A process for the preparation of amorphous letimovir

Abstract

The present application relates to a kind of amorphous preparation method of compound of formula I. Specifically, the present application provides a kind of amorphous preparation method of temivocine compound of formula I, the method of the present application reduces the potential risk of impurity increase, high production efficiency, the amorphous prepared has high purity, low residual, and the powder property is good, and no oil is generated in the preparation process.

Description

Technical Field

[0001] This invention belongs to the pharmaceutical field, specifically relating to a method for preparing lemetmovir amorphous form. Background Technology

[0002] Cytomegalovirus (CMV) belongs to the DNA virus family, Herpesviridae, and Betaherpesinae subfamily. CMV exhibits significant species specificity; human cytomegalovirus (HCMV) can only infect humans and replicate in human fibroblasts. Although they can be present throughout the body, HCMV infection is typically associated with the salivary glands. HCMV infection is often overlooked in healthy individuals. However, it can be life-threatening in immunocompromised subjects such as HIV-infected individuals, organ transplant recipients, or newborns. In particular, HCMV remains a leading viral cause of birth defects and a life-threatening disease in transplant recipients.

[0003] Letermovir's chemical name is (S)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-(2-methoxy-5-trifluoromethylphenyl)-3,4-dihydroquinazolin-4-yl}acetic acid, and its structural formula is represented by Formula I.

[0004]

[0005] Letermovir belongs to a new class of non-nucleoside CMV inhibitors (3,4-dihydroquinazoline) that inhibit viral replication by targeting the viral terminase complex. This compound is active only against human cytomegalovirus (HCMV) and therefore has high potential as a specific human anti-HCMV drug.

[0006] Patent WO2013 / 127971A1 mentions calcium and sodium salts of letermovir; patent WO2013 / 127968A1 mentions benzenesulfonate and toluenesulfonate of letermovir; and patent WO2021 / 170882A1 mentions potassium salt of letermovir. No crystalline form of letermovir has been described in existing literature. WO2014 / 202737A1 mentions a method for preparing amorphous letermovir, specifying that acetonitrile or acetone solvents can be used to obtain amorphous letermovir suitable for formulations. However, the amorphous form prepared by this method may have the potential risk of increased impurities, and may also have low production efficiency, failing to meet the needs of industrial production. If acetone is used as the solvent according to the method in WO2014 / 202737A1, isopropyl acetone impurities will be generated. If it is necessary to control this impurity to a low limit, acetone needs to be used to replace the MTBE (methyl tert-butyl ether) solvent for a long time under low temperature conditions, which results in extremely low production efficiency. If acetonitrile is used as the solvent, raising the temperature or using alkali will cause racemization, and acetonitrile is highly toxic and has a low residual limit, which also cannot meet the requirements of industrial production.

[0007] In summary, there is an urgent need in this field for a simple, easy-to-implement, and industrially feasible method for preparing lemetmovir that can both ensure product quality (purity, solvent residue, and impurities meet quality standards) and reduce costs while improving production efficiency. Summary of the Invention

[0008] To address the problems existing in the prior art, this invention provides a novel method for preparing amorphous 4(S)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-(2-methoxy-5-trifluoromethylphenyl)-3,4-dihydroquinazolin-4-yl}acetic acid. This method involves dissolving lemetmovir in a specific solvent and obtaining amorphous lemetmovir by back-dropping with water. This solves the technical problems of potential impurity generation and low production efficiency. Therefore, the method of this invention has significant advantages in terms of resources and cost, and is more suitable for industrial production.

[0009] In a first aspect of the invention, a method for preparing letermovir amorphous material is provided, characterized by comprising the steps of:

[0010] (1) Provide a first solution of Letermovir in a first solvent;

[0011] (2) Add the first solution to the second solvent to produce a precipitate and obtain a suspension;

[0012] (3) The suspension was separated and purified to obtain lemetmovir amorphous.

[0013] In some embodiments, the method for preparing the first solution includes the following steps:

[0014] (a) The salt, base, second solvent, and third solvent of termovir will be mixed in the future;

[0015] (b) The mixture obtained by extraction is added to the first solvent and the third solvent is removed by distillation;

[0016] (c) Optionally, add the first solvent, distill to remove the third solvent, and repeat once or more.

