CN102875340A - Sarpogrelate intermediate and preparation method thereof - Google Patents
Sarpogrelate intermediate and preparation method thereof Download PDFInfo
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- CN102875340A CN102875340A CN201110194204XA CN201110194204A CN102875340A CN 102875340 A CN102875340 A CN 102875340A CN 201110194204X A CN201110194204X A CN 201110194204XA CN 201110194204 A CN201110194204 A CN 201110194204A CN 102875340 A CN102875340 A CN 102875340A
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- 229950005789 sarpogrelate Drugs 0.000 title abstract description 31
- 238000002360 preparation method Methods 0.000 title abstract description 19
- FFYNAVGJSYHHFO-UHFFFAOYSA-N sarpogrelate Chemical compound COC1=CC=CC(CCC=2C(=CC=CC=2)OCC(CN(C)C)OC(=O)CCC(O)=O)=C1 FFYNAVGJSYHHFO-UHFFFAOYSA-N 0.000 title abstract 4
- 238000006243 chemical reaction Methods 0.000 claims abstract description 81
- 238000000034 method Methods 0.000 claims abstract description 25
- 150000004795 grignard reagents Chemical class 0.000 claims abstract description 23
- 238000003747 Grignard reaction Methods 0.000 claims abstract description 17
- 239000007818 Grignard reagent Substances 0.000 claims abstract description 15
- 150000001875 compounds Chemical class 0.000 claims abstract description 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 40
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 30
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 27
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 20
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical group [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 17
- 239000011777 magnesium Substances 0.000 claims description 17
- 229910052749 magnesium Inorganic materials 0.000 claims description 17
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 15
- 230000035484 reaction time Effects 0.000 claims description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 7
- 229910052736 halogen Inorganic materials 0.000 claims description 7
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical group [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 229910052725 zinc Chemical group 0.000 claims description 4
- 239000011701 zinc Chemical group 0.000 claims description 4
- 235000019270 ammonium chloride Nutrition 0.000 claims description 3
- 150000002367 halogens Chemical group 0.000 claims description 3
- 239000000010 aprotic solvent Substances 0.000 claims 2
- PBEJTRAJWCNHRS-UHFFFAOYSA-N 2-phenylmethoxybenzaldehyde Chemical compound O=CC1=CC=CC=C1OCC1=CC=CC=C1 PBEJTRAJWCNHRS-UHFFFAOYSA-N 0.000 claims 1
- 150000002148 esters Chemical class 0.000 claims 1
- 238000004128 high performance liquid chromatography Methods 0.000 abstract description 19
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 abstract description 10
- SMQUZDBALVYZAC-UHFFFAOYSA-N salicylaldehyde Chemical compound OC1=CC=CC=C1C=O SMQUZDBALVYZAC-UHFFFAOYSA-N 0.000 abstract description 6
- 238000001514 detection method Methods 0.000 abstract description 4
- 238000005265 energy consumption Methods 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 3
- 238000011031 large-scale manufacturing process Methods 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 45
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 41
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 33
- POQBIDFFYCYHOB-UHFFFAOYSA-N Sarpogrelate hydrochloride Chemical compound Cl.COC1=CC=CC(CCC=2C(=CC=CC=2)OCC(CN(C)C)OC(=O)CCC(O)=O)=C1 POQBIDFFYCYHOB-UHFFFAOYSA-N 0.000 description 28
- 239000000543 intermediate Substances 0.000 description 28
- 239000000047 product Substances 0.000 description 26
- 238000005406 washing Methods 0.000 description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 17
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 16
- 239000002904 solvent Substances 0.000 description 16
- WMPDAIZRQDCGFH-UHFFFAOYSA-N 3-methoxybenzaldehyde Chemical compound COC1=CC=CC(C=O)=C1 WMPDAIZRQDCGFH-UHFFFAOYSA-N 0.000 description 14
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 12
- 238000001035 drying Methods 0.000 description 12
- 238000000967 suction filtration Methods 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- 239000011630 iodine Substances 0.000 description 10
- 229910052740 iodine Inorganic materials 0.000 description 10
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 239000007788 liquid Substances 0.000 description 9
- 239000012044 organic layer Substances 0.000 description 9
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- 229940073608 benzyl chloride Drugs 0.000 description 8
- -1 ester hydrochloride Chemical class 0.000 description 8
- 238000003810 ethyl acetate extraction Methods 0.000 description 8
- 239000005457 ice water Substances 0.000 description 8
- 238000010907 mechanical stirring Methods 0.000 description 8
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 239000002253 acid Substances 0.000 description 7
- 238000009413 insulation Methods 0.000 description 7
- 239000003960 organic solvent Substances 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 6
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- 238000010792 warming Methods 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 5
- 238000005984 hydrogenation reaction Methods 0.000 description 5
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- FIQMHBFVRAXMOP-UHFFFAOYSA-N triphenylphosphane oxide Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=O)C1=CC=CC=C1 FIQMHBFVRAXMOP-UHFFFAOYSA-N 0.000 description 5
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 229960001701 chloroform Drugs 0.000 description 4
- 239000003999 initiator Substances 0.000 description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 229910000033 sodium borohydride Inorganic materials 0.000 description 4
- 239000012279 sodium borohydride Substances 0.000 description 4
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 4
- 238000001291 vacuum drying Methods 0.000 description 4
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- LRWZZZWJMFNZIK-UHFFFAOYSA-N 2-chloro-3-methyloxirane Chemical compound CC1OC1Cl LRWZZZWJMFNZIK-UHFFFAOYSA-N 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000007239 Wittig reaction Methods 0.000 description 3
- 230000002785 anti-thrombosis Effects 0.000 description 3
- 150000001555 benzenes Chemical class 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 230000006837 decompression Effects 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000010828 elution Methods 0.000 description 3
