JP5654532B2 - ベンゾインデンプロスタグランジンの合成のための中間体及びその製造法 - Google Patents
ベンゾインデンプロスタグランジンの合成のための中間体及びその製造法 Download PDFInfo
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- JP5654532B2 JP5654532B2 JP2012180637A JP2012180637A JP5654532B2 JP 5654532 B2 JP5654532 B2 JP 5654532B2 JP 2012180637 A JP2012180637 A JP 2012180637A JP 2012180637 A JP2012180637 A JP 2012180637A JP 5654532 B2 JP5654532 B2 JP 5654532B2
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- -1 benzoindene prostaglandins Chemical class 0.000 title claims description 121
- 229940094443 oxytocics prostaglandins Drugs 0.000 title description 7
- 239000000543 intermediate Substances 0.000 title description 6
- 230000015572 biosynthetic process Effects 0.000 title description 5
- 238000002360 preparation method Methods 0.000 title description 5
- 238000003786 synthesis reaction Methods 0.000 title description 5
- 150000001875 compounds Chemical class 0.000 claims description 151
- 239000002904 solvent Substances 0.000 claims description 45
- BGTOWKSIORTVQH-UHFFFAOYSA-N cyclopentanone Chemical compound O=C1CCCC1 BGTOWKSIORTVQH-UHFFFAOYSA-N 0.000 claims description 38
- 125000000217 alkyl group Chemical group 0.000 claims description 37
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 31
- 238000000034 method Methods 0.000 claims description 29
- 238000006243 chemical reaction Methods 0.000 claims description 27
- PAJMKGZZBBTTOY-ZFORQUDYSA-N treprostinil Chemical compound C1=CC=C(OCC(O)=O)C2=C1C[C@@H]1[C@@H](CC[C@@H](O)CCCCC)[C@H](O)C[C@@H]1C2 PAJMKGZZBBTTOY-ZFORQUDYSA-N 0.000 claims description 24
- 229960005032 treprostinil Drugs 0.000 claims description 23
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 22
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 20
- 239000000460 chlorine Substances 0.000 claims description 19
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 18
- 239000003153 chemical reaction reagent Substances 0.000 claims description 17
- 229910052736 halogen Inorganic materials 0.000 claims description 15
- 150000002367 halogens Chemical class 0.000 claims description 15
- 125000006239 protecting group Chemical group 0.000 claims description 13
- AMKGKYQBASDDJB-UHFFFAOYSA-N 9$l^{2}-borabicyclo[3.3.1]nonane Chemical group C1CCC2CCCC1[B]2 AMKGKYQBASDDJB-UHFFFAOYSA-N 0.000 claims description 11
- 229910052796 boron Inorganic materials 0.000 claims description 11
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 claims description 10
- 125000003118 aryl group Chemical group 0.000 claims description 10
- 238000004519 manufacturing process Methods 0.000 claims description 10
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 10
- 230000029936 alkylation Effects 0.000 claims description 9
- 238000005804 alkylation reaction Methods 0.000 claims description 9
- 238000005984 hydrogenation reaction Methods 0.000 claims description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 8
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 7
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 7
- 125000000468 ketone group Chemical group 0.000 claims description 7
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 6
- 239000002168 alkylating agent Substances 0.000 claims description 6
- 229940100198 alkylating agent Drugs 0.000 claims description 6
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 6
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 230000003301 hydrolyzing effect Effects 0.000 claims description 5
- 229910052740 iodine Inorganic materials 0.000 claims description 5
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 5
- JBQYATWDVHIOAR-UHFFFAOYSA-N tellanylidenegermanium Chemical compound [Te]=[Ge] JBQYATWDVHIOAR-UHFFFAOYSA-N 0.000 claims description 5
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 5
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 5
- 229910000761 Aluminium amalgam Inorganic materials 0.000 claims description 4
- 125000002947 alkylene group Chemical group 0.000 claims description 4
- 150000001450 anions Chemical class 0.000 claims description 4
- FJBFPHVGVWTDIP-UHFFFAOYSA-N dibromomethane Chemical compound BrCBr FJBFPHVGVWTDIP-UHFFFAOYSA-N 0.000 claims description 4
- 239000011877 solvent mixture Substances 0.000 claims description 4
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 claims description 4
- 125000004953 trihalomethyl group Chemical group 0.000 claims description 4
- 230000002152 alkylating effect Effects 0.000 claims description 3
- OQWUXWSLVBGOIX-UHFFFAOYSA-N methyl-methylimino-oxo-phenyl-$l^{6}-sulfane Chemical compound CN=S(C)(=O)C1=CC=CC=C1 OQWUXWSLVBGOIX-UHFFFAOYSA-N 0.000 claims description 3
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- 230000001035 methylating effect Effects 0.000 claims description 2
- 230000011987 methylation Effects 0.000 claims description 2
