DE1149003B - Method of making steroids - Google Patents
Method of making steroidsInfo
- Publication number
- DE1149003B DE1149003B DEO6717A DEO0006717A DE1149003B DE 1149003 B DE1149003 B DE 1149003B DE O6717 A DEO6717 A DE O6717A DE O0006717 A DEO0006717 A DE O0006717A DE 1149003 B DE1149003 B DE 1149003B
- Authority
- DE
- Germany
- Prior art keywords
- steroids
- general formula
- fluoro
- oil
- hydrogen
- 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.)
- Pending
Links
- 150000003431 steroids Chemical class 0.000 title claims description 16
- 238000004519 manufacturing process Methods 0.000 title claims description 8
- 238000000034 method Methods 0.000 claims description 8
- 241000813867 Streptomyces roseochromogenus Species 0.000 claims description 6
- 150000001875 compounds Chemical class 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 244000005700 microbiome Species 0.000 claims description 4
- 102000004190 Enzymes Human genes 0.000 claims description 3
- 108090000790 Enzymes Proteins 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 150000002431 hydrogen Chemical group 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 125000000468 ketone group Chemical group 0.000 claims description 2
- 230000001590 oxidative effect Effects 0.000 claims description 2
- 150000002367 halogens Chemical group 0.000 claims 1
- 239000005556 hormone Substances 0.000 claims 1
- 229940088597 hormone Drugs 0.000 claims 1
- 239000011782 vitamin Substances 0.000 claims 1
- 229940088594 vitamin Drugs 0.000 claims 1
- 229930003231 vitamin Natural products 0.000 claims 1
- 235000013343 vitamin Nutrition 0.000 claims 1
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- 239000000126 substance Substances 0.000 description 9
- 239000002609 medium Substances 0.000 description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 239000003925 fat Substances 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 241000187747 Streptomyces Species 0.000 description 3
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 3
- 235000014113 dietary fatty acids Nutrition 0.000 description 3
- 229930195729 fatty acid Natural products 0.000 description 3
- 239000000194 fatty acid Substances 0.000 description 3
- 150000004665 fatty acids Chemical class 0.000 description 3
- 238000000855 fermentation Methods 0.000 description 3
- 230000004151 fermentation Effects 0.000 description 3
- 230000033444 hydroxylation Effects 0.000 description 3
- 238000005805 hydroxylation reaction Methods 0.000 description 3
- 230000002906 microbiologic effect Effects 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 description 2
- 235000019764 Soybean Meal Nutrition 0.000 description 2
- 239000005862 Whey Substances 0.000 description 2
- 102000007544 Whey Proteins Human genes 0.000 description 2
- 108010046377 Whey Proteins Proteins 0.000 description 2
- 240000008042 Zea mays Species 0.000 description 2
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 2
- 239000012736 aqueous medium Substances 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 235000008504 concentrate Nutrition 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- KDCIHNCMPUBDKT-UHFFFAOYSA-N hexane;propan-2-one Chemical compound CC(C)=O.CCCCCC KDCIHNCMPUBDKT-UHFFFAOYSA-N 0.000 description 2
- 229960002899 hydroxyprogesterone Drugs 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 239000004455 soybean meal Substances 0.000 description 2
- 239000003549 soybean oil Substances 0.000 description 2
- 235000012424 soybean oil Nutrition 0.000 description 2
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 2
- PVNIQBQSYATKKL-UHFFFAOYSA-N tripalmitin Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCC PVNIQBQSYATKKL-UHFFFAOYSA-N 0.000 description 2
- DCXXMTOCNZCJGO-UHFFFAOYSA-N tristearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCCCC DCXXMTOCNZCJGO-UHFFFAOYSA-N 0.000 description 2
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 description 1
- WKAVAGKRWFGIEA-UHFFFAOYSA-N 11-Ketoprogesterone Natural products C1CC2=CC(=O)CCC2(C)C2C1C1CCC(C(=O)C)C1(C)CC2=O WKAVAGKRWFGIEA-UHFFFAOYSA-N 0.000 description 1
- TWJNQYPJQDRXPH-UHFFFAOYSA-N 2-cyanobenzohydrazide Chemical compound NNC(=O)C1=CC=CC=C1C#N TWJNQYPJQDRXPH-UHFFFAOYSA-N 0.000 description 1
- 206010000242 Abortion threatened Diseases 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 229920000742 Cotton Polymers 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 208000005171 Dysmenorrhea Diseases 0.000 description 1
- 206010013935 Dysmenorrhoea Diseases 0.000 description 1
- 240000001624 Espostoa lanata Species 0.000 description 1
- 235000009161 Espostoa lanata Nutrition 0.000 description 1
- 229930091371 Fructose Natural products 0.000 description 1
- 239000005715 Fructose Substances 0.000 description 1
