NO120793B - - Google Patents
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- NO120793B NO120793B NO162524A NO16252466A NO120793B NO 120793 B NO120793 B NO 120793B NO 162524 A NO162524 A NO 162524A NO 16252466 A NO16252466 A NO 16252466A NO 120793 B NO120793 B NO 120793B
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- Norway
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- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 64
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 32
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 22
- -1 1-formylmethylene compounds Chemical class 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 18
- 150000001875 compounds Chemical class 0.000 claims description 14
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 14
- 239000001257 hydrogen Substances 0.000 claims description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims description 11
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims description 11
- 125000004043 oxo group Chemical group O=* 0.000 claims description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
- 150000002334 glycols Chemical class 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 7
- 238000003776 cleavage reaction Methods 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- 239000012285 osmium tetroxide Substances 0.000 claims description 7
- 229910000489 osmium tetroxide Inorganic materials 0.000 claims description 7
- 230000007017 scission Effects 0.000 claims description 7
- PQUCIEFHOVEZAU-UHFFFAOYSA-N Diammonium sulfite Chemical compound [NH4+].[NH4+].[O-]S([O-])=O PQUCIEFHOVEZAU-UHFFFAOYSA-N 0.000 claims description 6
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 claims description 6
- 230000008569 process Effects 0.000 claims description 6
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 5
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 claims description 5
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 5
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims description 5
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- KRVSOGSZCMJSLX-UHFFFAOYSA-L chromic acid Substances O[Cr](O)(=O)=O KRVSOGSZCMJSLX-UHFFFAOYSA-L 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- AWJWCTOOIBYHON-UHFFFAOYSA-N furo[3,4-b]pyrazine-5,7-dione Chemical compound C1=CN=C2C(=O)OC(=O)C2=N1 AWJWCTOOIBYHON-UHFFFAOYSA-N 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 4
- 125000003172 aldehyde group Chemical group 0.000 claims description 3
- 230000032050 esterification Effects 0.000 claims description 3
- 238000005886 esterification reaction Methods 0.000 claims description 3
- 239000000543 intermediate Substances 0.000 claims description 3
- 229910052762 osmium Inorganic materials 0.000 claims description 3
- SYQBFIAQOQZEGI-UHFFFAOYSA-N osmium atom Chemical compound [Os] SYQBFIAQOQZEGI-UHFFFAOYSA-N 0.000 claims description 3
- KHIWWQKSHDUIBK-UHFFFAOYSA-N periodic acid Chemical compound OI(=O)(=O)=O KHIWWQKSHDUIBK-UHFFFAOYSA-N 0.000 claims description 3
- 230000008707 rearrangement Effects 0.000 claims description 3
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 3
- 125000000468 ketone group Chemical group 0.000 claims description 2
- 150000003128 pregnanes Chemical class 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- 229920006395 saturated elastomer Polymers 0.000 claims description 2
- 239000003470 adrenal cortex hormone Substances 0.000 claims 1
- JEHCHYAKAXDFKV-UHFFFAOYSA-J lead tetraacetate Chemical compound CC(=O)O[Pb](OC(C)=O)(OC(C)=O)OC(C)=O JEHCHYAKAXDFKV-UHFFFAOYSA-J 0.000 claims 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 42
- 239000000243 solution Substances 0.000 description 38
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 28
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 26
- 238000002844 melting Methods 0.000 description 24
- 230000008018 melting Effects 0.000 description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- QSKWJTXWJJOJFP-UHFFFAOYSA-N chloroform;ethoxyethane Chemical compound ClC(Cl)Cl.CCOCC QSKWJTXWJJOJFP-UHFFFAOYSA-N 0.000 description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 15
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 14
- 239000000047 product Substances 0.000 description 13
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 12
- 239000003054 catalyst Substances 0.000 description 11
- 239000000203 mixture Substances 0.000 description 11
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 10
- HWJHWSBFPPPIPD-UHFFFAOYSA-N ethoxyethane;propan-2-one Chemical compound CC(C)=O.CCOCC HWJHWSBFPPPIPD-UHFFFAOYSA-N 0.000 description 10
- 229910052938 sodium sulfate Inorganic materials 0.000 description 10
- 235000011152 sodium sulphate Nutrition 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 239000013078 crystal Substances 0.000 description 9
- 239000000706 filtrate Substances 0.000 description 9
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 8
- 239000007858 starting material Substances 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 7
- 230000009467 reduction Effects 0.000 description 7
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 7
- 235000017557 sodium bicarbonate Nutrition 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 239000005909 Kieselgur Substances 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 238000005984 hydrogenation reaction Methods 0.000 description 5
- 239000010410 layer Substances 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 4
- 229960000583 acetic acid Drugs 0.000 description 4
- VTYYLEPIZMXCLO-UHFFFAOYSA-L calcium carbonate Substances [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- 238000000354 decomposition reaction Methods 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 230000008020 evaporation Effects 0.000 description 4
- 230000033444 hydroxylation Effects 0.000 description 4
- 238000005805 hydroxylation reaction Methods 0.000 description 4
- 230000007935 neutral effect Effects 0.000 description 4
- 229910052763 palladium Inorganic materials 0.000 description 4
- OMIHGPLIXGGMJB-UHFFFAOYSA-N 7-oxabicyclo[4.1.0]hepta-1,3,5-triene Chemical compound C1=CC=C2OC2=C1 OMIHGPLIXGGMJB-UHFFFAOYSA-N 0.000 description 3
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 229910000019 calcium carbonate Inorganic materials 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000012362 glacial acetic acid Substances 0.000 description 3
- 150000002596 lactones Chemical class 0.000 description 3
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 3
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 3
- 235000015497 potassium bicarbonate Nutrition 0.000 description 3
- 239000011736 potassium bicarbonate Substances 0.000 description 3
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 229910052725 zinc Inorganic materials 0.000 description 3
- 239000011701 zinc Substances 0.000 description 3
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical group C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-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
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- CHIHQLCVLOXUJW-UHFFFAOYSA-N benzoic anhydride Chemical compound C=1C=CC=CC=1C(=O)OC(=O)C1=CC=CC=C1 CHIHQLCVLOXUJW-UHFFFAOYSA-N 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 239000003245 coal Substances 0.000 description 2
- NPOMSUOUAZCMBL-UHFFFAOYSA-N dichloromethane;ethoxyethane Chemical compound ClCCl.CCOCC NPOMSUOUAZCMBL-UHFFFAOYSA-N 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 230000036571 hydration Effects 0.000 description 2
- 238000006703 hydration reaction Methods 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 239000007800 oxidant agent Substances 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 150000003431 steroids Chemical class 0.000 description 2
- CWERGRDVMFNCDR-UHFFFAOYSA-N thioglycolic acid Chemical compound OC(=O)CS CWERGRDVMFNCDR-UHFFFAOYSA-N 0.000 description 2
- ZNOKGRXACCSDPY-UHFFFAOYSA-N tungsten trioxide Chemical compound O=[W](=O)=O ZNOKGRXACCSDPY-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 238000010626 work up procedure Methods 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-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-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- 230000005526 G1 to G0 transition Effects 0.000 description 1
- YZCKVEUIGOORGS-UHFFFAOYSA-N Hydrogen atom Chemical compound [H] YZCKVEUIGOORGS-UHFFFAOYSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- 150000001241 acetals Chemical class 0.000 description 1
- 230000021736 acetylation Effects 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 230000001919 adrenal effect Effects 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 229960002478 aldosterone Drugs 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 238000011001 backwashing Methods 0.000 description 1
- UENWRTRMUIOCKN-UHFFFAOYSA-N benzyl thiol Chemical compound SCC1=CC=CC=C1 UENWRTRMUIOCKN-UHFFFAOYSA-N 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 239000002026 chloroform extract Substances 0.000 description 1
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 150000002084 enol ethers Chemical class 0.000 description 1
- 150000002085 enols Chemical class 0.000 description 1
- 239000012259 ether extract Substances 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 229910010272 inorganic material Inorganic materials 0.000 description 1
- 239000011147 inorganic material Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- ACKFDYCQCBEDNU-UHFFFAOYSA-J lead(2+);tetraacetate Chemical compound [Pb+2].CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O ACKFDYCQCBEDNU-UHFFFAOYSA-J 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- MJGFBOZCAJSGQW-UHFFFAOYSA-N mercury sodium Chemical compound [Na].[Hg] MJGFBOZCAJSGQW-UHFFFAOYSA-N 0.000 description 1
- QLNWXBAGRTUKKI-UHFFFAOYSA-N metacetamol Chemical compound CC(=O)NC1=CC=CC(O)=C1 QLNWXBAGRTUKKI-UHFFFAOYSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- WURFKUQACINBSI-UHFFFAOYSA-M ozonide Chemical compound [O]O[O-] WURFKUQACINBSI-UHFFFAOYSA-M 0.000 description 1
- 238000004810 partition chromatography Methods 0.000 description 1
- 235000021395 porridge Nutrition 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229960003975 potassium Drugs 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000012286 potassium permanganate Substances 0.000 description 1
- 150000003126 pregnane derivatives Chemical class 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- 238000006894 reductive elimination reaction Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000003578 releasing effect Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 150000007659 semicarbazones Chemical class 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- CLDWGXZGFUNWKB-UHFFFAOYSA-M silver;benzoate Chemical compound [Ag+].[O-]C(=O)C1=CC=CC=C1 CLDWGXZGFUNWKB-UHFFFAOYSA-M 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 229910001023 sodium amalgam Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- MUUHXGOJWVMBDY-UHFFFAOYSA-L tetrazolium blue Chemical compound [Cl-].[Cl-].COC1=CC(C=2C=C(OC)C(=CC=2)[N+]=2N(N=C(N=2)C=2C=CC=CC=2)C=2C=CC=CC=2)=CC=C1[N+]1=NC(C=2C=CC=CC=2)=NN1C1=CC=CC=C1 MUUHXGOJWVMBDY-UHFFFAOYSA-L 0.000 description 1
- 150000007970 thio esters Chemical class 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/32—Oxygen atoms
- C07D209/34—Oxygen atoms in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/32—Oxygen atoms
- C07D209/38—Oxygen atoms in positions 2 and 3, e.g. isatin
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
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Description
Fremgangsmåte til fremstilling av hydrofenantrenforbindelser. Process for the production of hydrophenanthrene compounds.
