Preparation method of letemovir amorphous form

Abstract

The present invention relates to an amorphous process for the preparation of a compound of formula I. Specifically, the invention provides a method for preparing the letemovir amorphous form as shown in the formula I. The method reduces the potential risk of impurity increase and is high in production efficiency, the prepared amorphous form is high in purity, low in solvent residue and good in powder property, and no oily matter is generated in the preparation process. # imgabs0 #

Description

A method for preparing amorphous Letermovir Technical Field

[0001] The invention belongs to the field of pharmaceuticals, and particularly relates to a method for preparing amorphous letermovir. Background Art

[0002] Cytomegalovirus (CMV) is a DNA virus belonging to the family Herpesviridae and the subfamily Betaherpes. CMV has significant species specificity, while human cytomegalovirus (HCMV) can only infect humans and proliferate in human fibroblasts. Although they can be found throughout the body, HCMV infection is usually associated with the salivary glands. HCMV infection is often overlooked in healthy people. However, it can be life-threatening for immunocompromised subjects such as HIV-infected patients, organ transplant recipients, or newborns. In particular, HCMV remains the leading viral cause of birth defects and a life-threatening disease in transplant recipients.

[0003] The chemical name of Letermovir 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] Letermovir belongs to a new class of non-nucleoside CMV inhibitors (3,4-dihydroquinazolines) that inhibit viral replication by targeting the viral terminase complex. The compound is active only against human cytomegalovirus and therefore has high potential as a specific human anti-HCMV drug.

[0005] Patent WO2013 / 127971A1 mentions calcium and sodium salts of letermovir; patent WO2013 / 127968A1 mentions benzenesulfonate and toluenesulfonate salts of letermovir; and patent WO2021 / 170882A1 mentions potassium salt of letermovir. No crystal forms of letermovir have been found in existing literature. WO2014 / 202737A1 mentions a method for preparing an amorphous form of letermovir, specifying that an amorphous form of letermovir suitable for formulation can be obtained using acetonitrile or acetone solvents. However, the amorphous form prepared using this method may have the potential risk of increased impurities and may also result in low production efficiency, making it unsuitable for industrial production. If acetone is used as the solvent according to the method in WO2014 / 202737A1, mesityl oxide impurities will be produced. If this impurity needs to be controlled to a lower limit, the MTBE (methyl tert-butyl ether) solvent needs to be replaced with acetone for a long time under low temperature conditions, which results in extremely low production efficiency. If acetonitrile is used as the solvent, heating or alkali will cause racemization. In addition, acetonitrile is highly toxic and has a low residual solubility limit, which cannot meet the requirements of industrial production.

[0006] In summary, there is an urgent need in the art for a method for preparing amorphous letermovir that is simple, easy to implement, and easily industrialized, and can ensure product quality (quality indicators such as purity, residual solvents, and impurities) while reducing costs and improving production efficiency.

[0007] Summary of the Invention

[0008] To address the problems of the prior art, the present 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 dissolves letermovir in a specific solvent and then back-titrates it with water to obtain the amorphous letermovir. This method solves the technical problems of potential impurity generation and low production efficiency. Therefore, the method of the present invention offers significant advantages in terms of resources and cost, making it more suitable for industrial production.

[0009] In a first aspect of the present invention, a method for preparing amorphous Letermovir is provided, characterized in that it comprises the steps of:

[0010] (1) providing a first solution of letermovir in a first solvent;

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

[0012] (3) Separating and purifying the suspension to obtain amorphous Letermovir.

[0013] In some embodiments, the method for preparing the first solution comprises the steps of:

[0014] (a) mixing a salt of Temovir, a base, a second solvent, and a third solvent;

[0015] (b) extracting the obtained mixture, adding a first solvent, and distilling to remove the third solvent;

[0016] (c) optionally, adding a first solvent and removing a third solvent by distillation, repeating one or more times;

[0017] (d) obtaining a solution of Letermovir 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), before performing the extraction, part of the third solvent is distilled off.

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

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

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

[0024] In another preferred embodiment, after dissolving Temovir 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 isopropyl alcohol.

[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 by slow dropwise addition, and the precipitate is generated during the dropwise addition.

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

[0034] The suspension was filtered, the filter cake was rinsed with deionized water and dried in vacuo at 40-80°C.

