WO1993014106A1 - Halogenation a l'aide d'un reactif halo-vilsmeier - Google Patents

Halogenation a l'aide d'un reactif halo-vilsmeier Download PDF

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Publication number
WO1993014106A1
WO1993014106A1 PCT/US1993/000079 US9300079W WO9314106A1 WO 1993014106 A1 WO1993014106 A1 WO 1993014106A1 US 9300079 W US9300079 W US 9300079W WO 9314106 A1 WO9314106 A1 WO 9314106A1
Authority
WO
WIPO (PCT)
Prior art keywords
reagent
process according
vilsmeier reagent
halogen
chloride
Prior art date
Application number
PCT/US1993/000079
Other languages
English (en)
Inventor
Neil Howard Baine
Donald Nathaniel Kline
Richard Eric Mewshaw
Franklin Owings
Original Assignee
Smithkline Beecham Corporation
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 Corporation filed Critical Smithkline Beecham Corporation
Priority to KR1019940702343A priority Critical patent/KR940703849A/ko
Priority to JP5512542A priority patent/JPH07505138A/ja
Priority to EP93902957A priority patent/EP0643723A4/fr
Priority to BR9305786A priority patent/BR9305786A/pt
Priority to AU34348/93A priority patent/AU666167B2/en
Priority to SK800-94A priority patent/SK80094A3/sk
Publication of WO1993014106A1 publication Critical patent/WO1993014106A1/fr
Priority to FI943214A priority patent/FI943214A0/fi
Priority to NO942535A priority patent/NO942535L/no
Priority to BG98887A priority patent/BG98887A/bg

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • 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
    • 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

