Name: 878672-00-5|2-((5-Bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-yl)thio)acetic acid|98%
Brand: Ambeed
SKU: A440574
Price: 5.0 USD
Availability: InStock
Rating: 90 (25 reviews)

1
[ 878671-99-9 ]
[ 878672-00-5 ]

Yield	Reaction Conditions	Operation in experiment
93%	Stage #1: 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid methyl ester With lithium hydroxide; water In tetrahydrofuran; ethanol at 0℃; for 0.833333h; Stage #2: With hydrogenchloride In tetrahydrofuran; ethanol; water	15 [00361 ] A solution of lithium hydroxide (98mg, 4. Immol) in water (1OmL) was added dropwise over 5 mins to a solution of methyl 2-(5-bromo-4-(l-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazol-3- ylthio)acetate (prepared as described in example 1 above; 1.14g, 2.7mmol) in ethanol (1OmL) and THF (1OmL) at O°C. The mixture was stirred at O°C for a further 45 mins and then neutralized to pll 7 by the addition of 0.5N HCl solution at O°C. The resulting mixture was concentrated in vacuo to 1/5 th of its original volume, then diluted with water (~20mL) and acidified to pll 2-3 by the addition of 0.5N HCl to produce a sticky solid. (If the product comes out as an oil during acidification, extraction with DCM is recommended.) The tan solid was collected by vacuum filtration and dried under high vacuum at 50°C for 16 h hi the presence OfP2O5 to yield 2-(5- bromo-4-(l-cyclopropyinaphthalen-4-yl)-4H-1.2,4-triazol-3-ylthio)acetic acid (1.02g, 93%).
93%	Stage #1: 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid methyl ester With lithium hydroxide; ethanol; water In tetrahydrofuran at 0℃; for 0.833333h; Stage #2: With hydrogenchloride In tetrahydrofuran; water at 0℃;	To a solution of 2-[5-bromo-4-(4-cyclopropymaphthalen-l-yl)-4H-[l,2,4]triazol- 3 -ylsulfanyl] acetic acid methyl ester, in a mixture of THF and EtOH at O0C, was added a solution of LiOH in H2O dropwise over 5 min. The reaction was complete after stirring at O0C for an additional 45 min. The reaction was neutralized to pH 7 by the addition of 0.5 N HCl solution at O0C, and the resulting mixture was concentrated in vacuo to l/5th of its original volume. The mixture was diluted with H2O (~20 mL) and acidified to pH 2-3 by the addition of 0.5 N HCl to produce sticky solid. (If the product comes out as an oil during acidification, extraction with CH2Cl2 is recommended.) The tan solid was collected by vacuum filtration and dried under high vacuum at 5O0C for 16 h in the presence Of P2O5 to yield 1.02 g (93%) of the title compound.
93%	Stage #1: 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid methyl ester With water; lithium hydroxide In tetrahydrofuran; ethanol at 0℃; for 0.833333h; Stage #2: With hydrogenchloride In tetrahydrofuran; ethanol at 0℃;	2.2.H STEP H: 2-(5-Bromo-4-(l-cyclopropylnaphthalen-4-yl)-4H-l,2,4-triazol-3- )acetic acidA solution of lithium hydroxide (98 mg, 4.1 mmol) in water (10 mL) was added dropwise over 5 min to a solution of methyl 2-(5-bromo-4-(l-cyclopropylnaphthalen-4-yl)-4H-l,2,4- triazol-3-ylthio)acetate (1.14 g, 2.7 mmol) in ethanol (10 mL) and THF (10 mL) at 0 °C. The mixture was stirred at 0 °C for a further 45 min and then neutralized to pH 7 by the addition of 0.5N HC1 solution at 0 °C. The resulting mixture was concentrated in vacuo to l/5th of its original volume, then diluted with water (~20 mL) and acidified to pH 2-3 by the addition of 0.5N HC1 to produce a sticky solid. (If the product comes out as an oil during acidification, extraction with dichloromethane is recommended.) The tan solid wascollected by vacuum filtration and dried under high vacuum at 50 °C for 16 h in thepresence of P2O5 to yield 2-(5-bromo-4-(l-cyclopropylnaphthalen-4-yl)-4H-l,2,4-triazol-3- ylthio)acetic acid (1.02 g, 93%).

92%	With lithium hydroxide In tetrahydrofuran; ethanol at 0 - 20℃; for 0.75h;
90%	With methanol; sodium hydroxide at 16℃; for 0.333333h;	13 Example 13. Preparation of 2-(5-bromo-4-(4-cyclopropylnaphthalen-l-yl)-4H-l,2,4-triazol-3-ylthio)acetate Example 13. Preparation of 2-(5-bromo-4-(4-cyclopropylnaphthalen-l-yl)-4H-l,2,4-triazol-3-ylthio)acetate [078] Methyl 2-((5-bromo-4-(4-cyclopropylnaphthalen-l-yl)-4H-l,2,4-triazol-3-yl)thio)acetate (7.0 g), methanol (28 mL) and 1 mole sodium hydroxide solution (20 mL) were placed in a flask, the mixture was stirred at room temperature (16°C) for 20 min, then was added water (50 mL), and 0.5 mol/L of dilute hydrochloric acid was added to the reaction mixture till pH value was 2.5, after the addiction was complete, the mixture was extracted with CH2CI2, the organic phase was combined and CH2CI2 was removed under reduce pressure to obtain yellow solid 2-(5-bromo-4-(4-cyclopropylnaphthalen-l-yl)-4H-l,2,4-triazol-3-ylthio)acetate 6.0 g, yield 90%, LC-Ms: m/z (ESI): 404,406(M+H)+, 1H MR (400 MHz,CDCl3): δ 8.58 (d, J=8.0 Hz, 1 H), 7.71 (m, 1 H), 7.62 (m, 1 H), 7.40 (s, 2 H), 7.24 (d, J=8.4 Hz, 1 H), 4.00 (dd, J=16.0, 25.6 Hz, 2 H), 2.46 (m, 1 H), 1.21 (m, 2 H), 0.9 l(m, 2 H).
90%	With water; lithium oxide In tetrahydrofuran for 0.75h; Cooling with ice;	1.6 6) The compound 2 - ((5-bromo-4- (4-cyclopropyl-naphthalen-1-yl) -4H-1,2,4- triazol-3-yl) thio) acetic acid(Lesinuard, I) Synthesis The intermediate compound VIII (2.7mmol, 1.14g) was dissolved in 10mL of tetrahydrofuran, the ice bath was continued stirring dropwise under stirring an aqueous solution of lithium oxide 45min. Was added 2M hydrochloric pH = 7, was added 20mL of water was distilled off four-fifths of the solvent, continue adjusting pH = 2 ~ 3, the solid was filtered off, and then the precipitated solid was filtered and washed with water at 55-60 of Lesinuard dried in vacuo at a temperature of crude product, then recrystallized, filtered and dried to give the pure product Lesinuard0.99g, 90.0% yield.
89.1%	Stage #1: 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid methyl ester With water; sodium hydroxide at 20℃; for 24h; Stage #2: With hydrogenchloride In water	1.5 (5) Synthesis of Les-09 418 mg of 2-(5-bromo-4-(4-cyclopropyl-1-naphthalenyl)-4-hydro-1,2,4-triazol-3-ylsulfanyl)acetic acid AThe ester was placed in a 100 mL flask and 10 mL of a 2 mol/L sodium hydroxide aqueous solution was added. The reaction was carried out at room temperature for 2 h, and 24% hydrochloric acid was added.The pH of the mixture is 3, then it is extracted with 20 mL of ethyl acetate, 10 mL of n-heptane is added, crystallized, filtered, and dried to obtain the product 2-(5-Bromo-4-(4-cyclopropyl-1-naphthyl)-4-hydro-1,2,4-triazol-3-ylsulfanyl)acetic acid 360 mg, 89.1% yield; pureThe degree is 99.6%.
89%	With sodium hydroxide In tetrahydrofuran
	With water; sodium hydroxide In toluene at 18 - 25℃;	5 Compound 5. Example 5: Synthesis of Compound 1 from Compound 11 [0340] Compound 11 and methyl bromoacetate were dissolved in DMF and stirred at a temperature between 14 and 22 °C to give Compound 12. The product was isolated by cooling the reaction mixture to a temperature of 10-15 °C followed by an adjustment of the pH with aqueous sodium bicarbonate. The resulting solid, Compound 12, was filtered and was washed with water first, then with cold (0-5 °C) ethyl acetate. [0341] Compound 12 was mixed with copper (II) bromide and potassium nitrite in acetonitrile and stirred at a temperature between 14 and 20 °C until reaction completion. After addition of aqueous sodium hydroxide and citric acid to the reaction mixture, the product, Compound 3, was extracted using toluene and the organic layer was washed several times with aqueous solutions of ammonium hydroxide and sodium citrate to remove copper salts. [0342] Crude Compound 3 in solution underwent base-mediated hydrolysis with the addition of an aqueous sodium hydroxide solution. The biphasic mixture was stirred at 18-25 °C until completion of the ester hydrolysis then the pH of the aqueous layer was adjusted to between 8 and 9 using an aqueous solution of hydrobromic acid. After separation of the two phases, ethyl acetate was added to the aqueous layer, and the pH was adjusted to between 5.15 and 5.35 to extract the product, Compound 1 , into the organic layer. This process was repeated several times until all of Compound 1 was extracted. The combined organic layers were heated at 30-35 °C then circulated through a bed of activated carbon and then through a filter with porosity lower than 0.5 micron. An aqueous solution of sodium bicarbonate was added to extract Compound 1 into the aqueous layer, the layer was concentrated under reduced pressure at a temperature below 40 °C and acetic acid was added while maintaining the temperature between 40 and 60 °C. [0343] The mixture was heated to a temperature between 73 and 77 °C and crude free acid of Compound 1 crystallized, at which point water was added. The crude free acid was filtered at 7- 13 °C, washed with a cold mixture of acetic acid and water, and dried under reduced pressure at a temperature below 50 °C. [0344] The sodium salt (Compound 4) was formed by addition of an equimolar aqueous solution of sodium hydroxide to a suspension of crude Compound 1 in water stirred at 18-25 °C. Compound 4 crystallized upon cooling of the aqueous mixture, was filtered and washed with cold water, then was dissolved in warm water and filtered through a filter with porosity no higher than 1 micron. Ethyl acetate was added, the biphasic mixture was heated to 30-35 °C and an aqueous solution of hydrobromic acid was added. Compound 1 was extracted into the organic layer after addition of ethyl acetate. The organic layer containing the product was washed with water then concentrated under reduced pressure. Compound 1 crystallized from the solution. Variations in the amount of n-heptane are added to complete the crystallization. The crystalline Compound 1 was filtered and washed with a mixture of ethyl acetate and n-heptane and dried under reduced pressure while maintaining the temperature of the drier below 50 °C.
	Multi-step reaction with 2 steps 1: sodium hydroxide / toluene; water / 18 - 25 °C / Large scale 2: hydrogen bromide / water; ethyl acetate / 30 - 35 °C / pH 2 - 4 / Large scale
	With water; sodium hydroxide In toluene
	Multi-step reaction with 2 steps 1: sodium hydroxide / tetrahydrofuran; water / 2 h 2: hydrogenchloride / water
5.8 g	Alkaline conditions;	3.E E) Preparation of Lesinurad 5 - [(Methoxycarbonyl) methylthio] -4- (4-cyclopropylnaphthalen-1-yl) -4H- 1, 2,4- triazole-3-carboxylic acid (6.0 g, 16 mmol) was dissolved in chloroform (20 mL), potassium carbonate (2.4 g, 17 mmol) was added and the reaction mixture was stirred at 25 ° C for 10 min, slowly Into phosphorus tribromide (4.7g, 17mmol), the reaction mixture was stirred at 90 ° C for 12 hours, TLC point plate to determine the completion of the reaction, Concentration to dryness gave the crude intermediate 2 - [4- (4-cyclopropylnaphthalen-1-yl) -5-bromo-4H-1,2,4-triazol-3-yl] thio}Methyl acetate, and then under known ester hydrolysis reaction under alkaline conditions, the reaction is completed, concentrated to dryness by rotary evaporation, slowly added Ethanol (10 mL), crystallized by cooling to -10 ° C for 3 hours, filtered and recrystallized from isopropanol to give a solidorol, an off-white solid(5.8g), yield 92.1%, the reaction of this step with Example 1.
26.1 g	With sodium carbonate; sodium hydroxide at 20℃;	1.10 (10) 2-[[5-Bromo-4-(4-cyclopropyl-1-naphthalene)-4H-1,2,4-triazol-3-yl]thio] which is produced in the step (9) In 1330.1 g of methyl acetate, 100 ml of a mixed solution of an inorganic alkali sodium hydroxide and sodium carbonate was added, and at a normal temperature, a hydrolysis reaction occurred to generate a hydrolysis reaction.2-[[5-Bromo-4-(4-cyclopropyl-1-naphthalene)-4H-1,2,4-triazol-3-yl]thio]acetic acid 14 26.1 g, which is the present invention Resinad.
123.0 g	With water; sodium hydroxide for 2h;	The crude product of Resinard in the embodiment of the present invention is synthesized by referring to CN104736522A. In a 5L three-necked flask, add 160.0g of Intermediate 4 and 1.28L of tetrahydrofuran, start stirring, and raise the temperature to 3542.0.Stir until dissolved; lower the temperature to 2732, add 148.0g NBS, and react for 3.04.0h;Reduce the temperature to 5, add 800ml of toluene and 800ml of purified water, stir and separate the liquid, and use 800ml of 3% sodium bisulfite solution for the organic phase,Wash with 800ml of 5% sodium bicarbonate solution, let stand for liquid separation, collect the organic phase, add 580ml of 1mol/L sodium hydroxide to the organic phase, react for 2h,Separate the liquid, collect the aqueous phase, concentrate, cool the crystal, filter, and wash with water to obtain a wet product; add 720ml of purified water to the wet product,Heat to 35, stir to dissolve, add 1.6L of ethyl acetate, adjust the system pH=24 with 24% hydrobromic acid, stir for 30min,Separate the liquid, wash the organic phase once with 320ml of purified water, concentrate the organic phase until the solid precipitates,Keep warm at 3842, continue to stir and crystallize for 34h, then slowly reduce the temperature to 510, stir for 2h,Filtration, washing, and vacuum drying under reduced pressure to obtain 123.0 g of crude Recinald. The purity is 95.12%,
3.3 kg	With water; sodium hydroxide In tetrahydrofuran at 25 - 35℃; for 2h; Large scale;	3 Synthesis of Crude Lesinurad Under the condition of 20°C-30°C, add 2.5kg of formula III compound and DMF10L into the reaction kettle and stir, add DBU (18.5kg) into the reaction system and continue stirring;Continue to add 14.5kg of methyl thioglycolate,After the addition, continue to keep the temperature at 20°C-30°C and react for 2 hours.Continue to slowly add 3.5 kg of methyl chloroacetate into the reaction system, and continue to heat and stir the reaction for 1 hour to stop the reaction;Slowly add 25L of ethyl acetate to the system, keep warm and stir, continue to slowly add 10L of 1N hydrochloric acid to the system, stir for 10-20 minutes, and let stand for layering;Collect the organic phase, and evaporate the organic phase under reduced pressure to almost no fraction.Continue to add 18L of tetrahydrofuran to the concentrate to dissolve.Control the temperature at 25-35°C, drop the pre-prepared sodium hydroxide solution (9.3kg sodium hydroxide dissolved in 20L purified water) into it; after the addition, keep it warm and react for 2 hours,After the completion of the reaction, the reaction system was distilled under reduced pressure until the system was almost free of fractions. The pH of the reaction system was adjusted to 6-7 with hydrochloric acid, extracted twice with ethyl acetate, and the two ethyl acetate layers were combined to remove ethyl acetate.Get 3.3 kg of the crude Lesinurad for use (theoretical 2.57 kg).
	With lithium hydroxide In tetrahydrofuran; ethanol at 20℃;
	Multi-step reaction with 2 steps 1: sodium hydroxide / toluene; water / 10 - 15 °C 2: hydrogen bromide / water / pH 4 - 5

