A method for splitting isavuconazole intermediate 4

Abstract

The present invention provides a method for resolving isavuconazole intermediate 4, belonging to the field of pharmaceutical intermediates. The present invention uses R-(+)-α-methylbenzylamine as a resolving agent to resolve the crude product of isavuconazole intermediate 4, and utilizes the solubility differences of isavuconazole intermediate 4, enantiomers and diastereoisomers in the crude product of isavuconazole intermediate 4 at different pH values to achieve the purpose of separation and purification. The present invention simplifies the production processes such as drying of the crude product of isavuconazole intermediate 4 and recrystallization of amine salts, with simpler operation, lower energy consumption, and reduced material cost and production cost.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical intermediates, and particularly to a method for resolving isavuconazole intermediate 4. Background Art

[0002] Isavuconazole is a novel broad-spectrum antifungal drug, which is active against yeasts, molds and dimorphic fungi, and is mainly used for the treatment of invasive aspergillosis and mucormycosis.

[0003] The molecular weight of isavuconazole: 815; CAS registration number: 946075-13-4; the structural formula is shown in formula (1):

[0004]

[0005] The preparation of isavuconazole has a complex process. First, intermediate M8 (CAS No. 368421-58-3) needs to be prepared, and there are mainly the following two methods.

[0006] Method 1: The specific synthesis route is as shown in Route 1 [Organic Process Research & Development 2009, 13, 716–728]. In this synthesis route, LiHMDS is used, and the reaction needs to be carried out at low temperature, with harsh conditions and expensive reagents, which is not conducive to industrial production. Acetone cyanohydrin is used to introduce a cyano group in the synthesis process. Acetone cyanohydrin is a highly toxic substance, with a high safety risk and is not conducive to safe production.

[0007]

[0008] The synthesis route of Method 2 is as shown in Route 2 [CN105801500B and CN1223564C]. It avoids the expensive LiHMDS, and at the same time uses amide dehydration to generate a cyano group, avoiding the highly toxic reagent acetone cyanohydrin, which is conducive to industrial safe production. In Method 2, after ethyl 2-bromopropionate reacts with zinc to form a zinc reagent, it reacts with 1-(2,5-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone (T001-M2), and then the ester bond is hydrolyzed with sodium hydroxide to obtain a crude product of T001-M4 (crude product of isavuconazole intermediate 4), which contains four configurations: (2R,3R), enantiomer (2S,3S)), and diastereomers (2S,3R), (2R,3S). How to resolve the crude product of isavuconazole intermediate 4 to obtain (2R,3R)-3-(2,5-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butyric acid is a current research hotspot.

[0009]

[0010] Therefore, a splitting method is needed to remove the enantiomer ((2S,3S)) and diastereoisomers ((2S,3R) and (2R,3S)) in the isavuconazole intermediate 4 with the configuration of (2R,3R).

[0011] Chinese Patent CN104507917B discloses that the reaction solution of ethyl 3-(2,5-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl) butyrate (T001-M3) is precipitated, and the precipitate is collected after centrifugation to obtain the racemate ((2R,3R) and (2S,3S)). The diastereoisomers (2R,3S) and (2S,3R) are removed by remaining in the mother liquor, and then the racemate ((2R,3R) and (2S,3S)) of T001-M3 is subjected to enzymatic resolution to obtain T001-M3(2R,3R).

[0012] Based on Patent CN104507917B, Chinese Patent CN105801500B precipitates the reaction solution of ethyl 3-(2,5-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl) butyrate (T001-M3) (stir for 72 h) to remove the diastereoisomers (2R,3S) and (2S,3R). The obtained racemate ((2R,3R) and (2S,3S)) of T001-M3 is hydrolyzed to obtain the racemate ((2R,3R) and (2S,3S)) of T001-M4, and then with R-(+)-α-methylbenzylamine as the resolving agent, in an anhydrous lower alcohol such as methanol, ethanol, isopropanol or n-butanol, the racemate of T001-M4 is salted with the resolving agent under reflux conditions, cooled to 20 - 30 °C for crystallization, and the filter cake is obtained by filtration. The filter cake is recrystallized twice in an organic solvent and dried to obtain the amine salt. The amine salt is dissolved in an alkaline solution with pH > 9, and dichloromethane is used for extraction to recover the resolving agent R-(+)-α-methylbenzylamine. The pH of the aqueous phase is adjusted to 3 - 4 for crystallization, filtration, and drying to obtain T001-M4(2R,3R).