Foreliggende oppfinnelse angår en fremgangsmåte til fremstilling av forbindelser med formelen The present invention relates to a method for producing compounds with the formula
hvori Rt og R3 betyr en fri eller funksjonelt avledet oxy- eller oxogruppe og Ra også kan være et hydrogenatom, R2 betyr en metylgruppe eller et hydrogenatom, R-t en fri eller funksjonelt avledet aldehydgruppe eller en deri overførbar rest, Y betyr hydrogen eller en metyl- eller fri eller funksjonelt avledet oksymetylgruppe eller deres derivater som er umettet i ringsystemet, som er mellomprodukter til fremstilling av viktige fysiologisk aktive 18-oxygenerte pregnanderivater. Fremgangsmåten er karakterisert ved at man i ringsystemet mettede eller umettede forbindelser med formelen in which Rt and R3 mean a free or functionally derived oxy or oxo group and Ra can also be a hydrogen atom, R2 means a methyl group or a hydrogen atom, R-t a free or functionally derived aldehyde group or a residue transferable therein, Y means hydrogen or a methyl- or free or functionally derived oxymethyl group or their derivatives which are unsaturated in the ring system, which are intermediates for the preparation of important physiologically active 18-oxygenated pregnane derivatives. The method is characterized by saturated or unsaturated compounds with the formula in the ring system
hvori Ri og R:s betyr fri eller funksjonelt avledede oxy- eller oxo-grupper og R3 også kan bety et hydrogenatom, R2 og Ro en metylgruppe eller et hydrogenatom, Rt en fri eller funksjonelt avledet aldehydgruppe eller en deri overførbar rest og Rs betyr en kullvannstoffrest, hydroxylerer dobbeltbindingen av metallyl- henholdsvis allylresten eller tilleirer ozon til denne og spalter de erholdte ozonider, overfører den substituerte etinylrest i erholdte glykoler eller in which Ri and R's mean free or functionally derived oxy or oxo groups and R3 can also mean a hydrogen atom, R2 and Ro a methyl group or a hydrogen atom, Rt a free or functionally derived aldehyde group or a radical transferable therein and Rs means a carbon hydrogen residue, hydroxylates the double bond of the metalyl or allyl residue or adds ozone to this and cleaves the resulting ozonides, transfers the substituted ethynyl residue into the resulting glycols or
2-acetonylforbindelser ved reduksjon til en etylenrest, underkaster erholdte primær-tertiære glykoler en glykolspaltning, eller 2-acetonyl compounds upon reduction to an ethylene residue, subject the obtained primary-tertiary glycols to a glycol cleavage, or
i erholdte primær-sekundære glykoler, oxyderer den sekundære hydroxylgruppe til oxogruppe, omleirer de erholdte 1-oxy- in obtained primary-secondary glycols, oxidizes the secondary hydroxyl group to oxo group, rearranges the obtained 1-oxy-
1-etenyl- til 1-formylmetylenforbindelser og i disse avmetter den semicykliske dobbeltbinding med hydrogen. 1-ethenyl to 1-formylmethylene compounds and in these it desaturates the semicyclic double bond with hydrogen.
Særlig viktige utgangsstoffer er ketoderivater av forbindelser med formelen Particularly important starting materials are keto derivatives of compounds with the formula
hvori Ro og Rc, har den ovennevnte betydning og X betyr en oxo- eller fri eller funksjonelt avledet hydroxygruppe. wherein Ro and Rc have the above meaning and X means an oxo or free or functionally derived hydroxy group.
Hydroxyleringen av dobbeltbindingen i metallyl- og allylresten i 2-stilling lar seg oppnå med forskjellige oxydasjonsmidler. Særlig egnede oxydasjonsmidler er f. eks. osmiumtetroxyd, vannstoffperoxyd i nærvær av katalytiske mengder osmiumtetroxyd eller wolframtrioxyd, kaliumpermanga-nat, videre sølvbenzoat og jod. Spaltningen av osmiumsyreesteren kan også foretas uten samtidig hydrolyse av en for hånden værende 3,3-etylendioxy-gruppe, når man utfører denne reaksjon f. eks. ved hjelp av ammoniumsulfit. The hydroxylation of the double bond in the metallyl and allyl residue in the 2-position can be achieved with various oxidizing agents. Particularly suitable oxidizing agents are e.g. osmium tetroxide, hydrogen peroxide in the presence of catalytic amounts of osmium tetroxide or tungsten trioxide, potassium permanganate, further silver benzoate and iodine. The cleavage of the osmium acid ester can also be carried out without simultaneous hydrolysis of an available 3,3-ethylenedioxy group, when carrying out this reaction e.g. using ammonium sulphite.
Tilleiringen av ozon til dobbeltbindingen i metallylresten i 2-stilling foretas for-trinsvis i klorerte kullvannstoffer som opp-løsningsmiddel, f. eks. i kloroform. Spaltningen av de erholdte ozonider skjer med fordel på reduktiv måte, f. eks. med sink i vandig eddiksyre under tilsetning av pyridin. The addition of ozone to the double bond in the metalyl residue in the 2-position is preferably carried out in chlorinated coal water substances as a solvent, e.g. in chloroform. The cleavage of the obtained ozonides advantageously takes place in a reductive way, e.g. with zinc in aqueous acetic acid with the addition of pyridine.
Den substituerte etinylrest i 1-stilling kan særlig lett overføres til en etenylrest ved hjelp av katalytisk aktivert hydrogen. Som katalysatorer anvender man særlig palladium- eller blykatalysatorer, hensiktsmessig på bærestoffer, og arbeider i nærvær av et for den selektive reduksjon egnet oppløsningsmiddel, slik som pyridin. The substituted ethynyl residue in the 1-position can be particularly easily transferred to an ethenyl residue by means of catalytically activated hydrogen. As catalysts, in particular palladium or lead catalysts are used, suitably on carriers, and work in the presence of a solvent suitable for the selective reduction, such as pyridine.
For glykolspaltningen av de primær-tertiære glykoler, som oppstår ved hydroxylering av utgangsstoffet med en metall-ylrest i 2-stilling og etterfølgende omdan-ning av 1-etinylresten til en etinylrest, anvender man i første rekke perjodsyre eller blytetraacetat, videre også acyljodosoacyla-ter. For the glycol cleavage of the primary-tertiary glycols, which occurs by hydroxylation of the starting material with a metal-yl residue in the 2-position and subsequent conversion of the 1-ethynyl residue into an ethynyl residue, periodic acid or lead tetraacetate is primarily used, and also acyl iodosoacyl ter.
En variant av fremgangsmåten består i at man i primær-sekundære glykoler, som A variant of the method consists in primary-secondary glycols, such as
er dannet ved hydroxylering av utgangsstoffet med en allylrest i 2-stilling og etter-følgende reduksjon av etinylresten i 1-stilling til etenyl-resten, oxyderer den sekundære oxygruppe til oxogruppe, f. eks. ved hjelp av kromsyre i nærvær av en or-ganisk base, slik som pyridin. Før denne oxydasjon beskyttes den primære hydroxylgruppe i glykolet hensiktsmessig ved overføring til et funksjonelt derivat, f. eks. ved forestring. Forestringen foregår på i og for seg kjent måte, idet man arbeider med den for en hydroxylgruppe beregnede mengde acyleringsmiddel. is formed by hydroxylation of the starting material with an allyl residue in the 2-position and subsequent reduction of the ethynyl residue in the 1-position to the ethenyl residue, the secondary oxy group oxidizes to an oxo group, e.g. using chromic acid in the presence of an organic base, such as pyridine. Before this oxidation, the primary hydroxyl group in the glycol is suitably protected by transfer to a functional derivative, e.g. by esterification. The esterification takes place in a manner known per se, working with the amount of acylating agent calculated for a hydroxyl group.
Omleiringen av 1-oxy-l-etenyl-forbindelser til 1-formylmetylen-forbindelser foregår ved innvirkning av hydrolyserende henholdsvis isomeriserende virkende mid-ler. Hvis denne omleiring skal lykkes uten at samtidig tilstedeværende 3,3-etylendioxy-grupper angripes, anvender man for denne omsetning hensiktsmessig halogeni-der av fosfor- eller undersvovelsyrer, f. eks. fosfortribromid eller tionylklorid, i nærvær av egnede oppløsningsmidler, slik som metylenklorid, kloroform og organiske baser, f. eks. pyridin. The rearrangement of 1-oxy-1-ethenyl compounds to 1-formylmethylene compounds takes place under the influence of hydrolysing or isomerizing agents. If this rearrangement is to be successful without simultaneously present 3,3-ethylenedioxy groups being attacked, halides of phosphoric or hyposulphuric acids, e.g. phosphorus tribromide or thionyl chloride, in the presence of suitable solvents, such as methylene chloride, chloroform and organic bases, e.g. pyridine.
Forskjellige reduksjonsmetoder egner seg for overføringen av 1-formyl-metylen-til en 1-formylmetylrest. Den katalytiske hydrering i nærvær av palladium-eller nikkel-katalysatorer, innvirkning av nascerende hydrogen fremstilt f. eks. ved hjelp av natriumamalgam i vannholdige oppløsningsmidler, slik som fuktig eter, eller ved hjelp av et aikalimetall, slik som natrium, kalium eller litium i nærvær av flytende ammoniakk eller et lavere alifa-tisk amin skal nevnes. Sluttelig kan den selektive reduksjon av den semicykliske dobbeltbinding også foretas på indirekte måte, f. eks. ved tilleiring av en tioforbin-delse, f. eks. av benzylmerkaptan eller tio-glykolsyre, til dobbeltbindingen og påføl-gende reduktiv eliminering av den tillei-rede svovelholdige substituent, f. eks. ved hjelp av Raney-nikkel. Various reduction methods are suitable for the transfer of 1-formyl-methylene to a 1-formylmethyl residue. The catalytic hydrogenation in the presence of palladium or nickel catalysts, the effect of nascent hydrogen produced e.g. by means of sodium amalgam in aqueous solvents, such as moist ether, or by means of an alkali metal, such as sodium, potassium or lithium in the presence of liquid ammonia or a lower aliphatic amine should be mentioned. Finally, the selective reduction of the semicyclic double bond can also be carried out in an indirect way, e.g. by addition of a thio compound, e.g. of benzyl mercaptan or thio-glycolic acid, to the double bond and subsequent reductive elimination of the added sulphur-containing substituent, e.g. using Raney nickel.
Med funksjonelle derivater av ovenstående forbindelser forstår man slike som inneholder funksjonelt avledede oxy-, oxo-og/eller syregrupper, slik som f. eks. estere, etere, tioestere, tioetere, tiol- og tionester, acetaler, merkaptaler, ketaler, enolderiva-ter, slik som enolester, enoleter eller en-aminer, hydrazoler, semikarbazoner o. 1. By functional derivatives of the above compounds are understood those which contain functionally derived oxy-, oxo- and/or acid groups, such as e.g. esters, ethers, thioesters, thioethers, thiol and thionesters, acetals, mercaptals, ketals, enol derivatives, such as enol esters, enol ethers or en-amines, hydrazoles, semicarbazones etc. 1.
Fremgangsmåteproduktene er mellomprodukter til fremstilling av nye, viktige fysiologisk virksomme forbindelser fra pre-gnanrekken med en oxygenfunksjon i 18-stilling som har en virkning som binyrehor-monene, slik som f. eks. aldosteron eller det lakton av A<4->3,20-dioxo-ll|3-oxy-21-acet-oxy-pregnen-18-syre, som er karakterisert ved sin natriumutskillende virkning. The process products are intermediates for the production of new, important physiologically active compounds from the pregnane series with an oxygen function in the 18-position which has an effect like the adrenal hormones, such as e.g. aldosterone or the lactone of Δ<4->3,20-dioxo-11|3-oxy-21-acet-oxy-pregnen-18-acid, which is characterized by its sodium-releasing action.
