CN1966495A - Method for preparing 5-(4- fluobenzene sulphonyloxy) benzimidazole-2-amido methyl formate - Google Patents
Method for preparing 5-(4- fluobenzene sulphonyloxy) benzimidazole-2-amido methyl formate Download PDFInfo
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- CN1966495A CN1966495A CN 200610041560 CN200610041560A CN1966495A CN 1966495 A CN1966495 A CN 1966495A CN 200610041560 CN200610041560 CN 200610041560 CN 200610041560 A CN200610041560 A CN 200610041560A CN 1966495 A CN1966495 A CN 1966495A
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- CN
- China
- Prior art keywords
- fluorobenzene
- nitro
- sulfonyloxy
- benzimidazolyl
- radicals
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 238000000034 method Methods 0.000 title claims abstract description 49
- -1 benzimidazole-2-amido methyl Chemical group 0.000 title claims abstract description 38
- TZIHFWKZFHZASV-UHFFFAOYSA-N anhydrous methyl formate Natural products COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 title 1
- 238000006243 chemical reaction Methods 0.000 claims abstract description 63
- 239000002994 raw material Substances 0.000 claims abstract description 11
- PLIKAWJENQZMHA-UHFFFAOYSA-N 4-aminophenol Chemical compound NC1=CC=C(O)C=C1 PLIKAWJENQZMHA-UHFFFAOYSA-N 0.000 claims abstract description 8
- 238000002360 preparation method Methods 0.000 claims abstract description 8
- 239000012670 alkaline solution Substances 0.000 claims abstract description 4
- UYPLHJRXJHHRTH-UHFFFAOYSA-N (4-amino-3-nitrophenyl) 4-fluorobenzenesulfonate Chemical compound C1=C([N+]([O-])=O)C(N)=CC=C1OS(=O)(=O)C1=CC=C(F)C=C1 UYPLHJRXJHHRTH-UHFFFAOYSA-N 0.000 claims description 26
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 23
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- 238000003756 stirring Methods 0.000 claims description 20
- 238000009833 condensation Methods 0.000 claims description 19
- 230000005494 condensation Effects 0.000 claims description 19
- ASCHBOWFKWDVGW-UHFFFAOYSA-N fluorobenzene;sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O.FC1=CC=CC=C1 ASCHBOWFKWDVGW-UHFFFAOYSA-N 0.000 claims description 18
- 239000003513 alkali Substances 0.000 claims description 17
- 239000008367 deionised water Substances 0.000 claims description 17
- 229910021641 deionized water Inorganic materials 0.000 claims description 17
- 239000003795 chemical substances by application Substances 0.000 claims description 16
- 239000000243 solution Substances 0.000 claims description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 12
- 238000006460 hydrolysis reaction Methods 0.000 claims description 11
- ZSYJMXLJNPEAGP-UHFFFAOYSA-N methyl n-cyanocarbamate Chemical compound COC(=O)NC#N ZSYJMXLJNPEAGP-UHFFFAOYSA-N 0.000 claims description 11
- 238000007363 ring formation reaction Methods 0.000 claims description 11
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 10
- 239000011707 mineral Substances 0.000 claims description 10
- 239000000047 product Substances 0.000 claims description 10
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 10
- 230000007062 hydrolysis Effects 0.000 claims description 9
- 229910052759 nickel Inorganic materials 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 8
- 150000007530 organic bases Chemical class 0.000 claims description 7
- 230000002829 reductive effect Effects 0.000 claims description 7
- RMAHPRNLQIRHIJ-UHFFFAOYSA-N methyl carbamimidate Chemical compound COC(N)=N RMAHPRNLQIRHIJ-UHFFFAOYSA-N 0.000 claims description 6
- 239000007788 liquid Substances 0.000 claims description 5
- 235000010265 sodium sulphite Nutrition 0.000 claims description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 4
- 230000003197 catalytic effect Effects 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 239000006228 supernatant Substances 0.000 claims description 4
- 229910021586 Nickel(II) chloride Inorganic materials 0.000 claims description 3
- 230000002378 acidificating effect Effects 0.000 claims description 3
- 229910052751 metal Inorganic materials 0.000 claims description 3
- 239000002184 metal Substances 0.000 claims description 3
- QMMRZOWCJAIUJA-UHFFFAOYSA-L nickel dichloride Chemical compound Cl[Ni]Cl QMMRZOWCJAIUJA-UHFFFAOYSA-L 0.000 claims description 3
- 239000000843 powder Substances 0.000 claims description 3
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 claims description 3
- 239000010802 sludge Substances 0.000 claims description 3
- 238000005406 washing Methods 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 2
- 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 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- 230000001476 alcoholic effect Effects 0.000 claims description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 239000011701 zinc Substances 0.000 claims description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims 2
- IHYNKGRWCDKNEG-UHFFFAOYSA-N n-(4-bromophenyl)-2,6-dihydroxybenzamide Chemical compound OC1=CC=CC(O)=C1C(=O)NC1=CC=C(Br)C=C1 IHYNKGRWCDKNEG-UHFFFAOYSA-N 0.000 claims 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical group COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims 1
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 claims 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims 1
- 239000012346 acetyl chloride Substances 0.000 claims 1
- 150000008065 acid anhydrides Chemical class 0.000 claims 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 claims 1
- DVECBJCOGJRVPX-UHFFFAOYSA-N butyryl chloride Chemical compound CCCC(Cl)=O DVECBJCOGJRVPX-UHFFFAOYSA-N 0.000 claims 1
