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Title:
METHOD OF PREPARING 17β-(N-TERT-BUTYLCARBAMOYL)-3-ONE STEROID DERIVATIVES
Document Type and Number:
WIPO Patent Application WO/2003/027132
Kind Code:
A2
Abstract:
A highly pure 17β-N-tert-butylcarbamoyl-3-one steroid compound of formula (I) is prepared in a high yield under a mild condition, by reacting a 17β-carboxy-3-one steroid compound with a pivaloyl halide to obtain a pivaloyl acid anhydride and reacting the pivaloyl acid anhydride with t-butylamine in an organic solvent in the presence of a base formula (I) wherein X is CH2, CH, NH or N; is a single or double bond; and Y is Cl, Br or I.

Inventors:
MOON YOUNGHO (KR)
KIM NAMDU (KR)
LEE KYUNGIK (KR)
KIM CHEOLKYUNG (KR)
LEE GWANSUN (KR)
CHANG YOUNGKIL (KR)
Application Number:
PCT/KR2002/001776
Publication Date:
April 03, 2003
Filing Date:
September 19, 2002
Export Citation:
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Assignee:
HANMI PHARM IND CO LTD (KR)
MOON YOUNGHO (KR)
KIM NAMDU (KR)
LEE KYUNGIK (KR)
KIM CHEOLKYUNG (KR)
LEE GWANSUN (KR)
CHANG YOUNGKIL (KR)
International Classes:
C07D215/227; C07J41/00; C07J73/00; (IPC1-7): C07J/
Domestic Patent References:
WO2001002422A12001-01-11
Foreign References:
US4760071A1988-07-26
US5670643A1997-09-23
US5468860A1995-11-21
US5652365A1997-07-29
EP0599376A21994-06-01
Attorney, Agent or Firm:
Jang, Seongku (KEC Building #275-7, Yangjae-don, Seocho-ku 137-130 Seoul, KR)
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Claims:
What is claimed is:
1. A method of preparing a 17ßNtertbutylcarbamoyl3one steroid compound of formula (I), which comprises (i) reacting a compound of formula (III) with a compound of formula (IV) to obtain a compound of formula (V) and (ii) then reacting the compound of formula (V) with tbutylamine in an organic solvent in the presence of a base: wherein X is CH2, CH, NH or N; represents a single or double bond; and Y is Cl, Br or I.
2. The method of claim 1, wherein steps (i) and (ii) are conducted continuously without isolating the compound of formula (V).
3. The method of claim 1, wherein the compound of formula (IV) is employed in an amount ranging from 1.0 to 2.0 equivalents based on the amount of the compound of formula (III).
4. The method of claim 1, wherein tbutylamine is employed in an amount ranging from 1.0 to 4.0 equivalents based on the amount of the compound of formula (III).
5. The method of claim 1, wherein the base is selected from the group consisting of aniline, triethylamine, ntributylamine, tbutylamine, N, N dimethylaniline, pyridine, N, Ndimethylaminopyridine, benzylamine, cyclohexylamine, dicyclohexylamine and a mixture thereof.
6. The method of claim 1 or 5, wherein the base is employed in an amount ranging from 0.5 to 3.0 equivalents based on the amount of the compound of formula (III).
Description:
METHOD OF PREPARING 17p- (N-TERT-BUTYLCARBAMOYL)-3-ONE STEROID DERIVATIVES Field of the Invention The present invention relates to a method of preparing a 17p- (N-tert- butylcarbamoyl)-3-one steroid derivative which is an useful intermediate of finasteride.

Background of the Invention Finasteride, i. e., 17p- (N-tert-butylcarbamoyl)-5a-4-aza-androst-1-en-3- one of formula (II), is a useful medicament for treating benign prostatic hypertrophy and androgenic alopecia: Benign prostatic hypertrophy and androgenic alopecia are induced by binding of androgen receptor to excessive 5a-dehydrotestosterone ("DHT") which is formed from testosterone by the action of testosterone 5a-reductase.

Finasteride, a testosterone 5a-reductase inhibitor, is known to lower the concentration of DHT by preventing testosterone from converting to 5a- dehydrotestosterone in plasma and cells, thereby restoring the prostate gland and enhancing hair growth.

Finasteride may be prepared by various known methods that involve the step of converting the 17ß carboxyl group of 3-oxo-4-androsten-17p-carboxylic acid or 3-oxo-4-aza-5a-androstan-17p-carboxylic acid into a t-butylcarbamoyl group.

For example, US Patent No. 4,760, 071 discloses a method of preparing a 17p-t-butylcarbamoyl derivative by converting the 17 (3-carboxyl group into a pyridylthio ester which is subsequently reacted with t-butylamine. However, this method requires the use of expensive 2,2'-pyridyl disulfide; and the multi- step procedure is not economically feasible.

US Patent No. 5,670, 643 offers a method of converting the 17p- carboxyl group into an acid chloride and reacting the acid chloride with t- butylamine. However, this method necessitates the use of toxic thionyl chloride which is difficult to handle.