[0035] In the second aspect of the present invention, a pharmaceutical composition is provided, characterized in that the pharmaceutical composition comprises: (1) amorphous Letermovir prepared by the method described in the first aspect of the present invention; (2) optionally, a pharmaceutically acceptable carrier.

[0036] In the third aspect of the present invention, there is provided a use of the amorphous Letermovir prepared by the method according to the first aspect of the present invention or the pharmaceutical composition according to the second aspect of the present invention, characterized in that it is used to prepare a drug for preventing or treating diseases related to the herpes virus group.

[0037] In another preferred embodiment, the herpes virus group-related disease is a cytomegalovirus (CMV)-related disease.

[0038] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features described in detail 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 listed here one by one. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] FIG1 is an XRPD pattern of amorphous Letermovir prepared according to a preparation method according to an embodiment of the present invention. DETAILED DESCRIPTION

[0040] After extensive and intensive research, the inventors unexpectedly discovered that an amorphous form of letermovir can be obtained by dissolving letermovir in a specific solvent and then back-titrifying it with water. Furthermore, this amorphous form exhibits high purity, low residual solvent, low hygroscopicity, and excellent powder properties, while significantly reducing solvent replacement time. This makes it highly suitable for industrial production of the amorphous form. Based on this discovery, the inventors completed the present invention.

[0041] the term

[0042] Unless defined otherwise, 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 belongs.

[0043] Unless otherwise specified, in the present invention, the amorphous form refers to the amorphous form of Letermovir.

[0044] The main advantages of the present invention include:

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

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

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

[0048] (d) No oily matter is produced during the preparation of amorphous materials by the method of the present invention, the risk of residual dissolution is low, and the yield is high.

[0049] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention and are not intended to limit the scope of the invention. The experimental methods in the following examples, for which no specific conditions are specified, are generally based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight.

[0050] Unless otherwise specified, in the present invention, letermovir can be obtained from commercial sources or prepared according to methods known in the art, such as those described in WO2004 / 096778.

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

[0052] Detection method

[0053] The X-ray powder diffraction pattern (XRPD) of the present invention was collected on a Bruker D2Phaser X-ray powder diffractometer. The instrument parameters are as follows:

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

[0055] Scanning mode: θ / 2θ

[0056] Scanning range: 2-35°

[0057] Voltage: 30KV

[0058] Current: 10mA

[0059] In the present invention, the particle size is determined by a Mastersizer 2000 dry method. The specific detection parameters (referring to the method of patent WO2014 / 202737A1) are as follows:

[0060] Weighing amount: 0.3-0.4g

[0061] Measuring time: 20 seconds

[0062] Background time: 6 seconds

[0063] Shading limit: 0.5% to 6%

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

[0065] Feed rate: 45-55%

[0066] Dispersion pressure: 2.5Bar

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

[0068] In the present invention, the residual solvent (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, 2mL / mL (constant flow)

[0073] Injector temperature: 160°C

[0074] Detector / temperature: FID / 260℃

[0075] Hydrogen 30mL / min

[0076] Combustion gas: air 300mL / min

[0077] Composition gas (N2) 25mL / 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 1 μL

[0084] In the present invention, the purity is detected by high performance liquid chromatography, and the detection method (refer to the liquid phase detection method of patent WO2014 / 202737A1) is as follows:

[0085] Gradient reverse phase HPLC-purity

[0086] Example 1 Preparation of amorphous Letermovir in DMSO (dimethyl sulfoxide) at 35-40°C

[0087] A mixture of (2S,3S)-2,3-bis[(4-methylbenzoyl)oxy]succinate-{(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetate (1:1 salt) (61.6 g), sodium bicarbonate (32.8 g) and water (630 mL) was stirred with MTBE (320 mL). The phases were separated and the organic phase was treated with 70 mL of 7% sodium bicarbonate solution. The phases were separated again and the organic phase was treated with 250 mL of 4% sodium hydroxide solution.

[0088] The mixture of the organic and aqueous phases was heated under reflux. The mixture was distilled to remove MTBE. The aqueous phase of the reactor was stirred at 55-60° C. for a further 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 with 6% aqueous sodium chloride solution (60 mL).

