CS200509B2 - Process for preparing 17alpha-/3-r2-oxypropyl/-17beta-r1-oxy-4-gonen-3-ones - Google Patents
Process for preparing 17alpha-/3-r2-oxypropyl/-17beta-r1-oxy-4-gonen-3-ones Download PDFInfo
- Publication number
- CS200509B2 CS200509B2 CS786764A CS676478A CS200509B2 CS 200509 B2 CS200509 B2 CS 200509B2 CS 786764 A CS786764 A CS 786764A CS 676478 A CS676478 A CS 676478A CS 200509 B2 CS200509 B2 CS 200509B2
- Authority
- CS
- Czechoslovakia
- Prior art keywords
- hydroxy
- hydroxypropyl
- acid
- methyl
- methylene
- Prior art date
Links
- 238000004519 manufacturing process Methods 0.000 title claims description 5
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 120
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 38
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 37
- QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical group [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 claims description 23
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 23
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 20
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 20
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 19
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 17
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 16
- 125000004432 carbon atom Chemical group C* 0.000 claims description 13
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 10
- 238000004587 chromatography analysis Methods 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- 229910052786 argon Inorganic materials 0.000 claims description 8
- 238000002844 melting Methods 0.000 claims description 7
- 230000008018 melting Effects 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- 150000007524 organic acids Chemical group 0.000 claims description 5
- 238000001953 recrystallisation Methods 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 238000000746 purification Methods 0.000 claims description 3
- GSSFKPLLVATOAZ-NCIRKRJJSA-N (8r,9r,10s,14s)-1,2,4,5,6,7,8,9,10,11,14,15-dodecahydrocyclopenta[a]phenanthren-3-one Chemical class C1[C@@H]2[C@H]3CCC(=O)CC3CC[C@H]2[C@@H]2CC=CC2=C1 GSSFKPLLVATOAZ-NCIRKRJJSA-N 0.000 claims description 2
- 238000004090 dissolution Methods 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims description 2
- HZTZILUYYUBRRV-VMXHOPILSA-N (8s,9s,10r,13s,14s)-10,13-dimethyl-1,2,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthren-3-one Chemical compound C1=CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CCC[C@@]1(C)CC2 HZTZILUYYUBRRV-VMXHOPILSA-N 0.000 claims 1
- OIFBSDVPJOWBCH-UHFFFAOYSA-N Diethyl carbonate Chemical compound CCOC(=O)OCC OIFBSDVPJOWBCH-UHFFFAOYSA-N 0.000 claims 1
- 229960005181 morphine Drugs 0.000 claims 1
- 239000007787 solid Substances 0.000 claims 1
- 238000001665 trituration Methods 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 51
- 239000000243 solution Substances 0.000 description 38
- -1 aromatic carboxylic acids Chemical class 0.000 description 28
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 22
- 239000005457 ice water Substances 0.000 description 19
- 239000002253 acid Substances 0.000 description 17
- 238000000034 method Methods 0.000 description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- 239000011541 reaction mixture Substances 0.000 description 11
- 239000000126 substance Substances 0.000 description 11
- 150000001875 compounds Chemical class 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- 239000000741 silica gel Substances 0.000 description 8
- 229910002027 silica gel Inorganic materials 0.000 description 8
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 8
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 7
- 230000032050 esterification Effects 0.000 description 7
- 238000005886 esterification reaction Methods 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 229960000583 acetic acid Drugs 0.000 description 6
- 239000002244 precipitate Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- BPLKQGGAXWRFOE-UHFFFAOYSA-M trimethylsulfoxonium iodide Chemical compound [I-].C[S+](C)(C)=O BPLKQGGAXWRFOE-UHFFFAOYSA-M 0.000 description 6
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 5
- 150000008065 acid anhydrides Chemical class 0.000 description 5
- 150000007513 acids Chemical class 0.000 description 5
- 125000002252 acyl group Chemical group 0.000 description 5
- 238000010828 elution Methods 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 229910052708 sodium Inorganic materials 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- QVQLCTNNEUAWMS-UHFFFAOYSA-N barium oxide Chemical compound [Ba]=O QVQLCTNNEUAWMS-UHFFFAOYSA-N 0.000 description 4
- 238000009835 boiling Methods 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 230000008020 evaporation Effects 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- 239000003921 oil Substances 0.000 description 4
- 229910052700 potassium Inorganic materials 0.000 description 4
- 239000011591 potassium Substances 0.000 description 4
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 description 4
- 239000012312 sodium hydride Substances 0.000 description 4
- 229910000104 sodium hydride Inorganic materials 0.000 description 4
- FALRKNHUBBKYCC-UHFFFAOYSA-N 2-(chloromethyl)pyridine-3-carbonitrile Chemical compound ClCC1=NC=CC=C1C#N FALRKNHUBBKYCC-UHFFFAOYSA-N 0.000 description 3
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 230000007935 neutral effect Effects 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- 229940014800 succinic anhydride Drugs 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- HZDNNJABYXNPPV-UHFFFAOYSA-N (2-chloro-2-oxoethyl) acetate Chemical compound CC(=O)OCC(Cl)=O HZDNNJABYXNPPV-UHFFFAOYSA-N 0.000 description 2
- FCOGYPACUCYJOO-UHFFFAOYSA-N (2-ethoxyacetyl) 2-ethoxyacetate Chemical compound CCOCC(=O)OC(=O)COCC FCOGYPACUCYJOO-UHFFFAOYSA-N 0.000 description 2
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 2
- ALYNCZNDIQEVRV-UHFFFAOYSA-N 4-aminobenzoic acid Chemical compound NC1=CC=C(C(O)=O)C=C1 ALYNCZNDIQEVRV-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 150000008064 anhydrides Chemical class 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- KXDHJXZQYSOELW-UHFFFAOYSA-N carbonic acid monoamide Natural products NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 2
- 150000001735 carboxylic acids Chemical class 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- DKWOHBPRFZIUQL-UHFFFAOYSA-N dimethyl-methylidene-oxo-$l^{6}-sulfane Chemical compound C[S+](C)([CH2-])=O DKWOHBPRFZIUQL-UHFFFAOYSA-N 0.000 description 2
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- VANNPISTIUFMLH-UHFFFAOYSA-N glutaric anhydride Chemical compound O=C1CCCC(=O)O1 VANNPISTIUFMLH-UHFFFAOYSA-N 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000002480 mineral oil Substances 0.000 description 2
- 235000010446 mineral oil Nutrition 0.000 description 2
- 239000002798 polar solvent Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- BDHFUVZGWQCTTF-UHFFFAOYSA-N sulfonic acid Chemical compound OS(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-N 0.000 description 2
- KJAMZCVTJDTESW-UHFFFAOYSA-N tiracizine Chemical compound C1CC2=CC=CC=C2N(C(=O)CN(C)C)C2=CC(NC(=O)OCC)=CC=C21 KJAMZCVTJDTESW-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
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical compound CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 2
- KZFCUYQEGLVKTM-UHFFFAOYSA-N (2-chloro-2-oxoethyl) propanoate Chemical compound CCC(=O)OCC(Cl)=O KZFCUYQEGLVKTM-UHFFFAOYSA-N 0.000 description 1
- HFVMEOPYDLEHBR-UHFFFAOYSA-N (2-fluorophenyl)-phenylmethanol Chemical compound C=1C=CC=C(F)C=1C(O)C1=CC=CC=C1 HFVMEOPYDLEHBR-UHFFFAOYSA-N 0.000 description 1
- OUDFPLJCOFXBNI-JKEDJMADSA-N (8r,9s,10r,13s,14s)-13-ethyl-2,6,7,8,9,10,11,12,14,15,16,17-dodecahydro-1h-cyclopenta[a]phenanthren-3-one Chemical compound C1CC2=CC(=O)CC[C@@H]2[C@@H]2[C@@H]1[C@@H]1CCC[C@@]1(CC)CC2 OUDFPLJCOFXBNI-JKEDJMADSA-N 0.000 description 1
- VPWOIQAYKMCWOL-MKZSRGMASA-N (8r,9s,10s,13r)-10,13-dimethyl-1,2,4,5,6,7,8,9,11,12-decahydrocyclopenta[a]phenanthren-3-one Chemical class C([C@H]12)CC3CC(=O)CC[C@]3(C)[C@H]1CC[C@@]1(C)C2=CC=C1 VPWOIQAYKMCWOL-MKZSRGMASA-N 0.000 description 1
- FHJVQLWFUQMADH-XSYGEPLQSA-N (8r,9s,13s,14s)-13-ethyl-3-methoxy-7,8,9,11,12,14,15,16-octahydro-6h-cyclopenta[a]phenanthren-17-one Chemical compound COC1=CC=C2[C@H]3CC[C@](CC)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1 FHJVQLWFUQMADH-XSYGEPLQSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- PAWQVTBBRAZDMG-UHFFFAOYSA-N 2-(3-bromo-2-fluorophenyl)acetic acid Chemical compound OC(=O)CC1=CC=CC(Br)=C1F PAWQVTBBRAZDMG-UHFFFAOYSA-N 0.000 description 1
- ASDQMECUMYIVBG-UHFFFAOYSA-N 2-[2-(2-aminoethoxy)ethoxy]ethanol Chemical compound NCCOCCOCCO ASDQMECUMYIVBG-UHFFFAOYSA-N 0.000 description 1
- AWLVTQRRKPBQEQ-UHFFFAOYSA-N 2-benzylsulfanylacetic acid Chemical compound OC(=O)CSCC1=CC=CC=C1 AWLVTQRRKPBQEQ-UHFFFAOYSA-N 0.000 description 1
- BUTJLJIPWQEYOC-UHFFFAOYSA-N 2-cyclopropylideneacetic acid Chemical compound OC(=O)C=C1CC1 BUTJLJIPWQEYOC-UHFFFAOYSA-N 0.000 description 1
- CGMMPMYKMDITEA-UHFFFAOYSA-N 2-ethylbenzoic acid Chemical compound CCC1=CC=CC=C1C(O)=O CGMMPMYKMDITEA-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
- WUBBRNOQWQTFEX-UHFFFAOYSA-N 4-aminosalicylic acid Chemical compound NC1=CC=C(C(O)=O)C(O)=C1 WUBBRNOQWQTFEX-UHFFFAOYSA-N 0.000 description 1
- PQSUYGKTWSAVDQ-ZVIOFETBSA-N Aldosterone Chemical compound C([C@@]1([C@@H](C(=O)CO)CC[C@H]1[C@@H]1CC2)C=O)[C@H](O)[C@@H]1[C@]1(C)C2=CC(=O)CC1 PQSUYGKTWSAVDQ-ZVIOFETBSA-N 0.000 description 1
- PQSUYGKTWSAVDQ-UHFFFAOYSA-N Aldosterone Natural products C1CC2C3CCC(C(=O)CO)C3(C=O)CC(O)C2C2(C)C1=CC(=O)CC2 PQSUYGKTWSAVDQ-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 1
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- SGXDXUYKISDCAZ-UHFFFAOYSA-N N,N-diethylglycine Chemical compound CCN(CC)CC(O)=O SGXDXUYKISDCAZ-UHFFFAOYSA-N 0.000 description 1
- FFDGPVCHZBVARC-UHFFFAOYSA-N N,N-dimethylglycine Chemical compound CN(C)CC(O)=O FFDGPVCHZBVARC-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- BUEKDJQVNNNKOP-LJCDUQBNSA-N S-[[(8R,9S,10R,13R,14S)-10-methyl-3-oxo-1,2,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-13-yl]methyl] propanethioate Chemical compound C(CC)(=O)SC[C@@]12CCC[C@H]1[C@@H]1CCC3=CC(CC[C@]3(C)[C@H]1CC2)=O BUEKDJQVNNNKOP-LJCDUQBNSA-N 0.000 description 1
- 108010077895 Sarcosine Proteins 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical class [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- OGFZEDMIYDGMQJ-UHFFFAOYSA-N [Na].COC(C)=O Chemical compound [Na].COC(C)=O OGFZEDMIYDGMQJ-UHFFFAOYSA-N 0.000 description 1
- YMNQRZVVZAWBRD-UHFFFAOYSA-M acetyloxy(ethoxy)lead Chemical compound CCO[Pb]OC(C)=O YMNQRZVVZAWBRD-UHFFFAOYSA-M 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229960002478 aldosterone Drugs 0.000 description 1
