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Preparation method of eltrombopag

A technology of intermediates and raw materials, which is applied in the field of Eltrombopag preparation, can solve the problems of long preparation process and difficult industrialization, and achieve the effects of strong operability, rapid response and high purity

Inactive Publication Date: 2019-12-03
TIANJIN LISHENG PHARM CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Aiming at the deficiencies of the prior art, the present invention provides a preparation method of Eltrombopag, which has the advantages of high-efficiency preparation process and safer, etc., and solves the problems that the reaction process is difficult to industrialize and the preparation process is long

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  • Preparation method of eltrombopag
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  • Preparation method of eltrombopag

Examples

Experimental program
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Effect test

Embodiment 1

[0039] The preparation method of Eltrombopag:

[0040] 1) Weigh 34.10g of starting material I, 400ml of glacial acetic acid and 200ml of hydrobromic acid (48%) into a 1L three-neck flask, start stirring, raise the temperature to 120°C, react for 3 hours, and stop the reaction. Cool down to 25°C, filter with suction, beat the filter cake with about 400ml of water, and dry at 55°C for 6 hours to obtain 30.7g of intermediate I as a yellow-green solid with a yield of 94.9% and a purity of 96.5%. 1 HNMR (400MHz, d 6 DMSO)δ13.90(s,1H),10.66(s,1H),8.12(t,J=1.7Hz,1H),

[0041] 8.07(dd, J=8.4,1.7Hz,1H),7.98(dt,7.8,1.5Hz,1H),7.74(dd,J=7.5,1.7Hz,1H),7.17(dd,J=8.4,7.5Hz ,1H).

[0042] 2) Weigh 30g of intermediate Ⅰ, 1.2g of Pd / C, and 150ml of water into a 500ml three-neck bottle, and add 150ml of hydrazine hydrate (98%) dropwise to the system. During this period, heat and gas are released violently, and the temperature is controlled at 25°C. After the dropwise addition, the temperatur...

Embodiment 2

[0046] The preparation method of Eltrombopag:

[0047] 1) Weigh 341g of starting material I, 4L of glacial acetic acid and 2L of hydrobromic acid (48%) into a 1L three-necked flask, start stirring, raise the temperature to 120°C, and stop the reaction after 3 hours of reaction. Cool down to 25°C, filter with suction, beat the filter cake with about 4L of water, and dry at 55°C for 6 hours to obtain 310 g of yellow-green solid intermediate Ⅰ, with a yield of 95.8% and a purity of 96.7%.

[0048] 1 HNMR (400MHz, d 6 DMSO)δ13.90(s,1H),10.66(s,1H),8.12(t,J=1.7Hz,1H),8.07

[0049] (dd, J=8.4,1.7Hz,1H),7.98(dt,7.8,1.5Hz,1H),7.74(d d,J=7.5,1.7Hz,1H),7.17

[0050] (dd, J=8.4, 7.5Hz, 1H).

[0051] 2) Weigh 300g of intermediate Ⅰ, 6gPd / C, and 1.5L of water into a 5L three-neck bottle, and add 1.5L of hydrazine hydrate (98%) dropwise to the system. During this period, heat and gas are released violently, and the temperature is controlled at 25°C. After the dropwise addition, the tem...

Embodiment 3

[0055] The preparation method of Eltrombopag:

[0056] 1) Weigh 3.41g of starting material I, 40ml of glacial acetic acid and 20ml of 48% hydrobromic acid (48%) into a 100ml three-neck flask, start stirring, raise the temperature to 120°C, and stop the reaction after 3 hours of reaction. Cool down to 25°C, filter with suction, beat the filter cake with about 40ml of water and filter with suction, and dry at 55°C for 6 hours to produce 3.10g of yellow-green solid intermediate Ⅰ, yield: 92.7%, purity: 96.1%. 1 HNMR (400MHz, d 6 DMSO)δ13.9(s,1H),10.66(s,1H),8.12(t,J=1.7Hz,1H),

[0057] 8.07(dd,J=8.4,1.7Hz,1H), 7.98(dt,7.8,1.5Hz,1H),7.74(dd,J=7.5,1.7Hz,1H)

[0058] ,7.17(dd,J=8.4,7.5Hz,1H).

[0059] 2) Weigh 3g of intermediate I, 0.15g of Pd / C, and 15ml of water into a 100ml three-necked flask, and add 15ml of 98% hydrazine hydrate dropwise to the system. During this period, heat and gas are released violently, and the temperature is controlled at 25°C. After the dropwise addi...

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Abstract

The invention relates to the technical field of medicine manufacturing, and discloses a preparation method of eltrombopag. The preparation method comprises the following steps: 1, sequentially carrying out a continuous reaction on a starting material I, glacial acetic acid and hydrobromic acid until the reaction is completed to obtain an intermediate I; 2, reducing the intermediate I by hydrazinehydrate under catalytic action of palladium to obtain an intermediate II; and 3, carrying out diazotization addition on the intermediate II to obtain the eltrombopag. According to the method, nitryl is prevented from being directly reduced by hydrogen on the premise that the medicine quality is guaranteed, so that production can be safely amplified, and market competitiveness of the variety is improved.

Description

technical field [0001] The invention relates to the technical field of pharmaceutical manufacturing, in particular to a preparation method of Eltrombopag. Background technique [0002] Eltrombopag (chemical name 3'-[(2Z)-[1-(3,4-dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4H- Pyridin-4-ylidene]hydrazino-2'-carboxy-[1,1'-biphenyl]-3-carboxylic acid, molecular formula C 25 h 22 N 4 o 4 ): [0003] [0004] It is an oral thrombopoietin drug developed by GlaxoSmithKline, a small molecule thrombopoietin receptor agonist, which can interact with the thrombopoietin receptor in the transmembrane region of the human body to generate a signal cascade amplification effect , so as to induce the proliferation and differentiation of bone marrow megakaryocytes, the drug was approved by the US Food and Drug Administration (FDA) in November 2008 for marketing in the United States. Thrombocytopenia in patients with postoperative chronic idiopathic thrombocytopenic purpura (ITP), Eltro...

Claims

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Application Information

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IPC IPC(8): C07D231/46
CPCC07D231/46
Inventor 王浩姜根华霍志甲张杰
Owner TIANJIN LISHENG PHARM CO LTD
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