CN114181139B - 一种5-卤代烟酸的合成方法 - Google Patents
一种5-卤代烟酸的合成方法 Download PDFInfo
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- CN114181139B CN114181139B CN202111611815.XA CN202111611815A CN114181139B CN 114181139 B CN114181139 B CN 114181139B CN 202111611815 A CN202111611815 A CN 202111611815A CN 114181139 B CN114181139 B CN 114181139B
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- nicotinic acid
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- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical class OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 title claims abstract description 26
- 238000001308 synthesis method Methods 0.000 title claims abstract description 8
- 238000006243 chemical reaction Methods 0.000 claims abstract description 56
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 35
- 239000007787 solid Substances 0.000 claims abstract description 29
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 22
- 238000001914 filtration Methods 0.000 claims abstract description 19
- 238000003756 stirring Methods 0.000 claims abstract description 18
- 238000000034 method Methods 0.000 claims abstract description 17
- 238000010438 heat treatment Methods 0.000 claims abstract description 15
- 230000001105 regulatory effect Effects 0.000 claims abstract description 15
- GZPHSAQLYPIAIN-UHFFFAOYSA-N 3-pyridinecarbonitrile Chemical compound N#CC1=CC=CN=C1 GZPHSAQLYPIAIN-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000003513 alkali Substances 0.000 claims abstract description 14
- 239000002798 polar solvent Substances 0.000 claims abstract description 14
- 239000012074 organic phase Substances 0.000 claims abstract description 11
- 239000000010 aprotic solvent Substances 0.000 claims abstract description 10
- 239000003638 chemical reducing agent Substances 0.000 claims abstract description 10
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 9
- 238000004090 dissolution Methods 0.000 claims abstract description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 66
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 36
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 30
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 21
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical group ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 claims description 18
