NO170850B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE 6-OXOPROSTAGLAND INGREDIATES - Google Patents
ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE 6-OXOPROSTAGLAND INGREDIATES Download PDFInfo
- Publication number
- NO170850B NO170850B NO885058A NO885058A NO170850B NO 170850 B NO170850 B NO 170850B NO 885058 A NO885058 A NO 885058A NO 885058 A NO885058 A NO 885058A NO 170850 B NO170850 B NO 170850B
- Authority
- NO
- Norway
- Prior art keywords
- methyl
- acid
- solution
- yloxy
- hydroxy
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 11
- 238000002360 preparation method Methods 0.000 title claims description 4
- 230000001225 therapeutic effect Effects 0.000 title claims 2
- 150000001875 compounds Chemical class 0.000 claims description 35
- 229920000858 Cyclodextrin Polymers 0.000 claims description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- 125000002947 alkylene group Chemical group 0.000 claims description 4
- 150000001412 amines Chemical class 0.000 claims description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 claims description 4
- 229920001450 Alpha-Cyclodextrin Polymers 0.000 claims description 3
- HFHDHCJBZVLPGP-RWMJIURBSA-N alpha-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO HFHDHCJBZVLPGP-RWMJIURBSA-N 0.000 claims description 3
- 229940043377 alpha-cyclodextrin Drugs 0.000 claims description 3
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 claims description 3
- 229960004853 betadex Drugs 0.000 claims description 3
- GDSRMADSINPKSL-HSEONFRVSA-N gamma-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO GDSRMADSINPKSL-HSEONFRVSA-N 0.000 claims description 3
- 229940080345 gamma-cyclodextrin Drugs 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 239000012027 Collins reagent Substances 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- GRWVQDDAKZFPFI-UHFFFAOYSA-H chromium(III) sulfate Chemical compound [Cr+3].[Cr+3].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O GRWVQDDAKZFPFI-UHFFFAOYSA-H 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- RCBVKBFIWMOMHF-UHFFFAOYSA-L hydroxy-(hydroxy(dioxo)chromio)oxy-dioxochromium;pyridine Chemical compound C1=CC=NC=C1.C1=CC=NC=C1.O[Cr](=O)(=O)O[Cr](O)(=O)=O RCBVKBFIWMOMHF-UHFFFAOYSA-L 0.000 claims description 2
- NPRDHMWYZHSAHR-UHFFFAOYSA-N pyridine;trioxochromium Chemical compound O=[Cr](=O)=O.C1=CC=NC=C1.C1=CC=NC=C1 NPRDHMWYZHSAHR-UHFFFAOYSA-N 0.000 claims description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 2
- 239000000243 solution Substances 0.000 description 39
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 37
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 33
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 20
- 239000000203 mixture Substances 0.000 description 19
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 18
- 239000012230 colorless oil Substances 0.000 description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 17
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- 239000002253 acid Substances 0.000 description 16
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 12
- 235000019341 magnesium sulphate Nutrition 0.000 description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 11
- 239000000741 silica gel Substances 0.000 description 10
- 229910002027 silica gel Inorganic materials 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
- 235000019439 ethyl acetate Nutrition 0.000 description 7
- -1 tert.-butyl Chemical group 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- RHLVCLIPMVJYKS-UHFFFAOYSA-N 3-octanone Chemical compound CCCCCC(=O)CC RHLVCLIPMVJYKS-UHFFFAOYSA-N 0.000 description 6
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 238000011097 chromatography purification Methods 0.000 description 6
- 238000001704 evaporation Methods 0.000 description 6
- 239000003921 oil Substances 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 5
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
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- 150000003180 prostaglandins Chemical class 0.000 description 5
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- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
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- 230000002401 inhibitory effect Effects 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 150000004702 methyl esters Chemical class 0.000 description 4
- NMRPBPVERJPACX-UHFFFAOYSA-N octan-3-ol Chemical compound CCCCCC(O)CC NMRPBPVERJPACX-UHFFFAOYSA-N 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 210000002784 stomach Anatomy 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- 238000011282 treatment Methods 0.000 description 4
- 150000001298 alcohols Chemical class 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 3
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- 210000003734 kidney Anatomy 0.000 description 3
- 150000002596 lactones Chemical class 0.000 description 3
- 210000004185 liver Anatomy 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
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- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 238000011321 prophylaxis Methods 0.000 description 3
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- 238000010626 work up procedure Methods 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
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- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
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- 125000002252 acyl group Chemical group 0.000 description 2
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- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
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- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
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- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
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- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 238000007239 Wittig reaction Methods 0.000 description 1
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- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical group [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 1
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- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 1
- ANFZRGMDGDYNGA-UHFFFAOYSA-N ethyl acetate;propan-2-ol Chemical compound CC(C)O.CCOC(C)=O ANFZRGMDGDYNGA-UHFFFAOYSA-N 0.000 description 1
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- 229960002897 heparin Drugs 0.000 description 1
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- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
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- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000003199 leukotriene receptor blocking agent Substances 0.000 description 1
- OTCKOJUMXQWKQG-UHFFFAOYSA-L magnesium bromide Chemical compound [Mg+2].[Br-].[Br-] OTCKOJUMXQWKQG-UHFFFAOYSA-L 0.000 description 1
- 229910001623 magnesium bromide Inorganic materials 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
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- 150000007524 organic acids Chemical class 0.000 description 1
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- KVNYFPKFSJIPBJ-UHFFFAOYSA-N ortho-diethylbenzene Natural products CCC1=CC=CC=C1CC KVNYFPKFSJIPBJ-UHFFFAOYSA-N 0.000 description 1
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- 238000007254 oxidation reaction Methods 0.000 description 1
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- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
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- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
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- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
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- RZWIIPASKMUIAC-VQTJNVASSA-N thromboxane Chemical compound CCCCCCCC[C@H]1OCCC[C@@H]1CCCCCCC RZWIIPASKMUIAC-VQTJNVASSA-N 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Foreliggende oppfinnelse angår en analogifremgangsmåte for fremstilling av terapeutisk aktive 6-oxoprostaglandinderivater. The present invention relates to an analogue method for the production of therapeutically active 6-oxoprostaglandin derivatives.
Fra den meget omfangsrike teknikkens stand vedrør-ende prostaglandiner, i særdeleshet av E-type og deres analoger, vet man at denne stoffklasse på grunn av dens biologiske og farmakologiske egenskaper er egnet til behandling og profylakse av tromboser, infarkt og andre hjerte-kretsløpssykdommer. Strukturforandringer har derfor til mål å forlenge virkningsvarigheten, øke selektiviteten av virksomheten og samtidig redusere virkningsdosen. From the very extensive state of the art concerning prostaglandins, in particular of type E and their analogues, it is known that this class of substances is suitable for the treatment and prophylaxis of thrombosis, infarction and other cardiovascular diseases due to its biological and pharmacological properties. Structural changes therefore aim to extend the duration of the effect, increase the selectivity of the business and at the same time reduce the effective dose.
Det er nå overraskende funnet at ved innføring av en trippelbinding i 18,19- eller 19,20- og/eller 13,14-stilling, såvel som innføring av en methylgruppe i 16-og/eller 20-stilling av den nedre kjede av 6-oxoprostaglandin-E^-analogene kan virksomheten forbedres, selektiviteten økes og virkningsvarigheten forlenges. It has now surprisingly been found that by introducing a triple bond in the 18,19 or 19,20 and/or 13,14 position, as well as introducing a methyl group in the 16 and/or 20 position of the lower chain of The activity of the 6-oxoprostaglandin E^ analogues can be improved, the selectivity increased and the duration of action extended.
De nye forbindelser virker trombocyttaggregeringshemmende, blodtrykkssenkende, vaso- og bronchodilaterende. De er enn videre egnet til inhibering av magesyresekresjon såvel som til cytobeskyttelse i mage, hjerte, lever, pankreas og nyre. The new compounds inhibit platelet aggregation, lower blood pressure, vasodilate and bronchodilate. They are also suitable for inhibiting gastric acid secretion as well as for cytoprotection in the stomach, heart, liver, pancreas and kidney.
Oppfinnelsen angår en analogifremgangsmåte for fremstilling av terapeutisk aktive 6-oxoprostaglandinderivater av formel 1 The invention relates to an analogue method for the preparation of therapeutically active 6-oxoprostaglandin derivatives of formula 1
hvori in which
R<2> betyr hydrogen eller en C^-alkylgruppe, R<2> means hydrogen or a C 1 -alkyl group,
A er en E-konfigurert -CH=CH- eller en -C=C-gruppe, A is an E-configured -CH=CH- or a -C=C group,
W er a- eller (3-hydroxymethylen, W is α- or (3-hydroxymethylene,
D er en rettkjedet eller forgrenet alkylengruppe med 1-5 C- D is a straight-chain or branched alkylene group with 1-5 C-
atomer, atoms,
R3 er en <C>^g-alkylgruppe, og R 3 is a <C> 6 -alkyl group, and
hvis R2 betegner et hydrogenatom, deres salter med fysiologisk anvendbare baser, samt a-, p- eller y-cyclodextrinclathratene av forbindelsene av formel I. if R 2 denotes a hydrogen atom, their salts with physiologically applicable bases, as well as the α-, β- or γ-cyclodextrin clathrates of the compounds of formula I.
Som alkylgrupper R 2menes rettkjedede eller forgrenede alkylgrupper med 1-10 C-atomer, slik som f.eks. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.-butyl, pentyl, isopentyl, neopentyl, heptyl, hexyl, decyl. By alkyl groups R 2 are meant straight-chain or branched alkyl groups with 1-10 C atoms, such as e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.-butyl, pentyl, isopentyl, neopentyl, heptyl, hexyl, decyl.
Som foretrukne alkylgrupper R 2 skal nevnes slike med 1-4 C-atomer slik som f.eks. methyl, ethyl, propyl, dimethyl-aminopropyl, isobutyl og butyl. Preferred alkyl groups R 2 are those with 1-4 C atoms such as e.g. methyl, ethyl, propyl, dimethyl-aminopropyl, isobutyl and butyl.
Som alkylgrupper R kommer rettkjedede og forgrenede, mettede og umettede alkylrester, fortrinnsvis mettede med 1-10, i særdeleshet 1-7 C-atomer, i betraktning- As alkyl groups R, straight-chain and branched, saturated and unsaturated alkyl residues, preferably saturated with 1-10, in particular 1-7 C atoms, come into consideration-
Som alkylengruppe D kommer rettkjedede eller forgrenede, mettede og umettede alkylenrester, fortrinnsvis mettede med 1-5, C-atomer, i betraktning. Som eksempler kan nevnes methylen, ethylen, 1,2-propylen, ethylethylen, trimethylen, tetramethylen, pentamethylen, 1-methyl-tetramethylen og 1-methyl-trimethylen. As alkylene group D, straight-chain or branched, saturated and unsaturated alkylene residues, preferably saturated with 1-5, C atoms, come into consideration. Examples include methylene, ethylene, 1,2-propylene, ethylethylene, trimethylene, tetramethylene, pentamethylene, 1-methyl-tetramethylene and 1-methyl-trimethylene.
