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New preparation method of 1-bromo-methyl-2,3,5,6-tetrafluoro-4-(trifluoromethyl)benzene

A technology of bromomethyl and trifluoromethyl, applied in the field of medicinal chemistry, can solve the problems of high price, low yield, and difficult availability of raw materials

Active Publication Date: 2019-08-13
ZHEJIANG APELOA JIAYUAN PHARMA +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The raw material of this route is not easy to obtain, currently only one Russian company can customize it, and the price is expensive
Methyllithium is used in the reaction process, and the reaction conditions of methyllithium are harsh, requiring strict anhydrous and oxygen-free conditions, and industrialization is difficult
When bromination is carried out in the second step reaction, impurities of dibromine and tribromine are produced, and purification is relatively difficult
[0012] The above-mentioned methods are not suitable for industrialized large-scale production, the raw materials are expensive and difficult to obtain, the process will bring safety risks, environmental protection problems, and cumbersome operations will cause production efficiency to drop, etc.
There are many by-products in the reaction, the post-treatment work is cumbersome, and the yield is low. There is an urgent need for a 1-bromomethyl-2,3,5,6-tetrafluoro- The synthetic method of 4-(trifluoromethyl)benzene

Method used

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  • New preparation method of 1-bromo-methyl-2,3,5,6-tetrafluoro-4-(trifluoromethyl)benzene
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  • New preparation method of 1-bromo-methyl-2,3,5,6-tetrafluoro-4-(trifluoromethyl)benzene

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0056] The first step: Synthesis of 2,3,5,6-tetrafluoro-dimethyl terephthalate [compound of formula (8)]

[0057] The synthetic route is as follows:

[0058]

[0059] Dissolve 15 g of the raw material 2,3,5,6-tetrafluoro-terephthalic acid [compound of formula (3)] in 260 ml of methanol, add 22.9 ml of thionyl chloride dropwise, and keep the internal temperature at 0~10°C, naturally rise to room temperature after dropping, heat to reflux and react overnight. GC detects that the reaction is complete, concentrate the methanol to dryness, add 100ml of water, 100ml of methyl tert-butyl ether, stir and let it stand for liquid separation, wash the water phase twice with 50ml*2 methyl tert-butyl ether, combine the organic phase with 50ml for saturation Wash once with sodium bicarbonate solution, dry over anhydrous sodium sulfate, and concentrate to dryness to obtain 14.5 g of white solid with a yield of 86.51%.

[0060] The NMR detection product is 2,3,5,6-tetrafluoro-dimethyl te...

Embodiment 2

[0084] In the second step, the synthesis of 2,3,5,6-tetrafluoro-4-formic acid methyl ester-benzoic acid [compound of formula (9)], the base used is NaOH, and the rest of the steps are exactly the same as in Example 1.

[0085] The synthetic route is as follows:

[0086]

[0087] Dissolve 8.66 g of the raw material 2,3,5,6-dimethyl phthalate [compound of formula (8)] in 54 ml of methanol, lower the internal temperature to 0°C, and slowly add the prepared NaOH methanol solution dropwise ( 1.24gNaOH+55mlCH 3 OH), after the droplet was completed, it was naturally raised to room temperature, and heated under reflux to react overnight. The HPLC detection reaction is complete, methanol is concentrated to dryness, add 120ml of water, wash with 50ml*3 dichloromethane three times, adjust the pH of the water phase to 1~2, a white solid precipitates, stir for 1h, add 50ml*3 methyl tert-butyl The ether was extracted three times, the organic phase was dried over anhydrous sodium sulfat...

Embodiment 3

[0090] The fourth step is the synthesis of 2,3,5,6-tetrafluoro-4-trifluoromethylbenzyl alcohol [compound of formula (11)], using lithium aluminum hydride as the reducing agent, and the rest of the steps are exactly the same as in Example 1.

[0091] The synthetic route is as follows:

[0092]

[0093] Mix and stir 70g of fluoride compound and 450ml of 2-methyltetrahydrofuran, cool down in an ice-salt bath to below -10°C, add 14.5g of lithium aluminum hydride, keep the reaction for 5 hours, and detect by TLC.

[0094] Pour the reaction solution into 500ml of water and stir, add 200ml of methyl tert-butyl ether for extraction, separate the organic layer, stir and react with 200ml of 1N hydrochloric acid for 20 minutes, remove the acidic aqueous layer, and wash the organic layer with saturated sodium bicarbonate solution to the aqueous layer pH is 7-8. The water layer was separated, the organic layer was dried, and the solvent was distilled off to obtain 68 g of a light yello...

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Abstract

The invention discloses a new preparation method of 1-bromo-methyl-2,3,5,6-tetrafluoro-4-(trifluoromethyl)benzene. The method comprises the steps that with a compound 2,3,5,6-tetrafluoro-terephthalicacid as a raw material, through alkylation, 2,3,5,6-tetrafluoro-terephthalic acid diester is obtained firstly, then single hydrolysis is conducted, formic acid is fluorinated into trifluoromethyl so as to obtain 2,3,5,6-tetrafluoro-4-trifluoromethyl benzoate, and after the 2,3,5,6-tetrafluoro-4-trifluoromethyl benzoate is reduced into alcohol, through bromination, the target compound is obtained.According to the method, the reaction raw materials are easy to obtain and low in price, few reaction by-products are generated, and the product is easy to purify, high in yield and suitable for massindustrial production; therefore, reliable guarantee is provided for a key intermediate of a novel drug 2-hydroxyl-5-(2,3,5,6-tetrafluoro-4-trifluoromethyl benzylamino)benzoic acid.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to a new method for preparing high-purity 1-bromomethyl-2,3,5,6-tetrafluoro-4-(trifluoromethyl)benzene. Background technique [0002] Compound 1-bromomethyl-2,3,5,6-tetrafluoro-4-(trifluoromethyl)benzene, its structure is shown in formula (I): [0003] [0004] This compound is the key intermediate of the new drug 2-hydroxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoic acid, and its structure is shown in formula (II): [0005] [0006] The compounds shown in (II) and their similar tetrafluorobenzyl derivatives, as well as their preparation methods are disclosed in patents WO2001 / 079153 and WO2004 / 000786. The role of disease and ophthalmic disorders. [0007] The synthetic route of compound 1-bromomethyl-2,3,5,6-tetrafluoro-4-(trifluoromethyl)benzene is rarely reported, mainly the following route. [0008] The synthetic method of compoun...

Claims

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Application Information

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IPC IPC(8): C07C25/13C07C17/16C07C69/82C07C67/08C07C69/78C07C67/313C07C67/307C07C33/46C07C29/147
CPCC07C17/16C07C29/147C07C67/08C07C67/307C07C67/313C07C69/82C07C69/78C07C33/46C07C25/13
Inventor 刘剑郭康平周国川曾翊迅胡建杨勤
Owner ZHEJIANG APELOA JIAYUAN PHARMA
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