CN1749232A - Process for preparing 2,4,5-triflorophenylacetic acid - Google Patents
Process for preparing 2,4,5-triflorophenylacetic acid Download PDFInfo
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- CN1749232A CN1749232A CN 200510030162 CN200510030162A CN1749232A CN 1749232 A CN1749232 A CN 1749232A CN 200510030162 CN200510030162 CN 200510030162 CN 200510030162 A CN200510030162 A CN 200510030162A CN 1749232 A CN1749232 A CN 1749232A
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Abstract
The present invention relates to medicine intermediate, and is especially the preparation process of 2, 4, 5-trifluorophenylacetic acid. The preparation process includes the reaction of 1, 2, 4-trifluoro benzene, polyformaldehyde and chloridizing agent to obtain 2, 4, 5-trifluorobenzyl chloride; the subsequent cyanidation reaction in solvent to obtain 2, 4, 5-trifluorobenzyl cyanide; reflux hydrolysis in acid or alkali condition to obtain coarse 2, 4, 5-trifluorophenylacetic acid product; and re-crystallization to obtain 2, 4, 5-trifluorophenylacetic acid product with 2, 4, 5-trifluorophenylacetic acid content over 99.9 %. The preparation process of 2, 4, 5-trifluorophenylacetic acid has short synthesis path, mild reaction condition, easy industrial production application, high product purity and stable product quality, and the product is suitable for use as medicine intermediate.
Description
Technical field
The present invention relates to 2,4, preparation method's technical field of 5-trifluoro benzene acetic acid.
Background technology
2,4, the 5-trifluoro benzene acetic acid is a kind of synthetic important intermediate that is used for the treatment of the new drug of diabetes.United States Patent (USP) 6,395, reported in 921 with diester malonate under the alkali effect and the bromobenzene reaction after decarboxylation obtains toluylic acid after the hydrolysis, but this method is not suitable for suitability for industrialized production.United States Patent (USP) 6,870 has reported that with 2,4 the 5-trifluorobromobenzene is made Grignard reagent and bromine ethylene reaction, obtains 2,4 with the oxygenant oxidation again, the 5-trifluoro benzene acetic acid in 067.The raw material major part of using in this method is somewhat expensive, oxygenant sodium periodate particularly, catalyzer ruthenium trichloride etc.And because the chemical structure of raw material, 2,4, the Grignard reagent instability that the 5-trifluorobromobenzene is made, impurity is difficult to control in the product, finally influences quality product.
Summary of the invention
The objective of the invention is to overcome the defective of prior art, provide that a kind of technical process is simple, reaction conditions is gentle, the place, back buries easy and product purity is high, cost is low 2,4, the preparation method of 5-trifluoro benzene acetic acid.
Among the present invention 2,4, the preparation of 5-trifluoro benzene acetic acid realizes by following synthetic route:
Concrete steps are:
(1) 1,2, add chlorizating agent in 4-trifluoro-benzene and the Paraformaldehyde 96 and carry out chloromethylation, obtain 2,4,5-trifluoro benzyl chlorine;
(2) add 2,4 in the organic solvent of cyanating reagent, 5-trifluoro benzyl chlorine carries out cyanogenation, obtains 2,4,5-trifluoro benzyl cyanogen;
(3) with 2,4,5-trifluoro benzyl cyanogen heating hydrolysis in acidity or alkaline aqueous solution, reaction finishes, and obtains product through aftertreatment.
Chlorizating agent described in the step of the present invention (1) is the mixture etc. of mixture, phosphorus trichloride and hydrochloric acid, sulfuric acid, phosphoric acid or the acetic acid of chlorsulfonic acid, zinc chloride and hydrochloric acid, sulfuric acid, phosphoric acid or acetic acid, is preferably chlorsulfonic acid.1,2, the mol ratio of 4-trifluoro-benzene and chlorizating agent is preferably 1: (0.5～1.5), best is 1: (0.6～0.8).Temperature of reaction is not had strict restriction, and normal temperature reaction down gets final product.At-20～100 ℃ all is feasible, is preferably 15～30 ℃.
Organic solvent described in the step of the present invention (2) is ethanol, acetonitrile, sherwood oil, toluene, benzene, ethyl acetate, DMF or N-Methyl pyrrolidone etc., is preferably acetonitrile.For fast reaction speed, can add an amount of water and phase-transfer catalyst, the add-on of water is preferably 1/ (1～9) of organic solvent volume, and phase-transfer catalyst is preferably tetramethyl ammonium chloride or Tetrabutyl amonium bromide.Cyanidization agent used in the cyanogenation can be sodium cyanide, and potassium cyanide or cuprous cyanide etc. are preferably sodium cyanide; Temperature of reaction can be controlled in 20～100 ℃, is preferably 50～90 ℃.