For saltdannelse med de frie syrer (R 2= H) er uorganiske og organiske baser egnet, hvilket er kjent for fagmannen for dannelse av fysiologisk akseptable salter. For salt formation with the free acids (R 2 = H), inorganic and organic bases are suitable, which is known to the person skilled in the art for the formation of physiologically acceptable salts.
Som eksempler kan nevnes alkalihydroxyder slik som natrium-og kaliumhydroxyd, jordalkalihydroxyder slik som calciumhydroxyd, ammoniakk, aminer slik som ethanolamin, diethanol-amin, triethanolamin, N-methylglucamin, morfolin-, tris-(hydroxymethy1)-methylamin, etc. Examples include alkali hydroxides such as sodium and potassium hydroxide, alkaline earth hydroxides such as calcium hydroxide, ammonia, amines such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, morpholine, tris-(hydroxymethyl)methylamine, etc.
Analogifremgangsmåten ifølge oppfinnelsen er kjennetegnet ved at en forbindelse av formel II hvori R<2>, R<3>, A, W og D har de ovenfor angitte betydninger, og hvor fri OH-grupper er beskyttet, oxyderes med kromsvovelsyre, pyridiniumdikromat, pyridiniumklorkromat, Collins-reagens eller med komplekser av Cr03 og aminbaser, og at beskyttede hydroxygrupper frigis, og at fri hydroxygrupper eventuelt for-estres, forethres og at en forestret carboxylgruppe forsåpes, eller at en carboxylgruppe eventuelt overføres med en fysiologisk akseptabel base til et salt, eller omsettes med a-, p-eller y-cyclodextrin til et clathrat. The analogous method according to the invention is characterized by the fact that a compound of formula II in which R<2>, R<3>, A, W and D have the meanings given above, and where free OH groups are protected, is oxidized with chromosulfuric acid, pyridinium dichromate, pyridinium chlorochromate , Collins reagent or with complexes of Cr03 and amine bases, and that protected hydroxy groups are released, and that free hydroxy groups are optionally esterified, etherified and that an esterified carboxyl group is saponified, or that a carboxyl group is optionally transferred with a physiologically acceptable base to a salt, or reacted with α-, β- or γ-cyclodextrin to a clathrate.
Omsetningen av forbindelsene av generell formel II til forbindelsene av generell formel I utføres med Jones-reagens ved -40°C til 0°C, fortrinnsvis ved -30°C til -10°C, og utføres under anvendelse av de andre oxydasjonsmetoder fortrinnsvis ved -10°C til +25°C. Som løsningsmiddel egner seg methylenklorid, kloroform, ethylenklorid, aceton, pyridin, fortrinnsvis methylenklorid og aceton. The reaction of the compounds of general formula II to the compounds of general formula I is carried out with Jones reagent at -40°C to 0°C, preferably at -30°C to -10°C, and is carried out using the other oxidation methods preferably at -10°C to +25°C. Suitable solvents are methylene chloride, chloroform, ethylene chloride, acetone, pyridine, preferably methylene chloride and acetone.
Frigivelse av den funksjonelt modifiserte hydroxygruppe R 4 til forbindelsene av generell formel I Release of the functionally modified hydroxy group R 4 to the compounds of general formula I
skjer etter kjente metoder for fagmannen. Eksempelvis ut-føres avspaltningen av etherbeskyttelsesgruppene i en takes place according to methods known to the person skilled in the art. For example, the removal of the ether protecting groups is carried out in a
vandig løsning av en organisk syre slik som eddiksyre, pro-pionsyre, sitronsyre og lignende, eller i en vandig løsning av en uorganisk syre slik som f.eks. saltsyre, eller når det gjelder tetrahydropyranyletheren under anvendelse av pyridinium-p-toluensulfonat, fortrinnsvis i alkoholer som løsningsmiddel, eller under anvendelse av vannfritt magnes-iumbromid, fortrinnsvis i diethylether som løsningsmiddel. aqueous solution of an organic acid such as acetic acid, propionic acid, citric acid and the like, or in an aqueous solution of an inorganic acid such as e.g. hydrochloric acid, or in the case of the tetrahydropyranyl ether using pyridinium p-toluenesulfonate, preferably in alcohols as solvent, or using anhydrous magnesium bromide, preferably in diethyl ether as solvent.
For å forbedre løseligheten tilsettes ved anvendelse av vandig-sure reaksjonsbetingelser hensiktsmessig et med vann blandbart, inert løsningsmiddel. Egnede er eksempelvis alkoholer slik som methanol og ethanol, ethere slik som dimethoxyethan, dioxan og tetrahydrofuran, hvorved tetrahydrofuran fortrinnsvis anvendes. In order to improve the solubility, when using aqueous-acidic reaction conditions, a water-miscible, inert solvent is suitably added. Suitable examples are alcohols such as methanol and ethanol, ethers such as dimethoxyethane, dioxane and tetrahydrofuran, whereby tetrahydrofuran is preferably used.
Avspaltning av silyletherbeskyttelsesgruppen skjer eksempelvis med tetrabutylammoniumfluorid. Som løsnings-middel er eksempelvis tetrahydrofuran, diethylether, dioxan, methylenklorid, etc., egnet. Removal of the silyl ether protecting group takes place, for example, with tetrabutylammonium fluoride. Examples of suitable solvents are tetrahydrofuran, diethyl ether, dioxane, methylene chloride, etc.
Avspaltningen utføres fortrinnsvis ved temperaturer mellom 20°C og 80°C. The separation is preferably carried out at temperatures between 20°C and 80°C.
Forsåpningen av acylgruppene og prostaglandinesteren utføres etter kjente metoder for fagmannen, eksempelvis med basiske katalysatorer slik som f.eks. med alkali- The saponification of the acyl groups and the prostaglandin ester is carried out according to methods known to the person skilled in the art, for example with basic catalysts such as e.g. with alkali
og jordalkalicarbonater eller -hydroxyder, i en alkohol, eller i den vandige løsning av en alkohol. Som alkoholer kommer alifatiske alkoholer slik som f.eks. methanol, ethanol, butanol, etc, i betraktning, fortrinnsvis methanol. Som alkalicarbonater og -hydroxyder kan nevnes kalium- og natriumsalt. Foretrukket er kaliumsaltet. Som jordalkalicarbonater og -hydroxyder egner seg eksempelvis calcium-carbonat, calciumhydroxyd og bariumcarbonat. Omsetningen skjer generelt ved -10°C til +70°C, fortrinnsvis ved +25°C. 2 1 2 Innføring av estergruppen for R hvori R betegner en alkylgruppe med 1-10 C-atomer, skjer etter kjente metoder for fagmannen. 1-carboxyforbmdelsene (R 2= H) omsettes eksempelvis med diazohydrocarboner på i og for seg kjent måte. Forestringen med diazohydrocarboner skjer eksempelvis ved at en løsning av diazohydrocarbonat i et inert løsningsmiddel, fortrinnsvis i diethylether, blandes med 1-carboxyforbindelsen, oppløst i samme eller et andre inert løsningsmiddel slik som f.eks. methylenklorid. Etter endt omsetning i 1 til 60 minutter fjernes løsningsmidlet, og esteren renses på vanlig måte. Diazoalkaner er enten kjent eller kan fremstilles etter kjente metoder [Org. Reactions, bind 8, s. 389-394 (1954)]. and alkaline earth carbonates or hydroxides, in an alcohol, or in the aqueous solution of an alcohol. As alcohols, aliphatic alcohols such as e.g. methanol, ethanol, butanol, etc., in consideration, preferably methanol. Examples of alkali carbonates and hydroxides include potassium and sodium salts. Preferred is the potassium salt. Examples of suitable alkaline earth carbonates and hydroxides are calcium carbonate, calcium hydroxide and barium carbonate. The conversion generally takes place at -10°C to +70°C, preferably at +25°C. 2 1 2 Introduction of the ester group for R in which R denotes an alkyl group with 1-10 C atoms, takes place according to methods known to the person skilled in the art. The 1-carboxy compounds (R 2 = H) are reacted, for example, with diazohydrocarbons in a manner known per se. The esterification with diazohydrocarbons takes place, for example, by mixing a solution of diazohydrocarbonate in an inert solvent, preferably in diethyl ether, with the 1-carboxy compound, dissolved in the same or another inert solvent such as e.g. methylene chloride. After completion of reaction for 1 to 60 minutes, the solvent is removed, and the ester is purified in the usual way. Diazoalkanes are either known or can be prepared by known methods [Org. Reactions, vol. 8, pp. 389-394 (1954)].
Prostaglandinderivatene av formel I hvori R 2 betegner et hydrogenatom, kan med egnede mengder av tilsvarende uorganiske baser overføres til salter under nøytralisering. Eksempelvis erholdes ved oppløsning av den tilsvarende prostaglandinsyre i vann som inneholder støkiometriske mengder av basen, det faste, uorganiske salt etter avdamp-ning av vannet eller etter tilsetning av et med vann blandbart løsningsmiddel, eksempelvis alkohol eller aceton. The prostaglandin derivatives of formula I in which R 2 denotes a hydrogen atom can be transferred to salts during neutralization with suitable amounts of corresponding inorganic bases. For example, by dissolving the corresponding prostaglandin acid in water containing stoichiometric amounts of the base, the solid, inorganic salt is obtained after evaporation of the water or after the addition of a water-miscible solvent, for example alcohol or acetone.
Fremstilling av aminsaltet skjer på vanlig måte. Derved oppløses prostaglandinsyren i et egnet løsnings-middel slik som f.eks. ethanol, aceton, diethylether eller benzen, og 1 til 5 ekvivalenter av aminet tilsettes denne løsning. Derved utfelles saltet vanligvis i fast form eller isoleres på vanlig måte etter fordampning av løsningsmidlet. Preparation of the amine salt takes place in the usual way. Thereby, the prostaglandin acid is dissolved in a suitable solvent such as e.g. ethanol, acetone, diethyl ether or benzene, and 1 to 5 equivalents of the amine are added to this solution. Thereby, the salt is usually precipitated in solid form or isolated in the usual way after evaporation of the solvent.