US Patent Nos. 5, 468, 860 and 5,652, 365 and EP Patent No. 599,376 teach a method of reacting an organomagnesium halide with t-butylamine to obtain a t-butylaminomagnesium halide, and then reacting the t- butylaminomagnesium halide with a 17p-carboalkoxy compound. However, this method is not suitable for large-scale production due to moisture-sensitivity of the organomagnesium halide.

International patent application No. PCT/ES00/0239 provides a method of preparing a 17p-butylcarbamoyl compound by reacting lithium t-butylamide with a 17ß-carboxyalkoxy compound. However, this method makes use of t- butylamide which is difficult to handle and very dangerous due to flammability.

EP Patent No. 271,200 describes a method of converting the 17) 3- carboxyl group into a hydroxybenzothiazolyl ester or imidazolide which is subsequently reacted with butylamine. However, this method has problems in that the reaction yields a product of low purity or calls for an anhydrous condition.

Accordingly, there has been a need to develop an improved method for preparing a 17ß-(N-tert-butylcarbamoyl)-3-one steroid compound.

Summary of the Invention Accordingly, it is a primary object of the present invention to provide an improved method of preparing a 17ß-N-tert-butylcarbamoyl-3-one steroid derivative, an intermediate in the preparation of finasteride, under a mild condition in a high purity and yield.

In accordance with one aspect of the present invention, there is provided a method of preparing a 17p-N-tert-butylcarbonyl-3-one steroid compound of formula (I) which comprises reacting a 17ß-carboxy-3-one steroid

compound of formula (III) with a pivaloyl halide of formula (IV) to obtain a pivaloyl acid anhydride of formula (V) and reacting the pivaloyl acid anhydride of formula (V) with t-butylamine in an organic solvent in the presence of a base:

wherein X is CH2, CH, NH or N; is a single or double bond; and YisCl, BrorI.

Detailed Description of the Invention A 17p-carboxy-3-one steroid compound of formula (III) may be prepared in accordance with the method disclosed in [J. Med. Chem., 29, p2298, (1986)] or US Patent No. 4,760, 071.

Pivaloyl halide of formula (IV) which is commercially available or prepared in accordance with the known methods in the art (See Beil., 2,320), may be employed in an amount ranging from 1.0 to 2.0 equivalents, preferably from 1.1 to 1.3 equivalents, based on the amount of the 17p-carboxy-3-one steroid compound of formula (III).

The organic solvent employed in the present invention may be any one of the conventional organic solvents including methylene chloride, chloroform, tetrahydrofuran and dimethylformamide. The base employed in the present invention may be aniline, triethylamine, n-tributylamine, t-butylamine, N, N- dimethylaniline, pyridine, N, N-dimethylaminopyridine, benzylamine, cyclohexylamine dicyclohexylamine or a mixture thereof, preferably triethylamine. The base is employed in an amount ranging from 0.5 to 3.0 equivalents, preferably from 0.7 to 1.2 equivalents, based on the amount of the 17p-carboxy-3-one steroid compound of formula (III).

The pivaloyl acid anhydride of formula (V) which is formed by reacting the compound of formula (III) with the compound of formula (IV) may be reacted with t-butylamine without the isolation thereof from the reaction mixture. Since the pivaloyl acid anhydride is not sensitive to water, the

reaction does not require an anhydrous condition. t-butylamine is employed in an amount ranging from 1.0 to 4.0 equivalents, preferably from 1.5 to 2.5 equivalents, based on the amount of the 17p-carboxy-3-one steroid compound of formula (III).

The inventive reaction may be performed at a temperature ranging from - 10 to 30 °C, preferably from-5 to 20 °C for a period sufficient to complete the reaction, e. g. , about from 3 to 6 hours.

In accordance with the present invention, a 17p- (N-butylcarbamoyl)-3- one steroid compound of formula (I) can be easily obtained in a high purity of at least 98%, via a simple process conducted under a mild reaction condition.

The present invention is further described in the following Examples which are given only for the purpose of illustration, and are not intended to limit the scope of the invention.

Example 1 : Preparation of 17ß-(N-tert-butylcarbamoyl)-androst-4-en-3-one 3.16 g (10 mmol) of androst-4-en-3-one-17p-carboxylic acid (a compound of formula (III)) and 1 ml of triethylamine were dissolved in 50 ml of methylen chloride and 1.45 g (12 mmol) of pivaloyl chloride was slowly added thereto at about 0 °C. The mixture was stirred at a temperature ranging from 5 to 10 C for 1 hour and 1.46 g (20 mmol) of t-butylamine was slowly added thereto. This mixture was then stirred at room temperature for 2 hours, cooled to 0°C, and, thereafter, 50 ml of 1N HC1 was added thereto. The organic layer was separated, dried over anhydrous MgS04, filtered, concentrated under a reduced pressure, and then purified by column chromatography to obtain 3.45 g of the title compound as a pale white powder (Yield: 93%). The product was analyzed to have the following characteristics: H-NMR (6, CDC13) : 0.62 (3H, s, 18-CH3), 0.91 (3H, s, 19-CH3), 1. 20- 1.27 (4H, m, cyclo-CH), 1.25 (9H, 3, t-Bu), 1. 29-2. 11 (10H, m, cyclo-CH), 2. 43- 2.48 (2H, m, 2-CH2), 5.13 (lH, bs, -NH), 5.74 (lH, s, 4-CH) Example 2: Preparation of 17ß-(N-tert-butylcarbamoyl)-4-aza-androst-5-en-3- one

