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Preparation method of teriflunomide and intermediate thereof

A technology for teriflunomide and its intermediates is applied in the field of preparation of teriflunomide and its intermediates, which can solve the problems of corroded equipment, cumbersome steps, and low total yield, and achieve improved yield, simple operation, and effective Conducive to the effect of industrial production

Active Publication Date: 2014-06-11
HYBIO PHARMA WUHAN CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] Most of the existing methods for synthesizing teriflunomide need to undergo acylation reaction, which produces a large amount of acid mist, seriously corrodes equipment, pollutes the environment, and increases production costs; on the other hand, the intermediate products synthesized by these methods need to be purified, and the steps It is cumbersome and the total yield is low, which is not conducive to the reduction of production costs

Method used

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  • Preparation method of teriflunomide and intermediate thereof
  • Preparation method of teriflunomide and intermediate thereof
  • Preparation method of teriflunomide and intermediate thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0117] Embodiment 1 has the preparation of the compound of structure shown in formula II

[0118] In a 3L round-bottomed flask, 205g (3.15mol) of sodium azide, 400g (2.1mol, purchased from Aladdin), 52.4g (0.2mol, purchased from Aladdin), N-chlorosuccinimide 28g (0.2mol, purchased from Aladdin), tetrahydrofuran 2.4L, stirred and reacted at 15°C for 5 hours, followed the reaction until the reaction of the raw materials was completed. After the reaction was completed, 1.8 L of solvent was removed under reduced pressure, and then the reaction solution was poured into 2 L of distilled water, stirred for 30 min, filtered, and the filter cake was washed with 200 mL of distilled water and 200 mL of ethanol to obtain 388 g of off-white solid compound, the reaction weight yield was 86%.

[0119] The obtained off-white solid compound is identified by mass spectrometry, hydrogen nuclear magnetic resonance spectrum and carbon nuclear magnetic resonance spectrum, and its mass spectrum data...

Embodiment 2

[0121] Embodiment 2 has the preparation of the compound of structure shown in formula III

[0122] Transfer 388g (1.8mol) of the off-white solid compound obtained in Example 1 to a 3L round-bottomed flask, add 2.4L of toluene, heat and reflux at 110°C for 16 hours, follow the reaction and distill off the solvent after the reaction of the raw materials is complete, to obtain The crude product was washed with 300 mL of anhydrous ether and dried to obtain 354 g of light yellow solid compound.

[0123] The obtained light yellow solid compound was identified by mass spectrometry, proton nuclear magnetic resonance and proton nuclear magnetic resonance. The mass spectrum data of the compound is [M+H + ]=188.3, ​​its H NMR spectrum is: 1 H-NMR (DMSO-d6) δ: 7.41 (d, J=8.0Hz, 2H), 7.48 (d, J=8.0Hz, 2H), the carbon nuclear magnetic resonance spectrum is: 13 C-NMR (DMSO-d6) δ: 121.2, 121.9, 122.6, 123.3, 125.0, 126.8, 127.6, 133.3, 135.2ppm, so the compound prepared by the preparation ...

Embodiment 3

[0125] Example 3 Preparation of Teriflunomide

[0126] 354 g (1.8 mol) of the light yellow solid compound obtained in Example 2 was directly used in the synthesis of teriflunomide. Add 150 g (1.8 mol, purchased from Beijing Huawei Raycus Co., Ltd.), dry THF (1.5 L), and 80 g (2 mol, g / mL) of a compound having the structure shown in Formula IV into a 3 L round bottom flask , stored in kerosene at a mass volume ratio of 60%), stirred at 15°C for 1 hour, and then slowly added dropwise 800 mL of a THF solution of 354 g (1.8 mol) of the light yellow compound prepared in Example 2, and the dropwise addition was completed in 1 hour. After the addition was complete, the reaction solution was heated to reflux, and reacted at 65° C. for 40 hours, with nitrogen protection during the reaction. Add 500mL ice water after completion of the reaction to quench the reaction, adjust the pH of the reaction solution to neutrality with 2mol / L HCl, extract 3 times with EtOAc, each dosage is 500mL, ...

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Abstract

The invention belongs to the technical field of medicinal chemistry and discloses a preparation method of teriflunomide and an intermediate thereof. The preparation method of the teriflunomide provided by the invention comprises the following steps: getting a compound with a structure as shown in formula I and an azide in an organic solvent to generate nucleophilic substitution reaction to generate a compound with the structure as shown in formula II; getting and mixing the compound with the structure as shown in the formula II with the organic solvent, heating to obtain the compound with the structure as shown in formula III; under inert-gas protection and alkaline conditions, getting the compound with the structure as shown in the formula III and the compound with the structure as shown in the formula IV to generate electrophilic addition and isomerization reaction in the organic solvent to obtain the teriflunomide. According to the preparation method of the teriflunomide provided by the invention, the reaction intermediate is not needed to be purified, operation is simple, yield of the teriflunomide is improved, production cost of the teriflunomide is lowered, and therefore, the preparation method is more beneficial to industrial production of the teriflunomide.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, in particular to a preparation method of teriflunomide and an intermediate thereof. Background technique [0002] Teriflunomide is an oral pyrimidine synthase inhibitor and immunomodulator, the active metabolite of leflunomide, which blocks the de novo synthesis of pyrimidine by inhibiting dihydroorotate dehydrogenase. Teriflunomide was developed by Sanofi-aventis (Sanofi-Aventis) in the United States and was approved by the FDA on September 12, 2012. Its product name is Aubagio, and it is used for the treatment of relapsing multiple sclerosis. Conduct phase III clinical research. The molecular formula of teriflunomide is: C 12 h 9 f 3 N 2 0 2 , molecular weight is 270.2, has the structure shown in formula V: [0003] [0004] As an oral drug, teriflunomide has been approved for the treatment of relapsing-remitting multiple sclerosis in the United States at a dose of 7 mg; i...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C255/23C07C253/30C07C265/12C07C263/12
Inventor 陈新亮刘斌马亚平袁建成
Owner HYBIO PHARMA WUHAN CO LTD
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