CN102584565A - Preparation method for 2,4,5-trifluoro benzene acetic acid - Google Patents
Preparation method for 2,4,5-trifluoro benzene acetic acid Download PDFInfo
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- CN102584565A CN102584565A CN2012100263281A CN201210026328A CN102584565A CN 102584565 A CN102584565 A CN 102584565A CN 2012100263281 A CN2012100263281 A CN 2012100263281A CN 201210026328 A CN201210026328 A CN 201210026328A CN 102584565 A CN102584565 A CN 102584565A
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Abstract
The invention discloses a preparation method for 2,4,5-trifluoro benzene acetic acid, which belongs to the field of organic chemical synthesis and comprises the steps of (1) dissolving 1,2,4-trifluoro benzene acetic acid in a solvent, and then performing fourier alkylate reaction with chloroacetonitrile under the catalysis of lewis acid to obtain 2,4,5-trifluoro benzene acetonitrile; (2) enabling the 2,4,5-trifluoro benzene acetonitrile to perform hydrolysis reaction with acid, cooling and crystallizing to achieve the 2,4,5-trifluoro benzene acetic acid. The preparation method doesn't use toxic cyanide and avoids using a lot of concentrated sulfuric acid, thereby having the advantages of being low in pollution, short in line, capable of reducing equipment investment, low in cost, high in yield and the like.
Description
Technical field
The present invention relates to the synthetic field of organic chemistry, relate in particular to a kind of 2,4, the preparation method of 5-trifluoro benzene acetic acid.
Background technology
Sitagliptin phosphate is a kind of novel antidiabetic drug dipeptidyl peptidase-4 (DPP-4) suppressor factor, can improve the ability that human body self reduces too high blood glucose level.Sitagliptin phosphate (
) English name: Sitagliptin phosphate monohydrate, chemical name: 7-[(3R)-and 3-amino-1-oxo-4-(2,4, the 5-trifluorophenyl) butyl]-5; 6,7,8-tetrahydrochysene-3-Trifluoromethyl-1,2; 4-triazolo [4,3-a] pyrazine phosphoric acid salt, molecular formula is C
16H
15F
6N
5O H
3PO
4, on October 17th, 2006, Merck & Co., Inc. announced FDA's approved sitagliptin phosphate (Sitagliptin phosphata).This medicine becomes only up to now dipeptidyl peptidase-4 (DDP-4) the suppressor factor class medicine that is used to treat diabetes B of American market.
The sitagliptin of bibliographical information synthetic all is key intermediate 2,4, and 5-trifluoro benzene acetic acid (II) raw material is synthetic through long route, therefore how can the advantages of simplicity and high efficiency Synthetic 2, and 4, the 5-trifluoro benzene acetic acid is just very crucial.
The synthetic route of the trifluoro benzene acetic acid of reporting in the document probably has following several kinds, but be aimed at suitability for industrialized production part not fully up to expectations is arranged all.
Route 1:
This route is with 2,4, and the 5-trifluorobromobenzene is a starting raw material, reacts under strong alkaline condition with diethyl oxalate, and right hydrolysis obtains product, and this route is had relatively high expectations to reaction conditions, is inappropriate for suitability for industrialized production.
Route 2:
This route is equally with 2,4, and the 5-trifluorobromobenzene is a starting raw material, generates grignard reagent earlier, replaces with allyl bromide 98 then, and oxidation obtains trifluoro benzene acetic acid under catalyst action at last.Anhydrous the having relatively high expectations of this route using form reaction pair, and the catalyzer and the oxygenant that use cost an arm and a leg, and is not suitable for suitability for industrialized production.
Route 3:
This route uses trifluoro-benzene to be raw material, carries out acetylize earlier, Willgerodt-kindler reacted sulfo-trifluoro benzene acetic acid acid amides then, and hydrolysis obtains trifluoro benzene acetic acid then.Willgerodt-kindler reaction yield in this route is lower, and produces a large amount of stench sulfide in the reaction process, and environmental pollution is bigger, and aftertreatment is purified comparatively difficult, is difficult for realizing industriallization.
Route 4:
Route 5:
This route is starting raw material equally with the trifluoro-benzene, carries out chloromethylation equally earlier, carries out grignard reaction then, and logical carbonic acid gas finally obtains trifluoro benzene acetic acid in grignard reagent.This route on a route, the sodium cyanide of having avoided using severe toxicity of success, but shortcoming such as grignard reaction has difficult the initiation, and is wayward, the utmost point is unfavorable for industriallization.
More than comprehensive, the technology of existing production trifluoro benzene acetic acid all exists some deficiency, especially lacks the consideration to environment, therefore design a raw material be simple and easy to, simple to operate, cost is low, yield is high, and is and very necessary to the little route of environmental stress.