- 229910052757 nitrogen Inorganic materials 0.000 claims description 18
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 14
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 12
- GETTZEONDQJALK-UHFFFAOYSA-N (trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1 GETTZEONDQJALK-UHFFFAOYSA-N 0.000 claims description 10
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 10
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 claims description 10
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 claims description 10
- 230000002194 synthesizing effect Effects 0.000 claims description 10
- MENYRYNFSIBDQN-UHFFFAOYSA-N 5,5-dibromoimidazolidine-2,4-dione Chemical compound BrC1(Br)NC(=O)NC1=O MENYRYNFSIBDQN-UHFFFAOYSA-N 0.000 claims description 9
- ZKLFRQSZDUSMQE-UHFFFAOYSA-N 5,5-dichloroimidazolidine-2,4-dione Chemical compound ClC1(Cl)NC(=O)NC1=O ZKLFRQSZDUSMQE-UHFFFAOYSA-N 0.000 claims description 9
- JKZOMQGCLXJWFO-UHFFFAOYSA-N 5,5-diiodoimidazolidine-2,4-dione Chemical compound IC1(I)NC(=O)NC1=O JKZOMQGCLXJWFO-UHFFFAOYSA-N 0.000 claims description 9
- 238000001035 drying Methods 0.000 claims description 9
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 8
- YKYONYBAUNKHLG-UHFFFAOYSA-N propyl acetate Chemical compound CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 claims description 7
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Chemical compound IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 5
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 5
- 229940011051 isopropyl acetate Drugs 0.000 claims description 5
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 5
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 claims description 4
- HHBCEKAWSILOOP-UHFFFAOYSA-N 1,3-dibromo-1,3,5-triazinane-2,4,6-trione Chemical compound BrN1C(=O)NC(=O)N(Br)C1=O HHBCEKAWSILOOP-UHFFFAOYSA-N 0.000 claims description 4
- 229940043232 butyl acetate Drugs 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- 235000010265 sodium sulphite Nutrition 0.000 claims description 4
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 claims description 4
- 235000019345 sodium thiosulphate Nutrition 0.000 claims description 4
