WO2005075497A1 - PROCEDE DE PREPARATION DE DERIVES DE 17ss-SUBSTITUE-3-OXO-4-AZA-5ALPHA-ANDROSTANE - Google Patents

PROCEDE DE PREPARATION DE DERIVES DE 17ss-SUBSTITUE-3-OXO-4-AZA-5ALPHA-ANDROSTANE Download PDF

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Publication number
WO2005075497A1
WO2005075497A1 PCT/IB2004/004117 IB2004004117W WO2005075497A1 WO 2005075497 A1 WO2005075497 A1 WO 2005075497A1 IB 2004004117 W IB2004004117 W IB 2004004117W WO 2005075497 A1 WO2005075497 A1 WO 2005075497A1
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WIPO (PCT)
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formula
ammonium
compound
oxo
aza
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PCT/IB2004/004117
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English (en)
Inventor
Yatendra Kumar
Rakesh Singh
Saridi Madhava Dileep Kumar
Keshav Deo
Swargam Sathyanarayana
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Ranbaxy Laboratories Limited
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Publication of WO2005075497A1 publication Critical patent/WO2005075497A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J73/00—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms
    • C07J73/001—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom
    • C07J73/005—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom by nitrogen as hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J75/00—Processes for the preparation of steroids in general
    • C07J75/005—Preparation of steroids by cyclization of non-steroid compounds

