CN104744336B - A kind of Silodosin intermediate and preparation method thereof, and the method for preparing with the intermediate silodosin - Google Patents
A kind of Silodosin intermediate and preparation method thereof, and the method for preparing with the intermediate silodosin Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 119
- PNCPYILNMDWPEY-QGZVFWFLSA-N silodosin Chemical compound N([C@@H](CC=1C=C(C=2N(CCCO)CCC=2C=1)C(N)=O)C)CCOC1=CC=CC=C1OCC(F)(F)F PNCPYILNMDWPEY-QGZVFWFLSA-N 0.000 title claims abstract description 77
- 229960004953 silodosin Drugs 0.000 title claims abstract description 77
- 238000000034 method Methods 0.000 title claims abstract description 59
- 150000001875 compounds Chemical class 0.000 claims abstract description 286
- 238000006243 chemical reaction Methods 0.000 claims description 162
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 79
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 51
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 38
- 239000003960 organic solvent Substances 0.000 claims description 32
- 230000035484 reaction time Effects 0.000 claims description 30
- 239000002904 solvent Substances 0.000 claims description 30
- 238000006467 substitution reaction Methods 0.000 claims description 30
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 26
- 238000006722 reduction reaction Methods 0.000 claims description 21
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 20
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 18
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 15
- 238000006555 catalytic reaction Methods 0.000 claims description 15
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 15
- 150000003839 salts Chemical class 0.000 claims description 15
- -1 3- chloropropyl alcohols Chemical class 0.000 claims description 14
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- 239000001257 hydrogen Substances 0.000 claims description 12
- 230000009467 reduction Effects 0.000 claims description 12
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims description 12
- 238000006264 debenzylation reaction Methods 0.000 claims description 11
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 10
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 10
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 10
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 9
- 239000003513 alkali Substances 0.000 claims description 9
- 238000006482 condensation reaction Methods 0.000 claims description 9
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 claims description 8
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 claims description 8
- 229940073608 benzyl chloride Drugs 0.000 claims description 8
- 230000008859 change Effects 0.000 claims description 8
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 claims description 7
- 239000005695 Ammonium acetate Substances 0.000 claims description 7
- 229940043376 ammonium acetate Drugs 0.000 claims description 7
- 235000019257 ammonium acetate Nutrition 0.000 claims description 7
- 230000007062 hydrolysis Effects 0.000 claims description 7
- 238000006460 hydrolysis reaction Methods 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 6
- 239000003963 antioxidant agent Substances 0.000 claims description 6
- 230000003078 antioxidant effect Effects 0.000 claims description 6
- MCSAJNNLRCFZED-UHFFFAOYSA-N nitroethane Chemical compound CC[N+]([O-])=O MCSAJNNLRCFZED-UHFFFAOYSA-N 0.000 claims description 6
- 239000007800 oxidant agent Substances 0.000 claims description 6
- 230000001590 oxidative effect Effects 0.000 claims description 6
- 229910019020 PtO2 Inorganic materials 0.000 claims description 5
- 230000003197 catalytic effect Effects 0.000 claims description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- 239000012279 sodium borohydride Substances 0.000 claims description 5
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 5
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 4
- 230000003647 oxidation Effects 0.000 claims description 3
- 238000007254 oxidation reaction Methods 0.000 claims description 3
- OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 claims description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims description 2
- XEFQLINVKFYRCS-UHFFFAOYSA-N Triclosan Chemical compound OC1=CC(Cl)=CC=C1OC1=CC=C(Cl)C=C1Cl XEFQLINVKFYRCS-UHFFFAOYSA-N 0.000 claims description 2
- 238000005576 amination reaction Methods 0.000 claims description 2
- 229910052698 phosphorus Inorganic materials 0.000 claims description 2
- 239000011574 phosphorus Substances 0.000 claims description 2
- 229960003500 triclosan Drugs 0.000 claims description 2
- 239000002585 base Substances 0.000 claims 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims 2
- 239000005046 Chlorosilane Substances 0.000 claims 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims 1
- 239000000460 chlorine Substances 0.000 claims 1
- 229910052801 chlorine Inorganic materials 0.000 claims 1
- KOPOQZFJUQMUML-UHFFFAOYSA-N chlorosilane Chemical compound Cl[SiH3] KOPOQZFJUQMUML-UHFFFAOYSA-N 0.000 claims 1
- 150000002978 peroxides Chemical class 0.000 claims 1
- FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Chemical compound [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 7
- 238000003786 synthesis reaction Methods 0.000 abstract description 7
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 154
- 238000003756 stirring Methods 0.000 description 46
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 40
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 39
- 239000000243 solution Substances 0.000 description 37
- 239000002994 raw material Substances 0.000 description 34
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 33
- 238000001914 filtration Methods 0.000 description 28
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 26
- 238000001035 drying Methods 0.000 description 26
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 24
- 238000004128 high performance liquid chromatography Methods 0.000 description 24
- 235000021050 feed intake Nutrition 0.000 description 23
- 239000012065 filter cake Substances 0.000 description 23
- 239000000376 reactant Substances 0.000 description 23
- 239000003054 catalyst Substances 0.000 description 19
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethyl sulfoxide Natural products CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 19
- 239000012044 organic layer Substances 0.000 description 19
- 239000007787 solid Substances 0.000 description 18
- 229910052799 carbon Inorganic materials 0.000 description 16
- 239000000047 product Substances 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 239000000843 powder Substances 0.000 description 15
- 238000007792 addition Methods 0.000 description 13
- 239000012074 organic phase Substances 0.000 description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 229960000583 acetic acid Drugs 0.000 description 12
- 235000019441 ethanol Nutrition 0.000 description 12
- 229910052757 nitrogen Inorganic materials 0.000 description 12
- 238000010792 warming Methods 0.000 description 12
- 238000005406 washing Methods 0.000 description 12
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 10
- 239000013078 crystal Substances 0.000 description 10
- 238000001514 detection method Methods 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 9
- 239000000706 filtrate Substances 0.000 description 9
- 239000010410 layer Substances 0.000 description 9
- 239000012046 mixed solvent Substances 0.000 description 9
- 238000001556 precipitation Methods 0.000 description 9
- 238000010992 reflux Methods 0.000 description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 239000007864 aqueous solution Substances 0.000 description 8
- 239000004519 grease Substances 0.000 description 8
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 8
- 235000017557 sodium bicarbonate Nutrition 0.000 description 8
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- 238000002425 crystallisation Methods 0.000 description 7
- 230000008025 crystallization Effects 0.000 description 7
- 239000012535 impurity Substances 0.000 description 7
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 238000005119 centrifugation Methods 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 150000002148 esters Chemical class 0.000 description 6
- 239000003921 oil Substances 0.000 description 6
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 6
- 239000012266 salt solution Substances 0.000 description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- 238000000967 suction filtration Methods 0.000 description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 description 5
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 4
- 235000011114 ammonium hydroxide Nutrition 0.000 description 4
- 239000012141 concentrate Substances 0.000 description 4
- 238000010828 elution Methods 0.000 description 4
- 239000012362 glacial acetic acid Substances 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 235000010265 sodium sulphite Nutrition 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical group [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- 239000007832 Na2SO4 Substances 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- YKIOKAURTKXMSB-UHFFFAOYSA-N adams's catalyst Chemical compound O=[Pt]=O YKIOKAURTKXMSB-UHFFFAOYSA-N 0.000 description 3
- 239000012267 brine Substances 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 230000006837 decompression Effects 0.000 description 3
- 238000003810 ethyl acetate extraction Methods 0.000 description 3
- 125000005909 ethyl alcohol group Chemical group 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 230000000630 rising effect Effects 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229960001866 silicon dioxide Drugs 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000001632 sodium acetate Substances 0.000 description 3
- 235000017281 sodium acetate Nutrition 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 2
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000010520 demethylation reaction Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000012280 lithium aluminium hydride Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 238000009423 ventilation Methods 0.000 description 2
- MBXLGUFPIKCQTJ-UHFFFAOYSA-N 1,3,3-tribromopyrrolidin-2-one Chemical class BrN1CCC(Br)(Br)C1=O MBXLGUFPIKCQTJ-UHFFFAOYSA-N 0.000 description 1
- BFCFYVKQTRLZHA-UHFFFAOYSA-N 1-chloro-2-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1Cl BFCFYVKQTRLZHA-UHFFFAOYSA-N 0.000 description 1
- SBNOTUDDIXOFSN-UHFFFAOYSA-N 1h-indole-2-carbaldehyde Chemical class C1=CC=C2NC(C=O)=CC2=C1 SBNOTUDDIXOFSN-UHFFFAOYSA-N 0.000 description 1
- 125000004793 2,2,2-trifluoroethoxy group Chemical group FC(CO*)(F)F 0.000 description 1
- ASHGTJPOSUFTGB-UHFFFAOYSA-N 3-methoxyphenol Chemical compound COC1=CC=CC(O)=C1 ASHGTJPOSUFTGB-UHFFFAOYSA-N 0.000 description 1
- PGTANUNIOXCVLE-UHFFFAOYSA-N CC.[Br] Chemical compound CC.[Br] PGTANUNIOXCVLE-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- 238000005874 Vilsmeier-Haack formylation reaction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 230000017858 demethylation Effects 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 239000002024 ethyl acetate extract Substances 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- 229940035423 ethyl ether Drugs 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
- JMANVNJQNLATNU-UHFFFAOYSA-N glycolonitrile Natural products N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 0.000 description 1
- LHGVFZTZFXWLCP-UHFFFAOYSA-N guaiacol Chemical compound COC1=CC=CC=C1O LHGVFZTZFXWLCP-UHFFFAOYSA-N 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229940074869 marquis Drugs 0.000 description 1
- 238000003328 mesylation reaction Methods 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 230000007096 poisonous effect Effects 0.000 description 1
- VBUNOIXRZNJNAD-UHFFFAOYSA-N ponazuril Chemical compound CC1=CC(N2C(N(C)C(=O)NC2=O)=O)=CC=C1OC1=CC=C(S(=O)(=O)C(F)(F)F)C=C1 VBUNOIXRZNJNAD-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 210000003708 urethra Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
Abstract
The present invention relates to compound synthesis field, more particularly to a kind of Silodosin intermediate and preparation method thereof, and the method for preparing with the intermediate silodosin.The intermediate synthesis silodosin technique have economy, safety, high-purity, in high yield the characteristics of, be suitable for industrialized large-scaled production.
