A kind of new preparation method of macitentan intermediate

Abstract

The invention discloses a new preparation method of a macitentan intermediate, wherein the intermediate is N-(5-(4-bromophenyl)-6-chloro-4-pyrimidyl)-N'-propylsulfamide; the new preparation method comprises the steps of adding N-propylsulfamide and 5-(4-bromophenyl)-4,6-dichloropyrimidine to dimethyl sulfoxide, and then adding a metal alkoxide ROM, and stirring for reacting to obtain the N-(5-(4-bromophenyl)-6-chloro-4-pyrimidyl)-N'-propylsulfamide. The synthetic process of the new preparation method is simplified, and also the production efficiency is also improved virtually and the dosage of a solvent is reduced, and therefore, the new preparation method is more applicable to popularization and application at home and abroad. The yield is 51% higher than a documentary value, and the purity of the product is higher; the step of salification is omitted, so that the production efficiency is improved and the dosage of the solvent is reduced, and as a result, the preparation method is more environmentally friendly.

Description

technical field [0001] The invention belongs to the technical field of compound preparation, and in particular relates to a macitentan intermediate N-(5-(4-bromophenyl)-6-chloro-4-pyrimidinyl)-N'-propylaminosulfonamide Preparation. Background technique [0002] Macitentan (macitentan, with the structure shown in formula I) is a highly lipophilic, highly effective tissue-targeted endothelin receptor antagonist. , ETB receptors have dual inhibitory effects, and have tissue targeting. After endothelin binds to its receptor, it can promote the contraction of vascular smooth muscle, induce the proliferation and fibrosis of vascular smooth muscle cells through tissue mechanism, cause vascular inflammation, change the tissue structure, and play an important role in the occurrence and development of many cardiovascular diseases. effect. Clinically, macitentan can be used to treat pulmonary hypertension, pulmonary fibrosis and other diseases, and has shown good therapeutic prospec...

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Problems solved by technology

[0004] Document 1 (J.Med.Chem, 2012,55,7849-7861) and CN100432070A disclose the preparation method of macitentan, wherein, the intermediate N-(5-(4-bromophenyl) of macitentan The preparation method of -6-chloro-4-pyrimidinyl)-N'-propyl aminosulfonamide is as figure 1 As shown, the method prepares N-propylsulfamate potassium salt from N-propylsulfamate, and then prepares N-(5-( 4-bromophenyl)-6-chloro-4-pyrimidinyl)-N'-propylaminosulfonamide not only has the defect that the preparation cycle is long, but also the intermediates generated in the preparation method need to be separated and purified, especially Separation and purification of N-propylsulfamate potassium salt, which is very easy to absorb moisture, leads to problems such as transfer and storage difficulties of N-propylsulfamate potassium salt, and N-propylsulfamate potassium salt after moisture absorption Seriously affect the preparation yield and product purity of N-(5-(4-bromophenyl)-6-chloro-4-pyrimidinyl)-N'-propylaminosulfonamide, resulting in long preparation cycle and low yield , large amount of solvent, large amount of three wastes to be treated, high cost, and difficulties in industrialization, etc.

For example, the method adopts N-propylaminosulfonamide potassium salt as feed material, and the yield of synthesizing N-(5-(4-bromophenyl)-6-chloro-4-pyrimidinyl)-N'-propylaminosulfonamide The rate is less than 50% (calculated as 5-(4-bromophenyl)-4,6-dichloropyrimidine), and the prepared N-(5-(4-bromophenyl)-6-chloro-4-pyrimidine Base)-N'-propylsulfamate has a purity of less than 94%

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