Synthesis method of ketorolac

Abstract

The invention discloses a novel ketorolac synthesis method, which takes 2-(1H-pyrrole-1-yl) propionitrile as a raw material, and ketorolac is obtained through the steps of cyclization reaction, benzoylation reaction, Vanderson reaction, hydrolysis reaction and the like.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical chemistry, and specifically relates to the preparation of a nonsteroidal anti-inflammatory drug. Background Technology

[0002] Ketoroxyprostaglandin is a prostaglandin synthase inhibitor with potent analgesic and moderate anti-inflammatory and antipyretic effects. It primarily works by blocking cyclooxygenase, the enzyme that metabolizes arachidonic acid, thereby reducing prostaglandin synthesis. In standard animal models of analgesia, its analgesic activity is 800 times that of aspirin, stronger than indomethacin and naproxen, and comparable to or superior to phenylbutazone. In multiple studies, its anti-inflammatory activity is equivalent to or stronger than indomethacin, stronger than naproxen, and significantly superior to phenylbutazone. The advantages of this drug are the absence of central nervous system damage and addictive side effects, as well as respiratory depression or constipation. Ketoroxyprostaglandin tromethamine was developed by Syntex Pharmaceuticals in the United States and first marketed in Spain in 1988. It was included in the European Pharmacopoeia and the British Pharmacopoeia in 1998 and is now marketed in more than 20 countries, including the UK, Germany, France, and Spain. Clinically, it is used to relieve inflammation and pain caused by rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis, and is a safe and reliable drug for treating acute and chronic pain and inflammation.

[0003] The Chinese name for ketorolac is (+ / -)-5-benzoyl-2,3-dihydro-1H-pyrrolopyrrolidine-1-carboxylic acid, and its chemical structure is as follows: .

[0004] Currently, there are very few publicly available publications on the synthesis of ketorolac. Sichuan Pharmaceutical Co., Ltd. has disclosed a method for synthesizing ketorolac in CN 11403162. This method involves a substitution reaction, a cyclization reaction, and finally hydrolysis protection of 2-benzoylpyrrole to synthesize ketorolac. The process is as follows: .

[0005] This method involves complex synthesis steps, numerous side reactions, cumbersome post-reaction processing, and relatively low production efficiency. Summary of the Invention

[0006] In view of this, the present invention provides a novel method for preparing ketorolac. This method uses 2-(1H-pyrrolo-1-yl)propionitrile as a raw material and obtains ketorolac through steps including cyclization, acylation, van der Rohesen reaction, and hydrolysis. The route is as follows: .

[0007] The steps include: 1. Ring-closing reaction In the presence of PPA, 2-(1H-pyrrolo-1-yl)propionitrile undergoes a cyclization reaction to generate intermediate -1 (2,3-dihydro-1H-pyrroloazin-1-one). PPA serves as both the reaction solvent and catalyst.

[0008] 2. Acylation reaction Benzoyl chloride and intermediate-1 in an inert solvent were condensed under Lewis acid catalysis to yield intermediate-2 (5-phenylcarbonyl-2,3-dihydro-1H-pyrrin-1-one). Common Lewis acids such as aluminum trichloride, ferric chloride, boron trifluoride, and zinc chloride were used as catalysts, with ferric chloride exhibiting the best catalytic effect. The catalyst dosage was 10% (by weight) of the substrate. The reaction time was 2-3 hours.

[0009] Van Lesen reaction Intermediate-2 was reacted with TosMIC (p-methylbenzenesulfonylmethylisocyanate) in tert-butanol and ethylene glycol dimethyl ether in the presence of potassium tert-butoxide to give 5-phenylcarbonyl-2,3-dihydro-1H-pyridine-1-carboxynitrile (intermediate-3). The solvent was tert-butanol and ethylene glycol dimethyl ether in a 1:1 ratio, with the solvent volume being 5 times that of the substrate, and the base was potassium tert-butoxide, with the volume being 2 times that of the substrate.

[0010] hydrolysis reaction Intermediate 3 was hydrolyzed in an aqueous sodium hydroxide solution by heating to obtain ketorolac. The reaction temperature was 50-60℃, and the reaction time was 12-13 hours. The amount of sodium hydroxide used was twice the molar ratio of the substrate.

[0011] The present invention is characterized by employing a novel method to obtain high-purity ketorolac with high selectivity and high yield from inexpensive and readily available 2-(1H-pyrrolo-1-yl)propionitrile. This method has significant economic value. Detailed Implementation

[0012] Add 50g of 2-(1H-pyrrolo-1-yl)acetonitrile and 100ml of polyphosphoric acid to a 500ml reaction flask. Raise the temperature of the reaction vessel to 130-140℃ and maintain the reaction temperature for 4 hours. Pour the reaction solution into 200ml of ice water and stir at 0-5℃ for 30 minutes. Filter the solution, wash the filter cake with 50ml of water, and discard the filtrate. Dry the solid at 40-45℃ under normal pressure for 12 hours. The resulting residue is 52g of intermediate-1, with a yield of 91.2%, and is a white solid, which can be used directly in the next reaction step.