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 1
- 240000005979 Hordeum vulgare Species 0.000 description 1
- 235000007340 Hordeum vulgare Nutrition 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 description 1
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 1
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 1
- 235000021360 Myristic acid Nutrition 0.000 description 1
- TUNFSRHWOTWDNC-UHFFFAOYSA-N Myristic acid Natural products CCCCCCCCCCCCCC(O)=O TUNFSRHWOTWDNC-UHFFFAOYSA-N 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 208000005985 Threatened Abortion Diseases 0.000 description 1
- BAECOWNUKCLBPZ-HIUWNOOHSA-N Triolein Natural products O([C@H](OCC(=O)CCCCCCC/C=C\CCCCCCCC)COC(=O)CCCCCCC/C=C\CCCCCCCC)C(=O)CCCCCCC/C=C\CCCCCCCC BAECOWNUKCLBPZ-HIUWNOOHSA-N 0.000 description 1
- PHYFQTYBJUILEZ-UHFFFAOYSA-N Trioleoylglycerol Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC(OC(=O)CCCCCCCC=CCCCCCCCC)COC(=O)CCCCCCCC=CCCCCCCCC PHYFQTYBJUILEZ-UHFFFAOYSA-N 0.000 description 1
- 235000021307 Triticum Nutrition 0.000 description 1
- 244000098338 Triticum aestivum Species 0.000 description 1
- 229930003779 Vitamin B12 Natural products 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000016383 Zea mays subsp huehuetenangensis Nutrition 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 description 1
- 239000004067 bulking agent Substances 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- FDJOLVPMNUYSCM-WZHZPDAFSA-L cobalt(3+);[(2r,3s,4r,5s)-5-(5,6-dimethylbenzimidazol-1-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] [(2r)-1-[3-[(1r,2r,3r,4z,7s,9z,12s,13s,14z,17s,18s,19r)-2,13,18-tris(2-amino-2-oxoethyl)-7,12,17-tris(3-amino-3-oxopropyl)-3,5,8,8,13,15,18,19-octamethyl-2 Chemical compound [Co+3].N#[C-].N([C@@H]([C@]1(C)[N-]\C([C@H]([C@@]1(CC(N)=O)C)CCC(N)=O)=C(\C)/C1=N/C([C@H]([C@@]1(CC(N)=O)C)CCC(N)=O)=C\C1=N\C([C@H](C1(C)C)CCC(N)=O)=C/1C)[C@@H]2CC(N)=O)=C\1[C@]2(C)CCC(=O)NC[C@@H](C)OP([O-])(=O)O[C@H]1[C@@H](O)[C@@H](N2C3=CC(C)=C(C)C=C3N=C2)O[C@@H]1CO FDJOLVPMNUYSCM-WZHZPDAFSA-L 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 239000002385 cottonseed oil Substances 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000010685 fatty oil Substances 0.000 description 1
- 230000003152 gestagenic effect Effects 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 150000002484 inorganic compounds Chemical class 0.000 description 1
- 229910010272 inorganic material Inorganic materials 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000010699 lard oil Substances 0.000 description 1
- 239000000944 linseed oil Substances 0.000 description 1
- 235000021388 linseed oil Nutrition 0.000 description 1
- 235000009973 maize Nutrition 0.000 description 1
- 235000013372 meat Nutrition 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-N palmitic acid group Chemical group C(CCCCCCCCCCCCCCC)(=O)O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 229960003387 progesterone Drugs 0.000 description 1
- 239000000186 progesterone Substances 0.000 description 1
- 239000000583 progesterone congener Substances 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 239000003760 tallow Substances 0.000 description 1
- PHYFQTYBJUILEZ-IUPFWZBJSA-N triolein Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(OC(=O)CCCCCCC\C=C/CCCCCCCC)COC(=O)CCCCCCC\C=C/CCCCCCCC PHYFQTYBJUILEZ-IUPFWZBJSA-N 0.000 description 1
- 229940117972 triolein Drugs 0.000 description 1
- 229960001947 tripalmitin Drugs 0.000 description 1
- 239000011715 vitamin B12 Substances 0.000 description 1
- 235000019163 vitamin B12 Nutrition 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 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
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Zoology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Wood Science & Technology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Microbiology (AREA)
- General Chemical & Material Sciences (AREA)
- Biotechnology (AREA)
- Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Verfahren zur Herstellung von Steroiden Die Erfindung betrifft ein Verfahren zur Herstellung neuer Steroide der allgemeinen Formel in der R Wasserstoff, R' eine ß-Hydroxygruppe ist oder R und R' zusammen eine Ketogruppe sind, X Halogen und Z Wasserstoff' oder eine Hydroxylgruppe bedeutet. Die Verbindungen dienen unter anderem als Zwischenprodukte bei der Herstellung von physiologisch wirksamen Steroiden.Process for the production of steroids The invention relates to a process for the production of new steroids of the general formula in which R is hydrogen, R 'is a β-hydroxy group or R and R' together are a keto group, X is halogen and Z is hydrogen 'or a hydroxyl group. The compounds serve, among other things, as intermediate products in the production of physiologically active steroids.