Fremgangsmåteproduktene kan ved The process products can by
cyklisering ved hjelp av et alkalisk konden-sasjonsmiddel overføres til steroider med formelen cyclization using an alkaline condensing agent is transferred to steroids with the formula
eller deres derivater som er umettet i rin-gene A, B og C, idet Ri — Ri og Y har den betydning som er angitt ovenfor for fremgangsmåteproduktene. Etter metning av dobbeltbindingen i 16,17-stilling kan disse steroider overføres til de ovenfor nevnte fysiologisk virksomme forbindelser, ifølge den fremgangsmåte som er angitt i Norsk patent nr. 95 012 og Norsk patent nr. 95 014. Av de forbindelser som kan fåes ifølge foreliggende fremgangsmåte er særlig slike med formelen hvori X betyr en oxogruppe, eller en fri eller funksjonelt avledet hydroxylgruppe og R5 betyr et hydrogenatom eller en fri eller funksjonelt avledet hydroxylgruppe og deres 3-ketoderivater, av særlig betydning. Utgangsstoffene er av vilkårlig sterisk konfigurasjon og kan f. eks., idet man går ut fra kullstoffatom 8a, oppvise en dobbeltbinding. De kan fremstilles etter i og for seg kjente fremgangsmåter, f. eks. ifølge følgende reaksjonsskjema fra det kjente, såkalte «Sårett Keton». Reaksjonene ifølge oppfinnelsen kan f. eks. anskueliggjøres ved hjelp av følgende reaks j onsskj ema: or their derivatives which are unsaturated in the rings A, B and C, with Ri — Ri and Y having the meaning indicated above for the process products. After saturation of the double bond in the 16,17 position, these steroids can be transferred to the above-mentioned physiologically active compounds, according to the method stated in Norwegian patent no. 95 012 and Norwegian patent no. 95 014. Of the compounds that can be obtained according to present method are particularly those with the formula in which X means an oxo group, or a free or functionally derived hydroxyl group and R5 means a hydrogen atom or a free or functionally derived hydroxyl group and their 3-keto derivatives, of particular importance. The starting substances are of arbitrary steric configuration and can, for example, starting from carbon atom 8a, exhibit a double bond. They can be produced according to procedures known per se, e.g. according to the following reaction scheme from the well-known, so-called "Wounded Ketone". The reactions according to the invention can e.g. can be visualized using the following reaction scheme:
Oppfinnelsen beskrives i de følgende eksempler. Mellom volumdel og vektsdel består det samme forhpld som mellom gram og cm<3>. Temperaturen er angitt i Celsius-grader. The invention is described in the following examples. Between volume part and weight part there is the same ratio as between gram and cm<3>. The temperature is indicated in degrees Celsius.
Eksempel 1: Example 1:
En vannfri oppløsning av 4,43 vektsdeler av (2 -> 4|3)-lakton av A<8>a-l-etoxyeti-nyl-2a-metallyl-2|3-karboxy-4b(3-metyl-7-etylendioxy-l, 2, 3, 4a<x, 4b, 5, 6, 7, 8, 10, lOap-dodekahydrofenantren-1, 4|3-diol i 300 volumdeler eter og 2,1 volumedeler pyridin tilsettes under etterspyling med 25 volumdeler eter 2,80 vektsdeler osmiumtetroxyd og omrører blandingen 2 timer ved romtemperatur. Den utfelte osmium-syreester bringer man deretter ved tilsetning av 1000 volumdeler metanol i opp-løsning og tilsetter under omrøring 1000 volumdeler av en 0,25-molar vandig opp-løsning av ammoniumsulfit. Etter ennå en time suger man fra det utfelte anorga-niske materiale gjennom et lag av Super Cel og inndamper filtratet i vakuum ved romtemperatur til ca. en femtedel av det opprinnelige volum. Det i halvfast form utfelte hydroxyleringsprodukt opptas i metylenklorid-eterblanding (3 : 1), opp-løsningen vaskes med vann, tørkes med natriumsulfat og inndampes i vakuum Fra litt eter får man (2 _> 4|3)lakton av A<8>a-1-etoxyetinyl-2a-(2\ 3'-dioxy-isobutyl)-2(3-karboxy-4bp-metyl-7-etylen-dioxy-l, 2, 3, 4, 4aa, 4b, 5, 6, 7, 8, 10, 10a|3-dodekahydrofenantren-l,4|3-diol som epimerblanding med smeltepunkt 127—153,5° C (dekomponering) . An anhydrous solution of 4.43 parts by weight of (2 -> 4|3)-lactone of A<8>a-l-ethoxyethynyl-2a-methallyl-2|3-carboxy-4b(3-methyl-7-ethylenedioxy- 1, 2, 3, 4a<x, 4b, 5, 6, 7, 8, 10, 1Oap-dodecahydrophenanthrene-1, 4|3-diol in 300 parts by volume of ether and 2.1 parts by volume of pyridine are added while backwashing with 25 parts by volume ether 2.80 parts by weight osmium tetroxide and stir the mixture for 2 hours at room temperature. The precipitated osmium acid ester is then brought into solution by adding 1,000 parts by volume of methanol and, with stirring, 1,000 parts by volume of a 0.25-molar aqueous solution of ammonium sulphite are added. After another hour, the precipitated inorganic material is sucked through a layer of Super Cel and the filtrate is evaporated in a vacuum at room temperature to approx. one fifth of the original volume. The semi-solid precipitated hydroxylation product is taken up in a methylene chloride-ether mixture (3 : 1), the solution is washed with water, dried with sodium sulphate and evaporated in vacuo. α-1-ethoxyethynyl-2a-(2\ 3'-dioxy-isobutyl)-2(3-carboxy-4bp-methyl-7-ethylene-dioxy-1, 2, 3, 4, 4aa, 4b, 5, 6 , 7, 8, 10, 10a|3-dodecahydrophenanthrene-1,4|3-diol as epimer mixture with melting point 127-153.5° C (decomposition).
En oppløsning av 3,678 vektsdeler av (2 - y 4(5j-laktonet av A8a-l-etoxyetinyl-2<x-(2', 3'-dioxy-isobutyl) -2|3-karboxy-4bp-metyl-7-etylendioxy-l, 2, 3, 4, 4aa, 4b, 5, 6, 7, 8, 10, 10ap-dodekahydrofenantren-l,4|3-diol i 77,5 volumdeler vannfri pyridin rystes i nærvær av 1,54 vektsdeler av en 10 %'s palladium-kalsiumkarbonat-katalysator med hydrogen. Hydreringen kommer etter et gassopptak på en molekvivalent til stillstand. Det filtreres deretter gjennom et sjikt Super Cel fra katalysatoren og filtratet inndampes i vakuum. Ved krystallisasjon fra eter får man (2 4pj-laktonet av A<8>a-l-etoxyetenyl-2a-(2', 3'-dioxyisobutyl)-2p-karboxy-4bp-metyl-7-etylendioxy-l, 2,3, 4, 4aa, 4b, 5, 6, 7, 8, 10, 10ap-dodekah<y>dro-fenantren-l,4p-diol som epimerblanding i fine prismer med smeltepunkt 148—151° C. A solution of 3.678 wt. ethylenedioxy-l, 2, 3, 4, 4aa, 4b, 5, 6, 7, 8, 10, 10ap-dodecahydrophenanthrene-l,4|3-diol in 77.5 parts by volume of anhydrous pyridine is shaken in the presence of 1.54 parts by weight of a 10% palladium-calcium carbonate catalyst with hydrogen. The hydrogenation comes to a standstill after a gas absorption of one molar equivalent. It is then filtered through a layer of Super Cel from the catalyst and the filtrate is evaporated in vacuum. Crystallization from ether gives (2 4pj -lactone of A<8>a-1-ethoxyethenyl-2a-(2', 3'-dioxyisobutyl)-2p-carboxy-4bp-methyl-7-ethylenedioxy-1, 2,3, 4, 4aa, 4b, 5, 6 , 7, 8, 10, 10ap-dodecah<y>dro-phenanthrene-1,4p-diol as epimer mixture in fine prisms with melting point 148—151° C.
For glykolspaltning oppløser man 3,071 vektsdeler (2 _> 4p)-laktonet av A<8>a-l-etoxyetenyl-2a-(2', 3'-dioxyisobutyl)-2p-kar-boxy-4bp-metyl-7-etylendioxy-l, 2, 3, 4, For glycol cleavage, 3.071 parts by weight of the (2 _> 4p)-lactone of A<8>a-1-ethoxyethenyl-2a-(2', 3'-dioxyisobutyl)-2p-carboxy-4bp-methyl-7-ethylenedioxy-1 are dissolved , 2, 3, 4,
4aa, 4b, 5, 6, 7, 8, 10, 10ap-dodekahydrofenantren-l,4p-diol i 45,0 volumdeler metanol og 8,8 volumdeler pyridin og lar etter blanding med 9,65 volumdeler 1-molar vandig perjodsyreoppløsning stå 1 time ved romtemperatur. Man tilsetter deretter 26,5 volumdeler vann og 96,5 volumdeler 0,1-molar vandig natriumhydrogenkarbonat-oppløsning og inndamper blandingen i vakuum ved 20,25° C, sterkt. Ekstrahering med eter-metylenklorid-blanding (3 : 1), vasking med ekstrakten med iskold 0,5-molar o-fosforsyre, iskold 0,1-molar natriumhy-drogenkarbonatoppløsning og isvann, tør-king med natriumsulfat og inndampning gir en nesten fargeløs krystallinsk rest. Derav får man ved omkrystallisasjon fra eter og under anvendelse av metylenklorid som oppløsningsformidler (2 4p)-laktonet av A<8>a-l-etoxyetenyl-2a-acetonyl-2p-karboxy-4bp-metyl-7-etylendioxy-l, 2, 3, 4, 4aa, 4b, 5, 6, 7, 8, 10, 10ap-dodekahydrofenantren-1, 4p-diol i fargeløse fine prismer med smeltepunkt 122—124° C. 4aa, 4b, 5, 6, 7, 8, 10, 10ap-dodecahydrophenanthrene-1,4p-diol in 45.0 parts by volume methanol and 8.8 parts by volume pyridine and after mixing with 9.65 parts by volume 1-molar aqueous periodic acid solution 1 hour at room temperature. 26.5 parts by volume of water and 96.5 parts by volume of 0.1-molar aqueous sodium bicarbonate solution are then added and the mixture is evaporated in a vacuum at 20.25° C. vigorously. Extraction with an ether-methylene chloride mixture (3:1), washing with the extract with ice-cold 0.5-molar o-phosphoric acid, ice-cold 0.1-molar sodium bicarbonate solution and ice-water, drying with sodium sulfate and evaporation gives an almost colorless crystalline residue. From this, recrystallization from ether and using methylene chloride as a solvent gives the (2 4p)-lactone of A<8>a-1-ethoxyethenyl-2a-acetonyl-2p-carboxy-4bp-methyl-7-ethylenedioxy-1, 2, 3 , 4, 4aa, 4b, 5, 6, 7, 8, 10, 10ap-dodecahydrophenanthrene-1, 4p-diol in colorless fine prisms with melting point 122-124° C.