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - WO2009/70740, 2009, A2 Location in patent: Page/Page column 91
[2]Current Patent Assignee: ASTRAZENECA PLC - WO2006/26356, 2006, A2 Location in patent: Page/Page column 24
[3]Current Patent Assignee: ASTRAZENECA PLC - WO2011/85009, 2011, A2 Location in patent: Page/Page column 38-39
[4]Lei, Xiaofang; Wang, Yuanyuan; Fan, Erkang; Sun, Zhihua [Organic Letters, 2019, vol. 21, # 5, p. 1484 - 1487]
[5]Current Patent Assignee: SHENZHEN DONGYANGGUANG INDUSTRIAL DEVELOPMENT CO LTD - WO2014/198241, 2014, A1 Location in patent: Paragraph 077-078
[6]Current Patent Assignee: SHANDONG UNIVERSITY - CN105566237, 2016, A Location in patent: Paragraph 0075; 0076; 0077
[7]Current Patent Assignee: CHENGDU MIRACLE PHARMACEUTICAL - CN107955029, 2018, A Location in patent: Paragraph 0064-0066; 0080-0082; 0096-0098
[8]Li, Yaoqi; Sun, Zhihua [Heterocycles, 2020, vol. 100, # 7]
[9]Current Patent Assignee: ASTRAZENECA PLC - WO2014/8295, 2014, A1 Location in patent: Paragraph 0340-0344
[10]Current Patent Assignee: ASTRAZENECA PLC - WO2014/8295, 2014, A1
[11]Current Patent Assignee: CHINA RESOURCES NATIONAL CORPORATION - CN105985295, 2016, A Location in patent: Paragraph 0045; 0046; 0047
[12]Current Patent Assignee: SHANGHAI JINGXIN BIOLOGICAL MEDICAL; XINCHANG KANGLE CHEMICALS CO., LTD. - CN107098866, 2017, A
[13]Current Patent Assignee: HUNAN OUYA BIOLOGICAL - CN106632108, 2017, A Location in patent: Paragraph 0057; 0069; 0079; 0080
[14]Current Patent Assignee: Zhao Tiantian - CN107915689, 2018, A Location in patent: Paragraph 0011; 0012; 0013
[15]Current Patent Assignee: BEIJING XINKAIYUAN PHARMACEUTICALS TECH HAINAN BRANCH - CN111153862, 2020, A Location in patent: Paragraph 0032-0033
[16]Current Patent Assignee: ZHEJIANG HUAHAI PHARMACEUTICAL CO., LTD. - CN111320588, 2020, A Location in patent: Paragraph 0034-0037
[17]Zhao, Tong; Meng, Qing; Sun, Zhuosen; Chen, Yanyu; Ai, Wei; Zhao, Zean; Kang, Dongwei; Dong, Yue; Liang, Ruipeng; Wu, Ting; Pang, Jianxin; Liu, Xinyong; Zhan, Peng [Journal of Medicinal Chemistry, 2020, vol. 63, # 19, p. 10829 - 10854]
[18]Current Patent Assignee: CHINA RESOURES SAIKE PHARMACEUTICAL; CHINA RESOURCES NATIONAL CORPORATION - US2021/53928, 2021, A1

2
2-[5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}acetic acid [ No CAS ]
[ 1151516-14-1 ]

Yield	Reaction Conditions	Operation in experiment
100%	With sodium hydroxide; In ethanol; water; at 10℃; for 0.25h;	[0U362] Aqueous sodium hydroxide solution (IM, 2.OmL, 2.0mmol) was added dropwise over 5 mins to a solution of 2-(5-bromo-4-(l-cyclorhoropylnaphthalen-4-yl)-4H-1,2,4-triazoi-3-ylthio)acetic acid (8 lOmg, 2.0mmo.) in ethanol (1OmL) at 1OC. The mixture was stirred at 10C for a further 10 mins. Volatile solvents were removed in vacuo to dryness to provide sodium 2-(5-bromo-4-(4- cyclopropyInaphthalen-I-y.)-4H-1,2,4-triazol-3-ylthio)acetate as a solid (850mg, 100%).
100%	With sodium hydroxide; In ethanol; water; at 10℃; for 0.25h;	Example 1: Preparation of sodium 2-(5-bromo-4-(4-cyclopropylnaphthalen-l-yl)-4H-l,2,4- triazol-3-ylthio)acetateSodium 2-(5-bromo-4-(4-cyclopropylnaphthalen- 1 -yl)-4H- 1 ,2,4-triazol-3-ylthio)acetate was prepared according to previously described procedures (see US patent publication2009/0197825) and as outlined below.[00103] Aqueous sodium hydroxide solution (1M, 2.0 mL, 2.0 mmol) was added dropwise over 5 min to a solution of 2-(5-bromo-4-(l-cyclopropylnaphthalen-4-yl)-4H- l,2,4-triazol-3-ylthio)acetic acid (810 mg, 2.0 mmol) in ethanol (10 mL) at 10 C. The mixture was stirred at 10 C for a further 10 min. Volatile solvents were removed in vacuo to dryness to provide sodium 2-(5-bromo-4-(4-cyclopropylnaphthalen-l-yl)-4H-l,2,4- triazol-3-ylthio)acetate as a solid (850 mg, 100%).
97%	With sodium hydroxide; In ethanol; at 0 - 5℃; for 0.5h;	A 0.2 M ethanolic solution of Lesinurad (2.50 g, 6.18 mmol) was cooled to between 0 C to 5 C in an ice bath, and treated with a 1 M solution of sodium hydroxide (247 mg, 6.18 mmol) that was added drop wise from an addition funnel. The mixture was stirred for 0.5 h, clarified by filtration and concentrated. Co-distillation with dichloromethane was performed 3 times and the product further dried in vacuo at 35 C for 3.5 hours, affording Lesinurad sodium salt (2.54 g, 97 % yield). Lesinurad sodium salt prepared in this manner was used for the experiments described herein.

