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Preparation method of eltrombopag intermediate 2-hydroxy-3-(m-carboxyl phenyl)aniline

A carboxyphenyl and hydroxyl technology, which is applied in the field of preparation of Eltrombopag intermediate 2-hydroxy-3-aniline, can solve the problems of many side reactions, large equipment damage, and many waste acids

Active Publication Date: 2019-05-03
SHANGHAI TIANCI INT PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method has the following disadvantages: 1. There are many waste acids, and the pressure on environmental protection is high; 2. There are many side reactions, and the product purification is difficult; 3. The post-processing is cumbersome and the equipment is damaged.
The existence of these problems is unfavorable for suitability for suitability for industrialized production, therefore, need to develop a kind of condition mild and easy to control, safety and environmental protection, productive rate height, the 2-hydroxyl-3-(m-carboxyphenyl) aniline preparation method that is suitable for industrial production

Method used

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  • Preparation method of eltrombopag intermediate 2-hydroxy-3-(m-carboxyl phenyl)aniline

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preparation example Construction

[0082] Provide a kind of preparation method of formula I compound 2-hydroxyl-3-(m-carboxyphenyl) aniline, described method comprises steps:

[0083] (1) Amino substitution reaction occurs between the compound of formula II and the compound of formula III, and the amino group is protected to obtain the compound of formula IV;

[0084]

[0085] (2) the compound of formula IV is subjected to bromination reaction to obtain the compound of formula V;

[0086]

[0087] (3) The benzylation reaction occurs between the compound of formula V and the compound of formula VI to obtain the compound of formula VII;

[0088]

[0089] (4) Suzuki coupling reaction occurs between the compound of formula VII and the compound of formula VIII to obtain the compound of formula IX;

[0090]

[0091] (5) hydrolyzing and deprotecting the compound of formula IX to obtain the compound of formula X; and

[0092]

[0093] (6) the compound of formula X removes benzyl and chlorine, obtains t...

Embodiment 1

[0113] Preparation of 1,3-bis-(5-chloro-2-hydroxyphenyl)-urea (IV)

[0114] Add 143.5g (1.0mol) 2-amino-4-chlorophenol (II), 1.4L chlorobenzene, 36g (0.60mol) urea (III) to a 3L reaction flask, heat up to 120-130°C with mechanical stirring, and react for 2h. Slowly cool down to 20-30°C, filter, wash the filter cake once with petroleum ether, and dry at 50°C to constant weight to obtain 148.7g (0.474mol) of compound 1,3-bis-(5-chloro-2-hydroxy Phenyl)-urea, yield 95%. C13H10Cl2N2O3, ESI-MS (m / z):

[0115] 313.03 [M+H], 312.01.

Embodiment 2

[0117] Preparation of 1,3-bis-(5-chloro-3-bromo-2-hydroxyphenyl)-urea (V)

[0118] Add 125.3g (0.40mol) 1,3-bis-(5-chloro-2-hydroxyphenyl)-urea (IV), 600ml acetic acid, 250ml tetrahydrofuran to a 1L reaction flask, stir mechanically to dissolve, and control the temperature for 20- 153.6g (0.96mol) of liquid bromine was added dropwise at 30°C, reacted for 3 hours, recovered tetrahydrofuran and acetic acid by distillation, added 500ml of water, stirred, filtered, and dried to obtain compound 1,3-bis-(5-chloro-3- Bromo-2-hydroxyphenyl)-urea 169.5g (0.36mol), yield 90%. C13H8Br2Cl2N2O3, ESI-MS (m / z): 469.76 [M+H], 467.83.

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Abstract

The invention provides a preparation method of eltrombopag intermediate 2-hydroxy-3-(m-carboxyl phenyl)aniline. According to the preparation method, 2-amino-4-chlorophenol is taken as a raw material,urea is adopted for protection, bromination, benzylation, Suzuki coupling reaction, hydrolysis deprotection of urea protection, hydrogenation dechlorinating and debenzylation are carried out so as toobtain 2-hydroxy-3-(m-carboxyl phenyl)aniline. Compared with the prior art, the advantages are that: operation is simple; conditions are mild and easily controllable; the preparation method is safe, and is friendly to the environment; yield is high; and the preparation method is suitable for industrialized large scale production.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a preparation method of Eltrombopag intermediate 2-hydroxyl-3-(m-carboxyphenyl)aniline. Background technique [0002] Formula (I) compound 2-hydroxyl-3-(m-carboxyphenyl) aniline [0003] [0004] It is the key intermediate for the synthesis of Eltrombopag. US FDA approves GlaxoSmithKline's Eltrombopag tablets (Promacta) for the treatment of chronic idiopathic thrombocytopenic purpura (ITP) after glucocorticoids, immunoglobulin therapy or splenectomy Thrombocytopenia in patients. [0005] Eltrombopag is the first oral non-peptide thrombopoietin receptor agonist approved for the treatment of adults with chronic ITP. Preclinical and clinical studies have shown that stimulating this product can increase the proliferation and differentiation of bone marrow megakaryocytes in platelets. Its approval for the treatment of ITP patients is an important milestone. [000...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C227/16C07C229/52
Inventor 李勇刚王卓黄晓笠殷保胜沙飞
Owner SHANGHAI TIANCI INT PHARMA
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