Process for producing sodium 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetate trihydrate in crystalline form

Abstract

The present invention relates to an efficient method for preparing sodium 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetate trihydrate in crystalline form.

Description

Technical Field

[0001] The present invention relates to an efficient process for preparing sodium 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetate trihydrate in crystalline form. Background Art

[0002] Cytomegalovirus (CMV) is a common opportunistic infection that causes significant morbidity and preventable mortality after solid organ and allogeneic hematopoietic stem cell transplantation.

[0003] (S)-(+)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetic acid or 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetic acid is known as Letermovir. In WO 2004 / 096778, it was developed as an antiviral agent, in particular for use against infections caused by human cytomegalovirus (HCMV). Salts of 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetic acid are obtained in crystalline or amorphous form (WO 2013 / 127971 A1). In particular, some sodium or calcium salts of Letermovir are obtained mainly in amorphous form. In the case of the sodium salt of Letermovir, some crystalline sodium hydrates are also obtained.

[0004] However, there is still a need for an efficient process for producing sodium 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2]-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetate trihydrate in crystalline form, as is evident from the independent claims. Summary of the invention

[0005] In one aspect, the present invention relates to a crystalline sodium 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetate trihydrate of formula (I),

[0006]

[0007] It is essentially free of alcohol, in particular methanol or ethanol. No step in the preparation of the crystalline sodium 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetate trihydrate involves alcohol, in particular methanol or ethanol. This results in a product free of said alcohol.

[0008] In another aspect, the present invention relates to a process for the manufacture of sodium 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetate trihydrate of formula (I) in crystalline form,

[0009]

[0010] The method comprises the following steps:

[0011] Step 1) providing a solution of 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetic acid in a mixture of (C1-C6)alkyl acetate and (C1-C6)dialkyl ether with a concentration of 0.3M to 0.7M, wherein the molar ratio of (C1-C6)alkyl acetate:(C1-C6)dialkyl ether is 1:1 to 1:3, and wherein the temperature of the solution is preferably in the range of 30°C to 60°C;

[0012] step 2) adding an aqueous sodium hydroxide solution in an amount of 1.0 to 2.0 molar equivalents based on 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetic acid to the solution obtained in step 1 to provide a mixture;

[0013] Step 3) stirring the mixture obtained in step 2 at a temperature ranging from 30° C. to 60° C. for at least 30 minutes to obtain a suspension containing a solid compound;

[0014] Step 4) separating the solid compound from the suspension obtained in step 3; and

[0015] Step 5) Dry the solid compound obtained in step 4 at a temperature range of 30°C to 60°C for at least 1 hour to obtain crystalline sodium 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetate trihydrate.

[0016] In the prior art method, the sodium salt of Letermovir must be prepared separately, and then the sodium salt is treated in an aqueous alcohol such as methanol or ethanol for one week to obtain a crystalline solid and filter it. In the present invention, it is proved that the crystalline solid of the prior art is not Letermovir sodium trihydrate, but a mixed alcohol water solvate form of Letermovir.

[0017] In the case of using methanol as solvent, sodium 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetate methanol monohydrate is formed in crystalline form, such as Figure 1 Table 1 lists the X-ray structural data of the crystalline Letermovir sodium methanol monohydrate.

[0018] In the case of using ethanol as solvent, crystalline form of sodium 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetate ethanol monohydrate is formed, such as Figure 2 Table 2 lists the X-ray structural data of the crystalline Letermovir sodium ethanol monohydrate.

[0019] The crystals obtained, i.e., Letermovir sodium methanol monohydrate and Letermovir sodium ethanol monohydrate, must be dried at room temperature and ambient humidity for two weeks to be converted into crystalline sodium 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetate trihydrate, as Figure 4 shown.

[0020] Furthermore, the use of water as a co-solvent does not result in the formation of Letermovir sodium trihydrate. Therefore, there is no successful method for preparing Letermovir sodium salt trihydrate using water as a co-solvent in the prior art.