850 mg

With sodium hydroxide; In ethanol; water; at 10℃; for 0.25h;

At 10 ,Aqueous sodium hydroxide (IM, 2.0 mL, 2.0 mmol) was added over 5 min,(4-cyclopropylnaphthalen-1-yl) -4H-1,2,4-triazol-3-ylthio group was added dropwise to a solution of (-) or ) Acetic acid (810 mg, 2.0 mmol) in ethanol (10 mL).The mixture was stirred at 10 10 minutes.The volatiles were removed under vacuum and the solvent type in 30 ,The residue was dissolved in 15 mL of re-distilled water,Freeze drying to give a solid(4-cyclopropylnaphthalen-1-yl) -4H-1,2,4-triazol-3-ylthio) acetic acid sodium salt of (-) or 850 mg),

Reference： [1]Patent: WO2009/70740,2009,A2 .Location in patent: Page/Page column 91-92
[2]Patent: WO2011/85009,2011,A2 .Location in patent: Page/Page column 34-35
[3]Patent: WO2018/85932,2018,A1 .Location in patent: Paragraph 0079
[4]Patent: CN105985295,2016,A .Location in patent: Paragraph 0070; 0071
[5]Patent: CN104447589,2017,B

3
[ 878672-00-5 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
100%	With potassium hydroxide In ethanol; water at 10℃; for 0.25h;	17 [00363] Aqueous potassium hydroxide solution (IM, 2.OmL, 2.0mmol) was added dropwise over 5 mins to a solution of 2-(5-bromo-4-(l-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid (810mg, 2.0mmol) in ethanol (1OmL) at 1O°C. The mixture was stirred at 10°C for a further 10 mins. Volatile solvents were removed in vacuo to dryness to provide potassium 2-(5-bromojt-(4- cyclopropylnaphthalcn-1-yl)-4H-1,2,4-triazoI-3-yIthio)acetate as a solid, (884mg, 100%).
	With potassium hydroxide In ethyl acetate at 20℃; for 40h;	4 Example 4. Preparation of lesinurad potassium salt Form A In 0.6 mL of ethyl acetate was dissolved 10 mg of lesinurad, followed by the addition of 1.9 mg of potassium hydroxide. The mixture was stirred under ambient conditions for 40 hours. The solid was isolated by centrifugation and lesinurad potassium Form A was produced, which was analyzed by XRPD, DSC, and TGA. The XRPD pattern of lesinurad potassium salt Form A obtained from this example is displayed in FIG. 5, respectively.Potassium salt Form A has a DSC thermogram comprising two endothermic peaks with onset temperature of about 72.7 °C and 135.0 °C, and a TGA thermogram comprisingabout 6.0% weight loss up to 130 °C.
884 mg	With potassium hydroxide In ethanol; water at 10℃; for 0.25h;	4 Example 4:Optically pure2- (5-bromo-4- (4-cyclopropyl-naphthalen-1-yl) -4H-1,2,4- triazol-3-ylthio) acetic acid potassium saltPreparation At 10 ,An aqueous potassium hydroxide solution (1 M, 2.0 mL, 2.0 mmol) was added over 5 min,Was added dropwise to a solution of (-) or (+) - 2- (5-bromo-4- (4- ) Acetic acid (810 mg, 2.0 mmol)In ethanol (10mL) in a solution.The mixture was stirred at 10 10 minutes.The volatiles were removed under vacuum and the solvent type in 30 ,The residue was dissolved in 15 mL of re-distilled water,(-) or 2- (5-bromo-4- (4-cyclopropylnaphthalen-1-yl) -4H-1,2,4-triazol- ) Of potassium acetate (884 mg),

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - WO2009/70740, 2009, A2 Location in patent: Page/Page column 92
[2]Current Patent Assignee: CRYSTAL PHARMATECH CO., LTD.; SUZHOU PENGXU PHARMATECH CO., LTD. - WO2015/95703, 2015, A1 Location in patent: Page/Page column 12; 13
[3]Current Patent Assignee: CHINA RESOURCES NATIONAL CORPORATION - CN105985295, 2016, A Location in patent: Paragraph 0072; 0073

4
[ 878672-00-5 ]
[ 1158970-61-6 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 2-[5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}acetic acid With sodium hydroxide; hydroxylamine In tetrahydrofuran; methanol at 20℃; for 1h; Stage #2: With hydrogenchloride In water	18 [00364] A solution of 2-(5-bromo-4-(l-cycloproρylnaphthalen-4-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid(l .Ommol) in THF (2mL) and methanol (2mL) is added to a solution of sodium hydroxide (5mmol) and 50% aqueous hydroxy. amine (2 mL). After stirring for 1 hr at room temperature, water (4 mT ) is added and the volatile solvents removed in vacuo. The solution is then neutralized to pH 7-8 by addition of HCl (IN), and the resulting precipitate isolated by filtration to provide 2-(5-bromo^-(l- cyclopropyhiaphthalen-4-yl)-4H- l ,2,4-triazol-3-ylthio)-N-hydroxyacetamide.

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - WO2009/70740, 2009, A2 Location in patent: Page/Page column 92

5
[ 878670-89-4 ]
[ 878672-00-5 ]

Yield	Reaction Conditions	Operation in experiment
82%	Stage #1: VRX-480773 With sodium hydroxide; water In ethanol at 20℃; for 16h; Heating / reflux; Stage #2: With hydrogenchloride In water at 0℃;	8 [00343] Sodium hydroxide solution (2M aqueous, 33.7mL, 67mmol, 2eq) was added to a suspension of 2- (5-bromo-4-(4-cycloproρylnaphthalen-1-yl)-4II-l ,2,4-triazol-3-ylthio)-N-(2-chloro-4- sulfamoylphenyl)acetamide (prepared by previously published procedures; 2Og, 34mmol) in ethanol (20OmL) and the mixture heated at reflux for 4 hours. Charcoal (1Og) was added, the mixture stirred at room temperature for 12 hours and the charcoal removed by filtration. The charcoal was washed several times with ethanol and the filtrate then concentrated. Water (20OmL) was added and then concentrated to approx. one third volume, to remove all ethanol. Water (20OmL) and ethyl acetate (25OmL) were added, the mixture stirred vigorously for 15 imns and the organic layer removed. The aqueous layer was cooled to O°C and acidified by treatment with HCl (1 N) resulting in the formation of a cloudy oily precipitate. The mixture was extracted with ethyl acetate (3x) and the combined organic extracts dried over sodium sulfate and concentrated to give 2-(5-bromo-4-(4- cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid as an off white solid (11.2g, 82%)
82%	Stage #1: VRX-480773 With water; sodium hydroxide In ethanol for 4h; Reflux; Stage #2: With pyrographite In ethanol at 20℃; for 12h; Stage #3: With hydrogenchloride In water at 0℃;	2.1 Route i:Sodium hydroxide solution (2M aqueous, 33.7 mL, 67 mmol, 2 eq) was added to a suspension of 2-(5-bromo-4-(4-cyclopropylnaphthalen-l-yl)-4H-l,2,4-triazol-3-ylthio)-N- (2-chloro-4-sulfamoylphenyl)acetamide (prepared by previously published procedures, see US 2009/0197825; 20 g, 34 mmol) in ethanol (200 mL) and the mixture heated at reflux for 4 hours. Charcoal (10 g) was added, the mixture stirred at room temperature for 12 hours and the charcoal removed by filtration. The charcoal was washed several times with ethanol and the filtrate then concentrated. Water (200 mL) was added and then concentrated to approx. one third volume to remove all ethanol. Water (200 mL) and ethyl acetate (250 mL) were added, the mixture stirred vigorously for 15 min and the organic layer removed. The aqueous layer was cooled to 0 °C and acidified by treatment with HCl (IN) resulting in the formation of a cloudy oily precipitate. The mixture was extracted with ethyl acetate (3x) and the combined organic extracts dried over sodium sulfate and concentrated to give 2-(5- bromo-4-(4-cyclopropylnaphthalen-l-yl)-4H-l,2,4-triazol-3-ylthio)acetic acid as an off white solid (11.2 g, 82%).

