CN100516014C - Method for preparing 2,4,5 trifluorobenzene acetic acid - Google Patents
Method for preparing 2,4,5 trifluorobenzene acetic acid Download PDFInfo
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- CN100516014C CN100516014C CNB2007100678344A CN200710067834A CN100516014C CN 100516014 C CN100516014 C CN 100516014C CN B2007100678344 A CNB2007100678344 A CN B2007100678344A CN 200710067834 A CN200710067834 A CN 200710067834A CN 100516014 C CN100516014 C CN 100516014C
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Abstract
This invention provides a method for preparing 2, 4, 5-trifluorophenylacetic acid. The method comprises: (1) reacting 1,2,4-trifluorobenzene and chlorinating agent in paraformaldehyde to obtain 2,4,5-trifluorobenzyl chloride; (2) performing carbonylation reaction with CO in the presence of catalyst to obtain 2,4,5-trifluorophenylacetic acid. The catalyst is alkali cobalt tetracarbonyl. The method has such advantages as few reaction procedures, and mild reaction conditions, and is suitable for industrial production of 2, 4, 5-trifluorophenylacetic acid.
Description
Technical field
The present invention relates to 2,4,5-trifluoro benzene acetic acid preparation method.
Background technology
The medicine of dipeptidyl peptidase-IV (DP-IV or DPP-IV) enzyme inhibitors is to be used for the treatment of diabetes, especially non-insulin-depending type (II type) diabetes.And 2,4, the 5-trifluoro benzene acetic acid is the important intermediate of synthesizing new drugs such as dipeptidyl peptidase-IV enzyme inhibitors.U.S. Patent application US 2004,068,141 has adopted trifluorobromobenzene to carry out condensation through cuprous chloride catalysis and diester malonate under alkaline condition, obtain trifluoro benzene acetic acid with posthydrolysis, but this method is not suitable for suitability for industrialized production.U.S. Pat 6,870 has reported that trifluorobromobenzene carries out condensation with allyl bromide 98 after changing into Grignard reagent in 067, obtains trifluoro benzene acetic acid through catalyzed oxidation again, the Grignard reagent instability in this method, and used catalyzer and oxygenant are all expensive.Earlier trifluoro-benzene is carried out chloromethylation among the Chinese patent CN1749232A, again through cyaniding, last hydrolysis obtains trifluoro benzene acetic acid, and this method steps is long, and yield is low, pollute greatly, and there is serious potential safety hazard in the highly toxic substance sodium cyanide that is adopted.
Summary of the invention
Technical problem to be solved by this invention provides that a kind of technology is simple, cost is low, is easy to 2,4 of industrialization safety in production, the preparation method of 5-trifluoro benzene acetic acid.For this reason, the present invention is by the following technical solutions: it may further comprise the steps successively:
(1), 1,2, the 4-trifluoro-benzene carries out chloromethylation with chlorizating agent in Paraformaldehyde 96, obtain 2,4,5-trifluoro benzyl chlorine;
(2) 2,4,5-trifluoro benzyl chlorine and carbon monoxide carry out carbonylation reaction under the effect of catalyzer, obtain 2,4, and 5-trifluoro benzene acetic acid, described catalyzer are cobalt tetracarbonyl salt.
Trifluoro benzene acetic acid preparation method provided by the present invention, reactions steps is few, reagent is cheap, reaction conditions is gentle, has avoided major safety risks etc., for the suitability for industrialized production of trifluoro benzene acetic acid provides favourable condition.
In the present invention, described chlorizating agent be a kind of in zinc chloride, sulfur oxychloride, phosphorus trichloride, the chlorsulfonic acid and with the mixture of mineral acid or acetic acid, the purpose of described mixture generates hydrogenchloride for reaction, and their blending ratio is calculated according to the reaction equation that it generates hydrogenchloride.Wherein, chlorizating agent serves as preferred with the mixture of zinc chloride and hydrochloric acid.
Described step (1) is at room temperature reacted, and its reaction yield is the highest, and under liquid condition, its reaction also can both be carried out.
Described step (2) is reacted at 15～50 ℃, and its reaction yield is the highest, and under liquid condition, its reaction also can both be carried out.
Cobalt tetracarbonyl salt and 2,4 in the described step (2), the mol ratio of 5-trifluoro benzyl chlorine is 1: 20～100, wherein, serves as preferred with mol ratio 1: 50～70 again.
Embodiment
(1), 2,4, the preparation of 5-trifluoro benzyl chlorine
120mL hydrochloric acid, 70 gram zinc chloride and 31.2 gram Paraformaldehyde 96s (1.04mol) are joined in the there-necked flask, add 1,2 under the stirring at room, 4-trifluoro-benzene 106 grams (0.8mol), reaction insulation 5 hours, tell organic phase, be washed to neutrality, underpressure distillation gets 2,4,5-trifluoro benzyl chlorine 98.5 grams, content 99%, yield 68%.
