CH629828A5 - Process for the preparation of D-homosteroids - Google Patents
Process for the preparation of D-homosteroids Download PDFInfo
- Publication number
- CH629828A5 CH629828A5 CH598281A CH598281A CH629828A5 CH 629828 A5 CH629828 A5 CH 629828A5 CH 598281 A CH598281 A CH 598281A CH 598281 A CH598281 A CH 598281A CH 629828 A5 CH629828 A5 CH 629828A5
- Authority
- CH
- Switzerland
- Prior art keywords
- formula
- homosteroid
- hydroxy
- homosteroids
- dione
- Prior art date
Links
- 150000000795 D-homosteroids Chemical class 0.000 title claims abstract description 20
- 238000000034 method Methods 0.000 title claims description 14
- 238000002360 preparation method Methods 0.000 title claims description 8
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims abstract description 5
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 5
- 239000000460 chlorine Substances 0.000 claims abstract description 5
- 125000004423 acyloxy group Chemical group 0.000 claims abstract description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims abstract description 3
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 3
- 239000011737 fluorine Substances 0.000 claims abstract description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 3
- 239000001257 hydrogen Substances 0.000 claims abstract description 3
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims abstract description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 3
- 244000005700 microbiome Species 0.000 claims description 6
- 108090000790 Enzymes Proteins 0.000 claims description 2
- 102000004190 Enzymes Human genes 0.000 claims description 2
- 238000005805 hydroxylation reaction Methods 0.000 abstract description 4
- 230000003110 anti-inflammatory effect Effects 0.000 abstract description 2
- 230000033444 hydroxylation Effects 0.000 abstract description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- 240000008042 Zea mays Species 0.000 description 5
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 5
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 5
- 235000005822 corn Nutrition 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 229920002545 silicone oil Polymers 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 235000015097 nutrients Nutrition 0.000 description 3
- 235000012424 soybean oil Nutrition 0.000 description 3
- 239000003549 soybean oil Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 241000193422 Bacillus lentus Species 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 241000223211 Curvularia lunata Species 0.000 description 2
- 235000010469 Glycine max Nutrition 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Chemical compound 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 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 2
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 2
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000002518 antifoaming agent Substances 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- JPJALAQPGMAKDF-UHFFFAOYSA-N selenium dioxide Chemical compound O=[Se]=O JPJALAQPGMAKDF-UHFFFAOYSA-N 0.000 description 2
- 229910052710 silicon Inorganic materials 0.000 description 2
- 239000010703 silicon Substances 0.000 description 2
- 229910001220 stainless steel Inorganic materials 0.000 description 2
- 239000010935 stainless steel Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 150000003431 steroids Chemical class 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- FRPZMMHWLSIFAZ-UHFFFAOYSA-N 10-undecenoic acid Chemical compound OC(=O)CCCCCCCCC=C FRPZMMHWLSIFAZ-UHFFFAOYSA-N 0.000 description 1
- HZNVUJQVZSTENZ-UHFFFAOYSA-N 2,3-dichloro-5,6-dicyano-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(C#N)=C(C#N)C1=O HZNVUJQVZSTENZ-UHFFFAOYSA-N 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- ZRPLANDPDWYOMZ-UHFFFAOYSA-N 3-cyclopentylpropionic acid Chemical compound OC(=O)CCC1CCCC1 ZRPLANDPDWYOMZ-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 1
- RZCJSVRGPHXBSM-UHFFFAOYSA-N 8-chloro-[1,3]dioxolo[4,5-g]quinazoline Chemical compound C1=C2C(Cl)=NC=NC2=CC2=C1OCO2 RZCJSVRGPHXBSM-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- 241000235389 Absidia Species 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 244000309567 Acrodontium simplex Species 0.000 description 1
- 241000203809 Actinomycetales Species 0.000 description 1
- 241000819815 Arcte coerula Species 0.000 description 1
- 241000186063 Arthrobacter Species 0.000 description 1
- 241000235349 Ascomycota Species 0.000 description 1
- 241000228212 Aspergillus Species 0.000 description 1
- 241000193830 Bacillus <bacterium> Species 0.000 description 1
- 241000221198 Basidiomycota Species 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- QDHHCQZDFGDHMP-UHFFFAOYSA-N Chloramine Chemical compound ClN QDHHCQZDFGDHMP-UHFFFAOYSA-N 0.000 description 1
- 241000222199 Colletotrichum Species 0.000 description 1
- 241001133184 Colletotrichum agaves Species 0.000 description 1
- 241000235555 Cunninghamella Species 0.000 description 1
- 241000010215 Cunninghamella bainieri Species 0.000 description 1
- 241000010216 Cunninghamella blakesleeana Species 0.000 description 1
- 241001290628 Cunninghamella echinulata Species 0.000 description 1