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - WO2009/70740, 2009, A2 Location in patent: Page/Page column 79-80
[2]Current Patent Assignee: ASTRAZENECA PLC - WO2011/85009, 2011, A2 Location in patent: Page/Page column 35

6
[ 1151516-14-1 ]
2-[5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}acetic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
66%	With hydrogenchloride; In methanol; isopropyl alcohol; at 20 - 25℃; for 3.5h;	A mixture of Lesinurad sodium salt (250 mg, 0.587 mmol) in HPLC grade methanol (1 .3 mL) was sonicated to achieve dissolution. To this solution was added a hydrogen chloride solution (20 wt % in isopropanol, 107 mg, 0.587 mmol), resulting in immediate formation of a white suspension that was stirred at room temperature for about 3.5 hours. Filtration of the mixture afforded a white solid (168 mg, 66 % yield) having a PXRD consistent with Figure 1 .
	With acetic acid; In water; at 60 - 70℃;Product distribution / selectivity;	2-(5-Bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid-form 1 is prepared from crude <strong>[1151516-14-1]sodium 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate</strong> as described below: Step 1: Sodium 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate (60 g) and water (300 mL) were stirred and briefly heated (40-50 C.) until all solids dissolved. The solution was cooled and stirred in an ice bath for 1-2 hrs, after which time crystals began to form (or if crystallization had not begun, the solution was seeded with a small amount of <strong>[1151516-14-1]sodium 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate</strong> crystals). Stirring in the ice bath was continued until crystallization was complete, and then the solid isolated by filtration through a sintered filter funnel (medium porosity) under vacuum. The filter cake was washed with ice-cold water (sufficient to cover the filter cake) and the liquid completely drained under vacuum to provide wet filter cake (126.5 g).Step 2: The filter cake was dissolved in water (70 g present in the filter cake plus 130 mL; concentration 200-250 mg/mL) at 60-70 C., and slowly added to acetic acid (200 mL). The acetic acid/water (1:1 v/v) solution was cooled to room temperature under continuous stirring, and then further cooled to 0 C., resulting in the formation of crystals which were isolated by vacuum filtration over a medium porosity sintered filter funnel. The solids were washed with ice-cold acid/water (1:1 v/v) and dried in a vacuum oven to provide 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid (39.5 g, 78%).
	With hydrogen bromide; In water; ethyl acetate; at 30 - 35℃;pH 2 - 4;Large scale;	[0278] Charge Compound 2 (1.0 kg ± 1%) to a reactor. Add tetrahydrofuran (6.2 kg ± 1% <> 7.0 L ± 1%) to the same reactor. Heat the mixture to a temperature between 35C and 42C. Stir the mixture for at least 10 minutes at a temperature between 35C and 42C to obtain a clear solution. Cool the reaction mixture to a temperature between 27C and 32C. [0279] Add N-bromosuccinimide (0.734 kg ± 1%) to the reaction mixture whilst maintaining the temperature between 27C and 32C, e.g., between 27C and 30C. Stir the mixture at a temperature between 27C and 32C, e.g., between 27C and 30C, until the reaction is complete. [0280] The reaction is considered complete when the content of Compound 2 is lower than 1.5% area by HPLC, preferentially lower than 0.2% area by HPLC. [0281] The reaction is sampled for HPLC analysis after 20 to 40 minutes of stirring for the determination of the Compound 2 content. Based on HPLC analysis, optionally add extra quantity of N-bromosuccinimide (0.105 kg ± 1%) while maintaining the temperature between 27C and 32C, e.g., 27C and 30C. Otherwise, continue with the stirring at a temperature between 27C and 32C, e.g., between 27C and 30C, until the reaction is complete. [0282] Cool the reaction mixture to a temperature between 2C and 7C, e.g., between 2C and 5C. Add toluene (4.33 kg ± 5%) to the mixture, while maintaining the temperature between 2C and 7C, e.g., between 2C and 5C. [0283] Add to the reaction mixture, over at least 10 minutes, while maintaining the temperature between 2C and 7C, e.g., between 2C and 5C, ozonated deionised water (5.0 L ± 5%). The addition of the ozonated deionised water is exothermic and during the addition gaseous release may occur. Stir the mixture for at least 30 minutes maintaining the temperature between 2C and 7C, e.g., between 4C and 6C. [0284] Stop stirring and allow layers to separate for at least 30 minutes. Discharge the aqueous (lower phase). Add to the organic phase, over at least 10 minutes, while maintaining the temperature between 2C and 7C, a solution previously prepared by dissolution of sodium disulfite (0.112 kg ± 1%) in ozonated deionised water (5.0 L ± 5%). The addition of the sodium disulfite solution is exothermic. During the addition gaseous release may occur. [0285] Stir the suspension for at least 30 minutes maintaining the temperature between 2C and 7C. Take a sample of the mixture. If the aqueous phase of the sample is pale yellow, conduct another wash step with sodium disulfite. If the aqueous phase of the sample is colorless then send sample for HPLC analysis. If the peak of N-bromosuccinimide is detected by HPLC then conduct another wash with sodium disulfite and repeat the HPLC analysis till the NBS is not longer detectable by HPLC. [0286] Stop stirring and allow layers to separate for at least 15 minutes. Discharge the aqueous phase (lower phase) and combine with the previous aqueous phase. Heat the organic phase comprising Compound 3 to a temperature between 18C and 25C. Add to the organic phase, maintaining the temperature between 18C and 25C, ozonated deionised water (5.0 L ± 5%). Stir the mixture for at least 15 minutes maintaining the temperature between 18C and 25C. Stop stirring and allow layers to separate for at least 15 minutes. Discharge the aqueous phase (lower phase). [0287] Add to the organic phase, maintaining the temperature between 18C and 25C, a solution previously prepared by dissolution of sodium bicarbonate (0.35 kg ± 1%) in ozonated deionised water (5.0 L ± 5%). Stir the mixture for at least 15 minutes maintaining the temperature between 18C and 25C. Stop stirring and allow layers to separate for at least 15 minutes. Discharge the aqueous phase (lower phase). [0288] If the pH of the discharged aqueous phase is below 8.0, repeat the wash step with sodium bicarbonate until the pH of the aqueous phase is above 8.0. [0289] Add to the organic phase, comprising Compound 3, over at least 10 minutes, while maintaining the temperature between 18C and 25 C, a solution previously prepared by dissolution of sodium hydroxide (pure) (0.1473 kg ± 1%) in ozonated deionised water (3.61 L ± 5%). [0290] Stir the mixture at a temperature between 18C and 25C for at least 2 hours until the reaction is complete. The reaction is considered complete when the peak area by HPLC of Compound 3 in the organic phase is lower than 50 mAU. If reaction is incomplete then stir the reaction mixture an extra 2 hours before re-sampling. If reaction completion is not achieved after 6 hours stirring, add extra quantity of sodium hydroxide aqueous solution and re-sample 3 hours after the addition. The reaction mixture has two phases at this point. Stop stirring and allow layers to separate for at least 30 minutes. Discharge the aqueous phase (lower phase) to a reactor or receiver. Repeat this step and combine the aqueous layers. Discharge the organic phase (upper phase) for disposal. [0291] Concentrate the aqueous phases under a vacuum at a temperatur...

	With hydrogenchloride; In water;	Finally, Intermediate D with 1N hydrochloric acid under acidic conditions are adjusted to give <strong>[1151516-14-1]lesinurad</strong> shown in formula I.
30.25 g	With hydrogenchloride; In water; at 0℃; for 0.166667h;pH 2 - 3;Inert atmosphere;	Example 1 : Preparation of amorphous form of <strong>[1151516-14-1]lesinurad</strong> Lesinurad sodium (43 g, 0.10 moles) was added to water (430 ml) under stirring in nitrogen atmosphere. The mixture was cooled to 0eC and 2N hydrochloric acid (25 ml) was added till pH of 2-3 was reached and stirred at 0eC for ten minutes. The mixture was extracted with dichloromethane (3x350ml). The combined dichloromethane layer was dried over sodium sulfate and solvent was evaporated at 40eC under vacuum to give crude brown color sticky solid. The crude compound was purified by silica gel column chromatography with 50-70% ethyl acetate/hexane to provide the title compound as off-white solid. Yield: 30.25 g
	With hydrogenchloride; In dichloromethane; at 20℃; for 1h;	The material from example 3 is dissolved in dichloromethane. To this solution is added 1equivalent of HC1 (aqueous) and the reaction is stirred at ambient temperature for onehour. Water is then added to the reaction mass. The dichloromethane layer is separated and washed with water. The solvent dichloromethane is evaporated to yield solid material.
	With hydrogenchloride; In water;	The compound C (4.8 g, 0 . 0115 muM) dissolved in tetrahydrofuran (30 ml) in, adding 0.5 N aqueous sodium hydroxide solution (28 ml, 1.2 eq), stirring the reaction 2 h. Sampling detection compound C after the reaction is complete, and concentration of the reaction solution, the residue water re-crystallization, to obtain 2.7 g white solid, is intermediate D.Finally, intermediate for D 1 N hydrochloric acid under the condition regulating acid, of formula I shown <strong>[1151516-14-1]lesinurad</strong>

Reference： [1]Patent: WO2018/85932,2018,A1 .Location in patent: Paragraph 0032; 0066
[2]Patent: US2012/172405,2012,A1 .Location in patent: Page/Page column 12
[3]Patent: WO2014/8295,2014,A1 .Location in patent: Paragraph 0278-0308
[4]Patent: CN105399694,2016,A .Location in patent: Paragraph 0082; 0083; 0085; 0094; 0095
[5]Patent: WO2016/203436,2016,A1 .Location in patent: Page/Page column 13
[6]Patent: WO2017/36884,2017,A1 .Location in patent: Page/Page column 18
[7]Patent: CN107098866,2017,A .Location in patent: Paragraph 0091

7
[ 1639972-19-2 ]
[ 878672-00-5 ]

Yield	Reaction Conditions	Operation in experiment
93%	With sodium hydrogencarbonate In acetone at 65℃; for 12h;	14 Example 14. Preparation of 2-((5-bromo-4-(4-cyclopropylnaphthalen-l-yl)-4H-l,2,4-triazol-3-yl)thio)acetic acid Example 14. Preparation of 2-((5-bromo-4-(4-cyclopropylnaphthalen-l-yl)-4H-l,2,4-triazol-3-yl)thio)acetic acid [079] Phenyl 2-((5-bromo-4-(4-cyclopropylnaphthalen-l-yl)-4H-l,2,4-triazol-3-yl)thio)acetate (23.9g), and acetone (250 mL) were placed in a flask to form a mixture, after the mixture was stirred to a clear solution, the solution was added 1 mole NaHC03 solution to obtain a suspension, then the suspension was heated to 65°C. After refluxed for 12 hours, the reaction mixture was cooled to room temperature, distilled the acetone to obtain a solution, to the solution added 80 mL ethyl acetate. Adjusted the pH value of the solution to about 3.0 with 1 mole NaHS04 solution, stirred for 30 min at room temperature, then separated the organic phase, extracted the water layer with 80 mL ethyl acetate, and combined the organic phase. The organic phase was stirred at room temperature for 12 hours, then precipitate was filtered. The obtained solid was dried in vacuum to obtain 2-(5-bromo-4-(4-cyclopropylnaphthalen-l-yl)-4H-l,2,4-triazol-3-ylthio)acetate, yield 93%.