Definitions

  • the present invention relates to a process for the preparation of 17/3-substituted-3- oxo-4-aza-5 ⁇ -androstane derivatives, which are useful intermediates for the synthesis of 3- oxo-4-aza-5 ⁇ -androst-l-ene derivatives including fmasteride.
  • fmasteride is N-tert-butyl-3-oxo-4-aza-5o;-androst-l-ene-17/3- carboxamide and is known from U.S. Patent No. 4,760,071.
  • Finasteride is used in the treatment of hyperandrogenic conditions, such as acne vulgaris, seborrhea, female hirsutism and benign prostate hypertrophy.
  • hyperandrogenic conditions such as acne vulgaris, seborrhea, female hirsutism and benign prostate hypertrophy.
  • 4,377,584 disclose the use of methylamine in the presence of ethylene glycol or ethanol for the ring closure of 17/?-substituted-5-oxo-A-nor-3,5-secoandrostane-3-oic acid to 173-substituted- 3-oxo-4-methyl-4-aza-5 ⁇ :-androst-5-ene derivative, whereas the process of J Med. Chem., (1986), 29, p. 2298 uses liquid ammonia. In all the above references, the product was isolated and then hydrogenated in the presence of platinum oxide in acetic acid to obtain 17/3-substituted-3-oxo-4-aza-5 ⁇ -androstane derivative. Heterocycles, (1998), 47, p.
  • WO 02/46207 teaches the use of ammonium salt of lower alkyl carboxylic acids in the catalytic hydrogenation process.
  • J Med. Chem., (1984), 27, p. 1690 and U.S. Patent No. 4,377,584 disclose the preparation of N-alkyl-3-oxo-5 ⁇ -androst-4-ene-17/3-carboxamide comprising reacting 3- oxo-5 ⁇ -androst-4-ene-17/3-carboxylic acid with oxalyl chloride, pyridine and corresponding alkyl amine.
  • WO 03/27132 reports the use of pivaloyl chloride with tertiary butyl amine in the presence of a base for the conversion of androst- 4-en-3-one-17/3-carboxylic acid to 17/3(N-tert-butylcarbamoyl)-androst-4-ene-3-one.
  • R represents hydrogen; hydroxyl; C 1-6 straight or branched chain alkyl; C ⁇ -6 straight or branched chain alkoxy; aryl; or NHA wherein, A represents hydrogen, C ⁇ -6 straight or branched chain alkyl, aryl or arylalkyl.
  • the process can include reacting a compound of Formula II
  • Ri represents C ⁇ -6 straight or branched chain alkyl, comprising reacting 3-oxo-4- aza-5-Q!-androstene-17(3-carboxylic acid of Formula IN
  • R can be hydrogen; hydroxyl; C ⁇ -6 straight or branched chain alkyl; C ⁇ -6 straight or branched chain alkoxy; aryl; or NHA wherein, A represents hydrogen, C ⁇ -6 straight or branched chain alkyl, aryl or arylalkyl. In some particular examples R represents N-tertiary-butyl carboxamide.
  • ammonium salts include ammonium formate, ammonium acetate, ammonium propionate, ammonium sulfate, ammonium persulfate, ammonium sulfide, ammonium phosphate, ammonium nitrite, ammonium nitrate, ammonium carbonate, ammonium bicarbonate, ammonium chlorate, ammonium chloride, ammonium bromide, ammonium iodide and ammonium fluoride.
  • Suitable solvents for the reaction of compounds of Formula II with ammonium salt are inert organic solvents that do not undergo chemical change under the reaction conditions.
  • solvents examples include glycols such as ethylene glycol or propylene glycol; alkyl ethers such as diethylether, diisopropylether or dimethoxyethane; alcohols such as methanol, ethanol or isopropanol; ketones such as acetone or methyl ethyl ketone; chlorinated hydrocarbons such as methylene chloride, ethylene dichloride or carbon tetrachloride; esters such as ethylacetate or isopropylacetate; nitriles such as acetonitrile or benzonitrile; dipolar aprotic solvents such as dimethylsulfoxide or dimethylformamide; cyclic ethers such as dioxane or tetrahydrofuran; and mixtures thereof.
  • glycols such as ethylene glycol or propylene glycol
  • alkyl ethers such as diethylether, diisopropylether or dimethoxyethane
  • Temperatures for the reaction of compound of Formula II with ammonium salt are not critical and the reaction may be performed at temperatures of from about room temperature to about 220°C. The reaction may be performed at temperatures of from about 150°C to about 180°C in some particular embodiments.
  • examples of the alkyl group of the alkyl amine can include C ⁇ -6 straight or branched chain alkyl group. In some particular embodiments, tertiary butyl amine is used.
  • the reaction of compounds of Formula IN with phosphorous oxychloride, pyridine and alkyl amine may performed in inert solvents.
  • solvents examples include hydrocarbons such as benzene, xylene, toluene, heptane, hexane, cyclohexane or octane; alkyl ethers such as diethylether, diisopropylether or dimethoxyethane; alcohols such as methanol, ethanol or isopropanol; ketones such as acetone or methyl ethyl ketone; chlorinated hydrocarbons such as methylene chloride, ethylene dichloride or carbon tetrachloride; esters such as ethylacetate or isopropylacetate; nitriles such as acetonitrile or benzonitrile; dipolar aprotic solvents such as dimethylsulfoxide or dimethylformamide; cyclic ethers such as dioxane or tetrahydrofuran; and mixtures thereof.
  • hydrocarbons such as benzene, xylene, to
  • 17/3- substituted-3-oxo-4-aza-5c ⁇ -androst-4-ene-derivatives for example with sodium periodate and potassium permanganate, or using ozone.
  • 17/3- substituted-3-oxo-4-aza-5o!-androst-4-ene-derivative may be the compound of Formula VII,
  • Formula VII wherein R] is as defined above, which may be prepared from oxidation of compound of Formula III.
  • the compound of Formula III may prepared by the process comprising reacting compound of Formula IV with phosphorous oxychloride and alkyl amine of Formula R ⁇ NH , wherein Ri is as defined above in the presence of pyridine, as described herein. 17/3-substituted-3-oxo-4-aza-5 ⁇ !-androstane derivative of Formula I may be further converted to 3-oxo-4-aza-5- ⁇ -androst-l-ene derivative of Formula V,
  • Example 1 Preparation of N-tert-butyl-3-oxo-5 ⁇ -androst-4-ene-17 ⁇ -carboxamide A solution of 3-oxo-4-androst-4-ene-17 ⁇ -carboxylic acid (50 g, 2.37 mmol) in toluene (700 ml) was refluxed azeotropically to remove moisture. The reaction mixture was then cooled to room temperature and pyridine (13 g, 2.411 mmol) was added to it. It was thereafter cooled to 0 to 5°C and treated with phosphorous oxychloride (32 g, 3.13 mmol), maintaining anhydrous condition under nitrogen atmosphere. After addition, the reaction mixture was heated to room temperature and stirred for 3 hours.
  • Example 2 Preparation of 17 ⁇ -(N-tert-butyl) carbamoyl-5-oxo-A-nor-3,5- secoandrostane-3-oic acid A solution of N-tert-butyl-3-oxo-5 ⁇ -androst-4-ene-17 ⁇ -carboxamide (50 g, 2.153 m mol) in a mixture of tertiary butanol (1.5 1) and aqueous solution of sodium carbonate (22 g in 80 ml distilled water) was treated with a solution of sodium periodate (200 g,
  • Example 3 Preparation of N-tert-butyl-3-oxo-4-aza-5 ⁇ -androstane-17 ⁇ -carboxamide via N-tert-butyl-3-oxo-4-aza-5 ⁇ -androst-4-ene-17 ⁇ -carboxamide
  • a solution of 17 ⁇ -(N-tert-butyl) carbamoyl-5-oxo-A-nor-3,5-secoardrostane-3-oic acid (50 g, 1.532 mmol) and ammonium formate (100 g, 19.029 mmol) in ethylene glycol (375 ml) was stirred at room temperature for 2 hours. The reaction mixture was gradually heated to 160 - 170°C and was stirred for 4 hours.
  • Example 4 Preparation of N-tert-butyl-3-oxo-4-aza-5 ⁇ -androst-l-ene-17 ⁇ -carboxamide (Finasteride)
  • a suspension of N-tert-butyl-3-oxo-4-aza-5 ⁇ -androstane-17 ⁇ -carboxamide (50 g, 0.534 mmol) and benzeneseleninic anhydride (100 g, 1.11 mmol) in toluene (1.5 1) was refluxed for 18 hours at 110 - 112°C. The reaction was monitored by HPLC or TLC.
  • the dichloromethane layer was separated and treated with activated carbon (5 g) and neutral alumina (10 g). It was then filtered through hyflo and dichloromethane was recovered completely from the filtrate under reduced pressure at 35 - 40°C. The residue was crystallized by refluxing it in hexane for 30 minutes. The hot mixture was filtered at 60 - 65°C, washed with hot hexane and dried under reduced pressure. Yield: 25.6 g

