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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

Active Publication Date: 2013-10-30
SUZHOU NOVARTIS PHARMA TECHONOLOGY CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The disadvantage of route one 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, and 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 the cost of raw materials is still very high

Method used

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  • Preparation method of retigabine and intermediate thereof
  • Preparation method of retigabine and intermediate thereof
  • Preparation method of retigabine and intermediate thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0066] Embodiment 1: the preparation of formula RET25 compound

[0067]

[0068] Compound of formula RET20 (22.52g, 100mmol) and 4-fluorobenzaldehyde (11.59mL, 110mmol) were dissolved in 400ml of toluene, TsOHH was added 2 O (0.57g, 3mmol), heated to reflux and dewatered with a water separator, reacted for 4 hours, concentrated the solvent to obtain 33.1g of the compound of formula RET25, and the reaction yield was 100%.

Embodiment 2

[0069] Embodiment 2: the preparation of formula RET30 compound

[0070]

[0071] Dissolve the compound of formula RET25 (10 g, 30 mmol) prepared in Example 1 in ethyl acetate, keep the reaction temperature below 10° C., add sodium borohydride (1.7 g, 45 mmol), then drop methanol 15 ml, and react for 4 hours. After the reaction was complete, the reaction was quenched with 100ml of water, extracted with ethyl acetate (100ml×2), the organic phases were combined, and the organic phase was dissolved and washed with 5% sodium chloride water, and the organic phase was concentrated to obtain 9.2g of the compound of formula RET30, with a yield of 92 %.

Embodiment 3

[0072] Embodiment 3: the preparation of Retigabine

[0073]Dissolve the compound of formula RET30 (5 g, 15 mmol) prepared in Example 2 in ethyl acetate, add 0.6 g of Raney nickel, hydrogen pressure of 1.1 MPa, and react at 55-60° C. for 15 hours. After the reaction is completed, filter and remove Raney nickel, the reaction solution was concentrated, and recrystallized with ethyl acetate to obtain 3.8 g of retigabine with a yield of 83.6%.

[0074] HPLC analysis method:

[0075] Chromatograph: Shimadzu 20AD HPLC or other similar liquid chromatograph;

[0076] Chromatographic column: Agilent ZORBAX SB-C18, 150*4.6mm, 3.5μm;

[0077] Mobile phase A: weigh 1.36g KH 2 PO 4 In 1000ml of water, add 0.5g of sodium heptanesulfonate, adjust the pH to 2.5 with phosphoric acid, filter and degas;

[0078] Mobile phase B: acetonitrile;

[0079] Column temperature: 30°C;

[0080] Flow rate: 1.0ml / min;

[0081] Detection wavelength: UV 250nm;

[0082] Injection volume: 10μl;

[0083...

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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).

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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Application Information

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IPC IPC(8): C07C271/28C07C269/06
Inventor 郑建兵王向军李贵杰李原强赵建强黄超
Owner SUZHOU NOVARTIS PHARMA TECHONOLOGY CO LTD
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