- 238000007069 methylation reaction Methods 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 239
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 108
- 235000019439 ethyl acetate Nutrition 0.000 description 82
- 239000000203 mixture Substances 0.000 description 57
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 56
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 48
- 239000011541 reaction mixture Substances 0.000 description 47
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 45
- 239000012043 crude product Substances 0.000 description 38
- 238000004587 chromatography analysis Methods 0.000 description 34
- 239000003480 eluent Substances 0.000 description 34
- 239000000741 silica gel Substances 0.000 description 34
- 229910002027 silica gel Inorganic materials 0.000 description 34
- 239000000243 solution Substances 0.000 description 34
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 33
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 33
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 30
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 28
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 26
- 238000001914 filtration Methods 0.000 description 26
- 239000012044 organic layer Substances 0.000 description 26
- 239000007787 solid Substances 0.000 description 25
- 239000010410 layer Substances 0.000 description 24
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 22
- 238000005160 1H NMR spectroscopy Methods 0.000 description 20
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 18
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 17
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 0 CCCCC[C@@](C=C[C@]([C@@]1Cc2cc(*)ccc2)[C@](*C)CC1=O)O*1C(C)C1 Chemical compound CCCCC[C@@](C=C[C@]([C@@]1Cc2cc(*)ccc2)[C@](*C)CC1=O)O*1C(C)C1 0.000 description 14
- 229920006395 saturated elastomer Polymers 0.000 description 14
- 235000017557 sodium bicarbonate Nutrition 0.000 description 14
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 14
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 13
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 12
- 239000007795 chemical reaction product Substances 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 10
- 238000005481 NMR spectroscopy Methods 0.000 description 10
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 10
- 239000012267 brine Substances 0.000 description 10
- 229910052739 hydrogen Inorganic materials 0.000 description 10
- 239000001257 hydrogen Substances 0.000 description 10
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 238000002425 crystallisation Methods 0.000 description 9
- 230000008025 crystallization Effects 0.000 description 9
- 125000004093 cyano group Chemical group *C#N 0.000 description 9
- VUQUOGPMUUJORT-UHFFFAOYSA-N methyl 4-methylbenzenesulfonate Chemical compound COS(=O)(=O)C1=CC=C(C)C=C1 VUQUOGPMUUJORT-UHFFFAOYSA-N 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- 229910052763 palladium Inorganic materials 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- IXCSERBJSXMMFS-UHFFFAOYSA-N hcl hcl Chemical compound Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 7
- 125000004469 siloxy group Chemical group [SiH3]O* 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 6
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 6
- 239000012312 sodium hydride Substances 0.000 description 6
- 229910000104 sodium hydride Inorganic materials 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- ROYBZZKUOIHVSS-ZVRQOUSJSA-N (1r,2r,3as,9as)-2-[tert-butyl(dimethyl)silyl]oxy-1-[(e,3s)-3-[tert-butyl(dimethyl)silyl]oxyoct-1-enyl]-2,3,3a,4,9,9a-hexahydro-1h-cyclopenta[g]naphthalen-5-ol Chemical compound C1=CC=C2C[C@@H]3[C@@H](/C=C/[C@@H](O[Si](C)(C)C(C)(C)C)CCCCC)[C@H](O[Si](C)(C)C(C)(C)C)C[C@@H]3CC2=C1O ROYBZZKUOIHVSS-ZVRQOUSJSA-N 0.000 description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 5
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 5
- LMHIPJMTZHDKEW-XQYLJSSYSA-M Epoprostenol sodium Chemical compound [Na+].O1\C(=C/CCCC([O-])=O)C[C@@H]2[C@@H](/C=C/[C@@H](O)CCCCC)[C@H](O)C[C@@H]21 LMHIPJMTZHDKEW-XQYLJSSYSA-M 0.000 description 5
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 5
- 239000000908 ammonium hydroxide Substances 0.000 description 5
- 239000003054 catalyst Substances 0.000 description 5
- 238000010511 deprotection reaction Methods 0.000 description 5
- 239000012153 distilled water Substances 0.000 description 5
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 5
- KJCVRFUGPWSIIH-UHFFFAOYSA-N 1-naphthol Chemical compound C1=CC=C2C(O)=CC=CC2=C1 KJCVRFUGPWSIIH-UHFFFAOYSA-N 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 4
- 229910052794 bromium Inorganic materials 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 4
