CN101016272A - Synthetic method for 3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isooxazole formyl chloride - Google Patents
Synthetic method for 3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isooxazole formyl chloride Download PDFInfo
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- CN101016272A CN101016272A CN 200710067354 CN200710067354A CN101016272A CN 101016272 A CN101016272 A CN 101016272A CN 200710067354 CN200710067354 CN 200710067354 CN 200710067354 A CN200710067354 A CN 200710067354A CN 101016272 A CN101016272 A CN 101016272A
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- chloro
- fluorophenyl
- methyl
- organic solvent
- trichloromethyl
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- 238000010189 synthetic method Methods 0.000 title claims description 15
- GFAUNYMRSKVDJL-UHFFFAOYSA-N formyl chloride Chemical compound ClC=O GFAUNYMRSKVDJL-UHFFFAOYSA-N 0.000 title abstract 2
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 claims abstract description 75
- REIPZLFZMOQHJT-UHFFFAOYSA-N 3-(2-chloro-6-fluorophenyl)-5-methyl-1,2-oxazole-4-carboxylic acid Chemical compound OC(=O)C1=C(C)ON=C1C1=C(F)C=CC=C1Cl REIPZLFZMOQHJT-UHFFFAOYSA-N 0.000 claims abstract description 73
- 238000006243 chemical reaction Methods 0.000 claims abstract description 54
- 239000003960 organic solvent Substances 0.000 claims abstract description 50
- 239000003054 catalyst Substances 0.000 claims abstract description 49
- 150000001412 amines Chemical class 0.000 claims abstract description 16
- 239000002994 raw material Substances 0.000 claims abstract description 5
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 68
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 36
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 34
- 235000019253 formic acid Nutrition 0.000 claims description 34
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 24
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 23
- XJCUKCOLGJDGGN-UHFFFAOYSA-N 3-(2-chloro-6-fluorophenyl)-5-methyl-1,2-oxazole-4-carbonyl chloride Chemical compound ClC(=O)C1=C(C)ON=C1C1=C(F)C=CC=C1Cl XJCUKCOLGJDGGN-UHFFFAOYSA-N 0.000 claims description 22
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 20
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 17
- AVQQQNCBBIEMEU-UHFFFAOYSA-N 1,1,3,3-tetramethylurea Chemical compound CN(C)C(=O)N(C)C AVQQQNCBBIEMEU-UHFFFAOYSA-N 0.000 claims description 15
- MVPPADPHJFYWMZ-IDEBNGHGSA-N chlorobenzene Chemical group Cl[13C]1=[13CH][13CH]=[13CH][13CH]=[13CH]1 MVPPADPHJFYWMZ-IDEBNGHGSA-N 0.000 claims description 15
- OCJBOOLMMGQPQU-UHFFFAOYSA-N 1,4-dichlorobenzene Chemical compound ClC1=CC=C(Cl)C=C1 OCJBOOLMMGQPQU-UHFFFAOYSA-N 0.000 claims description 14
- 229940117389 dichlorobenzene Drugs 0.000 claims description 14
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 12
- LAYPMCGIWDGYKX-UHFFFAOYSA-N trichloromethyl hydrogen carbonate Chemical compound OC(=O)OC(Cl)(Cl)Cl LAYPMCGIWDGYKX-UHFFFAOYSA-N 0.000 claims description 11
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 10
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 9
- 238000003756 stirring Methods 0.000 claims description 9
- 238000010521 absorption reaction Methods 0.000 claims description 8
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 7
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 7
- KYVBNYUBXIEUFW-UHFFFAOYSA-N 1,1,3,3-tetramethylguanidine Chemical compound CN(C)C(=N)N(C)C KYVBNYUBXIEUFW-UHFFFAOYSA-N 0.000 claims description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 claims description 5
- AVFZOVWCLRSYKC-UHFFFAOYSA-N 1-methylpyrrolidine Chemical compound CN1CCCC1 AVFZOVWCLRSYKC-UHFFFAOYSA-N 0.000 claims description 5
- 239000000463 material Substances 0.000 claims description 5
- 239000000376 reactant Substances 0.000 claims description 5
- CYSGHNMQYZDMIA-UHFFFAOYSA-N 1,3-Dimethyl-2-imidazolidinon Chemical compound CN1CCN(C)C1=O CYSGHNMQYZDMIA-UHFFFAOYSA-N 0.000 claims description 4
- ITQTTZVARXURQS-UHFFFAOYSA-N 3-methylpyridine Chemical compound CC1=CC=CN=C1 ITQTTZVARXURQS-UHFFFAOYSA-N 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- OXHNLMTVIGZXSG-UHFFFAOYSA-N 1-Methylpyrrole Chemical compound CN1C=CC=C1 OXHNLMTVIGZXSG-UHFFFAOYSA-N 0.000 claims description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- 230000000694 effects Effects 0.000 claims description 2
- NZMAJUHVSZBJHL-UHFFFAOYSA-N n,n-dibutylformamide Chemical compound CCCCN(C=O)CCCC NZMAJUHVSZBJHL-UHFFFAOYSA-N 0.000 claims description 2
- 238000011084 recovery Methods 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Substances OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims 1
- 239000000126 substance Substances 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 17
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 abstract description 16
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 abstract description 12
- 239000002699 waste material Substances 0.000 abstract description 7
- 238000004519 manufacturing process Methods 0.000 abstract description 6
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- 238000005660 chlorination reaction Methods 0.000 abstract description 3
- UIOFUWFRIANQPC-JKIFEVAISA-N Floxacillin Chemical compound N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C(O)=O)=O)C(=O)C1=C(C)ON=C1C1=C(F)C=CC=C1Cl UIOFUWFRIANQPC-JKIFEVAISA-N 0.000 abstract description 2
- 230000003115 biocidal effect Effects 0.000 abstract description 2
- 229960004273 floxacillin Drugs 0.000 abstract description 2
- AOGYCOYQMAVAFD-UHFFFAOYSA-N chlorocarbonic acid Chemical compound OC(Cl)=O AOGYCOYQMAVAFD-UHFFFAOYSA-N 0.000 abstract 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 33
- 230000008018 melting Effects 0.000 description 32
- 238000002844 melting Methods 0.000 description 32
- -1 isoxazole formic acid Chemical compound 0.000 description 6
- 238000010992 reflux Methods 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 4
- WRHZVMBBRYBTKZ-UHFFFAOYSA-N pyrrole-2-carboxylic acid Chemical compound OC(=O)C1=CC=CN1 WRHZVMBBRYBTKZ-UHFFFAOYSA-N 0.000 description 3
- YBLSBWHFPXDRHC-UHFFFAOYSA-N 3-methyl-1,2-oxazole-4-carboxylic acid Chemical compound CC1=NOC=C1C(O)=O YBLSBWHFPXDRHC-UHFFFAOYSA-N 0.000 description 2
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 230000008014 freezing Effects 0.000 description 2
- 238000007710 freezing Methods 0.000 description 2
- 238000005057 refrigeration Methods 0.000 description 2
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- ZKAQPVQEYCFRTK-UHFFFAOYSA-N 5-methyl-1,2-oxazole-4-carbonyl chloride Chemical compound CC=1ON=CC=1C(Cl)=O ZKAQPVQEYCFRTK-UHFFFAOYSA-N 0.000 description 1
- VQBXUKGMJCPBMF-UHFFFAOYSA-N 5-methyl-1,2-oxazole-4-carboxylic acid Chemical compound CC=1ON=CC=1C(O)=O VQBXUKGMJCPBMF-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000005260 corrosion Methods 0.000 description 1
- 230000007797 corrosion Effects 0.000 description 1
- PQWGEGZUHVGSKG-UHFFFAOYSA-N formic acid;1,3-oxazole Chemical compound OC=O.C1=COC=N1 PQWGEGZUHVGSKG-UHFFFAOYSA-N 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- BHEPBYXIRTUNPN-UHFFFAOYSA-N hydridophosphorus(.) (triplet) Chemical compound [PH] BHEPBYXIRTUNPN-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明涉及一种抗生素氟氯西林钠的关键中间体3－(2′－氯－6′－氟苯基)－5－甲基－4－异恶唑甲酰氯的化学合成方法，即以双(三氯甲基)碳酸酯和3－(2′－氯－6′－氟苯基)－5－甲基－4－异恶唑甲酸为原料，在有机胺催化剂的作用下在有机溶剂中于0～120℃反应1～20小时，回收有机溶剂制得所述3－(2′－氯－6′－氟苯基)－5－甲基－4－异恶唑甲酰氯。本发明的工艺路线先进，工艺条件合理，革除了传统氯化试剂氯化亚砜、三氯氧磷的使用，从根本上消除了传统工艺安全隐患大、三废污染严重等问题，本工艺操作简单安全，反应收率高，生产成本低，基本无三废，具有大的实施价值和社会经济效益。The present invention relates to a chemical synthesis method of the key intermediate 3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazole carboxyl chloride of the antibiotic flucloxacillin sodium, that is to use bis (Trichloromethyl)carbonate and 3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazolecarboxylic acid as raw materials, under the action of an organic amine catalyst in an organic solvent React at 0-120°C for 1-20 hours, recover the organic solvent to prepare the 3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazole formyl chloride. The process route of the present invention is advanced, the process conditions are reasonable, and the use of traditional chlorination reagents such as thionyl chloride and phosphorus oxychloride is eliminated, and the problems of traditional process such as large safety hazards and serious pollution of three wastes are fundamentally eliminated, and the process is simple to operate It is safe, has high reaction yield, low production cost, basically no three wastes, and has great implementation value and social and economic benefits.