Step of the present invention (3) can hydrolysis under acid or alkaline condition, and acidic conditions is meant under conditions such as hydrochloric acid, acetic acid or sulfuric acid and reacts that its concentration of aqueous solution can be 5～70%, is preferably 30～50%; Temperature of reaction is 50～150 ℃, is preferably 90～110 ℃; Alkaline condition is meant under sodium hydroxide or potassium hydroxide aqueous solution condition and reacts that its concentration of aqueous solution is 2～50%, is preferably 10～20%; Temperature of reaction is 30～110 ℃, is preferably 80～100 ℃.
The present invention 2,4, and the preparation method of 5-trifluoro benzene acetic acid is with 1,2,4-trifluoro-benzene and Paraformaldehyde 96 and chlorination reaction, the crude product that obtains by distillation, obtain 2 again, 4,5-trifluoro benzyl chlorine in solvent and phase-transfer catalyst, carries out cyanogenation again, it is refining by distillation to obtain crude product, obtains 2,4,5-trifluoro benzyl cyanogen, hydrolysis under acid or alkaline condition obtains 2,4, the crude product of 5-trifluoro benzene acetic acid, by recrystallization, obtain 2,4,5-trifluoro benzene acetic acid content 〉=99.9%.
Beneficial effect of the present invention: the present invention 2,4, the preparation method of 5-trifluoro benzene acetic acid, and raw materials cost is low, mild condition, aftertreatment is simple, easily realizes industrialization, and the product purity height, steady quality meets the service requirements as pharmaceutical intermediate fully, is suitable for large-scale commercial production.
Embodiment
Following type reaction is used for illustrating the present invention, within the technical scheme that those skilled in that art all belong to the present invention to the simple replacement done of invention or improvement etc. and protected.
Embodiment 1:2,4, the preparation of 5-trifluoro benzyl chlorine
In the four-hole reaction flask of 250ml, add 1,2,4-trifluoro-benzene 84 grams (0.64mol), Paraformaldehyde 96 24 grams (0.8mol) at room temperature drip chlorsulfonic acid 52 grams (0.45mol), drip back insulation 1～2 hour, to going into hydrolysis in the frozen water, tell organic layer, be washed to neutrality, carry out underpressure distillation after the drying, obtain 2,4,5-trifluoro benzyl chlorine 75 grams, content 99.3%, yield 65%.
Embodiment 2:2,4, the preparation of 5-trifluoro benzyl chlorine
Press embodiment 1, replace chlorsulfonic acid, obtain 2,4,5-trifluoro benzyl chlorine 60 grams, content 97%, yield 52% with 100ml acetic acid and 77 gram phosphorus trichlorides.
Embodiment 3:2,4, the preparation of 5-trifluoro benzyl chlorine
Press embodiment 1, with 100ml hydrochloric acid and 50gZnCl
2Replace chlorsulfonic acid, 50 ℃ of temperature of reaction obtain 2,4,5-trifluoro benzyl chlorine 65 grams, content 96.8%, yield 56%.
Embodiment 4:2,4, the preparation of 5-trifluoro benzyl cyanogen
In 500ml four-hole reaction flask, add sodium cyanide 25.5 grams (0.52mol), water 25.5ml, it is molten substantially entirely to be warming up to sodium cyanide, add 2.2 gram tetramethyl ammonium chloride and 100ml ethanol, about 80 ℃, drip 2,4,5-trifluoro benzyl chlorine drips off back insulation 1～2 hour, and reaction is after suction filtration, tell organic layer behind the filtrate precipitation, carry out rectification under vacuum again, obtain 2,4,5-trifluoro benzyl cyanogen 47 grams, content 99.8%, yield 66%.
Embodiment 5:2,4, the preparation of 5-trifluoro benzyl cyanogen
Press embodiment 4, not with phase-transfer catalyst, obtain 2,4 in the reaction, 5-trifluoro benzyl cyanogen 35 grams, content 99%, yield 49%.
Embodiment 6:2,4, the preparation of 5-trifluoro benzyl cyanogen
Press embodiment 4, replace sodium cyanide, replace the second alcohol and water, obtain 2,4,5-trifluoro benzyl cyanogen 40 grams, content 98.5%, yield 56% with the 100mlN-methyl-2-pyrrolidone with 47 gram cuprous cyanides.
Embodiment 7:2,4, the preparation of 5-trifluoro benzene acetic acid
In 200ml four-hole reaction flask, add 2,4,5-trifluoro benzyl cyanogen 47 grams (0.275mol), 120ml hydrochloric acid and 34ml acetic acid, back flow reaction 3 hours, to going into hydrolysis in the frozen water, suction filtration gets filter cake, gets 2 after the oven dry, 4,5-trifluoro benzene acetic acid 52 grams, content 99%, yield 99.5%.
Embodiment 8:2,4, the preparation of 5-trifluoro benzene acetic acid
Press embodiment 7, replace hydrochloric acid and acetic acid with 10% sodium hydroxide solution 250ml, 90 ℃ of reactions after 3 hours acidifying obtain 2,4,5-trifluoro benzene acetic acid 48 grams, content 98.7%, yield 91%.