[0089] The 6% sodium chloride solution after the aqueous phase separated and the extracted organic phase is re-merged, and stirred with water (50mL) and MTBE (320mL). By means of 1mol / L hydrochloric acid, pH is adjusted to 6.5, the organic phase is separated, and the solvent is gently distilled to dryness. The residue is dissolved in DMSO (about 120mL). Distilled 2.0 hours at 35-40 ℃, realize the replacement of DMSO to MTBE, obtain DMSO solution. Subsequently by under the stirring condition (250rpm) in excess water (960mL) at 35-40 ℃, add DMSO solution, precipitate product.

[0090] After filtration, 170 mL of water was added for rinsing. The separated wet cake was dried at 40-80° C. in a vacuum dryer equipped with a spiral crushing roller.

[0091] By this procedure, (S)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-(2-methoxy-5-trifluoromethylphenyl)-3,4-dihydroquinazolin-4-yl}acetic acid was obtained as an amorphous form in a yield of 31.6 g with a molar yield of 92.3%.

[0092] The dried solid was a white powder, and its XRPD, as shown in Figure 1, indicated that the obtained product was amorphous. The amorphous form had high purity, low residual solubility, and low hygroscopicity.

[0093] Example 2 Preparation of amorphous Letermovir by back-titration of DMSO solution at 20-25°C

[0094] The amorphous form of Letermovir (1.0 g) obtained in Example 1 and DMSO (3.5 mL) were added to a 10 mL glass bottle at once. The mixture was stirred at 20-25° C. and clarified. 28 mL of purified water was added to a 50 mL three-necked flask and heated to 20-25° C. The insulated DMSO solution was slowly added dropwise at this temperature over a total addition time of 2 hours to obtain a white turbid solid suspension. After the addition was complete, stirring was continued for 1 hour, filtered, rinsed with 5 mL of purified water, and the solid was collected. After drying in a vacuum oven at 50° C. for 24 hours, 0.90 g of a white solid was obtained, with a molar yield of 90.0%.

[0095] The properties and XRPD of the product obtained by this process are the same as those in Example 1.

[0096] Example 3 Preparation of amorphous Letermovir by back-titration of DMSO solution at 35-40°C

[0097] The amorphous form of Letermovir (1.0 g) and DMSO (2.0 mL) obtained in Example 1 were added to a 10 mL glass bottle at once. The mixture was stirred at 35-40° C. and clarified. Hot filtration was performed through a 0.45 μm filter membrane, followed by rinsing with 0.5 mL of DMSO. The filtrate and rinsate were mixed and kept warm at 35-40° C. A 50 mL three-necked flask was added with 20 mL of purified water and heated to 35-40° C. The insulated DMSO solution was slowly added dropwise at this temperature for a total of 2 hours to obtain a white turbid solid suspension. After the addition was complete, the suspension was cooled to room temperature and stirred for 1 hour. The mixture was filtered with suction, rinsed with 5 mL of purified water, and the solid was collected. The mixture was dried in a vacuum oven at 50° C. for 24 hours to obtain 0.91 g of a white solid with a molar yield of 91.0%.

[0098] The properties and XRPD of the product obtained by this process are the same as those in Example 1.

[0099] Example 4 Preparation of amorphous Letermovir at 55-60°C in IPA (isopropyl alcohol)

[0100] A mixture of (2S,3S)-2,3-bis[(4-methylbenzoyl)oxy]succinate-{(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetate (1:1 salt) (30.8 g), sodium bicarbonate (16.4 g) and water (315 mL) was stirred with MTBE (160 mL). The phases were separated and the organic phase was treated with 35 mL of 7% sodium bicarbonate solution. The phases were separated again and the organic phase was treated with 125 mL of 4% sodium hydroxide solution.

[0101] The mixture of the organic and aqueous phases was heated under reflux. The mixture was distilled to remove MTBE. The aqueous phase of the reactor was stirred at 55-60°C for a further 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 6% aqueous sodium chloride solution (30 mL).

[0102] The separated aqueous phase and the 6% sodium chloride solution after the extraction of the organic phase were recombined and stirred with water (25 mL) and MTBE (160 mL). The pH was adjusted to 6.5 with the help of 1 mol / L hydrochloric acid. The organic phase was separated and the solvent was gently distilled to dryness. The residue was dissolved in IPA (about 60 mL). Distillation was performed at 35-40° C. for 2.0 hours and repeated once to replace MTBE with IPA to obtain an IPA solution. The product was subsequently precipitated by adding the IPA solution under stirring conditions (250 rpm) in excess water (480 mL) at 35-40° C.

