阅读说明：本技术 普瑞巴林内酰胺亚甲基二聚物及其制备方法 (Pregabalin lactam methylene dimer and preparation method thereof ) 是由 林金生 刘晓飞 李丹 王静 李月 朱文泉 陈文斌 李敏 于 2018-11-06 设计创作，主要内容包括：本申请提供了普瑞巴林内酰胺亚甲基二聚物及其制备方法,该方法包括将普瑞巴林溶解于在反应溶剂中,在酸性体系下与醛反应并经分离得到目标产物普瑞巴林内酰胺亚甲基二聚物。本申请所提供的普瑞巴林内酰胺亚甲基二聚物制备方法收率操作简单,产品收率高、纯度好并且成本低。(The method comprises the steps of dissolving pregabalin in a reaction solvent, reacting with aldehyde under an acid system, and separating to obtain a target product pregabalin lactam methylene dimer. The preparation method of the pregabalin lactam methylene dimer, provided by the application, has the advantages of simple yield operation, high product yield, good purity and low cost.)

Pregabalin lactam methylene dimer having the following structural formula:

a preparation method of pregabalin lactam methylene dimer comprises the following steps:

(a) adding pregabalin, acid and aldehyde into a reaction solvent to obtain a reaction system;

(b) heating the reaction system to 30-100 ℃, and reacting for 0.5-36 hours;

(c) after the reaction is finished, obtaining pregabalin lactam methylene dimer;

wherein the structural formula of the pregabalin lactam methylene dimer is as follows:

the preparation method according to claim 2, wherein the reaction solvent of step (a) is selected from water, a polar organic solvent, or a mixture of water and a polar organic solvent; preferably, the polar organic solvent is selected from one of methanol, ethanol, propanol, isopropanol, acetonitrile, acetone, N-dimethylformamide, dimethyl sulfoxide and N-methylpyrrolidone or any combination thereof.

The method according to claim 2 or 3, wherein the acid of step (a) is selected from an organic acid, an inorganic acid, or a combination thereof; preferably, the organic acid is selected from one or any combination of formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid; the inorganic acid is selected from one or any combination of hydrochloric acid, sulfuric acid and phosphoric acid.

The production method according to any one of claims 2 to 4, characterized in that: the aldehyde is selected from one or any combination of formaldehyde, paraformaldehyde, trioxymethylene and paraformaldehyde; preferably formaldehyde or trioxymethylene.

The preparation method according to any one of claims 2 to 5, wherein the molar ratio of the acid in the step (a) to the pregabalin molecule is 0.01:1 to 50:1, preferably 0.1:1 to 2.5: 1.

The preparation method according to any one of claims 2 to 6, wherein the molar ratio of the aldehyde in step (a) to the pregabalin molecule is 0.1:1 to 10:1, preferably 0.3:1 to 3: 1.

The production method according to any one of claims 2 to 7, wherein the temperature of the reaction system in the step (b) is raised to 55 to 75 ℃ for 12 to 24 hours.

The production method according to any one of claims 2 to 8, wherein step (c) comprises: after the reaction is finished, the reaction solvent is removed, and the pregabalin lactam methylene dimer is separated from the obtained solid.

The method of claim 9, wherein the separation method is selected from column chromatography or preparative liquid chromatography.