CS203913B2 - Process for preparing derivatives of estradiene - Google Patents
Process for preparing derivatives of estradiene Download PDFInfo
- Publication number
- CS203913B2 CS203913B2 CS795403A CS540379A CS203913B2 CS 203913 B2 CS203913 B2 CS 203913B2 CS 795403 A CS795403 A CS 795403A CS 540379 A CS540379 A CS 540379A CS 203913 B2 CS203913 B2 CS 203913B2
- Authority
- CS
- Czechoslovakia
- Prior art keywords
- methyl
- estradien
- group
- solution
- carbon
- Prior art date
Links
- 238000004519 manufacturing process Methods 0.000 title claims description 3
- 150000002158 estradienes Chemical class 0.000 title description 2
- 125000002252 acyl group Chemical group 0.000 claims abstract description 7
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 claims abstract description 6
- 238000000034 method Methods 0.000 claims description 7
- 239000011203 carbon fibre reinforced carbon Substances 0.000 claims description 5
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- 125000002603 chloroethyl group Chemical group [H]C([*])([H])C([H])([H])Cl 0.000 claims description 4
- 238000003776 cleavage reaction Methods 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 150000002443 hydroxylamines Chemical class 0.000 claims description 4
- 230000007017 scission Effects 0.000 claims description 4
- 125000006239 protecting group Chemical group 0.000 claims description 3
- HWCYISVQOIISSU-HULBTWJISA-N (8R,9R,10S,13R)-13-methyl-1,2,3,4,5,6,7,8,9,10,11,12-dodecahydrocyclopenta[a]phenanthrene Chemical class C([C@@H]12)CCCC1CC[C@@H]1[C@@H]2CC[C@@]2(C)C1=CC=C2 HWCYISVQOIISSU-HULBTWJISA-N 0.000 claims description 2
- HVFBTBBENYOYMU-YFRXESGTSA-N (8r,9r,10s,13s,14s)-13-methyl-2,3,4,5,6,7,8,9,10,11,12,14-dodecahydro-1h-cyclopenta[a]phenanthren-17-one Chemical compound C1CCC[C@@H]2[C@H]3CC[C@](C)(C(C=C4)=O)[C@@H]4[C@@H]3CCC21 HVFBTBBENYOYMU-YFRXESGTSA-N 0.000 claims description 2
- MZAGXDHQGXUDDX-JSRXJHBZSA-N (e,2z)-4-ethyl-2-hydroxyimino-5-nitrohex-3-enamide Chemical compound [O-][N+](=O)C(C)C(/CC)=C/C(=N/O)/C(N)=O MZAGXDHQGXUDDX-JSRXJHBZSA-N 0.000 claims description 2
- CREMABGTGYGIQB-UHFFFAOYSA-N carbon carbon Chemical compound C.C CREMABGTGYGIQB-UHFFFAOYSA-N 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000004043 oxo group Chemical group O=* 0.000 claims description 2
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 abstract description 38
- 238000006243 chemical reaction Methods 0.000 abstract description 8
- -1 chloroethynyl Chemical group 0.000 abstract description 3
- 125000000217 alkyl group Chemical group 0.000 abstract description 2
- 230000000694 effects Effects 0.000 abstract description 2
- 150000002148 esters Chemical class 0.000 abstract description 2
- 230000016087 ovulation Effects 0.000 abstract description 2
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 abstract 1
- 230000003111 delayed effect Effects 0.000 abstract 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 abstract 1
- 238000002513 implantation Methods 0.000 abstract 1
- KIWSYRHAAPLJFJ-DNZSEPECSA-N n-[(e,2z)-4-ethyl-2-hydroxyimino-5-nitrohex-3-enyl]pyridine-3-carboxamide Chemical group [O-][N+](=O)C(C)C(/CC)=C/C(=N/O)/CNC(=O)C1=CC=CN=C1 KIWSYRHAAPLJFJ-DNZSEPECSA-N 0.000 abstract 1
- 125000002524 organometallic group Chemical group 0.000 abstract 1
- 230000001072 progestational effect Effects 0.000 abstract 1
- 150000003431 steroids Chemical class 0.000 abstract 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 abstract 1
- 125000004665 trialkylsilyl group Chemical group 0.000 abstract 1
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 54
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 45
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 32
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 18
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 16
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 14
- 239000012043 crude product Substances 0.000 description 14
- 239000000741 silica gel Substances 0.000 description 14
- 229910002027 silica gel Inorganic materials 0.000 description 14
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 12
- 239000000203 mixture Substances 0.000 description 11
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 10
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 10
- 238000004587 chromatography analysis Methods 0.000 description 10
- 239000011541 reaction mixture Substances 0.000 description 10
- 229910052938 sodium sulfate Inorganic materials 0.000 description 10
- 235000011152 sodium sulphate Nutrition 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 9
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 239000003921 oil Substances 0.000 description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
- 235000019198 oils Nutrition 0.000 description 6
- 239000002585 base Substances 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 230000032050 esterification Effects 0.000 description 5
- 238000005886 esterification reaction Methods 0.000 description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 150000003512 tertiary amines Chemical class 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-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
- 239000004480 active ingredient Substances 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 239000012299 nitrogen atmosphere Substances 0.000 description 3
- 150000002902 organometallic compounds Chemical class 0.000 description 3
- 239000002798 polar solvent Substances 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 235000011121 sodium hydroxide Nutrition 0.000 description 3
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-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
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 150000008064 anhydrides Chemical class 0.000 description 2
- HOPRXXXSABQWAV-UHFFFAOYSA-N anhydrous collidine Natural products CC1=CC=NC(C)=C1C HOPRXXXSABQWAV-UHFFFAOYSA-N 0.000 description 2
- SESFRYSPDFLNCH-UHFFFAOYSA-N benzyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCC1=CC=CC=C1 SESFRYSPDFLNCH-UHFFFAOYSA-N 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- UTBIMNXEDGNJFE-UHFFFAOYSA-N collidine Natural products CC1=CC=C(C)C(C)=N1 UTBIMNXEDGNJFE-UHFFFAOYSA-N 0.000 description 2
- 238000006266 etherification reaction Methods 0.000 description 2
- OSVMTWJCGUFAOD-KZQROQTASA-N formestane Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1O OSVMTWJCGUFAOD-KZQROQTASA-N 0.000 description 2
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 2
- HTBVGZAVHBZXMS-UHFFFAOYSA-N lithium;tris[(2-methylpropan-2-yl)oxy]alumane Chemical compound [Li].[Al+3].CC(C)(C)[O-].CC(C)(C)[O-].CC(C)(C)[O-] HTBVGZAVHBZXMS-UHFFFAOYSA-N 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- DVSDBMFJEQPWNO-UHFFFAOYSA-N methyllithium Chemical compound C[Li] DVSDBMFJEQPWNO-UHFFFAOYSA-N 0.000 description 2
- 235000015097 nutrients Nutrition 0.000 description 2
- 235000006408 oxalic acid Nutrition 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- MWWATHDPGQKSAR-UHFFFAOYSA-N propyne Chemical group CC#C MWWATHDPGQKSAR-UHFFFAOYSA-N 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- VWDWKYIASSYTQR-UHFFFAOYSA-N sodium nitrate Chemical compound [Na+].[O-][N+]([O-])=O VWDWKYIASSYTQR-UHFFFAOYSA-N 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 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
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 2
- SBLHOJQRZNGHLQ-ATIFRJIPSA-N (8r,9s,10r,13s,14s)-13-ethyl-1,2,6,7,8,9,10,11,12,14,15,16-dodecahydrocyclopenta[a]phenanthrene-3,17-dione Chemical compound O=C1CC[C@@H]2[C@H]3CC[C@](CC)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1 SBLHOJQRZNGHLQ-ATIFRJIPSA-N 0.000 description 1
- SXNYYEPTQTZOHG-UHFFFAOYSA-N 1,8-diazacyclotetradecane-2,7-dione Chemical compound O=C1CCCCC(=O)NCCCCCCN1 SXNYYEPTQTZOHG-UHFFFAOYSA-N 0.000 description 1
- BFPYWIDHMRZLRN-UHFFFAOYSA-N 17alpha-ethynyl estradiol Natural products OC1=CC=C2C3CCC(C)(C(CC4)(O)C#C)C4C3CCC2=C1 BFPYWIDHMRZLRN-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
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 1
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 1
- BFPYWIDHMRZLRN-SLHNCBLASA-N Ethinyl estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 BFPYWIDHMRZLRN-SLHNCBLASA-N 0.000 description 1
- 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 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 241000228143 Penicillium Species 0.000 description 1
