NO134058B - - Google Patents
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- NO134058B NO134058B NO4651/69A NO465169A NO134058B NO 134058 B NO134058 B NO 134058B NO 4651/69 A NO4651/69 A NO 4651/69A NO 465169 A NO465169 A NO 465169A NO 134058 B NO134058 B NO 134058B
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- compounds
- carbon atoms
- alkyl
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- 238000000034 method Methods 0.000 claims abstract description 29
- 150000001875 compounds Chemical class 0.000 claims description 38
- 125000004432 carbon atom Chemical group C* 0.000 claims description 10
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 239000012442 inert solvent Substances 0.000 claims description 6
- -1 lithium aluminum hydride Chemical compound 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 3
- 239000007795 chemical reaction product Substances 0.000 claims description 3
- 229910052987 metal hydride Inorganic materials 0.000 claims description 3
- 150000004681 metal hydrides Chemical class 0.000 claims description 3
- 125000001424 substituent group Chemical group 0.000 claims description 3
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 2
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000002112 pyrrolidino group Chemical group [*]N1C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 35
- 239000000243 solution Substances 0.000 description 30
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 28
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- 239000000203 mixture Substances 0.000 description 19
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 14
- 230000008018 melting Effects 0.000 description 13
- 238000002844 melting Methods 0.000 description 13
- 239000000047 product Substances 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 9
- 238000001704 evaporation Methods 0.000 description 6
- 230000008020 evaporation Effects 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 229960000583 acetic acid Drugs 0.000 description 5
- 229960004132 diethyl ether Drugs 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- 239000012362 glacial acetic acid Substances 0.000 description 4
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 4
- 238000005191 phase separation Methods 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- LDYUIVOAQFHBIO-UHFFFAOYSA-N n,n-dimethylprop-1-yn-1-amine Chemical compound CC#CN(C)C LDYUIVOAQFHBIO-UHFFFAOYSA-N 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 description 2
- 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 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 239000010949 copper Substances 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 230000001076 estrogenic effect Effects 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 230000001072 progestational effect Effects 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 101150058668 tra2 gene Proteins 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- PQMRKLSVUBRLLQ-XSYGEPLQSA-N (8r,9s,13s,14s)-13-ethyl-3-methoxy-4,6,7,8,9,11,12,14,15,16-decahydro-1h-cyclopenta[a]phenanthren-17-one Chemical compound C1C=C(OC)CC2=C1[C@H]1CC[C@](CC)(C(CC3)=O)[C@@H]3[C@@H]1CC2 PQMRKLSVUBRLLQ-XSYGEPLQSA-N 0.000 description 1
- NSUVCVKCWGOYPV-VXNCWWDNSA-N (8r,9s,13s,14s)-3-methoxy-13-methyl-4,6,7,8,9,11,12,14,15,16-decahydro-1h-cyclopenta[a]phenanthren-17-one Chemical compound C1C[C@@H]2C(CC=C(C3)OC)=C3CC[C@H]2[C@@H]2CCC(=O)[C@]21C NSUVCVKCWGOYPV-VXNCWWDNSA-N 0.000 description 1
- QARAXUHORATRQJ-UHFFFAOYSA-N 1,4-dioxane;pyridine Chemical compound C1COCCO1.C1=CC=NC=C1 QARAXUHORATRQJ-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 1
- 238000006683 Mannich reaction Methods 0.000 description 1
- 208000019255 Menstrual disease Diseases 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 101100011750 Mus musculus Hsp90b1 gene Proteins 0.000 description 1
- 206010067572 Oestrogenic effect Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 241000786363 Rhampholeon spectrum Species 0.000 description 1
- JEDZLBFUGJTJGQ-UHFFFAOYSA-N [Na].COCCO[AlH]OCCOC Chemical compound [Na].COCCO[AlH]OCCOC JEDZLBFUGJTJGQ-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- NVQOFWZLYDVFMU-UHFFFAOYSA-N azane;oxolane Chemical compound N.C1CCOC1 NVQOFWZLYDVFMU-UHFFFAOYSA-N 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N benzyl-alpha-carboxylic acid Natural products OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 229940124558 contraceptive agent Drugs 0.000 description 1
- 239000003433 contraceptive agent Substances 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 1
- 239000002178 crystalline material Substances 0.000 description 1
- 210000003785 decidua Anatomy 0.000 description 1
- XQKRYBXCYCKQLL-UHFFFAOYSA-N dimethylaminomethanol Chemical compound CN(C)CO XQKRYBXCYCKQLL-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229960004756 ethanol Drugs 0.000 description 1
- 239000002024 ethyl acetate extract Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- ZGEGCLOFRBLKSE-UHFFFAOYSA-N methylene hexane Natural products CCCCCC=C ZGEGCLOFRBLKSE-UHFFFAOYSA-N 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 1
- 229960003424 phenylacetic acid Drugs 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000012419 sodium bis(2-methoxyethoxy)aluminum hydride Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical group CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 101150117196 tra-1 gene Proteins 0.000 description 1
- 238000002211 ultraviolet spectrum Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Fremgangsmåte for fremstilling av 17a-propadienyl-17B-hydroksy-steroider.Process for the preparation of 17α-propadienyl-17β-hydroxy steroids.
Description
Foreliggende oppfinnelse vedrorer en fremgangsmåte for fremstilling av 17a-propadienyl-l7(3-hydroksy-steroider med den generalle formel The present invention relates to a method for the production of 17α-propadienyl-17(3-hydroxy steroids with the general formula
I IN
hvori R., betyr alkyl med 1-3 karbonatomer og Z betyr ringene A og B samt substituenter som befinner seg på disse og er gjengitt med delformlene Zl, Z4 og Z6-Z9 in which R. means alkyl with 1-3 carbon atoms and Z means the rings A and B as well as substituents located on these and are represented by the partial formulas Zl, Z4 and Z6-Z9
hvori R- betyr hydrogen, alkyl med 1-3 karbonatomer eller cykloalkyl med 5-7 karbonatomer. in which R- means hydrogen, alkyl with 1-3 carbon atoms or cycloalkyl with 5-7 carbon atoms.