Reference： [1]Current Patent Assignee: SHENZHEN DONGYANGGUANG INDUSTRIAL DEVELOPMENT CO LTD - WO2014/198241, 2014, A1 Location in patent: Paragraph 078-079

8
[ 878672-00-5 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
	With calcium hydroxide In tetrahydrofuran; water at 20℃; for 24h;	1 Example 1. Preparation of lesinurad calcium salt Form A In 2.0 mL of tetrahydrofuranlwater (19:1, v/v) was dissolved 151.1 mg of lesinurad, followed by the addition of 14.2 mg of calcium hydroxide. The mixture was stirred under ambient conditions for 24 hours. The solid was isolated by centrifugation and lesinurad calcium salt Form A was produced, which was analyzed by XRPD, DSC, TGA and DVS.The XRPD pattern, DSC thermogram and DVS isotherm plot of lesinurad calcium salt Form A obtained from this example are displayed in FIGs. 1-3, respectively.The calcium salt Form A has a DSC thermogram comprising an endothermic peak with onset temperature of about 115.1 °C, and a TGA thermogram comprising about 11.4%weightlossupto 110 °C.

Reference： [1]Current Patent Assignee: CRYSTAL PHARMATECH CO., LTD.; SUZHOU PENGXU PHARMATECH CO., LTD. - WO2015/95703, 2015, A1 Location in patent: Page/Page column 11

9
[ 878672-00-5 ]
[ 1609182-28-6 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride In water; ethyl acetate at 20℃; for 40h;	5; 6 Example 5. Preparation of lesinurad hydrochloride Form A In 0.6 mL of ethyl acetate was dissolved 10 mg of lesinurad, followed by the addition of 2.5 tL of hydrochloride solution (36.5 wt%). The solution was stirred under ambientconditions for 40 hours. The solid was centrifuged and the lesinurad hydrochloride Form A was obtained, which was analyzed by XRPD, DSC, and TGA. The XRPD pattern of lesinurad hydrochloride Form A obtained from this example is displayed in FIG. 6, respectively.Hydrochloride Form A has a DSC thermogram comprising two endothermic peakswith onset temperature of about 122.4 °C and 153.5 °C, and a TGA thermogramcomprising about 18.2% weight loss up to 153 °C.

Reference： [1]Current Patent Assignee: CRYSTAL PHARMATECH CO., LTD.; SUZHOU PENGXU PHARMATECH CO., LTD. - WO2015/95703, 2015, A1 Location in patent: Page/Page column 13

10
[ 878672-00-5 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
822 mg	With lithium hydroxide In ethanol; water at 10℃; for 0.25h;	5 Example 5:Optically pure2- (5-bromo-4- (4-cyclopropyl-naphthalen-1-yl) -4H-1,2,4- triazol-3-ylthio) acetic acid lithium saltPreparation At 10 ,Aqueous lithium hydroxide (IM, 2.0 mL, 2.0 mmol) was added over 5 min,Was added dropwise to a solution of (-) or (+) - 2- (5-bromo-4- (4- ) Acetic acid (810 mg, 2.0 mmol)In ethanol (10mL) in a solution.The mixture was stirred at 10 10 minutes.The volatiles were removed under vacuum and the solvent type in 30 ,The residue was dissolved in 15 mL of re-distilled water,(-) or (+) - 2- (5-bromo-4- (4-cyclopropylnaphthalen- 1 -yl) -4H-l, 2,4-triazol- Ylthio) acetate (822 mg),

Reference： [1]Current Patent Assignee: CHINA RESOURCES NATIONAL CORPORATION - CN105985295, 2016, A Location in patent: Paragraph 0074; 0075

11
2-[5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}acetic acid [ No CAS ]
[ 64-17-5 ]
[ 1158970-52-5 ]

Yield	Reaction Conditions	Operation in experiment
95.4%	With sulfuric acid; at 5 - 25℃; for 145h;	Lesinurad, free form (0.25g), prepared according to W02009070740, purity 97.0 1% by HPLC analysis, was suspended in ethanol (1 .25mL) at 20C and the resulting slurry treated with sulfuric acid (75uL). The resulting solution was stirred for lh at 20C andthen temperature cycled between 5C and 25C for 144h. The solution was then concentrated on a rotary evaporator and the residue re-dissolved in dichloromethane (lOmL) and washed with sodium bicarbonate solution (lOmL). The layers were separated and the organic layer was washed with water (2x 1 OmL). The aqueous layer was then extracted with dichloromethane (2x 1 OmL) and the washings were combined with theorganic layer and dried over sodium sulfate. Evaporation of the dichloromethane yielded an oil (100% th. yield). The oil was analyzed by HPLC which indicated the presence of 95.4% lesinurad ethyl ester and 1.8% lesinurad, free form.
864 mg		At 5 ,Oxalyl chloride (257 mg, 2.0 mmol) was added over 5 min,Add dropwise to(-) Or (+) - 2- (5-bromo-4- (4-cyclopropyl-naphthalen-1-yl) -4H-1,2,4- triazol-3-ylthio) acetic acid (810mg , 2.0 mmol)In dichloromethane (10mL) in a solution.In the mixture was further stirred at 10 20 minutes,Ethanol was then added (dry, 1mL) at 0 ,Stir at room temperature for 20 minutes.The volatiles were removed under vacuum and the solvent type in 30 ,The residue was dissolved in 5 mL of ethanol,And concentrated under reduced pressure at 30 C,Then add 5mL ethanol,Diluted with 30 mL of re-distilled water,Lyophilizer lyophilized to give a solid (-) or (+) - 2- (5-bromo-4- (4-cyclopropyl-naphthalen-1-yl) -4H-1,2,4- triazol-3 Ylthio) acetic acidEthyl ester (864 mg),

Reference： [1]Patent: WO2017/36884,2017,A1 .Location in patent: Page/Page column 16
[2]Patent: CN105985295,2016,A .Location in patent: Paragraph 0078; 0079

12
[ 1684391-29-4 ]
[ 878672-00-5 ]

Yield	Reaction Conditions	Operation in experiment
98%	With sodium hydrogensulfite In dichloromethane at 20℃; for 2h;	2; 3 Example 2 High purity 2- [5-bromo-4- (4-cyclopropylnaphthalen-1-yl) -4H-1,2,4-triazol-3-ylthio] acetic acid preparation In a 250 mL single-mouth type flask equipped with polytetrafluoroethylene magnet,Was weighed into the preparation of Example 12- [5-bromo-4- (4-cyclopropylnaphthalen-1-yl) -4H-1,2,4-triazol-3-ylthio]Acetic acid dicyclohexylamine salt (15.0 g, 25.6 mmol)50 mL of dichloromethane and 10% sodium bisulfate solution (31 mL, 25.6 mmol) were added,Open the reaction, room temperature conditions for 2h reaction solution transferred to the separatory funnel,The organic phase was separated and the organic phase was washed with 10% NaCl solution (50 mL x 2)Dried over anhydrous magnesium sulfate, filtered to remove the desiccant, and the solvent methylene chloride was removed by steaming,A light yellow foamy solid was obtained2- [5-bromo-4- (4-cyclopropylnaphthalen-1-yl) -4H-1,2,4-triazol-3-ylthio]The yield was 98% and the HPLC purity (peak area) was 99.42%.

Reference： [1]Current Patent Assignee: SHENZHEN DONGYANGGUANG INDUSTRIAL DEVELOPMENT CO LTD - CN104447589, 2017, B Location in patent: Paragraph 0091; 0092; 0093; 0094; 0095; 0096

13
[ 878672-00-5 ]
[ 878672-00-5 ]

Yield	Reaction Conditions	Operation in experiment
2.2 g	With (1R,2S)-2-Amino-1,2-diphenylethanol In acetone at 70℃; for 1h;	4 1 R, 2 S) -2 - amino - 1, 2 - diphenyl ethanol The 10 g of racemic lesinurad (1.0 eq), 5 g chiral amino alcohol derivatives (1 R, 2 S) -2 - amino - 1, 2 - diphenyl ethanol (1.0 eq), acetone 65 ml mixed, in oil bath heated to 70 °C, to dissolve to clarify. In the 70 °C reflow reaction for 1 h, stop heating, in oil bath slowly cooling to the 7 - 8 °C, filtering, the filter cake is washed with ethyl acetate, to obtain 4.00 g white solid powder A (S configuration lesinurad salt), ee=98.2%. The 4.00 g white solid powder in the above-mentioned step A added to 23 ml acetone in the mixed solvent, setting the oil bath 70 °C, heating to dissolve to clarify, 1 h stop heating after, in oil bath slowly cooling to the 7 - 8 °C, filtering, the filter cake is washed with ethyl acetate, to obtain 3.5 g white solid powder B, ee=99.9%. The 3.5 g of solid powder B dissolved in 20 ml CH2 Cl2 , Add 30 ml water mixing, stirring into the HBr (concentration 48 wt %), adjusting pH=2 - 3, separating the organic phase, the organic phase for 20 ml wash once with water, dried with anhydrous sodium sulfate, and concentration, drying, be 1.96 g white solid (S)-2 - (5 - bromo -4 - (4 - ring propyl naphthalene -1 - yl) - 4 H - 1, 2, 4 - triazole -3 - controlling helicobacter) acetic acid, ee=99.9%. See Figure 1, in high performance liquid chromatography (HPLC) in the Figure, the retention time t=31. 22 min, total yield 39%. ESI (M + H)=404

Reference： [1]Current Patent Assignee: SHANGHAI JINGXIN BIOLOGICAL MEDICAL; XINCHANG KANGLE CHEMICALS CO., LTD. - CN107098866, 2017, A Location in patent: Paragraph 0093; 0094; 0095; 0096

14
[ 878672-00-5 ]
[ 878672-00-5 ]
[ 878672-00-5 ]

Yield	Reaction Conditions	Operation in experiment
1: 10.9 g 2: 4.05 g	With (1S,2R)-2-Amino-1,2-diphenylethanol In acetone at 60℃; for 1h;	2 (lS, 2R) -2_amino-1,2-diphenylethanol [0096] 10 g of racemic lesinurad (1 · Oeq), 5 g of chiral aminoalcohol derivative (IS, 2R) _2_amino-1,2,2-diphenyl Ethanol (1. Oeq), acetone 65mL mixed in the oil bath heated to 60 ° C, dissolved to clarify. Reaction at 60 ° C lh, stop adding Hot, slowly cooled to 7-8 ° C in an oil bath, filtered and the filter cake was washed with ethyl acetate (EA) to give 4.05 g of a white solid powder A (R configuration 1 es inurad salt), ee = 98.6%. The filtrate was concentrated by rotary distillation and dried to give 10.9 g of white solid C, = 24.4%
	With trifluoroacetic acid In tert-butyl methyl ether at 35℃; for 0.166667h; Resolution of racemate;	Analytical Method for Separation of Atropisomers Analysis of atropisomers was carried out using normal phase chiral chromatographyconsisting of an amylose-based chiral column (Daicel CHIRALPAKIA-3mm 4.6 100 mm; West Chester, PA) and an Agilent (Santa Clara, CA)1100 pump system connected to a UV diode array detector set at 226 nm.Separation of the atropisomers was achieved using an isocratic elution withmobile phase methyl tert-butyl ether and 0.1% trifluoroacetic acid at 35C. Therun time was 10 minutes and the retention times of lesinurad atropisomer 1 andatropisomer 2 were 2.7 and 4.2 minutes, respectively. The naming convention oflesinurad atropisomers in this paper was based on the order of elution as notedpreviously.