[0017] (d) Obtain a solution of levatin in the first solvent.

[0018] In another preferred embodiment, the third solvent is methyl tert-butyl ether (MTBE).

[0019] In another preferred embodiment, the base is an inorganic base.

[0020] In another preferred embodiment, in step (b), a portion of the third solvent is distilled off before the extraction is performed.

[0021] In another preferred embodiment, the distillation temperature in steps (b) and (c) is 20-60°C.

[0022] In some embodiments, the method for preparing the first solution in step (1) includes the step of dissolving termovir in a first solvent.

[0023] In another preferred embodiment, after the termovir is dissolved in the first solvent, the mixture is filtered, and the filtrate is retained as the first solution.

[0024] In another preferred embodiment, after the termovir is dissolved in the first solvent, the system is heated and / or stirred.

[0025] In another preferred embodiment, the heating temperature is 0-80°C.

[0026] In another preferred embodiment, the heating temperature is 20-60°C.

[0027] In some embodiments, the first solvent is an organic solvent.

[0028] In another preferred embodiment, the first solvent is dimethyl sulfoxide or isopropanol.

[0029] In some embodiments, the second solvent is water.

[0030] In some embodiments, in step (2), the temperature of the second solvent is 0-80°C.

[0031] In another preferred embodiment, the temperature of the second solvent is 20-60°C.

[0032] In some embodiments, in step (2), the solution is added slowly by dripping, and the precipitate is generated during the dripping process.

[0033] In some embodiments, the separation and purification described in step (3) includes the following steps:

[0034] The suspension was filtered, the filter cake was rinsed with deionized water, and then vacuum dried at 40-80℃.

[0035] In a second aspect of the invention, a pharmaceutical composition is provided, characterized in that the pharmaceutical composition comprises: (1) an amorphous form of lemetmovir prepared as described in the first aspect of the invention; and (2) optionally, a pharmaceutically acceptable carrier.

[0036] In a third aspect of the invention, there is provided the use of a lemetmovir amorphous prepared as described in the first aspect of the invention or a pharmaceutical composition as described in the second aspect of the invention, characterized in that it is used to prepare a medicament for the prevention or treatment of herpesvirus-related diseases.

[0037] In another preferred embodiment, the herpesvirus-associated disease is a cytomegalovirus (CMV)-associated disease.

[0038] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Attached Figure Description

[0039] Figure 1 Letermovir amorphous XRPD image prepared according to a preparation method according to an embodiment of the present invention. Detailed Implementation

[0040] Through extensive and in-depth efforts, the inventors unexpectedly discovered that by dissolving lemetmovir in a specific solvent and then adding water dropwise, an amorphous form of lemetmovir could be obtained. This amorphous form exhibits high purity, low solubility, low hygroscopicity, and good powder properties, while significantly reducing solvent replacement time, making it highly suitable for the industrial production of this amorphous form. Based on this, the inventors completed this invention.

[0041] the term

[0042] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0043] Unless otherwise specified, in this invention, amorphous refers to Letemove amorphous.

[0044] The main advantages of this invention include:

[0045] (a) Compared with the prior art, the method for preparing lemetmovir amorphous provided by the present invention reduces the potential risk of increased impurities.

[0046] (b) The method of the present invention can increase the temperature and improve production efficiency during the solvent replacement process, and its time efficiency is significantly better than the method in WO2014 / 202737A1 that uses acetone as a solvent.

[0047] (c) The amorphous powder prepared by the method of the present invention has high purity, low solubility residue and good powder properties.

[0048] (d) The method of the present invention produces no oily substances during the preparation of amorphous materials, has a low risk of residual dissolution, and a high yield.

[0049] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Unless otherwise stated, percentages and parts are weight percentages and parts by weight.

[0050] Unless otherwise specified, in this invention, Letermovir can be obtained commercially or prepared according to methods known in the art, as described in WO2004 / 096778.

[0051] Unless otherwise specified, the solvents and reagents used in the examples (such as dimethyl sulfoxide, isopropanol, etc.) are commercially available.