- 239000002170 aldosterone antagonist Substances 0.000 description 1
- 229940083712 aldosterone antagonist Drugs 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 229960004050 aminobenzoic acid Drugs 0.000 description 1
- 229960004909 aminosalicylic acid Drugs 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- AEMFNILZOJDQLW-QAGGRKNESA-N androst-4-ene-3,17-dione Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1 AEMFNILZOJDQLW-QAGGRKNESA-N 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 229910052614 beryl Inorganic materials 0.000 description 1
- UCMIRNVEIXFBKS-UHFFFAOYSA-N beta-alanine Chemical compound NCCC(O)=O UCMIRNVEIXFBKS-UHFFFAOYSA-N 0.000 description 1
- 239000002981 blocking agent Substances 0.000 description 1
- 150000003842 bromide salts Chemical class 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- FOCAUTSVDIKZOP-UHFFFAOYSA-N chloroacetic acid Chemical compound OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 0.000 description 1
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 108700003601 dimethylglycine Proteins 0.000 description 1
- HPYNZHMRTTWQTB-UHFFFAOYSA-N dimethylpyridine Natural products CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 description 1
- 238000002845 discoloration Methods 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 229940030606 diuretics Drugs 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 150000002084 enol ethers Chemical class 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 238000006266 etherification reaction Methods 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- KNFXXAGQEUUZAZ-UHFFFAOYSA-N ethyl ethaneperoxoate Chemical compound CCOOC(C)=O KNFXXAGQEUUZAZ-UHFFFAOYSA-N 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 125000001475 halogen functional group Chemical group 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 150000002440 hydroxy compounds Chemical class 0.000 description 1
- 150000004694 iodide salts Chemical class 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 229940046892 lead acetate Drugs 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- LPNBBFKOUUSUDB-UHFFFAOYSA-N p-toluic acid Chemical class CC1=CC=C(C(O)=O)C=C1 LPNBBFKOUUSUDB-UHFFFAOYSA-N 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- JTZQCHFUGHIPDF-RYVBEKKQSA-M potassium canrenoate Chemical compound [K+].O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@](CC4)(O)CCC([O-])=O)[C@@H]4[C@@H]3C=CC2=C1 JTZQCHFUGHIPDF-RYVBEKKQSA-M 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- TVDSBUOJIPERQY-UHFFFAOYSA-N prop-2-yn-1-ol Chemical compound OCC#C TVDSBUOJIPERQY-UHFFFAOYSA-N 0.000 description 1
- KOODSCBKXPPKHE-UHFFFAOYSA-N propanethioic s-acid Chemical compound CCC(S)=O KOODSCBKXPPKHE-UHFFFAOYSA-N 0.000 description 1
- WRHZVMBBRYBTKZ-UHFFFAOYSA-N pyrrole-2-carboxylic acid Chemical compound OC(=O)C1=CC=CN1 WRHZVMBBRYBTKZ-UHFFFAOYSA-N 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- FSYKKLYZXJSNPZ-UHFFFAOYSA-N sarcosine Chemical compound C[NH2+]CC([O-])=O FSYKKLYZXJSNPZ-UHFFFAOYSA-N 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000002689 soil Substances 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- UGNWTBMOAKPKBL-UHFFFAOYSA-N tetrachloro-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(Cl)=C(Cl)C1=O UGNWTBMOAKPKBL-UHFFFAOYSA-N 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- JBWKIWSBJXDJDT-UHFFFAOYSA-N triphenylmethyl chloride Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 JBWKIWSBJXDJDT-UHFFFAOYSA-N 0.000 description 1
- 210000005239 tubule Anatomy 0.000 description 1
- DGJTZXXNXZVULP-UHFFFAOYSA-N undecanoyl undecanoate Chemical compound CCCCCCCCCCC(=O)OC(=O)CCCCCCCCCC DGJTZXXNXZVULP-UHFFFAOYSA-N 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 1
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- Steroid Compounds (AREA)
Description
ČESKOSLOVENSKA SOCIALISTICKÁ REPUBLIKA (19) POPIS VYNÁLEZU K PATENTU 200509 (11) (B2) (22) Přihlášeno 04 03 77 (21) (PV 6764-78) (32) (31) (33) Právo přednosti od 05 03 76(P 26 09 694.6 a P 26 09 695.7) Německá spolková republika (40) Zveřejněno 31 12 79 (51) Int. Cl.3 C 07 J 1/00 // i) A 61 K 31/555 ÚŘAD PRO VYNÁLEZY A OBJEVY (45) Vydáno 15 08 83 172)CZECHOSLOVAK SOCIALIST REPUBLIC (19) DESCRIPTION OF THE INVENTION 200509 (11) (B2) (22) Registered 04 03 77 (21) (PV 6764-78) (32) (31) (33) Priority from 05 03 76 (P) 26 09 694.6 and P 26 09 695.7) Federal Republic of Germany (40) Published 31 12 79 (51) Int. Cl.3 C 07 J 1/00 // (i) A 61 K 31/555 OFFICE AND DISCOVERY (45) Issued 15 08 83 172)
Autor vynálezu (73)Author of the Invention (73)
Majitel patentu FHILÍPPSON RAINER dr, BERGKAMEN, KRIEGER BERNHARD dr,UNNA (NSR), CASALS-STENZEL JORGE dr, KERB ULRICH dr, LOSERT WOLFGANG dr, PREZEWOWSKY KLAUS dr, WIECHERT RUDOLF prof. dr. a BITTLER DIETER, ZÁPADNÍ BERLÍN(Západní Berlín) SCHERING AKTIENGESELLSCHAFT, ZÁPADNÍ BERLÍN (Západní Berlín) (54) Způsob výroby 17a-(3-R2-oxypropyl)-17/3-Ri-oxy-4-gonen-3-onů 1Patent holder FHILÍPPSON RAINER dr, BERGKAMEN, KRIEGER BERNHARD dr, UNNA (NSR), CASALS-STENZEL JORGE dr, KERB ULRICH dr, LOSERT WOLFGANG dr, PREZEWOWSKY KLAUS dr, WIECHERT RUDOLF prof. Dr. dr. and BITTLER DIETER, WESTERN BERLIN (West Berlin) SCHERING AKTIENGESELLSCHAFT, WESTERN BERLIN (West Berlin) (54) Method of production of 17α- (3-R 2 -oxypropyl) -17β-R-oxy-4-gonen-3-one 1
Tento vynález se týká způsobu výroby17tó-(3-R2-oxypropyl)-17/3-Ri-Oxy-4-gOnen-3--onů obecného vzorce I,The present invention relates to a process for the preparation of 17α- (3-R 2 -oxypropyl) -17β-R 1 -Oxy-4-genen-3-ones of formula I,
kdewhere
Ri znamená vodík nebo zbytek organickékyseliny až se 3 atomy uhlíku, R2 znamená vodík, alkyl až se 2 atomyuhlíku, aralkyl až s 19 atomy uhlíku nebozbytek organické kyseliny až s 12 atomyuhlíku, R3 představuje methylovou nebo ethylo-vou skupinu a Rá představuje vodík nebo methylovouskupinu.R 1 is hydrogen or an organic acid residue of up to 3 carbon atoms, R 2 is hydrogen, alkyl of up to 2 carbon atoms, aralkyl of up to 19 carbon atoms, or an organic acid of up to 12 carbon atoms, R 3 is methyl or ethyl, and R a is hydrogen or methyl; .
Jako zbytky kyseliny přicházejí v úvahuzbytky odvozené od netoxických kyselin,které jsou odvozené zvláště od alkanoylo- 2 vých kyselin s 1 až 12 atomy uhlíku, ze-jména 2 až 8 atomy uhlíku, například od-vozené od jednosytné alkanoylové kyseliny,jako kyseliny mravenčí, octové, propionové,máselné, isomáselné, αΐ-ethylmáselné, piva-lové, valerové, isovalerové, a-ethylvalerové,trimethyloctové, enanthové nebo kaprylo-vé, nebo odvozené od cyklické kyseliny, ze-jména cykloalifatické kyseliny, jako kyse-liny cyklopropylidenoctové, cyklobutylkar-boxylové, cyklopentylkarboxylové, cyklopen-tyloctové, 3-cyklopentylpropionové, cyklo-hexylkarboxylové, nebo též odvozené odkiarbocyklické arylové nebo aralkylové ky-seliny, jako kyseliny benzoové, 2-, 3- nebo 4-methylbenzoové.Acid residues include those derived from non-toxic acids which are derived in particular from alkanoyl acids having from 1 to 12 carbon atoms, in particular from 2 to 8 carbon atoms, for example derived from monobasic alkanoyl acids such as formic acid, acetic, propionic, butyric, isobutyric, α-ethylbutyric, beryl, valeric, isovaleric, α-ethylvaleric, trimethylacetic, enanthic or caprylic, or derived from cyclic acid, especially cycloaliphatic acids such as cyclopropylideneacetic acid, cyclobutylcarboxylic, cyclopentylcarboxylic, cyclopentyl acetic, 3-cyclopentylpropionic, cyclohexylcarboxylic, or also derived carbocyclic aryl or aralkyl acids such as benzoic, 2-, 3- or 4-methylbenzoic acids.
Protože chemický charakter acylové sku-piny není pro sloučeniny vyrobené způso-bem podle vynálezu významný, pokud acy-lová skupina nepůsobí toxicky nebo netvo-ří s primární hydroxylovou skupinou ester,jsou vhodné též jiné alifatické a aromatic-ké substituované a nesubstituované jedno-,dvoj- a vícesytné karboxylové kyseliny, na-sycené nebo nenasycené alifatické, arylali-fatické a aromatické karboxylové kyselinyaž s 12 atomy uhlíku, zejména však nejvý-še s 8 atomy uhlíku.Since the chemical nature of the acyl group is not significant for the compounds of the invention, unless the acyl group acts as an ester or toxic with a primary hydroxyl group, other aliphatic and aromatic substituted and unsubstituted mono- and di- double- and polybasic carboxylic acids, saturated or unsaturated aliphatic, arylaliphatic and aromatic carboxylic acids having 12 carbon atoms, in particular not more than 8 carbon atoms.
Je třeba uvést například kyselinu unde-cylovou, dodekanovou a 3-cyklohexylpro- 200509 200509 3 4 pionovou, 2,3-, 2,4-, 2,6-, 3,4- a 3,5-dimethyl-benzoovou, ethylbenzoovou, haftoovou, 3--methyl-a-naftoovou, /J-fenylpropionovou, di-fenyloctovou a ια-naftyloctovou, nebo dvoj-sytné alkanoylové kyseliny, například ! ky-selinu šťavelovou, maleinovou, fumarovou,jantarovou, malonovou, glutarovou, a-me-thylglutarovou, β-methylglutarovou, i/?,(3-di-methylglutarovou, adipovou, pimelovou asebakovou, dvojsytné aromatické kyselinyschopné tvořit vnitřní anhydridy, jako ky-selinu fialovou, karbamidové kyseliny, jakokyselinu karbamidovou, fenylkarbamidovou,n-butylkarbamidovou, dimethylkarbamido-vou, diethylkarbamidovou a lalofanovou, ne-bo heterocyklické kyseliny, jako kyselinud-furylkarboxylovou, pyrrolkarboxylovou, ',d--pyrrolidinopropionovou, N-methylpyrrolidi-no-2-karboxylovou, 6-hydroxyindolyl-3-octo-vou, N-methylmorfolino-2-karboxylovou apyrrol-2-karboxylovou nebo sulfonové ky-seliny s 1 až 12 atomy uhlíku, jako kyseli-ny alkansulŤonové, například kyselinu me-than- a etbansulfonovou, a arylsulfonovékyseliny, například kyselinu benzensulfo-novou a p-toluensulfonovou.For example, undecylic acid, dodecanoic acid, and 3-cyclohexylpro- 200509 200509 3,4-pionic, 2,3-, 2,4-, 2,6-, 3,4- and 3,5-dimethylbenzoic, ethylbenzoic acid are mentioned. , haftoic, 3-methyl-α-naphthoic, N-phenylpropionic, di-phenylacetic and α-naphthylacetic, or dibasic alkanoyl acids, for example! oxalic, maleic, fumaric, succinic, malonic, glutaric, .alpha.-methylglutaric, .beta.-methylglutaric, .beta.,... (3-dimethylglutaric, adipic, pimelic asebacic, dibasic aromatic acid-forming internal anhydrides such as violet, carbamic acid, carbamic acid, phenylcarbamic, n-butylcarbamic, dimethylcarbamic, diethylcarbamic and lalophanic, or heterocyclic acids such as f-furylcarboxylic acid, pyrrolecarboxylic acid, d-pyrrolidinopropionic acid, N-methylpyrrolidinoic acid 2-carboxylic, 6-hydroxyindolyl-3-octa, N-methylmorpholino-2-carboxylic apyrrole-2-carboxylic acid or sulphonic acid having 1 to 12 carbon atoms, such as alkane sulphonic acid, e.g. and ethanesulfonic acid, and arylsulfonic acids, for example benzenesulfonic acid and p-toluenesulfonic acid.
Acylové zbytky podle vynálezu mohou býtsubstituovány jedním nebo několika substi-tuenty.The acyl radicals of the invention may be substituted with one or more substituents.
