CN105646199A - 3-氯-2,4,5-三氟苯甲酸的制备工艺 - Google Patents
3-氯-2,4,5-三氟苯甲酸的制备工艺 Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- KBESHLYCSZINAJ-UHFFFAOYSA-N 3-chloro-2,4,5-trifluorobenzoic acid Chemical compound OC(=O)C1=CC(F)=C(F)C(Cl)=C1F KBESHLYCSZINAJ-UHFFFAOYSA-N 0.000 title abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims abstract description 85
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 48
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 41
- 238000003756 stirring Methods 0.000 claims description 38
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 36
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 32
- CWXRPYKMZOYGAX-UHFFFAOYSA-N 3,4,6-tris(fluoromethyl)-2-nitroaniline Chemical compound [N+](=O)([O-])C1=C(N)C(=CC(=C1CF)CF)CF CWXRPYKMZOYGAX-UHFFFAOYSA-N 0.000 claims description 31
- 239000012043 crude product Substances 0.000 claims description 30
- 239000000243 solution Substances 0.000 claims description 30
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 26
- 229960000583 acetic acid Drugs 0.000 claims description 24
- 239000012362 glacial acetic acid Substances 0.000 claims description 24
- 239000001117 sulphuric acid Substances 0.000 claims description 21
- 235000011149 sulphuric acid Nutrition 0.000 claims description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 19
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 19
- 238000010792 warming Methods 0.000 claims description 19
- 239000000376 reactant Substances 0.000 claims description 17
- 235000010288 sodium nitrite Nutrition 0.000 claims description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 claims description 14
- 230000006837 decompression Effects 0.000 claims description 14
- 238000001914 filtration Methods 0.000 claims description 14
- 238000001556 precipitation Methods 0.000 claims description 13
- 238000005406 washing Methods 0.000 claims description 13
- VBLXCTYLWZJBKA-UHFFFAOYSA-N 2-(trifluoromethyl)aniline Chemical compound NC1=CC=CC=C1C(F)(F)F VBLXCTYLWZJBKA-UHFFFAOYSA-N 0.000 claims description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 238000005516 engineering process Methods 0.000 claims description 12
- 238000010992 reflux Methods 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 12
- 238000009413 insulation Methods 0.000 claims description 11
- -1 6-trifluoromethyl anilines Chemical class 0.000 claims description 10
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 9
- 208000035126 Facies Diseases 0.000 claims description 8
