A method for preparing isavuconazole intermediate III

Abstract

The invention relates to the technical field of chemical synthesis, in particular to a method for preparing an isavuconazole intermediate III; the method comprises the following steps: using 1-(2,5-difluorophenyl)-2-(1H-1,2,4-triazole-1-yl)ethanone (Formula II) and 2-halogenated acetonitrile as raw materials, carrying out a Wittig reaction under suitable solvent and temperature conditions to prepare a compound represented by the isavuconazole intermediate Formula III; the intermediate III provided by the invention is a compound that can be used to prepare isavuconazole drugs, which has never been used in the prior art, and a nitrile group is introduced through the Wittig reaction when preparing Formula III, thereby improving a method for introducing a nitrile group by using highly toxic materials such as trimethylsilyl nitrile or acetone cyanohydrin in the later stage of the prior isavuconazole technology.

Description

[0001] This application is a divisional application of Chinese patent application 202310109522.4, filed on February 14, 2023, with the invention name “A method for preparing a key intermediate of isavuconazole drugs”. Technical Field

[0002] The invention relates to the technical field of chemical synthesis, in particular to a method for preparing an isavuconazole intermediate III. Background Art

[0003] Isavuconazole and ravuconazole are triazole drugs widely used in the treatment of systemic mycoses. They are also widely fungal. Isavuconazole sulfate is a water-soluble prodrug of the triazole isavuconazole, which is used to treat invasive Aspergillus infections and invasive Mucor infections in patients over 18 years old. Isavuconazole sulfate is a prodrug of the triazole antifungal drug isavuconazole. Isavuconazole inhibits the synthesis of ergosterol, an important component of the fungal cell membrane, by inhibiting 14-a-ergosterol demethylase in the cytochrome P450 enzyme system, thereby changing the chemical composition of the fungal cell membrane, causing membrane dysfunction, increased permeability, and overflow of intracellular fluid, thereby achieving antibacterial and bactericidal effects. Formula I is a key intermediate for the preparation of isavuconazole drugs, and a variety of preparation methods have been disclosed.

[0004]

[0005] Most routes introduce cyano groups after epoxidation. For example, WO2021245590A1 uses highly toxic trimethylsilylnitrile to prepare formula I in an epoxy system. The reaction formula is as follows:

[0006]

[0007] CN00815329.9 also uses a similar process, in which an active amine reacts with a Grignard reagent to form a ketone, which is further epoxidized, the triazole ring is opened, deprotected and split, and then epoxidized again, the ring is opened to introduce a cyano group, the cyano group forms a thioamide, and finally the ring is closed to form a thiazole.

[0008] The starting materials used in the present invention have already been introduced with nitrile groups before epoxidation. Summary of the invention

[0009] The purpose of the present invention is to overcome the deficiencies in the prior art and provide a method for preparing a key intermediate I of isavuconazole by introducing a nitrile group without using highly toxic and rare raw materials such as trimethylsilyl cyanide or acetone cyanohydrin, thereby improving the safety and environmental protection of the industrial production process.

[0010] To achieve the above purpose, the technical solution adopted in the present invention is as follows:

[0011] A method for preparing a key intermediate of isavuconazole drugs, the method comprising the following steps:

[0012] S1 The compound (Z)-3-(2,5-difluorophenyl)-4-(1H-1,2,4-triazol-1-yl)but-2-enenitrile shown in formula III is subjected to a Smith asymmetric epoxidation reaction to prepare the compound (2R,3R)-3-((1H-1,2,4-triazol-1-yl)methyl)-3-(2,5-difluorophenyl)oxirane-2-carbonitrile shown in formula IV:

[0013]

[0014] S2 The compound (2R,3R)-3-((1H-1,2,4-triazol-1-yl)methyl)-3-(2,5-difluorophenyl)oxirane-2-carbonitrile shown in formula IV reacts with a Grignard reagent to prepare the key intermediate I of isavuconazole:

[0015]

[0016] Furthermore, the specific steps of step S1 are: the specific steps of step S1 are: adding a solvent, disodium EDTA, a phase transfer catalyst and a substrate (Z)-3-(2,5-difluorophenyl)-4-(1H-1,2,4-triazol-1-yl)but-2-enenitrile shown in formula III in sequence into a reaction bottle, adjusting the pH value to be greater than 7, and then adding a ketone oxidant of formula II in batches, and after the reaction is complete, post-processing to obtain a compound shown in formula IV.

[0017] Furthermore, in step S1, the phase transfer catalyst used in the Smith oxidation is one of tetrabutylammonium hydrogen sulfate, tetrabutylammonium bromide, and tetrabutylammonium chloride; preferably tetrabutylammonium hydrogen sulfate.