Den funksjonelle modifisering av de fri hydroxygrupper skjer etter kjente metoder for fagmannen. For innføring av etherbeskyttelsesgruppene omsettes det eksempelvis med dihydropyran eller methylvinylether i methylenklorid eller kloroform under anvendelse av katalytiske mengder av et surt kondensasjonsmiddel slik som f.eks. p-toluensulfonsyre. Enoletheren tilsettes i overskudd, fortrinnsvis i 1,5- til den 10-doble mengde av det teoretiske behov. Omsetningen skjer normalt ved -10°C til +30°C og er avsluttet i løpet av 2-30 minutter. The functional modification of the free hydroxy groups takes place according to methods known to the person skilled in the art. For the introduction of the ether protecting groups, it is reacted, for example, with dihydropyran or methyl vinyl ether in methylene chloride or chloroform using catalytic amounts of an acidic condensation agent such as e.g. p-toluenesulfonic acid. The enol ether is added in excess, preferably in an amount 1.5 to 10 times the theoretical requirement. The turnover normally takes place at -10°C to +30°C and is completed within 2-30 minutes.
Innføring av acylbeskyttelsesgruppen skjer ved at en forbindelse av formel I på i og for seg kjent måte omsettes med et carboxylsyrederivat slik som f.eks. syre-klorid, syreanhydrid, etc. Introduction of the acyl protecting group takes place by reacting a compound of formula I in a manner known per se with a carboxylic acid derivative such as e.g. acid chloride, acid anhydride, etc.
Forbindelsene av generell formel I virker blodtrykkssenkende og bronchodilaterende. De egner seg til hemning av trombocyttaggregering, virker cytobeskyttende i mage, lever, nyre og pankreas og er derfor også anvendbare ved organtransplantasjoner. Derved utgjør de nye 6-oxoprostaglandin-E-derivater verdifulle farmasøytiske virkestoffer. Enn videre utviser de ved lignende virk-ningsspekter en høyere spesifisitet og lengre virknings-varighet sammenlignet med de tilsvarende prostaglandiner. The compounds of general formula I have blood pressure-lowering and bronchodilating effects. They are suitable for inhibiting platelet aggregation, have a cytoprotective effect in the stomach, liver, kidney and pancreas and are therefore also applicable in organ transplants. Thereby, the new 6-oxoprostaglandin-E derivatives constitute valuable pharmaceutical active substances. Furthermore, with a similar spectrum of action, they exhibit a higher specificity and a longer duration of action compared to the corresponding prostaglandins.
De nye prostaglandinanaloger utviser egenskaper som er typiske for prostaglandin E, slik som f.eks. senkning av den perifere, arterielle og koronare karmotstand, inhibering av trombocyttaggregering og oppløsning av blodplate-tromber, myocardial cytobeskyttelse og dermed senkning av det systemiske blodtrykk uten samtidig å senke slagvolum og koronar gjennomstrømning; og ytterligere indikasjoner kan prinsipielt være: slaganfall, profylakse og terapi av koronare hjertesykdommer, koronar trombose, hjerteinfarkt, perifere arteriesykdommer, arteriosklerose og trombose, astma, profylakse og behandling av ischemiske angrep på CNS-systemet, behandling av sjokk, inhibering av bronchokonstrik-sjon, inhibering av magesyresekresjon, cytobeskyttelse i mage- og tarmslimhuden, cytobeskyttelse i lever, nyre og i pankreas, senkning av den pulmonale, vaskulære motstand og det pulmonale blodtrykk, fremming av nyregjennomblød-ning, anvendelse istedenfor heparin eller som adjuvans ved dialyse eller hemofiltrering, konservering av blod- og trombocyttkonserver, transplantater, inhibering av fødsels-veer, økning av cerebral gjennomblødning, glaucombehandling, innbygning i kunstig vev, kirurgiske sømmaterialer, vene-katetere, etc. The new prostaglandin analogues exhibit properties that are typical of prostaglandin E, such as e.g. lowering of peripheral, arterial and coronary vessel resistance, inhibition of platelet aggregation and dissolution of platelet thrombi, myocardial cytoprotection and thus lowering of systemic blood pressure without simultaneously lowering stroke volume and coronary flow; and further indications can in principle be: stroke, prophylaxis and therapy of coronary heart diseases, coronary thrombosis, myocardial infarction, peripheral artery diseases, arteriosclerosis and thrombosis, asthma, prophylaxis and treatment of ischemic attacks on the CNS system, treatment of shock, inhibition of bronchoconstriction , inhibition of gastric acid secretion, cytoprotection in the stomach and intestinal mucosa, cytoprotection in the liver, kidney and pancreas, lowering of pulmonary, vascular resistance and pulmonary blood pressure, promotion of renal perfusion, use instead of heparin or as an adjuvant in dialysis or hemofiltration, preservation of blood and platelet preserves, transplants, inhibition of labor pains, increase of cerebral blood flow, glaucoma treatment, incorporation into artificial tissue, surgical suture materials, vein catheters, etc.
6-oxoprostaglandin-E-derivatene fremstilt ifølge oppfinnelsen kan også anvendes i kombinasjon med eksempelvis (3-blokkere, diuretika, fosfodiesterasehemmere, Ca-antagonister, t-PA, ikke-steroidale inflammasjonsinhiberende midler, leukotrien-syntetasehemmere, leukotrienantagonister, tromboxansynte-tasehemmere eller tromboxanantagonister. The 6-oxoprostaglandin-E derivatives produced according to the invention can also be used in combination with, for example, (3-blockers, diuretics, phosphodiesterase inhibitors, Ca antagonists, t-PA, non-steroidal anti-inflammatory agents, leukotriene synthetase inhibitors, leukotriene antagonists, thromboxane synthetase inhibitors or thromboxane antagonists.
Dosen av forbindelsene er 1-1000 ug/kg/dag når de administreres til humane pasienter. Enhetsdosen for den farmasøytisk akseptable bærer utgjør 10 ug til 100 ug. The dose of the compounds is 1-1000 ug/kg/day when administered to human patients. The unit dose of the pharmaceutically acceptable carrier is 10 µg to 100 µg.
I den etterfølgende tabell er angitt resultatene The following table shows the results
av en farmakologisk sammenligningsundersøkelse med forbindelsene fra eksempel 1 og 4 i sammenligning med 6-oxo-PGE^. of a pharmacological comparative study with the compounds of examples 1 and 4 in comparison with 6-oxo-PGE^.
I sammenligning med 6-oxo-PGE-l fremgår det klart In comparison with 6-oxo-PGE-1, it is clear
fra testresultatene at foreliggende forbindelser er opptil 80 ganger mer effektive ved trombocyttaggregerings-inhibering og reduserer blodtrykk opptil 100 ganger bedre enn PGE^ Enn videre har forbindelsene et høyt cytobeskyttende potensial spesielt for magen. from the test results that the present compounds are up to 80 times more effective in inhibiting platelet aggregation and reduce blood pressure up to 100 times better than PGE^ Furthermore, the compounds have a high cytoprotective potential especially for the stomach.
For parenteral administrering anvendes sterile, injiserbare, vandige eller oljeaktige løsninger. For oral administrering er eksempelvis tabletter, dragéer eller kapsler egnet. Oppfinnelsen angår således også legemidler på basis av forbindelsene av formel I og vanlige hjelpe-og bærerstoffer innbefattende cyclodextrinclathrater. For parenteral administration, sterile, injectable, aqueous or oily solutions are used. For oral administration, for example, tablets, dragées or capsules are suitable. The invention thus also relates to pharmaceuticals based on the compounds of formula I and common excipients and carriers including cyclodextrin clathrates.
De nye virkestoffer skal i forbindelse med de innen det galeniske fag, kjente og vanlige hjelpestoffer, eksempelvis tjene til fremstilling av blodtrykkssenkende midler, trombocyttaggregeringshemmende midler eller til cytobeskyttende midler. The new active substances shall, in conjunction with the known and common excipients within the galenic field, for example serve to produce blood pressure-lowering agents, platelet aggregation-inhibiting agents or cytoprotective agents.
Eksempel 1 Example 1
(13E)-(11R,15S,16RS)-6,9-di-oxo-ll,15-dihydroxy-16-methyl-18 , 18 , 19 , 19- tetradehydro- 13- prostensyre (13E)-(11R,15S,16RS)-6,9-di-oxo-11,15-dihydroxy-16-methyl-18, 18, 19, 19-tetrahydro-13-prostenic acid
160 mg (13E)-(11R,15S,16RS)-6,9-di-oxo-ll,15-bis-(tetrahydropyran-2-yloxy)-16-methyl-18,18,19,19-tetradehydro-13-prostensyre ble tilsatt 88 ml av en blanding av eddiksyre:vann:tetrahydrofuran (65:35:10) og fikk reagere i 15 timer ved romtemperatur. Reaksjonsblandingen ble inndampet i vakuum, og resten av eddiksyre og vann ble fjernet under tilsetning av toluen ved hjelp av gjentagende azeotrop vakuumdestillasjon. Den erholdte, urene olje ble renset ved kromatografi på glassplater belagt med kiselgel. Som elueringsmiddel ble anvendt en blanding av diklormethan og methanol. Det ble isolert 108 mg (98%) av tittelforbindelsen som farveløs olje. 160 mg (13E)-(11R,15S,16RS)-6,9-di-oxo-11,15-bis-(tetrahydropyran-2-yloxy)-16-methyl-18,18,19,19-tetrahydro- 13-prostenic acid was added to 88 ml of a mixture of acetic acid:water:tetrahydrofuran (65:35:10) and allowed to react for 15 hours at room temperature. The reaction mixture was evaporated in vacuo, and the remainder of acetic acid and water were removed while adding toluene by means of repeated azeotropic vacuum distillation. The crude oil obtained was purified by chromatography on glass plates coated with silica gel. A mixture of dichloromethane and methanol was used as eluent. 108 mg (98%) of the title compound was isolated as a colorless oil.
IR (film): 3380, 3600 - 2400, 2960, 2920, 2870, 1740, 1725, IR (film): 3380, 3600 - 2400, 2960, 2920, 2870, 1740, 1725,
1710, 1565, 1405, 1285, 1158, 1080, 1020, 973 cm"<1>. 1710, 1565, 1405, 1285, 1158, 1080, 1020, 973 cm"<1>.