[0021] In the present invention, the following parameters were tested during the development and optimization process:

[0022] -Solvent / Antisolvent Ratio

[0023] - Addition of antisolvent (addition rate and time)

[0024] -API concentration

[0025] - Addition of NaOH (directly or dissolved in water)

[0026] - Volume of water

[0027] - Reaction time

[0028] - Reaction temperature

[0029] - Seeding with seed crystals (optional)

[0030] By using the above-mentioned inventive method, crystalline sodium 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetate trihydrate of formula (I) is directly obtained by using water as a co-solvent.

[0031] The method of the present invention has the following technical advantages:

[0032] - sodium 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetate trihydrate can be prepared directly from Letermovir base;

[0033] - The whole process requires a relatively short reaction time (4 hours + 15 hours drying);

[0034] - The process directly produces Letermovir sodium trihydrate (without other transition forms);

[0035] - The process is repeatable and scalable.

[0036] In another aspect, the present invention relates to a pharmaceutical composition and a method for preparing the pharmaceutical composition, wherein the pharmaceutical composition comprises the crystalline sodium 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetate trihydrate. DETAILED DESCRIPTION OF THE INVENTION

[0038] It should be noted that the term “comprising” also includes the meaning of “consisting of”, for example, a component group comprising a set of components also includes a component group consisting of only these components.

[0039] As used herein, the term "room temperature" is synonymous with the term "standard room temperature" and refers to a temperature of 19° C. to 26° C. For example, "cooling the suspension to room temperature" means "cooling the suspension to a temperature in the range of 19° C. to 26° C.".

[0040] As used herein, the term "crystal" refers to any three-dimensional ordered array of molecules that diffracts X-rays.

[0041] As used herein, the term "unit cell" refers to a basic parallelepiped-shaped block. The entire crystal volume can be constructed by regular assembly of these blocks.

[0042] Each unit cell contains a complete representation of the pattern unit, the repetition of which builds the crystal.

[0043] As used herein, the term "space group" refers to the arrangement of the symmetry elements of a crystal.

[0044] As used herein, the term "asymmetric unit" refers to the smallest set of atomic coordinates that can be used to produce an entire repetition in a crystal.

[0045] The term "polymorph" refers to a specific crystal form (ie, lattice structure) of Letermovir potassium salt or a solvate thereof that is capable of existing in more than one crystal form in the solid state.

[0046] As used herein, the term "solvate" refers to those forms of a compound, particularly sodium 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetate trihydrate, which form a complex by coordination with solvent molecules. Hydrates are a special form of solvates in which coordination occurs with water.

[0047] As used herein, the term "(C1-C6) alkyl" refers to a saturated, linear or branched hydrocarbon group having 1 to 6 carbon atoms, i.e., the term "(C1-C6) alkyl" refers to: -CH3, -C2H5, -C3H7, -C4H9, -C5H 11 、-C6H 13 linear hydrocarbon radical; or -CH(CH3)2, -CH2-CH(CH3)2, -CH(CH3)-C2H5, -C(CH3)3, -CH(CH3)-C3H7, -CH2-CH(CH3)-C2H5, -CH(CH3)-CH(CH3)2, -C(CH3)2-C2H5, -CH2-C(CH3)3, -CH(C2H5)2, -C2H4-CH(CH3)2, -C3H6-CH(CH3)2, -C2H4-C A branched hydrocarbon group comprising: H(CH3)-C2H5, -CH(CH3)-C4H9, -CH2-CH(CH3)-C3H7, -CH(CH3)-CH2-CH(CH3)2, -CH(CH3)-CH(CH3)-C2H5, -CH2-CH(CH3)-CH(CH3)2, -CH2-C(CH3)2-C2H5, -C(CH3)2-C3H7, -C(CH3)2-CH(CH3)2, -C2H4-C(CH3)3 or -CH(CH3)-C(CH3)3.

[0048] As used herein, the term "dialkyl ether" refers to a group of the formula ROR, wherein each R group is an alkyl group.

[0049] Within the scope of the present invention, the terms "obtained by" and "obtainable by" have the same meaning and can be used interchangeably.

[0050] Within the scope of the present invention, the term "equivalent" is understood to mean "molar equivalent".

[0051] As used herein, the term "substantially free of alcohol, in particular methanol or ethanol" means that the content of alcohol in the unit cell is less than 1 mol%, preferably less than 0.5 mol% and more preferably less than 0.3 mol%.

