NO742378L - - Google Patents
Info
- Publication number
- NO742378L NO742378L NO742378A NO742378A NO742378L NO 742378 L NO742378 L NO 742378L NO 742378 A NO742378 A NO 742378A NO 742378 A NO742378 A NO 742378A NO 742378 L NO742378 L NO 742378L
- Authority
- NO
- Norway
- Prior art keywords
- formula
- compounds
- trans
- carbon atoms
- prostaglandin
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 claims description 69
- 125000004432 carbon atom Chemical group C* 0.000 claims description 23
- 125000002837 carbocyclic group Chemical group 0.000 claims description 16
- 239000001257 hydrogen Substances 0.000 claims description 14
- 229910052739 hydrogen Inorganic materials 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- 239000002253 acid Substances 0.000 claims description 13
- 125000000217 alkyl group Chemical group 0.000 claims description 13
- 229910052740 iodine Inorganic materials 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 7
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 6
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 5
- 150000007513 acids Chemical class 0.000 claims description 4
- 125000001559 cyclopropyl group Chemical class [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 4
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 4
- 125000004665 trialkylsilyl group Chemical group 0.000 claims description 4
- 150000007529 inorganic bases Chemical class 0.000 claims description 2
- 150000007530 organic bases Chemical class 0.000 claims description 2
- 125000006239 protecting group Chemical group 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 76
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 24
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 24
- -1 2-methylcyclopropyl Chemical group 0.000 description 22
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 17
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 16
- 239000000741 silica gel Substances 0.000 description 16
- 229910002027 silica gel Inorganic materials 0.000 description 16
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 150000002148 esters Chemical class 0.000 description 12
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical class C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 12
- 150000004702 methyl esters Chemical class 0.000 description 9
- 230000002829 reductive effect Effects 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 229960001760 dimethyl sulfoxide Drugs 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 7
- 229910052757 nitrogen Inorganic materials 0.000 description 7
- 239000007858 starting material Substances 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- 238000001816 cooling Methods 0.000 description 5
- 125000004494 ethyl ester group Chemical group 0.000 description 5
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 4
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 4
- 150000001942 cyclopropanes Chemical class 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 230000008020 evaporation Effects 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 230000002496 gastric effect Effects 0.000 description 3
- 150000004714 phosphonium salts Chemical class 0.000 description 3
- 230000028327 secretion Effects 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- 239000012312 sodium hydride Substances 0.000 description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- 101100352919 Caenorhabditis elegans ppm-2 gene Proteins 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 2
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 238000007239 Wittig reaction Methods 0.000 description 2
- PQLVXDKIJBQVDF-UHFFFAOYSA-N acetic acid;hydrate Chemical compound O.CC(O)=O PQLVXDKIJBQVDF-UHFFFAOYSA-N 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- YMGUBTXCNDTFJI-UHFFFAOYSA-N cyclopropanecarboxylic acid Chemical class OC(=O)C1CC1 YMGUBTXCNDTFJI-UHFFFAOYSA-N 0.000 description 2
- KWGRBVOPPLSCSI-UHFFFAOYSA-N d-ephedrine Natural products CNC(C)C(O)C1=CC=CC=C1 KWGRBVOPPLSCSI-UHFFFAOYSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000001632 sodium acetate Substances 0.000 description 2
- 235000017281 sodium acetate Nutrition 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 2
- KWGRBVOPPLSCSI-WPRPVWTQSA-N (-)-ephedrine Chemical compound CN[C@@H](C)[C@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WPRPVWTQSA-N 0.000 description 1
- KWGRBVOPPLSCSI-PSASIEDQSA-N (1s,2r)-2-(methylamino)-1-phenylpropan-1-ol Chemical compound CN[C@H](C)[C@@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-PSASIEDQSA-N 0.000 description 1
- 125000004343 1-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C([H])([H])[H] 0.000 description 1
- HZNVUJQVZSTENZ-UHFFFAOYSA-N 2,3-dichloro-5,6-dicyano-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(C#N)=C(C#N)C1=O HZNVUJQVZSTENZ-UHFFFAOYSA-N 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- ZPTVZXFLKDHHPE-UHFFFAOYSA-N 3-methyl-1-(4-methylphenyl)-2,4-dihydrotriazine Chemical compound N1N(C)CC=CN1C1=CC=C(C)C=C1 ZPTVZXFLKDHHPE-UHFFFAOYSA-N 0.000 description 1
- DMAYBPBPEUFIHJ-UHFFFAOYSA-N 4-bromobut-1-ene Chemical compound BrCCC=C DMAYBPBPEUFIHJ-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 239000012027 Collins reagent Substances 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 1
- 239000003810 Jones reagent Substances 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Natural products P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 1
- GOPYZMJAIPBUGX-UHFFFAOYSA-N [O-2].[O-2].[Mn+4] Chemical class [O-2].[O-2].[Mn+4] GOPYZMJAIPBUGX-UHFFFAOYSA-N 0.000 description 1
- VXDSLUMUNWTSDB-UHFFFAOYSA-N acetic acid;chloroform;methanol Chemical compound OC.CC(O)=O.ClC(Cl)Cl VXDSLUMUNWTSDB-UHFFFAOYSA-N 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical class N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 description 1
- 239000011260 aqueous acid Substances 0.000 description 1
- 230000004872 arterial blood pressure Effects 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 1
- ZCDOYSPFYFSLEW-UHFFFAOYSA-N chromate(2-) Chemical compound [O-][Cr]([O-])(=O)=O ZCDOYSPFYFSLEW-UHFFFAOYSA-N 0.000 description 1
- VTHIKKVKIVQWHV-UHFFFAOYSA-N chromium(6+) oxygen(2-) pyridine Chemical compound [O-2].[O-2].[O-2].[Cr+6].C1=CC=NC=C1 VTHIKKVKIVQWHV-UHFFFAOYSA-N 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000006547 cyclononyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 239000000850 decongestant Substances 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 229960001342 dinoprost Drugs 0.000 description 1
- 229960002986 dinoprostone Drugs 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- WBZBLFPAMBHEAZ-UHFFFAOYSA-N ethyl 1-(2-bromoethyl)cyclopropane-1-carboxylate Chemical compound CCOC(=O)C1(CCBr)CC1 WBZBLFPAMBHEAZ-UHFFFAOYSA-N 0.000 description 1
- YVPJCJLMRRTDMQ-UHFFFAOYSA-N ethyl diazoacetate Chemical compound CCOC(=O)C=[N+]=[N-] YVPJCJLMRRTDMQ-UHFFFAOYSA-N 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 1
- 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
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 210000004914 menses Anatomy 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- ZGEGCLOFRBLKSE-UHFFFAOYSA-N methylene hexane Natural products CCCCCC=C ZGEGCLOFRBLKSE-UHFFFAOYSA-N 0.000 description 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000035935 pregnancy Effects 0.000 description 1
- XEYBRNLFEZDVAW-UHFFFAOYSA-N prostaglandin E2 Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CC=CCCCC(O)=O XEYBRNLFEZDVAW-UHFFFAOYSA-N 0.000 description 1
- 230000002997 prostaglandinlike Effects 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- NPRDHMWYZHSAHR-UHFFFAOYSA-N pyridine;trioxochromium Chemical compound O=[Cr](=O)=O.C1=CC=NC=C1.C1=CC=NC=C1 NPRDHMWYZHSAHR-UHFFFAOYSA-N 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 229910052720 vanadium Inorganic materials 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D309/10—Oxygen atoms
- C07D309/12—Oxygen atoms only hydrogen atoms and one oxygen atom directly attached to ring carbon atoms, e.g. tetrahydropyranyl ethers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Nye cyklopropanforbindelser og fremgangsmåte for deres fremstilling. New cyclopropane compounds and process for their preparation.
Foreliggende -oppfinnelse vedrører optisk aktive cyklopropan» derivater med formel I eller racemiske forbindelser med denne formel, hvori D står for en av de fire karbocykliske ringer med. formler II"a, II b, II c eller II d .... og R1står for hydrogen eller en alkylrest med 1 til 8 karbon» atomer, en cykloalkylrest med 3 til 10 karbonatomer eller en aralkylrest med 7 til 12 karbonatomer, og R2og R^står for hydrogen eller en alkylrest med 1 til 4 karbonatomer, samt farmakologisk tålbare salter av disse forbindelser med formel I, når R^har betydningen hydrogen. The present invention relates to optically active cyclopropane derivatives of formula I or racemic compounds of this formula, in which D stands for one of the four carbocyclic rings with formulas II"a, II b, II c or II d .... and R1 represents hydrogen or an alkyl radical of 1 to 8 carbon atoms, a cycloalkyl radical of 3 to 10 carbon atoms or an aralkyl radical of 7 to 12 carbon atoms, and R2 and R^ stands for hydrogen or an alkyl residue with 1 to 4 carbon atoms, as well as pharmacologically tolerable salts of these compounds of formula I, when R^ means hydrogen.
I det følgende oppførte formler II a til II hIn the following listed formulas II a to II h
viser stiplede forbindelseslinjer at substituentene er til-__ knyttet cyklopentanringen i ct-konfigurasjon, det vil si lig-_ ger under planet for cyklopentanet. Portykkede forbindelseslinjer viser at substituentene er tilknyttet cyklopentanringen i p-konfigurasjon, d.v.s. ligger over planet av cyklopentanringen. Den bølgeformede forbindelseslinje ved C-15 i formel I viser at hydroksylgruppen foreligger som a- eller p-konfiguras j on. dashed connecting lines show that the substituents are attached to the cyclopentane ring in ct configuration, i.e. lie below the plane of the cyclopentane. Thick connecting lines show that the substituents are attached to the cyclopentane ring in p-configuration, i.e. lies above the plane of the cyclopentane ring. The wavy connecting line at C-15 in formula I shows that the hydroxyl group exists as an a- or p-configuration.
For formel I er eksempler på alkylgrupper med 1 til 8 karbonatomer gruppene metyl, etyl, propyl, butyl, pentyl, heksyl, heptyl, oktyl, inklusive de isomere former av disse. Eksempler på cykloalkylgrupper med ^ til 10 karbonatomer ( hertil hører også alkylsubstituerte cykloalkylgrupper) er cyklopropyl, 2- metylcyklopropyl, 2,2~dimetylcyklopropyl, 2,>-dietylcyklo-?propyl, 2-butylcyklopropyl, cyklobutyl, 2-metylcyklobutyl, 3- propyl cyklobutyl, 2, J>, 4-trietylcyklobutyl, cyklopentyl, 2,2,-dimetylcyklopentyl, 2-pentylcyklopentyl, J-tert.-butylcyklopentyl, cyklohexyl, 4-tert.- butylcyklohexyl, 3-isopropylcyklohexyl, 2,2-dimetylcyklohexyl, cykloheptyl, cyklooktyl, cyklononyl og cyklodecyl. Eksempler på aralkyl-grupper med 2 til 12 karbonatomer er benzyl, fenetyl, 1-fenyletyl, 2-fenylpropyl, 4-fenylbutyl, J-fenylbutyl, 2-(1-naftyletyl)og 1-(2-naftylmetyl). For formula I, examples of alkyl groups with 1 to 8 carbon atoms are the groups methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, including the isomeric forms of these. Examples of cycloalkyl groups with ^ to 10 carbon atoms (this also includes alkyl-substituted cycloalkyl groups) are cyclopropyl, 2-methylcyclopropyl, 2,2~dimethylcyclopropyl, 2,>-diethylcyclo-?propyl, 2-butylcyclopropyl, cyclobutyl, 2-methylcyclobutyl, 3-propyl cyclobutyl, 2, J>, 4-triethylcyclobutyl, cyclopentyl, 2,2,-dimethylcyclopentyl, 2-pentylcyclopentyl, J-tert.-butylcyclopentyl, cyclohexyl, 4-tert.- butylcyclohexyl, 3-isopropylcyclohexyl, 2,2-dimethylcyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and cyclodecyl. Examples of aralkyl groups with 2 to 12 carbon atoms are benzyl, phenethyl, 1-phenylethyl, 2-phenylpropyl, 4-phenylbutyl, J-phenylbutyl, 2-(1-naphthylethyl) and 1-(2-naphthylmethyl).