[0018] The reaction solvent in step S1 is one of acetonitrile, tetrahydrofuran and dichloromethane; preferably acetonitrile.

[0019] Furthermore, the temperature of the oxidation reaction in step S1 is -20°C to 20°C, preferably -5°C to 5°C, and the insulation reaction time after the addition of the ketone oxidizing agent (Formula ii) is 1-8 hours; preferably 2-4 hours.

[0020] Furthermore, in step S1, the molar ratio of the compound represented by formula III to the ketone oxidizing agent (formula ii) is 1.0:(1.2-5.0); preferably 1.0:(2.0-3.0).

[0021] Furthermore, in step S1, the pH value is adjusted to be greater than 7 using a mixture of potassium permonosulfate and sodium bicarbonate, and while the ketone oxidant of formula II is added in batches, a small amount of the mixture of potassium permonosulfate and sodium bicarbonate is continued to be added in batches to adjust the pH value to 7-8.

[0022] Furthermore, the molar ratio of formula III in step S1 to potassium peroxymonosulfate and sodium bicarbonate is 1:1.3:1.5.

[0023] Furthermore, the specific steps in step S2 are: under the Grignard reagent system, nitrogen protection, cooling, adding a certain amount of cuprous chloride, stirring evenly, slowly dripping the compound shown in formula IV, and keeping warm to react until complete after dripping. After adding saturated ammonium chloride to quench the reaction, adjust the pH value to between 3-4 with 3 mol / L hydrochloric acid, and then add a suitable solvent to help stratification and extract the product, and the obtained organic phase is desolvated to obtain the key intermediate of isavuconazole drugs shown in formula I.

[0024] Further, the reaction temperature in step S2 is -30°C to 0°C; preferably -10°C to -20°C;

[0025] The reaction time in step S2 is 2-6 hours, preferably 3-5 hours;

[0026] The reaction solvent in step S2 is tetrahydrofuran or methyltetrahydrofuran; preferably tetrahydrofuran;

[0027] The molar ratio of formula IV to cuprous chloride is 15.25:1.

[0028] Furthermore, in step S2, the molar ratio of formula IV to the Grignard reagent is 1.0:(1.0-1.5); preferably 1.0:(1.0-1.2).

[0029] The technical solution of the present invention has the following beneficial effects:

[0030] 1. The starting material (Z)-3-(2,5-difluorophenyl)-4-(1H-1,2,4-triazol-1-yl)but-2-enenitrile (Formula III) has already introduced a nitrile group, and is further epoxidized by the Smith oxidation reaction. The obtained intermediate IV no longer needs to use the highly toxic and rare raw materials trimethylsilyl cyanide or acetone cyanohydrin to introduce a nitrile group, and can be directly used for the further preparation of isavuconazole and its intermediates.

[0031] 2. A method for further preparing the key intermediate (2S,3R)-3-(2,5-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butyronitrile (Formula I) of isavuconazole using Formula III as the starting material. The obtained key intermediate of isavuconazole has good purity, high yield, and is easy to realize industrial production.

[0032] 3. The route provided by the present invention is economical, environmentally friendly and has little pollution. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 This is the hydrogen spectrum of the key intermediate I of isavuconazole. DETAILED DESCRIPTION

[0034] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0035] The compound III in this application is homemade, as follows:

[0036] Example A: Preparation of (Z)-3-(2,5-difluorophenyl)-4-(1H-1,2,4-triazol-1-yl)but-2-enenitrile (Formula III):

[0037] Add 196.7 g (0.75 mol) of triphenylphosphine and 800 ml of toluene into the reaction flask and start stirring. Then add 56.6 g (0.75 mol) of 2-chloroacetonitrile and stir at room temperature for 15 minutes until the system is uniform. Heat to 110 degrees and reflux for 5-6 hours, then naturally cool to about 25 degrees. A large amount of white solid precipitates. Filter by suction, rinse the filter cake with methyl tert-butyl ether (100 ml*3 times) to obtain an off-white solid. Add 800 ml of DMF to dissolve it, protect it with nitrogen, and set it aside.