Description
(一)技术领域(1) Technical field
本发明涉及一种抗生素氟氯西林钠的关键中间体3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酰氯的化学合成方法，特别涉及一种用双(三氯甲基)碳酸酯[bis(trichloro-methyl)carbonate]替代氯化亚砜、三氯氧磷直接与3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸反应制备3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酰氯的化学合成方法。The invention relates to a chemical synthesis method of the key intermediate 3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazolecarbonyl chloride of the antibiotic flucloxacillin sodium, in particular to a A kind of two (trichloromethyl) carbonate [bis (trichloro-methyl) carbonate] replaces thionyl chloride, phosphorus oxychloride directly with 3-(2'-chloro-6'-fluorophenyl)-5- A chemical synthesis method for preparing 3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazolecarbonyl chloride by reacting methyl-4-isoxazolecarboxylic acid.
(二)背景技术(2) Background technology
在本发明给出之前，现有的3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酰氯的化学合成方法多是以3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸和氯化亚砜或三氯氧磷等试剂氯代制备得到。如WO2004058732A1中将3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸422mg溶于10mL干燥四氢呋喃中，室温搅拌下滴加氯化亚砜0.5ml，加热回流过夜，减压浓缩得到3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酰氯。Before the present invention provides, the chemical synthesis method of existing 3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazolecarbonyl chloride is mostly based on 3-(2' -Chloro-6'-fluorophenyl)-5-methyl-4-isoxazole formic acid and thionyl chloride or phosphorus oxychloride and other reagents can be prepared by chlorination. For example, in WO2004058732A1, 422 mg of 3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazolecarboxylic acid was dissolved in 10 mL of dry tetrahydrofuran, and 0.5 ml of thionyl chloride was added dropwise with stirring at room temperature , heated to reflux overnight, and concentrated under reduced pressure to obtain 3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazolecarbonyl chloride.
三氯氧磷作为氯代试剂对设备的腐蚀严重，工艺得到的产物中大量含磷的废水很难处理，污染问题严重，环境问题突出。氯化亚砜法工艺尾气中含大量窒息性的二氧化硫(国家环保对大气严格控制的六个指标之一)，三废处理困难，费用高。另外氯化亚砜的运输和使用受到严格控制，对反应设备密封性要求高，投资也较大。生产安全性差，反应周期长。Phosphorus oxychloride, as a chlorinated reagent, severely corrodes equipment, and a large amount of phosphorous-containing wastewater in the product obtained by the process is difficult to treat, causing serious pollution problems and prominent environmental problems. The tail gas of the thionyl chloride process contains a large amount of asphyxiating sulfur dioxide (one of the six indicators strictly controlled by the national environmental protection on the atmosphere), and the treatment of the three wastes is difficult and expensive. In addition, the transportation and use of thionyl chloride are strictly controlled, requiring high sealing performance of the reaction equipment, and the investment is relatively large. The production safety is poor and the reaction cycle is long.
(三)发明内容(3) Contents of the invention
本发明的任务是克服现有技术的缺点，提供一种工艺合理、生产安全可靠、反应收率高、生产成本低、基本无三废的3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酰氯的合成方法。The task of the present invention is to overcome the shortcomings of the prior art and provide a 3-(2'-chloro-6'-fluorophenyl) with reasonable process, safe and reliable production, high reaction yield, low production cost and basically no three wastes -The synthetic method of 5-methyl-4-isoxazole carboxylic acid chloride.
一种如式II所示的3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酰氯的合成方法，其特征在于以双(三氯甲基)碳酸酯和如式I所示的3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸为原料，在有机胺催化剂的作用下在有机溶剂中于0～120℃反应1～20小时，回收有机溶剂制得所述的3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酰氯，所述反应物投料物质的量比3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸∶双(三氯甲基)碳酸酯∶有机胺催化剂为1∶0.33～3∶0.01～0.8。反应式如下：A kind of synthetic method of 3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazolecarbonyl chloride as shown in formula II, it is characterized in that bis(trichloromethyl ) carbonate and 3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazolecarboxylic acid as shown in formula I are raw materials, under the effect of organic amine catalyst in organic solvent reaction at 0-120°C for 1-20 hours, recovering the organic solvent to obtain the 3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazolecarbonyl chloride, the The amount ratio of the reactant feed material 3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazole formic acid: bis(trichloromethyl) carbonate: organic amine catalyst is 1: 0.33～3: 0.01～0.8. The reaction formula is as follows:
所述的有机溶剂为下列一种或一种以上任意比例的混合物：苯、甲苯、二甲苯、氯苯、二氯苯、正己烷、环己烷、二异丙基醚、二丁基醚、二恶烷、四氢呋喃、乙酸乙酯、三氯甲烷、四氯化碳、二氯乙烷。Described organic solvent is the following one or the mixture of more than one arbitrary ratio: benzene, toluene, xylene, chlorobenzene, dichlorobenzene, n-hexane, cyclohexane, diisopropyl ether, dibutyl ether, Dioxane, tetrahydrofuran, ethyl acetate, chloroform, carbon tetrachloride, dichloroethane.
所述的有机溶剂的用量为3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸质量的0.5～10倍。The amount of the organic solvent used is 0.5-10 times the mass of 3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazolecarboxylic acid.
所述的投料物质的量比3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸∶双(三氯甲基)碳酸酯∶有机胺催化剂优选为1∶0.34～0.8∶0.01～0.20。The amount ratio of the feed material is 3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazolecarboxylic acid: bis(trichloromethyl) carbonate: organic amine catalyst is preferred It is 1:0.34-0.8:0.01-0.20.
所述的有机溶剂优选为下列一种或一种以上任意比例的混合物：氯苯、四氢呋喃、二氯乙烷。The organic solvent is preferably one or a mixture of more than one of the following in any proportion: chlorobenzene, tetrahydrofuran, and dichloroethane.
所述的有机胺催化剂为下列之一：三乙胺、吡啶、3-甲基吡啶、N-甲基吡咯、1，3-二甲基-2-咪唑烷酮、N，N-二甲基乙酰胺、N，N-二甲基甲酰胺、N-甲基四氢吡咯、四甲基胍、四甲基脲、N，N-二丁基甲酰胺。优选为下列之一：1，3-二甲基-2-咪唑烷酮、四甲基胍。The organic amine catalyst is one of the following: triethylamine, pyridine, 3-picoline, N-methylpyrrole, 1,3-dimethyl-2-imidazolidinone, N,N-dimethyl Acetamide, N,N-dimethylformamide, N-methyltetrahydropyrrole, tetramethylguanidine, tetramethylurea, N,N-dibutylformamide. One of the following is preferred: 1,3-dimethyl-2-imidazolidinone, tetramethylguanidine.
推荐所述的反应于60～100℃反应3～8小时。It is recommended that the reaction be carried out at 60-100° C. for 3-8 hours.
具体推荐3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酰氯的合成方法，按如下步骤进行：将3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸、有机胺催化剂和有机溶剂加入到反应釜中，搅拌均匀后，在室温下缓慢滴加溶有双(三氯甲基)碳酸酯的有机溶剂，所述的反应物投料物质的量比3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸∶双(三氯甲基)碳酸酯∶有机胺催化剂为1∶0.34～0.8∶0.01～0.20，加入有机溶剂的用量为3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸质量的0.5～10倍，同时开启氯化氢吸收系统，然后升温到60～100℃，保温反应3～8小时，反应结束后回收有机溶剂后得所述3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酰氯，所述的有机溶剂为氯苯或四氢呋喃，所述的有机胺催化剂为四甲基胍。Specifically recommend the synthetic method of 3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazolecarbonyl chloride, proceed as follows: 3-(2'-chloro-6' -Fluorophenyl)-5-methyl-4-isoxazolecarboxylic acid, organic amine catalyst and organic solvent are added to the reaction kettle, after stirring evenly, slowly dropwise add bis(trichloromethyl)carbonic acid dissolved in it at room temperature The organic solvent of ester, the ratio of the amount of the reactant feed material to 3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazolecarboxylic acid: bis(trichloromethyl) Carbonate: organic amine catalyst is 1: 0.34～0.8: 0.01～0.20, the amount of organic solvent added is 3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazole formic acid 0.5 to 10 times the mass, and simultaneously open the hydrogen chloride absorption system, then raise the temperature to 60 to 100°C, and keep the temperature for 3 to 8 hours. After the reaction, the organic solvent is recovered to obtain the 3-(2'-chloro-6'-fluoro Phenyl)-5-methyl-4-isoxazolecarbonyl chloride, the organic solvent is chlorobenzene or tetrahydrofuran, and the organic amine catalyst is tetramethylguanidine.
所述的回收有机溶剂是在0.667KPa下收集168～170℃的馏分得到所述的3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酰氯。The recovery of the organic solvent is to collect the fraction at 168-170°C at 0.667KPa to obtain the 3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazolecarbonyl chloride .
本发明以双(三氯甲基)碳酸酯代替传统的氯化亚砜和三氯氧磷作为酰氯制备的氯代试剂，其有益效果体现在：工艺路线先进，工艺条件合理，革除了较毒的原料氯化亚砜和三氯氧磷的使用，根本上消除了传统工艺安全隐患大、三废污染严重等问题。操作简单安全，反应收率高，生产成本低，基本无三废，具有大的实施价值和社会经济效益。The present invention uses bis(trichloromethyl)carbonate instead of traditional thionyl chloride and phosphorus oxychloride as the chlorination reagent prepared by acid chloride, and its beneficial effects are reflected in: advanced process route, reasonable process conditions, eliminating the more toxic The use of thionyl chloride and phosphorus oxychloride as raw materials has fundamentally eliminated the problems of traditional technology such as large safety hazards and serious pollution of three wastes. The operation is simple and safe, the reaction yield is high, the production cost is low, the three wastes are basically free, and the method has great implementation value and social and economic benefits.