De nye cyklopropanderivater med formel I fremstilles ved at beskyttelsesgruppene avspaltes fra forbindelser med formel The new cyclopropane derivatives of formula I are prepared by removing the protective groups from compounds of formula I
III, III,
hvori R.^, Rg og R^ har den ovennevnte betydning, R^står for en trialkylsilyl- eller tetrahydropyranylgruppe, og A står for en av de karbocykliske ringer II a, II b, II e eller II f. in which R.sup., Rg and R.sup. have the above meaning, R.sup. stands for a trialkylsilyl or tetrahydropyranyl group, and A stands for one of the carbocyclic rings II a, II b, II e or II f.
Trialkylsilylgruppen har foretrukket 1 til 6 karbonatomer. The trialkylsilyl group preferably has 1 to 6 carbon atoms.
Hydrolysen av tetrahydropyranyl -og/eller trialkylsilylgrup-pene skjer på kjent måte, foretrukket med eddiksyre, tetrahydrofuran/vann med metanol/saltstyre eller svovelsyre ved en tempratur mellom - 10° og 150°C. The hydrolysis of the tetrahydropyranyl and/or trialkylsilyl groups takes place in a known manner, preferably with acetic acid, tetrahydrofuran/water with methanol/hydrochloric acid or sulfuric acid at a temperature between -10° and 150°C.
Forbindelser med formel I, hvori D betyr den karbocykliske ring II b og R^, Rg og R^har den ovennevnte betydning, kan også fremstilles direkte ved avspaltning av vann fra forbindelser med formel I, hvori D står for den karbocykliske ring II d og R^, Rg og R^har den ovennevnte betydning. Compounds of formula I, in which D represents the carbocyclic ring II b and R^, Rg and R^ have the above meaning, can also be prepared directly by splitting off water from compounds of formula I, in which D stands for the carbocyclic ring II d and R^, Rg and R^ have the above meaning.
Dehydratiseringen gjennomføres med fortynnede, vandige syre-løsninger, foretrukket med eddiksyre. Dehydration is carried out with dilute, aqueous acid solutions, preferably with acetic acid.
Utgangsmaterialet, d.v.s. forbindelser med formel III a, The starting material, i.e. compounds of formula III a,
hvori R^, Rg, ' R-^ og R^har den ovennevnte betydning og A' står for en av de karbocykliske ringer II a, II b eller II f; er nye forbindelser og kan fremstilles■ved at forbindelser med formel IV hvori R^, Rg, R^ og R^har den ovennevnte betydning og B står for en av de karbocykliske ringer II e, II g eller II h oksyderes. Et egnet reagens for oksydasjonen er Collins-Reagenset (pyridin-kromtrioksyd_}, Jones-Reagenset ( CrO^/H<+>/ Aceton) såvel som et sulfid-reagens, idet det i det siste tilfelle ved anvendelse av en karboksylsyre som utgangsmateriale denne foretrukket beskyttes. in which R^, Rg, 'R-^ and R^ have the above meaning and A' stands for one of the carbocyclic rings II a, II b or II f; are new compounds and can be prepared by oxidizing compounds of formula IV in which R^, Rg, R^ and R^ have the above meaning and B stands for one of the carbocyclic rings II e, II g or II h. A suitable reagent for the oxidation is the Collins Reagent (pyridine-chromium trioxide_}, the Jones Reagent (CrO^/H<+>/ Acetone) as well as a sulphide reagent, in the latter case when using a carboxylic acid as starting material this preferably protected.
For fremstilling av_ forbindelse med formel III a, hvori B står for den karbo-> cykliske ring II b, kan oksydasjonen' også gjennomføres med diklordicyanbénzokinon eller aktivert mangandioksyd. For the preparation of the compound of formula III a, in which B stands for the carbocyclic ring II b, the oxidation can also be carried out with dichlorodicyanbenzoquinone or activated manganese dioxide.
Forbindelsene med formel IV fremstilles ved at forbindelser med formel V The compounds of formula IV are prepared by compounds of formula V
hvori Rg, R^og R^har den ovennevnte betydning og E står for en av de tre karbocykliske ringer V a, V b eller V c idet resten R^i formelen V har den ovennevnte betydning, omsettes med forbindelser med formel VI in which Rg, R^ and R^ have the above meaning and E stands for one of the three carbocyclic rings V a, V b or V c as the residue R^ in the formula V has the above meaning, is reacted with compounds of formula VI
hvori R har den ovennevnte betydning, R_ står for en nafty1-eller en fenylgruppe som er usubstituert eller er substituert med en lavere alkylgruppe eller står for en lavere alkylgruppe og X- betyr klor, jod eller brom. wherein R has the above meaning, R_ represents a naphthy1- or a phenyl group which is unsubstituted or is substituted with a lower alkyl group or represents a lower alkyl group and X- represents chlorine, iodine or bromine.
Omsetningen skjer etter i og for seg kjente metoder, for eksempel ved wittig-reaksjon, foretrukket i dimetylsulfoksyd ved temperaturer mellom 20 og 80°C. The reaction takes place according to methods known per se, for example by wittig reaction, preferably in dimethylsulfoxide at temperatures between 20 and 80°C.
Utgangsmaterialet, forbindelsene med formel VI, hvori R^, R^og X har den ovennevnte betydning, er nye forbindelser og kan fremstilles ved at for eksempel et 4-halogen-l-buten med formel VII The starting material, the compounds of formula VI, in which R^, R^ and X have the above meaning, are new compounds and can be prepared by, for example, a 4-halo-1-butene of formula VII
hvori X står for klor, jod eller brom, omsettes med en diazoeddikalkylester med formel VIII in which X stands for chlorine, iodine or bromine, is reacted with a diazoacetic alkyl ester of formula VIII
hvori R^' står for en alkylrest, den dannede isomer-blanding av cyklopropankarboksylsyre alkylestere med formel in which R^' stands for an alkyl residue, the formed isomeric mixture of cyclopropane carboxylic acid alkyl esters of formula
IX IX
hvori R-^' og X har den ovennevnte betydning, oppdeles, heretter hydrolyseres eventuelt estergruppen og deretter gjennomføres eventuelt en racematspalting, deretter for» estres det eventuelt og deretter omsettes med en fosfin» forbindelse med formel X, in which R-^' and X have the above-mentioned meaning, are split, then the ester group is optionally hydrolysed and then a racemate cleavage is optionally carried out, then it is optionally esterified and then reacted with a phosphine compound of formula X,
hvori Rp. har den ovennevnte betydning. in which Rp. has the above meaning.
De nye oyklopropanderivater med formel I, hvori R^ har --betydninger hydrogen, kan omdannes-1- farmasøytisk -tålbare salter, idet forbiidelsene nøytraliseres med tilsvarende mengder egnede uorganiske eller organiske baser. The new cyclopropane derivatives of formula I, in which R 1 has the meaning hydrogen, can be converted into pharmaceutically acceptable salts, the precursors being neutralized with corresponding amounts of suitable inorganic or organic bases.
Farmakologisk tålbare salter av sluttproduktene med formel I er salter med.farmakologisk tålbare metallkationer, ammonium--og amin-kationer eller kvartiære ammoniumkationer. Pharmacologically tolerable salts of the final products of formula I are salts with pharmacologically tolerable metal cations, ammonium and amine cations or quaternary ammonium cations.
Optisk aktive- forbindelser erholdes--fra-optisk-aktive-mellomprodukter i henhold - til - de overfor beskrevne- -fremgangsmåte-, trinn. Anvendes-racemiske mellomprodukter .erholdes racemiske sluttprodukter, og disse eller-deres begynnertrinn--kan så Optically active compounds are obtained from optically active intermediates according to the process steps described above. Racemic intermediates are used, racemic final products are obtained, and these or their starting steps can then
på kjent måte oppdeles i sine optisk aktive isomerer. in a known manner are divided into their optically active isomers.
Fremgangsmåten i- henhold--til- oppfinnelsen--fører til forskjellige syrer ( når - R^ betyr hydrogen)-eller estere--( når R^. be tyr. en alkylrest med 1.til 8 karbonatomer, en-cykloalkylrest med-til 10 karbonatomer-eller en aralkylrest med 7 til-12 karbonatomer). Hvis en syre er fremstilt, kan denne.omdannes i-en ester. Hvis sluttproduktene erholdes i form av estere, kan disse overføres i de frie syrer. The process according to the invention leads to various acids (when R^ means hydrogen) or esters (when R^ means an alkyl residue with 1 to 8 carbon atoms, a cycloalkyl residue with to 10 carbon atoms -or an aralkyl residue with 7 to -12 carbon atoms). If an acid is produced, this can be converted into an ester. If the end products are obtained in the form of esters, these can be transferred into the free acids.
De nye oyklopropanderivater med formel I er ytterst virksomme for fremkalling av forskjellige-biologiske, reaks joner-og egner-seg derfor for farmakologiske formål. Noen av disse reaksjoner er for eksempel følgende: jj^uterus-stimulerende. virkning,- ^l^inhibering av mage sekresjonen>é^bronkodilaterende--virkning, nedsettelse av det arterielle blodtrykk, eji nasal dekongestasjon, -efC inhibering av blodplateaggregasjonen såvel som a*f hudtransplanta-sjons-fremmende virkning. The new oxycyclopropane derivatives of formula I are extremely effective for eliciting various biological reactions and are therefore suitable for pharmacological purposes. Some of these reactions are, for example, the following: jj^uterus-stimulating. effect, - ^l^inhibition of gastric secretion>é^bronchodilating--effect, reduction of arterial blood pressure, eji nasal decongestion, -efC inhibition of platelet aggregation as well as a*f skin transplantation-promoting effect.
De forskjellige PGF2a-aktige forbindelser med formel I er virksomme på uterus i.', doser på 1 til 100 \ ig in. situ..De.. The various PGF2a-like compounds of formula I are effective on the uterus i.', doses of 1 to 100 µg in. situ..They..
egner seg for innledning av f ødsler,. £or^j5l^^ uteblitt-abort-, for svangerskapsavbrytelse. og f or. menses-induksjon.— For dette formål anvender man 0,1 -_20 mg/kg alt etter behov pr. dag. De forskjellige 'PGE^cT alrblSe forbindelser med formel I egner seg videre for nedsettelse_ og undertrykkelse av en for sterk magesekres jon. Den mage-sekresjons-hemmende virkning kunne vises ved den pentagastrin- suitable for the initiation of births. £or^j5l^^ absent-abort-, for termination of pregnancy. and for. menses induction.— For this purpose, 0.1 -_20 mg/kg is used according to need per day. The various 'PGE^cT alrblSe compounds of formula I are further suitable for the reduction_ and suppression of an excessively strong gastric secretion. The gastric secretion-inhibiting effect could be shown by the pentagastrin-
og Jiistamin-induserte -mage sekres jon- -i rotter i-doser.-på- _and Jiistamin-induced -gastric secret ion- -in rats i-doses.-at- _
1 „ 100 mg /kg.- I rottemage-strim-ler-var de nye--forbindelser med-formel. -I virksomme - i. doser-på 1 100 mg.. De mengder som tilføres skal. utgjøre doser på omtrent 0,1 1 „ 100 mg /kg.- In rat stomach-strips-were the new--compounds with-formula. -In active - i. doses-of 1,100 mg.. The quantities that are supplied shall. amount to doses of about 0.1
20P<g>pr. kg. legemsvekt pr. dag.20P<g>pr. kg. body weight per day.