Jako případné substituenty je třeba uvéstnapříklad tyto zbytky: hydroxyskupinu, ha-logen, alkoxyskupinu, acyloxyskupinu, sul-fonyloxyskupinu, amidoskupinu, sulfátosku-pinu, nitroskupinu, merkaptoskupinu a kya-noskupinu, například zbytky kyseliny gly-kolové, mléčné, citrónové, vinné, maleino-vé, glycerové mannonové, glukonové a sa-licylové, nebo.·zbytky aminokyselin, jakoglycínu, kyseliny aminopropionové, digly-kolaminové a triglykolaminovq, methylgly-cin, dimet-hylglycin, diethyíglycin, kyselinup-aminosalicylovqu, p-aminobenzoovou, e-thylmerkaptooctovou, benzylmerkaptoocto-vou,. chloroctovou, fluoroctovou, trichlor-octovou, trifluoroctovou, thiogíykolovou, m-.-nitrobenzoovou, 2,3,4-trimetho.xybenzoovou,fenoxyoctovou a α-naftyloxyoctovou. ; - Zvlášť vhodné jsou především dvojsytnénasycené a... nenasycené karboxylové kyse-liny.Examples of substituents which may be mentioned are: hydroxy, halo, alkoxy, acyloxy, sulfonyloxy, amido, sulphate, nitro, mercapto and cyano, for example glycolic, lactic, citric, tartaric, maleic, glyceric, mannonic, gluconic, and succinic, or amino acid residues, such as yoglycine, aminopropionic acid, diglyco-amine and triglycolamine, methylglycine, dimethylglycine, diethylglycine, p-aminosalicylic acid, p-aminobenzoic acid, e- methylmercaptoacetic acid, benzylmercaptoacetic acid; chloroacetic, fluoroacetic, trichloroacetic, trifluoroacetic, thioglycol, m-nitrobenzoic, 2,3,4-trimethoxybenzoic, phenoxyacetic and α-naphthyloxyacetic. ; Particularly preferred are dibasic and unsaturated carboxylic acids.
Soli se odvozují, od příslušných hemiacy-látů těchto dvojsytných kyselin. Jako katio-ny přicházejí v úvahu zejména . alkalickékovy sodík a draslík, jakož .i amonium.Vhodné jsou však též dvojmocné kovy al-kalických zemin, jako vápník, přičemž najeden molekvivalent vápníku připadají 2molekvivalenty hemiacylátu.The salts are derived from the respective hemiacylic acids of these dibasic acids. Particularly suitable as cations are the following. Alkaline sodium and potassium as well as ammonium are also suitable. However, divalent metals of alkaline soils, such as calcium, are also suitable, with 2 mol equivalents of hemiacylate per mole equivalent of calcium.
Jako alkylové:zbytky Rz přicházejí v úva-hu methyl a ethyl.As alkyl, the radicals Rz are preferably methyl and ethyl.
Sloučeniny vyrobitelné způsobem podlevynálezu buď mají samy farmakologickycenné vlastnosti, nebo jsou meziproduktypro výrobu uznávaně dobrých léčiv. Tak jenapříklad 17ior- (3-hy droxypropyl) -17 /?-hydro-xy-7iai-thiO'acetyl-3-ándrosten-3-on výhodněpoužitelný jako meziprodukt pro výrobuznámé látky blokující aldosteron, spironol-aktonujlaktonu kyseliny 3-(17j3-hydroxy-7a'--thioacetyl-3-oxo-4-androsten-17tó-yl) pro-pionové].Compounds obtainable by the process of the invention either possess pharmacological properties themselves, or are intermediates for the production of recognized good drugs. Thus, for example, 17- (3-hydroxypropyl) -1 H -hydroxy-7-thiothioacetyl-3-indrosten-3-one is preferably used as an intermediate for the known aldosterone blocking agents, spironol actonujlactone acid 3- (17β-). hydroxy-7α-thioacetyl-3-oxo-4-androsten-17-thio-propionic].
Sloučeniny vyrobitelné způsobem 1 podlevynálezu působí též jako diuretika; typu al-ďosteronových antagonistů, to znamená, žeobracejí účinek desoxykortikústeronu navylučování sodíku a draslíku. Sloučeninyiakn 17d-hvdroxv-17./v- f3-hvdrnxvnrnnvl 1- 4 * </ ” K 4 4 i. ' i. 4 ' 4 -7ia-thioacetyl-4-androsten-3-on, 17j3-hydro-xy-17«t- (3-hydroxypropyl)-7a-ethylthio-4--androsten-3-on, 17/3-hydroxy-17ia- (3-acet-oxypr opyl) -7,ai-thioacetyl-6a-methyl-4-and-rosten-3-on, draselná sůl 17/í-hydroxy-17a-- (3-hemisukcinyloxypr opyl)-6-methyl-4,6--androstadien-3-onu a sodná sůl 17,/J-hydro-xy-lZa1- (3-hy droxysukcinyloxypropyl )-4,6--androstadien-3-onu vykazují v testovacímmodelu podle Hollmanna [G. Hollmann akol. Tubuláre Wirkungen und renale Elimi-nation von Spiroliactonen, Neunyn—Schmie-debergs Arch. Exp. Path. Pharmak. 247(1964) 419; P. Marx, Renale Wirkungen ďesd-Aldosterons und seines Antagonisten Spi-ronolacton, Diss. Med. Fak. FU Berlin 1966]překvapivě vyšší účinek než známé obdob-né sloučeniny (například Kalium—Canre-noat).The compounds obtainable by the process of the invention also act as diuretics; the type of aldosterone antagonists, i.e., the desoxicorticuronone excretion of sodium and potassium. 4'4H-thioacetyl-4-androsten-3-one, 17β-hydroxy-1-hydroxybenzoic acid. 17α- (3-hydroxypropyl) -7α-ethylthio-4-androsten-3-one, 17β-hydroxy-17α- (3-acetoxypropyl) -7, α-thioacetyl-6α-methyl- 4-and-rosten-3-one, potassium salt of 17β-hydroxy-17α- (3-hemisuccinyloxypropyl) -6-methyl-4,6-androstadien-3-one and sodium 17, the hydroxyl-1α- 1- (3-hydroxysuccinyloxypropyl) -4,6-androstadien-3-one exhibits in the test model of Hollmann [G. Hollmann et al. Tubul Wirkungen und Renale Elimi-nation von Spiroliactonen, Neunyn — Schmie-debergs Arch. Exp. Path. Pharmak. 247 (1964) 419; P. Marx, Renale Wirkungen Désd-Aldosterons and Seines Antagonisten Spirolacton, Diss. Copper. Fak. FU Berlin 1966] has a surprisingly higher effect than the known analogous compounds (e.g. Kalium-Canre-noat).
Sloučeniny obecného vzorce I se vyrá-bějí podle Vynálezu tím způsobem, že seΔ4;6—nenasycené 3-ketogonadieny obecného’The compounds of formula (I) are prepared according to the invention in such a way that they are unsaturated with 3-ketogonadienes in general.
Ri, Rž, Rs a R4 mají shora uvedený výz-nam, methylenují působením dimethylsul-foxoniummethylidu v dimethylsulfoxidu ja-ko rozpouštědle, popřípadě v přítomnostirozpouštědla usnadňujícího rozpouštění, apopřípadě potom etherifikují, esterifikují apopřípadě se hemiacyláty obecného vzorceIII, 5 6 200309R 1, R 2, R 5 and R 4 are as defined above, methylenated with dimethylsulfoxonium methylide in dimethylsulfoxide as solvent, optionally in the presence of a solvent to facilitate dissolution, and optionally etherified, esterified and, where appropriate, hemiacylates of general formula 5, 5 200309
-ÍCW, IrO-C- (CH,l-C-OH3 II A n IIO O kde R3 a R4 mají shora uvedený význam an značí 1 aíž 3, převedou na jejich solí.Zvláštní varianta způsobu podle vynále- zu spočívá v tom, že se v případě, kdy R?znamená zbytek dvojsytné kyseliny, hemi-acylát převede na amonnou sůl, sůl alka-lického kovu nebo sůl kovu alkalické zemi-ny.Where R 3 and R 4 are as defined above and denote 1 to 3, they are converted into their salts. A particular variant of the process according to the invention is that when R 1 is a dibasic residue, the hemi-acylate is converted to an ammonium salt, an alkali metal salt, or a metal salt of an alkaline earth.
Pro výrobu sloučenin obecného vzorce Ise Δ4:6—nenasycený 3-ketoandrostadien o-becného vzorce II účelně methylenuje di-methylsulfoxoniiummethylidem. Za tím úče-lem se přidá Δ4·6—steroid v atmosféře och-ranného plynu, jako dusíku nebo argonu,v suspenzi trimethylsulfoxoniumjodidu shydridem sodným v minerálním oleji a di-methylsulfoxidu nebo k roztoku trimethyl-sulfoxoniumjodidu a hydroxidu sodného vdimethylsulfoxidu. Reakce je při 20 až 40 °Cukončena po 10 až 30 hodinách. Reakčníprodukt se extrahuje a 6/J,7/3-methylenovýderivát se oddělí od 6ar,7«-methylenovéhoderivátu chromatografií a vyčistí.For the preparation of the compounds of formula (I), the :4: 6-unsaturated 3-ketoandrostadiene of formula (II) is conveniently methylenated with dimethylsulfoxonium methylide. To this end, 64 6-steroid is added in an atmosphere of dry gas, such as nitrogen or argon, in a suspension of trimethylsulfoxonium iodide with sodium hydride in mineral oil and dimethyl sulfoxide or a solution of trimethylsulfoxonium iodide and sodium hydroxide in dimethylsulfoxide. The reaction is complete at 20 to 40 ° C after 10 to 30 hours. The reaction product is extracted and the 6β, 7-methylene derivative is separated from the 6ar, 7-methylene derivative by chromatography and purified.
Pokud je účelné chránit volné hydroxy-lové síkupiny, pak lze zavést niťryloxysku-piny například podle Způsobu popsaného vDOS č. 1 618 998If it is expedient to protect the free hydroxyl groups, nitryloxy groups can be introduced, for example, according to the method described in DOS No. 1 618 998
Pokud sloučeniny obecného vzorce I ob-sahují esiterifikované hydroxylové skupiny,například ochra!nné skupiny, jež byly zave-deny během výrobního postupu, pak lzeesterové vazby hydrolyzovat známými me-todami. Nítryloxyesterové skupiny se účel-ně redukují zinkem v roztoku kyseliny oc-tové na hydroxylovou skupinu. Má-li se esterifikovat volná hydroxylováskupina, jako primární hydroxylová skupi-na, na 17oí-propylovém zbytku, lze použítznámé metody. Etherifikace se výhodněprovádí příslušným alkylhalogenidem. Jakohalogenidy jsou vhodné chloridy, bromidya zejména jodidy. Hydroxysloučenipa se na-příklad rozpustí v polárním rozpouštědlea zahřeje ve přítomnosti báze s alkylačnímčinidlem rta teploty v rozmezí teploty míst-nosti až 100 °C. Jako báze jsou vhodné na-příklad kysličník barnatý, hydrid sodný,uhličitan draselný a alkoholáty alkalickýchkovů, jako1 ethylát sodný. Jako polární roz-pouštědla přicházejí v úvahu dimethylfor-mamid, dimethylacetamid, tetrahydrofuran,dioxan, ketony, jako aceton a methylisobu-tylketoh, jakož i alkoholy, jako ethanol, bu-tanol, terč.butanol.If the compounds of formula I contain estersified hydroxyl groups, for example protecting groups introduced during the manufacturing process, the ester linkages can be hydrolyzed by known methods. Suitably, the oxyloxy groups are reduced with zinc in a solution of acetic acid to give a hydroxyl group. If the free hydroxyl group is to be esterified, such as the primary hydroxyl group on the 17-propyl radical, known methods can be used. The etherification is preferably carried out with the appropriate alkyl halide. Asohalides are suitable chlorides, bromides and especially iodides. For example, the hydroxy compound is dissolved in a polar solvent and heated in the presence of a base with an alkylation agent rta of temperature in the range of room temperature to 100 ° C. Suitable bases are, for example, barium oxide, sodium hydride, potassium carbonate and alkali alcoholates such as sodium ethylate. Suitable polar solvents are dimethylformamide, dimethylacetamide, tetrahydrofuran, dioxane, ketones such as acetone and methyl isobutyl ketone, and alcohols such as ethanol, butanol, tert-butanol.
Esterifikace primární hydroxyskupiny, po-případě hydroxypropylskupiny, se provádíznámými metodami. Vhodnou metodou jenapříklad reakce s anhýdridem kyseliny ne-bo halogenidem kyseliny v přítomnosti ter-ciárníbh aminu, například pyridinu, knlidi-nu, triethylaminu nebo 4-dimethylaminopy-ridinu alespoň při teplotě místnosti. Primár-ní hydroxyskupinu lze esterifikovat též an-hydridem kyseliny v přítomnosti silné ky-seliny, jako kyseliny p-toluensulfonové ne-bo příslušnou kyselinou a anhydridém ky-seliny trifluorocťcvé při teplotě místnosti. Má-li se volná hydroxylová skupina, jakoprimární hydroxylová skupina na 17«-pro-pylovém Zbytku, esterifikovat částečně, paklze i zde použít známých metod. Zvlášťvhodná je esterifikace solí těžkého kovupříslušné kyseliny, například octanem olov-natým nebo ethyoxyoctanem olovnatým, vpřítomnosti příslušného anhydridu kyseliny,například anhydridu kyseliny octové, po-případě anhydridu kyseliny ethoxyoctové,při teplotách kolem teploty místnosti.Esterification of the primary hydroxyl group, or hydroxypropyl group, with methods known per se. By a suitable method, for example, reaction with an acid anhydride or an acid halide in the presence of a tertiary amine such as pyridine, diidin, triethylamine or 4-dimethylaminopyridine at least at room temperature. The primary hydroxy group can also be esterified with an acid anhydride in the presence of a strong acid such as p-toluenesulfonic acid or the appropriate acid and trifluoroacetic anhydride at room temperature. If the free hydroxyl group, the primary hydroxyl group, is to be esterified in part on the 17'-propyl residue, then the known methods can be used. Especially preferred is the esterification of heavy metal salts with, for example, lead acetate or lead ethoxyacetate, in the presence of an appropriate acid anhydride, for example, acetic anhydride, or ethoxyacetic anhydride, at temperatures around room temperature.