En vannfri oppløsning av 8,930 vektsdeler (2^ 4p)-laktonet av A<R>il- 1-etoxyetenyl-2a-acetonyl-2p-karboxy-4bp-metyl-7-etylendioxy-1, 2, 3, 4, 4aa, 4b, 5, 6, 7, 8, 10, lOap-dodekahydrofenantren-l, 4p-diol i 96,0 volumdeler kloroform og 4,05 volumdeler pyridin tilsettes ved 0° C innen 15 minutter 100 volumdeler av en på fosfortribromid 0,5 molar og på pyridin 2-molar oppløsning i vannfri kloroform og omrøres i nitrogenatmosfære 4 timer ved 0° C. Man heller deretter blandingen i 750 volumdeler 1-molar natrium - hydrogenkarbonatoppløsning og is og ek-straherer med kloroform og eter. Kloroform- og kloroformeter-uttrekkene vaskes med 0,6-N.o-fosforsyre, 1-molar natrium-hydrogenkarbonatoppløsning og vann, deretter slås de sammen og etter tørking med natriumsulfat inndampes under formins-ket trykk. Resten omkrystalliseres fra aceton-eter-blanding (a. 1 : 3) under anvendelse av metylenklorid som oppløsnings-formidler. Man får det rene (2_>4pj-laktonet av A<8>"-l,l-formylmetylen-2a-aceton-yl-2p-karboxy-4bp-metyl-7-etylendioxy-l, 2, 3, 4, 4aa, 4b, 5, 6, 7, 8, 10, 10ap-dodekahydrofenantren-4p-ol i nesten fargeløse prismer med smeltepunkt = 183,5—187° C. For-bindelsen reduserer alkalisk sølvdiamin-oppløsning momentant. An anhydrous solution of 8.930 parts by weight of the (2^ 4p)-lactone of A<R>yl- 1-ethoxyethenyl-2a-acetonyl-2p-carboxy-4bp-methyl-7-ethylenedioxy-1, 2, 3, 4, 4aa, 4b, 5, 6, 7, 8, 10, lOap-dodecahydrophenanthrene-1, 4p-diol in 96.0 parts by volume of chloroform and 4.05 parts by volume of pyridine are added at 0° C within 15 minutes 100 parts by volume of a on phosphorus tribromide 0.5 molar and on pyridine 2-molar solution in anhydrous chloroform and stirred in a nitrogen atmosphere for 4 hours at 0° C. The mixture is then poured into 750 parts by volume of 1-molar sodium bicarbonate solution and ice and extracted with chloroform and ether. The chloroform and chloroform ether extracts are washed with 0.6-N.o-phosphoric acid, 1-molar sodium bicarbonate solution and water, then they are combined and, after drying with sodium sulphate, evaporated under reduced pressure. The residue is recrystallized from an acetone-ether mixture (a. 1:3) using methylene chloride as a solvent. The pure (2_>4pj-lactone of A<8>"-1,1-formylmethylene-2a-aceton-yl-2p-carboxy-4bp-methyl-7-ethylenedioxy-1, 2, 3, 4, 4aa .
For selektiv avmetning av den semicykliske dobbeltbinding rystes en suspen-sjon av 4,006 vektsdeler finpulverisert (2_^ 4pj-lakton av A<8>a-l,l-formylmetylen-2a-acetonyl-2|3-karboxy--4b|3-metyl - 7 -etylendioxy-1, '2, 3, 4, 4aa, 4b, 5, 6, 7, 8, 10, 10ap-dodekahydrofenantren-4p-ol i 800 volumdeler 95 %' s etanol i nærvær av 2,00 vektsdeler av en 10 %'s palladiumkalsiumkarbo-nat-katalysator med hydrogen av atmo-sfæretrykk. Utgangsmaterialet går derved litt etter litt i oppløsning og etter opptak av 1 molekvivalent gass kommer hydreringen praktisk talt til stillstand. Man filtrerer deretter katalysatoren fra gjennom et sjikt Super Cel og inndamper det blanke filtrat i vakuum til lite volum. Derved krystalliserer (2-^ 4p)-laktonet av A<8>"-ip-for-mylmetyl-2a-acetonyl-2p-karboxy-4bp-metyl-7-etylendioxy-l, 2, 3, 4, 4aa, 4b, 5, 6, 7, 8, 10, 10ap-dodekah<y>drofenantren-4p-ol i fargeløse krystaller med smeltepunkt 193— 204,4° C (delvis dekomponering). Forbin-delsen reduserer alkalisk sølvdiaminoppløs-ning hurtig og sterkt. For selective desaturation of the semicyclic double bond, a suspension of 4.006 parts by weight of finely powdered (2_^ 4pj-lactone of A<8>a-1,1-formylmethylene-2a-acetonyl-2|3-carboxy--4b|3-methyl - 7-ethylenedioxy-1, '2, 3, 4, 4aa, 4b, 5, 6, 7, 8, 10, 10ap-dodecahydrophenanthren-4p-ol in 800 parts by volume of 95% ethanol in the presence of 2.00 parts by weight of a 10% palladium calcium carbonate catalyst with hydrogen of atmospheric pressure. The starting material thereby dissolves little by little and after absorption of 1 mole equivalent of gas the hydrogenation practically comes to a standstill. The catalyst is then filtered out through a layer of Super Cel and evaporate the clear filtrate in vacuo to a small volume. Thereby crystallizes the (2-^ 4p)-lactone of A<8>"-ip-for-mylmethyl-2a-acetonyl-2p-carboxy-4bp-methyl-7-ethylenedioxy-l , 2, 3, 4, 4aa, 4b, 5, 6, 7, 8, 10, 10ap-dodecah<y>drophenanthren-4p-ol in colorless crystals with melting point 193— 204.4° C (partial decomposition). -division reduces alkaline silver diamine resolution fast and strong.
Eksempel 2: Example 2:
84 vektsdeler (2 4p)-laktonet av A<8>a-l-etoxyetinyl-2ce-metallyl-2p-karboxy-4bp^ metyl-7-etylendioxy-l, 2, 3, 4, 4aa, 4b, 5, 6, 7, 8, 10, 10ap-dodekahydrofenantren-l,4p-diol oppløses i 80 volumdeler pyridin og 520 volumdeler kloroform. Deretter ledes ved —15° C til —18° C under sterk omrø-ring i 142 minutter ozonholdig luft eller ozonholdig oxygen inn, idet det pr. minutt trer 0,056 vektsdeler ozon i reaksjon. Deretter fortrenger man det oppløste oxygen ved innledning av nitrogen og tilsetter en til —15° C avkjølt blanding av 100 volumdeler vann, 100 volumdeler iseddik og 200 volumdeler pyridin til reaksjonsoppløsnin-gen umiddelbart fulgt av en av 100 vektsdeler sinkstøv ved aktivering med fortyn-net iseddiksyre fremstilt vandig sinkgrøt i ca. 5 porsjoner. Reduksjonen av ozonidet er avsluttet ved —18° C til —3° C innen 15 minutter. Ved rask avsugning og etterspyling med benzol fjerner man overskuddet av sink. Det organiske sjikt av filtratet befris for sinksaltet og sure bestanddeler ved flere gangers vasking med vann og deretter med natriumhydrogenkarbonatopp-løsning. Det vandige sjikt ekstraheres igjen ved utrystning med benzol. De forenede med natriumsulfat grundig tørkede organiske oppløsninger inndampes i vakuum og resten befris for pyridin i høyvakuum. Man oppløser råproduktet i 1200 volumdeler benzol og filtrerer gjennom et 6 cm tykt sjikt av aluminiumoxyd (aktivitet 2). Ved inndampning av filtratet krystalliserer 60 vektsdeler av (2 _> 4|3)-laktonet av A<8>a-l-etoxyetinyl-2a-acetonyl-2(3-karboxy-4b(3-metyl-7-etylendioxy-l, 2, 3, 4, 4aa, 4b, 5, 6, 7, 8, 10, 10ap-dodekahydrofenantren-l,4p-diol i fargeløse krystaller som smelter under dekomponering ved 157—158° C. Som videre krystallf raks jon fåes det ved 179° C likeledes under dekomponering smeltende i 1-stilling isomere produkt. Ved kromatografi med aluminiumoxyd får man videre 11 til 13 vektsdeler av det som hoved-produkt erholdte isomere med smeltepunkt 157—158° C. 84 parts by weight (2 4p)-lactone of A<8>a-1-ethoxyethynyl-2ce-methallyl-2p-carboxy-4bp^ methyl-7-ethylenedioxy-1, 2, 3, 4, 4aa, 4b, 5, 6, 7 , 8, 10, 10ap-dodecahydrophenanthrene-1,4p-diol is dissolved in 80 parts by volume of pyridine and 520 parts by volume of chloroform. Then ozone-containing air or ozone-containing oxygen is introduced at -15° C to -18° C under vigorous stirring for 142 minutes, as per minute, 0.056 parts by weight of ozone react. The dissolved oxygen is then displaced by introducing nitrogen and a mixture cooled to -15° C of 100 parts by volume of water, 100 parts by volume of glacial acetic acid and 200 parts by volume of pyridine is added to the reaction solution immediately followed by one of 100 parts by weight of zinc dust by activation with the dilute Glacial acetic acid prepared aqueous zinc porridge for approx. 5 portions. The reduction of the ozonide is complete at -18°C to -3°C within 15 minutes. By quickly vacuuming and rinsing with benzene, the excess zinc is removed. The organic layer of the filtrate is freed from the zinc salt and acidic components by washing several times with water and then with sodium bicarbonate solution. The aqueous layer is extracted again by shaking with benzene. The thoroughly dried organic solutions combined with sodium sulphate are evaporated under vacuum and the residue is freed of pyridine under high vacuum. The crude product is dissolved in 1,200 parts by volume of benzene and filtered through a 6 cm thick layer of aluminum oxide (activity 2). On evaporation of the filtrate, 60 parts by weight of the (2 _> 4|3)-lactone of A<8>a-l-ethoxyethynyl-2a-acetonyl-2(3-carboxy-4b(3-methyl-7-ethylenedioxy-l, 2 , 3, 4, 4aa, 4b, 5, 6, 7, 8, 10, 10ap-dodecahydrophenanthrene-1,4p-diol in colorless crystals which melt during decomposition at 157-158° C. As a further crystal fraction, it is 179° C likewise during decomposition melting in the 1-position isomeric product. Chromatography with aluminum oxide gives 11 to 13 parts by weight of the isomer obtained as the main product with a melting point of 157-158° C.