- 241000223208 Curvularia Species 0.000 description 1
- 201000004624 Dermatitis Diseases 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 241000589565 Flavobacterium Species 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 244000068988 Glycine max Species 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 241000186660 Lactobacillus Species 0.000 description 1
- 240000001929 Lactobacillus brevis Species 0.000 description 1
- 241000193386 Lysinibacillus sphaericus Species 0.000 description 1
- 241000906049 Musicillium theobromae Species 0.000 description 1
- IOVCWXUNBOPUCH-UHFFFAOYSA-M Nitrite anion Chemical compound [O-]N=O IOVCWXUNBOPUCH-UHFFFAOYSA-M 0.000 description 1
- 241000187654 Nocardia Species 0.000 description 1
- 241000011719 Nomada opaca Species 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 239000001888 Peptone Substances 0.000 description 1
- 108010080698 Peptones Proteins 0.000 description 1
- 241001503951 Phoma Species 0.000 description 1
- 241000589516 Pseudomonas Species 0.000 description 1
- 241000813090 Rhizoctonia solani Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 241000187747 Streptomyces Species 0.000 description 1
- 241001062464 Streptomyces fradiae ATCC 10745 = DSM 40063 Species 0.000 description 1
- 241000601794 Trichothecium Species 0.000 description 1
- 241000215410 Trichothecium roseum Species 0.000 description 1
- 241000082085 Verticillium <Phyllachorales> Species 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 239000003377 acid catalyst Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 238000005273 aeration Methods 0.000 description 1
- 150000007933 aliphatic carboxylic acids Chemical class 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 229940041514 candida albicans extract Drugs 0.000 description 1
- KHAVLLBUVKBTBG-UHFFFAOYSA-N caproleic acid Natural products OC(=O)CCCCCCCC=C KHAVLLBUVKBTBG-UHFFFAOYSA-N 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000012876 carrier material Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- HJZLEGIHUQOJBA-UHFFFAOYSA-N cyclohexane propionic acid Chemical compound OC(=O)CCC1CCCCC1 HJZLEGIHUQOJBA-UHFFFAOYSA-N 0.000 description 1
- 238000006356 dehydrogenation reaction Methods 0.000 description 1
- 229940079919 digestives enzyme preparation Drugs 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 230000002140 halogenating effect Effects 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 239000013003 healing agent Substances 0.000 description 1
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid Chemical compound CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 150000003949 imides Chemical class 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- BIZCJSDBWZTASZ-UHFFFAOYSA-N iodine pentoxide Inorganic materials O=I(=O)OI(=O)=O BIZCJSDBWZTASZ-UHFFFAOYSA-N 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 229940039696 lactobacillus Drugs 0.000 description 1
- ACKFDYCQCBEDNU-UHFFFAOYSA-J lead(2+);tetraacetate Chemical compound [Pb+2].CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O ACKFDYCQCBEDNU-UHFFFAOYSA-J 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 235000019319 peptone Nutrition 0.000 description 1
- XHFXMNZYIKFCPN-UHFFFAOYSA-N perchloryl fluoride Chemical compound FCl(=O)(=O)=O XHFXMNZYIKFCPN-UHFFFAOYSA-N 0.000 description 1
- KHIWWQKSHDUIBK-UHFFFAOYSA-N periodic acid Chemical compound OI(=O)(=O)=O KHIWWQKSHDUIBK-UHFFFAOYSA-N 0.000 description 1
- 235000019271 petrolatum Nutrition 0.000 description 1
- 239000003279 phenylacetic acid Substances 0.000 description 1
- 229960003424 phenylacetic acid Drugs 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 229920001515 polyalkylene glycol Polymers 0.000 description 1
- JWMFYGXQPXQEEM-WZBAXQLOSA-N pregnane Chemical class C1CC2CCCC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](CC)[C@@]1(C)CC2 JWMFYGXQPXQEEM-WZBAXQLOSA-N 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- SMBZJSVIKJMSFP-UHFFFAOYSA-N trifluoromethyl hypofluorite Chemical compound FOC(F)(F)F SMBZJSVIKJMSFP-UHFFFAOYSA-N 0.000 description 1
- 229960002703 undecylenic acid Drugs 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 238000009423 ventilation Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000012138 yeast extract Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
- C07J63/008—Expansion of ring D by one atom, e.g. D homo steroids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pain & Pain Management (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Rheumatology (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Steroid Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
Die vorliegende Erfindung betrifft ein Verfahren zur Herstellung von neuen D-Homosteroiden der Pregnanreihe der Formel The present invention relates to a process for the preparation of new D-homosteroids of the Pregnan series of the formula
ÇH3 ÇH3
CO CO
HO HO
R6 R6
in der die punktierte 1,2-Bindung eine fakultative C-C-Bin-dung; R6 Wasserstoff, Fluor, Chlor oder Methyl; und R17a Hydroxy oder Acyloxy bedeuten. in which the dotted 1,2 bond is an optional C-C bond; R6 is hydrogen, fluorine, chlorine or methyl; and R17a is hydroxy or acyloxy.
