WO1993016097A1 - Procede d'elaboration de 3-carbonylandrostadiene 17-carboxamides - Google Patents
Procede d'elaboration de 3-carbonylandrostadiene 17-carboxamides Download PDFInfo
- Publication number
- WO1993016097A1 WO1993016097A1 PCT/US1993/001068 US9301068W WO9316097A1 WO 1993016097 A1 WO1993016097 A1 WO 1993016097A1 US 9301068 W US9301068 W US 9301068W WO 9316097 A1 WO9316097 A1 WO 9316097A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- process according
- formula
- moieties
- cyanide
- Prior art date
Links
- 0 CC1(CC2)[C@@](*)CCC1C1C2C(C)(CCC(C#N)=C2)C2=CC1 Chemical compound CC1(CC2)[C@@](*)CCC1C1C2C(C)(CCC(C#N)=C2)C2=CC1 0.000 description 1
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
- 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
- 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
- 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
- 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
- C07J41/0094—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 containing nitrile radicals, including thiocyanide radicals
Definitions
- the present invention relates to an improved process for the conversion of substituted steroidal 3- halogen 3 , 5 diene derivatives to substituted steroidal 3 , 5-diene-3-carboxylic acid derivatives .
- Such compounds are described in U . S . Patent No . 5 , 017 , 568 , issued on May 21 , 1991 to Holt , et al . as being useful in inhibiting steroid 5- ⁇ -reductase .
- N-butyl lithium and ethylmagnesium bromide and ethylmagnesium chloride are expensive reagents adding significant cost to an industrial process. Further, N-butyl lithium is flammable and the carboxylation reaction is performed at dilute concentrations, Thus, there is a need in the art for a safe, economical and reliable method to convert substituted steroidal 3-halogen 3,5 diene derivatives to substituted steroidal 3,5-diene-3-carboxylic acid derivatives.
- This invention relates to an improved process for converting steroidal 3-halogen 3,5 diene derivatives to steroidal 3,5-diene-3-carboxylic acid derivatives.
- This invention specifically relates to an improved process for the preparation of N-t-butyl-androst-3,5- diene-17 ⁇ -carboxamide-3-carboxylic acid.
- halogen as used herein and in the claims means chlorine, bromine or iodine.
- halogen as used herein means bromine or iodine.
- the present invention provides a process for the production of a compound of Formula (I)
- R 2 and R ⁇ are each independently selected from hydrogen, C3_gcycloalkyl and phenyl; or R 2 and R3 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; or
- X is halogen; in the presence of a cyanating reagent and an appropriate solvent, preferably dimethylformamide, to form a compound of Formula (III)
- R 1 is as defined above and subsequently saponifying the compound of Formula (III) to form a compound of Formula (I) and thereafter optionally forming a pharmaceutically acceptable salt, hydrate or solvate thereof.
- R 1 is; (i) CONR 2 R 3 , where R 2 and R 3 are each independently selected from hydrogen, C]__galkyl, C3_gcycloalkyl and phenyl; or
- R ⁇ is ⁇ -CONR R 3 , where R 2 and R 3 are each independently selected from hydrogen, C ⁇ -galkyl, C3_gcycloalkyl and phenyl.
- Compounds of Formula I comprise R ⁇ - or moieties which can be chemically converted to those of R 1 by known chemical reactions such as described in Arthur Barton and U.D. Ollis, Comprehensive Organic Chemistry:
- R 1 does not include any such moieties that render inoperative the presently invented process.
- Reactions to convert said moieties to R 1 are performed on products of the synthetic pathways disclosed or claimed herein or, where appropriate or preferable on certain intermediates in these synthetic pathways.
- carboxylic acid substituents can be converted to the carboxamide by conversion to the acid halide followed by reacting the same with an amine.
- Esters can be converted to the acid and treated as above.
- Nitriles can be converted to carboxamides by reaction with an alkylating agent, such as t- butylacetate or t-butanol, under acidic catalysis.
- R 1 is (i) CONR 2 R 3 , where R 2 and R 3 are each independently selected from hydrogen, C ⁇ _8alkyl, C3_gcycloalkyl and phenyl; or R 2 and R 3 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; or
- R 1 is; (i) CONR 2 R 3 , where R 2 and R 3 are each independently selected from hydrogen, Ci- ⁇ alkyl, C3_gcycloalkyl and phenyl; or
- R-1- is; ⁇ -CONR 2 R 3 , where R 2 and R 3 are each independently selected from hydrogen, C ⁇ _8alkyl, C3_gcycloalkyl and phenyl.