Reference： [1]Current Patent Assignee: SHANGHAI JINGXIN BIOLOGICAL MEDICAL; XINCHANG KANGLE CHEMICALS CO., LTD. - CN107098866, 2017, A Location in patent: Paragraph 0093; 0094; 0095; 0096
[2]Yang, Chun; Zhou, Dongmei; Shen, Zancong; Wilson, David M.; Renner, Matthew; Miner, Jeffrey N.; Girardet, Jean-Luc; Lee, Caroline A. [Drug Metabolism and Disposition, 2019, vol. 47, # 2, p. 104 - 113]

15
[ 878672-00-5 ]
[ 878672-00-5 ]

Yield	Reaction Conditions	Operation in experiment
2.2 g	With (1S,2R)-2-Amino-1,2-diphenylethanol In acetone at 80℃; for 1h;	3 In the light of the embodiment 2, will be 5 g racemic lesinurad (1.0 eq), 3.9 g chiral amino alcohol derivatives (1 S, 2 R) -2 - amino - 1, 2 - diphenyl ethanol (1.5 eq), 250 ml ethyl acetate/acetone=10/1 mixed, in oil bath heated to 80 °C, to dissolve to clarify. In the 80 °C lower reaction 1 h, stop heating, in oil bath slowly cooling to the 28 °C, filtering, the filter cake is washed with ethyl acetate, to obtain 2.2 g white solid powder (R configuration lesinurad salt), ee=96.5%.

Reference： [1]Current Patent Assignee: SHANGHAI JINGXIN BIOLOGICAL MEDICAL; XINCHANG KANGLE CHEMICALS CO., LTD. - CN107098866, 2017, A Location in patent: Paragraph 0093; 0094; 0095; 0096

16
[ 878672-00-5 ]
[ 2102896-34-2 ]

Yield	Reaction Conditions	Operation in experiment
1.79g	With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 100℃; for 4h;	3 Example 3 Preparation of 2 - ((5-bromo-4- (4-cyclopropylnaphthalen-1-yl) -4H-1,2,4-triazol-3-yl) sulfonyl) acetic acid (IV) 4.04 g of lesinurad was placed in a 250 ml single-necked flask,Add 100 ml of methylene chloride, stir and dissolve,3.80 g of m-chloroperoxybenzoic acid was added and the reaction was stirred at 100 ° C for 4 h. To the reaction solution was added 3.16 g of sodium thiosulfate, and the mixture was stirred at room temperature30 min, filtered, concentrated and dried. The residue was separated on a silica gel column and eluted with ethyl acetate-n-hexane (1: 4) to give a pale yellow solidBody 1.79g.
	With dihydrogen peroxide In ethanol at 20℃; for 24h;

Reference： [1]Current Patent Assignee: CHINA PHARMACEUTICAL UNIVERSITY - CN106831619, 2017, A Location in patent: Paragraph 0016; 0047; 0048
[2]Attia; El-Abassawi; El-Olemy; Abdelazim [New Journal of Chemistry, 2018, vol. 42, # 2, p. 995 - 1002]

17
[ 1158970-52-5 ]
2-[5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}acetic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
96%	With sodium hydroxide; In tetrahydrofuran; at 10 - 15℃;	70 g of the compound of formula 2 was dissolved in 300 mL of tetrahydrofuran,Add 30ml of 10% sodium hydroxide solution,10 ~ 15 reaction to the disappearance of raw materials,The reaction solution was adjusted to pH 1 with 5% hydrochloric acid solution,Add ethyl acetate extraction,After drying over anhydrous magnesium sulfate and concentrating under reduced pressure,Then add acetone recrystallization,Got Lesinurad 60g,The yield is 96%.As shown in Figure 3,The purity of Lesinurad obtained in this example is 99.79%

Reference： [1]Patent: CN106866560,2017,A .Location in patent: Paragraph 0041; 0047; 0053

18
[ 878672-00-5 ]
[ 121-44-8 ]
[ 2101819-58-1 ]

Yield	Reaction Conditions	Operation in experiment
93.7%	In ethanol at 35 - 40℃; for 2h;	3 Example 3:2 - [[5-bromo-4- (4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-yl] thio] acetic acidPreparation of Salt Crystalline Compound Take Lesinurad raw material 100g added to the reaction flask, add 700ml of ethanol solution,Add 5g activated carbon stirring 0.5 hours, filtered, washed with a small amount of ethanol. The filtrate was warmed to 35-40 , triethylamine solution of ethanol (37.54g triethylamine added to 257ml of ethanol) was added dropwise with stirring, the temperature was stirred for 2 hours, Dripping crystallization solvent n-heptane 1750ml, dropping was cooled to -5 ~ 5 , the cooling rate of 1 ~ 2 per minute, holding crystal insulation incubated for 3 hours,Filtration, washing, temperature control at 65 for 3 hours in vacuo to give 117.2g white-like solid, yield 93.7%.

Reference： [1]Current Patent Assignee: LUOXIN PHARMACEUTICALS GROUP STOCK CO LTD - CN106749058, 2017, A Location in patent: Paragraph 0046; 0047; 0048; 0049; 0050; 0051

19
2-[5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}acetic acid [ No CAS ]
[ 98-92-0 ]
lesinurad–nicotinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	In ethanol at 30 - 75℃; for 4h;	14 Example 14: Preparation of Lesinurad Form APO-III A suspension of Lesinurad (500 mg, 1 .24 mmol) and nicotinamide (166 mg, 1 .36 mmol) in anhydrous ethanol (10.5 mL) was dissolved by heating in a 75 °C oil bath. Upon dissolution, the set temperature was decreased to 60 °C and held for about 1 hour. The set temperature was then decreased to 50 °C and the temperature was subsequently decreased incrementally by 10 °C over the course of 2 hours, at which time a temperature of 30 °C was reached. The heating was turned off, and after stirring 1 additional hour, filtration afforded Lesinurad Form APO-III (590 mg, 90 %). The solid was further dried in vacuo at 40 °C for about 6 hours. PXRD of the sample was consistent with Figure 3.
1.4 g	In methanol; water at 50 - 55℃;	4 Preparation ofCrystalline Form L5 of Lesinurad co-crystal Lesinurad (2.Og) and nicotinamide (0.6g) were dissolved in 23 ml MeOH and 4 ml water at SO-SS. The solution was cooled to 1O followed by filtration of the white precipitate and dried under vacuum at 4S for 1S-16h to give 1.4 g of the desiredproduct.
42.1 g	In ethanol at 20℃; for 4h;	1.b Water (175 mL) was charged to the lithium salt and the tetrahydrofuran was removed in vacuo at 30-35° C. The reaction solution was cooled to room temperature, washed with ethyl acetate (2×175 mL), and the aqueous phase was acidified to pH 2-3 using 4 wt % hydrochloric acid (350 mL, 390.93 mmol). Dichloromethane (280 mL) was charged to the flask and the mixture was stirred at room temperature for 15 minutes. The organic and aqueous layers were then separated and the organic phase was washed with brine solution (175 mL). An emulsion formed during the wash but with time (1.25 hours), a clean separation of the aqueous and organic layers was attained. The organic phase was dried over anhydrous sodium sulfate and a 1H-NMR sample was taken using 1,4-dimethoxybenzene as an internal standard to determine the amount of Lesinurad (1) in solution (40.31 g, 99.71 mmol). This assay was used to determine the amount of nicotinamide used in the subsequent step. The reaction solution was concentrated in vacuo at 30-35° C. to 2 volumes (81 mL). Ethanol (363 mL) was charged to the flask and the reaction solution was again concentrated in vacuo at 30-35° C. to 2 volumes (81 mL). Ethanol (322 mL) and nicotinamide (13.67 g, 111.93 mmol, 1.1 equivalents based on the above assay) were charged to the flask and stirred at room temperature whereupon a thin suspension was formed. The reaction was heated to 72-77° C. for 4 hours, slowly cooled to room temperature over 4 hours, and then stirred at room temperature for 8 hours. The reaction was then further cooled to 0-5° C. for 4 hours, following which the product was collected by filtration, washed with cold (0-5° C.) ethanol (40 mL) and cold (0-5° C.) acetone (40 mL), and dried in vacuo at 35-40° C. for 16 hours to afford a Lesinurad nicotinamide co-crystal as an off-white solid (42.10 g; 77% yield from the compound of Formula (3-A)). 1H-NMR (d6-DMSO) δ=0.82-0.92 (m, 2H), 1.10-1.20 (m, 2H), 2.48-2.62 (m, 1H, overlapping with DMSO peak), 4.01 (s, 2H), 7.17 (d, 1H, J=8.3 Hz), 7.40-7.55 (m, 2H), 7.57-7.80 (m, 4H), 8.12-8.26 (m, 2H), 8.59 (d, 1H, J=8.4 Hz), 8.71 (d, 1H, J=4.7 Hz), 9.05 (s, 1H), 13.01 (br s, 1H) ppm.

In methanol; water at 45 - 50℃; for 0.5h;

2.1.4. Lesinurad-nicotinamide (LES-NAM, 1:1). Lesinurad(2.47 mmol, 1.0 g) and nicotinamide (2.47 mmol, 0.30 g) were dissolved in methanol (12 ml) and water (2 ml) and refluxed at 45-50 °C for 30 min. Colourless fine particles were crystallized during cooling to 10 °C at a rate of 1 °C min-1 (m.p. 178-180 °C).

