TW201433565A - 用於合成苯并茚前列腺素之中間物及其製備方法 - Google Patents
用於合成苯并茚前列腺素之中間物及其製備方法 Download PDFInfo
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- TW201433565A TW201433565A TW103117519A TW103117519A TW201433565A TW 201433565 A TW201433565 A TW 201433565A TW 103117519 A TW103117519 A TW 103117519A TW 103117519 A TW103117519 A TW 103117519A TW 201433565 A TW201433565 A TW 201433565A
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- compound
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- ethyl acetate
- mixture
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- -1 benzindene prostaglandins Chemical class 0.000 title claims abstract description 83
- 229940094443 oxytocics prostaglandins Drugs 0.000 title abstract description 10
- 238000002360 preparation method Methods 0.000 title abstract description 8
- 239000000543 intermediate Substances 0.000 title abstract description 7
- 230000015572 biosynthetic process Effects 0.000 title description 7
- 238000003786 synthesis reaction Methods 0.000 title description 6
- 238000000034 method Methods 0.000 claims abstract description 29
- 150000001875 compounds Chemical class 0.000 claims description 116
- 125000000217 alkyl group Chemical group 0.000 claims description 25
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 22
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 19
- 125000006239 protecting group Chemical group 0.000 claims description 14
- 229910052736 halogen Inorganic materials 0.000 claims description 10
- 150000002367 halogens Chemical class 0.000 claims description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
- 125000003118 aryl group Chemical group 0.000 claims description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 5
- 125000004953 trihalomethyl group Chemical group 0.000 claims description 3
- 230000027832 depurination Effects 0.000 claims 1
- BGTOWKSIORTVQH-UHFFFAOYSA-N cyclopentanone Chemical class O=C1CCCC1 BGTOWKSIORTVQH-UHFFFAOYSA-N 0.000 abstract description 60
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 219
- 235000019439 ethyl acetate Nutrition 0.000 description 77
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 77
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 56
- 239000000203 mixture Substances 0.000 description 54
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 48
- 239000011541 reaction mixture Substances 0.000 description 48
- 239000002904 solvent Substances 0.000 description 43
- 238000006243 chemical reaction Methods 0.000 description 35
- 239000012043 crude product Substances 0.000 description 35
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 33
- 238000010898 silica gel chromatography Methods 0.000 description 30
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 28
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 27
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 26
- 239000012044 organic layer Substances 0.000 description 26
- 239000000243 solution Substances 0.000 description 26
- 239000007787 solid Substances 0.000 description 25
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 24
- 239000010410 layer Substances 0.000 description 24
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 22
- 238000005191 phase separation Methods 0.000 description 22
- 238000005160 1H NMR spectroscopy Methods 0.000 description 20
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 19
- 239000002585 base Substances 0.000 description 19
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 17
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- 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
- 229920006395 saturated elastomer Polymers 0.000 description 14
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 12
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 12
- 150000004702 methyl esters Chemical class 0.000 description 12
- 229960005032 treprostinil Drugs 0.000 description 12
- 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 description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 11
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 10
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 10
- 238000005481 NMR spectroscopy Methods 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 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
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 8
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- 239000012267 brine Substances 0.000 description 8
- 239000003153 chemical reaction reagent Substances 0.000 description 8
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 7
- 229910052739 hydrogen Inorganic materials 0.000 description 7
- 239000001257 hydrogen Substances 0.000 description 7
- 238000005984 hydrogenation reaction Methods 0.000 description 7
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 6
- 239000005711 Benzoic acid Substances 0.000 description 6
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 230000029936 alkylation Effects 0.000 description 6
- 238000005804 alkylation reaction Methods 0.000 description 6
- 235000010233 benzoic acid Nutrition 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 235000017557 sodium bicarbonate Nutrition 0.000 description 6
- 229910000030 sodium bicarbonate Inorganic materials 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
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 6
- 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
- 239000000908 ammonium hydroxide Substances 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 229910052796 boron Inorganic materials 0.000 description 5
- 238000010511 deprotection reaction Methods 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 5
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 5
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 4
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 4
- BZKFMUIJRXWWQK-UHFFFAOYSA-N Cyclopentenone Chemical compound O=C1CCC=C1 BZKFMUIJRXWWQK-UHFFFAOYSA-N 0.000 description 4
- 239000005909 Kieselgur Substances 0.000 description 4
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 4
