CN101475541A - Preparation of 4-methyl thiazole-5-carboxyl acid - Google Patents
Preparation of 4-methyl thiazole-5-carboxyl acid Download PDFInfo
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- CN101475541A CN101475541A CNA2009100255226A CN200910025522A CN101475541A CN 101475541 A CN101475541 A CN 101475541A CN A2009100255226 A CNA2009100255226 A CN A2009100255226A CN 200910025522 A CN200910025522 A CN 200910025522A CN 101475541 A CN101475541 A CN 101475541A
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- methylthiazol
- reaction
- carboxylic acid
- preparation
- methane amide
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- 238000002360 preparation method Methods 0.000 title claims description 13
- 239000002253 acid Substances 0.000 title 1
- 238000006243 chemical reaction Methods 0.000 claims abstract description 38
- ZGWGSEUMABQEMD-UHFFFAOYSA-N 4-methyl-1,3-thiazole-5-carboxylic acid Chemical compound CC=1N=CSC=1C(O)=O ZGWGSEUMABQEMD-UHFFFAOYSA-N 0.000 claims abstract description 20
- 239000012074 organic phase Substances 0.000 claims abstract description 11
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 11
- CYQAYERJWZKYML-UHFFFAOYSA-N phosphorus pentasulfide Chemical compound S1P(S2)(=S)SP3(=S)SP1(=S)SP2(=S)S3 CYQAYERJWZKYML-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000001914 filtration Methods 0.000 claims abstract description 9
- 239000000047 product Substances 0.000 claims abstract description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims abstract description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 30
- -1 methane amide Chemical class 0.000 claims description 22
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 claims description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- JAEUQHNZRROYID-UHFFFAOYSA-N 2-chloroethyl 3-oxobutanoate Chemical compound CC(=O)CC(=O)OCCCl JAEUQHNZRROYID-UHFFFAOYSA-N 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 238000006460 hydrolysis reaction Methods 0.000 claims description 9
- 125000000446 sulfanediyl group Chemical group *S* 0.000 claims description 9
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 8
- 230000007062 hydrolysis Effects 0.000 claims description 7
- 238000010025 steaming Methods 0.000 claims description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- 239000012043 crude product Substances 0.000 claims description 6
- WISQBJLUORKXNY-UHFFFAOYSA-N ethyl 4-methyl-1,3-thiazole-5-carboxylate Chemical compound CCOC(=O)C=1SC=NC=1C WISQBJLUORKXNY-UHFFFAOYSA-N 0.000 claims description 6
- 239000000706 filtrate Substances 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- 238000000638 solvent extraction Methods 0.000 claims description 4
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 3
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims description 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 3
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 3
- 125000001033 ether group Chemical group 0.000 claims description 2
- 239000000376 reactant Substances 0.000 claims description 2
- 238000010792 warming Methods 0.000 claims description 2
- QMHIMXFNBOYPND-UHFFFAOYSA-N 4MTO Natural products CC1=CSC=N1 QMHIMXFNBOYPND-UHFFFAOYSA-N 0.000 claims 16
- 238000000034 method Methods 0.000 abstract description 21
- 239000002351 wastewater Substances 0.000 abstract description 4
- 230000007613 environmental effect Effects 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 abstract 1
- 239000007795 chemical reaction product Substances 0.000 abstract 1
- 125000001309 chloro group Chemical group Cl* 0.000 abstract 1
- 239000000203 mixture Substances 0.000 abstract 1
- KKCBUQHMOMHUOY-UHFFFAOYSA-N sodium oxide Chemical compound [O-2].[Na+].[Na+] KKCBUQHMOMHUOY-UHFFFAOYSA-N 0.000 abstract 1
- 229910001948 sodium oxide Inorganic materials 0.000 abstract 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- LELOWRISYMNNSU-UHFFFAOYSA-N hydrogen cyanide Chemical compound N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 description 6
- 238000005516 engineering process Methods 0.000 description 5
- CYEBJEDOHLIWNP-UHFFFAOYSA-N methanethioamide Chemical compound NC=S CYEBJEDOHLIWNP-UHFFFAOYSA-N 0.000 description 5
- WRQNANDWMGAFTP-UHFFFAOYSA-N Methylacetoacetic acid Chemical compound COC(=O)CC(C)=O WRQNANDWMGAFTP-UHFFFAOYSA-N 0.000 description 4