Eine Acyloxygruppe kann sich von einer gesättigten oder ungesättigten aliphatischen Carbonsäure, einer cycloaliphati-schen, aliphatischen oder einer aromatischen Carbonsäure mit vorzugsweise bis zu 15 C-Atomen ableiten. Beispiele solcher Säuren sind, Ameisensäure, Essigsäure, Trifluoressigsäure, Pi-valinsäure, Propionsäure, Buttersäure, Capronsäure, Önanth-säure, Undecylensäure, Ölsäure, Cyclopentylpropionsäure, Cy-clohexylpropionsäure, Phenylessigsäure und Benzoesäure. Besonders bevorzugt sind Q_ 7-Alkanoyloxygruppen. An acyloxy group can be derived from a saturated or unsaturated aliphatic carboxylic acid, a cycloaliphatic, aliphatic or an aromatic carboxylic acid with preferably up to 15 C atoms. Examples of such acids are formic acid, acetic acid, trifluoroacetic acid, pivalic acid, propionic acid, butyric acid, caproic acid, oenanthic acid, undecylenic acid, oleic acid, cyclopentylpropionic acid, cyclohexylpropionic acid, phenylacetic acid and benzoic acid. Q_7-Alkanoyloxy groups are particularly preferred.
Eine bevorzugte Gruppe von Verbindungen der Formel I sind die mit einer 1,2-Doppelbindung. A preferred group of compounds of formula I are those with a 1,2-double bond.
Beispiele von erfindungsgemässen Verbindungen der Formel I sind: Examples of compounds of the formula I according to the invention are:
17 a-Butyryloxy-11 ß-hydroxy-D-homopregna-1,4-dien-3,20-dion, 17 a-butyryloxy-11β-hydroxy-D-homopregna-1,4-diene-3,20-dione,
6a-Fluoro-11 ß, 17 a-dihydroxy-D -homopregna, 1,4-dien-3,20-dion, 6a-fluoro-11β, 17 a-dihydroxy-D-homopregna, 1,4-diene-3,20-dione,
6a-Chloro-l 1 ß,17a-dihydroxy-D-homopregna-l,4-dien-3,20-dion, 6a-chloro-l 1 ß, 17a-dihydroxy-D-homopregna-l, 4-diene-3,20-dione,
17a-Butyryloxy-6a-fluoro-llß-hydroxy-D-homopregna-1,4-dien-3,20-dion, 17a-butyryloxy-6a-fluoro-11ß-hydroxy-D-homopregna-1,4-diene-3,20-dione,
17a-Valeroyloxy-6a-chloro-llß-hydroxy-D-homopre-gna-1,4-dien-3,20-dion, 17a-valeroyloxy-6a-chloro-11ß-hydroxy-D-homopre-gna-1,4-diene-3,20-dione,
llß,17a-Dihydroxy-6a-methyl-D-homopregn-4-en-3,20-dion, llß, 17a-dihydroxy-6a-methyl-D-homopregn-4-en-3,20-dione,
17a-Butyryloxy-llß-hydroxy-6ot-methyl-D-homopregn-4-en-3,20-dion, 17a-butyryloxy-11ß-hydroxy-6ot-methyl-D-homopregn-4-en-3,20-dione,
llß,17a-Dihydroxy-6a-methyl-D-homopregna-l,4-dien-3,20-dion, llß, 17a-dihydroxy-6a-methyl-D-homopregna-l, 4-diene-3,20-dione,
17a-Butyryloxy-llß-hydroxy-6a-methyl-D-homopregna-l,4-dien-3,20-dion. 17a-butyryloxy-11ß-hydroxy-6a-methyl-D-homopregna-l, 4-diene-3,20-dione.
Die D-Homosteroide der Formel I werden erfindungsge-mäss dadurch hergestellt, dass man ein D-Homosteroid der Formel The D-homosteroids of the formula I are produced in accordance with the invention in that a D-homosteroid of the formula
CHo i 3 CHo i 3
CO CO
17a 17a
R6 R6
mittels Mikroorganismen oder daraus gewonnenen Enzymen in 11-Stellung hydroxyliert. hydroxylated in the 11-position by means of microorganisms or enzymes obtained therefrom.
Die Hydroxylierung einer Verbindung der Formel II kann mittels für die mikrobielle 11-Hydroxylierung von Steroiden an The hydroxylation of a compound of formula II can be used for the microbial 11-hydroxylation of steroids
5 5
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25 25th
30 30th
35 35
40 40
45 45
50 50
55 55
60 60
65 65
3 3rd
629 828 629 828
sich bekannter Methoden bewerkstelligt werden. Hierfür kommen Mikroorganismen der taxonomischen Einheit Fungi und Schizomycetes insbesondere der Untereinheiten Ascom ycetes, Phycomycetes, Basidiomycetes und Actinomycetales in Betracht. Es können auch auf chemischem Wege, z.B. durch Behandlung mit Nitrit, oder auf physikalischem Wege, z.B. durch Bestrahlung, erzeugte Mutanten sowie aus den Mikroorganismen erhaltene zellfreie Enzympräparate verwendet werden. Geeignete Mikroorganismen für die 1 lß-Hydroxylierung sind insbesondere solche der Genera Curvularia, z.B. C. lunata NRRL2380 und NRRL 2178; ATCC13633,13432,14678, IMI 77007, IFO 2811 ; Absidia, z.B. A. coerula IFO 4435 ; Colletotrichum, z.B. C. pisi ATCC 12520; Pellicolaria, z.B. P. filamentosa IFO 6675 ; Streptomyces, z.B. S. fradiae ATCC 10745 ; Cunninghamella, z.B. C. bainieri ATCC 9244, C. verti-cellata ATCC 8983 ; C. elegans NRRL 1392 und ATCC 