[0103] After filtration, 85 mL of water was added for rinsing. The separated wet cake was dried in a vacuum dryer equipped with a spiral crushing roller at 40-80°C. Through this procedure, a yield of 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 was obtained, with a molar yield of 94.6%.

[0104] The properties and XRPD of the product obtained by this process are the same as those in Example 1.

[0105] Example 5 Preparation of amorphous letermovir by back-titration of IPA solution at 20-25°C

[0106] The amorphous form of Letermovir (1.0 g) obtained in Example 1 and IPA (5.5 mL) were added to a 10 mL glass bottle at once. The mixture was stirred at 20-25° C. and clarified. 44 mL of purified water was added to a 100 mL three-necked flask and heated to 20-25° C. The insulated IPA solution was slowly added dropwise at this temperature over a total addition time of 2 hours to obtain a white turbid solid suspension. After the addition was complete, stirring was continued for 1 hour, filtered, rinsed with 5 mL of purified water, and the solid was collected. After drying in a vacuum oven at 50° C. for 24 hours, 0.89 g of a white solid was obtained, with a molar yield of 89.0%.

[0107] The properties and XRPD of the product obtained by this process are the same as those in Example 1.

[0108] Example 6 Preparation of amorphous Letermovir by back-titration of IPA solution at 35-40°C

[0109] The amorphous form of Letermovir (1.0 g) and IPA (3.0 mL) obtained in Example 1 were added to a 10 mL glass bottle at once. The mixture was stirred at 35-40° C. and clarified. Hot filtration was performed through a 0.45 μm filter membrane, and 0.5 mL of IPA was used for elution. The filtrate and the elution were mixed and kept warm at 35-40° C. 28 mL of purified water was added to a 50 mL three-necked flask and heated to 35-40° C. The insulated IPA solution was slowly added dropwise at this temperature. The total dropwise addition time was 2 hours to obtain a white turbid solid suspension. After the addition was complete, the suspension was cooled to room temperature and stirred for 1 hour. The suspension was filtered with suction, and the solid was washed with 5 mL of purified water and collected. The solid was dried in a vacuum oven at 50° C. for 24 hours to obtain 0.90 g of a white solid with a molar yield of 90.0%.

[0110] The properties and XRPD of the product obtained by this process are the same as those in Example 1.

[0111] Example 7 Back-titration experiment using water as anti-solvent

[0112] The amorphous form of Letermovir obtained in Example 1 was used as a raw material, dissolved in the solvents listed in the table below, and then added dropwise to water. The results are shown in Table 1. The specific implementation method is as follows:

[0113] In a 5 mL glass bottle, the amorphous form of Letermovir (0.2 g) obtained in Example 1 and DMSO (0.7 mL) were added in sequence. The mixture was heated to 35-40° C. and then stirred for 15 minutes until the solution became clear. 5.6 mL of purified water was added to a 50 mL three-necked flask and heated to 35-40° C. The clarified DMSO solution was slowly added dropwise at this temperature for a total of 2 hours to obtain a white turbid solid suspension. After the addition was complete, the suspension was cooled to room temperature and stirred for 1 hour. The suspension was filtered, rinsed with 1 mL of purified water, and the solid was collected. The suspension was dried in a vacuum oven at 50° C. for 24 hours to obtain a white solid.

[0114] The method for preparing amorphous letermovir with other solvents is similar to that of DMSO solvent, except that DMSO is replaced with other solvents.

[0115] Table 1 Back drop precipitation reaction with water as antisolvent

[0116] Except for acetone, acetonitrile, methanol, ethanol, dimethyl sulfoxide and isopropanol, the other solvents will show obvious oil formation during the dropwise addition process, which is not conducive to the precipitation of amorphous solids.

[0117] Example 8 Back-titration experiment using alkane as anti-solvent

[0118] The preparation method is consistent with that of Example 3, except that the dissolving solvent is replaced with the dissolving solvent in the table, and water is replaced with the alkane in the table.

[0119] Table 2 Back drop precipitation reaction with alkanes as antisolvents

[0120] All positive solvents will produce oil when dissolved and added dropwise to an alkane (cyclohexane or n-heptane) solvent, which is not conducive to the precipitation of amorphous solids.