- 239000002168 alkylating agent Substances 0.000 description 4
- 229940100198 alkylating agent Drugs 0.000 description 4
- 229910052794 bromium Inorganic materials 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- 239000012153 distilled water Substances 0.000 description 4
- 229910052740 iodine Inorganic materials 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- 229940098779 methanesulfonic acid Drugs 0.000 description 4
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 4
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 4
- DIOQZVSQGTUSAI-UHFFFAOYSA-N n-butylhexane Natural products CCCCCCCCCC DIOQZVSQGTUSAI-UHFFFAOYSA-N 0.000 description 4
- ZCYXXKJEDCHMGH-UHFFFAOYSA-N nonane Chemical compound CCCC[CH]CCCC ZCYXXKJEDCHMGH-UHFFFAOYSA-N 0.000 description 4
- BKIMMITUMNQMOS-UHFFFAOYSA-N normal nonane Natural products CCCCCCCCC BKIMMITUMNQMOS-UHFFFAOYSA-N 0.000 description 4
- 230000003647 oxidation Effects 0.000 description 4
- 238000007254 oxidation reaction Methods 0.000 description 4
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 4
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 4
- 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-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
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 3
- 125000003545 alkoxy group Chemical group 0.000 description 3
- 230000002152 alkylating effect Effects 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
- 239000013078 crystal Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 229960001123 epoprostenol Drugs 0.000 description 3
- 239000012456 homogeneous solution Substances 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
- 125000000468 ketone group Chemical group 0.000 description 3
- DVSDBMFJEQPWNO-UHFFFAOYSA-N methyllithium Chemical compound C[Li] DVSDBMFJEQPWNO-UHFFFAOYSA-N 0.000 description 3
- 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 3
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 3
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 3
- 238000009877 rendering Methods 0.000 description 3
- 239000012258 stirred mixture Substances 0.000 description 3
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 3
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 3
- 238000004809 thin layer chromatography Methods 0.000 description 3
- 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 description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 2
- 125000006701 (C1-C7) alkyl group Chemical group 0.000 description 2
- 125000004209 (C1-C8) alkyl group Chemical group 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
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- 229910000761 Aluminium amalgam Inorganic materials 0.000 description 2
- FMMWHPNWAFZXNH-UHFFFAOYSA-N Benz[a]pyrene Chemical compound C1=C2C3=CC=CC=C3C=C(C=C3)C2=C2C3=CC=CC2=C1 FMMWHPNWAFZXNH-UHFFFAOYSA-N 0.000 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-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
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-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
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 150000001450 anions Chemical class 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- FJBFPHVGVWTDIP-UHFFFAOYSA-N dibromomethane Chemical compound BrCBr FJBFPHVGVWTDIP-UHFFFAOYSA-N 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
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000006197 hydroboration reaction Methods 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 150000002430 hydrocarbons Chemical group 0.000 description 2
- 230000003301 hydrolyzing effect Effects 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
- 239000011159 matrix material Substances 0.000 description 2
- 229910052759 nickel Inorganic materials 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
- 239000011877 solvent mixture Substances 0.000 description 2
- 238000006277 sulfonation reaction Methods 0.000 description 2
- 125000005309 thioalkoxy group Chemical group 0.000 description 2
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 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
- 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
- YJTKZCDBKVTVBY-UHFFFAOYSA-N 1,3-Diphenylbenzene Chemical group C1=CC=CC=C1C1=CC=CC(C=2C=CC=CC=2)=C1 YJTKZCDBKVTVBY-UHFFFAOYSA-N 0.000 description 1
- CXBDYQVECUFKRK-UHFFFAOYSA-N 1-methoxybutane Chemical compound CCCCOC CXBDYQVECUFKRK-UHFFFAOYSA-N 0.000 description 1
- YFQACQLWKCTQKT-UHFFFAOYSA-N 1-oct-1-enoxydecane Chemical compound CCCCCCCCCCOC=CCCCCCC YFQACQLWKCTQKT-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
- MXVMRHIWTSFDPU-UHFFFAOYSA-N 2-chlorobenzenecarboximidamide Chemical compound NC(=N)C1=CC=CC=C1Cl MXVMRHIWTSFDPU-UHFFFAOYSA-N 0.000 description 1
- PSODBWOLLYALSQ-UHFFFAOYSA-N 3,4-dihydro-2h-chromene-2-carbonitrile Chemical compound C1=CC=C2OC(C#N)CCC2=C1 PSODBWOLLYALSQ-UHFFFAOYSA-N 0.000 description 1
- TTZAXFUDRPZRNU-UHFFFAOYSA-N 3-methyl-1H-indole-2-sulfonic acid Chemical compound CC1=C(NC2=CC=CC=C12)S(=O)(=O)O TTZAXFUDRPZRNU-UHFFFAOYSA-N 0.000 description 1
- BHNCZRFXNHVDDT-UHFFFAOYSA-N 4-methoxyoxane Chemical compound COC1CCOCC1 BHNCZRFXNHVDDT-UHFFFAOYSA-N 0.000 description 1
- AMKGKYQBASDDJB-UHFFFAOYSA-N 9$l^{2}-borabicyclo[3.3.1]nonane Chemical compound C1CCC2CCCC1[B]2 AMKGKYQBASDDJB-UHFFFAOYSA-N 0.000 description 1
- UKISDMCHNFMLGC-CVMIBEPCSA-N C(C)(C)(C)[C@@]1(OCCC(C1)(C)C)OC(CCI)CCCCC Chemical compound C(C)(C)(C)[C@@]1(OCCC(C1)(C)C)OC(CCI)CCCCC UKISDMCHNFMLGC-CVMIBEPCSA-N 0.000 description 1
- NXUNKAYTVYXOON-UHFFFAOYSA-N C(CCC)C(CCCCCCCCC(C)(C)Cl)(CCCC)CCCC Chemical compound C(CCC)C(CCCCCCCCC(C)(C)Cl)(CCCC)CCCC NXUNKAYTVYXOON-UHFFFAOYSA-N 0.000 description 1
- IGMMYVRKMDQNJK-UHFFFAOYSA-N C12CCCC(CCC1)C2.[B] Chemical compound C12CCCC(CCC1)C2.[B] IGMMYVRKMDQNJK-UHFFFAOYSA-N 0.000 description 1
- IZWQZFPMRBTVMK-UHFFFAOYSA-N CC1=C2C(=C(N(C2=CC=C1)C)S(=O)(=O)O)C1=CC=CC=C1 Chemical compound CC1=C2C(=C(N(C2=CC=C1)C)S(=O)(=O)O)C1=CC=CC=C1 IZWQZFPMRBTVMK-UHFFFAOYSA-N 0.000 description 1
