Method for synthesizing ketorolac ammonia butanetriol key intermediate compound benzoyl pyrrole

A technology of benzoylpyrrole and pyrrole, which is applied in the field of synthesis of benzoylpyrrole, a key intermediate of ketorolac tromethamine, can solve problems such as difficult treatment of phosphorus-containing wastewater, prominent environmental problems, and many reaction steps , to achieve the effects of low production cost, less waste, and good reaction performance

Inactive Publication Date: 2008-03-05
ZHEJIANG UNIV OF TECH +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] The synthesis of ketorolac tromethamine all takes the method that ketorolac directly forms a salt, and the synthesis of ketorolac, starting from starting materials, can be divided into two kinds of synthetic routes on the whole, namely (1) with 3- Keto-1,5-glutaric acid dimethyl ester is used as the starting material, after oximation, two-step ring closure reaction, benzoylation, hydrolysis, and decarboxylation to obtain ketorolac, bu

Method used

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  • Method for synthesizing ketorolac ammonia butanetriol key intermediate compound benzoyl pyrrole
  • Method for synthesizing ketorolac ammonia butanetriol key intermediate compound benzoyl pyrrole
  • Method for synthesizing ketorolac ammonia butanetriol key intermediate compound benzoyl pyrrole

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Experimental program
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Effect test

Embodiment 1

[0021] The molar ratio of the feed material is pyrrole: bis (trichloromethyl) carbonate: N, N-disubstituted benzamide is 1: 0.33: 1, N, N-disubstituted benzamide is N, N-diethyl Benzyl benzamide and 2-methyltetrahydrofuran are used as solvent, and its consumption is 20 times of the quality of bis(trichloromethyl)carbonate.

[0022] In a 150mL four-neck flask equipped with a thermometer, reflux condenser and mechanical stirring, add 75mmol (13.3g) of N,N-diethylbenzamide, and add 2-methyltetrahydrofuran (140.8g ) two (trichloromethyl) carbonate 25mmol (7.4g) of dissolving, solvent consumption is 20 times of two (trichloromethyl) carbonate quality, dropwise under ice bath, continue to stir 5h, intermediate is carried out insulation, Then add pyrrole 75mmol (5.03g), react for 4h, and the reaction temperature is 80°C. After the reaction is complete, add saturated brine, stir for 1 h, separate the liquids, and extract with dichloromethane. The obtained organic phase is distilled u...

Embodiment 2

[0024] The molar ratio of the feed material is pyrrole: bis(trichloromethyl) carbonate: N,N-disubstituted benzamide is 1:0.5:1.5, pyrrole is 75mmol (5.03g), N,N-disubstituted benzamide The amide is N,N-diethylbenzamide, and 2-methyltetrahydrofuran is used as a solvent, and the amount used is 20 times the mass of bis(trichloromethyl)carbonate. The reaction temperature was 0°C, the reaction time was 4 hours, and the intermediate was kept warm for 5 hours.

[0025] Other operations are the same as in Example 1, the product yield is 85.0%, and the purity is 98.2%.

Embodiment 3

[0027] The molar ratio of the feed material is pyrrole: bis(trichloromethyl) carbonate: N, N-disubstituted benzamide is 1: 0.75: 2.25, pyrrole is 75mmol (5.03g), N, N-disubstituted benzamide The amide is N,N-diethylbenzamide, and 2-methyltetrahydrofuran is used as a solvent, and the amount used is 20 times the mass of bis(trichloromethyl)carbonate. The reaction temperature is 80° C., the reaction time is 4 hours, and the intermediate is kept warm for 5 hours.

[0028] Other operations are the same as in Example 1, the product yield is 87.8%, and the purity is 96.8%.

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Abstract

The present invention discloses the synthesis process of benzoyl pyrrole as the key intermediate for ketorolac trometamol. Benzoyl pyrrole is synthesized through the reaction of bis(trichloromethyl) carbonate and N, N-disubstituent amide to form one intermediate, adding pyrrole and reaction in organic solvent at 0-120 deg.c for 2-20 hr, and post-treatment of the resultant to obtain benzoyl pyrrole. The technological scheme of the present invention has reasonable production process, safe and reliable operation, high reaction yield, low cost and other advantages, and possesses broad industrial application foreground.

Description

(1) Technical field [0001] The invention relates to a method for synthesizing benzoylpyrrole, a key intermediate of ketorolac tromethamine. (2) Background technology [0002] Ketorolac is a non-steroidal anti-inflammatory drug with strong analgesic, moderate anti-inflammatory and antipyretic effects. In 1988, the US FDA first approved its tromethamine salt for clinical use, and its trade name was Toradol. The currently marketed dosage forms include oral tablets, intramuscular injections, and eye drops. Because the analgesic effect of this drug is stronger than the anti-inflammatory effect, it is mainly used clinically for moderate or severe pain, especially postoperative pain. In addition, it can also be used to control cancer pain, renal colic, trauma pain, trauma pain and chronic injury pain, etc., and has great market value. And benzoylpyrrole is the important intermediate of preparing ketorolac trometamol at present. [0003] The synthesis of ketorolac tromethamine al...

Claims

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Application Information

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IPC IPC(8): C07D207/333
Inventor 李坚军翁意意蒲通苏为科谢媛媛
Owner ZHEJIANG UNIV OF TECH
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