Resolution method for axis chiral enantiomers of lesinurad
11365180 · 2022-06-21
Assignee
Inventors
Cpc classification
A61P19/06
HUMAN NECESSITIES
International classification
Abstract
A resolution method of axial chiral enantiomers of lesinurad (2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid) adopts inexpensive and readily available quinoline natural products and derivatives thereof, such as quinine, cinchonine, quinidine or cinconidine as resolving agents to react with lesinurad racemate in an organic solvent to form a salt, and the salt is dissociated by acidification so as to obtain optically pure (R)- or (S)-2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid. The method can give axial chiral enantiomer of lesinurad in R configuration with a chiral purity ee of up to 100% and a total yield of 90% or more. The obtained axial chiral enantiomer of lesinurad in S configuration can reach a chiral purity ee of up to 99.9% and a total yield of 80% or more.
Claims
1. A resolution method of axial chiral enantiomers of lesinurad, comprising: (1) reacting axial chiral lesinurad racemate with a first resolving agent in a first solvent to form a first reaction solution, filtering the first reaction solution to obtain a first solid and a mother liquor, and subjecting the first solid to acid hydrolysis in a second solvent to obtain a first compound; and (2) concentrating the mother liquor obtained in step (1) to obtain a second solid, and subjecting the second solid to acid hydrolysis in a third solvent to obtain a second compound, wherein the first resolving agent is quinine (CAS:130-95-0), quinidine (CAS:56-54-2), cinchonidine (CAS:485-71-2), or cinchonine (CAS:118-10-5), and wherein the first compound comprises more R-(−)-lesinurad than S-(+)-lesinurad and the second compound comprises more S-(+)-lesinurad than R-(−)-lesinurad, or wherein the first compound comprises more S-(+)-lesinurad than R-(−)-lesinurad and the second compound comprises R-(−)-lesinurad than S-(+)-lesinurad.
2. The method according to claim 1, wherein the first solvent, the second solvent, the third solvent are the same or different, and are independently selected from ester solvents, alcohol solvents, ketone solvents, ether solvents, aromatic hydrocarbon solvents, and mixtures thereof.
3. The method according to claim 1, wherein the acid hydrolysis in step (1) and the acid hydrolysis in step (2) are conducted at a same or different pH value independently ranging from 1 to 4.
4. The method according to claim 1, wherein the molar ratio of lesinurad racemate to the first resolving agent in step (1) is (0.5-1.5):1.
5. The method according to claim 1, wherein, in step (1), when the first resolving agent is quinine or quinidine, the first solvent is an ester solvent or a ketone solvent; and in step (1), when the first resolving agent is cinchonidine or cinchonine, the first solvent is an aromatic hydrocarbon solvent.
6. The method according to claim 1, further comprising cooling down the first reaction solution to a temperature of 10-30° C., or in an ice-water bath under stirring for 2-120 minutes.
7. The method according to claim 1, wherein, the method further comprises subjecting the first solid to one or more recrystallizations before the acid hydrolysis in step (1) and/or subjecting the second solid to one or more recrystallizations before the acid hydrolysis in step (2).
8. The method according to claim 1, further comprising step (3): reacting the second compound with a second resolving agent to form a second reaction solution, cooling down the second reaction solution, filtering the second reaction solution to obtain a third solid, and subjecting the third solid to acid hydrolysis, wherein the second resolving agent 2 is quinine, quinidine, cinchonidine, or cinchonine.
9. The method according to claim 1, further comprising recovering the first resolving agent by: separating the reaction solution from the acid hydrolysis in step (1) or in step (2) to obtain an aqueous phase; adjusting a pH value of the aqueous phase to 9-11; and precipitating and filtering the first resolving agent from the aqueous phase.
10. The method according to claim 8, further comprising recovering the second resolving agent by: separating the reaction solution from the acid hydrolysis in step (3) to obtain an aqueous phase; adjusting a pH value of the aqueous phase to 9-11; and precipitating and filtering the second resolving agent from the aqueous phase.
