Preparation method of retigabine and intermediate thereof

A technology of retigabine and its compound, which is applied in the field of pharmaceutical synthesis and can solve problems such as increased raw material costs, low selectivity, and poor selectivity of ethyl chloroformate
CN103373941AActive Publication Date: 2013-10-30SUZHOU NOVARTIS PHARMA TECHONOLOGY CO LTD
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Patent Information

Authority / Receiving Office
CN · China
Current Assignee / Owner
SUZHOU NOVARTIS PHARMA TECHONOLOGY CO LTD
Publication Date
2013-10-30

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Abstract

The invention relates to the medicine synthesis field and in particular relates to a preparation method of retigabine and an intermediate thereof. The method specifically comprises the following steps of: (1) preparing a compound with a structure of formula (RET25) by the compound with the structure of formula (RET20) and 4-fluorobenzaldehyde under the action of p-toluene sulfonic acid; (2) preparing the compound with the structure of formula (RET30) by the compound with the structure of formula (RET25) through sodium borohydride reduction; and (3) preparing the retigabine by the compound with the structure of the formula (RET30) through raney nickel hydrogenation reduction. The total impurity content of the retigabine obtained by the preparation method disclosed by the invention is less than 0.16% in terms of area percentage unit of HPLC (High Performance Liquid Chromatography).
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Description

technical field

[0001] The invention relates to the field of pharmaceutical synthesis, in particular to a preparation method of a retigabine intermediate. Background technique

[0002] Retigabine is a drug developed jointly by GlaxoSmithKline and Valeant for the treatment of epilepsy. Its structural formula is as follows:

[0003]

[0004] At present, there are few synthetic routes for retigabine, mainly three routes announced in US Patent No. 5,384,330:

[0005] Route 1:

[0006]

[0007] Route two:

[0008]

[0009] The disadvantage of route 1 is that the reaction yield of 4-fluorobenzaldehyde and 2-nitro-1,4-phenylenediamine is not high, and the impurities are not easy to purify. At the same time, the selectivity of ethyl chloroformate is poor, which greatly increases the cost of raw materials ; Line two is also the final stage using ethyl chloroformate, the selectivity is low, so that the cost of raw materials is still very high.

[0010] Route three: [00...

Claims

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