[0052] Detection methods

[0053] The X-ray powder diffraction (XRPD) pattern described in this invention was acquired using a Bruker D2Phaser X-ray powder diffractometer. The instrument parameters are as follows:

[0054] X-rays: Monochromatic Cu-Ka rays (λ = 1.5418)

[0055] Scanning method: θ / 2θ

[0056] Scan range: 2-35°

[0057] Voltage: 30KV

[0058] Current: 10mA

[0059] In this invention, particle size is detected using a Mastersizer 2000 dry method, and the specific detection parameters (refer to the method in patent WO2014 / 202737A1) are as follows:

[0060] Weight: 0.3-0.4g

[0061] Measurement time: 20 seconds

[0062] Background time: 6 seconds

[0063] Shading limit: 0.5% to 6%

[0064] Sample tray: micro-volume; small sieve with spheres

[0065] Feed rate: 45-55%

[0066] Distributed pressure: 2.5 Bar

[0067] Four independent analyses were performed and the results were averaged.

[0068] In this invention, residual solvent is detected by gas chromatography, and the detection method is as follows:

[0069] Direct injection gas chromatography:

[0070] Apparatus: Gas chromatography, such as Agilent 6890

[0071] Column: DB-WAX: 30m length, 0.53mm inner diameter, 1μm film thickness

[0072] Carrier gas, flow rate: Nitrogen, 2 mL / mL (constant flow).

[0073] Syringe temperature: 160℃

[0074] Detector / Temperature: FID / 260℃

[0075] Hydrogen gas 30 mL / min

[0076] Combustion gas: Air 300 mL / min

[0077] Composition gas (N2) 25 mL / min

[0078] Starting temperature 50℃

[0079] Keep warm for 2 minutes

[0080] Oven temperature program: Heating rate 20K / min

[0081] Final temperature 230℃

[0082] Keep warm for 15 minutes

[0083] Injection volume 1μL

[0084] In this invention, purity is detected using high-performance liquid chromatography (HPLC). The detection method (referencing the HPLC detection method in patent WO2014 / 202737A1) is as follows:

[0085] Gradient reverse HPLC-purity

[0086]

[0087] Example 1: Preparation of Letermovir amorphous form using DMSO (dimethyl sulfoxide) at 35-40℃

[0088] A mixture of (2S,3S)-2,3-bis[(4-methylbenzoyl)oxy]succinic acid-{(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}methyl acetate (1:1 salt) (61.6 g), sodium bicarbonate (32.8 g), and water (630 mL) was stirred with MTBE (320 mL). The resulting phases were separated and the organic phase was treated with 70 mL of 7% sodium bicarbonate solution. The resulting phases were separated again and the organic phase was treated with 250 mL of 4% sodium hydroxide solution.

[0089] The mixture of organic and aqueous phases was heated under reflux conditions. The mixture was distilled to remove MTBE. The aqueous phase in the reactor was stirred again at 55–60 °C for 5 hours. MTBE (320 mL) and water (130 mL) were added to the mixture while stirring at 22 °C. The resulting phases were separated again, and the organic phase was extracted using a 6% sodium chloride aqueous solution (60 mL).

[0090] The separated aqueous phase and the 6% sodium chloride solution after organic phase extraction were recombined and stirred with water (50 mL) and MTBE (320 mL). The pH was adjusted to 6.5 using 1 mol / L hydrochloric acid, the organic phase was separated, and the solvent was gently distilled to dryness. The residue was dissolved in DMSO (approximately 120 mL). Distillation was carried out at 35–40 °C for 2.0 h to replace MTBE with DMSO, yielding a DMSO solution. The product was then precipitated by adding the DMSO solution at 35–40 °C with stirring (250 rpm) in excess water (960 mL).

[0091] After filtration, 170 mL of water was added for rinsing. The resulting wet filter cake was dried in a vacuum dryer equipped with a spiral crusher at 40-80°C.

[0092] This procedure yielded 31.6 g of amorphous (S)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-(2-methoxy-5-trifluoromethylphenyl)-3,4-dihydroquinazolin-4-yl}acetic acid, with a molar yield of 92.3%.

[0093] The dried solid is a white powder, such as XRPD. Figure 1As shown, the obtained product is amorphous. This amorphous material has high purity, low solubility, and low hygroscopicity.

