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A kind of method of synthesizing bromfenac sodium

A technology of bromfenac sodium and its mixture, which is applied in chemical instruments and methods, preparation of organic compounds, preparation of carboxylic acid amides, etc., can solve problems such as safety production threat, bad smell, restricted application, etc. Effects that are simple and inexpensive to process

Active Publication Date: 2019-04-09
SHANGHAI PUKANG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] In this method, starting material 2-ethyl thioglycolate has bad smell, needs to carry out protection and special treatment during use, simultaneously 2-amino-4'-bromobenzophenone and 2-methyl thioglycolic acid ethyl ester Substituting and ring-closing under the catalysis of tert-butyl chlorate needs to be carried out at ultra-low temperature (below minus 65°C), and the subsequent demethylation of thiol needs to be performed on highly active Raney Ni, which poses a greater threat to safe production. The above defects limit Application of this route in industrial production

Method used

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  • A kind of method of synthesizing bromfenac sodium
  • A kind of method of synthesizing bromfenac sodium
  • A kind of method of synthesizing bromfenac sodium

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] (1) Preparation of N-(2-(4'-bromobenzoyl)phenyl)acetamide (formula III)

[0041] Add 414g of 2-amino-4'-bromobenzophenone (formula II) and 150g of triethylamine into 2.5L of 2-methyltetrahydrofuran, control the temperature at 0-20°C, add 94g of acetyl chloride dropwise, and stir until After the reaction was complete, the organic phase was washed with water, dried and concentrated to obtain 470 g of N-(2-(4'-bromobenzoyl)phenyl)acetamide with a yield of 98.5%.

[0042] (2) N-acetyl-N-(2-(4'-bromobenzoyl)phenyl)-2-bromoacetamide (Formula V). Wherein X is the preparation of Br):

[0043] Get 450g of N-(2-(4'-bromobenzoyl)phenyl)acetamide, 220g of diisopropylethylamine and 22g of 4-dimethylaminopyridine into 5L of toluene, add 280g of bromoacetyl bromide dropwise, add dropwise After completion, the temperature was controlled at 90-100°C until the reaction was complete. After cooling down to room temperature, the organic phase was washed with water, dried, and concentrated...

Embodiment 2

[0049] (1) Preparation of N-(2-(4'-bromobenzoyl)phenyl)acetamide

[0050] Add 700g of 2-amino-4'-bromobenzophenone and 425g of diisopropylethylamine into 5L of dichloromethane, add 300g of acetic anhydride dropwise, stir until the reaction is complete, wash the organic phase with water, dry and concentrate to obtain N- (2-(4'-bromobenzoyl)phenyl)acetamide 766g, yield 95%.

[0051] (2) Preparation of N-acetyl-N-(2-(4'-bromobenzoyl)phenyl)-2-bromoacetamide

[0052] Get 750g of N-(2-(4'-bromobenzoyl)phenyl)acetamide, 357g of triethylamine and 35g of 4-dimethylaminopyridine into 10L of toluene, add 675g of bromoacetic anhydride dropwise, after the addition is complete, The temperature was raised to reflux until the reaction was complete, and after cooling down to room temperature, the organic phase was washed with water, dried, and concentrated under reduced pressure to recover the organic solvent to obtain 955 g of N-acetyl-N-(2-(4'-bromobenzoyl)phenyl)-2 -Bromoacetamide, yield...

Embodiment 3

[0058] (1) Preparation of N-(2-(4'-bromobenzoyl)phenyl)acetamide

[0059] 500g of 2-amino-4'-bromobenzophenone and 300g of diisopropylethylamine were added to 5L of toluene, the temperature was controlled at 10-20°C, 170g of acetyl chloride was added dropwise, the temperature was naturally raised and stirred until the reaction was complete, organic The phase was washed with water, dried and concentrated to obtain 543 g of N-(2-(4'-bromobenzoyl)phenyl)acetamide with a yield of 94.3%.

[0060] (2) Preparation of N-acetyl-N-(2-(4'-bromobenzoyl)phenyl)-2-chloroacetamide

[0061] Get 510g of N-(2-(4'-bromobenzoyl)phenyl)acetamide, 320g of triethylamine and 50g of 4-dimethylaminopyridine into 5L of toluene, add 270g of chloroacetyl chloride dropwise, after the dropwise addition, Control the temperature at 100-110°C until the reaction is complete. After cooling down to room temperature, the organic phase is washed with water, dried, and concentrated under reduced pressure to recover...

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Abstract

The invention discloses a method for synthesizing bromfenac sodium. The method comprises the steps of (1) carrying out acetylation reaction on 2-amino-4'-bromo benzophenone as a raw material to obtain a formula III: N-(2-(4'-bromo benzoyl)phenyl)acetamide; (2) reacting the N-(2-(4'-bromo benzoyl)phenyl)acetamide in a formula IV with a halogen acetylation reagent to obtain a formula V: N-acetyl-N-(2-(4'-bromo benzoyl)phenyl)-2-haloacetamide; (3) carrying out friedel-crafts reaction on the N-acetyl-N-(2-(4'-bromo benzoyl)phenyl)-2-haloacetamide to obtain a formula IV: 1-acetyl-7-(4-bromo-benzoyl chloride) indoline-2-ketone; and (4) finally hydrolyzing the 1-acetyl-7-(4-bromo-benzoyl chloride) indoline-2-ketone to obtain a target product. The method is low in cost, reaction is easy to control, post-treatment is simple, the overall yield is high, the method is economical and environmentally friendly, and a novel method for synthesizing the bromfenac sodium is provided.

Description

technical field [0001] The invention relates to the field of medicine, chemical industry and medicine. Specifically, the invention relates to a method for synthesizing analgesics, more specifically, a new method for synthesizing bromfenac sodium. Background technique [0002] Bromfenac sodium (Bromfenac sodium), the chemical name is [2-amino-3-(4-bromobenzoyl)phenyl] sodium acetate; (2-amino-3-(4-bromobenzoyl)phenyl ) Sodium acetate, similar in structure to ketoprofen and diclofenac, can inhibit the synthesis of prostaglandin inflammatory mediators mediated by cyclooxygenase, is the most effective cyclooxygenase inhibitor, and has strong anti-inflammatory and analgesic effects. This compound is a quasi-non-steroidal anti-inflammatory drug developed by A.H.Robins Company of the United States. Later, the patent right was transferred to Wyeth-Ayers t Company of the United States and jointly developed with Senju Company of Japan. In 2000, Senju Company of Japan developed it into...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C227/22C07C229/42
CPCC07C227/22C07C231/02C07D209/34C07C229/42C07C233/91C07C233/33
Inventor 李勇刚汪迅沈小良孙彪张珍顾波
Owner SHANGHAI PUKANG PHARMA
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