De forskjellige forbindelser med formel.-! egner -seg som avsvellende middel- for nesen--ved pattedyr og-mennesker._ The various compounds with formula.-! suitable as a decongestant for the nose in mammals and humans._
For dette formål anvendes forbindelsene-i mengder på om-For this purpose, the compounds are used-in amounts of about-
trent lQi'ig -til omtrent 20 mg pr. ml av et farmakologisk egnet flytende middel. trained lQi'ig -to approximately 20 mg per ml of a pharmacologically suitable liquid agent.
De forskjellige PGE-,- PGF— -og PGA-forbindelser-med-formelThe various PGE-,- PGF— -and PGA-compounds-with-formula
I egner seg videre for-behandling av astma... Foretrukket - anvendes mengder på omtrent 0,1 til 20ty;.g pr. kg kroppsvekt 1 til 4 ganger daglig. It is also suitable for the treatment of asthma... Preferred - amounts of approximately 0.1 to 20ty;.g per kg body weight 1 to 4 times daily.
De forskjellige PGE- og PGFg^-f orbindelser- med.-formel -IThe various PGE and PGFg^ compounds with formula I
egner seg.også for hemming -av-blodplateaggregasjon. - De mengder som tilføres.utgjør-doser-fra omtrent 0,1 til.. omtrent 20 [^g pr. kg. kroppsvekt pr. dag. also suitable for inhibition of platelet aggregation. - The amounts supplied constitute doses from approximately 0.1 to approximately 20 [^g per kg. body weight per day.
De forskjellige PGA- og PGE-forbindelser med-formel I egner seg for senking av blodtrykket. -For dette.formål tilføres forbindelsene som. enkeldose . eller- -i f orm-av flere deldoser på ialt 0,1 til 20p<g>pr. kg. legemsvekt pr. dag. The various PGA and PGE compounds of formula I are suitable for lowering blood pressure. -For this purpose, the compounds are added which. single dose. or- -in the form-of several partial doses of a total of 0.1 to 20p<g>pr. kg. body weight per day.
Mens de tidligere kjente prostaglandiner ved mange anvendelses-måter bare viser en kort varighet for den biologiske virkning, utmerker de i henhold til oppfinnelsen fremstillbare nye forbindelser seg ved siden av_en-spesifikk virkning ved frem-bringelse av pro.staglandin-liknende reaksjoner også ved en betraktelig lengere virkningstid. Som følge av den lengere virkningstid er det ved de nye forbindelser tilstrekkelig med færre og mindre doser for å oppnå en bestemt virkning. For--de nevnte-.formål tilføres de nye forbindelser i forskjellige, doseringsformer, for eksempel oralt i form.av While the previously known prostaglandins in many ways of application only show a short duration of the biological effect, the new compounds that can be prepared according to the invention excel in addition to a specific effect in producing prostaglandin-like reactions also in a significantly longer duration of action. As a result of the longer duration of action, with the new compounds fewer and smaller doses are sufficient to achieve a specific effect. For the aforementioned purposes, the new compounds are supplied in different dosage forms, for example orally in the form of
tabletter, kapsler eller væsker, rektalt i form av supposi- tablets, capsules or liquids, rectally in the form of suppositories
torier eller subkutan, intramuskulært eller Intravenøst.tories or subcutaneously, intramuscularly or intravenously.
Som medisin kan de nye forbindelser tilføres i egnet preparat-form med farmakologisk indifferente hjelpestoffer. 1 de etterfølgende eksempler som skal illustrere oppfinnelsen er alle temperaturangivelser i grader -celsius. As medicine, the new compounds can be administered in suitable preparation form with pharmacologically indifferent excipients. 1 the following examples to illustrate the invention are all temperature indications in degrees Celsius.
E ksempel 1; 2, 3- trans- metano- prostaglandin F^aExample 1; 2, 3- trans- methano- prostaglandin F^a
40 mg, 2,5-metano-trans-ll, 1-5-bis-tetrahydropyranyl-prostaglandin FgQløses i 2 ml av en blanding av eddiksyre, tetrahydrofuran, vann (<J>>: 1 : l) og løsningen oppvarmes i 2 timer ved 60°C. 40 mg, 2,5-methano-trans-II, 1-5-bis-tetrahydropyranyl-prostaglandin FgQ Dissolve in 2 ml of a mixture of acetic acid, tetrahydrofuran, water (<J>>: 1 : l) and the solution is heated for 2 hours at 60°C.
Etter inndamping under redusert trykk oppdeles resten på 3g kieselgel med kloroform med i17$ metanol, idet.den rene i . overskriften nevnte forbindelse erholdes. Smp. 108 - 112°C. After evaporation under reduced pressure, the residue is partitioned on 3 g of silica gel with chloroform and 17% methanol, the pure i . the connection mentioned in the heading is obtained. Temp. 108 - 112°C.
MNR (CDCl^) 90 MHz blant annet signaler ved:MNR (CDCl^) 90 MHz, among other things, signals at:
4 H (m) 5,45 Vinylprotoner4 H (m) 5.45 Vinyl protons
3 H 5,8-4,2 ppm CH-OH3 H 5.8-4.2 ppm CH-OH
5 H (t) 0,9 ppm metyl5 H (t) 0.9 ppm methyl
På analog måte fremstilles 2,5 cis-metano-prostaglandinIn an analogous way, 2,5 cis-methano-prostaglandin is produced
Fgasåvel som de følgende estere: 2,5-cis-metano-prostaglandin F2a-metylester Fgas as well as the following esters: 2,5-cis-methano-prostaglandin F2a methyl ester
2,5-trans-metano-prostaglandin F2a-metylester 2,5-trans-methano-prostaglandin F2a methyl ester
2,5-trans-metano-prostaglandin Fga~etylester 2,5-trans-methano-prostaglandin Fga~ethyl ester
2,5-cis-metano-prostaglandin F2a-etylester 2,5-cis-methano-prostaglandin F2a ethyl ester
2,3-trans-metano-prostaglandin Fga-benzylester 2,3-cis-metano-prostaglandin F2a-benzylester 2,3-trans-methano-prostaglandin Fga benzyl ester 2,3-cis-methano-prostaglandin F2a benzyl ester
Det som utgangsmateriale anvendte 2,3-trans-metano-ll,15--bis-tetrahydropyranyl-prostaglandin F2afremstilles på følgende måte: The 2,3-trans-methanol-1,15-bis-tetrahydropyranyl-prostaglandin F2a used as starting material is produced in the following way:
a) 2- bromoetyl- cyklopropankarboksylsyreetylestera) 2-bromoethyl cyclopropane carboxylic acid ethyl ester
En til 100°C oppvarmet suspensjon av 2,48 g kopperpulver i 22 g 4-brom-l-buten tildryppes langsomt under sterk omrøring 40 ml diazoeddiksyreetylester. Etter 2 timer- ved 100°C foretas filtrering og de isomere cyklopropylkarboksylsyre-estere skilles ved kromatografering på 900 g kieselgel med benzen som elueringsmiddel. A suspension heated to 100°C of 2.48 g of copper powder in 22 g of 4-bromo-1-butene is slowly added dropwise with vigorous stirring to 40 ml of diazoacetic acid ethyl ester. After 2 hours at 100°C, filtration is carried out and the isomeric cyclopropylcarboxylic acid esters are separated by chromatography on 900 g of silica gel with benzene as eluent.
T rans- oyklopropan- l- 2- brometyl- 2- karboksylsyreetylester.T trans-cyclopropane-1-2-bromomethyl-2-carboxylic acid ethyl ester.
IR (metylenklorid) bl.a.bånd med:IR (methylene chloride) i.a. bands with:
1710, 1420, 1200, 1180 cm"1 1710, 1420, 1200, 1180 cm"1
NMR (CDCl^) 60 MHz bl.a. signaler ved:NMR (CDCl^) 60 MHz i.a. signals by:
2 H 4,17 ppm 0-CHg-CH^..2 H 4.17 ppm 0-CHg-CH^..
2 H 5,45 ppm -CH2-CH2-Br2 H 5.45 ppm -CH2-CH2-Br
5 H 1,25 ppm CH^-CH2-5 H 1.25 ppm CH^-CH2-
M<+>= 220 M<+>= 220
Ci s- cyklopropan- l- 2- brometyl- 2- karboksylsyreetylesterCis-cyclopropane-1-2-bromomethyl-2-carboxylic acid ethyl ester
IR (metylenklorid) bl.a. bånd ved:IR (methylene chloride) i.a. ties at:
1715, 1395, 1180 cm "V<1-..>1715, 1395, 1180 cm "W<1-..>
NMR (CDCl^) 60 MHz bl.a. signaler ved:NMR (CDCl^) 60 MHz i.a. signals by:
2H 4,l6 ppm O-CHg-CH^2H 4.16 ppm O-CHg-CH^
2H 3,42 ppm -CH2-CH2-Br2H 3.42 ppm -CH2-CH2-Br
2H 2,15 ppm -CH2-CH2-CH2H 2.15 ppm -CH2-CH2-CH
3H 1,28 ppm CH^-CHg-3H 1.28 ppm CH^-CHg-
M<+>220 M<+>220
b) Trans- cyklop ropan- l- 2- br omety l- 2- karboksylsyreb) Transcyclopropane-1-2-bromomethyl-2-carboxylic acid
En til 0°C avkjølt blanding av 6,4 ml 33$ bromhydrogensyre A cooled to 0°C mixture of 6.4 ml of 33% hydrobromic acid
og 1,7 ml konsentrert svovelsyre, tilsettes under sterk ... omrøring 1 g trans-cyklopropan-l-2-brometyl-2-karboksylsyreetylester. Etter en time ved romtemperatur oppvarmes løs-ningen i 15 minutter til 100°C. Den avkjølte, løsning uthelles på 60 ml kold mettet ammoniumsulfatløsning, ekstraheres 3 ganger med metylenklorid, de forenede- - ekstrakter vaskes med vann, tørres og. inndampes under, redusert trykk. Resten oppdeles på 40 g silicagel med kloroform med 1% metanol ( 50 ml-fraksjoner) idet den i overskriften nevnte forbindelse erholdes. and 1.7 ml of concentrated sulfuric acid, add under strong ... stirring 1 g of trans-cyclopropane-1-2-bromomethyl-2-carboxylic acid ethyl ester. After one hour at room temperature, the solution is heated for 15 minutes to 100°C. The cooled solution is poured onto 60 ml of cold saturated ammonium sulphate solution, extracted 3 times with methylene chloride, the combined extracts are washed with water, dried and. evaporated under, reduced pressure. The residue is divided on 40 g of silica gel with chloroform with 1% methanol (50 ml fractions), obtaining the compound mentioned in the title.