Definitions

  • the present invention relates to an improved 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 readily available in the bulk amounts needed for an industrial process.
  • This invention relates to a process for the halogenation of a compound with multiple functional groups on the same molecule.
  • This invention relates to an improved process for converting steroidal ⁇ , ⁇ -unsaturated ketones to their corresponding halo-1,3 diene derivatives.
  • This invention relates to an improved process for the formation of acid-halide from a steroidal carboxylic acid substituent followed by nucleophilic displacement of said halide.
  • This invention specifically relates to an improved process for the in situ conversion of steroidal carboxylic acids to steroidal carboxa ides.
  • This invention specifically relates to a process for the simultaneous bromination and amidation of 3-one- 4-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.
  • reduced temperature as used herein is meant below 25°C, preferably between -15 and 15°C, most preferably between 0 and 10°C.
  • coupling reagent a compound and/or conditions which are capable of reacting with a metalated moiety to form an acid, ester, C ⁇ _galkylcarbonyl or Ci- ⁇ O 3 ---- ⁇ --- moiety.
  • metalated moiety is a lithium metalated moiety prepared by reacting the corresponding halogenated moiety with an alkyllithium reagent.
  • Compounds useful as coupling reagents include chloro formates, alkyl bromides and acid chlorides.
  • said coupling reagent will utilize carbon dioxide as the reacting compound.
  • acid as used herein is meant any group which is capable of acting as a proton donor including but not limited to; -COOH, -P (0) (OH)2, PH(0)OH, -SO3H and - (CH ) 1-3-COOH.
  • esters as used herein is meant a group consisting of an acid, as defined above, in which the donatable proton or protons are replaced by alkyl substituents.
  • solvent or "appropriate solvent” as used herein is meant an organic solvent such as methylene chloride, ethylene chloride, chloroform. carbon tetrachloride, tetrahydrofuran (THF) , ethyl ether carbon, toluene or ethyl acetate.
  • organic solvent such as methylene chloride, ethylene chloride, chloroform. carbon tetrachloride, tetrahydrofuran (THF) , ethyl ether carbon, toluene or ethyl acetate.
  • halogen-Vilsmeier reagent as used herein is meant a halogenated disubstituted formamide reagent of the structure:
  • R ⁇ and R ⁇ are independently selected from an alkyl, aryl or arylalkyl group; and X is Br or I; and y is a counter ion, which is prepared by a) reacting, preferably at reduced temperatures, a chloride source such as oxalyl chloride or thionyl chloride, with a disubstituted formamide reagent, such as a dialkyl substitued formamide reagent preferably dimethylformamide, in an appropriate solvent, preferably ethylene chloride, to form a chloro-Vilsmeier reagent, said chloro-Vilsmeier reagent being reacted in situ, preferably at reduced temperatures, with a bromide source or an iodine source, preferably hydrogen bromide gas or b) reacting, preferably at reduced temperatures, a bromide source or an iodide source, preferably oxalyl bromide, with a disubstituted formamide reagent, such as
  • This invention therefore, relates to the in situ prepartation and use of a bromo-Vilsmeier reagent or an iodo-Vilsmeier reagent, said reagents being prepared safely and economically from known and readily available reagents preferably the corresponding chloro-Vilsmeier reagent.
  • this invention will have utility in all reactions wherein bromo-Vilsmeier reagents or iodo- Vilsmeier reagents are utilized.
  • Preferred alkyllithium reagents for use herein include n-butyllithium, sec-butyllithium and tert- butyllithium.
  • halogen and its derivatives as used herein means bromine or iodine.
  • the present invention provides a process for the production of a compound of formula (I)
  • R 1' is R3R 4 , where R ⁇ and R 4 are each independently selected from hydrogen, Ci-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 containing up to one other heteroatom selected from oxygen and nitrogen; and R2 is an acid, ester, C-]__galkylcarbonyl or C-]__2o alkyl; or .a pharmaceutically acceptable salt, hydrate or solvate thereof, which comprises reacting, at a reduced temperature, a compound of formula (II)
  • R*-- is as defined above and subsequently, in an appropriate solvent and at a reduced temperature, adding an alkyllithium reagent followed by a coupling reagent to form a compound of formula (I) , provided that when R3 and/or R 4 is H the compound of formula (III) is subjected to a basic medium suitable for the selective deprotination of the amide prior to the addition of the alkyllithium reagent, and thereafter optionally forming a pharmaceutically acceptable salt, hydrate or solvate thereof.
  • halogen-vilsmeier reagent is prepared by reacting, preferably at reduced temperatures, a chloride source such as oxalyl chloride or thionyl chloride, with a disubstituted formamide reagent, such as a dialkyl substitued formamide reagent preferably dimethylformamide, in an appropriate solvent, preferably methylene chloride, to form a chloro- Vilsmeier reagent, said chloro-Vilsmeier reagent being reacted in situ, preferably at reduced temperatures, with a bromide source or an iodide source, preferably hydrogen bromide gas.
  • a chloride source such as oxalyl chloride or thionyl chloride
  • a disubstituted formamide reagent such as a dialkyl substitued formamide reagent preferably dimethylformamide
  • C]__ n alkyl means a straight or branched hydrocarbon chain having C ⁇ _ n carbons.
  • alkyl means a straight or branched hydrocarbon chain.