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Steroid Compounds (AREA)

Abstract

L'invention porte sur un procédé de préparation de dérivés de 17ß-substitué-3-oxo-4-aza-5?-androstane qui sont utiles comme intermédiaires dans la synthèse des dérivés de 3-oxo-4-aza-5?-androst-1-ène comprenant finasteride.
PCT/IB2004/004117 2004-01-07 2004-12-14 PROCEDE DE PREPARATION DE DERIVES DE 17ss-SUBSTITUE-3-OXO-4-AZA-5ALPHA-ANDROSTANE WO2005075497A1 (fr)

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IN36DE2004 2004-01-07
IN36/DEL/2004 2004-01-07

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WO2005075497A1 true WO2005075497A1 (fr) 2005-08-18

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102532236A (zh) * 2012-01-05 2012-07-04 中国药科大学 甾体类5α-还原酶抑制剂、其制备方法及其医药用途
CN101775064B (zh) * 2010-02-05 2012-08-22 常州佳尔科药业集团有限公司 3-羰基-4-氮杂-5α-雄甾化合物的合成方法
CN103554210A (zh) * 2012-01-05 2014-02-05 中国药科大学 甾体类5α-还原酶抑制剂、其制备方法及其医药用途

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993023039A1 (fr) * 1992-05-20 1993-11-25 Merck & Co., Inc. 4-aza-5a-androstan ones substituees utilisees en tant qu'inhibitors de la 5a-reductase
WO2002046207A2 (fr) * 2000-11-03 2002-06-13 Glaxo Group Limited Procede
WO2004016595A1 (fr) * 2002-08-19 2004-02-26 Hanmi Pharm. Co., Ltd. Procede de preparation selective du compose 3-oxo-4-aza-5a-androstane

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993023039A1 (fr) * 1992-05-20 1993-11-25 Merck & Co., Inc. 4-aza-5a-androstan ones substituees utilisees en tant qu'inhibitors de la 5a-reductase
WO2002046207A2 (fr) * 2000-11-03 2002-06-13 Glaxo Group Limited Procede
WO2004016595A1 (fr) * 2002-08-19 2004-02-26 Hanmi Pharm. Co., Ltd. Procede de preparation selective du compose 3-oxo-4-aza-5a-androstane

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
HOUBEN-WEYL: "Methoden der Organischen Chemie Bd.E5, page 593", 1985, GEORG THIEME VERLAG, STUTTGART, NEW YORK, XP002328691 *
WU: "Synthesis of Finasteride, 5alpha-reductase Inhibitors", NAT.SCI.J.XIANGTAN UNIVERSITY, vol. 25, no. 2, 2003, pages 43 - 45, XP009047611 *
ZHENG ET AL.: "Synthesis of N-Substituted 4-Methyl-3-Oxo-4-Aza-5alpha-Androstane-17beta-Carboxamide Compounds", J.CHINA PHARM.UNIVERS., vol. 26, no. 1, 1995, pages 1 - 4, XP001196974 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101775064B (zh) * 2010-02-05 2012-08-22 常州佳尔科药业集团有限公司 3-羰基-4-氮杂-5α-雄甾化合物的合成方法
CN102532236A (zh) * 2012-01-05 2012-07-04 中国药科大学 甾体类5α-还原酶抑制剂、其制备方法及其医药用途
CN103554210A (zh) * 2012-01-05 2014-02-05 中国药科大学 甾体类5α-还原酶抑制剂、其制备方法及其医药用途
CN102532236B (zh) * 2012-01-05 2014-04-16 中国药科大学 甾体类5α-还原酶抑制剂、其制备方法及其医药用途

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