Summary of the invention
It is a kind of 2,4 that the present invention provides, the preparation method of 5-trifluoro benzene acetic acid, method of the present invention is not used hypertoxic prussiate, and avoids the use of a large amount of vitriol oils, have pollute low, route short, reduce facility investment, low, the yield advantages of higher of cost.
The technical scheme that the present invention taked is:
A kind of 2,4, the preparation method of 5-trifluoro benzene acetic acid,
Its preparation route is following:
The preparation method comprises the steps:
(1) with 1,2, the 4-trifluoro-benzene dissolves in solvent, under Louis acid catalysis, carries out the Fu Shi alkylated reaction with chloromethyl cyanide then, obtains 2,4,5-trifluoro-benzene acetonitrile;
(2) 2,4,5-trifluoro-benzene acetonitrile and the acid reaction that is hydrolyzed, crystallisation by cooling obtains 2,4, the 5-trifluoro benzene acetic acid.
Wherein, in the step (1) 1,2, the molar ratio of 4-trifluoro-benzene and chloromethyl cyanide is 1:1-2.5; Lewis acid is aluminum chloride, boron trifluoride, zinc chloride, iron(ic)chloride, tin tetrachloride; The Lewis acid consumption is 1,2, the 3%-30% of 4-trifluoro-benzene mole number; Reaction solvent is methylene dichloride, trichloromethane, tetracol phenixin, 1, and the 2-ethylene dichloride; Solvent load is 1,2,4-trifluoro-benzene (quality)/solvent (volume)=1:3-10; Temperature of reaction is 40-85 ℃, and the reaction times is 2-4 hour.
Used acid is one or more in concentrated hydrochloric acid, the vitriol oil, SPA and the Glacial acetic acid min. 99.5 in the step (2); Temperature of reaction is 60-150 ℃; Reaction times is 1-6 hour; 2,4,5-trifluoro-benzene acetonitrile is 2,4 with the ratio of the charging capacity of acid, 5-trifluoro-benzene acetonitrile (quality)/acid (volume)=1:1-1:10.
Optimal scheme is: in the step (1) 1,2, the ingredient proportion of 4-trifluoro-benzene and chloromethyl cyanide is 1:1.2-1.5; Lewis acid is aluminum chloride and zinc chloride; The Lewis acid consumption is 1,2,4-trifluoro-benzene mole number be 5%-10%; Said reaction solvent is methylene dichloride and trichloromethane; Solvent load is 1,2,4-trifluoro-benzene (quality)/solvent (volume)=1:4-6.
Temperature of reaction is 100-140 ℃ in the step (2); Reaction times is 3-4 hour; 2,4,5-trifluoro-benzene acetonitrile is 2,4 with the ratio of the charging capacity of acid, 5-trifluoro-benzene acetonitrile (quality)/acid (volume)=1:2-3.
Concentrated hydrochloric acid, the vitriol oil, SPA and Glacial acetic acid min. 99.5 are industrial concentrated hydrochloric acid, the vitriol oil, SPA and Glacial acetic acid min. 99.5 in the reaction, and mass concentration is respectively 37%, 98%, 85% and 99%.
Adopt the beneficial effect that technique scheme produced to be:
1. the use of having avoided hypertoxic prussiate of success, and avoided in the chloromethylation process use of a large amount of vitriol oils is polluted lowly, greatly reduces the pressure to environment.
2. compared with prior art, shortened reaction scheme, significantly reduced facility investment, reduced cost, and yield is high, is easy to realize suitability for industrialized production.
Embodiment
1-5 is 2,4 in following examples, the preparation of 5-trifluoro-benzene acetonitrile, and 6-10 is 2,4, the preparation of 5-trifluoro benzene acetic acid.
Embodiment 1
2,4, the preparation of 5-trifluoro-benzene acetonitrile
In the 1L reaction flask, add 132g1,2, the 4-trifluoro-benzene adds the dissolving of 396ml methylene dichloride, adds 8.05g iron(ic)chloride then, and the 75g chloromethyl cyanide is heated to 40 ℃, refluxes stopped reaction 4 hours.Be cooled to room temperature, filter, solvent is reclaimed in the filtrate decompression distillation, distill then 2,4,5-trifluoro-benzene acetonitrile 124g, yield 72.5%.
Embodiment 2
2,4, the preparation of 5-trifluoro-benzene acetonitrile
Add 132g 1,2 in the 1L reaction flask, the 4-trifluoro-benzene adds the dissolving of 1320ml trichloromethane, adds the 13.2g aluminum chloride then, and the 187.5g chloromethyl cyanide is heated to 60 ℃, refluxes stopped reaction 3 hours.Be cooled to room temperature, filter, solvent is reclaimed in the filtrate decompression distillation earlier, distill then 2,4,5-trifluoro-benzene acetonitrile 130g, yield 76.0%.