Reference： [1]Current Patent Assignee: APOTEX INC - WO2018/85932, 2018, A1 Location in patent: Paragraph 0076
[2]Current Patent Assignee: LUPIN LIMITED - WO2018/150335, 2018, A1 Location in patent: Page/Page column 14; 15
[3]Current Patent Assignee: APOTEX INC - US2018/258057, 2018, A1 Location in patent: Paragraph 0190; 0194-0196; 0201
[4]Palanisamy, Vasanthi; Sanphui, Palash; Prakash, Muthuramalingam; Chernyshev, Vladimir [Acta Crystallographica Section C: Structural Chemistry, 2019, vol. 75, p. 1102 - 1117]

20
[ 878672-00-5 ]
[ 609-36-9 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
68%	In ethyl acetate at 20 - 25℃; for 26h;	B Reference Example B: Preparation of the Lesinurad: Proline Co-Crystal of WO 2015/095703 A1 The title solid form of Lesinurad was prepared according to the procedure in Example 14 of WO 2015/095703 A1 . A suspension of Lesinurad (1 g) in ethyl acetate (63 mL) was sonicated at room temperature for 30 minutes in order to achieve dissolution. Proline (570 mg) was added to the solution, and the resulting suspension was stirred at room temperature for 26 hours, at which time the suspension was isolated by filtration to afford a solid (872.9 mg, 68 % yield) having a PXRD diffractogram consistent with Figure 22 in WO 2015/095703 A1 . The solid, in an open container, was placed in a stability chamber maintained at 40 °C/75 % RH for 7 days. Following storage, the Lesinurad proline co-crystal had shown itself to be hygroscopic, with a mass increase of 38 wt %.

Reference： [1]Current Patent Assignee: SK CAPITAL PARTNERS LP - WO2018/85932, 2018, A1 Location in patent: Paragraph 0032; 0080

21
[ 2195353-60-5 ]
[ 878672-00-5 ]

Yield	Reaction Conditions	Operation in experiment
86%	With sodium hydroxide In isopropyl alcohol at 40 - 45℃; for 6h;	6 Method 1 for the preparation of compound I In a 1L four-necked flask, 600 ml of isopropanol was added.Charge IIa (83.5g, 0.1 mol) under stirring, raise the temperature to 40-45°C, and start dropping 20% sodium hydroxide solution.The pH of the reaction solution was maintained between 10.5-11.0, after 6 hours of reaction,Sampling HPLC analysis requires that the content of IIa is less than 0.1%, and other impurities do not exceed 0.3%.Reaching this standard represents the end of the reaction. If this criterion is not met, the reaction must be continued.After the reaction is completed, cool down to -5°C, add 10% hydrochloric acid solution, and adjust the pH to between 3.0-3.5.After 30 minutes of stirring, the PH value is re-tested. If the pH is not in this range, it needs to be adjusted again until it is stable.When the pH is stable, the isopropyl alcohol is decompressed and the internal temperature does not exceed 35°C.Concentrate until a large amount of solids have precipitated. The residue is extracted twice with 500 ml of isopropyl acetate.The combined organic layers were washed with 100 ml of saturated brine. The resulting organic layer was dried and filtered over anhydrous sodium sulfate.After drying, the organic layer is decolorized with activated charcoal for 2 hours and filtered with a sand core filter.The filtrate was concentrated under reduced pressure until a large amount of solids precipitated, and the residue was heated with 500 ml of cyclohexane and refluxed for 1 hour.Slowly cool to 20-25°C, crystallize for 3-4 hours, and filter to obtain wet product of compound I.Vacuum drying gave compound I69.6g in 86% yield.
40.31 g	With lithium hydroxide; ascorbic acid In water at 5 - 20℃; for 1h;	1.b b. Preparation of Lesinurad Nicotinamide Co-Crystal A flask containing a clear yellow solution of the compound of Formula (3-A) (35 g, 51.71 mmol) in 11 tetrahydrofuran (245 mL) was wrapped in 12 aluminum foil to exclude light and then heated to 30° C. 13 1,3-Dibromo-5,5-dimethylhydantoin (DBDMH) (22.18 g, 77.57 mmol) was charged in portions over 10 minutes and the reaction was stirred at 30° C. for 4.5 hours and monitored by HPLC. Following the completion of the bromination to afford the 14 compound of Formula (2-A), the reaction solution was cooled to room temperature and an aqueous solution of ascorbic acid (19.13 g, 108.60 mmol in 88 mL water) was added. The solution of the compound of Formula (2-A) was cooled to 5-10° C. and lithium hydroxide (14.86 g, 620.56 mmol) was added in portions, keeping the internal temperature of the solution below 20° C., to afford the intermediate lithium salt of Lesinurad (1). After 1 hour, the reaction was deemed complete by direct TLC (thin layer chromatography) of the reaction mixture (100% ethyl acetate). Water (175 mL) was charged to the lithium salt and the tetrahydrofuran was removed in vacuo at 30-35° C. The reaction solution was cooled to room temperature, washed with ethyl acetate (2×175 mL), and the aqueous phase was acidified to pH 2-3 using 4 wt % hydrochloric acid (350 mL, 390.93 mmol). Dichloromethane (280 mL) was charged to the flask and the mixture was stirred at room temperature for 15 minutes. The organic and aqueous layers were then separated and the organic phase was washed with brine solution (175 mL). An emulsion formed during the wash but with time (1.25 hours), a clean separation of the aqueous and organic layers was attained. The organic phase was dried over anhydrous sodium sulfate and a 1H-NMR sample was taken using 1,4-dimethoxybenzene as an internal standard to determine the amount of Lesinurad (1) in solution (40.31 g, 99.71 mmol). This assay was used to determine the amount of nicotinamide used in the subsequent step.

Reference： [1]Current Patent Assignee: LEPU MEDICAL TECHNOLOGY (BEIJING) COMPANY LIMITED - CN107739344, 2018, A Location in patent: Paragraph 0104; 0105; 0106; 0107; 0108
[2]Current Patent Assignee: SK CAPITAL PARTNERS LP - US2018/258057, 2018, A1 Location in patent: Paragraph 0190; 0191; 0193-0194; 0200

22
[ 2195353-61-6 ]
[ 878672-00-5 ]

Yield	Reaction Conditions	Operation in experiment
83%	With sodium hydroxide In isopropyl alcohol at 55℃; for 6h;	6 Preparation Method of Compound I 2 In a 2L four-necked flask, 1000 ml of isopropanol was added.Charge IIb (87.9 g, 0.1 mol) with stirring and raise the temperature to 55°C.A 20% sodium hydroxide solution was added dropwise to control the pH of the reaction solution between 10.5-11.0.After 6 hours of reaction, sample HPLC analysis requires that the content of IIb is less than 0.1%, and other impurities do not exceed 0.3%.Reaching this criterion represents the end of the reaction. If this criterion is not met, the reaction must be continued.After the reaction is completed, cool down to -5°C and add 10% hydrochloric acid solution.Adjust the pH to between 3.0-3.5, re-test the pH for 30 minutes,If the PH value does not need to be adjusted again in this interval until stable.When the pH is stable, the isopropyl alcohol is decompressed and the internal temperature does not exceed 35°C.Concentrate until a large amount of solids have precipitated. The residue is extracted twice with 500 ml of isopropyl acetate.The combined organic layers were washed with 100 ml of saturated brine. The resulting organic layer was dried and filtered over anhydrous sodium sulfate.After drying, the organic layer is decolorized with activated charcoal for 2 hours and filtered with a sand core filter.The filtrate was concentrated under reduced pressure until a large amount of solids precipitated, and the residue was heated with 500 ml of cyclohexane and refluxed for 1 hour.Slowly cool to 20-25°C, crystallize for 3-4 hours, and filter to obtain wet product of compound I.Vacuum drying gave Compound I67.2g in 83% yield.

Reference： [1]Current Patent Assignee: LEPU MEDICAL TECHNOLOGY (BEIJING) COMPANY LIMITED - CN107739344, 2018, A Location in patent: Paragraph 0104; 0109; 0110; 0111; 0112

23
[ 2227667-54-9 ]
[ 878672-00-5 ]

Yield	Reaction Conditions	Operation in experiment
91%	In ethyl acetate Reflux;	2.1 Example 2 ; lesinurad impurity (10) purification process step one:Take Resonader crude 10g containing impurities (10)(purity 99.50%, impurity 10 content 0.37%),Add 150 ml of ethyl acetate and heat to reflux for 1-2 hours.Then it is filtered down to room temperature,60-70°C drying for 12 hours yields 9.1g of refined product with a yield of 91%.99.91% purity (impurity (10) not detected). The liquid-phase detection maps of crude products and refined products are shown in Figure 1 and Figure 2.

Reference： [1]Current Patent Assignee: BEIJING VOBAN PHARMACEUTICAL TECH - CN108047148, 2018, A Location in patent: Paragraph 0054-0055

24
[ 878672-00-5 ]
[ 57-13-6 ]
[ 2416400-93-4 ]

Yield	Reaction Conditions	Operation in experiment
4.8 g	In acetone at 45 - 50℃;	7 Preparation ofCrystalline Form L6 of Lesinurad co-crystal 5.Og Lesinurad and 0.8g urea were dissolved in 30 ml acetone at 45-50. Thecrystallization started at 45 immediate after dissolution. The reaction mixture wascooled to 1 0 followed by filtration of the precipitated solid, dried under vacuum at45 for 15-1 6h to give 4.8g of the desired product
	In acetone at 45 - 50℃; for 0.5h;	2.1.5. Lesinurad-urea (LES-URE, 1:1) Form I. Lesinurad(2.47 mmol, 1.0 g) and urea (2.47 mmol, 0.15 g) were dissolved in acetone (6 ml) and refluxed at 40-45 °C for 30 min. On cooling to 10 °C at a rate of 1 °C min1, colourless fineparticles were crystallized (m.p. 158-160 °C).

Reference： [1]Current Patent Assignee: LUPIN LIMITED - WO2018/150335, 2018, A1 Location in patent: Paragraph 15
[2]Palanisamy, Vasanthi; Sanphui, Palash; Prakash, Muthuramalingam; Chernyshev, Vladimir [Acta Crystallographica Section C: Structural Chemistry, 2019, vol. 75, p. 1102 - 1117]

25
[ 878672-00-5 ]
[ 58-08-2 ]
[ 2416400-89-8 ]

Yield	Reaction Conditions	Operation in experiment
0.6 g	In ethyl acetate at 65 - 80℃;	8 Preparation ofCrystalline Form L7 of Lesinurad co-crystal 1.0 g of Lesinurad and 0.5 g of caffeine were dissolved in 20 ml ethyl acetate at 65-80. The solution was cooled to SeC followed by filtration of the white precipitate formed. The solid obtained was dried under vacuum at 45 for 2-3 h to give 0.6 g of desired product
	In ethyl acetate at 65 - 70℃; for 0.5h;	2.1.3. Lesinurad-caffeine (LES-CAF, 1:1). Lesinurad(2.47 mmol, 1.0 g) and caffeine (2.47 mmol, 0.48 g) weredissolved in ethyl acetate (20 ml) by heating at a rate of 1 °C min-1 and then refluxing at 65-70 °C for 30 min. Oncooling to 10 °C, colourless needle-shaped crystals wereharvested. The crystals were filtered off and dried underambient conditions (m.p. 145-147 C).