3.17 g (10 mmol) of 4-aza-androst-5-en-3-one-17ß-carboxylic acid (a compound of formula (III)) and 1 ml of triethylamine were dissolved in 60 ml of tetrahydrofuran at room temperature. Then the mixture was cooled to about 0°C and 1.45 g (12 mmol) of pivaloyl chloride (a compound of formula (IV)) was slowly added thereto. The mixture was then stirred at 5 to 10°C for 2 hours and 1.46 g (20 mmol) of t-butylamine was added thererto. The reaction mixture was stirred at room temperature for 2 hours, cooled to 0°C, and then 50 ml of IN HC1 was added thereto. The organic layer was separated, dried over anhydrous MgS04, filtered, concentrated under a reduced pressure, and then purified by column chromatography, to obtain 3.38 g of the title compound as a pale white powder (Yield: 91%), having the following characteristics: H-NMR (o, CDC13) : 0.69 (3H, s, 18-CH3), 0. 86 (3H, s, 19-CH3), 1. 05- 1.27 (4H, m, cyclo-CH), 1.29 (9H, 3, t-Bu), 1. 32-2. 15 (10H, m, cyclo-CH), 2. 51- 2.55 (2H, m, 2-CH2), 4.81 (lH, s, 6-CH), 5.19 (lH, bs, -NH), 5. 87 (lH, bs, -NH) Example 3: Preparation of 17p- (N-tert-butylcarbamoyl)-4-aza-5a-androstan-3- one

1.60 g (5 mmol) of 5a-androstan-3-one-4-aza-17p-carboxylic acid (a compound of formula (III)) and 0.5 ml of triethylamine were dissolved in 30 ml of tetrahydrfuran and then 0.73 g (6 mmol) of pivaloyl chloride (a compound formula (IV) ) was slowly added thereto. The mixture was then stirred at a temperature below 10°C for 1 hour and 0.74 g (10 mmol) of t-butylamine was slowly added thereto. The solution was stirred at room temperature for 2 hours, cooled to 0°C, and then 50 ml of 1N HC1 was added thereto. An organic layer was separated, dried over anhydrous MgS04, filtered, concentrated under a reduced pressure and purified by column chromatography and recrystallization in ethyl acetate, to obtain 1.63 g of the title compound as a pale white powder (Yield: 88%), having the following properties: Melting point (mp): 273-275C H-NMR (S, CDC13) : 0.71 (3H, s, 18-CH3), 0.92 (3H, s, 19-CH3), 1. 05- 1.27 (4H, m, cyclo-CH), 1.25 (9H, 3, t-Bu), 1. 30-2. 10 (10H, m, cyclo-CH), 2. 47- 2.51 (2H, m, 2-CH2), 3.35 (lH, dd, 5a-CH), 5.38 (lH, bs, -NH), 5. 89 (lH, bs, -NH) Reference Example: Preparation of 17ß-(N-tert-butylcarbamoyl)-5a-4-aza- androst-l-en-3-one (finasteride) 3.74 g (10 mmol) of 17ß-(N-tert-butylcarbamoyl)-4-aza-5cc-androstan- 3-one obtained in Example 3 and 5.04 g (14 mmol) of benzeneseleninic anhydride were suspended in 10 ml of chlorobenzene. The suspension was refluxed for 3 hours using a Dean-stark apparatus and then concentrated under a reduced pressure to obtain a dark brown residue. The residue was diluted with 100 ml of methylene chloride, washed with 50 ml of saturated sodium bicarbonate and 50 ml of saturated brine. Then the residue was dried over anhydrous MgS04, filtered, and the solvent was removed. The residue was subjected to column chromatography and the product was recrystallized in. methylene chloride/ethyl acetate, to obtain 2. 83 g of the title compound as a

white crystalline (Yield: 76%), having the following properties: Melting point (mp): 256-258 °C H-NMR (o, CDC13) : 0.73 (3H, s, 18-CH3), 0.99 (3H, s, 19-CH3), 1. 05- 1.27 (4H, m, cyclo-CH), 1.27 (9H, 3, t-Bu), 1. 30-2. 10 (10H, m, cyclo-CH), 3.33 (lH, dd, 5a-CH), 5.31 (lH, bs, -NH), 5. 82 (lH, dd, 2-CH), 5.93 (lH, bs, -NH), 6.81 (1 H, dd, 1-CH) While the invention has been described with respect to the above specific embodiments, it should be recognized that various modifications and changes may be made to the invention by those skilled in the art which may also fall within the scope of the invention as defined by the appended claims.