3 , wherein in step (c), the chiral auxiliary is (4S)-4- phenyl-2-oxazolidinone.
6. The process according to claim 3 , wherein in step (d), the solvent is dichloromethane.
7. The process according to claim 3 , wherein in step (d), the organic amine base is N,N-diisopropylethylamine and the Lewis acid is TiCl 4 .
8. The process according to claim 3 , wherein in step (e), the alkalimetal alkoxide is sodium methoxide.
9. The process according to claim 3 , wherein in step (e), the solvent is dichloromethane.
10. The process according to claim 3 , wherein in step (f), the non-nucleophilic base is lithium bis(trimethylsilyl) amide or bistrimethyl acetamide.
11. The process of claim 1 further comprising the step of converting the (S)-5-(4-fluoro-phenyl)-5-hydroxy-1-morpholin-4-pentan-1-one to Ezetimibe.