- 244000000231 Sesamum indicum Species 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- MUCRYNWJQNHDJH-OADIDDRXSA-N Ursonic acid Chemical compound C1CC(=O)C(C)(C)[C@@H]2CC[C@@]3(C)[C@]4(C)CC[C@@]5(C(O)=O)CC[C@@H](C)[C@H](C)[C@H]5C4=CC[C@@H]3[C@]21C MUCRYNWJQNHDJH-OADIDDRXSA-N 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical compound [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 229940040526 anhydrous sodium acetate Drugs 0.000 description 1
- 239000002518 antifoaming agent Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 229960002903 benzyl benzoate Drugs 0.000 description 1
- YHASWHZGWUONAO-UHFFFAOYSA-N butanoyl butanoate Chemical compound CCCC(=O)OC(=O)CCC YHASWHZGWUONAO-UHFFFAOYSA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 229940124558 contraceptive agent Drugs 0.000 description 1
- 239000003433 contraceptive agent Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000006567 deketalization reaction Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 230000000994 depressogenic effect Effects 0.000 description 1
- 229940120124 dichloroacetate Drugs 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- 235000019797 dipotassium phosphate Nutrition 0.000 description 1
- 229910000396 dipotassium phosphate Inorganic materials 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 229910000397 disodium phosphate Inorganic materials 0.000 description 1
- 235000019800 disodium phosphate Nutrition 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- 229960002568 ethinylestradiol Drugs 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000011790 ferrous sulphate Substances 0.000 description 1
- 235000003891 ferrous sulphate Nutrition 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 230000003152 gestagenic effect Effects 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- DAPZDAPTZFJZTO-UHFFFAOYSA-N heptanoyl heptanoate Chemical compound CCCCCCC(=O)OC(=O)CCCCCC DAPZDAPTZFJZTO-UHFFFAOYSA-N 0.000 description 1
- KDCIHNCMPUBDKT-UHFFFAOYSA-N hexane;propan-2-one Chemical compound CC(C)=O.CCCCCC KDCIHNCMPUBDKT-UHFFFAOYSA-N 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 239000000852 hydrogen donor Substances 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- OUIQXDUPDANAAW-UHFFFAOYSA-N lithium;chloroethyne Chemical compound [Li+].ClC#[C-] OUIQXDUPDANAAW-UHFFFAOYSA-N 0.000 description 1
- ATKCLEUSJFRRKA-UHFFFAOYSA-N lithium;prop-1-yne Chemical compound [Li+].CC#[C-] ATKCLEUSJFRRKA-UHFFFAOYSA-N 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 229910052987 metal hydride Inorganic materials 0.000 description 1
- 150000004681 metal hydrides Chemical class 0.000 description 1
- 238000005555 metalworking Methods 0.000 description 1
- LLCOIQRNSJBFSN-UHFFFAOYSA-N methane;sulfurochloridic acid Chemical compound C.OS(Cl)(=O)=O LLCOIQRNSJBFSN-UHFFFAOYSA-N 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 229940127234 oral contraceptive Drugs 0.000 description 1
- 239000003539 oral contraceptive agent Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 239000000583 progesterone congener Substances 0.000 description 1
- GFCLUZSGMYOHRM-UHFFFAOYSA-N prop-1-yne Chemical class CC#[C-] GFCLUZSGMYOHRM-UHFFFAOYSA-N 0.000 description 1
- OVARTBFNCCXQKS-UHFFFAOYSA-N propan-2-one;hydrate Chemical compound O.CC(C)=O OVARTBFNCCXQKS-UHFFFAOYSA-N 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 229920002545 silicone oil Polymers 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000004317 sodium nitrate Substances 0.000 description 1
- 235000010344 sodium nitrate Nutrition 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000001256 steam distillation Methods 0.000 description 1
- 239000003270 steroid hormone Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- 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
- C07J1/0051—Estrane derivatives
- C07J1/0081—Substituted in position 17 alfa and 17 beta
-
- 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
- C07J1/0051—Estrane derivatives
- C07J1/0081—Substituted in position 17 alfa and 17 beta
- C07J1/0088—Substituted in position 17 alfa and 17 beta the substituent in position 17 alfa being an unsaturated hydrocarbon group
- C07J1/0096—Alkynyl derivatives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J31/00—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring
- C07J31/006—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring not covered by C07J31/003
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
- C07J41/0005—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring the nitrogen atom being directly linked to the cyclopenta(a)hydro phenanthrene skeleton
- C07J41/0016—Oximes
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J51/00—Normal steroids with unmodified cyclopenta(a)hydrophenanthrene skeleton not provided for in groups C07J1/00 - C07J43/00
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
Abstract
Description
Vynález se týká způsobu výroby derivátů estradienu obecného vzorce I,The present invention relates to a process for the production of estradien derivatives of the general formula I,
O/?1 O/? 1
kdewhere
R1 znamená atom vodíku nebo acylovou skupinu se 2 až 11 atomy uhlíku, R2 chlorethinylovou nebo propinylovou skupinu, X atom kyslíku nebo seskupeníR 1 represents a hydrogen atom or an acyl group having 2 to 11 carbon atoms, R 2 a chloroethyl or propynyl group, X an oxygen atom or a moiety
H použitelné ve farmacii. Vyznačují se silnou gestagenní účinností a účinkem potlačujícím ovulaci a nídaci. Vyšší estery sloučenin obecného vzorce I se vyznačují protrahovaným účinkem.H useful in pharmacy. They are characterized by a strong gestagenic effect and an ovulation and depressant effect. The higher esters of the compounds of the formula I are characterized by a protracted action.
Sloučeniny obecného vzorce I mohou být použity například v antikoncepčních preparátech, přičemž se přidávají jako gestagenová složka v kombinaci s estrogenně účinnou složkou, například ethinylestradiolem, nebo se používají jako jediná účinná látka. Nové sloučeniny se však mohou používat též při gynekologických poruchách.The compounds of the formula I can be used, for example, in contraceptives, being added as a gestagen component in combination with an estrogenically active component, for example ethinylestradiol, or used as the sole active compound. However, the novel compounds can also be used in gynecological disorders.
Proi aplikaci se sloučeniny obecného vzorce I zpracovávají s přísadami běžnými v galenické farmacii, nosnými látkami a s látkami ovlivňujícími chuť známými metodami na běžné lékové formy. Pro orální aplikaci přicházejí v úvahu zejména tablety, kapsle, dražé, pilulky, suspense nebo roztoky. Pro parenterální aplikaci přicházejí v úvahu zejména olejové roztoky, například v sesamovém nebo ricinovém oleji, které mohou popřípadě obsahovat ještě zřeďovadlo, například benzy lbenzoan nebo benzylalkohol. Koncentrace účinné látky je závislá na formlě aplikace. Tablety pro orální aplikaci obsahují například 0,01 až 0,5 mg účinné látky a roztoky pro parenterální aplikaci obsahují výhodně 1 až 100 mg účinné látky na 1 ml roztoku.For application, the compounds of formula (I) are formulated with conventional pharmaceutical ingredients, carriers and flavorants by known methods into conventional dosage forms. For oral administration, in particular tablets, capsules, dragees, pills, suspensions or solutions are suitable. For parenteral administration, particularly suitable are oily solutions, for example in sesame or castor oil, which may optionally contain a diluent, for example benzylbenzoate or benzyl alcohol. The concentration of the active ingredient is dependent on the form of application. Tablets for oral administration contain, for example, 0.01 to 0.5 mg of active ingredient and solutions for parenteral administration preferably contain 1 to 100 mg of active ingredient per ml of solution.
OH nebo NOR3, kde R3 značí atom vodíku, acylovou skupinu s 1 až 7 atomy uhlíku nebo methylovou skupinu.OH or NOR 3 , wherein R 3 represents a hydrogen atom, an acyl group having 1 to 7 carbon atoms or a methyl group.
Sloučeniny obecného vzorce I mají cenné vlastnosti steroidních hormonů a jsouThe compounds of formula I possess valuable steroid hormone properties and are
'Dávktíváni léčiv se může měnijxpddlecformý аг účelu áplikace. Nápříkladuderiní' kontraceptivní dáv.ka při orální aplikaci činí 0,01 až 0,5 mg.'Dávktíváni drugs may měnijxpddlecformý а г application purposes. For example, the oral contraceptive dose is 0.01 to 0.5 mg.