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N N-phenyl amine Natural products NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims description 8
- 239000007805 chemical reaction reactant Substances 0.000 claims description 8
- 239000002024 ethyl acetate extract Substances 0.000 claims description 8
- WIQDKNVLKKUUMI-UHFFFAOYSA-N n-(3,4-difluorophenyl)-2-fluoroacetamide Chemical compound FCC(=O)NC1=CC=C(F)C(F)=C1 WIQDKNVLKKUUMI-UHFFFAOYSA-N 0.000 claims description 8
- 229960004756 ethanol Drugs 0.000 claims description 7
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 6
- JNYLMODTPLSLIF-UHFFFAOYSA-N 6-(trifluoromethyl)pyridine-3-carboxylic acid Chemical group OC(=O)C1=CC=C(C(F)(F)F)N=C1 JNYLMODTPLSLIF-UHFFFAOYSA-N 0.000 claims description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 6
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 6
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 6
- 229910017604 nitric acid Inorganic materials 0.000 claims description 6
- 239000000843 powder Substances 0.000 claims description 6
- OOMNPYBQJCAHFY-UHFFFAOYSA-N 2,4,5-tris(fluoromethyl)aniline Chemical class FCC1=C(N)C=C(C(=C1)CF)CF OOMNPYBQJCAHFY-UHFFFAOYSA-N 0.000 claims description 5
- KWSLGOVYXMQPPX-UHFFFAOYSA-N 5-[3-(trifluoromethyl)phenyl]-2h-tetrazole Chemical compound FC(F)(F)C1=CC=CC(C2=NNN=N2)=C1 KWSLGOVYXMQPPX-UHFFFAOYSA-N 0.000 claims description 5
- 239000005711 Benzoic acid Substances 0.000 claims description 5
- XVPGNMRZBYZWBC-UHFFFAOYSA-N C1=C(C(=CC(=C1F)F)F)NC(=O)C[N+](=O)[O-] Chemical compound C1=C(C(=CC(=C1F)F)F)NC(=O)C[N+](=O)[O-] XVPGNMRZBYZWBC-UHFFFAOYSA-N 0.000 claims description 5
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims description 5
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 5
- QPLDLSVMHZLSFG-UHFFFAOYSA-N Copper oxide Chemical compound [Cu]=O QPLDLSVMHZLSFG-UHFFFAOYSA-N 0.000 claims description 5
- 239000005751 Copper oxide Substances 0.000 claims description 5
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 5
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 5
- 235000011089 carbon dioxide Nutrition 0.000 claims description 5
- 229910000431 copper oxide Inorganic materials 0.000 claims description 5
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 claims description 5
- 229960000935 dehydrated alcohol Drugs 0.000 claims description 5
- 125000000664 diazo group Chemical group [N-]=[N+]=[*] 0.000 claims description 5
- ULYZAYCEDJDHCC-UHFFFAOYSA-N isopropyl chloride Chemical compound CC(C)Cl ULYZAYCEDJDHCC-UHFFFAOYSA-N 0.000 claims description 5
- 229910001379 sodium hypophosphite Inorganic materials 0.000 claims description 5
