Preparation method of ketorolac tromethamine intermediate

A technology of ketorolac trometamol and intermediates, applied in organic chemistry and other fields, can solve the problems of being unsuitable for industrialized large-scale production, and achieve the effects of less impurities, improved reaction yield and purity, and fast reaction speed

Pending Publication Date: 2021-07-30
LUNAN PHARMA GROUP CORPORATION
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] Although this method avoids multiple alkylations, it requires strong oxidizing hydrogen peroxide as the oxidizing agent, which is not suitable for large-scale industrial production

Method used

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  • Preparation method of ketorolac tromethamine intermediate
  • Preparation method of ketorolac tromethamine intermediate
  • Preparation method of ketorolac tromethamine intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0029] 2,5-dimethoxytetrahydrofuran (13.2g, 0.1mol), 2-(2-aminoethyl)-diethyl malonate (24.36g, 0.12mol), copper sulfate (1g, 8%) , tetrahydrofuran (100ml), and water (5ml) were added to a 250ml reaction flask, refluxed for 10h, cooled, evaporated to remove the solvent under reduced pressure, the residue was added dichloromethane (100ml), suction filtered, and the filtrate was washed with water (50ml). Separate layers, add anhydrous sodium sulfate to the dichloromethane layer for drying, and evaporate the solvent to give 2-(2-(1H-pyrrol-1-yl)ethyl)diethyl malonate with a yield of 98.7%, HPLC purity 99.88%.

Embodiment 2

[0031] 2,5-dimethoxytetrahydrofuran (13.2g, 0.1mol), 2-(2-aminoethyl)-diethyl malonate (22.33g, 0.11mol), copper acetate (1g, 8%) , acetonitrile (100ml), and water (5ml) were added to a 250ml reaction flask, refluxed for 10h, cooled, and the solvent was evaporated under reduced pressure, the residue was added chloroform (100ml), suction filtered, and the filtrate was washed with water (50ml). Separate layers, add anhydrous sodium sulfate to the chloroform layer to dry, and evaporate the solvent to give 2-(2-(1H-pyrrol-1-yl)ethyl)diethyl malonate with a yield of 94.4%, HPLC purity 99.82%.

Embodiment 3

[0033] 2,5-dimethoxytetrahydrofuran (13.2g, 0.1mol), 2-(2-aminoethyl)-diethyl malonate (20.32g, 0.10mol), copper chloride (1g, 8% ), tetrahydrofuran (100ml), water (5ml) were added to a 250ml reaction flask, refluxed for 10h, lowered the temperature, evaporated the solvent under reduced pressure, added chloroform (100ml) to the residue, suction filtered, and washed the filtrate with water (50ml) , layered, the chloroform layer was dried by adding anhydrous sodium sulfate, and the solvent was evaporated to dryness to obtain 2-(2-(1H-pyrrol-1-yl)ethyl)diethyl malonate with a yield of 86.8%, HPLC 99.74% pure.

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Abstract

The invention belongs to the technical field of medicine synthesis, and relates to a preparation method of a ketorolac tromethamine intermediate. According to the preparation method, 2, 5-dimethoxy tetrahydrofuran reacts with a compound 2-(2-aminoethyl) diethyl malonate to generate the important intermediate 2-(2-(1H-pyrrole-1-yl) ethyl) diethyl malonate of ketorolac tromethamine. According to the novel method for synthesizing the ketorolac intermediate, use of dangerous chemical reagents is avoided, the synthesized intermediate does not generate new impurities, a traditional catalyst is replaced with a green catalyst, the reaction is milder, economical and environmentally friendly, the yield is high, and the method is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, and in particular relates to a preparation method of a ketorolac tromethamine intermediate. Background technique [0002] Ketorolac Tromethamine (Ketorolac Tromethamine), the chemical name is (±)-5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-formic acid tromethamine salt, is a Non-steroidal anti-inflammatory drugs, developed and marketed by Syntex Corporation of the United States, have strong analgesic and moderate anti-inflammatory and antipyretic effects, and can be taken orally or injected intramuscularly to relieve moderate to severe postoperative pain. Ketorolac tromethamine exerts analgesic, anti-inflammatory and antipyretic effects by inhibiting the synthesis of prostaglandins. The analgesic effect of 30 mg is equivalent to 12 mg of morphine, but it is not addictive. Its chemical structure is shown below: [0003] [0004] There are many synthetic routes about ketorolac tromethamine r...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/327
CPCC07D207/327
Inventor 张贵民朱安国张乃华
Owner LUNAN PHARMA GROUP CORPORATION
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