GB2104526A - 6-fluoro-9-hydroxyandrost-4- ene-3,17-diones and microbial preparation thereof - Google Patents
6-fluoro-9-hydroxyandrost-4- ene-3,17-diones and microbial preparation thereof Download PDFInfo
- Publication number
- GB2104526A GB2104526A GB08219483A GB8219483A GB2104526A GB 2104526 A GB2104526 A GB 2104526A GB 08219483 A GB08219483 A GB 08219483A GB 8219483 A GB8219483 A GB 8219483A GB 2104526 A GB2104526 A GB 2104526A
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- GB
- United Kingdom
- Prior art keywords
- fluoro
- sterol
- sterols
- fortuitum
- substituting
- Prior art date
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- JDCJGUOCZGANRP-BDOBEXJUSA-N (8S,9R,10S,13S,14S)-6-fluoro-9-hydroxy-10,13-dimethyl-1,2,6,7,8,11,12,14,15,16-decahydrocyclopenta[a]phenanthrene-3,17-dione Chemical class FC1C[C@H]2[C@@H]3CCC([C@@]3(C)CC[C@@]2([C@]2(CCC(C=C12)=O)C)O)=O JDCJGUOCZGANRP-BDOBEXJUSA-N 0.000 title claims description 3
- 238000002360 preparation method Methods 0.000 title claims description 3
- 230000000813 microbial effect Effects 0.000 title abstract 2
- 229930182558 Sterol Natural products 0.000 claims abstract description 26
- 150000003432 sterols Chemical class 0.000 claims abstract description 26
- 235000003702 sterols Nutrition 0.000 claims abstract description 26
- 241000186365 Mycobacterium fortuitum Species 0.000 claims abstract description 14
- 244000005700 microbiome Species 0.000 claims abstract description 12
- 241000193830 Bacillus <bacterium> Species 0.000 claims abstract description 8
- 241000186146 Brevibacterium Species 0.000 claims abstract description 8
- 241000186216 Corynebacterium Species 0.000 claims abstract description 8
- 241001467578 Microbacterium Species 0.000 claims abstract description 8
- 241000187654 Nocardia Species 0.000 claims abstract description 8
- 241000607720 Serratia Species 0.000 claims abstract description 8
- 241000186359 Mycobacterium Species 0.000 claims abstract description 7
- 241000586779 Protaminobacter Species 0.000 claims abstract description 7
- 241000186063 Arthrobacter Species 0.000 claims abstract description 5
- 241000187747 Streptomyces Species 0.000 claims abstract description 4
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 3
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 3
- 238000000034 method Methods 0.000 claims description 15
- LGJMUZUPVCAVPU-UHFFFAOYSA-N beta-Sitostanol Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(C)CCC(CC)C(C)C)C1(C)CC2 LGJMUZUPVCAVPU-UHFFFAOYSA-N 0.000 claims description 13
- KZJWDPNRJALLNS-VPUBHVLGSA-N (-)-beta-Sitosterol Natural products O[C@@H]1CC=2[C@@](C)([C@@H]3[C@H]([C@H]4[C@@](C)([C@H]([C@H](CC[C@@H](C(C)C)CC)C)CC4)CC3)CC=2)CC1 KZJWDPNRJALLNS-VPUBHVLGSA-N 0.000 claims description 7
- CSVWWLUMXNHWSU-UHFFFAOYSA-N (22E)-(24xi)-24-ethyl-5alpha-cholest-22-en-3beta-ol Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(C)C=CC(CC)C(C)C)C1(C)CC2 CSVWWLUMXNHWSU-UHFFFAOYSA-N 0.000 claims description 7
- KLEXDBGYSOIREE-UHFFFAOYSA-N 24xi-n-propylcholesterol Natural products C1C=C2CC(O)CCC2(C)C2C1C1CCC(C(C)CCC(CCC)C(C)C)C1(C)CC2 KLEXDBGYSOIREE-UHFFFAOYSA-N 0.000 claims description 7
- LPZCCMIISIBREI-MTFRKTCUSA-N Citrostadienol Natural products CC=C(CC[C@@H](C)[C@H]1CC[C@H]2C3=CC[C@H]4[C@H](C)[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C)C(C)C LPZCCMIISIBREI-MTFRKTCUSA-N 0.000 claims description 7