- RXQNKKRGJJRMKD-UHFFFAOYSA-N 5-bromo-2-methylaniline Chemical compound CC1=CC=C(Br)C=C1N RXQNKKRGJJRMKD-UHFFFAOYSA-N 0.000 claims description 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 4
- 239000011630 iodine Substances 0.000 claims description 4
- 229910052740 iodine Inorganic materials 0.000 claims description 4
- 239000000047 product Substances 0.000 claims description 4
- ZJPHDPZUAINCNU-UHFFFAOYSA-N 1-(2-aminophenyl)-2,2,2-trifluoroethanone Chemical compound NC1=CC=CC=C1C(=O)C(F)(F)F ZJPHDPZUAINCNU-UHFFFAOYSA-N 0.000 claims description 3
- PVLLRVLANBOYGO-UHFFFAOYSA-N 1-chloro-2,4,5-trifluorobenzene Chemical compound FC1=CC(F)=C(Cl)C=C1F PVLLRVLANBOYGO-UHFFFAOYSA-N 0.000 claims description 3
- NNXDLAJGVDPLRN-UHFFFAOYSA-N C1=C(C=C(C(=C1CF)CF)NCl)CF Chemical compound C1=C(C=C(C(=C1CF)CF)NCl)CF NNXDLAJGVDPLRN-UHFFFAOYSA-N 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- KIUWLCQIHAWSHJ-UHFFFAOYSA-N C1=C(C(=C(C(=C1CF)Cl)N)CF)CF Chemical compound C1=C(C(=C(C(=C1CF)Cl)N)CF)CF KIUWLCQIHAWSHJ-UHFFFAOYSA-N 0.000 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims description 2
- 239000011777 magnesium Substances 0.000 claims description 2
- 229910052749 magnesium Inorganic materials 0.000 claims description 2
- SLFVYFOEHHLHDW-UHFFFAOYSA-N n-(trifluoromethyl)aniline Chemical class FC(F)(F)NC1=CC=CC=C1 SLFVYFOEHHLHDW-UHFFFAOYSA-N 0.000 claims description 2
- 230000000630 rising effect Effects 0.000 claims description 2
- VLRGXXKFHVJQOL-UHFFFAOYSA-N 3-chloropentane-2,4-dione Chemical compound CC(=O)C(Cl)C(C)=O VLRGXXKFHVJQOL-UHFFFAOYSA-N 0.000 claims 3
- 239000002994 raw material Substances 0.000 abstract description 14
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- 238000000034 method Methods 0.000 abstract description 5
- QMYVWJVVVMIBMM-UHFFFAOYSA-N 2,4,5-trifluoroaniline Chemical compound NC1=CC(F)=C(F)C=C1F QMYVWJVVVMIBMM-UHFFFAOYSA-N 0.000 abstract 1
- 230000009286 beneficial effect Effects 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- 239000007787 solid Substances 0.000 description 9
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- NRBQKJUNWURJNV-UHFFFAOYSA-N 2-bromo-1,4,5-trifluoro-3-nitrobenzene Chemical class BrC1=C(C(=C(C=C1F)F)F)[N+](=O)[O-] NRBQKJUNWURJNV-UHFFFAOYSA-N 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 238000000605 extraction Methods 0.000 description 3