De delstrukturer A og B av forbindelser med formel I, som er gjengitt ved formlene Zl, Z4 og Z6-Z9 kan angripes under slike reaksjonsbetingelser hvorunder man enten fremstiller de i det siste trinn anvendte utgangsprodukter, eller arbeider ved selve det siste trinn. Det er derfor et trekk ved oppfinnelsen at man kan beskytte de Z-strukturer som kan angripes under de ovennevnte reaksjonsbetingelser, ved hjelp av vanlige beskyttelsesgrupper, som er stabile under de angjeldenede reaksjonsbetingelser. Tilsvarende beskyttede grupper lar seg uten videre på kjent måte overfore i de bnskede Z-strukturer . Ved de i det folgende beskrevne omsetninger kan derfor Z-strukturene i de tilfeller, hvori tilsvarende beskyttede former-er mulig, foreligge i ubeskyttet eller foretrukket, beskyttet form, når intet annet sies. The partial structures A and B of compounds of formula I, which are represented by the formulas Z1, Z4 and Z6-Z9, can be attacked under such reaction conditions under which one either prepares the starting products used in the last step, or works in the last step itself. It is therefore a feature of the invention that the Z-structures which can be attacked under the above-mentioned reaction conditions can be protected by means of common protecting groups, which are stable under the reaction conditions in question. Correspondingly protected groups can easily be transferred in a known manner in the desired Z-structures. In the reactions described in the following, the Z-structures in the cases in which correspondingly protected forms are possible can therefore be present in an unprotected or preferably protected form, when nothing else is said.
Det særegne ved fremgangsmåten i henhold til oppfinnelsen er at forbindelser med formel V The peculiarity of the method according to the invention is that compounds of formula V
hvori R^ og Z har den ovennevnte betydning, RJq og RI' er like eller forskjellige og står i det enkelte tilfelle for alkyl med 1-3 karbonatomer eller danner sammen med nitrogenatomet en pyrrolidino eller piperidino-ring, RlQ står for alkyl med 1-3 karbonatomer og Y~ betyr en nukleofob avspaltingsgruppe, omsettes med et kompleks metallhydrid i et inert losningsmiddel og beskyttede Z-strukturer i de erholdte reaksjonsprodukter overfores i ubeskyttede Z-strukturer. in which R^ and Z have the above meaning, RJq and RI' are the same or different and in each case stand for alkyl with 1-3 carbon atoms or together with the nitrogen atom form a pyrrolidino or piperidino ring, RlQ stands for alkyl with 1- 3 carbon atoms and Y~ means a nucleophobic leaving group, is reacted with a complex metal hydride in an inert solvent and protected Z structures in the obtained reaction products are transferred into unprotected Z structures.
Disse og andre trekk ved fremgangsmåten i henhold til oppfinnelsen fremgår av patentkravene. These and other features of the method according to the invention appear in the patent claims.
Ved fremgangsmåten i henhold til oppfinnels en kan man som kompleks metallhydrid anvende f.eks. litium-aluminium-hydrid. Omsetningen lar seg gjennomfore ved temperaturer mellom omtrent -80 og +80°C, idet man som inert losningsmiddel f.eks. kan anvende dietyleter eller tetrahydrofuran. Hverken temperatur eller losningsmiddel er kritiske. Den nukleofobe gruppe Y~ kan f.eks. være en klor-, brom-, jod-, metansulfonat- eller p-toluensulfonat-rest. Substituentene <R>10' R10°^ Rl6 er f°retru^cet i ^et enkelte tilfelle like og utgjor foretrukket tilfelle metyl. In the method according to the invention, the complex metal hydride can be used, e.g. lithium aluminum hydride. The reaction can be carried out at temperatures between approximately -80 and +80°C, using as an inert solvent e.g. can use diethyl ether or tetrahydrofuran. Neither temperature nor solvent are critical. The nucleophobic group Y~ can e.g. be a chlorine, bromine, iodine, methanesulfonate or p-toluenesulfonate residue. The substituents <R>10' R10°^ R16 are retru^cet in a single case equally and constitute methyl in the preferred case.
Isoleringen av de således erholdte forbindelser med formel I kan skje på kjent måte. The isolation of the thus obtained compounds of formula I can take place in a known manner.
De ved fremgangsmåten i henhold til oppfinnelsen som u1:gangs-forbindelser anvendte forbindelser med formel V kan fremstilles ved at forbindelser med formel III The compounds of formula V used as starting compounds in the method according to the invention can be prepared by compounds of formula III
hvori Rjy r{q/ R{q og Z har den ovennevnte betydning, i et inert losningsmiddel, f.eks. aceton, ved temperaturer mellom -20 og + 30°C omséttes med forbindelser med formel VI wherein Rjy r{q/ R{q and Z have the above meaning, in an inert solvent, e.g. acetone, at temperatures between -20 and + 30°C is reacted with compounds of formula VI
hvori R^q og Y~ har den ovennevnte betydning. Hverken temperatur eller losningsmiddel er ved denne fremgangsmåte kritisk*wherein R^q and Y~ have the above meaning. Neither temperature nor solvent is critical in this method*
Forbindelser med formel III kan erholdes ved at forbindelser med formel II hvori R.^ og Z har den ovennevnte betydning, omsettes med forbindelser med formel IV Compounds of formula III can be obtained by reacting compounds of formula II in which R 1 and Z have the above meaning with compounds of formula IV
Al Zn hvori X står for litium, natrium, kalium, -MgBr, -MgJ, 3 eller ~2~" og R10 Savel som Rio' ^ar ^en ovennevnte betydning, og reaksjons-produktet hydrolyseres. Al Zn in which X stands for lithium, sodium, potassium, -MgBr, -MgJ, 3 or ~2~" and R 10 Savel as Rio' has the above-mentioned meaning, and the reaction product is hydrolyzed.
Omsetningen kan gjennomfores i et inert losningsmiddel, ved temperaturer mellom -30 og +100°C, foretrukket mellom -20 og +50°C. Hydrolysen kan foretas på kjent måte i et noytralt eller basisk vandig medium, f.eks. vann eller en mettet ammonium-kloridldsning. Det for omsetningen anvendte losningsmiddel retter seg etter den The reaction can be carried out in an inert solvent, at temperatures between -30 and +100°C, preferably between -20 and +50°C. The hydrolysis can be carried out in a known manner in a neutral or basic aqueous medium, e.g. water or a saturated ammonium chloride solution. The solvent used for the transaction follows it
i det enkelte tilfelle foreliggende metallandel av forbindelsene med formel IV. Hvis X står for -MgBr, -MgJ eller litium, kan man anvende dietyleter eller tetrahydrofuran. Hvis X--h©tyr natrium, in the individual case the metal proportion of the compounds of formula IV present. If X stands for -MgBr, -MgJ or lithium, diethyl ether or tetrahydrofuran can be used. If X--represents sodium,
lar ammoniakk-dietyleter, flytende ammoniakk-tetrahydrofuran, dioksan, pyridin eller dioksan-pyridin seg anvende som losningsmiddel. Hverken temperatur eller losningsmiddel er kritisk. allows ammonia-diethylether, liquid ammonia-tetrahydrofuran, dioxane, pyridine or dioxane-pyridine to be used as a solvent. Neither temperature nor solvent is critical.
