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EP0626972A1 - Procede d'elaboration d'acylandrostadienes-3 - Google Patents

Procede d'elaboration d'acylandrostadienes-3

Info

Publication number
EP0626972A1
EP0626972A1 EP93904948A EP93904948A EP0626972A1 EP 0626972 A1 EP0626972 A1 EP 0626972A1 EP 93904948 A EP93904948 A EP 93904948A EP 93904948 A EP93904948 A EP 93904948A EP 0626972 A1 EP0626972 A1 EP 0626972A1
Authority
EP
European Patent Office
Prior art keywords
compound
formula
process according
nitrogen
pharmaceutically acceptable
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP93904948A
Other languages
German (de)
English (en)
Other versions
EP0626972A4 (en
Inventor
Neil Howard Baine
Michael A. Mcguire
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SmithKline Beecham Corp
Original Assignee
SmithKline Beecham Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by SmithKline Beecham Corp filed Critical SmithKline Beecham Corp
Publication of EP0626972A1 publication Critical patent/EP0626972A1/fr
Publication of EP0626972A4 publication Critical patent/EP0626972A4/en
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J75/00—Processes for the preparation of steroids in general
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/0066—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by a carbon atom forming part of an amide group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J3/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by one carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J3/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by one carbon atom
    • C07J3/005—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by one carbon atom the carbon atom being part of a carboxylic function