- MPORYQCGWFQFLA-ONPDANIMSA-N 7-[(7s)-7-amino-5-azaspiro[2.4]heptan-5-yl]-8-chloro-6-fluoro-1-[(1r,2s)-2-fluorocyclopropyl]-4-oxoquinoline-3-carboxylic acid;trihydrate Chemical compound O.O.O.C([C@H]1N)N(C=2C(=C3C(C(C(C(O)=O)=CN3[C@H]3[C@H](C3)F)=O)=CC=2F)Cl)CC11CC1.C([C@H]1N)N(C=2C(=C3C(C(C(C(O)=O)=CN3[C@H]3[C@H](C3)F)=O)=CC=2F)Cl)CC11CC1 MPORYQCGWFQFLA-ONPDANIMSA-N 0.000 description 2
- OUJUOLZKAYIMHF-UHFFFAOYSA-N BrC1=C(N)C(=C(C=C1CF)CF)CF Chemical class BrC1=C(N)C(=C(C=C1CF)CF)CF OUJUOLZKAYIMHF-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- 229960003177 sitafloxacin Drugs 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- WZJZMVSJWUHDOB-UHFFFAOYSA-N 3-chloropyrrolidine-2,5-dione Chemical compound ClC1CC(=O)NC1=O WZJZMVSJWUHDOB-UHFFFAOYSA-N 0.000 description 1
- ZWEDFZVJMFBOGV-UHFFFAOYSA-N C(=O)C1=C(O)C(O)=C(C(C)C)C2=CC(C)=C(C(O)=C12)C1=C(O)C2=C(C=O)C(O)=C(O)C(C(C)C)=C2C=C1C.C(C)O Chemical compound C(=O)C1=C(O)C(O)=C(C(C)C)C2=CC(C)=C(C(O)=C12)C1=C(O)C2=C(C=O)C(O)=C(O)C(C(C)C)=C2C=C1C.C(C)O ZWEDFZVJMFBOGV-UHFFFAOYSA-N 0.000 description 1
- VKNAQJWDLDLWHX-UHFFFAOYSA-N C1=C(C=C(C(=C1CF)CF)NBr)CF Chemical compound C1=C(C=C(C(=C1CF)CF)NBr)CF VKNAQJWDLDLWHX-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000003750 conditioning effect Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940124307 fluoroquinolone Drugs 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000006396 nitration reaction Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000004454 trace mineral analysis Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/16—Preparation of carboxylic acids or their salts, halides or anhydrides by oxidation
- C07C51/29—Preparation of carboxylic acids or their salts, halides or anhydrides by oxidation with halogen-containing compounds which may be formed in situ
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C17/00—Preparation of halogenated hydrocarbons
- C07C17/35—Preparation of halogenated hydrocarbons by reactions not affecting the number of carbon or of halogen atoms in the reaction
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/30—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of nitrogen-to-oxygen or nitrogen-to-nitrogen bonds
- C07C209/32—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of nitrogen-to-oxygen or nitrogen-to-nitrogen bonds by reduction of nitro groups
- C07C209/36—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of nitrogen-to-oxygen or nitrogen-to-nitrogen bonds by reduction of nitro groups by reduction of nitro groups bound to carbon atoms of six-membered aromatic rings in presence of hydrogen-containing gases and a catalyst
