KR840001722B1 - Process for the preparation of prostaglandin derivative - Google Patents
Process for the preparation of prostaglandin derivative Download PDFInfo
- Publication number
- KR840001722B1 KR840001722B1 KR1019800000263A KR800000263A KR840001722B1 KR 840001722 B1 KR840001722 B1 KR 840001722B1 KR 1019800000263 A KR1019800000263 A KR 1019800000263A KR 800000263 A KR800000263 A KR 800000263A KR 840001722 B1 KR840001722 B1 KR 840001722B1
- Authority
- KR
- South Korea
- Prior art keywords
- group
- compound
- formula
- tetrahydropyran
- acid
- Prior art date
Links
- 238000000034 method Methods 0.000 title description 24
- 238000002360 preparation method Methods 0.000 title description 17
- 150000003180 prostaglandins Chemical class 0.000 title description 10
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 6
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract description 5
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 5
- 125000000000 cycloalkoxy group Chemical group 0.000 claims abstract description 5
- 230000007062 hydrolysis Effects 0.000 claims abstract description 5
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims abstract description 5
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract 2
- -1 phosphoran compound Chemical class 0.000 claims description 172
- 150000001875 compounds Chemical class 0.000 claims description 71
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 25
- 125000004432 carbon atom Chemical group C* 0.000 claims description 14
- 125000000217 alkyl group Chemical group 0.000 claims description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 125000004187 tetrahydropyran-2-yl group Chemical group [H]C1([H])OC([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 125000006833 (C1-C5) alkylene group Chemical group 0.000 claims 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 abstract description 40
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 abstract description 20
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 abstract description 10
- NMRPBPVERJPACX-UHFFFAOYSA-N octan-3-ol Chemical compound CCCCCC(O)CC NMRPBPVERJPACX-UHFFFAOYSA-N 0.000 abstract description 7
- 125000002947 alkylene group Chemical group 0.000 abstract description 5
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 abstract description 5
- 239000000543 intermediate Substances 0.000 abstract description 5
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 abstract 1
- 229960000711 alprostadil Drugs 0.000 abstract 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 75
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 48
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 33
- 239000000243 solution Substances 0.000 description 33
- 239000000203 mixture Substances 0.000 description 31
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 30
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 22
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 16
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 15
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 15
- 125000006239 protecting group Chemical group 0.000 description 15
- 238000004809 thin layer chromatography Methods 0.000 description 15
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 14
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- 239000011541 reaction mixture Substances 0.000 description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 230000000704 physical effect Effects 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 238000005481 NMR spectroscopy Methods 0.000 description 11
- 238000006243 chemical reaction Methods 0.000 description 11
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 10
- 239000000741 silica gel Substances 0.000 description 10
- 229910002027 silica gel Inorganic materials 0.000 description 10
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 10
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 9
- 238000004440 column chromatography Methods 0.000 description 9
- 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 9
- 238000007254 oxidation reaction Methods 0.000 description 9
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 8
- 239000002253 acid Substances 0.000 description 8
- 239000003480 eluent Substances 0.000 description 8
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 8
- 235000019341 magnesium sulphate Nutrition 0.000 description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 7
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 7
- 239000003960 organic solvent Substances 0.000 description 7
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 7
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- 235000011054 acetic acid Nutrition 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 5
- 229910052799 carbon Inorganic materials 0.000 description 5
- 125000005678 ethenylene group Chemical group [H]C([*:1])=C([H])[*:2] 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 150000008282 halocarbons Chemical class 0.000 description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 5
- 229910052744 lithium Inorganic materials 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 4
- 125000001931 aliphatic group Chemical group 0.000 description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 4
- 239000012267 brine Substances 0.000 description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 4
- BGTOWKSIORTVQH-UHFFFAOYSA-N cyclopentanone Chemical compound O=C1CCCC1 BGTOWKSIORTVQH-UHFFFAOYSA-N 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 150000004678 hydrides Chemical class 0.000 description 4
- 150000004702 methyl esters Chemical class 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 4
- 239000011591 potassium Substances 0.000 description 4
- 229910052700 potassium Inorganic materials 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 238000006722 reduction reaction Methods 0.000 description 4
- 229940065287 selenium compound Drugs 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 238000011282 treatment Methods 0.000 description 4
- 229940086542 triethylamine Drugs 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical class C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 3
- 239000005977 Ethylene Substances 0.000 description 3
- 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 3
- 241000124008 Mammalia Species 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-Chlorosuccinimide Substances ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 3
- 208000008469 Peptic Ulcer Diseases 0.000 description 3
- BUGBHKTXTAQXES-UHFFFAOYSA-N Selenium Chemical compound [Se] BUGBHKTXTAQXES-UHFFFAOYSA-N 0.000 description 3
- 208000007536 Thrombosis Diseases 0.000 description 3
- 238000007239 Wittig reaction Methods 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 208000006673 asthma Diseases 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 238000005345 coagulation Methods 0.000 description 3
- 230000015271 coagulation Effects 0.000 description 3
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical group FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 description 3
- 150000002170 ethers Chemical class 0.000 description 3
- IIEWJVIFRVWJOD-UHFFFAOYSA-N ethyl cyclohexane Natural products CCC1CCCCC1 IIEWJVIFRVWJOD-UHFFFAOYSA-N 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 230000027119 gastric acid secretion Effects 0.000 description 3
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 150000007524 organic acids Chemical class 0.000 description 3
- 235000005985 organic acids Nutrition 0.000 description 3
- 208000011906 peptic ulcer disease Diseases 0.000 description 3
- 150000003165 prostaglandin E1 derivatives Chemical class 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 229910052711 selenium Inorganic materials 0.000 description 3
- 239000011669 selenium Substances 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- 150000003464 sulfur compounds Chemical class 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- YCQANBSROMMIQP-UHFFFAOYSA-N 1-chloropyrrolidine-2,5-dione;methylsulfanylmethane Chemical compound CSC.ClN1C(=O)CCC1=O YCQANBSROMMIQP-UHFFFAOYSA-N 0.000 description 2
- UWNADWZGEHDQAB-UHFFFAOYSA-N 2,5-dimethylhexane Chemical group CC(C)CCC(C)C UWNADWZGEHDQAB-UHFFFAOYSA-N 0.000 description 2
- 229910021555 Chromium Chloride Inorganic materials 0.000 description 2
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 2
- 206010020772 Hypertension Diseases 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- ZJQALQKVUGRLFF-UHFFFAOYSA-N [Cl].CSC Chemical compound [Cl].CSC ZJQALQKVUGRLFF-UHFFFAOYSA-N 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- YKIOKAURTKXMSB-UHFFFAOYSA-N adams's catalyst Chemical compound O=[Pt]=O YKIOKAURTKXMSB-UHFFFAOYSA-N 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 2
- QSWDMMVNRMROPK-UHFFFAOYSA-K chromium(3+) trichloride Chemical compound [Cl-].[Cl-].[Cl-].[Cr+3] QSWDMMVNRMROPK-UHFFFAOYSA-K 0.000 description 2
- VTHIKKVKIVQWHV-UHFFFAOYSA-N chromium(6+) oxygen(2-) pyridine Chemical compound [O-2].[O-2].[O-2].[Cr+6].C1=CC=NC=C1 VTHIKKVKIVQWHV-UHFFFAOYSA-N 0.000 description 2
- 210000001072 colon Anatomy 0.000 description 2
- MLIREBYILWEBDM-UHFFFAOYSA-N cyanoacetic acid Chemical compound OC(=O)CC#N MLIREBYILWEBDM-UHFFFAOYSA-N 0.000 description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 125000004851 cyclopentylmethyl group Chemical group C1(CCCC1)C* 0.000 description 2
- 239000002934 diuretic Substances 0.000 description 2
- 230000001882 diuretic effect Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 description 2
- 235000021588 free fatty acids Nutrition 0.000 description 2
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- NTNUDYROPUKXNA-UHFFFAOYSA-N methyl 2-(triphenyl-$l^{5}-phosphanylidene)acetate Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=CC(=O)OC)C1=CC=CC=C1 NTNUDYROPUKXNA-UHFFFAOYSA-N 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- QPNOPWWAMGQISP-UHFFFAOYSA-N n,n'-dicyclohexylmethanediimine;methylsulfinylmethane Chemical compound CS(C)=O.C1CCCCC1N=C=NC1CCCCC1 QPNOPWWAMGQISP-UHFFFAOYSA-N 0.000 description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 235000006408 oxalic acid Nutrition 0.000 description 2
- 125000004043 oxo group Chemical group O=* 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- VBQCHPIMZGQLAZ-UHFFFAOYSA-N phosphorane Chemical class [PH5] VBQCHPIMZGQLAZ-UHFFFAOYSA-N 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 235000019260 propionic acid Nutrition 0.000 description 2
- NRTYMEPCRDJMPZ-UHFFFAOYSA-N pyridine;2,2,2-trifluoroacetic acid Chemical compound C1=CC=NC=C1.OC(=O)C(F)(F)F NRTYMEPCRDJMPZ-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-O pyridinium Chemical compound C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 2
- 210000002460 smooth muscle Anatomy 0.000 description 2
- 150000003385 sodium Chemical class 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 239000011593 sulfur Substances 0.000 description 2
- UDYFLDICVHJSOY-UHFFFAOYSA-N sulfur trioxide pyridine complex Chemical class O=S(=O)=O.C1=CC=NC=C1 UDYFLDICVHJSOY-UHFFFAOYSA-N 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 1
- UCTWMZQNUQWSLP-VIFPVBQESA-N (R)-adrenaline Chemical compound CNC[C@H](O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-VIFPVBQESA-N 0.000 description 1
- 229930182837 (R)-adrenaline Natural products 0.000 description 1
- WIYMDOCSCMPUJI-UHFFFAOYSA-N 1-dimethoxyphosphoryl-3,3-dimethylheptan-2-one Chemical compound CCCCC(C)(C)C(=O)CP(=O)(OC)OC WIYMDOCSCMPUJI-UHFFFAOYSA-N 0.000 description 1
- 125000006218 1-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000006219 1-ethylpentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
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Classifications
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- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
본 발명은 트란스 -△2-프로스타글란딘 E1유도체 제조를 위한 중간체로서 신규화합물의 용도에 관한 것이다.The present invention relates to the use of the novel compounds as intermediates for the preparation of trans-Δ 2 -prostaglandin E 1 derivatives.
프로스타글란딘은 다음 구조식(I)을 가진 프로스타노산의 유도체이다.Prostaglandins are derivatives of prostinoic acid having the structure (I)
여러가지 유형의 프로스타글란딘이 알려졌고 이 유형은 그 중에서도 구조와 알리싸이클 고리중의 치환체에 좌우된다. 예를 들어 프로스타글란딘 E(PGE)의 알리싸이클 고리 구조는 다음 구조식(II)와 같다.Several types of prostaglandins are known, of which the type depends on the structure and the substituents in the alicycle ring. For example, the alicyclic ring structure of prostaglandin E (PGE) is represented by the following structural formula (II).
상기 구조식들과 본 명세서 전반에 걸쳐 있는 다른 구조식에서 점선은 일반적인 명명법에 따라 연결된 기가 고리평면의 뒷부분에 있음을 의미하며, 즉 그 기가 α-구조상태에 있음을 나타내며 두꺼운 선인
그러한 화합물들은 알리싸이클고리의 8- 및 12-위치에 붙어있는 측쇄중의 이중 결합위치에 따라 더 분류된다. 즉, PG1화합물은 C13-C14(트란스-△13)사이에 트란스-이중결합을 가지고 있고 PG2화합물은 C5-C6사이에 시스-이중 결합을 갖고 C13-C14(시스-△5, 트란스-△13)사이에 트란스-이중 결합을 가지고 있다. 예를들어 프로스타글란딘 E1(PGE1)은 다음 구조식(III)과 같다.Such compounds are further classified according to the double bond position in the side chain attached to the 8- and 12-positions of the alicycle. That is, the PG 1 compound has a trans-double bond between C 13 -C 14 (trans-Δ 13 ) and the PG 2 compound has a cis-double bond between C 5 -C 6 and C 13 -C 14 (cis -Δ 5 , trans-Δ 13 ) has a trans-double bond. For example, prostaglandin E 1 (PGE 1 ) is represented by the following structural formula (III).
