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Preparing method for (4-(4-cyclopropyl-naphthalene-1-yl)-5-nitr-4H-(1, 2, 4) triazole-3-ylsulfanyl)-ethyl acetate and intermediate (5-nitr-4H-(1, 2, 4) triazole-3-sulfenyl)-ethyl acetate thereof

An intermediate, cyclopropyl technology, applied in [4-(4-cyclopropylnaphthalen-1-yl)-5-nitro-4H-[1,2,4]triazol-3-ylthio The preparation of alkyl]-ethyl acetate and its intermediate (5-nitro-4H-[1,2,4]triazol-3-ylsulfanyl)-ethyl acetate field can solve the problem of long synthetic route and environmental problems. Large impact, inconvenient operation, etc.

Inactive Publication Date: 2015-10-21
ANHUI WANBANG MEDICAL TECH
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] Foreign patents WO2009070740A2, US2010056464A1, WO2011085009A2 and related patents report the synthesis route of Lesinurad, but most of these methods use thiophosgene, which is not easy for large-scale production
Chinese patent CN102040546A starts from 4-cyclopropyl-1-naphthaldehyde and synthesizes Lesinurad intermediate isocyanate in three steps. This method has a long synthetic route and low overall yield.
The Chinese patent uses 4-cyclopropyl-1-naphthylamine as the starting material to synthesize Lesinurad. This "naphthylamine method" is extremely inconvenient to operate, has a great impact on the environment, and has high labor protection costs.

Method used

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  • Preparing method for (4-(4-cyclopropyl-naphthalene-1-yl)-5-nitr-4H-(1, 2, 4) triazole-3-ylsulfanyl)-ethyl acetate and intermediate (5-nitr-4H-(1, 2, 4) triazole-3-sulfenyl)-ethyl acetate thereof
  • Preparing method for (4-(4-cyclopropyl-naphthalene-1-yl)-5-nitr-4H-(1, 2, 4) triazole-3-ylsulfanyl)-ethyl acetate and intermediate (5-nitr-4H-(1, 2, 4) triazole-3-sulfenyl)-ethyl acetate thereof
  • Preparing method for (4-(4-cyclopropyl-naphthalene-1-yl)-5-nitr-4H-(1, 2, 4) triazole-3-ylsulfanyl)-ethyl acetate and intermediate (5-nitr-4H-(1, 2, 4) triazole-3-sulfenyl)-ethyl acetate thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Example 1: Preparation of (4H-[1,2,4]triazol-3-ylthio)-ethyl acetate

[0027] Weigh (10.5 g; 103 mmol) 4H-[1,2,4]triazole-3-thiol, (15.7 g; 129 mmol) ethyl chloroacetate into a 500 mL three-necked flask, add 250 mL ethyl acetate , (31.5 g; 3 eq) triethylamine, heated up to 50 °C, LC followed the reaction, the raw material was completely converted in about 1.5 h, filtered with suction, and the insoluble matter in the reaction solution was removed, and the mother liquor was concentrated under reduced pressure at 50 °C to obtain light Yellow oily concentrate 18.1 g, yield 95%.

Embodiment 2

[0028] Example 2: Preparation of (5-nitro-4H-[1,2,4]triazol-3-ylthio)-ethyl acetate

[0029] Add (55 mL; 5 vol) acetic anhydride to the above concentrate, cool down to 0°C, and slowly add 40 mL of 20% sodium nitrite solution dropwise for 8 h, then rise to room temperature and stir for two hours after the drop is completed, and the reaction solution is Reduce to 0°C, add 100 mL of purified water dropwise, a yellow solid precipitates, stir at 0°C for 1 h, filter with suction, wash the filtrate with purified water until neutral, and dry under vacuum at 80°C to obtain 16.5 g of a yellow solid, yield 75% .

Embodiment 3

[0030] Example 3: Preparation of [4-(4-cyclopropylnaphthalen-1-yl)-5-nitro-4H-[1,2,4]triazol-3-ylsulfanyl]-ethyl acetate

[0031] Weigh (12.5 g; 54 mmol) of the above yellow solid, (15.9 g; 64.8 mmol) 4-cyclopropyl-1-bromonaphthalene, (3.4 g; 20% mmol) CuI 2 , (22.9 g; 2 eq) K 3 PO 4 , (195 mg, 20% mmol) H 2 O, (1.6 g; 20%mmol) 8-hydroxyquinoline, 100 mL of toluene was added to a 250 mL three-necked flask, nitrogen protection, the temperature was raised to reflux, LC followed the reaction, the raw material was less than 3% for about 16 h, the reaction was processed, and the The reaction solution was lowered to 10 °C, under the protection of nitrogen, 100 mL of purified water, 60 mL of methyl tert-butyl ether, and 125 mL of n-heptane were added to the reaction solution, and the temperature was kept below 10 °C, stirred for two hours, and suction filtered , the filter cake was washed twice with 30 mL of methyl tert-butyl ether, and vacuum-dried at 80 °C to obtain 13.9 g of ...

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Abstract

The invention provides a preparing method for (4-(4-cyclopropyl-naphthalene-1-yl)-5-nitr-4H-(1, 2, 4) triazole-3-ylsulfanyl)-ethyl acetate and an intermediate (5-nitr-4H-(1, 2, 4) triazole-3-ylsulfenyl)-ethyl acetate thereof. The intermediate is used for synthesizing an anti-gout drug Lesinurad, and has the advantages of being economical, environmentally friendly, efficient, high in yield and the like.

Description

technical field [0001] The invention relates to the intermediate [4-(4-cyclopropylnaphthalene-1-yl)-5-nitro-4H-[1,2,4]triazol-3-ylsulfur used in the synthesis of anti-gout drug Lesinurad Alkyl]-ethyl acetate and its preparation method, intermediate (5-nitro-4H-[1,2,4]triazol-3-ylsulfanyl)-acetate ethyl ester and its preparation method. Background technique [0002] Gout is a crystal-associated arthropathy caused by the precipitation of monosodium urate (MSU), which is directly related to hyperuricemia caused by disturbance of purine metabolism and decreased uric acid excretion. It is an oral drug that promotes uric acid excretion and can inhibit the renal proximal tubule uric acid transporter URAT1; Lesinurad (RDEA594) is also a xanthine oxidase inhibitor, which is approved for the treatment of hyperuricemia in gout, and the combined treatment of Lesinurad and Febuxostat Well tolerated and markedly lowers uric acid. [0003] Foreign patents WO2009070740A2, US2010056464A1, ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D249/12
CPCC07D249/12
Inventor 易加明陶春蕾陈国祥邵凤杨欣怡王慧
Owner ANHUI WANBANG MEDICAL TECH
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