IR (metylenklorid) bla., bånd ved:-IR (methylene chloride) i.a., band at:-
3450 - 2700, 1700, 1460, 1215 cm"<1>^3450 - 2700, 1700, 1460, 1215 cm"<1>^
NMR (CDCl^) 60 MHZ bla. signaler ved:NMR (CDCl^) 60 MHZ incl. signals by:
1 H 10,5 ppm (-C00H)1 H 10.5 ppm (-C00H)
.2 H ,3,42 ppm (-CH2-CH2-B.r).2 H .3.42 ppm (-CH2-CH2-B.r)
2 H 1,83 ppm (CH-CH2-CH2-)2 H 1.83 ppm (CH-CH2-CH2-)
M<+>= 193 M<+>= 193
C is- cyklopropan- l- 2- brometyl- 2- karboksylsyreC is- cyclopropane- 1- 2- bromomethyl- 2- carboxylic acid
Behandling som.beskrevet ovenfor gir den.tilsvarende ois-cyklopropan-l-2-brometyl-2-karboksylsyre. Treatment as described above gives the corresponding ois-cyclopropane-1-2-bromomethyl-2-carboxylic acid.
IR (metylenklorid) bl.a. bånd ved:IR (methylene chloride) i.a. ties at:
3450 -.2470, 1695, 1220 om"1 3450 -.2470, 1695, 1220 about"1
NMR (CDCl^, 60 MHz) bl.a. signaler ved:NMR (CDCl3, 60 MHz) i.a. signals by:
9,5 ppm (1H) - COOH9.5 ppm (1H) - COOH
3,47. ppm (2H) CH2-Br3.47. ppm (2H) CH2-Br
2,18 ppm (2H) -CH2- 2.18 ppm (2H) -CH2-
T rans- cyklopropan- l- 2- brometyl- 2- karboksylsyremetylester T trans- cyclopropane- 1- 2- bromomethyl- 2- carboxylic acid methyl ester
200 mg av transsyren løses, i 10 ml metanol og behandles, med en eterisk diazometanløsning ved romtemperatur 20°c. Etter fjernelse av løsningsmidlet under.redusert trykk kromatograferes resten (220 mg) på silicagel med benzen, idet den tilsvarende metylester erholdes. 200 mg of the trans acid are dissolved in 10 ml of methanol and treated with an ethereal diazomethane solution at room temperature 20°c. After removal of the solvent under reduced pressure, the residue (220 mg) is chromatographed on silica gel with benzene, the corresponding methyl ester being obtained.
IR (metylenklorid) bl.a. bånd ved:IR (methylene chloride) i.a. ties at:
1720, 1210, 1120 cm"<*1>1720, 1210, 1120 cm"<*1>
NMR (CDClj) 100 MHz bl.a. signaler ved:NMR (CDClj) 100 MHz i.a. signals by:
3 H 3,68 ppm COOCH^3 H 3.68 ppm COOCH^
2 H 3,45 (t) CH2-Br2 H 3.45 (t) CH2-Br
2 H. 1,9 (m) CH2-CH2-Br2 H. 1.9 (m) CH2-CH2-Br
Den samme forbindelse erholdes ved behandling av transsyren med 3-metyl-l-p-tolyltriazin.. The same compound is obtained by treating the trans acid with 3-methyl-l-p-tolyltriazine.
På analog måte fremstilles følgende estere: cis-cyklopropan-l-2-brometyl-2-karboksylsyremetylester trans-cyklopropan-l-2-brometyl-2-karboksylsyreetylester cis-cyklopropan-1-2-brometyl-2-karboksylsyreetylester trans-cyklopropan-l-2-brometyl-2-karboksylsyrebenzylester cis-cyklopropan-1-2-bromety1-2-karboksylsyrebenzylester c) Trifenylfosfoniumsalt av etyl- trans- cyklopropankarboksylsyre. The following esters are prepared in an analogous manner: cis-cyclopropane-1-2-bromomethyl-2-carboxylic acid methyl ester trans-cyclopropane-1-2-bromomethyl-2-carboxylic acid ethyl ester cis-cyclopropane-1-2-bromomethyl-2-carboxylic acid ethyl ester trans-cyclopropane- 1-2-bromomethyl-2-carboxylic acid benzyl ester cis-cyclopropane-1-2-bromomethyl-2-carboxylic acid benzyl ester c) Triphenylphosphonium salt of ethyl-trans-cyclopropanecarboxylic acid.
5. g (-)-trans-cyklopropan-l-2-brometyl-2-karboksylsyre i 100 ml absolutt benzen tilsettes 10 g trifenylfosfin og kokes under tilbakeløp i 42 timer. Etter fjernelse av løsningsmidlet under redusert trykk oppdeles resten på 5. g of (-)-trans-cyclopropane-1-2-bromomethyl-2-carboxylic acid in 100 ml of absolute benzene is added to 10 g of triphenylphosphine and boiled under reflux for 42 hours. After removal of the solvent under reduced pressure, the residue is partitioned
600 g silicagel med kloroform-metanol-eddiksyreblandinger600 g of silica gel with chloroform-methanol-acetic acid mixtures
( 300- ml fraks joner)-hvorved, den i overskriften nevnte forbindelse erholdes. (300-ml fraction ions)-whereby, the compound mentioned in the title is obtained.
IR (metylenklorid) bl.a. bånd ved:IR (methylene chloride) i.a. ties at:
3400 - 3000, 1725, 1440, 1115 cm"1! ■ 3400 - 3000, 1725, 1440, 1115 cm"1! ■
NMR (CDCl^) 60 MHz bl.a. signaler ved:NMR (CDCl^) 60 MHz i.a. signals by:
15 H 7,75 ppm (aromatiskeH)15 H 7.75 ppm (aromatic H)
2H - 3,8 ppm (CH2- P -)2H - 3.8 ppm (CH2- P -)
På analog måte fremstilles fosfoniumsaltene av følgende forbindelser: Etyl-cis-cyklopropankarboksylsyre.. - etyl-trans-cyklopropankarboksylsyre-etylester ety1-cis-cyklopropankarboksylsyre-etylester e tyl-trahs-cyklopropankarboksylsyre-metyle ste r etyl-cis-cyklopropankarboksylsyre-metylester -- - etyl-trans-cyklopropankarboksylsyre-benzylester etyl-cis-cyklopropankarboksylsyre-benzylester d) 2, 3- trans- metano- ll, 15- bis- tetrahydropyranyl-prostaglandin Fp a 70 mg natriumhydrid løses i 0,7 ml dimetylsulfoksyd og holdes under en nitrogen i 40 minutter ved 75°C. Etter avkjøling tilsettes den brune løsning trifenylfosfoniumsalt av (-) etyl-trans-cyklopropankarboksylsyre i 1 ml absolutt dimetylsulfoksyd. In an analogous way, the phosphonium salts are prepared from the following compounds: Ethyl-cis-cyclopropanecarboxylic acid.. - ethyl-trans-cyclopropanecarboxylic acid-ethyl ester ethyl1-cis-cyclopropanecarboxylic acid-ethylester ethyl-trahs-cyclopropanecarboxylic acid-methyl ester ethyl-cis-cyclopropanecarboxylic acid-methylester -- - ethyl-trans-cyclopropanecarboxylic acid benzyl ester ethyl-cis-cyclopropanecarboxylic acid benzyl ester d) 2, 3-trans-methanol-ll, 15-bis-tetrahydropyranyl-prostaglandin Fp a 70 mg of sodium hydride is dissolved in 0.7 ml of dimethylsulfoxide and kept under a nitrogen for 40 minutes at 75°C. After cooling, the brown solution is added to the triphenylphosphonium salt of (-) ethyl-trans-cyclopropanecarboxylic acid in 1 ml of absolute dimethyl sulphoxide.
Det omrøres.deretter i 1 1/2 time ved romtemperatur og deretter tilsettes 1,2 ml av denne løsning 145 mg 28-3'a-tetrahydropyranyloksy-1'-transoktenyl - 5a-hydroksy--3cx-tetrahydropyranyloksy- cyklopentan-acetaldehydlaktol. Blandingen for stå i 15 minutter v".ed romtemperatur, oppvarmes i 3 timer ved 75°cy deretter uthelles reaksjonsblandingen på 20 g is, innstilles forsiktig til pH 3 og ekstraheres med metylenklorid. Ved krornatografering på 20 g kieselgel med kloroform med 2% metanol erholdes den It is then stirred for 1 1/2 hours at room temperature and then 145 mg of 28-3'a-tetrahydropyranyloxy-1'-transoctenyl-5a-hydroxy-3cx-tetrahydropyranyloxy-cyclopentane-acetaldehyde lactol is added to 1.2 ml of this solution. The mixture is allowed to stand for 15 minutes at room temperature, heated for 3 hours at 75°C, then the reaction mixture is poured onto 20 g of ice, carefully adjusted to pH 3 and extracted with methylene chloride. When chromatographed on 20 g of silica gel with chloroform with 2% methanol it is obtained
1 overskriften nevnte forbindelse i ren form.1 the heading mentioned compound in pure form.
IR (metylenklorid) bl.a. bånd ved 3500,.1710 cm"1 .IR (methylene chloride) i.a. band at 3500,.1710 cm"1 .
NMR (CDCl^) 90 MHz bl.a. signaler ved:NMR (CDCl^) 90 MHz i.a. signals by:
4 H (m) 5,4 ppm4 H (m) 5.4 ppm
2 H 4,7 ppm2 H 4.7 ppm
3 H (t) 0,9 ppm3 H (t) 0.9 ppm
På analog måte fremstilles følgende forbindelser: 2,3-ois-metano-ll,'15-bis-tetrahydropyranyl-prostaglandin F^ a .............. 2,3-trans-metano-ll,15-bis-tetrahydropyranyl-prostaglandin..F.2a-metylester- --2,3- 0 i s -me t ano -11.,. 15- bi s -te trahydropyrany1-prostaglandin F2a-metylester • 2,3-trans-metano-ll,15-bis-tetrahydropyranyl-prostaglandin Fga-etylester 2,3-cis-metano-ll,15-bis-tetrahydropyranyl-prostaglandin Fga-etylester 2,3-trans-me tano-ll,15-bls-tet rahydropyrany1-prostaglandin F2a-benzylester: 2,3-cis-metano-ll,15-bis-tetrahydropyranyl-prostaglandin F2a-benzylester The following compounds are prepared in an analogous manner: 2,3-ois-methano-11,15-bis-tetrahydropyranyl-prostaglandin F^ a .............. 2,3-trans-methano- ll,15-bis-tetrahydropyranyl-prostaglandin..F.2a-methylester- --2,3- 0 i s -me t ano -11.,. 15- bis -te trahydropyrany1-prostaglandin F2a-methyl ester • 2,3-trans-methano-11,15-bis-tetrahydropyranyl-prostaglandin Fga-ethyl ester 2,3-cis-methano-11,15-bis-tetrahydropyranyl-prostaglandin Fga-ethyl ester 2,3-trans-methano-11,15-blstet rahydropyranyl-prostaglandin F2a-benzyl ester: 2,3-cis-methano-11,15-bis-tetrahydropyranyl-prostaglandin F2a-benzyl ester
idet esterne også kan erholdes direkte fra de tilsvarende syrer. since the esters can also be obtained directly from the corresponding acids.
Eksempel 2: l6,l 6- di mety l- 2,3- trans (+)- metano-prostaglandin F2aExample 2: l6,l6-dimethyl l-2,3-trans (+)-methano-prostaglandin F2a
200 mg l6,l6-dimetyl-2,3-(+)-metano-ll,15-bis-tetrahydropyranyl-prostaglandin P2a oppløses i-7 .ml av en blanding av eddiksyre, tetrahydrofuran, vann -( 3:- ± :. l) og holdes i 5 timer ved 40°C. Etter inndamping under ■ redusert trykk kromatograferes esteren på -23-g silicagel med kloroform med 7% metanol hvorved.den rene i overskriften nevnte forbindelse erholdes, 200 mg of 16,16-dimethyl-2,3-(+)-methanol-1,15-bis-tetrahydropyranyl-prostaglandin P2a is dissolved in 7 ml of a mixture of acetic acid, tetrahydrofuran, water -( 3:- ± : .l) and kept for 5 hours at 40°C. After evaporation under ■ reduced pressure, the ester is chromatographed on -23 g silica gel with chloroform with 7% methanol, whereby the pure compound mentioned in the title is obtained,
a ^° + 88°'/: ( c = 1,01 CHCL^) .a ^° + 88°'/: (c = 1.01 CHCl^) .
IR (metylenklorid) bl.a. bånd ved 36OO - 3400, 1695 cm"<1>IR (methylene chloride) i.a. band at 36OO - 3400, 1695 cm"<1>
NMR (CDCl^) 100 MHz bl.a. signaler ved:NMR (CDCl^) 100 MHz i.a. signals by:
4 H5,5 ppm vinyl-H_._4 H5.5 ppm vinyl-H_._
6 H<***>* 4 ppm 3 x CH-OH6 H<***>* 4 ppm 3 x CH-OH
6 H 1,28 ppm 2 x CH^-C6 H 1.28 ppm 2 x CH 2 -C
Analogt fremstilles følgende forbindelser: 16,l6-dimetyl-2,3-trans(+)-metano-prostaglandin F2a~metylester 16,l6-dimetyl-2,3-trans(-f-)-metano-prostaglandin F2a-e tyle s ter 16,l6-dimetyl-2,3-trans(+)-metano-prostaglandin F2a~benzylester og Analogously, the following compounds are prepared: 16,16-dimethyl-2,3-trans(+)-methano-prostaglandin F2a~methyl ester 16,16-dimethyl-2,3-trans(-f-)-methano-prostaglandin F2a-e tyle s ter 16,16-dimethyl-2,3-trans(+)-methano-prostaglandin F2a~benzyl ester and
2,3-trans(+)-metano-prostaglandin P2a . 2,3-trans(+)-methano-prostaglandin P2a .
2,3-trans(+)-metano-prostaglandin F2a-metylester 2,3-trans(+)-metano-prostaglandin F2a-etylester 2,3-trans(+)-metano-prostaglandin F2a-benzylester Det som utgangsmateriale anvendte 16,l6-dimetyl-2,3- • trans(+)-metano-11,15-bis-tetrahydropyrany1-prostaglandin F2afremstilles på følgende måte: 2,3-trans(+)-methano-prostaglandin F2a-methyl ester 2,3-trans(+)-methano-prostaglandin F2a-ethyl ester 2,3-trans(+)-methano-prostaglandin F2a-benzyl ester The starting material used 16 ,16-dimethyl-2,3- • trans(+)-methano-11,15-bis-tetrahydropyranyl-prostaglandin F2a is produced in the following way:
a) (+)- trans- cy klopropan- l- 2- brometyi- karboksyisyrea) (+)-trans-cyclopropane-1-2-bromoethyl-carboxylic acid
66 g trans-cyklopropan-l-2-brometyl-karboksylsyre tilsettes66 g of trans-cyclopropane-1-2-bromomethylcarboxylic acid are added
i 200 ml metylenklorid 29 g (-)-efedrin i 200 ml metylenklorid og settes bort i 2 1/2 time ved 20°C. Etter tilsetning av en heksan blandes krystaller. Det filtreres og omkrystal-liseres fra metylenklorid/heksan og metylenklorid/etylacetat. in 200 ml methylene chloride 29 g (-)-ephedrine in 200 ml methylene chloride and set aside for 2 1/2 hours at 20°C. After addition of a hexane, crystals are mixed. It is filtered and recrystallized from methylene chloride/hexane and methylene chloride/ethyl acetate.
Ved utrystning med metylenklorid/fortynnet saltsyre fri-gis (+)-syren: By shaking with methylene chloride/diluted hydrochloric acid, the (+)-acid is released:
Syren omdannes som beskrevet i eksempel 1 i de følgende estere: (+)-trans-cyklopropan-l-2-brometyl-karboksylsyre-metylester (+)-trans-cyklopropan-l-2-brometyl-karboksylsyre-etylester (+)-trans-cyklopropan-l-2-brometyl-karboksylsyre-benzylester b) Trifenyl fosfoniumsalt a v (+)-t rans-cyk lopropan- l- 2- brometyl-karboksylsyre 6,3 g (+)-trans-cyklopropan-l-2-brometyl-karboksylsyre i 150 ml abs. benzen tilsettes 10,3 g trifenylfosfin og kokeslander tilbakeløp i 65 timer. Etter avkjøling fra-filtreres de utskilte krystaller. The acid is converted as described in example 1 into the following esters: (+)-trans-cyclopropane-1-2-bromomethyl-carboxylic acid methyl ester (+)-trans-cyclopropane-1-2-bromomethyl-carboxylic acid ethyl ester (+)- trans-cyclopropane-1-2-bromomethyl-carboxylic acid benzyl ester b) Triphenyl phosphonium salt a v (+)-trans-cyclopropane-1-2- bromomethyl-carboxylic acid 6.3 g (+)-trans-cyclopropane-1-2 -bromomethyl-carboxylic acid in 150 ml abs. 10.3 g of triphenylphosphine is added to the benzene and refluxed for 65 hours. After cooling, the separated crystals are filtered off.
IR og NMR tilsvarer IR og NMR for den racemiske forbindelse. IR and NMR correspond to the IR and NMR of the racemic compound.
Analogt fremstilles fosfoniumsaltene av følgende forbindelser: Etyl-trans(+)-cyklopropankarboksylsyre-metylester etyl-trans(+)-cyklopropankarboksylsyre-etylester etyl-trans(+)-cyklopropankarboksylsyre-benzylester Analogously, the phosphonium salts are prepared from the following compounds: Ethyl trans(+)-cyclopropanecarboxylic acid methyl ester ethyl trans(+)-cyclopropanecarboxylic acid ethyl ester ethyl trans(+)-cyclopropanecarboxylic acid benzyl ester
c) 16, l6- dimetyl- 2, 3- trans(+)- metano- ll, 15- bis- tetrahydropyranyl- prostaglandin F^ a c) 16,16-dimethyl-2,3-trans(+)-methanol-11,15-bis-tetrahydropyranyl- prostaglandin F^ a
600 mg natriumhydrid oppløses i 6-ml abs. dimetylsulfoksyd og holdes under nitrogen 1 55 minutter ved 75°C. Etter avkjøling tildryppes langsomt 2,1 ml av denne løsning til en tilberedt løsning av 1,95 g trifenylfosfoniumsalt av (+)-transcyklopropan-l-2-brometyl-karboksylsyre i 5 ml abs. dimetylsulfoksyd og omrøres under nitrogen i 45 minutter. Dissolve 600 mg of sodium hydride in 6-ml abs. dimethylsulfoxide and kept under nitrogen for 155 minutes at 75°C. After cooling, 2.1 ml of this solution is slowly added dropwise to a prepared solution of 1.95 g of the triphenylphosphonium salt of (+)-transcyclopropane-1-2-bromomethylcarboxylic acid in 5 ml of abs. dimethylsulfoxide and stirred under nitrogen for 45 minutes.
En tilberedt løsning av 1 g 26-V., 4'-dimetyl-3'-a-tetra--hydr opyrany loksy-1' - trans oktenyl-5a-hydroksy-3ct-te trahydro-pyranyloksy-cyklopentanacetaldehydlaktol i 1 ml abs. di-metylsulf oksyd tilsettes ved 20°C 4,5 ml av den ovenfor beskrevne ylidløsning og- holdes i 50 minutter ved 6o°C. A prepared solution of 1 g of 26-V., 4'-dimethyl-3'-a-tetra--hydr opyrany loxy-1'-trans octenyl-5a-hydroxy-3ct-te trahydro-pyranyloxy-cyclopentaneacetaldehyde lactol in 1 ml of abs . dimethylsulfoxide is added at 20°C to 4.5 ml of the ylide solution described above and kept for 50 minutes at 6o°C.
Etter tilsetning av ytterligere 4,5 ml av ylidløsningen . omrøres ennå i 1 time ved 60°C. Den avkjølte reaksjonsblanding uthelles på is, den vandige fase innstilles til pH- 3 - 5 og ekstraheres 3 ganger med metylenklorid. Det erholdte råprodukt kromatograferes på 140 g silicagel.med kloroform og 1 til 5$ metanol, hvorved den rene i over-skrift nevnte forbindelse erholdes. After adding a further 4.5 ml of the ylide solution. stirred again for 1 hour at 60°C. The cooled reaction mixture is poured onto ice, the aqueous phase is adjusted to pH 3-5 and extracted 3 times with methylene chloride. The crude product obtained is chromatographed on 140 g of silica gel with chloroform and 1 to 5% methanol, whereby the pure compound mentioned in the title is obtained.