Diese Steroide werden nach dem erfindungsgemäßen Verfahren hergestellt, indem man eine Verbindung der allgemeinen Formel in der R, R', X und Z die oben angegebene Bedeutung haben, in an sich bekannter Weise mit den oxydierend wirkenden Enzymen des Mikroorganismus Streptomyces roseochromogenus hydroxyliert.These steroids are produced according to the process of the invention by adding a compound of the general formula in which R, R ', X and Z have the meaning given above, hydroxylated in a manner known per se with the oxidizing enzymes of the microorganism Streptomyces roseochromogenus.
Beispiele für geeignete Steroide, die zur mikrobiologischen Hydroxylierung verwendet werden können, sind 12a-Halogen-1 lß-hydroxyprogesterone (z. B. 12a-Fluor -11ß - hydroxyprogesteron), 12a - Halogen - 11-ketoprogesterone (z. B. 12a-Fluor-11-ketoprogesteron), 12x-Halogen-llß,17x-dihydroxyprogesterone (z. B. 12a-Fluor-llß,17x-dihydroxyprogesteron) oder 12x-Halogen-1 1-keto-17x-hydroxyprogesterone.Examples of suitable steroids that are used for microbiological hydroxylation can be used are 12a-halo-1 lβ-hydroxyprogesterone (e.g. 12a-fluoro -11ß - hydroxyprogesterone), 12a - halogen - 11-ketoprogesterone (e.g. 12a-fluoro-11-ketoprogesterone), 12x-halogen-llß, 17x-dihydroxyprogesterone (e.g. 12a-fluoro-llß, 17x-dihydroxyprogesterone) or 12x-halogen-1 1-keto-17x-hydroxyprogesterone.
Zur Durchführung des erfindungsgemäßen Verfahrens wird entweder das Steroid mit einer aeroben Kultur von Streptomyces roseochromogenus in Berührung gebracht, oder es werden das Steroid, Luft und Enzyme von nichtsprossenden Zellen des Mikroorganismus in einem wäßrigen Medium zusammengebracht. Die Bedingungen zum Züchten von Streptomyces rosechromogenus, der für das erfindungsgemäße Verfahren eingesetzt wird, sind die gleichen (vom Zusatz des umzuwandelnden Steroids abgesehen) wie beim Züchten von Streptomyces-Bakterien zur Herstellung von Antibiotika und/oder Vitamin B12, d. h., der Mikroorganismus wird in Berührung mit (in oder auf) einem geeigneten Gärungsmedium gezüchtet. Ein geeignetes Medium enthält im wesentlichen eine Stickstoffquelle und wachstumsfördernde Substanzen sowie eine Quelle für assimilierbaren Kohlenstoff und Energie. Letztere kann ein Kohlenhydrat und/oder das Steroid selbst ein. Das Medium enthält jedoch vorzugsweise neben dem Steroid eine Quelle für assimilierbaren Kohlenstoff und Energie, wobei diese Quelle vorzugsweise mindestens zu einem beträchtlichen Teil (1) eine Fettsäure mit mindestens 14 Kohlenstoffatomen oder (2) ein Fett ist. Die Verwendung eines derartigen Fettes als Kohlenstoff und Energiequelle (besonders die Verwendung eines Fettöls) ist vorteilhaft, weil dadurch die Zugänglichkeit des Steriods für die Umwandlung erhöht wird.To carry out the method according to the invention, either the Steroid in contact with an aerobic culture of Streptomyces roseochromogenus brought, or the steroid, air and enzymes from non-sprouting cells of the microorganism brought together in an aqueous medium. The conditions for Culturing Streptomyces rosechromogenus, which is suitable for the method according to the invention are the same (apart from the addition of the steroid to be converted) as in the cultivation of Streptomyces bacteria for the production of antibiotics and / or Vitamin B12, d. i.e., the microorganism is in contact with (in or on) a suitable fermentation medium. A suitable medium essentially contains a source of nitrogen and growth promoting substances as well as a source of assimilables Carbon and energy. The latter can be a carbohydrate and / or the steroid itself a. However, the medium preferably contains a source of assimilables in addition to the steroid Carbon and energy, this source preferably being at least a sizeable one Part (1) is a fatty acid of at least 14 carbon atoms or (2) a fat. The use of such a fat as a carbon and energy source (especially the use of a fatty oil) is advantageous because it increases the accessibility of the Steriods for conversion is increased.