Embodiment 3
2,4, the preparation of 5-trifluoro-benzene acetonitrile
Add 132g 1,2 in the 1L reaction flask, the 4-trifluoro-benzene adds the dissolving of 528ml tetracol phenixin, adds the 20.4g boron trifluoride then, and the 112.5g chloromethyl cyanide is heated to 80 ℃, refluxes stopped reaction 2 hours.Be cooled to room temperature, filter, solvent is reclaimed in the filtrate decompression distillation earlier, distill then 2,4,5-trifluoro-benzene acetonitrile 132g, yield 77.2%.
Embodiment 4
2,4, the preparation of 5-trifluoro-benzene acetonitrile
Add 132g 1,2 in the 1L reaction flask, the 4-trifluoro-benzene adds 792ml 1, and the dissolving of 2-ethylene dichloride adds the 7.77g tin tetrachloride then, and the 80g chloromethyl cyanide is heated to 85 ℃, refluxes stopped reaction 2 hours.Be cooled to room temperature, filter, solvent is reclaimed in the filtrate decompression distillation earlier, distill then 2,4,5-trifluoro-benzene acetonitrile 135g, yield 78.9%.
Embodiment 5
2,4, the preparation of 5-trifluoro-benzene acetonitrile
Add 132g 1,2 in the 1L reaction flask, the 4-trifluoro-benzene adds 792ml 1, and the dissolving of 2-ethylene dichloride adds the 18g zinc chloride then, and the 150g chloromethyl cyanide is heated to 85 ℃, refluxes stopped reaction 2 hours.Be cooled to room temperature, filter, solvent is reclaimed in the filtrate decompression distillation earlier, distill then 2,4,5-trifluoro-benzene acetonitrile 133g, yield 77.8%.
Embodiment 6
2,4, the preparation of 5-trifluoro benzene acetic acid
(1) in the 1L reaction flask, add 100g trifluoro-benzene acetonitrile, add the 100ml vitriol oil, be heated to 100 ℃, and under this temperature, reacted 3 hours, reaction solution is poured in the 5L frozen water, and a large amount of white solids are separated out, and cross and filter 2,4,5-trifluoro benzene acetic acid 106, yield 95.5%.
Embodiment 7
2,4, the preparation of 5-trifluoro benzene acetic acid
In the 1L reaction flask, add 100g trifluoro-benzene acetonitrile, add the 200ml concentrated hydrochloric acid, be heated to 80 ℃, and under this temperature, reacted 4 hours, reaction solution is poured in the 5L frozen water, and a large amount of white solids are separated out, and cross and filter 2,4,5-trifluoro benzene acetic acid 100g, yield 90.1%.
Embodiment 8
2,4, the preparation of 5-trifluoro benzene acetic acid
Add 100g trifluoro-benzene acetonitrile in the 1L reaction flask, add the 250ml SPA, 50ml acetic acid is heated to 60 ℃; And under this temperature, reacted 1 hour, reaction solution is poured in the 5L frozen water, and a large amount of white solids are separated out, and cross and filter 2; 4,5-trifluoro benzene acetic acid 110g, yield 99.1%.
Embodiment 9
2,4, the preparation of 5-trifluoro benzene acetic acid
Add 100g trifluoro-benzene acetonitrile in the 1L reaction flask, add the 400ml Glacial acetic acid min. 99.5,200ml hydrochloric acid is heated to 150 ℃; And under this temperature, reacted 2 hours, reaction solution is poured in the 5L frozen water, and a large amount of white solids are separated out, and cross and filter 2; 4,5-trifluoro benzene acetic acid 103g, yield 92.8%.
Embodiment 10
2,4, the preparation of 5-trifluoro benzene acetic acid
Add 100g trifluoro-benzene acetonitrile in the 1L reaction flask, add the 700ml concentrated hydrochloric acid, 300ml acetic acid is heated to 140 ℃; And under this temperature, reacted 6 hours, reaction solution is poured in the 5L frozen water, and a large amount of white solids are separated out, and cross and filter 2; 4,5-trifluoro benzene acetic acid 105g, yield 94.6%.
Claims (5)
1. one kind 2,4, the preparation method of 5-trifluoro benzene acetic acid is characterized in that comprising the steps:
(1) with 1,2, the 4-trifluoro-benzene dissolves in solvent, under Louis acid catalysis, carries out the Fu Shi alkylated reaction with chloromethyl cyanide then, obtains 2,4,5-trifluoro-benzene acetonitrile;
(2) 2,4,5-trifluoro-benzene acetonitrile and the acid reaction that is hydrolyzed, crystallisation by cooling obtains 2,4, the 5-trifluoro benzene acetic acid.
