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An intermediate of n1-(4-fluorobenzyl)-4-nitrophenyl-1,3-diamine and its preparation method

A technology of nitrophenyl and fluorobenzyl, applied in the field of N1--4-nitrophenyl-1,3-diamine intermediate and its preparation, can solve the problem of long reaction time and high boiling point of DMSO, which is difficult to remove , low yield and other problems, to achieve the effects of short reaction time, high reaction selectivity and yield, and low cost

Inactive Publication Date: 2015-10-28
盘锦中泓化工有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0020] This method is used to prepare N 1 -(4-fluorobenzyl)-4-nitrophenyl-1,3-diamine introduces 4-fluorobenzylamino group through aromatic substitution reaction, which is relatively direct, but the reaction time is longer, and it needs to be prepared in DMSO React for 30 hours, and DMSO has a high boiling point and is difficult to remove, and the yield is not high, only 85%

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  • An intermediate of n1-(4-fluorobenzyl)-4-nitrophenyl-1,3-diamine and its preparation method
  • An intermediate of n1-(4-fluorobenzyl)-4-nitrophenyl-1,3-diamine and its preparation method
  • An intermediate of n1-(4-fluorobenzyl)-4-nitrophenyl-1,3-diamine and its preparation method

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0068] The chemical structural formula of compound (VI): .

[0069] The melting point of compound (Ⅵ) is 170 ~ 173 ℃; the hydrogen spectrum features are: 1 H NMR (500MHz, CDCl 3 ) δ: 11.0 [s , 1H , Ar- NH -C(=O)CH 3 ] , 8.12 (dd , J = 6.5 , 4.0 Hz , 2H , ArH) , 7.30 (dd , J = 8.5, 5.0 Hz , 2H , ArH) , 7.05 (t , J = 8.5 Hz , 2H , ArH) , 6.27 (dd , J = 9.5, 2.5 Hz, 1H, ArH) , 5.00 (s , 1H , Ar- CH 2 -NH-Ar) , 4.41 (d , J = 5.5 Hz , Ar-CH 2 - NH -Ar) , 2.26 [s , 3H, -(C=O)CH 3 ]. NMR detection features: ESI-MS m / z : 304 [M+H] + , as attached figure 1 shown.

Embodiment 2

[0071] Synthesized by compound (Ⅵ) N 1 -(4-fluorobenzyl)-4-nitrophenyl-1,3-diamine method.

[0072] Its specific reaction is:

[0073]

[0074] Step 1: nitrification reaction: the N -(3-fluorophenyl)acetamide (compound Ⅲ, Hal=F) (76.5 g, 0.5 mol), ethylene glycol dimethyl ether (200 mL), concentrated nitric acid (65 mL, 1.1 mol) were added to 1L The reaction bottle was stirred, and concentrated sulfuric acid (200 mL, 3.6 mol) was added dropwise at room temperature. After 1.5 hours, the reaction solution was added dropwise into crushed ice, and a white solid precipitated out. Then add 1L of water, stir for 15 minutes and filter, wash the filter cake with water to obtain 88g of white solid, recrystallize the resulting crude product with petroleum ether: ethyl acetate = 1.1: 1, filter with suction, concentrate the mother liquor to obtain a white solid N -(5-fluoro-2-nitrophenyl)acetamide (compound IV, Hal=F) 74.2 g, yield 75%.

[0075] Compound (Ⅳ): mp 86 ~ 87 ℃. 1 H NMR...

Embodiment 3~7

[0082] Embodiment 3~7 to the selection of step-nitration reaction condition

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Abstract

The invention relates to a preparation method of a retigabine intermediate, and in particular relates to an intermediate of N1-(4-fluorobenzyl)-4-nitropheny-1,3-diamine and a preparation method of the intermediate. The intermediate is compound (VI), and the chemical structure is represented as in formula VI. A new compound VI is obtained by nitrifying and condensing N-(3-fluorobenzyl)acetamide, the compound VI is further hydrolyzed to obtain N1-(4-fluorobenzyl)-4-nitropheny-1,3-diamine, and the N1-(4-fluorobenzyl)-4-nitropheny-1,3-diamine is an important intermediate for preparing retigabine. The method provided by the invention is simple and convenient to operate, good in yield and low in cost, and the quality of the product is satisfied; a plurality of suppliers can provide used raw materials and solvent thereof, the price is low, and the intermediate can be further synthesized as antiepileptic drug retigabine.

Description

technical field [0001] The present invention relates to a kind of preparation method of retigabine intermediate, be specifically related to N 1 Intermediates of -(4-fluorobenzyl)-4-nitrophenyl-1,3-diamine and methods for their preparation. Background technique [0002] Retigabine (chemical name: N -[2-Amino-4-(4-fluorobenzylamino)phenyl]urethane, retigabine) has the following structure (see formula I): [0003] [0004] Formula Ⅰ [0005] Retigabine is an antiepileptic drug with multiple mechanisms including neuronal potassium channel opener and GABA enhancer. The drug was developed by GlaxoSmithKline / Valeant Pharmaceuticals. It was approved for marketing in the European Union (trade name Trobalt) on March 29, 2011, and was approved for marketing by the US FDA (trade name Potiga) in the same year for adults. Adjunctive treatment of partial seizures. In addition, the phase II clinical trial of this product for the treatment of postherpetic neuralgia is also in progre...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C233/43C07C211/52C07C209/62C07C231/12
Inventor 张勇王玮樊珊珊
Owner 盘锦中泓化工有限公司
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