9245, C. blakesleeana ATCC 8688,8688a, 8688b, 8983, und C. echi-nulata ATCC 8984; Pycnosporium, z.B. sp. ATCC 12231 ; Ver-ticillium, z.B. V. theobromae CBS 39858; Aspergillus, z.B. A. quadrilieatus JAM 2763 ; Trichothecium, z.B. T. roseum ATCC 12519; und Phoma, z.B. sp. ATCC 13145. known methods are accomplished. Microorganisms of the taxonomic unit Fungi and Schizomycetes, in particular of the subunits Ascom ycetes, Phycomycetes, Basidiomycetes and Actinomycetales, are suitable for this. It can also be done chemically, e.g. by treatment with nitrite, or by physical means, e.g. by radiation, mutants generated and cell-free enzyme preparations obtained from the microorganisms can be used. Suitable microorganisms for 1β-hydroxylation are in particular those of the Genera Curvularia, e.g. C. lunata NRRL2380 and NRRL 2178; ATCC13633,13432,14678, IMI 77007, IFO 2811; Absidia, e.g. A. coerula IFO 4435; Colletotrichum, e.g. C. pisi ATCC 12520; Pellicolaria, e.g. P. filamentosa IFO 6675; Streptomyces, e.g. S. fradiae ATCC 10745; Cunninghamella, e.g. C. bainieri ATCC 9244, C. verti-cellata ATCC 8983; C. elegans NRRL 1392 and ATCC 9245, C. blakesleeana ATCC 8688,8688a, 8688b, 8983, and C. echi-nulata ATCC 8984; Pycnosporium, e.g. sp. ATCC 12231; Ver-ticillium, e.g. V. theobromae CBS 39858; Aspergillus, e.g. A. quadrilieatus JAM 2763; Trichothecium, e.g. T. roseum ATCC 12519; and Phoma, e.g. sp. ATCC 13145.
Ein 1,2-gesättigtes D-Homosteroid der Formel I kann in an sich bekannter Weise, z.B. auf mikrobiologischem Wege oder mittels Dehydrierungsmitteln wie Jodpentoxyd, Perjodsäure oder Selendioxyd, 2,3-DichIor-5,6-dicyanobenzochinon, Chlor-anil oder Bleitetraacetat dehydriert werden. Geeignete Mikroorganismen für die 1,2-Dehydrierung sind beispielsweise Schizomyceten, insbesondere solche der Genera Arthrobacter, z.B. A. simplex ATCC 6946 ; Bacillus, z.B. B. lentus ATCC 13805 und B. sphaericus ATCC 7055 ; Pseudomonas, z.B. P. aeruginosa IFO 3505; Flavobacterium, z.B. F. flavenscens IFO 3058; Lactobacillus, z.B. L. brevis IFO 3345 und Nocardia, z.B. N. opaca ATCC 4276. A 1,2-saturated D-homosteroid of formula I can be prepared in a manner known per se, e.g. be dehydrated microbiologically or by means of dehydrating agents such as iodine pentoxide, periodic acid or selenium dioxide, 2,3-dichloro-5,6-dicyanobenzoquinone, chloroanil or lead tetraacetate. Suitable microorganisms for 1,2-dehydrogenation are, for example, schizomycetes, in particular those of the Genera Arthrobacter, e.g. A. simplex ATCC 6946; Bacillus, e.g. B. lentus ATCC 13805 and B. sphaericus ATCC 7055; Pseudomonas, e.g. P. aeruginosa IFO 3505; Flavobacterium, e.g. F. flavenscens IFO 3058; Lactobacillus, e.g. L. brevis IFO 3345 and Nocardia, e.g. N. opaca ATCC 4276.
Ein Steroid der Formel I kann in 6-Stellung in an sich bekannter Weise, durch Umsetzung mit einem Halogenierungs-mittel, wie einem N-Chloramid oder -imid (z.B. N-Chlorsuccin-imid) oder mit elementarem Chlor halogeniert werden [vergi. J. Am. Chem. 72,4534 (1950)]. Die Halogenierung in 6-Stellung wird vorzugsweise dadurch vorgenommen, dass man ein D-Homosteroid der Formel I in einen 3-Enolester oder 3-Enoläther, z.B. das 3-Enolacetat, überführt und danach mit Chlor [vgl. J. Am. Chem. Soc. 82,1230 (I960)]; mit einem N-Chlorimid [vgl. J. Am. Chem. Soc. 82,1230 (1960); 77,3827 (1955)] oder Perchlorylfluorid [vgl. J. Am. Chem. Soc. 81, 5259 (1959); Chem. and Ind. 1959,1317] umsetzt. Als Fuorierungsmittel kommt weiterhin Trifluormethylhypofluorit in Betracht. A steroid of the formula I can be halogenated in the 6-position in a manner known per se, by reaction with a halogenating agent, such as an N-chloramide or imide (e.g. N-chlorosuccinimide) or with elemental chlorine [forgi. J. Am. Chem. 72, 4534 (1950)]. The halogenation in the 6-position is preferably carried out by converting a D-homosteroid of formula I into a 3-enol ester or 3-enol ether, e.g. the 3-enol acetate, transferred and then with chlorine [cf. J. Am. Chem. Soc. 82, 1230 (I960)]; with an N-chloroimide [cf. J. Am. Chem. Soc. 82, 1230 (1960); 77, 3827 (1955)] or perchloryl fluoride [cf. J. Am. Chem. Soc. 81, 5259 (1959); Chem. And Ind. 1959, 1317]. Trifluoromethyl hypofluorite can also be used as the colorant.