- 239000011630 iodine Substances 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- MBABOKRGFJTBAE-UHFFFAOYSA-N methyl methanesulfonate Chemical compound COS(C)(=O)=O MBABOKRGFJTBAE-UHFFFAOYSA-N 0.000 description 4
- QCIWZIYBBNEPKB-UHFFFAOYSA-N tert-butyl(dimethyl)silane Chemical compound C[SiH](C)C(C)(C)C QCIWZIYBBNEPKB-UHFFFAOYSA-N 0.000 description 4
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 4
- 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 3
- RENMDAKOXSCIGH-UHFFFAOYSA-N Chloroacetonitrile Chemical compound ClCC#N RENMDAKOXSCIGH-UHFFFAOYSA-N 0.000 description 3
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 description 3
- 229960001123 epoprostenol Drugs 0.000 description 3
- 239000012456 homogeneous solution Substances 0.000 description 3
- 150000002430 hydrocarbons Chemical group 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 3
- 235000019341 magnesium sulphate Nutrition 0.000 description 3
- DVSDBMFJEQPWNO-UHFFFAOYSA-N methyllithium Chemical compound C[Li] DVSDBMFJEQPWNO-UHFFFAOYSA-N 0.000 description 3
- KZWCTFLBFSWYHS-UHFFFAOYSA-N naphthalen-1-yl benzoate Chemical compound C=1C=CC2=CC=CC=C2C=1OC(=O)C1=CC=CC=C1 KZWCTFLBFSWYHS-UHFFFAOYSA-N 0.000 description 3
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 3
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 238000004809 thin layer chromatography Methods 0.000 description 3
- UTGPMEMKMRVGNE-HUTLKBDOSA-N (1r,2r,3as,9as)-1-[(3s)-3-hydroxyoctyl]-2,3,3a,4,9,9a-hexahydro-1h-cyclopenta[g]naphthalene-2,5-diol Chemical compound C1=CC=C2C[C@@H]3[C@@H](CC[C@@H](O)CCCCC)[C@H](O)C[C@@H]3CC2=C1O UTGPMEMKMRVGNE-HUTLKBDOSA-N 0.000 description 2
- FTQOBTGSGBNEII-JZHBTDALSA-N (1r,2r,3r)-2-[(e,3s)-3-hydroxyoct-1-enyl]-4-methylidene-3-[(3-phenylmethoxyphenyl)methyl]cyclopentan-1-ol Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=C)[C@@H]1CC1=CC=CC(OCC=2C=CC=CC=2)=C1 FTQOBTGSGBNEII-JZHBTDALSA-N 0.000 description 2
- QRIZNMGCIBXULQ-UHFFFAOYSA-N 1h-cyclopenta[a]naphthalene-1-carbonitrile Chemical compound C1=CC=CC2=C3C(C#N)C=CC3=CC=C21 QRIZNMGCIBXULQ-UHFFFAOYSA-N 0.000 description 2
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 2
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 2
- BZKFMUIJRXWWQK-UHFFFAOYSA-N Cyclopentenone Chemical compound O=C1CCC=C1 BZKFMUIJRXWWQK-UHFFFAOYSA-N 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000012039 electrophile Substances 0.000 description 2
- 239000002024 ethyl acetate extract Substances 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 2
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 2
- 229910000105 potassium hydride Inorganic materials 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 208000002815 pulmonary hypertension Diseases 0.000 description 2
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 238000005694 sulfonylation reaction Methods 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 2
- 125000005309 thioalkoxy group Chemical group 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- 239000011701 zinc Substances 0.000 description 2
- 229910052725 zinc Inorganic materials 0.000 description 2
- NQPGGZXFBBKACQ-OPIYUDRISA-N (1r,2r,3as,9as)-1-[(e,3s)-3-hydroxyoct-1-enyl]-2,3,3a,4,9,9a-hexahydro-1h-cyclopenta[g]naphthalene-2,5-diol Chemical compound C1=CC=C2C[C@@H]3[C@@H](/C=C/[C@@H](O)CCCCC)[C@H](O)C[C@@H]3CC2=C1O NQPGGZXFBBKACQ-OPIYUDRISA-N 0.000 description 1
- UFVXZHZWZMKSEI-OWOAHHHJSA-N (2R,3R,4R)-2-[(3-phenylmethoxyphenyl)methyl]-4-triethylsilyloxy-3-[(E,3S)-3-triethylsilyloxyoct-1-enyl]cyclopentan-1-one Chemical compound CCCCC[C@H](O[Si](CC)(CC)CC)\C=C\[C@H]1[C@H](O[Si](CC)(CC)CC)CC(=O)[C@@H]1CC1=CC=CC(OCC=2C=CC=CC=2)=C1 UFVXZHZWZMKSEI-OWOAHHHJSA-N 0.000 description 1
- NHQFFVKAXMFBKX-NTUCGPGSSA-N (2R,3R,4R)-4-[tert-butyl(dimethyl)silyl]oxy-3-[(E,3S)-3-[tert-butyl(dimethyl)silyl]oxyoct-1-enyl]-2-[(3-phenylmethoxyphenyl)methyl]cyclopentan-1-one Chemical compound CCCCC[C@H](O[Si](C)(C)C(C)(C)C)\C=C\[C@H]1[C@H](O[Si](C)(C)C(C)(C)C)CC(=O)[C@@H]1CC1=CC=CC(OCC=2C=CC=CC=2)=C1 NHQFFVKAXMFBKX-NTUCGPGSSA-N 0.000 description 1
- GGIODFRWUKSMTA-ZPWLKWPPSA-N (2r,3r,4r)-2-[[3-[tert-butyl(dimethyl)silyl]oxyphenyl]methyl]-4-(oxan-2-yloxy)-3-[(e,3s)-3-(oxan-2-yloxy)oct-1-enyl]cyclopentan-1-one Chemical compound O([C@@H](CCCCC)\C=C\[C@@H]1[C@H](C(=O)C[C@H]1OC1OCCCC1)CC=1C=C(O[Si](C)(C)C(C)(C)C)C=CC=1)C1CCCCO1 GGIODFRWUKSMTA-ZPWLKWPPSA-N 0.000 description 1
- LPZRQNJVTDEXFR-OUPGAVJSSA-N (2r,3r,4r)-4-[tert-butyl(dimethyl)silyl]oxy-3-[(3s)-3-[tert-butyl(dimethyl)silyl]oxyoctyl]-2-[(3-phenylmethoxyphenyl)methyl]cyclopentan-1-one Chemical compound CCCCC[C@H](O[Si](C)(C)C(C)(C)C)CC[C@H]1[C@H](O[Si](C)(C)C(C)(C)C)CC(=O)[C@@H]1CC1=CC=CC(OCC=2C=CC=CC=2)=C1 LPZRQNJVTDEXFR-OUPGAVJSSA-N 0.000 description 1