2. according to claim 1 a kind of 2,4, the preparation method of 5-trifluoro benzene acetic acid is characterized in that described in the step (1) 1,2, and the molar ratio of 4-trifluoro-benzene and chloromethyl cyanide is 1:1-2.5; Said Lewis acid is aluminum chloride, boron trifluoride, zinc chloride, iron(ic)chloride, tin tetrachloride; Said Lewis acid consumption is 1,2, the 3%-30% of 4-trifluoro-benzene mole number; Said reaction solvent is methylene dichloride, trichloromethane, tetracol phenixin, 1, and the 2-ethylene dichloride; Solvent load is 1,2,4-trifluoro-benzene (quality)/solvent (volume)=1:3-10; Temperature of reaction is 40-85 ℃, and the reaction times is 2-4 hour.
3. according to claim 2 a kind of 2,4, the preparation method of 5-trifluoro benzene acetic acid is characterized in that saidly 1,2, and the ingredient proportion of 4-trifluoro-benzene and chloromethyl cyanide is 1:1.2-1.5; Said Lewis acid is aluminum chloride and zinc chloride; Said Lewis acid consumption is 1,2,4-trifluoro-benzene mole number be 5%-10%; Said reaction solvent is methylene dichloride and trichloromethane; Solvent load is 1,2,4-trifluoro-benzene (quality)/solvent (volume)=1:4-6.
4. according to claim 1 a kind of 2,4, the preparation method of 5-trifluoro benzene acetic acid is characterized in that acid described in the step (2) is in concentrated hydrochloric acid, the vitriol oil, SPA and the Glacial acetic acid min. 99.5 one or more; Temperature of reaction is 60-150 ℃; Reaction times is 1-6 hour; 2,4,5-trifluoro-benzene acetonitrile is 2,4 with the ratio of the charging capacity of acid, 5-trifluoro-benzene acetonitrile (quality)/acid (volume)=1:1-1:10.
5. according to claim 4 a kind of 2,4, the preparation method of 5-trifluoro benzene acetic acid is characterized in that said temperature of reaction is 100-140 ℃; Reaction times is 3-4 hour; 2,4,5-trifluoro-benzene acetonitrile is 2,4 with the ratio of the charging capacity of acid, 5-trifluoro-benzene acetonitrile (quality)/acid (volume)=1:2-3.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103232339A (en) * | 2013-04-19 | 2013-08-07 | 重庆紫光化工股份有限公司 | Preparation method of chlorinated phenylacetic acid |
| CN111393282A (en) * | 2020-05-21 | 2020-07-10 | 湖南复瑞生物医药技术有限责任公司 | Preparation method of 2,4, 5-trifluorophenylacetic acid |
| CN112457153A (en) * | 2020-11-10 | 2021-03-09 | 杭州臻挚生物科技有限公司 | Industrial preparation method of 2,4, 5-trifluoro-phenylacetic acid |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6870067B2 (en) * | 2002-10-08 | 2005-03-22 | Merck & Co., Inc. | Process for the synthesis of trifluorophenylacetic acids |
| CN101429115A (en) * | 2008-12-22 | 2009-05-13 | 浙江海翔药业股份有限公司 | Process for producing trifluoro benzene acetic acid and sitagliptin |
| CN101659611A (en) * | 2009-09-28 | 2010-03-03 | 浙江永太科技股份有限公司 | Method for preparing 2, 4, 5-trifluoro-phenylacetic-acid |
-
2012
- 2012-02-07 CN CN 201210026328 patent/CN102584565B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6870067B2 (en) * | 2002-10-08 | 2005-03-22 | Merck & Co., Inc. | Process for the synthesis of trifluorophenylacetic acids |
| CN101429115A (en) * | 2008-12-22 | 2009-05-13 | 浙江海翔药业股份有限公司 | Process for producing trifluoro benzene acetic acid and sitagliptin |
| CN101659611A (en) * | 2009-09-28 | 2010-03-03 | 浙江永太科技股份有限公司 | Method for preparing 2, 4, 5-trifluoro-phenylacetic-acid |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103232339A (en) * | 2013-04-19 | 2013-08-07 | 重庆紫光化工股份有限公司 | Preparation method of chlorinated phenylacetic acid |
| CN111393282A (en) * | 2020-05-21 | 2020-07-10 | 湖南复瑞生物医药技术有限责任公司 | Preparation method of 2,4, 5-trifluorophenylacetic acid |
| CN112457153A (en) * | 2020-11-10 | 2021-03-09 | 杭州臻挚生物科技有限公司 | Industrial preparation method of 2,4, 5-trifluoro-phenylacetic acid |
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