[0013] Add 52g of intermediate-1 obtained in the previous step and 250ml of dichloromethane to a 500ml three-necked flask. Cool to 0-5℃, add 5.2g of ferric chloride, maintain the temperature at 0-5℃, and add 60ml of benzoyl chloride dropwise. After the addition is complete, slowly raise the temperature to 20-25℃ and react for 2 hours. After the reaction is complete, pour the reaction solution into 200ml of 5% sodium hydroxide water, stir to separate the layers, and wash the dichloromethane layer three times with 3 x 100ml of 5% sodium hydroxide water. Dry the dichloromethane layer with 20g of magnesium sulfate, filter, and concentrate the filtrate under reduced pressure to dryness to obtain 82g of intermediate-2, with a yield of 84.8%. The solid is yellow and can be used directly in the next reaction.

[0014] Add 82 g of intermediate-2 obtained in the previous step to a 1000 ml three-necked flask, along with 200 ml of tert-butanol, 200 ml of ethylene glycol dimethyl ether, 78 g of p-toluenesulfonylmethylisocyanate, and 81.7 g of potassium tert-butoxide. React at 20-25 °C for 48 hours. After the reaction is complete, evaporate the reaction solvent to dryness at 40-45 °C, add 200 ml of water and 3 x 100 ml of dichloromethane, stir to separate the layers, extract the products from the layers, combine the dichloromethane layers, add 15 g of anhydrous sodium sulfate and dry for 10 min, filter, wash the filter cake with 50 ml of dichloromethane, discard the solid, and concentrate the filtrate under reduced pressure at no more than 40 °C until the flow stops, to obtain 75 g of intermediate-3, with a yield of 87.2%, which is a pale yellow liquid. It can be used directly in the next reaction.

[0015] Add 75g of intermediate-3 obtained in the previous step, 150ml of ethanol, and 12.7g of sodium hydroxide dissolved in 150ml of water to a 500ml three-necked flask. Heat the flask to 75-78℃ and reflux for 12-13 hours. After the reaction was complete, ethanol was removed under reduced pressure at 40-45℃. 100ml of water and 50ml of dichloromethane were added, and the mixture was stirred to separate the layers. The dichloromethane layer was discarded. The aqueous layer was adjusted to pH 1-2 with 30ml of hydrochloric acid. 100ml of dichloromethane was added three times, and the mixture was stirred to separate the layers and extract the product. The dichloromethane layers were combined, and 10g of anhydrous sodium sulfate was added. The mixture was dried for 10 minutes and filtered. The filter cake was washed with 30ml of dichloromethane, and the solid was discarded. The filtrate was concentrated under reduced pressure at no more than 40℃ until the flow stopped, yielding 72g of solid. 30ml of ethanol and 90ml of water were added, and the mixture was stirred for 30 minutes and filtered. The filter cake was washed with 30ml of ethanol:water = 3:1, and the filtrate was discarded. The solid was dried in an oven at 40-45℃ under normal pressure for 6 hours to obtain 65g of ketorolac, a white solid with a yield of 91%.

Claims

1. A method for synthesizing ketorolac, characterized by the following steps: ； (1) 2-(1H-pyrrolo-1-yl)propionitrile was reacted with PPA to generate intermediate-1 (2,3-dihydro-1H-pyrroloazin-1-one). (2) Benzoyl chloride and intermediate-1 were condensed under ferric chloride catalysis to obtain intermediate-2 (5-phenylcarbonyl-2,3-dihydro-1H-pyridine-1-one). (3) Intermediate-2 was reacted with p-methylbenzenesulfonylmethylisocyanate (TosMIC) in tert-butanol and ethylene glycol diethyl ether under the action of potassium tert-butanol to obtain intermediate-3 (5-phenylcarbonyl-2,3-dihydro-1H-pyridine-1-carboxynitrile). (4) Hydrolyze intermediate 3 under the action of alkali to obtain ketorolac.

2. The method as described in claim 1, characterized in that in step (1), 2-(1H-pyrrolo-1-yl)propionitrile is reacted with PPA to generate intermediate 1, and the reaction solvent and catalyst are both PPA (polyphosphoric acid); the optimal reaction temperature is 130-140℃.

3. The method as described in claim 1, characterized in that in step (2), benzoyl chloride and intermediate-1 are condensed under Lewis acid catalysis to obtain intermediate-2, and the best catalyst is ferric chloride.

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