CN106632372B - A kind of intermediate and its preparation method and application - Google Patents
A kind of intermediate and its preparation method and application Download PDFInfo
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- CN106632372B CN106632372B CN201610851108.0A CN201610851108A CN106632372B CN 106632372 B CN106632372 B CN 106632372B CN 201610851108 A CN201610851108 A CN 201610851108A CN 106632372 B CN106632372 B CN 106632372B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 76
- 229960002890 beraprost Drugs 0.000 claims abstract description 24
- -1 tert-butyldiphenylsilanyl Chemical group 0.000 claims abstract description 18
- 239000001257 hydrogen Substances 0.000 claims abstract description 17
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 17
- CTPOHARTNNSRSR-APJZLKAGSA-N beraprost Chemical compound O([C@H]1C[C@@H](O)[C@@H]([C@@H]21)/C=C/[C@@H](O)C(C)CC#CC)C1=C2C=CC=C1CCCC(O)=O CTPOHARTNNSRSR-APJZLKAGSA-N 0.000 claims abstract description 10
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 7
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 7
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims abstract description 6
- 150000003839 salts Chemical class 0.000 claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims description 123
- 239000012074 organic phase Substances 0.000 claims description 77
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 72
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 54
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 52
- 238000006243 chemical reaction Methods 0.000 claims description 52
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 39
- 239000003054 catalyst Substances 0.000 claims description 33
- 239000000243 solution Substances 0.000 claims description 33
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 30
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 27
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 27
- 239000003960 organic solvent Substances 0.000 claims description 27
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 26
- 239000000460 chlorine Substances 0.000 claims description 20
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 17
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 16
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 15
- 238000005406 washing Methods 0.000 claims description 15
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 14
- 230000035484 reaction time Effects 0.000 claims description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 12
- 238000000746 purification Methods 0.000 claims description 12
- 238000005984 hydrogenation reaction Methods 0.000 claims description 11
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 11
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 10
- 229940040526 anhydrous sodium acetate Drugs 0.000 claims description 10
- 238000001816 cooling Methods 0.000 claims description 10
- 238000000926 separation method Methods 0.000 claims description 10
- 239000003795 chemical substances by application Substances 0.000 claims description 9
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical group [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 claims description 7
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- 230000000694 effects Effects 0.000 claims description 6
- 150000002431 hydrogen Chemical class 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 5
- 239000007864 aqueous solution Substances 0.000 claims description 5
- UKLNMMHNWFDKNT-UHFFFAOYSA-M sodium chlorite Chemical compound [Na+].[O-]Cl=O UKLNMMHNWFDKNT-UHFFFAOYSA-M 0.000 claims description 5
- 229960002218 sodium chlorite Drugs 0.000 claims description 5
- YAXWOADCWUUUNX-UHFFFAOYSA-N 1,2,2,3-tetramethylpiperidine Chemical compound CC1CCCN(C)C1(C)C YAXWOADCWUUUNX-UHFFFAOYSA-N 0.000 claims description 4
- RKMGAJGJIURJSJ-UHFFFAOYSA-N 2,2,6,6-Tetramethylpiperidine Substances CC1(C)CCCC(C)(C)N1 RKMGAJGJIURJSJ-UHFFFAOYSA-N 0.000 claims description 4
- 239000005708 Sodium hypochlorite Substances 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 238000006555 catalytic reaction Methods 0.000 claims description 4
- 235000002639 sodium chloride Nutrition 0.000 claims description 4
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 claims description 4
- 238000007070 tosylation reaction Methods 0.000 claims description 4
- 230000021736 acetylation Effects 0.000 claims description 3
- 238000006640 acetylation reaction Methods 0.000 claims description 3
- 239000011261 inert gas Substances 0.000 claims description 3
- 229910000402 monopotassium phosphate Inorganic materials 0.000 claims description 3
- 235000019796 monopotassium phosphate Nutrition 0.000 claims description 3
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 claims description 3
- DLLFWZVLRWBBQC-UHFFFAOYSA-M [Na+].[Na+].Cl[O-].[O-]Cl=O Chemical compound [Na+].[Na+].Cl[O-].[O-]Cl=O DLLFWZVLRWBBQC-UHFFFAOYSA-M 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- 238000003883 substance clean up Methods 0.000 claims description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims 3
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims 1
- 125000002252 acyl group Chemical group 0.000 claims 1
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 claims 1
- 239000012267 brine Substances 0.000 claims 1
- 238000010438 heat treatment Methods 0.000 claims 1
- 229910052744 lithium Inorganic materials 0.000 claims 1
- 150000002825 nitriles Chemical class 0.000 claims 1
- 230000003647 oxidation Effects 0.000 claims 1
- 238000007254 oxidation reaction Methods 0.000 claims 1
- 239000011574 phosphorus Substances 0.000 claims 1
- 229910052698 phosphorus Inorganic materials 0.000 claims 1
- 229910052700 potassium Inorganic materials 0.000 claims 1
- 239000011591 potassium Substances 0.000 claims 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 claims 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 abstract description 4
- 238000005516 engineering process Methods 0.000 abstract description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 3
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 34
- 239000000543 intermediate Substances 0.000 description 23
- 238000005160 1H NMR spectroscopy Methods 0.000 description 19
- 238000003756 stirring Methods 0.000 description 19
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 18
- YTCZZXIRLARSET-VJRSQJMHSA-M beraprost sodium Chemical compound [Na+].O([C@H]1C[C@@H](O)[C@@H]([C@@H]21)/C=C/[C@@H](O)C(C)CC#CC)C1=C2C=CC=C1CCCC([O-])=O YTCZZXIRLARSET-VJRSQJMHSA-M 0.000 description 14
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 229910052757 nitrogen Inorganic materials 0.000 description 9
- 239000011734 sodium Substances 0.000 description 8
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 7
- 229910052708 sodium Inorganic materials 0.000 description 7
- IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical compound C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 description 6
- OBTZDIRUQWFRFZ-UHFFFAOYSA-N 2-(5-methylfuran-2-yl)-n-(4-methylphenyl)quinoline-4-carboxamide Chemical compound O1C(C)=CC=C1C1=CC(C(=O)NC=2C=CC(C)=CC=2)=C(C=CC=C2)C2=N1 OBTZDIRUQWFRFZ-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- 230000008859 change Effects 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 4
- 239000005864 Sulphur Substances 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 239000012230 colorless oil Substances 0.000 description 3
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 3
- 239000004519 grease Substances 0.000 description 3
- 150000002596 lactones Chemical class 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 159000000000 sodium salts Chemical group 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 3
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 239000003146 anticoagulant agent Substances 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229960001123 epoprostenol Drugs 0.000 description 2
- KAQKFAOMNZTLHT-VVUHWYTRSA-N epoprostenol Chemical compound O1C(=CCCCC(O)=O)C[C@@H]2[C@@H](/C=C/[C@@H](O)CCCCC)[C@H](O)C[C@@H]21 KAQKFAOMNZTLHT-VVUHWYTRSA-N 0.000 description 2
- 125000004185 ester group Chemical group 0.000 description 2
- 235000019441 ethanol Nutrition 0.000 description 2
- 238000003810 ethyl acetate extraction Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 description 2
- 229940017219 methyl propionate Drugs 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- LCPVQAHEFVXVKT-UHFFFAOYSA-N 2-(2,4-difluorophenoxy)pyridin-3-amine Chemical compound NC1=CC=CN=C1OC1=CC=C(F)C=C1F LCPVQAHEFVXVKT-UHFFFAOYSA-N 0.000 description 1
- MBNZWMLXHMPOTO-UHFFFAOYSA-N 2-hydroxy-4-phenylmethoxybutanal Chemical compound OC(CCOCc1ccccc1)C=O MBNZWMLXHMPOTO-UHFFFAOYSA-N 0.000 description 1
- BDUHKHWKUNVVRP-UHFFFAOYSA-N 4-methyloct-1-en-3-ol Chemical compound CCCCC(C)C(O)C=C BDUHKHWKUNVVRP-UHFFFAOYSA-N 0.000 description 1
- 200000000007 Arterial disease Diseases 0.000 description 1
- 102000009079 Epoprostenol Receptors Human genes 0.000 description 1
- 238000003747 Grignard reaction Methods 0.000 description 1
- 206010022562 Intermittent claudication Diseases 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 108091006335 Prostaglandin I receptors Proteins 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical class [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 1
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 1
- GFFGJBXGBJISGV-UHFFFAOYSA-N adenyl group Chemical group N1=CN=C2N=CNC2=C1N GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 1
- 102000030621 adenylate cyclase Human genes 0.000 description 1
- 108060000200 adenylate cyclase Proteins 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000000702 anti-platelet effect Effects 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- RFRXIWQYSOIBDI-UHFFFAOYSA-N benzarone Chemical compound CCC=1OC2=CC=CC=C2C=1C(=O)C1=CC=C(O)C=C1 RFRXIWQYSOIBDI-UHFFFAOYSA-N 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- VYLVYHXQOHJDJL-UHFFFAOYSA-K cerium trichloride Chemical compound Cl[Ce](Cl)Cl VYLVYHXQOHJDJL-UHFFFAOYSA-K 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000002024 ethyl acetate extract Substances 0.000 description 1
- 150000002240 furans Chemical class 0.000 description 1
- FUKUFMFMCZIRNT-UHFFFAOYSA-N hydron;methanol;chloride Chemical compound Cl.OC FUKUFMFMCZIRNT-UHFFFAOYSA-N 0.000 description 1
- 230000008676 import Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 description 1
- 208000021156 intermittent vascular claudication Diseases 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- GDOPTJXRTPNYNR-UHFFFAOYSA-N methyl-cyclopentane Natural products CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 description 1
- 210000002464 muscle smooth vascular Anatomy 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- DDBREPKUVSBGFI-UHFFFAOYSA-N phenobarbital Chemical compound C=1C=CC=CC=1C1(CC)C(=O)NC(=O)NC1=O DDBREPKUVSBGFI-UHFFFAOYSA-N 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
- 238000005498 polishing Methods 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical class [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 1
- 150000003815 prostacyclins Chemical class 0.000 description 1
- 150000003174 prostaglandin I2 derivatives Chemical class 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 208000002815 pulmonary hypertension Diseases 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- CHQMHPLRPQMAMX-UHFFFAOYSA-L sodium persulfate Substances [Na+].[Na+].[O-]S(=O)(=O)OOS([O-])(=O)=O CHQMHPLRPQMAMX-UHFFFAOYSA-L 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical class [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- RZWIIPASKMUIAC-VQTJNVASSA-N thromboxane Chemical compound CCCCCCCC[C@H]1OCCC[C@@H]1CCCCCCC RZWIIPASKMUIAC-VQTJNVASSA-N 0.000 description 1
- JBWKIWSBJXDJDT-UHFFFAOYSA-N triphenylmethyl chloride Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 JBWKIWSBJXDJDT-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
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Abstract
The present invention relates to pharmaceutical technology fields, more particularly to a kind of intermediate and its preparation method and application.The present invention provides a kind of intermediate, and the structure of the intermediate is as shown in general formula I:I wherein, R1Selected from hydrogen, benzyl, t-butyldimethylsilyi or tert-butyldiphenylsilanyl；R2Selected from hydrogen, hydroxyl ,-OR3；R3Selected from acetyl group or p-toluenesulfonyl；X is selected from hydrogen, Br or Cl.Intermediate provided by the present invention with general formula I is used to prepare beraprost and its salt.
