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Method for preparing levetiracetam intermediate

An intermediate, ethyl technology, applied in the field of preparation of levetiracetam intermediate - α-ethyl-2-oxo-1-pyrrolidine acetic acid, can solve the problem of low optical purity and achieve low toxicity , the effect of high splitting efficiency

Active Publication Date: 2008-12-31
ZHEJIANG HUAHAI PHARMACEUTICAL CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

We found in the test that the optical purity of (S)-α-ethyl-2-oxo-1-pyrrolidineacetic acid (R)-α-methylbenzylamine salt obtained by using toluene as a solvent resolution is also low, and generally requires Refining with toluene about 4 times can make the optical purity of compound II meet the feeding requirements of the next step ([α] 20 D =-25.0±1°(C=1, acetone))

Method used

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  • Method for preparing levetiracetam intermediate
  • Method for preparing levetiracetam intermediate
  • Method for preparing levetiracetam intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] Preparation of (S)-α-ethyl-2-oxo-1-pyrrolidineacetic acid (R)-α-methylbenzylamine salt

[0036] Put 26.4g of compound I and 80ml of acetone into a 250ml three-necked flask. Stirring was started, and a mixed solution of 9.33 g of (R)-α-methylbenzylamine and 7.83 g of triethylamine was added dropwise. After dropping, the temperature was raised to 50-60°C and refluxed for 2 hours. Remove insoluble matter by hot filtration, and the filtrate is cooled to 10-15° C., stirred and crystallized for 2 hours, filtered, the filtrate is the mother liquor to be recovered, the filter cake is washed with 10 ml of acetone, and dried to obtain 17 g.

[0037] Yield: 75.6% [α] 20 D =-18.5° (C=1, isopropanol)

[0038] Purification of (S)-α-ethyl-2-oxo-1-pyrrolidineacetic acid (R)-α-methylbenzylamine salt

[0039] Put 17g of (S)-α-ethyl-2-oxo-1-pyrrolidineacetic acid (R)-α-methylbenzylamine crude product into a 250ml three-necked flask, add 85ml of acetone, heat and reflux for 2 hours, a...

Embodiment 2

[0044]Preparation of (S)-α-ethyl-2-oxo-1-pyrrolidineacetic acid (R)-α-methylbenzylamine salt

[0045] 20g of compound I and 50ml of acetone were dropped into a 250ml three-necked flask. Stirring was started, and a mixed solution of 7 g of (R)-α-methylbenzylamine and 5.92 g of triethylamine was added dropwise. After dropping, the temperature was raised to 50-60°C and refluxed for 2 hours. Remove insoluble matter by hot filtration, and the filtrate is cooled to 10-15° C., stirred and crystallized for 2 hours, filtered, the filtrate is the mother liquor to be recovered, the filter cake is washed with 10 ml of acetone, and dried to obtain 11.7 g.

[0046] Yield: 68.5% [α] 20 D =-20.5° (C=1, isopropanol)

[0047] Preparation of (S)-α-ethyl-2-oxo-1-pyrrolidineacetic acid

[0048] 11.7g (S)-α-ethyl-2-oxo-1-pyrrolidineacetic acid (R)-α-methylbenzylamine salt ([α] 20 D =-20.5° (C=1, isopropanol)) was dissolved in 20ml of water, temperature control T≤10°C, adjusted to PH=11-12 wi...

Embodiment 3

[0050] Preparation of (S)-α-ethyl-2-oxo-1-pyrrolidineacetic acid (R)-α-methylbenzylamine salt

[0051] Put 20 g of compound I and 100 ml of ethyl acetate into a 250 ml three-necked flask. Stirring was started, and a mixed solution of 7 g of (R)-α-methylbenzylamine and 5.92 g of triethylamine was added dropwise. After dropping, the temperature was raised to 75-77°C and refluxed for 2 hours. Heat filtration to remove insoluble matter, the filtrate was cooled to 10-15° C. and stirred to crystallize for 2 hours, filtered, the filtrate was the mother liquor to be recovered, the filter cake was washed with 20 ml of ethyl acetate, and dried to obtain 14.4 g.

[0052] Yield: 84% [α] 20 D = -19° (C = 1, isopropanol)

[0053] Preparation of (S)-α-ethyl-2-oxo-1-pyrrolidineacetic acid

[0054] 14.4g (S)-α-ethyl-2-oxo-1-pyrrolidineacetic acid (R)-α-methylbenzylamine salt ([α] 20 D =-19 ° (C = 1, isopropanol)) was dissolved in 25.7ml of water, temperature control T ≤ 10 ° C with 30% ...

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Abstract

The invention discloses a preparation method for a levetiracetam intermediate (S)-alpha-ethyl-2-oxo-1-pyrrolidine acetic acid, which takes (RS)-alpha-ethyl-2-oxo-1- pyrrolidine acetic acid as the starting material and takes (R)-alpha-methyl benzylamine as resolving agent to get the product through resolving in resolving solvent. The invention is characterized in that the resolving solvent can be C1-C7 ketones, C1-C7 alcohols, C1-C4 esters or the mixture of the solvents. In addition, the by-product (R)-alpha-ethyl -2 - oxo -1 - pyrrolidine acetic acid can be recovered through racemization under the effect of alkali so as to regain the (RS)-alpha-ethyl -2-oxo-1- pyrrolidine acetic acid. Compared with the existing invention, the preparation method of the invention has the advantages that during resolving, the solvent selected for the compound (RS)-alpha-ethyl -2-oxo -1 - pyrrolidine acetic acid has high resolving efficiency and small toxicity; the resolving salt only needs to be refined once, so that the optical purity of (S)-alpha-ethyl -2-oxo -1 - pyrrolidine acetic acid can meet the requirement (alpha20D is equal to -25.0 plus or minus 1 degree (C is equal to 1, acetone)). In addition, the racemic recovery of the compound (R)-alpha-ethyl -2-oxo-1-pyrrolidine acetic acid can reduce environmental pollution and decrease the cost of the product.

Description

(1) Technical field [0001] The invention relates to a preparation method of levetiracetam intermediate (S)-α-ethyl-2-oxo-1-pyrrolidineacetic acid. (2) Background technology [0002] Levetiracetam involved in the present invention and its key intermediate structural formula are as follows: [0003] [0004] Levetiracetam (S)-α-Ethyl-2-oxo-1-pyrrolidineacetic acid [0005] Levetiracetam is an acetylcholine agonist developed by Belgian UCB Company, mainly used for the treatment of localized and secondary generalized epilepsy. [0006] Two synthetic routes are mentioned in the patent US4943639. Route 1 uses L-2-aminobutyramide hydrochloride as the starting material to condense with 4-chlorobutyryl chloride to prepare levetiracetam. Route 2 uses (RS)-α-ethyl-2-oxo-1-pyrrolidineacetic acid as the starting material, and (R)-α-methylbenzylamine as the resolving agent in the solvent benzene for resolution, free, Amidation gives levetiracetam. [0007] In the patent WO2006 / 053...

Claims

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Application Information

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IPC IPC(8): C07D207/27C07B57/00
Inventor 颜峰峰甘立新芦启峰李清泉
Owner ZHEJIANG HUAHAI PHARMACEUTICAL CO LTD
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