- ORTFAQDWJHRMNX-UHFFFAOYSA-N hydroxidooxidocarbon(.) Chemical compound O[C]=O ORTFAQDWJHRMNX-UHFFFAOYSA-N 0.000 description 4
- 238000006193 diazotization reaction Methods 0.000 description 3
- 238000003810 ethyl acetate extraction Methods 0.000 description 3
- BQSJTQLCZDPROO-UHFFFAOYSA-N febuxostat Chemical compound C1=C(C#N)C(OCC(C)C)=CC=C1C1=NC(C)=C(C(O)=O)S1 BQSJTQLCZDPROO-UHFFFAOYSA-N 0.000 description 3
- 229960005101 febuxostat Drugs 0.000 description 3
- 201000005569 Gout Diseases 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 2
- ZSPCITYHOYJDBW-UHFFFAOYSA-N (4-methyl-1,3-thiazol-5-yl)methanol Chemical compound CC=1N=CSC=1CO ZSPCITYHOYJDBW-UHFFFAOYSA-N 0.000 description 1
- HJZDPELYBYVCES-UHFFFAOYSA-N 2,4-bis(phenylsulfanyl)-2,4-bis(sulfanylidene)-1,3,2$l^{5},4$l^{5}-dithiadiphosphetane Chemical compound S1P(=S)(SC=2C=CC=CC=2)SP1(=S)SC1=CC=CC=C1 HJZDPELYBYVCES-UHFFFAOYSA-N 0.000 description 1
- SCVJRXQHFJXZFZ-KVQBGUIXSA-N 2-amino-9-[(2r,4s,5r)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-3h-purine-6-thione Chemical compound C1=2NC(N)=NC(=S)C=2N=CN1[C@H]1C[C@H](O)[C@@H](CO)O1 SCVJRXQHFJXZFZ-KVQBGUIXSA-N 0.000 description 1
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 1
- LEHOTFFKMJEONL-UHFFFAOYSA-N Uric Acid Chemical compound N1C(=O)NC(=O)C2=C1NC(=O)N2 LEHOTFFKMJEONL-UHFFFAOYSA-N 0.000 description 1
- TVWHNULVHGKJHS-UHFFFAOYSA-N Uric acid Natural products N1C(=O)NC(=O)C2NC(=O)NC21 TVWHNULVHGKJHS-UHFFFAOYSA-N 0.000 description 1
- 229940123769 Xanthine oxidase inhibitor Drugs 0.000 description 1
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N alpha-methyl toluene Natural products CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229910000037 hydrogen sulfide Inorganic materials 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 238000011020 pilot scale process Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 231100000004 severe toxicity Toxicity 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 238000013456 study Methods 0.000 description 1
- 229940116269 uric acid Drugs 0.000 description 1
- 239000003064 xanthine oxidase inhibitor Substances 0.000 description 1
Landscapes
- Thiazole And Isothizaole Compounds (AREA)
Abstract
The invention provides a method for preparing a 4-methylthiazol-5-carboxylic acid, which relates to the technical field of chemical synthesis. The method comprises: mixing methanamide and phosphorus pentasulfide for carrying out a sulpho-reaction; adding chloro acetylacetic ether into a mixture for carrying out a cyclization reaction; adding organic phases into a sodium oxide solution for carrying out a hydrolyzation reaction; filtering the reaction products and taking separated products, namely the 4-methylthiazol-5-carboxylic acid. The method for preparing the 4-methylthiazol-5-carboxylic acid has three reactions, namely the sulpho-reaction, the cyclization reaction and the hydrolyzation reaction. The method has the advantages of simple operation, simple and steady process, small amount of waste water, environmental protection, simple and feasible industrialization, and the like. A pilot plant test by the inventor shows that the method has steady process, stable yield, total yield reaching 75 percent, and purity more than 98 percent.
Description
Technical field
The present invention relates to technical field of chemical synthesis.
Background technology
4-methylthiazol-5-carboxylic acid is the raw material of synthetic 4-methylthiazol-5-carboxylic ester class, it also is the raw material of producing 4-methylthiazol-5-acyl chlorides and 4-methyl-5-hydroxymethylthiazole, and be the key intermediate of a new generation's treatment gout medicine Febuxostat, Febuxostat (Febuxostat) is an xanthine oxidase inhibitor of new generation, be used for the treatment of the too high disease of uric acid (gout) clinically, all clinical studyes have been finished at present, listing abroad.
The technology of at present synthetic 4-methylthiazol-5-carboxylic acid mainly contains following several:
Method one: by after the chlorination of methyl aceto acetate elder generation with thiocarbamide cyclization in the ethanol/water solvent, then carry out diazotization reaction and remove amino, generate 4-methylthiazol-5-carboxylic acid after the hydrolysis.