- PRXNKYBFWAWBNZ-UHFFFAOYSA-N trimethylphenylammonium tribromide Chemical compound Br[Br-]Br.C[N+](C)(C)C1=CC=CC=C1 PRXNKYBFWAWBNZ-UHFFFAOYSA-N 0.000 claims description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 3
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 3
- CEJLBZWIKQJOAT-UHFFFAOYSA-N dichloroisocyanuric acid Chemical compound ClN1C(=O)NC(=O)N(Cl)C1=O CEJLBZWIKQJOAT-UHFFFAOYSA-N 0.000 claims description 3
- IEJIGPNLZYLLBP-UHFFFAOYSA-N dimethyl carbonate Chemical compound COC(=O)OC IEJIGPNLZYLLBP-UHFFFAOYSA-N 0.000 claims description 3
- 239000011261 inert gas Substances 0.000 claims description 3
- ZNMZQKGJPXOEFD-UHFFFAOYSA-K trimethyl(phenyl)azanium trichloride Chemical compound [Cl-].[Cl-].[Cl-].C1(=CC=CC=C1)[N+](C)(C)C.C1(=CC=CC=C1)[N+](C)(C)C.C1(=CC=CC=C1)[N+](C)(C)C ZNMZQKGJPXOEFD-UHFFFAOYSA-K 0.000 claims description 3
- RHXJPCQWYPXLEH-UHFFFAOYSA-N trimethyl(phenyl)azanium;triiodide Chemical compound I[I-]I.C[N+](C)(C)C1=CC=CC=C1 RHXJPCQWYPXLEH-UHFFFAOYSA-N 0.000 claims description 3
- -1 dichloro hydantoin Chemical compound 0.000 claims description 2
- 229940091173 hydantoin Drugs 0.000 claims description 2
- 230000001376 precipitating effect Effects 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims description 2
- 230000002140 halogenating effect Effects 0.000 abstract description 5
- 239000003795 chemical substances by application Substances 0.000 abstract description 4
- 230000026030 halogenation Effects 0.000 abstract description 4
- 238000005658 halogenation reaction Methods 0.000 abstract description 4
- 239000007791 liquid phase Substances 0.000 abstract description 4
- 239000000047 product Substances 0.000 abstract description 4
- 239000006227 byproduct Substances 0.000 abstract description 3
- 150000001875 compounds Chemical class 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 238000001816 cooling Methods 0.000 description 21
- 239000000203 mixture Substances 0.000 description 20
- 239000000243 solution Substances 0.000 description 19
- 238000001291 vacuum drying Methods 0.000 description 13
- 239000012065 filter cake Substances 0.000 description 12
- FTFFHWWIPOQCBC-UHFFFAOYSA-N 5-bromopyridine-3-carbonitrile Chemical compound BrC1=CN=CC(C#N)=C1 FTFFHWWIPOQCBC-UHFFFAOYSA-N 0.000 description 10