- reagents and conditions used to convert 3-halogen steroidal-3,5-dienes to steroidal-3,5-diene 3-carboxylic acids are safe, inexpensive, can be reacted in high concentrations and result in high yields of the desired compound thereby rendering said processes appropriate for industrial scale utilization.
- Chalky means a straight or branched hydrocarbon chain having C ⁇ _ n carbons.
- cyanating reagent as used herein and in the claims is meant reagents which are capable of reacting, under certain conditions, with a halogenated moiety to form a cyanated moiety.
- a cyanating reagent is prepared by reacting the corresponding halogenated moiety with a cyanating reagent in an appropriate solvent, such as N,N-dimethyl- N,N-propylene urea (DMPU) , N,N-dimethylformamide (DMF) or N-methyl-2-pyrrolidinone (NMP) , preferably DMF, at increased temperatures.
- an appropriate solvent such as N,N-dimethyl- N,N-propylene urea (DMPU) , N,N-dimethylformamide (DMF) or N-methyl-2-pyrrolidinone (NMP) , preferably DMF
- saponifying as used herein and in the claims is meant a compound or reagent or a series of reagents which are capable of reacting with a nitrile to form a carboxylic acid substituted moiety under appropriate conditions.
- carboxylic acid substituted moiety is prepared by reacting the corresponding cyanated moiety with a hydroxide base, preferably aqueous sodium hydroxide, in an appropriate solvent, such as; ethylene glycol, isopropyl alcohol or ethanol, preferably ethanol, at increased temperatures with subsequent acidification.
- cyanating reagents for use in the presently invented process utilize cyanide complexes such as described in Richard C. Larock, Comphrehensive Organic Transforma ons: ft Guide tQ Functional GrOUP Prepara ons. Pub: VCH Publishers, Inc. (1989) P. 861.
- An example of a cyanide complex as used herein is the in situ co-mixture of KCN, iBr2 (PP ⁇ 13)2, Zn, PPh.3.
- NaCu(CN)2 refers to the reagent formed by co- mixing CuCN and NaCN in situ.
- Preferred among the above cyanating complexes are CuCN and NaCu(CN) 2 .
- Preferably said NaCu(CN)2 complex is prepared by adding 1 molar equivalent of sodium cyanide to cuprous cyanide in situ.
- solvent or "appropriate solvent” as used herein and in the claims is meant a solvent such as methylene chloride, ethylene chloride, chloroform, ethylene glycol, carbon tetrachloride, tetrahydrofuran (THF) , ethyl ether, toluene, ethyl acetate, dimethylsulfoxide, N,N l -dimethyl-N,N'-propylene urea, N- methyl-2-pyrrolidinone, methanol, isopropylalcohol, dimethylformamide, water, pyridine, quinoline or ethanol.
- the process of the present invention is particularly useful for preparing a compound of structure (IIIA)
- 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 organic phase was washed with three 200 mL portions of 50/50 v/v cone. aqueous ammonia/water, followed by two 200 L portions of water.
- the organic phase was concentrated under vacuum to 150 mL and 250 mL of ethanol were added.
- the solution was again concentrated under vacuum to 150 mL, and 250 L of ethanol were added.
- the solution was concentrated under vacuum to 300 mL, and 30 mL of water were added to induce crystallization.
- the resulting suspension was chilled for 2 hours at 0-5°C.
- N-t-butvl-androst-3.5-diene-3-cvano-17 ⁇ -carboxamide A 5 L 3-neck flask (Morton) equipped with a mechanical stirrer, thermometer, and reflux condenser was charged with 250 grams of N-t-butyl-androst-3,5- diene-3-bromo-17 ⁇ -carboxamide (prepared as in Example 1 (i) ) , 55 grams of cuprous cyanide, 29 grams of sodium cyanide, and 1 liter of dimethylformamide. The reaction mixture was heated to reflux (152-153°C) for at least 12 hours.
- the reaction mixture was slowly cooled to 25- 30°C with a cold water bath, and was quenched with one liter of 50% aqueous ammonium hydroxide (50/50 v/v cone, ammonia/water) with rapid stirring. After stirring 15- 20 minutes, one liter of methylene chloride was charged, and the two phase system was allowed to separate. The phases were separated and the aqueous phase was reextracted with 2 x 500 mL of methylene chloride. The combined methylene chloride extracts were passed through a celite filter pad to remove insoluble copper salts. The celite pad was washed with 150 mL of methylene chloride.
