CA1302923C - Process for producing 4-androstene -3,17-dione and 1,4-androstardiene -3,17-dione - Google Patents
Process for producing 4-androstene -3,17-dione and 1,4-androstardiene -3,17-dioneInfo
- Publication number
- CA1302923C CA1302923C CA000525244A CA525244A CA1302923C CA 1302923 C CA1302923 C CA 1302923C CA 000525244 A CA000525244 A CA 000525244A CA 525244 A CA525244 A CA 525244A CA 1302923 C CA1302923 C CA 1302923C
- Authority
- CA
- Canada
- Prior art keywords
- dione
- sitosterol
- mycobacterium
- nrrl
- androstene
- 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.)
- Expired - Lifetime
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P33/00—Preparation of steroids
- C12P33/005—Degradation of the lateral chains at position 17
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- Zoology (AREA)
- Wood Science & Technology (AREA)
- Health & Medical Sciences (AREA)
- General Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biotechnology (AREA)
- Biochemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Microbiology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Steroid Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
A process for producing 4-androstene-3,17-dione and 1,4-androstadiene-3,17-dione having the general formula wherein symbolizes a single bond or double bond, in which .alpha.-sitosterol
A process for producing 4-androstene-3,17-dione and 1,4-androstadiene-3,17-dione having the general formula wherein symbolizes a single bond or double bond, in which .alpha.-sitosterol
Description
The present invention relates to a process for pro-ducing 4-androstene-3,17-dione and 1,4-androstadiene-3,17-dione.
According to the present invention there is provided a process for producing 4-androstene-3,17-dione and 1,4-androstadiene-3,17-dione having the general formula ,~"~~
0~
wherein ' symboIizes a single bond or a double bond, in which ~-sitosterol ~ I
/C~' ~
110 ~
~l3H
is fermented with a culture of a microorganism strain capable of side-chain degradation of sterols.
It is known that numerous microorganisms (as for example, those of the species Arthrobacter, Brevibacterium, Microbacterium, Protamlnobacter, Bacill~s, Norcardia, Strepto-myces and particularly Mycobacterium) have the natural capa-bility of degrading naturally occurring 3 ~ ~hydroxy- ~ 5-sterols (such as cholesterol or sitosterol) to carbon dioxide and water and that 4-androstene-3,17-dione and 1,4-andros-tadiene-3,17-dione are intermediately formed in this degrada-tion.
It is also known that by adding inhibitors or mutated microorganisms it~is possible to so control the degra-dation of the sterols that a degradation of the 4-androstene-3,17-dione or 1,4-androstadiene-3,17-dione is avoided (see - 1 - ~k i;~O29~3 German Offenlegungsschriften 15 43 269 and 15 9~ 327 and ~.S.
Patent 3 684 657).
For a person skilled in the art it is surprising that under conventional conditions the side-chain of ~ -sitosterol is also degraded since it is known that the side-chain degradation of sterols is caused by a very complex fermentation system and it could not be expected that all the enzymes cooperating in the side-chain degradation of natural steroids also have the capability of causing the side-chain degradation of this compound. Furthermore, it could not be predicted that in this degradation the ~ 7 double bond of the ~-sitosterol hydrogenates and that the methyl group in the 4 position is split.
Apart from the use of other starting compounds the process according to the present invention is carried under the same fermentation conditions as those used in conventional microbiological side-chain degradation reactions of sterols.
According to the present invention the fermentation is,carried out by using the microorganisms culture usually applied for the side-chain degradation of sterols. Suitable cultures are, for example, bacteria cultures capable of side-chain degradation of sterols, i.e., of the species Arthrobac-ter, Brevibacterium, Microbacterium, Protaminobacter, Strepto-myces or particularly of the species Mycobacterium. The fol-lowing microorganisms are suitable: Microbacterium lactum IAM-1640, Protaminobacter alboflavus IAM-1040, Bacillus roseus IAM-1257, Bacillus spharicus ATTC-7055, Norcardia gardneri IAM-105, Norcardia minima IAM-374, Norcardia corallina IFO-3338, Streptomyces rubescens IAM-74 or particularly the microorganisms Mycobacterium avium IFO-3082, Mycobacterium pheli IFO-3158, Mycobacterium pheli (Institut fur Gesund-heitswesen, Budapest No. 29), Mycobacterium pheli ATCC-354, Mycobacterium smegmatis IF0-3084, Mycobacterium smegmatis ATCC-20, Mycobacterium smegmatis (Institut fur Gesundheitswe-sen, Budapest No. 27), Mycobacterium smegmatis ATCC-19979 and Mycobacterium fortuitum CBS-49566.