[0038] Take another clean reaction bottle, protect with nitrogen, add 1000ml of DMF and 18.0g (0.75mol) of sodium hydride in turn, stir evenly at room temperature, continue to drop the above-mentioned triphenylphosphine DMF solution at room temperature, stir for 1 hour after the addition is completed in about 2-3 hours, keep the temperature at 20 degrees and drop 1-(2,5-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone (Formula II) DMF solution [111.6g (0.5mol) Formula II and 500ml of DMF], after the addition is completed, continue to maintain 20 degrees for Wittig reaction for 6 hours, TLC control, the reaction is complete, add 500ml of autoclave The mixture was stirred and quenched with water for 30 minutes, and most of the triphenylphosphine was removed by suction. The reaction solution was extracted with ethyl acetate (600 ml * 5 times), and the organic phases were combined, washed with water (100 ml * 2 times), washed with saturated brine (100 ml * 1 time), and dissolved in 300 ml of acetonitrile after desolventizing. Then, 8.5 g (0.023 mol) (-) Riboflavin was added, stirred evenly, irradiated under a 402 nm ultraviolet lamp at room temperature for 24 hours, desolventized to dryness, slurried with 200 ml of methyl tert-butyl ether at room temperature for 1 hour, suction filtered, and dried to obtain 111.27 g of an off-white solid with HPLC purity of 98.33% and a molar yield of 90.38%.

[0039] Example B: Preparation of (Z)-3-(2,5-difluorophenyl)-4-(1H-1,2,4-triazol-1-yl)but-2-enenitrile (Formula III):

[0040] Add 196.7 g (0.75 mol) of triphenylphosphine and 800 ml of toluene into the reaction flask and start stirring. Then add 56.6 g (0.75 mol) of 2-chloroacetonitrile and stir at room temperature for 15 minutes until the system is uniform. Heat to 110 degrees and reflux for 5-6 hours, then naturally cool to about 25 degrees. A large amount of white solid precipitates. Filter by suction, rinse the filter cake with methyl tert-butyl ether (100 ml*3 times) to obtain an off-white solid. Add 800 ml of DMF to dissolve it, protect it with nitrogen, and set it aside.

[0041] Take another clean reaction bottle, protect with nitrogen, add 1000ml of DMF and 18.0g (0.75mol) of sodium hydride in turn, stir evenly at room temperature, continue to drop the above-mentioned triphenylphosphine DMF solution at room temperature, stir for 1 hour after the addition is completed in about 2-3 hours, keep the temperature at 30 degrees and drop 1-(2,5-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone (Formula II) DMF solution [111.6g (0.5mol) Formula II and 500ml of DMF], after the addition is completed, continue to maintain 30 degrees for Wittig reaction for 8 hours, TLC control, the reaction is complete, add 500ml of autoclave The mixture was stirred and quenched with water for 30 minutes, and most of the triphenylphosphine was removed by suction. The reaction solution was extracted with ethyl acetate (600 ml * 5 times), and the organic phases were combined, washed with water (100 ml * 2 times), washed with saturated brine (100 ml * 1 time), and dissolved in 300 ml of acetonitrile after desolventizing. Then, 8.5 g (0.023 mol) (-) Riboflavin was added, stirred evenly, irradiated under a 402 nm ultraviolet lamp at room temperature for 24 hours, desolventized to dryness, slurried with 200 ml of methyl tert-butyl ether at room temperature for 1 hour, suction filtered, and dried to obtain 112.34 g of an off-white solid with HPLC purity of 97.56% and a molar yield of 91.25%.

[0042] Example C: Preparation of (Z)-3-(2,5-difluorophenyl)-4-(1H-1,2,4-triazol-1-yl)but-2-enenitrile (Formula III):

[0043] Add 209.8 g (0.80 mol) of triphenylphosphine and 800 ml of toluene into the reaction flask and start stirring. Then add 60.4 g (0.80 mol) of 2-chloroacetonitrile and stir at room temperature for 15 minutes until the system is uniform. Heat to 110 degrees and reflux for 5-6 hours, then naturally cool to about 25 degrees to precipitate a large amount of white solid. Filter and rinse the filter cake with methyl tert-butyl ether (100 ml*3 times) to obtain an off-white solid. Add 800 ml of DMF to dissolve it, protect it with nitrogen, and set it aside.

[0044] Take another clean reaction bottle, protect with nitrogen, add 1000ml of DMF and 18.0g (0.75mol) of sodium hydride in turn, stir evenly at room temperature, continue to drop the above-mentioned triphenylphosphine DMF solution at room temperature, stir for 1 hour after the addition is completed in about 2-3 hours, keep the temperature at 30 degrees and drop 1-(2,5-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone (Formula II) DMF solution [111.6g (0.5mol) Formula II and 500ml of DMF], after the addition is completed, continue to maintain 30 degrees for Wittig reaction for 8 hours, TLC control, the reaction is complete, add 500ml of autoclave The mixture was stirred and quenched with water for 30 minutes, and most of the triphenylphosphine was removed by suction. The reaction solution was extracted with ethyl acetate (600 ml * 5 times), and the organic phases were combined, washed with water (100 ml * 2 times), washed with saturated brine (100 ml * 1 time), and dissolved in 300 ml of acetonitrile after desolventizing. Then, 8.5 g (0.023 mol) (-) Riboflavin was added, stirred evenly, irradiated under a 402 nm ultraviolet lamp at room temperature for 24 hours, desolventized to dryness, slurried with 200 ml of methyl tert-butyl ether at room temperature for 1 hour, suction filtered, and dried to obtain 112.87 g of an off-white solid with HPLC purity of 97.31% and a molar yield of 91.68%.