- 0 C[C@@](C[C@@](*)**)[C@]([C@@](*)C1)[C@@](Cc2cc(O)ccc2)C1=O Chemical compound C[C@@](C[C@@](*)**)[C@]([C@@](*)C1)[C@@](Cc2cc(O)ccc2)C1=O 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- 125000000641 acridinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3C=C12)* 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000001345 alkine derivatives Chemical class 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- NMVVJCLUYUWBSZ-UHFFFAOYSA-N aminomethylideneazanium;chloride Chemical compound Cl.NC=N NMVVJCLUYUWBSZ-UHFFFAOYSA-N 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
- 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
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- IMGUNTYROYTLIE-UHFFFAOYSA-N copper(1+);pent-1-yne Chemical compound [Cu+].CCCC#[C-] IMGUNTYROYTLIE-UHFFFAOYSA-N 0.000 description 1
- 239000013058 crude material Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 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
- XCIXKGXIYUWCLL-UHFFFAOYSA-N cyclopentanol Chemical compound OC1CCCC1 XCIXKGXIYUWCLL-UHFFFAOYSA-N 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
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- BADWIIDKTXQYLW-UHFFFAOYSA-N ethenylstannane Chemical compound [SnH3]C=C BADWIIDKTXQYLW-UHFFFAOYSA-N 0.000 description 1
- 125000004672 ethylcarbonyl group Chemical group [H]C([H])([H])C([H])([H])C(*)=O 0.000 description 1
- WHRIKZCFRVTHJH-UHFFFAOYSA-N ethylhydrazine Chemical compound CCNN WHRIKZCFRVTHJH-UHFFFAOYSA-N 0.000 description 1
- OJCSPXHYDFONPU-UHFFFAOYSA-N etoac etoac Chemical compound CCOC(C)=O.CCOC(C)=O OJCSPXHYDFONPU-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 229940001440 flolan Drugs 0.000 description 1
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 238000001990 intravenous administration Methods 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
- 238000004519 manufacturing process Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- YDCHPLOFQATIDS-UHFFFAOYSA-N methyl 2-bromoacetate Chemical compound COC(=O)CBr YDCHPLOFQATIDS-UHFFFAOYSA-N 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 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
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 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
- 229910052763 palladium Inorganic materials 0.000 description 1
- 125000005561 phenanthryl group Chemical group 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 125000005575 polycyclic aromatic hydrocarbon group Chemical group 0.000 description 1
- CUQOHAYJWVTKDE-UHFFFAOYSA-N potassium;butan-1-olate Chemical compound [K+].CCCC[O-] CUQOHAYJWVTKDE-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
- 238000000746 purification Methods 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 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
- 150000003839 salts Chemical class 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000005296 thioaryloxy group Chemical group 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 238000007738 vacuum evaporation Methods 0.000 description 1
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Abstract
本發明提供製備光學活性環戊酮1的新穎方法,所述環戊酮適用於製備苯并茚前列腺素,□並且提供新穎環戊酮。本發明還提供製備苯并茚前列腺素的新穎方法和苯并茚前列腺素的新穎中間體。
Description
本發明係關用於製備式1的環戊酮的新穎方法,
所述環戊酮適用於製備苯并茚前列腺素。本發明亦係關由所述方法製備的新穎環戊酮。
Flolan(依前列醇(Epoprostenol))是被食品和藥物管理局(Food and Drug Administration)批准用於治療肺高血壓的第一種藥物。然而,依前列醇極不穩定並且通常具有約3~5分鐘的半衰期,並且需要通過連續靜脈內投藥來投予以及儲藏在較低溫度下。苯并茚前列腺素(例如UT15(曲前列尼爾(Treprostinil)))是依前列醇的衍生物並且是新的一類用於治療肺高血壓的藥物。苯并茚前列腺素更穩定且因此在利用上相較於依前列醇,更便利並且更安全。
如流程1中所示,式1a的環戊酮是用於合成苯并茚前列腺素(例如UT15)的重要中間體(四面體通訊(Tetrahedron Letters),(1982),23(20),2067-70):
然而,如流程2中所示,式1a的環戊酮的合成應以中間體B開始並且經歷八個步驟(有機化學雜誌(J.Org.Chem.),第43卷,第11期,1978),並且將涉及20個以上化學步驟,包括合成中間體B的步驟。這種合成極其複雜並且僅獲得低的產量。
因此,產業中需要涉及較少步驟並且操作更便利的、用於製備式1的環戊酮以及苯并茚前列腺素的方法。
本發明提供製備光學活性環戊酮1的新穎方法和新穎環戊酮。
本發明尚提供製備苯并茚前列腺素的新穎方法和苯并茚前列腺素的新穎中間體。
I. 定義
本文中使用的術語「烷基」是指含有1到30個碳原子的直鏈或支鏈烴基,例如第三甲基、乙基、異丙基、第三丁基等;或具有3到10個碳原子的環狀飽和烴基,例如環丙基、環戊基、環己基、薄荷基等。
本文中使用的術語「低級烷基」是指含有1到6個碳原子的直鏈或支鏈烷基,例如甲基、乙基、丙基、異丙基、正丁基、第三丁基等。
本文中使用的術語「芳基」是指單環或多環芳香族烴基,例如苯基、萘基、蒽基、菲基等。芳基可視需要經一個或多個取代基取代,取代基包括(但不限於)鹵素、烷氧基、硫烷氧基、烷基和芳基。
本文中使用的術語「芳烷基」是指含有1到20個碳原子和一個或多個如上所述的芳基的直鏈或支鏈烴,例如苄基、二苯甲基、芴基甲基等。
上述烷基、芳基和芳烷基各自可視需要經一個或多個選自由以下組成的群組的取代基取代:鹵素、烷基、芳基、烷氧基、芳氧基、硫烷氧基、硫芳氧基、烷胺基、芳胺基、氰基、硝基、烷氧基羰基、芳基羰基、芳胺基羰基、烷胺基羰基、以及羰基或選自由吡啶基、噻吩基、呋喃基、咪唑基、嗎啉基、噁唑啉基、呱啶基、呱嗪基、四氫吡喃基、吡咯烷基、吡咯烷酮基等組成的群組的雜環基團。
於本說明書全文提供的化合物的描述中,加粗錐形線()表示取代基在β方向中(在分子平面或頁面上方),並且間斷火炬線()表示取代基在α方向中(在分子平面或頁面下方)。
II. 本發明的描述
式1的環戊酮
其中R2為單鍵或C1-4伸烷基或式-CH2O-的基團;R3為C1-7烷基或芳基或芳烷基,其各自未經取代或經C1-4烷基、鹵素或三鹵甲基取代;為單鍵或雙鍵;P1為酚基的保護基,其較佳地具酸穩定性並且包括(但不限於)未經取代的烷基、烯丙基、未經取代或經取代的苄基、乙醯基、烷基羰基、甲氧基甲基、甲氧基硫甲基、2-甲氧基乙氧基甲基、雙(2-氯乙氧基)甲基、四氫吡喃基、四氫硫代吡喃基、4-甲氧基四氫吡喃基、4-甲氧基四氫硫代吡喃基、四氫呋喃基、四氫硫代呋喃基、1-乙氧基乙基、1-甲基-1-甲氧基乙基、三苯基甲基或SiRaRbRc,其中Ra、Rb和Rc各自獨立地為C1-8烷基、苯基、苄基、經取代的苯基或經取代的苄基,並且P1更佳地選自烯丙基、未經取代或經取代的苄基、乙醯基、烷基羰基和SiRaRbRc,其中Ra、Rb和Rc各自獨立地為C1-8烷基、苯基、苄基、經取代的苯基或經取代的苄基;P2和P3相同或不同並且是羥基的保護基,較佳具鹼穩定性並且包括(但不限於)甲氧基甲基、甲氧基硫甲基、2-甲氧基乙氧基甲基、雙(2-氯乙氧基)甲基、四氫吡喃基、四氫硫代吡喃基、4-甲氧基四氫吡喃基、4-甲氧基四氫硫代吡喃基、四氫呋喃基、四氫硫代呋喃基、1-乙氧基乙基、1-甲基-1-甲氧基乙基、三苯基甲基和SiRaRbRc,其中Ra、Rb和Rc各自獨立地為C1-8烷基、苯基、苄基、經取代的苯基或經取代的苄基,是通過使衍生自式II-1的鹵化物、式II-2的乙烯基錫烷或式II-3的
炔的銅酸鹽的對映異構體富集的ω側鏈單元
其中X是鹵素;R4是低級烷基;並且、R2、R3和P3如上文所定義,如陳(Chen)等人,1978,有機化學雜誌(J.Org.Chem.),43,3450;USP 4,233,231、USP 4,415,501和USP 6,294,679中所述,所有文獻都以引用的方式併入本文中;與式III的光學活性環戊烯酮
其中P1和P2如上文所定義;在可為四氫呋喃、2-甲基四氫呋喃、乙醚、異丙醚、甲基丁基醚、二甲氧基乙烷、甲苯、庚烷或己烷或其混合物的適合溶劑中,並且較佳地在-100℃到40℃範圍內的溫度下進行偶合反應來製備。
式III的光學活性環戊烯酮可根據在同一日期申請並且名為「製備環戊烯酮化物之方法及供合成苯并茚前列腺素之環戊烯酮化物(PROCESSES FOR PREPARING CYCLOPENTENONES AND CYCLOPENTENONES FOR THE SYNTHESIS OF BENZINDENE PROSTAGLANDINS)」的同在申請中的專利申請案中所揭示的方法來製備。隨後,用例如氫氧化銨等鹼淬滅反應,並且以習知方式進行處理程序。所得粗產物可利用習知方法(例如柱色譜法或再結晶)純化,或未經純化的產物可直接用於下一反應中。根據本發明,粗產物1的純化包含脫除所得環戊酮1的P2和P3保護基,通過結晶去除由偶合反
應產生的雜質或異構體,並且再次對羥基進行保護以獲得高純度的式1環戊酮。
如流程3中所示,式6化合物(其中R2、R3、、P2和P3如上文所定義)是由式1環戊酮製備,
如流程3的步驟(a)中所示,式1的環戊酮以野琦-隆巴多試劑(Nozaki-Lombardo reagent)(日本化學會志(Bull.Chem.Soc.Jpn.),53.1698(1980))進行亞甲基化作用,形成式2化合物,所述野琦-隆巴多試劑由二溴甲烷、鋅和氯化鈦(IV)製備。反應可在任何適合溶劑中進行,例如選自二氯甲烷、四氫呋喃、乙醚、甲苯或己烷或其混合物的溶劑。反應在-50℃到100℃、較佳-20℃到室溫範圍內的溫度下進行。野琦-隆巴多試劑的使用量使得反應物如薄層色譜法(Thin Layer Chromatography,TLC)所監測完全反應。反應完成後,可利用例如去除過量試劑、萃取、脫水、濃縮等處理程序從反應混合物中分離出式
2化合物。可利用柱色譜法或利用結晶進一步純化產物。