Particularly preferred microorganisms are Mycobac-terium spec. NRRL B-3805, Mycobacterium spec. B-3683, Mycobac-terium pheli NRRL B-8154 and mycobacterium fortuitum NRRL s-8153. With the aid of these microorganisms, the fermentation of c~-sitosterol can be carried out without using additional agents for inhibiting the 9-hydroxylation.
Under the culture conditions conventionally used for these microorganisms submerse cultures are grown in a suitable nutrient medium while aerating. The substrate (dissolved in a suitable solvent or preferably in the emulsified form) is then added to the cultures and the fermentation is carried on until a maximal conversion of the substrate is attained.
Suitable substrate solvents are, for example, methanol, ethanol, glycol monomethyl ether, dimethyl formamide or dimethyl sulphoxide. The emulsification of the substrate can be carried out, for example, in that it is in;ected in a micronized form or dissolved in solvent miscible with water (such as methanol, ethanol, acetone, glycol monomethyl ether, dimethyl formamide or dimethyl sulphoxide) with intense turbu-lence in (preferably decalcified) water contalning the usual emulsifying aids. Non-ionogenic emulsifiers, as for example, ethyleneoxy adducts or fatty esters of polyglycols, are suit-able emulsifying aids. The commercial wetting agents Tegin(R), Tween(R) and Span(R) are examples of suitable emul-sifiers.
The optimal substrate concentration, the time of substrate addition and the fermentation time depend on the structure of the substrate used on the type of microorganism 13029~3 used. AS generally required in microbiological steroid con-versions these parameters must be determlned in the individual case by preliminary tests with which the person skilled in the art is familiar.
As is well known the 4-androstene-3,17-dione deriva-tives having the general formula I and producible by means of the process according to the present invention are valuable intermediate products which are today used for the synthesis of pharmacologically active steroids.
The process according to the present invention will be illustrated by the following Examples.
Example l A 2-litre Erlenmeyer flask with 500 ml of sterile nutrient medium containing 1% of yeast extract, 0.45% of disodium hydrogen phosphate, 0.34~ of potassium dihydrogen phosphate and 0.2% of Tween(R)80 - adjusted to pH 6.7 - is inoculated with a suspension of Mycobacterium spec. NRRL B-3805 dry culture and shaken for 3 days at 30C with l9O revo-lutions per minute.
Ten Erlenmeyer flasks (500 ml) each with 100 ml of nutrient medium containing 2.5% of cornsteep liquor, 0.3% of diammonium hydrogen phosphate, 0.25% of soybean mean and 0.25%
of Tween~R)80 - adjusted to p~ 7.0 - are inoculated with 5 ml of Myobacterium spec. growth culture and shaken for 24 hours at 30C with 220 revolutions per minute, whereupon 100 mg of ~ -sitosterol dissolved in 3.0 ml of dimethyl formamide are added to each culture. The fermentation is then carried on for further 96 hours at 30C.
The combined cultures are extracted with ethylene chloride, the extract is concentrated in vacuo and the residue is chromatographed via a silica gel column. On recrystalliz-ing from diisopropyl ether 160 mg of 4-androstene-3,l7-dione are obtained.
In addltion 385 mg of non-reacted ~-sitosterol are recovered.
Example 2 Under the conditions of Example 1 but using Mycobecterium spec. NRRL B-3683 a total of 1000 mg of ~-sitosterol is reacted and further treated. 140 mg of 1~4-androstadiene-3,17-dione are obtained in addition to 630 mg of non-reacted q-sitosterol.
According to the present invention there is provided a process for producing 4-androstene-3,17-dione and 1,4-androstadiene-3,17-dione having the general formula ,~"~~
0~
wherein ' symboIizes a single bond or a double bond, in which ~-sitosterol ~ I
/C~' ~
110 ~
~l3H
is fermented with a culture of a microorganism strain capable of side-chain degradation of sterols.
