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A kind of preparation method of buvaracetam

A compound, methanol technology, applied in organic chemistry methods, drug combinations, organic chemistry and other directions, can solve the problems of low yield of β-propyl butyrolactone, low atom economy, high comprehensive production cost, and achieve high yield High, highlighting the advantages of step economy and the effect of step economy

Active Publication Date: 2021-10-26
ZHEJIANG TIANYU PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] 1) The yield of β-propylbutyrolactone in the R configuration of the intermediate obtained by the enzymatic resolution process is very low in the subsequent conversion process to brivaracetam, resulting in high overall production costs
[0011] 2) The synthesis of R-3-hydroxymethylcapronitrile requires the use of expensive oxazolinone chiral auxiliary reagents, resulting in increased production costs, and the need to remove chiral auxiliary reagents during the synthesis process, and the utilization rate of raw materials is low low, atom economy is not high

Method used

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  • A kind of preparation method of buvaracetam
  • A kind of preparation method of buvaracetam
  • A kind of preparation method of buvaracetam

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0060] Embodiment 1: the synthesis of compound 3

[0061]

[0062] Put compound 2 (130g, 0.61mol, 1.0eq), LiBr (53g, 0.61mol, 1.0eq), DMF (650mL) and water (22.0g, 1.22mol, 2.0eq) into a 1L four-necked flask, and heat up to 130~ 140°C, keep warm for 4 hours, after the reaction is complete, cool down to 10-20°C, add saturated NH at 10-20°C 4 Cl aqueous solution (260mL), toluene (780mL) were stirred for 30 minutes, and the layers were allowed to stand. The aqueous layer was washed once with toluene (400mL). After drying with anhydrous sodium sulfate, the solvent was removed to dryness under reduced pressure to obtain 86.7 g of compound 3 as a colorless oil, with a yield of 92%. ESI-HRMS(m / z):C 8 h 14 NO 2 [M+H + ]Theoretical calculation value: 156.1019, measured value: 154.1023; 1 HNMR (400MHz, d 6 -Acetone) δ3.70(s,3H),2.82(m,1H),2.73(m,2H),1.70-1.62(m,2H),1.36(m,2H),0.92(t,J=7.2Hz ,3H); 13 CNMR (100Hz, d 6 -Acetone) δ174.1, 118.9, 52.3, 41.9, 34.2, 20.4, 14.1.

Embodiment 2

[0063] Embodiment 2: the synthesis of compound 4

[0064]

[0065] Put tris(hydroxymethyl)aminomethane (2.7g) and water (720mL) into a 2L four-necked bottle, start stirring and adjust the pH to about 8.1 with 1.0M HCl, add porcine pancreatic lipase (45.0g), and heat up to 28 ~33°C, add compound 3 (90.0g, 0.58mol, 1.0eq) prepared according to the method in Example 1, THF (90mL), control the temperature at 28~33°C, adjust the pH to 8.0~8.1 with 1.0M NaOH solution, and keep warm After 14 to 18 hours, the reaction is complete, add diatomaceous earth (45.0g) and stir for 30 minutes, filter, filter the residue with 450mL ethyl acetate, and filter, combine the filtrate to separate layers, wash the water layer with ethyl acetate 3 times, each time 450mL acetic acid Ethyl ester, the water layer was cooled to 0-5°C, and 1.0M H 2 SO 4 (248g) to adjust the pH to 1.9-2.1, after the adjustment, the temperature was raised to 20-25°C, 45g of diatomaceous earth was added, 900mL of ethyl a...

Embodiment 3

[0066] Embodiment 3: the synthesis of compound 5

[0067]

[0068] Put compound 4 (32.0g, 0.23mol, 1.0eq), methanol (128mL), refined 30% hydrochloric acid aqueous solution (5.8g, 0.058mol, 0.25eq) into a 250ml four-necked bottle, heat up to 35-45°C for 20 hours After the reaction is complete, remove the methanol under reduced pressure at 40-45°C, add 320mL of dichloromethane and 320ml of water after dehydration, stir for 10 minutes, let stand to separate and wash the water layer once with 1600mL of dichloromethane, let stand and separate , combined the organic layers, the organic layer was washed twice with saturated NaCl aqueous solution, and the organic layer was washed with 320ml saturated NaHCO 3 After the aqueous solution was washed once, the mixture was left to stand and separated, and the organic layer was dried over anhydrous sodium sulfate and desolvated under reduced pressure to obtain 32.6 g of compound 5 as a colorless oil, with a yield of 93%. ESI-HRMS(m / z):C ...

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Abstract

The invention provides a preparation method of buvaracetam, the synthesis route of which is as follows. The preparation method of Buvaracetam of the present invention is simple, economical, environmentally friendly and suitable for industrialization

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a preparation method of buvaracetam. Background technique [0002] Brivaracetam, its chemical name is (S)-2-((R)-2-oxo-4-propylpyrrolin-1-yl)butyramide, and its chemical structure is as follows: [0003] [0004] Brivaracetam is the third-generation antiepileptic drug newly developed by Belgian drugmaker UCB. There is a certain inhibitory effect. In 2016, buvaracetam was approved by the FDA for the treatment of epileptic seizures, and research results have shown that brivaracetam has a good effect on generalized epileptic seizures. [0005] UCB company discloses a preparation method of buvaracetam in the literature Org.Process Res.Dev.2016,20,1566-1575, the synthetic route of this method is as follows, wherein dimethyl malonate and tert-butyl bromoacetate through condensation and decarboxylation to synthesize tert-butyl beta-carboxyhexanoate, and the resulting tert-butyl beta-...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D207/27A61P25/08C07C255/24
CPCA61P25/08C07B2200/07C07C255/24C07D207/27
Inventor 王臻柯春龙刘君锋张鹏李启超朱国荣屠勇军
Owner ZHEJIANG TIANYU PHARMA
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