[0013] However, the above method has the following defects: (1) From theoretical analysis, the crude product of T001-M4 contains two chiral centers, that is, it contains three chiral impurities. This method uses a two-step purification method to remove these three chiral impurities. First, the M3 reaction solution precipitation method (stirring for 72 h) is used to remove the diastereoisomers (2R,3S) and (2S,3R) of ethyl 3-(2,5-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butyrate (T001-M3); the obtained T001-M3 racemate ((2R,3R) and (2S,3S)) is hydrolyzed to the T001-M4 racemate ((2R,3R) and (2S,3S)), and then the resolving agent R-(+)-α-methylbenzylamine is used for resolution to remove the enantiomer (2S,3S). (2) The crude product of this method needs to be dried. The solvent for salting with the resolving agent R-(+)-α-methylbenzylamine is a lower alcohol, the salting temperature is relatively high, and the amine salt needs to be recrystallized twice. The operation process is complex and the production cost is high. Summary of the Invention

[0014] In view of this, the present invention provides a method for resolving isavuconazole intermediate 4 (CAS No. 483340-19-8), which uses R-(+)-α-methylbenzylamine as a resolving agent to resolve the crude product of isavuconazole intermediate 4, and utilizes the solubility difference of different isomers after salting with the resolving agent at different pH values to achieve the purpose of separation and purification.

[0015] The crude product of isavuconazole intermediate 4 mainly contains the following four components: (2R,3R)-3-(2,5-difluorophenyl)-3-hydroxy-2-methyl-4-(1,2,4-triazol-1-yl)butyric acid (isavuconazole intermediate 4), as shown in formula (2); enantiomers, as shown in formula (3); and diastereoisomers, as shown in formula (4) and formula (5):

[0016]

[0017]

[0018] The method for resolving isavuconazole intermediate 4 in this application includes the following steps:

[0019] (1) Dissolve the crude product of isavuconazole intermediate 4 in an aqueous sodium hydroxide solution, and control the pH≥10;

[0020] (2) Add the resolving agent R-(+)-α-methylbenzylamine under the condition of a temperature of 20-30°C, stir and react, and then slowly adjust the pH to 8.00-8.30 with 10% hydrochloric acid by mass ratio. After stirring and crystal cultivation, centrifuge to obtain a filter cake and a filtrate. The enantiomer is removed by salting with the resolving agent in the filter cake, and M4 and the diastereoisomer are dissolved in water in the form of a salt with the resolving agent;

[0021] (3) Slowly add hydrochloric acid with a mass ratio of 10% dropwise to the filtrate, adjust the pH of the filtrate to 3.8 - 4.2, stir for crystal cultivation, collect the solid after centrifugation, and obtain (2R,3R)-3-(2,5-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butyric acid. After stirring for crystal cultivation, the target compound precipitates after being freed, and the isosaprazole intermediate 4 (T001-M4) can be obtained by centrifugation. The diastereoisomers are removed in the filtrate in the form of salts with the resolving agent.

[0022] Preferably, the crude isosaprazole intermediate 4 contains (2R,3R)-3-(2,5-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butyric acid, (2S,3S)-3-(2,5-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butyric acid, (2S,3R)-3-(2,5-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butyric acid, and (2R,3S)-3-(2,5-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butyric acid.

[0023] Preferably, the stirring reaction time in step (2) is 30 - 35 min.

[0024] Preferably, the stirring time for crystal cultivation in step (2) is 1 h.

[0025] Preferably, the stirring time for crystal cultivation in step (3) is 2 h.

