Ziprasidone key intermediate preparation method

Abstract

The present invention relates to a ziprasidone key intermediate preparation method, wherein benzo[d]isothiazole-3-ol (or one) is adopted as a raw material, and reacts with a substituted sulfonyl chloride or anhydride under an alkaline condition to obtain benzo[d]isothiazole-3-substituted sulfonate, and the benzo[d]isothiazole-3-substituted sulfonate reacts with piperazine to prepare the ziprasidone key intermediate 3-(1-piperazinyl)-1,2-benzoisothiazole. The method of the present invention has characteristics of simple operation, easily available raw materials, less byproducts, simple post-treatment, less industrial three-waste and the like, and is especially suitable for industrial production.

Description

technical field [0001] The invention relates to the field of chemical pharmacy, in particular to a method for preparing a key intermediate of ziprasidone. Background technique [0002] Ziprasidone, English name Ziparsidne, chemical name 5-[2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethyl]-6-chloro-1, 3-dihydro-2(1H)-indol-2-one], which belongs to a new type of atypical broad-spectrum antipsychotic drug, is used for the treatment of schizophrenia. It was developed by Pfizer Pharmaceuticals. In 1998, the oral dosage form was listed in Sweden. In September 2000, the intramuscular injection was launched in Sweden. It is a 5-hydroxytryptamine and dopamine receptor antagonist. It has a strong affinity for 5-HT A2 / DA D2 receptors and is effective for acute and chronic schizophrenia. It is also effective for the related symptoms of schizophrenia. Compared with traditional antipsychotic drugs, the drug can improve positive and negative symptoms, improve cognitive ability, can gre...

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Problems solved by technology

[0010] In US5883258A1, the synthetic method of route 1 is adopted, but phosgene is used as chlorination reagent in the process of synthetic formula (V), which brings severe test for safe production; US4590196, Journal of Medicinal Chemistry1986, V29, #3,359 -369 etc. have reported that the method of using phosphorus oxychloride instead of triphosgene to carry out chlorination reduces the appropriate risk, but in industrial production, the use, storage, production process and post-treatment of phosphorus oxychloride all have strict requirements. Recently, US2013 / 5983 mentioned the use of thionyl chloride as a chlorination reagent, but this method requires a higher reaction temperature, which is 70-150 degrees Celsius to improve the reaction process, and the production process and post-treatment will produce a large amount of acid gas and waste. Acid, many industrial wastes

At the same time, in this reaction process, there will be a disubstituted by-product, that is, a by-product formula (VI) compound 1,4-bis(benzo[d]isothiazol-3-yl)piperazine, and the content is usually greater than 0.2% (determination by high performance liquid phase method), difficult to remove, will affect the quality of ziprasidone

[0011] The synthetic method of route 2 is reported in US5935960, and the post-processing of this reaction is complicated, and the product with higher purity can be obtained after purification, meanwhile, the starting material bis(2-cyanophenyl) disulfide is a rare product, industrialized It is difficult to guarantee its supply at the time of production

[0012] The synthetic method of route three is reported in US4957916, and this method just improves method one, reacts with the piperazine after the protection, reduces the disubstituted product namely 1,4-bis(benzo[d]isothiazole-3 -base) the generation of piperazine formula (VI) by-product, carry out deprotection subsequently, but in this method, can't avoid the shortcoming that uses chlorination reagent to bring in the method one, simultaneously, the price of the piperazine of protection is far higher Due to the price of piperazine, it is the biggest shortcoming of this route, so it is difficult to implement industrially

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