Forbindelsene med formel III kan også fremstilles ved at forbindelser med formel VIII hvori R, og Z har den ovennevnte betydning, under Mannich-reaksjonsbetingelser omsettes med forbindelser med formel IX The compounds of formula III can also be prepared by reacting compounds of formula VIII in which R and Z have the above meaning under Mannich reaction conditions with compounds of formula IX
hvori R£q og RJ^ har den ovennevnte betydning. wherein R£q and RJ^ have the above meaning.
Omsetningen gjennomfores foretrukket i nærvær av Cu<+->ioner og små mengder av en svak syre, f.eks. eddiksyre, ved temperaturer mellom 10 og 80°C, foretrukket mellom 50 og 70°C, i et inert losningsmiddel, f.eks. dioksan eller tetrahydrofLiran. The reaction is preferably carried out in the presence of Cu<+> ions and small amounts of a weak acid, e.g. acetic acid, at temperatures between 10 and 80°C, preferably between 50 and 70°C, in an inert solvent, e.g. dioxane or tetrahydrofuran.
Enkelte forbindelser med formel II, VIII og IX er kjente og kan fremstilles etter fremgangsmåter som er beskrevet i litteraturen. Certain compounds of formula II, VIII and IX are known and can be prepared according to methods described in the literature.
De forbindelser med formel II, VIII og IX som ikke spesifikt er beskrevet i litteraturen, lar seg fremstille ved analoge metoder. The compounds of formula II, VIII and IX which are not specifically described in the literature can be prepared by analogous methods.
Forbindelsene med formler IV og VI er kjente og kan fremstilles etter fremgangsmåter beskrevet i litteraturen. The compounds with formulas IV and VI are known and can be prepared according to methods described in the literature.
Den avspaltbare gruppe Y~ kan enten være bundet ionisk (fcarbind-elsene med formel V) eller kovalent (forbindelsene med formel VI) „ The cleavable group Y~ can either be bound ionically (the compounds of formula V) or covalently (the compounds of formula VI)
Fremgangsmåter for beskyttelser av slike Z-strukturer, som må beskyttes, det vil si slike strukturer som inneholder karbonyl- Methods for the protection of such Z-structures, which must be protected, i.e. such structures containing carbonyl-
og hydroksy- grupper, er kjent fra litteraturen. Se f.eks. and hydroxy groups, are known from the literature. See e.g.
"The Protection of Carbonyl and Hydroxl Groups" av John F.W. "The Protection of Carbonyl and Hydroxyl Groups" by John F.W.
Keana i "Steroid Reactions, an Outline for Organic Chemists", Keana in "Steroid Reactions, an Outline for Organic Chemists",
Carl Djerassi, Holden-Day Inc., San Francisco (1963), Kapitel 1. Carl Djerassi, Holden-Day Inc., San Francisco (1963), Chapter 1.
Avspaltingen av beskyttelsesgruppene, spesielt tetrahydro-pyranylgruppen skjer foretrukket ved behandling med syrer i et under reaksjonsbetingelsene inert organisk losningsmiddel, f.eks. The removal of the protective groups, especially the tetrahydro-pyranyl group, preferably takes place by treatment with acids in an organic solvent inert under the reaction conditions, e.g.
ved hjelp av p-toluensulfonsyrehydrat eller llN saltsyre i metanol, etanol eller benzen eller iseddik og vann ved romtemperatur. using p-toluenesulfonic acid hydrate or 11N hydrochloric acid in methanol, ethanol or benzene or glacial acetic acid and water at room temperature.
US patentskrifter 3.392.165 og 3.392.166 omhandler forbindelser av samme type som de forbindelser som kan fremstilles ved hjelp av den foreliggende fremgangsmåte. De forbindelser som er omfattet av dé nevnte patentskrifter og som tilsvarer de ved den foreliggende fremgangsmåte fremstillbare forbindelser har ikke kunnet fremstilles ved de fremgangsmåter som er foreskrevet i de. nevnte patentskrifter, og de forbindelser med formel I som kan fremstilles ved hjelp av fremgangsmåten i henhold til den foreliggende oppfinnelse må således ansees som nye forbindelser. US patent documents 3,392,165 and 3,392,166 deal with compounds of the same type as the compounds that can be produced using the present method. The compounds which are covered by the aforementioned patents and which correspond to the compounds which can be produced by the present method have not been able to be produced by the methods prescribed in them. mentioned patents, and the compounds of formula I which can be prepared using the method according to the present invention must thus be considered as new compounds.
Forbindelsene med formel I utgjor verdifulle farmasoytika. De har The compounds of formula I constitute valuable pharmaceuticals. They have
en kombinert ostrogen og progestasjonal virkning (såkalt "decidua" - virkning). Ved forbindelser med formel I, hvor Z står for strukturen Zl er dog den ostrogene virkning mer utpreget. Ved forbindelser med formel I, hvor Z står for strukturene Z4 og Z6 a combined estrogenic and progestational effect (so-called "decidua" effect). However, with compounds of formula I, where Z stands for the structure Zl, the oestrogenic effect is more pronounced. In the case of compounds of formula I, where Z stands for the structures Z4 and Z6
til Z9, er.derimot den progestasjonale virkning utpreget. Tilsvarende kan forbindelsene med formel I anvendes i gynekologien, spesielt for behandling av menstruasjons-forstyrrelser, eller som befruktningshindrende middel. to Z9, on the other hand, the progestational effect is pronounced. Correspondingly, the compounds of formula I can be used in gynaecology, especially for the treatment of menstrual disorders, or as contraceptives.
Den daglig tilforte dose bor ligge mellom 0,01 og 10 mg. The daily added dose should be between 0.01 and 10 mg.
En foretrukket forbindelse er 17a-propadienyl6stra-4,9(10)-dien-170-0l3-on. A preferred compound is 17α-propadienylstra-4,9(10)-dien-170-013-one.
Den progrestasjonale virkningskomponent er overraskende sterk, se den folgende tabell med resultat av sammenligningsforsbk. The progressional impact component is surprisingly strong, see the following table with the results of the comparison experiment.
De i de folgende eksempler angitte NMR-spektre ble målt ved 60 megaherz i CDCl^-lbsning, under anvendelse av tetrametylsilan som standard. The NMR spectra given in the following examples were measured at 60 megahertz in CDCl 2 -lbsning, using tetramethylsilane as a standard.
