DK142143B - Analogous Process for Preparation of 2,3-Methylene Prostaglandin F2alfa or E2 Derivatives. - Google Patents
Analogous Process for Preparation of 2,3-Methylene Prostaglandin F2alfa or E2 Derivatives. Download PDFInfo
- Publication number
- DK142143B DK142143B DK352974AA DK352974A DK142143B DK 142143 B DK142143 B DK 142143B DK 352974A A DK352974A A DK 352974AA DK 352974 A DK352974 A DK 352974A DK 142143 B DK142143 B DK 142143B
- Authority
- DK
- Denmark
- Prior art keywords
- ppm
- trans
- methylene
- spectrum
- methylene chloride
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 10
- 238000002360 preparation method Methods 0.000 title claims description 6
- -1 2,3-Methylene Prostaglandin Chemical class 0.000 title description 47
- 238000002329 infrared spectrum Methods 0.000 claims description 45
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 claims description 45
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 32
- 125000004432 carbon atom Chemical group C* 0.000 claims description 25
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
- 239000001257 hydrogen Substances 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 5
- 125000004665 trialkylsilyl group Chemical group 0.000 claims description 4
- 150000002431 hydrogen Chemical class 0.000 claims description 3
- 125000006239 protecting group Chemical group 0.000 claims description 3
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 3
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 177
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 72
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 69
- 150000001875 compounds Chemical class 0.000 description 57
- 239000000243 solution Substances 0.000 description 52
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 42
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 36
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 35
- 239000000203 mixture Substances 0.000 description 29
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 28
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 24
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 24
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 22
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 22
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 21
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 229960000583 acetic acid Drugs 0.000 description 12
- 125000001931 aliphatic group Chemical group 0.000 description 12
- 229910052757 nitrogen Inorganic materials 0.000 description 12
- 239000007858 starting material Substances 0.000 description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 12
- 239000002253 acid Substances 0.000 description 10
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 10
- 229960002986 dinoprostone Drugs 0.000 description 8
- 238000001704 evaporation Methods 0.000 description 8
- 230000008020 evaporation Effects 0.000 description 8
- XEYBRNLFEZDVAW-UHFFFAOYSA-N prostaglandin E2 Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CC=CCCCC(O)=O XEYBRNLFEZDVAW-UHFFFAOYSA-N 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- 150000002148 esters Chemical class 0.000 description 7
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 6
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 6
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 6
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
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- 229910000104 sodium hydride Inorganic materials 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- PXGPLTODNUVGFL-BRIYLRKRSA-N (E,Z)-(1R,2R,3R,5S)-7-(3,5-Dihydroxy-2-((3S)-(3-hydroxy-1-octenyl))cyclopentyl)-5-heptenoic acid Chemical compound CCCCC[C@H](O)C=C[C@H]1[C@H](O)C[C@H](O)[C@@H]1CC=CCCCC(O)=O PXGPLTODNUVGFL-BRIYLRKRSA-N 0.000 description 5
- 101100352919 Caenorhabditis elegans ppm-2 gene Proteins 0.000 description 5
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- 238000004587 chromatography analysis Methods 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 238000002844 melting Methods 0.000 description 5
- 230000008018 melting Effects 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- WGCXTGBZBFBQPP-UHFFFAOYSA-N prostaglandin E2 methyl ester Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CC=CCCCC(=O)OC WGCXTGBZBFBQPP-UHFFFAOYSA-N 0.000 description 5
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- 125000001246 bromo group Chemical group Br* 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 150000001942 cyclopropanes Chemical class 0.000 description 4
- 230000002496 gastric effect Effects 0.000 description 4
- 230000007062 hydrolysis Effects 0.000 description 4
- 238000006460 hydrolysis reaction Methods 0.000 description 4
- 150000004702 methyl esters Chemical class 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N methyl pentane Natural products CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- 150000003180 prostaglandins Chemical class 0.000 description 4
- 230000028327 secretion Effects 0.000 description 4
- 229920002554 vinyl polymer Polymers 0.000 description 4
- ZTUZIGMVTFAJGH-AQHBPOCSSA-N 2-[(1S,2R)-2-carboxycyclopropyl]ethyl-triphenylphosphanium bromide Chemical compound [Br-].C(=O)(O)[C@H]1[C@@H](C1)CC[P+](C1=CC=CC=C1)(C1=CC=CC=C1)C1=CC=CC=C1 ZTUZIGMVTFAJGH-AQHBPOCSSA-N 0.000 description 3
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 3
- 238000011065 in-situ storage Methods 0.000 description 3
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 3
- 238000004809 thin layer chromatography Methods 0.000 description 3
- 210000004291 uterus Anatomy 0.000 description 3
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 2
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
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- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
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- 239000003795 chemical substances by application Substances 0.000 description 2
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- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
- XEYBRNLFEZDVAW-ARSRFYASSA-N dinoprostone Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1C\C=C/CCCC(O)=O XEYBRNLFEZDVAW-ARSRFYASSA-N 0.000 description 2
- 150000002009 diols Chemical class 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
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- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 230000002045 lasting effect Effects 0.000 description 2
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- 239000002243 precursor Substances 0.000 description 2
- 239000001632 sodium acetate Substances 0.000 description 2
- 235000017281 sodium acetate Nutrition 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 239000011701 zinc Substances 0.000 description 2
- 229910052725 zinc Inorganic materials 0.000 description 2
- DZUXGQBLFALXCR-UHFFFAOYSA-N (+)-(9alpha,11alpha,13E,15S)-9,11,15-trihydroxyprost-13-en-1-oic acid Natural products CCCCCC(O)C=CC1C(O)CC(O)C1CCCCCCC(O)=O DZUXGQBLFALXCR-UHFFFAOYSA-N 0.000 description 1
- KWGRBVOPPLSCSI-WPRPVWTQSA-N (-)-ephedrine Chemical compound CN[C@@H](C)[C@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WPRPVWTQSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
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- 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
- 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
- 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
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
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- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 239000012027 Collins reagent Substances 0.000 description 1
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- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 1
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- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
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- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
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- 239000000654 additive Substances 0.000 description 1
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- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
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- 238000001990 intravenous administration Methods 0.000 description 1
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
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- 239000000047 product Substances 0.000 description 1
- 150000003165 prostaglandin E1 derivatives Chemical class 0.000 description 1
- PJDMFGSFLLCCAO-UHFFFAOYSA-N prostaglandin-F2alpha methyl ester Natural products CCCCCC(O)C=CC1C(O)CC(O)C1CC=CCCCC(=O)OC PJDMFGSFLLCCAO-UHFFFAOYSA-N 0.000 description 1
- 230000002997 prostaglandinlike Effects 0.000 description 1
- 210000002307 prostate Anatomy 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
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- NKAAEMMYHLFEFN-ZVGUSBNCSA-M sodium;(2r,3r)-2,3,4-trihydroxy-4-oxobutanoate Chemical compound [Na+].OC(=O)[C@H](O)[C@@H](O)C([O-])=O NKAAEMMYHLFEFN-ZVGUSBNCSA-M 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000005346 substituted cycloalkyl group Chemical group 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 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
( »sar I(»I say
\Ra/ (11) FREMLÆGGELSESSKRIFT 1 421 43 DANMARK (51) int. ci.3 p 07 c 177/00 §(21) Ansøgning nr. 5529/74 (22) Indleveret den 1* Jul. 1974 (24) Løbedag 1 . jul. 197^· (44) Ansøgningen fremlagt og fremlæggelsesskriftet offentliggjort den 8. S ep. 1 980\ Ra / (11) PUBLICATION WRITING 1 421 43 DENMARK (51) int. ci.3 p 07 c Section 177/00 (21) Application No. 5529/74 (22) Filed on 1 * Jul. 1974 (24) Race day 1. Christmas. 197 ^ · (44) The application presented and the writ of publication published on the 8th S ep. 1 980
DIREKTORATET FORDIRECTORATE OF
PATENT- OG VAREMÆRKEVÆSENET <3°) Priori,et fre denTHE PATENT AND TRADEMARK BASIS <3 °) Prior, Fri.
Q. jul. 1975, 9959/75, CH 4. maj 1974, 6049/74, CHQ. Jul. 1975, 9959/75, CH 4 May 1974, 6049/74, CH
<71>SANDOZ A.G., CH-4002 Basel, CH.<71> SANDOZ A.G., CH-4002 Basel, CH.
(72) Opfinder: Pletro Bollinger, 58 Gustnekerstrasse, CK-41C3 Bott= mingen, CH.(72) Inventor: Pletro Bollinger, 58 Gustnekerstrasse, CK-41C3 Bott = mingen, CH.
(74) Fuldmægtig under sagens behandling:(74) Plenipotentiary in the proceedings:
Plougmann & Vlngtpft Patentbureau.__ (54) Analogifremgangsmåde til fremstilling af 2,5-methylenprostaglandin F2alfa- eller E2-derivater.Plougmann & Vlngtpft Patent Bureau. (54) Analogous Process for Preparation of 2,5-Methylene Prostaglandin F2alfa or E2 Derivatives.
Den foreliggende opfindelse angår en analogifremgangsmåde til fremstilling af hidtil ukendte racemiske eller optisk aktive cyclopropan-derivater med den almene formel I 1The present invention relates to an analogous process for the preparation of novel racemic or optically active cyclopropane derivatives of the general formula I
D ~2 3 COOITD ~ 2 3 COOIT
OHOH
hvor D betegner en carbocycel med formlen Ile eller Ild 2 U2U3 hon \where D represents a carbocycle of the formula Ile or Fire 2 U2U3 hon \
VV
110 ✓110 ✓
HOHAY
OISLAND
( Ild ✓(Fire ✓
HOHAY
hvor R^ betegner hydrogen eller en alkylgruppe med 1-8 carbonatomer, en eventuelt alkylsubstitueret cycloalkylgruppe med i alt 3-10 2is hydrogen or an alkyl group of 1-8 carbon atoms, an optionally alkyl-substituted cycloalkyl group having a total of 3-10 2
carbonatomer eller en aralkylgruppe med 7-12 carbonatomer, og Rcarbon atoms or an aralkyl group having 7-12 carbon atoms, and R
3 og R betegner hydrogen eller en alkylgruppe med 1-4 carbonatomer, eller farmakologisk tolerable salte med baser af forbindelser med den almene formel I, hvor R1 er hydrogen.3 and R represents hydrogen or an alkyl group of 1-4 carbon atoms, or pharmacologically tolerable salts with bases of compounds of the general formula I wherein R 1 is hydrogen.
I de her i beskrivelsen angivne formler angiver punkterede forbindelseslinjer, at substituenterne er bundet til cyclopentanringen i a-konfi-guration, dvs, ligger under cyclopentanplanen. Kraftigt optrukne forbindelseslinjer angiver, at substituenterne er bundne til cyclopentanringen i (3-kdnfiguration, dvs. ligger over cyclopentanplanen. Den bølgeformede forbindelseslinje ved carbonatomet i 15-stillingen i formlen I angiver, at hydroxygruppen foreligger i a- eller β-konfiguration.In the formulas set forth herein, dashed connecting lines indicate that the substituents are bound to the cyclopentane ring in α-configuration, i.e., are below the cyclopentane plane. Strongly drawn connecting lines indicate that the substituents are bound to the cyclopentane ring in (3-kdn configuration, i.e., above the cyclopentane plane. The wavy connecting line at the carbon atom at the 15-position of formula I indicates that the hydroxy group is in α or β configuration.
Med hensyn til formlen X kan som eksempler på eventuelt alkylsubstituerede cycloalkylgrupper med i alt 3-10 carbonatomer angives cyclopro-pyl, 2-methylcyclopropyl, 2,2-dimethylcyclopropy1, 2,3-diethylcyclopro-pyl, 2-butylcyclopropyl, cyclobutyl, 2-methylcyclobutyl, 3-propylcyclo-butyl, 2,3,4-triethylcyclobutyl, cyclopentyl, 2,2-dimethylcyclopentyl, 2-pentylcyclopenty1, 3-tert.butylcyclopentyl, cyclohexyl, 4-tert.butyl-cyclohexyl, 3-isopropylcyclohexyl, 2,2-dimethylcyclohexyl, cycloheptyl cyclooctyl, cyclononyl og cyclodecyl. Som eksempler på aralkylgrup-per med 7-12 carbonatomer kan angives benzyl, phenethyl, 1-phenyl-ethyl, 2-phenylpropyl, 4-phenylbutyl, 3-phenylbuty1, 2-(1-naphthylethyl) og 1-(2-naphthylmethy1)- U2U3 3With respect to Formula X, examples of optionally alkyl-substituted cycloalkyl groups having a total of 3-10 carbon atoms may be mentioned cyclopropyl, 2-methylcyclopropyl, 2,2-dimethylcyclopropyl, 2,3-diethylcyclopropyl, 2-butylcyclopropyl, cyclobutyl, 2- methylcyclobutyl, 3-propylcyclobutyl, 2,3,4-triethylcyclobutyl, cyclopentyl, 2,2-dimethylcyclopentyl, 2-pentylcyclopentyl, 3-tert.butylcyclopentyl, cyclohexyl, 4-tert.butylcyclohexyl, 3-isopropylcycloentyl 2-dimethylcyclohexyl, cycloheptyl cyclooctyl, cyclononyl and cyclodecyl. As examples of aralkyl groups having 7-12 carbon atoms may be mentioned benzyl, phenethyl, 1-phenylethyl, 2-phenylpropyl, 4-phenylbutyl, 3-phenylbutyl, 2- (1-naphthylethyl) and 1- (2-naphthylmethyl) - U2U3 3
De hidtil ukendte cyclopropanderivater med den almene formel IThe novel cyclopropane derivatives of the general formula I
fremstilles ved fremgangsmåden ifølge opfindelsen, der er ejendom- 4is produced by the method according to the invention, which is property 4
melig ved, at beskyttelsesgruppen eller -grupperne R ved hydrolyse fraspaltes i forbindelser med den almene formel IIIpreferably by splitting the protecting group or groups R by hydrolysis into compounds of the general formula III
COOR^- IIICOOR ^ - III
OR4 12 3 4 hvor R , R og R hver har den ovenfor angivne betydning, R betegner en trialkylsilyl- eller tetrahydropyranylgruppe, og A betegner en carbocyclen med formlen Ile eller IlfOR4 12 3 4 wherein R, R and R are each as defined above, R represents a trialkylsilyl or tetrahydropyranyl group, and A represents a carbocycle of formula Ile or Ilf
HOHAY
\ Ile\ Ile
Va / 4 /Va / 4 /
R^OR ^ O
0.0th
Χχχ 4 ^Χχχ 4 ^
R^OR ^ O
hvorefter, om ønsket, til fremstilling af forbindelser med den almene formel I, hvor er hydrogen, fremstillede forbindelser med den almene formel I, hvor R1 er en alkylgruppe med 1-8 carbonatomer, en eventuelt alkylsubstitueret cycloalkylgruppe med i alt 3 -10 carbonatomer eller en aralkylgruppe med 7-12 carbonatomer, ved hydrolyse omdannes til de frie syrer, hvorefter, om ønsket, til fremstilling af forbindelser med den almene formel I, hvor R"*- er en alkylgruppe med 1-8 carbonatomer, en eventuelt alkylsubstitueret cycloalkylgruppe med i alt 3-10 carbonatomer eller en aralkylgruppe med 7-12 carbonatomer, forbindelser med den almene formel I, hvor R er hydrogen, forestres med et til denne betydning af R svarende U2U3 4 forestringsmiddel, hvorefter, om ønsket, til fremstilling af farmaceutisk tolerable salte med baser af forbindelser med den almene formel I, forbindelser med den almene formel I, hvor R1 er hydrogen, behandles med tilsvarende uorganiske eller organiske baser.then, if desired, for the preparation of compounds of general formula I wherein hydrogen is prepared compounds of general formula I wherein R 1 is an alkyl group of 1-8 carbon atoms, an optionally alkyl-substituted cycloalkyl group having a total of 3-10 carbon atoms or an aralkyl group of 7-12 carbon atoms is converted by hydrolysis to the free acids and then, if desired, to prepare compounds of general formula I wherein R R is an alkyl group of 1-8 carbon atoms, an optionally alkyl-substituted cycloalkyl group having a total of 3-10 carbon atoms or an aralkyl group of 7-12 carbon atoms, compounds of the general formula I wherein R is hydrogen is esterified with an ester corresponding to R 2 U 2 U 3 4 esterifying agent and, if desired, for the preparation of pharmaceutically acceptable salts with bases of compounds of general formula I, compounds of general formula I wherein R 1 is hydrogen are treated with corresponding inorganic or organic bases.