Description
Technical field
The present invention relates to compound synthesis field, more particularly to a kind of Silodosin intermediate and preparation method thereof, and
The method that silodosin is prepared with the intermediate.
Background technology
Silodosin（silodosin）Structure type belongs to phenyl alkylamide compound.Its chemical name is：（R）-（-）-1-
（3- hydroxypropyls）- 5- [2- [2- [2- (2,2,2- trifluoro ethoxies) phenoxy group] ethylamino-] propyl group] -7- amine formyl indoles
Quinoline.Structural formula is as shown in formula I：
Silodosin shrinks to urethral smooth muscle has selective inhibitory, and reduces urethra internal pressure, and does not have to blood pressure
Have a significant impact, for treating benign prostatic hyperplasis.The process route for the synthesis silodosin that presently, there are all exists certain
The drawbacks of, so there is the demand of innovation silodosin synthesis technique in this area.
According to the synthetic route of silodosin in world new drug generated data storehouse, it is closed since starting material compound
Key intermediate 1- acetyl -7- amino -5-（2- aminopropyls）The overall conversion of indoline only has among 24% or so, and process
Used it is a large amount of it is poisonous contain cyanogen compound, azido compound and organic solvent, process is complicated, is difficult to control and to the pollution of environment
It is very big.Simultaneously as having used price tribromo pyrrolidones costly and oxidation during bromination and hydrogenating reduction
Platinum, cost is higher, is not easy to industrialized production.Another key intermediate 2- [2-（2,2,2- trifluoro ethoxies）Phenoxy group] bromine
Ethane experienced two step alkylated reactions and a step demethylation reaction, their reaction respectively from meta-methoxy phenol
Conversion ratio is 72%, 65.5% and 40%, and its comprehensive recovery rate only has 18% or so, and industrial value is not high.
EP600675 is reported using o-methoxyphenol as raw material, and etherified demethylation obtains 2- successively（2,2,2- trifluoros
Ethyoxyl）Phenol, then with a- bromoacetates through alkylation, Lithium Aluminium Hydride reduction and Mesylation obtain 2-（2,2,2 ,-trifluoro
Ethyoxyl）Benzene oxygen ethyl methane sulfonate ester.With Na2CO3、NaBH4, EtOH reactions obtain silodosin, this reaction scheme is long, impurity
Many purification conditions are harsh, and Lithium Aluminium Hydride is expensive, meet water explosive and decompose, are not suitable for industrialized production.
Xiao Chuan Luo etc.（Chin Chem Lett,19(1):59-60,2008）Report using o-chloronitrobenzene as
Raw material, successively through nucleophilic displacement of fluorine, reduction, diazotising, hydrolysis obtains 2-（2,2,2- trifluoro ethoxies）Phenol, then with 1,2- dibromos
Ethane reaction obtains 2-（2,2,2 ,-trifluoro ethoxy）Phenyl-bromide ethylether, reaction obtains silodosin, and this reaction scheme is long,
Yield is low, and four-step reaction yield is only 26%.
Therefore it provides a kind of Silodosin intermediate and preparation method thereof is significant.
The content of the invention
In view of this, the present invention provides a kind of Silodosin intermediate and preparation method thereof, and is prepared with the intermediate
The method of silodosin.The intermediate synthesis silodosin technique have economy, safety, high-purity, in high yield the characteristics of, fit
In industrialized production.
In order to realize foregoing invention purpose, the present invention provides following technical scheme：
The invention provides a kind of Silodosin intermediate, structure is as shown in formula II
Present invention also offers a kind of preparation method of the compound as shown in formula II, comprise the following steps：
Step 1：Take benzyl chloride that the first substitution reaction occurs under the catalysis of sodium acid carbonate and the mixture of water with indoline,
Compound shown in acquisition formula III；
Step 2：Compound shown in modus ponens III mixes generation Wei Er David Smails-Kazakhstan with dimethylformamide, phosphorous oxychloride
Gram reaction（Vilsmeier-Haack reaction）, obtain compound shown in formula IV；
Step 3：Under conditions of organic solvent and antioxidant are present, after compound shown in modus ponens IV is mixed with nitroethane
Condensation reaction occurs under the catalysis of ammonium acetate, the compound shown in formula V is obtained；
Step 4：Under conditions of organic solvent presence, with sodium borohydride reduction occurs for the compound shown in modus ponens V instead
Should, obtain compound shown in formula VI；
Step 5：Under conditions of organic solvent presence, compound shown in modus ponens VI and dimethylformamide, triclosan oxidation
Occur the second substitution reaction after phosphorus mixing, obtain compound shown in formula VII；
Step 6：Under conditions of organic solvent presence, after compound shown in modus ponens VII is mixed with hydroxylamine hydrochloride, in pyridine
Reacted under catalysis with the mixture of aceticanhydride, obtain compound shown in formula II；
In some embodiments of the invention, in the preparation method of compound as shown in formula II that the present invention is provided, step 1
The mol ratio of middle benzyl chloride, indoline and sodium acid carbonate is 1~4:1:1~4.
In other embodiments of the present invention, in the preparation method of compound as shown in formula II that the present invention is provided, step
The mol ratio of benzyl chloride, indoline and sodium acid carbonate is 2 in rapid 1:1:2
In some embodiments of the invention, in the preparation method of compound as shown in formula II that the present invention is provided, step 1
In the reaction temperature of the first substitution reaction be 0~95 DEG C, time of substitution reaction is 1~14h.
In other embodiments of the present invention, in the preparation method of compound as shown in formula II that the present invention is provided, step
The time of first substitution reaction is 6h in rapid 1.
Preferably, in the preparation method of compound as shown in formula II that the present invention is provided, the first substitution reaction in step 1
The step of also including purifying afterwards.
Preferably, in the preparation method of compound as shown in formula II that the present invention is provided, in step 1 after first substitution reaction
Purifying be specially add toluene stirring layering after, collected organic layer, drying, filtering and concentrating.
In some embodiments of the invention, in the preparation method of compound as shown in formula II that the present invention is provided, step 2
The mol ratio of compound, dimethylformamide and phosphorous oxychloride shown in Chinese style III is 1:2~9:2~4.
In other embodiments of the present invention, in the preparation method of compound as shown in formula II that the present invention is provided, step
The mol ratio of compound, dimethylformamide and phosphorous oxychloride shown in rapid 2 Chinese style III is 1:2:2
In some embodiments of the invention, in the preparation method of compound as shown in formula II that the present invention is provided, step 2
The reaction temperature of middle Wei Er David Smails-Haake reaction is -10~100 DEG C, and the time of Wei Er David Smails-Haake reaction is 1~6h.
In other embodiments of the present invention, in the preparation method of compound as shown in formula II that the present invention is provided, step
The time of Wei Er David Smails-Haake reaction is 3h in rapid 2.
Preferably, in the preparation method of compound as shown in formula II that the present invention is provided, phosphorous oxychloride is adopted in step 2
Reaction is participated in the mode of dropwise addition.
Preferably, in the preparation method of compound as shown in formula II that provides of the present invention, Wei Er David Smails in step 2-
The step of also including purifying after Haake reaction.
Preferably, in the preparation method of compound as shown in formula II that the present invention is provided, Wei Er David Smails-Kazakhstan in step 2
Gram reacted purifying is specially cooling, regulation pH value to 9, is collected by filtration after filter cake and ethyl acetate combination cooling and filters, wash
Wash.
In some embodiments of the invention, in the preparation method of compound as shown in formula II that the present invention is provided, step 3
Compound shown in Chinese style IV, the nitroethane, the mol ratio of the ammonium acetate are 1:1~9:1~4.
In other embodiments of the present invention, in the preparation method of compound as shown in formula II that the present invention is provided, step
Compound shown in rapid 3 Chinese style IV, nitroethane, the mol ratio of ammonium acetate are 1:6:2.
In some embodiments of the invention, in the preparation method of compound as shown in formula II that the present invention is provided, step 3
Compound shown in Chinese style IV, nitroethane, ammonium acetate, the mol ratio of antioxidant are 1:1~9:1~4：1~4.
In other embodiments of the present invention, in the preparation method of compound as shown in formula II that the present invention is provided, step
Compound shown in rapid 3 Chinese style IV, nitroethane, the mol ratio of ammonium acetate are 1:6:2:2.
In some embodiments of the invention, in the preparation method of compound as shown in formula II that the present invention is provided, step 3
The reaction temperature of middle condensation reaction is 30~100 DEG C, and the reaction time of condensation reaction is 2~16h.
In other embodiments of the present invention, in the preparation method of compound as shown in formula II that the present invention is provided, step
The reaction time of condensation reaction is 12h in rapid 3.
Preferably, in the preparation method of compound as shown in formula II that the present invention is provided, organic solvent is ring in step 3
Hexane.
Preferably, in the preparation method of compound as shown in formula II that the present invention is provided, in step 3 after condensation reaction also
The step of including purifying.
Preferably, it is pure after condensation reaction in step 3 in the preparation method of compound as shown in formula II that the present invention is provided
It is specially to be cooled to 0~60 DEG C to change, and the water, ethyl acetate with 25~35 DEG C are mixed, and are collected after organic phase, washed with brine, dry
It is dry, filtering, concentration obtain grease, take grease mixed with ethyl acetate after heating, then with isopropanol mixing crystallization, filtering,
Collect mixed solvent elution, the drying of filter cake ethyl acetate and isopropanol.
Preferably, in the adding procedure of ethyl acetate and isopropanol, the volume ratio of ethyl acetate and isopropanol is 1:
1.2。
In some embodiments of the invention, in the preparation method of compound as shown in formula II that the present invention is provided, step 4
The mol ratio of compound and sodium borohydride shown in Chinese style V is 1:3~6.