- 238000004896 high resolution mass spectrometry Methods 0.000 description 3
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 238000004949 mass spectrometry Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 229910052763 palladium Inorganic materials 0.000 description 3
- 238000007670 refining Methods 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 235000002639 sodium chloride Nutrition 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 3
- 238000012546 transfer Methods 0.000 description 3
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000006297 dehydration reaction Methods 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 230000002140 halogenating effect Effects 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 description 2
- 235000015320 potassium carbonate Nutrition 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000004321 preservation Methods 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- 235000017550 sodium carbonate Nutrition 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- 208000033386 Buerger disease Diseases 0.000 description 1
- RVFBSKYKYQEBTR-UHFFFAOYSA-N COc1cccc(CC(c2ccccc2OCC2C=CC=CC2)O)c1 Chemical compound COc1cccc(CC(c2ccccc2OCC2C=CC=CC2)O)c1 RVFBSKYKYQEBTR-UHFFFAOYSA-N 0.000 description 1
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 1
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical group COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 206010043540 Thromboangiitis obliterans Diseases 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 238000006856 Wolf-Kishner-Huang Minlon reduction reaction Methods 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000007806 chemical reaction intermediate Substances 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 238000005352 clarification Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 210000003608 fece Anatomy 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 239000002223 garnet Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910000039 hydrogen halide Inorganic materials 0.000 description 1
- 239000012433 hydrogen halide Substances 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000003215 serotonin 5-HT2 receptor antagonist Substances 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 125000005504 styryl group Chemical group 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a sarpogrelate intermediate and a preparation method thereof. The sarpogrelate intermediate is a compound shown as formula VI. The preparation method of the intermediate comprises a Grignard reaction of salicylic aldehyde with phenolic groups protected and a Grignard reagent. The method is mild in reaction conditions, low in energy consumption and small in pollutions, and has relatively high conversion rate and low cost of the raw materials. The obtained sarpogrelate hydrochloride has high purity with the detection purity of HPLC higher than 99%. The method is suitable for large-scale production conversion.
Description
Technical field
The invention belongs to the field of chemical synthesis of medicine, in particular to a kind of Sarpogrelate intermediate and preparation method thereof.
Background technology
Sarpogrelatehydrochloride (Sarpogrelate Hydrochloride, its chemical structural formula is shown in I), chemistry is by name: Succinic Acid list [2-(dimethylin)-1-[[2-[2-(3-p-methoxy-phenyl) ethyl] phenoxy group] methyl] ethyl] ester hydrochloride, CAS numbering: 135159-51-2.This medicine is 5-HT2 receptor antagonist and the platelet aggregation antagonist of Japanese Mitsubishi Tanabe Pharma company research and development, 1993 first at Japan's listing, the clinical ischemia symptoms such as chronic thromboangiitis obliterans that are mainly used in improving with ulcer, pain and creeping chill.
Existing document about Sarpogrelatehydrochloride mainly contains: 1) US Patent No. 4485258; 2) the open CN101239920A of Chinese patent application; 3) the open CN1824647A of Chinese patent application; 4) Wang Sheng and Chen Guohua, " synthesizing of Sarpogrelatehydrochloride ", Chinese Journal of Pharmaceuticals, 12 phases of 39 volumes in 2008; 5) people such as Kikumoto, " phenyl of Syntheses and platelet aggregation inhibitory and antithrombotic properties of[2-[(ω-aminoalkoxy)] ethyl] benzenes. ", J.Med.Chem., 1990,33:1818-1823; 6) Zhang Faxiang, " through the novel synthesis of the Sarpogrelatehydrochloride of Weinreb acid amides ", Shenyang Pharmaceutical University's master thesis in 2005, classification number TQ463.2.
Wherein, document 1 (US4485258) has directly adopted the intermediate 2-shown in the following formula ((3-methoxyl group) styroyl), and phenol is starting raw material, and the synthetic method of not mentioned this key intermediate.
Document 5 (the people such as Kikumoto, " phenyl of Syntheses and platelet aggregation inhibitory and antithrombotic properties of[2-[(ω-aminoalkoxy)] ethyl] benzenes. ", J.Med.Chem., 1990, all be to utilize Wittig reaction synthetic intermediate 2-((3-methoxyl group) styryl) phenol with document 2 (CN101239920A) 33:1818-1823), get intermediate 2-((3-methoxyl group) styroyl) phenol by Hydrogenation again, all to connect first inevitably triphenylphosphine and carry out Wittig reaction as active group, be difficult to greatly the by product triphenylphosphine oxide removed thereby produce to pollute.Although the triphenylphosphine oxide of 2 pairs of generations of document has carried out the aftertreatment improvement, but still can't avoid heavy-polluted triphenylphosphine oxide to produce.Wherein, the route disclosed in the document 5 is as follows:
And document 6 (Zhang Faxiang, " through the novel synthesis of the Sarpogrelatehydrochloride of Weinreb acid amides ", Shenyang Pharmaceutical University's master thesis in 2005, classification number TQ463.2) introduced the phenyl with 2-[2-(benzyloxy) in]-1-(3-p-methoxy-phenyl) ethyl ketone, take off benzyl by Wolff-Kishner-Huang Min-lon reduction, catalysis and produce intermediate 2-[2-(3-p-methoxy-phenyl) ethyl] phenol, reaction formula is as follows:
The inventor finds through experiment, although the method has also been avoided the generation of triphenylphosphine oxide, the reduction step in its technological process requires high to temperature of reaction, after reaction finishes under hot conditions, the product impurity of gained is more, is difficult to finally obtain highly purified Sarpogrelatehydrochloride.In addition, the pyroreaction condition causes the industrialization energy consumption high, can not satisfy the scale operation demand.
Summary of the invention
For solving above-mentioned problems of the prior art, the invention provides a kind of Sarpogrelate intermediate and preparation method thereof.
Particularly, the invention provides:
(1) a kind of Sarpogrelate intermediate, wherein, described Sarpogrelate intermediate is the compound shown in the formula VI:
(2) a kind of preparation (1) described Sarpogrelate intermediate method, said method comprising the steps of:
Make the Grignard reagent shown in the 2-benzyloxy phenyl aldehyde shown in the formula V and the formula IV that grignard reaction as follows occur, obtain described Sarpogrelate intermediate:
Wherein, in formula IV, M is magnesium or zinc, is preferably magnesium; X is halogen, is preferably chlorine or bromine.
(3) according to (2) described method, wherein, the temperature of reaction of described grignard reaction is-15 ℃ to 30 ℃, is preferably-5 ℃ to 5 ℃.
(4) according to (2) described method, wherein, the reaction times of described grignard reaction is 2-15 hour, is preferably 4-10 hour.
(5) according to (2) described method, wherein, described grignard reaction carries out in anhydrous non-protonic solvent, and described non-protonic solvent is selected from tetrahydrofuran (THF), ether or benzene, is preferably tetrahydrofuran (THF).
(6) according to (2) described method, wherein, described grignard reaction carries out cancellation with protic reagent, described protic reagent is selected from: the aqueous sulfuric acid of the aqueous hydrochloric acid of 5 % by weight, 1 % by weight or the aqueous ammonium chloride solution of 10 % by weight are preferably the aqueous hydrochloric acid of 5 % by weight.
The present invention compared with prior art has the following advantages and positively effect:
1. the present invention has avoided utilizing the Wittig reaction to synthesize, and pollutes triphenylphosphine oxide by product large and that be difficult to remove thereby avoided producing, and reaction conditions is gentle, energy consumption is low, it is little to pollute.
2. the invention provides a kind of novel method through intermediate 1-(2-(benzyloxy) phenyl)-2-(3-p-methoxy-phenyl) ethanol (VI) synthetic hydrochloric acid Sarpogrelate, wherein utilize Grignard reagent (IV) and aldehyde (V) to carry out grignard reaction, obtained key intermediate 1-(2-(benzyloxy) phenyl)-2-(3-p-methoxy-phenyl) ethanol (VI), obtain intermediate 1-(benzyloxy)-2-(3-methoxyl-styrene) benzene (VII) through dehydration again, then through reactions such as hydrogenations, obtain the product Sarpogrelatehydrochloride.This technique transformation efficiency is higher, and raw materials cost is low, and gained Sarpogrelatehydrochloride purity is high, and HPLC detects purity more than 99%, is fit to large production and transforms.
Embodiment
Below the invention will be further described for the description by embodiment, but this is not to be limitation of the present invention, those skilled in the art are according to basic thought of the present invention, can make various modifications or improvement, but only otherwise break away from basic thought of the present invention, all within the scope of the present invention.
In an embodiment of the invention, provide a kind of new Sarpogrelate intermediate, its chemical name is 1-(2-(benzyloxy) phenyl)-2-(3-p-methoxy-phenyl) ethanol, and its structural formula is suc as formula shown in the VI:
Grignard reagent used among the present invention can be prepared by the following method:
Particularly, can with m-methoxybenzaldehyde and sodium borohydride reaction, make 3-anisole methyl alcohol (II); With 3-anisole methyl alcohol and haloid acid reaction, make 3-methoxyl group halogen benzyl (III); In non-protonic solvent, under the nitrogen protection, utilize initiator, make 3-methoxyl group halogen benzyl (III) and reactive metal reaction, thereby make Grignard reagent (IV).Wherein, 3-methoxyl group halogen benzyl can for 3-methoxyl group benzyl chloride, 3-methoxyl group bromobenzyl or 3-methoxyl group iodine benzyl, be preferably 3-methoxyl group benzyl chloride or 3-methoxyl group bromobenzyl.Reactive metal can for magnesium or zinc, be preferably magnesium.Initiator can for iodine, glycol dibromide or methyl iodide, be preferably iodine.In formula IV, M is magnesium or zinc, is preferably magnesium; X is halogen, and for example: chlorine, bromine, iodine are preferably chlorine or bromine.
In yet another embodiment of the present invention; the method of a kind of synthetic Sarpogrelate intermediate (VI) is provided; wherein carry out grignard reaction, synthetic intermediate 1-(2-(benzyloxy) phenyl)-2-(3-p-methoxy-phenyl) ethanol (VI) by salicylic aldehyde (V) and Grignard reagent (IV) behind the protection phenolic hydroxyl group.In yet another embodiment of the present invention, a kind of novel method of synthesis of high purity Sarpogrelatehydrochloride is provided, wherein, by intermediate 1-(2-(benzyloxy) phenyl)-2-(3-p-methoxy-phenyl) ethanol (VI) is carried out dehydration reaction and obtains intermediate 1-(benzyloxy)-2-(3-methoxyl-styrene) benzene (VII) under acidic conditions, again by hydrogenation reaction and with the series reaction (comprising salt-forming reaction) of epoxy chloropropane, dimethylamine, Succinic anhydried, finally obtain Sarpogrelatehydrochloride.Reaction process can be reaction process as follows:
According to above reaction formula, method of the present invention can specifically may further comprise the steps:
1.-20 during ℃ to 60 ℃, in alcoholic solvent, m-methoxybenzaldehyde and sodium borohydride reaction make 3-anisole methyl alcohol (II):
The above-mentioned reaction times is 3-20 hour, is preferably 4-10 hour; Temperature of reaction is-20 ℃ to 60 ℃, is preferably 0 to 50 ℃; The mole number ratio of m-methoxybenzaldehyde and sodium borohydride is 1: (0.8-2.5), be preferably 1: 1.1; Alcohol in the above-mentioned reaction is selected from methyl alcohol, ethanol, Virahol, is preferably methyl alcohol; Extract the product solvent for use and be selected from ethyl acetate, methylene dichloride, trichloromethane, be preferably ethyl acetate.
2.-20 during ℃ to 80 ℃, 3-anisole methyl alcohol (II) is added to vigorous stirring reaction in the haloid acid, produces 3-methoxyl group halogen benzyl (III):
Haloid acid is selected from concentrated hydrochloric acid, Hydrogen bromide, hydroiodic acid HI in the above-mentioned halogenating reaction, is preferably concentrated hydrochloric acid and Hydrogen bromide; Temperature of reaction is-20 ℃ to 80 ℃, is preferably 0 ℃ to 55 ℃; The mol ratio of contained hydrogen halide is 1 in 3-anisole methyl alcohol and the haloid acid: (3-30), be preferably 1: 15;
The reaction times of above-mentioned halogenating reaction can be 5-30 hour, is preferably 8-15 hour.Extract the product solvent for use and be selected from ethyl acetate, methylene dichloride, trichloromethane, be preferably ethyl acetate.
3. in non-protonic solvent, under the nitrogen protection, utilize a small amount of initiator, prepare Grignard reagent (IV) with the magnesium chips reaction:
Above-mentioned temperature of reaction is preferably 10 ℃ to 55 ℃ at 0 ℃ to 60 ℃; Reaction times was preferably 2-7 hour at 1-15 hour; Non-protonic solvent is selected from ether, methyl tertiary butyl ether, tetrahydrofuran (THF), is preferably tetrahydrofuran (THF); Initiator is selected from iodine, glycol dibromide, methyl iodide, is preferably iodine.
4. salicylic aldehyde and benzyl chloride synthesize 2-benzyloxy phenyl aldehyde (V) under the mineral alkali condition in reaction solvent:
Above-mentioned temperature of reaction is preferably 0 ℃ to 110 ℃ at-5 ℃ to 130 ℃; Reaction times 3-20 hour, be preferably 5-10 hour; The mol ratio of salicylic aldehyde and benzyl chloride is 1: (1-1.5), be preferably 1: 1.
Used mineral alkali is selected from salt of wormwood, yellow soda ash, sodium bicarbonate, saleratus in the above-mentioned reaction; Be preferably salt of wormwood.
Above-mentioned reaction solvent can be DMF, methylene dichloride, trichloromethane, ethyl acetate; Be preferably DMF.
5.2-benzyloxy phenyl aldehyde (V) carries out grignard reaction with self-control Grignard reagent (IV) in anhydrous non-protonic solvent, then carry out cancellation with protic reagent and obtain 1-(2-(benzyloxy) phenyl)-2-(3-p-methoxy-phenyl) ethanol (VI):
Above-mentioned temperature of reaction is between-15 ℃ to 30 ℃, is preferably-5 ℃ to 5 ℃; Reaction times was preferably 4-10 hour within 2-15 hour.Solvent for use can for tetrahydrofuran (THF), ether, benzene, be preferably tetrahydrofuran (THF).
The used cancellation reagent of above-mentioned reaction can for 5% dilute hydrochloric acid, 1% dilute sulphuric acid, 10% aqueous ammonium chloride solution, be preferably 5% hydrochloric acid; Wherein each concentration is mass percentage concentration.
The mol ratio of above-mentioned reaction intermediate V and intermediate compound IV is 1: (1-3), be preferably 1: 1.
6. under the acidic conditions 1-(2-(benzyloxy) phenyl)-2-(3-p-methoxy-phenyl) ethanol (VI) is dewatered, produce intermediate 1-(benzyloxy)-2-(3-methoxyl-styrene) benzene (VII)
The used dewatering agent of above-mentioned reaction can for 50%-98% sulfuric acid or 30%-45% phosphoric acid, be preferably 80%-90% sulfuric acid; Wherein each concentration is mass percentage concentration.Temperature of reaction can be 20 ℃ to 100 ℃, is preferably 70 ℃-80 ℃.Reaction times can be 2-15 hour, is preferably 5-8 hour.Reaction can for ethanol, methyl alcohol, Virahol, be preferably ethanol to the used purification solvent of product intermediate VII after finishing.
7. in organic solvent, to intermediate 1-(benzyloxy)-2-(3-methoxyl-styrene) benzene (VII) high-pressure hydrogenation reduction ethylene linkage under catalyst, slough simultaneously benzyl, get 2-((3-methoxyl group) styroyl) phenol (VIII).
The used organic solvent of above-mentioned reaction can for ethyl acetate, methylene dichloride, ethyl formate, ethyl ester methyl esters, be preferably ethyl acetate; The used hydrogenation catalyst of above-mentioned reaction can for 5%Pd, 10%Pd, Raney's nickel, be preferably 5%Pd; The reaction pressure of above-mentioned reaction can be 2 more than the normal atmosphere, is preferably 5 normal atmosphere; The reaction times of above-mentioned reaction can be 2-15 hour, is preferably 3-8 hour.
8. the reference literature 5 (people such as Kikumoto, " phenyl of Syntheses and platelet aggregation inhibitory and antithrombotic properties of[2-[(ω-aminoalkoxy)] ethyl] benzenes. ", J.Med.Chem., 1990,33:1818-1823) reaction conditions of report reacts 2-((3-methoxyl group) styroyl) phenol (VIII) successively with epoxy chloropropane, dimethylamine, Succinic anhydried, last and HCl salify obtains the finished product Sarpogrelatehydrochloride.
9. Sarpogrelatehydrochloride is refining
Refining solvent for use can be preferably methyl alcohol for methyl alcohol, ethanol, Virahol, ethyl acetate, and products obtained therefrom purity is about 99%-99.5%.
Mode by the following examples further explains and describes content of the present invention, but these embodiment are not to be construed as limiting the scope of the invention.
Wherein, in following examples, it is Shimadzu LC-20A that HPLC detects instrument.
In following examples, m-methoxybenzaldehyde can derive from Li Deshi chemical industry company limited at sunshine; Salicylic aldehyde can derive from Zhangjiagang flight Industrial Co., Ltd.; Benzyl Chloride can derive from the happy Industrial Co., Ltd. of Shanghai Jin Jin; Magnesium can derive from the Hebi Glan and reach magnesium industry company limited; 5%Pd/C can derive from the happy Industrial Co., Ltd. of Shanghai Jin Jin; Sulfuric acid can derive from the light trade Co., Ltd of Tianjinization.
The preparation of embodiment 1:3-anisole methyl alcohol (II):
M-methoxybenzaldehyde, 170ml methyl alcohol and the 2g sodium hydroxide of 447.6g (3.29mol) are joined in the reaction flask, ice bath is cooled to about 0 ℃, under the mechanical stirring, add SODIUM BOROHYDRIDE POWDER 34.3g (0.91mol), control adding speed in batches, temperature is remained on below 50 ℃, finish, place 25 ℃ of lower reactions 4 hours, TLC (ethyl ester ethyl ester: normal hexane=1: 8) react completely, again under ice bath, add Glacial acetic acid in the yellow reaction liquid pH value is transferred to 4 to 5; Remove methyl alcohol under reduced pressure, add 300ml water, separatory, twice of 300ml ethyl acetate extraction of water layer.Merge organic layer and wash 2 times with the 200ml saturated aqueous sodium carbonate, separatory, anhydrous sodium sulfate drying filters, and removes desolventizing under reduced pressure, obtains title product, is weak yellow liquid 440.6g, and HPLC purity is 97%.
Embodiment 2:3-methoxyl group benzyl chloride (III) preparation:
440.6g (3.19mol) intermediate II is joined in the 1000ml reaction flask, ice bath is down to 0 ℃, add 420ml concentrated hydrochloric acid (37%) under the vigorous stirring, finish, 30 ℃ of lower reactions 2 hours, then be warmed up to 50 ℃ of reactions 7 hours, (the ethyl ester ethyl ester: normal hexane=1: 8) demonstration reacts completely TLC.Ice-water bath is cooled to 0 ℃ again, add 400ml water in the reaction solution, stirred 30 minutes, separatory is preserved the orange organic layer of lower floor, twice of 350ml ethyl acetate extraction of water layer, organic also laminated with the orange preservation that the upper step is told, with 400ml saturated sodium bicarbonate aqueous solution washing 2 times, separatory, anhydrous sodium sulfate drying, filter, the evaporated under reduced pressure solvent obtains weak yellow liquid, oil pump decompression (85 ℃ to 90 ℃ cuts, 1-5mmHg) distillation, obtain title product, be colourless liquid 458.5g, HPLC purity 99%, calculating molar yield from m-methoxybenzaldehyde is 89%.
Embodiment 3:3-methoxyl group bromobenzyl (III) preparation:
440.6g (3.19mol) intermediate II is joined in the 2000ml reaction flask, ice bath is down to 0 ℃, add 700ml Hydrogen bromide (40%) under the vigorous stirring, finish, 30 ℃ of lower reactions 2 hours, then be warmed up to 45 ℃ of reactions 6 hours, (the ethyl ester ethyl ester: normal hexane=1: 8) demonstration reacts completely TLC.Ice-water bath is cooled to 0 ℃ again, add 400ml water in the reaction solution, stirred 30 minutes, separatory is preserved the orange organic layer of lower floor, water layer 350ml ethyl acetate extraction 2 times, organic also laminated with the orange preservation that the upper step is told, again with 400ml saturated sodium bicarbonate aqueous solution washing 2 times, separatory, anhydrous sodium sulfate drying, keep in Dark Place, filter, the evaporated under reduced pressure solvent obtains weak yellow liquid, oil pump decompression (90 ℃ to 95 ℃ cuts, 1-3mmHg) distillation obtains title product, is colourless liquid 575.3g, HPLC purity 97%, calculating molar yield from m-methoxybenzaldehyde is 87%.
Embodiment 4: the preparation of Grignard reagent (IV):
Under nitrogen protection, 40 ℃; in the 2000ml reaction flask, add 300ml THF, magnesium chips 85.4g after pretreatment (3.51mol), iodine 8.92g (0.07mol); stirred 1 hour; be warmed up to 50 ℃; slowly dropping is dissolved in 458.5g (2.93mol) the 3-methoxyl group benzyl chloride (III) of 300ml THF and the mixture of 6.7g (0.053mol) iodine simultaneously, drips to finish insulation reaction 3 hours; be cooled to 20 ℃, stand-by.
The magnesium chips pretreatment process: the salt acid elution with 10% 30 minutes, suction filtration is used acetone drip washing fast, and vacuum-drying directly drops in the reaction and uses.
Embodiment 5: the preparation of Grignard reagent (IV):
Under nitrogen protection, 40 ℃; in the 2000ml reaction flask, add 300ml THF, magnesium chips 83.5g after pretreatment (3.43mol), iodine 8.7g (0.069mol); stirred 1 hour; be warmed up to 55 ℃; slowly dropping is dissolved in 575.3g (2.86mol) the 3-methoxyl group bromobenzyl (III) of 300ml THF and the mixture of 6.6g (0.052mol) iodine simultaneously, drips to finish insulation reaction 4 hours; be cooled to 20 ℃, stand-by.
The magnesium chips pretreatment process: the salt acid elution with 5% 30 minutes, suction filtration is used acetone drip washing fast, and vacuum-drying directly drops in the reaction and uses.
Embodiment 6: the preparation of Grignard reagent (IV):
Under nitrogen protection, 30 ℃; in the 2000ml reaction flask, add 300ml methyl tertiary butyl ether, magnesium chips 83.5g after pretreatment (3.43mol), iodine 8.7g (0.069mol); stirred 1 hour; be warmed up to 45 ℃; slowly dropping is dissolved in 575.3g (2.86mol) the 3-methoxyl group bromobenzyl (III) of 300ml methyl tertiary butyl ether and the mixture of 6.6g (0.052mol) iodine simultaneously, drips to finish insulation reaction 4 hours; be cooled to 20 ℃, stand-by.
The magnesium chips pretreatment process: the salt acid elution with 5% 30 minutes, suction filtration is used acetone drip washing fast, and vacuum-drying directly drops in the reaction and uses.
The preparation of embodiment 7:2-benzyloxy phenyl aldehyde (V):
In the reaction flask of 2000ml, add 491.4g (4mol) salicylic aldehyde, ice bath is down to 0 ℃, add Anhydrous potassium carbonate powder 330.2g (2.39mol) under the mechanical stirring, solid increases in the reaction solution, the DMF that adds 500ml, stirred 10 minutes, and added again Benzyl Chloride 508.4g (4mol).Be warmed up to 100 ℃ of reactions 7 hours, be cooled to room temperature (25 ℃), add 300ml water, stirred 10 minutes, use again 300ml dichloromethane extraction product 3 times, merge organic phase, 100ml saturated common salt water washing 2 times, use anhydrous sodium sulfate drying, filter, the evaporated under reduced pressure solvent obtains title product, is garnet liquid 793.5g, HPLC purity is 98.9%, yield 93.5%.
Embodiment 8: grignard reaction prepares 1-(2-(benzyloxy) phenyl)-2-(3-p-methoxy-phenyl) ethanol (VI):
Add 518.1g (2.44mol) 2-benzyloxy phenyl aldehyde (V) and 300mlTHF in the reaction flask, be cooled to-5 ℃, under the mechanical stirring, drip the Grignard reagent that embodiment 4 produces, temperature is controlled at-5 ℃ to 0 ℃, dropwises in about 4 hours, continues insulation reaction 2 hours, be warming up to 25 ℃, reacted again 1 hour.Remove THF under reduced pressure, add again 300ml toluene, add 5% hydrochloric acid under ice-water bath (0 ℃) mechanical stirring, transfer to pH and be about about 2-3.100ml saturated common salt water washing 2 times of separatory, organic layer, anhydrous sodium sulfate drying 2 hours, suction filtration steams except organic solvent, gets title product, is oily matter 788.5g, HPLC purity 96.2%.
The detection data of the title product that obtains by nucleus magnetic resonance and mass spectroscopy are as follows:
1HNMR (300MHz, CD
3OD): δ=6.93-7.55 (m, 7H), 6.72 (s, 1H), 5.37-6.65 (m, 5H), 5.01 (s, 2H), 4.68 (m, 1H), 3.51 (s, 3H), 3.02 (d, 1H), 2.80-2.98 (m, 2H);
13C NMR (75MHz, CD
3OD): δ=159.1,155.5,142.3,135.7,129.3,129.4,128.2,127.1,126.8,125.3,123.9,120.8,118.3,112.6,110.1,109.5,108.2,106.3,69.9,65.3,50.7,45.1; HR-MS (ESI): m/z=335.1623, C
22H
22O
3[M+H]
+Calculated value: 335.1623.
Embodiment 9: grignard reaction prepares 1-(2-(benzyloxy) phenyl)-2-(3-p-methoxy-phenyl) ethanol (VI):
Add 505.7g (2.38mol) 2-benzyloxy phenyl aldehyde (V) and 300mlTHF in the reaction flask, be cooled to-5 ℃, under the mechanical stirring, drip the Grignard reagent that embodiment 5 produces, temperature is controlled at-5 ℃ to 0 ℃, dropwises in about 4 hours, continues insulation reaction 2 hours, be warming up to 25 ℃, reacted again 1 hour.Remove THF under reduced pressure, add again 300ml toluene, add 5% hydrochloric acid under ice-water bath (0 ℃) mechanical stirring, transfer to pH and be about about 2-3.100ml saturated common salt water washing 2 times of separatory, organic layer, anhydrous sodium sulfate drying 2 hours, suction filtration steams except organic solvent, gets title product, is oily matter 778.6g, HPLC purity 96.9%.
The detection data of the title product that obtains by nucleus magnetic resonance and mass spectroscopy are as follows:
1HNMR (300MHz, CD
3OD): δ=6.93-7.55 (m, 7H), 6.72 (s, 1H), 5.37-6.65 (m, 5H), 5.01 (s, 2H), 4.68 (m, 1H), 3.51 (s, 3H), 3.02 (d, 1H), 2.80-2.98 (m, 2H);
13C NMR (75MHz, CD
3OD): δ=159.1,155.5,142.3,135.7,129.3,129.4,128.2,127.1,126.8,125.3,123.9,120.8,118.3,112.6,110.1,109.5,108.2,106.3,69.9,65.3,50.7,45.1; HR-MS (ESI): m/z=335.1623, C
22H
22O
3[M+H]
+Calculated value: 335.1623.
Embodiment 10: grignard reaction prepares 1-(2-(benzyloxy) phenyl)-2-(3-p-methoxy-phenyl) ethanol (VI):
Add 505.7g (2.38mol) 2-benzyloxy phenyl aldehyde (V) and 300ml ether in the reaction flask, be cooled to-5 ℃, under the mechanical stirring, drip the Grignard reagent that embodiment 5 produces, temperature is controlled at-5 ℃ to 0 ℃, dropwises in about 4 hours, continues insulation reaction 2 hours, be warming up to 25 ℃, reacted again 1 hour.Steam except ether, add again 300ml toluene, add 5% hydrochloric acid under ice-water bath (0 ℃) mechanical stirring, transfer to pH and be about about 2-3.100ml saturated common salt water washing 2 times of separatory, organic layer, anhydrous sodium sulfate drying 2 hours, suction filtration steams except organic solvent, gets title product, is oily matter 769.2g, HPLC purity 96.2%.
The detection data of the title product that obtains by nucleus magnetic resonance and mass spectroscopy are as follows:
1HNMR (300MHz, CD
3OD): δ=6.93-7.55 (m, 7H), 6.72 (s, 1H), 5.37-6.65 (m, 5H), 5.01 (s, 2H), 4.68 (m, 1H), 3.51 (s, 3H), 3.02 (d, 1H), 2.80-2.98 (m, 2H);
13C NMR (75MHz, CD
3OD): δ=159.1,155.5,142.3,135.7,129.3,129.4,128.2,127.1,126.8,125.3,123.9,120.8,118.3,112.6,110.1,109.5,108.2,106.3,69.9,65.3,50.7,45.1; HR-MS (ESI): m/z=335.1623, C
22H
22O
3[M+H]
+Calculated value: 335.1623.
The preparation of embodiment 11:1-(benzyloxy)-2-(3-methoxyl-styrene) benzene (VII):
Add the oily matter (containing 1-(2-(benzyloxy) phenyl)-about 758.5g of 2-(3-p-methoxy-phenyl) ethanol (VI) by the conversion of HPLC purity) of embodiment 8 gained and 90% sulfuric acid 500ml in the reaction flask, be warming up to 80 ℃, back flow reaction 8 hours, ice-water bath is cooled to 0 ℃, with 200ml ethyl acetate extraction product 3 times, separatory merges all organic phases, again with 100ml saturated common salt washing 2 times, ethyl acetate layer anhydrous sodium sulfate drying 1 hour, suction filtration removes organic solvent under reduced pressure, 20 ℃ of lower 400ml ethanol that add, separate out a large amount of white solids, 50 ℃ of lower backflows 2 hours are cooled to 0 ℃, suction filtration, with 50ml washing with alcohol filter cake twice, obtain title product, be white solid 684g, yield 95.3%, HPLC purity are 99.1%.
The preparation of embodiment 12:1-(benzyloxy)-2-(3-methoxyl-styrene) benzene (VII):
Add the oily matter (containing 1-(2-(benzyloxy) phenyl)-about 754.5g of 2-(3-p-methoxy-phenyl) ethanol (VI) by the conversion of HPLC purity) of embodiment 9 gained and 90% sulfuric acid 500ml in the reaction flask, be warming up to 80 ℃, back flow reaction 8 hours, ice-water bath is cooled to 0 ℃, with 200ml ethyl acetate extraction product 3 times, separatory merges all organic phases, use again 100ml saturated common salt water washing 2 times, ethyl acetate layer is used anhydrous sodium sulfate drying 1 hour, and suction filtration removes organic solvent under reduced pressure, 20 ℃ of lower 400ml ethanol that add, separate out a large amount of white solids, 50 ℃ of lower backflows 2 hours are cooled to 0 ℃, suction filtration, with 50ml washing with alcohol filter cake twice, obtain title product, be white solid 678.6g, yield 96.2%, HPLC purity are 99.3%.
The preparation of embodiment 13:2-(3-anisole ethyl) phenol (VIII):
In stainless steel autoclave, add 1-(benzyloxy)-2-(3-methoxyl-styrene) benzene (VII) 150g (0.474mol), ethyl acetate 1000ml, 5% Pd/C 10.5g, ethanol 100ml, glacial acetic acid 2ml, at 45 ℃, reaction is to not inhaling till the hydrogen about 4 hours of time spent under 5 normal atmosphere.Filtered and recycled Pd/C, filtrate decompression concentrates solvent evaporated, adds the 300ml washing, and water layer with the 200ml ethyl acetate extraction once merges organic layer, 300ml saturated common salt water washing 2 times, anhydrous sodium sulfate drying filters.Steaming desolventizes, and obtains title product, is yellow liquid 105.8g, and HPLC purity is 97.2%.
Embodiment 14: the preparation of intermediate X:
46.4g in the reaction flask (0.2mol) 2-(3-anisole ethyl) phenol (VIII), DMF500ml, (0 ℃) adds sodium hydride 7.2g (0.2mol) in batches under the ice bath, the control temperature is below 50 ℃, finish, 25 ℃ of lower stirrings 2 hours, drip epoxy chloropropane 82.8ml (1mol), maintain the temperature at 23 ℃ to 27 ℃, reacted 5 hours, (the ethyl ester ethyl ester: normal hexane=1: 8) demonstration reacts completely TLC, add frozen water and decompose unnecessary sodium hydride, 100ml saturated common salt solution washing 2 times of 100ml ethyl acetate extraction 3 times, organic layer.Anhydrous sodium sulfate drying filters, and concentrating under reduced pressure obtains weak yellow liquid (being directly used in next step reaction).
In reaction flask, add 146ml (1mol) dimethylamine agueous solution (33%), ice-cold lower, the weak yellow liquid of step gained droppings in, the control temperature is dripped and is finished below 20 ℃, reacts 4 hours under 25 ℃.(the ethyl ester ethyl ester: normal hexane=1: 8) demonstration reacts completely TLC, add 300ml water, with 100ml ethyl acetate extraction product 3 times, organic layer 100ml saturated common salt water washing 2 times, anhydrous sodium sulfate drying, evaporated under reduced pressure obtains title product, is faint yellow oily thing 61g, and HPLC purity is 95.5%.
Embodiment 15: the preparation of Sarpogrelatehydrochloride (I) crude product:
In the 500ml reaction flask, add 58.3g (0.177mol) intermediate X, acetone 200ml, Succinic anhydried 21g (0.21mol), then 25 ℃ of lower stirring reactions 3 hours refluxed 1 hour, TLC (chloroform: methyl alcohol=3: 1) show and react completely, be cooled to 5 ℃ under the ice bath, add the saturated HCl solution of Virahol 30ml, have solid to separate out, insulation was 5 ℃ of lower stirring and crystallizing 3 hours, suction filtration obtains title product, is white solid 75.9g, yield 92%, HPLC purity are 97.3%.
Embodiment 16: Sarpogrelatehydrochloride (I) refining:
In the reaction bottle, add 75.9g Sarpogrelatehydrochloride crude product (HPLC purity is 97.3%), methyl alcohol 100ml is warming up to 60 ℃, clarification, naturally after being down to room temperature, ice-water bath is down to 0 ℃, stirring and crystallizing 5 hours, suction filtration, 30 ℃ of lower vacuum-drying 1 hour, get the 72.5g Sarpogrelatehydrochloride, yield 95.5%, HPLC purity is 99.7%.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104496769A (en) * | 2014-11-26 | 2015-04-08 | 千辉药业（安徽）有限责任公司 | Synthetic method for 2-[2-(3-methoxyphenyl)ethyl]phenol |
| CN107324979A (en) * | 2017-08-16 | 2017-11-07 | 北京奥得赛化学股份有限公司 | A kind of preparation method of sarpogrelate hydrochloride intermediate |
| CN109824527A (en) * | 2019-03-18 | 2019-05-31 | 安徽峆一药业股份有限公司 | A kind of synthetic method of sarpogrelate hydrochloride |
| CN111741939A (en) * | 2018-02-20 | 2020-10-02 | 大塚制药株式会社 | Method for preparing 4-dihydroxyboronyl phenylalanine |
| CN113024360A (en) * | 2021-03-30 | 2021-06-25 | 国药集团化学试剂有限公司 | Synthesis method of m-methoxy benzyl alcohol |
-
2011
- 2011-07-12 CN CN201110194204.XA patent/CN102875340B/en active Active
Non-Patent Citations (2)
| Title |
|---|
| RYOJI KIKUMOTO ET AL.: "Substituted (w-Aminoa1koxy)stilbene Derivatives as a New Class of Anticonvulsants", 《JOURNAL OF MEDICINAL CHEMISTRY》 * |
| 王生等: "盐酸沙格雷酯的合成", 《中国医药工业杂志》 * |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104496769A (en) * | 2014-11-26 | 2015-04-08 | 千辉药业（安徽）有限责任公司 | Synthetic method for 2-[2-(3-methoxyphenyl)ethyl]phenol |
| CN104496769B (en) * | 2014-11-26 | 2016-05-11 | 千辉药业（安徽）有限责任公司 | A kind of 2-[2-(3-methoxyl group-phenyl)-ethyl] synthetic method of-phenol |
| CN107324979A (en) * | 2017-08-16 | 2017-11-07 | 北京奥得赛化学股份有限公司 | A kind of preparation method of sarpogrelate hydrochloride intermediate |
| CN111741939A (en) * | 2018-02-20 | 2020-10-02 | 大塚制药株式会社 | Method for preparing 4-dihydroxyboronyl phenylalanine |
| CN109824527A (en) * | 2019-03-18 | 2019-05-31 | 安徽峆一药业股份有限公司 | A kind of synthetic method of sarpogrelate hydrochloride |
| CN113024360A (en) * | 2021-03-30 | 2021-06-25 | 国药集团化学试剂有限公司 | Synthesis method of m-methoxy benzyl alcohol |
| WO2022206135A1 (en) * | 2021-03-30 | 2022-10-06 | 国药集团化学试剂有限公司 | Method for synthesizing 3-methoxybenzyl alcohol |
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