本发明与传统工艺相比较，具有生产安全，设备腐蚀小，操作方便，反应周期短，原料易得，反应收率高，三废少且易处理，产品质量好等优点，而且副产物氯化氢经双塔吸收可制备30％的工业盐酸，是一个较适应于工业化的方法。Compared with the traditional process, the present invention has the advantages of safe production, less equipment corrosion, convenient operation, short reaction period, easy to obtain raw materials, high reaction yield, less waste and easy to handle, good product quality, etc. Tower absorption can prepare 30% industrial hydrochloric acid, which is a method more suitable for industrialization.
(四)具体实施方式(4) Specific implementation methods
以下以具体实施例来说明本发明的技术方案，但本发明的保护范围不限于此：The technical scheme of the present invention is described below with specific examples, but protection scope of the present invention is not limited thereto:
实施例1Example 1
3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸∶双(三氯甲基)碳酸酯∶四甲基脲＝1∶0.33∶0.02(摩尔比)，3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸投料量为25.55g(100mmol)，双(三氯甲基)碳酸酯投料量为9.80g(33mmol)，催化剂用量为0.232g(2mmol)，甲苯用量为3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸质量的10倍。3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazolecarboxylic acid: bis(trichloromethyl) carbonate: tetramethylurea=1:0.33:0.02 (mol ratio), 3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazole formic acid charging capacity is 25.55g (100mmol), two (trichloromethyl) carbonate charging capacity 9.80g (33mmol), the amount of catalyst is 0.232g (2mmol), and the amount of toluene is 10 times of the mass of 3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazolecarboxylic acid .
3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸、四甲基脲和甲苯加到反应釜中，搅拌均匀后，在室温下45分钟内滴加双(三氯甲基)碳酸酯的甲苯溶液，同时开启氯化氢吸收系统，然后升温到110℃，回流反应2小时，反应结束后减压蒸馏回收甲苯，最后在0.667KPa下收集168～170℃的馏分，冷冻下固化。Add 3-(2′-chloro-6′-fluorophenyl)-5-methyl-4-isoxazolecarboxylic acid, tetramethylurea and toluene into the reaction kettle, stir evenly, within 45 minutes at room temperature Add the toluene solution of bis(trichloromethyl)carbonate dropwise, open the hydrogen chloride absorption system at the same time, then raise the temperature to 110°C, and reflux the reaction for 2 hours. The fraction at ℃ solidifies under refrigeration.
得产品26.22克，收率95.7％，熔点为48～52℃，含量(GC)99.9％。1H-NMR(CDCl3)δ：2.87(3H，s)，7.08(1H，t，J＝8.8Hz)，7.33(1H，t，J＝8.0Hz)，7.41-7.47(1H，m)。26.22 g of the product was obtained, the yield was 95.7%, the melting point was 48-52° C., and the content (GC) was 99.9%. 1 H-NMR (CDCl 3 ) δ: 2.87 (3H, s), 7.08 (1H, t, J = 8.8Hz), 7.33 (1H, t, J = 8.0Hz), 7.41-7.47 (1H, m).
实施例2Example 2
3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸∶双(三氯甲基)碳酸酯∶四甲基脲＝1∶0.5∶0.01(摩尔比)，3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸投料量为25.55g(100mmol)，双(三氯甲基)碳酸酯投料量为14.85g(50mmol)，催化剂用量为0.116g(1mmol)，二氯苯用量为3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸质量的5倍。3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazolecarboxylic acid: bis(trichloromethyl) carbonate: tetramethylurea=1:0.5:0.01 (mole ratio), 3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazole formic acid charging capacity is 25.55g (100mmol), two (trichloromethyl) carbonate charging capacity 14.85g (50mmol), catalyst consumption is 0.116g (1mmol), dichlorobenzene consumption is 3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazole formic acid quality 5 times.
3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸，四甲基脲和二氯苯加到反应釜中，搅拌均匀后，在室温下45分钟内滴加双(三氯甲基)碳酸酯的二氯苯溶液，同时开启氯化氢吸收系统，然后升温到115～120℃，保温反应1小时，反应结束后减压蒸馏回收二氯苯，最后在0.667KPa下收集168～170℃的馏分，冷冻下固化。3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazolecarboxylic acid, tetramethylurea and dichlorobenzene were added to the reaction kettle, after stirring evenly, at room temperature for 45 Add the dichlorobenzene solution of bis(trichloromethyl)carbonate dropwise within 1 minute, open the hydrogen chloride absorption system at the same time, then raise the temperature to 115-120°C, keep the temperature for 1 hour, and recover the dichlorobenzene by distillation under reduced pressure after the reaction is completed. The fractions at 168-170°C were collected at 0.667KPa and solidified under freezing.
得产品26.30克，收率96％，熔点为48～52℃，含量(GC)99.2％。1H-NMR(CDCl3)δ：2.87(3H，s)，7.08(1H，t，J＝8.8Hz)，7.33(1H，t，J＝8.0Hz)7.41-7.47(1H，m).26.30 g of the product was obtained, the yield was 96%, the melting point was 48-52° C., and the content (GC) was 99.2%. 1 H-NMR (CDCl 3 ) δ: 2.87 (3H, s), 7.08 (1H, t, J = 8.8Hz), 7.33 (1H, t, J = 8.0Hz), 7.41-7.47 (1H, m).
实施例3Example 3
3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸∶双(三氯甲基)碳酸酯∶四甲基脲＝1∶0.5∶0.01(摩尔比)，3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸投料量为25.55g(100mmol)，双(三氯甲基)碳酸酯投料量为14.85g(50mmol)，催化剂用量为0.116g(1mmol)，用实施例2回收的二氯苯用量为3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸3质量的5倍。3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazolecarboxylic acid: bis(trichloromethyl) carbonate: tetramethylurea=1:0.5:0.01 (mole ratio), 3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazole formic acid charging capacity is 25.55g (100mmol), two (trichloromethyl) carbonate charging capacity It is 14.85g (50mmol), and the amount of catalyst is 0.116g (1mmol), and the amount of dichlorobenzene reclaimed in Example 2 is 3-(2'-chloro-6'-fluorophenyl)-5-methyl-4- 5 times the quality of isoxazole formic acid 3.
3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸，四甲基脲和二氯苯加到反应釜中，搅拌均匀后，在室温下45分钟内滴加双(三氯甲基)碳酸酯的二氯苯溶液，其它同实例2。3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazolecarboxylic acid, tetramethylurea and dichlorobenzene were added to the reaction kettle, after stirring evenly, at room temperature for 45 Add dropwise the dichlorobenzene solution of two (trichloromethyl) carbonates in minutes, and the others are the same as example 2.
得产品26.24克，收率95.8％，熔点为48～52℃，含量(GC)99.0％。1H-NMR(CDCl3)δ：2.87(3H，s)，7.08(1H，t，J＝8.8Hz)，7.33(1H，t，J＝8.0Hz)7.41-7.47(1H，m).26.24 g of the product was obtained, the yield was 95.8%, the melting point was 48-52°C, and the content (GC) was 99.0%. 1 H-NMR (CDCl 3 ) δ: 2.87 (3H, s), 7.08 (1H, t, J = 8.8Hz), 7.33 (1H, t, J = 8.0Hz), 7.41-7.47 (1H, m).
实施例4Example 4
3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸∶双(三氯甲基)碳酸酯∶四甲基脲＝1∶0.75∶0.01(摩尔比)，3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸投料量为25.55g(100mmol)，双(三氯甲基)碳酸酯投料量为22.27g(75mmol)，催化剂用量为0.116g(1mmol)，用实施例2回收的二氯苯用量为3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸的5倍。3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazolecarboxylic acid: bis(trichloromethyl) carbonate: tetramethylurea=1: 0.75: 0.01 (mole ratio), 3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazole formic acid charging capacity is 25.55g (100mmol), two (trichloromethyl) carbonate charging capacity It is 22.27g (75mmol), and the amount of catalyst is 0.116g (1mmol), and the amount of dichlorobenzene reclaimed in Example 2 is 3-(2'-chloro-6'-fluorophenyl)-5-methyl-4- 5 times that of isoxazole formic acid.
操作同实施例3，得产品26.63克，收率97.2％，熔点为48～52℃，含量(GC)98.7％。1H-NMR(CDCl3)δ：2.87(3H，s)，7.08(1H，t，J＝8.8Hz)，7.33(1H，t，J＝8.0Hz)7.41-7.47(1H，m).The operation was the same as in Example 3 to obtain 26.63 grams of the product, the yield was 97.2%, the melting point was 48-52° C., and the content (GC) was 98.7%. 1 H-NMR (CDCl 3 ) δ: 2.87 (3H, s), 7.08 (1H, t, J = 8.8Hz), 7.33 (1H, t, J = 8.0Hz), 7.41-7.47 (1H, m).
实施例5Example 5
3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸∶双(三氯甲基)碳酸酯∶四甲基脲＝1∶0.5∶0.01(摩尔比)，3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸投料量为25.55g(100mmol)，双(三氯甲基)碳酸酯投料量为14.85g(50mmol)，催化剂用量为0.285g(1mmol)，四氢呋喃用量为3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸质量的8倍。3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazolecarboxylic acid: bis(trichloromethyl) carbonate: tetramethylurea=1:0.5:0.01 (mole ratio), 3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazole formic acid charging capacity is 25.55g (100mmol), two (trichloromethyl) carbonate charging capacity 14.85g (50mmol), the amount of catalyst is 0.285g (1mmol), the amount of tetrahydrofuran is 8 times the mass of 3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazolecarboxylic acid .
