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Preparation method of avatrombopag

A technology of atrobolism and cyclization reaction, which is applied in the field of organic synthesis route design and the preparation of raw materials and intermediates, can solve the problems of unavailable raw materials, affecting product quality and yield, and many reaction steps. Large-scale industrial production, the effect of overcoming the poor selectivity of dichloride

Inactive Publication Date: 2020-10-02
SUZHOU MIRACPHARMA TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] Analyzing the disclosed preparation methods of atrombopag and its intermediates, there are still problems such as unavailable raw materials and many reaction steps, especially when the amination reaction is carried out through the difference in activity between dichlorides, side reactions are likely to occur, thereby affecting Its product quality and yield

Method used

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  • Preparation method of avatrombopag
  • Preparation method of avatrombopag

Examples

Experimental program
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Effect test

Embodiment 1

[0029] Under nitrogen protection, add 6-amino-5-chloro-3-pyridinecarboxylic acid (II) (1.72g, 10mmol), condensing agent benzotriazol-1-yloxy tris(dimethylamino ) phosphonium hexafluorophosphate (BOP) (6.63 g, 15 mmol) and acetonitrile 100 mL. Under stirring, the base accelerator 1,8-diazabicyclo[5.4.0]-undec-7-ene (DBU) (2.28g, 15mmol) was added, the temperature was raised to 60-70°C, and the reaction was carried out for 12 hours. 4-(4-Chloro-2-thienyl)-5-(4-cyclohexyl-1-piperazinyl)-2-thiazolamine (III) (4.21 g, 11 mmol) was added, and the stirring reaction was continued for 12 hours. Cool to room temperature, quench the reaction with saturated brine, and adjust the pH to 4-5 with dilute hydrochloric acid. Concentrate under reduced pressure, and add ethyl acetate to extract the residue 3 times. The organic phases were combined, washed successively with pure water and brine, dried, and the solvent was recovered by distillation under reduced pressure. The obtained oily residu...

Embodiment 2

[0031] Add N-[4-(4-chloro-2-thienyl)-5-(4-cyclohexyl-1-piperazinyl)-2-thiazolyl]-6-amino-5-chloro- 3-Pyridinecarboxamide (IV) (2.69g, 5mmol), sodium lauryl sulfate (67mg, 2.5%w / w), sodium bicarbonate 0.92g, 11mmol) and water 500mL, after stirring at room temperature for 30 minutes, add 4-Bromo-2-(2-bromoethyl)butanoic acid (2.06g, 7.5mmol), heated up to 80-85°C, and reacted for 4-6 hours. It was filtered, extracted three times with dichloromethane, washed with saturated brine and water successively, dried and concentrated. The resulting residue was recrystallized from ethyl acetate to obtain 3.05 g of atrombopag (I), with a yield of 94.0%, EI-MS m / z: 650 [M+H] + ; 1H NMR(DMSO-d6)δ12.68(s,1H),12.29(brs,1H),10.50(d,J=1.6Hz,1H),8.83(d,J=1.6Hz,1H),8.40(d ,J=1.6Hz,1H),7.57(s,1H),7.49(s,1H),7.26(s,1H),3.98(m,2H),3.60(m,2H),3.34(m,7H) ,2.50(m,1H),2.17(m,2H),1.93(m,7H),1.66(m,5H).

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Abstract

The invention discloses a preparation method of avatrombopag (avatrombopag), which comprises the following steps: by using 6-amino-5-chloro-3-picolinic acid as an initial raw material, sequentially carrying out amidation and cyclization reactions to obtain the target product avatrombopag. The preparation process has the advantages of easily available raw materials, rapidness, convenience, economyand environmental protection, especially overcomes the problems of poor dichloro selectivity and the like in the existing process raw materials, and is suitable for large-scale industrial production.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis route design and preparation of raw materials and intermediates, and in particular relates to a preparation method of altrombopag, which can be used for treating thrombocytopenia. Background technique [0002] Avatrombopag is a small molecule thrombopoietin receptor agonist developed by Japan's Astellas Pharmaceutical Group and completed by AkaRx Pharmaceuticals, a subsidiary of Dova Pharmaceuticals in the United States. The drug was approved by the U.S. Food and Drug Administration (FDA) for marketing in the United States in May 2018 under the trade name Doptelet. For adults with chronic liver disease who have thrombocytopenia and are undergoing medical or dental surgery. Atrombopag is a second-generation oral thrombopoietin receptor agonist that mimics TPO as a master regulator of normal platelet production. Since the drug has not yet been officially launched in my country and does n...

Claims

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Application Information

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IPC IPC(8): C07D417/14
CPCC07D417/14
Inventor 许学农
Owner SUZHOU MIRACPHARMA TECH
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