[0094] Example 2: Preparation of Letermovir Amorphous Form by Back-Tipping Process with DMSO Solution at 20-25℃

[0095] Add 1.0 g of the amorphous lemetrol obtained in Example 1 and 3.5 mL of DMSO to a 10 mL glass bottle. Stir the mixture at 20-25 °C until clear. Add 28 mL of purified water to a 50 mL three-necked flask and heat to 20-25 °C. Slowly add the DMSO solution at this temperature over a total of 2 hours, obtaining a white, turbid solid suspension. After the addition is complete, continue stirring for 1 hour. Filter, wash with 5 mL of purified water, collect the solid, and dry in a vacuum oven at 50 °C for 24 hours to obtain 0.90 g of white solid, with a molar yield of 90.0%.

[0096] The properties of the product obtained by this process are the same as those in Example 1.

[0097] Example 3: Preparation of Letermovir Amorphous Form by Back-Tipping Process with DMSO Solution at 35-40℃

[0098] In a 10 mL glass bottle, add 1.0 g of the amorphous lemetrol obtained in Example 1 and 2.0 mL of DMSO. Stir and clarify the mixture at 35-40 °C. Filter hot through a 0.45 μm membrane, wash with 0.5 mL of DMSO, and mix the filtrate and eluent, then maintain the temperature at 35-40 °C. In a 50 mL three-necked flask, add 20 mL of purified water and heat to 35-40 °C. Slowly add the maintained DMSO solution at this temperature over a total of 2 hours, obtaining a white, turbid solid suspension. After the addition is complete, cool to room temperature and continue stirring for 1 hour. Filter, wash with 5 mL of purified water, and collect the solid. Dry in a vacuum oven at 50 °C for 24 hours to obtain 0.91 g of white solid, with a molar yield of 91.0%.

[0099] The properties of the product obtained by this process are the same as those in Example 1.

[0100] Example 4: Preparation of Letermovir amorphous form using IPA (isopropanol) at 55-60°C

[0101] A mixture of (2S,3S)-2,3-bis[(4-methylbenzoyl)oxy]succinic acid-{(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}methyl acetate (1:1 salt) (30.8 g), sodium bicarbonate (16.4 g), and water (315 mL) was stirred with MTBE (160 mL). The resulting phases were separated and the organic phase was treated with 35 mL of 7% sodium bicarbonate solution. The resulting phases were separated again and the organic phase was treated with 125 mL of 4% sodium hydroxide solution.

[0102] The mixture of organic and aqueous phases was heated under reflux conditions. The mixture was distilled to remove MTBE. The aqueous phase in the reactor was stirred again at 55–60 °C for 5 hours. MTBE (160 mL) and water (65 mL) were added to the mixture while stirring at 22 °C. The resulting phases were separated again, and the organic phase was extracted using a 6% sodium chloride aqueous solution (30 mL).

[0103] The separated aqueous phase and the 6% sodium chloride solution after organic phase extraction were recombined and stirred with water (25 mL) and MTBE (160 mL). The pH was adjusted to 6.5 using 1 mol / L hydrochloric acid, the organic phase was separated, and the solvent was gently distilled to dryness, dissolving the residue in IPA (approximately 60 mL). Distillation was carried out at 35–40 °C for 2.0 h, repeated once to achieve IPA substitution of MTBE, yielding an IPA solution. The product was then precipitated by adding the IPA solution to excess water (480 mL) at 35–40 °C with stirring (250 rpm).

[0104] After filtration, 85 mL of water was added for rinsing. The resulting wet filter cake was dried in a vacuum dryer equipped with a spiral crusher at 40–80 °C. This process yielded 16.2 g of amorphous (S)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-(2-methoxy-5-trifluoromethylphenyl)-3,4-dihydroquinazolin-4-yl}acetic acid, with a molar yield of 94.6%.

[0105] The properties of the product obtained by this process are the same as those in Example 1.

[0106] Example 5: Preparation of Letermovir Amorphous Form by Back-Tickling IPA Solution at 20-25°C

[0107] Add 1.0 g of lemetmovir amorphous solution and 5.5 mL of IPA obtained in Example 1 to a 10 mL glass bottle. Stir and clarify the mixture at 20-25 °C. Add 44 mL of purified water to a 100 mL three-necked flask and heat to 20-25 °C. Slowly add the incubated IPA solution at this temperature over a total of 2 hours, obtaining a white, turbid solid suspension. After the addition is complete, continue stirring for 1 hour. Filter, wash with 5 mL of purified water, and collect the solid. Dry in a vacuum oven at 50 °C for 24 hours to obtain 0.89 g of white solid, with a molar yield of 89.0%.