PG2그룹의 하나인 PGE2의 구조는 5와 6위치에 있는 탄소 사이에 시스-이중결합을 가진 (III)구조에 해당하고 PG1그룹의 것들은 13과 14위치의 탄소원자 사이에 있는 이중결합이 에틸렌으로 치환된 화합물은 디하이드로프로스타글란딘, 예를들어 디하이드로 프로스타글란딘 E1(디하이드로-PGE1)이라고 알려져 있다.The structure of PGE 2 , one of the PG 2 groups, corresponds to the (III) structure with a cis-double bond between the carbons at positions 5 and 6, and those of the PG 1 groups are double bonds between the carbon atoms at positions 13 and 14 The compound substituted with this ethylene is known as dihydroprostaglandin, for example dihydro prostaglandin E 1 (dihydro-PGE 1 ).
제2와 3탄소원자 사이에 트란스-이중결합을 가진 PGE화합물은 트란스-△2-PGE화합물로 알려져 있고 트란스-△2-PGE1의 구조는 제 2와 3탄소원자 사이에 트란스-이중결합을 가진 (III)구조와 같다.PGE compounds having trans-double bonds between the 2nd and 3rd carbon atoms are known as trans-Δ 2 -PGE compounds and the structure of trans-Δ 2 -PGE 1 forms a trans-double bond between the 2nd and 3rd carbon atoms. It is the same as (III) having a structure.
또한 하나 또는 그 이상의 메틸렌기가 프로스타글탄딘의 지방족 환고리의 12위치에 지방족기가 붙어있는 W-쇄, 또는 지방족기가 프로스타글란딘의 지방족 환고리의 8위에 붙어 있는 α-쇄에 부가되거나 제거되었을 때 이 화합물은 통상적인 유기화합물 명명법에 따라 호모-프로스타글란딘(메틸렌기가 부가된 것) 또는 노르-프로스타글탄딘(메틸렌기가 제거된 것)으로 알려져 있고 하나 이상의 메틸렌기가 부가되거나 제거되었을 때는 접두사 "호모"나 "노르"앞에 디-, 트리- 등과 같은 숫자를 표시한다.In addition, when one or more methylene groups are added to or removed from the W-chain having an aliphatic group at position 12 of the aliphatic ring of prostaglandin, or the α-chain having an aliphatic group attached to 8th position of aliphatic ring of prostaglandin Compounds are known as homo-prostaglandins (with methylene groups added) or nor-prostagtandine (with methylene groups removed) according to conventional organic compound nomenclature, and the prefix "homo" or when one or more methylene groups are added or removed A number such as a de-, tree- and so on is displayed in front of the "nor".
일반적으로 프로스타글란딘은 약리작용을 가지고 있는 것으로 알려져 있는데 예를들어 이 화합물은 평활근을 흥분시키고 형압강하작용, 이뇨작용, 기관지 이완작용 및 항동맥 경화작용을 가지며 또한 혈소판응고를 억제하고 위산분비를 억제하므로 고혈압, 혈전증, 천식 및 위궤양치료에 유용하고 임신중인 포유동물에 분만유도 및 유산을 유발시키는데 유용하고, 동맥경화증 예방이나 이뇨제로서 유용하다. 이 물질은 생체내에서 프로스타글란딘을 분비시키는 동물의 여러가지 조직으로부터 아주 소량 얻을 수 있는 지용성물질이다. 예를들어 PGE들은 위산분비를 억제하므로 소화성 궤양치료에 사용될 수 있다. 이들은 또한 에피네프린에 의한 유리 지방산 분비를 억제시키고 혈중 유리지방산의 농도를 감소시키므로 동백경화증과 과지방혈중 예방에 유용하다. PGE1은 혈소판 응고를 억제하고 혈전을 제거시키고 혈전증을 예방한다. PGE들은 평활근을 수축시키고 장의 연동운동을 증가시키므로 수술후 장폐색증에 유용하고 하제로서 치료효과를 나타낸다. 또한 PGE들은 분만촉진제로서 유용하고 제1 및 제2의 3개월 기간에 유산촉진제로서 사용될 수도 있다. 이들은 암컷 포유동물의 성주기를 조절하기 때문에 경구 피임제로서 또한 분만후의 태반의 유산을 촉진시킨다. PGE들은 혈관확장작용과 이뇨작용을 가지고 있다. 이 화합물들은 중추혈액의 흐름을 증가시키기 때문에 중추혈관 질환으로 고생하는 환자에 치료제로서 유용하고 기관지 확장작용을 가지고 있기 때문에 천식상태 치료에 유용하다. 프로스타글란딘의 제2와 3위치의 탄소원자 사이에 있는 트란스(또는 E)-이중결합을 도입시키는 두 가지 방법이 알려져 있다. 제1의 방법은 1975년 12월 3일 발간된 영국특허 명세서, 1,416,410에 기술되어 있다. 그러나 제5와 6위치의 탄소원자 사이에 이중 결합을 형성시키기 위해서는 카복시기(-COOH)가 공유되지 않은 포스포란 화합물(C6H5)3P=CHCH2COOH를 사용해야 한다. 포스포란 화합물은 불안정하기 때문에 고수율을 얻기는 어렵다.In general, prostaglandins are known to have pharmacological action. For example, these compounds excite smooth muscle, have hypotensive, diuretic, bronchial relaxation, and anti-arteriosclerosis effects, and also inhibit platelet coagulation and gastric acid secretion. It is useful for the treatment of hypertension, thrombosis, asthma and gastric ulcer, to induce delivery and miscarriage in pregnant mammals, and to prevent atherosclerosis or diuretics. It is a fat-soluble substance that can be obtained in very small amounts from various tissues of animals that secrete prostaglandins in vivo. For example, PGE can be used to treat peptic ulcer because it inhibits gastric acid secretion. They are also useful in preventing camellia and hyperlipidemia because they inhibit the release of free fatty acids by epinephrine and reduce the concentration of free fatty acids in the blood. PGE 1 inhibits platelet coagulation, eliminates blood clots and prevents thrombosis. PGE constricts smooth muscle and increases intestinal peristalsis, which is useful for postoperative ileus and has a therapeutic effect as a laxative. PGEs are also useful as labor accelerators and may be used as lactic acid promoters in the first and second three month periods. Because they regulate the sex cycle of female mammals, they also promote the abortion of the placenta as an oral contraceptive. PGE has vasodilator and diuretic effects. These compounds are useful as treatments for patients suffering from central vascular disease because they increase central blood flow and are useful for treating asthma because they have bronchial dilation. Two methods are known for introducing trans (or E) -double bonds between the carbon atoms at the second and third positions of prostaglandins. The first method is described in British Patent Specification 1,416,410, published December 3, 1975. However, in order to form a double bond between the 5th and 6th position carbon atoms, the phosphorane compound (C 6 H 5 ) 3 P = CHCH 2 COOH without carboxy group (-COOH) should be used. Phosphoran compounds are unstable, so high yields are difficult to obtain.
또한 트란스 -△2-프로스타글란딘을 제조하기 위한 일련의 반응에서 트란스 -△2- PGE1유도체를 얻으려면 선택적인 수소화반응이 필요하다. 제13과 14위치에 있는 탄소원자 사이의 이중결합은 그대로 두는 반면에 제 5 및 6탄소 사이의 이중결합은 수소화시켜야 한다. 두 개의 이중 결합을 수소화시키므로서 원하는 목적물의 수율을 낮추게 될 위험이 있다. 결국 원하는 W-쇄를 도입시키는데 필요한 비싼 기질이 많이 필요하기 때문에 W-쇄는 원하는 트란스 -△2-프로스타글란딘을 제조하는 일련의 반응에서 처음 단계에서 도입시키는 것이 필요하다.Also trans - △ 2 - △ 2 - - trans in a series of reactions for the production of prostaglandin PGE 1 derivative to achieve the require selective hydrogenation. The double bond between the carbon atoms at positions 13 and 14 should be left while the double bond between the fifth and sixth carbons should be hydrogenated. There is a risk of lowering the yield of the desired object by hydrogenating two double bonds. After all because they require a lot of expensive substrates required for introducing the desired W- chain W- chain is desired trans- it is necessary to introduce in the first step in the series of reaction for preparing the prostaglandin - △ 2.
두번째 방법은 1977년 8월 17일과 1979년 2월 14일 발간된 우리의 영국특허 1,483,240과 1,540,427에 각각 기술되어 있다. 제2와 3탄소사이에 이중결합을 도입시키려면 셀렌이나 황화합물이 필요하다. 이런 화합물은 극소량도 인간에 해롭고 만약 최종 트란스 -△2- 프로스타글란딘 생성물을 의약으로 사용하려면 이 황이나 셀렌 화합물은 제거되어야 한다. 이 제거 공정은 어렵고 상당한 주의를 하여야 한다. 또한 셀렌이나 황화합물은 아주 불괘한 악취를 가지고 있으므로 제조나 사용에 곤란하다.The second method is described in our British Patents 1,483,240 and 1,540,427, published August 17, 1977 and February 14, 1979, respectively. Selenium or sulfur compounds are required to introduce a double bond between the second and third carbons. These compounds are extremely harmful to humans and if sulfur is used, the sulfur or selenium compounds must be removed if the final trans-Δ 2 -prostaglandin product is used as a drug. This removal process is difficult and requires great care. In addition, selenium and sulfur compounds have a very unpleasant odor, making it difficult to manufacture or use.
계속적인 연구와 실험결과 트란스 -△2-PGE1유도체의 개선된 제조방법을 위한 중간체로서 유용한 새로운 화합물이 발견되었다. 트란스 -△2- 프로스타글란딘 E1유도체 제조에 유용한 신규화합물은 다음 구조식(Ⅳ) 화합물이다.Ongoing studies and experiments have found new compounds useful as intermediates for improved preparation of trans-Δ 2 -PGE 1 derivatives. A novel compound useful for preparing the trans-Δ 2 -prostaglandin E 1 derivative is the following formula (IV) compound.
상기식에서 Y는
본 명세서 및 첨부된 특허청구범위에서 알킬, 알킬렌기나 알킬 및 알킬렌 그룹은 직쇄 또는 분지쇄일 수 있다는 것을 이해하여야 한다.It is to be understood that the alkyl, alkylene groups or alkyl and alkylene groups in this specification and the appended claims may be straight or branched chains.
본 발명은 광학활성인 천연형태나 그의 대장체 또는 그의 혼합물, 특히 광학적으로 활성인 천연형과 그의 대장체형이 같은 몰 비율로 혼합된 라세미형 상태의 일반식 (Ⅳ)의 모든 화합물을 포함한다.The present invention encompasses all compounds of the general formula (IV) in racemic form in which the optically active native form or its colon or mixtures thereof, in particular the optically active native and its colon form, are mixed in the same molar ratio.