Eksempel 1 l7a- propadienvl- 3- metoksvbstra- l, 3, 5( lQ)- trien- 17B- ol a) J^a-J^-djimetylarcano^ l10) - tr ien-17(3 -ol. Example 1 17a-propadienvl-3-methoxyvbstra-l,3,5(lQ)-trien-17B-ol a) J^a-J^-djimethylarcano^ l10)-trien-17(3 -ol.
En blanding av 15,8 g l7a-etynyl-3-metoksybstra-l,3,5-(lO)-trien-17|3-ol, 15 ml dimetylaminometanol, 500 mg kobber-I-klorid, 8,5 ml iseddik og 125 ml dioksan holdes i 5 timer ved 70°C. Deretter tilsettes isblandet vann, pH innstilles på 10 og den i overskriften nevnte forbindelse ekstraheres med eter. Det blir tilbake et skum med [a]^<0> = -8,84° (c = 1, CHC13). b) 17 a-j3-dimetylamino- l^-proj?ynyl2-3_-me toksyb s tra-1 j_3^_5_(l 0) - ;^^en-]^7j3-oJL-metjodid. A mixture of 15.8 g of 17α-ethynyl-3-methoxysystra-1,3,5-(10)-trien-17|3-ol, 15 ml of dimethylaminomethanol, 500 mg of copper I chloride, 8.5 ml of glacial acetic acid and 125 ml of dioxane are kept for 5 hours at 70°C. Ice-cold water is then added, the pH is adjusted to 10 and the compound mentioned in the title is extracted with ether. A foam with [a]^<0> = -8.84° (c = 1, CHC13) remains. b) 17 α-j3-dimethylamino-1^-proj?ynyl2-3_-me toxyb s tra-1 j_3^_5_(l 0) -;^^en-]^7j3-oJL-methiodide.
En blanding av 10,0 g av det i trinn a) erholdte fremgangsmåteprodukt, 290 ml aceton og 87 ml metyljodid holdes i 24 timer ved 0°C. Det bnskede produkt faller ut i krystallinsk form og isoleres ved filtrering. Smeltepunkt 237-239°C. A mixture of 10.0 g of the process product obtained in step a), 290 ml of acetone and 87 ml of methyl iodide is kept for 24 hours at 0°C. The desired product precipitates out in crystalline form and is isolated by filtration. Melting point 237-239°C.
c) ^7a-£rojjadienyl-3_-metoksybstra-1^3^5_^10 )-txien=17|3-ol. c) 7a-£rojjadienyl-3_-methoxysybstra-1^3^5_^10 )-txien=17|3-ol.
En suspensjon av 3,006 g av det i trinn b) erholdte fremgangsmåteprodukt i 65 ml vannfri tetrahydrofuran tilsettes ved -75 oC A suspension of 3.006 g of the process product obtained in step b) in 65 ml anhydrous tetrahydrofuran is added at -75 oC
11,25 ml av en 0,525 molar litium-aluminiumhydrid-tetrahydrofuran-lbsning. Etter 2 timers omrbring ved -10°C erholdes en klar lbsning som holdes over natten på romtemperatur. Det avkjbles til 0°C, tilsettes mettet vandig amminiumklorid-lbsning og den i overskriften nevnte forbindelse ekstraheres med eter. Herved erholdes et kvantitativt utbytte, regnet over samtlige de ovennevnte fremgangsmåtetrinn, av et krystallinsk material med et smeltepunkt 129,5 til 130,5°C. 11.25 ml of a 0.525 molar lithium aluminum hydride tetrahydrofuran solution. After 2 hours of stirring at -10°C, a clear solution is obtained which is kept overnight at room temperature. It is cooled to 0°C, saturated aqueous ammonium chloride solution is added and the compound mentioned in the title is extracted with ether. A quantitative yield, calculated over all the above-mentioned process steps, of a crystalline material with a melting point of 129.5 to 130.5°C is thereby obtained.
[ct]D = +7,18° (c = 1, CHC13). [ct]D = +7.18° (c = 1, CHCl 3 ).
Eksempel 2: l7a- propadienvlbstra- 4- en- 3B- 173- diol. Example 2: 17a-propadienevlbstra-4-ene-3B-173-diol.
Under de i eksempel 1 beskrevne betingelser og anvendelse av utgangsforbindelsen l7a-etynylbstra-4-en-3,176-diol kommer man under midlertidig dannelse av 17a-(3-diraet<y>lamino-l-<p>ro<p>ynyl)-ostra-4-en-3B-17B-diol, som anvendes videre i form av dens metjodid, frem til l7a-propadienyl6stra-4-en-36-178-diol med et smeltepunkt 72 til 79°C. Under the conditions described in example 1 and using the starting compound 17a-ethynylstra-4-ene-3,176-diol, 17a-(3-diraet<y>lamino-l-<p>ro<p>ynyl) is temporarily formed -ostra-4-ene-3B-17B-diol, which is further used in the form of its metiodide, up to 17a-propadienyl6stra-4-ene-36-178-diol with a melting point of 72 to 79°C.
Eksempel 3: l7a- propadienvl- 3- metoksyostra- 2, 5 ( lQ)- dien- 17S- ol. Example 3: 17a-propadienevl-3-methoxystra-2,5 (1Q)-diene-17S-ol.
a) 17 a-13-dirrtetylamino-^-proj?^ ^dien-17^-olia) 17 α-13-Dirtethylamino-^-proj?^ ^dien-17^-ol
En av 150 g magnesium, 4,68 g etylbromid og 70 ml tetrahydrofuran fremstilt Grignard-blanding tilsettes dråpevis 5,3 g diraetyl-aminopropyn, lost i 10 ml tetrahydrofuran. Etter avsluttet etan-utvikling tilsettes en losnihg av 1,716 g 3-metoksyostra-2,5(10)-dien-17-on i 30 ml tetrahydrofuran dråpevis, idet temperaturen under tilsetningen holdes ved 0 til 5 oC, og man lar deretter blandingen reagere i 4 timer ved 20 til 25°C. Etter tilsetning av 100 ml vandig 2N natriumhydroksydlosning konsentreres blandingen i vakuum ved temperaturer på ikke over 30°C til et totalvolum, på 100 ml. Konsentratet ekstraheres med eter (5 x 25 ml), idet man for å lette fase-separeringen sentrifugerer. Ved inndamping av de torrede eterlosninger og avsuging av et tilstede-værende overskudd av dimétylaminopropyn erholdes 17a-(3-dimetyl-amino-l-propynyl )-3-metoksy6stra-2, 5 (I0)-dien-176-ol. b) l_7a-l3-dirætylaminq-^-prcjpy^ ) - dien-12B-ol-me tj odidjj. A Grignard mixture prepared from 150 g magnesium, 4.68 g ethyl bromide and 70 ml tetrahydrofuran is added dropwise to 5.3 g diraethylaminopropyne, dissolved in 10 ml tetrahydrofuran. After completion of ethane evolution, a solution of 1.716 g of 3-methoxyestran-2,5(10)-dien-17-one in 30 ml of tetrahydrofuran is added dropwise, the temperature during the addition being kept at 0 to 5 oC, and the mixture is then allowed to react for 4 hours at 20 to 25°C. After adding 100 ml of aqueous 2N sodium hydroxide solution, the mixture is concentrated in vacuo at temperatures not exceeding 30°C to a total volume of 100 ml. The concentrate is extracted with ether (5 x 25 ml), centrifuging to facilitate phase separation. By evaporation of the dried ether solutions and suction of a present excess of dimethylaminopropyne, 17a-(3-dimethyl-amino-1-propynyl)-3-methoxystra-2,5(10)-dien-176-ol is obtained. b) 1_7a-13-direthylamineq-^-prcjpy^ )-dien-12B-ol-me tj odidjj.
