EP0643723A1 - Halogenation a l'aide d'un reactif halo-vilsmeier - Google Patents

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

Info

Publication number
EP0643723A1
EP0643723A1 EP93902957A EP93902957A EP0643723A1 EP 0643723 A1 EP0643723 A1 EP 0643723A1 EP 93902957 A EP93902957 A EP 93902957A EP 93902957 A EP93902957 A EP 93902957A EP 0643723 A1 EP0643723 A1 EP 0643723A1
Authority
EP
European Patent Office
Prior art keywords
reagent
process according
vilsmeier reagent
halogen
chloride
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.)
Ceased
Application number
EP93902957A
Other languages
German (de)
English (en)
Other versions
EP0643723A4 (fr
Inventor
Neil Howard Baine
Donald Nathaniel Kline
Richard Eric Mewshaw
Franklin Owings
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 EP0643723A1 publication Critical patent/EP0643723A1/fr
Publication of EP0643723A4 publication Critical patent/EP0643723A4/fr
Ceased legal-status Critical Current

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)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (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.
EP93902957A 1992-01-06 1993-01-06 Halogenation a l'aide d'un reactif halo-vilsmeier. Ceased EP0643723A4 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US81717992A 1992-01-06 1992-01-06
US817179 1992-01-06
US94134892A 1992-09-04 1992-09-04
US941348 1992-09-04
PCT/US1993/000079 WO1993014106A1 (fr) 1992-01-06 1993-01-06 Halogenation a l'aide d'un reactif halo-vilsmeier

Publications (2)

Publication Number Publication Date
EP0643723A1 true EP0643723A1 (fr) 1995-03-22
EP0643723A4 EP0643723A4 (fr) 1995-05-10

Family

ID=27124147

Family Applications (1)

Application Number Title Priority Date Filing Date
EP93902957A Ceased EP0643723A4 (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) NO942535D0 (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)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
EA012414B1 (ru) 2004-06-08 2009-10-30 Темпл Юниверсити Оф Дзе Коммонвелт Систем Оф Хайер Эдьюкейшн Гетероарилсульфоны и сульфонамиды и их терапевтические применения

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ZA883034B (en) * 1987-04-29 1989-03-29 Smithkline Beckman Corp Steroid 5-alpha-reductase inhibitors

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
No further relevant documents disclosed *
See also references of WO9314106A1 *

Also Published As

Publication number Publication date
JPH07505138A (ja) 1995-06-08
OA09961A (en) 1995-12-11
AU3434893A (en) 1993-08-03
EP0643723A4 (fr) 1995-05-10
HUT68273A (en) 1995-06-28
MA22761A1 (fr) 1993-10-01
KR940703849A (ko) 1994-12-12
NZ246788A (en) 1996-11-26
CN1077201A (zh) 1993-10-13
SK80094A3 (en) 1994-12-07
RU94038223A (ru) 1997-04-20
HU9402030D0 (en) 1994-09-28
MX9300025A (es) 1994-01-31
AP370A (en) 1994-11-10
BG98887A (bg) 1995-05-31
BR9305786A (pt) 1997-02-18
WO1993014106A1 (fr) 1993-07-22
TW300226B (fr) 1997-03-11
FI943214A (fi) 1994-07-05
AP9300473A0 (en) 1993-01-31
IL104302A0 (en) 1993-05-13
CZ161994A3 (en) 1995-03-15
NO942535L (no) 1994-07-05
NO942535D0 (no) 1994-07-05
SI9300006A (en) 1993-09-30
CA2127272A1 (fr) 1993-07-22
AU666167B2 (en) 1996-02-01
IL104302A (en) 1998-02-22
FI943214A0 (fi) 1994-07-05

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