[0052] As used herein, the term "dry powder" refers to a solid dosage form containing a mixture of a final dispersed drug or chemical in a dry form for internal or external use. The final dispersed drugs or chemicals in a heterogeneous mixture do not show any physicochemical interaction, such as association or agglomeration, with each other.

[0053] As used herein, the term "treatment" is defined as: applying or administering a therapeutic agent, i.e., Letermovir sodium salt trihydrate, to a subject (alone or in combination with another drug); or applying or administering a therapeutic agent to an isolated tissue or cell line from a subject suffering from HCMV infection, symptoms of HCMV infection, or the likelihood of developing HCMV infection, for the purpose of treating, curing, alleviating, mitigating, altering, remedying, improving, enhancing, or affecting the HCMV infection, symptoms of HCMV infection, or the likelihood of developing HCMV infection. Such treatments can be specifically tailored or modified based on knowledge gained from the field of pharmacogenomics.

[0054] As used herein, the term "prevent" means that if any disorder or disease does not occur, the disorder or disease will not develop; or if a disorder or disease has already occurred, the disorder or disease will not develop further. The ability to prevent some or all symptoms associated with a disorder or disease is also contemplated. Preventing a disease also includes prevention of a disease.

[0055] As used herein, the term "subject" refers to a human or non-human mammal. Non-human mammals include, for example, livestock and pets, such as sheep, cattle, pigs, cats, dogs and mice. Preferably, the subject is a human.

[0056] As used herein, the term "pharmaceutically acceptable" refers to a material such as a carrier or diluent that does not abrogate the biological activity or properties of the compound and is relatively nontoxic, i.e., the material can be administered to a subject without causing undesirable biological effects or interacting in a deleterious manner with any component of the composition in which it is contained.

[0057] Preferably, in the process of the present invention, the (C1-C6) alkyl acetate is methyl acetate, propyl acetate, isopropyl acetate or butyl acetate or a mixture thereof, and the (C1-C6) dialkyl ether is diisopropyl ether, methoxypentane or methyl tert-butyl ether (MTBE) or a mixture thereof. More preferably, the (C1-C6) alkyl acetate is isopropyl acetate, and the (C1-C6) dialkyl ether is diisopropyl ether.

[0058] Preferably, in step 1 of the method mentioned herein, the concentration of the solution of 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetic acid is in the range of 0.3M to 0.6M.

[0059] Preferably, in step 2 of the method mentioned herein, the concentration of sodium hydroxide in the aqueous sodium hydroxide solution is in the range of 5M to 30M, more preferably in the range of 10M to 30M, still more preferably in the range of 10M to 27M, most preferably in the range of 15M to 25M.

[0060] Preferably, in step 2 of the process mentioned herein, 1.1 to 1.5 molar equivalents of sodium hydroxide based on the content of 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetic acid is added in the form of an aqueous solution having a sodium hydroxide concentration in the range of 5M to 30M, more preferably in the range of 10M to 30M, still more preferably in the range of 10M to 27M and most preferably in the range of 15M to 25M.

[0061] Preferably, in step 3 of the method mentioned herein, the mixture is stirred at a temperature range of 40°C to 60°C for 1 to 6 hours. More preferably, the mixture is stirred at a temperature range of 45°C to 55°C for 1 to 6 hours. More preferably, the mixture is stirred at a temperature of 50°C for 1 to 6 hours. Preferably, in step 3, the mixture is stirred at a temperature range of 40°C to 60°C for 2 to 5 hours. More preferably, the mixture is stirred at a temperature range of 45°C to 55°C for 2 to 5 hours. More preferably, the mixture is stirred at a temperature of 50°C for 2 to 5 hours. Preferably, in step 3, the mixture is stirred at a temperature range of 45°C to 55°C for 3 to 4 hours. More preferably, the mixture is stirred at a temperature range of 45°C to 55°C for 3 to 4 hours. More preferably, the mixture is stirred at a temperature of 50°C for 3 to 4 hours.

[0062] In one embodiment, step 3 of the method of the present invention further comprises the steps of: cooling the stirred suspension to room temperature at a cooling rate of 60K / hour or less; filtering the cooled suspension to provide a solid compound; and optionally washing the solid compound with a (C1-C6) dialkyl ether, wherein the (C1-C6) dialkyl ether is the same as the (C1-C6) dialkyl ether used in step 1.