Pro výrobu sloučenin obecného vzorce I,v nichž Ri a/nebo Rz znamenají zbytek or-ganické kyseliny, se uvedou v reakci 17^--hydroxy-17oj- (3-hydroxypr opyl ] -A4-3-keto-steroidy již substituované na kruhu B neboA46-3-ketosteroidy s anhydridém alkanky-seliny, přičemž se esterifikuje nejdříve pri-mární hydroxylová skupina a teprve potéterciární 17^-hydroxylová skupina po pro-dloužené reakční době, popřípadě při zvý-šené teplotě. Za tím účelem se účelně vý-chozí steroid rozpustí v bazickém rozpouš-tědle, jako pyridinu, piperidinu, kolodinu,triethylaminu nebo lutidinu, a přidá se pří-slušný anhydrid kyseliny. Příznivý je proesterifikaci též přídavek esťerifikačního ka-talyzátoru, jako dimethylaminopyridinu.For the preparation of compounds of formula I wherein R 1 and / or R 2 are an organic acid moiety, 17? -Hydroxy-17? - (3-hydroxypropyl) -? -? - keto-steroids already substituted at ring B or A46-3-ketosteroids with alkanoic anhydride, wherein the primary hydroxyl group is first esterified and only the tertiary 17-hydroxyl group after the extended reaction time, optionally at elevated temperature. the steroid is dissolved in a basic solvent such as pyridine, piperidine, colodine, triethylamine or lutidine, and the corresponding acid anhydride is added, and the addition of an esterification catalyst such as dimethylaminopyridine is also preferred.
Primární hydroxylová skupina se esteri-fikuje již po krátké době, to znamená po2 až 5 hodinách, zatímco esterifikace ter-ciární hydroxyskupiny vyžaduje delších es-terifikačních dob. Reakci lze přirozeně u-rychlit zahřátím, například zahřátím až kteplotě varu, přičemž se reakční doba zkrá-tí na několik hodin. V případě, že byla primární 23-hydroxy-lová skupina esterifikována. dvojsytnou ky-selinou, může se hemiacylát převést na pří-slušnou sůl alkalického kovu reakcí napří-klad s methylátem sodným nebo draselnýmv methanolovém roztoku. K přípravě a- 200509 7 irionné soli se účelně používá roztok amo-niaku v methanolu.The primary hydroxyl group is esterified after only a short time, i.e. after 2 to 5 hours, while the esterification of the tertiary hydroxy group requires longer esterification times. Naturally, the reaction can be quenched by heating, for example, by heating to boiling point, while the reaction time is shortened to several hours. When the primary 23-hydroxy group was esterified. with a dibasic acid, the hemiacylate can be converted into the appropriate alkali metal salt by reaction with, for example, sodium methylate or potassium in methanol solution. A solution of the ammonium nitrate in methanol is expediently used to prepare the irium salt.
Reakční produkty obecného vzorce I seznámými metodami, jako srážením, fitracínebo extrakcí, oddělí a například chromato-grafováním a/nebo překrystalováním vyčis-tí. Výchozí Δ4·6—nenasycený 3-ketoandrosta-dlen lze například získat takovým způso-bem, že se nejdříve podle způsobu popsa-ného v DOS č. 2 327 448 připraví z 3-keto--4-androsten-17-onu 17$-hýdroxy-17o*- (3-hyd-roixypropyl)-4-androsten a poté zavede dvoj-ná vazba Δ6—, například způsobem, kterýpopsal Agnello a kol. v J. Amer. Soc. 82(1960) 4293. Výchozí 17;/í-hydroxy-17ů!'- (3-hydroxypro-pyi j-lo-íněLhyl-4,6-e5tradíen-3-ún lze vyro-bit takto: K suspenzi 6,85 g terc.butylátu draselné-ho ve 32 mil absolutního tetrahydrofuranuse přidá 50 g 3-methoxy-18-methyl-l,3,5-(10)-estratrien-17-onu [C. Rufer a kol., Lie-bigs Ann. Chem. 752, 1 (1971)] a přikaperoztok 1,7 ml propargylalkoholu v 3,5 mltetrahydrofuranu, tak, že vnitřní teplota ne-přestoupí 35 °C. Míchá se 3 hodiny při 35stupních Celsia a reakční směs se okyselí13 ml 20% kyseliny sírové až k dosaženíhodnoty pH 3 a míchá se dále 10 minut podZpětným chladičem. Reakční směs se vlijedo ledové vody a sraženina se odfiltruje.Vyjme se ethylacetátem, promyje vodou, vy-suší a odpaří. Získá se 5,5 g 17$-hydroxy--17tf-(3-hydroxypropinyl]-3-methoxy-18-me-thyl-1,3,5 (10)-estratrienu.The reaction products of general formula (I) are separated by known methods, such as by precipitation, filtration or extraction, by purification, for example by chromatography and / or recrystallization. For example, the starting 64,6-unsaturated 3-keto-androstrostene can be obtained in such a way that 17 $ is first prepared from 3-keto-4-androsten-17-one according to the method described in DOS No. 2,327,448. -hydroxy-17α- (3-hydroxy-propyl) -4-androstene and then introduces a double bond Δ6, for example as described by Agnello et al. in J. Amer. Soc. 82 (1960) 4293. The starting 17β-hydroxy-17β- (3-hydroxypropyl-4-ynyl-4,6-ethanedien-3-ol can be extracted as follows: 6.85). g of potassium tert-butoxide in 32 ml of absolute tetrahydrofuran is added 50 g of 3-methoxy-18-methyl-1,3,5- (10) -estratrien-17-one [C. Rufer et al., Lie-bigs Ann Chem., 752, 1 (1971)] and a solution of 1.7 ml of propargyl alcohol in 3.5 ml of tetrahydrofuran is added so that the internal temperature does not exceed 35 DEG C. It is stirred for 3 hours at 35 DEG C. and the reaction mixture acidified with 13 ml of 20% sulfuric acid to a pH of 3 and further refluxing for 10 minutes, the ice-water was poured into the reaction mixture and the precipitate was filtered off, washed with ethyl acetate, washed with water, dried and evaporated to give 5.5 g of 17 $ -hydroxy N, N - (3-hydroxypropinyl) -3-methoxy-18-methyl-1,3,5 (10) -estratriene.
Roztok 5 g 17,/3'-hydroxy-17of-(3-hydroxy-propinyl) -3-methoxy-18-methyl-l,3,5 (10) --estratrienu v 50 ml tetrahydrofuranu setřepe s 500 mg paládia na uhličitanu vápe-natém (5%) pod vodíkem za teploty míst-nosti a atmosférického tlaku až k ukonče-ní absorpce vodíku. Pak se katalyzátor od-filtruje a filtrát odpaří. Získá se 4,8 g 17$--hiydroxy-17tf-(3-hydroxypropyl)-3-metho-xy-18-methyl-l,3,5 (10) -estratrienu.A solution of 5 g of 17β-hydroxy-17α- (3-hydroxy-propynyl) -3-methoxy-18-methyl-1,3,5 (10) -estratriene in 50 ml of tetrahydrofuran is shaken with 500 mg of palladium on calcium carbonate (5%) under hydrogen at room temperature and atmospheric pressure until hydrogen uptake is complete. The catalyst was then filtered off and the filtrate evaporated. 4.8 g of 17H-hydroxy-17H- (3-hydroxypropyl) -3-methoxy-18-methyl-1,3,5 (10) -estratriene are obtained.
Roztok 5 g 17$'-hydroxy-17a-(3-hydroxy-propyl) -3-methoxy-18-methyl-l,3,5 (10) -es-tratrieriu ve 200 ml absolutního tetrahyd-rofuranu se smísí při —60 °C s kapalnýmamoniakem a potom 5 g lithia v malýchkouskách. Modrý roztok se míchá 2,5 hodi-ny při —60 °C a pak rozloží přikapávánímethanolu až do odbarvení. Poté se necháamoniak odpařit, zbytek se vyjme etherem,promyje roztokem chloridu sodného do neu-trální reakce, vysuší a odpaří. Zbytek serozpustí ve 150 ml methanolu a 65 ml me-thyleinchloridu a zahřívá s 15 ml 3 N kyse-liny chlorovodíkové 1 hodinu k varu. Poštěpení enoletheru se roztok zahustí, zby-tek vyjme methylenchloridem a roztok pro-myje roztokem hydrogenuhličitanu sodné-ho do neutrální reakce, vysuší a odpaří.Získá se 2 g 17$-hydroxy-17cí-(3-hydroxy-propyl) -18-methyl-4-estren-3-onu.A solution of 5 g of 17? -Hydroxy-17? - (3-hydroxypropyl) -3-methoxy-18-methyl-1,3,5 (10) -es-tratrierium in 200 ml of absolute tetrahydrofuran is mixed at 0 ° C. 60 ° C with liquid ammonia and then 5 g of lithium in small cakes. The blue solution is stirred at -60 ° C for 2.5 hours and then quenched by dropwise addition of methanol until discoloration. The mixture was then evaporated to dryness, taken up in ether, washed with brine, dried and evaporated. The residue was dissolved in 150 ml of methanol and 65 ml of methylene chloride and heated with 15 ml of 3 N hydrochloric acid to reflux for 1 hour. The enol ether is concentrated by evaporation, the residue is taken up in methylene chloride and the solution is washed neutral with sodium bicarbonate solution, dried and evaporated to give 2 g of 17β-hydroxy-17α- (3-hydroxy-propyl) -18-. methyl 4-estren-3-one.
Roztok 2 g 17a-(3-hydroxypropyl)-18-me- 8 thyl-17$-hydroxy-4-estren-3-onu, 1,35 g chlor-anilu a 0,03 g kyseliny p-toluensulfonovéve 200 ml xylenu se zahřívá 1 hodinu k va-ru. Potom se Ve vakuu odpaří a zbytek sevyčistí gradientovou elucí na silikagelu.Získá se 140 mg 17$-hydroxy-17«-(3-hydro-xypr opyl) -18-methyl-4,6-estradien-3-onuve formě amorfní látky, UV: ezss — 22 000(methanol). Výchozí 17$-'hydroxy-17oř-(3-hydroxypro-pyl)-4,6-estradien-3on lze připravit tímtozpůsobem:A solution of 2 g of 17α- (3-hydroxypropyl) -18-methyl-17β-hydroxy-4-estren-3-one, 1.35 g of chloro-anil and 0.03 g of p-toluenesulfonic acid in 200 ml of xylene is heated for 1 hour. It is then evaporated in vacuo and the residue is purified by gradient elution on silica gel to give 140 mg of 17β-hydroxy-17β- (3-hydroxypropyl) -18-methyl-4,6-estradien-3-one in the form of an amorphous substance. , UV: ezss = 22,000 (methanol). The starting 17β-hydroxy-17α- (3-hydroxypropyl) -4,6-estradien-3-one can be prepared in the following manner:
Do 900 ml kapalného amoniaku se přidápři —60 °C roztok 10 g 17o?-(3-hydroxypro-pyl)-3-methoxy-l,3,5 (10)-estratrien-17$--olu [G. E. Arth a kol., J. Med. Chem. 6,618(1963)] ve 400 ml absolutního tetrahydro-í uranu. Potom se přidá po kouskách 10 glithia, pak se míchá 2,5 hodiny při —60 °C,načež se pozvolným přidáváním ethanoluroztok odbarví a za míchání se nechá od-pařit amoniak. Zbytek se vyjme etherem,promyje roztokem chloridu sodného do ne-utrální reakce, vysuší a odpaří. Zbytek serozpustí v 300 ml methanolu a 130 ml me-thylenchloridu a zahřívá 1 hodinu s 30 ml3 N kyseliny chlorovodíkové k varu. Po za-huštění roztoku se vyjme methylenchlori-dem, promyje roztokem hydrogenuhličitanusodného a vodou do neutrální reakce, vysu-ší a odpaří. Získá se 7,1 g 17tó-(3-hydroxy-pr>opyl)-17$-hydroxy-4-estren-3-onu o teplo-tě tání 166 až 167 °C (isopropylether/me-thylenchlorid), UV: ε24ΐ = 17 0'00 (metha-nol).To 900 ml of liquid ammonia is added a -60 ° C solution of 10 g of 17α- (3-hydroxypropyl) -3-methoxy-1,3,5 (10) -estratriene-17β-ol [G. E. Arth et al., J. Med. Chem. 6,618 (1963)] in 400 ml of absolute tetrahydrofuran. 10 g of lithium are then added, then stirred at -60 DEG C. for 2.5 hours, and then the ethanoluride solution is slowly decolorized and the ammonia is allowed to evaporate with stirring. The residue was taken up in ether, washed with brine, dried and evaporated. The residue was dissolved in 300 ml of methanol and 130 ml of methylene chloride and heated for 1 hour with 30 ml of 3 N hydrochloric acid to boil. After the solution has been concentrated, it is taken up in methylene chloride, washed with sodium bicarbonate solution and water neutralized, dried and evaporated. 7.1 g of 17? - (3-hydroxy-propyl) -17? -Hydroxy-4-estren-3-one, m.p. 166 DEG-167 DEG C. (isopropyl ether / methylene chloride), UV: ε24ΐ = 170000 (methanol).
