CN102584565B - Preparation method for 2,4,5-trifluoro benzene acetic acid - Google Patents

Abstract

The invention discloses a preparation method of 2,4,5-trifluorophenylacetic acid, which belongs to the field of organic chemical synthesis. The preparation method of 2,4,5-trifluorophenylacetic acid comprises the following steps: (1) dissolving 1,2,4-trifluorobenzene in a solvent, and then carrying out Friedel alkylation with chloroacetonitrile under Lewis acid catalysis (2) 2,4,5-trifluorophenylacetonitrile is hydrolyzed with acid, and cooled to crystallize to obtain 2,4,5-trifluorophenylacetic acid. The method of the invention does not use highly toxic cyanide and avoids the use of a large amount of concentrated sulfuric acid, and has the advantages of low pollution, short route, reduced equipment investment, low cost, high yield and the like.

Description

A kind of preparation method of 2,4,5-trifluorophenylacetic acid

technical field

The invention relates to the field of organic chemical synthesis, in particular to a preparation method of 2,4,5-trifluorophenylacetic acid.

Background technique

）英文名：Sitagliptin phosphate monohydrate，化学名：7-[(3R)-3-氨基-1-氧代-4-(2,4,5-三氟苯基)丁基]-5,6,7,8-四氢-3-三氟甲基-1,2,4-三唑并[4,3-a]吡嗪磷酸盐，分子式为C₁₆H₁₅F₆N₅O H₃PO₄，2006年10月17日默克公司宣布美国食品药品管理局已批准磷酸西他列汀（Sitagliptin phosphata）。该药成为美国市场迄今为止仅有的用于治疗2型糖尿病的二肽基肽酶-4（DDP-4）抑制剂类药物。 Sitagliptin phosphate is a new type of hypoglycemic drug dipeptidyl peptidase-4 (DPP-4) inhibitor, which can improve the body's own ability to reduce excessive blood sugar levels. Sitagliptin phosphate (

) English name: Sitagliptin phosphate monohydrate, chemical name: 7-[(3R)-3-amino-1-oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6,7 ,8-Tetrahydro-3-trifluoromethyl-1,2,4-triazolo[4,3-a]pyrazine phosphate, molecular formula C ₁₆ H ₁₅ F ₆ N ₅ O H ₃ PO ₄ , 2006 On October 17, Merck announced that the US Food and Drug Administration had approved sitagliptin phosphate (Sitagliptin phosphata). The drug has become the only dipeptidyl peptidase-4 (DDP-4) inhibitor drug for the treatment of type 2 diabetes in the US market so far.

The synthesis of sitagliptin reported in the literature is the key intermediate 2,4,5-trifluorophenylacetic acid (II) raw material, which is synthesized through a long route, so how to synthesize 2,4,5- Trifluorophenylacetic acid is very important.

The synthetic routes of trifluorophenylacetic acid reported in the literature are probably as follows, but they are all unsatisfactory for industrial production.

Route 1:

This route uses 2,4,5-trifluorobromobenzene as the starting material, reacts with diethyl oxalate under strong alkaline conditions, and then hydrolyzes to obtain the product. This route has high requirements for reaction conditions and is not suitable for industrialization Production.

Route 2:

This route also uses 2,4,5-trifluorobromobenzene as a starting material to generate Grignard reagent, then substitute with allyl bromide, and finally oxidize under the action of a catalyst to obtain trifluorophenylacetic acid. The Grignard reaction used in this route has higher requirements for anhydrous, and the catalyst and oxidizing agent used are expensive, and are not suitable for industrial production.

Route 3:

This route uses trifluorobenzene as a raw material, first acetylation, then Willgerodt-kindler reaction to produce thiotrifluorophenylacetic acid amide, and then hydrolysis to obtain trifluorophenylacetic acid. The yield of the Willgerodt-kindler reaction in this route is low, and a large amount of malodorous sulfides are produced in the reaction process, which is relatively polluting to the environment, and post-processing and purification are relatively difficult, making it difficult to realize industrialization.