- FOCAUTSVDIKZOP-UHFFFAOYSA-N chloroacetic acid Chemical compound OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 0.000 claims 1
- 235000019253 formic acid Nutrition 0.000 claims 1
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 claims 1
- 235000019260 propionic acid Nutrition 0.000 claims 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims 1
- PNQBEPDZQUOCNY-UHFFFAOYSA-N trifluoroacetyl chloride Chemical compound FC(F)(F)C(Cl)=O PNQBEPDZQUOCNY-UHFFFAOYSA-N 0.000 claims 1
- 238000006722 reduction reaction Methods 0.000 abstract description 18
- 238000006482 condensation reaction Methods 0.000 abstract description 4
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 239000000543 intermediate Substances 0.000 abstract 5
- KWGHOXYCFVULPS-UHFFFAOYSA-N 4-(4-fluorophenyl)sulfonyl-2-nitroaniline Chemical compound [N+](=O)([O-])C1=C(N)C=CC(=C1)S(=O)(=O)C1=CC=C(C=C1)F KWGHOXYCFVULPS-UHFFFAOYSA-N 0.000 abstract 2
- UJDYLKJUZKQNEJ-UHFFFAOYSA-N 4-(4-fluorophenyl)sulfonylbenzene-1,2-diamine Chemical compound FC1=CC=C(C=C1)S(=O)(=O)C1=CC(=C(C=C1)N)N UJDYLKJUZKQNEJ-UHFFFAOYSA-N 0.000 abstract 2
- BFXHJFKKRGVUMU-UHFFFAOYSA-N 4-fluorobenzenesulfonyl chloride Chemical compound FC1=CC=C(S(Cl)(=O)=O)C=C1 BFXHJFKKRGVUMU-UHFFFAOYSA-N 0.000 abstract 1
- 230000010933 acylation Effects 0.000 abstract 1
- 238000005917 acylation reaction Methods 0.000 abstract 1
- 230000003301 hydrolyzing effect Effects 0.000 abstract 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 26
- 238000009835 boiling Methods 0.000 description 12
- 238000000967 suction filtration Methods 0.000 description 11
- 239000012065 filter cake Substances 0.000 description 9
- 239000003814 drug Substances 0.000 description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 7
- 238000002425 crystallisation Methods 0.000 description 7
- 230000008025 crystallization Effects 0.000 description 7
- 238000001816 cooling Methods 0.000 description 6
- 239000001257 hydrogen Substances 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 238000001953 recrystallisation Methods 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 238000005303 weighing Methods 0.000 description 5
- IQXUIDYRTHQTET-UHFFFAOYSA-N 4-amino-3-nitrophenol Chemical compound NC1=CC=C(O)C=C1[N+]([O-])=O IQXUIDYRTHQTET-UHFFFAOYSA-N 0.000 description 4
- 239000007868 Raney catalyst Substances 0.000 description 4
- 229910000564 Raney nickel Inorganic materials 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- OZZKMZSOGAOIFX-UHFFFAOYSA-N n-(4-hydroxy-2-nitrophenyl)acetamide Chemical compound CC(=O)NC1=CC=C(O)C=C1[N+]([O-])=O OZZKMZSOGAOIFX-UHFFFAOYSA-N 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 3
- VBYPBYSNKMUPCK-UHFFFAOYSA-N 2,2,2-trifluoro-N-(4-hydroxy-2-nitrophenyl)acetamide Chemical compound OC1=CC=C(NC(=O)C(F)(F)F)C([N+]([O-])=O)=C1 VBYPBYSNKMUPCK-UHFFFAOYSA-N 0.000 description 3
- UBVCIOHXLYQDBB-UHFFFAOYSA-N C1=CC=C(C=C1)C(=O)C2=C(C(=C(C=C2)O)N)[N+](=O)[O-] Chemical compound C1=CC=C(C=C1)C(=O)C2=C(C(=C(C=C2)O)N)[N+](=O)[O-] UBVCIOHXLYQDBB-UHFFFAOYSA-N 0.000 description 3
- DHXXLVMWQPSBNE-UHFFFAOYSA-N CC(=O)NC1=C(C=CC(=C1[N+](=O)[O-])Cl)O Chemical compound CC(=O)NC1=C(C=CC(=C1[N+](=O)[O-])Cl)O DHXXLVMWQPSBNE-UHFFFAOYSA-N 0.000 description 3
- ZNSDSHADDNTUHM-UHFFFAOYSA-N N-(4-hydroxy-2-nitrophenyl)benzamide Chemical compound [O-][N+](=O)C1=CC(O)=CC=C1NC(=O)C1=CC=CC=C1 ZNSDSHADDNTUHM-UHFFFAOYSA-N 0.000 description 3
- KVGXKBUHPBEADC-UHFFFAOYSA-N N-(4-hydroxy-2-nitrophenyl)propanamide Chemical compound CCC(=O)NC1=CC=C(O)C=C1[N+]([O-])=O KVGXKBUHPBEADC-UHFFFAOYSA-N 0.000 description 3
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 3
- HYHCSLBZRBJJCH-UHFFFAOYSA-M sodium hydrosulfide Chemical compound [Na+].[SH-] HYHCSLBZRBJJCH-UHFFFAOYSA-M 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- ZVIDWFUBDDXAJA-UHFFFAOYSA-N [2-(methoxycarbonylamino)-3h-benzimidazol-5-yl] 4-fluorobenzenesulfonate Chemical compound C1=C2NC(NC(=O)OC)=NC2=CC=C1OS(=O)(=O)C1=CC=C(F)C=C1 ZVIDWFUBDDXAJA-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 238000006480 benzoylation reaction Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000032050 esterification Effects 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 229950001484 luxabendazole Drugs 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
- OGEMUNOAKYMNPW-UHFFFAOYSA-N FC1=CC=CC=C1.Cl Chemical compound FC1=CC=CC=C1.Cl OGEMUNOAKYMNPW-UHFFFAOYSA-N 0.000 description 1
- 241000244206 Nematoda Species 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 229910000831 Steel Inorganic materials 0.000 description 1
- 238000005576 amination reaction Methods 0.000 description 1
- OFZIGMRSKXKZLB-UHFFFAOYSA-N anilino 4-fluorobenzenesulfonate Chemical compound C1=CC=C(C=C1)NOS(=O)(=O)C2=CC=C(C=C2)F OFZIGMRSKXKZLB-UHFFFAOYSA-N 0.000 description 1
- 230000002141 anti-parasite Effects 0.000 description 1
- 150000001556 benzimidazoles Chemical class 0.000 description 1
- 230000006242 butyrylation Effects 0.000 description 1
- 238000010514 butyrylation reaction Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- ATDGTVJJHBUTRL-UHFFFAOYSA-N cyanogen bromide Chemical compound BrC#N ATDGTVJJHBUTRL-UHFFFAOYSA-N 0.000 description 1
- RBNPZEHAODHBPZ-UHFFFAOYSA-M dihydroxyaluminium Chemical compound O.O.NCC(=O)O[Al] RBNPZEHAODHBPZ-UHFFFAOYSA-M 0.000 description 1
- IEJIGPNLZYLLBP-UHFFFAOYSA-N dimethyl carbonate Chemical compound COC(=O)OC IEJIGPNLZYLLBP-UHFFFAOYSA-N 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000022244 formylation Effects 0.000 description 1
- 238000006170 formylation reaction Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 description 1