  • aryl means an aromatic carbocyclic or heterocyclic ring which is unsubstituted or substituted with non-reactive substituents.
  • halogen-vilsmeier reagents used in the dihalogenation of formula (II) compounds are prepared and utilized in situ.
  • halogen-Vilsmeien reagent is a bromo-Vilsmeier reagent.
  • bromo-Vilsmeier reagent is (bromomethylene) dimethyl ammonium bromide.
  • Preferred organic acids used to describe R-- in formula (I) include; -COOH, -P(0) (OH)2, -PH(0) (OH), -SO3H and - (CH2) 1-3COOH. Particularly preferred among the above acids is -COOH.
  • Preferred bases utilized in preparing the basic medium used to selectively deprotonate the amide of formula (III) compounds include metal hydrides, alkyllithium reagents, Grignard reagents and metal alkoxides.
  • Preferred amori'g the above disclosed bases are ethylmagnesium bromide, butyllithium and ethylmagnesium chloride.
  • Particularly preferred among the above disclosed bases is ethylmagensium chloride.
  • the selective deprotonation of said amide is conducted at a temperature above 25°C, most preferably between 30 and 50°C.
  • the alkyl lithium reagent used to initiate the halogen-metal exchange on formula (III) compounds is sec-butyllithium.
  • a preferred aspect of the invention is the preparation of steroidal halo-1,3-diene systems from steroidal ⁇ , ⁇ -unsaturated ketones utilizing a halogen- vilsmeier reagent prepared and utilized in _____i____.il.
  • a preferred aspect of the invention is the halogen- vilsmeier induced formation of an acid halide moiety from a steroidal carboxylic acid moiety, said acid- halide substituent being subject to displacement by a nucleophilic reagent.
  • Preferred nucleophilic reagents as used herein include H-R 1 where R*-- is as defined above. Especially preferred among the above nucleophilic reagents is tert-butyla ine.
  • the process of the present invention is particularly useful for preparing a compound of structure (IIIA)
  • Example 1 17ft- r ⁇ fl.l-dimethylethyl. aminolcarbonyl1andro ⁇ a-3.5- ⁇ ⁇ n - -ca boxy ⁇ li(-. acid
  • a flask under nitrogen atmosphere was charged with 100 mL of methylene chloride and 6.12 mL (2.5 molar equivalents) of dimethylformamide.
  • the solution was cooled to 0-5°C, and was treated with 6.9 mL (2.5 molar equivalents) of oxalyl chloride while maintaining the temperature between 0-10°C.
  • a white precipitate formed.
  • 50.1 grams (19.6 molar equivalents) of hydrogen bromide gas were bubbled through the solution while maintaining the temperature between 0-10°C.
  • the suspension became a clear colorless solution.
  • the solution was degassed by reducing the solution volume by about one-half by vacuum distillation and restoring to its original volume with methylene chloride. This concentration/refill procedure was repeated.
  • Androst-4-en-3-one-17 ⁇ -carboxylic acid 10.0 grams (1 molar equivalent) was added to the resulting white suspension and the mixture was warmed to room temperature and stirred for 2 hours.
  • the reaction mixture was quenched into a vessel containing 100 mL of methylene chloride and 23.1 grams (10 molar equivalents) of tert-butylamine while maintaining the temperature between 0-10°C.
  • the mixture was stirred for 30 minutes. About 100 mL of water were added and the biphase mixture was filtered through a pad of Celite. The organic phase was separated and reduced to about half its volume by vacuum distillation. The solution was restored to its original volume with acetone. This concentration/fill procedure was repeated twice more.
  • the gassing was continued as the solution was allowed to warm to room temperature.
  • the resulting suspension was then washed with 100 mL of 3.3M aq. hydrochloric acid and the aqueous phase was removed.
  • the organic phase was washed twice with about 150 mL of water. About 85 mL of water was added to the organic phase, and the organic phase was then removed by distillation under reduced pressure.
  • the resulting aqueous suspension of product was extracted into 100 mL of methyl ethyl ketone.
  • the aqueous phase was separated and the organic phase was washed with 100 mL of water.
  • the organic phase was treated with 0.6 g of decolorizing carbon and was filtered through celite.
  • a solution of 10 mL of methylene chloride containing 5 mg of p-quinone, and 0.328 g (1.8 molar equivalents) of dimethylformamide was cooled to 0°C and treated with 0.85 g (1.6 molar equivalents) of oxalyl bromide.
  • the reaction mixture was allowed to warm to room temperature and was stirred for 30 minutes.
  • the solution was cooled to about 5°C and 0.95 g (1 molar equivalent) of 3-bromo-androsta-3,5-diene-17 ⁇ -carboxylic acid in 20 mL of methylene chloride was added to the white suspension. The solution was allowed to warm to room temperature and was stirred for 1.5 hours.
  • the reaction mixture was quenched with 2.2 mL (8.4 molar equivalents) of t-butylamine and stirred for 5 minutes.
  • the mixture was poured into 100 mL of ethyl acetate and the organic phase was washed with 50 mL of 10% aq sodium hydroxide.
  • the aqueous phase was separated and extracted with 50 mL of ethyl acetate.
  • the combined organic phases were dried over magnesium sulfate and filtered. The filtrate was concentrated under vacuum to afford a crude solid which was triturated with 24 mL of 50/50 t- butylmethyl ether/hexane.
  • the reaction was treated with tert-butylamine 2.2 ml (8 molar equivalents) in methylene chloride (2 ml) while maintaining the temperature between 0-10°C.
  • the reaction was stirred for 10 minutes then poured into a mixture of ethyl acetate (150 ml) and 10% sodium hydroxide (50 ml) .
  • the organic phase was separated, washed with brine, dried over magnesium sulfate and concentrated to afford a solid.