Deriváty estradienu obecného vzorce I se podle vynálezu vyrábějí tím způsobem, že se 17-oxoěstren obecného vzorce II,According to the invention, the estradiene derivatives of the general formula (I) are prepared by the process of 17-oxo-ene-terene of the general formula (II),
kdewhere
Y značí oxoskupinu chráněnou výhodně ve formě ketalu a jedna z vazeb.......................v poloze 4,5-, 5,6- nebo 5,10- znamená dvojnou vazbu uhlík—-uhlík a ostatní jednoduché vazby uhlík—uhlík, ichlorethinyluje nebo propinyluje, původně, zavedená ochranná skupina se odštěpí a podle požadovaného ·významu R1 а. X ve výsledném produktu obecného vzorce I se popřípadě 17-hydroxyskupina před nebo po odštěpení ketalové skupiny esterifikuje a/nebo se. 3-ketoskupina redukuje, nebo se uvede v reakci s hydroxylaminovou solí v přítomnosti báze za vzniku 3-0iximu, jenž se popřípadě esterifikuje nebo etherifikuje.Y denotes an oxo group preferably protected in the form of a ketal and one of the bonds in the 4,5-, 5,6- or 5,10 position means a carbon-carbon double bond and the other carbon-carbon single bonds, chloro-ethynyl or propynyl, the initially introduced protecting group is cleaved and, depending on the desired meaning of R 1 а. In the final product of formula (I), optionally the 17-hydroxy group is esterified and / or is esterified before or after cleavage of the ketal group. The 3-keto group is reduced or reacted with a hydroxylamine salt in the presence of a base to give the 3-oxime which is optionally esterified or etherified.
Zavádění chlorethinylové nebo propinylové skupiny se může provádět známými metodami pomocí organokovových sloučenin chlorethinylových nebo propinylových. Takovými organokovQvými sloučeninami jsou například..chloracatylidy, nebo méthylacetylidy alkalických kovů, například čhloracetylid: lithný nebo methylačetylid lithný.The introduction of the chloroethyl or propynyl group can be carried out by known methods using organometallic compounds of chloroethyl or propynyl. Such organometallic compounds are, for example, alkali metal chloroacetylides or methylacetylides, for example lithium chloroacetylide or lithium methylacetylide.
Ořgaňokovové sloučeniny se mohou i též tvořit in šitu, a reagovat se 17-ketonem obecného vzorce II. Tak se může například nechat působit na 17-keton 1,2-dičhlořethylen v přítomnosti etherového roztoku methylllthia nebo.; methylacetylen v prítomnosttibutyllithia v tetřahydrofuranovém roztoku.The organometallic compounds can also be formed in situ and react with the 17-ketone of formula II. Thus, for example, the 17-ketone 1,2-dichloroethylene can be treated in the presence of an ethereal solution of methyl lithium or a methyl ether. methylacetylene in the presence of tibutyllithium in a tetrahydrofuran solution.
,p.ro; případně následující esterif ikaci přicházejí v·.úvahu způsoby používané běžně v. chemii k. esterif ikaci steróidů., p.ro ; optionally, the following esterification is contemplated by methods commonly used in the chemistry of steronide esterification.
Pro estérlfikaci 17-hydroxyskupiny se uvádí například reakce s .kyselinou nebo anhydridem. kyseliny za přítomnosti silné kyseliny, například kyseliny trifluoroctové, pří teplotě , místnosti nebo zvýšené nebo reakce s ánhydřldem kyseliny za přítomnosti terciárního aminu pří teplotě asi 20 až 200 °C.For esterification of the 17-hydroxy group, for example, reaction with an acid or anhydride is mentioned. an acid in the presence of a strong acid, for example trifluoroacetic acid, at room temperature or elevated, or reaction with an acid anhydride in the presence of a tertiary amine at a temperature of about 20 to 200 ° C.
Použijí-li .se, společně pyridin a 4-(dimethylaminpjpyridin jako terciární aminy, může se esterifikace. provádět při teplotě místnosti.When pyridine and 4- (dimethylamino) pyridine are used together as tertiary amines, the esterification can be carried out at room temperature.
. Odštěpení .ochranné, skupiny v poloze 3-, které může probíhat před nebo pp případnfa&sestenífikaci^ se /provádí známými metali daini. Pro RetalovéV štěpení přicházejí v úvahu například minerální kyseliny, jako kyi Tšelina: chTóristá, kyseliny sírová riebó kyse•lina chlorovodíková, nebo organické kyseliny, například kyselina šťavelová. Ketalové štěpení se provádí výhodně v alkoholickém roztoku nebo v jiném polárním rozpouštěůlepinapříklad, v. acetonu,· při teplotě v rozmezí 20 až 100 °C.. The cleavage of the protecting group at the 3-position, which can take place before or after the optional assembly, is carried out by known metalworking. Suitable for the retal cleavage are, for example, mineral acids such as tartaric acid, sulfuric acid or hydrochloric acid, or organic acids, such as oxalic acid. The ketal cleavage is preferably carried out in an alcoholic solution or in another polar solvent such as acetone at a temperature in the range of 20 to 100 ° C.
Redukce může probíhat známým· způsobem hydrogenací kovovým hydridem. Jako donory vodíku se osvědčily zejniénakompleixní 'ihydridy, ! · například hydřidobóritan sodný a lithium-tri-(terc.butoxy Jalumlniuinh hýdrid. Redukce hydridoboritanem sodným se provádí výhodně ve vodně-alkoholickém roztoku a redukce ;ltthium-tri-(terc.butoxy jaluminiumhydridem se provádí v etherovém roztoku. Aby se vyloučila současná redukce dvojné vazby uhlík—uhlík, pracuje se za mírných reakčních podmínek, to znamená; že i redukce /probíhá při teplotách v rozmezí O až 50 °C.The reduction can be carried out in a known manner by hydrogenation with a metal hydride. Especially the most complex hydrides have proved to be hydrogen donors. For example sodium borohydride and lithium tri- (tert-butoxy) aluminum hydride The reduction with sodium borohydride is preferably carried out in an aqueous-alcoholic solution and the reduction; The carbon-carbon double bonds are operated under mild reaction conditions, i.e. the reduction / reaction takes place at temperatures in the range of 0 to 50 ° C.
Reakce 3-ketonu -se solí hydroxylaminu na 3-oxim se provádí v přítomnosti báze, j jako. bázez; jsou/ vhodné například pyridin, kolidin neboi hydrogenuhličitan sodný, octan sodný a hydroxid sodný ve vodně-alkoholickém roztoku. ..Jako .soli hydroxylaminu jsou výhodné hydrochlorid nebo hydrogensíran. Reakce probíhá při teplotě v roz'mézí’'2O;ažr'í50’oC.The reaction of 3-ketone with hydroxylamine salt to 3-oxime is carried out in the presence of a base such as. a base of ; for example, pyridine, collidine or sodium bicarbonate, sodium acetate and sodium hydroxide in an aqueous-alcoholic solution are suitable. Hydrochloride or hydrogen sulphate are preferred as hydroxylamine salts. The reaction is carried out at a temperature in the range of 20 ° C ; to R i50 'o C.
3-0xlm se může esterifikovat nebo etherifikovat pomocí běžných metod. Esterifikace probíhá například pomocí požadované.kyseliny, popřípadě, jejího halogenidů nebo anhydridu v přítomnosti terciárního aminu, například pyridinu nebo kolidinu, při teplotě místnosti. Jako terciární amin je též vhodný 44 dimethylamino) pyridin v pyridinu.3-0xlm can be esterified or etherified using conventional methods. The esterification takes place, for example, with the desired acid or its halides or anhydrides in the presence of a tertiary amine, for example pyridine or collidine, at room temperature. Also suitable as a tertiary amine is 44 dimethylamino) pyridine in pyridine.
