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|Title:||New finasteride processes|
|Abstract:||Disclosed is a new process for producing finasteride which involves reacting the magnesium halide salt of 17.beta.B-carboalkoxy-4-aza-5.alpha.-androst-1-en-3-one with t-butylamino magnesium halide, present in at least a 2:1 molar ratio to the ester, formed from t-butyl amine and an aliphatic/aryl magnesium halide at ambient temperature in an inert organic solvent under an inert atmosphere followed by heating and recovering said product finasteride. Also disclosed are two polymorphic crystalline Forms I and II of finasteride, and methods of their production.|
|Inventor(s):||Dolling; Ulf H. (Westfield, NJ), McCauley; James A. (Belle Mead, NJ), Varsolona; Richard J. (Scotch Plains, NJ)|
|Assignee:||Merck & Co., Inc. (Rahway, NJ)|
|Filing Date:||Jan 29, 1993|
|Claims:||1. A process for producing finasteride 2: ##STR3## where R is methyl or ethyl, comprising the steps of |
(1) contacting the magnesium halide salt of the 4-aza steroid ester 1 with t-butylamino magnesium halide, wherein the molar ratio of t-butylamino magnesium halide to said ester magnesium halide salt is at least about 2:1, in an inert organic solvent under an inert atmosphere at ambient temperature,
(2) heating the reaction mixture in the range from 25.degree. C. to 100.degree. C., and
(3) recovering said product finasteride 2.
2. The process of claim 1 further comprising the step of reacting t-butylamine and an aliphatic or aryl magnesium halide wherein:
aryl is phenyl, in the range of -20.degree. C. to 10.degree. C. in an inert organic solvent to form said t-butylamino magnesium halide prior to contacting said magnesium halide salt of the ester 1.
3. The process of claim 2 wherein said aliphatic or aryl magnesium halide is an aliphatic magnesium halide wherein the aliphatic moiety is selected from: a methyl, an ethyl, a propyl, an isopropyl, an n-butyl, a sec-butyl, a t-butyl, a hexyl, an octyl, a decyl, a dodecyl, a tetradecyl, an octadecyl, an allyl, a vinyl, an ethynyl, a benzyl or a cyclohexyl radical.
4. The process of claim 3 wherein said aliphatic/aryl magnesium halide is an alkyl magnesium bromide.
5. The process of claim 2 further comprising the step of reacting the ester 1 with an aliphatic or aryl magnesium halide wherein:
aryl is phenyl, in the range of -20.degree. C. to 30.degree. C. in an inert organic solvent to form the magnesium halide salt of the ester 1 prior to contacting said t-butylamino magnesium halide.
6. The process of claim 1 wherein said inert solvent is a C.sub.4 -C.sub.8 linear or cyclic ether.
7. The process of claim 6 wherein said inert organic solvent is diethylether, di-n-butylether, dimethoxyethane, tetrahydrofuran, dioxane.
8. The process of claim 1 wherein R is methyl.
9. The process of claim 1 wherein said molar ratio of t-butylamino magnesium halide to ester 1 is 3:1.
10. The process of claim 1 wherein said molar ratio of t-butylamino magnesium halide to ester 1 is 4-5:1.
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