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Preparation method of brivaracetam

A reaction and selection technology, applied in the field of drug synthesis, can solve the problems of high production cost, cumbersome separation and purification steps, and unsuitability for industrial production

Active Publication Date: 2016-06-08
佛山市隆信医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] This route needs to be separated and purified by silica gel column three times, the production cost is high, the industrial feasibility is poor, and AD-Mix-Bata containing highly toxic substances is used
[0011] According to the existing bibliographical reports, the existing synthetic routes must be separated and purified by chromatographic columns to obtain buvaracetam, and the separation and purification steps are cumbersome and costly, and are not suitable for industrial production. Therefore, in this field, the development of A method that does not require column chromatography is very interesting

Method used

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  • Preparation method of brivaracetam
  • Preparation method of brivaracetam
  • Preparation method of brivaracetam

Examples

Experimental program
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Effect test

Embodiment 1

[0073] In this embodiment, Buvaracetam is prepared by the following method, which specifically includes the following steps:

[0074] (1) Lactone (II) (wherein R 1 For the preparation of phenyl)

[0075] Add toluene (300mL) and sodium amide (8.58g, 0.22mol) in a 1000mL three-necked flask with mechanical stirring, and cool down to 10°C, slowly drop diphenyl malonate (25.62g, 0.1mol), control The temperature does not exceed 15°C. After the drop is completed, stir at 10-15°C for 60 minutes. (R)-Epichlorohydrin (10.18g, 0.11mol) is slowly added dropwise to control the temperature not exceeding 30°C. Stir for 5 hours, slowly add water (100mL) to control the temperature not to exceed 30°C, separate layers, water (100mL) and saturated brine (100mL) in the toluene layer, concentrate part of the toluene, then cool down to precipitate a solid, filter and dry to obtain 19.96g of Yellow solid lactone (II) (R 1 For phenyl), the yield is 91%, ee (enantiomeric excess percentage)>99%.

[...

Embodiment 2

[0089] In this embodiment, Buvaracetam is prepared by the following method, which specifically includes the following steps:

[0090] (1) Lactone (II) (wherein R 1 For the preparation of phenyl)

[0091] Add toluene (300mL) and sodium amide (8.58g, 0.22mol) in a 1000mL three-necked flask with mechanical stirring, and cool down to 10°C, slowly drop diphenyl malonate (25.62g, 0.1mol), control The temperature does not exceed 15°C. After the drop is completed, stir at 10-15°C for 60 minutes. (R)-Epichlorohydrin (10.18g, 0.11mol) is slowly added dropwise to control the temperature not to exceed 30°C. Stir at ℃ for 5 hours, slowly add water (100mL) to control the temperature not to exceed 30℃, separate layers, water (100mL) and saturated brine (100mL) in the toluene layer, concentrate part of the toluene, then cool down to precipitate a solid, filter and dry to obtain 19.96g Pale yellow solid lactone (II) (R 1 For phenyl), the yield is 91%, ee>99%.

[0092] Step (1) product NMR ...

Embodiment 3

[0106] In this embodiment, Buvaracetam is prepared by the following method, which specifically includes the following steps:

[0107] (1) Lactone (II) (wherein R 1 For the preparation of phenyl)

[0108] Add toluene (300mL) and sodium amide (8.58g, 0.22mol) in a 1000mL three-necked flask with mechanical stirring, and cool down to 10°C, slowly drop diphenyl malonate (25.62g, 0.1mol), control The temperature does not exceed 15°C. After the addition, stir at 10-15°C for 60 minutes. (R)-Epichlorohydrin (9.25g, 0.1mol) is slowly added dropwise to control the temperature not exceeding 30°C. Stir for 8 hours, slowly add water (100mL) to control the temperature not to exceed 30°C, separate layers, water (100mL) and saturated brine (100mL) in the toluene layer, concentrate part of the toluene, then cool down to precipitate a solid, filter and dry to obtain 19.74g Yellow solid lactone (II) (R 1 For phenyl), the yield is 90%, ee>99%.

[0109] Step (1) product NMR characterization res...

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Abstract

The invention provides a preparation method of brivaracetam. The preparation method of brivaracetam comprises the following steps of in an alkaline reagent, reacting malonate ester and (R)-epichlorohydrin to obtain lactone (II), reacting the lactone (II) and an ethyl metal-based reagent to obtain an intermediate (III), removing carboxylase to obtain (R)-4-propyl-dihydrofuran-2-ketone (IV), performing ring-opening reaction under the action of a halogenated ring-opening reagent to obtain (R)-3-halogenarated methyl hexanoate or (R)-3- halogenarated methyl hexyl acetate (V), and reacting with (S)-2-aminobutanamide or an acceptable salt, so as to obtain the brivaracetam. The preparation method has the advantages that the high-purity brivaracetam (HPLC (high performance liquid chromatography: greater than 96%) and stereo rotary brivaracetam (chirality HPLC: greater than 98%) can be directly prepared; the silicagel column separation and purification or the chirality preparation column separation and purification is not used, so that the complicated separation and purification step is not performed, the cost is saved, and the preparation method is more suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of drug synthesis and relates to a preparation method of buvaracetam. Background technique [0002] Brivaracetam, the structural formula is as follows (I), the chemical name is (S)-2-((R)-3-propylpyrrolidin-1-yl)butyramide [0003] [0004] Brivaracetam is newly developed by the Belgian pharmaceutical manufacturer UCB. It belongs to the third generation of antiepileptic drugs. There is also a certain inhibitory effect. In 2005, brivaracetam was approved by the FDA and the European Union for the treatment of rare symptomatic myoclonic seizures. Currently, a number of phase III clinical trials including adjuvant treatment for partial seizures of epilepsy are being conducted. The research results show that brivaracetam is effective for Generalized seizures have a better curative effect. [0005] BenoitM. (J.Med.Chem.2004,47,530-549) reported that 2(5H)-furanone reacted with propylmagnesium bromide to obtain 4-propy...

Claims

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Application Information

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IPC IPC(8): C07D207/06
CPCC07D207/06
Inventor 黄绍智石磊陈奕文许雅文
Owner 佛山市隆信医药科技有限公司
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