Sofern bei den vorstehend beschriebenen Halogenierungen Isomerengemische, d.h. Gemische von 6a- und 6ß-Halogen-steroiden gebildet werden, können diese nach bekannten Methoden, wie Chromatographie, in die reinen Isomeren getrennt werden. If isomer mixtures, i.e. Mixtures of 6a and 6β-halogen steroids are formed, these can be separated into the pure isomers by known methods, such as chromatography.
Eine in einem D-Homosteroid der Formel I enthaltene 17a-Hydroxygrappe kann in an sich bekannter Weise, z.B. durch Behandlung mit einem Acylierungsmittel, wie einem Acylchlo-rid oder -anhydrid, in Gegenwart eines säurebindenden Mittels, z.B. Pyridin oder Triäthylamin, und eines geeigneten Katalysators, wie p-Dimethylaminopyridin, oder in Gegenwart eines starken Säurekatalysators, z.B. p-Toluolsulfonsäure acyliert werden. Als Lösungsmittel für die Acylierung kommen nicht-hydroxylgruppenhaltige organische Lösungsmittel, z.B. chlorierte Kohlenwasserstoffe, wie Methylenchlorid oder Kohlenwasserstoffe, wie Benzol, in Betracht. A 17a-hydroxy group contained in a D-homosteroid of formula I can be prepared in a manner known per se, e.g. by treatment with an acylating agent such as an acylchloride or anhydride in the presence of an acid binding agent, e.g. Pyridine or triethylamine and a suitable catalyst such as p-dimethylaminopyridine or in the presence of a strong acid catalyst e.g. p-Toluenesulfonic acid are acylated. Organic solvents which contain non-hydroxyl groups, e.g. chlorinated hydrocarbons such as methylene chloride or hydrocarbons such as benzene.
Die Ausgangsstoffe für das erfindungsgemässe Verfahren können, soweit sie nicht bekannt oder nachstehend beschrieben sind, in Analogie zu bekannten oder den nachstehend beschriebenen Methoden hergestellt werden. Unless they are known or described below, the starting materials for the process according to the invention can be prepared analogously to known methods or the methods described below.
Auf Grund ihrer entzündungshemmenden Wirksamkeit können die Verbindungen der Formel I z.B. zur Behandlung entzündlicher Erkrankungen, wie Ekzemen Verwendung finden. Because of their anti-inflammatory activity, the compounds of formula I can e.g. used to treat inflammatory diseases such as eczema.
Im allgemeinen können Präparate zur inneren Verabreichung 0,01 bis 5,0% eines D-Homosteroids der Formel I ent-5 halten. Die tägliche Dosis kann zwischen 0,05 bis 10,0 mg je nach dem zu behandelnden Zustand und der Dauer der gewünschten Behandlung schwanken. Der Anteil an aktivem D-Homosteroid der Formel I in topischen Präparaten liegt im allgemeinen im Bereich von 0,0001 bis 5 Gew.%, vorteilhafter-io weise im Bereich von 0,001 bis 0,5 % und vorzugsweise im Bereich von 0,01 bis 0,25 %. In general, preparations for internal administration can contain 0.01 to 5.0% of a D-homosteroid of the formula I. The daily dose can vary between 0.05 to 10.0 mg depending on the condition to be treated and the duration of the desired treatment. The proportion of active D-homosteroid of the formula I in topical preparations is generally in the range from 0.0001 to 5% by weight, advantageously in the range from 0.001 to 0.5% and preferably in the range from 0.01 to 0.25%.
Die Verfahrensprodukte können als Heilmittel z.B. in Form pharmazeutischer Präparate Verwendung finden, welche sie in Mischung mit einem für die enterale, perkutane oder parentera-ls le Applikation geeigneten pharmazeutischen, organischer oder anorganischen inerten Trägermaterial, wie z.B. Wasser, Gelatine, Gummi arabicum, Milchzucker, Stärke, Magnesiumstearat, Talk, pflanzliche öle, Polyalkylenglykole, Vaseline, usw. enthalten. Die pharmazeutischen Präparate können z.B. als Salben 20 oder als Lösungen, Suspensionen oder Emulsionen, vorliegen. Gegebenenfalls sind sie sterilisiert und bzw. oder enthalten Hilfsstoffe, wie Konservierungs-, Stabilisierungs-, Netz- oder Emulgiermittel, Salze zur Veränderung des osmotischen Druk-kes oder Puffer. Sie können auch noch andere therapeutisch 25 wertvolle Stoffe enthalten. The process products can be used as healing agents e.g. in the form of pharmaceutical preparations which are used in a mixture with a pharmaceutical, organic or inorganic inert carrier material suitable for enteral, percutaneous or parenteral administration, such as e.g. Contain water, gelatin, gum arabic, milk sugar, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, petroleum jelly, etc. The pharmaceutical preparations can e.g. as ointments 20 or as solutions, suspensions or emulsions. If necessary, they are sterilized and / or contain auxiliary substances such as preservatives, stabilizers, wetting agents or emulsifiers, salts for changing the osmotic pressure or buffers. They can also contain other therapeutically valuable substances.