IR (metylenklorid) bl.a.bånd ved 3500, 1695 cm"*1 IR (methylene chloride) i.a. bands at 3500, 1695 cm"*1
NMR (CDCl^) 90 MHz bl.a. signaler ved:NMR (CDCl^) 90 MHz i.a. signals by:
4 H ""^-»5,5 ppm vinyl-H4 H ""^-»5.5 ppm vinyl-H
2 H 4,6 ppm THP-H2 H 4.6 ppm THP-H
Analogt fremstilles følgende forbindelser: 16,l6-dimetyl-2,3-trans(+)-metano-ll,15-bis-tetrahydropyranyl-prostaglandin Fga-metylester .... 16,l6-dimetyl-2,3-trans (+), metano-11,15-bis-tetrahydropyranyl-prostaglandin P2a-etylester ....— ... 16,l6-dimetyl-2,3-trans(+)-metano-ll,15-bis-tetrahydropyranyl-prostaglandin Fg^-benzylester Analogously, the following compounds are prepared: 16,16-dimethyl-2,3-trans(+)-methano-11,15-bis-tetrahydropyranyl-prostaglandin Fga methyl ester .... 16,16-dimethyl-2,3-trans ( +), methane-11,15-bis-tetrahydropyranyl-prostaglandin P2a-ethyl ester ....— ... 16,16-dimethyl-2,3-trans(+)-methano-11,15-bis-tetrahydropyranyl- prostaglandin Fg^-benzyl ester
Gjennomføres V/ittigreaks jonen .med-2B- 3' q-tetrahydro- - pyranyloksy-1' -trans-oktenyl-5a-hydroksy-3a>tetrahyd-ro--pyranyloksy-cyklopentan-acetaldehydlaktol, fremstilles på analog måte følgende forbindelser: 2,3-trans(+)-metano-11,15-bis-tetrahydropyranyl-prostaglandin Fga . ■• • 2,3-trans(+)-metano-ll,15-bis-tetrahydropyranyl-prostaglandin Fga-metylester 2,3-trans(-+)-metano-11,15-bis-tetrahydropyranyl-prostaglandin P2a-etylester 2,3-trans (+) .:-metano-11, 15-bis-tetrahydropyranyl-prostaglandin Fga-benzylester If the reaction is carried out with 2B-3'q-tetrahydro-pyranyloxy-1'-trans-octenyl-5a-hydroxy-3a>tetrahydro-pyranyloxy-cyclopentane-acetaldehyde lactol, the following compounds are produced in an analogous manner: 2,3-trans(+)-methano-11,15-bis-tetrahydropyranyl-prostaglandin Fga . ■• • 2,3-trans(+)-methano-11,15-bis-tetrahydropyranyl-prostaglandin Fga methyl ester 2,3-trans(-+)-methano-11,15-bis-tetrahydropyranyl-prostaglandin P2a ethyl ester 2,3-trans (+) .:-methano-11, 15-bis-tetrahydropyranyl prostaglandin Fga benzyl ester
Eksempel 3: 16,l6-d imet yl-2,3-trans(+)- metano- prostag landin Eg Example 3: 16,16-dimethyl-2,3-trans(+)-methanoprostaglandin Eg
100 mg 16,l6-dimetyl-2,3-trans(+)-metano-ll,15-bis-tetrahydropyranyl-prostaglandin Fgaløses il ml abs. toluen og tilsettes under nitrogen 26,7 mg tert.-butyl-dimetylklor-silan. Reaksjonsløsningen avkjølres til 0°C og tilsettes 18 mg trietylamin, omrøres videre i 2 1/2 time ved 20°C, avkjøles til - 30°C og tildryppes langsomt til.en løsning., 100 mg 16,16-dimethyl-2,3-trans(+)-methano-11,15-bis-tetrahydropyranyl-prostaglandin Fgaloses 1 ml abs. toluene and 26.7 mg of tert.-butyl-dimethylchloro-silane are added under nitrogen. The reaction solution is cooled to 0°C and 18 mg of triethylamine is added, stirred for 2 1/2 hours at 20°C, cooled to -30°C and slowly added dropwise to a solution.
av 108 mg N-klorsukcinimid i 4 ml abs. toluen og 60 mg di-metylsulf id i løpet av 35 minutter.. Etter ytterligere 2 3/4 time ved - 20°C tildryppes 220 mg trietylamin i 1 ml pentan og behandles i ytterligere 10 minutter med eter/ of 108 mg N-chlorosuccinimide in 4 ml abs. toluene and 60 mg of dimethylsulphide in the course of 35 minutes. After a further 2 3/4 hours at - 20°C, 220 mg of triethylamine are added dropwise in 1 ml of pentane and treated for a further 10 minutes with ether/
vann. Resten (100 mg) kromatograferes på 8 g silicagel med kloroform med 2% metanol. Det erholdes dermed l6,l6-dimetyl-2,3-trans(+)-metano-ll,15-bis-tetrahydropyranyl-prostaglandin Eg - tert.-butyl-dimetylsilylester. water. The residue (100 mg) is chromatographed on 8 g of silica gel with chloroform with 2% methanol. 16,16-dimethyl-2,3-trans(+)-methano-1,15-bis-tetrahydropyranyl-prostaglandin Eg - tert-butyl-dimethylsilyl ester is thus obtained.
IR (metylenklorid) bl.a.- bånd ved 1735, 1695 cm,""<1>IR (methylene chloride) i.a. bands at 1735, 1695 cm,""<1>
50 mg av den ovenfor beskrevne, ester løses- i -.0,7 ml, -ved 0°C tildryppes 0,2 ml vann og-0,2-5 ml-av en-'løsning av 246 mg natriumacetat -i .3 ml .aceton, I.ml vann og-180 mg eddiksyre.. Det omrøres i - 45 -minutter- ved 0O-C og 1 1/2 time ;yed 25°C og behandles deretter med eter. 50 mg of the above-described ester is dissolved in 0.7 ml, at 0°C 0.2 ml of water and 0.2-5 ml of a solution of 246 mg of sodium acetate are added dropwise. 3 ml of acetone, 1 ml of water and 180 mg of acetic acid. It is stirred for 45 minutes at 0°C and 1 1/2 hours at 25°C and then treated with ether.
Resten løses i 2 ml eddiksyre, vann, tetråhydrofuranThe residue is dissolved in 2 ml of acetic acid, water, tetrahydrofuran
( 3: 1: 1) og holdes i 2 1/2 time ved 38°C. -Etter inndamping under redusert trykk kr ornat ogra feres jesten på-2,5 g silicagel med kloroform med 3$ metanol. Den rene i overskriften nevnte forbindelse erholdes. ( 3: 1: 1) and kept for 2 1/2 hours at 38°C. -After evaporation under reduced pressure, the yeast on 2.5 g of silica gel is treated with chloroform with 3% methanol. The pure compound mentioned in the title is obtained.
IR (metylenklorid) bl.a. bånd ved 1735, 1695 cm"<1>..IR (methylene chloride) i.a. band at 1735, 1695 cm"<1>..
NMR (CDCl^) 90 MHz bl.a. signaler ved:NMR (CDCl^) 90 MHz i.a. signals by:
4 H 5,3-5,8 ppm (vinyl-protoner)4 H 5.3-5.8 ppm (vinyl protons)
5 H 3,7 - 4,2 ppm 2 x -CH-0H + -C00H5 H 3.7 - 4.2 ppm 2 x -CH-OH + -COOH
Analogt fremstilles 2,3-trans(+)-metano-prostaglandin Eg. Analogously, 2,3-trans(+)-methano-prostaglandin Eg is produced.
Ved å gå ut fra de under eksempel 2 beskrevne estere fremstilles på analog måte de følgende forbindelser: 16,l6-dimetyl-2,3-trans(+)-metano-prostaglandin Eg-metylester 16,l6-dimetyl-2,3-trans(+)-metano-prostaglandin Eg-etylester 16,l6-dimetyl-2,3-trans(+)-metano-prostaglandin Eg-benzylester 2,3-trans(+)-metano-prostaglandin Eg-metylester 2,3-trans(+)-metano-prostaglandin Eg-etylester 2,3-trans(+)-metano-prostaglandin Eg-benzylester Starting from the esters described under example 2, the following compounds are prepared in an analogous manner: 16,16-dimethyl-2,3-trans(+)-methano-prostaglandin Eg-methyl ester 16,16-dimethyl-2,3- trans(+)-methano-prostaglandin Eg-ethyl ester 16,16-dimethyl-2,3-trans(+)-methano-prostaglandin Eg-benzyl ester 2,3-trans(+)-methano-prostaglandin Eg-methyl ester 2,3 -trans(+)-methano-prostaglandin Eg-ethyl ester 2,3-trans(+)-methano-prostaglandin Eg-benzyl ester
Ek sempel 4: 16, l6- dimetyi- 2, 3- trans(- )- metano-prostaglandin FgaExample 4: 16, 16-dimethyl-2, 3- trans(- )-methano-prostaglandin Fga
109 mg 16,l6-dimetyl-2,3-trans(-)-metano-ll,15-bis-tetrahydropyranyl-prostaglandln Fgaoppløses i 3,5 ml av en blanding av eddiksyre, tetrahydrofuran, vann (3-: 1 : 1) og holdes i 6 timer ved 40°C. Etter inndamping under redusert trykk kromatograferes resten på 5 g silicagel med kloroform med %% metanol, hvorved den rene i overskriften nevnte forbindelse erholdes. 109 mg of 16,16-dimethyl-2,3-trans(-)-methano-11,15-bis-tetrahydropyranyl-prostaglandin Fgadissolved in 3.5 ml of a mixture of acetic acid, tetrahydrofuran, water (3-: 1 : 1 ) and kept for 6 hours at 40°C. After evaporation under reduced pressure, the residue is chromatographed on 5 g of silica gel with chloroform with %% methanol, whereby the pure compound mentioned in the title is obtained.
a ^° - + 13,8° ( c<=>1,02 CHCl^)a ^° - + 13.8° ( c<=>1.02 CHCl^)
IR (metylenklorid) bl.a. bånd ved 36OO, 3400, 1695 cm"<1->IR (methylene chloride) i.a. bands at 36OO, 3400, 1695 cm"<1->
NMR (CDCl^)90 MHz bl.a. signaler ved:NMR (CDCl^) 90 MHz i.a. signals by:
4 H 5,3 - 5,7 ppm vinyl-H4 H 5.3 - 5.7 ppm vinyl-H
7 H 3,9 - 4,3 ppm 3 x>CH-0H + C00H7 H 3.9 - 4.3 ppm 3 x>CH-OH + COOH
Analogt fremstilles de følgende forbindelser: 16,l6-dimetyl-2,3-trans(-)-metano-prostaglandin Fga-metylester Analogously, the following compounds are prepared: 16,16-dimethyl-2,3-trans(-)-methano-prostaglandin Fga methyl ester
16,l6-dimetyl-2,3-trans(-)-metano-prostaglandin F^-etylester 16,16-dimethyl-2,3-trans(-)-methano-prostaglandin F^-ethyl ester
16,l6-dimetyl-2,3-trans(-)-metano-prostaglandin Fga-benzylester 16,16-dimethyl-2,3-trans(-)-methano-prostaglandin Fga benzyl ester
2,3-trans(-)-metano-prostaglandin Fga2,3-trans(-)-methano-prostaglandin Fga
2,3-trans(-)-metano-prostaglandin Fga-metylester 2,3-trans(-)-metano-prostaglandin Fg^-etylester 2,3-trans(-)-metano-prostaglandin F0 -benzylester 2,3-trans(-)-methano-prostaglandin Fga methyl ester 2,3-trans(-)-methano-prostaglandin Fg^-ethyl ester 2,3-trans(-)-methano-prostaglandin F0 -benzyl ester
Det som utgangsmateriale. anvendte .16,l6-dimetyl-2J3-trans-(-)-metano-11,15-bis-tetrahydropyranyl-prostaglandin Fa fremstilles på følgende måte: That as starting material. The .16,16-dimethyl-2J3-trans-(-)-methano-11,15-bis-tetrahydropyranyl-prostaglandin Fa used is prepared in the following way:
a) (-)- Trans- cyklopropan- l- 2- brometyl- karboksyisyrea) (-)- Trans- cyclopropane- 1- 2- bromomethyl- carboxylic acid
Analogt med eksempel 2a) erholdes med (+)-efedrin den i Analogous to example 2a) with (+)-ephedrine the i
overskriften, nevnte forbindelse,the heading, said connection,
cx 20 75,0° c= 1,56 CHC15). cx 20 75.0° c= 1.56 CHCl 5 ).
De spektroskopiske data for den i.overskriften nevnte .forbindelse er identiske med de tilsvarende for (+)-syren. The spectroscopic data for the compound mentioned in the title are identical to the corresponding data for the (+) acid.
