New method of preparation of finasteride

Abstract: Disclosed is a new process for producing finasteride which involves reacting the magnesium halide salt of 17β-carboalkoxy-4-aza-5α-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 the product finasteride. Also disclosed are two polymorphic crystalline Forms I and II of finasteride, and methods of their production.

Description: BACKGROUND OF THE INVENTION Finasteride, marketed under the tradename of PROSCAR®, by Merck & Co., Inc is 17β-(N-tert-butyl carbamoyl)-4-aza-5α-androst-1-en-3-one and is a 5α-reductase inhibitor for use in treating acne, female hirsutism, and particularly benign prostatic hyperplasia. See US Patent 4,760,071 (1988), the entire disclosure of which is incorporated herein by reference.. The synthesis of finasteride in US Patent 4,760,071 involves reacting the 17β-(2-pyridylthio) carboxylate of 4-aza-5α-androst-1-ene-3-one with t-butylamine. A further synthesis of finasteride is described in Synthetic Communications, 30 (17), p. 2683-2690 (1990). including the reacting of the 17-acylimidazole of 4-aza-5α-androst-1-en-3-one with t-butylamine. However, both of these reactions require the use of heterocyclic aromatic amines which are expensive and give rise to environmental safety and toxicity considerations. Both of these intermediates are prepared from the 17β-carboxylic acid. The Bodroux reaction, described by F. Bodroux in the references, Bull. Soc. Chim. France 33 , 831 ( 1905); 35, 519 (1906); 1 , 912 (1907); Compt. Rend. 138 , 1427 (1904); 140 , 1108 (1905); 142 , 401 (1906) discloses the reaction of the magnesium halide salts of amines with esters. However, there is no description or teaching that the reaction can be applied to the reaction of a sterically hindered amine, e.g. t-butyl amine, with a sterically hindered ester such as 1 . What is desired in the art is a method of synthesis of finasteride, which is environmentally safe and non-toxic, and does not utilize an aromatic heterocyclic amine. Preferably, the starting compound could be the 17-beta ester, ( 1 ) which would eliminate one step of the process in producing the above heterocyclic intermediates. SUMMARY OF THE INVENTION By this invention, there is provided a process for producing finasteride 2 wherein R is C 1 -C 10 linear, branched or cyclic alkyl, unsubstituted or substituted with one or more of phenyl, comprising the steps of: (1) contacting the ester 1 with t-butylamino magnesium halide, wherein the molar ratio of t-butylamino magnesium halide to ester is at least about 2:1, in an inert organic solvent under an inert atmosphere; (2) maintaining the reaction mixture at a temperature of at least 10 °C; and (3) recovering the product finasteride 2 . Also provided are intermediate compounds useful for the synthesis of finasteride. DETAILED DESCRIPTION OF THE INVENTION We have discovered that the 17β-carboalkoxy ester of 4-aza-5-alpha-androst-1-en-3-one ( 1 ) can be reacted with t-butyl amine together with an aliphatic/aryl magnesium halide reagent, e.g. ethyl magnesium bromide, where the magnesium halide reagent and t-butyl amine are present in at least about a 2:1 molar ratio to the ester ( 1 ), to produce finasteride ( 2 ) in good yield. The reaction between the aliphatic/aryl magnesium halide and t-butylamine produces t-butylamino magnesium halide. One mole of t-butylamino magnesium halide may be employed for the deprotonation of the ester A-ring lactam thereby solubilizing the steroid, a second mole required for the amidation reaction, and a third mole can be used for the deprotonation of the newly-formed amide. Alternatively, the ester ( 1 ) can be deprotonated with a Grignard reagent separately and then reacted with two moles of t-butylamino magnesium halide to undergo the amidation process. In another alternative, the t-butylamino magnesium halide can be first preformed at ambient temperature in the same or separate vessel and then contacted with the 4-aza-steroid ester 1 in at least a 3:1 molar ratio of halide reagent:ester, preferably followed by heating up to, e.g., about 100°C. As a further alternative, the t-butyl magnesium halide can be formed in the same or a separate vessel in a 2:1 molar ratio to the ester 1 , and then contacted with the ester 1 which has been previously contacted with the same or different Grignard reagent in a 1:1 molar ratio to deprotonate and solubilize the ester. In one particular embodiment of this invention, a process for producing finasteride 2 comprises the steps of: (1) contacting in one vessel the 4-aza-steroid ester 1 with t-butyl amine and aliphatic/aryl magnesium halide in an inert organic solvent under an inert atmosphere at a temperature in the range of -20° to 10°C, stirring the reaction mixture to produce the t-butyl magnesium halide in situ, in at least a 3:1 molar ratio to