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A kind of crystallization method of parp inhibitor intermediate

A technology of intermediates and inhibitors, which is applied in the field of crystallization of PARP inhibitor intermediates, can solve problems such as the difficulty of solvent selection and purification, and achieve the effect of improving purity and production quality

Active Publication Date: 2022-04-29
百济神州(苏州)生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] BG-11 is a key quality control point in the production process of Pamiparib, yet BG-11 is a less polar compound, and it has good solubility in a variety of polar solvents, for example, at room temperature in such as acetonitrile , tetrahydrofuran, ethyl acetate and even methyl tert-butyl ether have relatively good solubility, which brings certain difficulties to the solvent selection and purification of the crystallization of the compound

Method used

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  • A kind of crystallization method of parp inhibitor intermediate
  • A kind of crystallization method of parp inhibitor intermediate

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] The crude product solution containing 16.5g of BG-11 was distilled to remove the solvent through a distillation device under reduced pressure, and 67.5g of methanol was added, heated to 55°C, stirred for 2h until clarified, cooled to 40°C, added with seed crystals, slowly added 8.25g of water, and cooled to Stir at 5°C for 20h, filter, wash the filter cake with methanol / water mixed solution, and dry under vacuum at 45°C for 12h to obtain 13.9g of compound 1 with a purity of 99.53%. The crystal X-ray diffraction pattern of this compound is as follows: figure 1 As shown, the DSC of the compound is as figure 2 shown.

Embodiment 2

[0037] The crude product solution containing 16.5g of BG-11 was distilled to remove the solvent through a distillation device under reduced pressure, and 97.5g of methanol was added, heated to 55°C (reflux), stirred for 2h until clarified, cooled to 40°C, added with seed crystals, and slowly added with 8.25g of water , cooled to 5° C. and stirred for 20 h, filtered, the filter cake was washed with methanol / water mixed solution, and vacuum-dried at 45° C. for 12 h to obtain 13.13 g of compound 1 with a purity of 99.46%.

Embodiment 3

[0039] The crude product solution containing 16.5g of BG-11 was distilled under reduced pressure by a distillation device to remove the solvent, added 82.5g of methanol, heated to 50°C, stirred for 2h until clarified, cooled to 35°C, added seed crystals, slowly added 8.25g of water, and cooled to Stir at 5°C for 20h, filter, wash the filter cake with methanol / water mixed solution, and dry in vacuum at 45°C for 12h to obtain 13.96g of compound 1 with a purity of 99.48%.

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Abstract

The present invention relates to an intermediate (R)-2-(1-(2-(tert-butyloxy)-2-oxoethyl)-2-methylpyrrolidin-2 base) of a PARP inhibitor Pamiparib The crystallization method of -6-fluoro-1-toluenesulfonyl-1H-indole-4-carboxylate methyl ester, the crystallization method selects alcohols or alcohol / water mixed solvents as the crystallization solvent, and in the process of cooling and crystallization Reduce the temperature to below 20°C. The method will obtain intermediates with higher purity, and the process greatly improves the purity of intermediates in the large-scale production process and improves the production quality of pharmaceutical intermediates.

Description

technical field [0001] The present invention relates to a crystallization method of a PARP inhibitor intermediate, in particular to an intermediate (R)-2-(1-(2-(tert-butyloxy)-2-oxoethyl)-2- of Pamiparib Methylpyrrolidin-2-yl)-6-fluoro-1-toluenesulfonyl-1H-indole-4-carboxylic acid methyl ester crystallization method. Background technique [0002] WO2013 / 097225A1 discloses as inhibitors of poly(ADP-ribosyl)transferases (PARPs), and specifically discloses compounds Namely (R)-2-fluoro-10a-methyl-7,8,9,10,10a,11-hexahydro-5,6,7a,11-tetraazepine[def]cyclopenta Dieno[a]fluoren-4(5H)-one, a polyadenosine diphosphate (ADP) ribose polymerase (PARP) inhibitor with high selectivity for PARP-1 / 2, And can effectively inhibit the proliferation of cell lines with BRCA1 / 2 mutations or other HR defects, and significantly induce tumor regression in BRCA1 mutant breast cancer xenograft models at a much lower dose than olaparib. The compound has excellent DMPK properties and significant ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D403/04
CPCC07D403/04C07B2200/07
Inventor 掌子龙蒋群刘军涛杜争鸣
Owner 百济神州(苏州)生物科技有限公司