- QLMMADPYTQABCM-QHCPKHFHSA-N (4r)-4-[tert-butyl(dimethyl)silyl]oxy-2-[(3-phenylmethoxyphenyl)methyl]cyclopent-2-en-1-one Chemical compound CC(C)(C)[Si](C)(C)O[C@@H]1CC(=O)C(CC=2C=C(OCC=3C=CC=CC=3)C=CC=2)=C1 QLMMADPYTQABCM-QHCPKHFHSA-N 0.000 description 1
- CXBDYQVECUFKRK-UHFFFAOYSA-N 1-methoxybutane Chemical compound CCCCOC CXBDYQVECUFKRK-UHFFFAOYSA-N 0.000 description 1
- KXYGKDBONOVZOM-UHFFFAOYSA-N 1h-cyclopenta[a]naphthalene Chemical compound C1=CC=CC2=C3CC=CC3=CC=C21 KXYGKDBONOVZOM-UHFFFAOYSA-N 0.000 description 1
- FJZFZGZIPSPOEU-UHFFFAOYSA-N 1h-cyclopenta[g]naphthalene-2,5-diol Chemical compound C1=CC=C2C=C(CC(O)=C3)C3=CC2=C1O FJZFZGZIPSPOEU-UHFFFAOYSA-N 0.000 description 1
- NOGFHTGYPKWWRX-UHFFFAOYSA-N 2,2,6,6-tetramethyloxan-4-one Chemical compound CC1(C)CC(=O)CC(C)(C)O1 NOGFHTGYPKWWRX-UHFFFAOYSA-N 0.000 description 1
- NSNDHTCKHWJUTL-SXFAUFNYSA-N 2-[[(1r,2r,3as,9as)-2-hydroxy-1-[(3s)-3-hydroxyoctyl]-2,3,3a,4,9,9a-hexahydro-1h-cyclopenta[g]naphthalen-5-yl]oxy]acetonitrile Chemical compound C1=CC=C(OCC#N)C2=C1C[C@@H]1[C@@H](CC[C@@H](O)CCCCC)[C@H](O)C[C@@H]1C2 NSNDHTCKHWJUTL-SXFAUFNYSA-N 0.000 description 1
- ILZGLZKCNKQDPW-YCIAMDESSA-N 2-[[(1r,2r,3as,9as)-2-hydroxy-1-[(e,3s)-3-hydroxyoct-1-enyl]-2,3,3a,4,9,9a-hexahydro-1h-cyclopenta[g]naphthalen-5-yl]oxy]acetic acid Chemical compound C1=CC=C(OCC(O)=O)C2=C1C[C@@H]1[C@@H](/C=C/[C@@H](O)CCCCC)[C@H](O)C[C@@H]1C2 ILZGLZKCNKQDPW-YCIAMDESSA-N 0.000 description 1
- SYRVVWCHDSBOJB-UPBBQMFLSA-N 2-[[(1r,2r,3as,9as)-2-hydroxy-1-[(e,3s)-3-hydroxyoct-1-enyl]-2,3,3a,4,9,9a-hexahydro-1h-cyclopenta[g]naphthalen-5-yl]oxy]acetonitrile Chemical compound C1=CC=C(OCC#N)C2=C1C[C@@H]1[C@@H](/C=C/[C@@H](O)CCCCC)[C@H](O)C[C@@H]1C2 SYRVVWCHDSBOJB-UPBBQMFLSA-N 0.000 description 1
- 125000006291 3-hydroxybenzyl group Chemical group [H]OC1=C([H])C([H])=C([H])C(=C1[H])C([H])([H])* 0.000 description 1
- JPVUWCPKMYXOKW-UHFFFAOYSA-N 4-phenylbenzoyl chloride Chemical compound C1=CC(C(=O)Cl)=CC=C1C1=CC=CC=C1 JPVUWCPKMYXOKW-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- BOTNYLSAWDQNEX-UHFFFAOYSA-N C(c1ccccc1)Oc1ccccc1 Chemical compound C(c1ccccc1)Oc1ccccc1 BOTNYLSAWDQNEX-UHFFFAOYSA-N 0.000 description 1
- HVJQKZZQBUZMNA-OLZOCXBDSA-N CCCCCCCC[C@@H](CC1)[C@@H](C)C1=O Chemical compound CCCCCCCC[C@@H](CC1)[C@@H](C)C1=O HVJQKZZQBUZMNA-OLZOCXBDSA-N 0.000 description 1
- RPRUTCZSHKFCDY-GJZGRUSLSA-N CCCCCCCC[C@@H](CCC1)[C@H]1C#C Chemical compound CCCCCCCC[C@@H](CCC1)[C@H]1C#C RPRUTCZSHKFCDY-GJZGRUSLSA-N 0.000 description 1
- DPFLNSDSLBSUGV-VPYOMYJVSA-N CCCCC[C@@H](CC[C@@H]([C@@H](C1)O)[C@@H](C2)C1Cc1c2cccc1OC(c1ccccc1)=O)[O]=C Chemical compound CCCCC[C@@H](CC[C@@H]([C@@H](C1)O)[C@@H](C2)C1Cc1c2cccc1OC(c1ccccc1)=O)[O]=C DPFLNSDSLBSUGV-VPYOMYJVSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- RLSSMJSEOOYNOY-UHFFFAOYSA-N Cc1cc(O)ccc1 Chemical compound Cc1cc(O)ccc1 RLSSMJSEOOYNOY-UHFFFAOYSA-N 0.000 description 1
- MCBGBITUMUAJMT-UHFFFAOYSA-N Cc1cccc(O)c1C=C Chemical compound Cc1cccc(O)c1C=C MCBGBITUMUAJMT-UHFFFAOYSA-N 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 1
- IKGUFRCGRPWCSD-OJPHZXHRSA-N [(1r,2r,3as,9as)-2-[tert-butyl(dimethyl)silyl]oxy-1-[(e,3s)-3-[tert-butyl(dimethyl)silyl]oxyoct-1-enyl]-2,3,3a,4,9,9a-hexahydro-1h-cyclopenta[g]naphthalen-5-yl] acetate Chemical compound C1=CC=C(OC(C)=O)C2=C1C[C@@H]1[C@@H](/C=C/[C@@H](O[Si](C)(C)C(C)(C)C)CCCCC)[C@H](O[Si](C)(C)C(C)(C)C)C[C@@H]1C2 IKGUFRCGRPWCSD-OJPHZXHRSA-N 0.000 description 1
- KBVIRGFARMBXLJ-AQKWXWLBSA-N [(1r,2r,3as,9as)-2-hydroxy-1-[(e,3s)-3-hydroxyoct-1-enyl]-2,3,3a,4,9,9a-hexahydro-1h-cyclopenta[g]naphthalen-5-yl] acetate Chemical compound C1=CC=C(OC(C)=O)C2=C1C[C@@H]1[C@@H](/C=C/[C@@H](O)CCCCC)[C@H](O)C[C@@H]1C2 KBVIRGFARMBXLJ-AQKWXWLBSA-N 0.000 description 1
- DSVGQVZAZSZEEX-UHFFFAOYSA-N [C].[Pt] Chemical compound [C].[Pt] DSVGQVZAZSZEEX-UHFFFAOYSA-N 0.000 description 1
- NKKHTUBIHWHREA-DAFXYXGESA-N [Si](C)(C)(C(C)(C)C)O[C@H](CCC1CC(CC1)=O)CCCCC Chemical compound [Si](C)(C)(C(C)(C)C)O[C@H](CCC1CC(CC1)=O)CCCCC NKKHTUBIHWHREA-DAFXYXGESA-N 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 150000001345 alkine derivatives Chemical class 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 description 1
- 125000005140 aralkylsulfonyl group Chemical group 0.000 description 1
- 125000005100 aryl amino carbonyl group Chemical group 0.000 description 1
- 125000001769 aryl amino group Chemical group 0.000 description 1
- 125000005129 aryl carbonyl group Chemical group 0.000 description 1
- 125000004391 aryl sulfonyl group Chemical group 0.000 description 1
- 125000004104 aryloxy group Chemical group 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- IMGUNTYROYTLIE-UHFFFAOYSA-N copper(1+);pent-1-yne Chemical compound [Cu+].CCCC#[C-] IMGUNTYROYTLIE-UHFFFAOYSA-N 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical group C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 238000006197 hydroboration reaction Methods 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- SIAPCJWMELPYOE-UHFFFAOYSA-N lithium hydride Chemical compound [LiH] SIAPCJWMELPYOE-UHFFFAOYSA-N 0.000 description 1