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 1
- 239000010813 municipal solid waste Substances 0.000 description 1
- LAIZPRYFQUWUBN-UHFFFAOYSA-L nickel chloride hexahydrate Chemical compound O.O.O.O.O.O.[Cl-].[Cl-].[Ni+2] LAIZPRYFQUWUBN-UHFFFAOYSA-L 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 230000000590 parasiticidal effect Effects 0.000 description 1
- 239000002297 parasiticide Substances 0.000 description 1
- 235000011837 pasties Nutrition 0.000 description 1
- 238000007867 post-reaction treatment Methods 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 239000010959 steel Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000005583 trifluoroacetylation reaction Methods 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention relates to a preparation method for 5-(4-fluorophenyl-sulfonyl)-benzimidazole-2-methyl carbamate. The method includes (1) using p-aminophenol as raw materials, and preparing a number of new 3-nitro-4-substituted aminophenol intermediates through acylation and denitrification; (2) carrying out a condensation reaction of 3-nitro-4-substituted aminophenol intermediates with the 4-fluorophenylsulfonyl chloride in the alkaline solution, and hydrolyzing to obtain 2-nitro-4-(4-fluorophenyl-sulfonyl)-aniline intermediates; (3) carrying out a reduction reaction of 2-nitro-4-(4-fluorophenyl-sulfonyl)-aniline intermediates to obtain 4-(4-fluorophenyl-sulfonyl)-o-phenylenediamine intermediates; and (4) carrying out a closed loop reaction of closed-loop agents and 4-(4-fluorophenyl-sulfonyl)-o-phenylenediamine to obtain 5-(4-fluorophenyl-sulfonyl)-benzimidazole-2-methyl carbamate. This invention has the advantages of high yield, small unit consumption, and low cost. The raw materials are cheap and the method is easy for industrialized production.
Description
Technical field
The present invention relates to the preparation method of a kind of benzimidazoles dehelminthization chemical synthetic drug 5-(4-fluorobenzene sulfonyloxy) benzimidazolyl-2 radicals-Urethylane.
Background technology
5-(4-fluorobenzene sulfonyloxy) but benzimidazolyl-2 radicals-Urethylane beastly dual-purpose broad-spectrum de-worming medicine that is a kind of people has another name called luxabendazole, English luxabendazole by name belongs to the benzimidazole type chemical synthetic drug.
The structural formula of 5-(4-fluorobenzene sulfonyloxy) benzimidazolyl-2 radicals-Urethylane is:
At present, the benzimidazole type chemical synthetic drug is as the broad-spectrum anti-parasite medicine, efficient, the safe anti-intestinal nematodes medicine of a class especially, and its use is very wide.Being extensive use of of this class medicine makes parasiticide commonly used at present become to subtracting with medicament categories and quantity, and shorten the anti-parasitic-infectious course of treatment, and methods of treatment is further simplified.
At present, have only U.S.Patent 4,639,463 have reported the synthetic method of 5-(4-fluorobenzene sulfonyloxy) benzimidazolyl-2 radicals-Urethylane.In the patent, the author has reported three full chemical synthesis routes of 5-(4-fluorobenzene sulfonyloxy) benzimidazolyl-2 radicals-Urethylane, is respectively:
(1) synthetic route of " first condensation restores, last closed loop ".Promptly will obtain 2-nitro-4-(4-fluorobenzene sulfonyloxy)-aniline to fluorobenzene SULPHURYL CHLORIDE and 3-nitro-4-amino-phenol condensation earlier, select for use Raney nickel catalytic hydrogenating reduction to obtain 4-(4-fluorobenzene sulfonyloxy)-O-Phenylene Diamine then, adopting N at last, two (methylthio group) methylene radical of two (methoxycarbonyl)-S-methyl-isothioureas of N-or N-[] carbamate carries out ring-closure reaction and obtains 5-(4-fluorobenzene sulfonyloxy) benzimidazolyl-2 radicals-Urethylane.
(2) synthetic route of " reduction earlier, closed loop again, last condensation ".Promptly earlier 3-nitro-4-amino-phenol is obtained 4-hydroxyl O-Phenylene Diamine with Raney nickel hydrogenating reduction, use N again, two (the methoxycarbonyl)-S-methyl-isothioureas of N-carry out ring-closure reaction and obtain 5-hydroxy benzo imidazoles-2-Urethylane, and condensation obtains 5-(4-fluorobenzene sulfonyloxy) benzimidazolyl-2 radicals-Urethylane at last and to the fluorobenzene SULPHURYL CHLORIDE.
(3) synthetic route of " first condensation restores, closed loop and amination again, last esterification ".Promptly will obtain 2-nitro-4-(4-fluorobenzene sulfonyloxy)-aniline to fluorobenzene SULPHURYL CHLORIDE and 3-nitro-4-amino-phenol condensation earlier, select for use Raney nickel hydrogenating reduction to obtain 4-(4-fluorobenzene sulfonyloxy)-O-Phenylene Diamine then, carry out ring-closure reaction with cyanogen bromide again and obtain 2-amino-5-(4-fluorobenzene sulfonyloxy) benzoglyoxaline, use dimethyl carbonate (DMC) esterification to obtain 5-(4-fluorobenzene sulfonyloxy) benzimidazolyl-2 radicals-Urethylane at last.
But U.S.Patent 4,639, the reaction yield of 463 reported method is low, 3-nitro-4-amino-phenol of selecting for use, Raney nickel catalyzator and closed loop agent N, raw material unit price height such as two (the methoxycarbonyl)-S-methyl-isothioureas of N-, post-reaction treatment is more loaded down with trivial details, is unfavorable for industrial production.
Summary of the invention
The purpose of this invention is to provide a kind of yield height, production cost is low, and aftertreatment is simple, is convenient to the preparation method of industrial 5-(4-fluorobenzene sulfonyloxy) benzimidazolyl-2 radicals-Urethylane.