Die Stickstoff liefernden Substanzen können organische Substanzen, z. B. Sojabohnenmehl, Maisquellwasser, Fleischextrakt und/oder Destillationsrückstände oder synthetische Substanzen sein, z. B. einfache organische oder anorganische Verbindungen, wie Ammoniumsalze, Alkalinitrate, Aminosäuren, Harnstoff und ThioharnstofL Als energieliefernde Stoffe werden fettartige Substanzen (Lipoide) und besonders (1) Fettsäuren mit mindestens 14 Kolflenstoffatomen, (2) Fette oder (3) Gemische derselben bevorzugt. Beispiele für derartige Fette sind Schmalzöl, Sojabohnenöl, Leinsamenöl, Baumwollsamenöl, Erdnußöl, Hammeltalg, Spermöl, Olivenöl, Tristearin, Tripalmitin, Triolein und Trilaurein;Beispiele fürFettsäuren sind Stearin-, Palmitin; Öl-, Linol und Myristinsäure.The nitrogen-supplying substances can be organic substances, z. B. soybean meal, corn steep liquor, meat extract and / or distillation residues or synthetic substances, e.g. B. simple organic or inorganic compounds, such as ammonium salts, alkali nitrates, amino acids, urea and thiourea as Energy-supplying substances become fat-like substances (lipoids) and especially (1) Fatty acids with at least 14 bulking agents, (2) fats or (3) mixtures thereof preferred. Examples of such fats are lard oil, soybean oil, linseed oil, Cottonseed oil, peanut oil, mutton tallow, sperm oil, olive oil, tristearin, tripalmitin, Triolein and trilaurein; examples of fatty acids are stearic, palmitic; Oil, linoleum and myristic acid.
Es können auch andere Kohlenstoff' enthaltende Substanzen verwendet werden. So sind z. B. Glycerin, Glucose, Fructose, Rohrzucker, Lactose, Maltose, Dextrine, Stärke, Molken u. dgl. gleichwertige Kohlenstoff liefernde Substanzen. Diese Substanzen können entweder in gereinigtem Zustand oder in Form von Konzentraten, wie Molkenkonzentrat, Mais-, Weizen-oder Gerstenmaische oder deren Gemischen, verwendet werden. Es sei jedoch darauf hingewiesen, daß das Steroid dem Gärungsmedium im wesentlichen als Ausgangsmaterial und nicht als energieliefernde Substanz zugesetzt wird.Other carbon containing substances can also be used will. So are z. B. glycerine, glucose, fructose, cane sugar, lactose, maltose, Dextrins, starch, whey and the like. These substances can either be purified or in the form of concentrates, such as whey concentrate, maize, wheat or barley mash or mixtures thereof, are used will. It should be noted, however, that the steroid is essentially the fermentation medium is added as a starting material and not as an energy-supplying substance.
Für die Herstellung bzw. Gewinnung der verfahrensgemäß angewandten Streptomyceskulturen wird im Rahmen der vorliegenden Erfindung Schutz nicht begehrt.For the production or extraction of the process used In the context of the present invention, protection is not sought after for Streptomyces cultures.