Description
BRIEF DESCRIPTION OF THE DRAWINGS
(1)
(2)
(3)
(4)
(5)
EXAMPLES
(6) Hereinafter, the invention is further described in detail with reference to the specific examples. The following examples are intended to give an exemplary description and explanation of the invention, rather than limit the protection scope of the invention. All realizable technical solutions based on the above contents of the invention are deemed to fall within the protection scope of the invention.
(7) The invention involves the addition amounts, contents and concentrations of various substances, and the percentages mentioned herein all refer to percentages by mass, unless otherwise specified.
(8) Experimental Reagents and Detection Methods
(9) 1. Reagents
(10) Reagents: the organic solvents, acidifying agents and alkalinizing agents, etc., used in the examples of the invention, are all commercially available and of analytical grade, unless otherwise noted, and can be used directly.
(11) 2. Detection Methods
(12) Polarimeter: Automatic Polarimeter P850
(13) Mass spectrometer: Agilent 6120 Quadrupole LC/MS Mass Spectrometer (ES-API source, positive ion mode)
(14) The chromatographic conditions for chiral detection:
(15) Column: Chrialpak AD-H, 4.6×250 mm, 5 μm
(16) Mobile phase: n-hexane:anhydrous ethanol:diethylamine=90:10:0.2 Detection
(17) wavelength: 225 nm
(18) Column temperature: 30° C.
(19) Injection volume: 10 μl
(20) Flow rate: 1.0 ml/min.
Example 1
(21) Racemic lesinurad (2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid) was synthesized according to the method described in patent documents WO2009070740A2, CN103524440A or WO2014008295A1. The specific synthetic route is as follows:
(22) ##STR00006##
4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazol-thiol (compound A, 14.5 g, 54.2 mmol) was dissolved in 150 ml DMF, potassium carbonate (11.2 g, 81.3 mmol) was added to the solution, and then methyl bromoacetate (5.88 g, 54.2 mmol) was added dropwise. After the addition was complete, the solution was raised to 50° C. and kept for 4 hours. After the reaction was complete, the reaction solution was partitioned between water (100 ml) and ethyl acetate (100 ml). The aqueous phase was extracted with ethyl acetate (2×100 ml). The organic phases were combined, washed with saline (6×150 ml), dried over anhydrous sodium sulfate for 1 h, and filtrated with suction. The filtrate was evaporated to dryness to obtain 15.6 g white-like powder, which was intermediate B, with a yield of 85%. LC-MS (m/z): [M+H].sup.+=340.1.
(23) Intermediate B (46.0 g, 135.7 mmol) was dissolved in THE (300 ml) at 35-42° C. and stirred until clear. The solution was cooled down to 27-32° C., NBS (33.764 g, 189.7 mmol) was added, and the reaction solution was kept at the constant temperature for 30 mins (as the reaction was exothermic and the temperature would rise slowly, the temperature should be properly controlled). The reaction was monitored by TLC (PE:EA=1:1). After the reaction was complete, the reaction solution was cooled down to 2-7° C. While maintaining at that temperature, toluene (460 ml) was added to the solution, and then purified water (460 ml) was added dropwise (as the process was exothermic, water should be added slowly). The solution was stirred for 10 mins and then let stand. The system separated into layers. The aqueous phase was removed off. The organic phase was washed with sodium metabisulfite solution until the aqueous phase was colorless or of light-color (the temperature was kept at 2-7° C. during the washing process). The organic phase was heated to 18-25° C., and washed with water (230 ml) and then sodium bicarbonate solution until pH>8. The organic phase was a solution of intermediate C in toluene, which was directly used in the next step. LC-MS (m/z): [M+H].sup.+=420.0.