당업자에게는 분명하듯 이 구조식(Ⅳ)로 도시된 화합물은 C-8, C-11 및 C-12 탄소원자에 최소한 3개의 부재탄소위치가 있다. 또한 촉쇄알킬이나 알킬렌기에서나 또는 Y가
따라서 트란스 구조로 8과 12 위치의 싸이클로펜탄고리의 탄소에 붙은 치환기를 가진 일반식(Ⅳ)의 모든 이성체와 그의 혼합물은 일반식(Ⅳ) 화합물의 범주안에 포함되는 것으로 생각된다. 바람직한 -R3-R3기로는 예를 들면 메틸, 에틸, 1-메틸에틸프로필, 1-메틸프로필, 2-메틸프로필, 1-에틸프로필, 부틸, 1-메틸부틸, 2-메틸부틸, 3-메틸부틸, 1-에틸부틸, 2-에틸부틸, 펜틸, 1-메틸펜틸, 2-메틸펜틸, 3-메틸펜틸, 4-메틸펜틸, 1,1-디메틸펜틸, 1,2-디메틸펜틸, 1,4-디메틸펜틸, 1-에틸펜틸, 2-에틸펜틸, 1-프로필펜틸, 2-프로필펜틸, 헥실, 1-메틸헥실, 2-메틸헥실, 1,1-디메틸헥실, 1-에틸헥실, 2-에틱헥실, 헵틸, 2-에틸헵틸, 노닐, 운데실, 싸이클로부틸, 1-프로필싸이클로부틸, 1-부틸싸이클로부틸, 1-펜틸싸이클로부틸, 1-헥실싸이클로부틸, 2-메틸싸이클로부틸, 2-프로필싸이클로부틸, 3-에틸싸이클로부틸 3-프로필싸이클로부틸, 2,3,4-트리에틸싸이클로부틸, 싸이클로펜탈, 싸이클로펜틸메틸, 1-싸이클로펜틸에틸, 2-싸이클로펜틸에틸, 2-싸이클로펜틸프로필, 3-싸이클로펜틸프로필, 2-펜틸싸이클로펜틸, 2,2-디메틸싸이클로펜틸, 3-에틸싸이클로펜틸, 3-프로필싸이클로펜틸, 3-부틸싸이클로펜틸, 3-터트-부틸싸이클로펜틸, (1-메틸-3-프로필)싸이클로펜틸, (2-메틸-3프로필)싸이클로펜틸, (2-메틸-4-프로필)싸이클로펜틸, 싸이클로헥실, 싸이클로펜틸메틸, 1-싸이클로헥실에틸, 2-싸이클로헥실에틸, 3-싸이클로헥실프로필, (1-메틸-2-싸이클로헥실)에틸, 2-싸이클로헥실프로필, (1-메틸-1-사이클로헥실)에틸, 4-싸이클로헥실부틸, 3-에틸싸이클로헥실, 3-이소프로필싸이클로헥실, 4-메틸싸이클로헥실, 4-에틸싸이클로헥실, 4-프로필싸이클로헥실, 4-터트-부틸싸이클로헥실, 2,6-디메틸싸이클로헥실, 2,2-디메틸싸이클로헥실, (2,6-디메틸-4-프로필)싸이클로헥실, 1-메틸싸이클로헥실메틸, 싸이클로헵틸, 싸이클로헵틸메틸, 1-싸이클로헵틸에틸, 2-싸이클로헵틸에틸, 페닐, 벤질, 1-페닐에틸, 2-페닐에틸, 3-페닐프로필, 4-페닐부틸, 5-페닐펜틸, (1-메틸-2-페닐)에틸, (1,1-디메틸-2-페닐)에틸, (1-메틸-1-페닐)에틸, 1-페닐펜틸, 페녹시메틸, 2-페녹시에틸, 3-페녹시프로필, 4-페녹시부틸, 5-페녹시펜틸, 3-클로로페녹시메틸, 4-클로로페녹시메틸, 4-플루오로페녹시메틸, 3-플루오로메틸페녹시메틸, 2-메틸페녹시메틸, 3-메틸페녹시메틸, 4-메틸페녹시메틸, 4-에틸페녹시메틸, 4-터트-부틸페녹시메틸, 4-세크-부틸페녹시메틸, 프로폭시메틸, 이소프로폭시메틸, 부톡시메틸, 펜틸옥시메틸, 헥실옥시메틸, 1-에톡시에틸, 1-프로폭시에틸, 1-이소프로폭시에틸, 1-네오펜틸옥시에틸, 1-펜틸옥시에틸, (1-메틸-1-에톡시)에틸, (1-메틸-1-프로폭시)에틸, (1-메틸-1-이소부톡시)에틸, (1-메틸-1-네오펜틸옥시)에틸, (1-메틸-1-부톡시)에틸, (1-메틸-1-이소펜틸옥시)에틸, (1-메틸-1-펜틸옥시)에틸, 2-에톡시에틸, 2-프로폭시에틸, 2-부톡시에틸, 2-(1-에틸부톡시)에틸, 2-펜틸옥시에틸, 1-에톡시프로필, 1-프로폭시프로필, 1-(2-메틸부톡시)프로필, 1-펜틸옥시프로필, 2-메톡시프로필, 3-메톡시프로필, 3-에톡시프로필, 3-프로폭시프로필, 3-세크-부톡시프로필, 3-이소부톡시프로필, 3-부톡시프로필, (1-메틸-2-메톡시)에틸, (1-메틸-2-에톡시)에틸, (1-메틸-2-이소부톡시)에틸, 1-펜틸옥시부틸, (1-펜틸옥시-2-메틸)프로필, 4-메톡시부틸, 4-에톡시부틸, 4-프로폭시부틸, (1-메틸-3-메톡시)프로필, (1-메틸-3-프로폭시)프로필(2-메틸-3-메톡시)프로필, (1,1-디메틸-2-에톡시)에틸, (1,1-디메틸-2-프로폭시)에틸, (1,1-디메틸-2-이소부톡시)에틸, 5-메톡시페틸, 5-에톡시페틸, 1-페틸옥시페틸, (1-에틸-3-프로폭시)프로필, 싸이클로부틸옥시메틸, 싸이클로페틸옥시메틸, 싸이클로헥실 옥시메틸, 싸이클로헥틸옥시메틸, 2-싸이클로페틸옥시메틸 또는 2-싸이클로헥실옥시에틸이 있으며 특히 1,1-디메틸펜틸이 좋다.Therefore, all isomers of general formula (IV) having a substituent attached to carbon of cyclopentane ring at positions 8 and 12 in the trans structure and mixtures thereof are considered to be included in the category of general formula (IV) compounds. Preferred -R 3 -R 3 groups are, for example, methyl, ethyl, 1-methylethylpropyl, 1-methylpropyl, 2-methylpropyl, 1-ethylpropyl, butyl, 1-methylbutyl, 2-methylbutyl, 3 -Methylbutyl, 1-ethylbutyl, 2-ethylbutyl, pentyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylpentyl, 1,2-dimethylpentyl, 1,4-dimethylpentyl, 1-ethylpentyl, 2-ethylpentyl, 1-propylpentyl, 2-propylpentyl, hexyl, 1-methylhexyl, 2-methylhexyl, 1,1-dimethylhexyl, 1-ethylhexyl , 2-ethoxyhexyl, heptyl, 2-ethylheptyl, nonyl, undecyl, cyclobutyl, 1-propylcyclobutyl, 1-butylcyclobutyl, 1-pentylcyclobutyl, 1-hexylcyclobutyl, 2-methylcyclobutyl , 2-propylcyclobutyl, 3-ethylcyclobutyl 3-propylcyclobutyl, 2,3,4-triethylcyclobutyl, cyclopental, cyclopentylmethyl, 1-cyclopentylethyl, 2-cyclopentylethyl, 2- Cyclopentylpropyl, 3- Iclopentylpropyl, 2-pentylcyclopentyl, 2,2-dimethylcyclopentyl, 3-ethylcyclopentyl, 3-propylcyclopentyl, 3-butylcyclopentyl, 3-tert-butylcyclopentyl, (1-methyl- 3-propyl) cyclopentyl, (2-methyl-3propyl) cyclopentyl, (2-methyl-4-propyl) cyclopentyl, cyclohexyl, cyclopentylmethyl, 1-cyclohexylethyl, 2-cyclohexylethyl, 3 -Cyclohexylpropyl, (1-methyl-2-cyclohexyl) ethyl, 2-cyclohexylpropyl, (1-methyl-1-cyclohexyl) ethyl, 4-cyclohexylbutyl, 3-ethylcyclohexyl, 3-iso Propylcyclohexyl, 4-methylcyclohexyl, 4-ethylcyclohexyl, 4-propylcyclohexyl, 4-tert-butylcyclohexyl, 2,6-dimethylcyclohexyl, 2,2-dimethylcyclohexyl, (2,6 -Dimethyl-4-propyl) cyclohexyl, 1-methylcyclohexylmethyl, cycloheptyl, cycloheptylmethyl, 1-cyclo Heptylethyl, 2-cycloheptylethyl, phenyl, benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, (1-methyl-2-phenyl) ethyl, ( 1,1-dimethyl-2-phenyl) ethyl, (1-methyl-1-phenyl) ethyl, 1-phenylpentyl, phenoxymethyl, 2-phenoxyethyl, 3-phenoxypropyl, 4-phenoxybutyl, 5-phenoxypentyl, 3-chlorophenoxymethyl, 4-chlorophenoxymethyl, 4-fluorophenoxymethyl, 3-fluoromethylphenoxymethyl, 2-methylphenoxymethyl, 3-methylphenoxymethyl 4-methylphenoxymethyl, 4-ethylphenoxymethyl, 4-tert-butylphenoxymethyl, 4-cet-butylphenoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, pentyloxymethyl, Hexyloxymethyl, 1-ethoxyethyl, 1-propoxyethyl, 1-isopropoxyethyl, 1-neopentyloxyethyl, 1-pentyloxyethyl, (1-methyl-1-ethoxy) ethyl, (1 -Methyl-1-propoxy) ethyl, (1-methyl-1-isobutoxy) ethyl, (1-methyl-1-neopentyloxy) ethyl, (1-methyl-1- Methoxy) ethyl, (1-methyl-1-isopentyloxy) ethyl, (1-methyl-1-pentyloxy) ethyl, 2-ethoxyethyl, 2-propoxyethyl, 2-butoxyethyl, 2- ( 1-ethylbutoxy) ethyl, 2-pentyloxyethyl, 1-ethoxypropyl, 1-propoxypropyl, 1- (2-methylbutoxy) propyl, 1-pentyloxypropyl, 2-methoxypropyl, 3 -Methoxypropyl, 3-ethoxypropyl, 3-propoxypropyl, 3-cec-butoxypropyl, 3-isobutoxypropyl, 3-butoxypropyl, (1-methyl-2-methoxy) ethyl, ( 1-methyl-2-ethoxy) ethyl, (1-methyl-2-isobutoxy) ethyl, 1-pentyloxybutyl, (1-pentyloxy-2-methyl) propyl, 4-methoxybutyl, 4-e Methoxybutyl, 4-propoxybutyl, (1-methyl-3-methoxy) propyl, (1-methyl-3-propoxy) propyl (2-methyl-3-methoxy) propyl, (1,1-dimethyl 2-ethoxy) ethyl, (1,1-dimethyl-2-propoxy) ethyl, (1,1-dimethyl-2-isobutoxy) ethyl, 5-methoxypetyl, 5-ethoxypetyl, 1- Petyloxyfetyl, (1-ethyl-3-propoxy) propyl, Cycle and the butyl oxymethyl, cyclo petil oxymethyl, cyclo hexyl oxymethyl, cyclo hektil oxymethyl, 2-cyclo petil oxymethyl or 2-cyclo hexyl-oxyethyl good especially 1,1-dimethylpentyl.
본 명세서와 특허청구 범위에서 R4로 표시한 염기성하에서 제기될 수 있는 하이드록시보호기가 제거되는 동안 이 화합물의 다른 부위에 영향을 미치지 않는 기이고 약염기성에서 쉽게 제거되는 것이다. 바람직한 하이드록시 보호기의 예로는 아세틸, 클로로아세틸, 디클로로세틸, 트리클로로아세틸, 트리플루오로아세틸, 프로피오닐, 벤조일, P-페닐벤조일, 또는 나프틸오일 같은 아실기가 있고 특히 아세틸이 좋다.It is a group which does not affect other sites of this compound and is easily removed from weak bases while the hydroxyprotecting group which may be raised under the basicity indicated by R 4 in this specification and claims is removed. Examples of preferred hydroxy protecting groups are acyl groups such as acetyl, chloroacetyl, dichlorocetyl, trichloroacetyl, trifluoroacetyl, propionyl, benzoyl, P-phenylbenzoyl, or naphthyloil, with acetyl being particularly preferred.
본 발명은 R'이 포르밀기를 나타내고, Y는
상기식에서 R은 C1-C4의 알킬기를 나타내고, R2와 R3는 전술한 바와 같고, 제 2와 3탄소원자사이의 이중결합과 제13과 14탄소원자사이의 이중결합은 트란스이다.Wherein R represents a C 1 -C 4 alkyl group, R 2 and R 3 are as described above, and the double bond between the second and third carbon atoms and the double bond between the thirteenth and fourteen carbon atoms is trans.