Außer ihrer Verwendbarkeit als Zwischenprodukte für die Herstellung von 16x,17a-Acetalen oder Ketalen sind einige der erfindungsgemäß herstellbaren Steroide selbst als physiologisch wirksame Substanzen brauchbar. So besitzen die 17a-H-Verbindungen der allgemeinen Formell eine gestagene Wirkung und können an Stelle von bekannten Gestagenen, wie Progesteron, zur Behandlung von drohendem Abort, Dysmenorrhoe u. dgl. verwendet werden. -Die folgenden Beispiele erläutern das erfindungsgemäße Verfahren. Beispiel 1 12x-Fluor-1 lß,16a,17a-trihydroxyprogesteron Zunächst wird ein wäßriges Medium der folgenden Zusammensetzung hergestellt: Sojabohnenmehl .................. 15,0 g Glucose ......................... 10,0 g Sojabohnenöl .................... 2,2 g CaC0............................ 2,5 g Wasser........................... 11 Der pH-Wert des Mediums wird auf einen Wert von 7,0 ± 0,1 eingestellt. Anteile von 50 ccm des Mediums werden auf 250-ccm-Erlenmeyer-Kolben verteilt. Die Kolben werden mit Watte verstopft und in üblicher Weise durch Autoklavieren sterilisiert. Nach dem Abkühlen wird jeder Kolben mit 0,25 ccm einer sterilen Lösung von 12x-Fluor-1 lß,17oc-dihydroxyprogesteron in Dimethylformamid versetzt; dabei wird eine Steroidkonzentration von 0,05 °/ö in dem Medium erhalten. Jeder Kolben wird dann mit 5 bis 100/, einer vegetativen Kultur von Streptomyces roseochromogenus (Waksman Nr. 3689) angeimpft. Die beimpften Kolben werden unter kreisförmigem mechanischem Schütteln 3 bis 4 Tage bei einer Temperatur von 25°C bebrütet, worauf der Inhalt von 12 Kolben vereinigt, auf einen p11-Wert von 4 -I- 0,2 gebracht und durch einen Wattebausch auf einem Büchnertrichter filtriert wird. Die filtrierte Gärmaische wird mit vier 300-ccm-Anteilen Methylisobutylketon extrahiert, worauf nach Entfernen des Lösungsmittels im Vakuum etwa 200 mg des rahen.Steroids erhalten werden, das beim Stehenlassen kristallisiert. Nach dem Umkristallisieren aus Äthanol wird reines 12x-Fluor-llß,16a,17a-trihydroxyprogesteron erhalten. Fp. 220 bis 222°C, [x]' = -3-102° (c = 0,38 in CHC13); 2mäX = 240 m#t (a= 16200); AmeX°` = 2,90, 5,38, 6,02, 6,19 @..In addition to their usefulness as intermediates for the production of 16x, 17a-acetals or ketals, some of the steroids which can be produced according to the invention can themselves be used as physiologically active substances. The 17a-H compounds of the general formula have a gestagenic effect and can be used in place of known gestagens such as progesterone for the treatment of threatened abortion, dysmenorrhea and the like. The following examples explain the process according to the invention. Example 1 12x-Fluoro-11, 16a, 17a-trihydroxyprogesterone First, an aqueous medium with the following composition is prepared: Soybean meal .................. 15.0 g glucose .. ....................... 10.0 g soybean oil .................... 2, 2 g CaC0 ............................ 2.5 g water .............. ............. 11 The pH of the medium is adjusted to a value of 7.0 ± 0.1. 50 cc portions of the medium are divided into 250 cc Erlenmeyer flasks. The flasks are plugged with cotton wool and sterilized in the usual way by autoclaving. After cooling, each flask is admixed with 0.25 cc of a sterile solution of 12x-fluoro-11, 17oc-dihydroxyprogesterone in dimethylformamide; a steroid concentration of 0.05% is obtained in the medium. Each flask is then inoculated with 5 to 100% of a vegetative culture of Streptomyces roseochromogenus (Waksman No. 3689). The inoculated flasks are incubated with circular mechanical shaking for 3 to 4 days at a temperature of 25 ° C., after which the contents of 12 flasks are combined, brought to a p11 value of 4 -I-0.2 and passed through a cotton ball on a Buchner funnel is filtered. The filtered fermentation mash is extracted with four 300 cc portions of methyl isobutyl ketone, whereupon about 200 mg of the rahen.Steroid are obtained after removing the solvent in vacuo, which crystallizes on standing. After recrystallization from ethanol, pure 12x-fluoro-11ß, 16a, 17a-trihydroxyprogesterone is obtained. Mp 220-222 ° C, [x] '= -3-102 ° (c = 0.38 in CHCl3); 2mäX = 240 m # t (a = 16200); AmeX ° `= 2.90, 5.38, 6.02, 6.19 @ ..