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)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

L'invention se rapporte à un procédé de préparation d'un diène stéroïdien halogéné. Le procédé consiste en la transformation simultanée d'un acide stéroïdien 3-one en 3-halo et 17-carboxylique en 17-carboxamide en une seule réaction sans l'isolation d'un intermédiaire. On met en ÷uvre le procédé en faisant réagir le matériau stéroïden de départ avec un réactif halogène Vilsmeier.
PCT/US1993/000079 1992-01-06 1993-01-06 Halogenation a l'aide d'un reactif halo-vilsmeier WO1993014106A1 (fr)

Priority Applications (9)

Application Number Priority Date Filing Date Title
KR1019940702343A KR940703849A (ko) 1992-01-06 1993-01-06 할로-빌스메이어 시약을 사용한 할로겐화 방법(Halogenation using halo-Vilsmeier reagent)
JP5512542A JPH07505138A (ja) 1992-01-06 1993-01-06 ハロ−フィルスマイヤー試薬を使用するハロゲン化
EP93902957A EP0643723A4 (fr) 1992-01-06 1993-01-06 Halogenation a l'aide d'un reactif halo-vilsmeier.
BR9305786A BR9305786A (pt) 1992-01-06 1993-01-06 Halogenação utilizando reagento halo-vilsmeier
AU34348/93A AU666167B2 (en) 1992-01-06 1993-01-06 Halogenation using halo-vilsmeier reagent
SK800-94A SK80094A3 (en) 1992-01-06 1993-01-06 Method of preparation of halogenated stereoide dienes
FI943214A FI943214A0 (fi) 1992-01-06 1994-07-05 Halogenointi halogeeni-Vilsmeier-reagenssia käyttäen
NO942535A NO942535L (no) 1992-01-06 1994-07-05 Halogenering ved bruk av halogen-vilsmeirer-reagens
BG98887A BG98887A (bg) 1992-01-06 1994-07-05 Халогениране чрез използване на халогенен реагент на вилсмайер

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US81717992A 1992-01-06 1992-01-06
US07/817,179 1992-01-06
US94134892A 1992-09-04 1992-09-04
US07/941,348 1992-09-04

Publications (1)

Publication Number Publication Date
WO1993014106A1 true WO1993014106A1 (fr) 1993-07-22

Family

ID=27124147

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1993/000079 WO1993014106A1 (fr) 1992-01-06 1993-01-06 Halogenation a l'aide d'un reactif halo-vilsmeier

Country Status (23)

Country Link
EP (1) EP0643723A4 (fr)
JP (1) JPH07505138A (fr)
KR (1) KR940703849A (fr)
CN (1) CN1077201A (fr)
AP (1) AP370A (fr)
AU (1) AU666167B2 (fr)
BG (1) BG98887A (fr)
BR (1) BR9305786A (fr)
CA (1) CA2127272A1 (fr)
CZ (1) CZ161994A3 (fr)
FI (1) FI943214A0 (fr)
HU (1) HUT68273A (fr)
IL (1) IL104302A (fr)
MA (1) MA22761A1 (fr)
MX (1) MX9300025A (fr)
NO (1) NO942535L (fr)
NZ (1) NZ246788A (fr)
OA (1) OA09961A (fr)
RU (1) RU94038223A (fr)
SI (1) SI9300006A (fr)
SK (1) SK80094A3 (fr)
TW (1) TW300226B (fr)
WO (1) WO1993014106A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5641877A (en) * 1992-11-18 1997-06-24 Smithkline Beecham Corporation 17-α and 17-β substituted 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
US8143428B2 (en) 2004-06-08 2012-03-27 Temple University-Of The Commonwealth System Of Higher Education Heteroaryl sulfones and sulfonamides and therapeutic uses thereof

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5017568A (en) * 1987-04-29 1991-05-21 Smithkline Beecham Corporation Steriod 5-alpha-reductase inhibitors

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5017568A (en) * 1987-04-29 1991-05-21 Smithkline Beecham Corporation Steriod 5-alpha-reductase inhibitors

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5641877A (en) * 1992-11-18 1997-06-24 Smithkline Beecham Corporation 17-α and 17-β substituted acyl-3-carboxy-3, 5-dienes and use in inhibiting 5-α-reductase
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
US8143428B2 (en) 2004-06-08 2012-03-27 Temple University-Of The Commonwealth System Of Higher Education Heteroaryl sulfones and sulfonamides and therapeutic uses thereof

Also Published As

Publication number Publication date
HU9402030D0 (en) 1994-09-28
AU666167B2 (en) 1996-02-01
TW300226B (fr) 1997-03-11
AP9300473A0 (en) 1993-01-31
AU3434893A (en) 1993-08-03
FI943214A (fi) 1994-07-05
SK80094A3 (en) 1994-12-07
FI943214A0 (fi) 1994-07-05
NO942535D0 (no) 1994-07-05
MX9300025A (es) 1994-01-31
MA22761A1 (fr) 1993-10-01
OA09961A (en) 1995-12-11
AP370A (en) 1994-11-10
EP0643723A4 (fr) 1995-05-10
CN1077201A (zh) 1993-10-13
IL104302A (en) 1998-02-22
IL104302A0 (en) 1993-05-13
NZ246788A (en) 1996-11-26
SI9300006A (en) 1993-09-30
RU94038223A (ru) 1997-04-20
NO942535L (no) 1994-07-05
HUT68273A (en) 1995-06-28
BR9305786A (pt) 1997-02-18
KR940703849A (ko) 1994-12-12
CA2127272A1 (fr) 1993-07-22
EP0643723A1 (fr) 1995-03-22
CZ161994A3 (en) 1995-03-15
JPH07505138A (ja) 1995-06-08
BG98887A (bg) 1995-05-31

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