the ester 1 , without reacting the ester with the aliphatic/aryl magnesium halide to form undesired corresponding ketone and alcohol products, (2) heating the reaction to 15°C to 100°C to react the ester with the t-butyl amino magnesium halide, and (3) recovering said product finasteride 2 (where t-Bu indicates tertiary butyl). The intermediate magnesium halide salt of the 4-aza-steroid 1 has the following formula: wherein R is C 1 -C 10 linear, branched or cyclic alkyl, unsubstituted or substituted with one or more of phenyl. The starting ester 1 and its synthesis are described in US Patent 4,760,071. The compound used to make 1 is the known steroid ester that is saturated at the 1,2 position, which is dehydrogenated with a dehydrogenating agent such as benzeneselenic anhydride in refluxing chlorobenzene. The starting ester may be the compound in which R is a C 1 -C 10 linear, branched or cyclic alkyl, wherein the alkyl chain may be optionally substituted with one or more of phenyl. The ester moiety includes, e.g., methyl (Me), ethyl (Et), propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, iso-propyl (i-Pr), iso-butyl (i-Bu), tert-butyl (t-Bu), sec-butyl (s-Bu), iso-pentyl, cyclohexyl and the like, and benzyl, -CH 2 CH 2 -phenyl, -CH 2 CH 2 CH 2 -phenyl, and the like. R is particularly a straight chain alkyl which is unsubstituted or mono-substituted with phenyl, and more particularly methyl. Longer chain alkyl groups may be used as well, but are not required. The t-butyl amine and aliphatic/aryl magnesium halide are each used in at least a 3:1 molar ratio to the ester ( 1 ) to form a 3:1 molar ratio, and preferably 3.5:1 to 5.5:1 molar ratio, of t-butylamino magnesium halide to the ester ( 1 ), to ensure proper and complete conversion of ( 1 ) to ( 2 ) and to minimize impurities. The reaction can be visualized mechanistically as the reaction of 3 moles of t-butylamino magnesium halide, formed by the reaction between the aliphatic/aryl magnesium halide and t-butylamine, with one mole of the ester 1 . Alternatively, the reaction can be viewed as two moles of t-butyl magnesium halide reacting with one mole of the ester ( 1 ) magnesium halide salt. The aliphatic/aryl magnesium halide is conventional and can be selected where: (1) the aliphatic/aryl portion is C 1 -C 18 linear, branched or cyclic alkyl, e.g. methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, t-butyl, hexyl, cyclohexyl, octyl, decyl, dodecyl, tetradecyl, octadecyl, benzyl, allyl, vinyl, ethynyl, and the like; and (2) the aryl portion is phenyl, or mono-, di- or tri-substituted phenyl, wherein the substituents can include C 1 -C 4 alkyl, C 1 -C 4 alkoxy, e.g. methyl, methoxy, fluoro, and the like. The halide is chloride, bromide, fluoride or iodide, and particularly bromide or chloride, and more particularly bromide. Preferred is ethyl magnesium bromide. The term "aliphatic/aryl magnesium halide" encompasses aliphatic magnesium halide and aryl magnesium halide. The inert solvent used is a conventional Grignard solvent and can be a C 4 -C 8 linear or cyclic ether, including diethyl-ether, di-n-butyl ether, dimethoxyethane, tetrahydrofuran, dioxane, and the like. The solvent should be dry under the reaction conditions, which are usually carried out under an inert atmosphere, e.g. dry nitrogen, with stirring. The reaction is carried out initially at a temperature sufficient to obtain product formation, and can be run, for example between about -40° to 40°C, and more particularly at a reduced temperature, for example, from about -20° to 10°C, during: (1) reaction of t-butylamine and aliphatic/aryl magnesium halide to form the t-butylamino magnesium halide, and (2) the reaction between the ester 1 and t-butyl amino magnesium halide (or a Grignard reagent) to form the magnesium halide salt of the ester 1 . Subsequently, the reaction mixture is stirred and maintained at a temperature sufficient to allow the amidation process to proceed. The reaction may generally be allowed to warm to a temperature of, for example, about 10°C or up to room temperature, and it may be further heated to about 100°C, or up to the boiling point of the solvent. Generally the heating time is 2 to 12 hours. Alternatively, the t-butylamino magnesium halide may be preformed, for example at ambient temperature, and subsequently reacted with the 4-aza-ester steroid ( 1 ) at ambient temperature. Workup of the crude finasteride is conventional as well as the apparatus used to carry out the process. In general, chromatography on silica gel and/or crystallization from a suitable solvent, e.g. methylene chloride/ethyl acetate or acetic acid/water can serve to purify the finasteride. The order of the addition of ester, t-butyl amine and aliphatic/aryl magnesium halide can be modified and reversed, if desired, with good results. Particularly, the