It is known that numerous microorganisms (as for example, those of the species Arthrobacter, Brevibacterium, Microbacterium, Protamlnobacter, Bacill~s, Norcardia, Strepto-myces and particularly Mycobacterium) have the natural capa-bility of degrading naturally occurring 3 ~ ~hydroxy- ~ 5-sterols (such as cholesterol or sitosterol) to carbon dioxide and water and that 4-androstene-3,17-dione and 1,4-andros-tadiene-3,17-dione are intermediately formed in this degrada-tion.
It is also known that by adding inhibitors or mutated microorganisms it~is possible to so control the degra-dation of the sterols that a degradation of the 4-androstene-3,17-dione or 1,4-androstadiene-3,17-dione is avoided (see - 1 - ~k i;~O29~3 German Offenlegungsschriften 15 43 269 and 15 9~ 327 and ~.S.
Patent 3 684 657).
For a person skilled in the art it is surprising that under conventional conditions the side-chain of ~ -sitosterol is also degraded since it is known that the side-chain degradation of sterols is caused by a very complex fermentation system and it could not be expected that all the enzymes cooperating in the side-chain degradation of natural steroids also have the capability of causing the side-chain degradation of this compound. Furthermore, it could not be predicted that in this degradation the ~ 7 double bond of the ~-sitosterol hydrogenates and that the methyl group in the 4 position is split.
Apart from the use of other starting compounds the process according to the present invention is carried under the same fermentation conditions as those used in conventional microbiological side-chain degradation reactions of sterols.
According to the present invention the fermentation is,carried out by using the microorganisms culture usually applied for the side-chain degradation of sterols. Suitable cultures are, for example, bacteria cultures capable of side-chain degradation of sterols, i.e., of the species Arthrobac-ter, Brevibacterium, Microbacterium, Protaminobacter, Strepto-myces or particularly of the species Mycobacterium. The fol-lowing microorganisms are suitable: Microbacterium lactum IAM-1640, Protaminobacter alboflavus IAM-1040, Bacillus roseus IAM-1257, Bacillus spharicus ATTC-7055, Norcardia gardneri IAM-105, Norcardia minima IAM-374, Norcardia corallina IFO-3338, Streptomyces rubescens IAM-74 or particularly the microorganisms Mycobacterium avium IFO-3082, Mycobacterium pheli IFO-3158, Mycobacterium pheli (Institut fur Gesund-heitswesen, Budapest No. 29), Mycobacterium pheli ATCC-354, Mycobacterium smegmatis IF0-3084, Mycobacterium smegmatis ATCC-20, Mycobacterium smegmatis (Institut fur Gesundheitswe-sen, Budapest No. 27), Mycobacterium smegmatis ATCC-19979 and Mycobacterium fortuitum CBS-49566.
Particularly preferred microorganisms are Mycobac-terium spec. NRRL B-3805, Mycobacterium spec. B-3683, Mycobac-terium pheli NRRL B-8154 and mycobacterium fortuitum NRRL s-8153. With the aid of these microorganisms, the fermentation of c~-sitosterol can be carried out without using additional agents for inhibiting the 9-hydroxylation.
Under the culture conditions conventionally used for these microorganisms submerse cultures are grown in a suitable nutrient medium while aerating. The substrate (dissolved in a suitable solvent or preferably in the emulsified form) is then added to the cultures and the fermentation is carried on until a maximal conversion of the substrate is attained.
Suitable substrate solvents are, for example, methanol, ethanol, glycol monomethyl ether, dimethyl formamide or dimethyl sulphoxide. The emulsification of the substrate can be carried out, for example, in that it is in;ected in a micronized form or dissolved in solvent miscible with water (such as methanol, ethanol, acetone, glycol monomethyl ether, dimethyl formamide or dimethyl sulphoxide) with intense turbu-lence in (preferably decalcified) water contalning the usual emulsifying aids. Non-ionogenic emulsifiers, as for example, ethyleneoxy adducts or fatty esters of polyglycols, are suit-able emulsifying aids. The commercial wetting agents Tegin(R), Tween(R) and Span(R) are examples of suitable emul-sifiers.
The optimal substrate concentration, the time of substrate addition and the fermentation time depend on the structure of the substrate used on the type of microorganism 13029~3 used. AS generally required in microbiological steroid con-versions these parameters must be determlned in the individual case by preliminary tests with which the person skilled in the art is familiar.
As is well known the 4-androstene-3,17-dione deriva-tives having the general formula I and producible by means of the process according to the present invention are valuable intermediate products which are today used for the synthesis of pharmacologically active steroids.
The process according to the present invention will be illustrated by the following Examples.
Example l A 2-litre Erlenmeyer flask with 500 ml of sterile nutrient medium containing 1% of yeast extract, 0.45% of disodium hydrogen phosphate, 0.34~ of potassium dihydrogen phosphate and 0.2% of Tween(R)80 - adjusted to pH 6.7 - is inoculated with a suspension of Mycobacterium spec. NRRL B-3805 dry culture and shaken for 3 days at 30C with l9O revo-lutions per minute.
Ten Erlenmeyer flasks (500 ml) each with 100 ml of nutrient medium containing 2.5% of cornsteep liquor, 0.3% of diammonium hydrogen phosphate, 0.25% of soybean mean and 0.25%
of Tween~R)80 - adjusted to p~ 7.0 - are inoculated with 5 ml of Myobacterium spec. growth culture and shaken for 24 hours at 30C with 220 revolutions per minute, whereupon 100 mg of ~ -sitosterol dissolved in 3.0 ml of dimethyl formamide are added to each culture. The fermentation is then carried on for further 96 hours at 30C.
The combined cultures are extracted with ethylene chloride, the extract is concentrated in vacuo and the residue is chromatographed via a silica gel column. On recrystalliz-ing from diisopropyl ether 160 mg of 4-androstene-3,l7-dione are obtained.
In addltion 385 mg of non-reacted ~-sitosterol are recovered.
Example 2 Under the conditions of Example 1 but using Mycobecterium spec. NRRL B-3683 a total of 1000 mg of ~-sitosterol is reacted and further treated. 140 mg of 1~4-androstadiene-3,17-dione are obtained in addition to 630 mg of non-reacted q-sitosterol.
Claims (4)
1. A process for producing 4-androstene-3,17-dione and 1,4-androstadiene-3,17-dione having the general formula wherein symbolizes a single bond or a double bond, in which .alpha.-sitosterol is fermented with a culture of a microorganism strain capable of side-chain degradation of sterols.
2. A process according to claim 1 in which the fer-mentation is effected with a microorgansim of the species Arthrobacter, Brevibacterium, Microbacterium, Protaminobacter, Streptomyces or Mycobacterium.
3. A process according to claim 1 in which .alpha.-sitosterol is fermented with a microorganism strain of the species Micobacterium or Norcardia which is capable of side-chain degradation of sterols.
4. A process according to claim 1 in which .alpha.-sitosterol is fermented with Mycobacterium spec. NRRL B-=3805, Mycobacterium spec. NRRL B-3683, Microbacterium pheli NRRL B-8154 or Micobacterium fortuitum NRRL B-8153.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP3544662.5 | 1985-12-13 | ||
| DE19853544662 DE3544662A1 (en) | 1985-12-13 | 1985-12-13 | METHOD FOR PRODUCING 4-ANDROSTEN-3,17-DION AND 1,4-ANDROSTADIEN-3,17-DION |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1302923C true CA1302923C (en) | 1992-06-09 |
Family
ID=6288680
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000525244A Expired - Lifetime CA1302923C (en) | 1985-12-13 | 1986-12-12 | Process for producing 4-androstene -3,17-dione and 1,4-androstardiene -3,17-dione |
Country Status (17)
| Country | Link |
|---|---|
| EP (1) | EP0227588B1 (en) |
| JP (1) | JPH0720439B2 (en) |
| AT (1) | ATE69268T1 (en) |
| AU (1) | AU6772887A (en) |
| BG (1) | BG50613A3 (en) |
| CA (1) | CA1302923C (en) |
| CS (1) | CS271347B2 (en) |
| DD (1) | DD254025A5 (en) |
| DE (2) | DE3544662A1 (en) |
| DK (1) | DK419587D0 (en) |
| ES (1) | ES2038601T3 (en) |
| FI (1) | FI873489A (en) |
| GR (1) | GR3003640T3 (en) |
| HU (1) | HUT44082A (en) |
| NO (1) | NO873381L (en) |
| SU (1) | SU1679977A3 (en) |
