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New preparation method of macitentan intermediate

A technology for macitentan and intermediates, which is applied in the new preparation field of macitentan intermediates, can solve the problems of low product purity, can not be well solved, serious moisture absorption problems, etc., and achieves high product purity. , Improve production efficiency and reduce the effect of salt-forming steps

Inactive Publication Date: 2014-05-28
CHENGDU CLIMB PHARMA TECH
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  • Description
  • Claims
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AI Technical Summary

Problems solved by technology

[0006] In the traditional method, the combined yield of the above two steps is 47%, and the purity of the product is not high. In the steps of B2 to B3 synthesis, the problem of moisture absorption is very serious and cannot be solved well

Method used

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  • New preparation method of macitentan intermediate

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preparation example Construction

[0035] Such as figure 2 Shown, a kind of new preparation method of macitentan intermediate, this intermediate is N-(5-(4-bromophenyl)-6-chloro-4-pyrimidinyl)-N'-propylsulfonamide , including the following steps:

[0036] N-propylsulfonamide and 5-(4-bromophenyl)-4,6-dichloropyrimidine are added to dimethyl sulfoxide, then alkoxy metal compound ROM is added, and N-( 5-(4-bromophenyl)-6-chloro-4-pyrimidinyl)-N'-propylsulfonamide, its chemical reaction formula is as follows:

[0037]

[0038] in:

[0039] B2: N-propylsulfonamide;

[0040] A4: 5-(4-bromophenyl)-4,6-dichloropyrimidine;

[0041] A5: N-(5-(4-bromophenyl)-6-chloro-4-pyrimidinyl)-N'-propylsulfonamide.

[0042] As mentioned above, R is a C1-C4 alkane, preferably a tert-butyl group. M is an element of the first main group in the periodic table, preferably potassium. Such as figure 2 As shown, ROM is potassium tert-butoxide, because potassium tert-butoxide is a commercially available commodity. The molar rat...

Embodiment 1

[0047] Such as figure 2 Shown, a kind of preparation method of macitentan intermediate N-(5-(4-bromophenyl)-6-chloro-4-pyrimidinyl)-N'-propylsulfonamide comprises the following steps:

[0048] Step 1, add 272g (2.00mol) of N-propylsulfonamide B2 to 500g (1.65mol) of 5-(4-bromophenyl)-4,6-dichloropyrimidine A4 and 5000ml of dimethyl sulfide in sulfone;

[0049] Step 2, adding 220 g (2.00 mol) of potassium tert-butoxide to the reaction liquid, stirring and reacting at room temperature for 4 hours;

[0050]Step 3, adding 25000ml of saturated brine and 25000ml of ethyl acetate to the reaction liquid for extraction, and recrystallizing the organic layer with 2000ml of methanol to obtain N-(5-(4-bromophenyl)-6-chloro-4-pyrimidine Base)-N'-propylsulfonamide A5, 473g; based on A4, the molar yield was 71%; the HPLC purity was 99.2%.

Embodiment 2

[0052] A preparation method of macitentan intermediate N-(5-(4-bromophenyl)-6-chloro-4-pyrimidinyl)-N'-propylsulfonamide, comprising the following steps:

[0053] Step 1, add 272g (2.00mol) of N-propylsulfonamide B2 to 500g (1.65mol) of 5-(4-bromophenyl)-4,6-dichloropyrimidine A4 and 5000ml of dimethyl sulfide in sulfone;

[0054] Step 2, adding 168g (2.00mol) of potassium ethoxide to the reaction solution, stirring and reacting at room temperature for 4 hours;

[0055] Step 3, adding 25000ml of saturated brine and 25000ml of ethyl acetate to the reaction liquid for extraction, and recrystallizing the organic layer with 2000ml of methanol to obtain N-(5-(4-bromophenyl)-6-chloro-4-pyrimidine Base)-N'-propylsulfonamide A5, 446g; based on A4, the molar yield was 67%; HPLC purity was 99.5%.

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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 relates to a new preparation method of a macitentan intermediate N-(5-(4-bromophenyl)-6-chloro-4-pyrimidinyl)-N'-propylsulfonamide. Background technique [0002] Macitentan (macitentan) is a small molecule, highly effective tissue-targeted endothelin receptor antagonist with high lipophilicity, and is endothelin-1 (ET-1) and its two receptors (ETA, ETB receptor) has dual inhibitory effects and has tissue targeting. The combination of endothelin and its receptors can promote the contraction of vascular smooth muscle, and can also induce the proliferation and fibrosis of vascular smooth muscle cells through tissue mechanisms, causing vascular inflammation and changing tissue structure. Therefore, endothelin plays an important role in the occurrence and development of many cardiovascular diseases. play an important role in both. Therefore, as an endothelin receptor antagonist, macitentan has important clinical significance. [0003] In th...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/42
CPCC07D239/42
Inventor 叶丁龚义丁诚王晓玲
Owner CHENGDU CLIMB PHARMA TECH
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