위티그(Wittig) 반응은 미국의 죤윌리의 손스회사의 "유기반응" 제14권 3장(1965)에 기술되어 있다. 이 반응은 불활성유기용매, 예를들면 디에틸에테르, 테트라하이드로푸란, 디옥산이나 1,2-디메톡시에탄 같은 에테르, 벤젠, 톨루엔, 크실렌이나 헥산같은 탄화수소, 디메틸설폭사이드같은 디알킬 설폭사이드, N,N-디메틸포름아미드 같은 디알킬포름아미드, 메틸렌클로라이드나 클로로포름같은 할로겐화 탄화수소, 또는 메탄올이나 에탄올 같은 C1-C4의 알칸올, 또는 둘 이상의 이들의 혼합물내에서 -78℃ 내지 반응혼합물의 환류온도하에 수행된다.The Wittig reaction is described in John 14, Chapter 3 (1965), "Organic Reactions" of the Sons Company of the United States. The reaction is carried out with an inert organic solvent such as diethyl ether, tetrahydrofuran, ethers such as dioxane or 1,2-dimethoxyethane, hydrocarbons such as benzene, toluene, xylene or hexane, dialkyl sulfoxides such as dimethyl sulfoxide, From -78 ° C. to the reaction mixture in a dialkylformamide such as N, N-dimethylformamide, a halogenated hydrocarbon such as methylene chloride or chloroform, or a C 1 -C 4 alkanol such as methanol or ethanol, or a mixture of two or more thereof It is carried out at reflux temperature.
일반식(Ⅵ)의 포스포란 화합물은 잘 알려져 있거나 공지방법으로 쉽게 제조할 수 있다. "공지방법"이란 이제까지 언급된 방법이나 화학문헌에 기술된 방법을 의미한다.Phosphoran compounds of formula (VI) are well known or can be readily prepared by known methods. "Notification method" means the method described so far or the method described in the chemical literature.
R'이 -CH2OR4이고, Y가
상기식에서 R4a는 염기성에서 제거되는 하이드록시 보호기이고 R6는 C1-C4의 알킬기인데 메틸기나 에틸기가 좋고, 여러가지 부호는 상술한 바와 같다.In the above formula, R 4a is a hydroxy protecting group to be removed from the basic and R 6 is a C 1 -C 4 alkyl group, methyl or ethyl group is good, various symbols are as described above.
일반식(Ⅵ)인 디알킬포스포네이트의 나트륨 유도체는 디알킬포스포네이트와 수소화나트륨(NaH)을 반응시켜 제조할 수 있다.The sodium derivative of dialkylphosphonate of formula (VI) can be prepared by reacting dialkylphosphonate with sodium hydride (NaH).
위티그(Wittig)반응은 전술한 바와 같이 공지된 방법으로 수행될 수 있다.The Wittig reaction can be carried out in a known manner as described above.
일반식(Ⅶ)인 디알킬포스포네이트와 일반식의 포스포란화합물은 잘 알려져 있거나 공지방법으로 쉽게 제조할 수 있다.Dialkyl phosphonates of general formula and phosphorane compounds of general formula are well known or can be easily prepared by known methods.
R'이 -CH2OR4이고, Y가
상기식에서 여러가지 부호는 상술한 바와 같다.Various symbols in the above formula are as described above.
옥소기를 하이드록시기로 전환시키는 반응은 소디움보로하이드라이드, 포타슘 보로하이드라이드, 아연보로하이드, 리티움트리-터드-부톡시알루미늄하이드라이드, 리티움트리메톡시알루미늄하이드라이드, 소디움시아노보로하이드라이드, 포타슘트리-세크-부틸보호하이드라이드, 리티움알루미늄하이드라이드-퀴닌복합체, (-)-이소보르닐옥시마그네슘 요오다이드같은 어떤 적당한 환원제를 사용하여 메탄올, 에탄올이나 이소프로판올 같은 C1-C4의 알칸올, 테트라하이드로푸란, 디옥산이나 1,2-디메톡시에탄 같은 에테르 또는 둘 이상의 이들의 혼합물 같은 불활성 유기용매내에서 -78℃-실온하에서 수행된다.The reaction for converting an oxo group to a hydroxyl group is sodium borohydride, potassium borohydride, zinc borohydride, lithium riumtri-terd-butoxyaluminum hydride, lithium riumtrimethoxyaluminum hydride, sodium cyanoboro C 1 -such as methanol, ethanol or isopropanol using any suitable reducing agent such as hydride, potassium tri-sec-butylprotected hydride, lithium aluminum hydride-quinine complex, (-)-isobornyloxymagnesium iodide It is carried out at −78 ° C.-room temperature in an inert organic solvent such as C 4 alkanol, tetrahydrofuran, ether such as dioxane or 1,2-dimethoxyethane or mixtures of two or more thereof.
이 환원반응은 일본특허공개소 54-76552에 기술된 디이소보르닐옥시알루미늄이소프로폭사이드나 일본특허공개소 54-154739와 J.Org. Chem., 44. 1364(1979)에 기술된 디이소부틸(알킬치환 또는 비치환된)페녹시알루미늄, 또는 J. Amer. Chem. Soc., 101. 5843(1979)에 기술된 리티움 1,1'-비나프틸 -2,2'- 디옥시알루미늄하이드라이드를 사용하는 것이 더욱 좋다. 이렇게 얻어진 생성물은 15-하이드록시기가 α- 또는 β-구조를 가진 이성체 혼합물인데 이 혼합물은 예를들어 실리카겔상에서 박층, 컬럼, 또는 고속액체 크로마토그라피와 같은 통상의 수단으로 분리시켜 일반식(ⅣB)의 원하는 이성체를 얻을 수 있다.This reduction reaction is carried out by diisobornyloxyaluminum isopropoxide described in Japanese Patent Application Laid-Open No. 54-76552, or Japanese Patent Publication No. 54-154739 and J.Org. Diisobutyl (alkyl-substituted or unsubstituted) phenoxyaluminum, as described in Chem., 44. 1364 (1979), or J. Amer. Chem. Preference is given to using Lithium 1,1'-binafthyl-2,2'-dioxyaluminum hydride described in Soc., 101. 5843 (1979). Inde thus obtained product isomer mixture 15-hydroxy groups with a α- or β- structure in which a mixture, for example by separation by conventional means such as thin layer chromatography, and the column, or high performance liquid chromatography on silica gel Ⅳ formula (B Can yield the desired isomer.
R'이 -CH2OR4이고, Y가
상기식에서 여러가지 부호는 상술한 바와같다.Various symbols in the above formula are as described above.
R'이 -CH2OR4이고, Y가
R'이 포르밀이고, Y가
이 산화반응은 예를들어 (1) 테쓰지카미야, "합성유기화학 Ⅲ, 유기합성 1" PP 176-206(1976), 난코도(일본), 이나 (2) "유기합성방법개론" 제1권(1971), 2(1974) 및 3(1977) 제48절, 죤 월리 및 손스회사(미국)에 기술된 방법과 같은 하이드록시기를 옥소기로 전환시키는 공지방법으로 수행된다. 이 산화반응은 온화한 중성하에서 예를들어 디메틸설파이드 -N-클로로석신이미드 복합체, 티오아니솔 -N-클로로석신이미드 복합체, 디메틸설파이드-염소 복합체 또는 티오아니솔-염소 복합체 [참조 J. Amer. Chem.Soc,. 94, 7586(1972)]. 디싸이클로헥실카보디이미드-디메틸설폭사이드 복합체[참조 J. Amer. Chem.Soc,. 87, 5661(1965)]. 피리디니움클로로메이트(C5H5NHCrO3Cl)[참조. 테트라헤드론레터즈ㆍ2647(1975)]. 설퍼트리옥사이드-피리딘복합체 [참조. J. Amer. Chem. Soc,. 97, 5929(1975)]. 크로미움트리옥사이드-피리딘복합체(예, 콜린시약) 또는 존의 시약으로 수행하는 것이 좋다. 디메틸설파이드-N-클로로석신이미드 복합체, 티오아니솔-N-클로로석신이미드 복합체, 디메틸설파이드-염소 복합체나 티오아니솔-염소 복합체를 사용하는 산화반응은 클로로포름, 염화메틸렌이나 사염화탄소 같은 할로겐화 탄화수소, 또는 톨루엔 내에서 -30
일반식(Ⅴ)화합물은 다른 반응식 A에 도시한 일련의 반응에 따라 제조될 수 있으며 여기서 R8은 벤질기 또는 산성에서 테트라하이드로피란-2-일기보다 쉽게 제거될 수 있는 하이드록시 보호기이고, 이중결합은 E나 Z, 또는 그의 혼합물, 즉 EZ이고 다른 부호는 상술한 바와 같다. (1-메톡시-1-메틸)에틸, 1-메톡시싸이클로헥실, 1-메톡시-1-페닐에틸, 1-에톡시에틸, 테트라하이드로피란-2-일 트리메틸실릴기는 테트라하이드로피란-2-일기보다 쉽게 제거되는 적당한 하이드록시 보호기이다.Compounds of formula (V) may be prepared according to the series of reactions shown in other Scheme A, wherein R 8 is a hydroxy protecting group which can be removed more easily than the tetrahydropyran-2-yl group from benzyl or acid, The bond is E or Z, or a mixture thereof, ie EZ and the other symbols are as described above. (1-methoxy-1-methyl) ethyl, 1-methoxycyclohexyl, 1-methoxy-1-phenylethyl, 1-ethoxyethyl, tetrahydropyran-2-yl trimethylsilyl group is tetrahydropyran-2 -A suitable hydroxy protecting group that is easier to remove than diary.
[반응식 A]Scheme A
반응식 A에서 전환 [a]는 다음 일반식(ⅩⅡ)의 포스포니움 화합물의 일라이드를, 일반식(Ⅴ) 화합물을 일반식(ⅣA) 화합물로 전환시키는 상술한 방법으로 처리하여 수행한다.Conversion [a] in Scheme A is carried out by treating the lide of the phosphonium compound of the following general formula (XII) by the above-described method of converting the general formula (V) compound to the general formula (IV A ) compound.
상기식에서 X는 할로겐원자이고, R7은 상술한 바와 같다.Wherein X is a halogen atom and R 7 is as described above.
일반식(ⅩⅡ)의 포스포니움 화합물의 일라이드는 일반식(ⅩⅡ)의 포스포니움 화합물을 적당한 염기, 즉 부틸리티움, 또는 다음 일반식(ⅩⅢ)의 리티움 화합물, 예를들어 리티움 디이소프로필아마이드와 불활성 유기용매, 예를들어 일반식(Ⅴ) 화합물의 위티그 반응에 적당한 용매내에서 -78℃ 내지 실온으로 반응시켜 제조할 수 있다.The lide of the phosphonium compound of general formula (XII) may be selected from a suitable base, ie butylrium, or a lithium compound of the following general formula (XIII), for example It can be prepared by reacting diisopropylamide with an inert organic solvent such as the compound of formula (V) at -78 ° C to room temperature in a suitable solvent.
상기식에서 R9와 R10은 같거나 다르며 각각 C1-C6의 알킬, C3-C6의 싸이클로알킬기를 나타낸다.Wherein R 9 and R 10 are the same or different and represent C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl groups, respectively.
일반식(ⅩⅡ)의 포스포니움 화합물은 잘 알려져 있고, 또한 공지방법으로 쉽게 제조할 수도 있다.The phosphonium compound of general formula (XII) is well known, and can also be manufactured easily by a well-known method.
전환[b]는 예를 들어 R4a가 아실기일때 염화아실 R4aCl(여기서 R4a는 상술한 바와 같다), 또는 산무수물(R4a)20(여기서 R4a는 상술한 바와 같다)를 사용하여 염화메틸렌이나 피리딘 같은 불활성 유기용매내에서 피리딘이나 트리에틸아민 같은 3급 아민존재하에 실온이하, 좋기로는 0℃이하에서 수행할 수 있다.Conversion [b] uses, for example, acyl chloride R 4a Cl where R 4a is as described above when R 4a is an acyl group or acid anhydride (R 4a ) 20 where R 4a is as described above. In the presence of a tertiary amine such as pyridine or triethylamine in an inert organic solvent such as methylene chloride or pyridine.