100 vektsdeler av den ovenfor beskrevne etoxyetinylforbindelse med smeltepunkt 157—158° C rystes oppløst i 750 volumdeler pyridin etter tilsetning av 2 vektsdeler av en palladium-kalsiumkarbonat-katalysator med 10 % Pd-innhold i en hydrogenatmo-sfære, idet det ved avkjøling holdes på temperaturen 22—16° C. Etter opptak av 5150 volumdeler hydrogen faller hydrer-ingshastigheten til mindre enn 2 % av be-gynnelseshastigheten. Man skiller fra katalysatoren og fjerner pyridin et ved destil-lasjon i vakuum. Etter tilsetning av eter krystalliserer det i eksempel 1 beskrevne (2->- 4(3)- lakton av A<8>a-l-etoxy-etenyl-2a-acetonyl-2(3-karboxy-4b(3-metyl-7-etylendioxy-l,2,3,4,4aa,4b-5,6,7,8,10,10a(3-dodekahydrofenantren-l,4(3-diol. Det krystalli-serte produkt inneholder først ennå eter i krystallinsk bundet form. Ved koking med n-heksan får man 96 vektsdeler av den 100 parts by weight of the above-described ethoxyethynyl compound with a melting point of 157-158° C are shaken and dissolved in 750 parts by volume of pyridine after the addition of 2 parts by weight of a palladium-calcium carbonate catalyst with 10% Pd content in a hydrogen atmosphere, keeping it on cooling the temperature 22-16° C. After uptake of 5150 parts by volume of hydrogen, the rate of hydrogenation drops to less than 2% of the initial rate. It is separated from the catalyst and pyridine is removed by distillation in a vacuum. After addition of ether, the (2->- 4(3)-lactone of A<8>a-1-ethoxy-ethenyl-2a-acetonyl-2(3-carboxy-4b(3-methyl-7-) described in example 1 crystallizes ethylenedioxy-1,2,3,4,4aa,4b-5,6,7,8,10,10a(3-dodecahydrophenanthrene-1,4(3-diol. The crystallized product initially still contains ether in crystalline bound form. When boiling with n-hexane, 96 parts by weight of it are obtained
:rystalloppløsningsmiddelfri, ved 124° C idekomponert smeltende forbindelse. :rystal solvent-free, at 124° C idecomposed melting compound.
Overføringen av dette lakton til (2_> t[3)-laktonet av A<8>a-l-formylmetyl-2a-ace-;onyl-2p-karboxy-4b(3-metyl-7-etylendioxy-i, 2, 3, 4aa 4b, 5, 6, 7, 8, 10, 10a|3-dodekahy-lro-fenantren-4(3-ol kan utføres etter det The conversion of this lactone to the (2_> t[3)-lactone of A<8>a-l-formylmethyl-2a-ace-;onyl-2p-carboxy-4b(3-methyl-7-ethylenedioxy-i, 2, 3, 4aa 4b, 5, 6, 7, 8, 10, 10a|3-dodecahy-lro-phenanthrene-4(3-ol) can be carried out after
>om er angitt i eksempel 1. >if indicated in example 1.
Eksempel 3: Example 3:
0,899 vektsdeler ( 2-+ 4|3)-lakton av ^<8>a-l-etoxy-etinyl-2a-allyl-2(3-karboxy-lbp-metyl-7-etylendioxy-l,2,3,4,4aa,4b,5,6, r,8,10,10ap-dodekahydrofenantren-l,4(3-iiol med smeltepunkt 146—148° C oppløses . 2,7 volumdeler pyridin, fortynnes med 85 /olumdeler abs. eter og tilsettes ved 20° C ),585 vektsdeler osmiumtetroxyd i 18 vol-jmdeler abs. eter. Etter 130 min. ved 20° C fortynnes med 90 volumdeler eter og der-3tter lar man innen 10 min. langsomt 270 rolumdeler metanol og deretter 270 volum-leler 0,25-N. ammoniumsulfitoppløsning i vann strømme til. Etter 60 minutter ved 20° C suges fra gjennom et med kiselgur (Hyflo-Supercel) tettet filter og det klare filtrat inndampes i vakuum ved 30° C badtemperatur til 250 volumdeler. Den vandige oppløsning rystes ut med kloroform-eter, kloroformeter-oppløsningene vaskes 2 ganger med litt vann, tørkes over natriumsulfat og inndampes i vakuum. Resten, 0,935 vektsdeler, kromatograferes med 28 vektsdeler silikagel. Derved holdes fra de med benzol-eter-(80 : 20) erholdte fraksjoner i alt tilbake 0,061 vektsdeler utgangsmateriale. Fra de med eter-aceton-(80 : 20) og eter-aceton-(50 : 50) eluerte fraksjoner fåes 0,168 vektsdeler krystaller av (2-^4p)-laktonet av A<8>a-l-etoxyetinyl-2a-(2',3'-dioxy-propyl) -2p-karboxy-4bp-metyl-7 - etylendioxy-l,2,3,4,4aa,4b,5,6,7,8,10ap-dodekahydrofenantren-1,4|3-diolet med smeltepunkt 149—152° C. 0.899 parts by weight ( 2-+ 4|3)-lactone of ^<8>a-1-ethoxy-ethynyl-2a-allyl-2(3-carboxy-lbp-methyl-7-ethylenedioxy-1,2,3,4,4aa ,4b,5,6,r,8,10,10ap-dodecahydrophenanthrene-1,4(3-iiol with melting point 146-148° C is dissolved. 2.7 parts by volume of pyridine, diluted with 85 parts by volume of absolute ether and added at 20° C), 585 parts by weight of osmium tetroxide in 18 parts by volume of absolute ether. After 130 minutes at 20° C, dilute with 90 parts by volume of ether and then, within 10 minutes, slowly add 270 parts by volume of methanol and then 270 parts by volume of alcohol 0.25-N ammonium sulphite solution in water flow in. After 60 minutes at 20° C, suction is drawn through a filter sealed with diatomaceous earth (Hyflo-Supercel) and the clear filtrate is evaporated in vacuum at 30° C bath temperature to 250 parts by volume. solution is shaken out with chloroform-ether, the chloroform-ether solutions are washed 2 times with a little water, dried over sodium sulfate and evaporated in vacuo. The residue, 0.935 parts by weight, is chromatographed with 28 parts by weight of silica gel. This keeps it from those with the benzene are-(80 : 20) fractions obtained in all return 0.061 parts by weight starting material. From the fractions eluted with ether-acetone-(80 : 20) and ether-acetone-(50 : 50) 0.168 parts by weight of crystals of the (2-^4p)-lactone of A<8>a-1-ethoxyethynyl-2a-(2 ',3'-dioxy-propyl)-2p-carboxy-4bp-methyl-7-ethylenedioxy-1,2,3,4,4aa,4b,5,6,7,8,10ap-dodecahydrophenanthrene-1,4| The 3-diol with melting point 149-152° C.
0,072 vektsdeler av den ovenstående glykol med smeltepunkt 149—152° C hydreres i 6 volumdeler av en blanding av 1 volumdel pyridin og 9 volumdeler finsprit med 0,035 vektsdeler Pd-CaCO;i-katalysator (2-%'s) ved 25° C og 760 torr. Hydrogen-opptaket opphører innen 12 minutter etter opptak av 3,5 volumdeler (= 92 % av den beregnede mengde). Hydreroppløsningen suges gjennom et med kiselgur (hyflo-supercel) tettet filter og den klare oppløsning inndampes i vakuum. Resten krystalliseres fra aceton-eter-pentan og man får 0,067 vektsdeler av (2^- 4p)-laktonet av A8a-1-etoxyetylen-2a-(2',3'-dioxy-propyl)-2p-karboxy-4bp-metyl-7-etylendioxy-l,2,3,4, 4aa,4b,5,6,7,8,10,10ap-dodekahydrofenan- 0.072 parts by weight of the above glycol with a melting point of 149-152° C is hydrogenated in 6 parts by volume of a mixture of 1 part by volume of pyridine and 9 parts by volume of alcohol with 0.035 parts by weight of Pd-CaCO;i catalyst (2-%'s) at 25° C and 760 torr. Hydrogen uptake ceases within 12 minutes after uptake of 3.5 parts by volume (= 92% of the calculated amount). The hydrogen solution is sucked through a filter sealed with diatomaceous earth (hyflo-supercel) and the clear solution is evaporated in a vacuum. The residue is crystallized from acetone-ether-pentane and 0.067 parts by weight of the (2^-4p)-lactone of A8a-1-ethoxyethylene-2a-(2',3'-dioxy-propyl)-2p-carboxy-4bp-methyl are obtained -7-ethylenedioxy-1,2,3,4,4aa,4b,5,6,7,8,10,10ap-dodecahydrophenan-
tren-l,4(3-diolet med smeltepunkt = 174— 176° C. tren-1,4(3-diol with melting point = 174— 176° C.
0,062 vektsdeler av det ovenstående etoxyetenyl-derivat tørkes 45 minutter ved 60° C og 0,01 torr, tilsettes 0,026 volumdeler pyridin og 2,5 volumdeler av en oppløsning av 0,063 volumdeler eddiksyreanhydrid i 10 volumdeler abs. benzol og det står 18 timer ved 20° C. Det med 2-N. HC1, 2-N. Na2C03 og vann nøytralt vaskede acetyleringspro-dukt kromatograferes med 2 vektsdeler aluminiumoxyd. Fra de med kloroform-metanol (95 : 5) utløste fraksjoner fåes 0,016 vektsdeler krystaller av (2^ 4(3) - laktonet av A<8>a-etox<y>eten<y>l-2ct-(2'-oxy-3'-acetoxy-propyl)-2(3-karboxy-4bp-metyl-7-etylen-dioxy-l,2,3,4,4aa,4b,5,6,7,8,10,10ap-dodekahydrofenantren-l-4p-diolet, med smeltepunkt = 148—150,5° C. 0.062 parts by weight of the above ethoxyethenyl derivative are dried for 45 minutes at 60° C and 0.01 torr, 0.026 parts by volume of pyridine and 2.5 parts by volume of a solution of 0.063 parts by volume of acetic anhydride in 10 parts by volume abs are added. benzene and it stands for 18 hours at 20° C. That with 2-N. HCl, 2-N. Na2C03 and water neutrally washed acetylation product is chromatographed with 2 parts by weight of aluminum oxide. From the fractions precipitated with chloroform-methanol (95 : 5), 0.016 parts by weight of crystals of (2^ 4(3)-lactone of A<8>a-ethox<y>ethene<y>l-2ct-(2'- oxy-3'-acetoxy-propyl)-2(3-carboxy-4bp-methyl-7-ethylene-dioxy-1,2,3,4,4aa,4b,5,6,7,8,10,10ap- The dodecahydrophenanthrene-1-4p-diol, with melting point = 148—150.5° C.
0,027 vektsdeler av det ovenstående acetat oppløses i 1 volumdel pyridin og settes til 0,06 vektsdeler CrC-3 i 0,6 volumdeler pyridin. tter 16 timer opparbeides. Det nøy-trale råprodukt kromatograferes med 1,5 vektsdeler silikagel. Fra de med eter samt eter-kloroform (90 : 10) utløste fraksjoner fåes 0,008 vektsdeler sekskantede plater med smeltepunkt 150—152° C, som er (2_^ 4p)-laktonet av A<8>a-l-etoxyetenyl-2a-(2'-oxo-3'-acetoxy-propyl)-2p-karoxy-4bp-metyl-7-etylendioxy-l,2,3,4,4aa,4b,5,6,7,8, 10,10ap-dodekah<y>drofenantren-l,4p-diol. 0.027 parts by weight of the above acetate are dissolved in 1 part by volume of pyridine and added to 0.06 parts by weight of CrC-3 in 0.6 parts by volume of pyridine. after 16 hours is worked up. The neutral crude product is chromatographed with 1.5 parts by weight of silica gel. From the fractions precipitated with ether and ether-chloroform (90 : 10), 0.008 parts by weight of hexagonal plates with a melting point of 150-152° C are obtained, which is the (2_^ 4p)-lactone of A<8>a-l-ethoxyethenyl-2a-(2 '-oxo-3'-acetoxy-propyl)-2p-carboxy-4bp-methyl-7-ethylenedioxy-1,2,3,4,4aa,4b,5,6,7,8,10,10ap-dodecah< y>drophenanthrene-1,4p-diol.