Claims (14)
1.2,4, the preparation method of 5-trifluoro benzene acetic acid is characterized in that, realizes by following synthetic route:
Concrete steps are:
(1), adds chlorizating agent in 4-trifluoro-benzene and the Paraformaldehyde 96 and carry out chloromethylation and obtain 2,4,5-trifluoro benzyl chlorine 1,2;
(2) add 2,4 in the machine solvent of cyanating reagent, 5-trifluoro benzyl chlorine carries out cyanogenation, obtains 2,4,5-trifluoro benzyl cyanogen;
(3) with 2,4,5-trifluoro benzyl cyanogen heating hydrolysis in acidity or alkaline aqueous solution, reaction finishes, and obtains product through aftertreatment.
2. as claimed in claim 12,4, the preparation method of 5-trifluoro benzene acetic acid, it is characterized in that, chlorizating agent described in the step (1) is a chlorsulfonic acid, the mixture of zinc chloride and hydrochloric acid, sulfuric acid, phosphoric acid or acetic acid, the mixture of phosphorus trichloride and hydrochloric acid, sulfuric acid, phosphoric acid or acetic acid.
3. as claimed in claim 22,4, the preparation method of 5-trifluoro benzene acetic acid is characterized in that the chlorizating agent described in the step (1) is a chlorsulfonic acid.
4. as claimed in claim 12,4, the preparation method of 5-trifluoro benzene acetic acid is characterized in that the temperature of reaction of step (1) is-20～100 ℃.
5. as claimed in claim 42,4, the preparation method of 5-trifluoro benzene acetic acid, the temperature of reaction that it is characterized in that step (1) is 15～30 ℃.
6. as claimed in claim 12,4, the preparation method of 5-trifluoro benzene acetic acid is characterized in that 1,2 described in the step (1), and the mol ratio of 4-trifluoro-benzene and chlorizating agent is 1: (0.5～1.5).
7. as claimed in claim 62,4, the preparation method of 5-trifluoro benzene acetic acid is characterized in that 1,2 described in the step (1), and the mol ratio of 4-trifluoro-benzene and chlorizating agent is 1: (0.6～0.8).
8. as claimed in claim 12,4, the preparation method of 5-trifluoro benzene acetic acid is characterized in that the used cyanidization agent of step (2) is sodium cyanide, potassium cyanide or cuprous cyanide.
9. as claimed in claim 12,4, the preparation method of 5-trifluoro benzene acetic acid is characterized in that the cyanogenation of step (2) also adds phase-transfer catalyst.
10. as claimed in claim 92,4, the preparation method of 5-trifluoro benzene acetic acid is characterized in that the used phase-transfer catalyst of step (2) is tetramethyl ammonium chloride or Tetrabutyl amonium bromide.
11. as claimed in claim 12,4, the preparation method of 5-trifluoro benzene acetic acid is characterized in that the organic solvent described in the step (2) is ethanol, acetonitrile, sherwood oil, toluene, benzene, ethyl acetate, DMF or N-Methyl pyrrolidone.
12. as claimed in claim 11 2,4, the preparation method of 5-trifluoro benzene acetic acid is characterized in that the organic solvent described in the step (2) is an acetonitrile.
13. as claimed in claim 12,4, the preparation method of 5-trifluoro benzene acetic acid, the temperature of reaction that it is characterized in that step (2) is at 20～100 ℃.
14. as claimed in claim 15 2,4, the preparation method of 5-trifluoro benzene acetic acid, the temperature of reaction that it is characterized in that step (2) is 50～90 ℃.
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| CN101244994A (en) * | 2007-02-14 | 2008-08-20 | 常州亚邦制药有限公司 | Novel method for preparing 2,4, 5-trifluoro-phenylacetic acid |
| CN101659611B (en) * | 2009-09-28 | 2011-04-06 | 浙江永太科技股份有限公司 | Method for preparing 2, 4, 5-trifluoro-phenylacetic-acid |
| CN101665407B (en) * | 2009-09-28 | 2011-04-20 | 浙江永太科技股份有限公司 | Preparation method of 2,4,5-trifluorobenzyl chloride |
| CN101659630B (en) * | 2009-09-28 | 2011-05-18 | 浙江永太科技股份有限公司 | Method for preparing 2, 4, 5-trifluoro-phenylacetonitrile |
| CN101367721B (en) * | 2008-09-28 | 2011-07-20 | 浙江大学 | Method for preparing benzene acetic acid with phenylacetonitrile hydrolyzation in ammonia-containing high temperature liquid water medium |
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| US20040068141A1 (en) * | 2002-10-08 | 2004-04-08 | Armstrong Joseph D. | Process for the synthesis of trifluorophenylacetic acids |
| US6870067B2 (en) * | 2002-10-08 | 2005-03-22 | Merck & Co., Inc. | Process for the synthesis of trifluorophenylacetic acids |
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