Preparation method of lesinurad

A technology of lexanfoetol and cyclopropylnaphthalene, which is applied in the field of preparation of new anti-gout drug lexoxetine, can solve the problem of high cost and achieve the effects of less impurities, high yield and simplified process flow

Inactive Publication Date: 2017-05-10
湖南欧亚药业有限公司
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AI Technical Summary

Problems solved by technology

[0021] Although this route avoids the use of thiophosgene, it uses 3-mercapto-1,2,4-triazole as the starting material, which is costly. The third step involves Grignard reaction, and the scale-up production is potentially dangerous

Method used

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  • Preparation method of lesinurad

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] A) Preparation of 4-acetyl-1-(4-cyclopropylnaphthalene-1-yl) thiosemicarbazide:

[0045] 1-cyclopropylnaphthalen-4-yl isothiocyanate (5.0g, 22mmol) was dissolved in N,N-dimethylformamide (25mL), and acetylhydrazide (2.1g, 29mmol), potassium carbonate (5.2 g, 38mmol), the reaction mixture was stirred and reacted at 30°C for 8 hours, TLC was spotted to confirm that the reaction was complete, the reaction solution was cooled to room temperature, water (10mL) was added, cooled to -10°C for crystallization for 3 hours, filtered to obtain 4-acetyl -1-(4-cyclopropylnaphthalene-1-yl)thiosemicarbazide, white solid (6.1g), yield 92.3%, the reaction formula of this step is as follows:

[0046]

[0047] B) Preparation of 4-(4-cyclopropylnaphthalen-1-yl)-5-methyl-4H-1,2,4-triazole-3-thiol:

[0048] 4-acetyl-1-(4-cyclopropylnaphthalen-1-yl)thiosemicarbazide (6.0g, 20mmol) was dissolved in dichloromethane (23mL), sodium hydride (1.1g, 27mmol, 60%) was added, The reaction mixture ...

Embodiment 2

[0060] A) Preparation of 4-acetyl-1-(4-cyclopropylnaphthalene-1-yl) thiosemicarbazide:

[0061] 1-cyclopropylnaphthalene-4-yl isothiocyanate (6.0g, 27mmol) was dissolved in ethanol (30mL), acetylhydrazide (2.2g, 29mmol), sodium carbonate (3.9g, 37mmol) were added, and the reaction mixture 20 ℃ and stirred for 12 hours, TLC spotting confirmed the completion of the reaction, the reaction solution was cooled to room temperature, added water (15mL), cooled to -10 ℃ for 3 hours, filtered to obtain 4-acetyl-1-(4-cyclopropane Naphthalene-1-yl) thiosemicarbazide, white solid (7.2g), yield 90.5%, the reaction formula of this step is the same as that of Example 1;

[0062] B) Preparation of 4-(4-cyclopropylnaphthalen-1-yl)-5-methyl-4H-1,2,4-triazole-3-thiol:

[0063] 4-Acetyl-1-(4-cyclopropylnaphthalen-1-yl)thiosemicarbazide (7.0g, 23mmol) was dissolved in chloroform (25mL), potassium hydride (1.0g, 26mmol) was added, and the reaction mixture was stirred at 35°C After reacting for 11 ...

Embodiment 3

[0071] A) Preparation of 4-acetyl-1-(4-cyclopropylnaphthalene-1-yl) thiosemicarbazide:

[0072] 1-cyclopropylnaphthalen-4-yl isothiocyanate (8.0g, 36mmol) was dissolved in toluene (45mL), acetylhydrazide (4.0g, 53mmol), cesium carbonate (20.8g, 64mmol) were added, and the reaction mixture was 45 Stir the reaction at ℃ for 6 hours, TLC spotting plate confirms that the reaction is complete, the reaction solution is cooled to room temperature, water (20mL) is added, cooled to -10℃ and crystallized for 3 hours, filtered to obtain 4-acetyl-1-(4-cyclopropane Naphthalene-1-yl) thiosemicarbazide, white solid (9.4g), yield 88.0%, the reaction formula of this step is the same as Example 1;

[0073] B) Preparation of 4-(4-cyclopropylnaphthalen-1-yl)-5-methyl-4H-1,2,4-triazole-3-thiol:

[0074]4-Acetyl-1-(4-cyclopropylnaphthalen-1-yl)thiosemicarbazide (9.2g, 31mmol) was dissolved in methyl tert-butyl ether (35mL), potassium tert-butoxide (5.2g, 46mmol) was added ), the reaction mixture ...

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Abstract

The invention discloses a preparation method of lesinurad. The method comprises: allowing 1-cyclopropylnaphthalene-4-yl isorhodanate and acethydrazide to undergo an addition reaction, allowing the obtained 4-acetyl-1-(4-cyclopropylnaphthalene-1-yl) thiosemicarbazide to undergo a cyclization reaction in the function of an alkali reagent, allowing the obtained 4-(4-cyclopropylnaphthalene-1-yl)-5-methyl-4H-1,2,3-triazole-3-mercaptan and methyl chloroacetate (or methyl bromoacetate) to undergo a condensation reaction, allowing the obtained 2-{[4-(4-cyclopropylnaphthalene-1-yl)-5-methyl-4H-1,2,4-triazole-3-yl]sulfo} methyl acetate to undergo an oxidation reaction, allowing the obtained 5-[(methoxycarbonyl)methylthio]-4-(4-cyclopropylnaphthalene-1-yl)-4H-1,2,4-triazole-3-carboxylic acid undergo a bromination reaction, and carrying out an esterolysis reaction to obtain lesinurad. The method is reasonable and simple in technical route, simplified in operation and low in cost. The method is green and eco-friendly and suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of chemical synthesis of medicines, and in particular relates to a preparation method of a new anti-gout drug lesenolide. Background technique [0002] Lesinurad (RDEA594) is a new type of gout drug developed by Ardea Biosciences, with a chemical name of 2-{[4-(4-cyclopropylnaphthalen-1-yl)-5-bromo-4H -1,2,4-triazol-3-yl]thio}acetic acid, its chemical structural formula is: [0003] [0004] Lesnolide reduces uric acid levels by inhibiting urate transport protein l (uric acid salt transport protein l, URAT1), and promoting uric acid excretion. Reducing the level of uric acid in plasma, combined with xanthine oxidase inhibitors (allopurinol and febuxostat), can improve the response rate of gout patients who do not respond well to the above drugs, and can effectively accelerate the rate of uric acid in gout patients. Elimination, and has higher security. The development prospect of the drug is good, and ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D249/12
CPCC07D249/12
Inventor 陈健刘叶张建国钟云建黄伟林开朝李兴民莫国宁
Owner 湖南欧亚药业有限公司
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