- 229910000103 lithium hydride Inorganic materials 0.000 description 1
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- XVDBWWRIXBMVJV-UHFFFAOYSA-N n-[bis(dimethylamino)phosphanyl]-n-methylmethanamine Chemical compound CN(C)P(N(C)C)N(C)C XVDBWWRIXBMVJV-UHFFFAOYSA-N 0.000 description 1
- FZZQNEVOYIYFPF-UHFFFAOYSA-N naphthalene-1,6-diol Chemical compound OC1=CC=CC2=CC(O)=CC=C21 FZZQNEVOYIYFPF-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 125000005968 oxazolinyl group Chemical group 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 125000005561 phenanthryl group Chemical group 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 125000005575 polycyclic aromatic hydrocarbon group Chemical group 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 229910000080 stannane Inorganic materials 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- JXRVMRIUWRZUHM-ZDUSSCGKSA-N tert-butyl-[(3s)-1-iodooctan-3-yl]oxy-dimethylsilane Chemical compound CCCCC[C@@H](CCI)O[Si](C)(C)C(C)(C)C JXRVMRIUWRZUHM-ZDUSSCGKSA-N 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000005296 thioaryloxy group Chemical group 0.000 description 1
- 125000005147 toluenesulfonyl group Chemical group C=1(C(=CC=CC1)S(=O)(=O)*)C 0.000 description 1
- 125000004665 trialkylsilyl group Chemical group 0.000 description 1
- 238000007738 vacuum evaporation Methods 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/28—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group
- C07C67/297—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
-
- 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 System
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
- C07C255/11—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and singly-bound oxygen atoms bound to the same saturated acyclic carbon skeleton
- C07C255/13—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and singly-bound oxygen atoms bound to the same saturated acyclic carbon skeleton containing cyano groups and etherified hydroxy groups bound to the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
- C07C37/001—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by modification in a side chain
- C07C37/003—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by modification in a side chain by hydrogenation of an unsaturated part
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
- C07C37/01—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis
- C07C37/055—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis the substituted group being bound to oxygen, e.g. ether group
- C07C37/0555—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis the substituted group being bound to oxygen, e.g. ether group being esterified hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
- C07C37/50—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by reactions decreasing the number of carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
- C07C41/26—Preparation of ethers by reactions not forming ether-oxygen bonds by introduction of hydroxy or O-metal groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/08—Preparation of carboxylic acids or their salts, halides or anhydrides from nitriles
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/28—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group
- C07C67/283—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group by hydrogenation of unsaturated carbon-to-carbon bonds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/017—Esters of hydroxy compounds having the esterified hydroxy group bound to a carbon atom of a six-membered aromatic ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/02—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen
- C07C69/12—Acetic acid esters
- C07C69/18—Acetic acid esters of trihydroxylic compounds
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- C—CHEMISTRY; METALLURGY
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
- C07C69/78—Benzoic acid esters
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- 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 System
- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/02—Ortho- or ortho- and peri-condensed systems
- C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
- C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
- C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
- C07C2603/12—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings only one five-membered ring
- C07C2603/14—Benz[f]indenes; Hydrogenated benz[f]indenes
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- 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
Description