Route 4:

This route uses m-trifluorobenzene as the starting material, uses chloromethylation reaction to obtain trifluorochlorobenzyl, then uses highly toxic sodium cyanide to obtain trifluorophenylacetonitrile, and then undergoes hydrolysis to obtain trifluorophenylacetic acid. This route uses a large amount of concentrated sulfuric acid and highly toxic cyanide when carrying out chloromethylation, which causes great pressure on the environment.

Route 5:

This route also uses trifluorobenzene as the starting material, and also performs the chloromethylation reaction first, and then performs the Grignard reaction, and passes carbon dioxide into the Grignard reagent to finally obtain trifluorophenylacetic acid. Compared with the previous route, this route has successfully avoided the use of highly toxic sodium cyanide, but the Grignard reaction has the disadvantages of being difficult to initiate and difficult to control, which is extremely unfavorable for industrialization.

Based on the above, the existing technologies for producing trifluorophenylacetic acid all have certain deficiencies, especially the lack of environmental considerations. Therefore, the design of a production line is simple and easy to obtain, simple to operate, low in cost, high in yield, and has little pressure on the environment. route is very necessary.

Contents of the invention

The invention provides a method for preparing 2,4,5-trifluorophenylacetic acid. The method of the invention does not use highly toxic cyanide, and avoids the use of a large amount of concentrated sulfuric acid, and has the advantages of low pollution, short route, reduced equipment investment, and low cost , high yield and other advantages.

The technical scheme that the present invention takes is:

A kind of preparation method of 2,4,5-trifluorophenylacetic acid,

Its preparation route is as follows:

The preparation method comprises the following steps:

(1) Dissolve 1,2,4-trifluorobenzene in a solvent, and then carry out Friedel alkylation reaction with chloroacetonitrile under Lewis acid catalysis to obtain 2,4,5-trifluorophenylacetonitrile;

(2) 2,4,5-trifluorophenylacetonitrile is hydrolyzed with acid, and cooled to crystallize to obtain 2,4,5-trifluorophenylacetic acid.

Wherein, the molar ratio of 1,2,4-trifluorobenzene and chloroacetonitrile in step (1) is 1:1-2.5; Lewis acid is aluminum trichloride, boron trifluoride, zinc chloride, ferric chloride , tin tetrachloride; the amount of Lewis acid is 3%-30% of the moles of 1,2,4-trifluorobenzene; the reaction solvent is dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloro Ethane; the amount of solvent used is 1,2,4-trifluorobenzene (mass)/solvent (volume)=1:3-10; the reaction temperature is 40-85°C, and the reaction time is 2-4 hours.

The acid used in step (2) is one or more of concentrated hydrochloric acid, concentrated sulfuric acid, concentrated phosphoric acid and glacial acetic acid; the reaction temperature is 60-150°C; the reaction time is 1-6 hours; 2,4,5-tri The ratio of fluorophenylacetonitrile to acid is 2,4,5-trifluorophenylacetonitrile (mass)/acid (volume)=1:1-1:10.

The best plan is: the feeding ratio of 1,2,4-trifluorobenzene and chloroacetonitrile in step (1) is 1:1.2-1.5; the Lewis acid is aluminum trichloride and zinc chloride; the amount of Lewis acid is 1 , 2,4-trifluorobenzene moles are 5%-10%; the reaction solvent is dichloromethane and chloroform; solvent consumption is 1,2,4-trifluorobenzene (mass)/solvent (volume )=1:4-6.

In step (2), the reaction temperature is 100-140°C; the reaction time is 3-4 hours; the ratio of the amount of 2,4,5-trifluorophenylacetonitrile to the acid is 2,4,5-trifluorophenylacetonitrile ( mass)/acid (volume)=1:2-3.

In the reaction, concentrated hydrochloric acid, concentrated sulfuric acid, concentrated phosphoric acid and glacial acetic acid are industrial concentrated hydrochloric acid, concentrated sulfuric acid, concentrated phosphoric acid and glacial acetic acid, and the mass concentrations are 37%, 98%, 85% and 99% respectively.

