Organic compounds -- part of the class 532-570 series – Organic compounds – Cyclopentanohydrophenanthrene ring system containing
Reexamination Certificate
2001-12-11
2004-09-07
Qazi, Sabiha (Department: 1616)
Organic compounds -- part of the class 532-570 series
Organic compounds
Cyclopentanohydrophenanthrene ring system containing
C552S610000, C549S383000
Reexamination Certificate
active
06787659
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a process for the synthesis of oxandrolone. The present invention further relates to a process which provides oxandrolone in relatively high yields and purity.
BACKGROUND OF THE INVENTION
Oxandrolone (i.e., 17&bgr;-hydroxy-17&agr;-methyl-2-oxa-5&agr;-androstan-3-one) is a known anabolic steroid that has various therapeutic uses. Methods of producing oxandrolone are known. For example, U.S. Pat. No. 3,109,016 discloses a process of manufacture of 17-oxygenated 2-oxa-5&agr;-androstan-3-ones. The '016 patent discloses the reaction of 17&bgr;-hydroxy-17&agr;-methyl-5&agr;-androst-1-en-3-one in methylene chloride and methanol with ozone to produce methyl 17&bgr;-hydroxy-17&agr;-methyl-1-oxo-1,2,-seco-A-nor-5&agr;-androstan-2-oate and, alternatively, with ozone in methylene chloride to yield 17&bgr;-hydroxy-17&agr;-methyl-1-oxo-1,2,-seco-A-nor-5&agr;-androstan-2-oic formic anhydride. According to the '016 patent, the 1,2-seco intermediates are converted to the corresponding anabolic 2-oxa compound by treatment with a reducing agent in aqueous medium. The methyl 17&bgr;-hydroxy-17&agr;-methyl-1-oxo-1,2,-seco-A-nor-5&agr;-androstan-2-oate may be contacted with sodium borohydride in aqueous sodium hydroxide to form 17&bgr;-hydroxy-17&agr;-methyl-2-oxa-5&agr;-androstan-3-one (i.e., oxandrolone).
U.S. Pat. No. 3,128,283, which relates to 17-oxygenated androstane and estrane derivatives in which the A ring contains a lactone structure, also discloses an example of the production of oxandrolone. 17&bgr;-hydroxy-17&agr;-methyl-5&agr;-androst-1-en-3-one is reacted in aqueous acetic acid with osmium tetroxide and lead tetracetate to afford 17&bgr;-hydroxy-17&agr;-methyl-1-oxo-1,2,-seco-A-nor-5&agr;-androstan-2-oic acid. This compound is converted to 17&bgr;-hydroxy-17&agr;-methyl-2-oxa-5&agr;-androstan-3-one by reduction with sodium borohydride in aqueous sodium hydroxide. A disadvantage of methods that use lead tetracetate, however, is that lead tetracetate is a highly toxic compound.
17-hydroxy-17-methyl-5-androst-1-en-3-one may be formed from 17-hydroxy-17-methyl-5-androstan-3-one. For example, U.S. Pat. No. 2,260,328 discloses mixing 17-hydroxy-17-methyl-5-androstan-3-one in glacial acetic acid solution with bromine. This product is precipitated and purified. The product is then heated with dimethylaniline or potassium acetate in glacial acetic acid under pressure to eliminate hydrogen bromide, thus forming 17-hydroxy-17-methyl-5-androst-1-en-3-one.
Methods using bromination-dehydrobromination are disadvantageous due to low yields. For example, these methods typically generate the compound in a 15-30% overall yield with the compound being contaminated in approximately 5-10% of methyl testosterone. Such methods generally require the use of chromatography such as silica gel chromatography to obtain pure product.
It would be advantageous to provide a process for producing oxandrolone that results in the formation of oxandrolone in relatively high yields and purity.