[0121] Example 9: Forward droplet experiment using water as antisolvent

[0122] The amorphous form of Letermovir obtained in Example 1 was used as a raw material and dissolved in the solvents listed in the table below. Water was then added dropwise to the solution. The results are shown in Table 3. The specific implementation method is as follows:

[0123] In a 5 mL glass bottle, add the amorphous form of Letermovir (0.2 g) obtained in Example 1 and DMSO (0.7 mL) in sequence. 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 with suction, rinse with 1 mL of purified water, collect the solid, and dry in a 50°C vacuum oven for 24 hours to obtain a white solid.

[0124] The method for preparing amorphous Letermovir with other solvents is similar to that of DMSO solvent. DMSO is replaced with the dissolving solvents listed in the table.

[0125] Table 3 Forward precipitation reaction with water as antisolvent

[0126] Water added to any clear solution will form oil, which is not conducive to amorphous precipitation.

[0127] Example 10 Solution Stability Investigation

[0128] The amorphous phase obtained in Example 1 was added to the solvents listed in the table below to dissolve the solution, and the solution was placed at the corresponding temperature to investigate the stability of the solution. The results are shown in Table 4.

[0129] Table 4 Solution stability results

[0130] Both methanol and ethanol solutions produced new impurities, with the impurity levels increasing rapidly. These impurities are presumed to be methyl or ethyl ester impurities, significantly reducing purity. However, dimethyl sulfoxide solutions produced no new impurities, while isopropanol solutions produced a small amount of impurities, presumably isopropanol ester impurities. Dimethyl sulfoxide and isopropanol solutions showed minimal or no new impurities, making them suitable solvents for preparing amorphous products.

[0131] Comparative Example 1 Preparation of amorphous Letermovir in acetone at 20-25°C (prepared with reference to patent WO2014 / 202737A1)

[0132] A mixture of (2S,3S)-2,3-bis[(4-methylbenzoyl)oxy]succinate-{(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetate (1:1 salt) (30.8 g), sodium bicarbonate (16.4 g), and water (315 mL) was stirred with MTBE (160 mL). The phases were separated and the organic phase was treated with 35 mL of 7% sodium bicarbonate solution. The phases were separated again and the organic phase was treated with 125 mL of 4% sodium hydroxide solution.

[0133] The mixture of the organic and aqueous phases was heated under reflux. The mixture was distilled to remove MTBE. The aqueous phase of the reactor was stirred at 55-60°C for a further 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 6% aqueous sodium chloride solution (30 mL).

[0134] The 6% sodium chloride solution after the separated aqueous phase and the extracted organic phase is re-merged and stirred with water (25mL) and MTBE (160mL). With the help of 1mol / L hydrochloric acid, the pH is adjusted to 6.5. The separated organic phase is distilled gently with solvent to dry and the residue is dissolved in acetone (about 75mL). With the help of 6 distillation steps of each 130mL, the solution is replaced with acetone (20-25 ℃), obtaining acetone solution. Subsequently, acetone solution (about 60mL) is added under the stirring condition (250rpm) in excess water (492mL) at 20-25 ℃ to precipitate the product. After suction filtration, the separated product is dried at 40-80 ℃ in a vacuum dryer equipped with a spiral crushing roller. By this procedure, (S)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-(2-methoxy-5-trifluoromethylphenyl)-3,4-dihydroquinazolin-4-yl}acetic acid was obtained as an amorphous form in a yield of 16.0 g with a molar yield of 93.5%.

[0135] The properties and XRPD of the product obtained by this process are the same as those in Example 1.

[0136] Comparative Example 2 Preparation of Letermovir Amorphous Form in Acetone at 55-60°C

[0137] A mixture of (2S,3S)-2,3-bis[(4-methylbenzoyl)oxy]succinate-{(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetate (1:1 salt) (30.8 g), sodium bicarbonate (16.4 g) and water (315 mL) was stirred with MTBE (160 mL). The phases were separated and the organic phase was treated with 35 mL of 7% sodium bicarbonate solution. The phases were separated again and the organic phase was treated with 125 mL of 4% sodium hydroxide solution.

[0138] The mixture of the organic and aqueous phases was heated under reflux. The mixture was distilled to remove MTBE. The aqueous phase of the reactor was stirred at 55-60°C for a further 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 6% aqueous sodium chloride solution (30 mL).

