Blonanserin intermediate 4-fluorobenzoylacetonitrile synthesis method

Abstract

The invention provides a Blonanserin intermediate 4-fluorobenzoylacetonitrile synthesis method. The method comprises the following steps: (1) mixing acetonitrile, t-butanol, p-fluorobenzonitrile and organic solvent A into mixed solution; (2) adding potassium tert-butoxide and the organic solvent A to a reactor, then adding the mixed solution obtained in the step (1), and stirring for reaction to obtain 3-amino-3-p-fluorophenyl acrylonitrile; (3) hydrolyzing the 3-amino-3-p-fluorophenyl acrylonitrile with hydrochloric acid solution to obtain the 4-fluorobenzoylacetonitrile, wherein the organic solvent A is isopropyl ether and / or tetrahydrofuran. According to the method, the potassium tert-butoxide is used as a condensing agent, which greatly improves the safety of the process. The potassium t-butoxide is mild in nature, has hygroscopicity but is nonflammable, and can be used in wider temperature and humidity ranges, and is more conducive to industrial production. And meanwhile, the method is stable in yield and high in obtained product purity.

Description

technical field [0001] The invention relates to the field of pharmaceutical chemical synthesis, in particular to a method for synthesizing p-fluorobenzoylacetonitrile, an intermediate of blonanserin. Background technique [0002] p-Fluorobenzoylacetonitrile is an important intermediate in the synthesis of blonanserin and is widely used in industry. The finished product of blonanserin can be prepared from p-fluorobenzoylacetonitrile through cyclization, chlorination, and condensation reactions with cyclooctanone, and the synthetic route is as follows. [0003] [0004] At present, the existing preparation methods of p-fluorobenzoylacetonitrile mainly contain: [0005] Document 1: Refer to J.Med.Chem 1979 22.11.1385-1389. Using p-fluorobenzonitrile as the starting material, p-fluorobenzoyl acetonitrile is obtained through condensation with acetonitrile and hydrolysis. The synthetic route is as follows: [0006] [0007] Document 2: With reference to China Journal of Ph...

AI Technical Summary

Problems solved by technology

[0009] The defects of the above-mentioned process routes are: the dangerous chemical sodium hydride is used as the condensation agent of the reaction. This compound has strong water absorption and is flammable when exposed to water. There is a great potential safety hazard in production.

However, the product synthesized by this method will contain about 0.5% 4-methoxybenzoyl acetonitrile and about 0.5% benzoyl acetonitrile, because the properties of these two by-products are very similar to 4-fluorobenzoyl acetonitrile , it is difficult to remove them by common means such as recrystallization or column separation, and their derivatives must be less than 0.1% in the standard of the drug, so this synthetic method is very useful for the synthesis of 4-fluorobenzyl as a drug intermediate acetonitrile is clearly flawed

Images