The technical scheme that realizes above-mentioned purpose is: the method for a kind of 5-of preparation (4-fluorobenzene sulfonyloxy) benzimidazolyl-2 radicals-Urethylane, and preparation process is as follows:
A, be raw material, utilize acylating agent to carry out the acidylate protection earlier, again through the nitrated 3-nitro 4-substituted-amino phenol intermediate that makes with the p-aminophenol;
B, 3-nitro 4-substituted-amino phenol intermediate are in alkaline solution and to the condensation of fluorobenzene SULPHURYL CHLORIDE, and hydrolysis obtains 2-nitro-4-(4-fluorobenzene sulfonyloxy)-aniline intermediate;
C, 2-nitro-4-(4-fluorobenzene sulfonyloxy)-aniline intermediate is reduced, obtain 4-(4-fluorobenzene sulfonyloxy)-O-Phenylene Diamine intermediate with reduction method;
D, select for use closed loop agent and 4-(4-fluorobenzene sulfonyloxy)-O-Phenylene Diamine intermediate to carry out ring-closure reaction, make 5-(4-fluorobenzene sulfonyloxy) benzimidazolyl-2 radicals-Urethylane product.
The synthetic route of 5-(4-fluorobenzene sulfonyloxy) benzimidazolyl-2 radicals-Urethylane is as follows:
In 5-(4-fluorobenzene sulfonyloxy) benzimidazolyl-2 radicals-Urethylane was synthetic, the selected substituted-amino phenol intermediate of the present invention comprised 3-nitro-4-formamido group phenol, 3-nitro-4-acetoamidophenol, 3-nitro-4-propionamido phenol, 3-nitro-4-acylamino phenol, 3-nitro-4-benzoyl amino-phenol, 3-nitro-4-benzamido phenol, 3-nitro-4-trifluoroacetamido phenol and 3-nitro-4-chloro acetylamino phenol.In condensation reaction, the present invention selects the HCl that produces in multiple organic bases and mineral alkali and the aqueous solution absorption reaction process thereof for use, and reaction is moved to positive dirction.Wherein organic bases comprises organic amine compound, ammoniacal liquor, pyridine and derivative thereof, morpholine and derivative thereof, DMF, DBU, and mineral alkali comprises oxyhydroxide, carbonate, the supercarbonate of sodium and potassium.The mole dosage of alkali (comprising organic bases and mineral alkali) is for to 0.9～1.2 times of fluorobenzene SULPHURYL CHLORIDE (or substituted-amino phenol), preferably 1.0～1.1 times.
Based on dissolving characteristics to fluorobenzene SULPHURYL CHLORIDE and substituted-amino phenol raw material, the present invention selects for use among alcoholic solvent, acetone, methylene dichloride, ethylene dichloride, THF, the DMF such as methyl alcohol, ethanol one or more as solvent, raw material is fully dissolved, thereby realize homogeneous reaction.In addition, determine two more excellent reinforced order in condensation reaction, the first adds organic bases or mineral alkali and substituted-amino phenol raw material earlier, stirs to drip down the fluorobenzene chloride solution is reacted; It two is to add earlier substituted-amino phenol and to the fluorobenzene SULPHURYL CHLORIDE, stir and drip organic bases or mineral alkali and reactant aqueous solution thereof down.
The present invention mainly adopts three kinds of method reductase 12-nitro-4-(4-fluorobenzene sulfonyloxy)-aniline intermediate, makes 4-(4-fluorobenzene sulfonyloxy)-O-Phenylene Diamine intermediate.These three kinds of methods are respectively:
The active metal reduction method: the present invention selects for use zinc powder and acetate to form reductive agent nitro is reduced.
The sulfocompound reduction method: the present invention selects for use sodium sulphite and Sodium sulfhydrate reductase 12-nitro-4-(4-fluorobenzene sulfonyloxy)-aniline to make 4-(4-fluorobenzene sulfonyloxy)-O-Phenylene Diamine intermediate respectively.Wherein, the mole dosage of sodium sulphite is 1～8 times of 2-nitro-4-(4-fluorobenzene sulfonyloxy)-aniline, and preferably 4～6 times, the mole dosage of Sodium sulfhydrate is 2～6 times of 2-nitro-4-(4-fluorobenzene sulfonyloxy)-aniline.
The catalytic hydrogenating reduction method: it is catalyzer that the present invention adopts the cotton-shaped nickel of homemade porous, and hydrogenating reduction 2-nitro-4-under 1～10atm (4-fluorobenzene sulfonyloxy)-aniline makes 4-(4-fluorobenzene sulfonyloxy)-O-Phenylene Diamine intermediate.The cotton-shaped nickel catalyzator of porous that adopts prepares by the following method: in the mashed prod of Zn powder, 30% acidic silicasol furnishing, add nickel chloride solution rapidly; After several minutes, use the deionized water wash sludge; Add 20% acetum again, stirring reaction 0.5h; Leave standstill the cotton-shaped nickel of porous is sunk; The supernatant liquid that inclines washes with water to neutrality; Use the 50ml absolute ethanol washing again 3 times, in ethanol, preserve standby.
The present invention selects three kinds of new closed loop agent and 4-(4-fluorobenzene sulfonyloxy)-O-Phenylene Diamine intermediate reaction for use, makes 5-(4-fluorobenzene sulfonyloxy) benzimidazolyl-2 radicals-Urethylane product.These three kinds of closed loop agent are respectively Methyl cyanocarbamate, O-methyl-isourea methyl-formiate or S-methyl-isourea methyl-formiate.
(1) selecting for use Methyl cyanocarbamate to carry out in the process of ring-closure reaction, the concentration of Methyl cyanocarbamate is between 97g/l～200g/l, preferably between 170g/l～180g/l.If concentration is on the low side, the moisture that Methyl cyanocarbamate self brings can reduce reactive behavior; If concentration is higher, the easy crystallization of Methyl cyanocarbamate, inconvenient operation is simultaneously because the reaction solution volume is little and a large amount of solid inorganic salts are arranged, 4-(4-fluorobenzene the sulfonyloxy)-O-Phenylene Diamine intermediate that causes adding can not dissolve fully, thereby reaction is incomplete, yield reduces.The ratio (mol ratio) of consumption of mineral acid (in H+) and 4-in the reaction (4-fluorobenzene sulfonyloxy)-O-Phenylene Diamine intermediate is 1.5～3: 1.If acid very little, can not guarantee reaction and carry out fully; Hyper acid, then makes 5-(4-fluorobenzene sulfonyloxy) benzimidazolyl-2 radicals-Urethylane further generate salt, causes product yield to descend.