Reaction equation is:
(2), 2,4, the preparation of 5-trifluoro benzene acetic acid
The methanol solution 35mL of cobalt tetracarbonyl sodium (8.8mmol) is joined in the reactor that fills 150mL methyl alcohol, sealed reactor also charges into CO gas, pumps into 100 gram (0.55mol) 2,4 when being warming up to 40 ℃, the sodium hydroxide solution of 5-trifluoro benzyl chlorine and 120 grams 40%, reaction insulation 2 hours.Add water 300mL, methyl alcohol is reclaimed in distillation, transfers pH 2～3 with 20% hydrochloric acid, transfers pH 10 with 25% sodium hydrogen carbonate solution again, filter, and the filtrate acidifying, filtration drying obtains 2,4,5-trifluoro benzene acetic acid 93.7 grams, yield 89%, purity 99%, 120～121 ℃ of fusing points.
The solvent of this step also can adopt ethanol, acetonitrile, 1,4-dioxane, tetrahydrofuran (THF), benzene, toluene, methylene dichloride, chloroform, ethyl acetate, DMF, N-Methyl pyrrolidone etc. except that methyl alcohol.Usually be good to adopt methyl alcohol.
Reaction equation is:
Claims (4)
1,2,4, the preparation method of 5-trifluoro benzene acetic acid is characterized in that it may further comprise the steps successively:
(1), 1,2, the 4-trifluoro-benzene carries out chloromethylation with chlorizating agent in Paraformaldehyde 96, obtain 2,4,5-trifluoro benzyl chlorine, described chlorizating agent is the mixture of zinc chloride and hydrochloric acid;
(2) 2,4,5-trifluoro benzyl chlorine and carbon monoxide carry out carbonylation reaction under the effect of catalyzer, obtain 2,4, and 5-trifluoro benzene acetic acid, described catalyzer are cobalt tetracarbonyl salt.
2, as claimed in claim 12,4, the preparation method of 5-trifluoro benzene acetic acid is characterized in that described step (1) at room temperature reacts.
3, as claimed in claim 12,4, the preparation method of 5-trifluoro benzene acetic acid is characterized in that described step (2) reacts under 15～50 ℃.
4, as claimed in claim 12,4, the preparation method of 5-trifluoro benzene acetic acid is characterized in that cobalt tetracarbonyl salt and 2,4 in the described step (2), and the mol ratio of 5-trifluoro benzyl chlorine is 1: 20～100.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2007100678344A CN100516014C (en) | 2007-04-04 | 2007-04-04 | Method for preparing 2,4,5 trifluorobenzene acetic acid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2007100678344A CN100516014C (en) | 2007-04-04 | 2007-04-04 | Method for preparing 2,4,5 trifluorobenzene acetic acid |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101092345A CN101092345A (en) | 2007-12-26 |
| CN100516014C true CN100516014C (en) | 2009-07-22 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2007100678344A Active CN100516014C (en) | 2007-04-04 | 2007-04-04 | Method for preparing 2,4,5 trifluorobenzene acetic acid |
Country Status (1)
| Country | Link |
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| CN (1) | CN100516014C (en) |
Families Citing this family (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NZ608028A (en) * | 2009-03-30 | 2014-09-26 | Dong A Pharm Co Ltd | Improved method for preparing dipeptidyl peptidase-iv inhibitor and intermediate |
| 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 |
| CN102140062B (en) | 2011-03-13 | 2012-11-14 | 联化科技股份有限公司 | Method for preparing 2,5-dimethyl phenylacetic acid |
| CN105017026B (en) * | 2015-07-02 | 2017-10-10 | 南京杰运医药科技有限公司 | The synthetic method of 2,4 difluoro benzene methanamines |
| CN106496013A (en) * | 2016-09-08 | 2017-03-15 | 上海引盛生物科技有限公司 | A kind of preparation method of phenylacetic acid class compound |
| ES2733477T3 (en) | 2017-07-04 | 2019-11-29 | Fis Fabbrica Italiana Sintetici Spa | Effective procedure for the preparation of sitagliptin through a very effective preparation of the intermediate 2,4,5-trifluorophenylacetic acid |
| EP3524605B1 (en) | 2018-02-13 | 2019-11-27 | F.I.S.- Fabbrica Italiana Sintetici S.p.A. | New efficient process for the preparation of sitagliptin |
| CN110128258B (en) * | 2019-04-24 | 2022-04-01 | 深圳市第二人民医院 | Synthetic method of sitagliptin intermediate 2,4, 5-trifluorophenylacetic acid |
| CN114591141A (en) * | 2022-04-08 | 2022-06-07 | 浙江永太科技股份有限公司 | Preparation method of 2,4, 5-trifluorobenzyl bromide |
| CN115246762A (en) * | 2022-08-25 | 2022-10-28 | 上海朴颐化学科技有限公司 | Preparation method of 2,4,5-trifluorophenylacetic acid |
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2007
- 2007-04-04 CN CNB2007100678344A patent/CN100516014C/en active Active
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| Publication number | Publication date |
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| CN101092345A (en) | 2007-12-26 |
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