3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸，四甲基脲和四氢呋喃加到反应釜中，搅拌均匀后，在室温下45分钟内滴加双(三氯甲基)碳酸酯的四氢呋喃溶液，同时开启氯化氢吸收系统，然后升温到66℃回流，反应4小时，其它同实施例2。Add 3-(2′-chloro-6′-fluorophenyl)-5-methyl-4-isoxazolecarboxylic acid, tetramethylurea and tetrahydrofuran into the reaction kettle, stir evenly, within 45 minutes at room temperature The tetrahydrofuran solution of bis(trichloromethyl)carbonate was added dropwise, and the hydrogen chloride absorption system was opened at the same time, and then the temperature was raised to 66° C. for reflux, and the reaction was carried out for 4 hours. Others were the same as in Example 2.
得产品26.19克，收率95.6％，熔点为48～52℃，含量(GC)99.0％。1H-NMR(CDCl3)δ：2.87(3H，s)，7.08(1H，t，J＝8.8Hz)，7.33(1H，t，J＝8.0Hz)7.41-7.47(1H，m).26.19 g of the product was obtained, the yield was 95.6%, the melting point was 48-52° C., and the content (GC) was 99.0%. 1 H-NMR (CDCl 3 ) δ: 2.87 (3H, s), 7.08 (1H, t, J = 8.8Hz), 7.33 (1H, t, J = 8.0Hz), 7.41-7.47 (1H, m).
实施例6Example 6
3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸∶双(三氯甲基)碳酸酯∶四甲基脲＝1∶0.5∶0.01(摩尔比)，3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸投料量为25.55g(100mmol)，双(三氯甲基)碳酸酯投料量为14.85g(50mmol)，催化剂用量为0.116g(1mmol)，二氯乙烷用量为3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸质量的5倍。3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazolecarboxylic acid: bis(trichloromethyl) carbonate: tetramethylurea=1:0.5:0.01 (mole ratio), 3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazole formic acid charging capacity is 25.55g (100mmol), two (trichloromethyl) carbonate charging capacity 14.85g (50mmol), the amount of catalyst is 0.116g (1mmol), and the amount of dichloroethane is the mass of 3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazolecarboxylic acid 5 times.
3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸、四甲基脲和二氯乙烷加到反应釜中，搅拌均匀后，在室温下30分钟内滴加双(三氯甲基)碳酸酯的二氯乙烷溶液，同时开启氯化氢吸收系统，然后升温到80℃，回流反应4小时，反应结束后减压蒸馏回收二氯乙烷，最后在0.667KPa下收集168～170℃的馏分，冷冻下固化。3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazolecarboxylic acid, tetramethylurea and dichloroethane were added to the reaction kettle, after stirring evenly, at room temperature Add the dichloroethane solution of bis(trichloromethyl)carbonate dropwise within 30 minutes, open the hydrogen chloride absorption system at the same time, then raise the temperature to 80°C, and reflux the reaction for 4 hours. After the reaction, the dichloroethane is recovered by vacuum distillation. Finally, the fraction at 168-170°C was collected at 0.667KPa and solidified under freezing.
得产品26.60克，收率97.1％，熔点为48～52℃，含量(GC)99.6％。1H-NMR(CDCl3)δ：2.87(3H，s)，7.08(1H，t，J＝8.8Hz)，7.33(1H，t，J＝8.0Hz)，7.41-7.47(1H，m)。26.60 g of the product was obtained, the yield was 97.1%, the melting point was 48-52° C., and the content (GC) was 99.6%. 1 H-NMR (CDCl 3 ) δ: 2.87 (3H, s), 7.08 (1H, t, J = 8.8Hz), 7.33 (1H, t, J = 8.0Hz), 7.41-7.47 (1H, m).
实施例7Example 7
3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸∶双(三氯甲基)碳酸酯∶四甲基脲＝1∶0.5∶0.05(摩尔比)，3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸投料量为25.55g(100mmol)，双(三氯甲基)碳酸酯投料量为14.80g(50mmol)，催化剂用量为0.58g(5mmol)，苯用量为3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸质量的10倍。3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazolecarboxylic acid: bis(trichloromethyl) carbonate: tetramethylurea=1:0.5:0.05 (mole ratio), 3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazole formic acid charging capacity is 25.55g (100mmol), two (trichloromethyl) carbonate charging capacity 14.80g (50mmol), the amount of catalyst is 0.58g (5mmol), and the amount of benzene is 10 times of the mass of 3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazolecarboxylic acid .
3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸、四甲基脲和苯加到反应釜中，搅拌均匀后，在室温下45分钟内滴加双(三氯甲基)碳酸酯的苯溶液，同时开启氯化氢吸收系统，然后升温到80℃，回流反应6小时，反应结束后减压蒸馏回收苯，最后在0.667KPa下收集168～170℃的馏分，冷冻下固化。Add 3-(2′-chloro-6′-fluorophenyl)-5-methyl-4-isoxazolecarboxylic acid, tetramethylurea and benzene into the reaction kettle, stir evenly, within 45 minutes at room temperature Add the benzene solution of bis(trichloromethyl)carbonate dropwise, open the hydrogen chloride absorption system at the same time, then raise the temperature to 80°C, and reflux for 6 hours. After the reaction, benzene is recovered by distillation under reduced pressure, and finally 168-170 The fraction at ℃ solidifies under refrigeration.
得产品26.52克，收率96.8％，熔点为48～52℃，含量(GC)99.3％。1H-NMR(CDCl3)δ：2.87(3H，s)，7.08(1H，t，J＝8.8Hz)，7.33(1H，t，J＝8.0Hz)，7.41-7.47(1H，m)。26.52 g of the product was obtained, the yield was 96.8%, the melting point was 48-52° C., and the content (GC) was 99.3%. 1 H-NMR (CDCl 3 ) δ: 2.87 (3H, s), 7.08 (1H, t, J = 8.8Hz), 7.33 (1H, t, J = 8.0Hz), 7.41-7.47 (1H, m).
实施例8Example 8
3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸∶双(三氯甲基)碳酸酯∶1，3-二甲基-2-咪唑烷酮＝1∶0.7∶0.01(摩尔比)，3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸投料量为25.55g(100mmol)，双(三氯甲基)碳酸酯投料量为20.79g(70mmol)，催化剂用量为0.11g(1mmol)，有机溶剂为甲苯，其用量为3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸质量的2倍。3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazolecarboxylic acid: bis(trichloromethyl)carbonate: 1,3-dimethyl-2-imidazolidine Ketone=1: 0.7: 0.01 (molar ratio), 3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazole formic acid charging capacity is 25.55g (100mmol), bis( Trichloromethyl)carbonate charging amount is 20.79g (70mmol), catalyst consumption is 0.11g (1mmol), organic solvent is toluene, and its consumption is 3-(2'-chloro-6'-fluorophenyl)-5 - 2 times the mass of methyl-4-isoxazole formic acid.
反应温度为80～85℃，其它操作同实施例1，得产品26.17克，产品收率95.5％，熔点为48～52℃，含量(GC)99.0％。1H-NMR(CDCl3)δ：2.87(3H，s)，7.08(1H，t，J＝8.8Hz)，7.33(1H，t，J＝8.0Hz)，7.41-7.47(1H，m)。Reaction temperature is 80～85 ℃, other operation is the same as embodiment 1, obtains product 26.17 grams, product yield 95.5%, melting point is 48～52 ℃, content (GC) 99.0%. 1 H-NMR (CDCl 3 ) δ: 2.87 (3H, s), 7.08 (1H, t, J = 8.8Hz), 7.33 (1H, t, J = 8.0Hz), 7.41-7.47 (1H, m).
实施例9Example 9
3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸∶双(三氯甲基)碳酸酯∶吡啶＝1∶1∶0.02(摩尔比)，3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸投料量为25.55g(100mmol)，双(三氯甲基)碳酸酯投料量为29.7g(100mmol)，催化剂用量为0.16g(2mmol)，有机溶剂为四氢呋喃，其用量为3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸质量的2倍。3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazolecarboxylic acid:bis(trichloromethyl)carbonate:pyridine=1:1:0.02 (molar ratio), 3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazole carboxylic acid charging capacity is 25.55g (100mmol), bis(trichloromethyl)carbonate charging capacity is 29.7g (100mmol), the catalyst consumption is 0.16g (2mmol), and the organic solvent is tetrahydrofuran, and its consumption is 3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazole formic acid quality 2 times.
反应温度为40～45℃，反应时间为10小时，其它操作同实施例1，得产品26.08克，产品收率95.2％，熔点为48～52℃，含量(GC)99.0％。1H-NMR(CDCl3)δ：2.87(3H，s)，7.08(1H，t，J＝8.8Hz)，7.33(1H，t，J＝8.0Hz)，7.41-7.47(1H，m)。Reaction temperature is 40～45 ℃, and the reaction time is 10 hours, other operation is the same as embodiment 1, obtains product 26.08 grams, product yield 95.2%, fusing point is 48～52 ℃, content (GC) 99.0%. 1 H-NMR (CDCl 3 ) δ: 2.87 (3H, s), 7.08 (1H, t, J = 8.8Hz), 7.33 (1H, t, J = 8.0Hz), 7.41-7.47 (1H, m).
实施例10Example 10
3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸∶双(三氯甲基)碳酸酯∶吡啶＝1∶0.34∶0.01(摩尔比)，3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸投料量为25.55g(100mmol)，双(三氯甲基)碳酸酯投料量为10.09g(34mmol)，催化剂用量为0.079g(1mmol)，有机溶剂为四氢呋喃，其用量为3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸质量的2倍。3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazolecarboxylic acid:bis(trichloromethyl)carbonate:pyridine=1:0.34:0.01 (molar ratio), The amount of 3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazolecarboxylic acid is 25.55g (100mmol), and the amount of bis(trichloromethyl)carbonate is 10.09g (34mmol), catalyst consumption is 0.079g (1mmol), organic solvent is tetrahydrofuran, and its consumption is 3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazole formic acid quality 2 times.