(2) selecting for use O-methyl-isourea methyl-formiate or S-methyl-isourea methyl-formiate to carry out in the process of ring-closure reaction, the mole dosage of closed loop agent is 1.1～1.4 times of 4-(4-fluorobenzene sulfonyloxy)-O-Phenylene Diamine reduzate intermediate.The acid that ring-closure reaction is used can be selected mineral acid and organic acid for use.
Embodiment
The present invention is further detailed explanation below in conjunction with embodiment.
1 substituted-amino phenol preparation process
Embodiment one
Step 1
Have in the four-hole boiling flask of whipping appts and thermometer at 150ml, add 10.0g (0.092mol) p-aminophenol, 10ml (0.120mol) aceticanhydride successively, heated and stirred, back flow reaction 2h.Temperature constantly raises in the reaction process.After reaction finishes, reaction solution is poured in a small amount of frozen water, promptly had crystal to separate out, suction filtration, product alcohol recrystallization obtains acamol 13.2g, yield 94.9%, 170 ℃ of fusing points.
Step 2
Have in the four-hole boiling flask of whipping appts and thermometer at 150ml, add 80ml 98% sulfuric acid, be cooled to below 10 ℃ under stirring, add acamol 9.4g (0.062mol), be cooled to below 10 ℃, drip the mixed acid solution of 3.7ml98% sulfuric acid and 3.8ml96% nitric acid, add afterreaction 2h.The reaction stop after, under strong mixing, reaction solution is poured in a large amount of trash ices, separate out yellow crystals, suction filtration, dry 3-nitro-4-acetoamidophenol 9.2g, yield 75.6%, 162 ℃ of fusing points.
Embodiment two
With reference to embodiment one reactions steps, first formylation, the nitrated 3-nitro-4-formamido group phenol that obtains again.
Embodiment three
With reference to embodiment one reactions steps, first propionylization, the nitrated 3-nitro-4-propionamido phenol that obtains again.
Embodiment four
With reference to embodiment one reactions steps, first Butyrylation, the nitrated 3-nitro-4-acylamino phenol that obtains again.
Embodiment five
With reference to embodiment one reactions steps, first benzoylation, the nitrated 3-nitro-4-benzoyl amino-phenol that obtains again.
Embodiment six
With reference to embodiment one reactions steps, first benzoylation, the nitrated 3-nitro-4-benzamido phenol that obtains again.
Embodiment seven
With reference to embodiment one reactions steps, first trifluoroacetylation, the nitrated 3-nitro-4-trifluoroacetamido phenol that obtains again.
Embodiment eight
With reference to embodiment one reactions steps, first chloroacetylation, the nitrated 3-nitro-4-chloro acetylamino phenol that obtains again.
2 condensation reactions
Embodiment nine
Have in the four-hole boiling flask of whipping appts and thermometer at 250ml, add 100mlDMF, 14ml (0.1mol) triethylamine, 19.6g (0.1mol) 3-nitro-4-acetoamidophenol successively, stirring is all dissolved raw material.Other takes by weighing 19.5g (0.1mol) the fluorobenzene SULPHURYL CHLORIDE is dissolved among the 30mlDMF, after treating to dissolve fully, is added drop-wise in the reaction system.After dropwising, reaction 5h.After reaction finishes, suction filtration, filter cake is with a small amount of DMF washed twice.Merging filtrate moves in the 500ml reaction flask hydrolysis reaction 1h.After reaction finished, concentrating under reduced pressure added small amount of methanol and deionized water more successively, stirred 1.5h, suction filtration, filter cake deionized water wash, dry condenses 2-nitro-4-(4-fluorobenzene sulfonyloxy)-aniline 26.4g, yield 84.5%, 161 ℃ of the fusing points of getting.
Embodiment ten
Have in the four-hole boiling flask of whipping appts and thermometer at 250ml, add 19.6g (0.1mol) 3-nitro-4-acetoamidophenol, 19.5g (0.1mol) successively to fluorobenzene SULPHURYL CHLORIDE, 100mlDMF, heated and stirred is all dissolved raw material.Drip the NaOH aqueous solution in reaction system.Add back temperature reaction 5h.Hydrolysis reaction 1h again.React and finish back adding deionized water, suction filtration behind the stirring 1.0h, filter cake deionized water wash, dry condenses 2-nitro-4-(4-fluorobenzene sulfonyloxy)-aniline 26.8g, yield 85.8%, 161 ℃ of the fusing points of getting.
Embodiment 11
With reference to embodiment nine, embodiment ten reactions steps, molar equivalents such as employing to fluorobenzene SULPHURYL CHLORIDE, 3-nitro-4-formamido group phenol and alkali reaction, again through hydrolysis, obtain 2-nitro-4-(4-fluorobenzene sulfonyloxy)-aniline condensation thing intermediate, 161 ℃ of fusing points.
Embodiment 12
With reference to embodiment nine, embodiment ten reactions steps, molar equivalents such as employing to fluorobenzene SULPHURYL CHLORIDE, 3-nitro-4-propionamido phenol and alkali reaction, again through hydrolysis, obtain 2-nitro-4-(4-fluorobenzene sulfonyloxy)-aniline condensation thing intermediate, 161 ℃ of fusing points.
Embodiment 13
With reference to embodiment nine, embodiment ten reactions steps, molar equivalents such as employing to fluorobenzene SULPHURYL CHLORIDE, 3-nitro-4-acylamino phenol and alkali reaction, again through hydrolysis, obtain 2-nitro-4-(4-fluorobenzene sulfonyloxy)-aniline condensation thing intermediate, 161 ℃ of fusing points.
Embodiment 14
With reference to embodiment nine, embodiment ten reactions steps, molar equivalents such as employing to fluorobenzene SULPHURYL CHLORIDE, 3-nitro-4-benzoyl amino-phenol and alkali reaction, again through hydrolysis, obtain 2-nitro-4-(4-fluorobenzene sulfonyloxy)-aniline condensation thing intermediate, 161 ℃ of fusing points.
