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Preparation method of levetiracetam

A technology of ethyl and ethanol, applied in the direction of organic chemistry, can solve the problems of 4-chlorobutyryl chloride instability, strong base racemization, easy hydrolysis, etc., and achieve stable yield, small amount of solvent, and low solvent toxicity Effect

Inactive Publication Date: 2014-05-28
北京博泽德润医药科技开发有限公司
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Problems solved by technology

[0009] The two routes of synthesizing levetiracetam by using (S)-2-aminobutyramide hydrochloride as raw materials were experimentally studied. During the pilot test, the main problems of the acid chloride method were found to be: (1) The raw material 4-chlorobutanol Acyl chlorides are unstable and easy to hydrolyze; (2) the occurrence of racemization caused by strong base; (3) technical problems such as low yield

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

[0027] Step 1): Preparation of (S)-N-[1(aminocarbonyl)propyl]-4-chlorobutanamide (II)

[0028] Add (s)-2-aminobutyramide hydrochloride 2.5Kg (18.04mol), potassium carbonate 6220g (45.10mol), ethanol 30L into a 50L reactor and stir overnight, then add 4-chlorobutyryl chloride 3050g (21.65mol) dropwise , Stir for 30 minutes after dropping, TLC detection (developer: ethyl acetate / acetone=3 / 1, RfIII=0.1, RfII=0.7), filter after reaction, concentrate the filtrate to dryness under reduced pressure at 45°C, add acetic acid to the residue Ethyl ester / petroleum ether (1 / 4) 20L was beaten for 1-2 hours, filtered, and the solid was air-dried at 35°C overnight to obtain 2920g of white solid (II), with a yield of >74.2%.

[0029] Step 2: Preparation of (S)-α-ethyl-2-oxo-1-pyrrolidineacetamide (levetiracetam) (I)

[0030] Add (S)-N-[1(aminocarbonyl)propyl]-4-chlorobutanamide (II) 5760g (27.9mol), dichloromethane 45L, tetrabutylammonium bromide 463g (1.4 mol), stir and mix, lower the tem...

Embodiment 2

[0034] The key intermediate is (S)-N-[1(aminocarbonyl)propyl]-4-chlorobutanamide (II) quality control method:

[0035] The TLC method detected basically a single spot, and the HPLC detection purity was greater than 95%.

[0036] TLC detection conditions: developer: ethyl acetate / acetone; volume ratio = 1:3; color development method: phosphomolybdic acid spraying, high temperature color development.

[0037] HPLC detection conditions:

[0038] Instrument: Shimadzu 20A series high performance liquid chromatography

[0039] Chromatographic column: Ymc-pack ODS-AQ column (4.6′150mm, 3μm)

[0040] Buffer salt: 0.26g potassium dihydrogen phosphate, add water to 1000ml, adjust pH to 5.50 with 2% potassium hydroxide

[0041] Mobile phase A: buffer salt-acetonitrile=19:1

[0042] Mobile Phase B: Acetonitrile

[0043] Flow rate: 0.9ml / min;

[0044] Injection volume: 10μl

[0045] Column temperature: room temperature

[0046] Detection wavelength: 205nm

[0047] Elution gradient...

Embodiment 3

[0050] Step 1): Preparation of (S)-N-[1(aminocarbonyl)propyl]-4-chlorobutanamide (II)

[0051] Add (s)-2-aminobutyramide hydrochloride 2.5Kg (18.04mol), potassium carbonate 6220g (45.10mol), ethanol 50L into a 50L reactor and stir overnight, then add 4-chlorobutyryl chloride 3050g (21.65mol) dropwise , Stir for 30 minutes after dropping, TLC detection (developer: ethyl acetate / acetone=3 / 1, RfIII=0.1, RfII=0.7), filter after reaction, concentrate the filtrate to dryness under reduced pressure at 45°C, add acetic acid to the residue Ethyl ester / petroleum ether (1 / 4) 20L was beaten for 1-2 hours, filtered, and the solid was air-dried at 35°C overnight to obtain 2920g of white solid (II), with a yield of >74.2%.

[0052] Step 2: Preparation of (S)-α-ethyl-2-oxo-1-pyrrolidineacetamide (levetiracetam) (I)

[0053]Add (S)-N-[1(aminocarbonyl)propyl]-4-chlorobutanamide (II) 5760g (27.9mol), dichloromethane 45L, tetrabutylammonium bromide 463g (1.4 mol), stir and mix, lower the te...

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Abstract

The invention relates to a preparation method of a chiral anti-epileptic drug levetiracetam. The preparation method takes (S)-2-aminobutyramide as the primary raw material, comprises two preparation steps and one refining step, and specifically comprises the following steps: (1) preparation of (S)-N-[1(aminocarbonyl)propyl]-4-chlorobutyramide: orderly adding (S)-2-aminobutanamide hydrochloride, potassium carbonate, and ethanol to carry out reactions so as to obtain (S)-N-[1(aminocarbonyl)propyl]-4-chlorobutyramide; (2) preparation of (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide: orderly adding (S)-N-[1(aminocarbonyl)propyl]-4-chlorobutyramide prepared in the step (1), dichloromethane, and tetrabutylammonium bromide to carry out reactions so as to obtain coarse levetiracetam; (3) adding coarse levetiracetam obtained in the step (2) into a reactor, then adding a mixture of water and acetone according to a volume ratio of 1:25, heating to carry out refluxing dissolution, filtering, carrying out a filtrate thermo-dissolution treatment, stirring, cooling to the room temperature to crystallize, allowing the system to stand still for a night, filtering, washing the solid with acetone, drying at a low temperature so as to obtain the refined levetiracetam.

Description

technical field [0001] The invention relates to the preparation of a medicine, in particular to the preparation of a chiral antiepileptic drug levetiracetam. Background technique [0002] Levetiracetam is a biracetam compound and is an antiepileptic drug. Levetiracetam is an anti-epileptic drug first developed by UCB. Its metabolism does not depend on hepatic cytochrome P450, making it a safer anti-epileptic drug. It is approved for 4 years old and older. Adjunctive treatment of partial seizures in children over 4 years of age. [0003] Levetiracetam chemical name: (S)-α-ethyl-2-oxo-1-pyrrolidineacetamide, molecular formula: C8H14N2O2, molecular weight: 170.21, CAS: 102767-28-2. [0004] The chemical structural formula is as follows: [0005] [0006] The continuous exploration of its synthetic route is conducive to reducing the cost of drugs, improving the environmental friendliness of the drug synthesis process, and improving the quality of drugs. [0007] There are...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/27
CPCC07D207/27
Inventor 张荣立宋春光程璇王洪新
Owner 北京博泽德润医药科技开发有限公司
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