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Preparation method of 2-amino-4-bromo-3-fluoro-5-iodobenzamide

A technology of iodobenzamide and amino group, which is applied in the preparation of carboxylic acid amides, nitro compounds, organic compounds, etc., can solve the problem of low yield of iodobenzamide, 2-fluoro-3-bromonitrobenzene Expensive, unfavorable industrial scale-up and other problems, to achieve the effect of low cost and high yield

Active Publication Date: 2021-02-09
无锡双启科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] In the above synthetic method, in the process of synthesizing 2-amino-4-bromo-3-fluoro-5-iodobenzamide compound I, the price of starting material 2-fluoro-3-bromonitrobenzene is very expensive, and the last step The reaction is condensed with a condensing agent to produce 2-amino-4-bromo-3-fluoro-5-iodobenzamide. The yield is low, and it needs to be purified by a column method, which is not conducive to industrial scale-up.

Method used

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  • Preparation method of 2-amino-4-bromo-3-fluoro-5-iodobenzamide
  • Preparation method of 2-amino-4-bromo-3-fluoro-5-iodobenzamide

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Embodiment 1

[0031]A preparation method of 2-amino-4-bromo-3-fluoro-5-iodobenzamide, the preparation method comprising the following steps:

[0032](1) Synthesis of compound III

[0033]Add 193g (1mol) of 2,3-difluorobromobenzene, 1000ml of tetrahydrofuran to the reaction flask, and add 500ml of 2.5M butyllithium dropwise to -78°C. After the dropping, stir for 30min, and let carbon dioxide flow through it. Keep the temperature for 1 hour. The reaction was followed by HPLC until the 2,3-difluorobromobenzene reaction was completed; 1000ml of water was added to quench the reaction, 1000ml of ethyl acetate was added for layering, the aqueous layer was adjusted to pH=3, a solid was precipitated, filtered and dried to obtain 222g of compound III Molar yield: 93.6%.

[0034](2) Synthesis of compound IV

[0035]Add 200g (843.9mmol) of compound III, 1000ml of 98% concentrated sulfuric acid to the reaction flask, add 118.7g (1266mmol) of 68% concentrated nitric acid dropwise to 0°C, drop at 0°C and stir for 6h, and H...

Embodiment 2

[0049]A preparation method of 2-amino-4-bromo-3-fluoro-5-iodobenzamide, the preparation method comprising the following steps:

[0050](1) Synthesis of compound III

[0051]Add 193g (1mol) of 2,3-difluorobromobenzene, 1000ml of tetrahydrofuran to the reaction flask, add 400ml of 2.5M butyllithium dropwise to -78°C, and stir for 30min after dropping, then let it react with carbon dioxide at this temperature for 2 hours. The reaction was followed by HPLC until the 2,3-difluorobromobenzene reaction was complete; 1000ml of water was added to quench the reaction, 1000ml of ethyl acetate was separated into layers, the aqueous layer was adjusted to pH=3, a solid was precipitated, filtered and dried to obtain 201.8g of compound III , The molar yield: 85.1%.

[0052](2) Synthesis of compound IV

[0053]Add 200g (843.9mmol) of compound III, 1000ml of concentrated sulfuric acid to the reaction flask, add 98.9g (1055mmol) of 68% concentrated nitric acid dropwise to 30°C, slowly stir at 30°C for 2h, and HPL...

Embodiment 3

[0065]A preparation method of 2-amino-4-bromo-3-fluoro-5-iodobenzamide, the preparation method comprising the following steps:

[0066](1) Synthesis of compound III

[0067]Add 193g (1mol) of 2,3-difluorobromobenzene, 1000ml of tetrahydrofuran to the reaction flask, add 440ml of 2.5M butyllithium dropwise to -78°C, and stir for 30min after dropping, and then let it react at this temperature for 1.5 hours. The reaction was followed by HPLC until the 2,3-difluorobromobenzene reaction was complete; 1000ml of water was added to quench the reaction, 1000ml of ethyl acetate layered, the aqueous layer was adjusted to pH=3, a solid was precipitated, filtered and dried to obtain 211.4g of compound III , The molar yield: 89.1%.

[0068](2) Synthesis of compound IV

[0069]Add 200g (843.9mmol) of compound III, 1000ml of concentrated sulfuric acid to the reaction flask, drop 79.2g (843.9mmol) of 68% concentrated nitric acid, drop the temperature to 15°C, slowly warm to 15°C and stir for 4h, HPLC track the ...

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Abstract

The invention discloses a preparation method of 2-amino-4-bromo-3-fluoro-5-iodobenzamide, which comprises the following steps: (1) introducing carbon dioxide into a compound (II) under the condition of butyl lithium hydrogen extraction to generate a compound (III); (2) nitrifying the compound (III) by concentrated sulfuric acid and nitric acid to generate a compound (IV); (3) reacting the compound(IV) with acyl chloride to generate a compound (V); (4) reacting the compound (V) with ammonia water to generate an amide compound (VI); (5) reducing the amide compound (VI) with iron powder to obtain a compound (VII); (6) subjecting the compound (VII) to a Sandmeyer reaction to obtain a compound (VIII); and (7) carrying out high-pressure reaction on the compound (VIII) by introducing ammonia gasto generate the compound (I). The preparation method provided by the invention is higher in yield.

Description

Technical field[0001]The invention relates to the technical field of medicine and chemical engineering, in particular to a preparation method of 2-amino-4-bromo-3-fluoro-5-iodobenzamide.Background technique[0002]2-Amino-4-bromo-3-fluoro-5-iodobenzamide is a key intermediate. WO2018143315 and US20180015087 disclose the synthesis of 2-amino-4-bromo-3-fluoro-5-iodobenzamide as follows Route of compound I:[0003][0004]In the above synthesis method, in the process of synthesizing 2-amino-4-bromo-3-fluoro-5-iodobenzamide compound I, the starting material 2-fluoro-3-bromonitrobenzene is very expensive, and the last step is Condensation using a condensing agent to make 2-amino-4-bromo-3-fluoro-5-iodobenzamide yields low yields and requires column purification, which is not conducive to industrial amplification.Summary of the invention[0005]In view of the above-mentioned problems in the prior art, the applicant of the present invention provides a method for preparing 2-amino-4-bromo-3-fluoro-...

Claims

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Application Information

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IPC IPC(8): C07C231/12C07C237/30
CPCC07C231/12C07C231/02C07C201/12C07C201/08C07C51/15C07C237/30C07C233/65C07C205/58C07C63/70
Inventor 张国强
Owner 无锡双启科技有限公司
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