Embodiment 15
With reference to embodiment nine, embodiment ten reactions steps, molar equivalents such as employing to fluorobenzene SULPHURYL CHLORIDE, 3-nitro-4-benzamido phenol and alkali reaction, through hydrolysis, obtain 2-nitro-4-(4-fluorobenzene sulfonyloxy)-aniline condensation thing intermediate, 161 ℃ of fusing points again.
Embodiment 16
With reference to embodiment nine, embodiment ten reactions steps, molar equivalents such as employing to fluorobenzene SULPHURYL CHLORIDE, 3-nitro-4-trifluoroacetamido phenol and alkali reaction, through hydrolysis, obtain 2-nitro-4-(4-fluorobenzene sulfonyloxy)-aniline condensation thing intermediate, 161 ℃ of fusing points again.
Embodiment 17
With reference to embodiment nine, embodiment ten reactions steps, molar equivalents such as employing to fluorobenzene SULPHURYL CHLORIDE, 3-nitro-4-chloro acetylamino phenol and alkali reaction, through hydrolysis, obtain 2-nitro-4-(4-fluorobenzene sulfonyloxy)-aniline condensation thing intermediate, 161 ℃ of fusing points again.
3 reduction reaction processes
Embodiment 18
Have in the four-hole boiling flask of whipping appts and thermometer at 250ml, add 10.9g (0.195mol) zinc powder successively, 5ml acetate and 50ml deionized water stir and make the raw material thorough mixing.After the heated and boiled, cooling slightly.Other takes by weighing 15.6g (0.05mol) 2-nitro 4-(4-fluorobenzene sulfonyloxy)-aniline condensation thing intermediate and dissolves with DMF, moves into constant pressure funnel.Stir down, be added drop-wise in the reaction system and react.Finish heating reflux reaction 6h.Reaction can adopt following two kinds of methods to handle after finishing:
(1), pressure reducing and steaming water and DMF, after crystallization is separated out, leave standstill 1h, suction filtration, the filter cake deionized water wash, drying obtains 4-(4-fluorobenzene sulfonyloxy)-O-Phenylene Diamine reduzate intermediate.But the crude product recrystallization obtains crystal, but the present invention does not adopt the recrystallization operation, is directly used in the next step.
(2), add deionized water, benzene stirs the 0.5h after-filtration, filtrate is told upper strata (organic layer) with separating funnel.The benzene organic layer that contains 4-(4-fluorobenzene sulfonyloxy)-O-Phenylene Diamine reduzate intermediate that obtains is directly used in down the step ring-closure reaction.
Embodiment 19
Have in the four-hole boiling flask of whipping appts and thermometer at 250ml, add 31.2g (0.1mol) 2-nitro-4-(4-fluorobenzene sulfonyloxy)-aniline condensation thing intermediate, 100ml ethanol successively, heated and stirred adds 46.8g (0.6mol) sodium sulphite, heating reflux reaction 4h in batches.Reaction finishes, and cooling is poured reaction solution in the separating funnel into, divides and falls down layer, and the upper strata moves in the reaction flask, and normal pressure concentrates and reclaims ethanol, and raffinate can adopt following two kinds of methods to handle:
(1) stir and to add the deionized water crystallization down, leave standstill suction filtration behind the 1h, the filter cake deionized water wash, drying obtains 4-(4-fluorobenzene sulfonyloxy)-O-Phenylene Diamine reduzate intermediate.But the reduzate intermediate recrystallization that obtains obtains crystal, but the present invention does not adopt the recrystallization operation, is directly used in the next step.
(2) add deionized water, benzene stirs the 0.5h after-filtration, and filtrate is told upper strata (organic layer) with separating funnel.The benzene organic layer that contains 4-(4-fluorobenzene sulfonyloxy)-O-Phenylene Diamine reduzate intermediate that obtains is directly used in down the step ring-closure reaction.
Embodiment 20
Have in the four-hole boiling flask of whipping appts and thermometer at 500ml, add 31.2g (0.1mol) 2-nitro-4-(4-fluorobenzene sulfonyloxy)-aniline condensation thing intermediate, 100ml ethanol successively, heated and stirred.Other takes by weighing in 22.4g (0.4mol) the Sodium sulfhydrate adding reaction system, finishes heating reflux reaction 4h, and reaction finishes, cooling is poured reaction solution in the separating funnel into, divides and falls down layer, the upper strata moves in the reaction flask, and normal pressure concentrates and reclaims ethanol, and it is consistent that subsequent operations and embodiment 19 are adopted.
Embodiment 21
Step 1
Taking by weighing the 10.0g Nickel dichloride hexahydrate is dissolved in the 10mL water.Take by weighing the 12.6gZn powder again, add 30% acidic silicasol furnishing pasty state, stir down, nickel chloride solution is added rapidly in the zinc powder, react fierce heat release, have hydrogen to emit.After several minutes, use 50ml deionized water wash sludge 3 times.Add the 180ml20% acetum in precipitation, behind 40～50 ℃ of following stirring reaction 0.5h, the speed that hydrogen produces significantly slows down.By stirring, the cotton-shaped nickel of the porous of floating on liquid level is sunk.The supernatant liquid that inclines washes with water to neutrality, uses the 50ml absolute ethanol washing again 3 times, the cotton-shaped nickel catalyzator of porous, be stored in the ethanol standby.
Step 2
Have at 250ml on the four-hole boiling flask of whipping appts and thermometer, connect the hydrogen airway, inflated with nitrogen inspection units resistance to air loss.The laggard line replacement of passed examination, add 15.6g2-nitro-4-(4-fluorobenzene sulfonyloxy)-aniline condensation thing intermediate, the cotton-shaped nickel catalyzator of porous of preparation, 100ml ethanol subsequently successively, heated and stirred, after temperature rises to 40 ℃, with the hydrogen gas in the steel cylinder, through importing in the reaction flask behind the aerometer buret.Through after the inducing of certain hour, inhale the speed of hydrogen and accelerate.Treat that hydrogen-absorption speed reduces to 0.1～0.2ml/min, when total hydrogen is about 1100ml, stop to feed hydrogen and stirring, a moment is left standstill in cooling, allow catalyzer be sunken to bottle at the bottom of, the sucking-off supernatant liquid.Normal pressure concentrate to reclaim ethanol, and it is consistent that subsequent operations and embodiment 19 are adopted.