[0108] The properties of the product obtained by this process are the same as those in Example 1.

[0109] Example 6: Preparation of Letermovir Amorphous Form by Back-Tickling IPA Solution at 35-40℃

[0110] In a 10 mL glass bottle, add 1.0 g of lemetmovir amorphous solution and 3.0 mL of IPA obtained in Example 1. Stir and clarify the mixture at 35-40 °C. Hot filter through a 0.45 μm membrane, elute with 0.5 mL of IPA, and mix the filtrate and eluent, then maintain the temperature at 35-40 °C. In a 50 mL three-necked flask, add 28 mL of purified water and heat to 35-40 °C. Slowly add the maintained IPA solution at this temperature over a total adding time of 2 hours, obtaining a white, turbid solid suspension. After the addition is complete, cool to room temperature and continue stirring for 1 hour. Filter, elute with 5 mL of purified water, and collect the solid. Dry in a vacuum oven at 50 °C for 24 hours to obtain 0.90 g of white solid, with a molar yield of 90.0%.

[0111] The properties of the product obtained by this process are the same as those in Example 1.

[0112] Example 7: Anti-dropping experiment using water as an antisolvent

[0113] Using the amorphous levaline obtained in Example 1 as a raw material, it was dissolved in the solvents listed in the table below, and then water was added dropwise. The results are shown in Table 1. The specific implementation method is as follows:

[0114] Add 0.2 g of lemetmovir amorphous solution and 0.7 mL of DMSO obtained in Example 1 to a 5 mL glass bottle. Heat the mixture to 35-40 °C and stir for 15 minutes until the solution becomes clear. Add 5.6 mL of purified water to a 50 mL three-necked flask and heat to 35-40 °C. Slowly add the dissolved DMSO solution dropwise at this temperature for a total addition time of 2 hours to obtain a white, turbid solid suspension. After the addition is complete, cool to room temperature and continue stirring for 1 hour. Filter the solution, rinse with 1 mL of purified water and collect the solid. Dry the solid in a vacuum oven at 50 °C for 24 hours to obtain a white solid.

[0115] The method for preparing letemovir amorphous form using other solvents is similar to that using DMSO, except that DMSO is replaced with other solvents.

[0116] Table 1. Reverse precipitation reactions using water as the antisolvent

[0117]

[0118] Except for acetone, acetonitrile, methanol, ethanol, dimethyl sulfoxide, and isopropanol, the dropwise addition of other solvents will result in obvious oil formation, which is not conducive to the precipitation of amorphous solids.

[0119] Example 8: Back-tipping experiment using alkanes as antisolvents

[0120] The preparation method is the same as that in Example 3, except that the dissolving solvent is replaced with the dissolving solvent in the table and the water is replaced with the alkane in the table.

[0121] Table 2. Back-tip precipitation reactions using alkanes as antisolvents.

[0122]

[0123]

[0124] All positive solvents, when dissolved and added dropwise to alkane (cyclohexane or n-heptane) solvents, will produce oil, which is not conducive to the precipitation of amorphous solids.

[0125] Example 9: Positive Drop Experiment with Water as the Antisolvent

[0126] Using the amorphous levaline obtained in Example 1 as a raw material, it was dissolved in the solvents listed in the table below. Water was then added dropwise to each solution, and the results are shown in Table 3. The specific implementation method is as follows:

[0127] Add 0.2 g of lemetmovir amorphous solution and 0.7 mL of DMSO obtained in Example 1 to a 5 mL glass bottle. Heat the mixture to 35-40 °C and stir for 15 minutes until the solution becomes clear. Add 5.6 mL of purified water to a 25 mL three-necked flask and heat to 35-40 °C. At this temperature, slowly add the water dropwise to the DMSO solution over a total addition time of 2 hours to obtain a white, turbid solid suspension. After the addition is complete, cool to room temperature and continue stirring for 1 hour. Filter the solution, rinse with 1 mL of purified water, collect the solid, and dry it in a vacuum oven at 50 °C for 24 hours to obtain a white solid.