Trialkylsilylgruppen indeholder fortrinsvis 1-6 carbonatomer.The trialkylsilyl group preferably contains 1-6 carbon atoms.
Hydrolysen af tetrahydropyranyl- og/eller trialkylsilylgrupperne udføres på kendt måde, fortrinsvis med eddikesyre/tetrahydrofuran/vand eller med methanol/saltsyre eller svovlsyre ved temperaturer mellem -10 og +150"G.The hydrolysis of the tetrahydropyranyl and / or trialkylsilyl groups is carried out in known manner, preferably with acetic acid / tetrahydrofuran / water or with methanol / hydrochloric acid or sulfuric acid at temperatures between -10 and +150 ° G.
De som udgangsforbindelser anvendte forbindelser med den almene formel IllaThe starting compounds used are compounds of the general formula IIla
Illa OR4Bad OR4
hvor R*, R^, og R4 hver har den ovenfor angivne betydning/ og A' betegner carbocyclen med formlen IXf, er hidtil ukendte og kan fremstilles ved, at en forbindelse med den almene formel IVwherein R 1, R 2, and R 4 each have the meaning given above and A 'represents the carbocycle of formula IXf, are novel and can be prepared by a compound of general formula IV
3» 2 3 4 hvor R , R , R og r hver har den ovenfor angivne betydning, og G betegner carbocyclen med formlen Ile, oxideres. Et til oxidation egnet reagens er Collins-reagenset (pyridin-chromtrioxid), Jones-reagenset (Cr03/H'/acetone) samt sulfid-reagenset U2U3 "C;z ci eiier r>>3, 2 3 4 where R, R, R and r each have the meaning given above and G represents the carbocycle of formula Ile is oxidized. One oxidation suitable reagent is the Collins reagent (pyridine chromium trioxide), the Jones reagent (Cr03 / H '/ acetone) and the sulfide reagent U2U3 "C; z ci eier r >>
Cl- « o idet man i dette sidst angivne tilfælde, når der som udgangsmateriale anvendes en carboxylsyre, fortrinsvis beskytter denne, f.eks. med en tert.butyldimethylsilylgruppe.Cl - in the latter case, when a carboxylic acid is used as starting material, it preferably protects, e.g. with a tert.butyldimethylsilyl group.
Forbindelser med den almene formel IV kan fremstilles ved, at den kendte forbindelse med den almene formel VCompounds of general formula IV can be prepared by the known compound of general formula V
EE
OR4 2 3 4 hvor R , R og R hver har den ovenfor angivne betydning, og E betegner en carbocycel med formlen Vc A'OR4 2 3 4 wherein R, R and R each have the meaning given above and E represents a carbocycle of the formula Vc A '
,A, A
RORO
44
idet den ved symbolet R i formlen Vc angivne gruppe har den ovenfor angivne betydning, omsættes med en forbindelse med den almene formel VIwherein the group represented by the symbol R in the formula Vc has the meaning given above, is reacted with a compound of the general formula VI
*Θ Λ i* Θ Λ i
5 ff) / \ ^COOR5 ff) / \ ^ COOR
(r3)3p ^-ch2-ch^--VI(r3) 3p ^ -ch2-ch ^ - VI
1 5 hvor R har den ovenfor angivne betydning, R betegner en naphthyl- eller phenylgruppe, som er usubstitueret,eller som er substitueret 6 1421 A3 med en lavere alkylgruppe, eller betegner en lavere alkylgruppe, og X betegner chlor, iod eller brom.Wherein R is as defined above, R represents a naphthyl or phenyl group which is unsubstituted or substituted by a lower alkyl group, or represents a lower alkyl group, and X represents chlorine, iodine or bromine.
Omsætningen udføres på i og for sig kendt måde, f.eks. ved en Wittig--reaktion, fortrinsvis i dimethylsulfoxid ved temperaturer mellem 20 og 8QeC.The reaction is carried out in a manner known per se, e.g. by a Wittig reaction, preferably in dimethyl sulfoxide at temperatures between 20 and 8 ° C.
De som udgangsforbindelser anvendte forbindelser med den almene for-1 5The compounds used as starting compounds with the general precursor
mel VI, hvor R , R og X hver har den ovenfor angivne betydning, er hidtil ukendte og kan f.eks. fremstilles ved, at den kendte 4-halogen--1-buten med den almene formel VIIflour VI, wherein R, R and X each have the meaning given above, are novel and can e.g. is prepared by the known 4-halogen-1-butene of the general formula VII
x-ch2-ch2-ch=ch2 VIIx-ch2-ch2-ch = ch2 VII
hvor X betegner chlor, iod eller brom, omsættes med den kendte diazo-eddikesyrealkylester med den almene formel VIIIwherein X represents chloro, iodo or bromo, reacted with the known diazoacetic acid alkyl ester of the general formula VIII
n2ch-coor,;l VIIIn2ch-coor,; l VIII
hvor R' ^ betegner en alkylgruppe med 1-8 carbonatomer, den vundne isomerblanding bestående af cyclopropancarboxylsyrealkylestere med den almene formel IXrepresents an alkyl group of 1-8 carbon atoms, the isomer mixture obtained consisting of cyclopropane carboxylic acid alkyl esters of the general formula IX
CH_ 2 \ iCH_ 2 \ i
X-CH2-CH2-CH-CH-COOR'x IXX-CH2-CH2-CH-CH-COOR'x IX
hvor R'^ og X hver har den ovenfor anførte betydning, opspaltes i de cis- og trans-isomere, hvorefter estergruppen eventuelt hydrolyseres, hvorefter der eventuelt udføres en racematopspaltning, hvorefter den fri syre på i og for sig kendt måde eventuelt forestres til dannelse af en ester med en alkohol med formlen R'^-OH, hvor R"1 har samme betydning som R1, bortset fra hydrogen, og hvorefter der omsættes jwherein R 'and X each have the meaning given above are cleaved in the cis and trans isomers, then the ester group is optionally hydrolyzed, then a racemate cleavage is optionally performed, and the free acid is optionally esterified to form of an ester having an alcohol of the formula R 1 - OH, wherein R 1 is the same as R 1, except hydrogen, and then reacting
med en phosphinforbindelse med den almene formel Xwith a phosphine compound of the general formula X
5 i5 i
(R )3P X(R) 3P X
5 hvor R har den ovenfor angivne betydning.5 where R has the meaning given above.
De hidtil ukendte cyclopropanderivater med den almene formel I, hvor IThe novel cyclopropane derivatives of general formula I wherein I
R1 er hydrogen, kan omdannes til farmaceutisk tolerable salte ved, at de f.eks. neutraliseres med en tilsvarende mængde af uorganiske eller organiske baser.R 1 is hydrogen, can be converted to pharmaceutically tolerable salts by, e.g. neutralized with a corresponding amount of inorganic or organic bases.
7 U2U37 U2U3
Farmakologisk tolerable salte af slutprodukter med den almene formel I er sådanne med farmakologisk tolerable metalkationer, ammonium-og aminkationer eller kvaternære ammoniumkationer.Pharmacologically tolerable salts of end products of general formula I are those with pharmacologically tolerable metal cations, ammonium and amine cations or quaternary ammonium cations.
Optisk aktive forbindelser kan under anvendelse af den ovenfor beskrevne syntese fremstilles ud fra optisk aktive mellemprodukter. Såfremt der anvendes racemiske mellemprodukter, fås racemiske slutprodukter, og disse eller forstadiumforbindelser deraf kan derefter på i og for sig kendt måde opspaltes i de optisk aktive isomere deraf.Optically active compounds can be prepared from optically active intermediates using the synthesis described above. If racemic intermediates are used, racemic end products are obtained and these or precursor compounds thereof can then be resolved in a manner known per se in the optically active isomers thereof.
Ved fremgangsmåden ifølge opfindelsen fremstilles syrer, når er hydrogen, og estere, når R^ er en alkylgruppe med 1-8 carbonatomer, en eventuelt alkylsubstitueret cycloalkylgruppe med i alt 3-10 carbonatomer eller en aralkylgruppe med 7 - 12 carbonatomer. Såfremt der er fremstillet en syre, kan denne omdannes til en ester med formlen I, hvor R·*· betegner en alkylgruppe med 1-8 carbonatomer, en eventuelt substitueret cycloalkylgruppe med i ålt 3-10 carbonatomer eller en aralkylgruppe med 7-12 carbonatomer med et til denne betydning af R1 svarende forestringsmiddel. Såfremt slutprodukterne foreligger i form af estere, kan disse ved hydrolyse omdannes til de frie syrer.In the process of the invention, acids when hydrogen and esters are prepared when R 1 is an alkyl group of 1-8 carbon atoms, an optionally alkyl-substituted cycloalkyl group having a total of 3-10 carbon atoms, or an aralkyl group of 7-12 carbon atoms. If an acid is prepared, it can be converted to an ester of formula I wherein R R represents an alkyl group of 1-8 carbon atoms, an optionally substituted cycloalkyl group of 3-10 carbon atoms or an aralkyl group of 7-12 carbon atoms. with an ester corresponding to this meaning of R1. If the final products are in the form of esters, these can be converted to the free acids by hydrolysis.
De hidtil ukendte cyclopropanderivater med den almene formel I er yderst virksomme til at frembringe forskellige biologiske reaktioner og skal derfor anvendes til farmakologiske formål. Som eksempler på sådanne reaktioner kan angives: en uterusstimulerende virkning, en inhibering af mavesekretionen, en bronchodilatatorisk virkning, en formindskelse af det arterielle blodtryk, en nasal dekongestation, en inhibering af blodpladeaggregationen samt en hudtransplantations-fremmende virkning.The novel cyclopropane derivatives of the general formula I are highly effective in producing various biological reactions and must therefore be used for pharmacological purposes. Examples of such reactions may be cited: a uterine stimulating effect, an inhibition of gastric secretion, a bronchodilatory effect, a decrease in arterial blood pressure, a nasal decongestation, an inhibition of platelet aggregation, and a skin graft-promoting effect.
De forskellige PGFjq- analoge forbindelser med den almene formel i er virksomme på uterus in situ i doser på 1 - 100 mikrogram. Forbindelserne er egnede til igangsætning af fødsler, til elimination af en tilbageholdt abort og til menstruationsinduktion. Til dette formål anvendes 0,1 - 20 mg/kg afhængigt af applikationen pr. dag.The various PGFjq analogous compounds of the general formula i are effective on uterus in situ at doses of 1 - 100 micrograms. The compounds are suitable for initiating births, for eliminating a delayed abortion and for menstrual induction. For this purpose, 0.1 - 20 mg / kg is used depending on the application per day. day.
De forskellige PGF2a-analoge forbindelser med den almene formel I er endvidere egnede til formindskelse og undertrykkelse af en for stærk mavesekretion. Den mavesekretionshæmmende virkning kunne påvises på pentagastrin- og histamininducerede 142U3 δ mavesekretioner hos rotter i doser på 1 - lOO^ug/kg. De hidtil u-kendte forbindelser med den almene formel I er virksomme på rottemavestrimler i doser på 1 - 100^ug. Den mængde, som skal indgives, lig ger i doser på ca. 0,1 - 20^ug pr. kg legemsvægt pr. dag.Furthermore, the various PGF2α analogous compounds of general formula I are useful for reducing and suppressing excessive gastric secretion. The gastric secretion inhibitory effect was detectable on pentagastrin- and histamine-induced 142U3 δ gastric secretions in rats at doses of 1 - 100 µg / kg. The novel compounds of the general formula I are effective on rat stomach strips at doses of 1 - 100 µg. The amount to be administered is in doses of approx. 0.1-20 µg per kg body weight per day.
De forskellige forbindelser med den almene formel I er egnede som opsvulmningshæmmende. midler til næsen hos pattedyr såsom mennesker. Til dette formål anvendes forbindelserne i mængder på fra ca. 10^ug til ca. 20 mg pr. ml af et farmakologisk egnet flydende middel.The various compounds of general formula I are suitable as swelling inhibitors. remedies for the nose of mammals such as humans. For this purpose, the compounds are used in amounts of from ca. 10 µg to approx. 20 mg per ml of a pharmacologically suitable liquid agent.
De forskellige PGE2“ °9 PGF2a-forbindelser med den almene formel X er endvidere egnede til behandling af astma. Der kan fortrinsvis anvendes mængder på fra ca. 0,1 til 20^ug pr. kg legemsvægt 1 -4 gange pr. dag.Furthermore, the various PGE 2 9 PGF2a compounds of general formula X are suitable for the treatment of asthma. Preferably, amounts of from about 10 to about 100 may be used. 0.1 to 20 µg per kg body weight 1 -4 times per day.
De forskellige PGE2~ og PGF2a-forbindelser med den almene formel I er også egnede til hæmning af blodpladeaggregationen. Den mængde, som skal indgives, ligger i doser på ca. 0,1 og ca. 20^ug pr. kg legemsvægt pr. dag.The various PGE2 and PGF2a compounds of general formula I are also useful for inhibiting platelet aggregation. The amount to be administered is in doses of approx. 0.1 and approx. 20 µg pr. kg body weight per day.
De forskellige PGE^fo^indelser med den almene formel I er egnede til sænkning af blodtrykket. Til dette formål administreres forbindelserne i enkeltdoser eller i flere deldoser med i alt 0,1 -20^ug pr. kg legemsvægt pr. dag.The various PGE1 compounds of general formula I are suitable for lowering blood pressure. For this purpose, the compounds are administered in single doses or in multiple sub doses at a total of 0.1 -20 µg per ml. kg body weight per day.
Medens de kendte prostaglandiner inden for mange anvendelsesområder kun udviser en kortvarig biologisk virkning, udviser de ved fremgangsmåden ifølge opfindelsen fremstillede hidtil ukendte forbindelser foruden en mere specifik virkning ved fremkaldelse af prostaglandin-lignende reaktioner en betydelig længere varende virkning. På grund af den længere varende virkning er det tilstrækkeligt at anvende færre og mindre doser af de hidtil ukendte forbindelser til opnåelse af en bestemt virkning. Til de angivne formål administreres de hidtil ukendte forbindelser i forskellige doseringsformer, f.eks. oralt i form af tabletter, kapsler eller væsker, rektalt i form af suppositorier eller subcutant, intramuskulært eller intravenøst.While the known prostaglandins in many fields of application exhibit only a short-term biological effect, the novel compounds prepared by the process of the invention exhibit a significantly longer lasting effect in addition to a more specific effect in eliciting prostaglandin-like reactions. Due to the longer lasting effect, it is sufficient to use fewer and smaller doses of the novel compounds to achieve a particular effect. For the purposes stated, the novel compounds are administered in various dosage forms, e.g. orally in the form of tablets, capsules or fluids, rectally in the form of suppositories or subcutaneously, intramuscularly or intravenously.
9 U2U39 U2U3
Til påvisning af de ved fremgangsmåden ifølge opfindelsen fremstillede forbindelsers særlige fordelagtige virkning i forhold til kendte prostaglandiner er foretaget sammenligningsforsøg, og resultaterne fremgår af nedenstående tabel. Virkningen på rotteuterus in situ er bestemt efter metoden i henhold til G.W. Bisset, J. Haidar, Z.E. Lewin "Memoirs of the Society for Endocrinology",In order to demonstrate the particular beneficial effect of the compounds prepared by the process according to the invention compared to known prostaglandins, comparative experiments have been made and the results are shown in the table below. The effect on rat uterus in situ is determined by the method of G.W. Bisset, J. Haidar, Z.E. Lewin "Memoirs of the Society for Endocrinology",
No. 14, Endogenous substances affecting the myometrium, edited by V.R. Pickles and R.J. Fitzpatrick, Cambridge University Press 1966, 185 - 198.No. 14, Endogenous substances affecting the myometrium, edited by V.R. Pickles and R.J. Fitzpatrick, Cambridge University Press 1966, 185 - 198.
TabelTable
Virkning på rotteuterus in situ efter intravenøs administration (middelværdi, n = 3) Tærskel- " Virkningsvarighed dosis (2 x tærskeldosis,Effect on rat uterus in situ after intravenous administration (mean, n = 3) Threshold "Effect duration dose (2 x threshold dose,
Nr. Forbindelse ^,ug/kg minutter) 1 16,16-dimethyl-2,3-trans(+)--methylenorostaglandin F« (eksempel" 3) 6,7 135 2 Prostaglandin F2a(kendt) 6,7 6 3 16,16-dimethyl-2,3-trans(-)--methylenprostaglandin E2 (eksempel 9) 0,11 83 4 prostaglandin E2 (kendt) 5 10 5 16,16-dimethyl-2,3-trans(-)--methylenprostaglandin E2- -methylester (eksempel 10) 0,053 105 6 (5Ζ,11α,13Ε,15α,16a)-11,15--dihydroxy-9-keto-16-methyl--2,3-trans(-)methvlenprosta- -5,13-diensyre (eksempel 14) o,42 127 7 16,16-dimethylprostaglandin F2a (kendt) 0,83 14 8 Prostaglandin F2q (kendt) 8,3 9No. Compound (µg / kg minutes) 1 16,16-Dimethyl-2,3-trans (+) - methylenorostaglandin F (Example 3) 6.7 135 2 Prostaglandin F2a (known) 6.7 6 3 16, 16-dimethyl-2,3-trans (-) - methylene prostaglandin E2 (Example 9) 0.11 83 4 prostaglandin E2 (known) 5 10 5 16,16-dimethyl-2,3-trans (-) - methylene prostaglandin E2-methyl ester (Example 10) (5Ζ, 11α, 13Ε, 15α, 16a) -11,15-dihydroxy-9-keto-16-methyl-2,3-trans (-) methylene prostate 5,13-diacetic acid (example 14) o, 42 127 7 16,16-dimethylprostaglandin F2a (known) 0.83 14 8 Prostaglandin F2q (known) 8.3 9
Det fremgår af tabellen, at indføringen af hindrende grupper i stilling 16, f.eks. ved 16,16-dimethyl-prostaglandinF2a (tysk offentliggørelsesskrift nr. 2 217 044), allerede fører til en forlængelse af virkningsvarigheden, halveringstiden er af størrelsesordenen 10 minutter (forbindelse nr. 7). Først den samtidige tilstedeværelse af en cyclopropanrest i stilling 2,3 fører imidlertid 142143 ίο til en væsentlig forlængelse af virkningstiden (halveringstid flere timer, forbindelserne nr. 1, 3, 5 og 6 i tabellen). Til sammenligningsformål er der i tabellen ligeledes anført virkningsvarigheden af kendte prostaglandiner (forbindelserne nr.It can be seen from the table that the introduction of hindering groups in position 16, e.g. at 16,16-dimethyl-prostaglandin F2a (German Publication No. 2,217,044), already leads to an extension of the duration of action, the half-life being of the order of 10 minutes (compound # 7). First, however, the simultaneous presence of a cyclopropane residue at position 2.3 leads to a substantial extension of the action time (half-life of several hours, compounds Nos. 1, 3, 5 and 6 in the table). For comparison purposes, the table also lists the duration of action of known prostaglandins (compounds no.
2, 4, 7 oq 8).2, 4, 7 and 8).
De hidtil ukendte forbindelser kan som lægemidler administreres i egnede lægemiddelformer sammen med farmakologisk inerte hjælpestoffer.The novel compounds can be administered as drugs in suitable drug forms together with pharmacologically inert excipients.
Fremgangsmåden ifølge opfindelsen belyses nærmere ved de følgende eksempler:The process according to the invention is further illustrated by the following examples:
Eksempel 1.Example 1.
2,3-Trans-methylen-prostaglandin F2a· 40 mg 2,3-methylen-trans-ll,15-bis-tetrahydropyranylprostaglandin F2a opløses i 2 ml af en blanding af eddikesyre, tetrahydrofuran og vand (3:1:1), og opløsningen opvarmes i 2 timer ved 60*C.2,3-Trans-methylene-prostaglandin F2a · 40 mg of 2,3-methylene-trans-11, 15-bis-tetrahydropyranylprostaglandin F2a is dissolved in 2 ml of a mixture of acetic acid, tetrahydrofuran and water (3: 1: 1), and the solution is heated for 2 hours at 60 ° C.
Efter inddampning under reduceret tryk opspaltes remanensen på 3 g silicagel med chloroform indeholdende 17% methanol, hvorved der fås den rene i overskriften angivne forbindelse med smeltepunkt 108 - 112°C.After evaporation under reduced pressure, the residue is cleaved on 3 g of silica gel with chloroform containing 17% methanol to give the pure title compound, mp 108 - 112 ° C.
NMR-spektrum (CDClg) 90 MHz, bl.a. signaler ved: 4 H (m) 5,45 vinylprotoner 3 H 3,8 - 4,2 ppm CH-OH 3 H (^) 0,9 ppm methyl.NMR spectrum (CDCl3) 90 MHz, i.a. signals at: 4 H (m) 5.45 vinyl protons 3 H 3.8 - 4.2 ppm CH-OH 3 H (^) 0.9 ppm methyl.
Den som udgangsforbindelse anvendte 2,3-trans-methylen-ll,15-bis--tetrahydropyranylprostaglandin F2a fremstilles på følgende måde: a) 2-(2-Bromethyl)-cyclopropancarboxylsyreethylester.The 2,3-trans-methylene-1,1,15-bis-tetrahydropyranylprostaglandin F2a used as the starting compound is prepared as follows: a) 2- (2-Bromethyl) -cyclopropane carboxylic acid ethyl ester.
Til en til 100°C opvarmet suspension af 2,48 g kobberpudder i 22 g 4-brom-l-buten sættes langsomt under kraftig omrøring dråbevis 40 ml diazoeddikesyreethylester. Efter 2 timer ved 100°C filtreres blandingen, og de cis-trans-isomere cyclopropylcarboxylsyreestere opspaltes ved chromatografering på 900 g silicagel med benzen som eluerings-middel.To a suspension of 2.48 g of copper powder heated in 22 g of 4-bromo-1-butene, slowly add 40 ml of diazoacetic acid ethyl ester dropwise with vigorous stirring. After 2 hours at 100 ° C, the mixture is filtered and the cis-trans isomeric cyclopropylcarboxylic acid esters are decomposed by chromatography on 900 g of silica gel with benzene as the eluent.
u U2K3u U2K3
Trans-cyclopropan-2-(2-bromethy1)-carboxylsyreethylester.Trans-cyclopropane-2- (2-bromethy1) -carboxylic acid ethyl ester.
IR-spektrum (methylenchlorid), bl.a. bånd vad: 1710, 1420, 1200 og 1180 cm"1.IR spectrum (methylene chloride), i.a. bands what: 1710, 1420, 1200 and 1180 cm "1.
NMR-spektrum (CDC13) 60 MHz, bl.a. signaler ved: 2 H 4,17 ppm (0-CH2-CH3) 2 H 3,45 ppm (-CH2-CH2~Br) 3 H 1,25 ppm (CH3-CH2-} M+ = 220.NMR spectrum (CDCl3) 60 MHz, i.a. signals at: 2 H 4.17 ppm (0-CH 2 -CH 3) 2 H 3.45 ppm (-CH 2 -CH 2 ~ Br) 3 H 1.25 ppm (CH 3 -CH 2 -} M + = 220.
b) Trans-cyclopropan-2-(2-bromethyl)-carboxylsyre.b) Trans-cyclopropane-2- (2-bromethyl) carboxylic acid.
Til en til 0eC afkølet blanding af 6,4 ml 33%'s brombrintesyre og 1,7 ml koncentreret svovlsyre sættes under kraftig omrøring 1 g trans-cyclopropan-2-(2-bromethyl)-carboxylsyreethylester. Efter 1 time ved stuetemperatur opvarmes opløsningen i 15 minutter ved 100°C. Den afkølede opløsning hældes på 60 ml kold, mættet aramonium-sulfatopløsning og ekstraheres tre gange med methylenchlorid, og de samlede ekstrakter vaskes med vand, tørres og inddampes under reduceret tryk. Remanensen opspaltes på 40 g sillcagel med chloroform i 1% methanol (50 ml's fraktioner), hvorved fås den i overskriften angivne forbindelse.To a cooled mixture of 6.4 ml of 33% hydrochloric acid and 1.7 ml of concentrated sulfuric acid is added with vigorous stirring 1 g of trans-cyclopropane-2- (2-bromoethyl) carboxylic acid ethyl ester. After 1 hour at room temperature, the solution is heated for 15 minutes at 100 ° C. The cooled solution is poured onto 60 ml of cold saturated aramonium sulfate solution and extracted three times with methylene chloride and the combined extracts are washed with water, dried and evaporated under reduced pressure. The residue is cleaved on 40 g of sillcagel with chloroform in 1% methanol (50 ml fractions) to give the title compound.
IR-spektrum (methylenchlorid), bl.a. bårid ved: 3450 - 2700, 1700, 1460, 1215 cm"1.IR spectrum (methylene chloride), i.a. drilling time at: 3450 - 2700, 1700, 1460, 1215 cm "1.
NMR-spektrum (CDC13) 60 MHz, bl.a. signaler ved: 1 H 10,5 ppm (-COOH) 2 H 3,42 ppm (-CH2-OH2-Br) 2 H 1,83 ppm (CH-CH2-CH2-) M+ = 193.NMR spectrum (CDCl3) 60 MHz, i.a. signals at: 1H 10.5 ppm (-COOH) 2H 3.42 ppm (-CH2-OH2-Br) 2H 1.83 ppm (CH-CH2-CH2-) M + = 193.
Trans-cyclopropan-2-(2-bromethyl)-carboxylsyremethylester.Trans-cyclopropane-2- (2-bromoethyl) -carboxylic acid methyl ester.
200 mg af trans-syren opløses i 10 ml methanol og behandles ved stuetemperatur (20*C) med en etherisk diazomethanopløsning. Efter fjernelse af opløsningsmidlet under reduceret tryk chromatograferes remanensen (220 mg) på silicagel med benzen, hvorved fås den tilsvarende methylester.Dissolve 200 mg of the trans acid in 10 ml of methanol and treat at room temperature (20 ° C) with an ethereal diazomethane solution. After removal of the solvent under reduced pressure, the residue (220 mg) is chromatographed on silica gel with benzene to give the corresponding methyl ester.
142143 12 iR-spektrum (methylenchlorid), bl.a. bånd ved: 1720, 1210, 1120 cm"1.12R spectrum (methylene chloride), i.a. bands at: 1720, 1210, 1120 cm "1.
NMR-spektrum (CDCl^) 100 MHz, bl.a. signaler ved: 3 H 3,68 ppm COOCH-, 2 H 3,45 (t) CH2-Br 2 H 1,9 (m) CH2-CH2-Br.NMR spectrum (CDCl3) 100 MHz, i.a. signals at: 3H 3.68 ppm COOCH-, 2H 3.45 (t) CH2-Br 2H 1.9 (m) CH2-CH2-Br.
Den samme forbindelse kan fremstilles ved behandling af trans-syren med 3-methyl-l-p-tolyltriazin.The same compound can be prepared by treating the trans acid with 3-methyl-1-p-tolyltriazine.
c) 2-(2-Carboxy-l-trans-cyclopropyl)-ethyl-triphenylphosphonium-bromid.c) 2- (2-Carboxy-1-trans-cyclopropyl) -ethyl-triphenylphosphonium bromide.
Til 5 g (-)-trans-cyclopropan-2-(2-bromethyl)-carboxylsyre i 100 ml absolut benzen sættes 10 g triphenylphosphin, og der koges i 42 timer under tilbagesvaling. Efter fjernelse af opløsningsmiddel under reduceret tryk opspaltes remanensen på 600 g silicagel med en chlo-roform-methanol-eddikesyreblanding (300 ml's fraktioner), hvorved fås den i overskriften angivne forbindelse.To 5 g of (-) - trans-cyclopropane-2- (2-bromethyl) carboxylic acid in 100 ml of absolute benzene is added 10 g of triphenylphosphine and refluxed for 42 hours. After removal of solvent under reduced pressure, the residue is cleaved on 600 g of silica gel with a chloroform-methanol-acetic acid mixture (300 ml fractions) to give the title compound.
IR-spektrum (methylenchlorid), bl.a. bånd ved: 3400 - 3000, 1725, 1440, 1115 cm"1.IR spectrum (methylene chloride), i.a. bands at: 3400 - 3000, 1725, 1440, 1115 cm "1.
NMR-spektrum (CDCl^) 60 MHz, bl.a. signaler ved: 15 H 7,75 ppm (aromatisk H) 2 H 3,8 ppm (CHq - P -)· d) 2,3-Trans-methylen-ll,15-bis-tetrahydropyranylprostaglandin F2a.NMR spectrum (CDCl3) 60 MHz, i.a. signals at: 15 H 7.75 ppm (aromatic H) 2 H 3.8 ppm (CH 2 - P -) · d) 2,3-Trans-methylene-11, 15-bis-tetrahydropyranylprostaglandin F2a.
70 mg natriumhydrid opløses i 0,7 ml dimethylsulfoxid og holdes i 40 minutter ved 75°C under nitregen. Efter afkøling sættes triphenylphos-phoniumsaltet af (-)-ethyl-trans-cyclopropancarboxylsyre i 1 ml abso-. lut dimethylsulfoxid til den brune opløsning.70 mg of sodium hydride are dissolved in 0.7 ml of dimethyl sulfoxide and kept for 40 minutes at 75 ° C under the nitrate. After cooling, the triphenylphosphonium salt of (-) - ethyl trans-cyclopropane carboxylic acid is added in 1 ml of abso-. add dimethyl sulfoxide to the brown solution.
142143 13142143 13
Derefter omrøres i 1,5 timer ved stuetemperatur, hvorefter der til 1,2 ml af denne opløsning sættes 145 mg 2p^(3ra-tetrahydro-py ranyloxy-1'-transocteny1)-5«-hydroxy-3a~tettahydropyranyloxy-cyclopentan-acetaldehydlactol. Reaktionsblandingen lades henstå 1 15 minutter ved stuetemperatur, opvarmes i 3 timer ved 75’Cj hældes derefter på 20 g is, indstilles forsigtigt på en pH-værdi på 3 og ekstraheres med methylenchlorid. Ved chromatografering på 20 g silicagel med chloroform og 2% methanol fås den i overskriften angivne forbindelse i ren form.Then stir for 1.5 hours at room temperature, then 145 mg of 2β (3α-tetrahydro-pyranyloxy-1'-transoctenyl) -5β-hydroxy-3α-tetahydropyranyloxy-cyclopentane are added to 1.2 ml of this solution. acetaldehydlactol. The reaction mixture is allowed to stand for 15 minutes at room temperature, heated for 3 hours at 75 ° C, then poured onto 20 g of ice, carefully adjusted to a pH of 3 and extracted with methylene chloride. Chromatography on 20 g of silica gel with chloroform and 2% methanol gives the title compound in pure form.
iR-spektrum (methylenchlorid), bl.a. bånd vedi 3500, 1710 cm-1.iR spectrum (methylene chloride), i.a. ribbon at 3500, 1710 cm -1.
NMR-spektrum (CDCl-j) 90 MHz, bl.a. signaler ved,.: 4 H (m) 5,4 ppm 2 H 4,7 ppm 3 H (¾-) 0,9 ppm.NMR spectrum (CDCl3) 90 MHz, i.a. signals at: 4 H (m) 5.4 ppm 2 H 4.7 ppm 3 H (¾-) 0.9 ppm.
Eksempel 2.Example 2.
I analogi med eksempel 1 og under anvendelse af tilsvarende udgangsforbindelser fremstilles følgende forbindelser med fora- ; len I: a) 2,3-Cis-methylenprostaglandin NMR-spektrum (CDCl^) 90 MHz bl.a. signaler ved: 4H 0,68 - 0,91 ppm _CH3,/<2By analogy to Example 1 and using similar starting compounds, the following compounds are prepared with forums; lane I: a) 2,3-Cis-methylene prostaglandin NMR spectrum (CDCl3) 90 MHz i.a. signals at: 4H 0.68 - 0.91 ppm _CH3, / <2
7H 1,9 - 2,4 ppm aliphafisk H7H 1.9 - 2.4 ppm aliphaphic H
3H 3,51-4,16 ppm ^CHOH3H 3.51-4.16 ppm ^ CHOH
4H 5,15-5,75 ppm vinylprotoner.4H 5.15-5.75 ppm vinyl protons.
IR-spektrum (methylenchlorid), bl.a. bånd ved; 3580, 3400, 1710 - 1695 cm"1.IR spectrum (methylene chloride), i.a. ribbon by; 3580, 3400, 1710 - 1695 cm "1.
142143 14 b) 2/3-Cis-methylenprostaglandin P2a^methylester.B) 2/3-Cis-methylene prostaglandin P2a ^ methyl ester.
NMR-spektrum (CDGlj) 90 MHz bl.a. signaler ved: 4H 0,68 - 0,89 ppm -ΟΗ3,-<£Γ-NMR spectrum (CDG1) 90 MHz i.a. signals at: 4H 0.68 - 0.89 ppm -ΟΗ3, - <£ Γ-
7H 1,9 - 2,4 ppm aliphatisk H7H 1.9 - 2.4 ppm aliphatic H
3H 3,58 ppm -0-CH33H 3.58 ppm -0-CH3
3H 3,58 - 4,15 ppm >CHOH3H 3.58 - 4.15 ppm> CHOH
4H 5,2-5,2 ppm vinylprotoner.4H 5.2-5.2 ppm vinyl protons.
IR-spektrum (methylenchlorid), bl.a. bånd ved: 3580, 3400, 1725 - 1710 cm"1.IR spectrum (methylene chloride), i.a. bands at: 3580, 3400, 1725 - 1710 cm "1.
c) 2,3-Trans-methylenprostaglandin P2a-methylester.c) 2,3-Trans-methylene prostaglandin P2a methyl ester.
NMR-spektrum (CDC13) 90 MHz bl-a. signaler ved: 4H 0,7 - 0,89 ppmNMR spectrum (CDCl3) 90 MHz b1-a. signals at: 4H 0.7 - 0.89 ppm
7H 1,88-2,38 ppm aliphatisk H7H 1.88-2.38 ppm aliphatic H
3H 3,6 ppm -0-CH33H 3.6 ppm -0-CH3
3H 3,58-4,15 ppm >CHOH3H 3.58-4.15 ppm> CHOH
4H 5,1 - 5,7 ppm vinylprotoner.4H 5.1 - 5.7 ppm vinyl protons.
IR-spektrum (methylenchlorid), bl.a. bånd ved: 3580, 34Q0, 1725 - 1705 cm-1.IR spectrum (methylene chloride), i.a. bands at: 3580, 34Q0, 1725 - 1705 cm-1.
d) 2,3-Trans-methylenprostaglandin F2a-ethylester.d) 2,3-Trans-methylene prostaglandin F 2a ethyl ester.
NMR-spektrum (CDClg) 90 MHz bl.a. signaler ved: 7H 0,7 - 1,2 ppm -CH3 r<CaNMR spectrum (CDCl3) 90 MHz i.a. signals at: 7H 0.7 - 1.2 ppm -CH3 r <Ca
7H 1,88-2,38 ppm aliphatisk H7H 1.88-2.38 ppm aliphatic H
3H 3,6 - 4,1 ppm >CH0H3H 3.6 - 4.1 ppm> CHOH
2H 4,1 - 4,4 ppm -COOCI^" 4H 5,1 - 5,7 ppm vinylptotoner.2H 4.1 - 4.4 ppm -COOCl 4 4H 5.1 - 5.7 ppm vinylptotons.
IR-spektrum (methylenchlorid), bl.a. bånd ved: 3580, 3400, 1725 - 1705 cm”1.IR spectrum (methylene chloride), i.a. bands at: 3580, 3400, 1725 - 1705 cm ”1.
15 142143 e) 2,3-Cis-methylenprostaglandin F2a-ethylester.E) 2,3-Cis-methylene prostaglandin F2a ethyl ester.
NMR-spektrum (CDCl^) 90 MHz bl.a. signaler ved: 7H 0,7--1,18 ppmNMR spectrum (CDCl3) 90 MHz i.a. signals at: 7H 0.7--1.18 ppm
7H 1,88 - 2,38 ppm aliphatisk H7H 1.88 - 2.38 ppm aliphatic H
5H 3,6 - 4,4 ppm CHOH, -COOCHg- 4H 5,1 - 5,7 ppm vinylprotoner.5H 3.6 - 4.4 ppm CHOH, -COOCHg-4H 5.1 - 5.7 ppm vinyl protons.
IR-spektrum (methylenchlorid), bl.a. bånd ved: 3580, 3400, 1725 - 1705 cm"1.IR spectrum (methylene chloride), i.a. bands at: 3580, 3400, 1725 - 1705 cm "1.
Eksempel 3.Example 3
16,16-Dimethyl-2,3-trans(+)-methylenprostaglandih F2a· 200 mg 16,16-dimethyl-2,3-trans(+) -methylen-11,15-bis-tetrahydropyranyl- prostaglandin F2a opløses i 7 ml af en blanding af eddlkesyre/tetra- hydrofuran/vand (3:1:1) og holdes i 5 timer ved 40eC. Efter inddamp- ning under reduceret tryk chromatograferes remanensen på 23 g sili- cagel med chloroform 7% methanol, hvorved fåa den rene i overskriften 20 angivne forbindelse. [a]D = +88“ (c ** 1,01 CHClg).16,16-Dimethyl-2,3-trans (+) - methylene prostaglandin F2a · 200 mg of 16,16-dimethyl-2,3-trans (+) -methylene-11,15-bis-tetrahydropyranyl-prostaglandin F2a is dissolved in 7 ml of a mixture of acetic acid / tetrahydrofuran / water (3: 1: 1) and kept for 5 hours at 40 ° C. After evaporation under reduced pressure, the residue is chromatographed on 23 g of silica gel with chloroform 7% methanol to give the pure compound as heading 20. [α] D = +88 ° (c ** 1.01 CHClg).
IR-spektrum (methylenchlorid), bl.a. bånd ved: 3600 - 3400, 1695 cm"1.IR spectrum (methylene chloride), i.a. bands at: 3600 - 3400, 1695 cm "1.
NMR-spektrum (CDCl-j) 100 MHz, bl.a. signaler ved:NMR spectrum (CDCl3) 100 MHz, i.a. signals at:
4 H 5,5 ppm vinyl-H 6 H 'v' 4 ppm 3 x CH-OH4 H 5.5 ppm vinyl-H 6 H 'v' 4 ppm 3 x CH-OH
6 H 1,28 ppm 2 x CH^-C-.6 H 1.28 ppm 2 x CH 2 -C-.
Den som udgangsforbindelse anvendte 16,16-dimethyl-2,3-trans(+)--methylen-ll,15-bis-tetrahydropyranylprostaglandin F2a fremstilles på følgende måde: a) (+)-Trans-cyclopropan- 2-(2-bromethyl)carboxylsyre.The 16,16-dimethyl-2,3-trans (+) - methylene-11, 15-bis-tetrahydropyranylprostaglandin F2a used as the starting compound is prepared as follows: a) (+) - Trans-cyclopropane-2- (2- bromoethyl) carboxylic acid.
Til 66 g trans-cyclopropan-2-{2-bromethyl)carboxylsyre i 200 ml methylenchlorid sættes 29 g (-)-ephedrin i 200 ml methylenchlorid, og blandingen lades henstå i 2,5 timer ved 20"C. Ved tilsætning af n--hexan dannes krystaller. Der filtreres og omkrystalliseres af • 16 142143 methylenchlorid/hexan og methylenchlorid/ethylacetat. Smeltepunkt 125 - 126°C? lain 55 +22° (c - 1,26 CHCl-,). Ved udrystning med ^ * 20 methylenchlorid/fortyndet saltsyre frigøres (+)-syren: [a]D ~ +75,3° (c - 1,94 CHCI3).To 66 g of trans-cyclopropane-2- (2-bromethyl) carboxylic acid in 200 ml of methylene chloride is added 29 g of (-) - ephedrine in 200 ml of methylene chloride and the mixture is allowed to stand for 2.5 hours at 20 ° C. - Hexane crystals are formed, filtered and recrystallized from • 16 142143 methylene chloride / hexane and methylene chloride / ethyl acetate Melting point 125 - 126 ° C? lain 55 + 22 ° (c - 1.26 CHCl3). 20 methylene chloride / dilute hydrochloric acid releases the (+) acid: [a] D ~ + 75.3 ° (c - 1.94 CHCl 3).
b) 2- (2-Carboxy-l-(+)-trans-cyclopropyl)ethyl-triphenylphosphonium-bromid.b) 2- (2-Carboxy-1- (+) - trans-cyclopropyl) ethyl-triphenylphosphonium bromide.
Til 6,3 g (+)-trans-cyclopropan-2-(2-bromethyl)carboxylsyre i 150 ml absolut benzen sættes 10,3 g triphenylphosphin, og blandingen koges under tilbagesvaling i 65 timer. Efter afkøling frafiltreres de udon fældede krystaller. Smeltepunkt 121 - 125eC; [a]p = +17,5° (c = 1,18 CHCI3). IR- og NMR-spektret svarer til den racemiske forbindelses IR- og NMR-spektrum.To 6.3 g of (+) - trans-cyclopropane-2- (2-bromethyl) carboxylic acid in 150 ml of absolute benzene is added 10.3 g of triphenylphosphine and the mixture is refluxed for 65 hours. After cooling, the undone precipitated crystals are filtered off. Melting point 121 - 125 ° C; [α] p = + 17.5 ° (c = 1.18 CHCl 3). The IR and NMR spectrum correspond to the IR and NMR spectrum of the racemic compound.
c) 16,16-Dimethyl-2,3-trans(+)-methylen-11,15-bis-tetrahydropyranyl-prostaglandin ^a* 600 mg natriumhydrid opløses i 6 ml absolut dimethylsulfoxid og holdes under nitrogen i 55 minutter ved 75°C. Efter afkøling dryppes 2,1 ml af denne opløsning langsomt til en forud fremstillet opløsning af 1,95 g triphenylphosphoniumsalt af (+)-trans-cyclopropan-2-(2--bromethyl)carboxylsyre i 5 ml absolut dimethylsulfoxid, og blandingen omrøres under nitrogen i 45 minutter.c) 16,16-Dimethyl-2,3-trans (+) - methylene-11,15-bis-tetrahydropyranyl-prostaglandin * 600 mg of sodium hydride is dissolved in 6 ml of absolute dimethyl sulfoxide and kept under nitrogen for 55 minutes at 75 ° C. After cooling, 2.1 ml of this solution is slowly dropped into a pre-prepared solution of 1.95 g of triphenylphosphonium salt of (+) - trans-cyclopropane-2- (2-bromoethyl) carboxylic acid in 5 ml of absolute dimethyl sulfoxide and the mixture is stirred under nitrogen for 45 minutes.
Til en forud fremstillet opløsning af 1 g 28-^^^11116^^1-3^ -α-tetrahydropyranyloxy-l'-transcteny1)-5a-hydroxy-3a-tetrahydropy-ranyloxycyclopentanacetaldehydlactol i 1 ml absolut dimethylsulfoxid sættes ved 20°C 4,5 ml af den ovenfor fremstillede ylidopløsning, og blån dingen holdes i 50 minutter ved 60”C. Efter tilsætning af yderligere 4,5 ml af ylidopløsningen omrøres i yderligere 1 time ved 60°C. Den afkølede reaktionsblanding hældes på is, og den vandige fase indstilles på en pH-værdi på 3 - 5 og ekstraheres tre gange med methylen-chlorid. Det vundne råprodukt chromatograferes på 140 g silicagel med chloroform og 1-5% methanol, hvorved fås den rene i overskriften an- 20 givne forbindelse. [a]D = +35,5° (c = 1,07 CHC13).To a pre-prepared solution of 1 g of 28- (11116 ^^ 1-3) -α-tetrahydropyranyloxy-1'-transctenyl) -5α-hydroxy-3α-tetrahydropyranyloxycyclopentane acetaldehyde lactol in 1 ml of absolute dimethyl sulfoxide is added at 20 ° C. 4.5 ml of the above-prepared ylid solution and keep the mixture for 50 minutes at 60 ° C. After adding an additional 4.5 ml of the ylide solution, stir for an additional 1 hour at 60 ° C. The cooled reaction mixture is poured onto ice and the aqueous phase is adjusted to a pH of 3-5 and extracted three times with methylene chloride. The crude product obtained is chromatographed on 140 g of silica gel with chloroform and 1-5% methanol to give the title pure compound. [α] D = + 35.5 ° (c = 1.07 CHCl13).
IR-spektrum (methylenchlorid), bl.a. bånd ved: 3500, 1695 cm"·1.IR spectrum (methylene chloride), i.a. bands at: 3500, 1695 cm "· 1.
17 142143 NMR-spektrum (CDC13) 90 MHz, bl.a. signaler ved:NMR spectrum (CDCl3) 90 MHz, i.a. signals at:
4 5,5 ppm viny 1-H4 5.5 ppm viny 1-H
2 H 4,6 ppm THP-H.2 H 4.6 ppm THP-H.
Eksempel 4.Example 4
I analogi med eksempel 3 og under anvendelse af tilsvarende udgangsforbindelser fremstilles følgende forbindelser med formlen I: a) 16,16-Dimethyl-2,3-trans(+)-methylenprostaglandin F2a-methylester.By analogy to Example 3 and using similar starting compounds, the following compounds of formula I are prepared: a) 16,16-Dimethyl-2,3-trans (+) - methylene prostaglandin F 2a methyl ester.
NMR-spektrum (CDCl-j) 90 MHz bl.a. signaler ved: 10H 0,7 - 0,89 ppm “C23,-<ilrNMR spectrum (CDCl3) 90 MHz i.a. signals at: 10H 0.7 - 0.89 ppm C23, - <ilr
7H 1,88-2,38 . ppm aliphatisk H7H 1.88-2.38. ppm aliphatic H
3H 3,55-3,6 ppm "0CS33H 3.55-3.6 ppm "0CS3
3H 3,58-4,15 ppm ^CHOH3H 3.58-4.15 ppm ^ CHOH
4H 5,2 - 5,8 ppm vinylprotoner.4H 5.2 - 5.8 ppm vinyl protons.
IR-spektrum (methylenchlorid), bl.a. bånd ved: 3580, 3400, 1725 - 1705 cm-1.IR spectrum (methylene chloride), i.a. bands at: 3580, 3400, 1725 - 1705 cm-1.
b) 16,16-Dimethyl-2,3-trans(+)-methylenprostaglandin F2a-ethylester.b) 16,16-Dimethyl-2,3-trans (+) - methylene prostaglandin F 2a ethyl ester.
NMR-spektrum (CDCl3) 90 MHz bl.a. signaler ved: 13H 0,7 - 1,2 ppm -¾NMR spectrum (CDCl3) 90 MHz i.a. signals at: 13H 0.7 - 1.2 ppm -¾
7H 1,88 - 2,38 ppm aliphatisk H7H 1.88 - 2.38 ppm aliphatic H
3H 3,6 - 4,1 ppm ^CHOH3H 3.6 - 4.1 ppm ^ CHOH
2H 4,1 - 4,4 ppm -COOCH2- 4H 5,1 - 5,7 ppm vinylprotoner.2H 4.1 - 4.4 ppm - COOCH 2 - 4H 5.1 - 5.7 ppm vinyl protons.
IR-spektrum (methylenchlorid), bl.a. bånd ved: 3580, 3400, 1725 - 1705 cm-1.IR spectrum (methylene chloride), i.a. bands at: 3580, 3400, 1725 - 1705 cm-1.
c) 2,3-Trans(+)-methylenprostaglandin F2a' 142143 18 NMR-spektrum (CDC13) 90 MHz bl.a. signaler ved: 3H 0,9 ppm -CH3c) 2,3-Trans (+) - methylene prostaglandin F2a 'NMR spectrum (CDCl3) 90 MHz i.a. signals at: 3H 0.9 ppm -CH3
3H 3,8 - 4,2 ppm ^>CHOH3H 3.8 - 4.2 ppm 2> CHOH
4H 5,3 - 5,6 ppm vinylprotoner.4H 5.3 - 5.6 ppm vinyl protons.
IR-spektrum (methylenchlorid), bl.a, bånd ved: 3600, 3400, 1730 - 1710 cm"1.IR spectrum (methylene chloride), inter alia, bands at: 3600, 3400, 1730 - 1710 cm -1.
d) 2,3-Trans(+)-methylenprostaglandin F2a"methylester.d) 2,3-Trans (+) - methylene prostaglandin F 2a "methyl ester.
NMR-spektrum (CPC13) 90 MHz bl.a. signaler ved:NMR spectrum (CPC13) 90 MHz i.a. signals at:
4H 0,7 - 0,89 ppm -CH3 ,-CCS4H 0.7 - 0.89 ppm -CH 3, -CCS
7H 1,88-2,38 ppm aliphatisk H7H 1.88-2.38 ppm aliphatic H
3H 3,6 ppm ~0-CH33H 3.6 ppm ~ 0-CH3
3H 3,58-4,15 ppm ^CHOH3H 3.58-4.15 ppm ^ CHOH
4H 5,1 - 5,7 ppm vinylprotoner.4H 5.1 - 5.7 ppm vinyl protons.
IR-spektrum (methylenchlorid), bl.a. bånd ved: 3580, 3400, 1725 - 1705 cm"1.IR spectrum (methylene chloride), i.a. bands at: 3580, 3400, 1725 - 1705 cm "1.
e) 2,3-Trans (+)-methylenprostaglandin F2a-ethylester.e) 2,3-Trans (+) - methylene prostaglandin F 2a ethyl ester.
NMR-spektrum (CDC13) 90 MHz bl.a. signaler ved: 7H 0,7 - 1,2 ppmNMR spectrum (CDCl3) 90 MHz i.a. signals at: 7H 0.7 - 1.2 ppm
7H 1,88-2,38 ppm aliphatisk H7H 1.88-2.38 ppm aliphatic H
3H 3,6 - 4,1 ppm >CHOH3H 3.6 - 4.1 ppm> CHOH
2H 4,1 - 4,4 ppm -COOCH2~ 4h 5,1 - 5,7 ppm vinylprotoner.2H 4.1 - 4.4 ppm -COOCH2 ~ 4h 5.1 - 5.7 ppm vinyl protons.
IR-spektrum (methylenchlorid), bl.a. bånd ved: 3580, 3400, 1725 - 1705 cm”1.IR spectrum (methylene chloride), i.a. bands at: 3580, 3400, 1725 - 1705 cm ”1.
Eksempel 5, 16,16-Dimethyl-2,3-trans (+) -meth ylenprostaglandin E2 · 100 mg 16,16-dimethyl- 2,3-trans (+) -meth ylen-11,15-bis-tetrahydropy-ranylprostaglandin F2a opløses i 1 ml absolut toluen, og under nitrogen tilsættes 26,7 mg tert.butyldimethylchlorsilan. Reaktionsop- 1421 A3 19 løsningen afkøles til 0°C, tilsættes 18 mg triethylamin, omrøres i 2,5 timer ved 20°C, afkøles til -30'C og dryppes langsomt i løbet af 35 minutter til en opløsning af 108 mg N-chlorsuccinimid i 4 ml absolut toluen og 60 mg dimethylsulfoxid. Efter yderligere 2,75 timer ved -20*0 tildryppes 220 mg triethylamin i 1 ml pentan, og der oparbejdes i yderligere 10 minutter med ether/vand. Remanensen (100 mg) chromatograferes på 8 g silicagel med chloroform indeholdende 2% methanol. På denne måde fås 16,16-dimethyl-2,3'-trans (+)-methylen-ll,15--bis-tetrahydropyranylprostaglandin E2-tert.butyldimethylsilylester.Example 5, 16,16-Dimethyl-2,3-trans (+) -methylene prostaglandin E2 · 100 mg of 16,16-dimethyl-2,3-trans (+) -methylene-11,15-bis-tetrahydropylamine Dissolve ranyl prostaglandin F2a in 1 ml of absolute toluene and add 26.7 mg of tert.butyldimethylchlorosilane under nitrogen. The reaction solution is cooled to 0 ° C, 18 mg of triethylamine is added, stirred for 2.5 hours at 20 ° C, cooled to -30 ° C and slowly dropped over 35 minutes to a solution of 108 mg of N chlorosuccinimide in 4 ml of absolute toluene and 60 mg of dimethylsulfoxide. After a further 2.75 hours at -20 ° 0, 220 mg of triethylamine is added dropwise into 1 ml of pentane and worked up for an additional 10 minutes with ether / water. The residue (100 mg) is chromatographed on 8 g of silica gel with chloroform containing 2% methanol. In this way, 16,16-dimethyl-2,3'-trans (+) - methylene-11, 15 - bis-tetrahydropyranylprostaglandin E2-tert.butyldimethylsilylester is obtained.
IR-spektrum (methylenchlorid), bl.a. bånd ved: 1735, 1695 cm-1.IR spectrum (methylene chloride), i.a. bands at: 1735, 1695 cm-1.
50 mg af den ovenfor angivne ester opløses 1 0,7 ml acetone, og ved 0eC tildryppes 0,2 ml vand og 0,25 ml af en opløsning af 246 mg natriumacetat i 3 ml acetone, 1 ml vand og 180 mg eddikesyre. Efter 45 minutter ved 0*C og 1,5 timer ved 25eC omrøres blandingen og oparbejdes derefter med ether.50 mg of the above ester are dissolved in 0.7 ml of acetone, and at 0.2 ° C are added 0.2 ml of water and 0.25 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. After 45 minutes at 0 ° C and 1.5 hours at 25 ° C, the mixture is stirred and then worked up with ether.
Remanensen, der består af syren, opløses i 2 ml elclikesyre/vand/tetra-hydrofuran (3:1:1) og lades henstå i 2,5 timer ved 38°C. Efter inddamp-ning under reduceret tryk chromatograferes remanensen på 2,5 g silicagel med chloroform indeholdende 3% methanol. Der fås den rene i overskriften angivne forbindelse.The residue consisting of the acid is dissolved in 2 ml of acetic acid / water / tetrahydrofuran (3: 1: 1) and allowed to stand for 2.5 hours at 38 ° C. After evaporation under reduced pressure, the residue is chromatographed on 2.5 g of silica gel with chloroform containing 3% methanol. The pure connection specified in the heading is obtained.
IR-spektrum (methylenchlorid, bl.a. bånd ved: 1735, 1695 cm"1.IR spectrum (methylene chloride, including bands at: 1735, 1695 cm -1
NMR-spektrum (CDCl^) 90 MHz, bl.a. signaler ved: 4 H 5,3 - 5,8 ppm (vinyl-protoner) 5 H 3,7 - 4,2 ppm 2 x -CH-OH + -COOH.NMR spectrum (CDCl3) 90 MHz, i.a. signals at: 4 H 5.3 - 5.8 ppm (vinyl protons) 5 H 3.7 - 4.2 ppm 2 x -CH-OH + -COOH.
Eksempel 6.Example 6
I analogi med eksempel 5 og under anvendelse af tilsvarende udgangsforbindelser fås følgende forbindelser med formlen I: 20 U2U3 16,16-Dimethyl-2,3-trans(+)-methylenprostaglandin E2-methylester.By analogy to Example 5 and using similar starting compounds, the following compounds of Formula I are obtained: 16,16-Dimethyl-2,3-trans (+) - methylene prostaglandin E2 methyl ester.
NMR-spektrum (CDC10) 90 MHz bl.a. signaler ved: 10H 0,8 - 1,0 ppm -CH-j, 2H 2,56-3,2 ppm )C0CH2“ 3H 3,6 ppm -COOCH^ 4H 5,1-5,7 ppm vinylprotoner.NMR Spectrum (CDC10) 90 MHz i.a. signals at: 10H 0.8 - 1.0 ppm -CH-2, 2H 2.56-3.2 ppm) COCH2 + 3H 3.6 ppm -COOCH ^ 4H 5.1-5.7 ppm vinyl protons.
IR-spektrum (methylenchlorid), bl.a. bånd ved: 3600, 3400, 1745 - 1705 cm"1.IR spectrum (methylene chloride), i.a. bands at: 3600, 3400, 1745 - 1705 cm "1.
b) 16,16-Dimethyl-2,3-trans(+)-methylenprostaglandin E2-ethylester.b) 16,16-Dimethyl-2,3-trans (+) - methylene prostaglandin E2 ethyl ester.
NMR-spektrum (CDC13) 90 MHz bl.a. signaler ved:NMR spectrum (CDCl3) 90 MHz i.a. signals at:
13H 0,8 - 1,1 ppm -CH3, -O13H 0.8 - 1.1 ppm -CH3, -O
•'ll 2H 2,6 - 3,3 ppm -C-CH2— 2H 4,1 - 4,3 ppm -C00CH2“ 4H 5,15 - 5,7 ppm vinylprotoner.1H 2H 2.6 - 3.3 ppm - C - CH 2 - 2H 4.1 - 4.3 ppm - COCH 2 - 4H 5.15 - 5.7 ppm vinyl protons.
IR-spektrum (methylenchlorid), bl.a. bånd ved: 3600, 3400, 1745 - 1705 cm"1.IR spectrum (methylene chloride), i.a. bands at: 3600, 3400, 1745 - 1705 cm "1.
c) 2,3-Trans(+)-methylenprostaglandin E2~methylester.c) 2,3-Trans (+) - methylene prostaglandin E2 methyl ester.
NMR-spektrum (CDCl,) 90 MHz bl.a. signaler ved: 4H 0,7 - 0,9 ppm -CH3, 0 2H 2,55 - 2,95 ppm -C-CH2- 3H 3,65 ppm -COOCH3 4H 5,1 - 5,65 ppm vinylprotoner.NMR spectrum (CDCl3) 90 MHz i.a. signals at: 4H 0.7 - 0.9 ppm - CH 3, 0 2H 2.55 - 2.95 ppm - C - CH 2 - 3H 3.65 ppm - COOCH 3 4H 5.1 - 5.65 ppm vinyl protons.
IR-spektrum (methylenchlorid), bl.a. bånd ved: 3600, 3400, 1740 - 1705 cm"1.IR spectrum (methylene chloride), i.a. bands at: 3600, 3400, 1740 - 1705 cm "1.
d) 2,3-Trans(+)-methylenprostaglandin E2~ethylester.d) 2,3-Trans (+) - methylene prostaglandin E2-ethyl ester.
1421 A3 21 NMR-spektrum (CDCl^) 90 MHz bl.a. signaler ved: 7H 0,8 - 1,1 ppm “CS3~1421 A3 21 NMR spectrum (CDCl3) 90 MHz i.a. signals at: 7H 0.8 - 1.1 ppm “CS3 ~
OISLAND
2H 2,6 - 2,9 ppm -C-CH2~ 2H 4,1 - 4,25 ppm -COOCH2" 4H 5,2 - 5,7 ppm vinylprotoner.2H 2.6 - 2.9 ppm - C - CH2 ~ 2H 4.1 - 4.25 ppm - COOCH2 - 4H 5.2 - 5.7 ppm vinyl protons.
IR-spektrum (methylenchlorid). bl.a. bånd ved: 3400, 1740 - 1705 cm"1.IR spectrum (methylene chloride). Among other things, bands at: 3400, 1740 - 1705 cm "1.
Eksempel 7.Example 7
16,16-Dimethyl-2,3—trans(-)-methylenprostaglandin F2a.16,16-Dimethyl-2,3-trans (-) - methylene prostaglandin F2a.
109 mg 16,16-dimethyl-2,3—trans(-)-methylen-ll,15-bis-tetrahydro-pyranylprostaglandin F2o opløses i 3,5 ml af en blanding af eddikesyre, tetrahydrofuran og vand (3:1:1) og lades henstå i 6 timer ved 40"C. Efter inddampning under reduceret tryk chromatograferes remanensen på 5 g silicagel med chloroform indeholdende 7% methanol, hvor- ΟΛ ved fås den rene i overskriften angivne forbindelse. [o]* * +13,8* (c = 1,02 ct;ci3).109 mg of 16,16-dimethyl-2,3-trans (-) - methylene-11, 15-bis-tetrahydro-pyranylprostaglandin F₂O are dissolved in 3.5 ml of a mixture of acetic acid, tetrahydrofuran and water (3: 1: 1 ) and allowed to stand for 6 hours at 40 ° C. After evaporation under reduced pressure, the residue is chromatographed on 5 g of silica gel with chloroform containing 7% methanol to give ΟΛ the pure title compound. [o] * +13, 8 * (c = 1.02 ct; ci3).
IR-spektrum (methylenchlorid), bl.a. bånd ved: 3600, 3400, 1695 cm-1.IR spectrum (methylene chloride), i.a. bands at: 3600, 3400, 1695 cm-1.
NMR-spektrum (CDCl^) 90 MHz, bl.a. signaler ved:NMR spectrum (CDCl3) 90 MHz, i.a. signals at:
4 H 5,3 - 5,7 ppm vinyl-H 7 H 3,9 - 4,3 ppm 3 x ^CH-OH + COOH4 H 5.3 - 5.7 ppm vinyl-H 7 H 3.9 - 4.3 ppm 3 x 3 CH-OH + COOH
CH3 \ 1,28 ppm ^ ch3^CH3 \ 1.28 ppm ^ ch3 ^
Den som udgangsforbindeIse anvendte 16,16-dimethyl-2,3-trans(-)-methy-len-ll,15-bis-tetrahydropyranylprostaglandln F2a kan fremstilles på følgende måde: a) (-)-Trans-cyclopropan-2-(2-bromethyl)carboxylsyre.The 16,16-dimethyl-2,3-trans (-) - methyl-11,15-bis-tetrahydropyranylprostaglandin F2a used as the starting compound can be prepared as follows: a) (-) - Trans-cyclopropane-2- ( 2-bromoethyl) carboxylic acid.
På analog måde som beskrevet i eksempel 3 a) fremstilles med (+)- 20 -ephedrin den i overskriften angivne forbindelse. [a]D = -75,0° (c = 1,56 CHCI3).By analogy as described in Example 3 a), with (+) - 20-ephedrine, the title compound is prepared. [α] D = -75.0 ° (c = 1.56 CHCl 3).
142143 22142143 22
Den i overskriften angivne forbindelses spektroskopiske data er identiske med (+)-syrens data.The spectroscopic data of the title compound are identical to the (+) acid data.
b) 2-(2-Carboxy-l-(-)-trans-cyclopropyl)ethyl-triphenylphosphonium-bromid.b) 2- (2-Carboxy-1- (-) - trans-cyclopropyl) ethyl-triphenylphosphonium bromide.
Til 61 g (-)-trans-cyclopropan-2-(2-bromethyl)carboxylsyre i 200 ml absolut benzen sættes 10 g triphenylphosphin, og blandingen koges i 63 timer under tilbagesvaling. Efter afkøling frafiltreres de udfæl-dede krystaller. Smeltepunkt 120 - 122°C» [a]^ = ”17,3 (c - 1,19 CHC13).To 61 g of (-) - trans-cyclopropane-2- (2-bromethyl) carboxylic acid in 200 ml of absolute benzene is added 10 g of triphenylphosphine and the mixture is refluxed for 63 hours. After cooling, the precipitated crystals are filtered off. Melting point 120 - 122 ° C [α] D = 17.3 (c - 1.19 CHCl 3).
IR- og NMR-spektret svarer til den enantiomere forbindelses spektra.The IR and NMR spectra correspond to the spectra of the enantiomeric compound.
c) 16,16-Dimethy1-2,3-trans(-)-methylen-11,15-bis-tetrahydropyranyl-prostaglandin ?2α* 300 mg natriumhydrid suspenderes i 3 ml absolut dimethylsulfoxid og lades henstå under nitrogen i 45 minutter ved 75"C. Efter afkøling dryppes 0,9 ml af denne opløsning langsomt til en forud fremstillet opløsning af 1 g triphenylphosphoniumsalt af (-)-trans-cyclopropan-- 2-(2-bromethyl)carboxylsyre i 2,5 ml absolut dimethylsulfoxid, og der omrøres i 45 minutter under nitrogen.c) 16,16-Dimethyl-2,3-trans (-) - methylene-11,15-bis-tetrahydropyranyl-prostaglandin 2α * 300 mg sodium hydride is suspended in 3 ml of absolute dimethyl sulfoxide and left under nitrogen for 45 minutes at 75 After cooling, 0.9 ml of this solution is slowly dripped to a pre-prepared solution of 1 g of triphenylphosphonium salt of (-) - trans-cyclopropane-2- (2-bromethyl) carboxylic acid in 2.5 ml of absolute dimethyl sulfoxide, and stir for 45 minutes under nitrogen.
Til en opløsning af 500 mg 23—(41,4'-dimethyl-3,a-tetrahydropyranyl-oxy-11-trans-octenyl)-5a-hydroxy-3a-tetrahydropyranyloxycyclopentan-acetaldehydlactol i 0,6 ml absolut tetrahydrofuran dryppes langsomt 1,9 ml af den ovenfor fremstillede ylidopløsning. Efter 40 minutter ved 60°C tildryppes yderligere 1,9 ml ylidopløsning, og blandingen holdes i yderligere 1 time ved 60°C. Den afkølede reaktionsblanding hældes på 100 g is, og den vandige fase indstilles på en pH-værdi på 3 - 4 og ek-straheres tre gange med methylenchlorid. Det vundne råprodukt renses ved chromatografering på 40 g silicagel, idet den rene i overskriften angivne forbindelse fås med chloroform og 2% methanol.To a solution of 500 mg of 23- (41,4'-dimethyl-3, a-tetrahydropyranyl-oxy-11-trans-octenyl) -5a-hydroxy-3a-tetrahydropyranyloxycyclopentane-acetaldehyde lactol in 0.6 ml of absolute tetrahydrofuran is slowly dripped 1 , 9 ml of the above-prepared ylid solution. After 40 minutes at 60 ° C, an additional 1.9 ml of ylide solution is added dropwise and the mixture is kept for an additional 1 hour at 60 ° C. The cooled reaction mixture is poured onto 100 g of ice and the aqueous phase is adjusted to a pH of 3 - 4 and extracted three times with methylene chloride. The crude product obtained is purified by chromatography on 40 g of silica gel to give the pure title compound with chloroform and 2% methanol.
IR-spektrum (methylenchlorid), bl.a. bånd ved: 3500, 1695 cm-1.IR spectrum (methylene chloride), i.a. bands at: 3500, 1695 cm-1.
23 14214323 142143
Eksempel δ.Example δ.
I analogi med eksempel 7 og under anvendelse af tilsvarende udgangsforbindelser fremstilles følgende forbindelser med formlen I: a) 16,16-Dimethyl-2,3-trans (-) -methylenprostaglandin F2(j-methylester.By analogy to Example 7 and using similar starting compounds, the following compounds of formula I are prepared: a) 16,16-Dimethyl-2,3-trans (-) -methylene prostaglandin F 2 (j-methyl ester).
NMR-spektrum (CDCl^) 90 MHz bl.a. signaler ved: 10H 0,7 - 0,89 ppm -CH3,NMR spectrum (CDCl3) 90 MHz i.a. signals at: 10H 0.7 - 0.89 ppm -CH
7H 1,88 - 2,38 ppm aliphatisk H7H 1.88 - 2.38 ppm aliphatic H
3H 3,6 ppm -COOCELj3H 3.6 ppm -COOCELj
3H 3,58-4,15 ppm >CHOH3H 3.58-4.15 ppm> CHOH
4h 5,1 - 5,7 ppm vinylprotoner.4h 5.1 - 5.7 ppm vinyl protons.
IR-spektrum (methylenchlorid), bl.a. bånd ved: 3580, 3400, 1725 - 1705 cm"1.IR spectrum (methylene chloride), i.a. bands at: 3580, 3400, 1725 - 1705 cm "1.
b) 16,16-Dimethyl-2,3-trans(-)-methylenprostaglandin F2a-ethylester.b) 16,16-Dimethyl-2,3-trans (-) - methylene prostaglandin F 2a ethyl ester.
NMR-spektrum (CDCl^) 90 MHz bl.a. signaler ved: 13H 0,7 - 1,2 ppmNMR spectrum (CDCl3) 90 MHz i.a. signals at: 13H 0.7 - 1.2 ppm
7H 1,88 - 2,38 ppm aliphatisk H7H 1.88 - 2.38 ppm aliphatic H
3H 3,6 - 4,1 ppm >CHOH3H 3.6 - 4.1 ppm> CHOH
2H 4,1 - 4,4 ppm -COOCH2 4H 5,1 - 5,7 ppm vinylprotoner.2H 4.1 - 4.4 ppm - COOCH 2 4H 5.1 - 5.7 ppm vinyl protons.
IR-spektrum (methylenchlorid), bl.a. bånd ved: 3580, 3400, 1725 - 1705 cm"1.IR spectrum (methylene chloride), i.a. bands at: 3580, 3400, 1725 - 1705 cm "1.
c) 2,3-Trans(-)-methylenprostaglandin SmeltePhnkt 103 - 105°C.c) 2,3-Trans (-) - Methylene Prostaglandin Melting Point 103 - 105 ° C.
NMR-spektrum (CDCl^) 90 MHz bl.a. signaler ved: 4H 0,9 ppmNMR spectrum (CDCl3) 90 MHz i.a. signals at: 4H 0.9 ppm
3H 3,7 - 4,3 ppm )CH0H3H 3.7 - 4.3 ppm) CHOH
4H 5,3 - 5,6 ppm vinylprotoner.4H 5.3 - 5.6 ppm vinyl protons.
IR-spektrum (methylenchlorid), bl.a. bånd ved: 3600, 3500, 1695 - 1710 cm"1.IR spectrum (methylene chloride), i.a. bands at: 3600, 3500, 1695 - 1710 cm "1.
142143 24 d) 2,3-Trans(-)-methylenprostaglandin F^-methylester.D) 2,3-Trans (-) - methylene prostaglandin F 1 -methyl ester.
NMR-spektrum (CDC13) 90 MHz bl.a. signaler ved: 4H 0,7 - 0,89 ppmNMR spectrum (CDCl3) 90 MHz i.a. signals at: 4H 0.7 - 0.89 ppm
7H 1,88 - 2,38 ppm aliphatisk H7H 1.88 - 2.38 ppm aliphatic H
3H 3,6 ppm -COOCH33H 3.6 ppm -COOCH3
3H 3,58 - 4,15 ppm >CHOH3H 3.58 - 4.15 ppm> CHOH
4H 5,1 -5,.7 ppm vinylprotaner.4H 5.1 -5.7 ppm vinyl protanes.
IR-spektrum (methylenchlorid), bl.a. bånd ved: 3580, 3400, 1725 -1705 cm”1.IR spectrum (methylene chloride), i.a. bands at: 3580, 3400, 1725 -1705 cm ”1.
e) 2,3-Trans(-)-methylenprostaglandin F2a-ethylester.e) 2,3-Trans (-) - methylene prostaglandin F 2a ethyl ester.
NMR-spektrum (CDC13) 90 MHz bl.a. signaler ved: 7H 0,7 - 1,2 ppm -CH^, -<r:sNMR spectrum (CDCl3) 90 MHz i.a. signals at: 7H 0.7 - 1.2 ppm -CH 2, - <r: p
7H 1,88 - 2,38 ppm aliphatisk H7H 1.88 - 2.38 ppm aliphatic H
3H 3,6 - 4,1 ppm >CHQH3H 3.6 - 4.1 ppm> CHQH
2H .4,1 - 4,4 ppm . -COOCHg 4H 5,1 - 5,7 ppm vinylprotoner.2H .4.1 - 4.4 ppm. -COOCHg 4H 5.1 - 5.7 ppm vinyl protons.
IR-spektrum, (methylenchlorid), bl.a, bånd ved: 3580, 3400, 1725 - 1705 cm”1.IR spectrum, (methylene chloride), inter alia, bands at: 3580, 3400, 1725 - 1705 cm -1.
Eksempel 9.Example 9
16,16-Dimethyl-2,3-trans (-) -methylenprostaglandin E2.16,16-Dimethyl-2,3-trans (-) -methylene prostaglandin E2.
177 mg 16,16-dimethyl-2,3-trans(-)-methano-11,15-bis—tetrahydro-pyranylprostaglandin F2a opløses i 1,5 ml absolut toluen. En opløsning af 47,2 mg tert.butyldimethylchlorsilan i toluen tildryppes under nitrogen· Reaktiohsopløsningen afkøles til 0°C, tilsættes 32 mg triethylamin, omrøres i 2,5 timer ved 2Q°C, afkøles til -30°C og dryppes langsomt til en opløsning af 191 mg N-chlorsuccinimid i 6 ml absolut toluen og 106,3 mg dimethylsulfid. Efter 2 timer ved -30aC/-20°C tilsættes 300 mg triethylamin i 1 ml pentan, der omrøres i 10 minutter og oparbejdes med ether/vand. Remanensen (192 mg) chro-matograferes på 12 g silicagel med chloroform indeholdende 1¾ methanol.177 mg of 16,16-dimethyl-2,3-trans (-) - methano-11,15-bis-tetrahydro-pyranylprostaglandin F2a are dissolved in 1.5 ml of absolute toluene. A solution of 47.2 mg of tert.butyldimethylchlorosilane in toluene is dropped under nitrogen. The reaction solution is cooled to 0 ° C, 32 mg of triethylamine is added, stirred for 2.5 hours at 2 ° C, cooled to -30 ° C and slowly drizzled to a solution of 191 mg of N-chlorosuccinimide in 6 ml of absolute toluene and 106.3 mg of dimethyl sulfide. After 2 hours at -30 ° C / -20 ° C, 300 mg of triethylamine is added in 1 ml of pentane which is stirred for 10 minutes and worked up with ether / water. The residue (192 mg) is chromatographed on 12 g of silica gel with chloroform containing 1¾ methanol.
142143 25142143 25
Den vundne silylester (IR-spektrum (methylenchlorid), bl.a. bånd ved 1735 og 1675 cm "*") opløses i 2,7 ml acetone. Til den til 0eC afkølede opløsning sættes 0,9 ml vand og 1,2 ml af en opløsning af 246 mg natriumacetat i 3 ml acetone, 1 ml vand og 180 mg eddikesyre. Reaktionsblandingen omrøres i 30 minutter ved 0*C og i 1,5 timer ved 25 - 30‘C og oparbejdes derefter med ether. Remanensen (IR-spek- i trum (methylenchlorid) , bl.a. bånd ved 3500, 1735 og 1695 cm'" ) opløses i 3 ml eddikesyre, vand og tetrahydrofuran (3:1:1) og omrøres i 6 timer ved 40°C. Efter inddampnlng under reduceret tryk chromatogra-feres remanensen på 4,5 g silicagel med chloroform indeholdende 2% methanol. Der fås den rene i overskriften angivne forbindelse.The obtained silylester (IR spectrum (methylene chloride), including bands at 1735 and 1675 cm -1) is dissolved in 2.7 ml of acetone. To the solution cooled to 0 ° C is added 0.9 ml of water 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 and for 1.5 hours at 25-30 ° C and then worked up with ether. The residue (IR spec. Drum (methylene chloride), including bands at 3500, 1735 and 1695 cm -1) is dissolved in 3 ml of acetic acid, water and tetrahydrofuran (3: 1: 1) and stirred for 6 hours at 40 ° C. After evaporation under reduced pressure, the residue is chromatographed on 4.5 g of silica gel with chloroform containing 2% methanol to give the title compound.
IR-spektrum (methylenchlorid), bl.a. bånd ved: 3600, 3400, 1735 og 1695 cm"1.IR spectrum (methylene chloride), i.a. bands at: 3600, 3400, 1735 and 1695 cm "1.
NMR-spektrum (CDClg) 90 MHz, bl.a. signaler ved ca.:NMR spectrum (CDCl3) 90 MHz, i.a. signals at approx .:
OISLAND
2,6 - 2,85 ppm (1 H) H2.6 - 2.85 ppm (1H) H
OHOH
5,2 - 5,6 ppm (4 H)5.2 - 5.6 ppm (4H)
HH
Eksempel 10.Example 10.
I analogi med eksempel 9 og under anvendelse af tilsvarende udgangsforbindelser fremstilles følgende forbindelser med formlen I; a) 2,3-Trans(-)-methylenprostaglandin Ej.By analogy to Example 9 and using similar starting compounds, the following compounds of formula I are prepared; a) 2,3-Trans (-) - methylene prostaglandin Ej.
Smeltepunkt 105 - 107°C.Melting point 105 - 107 ° C.
NMR-Spektrum (CDCl^) 90 MHz bl.a. signaler ved:NMR Spectrum (CDCl3) 90 MHz i.a. signals at:
2H 3,8 -4,2 ppm CH-GH2H 3.8 -4.2 ppm CH-GH
3H 0,85 - 0,90 ppm -CH3 4H 5,2 -5,6 ppm vinylprotoner.3H 0.85 - 0.90 ppm -CH 3 4H 5.2 -5.6 ppm vinyl protons.
IR-spektrum (methylenchlorid), bl.a. bånd ved: 142143 26 3600, 3500, 173Q - 1735, 1695 cm”1.IR spectrum (methylene chloride), i.a. bands at: 142143 26 3600, 3500, 173Q - 1735, 1695 cm ”1.
b) 16,16-Dimethyl-2,3-trans(-)-methylenprostaglandin E2-methylester.b) 16,16-Dimethyl-2,3-trans (-) - methylene prostaglandin E2 methyl ester.
NMR-spektrum (CDC13) 90 MHz bl.a. signaler ved: 10H 0,8 - 1,0 ppm ~CH3,-<i^- 2H 2,56 - 3,2 ppm -COCH2~ 3H 3,6 ppm -C00CH3 4h 5,1 - 5,7 ppm vinylprotoner.NMR spectrum (CDCl3) 90 MHz i.a. signals at: 10H 0.8 - 1.0 ppm ~ CH3, - <1 ^ - 2H 2.56 - 3.2 ppm -COCH2 ~ 3H 3.6 ppm -C00CH3 4h 5.1 - 5.7 ppm vinyl protons.
IR-spektrum (methylenchlorid), bl.a. bånd ved: 3600, 3400, 1740 - 1705 cm”1.IR spectrum (methylene chloride), i.a. bands at: 3600, 3400, 1740 - 1705 cm ”1.
c) 16,16“Dimethyl-2,3-trans(-)-methylenprostaglandin E2~ethylester.c) 16.16 "Dimethyl-2,3-trans (-) - methylene prostaglandin E2 ethyl ester.
NMR-spektrum (CDC13) 90 MHz bl.a. signaler ved: 13H 0,8 - 1,1 ppm -CH3, 2H 2,6 - 3,3 ppm -C0CH2- 2H 4,1 - 4,3 ppm -CQ0CH2- 4H 5,15-5,7 ppm vinylprotoner.NMR spectrum (CDCl3) 90 MHz i.a. signals at: 13H 0.8 - 1.1 ppm - CH3, 2H 2.6 - 3.3 ppm - COCH2 - 2H 4.1 - 4.3 ppm - COQCH2 - 4H 5.15 - 5.7 ppm vinyl protons.
IR-spektrum (methylenchlorid), bl.a. bånd ved: 3600, 3400, 1745 - 1705 cm”1.IR spectrum (methylene chloride), i.a. bands at: 3600, 3400, 1745 - 1705 cm ”1.
d) 2,3-Trans{-)-methylenprostaglandin E2~methylester.d) 2,3-Trans (-) - methylene prostaglandin E 2 -methyl ester.
NMR-spektrum (CDC13) 90 MHz bl.a. signaler ved: 4H 0,7 - 0,9 ppm -CH3,*<iI- 2H 2,5 - 2,95 ppm -C0CH2- 3H 3,65 ppm -COOCH3 4H 5,1 - 5,65 ppm vinylprotoner.NMR spectrum (CDCl3) 90 MHz i.a. signals at: 4H 0.7 - 0.9 ppm - CH3, * <1I - 2H 2.5 - 2.95 ppm - COCH2 - 3H 3.65 ppm - COOCH3 4H 5.1 - 5.65 ppm vinyl protons.
IR-spektrum (methylenchlorid), bl.a. bånd ved: 3600, 3400, 1740 - 1705 cm-1.IR spectrum (methylene chloride), i.a. bands at: 3600, 3400, 1740 - 1705 cm-1.
e) 2,3-Trans(-)-methylenprostaglandin E2-ethylester.e) 2,3-Trans (-) - methylene prostaglandin E2 ethyl ester.
27 142U3 NMR-spektrum (CDCl-j) 90 MHz bl.a. signaler ved: 7H 0,8 - 1,1 ppm 2H 2,6 - 2,9 ppm -COCH2- 2H 4,1 - 4,25 ppm -COOCH^ 4H 5,2 -5,7 ppm vinylprotoner.272U3 NMR spectrum (CDCl3) 90 MHz i.a. signals at: 7H 0.8 - 1.1 ppm 2H 2.6 - 2.9 ppm - COCH2 - 2H 4.1 - 4.25 ppm - COOCH ^ 4H 5.2 - 5.7 ppm vinyl protons.
IR-spektrum (methylenchlorid), bl.a. bånd ved: 3400, 1740 - 1705 cm-1.IR spectrum (methylene chloride), i.a. bands at: 3400, 1740 - 1705 cm-1.
Eksempel 11.Example 11.
16,16-Dimethyl-9α, 11α, 158-trihydroxy-2,3- ( + ) -methylen-prosta’-’S-cis, -13-trans-diensyre.16,16-Dimethyl-9α, 11α, 158-trihydroxy-2,3- (+) -methylene-prosta '-' S-cis, -13-trans-diacetic acid.