Fra de med eter-kloroform (90 : 10), eter-kloroform (75 : 25) samt eter-kloroform-(25 : 75) utløste fraksjoner fås ennå 0,006 vektsdeler utgangsmateriale. From the fractions precipitated with ether-chloroform (90 : 10), ether-chloroform (75 : 25) and ether-chloroform (25 : 75) a further 0.006 parts by weight of starting material are obtained.
0,15 vektsdeler av det ovenstående keton med smeltepunkt 150—152° C tilsettes 5,0 volumdeler av en oppløsning av 0,14 volumdeler fosfortribromid, 0,476 volumdeler metylenklorid og omrøres under nitrogen i 4 timer ved 25° C. Deretter tilsettes is og en oppslemning av 2 vektsdeler na-triumhydrogenkarbonat i 10 volumdeler vann. Den med 0,6-N. fosforsyre, 10 %'s kaliumhydrogenkarbonat-oppløsning og vann nøytralt vaskede oppløsning gir etter tørking og inndamping i vakuum 0,12 vektsdeler av et fargeløst skum, som av aceton-eter gir 0,043 vektsdeler små blader med smeltepunkt 216—222° C. X maks: 245 m^i log e = 4,09; 333 m|.i log e = 1,76 i diok-san. Det erholdte produkt er (2-^ 4p)-laktonet av A<8>a-l,l-formylmetylen-2a-(2'-oxo-3'-acetoxy-propyl)-2p-karboxy-4bp-metyl-7-etylendioxy-l,2,3,4,4aa,4b,5,6,7,8, 10,10ap-dodekah<y>drofenantren-4p-olet. 0.15 parts by weight of the above ketone with a melting point of 150-152° C are added to 5.0 parts by volume of a solution of 0.14 parts by volume phosphorus tribromide, 0.476 parts by volume methylene chloride and stirred under nitrogen for 4 hours at 25° C. Ice is then added and a slurry of 2 parts by weight of sodium bicarbonate in 10 parts by volume of water. The one with 0.6-N. phosphoric acid, 10% potassium hydrogencarbonate solution and water neutrally washed solution gives, after drying and evaporation in vacuum, 0.12 parts by weight of a colorless foam, which of acetone-ether gives 0.043 parts by weight small leaves with melting point 216-222° C. X max : 245 m^i log e = 4.09; 333 m|.in log e = 1.76 in diok-san. The product obtained is the (2-^ 4p)-lactone of A<8>a-1,1-formylmethylene-2a-(2'-oxo-3'-acetoxy-propyl)-2p-carboxy-4bp-methyl-7-ethylenedioxy -1,2,3,4,4aa,4b,5,6,7,8,10,10ap-dodecah<y>drophenanthrene-4p-olet.
0,2 vektsdeler av den ovenfor nevnte a,p-umettede aldehyd oppløses i 8,5 volumdeler a-pyrrolidon, spyles med 8,5 volumdeler tetrahydrofuran til 0,1 vektsdeler Pd- 0.2 parts by weight of the above-mentioned a,p-unsaturated aldehyde are dissolved in 8.5 parts by volume of a-pyrrolidone, flushed with 8.5 parts by volume of tetrahydrofuran to 0.1 parts by weight of Pd-
kull (10 %'s) og hydreres ved 25° C og 760 torr. Hydreringen opphører etter 65 minutter etter opptak av 9,5 volumdeler hydrogen. Hydreringsoppløsningen suges gjennom et med kiselgur (hyflo-supercel) tettet filter og det klare filtrat fortynnes med ca. 100 volumdeler kloroformeter (1 : 3) og oppløsningen rystes ut seks ganger med hver gang 8 volumdeler vann. De over natriumsulfat tørkede og i vakuum inndampede kloroform-eter-oppløsninger gir 0,222 vektsdeler rest, som oppløses i 11 volumdeler xylol og kokes med 0,22 volumdeler trietylamin og 0,11 volumdeler iseddik under tilbakeløpskjøling i nitrogen-atmosfære i 7 timer. Etter avkjøling fortynnes med kloroform-eter og vaskes med 8 volumdeler isvann (2 ganger), 0,5-N. sodaopp-løsning under tilsetning av is (4 ganger), 0,6-N. fosforsyre under tilsetning av is (5 ganger) og vann (3 ganger). De over natriumsulfat tørkede kloroform-eteroppløs-ninger inndampes i vakuum. Resten opp-løses i 25 volumdeler benzol, tilsettes 0,3 volumdeler pyridin og 0,3 volumdeler eddiksyreanhydrid og står i 14 timer ved 20° C. Deretter fortynnes med kloroform-eter og vaskes nøytralt på samme måte som ovenfor.. Resten kromatograferes ved 4,5 vektsdeler silikagel. De med benzol-eter (80 : 20), benzol-eter (65 : 35) og benzol-eter (50 : 50) eluerte fraksjoner (0,064 vektsdeler) fordeles på Whatman no. 1-papir. Fordelingskromatografien utføres i systemet benzol-cykloheksan-(l : 1) som mobil fase og formamid som stasjonær fa-se (utvikling med blåtetrazolium). Sonene med RF 0,25—0,30 skjæres av og elueres med metanolvann (50:50); metanolvann (130 : 130), metanol og kloroform. De i vakuum inndampede eluater rystes ut 6 ganger med hver gang 100 volumdeler kloroform og kloroformoppløsningene vaskes med hver gang 10 volumdeler 10%'s ka-liumhydrogenkarbonatoppløsning og vann, tørkes over natriumsulfat og inndampes i vakuum. Resten (0,0085 vektsdeler) kromatograferes med 0,45 vektsdeler silikagel. Fra de med benzoleter (80 : 20) og benzol-eter (50 : 50) eluerte fraksjoner fåes 0,003 vektsdeler krystaller med smeltepunkt 153 —159° C. Disse omkrystalliseres fra aceton-eterpentan. Små staver, sm. p. 159—161° C; a maks. 240 m^i log s = 3,74 i alkohol. Produktet er (18 11(3) -laktonet av d,l-A5,16-3-etylendioxv-lip-oxy-21-acetoxy-20-oxopregnadien-18-syre. coal (10%'s) and is hydrated at 25° C and 760 torr. The hydrogenation ceases after 65 minutes after absorption of 9.5 parts by volume of hydrogen. The hydration solution is sucked through a filter sealed with diatomaceous earth (hyflo-supercel) and the clear filtrate is diluted with approx. 100 parts by volume of chloroform ether (1 : 3) and the solution is shaken out six times with 8 parts by volume of water each time. The chloroform-ether solutions dried over sodium sulfate and evaporated in vacuum yield 0.222 parts by weight of residue, which is dissolved in 11 parts by volume of xylol and boiled with 0.22 parts by volume of triethylamine and 0.11 parts by volume of glacial acetic acid under reflux cooling in a nitrogen atmosphere for 7 hours. After cooling, dilute with chloroform-ether and wash with 8 volumes of ice water (2 times), 0.5-N. soda solution while adding ice (4 times), 0.6-N. phosphoric acid while adding ice (5 times) and water (3 times). The chloroform-ether solutions dried over sodium sulphate are evaporated in vacuo. The residue is dissolved in 25 parts by volume of benzene, 0.3 parts by volume of pyridine and 0.3 parts by volume of acetic anhydride are added and left for 14 hours at 20° C. It is then diluted with chloroform-ether and washed neutrally in the same way as above. The residue is chromatographed at 4.5 parts by weight silica gel. The fractions (0.064 parts by weight) eluted with benzene ether (80 : 20), benzene ether (65 : 35) and benzene ether (50 : 50) are distributed on Whatman no. 1-paper. The partition chromatography is carried out in the system benzene-cyclohexane-(1:1) as mobile phase and formamide as stationary phase (development with blue tetrazolium). The zones with RF 0.25-0.30 are cut off and eluted with methanol water (50:50); methanol water (130 : 130), methanol and chloroform. The eluates evaporated in vacuum are shaken out 6 times with each time 100 parts by volume of chloroform and the chloroform solutions are washed with each time 10 parts by volume of 10% potassium hydrogen carbonate solution and water, dried over sodium sulfate and evaporated in vacuum. The remainder (0.0085 parts by weight) is chromatographed with 0.45 parts by weight of silica gel. From the fractions eluted with benzoyl ether (80 : 20) and benzol ether (50 : 50), 0.003 parts by weight of crystals with a melting point of 153-159° C are obtained. These are recrystallized from acetone-etherpentane. Small letters, sm. mp 159-161°C; a max. 240 m^i log s = 3.74 i alcohol. The product is the (18 11(3)-lactone of d,l-A5,16-3-ethylenedioxv-lip-oxy-21-acetoxy-20-oxopregnadiene-18-acid.
Eksempel 4: Example 4:
0,456 vektsdeler (2 4p)-laktonet av A8a-l-etoxy-etinyl-2a-allyl-2p-karboxy-4b(3-metyl-7-etylen-dioxy-l, 2, 3, 4, 4aa, 4b, 5, 6, 7, 8, 10, 10ap-dodekahydrofenantren-l,4|3-diolet med smeltepunkt 182° C (iso-meret av utgangsstoffet i eksempel 3) opp-løses i 1,40 volumdeler pyridin, fortynnes med 45 volumdeler eter og tilsettes oppløs-ningen av 0,3 vektsdeler osmiumtetroxyd i 12 volumdeler abs. eter. Etter 150 minutter ved 25° C fortynnes med 45 volumdeler eter og deretter lar man innen 15 minutter langsomt 135 volumdeler metanol og 135 volumdeler vandig 0,25-N. ammoniumsul-fittoppløsning strømme til. Etter 60 minutter ved 25° C avdestilleres eteren og meta-nolet ved 30° C badtemperatur i vakuum og den vandige oppløsning rystes ut fire ganger med kloroform. De med vann vaskede over natriumsulfat tørkede kloro-formuttrekk inndampes i vakuum og resten krystalliseres fra aceton. Man får 0,301 vektsdeler korte staver av (2 _> 4pj -laktonet av i 1-stilling isomere A8a-l-etoxyeti-nyl-2ct-(2', 3'-dioxy-propyl)-2p-karboxy-4bp-metyl-7-etylendioxy-l, 2, 3, 4, 4aa, 4b, 5, 6, 7, 8, 10, 10ap-dodekahydrofenantren-l,4p-diolet, med smeltepunkt 222,4—224° C. Ved kromatografi av moderlutene fåes en-nå 0,093 vektsdeler av det samme produkt. 0.456 parts by weight of the (2 4p )-lactone of A8a-1-ethoxy-ethynyl-2a-allyl-2p-carboxy-4b(3-methyl-7-ethylene-dioxy-1, 2, 3, 4, 4aa, 4b, 5 , 6, 7, 8, 10, 10ap-dodecahydrophenanthrene-1,4|3-diol with melting point 182° C (the isomer of the starting material in example 3) is dissolved in 1.40 parts by volume of pyridine, diluted with 45 parts by volume of ether and the solution of 0.3 parts by weight of osmium tetroxide in 12 parts by volume of absolute ether is added. After 150 minutes at 25° C, dilute with 45 parts by volume of ether and then, within 15 minutes, slowly add 135 parts by volume of methanol and 135 parts by volume of aqueous 0.25-N ammonium sulphite solution flow in. After 60 minutes at 25° C, the ether and methanol are distilled off at 30° C bath temperature in a vacuum and the aqueous solution is shaken out four times with chloroform. The water-washed over sodium sulphate dried chloroform extracts are evaporated in vacuum and the residue is crystallized from acetone. 0.301 parts by weight of short sticks of the (2 _> 4pj -lactone of in the 1-position isomers A8a-1-ethoxyethynyl-2ct-(2', 3' -dioxy-propyl)-2p-carboxy-4bp-methyl-7-ethylenedioxy-1, 2, 3, 4, 4aa, 4b, 5, 6, 7, 8, 10, 10ap-dodecahydrophenanthrene-1,4p-diol, with a melting point of 222.4-224° C. Chromatography of the mother liquors yields 0.093 parts by weight of the same product.