Etherifikacé 3.-oximu· alkylovou skupinou se výhodně provádí: příslušným alkylhalogenidem v přítomnosti silné zásady, například hydroxidu sodného, a v přítomnosti polárního rozpouštědla; například hexamethyltriamidu kysbllny fosforečné, při teplotě v rozmezí 0 až 30 °C, nebo v přítomnosti silné zásady, například hydridu sodného, v přítomnosti etheru, například tetrahydrofuranu, nebo, polárního rozpouštědla,..například diměthylšúlfoxidu, při teplotě v .rozmezí 30 až ÍOO OC. Ethérifikacě 3-oxim,u je také možná diazóálkanem, zejména diazomethanem.The 3-oxime etherification with the alkyl group is preferably carried out by: an appropriate alkyl halide in the presence of a strong base, for example sodium hydroxide, and in the presence of a polar solvent; for example hexamethylphosphoric triamide, at a temperature in the range of 0 to 30 ° C, or in the presence of a strong base such as sodium hydride in the presence of an ether such as tetrahydrofuran or a polar solvent such as dimethylsulfoxide at a temperature of 30 to 100. C. the etherification of the 3-oxime is also possible with a diazoalkane, especially diazomethane.
Příprava 17-oxosteroidů obecného vzorce II používaných jako výchozích produktů je popsána v následujících příkladech:The preparation of 17-oxosteroids of formula II used as starting products is described in the following examples:
A. 15a-Hydroxy-18-methyl-4-eštren-3,17-dionA. 15α-Hydroxy-18-methyl-4-estene-3,17-dione
Erlenmeyerová baňka o objemu 500 ml, obsahující 500 ml živného .roztoku složeného z' 3,Q . glukózy, .1,0 % kukuřičného extraktu, 0,2 % dusičnanu sodného, 0,1 °/o díhydrogénfósforéčnanu - - doašelného,' ' - 0,2 % hydrogéníOsforečnanu·' - draselného, 0,05 % ' síranů - 'horečnatého, '0,002 - % 'síranů ' železnatého· a - 0,05 % ' chloridu draselného a ' sterílísovahého: -- po ' dobu - 30 - minut ' v . autoklávu pří - teplotě 120- ' °C, se ' zaočkuje - kulturou - Penicillium raistríckií (ATCC 10 490) a třepe se v rotační ' třepačce po dobu 72' hodín pří teplotě 30 °C. Dvaceeiíitrový feomentoo naplněný 15 lítry média o stejném složení, které bylo sterílisováno pří teplotě 121 °C a tlaku 0,11 'MPa, - - se ' zaočkuje '250 - ml kultury připravené výše uvedeným postupem. Za přídavku silikonového odpěňovadla se kultivuje ' při ' teplotě 29 - °C - 'za poovzdušňování (10 ' litrů ' ' za' - minutu), ' tlaku ' 70 kPa a míchání (;220' ' otáček ' 'za minutu) ' po ' dobu 24 hbdín; 1,8 - litru ' - kultivační - břečky se - za sterilních ' podmínek ' ' převede ' ' do' - 26' litrů výše uvedeného - sterilizovaného' ' živného roztoku· á- - kultivuje - se . - za' stejných - ' podmínek. ' Po '-12 ' hodinách se ' přidají 2 litry - jemné - 'suspense' Ί20 g 18-methyl-4-estren-3,17-dionu v ' 'destilované - vodě 'za . přídavku - smáčédla á ' kultivuje - se' - dále.500 ml Erlenmeyer flask containing 500 ml of a nutrient solution composed of 3.0 ml. glucose, 1.0% corn extract, 0.2% sodium nitrate, 0.1% sodium phosphate dibasic, tertiary, 0.2% potassium hydrogenphosphate, 0.05% magnesium sulfate. , '0,002 -%' of ferrous sulphate 'and - 0,05%' of potassium chloride and 'sterile': - 'for - 30 - minutes' in. of an autoclave at a temperature of 120 ° C, inoculated with a culture of Penicillium raistrici (ATCC 10 490) and shake in a rotary shaker for 72 hours at 30 ° C. A two liter flask filled with 15 liters of medium of the same composition, which was sterilized at 121 ° C and 0.11 MPa, was seeded with 250 ml of culture prepared as described above. With the addition of silicone antifoam was cultivated 'at' a temperature of 29 - C - 'for poovzdušňování (10' L 'for' - minute), "pressure" of 70 mbar and stirring (; 220 'turns' per minute)' after 24 hours; The 1.8 liter culture slurry is transferred under sterile conditions to 26 liter liters of the above-sterilized nutrient solution and cultured. - under the same conditions. After 12 hours, 2 liters of fine suspension of g20 g of 18-methyl-4-estrene-3,17-dione in distilled water are added. the addition of a wetting agent and 'cultivates' further.
Průběh ' se ' sleduje - pomocí chromatografie na' - ' tenké : ' vrstvě ' - methylisobutylketonového extraktu ' vzorků z fermentoru. - Asi ' - po - 70 hodinách ' 'doby -' styku' - je ' konverze . úplná. Nyní se mycelium - 'odfiltruje ' a . - kultivační břečka se extrahuje dvakrát, po' 20 · litrech methylisobutylketonu. Současně se odfiltrované mycelium několikrát ' promísí . se směsí methylisobutylketonu, acetonu a vody a ..extrahuje - 'až' - není - prokazatelná žádná steroldní látka.Progress 'is' monitored - by chromatography on '-' thin 'layer' - methyl isobutyl ketone extract of sample from the fermentor. - About - after - 70 hours of 'contact time' - is 'conversion'. complete. Now the mycelium - 'filtered' a. - the culture broth is extracted twice, after 20 liters of methyl isobutyl ketone. At the same time, the filtered mycelium is mixed several times. with a mixture of methyl isobutyl ketone, acetone and water, and no sterile substance is detectable.
Organické extrakční roztoky se spojí a ve vakuu -- odpaří k suchu 'při teplotě lázně - 50 stupňů Celsia. - Zbylé hnědé.· krystalky - se několikrát 'promyjí ' hexanem ' k - - odstranění ' silikonového' -' oleje, '-vysuší - a ' nakonec se po zpracování - aktivním uhlím - - překrystalují z ethylačetátu,' - přičemž se - získá 97,5 g (76,5 proč, ' - -' teorie) - čistého : 15a-hydroxy-18-methyl-4-estrcn-3,l·7-diΌnů s - teplotou; .. tání ' 175 až 177 °C.The organic extraction solutions were combined and evaporated to dryness under vacuum at a bath temperature of 50 degrees Celsius. The residual brown crystals are washed several times with hexane to remove silicone oil, dried, and finally, after treatment with activated carbon, recrystallize from ethyl acetate, recovering 97.5 g (76.5 why, " - " of theory) - pure: 15? -Hydroxy-18-methyl-4-estrone-3,1,7-dione with - temperature; mp 175-177 ° C.
B.15a-Hydroox-18-meehyl-3,3-(2',2'-diméehyl-r,3'-.propylendioxy )-5-estren-17-on a -5(10j-ešel^re^-1^7-on g 15α-hydroxy-18-meC]Уyl-4-cstгen13,17-dio.nu se míchá ve 150 ml methylench-loridu a 40 ml trictУdlcstcrů kyseliny mravenčí se 60 g 2,2-dimeehyl-l,3-propa.ndiolu a 200' 'mg kyseliny p-toluensulfonové po dobu 20 hodin při teplotě - místnosti.' Roztok se zředí ethylacetátem, neutralizuje roztokem - - hydrogenuhličitanu sodného a promyje vodou. Potom ' ' se -- roztok - vysuší síranem ' ' sodným' a zahustí' ve vakuu. ' Surový produkt se cňromatogгafujc na - ' silikagelu gradientem - aceton—hexan ' (0 až '' '20 ' - % acetonu); '20% acetonem, se eluuje 10,0 g -15a-hydro^x^y-^S,-- (2’,2·-dimeChy-lT,3·-propylcn)dioXy)-18-methyl-5-estren-17-onu - s ' teplotou ' tání ' '206 'až - 209 °C. ' Dále se ' získá 15' g olejóvité směsi ' 15α-hydooxy-18-methdl-3i3- (2’',2'-di.rňbtthyll’',3'-propylendi.oxy) -5-estreh,-17-onu a - -5(10)estren-17-onu.B.15a-Hydroox-18-methyl-3,3- (2 ', 2'-dimethyl-1,3' - propylenedioxy) -5-estren-17-one and -5 (10'-bis-methyl) - 15-Hydroxy-18-methyl-4-styrene-13,17-dione is stirred in 150 ml of methylene chloride and 40 ml of formic acid triethyl chloride with 60 g of 2,2-dimethyl-1-carboxylic acid. 3-propanediol and 200 mg of p-toluenesulfonic acid for 20 hours at room temperature The solution was diluted with ethyl acetate, neutralized with sodium bicarbonate solution and washed with water, then the solution was dried over sulfate. The crude product is chromatographed on silica gel with an acetone-hexane gradient (0 to 20% acetone), 20% acetone eluting with 10.0 g -15a. - (2 ', 2'-Dimethyl-1', 3'-propylcyclohexyl) -18-methyl-5-estren-17-one - with 'melting point' 206 DEG-209 DEG. 'Further' afforded 15 'g of an oily mixture' hydooxy 15α-18-methdl-3 and 3- (2 ', 2'-di.rňbtthyll', 3'-propylendi.oxy) -5-estreh - 17-one and -5 (10) estren-17-one.