Eksempel 2 Example 2
(13E)-(11R,15S,16RS)-6,9-di-oxo-ll,15-bis-(tetrahydropyran-2- yloxy)- 16- methyl- 18, 18, 19, 19- tetradehydro- 13- prostensyre (13E)-(11R,15S,16RS)-6,9-di-oxo-11,15-bis-(tetrahydropyran-2-yloxy)- 16- methyl- 18, 18, 19, 19- tetradehydro- 13- prostenic acid
En løsning av 396 mg (13E)-(9S,11R,15S,16RS)-6-oxo-9-hydroxy-ll,15-bis-(tetrahydropyran-2-yloxy)-16-methyl-18,18,19,19-tetradehydro-13-prostensyre i 8 ml absolutt dimethylketon ble avkjølt under utelukkelse av fuktighet til -30°C, ble tilsatt 270 ul Jones-løsning og ble omrørt i 1,5 time ved -30°C til -20°C. Etter tilsetning av 2 ml isopropanol ble 50 ml isvann tilsatt, blandingen ble ekstrahert flere ganger med totalt 100 ml diethylether, ble vasket med mettet natriumkloridløsning, tørket over magnesiumsulfat, filtrert og inndampet i vakuum. Den fargeløse, urene olje ble kromatografert på kiselgelbelagte plater med hexan-ethylacetat. Ved siden av utgangsmateriale ble det isolert 160 mg (41%) av tittelforbindelsen som fargeløs ol je. A solution of 396 mg of (13E)-(9S,11R,15S,16RS)-6-oxo-9-hydroxy-11,15-bis-(tetrahydropyran-2-yloxy)-16-methyl-18,18,19 ,19-Tetradehydro-13-prostenic acid in 8 ml of absolute dimethyl ketone was cooled to -30°C with exclusion of moisture, 270 µl of Jones solution was added and stirred for 1.5 hours at -30°C to -20°C . After adding 2 ml of isopropanol, 50 ml of ice water was added, the mixture was extracted several times with a total of 100 ml of diethyl ether, was washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and evaporated in vacuo. The colorless crude oil was chromatographed on silica gel coated plates with hexane-ethyl acetate. Next to the starting material, 160 mg (41%) of the title compound was isolated as a colorless oil.
IR (film): 3600 - 2500, 2940, 2870, 1742, 1726, 1710, 1452, 1440, 1380, 1380, 1352, 1200, 1125 (bred), 1078, 1035, 1022, 972, 912, 870, 816 cm"<1.>IR (film): 3600 - 2500, 2940, 2870, 1742, 1726, 1710, 1452, 1440, 1380, 1380, 1352, 1200, 1125 (wide), 1078, 1035, 1022, 972, 912, 870, 816 cm "<1.>
Utgangsmaterialet ble fremstilt som beskrevet i eksempel 2a til 2h. The starting material was prepared as described in examples 2a to 2h.
Eksempel 2a Example 2a
(13E) -(9S,11R,15S,16RS)-6-oxo-9-hydroxy-ll,15-bis-(tetra-hydropyran-2-yloxy)-16-methyl-18,18,19,19-tetradehydro-13-prostensyre (13E)-(9S,11R,15S,16RS)-6-oxo-9-hydroxy-11,15-bis-(tetra-hydropyran-2-yloxy)-16-methyl-18,18,19,19- tetrahydro-13-prostenic acid
690 mg (5RS,6RS,16RS)-5-jod-16-methyl-18,18,19,19-tetradehydro-prostaglandin 1^-11,15-bis-(tetrahydropyranylether)-methylester ble oppløst i 30 ml absolutt benzen, 690 mg of (5RS,6RS,16RS)-5-iodo-16-methyl-18,18,19,19-tetrahydro-prostaglandin 1^-11,15-bis-(tetrahydropyranyl ether)-methyl ester were dissolved in 30 ml of absolute benzene ,
ble tilsatt 2,3 ml diazabicycloundecan og ble oppvarmet under utelukkelse av fuktighet i 2 timer til 50°C. Den av-kjølte løsning ble fortynnet med 60 ml ethylacetat, ble vasket to ganger med en mettet natriumhydrogencarbonatløs-ning, og den organiske fase ble tørket over en blanding av magnesiumsulfat og kaliumcarbonat. Etter filtrering og inndampning i vakuum ble den erholdte, urene olje tatt opp i 25 ml methanol, ble tilsatt en løsning av 600 mg kaliumhydroxyd i 5 ml vann og ble omrørt i 16 timer. Reaksjonsblandingen ble inndampet i vakuum til 5 ml, ble fortynnet med 70 ml vann og ekstrahert med 50 ml ether. Den fra-skilte, organiske fase ble vasket med 2n natronlut, de forenede, basiske ekstrakter ble surgjort med mettet sitronsyre til pH 4,5 og ekstrahert flere ganger med totalt 100 ml triklormethan. De organiske ekstrakter ble vasket nøytralt med mettet natriumkloridløsning, ble tørket over magnesiumsulfat, filtrert og inndampet i vakuum. Det ble erholdt 609 mg av en gul olje som ble kromatografert på kiselgel med ethylacetat-isopropanol. Som hovedkomponent ble det isolert 396 mg (70%) av tittelforbindelsen som fargeløs olje. was added 2.3 ml of diazabicycloundecane and was heated under exclusion of moisture for 2 hours at 50°C. The cooled solution was diluted with 60 ml of ethyl acetate, was washed twice with a saturated sodium bicarbonate solution, and the organic phase was dried over a mixture of magnesium sulfate and potassium carbonate. After filtration and evaporation in vacuo, the crude oil obtained was taken up in 25 ml of methanol, a solution of 600 mg of potassium hydroxide in 5 ml of water was added and stirred for 16 hours. The reaction mixture was evaporated in vacuo to 5 ml, diluted with 70 ml of water and extracted with 50 ml of ether. The separated organic phase was washed with 2N caustic soda, the combined basic extracts were acidified with saturated citric acid to pH 4.5 and extracted several times with a total of 100 ml of trichloromethane. The organic extracts were washed neutral with saturated sodium chloride solution, were dried over magnesium sulfate, filtered and evaporated in vacuo. 609 mg of a yellow oil was obtained which was chromatographed on silica gel with ethyl acetate-isopropanol. As the main component, 396 mg (70%) of the title compound was isolated as a colorless oil.
IR (film): 3420, 3600 - 2500, 2940, 2870, 1730, 1710, 1450, IR (film): 3420, 3600 - 2500, 2940, 2870, 1730, 1710, 1450,
1440, 1382, 1350, 1200, 1125 (bred), 1075, 1020, 973, 908, 868, 813 cm<-1>. 1440, 1382, 1350, 1200, 1125 (wide), 1075, 1020, 973, 908, 868, 813 cm<-1>.
Eksempel 2b Example 2b
(5RS,6RS,16RS)-5-jod-16-methyl-18,18,19,19-tetradehydro-prostaglandin 1-l~11 r 15-bis- (tetrahydropyranylether) - methylester (5RS,6RS,16RS)-5-iodo-16-methyl-18,18,19,19-tetrahydro-prostaglandin 1-l~11 r 15-bis-(tetrahydropyranyl ether) - methyl ester
En løsning av 1,72 g (5E/Z,13E)-(9S,11R,15S,16RS)-9-hydroxy-ll,15-bis-(tetrahydropyran-2-yloxy)-16-methyl-18,18,19,19-tetradehydro-prostadiensyre-methylester i 50 ml diethylether ble tilsatt en løsning av 4,10 g natrium-hydrogencarbonat i 70 ml vann, ble avkjølt til 0-5°C, og i løpet av 90 minutter ble en løsning av 1,77 g jod i 65 ml diethylether dråpevis tilsatt. Reaksjonsblandingen fikk reagere i ytterligere 3 timer ved 0-5°C, overskudd av jod ble redusert under tilsetning av den tilsvarende mengde av en ca. 20% natriumthiosulfatløsning, den organiske fase ble fraskilt og vasket med mettet natriumkloridløsning. Etter tørking over magnesiumsulfat, filtrering og inndamping i vakuum ble det isolert 2,11 g (100%) av tittelforbindelsen som en gul olje. A solution of 1.72 g of (5E/Z,13E)-(9S,11R,15S,16RS)-9-hydroxy-11,15-bis-(tetrahydropyran-2-yloxy)-16-methyl-18,18 . 1.77 g of iodine in 65 ml of diethyl ether added dropwise. The reaction mixture was allowed to react for a further 3 hours at 0-5°C, excess iodine was reduced by adding the corresponding amount of an approx. 20% sodium thiosulfate solution, the organic phase was separated and washed with saturated sodium chloride solution. After drying over magnesium sulfate, filtration and evaporation in vacuo, 2.11 g (100%) of the title compound was isolated as a yellow oil.
IR (film): 2970, 2870, 1738, 1450, 1438, 1200, 1120 (bred), IR (film): 2970, 2870, 1738, 1450, 1438, 1200, 1120 (wide),
1075, 1034, 1020, 974, 907, 868, 815 cm"<1>. 1075, 1034, 1020, 974, 907, 868, 815 cm"<1>.
Eksempel 2c Example 2c
(5Z,13E)-OS,11R,15S,16RS)-9-hydroxy-ll,15-bis-(tetrahydro-pyran-2-yloxy)-16-methyl-18,18,19,19-tetradehydro-prostadiensyre- methylester (5Z,13E)-OS,11R,15S,16RS)-9-hydroxy-11,15-bis-(tetrahydro-pyran-2-yloxy)-16-methyl-18,18,19,19-tetrahydro-prostadic acid - methyl ester
En løsning av 16,54 g carboxybutyltrifenylfosfonium-bromid i en blanding av 35 ml absolutt dimethylsulfoxyd og 15 ml absolutt tetrahydrofuran ble avkjølt til 3°C og ble under utelatelse av fuktighet porsjonsvis tilsatt totalt 8,0 g kalium-tert.-butanolat. Deretter ble i løpet av 1 time en løsning av 1,81 g (IS,3RS,5R,6R,7R)-7-(tetrahydro-pyran-2-yloxy)-6[(13E,3S,4RS)-4-methyl-3-(tetrahydropyran-2-yloxy)-l-octen-6-inyl)]-bicyclo[3.3•0]octan-3-ol i 200 ml absolutt tetrahydrofuran dråpevis tilsatt, blandingen ble oppvarmet til romtemperatur og fikk reagere i ytterligere 30 minutter. Under kraftig omrøring ble blandingen helt over i 200 ml iskaldt vann, ble innstilt til pH 3 med 1 n HC1 og ekstrahert flere ganger med totalt 200 ml diethylether. Den organiske fase ble vasket nøytral med mettet natriumkloridløsning, ble tørket over magnesiumsulfat og filtrert fra. Filtratet ble tilsatt en etherisk løsning av diazomethan, filtrert på nytt og inndampet i vakuum. Etter kromatografi av residuet på kiselgel med hexan/ethylacetat ble det isolert 1,72 g (78%) av tittelforbindelsen ved siden av spor av 5E-isomeren som fargeløs olje. A solution of 16.54 g of carboxybutyltriphenylphosphonium bromide in a mixture of 35 ml of absolute dimethylsulfoxide and 15 ml of absolute tetrahydrofuran was cooled to 3°C and, while omitting moisture, a total of 8.0 g of potassium tert-butanolate was added in portions. Then, in the course of 1 hour, a solution of 1.81 g of (IS,3RS,5R,6R,7R)-7-(tetrahydro-pyran-2-yloxy)-6[(13E,3S,4RS)-4- methyl-3-(tetrahydropyran-2-yloxy)-1-octen-6-ynyl)]-bicyclo[3.3•0]octan-3-ol in 200 ml absolute tetrahydrofuran added dropwise, the mixture was warmed to room temperature and allowed to react in another 30 minutes. With vigorous stirring, the mixture was poured into 200 ml of ice-cold water, adjusted to pH 3 with 1 N HCl and extracted several times with a total of 200 ml of diethyl ether. The organic phase was washed neutral with saturated sodium chloride solution, was dried over magnesium sulfate and filtered off. The filtrate was added to an ethereal solution of diazomethane, filtered again and evaporated in vacuo. After chromatography of the residue on silica gel with hexane/ethyl acetate, 1.72 g (78%) of the title compound was isolated alongside traces of the 5E isomer as a colorless oil.