反应温度为60～65℃，其它操作同实施例1，得产品24.79克，产品收率90.5％，熔点为48～52℃，含量(GC)98.5％。1H-NMR(CDCl3)δ：2.87(3H，s)，7.08(1H，t，J＝8.8Hz)，7.33(1H，t，J＝8.0Hz)，7.41-7.47(1H，m)。Reaction temperature is 60～65 ℃, other operation is the same as embodiment 1, obtains product 24.79 grams, product yield 90.5%, melting point is 48～52 ℃, content (GC) 98.5%. 1 H-NMR (CDCl 3 ) δ: 2.87 (3H, s), 7.08 (1H, t, J = 8.8Hz), 7.33 (1H, t, J = 8.0Hz), 7.41-7.47 (1H, m).
实施例11Example 11
3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸∶双(三氯甲基)碳酸酯∶N-甲基四氢吡咯＝1∶0.34∶0.02(摩尔比)，3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸投料量为25.55g(100mmol)，双(三氯甲基)碳酸酯投料量为10.09g(34mmol)，催化剂用量为0.17g(2mmol)，有机溶剂为氯苯，其用量为3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸质量的3.5倍。3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazolecarboxylic acid:bis(trichloromethyl)carbonate:N-methyltetrahydropyrrole=1:0.34: 0.02 (molar ratio), 3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazole formic acid charging capacity is 25.55g (100mmol), bis(trichloromethyl)carbonic acid The ester dosage is 10.09g (34mmol), the catalyst consumption is 0.17g (2mmol), the organic solvent is chlorobenzene, and its consumption is 3-(2'-chloro-6'-fluorophenyl)-5-methyl-4 - 3.5 times the mass of isoxazole formic acid.
反应温度为85～90℃，其它操作同实施例1，得产品25.61克，产品收率93.5％，熔点为48～52℃，含量(GC)98.5％。1H-NMR(CDCl3)δ：2.87(3H，s)，7.08(1H，t，J＝8.8Hz)，7.33(1H，t，J＝8.0Hz)，7.41-7.47(1H，m)。Reaction temperature is 85～90 ℃, other operation is the same as embodiment 1, obtains product 25.61 grams, product yield 93.5%, melting point is 48～52 ℃, content (GC) 98.5%. 1 H-NMR (CDCl 3 ) δ: 2.87 (3H, s), 7.08 (1H, t, J = 8.8Hz), 7.33 (1H, t, J = 8.0Hz), 7.41-7.47 (1H, m).
实施例12Example 12
3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸∶双(三氯甲基)碳酸酯∶吡啶＝1∶0.34∶0.05(摩尔比)，3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸投料量为25.55g(100mmol)，双(三氯甲基)碳酸酯投料量为10.09g(34mmol)，催化剂用量为0.40g(5mmol)，有机溶剂为氯苯，其用量为3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸质量的2.5倍。3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazolecarboxylic acid:bis(trichloromethyl)carbonate:pyridine=1:0.34:0.05 (molar ratio), The amount of 3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazolecarboxylic acid is 25.55g (100mmol), and the amount of bis(trichloromethyl)carbonate is 10.09g (34mmol), catalyst consumption is 0.40g (5mmol), and organic solvent is chlorobenzene, and its consumption is 3-(2 '-chloro-6'-fluorophenyl)-5-methyl-4-isoxazole formic acid quality 2.5 times.
反应温度为90～95℃，其它操作同实施例1，得产品23.84克，产品收率87.0％，熔点为48～52℃，含量(GC)98.0％。1H-NMR(CDCl3)δ：2.87(3H，s)，7.08(1H，t，J＝8.8Hz)，7.33(1H，t，J＝8.0Hz)，7.41-7.47(1H，m)。Reaction temperature is 90～95 ℃, other operation is the same as embodiment 1, obtains product 23.84 grams, product yield 87.0%, melting point is 48～52 ℃, content (GC) 98.0%. 1 H-NMR (CDCl 3 ) δ: 2.87 (3H, s), 7.08 (1H, t, J = 8.8Hz), 7.33 (1H, t, J = 8.0Hz), 7.41-7.47 (1H, m).
实施例13Example 13
3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸∶双(三氯甲基)碳酸酯∶N，N-二甲基甲酰胺＝1∶0.7∶0.1，3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸投料量为25.55g(100mmol)，双(三氯甲基)碳酸酯投料量为20.79g(70mmol)，催化剂用量为0.73g(10mmol)，有机溶剂为氯苯，其用量为3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸质量的1.0倍。3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazolecarboxylic acid: bis(trichloromethyl)carbonate: N,N-dimethylformamide=1: 0.7:0.1, 3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazole carboxylic acid charging amount is 25.55g (100mmol), bis(trichloromethyl) carbonate feeding The amount is 20.79g (70mmol), the catalyst consumption is 0.73g (10mmol), the organic solvent is chlorobenzene, and its consumption is 3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-iso 1.0 times the mass of oxazole formic acid.
反应温度为100～105℃，其它操作同实施例1，得产品26.17克，产品收率95.5％，熔点为48～52℃，含量(GC)98.5％。1H-NMR(CDCl3)δ：2.87(3H，s)，7.08(1H，t，J＝8.8Hz)，7.33(1H，t，J＝8.0Hz)，7.41-7.47(1H，m)。Reaction temperature is 100～105 ℃, other operation is the same as embodiment 1, obtains product 26.17 grams, product yield 95.5%, melting point is 48～52 ℃, content (GC) 98.5%. 1 H-NMR (CDCl 3 ) δ: 2.87 (3H, s), 7.08 (1H, t, J = 8.8Hz), 7.33 (1H, t, J = 8.0Hz), 7.41-7.47 (1H, m).
实施例14Example 14
3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸∶双(三氯甲基)碳酸酯∶N，N-二甲基甲酰胺＝1∶1.0∶0.2(摩尔比)，3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸投料量为25.55g(100mmol)，双(三氯甲基)碳酸酯投料量为29.7g(100mmol)，催化剂用量为1.46g(20mmol)，有机溶剂为氯苯，其用量为3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸质量的3倍。3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazolecarboxylic acid: bis(trichloromethyl)carbonate: N,N-dimethylformamide=1: 1.0:0.2 (molar ratio), 3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazolecarboxylic acid dosage is 25.55g (100mmol), bis(trichloromethyl ) carbonate charging capacity is 29.7g (100mmol), catalyst consumption is 1.46g (20mmol), organic solvent is chlorobenzene, and its consumption is 3-(2'-chloro-6'-fluorophenyl)-5-methyl -3 times the mass of 4-isoxazole formic acid.
反应温度为110～115℃，其它操作同实施例1，得产品24.66克，产品收率90.0％，熔点为48～52℃，含量(GC)98.5％。1H-NMR(CDCl3)δ：2.87(3H，s)，7.08(1H，t，J＝8.8Hz)，7.33(1H，t，J＝8.0Hz)，7.41-7.47(1H，m)。Reaction temperature is 110～115 ℃, other operation is the same as embodiment 1, obtains product 24.66 grams, product yield 90.0%, melting point is 48～52 ℃, content (GC) 98.5%. 1 H-NMR (CDCl 3 ) δ: 2.87 (3H, s), 7.08 (1H, t, J = 8.8Hz), 7.33 (1H, t, J = 8.0Hz), 7.41-7.47 (1H, m).
实施例15Example 15
3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸∶双(三氯甲基)碳酸酯∶N，N-二甲基甲酰胺＝1∶1.0∶0.01(摩尔比)，3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸投料量为25.55g(100mmol)，双(三氯甲基)碳酸酯投料量为29.7g(100mmol)，催化剂用量为0.073g(1mmol)，有机溶剂为氯苯，其用量为3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸质量的3倍。3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazolecarboxylic acid: bis(trichloromethyl)carbonate: N,N-dimethylformamide=1: 1.0:0.01 (molar ratio), 3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazolecarboxylic acid dosage is 25.55g (100mmol), bis(trichloromethyl ) carbonate charging capacity is 29.7g (100mmol), catalyst consumption is 0.073g (1mmol), organic solvent is chlorobenzene, and its consumption is 3-(2'-chloro-6'-fluorophenyl)-5-methyl -3 times the mass of 4-isoxazole formic acid.
反应温度为110～11 5℃，其它操作同实施例1，得产品24.79克，产品收率90.5％，熔点为48～52℃，含量(GC)99.0％。1H-NMR(CDCl3)δ：2.87(3H，s)，7.08(1H，t，J＝8.8Hz)，7.33(1H，t，J＝8.0Hz)，7.41-7.47(1H，m)。The reaction temperature was 110-115° C., and other operations were the same as in Example 1 to obtain 24.79 grams of the product, with a product yield of 90.5%, a melting point of 48-52° C., and a content (GC) of 99.0%. 1 H-NMR (CDCl 3 ) δ: 2.87 (3H, s), 7.08 (1H, t, J = 8.8Hz), 7.33 (1H, t, J = 8.0Hz), 7.41-7.47 (1H, m).
实施例16Example 16
3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸∶双(三氯甲基)碳酸酯∶N，N-二甲基甲酰胺＝1∶1.0∶0.02(摩尔比)，3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸投料量为25.55g(100mmol)，双(三氯甲基)碳酸酯投料量为29.7g(100mmol)，催化剂用量为0.146g(2mmol)，有机溶剂为氯苯，其用量为3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸质量的5倍。3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazolecarboxylic acid: bis(trichloromethyl)carbonate: N,N-dimethylformamide=1: 1.0:0.02 (molar ratio), 3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazolecarboxylic acid dosage is 25.55g (100mmol), bis(trichloromethyl ) carbonate charging capacity is 29.7g (100mmol), catalyst consumption is 0.146g (2mmol), organic solvent is chlorobenzene, and its consumption is 3-(2'-chloro-6'-fluorophenyl)-5-methyl -5 times the mass of 4-isoxazole formic acid.