The ring-closure reaction process
Embodiment 22
Have in the four-hole boiling flask of whipping appts and thermometer at 250ml, add solid reduction thing 4-(4-fluorobenzene the sulfonyloxy)-O-Phenylene Diamine 27.6g (0.098mol), the 100ml benzene that adopt treatment process (1) operation to obtain among the embodiment of reduction reaction process successively, add after the stirring and dissolving and contain 10.8g (0.108mol) the Methyl cyanocarbamate aqueous solution (concentration of Methyl cyanocarbamate is 97g/l).Other measures 29.4ml (0.294mol) concentrated hydrochloric acid, is added drop-wise in the system and reacts.Dropwise, heating reflux reaction 3h, cooling, suction filtration, the filter cake deionized water wash is used methyl alcohol/DMF solution weight crystallization again, dry 5-(the 4-fluorobenzene sulfonyloxy) benzimidazolyl-2 radicals-Urethylane product 27.0g that gets, yield 74.0% (so that 2-nitro-4-(4-fluorobenzene sulfonyloxy)-aniline is reference), 236 ℃ of fusing points.
Embodiment 23
Have in the four-hole boiling flask of whipping appts and thermometer at 250ml, add solid reduction thing 4-(4-fluorobenzene the sulfonyloxy)-O-Phenylene Diamine 27.6g (0.098mol), the 100ml benzene that adopt treatment process (1) operation to obtain among the embodiment of reduction reaction process successively, add after the stirring and dissolving and contain 10.8g (0.108mol) the Methyl cyanocarbamate aqueous solution (concentration of Methyl cyanocarbamate is 200g/l).Other measures 15ml (0.15mol) concentrated hydrochloric acid, is added drop-wise in the system and reacts.Dropwise, heating reflux reaction 3h, cooling, suction filtration, the filter cake deionized water wash is used methyl alcohol/DMF solution weight crystallization again, dry 5-(the 4-fluorobenzene sulfonyloxy) benzimidazolyl-2 radicals-Urethylane product 27.4g that gets, yield 75.0% (so that 2-nitro-4-(4-fluorobenzene sulfonyloxy)-aniline is reference), 236 ℃ of fusing points.
Embodiment 24
Have in the four-hole boiling flask of whipping appts and thermometer at 250ml, add solid reduction thing 4-(4-fluorobenzene the sulfonyloxy)-O-Phenylene Diamine 27.6g (0.098mol) that adopts treatment process (1) operation to obtain among the embodiment of reduction reaction process successively, 100ml benzene, add 15.0g (0.113mol) O-methyl-isourea methyl-formiate and small amount of acid after the stirring and dissolving, heated and stirred, react 4h down at 60 ℃, suction filtration, the filter cake deionized water wash, use methyl alcohol/DMF solution weight crystallization again, dry 5-(the 4-fluorobenzene sulfonyloxy) benzimidazolyl-2 radicals-Urethylane product 28.5g that gets, yield 78.0% (so that 2-nitro-4-(4-fluorobenzene sulfonyloxy)-aniline is reference), 236 ℃ of fusing points.
Embodiment 25
Have in the four-hole boiling flask of whipping appts and thermometer at 250ml, add the reduzate benzole soln (4-(4-fluorobenzene sulfonyloxy)-O-Phenylene Diamine 27.6g (0.098mol) that adopts treatment process (2) operation to obtain among the embodiment of reduction reaction process, 100ml benzene, add 18.1g (0.137mol) O-methyl-isourea methyl-formiate and small amount of acid after the stirring and dissolving, heated and stirred, 60 ℃ are reacted 4h down, suction filtration, the filter cake deionized water wash, use methyl alcohol/DMF solution weight crystallization again, dry 5-(the 4-fluorobenzene sulfonyloxy) benzimidazolyl-2 radicals-Urethylane product 28.5g that gets, yield 78.8% (so that 2-nitro-4-(4-fluorobenzene sulfonyloxy)-aniline is reference), 236 ℃ of fusing points.
Embodiment 26
With reference to embodiment 24,25 reactions steps and charging capacity, selecting S-methyl-isourea methyl-formiate for use is the closed loop agent, obtains 5-(4-fluorobenzene sulfonyloxy) benzimidazolyl-2 radicals-Urethylane product, 236 ℃ of fusing points.
Claims (10)
1, a kind of method for preparing 5-(4-fluorobenzene sulfonyloxy) benzimidazolyl-2 radicals-Urethylane is characterized in that preparation process is as follows:
A, be raw material, utilize acylating agent to carry out the acidylate protection earlier, again through the nitrated 3-nitro-4-substituted-amino phenol intermediate that makes with the p-aminophenol;
B, 3-nitro-4-substituted-amino phenol intermediate is in alkaline solution and to the condensation of fluorobenzene SULPHURYL CHLORIDE, and hydrolysis obtains 2-nitro-4-(4-fluorobenzene sulfonyloxy)-aniline intermediate;
C, 2-nitro-4-(4-fluorobenzene sulfonyloxy)-aniline intermediate is reduced, obtain 4-(4-fluorobenzene sulfonyloxy)-O-Phenylene Diamine intermediate with reduction method;
D, select for use closed loop agent and 4-(4-fluorobenzene sulfonyloxy)-O-Phenylene Diamine intermediate to carry out ring-closure reaction, make 5-(4-fluorobenzene sulfonyloxy) benzimidazolyl-2 radicals-Urethylane product;
Wherein said acylating agent is formic acid, acetate, trifluoroacetic acid, Mono Chloro Acetic Acid, propionic acid, butyric acid, phenylformic acid; First and second acid anhydrides, diacetyl oxide; Acetyl Chloride 98Min., chloroacetyl chloride, trifluoroacetyl chloride, propionyl chloride, butyryl chloride, Benzoyl chloride;
Wherein the alkali in the alkaline solution in the b step is organic bases or mineral alkali, organic bases is one or more among organic amine compound, ammoniacal liquor, pyridine and derivative thereof, morpholine and derivative thereof, DMF, the DBU, and mineral alkali is one or more in the oxyhydroxide, carbonate, supercarbonate of sodium and potassium; The mole dosage of alkali is 0.9～1.2 times to the fluorobenzene SULPHURYL CHLORIDE.
