1-(6-bromoquinolin-4-yl)sulfanylcyclobutane-1-carboxylic acid

COMING………….

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MS m/z (ESI): 338.0 [M+l]

1H NMR (400 MHz, DMSO) δ 13.17 (s, 1H), 8.75-8.79 (m, 1H), 8.24 (s, 1H), 7.87-7.98 (m, 2H), 7.21-7.25 (m, 1H), 2.83-2.95 (m, 2H), 2.30-2.41 (m, 2H), 2.16-2.27 (m, 1H), 1.97-2.08 (m, 1H)

WO-2014183555-A1 / 2014-11-20

http://www.google.co.in/patents/WO2014183555A1?cl=en

PROCEDURE

6-溴喹啉 -4-硫醇

将 6-溴 -4-氯喹啉 3a (260 mg， 1.1 mmol , 采用公知的方法 ” Bioorganic &

Medicinal Chemistry Letters, 2012, 22(4), 1569-1574 “制备而得)和硫化钠（100 mg， 1.3 mmol)加入到 4 mL的 N，N-二甲基甲酰胺中，加毕，加热至 80°C，搅拌反应 2小时。 向反应液中加入 50 mL水，滴加 1 M盐酸至反应液 pH为 5~6，用乙酸乙酯萃取 (50 mL X 3) , 合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩，得到标题产物 6-溴喹啉 -4-硫醇 3b (257 mg，黄色油状物)，直接用于下步反应。

第二步

1 -((6-溴喹啉 -4-基)硫)环丁基甲酸乙酯

氩气氛下，将 6-溴喹啉 -4-硫醇 3b (257 mg， 1.1 mmol), 1-溴环丁垸甲酸乙酯 (266 mg， 1.3 mmol)和碳酸铯 (371 mg， 1.1 mmol)依次加入到 5 mL的 N，N-二甲基甲酰胺 中，加热至 60°C，搅拌反应 2小时。反应液过滤，滤饼用乙酸乙酯洗涤 (10 mL X 3)， 滤液减压浓缩，得到标题产物 1-((6-溴喹啉 -4-基)硫)环丁基甲酸乙酯 3c (300 mg， 棕色油状物)，产率： 77%。

MS m/z (ESI): 368.2 [M+l]

1H MR (400 MHz, CDC1₃) δ 8.67 (d, =4.77Hz, IH), 8.31 (d, =2.13Hz, IH), 7.94 (d, =8.91Hz, IH), 7.78 (dd, =9.03, 2.13Hz, IH), 7.15 (d, =4.89Hz, IH), 4.16 (q, =7.15Hz, 2H), 2.86-3.04 (m, 2H), 2.39-2.51 (m, 2H), 2.25-2.37 (m, IH), 2.00-2.15 (m, IH), 1.16 (t, =7.09Hz, 3H)

第三步

1 -((6-溴喹啉 -4-基)硫)环丁基甲酸

将 1-((6-溴喹啉 -4-基)硫)环丁基甲酸乙酯 3c (100 mg， 0.27 mmol)和水合氢氧化 锂 (23 mg， 0.55 mmol)溶解于 6 mL四氢呋喃，乙醇和水( ^=4: 1 : 1)的混合溶剂 中，搅拌反应 3小时。滴加 1M盐酸至反应液 pH为 5~6，分液，水相用二氯甲垸 萃取 (10 mL X 3)，合并有机相，有机相用饱和氯化钠溶液洗涤 (10 mL X I), 无水硫 酸钠干燥，过滤，滤液减压浓缩，用薄层层析以展开剂体系 A纯化所得残余物， 得到标题产物 1-((6-溴喹啉 -4-基)硫)环丁基甲酸 3 (20 mg，白色固体)，产率： 22%。

MS m/z (ESI): 338.0 [M+l]

1H NMR (400 MHz, DMSO) δ 13.17 (s, 1H), 8.75-8.79 (m, 1H), 8.24 (s, 1H), 7.87-7.98 (m, 2H), 7.21-7.25 (m, 1H), 2.83-2.95 (m, 2H), 2.30-2.41 (m, 2H), 2.16-2.27 (m, 1H), 1.97-2.08 (m, 1H)

L – ((6-bromo-quinolin-4-yl) thio) cyclobutyl acid

First step

6-bromo-quinoline-4-thiol

A mixture of 6-bromo-4-chloro-quinoline 3a (260 mg, 1.1 mmol, a known method of “Bioorganic &

Medicinal Chemistry Letters, 2012, 22 (4), 1569-1574 “prepared to give) and sodium sulfide (100 mg, 1.3 mmol) was added to 4 mL of N, N- dimethyl formamide, plus complete, heated 80 ° C, the reaction was stirred for 2 hours. To the reaction mixture was added 50 mL of water, 1 M hydrochloric acid was added dropwise to the reaction solution to pH 5-6, extracted with ethyl acetate (50 mL X 3), the combined organic phases, with no over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give the title product 6-bromo-quinolin-4-thiol 3b (257 mg, yellow oil), it was used directly in the next reaction.