- the combined methylene chloride phases were washed with 3 x 500 mL ammonium hydroxide to remove last traces of copper salts.
- the organic phase was concentrated by atmospheric distillation, removing approximately 1.5 liters of methylene chloride.
- a 600 mL portion of ethanol was charged to the reactor and the concentration/displacement of methylene chloride was continued by distilling a second 500 mL portion of solvent.
- a second 600 mL portion of ethanol was charged to the reactor and the atmospheric distillation was continued until the vapor temperature reached 82-84°C.
- a 60 mL portion of water was charged to the reactor and the resulting suspension was chilled at 0-5°C for at least two hours.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Toxicology (AREA)
- Steroid Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Priority Applications (9)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA002129342A CA2129342A1 (fr) | 1992-02-07 | 1993-02-05 | Methode de preparation de 3-carbonylandrostadiene-17-carboxamides |
JP5514208A JPH07505140A (ja) | 1992-02-07 | 1993-02-05 | 3−カルボニルアンドロスタジエン17−カルボキシアミドの製法 |
EP93904946A EP0643724A4 (fr) | 1992-02-07 | 1993-02-05 | Procede d'elaboration de 3-carbonylandrostadiene 17-carboxamides. |
AU36126/93A AU666177B2 (en) | 1992-02-07 | 1993-02-05 | Process of preparing 3-carbonylandrostadiene 17-carboxamides |
BR9305837A BR9305837A (pt) | 1992-02-07 | 1993-02-05 | Processo de preparação de 3-carbonilandrostadieno 17-carboxamidas |
KR1019940702656A KR950700319A (ko) | 1992-02-07 | 1994-08-02 | 3-카르보닐안드로스타디엔 17-카르복스아미드를 제조하는 방법(Process of preparing 3-carbonylandrostadiene 17-carboxamides) |
BG98955A BG98955A (bg) | 1992-02-07 | 1994-08-04 | Метод за получаване на 3-карбониландростадиен 17-карбоксамиди |
FI943660A FI943660A (fi) | 1992-02-07 | 1994-08-05 | Menetelmä 3-karbonyyliandrostadieeni-17-karboksamidien valmistamiseksi |
NO942925A NO942925L (no) | 1992-02-07 | 1994-08-05 | Fremgangsmåte for fremstilling av 3-karbonylandrostadien-17-karboksamider |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US83228092A | 1992-02-07 | 1992-02-07 | |
US07/832,280 | 1992-02-07 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1993016097A1 true WO1993016097A1 (fr) | 1993-08-19 |
Family
ID=25261209
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1993/001068 WO1993016097A1 (fr) | 1992-02-07 | 1993-02-05 | Procede d'elaboration de 3-carbonylandrostadiene 17-carboxamides |
Country Status (23)
Country | Link |
---|---|
EP (1) | EP0643724A4 (fr) |
JP (1) | JPH07505140A (fr) |
KR (1) | KR950700319A (fr) |
CN (1) | CN1078475A (fr) |
AP (1) | AP9600790A0 (fr) |
AU (1) | AU666177B2 (fr) |
BG (1) | BG98955A (fr) |
BR (1) | BR9305837A (fr) |
CA (1) | CA2129342A1 (fr) |
CZ (1) | CZ188794A3 (fr) |
FI (1) | FI943660A (fr) |
HU (1) | HUT68303A (fr) |
IL (1) | IL104602A (fr) |
MA (1) | MA22788A1 (fr) |
MX (1) | MX9300676A (fr) |
NO (1) | NO942925L (fr) |
NZ (1) | NZ249382A (fr) |
OA (1) | OA10090A (fr) |
RU (1) | RU94045824A (fr) |
SI (1) | SI9300065A (fr) |
TW (1) | TW327175B (fr) |
WO (1) | WO1993016097A1 (fr) |
ZA (1) | ZA93801B (fr) |
Cited By (2)
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 |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB9206413D0 (en) * | 1992-03-24 | 1992-05-06 | Smithkline Beecham Corp | N-t-butyl-androst-3,5-diene-17b-carboxamide-3-carboxylic acid polymorph a |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5017568A (en) * | 1987-04-29 | 1991-05-21 | Smithkline Beecham Corporation | Steriod 5-alpha-reductase inhibitors |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IL104601A0 (en) * | 1992-02-07 | 1993-07-08 | Smithkline Beecham Corp | Process for the preparation of steroidal dienes |