Method two: generate thioformamide by prussic acid and hydrogen sulfide through High Temperature High Pressure, then, obtain 4-methylthiazol-5-carboxylic acid after the hydrolysis with chlorizate cyclization in the ethanol/water solvent of methyl aceto acetate.
Method three: in inert solvent, react by methane amide and thiophosphoric anhydride, solvent extraction, steaming desolventizes, and underpressure distillation obtains thioformamide, then, obtain 4-methylthiazol-5-carboxylic acid after the hydrolysis with chlorizate cyclization in the ethanol/water solvent of methyl aceto acetate.
Method four: methane amide and Japanese reagent [chemistry by name 2, two (the phenyl sulfenyls)-1 of 4-, 3-two sulphur-2,4-two phosphorus heterocycle butane-2,4 disulphide] reaction generation thioformamide, then, obtain 4-methylthiazol-5-carboxylic acid after the hydrolysis with chlorizate cyclization in the ethanol/water solvent of methyl aceto acetate.
All there are different relative merits in above method, and method one diazotization reaction produces a large amount of waste water, and the diazotization reaction yield is very low; Though method two technology is simple, use the prussic acid of severe toxicity, and reaction process needs High Temperature High Pressure, to the equipment requirements height, and cause prussic acid excessive easily, cause severe contamination to environment; Method three need be used a large amount of solvents, and the unit volume utilization ratio is extremely low, and the thioformamide yield is low, and making it can not industrialization, and the method four-function yield of thioformamide is improved, but complex process is difficult to carry out industrialization more to oxygen thioated reagent.
Summary of the invention
The object of the invention is to invent that a kind of technology is simple, a kind of preparation method of no waste water, production process environmental protection, 4-methylthiazol-5-carboxylic acid that yield is high.
The present invention carries out thio reaction first methane amide is mixed with thiophosphoric anhydride; Add chloro ethyl acetoacetate again and carry out cyclization reaction, get organic phase and add the sodium hydroxide solution reaction that is hydrolyzed, the product of separating out is got in filtration, is 4-methylthiazol-5-carboxylic acid.
The method that the present invention produces 4-methylthiazol-5-carboxylic acid has three-step reaction, promptly obtains 4-methylthiazol-5-carboxylic acid through sulfo-, cyclization, hydrolysis.Present method has simple to operate, the technology simple and stable, and wastewater flow rate is few, and is environmentally friendly, advantages such as industrialization simple possible.The contriver has carried out pilot scale with present method, process stabilizing, and stable yield, total recovery reaches 75%, and purity is greater than 98%.
In addition, during thio reaction of the present invention, earlier methane amide is dissolved in the solvent, described solvent is ether or tetrahydrofuran (THF) or sherwood oil or Skellysolve A or normal hexane or hexanaphthene or chloroform or benzene or toluene or ethyl acetate or ethyl formate; Described methane amide molten with mol ratio solvent be 1: 10～50.
The thio reaction temperature is-10～70 ℃, and the mol ratio of described methane amide and thiophosphoric anhydride is 1: 0.2～1.
Preferred thio reaction temperature is 30～55 ℃.
Thio reaction is warming up to 10～90 ℃ after finishing, and adds chloro ethyl acetoacetate again, the reaction back that finishes adds the shrend reaction of going out, separatory then, and water is used above-mentioned solvent extraction once again, merge organic phase, steaming desolventizes, and obtains 4-methylthiazol-5-formic acid ethyl ester crude product.Preferred cyclization temperature of reaction is 75～80 ℃.
The mol ratio of described methane amide and chloro ethyl acetoacetate is 1: 0.5～1.5.
When the organic phase temperature was 40～100 ℃, the adding volumetric molar concentration was 5%～40% sodium hydroxide solution, and insulated and stirred to hydrolysis reaction finishes; The mol ratio of described methane amide and sodium hydroxide is 1: 1～2.5.Preferred hydrolysising reacting temperature is 85～90 ℃.
Add gac in hydrolysis reactant, after the filtration, it is 5%-35% hydrochloric acid that filtrate adds volumetric molar concentration, regulates pH value to 1～5, filters the 4-methylthiazol-5-carboxylic acid of separating out; The mol ratio of described methane amide and hydrochloric acid is 1: 1～2.5.
