Process

Details Process Process

2003-05-05

2004-09-21

Aulakh, Charanjit S. (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S061000

Reexamination Certificate

active

06794508

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to an improvement in a process for the preparation of steroids. More particularly, the invention Is concerned with improvements in a process for preparing steroids, such as 3-oxo-4-azasteroids, by hydrogenation of the corresponding steroid alkene. Compounds of this type are known to be useful in the preparation of compounds having 5&agr;-reductase inhibitor activity.
BACKGROUND OF THE INVENTION
Steroid 5&agr;-reductases catalyze conversion of testosterone to DHT in an NADPH dependent fashion as shown in Scheme A.
The inhibition of the conversion of testosterone to DHT is anticipated to be useful in the treatment of a variety of androgen responsive diseases, e.g., benign prostate hyperplasia, prostate cancer, acne, male pattern baldness and hirsutism. Hence, 5&agr;-reductase inhibitors have been the subject of active research worldwide. For example, see: Hsla, S. and Voight, W.,
J. Invest. Derm
., 62, 224 (1973); Robaire, B. et al.,
J. Steroid Biochem
., 8, 307 (1977); Petrow, V. et al.,
Steroids
, 38, 121 (1981); Liang, T. et al.,
J. Steroid Biochem
., 19, 385 (1983); Holt, D. et al.,
J. Med. Chem
., 33, 937 (1990); U.S. Pat. No. 4,377,584, U.S. Pat. No. 4,760,071 and U.S. Pat. No. 5,017,568. One particularly promising 5&agr;-reductase inhibitor is MK-906 (Merck), known by the generic name, finasteride, and marketed under the trademark, Proscar, is an inhibitor of type 2 5&agr;-reductase. In addition, dual inhibitors of type 1 and 2 human 5&agr;-reductase are disclosed in WO 95/07926 and WO 95/07927, the contents of which are incorporated herein by reference.
Processes for the preparation of the 5&agr;-reductase inhibitors are described in WO 95/07926, WO 95/07927, U.S. Pat. No. 4,760,071, U.S. Pat. No. 4,377,584, U.S. Pat. No. 4,179,453, U.S. Pat. No. 5,670,643 and Bhattacharya, A. et al.,
J. Am. Chem. Soc
., 110, 3318 (1988). Important intermediates in the preparation of 5&agr;-reductase inhibitors are 4-aza-5&agr;-androstan-3-ones, e.g. 3-oxo-4-azaandrost-17&bgr;-carboxylic acid, which can be prepared by hydrogenation of the corresponding 4-aza-androst-5-en-3-one, e.g. 3-oxo-4-azaandrost-5-en-17&bgr;-carboxylic acid. WO 95/07926 and WO95/07927 describe a process by which a 17&bgr;-substituted 4-aza-androst-5-en-3-one is converted to the corresponding 17&bgr;-substituted 4-aza-5&agr;-androstan-3-one by hydrogenation. For example, the hydrogenation may be carried out in acetic acid at 60 to 70° C. and 276-414 kPa (40-60 psi) hydrogen pressure in the presence of catalytic platinum oxide.
The problem to be solved by the present invention is the provision of a superior, and more selective process for the hydrogenation of steroid alkenes.
SUMMARY OF THE INVENTION
Scheme 1 shows the hydrogenation of a steroid, 3-oxo-4-azaandrost-5-en-17&bgr;-carboxylic acid, to the corresponding 5&agr;-androstane and 5&bgr;-androstane isomers. 5&agr;-androstane isomer produced using the reaction can be used in the preparation of 5&agr;-reductase inhibitors. For large scale manufacture, a hydrogenation process which could be carried out at atmospheric pressure was desired. However, as demonstrated by the experiments below, considerable problems relating to &agr;:&bgr; ratios were experienced when hydrogenation was carried out at atmospheric pressure.
The present inventors have found a process for hydrogenating steroid alkenes which can be performed at atmospheric pressure. The problem of low &agr;:&bgr; ratios was solved by carrying out the hydrogenation in the presence of ammonium acetate, ammonium formate or ammonium propionate.
Accordingly, the present invention provides a process for hydrogenating steroid alkenes comprising the step of hydrogenating one or more double bonds in the presence of ammonium acetate, ammonium formate, ammonium propionate, or mixtures thereof and an appropriate catalyst.
A further aspect of the invention is the use of the process of the invention in the preparation of a 5&agr;-reductase inhibitor.


REFERENCES:
patent: 0 155 096 (1985-09-01), None
patent: 2 264 494 (1993-09-01), None
patent: WO 95/07926 (1995-03-01), None
Pande, P.P. et al., “Catalytic Transfer Hydrogenation of Unsaturated Ketones and Imides Via Ammonium Formate,”Synthetic Communications,vol. 28, No. 22, 1998, pp. 4193-4200.
Rasmusson, G.H. et al., “Azasteroids as Inhibitors of Rat Prostatic 5Alpha-Reductase,”Journal of Medicinal Chemistry,vol. 27, No. 12 Dec. 1, 1984, pp. 1690-1701.
Rasmusson, G.H. et al., “Azasteroids: Structure-Activity Relationships for Inhibition of 5Alpha-Reductase and of Androgen Receptor Binding,”Journal of Medicinal Chemistry,vol. 29, No. 11, Nov. 1, 1986, pp. 2298-2315.
Bakshi, R.K. et al., “4, 7-Dimethyl-4-azacholestan-3-one (MK-386) and related 4-azasteroids as selective inhibitors of human type 1 5-alpha-reductase,”Journal of Medicinal Chemistry,vol. 37, No. 23, 1994, pp. 3871-3874.
Kurata et al., “Synthesis and Testosterone 5Alpha-Reductase-Inhibitory Activity of 4-Aza-5 Alpha-Androstane-17-Carboxamide Compound with Aromatic Moiety in the C-17 Carbamoyl Group,”Chemical and Pharmaceutical Bulletin,vol. 44, No. 1, 1996, pp. 115-121.
Bakshi, R.K. et al., “4-Aza-3-oxo-5 alpha.-androst-1-ene-17.beta.-N-arylcarboxamides as Dual Inhibitors of Human Type 1 and Type 2 Steroid 5.alpha.-Reductases. Dramatic Effect of N-Aryl Substituents on Type 1 and Type 2 5.alpha.-Reductase Inhibitory Potency,”Journal of Medicinal Chemistry,vol. 38, No. 17, Aug. 18, 1995, pp. 3189-3192.

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