[0139] The separated aqueous phase and the 6% sodium chloride solution after the extraction of the organic phase were recombined and stirred with water (25 mL) and MTBE (160 mL). The pH was adjusted to 6.5 with the help of 1 mol / L hydrochloric acid. The organic phase was separated, the solvent was gently distilled to dryness and the residue was dissolved in acetone (about 75 mL). The solution was replaced with acetone (35-40 ° C) by 6 distillation steps of 130 mL each time to obtain an acetone solution, which was subsequently precipitated by adding an acetone solution (about 60 mL) under stirring conditions (250 rpm) in excess water (492 mL) at 35-40 ° C.

[0140] After suction filtration, the separated product was dried in a vacuum dryer equipped with a spiral crushing roller at 40-80° C. By this procedure, a yield of 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 was obtained, with a molar yield of 93.2%.

[0141] The properties and XRPD of the product obtained by this process are the same as those in Example 1.

[0142] Comparative Example 3 Preparation of Letermovir Amorphous Form from Acetonitrile at 35-40°C MTBE

[0143] A mixture of (2S,3S)-2,3-bis[(4-methylbenzoyl)oxy]succinate-{(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetate (1:1 salt) (30.8 g), sodium bicarbonate (16.4 g) and water (315 mL) was stirred with MTBE (160 mL). The phases were separated and the organic phase was treated with 35 mL of 7% sodium bicarbonate solution. The phases were separated again and the organic phase was treated with 125 mL of 4% sodium hydroxide solution.

[0144] The mixture of the organic phase and the aqueous phase was heated under reflux conditions. The mixture was distilled to remove MTBE. The aqueous phase of the reactor was stirred at 55-60° C. for another 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 the aid of a 6% sodium chloride aqueous solution (30 mL). The separated aqueous phase and the 6% sodium chloride solution after the organic phase extraction were recombined and stirred with water (25 mL) and MTBE (160 mL). The pH was adjusted to 6.5 with the aid of 1 mol / L hydrochloric acid. The organic phase was separated, the solvent was gently distilled to dryness, and the residue was dissolved in acetonitrile (about 75 mL). Distilled at 35-40° C. for 2.0 hours, and repeated 1 time to achieve the replacement of MTBE with acetonitrile to obtain an acetonitrile solution. The product was subsequently precipitated by adding an acetonitrile solution (about 60 mL) under stirring conditions (250 rpm) in excess water (492 mL) at 35-40° C.

[0145] After suction filtration, the separated product was dried in a vacuum dryer equipped with a spiral crushing roller at 40-80° C. By this procedure, a yield of 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 was obtained, with a molar yield of 92.3%.

[0146] The properties and XRPD of the product obtained by this process are the same as those in Example 1.

[0147] Comparative Example 4 Preparation of Letermovir Amorphous by One-time Replacement of MTBE with Acetone

[0148] A mixture of (2S,3S)-2,3-bis[(4-methylbenzoyl)oxy]succinate-{(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetate (1:1 salt) (30.8 g), sodium bicarbonate (16.4 g) and water (315 mL) was stirred with MTBE (160 mL). The phases were separated and the organic phase was treated with 35 mL of 7% sodium bicarbonate solution. The phases were separated again and the organic phase was treated with 125 mL of 4% sodium hydroxide solution.

[0149] The mixture of the organic and aqueous phases was heated under reflux. The mixture was distilled to remove MTBE. The aqueous phase of the reactor was stirred at 55-60°C for a further 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 6% aqueous sodium chloride solution (30 mL).

[0150] The separated aqueous phase and the 6% sodium chloride solution after the extraction of the organic phase were recombined and stirred with water (25 mL) and MTBE (160 mL). The pH was adjusted to 6.5 with the help of 1 mol / L hydrochloric acid. The organic phase was separated and the solvent was gently distilled to dryness. The residue was dissolved in acetone (about 75 mL). The solution was replaced with acetone (20-25 ° C) by a distillation step of 130 mL of acetone to obtain an acetone solution, which was subsequently added under stirring conditions (250 rpm) in excess water (492 mL) at 20-25 ° C to precipitate the product.

[0151] After suction filtration, the separated product was dried in a vacuum dryer equipped with a spiral crushing roller at 40-80° C. By this procedure, a yield of 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 was obtained, with a molar yield of 89.4%.

[0152] This process yielded a light yellow solid after drying, and its XRPD was consistent with that of Example 1.

[0153] Effect Example 1 Comparative Study of Different Solvent Processes

[0154] Examples 1 and 4 were compared with Comparative Examples 1, 2, 3, and 4 to compare the MTBE replacement time, purity, residual solvent, mesityl oxide impurity, racemic impurity, and particle size of the different preparation methods.

