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Levetiracetam preparation method

A technology of protic solvent and hydrochloride, applied in the direction of organic chemistry, etc., can solve the problems of large influence of environmental factors, instability, high toxicity of 4-chlorobutyryl chloride, etc., and achieve simple reaction process, few reaction steps and low price Effect

Active Publication Date: 2016-01-27
CHONGQING SHENGHUAXI PHARMA CO LTD +1
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Problems solved by technology

[0008] The preparation methods reported in the above literature all have unfavorable factors to production or product quality or the environment: as the method for preparing levetiracetam by resolution of chiral α-phenylethylamine, the resolution quality and resolution yield are not good. Ideally, to obtain a qualified product of optical purity, multiple resolutions and multiple refinements are required; another example is the preparation method using (s)-2-aminobutyramide hydrochloride or its derivatives as starting raw materials, although this method Avoid complicated splitting methods, but the price of 4-chlorobutyryl chloride used is higher, influenced by environmental factors, unstable, unfavorable for storage and transportation, and the preparation of 4-chlorobutyryl chloride often requires high-risk, Highly toxic and highly polluting chlorinated reagents (phosgene or thionyl chloride), which also produce a large amount of acid gas

Method used

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Embodiment 1

[0029] (1) Synthesis of (S)-N-(1-amino-1-oxo-2-butyl)-4-hydroxybutanamide (III)

[0030] Add (s)-2-aminobutyramide hydrochloride (I) (20g, 144.4mmol) and sodium bicarbonate (12g, 144.4mmol) into 200mL of ethanol, raise the temperature to 78°C and reflux for 1h, then add 1,4 - Butyrolactone (II) (13.7g, 158.8mmol), keep warm for 6h. Cool down to room temperature, remove inorganic salts by suction filtration, concentrate the filtrate to 1 / 4 of the original volume, stir and crystallize at room temperature for 1 h, filter with suction, and dry to obtain (S)-N-(1-amino-1-oxo-2- Butyl)-4-hydroxybutyramide (III) 24.5g, molar yield 90%. HPLC method measured content 97.2%, chiral purity 99.5%; MS[M+H](m / z): 189.1; MS[M+Na](m / z): 211.1; 1 H-NMR (400MHz, CDCl 3 ,D 2 O)δ:0.96(t, J =7.5Hz,3H),1.85-1.92(m,2H),2.05-2.10(m,2H),2.4-2.45(m,2H),3.60(t, J =6.4Hz,2H),4.45(q, J =6.9Hz, 1H).

[0031] (2) Synthesis of Levetiracetam

[0032] Add (S)-N-(1-amino-1-oxo-2-butyl)-4-hydroxybuta...

Embodiment 2

[0034] (1) Synthesis of (S)-N-(1-amino-1-oxo-2-butyl)-4-hydroxybutanamide (III)

[0035] Add (s)-2-aminobutyramide hydrochloride (I) (20g, 144.4mmol) and triethylamine (14.6g, 144.4mmol) into 200mL of n-butanol, raise the temperature to 118°C and reflux for 1h, then add 1,4-Butyrolactone (II) (11.2g, 130mmol), keep warm for 4h. Cool down to room temperature, remove salt by suction filtration, concentrate the filtrate to 1 / 4 of the original volume, stir and crystallize at room temperature for 1 h, filter with suction, and dry to obtain (S)-N-(1-amino-1-oxo-2-butane Base)-4-hydroxybutyramide (III) 21.5g, molar yield 88%. The content measured by HPLC method is 95.8%, and the chiral purity is 99.0%.

[0036] (2) Synthesis of Levetiracetam

[0037] Add (S)-N-(1-amino-1-oxo-2-butyl)-4-hydroxybutyramide (III) (20g, 106.4mmol) into 200mL of toluene, add 1g of polyphosphoric acid, and heat up to Reaction at 110°C for 2h. Cool to room temperature, filter with suction, and dry t...

Embodiment 3

[0039] (1) Synthesis of (S)-N-(1-amino-1-oxo-2-butyl)-4-hydroxybutanamide (III)

[0040]Add (s)-2-aminobutyramide hydrochloride (I) (20g, 144.4mmol) and sodium hydroxide (5.8g, 144.4mmol) into methanol 200mL, heat up to 65°C and reflux for 1h, then add 1, 4-Butyrolactone (II) (24.8g, 288.8mmol), keep warm for 9h. Cool down to room temperature, remove inorganic salts by suction filtration, concentrate the filtrate to 1 / 4 of the original volume, stir and crystallize at room temperature for 1 h, filter with suction, and dry to obtain (S)-N-(1-amino-1-oxo-2- Butyl)-4-hydroxybutyramide (III) 25g, molar yield 92%. The content measured by HPLC method is 98.5%, and the chiral purity is 99.6%.

[0041] (2) Synthesis of Levetiracetam

[0042] Add (S)-N-(1-amino-1-oxo-2-butyl)-4-hydroxybutanamide (III) (20g, 106.4mmol) into 200mL of xylene, add 0.8g of concentrated sulfuric acid, and heat up Reaction at 100°C for 3h. Cool to room temperature, filter with suction, and dry to obtain...

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Abstract

The present invention discloses a levetiracetam preparation method, wherein (s)-2-aminobutanamide and 1,4-butyrolactone are adopted as starting raw material, and two reactions such as aminolysis ring opening and acid-catalyzed dehydration cyclization are performed to prepare the levetiracetam. According to the present invention, the method has characteristics of low price of the used starting materials, environmental protection, high product yield, high product optical purity, simple reaction process, and no requirement of repeated chiral resolution; and the levetiracetam preparation method provides the new selection for the preparation and the production of the drug levetiracetam.

Description

Technical field [0001] The present invention involves a method of preparation of a drug, which specifically involves a method for preparing Zuo Yiratan. Background technique [0002] Levetiraltam is the second-generation acetylcholine receptor agonist developed by Belgium UCB.Prevention and therapeutic limitations and secondary systemic epilepsy.The anti -epilepsy effect of this drug is significant. The medicine is close to the ideal state and has good safety. It has no drug interaction with other antiepileptic drugs. It is widely used clinically and has high market demand.The structural format of Zuo Yiraistein is as follows: [0003] [0004] At present, there are a large number of literature reports in Zuo Yicatin's preparation.It is roughly divided into two types: one is based on (s) -2-aminoboboboblecamide hydrochloride or its derivatives as the starting raw material., CN101550100, US4943639, CN102702063, CN102675181, CN102558012). [0005] [0006] The other is the left...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/27
Inventor 刘军
Owner CHONGQING SHENGHUAXI PHARMA CO LTD
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