[0063] In a preferred embodiment, the (C1-C6)alkyl acetate is methyl acetate, propyl acetate, isopropyl acetate or butyl acetate or a mixture thereof, and the (C1-C6)dialkyl ether is diisopropyl ether, methoxypentane or methyl tert-butyl ether or a mixture thereof, preferably, the (C1-C6)alkyl acetate is isopropyl acetate and the (C1-C6)dialkyl ether is diisopropyl ether, more preferably, the (C1-C6)alkyl acetate is isopropyl acetate and the (C1-C6)dialkyl ether is diisopropyl ether and the molar ratio of isopropyl acetate:dialkyl ether is 1:2.

[0064] In one embodiment, the solid compound is dried under reduced pressure below 10 hPa in step 5 of the process mentioned herein. In a preferred embodiment, the solid compound is dried under reduced pressure of about 2 hPa to 3 hPa at 50° C. for 15 hours in step 5 of the process mentioned herein.

[0065] Therefore, in a particularly preferred embodiment, another aspect of the present invention relates to a method for preparing a crystalline form of sodium 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetate trihydrate of formula (I), the method comprising the following steps:

[0066] Step 1) providing a solution of 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetic acid in a concentration range of 0.3M to 0.6M in a mixture of isopropyl acetate and diisopropyl ether, wherein the molar ratio of isopropyl acetate: diisopropyl ether is 1:1 to 1:3, and wherein the temperature of the solution is in the range of 30°C to 60°C;

[0067] step 2) adding an aqueous sodium hydroxide solution in an amount of 1.1 to 1.5 molar equivalents based on 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetic acid to the solution obtained in step 1 to provide a mixture, wherein the concentration of sodium hydroxide in the aqueous sodium hydroxide solution is 15 M to 25 M;

[0068] Step 3) stirring the mixture obtained in step 2 at a temperature of 50° C. for 3 to 4 hours to obtain a suspension containing a solid compound;

[0069] step 4) cooling the stirred suspension to room temperature at a cooling rate of 60K / hour or less, filtering the cooled suspension to provide a solid compound, and washing the solid compound with diisopropyl ether; and

[0070] Step 5) Dry the solid compound obtained in step 4 at a temperature range of 30°C to 60°C for at least 1 hour to obtain crystalline sodium 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetate trihydrate.

[0071] In another embodiment of the method mentioned herein, step 2 further comprises:

[0072] The solution was seeded with sodium 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetate trihydrate seeds in an amount of 0.5 to 1 wt % based on the total weight of 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetic acid provided in step 1.

[0073] In another embodiment, the present invention relates to a process for the manufacture of sodium 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy]-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetate trihydrate of formula (I) in crystalline form, the process further comprising the additional subsequent step of:

[0074] Step 6) Micronizing or nano-milling the crystalline sodium 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetate trihydrate obtained in step 5) to obtain a pharmaceutical composition comprising micronized crystalline sodium 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetate trihydrate.

[0075] In a preferred embodiment, the micronized or nanomilled crystalline sodium 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetate trihydrate has a particle size in the range of 0.3 to 1000 μm, and the particle size distribution is preferably defined by d(0.1) of 1 to 100 μm, d(0.5) of 30 to 250 μm and d(0.9) of 100 to 800 μm, more preferably defined by d(0.1) of 2 to 50 μm, d(0.5) of 25 to 100 μm and d(0.9) of 200 to 600 μm.

[0076] In the method disclosed herein, the crystalline sodium 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetate trihydrate has a trigonal system, an R3 space group and Unit cell dimensions of α = 90 ± 3°, β = 90 ± 3° and γ = 120 ± 3°.

[0077] In the method disclosed herein, the X-ray diffraction pattern of the crystalline sodium 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy]-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetate trihydrate includes 2θ angle values ​​of 6.2, 9.5, 12.4, 15.6, 18.0, 19.0, 21.0, 22.5 and 26.8°, and the standard deviation of the 2θ angle values ​​is ±0.1°.

