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New intermediate of buvaracetam with imidazole ring and its synthesis method and application

A synthesis method and synthesis route technology, applied in organic chemistry methods, organic chemistry and other directions, can solve the problems of difficult and effective central control, low yield, many by-products, etc., and achieve easy handling, high yield and short reaction route. Effect

Active Publication Date: 2020-05-19
LIVZON NEW NORTH RIVER PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This route has problems such as low yield, many by-products, and difficulty in effective central control.

Method used

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  • New intermediate of buvaracetam with imidazole ring and its synthesis method and application
  • New intermediate of buvaracetam with imidazole ring and its synthesis method and application
  • New intermediate of buvaracetam with imidazole ring and its synthesis method and application

Examples

Experimental program
Comparison scheme
Effect test

preparation example 1

[0049] Dissolve the compound of formula II (20.8g, 100mmol) in anhydrous dichloromethane (60ml), add carbonyldiimidazole (16.2g, 100mmol), stir at room temperature for 2 hours, distill off the dichloromethane under reduced pressure to obtain a light yellow oil 25.5 g of the product is the compound of formula III.

[0050] The yield is 99%, HPLC>97%, ee>99%, 1H NMR (300MHz, CDCl 3 ): δ8.26(1H,s), 7.69(1H,d), 7.25(1H,d), 3.38(1H,dd), 3.13(1H,dd), 2.48(1H,dd), 2.23(1H,dd ), 2.12 (1H, dd), 1.25-1.33 (4H, m), 0.98 (3H, t).

preparation example 2

[0052] Dissolve the compound of formula II (31.2g, 150mmol) in anhydrous dichloromethane (90ml), add carbonyldiimidazole (24.3g, 150mmol), react under reflux for 2 hours, and distill off the dichloromethane under reduced pressure to obtain 38.5 g of light yellow oily substance is the compound of formula III.

[0053] The yield is 99%, HPLC>97%, ee>99%, 1H NMR (300MHz, CDCl 3 ): δ8.26(1H,s), 7.69(1H,d), 7.25(1H,d), 3.38(1H,dd), 3.13(1H,dd), 2.48(1H,dd), 2.23(1H,dd ), 2.12 (1H, dd), 1.25-1.33 (4H, m), 0.98 (3H, t).

preparation example 3

[0055]Dissolve the compound of formula II (20.8g, 100mmol) in anhydrous acetonitrile (60ml), add carbonyldiimidazole (16.2g, 100mmol), stir at 10°C for 2 hours, evaporate the acetonitrile under reduced pressure, and obtain a light yellow oily substance 25.7 g, is the compound of formula III.

[0056] The yield is 99%, HPLC > 97%, ee > 99%, 1H NMR (300MHz, CDCl 3 ): δ8.26(1H,s), 7.69(1H,d), 7.25(1H,d), 3.38(1H,dd), 3.13(1H,dd), 2.48(1H,dd), 2.23(1H,dd ), 2.12 (1H, dd), 1.25-1.33 (4H, m), 0.98 (3H, t).

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Abstract

The invention discloses a brivaracetam new intermediate with an imidazole ring, and a synthesis method and an application thereof. A structural formula of the brivaracetam new intermediate is shown inthe following formula. The brivaracetam new intermediate is used for synthesizing brivaracetam and is advantageous in that raw materials are cheap and easy to obtain, a reaction route is short, the yield is high, and impurities are less. At the same time, due to introduction of carbonyl imidazole, the problem that center control by HPLC and purity detection of intermediates cannot be carried outin a reaction process is solved.

Description

technical field [0001] The invention belongs to the field of pharmacy, and in particular relates to a new intermediate of buvaracetam and its synthesis method and application. Background technique [0002] Brivaracetam is a new generation of antiepileptic drugs, which is a structural derivative of levetiracetam. In 2005, Brivaracetam was approved by the FDA and the European Union for the treatment of rare symptomatic myoclonic seizures, and has good pharmacodynamic effects and market prospects. [0003] The original research patent CN1882535A published by UCB in Belgium is the reductive amination of 5-hydroxy-4-n-propyl-2-furanone and S-2-aminobutyramide under the action of sodium borohydride, and then hydrogenation reduction to obtain racemic Bois Racetam, prepare Buvaracetam through chiral chromatographic separation; this route involves chiral preparative chromatographic separation, and the cost is too high. [0004] [0005] Literature Schülé A, Merschaert A, Szczepa...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D233/60C07D207/27
CPCC07B2200/07C07D207/27C07D233/60
Inventor 王龙书姜桥卢增杰陈月嫦陈果李敬辉唐阳刚
Owner LIVZON NEW NORTH RIVER PHARMA