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Brivaracetam and preparation method of intermediate thereof

An intermediate and volumetric technology, applied in the field of medicine, can solve the problems of poor industrial feasibility and high production cost, and achieve the effects of reduced preparation cost, easy operation and high yield

Active Publication Date: 2017-05-31
宜宾市南溪区红光制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] In view of the high production cost and poor industrial feasibility of the existing preparation method, it is urgent to provide a simpler and economical method for preparing buvaracetam

Method used

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  • Brivaracetam and preparation method of intermediate thereof
  • Brivaracetam and preparation method of intermediate thereof
  • Brivaracetam and preparation method of intermediate thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0060] Embodiment 1 The preparation technology of Bu Waracetam of the present invention

[0061] synthetic route:

[0062]

[0063] The specific process includes the following steps:

[0064] (1) Preparation of 5-hydroxyl-4-propylfuran-2(5H)-ketone (i.e. B-I)

[0065] Add 50% glyoxylic acid aqueous solution (60g, 0.411mol), n-heptane (100ml), water (30ml) in the 500ml there-necked flask with mechanical stirring function, cool down to below 10 ℃, add dropwise morphine (35.7g , 0.411mol), the dropwise temperature was raised to 25°C, reacted for 2h, added n-valeraldehyde (35.3g, 0.411mol), the temperature was raised to 45°C, after the reaction for 5h, the temperature was lowered to below 10°C, and concentrated hydrochloric acid ( 50ml), reacted for 3h, separated, separated the n-heptane phase, and washed the water phase (30ml×3) with n-heptane, the water phase was extracted with isopropyl ether (60ml×3), and the isopropyl ether phase was extracted with a concentration of Wa...

Embodiment 2

[0080] Embodiment 2 The preparation technology of Bu Waracetam of the present invention

[0081] (1) Preparation of B-I

[0082] Add 50% glyoxylic acid aqueous solution (60g, 0.411mol), n-heptane (100ml), water (30ml) in the 500ml there-necked flask with mechanical stirring function, cool down to below 10 ℃, add dropwise morphine (53.55g , 0.6155mol), the dropwise temperature was raised to 25°C, reacted for 2h, added n-valeraldehyde (52.95g, 0.6165mol), the temperature was raised to 60°C after the addition, after the reaction for 3h, the temperature was lowered to below 10°C, and concentrated hydrochloric acid ( 50ml), heated to 40°C for 1h, separated, separated the n-heptane phase, and washed the water phase with n-heptane (30ml×3), the water phase was extracted with isopropyl ether (60ml×3), and the isopropyl ether phase Wash with 30% sodium bicarbonate aqueous solution (30ml×2), saturated brine (30ml×1), dry over anhydrous sodium sulfate, concentrate the isopropyl ether ph...

Embodiment 3

[0097] Embodiment 3 The preparation technology of Bu Waracetam of the present invention

[0098] (1) Preparation of B-I

[0099] Add 50% glyoxylic acid aqueous solution (60g, 0.411mol), n-heptane (100ml), water (30ml) in the 500ml there-necked flask with mechanical stirring function, cool down to below 10 ℃, add dropwise morphine (42.84g , 0.4932mol), the dropwise temperature was raised to 25°C, reacted for 2h, added n-valeraldehyde (70.6g, 0.822mol), the temperature was raised to 45°C after the addition, after the reaction for 7h, the temperature was lowered to below 10°C, and concentrated hydrochloric acid ( 50ml), heated to 40°C for 1h, separated, separated the n-heptane phase, and washed the water phase with n-heptane (30ml×3), the water phase was extracted with isopropyl ether (60ml×3), and the isopropyl ether phase Wash with 30% sodium bicarbonate aqueous solution (30ml×2), saturated brine (30ml×1), dry over anhydrous sodium sulfate, concentrate the isopropyl ether phas...

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Abstract

The invention discloses a preparation method of a brivaracetam intermediate shown in B-VI. The preparation method comprises the following steps of dissolving B-IV and R-phenylethylamine into a solvent, crystallizing, filtering, and recrystallizing, so as to obtain B-V; then, converting into B-VI. The preparation method has the advantages that a chiral chromatographic column separation isomer is not needed in the preparation process, and only the simple steps of extraction, washing, drying, concentration and the like are performed, so as to separate effective ingredients; the separation process is simple, and the production cost of brivaracetam is greatly reduced. A formula is shown in the description.

Description

technical field [0001] The invention relates to a preparation method of buvaracetam and an intermediate thereof, belonging to the field of medicine. Background technique [0002] Brivaracetam, the chemical name is (S)-2-(R)-3-propylpyrrolidin-1-ylbutanamide, and its structural formula is as follows: [0003] [0004] Brivaracetam is the third-generation antiepileptic drug newly developed by Belgian pharmaceutical manufacturer UCB. There is 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 underway. Generalized seizures have a better curative effect. [0005] At present, the preparation process of brivaracetam almost all needs to use chiral chromatographic column to separate isomers, which requires high equipment and greatly increases the production cos...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/27
Inventor 王春燕陈志勇王聪
Owner 宜宾市南溪区红光制药有限公司
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