[0045] Compound III is used to prepare the key intermediate I of isavuconazole, as follows:

[0046] Example 1: Preparation of (2R,3R)-3-((1H-1,2,4-triazol-1-yl)methyl)-3-(2,5-difluorophenyl)oxirane-2-carbonitrile (Formula IV):

[0047] At room temperature, 100 g (0.406 mol) of (Z)-3-(2,5-difluorophenyl)-4-(1H-1,2,4-triazol-1-yl)but-2-enenitrile (Formula III) prepared in Example B and 1000 ml of acetonitrile were added to the reaction flask, stirring was started, and then 1.0 g (0.003 mol) of EDTA disodium salt, 0.5 g of catalytic amount of tetrabutylammonium hydrogen sulfate and 300 ml of water were added in sequence, and stirred for 30 minutes until all dissolved. The temperature was lowered to -5 degrees, and 324.6 g (0.528 mol) of potassium permonosulfate and 51.2 g (0.609 mol) of sodium bicarbonate solid, which were mixed in advance, were added in batches to the reaction system. At the same time, the pH value of the reaction system was monitored at any time with a pH meter. When the pH value was just greater than 7, the addition was stopped. Continue stirring at -5 degrees for 15 minutes, start adding 209.7g (0.812mol) of ketone oxidant in batches (it takes about 1.5 hours to add), and continue to use potassium permonosulfate and sodium bicarbonate mixture to adjust the pH value to between 7.0 and 8.0. After the addition is completed, continue stirring at -5 degrees for 2 hours. The reaction is complete as controlled by TLC, and 300ml of water is added and stirred for 15 minutes. The product is extracted with n-hexane (500ml*3 times), the organic phases are combined, and finally washed with saturated brine (150ml*1 time). The obtained organic phase is desolvated to obtain 87.4g of a yellow oil with a molar yield of 82.1% and a HPLC purity of 96.75%.

[0048] Example 2: Preparation of Isavuconazole Key Intermediate I:

[0049] Under nitrogen protection, 200 mol THF was added to the reaction flask, and then 22.8 g (0.305 mol) of methyl Grignard reagent was added, stirring was started, the temperature was cooled to -10 degrees, 2.0 g (0.02 mol) of cuprous chloride was added, and the temperature was maintained at -10 degrees. 80 g (0.305 mol) of (2R, 3R)-3-((1H-1,2,4-triazol-1-yl)methyl)-3-(2,5-difluorophenyl)oxirane-2-carbonitrile (Formula IV) prepared in Example 1 and 150 mol of THF were slowly added dropwise. The addition was completed in about 1 hour, and the reaction was maintained at -10 degrees for 2 hours. The basic reaction was controlled to be complete by TLC. 50g of saturated ammonium chloride aqueous solution was added dropwise to quench the reaction, and the product was extracted with methyl tert-butyl ether (300ml*5 times), combined with the camera, washed with saturated brine (150ml*1 time), and after the organic phase was desolventized, 260ml of isopropanol was added and stirred at 10-15 degrees for 1 hour, then filtered and dried to obtain 78.3g of off-white solid, with a molar yield of 92.31% and a HPLC purity of 99.26%. A small amount was taken for NMR structure confirmation, and the test results are shown in Figure 1 .

[0050] Example 3: Preparation of (2R,3R)-3-((1H-1,2,4-triazol-1-yl)methyl)-3-(2,5-difluorophenyl)oxirane-2-carbonitrile (Formula IV):