IR (film): 3450,.2940, 2870, 1738, 1450, 1437, 1200, 1130, IR (film): 3450,.2940, 2870, 1738, 1450, 1437, 1200, 1130,
1077, 1021, 974, 907, 868, 813 cm"<1>. 1077, 1021, 974, 907, 868, 813 cm"<1>.
Eksempel 2d Example 2d
(1S,3RS,5R,6S,7R)-7-(tetrahydropyran-2-yloxy)-6-[(13E, 3S,4RS)-4-methyl-3-(tetrahydropyran-2-yloxy-l-octen-6-inyl)]- 2- oxa- bicyclo[ 3. 3. 0] octan- 3- ol (1S,3RS,5R,6S,7R)-7-(tetrahydropyran-2-yloxy)-6-[(13E,3S,4RS)-4-methyl-3-(tetrahydropyran-2-yloxy-1-octen- 6-inyl)]- 2- oxa- bicyclo[ 3. 3. 0] octan- 3-ol
Ved -70°C ble en løsning av 1,98 g lacton i 60 ml absolutt toluen tilsatt 15 ml av en 1 M løsning av diiso-butylaluminiumhydrid i toluen, og blandingen ble omrørt i 50 minutter ved -65°C under en atmosfære av tørt argon. Etter tilsetning av 1,3 ml isopropanol og deretter 10 ml vann fikk blandingen oppvarmes til romtemperatur, det finkornige bunnfall ble fraskilt, og løsningen ble inndampet i vannstrålevakuum. Det ble isolert 1,81 g (91%) av en fargeløs olje som ble ytterligere omsatt uten rensing. At -70°C, a solution of 1.98 g of lactone in 60 ml of absolute toluene was added to 15 ml of a 1 M solution of diisobutylaluminum hydride in toluene, and the mixture was stirred for 50 minutes at -65°C under an atmosphere of dry argon. After addition of 1.3 ml of isopropanol and then 10 ml of water, the mixture was allowed to warm to room temperature, the fine-grained precipitate was separated, and the solution was evaporated in a water jet vacuum. 1.81 g (91%) of a colorless oil was isolated which was further reacted without purification.
Eksempel 2e Example 2e
(1S,5R,6S,7R)-6-[(E)-(3S,4RS)-4-methyl-3-(tetrahydropyran-2- yloxy)-oct-l-en-6-inyl]-7-(tetrahydropyran-2-yloxy)-2-oxabicyco[ 3 . 3 . 0] octan- 3- on (1S,5R,6S,7R)-6-[(E)-(3S,4RS)-4-methyl-3-(tetrahydropyran-2-yloxy)-oct-1-en-6-inyl]-7- (tetrahydropyran-2-yloxy)-2-oxabicyclo[ 3 . 3. 0] octan-3-one
En løsning av 2,16 g (IS,5R,6R,7R)-6-[(E)-(3S,4RS)-3- hydroxy-4-methyl-oct-l-en-6-inyl]-7-hydroxy-2-oxa-bicyclo[3.3.0]octan-3-on i 50 ml vannfritt methylenklorid ble tilsatt 1,7 ml dihydropyran, en mikrospatelspiss av p-toluensulfonsyre og ble omrørt i 30 minutter ved 25°C A solution of 2.16 g of (IS,5R,6R,7R)-6-[(E)-(3S,4RS)-3-hydroxy-4-methyl-oct-1-en-6-inyl]-7 -hydroxy-2-oxa-bicyclo[3.3.0]octan-3-one in 50 ml of anhydrous methylene chloride was added to 1.7 ml of dihydropyran, a microspatula tip of p-toluenesulfonic acid and was stirred for 30 minutes at 25°C
og under en atmosfære av tørt argon. 20 ml av en 10% vandig bicarbonatløsning ble tilsatt, den organiske fase ble fraskilt, vasket med vann og tørket over magnesiumsulfat. Det urene produkt ble kromatografert med et gradi-entsystem av hexan/eddiksyreethylester på kiselgel, og det ble isolert 2,96 g (85%) av tittel forbindelsen som fargeløs, olje. and under an atmosphere of dry argon. 20 ml of a 10% aqueous bicarbonate solution was added, the organic phase was separated, washed with water and dried over magnesium sulfate. The crude product was chromatographed with a gradient system of hexane/ethyl acetate on silica gel and 2.96 g (85%) of the title compound was isolated as a colorless oil.
IR (CHC13): 2945, 2870, 1767, 1452, 1440, 1352, 1261, 1182, IR (CHC13): 2945, 2870, 1767, 1452, 1440, 1352, 1261, 1182,
1128, 1074, 1020, 973, 910, 870, 869, 811 cm"<1>. 1128, 1074, 1020, 973, 910, 870, 869, 811 cm"<1>.
Eksempel 2 f Example 2 f
(1S,5R, 6S, 7R) -6-[ (E) -(3S,4RS) -3-hydroxy-4-methy 1-oct-l-en-6-inyl]-7-hydroxy-2-oxabicyclo[3.3.0]octan-3-on (1S,5R,6S,7R)-6-[(E)-(3S,4RS)-3-hydroxy-4-methyl 1-oct-1-en-6-inyl]-7-hydroxy-2-oxabicyclo [3.3.0]octan-3-one
En løsning av 4,78 g (IS,5R,6R,7R)-6-[ (E)-(3S,4RS)-3-hydroxy-4-methyl-oct-l-en-6-inyl]-7-benzoyloxy-2-oxabicyclo[3.3.0]octan-3-on i 50 ml vannfri methanol ble tilsatt 2,1 g finpulverisert kaliumcarbonat, og blandingen ble omrørt i 5 timer ved 25°C og under en atmosfære av tørt argon. pH ble innstilt på 7 med en 10%-ig vandig sitronsyreløsning, løsningen ble inndampet i vakuum til 60 ml restvolum, ble tilsatt 100 ml vann og ekstrahert flere ganger med 300 ml diklormethan. De forenede, organiske faser ble vasket med vann, tørket over magnesiumsulfat og inndampet etter filtrering i vakuum. Den gule, urene olje ble kromatografert under trykk på en kiselgelsøyle med en gradientblanding av hexan og aceton. Det ble isolert 2,96 g (85%) av tittelforbindelsen som fargeløs olje. A solution of 4.78 g of (1S,5R,6R,7R)-6-[(E)-(3S,4RS)-3-hydroxy-4-methyl-oct-1-en-6-inyl]-7 -benzoyloxy-2-oxabicyclo[3.3.0]octan-3-one in 50 ml of anhydrous methanol was added 2.1 g of finely powdered potassium carbonate, and the mixture was stirred for 5 hours at 25°C and under an atmosphere of dry argon. The pH was adjusted to 7 with a 10% aqueous citric acid solution, the solution was evaporated in vacuo to a 60 ml residual volume, 100 ml of water was added and extracted several times with 300 ml of dichloromethane. The combined organic phases were washed with water, dried over magnesium sulfate and evaporated after filtration in vacuo. The yellow crude oil was chromatographed under pressure on a silica gel column with a gradient mixture of hexane and acetone. 2.96 g (85%) of the title compound was isolated as a colorless oil.
IR (film): 3350, 2960, 2870, 1760, 1640, 1435, 1420, 1350, IR (film): 3350, 2960, 2870, 1760, 1640, 1435, 1420, 1350,
1180, 1075, 1020, 970> 908 cm"<1.>1180, 1075, 1020, 970> 908 cm"<1.>
Eksempel 2g Example 2g
(IS, 5R, 6 S,7R) - 6-[ (E) -{3S,4RS) -3-hydroxy-4-methyl-oct-l-en-6- inyl]- 7- benzoyloxy- 3- oxabicyclo[ 3. 3. 0] octan- 3- on (IS, 5R, 6S,7R)-6-[(E)-{3S,4RS)-3-hydroxy-4-methyl-oct-1-en-6-inyl]- 7- benzoyloxy- 3- oxabicyclo [ 3. 3. 0] octan- 3- one
En løsning av 12,5 g (IS,5R,6R,7R)-6-[(E)-(4RS)-3-oxo-4-methyl-oct-l-en-6-inyl]-7-benzoyloxy-2-oxabicyclo-[3.3.0]octan-3-on i en blanding av 300 ml methanol og 80 ml tetrahydrofuran ble under utelukkelse av fuktighet ved -40°C tilsatt 1,84 g CeCl3«7H20 og deretter porsjonsvis totalt 1,8 5 g natriumborhydrid. Etter 1 time ved -40°C ble 50 ml aceton og 10 ml av en 2 n H2S04 tilsatt, og pH ble innstilt på 7 med 10% vandig sitronsyre. Reaksjonsblandingen fikk anta romtemperatur, ble inndampet i vakuum til et restvolum på 100 ml, ble tilsatt vann og ekstrahert flere ganger med totalt 800 ml diklormethan. De forenede, organiske ekstrakter ble vasket med vann, tørket over magnesiumsulfat og inndampet i vakuum. Det ble erholdt 13,6 g av en gul olje som ble kromatografert under trykk på kiselgel med ether/pentan. Ved siden av en liten mengde utgangsmateriale ble det isolert 7,43 g (59%) av tittelforbindelsen, såvel som 5,12 g (41%) av polar komponent (1S,5R,6R,7R)-6[(E)-(3R,4RS)-3-hydroxy-4-methyl-oct-l-en-6- inyl)]-7-benzoyloxy-2-oxabicyclo[3.3.0]octan-3-on. A solution of 12.5 g of (IS,5R,6R,7R)-6-[(E)-(4RS)-3-oxo-4-methyl-oct-1-en-6-inyl]-7-benzoyloxy -2-oxabicyclo-[3.3.0]octan-3-one in a mixture of 300 ml of methanol and 80 ml of tetrahydrofuran, while excluding moisture at -40°C, 1.84 g of CeCl3«7H20 were added and then in portions a total of 1, 8 5 g sodium borohydride. After 1 hour at -40°C, 50 ml of acetone and 10 ml of a 2 N H 2 SO 4 were added and the pH was adjusted to 7 with 10% aqueous citric acid. The reaction mixture was allowed to reach room temperature, evaporated in vacuo to a residual volume of 100 ml, water was added and extracted several times with a total of 800 ml of dichloromethane. The combined organic extracts were washed with water, dried over magnesium sulfate and evaporated in vacuo. 13.6 g of a yellow oil was obtained which was chromatographed under pressure on silica gel with ether/pentane. Besides a small amount of starting material, 7.43 g (59%) of the title compound was isolated, as well as 5.12 g (41%) of the polar component (1S,5R,6R,7R)-6[(E)- (3R,4RS)-3-hydroxy-4-methyl-oct-1-en-6-inyl)]-7-benzoyloxy-2-oxabicyclo[3.3.0]octan-3-one.