.C. .l·5α-Meey-ooχ-11-meChy--3,3-(2’,2’-dimethyl-,l’,3’-.poppdlendioxd. ) -З^-оп-^-on a.-5( 10) -estrcn-17-on g ' 15α-hydroxy118-me-hyl-3,3-(2’,2’-dime-hyllΓ,3’’propylendioxy) -5,-estren-17-onu a^ -5(10)-cst'rcn-17-onu - - se- za -' chlazení ledem smísí s 27,1 ml - - methansulfochlóridu a poté míchá po dobu 3 hodin při teplotě ledové lázně. Potom se reakční směs vmísí do směsi ledu a vody, sraženina se odsaje· a- promyje - vbdou. Poté 'se' - -vyjme do methylenchloridu a - vysuší. Získá - - se - -' směs (40 g), sestávající z 15a-mesyloxy-18-methyl-3,3- (2’,2’)dimethyl-Γí3’-propyleňdioxd)-51cst-cn-l·7-onιг ' a - ' 5 (10 )-estoen-17-onu ve -formě oleje..C. .alpha.-5α-Meey-ooχ-11-methyl-3,3- (2 ', 2 ' -dimethyl-, 1 ', 3 ' 5 (10) -estren-17-one g '15α-hydroxy-118-methyl-3,3- (2', 2'-dimethyl-3 ', 3'-propylenedioxy) -5, -estren-17-one; and The -5- (10) -piperidin-17-one was treated with 27.1 ml of methanesulfochloride under ice cooling and then stirred for 3 hours at an ice bath temperature. The reaction mixture is then mixed into ice-water, the precipitate is filtered off with suction and washed. It is then taken up in methylene chloride and dried. A mixture (40 g) consisting of 15α-mesyloxy-18-methyl-3,3- (2 ', 2') dimethyl-33'-propylenedioxide) -51cst-cn-1 · 7 - was obtained. and 5 '(10) -estoen-17-one in the form of an oil.
D. ' '18-M eChyl-3,3-(2’,2’-dime-hy--l’,·3’-po01 pylendioxyj)-5,15-estoadieň-17-on a - -5(10), 15iestťadien-17-on : 35 g l5α-mesyloxy'-18'·metňdl-3,3--' (2’,2’)dimé-hy-lΓ,3’-propyiendioxy) ---estoen-n-onu - - a- ' -5(10 )-estren-'17-oi'iu- - se: -- míchá' . -. ve 350 ' ml ' - dimctУylformαmidu- se ' 105 g bezvodého octanu -' sod-ňého-po ' dobu '20 - .hodin při teplotě místnosti. Poté= -se reakční - .'směs vmísí do ledu a vody a vzniklá ' sraženina odsaje. Sraženina se promyje vodou a vyjme do methylenchloridu. Po' odpaření rozpouštědla se· získá ' 28,9 g - surového 18- -- methdl-3,3-(2’,2’-dime-hyl'-Γ,3’-poopylcndioxd)) )5,15-estradien)17-onu a -5(10),15-estoadien-17-onu.D. '18-Methyl-3,3- (2', 2'-dimethyl-1 ', 3'-poly-1-ethylenedioxy) -5,15-estoadien-17-one and -5 ( 10), 15 and estťadien-17-one 35 g l5α-mesyloxy'-18 '· metňdl-3,3--' (2 ', 2') diMeO-hydroxy-lΓ, 3'-propyiendioxy) --- estoen-n-one -? -? - (5) (10) -estren-17-ol - is stirred. -. in 350 ml of dimethylformamide with 105 g of anhydrous sodium acetate for 20 hours at room temperature. The reaction mixture is then added to ice and water and the precipitate formed is filtered off with suction. The precipitate was washed with water and taken up in methylene chloride. Evaporation of the solvent gave 28.9 g of crude 18-methyl-3,3- (2 ', 2'-dimethyl'-Γ, 3'-propylindioxide)) 5,15-estradien 17-one and -5 (10), 15-estoadien-17-one.
Způsob výroby - derivátů ' est-adienu - - podle vynálezů jé - ' blíže objasněn - v následujících příkladech' ' provedení:The process for the preparation of the est-adiene derivatives according to the invention is explained in more detail in the following examples:
Př í k1 a d 1Example 1 and d 1
17a-C hlorěthínyM17ι3-hydroxy-18-methyl) ^IS-estradien-U-on17a-C hlorethines (17β-hydroxy-18-methyl) -I-estradien-U-one
K '2,3 ml 1,2-dichloocthdlcnu . ve 40 ml absolutního '' .etheru . ' se ' přidá ' < pod . ochrannou atmosférou argonu a při teplotě .' místnosti ' 32 ml 2 M roztoku (etherového) methyl· lithia. Po 30 minutách se přikape ' 2,0 ' g 18-methdl-3,3-(2’,2’)dime-hy--Γ,3’-propdlendioxy)-5,15-estradieIl.-17-onu a. -5(10)-,15-estoadien-17-onu v 70 . ' ml. .' tetraУydгofuranu a reakční směs se míchá po dobu 1,5 hodiny ' při. ' teplotě' ' 60 · C. Po' ' ochlazení se roztok ''opatrně smísí ^^-τ-ιιΙιιι roztokem chloridu ' amonného- ' a ' zředí . .se etherem. Potom se - ' roztok - promyje vodou . a vysuší síranem ' sodným. ' Surový ' - produkt se - chromatogoafuje - - na - silikagelu - směsí . aceton/hexan. Získá ' se - 1,2 - g - 17ατChlorβthi·nyl·3j3-(2’,2’1 -dimё-hyl-Γ,3’-poopylcndioxy)-18-metУyl) -5,15-estradien-17lЗ)01u a - 15(.10),15-cstoadien-17J-olu, -' - které - .se- míchají v .. 10- -. ml ethylal'koňolu - a . 1 - . ml - -vody -se -400- g- kyselí203913 ny šťavelové po dobu 4 hodin při teplotě 65 °C. Roztok se neutralizuje roztokem hydrogenuhličitanu sodného a ve vakuu se zahustí. Zbytek se rozpustí v ethylacetátu, promyje vodou a vysuší síranem sodným. Poi čištění preparativní chromatografií na vrstvě (soustava ether/chloroform — 8:2) a rekrystalizaci ze směsi aceton/hexan se získá 170 mg 17a-chlorethinyl-17p-hydroxy-18-méthyl-4,15'estradien-3-onu. Teplota tání 153 až 154 °C.To 2.3 ml of 1,2-dichloroacetate. in 40 ml of absolute ether. 'add'<below. protective atmosphere of argon at temperature. 32 ml of a 2M solution of (ether) methyl lithium. After 30 minutes, 18-methyl-3,3- (2 ', 2') dimethyl-d, 3'-propenedenedioxy) -5,15-estradiol-17-one was added dropwise and -5 (10) -, 15-estoadien-17-one in the 1970s. 'ml. . ' of tetrahydrofuran and the reaction mixture is stirred for 1.5 hours at room temperature. After cooling, the solution is carefully mixed with an ammonium chloride solution and diluted. .with ether. The solution is then washed with water. and dried over sodium sulfate. The 'crude' product is - chromatographed - on silica gel with a mixture. acetone / hexane. Obtained 'was - 1.2 - G - 17ατChlorβthi phenyl · 3 · j 3- (2', 2'1-ethyl--dimё Γ, 3'-poopylcndioxy) -18-metУyl) -5,15-diene-17 З l) and 01U - 15 (.10) 15 cstoadien-17J-ol, - '- which - .se- stirred at 10- .. -. ml of ethyl alcohol - a. 1 -. ml - water - is -400 g of acidic oxalic acid for 4 hours at 65 ° C. The solution was neutralized with sodium bicarbonate solution and concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with water and dried over sodium sulfate. Purification by preparative layer chromatography (ether / chloroform - 8: 2) and recrystallization from acetone / hexane gave 170 mg of 17α-chloroethyl-17β-hydroxy-18-methyl-4,15'-estradien-3-one. Mp 153-154 ° C.
