阅读说明：本技术 一种消旋卡巴拉汀的拆分方法 (Resolution method of racemic rivastigmine ) 是由 李恩民 赵国磊 于 2018-08-01 设计创作，主要内容包括：本发明涉及一种消旋卡巴拉汀的拆分方法其特征在于,包括以下步骤：将消旋卡巴拉汀溶于低级醇-乙腈-水混合体系,加入D-(+)-二对甲基苯甲酰酒石酸加热回流搅拌,趁热抽滤后降温搅拌析晶,重复2-3次操作可得到光学纯度99.5%以上的卡巴拉汀D-(+)-二对甲基苯甲酰酒石酸盐。(The invention relates to a resolution method of racemic rivastigmine, which is characterized by comprising the following steps: dissolving racemic rivastigmine in a lower alcohol-acetonitrile-water mixed system, adding D- (+) -di-p-methylbenzoyl tartaric acid, heating, refluxing and stirring, carrying out suction filtration while the mixture is hot, cooling, stirring and crystallizing, and repeating the operation for 2-3 times to obtain the rivastigmine D- (+) -di-p-methylbenzoyl tartrate with the optical purity of more than 99.5%.)

1. The resolution method of racemic rivastigmine is characterized by comprising the following steps:

dissolving racemic rivastigmine in a lower alcohol-acetonitrile-water mixed system, adding D- (+) -di-p-methylbenzoyl tartaric acid, heating, refluxing and stirring, carrying out suction filtration while the mixture is hot, cooling, stirring and crystallizing, and repeating the operation for 2-3 times to obtain the rivastigmine D- (+) -di-p-methylbenzoyl tartrate with the optical purity of more than 99.5%.

2. A method according to claim 1, characterized in that: the refining system is lower alcohol-acetonitrile-water mixed system, and the lower alcohol is C1-4 side chain alcohol, preferably methanol-acetonitrile-water system.

3. A method according to claim 2, characterized in that: the system ratio of lower alcohol-acetonitrile-water is 2: 1:5 to 20:1:10, wherein the ratio of lower alcohol to acetonitrile is 10:1, most preferably the ratio is methanol: acetonitrile: water =10:1: 5.

4. The method according to claim 1, wherein the mass ratio of the rivastigmine racemate to the mixed solvent is 1:8 to 1:30, preferably 1: 16.

Technical Field

The invention belongs to the field of pharmaceutical chemistry, and relates to resolution of rivastigmine bitartrate optical isomers.

Background

Rivastigmine (rivastigmine), also known as Rivastigmine, belongs to the second generation of central AChE inhibitor, has selective inhibition effect on AChE of cerebral cortex and hippocampus, has little influence on AChE of striatum and heart, and can slow down the formation of amyloid precursor (APP).

At present, 2 main flow preparation routes of rivastigmine exist, one is to obtain rivastigmine with optical purity meeting the requirement by preparing racemic rivastigmine and then splitting, the method has the defects of more refining times and lower yield at present, the other is to prepare rivastigmine by adopting an asymmetric synthesis method, and the method has the problems of responsible reaction conditions, difficult industrialization and higher material cost.

Aiming at the first route, the splitting process is optimized to a certain extent, so that the splitting times are reduced, the product yield is improved, the solvent recovery can be ensured, and the production cost is reduced.

Disclosure of Invention

The invention relates to a splitting condition of rivastigmine racemate, which is specifically characterized in that rivastigmine is prepared by using a mixed solvent of short-chain alcohol, acetonitrile and water in a certain proportion, adding a proper amount of a splitting agent, heating until the mixture is completely dissolved, cooling, stirring and crystallizing, and repeating for 2-3 times to obtain the rivastigmine with the optical purity of more than 99.5 percent. Compared with the literature, the method has the advantages of obviously reduced refining times, higher yield improvement and 30 percent of total yield.

Detailed Description

The invention is further illustrated by the following examples, which are not to be construed as limiting the invention thereto.