In some embodiments of the invention, in the preparation method of compound as shown in formula II that the present invention is provided, step 4
The reaction temperature of middle reduction reaction is 10~25 DEG C, and the reaction time of reduction reaction is 2~4h.
In other embodiments of the present invention, in the preparation method of compound as shown in formula II that the present invention is provided, step
The reaction time of reduction reaction is 2h in rapid 4.
Preferably, in the preparation method of compound as shown in formula II that the present invention is provided, organic solvent is four in step 4
The mixture of hydrogen furans, absolute ethyl alcohol.
Preferably, in the preparation method of compound as shown in formula II that the present invention is provided, organic solvent tetrahydrochysene furan in step 4
Mutter, the volume ratio of tetrahydrofuran and absolute ethyl alcohol is 9 in the mixture of absolute ethyl alcohol:2.
Preferably, in the preparation method of compound as shown in formula II that the present invention is provided, in step 4 after reduction reaction also
The step of including purifying.
Preferably, it is pure after reduction reaction in step 4 in the preparation method of compound as shown in formula II that the present invention is provided
Change specially with regulation pH value is mixed after glacial acetic acid regulation pH value to 4~5 with sodium acid carbonate to 7~8, mixed with ethyl acetate,
Collected organic layer is washed with brine, dry, filtering, concentration the step of.
In some embodiments of the invention, in the preparation method of compound as shown in formula II that the present invention is provided, step 5
The mol ratio of compound, dimethylformamide and phosphorous oxychloride shown in Chinese style VI is 1:2~9:2~4.
In other embodiments of the present invention, in the preparation method of compound as shown in formula II that the present invention is provided, step
The mol ratio of compound, dimethylformamide and phosphorous oxychloride shown in rapid 5 Chinese style VI is 1:6:2.
In some embodiments of the invention, in the preparation method of compound as shown in formula II that the present invention is provided, step 5
In the second substitution reaction reaction temperature be 45~55 DEG C, in step 5 reaction time of second substitution reaction be 2~4h.
In other embodiments of the present invention, in the preparation method of compound as shown in formula II that the present invention is provided, step
The reaction temperature of second substitution reaction is 45~55 DEG C in rapid 5, and the reaction time of second substitution reaction is 2h in step 5.
Preferably, in the preparation method of compound as shown in formula II that the present invention is provided, organic solvent is two in step 5
NMF.
Preferably, in the preparation method of compound as shown in formula II that the present invention is provided, compound shown in step 5 Chinese style VI
Mol ratio with organic solvent is 1:4.
Preferably, in the preparation method of compound as shown in formula II that the present invention is provided, the second substitution reaction in step 5
The step of also including purifying afterwards.
Preferably, in the preparation method of compound as shown in formula II that the present invention is provided, in step 5 after second substitution reaction
Purifying is specially that the water being cooled to after 0~40 DEG C with 10~15 DEG C is mixed, crystallization, and centrifugation collected and washed after filter cake, with anhydrous second
80 DEG C are heated to after alcohol mixing and is cooled to 30~55 DEG C plus crystal seed crystallization, 0~35 DEG C of centrifugation is cooled to, and collect filter cake, drying.
In some embodiments of the invention, in the preparation method of compound as shown in formula II that the present invention is provided, step 6
The mol ratio of compound, hydroxylamine hydrochloride and pyridine and aceticanhydride shown in Chinese style VII is 1:2~4:3~9:1~4.
In other embodiments of the present invention, in the preparation method of compound as shown in formula II that the present invention is provided, step
The mol ratio of compound, hydroxylamine hydrochloride and pyridine and aceticanhydride shown in rapid 6 Chinese style VII is 1:2:5:2
In some embodiments of the invention, in the preparation method of compound as shown in formula II that the present invention is provided, step 6
The reaction temperature of middle reaction is 10~100 DEG C, and the reaction time of reaction is 1~8h.
In other embodiments of the present invention, in the preparation method of compound as shown in formula II that the present invention is provided, step
The reaction time reacted in rapid 6 is 1.5h.
Preferably, in the preparation method of compound as shown in formula II that the present invention is provided, organic solvent is four in step 6
The mixture of hydrogen furans and dichloromethane.
Preferably, in the preparation method of compound as shown in formula II that the present invention is provided, organic solvent tetrahydrochysene furan in step 6
It is 1 to mutter with the volume ratio of tetrahydrofuran and dichloromethane in the mixture of dichloromethane:4.5.
Preferably, in the preparation method of compound as shown in formula II that the present invention is provided, also including after being reacted in step 6
The step of purifying.
Preferably, in the preparation method of compound as shown in formula II that the present invention is provided, purified after being reacted in step 6 specific
To be mixed with frozen water, marquis She and organic phase are extracted with ethyl acetate, successively with hydrochloric acid, sodium bicarbonate aqueous solution, salt water washing, plus
Activated carbon dry after filtering and concentrating, then be heated to after mix with acetone, isopropanol temperature be not less than 40 DEG C dissolve after be cooled to 0~
35 DEG C of crystallizations, are collected by centrifugation filter cake and are washed with the mixed solvent of isopropanol and acetone, in 40~50 DEG C of drying.
It is highly preferred that the volume ratio of isopropanol and acetone is 5 in the mixed solvent of isopropanol and acetone:1.
Present invention also offers a kind of method that silodosin is prepared based on compound shown in formula II, comprise the following steps：
Step 1：In the presence of a solvent, at Pd (OH) after compound shown in modus ponens II is mixed with trifluoroacetic acid2/C
Catalysis under occur the first debenzylation, obtain compound shown in formula VIII；
Step 2：Under conditions of organic solvent presence, in potassium carbonate after compound is mixed with 3- chloropropyl alcohols shown in modus ponens VIII
Catalysis under occur substitution reaction, obtain compound shown in formula Ⅸ；
Step 3：Under conditions of organic solvent presence, compound shown in modus ponens Ⅸ exists with trim,ethylchlorosilane, oxidant
React compound shown in acquisition formula Ⅹ under the catalysis of triethylene diamine；
Step 4：Under conditions of organic solvent presence, compound and R- shown in modus ponens Ⅹ（+）- a- phenyl ethylamines, acetic acid exist
In reducing environment, through PtO2Catalytic reaction gives birth to reduction amination, obtains compound shown in formula Ⅺ；
Step 5：Under conditions of organic solvent presence, compound is catalyzed in reducing environment through pd/c shown in modus ponens Ⅺ
Occur the second debenzylation, obtain compound shown in formula Ⅻ；
Step 6：Under conditions of organic solvent presence, compound shown in modus ponens Ⅻ is urged with compound shown in Formula X III in alkali
Change lower generation substitution reaction, obtain compound shown in Formula X IV；
Step 7：Compound shown in modus ponens XIV is under conditions of organic solvent presence, with hydrogen peroxide, alkali metal hydroxide
Thing catalytic reaction gives birth to hydrolysis, produces；
In some embodiments of the invention, the side that silodosin is prepared based on compound shown in formula II that the present invention is provided
In method, compound shown in step 1 Chinese style II and the mol ratio of trifluoroacetic acid are 1:5~60.
In other embodiments of the present invention, what the present invention was provided prepares silodosin based on compound shown in formula II
In method, compound shown in step 1 Chinese style II and the mol ratio of trifluoroacetic acid are 1:45.6.
In some embodiments of the invention, the side that silodosin is prepared based on compound shown in formula II that the present invention is provided
In method, the reaction temperature of first debenzylation is 20~100 DEG C in step 1, reaction time of the first debenzylation for 1~
10h。
In other embodiments of the present invention, what the present invention was provided prepares silodosin based on compound shown in formula II
In method, the reaction time of first debenzylation is 1h in step 1.
Preferably, in the method that silodosin is prepared based on compound shown in formula II that the present invention is provided, it is molten in step 1
Agent is the mixture of methanol and water.
Preferably, in the method that silodosin is prepared based on compound shown in formula II that provides of the present invention, the in step 1
The step of also including purifying after one debenzylation.
Preferably, in the method that silodosin is prepared based on compound shown in formula II that the present invention is provided, first in step 1
Purifying after debenzylation is specially to be cooled to room temperature, and filtering removes catalyst, is mixed with ethyl acetate, and pH is adjusted with ammoniacal liquor
Value is not less than 8, collected organic layer, washed with brine, dry, filtering, concentration.
In some embodiments of the invention, the side that silodosin is prepared based on compound shown in formula II that the present invention is provided
In method, compound shown in step 2 Chinese style VIII, 3- chloropropyl alcohols, the mol ratio of potassium carbonate are 1:1~3:1~3.
In some embodiments of the invention, the side that silodosin is prepared based on compound shown in formula II that the present invention is provided
In method, the reaction temperature of substitution reaction is 50~120 DEG C in step 2, and the reaction time of substitution reaction is 2~12h.
Preferably, in the method that silodosin is prepared based on compound shown in formula II that the present invention is provided, having in step 2
Machine solvent is toluene.
Preferably, in the method that silodosin is prepared based on compound shown in formula II that the present invention is provided, step 2 Chinese style VIII
Shown compound and the mol ratio of organic solvent toluene are 1:1.2~2.
In some embodiments of the invention, the side that silodosin is prepared based on compound shown in formula II that the present invention is provided
In method, compound shown in step 3 Chinese style Ⅸ, trim,ethylchlorosilane, the mol ratio of oxidant and triethylene diamine are 1:1~6:1
~4:1~5
In some embodiments of the invention, the side that silodosin is prepared based on compound shown in formula II that the present invention is provided
In method, the reaction temperature reacted in step 3 is -5~30 DEG C, and the reaction time reacted in step 3 is 0.5~5h.
Preferably, in the method that silodosin is prepared based on compound shown in formula II that the present invention is provided, having in step 3
Machine solvent is acetonitrile.
Preferably, in the method that silodosin is prepared based on compound shown in formula II that the present invention is provided, step 3 Chinese style Ⅸ
Shown compound and the mol ratio of organic solvent acetonitrile are 1:0.5~1.
Preferably, in the method that silodosin is prepared based on compound shown in formula II that the present invention is provided, it is anti-in step 3
Should after also include purifying the step of.