0,227 vektsdeler av den ovenstående glykol med smeltepunkt 222,5—224° C opp-løses i 2 volumdeler pyridin, fortynnes med 18 volumdeler ren alkohol og tilsettes til 0,12 vektsdeler Pd/CaCO.i-katalysator. Hydreringen ved 760 torr og 25° C opphører etter opptak av 10,2 volumdeler hydrogen innen 6 minutter. Hydreringsoppløsningen suges gjennom kiselgur (hyflo-supercel) og filtratet inndampes i vakuum. Resten gir fra aceton-eter 0,213 vektsdeler nåler med smeltepunkt 221—226° C, som smelter etter omkrystallisasjon fra aceton-eter ved 224—227° C og som er (2 _^ 4p)-laktonet av det i 1-stilling isomere A<8>a-l-etoxy-etenyl-2a-(2', 3'-dioxy-propyl)-2p-karboxy-4bp-metyl-7-etylendioxy-l, 2, 3, 4, 4aa, 4p, 5, 6, 7, 8, 10, 10ap-dodekah<y>drofenantren-l,4p-diolet. 0.227 parts by weight of the above glycol with a melting point of 222.5-224° C are dissolved in 2 parts by volume of pyridine, diluted with 18 parts by volume of pure alcohol and added to 0.12 parts by weight of Pd/CaCO.i catalyst. The hydrogenation at 760 torr and 25° C ceases after absorption of 10.2 parts by volume of hydrogen within 6 minutes. The hydration solution is sucked through diatomaceous earth (hyflo-supercel) and the filtrate is evaporated in vacuo. The residue yields from acetone-ether 0.213 parts by weight of needles with melting point 221-226° C, which melt after recrystallization from acetone-ether at 224-227° C and which is the (2 _^ 4p)-lactone of the 1-position isomeric A <8>a-1-ethoxy-ethenyl-2a-(2', 3'-dioxy-propyl)-2p-carboxy-4bp-methyl-7-ethylenedioxy-1, 2, 3, 4, 4aa, 4p, 5, 6 , 7, 8, 10, 10ap-dodecah<y>drophenanthrene-1,4p-diol.
Eksempel 5: Example 5:
0,89 vektsdeler (2 -> 4p) -laktonet av A8a-l-etoxy—etenyl-2a-allyl-2p-karboxy-4bp-metyl-7-etylendioxy-l, 2, 3, 4, 4aa, 4b, 5, 6, 7, 8, 10, 10ap-dodekahydrofenantren-l,4p-diolet med smeltepunkt 195—200° C (erholdt ved selektiv reduksjon av den til-svarende etoxyetinylforbindelse) oppløses i 50 volumdeler abs. benzol og 1 volumdel pyridin og tilsettes ved 20° C 0,590 vektsdeler osmiumtetroxyd i 20 volumdeler abs. eter. Etter 2y2 time ved 20° C fortynnes med 70 volumdeler eter og deretter tilset tes innen 10 minutter langsomt 150 volumdeler metanol og deretter 8 vektsdeler am-moniumsulfitt i 150 volumdeler vann. Etter 1 time suges gjennom et med kiselgur (hyflo-supercel) tettet filter og det klare filtrat inndampes i vakuum ved 30° C badtemperatur til ca. 150 volumdteler. Den vandige oppløsning rystes ut med kloroform-eter ; klorof orm-eter-oppløsningene vaskes to ganger med litt vann, tørkes over natriumsulfat og inndampes i vakuum. (Rest: 0,892 vektsdeler). Fra acetoneter fåes 0,22 vektsdeler krystaller med sm.p. 232—236° C. Denne forbindelse er det i 1-stilling isomere (2 4p)-lakton av A8a-l-etoxyetenyl-2a-(2', 3'-dioxy-propyl)-2p-karboxy-4bp-metyl-7-etylendioxy-l, 2, 3, 4, 4aa, 4b, 5, 6, 7, 8, 10, 10ap-dodekahydrofenantren-l,4p-diolet. Moderluten av det ovenstående produkt (0,682 vektsdeler) kromatograferes med 20 vektsdeler silikagel. Fra de med benzoleter (50 : 50) erholdte fraksjoner holdes det tilbake i alt 0,27 vektsdeler utgangsmateriale. Fra de med bare eter, og eter og 10 til 20 % aceton eluerte fraksjoner, fåes ennå 0,025 vektsdeler krystaller med smp.p 232—366° C. De videre med eter-aceton-(70 : 30) eluerte fraksjoner gir fra aceton-eter 0,176 vektsdeler krystaller med dobbelt sm.p. 140° C/ 185—190° C, som er et isomer av det ovenstående glykol med sm.p. 232—236° C. a) 0,45 vektsdeler av glykolet med sm. p. 232—236° C tørkes i y2 time i høyvakuum ved 50° C, oppløses i 5 volumdeler abs. benzol og 3 volumdeler abs. kloroform, tilsettes 0,3 volumdeler pyridin og 0,16 volumdeler eddiksyreanhydrid og står i 2 dager ved 20° C. Opparbeidelsen gir 0,513 vektsdeler av et råprodukt, som etter omkrystallisasjon fra aceton-eter gir 0,29 vektsdeler av (2 4p)-laktonet av den i 1-stilling isomere A<8>a-l-etoxyetenyl-2a-(2'-oxy-3'-acet-oxy-propyl)-2p-karboxy-4bp-metyl-7-ety-len-dioxy-1, 2, 3, 4, 4aa, 4b, 5, 6, 7, 8, 10, 10ap-dodekah<y>drofenantren-l,4p- diolet med sm. p. 191—193° C. b) 0,224 vektsdeler av den isomere glykol med dobbelt smeltepunkt 140/185— 0.89 parts by weight (2 -> 4p)-lactone of A8a-1-ethoxy—ethenyl-2a-allyl-2p-carboxy-4bp-methyl-7-ethylenedioxy-1, 2, 3, 4, 4aa, 4b, 5 , 6, 7, 8, 10, 10ap-dodecahydrophenanthrene-1,4p-diol with melting point 195-200° C (obtained by selective reduction of the corresponding ethoxyethynyl compound) is dissolved in 50 parts by volume abs. benzene and 1 part by volume of pyridine and add at 20° C 0.590 parts by weight of osmium tetroxide in 20 parts by volume abs. ether. After 2y2 hours at 20° C, dilute with 70 parts by volume of ether and then add within 10 minutes slowly add 150 parts by volume of methanol and then 8 parts by weight of ammonium sulphite in 150 parts by volume of water. After 1 hour, suck through a filter sealed with diatomaceous earth (hyflo-supercel) and the clear filtrate is evaporated in vacuum at 30° C bath temperature to approx. 150 parts by volume. The aqueous solution is shaken out with chloroform-ether; the chloroform-ether solutions are washed twice with a little water, dried over sodium sulfate and evaporated in vacuo. (Residue: 0.892 parts by weight). 0.22 parts by weight of crystals with m.p. 232—236° C. This compound is in the 1-position isomeric (2 4p)-lactone of A8a-1-ethoxyethenyl-2a-(2', 3'-dioxy-propyl)-2p-carboxy-4bp-methyl- 7-ethylenedioxy-1, 2, 3, 4, 4aa, 4b, 5, 6, 7, 8, 10, 10ap-dodecahydrophenanthrene-1,4p-diol. The mother liquor of the above product (0.682 parts by weight) is chromatographed with 20 parts by weight of silica gel. A total of 0.27 parts by weight of starting material is retained from the fractions obtained with benzoyl ether (50:50). From the fractions eluted with only ether, and ether and 10 to 20% acetone, a further 0.025 parts by weight of crystals with m.p. 232-366° C are obtained. The further fractions eluted with ether-acetone (70 : 30) give from acetone- ether 0.176 parts by weight crystals of double m.p. 140° C/ 185—190° C, which is an isomer of the above glycol with m.p. 232—236° C. a) 0.45 parts by weight of the glycol with sm. p. 232-236° C, dry for y2 hours in high vacuum at 50° C, dissolve in 5 parts by volume abs. benzene and 3 parts by volume abs. chloroform, 0.3 parts by volume of pyridine and 0.16 parts by volume of acetic anhydride are added and left for 2 days at 20° C. The work-up gives 0.513 parts by weight of a crude product, which after recrystallization from acetone-ether gives 0.29 parts by weight of (2 4p)- the lactone of the 1-position isomeric A<8>a-1-ethoxyethenyl-2a-(2'-oxy-3'-acet-oxy-propyl)-2p-carboxy-4bp-methyl-7-ethylene-dioxy- 1, 2, 3, 4, 4aa, 4b, 5, 6, 7, 8, 10, 10ap-dodecah<y>drophenanthrene-1,4p-diol with sm. p. 191—193° C. b) 0.224 parts by weight of the isomeric glycol with double melting point 140/185—
190° C tørkes analogt, oppløses i 4 volumdeler abs. benzol og 1 volumdel abs. kloroform, tilsettes 0,2 volumdeler pyridin og 0,08 volumdeler eddiksyreanhydrid og står 1 dag ved 20° C. Opparbeidelsen gir 0,224 vektsdeler av et råprodukt som av aceton-eter gir 0,07 vektsdeler av det isomere acetat av sm.p. 195—199° C. I blanding med det ovenstående acetat med sm.p. 191— 193° C iakttas en sterk smeltepunkt-depre-sjon. 190° C dry analogously, dissolve in 4 parts by volume abs. benzene and 1 volume part abs. chloroform, 0.2 parts by volume of pyridine and 0.08 parts by volume of acetic anhydride are added and left for 1 day at 20° C. The work-up yields 0.224 parts by weight of a crude product which, from acetone-ether, yields 0.07 parts by weight of the isomeric acetate of m.p. 195—199° C. In mixture with the above acetate with m.p. 191—193° C a strong melting point depression is observed.