[0078] In a preferred embodiment of the process disclosed herein, the crystalline sodium 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetate trihydrate has an X-ray diffraction pattern comprising 2θ angle values ​​of 6.2, 9.5, 11.3, 12.4, 12.9, 15.6, 16.5, 16.8, 18.0, 19.0, 20.0, 21.0, 21.6, 21.9, 22.5, 22.8, 23.6, 25.0, 25.2, 26.0, 26.8, 27.3, 27.5 and 26.8°, with a standard deviation of ±0.1°.

[0079] The purity of the crystalline sodium 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetate trihydrate obtained by any of the above methods as determined by HPLC is at least 98%, preferably 99%, more preferably 99.5%, and most preferably 99.9%.

[0080] In another aspect, the present invention relates to sodium 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetate trihydrate obtainable by the process described herein.

[0081] In a preferred embodiment, sodium 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetate trihydrate obtainable by the methods described herein is substantially free of ethanol.

[0082] The crystalline sodium 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetate trihydrate can exist in different polymorphic forms. Polymorphs are different crystalline forms of the same compound, which may have significantly different physicochemical properties such as solubility, stability and bioavailability. The evaluation of drug polymorphism plays a vital role in formulation research because polymorphism may affect drug behavior. For example, the dissolution rate of the raw material can affect the bioavailability of the final product. Solubility, in turn, depends on the polymorphic nature of the drug. Different polymorphs may have different solubilities, and therefore the corresponding drug products may have different bioavailabilities.

[0083] Different methods can be used to examine polymorphs. Such methods include microscopy, infrared spectroscopy, Raman spectroscopy, solid-state NMR, TGA, DSC, XRPD, PDF and other techniques. A combination of different techniques can be applied. In particular, PXRD is a powerful technique for examining polymorphs. X-rays are reflected from a crystal only when the angle between the beam and the crystal plane meets the Bragg condition. There are an infinite number of possible planes in a crystal. Each molecular repeat produces a unique set of reflections and therefore a unique pattern that can be recorded as a spectrum.

[0084] However, conventional XRPD analysis produces the average structure of the material, such as average position, displacement parameters and occupancy, and cannot provide information about the local disorder of the material. For this reason, the pair distribution function (PDF) can be used, which gives the possibility of finding an atom at a certain distance from a given atom. PDF is a sine Fourier transform of the total scattering diffraction pattern, which provides information about the average interatomic distance, structural disorder or distortion, and average coordination characteristics. Therefore, PDF can distinguish different solid forms of the same compound that cannot be distinguished by conventional PXRD analysis. In particular, different amorphous forms with different degrees of disorder can be determined by PDF analysis (Boetker et al., Pharmaceutics 2012, 4, 93-103).

[0085] Pharmaceutical composition

[0086] In another aspect, the present invention relates to a pharmaceutical composition comprising sodium 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetate trihydrate according to formula (I) as described herein.

[0087] In a preferred embodiment, the pharmaceutical composition is a dry powder.

[0088] In another preferred embodiment, the pharmaceutical composition according to the invention is substantially free of ethanol.

[0089] In another aspect, the present invention relates to a method for preparing a pharmaceutical composition disclosed herein, comprising sodium 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetate trihydrate, the method further comprising the additional subsequent step of:

[0090] Step 6) Micronizing or nano-milling the crystalline sodium 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetate trihydrate obtained in step 5) to obtain a pharmaceutical composition comprising micronized crystalline sodium 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetate trihydrate.

[0091] In another preferred embodiment, the method comprises an additional subsequent step of adding at least one pharmaceutically acceptable carrier, excipient and / or diluent to the crystalline sodium 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetate trihydrate obtained in step 6).