t-butyl amine may be reacted first with the aliphatic/aryl magnesium halide to preform the t-butylamino magnesium halide prior to contacting the ester 1 . The following Examples are illustrative of the method claimed herein and should not be construed to represent limitations or restrictions on the scope or spirit of the invention as disclosed. EXAMPLE 1 In a flask equipped with an overhead stirrer, a nitrogen inlet, and reflux condenser was placed 840 ml of dry THF and 20.0 g of Δ 1 -methyl ester (1). The resulting slurry was cooled to -5° to -10°C, and 27.6 mL of t-butylamine was added. A solution of ethylmagnesium bromide in THF (122 mL, 2 M) was added maintaining the temperature of the reaction mixture below 10°C. The reaction was heated at reflux for 12 hours and was added to a cold (10°C) solution of 25% ammonium chloride in water. The mixture was warmed to 25°C and allowed to settle. The THF solution was separated and concentrated by atmospheric distillation to 200 mL and the product was crystallized by adding approximately 600 mL of dilute aqueous HCl. The resulting white solid was isolated by filtration and was dried at 70°C under vacuum to give 21.7 g (97% yield) of finasteride. The product finasteride can be purified by conventional procedures, e.g. recrystallization from methylene chloride/ethyl acetate or acetic acid/water, mp. 261°C. EXAMPLE 2 In a flask equipped with an overhead stirrer, a nitrogen inlet, and reflux condenser was placed 516 mL of dry THF and 27.6 mL of t-butylamine. The solution was cooled to 10°C and 244 mL of 1 M ethylmagnesium bromide in THF was added maintaining the reaction temperature below 30°C. A slurry containing 10.0 g of Δ 1 -methyl ester 1 in 100 mL of dry THF was added. The reaction was heated at reflux for 4-6 hours and was added to a cold (10°C) solution of 25% ammonium chloride in water. The mixture was warmed to 25°C and allowed to settle. The THF solution was separated and concentrated by atmospheric distillation to 200 mL and the product was crystallized by adding 200 mL of dilute HCl. The resulting white solid was isolated by filtration and was dried at 70°C under vacuum to give 21.6 g (97% yield) of finasteride.

Claims: A process for producing finasteride 2 wherein R is C 1 -C 10 linear, branched or cyclic alkyl, unsubstituted or substituted with one or more of phenyl, comprising the steps of: (1) contacting the ester 1 with t-butylamino magnesium halide, wherein the molar ratio of t-butylamino magnesium halide to ester is at least about 2:1, in an inert organic solvent under an inert atmosphere; (2) maintaining the reaction mixture at a temperature of at least 10 °C; and (3) recovering the product finasteride 2 . The process of claim 1 further comprising the step of reacting t-butylamine and an aliphatic or aryl magnesium halide in an inert organic solvent to form the t-butylamino magnesium halide prior to contact with the ester 1 . The process of claim 2 further comprising the step of reacting the ester 1 with an aliphatic or aryl magnesium halide in the range of -20°C to 30°C in an inert organic solvent to form the magnesium halide salt of the ester 1 prior to contact with the t-butylamino magnesium halide. The process of claim 1 wherein the halide is selected from bromide and chloride. The process of Claim 2 wherein the aliphatic/aryl magnesium halide contains a C 1 -C 18 linear, branched or cyclic alkyl, benzyl, allyl, vinyl or ethynyl radical, and the aryl radical is phenyl or phenyl substituted with 1-3 of C 1 -C 4 alkyl, C 1 -C 4 alkoxy or fluoro. The process of claim 5 wherein the aliphatic/aryl magnesium halide is selected from an alkyl magnesium bromide or a cycloalkyl magnesium bromide. The process of claim 1 wherein the inert solvent is a C 4 -C 8 linear or cyclic ether. The process of claim 7 wherein the inert organic solvent is selected from diethylether, di-n-butylether, dimethoxyethane, tetrahydrofuran, and dioxane. The process of claim 1 wherein R is selected from methyl, ethyl, propyl and butyl. The process of claim 9 wherein R is methyl. The process of claim 1 wherein the molar ratio of t-butylamino magnesium halide to ester 1 is in the range of about 3.5:1 to 5.5 to 1. The process of claim 11 wherein the molar ratio of t-butylamino magnesium halide to ester 1 is in the range of about 4:1 to 5:1. A compound of the formula wherein R is C 1 -C 10 linear, branched or cyclic alkyl, unsubstituted or substituted with one or more of phenyl. The compound of claim 13 wherein the halide is selected from bromide and chloride.

Inventors: DOLLING ULF H, MCCAULEY JAMES A, VARSOLONA RICHARD J, DOLLING, ULF H., MCCAULEY, JAMES A., VARSOLONA, RICHARD J.
Applicants: MERCK & CO INC, MERCK & CO., INC.
Application year: 1993
Main classification: C07J73
IPC codes: H04N5, C07J73, A61K31, C07F3, C07J75, C07J9