Příklad 2Example 2
17|0-Acetoxy-17a-chloethinyl-18-methyl-4,15-estradien-3-on17β-Acetoxy-17α-chloethinyl-18-methyl-4,15-estradien-3-one
1,0 g 17a-chlorethinyl-17/S-hydroxy-18-methyl-4,15-estradien-3-onu se míchá v 10 ml pyridinu s 5 ml acetanhydridu a 50 mg1.0 g of 17α-chloroethynyl-17 / S-hydroxy-18-methyl-4,15-estradien-3-one is stirred in 10 ml of pyridine with 5 ml of acetic anhydride and 50 mg.
4-(dimethylamino)pyridinu po dobu 4 hodin pod dusíkovou atmosférou při teplotě místnosti. Roztok se poté vlije do směsi ledu a vody obsahující kyselinu sírovou. Vysrážený produkt se odsaje, rozpustí v methylenchloridu, promyje vodou a vysuší síranem sodným. Po chromatografování surového produktu na silikagelu směsí aceton/hexan se získá 760 mg 17/J-acetoxy-17a-chlorethinyl-18-methyl-4,15-estradien-3-onu. Teplota tání — 122 °C.Of 4- (dimethylamino) pyridine for 4 hours under a nitrogen atmosphere at room temperature. The solution is then poured into a mixture of ice and water containing sulfuric acid. The precipitated product is filtered off with suction, dissolved in methylene chloride, washed with water and dried over sodium sulfate. Chromatography of the crude product on silica gel with acetone / hexane yields 760 mg of 17.alpha.-acetoxy-17.alpha.-chloroethyl-18-methyl-4,15-estradien-3-one. Melting point - 122 ° C.
Příklad 3Example 3
17/?-Butyryloxy-17a-chlorethinyl-18-methyl-4,15-estradien-3-on17.beta.-Butyryloxy-17.alpha.-chloroethyl-18-methyl-4,15-estradien-3-one
400 mg 17a-chlorethinyl-17í3-hydroxy-18-methyl-4,15-estradien-3-onu ve 4 ml pyridinu a 2 ml anhydridu kyseliny máselné a 20 mg 4-(dimethylamino) pyridinu se míchá při teplotě místnosti po dobu 8 hodin. Reakční produkt se vlije do směsi ledu a vody obsahující kyselinu sírovou a zpracuje se dále analogicky jako v příkladu 2. Po chromatografování surového produktu na silikagelu směsí aceton/hexan se získá 220 mg 17l/3-butyryloixy-17a-chlorethinyl-18-methyl-4,15-estradien-3-onu ve formě olejovité látky.400 mg of 17.alpha.-chlorethinyl 17 g 3-hydroxy-18-methyl-4,15-diene-3-one in 4 ml of pyridine and 2 ml of butyric anhydride and 20 mg of 4- (dimethylamino) pyridine was stirred at room temperature for 8 hours. The reaction product was poured into ice-water containing sulfuric acid and worked up in analogy to Example 2. Chromatography of the crude product on silica gel with acetone / hexane gave 220 mg of 17 L / 3-butyryloix-17α-chloroethyl-18-methyl -4,15-estradien-3-one as an oily substance.
Příklad 4Example 4
17a-Chlorethinyl-18-methyl-17:/3-undekanoyloxy-4,15-estradien-3-on17α-Chloroethyl-18-methyl-17: β-undecanoyloxy-4,15-estradien-3-one
Z roztoku 3,5 g kyseliny nudecylové ve 300 ml benzenu se oddestiluje 70 ml. Po ochlazení na teplotu místnosti se smísí se 4 ml anhydridu kyseliny trifluoroctové. Po 30 minutách se přidá 3,2 g 17a-chlorethinyl-17,/3-hydroxy-18-methyl-4,15-estradlen-3-onu. Reakční směs se míchá po dobu 2,5 hodiny. Za chlazení ledem se přidá 50 ml směsi aceton voda (1 : 1), směs se míchá po dobu 30 minut a nakonec se zahustí ve vakuu. Zbytek se vyjme do methylenchlori du, promyje roztokem hydrogenuhličitanu sodného a vodou a nakonec se vysuší síranem sodným. Surový produkt se chromatografuje na silikagelu. Získá se 1,1 g 17a-chlorethinyl-18-methyl-17/3-undekanoyloxy-4,15-estradien-3-onu ve formě olejovité látky.70 ml is distilled from a solution of 3.5 g of nudecylic acid in 300 ml of benzene. After cooling to room temperature, 4 ml of trifluoroacetic anhydride are added. After 30 minutes, 3.2 g of 17α-chloroethynyl-17β-hydroxy-18-methyl-4,15-estradlen-3-one is added. The reaction mixture was stirred for 2.5 hours. 50 ml of acetone water (1: 1) are added under ice-cooling, the mixture is stirred for 30 minutes and finally concentrated in vacuo. The residue was taken up in methylene chloride, washed with sodium bicarbonate solution and water and finally dried over sodium sulfate. The crude product is chromatographed on silica gel. 1.1 g of 17α-chloroethynyl-18-methyl-17β-undecanoyloxy-4,15-estradien-3-one is obtained as an oil.
UV (methanol): гиэ = 17 900.UV (methanol): γ = 17,900.
Příklad 5Example 5
17ar-Chlorethinyl-18-methyl-4,15-estradien-3$-17|/3-diol17α-Chloroethynyl-18-methyl-4,15-estradien-3 $ -17 / 3-diol
К 1,2 g 17a-chlorethinyl-171S-hydroxy-18-methyl-4,15-estradien-3-onu ve 30 ml tetrahydrofuranu se přidá pozvolna roztok 3,0 g lithium-tri-(terc.butoxy)-aluminiumhydridu ve 25 ml tetrahydrofuranu a reakční směs se míchá po dobu jedné hodiny při teplotě místnosti pod dusíkovou atmosférou. Potom se roztok vlije do směsi ledu a vody obsahující kyselinu síroivou. Vysrážený produkt se odfiltruje, rozpustí v ethylacetátu, promyje vodou a vysuší síranem sodným. Po chromatografování surového produktu na silikagelu směsí aceton/hexan se získá 380 mg 17a-chlorethinyl-18-methyl-4,15-estradien-3jS,17/J-diolu ve formě pěnovitého produktu.To 1.2 g of 17α-chloroethynyl-17 1 S-hydroxy-18-methyl-4,15-estradien-3-one in 30 ml of tetrahydrofuran is added slowly a solution of 3.0 g of lithium tri- (tert-butoxy) - of aluminum hydride in 25 ml of tetrahydrofuran and the reaction mixture was stirred for one hour at room temperature under a nitrogen atmosphere. The solution is then poured into a mixture of ice and water containing sulfuric acid. The precipitated product is filtered off, dissolved in ethyl acetate, washed with water and dried over sodium sulfate. Chromatography of the crude product on silica gel with acetone / hexane gave 380 mg of 17α-chloroethynyl-18-methyl-4,15-estradien-3,15,17-diol as a foamy product.
[ia]Dzo = —109,8 °C. [I] = D of -109.8 ° C.
Příklad 6Example 6
17i/J-Acetoxy-17a-chlorethinyl-18-methyl-4,15-estradien-3$-ol17i / J-Acetoxy-17α-chloroethyl-18-methyl-4,15-estradien-3-ol
900 mg· 17/3-acetoxy-17ce-ethinyl-18-methyl-4,15-estradlen-3-onu ve 25 ml tetrahydrofuranu se nechá reagovat se 2,3 g llthium-tri- (terc.butoxy) aluminiumhy dridu ve 20 ml tetrahydrofuranu stejně jak je popsáno v příkladu 5. Po jedné hodině se roztok vlije do směsi ledu a vody obsahující kyselinu sírovou a zpracuje se analogicky jak je popsáno v příkladu 5. Po čištění surového produktu preparativní chromatografií na vrstvě (soustava ether/chloroform — 8 : 2) se získá 410 mg 17/J-acetoixy-17a-chlorethinyl-18-methyl-4,15-estradien-3i/J-Oilu.900 mg of 17β-acetoxy-17α-ethynyl-18-methyl-4,15-estradlen-3-one in 25 ml of tetrahydrofuran is treated with 2.3 g of lithium tri- (tert-butoxy) aluminum hydride in 20 ml of tetrahydrofuran as described in Example 5. After one hour, the solution is poured into a mixture of ice and water containing sulfuric acid and worked up analogously to Example 5. After purification of the crude product by preparative layer chromatography (ether / chloroform - 8: 2) 410 mg of 17.alpha.-acetoxy-17.alpha.-chloroethyl-18-methyl-4,15-estradien-3.alpha.-J-Oil is obtained.