- 239000004289 sodium hydrogen sulphite Substances 0.000 description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 6
- 238000001704 evaporation Methods 0.000 description 6
- 238000011010 flushing procedure Methods 0.000 description 6
- 239000012452 mother liquor Substances 0.000 description 6
- 229910052938 sodium sulfate Inorganic materials 0.000 description 6
- 235000011152 sodium sulphate Nutrition 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- FQIUCPGDKPXSLL-UHFFFAOYSA-N 5-bromopyridine-3-carboxylic acid Chemical compound OC(=O)C1=CN=CC(Br)=C1 FQIUCPGDKPXSLL-UHFFFAOYSA-N 0.000 description 5
- VHVCXRPJVSZARD-UHFFFAOYSA-N 5-chloropyridine-3-carbonitrile Chemical compound ClC1=CN=CC(C#N)=C1 VHVCXRPJVSZARD-UHFFFAOYSA-N 0.000 description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 4
- 229910052794 bromium Inorganic materials 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 229960003512 nicotinic acid Drugs 0.000 description 3
- 235000001968 nicotinic acid Nutrition 0.000 description 3
- 239000011664 nicotinic acid Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 230000001276 controlling effect Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 238000010587 phase diagram Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- UZGLOGCJCWBBIV-UHFFFAOYSA-N 3-(chloromethyl)pyridin-1-ium;chloride Chemical compound Cl.ClCC1=CC=CN=C1 UZGLOGCJCWBBIV-UHFFFAOYSA-N 0.000 description 1
- CJAUTVHMRSAZGG-UHFFFAOYSA-N 3-bromo-5-(chloromethyl)pyridine;hydrochloride Chemical compound Cl.ClCC1=CN=CC(Br)=C1 CJAUTVHMRSAZGG-UHFFFAOYSA-N 0.000 description 1
- RNRLTTNKVLFZJS-UHFFFAOYSA-N 5,6-dichloropyridine-3-carboxylic acid Chemical compound OC(=O)C1=CN=C(Cl)C(Cl)=C1 RNRLTTNKVLFZJS-UHFFFAOYSA-N 0.000 description 1
- XYLPLVUYPAPCML-UHFFFAOYSA-N 5-chloropyridine-3-carboxylic acid Chemical compound OC(=O)C1=CN=CC(Cl)=C1 XYLPLVUYPAPCML-UHFFFAOYSA-N 0.000 description 1
- UPFHREFMESXXLW-UHFFFAOYSA-N 5-iodopyridine-3-carboxylic acid Chemical compound OC(=O)C1=CN=CC(I)=C1 UPFHREFMESXXLW-UHFFFAOYSA-N 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- YSEXMKHXIOCEJA-FVFQAYNVSA-N Nicergoline Chemical compound C([C@@H]1C[C@]2([C@H](N(C)C1)CC=1C3=C2C=CC=C3N(C)C=1)OC)OC(=O)C1=CN=CC(Br)=C1 YSEXMKHXIOCEJA-FVFQAYNVSA-N 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 238000005260 corrosion Methods 0.000 description 1
