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A kind of preparation method of bripiprazole intermediate 7-hydroxy-1h-quinolin-2-one
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A -1H, quinoline technology, applied in the field of preparation of bripiprazole intermediate 7-hydroxy-1H-quinolin-2-one, can solve the problem of low yield, damage to analysts and the environment, instability, etc. question
Active Publication Date: 2022-07-12
NHWA PHARMA CORPORATION
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DDQ (2,3-dichloro-5,6-dicyano-benzoquinone) is used as an aromatizationreagent in the route, but the properties of DDQ limit its use: (1) Since DDQ is a p-benzoquinone structure, It has a genotoxic warning structure; (2) DDQ is very unstable to water, and it will produce highly toxic hydrocyanic acid when it meets water, which will cause great harm to the environment and personnel; (3) new by-product impurities are introduced in the reaction; (4) The post-processing is cumbersome and the yield is not high (about 70%); (5) use DDQ to prepare the pharmaceutical intermediate 7-hydroxy-1H-2-ketone, in its purity detection, DDQ must be detected and controlled as an aromatizationreagent its limit, due to the highly toxic hydrocyanic acid produced by DDQ in contact with water, which is potentially harmful to analysts and the environment
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Embodiment 1
[0038] 20.00g (122.6mmol) 7-hydroxy-3,4-dihydro-1H-quinolin-2-one, 10.00g Pd / C (10%, 58% water wet) and 200ml acetic acid were added to the reaction flask, Into the air, heated to reflux (110-116 ° C) for 24 hours, TLC monitoring the reaction is complete.
[0039] The reaction solution was filtered hot, the filter cake was washed with acetic acid, the filtrate was evaporated under reduced pressure to obtain an off-white solid, 200 ml of absolute ethanol was added to reflux for 1 hour, stirred at room temperature for 2 hours, suction filtered, and dried to obtain 18.32 g of off-white solid. The yield was 92.8%, and the HPLC purity was 99.6%.
Embodiment 2
[0044] 20.00g (122.6mmol) 7-hydroxy-3,4-dihydro-1H-quinolin-2-one, 10.00g Pd / C (10%, 58% water wet) and 200ml acetic acid were added to the reaction flask, heated Reflux (110-116°C) for 60 hours, complete by TLC monitoring.
[0045] The reaction solution was filtered hot, the filter cake was washed with acetic acid, the filtrate was evaporated under reduced pressure to obtain an off-white solid, 200 ml of anhydrousethanol was added to reflux for 1 hour, stirred at room temperature for 2 hours, suction filtered, and dried to obtain 18.16 g of off-white solid. The yield was 91.9%, and the HPLC purity was 99.6%.
Embodiment 3
[0047]20.00g (122.6mmol) 7-hydroxy-3,4-dihydro-1H-quinolin-2-one, 10.00g Pd / C (10%, 58% water wet) and 200ml acetic acid were added to the reaction flask, Oxygen was introduced, heated to reflux (110-116° C.) for 18 hours, and the reaction was completed by TLC monitoring.
[0048] The reaction solution was filtered hot, the filter cake was washed with acetic acid, the filtrate was evaporated under reduced pressure to obtain an off-white solid, 200 ml of absolute ethanol was added to reflux for 1 hour, stirred at room temperature for 2 hours, suction filtered, and dried to obtain 18.61 g of off-white solid. The yield was 94.2%, and the HPLC purity was 99.5%.
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Abstract
The invention belongs to the field of chemical industry, and in particular relates to a preparation method of bripiprazole intermediate 7-hydroxy-1H-quinoline-2-ketone. The invention provides a new method for preparing 7-hydroxy-1H-quinoline-2-ketone. The method replaces DDQ with palladium carbon, and the obtained product has high yield, less impurities, simple operation, and can realize the recycling of catalyst, The target compound is synthesized by direct catalytic dehydrogenation, which has green atom economy and is suitable for industrial production.
Description
Technical field: [0001] The invention belongs to the field of chemical industry, in particular to a preparation method of bripiprazole intermediate 7-hydroxy-1H-quinolin-2-one. Background technique: [0002] Brexpiprazole, jointly developed by Lundbeck Pharma and Otsuka Pharma, is an experimental serotonin-dopamine activity modulator (SDAM) that acts on dopamine D2 and 5-HT 2A receptor. Among the dopamine D2 receptors, partial agonists of D2 receptors can have a functional antagonism on the mesolimbic pathway, which can effectively improve the positive symptoms of schizophrenia caused by D2 overactivity; Sexual agonism can improve negative symptoms and cognitive impairment caused by low D2 function. [0003] Brexpiprazole is a novel multi-target mechanism of action for the treatment of mental disorders. In addition to the partial agonism of dopamine D2 receptors, it also has partial agonism of D3 receptors, 5-HT 1A Partial receptor agonism and 5-HT 2A Partial receptor an...
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