-
1993
- 1993-02-03 IL IL104602A patent/IL104602A/xx not_active IP Right Cessation
- 1993-02-05 EP EP93904946A patent/EP0643724A4/fr not_active Ceased
- 1993-02-05 CA CA002129342A patent/CA2129342A1/fr not_active Abandoned
- 1993-02-05 NZ NZ249382A patent/NZ249382A/en unknown
- 1993-02-05 AP APAP/P/1996/000790A patent/AP9600790A0/en unknown
- 1993-02-05 HU HU9402303A patent/HUT68303A/hu unknown
- 1993-02-05 WO PCT/US1993/001068 patent/WO1993016097A1/fr not_active Application Discontinuation
- 1993-02-05 SI SI19939300065A patent/SI9300065A/sl unknown
- 1993-02-05 RU RU94045824/04A patent/RU94045824A/ru unknown
- 1993-02-05 JP JP5514208A patent/JPH07505140A/ja active Pending
- 1993-02-05 CZ CZ941887A patent/CZ188794A3/cs unknown
- 1993-02-05 BR BR9305837A patent/BR9305837A/pt not_active Application Discontinuation
- 1993-02-05 AU AU36126/93A patent/AU666177B2/en not_active Ceased
- 1993-02-05 ZA ZA93801A patent/ZA93801B/xx unknown
- 1993-02-05 MA MA23079A patent/MA22788A1/fr unknown
- 1993-02-06 TW TW082100820A patent/TW327175B/zh active
- 1993-02-06 CN CN 93102531 patent/CN1078475A/zh active Pending
- 1993-02-08 MX MX9300676A patent/MX9300676A/es unknown
-
1994
- 1994-08-02 KR KR1019940702656A patent/KR950700319A/ko not_active Application Discontinuation
- 1994-08-03 OA OA60547A patent/OA10090A/en unknown
- 1994-08-04 BG BG98955A patent/BG98955A/bg unknown
- 1994-08-05 FI FI943660A patent/FI943660A/fi unknown
- 1994-08-05 NO NO942925A patent/NO942925L/no unknown
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5017568A (en) * | 1987-04-29 | 1991-05-21 | Smithkline Beecham Corporation | Steriod 5-alpha-reductase inhibitors |
Non-Patent Citations (5)
Title |
---|
FIESER and FIESER, Reagents for Organic Synthesis, Vol. 1 (New York, J. Wiley and Sons, 1967), p. 391. * |
HOLT et al., J. Medicinal Chemistry 1990, 33, 943-950, "Inhibition of Steroidal 5alpha-reductase by Unsaturated 3-carboxysteroids", see p. 943, col. 2, schemes VI, VII, and p. 947, column 1. * |
LAROCK, Comprehensive Organic Transformations (New York, VCH, 1989), p. 861. * |
MORRISON and BOYD, Organic Chemistry 3rd Edition (Boston, Allyn and Bacon, 1979), pp. 588-589. * |
See also references of EP0643724A4 * |
Cited By (3)
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 |
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 |
Also Published As
Publication number | Publication date |
---|---|
MX9300676A (es) | 1994-07-29 |
OA10090A (en) | 1996-12-18 |
SI9300065A (en) | 1993-09-30 |
KR950700319A (ko) | 1995-01-16 |
TW327175B (en) | 1998-02-21 |
AU3612693A (en) | 1993-09-03 |
IL104602A (en) | 1997-07-13 |
MA22788A1 (fr) | 1993-10-01 |
RU94045824A (ru) | 1996-07-10 |
CA2129342A1 (fr) | 1993-08-19 |
BG98955A (bg) | 1995-06-30 |
AU666177B2 (en) | 1996-02-01 |
CZ188794A3 (en) | 1994-12-15 |
FI943660A0 (fi) | 1994-08-05 |
HUT68303A (en) | 1995-06-28 |
JPH07505140A (ja) | 1995-06-08 |
FI943660A (fi) | 1994-08-05 |
ZA93801B (en) | 1993-11-05 |
CN1078475A (zh) | 1993-11-17 |
NZ249382A (en) | 1996-05-28 |
IL104602A0 (en) | 1993-07-08 |
EP0643724A4 (fr) | 1995-05-10 |
NO942925L (no) | 1994-08-08 |
AP9600790A0 (en) | 1996-04-30 |
BR9305837A (pt) | 1997-02-18 |
EP0643724A1 (fr) | 1995-03-22 |
NO942925D0 (fr) | 1994-08-05 |
HU9402303D0 (en) | 1994-10-28 |
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