230 mg 16,16-dimethyl-9a-hydroxy-lla,158'-bis-tetrahydropyranyl-oxy-2,3-(+)-methylerr-prosta-5-cis,13-trans-diensyre opløses i 15 ml af en blanding af eddikesyre, tetrahydrofuran og vand (3:1:1) og lades henstå i 42 timer ved stuetemperatur. Efter inddampning under reduceret tryk chromatograferes remanensen på 14 g silicagel med chloroform og 4% methanol, hvorved fås den rene 1 overskriften angivne forbindelse.230 mg of 16,16-dimethyl-9a-hydroxy-11a, 158'-bis-tetrahydropyranyl-oxy-2,3 - (+) - methylerr-prosta-5-cis, 13-trans-diacetic acid is dissolved in 15 ml of a mixture of acetic acid, tetrahydrofuran and water (3: 1: 1) and allowed to stand for 42 hours at room temperature. After evaporation under reduced pressure, the residue is chromatographed on 14 g of silica gel with chloroform and 4% methanol to give the pure title compound.
Tyndtlagschromatografering: benzen/dioxan/addikegyre (20:10:1) R^-værdi =0,52.Thin layer chromatography: benzene / dioxane / additive (20: 10: 1) R R value = 0.52.
IR-spektrum (methylenchlorid): bl.a. bånd ved 3600, 3500, 1710 -1695 cm"1.IR spectrum (methylene chloride): bands at 3600, 3500, 1710 -1695 cm "1.
NMR-spektrum (CDC13): bl.a. signaler ved:NMR spectrum (CDCl3): i.a. signals at:
4 H ca. 5,5 ppm vinyl H4 H approx. 5.5 ppm vinyl H
3 H ca. 4 ppm 3 x CHOH3 H approx. 4 ppm 3 x CHOH
Den som udgangsmateriale anvendte 16,16-dimethyl-9a-hydroxy-lla,15β--bis-tetrahydropyranyloxy-2,3-( + ) -metbylen-prosta-5-cis,13-trans--diensyre kan fremstilles på følgende mådes a) 5a-Hydroxy-28-(3,-oxo-4,,4,-dimethyl-trans-l,“Octenyl)^3a-p--phenylbenzoyloxy-la-cyclopentaneddikesyre-Y-lacton.The 16,16-dimethyl-9α-hydroxy-11α, 15β-bis-tetrahydropyranyloxy-2,3- (+) -methylbenzene-prosta-5-cis, 13-trans-diacetic acid used as starting material can be prepared as follows a) 5a-Hydroxy-28- (3, -oxo-4,4,4-dimethyl-trans-1, "octenyl) 3a-p - phenylbenzoyloxy-1a-cyclopentaneacetic acid Y-lactone.
142143 28142143 28
En opløsning af 124,8 g dimethyl-2-oxo-3,3-dimethylheptylphosphonat i 170,3 ml absolut dimethoxyethan sættes under omrøring til en kold (5°C) suspension af 11,35 g natriumhydrid i 994,5 ml absolut dime-thoxyethan. Blandingen omrøres i 1 time ved 20°C, den klare gule opløsning afkøles til -18°C, og derefter tilsættes en til 0°C afkølet opløsning af det optisk aktive aldehyd (2(3-carboxaldehyd--5a-hydroxy-3a-p-phenylbenzoyloxycyclopentaneddikesyre-Y-lacton) i 2109 ml absolut dimethoxyethan, Efter 2 timers forløb ved ca. 0°C afkøles blandingen til ca. -15°C og indstilles på en pH-værdi på 6 ved dråbevis tilsætning af iseddike. Opløsningsmidlet sidestilleres 1 vakuum, og der sættes 2 liter petroleumsether til remanensen (201,6 g gulbrun olie), hvorved der i løbet af natten udskilles hvide krystaller. Smeltepunkt 100 - 101,5°C.A solution of 124.8 g of dimethyl 2-oxo-3,3-dimethylheptyl phosphonate in 170.3 ml of absolute dimethoxyethane is added with stirring to a cold (5 ° C) suspension of 11.35 g of sodium hydride in 994.5 ml of absolute dime. -thoxyethan. The mixture is stirred for 1 hour at 20 ° C, the clear yellow solution is cooled to -18 ° C and then a solution of the optically active aldehyde (2 (3-carboxaldehyde-5α-hydroxy-3α) cooled to 2 ° C is added). p-phenylbenzoyloxycyclopentaneacetic acid-Y-lactone) in 2109 ml of absolute dimethoxyethane. After 2 hours at about 0 ° C, the mixture is cooled to about -15 ° C and adjusted to a pH of 6 by dropwise addition of glacial acetic acid. In vacuo, and 2 liters of petroleum ether are added to the residue (201.6 g of tan oil) to give off white crystals during the night, mp 100 - 101.5 ° C.
b) 5a-Hydroxy-2fi- (3'-hydroxy-4',4'-dimethyl-trans-11 -octenyl)-3a-p--phenylbenzoyl-la-cyclopentaneddikesyre-Y-lacton.b) 5α-Hydroxy-2β- (3'-hydroxy-4 ', 4'-dimethyl-trans-11-octylene) -3α-β-phenylbenzoyl-1α-cyclopentaneacetic acid Y-lactone.
En opløsning af 53,6 g keton (eksempel 11a) i 281 ml absolut dimethoxyethan sættes dråbevis i løbet af 5 minutter til 734,6 ml af en til -18°C afkølet zinkborhydrid-dimethoxyethanblanding (1 ml indeholder 28,7 mg zinkborhydrid). Blandingen omrøres i 3,5 timer ved 2 - 5°C og i yderligere 45 minutter ved 5 -1Q°C. Derefter afkøles blandingen til -15°C og indstilles på en pH-værdi på 6 med en 10%'s vandig natriumhydrogentartratopløsning (ca. 150 ml). Til reaktions-blandingen sættes 3x1 liter ether, og der fradekanteres. Den organiske fase vaskes to gange med hver gang 1 liter mættet kogsaltopløsning, tørres og inddampes i vakuum, hvorved fås 59 g af en blanding af den a- og β-isomere, som opspaltes ved chromatografering på 9 kg silicagel. Med methylenchlorid/ethylacetat (92:8) isoleres 30 g af den apolære α-isomere, og med methylenchlorid/ethylacetat (91:9) elueres 9 g af den Ø-isomere.A solution of 53.6 g of ketone (Example 11a) in 281 ml of absolute dimethoxyethane is added dropwise over 5 minutes to 734.6 ml of a cooled zinc borohydride-dimethoxyethane mixture (1 ml contains 28.7 mg of zinc borohydride). . The mixture is stirred for 3.5 hours at 2 - 5 ° C and for an additional 45 minutes at 5 -1 ° C. The mixture is then cooled to -15 ° C and adjusted to a pH of 6 with a 10% aqueous sodium hydrogen tartrate solution (about 150 ml). To the reaction mixture is added 3x1 liters of ether and decanted off. The organic phase is washed twice with 1 liter of saturated saline solution each time, dried and evaporated in vacuo to give 59 g of a mixture of the α- and β-isomers which is decomposed by chromatography on 9 kg of silica gel. With methylene chloride / ethyl acetate (92: 8), 30 g of the apolar α-isomer is isolated and with methylene chloride / ethyl acetate (91: 9) elute 9 g of the isomer.
c) 3a,5a-Dihydroxy-2p-(3'B-hydroxy-4',4'-dimethyl-trans-]1-octenyl)--la-cyclopentaneddikesyre-Y-lacton.c) 3a, 5a-Dihydroxy-2β- (3'B-hydroxy-4 ', 4'-dimethyl-trans- [1-octenyl) - 1a-cyclopentaneacetic acid Y-lactone.
7,3 g B-alkohol (eksempel 11b) opløses i 306 ml absolut methanol, og under nitrogen tilsættes 306 mg natrium i 15,3 ml absolut methanol, og blandingen lades henstå ved stuetemperatur i 5 timer. Derefter afkøles reaktionsblandingen under anvendelse af et isbad, og i løbet af 20 minutter tilsættes 26 ml af en 101's methanolisk vinsyreopløs-ning. Efter afdestillation af opløsningsmidlet i vakuum fordeles den 142143 29 krystallinske remanens mellem methylenchlorid og mættet kogsaltopløsning, den organiske fase tørres og inddampes, og den krystallinske remanens chromatograferes på 500 g silicagel med benzen og 5% acetone. Herved fås 5,0 g diol i form af en viskos olie.Dissolve 7.3 g of B-alcohol (Example 11b) in 306 ml of absolute methanol and, under nitrogen, add 306 mg of sodium in 15.3 ml of absolute methanol and allow the mixture to stand at room temperature for 5 hours. Then, the reaction mixture is cooled using an ice bath and over 20 minutes, 26 ml of a 101 methanolic tartaric acid solution is added. After distilling off the solvent in vacuo, the crystalline residue is partitioned between methylene chloride and saturated brine, the organic phase is dried and evaporated, and the crystalline residue is chromatographed on 500 g of silica gel with benzene and 5% acetone. This gives 5.0 g of diol in the form of a viscous oil.
Tyndtlagschromatogram: toluen/acetone (2:1) Rf-værdi = 0,2.Thin layer chromatogram: toluene / acetone (2: 1) Rf value = 0.2.
d) 3a,5a-Dihydroxy-2p-(3'p-hydroxy-4 *,4'-dimethyl-trans-l'-octenyl)--la-cyclopentaneddikesyre-Y-lacton-3,3'-bis-tetrahydropvranyl-ether.d) 3α, 5α-Dihydroxy-2β- (3′β-hydroxy-4β, 4′-dimethyl-trans-1′-octenyl) - 1-cyclopentaneacetic acid-Y-lactone-3,3′-bis-tetrahydropyranyl ether.
En opløsning af 5 g diol (eksempel u c) i 285 ml absolut toluen sættes ved -10°C til en opløsning af 4,28 g dihydropvran og 100 mg p-toluensulfonsyre i 40,7 ml absolut toluen og omrøres i 1,5 timer ved stuetemperatur. Derefter vaskes blandingen med 150 ml 10%'s ka-liumhydrogencarbonatopløsning og derefter med 400 ml mættet kogsaltopløsning. De vandige faser ekstraheres med benzen, og de organiske faser inddampes i vakuum. Der fås 8,4 g olieagtigt råprodukt, som chromatograferes på 450 g silicagel. Under anvendelse af toluen og 5% acetone elueres 7,0 g af den rene i overskriften angivne forbindelse.A solution of 5 g of diol (example uc) in 285 ml of absolute toluene is added at -10 ° C to a solution of 4.28 g of dihydropyran and 100 mg of p-toluenesulfonic acid in 40.7 ml of absolute toluene and stirred for 1.5 hours. at room temperature. Then the mixture is washed with 150 ml of 10% potassium hydrogen carbonate solution and then with 400 ml of saturated brine. The aqueous phases are extracted with benzene and the organic phases are evaporated in vacuo. 8.4 g of oily crude product are obtained which are chromatographed on 450 g of silica gel. Using toluene and 5% acetone, elute 7.0 g of the pure title compound.
e) 2β-(4’,4'-Dimethyl-31β-tetrahydropyranyloxy-l'-trans-ocfenyl)-5a--hydroxy-3a-tetrahydropyranyloxycyclopentanacetaldehyd-Y-lactql.e) 2β- (4 ', 4'-Dimethyl-31β-tetrahydropyranyloxy-1'-trans-ocphenyl) -5α-hydroxy-3α-tetrahydropyranyloxycyclopentane acetaldehyde-Y-lactyl.
En opløsning af 7,0 g af bis-tetrahydropyranether (eksempelil d) i 300 ml absolut toluen afkøles til -70°C, og der tilsættes i løbet af 25 minutter 25 ml dlisobutylaluminiumhydridopløsning (20% i toluen). Efter 1 times forløb sættes 185 ml tetrahydrofuran/vand (2:1) til opløsningen, som filtreres, og filtratet vaskes med mættet na-triumchloridopløsning, tørres og inddampes. Herved fås 5,9 g af den i overskriften angivne forbindelse (isomerblanding).A solution of 7.0 g of bis-tetrahydropyran ether (example d) in 300 ml of absolute toluene is cooled to -70 ° C and 25 ml of dlisobutyl aluminum hydride solution (20% in toluene) is added over 25 minutes. After 1 hour, 185 ml of tetrahydrofuran / water (2: 1) is added to the solution which is filtered and the filtrate is washed with saturated sodium chloride solution, dried and evaporated. This gives 5.9 g of the title compound (isomer mixture).
f) 16,16-Dimethyl-9a-hydroxy-lla, 15|3-bis-tetrahydropyranyloxy-213-- (+) -methylen -prosta-5-cis, 13-trans-diensyre, 800 mg natriumhydrid suspenderes i 8,3 ml absolut diraethylsulfoxid og holdes i 45 minutter ved 75°C under nitrogen. 2,8 ml af denne opløsning dryppes langsomt ved stuetemperatur til en forud fremstillet opløsning af 2,55 g triphenylphosphoniumsalt af (+)-trans-cyclo-propan-1-(2-bromethyl)carboxylsyre i 6 ml absolut dimethylsulfoxid og omrøres under nitrogen i yderligere 80 minutter.f) 16,16-Dimethyl-9a-hydroxy-11a, 15β-bis-tetrahydropyranyloxy-213- (+) -methylene-prosta-5-cis, 13-trans-diacetic acid, 800 mg of sodium hydride is suspended in 8, 3 ml of absolute diraethylsulfoxide and kept for 45 minutes at 75 ° C under nitrogen. 2.8 ml of this solution is slowly dropped at room temperature to a pre-prepared solution of 2.55 g of triphenylphosphonium salt of (+) - trans-cyclopropane-1- (2-bromethyl) carboxylic acid in 6 ml of absolute dimethyl sulfoxide and stirred under nitrogen. for another 80 minutes.
1421 A3 301421 A3 30
Til en opløsning af 644 mg 20-(41,4'-dimethyl-3'3--tetrahyclropyra-nyloxy-1'-trans-octenyl)-5a-hydroxy-3a-tetrahydropyranyloxycyclo-pentanacetaldehyd-y-lactol i 2 ml absolut dimethylsulfoxid og 1 ml absolut tetrahydrofuran dryppes langsomt 2,8 ml af den ovenfor fremstillede ylidopløsning. Efter 40 minutters henstand ved 55°C tildryppes yderligere 2,7 ml ylidopløsning, og der omrøres i yderligere 2 timer ved 55°C, Den afkølede reaktionsblanding hældes på 120 g is, og den vandige fase indstilles på en pH-værdi på 3 - 4 og ekstraileres fire gange med hver gang 120 ml methylenchlorid. Den organiske fase vaskes to gange med vand, tørres med natriumsulfat og inddampes under reduceret tryk. Det resulterende råprodukt chromatograferes på 75 g silicagel, hvorved der med chloroform og 2 - 3% methanol fås den rene i overskriften angivne forbindelse.To a solution of 644 mg of 20- (41,4'-dimethyl-3'3-tetrahyclropyra-nyloxy-1'-trans-octenyl) -5α-hydroxy-3α-tetrahydropyranyloxycyclopentanacetaldehyde-γ-lactol in 2 ml of absolute dimethyl sulfoxide and 1 ml of absolute tetrahydrofuran slowly drop 2.8 ml of the ylide solution prepared above. After 40 minutes standing at 55 ° C, an additional 2.7 ml of ylide solution is added dropwise and stirred for another 2 hours at 55 ° C. The cooled reaction mixture is poured onto 120 g of ice and the aqueous phase is adjusted to a pH of 3- 4 and extracted four times with 120 ml of methylene chloride each time. The organic phase is washed twice with water, dried with sodium sulfate and evaporated under reduced pressure. The resulting crude product is chromatographed on 75 g of silica gel to give the purified title compound with chloroform and 2 - 3% methanol.
Tyndtlagschromatografering: ethylacetat og 10% methanol R^-værdi = 0,49.Thin layer chromatography: ethyl acetate and 10% methanol R 2 value = 0.49.
IR-spektrum (methylenchlorid): bl.a. bånd ved 3500, 1710 - 1695, 1200 og 1030 cm "*.IR spectrum (methylene chloride): bands at 3500, 1710 - 1695, 1200 and 1030 cm "*.
NMR-spektrum (CDClg): 100 MHz, bl.a. signaler ved: 4 H 5,8-5,2 ppm vinylprotonerNMR Spectrum (CDCl)): 100 MHz, i.a. signals at: 4 H 5.8-5.2 ppm vinyl protons
2 H 4,7-4,4 ppm THP-H2 H 4.7-4.4 ppm THP-H
9 H 0,9-0,8 ppm methyl-H.9 H 0.9-0.8 ppm methyl-H.
Eksempel 12.Example 12.
16,16-Dimethyl-lla,150-dihydroxy-9-keto-2,3-(+)-methylen-prosta--5-cis,13 -trans-diensyre.16,16-Dimethyl-11a, 150-dihydroxy-9-keto-2,3 - (+) - methylene-prosta-5-cis, 13-trans-diacetic acid.