2,0 g av den i avsnitt a) erholdte fremgangsmåteprodukt loses i 30 ml aceton. Etter tilsetning av 3,5 g metyljodid holdes blandingen i 18 timer ved 8°C. 17a-(3-dimetylamino-l-propynyl)-3-metoksyostra-2,5(l0)-dien-17B-ol-metjodidet utkrystalliserer, fra-fil treres og vaskes med vannfri eter. Dissolve 2.0 g of the process product obtained in section a) in 30 ml of acetone. After adding 3.5 g of methyl iodide, the mixture is kept for 18 hours at 8°C. The 17α-(3-dimethylamino-1-propynyl)-3-methoxyostra-2,5(10)-dien-17B-ol-methiodide crystallizes out, is filtered off and washed with anhydrous ether.
c) 17 a-p_rcj)adienyl-3-metoksy_6 s tra-2^5 J_l 0) -dien-173-ol. c) 17 α-p_rcj)adienyl-3-methoxy_6 s tra-2^5 J_l 0)-dien-173-ol.
Til en suspensjon av 2,5 g av det i avsnitt b) erholdte fremgangsmåteprodukt i 50 ml tetrahydrofuran tilsettes ved -75°C 9,3 ml av en 0,525 molar litium-aluminiumhydrid-tetrahydrofuran-lbsning. Blandingen bringes til -10°C og omrores til en klar losning erholdes (omtrent 90 minutter), og holdes deretter i 12 timer på romtemperatur. Det tilsettes 100 ml vandig 2N natriumhydroksydlosning, som inneholder 50 ml di-tert.-butylcresol, hvoretter blandingen inndampes i vakuum til et total-volum på To a suspension of 2.5 g of the process product obtained in section b) in 50 ml of tetrahydrofuran, 9.3 ml of a 0.525 molar lithium aluminum hydride tetrahydrofuran solution is added at -75°C. The mixture is brought to -10°C and stirred until a clear solution is obtained (about 90 minutes), and then kept for 12 hours at room temperature. 100 ml of aqueous 2N sodium hydroxide solution is added, which contains 50 ml of di-tert.-butylcresol, after which the mixture is evaporated in vacuo to a total volume of
100 ml. Etter ekstahering med 5 x 20 ml eter, faseseparering ved hjelp av en sentrifuge, torring av eterlosningene over kalium-karbonat og inndaming erholdes l7a-propadienyl-3-metoksyostra-2,5(10)-dien-178-ol med et smeltepunkt 160 til 163°C (fra metanol) (beskyttet form av de i eksemplene 4 og 5 beskrevne forbindelser). 100 ml. After extraction with 5 x 20 ml of ether, phase separation using a centrifuge, drying of the ether solutions over potassium carbonate and concentration, 17a-propadienyl-3-methoxyestro-2,5(10)-dien-178-ol is obtained with a melting point of 160 to 163°C (from methanol) (protected form of the compounds described in examples 4 and 5).
Eksempel 4: l7a- propadienvlbstra- 5( l0)- en- l70- ol- 3- on. Example 4: 17a-propadienevlbstra-5(10)-ene-170-ol-3-one.
2,0 g l7a-propadienyl-3-metoksyostra-2,5(I0)-dien-17@-ol, 2.0 g of 17α-propadienyl-3-methoxyostra-2,5(I0)-dien-17@-ol,
erholdt i henhold til eksempel 3, loses i en blanding av 20 ml iseddik og 2 ml vann. Etter 2 timer tilsettes 200 ml vann og produktet ekstraheres med etylacetat (5 x 10 ml). Etter av-damping av etylacetat-ekstrakten kommer man frem til 17a-propadienylbstra-5(10)-en-176-ol-3-on som krystallinsk faststoff med et smeltepunkt 110 til 112°C. obtained according to example 3, is dissolved in a mixture of 20 ml of glacial acetic acid and 2 ml of water. After 2 hours, 200 ml of water are added and the product is extracted with ethyl acetate (5 x 10 ml). After evaporation of the ethyl acetate extract, 17a-propadienylstra-5(10)-en-176-ol-3-one is obtained as a crystalline solid with a melting point of 110 to 112°C.
Eksempel 5; 17g- propadienylbstra- 4- en- 173- ol- 3- on. Example 5; 17g- propadienyl ester- 4- one- 173- ol- 3- one.
5,5 g 17a-propadienyl-3-metoksybstra-2,5(I0)-dien-173-ol, erholdt i henhold til eksempel 3, loses i en blanding av 50 ml metanol og 1,5 ml 11N vandig saltsyre og holdes i 30 minutter ved 30°C. Etter fortynning med 100 ml vann ekstraheres produktet med metylenklorid (5 x 15 ml). Etter inndamping av de tbrrede metylenklorid-lbsninger og påfblgende omkrystallisering av resten fra cykloheksan erholdes rent l7a-propadienylbstra-4-en-17(3-ol-3-on med et smeltepunkt 130-133°C. 5.5 g of 17α-propadienyl-3-methoxysybstra-2,5(10)-dien-173-ol, obtained according to Example 3, are dissolved in a mixture of 50 ml of methanol and 1.5 ml of 11N aqueous hydrochloric acid and kept for 30 minutes at 30°C. After dilution with 100 ml of water, the product is extracted with methylene chloride (5 x 15 ml). After evaporation of the diluted methylene chloride solutions and subsequent recrystallization of the residue from cyclohexane, pure 17a-propadienyl ester-4-en-17(3-ol-3-one) with a melting point of 130-133°C is obtained.