還可以通過如詹森(Johnson)於美國化學會志(J.Am.Chem.Soc.),95,6462(1973)所教示的兩步驟程序來引入亞甲基。舉例來說,式1環戊酮與甲基苯基-N-甲基-磺基肟的陰離子在適合溶劑中反應,然後在水-乙酸-四氫呋喃的溶劑混合物中用鋁汞齊(aluminium amalgam)處理所得粗製加合物,獲得式2化合物。
可通過去除P2和P3保護基以獲得相應式2環戊酮(其中P2和P3經H置換),利用結晶來純化相應式2環戊酮同時去除式2的雜質或異構體,並且再次對羥基進行保護以獲得高純度的具有相同或不同的羥基保護基的式2環戊酮,來純化式2化合物。
如流程3的步驟(b)中所示,式2化合物進一步轉化為式3的醇化合物。根據本發明,式2化合物與硼試劑(例如9-硼雙環[3,3,1]壬烷(9-BBN))反應,然後用鹼性過氧化氫進行氧化,得到式3的醇化合物。
如流程3的步驟(c)中所示,式3的醇化合物進一步經受磺醯化反應以獲得式4化合物,其中X1為烷基磺醯基、芳基磺醯基或芳烷基磺醯基,例如甲烷磺醯基或對甲苯磺醯基。磺醯化反應是在鹼(諸如胺,例如三乙胺)存在下,通過使用適當磺醯基供體(例如甲烷磺醯氯或對甲苯磺醯氯)來實現。
如流程3的步驟(d)中所示,式4化合物經受脫保護反應以使得P1經H置換,或經受脫保護反應連同對ω側鏈的雙鍵進行氫化。適於脫保護的條件取決於變數P1。當P1為三烷基矽烷基時,使用氟離子(例如四丁基氟化銨)實現脫保護反應。當P1為未經取代或經取代的苄基時,使用氫化催化劑和適合的鹼/親電子試劑在適合溶劑中以及在氫存在下實現脫保護反應。適合的氫化催化劑含有選自由鈀、鉑、銠和鎳以及其混合物組成的群組的金屬。催化劑的實例包括Pd-C、Pt-C和Ni。適合的溶劑可選自四氫呋喃、乙酸乙酯、甲醇、乙醇、或甲苯、
或其混合物。對於其中P1為未經取代或經取代的苄基並且為雙鍵的式4化合物,氫化可以獲得其中為雙鍵的式5化合物而結束,或可連續進行以獲得其中為單鍵的式5化合物,如由HPLC或TLC所監測。
如流程3的步驟(e)中所示,式5化合物進一步經受分子內烷基化作用。分子內烷基化是使用適合的鹼在適合的溶劑中實現。適合的鹼可選自氫化鈉、氫化鉀、氫化鋰、第三丁氧化鉀或丁基鋰、或其混合物。適合的溶劑可選自四氫呋喃、2-甲基四氫呋喃、甘醇二甲醚、或甲苯、或其混合物。分子內烷基化將產生少量式IV的對位環化異構體。
對位環化異構體可通過柱色譜法去除,或在用於獲得苯并茚前列腺素的結晶中間體的後續結晶步驟中去除。
根據本發明的一個實施例,本發明提供一種製備式6c化合物的方法,
其中P2、P3、R2和R3如上文所定義;所述方法包含以下步驟:(1)使式III化合物
其中P1和P2如上文所定義;與衍生自式II-1a、式II-2或式II-3的化合物的銅酸鹽反應,
其中X、R2、R3、R4和P3如上文所定義;形成式1c化合物
(2)使式1c化合物的酮基進行亞甲基化,形成式2c亞甲基化合物
(3)使式2c化合物經硼試劑(例如9-硼雙環[3,3,1]壬烷)進行硼氫化,然後用鹼性過氧化氫進行氧化,得到式3c的醇化合物
(4)用磺醯基供體(例如甲烷磺醯氯或對甲苯磺醯氯)在鹼存在下使式3c化合物進行磺醯化,形成式4c化合物
其中X1為磺醯基;(5)去除P1基團並且使ω側鏈中的雙鍵進行氫化,形成式5c化合物;和(6)使式5c化合物進行分子內烷基化,形成式6c化合物。
步驟(2)的亞甲基化可在由二溴甲烷、鋅和氯化鈦(IV)製備的野琦-隆巴多試劑存在下進行,或通過使式1c化合物與甲基苯基-N-甲基-磺基肟的陰離子在適合溶劑中反應且然後在水-乙酸-四氫呋喃的溶劑混合物中用鋁汞齊處理所得粗製加合物來進行。
根據本發明的一個較佳具體實施例,在式6c中,R2為單鍵並且R3為戊基,P1為未經取代或經取代的苄基,P2和P3獨立地為羥基的保護
基,其較佳地選自甲氧基甲基、甲氧基硫甲基、2-甲氧基乙氧基甲基、雙(2-氯乙氧基)甲基、四氫吡喃基、四氫硫代吡喃基、4-甲氧基四氫吡喃基、4-甲氧基四氫硫代吡喃基、四氫呋喃基、四氫硫代呋喃基、1-乙氧基乙基、1-甲基-1-甲氧基乙基、三苯基甲基和SiRaRbRc,其中Ra、Rb和Rc各自獨立地為C1-8烷基。
如流程4中所示,UT-15可容易地由式6b化合物製備,式6b化合物對應於其中為單鍵;R2為單鍵;R3為戊基;P2和P3為羥基的保護基的式6化合物。
流程4中所示的方法包含:(a)用烷基化劑XCH2CN或XCH2COOR5(其中X為鹵素,例如Cl、Br或I;R5為烷基)使式6b化合物的酚基進行烷基化;(b)用鹼使-CN或-COOR5基團水解,形成-COOH基團;和(c)去除保護基P2和P3。
上述製備UT-15的步驟可以任何次序進行,例如以(a)(b)(c)、(a)(c)(b)或(c)(a)(b)次序。較佳地,以(c)(a)(b)次序進行所述方法。
如流程5中所示,UT-15還可自式6d化合物來製備,式6d化合物對應於其中為雙鍵;R2為單鍵;R3為戊基;P2和P3為羥基的保護
基的式6化合物。
除上述步驟(a)、(b)和(c)之外,所述方法包含(d)在氫化催化劑和適合的鹼/親電子試劑存在下,在適合的溶劑中,用氫氣來氫化式6d化合物的雙鍵;或其中B、P2'和P3'為H的式9化合物的雙鍵;或其中B為-CH2COOR5並且P2'和P3'為H或保護基的式9化合物的雙鍵;或其中B為-CH2COOH並且P2'和P3'為H或保護基的式9化合物的雙鍵。
這些步驟可以任何次序進行,例如以(a)(b)(c)(d)、(a)(b)(d)(c)、(d)(a)(b)(c)、(a)(c)(b)(d)、(a)(c)(d)(b)、(a)(d)(c)(b)、(d)(a)(c)(b)、(c)(a)(b)(d)、(c)(a)(d)(b)或(c)(d)(a)(b)次序。舉例來說,式6d化合物可首先氫化成式6b化合物(即進行步驟(d)),隨後以任何次序進行步驟(a)、(b)和(c)。步驟較佳以(c)(d)(a)(b)、(a)(c)(b)(d)或(a)(b)(c)(d)的次序進行。
根據一個具體實施例,本發明提供一種製備曲前列尼爾(UT-15)的方法,所述方法包含以下步驟:(1)使式IIIa化合物
其中P1為烯丙基、未經取代或經取代的苄基、乙醯基、烷基羰基和SiRaRbRc,其中Ra、Rb和Rc各自獨立地為C1-8烷基、苯基、苄基、經取代的苯基或經取代的苄基;並且P2如上文所定義;與衍生自式II-1a、式II-2或式II-3的化合物的銅酸鹽反應:
其中X、R2、R3、R4和P3如上文所定義;形成式1d化合物
(2)使式1d化合物的酮基進行亞甲基化,形成式2d亞甲基化合物
(3)用硼試劑(例如9-硼雙環[3,3,1]壬烷)使式2d化合物進行硼氫化,然後用鹼性過氧化氫進行氧化,得到式3d的醇化合物
(4)用磺醯基供體(例如甲烷磺醯氯或對甲苯磺醯氯)在鹼存在下
使式3d化合物進行磺醯化,形成式4d化合物
其中X1為磺醯基;(5)去除P1基團,形成式5d化合物,
(6)使式5d化合物進行分子內烷基化,形成式6d化合物
(7)去除P2和P3基團,形成式7d化合物
(8)使式7d化合物的ω側鏈中的雙鍵進行氫化,形成式8d化合物
(9)用烷基化劑XCH2CN或XCH2COOR5(其中X為鹵素,例如Cl、Br或I;R5為烷基)使酚基進行烷基化,形成式9d化合物
其中Z為-CN或-COOR5;和(10)用鹼水解式9d化合物的-CN或-COOR5基團,形成曲前列尼爾。
根據一個具體實施例,本發明提供一種製備曲前列尼爾(UT-15)的方法,所述方法包含上述(1)~(6)的步驟,形成式6d化合物,隨後
(7)用烷基化劑XCH2CN或XCH2COOR5(其中X為鹵素,例如Cl、Br或I;R5為烷基)使酚基進行烷基化,形成式7D化合物
其中Z為-CN或-COOR5;以及(8)去除P2和P3基團,形成式8D化合物
(9)用鹼水解式8D化合物的-CN或-COOR5基團,形成式9D
(10)使式9D化合物的ω側鏈中的雙鍵進行氫化,形成曲前列尼爾。
根據另一個具體實施例,本發明提供一種製備曲前列尼爾(UT-15)的替代方法,所述方法包含以下步驟:(1)使式IIIa化合物
其中P1為烯丙基、未經取代或經取代的苄基、乙醯基、烷基羰基和SiRaRbRc,其中Ra、Rb和Rc各自獨立地為C1-8烷基、苯基、苄基、經取代的苯基或經取代的苄基;並且P2如上文所定義;與衍生自式II-1b化合物的銅酸鹽反應
其中X、R2、R3和P3如上文所定義;形成式1b化合物
(2)使式1b化合物的酮基進行亞甲基化,形成式2b的亞甲基化合物
(3)用硼試劑(例如9-硼雙環[3,3,1]壬烷)使式2b化合物進行硼氫化,然後用鹼性過氧化氫進行氧化,得到式3b的醇化合物
(4)用磺醯基供體(例如甲烷磺醯氯或對甲苯磺醯氯)在鹼存在下
使式3b化合物進行磺醯化,形成式4b化合物
其中X1為磺醯基;(5)去除P1基團,形成式5b化合物;
(6)使式5b化合物進行分子內烷基化,形成式6b化合物
(7)去除P2和P3基團,形成式8d化合物
(8)用烷基化劑XCH2CN或XCH2COOR5(其中X為鹵素,例如Cl、Br或I;R5為烷基)使酚基進行烷基化,形成式9d化合物
其中Z為-CN或-COOR 5 ;和(9)用鹼水解式9d化合物的-CN或-COOR5基團,形成曲前列尼爾。
根據另一個具體實施例,本發明提供另一種製備高純度式8d化合物的替代方法,
所述方法包含以下步驟:(1)在例如吡啶、三乙胺、氫化鈉或氫化鉀的鹼存在下,用醯基供體(例如乙酸酐、乙醯氯、苯甲酸酐、苯甲醯氯或4-聯苯甲醯氯)酯化式6d化合物,形成式10d的酯化合物
其中M為低級烷基或未經取代或經取代的苯基;M較佳為甲基、苯基或4-苯基苯基;(2)去除P2和P3基團,形成式11d的結晶化合物
;和
(3)使式11d化合物的ω側鏈中的雙鍵進行氫化並且使已氫化的化合物進行脫醯化;或首先使式11d化合物進行脫醯化並且隨後使已脫醯化的化合物的ω側鏈中的雙鍵進行氫化,形成式8d化合物。
本發明還係關一種新穎的式1d化合物
其中為單鍵或雙鍵;R2為單鍵或C1-4伸烷基或式-CH2O-的基團;R3為C1-7烷基或芳基或芳烷基,其各自未經取代或經C1-4烷基、鹵素或三鹵甲基取代;P1為未經取代或經取代的苄基;P2'和P3'分別為如上文定義為羥基的保護基的P2和P3或彼此獨立地為H。當P2'和P3'分別為P2和P3時,其具鹼穩定性,並且可獨立地選自甲氧基甲基、甲氧基硫甲基、2-甲氧基乙氧基甲基、雙(2-氯乙氧基)甲基、四氫吡喃基、四氫硫代吡喃基、4-甲氧基四氫吡喃基、4-甲氧基四氫硫代吡喃基、四氫呋喃基、四氫硫代呋喃基、1-乙氧基乙基、1-甲基-1-甲氧基乙基、三苯基甲基和SiRaRbRc,其中Ra、Rb和Rc各自獨立地為C1-8烷基、苯基、苄基、經取代的苯基或經取代的苄基。
本發明還係關一種新穎的式8D-1結晶化合物
其中Z為-CN。
本發明還係關一種新穎的式11-1化合物
其中M為甲基、苯基或4-苯基苯基;並且為單鍵或雙鍵。
使用以下實例來進一步說明本發明,但不意欲限制本發明的範圍。所屬領域的技術人員可容易地實現的任何修改或改變均在本說明書之揭露內容和隨附申請專利範圍的範圍內。
(2R,3R,4R)-2-(3-(苄氧基)苄基)-4-第三丁基二甲基矽烷氧基-3-((S,E)-3-第三丁基二甲基矽烷氧基辛-1-烯基)環戊酮
將12升三頸燒瓶火焰乾燥並且使其冷卻。將(1E)-三丁基-錫烷基-(3S)-第三丁基二甲基矽烷氧基辛烯(520g,0.98mol)和4升四氫呋喃(THF)加入反應燒瓶中,然後在-70℃下逐滴加入正丁基鋰(612ml,1.6M於己烷中)。將氰化銅(87.7g,0.98mol)和甲基鋰(490ml,2M
於乙醚中)於1升THF中的均質溶液從-10℃冷卻到-70℃並且在攪拌的同時加入反應燒瓶中持續30分鐘。隨後,在-70℃下將(R)-1-(3-苄氧基)苄基-5-氧代-3-第三丁基二甲基矽烷氧基環戊烯(200g,0.49mol)於1升THF中的溶液加入反應混合物中持續30分鐘。用含有500ml氫氧化銨的5升飽和氯化銨(水溶液)淬滅反應。使反應混合物相分離並且用乙酸乙酯萃取水層。結合有機層並且經無水硫酸鎂乾燥。濾出固體。在真空下蒸發出溶劑。通過使用己烷與乙酸乙酯的混合物作為梯度洗提劑的矽膠色譜法純化粗產物。標題化合物的產量為280g(88%)。
1H-NMR(CDCl3):δ 7.43(d,2H),7.39(t,2H),7.32(t,1H),7.16(t,1H),6.81(d,1H),6.78(s,1H),6.73(d,1H),5.55(dd,1H),5.48(dd,1H),5.02(s,2H),4.10~4.02(m,2H),3.05(d,1H),2.80(d,1H),2.60(d,1H),2.42(dt,1H),2.30~2.25(m,1H),2.04(dd,1H),1.47~1.25(m,8H),0.92~0.77(m,21H),0.12~0.01(m,12H)。
13C-NMR(CDCl3):δ 215.40,158.77,140.51,137.08,136.61,129.27,128.52,128.42,127.85,127.44,122.31,115.97,112.84,73.33,72.69,69.78,55.14,51.64,47.68.,38.49,33.28,31.85,25.89,25.09,22.62,18.22,18.04,14.05,-4.66,-4.67,-4.71。
(2R,3R,4R)-2-(3-(苄氧基)苄基)-4--三乙基矽烷氧基-3-((S,E)-3-三乙基矽烷氧基辛-1-烯基)環戊酮
將2升三頸燒瓶火焰乾燥並且使其冷卻。將(1E)-三丁基-錫烷基-(3S)-三乙基矽烷氧基辛烯(127g,0.24mol)和1升THF加入反應燒瓶中,然後在-70℃下逐滴加入正丁基鋰(150ml,1.6M於己烷中)。將氰化銅(21.5g,0.24mol)和甲基鋰(120ml,2M於乙醚中)於50ml THF中的均質溶液從-10℃冷卻到-70℃並且在攪拌的同時加入反應燒瓶中持續30分鐘。隨後,在-70℃下將(R)-1-(3-苄氧基)苄基-5-氧代-3-三乙基矽烷氧基-環戊烯(50g,0.12mol)於500ml THF中的溶液加入反應混合物中持續30分鐘。用含有125ml氫氧化銨的1.25升飽和氯化銨(水溶液)淬滅反應。使反應混合物進行相分離並且用乙酸乙酯萃取水層。結合有機層並且經無水硫酸鎂乾燥。濾出固體。在真空下蒸發出溶劑。通過使用己烷與乙酸乙酯的混合物作為梯度洗提劑的矽膠色譜法純化粗產物。標題化合物的產量為75g(94%)。