295 mg 16,16-dimethyl-9a-hydroxy-lla,150-bis-tetrahydropyranyl-oxy-2,3-(+)-metbylen-prosta-5-cis,13-trans-diensyre opløses i 3 ml absolut toluen, og under nitrogen tilsættes 89 mg tert.butyldime-thylchlorsilan. Reaktionsopløsningen afkøles til 0°C, og der tildryppes langsomt en opløsning af 60 ml triethylamin i 0,6 ml absolut toluen. Efter 48 timers forløb ved stuetemperatur afkøles blandingen til -25°C, og der tildryppes langsomt i løbet af 30 minutter en forud afkølet opløsning af 324 mg N-chlorsuccinimid i 13 ml absolut toluen og 180 mg dimethylsulfid. Efter yderligere 2,5 timers henstand tildryppes 502 mg triethylamin i 2 ml pentan, og bian- 31 U2U3 dingen omrøres i yderligere 20 minutter ved stuetemperatur og oparbejdes med ether/vand. Remanensen opløses i 15 ml eddikesyre/ tetrahydrofuran/vand (3:1:1), og lades henstå i 43 timer ved stuetemperatur. Efter inddampning under reduceret tryk chromatograferes remanensen på 15 g silicagel. Den rene i overskriften angivne forbindelse elueres med chloroform og 3% methanol.295 mg of 16,16-dimethyl-9a-hydroxy-11a, 150-bis-tetrahydropyranyl-oxy-2,3 - (+) - methylbene-prosta-5-cis, 13-trans-diacetic acid are dissolved in 3 ml of absolute toluene, and under nitrogen 89 mg of tert.butyldimethylchlorosilane is added. The reaction solution is cooled to 0 ° C and slowly a solution of 60 ml of triethylamine in 0.6 ml of absolute toluene is added dropwise. After 48 hours at room temperature, the mixture is cooled to -25 ° C and a pre-cooled solution of 324 mg of N-chlorosuccinimide in 13 ml of absolute toluene and 180 mg of dimethyl sulfide is slowly added dropwise over 30 minutes. After a further 2.5 hours standing, 502 mg of triethylamine is dropped into 2 ml of pentane and the mixture is stirred for an additional 20 minutes at room temperature and worked up with ether / water. The residue is dissolved in 15 ml of acetic acid / tetrahydrofuran / water (3: 1: 1) and allowed to stand for 43 hours at room temperature. After evaporation under reduced pressure, the residue is chromatographed on 15 g of silica gel. The pure title compound is eluted with chloroform and 3% methanol.
Tyndtlagschromatografering: chloroform og 10% methanol R^-værdi = 0,27.Thin layer chromatography: chloroform and 10% methanol R 2 value = 0.27.
IR-spektrum (methylenchlorid): bl.a. bånd ved 3600, 1740 og 1695 cm NMR-spektrum (CDC13): bl.a. signaler ved:IR spectrum (methylene chloride): bands at 3600, 1740 and 1695 cm NMR spectrum (CDCl3): i.a. signals at:
4 H 5,8-5,3 ppm vinyl H4 H 5.8-5.3 ppm vinyl H
4 H 3,7 - 4,2 ppm 2 x CH-OH4 H 3.7 - 4.2 ppm 2 x CH-OH
Eksempel 13.Example 13
(5Z,9a,11a,13E,15a)-9,11,15-trihydroxy-16-n-butyl-2,3-trans(-)--methylen-prosta-5,13-diensyre. * 600 mg natriumhydrid suspenderes i 6 ml absolut dimethylsulfoxld og holdes under nitrogen i 45 minutter ved 75°C. Efter afkøling dryppes 4,5 ml af denne opløsning langsomt til en forud fremstillet opløsning af 4,08 g 2-(2-carboxy-l-(-)-trans-cyclopropyl)ethyl-triphenylphosphoniumbromid i 10 ml absolut dimethylsulfoxid, og der omrøres derefter i 35 minutter under nitrogen.(5Z, 9a, 11a, 13E, 15a) -9,11,15-trihydroxy-16-n-butyl-2,3-trans (-) - methylene-prosta-5,13-dienoic acid. * 600 mg of sodium hydride is suspended in 6 ml of absolute dimethylsulfoxide and kept under nitrogen for 45 minutes at 75 ° C. After cooling, 4.5 ml of this solution is slowly dripped to a pre-prepared solution of 4.08 g of 2- (2-carboxy-1 - (-) - trans-cyclopropyl) ethyl-triphenylphosphonium bromide in 10 ml of absolute dimethyl sulfoxide and stirred. then for 35 minutes under nitrogen.
Til en opløsning af 2,1 g 2β-(4'-n-butyl-3'a-tetrahydropyranyloxy--1'-trans-octenyl)-5a-hydroxy-3a-tetrahydropyranyloxycyclopentan-acetaldehydlactol i 6 ml absolut tetrahydrofuran og 6 ml dimethylsulfoxid dryppes langsomt 8 ml af den ovenfor fremstillede ylidopløs-ning. Efter 60 minutter ved 50°C tildryppes atter 8 ml ylidopløs-ning, og blandingen holdes i yderligere 1 time ved 50°C. Den afkølede reaktionsblanding hældes på 150 g is, og den vandige fase indstilles på en pH-værdi på 3 - 4 og ekstraheres tre gange med methylenchlorid. Det vundne råprodukt renses ved chromatografering på 190 g silicagel, hvorved der med chloroform og 2% methanol fås (5Z,9a,11a,13E,15a)-9,11,15-trihydroxy-16-n-butyl-2,3-trans-(-)--methylen-prosta-5,13-diensyre-ll,15-bis-tetrahydropyranylether.To a solution of 2.1 g of 2β- (4'-n-butyl-3'a-tetrahydropyranyloxy-1'-trans-octenyl) -5a-hydroxy-3a-tetrahydropyranyloxycyclopentane-acetaldehyde lactol in 6 ml of absolute tetrahydrofuran and 6 ml dimethylsulfoxide is slowly dipped 8 ml of the above-prepared ylid solution. After 60 minutes at 50 ° C, 8 ml of ylide solution is again dripped and the mixture is kept for an additional 1 hour at 50 ° C. The cooled reaction mixture is poured onto 150 g of ice and the aqueous phase is adjusted to a pH of 3 - 4 and extracted three times with methylene chloride. The crude product obtained is purified by chromatography on 190 g silica gel to give chloroform and 2% methanol (5Z, 9a, 11a, 13E, 15a) -9,11,15-trihydroxy-16-n-butyl-2,3- trans - (-) - methylene-prosta-5,13-dienoic acid-ll, 15-bis-tetrahydropyranyl ether.
32 1421 A3 200 mg (5Ζ,9α,lla,13E,15a)-9,ll,15-trihydroxy-16-n-butyl-2,3-- trans- (-) -methylen-prosta-5,13-diensyre-ll, 15-bis-tetrahydro-pyranylether opløses i 7 ml af en blanding af eddikesyre, tetra-bydrofuran og vand (3:1:1) og holdes i 2 timer ved 35°C. Efter ind-dampning under reduceret tryk ved 25°C chromatograferes remanensen på silicagel med chloroform og 2 - 5% methanol, hvorved fås den rene i overskriften angivne forbindelse.200 mg (53, 9α, 11a, 13E, 15a) -9,11,15-trihydroxy-16-n-butyl-2,3-trans- (-) -methylene-prosta-5,13- diacid-11, 15-bis-tetrahydro-pyranyl ether is dissolved in 7 ml of a mixture of acetic acid, tetra-hydrodrofuran and water (3: 1: 1) and kept for 2 hours at 35 ° C. After evaporation under reduced pressure at 25 ° C, the residue is chromatographed on silica gel with chloroform and 2 - 5% methanol to give the pure title compound.
IR-spektrum (methylenchlorid), bl.a. bånd ved 3600 - 3300 og 1720 - 1630 cirf1, NMR-spektrum (CDC13) 90 MHz, bl.ft. signaler ved ca: 0,7 - 1,0. ppm (7H) -CH3,IR spectrum (methylene chloride), i.a. bands at 3600 - 3300 and 1720 - 1630 cirf1, NMR spectrum (CDCl3) 90 MHz, bl.ft. signals at about: 0.7 - 1.0. ppm (7H) -CH
3.8 - 4,2 ppm (7H) «QH, -COQH, X3.8 - 4.2 ppm (7H) + QH, -COQH, X
H OHH OH
5,35 - 5,6 ppm (4H) vinylprotoner.5.35 - 5.6 ppm (4H) vinyl protons.
På analog måde fås (5Z,9a,lla,13E,15a,16a)-9,ll,15-trihydroxy-16-methyl-2,3-trans-(-) -methylen-prosta-5,13-<iiensyre.Analogously, (5Z, 9a, 11a, 13E, 15a, 16a) -9,11,15-trihydroxy-16-methyl-2,3-trans - (-) -methylene-prosta-5,13- .
IR-Spektrum (KBr), bl.a. bånd ved 3400 " 3600 og 1695 cm NMR-Spektrum (QDCl^) 90 MHz, bl.a. signaler ved: 0,88 ppm (3H) -CH3 (C2q) 0,92 ppm (3H) -CH3 (Clg)IR Spectrum (KBr), i.a. bands at 3400 "3600 and 1695 cm NMR Spectrum (QDCl 3) 90 MHz, including signals at: 0.88 ppm (3H) -CH3 (C2q) 0.92 ppm (3H) -CH3 (Clg)
HH
0,8-1 ppm (IH) ..0.8-1 ppm (1H).
3.8 - 4,2 ppm (3H) >CHOB(C9,C10,C15) 4,4 - 4,8 ppm (2H) (-COOH,OH) 5,3 - 5,7 ppm (4H) vinylprotoner.3.8 - 4.2 ppm (3H)> CHOB (C9, C10, C15) 4.4 - 4.8 ppm (2H) (-COOH, OH) 5.3 - 5.7 ppm (4H) vinyl protons.
33 14214333 142143
Eksempel 14.Example 14.
(5Z,11α,13E,15α)-11,15-dihydroxy-16-n-butyl-9-keto-2,3-trans (-)--methylen-prosta-5,13-diensyre.(5Z, 11α, 13E, 15α) -11,15-dihydroxy-16-n-butyl-9-keto-2,3-trans (-) - methylene-prosta-5,13-diacetic acid.
600 mg af den i eksempel 13 beskrevne (5Ζ,9α,11α,13Ε,15α)~9,11,15--trihydroxy-16-n-butyl-2,3-trans (-)-methylen-prosta-5,13-diensyre--11,15-bis-tetrahydropyranylether opløses i 100 ml absolut acetone og oxideres ved -20°C ifølge Jones. Efter 1 times forløb tilsættes 0,5 ml methanol, efter yderligere 10 minutters forløb hældes suspensionen på 200 ml isvand og ekstraheres tre gange med methylen-chlorid, den organiske fase vaskes med vand, tørres med natriumsulfat og inddampes, og remanensen holdes i 40 minutter ved 409C . .600 mg of the (5Ζ, 9α, 11α, 13Ε, 15α) described in Example 13 ~ 9,11,15 - trihydroxy-16-n-butyl-2,3-trans (-) - methylene-prosta-5, 13-diacetic acid - 11,15-bis-tetrahydropyranyl ether is dissolved in 100 ml of absolute acetone and oxidized at -20 ° C according to Jones. After 1 hour 0.5 ml of methanol is added, after a further 10 minutes the suspension is poured into 200 ml of ice water and extracted three times with methylene chloride, the organic phase is washed with water, dried with sodium sulfate and evaporated and the residue is kept for 40 minutes. at 409C. .
i 60 ml acetone/vand (2:1) og 0,5 ml 2N saltsyre. Der neutraliseres med 2N natriumhydroxidopløsning, acetonet afdampes, og den vandige opløsning ekstraheres fire gange med methylenchlorid, tørres over natriumsulfat, inddampes og chromatograferes over 45 g silicagel med en chloroform-methanolblanding.in 60 ml of acetone / water (2: 1) and 0.5 ml of 2N hydrochloric acid. Neutralize with 2N sodium hydroxide solution, evaporate the acetone and extract the aqueous solution four times with methylene chloride, dry over sodium sulfate, evaporate and chromatograph over 45 g of silica gel with a chloroform-methanol mixture.
IR-spektrum (methylenchlorid), bl.a. bånd veds 3600 - 3300 og 1740 - 1690 cm-1.IR spectrum (methylene chloride), i.a. bands at 3600 - 3300 and 1740 - 1690 cm-1.
NMR-spektrum (CDC13) 90 MHz, bl.a. signaler ved ca.: 0,75 - 1,0 ppm (7H) , -CH, J-NMR spectrum (CDCl3) 90 MHz, i.a. signals at about: 0.75 - 1.0 ppm (7H), -CH, J-
2,6 - 2,9 ppm (2H) HY2.6 - 2.9 ppm (2H) HY
3,9 - 4,2 ppm (2H)3.9 - 4.2 ppm (2H)
g OHg OH
5,3 - 5,7 ppm (4H) vinylprotoner.5.3 - 5.7 ppm (4H) vinyl protons.
Pa analog made fås ( 5Z, 11α, 13E, 15a ,16cx) —11,15—dihydroxy— 9—keto—16— -methyl-2,3-trans(-)-methylen-prosta-5,13-diensyre.Analogously, (5Z, 11α, 13E, 15a, 16cx) is obtained - 11,15-dihydroxy-9-keto-16-methyl-2,3-trans (-) - methylene-prosta-5,13-diacetic acid.
Claims (1)
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CH995973A CH599147A5 (en) | 1973-07-09 | 1973-07-09 | Long-acting synthetic prostaglandins |
CH995973 | 1973-07-09 | ||
CH604974 | 1974-05-04 | ||
CH604974 | 1974-05-04 |
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DK352974A DK352974A (en) | 1975-03-03 |
DK142143B true DK142143B (en) | 1980-09-08 |
DK142143C DK142143C (en) | 1981-02-09 |
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DK352974AA DK142143B (en) | 1973-07-09 | 1974-07-01 | Analogous Process for Preparation of 2,3-Methylene Prostaglandin F2alfa or E2 Derivatives. |
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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) | GB1479964A (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 FI FI2011/74A patent/FI58117C/en active
- 1974-07-01 SE SE7408689A patent/SE7408689L/xx unknown
- 1974-07-01 NO NO742378A patent/NO742378L/no unknown
- 1974-07-01 DK DK352974AA patent/DK142143B/en unknown
- 1974-07-03 DE DE2431930A patent/DE2431930A1/en not_active Withdrawn
- 1974-07-05 NL NL7409119A patent/NL7409119A/en not_active Application Discontinuation
- 1974-07-05 DD DD179745A patent/DD113348A5/xx unknown
- 1974-07-05 FR FR7423427A patent/FR2236490B1/fr not_active Expired
- 1974-07-08 GB GB30268/74A patent/GB1479964A/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
- 1974-07-08 CA CA204,340A patent/CA1050976A/en not_active Expired
- 1974-07-08 GB GB1901/77A patent/GB1479965A/en not_active Expired
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- 1974-07-08 JP JP49077462A patent/JPS5040549A/ja active Pending
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1975
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1976
- 1976-05-17 ES ES448000A patent/ES448000A1/en not_active Expired
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FR2318169A1 (en) | 1977-02-11 |
GB1479965A (en) | 1977-07-13 |
ATA559874A (en) | 1979-07-15 |
FI201174A (en) | 1975-01-10 |
NL7409119A (en) | 1975-01-13 |
ES448000A1 (en) | 1977-11-01 |
FI58117C (en) | 1980-12-10 |
FR2236490A1 (en) | 1975-02-07 |
IL45215A (en) | 1977-07-31 |
DK142143C (en) | 1981-02-09 |
IE41342L (en) | 1975-01-09 |
IE41342B1 (en) | 1979-12-05 |
FR2236490B1 (en) | 1978-07-21 |
AT355233B (en) | 1980-02-25 |
CA1050976A (en) | 1979-03-20 |
NO742378L (en) | 1975-02-03 |
SE7408689L (en) | 1975-01-10 |
ES428063A1 (en) | 1977-02-01 |
DE2431930A1 (en) | 1975-01-30 |
FR2318169B1 (en) | 1978-11-03 |
IL45215A0 (en) | 1975-02-10 |
JPS5040549A (en) | 1975-04-14 |
SE7512194L (en) | 1975-10-30 |
DK352974A (en) | 1975-03-03 |
DD113348A5 (en) | 1975-06-05 |
FI58117B (en) | 1980-08-29 |
GB1479964A (en) | 1977-07-13 |
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