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Preparation method of related impurities of ketorolac or salts thereof

A technology of ketorolac and ketorolac, which is applied in the direction of organic chemistry, can solve the problems of numerous by-products, cumbersome reaction process, and high cost, and achieve the effects of convenient and easy-to-obtain raw materials, simple preparation methods, and few by-products

Pending Publication Date: 2022-03-15
四川仁安药业有限责任公司
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AI Technical Summary

Problems solved by technology

In foreign countries, potassium permanganate is added to ketorolac tromethamine, and (1RS)-5-benzoyl-2,3-dihydro-1H-pyrrolizine-1- Alcohol (EP10.0 version impurity A), but its recovery rate is not high, in addition also needs column separation, the reaction process is loaded down with trivial details
In addition, foreign countries also add polar solvents and ferric chloride to ketorolac, react in an oxygen atmosphere, and obtain 5-benzoyl-2,3-dihydropyrrolidin-1-one (EP10 .0 version of impurity B), this method needs to control the reaction under anhydrous conditions, selective crossover, numerous by-products, complex reaction process, low product yield and high cost

Method used

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  • Preparation method of related impurities of ketorolac or salts thereof
  • Preparation method of related impurities of ketorolac or salts thereof
  • Preparation method of related impurities of ketorolac or salts thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0042] Take a 500ml single-neck bottle, add 20g of ketorolac, add 100g of DMF (ie dimethylformamide), add 5g of copper powder, and react with magnetic stirring at 140°C for 12h, TLC (ie, thin layer chromatography) to monitor the reaction progress. 40°C, filter to remove excess copper powder, add 200 g of water, the system becomes turbid, extract three times with 50 g of ethyl acetate each time, combine the organic phases and concentrate to dryness to obtain a pale yellow crystalline solid 6,7-dihydro-5H-pyrrolizine-3 -Base (phenyl) ketone 15.2g (the specific structure confirms the map to participate in Figure 1-3 ), purity 99.56%, yield 92%.

[0043] Take a 500ml single-neck bottle, add 5g of 6,7-dihydro-5H-pyrrolizin-3-yl (phenyl) ketone, add 50g of acetic acid, add 20g of 20% potassium permanganate aqueous solution, control the temperature to 80°C, and magnetically stir 6h, TLC monitored the reaction progress and the reaction was completed, cooled to 25°C, poured into 200g...

Embodiment 2

[0046] Take a 500ml single-neck bottle, add 20g of ketorolac, add 100g of ethylene glycol, add 6g of iron powder, and react with magnetic stirring at 150°C for 12h. TLC monitors the reaction progress and the reaction is completed. After the reaction is completed, the temperature is lowered to 40°C, the excess iron powder is removed by filtration, and 200g of water is added. The system became cloudy, extracted three times with 50 g of ethyl acetate each time, and the combined organic phases were concentrated to dryness to obtain 12.06 g of pale yellow crystalline solid 6,7-dihydro-5H-pyrrolizin-3-yl(phenyl)methanone, with a purity of 12.06 g. 99.43%, yield 73%.

[0047] Take a 500ml single-neck bottle, add 5g of 6,7-dihydro-5H-pyrrolizin-3-yl (phenyl) ketone, add 50g acetic acid, add 20g 20% ​​high chromium trioxide aqueous solution, control the temperature to 70°C, and stir magnetically for 3h , TLC monitored the reaction progress and the reaction was completed, cooled to 25°C...

Embodiment 3

[0050] Take a 500ml single-neck bottle, add 20g of ketorolac, add 100g of p-xylene, add 5g of copper powder, magnetic stirring and reflux for 16h, TLC to monitor the reaction progress and complete the reaction, cool down to 40°C, filter to remove excess copper powder, add 200g of water and the system becomes cloudy , extracted three times with 50 g of ethyl acetate each time, and the combined organic phases were concentrated to dryness to obtain a pale yellow crystalline solid 6,7-dihydro-5H-pyrrolizin-3-yl (phenyl) ketone 6.58 g with a purity of 99.24%, Yield 59%.

[0051] Take a 500ml single-neck bottle, add 5g of 6,7-dihydro-5H-pyrrolizin-3-yl (phenyl) ketone, add 50g of acetic acid, add 20g of 20% ammonium cerium nitrate aqueous solution, control the temperature to 80°C, and stir magnetically for 3h , TLC monitored the reaction progress and the reaction was completed, cooled to 25°C, poured into 200g ice water to quench the reaction, the system changed from reddish-brown t...

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Abstract

The invention discloses a preparation method of related substances of ketorolac or ketorolac salt, which comprises the following steps: by taking ketorolac or ketorolac salt as an initial raw material, adding a metal catalyst into an organic solvent, filtering out the residual metal catalyst after reaction, and crystallizing to obtain 6, 7-dihydro-5H-pyrrolizine-3-yl (phenyl) ketone; the preparation method comprises the following steps: dissolving 6, 7-dihydro-5H-pyrrolizine-3-yl (phenyl) ketone in a solvent, oxidizing the 6, 7-dihydro-5H-pyrrolizine-3-yl (phenyl) ketone with an oxidizing agent, and crystallizing the 6, 7-dihydro-5H-pyrrolizine-3-yl (phenyl) ketone to obtain 5-benzoyl-2, 3-dihydropyrrolizine-1-ketone; the preparation method comprises the following steps: adding 5-benzoyl-2, 3-dihydropyrrolizine-1-ketone into a polar solvent, reducing the 5-benzoyl-2, 3-dihydropyrrolizine-1-ketone by using a reducing agent, and crystallizing to obtain the (1RS)-5-benzoyl-2, 3-dihydro-1H-pyrrolizine-1-alcohol. The method is easy to operate, raw materials are convenient and easy to obtain, and the total yield can reach 70% or above. Compared with a preparation method in the prior art, the preparation method has the advantages that byproducts are few, the yield is obviously increased, the preparation method is simple and convenient, and high-purity and high-yield related substances can be obtained without tedious and harsh conditions.

Description

technical field [0001] The invention relates to the technical field of organic synthesis, in particular to a method for preparing related impurities of ketorolac or its salts. Background technique [0002] Ketorolac trometamol is a non-steroidal anti-inflammatory drug that can inhibit the biosynthesis of prostaglandins, has analgesic effect, and has no sedative or anxiolytic effect, so it is widely used in perioperative analgesia. For the product quality of the controller, the United States Pharmacopoeia (USP) 43 edition and the European Pharmacopoeia (EP) 10.0 edition have recorded its quality standards. [0003] During the investigation of product quality research, it was found that several related substances were included in the pharmacopoeias of various countries, including (1RS)-5-benzoyl-2,3-dihydro-1H-pyrrolizin-1-ol (EP10.0 Version impurity A), 6,7-dihydro-5H-pyrrolizin-3-yl (phenyl) ketone (EP10.0 version impurity I), 5-benzoyl-2,3-dihydropyrrolizine -1-ketone (EP...

Claims

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Application Information

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IPC IPC(8): C07D487/04
CPCC07D487/04Y02P20/584
Inventor 冯建科何勇侯正波张皓文沈建辛
Owner 四川仁安药业有限责任公司
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