Method for synthesizing Eltrombopag using microchannel reactor

A microchannel reactor and reaction technology, applied in chemical instruments and methods, chemical/physical/physical chemical reactors, organic chemistry, etc., can solve problems such as easy decomposition, reduce side reactions, increase overall yield and Product quality, effect of inhibiting decomposition

Active Publication Date: 2022-03-11
LIVZON GROUP CHANGZHOU KONY PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Thus, the synthesis of Eltrombopag and its intermediates in the prior art are all synthesized by the traditional still-type diazotization process, but the traditional still-type diazotization process has certain dangers. Slightly higher or under the action of light, especially diazonium salts containing nitro groups are easy to decompose, and some can even decompose at room temperature

Method used

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  • Method for synthesizing Eltrombopag using microchannel reactor
  • Method for synthesizing Eltrombopag using microchannel reactor
  • Method for synthesizing Eltrombopag using microchannel reactor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] ①Put 36.7g of 3,4-dimethylaniline into 90g of concentrated hydrochloric acid and 220g of water, stir and dissolve to obtain material 1.

[0054] ②Put 21.9g of sodium nitrite into 178g of water, stir and dissolve to obtain material 2.

[0055] ③Put 38g of sodium bisulfite and 13g of sodium hydroxide into 200g of water, stir and dissolve to obtain material three.

[0056] ④ Add 100 g of concentrated hydrochloric acid into 50 g of water and stir to obtain material 4.

[0057] ⑤ Control the temperature of the first temperature zone (the first, second, third, fourth and fifth reaction modules) to be 5°C, and the temperature of the second temperature zone (the sixth, seventh, eighth and ninth reaction modules) The temperature is 85°C, and the temperature in the third temperature zone (the tenth reaction module) is 25°C.

[0058] ⑥ The material flow rate of 20g / min is injected into the first reaction module by the pump, and the material two flow rate of 7.9g / min is injected ...

Embodiment 2

[0061] This embodiment and embodiment 1 are different from the diazonium reaction temperature in the first temperature zone described in step ⑤ of this embodiment is 10 ℃, and the 3,4-dimethylphenylhydrazine hydrochloride obtained is 46.2g, and the yield is 88.3%, HPLC purity 99.3%.

Embodiment 3

[0063] This embodiment is different from Example 1 in that the diazonium reaction temperature in the first temperature zone described in step ⑤ of this embodiment is 20 ° C, and 43.7 g of 3,4-dimethylphenylhydrazine hydrochloride is obtained, and the yield is 83.6%, HPLC purity 99.0%.

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Abstract

The invention discloses a method for synthesizing Eltrombopag by using a microchannel reactor. The method includes the following steps: S1, material synthesis: adding the raw material 3,4-dimethylaniline into the acid aqueous solution, and the dissolved material is a Dissolving sodium nitrite in water to obtain material two, dissolving sodium bisulfite and sodium hydroxide in water to obtain material three, the solution made of hydrochloric acid and water is material four, and the raw material 3-amino-2 hydroxyl-[ 1,1-biphenyl]-3 formic acid is added to the acid aqueous solution, and the material five is obtained by dissolving, and the sodium nitrite is dissolved in water to obtain the material six; S2, the material is passed into the microchannel reactor S3, and the first intermediate 3,4 is obtained ‑Dimethylphenylhydrazine hydrochloride, reacted with ethyl acetoacetate to give the second intermediate 2‑(3,4‑dimethylphenyl)‑5‑methyl‑1H‑pyrazole‑3(2H)‑ Ketone; S4, material five and material six are passed into the microchannel reactor to react, and the reaction solution flowing out directly flows into the 2-(3,4-dimethylphenyl)-5-methyl-1H-pyrazole ‑3(2H)‑ketone solution in the reaction flask, to obtain Eltrombopag.

Description

technical field [0001] The invention belongs to the field of drug synthesis in organic synthesis, and in particular relates to a method for synthesizing Eltrombopag by using a microchannel reactor. Background technique [0002] Eltrombopag was developed by GlaxoSmithKline in the UK and was approved by the US FDA in November 2008 for marketing in the US. Eltrombopag is a thrombopoietin receptor agonist indicated for the treatment of thrombocytopenia in patients with chronic immune thrombocytopenic purpura and in patients who do not respond well to corticosteroids, immunoglobulins, or splenectomy. 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 chemical name is 3'-{(2Z)-2-[1-(3,4-xylyl)-3-methyl-5-oxo-1,5-dihydro-4H-pyrazole-4...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D231/46B01J19/00
CPCC07D231/46B01J19/0093
Inventor 张之建陈争一潘亮宋帅娟黄立本
Owner LIVZON GROUP CHANGZHOU KONY PHARMA
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