Embodiment
Embodiment one
1 mole of methane amide is dissolved in the ether or the sherwood oil of 20 times of amounts, controlled temperature at-10 ℃ under 35 ℃, the thiophosphoric anhydride that progressively adds 0.2 mole, after reaction finishes, temperature is controlled at 10～35 ℃, add 1 mole of chloro ethyl acetoacetate, reaction shrend that the back the adds 5 times of amounts reaction of going out that finishes, separatory, water are used above-mentioned solvent extraction once again, merge organic phase, steaming desolventizes, obtain 4-methylthiazol-5-formic acid ethyl ester crude product, being controlled at 85～90 ℃, to add volumetric molar concentrations be 150 milliliters of 40% sodium hydroxide solutions, continues to be stirred to react completely under this temperature.Add gac 10 grams, filter, filtrate adding volumetric molar concentration is 10% hydrochloric acid, regulates pH to 3.The product that filtration is separated out, H
1NMR (CDCl
3): (CH
3, s, 2.644 .COOH, s, 13.33 .CH, s, 9.13), purity 98.6%; Yield 72%.
Embodiment two
1 mole of methane amide is dissolved in the tetrahydrofuran (THF) or Skellysolve A or normal hexane of 15 times of amounts, controlled temperature progressively adds 0.5 mole thiophosphoric anhydride under 25 ℃ to 50 ℃, after reaction finishes, temperature is controlled at 60～75 ℃, add 0.8 mole of chloro ethyl acetoacetate, reaction shrend that the back the adds 10 times of amounts reaction of going out that finishes, add the ethyl acetate separatory, water again with ethyl acetate extraction once, merge organic phase, steaming desolventizes, and obtains 4-methylthiazol-5-formic acid ethyl ester crude product, being controlled at 40～100 ℃ of adding volumetric molar concentrations is 250 milliliters of 20% sodium hydroxide solutions, continues to be stirred to react completely under this temperature.Add gac, filter, it is 5%～35% hydrochloric acid that filtrate adds volumetric molar concentration, regulates pH to 3.The product that filtration is separated out, purity〉98.5%; H
1NMR (CDCl
3): (CH
3, s, 2.644 .COOH, s, 13.33 .CH, s, 9.13), yield 71%.
Embodiment three
1 mole of methane amide is dissolved in the ethyl acetate or hexanaphthene or chloroform of 10 times of amounts, controlled temperature progressively adds 1 mole thiophosphoric anhydride under 25 ℃ to 50 ℃, after reaction finishes, temperature is controlled at 60～75 ℃, add 1.5 moles of chloro ethyl acetoacetates, reaction shrend that the back the adds 5 times of amounts reaction of going out that finishes, separatory, water again with ethyl acetate extraction once, merge organic phase, steaming desolventizes, and obtains 4-methylthiazol-5-formic acid ethyl ester crude product, being controlled at 40～100 ℃ of adding volumetric molar concentrations is 0.5 liter of 10% sodium hydroxide solution, continues to be stirred to react completely under this temperature.Add gac 10 grams, filter, it is 5% hydrochloric acid that filtrate adds volumetric molar concentration, regulates pH to 1.The product that filtration is separated out, purity 98.2%; H
1NMR (CDCl
3): (CH
3, s, 2.644 .COOH, s, 13.33 .CH, s, 9.13), yield 65%.
Embodiment four
1 mole of methane amide is dissolved in the ethyl acetate or ethyl formate or benzene or toluene of 50 times of amounts, controlled temperature progressively adds 0.2 mole thiophosphoric anhydride under 30 ℃ to 55 ℃, after reaction finishes, temperature is controlled at 75～80 ℃, add 0.5 mole of chloro ethyl acetoacetate, reaction shrend that the back the adds 10 times of amounts reaction of going out that finishes, separatory, water again with ethyl acetate extraction once, merge organic phase, steaming desolventizes, and obtains 4-methylthiazol-5-formic acid ethyl ester crude product, being controlled at 85～90 ℃ of adding volumetric molar concentrations is 0.5 liter of 15% sodium hydroxide solution, continues to be stirred to react completely under this temperature.Add gac 10 grams, filter, it is 15% hydrochloric acid that filtrate adds volumetric molar concentration, regulates pH to 5.The product that filtration is separated out, purity 99.1%; H
1NMR (CDCl
3): (CH
3, s, 2.644 .COOH, s, 13.33 .CH, s, 9.13), yield 76%.
Claims (10)
1, a kind of preparation method of 4-methylthiazol-5-carboxylic acid is characterized in that earlier methane amide and thiophosphoric anhydride being mixed in solvent carrying out thio reaction; Add chloro ethyl acetoacetate again and carry out cyclization reaction, get organic phase and add the sodium hydroxide solution reaction that is hydrolyzed, the product of separating out is got in filtration, is 4-methylthiazol-5-carboxylic acid.
