Novel brivaracetam intermediate as well as synthesis method thereof and application

A synthetic method and synthetic route technology, applied in the direction of organic chemical methods, chemical instruments and methods, and the preparation of organic compounds, can solve the problems that are not suitable for industrial production, the difficulty of amide condensation, and low yields, and achieve the goal of raw materials The effect of low price, low price, and short reaction route

Inactive Publication Date: 2018-08-17
LIVZON NEW NORTH RIVER PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] CN101263113A discloses the route shown in formula 2, this route reaction is loaded down with trivial details, and production cost is too high, is not suitable for industrialized production
Due to the difficulty of leaving the chloro group, the route is difficult to condense with the amide, resulting in low yield and more impurities

Method used

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  • Novel brivaracetam intermediate as well as synthesis method thereof and application
  • Novel brivaracetam intermediate as well as synthesis method thereof and application
  • Novel brivaracetam intermediate as well as synthesis method thereof and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] Compound of formula II Preparation of:

[0054] 1) Dissolve R-4-n-propyl-dihydrofuran-2-one (20g, 156mmol) in acetic acid, add 33% HBr in acetic acid solution (100ml) dropwise, and react at 55°C for 3h;

[0055] 2) Cool to room temperature, add toluene (120ml) and water (20ml), stir and separate the liquids, extract the water phase with toluene (2*60ml), combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, and filter , and concentrated in vacuo to obtain 14.7 g of light yellow oil, which is the compound of formula II.

[0056] Yield is 90%, HPLC purity > 97%, ee purity > 99%, 1 H NMR (300MHz, CDCl 3 ): δ11.0(1H,s), 3.20(1H,dd), 3.10(1H,dd), 2.32(1H,dd), 2.20(1H,dd), 1.25-1.33(4H,m), 0.96( 3H,t).

[0057] Compound of formula III Preparation of:

[0058] Take the compound of formula II (20.8g, 100mmol) and dissolve it in toluene (60ml), then add thionyl chloride (35.7g, 300mmol) dropwise, stir at room temperature for 6 hours, ...

Embodiment 2

[0066] Compound of formula II Preparation of:

[0067] 1) Dissolve R-4-n-propyl-dihydrofuran-2-one (40g, 312mmol) in acetic acid, add 33% HBr in acetic acid solution (200ml) dropwise, and react at 40-50°C for 4h;

[0068] 2) Cool to room temperature and add toluene (240ml) and water (40ml), stir and separate the liquids, extract the aqueous phase with toluene (2*120ml), combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, and filter , and concentrated in vacuo to obtain 29.7 g of light yellow oil, which is the compound of formula II.

[0069] Yield is 91%, HPLC purity > 97%, ee purity > 99%, 1 H NMR (300MHz, CDCl 3 ): δ11.0(1H,s), 3.20(1H,dd), 3.10(1H,dd), 2.32(1H,dd), 2.20(1H,dd), 1.25-1.33(4H,m), 0.96( 3H,t).

[0070] Compound of formula III Preparation of:

[0071] Dissolve the compound of formula II (20.8g, 100mmol) in dichloromethane (60ml), then add triphosgene (44.5g, 150mmol) dropwise, stir at room temperature for 6 hours, ...

Embodiment 3

[0079] Compound of formula II Preparation of:

[0080] 1) Dissolve R-4-n-propyl-dihydrofuran-2-one (5.0Kg, 39mol) in acetic acid, add 33% HBr in acetic acid solution (25L) dropwise, and react at 20°C for 6h;

[0081] 2) Cool to room temperature, add toluene (30L) and water (5L), stir and separate the liquids, extract the water phase with toluene (2*15L), combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, and filter , and concentrated in vacuo to obtain 3.8 Kg of light yellow oil, which is the compound of formula II.

[0082] Yield is 93%, HPLC purity > 97%, ee purity > 99%, 1 H NMR (300MHz, CDCl 3 ): δ11.0(1H,s), 3.20(1H,dd), 3.10(1H,dd), 2.32(1H,dd), 2.20(1H,dd), 1.25-1.33(4H,m), 0.96( 3H,t).

[0083] Compound of formula III Preparation of:

[0084] Take the compound of formula II (5.2Kg, 25mol) and dissolve it in toluene (15L), then add thionyl chloride (8.9kg, 75mol) dropwise, stir at room temperature for 6 hours, distill off ...

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Abstract

The invention discloses a novel brivaracetam intermediate as well as a synthesis method thereof and application. A structural form of the intermediate is shown in the description. A reaction route forsynthesizing brivaracetam from the intermediate is shown in the description. The novel brivaracetam intermediate disclosed by the invention is used for synthesizing brivaracetam, and has the following beneficial effects: raw materials are cheap and easily available, the reaction route is short, the yield is high, and brivaracetam with high optical purity can be obtained without chiral resolutionor column chromatography separation. According to the brivaracetam synthesis process, the raw materials are cheap and easily available, the reaction route is short, the yield is high, and brivaracetamwith high optical purity can be obtained without chiral resolution or column chromatography separation.

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 type of antiepileptic drug developed by UCB in Belgium. It has good efficacy and tolerance. It is expected to replace levetiracetam as the third generation antiepileptic drug. It has good medicinal value and market prospect. [0003] So far, a number of synthetic routes have been disclosed at home and abroad, as follows: [0004] CN1882535A discloses reductive amination of 5-hydroxyl-4-n-propyl-2-furanone and S-2-aminobutyramide under sodium borohydride, and then hydrogenation reduction to obtain racemic buvaracetam, which is purified by column Chromatographic separation and preparation of buvaracetam, the synthetic route is shown in formula 1: [0005] [0006] CN101263113A discloses a route as shown in Formula 2, which is cumbersome to react, ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C51/60C07C53/50C07D207/27
CPCC07B2200/07C07C51/60C07C53/50C07D207/27
Inventor 王龙书姜桥卢增杰唐阳刚李敬辉邓意
Owner LIVZON NEW NORTH RIVER PHARMA
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