[0128] The preparation of lemetmovir amorphous form using other solvents is similar to that using DMSO. Replace DMSO with the solvents listed in the table.

[0129] Table 3. Forward titration reactions with water as the antisolvent

[0130]

[0131]

[0132] Adding water droplets to any solution will cause it to turn into oil, which is not conducive to amorphous precipitation.

[0133] Example 10 Solution Stability Study

[0134] The amorphous materials obtained in Example 1 were dissolved in the solvents listed in the table below, and the solutions were placed at the corresponding temperatures to examine their stability. The results are shown in Table 4.

[0135] Table 4 Solution stability results

[0136]

[0137] In both methanol and ethanol solutions, new impurities are generated, and these impurities increase rapidly, presumably due to methyl or ethyl ester impurities, leading to a significant decrease in purity. In contrast, no new impurities are generated in the dimethyl sulfoxide solution, while a small amount of impurities are generated in the isopropanol solution, presumably due to isopropanol esterification impurities. Since dimethyl sulfoxide and isopropanol solutions produce little or no new impurities, they are suitable as solvents for preparing amorphous materials.

[0138] Comparative Example 1: Letermovir amorphous form was prepared with acetone at 20-25°C (prepared according to patent WO2014 / 202737A1).

[0139] A mixture of (2S,3S)-2,3-bis[(4-methylbenzoyl)oxy]succinic acid-{(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}methyl acetate (1:1 salt) (30.8 g), sodium bicarbonate (16.4 g), and water (315 mL) was stirred with MTBE (160 mL). The resulting phases were separated and the organic phase was treated with 35 mL of 7% sodium bicarbonate solution. The resulting phases were separated again and the organic phase was treated with 125 mL of 4% sodium hydroxide solution.

[0140] The mixture of organic and aqueous phases was heated under reflux conditions. The mixture was distilled to remove MTBE. The aqueous phase in the reactor was stirred again at 55–60 °C for 5 hours. MTBE (160 mL) and water (65 mL) were added to the mixture while stirring at 22 °C. The resulting phases were separated again, and the organic phase was extracted using a 6% sodium chloride aqueous solution (30 mL).

[0141] The separated aqueous phase and the 6% sodium chloride solution after organic phase extraction were recombined and stirred with water (25 mL) and MTBE (160 mL). The pH was adjusted to 6.5 using 1 mol / L hydrochloric acid. The organic phase was separated, the solvent was gently distilled to dryness, and the residue was dissolved in acetone (approximately 75 mL). The solution was replaced with acetone (20–25 °C) in six distillation steps of 130 mL each, to obtain an acetone solution. The product was then precipitated by adding the acetone solution (approximately 60 mL) to excess water (492 mL) at 20–25 °C with stirring (250 rpm). After filtration, the separated product was dried in a vacuum dryer equipped with a screw crusher at 40–80 °C. This procedure yielded 16.0 g of amorphous (S)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-(2-methoxy-5-trifluoromethylphenyl)-3,4-dihydroquinazolin-4-yl}acetic acid, with a molar yield of 93.5%.

[0142] The properties of the product obtained by this process are the same as those in Example 1.

[0143] Comparative Example 2: Preparation of Letermovir amorphous form at 55-60℃ using acetone

[0144] A mixture of (2S,3S)-2,3-bis[(4-methylbenzoyl)oxy]succinic acid-{(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}methyl acetate (1:1 salt) (30.8 g), sodium bicarbonate (16.4 g), and water (315 mL) was stirred with MTBE (160 mL). The resulting phases were separated and the organic phase was treated with 35 mL of 7% sodium bicarbonate solution. The resulting phases were separated again and the organic phase was treated with 125 mL of 4% sodium hydroxide solution.

[0145] The mixture of organic and aqueous phases was heated under reflux conditions. The mixture was distilled to remove MTBE. The aqueous phase in the reactor was stirred again at 55–60 °C for 5 hours. MTBE (160 mL) and water (65 mL) were added to the mixture while stirring at 22 °C. The resulting phases were separated again, and the organic phase was extracted using a 6% sodium chloride aqueous solution (30 mL).