The beneficial effects produced by adopting the above-mentioned technical scheme are:

1. Successfully avoided the use of highly toxic cyanide, and avoided the use of a large amount of concentrated sulfuric acid in the chloromethylation process, with low pollution and greatly reduced the pressure on the environment.

2. Compared with the prior art, the reaction route is shortened, the equipment investment is greatly reduced, the cost is reduced, and the yield is high, so it is easy to realize industrial production.

Detailed ways

In the following examples, 1-5 are the preparation of 2,4,5-trifluorophenylacetonitrile, and 6-10 are the preparation of 2,4,5-trifluorophenylacetic acid.

Example 1

Preparation of 2,4,5-trifluorophenylacetonitrile

Add 132g of 1,2,4-trifluorobenzene to a 1L reaction flask, add 396ml of dichloromethane to dissolve, then add 8.05g of ferric chloride and 75g of chloroacetonitrile, heat to 40°C, and reflux for 4 hours to stop the reaction. Cool to room temperature, filter, and distill the filtrate under reduced pressure to recover the solvent, then distill to obtain 124 g of 2,4,5-trifluorophenylacetonitrile with a yield of 72.5%.

Example 2

Preparation of 2,4,5-trifluorophenylacetonitrile

Add 132g of 1,2,4-trifluorobenzene to a 1L reaction flask, add 1320ml of chloroform to dissolve, then add 13.2g of aluminum trichloride and 187.5g of chloroacetonitrile, heat to 60°C, and reflux for 3 hours to stop the reaction. Cool to room temperature, filter, and distill the filtrate under reduced pressure, recover the solvent first, and then distill to obtain 130 g of 2,4,5-trifluorophenylacetonitrile with a yield of 76.0%.

Example 3

Preparation of 2,4,5-trifluorophenylacetonitrile

Add 132g of 1,2,4-trifluorobenzene to a 1L reaction flask, add 528ml of carbon tetrachloride to dissolve, then add 20.4g of boron trifluoride and 112.5g of chloroacetonitrile, heat to 80°C, and reflux for 2 hours to stop the reaction. Cool to room temperature, filter, and distill the filtrate under reduced pressure, recover the solvent first, and then distill to obtain 132 g of 2,4,5-trifluorophenylacetonitrile with a yield of 77.2%.

Example 4

Preparation of 2,4,5-trifluorophenylacetonitrile

Add 132g of 1,2,4-trifluorobenzene to a 1L reaction flask, add 792ml of 1,2-dichloroethane to dissolve, then add 7.77g of tin tetrachloride and 80g of chloroacetonitrile, heat to 85°C, and reflux for 2 hours. stop responding. Cool to room temperature, filter, and distill the filtrate under reduced pressure, recover the solvent first, and then distill to obtain 135 g of 2,4,5-trifluorophenylacetonitrile with a yield of 78.9%.

Example 5

Preparation of 2,4,5-trifluorophenylacetonitrile

Add 132g 1,2,4-trifluorobenzene to a 1L reaction bottle, add 792ml 1,2-dichloroethane to dissolve, then add 18g zinc chloride, 150g chloroacetonitrile, heat to 85°C, reflux for 2 hours, stop the reaction . Cool to room temperature, filter, and distill the filtrate under reduced pressure, recover the solvent first, and then distill to obtain 133 g of 2,4,5-trifluorophenylacetonitrile with a yield of 77.8%.

Example 6

Preparation of 2,4,5-trifluorophenylacetic acid

(1) Add 100g of trifluorophenylacetonitrile and 100ml of concentrated sulfuric acid into a 1L reaction flask, heat to 100°C, and react at this temperature for 3 hours. , 4,5-trifluorophenylacetic acid 106, the yield was 95.5%.

Example 7

Preparation of 2,4,5-trifluorophenylacetic acid

Add 100g of trifluorophenylacetonitrile to a 1L reaction flask, add 200ml of concentrated hydrochloric acid, heat to 80°C, and react at this temperature for 4 hours. The reaction solution is poured into 5L of ice water, and a large amount of white solid is precipitated. 5-trifluorophenylacetic acid 100g, yield 90.1%.