[0092] As pharmaceutically acceptable carriers, excipients and / or diluents, carriers can be used, for example, preferably inert carriers such as lactose, starch, sucrose, cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, talc, mannitol, ethanol (liquid-filled capsules); suitable binders include: starch, gelatin, natural sugars, corn sweeteners, natural and synthetic gums such as gum arabic, sodium alginate, carboxymethylcellulose, polyethylene glycol and waxes; sugars such as sucrose, starches derived from wheat, corn, rice and potatoes, natural gums such as gum arabic, gelatin and tragacanth, derivatives of seaweed such as alginic acid, sodium alginate and calcium ammonium alginate, cellulosic materials such as methylcellulose, sodium carboxymethylcellulose and hydroxypropyl methylcellulose, polyvinyl pyrrolidone and inorganic compounds such as magnesium aluminum silicate, lubricants such as boric acid, sodium benzoate, sodium acetate, sodium chloride, magnesium stearate, calcium stearate or potassium stearate, stearic acid, high melting point waxes. and other water-soluble lubricants such as sodium chloride, sodium benzoate, sodium acetate, sodium oleate, polyethylene glycol and D,L-leucine; disintegrants (disintegrants) such as starch, methylcellulose, guar gum, modified starches such as sodium carboxymethyl starch, natural and synthetic gums such as locust bean, karaya, guar gum, tragacanth and agar, cellulose derivatives such as methylcellulose and sodium carboxymethyl cellulose, microcrystalline cellulose, and cross-linked microcrystalline cellulose such as cross-linked sodium carboxymethyl cellulose, alginics such as alginic acid and sodium alginate, clays such as bentonite, and effervescent mixtures; colorants, sweeteners, flavorings, preservatives; glidants are, for example, silicon dioxide and talc; suitable adsorbents are clay, alumina, suitable diluents are water or water / propylene glycol solutions for parenteral injection, fruit juices, sugars such as lactose, sucrose, mannitol and sorbitol, starches derived from wheat, corn, rice and potato, and celluloses such as microcrystalline cellulose.

[0093] The pharmaceutical compositions of the present invention can be prepared in a known manner in conventional solid or liquid carriers or diluents and conventional pharmaceutically prepared adjuvants at suitable dosage levels. Preferred formulations are suitable for oral administration. These administration forms include, for example, pills, tablets, film tablets, coated tablets, capsules, powders and deposits.

[0094] In addition, the present invention also includes pharmaceutical formulations for parenteral application, including dermal, intradermal, intragastric, intradermal, intravascular, intravenous, intramuscular, intraperitoneal, intranasal, intravaginal, intrabuccal, transdermal, rectal, subcutaneous, sublingual, topical or transdermal application, which formulations contain sodium 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetate trihydrate in addition to typical vehicles and / or diluents.

[0095] The pharmaceutical composition according to the present invention containing sodium 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetate trihydrate according to the present invention as the active ingredient is usually administered together with a suitable carrier material selected according to the intended form of administration, i.e. oral administration in the form of tablets, capsules (solid-filled, semi-solid-filled or liquid-filled), powders for formulation, extrudates, sediments, gels, elixirs, dispersible granules, syrups, suspensions, etc., and in accordance with conventional pharmaceutical practice. For example, for oral administration in the form of tablets or capsules, the active drug component can be combined with any oral non-toxic pharmaceutically acceptable carrier, preferably with an inert carrier such as lactose, starch, sucrose, cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, talc, mannitol, ethanol (liquid-filled capsules), etc. In addition, suitable binders, lubricants, disintegrants and colorants can also be incorporated into the tablets or capsules. The powders and tablets may contain about 5 to about 95% by weight of sodium 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetate trihydrate of formula (I) of the present invention as an active ingredient.

[0096] Suitable adhesives include starch, gelatin, natural sugars, corn sweeteners, natural and synthetic gums such as gum arabic, sodium alginate, carboxymethyl cellulose, polyethylene glycol and wax. Among suitable lubricants, boric acid, sodium benzoate, sodium acetate, sodium chloride, etc. can be mentioned. Suitable disintegrants include starch, methyl cellulose, guar gum, etc. Sweeteners and flavorings and preservatives may also be included when appropriate. Disintegrants, diluents, lubricants, adhesives, etc. will be discussed in more detail below.

[0097] In addition, the pharmaceutical compositions of the present invention may be formulated in a sustained release form to provide a rate-controlled release of any one or more components or active ingredients, thereby optimizing the therapeutic effect, such as antihistamine activity, etc. Suitable dosage forms for sustained release include tablets having layers of different disintegration rates or a controlled release polymer matrix impregnated with an active component and shaped into a tablet form or capsule containing such an impregnated or encapsulated porous polymer matrix.