- C07C209/365—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of nitrogen-to-oxygen or nitrogen-to-nitrogen bonds by reduction of nitro groups by reduction of nitro groups bound to carbon atoms of six-membered aromatic rings in presence of hydrogen-containing gases and a catalyst by reduction with preservation of halogen-atoms in compounds containing nitro groups and halogen atoms bound to the same carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/62—Preparation of compounds containing amino groups bound to a carbon skeleton by cleaving carbon-to-nitrogen, sulfur-to-nitrogen, or phosphorus-to-nitrogen bonds, e.g. hydrolysis of amides, N-dealkylation of amines or quaternary ammonium compounds
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/68—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton
- C07C209/74—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton by halogenation, hydrohalogenation, dehalogenation, or dehydrohalogenation
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
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Abstract
本发明公开了一种3-氯-2,4,5-三氟苯甲酸的制备工艺,从原料2,4,5-三氟苯胺出发,经一系列反应得到成品2-3-氯-2,4,5-三氟苯甲酸,本发明原料简单易得,成本低,反应条件温和,无异构体,纯度高,收率高,更易于工业化生产。
Description
技术领域
本发明涉及有机化学合成领域,具体涉及到一种制备3-氯-2,4,5-三氟苯甲酸的方法。
背景技术
3-氯-2,4,5-三氟苯甲酸是合成西他沙星(sitafloxacin)等新氟喹诺酮类抗菌药的关键中间体。3-氯-2,4,5-三氟苯甲酸作为新型抗菌药物的重要合成中间体,具有广阔的市场发展前景。
目前市场上有很多种制备3-氯-2,4,5-三氟苯甲酸的,反应步骤较长,收率较低,实现工业化生产有较大的难度。目前最先进,反应较温和的制备路线如下:
该工艺最后一步反应易生成异构体4-氯-2,3,5-三氟苯甲酸,因而,在工业生产过程中,该工艺纯化难,产品收率低。
发明内容
本发明提供了一种制备3-氯-2,4,5-三氟苯甲酸的方法,原料简单易得,成本低,反应条件温和,无异构体,纯度高,收率高,更易于工业化生产。
本发明采用的技术方案如下:一种3-氯-2,4,5-三氟苯甲酸的制备工艺,包括如下步骤:
步骤1:于反应容器中,加入2,4,5-三氟苯胺和溶剂冰醋酸,于35-40℃下搅拌,滴加醋酐,反应完毕后将反应液倒入冰水中,趁冷过滤,水洗得2,4,5-三氟乙酰苯胺粗品;
步骤2:于反应容器中,加入浓硫酸及冰醋酸或醋酐,再加入2,4,5-三氟乙酰苯胺粗品,搅拌下,滴加由发烟硝酸和浓硫酸制成的硝硫混酸,温度控制在45~55℃,反应完毕后倒入冰水中,趁冷过滤,水洗得2-硝基-3,4,6-三氟乙酰苯胺粗品;
步骤3:于反应容器中,加入乙醇和浓盐酸,再加入2-硝基-3,4,6-三氟乙酰苯胺粗品,搅拌下升温回流85~95℃,反应完毕后将反应液倒入冰水中,趁冷过滤,水洗得2-硝基-3,4,6-三氟苯胺粗品;
步骤4:于反应容器中,加入2-硝基-3,4,6-三氟苯胺粗品和溶剂冰醋酸,搅拌下,冷却至25~30℃,滴加由浓硫酸和亚硝酸钠制成的亚硝酰硫酸溶液,得到重氮化溶液,然后将该溶液滴加到由氢溴酸和溴化亚铜制成的溶液中,温度不超过40℃,滴加完毕后再升温至80±5℃下反应后得2-溴-3,5,6-三氟硝基苯粗品;或者于反应容器中,加入氢溴酸、水、铜粉及2-硝基-3,4,6-三氟苯胺粗品,搅拌下,升温至40~45℃,滴加由亚硝酸钠和水制成的水溶液反应,反应完毕后将反应液倒入冰水中,水层用乙酸乙酯萃取,合并有机相,水洗,干燥,减压脱溶后得2-溴-3,5,6-三氟硝基苯粗品;
步骤5:于反应容器中,加入水、冰醋酸、还原铁粉和溶剂无水乙醇或甲醇,搅拌下升温至85~95℃下回流反应后,分批加入2-溴-3,5,6-三氟硝基苯粗品,加完后继续回流反应1小时以上,反应完毕后将反应液倒入冰水中,水层用乙酸乙酯萃取,合并有机相,水洗,干燥,减压脱溶后得2-溴-3,5,6-三氟苯胺粗品;
步骤6:于反应容器中,加入-溴-3,5,6-三氟苯胺粗品和溶剂DMF,搅拌下降温至20~35℃,分批加入NCS(N-氯代丁二酰亚胺),加完后升温至50~60℃下保温反应2小时以上,反应完毕后将反应液倒入冰水中,趁冷过滤,水洗烘干得2-溴-4-氯-3,5,6-三氟苯胺粗品;
步骤7:于反应容器中,加入2-溴-4-氯-3,5,6-三氟苯胺粗品和冰醋酸,搅拌下,冷却至10~15℃,滴加由浓硫酸及亚硝酸钠配制好的亚硝酰硫酸溶液,得到重氮化溶液,然后将该溶液滴加到由磷酸/次亚磷酸钠、水和氧化铜配成的混合液中,温度控制在30~35℃,滴加完毕后再升温至60~70℃反应,反应完毕后将反应液倒入冰水中,水层用乙酸乙酯萃取,合并有机相,水洗,干燥,减压脱溶后得1-溴-3-氯-2,4,5-三氟苯粗品,精馏得纯品;