Preferably, in the method that silodosin is prepared based on compound shown in formula II that the present invention is provided, reacted in step 3
Purifying is specially collected organic layer after being mixed with water, ethyl acetate afterwards, successively with sodium sulfite, salt water washing, anhydrous sodium sulfate
Purified after dry, filtering, concentration with silicagel column.
In some embodiments of the invention, the side that silodosin is prepared based on compound shown in formula II that the present invention is provided
In method, compound, R- shown in step 4 Chinese style Ⅹ（+）The mol ratio of-a- phenyl ethylamines and acetic acid is 1:1~3:1~6.
In some embodiments of the invention, the side that silodosin is prepared based on compound shown in formula II that the present invention is provided
In method, the reaction temperature of catalytic hydrogen reduction aminating reaction is 30~100 DEG C in step 4, catalytic hydrogen reduction aminating reaction
Reaction time is 6~45h.
In some embodiments of the invention, the side that silodosin is prepared based on compound shown in formula II that the present invention is provided
In method, the reaction time of catalytic hydrogen reduction aminating reaction is 25~30h in step 4.
Preferably, in the method that silodosin is prepared based on compound shown in formula II that the present invention is provided, having in step 4
Machine solvent is tetrahydrofuran.
Preferably, in the method that silodosin is prepared based on compound shown in formula II that the present invention is provided, being urged in step 4
Change the step of also including purifying after hydro-reduction aminating reaction.
Preferably, in the method that silodosin is prepared based on compound shown in formula II that the present invention is provided, it is catalyzed in step 4
Purifying after hydro-reduction aminating reaction is specially to adjust pH value to 9~10 with alkali, is extracted with ethyl acetate, dried over sodium sulfate
Filter, concentrate afterwards.
Preferably, in the method that silodosin is prepared based on compound shown in formula II that the present invention is provided, having in step 5
Machine solvent is methanol.
In some embodiments of the invention, the side that silodosin is prepared based on compound shown in formula II that the present invention is provided
In method, compound shown in step 6 Chinese style XIII, compound shown in formula Ⅻ and the mol ratio of alkali are 1:1~4:1~3.Alkali is preferably
Sodium carbonate.
Preferably, in the method that silodosin is prepared based on compound shown in formula II that the present invention is provided, having in step 6
Machine solvent is acetonitrile.
Preferably, it is organic in step 6 in the method that silodosin is prepared based on compound shown in formula II that the present invention is provided
Solvent is acetonitrile.
It is highly preferred that in the method that silodosin is prepared based on compound shown in formula II that the present invention is provided, step 6 Chinese style
Compound shown in XIII and the mol ratio of organic solvent acetonitrile are 1:0.5~2.
Preferably, in the method that silodosin is prepared based on compound shown in formula II that the present invention is provided, being taken in step 6
The step of also including purifying after generation reaction.
Preferably, in the method that silodosin is prepared based on compound shown in formula II that the present invention is provided, replace in step 6
Reacted purifying is specially to be cooled to room temperature, and layering is stirred after being mixed with water and ethyl acetate, collects organic phase, is washed through salt
Wash, be dried in vacuo.
In some embodiments of the invention, the side that silodosin is prepared based on compound shown in formula II that the present invention is provided
In method, compound shown in step 7 Chinese style XIV, hydrogen peroxide, the mol ratio of alkali metal hydroxide are 1:0.1~2:0.2~3.
In some embodiments of the invention, the side that silodosin is prepared based on compound shown in formula II that the present invention is provided
In method, the reaction temperature of hydrolysis is 10~40 DEG C in step 7, and the reaction time of hydrolysis is 4~6h.
Preferably, in the method that silodosin is prepared based on compound shown in formula II that the present invention is provided, having in step 7
Machine solvent is dimethyl sulfoxide (DMSO).
Preferably, in the method that silodosin is prepared based on compound shown in formula II that the present invention is provided, step 7 Chinese style
Compound shown in XIV is 1 with the mol ratio of organic solvent dimethyl sulfoxide (DMSO):4~8.
Preferably, in the method that silodosin is prepared based on compound shown in formula II that the present invention is provided, step 7 reclaimed water
The step of also including purifying after solution reaction.
Preferably, in the method that silodosin is prepared based on compound shown in formula II that the present invention is provided, hydrolyzed in step 7
Reacted purifying is specially to be extracted through ethyl acetate, organic phase is collected through salt acid extraction, again through second after being neutralized with sodium acid carbonate
Acetoacetic ester is extracted, and collects organic phase successively through bag and sodium bicarbonate aqueous solution and salt water washing, anhydrous sodium sulfate drying, concentration
Afterwards, dissolved, cooled down with ethyl acetate.
The present invention provides a kind of Silodosin intermediate and preparation method thereof, and prepares silodosin with the intermediate
Method.The technique of intermediate synthesis silodosin have economy, safety, high-purity, in high yield the characteristics of, it is big suitable for industrialization
Production.
Brief description of the drawings
Fig. 1 shows the nuclear magnetic resonance map of compound shown in obtained formula II in embodiment 1；
Fig. 2 shows the NMR spectra of obtained silodosin in embodiment 2.
Embodiment
Silodosin is prepared the invention discloses a kind of Silodosin intermediate and preparation method thereof, and with the intermediate
Method, those skilled in the art can use for reference present disclosure, be suitably modified technological parameter realization.In particular,
All similar replacements and change are apparent to those skilled in the art, and they are considered as being included in this hair
It is bright.The method of the present invention and application are described by preferred embodiment, and related personnel can substantially not depart from this hair
Method described herein and application are modified in bright content, spirit and scope or suitably change is with combining, to realize and answer
Use the technology of the present invention.
Silodosin intermediate that the present invention is provided and preparation method thereof, and prepare with the intermediate side of silodosin
Agents useful for same can be bought by market in method.
With reference to embodiment, the present invention is expanded on further：
The preparation of compound shown in the formula II of embodiment 1
The preparation of compound shown in formula III：
Raw material：
A, benzyl chloride（M=126.5） 1265g(10.0mol)
B, indoline（M=119.17） 596g(5.0mol)
C, water 1Kg (55.5mol)
D, sodium acid carbonate（M=84） 840g(10.0mol)
Feed intake：a：b：d=2：1：2（Mol ratio）, a, b reactant, c, d are catalyst.
A, c, d are added in 3L reaction bulbs, 60-90 DEG C is risen to, b is added dropwise into reaction solution, is dripped off small in 95 DEG C of stirrings 1
When, HPLC detections.
Reaction terminates in backward reaction solution plus toluene 2L, and stirring layering, organic layer are washed once with water 1L, are dried, and filtering is dense
Contracting, obtains compound 1.17Kg shown in formula III（87.9%）.
The preparation of compound shown in formula IV：
Raw material：
A, dimethylformamide（M=73.09） 730.9Kg（10.0mol）
B, phosphorous oxychloride（M=153.5） 1535Kg（10.0mol）
Compound shown in c, formula III（M=209 87.9%）1.17Kg (is calculated) with 5mol
Feed intake：a：b：c=2：2：1；
A is added in reaction bulb, external application ice bath is cooled to 0-10 DEG C, and b is slowly added dropwise（2h）, drip off and reacted at a temperature of this
Half an hour, then by c in less than 25 DEG C additions, add after rising to 10-30 DEG C of reaction 6 hours, HPLC detections, reaction is complete.
Reaction solution is cooled down to 0-5 DEG C, in the frozen water that reaction solution is poured into 5.5Kg, the 24%NaOH aqueous solution is used in stirring（Consumption
3L）PH to 9 is adjusted, stirring has solid precipitation, filters, filter cake obtains wet product G=with being largely originally washed to neutrality, refiltering
1.3Kg（Colour of loess particle）, into wet product plus ethyl acetate 2.5L, be heated to it is complete it is molten after, half an hour mistake is stirred in the cooling of external application frozen water
Filter, after filter cake is washed once with ethyl acetate, buff powder G=675g is obtained in 50-80 DEG C of drying（Purity 95%）, filtrate recovery
Obtain compound 235g shown in formula IV.
The preparation of compound shown in formula V：
Raw material：
Feed intake：a：b：c：e=1：2：6：2, a, c reactants, b catalyst, d solvents, e antioxidant.
A, b, c, d, e are added in reaction bulb in the lump, reacted 16 hours in 80 DEG C under band water knockout drum, nitrogen protection, HPLC
Detect starting material left 2%, you can stop reaction.
Reaction solution is cooled to 0-60 DEG C, in the frozen water for pouring into 800g（Control temperature best near 25-35 DEG C）, then add
Enter ethyl acetate 1.35Kg, stirring layering, water layer is extracted once again with ethyl acetate 680g again, merges organic phase, with 500ml ×
2 salt are washed twice, are dried, and filtering is concentrated to give 780g grease.Add ethyl acetate 700g into this grease, be heated to
Dissolving, then add isopropanol 890g, it is stirred at room temperature 12 hours（Plus crystal seed）Crystallization, filtering, filter cake mixed solvent（Acetic acid second
Ester：Isopropanol=1:1.2）A little elution, obtains red powder 530g, i.e., compound shown in formula V in 50 DEG C of drying（Purity 96~
98%, yield 70%）
The preparation of compound shown in formula VI：
Raw material：
Feed intake：a:b=1:3, a reactants, b is reducing agent, and other are solvent.
B, c, d are added in reaction bulb, nitrogen protection, external application ice salt bath is cooled to after 0 DEG C, a, e preparation drop are entered, protected
Dropping temperature is held near 0 DEG C（-5-5℃）, drip off warm naturally to 10~25 DEG C react 2 hours.HPLC detects raw material reaction
Completely.
Reaction solution is slowly poured into 560g frozen water, stirring is lower to be adjusted near pH to 4~5 with 50% glacial acetic acid（About consume ice second
Sour 100g）, stir 1 hour, then add sodium bicarbonate solid thereto（About 226g）Adjust pH to 7~8（Stir 1 hour）, plus acetic acid second
After ester 670g, stir 20 minutes, layering, water layer is extracted once again with 300g ethyl acetate, merge organic layer, use salt solution
225mL × 2 are washed twice, are dried, and are filtered, and concentration obtains brown oil 145g, i.e., compound shown in formula VI, and purity 90~
96%。
The preparation of compound shown in formula VII：
Raw material：
Compound shown in a, formula VI（M=294） 42.6g（0.145mol）
B, dimethylformamide（M=73.09） 63.1g（0.870mol）
C, phosphorous oxychloride（M=153.5） 44.2g（0.290mol）
D, dimethylformamide（M=73.09） 88.4g（0.580mol）
Feed intake：a：b：c：d=1：6：2：4, a, b, c are reactant, and d is solvent.
B is added in reaction bulb, nitrogen protection, cryosel is cooled near -5-5 DEG C, c is added dropwise, dropping temperature is no more than 5 DEG C
It is advisable, drips off and reacted half an hour after in -5~5 DEG C of ice baths, then preparation liquid is added dropwise（A is dissolved in d）, do not exceed 30 DEG C, plus
After complete, it be warming up to 45~55 DEG C and react 2 hours, HPLC detection raw materials, which are basically unchanged, stops reaction.
Reaction solution is cooled down less than 40 DEG C, then it is slowly instilled in 530g 10~15 DEG C of running water, heat release（External application
Running water is incubated near 30 DEG C, does not exceed 35 DEG C）, add within about 1 hour, gradually there is solid precipitation during dropwise addition（Such as nothing
Solid, can add crystal seed）, stirring half an hour is added, is then nearby stirred 4 hours in 20 DEG C, suction filtration, filter cake is drenched with a large amount of water
Wash.
Into filter cake plus absolute ethyl alcohol 153g, be heated to 80 DEG C it is complete molten, when 40~55 DEG C are cooled under stirring, plus crystal seed,
Treat that temperature is down to 0-35 DEG C, you can suction filtration, wet product 53g of the purity 98~99% is obtained, if above-mentioned crude product is yellow powder entirely
End, refines an impurity just qualified.If impurity is unqualified, then use 125Kg absolute ethyl alcohols again, with same method essence
System, obtains wet product 48g, compound shown in 30g formulas VII, purity 98~99.5% is obtained in 50 DEG C of drying.
The preparation of compound shown in formula II：
Raw material：
Feed intake：a：b：c：d=1：4：2：1.8；A, c, d are reactant, and b is catalyst, and e, f are solvent.
A, b, c, e, f are added in reaction bulb, nitrogen protection after temperature is risen into 40 DEG C of isothermal reactions 8 hours, is turned off
Heating is initially added into d from 40 DEG C, there is warming phenomenon during dropwise addition（Maintain the reflux for）, drip off and be warming up to back flow reaction half an hour
（Temperature is about at 50-60 DEG C）HPLC is detected afterwards.
Reaction solution is poured into 100L frozen water while hot, is extracted twice with ethyl acetate 70Kg and 30Kg, merges organic layer, according to
It is secondary respectively to be washed once with 1N hydrochloric acid 50L, sodium bicarbonate aqueous solution 40L, salt solution 40L, dry（Add activated carbon 4Kg when drying）, filtering,
Concentration, obtains 32Kg brown oil.Add acetone 18Kg, isopropanol 90Kg into concentrate, be heated to more than 40 DEG C, Quan Rong
Xie Hou, is put in stirring and crystallizing 12 hours at room temperature, centrifugation, filter cake mixed solvent（Isopropanol：Acetone=5：1）Wash a little, product
Yellow is obtained to off-white powder 22Kg in drying at 40-50 DEG C.The nuclear magnetic spectrum of the compound is as shown in figure 1, the i.e. institute of formula II
Show compound.
The preparation of the silodosin of embodiment 2
The preparation of compound shown in formula VIII：
Raw material：
Feed intake：a：e=1:45.6；A, e are reactant, and b is catalyst, and c, d are solvent.
A, c, d, e are added in reaction bulb, stirred after half an hour, then b is added thereto, b is added, starts logical hydrogen, leads to
After hydrogen one minute, it is warming up to 60 DEG C and reacts 1 hour, HPLC detections, raw material reaction is complete, you can processing.
Reaction solution is cooled to after room temperature, filtered, catalyst is removed, 150ml ethyl acetate is added into filtrate, is adjusted with ammoniacal liquor
PH is to PH >=8, after stirring half an hour, repetition measurement PH, layering, and water layer is extracted once with 100ml ethyl acetate again, is merged organic
Layer, is washed twice with 50ml saturated brine, is dried, and filtering is concentrated to give compound 1.96g shown in formula VIII（Yield 85%）.
The preparation of compound shown in formula Ⅸ：
3- chloropropyl alcohols are taken to be reacted with compound shown in formula VIII, toluene is solvent, and potassium carbonate is catalyst, chemical combination shown in formula VIII
The ratio of thing and 3- chloropropyl alcohols is 1：3；Compound shown in formula VIII and the ratio of potassium carbonate are 1：1, occur substitution reaction in 80 DEG C,
Reaction time is 7h, obtains compound shown in formula Ⅸ, and yield is 80%.
The preparation of compound shown in formula Ⅹ：
Compound and b shown in formula Ⅸ are added in reaction vessel, C is added in 30 DEG C, d was added in 30 minutes, is continued
Reaction 1 hour, e is added dropwise in 30 DEG C, and 30 DEG C are reacted 1 hour, 500ml water are added after reaction completely, with 2 × 500ml ethyl acetate
Extract, organic layer sodium sulfite solution, salt water washing, anhydrous sodium sulfate drying, filtering, concentration（Decompression）, residue silicon
Glue post is purified, and obtains micro-yellow powder 74.2g, i.e., compound shown in formula Ⅹ, yield 81.5%, purity 97.8%.
The preparation of compound shown in formula Ⅺ：
Compound shown in 0.1mol formulas Ⅹ is dissolved in 300mlTHF, adds R-（+）- a- phenyl ethylamines 12.1g（0.1mol）,
Add AcOH36g (0.6mol), 0.5gPtO2, H2, 60 DEG C, in stirring 22h under 2.5 atmospheric pressure, filter off PtO2, are concentrated under reduced pressure.
Alkali is adjusted to pH9-10, ethyl acetate extraction, Na2SO4Dry, filter, concentration obtains compound shown in formula Ⅺ
31.0g（Yield 85%）.
The preparation of compound shown in formula Ⅻ：
By compound 31.0g shown in formula Ⅺ（85mmol）It is placed in 50ml methanol, addition pd/c (4.84g,
47.91mmol), H is then passed to2, react 28 hours.Filter out Pd/C, filtrate concentration.Acetone is heated to reflux dissolving, naturally cold
But, white solid precipitation is obtained.HPLC determines reaction solution, compound 18.9g as shown in formula Ⅻ（Yield 86%, purity 94%）.
The preparation of compound shown in Formula X IV：
Add compound, 318g shown in 259g (1mol) formula Ⅻ（3mol）Sodium carbonate and 79.6g（0.254mol）Formula X III
Shown compound is in acetonitrile（Compound shown in Formula X III and the mol ratio of acetonitrile are 1:0.5）Middle reaction, is heated to reflux temperature,
Terminate to reaction.After reaction terminates, cooling reactant to room temperature adds water and ethyl acetate, and stirring layering has with salt water washing
Machine phase, obtains compound shown in Formula X IV, is dried under vacuum, obtains product 110g, yield 91%.
The preparation of silodosin：
Using dimethyl sulfoxide (DMSO) as solvent, by compound shown in Formula X IV 48% hydrogen peroxide and 20% naoh treatment,
It is stirred at room temperature to reaction and terminates, wherein, the mol ratio of compound, hydrogen peroxide and alkali metal hydroxide shown in Formula X IV
For 1:1:1.6, reaction temperature is 25 DEG C, and the reaction time of reaction is 4h.After reaction terminates, reactant adds 5% sulfurous acid
In sodium and ethyl acetate, extracted with ethyl acetate, sodium chloride solution washing organic phase, anhydrous sodium sulfate drying, filtering, concentration,
Solid silodosin is obtained, yield is 95 %.
Detect spectrogram as shown in Fig. 2 NMR（DMSO-d6）：0.91-1.01（3H）, 1.51-1.62（1H）, 1.63-1.71
（2H）, 2.31-2.42（1H）, 2.61-2.73（1H）, 2.80-3.02（5H）, 3.11-3.25（2H）, 3.31-3.42（2H）,
3.40-3.52（2H）, 4.01-4.13（2H）, 4.24-4.32（1H）, 4.62-4.81（2H）, 6.91-7.15（6H）, 7.21-
7.33（1H）, 7.51-7.62（1H）.
The preparation of compound shown in the formula II of embodiment 3
The preparation of compound shown in formula III：
Raw material：
A, benzyl chloride（M=126.5） 2530g（20.0mol）
B, indoline（M=119.17） 596g（5.0mol）
C, water 1Kg（55.5mol）
D, sodium acid carbonate（M=84） 1680g（20.0mol）
Feed intake：a：b：d=4：1：4（Mol ratio）, a, b are reactant, and c, d are catalyst.
A, c, d are added in 3L reaction bulbs and rise to 60-90 DEG C, b is added dropwise into reaction solution, is dripped off small in 95 DEG C of stirrings 14
When, HPLC detections.
Reaction terminates in backward reaction solution plus toluene 2L, and stirring layering, organic layer are washed once with water 1L, dried, are filtered dense
Contracting, obtains compound 1.17Kg shown in formula III（Purity 87.9%）.
The preparation of compound shown in formula IV：
Raw material：
A, dimethylformamide（M=73.09） 3289.05Kg（35.0mol）
B, phosphorous oxychloride（M=153.5） 3070Kg（20.0mol）
Compound shown in c, formula III（M=209 87.9%）1.17Kg (is calculated) with 5mol
Feed intake：a：b：c=9：4：1；
A is added in reaction bulb, external application ice bath is cooled to 0-10 DEG C, and b is slowly added dropwise（2h）, drip off and reacted at a temperature of this
Half an hour, then by c in less than 25 DEG C additions, add after rising to 10-30 DEG C of reaction 6 hours, HPLC, reaction is complete.
Reaction solution is cooled down to 0-5 DEG C, in the frozen water that reaction solution is poured into 5.5Kg, the 24%NaOH aqueous solution is used in stirring（Consumption
3L）PH to 9 is adjusted, stirring has solid precipitation, filters, filter cake obtains wet product G=with being largely originally washed to neutrality, refiltering
1.3Kg（Colour of loess particle）, into wet product plus ethyl acetate 2.5L, be heated to it is complete it is molten after, half an hour mistake is stirred in the cooling of external application frozen water
Filter, filter cake is washed once with ethyl acetate, and buff powder G=675g is obtained in 50-80 DEG C of drying（Purity 95%）, filtrate reclaims
To compound 235g shown in formula IV.
The preparation of compound shown in formula V：
Raw material：
Feed intake：a：b：c：e=1：4：9：4, a, c reactants, b catalyst, d solvents, e antioxidant.
A, b, c, d, e are added in reaction bulb in the lump, reacted 16 hours in 80 DEG C under band water knockout drum, nitrogen protection, HPLC
Detect starting material left 2%, you can stop reaction.
Reaction solution is cooled to 0-60 DEG C, in the frozen water for pouring into 800g（Control temperature best near 25-35 DEG C）, then add
Enter ethyl acetate 1.35Kg, stirring layering, water layer is extracted once again with ethyl acetate 680g again, merges organic phase, with 500ml ×
2 salt are washed twice, are dried, and filtering is concentrated to give 780g grease.Add ethyl acetate 700g into this grease, be heated to
Dissolving, then add isopropanol 890g, it is stirred at room temperature 12 hours（Plus crystal seed）Crystallization, filtering, filter cake mixed solvent（Acetic acid second
Ester：Isopropanol=1:1.2）A little elution, obtains red powder 530g, i.e., compound shown in formula V in 50 DEG C of drying（Purity 96~
98%, yield 70%）
The preparation of compound shown in formula VI：
Raw material：
Feed intake：a:b=1:6, a, b reactants, other are solvent.
B, c, d are added in reaction bulb, nitrogen protection, external application ice salt bath is cooled to after 0 DEG C, a, e preparation drop are entered, protected
Dropping temperature is held near 0 DEG C（-5-5℃）, drip off warm naturally to 10~25 DEG C react 2 hours.HPLC detects raw material reaction
Completely.
Reaction solution is slowly poured into 560g frozen water, stirring is lower to be adjusted near pH to 4~5 with 50% glacial acetic acid（About consume ice second
Sour 100g）, stir 1 hour, then add sodium bicarbonate solid thereto（About 226g）Adjust pH to 7~8（Stir 1 hour）, plus acetic acid second
After ester 670g, stir 20 minutes, layering, water layer is extracted once again with 300g ethyl acetate, merge organic layer, use salt solution
225mL × 2 are washed twice, are dried, and are filtered, and concentration obtains brown oil 145g, i.e., compound shown in formula VI, and purity 90~
96%。
The preparation of compound shown in formula VII：
Raw material：
Compound shown in a, formula VI（M=294） 42.6g（0.145mol）
B, dimethylformamide（M=73.09） 94.67g（1.305mol）
C, phosphorous oxychloride（M=153.5） 88.4g（0.580mol）
D, dimethylformamide（M=73.09） 88.4g（0.580mol）
Feed intake：a：b：c：d=1：9：4：4, a, b, c are reactant, and d is solvent.
B is added in reaction bulb, nitrogen protection, cryosel is cooled near -5-5 DEG C, c is added dropwise, dropping temperature is no more than 5 DEG C
It is advisable, drips off and reacted half an hour after in -5~5 DEG C of ice baths, then preparation liquid is added dropwise（A is dissolved in d）, do not exceed 30 DEG C, plus
After complete, it be warming up to 45~55 DEG C and react 2 hours, HPLC detection raw materials, which are basically unchanged, stops reaction.
Reaction solution is cooled down less than 40 DEG C, then it is slowly instilled in 530g 10~15 DEG C of running water, heat release（External application
Running water is incubated near 30 DEG C, does not exceed 35 DEG C）, add within about 1 hour, gradually there is solid precipitation during dropwise addition（Such as nothing
Solid, can add crystal seed）, stirring half an hour is added, is then nearby stirred 4 hours in 20 DEG C, suction filtration, filter cake is drenched with a large amount of water
Wash.
Into filter cake plus absolute ethyl alcohol 153g, be heated to 80 DEG C it is complete molten, when 40~55 DEG C are cooled under stirring, plus crystal seed,
Treat that temperature is down to 0-35 DEG C, you can suction filtration, wet product 53g of the purity 98~99% is obtained, if above-mentioned crude product is yellow powder entirely
End, refines an impurity just qualified.If impurity is unqualified, then use 125Kg absolute ethyl alcohols again, with same method essence
System, obtains wet product 48g, compound shown in 30g formulas VII, purity 98~99.5% is obtained in 50 DEG C of drying.
The preparation of compound shown in formula II：
Raw material：
Feed intake：a：b：c：d=1：6：4：3；A, c, d are reactant, and b is catalyst, and e, f are solvent.
A, b, c, e, f are added in reaction bulb, nitrogen protection after temperature is risen into 40 DEG C of isothermal reactions 8 hours, is turned off
Heating is initially added into d from 40 DEG C, there is warming phenomenon during dropwise addition（Maintain the reflux for）, drip off and be warming up to back flow reaction half an hour
（Temperature is about at 50-60 DEG C）HPLC is detected afterwards.
Reaction solution is poured into 100L frozen water while hot, is extracted twice with ethyl acetate 70Kg and 30Kg, merges organic layer, according to
It is secondary respectively to be washed once with 1N hydrochloric acid 50L, sodium bicarbonate aqueous solution 40L, salt solution 40L, dry（Add activated carbon 4Kg when drying）, filtering,
Concentration, obtains 32Kg brown oil.Add acetone 18Kg, isopropanol 90Kg into concentrate, be heated to more than 40 DEG C, Quan Rong
Xie Hou, is put in stirring and crystallizing 12 hours at room temperature, centrifugation, filter cake mixed solvent（Isopropanol：Acetone=5：1）Wash a little, product
Yellow is obtained to off-white powder 22Kg in drying at 40-50 DEG C.The nuclear magnetic spectrum of the compound is as shown in figure 1, the i.e. institute of formula II
Show compound.
The preparation of the silodosin of embodiment 4
The preparation of compound shown in formula VIII：
Raw material：
Feed intake：a：e=1:60；A and e is reactant, and b is catalyst, and c, d are solvent.
A, c, d, e are added in reaction bulb, stirred after half an hour, then b is added thereto, after b is added, starts logical hydrogen,
After ventilation 1 minute, it is warming up to 100 DEG C and reacts 4 hours, HPLC detections, raw material reaction is complete, that is, handles.
Reaction solution is cooled to after room temperature, filtered, catalyst is removed, 150ml ethyl acetate is added into filtrate, is adjusted with ammoniacal liquor
PH is to PH >=8, after stirring half an hour, repetition measurement PH, layering, and water layer is extracted once with 100ml ethyl acetate again, is merged organic
Layer, is washed twice with 50ml saturated brine, is dried, and filtering is concentrated to give compound 1.96g shown in formula VIII（Yield 85%）.
The preparation of compound shown in formula Ⅸ：
3- chloropropyl alcohols are taken to be reacted with compound shown in formula VIII, toluene is solvent, and potassium carbonate is catalyst, chemical combination shown in formula VIII
The ratio of thing and 3- chloropropyl alcohols is 1：1；Compound shown in formula VIII and the ratio of potassium carbonate are 1：3, occur substitution in 120 DEG C anti-
Should, the reaction time is 2h, obtains compound shown in formula Ⅸ, and yield is 80%.
The preparation of compound shown in formula Ⅹ：
Raw material：
Feed intake：Compound shown in formula Ⅸ, trim,ethylchlorosilane, the mol ratio of oxidant and triethylene diamine are 1:3:1:5.
Compound and b shown in formula Ⅸ are added in reaction vessel, C is added in 0 DEG C, d was added in 30 minutes, continues anti-
Answer 1 hour, e is added dropwise in less than 20 DEG C, 20 DEG C are reacted 0.5 hour, 500ml water are added after reaction completely, with 2 × 500ml acetic acid
Ethyl ester is extracted, organic layer sodium sulfite solution, salt water washing, anhydrous sodium sulfate drying, filtering, concentration（Decompression）, residue
Purified with silicagel column, obtain micro-yellow powder 74.2g, i.e., compound shown in formula Ⅹ, yield 81.5%, purity 97.8%.
The preparation of compound shown in formula Ⅺ：
Compound shown in 0.1mol formulas Ⅹ is dissolved in 300mlTHF, adds R-（+）- a- phenyl ethylamines 36.3g（0.3mol）,
Add AcOH6.0g (0.1mol), 0.5gPtO2, H2, 30 DEG C, in stirring 45h under 2.5 atmospheric pressure, filter off PtO2, are concentrated under reduced pressure.
Alkali is adjusted to pH9-10, ethyl acetate extraction, Na2SO4Dry, filter, concentration obtains compound shown in formula Ⅺ
31.0g（Yield 85%）.
The preparation of compound shown in formula Ⅻ：
By compound 31.0g shown in formula Ⅺ（85mmol）It is placed in 50ml methanol, addition pd/c (4.84g,
47.91mmol), H is then passed to2, react 28 hours.Filter out Pd/C, filtrate concentration.Acetone is heated to reflux dissolving, naturally cold
But, the precipitation of 18.9g white solids is obtained.HPLC measure reaction solutions, compound as shown in formula Ⅻ, yield is 86%, purity 94%.
The preparation of compound shown in Formula X IV：
Compound is in acetonitrile shown in compound shown in addition 4mol formulas Ⅻ, 2mol sodium carbonate and 1mol Formula X III（Formula X III
Shown compound and the mol ratio of acetonitrile are 1:2）Middle reaction, is heated to reflux temperature, terminates to reaction.It is cold after reaction terminates
But reactant adds water and ethyl acetate to room temperature, and stirring layering, with salt water washing organic phase, obtains compound shown in Formula X IV
420g, is dried under vacuum, and yield is 88%.