In den folgenden Beispielen sind die Temperaturen in Celsiusgraden angegeben. In the following examples, the temperatures are given in degrees Celsius.
Beispiel 1 example 1
3o Ein 21-Erlenmeyerkolben, der 500 ml einer 30 Minuten bei 120° im Autoklaven sterilisierten Nährlösung aus 1 % Corn steep liquor, 1 % Sojapuder und 0,005 % Sojaöl, eingestellt auf pH 6,2, enthält, wird mit einer Lyophilkultur von Curvularia lunata (NRRL 2380) beimpft und 72 Stunden bei 30° auf einem 35 Rotationsschüttler geschüttelt. Mit dieser Vorkultur wird dann ein 201-Fermenter aus rostfreiem Stahl, der 151 eines bei 121° und 1,1 atü sterilisierten Mediums aus 1 % Corn steep liquor, 0,5 % Stärkezucker und 0,005 % Sojaöl, eingestellt auf pH 6,2, enthält, beimpft. Unter Zugabe eines Siliconöls (Silicon SH) als 40 Antischaummittel wird bei 29° unter Belüftung (101/Min) 0,7 atü Druck und Rühren (220 U/Min.) 24 Stunden germiniert. 1 Liter der Kulturbrühe wird unter sterilen Bedingungen in 141 eines wie oben sterilisierten Mediums aus 1 % Corn steep liquor, 1,25 % Sojapuder und 0,005 % Sojaöl überführt und unter glei-45 chen Bedingungen angezüchtet. Nach 12 Stunden wird eine Lösung von 4 g 17aa-Acetoxy-D-homo-4-pregnen-3,20-dion in 100 ml Dimethylformamid zugegeben. Nach 52 Stunden Kontaktzeit wird der Fermenterinhalt zweimal mit je 101 Methyliso-butylketon ausgerührt und der Extrakt bei 50° Badtemperatur so im Vakuum eingedampft. Der Rückstand wird zur Entfernung des Siliconöls mehrmals mit Hexan gewaschen und durch Säulenchromatographie an Silicagel (Gradientenelution: Hexan + Hexan/Essigesterl + (Vi) von unumgewandelten Ausgangsmaterial abgetrennt. Das 17aa-Acetoxy-llß-hydroxy-D-ho-55 mo-4-pregnen- 3,20-dion wurde aus Isopropyläther umkristallisiert; Fp. 234/235-237°, e242 = 16700. 3o A 21-Erlenmeyer flask containing 500 ml of a nutrient solution sterilized for 30 minutes at 120 ° in an autoclave from 1% corn steep liquor, 1% soybean powder and 0.005% soybean oil, adjusted to pH 6.2, is mixed with a lyophil culture from Curvularia lunata (NRRL 2380) and inoculated for 72 hours at 30 ° on a 35 rotary shaker. This preculture is then used to produce a 201 stainless steel fermenter, the 151 of a medium sterilized at 121 ° and 1.1 atm of 1% corn steep liquor, 0.5% starch sugar and 0.005% soybean oil, adjusted to pH 6.2. contains, inoculates. With the addition of a silicone oil (Silicon SH) as a 40 anti-foaming agent, the pressure at 29 ° with ventilation (101 / min) is 0.7 atm and stirring (220 rpm) for 24 hours. 1 liter of the culture broth is transferred under sterile conditions into 141 of a medium, sterilized as above, from 1% corn steep liquor, 1.25% soy powder and 0.005% soybean oil and grown under the same conditions. After 12 hours, a solution of 4 g of 17aa-acetoxy-D-homo-4-pregnen-3,20-dione in 100 ml of dimethylformamide is added. After a contact time of 52 hours, the fermenter contents are stirred twice with 101 methyl isobutyl ketone each and the extract is evaporated in vacuo at a bath temperature of 50 °. The residue is washed several times with hexane to remove the silicone oil and separated from unconverted starting material by column chromatography on silica gel (gradient elution: hexane + hexane / ethyl acetate + (Vi). The 17aa-acetoxy-11β-hydroxy-D-ho-55 mo-4 -pregnen- 3,20-dione was recrystallized from isopropyl ether; mp. 234 / 235-237 °, e242 = 16700.