反应温度为110～115℃，其它操作同实施例1，得产品24.39克，产品收率89.0％，熔点为48～52℃，含量(GC)98.0％。1H-NMR(CDCl3)δ：2.87(3H，s)，7.08(1H，t，J＝8.8Hz)，7.33(1H，t，J＝8.0Hz)，7.41-7.47(1H，m)。Reaction temperature is 110～115 ℃, other operation is the same as embodiment 1, obtains product 24.39 grams, product yield 89.0%, melting point is 48～52 ℃, content (GC) 98.0%. 1 H-NMR (CDCl 3 ) δ: 2.87 (3H, s), 7.08 (1H, t, J = 8.8Hz), 7.33 (1H, t, J = 8.0Hz), 7.41-7.47 (1H, m).
实施例17Example 17
3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸∶双(三氯甲基)碳酸酯∶1，3-二甲基-2-咪唑烷酮＝1∶0.7∶0.03(摩尔比)，3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸投料量为25.55g(100mmol)，双(三氯甲基)碳酸酯投料量为20.79g(70mmol)，催化剂用量为0.342g(3mmol)，有机溶剂为二丁基醚，其用量为3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸质量的2倍。3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazolecarboxylic acid: bis(trichloromethyl)carbonate: 1,3-dimethyl-2-imidazolidine Ketone=1: 0.7: 0.03 (molar ratio), 3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazole formic acid charging capacity is 25.55g (100mmol), bis( Trichloromethyl) carbonate charging amount is 20.79g (70mmol), and catalyst consumption is 0.342g (3mmol), and organic solvent is dibutyl ether, and its consumption is 3-(2'-chloro-6'-fluorophenyl )-5-methyl-4-isoxazole carboxylic acid 2 times the mass.
反应温度为80～85℃，其它操作同实施例1，得产品25.07克，产品收率91.5％，熔点为48～52℃，含量(GC)98.0％。1H-NMR(CDCl3)δ：2.87(3H，s)，7.08(1H，t，J＝8.8Hz)，7.33(1H，t，J＝8.0Hz)，7.41-7.47(1H，m)。Reaction temperature is 80～85 ℃, other operation is the same as embodiment 1, obtains product 25.07 grams, product yield 91.5%, melting point is 48～52 ℃, content (GC) 98.0%. 1 H-NMR (CDCl 3 ) δ: 2.87 (3H, s), 7.08 (1H, t, J = 8.8Hz), 7.33 (1H, t, J = 8.0Hz), 7.41-7.47 (1H, m).
实施例18Example 18
3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸∶双(三氯甲基)碳酸酯∶1，3-二甲基-2-咪唑烷酮＝1∶0.7∶0.01(摩尔比)，3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸投料量为25.55g(100mmol)，双(三氯甲基)碳酸酯投料量为20.79g(70mmol)，催化剂用量为0.114g(1mmol)，有机溶剂为二氯苯，其用量为3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸质量的2倍。3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazolecarboxylic acid: bis(trichloromethyl)carbonate: 1,3-dimethyl-2-imidazolidine Ketone=1: 0.7: 0.01 (molar ratio), 3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazole formic acid charging capacity is 25.55g (100mmol), bis( Trichloromethyl)carbonate charging capacity is 20.79g (70mmol), and catalyst consumption is 0.114g (1mmol), and organic solvent is dichlorobenzene, and its consumption is 3-(2'-chloro-6'-fluorophenyl) -2 times the mass of 5-methyl-4-isoxazolecarboxylic acid.
反应温度为80～85℃，其它操作同实施例1，得产品24.11克，产品收率88.0％，熔点为48～52℃，含量(GC)99.0％。1H-NMR(CDCl3)δ：2.87(3H，s)，7.08(1H，t，J＝8.8Hz)，7.33(1H，t，J＝8.0Hz)，7.41-7.47(1H，m)。Reaction temperature is 80～85 ℃, other operation is the same as embodiment 1, obtains product 24.11 grams, product yield 88.0%, melting point is 48～52 ℃, content (GC) 99.0%. 1 H-NMR (CDCl 3 ) δ: 2.87 (3H, s), 7.08 (1H, t, J = 8.8Hz), 7.33 (1H, t, J = 8.0Hz), 7.41-7.47 (1H, m).
实施例19Example 19
3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸∶双(三氯甲基)碳酸酯∶吡啶＝1∶1∶0.04(摩尔比)，3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸投料量为25.55g(100mmol)，双(三氯甲基)碳酸酯投料量为29.7g(100mmol)，催化剂用量为0.32g(4mmol)，有机溶剂为二异丙基醚，其用量为3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸质量的2倍。3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazolecarboxylic acid:bis(trichloromethyl)carbonate:pyridine=1:1:0.04 (molar ratio), 3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazole carboxylic acid charging capacity is 25.55g (100mmol), bis(trichloromethyl)carbonate charging capacity is 29.7g (100mmol), the amount of catalyst is 0.32g (4mmol), the organic solvent is diisopropyl ether, and the amount is 3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxane 2 times the mass of azole carboxylic acid.
反应温度为65～68℃，其它操作同实施例1，得产品24.38克，产品收率89.0％，熔点为48～52℃，含量(GC)99.0％。1H-NMR(CDCl3)δ：2.87(3H，s)，7.08(1H，t，J＝8.8Hz)，7.33(1H，t，J＝8.0Hz)，7.41-7.47(1H，m)。Reaction temperature is 65～68 ℃, other operation is the same as embodiment 1, obtains product 24.38 grams, product yield 89.0%, melting point is 48～52 ℃, content (GC) 99.0%. 1 H-NMR (CDCl 3 ) δ: 2.87 (3H, s), 7.08 (1H, t, J = 8.8Hz), 7.33 (1H, t, J = 8.0Hz), 7.41-7.47 (1H, m).
实施例20Example 20
3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸∶双(三氯甲基)碳酸酯∶吡啶＝1∶0.34∶0.06(摩尔比)，3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸投料量为25.55g(100mmol)，双(三氯甲基)碳酸酯投料量为10.10g(34mmol)，催化剂用量为0.47g(6mmol)，有机溶剂为氯苯，其用量为3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸质量的2倍。3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazolecarboxylic acid:bis(trichloromethyl)carbonate:pyridine=1:0.34:0.06 (molar ratio), The amount of 3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazolecarboxylic acid is 25.55g (100mmol), and the amount of bis(trichloromethyl)carbonate is 10.10g (34mmol), catalyst consumption is 0.47g (6mmol), and organic solvent is chlorobenzene, and its consumption is 3-(2 '-chloro-6'-fluorophenyl)-5-methyl-4-isoxazole formic acid quality 2 times.
反应温度为90～95℃，其它操作同实施例1，得产品26.44克，产品收率96.5％，熔点为48～52℃，含量(GC)98.5％。1H-NMR(CDCl3)δ：2.87(3H，s)，7.08(1H，t，J＝8.8Hz)，7.33(1H，t，J＝8.0Hz)，7.41-7.47(1H，m)。Reaction temperature is 90～95 ℃, other operation is the same as embodiment 1, obtains product 26.44 grams, product yield 96.5%, melting point is 48～52 ℃, content (GC) 98.5%. 1 H-NMR (CDCl 3 ) δ: 2.87 (3H, s), 7.08 (1H, t, J = 8.8Hz), 7.33 (1H, t, J = 8.0Hz), 7.41-7.47 (1H, m).
实施例21Example 21
3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸∶双(三氯甲基)碳酸酯∶N-甲基四氢吡咯＝1∶0.34∶0.08(摩尔比)，3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸投料量为25.55g(100mmol)，双(三氯甲基)碳酸酯投料量为10.10g(34mmol)，催化剂用量为0.68g(8mmol)，有机溶剂为氯苯，其用量为3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸质量的3.5倍。3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazolecarboxylic acid:bis(trichloromethyl)carbonate:N-methyltetrahydropyrrole=1:0.34: 0.08 (molar ratio), 3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazole formic acid charging capacity is 25.55g (100mmol), bis(trichloromethyl)carbonic acid The ester dosage is 10.10g (34mmol), the catalyst consumption is 0.68g (8mmol), the organic solvent is chlorobenzene, and its consumption is 3-(2'-chloro-6'-fluorophenyl)-5-methyl-4 - 3.5 times the mass of isoxazole formic acid.
反应温度为110～115℃，其它操作同实施例1，得产品25.62克，产品收率93.5％，熔点为48～52℃，含量(GC)99.0％。1H-NMR(CDCl3)δ：2.87(3H，s)，7.08(1H，t，J＝8.8Hz)，7.33(1H，t，J＝8.0Hz)，7.41-7.47(1H，m)。Reaction temperature is 110～115 ℃, other operation is the same as embodiment 1, obtains product 25.62 grams, product yield 93.5%, melting point is 48～52 ℃, content (GC) 99.0%. 1 H-NMR (CDCl 3 ) δ: 2.87 (3H, s), 7.08 (1H, t, J = 8.8Hz), 7.33 (1H, t, J = 8.0Hz), 7.41-7.47 (1H, m).
实施例22Example 22
3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸∶双(三氯甲基)碳酸酯∶N，N-二甲基甲酰胺＝1∶0.7∶0.1(摩尔比)，3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸投料量为25.55g(100mmol)，双(三氯甲基)碳酸酯投料量为20.79g(70mmol)，催化剂用量为0.73g(10mmol)，有机溶剂为二氯苯，其用量为3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸质量的3倍。3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazolecarboxylic acid: bis(trichloromethyl)carbonate: N,N-dimethylformamide=1: 0.7:0.1 (molar ratio), 3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazolecarboxylic acid dosage is 25.55g (100mmol), bis(trichloromethyl ) carbonate charging capacity is 20.79g (70mmol), catalyst consumption is 0.73g (10mmol), organic solvent is dichlorobenzene, and its consumption is 3-(2'-chloro-6'-fluorophenyl)-5-methyl 3 times the mass of base-4-isoxazolecarboxylic acid.