IR (film): 3460, 2970, 2930, 1760, 1720, 1455, 1320, 1270, IR (film): 3460, 2970, 2930, 1760, 1720, 1455, 1320, 1270,
1175, 1110, 1070, 740, 715 cm<-1>. 1175, 1110, 1070, 740, 715 cm<-1>.
Eksempel 2h Example 2h
(1S,5R,6S,7R)-6-[(E)-(4RS)-3-oxo-4-methyl-oct-l-en-6-iny1]-7- benzoyloxy- 2- oxabicyclo[ 3. 3. 0] octan- 3- on (1S,5R,6S,7R)-6-[(E)-(4RS)-3-oxo-4-methyl-oct-1-en-6-iny1]-7- benzoyloxy- 2- oxabicyclo[ 3. 3. 0] octan- 3- one
Til en oppslemming av 1,75 g NaH i 190 ml dimethoxyethan ble under utelukkelse av fuktighet dråpevis tilsatt en løsning av 9,73 g dimethyl-(2-oxo-3-methyl-hept-5-inyl)-fosfonat i 90 ml vannfritt dimethoxyethan. Blandingen fikk reagere i ytterligere 30 minutter ved 23°C, og ved -45°C ble en løsning av 10,0 g Corey-lacton i 150 ml dimethoxyethan dråpevis tilsatt i løpet av 50 minutter. For fullførelse av reaksjonen ble blandingen omrørt i ytterligere 3 timer ved -20°C, ble tilsatt 3 ml ethylacetat, To a slurry of 1.75 g of NaH in 190 ml of dimethoxyethane, a solution of 9.73 g of dimethyl-(2-oxo-3-methyl-hept-5-inyl)-phosphonate in 90 ml of anhydrous was added dropwise while excluding moisture dimethoxyethane. The mixture was allowed to react for a further 30 minutes at 23°C, and at -45°C a solution of 10.0 g of Corey lactone in 150 ml of dimethoxyethane was added dropwise over 50 minutes. To complete the reaction, the mixture was stirred for a further 3 hours at -20°C, 3 ml of ethyl acetate was added,
500 ml ether og ble vasket flere ganger med en mettet natrium-kloridløsning inntil nøytral reaksjon. Den organiske fase ble tørket over magnesiumsulfat, ble filtrert og inndampet i vakuum til tørrhet. Det ble isolert 13,2 g (98%) av tittelforbindelsen som et voksaktig, fast stoff. 500 ml ether and was washed several times with a saturated sodium chloride solution until neutral reaction. The organic phase was dried over magnesium sulfate, filtered and evaporated in vacuo to dryness. 13.2 g (98%) of the title compound was isolated as a waxy solid.
IR (CHC13): 2970, 2920, 1775, 1715, 1628, 1450, 1362, IR (CHC13): 2970, 2920, 1775, 1715, 1628, 1450, 1362,
1315, 1270, 1176, 1110, 1070, 980 cm<-1>. 1315, 1270, 1176, 1110, 1070, 980 cm<-1>.
EKsempel 3 EXAMPLE 3
(13E)-(11R,15S,16RS)-6,9-di-oxo-ll,15-dihydroxy-16-methyl-18, 18, 19, 19- tetradehydro- 13- prostensyre- methylester (13E)-(11R,15S,16RS)-6,9-di-oxo-11,15-dihydroxy-16-methyl-18, 18, 19, 19- tetradehydro- 13-prostenic acid methyl ester
Til 50 mg (13E)-(11R,15S,16RS)-6,9-di-oxo-ll,15-dihydroxy-16-methyl-18,18,19,19-tetradehydro-13-prostensyre overlagt med 5 ml ether, ble under kraftig omrøring dråpevis tilsatt en etherisk løsning av diazomethan inntil en homogen løsning var blitt dannet. Reaksjonsblandingen ble inndampet i vakuum, og den erholdte, urene olje ble renset ved preparativ skiktkromatografi på silicagel-belagte glassplater. Som elueringsmiddel ble det anvendt en blanding av diklormethan og isopropanol. Det ble isolert 36 mg (69%) av tittelforbindelsen som fargeløs olje. To 50 mg of (13E)-(11R,15S,16RS)-6,9-di-oxo-11,15-dihydroxy-16-methyl-18,18,19,19-tetrahydro-13-prostenic acid overlaid with 5 ml ether, an ethereal solution of diazomethane was added dropwise with vigorous stirring until a homogeneous solution had been formed. The reaction mixture was evaporated in vacuo, and the crude oil obtained was purified by preparative layer chromatography on silica gel-coated glass plates. A mixture of dichloromethane and isopropanol was used as eluent. 36 mg (69%) of the title compound was isolated as a colorless oil.
IR (film): 3380, 2980 - 2820, 1735, 1450, 1440, 1200, 1075, IR (film): 3380, 2980 - 2820, 1735, 1450, 1440, 1200, 1075,
1025, 975, 908 cm"<1>. 1025, 975, 908 cm"<1>.
Eksempel 4 Example 4
(11R,15S,16S)-6,9-di-oxo-ll,15-dihydroxy-16,20-dimethyl-13, 14, 18, 18, 19, 19- hexadehydro- 13- prostensyre (11R,15S,16S)-6,9-di-oxo-11,15-dihydroxy-16,20-dimethyl-13, 14, 18, 18, 19, 19- hexadehydro- 13-prostenic acid
410 mg (11R,15S,16S)-6,9-di-oxo-ll,15-bis-(tetra-hydropyran-2-yloxy)-16,20-dimethyl-13,14,18,18,19,19-hexadehydro-13-prostensyre ble avbeskyttet analogt med hva som er beskrevet i eksempel 1. Etter kromatografisk rensing ble det erholdt 236 mg (82%) av tittelforbindelsen som fargeløs olje. 410 mg (11R,15S,16S)-6,9-di-oxo-11,15-bis-(tetra-hydropyran-2-yloxy)-16,20-dimethyl-13,14,18,18,19, 19-hexadehydro-13-prostenic acid was deprotected analogously to what is described in example 1. After chromatographic purification, 236 mg (82%) of the title compound was obtained as a colorless oil.
IR (film): 3400, 3600 - 2500, 2980, 2230, 1740, 1730, 1710, IR (film): 3400, 3600 - 2500, 2980, 2230, 1740, 1730, 1710,
1570, 1410, 1280, 1160, 1075, 1020, 970 cm"<1.>1570, 1410, 1280, 1160, 1075, 1020, 970 cm"<1.>
Eksempel 5 Example 5
(11R,15S,16S)-6,9-di-oxo-ll,15-bis-(tetrahydropyran-2-yloxyl)-16,20-dimethyl-13,14,18,18,19,19-hexadehydro-13-prostensyre (11R,15S,16S)-6,9-di-oxo-11,15-bis-(tetrahydropyran-2-yloxyl)-16,20-dimethyl-13,14,18,18,19,19-hexadehydro- 13-prostenic acid
628 mg (9S,11R,15S,16S)-6-oxo-9-hydroxy-ll,15-bis-(tetrahydropyran-2-yloxy)-16,20-dimethyl-13,14,18,18,19,19-hexadehydro-13-prostensyre ble oxydert på analog måte med hva som er beskrevet i eksempel 2, med Jones-løsning. 628 mg (9S,11R,15S,16S)-6-oxo-9-hydroxy-11,15-bis-(tetrahydropyran-2-yloxy)-16,20-dimethyl-13,14,18,18,19, 19-hexadehydro-13-prostenic acid was oxidized in an analogous manner to what is described in example 2, with Jones solution.
Etter etterfølgende kromatografisk rensing ble det erholdt 458 mg (73%) av tittelforbindelsen som fargeløs olje. After subsequent chromatographic purification, 458 mg (73%) of the title compound was obtained as a colorless oil.
IR (film): 3600 - 2500, 2940, 2870, 2230, 1742, 1730, 1700, 1450, 1440, 1380, 1352, 1320, 1280, 1260, 1200, 1180, 1150, 1125, 1075, 1034, 1020, 968, 910, 868, 815 cm"<1>. IR (Film): 3600 - 2500, 2940, 2870, 2230, 1742, 1730, 1700, 1450, 1440, 1380, 1352, 1320, 1280, 1260, 1200, 1180, 1150, 1125, 10375, 1086, 92045 , 910, 868, 815 cm"<1>.
Utgangsmaterialet ble fremstilt som beskrevet i eksempel 5a til 5. The starting material was prepared as described in examples 5a to 5.
Eksempel 5a Example 5a
(9S,11R,15S,16S)-6-oxo-9-hydroxy-ll,15-bis-(tetrahydro-pyran-2-yloxy)-16,20-dimethyl-13,14,18,18,19,19-hexadehydro-13- prostensyre (9S,11R,15S,16S)-6-oxo-9-hydroxy-11,15-bis-(tetrahydro-pyran-2-yloxy)-16,20-dimethyl-13,14,18,18,19, 19-hexadehydro-13-prostenic acid
1000 mg (5RS,6RS,16S)-5-jod-16,20-dimethyl-13,14,18,18,19,19-hexadehydro-prostaglandin I1~ll,15-bis-(tetrahydropyranylether)-methylester ble analogt med eksempel 2a omsatt og renset. Det ble isolert 630 mg (77%) av tittelforbindelsen som gul olje. 1000 mg of (5RS,6RS,16S)-5-iodo-16,20-dimethyl-13,14,18,18,19,19-hexadehydro-prostaglandin I1~11,15-bis-(tetrahydropyranyl ether)-methyl ester was analog with example 2a reacted and purified. 630 mg (77%) of the title compound was isolated as a yellow oil.
