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3-chloro-7(5)-bromo-benzo-isoxazole compounding method

A technology of benzisoxazolone and synthesis method, applied in the direction of organic chemistry, etc., can solve the problems of harsh reaction conditions, expensive raw materials, cumbersome reaction steps, etc., and achieve fewer reaction steps, simple post-treatment, and high overall yield Effect

Inactive Publication Date: 2013-11-06
SYNTHESIS MED SHANGHAI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The raw material in this method is expensive, and the cost is high. The most important thing is that the derivative with benzisoxazole skeleton can be obtained only through ring closure and hydrogenation at the end of this method. The reaction steps are cumbersome, and the reaction conditions are harsh, and the product yield is low.

Method used

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  • 3-chloro-7(5)-bromo-benzo-isoxazole compounding method

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Experimental program
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Effect test

Embodiment 1

[0045] One, the synthesis of 3-chloro-7-bromobenzisoxazole

[0046] (1) Synthesis of 2-fluoro-3-bromobenzoic acid

[0047] Dissolve 13.5g of o-fluorobromobenzene in 140mL of anhydrous tetrahydrofuran and cool to -70°C, add 105mL of LDA with a concentration of 1.0mol / L dropwise under the protection of nitrogen, and the LDA is added dropwise within 30min. After the addition, continue to stir for 30 minutes at a constant temperature of -70°C, then pour the reaction solution into a reaction container filled with 200g of dry ice, stir until no bubbles are generated, spin dry, add 200mL of water to the reaction container to dilute to obtain a dilution , adjust the pH of the diluent to 5, filter, wash the filter cake with ice water, and dry it in vacuum at 50°C to obtain 16.2 g of white solid, namely 2-fluoro-3-bromobenzoic acid, with a yield of 95.9%.

[0048] LC-MS [ESI, m / z]: [M+1] + =218.9 / 220.8(1 / 1).

[0049] 1 H NMR (400MHz, DMSO-d 6 )δ13.60(s,1H),7.94(ddd,J=8.0,6.4,1.7Hz,...

Embodiment 2

[0075] One, the synthesis of 3-chloro-7-bromobenzisoxazole

[0076] (1) Synthesis of 2-fluoro-3-bromobenzoic acid

[0077] Dissolve 14g of o-fluorobromobenzene in 145mL of anhydrous tetrahydrofuran and cool to -67°C, add 102mL of LDA with a concentration of 1.1mol / L dropwise under nitrogen protection. After completion, continue to stir for 35 minutes at a constant temperature of -67°C, then pour the reaction solution into a reaction container filled with 205 g of dry ice, stir until no bubbles are generated, spin dry, and add 205 mL of water to the reaction container to dilute to obtain a dilution. Adjust the pH of the diluent to 4.5, filter, wash the filter cake with ice water, and dry it under vacuum at 55°C to obtain 16.95 g of white solid, namely 2-fluoro-3-bromobenzoic acid, with a yield of 96.8%.

[0078] LC-MS [ESI, m / z]: [M+1] + =218.9 / 220.8(1 / 1).

[0079] 1 H NMR (400MHz, DMSO-d 6 )δ13.60(s,1H),7.94(ddd,J=8.0,6.4,1.7Hz,1H),7.86(ddd,J=8.3,6.8,1.7Hz,1H),7.26(t,J=8....

Embodiment 3

[0105] One, the synthesis of 3-chloro-7-bromobenzisoxazole

[0106] (1) Synthesis of 2-fluoro-3-bromobenzoic acid

[0107] Dissolve 14.5g of o-fluorobromobenzene in 150mL of anhydrous tetrahydrofuran and cool to -65~-70°C, add 105mL of LDA with a concentration of 1.0mol / L dropwise under the protection of nitrogen, the LDA is added dropwise within 30min, and the Stir, after the dropwise addition, continue to stir for 40min at a constant temperature of -65°C, then pour the reaction solution into a reaction vessel with 210g of dry ice, stir until no bubbles are generated, spin dry, add 210mL of water to the reaction vessel to dilute The diluted solution was obtained, and the pH of the diluted solution was adjusted to 4, then filtered, the filter cake was washed with ice water, and dried under vacuum at 60°C to obtain 17.32 g of white solid, namely 2-fluoro-3-bromobenzoic acid, with a yield of 95.4%.

[0108] LC-MS [ESI, m / z]: [M+1] + =218.9 / 220.8(1 / 1).

[0109] 1 H NMR (400MH...

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Abstract

The invention discloses a 3-chloro-7(5)-bromo-benzo-isoxazole compounding method which includes utilizing bromofluorobenzene as a raw material, acidizing the raw material to obtain 2-fluoro-3-bromobenzoic-acid, esterifying the 2-fluoro-3-bromobenzoic-acid to obtain 2-fluoro-3-methyl-bromobenzoate, enabling the 2-fluoro-3-methyl-bromobenzoate to react with N-acetyl-hydroxylamine to obtain 7-bromo-3-benzo-isoxazolone, and finally chloridizing the 7-bromo-3-benzo-isoxazolone to obtain 3-chloro-7-bromo-benzo-isoxazole; utilizing 2-fluoro-5-bromobenzoic-acid as a raw material, esterifying the 2-fluoro-5-bromobenzoic-acid to obtain 2-fluoro-5-methyl-bromobenzoate, enabling the 2-fluoro-5-methyl-bromobenzoate to react with the N-acetyl-hydroxylamine to obtain 5-bromo-3-benzo-isoxazolone, and finally chloridizing the 5-bromo-3-benzo-isoxazolone to obtain the 3-chloro-5-bromo-benzo-isoxazole. The method is low in raw material price and cost, fewer in reaction steps, simple in post treatment, high in total recovery and capable of reducing environment pollution.

Description

technical field [0001] The invention relates to the technical field of organic synthesis, in particular to a method for synthesizing 3-chloro-7-bromobenzisoxazole and its isomer 3-chloro-5-bromobenzisoxazole. Background technique [0002] The synthesis of modern new drugs requires novel skeleton structures. Most of the new chemical drugs reported so far have a heterocyclic structure in their molecular skeletons. For example, the main component of the second-generation antipsychotic risperidone is benzisoxazoles. The most basic skeleton of benzisoxazole derivatives is benzisoxazole. The skeleton structure has obvious structural characteristics. One side is a hydrophilic structure and the other side is a lipophilic structure, which can smoothly enter the cell membrane. It acts in vivo; there are two hydrogen-bonded acceptor sites in its structure, which can well bind to the receptor; benzisoxazole is also the bioelectronic isostere of benzamide, and benzamide is known to be ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D261/20
Inventor 杨少龙部先永张慧敏
Owner SYNTHESIS MED SHANGHAI
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