Beispiel 2 Example 2
Ein 21-Erlenmeyerkolben, der 500 ml einer 30 Minuten bei 60 120 ° im Autoklaven sterilisierten Nährlösung aus 1,5 % Pepton, 1,2% Corn steep und 0,2% MgS04, eingestellt auf pH 6,5, enthält, wird mit einer Lyophilkultur von Bacillus lentus (ATCC 13805) beimpft und 24 Stunden bei 30° geschüttelt. Mit dieser Vorkultur wird dann ein 201-Fermenter aus rostfreiem Stahl, 6s der 151 eines bei 121° und 1,1 atü sterilisierten flüssigen Nährmediums aus 0,2% Hefextrakt, 1 % Corn steep liquor und 0,1 % Stärkezucker, eingestellt auf pH 7,0, enthält, beimpft. Unter Zugabe eines Siliconöls (Silicon SH) als Antischaummittel wird A 21-Erlenmeyer flask containing 500 ml of a nutrient solution of 1.5% peptone, 1.2% corn steep and 0.2% MgSO4, adjusted to pH 6.5, sterilized in an autoclave for 30 minutes at 60 120 °, is also with inoculated with a Lyophil culture of Bacillus lentus (ATCC 13805) and shaken at 30 ° for 24 hours. This preculture is then used to make a 201 fermenter made of stainless steel, 6s of 151 a liquid nutrient medium sterilized at 121 ° and 1.1 atm of 0.2% yeast extract, 1% corn steep liquor and 0.1% starch sugar, adjusted to pH 7.0, contains, inoculates. With the addition of a silicone oil (Silicon SH) as an anti-foaming agent
629 828 629 828
bei 29° unter Belüftung und Rühren germiniert. Nach einer Anwachsphase von 6 Stunden setzt man eine Lösung von 1,6 g 17aa-Acetoxy-llß-hydroxy-D-homo-4-pregnen-3,20-dion in 50 ml Dimethylformamid zu. Nach 15 Stunden Kontaktzeit wird der Fermenterinhalt zweimal mit je 10 ml Methylisobutyl-keton extrahiert und der Extrakt im Vakuum eingedampft. Der Rückstand wurde zur Entfernung des Siliconöls mit Hexan gewaschen und aus Aceton-Diiospropyläther in Gegenwart von Aktivkohle umkristallisiert, und man erhält 17aa-Acetoxy-11 ß-hydroxy-D-homo-1,4-pregnadien-3,20-dion vom Schmelzpunkt 218/219-220° und e244 = 15100. Germinated at 29 ° with aeration and stirring. After a growth phase of 6 hours, a solution of 1.6 g of 17aa-acetoxy-11ß-hydroxy-D-homo-4-pregnen-3,20-dione in 50 ml of dimethylformamide is added. After a contact time of 15 hours, the fermenter contents are extracted twice with 10 ml each of methyl isobutyl ketone and the extract is evaporated in vacuo. The residue was washed with hexane to remove the silicone oil and recrystallized from acetone-diiospropyl ether in the presence of activated carbon, and 17aa-acetoxy-11β-hydroxy-D-homo-1,4-pregnadiene-3,20-dione from the melting point is obtained 218 / 219-220 ° and e244 = 15100.
Beispiel 3 Example 3
In zu den Beispielen 1 und 2 analoger Weise erhält man das 6a-Fluoro-11 ß, 17 a-dihydroxy-D-homopregna-1,4-dien-3,20-dion, Smp. 183—184°, UV: s 2n — 14400, [a]D = 5 +56° (c = 0,1 % in Dioxan), In a manner analogous to Examples 1 and 2, 6a-fluoro-11β, 17α-dihydroxy-D-homopregna-1,4-diene-3,20-dione is obtained, mp. 183-184 °, UV: s 2n - 14400, [a] D = 5 + 56 ° (c = 0.1% in dioxane),
das 17a-Butyryloxy-l lß-hydroxy-D-homopregna-1,4-dien-3,20-dion, 8244 = 13940 [a]D - +22° (Dioxan c = 0,1%), 17a-butyryloxy-lß-hydroxy-D-homopregna-1,4-diene-3,20-dione, 8244 = 13940 [a] D - + 22 ° (dioxane c = 0.1%),
das 17a-Butyryloxy-6a-fluoro-l lß-hydroxy-D-homopre-io gna-l,4-dien-3,20-dion, Smp. 168—169°, UV: e242 = 16600, [a] D = +13° (Dioxan, c = 0,1%). the 17a-butyryloxy-6a-fluoro-l lß-hydroxy-D-homopre-io gna-l, 4-diene-3,20-dione, mp. 168-169 °, UV: e242 = 16600, [a] D = + 13 ° (dioxane, c = 0.1%).
C C.
