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Preparation method of brivaracetam intermediate

A compound and reaction technology, applied in the field of preparation of brivaracetam intermediates, can solve the problems of complicated synthesis process operation, high production cost, difficult realization and the like

Pending Publication Date: 2021-06-11
广东东阳光药业股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The reagents involved in the synthesis process of the prior art are flammable and dangerous goods, which are difficult to be used in industrial production, such as epichlorohydrin and ethyl metal reagents in CN105646319; For industrial production, such as the ultra-low temperature reaction in Chinese patent application CN106008411; the ultra-low temperature reaction in CN107652254; the multi-step reaction operation in CN107698543 and involves catalytic hydrogenation
[0007] In view of the technical problems such as high production cost and poor industrial feasibility in the existing preparation method, it is urgent to provide a simpler and economical method for preparing buvaracetam or its intermediate

Method used

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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0084] Example 1 Preparation of Compound III-A

[0085]

[0086] Take compound II-a (3-propylglycidic acid) (10.0 g, 1.0eq) and urea (3.4 g, 1.0eq), mixed, stirred in an oil bath of 80 ° C for about 12 h, then cool down to about 40 ° C, add NaOH (2.3 g, 1.0 eq) and water (20 mL) NaOH aqueous solution, stirred at 80 ° C for 3 h; cooling to room temperature, adding hydrochloric acid solution containing concentrated hydrochloric acid (9.9 g) and water (38 mL), and continued The slow temperature elimination was stirred at 5 ° C and stirred for 1 h; filtered, the filter cake was washed with 1N dilute hydrochloric acid (5 mL), and the vacuum dried at 50 ° C to obtain a compound III-A: white solid, 9.1 g, yield of 92%; The resulting compound III-A was detected by hydrogen spectrum, carbon spectrum and mass spectrometry, as follows:

[0087] 1 H NMR (400 MHz, DMSO) δ12.04 (S, 1H), 7.33 (S, 1H), 6.80 (S, 1H), 2.24 (S, 4H), 0.82 (T, J = 5.9 Hz, 3H);

[0088] 13 C NMR (151 MHz, DMSO) Δ174....

Embodiment 2

[0090] Example 2 Preparation of Compound IV-A

[0091]

[0092] Compound III-a (7.8 g, 1.0 eq), S - (-) - α-phenylamine (4.0 g, 0.72 eq), ethanol (2.4 g, 1.12eq) and DCM (150 ml), mix, 50 ° C The mixture was stirred for about 2.5 h, cooled to 25 ° C, stirred for 2 h; then continued to cool down to 0 ° C for 12 h, there was solid precipitation, filtration, filter cake was washed with 50 ml of DCM (0 ° C cooling treatment), 50 ° C drying 12h, resulting shallow Red solid; add 50 ml of water, stirred under 30 ° C for solid dissolution; cool down to 20 ° C, add concentrated hydrochloric acid (3.6 g) and water (10 mL) hydrochloric acid solution, there is solid precipitation, stirring is stirred after 30min, cool down After 5 ° C, it continued to be pulp for 1 h; filtration, the filter cake was washed once with concentrated hydrochloric acid (2.0 g) and aqueous solution (10 mL), and dried at 50 ° C for 12 h to give Compound IV-A: white solid, 3.6g, The yield was 46%; the obtained compo...

Embodiment 3

[0096] Example 3 Preparation of Compound V-A

[0097]

[0098] The compound IV-A (5.0 g, 1.0 eq) and NaOH (1.2 g, 1.0 eq) and water (6 ml) NaOH aqueous solution were mixed, stirred at 25 ° C to dissolve, cooled to about 0 ° C, and NaOH (2.1) g, 1.8 eq) and water (4 mL) NaOH aqueous NaOH aqueous solution and sodium hypochlorite solution (22.5 g, 10% effective chlorine) mixed solution continued at 0 ° C for 1.5 h; 30 ° C for 12 h; cool down to 20 ° C, drop 12N thick Hydrochloric acid (13.0 g), solid production, yellow green, 0.5 g of NaOH (2.5 g) and water (5 mL) NaOH aqueous solution, adjusting pH to 7 ~ 8, solid loss; concentrated to have solid precipitation, Covered to 0 ° C to be pulp 3H; filtration, filter cake was dried in vacuo to 50 ° C for 12 h, resulting in a compound VA: white solid, 4.0 g, yield of 93%; to take an appropriate amount of compound VA to detect hydrogen spectrum, carbon spectrum and mass spectrometry, as follows:

[0099] 1 H NMR (400MHz, D 2 O) δ3.32 (DDD...

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Abstract

The invention relates to a preparation method of a brivaracetam intermediate, and belongs to the field of medicinal chemistry. The preparation method comprises the following steps: reacting a compound II with urea to generate dilactam, and hydrolyzing under an alkaline condition to obtain a compound III; performing chiral resolution on the compound III to obtain a compound IV; reacting the compound IV with sodium hypochlorite to obtain a compound V; and reacting the compound V with nitrite to obtain a compound I. The raw materials used in the method are low in cost and easy to obtain, the intermediate compound is easy to purify, the process reaction steps are few, the operation is simple, the stereoselectivity is good, and the yield is high; and the method is suitable for industrial production.

Description

Technical field [0001] The present invention relates to the field of pharmaceutical chemistry, and more particularly to a method of preparation of a Bavathin intermediate. Background technique [0002] Bavi Tam (English name BrivaRetam, trade name ), The chemical name is (S) -2 - ((R) -2-oxo-4-propylpyrrolidine-1-yl) butam, a 2-pyrrolidone derivative, the structural formula is as follows: [0003] [0004] Babathi is a new type of synaptic cyst 2a (SV2A) high affinity ligand, which can be used for intractable partial epilepsy, no secondary patients with or without secondary systemic acute patients It can also be used to treat children's epilepsy. [0005] At present, the preparation process of Babathi is almost needed to use chromatographic column separation isomers, which has greatly increased production costs. For example, Patent CN1882535A discloses a method of preparing Baviwi, which is finally obtained by Bavxi and its diastereomers (2S) -2 - ((4S) -2-oxo-4- The mixture o...

Claims

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Application Information

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IPC IPC(8): C07D307/33
CPCC07D307/33C07B2200/07
Inventor 王仲清廖守主陈红军覃军海杨再友
Owner 广东东阳光药业股份有限公司
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