| WO (1) | WO1987003620A1 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6071714A (en) * | 1998-03-26 | 2000-06-06 | Forbes Medi-Tech, Inc. | Process for the microbial conversion of phytosterols to androstenedione and androstadienedione |
| KR100422161B1 (en) | 2001-05-11 | 2004-03-10 | (주)유진사이언스 | A method for preparation of Androst-4-ene-3,17-dione and Androsta-1,4-diene-3,17-dione |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS4826549B1 (en) * | 1968-11-14 | 1973-08-11 | ||
| US3684657A (en) * | 1970-05-11 | 1972-08-15 | Searle & Co | Selective microbiological degradation of steroidal 17-alkyls |
| US3759791A (en) * | 1970-12-10 | 1973-09-18 | Searle & Co | Selective microbiological preparation of androst-4-ene-3,17-dione |
| JPS512670Y2 (en) * | 1971-06-28 | 1976-01-26 | ||
| US4293645A (en) * | 1976-03-01 | 1981-10-06 | The Upjohn Company | Process for preparing androsta-1,4-diene-3,17-dione and androst-4-ene-3,17-dione |
| DE2703645C3 (en) * | 1976-03-01 | 1981-11-12 | The Upjohn Co., 49001 Kalamazoo, Mich. | Process for the preparation of a mixture of androsta-1,4-diene-3,17-dione and androst-4-ene-3,17-dione |
| JPS52115548A (en) * | 1976-03-24 | 1977-09-28 | Matsushita Electric Ind Co Ltd | Heat pump type air conditioning system |
-
1985
- 1985-12-13 DE DE19853544662 patent/DE3544662A1/en not_active Withdrawn
-
1986
- 1986-12-09 EP EP86730207A patent/EP0227588B1/en not_active Expired - Lifetime
- 1986-12-09 HU HU86458A patent/HUT44082A/en unknown
- 1986-12-09 DE DE86730207T patent/DE3682379D1/de not_active Expired - Fee Related
- 1986-12-09 WO PCT/DE1986/000508 patent/WO1987003620A1/en active Application Filing
- 1986-12-09 JP JP62500101A patent/JPH0720439B2/en not_active Expired - Lifetime
- 1986-12-09 AU AU67728/87A patent/AU6772887A/en not_active Abandoned
- 1986-12-09 ES ES198686730207T patent/ES2038601T3/en not_active Expired - Lifetime
- 1986-12-09 AT AT86730207T patent/ATE69268T1/en not_active IP Right Cessation
- 1986-12-12 CS CS869282A patent/CS271347B2/en not_active IP Right Cessation
- 1986-12-12 CA CA000525244A patent/CA1302923C/en not_active Expired - Lifetime
- 1986-12-12 DD DD86297530A patent/DD254025A5/en not_active IP Right Cessation
-
1987
- 1987-07-07 BG BG080473A patent/BG50613A3/en unknown
- 1987-08-10 SU SU4203113A patent/SU1679977A3/en active
- 1987-08-11 FI FI873489A patent/FI873489A/en not_active IP Right Cessation
- 1987-08-12 NO NO873381A patent/NO873381L/en unknown
- 1987-08-12 DK DK419587A patent/DK419587D0/en not_active Application Discontinuation
-
1992
- 1992-01-23 GR GR910402032T patent/GR3003640T3/el unknown
Also Published As
| Publication number | Publication date |
|---|---|
| DK419587A (en) | 1987-08-12 |
| NO873381D0 (en) | 1987-08-12 |
| BG50613A3 (en) | 1992-09-15 |
| EP0227588A1 (en) | 1987-07-01 |
| NO873381L (en) | 1987-08-12 |
| DE3544662A1 (en) | 1987-06-19 |
| FI873489A0 (en) | 1987-08-11 |
| JPS63501922A (en) | 1988-08-04 |
| DE3682379D1 (en) | 1991-12-12 |
| CS271347B2 (en) | 1990-09-12 |
| JPH0720439B2 (en) | 1995-03-08 |
| DK419587D0 (en) | 1987-08-12 |
| DD254025A5 (en) | 1988-02-10 |
| ES2038601T3 (en) | 1993-08-01 |
| AU6772887A (en) | 1987-06-30 |
| EP0227588B1 (en) | 1991-11-06 |
| WO1987003620A1 (en) | 1987-06-18 |
| GR3003640T3 (en) | 1993-03-16 |
| FI873489A (en) | 1987-08-11 |
| HUT44082A (en) | 1988-01-28 |
| CS928286A2 (en) | 1990-02-12 |
| ATE69268T1 (en) | 1991-11-15 |
| SU1679977A3 (en) | 1991-09-23 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKLA | Lapsed |