Roztok 4,0 g 17«-(3-hydroxypropyl)-17$--hydroxy-4-estren-3-onu, 3,3 g chloranilu a0,05 g kyseliny p-toluensulfonové ve 400 mlxylenu se zahřívá 1 hodinu k varu. Poté seodpaří ve vakuu a zbytek se vyčistí chro-matografií s gradientovou elucí na silika-gelu. Získá se 350 mg 17$-hydroxy-17oř-(3--hydroxypropyl)-4,6-estradien-3-onu o tep-lotě tání 193 až 194 °C (aceton/hexan), UV:£284 = 26 900 (methanol).A solution of 4.0 g of 17? - (3-hydroxypropyl) -17 $ -hydroxy-4-estren-3-one, 3.3 g of chloranil and 0.05 g of p-toluenesulfonic acid in 400 mlxylene is heated to boiling for 1 hour. . It was then evaporated in vacuo and the residue purified by chromatography eluting with a silica gel gradient elution. 350 mg of 17β-hydroxy-17α- (3-hydroxypropyl) -4,6-estradien-3-one of melting point 193 DEG-194 DEG C. (acetone / hexane) are obtained, UV: ε 284 = 26,900. (methanol).
Farmakologicky účinné látky obecnéhovzorce I lze známými způsoby použít proléčiva, zejména pro orální aplikaci. Dávky sloučenin obecného vzorce I činíu člověka 20 až 500 mg/den.Prodrugs, particularly for oral administration, can be used in known manner by the pharmacologically active compounds of general formula (I). The doses of the compounds of the formula I make humans 20 to 500 mg / day.
Způsob podle vynálezu je blíže objasněndále v příkladech provedení. Přikladl 3,4 g surového 4,7a-(aminomethylidin)-5--kyano-17$-nitryloxy-17a- (3-nitryloxypro-pyl )-5$-androstan-3-onu se zahřívá ve 100ml 1 N kyseliny chlorovodíkové 6 hodin zamíchání na parní lázni. Reakční směs seochladí, vzniklý 4«,7a-karbonyl-5-kyano-17$--nitryloxy-17a- (3-nitryloxypropyl) -5$-and-rostan-3-onu se odsaje, promyje vodou avysuší ve vakuu, 2,1 g sodíku se rozpustí ve 200 ml etha-nolu, přidají 3 g 4a,7or-karbonyl-5-kyano--17$-nitryloxy-17a- (3-nitryloxypropyl) -5$- 2 80 9 -androstan-3-onu a zahřívá 23 hodin podzpětným chladičem. Roztok se zahustí vevakuu, vlije na led a okyselí kyselinou sí-rovou. Vypadlý produkt se odsaje, promy-je vodqu, vysuší a překrystaluje z metha-nolu. Získá se 1,7 g ethylesteru kyseliny 17j3--nitryloxy-17a-(3-nitryloxypropyl]-3-oxo-4--4-androsten-7«-karboxylové o teplotě tání178 až 180 °C.The process according to the invention is explained in more detail in the examples. EXAMPLE 1 3.4 g of crude 4,7a- (aminomethylidin) -5-cyano-17β-nitryloxy-17α- (3-nitryloxypropyl) -5α-androstan-3-one are heated in 100 ml of 1N hydrochloric acid. 6 hours on the steam bath. The reaction mixture is cooled, the resulting 4, 7α-carbonyl-5-cyano-17-nitryloxy-17α- (3-nitryloxypropyl) -5α -and-rostan-3-one is filtered off with suction, washed with water and dried under vacuum. 1 g of sodium is dissolved in 200 ml of ethanol, 3 g of 4α, 7α-carbonyl-5-cyano-17β-nitryloxy-17α- (3-nitryloxypropyl) -5 $ - 2,809 -androstane-3 are added -on and reflux for 23 hours. The solution was concentrated in vacuo, poured onto ice and acidified with sulfuric acid. The precipitated product is filtered off with suction, washed with water, dried and recrystallized from methanol. 1.7 g of 17β-nitryloxy-17α- (3-nitryloxypropyl) -3-oxo-4-4-androstene-7β-carboxylic acid ethyl ester of melting point 178 DEG-180 DEG C. are obtained.
Za účelem redukce takto získaného este-ru se 1,6 g esteru v 10 ml tetrahydrofura-nu a 10 ml ledové kyseliny octové mícháse 2,5 g zinkového prachu 10 minut při 0až 5 °C. Zinkový prach se odfiltruje, filtrátse zahustí ve vakuu a vlije do ledové vody.Vypadlý ethylester kyseliny 17j3-hydroxy-17a·- í 3-hydroxypropyl j -3-oxo-4-anarosten--7a-karboxylo>vé se odsaje a překrystalujeze směsi acetonu a hexanu. Teplota tání či-ní 152 až 153,5 °C. Příklad 2 4a,7os-Karbonyl-5-kyano-17(3-nitryloxy-17,0·- {3-nitryloxypropyl j -5(S-androstan-3-onse obdobně jak je popsáno v předchozímpříkladu, převede methylátem sodným namethylester kyseliny 17/2-nitryloxy-17a-[3--nitryloxypťopyl) -3-oxo-4-androsten-7ior-kar-boxylové a ochranné skupiny se odstraníredukcí. Získá se methylester kyseliny 17^-hydro-xy-17w- (3-hydroxypropyl j-3-oxo-4-andro-sten-7ai-karboxylové o teplotě tání 181 až183 °C. Příklad 3 K 1 g 17i/3-hydroxy-17oí-(3-hydroxypropylj--7í«-acetylthio-4-androsten-3-onu ve 20 mldimethylformataidu se přidá 1,2 g ethoxy-octanu olovnatého a 10 ml anhydridu ky-seliny ethoxyoctové a ponechá stát 68 ho-din při teplotě místnosti, vysráží v ledovéVodě, odsaje, promyje vodou a vysuší. Dvo-jím překrystalováním ze směsi acetonu ahexanu se získá 790 mg 17(2-hydroxy-17ia- - (3-ethoxyacetoxypropy1) -7 oť-acety lthio-4--androsten-3-onu o teplotě tání 130 až 131stupňů Celsia. Příklad 4 1,8 g trimethylsulfoxoniumjodidu a 2,8 ghydroxidu sodného se míchá 15 minut ve32 ml dimethylsulfoxidu pod argonovou at-mosférou. Potom se přidá 1 g 17j^-hydroxy- - 17 a- (3-hydroxypropyl ] -4,6-andr ostadien-3--onu a míchá dále 24 hodin při 35 °C, stá-le pod argonovou atmosférou. Poté se směsvylije do, ledové vody okyselené kyselinouoctovou, vy&rážený produkt se odsaje a roz-pustí v methylenchloridu. Methylenchlori-'dový extrakt se promyje vodou, vysuší sí-ranem sodným a odpaří ve vakuu. Zbytekse vyčistí chromátografií na vrstvě při po- 09 10 užití systému cltforoíorm-methanol v pomě-ru 9 : 1: Po překrystalování z acetonu sezíská 530 mg 17j3-hydroxy-17a43-hydroxy-propyl)- 6^,7|jS-methylen-4-androsten-3-onu oteplotě tání 170 až 172 °C, UV: £263 = 18 300. Příklad 5 K roztoku 3 g (13,8 mmol) trimethylsul-foxoniumjodidu v 60 ml absolutního dime-thylsulfoxidjU se přidá 330 mg (13,8 mmol]hydridu sodného ve formě 50% suspenzev minerálním oleji. Roztok se míchá přiteplotě místnosti pod dusíkovou atmosférouaž do ukončení vyvíjení vodíku. Potom sepřidají 3 g (0,87 mmol] 17jS-hydroxy-17oř--(3-hydroxypropyl ]-18-methyl-4,6-estradien--3-onu a míchá se při teplotě místnosti takdlouho, až výchozí látku nelze dokázatchromatografií na tenké vrstvě. Směs sevlije do, ledové vody okyselené kyselinouoctovou a extrahuje octanem ethylnatým.Po odpaření rozpouštědla se zbytek přečis-tí gradientovou chromatografií na silikage-lu. Jako první se eluuje 790 mg 17jj3-hydro-xy-17 o»- (3-hydroxypropyl)-18-methyl-6a,7«--methylen-4-estren-3-on o teplotě tání 185až 193 σϋ (hexan/aceton), UV (methanol):ε259 — 17 300, a poté 180 mg 17^-hydroxy--17oj- (3-hydroxypropyl ] -18-methyl-6,/3,7,/3--methylen-4-estren-3-onu o teplotě tání 168až 175 °C (hexan/methylenchloridj, UV (me-thanol ] £264 = 18 600. P ř í k 1 a d 6 K roztoku 400 mg 7o*-acetylthiO'-17;j3-hyd-roxy-17io·- {3-hydroxypropyl) -18-methyl-4--estren-3-onu ve 3 ml pyridinu se přidá 200mg propionyloxyacetylchloridu a ponechástát 24 hodin při teplotě místnosti. Poté sereakční směs vlije do ledové vody a sraže-nina se odfiltruje. Zbytek se rozpustí v me-thylenchloridu, promyje, vysuší a odpaří.Získá se 320 mg 7,«-acetylthio-17,;3-hydroxy--18-methyl-17ď- (3-propionyloxyacetoxypro-pyl]-4-estren-3-onu ve formě olejovlté lát-ky, UV (methanolj: £238 = 18 700. Příklad 7 K roztoku 800 mg 17/3-hydroxy-17a-(3--hydroxypropyl ] -18-methyl-6/á,7/3-methylen--4-estren-3-onu v 5 ml pyridinu se přidá 400g chloridu kyseliny acetoxyoctové a pone-chá 20 hodin stát při teplotě místnosti. Po-té se reakční směs vlije do ledové vody azpracuje, jak je popsáno v příkladu 6. Zís-ká se 730 mg 17/3-hydroxy-17,a-(3-acetoxy-acetyloxypropyl ] -18-methy 1-8^3,7/3-methylen--4-estren-3-onu ve formě olejovité látky, UV(methanol): £265 = 18 300. Příklade 250 mg 7a-aoetylthio-17/3-hydroxy-17a-(3--hydroxypr opyl) ’18-methyl-4-estren-3-onu 200509 11 se rozpustí ve 2 ml pyridinu, přidá se 1 mlanhydridu kyseliny octové a ponechá státpři teplotě místnosti 20 hodin. Poté se pro-vede srážení ledovou vodou, látka se vyj-me methylenchloridem, roztok se promyje,vysuší a odpaří. Získá se 180 mg 7a-acetyl-thio-17ij3;-hydroixy-17oř-(3-acetoxypropyl]-18--methyl-4-estren-3-onu o teplotě tání 85 až90 °C (hexan/methylenchlorid), UV (me-thanol) : £239 = 18 400. P ř í k 1 a d 9In order to reduce the ester thus obtained, 1.6 g of the ester in 10 ml of tetrahydrofuran and 10 ml of glacial acetic acid are stirred for 2.5 g of zinc dust for 10 minutes at 0-5 ° C. The zinc dust is filtered off, the filtrate is concentrated in vacuo and poured into ice water. The precipitated ethyl ester of 17β-hydroxy-17α-3-hydroxypropyl-3-oxo-4-anarostene-7α-carboxylate is filtered off with suction and recrystallized. acetone and hexane. Melting point 152-153.5 ° C. EXAMPLE 2 4a, 7os-Carbonyl-5-cyano-17 (3-nitryloxy-17.0 - {3-nitryloxypropyl] -5- (S-androstan-3-one) similarly as described in the previous example converts sodium methylate to methyl acid 17β-Nitryloxy-17α- [3-nitryloxypropyl] -3-oxo-4-androstene-7-carboxylic acid and protecting groups were removed by reduction to give 17β-hydroxy-17β- (3- of hydroxypropyl-3-oxo-4-andro-sten-7α-carboxylic acid, m.p. 181-183 ° C. EXAMPLE 3 To 1 g of 17β-3-hydroxy-17α- (3-hydroxypropyl) -7β-acetylthio-4 androsten-3-one in 20 billion dimethylformamide is added with 1.2 g of ethoxy lead acetate and 10 ml of ethoxyacetic anhydride and left to stand for 68 hours at room temperature, precipitated in ice water, filtered off with suction, washed with water and dried. recrystallization from acetone / hexane gave 790 mg of 17 (2-hydroxy-17α- (3-ethoxyacetoxypropyl) -7α-acetylthio-4-androsten-3-one, m.p. 130-131 ° C. , 8 g of trimethylsulfoxonium iodide and 2.8 g of sodium hydroxide were stirred for 15 minutes in 32 ml of dimethyl sulfoxide under argon. Then 1 g of 17β-hydroxy-17α- (3-hydroxypropyl) -4,6-androstadien-3-one is added and stirred further at 35 ° C for 24 hours, under an argon atmosphere. The mixture is poured into ice-water, acidified with acetic acid, the precipitated product is filtered off with suction and dissolved in methylene chloride, the methylene chloride extract is washed with water, dried over sodium sulphate and evaporated in vacuo. using a 9: 1 ratio of chloroform-methanol: After recrystallization from