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Wherein (S)-4-chloro-3-hydroxybutyrate and glycinamide react under alkaline conditions to obtain the final product oxiracetam and control the alkalinity of the reaction solution by adding alkali at one time, but due to Ola Racetam is easily destroyed in a strong alkaline solution, which directly affects the purity and yield of oxiracetam; in addition, silica gelcolumn chromatography is used in the purification of the final product oxiracetam, and the eluent used is an organic mixture Solvent, the amount of solvent is large, it is not easy to recycle, the cost is high, and the silica gelcolumn chromatography method is not suitable for industrial scale-up production
[0008] Chinese patent CN10575309A reports a synthesis route that uses glycine and S-4-halo-3-hydroxybutyrate as raw materials for condensation and then esterification and ammonolysis, but this method also uses the method of dropping and strengthening alkali under high temperature conditions Condensation will be accompanied by various side reactions such as hydrolysis of S-4-halo-3-hydroxybutyrate, resulting in low condensation yield and more by-products, and the final product S-oxiracetam At this purity, direct crystallization is not possible, and ion-exchange resin chromatography is required to remove impurities. The cost is high, the purity is low, and it is difficult to industrialize
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Embodiment 1
[0057] A kind of synthetic method of (S)-oxiracetam, it carries out as follows,
[0058] (l) Preparation of Intermediate I:
[0059] Take 50g of the raw material S-4-amino-3-hydroxybutyric acid, put it into a single-neck bottle, add 50ml of methanol, stir, cool in an ice-water bath, slowly add 150ml of concentrated hydrochloric acid, keep the temperature not exceeding 40°C, and the solid will first have a During the dissolution process, it precipitates again, and when the dripping speed is completed, the solid dissolves again, and finally forms a light yellow clear liquid. Stirring was continued for 3 hours, and the raw materials were basically completely reacted by pointing the board. The reaction was stopped, and the solvent was directly concentrated to remove a light yellow oil, which was solidified at a low temperature to obtain intermediate I. After nuclear magnetic detection, intermediate I is: 1H-NMR (300MHz, D2O): δ2.76-2.67 (AB system, m, 2H,), 3.31-3.23 (AB system, ...
Embodiment 2
[0073] 1, a kind of synthetic method of (S)-oxiracetam, follow the steps:
[0074] (1) Stir S-4-amino-3-hydroxybutyric acid and ethanol accounting for 18 times its weight, and react esterification reaction at 60 ° C for about 5 hours. The raw materials basically react completely, stop the reaction, and directly concentrate to remove the solvent. Solidify at low temperature to obtain intermediate I; at the same time, methanol, n-propanol, isopropanol, n-butanol, tert-butanol, cyclohexanol or cyclopentanol are used to prepare intermediate I as the above solvent, and finally tested by NMR , the prepared intermediate I is: 1H-NMR (300MHz, D2O): δ1.30 (m, 3H), 2.76-2.67 (AB system, m, 2H,), 3.31-3.23 (AB system, m, 2H), 4.12(m, 2H), 4.40(m, 1H), 4.70(bs, 3H).
[0075] (2) The intermediate I obtained from step (1) is stirred and cooled in ethanol that is 15 times by weight of S-4-amino-3-hydroxybutyric acid, and is added dropwise with n-butyl bromoacetate for condensation reaction ...
Embodiment 3-12
[0078] Embodiment 3-12: Compared with Embodiment 2, it is a further optimized embodiment of the present invention, according to the steps and parameters in Table 1 below, and the others are the same as Embodiment 1.
[0079] Table 1
[0080]
[0081]
[0082]
[0083] Through nuclear magnetic detection, the intermediate prepared in embodiment 3-12 and levoxiracetam are as shown in table 2:
[0084]
[0085]
[0086]
[0087]
[0088] The purity of levoxiracetam obtained according to the above Examples 3-12 is 99.5-99.9% as determined by HPLC, and the calculated yield is 35-45%.
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Abstract
The invention provides a synthesis method of oxiracetam. The synthesis method comprises the following steps: (1) taking S-4-amino-3-hydroxybutyric acid as a starting raw material and carrying out an esterification reaction on the starting raw material and alcohol to obtain an intermediate I; (2) carrying out a condensation reaction on the intermediate I and halogenated acetate to obtain an intermediate II; (3) carrying out a ring closing reaction on the intermediate II to obtain an intermediate III; (4) carrying out an ammonolysis reaction on the intermediate III to obtain a target product (S)-oxiracetam. With the adoption of a synthetic route of the oxiracetam, the (S)-oxiracetam product with the relatively ideal yield being 20 percent or above can be obtained at least, and a new oxiracetam synthetic route is explored.
Description
[0001] This application is a divisional application of an invention patent application with the application number "201310243165.7" and the invention title "a method for synthesizing oxiracetam". technical field [0002] The present invention relates to a synthesis method of oxiracetam, in particular to a synthesis method of (S)-oxiracetam. Background technique [0003] Oxiracetam is a nootropic drug synthesized for the first time in 1974 by the Italian Shi Kebichem Company. It is composed of two isomers (S)-oxiracetam ((S)-oxiracetam) and (R)- Oxiracetam ((R)-oxiracetam) composed of racemate. (S)-Oxiracetam is a single enantiomer of oxiracetam with the chemical name: (S)-4-hydroxy-2oxo-1-pyrrolidineacetamide. The nootropic drug oxiracetam is a synthetic hydroxyaminobutyric acid (GABOB) derivative, which is a central nervous systemdrug that can promote learning, enhance memory, and protect damaged nerve cells. [0004] At present, there are four methods for the synthesis ...
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