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Macitentan preparation method

一种马西替坦、化合物的技术，应用在药物化学合成领域，能够解决增加溶剂回收和三废处理费用、不能满足原料药质量要求、产物马西替坦纯度低等问题，达到反应时间缩短、简化溶剂回收、后处理简单的效果

Active Publication Date: 2018-04-03
SEASONS BIOTECHNOLOGY (TAIZHOU) CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The inventor repeated the preparation method of the above-mentioned literature and carried out analysis and detection, and found that there are deficiencies: the high temperature reaction time of step (b) is long, the product needs column chromatography purification, and the product purity is low, especially wherein impurity A and impurity The content of B is high (the chemical structural formulas of impurity A and impurity B are as follows), which causes the increase of subsequent reaction by-products; step (c), the reaction temperature is not easy to control, and is not suitable for industrialization; The medium solubility is low, and it is in a suspended state. It needs to be dissolved by adding DMF, a high-boiling polar solvent that is harmful to the environment. The use of mixed solvents increases the cost of solvent recovery and waste treatment; the purity of the product macitentan is low, especially among them The content of impurity C is high (the chemical structural formula of impurity C is as follows), greater than 0.5%, which cannot meet the quality requirements of raw materials

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0074] Example 1 The preparation of formula III compound

[0075] In a 10L flask, add 608g (2mol) of compound of formula IV, 880g (5mol) of potassium salt of compound of formula V and 5L of DMF, under nitrogen protection, heat up to 70°C, keep warm for 4 hours, recover 3.6L of DMF by distillation under reduced pressure, and the residue Add 3L of water, adjust the pH to 6-7 with hydrochloric acid, precipitate a solid, suction filter, dry and dehydrate the solid to obtain a crude product, recrystallize with 2L of acetonitrile to obtain 700g of the compound of formula III, a white solid, the molar yield is 86%, and the HPLC purity is 99.7% .

[0076] 1 H NMR (400MHz, CDCl 3 ): δ8.65(s, 1H), 7.68-7.74(m, 2H), 7.16-7.21(m, 2H), 6.90(s br, 1H), 5.52(s br, 1H), 2.94-3.03(m , 2H), 1.50-1.66 (m, 2H), 0.96 (t, J=7.6Hz, 3H).

Embodiment 2

[0077] Example 2 The preparation of formula II compound

[0078] In a 2000mL flask, add 40.6g (0.1mol) of the compound of formula III prepared in Example 1 and 250mL of ethylene glycol, add 65g of cesium carbonate under stirring, raise the temperature to 130°C under nitrogen protection, and keep the reaction for 5 hours. Cool the reaction solution below 50°C, add 300mL water and 300mL ethyl acetate, adjust the pH to 2-3 with hydrochloric acid, separate the layers, wash the organic phase with 100mL water, separate the layers, concentrate the organic phase to dry the solvent, and wash the residue with 300mL acetic acid Isopropyl ester was recrystallized to obtain 38.8g of compound of formula II, HPLC purity: 99.4%, impurity A content: 0.15%, impurity B content: 0.20%, molar yield: 90%.

[0079] 1 H NMR (400MHz, CDCl 3 ): δ8.48(s, 1H), 7.61-7.67(m, 2H), 7.13-7.22(m, 2H), 5.70(s br, 1H), 4.47-4.51(m, 2H), 3.82-3.86( m, 2H), 2.98 (t, J = 7.0 Hz, 2H), 1.50-1.66 (m, 2H), 0.95 (...

Embodiment 3

[0080] Example 3 The preparation of formula II compound

[0081] In a 2000mL flask, add 40.6g (0.1mol) of the compound of formula III and 500mL of ethylene glycol, add 98g of cesium carbonate under stirring, raise the temperature to 110°C under nitrogen protection, and keep the reaction for 4 hours. Cool the reaction solution below 50°C, add 400mL water and 300mL ethyl acetate, adjust the pH to 2-3 with hydrochloric acid, separate the layers, wash the organic phase with 100mL water, separate the layers, concentrate the organic phase to dry the solvent, and wash the residue with 300mL methanol Recrystallized to obtain 39.6g of compound of formula II, HPLC purity: 99.5%, impurity A content: 0.12%, impurity B content: 0.20%, molar yield: 92%.

[0082] 1 H NMR (400MHz, CDCl 3 ): δ8.48(s, 1H), 7.61-7.67(m, 2H), 7.13-7.22(m, 2H), 5.70(s br, 1H), 4.47-4.51(m, 2H), 3.82-3.86( m, 2H), 2.98 (t, J = 7.0 Hz, 2H), 1.50-1.66 (m, 2H), 0.95 (t, J = 7.0 Hz, 3H).

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Abstract

The invention relates to a Macitentan preparation method. According to the preparation method, the process is simple, convenient and easy to control, reaction selectivity is good, product quality is high, and the method is suitable for industrial production.

Description

technical field [0001] The invention relates to the technical field of medicinal chemical synthesis. Specifically, it relates to a preparation method of macitentan. Background technique [0002] Macitentan (Macitentan) is a dual endothelin receptor antagonist developed by the Swiss Actelion Pharmaceutical Company, which has been approved by the US Food and Drug Administration (FDA) for the treatment of pulmonary hypertension in adults, with the trade name Opsumit . The chemical structural formula of macitentan is shown in formula I below: [0003] [0004] Martin H.Bolli et al., J.Med.Chem., 2012, 55, 7849-7861, disclose a general preparation method of macitentan, comprising the following steps: (a) compound 14 and compound 13 in two React in methyl sulfoxide (DMSO) to obtain compound 15; (b) Dissolve ethylene glycol in ethylene glycol dimethyl ether (DME), add potassium tert-butoxide, raise the temperature to 40°C, stir for 10 minutes and then add compound 15, reacte...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/47
CPCC07D239/47
Inventor 贾强唐方辉马驰杨正伟鲍继宇杨金金
Owner SEASONS BIOTECHNOLOGY (TAIZHOU) CO LTD
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