전환 [c]에서 R8이 벤질기일때 일반식(XI)화합물은 일반식(X)화합물을 환원시켜 비닐렌과 벤질옥시기를 동시에 각각 에틸렌과 하이드록시기로 전환시켜 제조할 수 있다. 이 환원 반응은 팔라듐탄소, 팔라듐블랜, 플라티늄 디옥사이드 또는 라니니켈같은 환원촉매 존재하에 수소기류하에서 메탄올이나 에탄올 같은 C1-C4이 알칸올, 에틸아세테이트, 또는 둘이상의 이들의 혼합물과 같은 불활성 유기용매내에서 보통 또는 상승기압 예를들어 대기압 -15kg/cm2의 수소압으로 실온 내지 반응혼합물의 환류온도에서 적절하게 수행될 수 있다.In the conversion [c], when R 8 is a benzyl group, the compound of formula (XI) may be prepared by reducing the compound of formula (X) to convert vinylene and benzyloxy groups into ethylene and hydroxyl groups, respectively. This reduction reaction is carried out in the presence of a reducing catalyst such as palladium carbon, palladium blanc, platinum dioxide or raninickel in an inert organic solvent such as C 1 -C 4 dialkanol, ethyl acetate, or mixtures of two or more thereof, in the hydrogen stream. It can be suitably carried out at room temperature to the reflux temperature of the reaction mixture at a normal or elevated atmospheric pressure, for example at atmospheric pressure of -15 kg / cm 2 .
R8이 벤질기가 아닐때 일반식(X) 화합물은 테트라하이드로피란 -2-일기가 제거되지 않게 하여 산성에서 온화한 가수분해를 하고 R8이 벤질기인 일반식(Ⅴ) 화합물을 일반식(XI) 화합물로 전환시킬때와 같은 방법으로 얻어진 일반식(XIV)화합물을 환원시키고 일반식(XIV) 중의 비닐렌기를 에틸렌기로 전환시킨다.When R 8 is not a benzyl group, the general formula (X) compound does not remove the tetrahydropyran-2-yl group, so that it is mildly hydrolyzed in acid, and a general formula (V) compound wherein R 8 is a benzyl group is represented by the general formula (XI). The compound of formula (XIV) obtained in the same manner as when converted to a compound is reduced and the vinylene group in formula (XIV) is converted to an ethylene group.
상기식에서 여러가지 부호들은 상술한 바와 같다.Various symbols in the above formula are as described above.
산성하에서의 온화한 가수분해는 (1) 초산, 프로피온산, 옥살산이나 P-톨루엔설폰산 같은 유기산, 또는 염산, 황산이나 인산같은 무기산의 수용액으로 메탄올이나 에탄올, 좋기로는 메탄올과 같은 C1-C4의 알칸올, 또는 1,2-디메톡시에탄, 디옥산 또는 테트라하이드로푸란, 좋기로는 테트라히이드로푸란과 같은 에테르등의 물과 혼화될 수 있는 유기응매존재하에 실온 또는 그 이하의 온도, 좋기로는 0℃에서 수행하거나 (2) 무수메탄올이나 에탄올 같은 C1-C4의 무수알칸올 내에서 0℃ 또는 그 이하의 온도로 p-톨루엔설폰산이나 트리플루오로 초산 같은 유기산무수용액으로 처리하여 수행할 수 있다.Mild hydrolysis under acidic conditions (1) is a solution of organic acids such as acetic acid, propionic acid, oxalic acid or P-toluenesulfonic acid, or inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid, such as methanol, ethanol and preferably C 1 -C 4 At room temperature or below, preferably in the presence of an organic cosolvent that may be miscible with water such as an alkanol, or ether such as 1,2-dimethoxyethane, dioxane or tetrahydrofuran, preferably tetrahydrofuran Is carried out at 0 ° C. or (2) treated with an organic anhydride solution such as p-toluenesulfonic acid or trifluoroacetic acid at a temperature of 0 ° C. or lower in a C 1 -C 4 anhydrous alkanol such as methanol or ethanol. Can be done.
전환 [d]는 일반식(ⅣD) 화합물을 일반식(ⅣE) 화합물로 전환시키는 방법으로 수행될 수 있다.Conversion [d] can be carried out by converting the general formula (IV D ) compound into the general formula (IV E ) compound.
R8이 벤질기인 일반식(Ⅷ)의 출발물질은 J. Org. Chem., 37. 2921(1972)에 기술된 공지화합물이다. R8이 벤질기가 아닌 일반식(Ⅷ)의 출발물질은 일본특허공개소 53-149954에 기술된 방법으로 제조된다.Starting materials of the general formula (III) wherein R 8 is benzyl group are described in J. Org. Chem., 37. 2921 (1972). A starting material of the general formula (VII) wherein R 8 is not a benzyl group is prepared by the method described in Japanese Patent Laid-Open No. 53-149954.
테트라하이드로피란 -2-일옥시기를 산성 조건하에서 하이드록시기로 전환시키는 일반식(Ⅶ)의 화합물의 가수분해는 잘 알려져 있고 이 가수분해는 예를들어.Hydrolysis of compounds of the general formula for converting tetrahydropyran-2-yloxy groups to hydroxy groups under acidic conditions is well known and this hydrolysis is for example.
(1) 초산, 프로피온산, 옥살산, p-톨루엔설폰산 같은 유기산, 염산, 황산, 인산 같은 무기산 수용액으로 좋기로는 메탄올이나 에탄올, 좋기로는 메탄올 같은 저급 알칸올, 또는 1,2-디메톡시에탄, 디옥산, 테트라하이드로푸란, 좋기로는 테트라하이드로푸란 같은 에테르등 물과 혼화될 수 있는 불활성 유기용매 존재하에 실온 내지 75℃에서 수행 하거나,(1) aqueous solutions of organic acids such as acetic acid, propionic acid, oxalic acid, p-toluenesulfonic acid, inorganic acids such as hydrochloric acid, sulfuric acid, and phosphoric acid, preferably methanol, ethanol, lower alkanols such as methanol, or 1,2-dimethoxyethane At room temperature to 75 ° C. in the presence of an inert organic solvent which may be miscible with water such as ethers such as dioxane, tetrahydrofuran and preferably tetrahydrofuran,
(2) 0-45℃에서 메탄올이나 에탄올 같은 저급알칸올 내에서 p-톨루엔설폰산이나 트리플루오로초산 같은 유기산의 무수용액으로 수행하거나,(2) at 0-45 ° C. with anhydrous solutions of organic acids such as p-toluenesulfonic acid or trifluoroacetic acid in lower alkanols such as methanol or ethanol, or
(3) 10-60℃에서 메탄올이나 에탄올 같은 저급알칸올 내에서 p-톨루엔설폰산-피리딘복합체나 트리플루오로초산-피리딘 복합체의 무수용액으로 수행한다. 산성조건하에서의 온화한 가수분해 반응은 묽은 염산과 테트라하이드로푸란 혼합물, 묽은 염산과 메탄올 혼합물, 초산, 물 및 테트라하이드로푸란 혼합물, 인산물 및 테트라하이드로푸란 혼합물, p-톨루엔설폰산과 메탄올혼합물, p-톨루엔설폰산-피리딘 복합체와 메탄올의 혼합물, 또는 트리플루오로초산-피리딘 복합체와 메탄올 혼합물로 수행될 수 있다.(3) at 10-60 ° C. with anhydrous solution of p-toluenesulfonic acid-pyridine complex or trifluoroacetic acid-pyridine complex in lower alkanol such as methanol or ethanol. Mild hydrolysis reactions under acidic conditions include dilute hydrochloric acid and tetrahydrofuran mixtures, dilute hydrochloric acid and methanol mixtures, acetic acid, water and tetrahydrofuran mixtures, phosphoric acid and tetrahydrofuran mixtures, p-toluenesulfonic acid and methanol mixtures, p-toluene Or a mixture of sulfonic acid-pyridine complex and methanol, or a trifluoroacetic acid-pyridine complex and methanol mixture.
이렇게 얻어진 일반식(V)의 트란스-△2-프로스타글란딘 E1유도체 영국특허 1,416,410, 1483240 및 1,540,427에 기술된 바와 같이 의약 또는 수의약품으로서 유용하다. 이 화합물들은 특히 혈압 강하작용, 혈소판응고 억제작용, 위산분비 및 소화성궤양 억제작용과 기관지 이완작용 등 프로스타글란딘에 전형적인 약리작용을 가지고 있으므로 고혈압치료제, 말초순환질환치료제, 중추혈전증 예방 및 치료제 및 심근경색예방과 치료 또는 소화성궤양 및 천식치료제로서 유용하다.Thus obtained of formula trans- (V) - △ 2 - is useful as a prostaglandin E 1 derivative 1.41641 million British Patent, the medicament or drug, as described in 1.48324 million and 1,540,427. Since these compounds have typical pharmacological effects on prostaglandins, such as lowering blood pressure, inhibiting platelet coagulation, suppressing gastric acid secretion and peptic ulcer and bronchial relaxation, hypertension, peripheral circulatory disease, central thrombosis prevention and treatment, and myocardial infarction prevention It is useful as a medicine for treating or treating peptic ulcer and asthma.
-R2-R3는 1,1-디메틸펜틸기이고, R은 메틸기인 구조식(Ⅴ)의 트란스 -△2-프로스타글란딘 E1유도체, 즉, 영국특허 1540427에 기술된(2E, 13E)-(11α, 15R)-9-옥소 11,15-디하이드록시 -16,16-디메틸프로스타 -2,13-디에노산 메틸에스테르는 임신조절 및 포유동물의 분만유도, 포유동물에서 발정기 조절, 피임 및 멘스조절제로 유용하다.-R 2 -R 3 is 1,1-dimethyl pentyl group, and, R is a methyl group trans structural formula (Ⅴ) - △ 2-prostaglandin E 1 derivative, i.e., a (2E, 13E) described in British Patent 1,540,427 ( 11α, 15R) -9-oxo 11,15-dihydroxy-16,16-dimethylprostar-2,13-dienoic acid methylesters induces pregnancy control and delivery of mammals, estrus control, control of birth control and Useful as a mens regulator.
그러므로 일반식(ⅣE)의 본 발명의 신규물질, 즉 일반식(ⅣA), (ⅣB), (ⅣC) 및 (ⅣD) 화합물은 치료상 유용한 트란스-△2-프로스타글란딘 E1유도체 제조에 중요한 중간체로서 유용하다는 것을 알 수 있을 것이다.Therefore, formula (Ⅳ E) of new material of the present invention, namely formula (Ⅳ A), (Ⅳ B ), (Ⅳ C) and (Ⅳ D) compounds are therapeutically useful trans - △ 2 - prostaglandin E 1 derivative It will be appreciated that it is useful as an important intermediate for preparation.
일반식(Ⅴ), (Ⅸ), (Ⅹ), (ⅩⅠ), 및 (ⅩⅣ)인 신규물질, 즉 다음 일반식 (ⅩⅤⅢ)화합물도 유용하고 트란스-△2-프로스타글란딘 E1유도체 제조 중간체로서 중요하다.Formula (Ⅴ), (Ⅸ), (Ⅹ), (ⅩⅠ), and (ⅩⅣ) it is a new material, that is, the following formula (ⅩⅤⅢ) compounds are also useful and trans - △ 2 - important as a prostaglandin E 1 derivative prepared intermediate Do.
상기식에서 X 는 에틸렌 또는 비닐렌기이고, R12는 수소원자, 또는 염기성에서 제거되는 하이드록시보호기이고, R13은 포르밀기, 하이드록시메틸기(-CH2OH), 또는 -CH2OR8기(여기서 R8은 상술한 바와같다)이고 다른 부호들은 상술한 바와같다. 다만 (i) R13이 포르밀기일때, X는 에틸렌기이고, R12는 염기성에서 제거되는 하이드록시 보호기이며 (ii) R13이 하이드록시 메틸기일때 R12는 염기성에서 제거되는 하이드록시 보호기이며 (iii) R13이 -CH2OR8기일때 X는 비닐렌기이다. X가 비닐렌기일때 이중 결합은 E, Z 또는 그의 혼합물일 수 있다.Wherein X is an ethylene or vinylene group, R 12 is a hydrogen atom or a hydroxy protecting group removed from basic, and R 13 is a formyl group, hydroxymethyl group (-CH 2 OH), or -CH 2 OR 8 group ( Where R 8 is as described above) and other symbols are as described above. (I) when R 13 is a formyl group, X is an ethylene group, R 12 is a hydroxy protecting group which is removed from basic and (ii) when R 13 is a hydroxy methyl group, R 12 is a hydroxy protecting group which is removed from basic ( iii) X is a vinylene group when R 13 is a -CH 2 OR 8 group. When X is a vinylene group, the double bond may be E, Z or a mixture thereof.