Eksempel 6; Etter fremgangsmåten i eksempel 3 og 5 erholdes Example 6; Following the procedure in examples 3 and 5 is obtained
under anvendelse av folgende utgangsprodukter: using the following starting products:
a) b s tron-3-te trahydropyranyle ter a) b s tron-3-te trahydropyranyl ter
b) 3-metoksy-13-etylgona-2,5(I0)-dien-17-on b) 3-methoxy-13-ethylgona-2,5(10)-dien-17-one
de folgende forbindelser: the following compounds:
a) 17a-propadienylbstra-l,3,5(l0)-trien-3,178-diol, smeltepunkt 134-136°C (fra metylen-klorid/heksan (1:5) a) 17a-propadienyl tetra-1,3,5(10)-triene-3,178-diol, melting point 134-136°C (from methylene chloride/hexane (1:5)
b) 13-etyl-l7a-propadienylgona-4-en-178-ol-3-on, b) 13-ethyl-17a-propadienylgona-4-ene-178-ol-3-one,
smeltepunkt 122-125°C. melting point 122-125°C.
Eksempel 7: 17g- propadienylostra- 4, 9( 10)- dien- 170- ol- 3- on Example 7: 17g-propadienylostra-4,9(10)-diene-170-ol-3-one
a) I7ac- (3-dimetvlamino-l-propynyl )-3-etylendioksyostra-IS (10). 9(111-dien-l70-ol. a) 17ac-(3-Dimethylamino-1-propynyl)-3-ethylenedioxystra-IS (10). 9(111-dien-170-ol.
En av 1,50 g magnesium, 4,68 g etylbromid og 70 ml tetrahydrofuran fremstilt Grignard-blahding tilsettes dråpevis 5,3 g dimetylaminopropyn, lost i 10 ml tetrahydrofuran. Etter opphor av etan-utviklingen tilsettes en losning av 1,9 g 3-etylendioksy-6stra-5(10),9,(11)-dien-17-on i 30 ml tetrahydrofuran dråpevis, idet temperaturen under tilsetningen holdes ved 0 til 5°C, og blandingen får deretter reagere i 4 timer ved 20 til 25°C. Etter To a Grignard solution prepared from 1.50 g of magnesium, 4.68 g of ethyl bromide and 70 ml of tetrahydrofuran, 5.3 g of dimethylaminopropyne, dissolved in 10 ml of tetrahydrofuran, is added dropwise. After the ethane evolution has ceased, a solution of 1.9 g of 3-ethylenedioxy-6stra-5(10),9,(11)-dien-17-one in 30 ml of tetrahydrofuran is added dropwise, the temperature during the addition being kept at 0 to 5°C, and the mixture is then allowed to react for 4 hours at 20 to 25°C. After
i in
tilsetning av 100 ml vandig 2N natriumhydroksydlosning inndampes blandingen i vakuum ved temperaturer på ikke over 30°C til et totalvolum på 100 ml. Konsentratet ekstraheres med eter (5 x 25 ml), idet man for å lette fase-separeringen sentrifugerer. Ved inndamping av torrede eterlosninger og avsuging av et tilstede-værende overskudd av dimetylaminopropyn erholdes den i overskriften nevnte forbindelse. addition of 100 ml of aqueous 2N sodium hydroxide solution, the mixture is evaporated in vacuo at temperatures not exceeding 30°C to a total volume of 100 ml. The concentrate is extracted with ether (5 x 25 ml), centrifuging to facilitate phase separation. By evaporation of dried ether solutions and suction of a present excess of dimethylaminopropyne, the compound mentioned in the title is obtained.
b) l7a-13-dimetylarrujiq-i-proj)^ (10J_. _ 9(lli-dien-170-ol-metjqdid^b) 17α-13-dimethylarrujiq-i-proj)^ (10J_. _ 9(lli-dien-170-ol-metjqdid^
2,1 g av det ovenfor erholdte fremgangsmåteprodukt loses i 30 na aceton. Etter tilsetning av 3/5 g metyljodid holdes blandingen i 18 timer ved 8°C. Den i overskriften nevnte forbindelse utkrystalliserer, frafiltreres og vaskes med vannfri eter. c) 3-ety_lendioksjy-12ariP£0£adienYlbs^a-5 (10J., 9 (i12-dien-l 70-ol. 2.1 g of the process product obtained above is dissolved in 30 na acetone. After adding 3/5 g of methyl iodide, the mixture is kept for 18 hours at 8°C. The compound mentioned in the title crystallizes out, is filtered off and washed with anhydrous ether. c) 3-ethyl_lendioxy-12ariP£0£adienYlbs^a-5 (10J., 9 (i12-dien-1 70-ol.
Til en suspensjon av 2,6 g av det ovenfor erholdte fremgangsmåteprodukt i 50 ml tetrahydrofuran tilsettes ved -75°C 9,3 ml av en , 0. 525 molar litiumaluminiumhydrid-tetrahydrofuranlosning. Blandingen bringes til -10°C og omrores til det erholdes en klar losning (omtrent 90 minutter) og holdes deretter i 12 timer ved romtemperatur. Det tilsettes 100 ml vandig 2N natriumhydroksydlosning, som inneholder 50 ml di-tert.-butylcresol, hvoretter blandingen inndampes i vakuum til et totalvolum på 100 ml. Etter ekstrahering med 5 x 20 ml eter, fase-separering ved hjelp av en sentrifuge, torring av eterlosningen over kaliumkarbonat og inndamping erholdes 3-etylendioksy-17a-propadienyl6stra-5(10),9 (ll)-dien-173-ol. To a suspension of 2.6 g of the process product obtained above in 50 ml of tetrahydrofuran, 9.3 ml of a 0.525 molar lithium aluminum hydride-tetrahydrofuran solution is added at -75°C. The mixture is brought to -10°C and stirred until a clear solution is obtained (about 90 minutes) and then kept for 12 hours at room temperature. 100 ml of aqueous 2N sodium hydroxide solution is added, which contains 50 ml of di-tert.-butylcresol, after which the mixture is evaporated in vacuo to a total volume of 100 ml. After extraction with 5 x 20 ml of ether, phase separation using a centrifuge, drying of the ether solution over potassium carbonate and evaporation, 3-ethylenedioxy-17a-propadienylstra-5(10),9(11)-dien-173-ol is obtained.
d) i7a-£rpj>a^dienylbstra-4J_9J^l0 )-dien-17J3-ql-3-on. d) i7a-£rpj>a^dienylbstra-4J_9J^l0 )-dien-17J3-ql-3-one.
