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Synthetic method for eslicarbazepine acetate

A technology of eslicarbazepine acetate and synthesis method, which is applied in the field of drug synthesis, can solve the problem of insufficient ee value, and achieve the effect of simplifying the operation steps and improving the yield and purity

Inactive Publication Date: 2015-12-09
ANHUI NEW STAR PHARMA DEV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The preparation method is simple to operate and the yield is high, but the ee value of the obtained eslicarbazepine is still not high enough even after a complicated purification process

Method used

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  • Synthetic method for eslicarbazepine acetate
  • Synthetic method for eslicarbazepine acetate
  • Synthetic method for eslicarbazepine acetate

Examples

Experimental program
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Effect test

Embodiment 110

[0035] Example 110-Hydroxy-10,11-dihydro-5H-dibenzo[b,f]azepine -Preparation of 5-carboxamide (licarbazepine, Ⅲ)

[0036] In a 50L reaction kettle equipped with an electric stirrer, add 3.0kg (11.9mol) of oxcarbazepine, 14L of 95% ethanol and 7L of purified water, and stir to dissolve it. Slowly add 360g (9.13mol) of sodium borohydride to the mixed solution in batches at 10-15°C (completely added in about 1 hour), continue to stir and react for 10 minutes, then slowly raise the temperature to 45°C, and keep the reaction for 2 hours. TLC detection (ethyl acetate: methanol = 2:3), after the reaction was completed, the reaction solution was cooled to 10°C-15°C, and 5.2L of acetone was slowly added. The mixture was distilled to near dryness at 40°C under reduced pressure, stirred and added with 13L of purified water, a large amount of solids were precipitated, and crystallized by cooling. After filtering and washing (2×1.5 L of water), the resulting solid was dried at 100°C for...

Embodiment 2

[0037] Example 2 (2S,3S)-4-[((S)-5-carbamoyl-10,11-dihydro-5H-dibenzo[b,f]azepine Preparation of -10-yl)oxy]-2,3-bis((4-methylbenzoyl)oxy)-4-oxobutanoic acid (V)

[0038] In the reaction kettle equipped with electric stirrer, add 15L dichloromethane, 2.21kg (8.7mol) licarbazepine, 47g (0.38mol) DMAP, D-p-methyldibenzoyl tartaric anhydride 3.64kg (9.88 mol) was stirred at room temperature for 30 min, and 635 g (8.03 mol) of pyridine was added dropwise. The mixture was stirred and reacted at 20°C for 24 hours, and detected by TLC (ethyl acetate:methanol=3:2). After the reaction, the mixture was washed with water (10L×2), and the organic layer was evaporated to dryness under reduced pressure to obtain 5kg of white powder. The obtained powder was dissolved by heating with 11L of acetonitrile, stirred for 1 h, and frozen in the refrigerator for about 12 h (-7°C). The precipitated solid was suction filtered, and the filter cake was dried to obtain a white solid (2S,3S)-4-[((S)-5-...

Embodiment 3

[0039] Example 3 (S)-10-hydroxyl-10,11-dihydro-5H-dibenzo[b,f]azepine -Preparation of 5-carboxamide (eslicarbazepine, VI)

[0040] In a three-neck flask equipped with an electric stirrer, add 1.8kg (2.91mol) of V, 3L of methanol, 3L of water, and 140g of NaOH, and stir and react for 2 hours at room temperature. TLC detection (ethyl acetate: methanol = 2:3), after the reaction, filter, wash (2×1L methanol), collect the filtrate, concentrate and distill methanol at about 45°C. 2L of water was added to the residue at 10-15°C, a large amount of solids were precipitated, and crystallized by cooling. Filter, wash (2×1L water), and dry the obtained solid at 45°C-50°C for 2 hours, then raise the temperature to 100°C and dry for 6-8 hours to obtain 628g of white solid LKXP-Ⅵ, with a yield of 85% and an ee value of 96.7% , melting point 186°C-187°C.

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Abstract

The invention discloses a synthetic method for eslicarbazepine acetate. The synthetic method comprises the following steps: (1) carrying out a reduction reaction on oxcarbazepine under the action of a reducer to obtain licarbazepine; (2) splitting the licarbazepine obtained in the step (1) under the action of D-p-methyl diphenylethanedione tartrate and after splitting, carrying out post-treatment to obtain a compound V; (3) carrying out a hydrolysis reaction on the compound V obtained in the step (2) to obtain eslicarbazepine; and (4) carrying out an esterification reaction on the eslicarbazepine obtained in the step (3) and acetic acid, and after reaction, carrying out post-treatment to obtain eslicarbazepine acetate. By adopting a novel splitting agent, the preparation method simplifies the operating process and improves the reaction yield and product purity.

Description

technical field [0001] The invention belongs to the field of drug synthesis, in particular to a method for synthesizing eslicarbazepine acetate. Background technique [0002] Eslicarbazepine acetate, whose structure is shown in formula (I), is a prodrug of (S)-licarbazepine, and S-licarbazepine is the main active metabolite of oxcarbazepine, which can block the voltage-dependent Na + Channel, eslicarbazepine acetate was better tolerated than oxcarbazepine. [0003] [0004] The Chinese patent application with the publication number CN1543454A discloses a preparation method of eslicarbazepine. The preparation method firstly mixes racemic licarbazepine with (2R,3R)-di-O,O'-substituted tartaric anhydride The reaction yields a pair of diastereoisomers, and water is added to precipitate the less soluble diastereomer, which is separated by filtration, followed by base-catalyzed hydrolysis of the less soluble diastereomer to give optical Pure licarbazepine. Wherein, the struc...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D223/22
CPCC07D223/22
Inventor 徐自奥赵永海李晓祥
Owner ANHUI NEW STAR PHARMA DEV
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