[0146] The separated aqueous phase and the 6% sodium chloride solution after organic phase extraction were recombined and stirred with water (25 mL) and MTBE (160 mL). The pH was adjusted to 6.5 using 1 mol / L hydrochloric acid. The organic phase was separated, the solvent was gently distilled to dryness, and the residue was dissolved in acetone (approximately 75 mL). The solution was replaced with acetone (35–40 °C) in six distillation steps of 130 mL each, to obtain an acetone solution. The product was then precipitated by adding the acetone solution (approximately 60 mL) at 35–40 °C with stirring (250 rpm) in excess water (492 mL).

[0147] After filtration, the separated product was dried at 40-80°C in a vacuum dryer equipped with a spiral crushing roller. This process yielded 16.0 g of amorphous (S)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-(2-methoxy-5-trifluoromethylphenyl)-3,4-dihydroquinazolin-4-yl}acetic acid, with a molar yield of 93.2%.

[0148] The properties of the product obtained by this process are the same as those in Example 1.

[0149] Comparative Example 3: Preparation of Letermovir amorphous MTBE by acetonitrile at 35-40℃

[0150] A mixture of (2S,3S)-2,3-bis[(4-methylbenzoyl)oxy]succinic acid-{(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}methyl acetate (1:1 salt) (30.8 g), sodium bicarbonate (16.4 g), and water (315 mL) was stirred with MTBE (160 mL). The resulting phases were separated and the organic phase was treated with 35 mL of 7% sodium bicarbonate solution. The resulting phases were separated again and the organic phase was treated with 125 mL of 4% sodium hydroxide solution.

[0151] The mixture of organic and aqueous phases was heated under reflux. The mixture was distilled to remove MTBE. The aqueous phase in the reactor was stirred again at 55–60 °C for 5 hours. MTBE (160 mL) and water (65 mL) were added to the mixture while stirring at 22 °C. The resulting phases were separated again, and the organic phase was extracted with a 6% sodium chloride aqueous solution (30 mL). The separated aqueous phase and the 6% sodium chloride solution after organic phase extraction were combined again and stirred with water (25 mL) and MTBE (160 mL). The pH was adjusted to 6.5 using 1 mol / L hydrochloric acid. The organic phase was separated, the solvent was gently distilled to dryness, and the residue was dissolved in acetonitrile (approximately 75 mL). Distillation was carried out at 35–40 °C for 2.0 hours, and repeated once to replace MTBE with acetonitrile, yielding an acetonitrile solution. The product was then precipitated by adding the acetonitrile solution (approximately 60 mL) with stirring (250 rpm) in excess water (492 mL) at 35–40 °C.

[0152] After filtration, the separated product was dried at 40-80°C in a vacuum dryer equipped with a spiral crushing roller. This process yielded 15.8 g of amorphous (S)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-(2-methoxy-5-trifluoromethylphenyl)-3,4-dihydroquinazolin-4-yl}acetic acid, with a molar yield of 92.3%.

[0153] The properties of the product obtained by this process are the same as those in Example 1.

[0154] Comparative Example 4: Preparation of Letermovir Amorphous by One-Time Replacement of MTBE with Acetone

[0155] A mixture of (2S,3S)-2,3-bis[(4-methylbenzoyl)oxy]succinic acid-{(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}methyl acetate (1:1 salt) (30.8 g), sodium bicarbonate (16.4 g), and water (315 mL) was stirred with MTBE (160 mL). The resulting phases were separated and the organic phase was treated with 35 mL of 7% sodium bicarbonate solution. The resulting phases were separated again and the organic phase was treated with 125 mL of 4% sodium hydroxide solution.

[0156] The mixture of organic and aqueous phases was heated under reflux conditions. The mixture was distilled to remove MTBE. The aqueous phase in the reactor was stirred again at 55–60 °C for 5 hours. MTBE (160 mL) and water (65 mL) were added to the mixture while stirring at 22 °C. The resulting phases were separated again, and the organic phase was extracted using a 6% sodium chloride aqueous solution (30 mL).

[0157] The separated aqueous phase and the 6% sodium chloride solution after organic phase extraction were recombined and stirred with water (25 mL) and MTBE (160 mL). The pH was adjusted to 6.5 using 1 mol / L hydrochloric acid. The organic phase was separated, and the solvent was gently distilled to dryness. The residue was dissolved in acetone (approximately 75 mL). The solution was replaced with acetone (20–25 °C) by a single distillation step of 130 mL of acetone, yielding an acetone solution. The product was then precipitated by adding the acetone solution at 20–25 °C with stirring in excess water (492 mL) at an excess of acetone (250 rpm).