IR (film): 3500 - 2500, 2940, 2870, 2230, 1732, 1709, 1450, IR (film): 3500 - 2500, 2940, 2870, 2230, 1732, 1709, 1450,
1440, 1380, 1354, 1320, 1200, 1117, 1076, 1035, 1020, 970, 908, 870, 815 cm"<1.>1440, 1380, 1354, 1320, 1200, 1117, 1076, 1035, 1020, 970, 908, 870, 815 cm"<1.>
Eksempel 5b Example 5b
(5RS,6RS,16S)-5-jod-16,20-dimethy1-13,14,18,18,19,19-hexadehydro-prostaglandin 1^-11,15-bis-(tetrahydropyranylether)- methylester (5RS,6RS,16S)-5-iodo-16,20-dimethyl1-13,14,18,18,19,19-hexadehydro-prostaglandin 1^-11,15-bis-(tetrahydropyranyl ether)- methyl ester
1,03 g (5Z)-(9S,11R,15S,16S)-9-hydroxy-ll,15-bis-(tetrahydropyran-2-yloxy)-16,20-dimethyl-13,14,18,18,19,19-hexadehydro-prostadiensyre-methylester ble analogt med eksempel 2b omsatt. Etter tilsvarende utført opparbeidelse ble det isolert 1,24 g (98%) av tittelforbindelsen som gul olje. 1.03 g (5Z)-(9S,11R,15S,16S)-9-hydroxy-11,15-bis-(tetrahydropyran-2-yloxy)-16,20-dimethyl-13,14,18,18, 19,19-hexadehydro-prostadienic acid methyl ester was reacted analogously to example 2b. After similar work-up, 1.24 g (98%) of the title compound was isolated as a yellow oil.
IR (film): 2940, 2870, 2230, 1738, 1450, 1438, 1352, 1320, IR (film): 2940, 2870, 2230, 1738, 1450, 1438, 1352, 1320,
1200, 1118, 1076, 1035, 1020, 972, 908, 870, 1200, 1118, 1076, 1035, 1020, 972, 908, 870,
817 cm"<1>. 817 cm"<1>.
Eksempel 5c Example 5c
(5Z)-9S,11R,15S,16S)-9-hydroxy-ll,15-bis-(tetrahydropyran-2-yloxy)-16,20-dimethyl-13,14,18,18,19,19-hexadehydro-prostadiensyre- methylester (5Z)-9S,11R,15S,16S)-9-hydroxy-11,15-bis-(tetrahydropyran-2-yloxy)-16,20-dimethyl-13,14,18,18,19,19-hexadehydro -prostadic acid methyl ester
2,39 g (5Z,13E)-(9S,11R,15S,16S)-9-hydroxy-ll,15-bis- (tetrahydropyran-2-yloxy)-14-brom-16,20-dimethyl-18,18,19,19-tetradehydro-prostadiensyre-methylester ble løst i en blanding av 11 ml vannfritt THF og 26 ml vannfritt dimethylsulfoxyd, ble tilsatt 1,23 g kalium-tert.-butanolat og ble omrørt i 5 timer ved 25°C under en atmosfære av tørt argon. Blandingen ble helt over i isvann, ble surgjort med 10% sitronsyreløsning, ble ekstrahert flere ganger med diethylether, og de forenede, organiske ekstrakter ble tørket over magnesiumsulfat. Etter filtrering og av-dampning av løsningsmidlet i vakuum ble det isolert 2,01 g (99%) (5Z)-(9S,11R,15S,16S)-9-hydroxy-ll,15-bis-(tetra-hydropyran-2-yloxy)-16,20-dimethyl-13,14,18,18,19,19-hexadehydro-prostadiensyre som uten ytterligere rensing ble forestret med en etherisk løsning av diazomethan på analog måte som angitt i eksempel 2c. Residuet ble kromatografert under trykk på kiselgel med hexan/ethylacetat, og 1,22 g (58%) av tittelforbindelsen ble isolert som fargeløs olje. 2.39 g of (5Z,13E)-(9S,11R,15S,16S)-9-hydroxy-11,15-bis-(tetrahydropyran-2-yloxy)-14-bromo-16,20-dimethyl-18, 18,19,19-tetrahydro-prostadic acid methyl ester was dissolved in a mixture of 11 ml of anhydrous THF and 26 ml of anhydrous dimethylsulfoxide, 1.23 g of potassium tert.-butanolate was added and stirred for 5 hours at 25°C under an atmosphere of dry argon. The mixture was poured into ice water, acidified with 10% citric acid solution, extracted several times with diethyl ether, and the combined organic extracts were dried over magnesium sulfate. After filtering and evaporating the solvent in vacuo, 2.01 g (99%) of (5Z)-(9S,11R,15S,16S)-9-hydroxy-11,15-bis-(tetra-hydropyran- 2-yloxy)-16,20-dimethyl-13,14,18,18,19,19-hexadehydro-prostadienic acid which without further purification was esterified with an ethereal solution of diazomethane in an analogous manner as stated in example 2c. The residue was flash chromatographed on silica gel with hexane/ethyl acetate, and 1.22 g (58%) of the title compound was isolated as a colorless oil.
IR (film): 3500 (bred), 2940, 2870, 2230, 1738, 1452, 1436, IR (film): 3500 (wide), 2940, 2870, 2230, 1738, 1452, 1436,
1373, 1354, 1320, 1240, 1200, 1130, 1076, 1020, 970, 908, 870, 816 cm<-1>. 1373, 1354, 1320, 1240, 1200, 1130, 1076, 1020, 970, 908, 870, 816 cm<-1>.
Eksempel 5d Example 5d
(5Z,13E)-(9S,11R,15S,16S)-9-hydroxy-ll,15-bis-(tetrahydro-pyran-2-yloxy)-14-brom-16,20-dimethyl-18,18,19,19-tetradehydro- prostadiensyre- methylester (5Z,13E)-(9S,11R,15S,16S)-9-hydroxy-11,15-bis-(tetrahydro-pyran-2-yloxy)-14-bromo-16,20-dimethyl-18,18, 19,19-Tetradehydroprostadic acid methyl ester
2,53 g (1S,3RS,5R,6R,7R)-6-[(E)-(3S,4S)-2-brom-3-(tetrahydropyran-2-yloxy)-4-methyl-non-l-en-6-inyl]-7-(tetrahydropyran-2-yloxy)-2-oxa-bicyclo[3.3.0]octan-3-ol ble analogt med eksempel 2c underkastet Wittig-reaksjonsbetingelser og derpå følgende forestringsbetingelser med diazomethan. Etter kromatografisk rensing ble det isolert 2,40 g (80%) av tittelforbindelsen som fargeløs olje. 2.53 g (1S,3RS,5R,6R,7R)-6-[(E)-(3S,4S)-2-bromo-3-(tetrahydropyran-2-yloxy)-4-methyl-non-1 -en-6-ynyl]-7-(tetrahydropyran-2-yloxy)-2-oxa-bicyclo[3.3.0]octan-3-ol was analogously to example 2c subjected to Wittig reaction conditions and then the following esterification conditions with diazomethane. After chromatographic purification, 2.40 g (80%) of the title compound was isolated as a colorless oil.
IR (film): 3460 (bred), 2940, 2870, 1738, 1650, 1450, 1438, IR (film): 3460 (wide), 2940, 2870, 1738, 1650, 1450, 1438,
1374, 1350, 1338, 1320, 1240, 1200, 1128, 1115, 1076, 1052, 1020, 970, 908, 870, 815, 736 cm"<1>. 1374, 1350, 1338, 1320, 1240, 1200, 1128, 1115, 1076, 1052, 1020, 970, 908, 870, 815, 736 cm"<1>.
Eksempel 5e Example 5e
(1S,3RS,5R,6S)-6-[(E)-(3S,4S)-2-brom-3-(tetrahydropyran-2- yloxy)-4-methyl-non-l-en-6-inyl]-7-(tetrahydropyran-2-yloxy)- 2- oxa- bicyclo[ 3. 3. 0] octan- 3- on (1S,3RS,5R,6S)-6-[(E)-(3S,4S)-2-bromo-3-(tetrahydropyran-2-yloxy)-4-methyl-non-1-en-6-inyl ]-7-(tetrahydropyran-2-yloxy)-2-oxa-bicyclo[3.3.0]octan-3-one
2,77 g (1S,3RS,5R,6R,7R)-6-[(E)-(3S,4S)-2-brom-3- (tetrahydropyran-2-yloxy)-4-methyl-non-l-en-6-inyl]-7-(tetrahydropyran-2-yloxy)-2-oxa-bicyclo[3.3.0]octan-3-on ble redusert analogt med eksempel 2d. Etter opparbeidelse og kromatografisk rensing ble det isolert 2,54 g (91%) av tittelforbindelsen som fargeløs olje. 2.77 g (1S,3RS,5R,6R,7R)-6-[(E)-(3S,4S)-2-bromo-3-(tetrahydropyran-2-yloxy)-4-methyl-non-1 -en-6-ynyl]-7-(tetrahydropyran-2-yloxy)-2-oxa-bicyclo[3.3.0]octan-3-one was reduced analogously to example 2d. After work-up and chromatographic purification, 2.54 g (91%) of the title compound was isolated as a colorless oil.
IR (film): 3400 (bred), 2940, 2870, 1736, 1648, 1452, 1440, IR (film): 3400 (wide), 2940, 2870, 1736, 1648, 1452, 1440,
1375, 1352, 1340, 1322, 1260, 1200, 1184, 1120, 1070, 1020, 970, 908, 868, 815 cm"<1.>1375, 1352, 1340, 1322, 1260, 1200, 1184, 1120, 1070, 1020, 970, 908, 868, 815 cm"<1.>
Eksempel 5f Example 5f
(1S,5R,6S.,7R) -6-[ (E) - (3S,4S) -2-brom-3- (tetrahydropyran-2-yloxy)-4-methyl-non-l-en-6-inyl]-7-(tetrahydropyran-2-yloxy)- 2- oxa- bicyclo[ 3. 3. 0] octan- 3- on (1S,5R,6S.,7R)-6-[ (E)-(3S,4S)-2-bromo-3-(tetrahydropyran-2-yloxy)-4-methyl-non-1-en-6- inyl]-7-(tetrahydropyran-2-yloxy)-2-oxa-bicyclo[3.3.0]octan-3-one
2,00 g (lS,5R,6R,7R)-6-[(E)-(3S,4S)-2-brom-3-hydroxy-4-methyl-non-l-en-6-inyl]-7-hydroxy-2-oxa-bicyclo[3.3.0]octan-3-on ble omsatt på analog måte som beskrevet i eksempel 2e. Etter kromatografisk rensing ble det erholdt 2,78 g (96%) av tittelforbindelsen som fargeløs olje. 2.00 g (1S,5R,6R,7R)-6-[(E)-(3S,4S)-2-bromo-3-hydroxy-4-methyl-non-1-en-6-inyl]- 7-hydroxy-2-oxa-bicyclo[3.3.0]octan-3-one was reacted in an analogous manner as described in example 2e. After chromatographic purification, 2.78 g (96%) of the title compound was obtained as a colorless oil.
