Method for synthesizing teriflunomide

A synthesis method and technology of teriflunomide are applied in the field of pharmaceutical synthesis, and can solve the problems of being unsuitable for large-scale industrial production, inflammable and explosive, etc.

Inactive Publication Date: 2015-06-10
HYBIO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Acetic anhydride is a precursor reagent, and NaH is flammable and ex

Method used

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  • Method for synthesizing teriflunomide
  • Method for synthesizing teriflunomide
  • Method for synthesizing teriflunomide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0051] Example 1 Preparation of teriflunomide with cyanoacetic acid as initial raw material

[0052] Add 3.0 g of cyanoacetic acid to 130 mL of thionyl chloride, reflux at 75°C for 2 hours, remove excess thionyl chloride on a rotary evaporator to obtain a yellow oil, add anhydrous dichloromethane to dissolve, and obtain a yellow oil Anhydrous dichloromethane solution, set aside.

[0053] Dissolve 4.40 mL of p-trifluoromethylaniline in anhydrous dichloromethane, add 7.32 mL of triethylamine, and add the obtained yellow oil in anhydrous dichloromethane dropwise at 0°C. Stir overnight at °C, remove the solvent, and recrystallize the crude product from ethanol to obtain 4.51 g of solid, with a yield of 57%. Gained solid is carried out proton nuclear magnetic resonance spectrum detection, gained data is 1 H-NMR(400MHz,DMSO)δ10.64(s,1H),7.76(d,J=8.7Hz,2H),7.70(d,J=8.9Hz,2H),3.96(s,2H), such as figure 1 As shown, the measured data is consistent with the 2-cyano-N-(4-trifluoromethy...

Embodiment 2

[0055] Example 2 The preparation of teriflunomide with cyanoacetic acid as the initial raw material

[0056] Take 3.0 g of cyanoacetic acid and add it to 130 mL of thionyl chloride, reflux at 75 ° C for 1 h, remove excess thionyl chloride on a rotary evaporator to obtain a yellow oil, add chloroform to dissolve, and obtain a chloroform solution of the yellow oil. spare.

[0057] Dissolve 4.40 mL of p-trifluoromethylaniline in chloroform, add 7.32 mL of triethylamine, and add dropwise at 0°C to obtain a solution of yellow oil in chloroform. After the dropwise addition, stir at 0-50°C for 1 h, The solvent was removed, and the crude product was recrystallized from ethanol to obtain 4.82 g of solid, with a yield of 61%. Gained solid is carried out proton nuclear magnetic resonance spectrum detection, gained data is 1 H-NMR (400MHz, DMSO) δ10.64(s, 1H), 7.76(d, J=8.7Hz, 2H), 7.70(d, J=8.9Hz, 2H), 3.96(s, 2H), measured The data are consistent with the 2-cyano-N-(4-trifluoromethyl...

Embodiment 3

[0059] Example 3 Preparation of teriflunomide with cyanoacetic acid as initial raw material

[0060] Take 3.0 g of cyanoacetic acid and add it to 130 mL of thionyl chloride, reflux at 85 ° C for 8 h, remove excess thionyl chloride on a rotary evaporator to obtain a yellow oil, add carbon tetrachloride to dissolve, and obtain a yellow oil Carbon tetrachloride solution, spare.

[0061] Dissolve 4.40 mL of p-trifluoromethylaniline in carbon tetrachloride, add 7.32 mL of triethylamine, and add dropwise at 0°C to obtain a solution of yellow oil in carbon tetrachloride. After stirring for 2 h, the solvent was removed, and the crude product was recrystallized from ethanol to obtain 4.22 g of solid, with a yield of 53%. Gained solid is carried out proton nuclear magnetic resonance spectrum detection, gained data is 1 H-NMR (400MHz, DMSO) δ10.64(s, 1H), 7.76(d, J=8.7Hz, 2H), 7.70(d, J=8.9Hz, 2H), 3.96(s, 2H), measured The data are consistent with the 2-cyano-N-(4-trifluoromethylphen...

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Abstract

The invention belongs to the technical field of drug synthesis, and particularly relates to a method for synthesizing teriflunomide. The method comprises the following step: by taking 2-cyano-group-N-(4-trifluoromethyl phenyl)-acetamide and acetyl chloride as raw materials, carrying out carbanion nucleophilic substitution reaction in the presence of alkali used as a catalyst to generate the teriflunomide, wherein the alkali is any one or a mixture of more than two of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, triethylamine, diisopropyl ethylamine, 1,8-diazabicyclo[5.4.0]C11-7-alkene, sodium hydrogen carbonate, potassium hydrogen carbonate, potassium phosphate, potassium dihydrogen phosphate or sodium sulfite. According to the method, sodium hydroxide is introduced to isothermally participate in reaction with alkali and acetyl chloride, so that the usage of a dangerous chemical is prevented; in addition, the reaction condition is moderate, so that the industrial production is facilitated.

Description

technical field [0001] The invention relates to the technical field of medicine synthesis, in particular to a synthesis method of teriflunomide. Background technique [0002] Teriflunomide, the chemical name is (Z)-2-cyano-3-hydroxy-N-(4-trifluoromethylphenyl)-2-butenamide, and its structural formula is shown in Formula I. Teriflunomide is an active metabolite of leflunomide, a dihydroorotate dehydrogenase (DHODH) inhibitor, and belongs to immunomodulatory drugs. Teriflunomide was developed by Sanofi-Aventis and was approved by the FDA for marketing on September 12, 2012. It is mainly used for the treatment of multiple sclerosis (MS). Multiple sclerosis is a chronic, inflammatory, demyelinating central nervous system disease that can cause a variety of symptoms that can lead to mobility impairment and even disability in severe cases. The listing of teriflunomide provides more options for the treatment of multiple sclerosis. [0003] [0004] Formula Ⅰ [0005] The pre...

Claims

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Application Information

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IPC IPC(8): C07C255/23C07C253/30
Inventor 李国弢刘斌马亚平袁建成
Owner HYBIO PHARMA
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