步骤8:于反应容器中,氮气保护下,加入溶剂无水四氢呋喃、碘和镁条,搅拌下升温至60~65℃,滴加由无水四氢呋喃和异丙基氯制成的溶液,温度控制在55~70℃下反应,反应完毕后降温至10~15℃,滴加由无水四氢呋喃和1-溴-3-氯-2,4,5-三氟苯制成的溶液,降温至-5~(-10)℃,分批加入干冰,半小时加完,自然升至室温反应,反应完毕后将反应液倒入冰水中,水层用乙酸乙酯萃取,合并有机相,水洗,干燥,减压脱溶后得成品2-3-氯-2,4,5-三氟苯甲酸。
步骤1中,所述的2,4,5-三氟苯胺与醋酐的摩尔比为1:(1.05~1.15);反应时间为1-3h。
步骤2中,所述的2,4,5-三氟乙酰苯胺与浓硝酸摩尔比为1:(2.0~3.0),2-硝基-3,4,6-三氟苯胺与浓硫酸总量的摩尔比为1:(8~10),硝硫混酸中,浓硝酸与浓硫酸的比为1:1g/ml;2-硝基-3,4,6-三氟苯胺与冰醋酸的摩尔比为1:(15~20);2-硝基-3,4,6-三氟苯胺与醋酐的摩尔比为1:(15~20),反应时间为3~5h。
步骤3中,所述2-硝基-3,4,6-三氟乙酰苯胺与浓盐酸的摩尔比为1:(5~8),所述的溶剂为乙醇,2-硝基-3,4,6-三氟乙酰苯胺与乙醇的摩尔比为1:(5~10),反应时间为2~5h。
步骤4中,所述2-硝基-3,4,6-三氟苯胺与亚硝酸钠的摩尔比为1:(1.05~1.15),2-硝基-3,4,6-三氟苯胺与氢溴酸的摩尔比为1:(4~6);2-硝基-3,4,6-三氟苯胺与溴化亚铜的摩尔比为1:(0.5~1.0);2-硝基-3,4,6-三氟苯胺与铜粉的摩尔比为1:(0.8~1.2);2-硝基-3,4,6-三氟苯胺与浓硫酸的摩尔比为1:(8~10),2-硝基-3,4,6-三氟苯胺与冰醋酸的摩尔比为1:(15~20);反应时间为1.5~2.5h。
步骤5中,所述2-溴-3,5,6-三氟硝基苯与还原铁粉的摩尔比为1:(1.2~1.6),2-硝基-3,4,6-三氟苯胺与冰醋酸的摩尔比为1:(0.3~1.0);2-硝基-3,4,6-三氟苯胺与水的摩尔比为1:(90~110);2-硝基-3,4,6-三氟苯胺与无水乙醇或甲醇的摩尔比为1:(4~6);反应时间为2~4h。
步骤6中,所述2-溴-3,5,6-三氟苯胺与NCS的摩尔比为1:(1.1~1.2),2-硝基-3,4,6-三氟苯胺与DMF的摩尔比为1:(10~15);反应时间为4~6h。
步骤7中,所述2-溴-4-氯-3,5,6-三氟苯胺与亚硝酸钠的摩尔比为1:(1.05~1.15),2-溴-4-氯-3,5,6-三氟苯胺与磷酸的摩尔比为1:(10~15),2-溴-4-氯-3,5,6-三氟苯胺与次亚磷酸钠的摩尔比为1:(1.2~1.6);2-溴-4-氯-3,5,6-三氟苯胺与氧化铜的摩尔比为1:(0.2~0.3);2-硝基-3,4,6-三氟苯胺与水的摩尔比为1:(10~15),2-硝基-3,4,6-三氟苯胺与浓硫酸的摩尔比为1:(8~10),2-硝基-3,4,6-三氟苯胺与冰醋酸的摩尔比为1:(15~20);反应时间为3~5h。
步骤8中,所述1-溴-3-氯-2,4,5-三氟苯与镁的摩尔比为1:(1.2~1.3),1-溴-3-氯-2,4,5-三氟苯与异丙基氯的摩尔比为1:(2.0~2.5),1-溴-3-氯-2,4,5-三氟苯与干冰的摩尔比为1:(3.0~4.0);1-溴-3-氯-2,4,5-三氟苯与碘的摩尔比为1:(0.005~0.015);反应时间为5~8h。
与现有技术相比,本发明具有如下优点:
原料简单易得,成本低,反应条件温和,无异构体,纯度高,收率高,更易于工业化生产。
具体实施方式
本发明所述的3-氯-2,4,5-三氟苯甲酸的合成路线如下:
实施例1原料比:2,4,5-三氟苯胺:醋酐=1:1.1(摩尔比)
装有搅拌器,回流冷凝管,温度计的2.5L反应烧瓶中,加入1L冰醋酸及294.2g[2.0mol]2,4,5-三氟苯胺,搅拌下滴加醋酐234.6g[2.3mol],控制滴加速度使得反应温度保持在35-40℃,滴加完毕后继续反应30分钟,取样GC跟踪反应完毕。将反应液倒入5L冰水中,搅拌15分钟后趁冷过滤,水洗3次,每次300ml,烘干得351g2,4,5-三氟乙酰苯胺,淡黄色固体,收率93%,含量98.7%。
实施例2原料比:2,4,5-三氟乙酰苯胺:硝酸=1:2.4(摩尔比)
装有搅拌器,回流冷凝管,温度计的5.0L反应烧瓶中,加入600ml浓硫酸及300ml冰醋酸,搅拌下分批加入340g[1.8mol]2,4,5-三氟乙酰苯胺,升温至45-50度,滴加300g发烟硝酸+300ml浓硫酸配成的硝硫混酸溶液,控制滴加速度使得反应温度保持在45-50℃,1小时左右滴加完毕,继续在该温度反应下1-2小时,取样GC跟踪至反应完毕。将反应液倒入10L冰水中,搅拌15分钟后趁冷过滤,水洗3次,每次300ml,烘干得358g黄色固体2-硝基-3,4,6-三氟乙酰苯胺,收率85%,含量97.6%。(过滤得硝化产物400g,可用乙醇-氯仿重结晶得无色固体,熔点:142-143℃。)
实施例4原料比:2,4,5-三氟苯胺:醋酐:硝酸=1:1.1:2.4(摩尔比)
装有搅拌器,回流冷凝管,温度计的2.5L反应烧瓶中,加入1L冰醋酸,搅拌下加入294.2g[2.0mol]2,3,4-三氟苯胺,滴加234.6g[2.3mol]醋酐,温度控制在35-40℃,半小时滴加完毕,在次温度继续反应30分钟,GC跟踪反应完全后滴加300g发烟硝酸+300ml浓硫酸配的混酸溶液,控制反应温度45-50℃,1小时内滴加完毕,该温度下继续保温反应1-2小时,GC跟踪反应完毕。将反应液倒入2L冰水中,搅拌15分钟后趁冷过滤,水洗3次,每次500ml,烘干得350g2-硝基-3,4,6-三氟乙酰苯胺,黄色固体,收率84%,含量97.2%。
实施例5原料比:2-硝基-3,4,6-三氟乙酰苯胺:浓盐酸=1:7.2(摩尔比)