The preparation of silodosin：
Using dimethyl sulfoxide (DMSO) as solvent, by compound shown in Formula X IV 48% hydrogen peroxide and 20% naoh treatment,
It is stirred at room temperature to reaction and terminates, wherein, the mol ratio of compound, hydrogen peroxide and alkali metal hydroxide shown in Formula X IV
For 1:2:0.2, reaction temperature is 10 DEG C, and the reaction time of reaction is 6h.After reaction terminates, reactant adds 5% sulfurous acid
In sodium and ethyl acetate, extracted with ethyl acetate, sodium chloride solution washing organic phase, anhydrous sodium sulfate drying, filtering, concentration,
Solid silodosin is obtained, yield is 95%.
The preparation of compound shown in the formula II of embodiment 5
The preparation of compound shown in formula III：
Raw material：
A, benzyl chloride（M=126.5） 632.5g（5.0mol）
B, indoline（M=119.17） 596g（5.0mol）
C, water 1Kg
D, sodium acid carbonate（M=84） 420g（5.0mol）
Feed intake：a：b：d=1：1：1（Mol ratio）, a, b reaction, c, d are catalyst.
A, c, d are added in 3L reaction bulbs and rise to 60-90 DEG C, b is added dropwise into reaction solution, is dripped off small in 95 DEG C of stirrings 14
When, HPLC detections.
Reaction terminates in backward reaction solution plus toluene 2L, and stirring layering, organic layer are washed once with water 1L, dried, are filtered dense
Contracting, obtains compound 1.17Kg shown in formula III（Purity 87.9%）.
The preparation of compound shown in formula IV：
Raw material：
A, dimethylformamide（M=73.09） 2558.2Kg（35.0mol）
B, phosphorous oxychloride（M=153.5） 2302.5Kg（15.0mol）
Compound shown in c, formula III（M=209 87.9%）1.17Kg (is calculated) with 5mol
Feed intake：a：b：c=7：3：1；
A is added in reaction bulb, external application ice bath is cooled to 0-10 DEG C, and b is slowly added dropwise（2h）, drip off and reacted at a temperature of this
Half an hour, then by c in less than 25 DEG C additions, add after rising to 10-30 DEG C of reaction 6 hours, HPLC, reaction is complete.
Reaction solution is cooled down to 0-5 DEG C, in the frozen water that reaction solution is poured into 5.5Kg, the 24%NaOH aqueous solution is used in stirring（Consumption
3L）PH to 9 is adjusted, stirring has solid precipitation, filters, filter cake obtains wet product G=with being largely originally washed to neutrality, refiltering
1.3Kg（Colour of loess particle）, into wet product plus ethyl acetate 2.5L, be heated to it is complete it is molten after, half an hour mistake is stirred in the cooling of external application frozen water
Filter, filter cake is washed once with ethyl acetate, and buff powder G=675g is obtained in 50-80 DEG C of drying（Purity 95%）, filtrate reclaims
To compound 235g shown in formula IV.
The preparation of compound shown in formula V：
Raw material：
Feed intake：a：b：c：e=1：1：：1：1, a, c is reactant, b catalyst, d solvents, e antioxidant.
A, b, c, d, e are added in reaction bulb in the lump, reacted 16 hours in 80 DEG C under band water knockout drum, nitrogen protection, HPLC
Detect starting material left 2%, you can stop reaction.
Reaction solution is cooled to 0-60 DEG C, in the frozen water for pouring into 800g（Control temperature best near 25-35 DEG C）, then add
Enter ethyl acetate 1.35Kg, stirring layering, water layer is extracted once again with ethyl acetate 680g again, merges organic phase, with 500ml ×
2 salt are washed twice, are dried, and filtering is concentrated to give 780g grease.Add ethyl acetate 700g into this grease, be heated to
Dissolving, then add isopropanol 890g, it is stirred at room temperature 12 hours（Plus crystal seed）Crystallization, filtering, filter cake mixed solvent（Acetic acid second
Ester：Isopropanol=1:1.2）A little elution, obtains red powder 530g, i.e., compound shown in formula V in 50 DEG C of drying（Purity 96~
98%, yield 70%）
The preparation of compound shown in formula VI：
Raw material：
Feed intake：a：b=1:5, a, b is reactant, and other are solvent.
B, c, d are added in reaction bulb, nitrogen protection, external application ice salt bath is cooled to after 0 DEG C, a, e preparation drop are entered, protected
Dropping temperature is held near 0 DEG C（-5-5℃）, drip off warm naturally to 10~25 DEG C react 2 hours.HPLC detects raw material reaction
Completely.
Reaction solution is slowly poured into 560g frozen water, stirring is lower to be adjusted near pH to 4~5 with 50% glacial acetic acid（About consume ice second
Sour 100g）, stir 1 hour, then add sodium bicarbonate solid thereto（About 226g）Adjust pH to 7~8（Stir 1 hour）, plus acetic acid second
After ester 670g, stir 20 minutes, layering, water layer is extracted once again with 300g ethyl acetate, merge organic layer, use salt solution
225mL × 2 are washed twice, are dried, and are filtered, and concentration obtains brown oil 145g, i.e., compound shown in formula VI, and purity 90~
96%。
The preparation of compound shown in formula VII：
Raw material：
Compound shown in a, formula VI（M=294） 42.6g（0.145mol）
B, dimethylformamide（M=73.09） 21.2g（0.290mol）
C, phosphorous oxychloride（M=153.5） 66.8g（0.435mol）
D, dimethylformamide（M=73.09） 42.4g（0.580mol）
Feed intake：a：b：c：d=1：2：3：4, a, b, c are reactant, and d is solvent.
B is added in reaction bulb, nitrogen protection, cryosel is cooled near -5-5 DEG C, c is added dropwise, dropping temperature is no more than 5 DEG C
It is advisable, drips off and reacted half an hour after in -5~5 DEG C of ice baths, then preparation liquid is added dropwise（A is dissolved in d）, do not exceed 30 DEG C, plus
After complete, it be warming up to 45~55 DEG C and react 2 hours, HPLC detection raw materials, which are basically unchanged, stops reaction.
Reaction solution is cooled down less than 40 DEG C, then it is slowly instilled in 530g 10~15 DEG C of running water, heat release（External application
Running water is incubated near 30 DEG C, does not exceed 35 DEG C）, add within about 1 hour, gradually there is solid precipitation during dropwise addition（Such as nothing
Solid, can add crystal seed）, stirring half an hour is added, is then nearby stirred 4 hours in 20 DEG C, suction filtration, filter cake is drenched with a large amount of water
Wash.
Into filter cake plus absolute ethyl alcohol 153g, be heated to 80 DEG C it is complete molten, when 40~55 DEG C are cooled under stirring, plus crystal seed,
Treat that temperature is down to 0-35 DEG C, you can suction filtration, wet product 53g of the purity 98~99% is obtained, if above-mentioned crude product is yellow powder entirely
End, refines an impurity just qualified.If impurity is unqualified, then use 125Kg absolute ethyl alcohols again, with same method essence
System, obtains wet product 48g, compound shown in 30g formulas VII, purity 98~99.5% is obtained in 50 DEG C of drying.
The preparation of compound shown in formula II：
Raw material：
Feed intake：a：b：c：d=1：5：3：2.4；A, c, d are reactant, and b is catalyst, and e, f are solvent.
A, b, c, e, f are added in reaction bulb, nitrogen protection after temperature is risen into 40 DEG C of isothermal reactions 8 hours, is turned off
Heating is initially added into d from 40 DEG C, there is warming phenomenon during dropwise addition（Maintain the reflux for）, drip off and be warming up to back flow reaction half an hour
（Temperature is about at 50-60 DEG C）HPLC is detected afterwards.
Reaction solution is poured into 100L frozen water while hot, is extracted twice with ethyl acetate 70Kg and 30Kg, merges organic layer, according to
It is secondary respectively to be washed once with 1N hydrochloric acid 50L, sodium bicarbonate aqueous solution 40L, salt solution 40L, dry（Add activated carbon 4Kg when drying）, filtering,
Concentration, obtains 32Kg brown oil.Add acetone 18Kg, isopropanol 90Kg into concentrate, be heated to more than 40 DEG C, Quan Rong
Xie Hou, is put in stirring and crystallizing 12 hours at room temperature, centrifugation, filter cake mixed solvent（Isopropanol：Acetone=5：1）Wash a little, product
Yellow is obtained to off-white powder 22Kg in drying at 40-50 DEG C.The nuclear magnetic spectrum of the compound is as shown in figure 1, the i.e. institute of formula II
Show compound.
The preparation of the silodosin of embodiment 6
The preparation of compound shown in formula VIII：
Raw material：
Feed intake：a：e=1:50；A and e is reactant, and b is catalyst, and c, d are solvent.
A, c, d, e are added in reaction bulb, stirred after half an hour, then b is added thereto, after b is added, starts logical hydrogen,
After ventilation 1 minute, it is warming up to 20 DEG C and reacts 10 hours, HPLC detections, raw material reaction is complete, that is, handles.
Reaction solution is cooled to after room temperature, filtered, catalyst is removed, 150ml ethyl acetate is added into filtrate, is adjusted with ammoniacal liquor
PH is to PH >=8, after stirring half an hour, repetition measurement PH, layering, and water layer is extracted once with 100ml ethyl acetate again, is merged organic
Layer, is washed twice with 50ml saturated brine, is dried, and filtering is concentrated to give compound 1.96g shown in formula VIII（Yield 85%）.
The preparation of compound shown in formula Ⅸ：
3- chloropropyl alcohols are taken to be reacted with compound shown in formula VIII, toluene is solvent, and potassium carbonate is catalyst, chemical combination shown in formula VIII
The ratio of thing and 3- chloropropyl alcohols is 1：2；Compound shown in formula VIII and the ratio of potassium carbonate are 1：2.5, occur substitution in 50 DEG C anti-
Should, the reaction time is 12h, obtains compound shown in formula Ⅸ, and yield is 80%.
The preparation of compound shown in formula Ⅹ：
Raw material：
Feed intake：Compound shown in formula Ⅸ, trim,ethylchlorosilane, the mol ratio of oxidant and triethylene diamine are 1:6:3：1.
