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A kind of preparation method of methyl 3-bromo-4-difluoromethoxybenzoate

A technology of methyl difluoromethoxybenzoate and sodium difluorochloroacetate, which is applied in the field of preparation of methyl 3-bromo-4-difluoromethoxybenzoate, and can solve the problem of long reaction time and cumbersome post-treatment , low yield and other problems, to achieve the effect of high conversion rate, simple post-processing and high purity

Inactive Publication Date: 2015-09-23
SHANGHAI INST OF PHARMA IND +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The technical problem to be solved by this invention is in order to overcome the preparation method of existing 3-bromo-4-difluoromethoxymethyl benzoate, reaction time Shortcomings such as long, yield is low, post-processing is loaded down with trivial details, and a kind of preparation method of 3-bromo-4-difluoromethoxymethyl benzoate shown in formula 3 is provided

Method used

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  • A kind of preparation method of methyl 3-bromo-4-difluoromethoxybenzoate
  • A kind of preparation method of methyl 3-bromo-4-difluoromethoxybenzoate

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0017] Add methyl 3-bromo-4-hydroxybenzoate (6.61g, 28.6mmol, 1eq) and sodium chlorodifluoroacetate (8.721, 57.2mmol, 2eq) into anhydrous DMF (43ml), stir until completely dissolved, Add K to it 2 CO 3 (5.933g, 42.9mmol, 1.5eq), stirred, heated to 95°C, controlled at 93-98°C, and reacted for 1.5h. After the reaction was completed, the temperature dropped below 20°C, 86ml of water was added, stirred for 1h, the solid precipitated, filtered, washed with water (2×20ml), and dried in vacuo to obtain 7.2g of white crystals, yield: 89.6%, HPLC: 99.1%, MS (EI + ): isotope peak 280:282=1:1, 1 H-NMR (CDCl 3 ): δ8.31(dd, H), 8.22(dd, 1H), 7.05(m, 1H), 6.61(t, 1H), 3.93(s, 3H).

Embodiment 2

[0019] Add methyl 3-bromo-4-hydroxybenzoate (1eq) and sodium chlorodifluoroacetate (1.5eq) into anhydrous DMF, stir until completely dissolved, and add K 2 CO 3 (1.5eq), stirred, heated to 95°C, controlled at 93-98°C, and reacted for 1-1.5h. After the reaction was completed, the temperature dropped below 20°C, 86ml of water was added, and the mixture was stirred for 1 hour. The solid was precipitated, filtered, washed with water, and dried in vacuo to obtain white crystals with a yield of 74.5%. HPLC: 92.6%, MS (EI + ): isotope peak 280:282=1:1, 1 H-NMR (CDCl 3 ): 58.31(dd,H), 8.22(dd,1H), 7.05(m,1H), 6.61(t,1H), 3.93(s,3H).

Embodiment 3

[0021] Add methyl 3-bromo-4-hydroxybenzoate (1eq) and sodium chlorodifluoroacetate (2.5eq) into anhydrous DMF, stir until completely dissolved, and add K 2 CO 3 (1.5eq), stirred, heated to 95°C, controlled at 93-98°C, and reacted for 1-1.5h. After the reaction was completed, the temperature dropped below 20°C, 86ml of water was added, stirred for 1 hour, solid precipitated, filtered, washed with water, and dried in vacuo to obtain white crystals, yield: 88.3%, HPLC: 98.7%. MS (EI + ): isotope peak 280:282=1:1, 1 H-NMR (CDCl 3 ): δ8.31(dd, H), 8.22(dd, 1H), 7.05(m, 1H), 6.61(t, 1H), 3.93(s, 3H).

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Abstract

The present invention discloses a preparation method for 3-bromo-4-difluoromethoxy methyl benzoate represented by a formula 3. The method comprises: mixing a compound 2, sodium chlorodifluoroacetate, an inorganic weak base and an organic solvent, and carrying out a reaction at a temperature of 85-110 DEG C to obtain the finished product, wherein a molar ratio of the compound 2 to the sodium chlorodifluoroacetate to the inorganic weak base to the organic solvent is 1.0:(1.5-2.5):(1.0-2.0):(15-25), a reaction temperature is 85-110 DEG C, the organic solvent is one or a plurality of materials selected from DMF, isopropanol and 1,4-dioxane, and the inorganic weak base is one or a plurality of materials selected from potassium carbonate, cesium carbonate and sodium carbonate. The preparation method has characteristics of high conversion rate, simple post-treatment, high product yield and high product purity, and is suitable for industrial production.

Description

technical field [0001] The present invention specifically relates to a preparation method of methyl 3-bromo-4-difluoromethoxybenzoate. Background technique [0002] Methyl 3-bromo-4-difluoromethoxybenzoate is an important intermediate for the preparation of some PDF4 kinase inhibitors. There are relatively few reports on the preparation of this compound. Only one patent WO9749710A1 describes the synthesis method of this compound. , the specific method is ethyl chlorodifluoroacetate and methyl 3-bromo-4-hydroxybenzoate, potassium carbonate is heated to 65 ° C in DMF, and the reaction is 16h. Ethyl chlorodifluoroacetate, 3-bromo-4-hydroxy The molar ratio of methyl benzoate and potassium carbonate was 1:1:1, extracted with ethyl acetate in post-treatment, separated and purified by chromatographic column, and the yield was 49%. The main disadvantages of this method are: long reaction time, low yield, troublesome post-processing. [0003] Jeffrey B.Sperry and Karen Sutherland.O...

Claims

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Application Information

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IPC IPC(8): C07C69/76C07C67/30
Inventor 肖旭华孙占莉袁博
Owner SHANGHAI INST OF PHARMA IND
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