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Preparation method of eltrombopag

A benzyl compound technology, applied in the field of preparation of Eltrombopag, can solve the problems of no practical industrialization value, high production cost, and many reaction steps

Active Publication Date: 2018-06-01
SUZHOU KELUN PHARMA RES CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] This route has the problems of expensive starting materials and the use of expensive catalyst tetrakis(triphenylphosphine)palladium dichloride in Suzuki coupling reaction, which leads to high production cost of Eltrombopag, difficult storage and no practical industrial value
[0009] In summary, the preparation methods of Eltrombopag and its intermediates in the prior art have disadvantages such as many reaction steps, high pressure on environmental protection, high price of starting materials, expensive catalyst used in Suzuki coupling, high production cost, etc., so the development is more difficult. The synthesis process of Eltrombopag, which is simple and convenient, with easy-to-obtain raw materials and low cost and controllable cost, has very important economic and technical value

Method used

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  • Preparation method of eltrombopag

Examples

Experimental program
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Effect test

Embodiment 1

[0129] Embodiment 1: Preparation of tetrafluoroboric acid-3-formic acid methyl benzene diazo

[0130] 3-Aminobenzoic acid methyl ester hydrochloride (191.0mmol) was dissolved in 120mL of water, then concentrated hydrochloric acid (398.0mmol) was added, cooled and stirred at low temperature to about -8°C, and the temperature was controlled at about -8°C. Sodium nitrate aqueous solution (191.0mmol sodium nitrite, 24mL water), temperature control about -8°C, stirring reaction for about 2h, temperature control about -3°C, slowly add sodium tetrafluoroborate aqueous solution (3.0eq. sodium tetrafluoroborate, 600mL water ), about 20 minutes after the dropwise addition was completed, the temperature was controlled at -3°C and the reaction was stirred for about 30 minutes. Filtered, the filter cake was washed once with 100mL ice water to obtain a white solid, namely 44.0g of methyl tetrafluoroborate-3-carboxylate diazobenzene, collected The rate is 91.7%.

Embodiment 2

[0131] Embodiment 2: the preparation of chloro-3-formic acid methyl benzene diazo

[0132] Dissolve 3-aminobenzoic acid methyl ester hydrochloride (16.0mmol) in 15mL of methanol, add concentrated hydrochloric acid (32.0mmol), cool and stir at low temperature to about -8°C, and slowly add dropwise to the above solution under temperature control of about -8°C Sodium nitrite aqueous solution (16.0mmol sodium nitrite, 2.0mL water), temperature control at about -8°C, stirring reaction for about 2h, filtering to obtain the filtrate, which is methyl chloride-3-carboxylate diazobenzyl alcohol solution, which can be used directly react in the next step.

Embodiment 3

[0133] Embodiment 3: the preparation of hydrosulfate-3-formic acid methyl benzene diazo

[0134] To a solution of methyl 3-aminobenzoate (19.87 mmol) in concentrated sulfuric acid (10 mL) was slowly added dropwise 1.56M nitrosylsulfuric acid at 0-5°C, and the addition was completed in about one hour. After dropping, keep warm at 0-5°C until the reaction of the raw materials is complete, and then the hydrosulfate-3-formic acid methyl diazobenzene solution is obtained, which can be directly used in the next reaction step.

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Abstract

The invention discloses a preparation method of eltrombopag, which includes steps of with a low-cost and easy-to-obtain amine or a salt thereof as a raw material, performing diazotization and couplingto form an intermediate IV; and performing nitration, reduction, coupling and hydrolysis to produce the eltrombopag. The preparation method is simple in operation and good in reaction selectivity, has gentle conditions and low production cost, and is easy to carry out in industrial production.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a preparation method of Eltrombopag. Background technique [0002] Eltrombopag is an oral thrombopoietin drug developed by GlaxoSmithKline, UK. It is a small molecule, non-peptide thrombopoietin (TPO) receptor agonist that stimulates the proliferation and differentiation of megakaryocytes. The drug was approved by the FDA in November 2008 and launched in the United States for the treatment of patients with chronic idiopathic thrombocytopenic purpura (ITP) after glucocorticoids, immunoglobulin therapy or after splenectomy. On November 19, 2012, it was approved for the treatment of thrombocytopenia in patients with chronic hepatitis C. [0003] The chemical name of Eltrombopag is: 3'-{(2Z)-2[1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydro-4H -pyrazol-4-ylidene]hydrazino}-2'-hydroxy-3-biphenylcarboxylic acid, which has the following chemical structure: [0004] [0...

Claims

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Application Information

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IPC IPC(8): C07D231/46
CPCC07D231/46
Inventor 季明华邵栋刘远瑞何成江王琦王利春王晶翼
Owner SUZHOU KELUN PHARMA RES CO LTD
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