装有搅拌器,回流冷凝管,温度计的2.5L反应烧瓶中,加入358g[1.53mol]2-硝基-3,4,6-三氟乙酰苯胺,1.3kg浓盐酸,200g乙醇,搅拌下升温至回流反应2小时,GC跟踪分析反应完毕。将反应液倒入2L冰水中,搅拌15分钟后趁冷过滤,水洗3次,每次250ml,烘干得220g2-硝基-3,4,6-三氟苯胺,黄色固体,收率74.9%,含量97.0%。
实施例6原料比:2-硝基-3,4,6-三氟苯胺:亚硝酸钠=1:1.1(摩尔比)
装有搅拌器,回流冷凝管,温度计的2.5L反应烧瓶中,加入200g[1.04mol]2-硝基-3,4,6-三氟苯胺及500ml冰醋酸,搅拌下滴加由80g[1.15mol]亚硝酸钠+500ml浓硫酸配成的溶液,温度控制在30℃以内,滴加完毕后继续保温反应1小时。同时在另外一个5L反应瓶中加入600ml48%的氢溴酸溶液及115g溴化亚铜,搅拌下滴加上面制备好的重氮化溶液,,温度不超过40℃,半小时内加完并在此温度下保温反应1小时后再升温至80℃下反应1.5小时,GC跟踪反应完毕后。将反应液倒入5L冰水中,搅拌30分钟,乙酸乙酯萃取3次,每次用量1L,合并有机层,水洗3次,每次300ml,无水硫酸镁干燥,减压脱溶得195g浅棕色固体2-溴-3,5,6-三氟硝基苯,收率84.5%,含量92%。
实施例7原料比:2-硝基-3,4,6-三氟苯胺:亚硝酸钠=1:1.2(摩尔比)
装有搅拌器,回流冷凝管,温度计的2.5L反应烧瓶中,分别加入800g48%的氢溴酸溶液,400g水,60g铜粉及200g[1.04mol]2-硝基-3,4,6-三氟苯胺,搅拌下升温至40-45℃,滴加由86g亚硝酸钠+340g水配成的溶液,1小时内加完后继续保温反应0.5小时,GC跟踪反应完毕后。将反应液倒入5L冰水中,搅拌30分钟,乙酸乙酯萃取3次,每次用量1L,合并有机层,水洗3次,每次300ml,无水硫酸镁干燥,减压脱溶得190g浅棕色固体2-溴-3,5,6-三氟硝基苯,收率71.5%,含量95%。
实施例8原料比:2-溴-3,5,6-三氟硝基苯:还原铁粉=1:1.5(摩尔比)
装有搅拌器,回流冷凝管,温度计的2.5L反应烧瓶中,分别加入1.5L水,200ml无水乙醇,20ml冰醋酸及65g[2.0mol]还原铁粉,搅拌下升温至回流后,分批加入200g[0.78mol]2-溴-3,5,6-三氟硝基苯,1小时内全部加完并继续回流反应1小时。GC跟踪反应完毕后。将反应液倒入2L冰水中,搅拌30分钟,乙酸乙酯萃取3次,每次用量350L,合并有机层,水洗3次,每次200ml,无水硫酸镁干燥,减压脱溶得145g浅棕色固体2-溴-3,5,6-三氟苯胺,收率82.2%,含量90%。
实施例9原料比:2-溴-3,5,6-三氟苯胺:NCS=1:1.13(摩尔比)
装有搅拌器,回流冷凝管,温度计的2L反应烧瓶中,分别加入800mlDMF及200g[0.885mol]2-溴-3,5,6-三氟苯胺,搅拌下降温至20-30℃分批加入133.5g[1.0mol]NCS,半小时加完,继续保温反应1小时后再升温至50-55℃,保温反应2小时,GC跟踪反应完毕。将反应液倒入2L冰水中,搅拌30分钟,,搅拌15分钟后趁冷过滤,水洗3次,每次200ml,烘干得219g2-溴-4-氯-3,5,6-三氟苯胺,收率95.1%,含量92%。
实施例10原料比:2-溴-4-氯-3,5,6-三氟苯胺:亚硝酸钠=1:1.1(摩尔比)
装有搅拌器,回流冷凝管,温度计的5L反应烧瓶中,加入700ml冰醋酸及200g[0.768mol]2-溴-4-氯-3,5,6-三氟苯胺,搅拌下降温至10-15℃,滴加由59g[0.85mol]亚硝酸钠+600ml浓硫酸配成的溶液,温度控制在15℃以内,滴加完毕后继续保温反应1小时。继续滴加由600ml磷酸,200g次亚磷酸钠,140g水及15g氧化铜配成的混合液,控制反应温度在30-35℃,1小时内滴加完毕。缓慢升温至60-70℃反应2小时,GC跟踪反应完毕。用乙酸乙酯萃取3次,每次用量500L,合并有机层,水洗3次,每次300ml,无水硫酸镁干燥,减压脱溶得135g浅棕色液体1-溴-3-氯-2,4,5-三氟苯,收率71.6%,含量92.5%。精馏得110g纯品,含量98.8%。
实施例11原料比:1-溴-3-氯-2,4,5-三氟苯:镁条=1:1.26(摩尔比)
装有搅拌器,回流冷凝管,温度计的2.5L反应烧瓶中,氮气保护下加入150ml无水四氢呋喃,24.4g[1.0mol]镁条及2g碘,搅拌下升温至60-65度,滴加由350ml无水四氢呋喃+130g异丙基氯配成的溶液,温度控制55-65℃,1小时加完,继续保温反应1小时后降温至10-15℃,滴加由350ml无水四氢呋喃+200g[0.815mol]1-溴-3-氯-2,4,5-三氟苯配成的溶液,加完后在此温度下继续保温反应1.5小时,GC跟踪反应完毕。降温至-5~(-10)℃,分批加入120g干冰,半小时加完,自然升至室温反应2-3小时。加入1L冰水,用盐酸调节溶液至PH=1-2,减压蒸去反应液中的四氢呋喃,降至室温,用乙酸乙酯萃取3次,每次用量500L,合并有机层,水洗3次,每次300ml,无水硫酸镁干燥,减压脱溶得118g灰白色固体3-氯-2,4,5-三氟苯甲酸,收率68.8%,含量98.2%。
Claims (9)
1.一种3-氯-2,4,5-三氟苯甲酸的制备工艺,其特征在于,包括如下步骤:
步骤1:于反应容器中,加入2,4,5-三氟苯胺和溶剂冰醋酸,于35-40℃下搅拌,滴加醋酐,反应完毕后将反应液倒入冰水中,趁冷过滤,水洗得2,4,5-三氟乙酰苯胺粗品;
步骤2:于反应容器中,加入浓硫酸及冰醋酸或醋酐,再加入2,4,5-三氟乙酰苯胺粗品,搅拌下,滴加由发烟硝酸和浓硫酸制成的硝硫混酸,温度控制在45~55℃,反应完毕后倒入冰水中,趁冷过滤,水洗得2-硝基-3,4,6-三氟乙酰苯胺粗品;
步骤3:于反应容器中,加入乙醇和浓盐酸,再加入2-硝基-3,4,6-三氟乙酰苯胺粗品,搅拌下升温回流85~95℃,反应完毕后将反应液倒入冰水中,趁冷过滤,水洗得2-硝基-3,4,6-三氟苯胺粗品;