反应温度为115～120℃，其它操作同实施例1，得产品26.17克，产品收率95.5％，熔点为48～52℃，含量(GC)98.5％。1H-NMR(CDCl3)δ：2.87(3H，s)，7.08(1H，t，J＝8.8Hz)，7.33(1H，t，J＝8.0Hz)，7.41-7.47(1H，m)。Reaction temperature is 115～120 ℃, other operation is the same as embodiment 1, obtains product 26.17 grams, product yield 95.5%, melting point is 48～52 ℃, content (GC) 98.5%. 1 H-NMR (CDCl 3 ) δ: 2.87 (3H, s), 7.08 (1H, t, J = 8.8Hz), 7.33 (1H, t, J = 8.0Hz), 7.41-7.47 (1H, m).
实施例23Example 23
3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸∶双(三氯甲基)碳酸酯∶N，N-二甲基甲酰胺＝1∶1.5∶0.4(摩尔比)，3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸投料量为25.55g(100mmol)，双(三氯甲基)碳酸酯投料量为44.55g(70mmol)，催化剂用量为2.92g(40mmol)，有机溶剂为氯苯，其用量为3-(2′-氯-6′-氟苯基)-甲基-4-异恶唑甲酸质量的0.5倍。3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazolecarboxylic acid: bis(trichloromethyl)carbonate: N,N-dimethylformamide=1: 1.5:0.4 (molar ratio), 3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazole formic acid dosage is 25.55g (100mmol), bis(trichloromethyl ) carbonate charging capacity is 44.55g (70mmol), catalyst consumption is 2.92g (40mmol), organic solvent is chlorobenzene, and its consumption is 3-(2'-chloro-6'-fluorophenyl)-methyl-4 - 0.5 times the mass of isoxazole formic acid.
反应温度为100～105℃，其它操作同实施例1，得产品26.17克，产品收率95.5％，熔点为48～52℃，含量(GC)98.5％。1H-NMR(CDCl3)δ：2.87(3H，s)，7.08(1H，t，J＝8.8Hz)，7.33(1H，t，J＝8.0Hz)，7.41-7.47(1H，m)。Reaction temperature is 100～105 ℃, other operation is the same as embodiment 1, obtains product 26.17 grams, product yield 95.5%, melting point is 48～52 ℃, content (GC) 98.5%. 1 H-NMR (CDCl 3 ) δ: 2.87 (3H, s), 7.08 (1H, t, J = 8.8Hz), 7.33 (1H, t, J = 8.0Hz), 7.41-7.47 (1H, m).
实施例24Example 24
3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸∶双(三氯甲基)碳酸酯∶N，N-二甲基甲酰胺＝1∶1.5∶0.4(摩尔比)，3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸投料量为25.55g(100mmol)，双(三氯甲基)碳酸酯投料量为44.55g(150mmol)，催化剂用量为2.92g(40mmol)，有机溶剂为氯苯，其用量为3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸质量的3倍。3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazolecarboxylic acid: bis(trichloromethyl)carbonate: N,N-dimethylformamide=1: 1.5:0.4 (molar ratio), 3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazole formic acid dosage is 25.55g (100mmol), bis(trichloromethyl ) carbonate charging capacity is 44.55g (150mmol), catalyst consumption is 2.92g (40mmol), and organic solvent is chlorobenzene, and its consumption is 3-(2'-chloro-6'-fluorophenyl)-5-methyl -3 times the mass of 4-isoxazole formic acid.
反应温度为110～115℃，其它操作同实施例1，得产品24.66克，产品收率90.0％，熔点为48～52℃，含量(GC)98.5％。1H-NMR(CDCl3)δ：2.87(3H，s)，7.08(1H，t，J＝8.8Hz)，7.33(1H，t，J＝8.0Hz)，7.41-7.47(1H，m)。Reaction temperature is 110～115 ℃, other operation is the same as embodiment 1, obtains product 24.66 grams, product yield 90.0%, melting point is 48～52 ℃, content (GC) 98.5%. 1 H-NMR (CDCl 3 ) δ: 2.87 (3H, s), 7.08 (1H, t, J = 8.8Hz), 7.33 (1H, t, J = 8.0Hz), 7.41-7.47 (1H, m).
实施例25Example 25
3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸∶双(三氯甲基)碳酸酯∶N，N-二甲基甲酰胺＝1∶2∶0.6(摩尔比)，3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸投料量为25.55g(100mmol)，双(三氯甲基)碳酸酯投料量为59.4g(200mmol)，催化剂用量为4.38g(60mmol)，有机溶剂为氯苯，其用量为3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸质量的3倍。3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazolecarboxylic acid: bis(trichloromethyl)carbonate: N,N-dimethylformamide=1: 2:0.6 (molar ratio), 3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazolecarboxylic acid dosage is 25.55g (100mmol), bis(trichloromethyl ) carbonate charging capacity is 59.4g (200mmol), catalyst consumption is 4.38g (60mmol), organic solvent is chlorobenzene, and its consumption is 3-(2'-chloro-6'-fluorophenyl)-5-methyl -3 times the mass of 4-isoxazole formic acid.
反应温度为110～115℃，其它操作同实施例1，得产品24.79克，产品收率90.5％，熔点为48～52℃，含量(GC)99.0％。1H-NMR(CDCl3)δ：2.87(3H，s)，7.08(1H，t，J＝8.8Hz)，7.33(1H，t，J＝8.0Hz)，7.41-7.47(1H，m)。Reaction temperature is 110～115 ℃, other operation is the same as embodiment 1, obtains product 24.79 grams, product yield 90.5%, melting point is 48～52 ℃, content (GC) 99.0%. 1 H-NMR (CDCl 3 ) δ: 2.87 (3H, s), 7.08 (1H, t, J = 8.8Hz), 7.33 (1H, t, J = 8.0Hz), 7.41-7.47 (1H, m).
实施例26Example 26
3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸∶双(三氯甲基)碳酸酯∶N，N-二甲基甲酰胺＝1∶2∶0.6(摩尔比)，3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸投料量为25.55g(100mmol)，双(三氯甲基)碳酸酯投料量为59.4g(200mmol)，催化剂用量为4.38g(60mmol)，有机溶剂为二丁基醚，其用量为3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸质量的5倍。3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazolecarboxylic acid: bis(trichloromethyl)carbonate: N,N-dimethylformamide=1: 2:0.6 (molar ratio), 3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazolecarboxylic acid dosage is 25.55g (100mmol), bis(trichloromethyl ) carbonate charging capacity is 59.4g (200mmol), catalyst consumption is 4.38g (60mmol), organic solvent is dibutyl ether, and its consumption is 3-(2'-chloro-6'-fluorophenyl)-5- 5 times the mass of methyl-4-isoxazolecarboxylic acid.
反应温度为110～115℃，其它操作同实施例1，得产品25.48克，产品收率93.0％，熔点为48～52℃，含量(GC)98.0％。1H-NMR(CDCl3)δ：2.87(3H，s)，7.08(1H，t，J＝8.8Hz)，7.33(1H，t，J＝8.0Hz)，7.41-7.47(1H，m)。Reaction temperature is 110～115 ℃, other operation is the same as embodiment 1, obtains product 25.48 grams, product yield 93.0%, melting point is 48～52 ℃, content (GC) 98.0%. 1 H-NMR (CDCl 3 ) δ: 2.87 (3H, s), 7.08 (1H, t, J = 8.8Hz), 7.33 (1H, t, J = 8.0Hz), 7.41-7.47 (1H, m).
实施例27Example 27
3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸∶双(三氯甲基)碳酸酯∶1，3-二甲基-2-咪唑烷酮＝1∶2∶0.6(摩尔比)，3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸投料量为25.55g(100mmol)，双(三氯甲基)碳酸酯投料量为59.4g(200mmol)，催化剂用量为6.84g(60mmol)，有机溶剂为二丁基醚，其用量为3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸质量的2倍。3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazolecarboxylic acid: bis(trichloromethyl)carbonate: 1,3-dimethyl-2-imidazolidine Ketone=1: 2: 0.6 (molar ratio), 3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazole formic acid charging capacity is 25.55g (100mmol), bis( Trichloromethyl)carbonate charging capacity is 59.4g (200mmol), and catalyst consumption is 6.84g (60mmol), and organic solvent is dibutyl ether, and its consumption is 3-(2'-chloro-6'-fluorophenyl )-5-methyl-4-isoxazole carboxylic acid 2 times the mass.
反应温度为110～115℃，其它操作同实施例1，得产品24.3克，产品收率88.7％，熔点为48～52℃，含量(GC)98.0％。1H-NMR(CDCl3)δ：2.87(3H，s)，7.08(1H，t，J＝8.8Hz)，7.33(1H，t，J＝8.0Hz)，7.41-7.47(1H，m)。Reaction temperature is 110～115 ℃, other operation is the same as embodiment 1, obtains product 24.3 grams, product yield 88.7%, melting point is 48～52 ℃, content (GC) 98.0%. 1 H-NMR (CDCl 3 ) δ: 2.87 (3H, s), 7.08 (1H, t, J = 8.8Hz), 7.33 (1H, t, J = 8.0Hz), 7.41-7.47 (1H, m).