[0026] Compared with the prior art, the present invention has the following beneficial effects:

[0027] The present application provides a method for resolving the isosaprazole intermediate. Using R-(+)-α-methylbenzylamine as the resolving agent, the crude isosaprazole intermediate 4 is resolved. (2R,3R)-3-(2,5-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butyric acid, enantiomers, and diastereoisomers contain carboxyl groups, and the resolving agent contains an amino group. After the carboxyl group and the amino group form a salt, the separation and purification are achieved by utilizing the solubility differences at different pH values. The present invention separates and removes enantiomers and diastereoisomers through different pH values by forming a salt once. Moreover, the present invention simplifies the production processes such as drying the crude isosaprazole intermediate 4 and recrystallizing the amine salt, with simpler operation, lower energy consumption, and reduced material and production costs. Detailed Embodiments

[0028] The present invention will be further described below in conjunction with embodiments.

[0029] Example 1

[0030] A method for resolving an isavuconazole intermediate is as follows:

[0031] Synthesis of crude isavuconazole intermediate 4:

[0032] Under stirring, 107 g of anhydrous tetrahydrofuran and 21 g of zinc powder were added to a dry reaction kettle. 2.4 g of TMSCl was added dropwise under nitrogen protection, and the internal temperature was controlled not to exceed 45 °C. After stirring for 0.5 h, the temperature was lowered to 25 - 30 °C, and 39 g of ethyl 2-bromopropionate was added dropwise. After the addition was complete, the temperature was lowered to 5 - 10 °C, and 24 g of 1-(2,5-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone (T001-M2) was added. After the reaction was complete, 72 ml of saturated ammonium chloride was added to quench the reaction. The mixture was filtered, and the filter cake was washed with 120 ml of ethyl acetate. After liquid separation, the organic phase was concentrated under reduced pressure at 50 - 60 °C until almost no distillate was obtained to give 46 g of crude T001-M3.

[0033] 50 g of water was added to the reaction kettle, and stirring was started. 12.5 g of sodium hydroxide was added and stirred until completely dissolved, then transferred to 46 g of crude T001-M3. The temperature was raised to 70 - 75 °C for reaction, and in HPLC, T001-M3 was controlled ≤ 0.5%. After the reaction was complete, the system was cooled to room temperature, 96 g of ethyl acetate and 76 g of water were added, and the system was pressure-filtered. The filter cake was washed with 90 g of water. After liquid separation, the aqueous phase was adjusted to pH 3.9 - 4.0 with 10% hydrochloric acid by mass ratio, stirred for crystal cultivation for 2 h, and then centrifuged. The filter cake was washed with water until neutral to obtain 44.0 g of crude isavuconazole intermediate 4 (wet product, HPLC: diastereoisomer 12.91%, chiral HPLC: enantiomer 50.17%, ee value: 0.34%), which was directly used for the next resolution.

[0034] Resolution of crude isavuconazole intermediate 4:

[0035] (1) 216.7 g of water was added to the reaction kettle, and stirring was started. 15.5 g of sodium hydroxide was added. After complete dissolution, 83.4 g of crude isavuconazole intermediate 4 was added, and stirred thoroughly to completely dissolve the crude isavuconazole intermediate 4, and the pH of the system was ≥ 10;

[0036] (2) While controlling the temperature at 20 - 30 °C, 35.4 g of R-(+)-α-methylbenzylamine was added, and the mixture was stirred for 30 min. While controlling the temperature at 20 - 30 °C, 10% hydrochloric acid by mass ratio was slowly added dropwise to the system to adjust the pH of the system to 8.00 - 8.30. Solids gradually precipitated in the system, which were enantiomeric amine salts and were removed by centrifugation;

[0037] (3) The filtrate was continuously added with hydrochloric acid with a mass ratio of 10% to adjust the pH to 3.80 - 3.90, stirred for crystal growth for 2 h, centrifuged, the filter cake was washed with water until neutral, and dried to obtain 8.7 g of (2R,3R)-3-(2,5-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butyric acid (HPLC: diastereoisomer 0.22%, chiral HPLC: enantiomer 1.43%, ee value: 97.14%), and the yield was 27.2%.