acetone, 530 mg of 17β-hydroxy-17α-43-hydroxypropyl) -6,7,7-methylene-4-androsten-3-one is recovered by melting point 170 Example 5 To a solution of 3 g (13.8 mmol) of trimethylsulfoxonium iodide in 60 ml of absolute dimethyl sulfoxide was added 330 mg (13.8 mmol) of sodium hydride in form 50 The suspension is stirred at room temperature under nitrogen for 5 minutes until the evolution of hydrogen is complete. giving 3 g (0.87 mmol) of 17β-hydroxy-17α- (3-hydroxypropyl) -18-methyl-4,6-estradien-3-one and stirring at room temperature until the starting material can be detected by chromatography on thin layer. The mixture is poured into ice-water acidified with acetic acid and extracted with ethyl acetate. After evaporation of the solvent, the residue is purified by gradient chromatography on silica gel. First, 790 mg of 17β-hydroxy-17α- (3-hydroxypropyl) -18-methyl-6α, 7β-methylene-4-estren-3-one, m.p. acetone), UV (methanol): ε259-1700, then 180 mg 17β-hydroxy-17α- (3-hydroxypropyl) -18-methyl-6,7,7,3-methylene-4- 168 DEG-175 DEG C. (hexane / methylene chloride, UV (methanol) 264 264 = 18 600. Example 6) To a solution of 400 mg of *O-acetylthio-17; Hydroxy-17? - (3-hydroxypropyl) -18-methyl-4-estren-3-one in 3 ml of pyridine is added 200 mg of propionyloxyacetyl chloride and left for 24 hours at room temperature, after which the reaction mixture is poured into ice water and precipitate. The residue was dissolved in methylene chloride, washed, dried and evaporated to give 320 mg of 7-acetylthio-17,3-hydroxy-18-methyl-17H- (3-propionyloxyacetoxypropyl). -4-estren-3-one as an oil-yellow substance, UV (methanol: δ 238 = 18,700). Example 7 To a solution of 800 mg of 17β-hydroxy-17α- (3-hydroxypropyl) -18- methyl 6 H, 7β-methylene-4-estren-3-one in 5 mL of pyridine was added 400 g of acetoxyacetic acid chloride and allowed to stand at room temperature for 20 hours. The reaction mixture is then poured into ice-water and worked up as described in Example 6. 730 mg of 17β-hydroxy-17α- (3-acetoxy-acetyloxypropyl) -18-methyl-1-8β are obtained. 3,7 / 3-methylene-4-estren-3-one as an oily substance, UV (methanol): δ 265 = 18 300. Example 250 mg of 7α-acetylthio-17β-hydroxy-17α- (3- Hydroxypropyl) 18-methyl-4-estren-3-one 200509 11 is dissolved in 2 ml of pyridine, 1 acetic acid anhydride is added and the mixture is left to stand at room temperature for 20 hours. with methylene chloride, the solution was washed, dried and evaporated to give 180 mg of 7α-acetyl-thio-17β-hydroxy-17α- (3-acetoxypropyl) -18-methyl-4-estren-3-one at a temperature of mp 85-90 ° C (hexane / methylene chloride), UV (methanol): 239 239 = 18,400.
Podle postupů z příkladu 8 se Uvede vreakci 17/3-hydrO'Xy-17,a-(3-hydroxypropyl)--18-methyl-6/3,7|/3-methylen-4-estren-3-on s an-hydridem kyseliny octové a připraví se17,(3-hydroxy-17Qf- {3-acetoxypropyi ] -18-me-thyl-6j3,7/?-methylěn-4-estren-3-on o teplotětání 60-až 68 °C (pentan), UV (methanol):£263 — 18 300. Příklad 10 K roztoku 5 g Ťa-acetylthio-17/í-hydroxy--17«- (3-hydroxypropyl) -18-methyl-4-estren--3-onu v 50 ml absolutního dimethylforma-midu se přidá 15 ml methyljodidu a 18 gpráškového kysličníku barnatého. Za inten-zivního míchání se nechá reakce proběh-nout zhruba při 40 °C. Po 6 hodinách sereakční směs vyjme methylenchloridem aodfiltruje od zbytku. Organická fáze se pro-myje, vysuší a odpaří. Zbytek se přečistígradientovou elucí. Získá se 2,3 g 7a-ace-tylthio-17i/3-hydroXy-17a- (3-methoxypro-pyl)-18-methyl-4-estren-3-onu ve fdrmě ole-jovité látky, UV (methanol): £237 — 18 500.Přikladli K roztoku 1,4 g trifenylchlormethanu v5 ml absolutního pyridinu se přidá 1,62 g7ař-acetylthio-17/3-hydroxy-17a- (3-hydroxy-propyl )-18-methyl-4-estren-3-onu a ponechástát 3 dny při teplotě místnosti. Poté sesměs vlije do ledové vody, sraženina od-filtruje a promyje vodou do neutrální reak-ce. Zbytek se přečistí gradientovou elucí.Získá se 1,25 g 7a-acetylthio-17,/3-hydroxy--18-methyl-17a- (3-trif enylmethoxypropyl) --4-estren-3-onu ve formě olejovité látky, UV(methanol): λ εAccording to the procedures of Example 8, 17 [beta] -hydroxy-17, [alpha] - (3-hydroxypropyl) -18-methyl-6,7,7,3-methylene-4-estren-3-one is reacted with acetic anhydride and 17,1 (3-hydroxy-17β- (3-acetoxypropyl) -18-methyl-6,3,7β-methylene-4-estren-3-one of 60-68 ° C) are prepared. C (pentane), UV (methanol): 263 263 - 18 300. Example 10 To a solution of 5 g of--acetylthio-17β-hydroxy-17β- (3-hydroxypropyl) -18-methyl-4-estreno- 15 ml of methyl iodide and 18 g of powdered barium oxide are added in 50 ml of absolute dimethylformamide, and the reaction is allowed to proceed at about 40 DEG C. with intensive stirring, after 6 hours the reaction mixture is taken up in methylene chloride and filtered from the residue. The organic phase is washed, dried and evaporated, and the residue is purified by gradient elution to give 2.3 g of 7α-acetylthio-17β-hydroxy-17α- (3-methoxypropyl) -18-methyl-4- estren-3-one in oleaginous material, UV (methanol): 237 237 - 18,500. of methanol in 5 ml of absolute pyridine was added 1.62 gm-acetylthio-17β-hydroxy-17α- (3-hydroxypropyl) -18-methyl-4-estren-3-one and left for 3 days at room temperature. The mixture is then poured into ice water, the precipitate is filtered off and washed with water until neutral. The residue was purified by gradient elution to give 1.25 g of 7α-acetylthio-17β-hydroxy-18-methyl-17α- (3-triphenylmethoxypropyl) -4-estren-3-one as an oily substance. UV (methanol): λ ε
204 45 800 EA (223 14 300) (230 11200) 238 18 100. Příklad 12 K roztoku 2 g (9,2 mmol) trimethylsul-foxoniumjodidu ve 40 ml absolutního dime-thylsulfoxidu se přidá 220 mg (9,2 mmol)hydridu sodného: ve formě 50% suspenze v 12 minerálním oleji. Roztok se míchá při tep-lotě místnosti pod dusíkovou atmosférou aždb skončení vyvíjení vodíku. Poté se při-dají '2 g (7 mmol) 17ýf-hydroxý-:l7a-(3-hyd-roxýpropyl)-4,6-estradien-3-onu á míchá, přiteplotě místnosti pod dusíkem, až se výcho1-zí materiál již nedá dokázat chromatogřa-fií na tenké vrstvě. Násada se vylije do le-dové vody okyselené kyselinou octovou aextrahuje octanem ethylnatým. Po odpaře-ní rozpouštědla se zbytek přečistí chroma-fcografií s gradientovou elucí na silikagelu.Izoluje se nejdříve 850 mg 17^-hydroxy-17a--(3-hydroxypropyl)-6a,7a-methylen-4-es-tren-3-onu, potom 190 mg žádaného 17fí--hydroxy-17a- (3-hydroxypropyl) -6^,7(3-me-thylen-4-estren-3-onu o teplotě tání 158 až164 CC (hexan/aceton), UV (methanol);£263 = 18 200. Příklad 13 K roztoku 800 mg 7a-acetylthio-17,/J-hyd-roxy-17a- (3-hydroxypropyl) -4-estren-3-onuv 5 ml pyridinu se přidá 400 mg propionyl-oxyácetylchloridu a ponechá stát 24 hodinpři teplotě místnosti. Poté se reakční směsvlije do ledové vody a sraženina se odfil-truje. Sraženina se rozpustí v methylen-chloridu, promyje, vysuší a odpaří. Získá se650 mg 7a-acetyl-thio-17i/3-hydroxy-r7a-(3--propionyloxyacetyloxypropyl) -4-estren-3--on ve formě olejovité látky, UV (metha-nol): £238 = 18 700. Příklad 14 K roztoku 850 mg 17/3-hydroxy-17a-(3--hydroxypropyl)-6j3,7/2-methylen-4-estren--3-onu v 5 ml pyridinu se přidá 450 mgchloridu kyseliny acetoxyoctové a nechá 20hodin stát při teplotě místnosti. Pak se re-akční směs vlije do ledové vody a zpracu-je, jak popsáno v příkladu 13. Získá se 530mg 17i/í-hydroxy-17a- (3-acetoxyacetyloxypro-pyl)-6'(3,7i/3-methylen-4-estren-3-onu ve for-mě oleje, UV (methanol): £263 = 18 100.Příklad 15 500 mg 7a-acetylthio-17^-hydroxy-17a-(3--hydroixypropyl)-4-estren-3-onu se rozpustíve 2 ml pyridinu, přidá se 1 ml anhydridukyseliny octové a nechá 20 hodin stát přiteplotě místnosti. Potom se reakční směs vy-sráží v ledové vodě, látka se vyjme methy-lenchloridem, roztok se promyje, vysuší aodpaří. Získá se 375 mg 7a-acetylthio-17{3--hydroxy-17a-( 3-acetoxypropyl )-4-estren-3--onu o teplotě tání 77 až 80 °C (pentan/iso-propylether), UV: ε237 — 19 000 (metha-nol). Příklad 16204 45 800 EA (223 14 300) (230 11200) 238 18 100. Example 12 To a solution of 2 g (9.2 mmol) of trimethylsulfoxonium iodide in 40 ml of absolute dimethyl sulfoxide was added 220 mg (9.2 mmol) of hydride sodium: as a 50% suspension in 12 mineral oil. The solution was stirred at room temperature under a nitrogen atmosphere until the evolution of hydrogen ceased. Then 17 g of 17? -Hydroxy-17? - (3-hydroxypropyl) -4,6-estradien-3-one is added and stirred at room temperature under nitrogen until the starting material is added. can no longer be detected by thin layer chromatography. The batch is poured into ice water acidified with acetic acid and extracted with ethyl acetate. After evaporation of the solvent, the residue was purified by silica gel gradient chromatography eluting first with 850 mg of 17β-hydroxy-17α- (3-hydroxypropyl) -6α, 7α-methylene-4-esters-3- then 190 mg of the desired 17β-hydroxy-17α- (3-hydroxypropyl) -6,7,7 (3-methylene-4-estren-3-one, m.p. 158-164 ° C (hexane / acetone), UV Example 13 To a solution of 800 mg of 7α-acetylthio-17β-hydroxy-17α- (3-hydroxypropyl) -4-estren-3-one in 5 ml of pyridine was added 400 ml of methanol. The reaction mixture was poured into ice water and the precipitate was filtered off, the precipitate was dissolved in methylene chloride, washed, dried and evaporated to give 650 mg of 7α-acetyl-thio-17i. 3-hydroxy-η 7 - (3-propionyloxyacetyloxypropyl) -4-estren-3-one as an oily substance, UV (methanol): δ 238 = 18,700. Example 14 To a 850 mg 17 / 3- solution hydroxy-17α- (3-hydroxypropyl) -6β, 3,7 / 2-methylene-4-estren-3-one in 5 ml of pyridine is added with 450 mg of acetoxyacetic acid chloride and left for 20 hours at room temperature. The reaction mixture was poured into ice water and worked up as described in Example 13. 530 mg of 17β-hydroxy-17α- (3-acetoxyacetyloxypropyl) -6 '(3,7i / 3-methylene) was obtained. -4-estren-3-one in the form of oil, UV (methanol): 263 263 = 18 100. Example 15 500 mg of 7α-acetylthio-17β-hydroxy-17α- (3-hydroxy-propyl) -4-estrene Pyridine (2 ml) was added, acetic anhydride (1 ml) was added and the mixture was allowed to stand at room temperature for 20 hours, then the reaction mixture was precipitated in ice water, taken up in methylene chloride, washed, dried and evaporated. with 375 mg of 7α-acetylthio-17 {3-hydroxy-17α- (3-acetoxypropyl) -4-estren-3-one, m.p. 77-80 ° C (pentane / isopropyl ether), UV: ε237 - 19,000 (methanol) Example 16