实施例28Example 28
3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸∶双(三氯甲基)碳酸酯∶1，3-二甲基-2-咪唑烷酮＝1∶2.5∶0.6(摩尔比)，3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸投料量为25.55g(100mmol)，双(三氯甲基)碳酸酯投料量为74.25g(250mmol)，催化剂用量为6.84g(60mmol)，有机溶剂为二氯苯，其用量为(2′-氯-6′-氟苯基)-5-甲基4-异恶唑甲酸质量的2倍。3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazolecarboxylic acid: bis(trichloromethyl)carbonate: 1,3-dimethyl-2-imidazolidine Ketone=1: 2.5: 0.6 (molar ratio), 3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazole formic acid charging capacity is 25.55g (100mmol), bis( Trichloromethyl)carbonate charging capacity is 74.25g (250mmol), and catalyst consumption is 6.84g (60mmol), and organic solvent is dichlorobenzene, and its consumption is (2'-chloro-6'-fluorophenyl)-5 - Twice the mass of methyl 4-isoxazole formic acid.
反应温度为80～85℃，其它操作同实施例1，得产品24.03克，产品收率87.7％，熔点为48～52℃，含量(GC)99.0％。1H-NMR(CDCl3)δ：2.87(3H，s)，7.08(1H，t，J＝8.8Hz)，7.33(1H，t，J＝8.0Hz)，7.41-7.47(1H，m)。Reaction temperature is 80～85 ℃, other operation is the same as embodiment 1, obtains product 24.03 grams, product yield 87.7%, melting point is 48～52 ℃, content (GC) 99.0%. 1 H-NMR (CDCl 3 ) δ: 2.87 (3H, s), 7.08 (1H, t, J = 8.8Hz), 7.33 (1H, t, J = 8.0Hz), 7.41-7.47 (1H, m).
实施例29Example 29
3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸∶双(三氯甲基)碳酸酯∶吡啶＝1∶2.5∶0.8(摩尔比)，3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸投料量为25.55g(100mmol)，双(三氯甲基)碳酸酯投料量为74.25g(250mmol)，催化剂用量为6.3g(80mmol)，有机溶剂为二异丙基醚，其用量为3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸质量的2倍。3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazolecarboxylic acid:bis(trichloromethyl)carbonate:pyridine=1:2.5:0.8 (molar ratio), The amount of 3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazolecarboxylic acid is 25.55g (100mmol), and the amount of bis(trichloromethyl)carbonate is 74.25g (250mmol), the amount of catalyst is 6.3g (80mmol), the organic solvent is diisopropyl ether, and the amount is 3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxane 2 times the mass of azole carboxylic acid.
反应温度为65～68℃，其它操作同实施例1，得产品24.39克，产品收率89.0％，熔点为48～52℃，含量(GC)99.0％。1H-NMR(CDCl3)δ：2.87(3H，s)，7.08(1H，t，J＝8.8Hz)，7.33(1H，t，J＝8.0Hz)，7.41-7.47(1H，m)。Reaction temperature is 65～68 ℃, other operation is the same as embodiment 1, obtains product 24.39 grams, product yield 89.0%, melting point is 48～52 ℃, content (GC) 99.0%. 1 H-NMR (CDCl 3 ) δ: 2.87 (3H, s), 7.08 (1H, t, J = 8.8Hz), 7.33 (1H, t, J = 8.0Hz), 7.41-7.47 (1H, m).
实施例30Example 30
3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸∶双(三氯甲基)碳酸酯∶吡啶＝1∶2.5∶0.8(摩尔比)，3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸投料量为25.55g(100mmol)，双(三氯甲基)碳酸酯投料量为74.25g(250mmol)，催化剂用量为6.3g(80mmol)，有机溶剂为氯苯，其用量为3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸 量的2倍。3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazolecarboxylic acid:bis(trichloromethyl)carbonate:pyridine=1:2.5:0.8 (molar ratio), The amount of 3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazolecarboxylic acid is 25.55g (100mmol), and the amount of bis(trichloromethyl)carbonate is 74.25g (250mmol), catalyst consumption is 6.3g (80mmol), organic solvent is chlorobenzene, and its consumption is 3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazole formic acid amount 2 times.
反应温度为90～95℃，其它操作同实施例1，得产品26.44克，产品收率96.5％，熔点为48～52℃，含量(GC)98.5％。1H-NMR(CDCl3)δ：2.87(3H，s)，7.08(1H，t，J＝8.8Hz)，7.33(1H，t，J＝8.0Hz)，7.41-7.47(1H，m)。Reaction temperature is 90～95 ℃, other operation is the same as embodiment 1, obtains product 26.44 grams, product yield 96.5%, melting point is 48～52 ℃, content (GC) 98.5%. 1 H-NMR (CDCl 3 ) δ: 2.87 (3H, s), 7.08 (1H, t, J = 8.8Hz), 7.33 (1H, t, J = 8.0Hz), 7.41-7.47 (1H, m).
实施例31Example 31
3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸∶双(三氯甲基)碳酸酯∶N-甲基四氢吡咯＝1∶3∶0.8(摩尔比)，3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸投料量为25.55g(100mmol)，双(三氯甲基)碳酸酯投料量为89.1g(300mmol)，催化剂用量为6.8g(80mmol)，有机溶剂为氯苯，其用量为3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸质量的3.5倍。3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazolecarboxylic acid:bis(trichloromethyl)carbonate:N-methyltetrahydropyrrole=1:3: 0.8 (molar ratio), 3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazole formic acid charging capacity is 25.55g (100mmol), bis(trichloromethyl)carbonic acid The ester dosage is 89.1g (300mmol), the catalyst consumption is 6.8g (80mmol), the organic solvent is chlorobenzene, and its consumption is 3-(2'-chloro-6'-fluorophenyl)-5-methyl-4 - 3.5 times the mass of isoxazole formic acid.
反应温度为110～115℃，其它操作同实施例1，得产品25.62克，产品收率93.5％，熔点为48～52℃，含量(GC)99.0％。1H-NMR(CDCl3)δ：2.87(3H，s)，7.08(1H，t，J＝8.8Hz)，7.33(1H，t，J＝8.0Hz)，7.41-7.47(1H，m)。Reaction temperature is 110～115 ℃, other operation is the same as embodiment 1, obtains product 25.62 grams, product yield 93.5%, melting point is 48～52 ℃, content (GC) 99.0%. 1 H-NMR (CDCl 3 ) δ: 2.87 (3H, s), 7.08 (1H, t, J = 8.8Hz), 7.33 (1H, t, J = 8.0Hz), 7.41-7.47 (1H, m).
实施例32Example 32
3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸∶双(三氯甲基)碳酸酯∶吡啶＝为1∶3∶0.8(摩尔比)，3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸投料量为25.55g(100mmol)，双(三氯甲基)碳酸酯投料量为89.1g(300mmol)，催化剂用量为6.3g(80mmol)，有机溶剂为二氯乙烷，其用量为3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸质量的2.5倍。3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazolecarboxylic acid:bis(trichloromethyl)carbonate:pyridine=1:3:0.8 (molar ratio) , 3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazole carboxylic acid charging capacity is 25.55g (100mmol), two (trichloromethyl) carbonate charging capacity is 89.1 g (300mmol), the amount of catalyst is 6.3g (80mmol), the organic solvent is dichloroethane, and the amount is 3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxane 2.5 times the mass of azole carboxylic acid.
反应温度为70～75℃，其它操作同实施例1，得产品26.30克，产品收率96.0％，熔点为48～52℃，含量(GC)99.0％。1H-NMR(CDCl3)δ：2.87(3H，s)，7.08(1H，t，J＝8.8Hz)，7.33(1H，t，J＝8.0Hz)，7.41-7.47(1H，m)。Reaction temperature is 70～75 ℃, other operation is the same as embodiment 1, obtains product 26.30 grams, product yield 96.0%, melting point is 48～52 ℃, content (GC) 99.0%. 1 H-NMR (CDCl 3 ) δ: 2.87 (3H, s), 7.08 (1H, t, J = 8.8Hz), 7.33 (1H, t, J = 8.0Hz), 7.41-7.47 (1H, m).
实施例33Example 33
3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸∶双(三氯甲基)碳酸酯∶N，N-二甲基甲酰胺＝1∶3∶0.8(摩尔比)，3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸投料量为25.55g(100mmol)，双(三氯甲基)碳酸酯投料量为89.1g(300mmol)，催化剂用量为5.8g(80mmol)，有机溶剂为二氯苯，其用量为3-(2′-氯-6′-氟苯基)-5-甲基-4-异恶唑甲酸质量的3倍。3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazolecarboxylic acid: bis(trichloromethyl)carbonate: N,N-dimethylformamide=1: 3:0.8 (molar ratio), 3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isoxazolecarboxylic acid dosage is 25.55g (100mmol), bis(trichloromethyl ) carbonate charging capacity is 89.1g (300mmol), catalyst consumption is 5.8g (80mmol), organic solvent is dichlorobenzene, and its consumption is 3-(2'-chloro-6'-fluorophenyl)-5-methyl 3 times the mass of base-4-isoxazolecarboxylic acid.
反应温度为115～120℃，其它操作同实施例1，得产品25.89克，产品收率94.5％，熔点为48～52℃，含量(GC)98.5％。1H-NMR(CDCl3)δ：2.87(3H，s)，7.08(1H，t，J＝8.8Hz)，7.33(1H，t，J＝8.0Hz)，7.41-7.47(1H，m)。Reaction temperature is 115～120 ℃, other operation is the same as embodiment 1, obtains product 25.89 grams, product yield 94.5%, melting point is 48～52 ℃, content (GC) 98.5%. 1 H-NMR (CDCl 3 ) δ: 2.87 (3H, s), 7.08 (1H, t, J = 8.8Hz), 7.33 (1H, t, J = 8.0Hz), 7.41-7.47 (1H, m).
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