Syren omdannes som beskrevet i eksempel 1 til de følgende estere: (_)-Trans-cyklopropan-l-2-brometyl-karboksylsyre-metylester The acid is converted as described in example 1 into the following esters: (_)-Trans-cyclopropane-1-2-bromomethyl-carboxylic acid methyl ester
(-)-trans-cyklopropan-l-2-brometyl-karboksylsyre-etylester-(-)-trans-cyklopropan-l-2-brometyl-karboksylsyre-benzylester (-)-trans-cyclopropane-1-2-bromomethyl-carboxylic acid ethyl ester-(-)-trans-cyclopropane-1-2-bromomethyl-carboxylic acid benzyl ester
b) Trifenylfosfoniumsalt av (-)- Trans- cyklopropan- l- 2-- brometyl- karboksylsyre b) Triphenylphosphonium salt of (-)-Trans-cyclopropane-1-2--bromomethyl-carboxylic acid
6l. g (-)-trans-cyklopropan-l-2-brometyl-karboksylsyre i 200 ml abs. benzen tilsettes 10 g trifenylfosfin og kokes under tilbakeløp i 63 timer. Etter avkjøling fra-filtreres de utskilte krystaller. 6l. g (-)-trans-cyclopropane-1-2-bromomethyl-carboxylic acid in 200 ml abs. benzene, 10 g of triphenylphosphine is added and refluxed for 63 hours. After cooling, the separated crystals are filtered off.
Smp. 120 - 122°C; a<20>= 17,3° ( c= 1,19CHC1 ) Temp. 120 - 122°C; a<20>= 17.3° ( c= 1.19CHC1 )
D 3 D 3
IR og NMR tilsvarer IR og NMR for den enantiomere forbindelse. IR and NMR correspond to IR and NMR for the enantiomeric compound.
Analogt fremstilles fosfoniumsaltene av de følgende forbindelser: Etyl-trans(-)-cyklopropankarboksylsyre-metylester e tyl-trans (-)-cyklopropankarboksylsyr-e-etylester- - - etyl-trans(-)-cyklopropankarboksylsyre-benzylester Analogously, the phosphonium salts are prepared from the following compounds: Ethyl-trans(-)-cyclopropanecarboxylic acid-methyl ester e ethyl-trans (-)-cyclopropanecarboxylic acid-e-ethyl ester- - - ethyl-trans(-)-cyclopropanecarboxylic acid-benzyl ester
c) l6- dimetyl- 2, 3- trans (- )- metano- ll, 15- bis- tetra-hyd ropyranyl- prostaglandin Fgac) 16- dimethyl- 2, 3- trans (- )- methanol- 11, 15- bis- tetrahydropyranyl- prostaglandin Fga
300 mg natriumhydrid suspenderes i 3 ml abs. dimetylsulfoksyd og holdes under'nitrogen i 45 minutter ved 75°C. Etter avkjøling tildryppes 0,9 ml av denne løsning-langsomt til en tilberedt løsning av -1 g trifenylfosfoniumsalt av--(-)-trans-cyklopropan-l-2-brometyl-karboksylsyre i 2,5.ml abs. dimetylsulfoksyd og etter-røres under nitrogen i 45 minutter. 300 mg of sodium hydride is suspended in 3 ml of abs. dimethylsulfoxide and kept under nitrogen for 45 minutes at 75°C. After cooling, 0.9 ml of this solution is slowly added dropwise to a prepared solution of -1 g of the triphenylphosphonium salt of --(-)-trans-cyclopropane-1-2-bromomethyl-carboxylic acid in 2.5 ml of abs. dimethyl sulphoxide and then stirred under nitrogen for 45 minutes.
Til en løsning av 500 mg 26-4',4'-dimetyl-3'a-tetrahydro-pyranyloksy-1 1 -trans-oktenyl-5a-hydroksy-3ct-tetrahydro-pyranyloksy-cyklopentan-acetaldehydlaktol i 0,6 ml abs. tetrahydrofuran tildryppes langsomt 1,9 ml av den ovenfor beskrevne ylidløsning. Etter 40 minutter ved 60°C tildryppes på nytt 1,9 ml ylidløsning og holdes i ytterligere 1 time ved 60°C. Den avkjølte reaksjonsblanding uthelles på 100 g is, den vandige fase innstilles til pH= 3-4 To a solution of 500 mg of 26-4',4'-dimethyl-3'a-tetrahydro-pyranyloxy-1 1 -trans-octenyl-5a-hydroxy-3ct-tetrahydro-pyranyloxy-cyclopentane-acetaldehyde lactol in 0.6 ml abs . tetrahydrofuran is slowly added dropwise to 1.9 ml of the ylide solution described above. After 40 minutes at 60°C, 1.9 ml of ylide solution is added dropwise and kept for a further 1 hour at 60°C. The cooled reaction mixture is poured onto 100 g of ice, the aqueous phase is adjusted to pH= 3-4
og ekstraheres 3 ganger med metylenklorid.. Det erholdte råprodukt renses ved kromatografering på 40 g silicagel hvorved det med kloroform og 2.% metanol erholdes den rene i overskriften nevnte forbindelse. and extracted 3 times with methylene chloride. The crude product obtained is purified by chromatography on 40 g of silica gel, whereby the pure compound mentioned in the title is obtained with chloroform and 2% methanol.
IR (metylenklorid) bl.a. bånd ved 3500, 1695 cm"1 , . IR (methylene chloride) i.a. bands at 3500, 1695 cm"1 , .
Analogt fremstilles de følgende forbindelser: 16,l6-dimetyl-2,3-trans(-)-metano-ll,15-bis-tetrahydropyranyl-prostaglandin F^-met.ylester 16,l6-dimetyl-2,3-trans(-)-metano-ll,15-bis-tetrahydropyranyl-prostaglandin Fg^-etylester 16,l6-dimetyl-2,3-trans(-)-metano-ll,15-bis-tetrahydropyranyl-pr os taglandin F^-benzylester Analogously, the following compounds are prepared: 16,16-dimethyl-2,3-trans(-)-methanol-1,15-bis-tetrahydropyranyl-prostaglandin F^-methyl ester 16,16-dimethyl-2,3-trans( -)-methano-11,15-bis-tetrahydropyranyl-prostaglandin Fg^-ethyl ester 16,16-dimethyl-2,3-trans(-)-methano-11,15-bis-tetrahydropyranyl-prostaglandin F^-benzyl ester
Gjennomføres wittig-reaksjonen med. 26- 3'a-tetrahydropyranyl-oksy-1' -trans-oktenyl-5cx-hydroksy-3cx-tetrahydropyranyl-oksy-cyklopentan-acetaldehydlaktol, fremstxlies på analog måte følgende forbindelser: 2,3-trans(-)-metano-ll,15-bis-tetrahydropyranyl-pr os taglandin F2a2,3-trans(-)-metano-ll,15-bis-tetrahydropyranyl-prostaglandin F2a-metylester - ... 2,3-trans(-)-metano-ll,15-bis-tetrahydropyranyl-prostaglandin F2a-etylester 2,3-trans(-)-me tano-11,15-bi s-te trahydropyrany1-prostaglandin Fg^-benzylester Carry out the wittig reaction with 26- 3'a-tetrahydropyranyl-oxy-1'-trans-octenyl-5cx-hydroxy-3cx-tetrahydropyranyl-oxy-cyclopentane-acetaldehyde lactol, the following compounds are prepared in an analogous manner: 2,3-trans(-)-methane-ll ,15-bis-tetrahydropyranyl-prostaglandin F2a2,3-trans(-)-methano-ll,15-bis-tetrahydropyranyl-prostaglandin F2a-methyl ester - ... 2,3-trans(-)-methano-ll, 15-bis-tetrahydropyranyl-prostaglandin F2a-ethyl ester 2,3-trans(-)-methano-11,15-bi s-te trahydropyrany1-prostaglandin Fg^-benzyl ester
Ek sempel 5: 16, l6- dimetyl- 2, 3- trans(-)- metano- prostaglandin E2Example 5: 16,16-dimethyl-2,3-trans(-)-methano- prostaglandin E2
177 mg l6,l6-dimetyl-2,3-trans(-)-metano-ll,15-bis-tetrahydropyranyl-prostaglandin F2aløses i 1,5 ml abs. toluen. Under nitrogen tildryppes en løsning av 47,2 mg tert.-butyldimetyl-klorsilan i toluen. Reaksjonsløsningen av-kjøles til 0°C, tilsettes 32 mg trietylamin og omrøres i 2 1/2 time ved 20°C, avkjøles til - 30°C og tildryppes langsomt til en løsning av 191 mg N-klorsukcinimid i 6 ml abs. toluen og 106, 3 mg.dimetylsulfid. Etter 2 timer ved 177 mg of 16,16-dimethyl-2,3-trans(-)-methano-11,15-bis-tetrahydropyranyl-prostaglandin F2 is dissolved in 1.5 ml abs. toluene. A solution of 47.2 mg of tert-butyldimethylchlorosilane in toluene is added dropwise under nitrogen. The reaction solution is cooled to 0°C, 32 mg of triethylamine is added and stirred for 2 1/2 hours at 20°C, cooled to -30°C and slowly added dropwise to a solution of 191 mg of N-chlorosuccinimide in 6 ml of abs. toluene and 106.3 mg. dimethyl sulphide. After 2 hours at
- 30°C/-20°C tilsettes. 300 mg trietylamin i 1 ml pentan,- 30°C/-20°C is added. 300 mg triethylamine in 1 ml pentane,
det omrøres videre i 10 minutter og behandles med eter/vann. Resten (192 mg) kromatograferes på 12 g silicagel med kloroform med Vfo metanol. it is stirred further for 10 minutes and treated with ether/water. The residue (192 mg) is chromatographed on 12 g of silica gel with chloroform with Vfo methanol.
Den erholdte silylester (IR i-metylenklorid- bl.a. bånd ved 1735, 1675 cm .-'" V) oppløses i 2,7 ml aceton. Til -den til 0°C avkjølte løsning tilsettes 0,9 ml vann og -1,2 ml av en løsning av 246 mg natriumacetat i 3 ml aceton, 1 ml vann og l80 mg eddiksyre. Reaksjonsblandingen omrøres i 30 minutter ved 0°C, omrøres i 1 1/2 time ved 25 - 30°C, og. behandles-deretter med eter. -Resten (IR -.i-metylenklorid bl-.a. bånd ved -3500,--1-735,--16-9-5-.cmoppløses i .3. ml - eddiksyre, vann, " tet rah yd ro f ur an- -( 3-:-l--:- -I-)- -og- omrøres i 6 timer ved 40°.C. Etter inndamping- under- -redusert-trykk kromat ogra fe res resten på 4,5 - g -silicagel..med-, kloroform med 2.% metanol. Den rene i overskriften nevnte forbindelse erholdes. The silyl ester obtained (IR i-methylene chloride - i.a. bands at 1735, 1675 cm .-'" V) is dissolved in 2.7 ml of acetone. To - the solution cooled to 0°C, 0.9 ml of water is added and - 1.2 ml of a solution of 246 mg of sodium acetate in 3 ml of acetone, 1 ml of water and 180 mg of acetic acid.The reaction mixture is stirred for 30 minutes at 0° C., stirred for 1 1/2 hours at 25 - 30° C., and. is then treated with ether. , " tet rah yd ro f ur an- -( 3-:-l--:- -I-)- -and- stirred for 6 hours at 40°.C. After evaporation- under- -reduced-pressure chromate andgra The residue is concentrated on 4.5 g of silica gel with chloroform with 2% methanol.The pure compound mentioned in the title is obtained.
IR (metylenklorid) bl.a. bånd ved 36OO, 3400, 1735, 1695 cm"-1:. IR (methylene chloride) i.a. bands at 36OO, 3400, 1735, 1695 cm"-1:.
