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Synthetic method of eltrombopag intermediate

A synthetic method and intermediate technology, applied in the field of drug synthesis, can solve the problems of high environmental pressure, high cost, and many reaction steps, and achieve the effects of less waste disposal, fewer reaction steps, and fewer reaction steps

Active Publication Date: 2019-03-19
WUHAN WUYAO SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0013] Analyzing the published synthesis method of Eltrombopag intermediate BPCA, there are generally disadvantages of many reaction steps, high environmental pressure and high cost

Method used

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  • Synthetic method of eltrombopag intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0055] One of the preparation method of embodiment 1 BPCA:

[0056] Add 10g N-(2-hydroxyphenyl) benzyl carbamate, 9g 3-bromobenzoic acid, 0.73gRhCl(cod) in a 250ml reaction flask 2 , 1.28g triphenoxyphosphine, 40g cesium carbonate and 100ml toluene, reflux reaction under the protection of nitrogen, TLC monitors that the reaction is complete. Add 100ml of water, extract with ethyl acetate, dry and concentrate to obtain the product (13g, yield: 87%, HPLC purity: 97%).

[0057] Add the above product into a hydrogenation kettle, add 2g of 10% palladium carbon (about 63% of water content), and 150ml of methanol, and stir at room temperature by feeding hydrogen gas at 0.1-0.3MPa. After the reaction was complete, filter, concentrate, add 100ml of water to dissolve, adjust the pH to about 5.5 with 1M hydrochloric acid, precipitate a solid, filter with suction, and dry to obtain a reddish-brown solid (9g, yield: 95%, HPLC purity: 99%).

[0058] 1H NMR (600MHz, DMSO-d6): δ6.50(dd, J=1...

Embodiment 2

[0059] One of the preparation methods of embodiment 2 BPCA:

[0060] Add 10 grams of N-(2-hydroxyphenyl) tert-butyl carbamate, 13g 3-iodobenzoic acid, 0.85g RhCl(cod) in a 250ml reaction flask 2 , 1.5g triphenoxyphosphine, 46g cesium carbonate and 100ml toluene, reflux reaction under the protection of nitrogen, TLC monitors that the reaction is complete. Add 100ml of water, extract with ethyl acetate, dry and concentrate to obtain the product (13g, yield: 83%, HPLC purity: 97%).

[0061] The above product was added in 100ml of water, 120ml of 1M hydrochloric acid and 4.4g of thiophenol were added and stirred at room temperature for 5-8 hours. After the reaction was completed, it was filtered, and the solid was washed with 30ml of ethanol to obtain a light yellow solid (9.5g, yield: 90%, HPLC Purity: 99%)

[0062] 1H NMR (600MHz, DMSO-d6,): δ6.52(dd, J=1.8, 7.2Hz, 1H), 6.67~6.73(m, 2H), 7.52(t, J=7.8Hz, 1H), 7.72~ 7.74(m,1H),7.87(dt,J=1.2,7.8Hz,1H),8.09(t,J=1.2Hz,1H),MS m / z:...

Embodiment 3

[0063] One of the preparation methods of embodiment 3 BPCA:

[0064] In the 250ml reaction flask, add 10g 2-nitrophenol, 20g 3-iodobenzoic acid, 1.3g RhCl (cod) 2 , 1.3g tris(dimethylamino)phosphine, 40g potassium carbonate and 100ml xylene were reacted at 120°C under the protection of nitrogen, and the reaction was monitored by TLC to be complete. Add 100ml of water, extract with ethyl acetate, dry and concentrate to obtain the product (12g, yield: 65%, HPLC purity: 98%).

[0065] Add the above product into a hydrogenation kettle, add 2g of 10% palladium carbon (about 63% of water content), and 150ml of ethanol, and feed hydrogen gas at 0.5-1.0MPa / 50°C for reaction. After the reaction was completed, filter, concentrate, add 100ml of water to dissolve, adjust the pH to about 5.5 with 1M hydrochloric acid, precipitate a solid, filter with suction, and dry to obtain a light yellow solid (9g, yield: 95%, HPLC purity: 99%).

[0066] 1H NMR (600MHz, DMSO-d6,): δ6.51(dd, J=1.8, 7....

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Abstract

The application discloses a synthetic method of an eltrombopag intermediate, comprising: subjecting 2-aminophenol derivative shown as formula (II) as a raw material to react with an aromatic reagent shown as formula (III) to obtain an intermediate product shown as formula (IV); using the intermediate product shown as formula (IV) as a raw material to prepare the eltrombopag intermediate shown as formula (I), wherein R1 is selected from amino derivatives, and R2 is selected from halogen and sulfonyloxy group. The synthetic method has few reaction steps; the starting material is simple; the synthetic method is simpler, more economical and greener.

Description

technical field [0001] The application relates to a synthesis method of an Eltrombopag intermediate, which belongs to the field of drug synthesis. Background technique [0002] Chronic idiopathic thrombocytopenic purpura (ITP) is an autoimmune disease caused by an autoimmune reaction that causes thrombocytopenia, characterized by a low platelet count, and its patients are at high risk of bleeding, often resulting in patients with small blood vessels Bleeding, symptoms are bruising, epistaxis and bleeding gums, severe cases may cause fatal gastrointestinal and intracerebral hemorrhage. Preventing platelets from being destroyed has been the mainstay of treatment for ITP patients. [0003] Eltrombopag (1, eltrombopag, trade name Promacta), developed by the British GlaxoSmithKline, was approved by the FDA in November 2008 and listed in the United States. It is an oral thrombopoietic factor drug and is a small molecule thrombopoietin Receptor agonist, it can interact with the h...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C227/20C07C229/52C07C227/04
CPCC07C201/12C07C227/04C07C227/20C07C271/28C07C229/52C07C205/59
Inventor 翁飞杨波郭亚兵朱墨姚晶张静
Owner WUHAN WUYAO SCI & TECH
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