[0038] Example 2

[0039] A method for resolving an isavuconazole intermediate, the steps are as follows:

[0040] Synthesis of crude isavuconazole intermediate 4:

[0041] 142 g of anhydrous tetrahydrofuran and 27.8 g of zinc powder were added to a dry reaction kettle under stirring, 3.2 g of TMSCl was added dropwise under nitrogen protection, the internal temperature was controlled not to exceed 45 °C, after stirring for 0.5 h, the temperature was lowered to 25 - 30 °C, and 51.5 g of ethyl 2-bromopropionate was added dropwise. After the addition was completed, the temperature was lowered to 5 - 10 °C, and 31.7 g of 1-(2,5-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone (T001-M2) was added and stirred. After the reaction was completed, 96 ml of saturated ammonium chloride was added to quench the reaction, filtered, the filter cake was washed with 160 ml of ethyl acetate, separated, and the organic phase was concentrated under reduced pressure at 50 - 60 °C until almost no distillate was obtained to obtain 58 g of crude T001-M3.

[0042] 66 g of water was added to the reaction kettle, stirring was started, 16.5 g of sodium hydroxide was added, and after stirring and complete dissolution, it was transferred to 58 g of crude T001-M3, and the temperature was raised to 70 - 75 °C for reaction. The reaction was monitored by HPLC until T001-M3 ≤ 0.5%. After the reaction was completed, the system was cooled to room temperature, 127 g of ethyl acetate and 100 g of water were added, the system was pressure-filtered, the filter cake was washed with 120 g of water, separated, and the aqueous phase was adjusted to pH 3.9 - 4.0 with hydrochloric acid with a mass ratio of 10%, stirred for crystal growth for 2 h and then centrifuged, and the filter cake was washed with water until neutral to obtain 60 g of crude isavuconazole intermediate 4 (wet product, HPLC: diastereoisomer 16.92%, chiral HPLC: enantiomer: 49.42%, ee value: 1.16%), which was directly used for the next resolution.

[0043] Resolution of crude isavuconazole intermediate 4:

[0044] (1) 285 g of water was added to the reaction kettle, stirring was started, 20.5 g of sodium hydroxide was added, and after complete dissolution, 60 g of crude isavuconazole intermediate 4 was added, and stirred thoroughly to completely dissolve the crude isavuconazole intermediate 4, and the pH of the system was ≥ 10;

[0045] (2) Add 46.5 g of R-(+)-α-methylbenzylamine at a controlled temperature of 20-30 °C, stir and react for 30 min. Control the temperature at 20-30 °C, slowly add 10% hydrochloric acid by mass to the system to adjust the pH of the system to 8.00-8.30. Solids gradually precipitate in the system, which are enantiomeric amine salts. Centrifuge and remove them;

[0046] (3) Continue to add 10% hydrochloric acid by mass to the filtrate to adjust the pH to 3.80-3.90, stir and crystallize for 2 h, centrifuge, wash the filter cake with water until neutral, and dry to obtain 11.8 g of (2R,3R)-3-(2,5-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butyric acid (HPLC: diastereoisomer 0.46%, chiral HPLC: enantiomer 0.49%, ee value: 99.02%), with a yield of 27.9%.

[0047] Example 3

[0048] A method for resolving an isavuconazole intermediate is as follows:

[0049] Synthesis of crude isavuconazole intermediate 4:

[0050] Add 284 g of anhydrous tetrahydrofuran and 55.6 g of zinc powder to a dry reaction kettle under stirring. Dropwise add 6.4 g of TMSCl under nitrogen protection, control the internal temperature not exceeding 45 °C, stir for 0.5 h, then cool down to 25-30 °C, and dropwise add 103 g of ethyl 2-bromopropionate. After dropping, cool down to 5-10 °C, stir for 0.5 h, add 63.4 g of 1-(2,5-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone (T001-M2). After the reaction is completed, add 192 ml of saturated ammonium chloride to quench the reaction, filter, wash the filter cake with 320 ml of ethyl acetate, separate the layers, and concentrate the organic phase under reduced pressure at 50-60 °C until almost no distillate is obtained to obtain 116 g of crude T001-M3.