Example 8

Preparation of 2,4,5-trifluorophenylacetic acid

Add 100g of trifluorophenylacetonitrile to a 1L reaction flask, add 250ml of concentrated phosphoric acid, and 50ml of acetic acid, heat to 60°C, and react at this temperature for 1 hour. The reaction solution is poured into 5L of ice water, and a large amount of white solids are precipitated. 110g of 4,5-trifluorophenylacetic acid, yield 99.1%.

Example 9

Preparation of 2,4,5-trifluorophenylacetic acid

Add 100g of trifluorophenylacetonitrile to a 1L reaction flask, add 400ml of glacial acetic acid, and 200ml of hydrochloric acid, heat to 150°C, and react at this temperature for 2 hours. The reaction solution is poured into 5L of ice water, and a large amount of white solids are precipitated. 103g of 4,5-trifluorophenylacetic acid, yield 92.8%.

Example 10

Preparation of 2,4,5-trifluorophenylacetic acid

Add 100g of trifluorophenylacetonitrile to a 1L reaction flask, add 700ml of concentrated hydrochloric acid, and 300ml of acetic acid, heat to 140°C, and react at this temperature for 6 hours. The reaction solution is poured into 5L of ice water, and a large amount of white solid is precipitated. 105g of 4,5-trifluorophenylacetic acid, yield 94.6%.

Claims (4)

1. a preparation method of 2,4,5-trifluorophenylacetic acid, is characterized in that comprising the steps: (1) Dissolving 1,2,4-trifluorobenzene in a solvent, and then performing Friedel alkylation reaction with chloroacetonitrile under Lewis acid catalysis to obtain 2,4,5-trifluorophenylacetonitrile; the 1 , the molar ratio of 2,4-trifluorobenzene and chloroacetonitrile is 1:1-2.5; the Lewis acid is aluminum trichloride, boron trifluoride, zinc chloride, ferric chloride, tin tetrachloride; The amount of the Lewis acid is 3%-30% of the moles of 1,2,4-trifluorobenzene; the reaction solvent is dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane ; The amount of solvent used is 1,2,4-trifluorobenzene and the mass volume ratio of the solvent is 1:3-10; the reaction temperature is 40-85°C, and the reaction time is 2-4 hours; (2) 2,4,5-trifluorophenylacetonitrile is hydrolyzed with acid, and cooled to crystallize to obtain 2,4,5-trifluorophenylacetic acid. 2. the preparation method of a kind of 2,4,5-trifluorophenylacetic acid according to claim 1, is characterized in that the feeding ratio of described 1,2,4-trifluorobenzene and chloroacetonitrile is 1:1.2- 1.5; the Lewis acid is aluminum trichloride and zinc chloride; the Lewis acid consumption is 5%-10% for 1,2,4-trifluorobenzene moles; the reaction solvent is dichloromethane and Chloroform; solvent dosage is 1,2,4-trifluorobenzene and solvent mass volume ratio is 1:4-6. 3. The preparation method of a kind of 2,4,5-trifluorophenylacetic acid according to claim 1, characterized in that the acid described in step (2) is concentrated hydrochloric acid, concentrated sulfuric acid, concentrated phosphoric acid and glacial acetic acid One or more; the reaction temperature is 60-150°C; the reaction time is 1-6 hours; the ratio of 2,4,5-trifluorophenylacetonitrile to acid is The mass volume ratio with acid is 1:1-1:10. 4. the preparation method of a kind of 2,4,5-trifluorophenylacetic acid according to claim 3, is characterized in that described reaction temperature is 100-140 ℃; The reaction time is 3-4 hour; 2,4, The ratio of the feeding amount of 5-trifluorophenylacetonitrile to the acid is that the mass volume ratio of 2,4,5-trifluorophenylacetonitrile to the acid is 1:2-3.