Den under avsnitt c) erholdte 3-etylendioksy-17oc-propadienyl-6stra-5(l0), 9(11 )-dien-17(3-ol loses i en blanding av 50 ml metanol og 1,5 ml UN vandig saltsyre og holdes i 30 minutter ved 30°C. Etter fortynning med 100 ml vann ekstraheres produktet med metylenklorid (5 x 15 ml). Etter inndamping av de torrede metylen-kloridlosninger og etterfolgende omkrystallisering av resten fra cykloheksan erholdes rent l7a-propadienylostra-4,9(10)-dien-170-ol-3-on med et smeltepunkt111-113°C. The 3-ethylenedioxy-17oc-propadienyl-6stra-5(l0),9(11)-dien-17(3-ol) obtained under section c) is dissolved in a mixture of 50 ml methanol and 1.5 ml UN aqueous hydrochloric acid and kept for 30 minutes at 30° C. After dilution with 100 ml of water, the product is extracted with methylene chloride (5 x 15 ml). After evaporation of the dried methylene chloride solutions and subsequent recrystallization of the residue from cyclohexane, pure 17a-propadienylstra-4,9 is obtained (10)-dien-170-ol-3-one with a melting point of 111-113°C.
U.V. spektrum i etanol med ^ maks = 302,5 m, = 14.100 NMR-spektrum med singletter ved 5,7 ppm og -1,08 ppm. UV spectrum in ethanol with ^ max = 302.5 m, = 14,100 NMR spectrum with singlets at 5.7 ppm and -1.08 ppm.
1. R.-spektrum med 3590 cm"^ og 1950 cm"^. 1. R. spectrum at 3590 cm"^ and 1950 cm"^.
Eksempel 8: 3- metoksy- l7g- propadienylostra- 2, 5( 10)- dien- 170- ol. Example 8: 3-methoxy-17g-propadienylstra-2,5(10)-diene-170-ol.
a) 17 a-13 -NrPiper idino-J-^propynyl) - 3 -me otksyo s tr a- 2, 5 (i0j_-di en-170_-ol^ a) 17 a-13 -NrPiper idino-J-^propynyl) - 3 -me otksyo s tr a- 2, 5 (i0j_-di en-170_-ol^
Til en losning av 50g l7a-etyl-3-metoksyostra-2,5(10)-dien-170-ol For a solution of 50g of 17a-ethyl-3-methoxyestr-2,5(10)-dien-170-ol
i 50 ml dioksan tilsettes 200 mg kobber(I)klorid, 5 g N-piperidino-karbinol og 0,2 ml iseddik. Blandingen holdes i 1 time ved 200 mg of copper (I) chloride, 5 g of N-piperidinocarbinol and 0.2 ml of glacial acetic acid are added to 50 ml of dioxane. The mixture is kept for 1 hour at
en temperatur mellom 40 og 50°C, avkjbles deretter og pH-verdien innstilles ved tilsetning av en 2N vandig natriumhydroksydlosning til 9. Blandingen fortynnes fderetter med vann og den utfelte a temperature between 40 and 50°C, is then cooled and the pH value is adjusted by adding a 2N aqueous sodium hydroxide solution to 9. The mixture is then diluted with water and the precipitated
olje ekstraheres med metylenklorid. Metylenkloirdekstakten vaskes 3 ganger med vann, torres deretter over vannfritt snatrium-sulfat, filtreres og inndampes til tbrrhet. Herved erholdes 17a-(3-N-piperidino-l-propynyl)-3-metoksy-bstra-2,5(I0)-dien-l70-ol. oil is extracted with methylene chloride. The methylene chloride extract is washed 3 times with water, then dried over anhydrous sodium sulfate, filtered and evaporated to dryness. This gives 17a-(3-N-piperidino-1-propynyl)-3-methoxy-stra-2,5(10)-dien-170-ol.
b) 17a(3-N-p.ip.eridino-l^propynyl)-3-metoksyostra-2, 5 (IQ)-dien-17£-ol-metjpdid. 50 g 17a-(3-N-piperidino-l-propynyl)-3-metoksybstra-2,5(lO)-dien-170-ol loses i 50 ml aceton og losningen tilsettes under omroring 5 ml metyljodid. Deretter omrores videre i 30 minutter ved romtemperatur. Blandingen fortynnes med 150 ml dietyleter, hvorved det dannes et bunnfall, som frafiltreres og vaskes med dietyleter. Etter torring erholdes 17a-(3-N-piperidino-l-propynyl)-3-metoksyostra-2,5(I0)-dien-170-ol-metjodid. b) 17a(3-N-p.ip.eridino-1^propynyl)-3-methoxystra-2,5(IQ)-diene-17£-ol-methjpdid. 50 g of 17a-(3-N-piperidino-1-propynyl)-3-methoxysybstra-2,5(10)-dien-170-ol are dissolved in 50 ml of acetone and 5 ml of methyl iodide is added to the solution while stirring. It is then stirred for 30 minutes at room temperature. The mixture is diluted with 150 ml of diethyl ether, whereby a precipitate is formed, which is filtered off and washed with diethyl ether. After drying, 17a-(3-N-piperidino-1-propynyl)-3-methoxyestra-2,5(10)-dien-170-ol-methiodide is obtained.
c) 17 a-propadieny1-3 -me toksyb s tra^^S Jl 0) -di en-17£-ol^ c) 17 a-propadieny1-3 -me toxyb s tra^^S Jl 0) -di en-17£-ol^
14 g 17a-(3-N-piperidino-l-propynyl)-3-metoksybstra-2,5(10)-dien-170-ol-metjodid oppslemmes i 420 ml tetrahydrofuran og suspensjonen tilsettes under sterk omroring 4,5 ml av en 70%-lbsning av natriumbis-(2-metoksyetoksy)-aluminiumhydrid i benzen, idet tilsetningen skjer i 3 porsjoner. Den erholdte suspensjon omrores ved romtemperatur i 4 timer. Overskuddet av hydridet spaltes deretter ved tilsetning av 1 ml vann og deretter av 5 ml av en 10%-vandig natriumhydroksydlosning. Det herved dannede bunnfall frafiltreres og vaskes med tetrahydrofuran. Filtratet og vaskelbsningen forenes og inndampes i vakuum til en sirupaktig rest. Resten loses i metylenklorid og den erholdte losning vaskes flere ganger med vann til vaskelbsningen reagerer nbytral. Deretter torres losningen over natriumsulfat, frafiltreres og inndampes til tbrrhet. Herved kommer man frem til 17a-propadienyl-3-metoksybstra-2,5(10)-dien-170-ol med et smeltepunkt 160 til 163°C (fra metanol) 14 g of 17a-(3-N-piperidino-1-propynyl)-3-methoxysystra-2,5(10)-dien-170-ol-methiodide are suspended in 420 ml of tetrahydrofuran and the suspension is added with vigorous stirring to 4.5 ml of a 70% solution of sodium bis-(2-methoxyethoxy)-aluminum hydride in benzene, the addition being made in 3 portions. The resulting suspension is stirred at room temperature for 4 hours. The excess of the hydride is then cleaved by the addition of 1 ml of water and then of 5 ml of a 10% aqueous sodium hydroxide solution. The resulting precipitate is filtered off and washed with tetrahydrofuran. The filtrate and washing solution are combined and evaporated in vacuo to a syrupy residue. The residue is dissolved in methylene chloride and the resulting solution is washed several times with water until the washing solution reacts neutrally. The solution is then dried over sodium sulphate, filtered off and evaporated to dryness. This leads to 17a-propadienyl-3-methoxysybstra-2,5(10)-dien-170-ol with a melting point of 160 to 163°C (from methanol)
(beskyttet form av de i eksemplene 4 og 5 beskrevne forbindelser). (protected form of the compounds described in examples 4 and 5).
