Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1995-03-30
1997-07-29
Daus, Donald G.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C07J 7300
Patent
active
056523653
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
Finasteride, marketed under the tradename of PROSCAR.RTM., by Merck & Co., Inc. is 17.beta.-(N-tert-butyl carbamoyl)-4-aza-5.alpha.-androst-1-en-3-one and is a 5.alpha.-reductase inhibitor for use in treating acne, female hirsutism, and particularly benign prostatic hyperplasia. See U.S. Pat. No. 4,760,071 (1988), the entire disclosure of which is incorporated herein by reference.
The synthesis of finasteride in U.S. Pat. No. 4,760,071 involves reacting the 17.beta.-(2-pyridylthio)carboxylate of 4-aza-5.alpha.-androst-1-ene-3-one with t-butylamine. A further synthesis of finasteride is described in Synthetic Communications, 30 (17), p. 2683-2690 (1990), the entire disclosure of which is incorporated herein by reference including the reacting of the 17-acylimidazole of 4-aza-5.alpha.-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 17.beta.-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 teachings 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 ##STR1## wherein R is C.sub.1 -C.sub.10 linear, branched or cyclic alkyl, unsubstituted or substituted with one or more of phenyl, comprising the steps of: molar ratio of t-butylamino magnesium halide to ester is at least about 2:1, in an inert organic solvent under an inert atmosphere; 10.degree. C.; and
Also provided are intermediate compounds useful for the synthesis of finasteride. There is additionally provided a method for the synthesis, including separation and crystallization, of certain polymorphic crystalline forms of finasteride, as well as the polymorphic forms themselves.
DETAILED DESCRIPTION OF THE INVENTION
We have discovered that the 17.beta.-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.degree. 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 pre
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McCauley James A.
Varsolona Richard J.
Daus Donald G.
Fitch Catherine D.
Merck & Co. , Inc.
Winokur Melvin
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