- 230000007797 corrosion Effects 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000002274 desiccant Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 229940093499 ethyl acetate Drugs 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical group 0.000 description 1
- 239000000383 hazardous chemical Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229960003642 nicergoline Drugs 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229940090181 propyl acetate Drugs 0.000 description 1
- OYSBZLVHMPNJMR-UHFFFAOYSA-N pyridine-3-carboxylic acid Chemical compound OC(=O)C1=CC=CN=C1.OC(=O)C1=CC=CN=C1 OYSBZLVHMPNJMR-UHFFFAOYSA-N 0.000 description 1
- 239000012852 risk material Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- HIFJUMGIHIZEPX-UHFFFAOYSA-N sulfuric acid;sulfur trioxide Chemical compound O=S(=O)=O.OS(O)(=O)=O HIFJUMGIHIZEPX-UHFFFAOYSA-N 0.000 description 1
- DHCDFWKWKRSZHF-UHFFFAOYSA-N sulfurothioic S-acid Chemical compound OS(O)(=O)=S DHCDFWKWKRSZHF-UHFFFAOYSA-N 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/80—Acids; Esters in position 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/803—Processes of preparation
Abstract
本发明公开了一种5‑卤代烟酸的合成方法,包括如下步骤:在非质子性溶剂中加入3‑氰基吡啶和固体卤代试剂,升温至50‑150℃反应,反应时间为6~30h;加入萃取剂、水、还原剂搅拌10~30分钟后,用碱液调pH至碱性,浓缩有机相;加入极性溶剂溶解,滴加水析出固体,过滤收集固体;向该固体中加入浓盐酸,升温至95~100℃反应30~60分钟后,用碱液调pH至1~4,析出白色固体,得5‑卤代烟酸成品。本发明使用固体卤代试剂卤化,条件温和,无需高温高压,对设备要求低,反应过程可控,副产物少,制备的5‑卤代烟酸液相纯度大于99%;不涉及高风险化合物使用,对环境友好,整个工艺适合工业化生产,实现生产的绿色无污染。
Description
技术领域
本发明涉及有机合成技术领域,尤其涉及一种5-卤代烟酸的合成方法。
背景技术
烟酸衍生物中较引人注目的系列化合物为卤代烟酸衍生物,可用作医药及医药中间体等,如5-溴烟酸(5-Bromonicotinic acid,简称5-BrNA)是合成尼麦角林等原料药的重要中间体。
目前,合成5-卤代烟酸最常用的方法是以烟酸(Nicotinic acid)为原料。烟酸与二氯亚砜反应生成烟酰氯盐酸盐,再加溴素在160℃下反应10小时溴化合成5-溴烟酰氯盐酸盐,再经水解制备得5-溴烟酸。如烟酸与二氯亚砜温热5天,再升温至180℃反应12h,则可得到5-氯烟酸和5,6-二氯烟酸的混合物。如采用发烟硫酸催化,烟酸与碘在320℃左右可得到5-碘烟酸。上述合成路线需要使用大量的二氯亚砜、溴素、硫酸、碘等高风险物料,对环境产生的影响很不友好;且卤化温度要求高(甚至300℃以上),对设备要求极为严格,耐腐蚀、抗高压等,而且后处理操作繁琐;反应过程不可控,副产物较多,制备的5-卤代烟酸纯度较低。
因此,本领域急需开发一种5-卤代烟酸合成新方法,避免以上卤代步骤中严苛的反应条件,以及避免对环境造成严重的危害。
发明内容
本发明提供了一种5-卤代烟酸的合成方法,以解决现有合成方法中工艺复杂,条件苛刻和环境污染的问题。
本发明采用的技术方案是:提供一种5-卤代烟酸的合成方法,包括如下合成路线:
,
其中X选自卤素,所述合成路线包括如下步骤:
(1)在非质子性溶剂中加入3-氰基吡啶和固体卤代试剂,在氮气或惰性气体保护下,升温至50-150℃反应,反应时间为6~30h;
(2)加入萃取剂、水、还原剂搅拌10~30分钟后,用碱液调pH至碱性,浓缩有机相;
(3)加入极性溶剂溶解,滴加水析出固体,过滤并收集固体;
(4)向步骤(3)所述固体中加入浓盐酸,升温至95~100℃反应30~60分钟后,用碱液调pH,析出白色固体,得到5-卤代烟酸成品。