[0051] At room temperature, 100 g (0.406 mol) of (Z)-3-(2,5-difluorophenyl)-4-(1H-1,2,4-triazol-1-yl)but-2-enenitrile (Formula III) prepared in Example C and 1000 ml of acetonitrile were added to the reaction flask, stirring was started, and then 1.0 g (0.003 mol) of EDTA disodium salt, 0.5 g of catalytic amount of tetrabutylammonium hydrogen sulfate and 300 ml of water were added in sequence, and stirred for 30 minutes until all dissolved. The temperature was lowered to 5 degrees, and 324.6 g (0.528 mol) of potassium permonosulfate and 51.2 g (0.609 mol) of sodium bicarbonate solid, which had been mixed in advance, were added in batches to the reaction system. At the same time, the pH value of the reaction system was monitored at any time with a pH meter. When the pH value was just greater than 7, the addition was stopped. Continue stirring at 5 degrees for 15 minutes, start adding 314.6g (1.218mol) of ketone oxidant in batches (it takes about 1.5 hours to add), and continue to use potassium persulfate and sodium bicarbonate mixture to adjust the pH value to between 7.0 and 8.0. After the addition is completed, continue stirring at 5 degrees for 4 hours, and the reaction is complete by TLC. Add 300ml of water and stir for 15 minutes. Extract the product with n-hexane (500ml*3 times), combine the organic phases, and finally wash with saturated brine (150ml*1 time). The obtained organic phase is desolvated to obtain 88.1g of yellow oil with a molar yield of 82.76% and a HPLC purity of 96.02%.

[0052] Example 4: Preparation of Isavuconazole Key Intermediate I:

[0053] Under nitrogen protection, 200 mol THF was added to the reaction bottle, and then 27.4 g (0.366 mol) of methyl Grignard reagent was added, stirring was started, the temperature was cooled to -20 degrees, 2.0 g (0.02 mol) of cuprous chloride was added, and the temperature was kept at -20 degrees. 80 g (0.305 mol) of (2R, 3R)-3-((1H-1,2,4-triazol-1-yl)methyl)-3-(2,5-difluorophenyl)oxirane-2-carbonitrile (Formula IV) prepared in Example 3 and 150 mol THF were slowly added dropwise. The addition was completed in about 1 hour, and the reaction was maintained at -20 degrees for 4 hours. The reaction was controlled to be complete by TLC. 50 g of saturated aqueous ammonium chloride solution was added dropwise to quench the reaction, and the product was extracted with methyl tert-butyl ether (300 ml*5 times), combined with a camera, washed with saturated brine (150 ml*1 time), and after the organic phase was desolventized, 260 ml of isopropanol was added and stirred at 10-15 degrees for 1 hour, then filtered and dried to obtain 78.8 g of an off-white solid with a molar yield of 92.85% and an HPLC purity of 99.35%.

[0054] The above-mentioned embodiments only express several implementation methods of the present invention, and the description thereof is relatively specific and detailed, but it cannot be understood as limiting the scope of the invention patent. It should be pointed out that for ordinary technicians in this field, several modifications and improvements can be made without departing from the concept of the present invention, which all belong to the protection scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the attached claims.

Claims

1. A method for preparing isavuconazole intermediate III, characterized in that: The structural formula of intermediate III is as follows: The preparation method The following steps are involved: Add 0.75 mol triphenylphosphine and 800 ml toluene to the reaction flask and start stirring. Then add 0.75 mol 2-chloroacetonitrile and stir at room temperature for 15 minutes until the system is uniform. Heat to 110 degrees and reflux for 5-6 hours, then naturally cool to 25 degrees. A large amount of white solid precipitates. Filter by suction. Rinse the filter cake with 100 ml of methyl tert-butyl ether 3 times to obtain an off-white solid. Add 800 ml of DMF to dissolve it, protect it with nitrogen, and set it aside. Take another clean reaction bottle, protect with nitrogen, add 1000ml of DMF and 0.75mol of sodium hydride in turn, stir evenly at room temperature, continue to drop the above-mentioned triphenylphosphine DMF solution at room temperature, stir for 1 hour after the addition is completed in 2-3 hours, and keep the temperature at 20 degrees. Dropwise add 1-(2,5-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone DMF solution, the concentration of the 1-(2,5-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone DMF solution is 0.5mol dissolved in 500ml DMF. 1-(2,5-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone, after the addition is completed, continue to maintain 20 degrees for Wittig reaction for 6 hours, TLC control, the reaction is complete, add 500ml of tap water, stir and extract for 30 minutes, filter and remove most of the triphenylphosphine oxide, the resulting reaction solution is extracted with ethyl acetate 600ml*5 times, the organic phases are combined, washed with water 100ml*2 times, washed with saturated brine 100m*1 time, and after desolventizing, it is dissolved in 300ml of acetonitrile, and then 0.023mol (-) Riboflavin is added, stirred evenly, irradiated under 402nm ultraviolet lamp environment at room temperature for 24 hours, desolventized to dryness, slurried with 200ml methyl tert-butyl ether at room temperature for 1 hour, filtered, and dried to obtain 111.27g of off-white solid with HPLC purity of 98.33%.

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