[0051] Add 125 g of water to the reaction kettle, start stirring, add 31.3 g of sodium hydroxide, stir until completely dissolved, then transfer to the crude T001-M3, heat up to 70-75 °C for reaction, monitor by HPLC until T001-M3 ≤ 0.5%. After the reaction is completed, cool the system to room temperature, add 240 g of ethyl acetate and 190 g of water, filter the system under pressure, wash the filter cake with 225 g of water, separate the layers, adjust the pH of the aqueous phase to 3.9-4.0 with 10% hydrochloric acid by mass, stir and crystallize for 2 h, then centrifuge, wash the filter cake with water until neutral to obtain 110 g of crude isavuconazole intermediate 4 (wet product, HPLC: diastereoisomer 8.65%, chiral HPLC: enantiomer: 49.24%, ee value: 1.52%), which is directly used for the next resolution.

[0052] Resolution of crude isavuconazole intermediate 4:

[0053] (1) Add 540 g of water to the reaction kettle, start stirring, add 39 g of sodium hydroxide. After complete dissolution, add 110 g of crude isavuconazole intermediate 4, and stir well to completely dissolve the crude isavuconazole intermediate 4, with the pH of the system ≥ 10;

[0054] (2) Control the temperature at 20 - 30 °C and add 88 g of R-(+)-α-methylbenzylamine, stir and react for 30 min. Control the temperature at 20 - 30 °C, slowly add 10% hydrochloric acid by mass to the system to adjust the pH of the system to 8.00 - 8.30. Solids gradually precipitate in the system, which are enantiomeric amine salts, and they are removed by centrifugation;

[0055] (3) Continue to add 10% hydrochloric acid by mass to the filtrate to adjust the pH to 3.80 - 3.90, stir and crystallize for 2 h, centrifuge, wash the filter cake with water until neutral, and dry to obtain 24.3 g of (2R,3R)-3-(2,5-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butyric acid (HPLC: diastereomer 0.46%, chiral HPLC: enantiomer 0.37%, ee value: 99.26%), with a yield of 28.8%.

[0056] The above are only the preferred embodiments of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the principle of the present invention, several improvements and refinements can be made, and these improvements and refinements should also be regarded as the protection scope of the present invention.

Claims

1. A method for splitting isavuconazole intermediate 4, characterized in that, It includes the following steps: (1) Dissolve the crude isavuconazole intermediate 4 in an aqueous sodium hydroxide solution, and control the pH≥10; (2) Add the resolving agent R-(+)-α-methylbenzylamine under the condition of a temperature of 20~30°C, stir and react, then slowly adjust the pH to 8.00~8.30 with 10% hydrochloric acid by mass ratio, stir and crystallize, and then centrifuge to obtain a filter cake and a filtrate; (3) Slowly dropwise add 10% hydrochloric acid by mass ratio to the filtrate, adjust the pH of the filtrate to 3.8~4.2, stir and crystallize, and collect the solid after centrifugation to obtain (2R,3R)-3-(2,5-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butyric acid; The crude isavuconazole intermediate 4 contains (2R,3R)-3-(2,5-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butyric acid, (2S,3S)-3-(2,5-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butyric acid, (2S,3R)-3-(2,5-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butyric acid, and (2R,3S)-3-(2,5-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butyric acid.

2. The method for splitting isavuconazole intermediate 4 according to claim 1, wherein, The stirring reaction time in step (2) is 30~35 min.

3. The method for splitting isavuconazole intermediate 4 according to claim 1, characterized in that, The stirring and crystallization time in step (2) is 1 h.

4. The method for splitting isavuconazole intermediate 4 according to claim 1, characterized in that, The stirring and crystallization time in step (3) is 2 h.

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