进一步地,前述步骤(4)中,所述pH为1~4,优选1.5~3,更优选2~3。进一步优选地,本发明某些实施方式,所述pH为2.5。
进一步地,前述非质子性溶剂为三氟甲苯、四氯化碳、氯仿、二氯甲烷、1,2-二溴乙烷、1,2-二氯乙烷、二氧六环、碳酸二甲酯、乙酸甲酯、乙酸乙酯、乙酸丙酯、乙酸异丙酯、乙酸丁酯中的一种或者它们的组合物。优选三氟甲苯、四氯化碳、氯仿、乙酸异丙酯、乙酸丁酯,进一步优选三氟甲苯。
进一步地,前述固体卤代试剂选自N-氯代丁二酰亚胺(NCS)、N-溴代丁二酰亚胺(NBS)、N-碘代丁二酰亚胺(NIS)、苯基三甲基三氯化铵、苯基三甲基三溴化铵、苯基三甲基三碘化铵、二氯海因、二溴海因、二碘海因、二氯异氰尿酸或二溴异氰尿酸;优选,N-氯代丁二酰亚胺(NCS)、N-溴代丁二酰亚胺(NBS)、N-碘代丁二酰亚胺(NIS)、二氯海因、二溴海因、二碘海因;更优选二氯海因、二溴海因、二碘海因。申请人惊喜的发现,在某些具体实施例中,本发明步骤(1)中非质子性溶剂为三氟甲苯,固体卤代试剂选自二氯海因、二溴海因、二碘海因时,中间体收率还能够进一步大幅提高。
进一步地,在步骤(1)中,升温至75~125℃反应。在该温度范围,可使卤化过程更加充分。
进一步地,在步骤(3)中,前述极性溶剂为甲醇、乙醇、异丙醇、丙酮中的至少一种。
进一步地,在步骤(3)中,前述水的体积与极性溶剂体积比优选0.4~1.0。通过加入特定比例的水,能进一步提高收率,保证纯度。
进一步地,在步骤(2)和步骤(4)中,前述碱液为无机碱的水溶液,优选氢氧化钠、氢氧化钾、碳酸钠、碳酸钾的水溶液中的一种或它们的组合物。
本发明的某些具体实施例中,前述步骤(2)中的pH优选8~10,能够进一步除去酸性不良杂质。
进一步地,前述步骤(2)中的还原剂为选自亚硫酸盐、亚硫酸氢盐或硫代硫酸盐,优选亚硫酸氢钠、亚硫酸钠或硫代硫酸钠。
本发明某些实施方式,提供一种5-卤代烟酸的合成方法,所述方法包括如下步骤:
(1)在非质子性溶剂中加入3-氰基吡啶和固体卤代试剂,在氮气或惰性气体保护下,升温至50~150℃反应,优选温度范围为75~128℃,反应时间为6~30h,反应完成后冷却至室温为反应液1;固体卤代试剂为N-氯代丁二酰亚胺(NCS)、N-溴代丁二酰亚胺(NBS)、N-碘代丁二酰亚胺(NIS)、苯基三甲基三氯化铵、苯基三甲基三溴化铵、苯基三甲基三碘化铵、二氯海因、二溴海因、二碘海因、二氯异氰尿酸或二溴异氰尿酸;所述卤代试剂优选N-氯代丁二酰亚胺(NCS)、N-溴代丁二酰亚胺(NBS)、N-碘代丁二酰亚胺(NIS)、二氯海因、二溴海因、二碘海因;更优选二氯海因、二溴海因、二碘海因。
(2)向上述反应液1中加入萃取剂、水、还原剂搅拌10~30分钟;再用碱液调pH至8~10,分出的有机相用干燥剂干燥,浓缩得5-卤代-3-氰基吡啶粗品;
(3)向上述5-卤代-3-氰基吡啶粗品中,加入极性溶剂,加热搅拌至溶清,降温至10~25℃,滴加水,过滤并真空干燥得5-卤代-3-氰基吡啶;
(4)将上述5-卤代-3-氰基吡啶中加入浓盐酸,升温至95~100℃反应30~60分钟,然后冷却至15~30℃;用碱液调pH至2~3,析出白色固体,过滤,水洗并干燥,得5-卤代烟酸成品。
在步骤(1)中,非质子性溶剂可以为三氟甲苯、四氯化碳、氯仿、二氯甲烷、1,2-二溴乙烷、1,2-二氯乙烷、二氧六环、碳酸二甲酯、乙酸甲酯、乙酸乙酯、乙酸正丙酯、乙酸异丙酯、乙酸丁酯等中的一种或者它们的组合物。
在步骤(2)中,萃取剂可以为乙酸乙酯,二氯甲烷,氯仿等有机溶剂;还原剂可以为亚硫酸氢钠,亚硫酸钠,硫代硫酸钠等还原剂;碱液可以为氢氧化钠、氢氧化钾、碳酸钠、碳酸钾等的水溶液中的一种或它们的组合物。
在步骤(3)中,极性溶剂可以为甲醇、乙醇、异丙醇、丙酮中的至少一种;溶清温度45~65℃;滴入水的体积约为极性溶剂体积的0.4~1.0。
在步骤(4)中,碱液可以为氢氧化钠、氢氧化钾、碳酸钠、碳酸钾等的水溶液中的一种或它们的组合物。
整个反应方程式如下:
本发明的有益效果是:本发明所述的是一种5-卤代烟酸的合成方法的工艺。该工艺与现有技术相比,主要优点在于:使用固体卤代试剂卤化,条件温和,无需高温高压,对设备要求低;反应过程可控,副产物少,制备的5-卤代烟酸液相纯度大于99%;不涉及高风险化合物使用,对环境友好,整个工艺适合工业化生产,实现生产的绿色无污染。
附图说明
图1为本发明公开的合成5-卤代烟酸的工艺流程图。
图2为本发明实施例1所合成的5-溴-3-氰基吡啶液相图谱。
图3为本发明实施例1所合成的5-溴烟酸液相图谱。
图4为本发明实施例1所合成的5-溴烟酸核磁氢谱。
具体实施方式
为了使本发明的目的、技术方案和优点更加清楚,下面将结合附图对本发明作进一步详细描述,但本发明的实施方式不限于此。
实施例1
在装有磁力搅拌器、冷凝管和通氮气装置的250mL反应瓶中依次加入10g(96.05mmol)3-氰基吡啶、100mL三氟甲苯、25.64g(144.8mmol)N-溴代琥珀酰亚胺,氮气保护下,加热至85~95℃搅拌反应15h。将反应液冷却至10~30℃,加入100mL乙酸乙酯、100mL水、4g亚硫酸氢钠,控温10~30℃搅拌30分钟,再用15%氢氧溶液调节pH至9;静置分液,有机相加入2g硫酸钠干燥并过滤,母液于40~50℃浓缩至无流出,再加入100mL甲醇搅拌均匀并蒸干;加入45mL甲醇加热至40~65℃溶清,冷却至15~25℃,然后滴入22.5mL水,降温至0~5℃析晶1.5小时,过滤,滤饼用5mL-10~0℃的冷甲醇冲洗,然后40℃真空干燥得8.8g 5-溴-3氰基吡啶,收率49.7%;HPLC图谱如图2所示,纯度大于99%。