Reference： [1]Current Patent Assignee: LUPIN LIMITED - WO2018/150335, 2018, A1 Location in patent: Page/Page column 15; 16
[2]Palanisamy, Vasanthi; Sanphui, Palash; Prakash, Muthuramalingam; Chernyshev, Vladimir [Acta Crystallographica Section C: Structural Chemistry, 2019, vol. 75, p. 1102 - 1117]

26
[ 2243781-62-4 ]
[ 878672-00-5 ]

Yield	Reaction Conditions	Operation in experiment
	With lithium hydroxide; ascorbic acid In water at 20℃; for 20h;	3.c c. Preparation of Lesinurad (1) A flask containing a solution of the compound of Formula (3-B), 2 g, 1.97 mmol) in tetrahydrofuran (14 mL) was covered with foil to exclude light and heated to 30-35° C. 1,3-Dibromo-5,5-dimethylhydantoin (1.27 g, 4.44 mmol) was then added in 3 portions over 5 minutes, and stirred at 30-35° C. for 2 hours at which point the reaction was deemed complete by 1H NMR and TLC, and was quenched with aqueous ascorbic acid (1.04 g, 5.91 mmol in 5 mL water) to afford a solution containing compound (2-B). Lithium hydroxide (0.57 g, 23.64 mmol) was gradually charged to the mixture containing the compound of Formula (2-B) at room temperature in several portions to control the reaction temperature. After 2 hours, a second portion of lithium hydroxide (0.10 g, 3.94 mmol) was charged to the reaction to ensure basic conditions, following which the mixture was stirred at room temperature for 18 hours. After the hydrolysis was deemed complete by TLC, the tetrahydrofuran was removed in vacuo at 30-35° C. and the reaction was cooled to room temperature. Water (10 mL) was charged to the flask and the mixture was acidified to pH 2-3 using 4 wt % hydrochloric acid (14 mL, 15.63 mmol) to form a solution with a gummy precipitate. Dichloromethane (16 mL) was charged to the flask and stirred for 20 minutes. The resulting layers were separated and the organic phase was washed brine (10 mL) and dried over anhydrous sodium sulfate before being concentrated in vacuo at 30-35° C. to afford Lesinurad (1) as a foamy off-white solid (1.70 g; 30% yield from the compound of Formula (7-B); HPLC purity=93 area %).

Reference： [1]Current Patent Assignee: SK CAPITAL PARTNERS LP - US2018/258057, 2018, A1 Location in patent: Paragraph 0207-0208; 0210

27
[ 1158970-76-3 ]
[ 79-08-3 ]
[ 878672-00-5 ]

Yield	Reaction Conditions	Operation in experiment
80%	With potassium hydrogencarbonate In water at 60℃; for 2h;	5.d d. Preparation of Lesinurad (1) A flask was charged with the compound of Formula (9) (0.2 g, 0.58 mmol), water (1 mL), and potassium bicarbonate (0.06 g, 0.62 mmol) and the resulting white suspension was stirred at room temperature. Bromoacetic acid (0.09 g, 0.62 mmol) was charged to the reaction and a vigorous effervescence was observed. A second portion of potassium bicarbonate (0.06 g, 0.62 mmol) was then charged, and the reaction suspension was heated to 60° C. After 2 hours, a clear solution was observed and was then cooled to room temperature after confirming reaction completion by TLC (1:1 ethyl acetate:heptanes; starting material Rf=0.44, product Rf=baseline). The reaction mixture was acidified to a pH of 2-3 using 4 wt % hydrochloric acid whereupon a white precipitate was observed. The precipitate was collected by filtration, washed with water (2×0.4 mL), and dried in vacuo at 35-40° C. to afford Lesinurad (1) as a white solid (0.19 g; 80% yield from the compound of Formula (9).

Reference： [1]Current Patent Assignee: SK CAPITAL PARTNERS LP - US2018/258057, 2018, A1 Location in patent: Paragraph 0230-0231

28
[ 98-10-2 ]
[ 878672-00-5 ]
[ 2303904-01-8 ]

Yield	Reaction Conditions	Operation in experiment
40.1%	Stage #1: 2-[5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}acetic acid With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane for 0.5h; Cooling with ice; Stage #2: benzenesulfonamide In dichloromethane at 20℃; for 12h;
39.8%	Stage #1: benzenesulfonamide; 2-[5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}acetic acid With dmap In dichloromethane for 0.25h; Cooling with ice; Stage #2: With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20 - 30℃; for 12h; Cooling with ice;	1 Example 1. Synthesis of Compound S1 Will Lesinurad (1g, 2.47mmol),4-dimethylaminopyridine (0.36 g, 2.97 mmol),Methylsulfonamide (0.28 g, 2.97 mmol) was dissolved in 50 mL of anhydrous dichloromethane and stirred in ice bath15 minutes,Add EDC·HCl(0.57g, 2.97mmol),The temperature was slowly raised to room temperature, and the reaction was further stirred for 12 hours (the reaction was completed by TLC). Reaction mixtureConcentration under reduced pressure, purification by column chromatography (300-400 mesh silica gel column, eluent methanol: dichloromethane: glacial acetic acid = 1:20:0.35) gave 0.90 g of a white solid, yield 39.8%,

Reference： [1]Zhao, Tong; Meng, Qing; Sun, Zhuosen; Chen, Yanyu; Ai, Wei; Zhao, Zean; Kang, Dongwei; Dong, Yue; Liang, Ruipeng; Wu, Ting; Pang, Jianxin; Liu, Xinyong; Zhan, Peng [Journal of Medicinal Chemistry, 2020, vol. 63, # 19, p. 10829 - 10854]
[2]Current Patent Assignee: SHANDONG UNIVERSITY - CN109134391, 2019, A Location in patent: Paragraph 0023; 0037-0039

29
[ 1158970-76-3 ]
[ CAS Unavailable ]
[ 878672-00-5 ]

Yield	Reaction Conditions	Operation in experiment
92.2%	Stage #1: 5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazole-3-thiol; sodium monochloroacetic acid With N-ethyl-N,N-diisopropylamine In acetone at 35 - 40℃; Stage #2: With hydrogenchloride In water at 0 - 5℃;	7 Example 7 Add compound 5 (34.62g, 100mmol) and acetone (173mL) to the three-necked flask. After stirring, add DIPEA (25.85g, 200mol), sodium chloroacetate (12.23g, 105mmol), heat to 35 ~ 40C, and react for 6 ~ 8 hours. Finish concentrating to remove some solvents, slowly add dilute hydrochloric acid (5%, 323mL), slowly cool to 0 ~ 5C to beat, filter, and reuse the crude productMethanol and water were recrystallized to obtain Resinade product 6 (37.27 g, 92.2%, purity greater than 99.8%)

Reference： [1]Current Patent Assignee: JIANGSU YUTIAN PHARMACEUTICAL - CN110878057, 2020, A Location in patent: Paragraph 0051-0053

Purity	Size	Price	VIP Price	USA Stock *0-1 Day	Global Stock *5-7 Days	Quantity
{[ item.p_purity ]}	{[ item.pr_size ]}	{[ getRatePrice(item.pr_usd, 1,1) ]} {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]}	{[ getRatePrice(item.pr_usd, 1,1) ]}	Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} {[ getRatePrice(item.pr_usd,1,item.mem_rate) ]}	{[ item.pr_usastock ]}	Inquiry -	{[ item.pr_chinastock ]}	Inquiry -

CAS No. :	878672-00-5	MDL No. :	MFCD22572730
Formula :	C₁₇H₁₄BrN₃O₂S	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	FGQFOYHRJSUHMR-UHFFFAOYSA-N
M.W :	404.28	Pubchem ID :	53465279
Synonyms :	RDEA594	Chemical Name :	2-((5-Bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-yl)thio)acetic acid

Num. heavy atoms :	24
Num. arom. heavy atoms :	15
Fraction Csp3 :	0.24
Num. rotatable bonds :	5
Num. H-bond acceptors :	4.0
Num. H-bond donors :	1.0
Molar Refractivity :	97.33
TPSA :	93.31 Å²

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	Yes
CYP2C9 inhibitor :	Yes
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.42 cm/s

Log Po/w (iLOGP) :	2.53
Log Po/w (XLOGP3) :	4.71
Log Po/w (WLOGP) :	4.17
Log Po/w (MLOGP) :	3.57
Log Po/w (SILICOS-IT) :	3.41
Consensus Log Po/w :	3.68

[ CAS No. 878672-00-5 ] {[proInfo.proName]}

Quality Control of [ 878672-00-5 ]

Related Doc. of [ 878672-00-5 ]

Product Details of [ 878672-00-5 ]

Calculated chemistry of [ 878672-00-5 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 878672-00-5 ]

Application In Synthesis of [ 878672-00-5 ]

[ 878672-00-5 ] Synthesis Path-Downstream 1~29

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	0.0
Bioavailability Score :	0.56

Log S (ESOL) :	-5.45
Solubility :	0.00145 mg/ml ; 0.00000358 mol/l
Class :	Moderately soluble
Log S (Ali) :	-6.4
Solubility :	0.000162 mg/ml ; 0.0000004 mol/l
Class :	Poorly soluble
Log S (SILICOS-IT) :	-5.49
Solubility :	0.00131 mg/ml ; 0.00000324 mol/l
Class :	Moderately soluble

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	2.0
Synthetic accessibility :	2.86

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Precautionary Statements-General
Code	Phrase
P101	If medical advice is needed,have product container or label at hand.
P102	Keep out of reach of children.
P103	Read label before use
Prevention
Code	Phrase
P201	Obtain special instructions before use.
P202	Do not handle until all safety precautions have been read and understood.
P210	Keep away from heat/sparks/open flames/hot surfaces. - No smoking.
P211	Do not spray on an open flame or other ignition source.
P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
P223	Keep away from any possible contact with water, because of violent reaction and possible flash fire.
P230	Keep wetted
P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
P234	Keep only in original container.
P235	Keep cool
P240	Ground/bond container and receiving equipment.
P241	Use explosion-proof electrical/ventilating/lighting/equipment.
P242	Use only non-sparking tools.
P243	Take precautionary measures against static discharge.
P244	Keep reduction valves free from grease and oil.
P250	Do not subject to grinding/shock/friction.
P251	Pressurized container: Do not pierce or burn, even after use.
P260	Do not breathe dust/fume/gas/mist/vapours/spray.
P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling