Preparation method of levetiracetam

A technology of aminobutanamide and amide, which is applied in the field of compound preparation, can solve the problems of complicated reaction operation, high cost, unsatisfactory product purity, etc., and achieves the effects of reducing environmental pollution and cost

Active Publication Date: 2012-09-19
BEIJING SHIHONG PHARMACEUTICAL CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The synthetic method of above relevant literature report, all use a large amount of organic solvents in the reaction, cyclization reaction also needs to add catalyzer or phase-transfer catalyst etc., and reaction generally will carry out at about 0 ℃, and cost is high, and reaction operation is complicated, and product purity is not high. ideal

Method used

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  • Preparation method of levetiracetam
  • Preparation method of levetiracetam
  • Preparation method of levetiracetam

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] (1) Synthesis of (S)-N-(1-amino-1-oxo-2-butyl)-4-chlorobutanamide

[0031] Mix α-aminobutyramide hydrochloride (3g, 21.65mmol) and water (15ml), add triethylamine (7.55ml, 54.13mmol), add 4-chlorobutyryl chloride (3.15ml, 28.14mmol) dropwise under stirring ), after the dropwise addition, continue to stir for 1h. Add an appropriate amount of sodium chloride and stir, and a solid precipitates out. Suction filter, and wash the solid with a small amount of 5ml ethyl acetate. Gained solid weighs 3.57g in air, productive rate 79.8%, melting point 118-123 DEG C, α D 25 = -22.3° (c=1, methanol). 1 HNMR (CDCl 3 , 400MHz): δ0.96(t, J=7.5Hz, 3H), 1.64-1.71(m, 1H), 1.87-1.92(m, 1H), 2.10-2.15(m, 2H), 2.40-2.45(m ,2H),3.60(t,J=6.4Hz,2H),4.43(q,J=6.8Hz,1H),5.62(br,1H),6.24(br,1H),6.34(d,J=7.4Hz ,1H).

[0032] (2) Synthesis of Levetiracetam

[0033] Potassium hydroxide (0.17 g, 2.18 mmol) and 1 g of anhydrous sodium sulfate were mixed and ground in a mortar for 3 min. Add (S)...

Embodiment 2

[0035] (1) Synthesis of (S)-N-(1-amino-1-oxo-2-butyl)-4-chlorobutanamide

[0036] Mix α-aminobutyramide hydrochloride (3g, 21.65mmol) and water (9ml), add sodium bicarbonate (5.64g, 67mmol), add dropwise 4-chlorobutyryl chloride (4.85ml, 43.3mmol) under stirring , Continue to stir for 1h after the dropwise addition. Suction filtration, the solid was washed with a small amount of ethyl acetate. After drying in air, 3.45 g of solid was obtained, with a yield of 77.2%.

[0037] (2) Synthesis of Levetiracetam

[0038] Potassium hydroxide (0.29 g, 7.26 mmol) and 3 g of anhydrous sodium sulfate were mixed and ground in a mortar and pestle for 3 min. (S)-N-(1-amino-1-oxo-2-butyl)-4-chlorobutanamide (1.00 g, 4.84 mmol) was added, and the grinding was continued for 15 min, followed by TLC until the reaction was complete. Heat to dissolve with ethyl acetate, cool after hot filtration, crystals are precipitated, and 0.63g product is obtained by suction filtration, yield 76.8%, meltin...

Embodiment 3

[0040] (1) Synthesis of (S)-N-(1-amino-1-oxo-2-butyl)-4-chlorobutanamide

[0041] Mix α-aminobutyramide hydrochloride (3g, 21.65mmol) and water (9ml), add potassium hydroxide (3.64g, 64.95mmol), add 4-chlorobutyryl chloride (4.85ml, 43.3mmol) dropwise under stirring ), and continued to stir for 1 h after the dropwise addition. Suction filtration, the solid was washed with a small amount of ethyl acetate. After drying in air, 3.51 g of solid was obtained, with a yield of 78.5%.

[0042] (2) Synthesis of Levetiracetam

[0043] Same as the second step of Example 2, obtain 0.60g product, productive rate 73.2%, 115.6-117.2 ℃ of fusing points, α D 25 =-81.2° (c=2, water).

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Abstract

The invention provides a preparation method of levetiracetam. The method includes utilizing alpha-amino-butyrylamide-hydrochloride and 4-chlorobutyryl chloride as raw materials, first conducting acylation reaction in water solution to obtain a middle body and enabling the middle body, an organic carrier and alkali to be ground in mixing mode to be subjected to intramolecular cyclization reaction to obtain the levetiracetam. The preparation method utilizes water as the catalyst in the acylation reaction, adopts a non-solvent grinding method and does not need adding a phase transfer catalyst in the intramolecular cyclization reaction. Organic solvents are not used in the two steps of reaction, so that the preparation method is environment-friendly, remarkably reduces cost, is simple in operation and high in yield and provides a new choice for preparation of the levetiracetam.

Description

technical field [0001] The invention relates to a preparation method of a compound, in particular to a preparation method of levetiracetam. Background technique [0002] Levetiracetam is the second-generation acetylcholine agonist developed by UCB Company in Belgium. Its chemical name is levetiracetam. It is used for the treatment of localized and secondary generalized epilepsy. The drug was approved by the U.S. FDA in April 2000 and launched in the U.S. The drug has obvious antiepileptic effect, has good tolerance, has few side effects, is easy to absorb when taken orally, has high bioavailability, and does not interact with other antiepileptic drugs, and is widely used as an antiepileptic drug. The structure of levetiracetam is as follows: [0003] [0004] At present, the synthetic method of levetiracetam has been reported in many documents, and the U.S. Patent (USP4696943A) has reported two synthetic methods, one is to use (S)-2-aminobutyramide hydrochloride as the ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/27
Inventor 张站斌顼兴宇李贞翔唐志刚张现忠张俊波关淑贞王学斌
Owner BEIJING SHIHONG PHARMACEUTICAL CO LTD
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