New preparation method of anti-gout medicine Lesinurad and its key intermediate

A technology of intermediate and general formula, applied in the field of pharmaceutical synthesis, can solve the problems of high production cost, complicated operation, expensive raw materials or reagents, etc., and achieve the effects of simple operation and high total yield

Active Publication Date: 2018-12-07
SHANGHAI AOBO PHARMTECH INC LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the method has long reaction steps, and highly toxic carbon disulfide is used in the route. The process needs column purification in the bromination step, and the operation is complicated, so it is not suitable for industrial production.
[0016] A comprehensive analysis of the existing Lesinurad preparation methods shows that most of the bromine on the Lesinurad structure is converted from an amino group. This step is complicated to operate and the raw materials or reagents used are expensive, and the production cost is high.
In addition, most of the existing preparation methods use highly toxic thiophosgene or carbon disulfide, resulting in many unfavorable factors in the safety of reaction operation, economy and large-scale production of these routes.

Method used

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  • New preparation method of anti-gout medicine Lesinurad and its key intermediate
  • New preparation method of anti-gout medicine Lesinurad and its key intermediate
  • New preparation method of anti-gout medicine Lesinurad and its key intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] Example 1: Preparation of 4-(4-cyclopropylnaphthalene)-1,2,4-triazole

[0049]

[0050] In the three-necked flask, add 4-cyclopropyl-1-naphthylamine (compound 1, 110.00mmol), diformyl hydrazide (330.00mmol) and pyridine (10V), and slowly add trimethylchlorosilane dropwise at room temperature (550mmol), the reaction was then heated to reflux for 2 hours. After LC confirms that the reaction is complete, remove the insoluble solid salt by filtration, concentrate the filtrate to dryness, add ethyl acetate to dissolve the obtained residue, wash the organic phase twice with water, dry the organic phase, concentrate under reduced pressure to about 30ml, and add methyl alcohol to the concentrated solution. 90ml of tert-butyl ether, the resulting suspension was beaten and stirred for 1 hour, and filtered with suction to obtain compound 2 (purity: 98%), yield (70%).

[0051] 1 H NMR (400MHz, CDCl 3)δ8.56(d, J=8.4Hz, 1H), 8.41(s, 2H), 7.70-7.66(m, 1H), 7.60-7.56(m, 1H), 7.44...

Embodiment 2

[0052] Example 2: Preparation of 4-(4-cyclopropylnaphthalene)-3,5-dibromo-1,2,4-triazole

[0053]

[0054] In the three-necked flask, add 4-(4-cyclopropylnaphthalene)-1,2,4-triazole (compound 2, 48.91 mmol), tetrahydrofuran (6V), and add N-bromo Succinimide (122.28 mmol). The reaction was then stirred at 40°C for 2 hours. After LC confirms that the reaction is over. The reaction solution was diluted with ethyl acetate, and the organic phase was washed twice with 30% sodium thiosulfate and saturated sodium bicarbonate solution, dried and concentrated. Add 40ml of methyl tert-butyl ether to the residue, stir and beat the suspension for 1 hour, filter with suction, wash the filter cake twice with 10ml of methyl tert-butyl ether to obtain compound 3 (purity: 99%), yield (85% )

[0055] 1 H NMR (400MHz, CDCl 3 )δ8.58(d,J=8.4Hz,1H),7.71-7.67(m,1H),7.62-7.58(m,1H),7.41(d,7.6Hz,1H),7.35(d,7.6Hz, 1H), 7.18(d, J=8.4Hz, 1H), 2.47-2.44(m, 1H), 1.21-1.18(m, 2H), 0.92-0.88(m, 2H);...

Embodiment 3A

[0056] Example 3A: Preparation of 4-(4-cyclopropylnaphthalene)-3-methyl thioacetate-5-bromo-1,2,4-triazole

[0057]

[0058] In the three-necked flask, add 4-(4-cyclopropylnaphthalene)-3,5-dibromo-1,2,4-triazole (compound 3, 10.18mmol), N,N-dimethylformamide (10V), at room temperature, potassium carbonate (15.26mmol) and methyl thioglycolate (15.26mmol) were added successively. The reaction was stirred at room temperature for 1 hour, and the reaction of the raw materials was detected by LC. Add ethyl acetate to dilute the reaction solution, wash the organic phase once with 0.5N hydrochloric acid solution, then wash three times with water, dry and concentrate to obtain the crude product of 4, and separate through a silica gel column to obtain compound 4 (purity: 90%), the yield ( 50%)

[0059] 1 H NMR (400MHz, CDCl 3 )δ8.55(d, J=8.4Hz, 1H), 7.68-7.64(m, 1H), 7.60-7.56(m, 1H), 7.36(s, 2H), 7.26(d, J=8.4Hz, 1H ),4.09(d,J=16.4Hz,1H),4.03(d,J=16.4Hz,1H),3.72(s,3H),2.45-2.41...

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Abstract

The invention provides a new preparation method of an anti-gout medicine Lesinurad and its key intermediate. By using the process provided by the invention, a compound IV can be directly converted into a product III without separation, the reaction yield is greatly increased, and the operation step can be simplified. In addition, the synthesis of the novel intermediate provided by the invention does not require the high-toxicity thiophosgene and carbon disulfide, which greatly improves the safety and environmental protection of the process. The novel synthesis preparation process of Lesinuradis highly efficient, economical, safe, environmentally friendly and suitable for industrial production. In the specification, wherein R is cyclopropane, halogen, trifluoro mesylate, mesylate, and p-toluenesulfonate, and preferably R is cyclopropane; R3 represents COCH3, or R3 represents benzyl or CH2R4, wherein R4 represents an ester group, CN, CH2OH or a phenyl group substituted with one or moreselected from C1-C6 alkyl group and halogen; and X is a halogen.

Description

technical field [0001] The invention belongs to the technical field of medicine synthesis and provides a novel preparation method of Lesinurad and its key intermediate. Background technique [0002] Gout is a crystal-associated arthropathy caused by deposition of monosodium urate (MSU), which is directly related to hyperuricemia caused by disturbance of purine metabolism and / or decreased uric acid excretion. There are more than 20 million gout patients worldwide. Lesinurad is an orally available inhibitor of SLC22A12, also known as urate transporter 1 (URAT1) and organic anion transporter 4 (OAT4). In December 2015, the European Medicines Agency (EMA) approved AstraZeneca's drug Lesinurad in combination with another xanthine oxidase inhibitor that reduces uric acid production in the body as a treatment for hyperuricemia associated with gout. [0003] The following literature reports the synthetic route of this compound: [0004] (1) The synthetic route reported in patent ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D249/12C07D249/08
CPCC07D249/08C07D249/12Y02P20/55
Inventor 李青夏丰敏黄超郭效文陶安平黄鲁宁安建国陈茜顾虹
Owner SHANGHAI AOBO PHARMTECH INC LTD
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