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Preparation method of 2,4,5-trifluorophenylacetic acid

A technology of trifluorophenylacetic acid and fluoroborate, which is applied in 2 fields, can solve problems such as poor safety, and achieve the effect of high safety, good comprehensive effect and less by-products

Inactive Publication Date: 2018-08-10
江苏八巨药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] Although the above-mentioned problems have been solved to a certain extent, the -NH in the starting material it adopts 2 It is easy to convert into -F by-product during the reaction process, and the raw material liquid bromine and NaH used in the reaction process are also dangerous substances, and the safety is poor

Method used

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  • Preparation method of 2,4,5-trifluorophenylacetic acid
  • Preparation method of 2,4,5-trifluorophenylacetic acid
  • Preparation method of 2,4,5-trifluorophenylacetic acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] Put 36.5g of 2-methyl-4-nitrobenzoic acid and 200mL of glacial acetic acid into the reactor, then slowly cool down to below 5°C and then put in 17g of sodium nitrite, after the end, add 14g of hydrofluoric acid dropwise, drop After completion, control the temperature below 5°C to carry out the fluorination reaction. After the central control confirms that the raw materials have been reacted, then raise the temperature at 20°C to 25°C for pyrolysis for 30 minutes, then add 150mL of dichloromethane and 50mL of water, stir for 30 minutes, and then statically Place and separate layers to obtain a dichloromethane solution containing the compound of formula II, which is directly used in the next reaction, and the single-step yield reaches 95.8%;

[0043] Put the above-mentioned methylene chloride solution containing the compound of formula II into another reaction bottle, then put in 16g of pyridine, control the temperature at room temperature, add 36g of trichloroacetyl chlor...

Embodiment 2

[0046] Put 36.5g of 2-methyl-4-nitrobenzoic acid and 200mL of formic acid into the reactor, then slowly lower the temperature to below 5°C and then put in 20.7g of sodium nitrite. After the completion, control the temperature below 5°C to continue the fluorination reaction. After the central control confirms that the raw materials have been reacted, then heat up at 20°C to 25°C for 30 minutes of pyrolysis, then add 150mL of dichloromethane and 50mL of water, and stir for 30 minutes. After standing and layering, the obtained dichloromethane solution containing the compound of formula II was directly used in the next reaction, and the single-step yield reached 94.6%;

[0047] Put the above dichloromethane solution containing the compound of formula II into another reaction bottle, then put in 18g of pyridine, control the temperature at room temperature, add 40g of trichloroacetyl chloride dropwise, and make the reaction complete after the dropwise addition, then transfer the mate...

Embodiment 3

[0050] Put 36.5g of 2-methyl-4-nitrobenzoic acid and 200mL of formic acid into the reactor, then slowly cool down to below 10°C and then put in 29.5g of sodium nitrite, after the end, add 82g of sodium fluoroborate dropwise, drop After completion, control the temperature at 5°C to 10°C to continue the fluorination reaction. After the central control confirms that the raw materials have been reacted, then heat up at 20°C to 25°C for 30 minutes of pyrolysis, then add 200 mL of ethyl acetate and 50 mL of water, and stir for 30 minutes. After standing still and layering, the obtained ethyl acetate solution containing the compound of formula II was directly used in the next reaction, and the single-step yield reached 94.8%;

[0051] Put the above-mentioned ethyl acetate solution containing the compound of formula II into another reaction bottle, and then put in 30g of diisopropylethylamine, under the condition of controlling the temperature at 20-25°C, add 42g of trichloroacetyl chl...

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Abstract

The invention relates to a preparation method of 2,4,5-trifluorophenylacetic acid, belongs to the technical field of drug intermediate synthesizing, and aims to solve the problem that existing raw materials are high in risks. The method includes: allowing 2-methyl-4-nitrobenzoic acid to have reaction with nitrite under the effect of strong acid to generate diazotizing salt, adding hydrofluoric acid or fluoborate to perform fluorination, and performing pyrolysis to obtain a compound as shown in formula II; in the presence of an acid-binding agent, allowing the compound as shown in formula II tohave acylation reaction with halogenated acetyl chloride to obtain a compound as shown in formula III; under the effect of alkali metal alkoxide, allowing the compound as shown in formula III to havereaction with alcohol to obtain a compound as shown in formula IV; performing hydrolysis and decarboxylation on the compound as shown in formula IV in an acid system, performing reduction, and then performing diazotization and pyrolysis to obtain the 2,4,5-trifluorophenylacetic acid. The preparation method has the advantages that raw material conversion rate is increased, quality requirements onproduct yield and purity are satisfied, and high final-product total yield is achieved.

Description

technical field [0001] The invention relates to a preparation method of 2,4,5-trifluorophenylacetic acid, belonging to the technical field of pharmaceutical intermediate synthesis. Background technique [0002] Sitagliptin is a dipeptidyl peptidase Ⅳ (DDP-4) inhibitor drug used to treat type Ⅱ diabetes. It is a new type of hypoglycemic drug. Equivalent to market demand. And 2,4,5-trifluoroacetic acid, as a key intermediate in the synthesis of sitagliptin, has broad market prospects. [0003] In the existing literature, there are mainly the following routes for the synthesis of 2,4,5-trifluoroacetic acid. Such as the Chinese patent (authorized announcement number: CN104387259B) discloses a kind of trifluorobromobenzene first converted into a Grignard reagent, then in the presence of TMEDA with diethyl oxalate through addition reaction, and then with hydrazine hydrate / potassium hydroxide / Diethylene glycol reaction, after acidification to the corresponding 2,4,5-trifluoroac...

Claims

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Application Information

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IPC IPC(8): C07C57/58C07C51/377C07C201/12C07C205/58C07C205/61C07C205/56
CPCC07C51/377C07C201/12C07C205/58C07C205/61C07C205/56C07C57/58
Inventor 王福军蒋荣彪刘玉坤杨胜利张锦涛
Owner 江苏八巨药业有限公司
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