a) 0,12 vektsdeler av det ovenstående acetat med sm.p. 191—193° C oppløses i 4 volumdeler pyridin og settes til 0,53 vekts- a) 0.12 parts by weight of the above acetate with m.p. 191-193° C is dissolved in 4 parts by volume of pyridine and added to 0.53 wt.
deler kromsyre i 8 volumdeler pyridin. Etter 24 timer opparbeides. Det nøytrale råpro- parts of chromic acid in 8 parts by volume of pyridine. After 24 hours processed. The neutral raw pro-
dukt (0,103 vektsdeler) gir etter krystalli- duct (0.103 parts by weight) gives after crystallization
sasjon fra aceton-eter 0,046 vektsdeler (2 4(3)-laktonet av det i 1-stilling isomere A<8>a-l-etoxyetenyl-2a-(2'-oxo-3'-acetoxy-pro-pyl)-2[3-karboxy-4b|3-metyl-7-etylendioxy- sation from acetone ether 0.046 parts by weight (2 4(3)-lactone of the 1-position isomeric A<8>a-1-ethoxyethenyl-2a-(2'-oxo-3'-acetoxy-propyl)-2[ 3-carboxy-4b|3-methyl-7-ethylenedioxy-
1, 2, 3, 4, 4aa, 4b, 5, 6, 7, 8, 10, 10a|3-dodekahydrofenantren-l,4|3-diolet med sm.p. 192 —196° C. 1, 2, 3, 4, 4aa, 4b, 5, 6, 7, 8, 10, 10a|3-dodecahydrophenanthrene-1,4|3-diol with m.p. 192 -196°C.
b) 0,165 vektsdeler av det isomere ace- b) 0.165 parts by weight of the isomeric ace-
tat med sm.p. 195—199° C oppløses i 5 vo- take with sm.p. 195—199° C dissolve in 5 vo-
lumdeler pyridin og settes til 0,32 vektsde- parts of pyridine and set to 0.32 parts by weight
ler kromsyre i 5 volumdeler pyridin. Etter 24 timer opparbeides. Av det nøytrale rå- ler chromic acid in 5 parts by volume of pyridine. After 24 hours processed. Of the neutral raw
produkt får man etter krystallisasjon fra aceton-eter 0,071 vektsdeler av det under a) beskrevne ketolacetat med sm.p. 192— product is obtained after crystallization from acetone-ether 0.071 parts by weight of the ketol acetate described under a) with m.p. 192—
196° C. 196°C.
0,12 vektsdeler av ketolacetatet med sm.p. 192—196° C tilsettes 5 volumdeler av en oppløsning av 0,14 volumdeler fosfortribromid, 0,476 volumdeler pyridin og 19,4 volumdeler metylenklorid og står under ni- 0.12 parts by weight of the ketol acetate with m.p. 192-196° C, 5 parts by volume of a solution of 0.14 parts by volume phosphorus tribromide, 0.476 parts by volume pyridine and 19.4 parts by volume methylene chloride are added and stand under nine
trogen i 4 timer ved 0° C. Deretter helles ved 0° C i en natriumhydrogenkarbonat-oppløsning (10 vektsdeler i 10 volumdeler vann), utrystes med kloroform-eter. Den med 0,6 mol fosforsyre, 10 %'s kaliumbi-karbonatoppløsning og vann nøytralt vas- trogen for 4 hours at 0° C. Then pour at 0° C into a sodium bicarbonate solution (10 parts by weight in 10 parts by volume of water), shake out with chloroform-ether. The one with 0.6 mol of phosphoric acid, 10% potassium bicarbonate solution and neutral water
kede oppløsning gir etter inndampning 0,102 vektsdeler av et råprodukt. Fra kloroform-eter fåes 0,055 vektsdeler av det i eksempel 3 beskrevne (2 _^ 4(3)-lakton av A<8>a-l,l-formyl-metylen-2a-(2'-oxo-3'-acetoxy-propyl) -2(3-karboxy-4b(3~metyl-7 - etylendioxy-1, 2, 3, 4, 4aa, 4b, 5, 6, 7, 8, 10, 10a(3-dodekahydrofenantren-4|3-olet. ked solution yields after evaporation 0.102 parts by weight of a crude product. 0.055 parts by weight of the (2 _^ 4(3)-lactone of Δ<8>a-1,1-formyl-methylene-2a-(2'-oxo-3'-acetoxy-propyl) described in example 3 are obtained from chloroform-ether ) -2(3-carboxy-4b(3~methyl-7 - ethylenedioxy-1, 2, 3, 4, 4aa, 4b, 5, 6, 7, 8, 10, 10a(3-dodecahydrophenanthrene-4|3- olet
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Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH496165A CH460804A (en) | 1965-04-08 | 1965-04-08 | Process for the production of new substituted phenylacetic acids |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NO120793B true NO120793B (en) | 1970-12-07 |
Family
ID=4285534
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO162524A NO120793B (en) | 1965-04-08 | 1966-04-06 |
Country Status (16)
| Country | Link |
|---|---|
| AT (4) | AT262983B (en) |
| BE (1) | BE679315A (en) |
| CH (1) | CH460804A (en) |
| CY (1) | CY637A (en) |
| DE (1) | DE1543639B2 (en) |
| DK (1) | DK117639B (en) |
| DO (2) | DOP1977002615A (en) |
| ES (2) | ES325270A1 (en) |
| FI (1) | FI44619C (en) |
| FR (2) | FR1487352A (en) |
| GB (1) | GB1139332A (en) |
| IL (1) | IL25545A (en) |
| MY (1) | MY7200118A (en) |
| NL (2) | NL6604752A (en) |
| NO (1) | NO120793B (en) |
| SE (1) | SE322527B (en) |
Families Citing this family (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3513199A (en) * | 1967-05-05 | 1970-05-19 | Smithkline Corp | Substituted anilino benzyl alcohols |
| CH506480A (en) * | 1969-02-20 | 1971-04-30 | Ciba Geigy Ag | Process for the production of new, substituted o-anilino-phenethyl alcohols |
| JPS549240A (en) * | 1977-06-23 | 1979-01-24 | Asahi Chem Ind Co Ltd | New derivative of phenylglycolic acid, its preparation and analgesic and antiinflammatory agent contining it as effective component |
| JPS58194814A (en) * | 1982-05-11 | 1983-11-12 | Nippon Shinyaku Co Ltd | Drug having immunoregulating activity |
| US5237070A (en) * | 1985-07-22 | 1993-08-17 | Riker Laboratories, Inc. | Substituted DI-t-butylphenols |
| ZA865090B (en) * | 1985-07-22 | 1988-02-24 | Riker Laboratories Inc | Substituted di-t-butylphenols |
| DE3623193A1 (en) * | 1986-07-10 | 1988-01-14 | Gruenenthal Gmbh | NEW COMPOUNDS, THIS MEDICINAL PRODUCT AND METHOD FOR THE PRODUCTION THEREOF |
| ES2011588A6 (en) * | 1989-05-29 | 1990-01-16 | Vinas Lab | Phenylacetic acid derivative. |
| EP0405602A1 (en) * | 1989-06-30 | 1991-01-02 | Laboratorios Vinas S.A. | New Zinc derivatives of anti-inflammatory drugs having improved therapeutic activity |
| US6355680B1 (en) * | 1996-02-20 | 2002-03-12 | Exocell, Inc. | Albumin-binding compounds that prevent nonenzymatic glycation and that may be used for treatment of glycation-related pathologies |
| AR061623A1 (en) | 2006-06-26 | 2008-09-10 | Novartis Ag | PHENYLACETIC ACID DERIVATIVES |
| CN114539086B (en) | 2022-02-25 | 2023-10-03 | 复旦大学 | Synthesis method of diclofenac sodium |
| CN114516813B (en) | 2022-02-25 | 2024-05-28 | 复旦大学 | Continuous flow preparation method of diclofenac sodium |
-
0
- NL NL133740D patent/NL133740C/xx active
-
1965
- 1965-04-08 CH CH496165A patent/CH460804A/en unknown
- 1965-04-08 FR FR57111A patent/FR1487352A/en not_active Expired
-
1966
- 1966-04-06 DK DK180566AA patent/DK117639B/en unknown
- 1966-04-06 ES ES0325270A patent/ES325270A1/en not_active Expired
- 1966-04-06 FI FI660898A patent/FI44619C/en active
- 1966-04-06 NO NO162524A patent/NO120793B/no unknown
- 1966-04-06 ES ES0325271A patent/ES325271A1/en not_active Expired
- 1966-04-07 AT AT619667A patent/AT262983B/en active
- 1966-04-07 SE SE4833/66A patent/SE322527B/xx unknown
- 1966-04-07 AT AT619767A patent/AT266096B/en active
- 1966-04-07 DE DE1966G0046553 patent/DE1543639B2/en active Granted
- 1966-04-07 AT AT619567A patent/AT262982B/en active
- 1966-04-07 NL NL6604752A patent/NL6604752A/xx unknown
- 1966-04-07 IL IL25545A patent/IL25545A/en unknown
- 1966-04-07 GB GB15497/66A patent/GB1139332A/en not_active Expired
- 1966-04-07 AT AT334966A patent/AT263755B/en active
- 1966-04-08 BE BE679315D patent/BE679315A/xx not_active IP Right Cessation
- 1966-07-06 FR FR68443A patent/FR5524M/fr not_active Expired
-
1972
- 1972-04-19 CY CY63772A patent/CY637A/en unknown
- 1972-12-31 MY MY1972118A patent/MY7200118A/en unknown
-
1977
- 1977-11-21 DO DO1977002615A patent/DOP1977002615A/en unknown
- 1977-12-09 DO DO1977002614A patent/DOP1977002614A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| DOP1977002615A (en) | 1983-05-27 |
| FR1487352A (en) | 1967-07-07 |
| DE1543639A1 (en) | 1970-02-05 |
| AT263755B (en) | 1968-08-12 |
| ES325271A1 (en) | 1967-04-01 |
| DE1543639B2 (en) | 1977-02-24 |
| DOP1977002614A (en) | 1983-05-27 |
| FI44619C (en) | 1971-12-10 |
| MY7200118A (en) | 1972-12-31 |
| DK117639B (en) | 1970-05-19 |
| DE1793592A1 (en) | 1972-04-20 |
| AT266096B (en) | 1968-11-11 |
| NL6604752A (en) | 1966-10-10 |
| GB1139332A (en) | 1969-01-08 |
| SE322527B (en) | 1970-04-13 |
| FI44619B (en) | 1971-08-31 |
| ES325270A1 (en) | 1967-04-01 |
| AT262983B (en) | 1968-07-10 |
| CY637A (en) | 1972-04-19 |
| AT262982B (en) | 1968-07-10 |
| CH460804A (en) | 1968-08-15 |
| FR5524M (en) | 1967-11-06 |
| NL133740C (en) | |
| BE679315A (en) | 1966-10-10 |
| IL25545A (en) | 1970-07-19 |
| DE1793592B2 (en) | 1977-06-16 |
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