일반식(Ⅳ)와 (ⅩⅤⅢ)화합물을 사용하면 상술한 두 가지 공지방법의 단점을 피하고 상술한 방법으로 트란스-△2-프로스타글란딘 E1유도체를 합성할 수 있다.Can be synthesized in a prostaglandin E 1 derivative - △ 2 - using the formula (Ⅳ) and (ⅩⅤⅢ) compound when avoiding the drawbacks of the two known processes described above trans by the aforementioned method.
일반식(ⅩⅡ)의 포스포니움 화합물을 사용하면 영국특허 1,416,410에서 필요한 불안정한 포스포란 화합물을 사용할 필요가 없고 (일반식(ⅩⅡ)화합물은 공유결합되지 않은 카복시기 대신에 -CH2OH기를 가지고 있으므로 더 안정하여 높은 수율을 얻게된다), 목적물의 수율이 감소될 우려가 있는 선택적인 환원반응이 필요없으며 w-쇄는 비교적으로 나중 단계에서 도입된다. 더욱이 셀렌이나 황화합물을 사용하거나 최종프로스타글란딘 생성물중의 최소한 그런 화합물을 제거하기 위해 필요한 세심한 정제단계가 필요없게된다.The use of the phosphonium compound of formula (XII) eliminates the need for the use of unstable phospholane compounds required in British Patent 1,416,410 (since the formula (XII) compounds have a -CH 2 OH group instead of a covalently bonded carboxyl group). More stable, resulting in higher yields), eliminating the need for selective reduction reactions where the yield of the desired product may be reduced and the w-chain being introduced at a later stage in comparison. Moreover, the use of selenium or sulfur compounds or the careful purification steps necessary to remove at least such compounds in the final prostaglandin product is eliminated.
다음 실시예들은 본 발명을 설명하기 위한 것이다. 실시예에서 "TLC", "IR" 및 "NMR"란 각각 "박층크로마토그라피" "적외선흡수스펙트럼" 및 "핵자기공명스펙트럼"을 나타낸다.The following examples are intended to illustrate the present invention. In the Examples, "TLC", "IR" and "NMR" refer to "Thin Layer Chromatography" "Infrared Absorption Spectrum" and "Nuclear Magnetic Resonance Spectrum", respectively.
크로마토 그라피 분리에서 기술된 용매비율은 부피비율이고 괄호안의 용매는 사용된 전개용매를 나타낸다. 따로 언급이 없는한 적외선 스펙트라는 액체필름 방법으로 기록된 것이고 핵자기공명스펙트라는 도이테로 클로로포름(CDCl3)용액에서 기록된 것이다.The solvent ratio described in chromatographic separation is the volume ratio and the solvents in parentheses represent the developing solvent used. Unless otherwise stated, infrared spectra were recorded by the liquid film method and nuclear magnetic resonance spectra were recorded in Deutscher chloroform (CDCl 3 ) solution.
[실시예 1]Example 1
(EZ)-2α-(5-하이드록시펜트-2-에닐)-3β-(1-메톡시-1-메틸)-에톡시메틸-4α-(테트라하이드로피란-2-일옥시) 싸이클로펜탄-1α올의 제조 ;(EZ) -2α- (5-hydroxypent-2-enyl) -3β- (1-methoxy-1-methyl) -ethoxymethyl-4α- (tetrahydropyran-2-yloxy) cyclopentane- Preparation of 1α ol;
질소대기하에서 헥산에 부틸리티움을 넣은 1.5M 용액 29.1ml를 테트라하이드로푸란 70ml에 3-하이드록시프로필트리페닐포스포니움브로마이드 8.748g을 넣은 현탁액에 가하고 실온에서 10분간 교반하여 일라이드 용액을 얻었다. 이 용액을 일본 특허공개소 53-149954의 참고 실시예 2에서 제조한 2-옥사-6-신(1-메톡시-1-메틸)에톡시 메틸-7-안티-(테트라히이드로피란-2-일옥시)-시스-비싸이클로 [3,3,0] 옥탄-3-올 3g을 테트라하이드로푸란 10ml에 넣은 용액을 가하고 실온에서 1시간, 40℃에서 30분간 교반하였다. 이 반응혼합물을 포화염화암모늄 수용액에 붓고 에틸아세테이트로 추출하였다. 이 추출액을 물과 포화식염수로 씻고 황산 마그네슘상에서 건조시킨 다음 감압농축시켜 다음과 같은 물리적 성상을 가진 불순한 표제 화합물을 얻었다.Under nitrogen atmosphere, 29.1 ml of a 1.5 M solution of butylitium in hexane was added to a suspension of 8.748 g of 3-hydroxypropyltriphenylphosphonium bromide in 70 ml of tetrahydrofuran, and stirred at room temperature for 10 minutes to obtain an illide solution. . This solution was prepared in 2-oxa-6-cin (1-methoxy-1-methyl) ethoxy methyl-7-anti- (tetrahydropyran-2) prepared in Reference Example 2 of Japanese Patent Publication No. 53-149954. A solution containing 3 g of [3,3,0] octane-3-ol in 10 ml of tetrahydrofuran was added to -yloxy) -cis-bicycle, followed by stirring at room temperature for 1 hour and 40 ° C for 30 minutes. The reaction mixture was poured into saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The extract was washed with water and brine, dried over magnesium sulfate, and concentrated under reduced pressure to obtain the title compound having the following physical properties.
이 조생성물은 다음단계에서 정제하지 않고 사용되었다.This crude product was used without purification in the next step.
TLC(에틸아세테이트 ; 싸이클로헥산=2:1) : Rf=0.23. (a) 상기와 같은 공정을 이용하여 2-옥사-6-신-(1-메톡시-1-메틸)에톡시메틸-7-안티-(테트라하이드로피란-2-일옥시)-시스-비싸이클로[3,3,0]옥탄-3-올 대신에 2-옥사-6-syn-벤질옥시메틸-7-안티-(테트라하이드로피란-2-일옥시)-시스-비싸이클로[3,3,0] 옥탄-3-올[J. Org. Chem., 37. 2921(1972)에 기술된 방법으로 제조]을 사용하여 다음과 같은 물리적 특성을 가진 (EZ)-2α(5-하이드록시펜트 2-에닐)-3β-벤질옥시메틸-4α-(테트라하이드로피란-2-일옥시)싸이클로펜탄-1α-올 얻었다. TLC(에틸아세테이트 : 싸이클로헥산 = 2:1) : Rf=0.25.TLC (ethyl acetate; cyclohexane = 2: 1): Rf = 0.23. (a) 2-oxa-6-cin- (1-methoxy-1-methyl) ethoxymethyl-7-anti- (tetrahydropyran-2-yloxy) -cis-ratio using the same process as above 2-oxa-6-syn-benzyloxymethyl-7-anti- (tetrahydropyran-2-yloxy) -cis-bicyclo [3,3 instead of cyclo [3,3,0] octan-3-ol , 0] octan-3-ol [J. Org. Chem., 37. Prepared by the method described in 2921 (1972)], (EZ) -2α (5-hydroxypent 2-enyl) -3β-benzyloxymethyl-4α- having the following physical properties: (Tetrahydropyran-2-yloxy) cyclopentan-1α-ol was obtained. TLC (ethyl acetate: cyclohexane = 2: 1): Rf = 0.25
[실시예 2]Example 2
(EZ)-1α-아세톡시-2α-(5-아세톡시펜트-2-에닐)-3β-(1-메톡시-1-메틸)에톡시메틸-4α-(테트라하이드로피란-2- 일옥시)싸이클로 펜탄의 제조 :(EZ) -1α-acetoxy-2α- (5-acetoxypent-2-enyl) -3β- (1-methoxy-1-methyl) ethoxymethyl-4α- (tetrahydropyran-2-yloxy Preparation of cyclopentane:
실시예 1에서 제조된 조생성물을 초산무수물 14ml 및 피리딘 33ml와 실온에서 하룻밤 교반하고 에틸아세테이트로 희석한 다음 0.5N-염산, 물 및 포화식염수로 씻고 황산마그네슘상에서 건조시키고 감압 농축시켜 다음과 같은 물리적 특성을 가진 조생성물을 얻고 이 조생성물은 다음 단계에서 정제하지 않고 사용되었다.The crude product prepared in Example 1 was stirred overnight at room temperature with 14 ml of acetic anhydride and 33 ml of pyridine, diluted with ethyl acetate, washed with 0.5N hydrochloric acid, water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The crude product with the properties was obtained and used without purification in the next step.
TLC(에틸아세테이트 : 싸이클로헥산=2:1) : Rf=0.79 (a) 출발물질로서 실시예 1의 조생성물 대신에 실시예 1(a)의 조생성물을 사용하여 상기 방법에 따라 다음 화합물이 제조되었다.TLC (ethyl acetate: cyclohexane = 2: 1): Rf = 0.79 (a) The following compound was prepared according to the above method using the crude product of Example 1 (a) instead of the crude product of Example 1 as a starting material. It became.
이 생성물은 용출제로서 에틸아세테이트와 싸이클로헥산(1:2)의 혼합물을 사용하여 실리카겔에서 컬럼크로마토그라피로 정제하여 실시예 1(a) 출발물질을 기준하여 73%의 수율로 (EZ)-1α-아세톡시-2α-(5-아세톡시펜트-2-에닐)-3β-벤질옥시메틸-4α-(테트라하이드로피란-2-일옥시)싸이클로펜탄을 얻었다.This product was purified by column chromatography on silica gel using a mixture of ethyl acetate and cyclohexane (1: 2) as eluent to give (EZ) -1α in a yield of 73% based on the starting material of Example 1 (a). -Acetoxy-2α- (5-acetoxypent-2-enyl) -3β-benzyloxymethyl-4α- (tetrahydropyran-2-yloxy) cyclopentane was obtained.
TLC(싸이클로헥산 : 에틸아세테이트 = 2 : 1) : Rf = 0.82 IR : ν=1740, 1243, 1021cm-1;TLC (cyclohexane: ethyl acetate = 2: 1): Rf = 0.82 IR: ν = 1740, 1243, 1021 cm -1 ;
NMR(CCl4용액) : δ=7.12(5H,m), 5.40(2H,m), 5.00(1H,m), 4.61(1H,m), 4.36(2H,s), 3.92(2H,t), 3.40(2H,d), 4.20-3.20(3H,m), 2.00(6H,s).NMR (CCl 4 solution): δ = 7.12 (5H, m), 5.40 (2H, m), 5.00 (1H, m), 4.61 (1H, m), 4.36 (2H, s), 3.92 (2H, t) , 3.40 (2H, d), 4.20-3.20 (3H, m), 2.00 (6H, s).
[실시예 3]Example 3
(EZ)-1α-아세톡시-2α-(5-아세톡시펜트-2-에닐)-3β-하이드록시메틸-4α-(테트라하이드로피란-2- 일옥시)싸이클로 펜탄의 제조Preparation of (EZ) -1α-acetoxy-2α- (5-acetoxypent-2-enyl) -3β-hydroxymethyl-4α- (tetrahydropyran-2-yloxy) cyclopentane
실시예 2에서 얻은 조생성물을 테트라하이드로푸란 40ml 및 1N-염산 15ml와 0℃에서 30분간 교반하고 이 혼합물을 포화중조수용액으로 중화시킨 다음 물과 포화식염수로 씻은뒤 황산마그네슘상에서 건조시키고 감압하에 농축시켰다. 잔사를 용출제로서 디에틸에테르를 사용하여 실리카겔상에서 컬럼크로마토그라피로 정제하여 다음 물리적 특성을 가진 표제화합물 2.30g을 얻었다.The crude product obtained in Example 2 was stirred with 40 ml of tetrahydrofuran and 15 ml of 1N hydrochloric acid for 30 minutes at 0 ° C., the mixture was neutralized with saturated aqueous sodium bicarbonate solution, washed with water and brine, dried over magnesium sulfate and concentrated under reduced pressure. I was. The residue was purified by column chromatography on silica gel using diethyl ether as eluent to afford 2.30 g of the title compound having the following physical properties.