[0158] After filtration, the separated product was dried at 40-80°C in a vacuum dryer equipped with a spiral crushing roller. This process yielded 15.3 g of amorphous (S)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-(2-methoxy-5-trifluoromethylphenyl)-3,4-dihydroquinazolin-4-yl}acetic acid, with a molar yield of 89.4%.

[0159] After drying, the process yields a light yellow solid, and the XRPD is consistent with that of Example 1.

[0160] Example 1: Comparative Study of Different Solvent Processes

[0161] Examples 1 and 4 are compared with Comparative Examples 1, 2, 3, and 4 to compare the MTBE replacement time, purity, solvent residue, isopropyl acetone impurities, racemic impurities, and particle size of different preparation methods.

[0162] Table 5 Comparison of different solvent processes

[0163]

[0164] The six methods used in Examples 1, 4, and Comparative Examples 1, 2, 3, and 4 yielded consistent lemetomovir, exhibiting high purity, low solvent residue, and largely uniform particle size. However, acetone and MTBE have similar boiling points. In industrial production, low-temperature substitution is time-consuming and requires large amounts of solvent, severely impacting production efficiency. High-temperature substitution may result in the inability to effectively control the impurity isopropyl acetone, posing a significant risk of contamination. If only one acetone substitution was used in Comparative Example 4, the product was a light yellow solid with MTBE solvent residue exceeding the ICH limit (<0.5%), failing to meet quality requirements, and the yield was significantly lower.

[0165] Acetonitrile has the risks of low residual solubility, high toxicity, and potential generation of racemic impurities. DMSO and isopropanol, on the other hand, do not introduce impurities or residual solubility risks. DMSO, in particular, has a significantly different boiling point from MTBE, allowing for complete replacement of MTBE with a single distillation, greatly improving production efficiency. Therefore, DMSO and isopropanol are more suitable as replacement and dissolving solvents for lutemoril amorphous compounds.

[0166] Example 2: Accelerated Stability Study with Different Solvents

[0167] Amorphous openings obtained from different solvent systems were placed under accelerated conditions of 40℃ / 75%RH to investigate changes in crystal form and purity.

[0168] Table 6. Accelerated stability results of products obtained by different preparation methods.

[0169]

[0170] The amorphous materials prepared by the five methods showed good stability and remained unchanged after being placed at 40℃ / 75%RH for 3 months.

[0171] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A method for preparing letermovir amorphous form, characterized in that, Including the following steps: (1) Provide a first solution of levofloxacin in a first solvent; (2) Add the first solution to the second solvent to produce a precipitate and obtain a suspension; (3) The suspension was separated and purified to obtain lemetmovir amorphous form. The first solvent is dimethyl sulfoxide; The second solvent is water; The solution is added slowly dropwise, and the precipitate is formed during the dropwise addition process; The method for preparing the first solution includes the following steps: (a) A mixture of a salt, a base, a second solvent, and a third solvent of termovir; wherein the third solvent is methyl tert-butyl ether (MTBE); (b) The mixture obtained by extraction is added to the first solvent and distilled at 35-40℃ for 2.0 hours to replace MTBE with DMSO and obtain a DMSO solution; (c) Optionally, add the first solvent, distill to remove the third solvent, and repeat once or more; (d) Obtain a solution of Letermovir in the first solvent.

2. The method as described in claim 1, characterized in that, The alkali mentioned is an inorganic alkali.

3. The method as described in claim 1, characterized in that, The alkali mentioned is sodium bicarbonate.

4. The method as described in claim 1, characterized in that, In step (b), prior to the extraction, a portion of the third solvent is removed by distillation.

5. The method as described in claim 1, characterized in that, In step (2), the temperature of the second solvent is 0-80°C.

6. The method as described in claim 5, characterized in that, The temperature of the second solvent is 20-60°C.

7. The method as described in claim 1, characterized in that, The separation and purification described in step (3) includes the following steps: The suspension was filtered, the filter cake was rinsed with deionized water, and then vacuum dried at 40-80℃.

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