2, according to a kind of preparation method of the described 4-methylthiazol of claim 1-5-carboxylic acid, when it is characterized in that thio reaction, earlier methane amide is dissolved in the solvent, described solvent is ether or tetrahydrofuran (THF) or sherwood oil or Skellysolve A or normal hexane or hexanaphthene or chloroform or benzene or toluene or ethyl acetate or ethyl formate; Described methane amide molten with mol ratio solvent be 1: 10～50.
3, according to a kind of preparation method of the described 4-methylthiazol of claim 2-5-carboxylic acid, it is characterized in that the thio reaction temperature is-10～70 ℃, the mol ratio of described methane amide and thiophosphoric anhydride is 1: 0.2～1.
4,, it is characterized in that the thio reaction temperature is 30～55 ℃ according to a kind of preparation method of the described 4-methylthiazol of claim 3-5-carboxylic acid.
5, according to a kind of preparation method of the described 4-methylthiazol of claim 1-5-carboxylic acid, after it is characterized in that thio reaction finishes, be warming up to 10～90 ℃, add chloro ethyl acetoacetate again, the reaction back that finishes adds shrend go out reaction, separatory then, water is used above-mentioned solvent extraction once again, merge organic phase, steaming desolventizes, and obtains 4-methylthiazol-5-formic acid ethyl ester crude product.
6,, it is characterized in that the cyclization temperature of reaction is 75～80 ℃ according to a kind of preparation method of the described 4-methylthiazol of claim 5-5-carboxylic acid.
7, according to a kind of preparation method of claim 1 or 6 described 4-methylthiazol-5-carboxylic acids, the mol ratio that it is characterized in that described methane amide and chloro ethyl acetoacetate is 1: 0.5～1.5.
According to a kind of preparation method of the described 4-methylthiazol of claim 1-5-carboxylic acid, it is characterized in that when the organic phase temperature is 40～100 ℃ that 8, the adding volumetric molar concentration is 5%～40% sodium hydroxide solution, insulated and stirred to hydrolysis reaction finishes; The mol ratio of described methane amide and sodium hydroxide is 1: 1～2.5.
9,, it is characterized in that hydrolysising reacting temperature is 85～90 ℃ according to a kind of preparation method of the described 4-methylthiazol of claim 1-5-carboxylic acid.
10, according to a kind of preparation method of the described 4-methylthiazol of claim 1-5-carboxylic acid, it is characterized in that adding gac in hydrolysis reactant, after the filtration, it is 5%-35% hydrochloric acid that filtrate adds volumetric molar concentration, regulate pH value to 1～5, filter the 4-methylthiazol-5-carboxylic acid of separating out; The mol ratio of described methane amide and hydrochloric acid is 1: 1～2.5.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009100255226A CN101475541B (en) | 2009-02-09 | 2009-02-09 | Preparation of 4-methyl thiazole-5-carboxyl acid |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009100255226A CN101475541B (en) | 2009-02-09 | 2009-02-09 | Preparation of 4-methyl thiazole-5-carboxyl acid |
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| Publication Number | Publication Date |
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| CN101475541A true CN101475541A (en) | 2009-07-08 |
| CN101475541B CN101475541B (en) | 2011-05-25 |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105130924A (en) * | 2015-07-22 | 2015-12-09 | 蚌埠中实化学技术有限公司 | Preparation method of 4-methylthiazole-5-ethyl formate |
| CN115925649A (en) * | 2022-10-09 | 2023-04-07 | 深圳市茵诺圣生物科技有限公司 | Method for preparing 4-methylthiazole-5-formaldehyde by continuous flow |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2073981C (en) * | 1990-11-30 | 2002-01-08 | Shiro Kondo | 2-arylthiazole derivatives and pharmaceutical composition thereof |
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2009
- 2009-02-09 CN CN2009100255226A patent/CN101475541B/en not_active Expired - Fee Related
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105130924A (en) * | 2015-07-22 | 2015-12-09 | 蚌埠中实化学技术有限公司 | Preparation method of 4-methylthiazole-5-ethyl formate |
| CN105130924B (en) * | 2015-07-22 | 2017-03-15 | 蚌埠中实化学技术有限公司 | A kind of method for preparing 4 methylthiazol, 5 Ethyl formate |
| CN115925649A (en) * | 2022-10-09 | 2023-04-07 | 深圳市茵诺圣生物科技有限公司 | Method for preparing 4-methylthiazole-5-formaldehyde by continuous flow |
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| Publication number | Publication date |
|---|---|
| CN101475541B (en) | 2011-05-25 |
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