Jak popsáno v příkladu 15, reakcí 17^3--hydroxy-17a- (3-hydroxypropyl)-6/3,7,/J-me- 200509 13 14 thylen-4-estren-3-onu s anhydridem kyselinyoctové se získá 17,^-hydroxy-17«-(3-acetoxy-propyl)-6,/3,7/3-methylen-4-estren-3-on o tep-lotě tání 95 až 99 °C (hexan/aceton), UV(methanol): ε265 = 18 400. Příklad 17 350 mg 17/3-hydroxy-17a-(3-hydroxypro-pyl)-6-methyl-4,6-androstadien-3-onu se za-hřívá ve 3,5 ml pyridinu a 350 mg anhyd-rídu kyseliny jantarové 1 hodinu pod zpět-ným chladičem. Roztok se vylije za míchá-ní do ledové vody, vyloučený olej odfiltru-je, vyjme methylenchloridem, vysuší a od-paří. Zbytek se chromatografuje na silika-gelu. Získá se 420 mg 17/3-hydroixy-6-me-thyl-17a- (3-hemisukcinyloxypropyl )-4,6--androstadien-3-onu ve formě amorfní lát-ky, UV: £291 = 20 500. P ř í k 1 a d 1 8 420 mg 17,/3'-hydroxy-6-methyl-17a-(3-he-misukcinyloixypropyl) -4,6-androstadien-3--onu se rozpustí ve 20 ml absolutního me-tanolu a uvádí v reakci s 6,4 ml methano-lového 0,1 N roztoku methylátu. draselnéhoaž do bodu ekvivalence. Reakční roztok sevysráží v absolutním etheru, sraženina od-saje, protnyje etherem a vysuší. Získá se340 mg 17β-hydroxy-6-methy 1-17a-(3-hemi-sukcinyloxypropyl)-4,6-androstadien-3-onuve formě draselné soli, tvořící amorfní lát-ku. Teplota tání: 130 °C (za rozkladu), UV:ε29ΐ = 21 300. Příklad 19 350 mg 17i/3-hydro,xy-6-méthyl-17a-(3-he-misukciny loxypropyl) -4,6-androstadien-3--onu se uvede v reakci s methanolovým roz-tokem methylátu sodného a zpracuje. Získáse 310 mg 17/3-hydroxy-6-methyl-17a-(3-he-misukcinyloíxypropyl) -4,6-androstadien-3--onu ve formě sodné soli, UV: ε29ΐ = 21 000. Příklad 20 jak popsáno v příkladu 17, reakcí 17f/3--hydroxy-17a- (3-hydroxypropyl) -18-methyl--4,6-estradien-3-o‘nu s anhydridem kyselinyjantarové v pyridinu se získá 17/3-hydroxy--17a- (3-hydroxysukcinyloxypropyl) -18-me-thyl-4,6-estradien-3-on ve formě amorfní lát-ky, UV: ε284 = 24 100 (methanol). Příklad 21As described in Example 15, by the reaction of 17β-hydroxy-17α- (3-hydroxypropyl) -6 / 3,7, (J-200509-1314 thylene-4-estren-3-one with acetic anhydride is obtained). 17,16-hydroxy-17β- (3-acetoxy-propyl) -6,7 / 3/3-methylene-4-estren-3-one, m.p. 95-99 ° C (hexane / acetone) , UV (methanol): ε265 = 18,400. Example 17 350 mg of 17β-hydroxy-17α- (3-hydroxypropyl) -6-methyl-4,6-androstadien-3-one are heated in 3 5 ml of pyridine and 350 mg of succinic anhydride under reflux for 1 hour. The solution is poured into ice water with stirring, the precipitated oil is filtered off, taken up in methylene chloride, dried and evaporated. The residue is chromatographed on silica gel. 420 mg of 17β-hydroxy-6-methyl-17α- (3-hemisuccinyloxypropyl) -4,6-androstadien-3-one are obtained in the form of an amorphous substance, UV: ε 291 = 20,500. 1 18 420 mg of 17, 3'-hydroxy-6-methyl-17α- (3-hissuccinyloixypropyl) -4,6-androstadien-3-one was dissolved in 20 ml of absolute methanol and reacted with 6.4 ml of methanolic 0.1 N methylate solution. to potassium endpoint. The reaction solution precipitated in absolute ether, the precipitate was collected, passed through ether and dried. 340 mg of 17β-hydroxy-6-methyl-17α- (3-hemi-succinyloxypropyl) -4,6-androstadien-3-one is obtained in the form of the potassium salt forming the amorphous substance. Melting point: 130 [deg.] C. (decomposition), UV: [lambda] 29 [delta] = 21,300. The 3-one is reacted with methanolic sodium methylate solution and worked up. 310 mg of 17β-hydroxy-6-methyl-17α- (3-hexisuccinyloxypropyl) -4,6-androstadien-3-one are obtained in the form of the sodium salt, UV: ε29ΐ = 21,000. Example 20 as described in of Example 17, by reacting 17β- (3-hydroxy-17α- (3-hydroxypropyl) -18-methyl-4,6-estradien-3-one with succinic anhydride in pyridine to yield 17β-hydroxy-17α - (3-hydroxysuccininyloxypropyl) -18-methyl-4,6-estradien-3-one as an amorphous substance, UV: ε284 = 24,100 (methanol). Example 21
Jak je popsáno v příkladu 18, ze 17,/3-hyd-r otxy-17a- (3-hydroxysukcinyloxypropyl) -18--methyl-4,6-estradien-3-onu se získá jehodraselná sůl ve formě amorfní látky, (JV:£285 = 22 900 (methanol). Příklad 22 0,64 g 17a-(3-pr opionyloxypr opyl )-17,/3--hydroxy-7a-propionylthio-4-androsten-3--onu [připraveného ze 2 g 17^-hydroxy--17 a- (3-hydroxypropyl) -4,6-androsťadien--3-oniív 5,4 ml kyseliny thiopropionové zamíchání a ohřevu na 90 °C pod argonovouatmosférou během 4 hodin, odpařením vevakuu a chromatografováním zbytku na si-likagelu, elucí směsi hexanu a octanu ethyl-natého v poměru 1:1, při získání 1,89 golejovitého 17 a-(3-propiony loxypr opy 1 )-17,/3--hydroixy-7,a-propionylthio-4-androsten-3--onu, UV: ε239 = 17 200) se rozpustí ve 2,5ml pyridinu, přidá se 1,25 ml acetanhydri-du a- 60 mg 4-dimethylaminopyrídinu a mí-chá se při teplotě místnosti 67 hodin. Při-dá se ledová voda, extrahuje se methylen-chloridem, roztok se promyje 1 N kyselinousírovou a vodou a odpaří ve vakuu. Po- pře-čištění zbytku chromatografií na vrstvě sezíská amorfní 17a-(3-propionyloxypropyl)--17;/3-acetoxy-7a-propionyl-thio-4-androsten--3-onu, UV: £238 = 17 800 (methanol). Příklad 23 150 mg 17|/3-hydroxy-17a- (3-hydroxypro-pyl )-6,/3,7|/3-methylen-4-androsten-3-onu sezahřívá ve 2 ml pyridinu a 1 ml acetanhyd-ridu pod argonovou atmosférou 8 hodinpod zpětným chladičem. Po zpracování ja-ko v příkladu 32 se získá 17/3-acetoxy-17a-- (3-acetolxypropyl) -6/3,7./3 -methylen-4-and-rosten-3-on, UV: £246 = 18 100 (methanol). Příklad 24 100 mg 17i/3-hydroxy-17a-( 3-hydroxypro-pyl )-7a-thioacetyl-4-androsten-3-onu se mí-chá ve 2 ml pyridinu se 2 ml anhydridu ky-seliny undecylové za přídavku 30 mg di-methylamipopyridinu 7 hodin při 50 °C. Po-té se reakční směs vlije do ledové vody,rozmíchá s pentanem a odsaje, zbytek seextrahuje methylenchloridem, promyje 1 Nkyselinou chlorovodíkovou a vodou a zby-tek se zahustí, přičemž se získá 17/3-hydro-xy-17a- (3-undecy loxypropyl) -7 ai-thioacety 1--4-androsten-3-on ve formě oleje, UV (me-thanol): £237 = 17 500. Příklad 25 1,5 g 17,/3-hydroxy-17a-( 3-hydroxypropyl)--4,6-androstadienr3-onu se rozpustí v 5 mlpyridinu, přidá se 1,5 g anhydridu kyselinyjantarové a zahřívá 1 hodinu pod argono-vou atmosférou k varu. Po ochlazení sevmíchá do ledové vody, okyselí kyselinouchlorovodíkovou a extrahuje octanem ethyl-natým. Octanový extrakt se promyje vodoudo neutrální reakce, vysuší síranem sod- 200509 15 ným a odpaří ve vakuu. Získají se takto2 g 17i/í-hydroXy-17a-(3-hydroxysukeinyloxy-propyl)-4,6-androstadien-3-onu ve formě a-morfní látky, UV: £285 = 23 700. Příklad26 300 mg hemisukcinátu připraveného vpříkladu 25 se rozpustí v 15 ml absolutní-ho methanolu a pH se upraví 5,5 ml 0,1 Nmethylátu sodného na hodnotu 8. Roztokse zahustí ve vakuu a vysráží ve 200 ml e-theru. Vypadlá sůl se odsaje, rozpustí v me-thanolu a znovu vysráží v etheru. Získá se210 mg sodné soli 17,/3-hydroxy-17a-(3-hyd-roxysukcinyloxypropyl) -4,6-androstadien-3--onu o teplotě tání 120 °C (za rozkladu),UV: £285 = 24 1UU. Příklad 27 400 mg hemisukcinátu vyrobeného v pří-kladu 25 s rozpustí ve 20 ml absolutníhomethanolu a pH se upraví 5,4 ml 0,1 N roz-tokem methylátu draselného na hodnotu 8.Po přesrážení v etheru se získá 285 mg dra-selné soli 17,/3-hydroxy-17a-(3-hydroxysukci-nyloixypropyl)-4,6-androstadien-3-onu o tep-lotě tání 145 °C (za rozkladu). Příklad 28As described in Example 18, the 17β-hydroxy-17α- (3-hydroxysuccinyloxypropyl) -18-methyl-4,6-estradien-3-one yields the potassium salt as an amorphous substance ( JV: g285 = 22,900 (methanol) Example 22 0.64 g of 17α- (3-propionionoxypropyl) -17,13-hydroxy-7α-propionylthio-4-androsten-3-one [prepared from 2 g of 17? -Hydroxy-17? - (3-hydroxypropyl) -4,6-androstanadien-3-one 5,4 ml of thiopropionic acid by stirring and heating to 90 ° C under argon for 4 hours, by evaporation of vevacu and chromatography of the residue on silica gel, eluting with a 1: 1 mixture of hexane and ethyl acetate, yielding 1.89 gol of 17? - (3-propionyl-oxypropyl) -17,? -hydroxy-7, and propionylthio-4-androsten-3-one, UV: ε239 = 17,200) is dissolved in 2.5 ml of pyridine, 1.25 ml of acetic anhydride and 60 mg of 4-dimethylaminopyridine are added and stirred at room temperature. 67 hours. Ice water is added, extracted with methylene chloride, the solution is washed with 1 N acid / water and evaporated in vacuo. After purification of the residue by layer chromatography, amorphous 17α- (3-propionyloxypropyl) -1H-3-acetoxy-7α-propionylthio-4-androsten-3-one was obtained, UV: δ 238 = 17,800 ( methanol). EXAMPLE 23 150 mg of 17β-hydroxy-17α- (3-hydroxypropyl) -6.7 (3-methylene-4-androsten-3-one) are heated in 2 ml of pyridine and 1 ml of acetic anhydride. under argon for 8 hours under reflux. After treatment as in Example 32, 17β-acetoxy-17α- (3-acetolxypropyl) -6 / 3,7 / 3-methylene-4-and-rosten-3-one is obtained, UV: 246. = 18,100 (methanol). EXAMPLE 24 100 mg of 17 [beta] -hydroxy-17 [alpha] - (3-hydroxypropyl) -7 [alpha] -thioacetyl-4-androsten-3-one are stirred in 2 ml of pyridine with 2 ml of undecylic anhydride in 30 ml. mg of dimethylamipopyridine at 50 ° C for 7 hours. Then the reaction mixture is poured into ice water, stirred with pentane and filtered off with suction, the residue is extracted with methylene chloride, washed with 1 N hydrochloric acid and with water and the residue is concentrated to give 17.3-hydroxy-17α- (3- undecyloxypropyl) -7-thioacetyl-4-androsten-3-one in the form of an oil, UV (methanol): 17 237 = 17 500. Example 25 1.5 g of 17, 3-hydroxy-17α (3-hydroxypropyl) -4,6-androstadienr-3-one is dissolved in 5 ml of pyridine, 1.5 g of succinic anhydride are added and boiling under argon for 1 hour. After cooling, it is stirred into ice water, acidified with hydrochloric acid and extracted with ethyl acetate. The acetate extract was washed with water to neutral, dried over sodium sulfate and evaporated in vacuo. 2 g of 17β-hydroxy-17α- (3-hydroxysukeinyloxy-propyl) -4,6-androstadien-3-one in the form of an amorphous substance are obtained, UV: δ285 = 23,700. Example 26 300 mg of the hemisuccinate prepared in the example 25 was dissolved in 15 mL of absolute methanol and the pH was adjusted to 8 with 5.5 mL of 0.1 N sodium methylate. The solution was concentrated in vacuo and precipitated in 200 mL of ether. The precipitated salt was filtered off with suction, dissolved in methanol and re-precipitated in ether. 210 mg of 17β-hydroxy-17α- (3-hydroxysuccininyloxypropyl) -4,6-androstadien-3-one sodium salt are obtained, m.p. 120 DEG C. (decomp.), UV: 285 DEG -24 DEG. . EXAMPLE 27 400 mg of the hemisuccinate prepared in Example 25 are dissolved in 20 ml of absolute methanol and the pH is adjusted to 8 with 5.4 ml of a 0.1 N potassium methylate solution. 17 [beta] -hydroxy-17 [alpha] - (3-hydroxysuccynyloixypropyl) -4,6-androstadien-3-one, m.p. 145 [deg.] C. (dec.). Example 28
