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Method for preparing ketorolac tromethamine

A technology of ketorolac tromethamine and triethyl ester, applied in directions such as organic chemistry, can solve problems such as unsatisfactory yield, high cost of industrialized production, insufficient simplification of steps, etc., and achieves reduced labor intensity, reduced loss, Yield-enhancing effect

Active Publication Date: 2008-03-19
LUNAN PHARMA GROUP CORPORATION
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] In U.S. Patent No. 4,089,969, a method for synthesizing ketorolac with 3-keto-1,5-glutaric acid dimethyl ester as a starting material is disclosed, but the yield is not high, the steps are too complicated, and the cost of industrial production is too high. high
[0006] In U.S. Patent No. 5,082,950, a process route for preparing ketorolac tromethamine salt using pyrrole as a starting material is disclosed, but the steps are not simplified enough, and the industrial production cost is too high
[0007] "Chinese Journal of Medicinal Chemistry" published an improved method for synthesizing ketorolac in the third issue of 1995. Ketorolac was obtained through a 4-step reaction. The yield is not particularly ideal and the operation is cumbersome.

Method used

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  • Method for preparing ketorolac tromethamine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0013] Put 13g of triethyl 5-benzoylpyrrole-2-methanetricarboxylate, K 2 CO 3 30g, 10g of n-tetrabutylammonium bromide, and 1.5L of 1,2-dichloroethane were placed in a reaction flask, stirred and refluxed for 24 hours, cooled to 10°C, filtered, concentrated under reduced pressure, and then added 300ml of methanol and 150ml of 25gNaOH Aqueous solution, reflux and stir for 12 hours, evaporate methanol, lower to room temperature, wash twice with diethyl ether, adjust pH value to ph=1 with concentrated hydrochloric acid, precipitate oil, dissolve 5 g of tromethamine in 100 ml of methanol and add to the oil, Then add 3g of activated carbon, heat to reflux for 2h, cool to 05°C, an off-white solid precipitates, filter with suction, wash twice with ethanol and ethyl acetate respectively, and dry to obtain 6g of off-white compound I solid, mp164~166°C, crude product Yield 89%.

Embodiment 2

[0015] Put 28g of triethyl 5-benzoylpyrrole-2-methanetricarboxylate, K 2 CO 3 56g, 23g of n-tetrabutylammonium bromide, and 3.0L of 1,2-dichloroethane were placed in a reaction flask, stirred and refluxed for 24 hours, cooled to 5°C, filtered, concentrated under reduced pressure, and then added 300ml of 500ml of methanol and 43g of NaOH Aqueous solution, reflux and stir for 12h, evaporate methanol, lower to room temperature, wash twice with ether, adjust pH value to 2 with concentrated hydrochloric acid, precipitate oil, dissolve tromethamine 12g in 300ml methanol and add to the oil, then add Activated carbon 8g, heated to reflux for 2h, cooled to 0-5°C, an off-white solid precipitated, filtered with suction, washed twice with ethanol and ethyl acetate respectively, and dried to obtain 13g of off-white compound I solid, mp164-166°C, crude product Yield 91%.

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Abstract

The present invention relates to a non-steroidal anti-inflammatory drug of ketorolac tromethamine salt, which has the functions of strong acesodyne, moderate anti-inflammation and antipyresis. The present invention applies a synthesis route preparing the compound ketorolac tromethamine salt, the technique applies an one-pot method, the reaction process from 2-benzoyl pyrrole to the ketorolac tromethamine salt can be continuously carried out, extraction and purification are not needed, materials can be easily obtained, labor intensity is reduced, the operational environment is improved, the cost of industrialized production is greatly reduced, environmental pollution is reduced, the loss of materials and products is reduced, and the yield rate is increased.

Description

technical field [0001] The invention belongs to the field of pharmaceutical synthesis, and in particular relates to a new preparation method of ketorolac trometamol. Background technique [0002] Ketorolac tromethamine (ketorolac tromethamine) is a non-steroidal anti-inflammatory drug developed and marketed by Syntex Corporation of the United States. It has strong pain relief and moderate anti-inflammatory and antipyretic effects. It can be taken orally or intramuscularly. Synthesized to exert analgesic, anti-inflammatory and antipyretic effects, the analgesic effect of 30mg is equivalent to 12mg morphine, but it is not addictive. Its tromethamine salt is clinically used, and its chemical name is (±)-5-benzoyl-2, 3-dihydro-1H-pyrrolazine-1-carboxylic acid and 2-amino-2-hydroxymethyl-1 , 3 propylene glycol salts (1: 1) compound, structural formula is (I): [0003] [0004] There have been many reports on the synthetic route and process of (I) at home and abroad, and ther...

Claims

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Application Information

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IPC IPC(8): C07D487/04
Inventor 赵志全
Owner LUNAN PHARMA GROUP CORPORATION
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