(24) At 10-15° C., to the organic phase of intermediate C, a sodium hydroxide solution (230 ml) was added and then stirred for 2-3 h. The organic phase was monitored by TLC (PE:EA=1:1). After the reaction was complete, the solution was partitioned, the organic phase was washed with water (100 ml) and the aqueous phases were combined. Ethyl acetate (100 ml) was added to the aqueous phase and the organic phase was discarded. At 40° C., the aqueous phase was evaporated under reduced pressure until no distillate was evaporated out. The aqueous phase was cooled down to 0-5° C. and stirred for 2 h, and a white solid was precipitated. After suction filtration, the filter cake was washed with purified water, and dried under vacuum at 40-45° C. for 30 h to obtain intermediate D. Intermediate D was dissolved in water. HBr (2 M) was added dropwise to the solution, the pH of the system was adjusted to 4-5, and a white solid was precipitated. After suction filtration and drying, 41.7 g white solid was obtained, which was lesinurad, with a yield of 76%. LC-MS (m/z): [M+H].sup.+=404.0. (Specific rotation [a].sup.20.sub.D=0, C=1, CH.sub.3OH). It was detected by high-performance liquid chromatography (HPLC, with the result shown in
Example 2
(25) ##STR00007##
(26) Salt formation: 10 g of lesinurad racemate (1.0 eq.) was added to ethyl acetate (100 ml). The mixture was heated to 70° C., and quinine (8.1 g, 1.0 eq.) was slowly added under stirring. The mixture was heated to reflux, and kept at the constant temperature for 1 h. The reaction system was slowly and naturally cooled down to room temperature, then kept in an ice-water bath and stirred for 30 mins. After filtration, the filter cake was washed with ethyl acetate (20 ml) to obtain 9.1 g white solid powder A (salt of lesinurad in R configuration), ee=97.9%. The filtrate was concentrated by rotary evaporation and dried to obtain 9.0 g white solid powder C (salt of lesinurad in S configuration), ee=94.5%.
(27) Recrystallization: 9.1 g of the above white solid powder A was added to ethyl acetate (90 ml) under stirring. The mixture was heated to reflux, and kept at the constant temperature for 1 h. The reaction system was slowly and naturally cooled down to room temperature, then kept in an ice-water bath and stirred at the constant temperature for 30 mins. After filtration, the filter cake was washed with ethyl acetate (20 ml) to obtain 8.5 g white solid powder B (salt of lesinurad in R configuration), ee=100%. It was detected by high-performance liquid chromatography (HPLC), with the result shown in
(28) Acid dissociation: 8.5 g of the above white solid powder B was dissolved in dichloromethane (85 ml), and then H.sub.2O (85 ml) was added. To the mixture, diluted hydrochloric acid (2 mol/L) was added dropwise under stirring to adjust the pH to 2-3. The mixture was further stirred at room temperature for 15 mins, and then separated into phases. The obtained aqueous phase was recovered for use. The organic phase was washed with water/diluted hydrochloric acid (2 mol/L) (20 ml/0.5 ml), then washed with water (20 ml), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and dried to obtain 4.54 g white solid, i.e. (R)-2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid (specific rotation [a].sup.20.sub.D=−9.0°−−12.5°, C=1, CH.sub.3OH), ee=100%. It was detected by high-performance liquid chromatography (HPLC), with the result shown in
(29) The recovered aqueous phase after the above acid dissociation was added into a 500 ml reaction flask, and a NaOH solution (2 mol/L) was dropwise added under stirring at 0° C. to adjust the pH to 10. The system turned into a white cloudy mixture. The mixture was further stirred at room temperature for 15 mins, filtered, and dried to obtain 3.5 g white solid quinine. ESI(M+H)=325.
Example 3
(30) ##STR00008##
(31) Salt formation: 10 g of lesinurad racemate (1.0 eq.) was added to toluene (100 ml). The mixture was heated to 105° C., and cinchonine (7.3 g, 1.0 eq.) was slowly added under stirring. The mixture was heated to reflux, and kept at the constant temperature for 1 h. The reaction system was slowly and naturally cooled down to room temperature, then kept in an ice-water bath and stirred for 30 mins.
(32) After filtration, the filter cake was washed with toluene (20 ml) to obtain 8.9 g white-like solid (salt of lesinurad in S configuration, a crude product), ee=80%. The filtrate was concentrated by rotary evaporation and dried to obtain 9.1 g white solid powder (salt of lesinurad in R configuration, a crude product), ee=40%.