Compound and b shown in formula Ⅸ are added in reaction vessel, c is added in -5 DEG C, d was added in 30 minutes, is continued
Reaction 1 hour, e is added dropwise in less than 10 DEG C, and 10 DEG C are reacted 5 hours, 500ml water are added after reaction completely, with 2 × 500ml acetic acid
Ethyl ester is extracted, organic layer sodium sulfite solution, salt water washing, anhydrous sodium sulfate drying, filtering, concentration（Decompression）, residue
Purified with silicagel column, obtain micro-yellow powder 74.2g, i.e., compound shown in formula Ⅹ, yield 81.5%, purity 97.8%.
The preparation of compound shown in formula Ⅺ：
Compound shown in 0.1mol formulas Ⅹ is dissolved in 300mlTHF, adds R-（+）- a- phenyl ethylamines 24.2g（0.2mol）,
Add AcOH24.0g (0.4mol), 0.5gPtO2, H2, 100 DEG C, in stirring 6h under 2.5 atmospheric pressure, filter off PtO2, depressurize dense
Contracting.
Alkali is adjusted to pH9-10, ethyl acetate extraction, Na2SO4Dry, filter, concentration obtains compound shown in formula Ⅺ
31.0g（Yield 85%）.
The preparation of compound shown in formula Ⅻ：
By compound 31.0g shown in formula Ⅺ（85mmol）It is placed in 50ml methanol, addition pd/c (4.84g,
47.91mmol), H is then passed to2, react 28 hours.Filter out Pd/C, filtrate concentration.Acetone is heated to reflux dissolving, naturally cold
But, the precipitation of 18.9g white solids is obtained.HPLC measure reaction solutions, compound as shown in formula Ⅻ, yield is 86%, purity 94%.
The preparation of compound shown in Formula X IV：
Compound is in acetonitrile shown in compound shown in addition 2mol formulas Ⅻ, 1mol sodium carbonate and 1mol Formula X III（Formula X III
Shown compound and the mol ratio of acetonitrile are 1:1）Middle reaction, is heated to reflux temperature, terminates to reaction.It is cold after reaction terminates
But reactant adds water and ethyl acetate to room temperature, and stirring layering, with salt water washing organic phase, obtains compound shown in Formula X IV
418g, is dried under vacuum, and yield is 87.6%.
The preparation of silodosin：
Using dimethyl sulfoxide (DMSO) as solvent, by compound shown in Formula X IV 48% hydrogen peroxide and 20% naoh treatment,
It is stirred at room temperature to reaction and terminates, wherein, compound shown in Formula X IV, hydrogen peroxide and alkali metal wonder mole of oxide
Than for 1:0.1:3, reaction temperature is 25 DEG C, and the reaction time of reaction is 5h.After reaction terminates, reactant adds 5% sulfurous
In sour sodium and ethyl acetate, extracted with ethyl acetate, sodium chloride solution washing organic phase, it is anhydrous sodium sulfate drying, filtering, dense
Contracting, obtains solid silodosin, yield is 95%.
The above is only the preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art
For member, under the premise without departing from the principles of the invention, some improvements and modifications can also be made, these improvements and modifications also should
It is considered as protection scope of the present invention.
Claims (15)
1. a kind of Silodosin intermediate, it is characterised in that structure is as shown in formula II
2. a kind of preparation method of the compound as shown in formula II, it is characterised in that comprise the following steps：
Step 1：Take benzyl chloride that the first substitution reaction occurs under the catalysis of sodium acid carbonate and the mixture of water with indoline, obtain
Compound shown in formula III；
Step 2：Compound shown in the formula III is taken to mix generation Wei Er David Smails-Kazakhstan with dimethylformamide, phosphorous oxychloride
Gram reaction, obtain formula IV shown in compound；
Step 3：Under conditions of organic solvent and antioxidant are present, take after compound shown in the formula IV mixes with nitroethane
Condensation reaction occurs under the catalysis of ammonium acetate, the compound shown in formula V is obtained；
Step 4：Under conditions of organic solvent presence, the compound shown in the formula V is taken to occur reduction with sodium borohydride anti-
Should, obtain compound shown in formula VI；
Step 5：Under conditions of organic solvent presence, compound shown in the formula VI and dimethylformamide, triclosan oxidation are taken
Occur the second substitution reaction after phosphorus mixing, obtain compound shown in formula VII；
Step 6：Under conditions of organic solvent presence, take after compound shown in the formula VII mixes with hydroxylamine hydrochloride, in pyridine
Reacted under catalysis with the mixture of aceticanhydride, obtain compound shown in formula II；
3. preparation method according to claim 2, it is characterised in that benzyl chloride described in step 1, the indoline and institute
The mol ratio for stating sodium acid carbonate is 1~4:1:1~4, the reaction temperature of the first substitution reaction described in step 1 is 0~95 DEG C, institute
The time for stating the first substitution reaction is 1~14h.
4. preparation method according to claim 2, it is characterised in that compound shown in formula III described in step 2, described two
NMF is 1 with the mol ratio of the phosphorous oxychloride:2~9:2~4, Wei Er described in step 2 David Smail-Haake are anti-
The reaction temperature answered is -10~100 DEG C, and the time of the Wei Er David Smails-Haake reaction response is 1~6h.
5. preparation method according to claim 2, it is characterised in that compound shown in formula IV described in step 3, the nitre
Base ethane, the mol ratio of the ammonium acetate are 1:1~9:1~4, the reaction temperature of condensation reaction described in step 3 is 30~100
DEG C, the reaction time of the condensation reaction is 2~16h.
6. preparation method according to claim 2, it is characterised in that compound and institute shown in formula V described in step 4
The mol ratio for stating sodium borohydride is 1:3~6, the reaction temperature of reduction reaction described in step 4 is 10~25 DEG C, and the reduction is anti-
The reaction time answered is 2~4h.
7. preparation method according to claim 2, it is characterised in that compound shown in formula VI described in step 5, described two
NMF is 1 with the mol ratio of the phosphorous oxychloride:2~9:2~4, the reaction of the second substitution reaction described in step 5
Temperature is 0~100 DEG C, and the reaction time of second substitution reaction is 1~8h.
8. preparation method according to claim 2, it is characterised in that compound shown in formula VII described in step 6, the salt
Sour azanol is 1 with the mol ratio of pyridine and aceticanhydride:2~4:3~9:1~4, reaction temperature described in step 6 is 10~100 DEG C,
The reaction time of the reaction is 1~8h.
9. a kind of method that silodosin is prepared based on the compound shown in formula II as described in any one of claim 2 to 8, its feature
It is to comprise the following steps：
Step 1：In the presence of a solvent, take compound shown in the formula II mixed with trifluoroacetic acid after at Pd (OH)2/ C's
Catalysis is lower to occur the first debenzylation, obtains compound shown in formula VIII；
Step 2：Organic solvent presence under conditions of, take compound shown in the formula VIII mixed with 3- chloropropyl alcohols after in potassium carbonate
Catalysis under occur substitution reaction, obtain compound shown in formula Ⅸ；
Step 3：Under conditions of organic solvent presence, compound shown in the formula Ⅸ is taken to exist with trim,ethylchlorosilane, oxidant
React compound shown in acquisition formula Ⅹ under the catalysis of triethylene diamine；
Step 4：Under conditions of organic solvent presence, compound shown in the formula Ⅹ is taken to exist with R- (+)-a- phenyl ethylamines, acetic acid
In reducing environment, through PtO2Reduction amination occurs for catalytic hydrogenation, obtains compound shown in formula Ⅺ；
Step 5：Under conditions of organic solvent presence, compound shown in the formula Ⅺ is taken in reducing environment, to be catalyzed through pd/c
Occur the second debenzylation, obtain compound shown in formula Ⅻ；
Step 6：Under conditions of organic solvent presence, compound shown in the formula Ⅻ is taken to be urged with compound shown in Formula X III in alkali
Change lower generation substitution reaction, obtain compound shown in Formula X IV；
Step 7：Compound shown in the Formula X IV is taken under conditions of organic solvent presence, with hydrogen peroxide, alkali metal hydroxide
Thing catalytic reaction gives birth to hydrolysis, produces；
10. preparation method according to claim 9, it is characterised in that compound shown in formula II described in step 1 with it is described
The mol ratio of trifluoroacetic acid is 1:5~60, the reaction temperature of the first debenzylation described in step 1 is 20~100 DEG C, described
The reaction time of first debenzylation is 1~10h.
11. preparation method according to claim 9, it is characterised in that compound shown in formula VIII described in step 2,3- chlorine
Propyl alcohol, the mol ratio of potassium carbonate are 1:1~3:1~3, the reaction temperature of substitution reaction described in step 2 is 50~120 DEG C, institute
The reaction time for stating substitution reaction is 2~12h.
12. preparation method according to claim 9, it is characterised in that compound, front three shown in formula Ⅸ described in step 3
The mol ratio of base chlorosilane, oxidant and triethylene diamine is 1:1~6:1~4:1~5, the reaction temperature reacted described in step 3
Spend for -5~30 DEG C, the reaction time of the reaction is 0.5~5h.
13. preparation method according to claim 9, it is characterised in that compound, R- shown in formula Ⅹ described in step 4
The mol ratio of (+)-a- phenyl ethylamines and acetic acid is 1:1~3:1~6, the reaction of catalytic hydrogen reduction aminating reaction described in step 4
Temperature is 30~100 DEG C, and the reaction time of the catalytic hydrogen reduction aminating reaction is 6~45h.
14. preparation method according to claim 9, it is characterised in that compound shown in Formula X III described in step 6, institute
It is 1 to state compound shown in formula Ⅻ and the mol ratio of alkali:1~4:1~3.
15. preparation method according to claim 9, it is characterised in that compound, peroxide shown in Formula X IV described in step 7
Change hydrogen, the mol ratio of alkali metal hydroxide is 1:0.1~2:0.2~3, the reaction temperature of hydrolysis described in step 7 is
10~40 DEG C, the reaction time of the hydrolysis is 1~6h.
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