Description
Technical field
The present invention relates to pharmaceutical technology fields, more particularly to a kind of intermediate and its preparation method and application.
Background technique
Beraprost (Beraprost) is a kind of prostacyclin (PGI2) derivative, in the secondary five of prostacyclin
A phenyl ring in parallel, increases the stability of molecule in member ring.Beraprost sodium (Beraprost sodium) is anticoagulant
The sodium-salt form of beraprost, be suitable for pulmonary hypertension, intermittent claudication caused by Chronic occlusive arterial disease, pain and
The symptoms such as creeping chill.Beraprost sodium (English name: Beraprost sodium, trade name: Kai Na or moral are received, molecular formula:
C24H29O5Molecular weight: 420.48) Na has structure shown in Formula V, chemical name are as follows: (±) -2,3,3a, 8b- tetrahydro -2- hydroxyl
Base -1- (3- hydroxy-4-methyl -1- octene -6- alkynyl) -1H- cyclopentano [b] benzofuran -5- sodium butyrate.
Beraprost sodium, which is first, to be taken orally, and the prostacyclin analogs that chemical property is stable, small by blood
The prostacyclin receptor of plate and vascular smooth muscle, activated adenyl cyclase increase intracellular cAMP concentration, inhibit Ca2+Stream
Enter and thromboxane A2Generate etc., to play the role of antiplatelet and expansion blood vessel.Beraprost sodium is public by Hungary's Cino Da Pistoia English
Department (Chinoin) and toray Co., Ltd. (Toray) develop respectively, with trade name it is triumphant that with De Na respectively in China
City.People constantly rise the demand of the drug, domestic at present without the production of raw medicine, and only co-partnership company is from Japan and breast
Tooth benefit import.So developing the preparation method an of beraprost sodium and its intermediate has very important meaning and valence
Value.
Document Tetrahedron, 1999,55,2449-2474 report the side for preparing beraprost sodium and its intermediate
Method, intermediate I, chemical name: 4- (trans- -3- methyl-1 of 4a, 5a, 10b- cis- -4a, 10c-, 4a, 5,5a, 10b, 10c- hexahydro
Two dislike simultaneously [5,4-a] cyclopentano [b] benzofuran -7- base) butyric acid, synthetic route is as follows:
The synthetic line is to obtain lactone intermediate through grignard reaction with 3- aldehyde radical methyl propionate VII with starting material VI
The mixture of VIII and hydroxy ester intermediate compound I X, then convert lactone VIII for this mixture, then hydrogenate, and amount to three-step reaction
Key intermediate IV is obtained, the main ring structure of beraprost sodium is constructed.Wherein, 3- aldehyde radical methyl propionate VII is expensive, institute
Containing ester group the reaction the poor easy generation side reaction of stable under alkaline conditions, in addition, also easy open loop obtains product lactone VIII
To a part of hydroxy ester intermediate compound I X, it is unfavorable for the control of reaction.
EP00848856 reports the intermediate compound IV that another route prepares beraprost sodium, and synthetic route is as follows.
This method is raw material with 3a, 8b- cis-dihydro -3H-5- carboxyl -7- bromine cyclopentadiene [b] benzofuran, is needed
Eight steps react the intermediate compound IV that beraprost sodium is prepared, and step is too long.
China Patent Publication No. CN1537107A and CN100347165C are reported using the methyl esters of intermediate compound IV as raw material system
The method of standby beraprost and its sodium salt.China Patent Publication No. CN103509044A is also only reported with the centre containing protecting group
The ester of body IV is the method that raw material prepares beraprost and its sodium salt, is not directed to the preparation side of the intermediate compound IV of beraprost sodium
Method.
Summary of the invention
In view of the foregoing deficiencies of prior art, the purpose of the present invention is to provide a kind of intermediates and preparation method thereof
And purposes, for solving the problems, such as one or more in the prior art.
In order to achieve the above objects and other related objects, first aspect present invention provides a kind of intermediate, the intermediate
Structure as shown in general formula I:
Wherein, R1Selected from hydrogen, benzyl, t-butyldimethylsilyi or tert-butyldiphenylsilanyl；R2Selected from hydrogen, hydroxyl
Base ,-OR3；R3Selected from acetyl group or p-toluenesulfonyl；X is selected from hydrogen, Br or Cl.
Preferably, the structure of the intermediate is as shown in general formula I-1:
Wherein, R1Selected from benzyl, t-butyldimethylsilyi or tert-butyldiphenylsilanyl；R2For hydroxyl；X is selected from
Br or Cl.
It is highly preferred that the intermediate is selected from the group compound:
Preferably, the structure of the intermediate is as shown in general formula I-2:
Wherein, R1Selected from benzyl, t-butyldimethylsilyi or tert-butyldiphenylsilanyl；R3Selected from acetyl group or
P-toluenesulfonyl；X is selected from Br or Cl.
It is highly preferred that the intermediate is selected from the group compound:
Preferably, the structural formula of the intermediate is as shown in Formulas I -3:
Wherein, R1For hydrogen；R2For hydrogen；X is hydrogen.
Second aspect of the present invention provides a kind of preparation method of -1 compound of Formulas I, by Formula II compound and formula III compound
Under the effect of the catalyst, reaction prepares, and reaction equation is as follows:
Preferably, further include any one of following characteristics or multinomial:
A1) Formula II compound is dissolved in organic solvent, cooling, under inert gas protection, catalyst is added dropwise, is then added dropwise
The organic solution of formula III compound, reaction prepare -1 compound of Formulas I；
A2) molar ratio of Formula II compound, catalyst and formula III compound is 1:1~1.2:1.2~3；
A3) volume ratio of organic solvent and Formula II compound is 8~15:1；
A4) catalyst is n-BuLi or s-butyl lithium；
A5) organic solvent is tetrahydrofuran, toluene or ether；
A6) organic solvent is tetrahydrofuran, toluene or ether in the organic solution of the formula III compound；
A7) temperature that is cooled to is -60~-80 DEG C；
A8 the reaction time is 10~30 minutes after catalyst) is added dropwise；
A9 the reaction time is 10~60 minutes after the organic solution of formula III compound) is added dropwise；
A10) further include -1 compound of Formulas I purification procedures: heat up after reaction, be added saturated ammonium chloride it is molten
Then liquid is added water, and is extracted with ethyl acetate, separation obtains organic phase, after then using saturated common salt water washing, with anhydrous sulphur
Sour sodium is dried, and filters, and is concentrated under reduced pressure, obtains -1 compound of Formulas I.