Teplota tání 103 až 108 °C.Melting point 103-108 ° C.
Příklad 7Example 7
17a-Chlorethinyl-18-methyl-3-oximino-4,15-estradien-17i/J-ol17α-Chloroetinyl-18-methyl-3-oximino-4,15-estradien-17i / J-ol
К 2,3 g 17a-chlorethinyl-17/S-hydroxy-18-methyl-4,15-estradien-3-onu v 60 ml methylalkoholu a 2 ml vody se přidá 1,0 g hydrochloridu hydroxylaminu a 1,0 g hydrogenuhličítanu sodného. Reakční směs se míchá po dobu 3 hodin při teplotě 65 °C a poté ve vakuu zahustí. Zbytek se vyjme do ethylacetátu, promyje vodou a vysuší síranem sodným. Po chromatografování suro203913 vého produktu na silikagelu směsí aceton/hexan se získá 1,4 g 17a-chlorethinyl-18-methyl-3-oximino-4,15-estradien-17/3-olu ve formě pěnovitého produktu.To 2.3 g of 17α-chloroethynyl-17 / S-hydroxy-18-methyl-4,15-estradien-3-one in 60 ml of methanol and 2 ml of water add 1.0 g of hydroxylamine hydrochloride and 1.0 g of bicarbonate sodium. The reaction mixture was stirred for 3 hours at 65 ° C and then concentrated in vacuo. The residue was taken up in ethyl acetate, washed with water and dried over sodium sulfate. Chromatography of the crude product on silica gel with acetone / hexane gave 1.4 g of 17α-chloroethyl-18-methyl-3-oximino-4,15-estradien-17/3-ol as a foam.
UV (methanol): ε24ΐ = 21 800.UV (methanol): ε24ΐ = 21,800.
Příklad 8 íyjS-Acetoxy-iyjS-chlorethmyl-ie-methyl-4,15-estradien-3-onoximEXAMPLE 8 β-Acetoxy-γ-S-chloroethyl-1-methyl-4,15-estradien-3-one oxime
1,2 g 17^-acetoxy-17a-chlorethinyl-18-methyl-4,15-estradien-3-onu ve 35 ml methylalkoholu a 1,2 ml vody se nechá reagovat stejně jak je popsáno v příkladu 7, se 600 mg hydrochloridu hydroxylaminu a 700 mg hydrogenuhličitanu sodného. Po jedné hodině se reakční směs zpracuje analogicky jako v příkladu 7. Po chromatografování surového produktu na silikagelu směsí aceton/hexan se získá 750 mg 17|j3-acetoxy-17a-chlorethinyl-18-methyl-4,15-estradien-3-onoximu ve formě pěnovitého produktu. UV (imethanol): s240 — 20 900.1.2 g of 17.beta.-acetoxy-17.alpha.-chloroethyl-18-methyl-4,15-estradien-3-one in 35 ml of methanol and 1.2 ml of water were reacted as described in Example 7 with 600 mg. hydroxylamine hydrochloride and 700 mg of sodium bicarbonate. After one hour, the reaction mixture was worked up analogously to Example 7. After chromatography of the crude product on silica gel with acetone / hexane, 750 mg of 17β-acetoxy-17α-chloroethyl-18-methyl-4,15-estradien-3-onoxime was obtained. in the form of a foamed product. UV (imethanol): s240-20900.
Příklad 9Example 9
17a-Chlorethinyl-3-heptanoyloximino-18-methyl-4,15-estradien-i17./í-ol17a-Chlorethinyl heptanoyloximino-3-18-methyl-4,15-estradien- i 17./í-ol
850 m!g 17a-chlorethinyl-18-methyl-3-oximino-4,15-estradien-17/S-olu se míchá v 6 ml pyridinu se 3,5 ml anhydridu kyseliny enanthové po dobu 3 hodin při teplotě místnosti. Roztok se zředí benzenem a podrobí destilaci vodní párou. Reakční produkt se z vodného destilačního zbytku extrahuje methylenchloridem. Po chromatografování surového produktu na silikagelu směsí aceton/hexan se získá 210 mg 17 a-chlorethinyl-3-heptanoyloximino-18-methyl-4,15-estradien-17/Í-olu ve formě olejovité látky.850 µg of 17α-chloroethynyl-18-methyl-3-oximino-4,15-estradien-17 / S-ol is stirred in 6 ml of pyridine with 3.5 ml of enanthic anhydride for 3 hours at room temperature. The solution is diluted with benzene and subjected to steam distillation. The reaction product was extracted from the aqueous distillation residue with methylene chloride. Chromatography of the crude product on silica gel with acetone / hexane afforded 210 mg of 17? -Chloroetinyl-3-heptanoyloximino-18-methyl-4,15-estradien-17H-ol as an oil.
UV (methanol): ε243 = 20 800.UV (methanol): ε243 = 20,800.
Příklad 10Example 10
17a-Chlorethinyl-3-methoximino-18-methy l-4,15-estradien-17/3-ol17α-Chloroetinyl-3-methoximino-18-methyl-4,15-estradien-17/3-ol
2,6 g 17ia-chIorethinyl-18-methyl-3-oximino-4,15-estradien-17/3-olu v 50 ml triamidu kyseliny hexamethylfosforečné se za chlazení ledem a přívodu dusíku smísí se 2 ml 25% roztoku hydroxidu sodného a 5 ml fflethyljodidu. Po jedné hodině se tento roztok vlije do směsi ledu a vody, obsahující kyselinu chlorovodíkovou. Extrahuje se etherem, roztok se promyje vodou a vysuší síranem sodným. Surový produkt se chromatografuje na silikagelu směsí aceton/hexan. Získá se 510 mg 17a-chlorethinyl-3-methoximino-18-methyl-4,15-estradien-17/3-olu ve formě olejovité látky. UV (methanol): ε249 = 22 000.2.6 g of 17α-chloroethynyl-18-methyl-3-oximino-4,15-estradien-17/3-ol in 50 ml of hexamethylphosphoric triamide are mixed with 2 ml of 25% sodium hydroxide solution under ice-cooling and nitrogen inlet; 5 ml of ethyl iodide. After one hour, the solution was poured into a mixture of ice and water containing hydrochloric acid. Extract with ether, wash the solution with water and dry over sodium sulfate. The crude product is chromatographed on silica gel with acetone / hexane. 510 mg of 17α-chloroethynyl-3-methoximino-18-methyl-4,15-estradien-17/3-ol are obtained as an oil. UV (methanol): ε249 = 22,000.