SUMMARY OF THE INVENTION
The present invention relates to a process for the synthesis of oxandrolone from mestanolone. In one aspect of the present invention, a process is provided comprising the steps of: (a) oxidizing mestanolone to form 17&bgr;-hydroxy-17&agr;-methyl-5&agr;-androst-1-en-3-one; (b) hydroxylating the 17&bgr;-hydroxy-17&agr;-methyl-5&agr;-androst-1-en-3-one to form 1&agr;, 2&agr;, 17&bgr;-trihydroxy-17&agr;-methylandrostan-3-one; (c) cleaving the 1&agr;, 2&agr;, 17&bgr;-trihydroxy-17&agr;-methylandrostan-3-one to form 17&bgr;-hydroxy-17&agr;-methyl-1-oxo-1,2,-seco-A-nor-5&agr;-androstan-2-oic acid; and (d) reducing the 17&bgr;-hydroxy-17&agr;-methyl-1-oxo-1,2,-seco-A-nor-5&agr;-androstan-2-oic acid to form oxandrolone.
In another aspect of the present invention, a process is provided for the production of oxandrolone comprising the steps of: (a) oxidizing mestanolone using o-iodoxybenzoic acid (IBX) to form 17&bgr;-hydroxy-17&agr;-methyl-5&agr;-androst-1-en-3-one; (b) hydroxylating the 17&bgr;-hydroxy-17&agr;-methyl-5&agr;-androst-1-en-3-one to form 1&agr;, 2&agr;, 17&bgr;-trihydroxy-17&agr;-methylandrostan-3-one; (c) cleaving the 1&agr;, 2&agr;, 17&bgr;-trihydroxy-17&agr;-methylandrostan-3-one to form 17&bgr;-hydroxy-17&agr;-methyl-1-oxo-1,2,-seco-A-nor-5&agr;-androstan-2-oic acid; and (d) reducing the 17&bgr;-hydroxy-17&agr;-methyl-1-oxo-1,2,-seco-A-nor-5&agr;-androstan-2-oic acid to form oxandrolone. At least two by-products are formed in step (a) that are non-reactive to steps (b) and (c).
In a further aspect of the present invention, mestanolone is oxidized using IBX to form 17&bgr;-hydroxy-17&agr;-methyl-5&agr;-androst-1-en-3-one. The 17&bgr;-hydroxy-17&agr;-methyl-5&agr;-androst-1-en-3-one is hydroxylated using osmium tetroxide to form 1&agr;, 2&agr;, 17&bgr;-trihydroxy-17&agr;-methylandrostan-3-one. The 1&agr;, 2&agr;, 17&bgr;-trihydroxy-17&agr;-methylandrostan-3-one is cleaved using sodium metaperiodate to form 17&bgr;-hydroxy-17&agr;-methyl-1-oxo-1,2,-seco-A-nor-5&agr;-androstan-2-oic acid. The 17&bgr;-hydroxy-17&agr;-methyl-1-oxo-1,2,-seco-A-nor-5&agr;-androstan-2-oic acid is then reduced using sodium borohydride followed by an acid treatment to form oxandrolone.
In yet another aspect of the present invention, mestanolone is reacted with IBX to form 17&bgr;-hydroxy-17&agr;-methyl-5&agr;-androst-1-en-3-one. The 17&bgr;-hydroxy-17&agr;-methyl-5&agr;-androst-1-en-3-one is reacted with osmium tetroxide and N-methylmorpholine N-oxide to form 1&agr;, 2&agr;, 17&bgr;-trihydroxy-17&agr;-methylandrostan-3-one. The 1&agr;, 2&agr;, 17&bgr;-trihydroxy-17&agr;-methylandrostan-3-one is reacted with sodium metaperiodate to form 17&bgr;-hydroxy-17&agr;-methyl-1-oxo-1,2,-seco-A-nor-5&agr;-androstan-2-oic acid. Oxandrolone is then formed from the 17&bgr;-hydroxy-17&agr;-methyl-1-oxo-1,2,-seco-A-nor-5&agr;-androstan-2-oic acid by reacting the 17&bgr;-hydroxy-17&agr;-methyl-1-oxo-1,2,-seco-A-nor-5&agr;-androstan-2-oic acid with sodium borohydride followed by an acid treatment comprising addition of hydrochloric acid.
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Pappo, R.
Desai Shaileshkumar Ramanlal
Ray, Jr. David Wayne
Sayed Yousry A.
Barr Laboratories, Inc.
Burns Doane Swecker & Mathis L.L.P.
Qazi Sabiha
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