スキーム1
本明細書において「アルキル」とは、メチル、エチル、イソプロピル、tert−ブチル等、1〜30個の炭素原子を有する直鎖若しくは分岐鎖の炭化水素基、又はシクロプロピル、シクロペンチル、シクロヘキシル、メンチル等、3〜10個の炭素原子を有する環状飽和炭化水素基を意味する。
を含む、式6cで表される化合物の製造方法を提供する。
スキーム4
(a)式6bで表される化合物のフェノール基を、XCH2CN又はXCH2COOR5(式中、Xは、塩素(Cl)、臭素(Br)又はヨウ素(I)等のハロゲンであり;R5はアルキルである)で表されるアルキル化剤でアルキル化することと、
(b)−CN基又は−COOR5基を塩基で加水分解して−COOH基を生成することと、
(c)保護基P2及びP3を除去することと、
を含む。
スキーム5
実施例1
(2R,3R,4R)−2−(3−(ベンジルオキシ)ベンジル)−4−tert−ブチルジメチルシリオキシ−3−((S,E)−3−tert−ブチルジメチルシリオキシオクト−1−エニル)シクロペンタノン
実施例2
(2R,3R,4R)−2−(3−(ベンジルオキシ)ベンジル)−4−−トリエチルシリオキシ−3−((S,E)−3−トリエチルシリオキシオクト−1−エニル)シクロペンタノン
実施例3
(2R,3R,4R)−2−(3−(ベンジルオキシ)ベンジル)−4−tert−ブチルジメチルシリオキシ−3−((S)−3−tert−ブチルジメチルシリオキシオクチル)シクロペンタノン
実施例4
(2R,3R,4R)−2−(3−(tert−ブチルジメチルシリオキシ)ベンジル)−4−(テトラヒドロ−2H−ピラン−2−イルオキシ)−3−((S,E)−3−(テトラヒドロ−2H−ピラン−2−イルオキシ)オクト−1−エニル)シクロペンタノン
実施例5
((S,E)−1−((1R,2R,5R)−2−(3−(ベンジルオキシ)ベンジル)−3−メチレン−5−(tert−ブチルジメチルシリオキシ)シクロペンチル)オクト−1−エン−3−イルオキシ)(tert−ブチル)ジメチルシラン
実施例6
((S)−1−((1R,2R,5R)−2−(3−(ベンジルオキシ)ベンジル)−3−メチレン−5−(tert−ブチルジメチルシリオキシ)シクロペンチル)オクタン−3−イルオキシ)(tert−ブチル)ジメチルシラン
実施例7
(1R,2R,3R)−3−(3−(ベンジルオキシ)ベンジル)−2−((S,E)−3−ヒドロキシオクト−1−エニル)−4−メチレンシクロ−ペンタノール
実施例8
((S,E)−1−((1R,2R,5R)−2−(3−(ベンジルオキシ)ベンジル)−3−メチレン−5−(tert−ブチルジメチルシリオキシ)シクロペンチル)オクト−1−エン−3−イルオキシ)(tert−ブチル)ジメチルシラン
実施例9
((1S,2S,3R,4R)−2−(3−(ベンジルオキシ)ベンジル)−4−(tert−ブチルジメチルシリオキシ)−3−((S,E)−3−(tert−ブチルジメチルシリオキシ)オクト−1−エニル)シクロペンチル)メタノール
実施例10
((1S,2S,3R,4R)−2−(3−(ベンジルオキシ)ベンジル)−4−(tert−ブチルジメチルシリオキシ)−3−((S)−3−(tert−ブチルジメチルシリオキシ)オクチル)シクロペンチル)メタノール
実施例11
((1S,2S,3R,4R)−2−(3−(ベンジルオキシ)ベンジル)−4−(tert−ブチルジメチルシリオキシ)−3−((S,E)−3−(tert−ブチルジメチルシリオキシ)オクト−1−エニル)シクロペンチル)メチルメタンスルホネート
実施例12
((1S,2S,3R,4R)−2−(3−(ベンジルオキシ)ベンジル)−4−(tert−ブチルジメチルシリオキシ)−3−((S,E)−3−(tert−ブチルジメチルシリオキシ)オクト−1−エニル)シクロペンチル)メチル4−メチルベンゼンスルホネート
実施例13
((1S,2S,3R,4R)−2−(3−(ベンジルオキシ)ベンジル)−4−(tert−ブチルジメチルシリオキシ)−3−((S)−3−(tert−ブチルジメチルシリオキシ)オクチル)シクロペンチル)メチル4−メチルベンゼンスルホネート
実施例14
((1S,2S,3R,4R)−2−(3−ヒドロキシベンジル)−4−(tert−ブチルジメチルシリオキシ)−3−((S,E)−3−(tert−ブチルジメチルシリオキシ)オクト−1−エニル)シクロペンチル)メチルメタンスルホネート
実施例15
((1S,2S,3R,4R)−2−(3−ヒドロキシベンジル)−4−(tert−ブチルジメチルシリオキシ)−3−((S,E)−3−(tert−ブチルジメチルシリオキシ)オクト−1−エニル)シクロペンチル)メチル4−メチルベンゼンスルホネート
実施例16及び17
((1S,2S,3R,4R)−2−(3−ヒドロキシベンジル)−4−(tert−ブチルジメチルシリオキシ)−3−((S)−3−(tert−ブチルジメチルシリオキシ)オクチル)シクロペンチル)メチル4−メチルベンゼンスルホネート
実施例18及び19
(1R,2R,3aS,9aS)−2,3,3a,4,9,9a−ヘキサヒドロ−2−(tert−ブチルジメチルシリオキシ)−1−((S,E)−3−(tert−ブチルジメチルシリオキシ)オクト−1−エニル)−1H−シクロペンタ[b]ナフタレン−5−オール
実施例20
(1R,2R,3aS,9aS)−2,3,3a,4,9,9a−ヘキサヒドロ−2−(tert−ブチルジメチルシリオキシ)−1−((S)−3−(tert−ブチルジメチルシリオキシ)オクチル)−1H−シクロペンタ[b]ナフタレン−5−オール
実施例21及び22
(1R,2R,3aS,9aS)−2,3,3a,4,9,9a−ヘキサヒドロ−1−((S,E)−3−ヒドロキシオクト−1−エニル)−1H−シクロペンタ[b]ナフタレン−2,5−ジオール
実施例23
(1R,2R,3aS,9aS)−2,3,3a,4,9,9a−ヘキサヒドロ−2−ヒドロキシ−1−((S,E)−3−ヒドロキシオクト−1−エニル)−1H−シクロペンタ[b]ナフタレン−5−イルアセテート
実施例24
(1R,2R,3aS,9aS)−2,3,3a,4,9,9a−ヘキサヒドロ−2−ヒドロキシ−1−((S,E)−3−ヒドロキシオクト−1−エニル)−1H−シクロペンタ[b]ナフタレン−5−イルベンゾエート
実施例25
(1R,2R,3aS,9aS)−2,3,3a,4,9,9a−ヘキサヒドロ−2−ヒドロキシ−1−((S)−3−ヒドロキシオクチル)−1H−シクロペンタ[b]ナフタレン−5−イルベンゾエート
実施例26
メチル2−((1R,2R,3aS,9aS)−2,3,3a,4,9,9a−ヘキサヒドロ−2−ヒドロキシ−1−((S,E)−3−ヒドロキシオクト−1−エニル)−1H−シクロペンタ[b]ナフタレン−5−イルオキシ)アセテート
実施例27〜30
(1R,2R,3aS,9aS)−2,3,3a,4,9,9a−ヘキサヒドロ−1−((S)−3−ヒドロキシオクチル)−1H−シクロペンタ[b]ナフタレン−2,5−ジオール
反応に用いた等モルの基質として、(1R,2R,3aS,9aS)−2,3,3a,4,9,9a−ヘキサヒドロ−2−(tert−ブチルジメチルシリオキシ)−1−((S,E)−3−(tert−ブチルジメチルシリオキシ)オクト−1−エニル)−1H−シクロペンタ[b]ナフタレン−5−オールの代わりに(1R,2R,3aS,9aS)−2,3,3a,4,9,9a−ヘキサヒドロ−2−(tert−ブチルジメチルシリオキシ)−1−((S)−3−(tert−ブチルジメチルシリオキシ)オクチル)−1H−シクロペンタ[b]ナフタレン−5−オール(実施例20より)を用いた以外は実施例22の記載と同様の操作を行って、標題化合物を製造し、結晶形態で得た(収率:83%)。
乾燥メタノール(25mL)に溶解した(1R,2R,3aS,9aS)−2,3,3a,4,9,9a−ヘキサヒドロ−1−((S,E)−3−ヒドロキシオクト−1−エニル)−1H−シクロペンタ[b]ナフタレン−2,5−ジオール(2.5g、0.008mol、実施例21又は22で得た)を水酸化カリウム(0.5g、0.008mol)で処理し、続いて5%Pd/C(0.5g、20%wt)で水素下にて一晩室温で処理した。続いて、この反応混合物をセライトパッドで濾過した。溶媒を真空下で蒸発させた。シリカゲルを用いたクロマトグラフィー(勾配溶離液:ヘキサン及び酢酸エチルの混合物)により粗生成物を精製した。標題化合物を結晶形態で得た。収率:72%。
(1R,2R,3aS,9aS)−2,3,3a,4,9,9a−ヘキサヒドロ−2−ヒドロキシ−1−((S)−3−ヒドロキシオクチル)−1H−シクロペンタ[b]ナフタレン−5−イルベンゾエート(0.2g、0.008mol、実施例25から)を水酸化ナトリウム(5%となるようメタノールに溶解)(1mL)で処理し、次に室温で60分間攪拌した。この反応混合物を3N塩酸(HCl)(1mL)及び酢酸エチル(10mL)で希釈した。反応混合物を分相し、水層を酢酸エチルで抽出した。有機層を合一し、無水硫酸マグネシウムで乾燥した。濾過により固形物を除去し、溶媒を真空下で蒸発させた。シリカゲルを用いたクロマトグラフィー(勾配溶離液:ヘキサン及び酢酸エチルの混合物)により粗生成物を精製した。標題化合物を結晶形態で得た。収率:85%。
乾燥メタノール(2mL)に溶解した(1R,2R,3aS,9aS)−2,3,3a,4,9,9a−ヘキサヒドロ−2−ヒドロキシ−1−((S,E)−3−ヒドロキシオクト−1−エニル)−1H−シクロペンタ[b]ナフタレン−5−イルベンゾエート(0.25g、0.6mmol、実施例24から)を5%Pd/C(0.05g、20%wt)で処理し、水素下にて28時間室温で攪拌した。続いて、この反応混合物をセライトパッドで濾過した。溶媒を真空下で蒸発させた。シリカゲルを用いたクロマトグラフィー(勾配溶離液:ヘキサン及び酢酸エチルの混合物)により粗生成物を精製した。標題化合物を結晶形態で得た。収率:73%。
実施例31及び32
2−((1R,2R,3aS,9aS)−2,3,3a,4,9,9a−ヘキサヒドロ−2−ヒドロキシ−1−((S,E)−3−ヒドロキシオクト−1−エニル)−1H−シクロペンタ[b]ナフタレン−5−イルオキシ)アセトニトリル
乾燥アセトン(16mL)に溶解した(1R,2R,3aS,9aS)−2,3,3a,4,9,9a−ヘキサヒドロ−1−((S,E)−3−ヒドロキシオクト−1−エニル)−1H−シクロペンタ[b]ナフタレン−2,5−ジオール(1.6g、0.004mol)を炭酸カリウム(K2CO3)(1.66g、0.012mol)、クロロアセトニトリル(0.51mL、0.008mol)及び臭化テトラブチルアンモニウム(0.32g、0.001mmol)で処理した。この混合物を30℃で一晩加熱した。続いて、この反応混合物をセライトパッドで濾過した。濾液を真空下で蒸発させた。シリカゲルを用いたクロマトグラフィー(勾配溶離液:ヘキサン及び酢酸エチルの混合物)により粗生成物を精製した。標題化合物を結晶形態で得た。収率:89%。