NMR (CDCl^) 90 MHz bl.a. signaler ved ca.:NMR (CDCl^) 90 MHz i.a. signals at approx.:
Analogt fremstilles 2,3-trans(-)-metano-prostaglandin Eg. Analogously, 2,3-trans(-)-methano-prostaglandin Eg is produced.
Ved å gå ut fra de under eksempel 4 beskrevne estere fremstilles på analog måte de følgende forbindelser: 16,l6-dimetyl-2,3-trans(-)-metano-prostaglandin Eg-metylester Starting from the esters described under example 4, the following compounds are prepared in an analogous manner: 16,16-dimethyl-2,3-trans(-)-methano-prostaglandin Eg-methyl ester
16,l6-dimetyl-2,3-trans(-)-metano-prostaglandin Eg-etylester 16,16-dimethyl-2,3-trans(-)-methano-prostaglandin Eg-ethyl ester
16,l6-dimetyl-2,3-trans(-)-metano-prostaglandin Eg-benzylester 16,16-dimethyl-2,3-trans(-)-methano-prostaglandin Eg-benzyl ester
2,3-trans(-)-metano-prostaglandin Eg-metylester 2,3-trans(-)-metano-prostaglandin Eg-etylester 2,3-trans(-)-metano-prostaglandin Eg-benzylester 2,3-trans(-)-methano-prostaglandin Eg-methyl ester 2,3-trans(-)-methano-prostaglandin Eg-ethyl ester 2,3-trans(-)-methano-prostaglandin Eg-benzyl ester
E ksempel 6: 16,l6-dimetyl-2,3-trans(+)- metano-prosta giandln Ag 50 mg 16,l6-dimetyl-2,3-trans(^)-metano-prostaglandin Eg fra eksempel 3 løses i 2 ml eddiksyre-vann ( 9 :- 1 -) og holdes ved 60°C i 5 1/2 time. Etter tilsetning-av .. - toluen inndampes under redusert trykk og- resten kromatograferes på 0,5 g silicagel med-kloroform med 0,-5#---metanol. Den rene i overskriften nevnte forbindelse har følgende karakteristikker: Example 6: 16,16-dimethyl-2,3-trans(+)-methano-prostaglandin Ag 50 mg 16,16-dimethyl-2,3-trans(^)-methano-prostaglandin Eg from example 3 is dissolved in 2 ml acetic acid-water ( 9 :- 1 -) and kept at 60°C for 5 1/2 hours. After addition of .. - toluene is evaporated under reduced pressure and the residue is chromatographed on 0.5 g of silica gel with chloroform with 0.5% methanol. The pure compound mentioned in the title has the following characteristics:
IR. (metylenklorid) bl..a. bånd ved:IR. (methylene chloride) i.a. ties at:
3600, 1700, 1690, 1140 cm"1 3600, 1700, 1690, 1140 cm"1
NMR (CDCl-^) 90 MHz bl.a. signaler ved:NMR (CDCl-^) 90 MHz i.a. signals by:
På analog måte fremstilles følgende forbindelser: l6,l6-dimetyl-2,3-trans(+)-metano-prostaglandin Ag . 16,l6-dimetyl-2,3-trans(+)-metano-prostaglandin Ag-metylester The following compounds are prepared in an analogous manner: 16,16-dimethyl-2,3-trans(+)-methano-prostaglandin Ag. 16,16-dimethyl-2,3-trans(+)-methano-prostaglandin Ag methyl ester
16,l6-dimetyl-2,3-trans(+)-metano-prostaglandin Ag-etylester 16,16-dimethyl-2,3-trans(+)-methano-prostaglandin Ag ethyl ester
16, l6-dimetyl-2,3-trans(+)-metano-prostaglandin Ag-benzylester 16, 16-dimethyl-2,3-trans(+)-methano-prostaglandin Ag benzyl ester
2,3-trans(+)-metano-prostaglandin A og 2,3-trans(+)-metano-prostaglandin Ag2-met<y>leste<r>2,3-trans(+)-metano-prostaglandin Ag-etylester 2,3-trans(+)-metano-prostaglandin Ag-benzylester 2,3-trans(+)-methano-prostaglandin A and 2,3-trans(+)-methano-prostaglandin Ag2-met<y>read<r>2,3-trans(+)-methano-prostaglandin Ag- ethyl ester 2,3-trans(+)-methano-prostaglandin Ag benzyl ester
E ksempel 7: 16, l6- dimetyl-2,3- trans(-)- metano-prostaglandin Ag Example 7: 16, 16-dimethyl-2,3-trans(-)-methano-prostaglandin Ag
120 mg l6,l6-dimety.l-2,3-trans (--)-metano-pros taglandin 120 mg l6,l6-dimethyl.l-2,3-trans (--)-methano-prostaglandin
Eg fra eksempel 5 løses i.5 ml eddiksyre-vann-(9--: l) --og holdes i 15 timerved 55 - 60°C, - Reaksjonsblandingen inndampes under redusert trykk og resten kromatograferes på 5 g silicagel. Eg from example 5 is dissolved in 5 ml of acetic acid-water (9--: l) -- and kept for 15 hours at 55 - 60°C, - The reaction mixture is evaporated under reduced pressure and the residue is chromatographed on 5 g of silica gel.
Med kloroform-metanol-blanding isoleres den rene i overskriften nevnte forbindelse: With a chloroform-methanol mixture, the pure compound mentioned in the title is isolated:
IR. (metylenklorid) bl,a. bånd ved.: -IR. (methylene chloride) i.a. band by.: -
3600, 1700, 1690, 1590, 1065,1030cm"<1>r NMR (CDCl-^) 90 MHz bl.a. signaler ved: 3600, 1700, 1690, 1590, 1065, 1030cm"<1>r NMR (CDCl-^) 90 MHz i.a. signals at:
På analog måte fremstilles de følgende forbindelser: 16,l6-dimetyl-2,3-trans(-)-metano-prostaglandin Ag 16,l6-dimetyl-2,3-trans(-)-metano-prostaglandin Ag-metylester The following compounds are prepared in an analogous manner: 16,16-dimethyl-2,3-trans(-)-methano-prostaglandin Ag 16,16-dimethyl-2,3-trans(-)-methano-prostaglandin Ag methyl ester
16,l6-dimetyl-2,3-trans(-)-metano-prostaglandin Ag-etylester 16,16-dimethyl-2,3-trans(-)-methano-prostaglandin Ag ethyl ester
16,l6-dimetyl-2,3-trans(-)-metano-prostaglandin Ag-benzylester 16,16-dimethyl-2,3-trans(-)-methano-prostaglandin Ag benzyl ester
2,3-trans(-)-metano-prostaglandin Ag og 2,3-trans(-)-metano-prostaglandin Ag-metylester 2,3-trans(-)-metano-prostaglandin Ag-etylester 2,3-trans(-)-metano-prostaglandin Ag-benzylester 2,3-trans(-)-methano-prostaglandin Ag and 2,3-trans(-)-methano-prostaglandin Ag methyl ester 2,3-trans(-)-methano-prostaglandin Ag ethyl ester 2,3-trans( -)-methano-prostaglandin Ag benzyl ester
Claims (4)
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH995973A CH599147A5 (en) | 1973-07-09 | 1973-07-09 | Long-acting synthetic prostaglandins |
| CH604974 | 1974-05-04 |
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| NO742378L true NO742378L (en) | 1975-02-03 |
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| AT (1) | AT355233B (en) |
| CA (1) | CA1050976A (en) |
| DD (1) | DD113348A5 (en) |
| DE (1) | DE2431930A1 (en) |
| DK (1) | DK142143B (en) |
| ES (2) | ES428063A1 (en) |
| FI (1) | FI58117C (en) |
| FR (2) | FR2236490B1 (en) |
| GB (2) | GB1479965A (en) |
| IE (1) | IE41342B1 (en) |
| IL (1) | IL45215A (en) |
| NL (1) | NL7409119A (en) |
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| DE2638401A1 (en) * | 1975-09-05 | 1977-03-17 | Sandoz Ag | NEW PROSTAGLANDIN, THEIR USE AND MANUFACTURING |
| JPS52116930U (en) * | 1976-03-03 | 1977-09-05 | ||
| JPS55147056U (en) * | 1979-04-06 | 1980-10-22 | ||
| US4431669A (en) * | 1982-12-17 | 1984-02-14 | Schering Corporation | Cyclopropyl substituted polyenes |
| JPH04204679A (en) * | 1990-11-30 | 1992-07-27 | Fuji Photo Film Co Ltd | Electrophotographic image recorder |
-
1974
- 1974-07-01 DK DK352974AA patent/DK142143B/en unknown
- 1974-07-01 NO NO742378A patent/NO742378L/no unknown
- 1974-07-01 SE SE7408689A patent/SE7408689L/xx unknown
- 1974-07-01 FI FI2011/74A patent/FI58117C/en active
- 1974-07-03 DE DE2431930A patent/DE2431930A1/en not_active Withdrawn
- 1974-07-05 DD DD179745A patent/DD113348A5/xx unknown
- 1974-07-05 FR FR7423427A patent/FR2236490B1/fr not_active Expired
- 1974-07-05 NL NL7409119A patent/NL7409119A/en not_active Application Discontinuation
- 1974-07-08 GB GB1901/77A patent/GB1479965A/en not_active Expired
- 1974-07-08 IL IL45215A patent/IL45215A/en unknown
- 1974-07-08 IE IE1443/74A patent/IE41342B1/en unknown
- 1974-07-08 JP JP49077462A patent/JPS5040549A/ja active Pending
- 1974-07-08 GB GB30268/74A patent/GB1479964A/en not_active Expired
- 1974-07-08 CA CA204,340A patent/CA1050976A/en not_active Expired
- 1974-07-08 AT AT559874A patent/AT355233B/en not_active IP Right Cessation
- 1974-07-08 ES ES74428063A patent/ES428063A1/en not_active Expired
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1975
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1976
- 1976-05-17 ES ES448000A patent/ES448000A1/en not_active Expired
- 1976-10-01 FR FR7629555A patent/FR2318169A1/en active Granted
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| Publication number | Publication date |
|---|---|
| DE2431930A1 (en) | 1975-01-30 |
| FI58117B (en) | 1980-08-29 |
| FR2318169A1 (en) | 1977-02-11 |
| SE7408689L (en) | 1975-01-10 |
| AT355233B (en) | 1980-02-25 |
| FR2318169B1 (en) | 1978-11-03 |
| ES448000A1 (en) | 1977-11-01 |
| GB1479965A (en) | 1977-07-13 |
| DK142143B (en) | 1980-09-08 |
| DK142143C (en) | 1981-02-09 |
| SE7512194L (en) | 1975-10-30 |
| DK352974A (en) | 1975-03-03 |
| FR2236490B1 (en) | 1978-07-21 |
| IL45215A (en) | 1977-07-31 |
| NL7409119A (en) | 1975-01-13 |
| IE41342L (en) | 1975-01-09 |
| FR2236490A1 (en) | 1975-02-07 |
| FI201174A (en) | 1975-01-10 |
| IE41342B1 (en) | 1979-12-05 |
| FI58117C (en) | 1980-12-10 |
| JPS5040549A (en) | 1975-04-14 |
| GB1479964A (en) | 1977-07-13 |
| DD113348A5 (en) | 1975-06-05 |
| IL45215A0 (en) | 1975-02-10 |
| ES428063A1 (en) | 1977-02-01 |
| ATA559874A (en) | 1979-07-15 |
| CA1050976A (en) | 1979-03-20 |
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