TLC(에틸아세테이트 : 싸이클로헥산 = 2:1) : Rf=0.42, IR : ν = 3460, 1737, 1243, 1023 cm-1 TLC (ethyl acetate: cyclohexane = 2: 1): Rf = 0.42, IR: ν = 3460, 1737, 1243, 1023 cm -1
NMR(CCl4용액) : δ=5.35(2H,m), 4.97(1H.m), 4.56(1H,m), 3.95(2H,t), 4.20-3.16(5H,m), 1.97(6H,s).NMR (CCl 4 solution): δ = 5.35 (2H, m), 4.97 (1H.m), 4.56 (1H, m), 3.95 (2H, t), 4.20-3.16 (5H, m), 1.97 (6H, s).
[실시예 4]Example 4
1α-아세톡시-2α-(5-아세톡시펜틸) 3-β-하이드록시메틸 4α-(테트라하이드로피란-2- 일옥시) 싸이클로펜탄의 제조 :Preparation of 1α-Acetoxy-2α- (5-acetoxypentyl) 3-β-hydroxymethyl 4α- (tetrahydropyran-2-yloxy) cyclopentane:
수소기류하에서 실시예 3에서 얻은 펜테닐화합물 10.402g 메탄올 120ml 및 플라티늄디옥사이드 100mg의 혼합물을 실온에서 3시간 교반하고 여과한 다음 여액을 감압농축시켜 다음과 같은 물리적 특성을 가진 표제화합물 10.264g을 얻었다.Under hydrogen stream, a mixture of 10.402 g of the pentenyl compound obtained in Example 3 and 120 ml of methanol and 100 mg of platinum dioxide was stirred at room temperature for 3 hours, filtered, and the filtrate was concentrated under reduced pressure to obtain 10.264 g of the title compound having the following physical properties.
TLC(에틸아세테이트 : 벤젠 = 2 : 1, 질산온으로 전처리한 실리카겔을 사용) : Rf = 0.47TLC (ethyl acetate: benzene = 2: 1, using silica gel pretreated with nitric acid): Rf = 0.47
IR : ν = 3460, 1740, 1247, 1020cm-1 IR: ν = 3460, 1740, 1247, 1020 cm -1
NMR(CCl4용액) : δ=4.96(1H,m), 4.52(1H,m), 3.93(2H,t), 4.20-3.15(5H,m), 1.97(6H,s).NMR (CCl 4 solution): δ = 4.96 (1H, m), 4.52 (1H, m), 3.93 (2H, t), 4.20-3.15 (5H, m), 1.97 (6H, s).
[실시예 5]Example 5
1α-아세톡시-2α-(5-아세톡시펜틸)-3β-포르밀-4α-(테트라하이드로피란-2- 일옥시)싸이클로펜탄의 제조 :Preparation of 1α-Acetoxy-2α- (5-acetoxypentyl) -3β-formyl-4α- (tetrahydropyran-2-yloxy) cyclopentane:
톨루엔 300ml 에 N-클로로석신이미드 5.79g을 넣은 현탁액에 0℃에서 디메틸설파이드 3.94ml를 가하고 같은 온도로 40분간 교반하였다. 얻어진 이 용액에 톨루엔 20ml에 실시예 4에서 제조한 하이드록시메틸화합물 11.1g을 넣은 용액을 -20℃에서 가하고 같은 온도로 1시간 교반한 다음 -20℃에서 트리에틸아민 12.1ml와 30분간 교반하였다. 이 반응혼합물을 0.1N-염산으로 중화시키고 디에틸에테르로 희석한 다음 0.1N-염산, 포화중조수용액, 물 및 포화식염수로 씻고 황산마그네슘상에서 건조시킨 뒤 감압농축시켰다.3.94 ml of dimethyl sulfide was added at 0 degreeC to the suspension which added 5.79 g of N-chlorosuccinimide to 300 ml of toluene, and stirred for 40 minutes at the same temperature. To this obtained solution, a solution obtained by adding 11.1 g of the hydroxymethyl compound prepared in Example 4 to 20 ml of toluene was added at -20 ° C, and stirred at the same temperature for 1 hour, followed by stirring for 1 minute with 12.1 ml of triethylamine at -20 ° C. . The reaction mixture was neutralized with 0.1 N hydrochloric acid, diluted with diethyl ether, washed with 0.1 N hydrochloric acid, saturated aqueous sodium bicarbonate, water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure.
잔사를 용출제로서 에틸아세테이트와 싸이클로헥산(1:1) 혼합물을 사용하여 실리카겔상에서 컬럼크로마토그라피로 정제하여 다음과 같은 물리적 특성을 가진 표제화합물 10,327g을 얻었다.The residue was purified by column chromatography on silica gel using a mixture of ethyl acetate and cyclohexane (1: 1) as eluent to obtain 10,327 g of the title compound having the following physical properties.
TLC(에틸아세테이트 : 벤젠 = 2:1) : Rf=0.74TLC (ethyl acetate: benzene = 2: 1): Rf = 0.74
IR : ν=1740, 1377, 1247, 1025cm-1.IR: ν = 1740, 1377, 1247, 1025 cm -1 .
NMR : δ=9.65(1H,T), 5.30-4.85(1H,m), 4.8-3.1(6H,m).NMR: delta = 9.65 (1H, T), 5.30-4.85 (1H, m), 4.8-3.1 (6H, m).
[실시예 6]Example 6
1α-아세톡시-2α-(5-아세톡시펜틸)-3β-하이드록시메틸-4α-(테트라하이드로피란-2- 일옥시)싸이클로펜탄의 제조 :Preparation of 1α-Acetoxy-2α- (5-acetoxypentyl) -3β-hydroxymethyl-4α- (tetrahydropyran-2-yloxy) cyclopentane:
수소기류하에서 실시예 2(a)에서 제조한 벤질옥시메틸화합물 4.74g, 에탄올 100ml 및 라니니켈(w-7)20g의 혼합물을 환류하에 2시간 가열하고 반응혼합물을 여과하여 여액을 감압농축시켜 실시예 4화합물과 같은 물리적 특성을 가진 표제화합물 3.48g을 얻었다.Under hydrogen stream, a mixture of 4.74 g of benzyloxymethyl compound prepared in Example 2 (a), 100 ml of ethanol, and 20 g of lannickel (w-7) was heated under reflux for 2 hours, and the reaction mixture was filtered to concentrate the filtrate under reduced pressure. Example 4 3.48 g of the title compound having the same physical properties as the compound was obtained.
[실시예 7]Example 7
(E)-1α-아세톡시-2α-(5-아세톡시펜틸-3β-(3-옥소-4,4-디메틸옥트-1-에닐)-4α-(테트라하이드로피란-2- 일옥시)싸이클로펜탄의 제조 :(E) -1α-acetoxy-2α- (5-acetoxypentyl-3β- (3-oxo-4,4-dimethyloct-1-enyl) -4α- (tetrahydropyran-2-yloxy) cyclo Preparation of pentane:
질소기류하에 테트라하이드로푸란 50ml에 디메틸 2-옥소-3,3-디메틸헵틸포스포네이트 11.154g을 넣은 용액을 테트라하이드로푸란 250ml에 소디움하이드라이드(함량 63.5%) 1.317g을 넣은 현탁액에 실온에서 적가시키고 실온에서 30분간 교반하였다.A solution containing 11.154 g of dimethyl 2-oxo-3,3-dimethylheptylphosphonate in 50 ml of tetrahydrofuran under nitrogen stream was added dropwise to a suspension of 1.317 g of sodium hydride (content 63.5%) in 250 ml of tetrahydrofuran at room temperature. And stirred at room temperature for 30 minutes.
이렇게 얻은 용액에 테트라하이드로푸란 100ml에 실시예 5에서 얻은 포르밀화합물 10.987g을 넣은 용액을 가하고 이 혼합물을 실온에서 2.5시간 교반하였다. 이 반응혼합물을 초산으로 산성화시키고 여과한 뒤 여액을 감압농축하여 얻은 잔사를 용출제로서 싸이클로헥산과 에틸아세테이트(3:1)혼합물을 사용하여 실리카겔상에서 컬럼크로마토그라피로 정제하여 다음과 같은 물리적 특성을 가진 표제화합물 12.3g을 얻었다.The solution obtained by adding 10.987 g of the formyl compound obtained in Example 5 to 100 ml of tetrahydrofuran was added thereto, and the mixture was stirred at room temperature for 2.5 hours. The reaction mixture was acidified with acetic acid, filtered and the residue obtained by concentrating the filtrate under reduced pressure was purified by column chromatography on silica gel using a mixture of cyclohexane and ethyl acetate (3: 1) as eluent. 12.3 g of the title compound were obtained.
TCL(싸이클로헥산 : 에틸아세테이트 = 1: 1) : Rf=0.70TCL (cyclohexane: ethyl acetate = 1: 1): Rf = 0.70
IR : ν = 1740, 1695, 1675, 1246, 1025cm-1 IR: ν = 1740, 1695, 1675, 1246, 1025cm -1
NMR=δ=7.10-6.30(2H,m), 5.40-5.00(1H,m), 4.80-4.35(1H,m), 4.35-3.10(5H,m).NMR = δ = 7.10-6.30 (2H, m), 5.40-5.00 (1H, m), 4.80-4.35 (1H, m), 4.35-3.10 (5H, m).
[실시예 8]Example 8
(E)-1α-아세톡시-2α-(5-아세톡시펜틸)-3β-(3R-하이드록시-4,4-디메틸옥트-1-에닐)-4α-(테트라하이드로피란-2- 일옥시)싸이클로펜탄의 제조 :(E) -1α-acetoxy-2α- (5-acetoxypentyl) -3β- (3R-hydroxy-4,4-dimethyloct-1-enyl) -4α- (tetrahydropyran-2-yloxy Preparation of cyclopentane:
질소기류하에서 톨루엔에 디이소부틸알루미늄 하이드라이드를 넣은 25%(W/V)용액 100ml를 톨루엔 660ml에 2,6-디-터트-부틸-4-메틸페놀 8.8g을 넣은 용액에 0-5℃에서 적가하고 같은 온도에서 1시간 교반하였다. 이 용액에 톨루엔 60ml에 실시예 7에서 제조한 3-옥소화합물 8.64g을 넣은 용액을 -78℃에서 가하고 -30℃~-20℃로 3시간 교반하였다. 이 반응혼합물을 40℃에서 물 80ml와 30분간 교반하고 여과하여 여액을 감압농축시켰다. 잔사를 용출제로서 염화메틸렌과 에틸아세테이트(4:1)의 혼합물을 사용하여 실리카겔상에서 컬럼크로마토그라피로 정제하여 다음과 같은 물리적 특성을 가진 표제화합물 7.5g을 얻었다.Under nitrogen stream, 100 ml of 25% (W / V) solution containing diisobutylaluminum hydride in toluene was added to 660 ml of toluene in a solution containing 8.8 g of 2,6-di-tert-butyl-4-methylphenol. It was added dropwise at and stirred at the same temperature for 1 hour. The solution which added 8.64 g of 3-oxo compounds prepared in Example 7 to 60 ml of toluene was added to this solution at -78 degreeC, and it stirred at -30 degreeC--20 degreeC for 3 hours. The reaction mixture was stirred at 80 ° C. with 80 ml of water for 30 minutes, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of methylene chloride and ethyl acetate (4: 1) as eluent to obtain 7.5 g of the title compound having the following physical properties.
TCL(벤젠 : 에틸아세테이트 = 3 : 1) : Rf=0.30 (3s-이성체 Rf=0.39)TCL (benzene: ethyl acetate = 3: 1): Rf = 0.30 (3s-isomer Rf = 0.39)
IR : ν = 3740, 1738, 1372, 1243, 1017cm-1 IR: ν = 3740, 1738, 1372, 1243, 1017 cm -1
NMR(CCl4용액 : δ= 5.42(2H,m), 4.96(1H,m), 4.46(1H,m), 3.90(2H,t), 4.10-3.15(4H,m), 1.97(3H,s), 1.93(3H,s).NMR (CCl 4 solution: δ = 5.42 (2H, m), 4.96 (1H, m), 4.46 (1H, m), 3.90 (2H, t), 4.10-3.15 (4H, m), 1.97 (3H, s ), 1.93 (3H, s).