C"H"0sF (380,44).C "H" 0sF (380.44).
Berechnet ... C 66,29, H 7,68; gefunden ... C 66,28, H 7,67. Beispiel 2 12-Fluor-l lß,16x-dihydroxyprogesteron Die im Beispiel l beschriebene mikrobiologische Hydroxylierung von 12oc-Fluor-llß-hydroxyprogesteron mit Streptomyces roseochromogenus (Waksman Nr.3689) liefert 12x-Fluor-Ilß,16x-dihydroxyprogesteron, das aus dem Kulturfiltrat mit Chloroform extrahiert wird. Nach Entfernung des Lösungsmittels im Vakuum wird der Rückstand aus Aceton-Hexan umkristallisiert, wobei die reine Verbindung mit den folgenden Eigenschaften erhalten wird: Schmelzpunkt etwa 218 bis 219°C; [x]D = -3-164° (c = 0,50 in CHC13); 2meX = 240 m#I (e = 16 000); )#m 2°` 2,98, 5,86, 6,03, 6,20 @,.Calculated ... C 66.29, H 7.68; Found ... C 66.28, H 7.67. Example 2 12-fluoro-1ß, 16x-dihydroxyprogesterone The microbiological hydroxylation of 12oc-fluoro-11ß-hydroxyprogesterone with Streptomyces roseochromogenus (Waksman No. 3689), described in Example 1, yields 12x-fluoro-ILß, 16x-dihydroxyprogesterone, which from the Culture filtrate is extracted with chloroform. After removing the solvent in vacuo, the residue is recrystallized from acetone-hexane, the pure compound having the following properties being obtained: melting point about 218 to 219 ° C .; [x] D = -3-164 ° (c = 0.50 in CHCl3); 2meX = 240 m # I (e = 16,000); ) #m 2 ° `2.98, 5.86, 6.03, 6.20 @ ,.
C"H"04F (364,44).C "H" 04F (364.44).
Berechnet ... C 69,2 1, H 8,02; gefunden ... C 68,97, H 7,85. Beispiel 3 12a-Brom-1 lß,16x-dihydroxyprogesteron Die im Beispiel l beschriebene mikrobiologische Hydroxylierung von 12x-Brom-llß-hydroxyprogesteron mit Streptomyces roseochromogenus (Waksman Nr. 3689) liefert 12x-Brom-1 Iß,16x-dihydroxyprogesteron, das aus dem Kulturfiltrat mit Chloroform extrahiert wird. Nach Entfernung des Lösungsmittels im Vakuum wird der kristalline Rückstand aus Aceton-Hexan umkristallisiert. Die reine Verbindung hat die folgenden Eigenschaften: Schmelzpunkt etwa 211 bis 212°C; [x]' = -I-101° (in Chloroform); = 2,87, 3,01, 5,85, 5,86, 6,16 C2iHzs04Br (425,35).Calculated ... C 69.2 L, H 8.02; found ... C 68.97, H 7.85. Example 3 12a-bromine-11b, 16x-dihydroxyprogesterone The microbiological hydroxylation of 12x-bromo-11b-hydroxyprogesterone with Streptomyces roseochromogenus (Waksman No. 3689), described in Example 1, yields 12x-bromine-1b, 16x-dihydroxyprogesterone, which from the culture filtrate is extracted with chloroform. After removing the solvent in vacuo, the crystalline residue is recrystallized from acetone-hexane. The pure compound has the following properties: melting point about 211 to 212 ° C; [x] '= -I-101 ° (in chloroform); = 2.87, 3.01, 5.85, 5.86, 6.16 C2iHzs04Br (425.35).
Berechnet ... C 59,29, H 6,87, Br 18,79; gefunden ... C 59,11, H 7;00, Br 18,40.Calculated ... C 59.29, H 6.87, Br 18.79; Found ... C 59.11, H 7; 00, Br 18.40.
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| US2602769A (en) * | 1952-02-23 | 1952-07-08 | Upjohn Co | Oxygenation of steroids by mucorales fungi |
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| US2602769A (en) * | 1952-02-23 | 1952-07-08 | Upjohn Co | Oxygenation of steroids by mucorales fungi |
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