Příklad 11Example 11
17/?-Hydroxy-18-methyl-17a-propin-l-yl-4,15-estradien-3-on17β-Hydroxy-18-methyl-17α-propyn-1-yl-4,15-estradien-3-one
Do roztoku 60 ml butyllithia (15% v hexanu) ve 220 ml tetrahydrofuranu, chlazeného směsí ledu a vody, se zavádí methylacetylen po dobu 30 minut. Potom se za míchání přikape 3,8 g 18-methyl-3,3-(2’,2’-dimethyl-l’,3’-propylendioxy) -5,15-estradien-'17-onu a -5(10),15-estradien-17-onu v 60 ml tetrahydrofuranu. Po dvou hodinách se roztok opatrně smísí s nasyceným roztokem chloridu amonného,t zředí ethylacetátem, promyje vodou a vysuší síranem sodným. Roztok se ve vakuu zahustí к suchu, přičemž se získá 4,6 g surového 18-methyl-3,3-(2’,2’-dimethyl-l’,3’-propylendioxy)-17a-propin-l-yl-5,15-estradien-17j3-olu a -5(10),15-estradien-17-olu, který se suspenduje v 50 ml acetonu, a při teplotě místnosti se smísí s 0,1 ml koncentrované kyseliny chlorovodíkové. Po jedné hodině se reakční směs vlije do směsi ledu a vody. Vysrážený produkt se odsaje, rozpustí v ethylacetátu a vysuší síranem sodným. Surový produkt se chromatografuje na silikagelu směsí aceton/hexan. Získá se 1,8 g 17i/3-hydroxy-18-methyl-17a-propin-l-yl-4,15-estradien-3-onu ve formě olejovité látky.Methylacetylene was added to a solution of 60 ml of butyllithium (15% in hexane) in 220 ml of tetrahydrofuran, cooled with a mixture of ice and water, for 30 minutes. Then 3.8 g of 18-methyl-3,3- (2 ', 2'-dimethyl-1', 3'-propylenedioxy) -5,15-estradien-17-one and -5 (10) are added dropwise with stirring. 15-estradien-17-one in 60 ml tetrahydrofuran. After two hours the solution was carefully treated with saturated ammonium chloride solution, diluted with ethyl acetate t, washed with water and dried over sodium sulfate. The solution was concentrated to dryness in vacuo to give 4.6 g of crude 18-methyl-3,3- (2 ', 2'-dimethyl-1', 3'-propylenedioxy) -17α-propyn-1-yl- 5,15-estradien-17β-ol and -5 (10), 15-estradien-17-ol, which is suspended in 50 mL of acetone and treated at room temperature with 0.1 mL of concentrated hydrochloric acid. After one hour, the reaction mixture was poured into ice-water. The precipitated product is filtered off with suction, dissolved in ethyl acetate and dried over sodium sulfate. The crude product is chromatographed on silica gel with acetone / hexane. 1.8 g of 17β / 3-hydroxy-18-methyl-17α-propyn-1-yl-4,15-estradien-3-one is obtained as an oil.
UV (methanol): εζ40 = 17 300.UV (methanol): εζ40 = 17,300.
Příklad 12Example 12
17^-Acetoxy-18-methyl-17a-propin-l-yl-4,15-estradien-3-on17β-Acetoxy-18-methyl-17α-propyn-1-yl-4,15-estradien-3-one
250 mg 17j3-hydroxy-18-methyl-17a-propin.-l-yl-4,15-estradien-3-onu ve 2,5 ml pyridinu se míchá s 1 ml acetanhydridu a 10 mg 4-(dimethylamino) pyridinu po dobu 2 hodin při teplotě místnosti a pod dusíkovou atmosférou. Po analogickém zpracování jako v příkladu 2 a chromatografování surového produktu na silikagelu směsí acetOn/hexan se získá 110 mg 17^-acetoxy-18-methyl-17a-propin-l-yl-4,15-estradien-3-onu ve formě olejovité látky. UV (methanol): ейзэ = 17 300.250 mg of 17β-hydroxy-18-methyl-17α-propyn-1-yl-4,15-estradien-3-one in 2.5 ml of pyridine are stirred with 1 ml of acetic anhydride and 10 mg of 4- (dimethylamino) pyridine after for 2 hours at room temperature and under a nitrogen atmosphere. After working up analogously to Example 2 and chromatographing the crude product on silica gel with acetone / hexane, 110 mg of 17.beta.-acetoxy-18-methyl-17.alpha.-propyn-1-yl-4,15-estradien-3-one is obtained as an oily oil. substances. UV (methanol): εйзэ = 17 300.
Příklad 13Example 13
18-Methyl-3-oximino-17a-propin-l-yl-4,15-estradien-17$-ol18-Methyl-3-oximino-17α-propyn-1-yl-4,15-estradien-17-ol
1,2 g 17|3-hydroixy-18-methyl-17a-propin-l-yl-4,15-estradien-3-onu ve 30 ml methylalkoholu a 1 ml vody se míchá s 800 mg hydrochloridu hydroxylaminu a 800 mg hydrogenuhličitanu sodného po dobu 3 hodin a při teplotě 65 °C. Reakční směs se poté zahustí ve vakuu. Zbytek se rozpustí v ethylacetátu, promyje vodou a vysuší síranem sodným. Po chromatografování surového produktu na silikagelu směsí асе- ton/hexan se získá 430 mg 18-methyl-3-oximino-17ar-propin-l-yl-4,15-estradien-17^-olu ve formě pěnovitého produktu.1.2 g of 17β-Hydroxy-18-methyl-17α-propyn-1-yl-4,15-estradien-3-one in 30 ml of methanol and 1 ml of water are mixed with 800 mg of hydroxylamine hydrochloride and 800 mg of hydrogen carbonate sodium for 3 hours at 65 ° C. The reaction mixture was then concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with water and dried over sodium sulfate. Chromatography of the crude product on silica gel with acetone / hexane yielded 430 mg of 18-methyl-3-oximino-17α-propyn-1-yl-4,15-estradien-17β-ol as a foamy product.
UV (methanol): ε240 = 21 200.UV (methanol): ε240 = 21,200.
Příklad 14Example 14
17i^-Acetoxy-18-methyl-17a-propin-l-yl-4,15-estradien-3-onoxim17β-Acetoxy-18-methyl-17α-propyn-1-yl-4,15-estradien-3-one oxime
700 mg 17|(3-acetoxy-18-methyl-17a-propiri-l-yl-4,15-estradien-3-onu ve 30 ml me thylalkoholu a 1 ml vody se nechá reagovat, analogicky jak je popsáno v příkladu 13, se 600 mg hydrochloridu hydroxylaminu a 700 mg hydrogenuhličitanu sodného. Po jedné hodině se reakční směs zpracuje analogicky jako v příkladu 13. Surový produkt se chromatografuje na silikagelu směsí aceton/hexan. Získá se 240 mg 17/?-acetoxy-18-methyl-17a-propin-l-yl-4,15-estradien-3-onoximu ve formě olejovité látky. UV (methanol): ε240 = 20 600.700 mg of 17? (3-acetoxy-18-methyl-17? -Propiri-1-yl-4,15-estradien-3-one in 30 ml of methyl alcohol and 1 ml of water was reacted analogously to Example 13 600 mg of hydroxylamine hydrochloride and 700 mg of sodium bicarbonate After 1 hour, the reaction mixture was worked up in analogy to Example 13. The crude product was chromatographed on silica gel with acetone / hexane to give 240 mg of 17.beta.-acetoxy-18-methyl-. 17a-propyn-1-yl-4,15-estradien-3-onoxime as an oily substance UV (methanol): ε240 = 20,600.
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS795403A CS203913B2 (en) | 1976-08-12 | 1979-08-06 | Process for preparing derivatives of estradiene |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19762636405 DE2636405C2 (en) | 1976-08-12 | 1976-08-12 | ?? 1?? 5? -17? -Chlorethinyl and propinyl steroids of the estran series, processes for their preparation and pharmaceutical preparations containing them |
| CS766516A CS203912B2 (en) | 1975-10-10 | 1976-10-08 | Process for preparing derivatives of estradiene |
| CS795403A CS203913B2 (en) | 1976-08-12 | 1979-08-06 | Process for preparing derivatives of estradiene |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CS203913B2 true CS203913B2 (en) | 1981-03-31 |
Family
ID=5985347
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CS795403A CS203913B2 (en) | 1976-08-12 | 1979-08-06 | Process for preparing derivatives of estradiene |
Country Status (2)
| Country | Link |
|---|---|
| CS (1) | CS203913B2 (en) |
| DE (1) | DE2636405C2 (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2468617A1 (en) * | 1979-10-26 | 1981-05-08 | Roussel Uclaf | NOVEL CHLORINATED ACETYLENIC DERIVATIVES OF ANDROST-4-ENE, THEIR PREPARATION PROCESS, AND THEIR APPLICATION AS MEDICAMENTS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
| DE3042529A1 (en) * | 1980-11-07 | 1982-06-24 | Schering Ag, 1000 Berlin Und 4619 Bergkamen | 11-METHYLENE (DELTA) (UP ARROW) 1 (UP ARROW) (UP ARROW) 5 (UP ARROW) STEROIDS, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL PREPARATIONS CONTAINING THEM |
| FR2522328B1 (en) * | 1982-03-01 | 1986-02-14 | Roussel Uclaf | NEW PRODUCTS DERIVED FROM THE STRUCTURE 3-CETO 4,9 19-NOR STEROIDS, THEIR PREPARATION PROCESS AND THEIR APPLICATION AS MEDICAMENTS |
-
1976
- 1976-08-12 DE DE19762636405 patent/DE2636405C2/en not_active Expired
-
1979
- 1979-08-06 CS CS795403A patent/CS203913B2/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| DE2636405A1 (en) | 1978-02-16 |
| DE2636405C2 (en) | 1982-07-08 |
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