Patent EA-001405-B1 (EA)
Title: Method of docetaxel production
Inventor: SISTI NICHOLAS J
IPC: C07D305/14
Filed: 1997-02-27
Abstract: 1. A method of producing docetaxel, comprosing the steps of: (a) esterification C7, C10-di-carbobenzyloxy deacetylbacatin III of formula   side chain N-   forming a first intermediate compound of formula   in which P1 is a hydroxy-protecting group of benzyl type; (b) substitution C7, C10- carbobenzyloxy groups by hydrogene and substitution of a carbobenzyloxy group with C3' nitrogene by tertbytoxycarbonyl, forming a second intermediate compound of formula   in which P1 is a hydroxy-protecting group of benzyl type; and (c) deprotection of the second intermediate compound by substitution P1 with hydrogene and obtaining docetaxel. 2. A method according to claim 1, wherein P1 is is chosen from the group comprising benzyloxymethyl and benzyl. 3. A method according to claim 1, in which during the step of the esterification 6 equivalents of the side chain N- carbobenzyloxy-C2<'>-protected 3-phenylisoserine are used for each equivalent C7, C10 di-carbobenzyloxy-10- deacetylbacatin III. 4. A method according to claim 1, in which side chain N- carbobenzyloxy-C2<'>-protected 3-phenylisoserine and  C7, C10 di-carbobenzyloxy-10- deacetylbacatin III are dissolved in toluene to form a first solution, after which dimethylaminopyridine and dialkylcarbodiimide are added to the first solution to form a second solution, comprising the first intermediate compound. 5. A method according to claim 4, in which dialkylcarbodiimide is in an equal proportion respective to N- carbobenzyloxy-C2<'>-protected 3-phenylisoserine. 6. A method according to claim 4, in which the esterification step is carried out at a temperature between 60 degree C and 80 degree C during 1 to five hours. 7. A method according to claim 6, in which diethyl ether is added to the second solution to form a third solution, which is then cooled to 0 degree C. 8. A method according to claim 1, in which substitution C7, C10- carbobenzyloxy groups by hydrogene and substitution of a carbobenzyloxy group with C3' nitrogene by tertbytoxycarbonyl are carried out primeraly to obtain amine, after which the tertbytoxycarbonyl group  ia added to C3' nitrogene, thus obtaining the second intermediate compound. 9. A method according to claim 8, in which the step of which substitution C7, C10- carbobenzyloxy groups by hydrogene and substitution of a carbobenzyloxy group with C3' nitrogene by tertbytoxycarbonyl are carried out by obtaining the first mixture. 10. A method according to claim 9, in which the first mixture is hydrated for, at least, 24 hours. 11. A method according to claim 8, in which the step of adding tertbytoxycarbonyl group to C3' nitrogene is carried out by adding amine to tetrahydrofuran. 12. A method according to claim 11, in which tert amine base is added to amine and to tetrahydrofuran. 13. A method according to claim 11, in which di-tret-bytildicarbonate is added to amine and tetrahydrofuran to form thr second mixture. 14. A method according to claim 13, in which the second mixture is stirred for about 24 hours and evaporate in vacuum, repeatedly solved in ethylacetate, wash with water and brine to form an aorganic phase remove and chromatographize thereafter using the ethylacetate/hexane mixture and obtaining eluant, comprising the purified second intermediate compound. 15 A method according to claim 14, in which the eluant is evaporated in vacuum to a residue which is recrystalized thereafter, obtaining the second intermediate purified compound.