A kind of resolution method of pyrazole derivative or its salt

Abstract

The invention discloses a resolution method for a pyrazole derivative or a salt thereof. The method comprises the following steps: reacting a raceme compound as represented by formula 1 or a salt thereof with a resolving reagent in a resolving solvent at a temperature of -10 to 50 DEG C to produce a diastereomer chiral acid salt and allowing the diastereomer chiral acid salt to be precipitated from the resolving solvent at a temperature of -10 to 50 DEG C; placing the diastereomer chiral acid salt in a crystallization solvent for one crystallization or multiple times of recrystallization; and subjecting the chiral acid salt as represented by formula 2 or formula 3 and an alkali to a neutralization reaction to dissociate a compound as represented by formula 2 or formula 3. The method provided by the invention has the following advantages: a process is stable; quality is controllable; raw and accessory materials are easily available; the method is simple to operate; the compound as represented by formula 1 is used as a raw material for resolution, which enables cost to be low; and a single chiral compound obtained after resolution has optical purity as high as 99.9%, meeting medicinal standard.

Description

technical field [0001] The invention belongs to the field of racemic resolution, in particular to a racemic compound 3-methyl-1-(pyrrolidin-3-yl)-6,7,8,9-tetrahydro-3H-pyrazole Resolution method of [3,4-c]isoquinolin-5(4H)-one or its salt. Background technique [0002] Single configuration compound 3-methyl-1-(pyrrolidin-3-yl)-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c]isoquinoline-5(4H )-ketone (Formula 2 or Formula 3) is a key intermediate of the PARP inhibitor drug disclosed in patent WO2007095628A1. [0003] [0004] Wherein M is none or but not limited to inorganic acids, such as hydrochloric acid, hydrogen bromide, carbonic acid; and organic acids, such as benzenesulfonic acid, acetic acid, formic acid. [0005] PARP is one of the most important new targets in the recent research and development of new anti-tumor drugs in the world. In 2009, the American "Prevention" magazine rated PARP inhibitors against the most stubborn cancers as the nine most valuable in the world'...

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Problems solved by technology

However, the research results show that the compound of formula 5 is used as a raw material, according to the synthesis method of a compound with a similar structure mentioned in the patent WO2007095628A1, that is, using n-butyllithium as a base, and reacting at -78°C, the product is also prone to disappear. Rotation, thus, the target compound (formula 2 or formula 3) cannot be obtained in a single chiral configuration

Even if the reaction conditions are changed, the target compound (Formula 2 or Formula 3) can be obtained, but the compound with a single chiral configuration is expensive as a starting material, and the overall yield of the multi-step reaction is low, further increasing the synthesis cost

In addition, the inventor has also carried out the separation research of chiral column chromatography. Although the separation is successful, it is found that the cost is relatively high and it is not suitable for industrialization.

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