Claims (6)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AT656076A AT356301B (en) | 1976-09-03 | 1976-09-03 | METHOD FOR THE PRODUCTION OF NEW D-HOMOSTEROIDS |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH629828A5 true CH629828A5 (en) | 1982-05-14 |
Family
ID=3587531
Family Applications (4)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH973377A CH629827A5 (en) | 1976-09-03 | 1977-08-09 | Process for the preparation of D-homosteroids |
| CH598381A CH629829A5 (en) | 1976-09-03 | 1981-09-16 | Process for the preparation of D-homosteroids |
| CH598281A CH629828A5 (en) | 1976-09-03 | 1981-09-16 | Process for the preparation of D-homosteroids |
| CH598481A CH629830A5 (en) | 1976-09-03 | 1981-09-16 | Process for the preparation of D-homosteroids |
Family Applications Before (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH973377A CH629827A5 (en) | 1976-09-03 | 1977-08-09 | Process for the preparation of D-homosteroids |
| CH598381A CH629829A5 (en) | 1976-09-03 | 1981-09-16 | Process for the preparation of D-homosteroids |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
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| CH598481A CH629830A5 (en) | 1976-09-03 | 1981-09-16 | Process for the preparation of D-homosteroids |
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| JP (1) | JPS5910680B2 (en) |
| AR (1) | AR220320A1 (en) |
| AT (1) | AT356301B (en) |
| AU (1) | AU516174B2 (en) |
| BE (1) | BE858354A (en) |
| CA (1) | CA1098897A (en) |
| CH (4) | CH629827A5 (en) |
| DE (1) | DE2738363A1 (en) |
| DK (1) | DK140947B (en) |
| ES (3) | ES462076A1 (en) |
| FI (1) | FI57600C (en) |
| FR (1) | FR2363580A1 (en) |
| GB (1) | GB1586504A (en) |
| GR (1) | GR73039B (en) |
| HK (1) | HK26484A (en) |
| HU (2) | HU184769B (en) |
| IE (1) | IE45671B1 (en) |
| IL (1) | IL52831A (en) |
| IT (1) | IT1085032B (en) |
| LU (1) | LU78064A1 (en) |
| MC (1) | MC1166A1 (en) |
| MY (1) | MY8500293A (en) |
| NL (1) | NL182314C (en) |
| NO (1) | NO145621C (en) |
| NZ (1) | NZ185046A (en) |
| PH (1) | PH14434A (en) |
| PT (1) | PT66983B (en) |
| SE (1) | SE440783B (en) |
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| CH571018A5 (en) * | 1972-03-29 | 1975-12-31 | Hoffmann La Roche | |
| NO140672C (en) * | 1973-03-28 | 1979-10-17 | Hoffmann La Roche | ANALOGICAL PROCEDURES FOR THE MANUFACTURE OF NEW ANTI-INFLAMMATORY EFFECTIVE STEROIDS |
| DE2349023A1 (en) * | 1973-09-26 | 1975-04-10 | Schering Ag | NEW D-HOMO-STEROIDS |
| DE2349022A1 (en) * | 1973-09-26 | 1975-04-10 | Schering Ag | NEW D-HOMO-STEROIDS |
| CH601351A5 (en) * | 1973-09-26 | 1978-07-14 | Hoffmann La Roche | |
| DE2442615A1 (en) * | 1974-09-04 | 1976-03-18 | Schering Ag | NEW D-HOMO-STEROIDS |
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1976
- 1976-09-03 AT AT656076A patent/AT356301B/en not_active IP Right Cessation
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1977
- 1977-08-09 CH CH973377A patent/CH629827A5/en not_active IP Right Cessation
- 1977-08-22 YU YU2009/77A patent/YU40009B/en unknown
- 1977-08-25 DE DE19772738363 patent/DE2738363A1/en active Granted
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- 1977-08-29 AU AU28304/77A patent/AU516174B2/en not_active Expired
- 1977-08-29 IE IE1800/77A patent/IE45671B1/en unknown
- 1977-08-29 NZ NZ185046A patent/NZ185046A/en unknown
- 1977-08-30 CA CA285,723A patent/CA1098897A/en not_active Expired
- 1977-08-31 HU HU80306A patent/HU184769B/en unknown
- 1977-08-31 NL NLAANVRAGE7709585,A patent/NL182314C/en not_active IP Right Cessation
- 1977-08-31 PH PH20179A patent/PH14434A/en unknown
- 1977-08-31 HU HU77HO2011A patent/HU176255B/en unknown
- 1977-08-31 IT IT27147/77A patent/IT1085032B/en active
- 1977-09-01 FR FR7726562A patent/FR2363580A1/en active Granted
- 1977-09-01 MC MC771258A patent/MC1166A1/en unknown
- 1977-09-01 AR AR269060A patent/AR220320A1/en active
- 1977-09-01 FI FI772599A patent/FI57600C/en not_active IP Right Cessation
- 1977-09-01 PT PT66983A patent/PT66983B/en unknown
- 1977-09-01 LU LU78064A patent/LU78064A1/xx unknown
- 1977-09-02 SE SE7709916A patent/SE440783B/en not_active IP Right Cessation
- 1977-09-02 JP JP52105054A patent/JPS5910680B2/en not_active Expired
- 1977-09-02 DK DK393277AA patent/DK140947B/en not_active IP Right Cessation
- 1977-09-02 NO NO773057A patent/NO145621C/en unknown
- 1977-09-02 BE BE180635A patent/BE858354A/en not_active IP Right Cessation
- 1977-09-02 GB GB36737/77A patent/GB1586504A/en not_active Expired
- 1977-09-02 ES ES462076A patent/ES462076A1/en not_active Expired
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1978
- 1978-05-08 ES ES469574A patent/ES469574A1/en not_active Expired
- 1978-05-08 ES ES469573A patent/ES469573A1/en not_active Expired
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1979
- 1979-09-01 GR GR54275A patent/GR73039B/el unknown
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1981
- 1981-09-16 CH CH598381A patent/CH629829A5/en not_active IP Right Cessation
- 1981-09-16 CH CH598281A patent/CH629828A5/en not_active IP Right Cessation
- 1981-09-16 CH CH598481A patent/CH629830A5/en not_active IP Right Cessation
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1982
- 1982-10-08 YU YU2277/82A patent/YU40089B/en unknown
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1984
- 1984-03-22 HK HK264/84A patent/HK26484A/en unknown
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1985
- 1985-12-30 MY MY293/85A patent/MY8500293A/en unknown
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