Eksempel 9: l7a- propadienyl- 3- metoksyostra- 2, 5( 10)- dien- 170- ol. a) 17a-jS-N^yrrol^idino-1-propinyl)-3-metoksyqstra-2_, 5 U0_)_-dien-170-ol. Example 9: 17a-propadienyl-3-methoxystra-2,5(10)-diene-170-ol. a) 17a-[S-N-[pyrrole]idino-1-propynyl)-3-methoxystra-2_, 5 O_)_-dien-170-ol.
Under anvendelse av den i avsnitt a) av eksempel 8 beskrevne fremgangsmåte, men ved erstatning av den der anvendte N-piperidino-karbinol med ekvivalente mengder av N-pyrrolidino-karbinol kommer man frem til 17a-(3-N-pyrrolidino-l-propynyl)-3-metoksy-bstra-2,5(I0)-dien-170-ol. Using the method described in section a) of example 8, but by replacing the N-piperidino-carbinol used there with equivalent amounts of N-pyrrolidino-carbinol, 17a-(3-N-pyrrolidino-1- propynyl)-3-methoxy-bstra-2,5(10)-dien-170-ol.
b) 17a-13-N^pyrrolidino^l^pcppynyl)-3-metoksyostra-2.,.5 (!0j-di en-120 -ol -me tj odid^ b) 17a-13-N^pyrrolidino^1^pcppynyl)-3-methoxystra-2.,.5 (!0j-di en-120 -ol -me tj odid^
Under anvendelse av den i avsnitt b) av eksempel 8 beskrevne fremgangsmåte, men ved erstatning av den der anvendte 17a-(3-N-piperidion-l-propynyl)-3-metoksy6stra-2,5(10)-dien-170-ol med ekvivalente mengder av 17a-(3-N-pyrrolidino-lpropynyl)-3-metoksy-bstra-2,5(I0)-dien-170-ol kommer man frem til 17a-(3-N-pyrrolidino-l-propynyl )-3-metoksyos tra-2 , 5(I0)-dien-170-ol-metjodid. Using the method described in section b) of example 8, but by replacing the 17a-(3-N-piperidione-1-propynyl)-3-methoxystrata-2,5(10)-diene-170- ol with equivalent amounts of 17a-(3-N-pyrrolidino-1propynyl)-3-methoxy-bstra-2,5(10)-dien-170-ol one arrives at 17a-(3-N-pyrrolidino-1- propynyl )-3-methoxyisos tra-2 , 5(10)-dien-170-ol-methiodide.
c) 17 a-propadienyl-3-me toksyos tra-2, 5(10) -di^en-17|3-ol^ c) 17 α-propadienyl-3-me toxyose tra-2, 5(10)-di^ene-17|3-ol^
Under anvendelse av den i avsnitt c) av eksempel 8 beskrevne Using the one described in section c) of example 8
fremgangsmåte, men ved erstatning av det der anvendte 17a-(3-N-piperidino-l-propynyl ) -3-me toksyos tra-2, 5(I0)-dien-170-ol-metjodid med ekvivalente mengder av 17a-(3-N-pyrrolidino-l-propynyl)-3-metoksyostra-2, 5(10)-dien-l70-ol-metjodid kommer man frem til 17a-propadienyl-3-metoksyostra-2,5(10)-dien-170-ol med et smeltepunkt 160-163°C .(fra metanol) (beskyttet form av de i eksemplene 4 og 5 beskrevne forbindelser.) method, but by replacing the 17a-(3-N-piperidino-1-propynyl)-3-methoxyostra-2,5(10)-dien-170-ol-methiodide used there with equivalent amounts of 17a-( 3-N-pyrrolidino-1-propynyl)-3-methoxystra-2, 5(10)-dien-170-ol-methiodide gives 17a-propadienyl-3-methoxystra-2,5(10)-dien- 170-ol with a melting point 160-163°C. (from methanol) (protected form of the compounds described in examples 4 and 5.)
Eksempel 10: Example 10:
Under anvendelse av de i avsnittene a), b) og c) i eksempel 1 beskrevne fremgangsmåter og utgangsforbindelsene Using the methods described in sections a), b) and c) in example 1 and the starting compounds
a) l7a-etynyl6stra-4-en-170-ol og a) 17a-ethynyl6stra-4-en-170-ol and
b) 17a-etynyl-3-cyklopentyloksyostra-l, 3, 5 (10 )-trien-170-ol b) 17α-ethynyl-3-cyclopentyloxystra-1, 3, 5 (10 )-trien-170-ol
kommer man frem til you arrive at
a) 17a-propadienyl6stra-4-en-17|3-ol med et smeltepunkt 120-125°C og a) 17a-propadienylstra-4-en-17|3-ol with a melting point of 120-125°C and
b) 3-cyklopentyloksy-17a-propadienylbstra-l,3,5(10)-trien-l70- b) 3-cyclopentyloxy-17a-propadienylstra-1,3,5(10)-trien-170-
ol med et smeltepunkt 105-109°C. etc. with a melting point of 105-109°C.
Claims (2)
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NO742821A NO134059C (en) | 1968-11-25 | 1974-08-05 |
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CS (5) | CS150692B2 (en) |
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ES (2) | ES387606A1 (en) |
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US3385871A (en) * | 1965-12-15 | 1968-05-28 | Syntex Corp | Halogenated cyclopropyl and cyclopropenyl estratrienes and process for their preparation |
US3392166A (en) * | 1966-03-30 | 1968-07-09 | Syntex Corp | Androst-4-enes and estr-4-enes having a 17alpha-diethylenically unsaturated side chain |
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1969
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