Preparation method of ketorolac tromethamine

A technology for ketorolac tromethamine and tromethamine is applied in the field of preparation of anti-inflammatory and analgesic ketorolac tromethamine, and can solve the problems of poor chromaticity, long hydrolysis reaction time, and ketorolac tromethamine. Alcohol content and other problems, to achieve the effect of simple process, short reaction time and improved reaction yield

Active Publication Date: 2009-11-11
LUNAN PHARMA GROUP CORPORATION
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  • Abstract
  • Description
  • Claims
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Problems solved by technology

[0012] In view of the long hydrolysis reaction time in the prior art, complex operations such as extraction and decarboxylation after acidification, and problems such as ketorolac tromethamine content and chromaticity difference due to the property of ketorolac itself being easily oxidized, the inventors Repeated experiments found that during the acidification process after alkali hydrolysis of 5-benzoyl-2,3-dihydro-1H-pyrrolazine-1,1-dicarboxylate, a large number of bubbles were generated first, followed by precipitation
The method does not need a complex decarboxylation process, effectively avoids the problems of low purity and poor chroma caused by easy oxidation of ketorolac, and has the advantages of simple operation, energy saving and environmental protection, low cost, high yield and purity (two-step total The yield reaches 95%, and the purity is more than 99.9%), which is suitable for large-scale industrial production

Method used

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

Examples

Experimental program
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Embodiment 1

[0032] The synthesis of embodiment 1 ketorolac

[0033] In a 500mL three-neck round bottom flask, add compound II (142g, 0.4mol), 95% ethanol (100ml), 10% aqueous sodium hydroxide solution (50ml), heat to 70°C and stir for 2h, TLC (ethyl acetate Esters: Petroleum ether=1: 2) detect that the reaction is complete, evaporate the ethanol under reduced pressure, adjust the pH to 2 with concentrated hydrochloric acid in the -5°C water layer, and precipitate a solid, and obtain khaki solid 101.9g by suction filtration, and use methanol: water=3 : 1 (volume ratio) to obtain 96.8 g of white solid compound III with a yield of 95%.

Embodiment 2

[0034] The synthesis of embodiment 2 ketorolac

[0035] In a 500mL three-neck round bottom flask, add compound II (142g, 0.4mol), methanol (110ml), 10% potassium hydroxide aqueous solution (55ml), heat to 60°C and stir for 4h, TLC detects ethyl acetate:petroleum Ether=1:2 (volume ratio) The reaction is complete. The methanol was distilled off under reduced pressure, and the pH of the -10°C water layer was adjusted to 2.5 with 3mol / L sulfuric acid, and a solid was precipitated, which was filtered with suction to obtain 95.8 g of a khaki solid, which was refined with methanol:water=1:1 (volume ratio) to obtain a white solid 88.8 g g, yield 87%.

Embodiment 3

[0036] Example 3 Synthesis of ketorolac

[0037] In a 500mL three-neck round bottom flask, add compound II (142g, 0.4mol), 95% ethanol (120ml), 10% aqueous sodium hydroxide solution (60ml), heat to 50°C and stir for 4.5h, TLC detects acetic acid Ethyl:petroleum ether=1:2 (volume ratio) The reaction is completed, and the ethanol is evaporated under reduced pressure, and the pH of the 10°C water layer is adjusted to 2 with concentrated hydrochloric acid, and the solid is precipitated, and the khaki solid 103.4g is obtained by suction filtration. = 3:1 (volume ratio) Purified to obtain 97.9 g of white solid compound III with a yield of 96%.

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Abstract

The invention provides a preparation method of ketorolac tromethamine. 5-benzoyl-2, 3-dihydro-1H-dilazine-1 and 1-diethyl azodicarboxylate are the starting materials and are prepared into salt by alkaline hydrolysis and acidification when reducers exist, and finally, the salt is prepared into ketorolac tromethamine. The method does not need complicated decarboxylation process, and effectively solves the problems of low purity, poor color and the like caused by the oxidizability of ketorolac. The invention has the advantages of simple operation, high yield and high purity (the total yield in two steps reaches 95% and the purity reaches more than 99.9%); thus, the preparation method is suitable for large-scale commercial process.

Description

Technical field: [0001] The invention belongs to the field of pharmaceutical synthesis, and in particular relates to a preparation method of ketorolac trometamol, an anti-inflammatory and analgesic drug. Background technique: [0002] Ketorolac tromethamine (ketorolac tromethamine) is a new non-steroidal powerful analgesic and moderate anti-inflammatory antipyretic drug, chemical name: (±)-5-benzoyl-2,3 dihydro-1H -Pyrrolazine-1-carboxylic acid 2-amino-2-hydroxymethyl 1,3-propanediol salt, the structural formula is: [0003] [0004] Ketorolac trometamol is a new type of NSAID drug available for injection, which was developed by Cindy's Pharmaceutical Company of the United States and first listed in Italy in 1990. The analgesic effect of ketorolac tromethamine is stronger than the anti-inflammatory effect. Many research results show that it is better than morphine in relieving postoperative pain. Degree or severe peripheral pain, etc. [0005] At present, there are man...

Claims

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Application Information

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IPC IPC(8): C07D487/04A61P29/00
Inventor 赵志全李月王斯坦
Owner LUNAN PHARMA GROUP CORPORATION
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