[0155] Table 5 Comparison results of different solvent processes

[0156] The six methods for preparing letermovir, including Examples 1 and 4 and Comparative Examples 1, 2, 3, and 4, showed consistent yields, high purity, low residual solvent content, and essentially identical particle sizes. However, acetone and MTBE have similar boiling points. Low-temperature substitution in industrial production is time-consuming and requires large amounts of solvent, severely impacting production efficiency. High-temperature substitution may prevent effective control of the impurity mesityl oxide, posing a significant impurity risk. Using only one acetone substitution, as in Comparative Example 4, resulted in a light yellow solid with residual MTBE exceeding the ICH limit (<0.5%), failing to meet quality requirements, and a significantly lower yield.

[0157] Acetonitrile has a low residual solubility limit, high toxicity, and the risk of producing racemic impurities. DMSO and isopropanol do not increase impurities or risk of residual solubility. DMSO, in particular, has a significantly different boiling point from MTBE and can be completely replaced with MTBE using a single distillation, greatly improving production efficiency. Therefore, DMSO and isopropanol are more suitable solvents for replacing and dissolving the amorphous form of letermovir.

[0158] Effect Example 2 Accelerated Stability Study of Different Solvent Processes

[0159] The amorphous openings obtained from different solvent systems were placed under accelerated conditions of 40°C / 75% RH to investigate the changes in crystal form and purity.

[0160] Table 6 Accelerated stability results of products obtained by different preparation methods

[0161] The amorphous structures prepared by the five methods were more stable and did not change after being placed at 40℃ / 75%RH for 3 months.

[0162] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. A method for preparing amorphous Letermovir, characterized in that: Including steps: (1) providing a first solution of letermovir in a first solvent; (2) adding the first solution to the second solvent to generate a precipitate and obtain a suspension; (3) Separating and purifying the suspension to obtain amorphous Letermovir.

2. The method according to claim 1, wherein The method for preparing the first solution comprises the steps of: (a) mixing a salt of Temovir, a base, a second solvent, and a third solvent; (b) extracting the obtained mixture, adding a first solvent, and distilling to remove the third solvent; (c) optionally, adding a first solvent and removing a third solvent by distillation, repeating one or more times; (d) obtaining a solution of Letermovir in the first solvent. In another preferred embodiment, the third solvent is methyl tert-butyl ether (MTBE). In another preferred embodiment, the base is an inorganic base. In another preferred embodiment, in step (b), before performing the extraction, part of the third solvent is distilled off. In another preferred embodiment, the distillation temperature in step (b) and step (c) is 20-60°C.

3. The method according to claim 1, wherein The method for preparing the first solution in step (1) comprises the steps of: dissolving temovir in a first solvent. In another preferred embodiment, after dissolving Temovir in the first solvent, the mixture is filtered and the filtrate is retained, and the filtrate is the first solution. In another preferred embodiment, after dissolving Temovir in the first solvent, the system is heated and / or stirred. In another preferred embodiment, the heating temperature is 0-80°C. In another preferred embodiment, the heating temperature is 20-60°C.

4. The method according to claim 1, wherein The first solvent is an organic solvent. In another preferred embodiment, the first solvent is dimethyl sulfoxide or isopropyl alcohol.

5. The method according to claim 1, wherein The second solvent is water.

6. The method according to claim 1, wherein In step (2), the temperature of the second solvent is 0-80°C. In another preferred embodiment, the temperature of the second solvent is 20-60°C.

7. The method according to claim 1, wherein In step (2), the solution is added by slow dropwise addition, and the precipitate is generated during the dropwise addition process.

8. The method according to claim 1, wherein The separation and purification described in step (3) comprises the steps of: The suspension was filtered, the filter cake was rinsed with deionized water and dried in vacuo at 40-80°C.

9. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises: (1) amorphous Letermovir prepared by the method according to claim 1; and (2) optionally, a pharmaceutically acceptable carrier.

10. Use of the amorphous Letermovir prepared by the method according to claim 1 or the pharmaceutical composition according to claim 9, characterized in that: Used for preparing medicines for preventing or treating diseases related to the herpes virus group. In another preferred embodiment, the herpes virus group-related disease is a cytomegalovirus (CMV)-related disease.

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