在装有磁力搅拌器、冷凝管和通氮气装置的250mL反应瓶中依次加入44mL浓盐酸、8.8g 5-溴-3-氰基吡啶,升温至95~100℃反应50分钟,冷却至10~30℃,用15%氢氧化钠调节pH至2.5,于15~25℃搅拌1.5小时,过滤,滤饼用10mL水淋洗,55℃真空干燥得9g,收率92%,HPLC图谱如图3所示,纯度大于99%;核磁氢谱如图4所示;
测试结果:H1-NMR(400MHz,DMSO,ppm):13.76(s,1H),9.0(d,1H),8.91(d,1H),8.38(t,1H)。
实施例2
在装有磁力搅拌器、冷凝管和通氮气装置的250mL反应瓶中依次加入10g(96.05mmol)3-氰基吡啶、100mL四氯化碳、25.64g(144.8mmol)N-溴代琥珀酰亚胺,氮气保护下,加热至75~80℃搅拌反应25h。将反应液冷却至10~30℃,加入100mL二氯甲烷、100mL水、4g亚硫酸氢钠,控温10~30℃搅拌30分钟,再用15%氢氧溶液调节pH至9;静置分液,有机相加入2g硫酸钠干燥并过滤,母液于40~50℃浓缩至无流出,再加入100mL甲醇搅拌均匀并蒸干;加入45mL甲醇加热至40~65℃溶清,冷却至15~25℃,然后滴入22.5mL水,降温至0~5℃析晶1.5小时,过滤,滤饼用5mL-10~0℃的冷甲醇冲洗,然后40℃真空干燥得8.5g 5-溴-3氰基吡啶,收率48.3%,纯度大于99%。
在装有磁力搅拌器、冷凝管和通氮气装置的250mL反应瓶中依次加入44mL浓盐酸、8.5g 5-溴-3-氰基吡啶,升温至95~100℃反应50分钟,冷却至10~30℃,用15%氢氧化钠调节pH至2.5,于15~25℃搅拌1.5小时,过滤,滤饼用10mL水淋洗,55℃真空干燥得8.8g,收率94.3%,纯度大于99%。
实施例3
在装有磁力搅拌器、冷凝管和通氮气装置的250mL反应瓶中依次加入10g(96.05mmol)3-氰基吡啶、100mL醋酸丁酯、28.92g(100.8mmol)二溴异氰尿酸,氮气保护下,加热至110~115℃搅拌反应10h。将反应液冷却至10~30℃,加入100mL乙酸乙酯、100mL水、4g亚硫酸氢钠,控温10~30℃搅拌30分钟,再用15%氢氧溶液调节pH至9;静置分液,有机相加入2g硫酸钠干燥并过滤,母液于50~60℃浓缩至无流出,再加入100mL甲醇搅拌均匀并蒸干;加入45mL甲醇加热至40~65℃溶清,冷却至15~25℃,然后滴入22.5mL水,降温至0~5℃析晶1.5小时,过滤,滤饼用5mL-10~0℃的冷甲醇冲洗,然后40℃真空干燥得8.6g 5-溴-3氰基吡啶,收率48.8%,纯度大于99%。
在装有磁力搅拌器、冷凝管和通氮气装置的250mL反应瓶中依次加入44mL浓盐酸、8.6g 5-溴-3-氰基吡啶,升温至95~100℃反应50分钟,冷却至10~30℃,用15%氢氧化钠调节pH至1.5,于15~25℃搅拌1.5小时,过滤,滤饼用10mL水淋洗,55℃真空干燥得7.5g,收率80%,纯度大于99%。
实施例4
在装有磁力搅拌器、冷凝管和通氮气装置的250mL反应瓶中依次加入10g(96.05mmol)3-氰基吡啶、100mL1,2-二溴乙烷、60.26g(160.3mmol)苯基三甲基三溴化铵,氮气保护下,加热至120~125℃搅拌反应6h。将反应液冷却至10~30℃,加入100mL三氯甲烷、100mL水、4g亚硫酸氢钠,控温10~30℃搅拌30分钟,再用15%氢氧溶液调节pH至9;静置分液,有机相加入2g硫酸钠干燥并过滤,母液于50~80℃浓缩至无流出,再加入100mL甲醇搅拌均匀并蒸干;加入45mL甲醇加热至40~65℃溶清,冷却至15~25℃,然后滴入22.5mL水,降温至0~5℃析晶1.5小时,过滤,滤饼用5mL-10~0℃的冷甲醇冲洗,然后40℃真空干燥得8.0g 5-溴-3氰基吡啶,收率45.5%,纯度大于99%。
在装有磁力搅拌器、冷凝管和通氮气装置的250mL反应瓶中依次加入44mL浓盐酸、8.0g 5-溴-3-氰基吡啶,升温至95~100℃反应50分钟,冷却至10~30℃,用15%氢氧化钠调节pH至3.5,于15~25℃搅拌1.5小时,过滤,滤饼用10mL水淋洗,55℃真空干燥得7.5g,收率85%,纯度大于99%。
实施例5
在装有磁力搅拌器、冷凝管和通氮气装置的250mL反应瓶中依次加入10g(96.05mmol)3-氰基吡啶、100mL三氟甲苯、37.85g(192.1mmol)二氯海因,氮气保护下,加热至85~95℃搅拌反应15h。将反应液冷却至10~30℃,加入100mL乙酸乙酯、100mL水、6g亚硫酸氢钠,控温10~30℃搅拌30分钟,再用15%氢氧溶液调节pH至9;静置分液,有机相加入2g硫酸钠干燥并过滤,母液于40~50℃浓缩至无流出,再加入100mL甲醇搅拌均匀并蒸干;加入45mL甲醇加热至40~65℃溶清,冷却至15~25℃,然后滴入25mL水,降温至0~5℃析晶1.5小时,过滤,滤饼用5mL-10~0℃的冷甲醇冲洗,然后40℃真空干燥得9.2g 5-氯-3氰基吡啶,收率68.7%,纯度大于99%。