步骤4:于反应容器中,加入2-硝基-3,4,6-三氟苯胺粗品和溶剂冰醋酸,搅拌下,冷却至25~30℃,滴加由浓硫酸和亚硝酸钠制成的亚硝酰硫酸溶液,得到重氮化溶液,然后将该溶液滴加到由氢溴酸和溴化亚铜制成的溶液中,温度不超过40℃,滴加完毕后再升温至80±5℃下反应后得2-溴-3,5,6-三氟硝基苯粗品;或者于反应容器中,加入氢溴酸、水、铜粉及2-硝基-3,4,6-三氟苯胺粗品,搅拌下,升温至40~45℃,滴加由亚硝酸钠和水制成的水溶液反应,反应完毕后将反应液倒入冰水中,水层用乙酸乙酯萃取,合并有机相,水洗,干燥,减压脱溶后得2-溴-3,5,6-三氟硝基苯粗品;
步骤5:于反应容器中,加入水、冰醋酸、还原铁粉和溶剂无水乙醇或甲醇,搅拌下升温至85~95℃下回流反应后,分批加入2-溴-3,5,6-三氟硝基苯粗品,加完后继续回流反应1小时以上,反应完毕后将反应液倒入冰水中,水层用乙酸乙酯萃取,合并有机相,水洗,干燥,减压脱溶后得2-溴-3,5,6-三氟苯胺粗品;
步骤6:于反应容器中,加入-溴-3,5,6-三氟苯胺粗品和溶剂DMF,搅拌下降温至20~35℃,分批加入N-氯代丁二酰亚胺,加完后升温至50~60℃下保温反应2小时以上,反应完毕后将反应液倒入冰水中,趁冷过滤,水洗烘干得2-溴-4-氯-3,5,6-三氟苯胺粗品;
步骤7:于反应容器中,加入2-溴-4-氯-3,5,6-三氟苯胺粗品和冰醋酸,搅拌下,冷却至10~15℃,滴加由浓硫酸及亚硝酸钠配制好的亚硝酰硫酸溶液,得到重氮化溶液,然后将该溶液滴加到由磷酸/次亚磷酸钠、水和氧化铜配成的混合液中,温度控制在30~35℃,滴加完毕后再升温至60~70℃反应,反应完毕后将反应液倒入冰水中,水层用乙酸乙酯萃取,合并有机相,水洗,干燥,减压脱溶后得1-溴-3-氯-2,4,5-三氟苯粗品,精馏得纯品;
步骤8:于反应容器中,氮气保护下,加入溶剂无水四氢呋喃、碘和镁条,搅拌下升温至60~65℃,滴加由无水四氢呋喃和异丙基氯制成的溶液,温度控制在55~70℃下反应,反应完毕后降温至10~15℃,滴加由无水四氢呋喃和1-溴-3-氯-2,4,5-三氟苯制成的溶液,降温至-5~(-10)℃,分批加入干冰,半小时加完,自然升至室温反应,反应完毕后将反应液倒入冰水中,水层用乙酸乙酯萃取,合并有机相,水洗,干燥,减压脱溶后得成品2-3-氯-2,4,5-三氟苯甲酸。
2.如权利要求1所述的3-氯-2,4,5-三氟苯甲酸的制备工艺,其特征在于,步骤1中,所述的2,4,5-三氟苯胺与醋酐的摩尔比为1:(1.05~1.15);反应时间为1-3h。
3.如权利要求1所述的3-氯-2,4,5-三氟苯甲酸的制备工艺,其特征在于,步骤2中,所述的2,4,5-三氟乙酰苯胺与浓硝酸摩尔比为1:(2.0~3.0),2-硝基-3,4,6-三氟苯胺与浓硫酸总量的摩尔比为1:(8~10),硝硫混酸中,浓硝酸与浓硫酸的比为1:1g/ml;2-硝基-3,4,6-三氟苯胺与冰醋酸的摩尔比为1:(15~20);2-硝基-3,4,6-三氟苯胺与醋酐的摩尔比为1:(15~20),反应时间为3~5h。
4.如权利要求1所述的3-氯-2,4,5-三氟苯甲酸的制备工艺,其特征在于,步骤3中,所述2-硝基-3,4,6-三氟乙酰苯胺与浓盐酸的摩尔比为1:(5~8),所述的溶剂为乙醇,2-硝基-3,4,6-三氟乙酰苯胺与乙醇的摩尔比为1:(5~10),反应时间为2~5h。
5.如权利要求1所述的3-氯-2,4,5-三氟苯甲酸的制备工艺,其特征在于,步骤4中,所述2-硝基-3,4,6-三氟苯胺与亚硝酸钠的摩尔比为1:(1.05~1.15),2-硝基-3,4,6-三氟苯胺与氢溴酸的摩尔比为1:(4~6);2-硝基-3,4,6-三氟苯胺与溴化亚铜的摩尔比为1:(0.5~1.0);2-硝基-3,4,6-三氟苯胺与铜粉的摩尔比为1:(0.8~1.2);2-硝基-3,4,6-三氟苯胺与浓硫酸的摩尔比为1:(8~10),2-硝基-3,4,6-三氟苯胺与冰醋酸的摩尔比为1:(15~20);反应时间为1.5~2.5h。
6.如权利要求1所述的3-氯-2,4,5-三氟苯甲酸的制备工艺,其特征在于,步骤5中,所述2-溴-3,5,6-三氟硝基苯与还原铁粉的摩尔比为1:(1.2~1.6),2-硝基-3,4,6-三氟苯胺与冰醋酸的摩尔比为1:(0.3~1.0);2-硝基-3,4,6-三氟苯胺与水的摩尔比为1:(90~110);2-硝基-3,4,6-三氟苯胺与无水乙醇或甲醇的摩尔比为1:(4~6);反应时间为2~4h。
7.如权利要求1所述的3-氯-2,4,5-三氟苯甲酸的制备工艺,其特征在于,步骤6中,所述2-溴-3,5,6-三氟苯胺与N-氯代丁二酰亚胺的摩尔比为1:(1.1~1.2),2-硝基-3,4,6-三氟苯胺与DMF的摩尔比为1:(10~15);反应时间为4~6h。
8.如权利要求1所述的3-氯-2,4,5-三氟苯甲酸的制备工艺,其特征在于,步骤7中,所述2-溴-4-氯-3,5,6-三氟苯胺与亚硝酸钠的摩尔比为1:(1.05~1.15),2-溴-4-氯-3,5,6-三氟苯胺与磷酸的摩尔比为1:(10~15),2-溴-4-氯-3,5,6-三氟苯胺与次亚磷酸钠的摩尔比为1:(1.2~1.6);2-溴-4-氯-3,5,6-三氟苯胺与氧化铜的摩尔比为1:(0.2~0.3);2-硝基-3,4,6-三氟苯胺与水的摩尔比为1:(10~15),2-硝基-3,4,6-三氟苯胺与浓硫酸的摩尔比为1:(8~10),2-硝基-3,4,6-三氟苯胺与冰醋酸的摩尔比为1:(15~20);反应时间为3~5h。
9.如权利要求1所述的3-氯-2,4,5-三氟苯甲酸的制备工艺,其特征在于,步骤8中,所述1-溴-3-氯-2,4,5-三氟苯与镁的摩尔比为1:(1.2~1.3),1-溴-3-氯-2,4,5-三氟苯与异丙基氯的摩尔比为1:(2.0~2.5),1-溴-3-氯-2,4,5-三氟苯与干冰的摩尔比为1:(3.0~4.0);1-溴-3-氯-2,4,5-三氟苯与碘的摩尔比为1:(0.005~0.015);反应时间为5~8h。
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