Obdobně jako v příkladu 25 se připravíesterifikací anhydridem kyseliny glutarovév pyridinu a následující reakcí s methylá-tem draselným jako v příkladu 27 draselnásůl 17,/3--hydroxy-17a- (3-hydroxyglutarylox.y-propyl)-4,6-androstadien-3-onu o teplotě tá-ní 98 °C (za rozkladu). Příklad 29Similarly to Example 25, the 17, 3-hydroxy-17α- (3-hydroxyglutaryloxyl-propyl) -4,6-androstadiene potassium salt was prepared by esterification with glutaric anhydride in pyridine followed by reaction with potassium methylate as in Example 27. 3-one with a melting point of 98 ° C (decomposition). Example 29
Roztok 1 g 17/3-hydroxy-17«-(3-hydroxy-propyl)-4,6-estradien-3-onu ve 4 ml pyridi-nu se zahřívá s 1 g anhydridu kyseliny jan-tarové 1 hodinu pod argonovou atmosférouk varu. Nechá se vychladnout a vmíchá sedo ledové vody, okyselí zředěnou kyselinouchlorovodíkovou a extrahuje octanem ethyl-natým. Spojené extrakty se promyjí vodou,vysuší síranem sodným a odpaří do sucha.Získá se 1 g surového 17/S-hydroxy-17a-(3--hydroxysukcinyloxypropyl)-4,6-estradien--3-onu ve formě amorfní látky, UV: £284 == 26 800 (methanol). P ř í k 1 a d 3 0A solution of 1 g of 17β-hydroxy-17β- (3-hydroxypropyl) -4,6-estradien-3-one in 4 ml of pyridine was heated with 1 g of jan-anhydride under argon for 1 hour boiling. Allow to cool and stir seven ice water, acidify with dilute hydrochloric acid and extract with ethyl acetate. The combined extracts were washed with water, dried over sodium sulfate and evaporated to dryness to give 1 g of crude 17β-hydroxy-17α- (3-hydroxysuccinyloxypropyl) -4,6-estradien-3-one as an amorphous, UV : £ 284 == 26,800 (methanol). Example 3 3
Roztok 500 mg 17/3-hydroxy-17a:-(3-hyd-roxysukcinyloxypropyl) -4,6-estradien-3-onuv 15 ml absolutního methanolu se upravípomocí pH—metru 0,1 N roztokem methy-látu sodného na hodnotu pH 8, zahustí vevakuu a vysráží 200 ml etheru. Sodná sůlse odsaje, rozpustí v methanolu a opět vy-sráží etherem. Získá se 350 mg sodné soli17/Miydroxy-17a-(3-hydroxysukcinyloxypro- 16 pyl)-4,6-estradien-3-onu, UV: £285 = 25 900(methanol). Příklad 31A solution of 500 mg of 17β-hydroxy-17α :-( 3-hydroxy-succininyloxypropyl) -4,6-estradien-3-one in 15 ml of absolute methanol is adjusted to pH = 0.1 with a pH-meter of 0.1 N sodium methyl acetate. 8, concentrated in vacuo and precipitated with 200 mL of ether. The sodium salt is filtered off with suction, dissolved in methanol and precipitated again with ether. 350 mg of sodium 17-hydroxy-17α- (3-hydroxysuccinyloxypropyl) -4,6-estradien-3-one are obtained, UV: δ285 = 25,900 (methanol). Example 31
Roztok 600 mg 17/3-hydroxy-17cr-(3-hydro-xysukcinyloxypropyl) -4,6-estradien-3-onu ve30 ml absolutního methanolu se upraví 0,1N roztokem methylátu draselného na hod-notu ρΗ 8. 'Po přesrážení v etheru se získá320 mg draselné soli 17/3’-hydroxy-17a-(3--hydroxysukcinyloxypropyl) -4,6-estradien--3-onu, UV: £284 = 26 300 (methanol).Příklad 32A solution of 600 mg of 17β-hydroxy-17α- (3-hydroxy-succininyloxypropyl) -4,6-estradien-3-one in 30 ml of absolute methanol was treated with 0.1 N potassium methylate at ρΗ8. in ether, 320 mg of 17 / 3'-hydroxy-17α- (3-hydroxysuccinyloxypropyl) -4,6-estradien-3-one potassium salt are obtained, UV: 284 = 26,300 (methanol).
Jak popsáno shora esterifikací 17|/3-hyd-roxy-r/a-(3-hydroxypropyij-4,b-estradien--3-onu anhydridem kyseliny glutarové v py-ridinu a následující reakcí s methylátemdraselným se připraví draselná sůl 17,/3-hyd-roxy-17a- (3-hydroxyglutaryloxypropyl) -4,6--estradien-3-onu ve formě amorfního práš-ku, UV (methanol): £285 = 24 100. P ř í k 1 a d 3 3 55 g lZjí-hydroxy-iya-fS-hydroxypropyl)--4,6-androstadien-3-onu se zahřívá v 350 mlpyridinu se 70 g trifenylmethylchloridu 40minut na parní lázni. Reakční směs se o-chladí, nalije pozvolna do 8 1 ledové vody,vysrážená látka se odsaje, promyje vodoua vysuší. Surový produkt se chromatogra-fuje na silikagelu a překrystaluje ze směsietheru a pentanu. Získá se 61,4 g 17/3-hyd-roxy-17a- (3-trif enylmethyloxypropyl) -4,6--androstadien-3-onu o teplotě tání 168 až169 °C. Příklad 34 27 g trimethylsulfoxoniumjodidu a 4,6 g55'% disperze hydridu sodného v oleji semíchá v 500 ml dimethylsulfoxidu 1,5 hodi-ny pod argonovou atmosférou. Poté se při-dá 55 g 17í/3-hydroxy-17a-(3-trifenylmethyl-oxypropyl)-4,6-androstadien-3-onu a míchá24 hodin při teplotě místnosti. Pak se při-dá voda, efxtrahuje octanem ethylnatým aoddělený octanový roztok se promyje vodoua odlpaří. Zbytek se chromatografuje na si-likagelu. Elucí směsi hexanu a octanu ethyl-n&tého se získá 26,5 g 6,7-methylenovéhoaduktu, sestávajícího ze 70 % z ;/3-methylen-a z 30 °/o z «i-methylensloučeniny. K rozštěpení etherové vazby se rozpustí 26,5 g 6,7-methylensloučeniny ve 170 ml80% kyseliny octové a zahřívá se 15 minutna parní lázni. Roztok se poté vlije do le-dové vody, vysrážený produkt se odsaje, vy-suší a překrystaluje ze směsi acetonu a he-xanu. Získá se 10 g 17í/3-hydroxy-17ai-.(i3--hydroxypropyl) -6/3',7./3-methylen-4-andros-ten-3-onu o teplotě tání 182 až 184 °C, UV:£266 = 18 800.As described above, the potassium salt of 17 is prepared by esterification of 17β-hydroxy-.alpha .- (3-hydroxypropyl-4, b-estradien-3-one with glutaric anhydride in pyridine and subsequent reaction with potassium methylate). 3-Hydroxy-17α- (3-hydroxyglutaryloxypropyl) -4,6-estradien-3-one as amorphous powder, UV (methanol): δ 285 = 24,100. 55 g of 1-hydroxy-3-hydroxypropyl) -4,6-androstadien-3-one are heated in 350 ml of pyridine with 70 g of triphenylmethyl chloride for 40 minutes on a steam bath. The reaction mixture is cooled, poured slowly into 8 l of ice water, the precipitated material is filtered off with suction, washed with water and dried. The crude product is chromatographed on silica gel and recrystallized from a mixture of ether and pentane. 61.4 g of 17β-hydroxy-17α- (3-triphenylmethyloxypropyl) -4,6-androstadien-3-one are obtained, m.p. 168 DEG -169 DEG. EXAMPLE 34 27 g of trimethylsulfoxonium iodide and 4.6 g of a 55% dispersion of sodium hydride in oil are mixed in 500 ml of dimethylsulfoxide under argon for 1.5 hours. Then 55 g of 17β-3-hydroxy-17α- (3-triphenylmethyl-oxypropyl) -4,6-androstadien-3-one are added and stirred for 24 hours at room temperature. Water was then added, extracted with ethyl acetate, and the separated acetate solution was washed with water and stripped. The residue is chromatographed on silica gel. Elution of a mixture of hexane and ethyl acetate gave 26.5 g of 6,7-methyleneductate, consisting of 70% (3-methylene) and 30% of the i-methylene compound. 26.5 g of the 6,7-methylene compound are dissolved in 170 ml of 80% acetic acid to dissolve the ether bond and heated in a steam bath for 15 minutes. The solution is then poured into ice water, the precipitated product is filtered off with suction, dried and recrystallized from acetone / hexane. 10 g of 17 [beta] -hydroxy-17 [alpha] - (3-hydroxypropyl) -6 [3 ', 7 ' -methylene-4-androsen-3-one are obtained, m.p. UV: 266 266 = 18,800.
Chromatografováním matečných louhů aChromatography of mother liquors a
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS786764A CS200509B2 (en) | 1976-03-05 | 1978-10-17 | Process for preparing 17alpha-/3-r2-oxypropyl/-17beta-r1-oxy-4-gonen-3-ones |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19762609694 DE2609694C3 (en) | 1976-03-05 | 1976-03-05 | 17 a- (3-Hydroxpropyl) -17 ß-hydroxy-7 a-thioalkanoyl-4-androsten-3-ones and process for their preparation |
| DE19762609695 DE2609695A1 (en) | 1976-03-05 | 1976-03-05 | (17-Alpha)-(3)-hydroxypropyl-(17-beta)-hydroxy androstenones - aldosterone antagonist type diuretics and intermediates for spironolactone |
| CS148077A CS200507B2 (en) | 1976-03-05 | 1977-03-04 | Process for preparing 17alpha-/3-r2-oxypropyl/-17beta-r1-oxy-4- genon-3-ones |
| CS786764A CS200509B2 (en) | 1976-03-05 | 1978-10-17 | Process for preparing 17alpha-/3-r2-oxypropyl/-17beta-r1-oxy-4-gonen-3-ones |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CS200509B2 true CS200509B2 (en) | 1980-09-15 |
Family
ID=27179333
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CS786764A CS200509B2 (en) | 1976-03-05 | 1978-10-17 | Process for preparing 17alpha-/3-r2-oxypropyl/-17beta-r1-oxy-4-gonen-3-ones |
Country Status (1)
| Country | Link |
|---|---|
| CS (1) | CS200509B2 (en) |
-
1978
- 1978-10-17 CS CS786764A patent/CS200509B2/en unknown
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