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Synthesis method of eslicarbazepine acetate with high purity and stable crystal form

A technology of eslicarbazepine acetate and crystal form, which is applied to the synthesis method of high-purity eslicarbazepine acetate and the field of stable crystal forms thereof, can solve the problem that industrialized production cannot be realized, heavy metal residues in the final product, and by-products are difficult to remove and other problems, to achieve the effects of good chemical stability, low cost and easy availability of raw materials

Pending Publication Date: 2022-02-18
XIAN XINTONG PHARM RES CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The by-products of the reduction reaction in this route are difficult to remove, and need to be separated and purified by column chromatography, which cannot realize industrial production, and the chiral catalyst RuC l2 The cost is very high, the dosage is large, and it will also cause hidden dangers of heavy metal residues in the final product

Method used

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  • Synthesis method of eslicarbazepine acetate with high purity and stable crystal form
  • Synthesis method of eslicarbazepine acetate with high purity and stable crystal form
  • Synthesis method of eslicarbazepine acetate with high purity and stable crystal form

Examples

Experimental program
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Effect test

Embodiment 1

[0031] Example 1: Take 43g of 10-methoxyiminostilbene, add 101g of tetrahydrofuran, add 72g of hydrochloric acid, heat to 60-65°C, react for 5h, add about 258g of tap water, stir for 10min, and suction filter to obtain a yellow sandy solid in the middle Body I is about 38g, and the yield is 95%.

Embodiment 2

[0032] Example 2: Take 25g of intermediate I, add dichloromethane, lower the temperature by 5-10°C, and add BH dropwise 2 .Me 2 S 95.g and R-2-Me-CBS 33g, stirred for 3h, added 405g of hydrochloric acid, separated, and the organic phase was concentrated under reduced pressure to obtain 29g of intermediate II with a yield of 75%.

Embodiment 3

[0033] Example 3: Take 25g of intermediate I, add dichloromethane, lower the temperature by 5-10°C, and add BH dropwise 2 .Me 2 85.g of S and 28g of R-2-Me-CBS were stirred for 3h, 405g of hydrochloric acid was added, the layers were separated, and the organic phase was concentrated under reduced pressure to obtain 27g of intermediate II with a yield of 70%.

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Abstract

The invention discloses a synthesis method of high-purity eslicarbazepine acetate and a novel stable crystal form of the eslicarbazepine acetate. The preparation method disclosed by the invention is realized by the following steps of: dissolving 10-methoxy iminostilbene serving as a starting raw material in acetone, and performing deprotection to generate 10-carbonyliminostilbene; carrying out asymmetric reduction on dichloromethane, borane dimethyl sulfide and (R)-2-methyl-CBS-oxazole borane to generate (10S)-10-hydroxyiminostilbene; and acylating (10S)-10-hydroxyiminostilbene into ester, and conducting amidation by using chlorosulfonyl isocyanate to obtain eslicarbazepine acetate and a stable new crystal form thereof. The preparation method provided by the invention has the advantages of simple synthesis process, few reaction steps, less pollution, usage of easily available raw materials, low price, easy purification and separation of the final product, stable crystal form and wide industrial application prospect.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and relates to a synthesis method of high-purity eslicarbazepine acetate and its stable crystal form. Background technique [0002] Eslicarbazepine Acetate (1) chemical name is (S)-10-acetoxy-10,11-dihydro-5H-dibenzo[b,f]azepine-5-carboxamide, It is the acetate prodrug of S-licarbazepine developed by SunovionPharma. S-licarbazepine is the main active metabolite of oxcarbazepine, which can block the voltage-dependent Na + Channel, eslicarbazepine acetate was better tolerated than oxcarbazepine. Eslicarbazepine acetate was launched in Europe in 2009 under the trade name Zebinix. In November 2013, the US FDA approved the drug for the treatment of partial seizures in adults. At present, the drug has not been marketed in China. The author of this paper studies the synthesis process of a stable crystal form of eslicarbazepine acetate. [0003] Literature (improved synthetic process of e...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D223/22
CPCC07D223/22C07B2200/13
Inventor 温秀红郭芳郭维博柳小秦罗晶东丽丽
Owner XIAN XINTONG PHARM RES CO LTD
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