2, the method for preparing 5-(4-fluorobenzene sulfonyloxy) benzimidazolyl-2 radicals-Urethylane according to claim 1, it is characterized in that: in the b step contract and process is selected alcoholic solvent methyl alcohol or ethanol for use, and in the acetone, methylene dichloride, ethylene dichloride, THF, DMF one or more are as solvent.
3, the method for preparing 5-(4-fluorobenzene sulfonyloxy) benzimidazolyl-2 radicals-Urethylane according to claim 1, it is characterized in that: the reduction method of c step is selected any one in active metal reduction method, sulfocompound reduction method and the catalytic hydrogenating reduction method for use.
4, the method for preparing 5-(4-fluorobenzene sulfonyloxy) benzimidazolyl-2 radicals-Urethylane according to claim 3 is characterized in that: the active metal reduction method adopts zinc powder and acetate to form reductive agent.
5, the method for preparing 5-(4-fluorobenzene sulfonyloxy) benzimidazolyl-2 radicals-Urethylane according to claim 3, it is characterized in that: the sulfocompound reduction method adopts sodium sulphite and sodium bisulfide as reductive agent, the mole dosage of sodium sulphite is 1～8 times of 2-nitro-4-(4-fluorobenzene sulfonyloxy)-aniline, and the mole dosage of sodium bisulfide is 2～6 times of 2-nitro-4-(4-fluorobenzene sulfonyloxy)-aniline.
6, the method for preparing 5-(4-fluorobenzene sulfonyloxy) benzimidazolyl-2 radicals-Urethylane according to claim 3 is characterized in that: the catalytic hydrogenating reduction method adopts the cotton-shaped nickel of porous as catalyzer.
7, the method for preparing 5-(4-fluorobenzene sulfonyloxy) benzimidazolyl-2 radicals-Urethylane according to claim 6, it is characterized in that: the cotton-shaped nickel catalyzator of the porous of employing prepares by the following method: in the mashed prod of Zn powder, 30% acidic silicasol furnishing, add nickel chloride solution rapidly; After several minutes, use the deionized water wash sludge; Add 20% acetum again, stirring reaction 0.5h; Leave standstill the cotton-shaped nickel of porous is sunk; The supernatant liquid that inclines washes with water to neutrality; Use the 50ml absolute ethanol washing again 3 times, in ethanol, preserve standby.
8, the method for preparing 5-(4-fluorobenzene sulfonyloxy) benzimidazolyl-2 radicals-Urethylane according to claim 1, it is characterized in that: the closed loop agent in the d step is any one in Methyl cyanocarbamate, O-methyl-isourea methyl-formiate, the S-methyl-isourea methyl-formiate.
9, the method for preparing 5-(4-fluorobenzene sulfonyloxy) benzimidazolyl-2 radicals-Urethylane according to claim 8, it is characterized in that: the concentration of the closed loop agent Methyl cyanocarbamate in the d step is between 97g/l～200g/l, and the mole dosage of mineral acid (in H+) is 1.5～3 times of 4-(4-fluorobenzene sulfonyloxy)-O-Phenylene Diamine in the reaction.
10, the method for preparing 5-(4-fluorobenzene sulfonyloxy) benzimidazolyl-2 radicals-Urethylane according to claim 8 is characterized in that: the closed loop agent O-methyl-isourea methyl-formiate in the d step, the mole dosage in the S-methyl-isourea methyl-formiate are 1.1～1.4 times of 4-(4-fluorobenzene sulfonyloxy)-O-Phenylene Diamine.
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|---|---|---|---|---|
| CN101270091B (en) * | 2008-04-23 | 2010-12-29 | 常州亚邦齐晖医药化工有限公司 | Method for preparing albendazole |
| CN103242238A (en) * | 2013-05-10 | 2013-08-14 | 常州亚邦齐晖医药化工有限公司 | Preparation method of fenbendazole |
| CN104478808A (en) * | 2014-12-05 | 2015-04-01 | 常州齐晖药业有限公司 | Pharmaceutically acceptable salt of imidazole insectifuge as well as preparation method and application of salt |
| CN111423442A (en) * | 2020-04-03 | 2020-07-17 | 重庆美莱德生物医药有限公司 | Epinastine hydrochloride intermediate and synthesis method thereof |
| CN112094237A (en) * | 2020-11-06 | 2020-12-18 | 江苏宝众宝达药业有限公司 | Synthesis method of fluorobenzene imidazole |
| CN114478293A (en) * | 2021-12-30 | 2022-05-13 | 蚌埠丰原医药科技发展有限公司 | Preparation method of acetaminophen |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3247615A1 (en) * | 1982-12-23 | 1984-07-05 | Hoechst Ag, 6230 Frankfurt | SUBSTITUTED PHENYLSULFONYLOXYBENZIMIDAZOLE CARBAMINATES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS A MEDICINAL PRODUCT |
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101270091B (en) * | 2008-04-23 | 2010-12-29 | 常州亚邦齐晖医药化工有限公司 | Method for preparing albendazole |
| CN103242238A (en) * | 2013-05-10 | 2013-08-14 | 常州亚邦齐晖医药化工有限公司 | Preparation method of fenbendazole |
| CN103242238B (en) * | 2013-05-10 | 2016-04-20 | 常州齐晖药业有限公司 | A kind of preparation method of fenbendazole |
| CN104478808A (en) * | 2014-12-05 | 2015-04-01 | 常州齐晖药业有限公司 | Pharmaceutically acceptable salt of imidazole insectifuge as well as preparation method and application of salt |
| CN111423442A (en) * | 2020-04-03 | 2020-07-17 | 重庆美莱德生物医药有限公司 | Epinastine hydrochloride intermediate and synthesis method thereof |
| CN111423442B (en) * | 2020-04-03 | 2022-09-27 | 重庆美莱德生物医药有限公司 | Epinastine hydrochloride intermediate and synthesis method thereof |
| CN112094237A (en) * | 2020-11-06 | 2020-12-18 | 江苏宝众宝达药业有限公司 | Synthesis method of fluorobenzene imidazole |
| CN112094237B (en) * | 2020-11-06 | 2023-01-20 | 江苏宝众宝达药业股份有限公司 | Synthesis method of fluorobenzene imidazole |
| CN114478293A (en) * | 2021-12-30 | 2022-05-13 | 蚌埠丰原医药科技发展有限公司 | Preparation method of acetaminophen |
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