Definitions

  • the present invention relates to an improved 15 process for the preparation of substituted steroidal dienes.
  • Such compounds are described in US Patent No, 5,017,568, issued on May 21, 1991 to Holt et al., as being useful in inhibiting steroid 5- ⁇ -reductase.
  • oxalyl bromide is a toxic, expensive liquid which is difficult to store and is not commercially available in the bulk amounts needed for an industrial process.
  • This invention relates to a process for the fluorosulphonylation of multiple functional groups on the same molecule.
  • This invention specifically relates to a process for the simultaneous fluorosulphonylation and amidation of 3-one- -ene-17-carboxylic acid steroidal compounds.
  • This invention specifically relates to an improved process for the preparation of N-t-butyl-androst-3, 5- diene-17 ⁇ -carboxamide-3-carboxylic acid.
  • the present invention provides a process for the production of a compound of formula (I)
  • R 1 is R ⁇ R 4 , where R ⁇ and R 4 are each independently selected from hydrogen, C ⁇ -galkyl, C3_gcycloalkyl, phenyl; or R ⁇ and R 4 taken together with the nitrogen to which they are attached represent a 5-6 membered saturated ring comprising up to one other heteroatom selected from oxygen and nitrogen; and
  • R2 is an acid or ester; or a pharmaceutically acceptable salt, hydrate or solvate thereof, which comprises
  • reaction to convert Formula II compounds to formula III is performed at a temperature from -78°C to 20°C; A particularly preferred temperature range is from -10°C to 10°C.
  • the reaction to convert Formula III compounds to Formula I compounds is performed at a temperature of 25°C to 100°C; a particularly preferred temperature range is from 50 to 90°C.
  • compounds of the Formula III are particularly useful as intermediates in the preparation of Formula I compounds.
  • C ⁇ _ n alkyl means a straight or branched hydrocarbon chain having 1-n carbons.
  • acid as used herein and in the claims is meant any group which is capable of acting as i proton donor including but not limited to; -COOH, -P(0) (OH)2, -PH(0)OH, -SO3H and - (CH 2 ) i-3-COOH.
  • esters as used herein and in the claims is meant a group consisting of an acid, as defined above, in which the donatable proton or protons are replaced by alkyl substituents.
  • solvent an organic solvent such as methylene chloride, ethylene chloride, chloroform, carbon tetrachloride, tetrahydrofuran (THF) , ethyl ether, toluene, ethyl acetate, dimethylsufloxide, methanol or dimethylforamide.
  • organic solvent such as methylene chloride, ethylene chloride, chloroform, carbon tetrachloride, tetrahydrofuran (THF) , ethyl ether, toluene, ethyl acetate, dimethylsufloxide, methanol or dimethylforamide.
  • the base utilized to prepare compounds of Formula II is triethylamine or pyridine, most preferably pyridine.
  • the solvent utilized to prepare compounds of Formula II is methylene chloride.
  • the catalyst utilized in said metal catalyzed coupling reaction is palladium (II) acetate.
  • Preferred acids used to describe R ⁇ in Formula (I) include; -COOH, -P(0) (OH) 2 , -PH(0)OH, -SO3H, and (CH 2 ) ⁇ -COOH. Particularly preferred among the above acids is -COOH.
  • metal-catalyzed coupling reaction as used herein and in the claims is meant that the prepared -b-
  • fluorosulfonated compound is reacted in a suitable organic solvent; preferably a dimethylsulfoxide- alkanol (C]_-Cg ) solution (when an ester is desired) or toluene, dimethylformamide, THF or C ⁇ g-CgOH (when an acid is desired) with a base, preferably a tertiary amine base such as triethylamine, pyridine or tributylamine or aqueous KOH or aqueous NaOH; a phosphine such as bis (diphenylphosphino)alkane, preferably 1,3 bis (diphenylphosphino)propane or tri-o-tolylphosphine, and a metal catalyst, preferably a palladium catalyst such as palladium (II) acetate, palladium (II) chloride and bis (triphenylphosphine) palladium II acetate, thereby forming a metalated complex
  • coupling reagent as used herein and in the claims is meant a compound which is capable of inserting into said metalated complex with subsequent elimination to yield the corresponding ester or acid.
  • Preferred coupling reagents which.when added to the metal-catalyzed coupling reaction, as described herein, yield preferred acid and ester groups, as disclosed herein, are carbon monoxide (to yield -COOC ⁇ - ⁇ ) , formic acid (to yield -COOH) , ethyltributylstannyl acetate (to yield -CH2COOH) , dimethyl phosphite (to yield
  • C3_gcycloalkyl, phenyl; or R ⁇ and R 4 taken together with the nitrogen to which they are attached represent a 5-6 membered saturated ring comprising up to one other heteroatom selected from oxygen and nitrogen.
  • the process of the present invention is particularly useful for preparing a compound of Structure IIA
  • 1,3-Bis(diphenylphosphino)propane, bis (triphenylphosphine)palladium acetate, and palladium acetate, are commonly available.
  • Androst ⁇ 4-en-3-one- 17 ⁇ -carboxylic acid is available from Berlichem, Inc. (Wayne, NJ) .
  • Fluorosufonic anhydride was prepared as described by S. Kongpricha, et. al., Inorgr. Syn . 1968, XI, 151.
  • a stirred mixture of androst-4-en-3-one-17 ⁇ - carboxylic acid (1 molar equivalent) and pyridine (3 molar equivalents) in 1000 mL of methylene chloride is cooled to 0-5°C, and is treated with fluorosulfonic anhydride (2.5 molar equivalents) while maintaining the temperature between 0-10°C.
  • the reaction mixture is quenched into a solution of tert-butylamine (10 molar equivalents) in methylene chloride while maintaining the temperature between 0- 10°C.
  • the mixture is stirred for 30 minutes. About 100 ' mL of water is added.
  • the organic phase is separated and reduced to about half its volume by vacuum distillation.
  • the solution is restored to its original volume with acetone.
  • a vessel is charged with dimethylsulfoxide (1350 mL) , methanol (75 mL, 5.4 molar equivalents), N-t-butyl- androst-3,5-diene-3-fluorosulphonyl-17 ⁇ -carboxamide (150 g, 1 molar equivalent), triethylamine (76.3 g, 2.2 molar equivalents), and 1,3-bis (diphenylphosphino)propane (1.4 g, 0.01 molar equivalent). The mixture is stirred until a solution is obtained. Palladium acetate (0.768 g, 0.01 molar equivalent) is added and the flask is filled and evacuated with carbon monoxide three times.
  • the vessel is pressurized with 7 psi carbon monoxide and the reaction is stirred rapidly.
  • the reaction solution is heated to 75°C.
  • the carbon monoxide uptake is finished in about 1.5 hours.
  • the reaction is cooled to 15°C and stirred for 2 hours.
  • the solid product is isolated by suction filtration, and the mother liquors are used to rinse out the inside of the reactor.
  • the solid product is thoroughly washed with water (1.5 L) and dried under vacuum at 95°C to afford pure methyl 17 ⁇ - (N-tert- butylcarboxamide)-androst-3,5-diene-3-carboxylate.
  • the hot reaction solution is filtered through celite and the filter pad is washed with 60°C water (80 L) .
  • the filtrate is diluted with water (80 mL) .
  • the methanol is removed by distillation to a head temperature of 100°C.
  • the mixture is cooled to 60°C and is quenched with vigorous stirring into 1.5 N hydrochloric acid (160 mL) .
  • a vessel is charged with 5 volumes of dimethylformamide, N-t-butyl-androst-3,5-diene-3- fluorosul ⁇ honyl-17 ⁇ -carboxamide (1 molar equivalent, prepared as described in Example 1 (i) ) , tri-n-butylamine (4.5 molar equivalents), formic acid (2 molar equivalents) and bis(triphenylphosphine)palladium acetate (0.02 molar equivalents).
  • the flask is evacuated and filled with carbon monoxide three times.
  • the vessel is pressurized with 7 psi carbon monoxide and the reaction is stirred rapidly.
  • the reaction solution is heated to 75°C until the uptake of carbon monoxide is complete.
  • the reaction is cooled to room temperature.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Steroid Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Nouveaux procédés d'élaboration de diènes stéroïdes substitués.
EP93904948A 1992-02-07 1993-02-05 Process of preparing 3-acylandrostadienes. Withdrawn EP0626972A4 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US83227992A 1992-02-07 1992-02-07
US832279 1992-02-07
PCT/US1993/001071 WO1993016098A1 (fr) 1992-02-07 1993-02-05 Procede d'elaboration d'acylandrostadienes-3