乾燥アセトン(64mL)に溶解した(1R,2R,3aS,9aS)−2,3,3a,4,9,9a−ヘキサヒドロ−2−(tert−ブチルジメチルシリオキシ)−1−((S,E)−3−(tert−ブチルジメチルシリオキシ)オクト−1−エニル)−1H−シクロペンタ[b]ナフタレン−5−オール(6.4g、0.011mmol)を炭酸カリウム(K2CO3)(6.64g、0.048mol)、クロロアセトニトリル(2mL、0.032mol)及び臭化テトラブチルアンモニウム(1.28g、0.004mmol)で処理した。この混合物を30℃で一晩加熱した。続いて、この反応混合物をセライトパッドで濾過した。濾液を真空下で蒸発させた。未精製の保護されたベンゾインデンニトリル[2−((1R,2R,3aS,9aS)−2,3,3a,4,9,9a−ヘキサヒドロ−2−(tert−ブチルジメチルシリオキシ)−1−((S,E)−3−(tert−ブチルジメチルシリオキシ)オクト−1−エニル)−1H−シクロペンタ[b]ナフタレン−5−イルオキシ)アセトニトリル]を得た。次に、未精製の保護されたベンゾインデンニトリルをTHF(19.2mL)に溶解し、続いて酢酸(57.6mL)及び蒸留水(19.2mL)に一晩室温で溶解した。この反応混合物を飽和炭酸水素ナトリウム水溶液(200mL)に注ぎ、30分間攪拌した。この反応混合物を分相し、水層を酢酸エチル(300mL)で抽出した。有機層を合一し、無水硫酸マグネシウムで乾燥した。濾過により固形物を除去し、溶媒を真空下で蒸発させた。シリカゲルを用いたクロマトグラフィー(勾配溶離液:ヘキサン及び酢酸エチルの混合物)により粗生成物を精製した。標題化合物の収量は3.43gであり、これは微量のパラ環化異性体を含有した。パラ環化異性体を結晶化によりイソプロピルエーテル/ヘプタンから除去した。標題化合物(2.74g)を結晶形態(白色からオフホワイト粉末)で得た。融点(MP):58℃(収率:67%)。
実施例33
2−((1R,2R,3aS,9aS)−2,3,3a,4,9,9a−ヘキサヒドロ−2−ヒドロキシ−1−((S)−3−ヒドロキシオクチル)−1H−シクロペンタ[b]ナフタレン−5−イルオキシ)アセトニトリル
実施例34及び35
2−((1R,2R,3aS,9aS)−2,3,3a,4,9,9a−ヘキサヒドロ−2−ヒドロキシ−1−((S,E)−3−ヒドロキシオクト−1−エニル)−1H−シクロペンタ[b]ナフタレン−5−イルオキシ)酢酸
イソプロピルアルコール(16mL)に溶解した2−((1R,2R,3aS,9aS)−2,3,3a,4,9,9a−ヘキサヒドロ−2−ヒドロキシ−1−((S,E)−3−ヒドロキシオクト−1−エニル)−1H−シクロペンタ[b]ナフタレン−5−イルオキシ)アセトニトリル(1.6g、0.004mol)を20%水酸化カリウム(KOH)(5mL)で処理し、3時間還流し、次に10℃に冷却し、3N塩酸(HCl)をpHが8となるまで徐々に添加した。溶媒を真空中で除去した。酢酸エチル及び塩水を添加し、次に、3N塩酸(HCl)をpHが2となるまで徐々に添加した。この反応混合物を酢酸エチルで抽出した。組み合わせた酢酸エチル抽出液を無水硫酸マグネシウムで乾燥した。濾過により固形物を除去し、溶媒を真空下で蒸発させた。粗生成物を結晶化によりエタノール/水(H2O)から精製した。標題化合物(1.2g)を結晶形態で得た。
反応に用いた等モルの基質として、メチル2−((1R,2R,3aS,9aS)−2,3,3a,4,9,9a−ヘキサヒドロ−2−ヒドロキシ−1−((S,E)−3−ヒドロキシオクト−1−エニル)−1H−シクロペンタ[b]ナフタレン−5−イルオキシ)アセテートを用いた以外は、実施例29に記載の操作を行った。標題化合物を製造し、結晶形態で得た。収率:82%。
実施例36及び37
トレプロスチニルの製造
2−((1R,2R,3aS,9aS)−2,3,3a,4,9,9a−ヘキサヒドロ−2−ヒドロキシ−1−((S)−3−ヒドロキシオクチル)−1H−シクロペンタ[b]ナフタレン−5−イルオキシ)酢酸
メタノール(18mL)に溶解した2−((1R,2R,3aS,9aS)−2,3,3a,4,9,9a−ヘキサヒドロ−2−ヒドロキシ−1−((S)−3−ヒドロキシオクチル)−1H−シクロペンタ[b]ナフタレン−5−イルオキシ)アセトニトリル(2g、0.005mol)を20%水酸化カリウム(KOH)(6mL)で処理し、3時間還流した。次に、反応生成物を10℃に冷却し、3N塩酸(HCl)をpHが約8となるよう徐々に添加した。溶媒を真空中で除去した。酢酸エチル及び塩水を添加し、次に、3N塩酸(HCl)をpHが2となるまで徐々に添加した。この反応混合物を酢酸エチルで抽出した。組み合わせた酢酸エチル抽出液を無水硫酸マグネシウムで乾燥した。濾過により固形物を除去した。溶媒を真空下で蒸発させた。粗生成物を結晶化によりエタノール/水(H2O)から精製した。標題化合物を結晶形態で得た。収率:81%。
乾燥メタノール(25mL)に溶解した2−((1R,2R,3aS,9aS)−2,3,3a,4,9,9a−ヘキサヒドロ−2−ヒドロキシ−1−((S,E)−3−ヒドロキシオクト−1−エニル)−1H−シクロペンタ[b]ナフタレン−5−イルオキシ)酢酸(2.5g、0.008mol)を水酸化カリウム(0.5g、0.008mol)で処理し、次に5%Pd/C(0.5g、20%wt)で水素下にて一晩室温で処理した。続いて、この反応混合物をセライトパッドで濾過した。溶媒を真空下で蒸発させた。残渣を酢酸エチル(50m)及び飽和炭酸水素ナトリウム水溶液(50mL)で希釈した。この混合物を分相し、有機層を飽和炭酸水素ナトリウム水溶液(50mL)で抽出した。水層を組み合わせ、次に3N塩酸(HCl)をpHがほぼ2となるまで徐々に添加した。水層を酢酸エチル(100mL)で抽出した。有機層を合一し、無水硫酸マグネシウムで乾燥した。濾過により固形物を除去し、溶媒を真空下で蒸発させた。粗生成物を結晶化により精製した。標題化合物を結晶形態で得た。収率:88%。
Claims (22)
- 式1:
(1)
式III:
- P1は、非置換アルキル、アリル、非置換若しくは置換ベンジル、アセチル、アルキルカルボニル、メトキシメチル、メトキシチオメチル、2−メトキシエトキシメチル、ビス(2−クロロエトキシ)メチル、テトラヒドロピラニル、テトラヒドロチオピラニル、4−メトキシテトラヒドロピラニル、4−メトキシテトラヒドロチオピラニル、テトラヒドロフラニル、テトラヒドロチオフラニル、1−エトキシエチル、1−メチル−1−メトキシエチル、トリフェニルメチル又はSiRaRbRc(式中、Ra、Rb及びRcは、それぞれ独立してC1〜8アルキル、フェニル、ベンジル、置換フェニル又は置換ベンジルを表す)である、請求項1に記載の方法。
- P1は、アリル、非置換又は置換ベンジル、アセチル、アルキルカルボニル及びSiRaRbRc(式中、Ra、Rb及びRcは、それぞれ独立してC1〜8アルキル、フェニル、ベンジル、置換フェニル又は置換ベンジルを表す)から選択される、請求項1に記載の方法。
- R2が単結合であり、R3がアミルである、請求項1に記載の方法。
- 式6:
(1)式III:
(2)式1で表される化合物のケトン基をメチレン化して、式2:
(3)式2で表される化合物をホウ素試薬によりヒドロホウ素化し、続いて塩基性過酸化水素で酸化して、式3:
(4)式3で表される化合物を塩基の存在下でスルホニル供与体によりスルホニル化して、式4:
(5)P1基を除去して、式5:
(6)式5で表される化合物を分子内アルキル化して、式6で表される化合物を生成するステップと、を含む、式6で表される化合物の製造方法。 - メチレン化試薬は、ジブロモメタン(CH2Br2)、亜鉛(Zn)及び四塩化チタン(TiCl4)から製造される、請求項5に記載の方法。
- メチレン化は、式1で表されるシクロペンタノンを適切な溶媒中でメチルフェニル−N−メチル−スルホキシイミンの陰イオンと反応させ、続いて、得られた粗付加物を水−酢酸−テトラヒドロフランの溶媒混合物中においてアルミニウムアマルガムで処理し、式2で表される化合物を得ることを含む、請求項5に記載の方法。
- ホウ素試薬は、9−ボラビシクロ[3,3,1]ノナン(9−BBN)である、請求項5に記載の方法。
- X1のスルホニル基は、メタンスルホニル又はp−トルエンスルホニルである、請求項5に記載の方法。
- R2が単結合であり、R3がアミルである、請求項5に記載の方法。
- 式6c:
(1)式III:
(2)式1cで表される化合物のケトン基をメチレン化試薬によりメチレン化して、式2c:
(3)式2cで表される化合物をホウ素試薬によりヒドロホウ素化し、続いて塩基性過酸化水素により酸化して、式3c:
(4)式3cで表される化合物を塩基の存在下でスルホニル供与体によりスルホニル化して、式4c:
(5)P1基を除去し、ω−側鎖における二重結合を水素化して、式5c:
(6)式5cで表される化合物を分子内アルキル化させて、式6cで表される化合物を生成するステップと、
を含む、式6cで表される化合物の製造方法。 - メチレン化試薬は、ジブロモメタン(CH2Br2)、亜鉛(Zn)及び四塩化チタン(TiCl4)から製造される、請求項11に記載の方法。
- メチレン化は、式1cで表されるシクロペンタノンを適切な溶媒中でメチルフェニル−N−メチル−スルホキシイミンの陰イオンと反応させ、続いて、得られた粗付加物を、水−酢酸−テトラヒドロフランの溶媒混合物中においてアルミニウムアマルガムで処理して、式2cで表される化合物を得ることを含む、請求項11に記載の方法。
- ホウ素試薬は、9−ボラビシクロ[3,3,1]ノナン(9−BBN)である、請求項11に記載の方法。
- スルホニル基は、メタンスルホニル又はp−トルエンスルホニルである、請求項11に記載の方法。
- R2が単結合であり、R3がアミル基である、請求項11に記載の方法。
- トレプロスチニルの製造方法であって、該方法は、
(1)式IIIa:
(2)式1dで表される化合物のケトン基をメチレン化して、式2d:
(3)式2dで表される化合物をホウ素試薬によりヒドロホウ素化し、続いて塩基性過酸化水素により酸化して、式3d:
(4)式3dで表される化合物を塩基の存在下でスルホニル供与体によりスルホニル化して、式4d:
(5)P1基を除去して、式5d:
(6)式5dで表される化合物を分子内アルキル化して、式6d:
(7)P2及びP3基を除去して、式7d:
(8)式7dで表される化合物のω−側鎖における二重結合を水素化して、式8d:
(9)フェノール基をXCH2CN又はXCH2COOR5(式中、Xは、ハロゲンを表し;R5は、アルキルを表す)で表されるアルキル化剤によりアルキル化して、式9d:
(10)式9dで表される化合物の−CN基又は−COOR5基を塩基で加水分解して、トレプロスチニルを生成するステップと、
を含む、トレプロスチニルの製造方法。 - P1は、アリル、非置換又は置換ベンジル、アセチル、アルキルカルボニル及びSiRaRbRc(式中、Ra、Rb及びRcは、それぞれ独立してC1〜8アルキル、フェニル、ベンジル、置換フェニル又は置換ベンジルを表す)から選択される、請求項17に記載の方法。