[실시예 9]Example 9
(E)-1α-아세톡시-2α-(5-아세톡시펜틸)-3β-[3R-(테트라하이드로피란-2-일옥시)-4,4-디메틸옥트-1-에닐]-4α-(테트라하이드로피란-2-일옥시)싸이클로펜탄의 제조 :(E) -1α-acetoxy-2α- (5-acetoxypentyl) -3β- [3R- (tetrahydropyran-2-yloxy) -4,4-dimethyloct-1-enyl] -4α- ( Preparation of Tetrahydropyran-2-yloxy) cyclopentane:
실시예 8에서 제조한 3R-하이드록시화합물 7.5g, 2,3-디하이드로피란 3ml, P-톨루엔설폰산 25mg 및 염화메틸렌 80ml의 혼합물을 실온에서 15분간 교반하고 포화중조수용액으로 중화시킨 다음 에틸아세테이트로 추출하였다. 이 추출액을 물과 포화 식염수로 씻고 황산마그네슘상에서 건조시킨 후 감압농축시켜 다음과 같은 물리적 특성을 가진 표제화합물 8.88g을 얻었다.A mixture of 7.5 g of 3R-hydroxy compound prepared in Example 8, 3 ml of 2,3-dihydropyran, 25 mg of P-toluenesulfonic acid and 80 ml of methylene chloride was stirred at room temperature for 15 minutes, neutralized with saturated aqueous sodium bicarbonate solution, and then ethyl. Extracted with acetate. The extract was washed with water and brine, dried over magnesium sulfate, and concentrated under reduced pressure to obtain 8.88 g of the title compound having the following physical properties.
TLC(싸이클로헥산 : 에틸아세테이트= 2 : 1) : Rf=0.57.TLC (cyclohexane: ethyl acetate = 2: 1): Rf = 0.55.
[실시예 10]Example 10
(E)-2α-(5-하이드록시펜틸-3β-[3R-(테트라하이드로피란-2-일옥시)-4,4-디메틸옥트-1-에닐]-4α-(테트라하이드로피란-2-일옥시)싸이클로 펜탄-1α-올의 제조:(E) -2α- (5-hydroxypentyl-3β- [3R- (tetrahydropyran-2-yloxy) -4,4-dimethyloct-1-enyl] -4α- (tetrahydropyran-2- Preparation of yloxy) cyclopentane-1α-ol:
실시예 9에서 제조한 아세톡시화합물 8.88g, 탄산칼륨 4.05g, 및 메탄올 80ml의 혼합물을 50℃에서 1.5시간 교반하고 반응혼합물을 에틸아세테이트로 희석한 다음 포화염화암모늄수용액으로 씻고 황산마그네슘상에서 건조시킨후 감압하에 농축하였다. 잔사를 용출제로서 에틸아세테이트와 싸이클로헥산(2:1)의 혼합물을 사용하여 실리카겔상에서 컬럼크로마토그라피로 정제하여 다음과 같은 물리적 특성을 가진 표제화합물 7.2g을 얻었다.A mixture of 8.88 g of the acetoxy compound prepared in Example 9, 4.05 g of potassium carbonate, and 80 ml of methanol was stirred at 50 ° C. for 1.5 hours, the reaction mixture was diluted with ethyl acetate, washed with saturated aqueous ammonium chloride solution, and dried over magnesium sulfate. Then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of ethyl acetate and cyclohexane (2: 1) as eluent to obtain 7.2 g of the title compound having the following physical properties.
TLC(에틸아세테이트 : 싸이클로헥산 = 2 : 1) : Rf=0.27TLC (ethyl acetate: cyclohexane = 2: 1): Rf = 0.27
IR : ν = 3400, 1137, 1026, 978cm-1 IR: ν = 3400, 1137, 1026, 978cm -1
NMR : δ= 5.60-5.23(2H,m), 4.60(2H,m), 4.30-3.20(9H,m).NMR: delta = 5.60-5.23 (2H, m), 4.60 (2H, m), 4.30-3.20 (9H, m).
[실시예 11]Example 11
(E)-2α-(4-포르밀부틸)-3β-[3R-(테트라하이드로피란-2-일옥시)-4,4-디메틸옥트-1-에닐]-4α-(테트라하이드로피란-2-일옥시)싸이클로펜탄-1-온의 제조 :(E) -2α- (4-formylbutyl) -3β- [3R- (tetrahydropyran-2-yloxy) -4,4-dimethyloct-1-enyl] -4α- (tetrahydropyran-2 Preparation of -yloxy) cyclopentan-1-one:
사염화탄소 2ml의 염화크롬 0.335ml를 넣은 용액을 염화메틸렌 13ml에 3급부탄올 0.786ml와 피리딘 1.01ml를 넣은 용액에 -78℃에서 적가하고 여기에 실온에서 염화메틸렌 5ml에 실시예 10에서 제조한 싸이클로펜탄-1α-올 화합물 902mg을 넣은 용액을 가하고 실온에서 2시간, 34℃에서 40분간 교반하였다.A solution containing 0.335 ml of chromium chloride of 2 ml of carbon tetrachloride was added dropwise to a solution containing 0.786 ml of tert-butanol and 1.01 ml of pyridine in 13 ml of methylene chloride at -78 ° C, and 5 ml of methylene chloride at room temperature, and the cyclopentane prepared in Example 10 was added. A solution containing 902 mg of -1α-ol compound was added thereto, followed by stirring at room temperature for 2 hours and 34 ° C for 40 minutes.
이 반응혼합물을 실온에서 디메틸설파이드 0.5ml와 10분간 교반하고 디에틸에테르 60ml와 물 20ml를 가한 다음 적층토판으로 여과하였다.The reaction mixture was stirred for 10 minutes with 0.5 ml of dimethylsulfide at room temperature, 60 ml of diethyl ether and 20 ml of water were added, and the mixture was filtered through a laminated plate.
여액의 에테르층을 포화식염수로 씻고 황산마그네슘상에서 건조시킨 다음 감압농축시켰다.The ether layer of the filtrate was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure.
잔사를 용출제로서 싸이클로헥산과 에틸아세테이트(3:1) 혼합물을 사용하여 실리카겔상에서 컬럼크로마토그라피로 정제하여 다음과 같은 물리적 특성을 가진 표제화합물 675mg을 얻었다.The residue was purified by column chromatography on silica gel using a mixture of cyclohexane and ethyl acetate (3: 1) as eluent to obtain 675 mg of the title compound having the following physical properties.
TLC(싸이클로헥산 : 에틸아세테이트 = 2 : 1) : Rf=0.44TLC (cyclohexane: ethyl acetate = 2: 1): Rf = 0.44
IR : ν= 1745, 1730, 1130, 1078, 1037, 1023m-1 IR: ν = 1745, 1730, 1130, 1078, 1037, 1023m -1
NMR(CCl4용액) : δ= 9.50(1H,t), 5.70-5.30(2H,m), 4.71-4.42(2H,m), 4.31-3.07(6H,m).NMR (CCl 4 solution): δ = 9.50 (1H, t), 5.70-5.30 (2H, m), 4.71-4.42 (2H, m), 4.31-3.07 (6H, m).
[실시예 12]Example 12
(2E,13E)-(11α,15R)-9-옥소-11,15-비스-(테트라하이드로피란-2-일옥시)-16,16-디메틸프로스타-2,13-디에노산메틸에스테르의 제조 :Of (2E, 13E)-(11α, 15R) -9-oxo-11,15-bis- (tetrahydropyran-2-yloxy) -16,16-dimethylprostar-2,13-dienoic acid methyl ester Produce :
질소 기류하에서 실시예 11에서 제조한 싸이클로펜탄-1-온 184mg, 메톡시카보닐메틸리덴트리페닐포스포란 231mg 및 클로로포름 2ml의 혼합물을 실온에서 2시간 교반하고 감압농축하였다. 잔사를 용출제로서 싸이클로헥산과 에틸아세테이트(3:1)의 혼합물을 사용하여 실리카겔상에서 컬럼크로마토그라피로 정제하여 다음과 같은 물리적 특성을 가진 표제화합물 192mg을 얻었다.Under a stream of nitrogen, a mixture of 184 mg of cyclopentan-1-one, 231 mg of methoxycarbonylmethylidenetriphenylphosphorane, and 2 ml of chloroform was stirred at room temperature for 2 hours and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of cyclohexane and ethyl acetate (3: 1) as eluent to obtain 192 mg of the title compound having the following physical properties.
TLC(벤젠 : 에틸아세테이트 = 2 : 1) : Rf=0.74TLC (benzene: ethyl acetate = 2: 1): Rf = 0.74
IR : ν = 1745, 1726, 1654, 1196, 1128, 1030m-1 IR: ν = 1745, 1726, 1654, 1196, 1128, 1030m -1
NMR : δ= 6.90(1H,dt), 5.70(1H,d), 5.80-5.40(2H,m), 4.60(2H,m)NMR: δ = 6.90 (1H, dt), 5.70 (1H, d), 5.80-5.40 (2H, m), 4.60 (2H, m)
또한 상기표제화합물은 상술한 방법으로 메톡시카보닐메틸리덴트리페닐 포스포란 대신에 포스포란화합물(R7)3P=CHCOOCH3(여기서 R7은 아래표에 나타낸 바와 같다)을 사용하여 아래표와 같이 반응온도, 반응시간 및 용매를 변형시켜 제조하였다.In addition, the title compound in the above-described method using a phosphoran compound (R 7 ) 3 P = CHCOOCH 3 (wherein R 7 is shown in the table below) instead of methoxycarbonylmethylidenetriphenyl phosphorane It was prepared by modifying the reaction temperature, reaction time and solvent as described above.
[실시예 13]Example 13
(2E,13E)-(11α,15R)-9-옥소-11,15-디하이드록시-16,16-디메틸프로스타-2,13-디에노산메틸에스테르의 제조 :Preparation of (2E, 13E)-(11α, 15R) -9-oxo-11,15-dihydroxy-16,16-dimethylprostar-2,13-dienoic acid methyl ester:
테트라하이드로푸란 119ml에 (2E,13E)-(11α,5R)-9-옥소-11,15-비스-(테트라하이드로피란-2-일옥시)-16,16-디메틸프로스타-2,13-디에노산메틸에스테르(실시예 12에 기술된 방법으로 제조될 수 있음) 732mg을 넣은 용액에 65%(v/v)초산수용액 19ml를 가하고 이 용액을 55-60℃에서 1시간동안 교반하였다.To 119 ml of tetrahydrofuran (2E, 13E)-(11α, 5R) -9-oxo-11,15-bis- (tetrahydropyran-2-yloxy) -16,16-dimethylprostar-2,13- To a solution containing 732 mg of dienoic acid methyl ester (which may be prepared by the method described in Example 12), 19 ml of 65% (v / v) acetic acid solution was added and the solution was stirred at 55-60 ° C. for 1 hour.
이 반응혼합물을 에틸아세테이트로 추출하고 추출액을 물과 식염수수용액으로 씻고 황산마그네슘상에서 건조시킨 다음 감압농축시켜 다음과 같은 물리적 특성을 가진 표제화합물 119mg을 얻었다.The reaction mixture was extracted with ethyl acetate, the extract was washed with water and brine, dried over magnesium sulfate and concentrated under reduced pressure to obtain 119 mg of the title compound having the following physical properties.
TLC(전개용매, 클로로포름 : 테트라하이드로푸란 : 초산 = 10 : 2 : 1) : Rf=0.51TLC (developing solvent, chloroform: tetrahydrofuran: acetic acid = 10: 2: 1): Rf = 0.51
IR : ν = 3400, 2940, 2850, 1750, 1730, 1660, 1440, 1280m-1 IR: ν = 3400, 2940, 2850, 1750, 1730, 1660, 1440, 1280m -1
NMR : δ= 7.10-6.75(1H,m), 5.95-5.40(3H,m), 3.71(3H,S), 4.20-3.60(2H,m), 2.75(1H,dd), 1.00-0.75(9H,m)NMR: δ = 7.10-6.75 (1H, m), 5.95-5.40 (3H, m), 3.71 (3H, S), 4.20-3.60 (2H, m), 2.75 (1H, dd), 1.00-0.75 (9H , m)
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| KR1019800000263A KR840001722B1 (en) | 1980-01-23 | 1980-01-23 | Process for the preparation of prostaglandin derivative |
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| KR1019800000263A KR840001722B1 (en) | 1980-01-23 | 1980-01-23 | Process for the preparation of prostaglandin derivative |
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