在装有磁力搅拌器、冷凝管和通氮气装置的250mL反应瓶中依次加入50mL浓盐酸、7.3g 5-氯-3-氰基吡啶,升温至95~100℃反应50分钟,冷却至10~30℃,用15%氢氧化钠调节pH至5.0,于15~25℃搅拌1.5小时,过滤,滤饼用10mL水淋洗,55℃真空干燥得1.2g,收率15.0%,纯度大于99%。
实施例6
在装有磁力搅拌器、冷凝管和通氮气装置的250mL反应瓶中依次加入10g(96.05mmol)3-氰基吡啶、100mL醋酸丁酯、37.85g(192.1mmol)二氯海因,氮气保护下,加热至85~95℃搅拌反应15h。将反应液冷却至10~30℃,加入100mL乙酸丁酯、100mL水、6g亚硫酸氢钠,控温10~30℃搅拌30分钟,再用15%氢氧溶液调节pH至9;静置分液,有机相加入2g硫酸钠干燥并过滤,母液于40~50℃浓缩至无流出,再加入100mL甲醇搅拌均匀并蒸干;加入45mL甲醇加热至40~65℃溶清,冷却至15~25℃,然后滴入25mL水,降温至0~5℃析晶1.5小时,过滤,滤饼用5mL-10~0℃的冷甲醇冲洗,然后40℃真空干燥得6.5g 5-氯-3氰基吡啶,收率48.6%,纯度大于99%。
在装有磁力搅拌器、冷凝管和通氮气装置的250mL反应瓶中依次加入50mL浓盐酸、6.5g 5-氯-3-氰基吡啶,升温至95~100℃反应50分钟,冷却至10~30℃,用15%氢氧化钠调节pH至2.5,于15~25℃搅拌1.5小时,过滤,滤饼用10mL水淋洗,55℃真空干燥得6.7g,收率90.4%,纯度大于99%。
对比例1
在装有磁力搅拌器、冷凝管和通氮气装置的250mL反应瓶中依次加入10g(96.05mmol)3-氰基吡啶、100mL三氟甲苯、32.03g(200mmol)液溴,梯度升温至85~95℃,反应瓶内有大量溴蒸汽溢出而无法正常操作;冷却后将物料转入250ml闷罐中再升温至85~95℃搅拌反应15h。将反应液冷却至10~30℃,取样用TLC检测,发现大量原料3-氰基吡啶残留,紧少量目标中间体5-溴-3-氰基吡啶生成,反应不理想,中止后处理。
通过对比例1可以看出,使用液溴会使溴蒸汽溢出而无法正常操作,同时反应效果较差,原料3-氰基吡啶出现大量残留。
以上实施例仅用以说明本发明的技术方案,而非对其限制;尽管参照前述实施例对发明进行了详细的说明,本领域的普通技术人员应当理解:其依然可以对前述各实施例所记载的技术方案进行修改,或者对其中部分技术特征进行等同替换;而这些修改或者替换,并不使相应技术方案的本质脱离本发明各实施例技术方案的精神和范围。
Claims (5)
1.一种5-卤代烟酸的合成方法,其特征在于,所述方法包括如下步骤:
(1)在非质子性溶剂中加入3-氰基吡啶和固体卤代试剂,升温至50-150℃反应,反应时间为6~30h;
(2)加入萃取剂、水、还原剂搅拌10~30分钟后,用碱液调pH至碱性,浓缩有机相;
(3)加入极性溶剂溶解,滴加水析出固体,过滤收集固体;
(4)向步骤(3)中所述固体中加入浓盐酸,升温至95~100℃反应30~60分钟后,用碱液调pH至1~4,析出白色固体,得5-卤代烟酸成品;
所述非质子性溶剂为三氟甲苯、四氯化碳、氯仿、二氯甲烷、1,2-二溴乙烷、1,2-二氯乙烷、二氧六环、碳酸二甲酯、乙酸甲酯、乙酸乙酯、乙酸正丙酯、乙酸异丙酯、乙酸丁酯中的一种或者它们的组合物;
所述固体卤代试剂为N-氯代丁二酰亚胺、N-溴代丁二酰亚胺、N-碘代丁二酰亚胺、苯基三甲基三氯化铵、苯基三甲基三溴化铵、苯基三甲基三碘化铵、二氯海因、二溴海因、二碘海因、二氯异氰尿酸或二溴异氰尿酸;
在步骤(3)中,所述极性溶剂为甲醇、乙醇、异丙醇、丙酮中的至少一种;
步骤(2)和步骤(4)中,所述碱液为氢氧化钠、氢氧化钾、碳酸钠、碳酸钾的水溶液中的一种或它们的组合物;
步骤(2)中所述还原剂为亚硫酸钠、亚硫酸氢钠或硫代硫酸钠。
2.根据权利要求1所述的5-卤代烟酸的合成方法,其特征在于,步骤(4)中,所述pH为1.5~3。
3.根据权利要求1所述的5-卤代烟酸的合成方法,其特征在于,在步骤(1)中,升温至75~128℃反应。
4.根据权利要求1所述的5-卤代烟酸的合成方法,其特征在于,在步骤(3)中,所述水的体积为所述极性溶剂体积的0.4~1.0倍。
5.一种5-卤代烟酸的合成方法,其特征在于,包括如下步骤:
(1)在非质子性溶剂中加入3-氰基吡啶和固体卤代试剂,在氮气或惰性气体保护下,升温至75~128℃反应,反应时间为6~30h;
(2)加入萃取剂、水、还原剂搅拌10~30分钟后,用碱液调pH至8~10,浓缩有机相;
(3)加入极性溶剂溶解,滴加水析出固体,过滤收集固体;
(4)向步骤(3)中所述固体中加入浓盐酸,升温至95~100℃反应30~60分钟后,用碱液调pH至2~3,析出白色固体,过滤水洗并干燥得5-卤代烟酸成品;
其中步骤(1)中所述固体卤代试剂选自二氯海因、二溴海因、二碘海因,所述非质子性溶剂选自三氟甲苯、四氯化碳、氯仿、乙酸正丙酯、乙酸异丙酯、乙酸丁酯;步骤(2)中所述还原剂选自硫代硫酸钠、亚硫酸钠、亚硫酸氢钠;步骤(3)中所述极性溶剂选自甲醇、乙醇、异丙醇、丙酮,水与所述极性溶剂体积比为0.4~10。
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