(33) Recrystallization: 8.9 g of the above white-like solid (salt of lesinurad in S configuration, a crude product) was added to toluene (90 ml) under stirring. The mixture was heated to reflux, and then kept at the constant temperature for 1 h. The reaction system was slowly and naturally cooled down to room temperature, then kept in an ice-water bath and stirred for 30 mins. After filtration, the filter cake was washed with toluene (20 ml) to obtain 5.5 g white solid (salt of lesinurad in S configuration), ee=99.9%. It was detected by high-performance liquid chromatography (HPLC), with the result shown in
(34) Acid dissociation: 5.5 g of the above white solid was dissolved in dichloromethane (60 ml), and H.sub.2O (60 ml) was added. To the mixture, diluted hydrochloric acid (2 mol/L) was added dropwise under stirring to adjust the pH to 2-3. The solution was further stirred at room temperature for 15 mins, and then separated into phases. The obtained aqueous phase was recovered for use. The organic phase was washed with water/diluted hydrochloric acid (2 mol/l) (15 ml/0.4 ml), then washed with water (15 ml), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and dried to obtain 3.1 g white solid, i.e. (S)-2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid, ee=99.9% (specific rotation [a].sup.20.sub.D=+9.5°-+12.5°, C=1, CH.sub.3OH). It was detected by high-performance liquid chromatography (HPLC), with the result shown in
Example 4
(35) ##STR00009##
(36) Acid dissociation: 9.0 g of the obtained white solid powder C (salt of lesinurad in S configuration) in Example 2 was dissolved in dichloromethane (90 ml), and H.sub.2O (90 ml) was added. To the mixture, diluted hydrochloric acid (2 mol/l) was added dropwise under stirring to adjust the pH to 2-3. The solution was further stirred at room temperature for 15 mins, and then separated into phases. The obtained aqueous phase was recovered for use. The organic phase was washed with water/diluted hydrochloric acid (2 mol/l) (20 ml/0.5 ml), then washed with water (20 ml), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and dried to obtain 4.75 g white solid, i.e. (S)-2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid (a crude product). ESI(M+H)=404.
(37) Salt formation: 4.75 g of the above white solid was added to toluene (50 ml). The mixture was heated to 105° C., and cinchonine (3.5 g, 1.0 eq.) was slowly added under stirring. The mixture was heated to reflux, and kept at the constant temperature for 1 h. The reaction system was slowly and naturally cooled down to room temperature, then kept in an ice-water bath and stirred for 30 mins. After filtration, the filter cake was washed with toluene (20 ml) to obtain 7.8 g white-like solid (salt of lesinurad in S configuration), ee=98.7%.
(38) Recrystallization: 7.8 g of the above white-like solid (salt of lesinurad in S configuration) was added to toluene (90 ml) under stirring. The mixture was heated to reflux, and kept at the constant temperature for 1 h. The reaction system was slowly and naturally cooled down to room temperature, then kept in an ice-water bath and stirred at the constant temperature for 30 mins. After filtration, the filter cake was washed with toluene (20 ml) to obtain 7.3 g white solid (salt of lesinurad in S configuration), ee=99.9%.
(39) Acid dissociation: 6.9 g of the above white solid was dissolved in dichloromethane (70 ml), and H.sub.2O (70 ml) was added. To the mixture, diluted hydrochloric acid (2 mol/l) was added dropwise under stirring to adjust the pH to 2-3. The solution was further stirred at room temperature for 15 mins, and then separated into phases. The obtained aqueous phase was recovered for use. The organic phase was washed with water/diluted hydrochloric acid (2 mol/l) (15 ml/0.4 ml), then washed with water (15 ml), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and dried to obtain 4.2 g white solid, i.e. (S)-2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazole-3-ylthio)acetic acid, ee=99.9%, with a total yield of 82.8%. ESI(M+H)=404.
(40) The above illustrates the exemplary embodiments of the invention. However, the embodiments are not intended to limit the protection scope of the invention. Any modification, equivalent alternative, and improvement made without departing from the spirit and principle of the invention should fall within the protection scope of the invention.