- ARVGMISWLZPBCH-UHFFFAOYSA-N Dehydro-beta-sitosterol Natural products C1C(O)CCC2(C)C(CCC3(C(C(C)CCC(CC)C(C)C)CCC33)C)C3=CC=C21 ARVGMISWLZPBCH-UHFFFAOYSA-N 0.000 claims description 7
- MJVXAPPOFPTTCA-UHFFFAOYSA-N beta-Sistosterol Natural products CCC(CCC(C)C1CCC2C3CC=C4C(C)C(O)CCC4(C)C3CCC12C)C(C)C MJVXAPPOFPTTCA-UHFFFAOYSA-N 0.000 claims description 7
- NJKOMDUNNDKEAI-UHFFFAOYSA-N beta-sitosterol Natural products CCC(CCC(C)C1CCC2(C)C3CC=C4CC(O)CCC4C3CCC12C)C(C)C NJKOMDUNNDKEAI-UHFFFAOYSA-N 0.000 claims description 7
- 150000001875 compounds Chemical class 0.000 claims description 7
- 238000000855 fermentation Methods 0.000 claims description 7
- 230000004151 fermentation Effects 0.000 claims description 7
- KZJWDPNRJALLNS-VJSFXXLFSA-N sitosterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CC[C@@H](CC)C(C)C)[C@@]1(C)CC2 KZJWDPNRJALLNS-VJSFXXLFSA-N 0.000 claims description 7
- 235000015500 sitosterol Nutrition 0.000 claims description 7
- 229950005143 sitosterol Drugs 0.000 claims description 7
- NLQLSVXGSXCXFE-UHFFFAOYSA-N sitosterol Natural products CC=C(/CCC(C)C1CC2C3=CCC4C(C)C(O)CCC4(C)C3CCC2(C)C1)C(C)C NLQLSVXGSXCXFE-UHFFFAOYSA-N 0.000 claims description 7
- OILXMJHPFNGGTO-UHFFFAOYSA-N (22E)-(24xi)-24-methylcholesta-5,22-dien-3beta-ol Natural products C1C=C2CC(O)CCC2(C)C2C1C1CCC(C(C)C=CC(C)C(C)C)C1(C)CC2 OILXMJHPFNGGTO-UHFFFAOYSA-N 0.000 claims description 6
- OQMZNAMGEHIHNN-UHFFFAOYSA-N 7-Dehydrostigmasterol Natural products C1C(O)CCC2(C)C(CCC3(C(C(C)C=CC(CC)C(C)C)CCC33)C)C3=CC=C21 OQMZNAMGEHIHNN-UHFFFAOYSA-N 0.000 claims description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 6
- HZYXFRGVBOPPNZ-UHFFFAOYSA-N UNPD88870 Natural products C1C=C2CC(O)CCC2(C)C2C1C1CCC(C(C)=CCC(CC)C(C)C)C1(C)CC2 HZYXFRGVBOPPNZ-UHFFFAOYSA-N 0.000 claims description 6
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims description 6
- 150000003431 steroids Chemical class 0.000 claims description 6
- HCXVJBMSMIARIN-PHZDYDNGSA-N stigmasterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)/C=C/[C@@H](CC)C(C)C)[C@@]1(C)CC2 HCXVJBMSMIARIN-PHZDYDNGSA-N 0.000 claims description 6
- 235000016831 stigmasterol Nutrition 0.000 claims description 6
- 229940032091 stigmasterol Drugs 0.000 claims description 6
- BFDNMXAIBMJLBB-UHFFFAOYSA-N stigmasterol Natural products CCC(C=CC(C)C1CCCC2C3CC=C4CC(O)CCC4(C)C3CCC12C)C(C)C BFDNMXAIBMJLBB-UHFFFAOYSA-N 0.000 claims description 6
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 4
- NYOXRYYXRWJDKP-UHFFFAOYSA-N cholestenone Natural products C1CC2=CC(=O)CCC2(C)C2C1C1CCC(C(C)CCCC(C)C)C1(C)CC2 NYOXRYYXRWJDKP-UHFFFAOYSA-N 0.000 claims description 4
- -1 e.g. Natural products 0.000 claims description 4
- 239000000543 intermediate Substances 0.000 claims description 4
- 235000015097 nutrients Nutrition 0.000 claims description 4
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 4
- 229920000053 polysorbate 80 Polymers 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- SGNBVLSWZMBQTH-FGAXOLDCSA-N Campesterol Natural products O[C@@H]1CC=2[C@@](C)([C@@H]3[C@H]([C@H]4[C@@](C)([C@H]([C@H](CC[C@H](C(C)C)C)C)CC4)CC3)CC=2)CC1 SGNBVLSWZMBQTH-FGAXOLDCSA-N 0.000 claims description 3
- BTEISVKTSQLKST-UHFFFAOYSA-N Haliclonasterol Natural products CC(C=CC(C)C(C)(C)C)C1CCC2C3=CC=C4CC(O)CCC4(C)C3CCC12C BTEISVKTSQLKST-UHFFFAOYSA-N 0.000 claims description 3
- 235000013405 beer Nutrition 0.000 claims description 3
- SGNBVLSWZMBQTH-PODYLUTMSA-N campesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CC[C@@H](C)C(C)C)[C@@]1(C)CC2 SGNBVLSWZMBQTH-PODYLUTMSA-N 0.000 claims description 3
- 235000000431 campesterol Nutrition 0.000 claims description 3
- 235000012000 cholesterol Nutrition 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- JHVIIDLZSOMCBJ-BMEOTQTRSA-N 2-[(8s,9r,10s,13s,14s,17r)-9-hydroxy-10,13-dimethyl-3-oxo-2,6,7,8,11,12,14,15,16,17-decahydro-1h-cyclopenta[a]phenanthren-17-yl]propanoic acid Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@]2(O)[C@@H]1[C@@H]1CC[C@H](C(C)C(O)=O)[C@@]1(C)CC2 JHVIIDLZSOMCBJ-BMEOTQTRSA-N 0.000 claims description 2
- MYYIMZRZXIQBGI-HVIRSNARSA-N 6alpha-Fluoroprednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3C[C@H](F)C2=C1 MYYIMZRZXIQBGI-HVIRSNARSA-N 0.000 claims description 2
- SNMVJSSWZSJOGL-PLOWYNNNSA-N 9alpha-hydroxyandrost-4-en-3,17-dione Chemical compound O=C1CC[C@]2(C)[C@@]3(O)CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1 SNMVJSSWZSJOGL-PLOWYNNNSA-N 0.000 claims description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 2
- WJOHZNCJWYWUJD-IUGZLZTKSA-N Fluocinonide Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@H]3OC(C)(C)O[C@@]3(C(=O)COC(=O)C)[C@@]2(C)C[C@@H]1O WJOHZNCJWYWUJD-IUGZLZTKSA-N 0.000 claims description 2
- POPFMWWJOGLOIF-XWCQMRHXSA-N Flurandrenolide Chemical compound C1([C@@H](F)C2)=CC(=O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]2(C)C[C@@H]1O POPFMWWJOGLOIF-XWCQMRHXSA-N 0.000 claims description 2
- 239000007836 KH2PO4 Substances 0.000 claims description 2
- MKPDWECBUAZOHP-AFYJWTTESA-N Paramethasone Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]2(C)C[C@@H]1O MKPDWECBUAZOHP-AFYJWTTESA-N 0.000 claims description 2
- 241000364057 Peoria Species 0.000 claims description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 2
- 230000036983 biotransformation Effects 0.000 claims description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 2
- 235000010216 calcium carbonate Nutrition 0.000 claims description 2
- 229940041514 candida albicans extract Drugs 0.000 claims description 2
- 239000004202 carbamide Substances 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 claims description 2
- GGCLNOIGPMGLDB-GYKMGIIDSA-N cholest-5-en-3-one Chemical compound C1C=C2CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 GGCLNOIGPMGLDB-GYKMGIIDSA-N 0.000 claims description 2
- 229940107161 cholesterol Drugs 0.000 claims description 2
- 238000004587 chromatography analysis Methods 0.000 claims description 2
- 239000001064 degrader Substances 0.000 claims description 2
- 239000012153 distilled water Substances 0.000 claims description 2
- 239000000284 extract Substances 0.000 claims description 2
- 229960004511 fludroxycortide Drugs 0.000 claims description 2
- 229960001347 fluocinolone acetonide Drugs 0.000 claims description 2
- FEBLZLNTKCEFIT-VSXGLTOVSA-N fluocinolone acetonide Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]2(C)C[C@@H]1O FEBLZLNTKCEFIT-VSXGLTOVSA-N 0.000 claims description 2
- 229960000785 fluocinonide Drugs 0.000 claims description 2
- 229960000618 fluprednisolone Drugs 0.000 claims description 2
- XLYOFNOQVPJJNP-ZSJDYOACSA-N heavy water Substances [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 claims description 2
- 238000011534 incubation Methods 0.000 claims description 2
- 150000004702 methyl esters Chemical class 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 229910000402 monopotassium phosphate Inorganic materials 0.000 claims description 2
- 235000019796 monopotassium phosphate Nutrition 0.000 claims description 2
- 229960002858 paramethasone Drugs 0.000 claims description 2
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 claims description 2
- 238000011218 seed culture Methods 0.000 claims description 2
- 239000011877 solvent mixture Substances 0.000 claims description 2
- 239000008399 tap water Substances 0.000 claims description 2
- 235000020679 tap water Nutrition 0.000 claims description 2
- 239000012138 yeast extract Substances 0.000 claims description 2
- 230000015556 catabolic process Effects 0.000 abstract 1
- 238000006731 degradation reaction Methods 0.000 abstract 1
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
- C12P33/06—Hydroxylating
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
- C07J1/0003—Androstane derivatives
- C07J1/0011—Androstane derivatives substituted in position 17 by a keto group
-
- 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
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Wood Science & Technology (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- Zoology (AREA)
- General Health & Medical Sciences (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Microbiology (AREA)
- General Chemical & Material Sciences (AREA)
- Biochemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Engineering & Computer Science (AREA)
- Biotechnology (AREA)
- Genetics & Genomics (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Steroid Compounds (AREA)
Abstract
6-fluoro-9 alpha -hydroxyandrost-4 ene-3,17-diones, including the novel 6 alpha -isomer, are prepared by microbial degradation of the 6-fluoro- DELTA <4>-3- keto derivatives of sterols using a mutant microorganism selected from Arthrobacter, Bacillus, Brevibacterium, Corynebacterium, Mycobacterium, Microbacterium, Nocardia, Protaminobacter, Serratia and Streptomyces, esp. Mycobacterium fortuitum NRRL B-8119. The products are of use in the synthesis of 6-fluoro- corticoids.
Description
SPECIFICATION
Steroid bioconversion process and product
US Patent Specifications Nos. 4,029,549; 4,214,051 and 4,035,236 disclose the use of Mycabacterium fortuitum NRRLB-8119to make 9-hydroxy - 3 - oxo - 4 - pregnene - 20 - carboxylic acid (9 - hydroxybisnoracid), its methyl ester, and 9 - hydroxy - 4 androstene - 3,17 - dione, respectively.
According to the present invention, a 6 - fluoro - 9a hydroxyandrost - 4- ene - 3,17 - dione (6 - fluoro
HAD) is prepared by conversion of a 6 - fluoro - A4 - 3 ketone derivative of a sterol, e.g. one or more of cholesterol, sitosterol, stigmasterol and campesterol. This process is preferably conducted by use of
M. fortuitum NRRL B-8119. The invention also encompasses the use of mutants obtained from the genera of micro-organisms disclosed in US Patent
Specification No 4,029,549, i.e. Arthrobacter, Bacillus, Brevibacterium, Coryn ebacterium, Microbacterium, Mycobacterium, Nocardia, Protaminobacter,
Serratia and Strepomyces. The micro-organisms of these genera are all well known sterol-degraders.
The wild-type strains of these genera degrade sterols non-selectively to small molecular weight compounds, e.g. CO2 + H2O. Mutants can be made from these wild types by following the procedures disclosed in Example 1 of US Patent Specification No 4,029,549. This example discloses the preparation of
M. fortuitum NRRLB-8119.
6c-fluoro - HAD is a novel compound. The products ofthe invention are useful intermediates.
Mutants which are characterised by their ability to selectively convert 6 - fluoro - A4 - 3 - ketone derivatives of sterols having 17-alkyl side chains and accumulate 6 - fluoro - HAD in the fermentation beer can be obtained by mutating micro-organisms ofthe genera: Arthrobacter, Bacillus, Brevibacterium,
Corynebacterium, Microbacterium, Mycobacterium,
Nocardia, Protaminobacter, Serratia and Strep tomyces Mycobacterium fortuitum NRRL 8-8119 is described in U.S. Patent 4,029,549. M. fortuitum
NRRL B-8119 has been deposited in the permanent collection at the Northern Regional Research
Laboratory, U.S. Department of Agriculture, Peoria,
Illinois, U.S.A. It has been available to the public at least since issuance of the above-mentioned U.S.
patents disclosing the microbe. It should be understood that the availability of the culture does not constitute a license to practice the subject invention in derogation of patent rights granted with the subject instrument by governmental action.
6-Fluoro-HAD is useful as an intermediate in the synthesis of valuable corticoids. For example, by application of current technology as disclosed in the steroid literature, the fluoro-HAD derivatives can be transformed to the pharmacologically important steroids such as fluocinolone acetonide, fluocinonide, flurandrenolide, paramethasone, fluprednisolone.
Following are examples which illustrate the fermentation process of the subject invention. These examples are merely illustrative, and, thus, should not be construed as limiting. All percentages are by weight and all solvent mixture proportions are by volume unless otherwise noted.
Example 1 - Fermentation of 6P - F - Cholestenone
The biotransformation medium contains (per liter) Ucon, 8.0 g; Cerelose, 5.0 g; NH4CI, 3.0 g; CaCO3, 3.0 g; Na3 [citrate] 2H2O, 3.0 g; Tween 80, 2.0 g; soyf lour, 1.0 g; KH2PO4, 0.5 g; urea, 0.5 g and 6P-F cholestenone, 2.0 g in tap water with the pH adjusted to 7.0.Flasks containing 100 ml portions of this medium are innoculated with 10 ml of seed cultures ofM. fortuitum NRRL B-8119, grown at 28 in a medium containing (per liter) nutrient broth, 8.0 g; glycerol, 5.0 g; yeast extract, 1.0 g and Tween 80, 1.0 g in distilled water with the pH adjusted to 7.0. The cultures are then incubated at 28" for 336 hr on a rotary shaker. Following incubation, the mixture is extracted with an equal volume of CH3Cl2 and the product, 6ssfiuoro-HAD, is isolated from this extract using standard chromatography.
Example 2
Upon substituting 6 a-fluorocholestenone for 6p- fluorocholestenone in Example 1, there is obtained 6a-fluoro-9cr-hydroxy-AD.
Example 3
Upon substituting 6ss-fluorocholestenone in
Example 1 with a P-fluoroketone derivative of another sterol, e.g., sitosterol, stigmasterol, and the like, there is obtained 6ssfluoro-HAD. The sterols can be used singiy or in combination and in pure or crude form.
Example 4
By substituting a sterol-degrading microorganism from the generaArthrobacter, Bacillus, Brevibacterium, Coryn ebacterium, Microbacterium, Nocardia, Protaminobacter, Serratia, and Streptmyces, for
Mycobacterium fortuitum NRRL B-8119 in the process disclosed in U.S. Patent 4,029,549 for preparing
M. fortuitum NRRL B-8119, there are obtained mutant microorganisms which are characterized by their ability to selectively convert 6-fluoro-A4-3-ketone derivatives of sterols with a C-17 side chain and accumulate 6-fluoro-HAD as a product.
Example 5
Upon substituting Gp-fluorocholestenone in
Example 1 with a 6a-fluoro-A4-3-ketone derivative of another sterol, e.g., sitosterol, stigmasterol, and the like, there is obtained 6a-fluoro-HAD. The sterols can be used singly or in combination and in pure or crude form.
Example 6
By substituting the mutants obtained in Example 4 forM. fortuitum NRRL B-8119 in Examples 1 and 3, there is obtained 6ssfluoro-HAD.
Example 7
By substituting the mutants obtained in Example 4 forM. fortuitum NRRL B-8119 in Examples 2 and 5, there is obtained 6a-fluoro-HAD.
Example 8
The 6-fluoro-A4-3-ketone derivatives of sterols can be prepared by following the procedures disclosed in U.S. Patent 4,100,027.
1. A process for preparing a compound of the formula
**WARNING** end of DESC field may overlap start of CLMS **.
Claims (8)
1. A process for preparing a compound of the formula
which comprises cultivating a mutant microorganism selected from the generaArthrobacter,
Bacillus, Brevibacterium, Corynebacterium, Myco bacterium, Microb acterium, Nocardia,
Proaminobacter, Serratia and Streptomyces, the mutant being characterised by its ability to selectively convert the 6-fluoro-A4-3-ketone derivative of a sterol with a C-17 side-chain and accumulate 6-fluoro-HAD in the fermentation beer, in an aqueous nutrient medium, under aerobic conditions, in the presence of a 6-fluoro-A4-3-ketone derivative of a sterol with or without a C-17 side-chain.
2. A process according to claim 1, wherein the mutant is of the Mycobacterium genus and the sterol has a C-17 side-chain.
3. A process for preparing a compound as defined in claim 1, which comprises cultivating
Mycobacterium fortuitum NRRL B-8119 in an aqueous nutrient medium, under aerobic conditions, in the presence of a 6-fluoro-ss4-3-ketone derivative of a sterol with a C-17 side-chain.
4. A process according to any preceding claim, wherein the sterol is one or more of sitosterol, cholesterol, stimasterol and campesterol.
5. A process according to claim 4, wherein the sterol derivative is 6,3-fluorocholestenone.
6. A process according to claim 4, wherein the sterol derivative is 6c-fluorocholestenone.
7. A process according to claim 1, substantially as described in any of the Examples.
8. Gcr-Fluoro-Sa- hydroxyandrost-4- ene-3,17 dione.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US28630781A | 1981-07-24 | 1981-07-24 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB2104526A true GB2104526A (en) | 1983-03-09 |
| GB2104526B GB2104526B (en) | 1985-06-05 |
Family
ID=23098003
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB08219483A Expired GB2104526B (en) | 1981-07-24 | 1982-07-06 | 6-fluoro-9-hydroxyandrost-4-ene-3,17-diones and microbial preparation thereof |
Country Status (6)
| Country | Link |
|---|---|
| JP (1) | JPS5851897A (en) |
| DE (1) | DE3225747A1 (en) |
| FR (1) | FR2510120A1 (en) |
| GB (1) | GB2104526B (en) |
| IT (1) | IT1158018B (en) |
| NL (1) | NL8202848A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2121043A (en) * | 1982-05-25 | 1983-12-14 | Wisconsin Alumni Res Found | Side-chain degradation of phytosterols to give androstanes |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP4874553B2 (en) | 2005-01-31 | 2012-02-15 | 株式会社貝印刃物開発センター | Safety razor for shaving the hair of legs and arms as well as the face |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4035236A (en) * | 1975-10-24 | 1977-07-12 | The Upjohn Company | Process for preparing 9α-hydroxyandrostenedione |
| DE2558088C2 (en) * | 1975-12-19 | 1985-05-30 | Schering AG, 1000 Berlin und 4709 Bergkamen | Process for the preparation of 4-androstene-3,17-dione derivatives |
-
1982
- 1982-07-06 GB GB08219483A patent/GB2104526B/en not_active Expired
- 1982-07-09 DE DE19823225747 patent/DE3225747A1/en not_active Withdrawn
- 1982-07-14 NL NL8202848A patent/NL8202848A/en not_active Application Discontinuation
- 1982-07-15 JP JP57122244A patent/JPS5851897A/en active Pending
- 1982-07-19 IT IT48846/82A patent/IT1158018B/en active
- 1982-07-23 FR FR8212930A patent/FR2510120A1/en active Granted
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2121043A (en) * | 1982-05-25 | 1983-12-14 | Wisconsin Alumni Res Found | Side-chain degradation of phytosterols to give androstanes |
Also Published As
| Publication number | Publication date |
|---|---|
| FR2510120A1 (en) | 1983-01-28 |
| FR2510120B1 (en) | 1984-12-14 |
| GB2104526B (en) | 1985-06-05 |
| IT1158018B (en) | 1987-02-18 |
| JPS5851897A (en) | 1983-03-26 |
| DE3225747A1 (en) | 1983-02-10 |
| IT8248846A0 (en) | 1982-07-19 |
| NL8202848A (en) | 1983-02-16 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PCNP | Patent ceased through non-payment of renewal fee |