1H-NMR(CDCl3):δ 7.42(d,2H),7.37(t,2H),7.31(t,1H),7.15(d,1H),6.80(d,1H),6.77(s,1H),6.73(d,1H),5.57~5.48(m,2H),5.04(s,2H),4.10~4.02(m,2H),3.06(dd,1H),2.80(dd,1H),2.59(dd,1H),2.45(dt,1H),2.31~2.27(m,1H),2.05(dd,1H),1.49~1.27(m,8H),0.97~0.86(m,21H),0.64~0.55(m,12H)。
13C-NMR(CDCl3):δ 215.50,158.77,140.47,137.07,136.40,129.26,128.51,128.49,127.82,127.42,122.28,115.95,112.81,73.10,72.84,69.76,55.02,51.34,47.79.,38.54,33.37,31.86,25.09,22.62,14.04,6.91,6.75,4.99,4.73。
(2R,3R,4R)-2-(3-(苄氧基)苄基)-4-第三丁基二甲基矽烷氧基-3-((S)-3-第三丁基二甲基矽烷氧基辛基)環戊酮
將25ml雙頸燒瓶火焰乾燥並且使其冷卻。將(S)-第三丁基(1-碘辛-3-基氧基)二甲基矽烷(1.18g,3.2mmol)和11.8L乙醚加入反應燒瓶中,然後在-70℃下逐滴加入第三丁基鋰(3.75ml,1.7M於戊烷中)。將氰化銅(0.29g,3.2mmol)和甲基鋰(1.6ml,2M於乙醚中)於5.8ml乙醚中的均質溶液從室溫冷卻到-70℃並且在攪拌的同時加入反應燒瓶中持續30分鐘。隨後,在-70℃下將(R)-2-(3-(苄氧基)苄基)-4-(第三丁基二甲基矽烷基氧基)環戊-2-烯酮(0.65g,1.6mmol)於6.5ml乙醚中的溶液加入反應混合物中持續30分鐘。用含有0.4ml氫氧化銨的40ml飽和氯化銨(水溶液)淬滅反應。使反應混合物進行相分離並且用乙酸乙酯萃取水層。結合有機層並且經無水硫酸鎂乾燥。濾出固體。在真空下蒸發出溶劑。通過使用己烷與乙酸乙酯的混合物作為梯度洗提劑的矽膠色譜法純化粗產物。標題化合物的產量為1.1g(85%)。
1H NMR(500MHz,CDCl3)δ 0.00~0.10(12H,m),0.88~0.91(21H,m),1.19~1.49(12H,m),1.91(1H,m),1.49~2.17(2H,m),2.58(1H,dd,J=6,17.5Hz),2.86(1H,ab),3.02(1H,ab),3.50(1H,m),4.09(1H,q,J=5.5Hz),5.04(2H,s),6.77-6.84(3H,m),7.19(1H,t,J=7.5Hz),7.33(1H,m),7.39(2H,m),7.44(2H,m)。
13C NMR(125MHz,CDCl3)δ -4.8,-4.5,-4.43,-4.41,14.0,17.9,18.0,22.6,24.8,25.8,25.9,27.9,32.0,33.9,35.9,37.1,47.5,48.7,54.8,69.8,72.3,73.4,112.7,115.7,121.9,127.4,127.8,128.5,129.4,137.0,141.3,158.8,217.6。
(2R,3R,4R)-2-(3-(第三丁基二甲基矽烷氧基)苄基)-4-(四氫-2H-吡喃-2-基氧基)-3-((S,E)-3-(四氫-2H-吡喃-2-基氧基)辛-1-烯基)環戊酮
將2升三頸燒瓶火焰乾燥並且使其冷卻。將(1E)-碘-(3S)-(四氫-2H-吡喃-2-基氧基)-1-辛烯(5.84g,17mmol)和50ml乙醚加入反應燒瓶中,然後在-70℃下逐滴加入正丁基鋰(12ml,1.6M於己烷中)。加入先前製備的2.35g戊炔基-銅與5.87g三(二甲基胺基)膦於30ml乙醚中的溶液。混合物在此溫度下再保持30分鐘,並且在-70℃下將(R)-1-(3-(第三丁基二甲基矽烷氧基)苄基)-5-氧代-3-(四氫-2H-吡喃-2-基氧基)-環戊烯(5.66g,15mmol)於500ml THF中的溶液加入反應混合物中持續30分鐘。用含有10ml氫氧化銨的100ml飽和氯化銨(水溶液)淬滅反應。使反應混合物進行相分離並且用乙酸乙酯萃取水層。結合有機層並且經無水硫酸鎂乾燥。濾出固體。在真空下蒸發出溶劑。通過使用己烷與乙酸乙酯的混合物作為梯度洗提劑的矽膠色譜法純化粗產物。標題化合物的產量為6.65g(75%)。
((S,E)-1-((1R,2R,5R)-2-(3-(苄氧基)苄基)-3-亞甲基-5-(第三丁基二
甲基矽烷氧基)環戊基)辛-1-烯-3-基氧基)(第三丁基)二甲基矽烷
將Zn-CH2Br2-TiCl4(500ml,0.6M於THF中)和100ml二氯甲烷(CH2Cl2)的亞甲基化溶液加入冰水浴中的5升三頸燒瓶中。向經攪拌混合物中加入含(2R,3R,4R)-2-(3-(苄氧基)苄基)-4-第三丁基二甲基矽烷氧基-3-((S,E)-3-第三丁基二甲基矽烷氧基辛-1-烯基)環戊酮(200g,0.307mol)的1升CH2Cl2。10分鐘後,去除冷卻浴並且在室溫(25℃)下攪拌混合物1.5小時。隨後,用1升乙酸乙酯和500ml飽和碳酸氫鈉水溶液稀釋混合物。使反應混合物進行相分離並且用乙酸乙酯萃取水層。結合有機層並且經無水硫酸鎂乾燥。濾出固體。在真空下蒸發出溶劑。通過使用己烷與乙酸乙酯的混合物作為梯度洗提劑的矽膠色譜法純化粗產物。標題化合物的產量為179.4g(90%)。
1H-NMR(CDCl3):δ 7.44(d,2H),7.39(t,2H),7.33(t,1H),7.17(t,1H),6.84(s,1H),6.80(d,2H),5.48~5.39(m,2H),5.04(s,2H),4.88(s,1H),4.66(s,1H),4.04(q,1H),3.87(q,1H),2.95(dd,1H),2.68(dd,1H),2.60(dd,1H),2.51~2.47(m,1H),2.31~2.21(m,2H),1.32~1.26(m,8H),0.91~0.86(m,21H),0.05~0.01(m,12H)。
13C-NMR(CDCl3):δ 158.64,150.94,142.36,137.18,135.20,130.20,128.98,128.51,127.83,127.43,122.22,116.04,112.11,107.01,72.95,69.82,55.70,48.03.,42.73,39.20,38.57,31.85,25.92,25.89,25.14,22.83,18.23,18.11,14.06,-4.17,-4.56,-4.74。
((S)-1-((1R,2R,5R)-2-(3-(苄氧基)苄基)-3-亞甲基-5-(第三丁基二甲基矽烷氧基)環戊基)辛-3-基氧基)(第三丁基)二甲基矽烷
將Zn-CH2Br2-TiCl4(6ml,0.6M於THF中)和3.3ml二氯甲烷(CH2Cl2)的亞甲基化溶液加入冰水浴中的25ml雙頸燒瓶中。向經攪拌混合物中加入含(2R,3R,4R)-2-(3-(苄氧基)苄基)-4-(第三丁基二甲基矽烷基氧基)-3-((S)-3-(第三丁基二甲基矽烷基氧基)辛基)環戊酮(1.1g,1.68mmol)的10ml CH2Cl2。10分鐘後,去除冷卻浴並且在室溫(25℃)下攪拌混合物1.5小時。直到反應完成才用20ml EtOAc稀釋混合物並且過濾以去除沉澱物。用EtOAc萃取濾液,經MgSO4乾燥並且蒸發。通過使用己烷-EtOAc作為洗提劑的矽膠柱色譜法純化所得殘餘物,得到標題化合物:0.85g(產率:78%)。
1H NMR(500MHz,CDCl3)δ 0.00~0.12(12H,m),0.90~0.94(21H,m),1.26~1.46(12H,m),1.68(1H,m),2.32~2.40(2H,m),2.58(1H,dd,J=6,15.5Hz),2.79~2.91(2H,m),3.53(1H,m),3.85(1H,q,J=5.5Hz),4.68(1H,s),4.90(1H,s),5.07(2H,s),6.82-6.88(3H,m),7.21(1H,t,J=7.5Hz),7.35(1H,m),7.41(2H,t,J=7Hz),7.47(2H,m)。
13C NMR(125MHz,CDCl3)δ -4.7,-4.41,-4.38,14.1,18.0,18.2,22.7,25.0,25.5,25.9,28.6,32.1,34.6,37.1,41.9,42.6,49.1,52.3,69.8,72.3,72.6,107.5,112.1,116.0,122.1,127.4,127.8,128.5,129.0,137.2,142.8,152.4,158.7。
(1R,2R,3R)-3-(3-(苄氧基)苄基)-2-((S,E)-3-羥基辛-1-烯基)-4-亞甲基環-戊醇
將Zn-CH2Br2-TiCl4(80ml,0.6M於THF中)和10ml二氯甲烷(CH2Cl2)的溶液加入冰水浴中的500ml三頸燒瓶中。向經攪拌混合物中加入含(1R,2R,3R)-1-(3-苄氧基)苄基-5-氧代-3-三乙基矽烷氧基-2-[(3S)-三乙基矽烷氧基-1-辛烯基]-環戊烷(20g,30.7mmol)的100mlCH2Cl2。10分鐘後,去除冷卻浴並且在室溫(25℃)下攪拌混合物1.5小時。隨後,用150ml乙酸乙酯和50ml飽和碳酸氫鈉水溶液稀釋混合物。使反應混合物進行相分離並且用乙酸乙酯萃取水層。合併有機層並且經無水硫酸鎂乾燥。濾出固體。在真空下蒸發出溶劑。將殘餘物進一步溶解於100ml丙酮和20ml水中,然後加入0.5g對甲苯磺酸單水合物。反應溶液在室溫下攪拌1小時並且進一步經受真空蒸發直到形成兩個分離的層。將1.5L乙酸乙酯加入反應物中並且使反應物進行相分離。有機層以飽和碳酸氫鈉溶液和鹽水洗滌,經無水硫酸鎂乾燥,並且蒸發到乾燥。通過使用己烷與乙酸乙酯的混合物作為梯度洗提劑的矽膠色譜法純化粗產物。標題化合物的產量為12.83g,含有痕量的15-差向異構體。通過從乙醚/己烷中結晶來去除15-差向異構體。獲得呈結晶形式的9.7g標題化合物(白色到灰白色粉末)。熔點:58℃。
1H-NMR(CDCl3):δ 7.43(d,2H),7.38(t,2H),7.32(t,1H),7.15(t,1H),6.81~6.76(m,3H),5.45~5.29(m,2H),5.03(s,2H),4.95(s,1H),
4.81(s,1H),3.92(q,1H),3.80(q,1H),2.85~2.69(m 3H),2.55~2.52(m,1H),2.30~2.24(m,1H),2.10(q,1H),1.45~1.25(m,8H),0.87(t,3H)。
13C-NMR(CDCl3):δ 158.68,149.97,141.77,137.08,135.83,132.14,129.02,128.55,127.90,127.45,122.24,116.22,112.19,107.76,75.33,72.73,69.86,56.67,48.11.,41.09,39.13,37.14,31.73,25.16,22.59,14.03。
((S,E)-1-((1R,2R,5R)-2-(3-(苄氧基)苄基)-3-亞甲基-5-(第三丁基二甲基矽烷氧基)環戊基)辛-1-烯-3-基氧基)(第三丁基)二甲基矽烷
將(1R,2R,3R)-3-(3-(苄氧基)苄基)-2-((S,E)-3-羥基辛-1-烯基)-4-亞甲基環戊醇(12.7g,64mmol)溶解於300ml乙酸乙酯中,加入咪唑(22g,320mmol),並且攪拌直到反應系統變成均質。將第三丁基二甲基矽烷基氯化物(24g,160mmol)加入反應混合物中。使經攪拌的反應混合物達到室溫並且攪拌整夜。隨後,反應混合物以300ml飽和碳酸氫鈉水溶液洗滌兩次,進一步用鹽水洗滌,經無水硫酸鎂乾燥,過濾,並且濃縮,獲得粗產物。通過使用己烷與乙酸乙酯的混合物作為梯度洗提劑的矽膠色譜法純化粗產物。產率:80%。
1H-NMR(CDCl3):δ 7.44(d,2H),7.39(t,2H),7.33(t,1H),7.17(t,1H),6.84(s,1H),6.80(d,2H),5.48~5.39(m,2H),5.04(s,2H),4.88(s,1H),4.66(s,1H),4.04(q,1H),3.87(q,1H),2.95(dd,1H),2.68(dd,
1H),2.60(dd,1H),2.51~2.47(m,1H),2.31~2.21(m,2H),1.32~1.26(m,8H),0.91~0.86(m,21H),0.05~0.01(m,12H)。
13C-NMR(CDCl3):δ 158.64,150.94,142.36,137.18,135.20,130.20,128.98,128.51,127.83,127.43,122.22,116.04,112.11,107.01,72.95,69.82,55.70,48.03.,42.73,39.20,38.57,31.85,25.92,25.89,25.14,22.83,18.23,18.11,14.06,-4.17,-4.56,-4.74。
((1S,2S,3R,4R)-2-(3-(苄氧基)苄基)-4-(第三丁基二甲基矽烷氧基)-3-((S,E)-3-(第三丁基二甲基矽烷氧基)辛-1-烯基)環戊基)甲醇
將經脫氣的(1R,2R,3R)-1-(3-苄氧基)苄基-3-第三丁基-二-甲基矽烷氧基-2-[(3S)-第三丁基二甲基矽烷氧基-1-辛烯基]-5-亞甲基-環戊烷(160g,0.246mol)於1.6升無水THF中的溶液在氮氣下冷卻到0℃,經5分鐘逐滴加入9-硼雙環[3,3,1]壬烷(1280ml,0.5M於THF中)。將無色溶液在0℃下攪拌整夜並且依次用30%過氧化氫(640ml)和3N氫氧化鉀(640ml)處理。所得懸浮液在0℃下再攪拌30分鐘,並且在升溫到室溫的同時攪拌75分鐘。將反應混合物轉移到分液漏斗中,用3升鹽水和1升乙酸乙酯稀釋。使反應混合物進行相分離並且用乙酸乙酯萃取水層。合併有機層並且經無水硫酸鎂乾燥。濾出固體。在真空下蒸發出溶劑。通過使用己烷與乙酸乙酯的混合物作為梯度洗提劑的矽膠色譜法純化粗產物。產率:97%。
1H-NMR(CDCl3):δ 7.45~7.29(m,5H),7.17(t,1H),6.83~6.77(m,
3H),5.50~5.35(m,2H),5.03(s,2H),4.13~4.02(m,2H),3.77(t,1H),3.61(d,1H),3.42(d,1H),2.80~2.75(m,1H),2.43~2.39(m,2H),2.05~1.86(m,4H),1.66~1.26(m,8H),0.90~0.84(m,21H),0.08~0.00(m,12H)。
13C-NMR(CDCl3):δ 158.74,143.51,137.07,135.03,131.13,129.22,128.52,127.86,127.43,121.30,115.22,111.86,79.11,73.05,69.80,63.62,58.59,49.44.,41.45,40.58,38.63,31.83,25.91,25.76,25.12,22.64,18.29,17.87,14.66,-4.22,-4.45,-4.83。
((1S,2S,3R,4R)-2-(3-(苄氧基)苄基)-4-(第三丁基二甲基矽烷氧基)-3-((S)-3-(第三丁基二甲基矽烷氧基)辛基)環戊基)甲醇
將經脫氣的((1R,2R,3R)-3-(3-(苄氧基)苄基)-2-((S)-3-(第三丁基二甲基矽烷基氧基)辛基)-4-亞甲基環戊基氧基)(第三丁基)二甲基矽烷(0.75g,1.15mmol)於8ml無水THF中的溶液在氮氣下冷卻到0℃,並且將9-硼雙環[3,3,1]壬烷(6.9ml,0.5M於THF中)逐滴加入混合物中。無色溶液在0℃下攪拌整夜並且依次用30%過氧化氫(3ml)和3N氫氧化鉀(3ml)處理。所得懸浮液在室溫下攪拌1小時。用EtOAc萃取混合物,並且有機層以20ml鹽水洗滌,經MgSO4乾燥並且蒸發。通過使用己烷-EtOAc作為洗提劑的矽膠柱色譜法純化所得殘餘物,得到標題化合物:0.6g(產率78%)。
1H NMR(500MHz,CDCl3)δ 0.02~0.12(12H,m),0.90~0.92(21H,
m),1.22~1.43(9H,m),1.55~1.57(2H,m),1.72~1.74(2H,m),1.92~2.07(4H,m),2.80~2.94(2H,m),3.50~3.57(2H,m),3.63(1H,dd,J=3,11Hz),3.76(1H,br)3.96(1H,d,J=6.5Hz),5.05(2H,s),6.81(1H,dd,J=2,8Hz),6.87(2H,m),7.19(1H,t,J=8Hz),7.33(1H,m),7.39(2H,t,J=7.5Hz),7.44(2H,m)。
13C NMR(125MHz,CDCl3)δ -4.7,-4.5,-4.43,-4.41,14.0,17.8,18.1,22.6,24.8,25.7,25.9,29.9,32.0,35.2,35.9,37.1,40.2,42.5,48.5,54.9,63.7,69.8,72.5,79.2,111.9,115.3,121.4,127.4,127.8,128.5,129.2,137.1,143.7,158.8。
甲烷磺酸((1S,2S,3R,4R)-2-(3-(苄氧基)苄基)-4-(第三丁基二甲基矽烷氧基)-3-((S,E)-3-(第三丁基二甲基矽烷氧基)辛-1-烯基)環戊基)甲酯
在氮氣下將((1S,2S,3R,4R)-2-(3-(苄氧基)苄基)-4-(第三丁基二甲基矽烷氧基)-3-((S,E)-3-(第三丁基二甲基矽烷氧基)辛-1-烯基)環戊基)甲醇(50g,0.075mol)於無水CH2Cl2(500ml)中的溶液冷卻到0℃並且依次用三乙胺(31.3ml,0.225mol)和甲烷磺醯氯(11.6ml,0.15mol)處理。將混合物倒入飽和碳酸氫鈉水溶液中並且攪拌30分鐘。使反應混合物進行相分離並且用500ml乙酸乙酯萃取水層。合併有機層並且經無水硫酸鎂乾燥。濾出固體。在真空下蒸發出溶劑。通過使用己烷與乙酸乙酯的混合物作為梯度洗提劑的矽膠色譜法純化粗產物。產
率:81%。
1H-NMR(CDCl3):δ 7.45~7.29(m,5H),7.19(t,1H),6.82~6.78(m,3H),5.48~5.33(m,2H),5.05(s,2H),4.38(dd,1H),4.28~4.22(m,1H),4.05~3.96(m,2H),2.89(s,3H),2.80(dd,1H),2.52(dd,1H),2.29~2.20(m,2H),2.11~2.02(m,1H),1.68~1.59(m,2H),1.44~1.24(m.,8H),0.89~0.67(m,21H),0.07~0.00(m,12H)。
4-甲基苯磺酸((1S,2S,3R,4R)-2-(3-(苄氧基)苄基)-4-(第三丁基二甲基矽烷氧基)-3-((S,E)-3-(第三丁基二甲基矽烷氧基)辛-1-烯基)環戊基)甲酯
在氮氣下將((1S,2S,3R,4R)-2-(3-(苄氧基)苄基)-4-(第三丁基二甲基矽烷氧基)-3-((S,E)-3-(第三丁基二甲基矽烷氧基)辛-1-烯基)環戊基)甲醇(15g,0.023mol)於無水CH2Cl2(500ml)中的溶液冷卻到0℃並且依次用三乙胺(9.6ml,0.068mol)和對甲苯磺醯氯(8.77g,0.046mol)處理。將混合物倒入飽和碳酸氫鈉水溶液中並且攪拌30分鐘。使反應混合物進行相分離並且用500ml乙酸乙酯萃取水層。合併有機層並且經無水硫酸鎂乾燥。濾出固體。在真空下蒸發出溶劑。通過使用己烷與乙酸乙酯的混合物作為梯度洗提劑的矽膠色譜法純化粗產物。產率:85%。
1H-NMR(CDCl3):δ 7.72(d,2H),7.46~7.29(m,8H),7.13(t,1H),6.80~6.64(m,3H),5.57~5.32(m,2H),5.04(s,2H),4.15~3.88(m,4H),
2.67(dd,1H),2.41(m,4H),2.17~1.94(m,4H),1.49~1.28(m,8H),0.92~0.82(m,21H),0.04~0.00(m,12H)。
13C-NMR(CDCl3):δ 158.86,144.53,142.20,137.10,135.60,133.05,130.20,129.78,128.53,127.88,127.86,127.48,121.19,115.06,112.23,78.00,72.87,69.83,56.22,46.62.,38.56,38.00,37.85,34.50,31.81,25.88,25.83,25.62,25.06,22.61,21.59,18.22,17.93,14.03,-4.23,-4.61,-4.77。
4-甲基苯磺酸((1S,2S,3R,4R)-2-(3-(苄氧基)苄基)-4-(第三丁基二甲基矽烷氧基)-3-((S)-3-(第三丁基二甲基矽烷氧基)辛基)環戊基)甲酯
在氮氣下將((1S,2S,3R,4R)-2-(3-(苄氧基)苄基)-4-(第三丁基二甲基矽烷基氧基)-3-((S)-3-(第三丁基二甲基矽烷基氧基)辛基)環戊基)甲醇(0.3g,0.45mmol)於無水CH2Cl2(3ml)中的溶液冷卻到0℃並且用三乙胺(0.12ml,0.9mmol)和痕量4-(二甲基胺基)吡啶(DMAP)處理,隨後加入對甲苯磺醯氯(0.13g,0.67mmol)並且在室溫下攪拌反應物。反應完成後,加入20ml飽和NaHCO3並且用CH2Cl2萃取,經MgSO4乾燥並且蒸發。通過使用己烷-EtOAc作為洗提劑的矽膠柱色譜法純化所得殘餘物,得到標題化合物(0.2g,產率54%)。
1H NMR(500MHz,CDCl3)δ -0.03~0.04(12H,m),0.85~0.90(21H,m),1.06~1.09(2H,m),1.17~1.30(8H,m),1.48(1H,m),1.55(1H,m),1.90~1.95(3H,m),2.28(1H,q,J=7Hz),2.41(3H,s),2.49~2.59(3H,
m),3.45(1H,m),3.82(1H,m),4.07~4.18(2H,m),5.04(2H,s),6.70(1H,d,J=7.5Hz),6.76(1H,s),6.79(1H,m),7.15(1H,t,J=8Hz),7.29~7.34(3H,m),7.39(2H,t,J=5.5Hz),7.45(2H,m),7.65(2H,d,J=8Hz)。
13C NMR(125MHz,CDCl3)δ -4.8,-4.45,-4.41,14.0,17.8,18.1,21.6,22.6,24.8,25.82,25.88,25.91,29.0,32.0,34.8,35.5,37.1,37.9,39.2,46.4,52.7,69.8,71.8,72.4,78.3112.2,115.4,121.6,127.4,127.9,128.51,128.54,129.2,129.8,133.0,137.1,142.4,144.6,158.8。
甲烷磺酸((1S,2S,3R,4R)-2-(3-羥基苄基)-4-(第三丁基二甲基矽烷氧基)-3-((S,E)-3-(第三丁基二甲基矽烷氧基)辛-1-烯基)環戊基)甲酯
將甲烷磺酸((1S,2S,3R,4R)-2-(3-(苄氧基)苄基)-4-(第三丁基二甲基矽烷氧基)-3-((S,E)-3-(第三丁基二甲基矽烷氧基)辛-1-烯基)環戊基)甲酯(45g,0.06mol)於無水甲醇(450ml)中的溶液在氫氣下依次用氫氧化鉀(9.72g,0.18mol)和5% Pd/C(13.5g,30重量%)處理2小時。隨後,用矽藻土墊過濾反應混合物。濃縮濾液,獲得粗產物(50g)。
1H-NMR(CDCl3):δ 7.11(t,1H),6.73(d,1H),6.68(s,1H),6.64(d,1H),5.45~5.34(m,2H),5.28(br s,1H),4.28~4.24(m,1H),4.10~4.02(m,2H),3.97~3.93(m,1H),2.71(dd,1H),2.53(dd,1H),2.26~2.22(m,2H),2.05~1.98(m,5H),1.61~1.57(m,1H),1.44~1.25(m,10H),0.92~0.85(m,21H),0.11~0.02(m,12H)。
4-甲基苯磺酸((1S,2S,3R,4R)-2-(3-羥基苄基)-4-(第三丁基二甲基矽烷氧基)-3-((S,E)-3-(第三丁基二甲基矽烷氧基)辛-1-烯基)環戊基)甲酯
將4-甲基苯磺酸((1S,2S,3R,4R)-2-(3-(苄氧基)苄基)-4-(第三丁基二甲基矽烷氧基)-3-((S,E)-3-(第三丁基二甲基矽烷氧基)辛-1-烯基)環戊基)甲酯(15.7g,0.019mol)於無水甲醇(150ml)中的溶液在氫氣下依次用氫氧化鉀(3.25g,0.057mol)和5% Pd/C(6.28g,40重量%)處理5小時。隨後,用矽藻土墊過濾反應混合物。在真空下蒸發出溶劑。通過使用己烷與乙酸乙酯的混合物作為梯度洗提劑的矽膠色譜法純化粗產物。產率:90%。
1H-NMR(CDCl3):δ 7.81(d,2H),7.35(d,2H),7.05(t,1H),6.69(d,1H),6.66(d,1H),6.06(s,1H),5.79~5.68(m,2H),4.19~4.16(m,1H),4.01~3.95(m,2H),3.34(t,1H),2.77(dd,1H),2.64(t,1H),2.45~2.39(m,4H),2.18~2.13(m,1H),2.08~2.00(m,2H),1.78~1.73(m,1H),1.68~1.16(m,1H),1.41~1.21(m,8H),0.91~0.81(m,21H),0.10~-0.01(m,12H)。
4-甲基苯磺酸((1S,2S,3R,4R)-2-(3-羥基苄基)-4-(第三丁基二甲基矽烷氧基)-3-((S)-3-(第三丁基二甲基矽烷氧基)辛基)環戊基)甲酯
實例16:將4-甲基苯磺酸((1S,2S,3R,4R)-2-(3-(苄氧基)苄基)-4-(第三丁基二甲基矽烷氧基)-3-((S,E)-3-(第三丁基二甲基矽烷氧基)辛-1-烯基)環戊基)甲酯(15.7g,0.019mol)于無水甲醇(150ml)中的溶液在氫氣下在室溫下依次用氫氧化鉀(3.25g,0.057mol)和5% Pd/C(6.28g,40重量%)處理6小時並且在50℃下處理24小時。隨後,用矽藻土墊過濾反應混合物。在真空下蒸發出溶劑。通過使用己烷與乙酸乙酯的混合物作為梯度洗提劑的矽膠色譜法純化粗產物。產量:72%。
實例17:將4-甲基苯磺酸((1S,2S,3R,4R)-2-(3-(苄氧基)苄基)-4-(第三丁基二甲基矽烷基氧基)-3-((S)-3-(第三丁基二甲基矽烷基氧基)辛基)環戊基)甲酯(0.15g,0.18mmol)于無水甲醇(2ml)中的溶液在氫氣下在室溫下依次用氫氧化鉀(0.03g,0.54mmol)和5% Pd/C(0.045g,30重量%)處理2小時。反應完成後,用矽藻土墊過濾混合物,並且蒸發濾液。通過使用己烷-EtOAc作為洗提劑的矽膠柱色譜法純化所得殘餘物,得到標題化合物(0.12g,產率90%)。
1H NMR(500MHz,CDCl3)δ -0.01~0.10(12H,m),0.79~0.91(21H,m),1.12~1.46(12H,m),1.90(1H,m),2.02(1H,m),2.28(1H,m),2.31(1H,s),2.43(3H,s),2.54~2.72(3H,m),3.49~3.58(2H,m),3.91(1H,m),4.08(1H,m),6.60~6.72(3H,m),7.11(1H,m),7.22(1H,d,J=10Hz),7.32(1H,m),7.72~7.78(2H,m)。
13C NMR(125MHz,CDCl3)δ -4.3,-3.6,-3.0,14.1,18.0,18.1,22.6,22.7,25.2,25.325.7,25.8,30.3,31.9,35.1,35.6,37.3,37.4,41.0,
48.3,51.1,66.5,71.8,80.0,113.0,115.8,120.9,126.7,127.8,129.6,129.89,129.93,143.7,155.9。
(1R,2R,3aS,9aS)-2,3,3a,4,9,9a-六氫-2-(第三丁基二甲基矽烷氧基)-1-((S,E)-3-(第三丁基二甲基矽烷氧基)辛-1-烯基)-1H-環戊二烯並[b]萘-5-酚
實例18:在氮氣下在-40℃下用60%氫化鈉(7.2g,0.18mol)處理經脫氣的甲烷磺酸((1S,2S,3R,4R)-2-(3-羥基苄基)-4-(第三丁基二甲基矽烷氧基)-3-((S,E)-3-(第三丁基二甲基矽烷氧基)辛-1-烯基)環戊基)甲酯(50g,粗製化合物)於無水甘醇二甲醚(500ml)中的溶液。所得懸浮液隨後在-40℃下攪拌40分鐘,然後在0℃下攪拌15分鐘。將懸浮液再攪拌20分鐘同時升溫到室溫並且隨後在回流下攪拌2.5小時。隨後將反應物冷卻到10℃,用冰冷鹽水(250ml)和乙酸乙酯(500ml)稀釋。使反應混合物進行相分離並且用乙酸乙酯萃取水層。合併有機層並且經無水硫酸鎂乾燥。濾出固體。在真空下蒸發出溶劑。通過使用己烷與乙酸乙酯的混合物作為梯度洗提劑的矽膠色譜法純化粗產物。產率:75%。
實例19:在氮氣下在0℃下用60%氫化鈉(2.04g,0.051mol)處理經脫氣的4-甲基苯磺酸((1S,2S,3R,4R)-2-(3-羥基苄基)-4-(第三丁基二甲基矽烷氧基)-3-((S,E)-3-(第三丁基二甲基矽烷氧基)辛-1-烯基)環戊基)甲酯(12.6g,0.017mol)于無水THF(250ml)中的溶液。所得懸浮液
在回流下攪拌4小時。隨後將反應物冷卻到10℃,用冰冷鹽水(250ml)和乙酸乙酯(500ml)稀釋。使反應混合物進行相分離並且用乙酸乙酯萃取水層。合併有機層並且經無水硫酸鎂乾燥。濾出固體。在真空下蒸發出溶劑。通過使用己烷與乙酸乙酯的混合物作為梯度洗提劑的矽膠色譜法純化粗產物。產率:90%。
1H-NMR(CDCl3):δ 7.00(t,1H),6.69(d,1H),6.65(d,1H),5.48~5.46(m,2H)4.70(br s,1H),4.11~4.08(m,1H),3.78~3.75(m,1H),2.70~2.62(m,2H),2.52~2.38(m,2H),2.38~2.20(m,1H),2.16~2.04(m,2H),2.02~1.81(m,2H),1.42~1.25(m,8H),0.90~0.84(m,21H),0.06~0.00(m,12H)。
13C-NMR(CDCl3):δ 152.40,140.99,135.10,130.58,126.23,124.44,120.71,112.90,73.08,55.86,41.40.,39.80,38.65,32.56,31.85,25.94,25.91,25.19,22.65,18.27,18.19,14.07,-4.19,-4.55,-4.73。
(1R,2R,3aS,9aS)-2,3,3a,4,9,9a-六氫-2-(第三丁基二甲基矽烷氧基)-1-((S)-3-(第三丁基二甲基矽烷氧基)辛基)-1H-環戊二烯並[b]萘-5-酚
在氮氣下在0℃下用60%氫化鈉(2.04g,0.051mol)處理經脫氣的4-甲基苯磺酸((1S,2S,3R,4R)-2-(3-羥基苄基)-4-(第三丁基二甲基矽烷氧基)-3-((S)-3-(第三丁基二甲基矽烷氧基)辛基)環戊基)甲酯(12.4g,
0.017mol)于無水THF(250ml)中的溶液。所得懸浮液在回流下攪拌4小時。隨後將反應物冷卻到10℃,用冰冷鹽水(250ml)和乙酸乙酯(500ml)稀釋。使反應混合物進行相分離並且用乙酸乙酯萃取水層。合併有機層並且經無水硫酸鎂乾燥。濾出固體。在真空下蒸發出溶劑。通過使用己烷與乙酸乙酯的混合物作為梯度洗提劑的矽膠色譜法純化粗產物。產率:87%。
1H-NMR(CDCl3):δ 7.00(t,1H),6.73(d,1H),6.63(d,1H),4.67(br s,1H),3.69~3.62(m,1H),2.83~2.74(m,2H),2.49~2.35(m,2H),2.19~2.05(m,3H),1.83~1.81(m,1H),1.43~1.21(m,13H),0.97~0.86(m,21H),0.56~0.00(m,12H)
13C-NMR(CDCl3):δ 152.06,141.50,126.13,124.72,120.32,112.82,72.76,52.61,41.32,40.42,37.01,34.85,34.31,33.27,32.07,28.01,26.38,25.96,25.90,24.98,22.67,18.17,18.03,14.07,-4.25,-4.34,-4.72。
(1R,2R,3aS,9aS)-2,3,3a,4,9,9a-六氫-1-((S,E)-3-羥基辛-1-烯基)-1H-環戊二烯並[b]萘-2,5-二酚
實例21:在室溫下用四丁基氟化銨(180ml,1M於THF中)處理(1R,2R,3aS,9aS)-2,3,3a,4,9,9a-六氫-2-(第三丁基二甲基矽烷氧基)-1-((S,E)-3-(第三丁基二甲基矽烷氧基)辛-1-烯基)-1H-環戊二烯並[b]萘-5-酚(10g,0.018mmol)整夜。將反應混合物倒入飽和碳酸氫鈉水溶
液(200ml)中並且攪拌30分鐘。使反應混合物進行相分離並且用300ml乙酸乙酯萃取水層。合併有機層並且經無水硫酸鎂乾燥。濾出固體。在真空下蒸發出溶劑。通過使用己烷與乙酸乙酯的混合物作為梯度洗提劑的矽膠色譜法純化粗產物。獲得呈結晶形式的標題化合物。產率:70%。
實例22:在室溫下將(1R,2R,3aS,9aS)-2,3,3a,4,9,9a-六氫-2-(第三丁基二甲基矽烷氧基)-1-((S,E)-3-(第三丁基二甲基矽烷氧基)辛-1-烯基)-1H-環戊二烯並[b]萘-5-酚(6.4g,0.011mmol)依次溶解於THF(12.8ml)、乙酸(38.4ml)和蒸餾水(12.8ml)中整夜。將反應混合物倒入飽和碳酸氫鈉水溶液(150ml)中並且攪拌30分鐘。使反應混合物進行相分離並且用200ml乙酸乙酯萃取水層。合併有機層並且經無水硫酸鎂乾燥。濾出固體。在真空下蒸發出溶劑。通過使用己烷與乙酸乙酯的混合物作為梯度洗提劑的矽膠色譜法純化粗產物。獲得呈結晶形式的標題化合物(產量:88%)。
1H-NMR(CDCl3):δ 6.98(t,1H),6.70~6.64(m,2H),5.60(br s,1H),5.53~5.42(m,2H),4.11~4.05(m,1H),3.75~3.66(m,1H),2.64~2.56(m,4H),2.40~2.33(m,3H),2.17~2.16(m,1H),2.05~2.02(m,1H),1.50~1.32(m,8H),1.09~1.05(m,1H),0.90~0.88(m,3H)。
13C-NMR(CDCl3):δ 152.81,140.47,135.98,133.13,126.26,124.37,120.58,113.18,75.70,73.33,56.52,45.13,40.36,37.10,32.52,31.90,31.66,25.58,25.20,22.61,14.01。
乙酸(1R,2R,3aS,9aS)-2,3,3a,4,9,9a-六氫-2-羥基-1-((S,E)-3-羥基辛-1-烯基)-1H-環戊二烯並[b]萘-5-基酯
在室溫下用乙酸酐(0.1ml,1.07mol)和DMAP(1.1mg,0.09mmol)處理含(1R,2R,3aS,9aS)-2,3,3a,4,9,9a-六氫-2-(第三丁基二甲基矽烷氧基)-1-((S,E)-3-(第三丁基二甲基矽烷氧基)辛-1-烯基)-1H-環戊二烯並[b]萘-5-酚(0.5g,0.89mmol)的甲苯(5ml)30分鐘。反應物用飽和碳酸氫鈉水溶液(10ml)稀釋並且用乙酸乙酯(10ml)萃取。使反應混合物進行相分離並且用乙酸乙酯萃取水層。合併有機層並且經無水硫酸鎂乾燥。濾出固體。在真空下蒸發出溶劑。通過使用己烷與乙酸乙酯的混合物作為梯度洗提劑的矽膠色譜法純化粗產物。獲得0.45g乙酸(1R,2R,3aS,9aS)-2,3,3a,4,9,9a-六氫-2-(第三丁基二甲基-矽烷氧基)-1-((S,E)-3-(第三丁基二甲基矽烷氧基)辛-1-烯基)-1H-環戊二烯並[b]萘-5-基酯。隨後將產物溶解於四氫呋喃(0.9ml)中,並且在室溫下用乙酸(2.7ml)和蒸餾水(0.9ml)處理整夜。反應物隨後用飽和碳酸氫鈉水溶液(12ml)稀釋並且用乙酸乙酯(15ml)萃取。使反應混合物進行相分離並且用乙酸乙酯萃取水層。合併有機層並且經無水硫酸鎂乾燥。濾出固體。在真空下蒸發出溶劑。通過使用己烷與乙酸乙酯的混合物作為梯度洗提劑的矽膠色譜法純化粗產物。獲得呈結晶形式的標題化合物。熔融範圍為54~65℃。產率:65%。
1H-NMR(CDCl3):δ 7.13(t,1H),6.96(d,1H),6.85(d,1H),5.39~5.38(m,2H),3.98~3.93(m,1H),3.62~3.56(m,1H),3.19(br s,2H),2.62(dd,1H),2.50(dd,1H),2.38(dd,1H),2.32~2.24(m,5H),2.14~2.09(m,1H),2.00~1.95(m,1H),1.70~1.66(m,1H),1.55~1.51
(m,1H),1.43~1.29(m,8H),1.02(q,1H),0.89(t,3H)。
13C-NMR(CDCl3)δ 169.63,148.10,140.71,136.11,133.34,130.57,126.32,125.66,119.47,75.48,73.05,56.65,40.13,40.02,36.89,32.20,32.00,31.64,27.02,25.11,22.55,20.71,13.94。
苯甲酸(1R,2R,3aS,9aS)-2,3,3a,4,9,9a-六氫-2-羥基-1-((S,E)-3-羥基辛-1-烯基)-1H-環戊二烯並[b]萘-5-基酯
在0℃下用氫化鈉(0.29g,7.16mol)處理含2g(3.58mmol,來自實例18)(1R,2R,3aS,9aS)-2,3,3a,4,9,9a-六氫-2-(第三丁基二甲基-矽烷氧基)-1-((S,E)-3-(第三丁基二甲基矽烷氧基)辛-1-烯基)-1H-環戊二烯並[b]萘-5-酚(其含有6%對位環化異構體)的無水四氫呋喃(20ml)並且在室溫下攪拌10分鐘,然後逐滴加入苯甲醯氯(0.63ml,5.37mmol)。30分鐘後,將反應物冷卻到10℃,用冰冷鹽水(10ml)稀釋並且用乙酸乙酯(10ml)萃取。使反應混合物進行相分離並且用乙酸乙酯萃取水層。合併有機層並且經無水硫酸鎂乾燥。濾出固體。在真空下蒸發出溶劑。通過使用己烷與乙酸乙酯的混合物作為梯度洗提劑的矽膠色譜法純化粗產物。獲得2.1g苯甲酸(1R,2R,3aS,9aS)-2,3,3a,4,9,9a-六氫-2-(第三丁基二甲基矽烷氧基)-1-((S,E)-3-(第三丁基二甲基矽烷氧基)辛-1-烯基)-1H-環戊二烯並[b]萘-5-基酯。隨後將產物溶解於四氫呋喃(4.2ml)中,並且在室溫下用乙酸(12.6ml)和蒸餾水(4.2ml)處理整夜。反應物隨後用飽和碳酸氫鈉水溶液(50ml)稀釋並且用乙酸乙酯
(60ml)萃取。使反應混合物進行相分離並且用乙酸乙酯萃取水層。合併有機層並且經無水硫酸鎂乾燥。濾出固體。在真空下蒸發出溶劑。通過使用己烷與乙酸乙酯的混合物作為梯度洗提劑的矽膠色譜法純化粗產物。獲得呈結晶形式的產物。熔點:140~141℃。產量:68%。
通過HPLC進一步分析產物以確定結晶產物中未見到對位環化異構體。
1H-NMR(CDCl3):δ 8.19(d,2H),7.63(t,1H),7.50(t,2H),7.18(t,1H),7.03(d,1H),6.99(d,1H),5.50~5.40(m,2H),4.04~4.00(m,1H),3.66~3.62(m,1H),3.04(br s,1H),2.88(br s,1H),2.68(dd,1H),2.56(dd,1H),2.44(dd,1H),2.38(dd,1H),2.32~2.28(m,1H),2.14~2.00(m,2H),1.76~1.71(m,1H),1.58~1.53(m,1H),1.48~1.32(m,7H),1.08(q,1H),0.90(t,3H)。
13C-NMR(CDCl3)δ 165.31,148.44,140.86,136.22,133.60,133.21,130.83,130.19,129.38,128.60,126.49,125.80,119.70,75.69,73.06,53.73,40.14,37.10,32.29,32.11,31.72,27.12,25.18,22.62,14.01。
苯甲酸(1R,2R,3aS,9aS)-2,3,3a,4,9,9a-六氫-2-羥基-1-((S)-3-羥基辛基)-1H-環戊二烯並[b]萘-5-基酯
用5% Pd/C(0.05g,20重量%)處理含苯甲酸(1R,2R,3aS,9aS)-2,3,3a,4,9,9a-六氫-2-羥基-1-((S,E)-3-羥基辛-1-烯基)-1H-環戊二烯並
[b]萘-5-基酯(0.35g,0.8mmol)的無水甲醇(2.5ml)並且在氫氣下在室溫下攪拌5小時。隨後,用矽藻土墊過濾反應混合物。在真空下蒸發出溶劑。通過使用己烷與乙酸乙酯的混合物作為梯度洗提劑的矽膠色譜法純化粗產物。產率:87%。
1H-NMR(CDCl3):δ 8.20(d,2H),7.62(t,1H),7.50(t,2H),7.18(t,1H),7.05(d,1H),6.90(d,1H),3.73~3.66(m,1H),3.61~3.59(m,1H),2.80(dd,1H),2.64(dd,1H),2.51(dd,1H),2.34(dd,1H),2.23~2.18(m,1H),2.13~2.03(m,1H),1.92~1.86(m,2H),1.66~1.63(m,2H),1.56~1.52(m,2H),1.46~1.41(m,3H),1.32~1.16(m,7H),1.14~1.11(m,1H),0.88(t,3H)。
13C-NMR(CDCl3):δ 165.16,148.30,141.09,133.52,131.03,130.18,129.51,128.58,126.39,125.56,119.60,75.52,52.32,41.25,37.44,34.94,33.72,32.59,31.89,28.56,27.38,25.34,22.61,14.00。
2-((1R,2R,3aS,9aS)-2,3,3a,4,9,9a-六氫-2-羥基-1-((S,E)-3-羥基辛-1-烯基)-1H-環戊二烯並[b]萘-5-基氧基)乙酸甲酯
用50% NaOH(1g)處理含(1R,2R,3aS,9aS)-2,3,3a,4,9,9a-六氫-2-(第三丁基二甲基矽烷氧基)-1-((S,E)-3-(第三丁基二甲基矽烷氧基)辛-1-烯基)-1H-環戊二烯並[b]萘-5-酚(0.5g,0.89mmol)的溴乙酸甲酯(3ml)。混合物在室溫下攪拌60分鐘。將反應混合物冷卻到10℃並且緩慢加入3N HCl直到pH=7,隨後用乙酸乙酯萃取反應物。合併有機層並且經無水硫酸鎂乾燥。濾出固體。在真空下蒸發出溶劑。通過使用
己烷與乙酸乙酯的混合物作為梯度洗提劑的矽膠色譜法純化粗產物。獲得0.2g 2-((1R,2R,3aS,9aS)-2,3,3a,4,9,9a-六氫-2-(第三丁基二甲基矽烷氧基)-1-((S,E)-3-羥基辛-1-烯基)-1H-環戊二烯並[b]萘-5-基氧基)乙酸甲酯。隨後在室溫下將產物溶解於THF(1.3ml)、乙酸(3.9ml)和蒸餾水(1.3ml)中整夜。將反應混合物倒入飽和碳酸氫鈉水溶液(10ml)中並且攪拌30分鐘。使反應混合物進行相分離並且用20ml乙酸乙酯萃取水層。合併有機層並且經無水硫酸鎂乾燥。濾出固體。在真空下蒸發出溶劑。通過使用己烷與乙酸乙酯的混合物作為梯度洗提劑的矽膠色譜法純化粗產物。獲得呈結晶形式的標題化合物(產率:58%)。
(1R,2R,3aS,9aS)-2,3,3a,4,9,9a-六氫-1-((S)-3-羥基辛基)-1H-環戊二烯並[b]萘-2,5-二酚
實例27:重複與實例22中所述相同的程式,其中例外為反應中使用的等摩爾基質為(1R,2R,3aS,9aS)-2,3,3a,4,9,9a-六氫-2-(第三丁基二甲基矽烷氧基)-1-((S)-3-(第三丁基二甲基矽烷氧基)辛基)-1H-環戊二烯並[b]萘-5-酚(來自實例20)而非(1R,2R,3aS,9aS)-2,3,3a,4,9,9a-六氫-2-(第三丁基二甲基矽烷氧基)-1-((S,E)-3-(第三丁基二甲基矽烷氧基)辛-1-烯基)-1H-環戊二烯並[b]萘-5-酚。製備標題化合物且以結晶形式獲得。(產率:83%)。
實例28:在氫氣下在室溫下依次用氫氧化鉀(0.5g,0.008mol)和
5% Pd/C(0.5g,20重量%)處理含(1R,2R,3aS,9aS)-2,3,3a,4,9,9a-六氫-1-((S,E)-3-羥基辛-1-烯基)-1H-環戊二烯並[b]萘-2,5-二酚(2.5g,0.008mol,來自實例21或22)的無水甲醇(25ml)整夜。隨後用矽藻土墊過濾反應混合物。在真空下蒸發出溶劑。通過使用己烷與乙酸乙酯的混合物作為梯度洗提劑的矽膠色譜法純化粗產物。獲得呈結晶形式的標題化合物。產率:72%。
實例29:用1mL氫氧化鈉(5%於甲醇中)處理苯甲酸(1R,2R,3aS,9aS)-2,3,3a,4,9,9a-六氫-2-羥基-1-((S)-3-羥基辛基)-1H-環戊二烯並[b]萘-5-基酯(0.2g,0.008mol,來自實例25),隨後在室溫下攪拌60分鐘。用3N HCl(1ml)和乙酸乙酯(10mL)稀釋反應混合物。使反應混合物進行相分離並且用乙酸乙酯萃取水層。合併有機層並且經無水硫酸鎂乾燥。濾出固體。在真空下蒸發出溶劑。通過使用己烷與乙酸乙酯的混合物作為梯度洗提劑的矽膠色譜法純化粗產物。獲得呈結晶形式的標題化合物。產率:85%。
實例30:用5% Pd/C(0.05g,20重量%)處理含苯甲酸(1R,2R,3aS,9aS)-2,3,3a,4,9,9a-六氫-2-羥基-1-((S,E)-3-羥基辛-1-烯基)-1H-環戊二烯並[b]萘-5-基酯(0.25g,0.6mmol,來自實例24)的無水甲醇(2ml)並且在氫氣下在室溫下攪拌28小時。隨後用矽藻土墊過濾反應混合物。在真空下蒸發出溶劑。通過使用己烷與乙酸乙酯的混合物作為梯度洗提劑的矽膠色譜法純化粗產物。獲得呈結晶形式的標題化合物。產率:73%。
1H-NMR(CD3OD):δ 6.98(t,1H),6.62(d,2H),3.63~3.56(m,1H),3.52~3.51(m,1H),2.71~2.56(m,3H),2.49~2.42(m,1H),2.36~2.29(m,1H),2.07~2.03(m,1H),1.95~1.83(m,1H),1.76~1.50(m,3H),1.48~1.21(m,9H),1.20~1.02(m,2H),0.91(t,3H)。
13C-NMR(CD3OD):δ 154.36,140.87,126.00,125.03,119.48,
112.78,76.58,71.92,51.55,41.33,41.00,37.29,35.05,33.57,33.15,32.16,28.66,25.55,25.50,22.70,13.44。
2-((1R,2R,3aS,9aS)-2,3,3a,4,9,9a-六氫-2-羥基-1-((S,E)-3-羥基辛-1-烯基)-1H-環戊二烯並[b]萘-5-基氧基)乙腈
實例31:用K2CO3(1.66g,0.012mol)、氯乙腈(0.51ml,0.008mol)和四丁基溴化銨(0.32g,0.001mmol)處理含(1R,2R,3aS,9aS)-2,3,3a,4,9,9a-六氫-1-((S,E)-3-羥基辛-1-烯基)-1H-環戊二烯並[b]萘-2,5-二酚(1.6g,0.004mol)的無水丙酮(16ml)。混合物在30℃下加熱整夜。隨後用矽藻土墊過濾反應混合物。在真空下蒸發出濾液。通過使用己烷與乙酸乙酯的混合物作為梯度洗提劑的矽膠色譜法純化粗產物。獲得呈結晶形式的標題化合物。產率:89%。
實例32:用K2CO3(6.64g,0.048mol)、氯乙腈(2ml,0.032mol)和四丁基溴化銨(1.28g,0.004mmol)處理含(1R,2R,3aS,9aS)-2,3,3a,4,9,9a-六氫-2-(第三丁基二甲基矽烷氧基)-1-((S,E)-3-(第三丁基二甲基矽烷氧基)辛-1-烯基)-1H-環戊二烯並[b]萘-5-酚(6.4g,0.011mmol)的無水丙酮(64ml)。混合物在30℃下加熱整夜。隨後用矽藻土墊過濾反應混合物。在真空下蒸發出濾液。獲得粗制經保護的苯并茚腈[2-((1R,2R,3aS,9aS)-2,3,3a,4,9,9a-六氫-2-(第三丁基二甲基矽烷氧基)-1-((S,E)-3-(第三丁基二甲基矽烷氧基)辛-1-烯基)-1H-環戊二烯並[b]萘-5-基氧基)乙腈]。隨後在室溫下將粗製經保護的苯并茚腈依次
溶解於THF(19.2ml)、乙酸(57.6ml)和蒸餾水(19.2ml)中整夜。將反應混合物倒入飽和碳酸氫鈉水溶液(200ml)中並且攪拌30分鐘。使反應混合物進行相分離並且用300ml乙酸乙酯萃取水層。合併有機層並且經無水硫酸鎂乾燥。濾出固體。在真空下蒸發出溶劑。通過使用己烷與乙酸乙酯的混合物作為梯度洗提劑的矽膠色譜法純化粗產物。標題化合物的產量為3.43g,含有痕量的對位環化異構體。通過從異丙醚/庚烷中結晶來去除對位環化異構體。獲得2.74g呈結晶形式的標題化合物(白色到灰白色粉末)。熔點:58℃(產率:67%)。
1H-NMR(CDCl3):δ 7.15(t,1H),6.87(d,1H),6.83(d,1H),5.53~5.46(m,2H),4.76(s,2H),4.09~4.01(m,1H),3.76~3.70(m,1H),2.68~2.59(m,2H),2.43~2.32(m,2H),2.24~2.18(m,1H),2.07~2.03(m,1H),1.58~1.55(m,1H),1.51~1.48(m,1H),1.40~1.31(m,8H),1.07(q,1H),0.91(t,3H)。
13C-NMR(CDCl3):δ 153.85,141.16,136.18,132.71,128.08,126.58,123.24,115.41,110.49,75.60,73.06,56.72,54.44,40.30,37.21,32.40,31.99,31.69,25.60,25.21,22.62,14.02。
2-((1R,2R,3aS,9aS)-2,3,3a,4,9,9a-六氫-2-羥基-1-((S)-3-羥基辛基)-1H-環戊二烯並[b]萘-5-基氧基)乙腈
用K2CO3(2.07g,0.015mol)、氯乙腈(0.64ml,0.010mol)和四丁基溴化銨(0.32g,0.001mmol)處理含(1R,2R,3aS,9aS)-2,3,3a,4,9,9a-六
氫-1-((S)-3-羥基辛基)-1H-環戊二烯並[b]萘-2,5-二酚(2g,0.005mol)的無水丙酮(20ml)。混合物在30℃下加熱整夜。隨後用矽藻土墊過濾反應混合物。在真空下蒸發出濾液。通過使用己烷與乙酸乙酯的混合物作為梯度洗提劑的矽膠色譜法純化粗產物。產率:82%。
2-((1R,2R,3aS,9aS)-2,3,3a,4,9,9a-六氫-2-羥基-1-((S,E)-3-羥基辛-1-烯基)-1H-環戊二烯並[b]萘-5-基氧基)乙酸
實例34:用20% KOH(5ml)處理含2-((1R,2R,3aS,9aS)-2,3,3a,4,9,9a-六氫-2-羥基-1-((S,E)-3-羥基辛-1-烯基)-1H-環戊二烯並[b]萘-5-基氧基)乙腈(1.6g,0.004mol)的異丙醇(16ml)並且回流3小時,隨後冷卻到10℃,並且緩慢加入3N HCl直到pH=8。在真空中去除溶劑。加入乙酸乙酯和鹽水並且隨後緩慢加入3N HCl直到pH=2。用乙酸乙酯萃取反應混合物。經合併的乙酸乙酯萃取物經無水硫酸鎂乾燥。濾出固體。在真空下蒸發出溶劑。通過從乙醇/H2O中結晶來純化粗產物。獲得1.2g呈結晶形式的標題化合物。
實例35:重複如實例29中所述的程式,其中例外為在反應中使用的等摩爾基質為2-((1R,2R,3aS,9aS)-2,3,3a,4,9,9a-六氫-2-羥基-1-((S,E)-3-羥基辛-1-烯基)-1H-環戊二烯並[b]萘-5-基氧基)乙酸甲酯。製備標題化合物並且以結晶形式獲得。產率:82%。
1H-NMR(CD3OD):δ 7.06(t,1H),6.74(d,1H),6.71(d,1H),5.53
(dd,1H),5.44(dd,1H),4.62(s,2H),4.01(q,1H),3.72~3.66(m,1H),2.77(dd,1H),2.62(dd,2H),2.44(dd,1H),2.41~2.35(m,1H),2.16~2.02(m,2H),1.67(q,1H),1.59~1.34(m,8H),1.06(q,1H),0.93(t,3H)。
13C-NMR(CD3OD):δ 172.94,156.75,141.80,136.45,134.11,128.48,127.32,122.58,110.88,76.66,73.94,66.54,57.22,41.79,41.64,38.31,33.74,32.94,32.81,26.41,26.34,23.75,14.41。
製備曲前列尼爾
2-((1R,2R,3aS,9aS)-2,3,3a,4,9,9a-六氫-2-羥基-1-((S)-3-羥基辛基)-1H-環戊二烯並[b]萘-5-基氧基)乙酸
實例36:由實例33的產物製備曲前列尼爾 用20% KOH(6ml)處理含2-((1R,2R,3aS,9aS)-2,3,3a,4,9,9a-六氫-2-羥基-1-((S)-3-羥基辛基)-1H-環戊二烯並[b]萘-5-基氧基)乙腈(2g,0.005mol)的甲醇(18ml)並且回流3小時。隨後將反應物冷卻到10℃並且緩慢加入3N HCl直到pH=~8。在真空中去除溶劑。加入乙酸乙酯和鹽水並且隨後緩慢加入3N HCl直到pH=2。用乙酸乙酯萃取反應混合物。合併的乙酸乙酯萃取物經無水硫酸鎂乾燥。濾出固體。在真空下蒸發出溶劑。通過從乙醇/H2O中結晶來純化粗產物。獲得呈結晶形式的標題化合物。產率:81%。
實例37:由實例34和35的產物製備曲前列尼爾 在氫氣下在室溫
下依次用氫氧化鉀(0.5g,0.008mol)和5% Pd/C(0.5g,20重量%)處理含2-((1R,2R,3aS,9aS)-2,3,3a,4,9,9a-六氫-2-羥基-1-((S,E)-3-羥基辛-1-烯基)-1H-環戊二烯並[b]萘-5-基氧基)乙酸(2.5g,0.008mol)的無水甲醇(25ml)整夜。隨後用矽藻土墊過濾反應混合物。在真空下蒸發出溶劑。用50ml乙酸乙酯和50ml飽和碳酸氫鈉水溶液稀釋殘餘物。使混合物進行相分離並且用50ml飽和碳酸氫鈉水溶液萃取有機層。合併水層並且隨後緩慢加入3N HCl直到pH=~2。用100ml乙酸乙酯萃取水層。合併有機層並且經無水硫酸鎂乾燥。濾出固體。在真空下蒸發出溶劑。通過結晶來純化粗產物。獲得呈結晶形式的標題化合物。產率:88%。
1H-NMR(CDCl3):δ 7.08(t,1H),6.83(d,1H),6.69(d,1H),4.65(s,2H),3.75(q,1H),3.67~3.58(m,1H),2.82~2.73(m,2H),2.62~2.58(m,1H),2.51~2.47(m,1H),2.29~2.27(m,1H),2.20~2.15(m,1H),1.91~1.84(m,1H),1.66~1.65(m,1H),1.49~1.33(m,4H),1.32~1.21(m,8H),1.17(q,1H),0.91(t,3H)。
13C-NMR(CDCl3):δ 170.86,154.80,141.12,127.92,126.32,122.18,110.25,76.75,72.75,65.96,52.28,41.51,41.39,37.47,35.02,33.60,32.98,31.94,28.69,26.06,25.35,22.61,13.94。
Claims (5)
- 一種製備式8d化合物的方法,
- 如請求項1之方法,其中M為苯基或4-苯基苯基。
- 一種式1e化合物,
- 一種式8D-1化合物,
- 一種式11-1化合物,
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