Publications (2)

Publication Number Publication Date
EP0626972A1 true EP0626972A1 (fr) 1994-12-07
EP0626972A4 EP0626972A4 (en) 1995-01-04

Family

ID=25261205

Family Applications (1)

Application Number Title Priority Date Filing Date
EP93904948A Withdrawn EP0626972A4 (en) 1992-02-07 1993-02-05 Process of preparing 3-acylandrostadienes.

Country Status (13)

Country Link
EP (1) EP0626972A4 (fr)
JP (1) JPH07505618A (fr)
KR (1) KR950700320A (fr)
CN (1) CN1078474A (fr)
AU (1) AU3612893A (fr)
CA (1) CA2129347A1 (fr)
IL (1) IL104601A0 (fr)
MA (1) MA22787A1 (fr)
MX (1) MX9300677A (fr)
SI (1) SI9300067A (fr)
TW (1) TW241266B (fr)
WO (1) WO1993016098A1 (fr)
ZA (1) ZA93802B (fr)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IL104602A (en) * 1992-02-07 1997-07-13 Smithkline Beecham Corp Process for the preparation of 3-carbonylandrostadiene- 17-carboxamides and intermediates for this process
US5641765A (en) * 1992-11-18 1997-06-24 Smithkline Beecham Corporation 17-αand 17-βsubstituted acyl-3-carboxy-3,5-dienes and use in inhibiting 5-α-reductase
US5683995A (en) * 1992-11-18 1997-11-04 Smithkline Beecham Corporation 17 substituted acyl-3-carboxy 3,5-diene steroidals as α-reductase inhibitors

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0465141A2 (fr) * 1990-06-28 1992-01-08 Merck & Co. Inc. 17-Bêta-carbamides des 3-carboxy-androst-3,5-diènes, N-monosubstitués par adamantane ou norborane

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4946834A (en) * 1988-12-23 1990-08-07 Smithkline Beecham Corporation Phosphonic acid substituted steroids as steroid 5α-reductase inhibitors
US5032586A (en) * 1989-08-24 1991-07-16 Smithkline Beecham Corporation 7-keto or hydroxy 3,5-diene steroids as inhibitors of steroid 5-alpha reductase

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0465141A2 (fr) * 1990-06-28 1992-01-08 Merck & Co. Inc. 17-Bêta-carbamides des 3-carboxy-androst-3,5-diènes, N-monosubstitués par adamantane ou norborane

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of WO9316098A1 *

Also Published As

Publication number Publication date
IL104601A0 (en) 1993-07-08
MX9300677A (es) 1994-07-29
CA2129347A1 (fr) 1993-08-19
JPH07505618A (ja) 1995-06-22
CN1078474A (zh) 1993-11-17
KR950700320A (ko) 1995-01-16
ZA93802B (en) 1993-11-05
MA22787A1 (fr) 1993-10-01
EP0626972A4 (en) 1995-01-04
WO1993016098A1 (fr) 1993-08-19
SI9300067A (en) 1993-09-30
TW241266B (fr) 1995-02-21
AU3612893A (en) 1993-09-03

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