The second step

L – ((6-bromo-quinolin-4-yl) thio) ethyl cyclobutyl

Under an argon atmosphere, 6-bromo-quinolin-4-thiol 3b (257 mg, 1.1 mmol), 1- bromo-cyclobutyloxy embankment carboxylate (266 mg, 1.3 mmol) and cesium carbonate (371 mg, 1.1 mmol) were added to 5 mL of N, N- dimethylformamide and heated to 60 ° C, the reaction was stirred for 2 hours. The reaction mixture was filtered, the filter cake washed with ethyl acetate (10 mL X 3) and the filtrate was concentrated under reduced pressure to give the title product l – ((6-bromo-quinolin-4-yl) thio) ethyl cyclobutyl 3c ( 300 mg, brown oil). Yield: 77%.

MS m / z (ESI): 368.2 [M + l]

1H MR (400 MHz, CDC1 ₃₎ δ 8.67 (d, = 4.77Hz, IH), 8.31 (d, = 2.13Hz, IH), 7.94 (d, = 8.91Hz, IH), 7.78 (dd, = 9.03, 2.13Hz, IH), 7.15 (d, = 4.89Hz, IH), 4.16 (q, = 7.15Hz, 2H), 2.86-3.04 (m, 2H), 2.39-2.51 (m, 2H), 2.25-2.37 ( m, IH), 2.00-2.15 (m, IH), 1.16 (t, = 7.09Hz, 3H) Step

L – ((6-bromo-quinolin-4-yl) thio) cyclobutyl acid

L – ((6-bromo-quinolin-4-yl) thio) ethyl cyclobutyl 3c (100 mg, 0.27 mmol) and lithium hydroxide monohydrate (23 mg, 0.55 mmol) was dissolved in 6 mL of tetrahydrofuran, ethanol and water (^ = 4: 1: 1) mixed solvent, the reaction was stirred for 3 hours. 1M hydrochloric acid was added dropwise to the reaction solution pH of 5 to 6, liquid separation, the aqueous phase was extracted (10 mL X 3) with dichloromethane, the combined organic phases, the organic phase was washed with a saturated sodium chloride solution (10 mL XI), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, to the resulting thin layer chromatography using a developing solvent system A and the residue was purified to give the title product l – ((6-bromo-quinolin-4-yl) thio) cyclobutyl acid 3 (20 mg, white solid), yield: 22%. MS m / z (ESI): 338.0 [M + l]

1H NMR (400 MHz, DMSO) δ 13.17 (s, 1H), 8.75-8.79 (m, 1H), 8.24 (s, 1H), 7.87-7.98 (m, 2H), 7.21-7.25 (m, 1H), 2.83-2.95 (m, 2H), 2.30-2.41 (m, 2H), 2.16-2.27 (m, 1H), 1.97-2.08 (m, 1H)

Discovery of potent and orally bioavailable inhibitors of Human Uric Acid Transporter 1 (hURAT1) and binding mode prediction using homology model

• Jianbiao Peng^, ,

• Shanghai Hengrui Pharmaceutical Co. Ltd, 279 Wenjing Rd., Shanghai 200245, China

This Letter describes the discovery of a series of potent inhibitors of Human Uric Acid Transporter 1 (hURAT1). Lead generation and optimization via 3D pharmacophore analysis resulted in compound 41. With an IC₅₀ of 33.7 nM, 41 also demonstrated good oral bioavailability in rat (74.8%) and displayed a consistent PK profile across all species tested (rat, dog and monkey).

http://www.sciencedirect.com/science/article/pii/S0960894X1530353X

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////////Shanghai Hengrui, inhibitors of Human Uric Acid Transporter 1 (hURAT1), 1-(6-bromoquinolin-4-yl)sulfanylcyclobutane-1-carboxylic acid

c13cc(ccc3nccc1SC2(C(=O)O)CCC2)Br

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