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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),
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid methyl ester[ No CAS ]
[ 1151516-14-1 ]
Yield
Reaction Conditions
Operation in experiment
94.12%
With sodium hydroxide; In ethanol; water; at 50℃; for 2h;
In a 100 ml three-necked flask equipped with a stirrer and a thermometer, 25 ml of ethanol was added, the intermediate (V) 4.18g, stirring at room temperature, adding sodium hydroxide / water = 0.42g / 20ml,The temperature was raised to 50 C and stirred for 2 hours. After completion of the reaction, the solvent was removed by concentration, recrystallized from 95% ethanol, filtered and dried to obtain 4.00 g of exocetrol (VI), yield 94.12%. The resulting product spectrum is consistent with the literature.
With water; sodium hydroxide; In ethanol; at 20 - 25℃;pH 12;
Aqueous sodium hydroxide solution (1N, 3.0 L, 3.0 mol, 1.25 eq) was added to a cooled (15-18 C.) mixture of methyl 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate-form 2 (1.0 kg, 2.39 mol, 1 eq) and ethanol (9 L), at a rate to maintain an internal temperature<25 C.: The mixture was then stirred at 20-25 C. (maintaining pH>12), while monitoring by HPLC and considered complete when the sum of methyl and ethyl esters<0.5%, (3 hours). The mixture was filtered through a medium frit funnel (10-16 micron) and the filtrate concentrated in vacuo (40 C.) to a final volume of 5.2 L. Water (0.6 L) was added and the solution cooled to 0-5 C. with stirring. The resulting slurry was warmed (17-18 C.) over 1 h, then cooled (0-5 C.) over 2-3 h, and held at 0-5 C. for an additional 6-9 h. The slurry was then filtered through a jacketed filter funnel (0-5 C.) lined with filter paper (3 micron) or filter cloth. The resulting cake was washed with pre-chilled (3-5 C.) water (3×1.25 L), allowed to de-liquor on the funnel (at least 3 h), and further dried in a vacuum oven (18-25 C., nitrogen sweep) until water content<13% w/w (0.8 days). Sodium 2-(5-amino-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate was isolated as a light yellow solid (696.4 g; KF=13%).
With sodium hydroxide; In water; toluene; at 18 - 25℃;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...
2.7 g
With water; sodium hydroxide; In tetrahydrofuran; for 2h;
Compound C (4.8g, 0.0115mol) was dissolved in tetrahydrofuran (30 mL) was added 0.5N aqueous sodium hydroxideLiquid (28mL, 1.2eq), the reaction was stirred 2h. Sampling test compound C after completion of the reaction, the reaction solution was spin-dry the residueRecrystallization from water to give 2.7g of white solid which is intermediate D.
2.7 g
With sodium hydroxide; In tetrahydrofuran; water; for 2h;
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.
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>
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid dicyclohexylamine[ No CAS ]
[ 1151516-14-1 ]
Yield
Reaction Conditions
Operation in experiment
99%
In a 250 mL single-mouth type flask equipped with polytetrafluoroethylene magnet,(5-bromo-4- (4-cyclopropylnaphthalen-1-yl) -4H-1,2,4-triazol-3-ylthio] acetic acid dicyclohexylamine salt , 17.1 mmol),Add 50mL methanol, stir, room temperature reaction 30min,NaOH (0.68 g, 17.1 mmol) was added,The reaction was continued at room temperature for 2 h, 50 mL of cyclohexane was added,Continue stirring for 1 h.The reaction solution was transferred to a separatory funnel, the lower methanol phase was separated, washed three times with cyclohexane (50 mL x 3)The solvent was removed by steaming,To give a pale yellow solid2- [5-bromo-4- (4-cyclopropylnaphthalen-1-yl) -4H-1,2,4-triazol-3-ylthio]Yield 99%.