Third aspect present invention provides a kind of preparation method of -2 compound of Formulas I, by -1 compound of Formulas I through acetylation or right
Tosylation prepares, and reaction equation is as follows:
Preferably, further include any one of following characteristics or multinomial:
B1) -1 compound of Formulas I is dissolved in organic solvent, and acylating agent is added, and adds 4-dimethylaminopyridine, reaction preparation
Obtain -2 compound of Formulas I；
B2) molar ratio of -1 compound of Formulas I, organic solvent, acylating agent and 4-dimethylaminopyridine is 1:5~10:2~5:
0.1~2；
B3) organic solvent is pyridine；
B4) acylating agent is acetic anhydride or paratoluensulfonyl chloride；
B5) reaction temperature is 20~50 DEG C；
B6) reaction time is 8~24 hours；
B7) further include -2 compound of Formulas I purification procedures: cool down after reaction, water be added, and uses methylene chloride
Extraction, separation obtain organic phase, then with after saturated common salt water washing, are dried with anhydrous sodium sulfate, filter, obtain Formulas I-
2 compounds.
Fourth aspect present invention provides a kind of preparation method of -3 compound of Formulas I, adds hydrogen to prepare by -2 compound for catalysis of Formulas I
It obtains, reaction equation is as follows:
Preferably, further include any one of following characteristics or multinomial:
C1) -2 compound of Formulas I is dissolved in organic solvent, and anhydrous sodium acetate and catalyst is added, and hydrogen hydrogenation is added to prepare
Obtain -3 compound of Formulas I；
C2) -2 compound of Formulas I, anhydrous sodium acetate, catalyst molar ratio be 1:2~5:0.1~0.5；
C3) organic solvent is selected from one of methanol, ethyl alcohol, isopropanol, ethyl acetate and tetrahydrofuran or a variety of；
C4) catalyst is 10% or 5% palladium carbon；
C5) reaction time is 3~18 hours；
C6) reaction relative pressure is 1~5MPa；
C7) further include -3 compound of Formulas I purification procedures: filter out catalyst after reaction, organic phase be concentrated, adds
Enter water, and be extracted with ethyl acetate, separation obtains organic phase, then with after saturated common salt water washing, is carried out with anhydrous sodium sulfate
It dries, filters, is concentrated under reduced pressure to give -3 compound of Formulas I.
Fifth aspect present invention provides a kind of preparation method of formula IV compound, including step d): by -3 compound oxygen of Formulas I
Change prepares formula IV compound, and reaction equation is as follows:
Preferably, further include any one of following characteristics or multinomial:
D1) -3 compound of Formulas I is dissolved in acetonitrile and saturation potassium dihydrogen phosphate aqueous solution, and tetramethyl piperidine, secondary chlorine is added
Acid sodium aqueous solution and sodium chlorite, reaction prepare formula IV compound；
D2) -3 compound of Formulas I, acetonitrile, potassium dihydrogen phosphate, tetramethyl piperidine, sodium hypochlorite sodium chlorite molar ratio be
1:5~20:5~20:0.1~0.5:1~3:1~3；
D3) concentration of aqueous sodium hypochlorite solution is 6~14.5%；
D4) concentration of sodium chlorite is 80~100%；
D5) reaction time is 1~5 hour；
D6) further include formula IV compound purification procedures: water is added after reaction, and is extracted with ethyl acetate,
Separation obtains organic phase, then successively uses anhydrous sodium sulfate with after saturated sodium thiosulfate solution, water and saturated common salt water washing
It is dried, filters, be concentrated under reduced pressure to give formula IV compound.
Preferably, the preparation method further includes following steps before step d):
Step a): under the effect of the catalyst by Formula II compound and formula III compound, reaction prepares the change of Formulas I -1
Object is closed, reaction equation is as follows:
It is highly preferred that further including any one of following characteristics or multinomial:
A1) Formula II compound is dissolved in organic solvent, cooling, under inert gas protection, catalyst is added dropwise, is then added dropwise
The organic solution of formula III compound, reaction prepare -1 compound of Formulas I；
A2) molar ratio of Formula II compound, catalyst and formula III compound is 1:1~1.2:1.2~3；
A3) volume ratio of organic solvent and Formula II compound is 8~15:1；
A4) catalyst is n-BuLi, s-butyl lithium；
A5) organic solvent is tetrahydrofuran, toluene or ether；
A6) organic solvent is tetrahydrofuran, toluene or ether in the organic solution of the formula III compound；
A7) temperature that is cooled to is -60~-80 DEG C；
A8 the reaction time is 10~30 minutes after catalyst) is added dropwise；
A9 the reaction time is 10~60 minutes after the organic solution of formula III compound) is added dropwise；
A10) further include -1 compound of Formulas I purification procedures: heat up after reaction, be added saturated ammonium chloride it is molten
Then liquid is added water, and is extracted with ethyl acetate, separation obtains organic phase, after then using saturated common salt water washing, with anhydrous sulphur
Sour sodium is dried, and filters, and is concentrated under reduced pressure, obtains -1 compound of Formulas I；
Step b): preparing -2 compound of Formulas I through acetylation or tosylation for -1 compound of Formulas I, reaction
Equation is as follows:
It is highly preferred that further including any one of following characteristics or multinomial:
B1) -1 compound of Formulas I is dissolved in organic solvent, and acylating agent is added, and adds 4-dimethylaminopyridine, reaction preparation
Obtain -2 compound of Formulas I；
B2) molar ratio of -1 compound of Formulas I, organic solvent, acylating agent and 4-dimethylaminopyridine is 1:5~10:2~5:
0.1~2；
B3) organic solvent is pyridine；
B4) acylating agent is acetic anhydride or paratoluensulfonyl chloride；
B5) reaction temperature is 20~50 DEG C；
B6) reaction time is 8~24 hours；
B7) further include -2 compound of Formulas I purification procedures: cool down after reaction, water be added, and uses methylene chloride
Extraction, separation obtain organic phase, then with after saturated common salt water washing, are dried with anhydrous sodium sulfate, filter, obtain Formulas I-
2 compounds；
Step c): hydrogen is added to prepare -3 compound of Formulas I -2 compound for catalysis of Formulas I, reaction equation is as follows:
It is highly preferred that further including any one of following characteristics or multinomial:
C1) -2 compound of Formulas I is dissolved in organic solvent, and anhydrous sodium acetate and catalyst is added, and hydrogen hydrogenation is added to prepare
Obtain -3 compound of Formulas I；
C2) -2 compound of Formulas I, anhydrous sodium acetate, catalyst molar ratio be 1:2~5:0.1~0.5；
C3) organic solvent is selected from one of methanol, ethyl alcohol, isopropanol, ethyl acetate and tetrahydrofuran or a variety of；
C4) catalyst is 10% or 5% palladium carbon；
C5) reaction time is 3~18 hours；
C6) reaction relative pressure is 1~5MPa；
C7) further include -3 compound of Formulas I purification procedures: filter out catalyst after reaction, organic phase be concentrated, adds
Enter water, and be extracted with ethyl acetate, separation obtains organic phase, then with after saturated common salt water washing, is carried out with anhydrous sodium sulfate
It dries, filters, is concentrated under reduced pressure to give -3 compound of Formulas I.
Sixth aspect present invention provides above-mentioned intermediate and is used to prepare beraprost and its salt.
Preparation method through the invention obtains formula IV compound, then obtains beraprost by prior art preparation again
And its salt, the prior art can refer to background technique Literature Tetrahedron, 1999,55,2449-2474, CN1537107A,
CN100347165C and CN103509044A.Formula IV compound prepares beraprost and its salt by following reaction route:
Wherein, R4Selected from acetyl group, t-butyldimethylsilyi or tert-butyldiphenylsilanyl.
It is reacted under the effect of the catalyst by Formula II compound with formula III compound and prepares -1 compound of Formulas I, formula
III compound replaces the ester group of VII with ehter bond group, and structure is more stable, and formula III compound is easily from cheap Isosorbide-5-Nitrae-
Butanediol is made；It is reacted in preparation process and generates single product, it is stably and controllable, it is environmental-friendly, have yield good, process safety
The features such as；When X=Cl, reaction selectivity is than document Tetrahedron, and X=Br is more preferable in 1999,55,2449-2474, obtains
Product purity it is higher.Preparation method prepares through the invention intermediate compound IV yield and superior in quality, has stability
The advantages that good, with high purity, convenient for storage.This patent is to adapt to new drug development, avoids the route of patent concentration, while being easy to carry out
Polishing purification, easily prepared and each related impurities of control, optimize preparation process route, convenient for amplification.
Detailed description of the invention
Fig. 1 is shown as the formula IV compound that the embodiment of the present invention 13 is prepared1H-NMR spectrum.
Fig. 2 is shown as the mass spectrogram for the formula IV compound that the embodiment of the present invention 13 is prepared.
Specific embodiment
Illustrate embodiments of the present invention below by way of specific specific example, those skilled in the art can be by this specification
Other advantages and efficacy of the present invention can be easily understood for disclosed content.The present invention can also pass through in addition different specific realities
The mode of applying is embodied or practiced, the various details in this specification can also based on different viewpoints and application, without departing from
Various modifications or alterations are carried out under spirit of the invention.
It should be clear that in the following example not specifically dated process equipment or device be all made of conventional equipment in the art or
Device.
In addition, it should also be understood that, one or more method and step mentioned in the present invention does not repel before and after the combination step
It can also be inserted into other methods step there may also be other methods step or between these explicitly mentioned steps, unless separately
It is described；It should also be understood that the combination connection relationship between one or more equipment/device mentioned in the present invention is not repelled
The two equipment/devices specifically mentioned before and after the unit equipment/device there may also be other equipment/device or at these it
Between can also be inserted into other equipment/device, unless otherwise indicated.Moreover, unless otherwise indicated, the number of various method steps is only
Identify the convenient tool of various method steps, rather than for the arrangement order of limitation various method steps or limits the enforceable model of the present invention
It encloses, relativeness is altered or modified, and without material changes in technical content, when being also considered as, the present invention is enforceable
Scope.
Embodiment 1.I-1 (R1=Bn, X=Cl) preparation
II (X=Cl) 14g (40.5mmol) is added in 500ml there-necked flask, dry tetrahydrofuran 140ml is added, it is cooling
To -78 DEG C.Under nitrogen protection, the tetrahydrofuran solution (48.6mmol) of 19.5ml n-BuLi is slowly added dropwise into bottle, is added dropwise
It finishes, -78 DEG C are continued stirring 20 minutes.Start the tetrahydrofuran solution that 10.8g 4- benzyloxy hydroxybutyraldehyde is added dropwise
(60.75mmol), is added dropwise, and -78 DEG C are continued stirring 20 minutes, rises to -40 DEG C of dropwise addition 30ml saturated ammonium chloride solutions, stirs
It mixes, is warmed to room temperature, water is added, is extracted with ethyl acetate 3 times, collect organic phase, washed organic phase 1 time with saturated common salt, it is organic
Organic phase mutually is dried, filtered with anhydrous sodium sulfate and is concentrated under reduced pressure to give I-1 crude product, obtains I-1 14g after column chromatographic purifying, mole receipts
Rate 78%, purity 95%.1H-NMR(CDCl3, 400MHz) and δ 1.35 (3H, d, J=5.2Hz, CH3), 1.67-1.98 (4H, m,
2CH2), 2.69-2.76 (1H, m, CH), 3.08-3.14 (1H, m, CH), 3.20 (1H, d, J=4.8Hz, OH), 3.36-3.55
(4H, m, 2CH2), 3.70 (1H, t, J=10.4Hz, CH), 4.38 (1H, dd, J=4.4,4.4Hz, CH), 4.47-4.50 (1H,
M, CH), 4.52 (2H, d, J=2.4Hz, CH2), 4.69-4.79 (2H, m, CH2), 5.10-5.17 (1H, m, CH), 6.94 (1H,
D, J=1.6Hz, ArH), 7.20 (1H, dd, J=2.4,2.4Hz, ArH), 7.27-7.37 (5H, m, ArH)；MS (ESI, m/z):
445[M+H]+。
Embodiment 2.I-1 (R1=TBS, X=Cl) preparation
II (X=Cl) 5.4g (15.6mmol) is added in 250ml there-necked flask, dry tetrahydrofuran 54ml is added, it is cooling
To -78 DEG C.Under nitrogen protection, the tetrahydrofuran solution (18.7mmol) of 7.5ml n-BuLi is slowly added dropwise into bottle, drips
Finish, -78 DEG C are continued stirring 20 minutes.Start the tetrahydrofuran solution that 4.7g 4- tert-butyl diformazan silicon oxygen hydroxybutyraldehyde is added dropwise
(23.4mmol), is added dropwise, and -78 DEG C are continued stirring 20 minutes, rise to -40 DEG C of dropwise addition 10ml saturated ammonium chloride solutions, stirs,
It is warmed to room temperature, water is added, is extracted with ethyl acetate 3 times, collect organic phase, washed organic phase 1 time with saturated common salt, organic phase is used
Anhydrous sodium sulfate dries, filters organic phase and is concentrated under reduced pressure to give I-1 crude product, obtains I-1 5.4g, molar yield after column chromatographic purifying
73%, purity 95%.1H-NMR(CDCl3, 400MHz) and δ 0.07-0.09 (6H, m, 2CH3), 0.91-0.92 (9H, m, 3CH3),
1.36 (3H, d, J=4.8Hz, CH3), 1.60-1.69 (2H, m, CH2), 1.74-1.98 (4H, m, 2CH2), 2.70-2.77 (1H,
M, CH), 3.09-3.15 (1H, m, CH), 3.37-3.46 (1H, m, CH), 3.52 (1H, d, J=4.8Hz, OH), 3.63-3.74
(3H, m, CH+CH2), 4.39 (1H, dd, J=4.4,7.6Hz, CH), 4.70-4.82 (2H, m, CH2), 5.11-5.18 (1H, m,
CH), 6.94 (1H, m, ArH), 7.22-7.27 (1H, m, ArH)；MS (ESI, m/z): 469 [M+H]+。
Embodiment 3.I-1 (R1=TBS, X=Br) preparation
II (X=Br) 3.2g (8.2mmol) is added in 100ml there-necked flask, dry tetrahydrofuran 32ml is added, it is cooling
To -78 DEG C.Under nitrogen protection, the tetrahydrofuran solution (9.8mmol) of 3.9ml n-BuLi is slowly added dropwise into bottle, drips
Finish, -78 DEG C are continued stirring 20 minutes.Start the tetrahydrofuran solution that 2.5g 4- tert-butyl diformazan silicon oxygen hydroxybutyraldehyde is added dropwise
(12.3mmol), is added dropwise, and -78 DEG C are continued stirring 20 minutes, rise to -40 DEG C of dropwise addition 10ml saturated ammonium chloride solutions, stirs,
It is warmed to room temperature, water is added, is extracted with ethyl acetate 3 times, collect organic phase, washed organic phase 1 time with saturated common salt, organic phase is used
Anhydrous sodium sulfate dries, filters organic phase, is concentrated under reduced pressure to give I-1 crude product, obtains I-1 2.4g, molar yield after column chromatographic purifying
57%, purity 95%.1H-NMR(CDCl3, 400MHz) and δ 0.07-0.09 (6H, m, 2CH3), 0.91-0.92 (9H, m, 3CH3),
1.36 (3H, d, J=4.8Hz, CH3), 1.60-1.69 (2H, m, CH2), 1.74-1.98 (4H, m, 2CH2), 2.70-2.77 (1H,
M, CH), 3.09-3.15 (1H, m, CH), 3.37-3.46 (1H, m, CH), 3.52 (1H, d, J=4.8Hz, OH), 3.63-3.74
(3H, m, CH+CH2), 4.39 (1H, dd, J=4.4,7.6Hz, CH), 4.70-4.82 (2H, m, CH2), 5.11-5.18 (1H, m,
CH), 6.94 (1H, m, ArH), 7.22-7.27 (1H, m, ArH)；MS (ESI, m/z): 515 [M+H]+。
Embodiment 4.I-1 (R1=TBDPS, X=Cl) preparation
II (X=Cl) 2.2g (6.4mmol) is added in 100ml there-necked flask, dry tetrahydrofuran 22ml is added, it is cooling
To -78 DEG C.Under nitrogen protection, the tetrahydrofuran solution (7.6mmol) of 3.05ml n-BuLi is slowly added dropwise into bottle, drips
Finish, -78 DEG C are continued stirring 20 minutes.Start the tetrahydrofuran solution that 3.11g 4- tert-butyl diphenyl silicon oxygen hydroxybutyraldehyde is added dropwise
(9.5mmol), is added dropwise, and -78 DEG C are continued stirring 20 minutes, rise to -40 DEG C of dropwise addition 10ml saturated ammonium chloride solutions, stirs,
It is warmed to room temperature, water is added, is extracted with ethyl acetate 3 times, collect organic phase, washed organic phase 1 time with saturated common salt, organic phase is used
Anhydrous sodium sulfate dries, filters organic phase, is concentrated under reduced pressure to give I-1 crude product, obtains I-1 2.82g after column chromatographic purifying, mole receipts
Rate 75%, purity 95%.1H-NMR (CDCl3,400MHz) δ 0.91-0.92 (9H, m, 3CH3), 1.36 (3H, d, J=4.8Hz,
CH3), 1.60-1.69 (2H, m, CH2), 1.74-1.98 (4H, m, 2CH2), 2.70-2.77 (1H, m, CH), 3.09-3.15
(1H, m, CH), 3.37-3.46 (1H, m, CH), 3.52 (1H, d, J=4.8Hz, OH), 3.63-3.74 (3H, m, CH+CH2),
4.39 (1H, dd, J=4.4,7.6Hz, CH), 4.70-4.82 (2H, m, CH2), 5.11-5.18 (1H, m, CH), 6.94-7.59
(12H, m, ArH)；MS (ESI, m/z): 593 [M+H]+.
Embodiment 5.I-2 (R1=Bn, R3=Ac, X=Cl) preparation
I-1 14g is added in 100ml single port bottle (31.5mmol comes from embodiment 1)；Pyridine 84ml, under nitrogen protection, to
DMAP 1.15g (9.5mmol) is added in bottle, acetic anhydride 9.65g (94.6mmol) is warming up to 40 DEG C and stirs 3 hours.It is down to room
Temperature is added water, is extracted with dichloromethane 3 times, collects organic phase, is washed organic phase 1 time with saturated common salt, the anhydrous sulphur of organic phase
Sour sodium dries, filters organic phase, and I-2 14.9g, molar yield 97.2%, purity 90%, without purifying are obtained after reduced pressure
Directly carry out next step reaction.1H-NMR(CDCl3, 400MHz) and δ 1.35 (3H, d, J=5.2Hz, CH3), 1.67-1.98 (4H,
M, 2CH2), 2.19 (3H, s, CH3), 2.69-2.76 (1H, m, CH), 3.08-3.14 (1H, m, CH), 3.36-3.55 (4H, m,
2CH2), 3.70 (1H, t, J=10.4Hz, CH), 4.38 (1H, dd, J=4.4,4.4Hz, CH), 4.47-4.50 (1H, m, CH),
4.52 (2H, d, J=2.4Hz, CH2), 4.69-4.79 (2H, m, CH2), 5.10-5.17 (1H, m, CH), 6.94 (1H, d, J=
1.6Hz, ArH), 7.20 (1H, dd, J=2.4,2.4Hz, ArH), 7.27-7.37 (5H, m, ArH)；MS (ESI, m/z): 487 [M
+H]+。
Embodiment 6.I-2 (R1=TBS, R3=Ac, X=Cl) preparation
I-1 5.4g is added in 100ml single port bottle (11.5mmol comes from embodiment 2)；Pyridine 32.4ml, nitrogen protection
Under, DMAP 0.28g (2.2mmol) is added into bottle, acetic anhydride 3.5g (34.5mmol) is warming up to 40 DEG C and stirs 3 hours.Drop
To room temperature, water is added, is extracted with dichloromethane 3 times, collect organic phase, is washed organic phase 1 time with saturated common salt, organic phase nothing
Aqueous sodium persulfate dries, filters organic phase, and I-2 5.8g, molar yield 95.2%, purity 90%, without pure are obtained after reduced pressure
Change and directly carries out next step reaction.1H-NMR(CDCl3, 400MHz) and δ 0.07-0.09 (6H, m, 2CH3), 0.91-0.92 (9H, m,
3CH3), 1.36 (3H, d, J=4.8Hz, CH3), 1.60-1.69 (2H, m, CH2), 1.74-1.98 (4H, m, 2CH2), 2.19
(3H, s, CH3), 2.70-2.77 (1H, m, CH), 3.09-3.15 (1H, m, CH), 3.37-3.46 (1H, m, CH), 3.63-3.74
(3H, m, CH+CH2), 4.39 (1H, dd, J=4.4,7.6Hz, CH), 4.70-4.82 (2H, m, CH2), 5.11-5.18 (1H, m,
CH), 6.94 (1H, m, ArH), 7.22-7.27 (1H, m, ArH)；MS (ESI, m/z): 511 [M+H]+。
Embodiment 7.I-2 (R1=TBS, R3=Ts, X=Br) preparation
I-1 2.4g is added in 100ml single port bottle (4.7mmol comes from embodiment 3)；Methylene chloride 24ml, to toluene sulphur
Acyl chlorides 0.94g (4.9mmol) under nitrogen protection, is added dropwise triethylamine 1.4g (14mmol) into bottle, stirs 12 hours at room temperature,
Water is added, is extracted with dichloromethane 3 times, collects organic phase, is washed organic phase 1 time with saturated common salt, organic phase anhydrous slufuric acid
Sodium dries, filters organic phase, and I-2 2.93g, molar yield 94%, purity 90%, without purifying directly are obtained after reduced pressure
Carry out next step reaction.1H-NMR(CDCl3, 400MHz) and δ 0.07-0.09 (6H, m, 2CH3), 0.91-0.92 (9H, m, 3CH3),
1.36 (3H, d, J=4.8Hz, CH3), 1.60-1.69 (2H, m, CH2), 1.74-1.98 (4H, m, 2CH2), 2.43 (3H, s,
CH3), 2.70-2.77 (1H, m, CH), 3.09-3.15 (1H, m, CH), 3.37-3.46 (1H, m, CH), 3.63-3.74 (3H, m,
CH+CH2), 4.39 (1H, dd, J=4.4,7.6Hz, CH), 4.70-4.82 (2H, m, CH2), 5.11-5.18 (1H, m, CH),
(6.94-7.75 6H, m, ArH)；MS (ESI, m/z): 667 [M+H]+。
Embodiment 8.I-2 (R1=TBDPS, R3=Ts, X=Cl) preparation
I-1 2.82g is added in 100ml single port bottle (4.8mmol comes from embodiment 4)；Methylene chloride 28ml, to toluene sulphur
Acyl chlorides 0.94g (4.9mmol) under nitrogen protection, is added dropwise triethylamine 1.4g (14mmol) into bottle, stirs 12 hours at room temperature,
Water is added, is extracted with dichloromethane 3 times, collects organic phase, is washed organic phase 1 time with saturated common salt, organic phase anhydrous slufuric acid
Sodium dries, filters organic phase, and I-2 3.33g, molar yield 94%, purity 90%, without purifying directly are obtained after reduced pressure
Carry out next step reaction.1H-NMR(CDCl3, 400MHz) and 0.91-0.92 (9H, m, 3CH3), 1.36 (3H, d, J=4.8Hz,
CH3), 1.60-1.69 (2H, m, CH2), 1.74-1.98 (4H, m, 2CH2), 2.43 (3H, s, CH3), 2.70-2.77 (1H, m,
CH), 3.09-3.15 (1H, m, CH), 3.37-3.46 (1H, m, CH), 3.63-3.74 (3H, m, CH+CH2), 4.39 (1H, dd, J
=4.4,7.6Hz, CH), 4.70-4.82 (2H, m, CH2), 5.11-5.18 (1H, m, CH), 6.94-7.75 (16H, m, ArH)；
MS (ESI, m/z): 747 [M+H]+。
Embodiment 9.I-3 (R1=Bn, R3=Ac, X=Cl) preparation
I-2 14.5g is added in 500ml high-pressure hydrogenation kettle (29.6mmol comes from embodiment 5)；Anhydrous sodium acetate
4.9g(59.2mmol)；10% palladium carbon hydrogenation catalyst 3.6g (2.9mmol, it is aqueous 60%)；Methanol 140ml.Pressure limit: 1
~5MPa is stirred 5 hours at room temperature, filters out palladium carbon, and organic phase is concentrated, and water is added, is extracted with ethyl acetate 3 times, is collected organic
Phase is washed organic phase 1 time with saturated common salt, and organic phase dries, filters organic phase with anhydrous sodium sulfate, obtains I- after reduced pressure
3 8.1g, molar yield 90%, purity 98%.1H-NMR(CDCl3, 400MHz) and δ 1.36 (3H, d, J=5.2Hz, CH3),
1.56-2.06 (7H, m, CH2), 2.59 (2H, t, J=7.6Hz, CH2), 2.71-2.78 (1H, m, CH), 3.13-3.18 (1H, m,
CH), 3.39-3.46 (1H, m, CH), 3.64-3.75 (3H, m, CH2), 4.39 (1H, dd, J=4.4,4.0Hz, CH), 4.71-
4.74 (1H, m, OH), 5.08-5.13 (1H, m, CH), 6.77 (1H, t, J=8.0Hz, ArH), 6.93 (1H, d, J=7.2Hz,
ArH), 6.97 (1H, d, J=7.6Hz, ArH)；MS (ESI, m/z): 305 [M+H]+。
Embodiment 10.I-3 (R1=TBS, R3=Ac, X=Cl) preparation
I-2 5.8g is added in 250ml high-pressure hydrogenation kettle (11.3mmol comes from embodiment 6)；Anhydrous sodium acetate
1.9g(22.7mmol)；10% palladium carbon hydrogenation catalyst 1.5g (1.1mmol, it is aqueous 60%)；Methanol 60ml.Pressure limit: 1~
5MPa is stirred 5 hours at room temperature, filters out palladium carbon, and organic phase is concentrated, and water is added, is extracted with ethyl acetate 3 times, collects organic phase,
It is washed organic phase 1 time with saturated common salt, organic phase dries, filters organic phase with anhydrous sodium sulfate, obtains after reduced pressure colourless
Tetrahydrofuran 60ml is added in grease；Tetrabutyl ammonium fluoride 5.9g (22.6mmol), is stirred overnight at room temperature.Water is added, uses second
Acetoacetic ester extracts 3 collection organic phases, is washed organic phase 1 time with saturated common salt, organic phase has been dried, filtered with anhydrous sodium sulfate
Machine phase obtains I-3 3g, molar yield 87%, purity 98% after reduced pressure.1H-NMR(CDCl3, 400MHz) δ 1.36 (3H,
D, J=5.2Hz, CH3), 1.56-2.06 (7H, m, CH2), 2.59 (2H, t, J=7.6Hz, CH2), 2.71-2.78 (1H, m,
CH), 3.13-3.18 (1H, m, CH), 3.39-3.46 (1H, m, CH), 3.64-3.75 (3H, m, CH2), 4.39 (1H, dd, J=
4.4,4.0Hz, CH), 4.71-4.74 (1H, m, OH), 5.08-5.13 (1H, m, CH), 6.77 (1H, t, J=8.0Hz, ArH),
6.93 (1H, d, J=7.2Hz, ArH), 6.97 (1H, d, J=7.6Hz, ArH)；MS (ESI, m/z): 305 [M+H]+。
The preparation of embodiment 11.I-3 (R1=TBS, R3=Ts, X=Br)
I-2 2.93g is added in 100ml high-pressure hydrogenation kettle (4.4mmol comes from embodiment 7)；Anhydrous sodium acetate
0.7g(8.8mmol)；10% palladium carbon hydrogenation catalyst 0.7g (1.1mmol, it is aqueous 60%)；Methanol 30ml.Pressure limit: 1~
5MPa is stirred 5 hours at room temperature, filters out palladium carbon, and organic phase is concentrated, and water is added, is extracted with ethyl acetate 3 times, collects organic phase,
It is washed organic phase 1 time with saturated common salt, organic phase dries, filters organic phase with anhydrous sodium sulfate, obtains after reduced pressure colourless
Tetrahydrofuran 30ml is added in grease；Tetrabutyl ammonium fluoride 2.3g (8.8mmol), is stirred overnight at room temperature.Water is added, uses second
Acetoacetic ester extracts 3 collection organic phases, is washed organic phase 1 time with saturated common salt, organic phase has been dried, filtered with anhydrous sodium sulfate
Machine phase obtains I-3 1.16g, molar yield 87%, purity 98% after reduced pressure.1H-NMR(CDCl3, 400MHz) and δ 1.36
(3H, d, J=5.2Hz, CH3), 1.56-2.06 (7H, m, CH2), 2.59 (2H, t, J=7.6Hz, CH2), 2.71-2.78 (1H,
M, CH), 3.13-3.18 (1H, m, CH), 3.39-3.46 (1H, m, CH), 3.64-3.75 (3H, m, CH2), 4.39 (1H, dd, J
=4.4,4.0Hz, CH), 4.71-4.74 (1H, m, OH), 5.08-5.13 (1H, m, CH), 6.77 (1H, t, J=8.0Hz,
ArH), 6.93 (1H, d, J=7.2Hz, ArH), 6.97 (1H, d, J=7.6Hz, ArH)；MS (ESI, m/z): 305 [M+H]+。
The preparation of embodiment 12.I-3 (R1=TBDPS, R3=Ts, X=Cl)
I-2 3.33g is added in 100ml high-pressure hydrogenation kettle (4.4mmol comes from embodiment 8)；Anhydrous sodium acetate
0.7g(8.8mmol)；10% palladium carbon hydrogenation catalyst 0.7g (1.1mmol, it is aqueous 60%)；Methanol 30ml.Pressure limit: 1~
5MPa is stirred 5 hours at room temperature, filters out palladium carbon, and organic phase is concentrated, and water is added, is extracted with ethyl acetate 3 times, collects organic phase,
It is washed organic phase 1 time with saturated common salt, organic phase dries, filters organic phase with anhydrous sodium sulfate, obtains after reduced pressure colourless
Tetrahydrofuran 30ml is added in grease；Tetrabutyl ammonium fluoride 2.3g (8.8mmol), is stirred overnight at room temperature.Water is added, uses second
Acetoacetic ester extracts 3 collection organic phases, is washed organic phase 1 time with saturated common salt, organic phase has been dried, filtered with anhydrous sodium sulfate
Machine phase obtains I-3 1.0g, molar yield 75%, purity 98% after reduced pressure.1H-NMR(CDCl3, 400MHz) and δ 1.36
(3H, d, J=5.2Hz, CH3), 1.56-2.06 (7H, m, CH2), 2.59 (2H, t, J=7.6Hz, CH2), 2.71-2.78 (1H,
M, CH), 3.13-3.18 (1H, m, CH), 3.39-3.46 (1H, m, CH), 3.64-3.75 (3H, m, CH2), 4.39 (1H, dd, J
=4.4,4.0Hz, CH), 4.71-4.74 (1H, m, OH), 5.08-5.13 (1H, m, CH), 6.77 (1H, t, J=8.0Hz,
ArH), 6.93 (1H, d, J=7.2Hz, ArH), 6.97 (1H, d, J=7.6Hz, ArH)；MS (ESI, m/z): 305 [M+H]+。
Embodiment 13.IV:4- (trans- -3- methyl-1 of 4a, 5a, 10b- cis- -4a, 10c-, 4a, 5,5a, 10b, 10c- six
Hydrogen two dislikes simultaneously [5,4-a] cyclopentano [b] benzofuran -7- base) preparation of butyric acid
I-3 12g (39.5mmol) is added in 1L single port bottle, acetonitrile 200ml is saturated potassium dihydrogen phosphate aqueous solution 200ml,
TEMPO 0.74g (4.7mmol), 14.5% aqueous sodium hypochlorite solution 28.4ml (55.3mmol), 80% sodium chlorite 8.9g
(79mmol).It stirs 3 hours at room temperature.Water is added, stirring is added ethyl acetate and extracts 3 times, collect organic phase, saturation is added
Hypo solution cleans 1 time, and water is added and cleans 1 time, and saturated salt solution cleans 1 time, and organic phase is dry with anhydrous sodium sulfate,
Organic phase is filtered, intermediate compound IV 11g, molar yield 91%, purity 97% are obtained after reduced pressure.1H-NMR(CDCl3,
400MHz) 1.36 (3H, d, J=5.2Hz, CH of δ3), 1.80-2.05 (4H, m, 2CH2), 2.37 (2H, t, J=15.2Hz, CH2),
2.56-2.66 (2H, m, CH2), 2.70-2.77 (1H, m, CH), 3.13-3.18 (1H, m, CH2), 3.39-3.46 (1H, m,
CH2), 3.68-3.75 (1H, m, CH), 4.41 (1H, dd, J=4.4,4.4Hz, CH), 4.71-4.75 (1H, m, CH), 5.08-
5.13 (1H, m, CH), 6.76-6.80 (1H, m, ArH), 6.90-6.98 (2H, m, ArH)；MS (ESI, m/z): 317 [M-H]-。
The preparation of embodiment 14. V
IV 11g (34.6mmol comes from embodiment 13), DMF110ml, potassium carbonate 14.32g are added in 250ml single port bottle
(103.7mmol) and iodomethane 9.8g (69.18mmol).It stirs 3 hours at room temperature, water is added, ethyl acetate extracts anhydrous sulphur
It is concentrated to give V crude product after sour sodium is dry, column purification is crossed and obtains white solid: 10.5g, molar yield: 91.6%, purity: 94%.1H-NMR(CDCl3, 400MHz) and δ 1.86-2.17 (5H, m, 2CH2+ OH), 2.30-2.34 (2H, m, CH2), 2.51-2.63 (4H,
M, CH2+ CH+OH), 3.41-3.45 (1H, m, CH2), 3.67 (3H, s, CH3), 3.68-3.78 (1H, m, CH2), 3.86-3.90
(1H, m, CH), 4.08-4.14 (1H, m, CH), 5.13-5.18 (1H, m, CH), 6.93 (1H, t, J=7.2Hz, ArH), 7.21-
7.28 (2H, m, ArH)；MS (ESI, m/z): 333 [M+H]-。
The preparation of embodiment 15. VI
V 10.5g (31.6mmol comes from embodiment 14), methanol 100ml, 1M HCl are added in 250ml single port bottle
15ml is stirred 5 hours at room temperature, and methanol is concentrated, and water is added, and ethyl acetate extraction is concentrated after anhydrous sodium sulfate is dry.It is pure to cross column
Change obtains VI 9.6g.Molar yield: 99%, purity: 95%.1H-NMR(CDCl3, 400MHz) δ 1.37 (3H, d, J=5.2Hz,
CH3), 1.81-2.00 (4H, m, 2CH2), 2.31-2.35 (2H, m, CH2), 2.55-2.63 (2H, m, CH2), 2.71-2.78
(1H, m, CH), 3.13-3.18 (1H, m, CH2), 3.40-3.47 (1H, m, CH2), 3.66 (3H, s, CH3), 3.67-3.76 (1H,
M, CH), 4.39-4.42 (1H, m, CH), 4.71-4.75 (1H, m, CH), 5.08-5.14 (1H, m, CH), 6.78 (1H, t, J=
7.2Hz, ArH), 6.90-6.98 (2H, m, ArH)；MS (ESI, m/z): 333 [M+H]-。
16. VII (R of embodiment4=Ac) preparation
V 1.74g (5.68mmol comes from embodiment 15) is added in 250ml single port bottle and is dissolved in the dry tetrahydrofuran of 25ml
In, dry triethylamine 2.86mL (20.4mmol) and triphenylchloromethane 2.87g (10.29mmol) is added, is stirred at 60 DEG C
React 6h.Acetic anhydride 7.41mL (78.4mmol) is added after being cooled to room temperature and refines pyridine 5.9mL (73.3mmol), at 50 DEG C
It is stirred to react 14h.Ice bath is cooling, and the methanol hydrochloride solution tune pH to 1 of 15mL3.7mol/L is added dropwise, and reaction 6h is stirred at room temperature.Ice
Under bath, it is slowly added to sodium bicarbonate 1g tune pH to 6, is concentrated, water, dilute hydrochloric acid, saturated common salt washing are successively used in ethyl acetate dissolution
It washs, anhydrous sodium sulfate dries, filters, and after concentration, is purified by silica gel column chromatography to obtain VII 1.19g of colorless oil compound, mole receipts
Rate: 60.1%.Purity 97%.1H-NMR(CDCl3, 400MHz): δ 1.83 (3H, s, CH3), 1.92-1.96 (2H, m, CH2),
2.20-2.29 (2H, m, CH2), 2.33-2.36 (2H, m, CH2), 2.53-2.63 (3H, m, CH2+ CH), 3.66 (4H, m, CH3+
CH), 3.67-3.72 (2H, m, CH2), 5.05-5.09 (1H, m, CH), 5.17-5.22 (1H, m, CH), 6.77 (1H, t, J=
8.0Hz, ArH), 6.94 (1H, d, J=8.0Hz, ArH), 7.03 (1H, d, J=8.0Hz, ArH)；MS (ESI, m/z): 349 [M+
H]+。
17. Ⅸ (R of embodiment4=Ac) preparation
In 100ml single port bottle, VII 1.19g of compound (3.4mmol, from embodiment 16) is dissolved in the tetrahydro of 20mL purification
It in furans, sequentially adds dimethyl sulfoxide 3.65mL (51.4mmol), pyridine 55.5 μ L (0.69mmol), 51.5 μ L of trifluoroacetic acid
(0.69mmol) and DCC 0.85g (4.13mmol), nitrogen protection are stirred to react 10h at room temperature, chemical combination are added after ice bath is cooling
The tetrahydrofuran solution 15mL of VIII 1.065g of object (4.59mmol) and 60%NaH 178mg (4.45mmol) are stirred under ice bath anti-
10min is answered, is warmed to room temperature, 3h is stirred to react.Acetic acid 0.26mL tune pH to 6 is added dropwise in mixture, and 50mL ethyl acetate is added in concentration
Dissolution, saturated common salt water washing, anhydrous sodium sulfate dries, filters, and after concentration, is purified by silica gel column chromatography to obtain colorless oil chemical combination
Object 1.1g, molar yield: 71.16%, purity: 97%.1H-NMR (400MHz, CDCl3) δ 1.21 (3H, d, J=7.6Hz,
CH3), 1.76-1.78 (6H, m, CH3+CH2+ CH), 1.90-1.98 (2H, m, CH2), 2.13-2.17 (1H, m, CH2), 2.26
(1H, dd, J=6.0Hz, 16.4Hz, CH2), 2.35 (2H, t, J=7.6Hz, CH2), 2.56-2.59 (1H, m, CH), 2.60-
2.67 (3H, m, CH2+ CH), 2.90-2.97 (2H, m, CH2), 3.66 (3H, s, CH3), 3.66-3.69 (1H, m, CH), 4.99-
5.02 (1H, m, CH), 5.23-5.24 (1H, m, CH), 6.29 (1H, dd, J=5.6Hz, 15.6Hz, CH), 6.75-6.86 (2H,
M, ArH), 6.94-6.97 (2H, m, ArH)；MS (ESI, m/z): 453 [M+H]+。
The preparation of embodiment 18. Ⅹ
In 100ml single port bottle, by Ⅸ 600mg of compound (1.33mmol comes from embodiment 17) and cerium chloride seven-hydrate 737mg
(1.97mmol) is dissolved in 50mL methanol, and sodium borohydride 73.7mg (1.97mmol) is added at 0 DEG C, after being stirred to react 30min, adds
Enter saturated sodium bicarbonate solution 10mL, is stirred to react 30min at 0 DEG C.100mL ethyl acetate, saturated common salt is added in filtering, concentration
Water washing, anhydrous sodium sulfate dry, filter, and after concentration, are purified by silica gel column chromatography to obtain colorless oil mixture 574mg.It is dissolved in
50mL is refined in methanol, and the methanol solution of 200 μ L1.8mol/L sodium methoxides is added.It is stirred to react 8h at room temperature, 25 μ L are added
50mL ethyl acetate, saturated common salt water washing is added in CH3COOH tune pH to 7 after concentration, anhydrous sodium sulfate dries, filters, and is concentrated
Afterwards, it is purified by silica gel column chromatography to obtain Ⅹ 240mg of oily compound, molar yield: 43.9%, purity 99%.1H NMR(CDCl3,
400MHz): δ 0.98-1.02 (3H, m, CH3), 1.74-1.79 (4H, m, CH3+ CH), 1.90-2.12 (4H, m, 2CH2), 2.24-
2.25 (1H, m, CH), 2.32 (2H, t, J=7.2Hz, CH2), 2.41 (1H, t, J=8.0Hz, CH), 2.58-2.68 (3H, m,
CH2+ CH), 3.42 (1H, m, CH), 3.64 (3H, s, CH3), 3.89-4.00 (1H, m, CH), 4.03-4.15 (1H, m, CH),
5.07-5.10 (1H, m, CH), 5.58-5.67 (2H, m, CH2), 6.74-6.78 (1H, m, ArH), 6.94 (2H, t, J=
7.2Hz, ArH)；MS (ESI, m/z): 413 [M+H]+。
The preparation of 19. Ⅺ beraprost sodium of embodiment
In 100ml single port bottle, Ⅹ 240mg (0.06mmol comes from embodiment 18) is added and is dissolved in 24mL methanol, is added
The NaOH aqueous solution of 6mL1mol/L, 30 DEG C are stirred to react 18h.10mL water is added, after concentration, uses 0.1mol/L under ice bath
HCl tune pH to 4, ethyl acetate extraction, saturated common salt water washing, anhydrous sodium sulfate dries, filters, after concentration, through silica gel column layer
Analyse compound 180mg (0.45mmol) is dissolved in 10mL tri-distilled water by white solid, be added 0.45mL 1mol/L NaOH it is molten
Liquid is stirred to react 30min under ice bath, and pH is 7~8 at this time, and beraprost sodium 175mg, molar yield: 92.6% is lyophilized to obtain.It is pure
Degree 99%.1H-NMR (d-DMSO, 400MHz) δ 0.92 (3H, d, J=6.4Hz, CH3), 1.57-1.79 (8H, m, CH3+2CH2+
CH), 1.98-2.05 (1H, m, CH), 2.13-2.21 (4H, m, 2CH2), 2.24-2.30 (1H, m, CH), 3.70-3.82 (2H,
M, CH2), 4.72-4.79 (2H, m, 2CH), 5.01-5.06 (1H, m, CH), 5.43-5.48 (1H, m, CH=CH), 5.61-
5.67 (1H, m, CH=CH), 6.73 (1H, t, J=7.6Hz, ArH), 6.91-6.93 (2H, m, ArH)；MS (ESI, m/z): 399
[M-Na+H]+。
In conclusion the present invention effectively overcomes various shortcoming in the prior art and has high industrial utilization value.
The above-described embodiments merely illustrate the principles and effects of the present invention, and is not intended to limit the present invention.It is any ripe
The personage for knowing this technology all without departing from the spirit and scope of the present invention, carries out modifications and changes to above-described embodiment.Cause
This, institute is complete without departing from the spirit and technical ideas disclosed in the present invention by those of ordinary skill in the art such as
At all equivalent modifications or change, should be covered by the claims of the present invention.
Claims (41)
1. a kind of intermediate, which is characterized in that the structure of the intermediate is as shown in general formula I-1:
Wherein, R1Selected from benzyl, t-butyldimethylsilyi or tert-butyldiphenylsilanyl；X is selected from Br or Cl.
2. intermediate as described in claim 1, which is characterized in that the intermediate is selected from the group compound:
3. a kind of intermediate, which is characterized in that the structure of the intermediate is as shown in general formula I-2:
Wherein, R1Selected from benzyl, t-butyldimethylsilyi or tert-butyldiphenylsilanyl；R3Selected from acetyl group or to first
Benzenesulfonyl；X is selected from Br or Cl.
4. intermediate as claimed in claim 3, which is characterized in that the intermediate is selected from the group compound:
5. a kind of intermediate, which is characterized in that the structural formula of the intermediate is as shown in Formulas I -3:
6. a kind of preparation method of intermediate as claimed in claim 1 or 2, which is characterized in that by Formula II compound and formula III
Under the effect of the catalyst, reaction prepares compound, and reaction equation is as follows:
7. the preparation method of intermediate as claimed in claim 6, which is characterized in that Formula II compound, catalyst and formula III
The molar ratio for closing object is 1:1~1.2:1.2~3.
8. the preparation method of intermediate as claimed in claim 6, which is characterized in that the catalyst is n-BuLi or Zhong Ding
Base lithium.
9. the preparation method of intermediate as claimed in claim 6, which is characterized in that Formula II compound is dissolved in organic solvent,
Catalyst is added dropwise under inert gas protection in cooling, and the organic solution of formula III compound is then added dropwise, and reaction prepares formula
I-1 compound.
10. the preparation method of the intermediate as described in claim 6 or 9, which is characterized in that further include point of -1 compound of Formulas I
From purification step: heating up after reaction, saturated ammonium chloride solution is added, water is then added, and be extracted with ethyl acetate, separate
Organic phase is obtained, then with after saturated common salt water washing, is dried, is filtered with anhydrous sodium sulfate, be concentrated under reduced pressure, obtain Formulas I-
1 compound.
11. the preparation method of intermediate as claimed in claim 9, which is characterized in that the body of organic solvent and Formula II compound
Product is than being 8~15:1.
12. the preparation method of intermediate as claimed in claim 9, which is characterized in that the organic solution of the formula III compound
Middle organic solvent is tetrahydrofuran, toluene or ether.
13. the preparation method of intermediate as claimed in claim 9, which is characterized in that the reaction time is 10 after catalyst is added dropwise
~30 minutes.
14. the preparation method of intermediate as claimed in claim 9, which is characterized in that the organic solution of formula III compound is added dropwise
The reaction time is 10~60 minutes afterwards.
15. the preparation method of intermediate as claimed in claim 9, which is characterized in that the organic solvent is tetrahydrofuran, first
Benzene or ether.
16. the preparation method of intermediate as claimed in claim 9, which is characterized in that the temperature that is cooled to is -60~-80
℃。
17. a kind of preparation method of intermediate as described in claim 3 or 4, which is characterized in that by -1 compound of Formulas I through second
Acylated or tosylation prepares, and reaction equation is as follows:
18. the preparation method of intermediate as claimed in claim 17, which is characterized in that the acylating agent is for acetic anhydride or to first
Benzene sulfonyl chloride.
19. the preparation method of intermediate as claimed in claim 17, which is characterized in that reaction temperature is 20~50 DEG C.
20. the preparation method of intermediate as claimed in claim 17, which is characterized in that the reaction time is 8~24 hours.
21. the preparation method of intermediate as claimed in claim 17, which is characterized in that -1 compound of Formulas I is dissolved in organic solvent
In, acylating agent is added, adds 4-dimethylaminopyridine, reaction prepares -2 compound of Formulas I.
22. the preparation method of intermediate as claimed in claim 21, which is characterized in that -1 compound of Formulas I, organic solvent, acyl
The molar ratio of agent and 4-dimethylaminopyridine is 1:5~10:2~5:0.1~2.
23. the preparation method of the intermediate as described in claim 17 or 21, which is characterized in that further include -2 compound of Formulas I
Purification procedures: cooling down after reaction, water is added, and be extracted with dichloromethane, and separation obtains organic phase, then with saturation
It after brine It, is dried with anhydrous sodium sulfate, filters, obtain -2 compound of Formulas I.
24. the preparation method of intermediate as claimed in claim 21, which is characterized in that the organic solvent is pyridine.
25. a kind of preparation method of intermediate as claimed in claim 5, which is characterized in that add hydrogen by -2 compound for catalysis of Formulas I
It prepares, reaction equation is as follows:
26. the preparation method of intermediate as claimed in claim 25, which is characterized in that the reaction time is 3~18 hours.
27. the preparation method of intermediate as claimed in claim 25, which is characterized in that reaction relative pressure is 1~5MPa.
28. the preparation method of intermediate as claimed in claim 25, which is characterized in that -2 compound of Formulas I is dissolved in organic solvent
In, anhydrous sodium acetate and catalyst is added, hydrogen hydrogenation is added to prepare -3 compound of Formulas I.
29. the preparation method of intermediate as claimed in claim 28, which is characterized in that -2 compound of Formulas I, anhydrous sodium acetate,
The molar ratio of catalyst is 1:2~5:0.1~0.5.
30. the preparation method of intermediate as claimed in claim 28, which is characterized in that the catalyst is 5% or 10% palladium
Carbon.
31. the preparation method of the intermediate as described in claim 25 or 28, which is characterized in that further include -3 compound of Formulas I
Purification procedures: filtering out catalyst after reaction, and organic phase is concentrated, and water is added, and be extracted with ethyl acetate, and separation obtains
Organic phase is dried then with after saturated common salt water washing with anhydrous sodium sulfate, is filtered, is concentrated under reduced pressure to give -3 chemical combination of Formulas I
Object.
32. the preparation method of intermediate as claimed in claim 28, which is characterized in that the organic solvent is selected from methanol, second
One of alcohol, isopropanol, ethyl acetate and tetrahydrofuran are a variety of.
33. a kind of preparation method of formula IV compound, which is characterized in that including step d): being obtained by the preparation of -3 compound oxidation of Formulas I
Formula IV compound is obtained, reaction equation is as follows:
34. the preparation method of formula IV compound as claimed in claim 33, which is characterized in that the reaction time is 1~5 hour.
35. the preparation method of formula IV compound as claimed in claim 33, which is characterized in that -3 compound of Formulas I is dissolved in second
In nitrile and saturation potassium dihydrogen phosphate aqueous solution, tetramethyl piperidine, aqueous sodium hypochlorite solution and sodium chlorite is added, reaction preparation obtains
Obtain formula IV compound.
36. the preparation method of formula IV compound as claimed in claim 35, which is characterized in that -3 compound of Formulas I, acetonitrile, phosphorus
Acid dihydride potassium, tetramethyl piperidine, sodium hypochlorite sodium chlorite molar ratio be 1:5~20:5~20:0.1~0.5:1~3:1~
3。
37. the preparation method of formula IV compound as claimed in claim 35, which is characterized in that the concentration of aqueous sodium hypochlorite solution
It is 6~14.5%.
38. the preparation method of formula IV compound as claimed in claim 35, which is characterized in that the concentration of sodium chlorite be 80~
100%.
39. the preparation method of the formula IV compound as described in claim 33 or 35, which is characterized in that further include formula IV compound
Purification procedures: water is added after reaction, and is extracted with ethyl acetate, separation obtains organic phase, then successively with full
It after hypo solution, water and saturated common salt water washing, is dried with anhydrous sodium sulfate, filters, be concentrated under reduced pressure to give
Formula IV compound.
40. the preparation method of formula IV compound as claimed in claim 33, which is characterized in that the preparation method is in step d)
Before further include following steps:
Step a): under the effect of the catalyst by Formula II compound and formula III compound, reaction prepares -1 compound of Formulas I,
Its reaction equation is as follows:
Step b): -1 compound of Formulas I is prepared into -2 compound of Formulas I, reactional equation through acetylation or tosylation
Formula is as follows:
Step c): hydrogen is added to prepare -3 compound of Formulas I -2 compound for catalysis of Formulas I, reaction equation is as follows:
Wherein, R1Selected from benzyl, t-butyldimethylsilyi or tert-butyldiphenylsilanyl；R3Selected from acetyl group or to first
Benzenesulfonyl；X is selected from Br or Cl.
41. as intermediate described in any one of claim 1 to 5 is used to prepare beraprost and its salt.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0084856A1 (en) * | 1982-01-20 | 1983-08-03 | Toray Industries, Inc. | 5,6,7-Trinor-4, 8-inter-m-phenylene prostaglandin I2 derivatives |
-
2016
- 2016-09-26 CN CN201610851108.0A patent/CN106632372B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0084856A1 (en) * | 1982-01-20 | 1983-08-03 | Toray Industries, Inc. | 5,6,7-Trinor-4, 8-inter-m-phenylene prostaglandin I2 derivatives |
Non-Patent Citations (2)
| Title |
|---|
| Catalytic asymmetric formal synthesis of beraprost;Yusuke Kobayashi et al.;《Beilstein J. Org. Chem.》;20151218;第11卷;第2654–2660页，第2655页Scheme 1,第2658页Scheme 4 |
| 贝前列素钠的合成及工艺研究;侯大龙;《中国优秀硕士学位论文全文数据库 医药卫生科技辑》;20150815;第E079-36页，正文第11页路线2.1，第19页第2.3.2.2-2.3.2.3节 |
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