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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, fast response and improved preparation speed

Pending Publication Date: 2022-05-17
TIANJIN LISHENG PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] 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

Method used

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  • Preparation method of eltrombopag
  • Preparation method of eltrombopag
  • Preparation method of eltrombopag

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] The preparation method of Eltrombopag:

[0043] 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 yellow-green solid intermediate Ⅰ with a yield of 94.9% and a purity of 96.5%;

[0044] 1 HNMR (400MHz, d 6 DMSO)δ13.90(s,1H),10.66(s,1H),8.12(t,J=1.7Hz,1H),

[0045] 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);

[0046] 2) Weigh 30g of intermediate I, 1.2g of Pd / C, 21.89g of ammonium formate, 33.2g of sodium acetate, and 150ml of water in a 500ml three-neck flask, heat up to 85°C, react for two hours and then cool down to room temperature for suction filtration, and cool the filtrate for 5 °C, adjust the pH to 7-8 ...

Embodiment 2

[0052] The preparation method of Eltrombopag:

[0053] 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 310g of yellow-green solid intermediate Ⅰ, with a yield of 95.8% and a purity of 96.7%;

[0054] 1 HNMR (400MHz, d 6 DMSO)δ13.90(s,1H),10.66(s,1H),8.12(t,J=1.7Hz,1H),8.07

[0055] (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

[0056] (dd,J=8.4,7.5Hz,1H);

[0057] 2) Weigh 300g of intermediate I, 6gPd / C, 265.26g of ammonium formate, 388.56g of sodium acetate, and 1.5L of water in a 5L three-neck flask, heat up to 85°C, react for two hours and then cool down to room temperature for suction filtration, and cool the filtrate for 5 ℃, adjust the pH to 7-8...

Embodiment 3

[0062] The preparation method of Eltrombopag:

[0063] 1) Weigh 3.41g of starting material I, 40ml of glacial acetic acid and 20ml of 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, dry at 55°C for 6 hours, 3.10g of yellow-green solid intermediate Ⅰ, yield: 92.7%, purity: 96.1%;

[0064] 1 HNMR (400MHz, d 6 DMSO)δ13.9(s,1H),10.66(s,1H),8.12(t,J=1.7Hz,1H),

[0065] 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)

[0066] ,7.17(dd,J=8.4,7.5Hz,1H);

[0067] 2) Weigh 3g of intermediate Ⅰ, 0.3g of Pd / C, 1.33g of ammonium formate, 2.18g of sodium acetate and 15ml of water in a 100ml three-neck flask, heat up to 85°C, react for two hours and then cool down to room temperature for suction filtration, and cool down the filtrate by 5°C , adjust the ...

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Abstract

The invention discloses a preparation method of eltrombopag. The preparation method comprises the following steps: 1, sequentially and continuously reacting a starting material I, glacial acetic acid and hydrobromic acid to obtain an intermediate I; 2, reducing the intermediate I through ammonium formate under the catalytic action of palladium to obtain an intermediate II; and 3, carrying out diazotization addition on the intermediate II to obtain eltrombopag. According to the method, on the premise of ensuring the medicine quality, direct reduction of nitryl by hydrogen is avoided, so that safe production amplification can be realized. Meanwhile, on the basis that the single maximum impurity of eltrombopag is controlled not to exceed 0.1% and the total impurity is controlled not to exceed 1.0%, the reaction can be completed more quickly, the time of the preparation process can be further shortened, the preparation speed of eltrombopag is increased, and the market competitiveness of the eltrombopag is enhanced.

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] [0003] 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 ) 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), Eltrombopag is the ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D231/48
CPCC07D231/48
Inventor 王浩姜根华霍志甲张瑜张杰
Owner TIANJIN LISHENG PHARM CO LTD
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