IR (film): 2970, 2930, 1770, 1640, 1450, 1430, 1360, 1335, IR (film): 2970, 2930, 1770, 1640, 1450, 1430, 1360, 1335,
1235, 1120, 1070, 1025, 910, 868, 812 cm"<1.>1235, 1120, 1070, 1025, 910, 868, 812 cm"<1.>
Eksempel 5g Example 5g
(IS,5R,6S,7R)-6-[(E)-(3S,4S)-2-brom-3-hydroxy-4-methyl-non- l- en- 6- inyl]- 7- hydroxy- 2- oxa- bicyclo[ 3. 3. 0] octan- 3- on (IS,5R,6S,7R)-6-[(E)-(3S,4S)-2-bromo-3-hydroxy-4-methyl-non-1-en-6-inyl]-7-hydroxy- 2-oxa-bicyclo[3.3.0]octan-3-one
3,12 g (lS,5R,6R,7R)-6-[(E)-(3S,4S)-2-brom-3-hydroxy-4-methyl-non-l-en-6-inyl]-7-benzoyloxy-2-oxa-bicyclo[3.3.0]octan-3-on ble oppløst i 18 ml methanol av analysekvalitet, ble tilsatt 290 mg finpulverisert kaliumcarbonat og ble omrørt i 3 timer ved 25°C. Etter tilsetning av 50%-ig saltsyre ble pH innstilt på 7, og blandingen ble inndampet ved 30°C ved vannstrålevakuum. Residuet ble tatt opp i methylenklorid, ble filtrert over magnesiumsulfat og celitt, ble inndampet på nytt i vannstrålevakuum og ble under trykk kromatografert på ca. 200 ml fin kiselgel under anvendelse av en gradient av hexan/eddikester. Det ble isolert 2,00 g (82%) av tittelforbindelsen som fargeløs olje. 3.12 g (1S,5R,6R,7R)-6-[(E)-(3S,4S)-2-bromo-3-hydroxy-4-methyl-non-1-en-6-inyl]- 7-benzoyloxy-2-oxa-bicyclo[3.3.0]octan-3-one was dissolved in 18 ml of analytical grade methanol, 290 mg of finely powdered potassium carbonate was added and stirred for 3 hours at 25°C. After addition of 50% hydrochloric acid, the pH was adjusted to 7, and the mixture was evaporated at 30°C under a water jet vacuum. The residue was taken up in methylene chloride, filtered over magnesium sulfate and celite, re-evaporated in a water jet vacuum and chromatographed under pressure at approx. 200 ml of fine silica gel using a gradient of hexane/acetic ester. 2.00 g (82%) of the title compound was isolated as a colorless oil.
IR (film): 3400, 2950, 2910, 1755, 1640, 1440, 1415, 1340, IR (film): 3400, 2950, 2910, 1755, 1640, 1440, 1415, 1340,
1300, 1180, 1075, 1030, 968, 905 cm<-1>. 1300, 1180, 1075, 1030, 968, 905 cm<-1>.
Eksempel 5h Example 5h
(1S,5R,6S,7R)-6-[(E)-(3S,4S)-2-brom-3-hydroxy-4-methyl-non-l- en- 6- inyl]- 7- benzoyloxy- 2- oxa- bicyclo[ 3. 3. 0] octan- 3- on (1S,5R,6S,7R)-6-[(E)-(3S,4S)-2-bromo-3-hydroxy-4-methyl-non-1- en- 6-inyl]- 7- benzoyloxy- 2-oxa-bicyclo[3.3.0]octan-3-one
16,7 g (1S,5R,6R,7R)-6-[(E)-(4S)-2-brom-3-oxo-4-methyl-non-l-en-6-inyl]-7-benzoyloxy-2-oxa-bicyclo[3.3.0]-octan-3-on ble redusert på analog måte som beskrevet i eksempel 2g. Etter kromatografisk rensing ble det isolert 4,1 g (24%) av tittelforbindelsen, såvel som 6,6 g (1S,5R,6R,7R)-6-[(E)-(3S,4S)-2-brom-3-oxo-4-methyl-non-l-en-6-inyl]-7-benzoyloxy-2-oxa-bicyclo[3.3.0]octan-3-on (39%). IR (film): 3460 (bred), 3060, 2970, 2930, 1770, 1714, 1602, 16.7 g (1S,5R,6R,7R)-6-[(E)-(4S)-2-bromo-3-oxo-4-methyl-non-1-en-6-inyl]-7- benzoyloxy-2-oxa-bicyclo[3.3.0]-octan-3-one was reduced in an analogous manner as described in example 2g. After chromatographic purification, 4.1 g (24%) of the title compound was isolated, as well as 6.6 g of (1S,5R,6R,7R)-6-[(E)-(3S,4S)-2-bromo- 3-oxo-4-methyl-non-1-en-6-inyl]-7-benzoyloxy-2-oxa-bicyclo[3.3.0]octan-3-one (39%). IR (film): 3460 (wide), 3060, 2970, 2930, 1770, 1714, 1602,
1450, 1317, 1272, 1178, 1115, 1070, 1026, 737, 715 cm <1>. 1450, 1317, 1272, 1178, 1115, 1070, 1026, 737, 715 cm <1>.
Eksempel 5i Example 5i
(1S,5R,6S,7R)-6-[(E)-(4S)-2-brom-3-oxo-4-methyl-non-l-en-6- iny1]- 7- benzoyloxy- 2- oxa- bicyclo[ 3. 3. 0] octan- 3- on (1S,5R,6S,7R)-6-[(E)-(4S)-2-bromo-3-oxo-4-methyl-non-1-en-6- iny1]- 7- benzoyloxy- 2- oxa-bicyclo[3.3.0]octan-3-one
Til en oppslemming av 2,58 g NaH i 225 ml dimethoxyethan ble under utelatelse av fuktighet dråpevis tilsatt en løsning av 13,7 g dimethyl-[(3S)-2-oxo-3-methyl-oct-5-inyl]-fosfonat i 135 ml dimethoxyethan ved 0°C. Etter 20 minutters omrøring ble den nå klare løsning tilsatt 9,89 g finpulverisert N-bromsuccinimid, ble omrørt i 1 time ved 0°C, ble dråpevis tilsatt en løsning av 12,3 g Corey-lacton og fikk reagere i ytterligere 2 timer ved 0°C. Under kraftig omrøring ble reaksjonsløsningen helt over i 800 ml 10%-ig vandig ammoniumkloridløsning, blandingen ble ekstrahert flere ganger med totalt 1,5 1 diethylether, den organiske fase ble vasket med vann, tørket over magnesiumsulfat, og etter filtrering og inndampning i vakuum ble det isolert 27,4 g av en gul, uren olje som under trykk ble kromatografisk renset ved hjelp av en gradient av hexan og eddikester. To a slurry of 2.58 g of NaH in 225 ml of dimethoxyethane, a solution of 13.7 g of dimethyl-[(3S)-2-oxo-3-methyl-oct-5-inyl]-phosphonate was added dropwise while omitting moisture. in 135 ml of dimethoxyethane at 0°C. After 20 minutes of stirring, 9.89 g of finely powdered N-bromosuccinimide was added to the now clear solution, stirred for 1 hour at 0°C, a solution of 12.3 g of Corey lactone was added dropwise and allowed to react for a further 2 hours at 0°C. Under vigorous stirring, the reaction solution was poured into 800 ml of 10% aqueous ammonium chloride solution, the mixture was extracted several times with a total of 1.5 1 of diethyl ether, the organic phase was washed with water, dried over magnesium sulfate, and after filtration and evaporation in vacuo 27.4 g of a yellow impure oil was isolated which was chromatographically purified under pressure using a gradient of hexane and ethyl acetate.
Det ble isolert 16,9 g (72%) av tittelforbindelsen som fargeløs olje. 16.9 g (72%) of the title compound was isolated as a colorless oil.
IR (film): 2970, 2920, 1765, 1720, 1600, 1450, 1360, 1315, IR (film): 2970, 2920, 1765, 1720, 1600, 1450, 1360, 1315,
1270, 1170, 1105, 1070, 965 cm"<1>. 1270, 1170, 1105, 1070, 965 cm"<1>.
Eksempel 6 Example 6
(11R,15S,16S)-6,9-di-oxo-ll,15-dihydroxy-16,20-dimethyl-13, 14, 18, 18, 19, 19- hexadehydro- 13- prostensyre- methylester (11R,15S,16S)-6,9-di-oxo-11,15-dihydroxy-16,20-dimethyl-13, 14, 18, 18, 19, 19- hexadehydro- 13- prostenic acid methyl ester
Til en kraftig omrørt emulsjon av 63 mg (11R,15S,16S)-6,9-di-oxo-ll,15-dihydroxy-16,20-dimethyl-13,14,18,18,19,19-hexadehydro-13-prostensyre i 10 ml ether ble ved 0 til 5°C dråpevis tilsatt en etherisk løsning av diazomethan. Opparbeidelsen og rensningen fant sted på lignende måte som beskrevet i eksempel 3. Det ble isolert 46 mg (70%) av tittelforbindelsen som fargeløs olje. To a vigorously stirred emulsion of 63 mg of (11R,15S,16S)-6,9-di-oxo-11,15-dihydroxy-16,20-dimethyl-13,14,18,18,19,19-hexadehydro- 13-prostenic acid in 10 ml of ether was added dropwise to an ethereal solution of diazomethane at 0 to 5°C. The work-up and purification took place in a similar manner as described in Example 3. 46 mg (70%) of the title compound was isolated as a colorless oil.
IR (film): 3400, 2980 - 2820, 2230, 1737, 1450, 1440, 1200, IR (film): 3400, 2980 - 2820, 2230, 1737, 1450, 1440, 1200,
1078, 1020, 970, 910 cm"<1.>1078, 1020, 970, 910 cm"<1.>
Claims (1)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19873708537 DE3708537A1 (en) | 1987-03-13 | 1987-03-13 | 6-OXOPROSTAGLANDIN-E DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THEIR PHARMACEUTICAL USE |
| PCT/DE1988/000151 WO1988007037A1 (en) | 1987-03-13 | 1988-03-11 | 6-oxoprostaglandin-e derivatives, process for their production and their pharmaceutical application |
Publications (4)
| Publication Number | Publication Date |
|---|---|
| NO885058L NO885058L (en) | 1988-11-11 |
| NO885058D0 NO885058D0 (en) | 1988-11-11 |
| NO170850B true NO170850B (en) | 1992-09-07 |
| NO170850C NO170850C (en) | 1992-12-16 |
Family
ID=25853549
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO885058A NO170850C (en) | 1987-03-13 | 1988-11-11 | ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE 6-OXOPROSTAGLAND INGREDIATES |
Country Status (1)
| Country | Link |
|---|---|
| NO (1) | NO170850C (en) |
-
1988
- 1988-11-11 NO NO885058A patent/NO170850C/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| NO170850C (en) | 1992-12-16 |
| NO885058L (en) | 1988-11-11 |
| NO885058D0 (en) | 1988-11-11 |
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