Method for preparing 2,4,5-trifluorophenylacetic acid

A technology of trifluorophenylacetic acid and trifluorophenylacetic acid salt, which is used in pharmaceutical chemical intermediates and related chemical fields, can solve the problems of harsh reaction conditions, difficult to control impurities, long process routes, etc., and achieves short synthesis routes and mild conditions. , Environmentally friendly effect

Inactive Publication Date: 2010-09-08
DALIAN UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] U.S. Patent US20040068141 reported that 2,4,5-trifluorobromobenzene and diethyl malonate were used as raw materials to obtain 2,4,5-trifluorophenylacetic acid through substitution reaction and hydrolysis decarboxylation reaction, but there is a reaction in this method Disadvantages of harsh conditions, not suitable for industrial production
The U.S. Patent (US 20040077901) reported that 2,4,5-trifluorobromobenzene was used as a raw material to make Grignard reagent with metal magnesium, react with allyl bromide, and then oxidize to obtain

Method used

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  • Method for preparing 2,4,5-trifluorophenylacetic acid

Examples

Experimental program
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Effect test

Embodiment 1

[0037] Step 1: Preparation of 2,4,5-trifluorobenzylmagnesium chloride

[0038] In a 250mL three-necked flask, 120mL of tetrahydrofuran and magnesium chips (7.2g, 0.45mol) were successively added at room temperature under nitrogen protection, and 1,2-dibromoethane (0.56g, 0.003mol) was slowly added dropwise under stirring and waited for temperature Raised to 30°C, slowly added 2,4,5-trifluorobenzyl chloride (9g, 0.05mol) dropwise, and then continued to slowly drop 2,4,5-trifluorobenzyl chloride (45g, 0.25mol) after the temperature rose to 60°C mol) to keep the solution slightly boiling, reflux reaction for 5-6 hours after the dropwise addition, until the magnesium chips basically disappear, and 2,4,5-trifluorobenzylmagnesium chloride is obtained.

[0039] Step 2: Preparation of 2,4,5-trifluorophenylacetic acid

[0040] Under the protection of nitrogen, add solid dry ice 10g×3 in batches to the reaction liquid containing 61g of 2,4,5-trifluorobenzylmagnesium chloride obtained i...

Embodiment 2

[0042] Step 1: Preparation of 2,4,5-trifluorobenzylmagnesium bromide

[0043] In a 250mL three-necked flask, 140mL of tetrahydrofuran and magnesium powder (7.2g, 0.45mol) were sequentially added at room temperature under nitrogen protection, and 2,4,5-trifluorobenzyl bromide (5g, 0.02mol) was slowly added dropwise under stirring. After the temperature rises to 65°C, continue to slowly add 2,4,5-trifluorobenzyl bromide (70g, 0.31mol) dropwise to keep the solution slightly boiling. After the dropwise addition, reflux for 2-3 hours. After the magnesium powder basically disappears, the preparation In 2,4,5-trifluorobenzylmagnesium bromide.

[0044] Step 2: Preparation of 2,4,5-trifluorophenylacetic acid

[0045]Under the protection of nitrogen, add solid dry ice 10g×3 in batches to the reaction liquid containing 61g of 2,4,5-trifluorobenzylmagnesium chloride obtained in Example 1, add once every 3 hours, and control the reaction temperature at 0°C -15°C. After the dry ice is co...

Embodiment 3

[0047] Step 1: Preparation of 2,4,5-trifluorobenzylmagnesium chloride

[0048] In a 250mL three-necked flask, 120mL of methyl tert-butyl ether and magnesium chips (7.2g, 0.45mol) were successively added at room temperature under nitrogen protection, and 1,2-dibromoethane (0.56g, 0.003m0l) when the temperature rises to 30°C, slowly add 2,4,5-trifluorobenzyl chloride (9g, 0.05mol) dropwise, and then slowly add 2,4,5-trifluorobenzyl chloride after the temperature rises to 60°C Chlorine (45g, 0.25mol) kept the solution slightly boiling. After the dropwise addition, the solution was refluxed for 5-6 hours. After the magnesium dust basically disappeared, 2,4,5-trifluorobenzylmagnesium chloride was obtained.

[0049] Step 2: Preparation of 2,4,5-trifluorophenylacetic acid

[0050] Under the protection of nitrogen, add solid dry ice 10g×3 in batches to the reaction liquid containing 61g of 2,4,5-trifluorobenzylmagnesium chloride obtained in Example 1, add once every 3 hours, and cont...

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Abstract

The invention belongs to the field of fine chemical engineering, and relates to a method for preparing 2,4,5-trifluorophenylacetic acid. The method is characterized by comprising the following steps of: reacting 2,4,5-trifluorobenzyl halogen serving as a raw material with magnesium metal in an anhydrous organic solvent to obtain a 2,4,5-trifluorobenzyl Grignard reagent, wherein an initiator is used or not used during the preparation of the Grignard reagent; reacting the 2,4,5-trifluorobenzyl Grignard reagent with carbon dioxide to obtain 2,4,5-trifluorophenylacetate; and finally, acidifying and extracting the 2,4,5-trifluorophenylacetate to obtain a coarse 2,4,5-trifluorophenylacetic acid product, and re-crystallizing the coarse product to obtain the 2,4,5-trifluorophenylacetic acid. The method has the advantages of short synthetic route, mild condition, environmental friendliness and easy implementation of industrialization; the obtained product has high purity; and the method uses carbon dioxide greenhouse gas as a carbon source, so the raw material is easily obtained and cheap.

Description

technical field [0001] The invention belongs to the field of pharmaceutical and chemical intermediates and related chemical technologies, and relates to a known preparation method of 2,4,5-trifluorophenylacetic acid (formula III). Background technique [0002] 2,4,5-Trifluorophenylacetic acid is an intermediate in the synthesis of sitagliptin, a new drug for the treatment of type 2 diabetes. Sitagliptin is the first DPP-IV inhibitor newly launched by Merck, and it has good curative effect in the treatment of type 2 diabetes , small side effects, good safety and tolerance, and has broad market prospects. [0003] U.S. Patent US20040068141 reported that 2,4,5-trifluorobromobenzene and diethyl malonate were used as raw materials to obtain 2,4,5-trifluorophenylacetic acid through substitution reaction and hydrolysis decarboxylation reaction, but there is a reaction in this method The disadvantage of harsh conditions is not suitable for industrial production. The U.S. Patent (U...

Claims

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Application Information

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IPC IPC(8): C07C57/58C07C51/15
Inventor 冯秀娟谭君杨帆包明
Owner DALIAN UNIV OF TECH
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