- 式6d:
(7)フェノール基をXCH2CN又はXCH2COOR5(式中、Xは、塩素原子(Cl)、臭素原子(Br)又はヨウ素原子(I)等のハロゲンを表し;R5は、アルキルを表す)で表されるアルキル化剤によりアルキル化して、式7D:
(8)P2及びP3基を除去して、式8D:
(9)式8Dで表される化合物の−CN基又は−COOR5基を塩基で加水分解して、式9D:
(10)式9Dで表される化合物の(−側鎖における二重結合を水素化して、トレプロスチニルを生成するステップと、
を含む、請求項17に記載の方法。 - トレプロスチニルの製造方法であって、該方法は、
(1)式IIIa:
(2)式1bで表される化合物のケトン基をメチレン化して、式2b:
(3)式2bで表される化合物をホウ素試薬によりヒドロホウ素化し、続いて塩基性過酸化水素により酸化して、式3b:
(4)式3bで表される化合物を塩基の存在下でスルホニル供与体によりスルホニル化して、式4b:
(5)P1基を除去して、式5b:
(6)式5bで表される化合物を分子内アルキル化して、式6b:
(7)P2及びP3基を除去して、式8d:
(8)フェノール基をXCH2CN又はXCH2COOR5(式中、Xは、ハロゲンを表し;R5は、アルキルを表す)で表されるアルキル化剤によりアルキル化して、式9d:
(9)式9dで表される化合物の−CN基又は−COOR5基を塩基で加水分解して、トレプロスチニルを生成するステップと、
を含む、トレプロスチニルの製造方法。
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MX369094B (es) | 2012-12-07 | 2019-10-29 | Cayman Chemical Co Inc | Metodos para sintetizar un analogo de prostaciclina. |
US9505737B2 (en) | 2013-01-11 | 2016-11-29 | Corsair Pharma, Inc. | Treprostinil derivative compounds and methods of using same |
WO2014110491A1 (en) | 2013-01-11 | 2014-07-17 | Theratrophix Llc | Prodrugs of treprostinil |
CA2905720C (en) * | 2013-03-14 | 2021-10-19 | United Therapeutics Corporation | Solid forms of treprostinil |
KR102296259B1 (ko) | 2013-10-25 | 2021-08-30 | 인스메드 인코포레이티드 | 프로스타사이클린 화합물, 조성물 및 이의 사용 방법 |
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EP3904326A1 (en) | 2014-11-18 | 2021-11-03 | Insmed Incorporated | Methods of manufacturing treprostinil and treprostinil derivative prodrugs |
WO2016088119A1 (en) | 2014-12-03 | 2016-06-09 | Steadymed Ltd | Preservative-free treprostinil formulations and methods and devices for use with same |
US9394227B1 (en) | 2015-06-17 | 2016-07-19 | Corsair Pharma, Inc. | Treprostinil derivatives and compositions and uses thereof |
US9643911B2 (en) | 2015-06-17 | 2017-05-09 | Corsair Pharma, Inc. | Treprostinil derivatives and compositions and uses thereof |
CN105061391B (zh) * | 2015-08-26 | 2017-09-01 | 潍坊医学院 | 一种芳炔基取代杂环酮类化合物的合成方法 |
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US10106499B1 (en) * | 2017-11-10 | 2018-10-23 | Chirogate International Inc. | Processes for preparing cyclopenta[b]naphthalenol derivatives and intermediates thereof |
EP3962472A4 (en) | 2019-04-29 | 2023-01-25 | Insmed Incorporated | DRY POWDER COMPOSITIONS OF TREPROSTINIL PRODRUGS AND METHODS OF USE THEREOF |
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Family Cites Families (18)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4233231A (en) | 1977-11-22 | 1980-11-11 | American Cyanamid Company | Novel vinyl-stannyl derivatives |
US4306075A (en) * | 1980-03-28 | 1981-12-15 | The Upjohn Company | Composition and process |
JPS57171965A (en) * | 1981-04-15 | 1982-10-22 | Teijin Ltd | Novel prostaglandin intermediate and its preparation |
US4415501A (en) | 1981-12-16 | 1983-11-15 | American Cyanamid Company | Alkenylzirconium reagents useful for prostaglandin analog synthesis |
JPS6187638A (ja) * | 1984-10-08 | 1986-05-06 | Teijin Ltd | 2,3−二置換−4−置換シクロペンタノン類の製造法 |
JPH0794400B2 (ja) * | 1993-07-19 | 1995-10-11 | 日本ゼオン株式会社 | ステロイド中間体の製造法 |
PT1025083E (pt) * | 1997-10-24 | 2003-10-31 | United Therapeutics Corp | Processo para a sintese estereo-selectiva de derivados da prostaciclina |
US6294679B1 (en) | 1999-04-12 | 2001-09-25 | Chirotech Technology Limited | Intermediate for the synthesis of prostaglandins |
US6700025B2 (en) * | 2001-01-05 | 2004-03-02 | United Therapeutics Corporation | Process for stereoselective synthesis of prostacyclin derivatives |
US6803386B2 (en) * | 2002-01-16 | 2004-10-12 | United Therapeutics Corporation | Prostacyclin derivative containing compositions and methods of using the same for the treatment of cancer |
US7511168B2 (en) * | 2006-01-18 | 2009-03-31 | Shih-Yi Wei | Processes and intermediates for the preparations of prostaglandins |
TWI310763B (en) * | 2006-01-18 | 2009-06-11 | Chirogate Int Inc | Processes and intermediates for the preparations of prostaglandins |
EP1810967B1 (en) * | 2006-01-18 | 2014-07-30 | Chirogate International Inc. | Processes and intermediates for the preparations of prostaglandins |
WO2009078965A1 (en) * | 2007-12-17 | 2009-06-25 | United Therapeutics Corporation | An improved process to prepare treprostinil, the active ingredient in remodulin |
WO2010109476A2 (en) * | 2009-01-19 | 2010-09-30 | Matrix Laboratories Ltd | Improved process for the preparation of prostaglandins and analogues thereof |
CN101891715B (zh) * | 2009-05-22 | 2015-09-02 | 上海天伟生物制药有限公司 | 一种化合物及其制备方法和用途 |
CN101891596B (zh) * | 2009-05-22 | 2013-12-11 | 上海天伟生物制药有限公司 | 一种化合物及其制备方法和用途 |
CA2710726C (en) * | 2010-07-22 | 2016-02-23 | Alphora Research Inc. | Synthesis of treprostinil and intermediates useful therein |
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