[0098] Preparations in liquid form include solutions, suspensions and emulsions. For example, water or water / propylene glycol solutions for parenteral injections or sweeteners and opacifiers for oral solutions, suspensions and emulsions may be mentioned. Preparations in liquid form may also include solutions for intranasal administration. Aerosol formulations suitable for suction may include solids in solution and powder form, which may be present in combination with pharmaceutically acceptable carriers such as inert compressed gases such as nitrogen. In order to prepare suppositories, low melting point fat or wax, for example a mixture of fatty acid glycerides (such as cocoa butter), is first melted, and then, for example, active ingredients are uniformly dispersed therein by stirring. The molten homogeneous mixture is then poured into a mold of suitable size, cooled, and thereby solidified.

[0099] The present invention also includes solid form preparations which are intended to be converted shortly before use to liquid form preparations for oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions.

[0100] 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetate sodium trihydrate can also be delivered transdermally. Transdermal compositions can have the form of creams, lotions, aerosols and / or emulsions and can be included in transdermal patches of the matrix or reservoir type known in the art for this purpose.

[0101] The term capsule as described herein refers to a specific container or shell made of, for example, methylcellulose, polyvinyl alcohol or modified gelatin or starch, for holding or containing a composition comprising an active ingredient. Capsules with hard shells are usually mixed with relatively high gelatin from bones or pigskin. The capsule itself may contain a small amount of dye, sunscreen, plasticizer and / or preservative. Tablets are understood to be compressed or molded solid dosage forms comprising active ingredients and suitable diluents. Tablets can be prepared by compression of a mixture or microparticles, which are obtained by wet granulation, dry granulation or by compaction known to those of ordinary skill in the art.

[0102] Oral gel refers to the active ingredient dispersed or dissolved in a hydrophilic semisolid matrix. Powders for formulation refer to a powder blend containing the active ingredient and a suitable diluent, which can be suspended in, for example, water or juice.

[0103] Suitable diluents are substances that usually constitute the major part of the composition or dosage form. Suitable diluents include: sugars such as lactose, sucrose, mannitol and sorbitol; starches obtained from wheat, corn and potato; and celluloses such as microcrystalline cellulose. The amount of diluent in the composition can be about 5 to about 95% by weight of the total composition, preferably about 25 to about 75% by weight, more preferably about 30 to about 60% by weight.

[0104] The term disintegrant refers to a material added to a composition to support the breakdown (disintegration) and release of the pharmaceutically active ingredient of the drug. Suitable disintegrants include: starch, "cold water soluble" modified starches such as sodium carboxymethyl starch; natural and synthetic gums such as locust bean, karaya, guar gum, tragacanth and agar; cellulose derivatives such as methylcellulose and sodium carboxymethylcellulose, microcrystalline cellulose and cross-linked microcrystalline cellulose such as cross-linked sodium carboxymethylcellulose; alginates such as alginic acid and sodium alginate; clays such as bentonite, and effervescent mixtures. The amount of disintegrant in the composition may be from about 2 to about 20% by weight of the composition, more preferably from about 5 to about 10% by weight.

[0105] Binders are substances that bind or "glue" the powder particles together and agglomerate them by forming granules, thereby acting as a "glue" in the formulation. Binders increase the agglomeration strength already present in the diluent or filler. Suitable binders include: sugars such as sucrose; starches derived from wheat, corn, rice and potatoes; natural gums such as gum arabic, gelatin and tragacanth; seaweed derivatives such as alginic acid, sodium alginate and calcium ammonium alginate; cellulosic materials such as methylcellulose, sodium carboxymethylcellulose and hydroxypropyl methylcellulose; polyvinylpyrrolidone; and inorganic compounds such as magnesium aluminum silicate. The amount of binder in the composition can be from about 2 to about 20% by weight of the composition, preferably from about 3 to about 10% by weight, and more preferably from about 3 to about 6% by weight.

[0106] Lubricants refer to a class of substances added to the dosage form to enable tablet particles, etc. to be demolded from a mold or die after compression by reducing friction or wear. Suitable lubricants include: metal stearates such as magnesium stearate, calcium stearate or potassium stearate; stearic acid; high melting point waxes; and other water-soluble lubricants such as sodium chloride, sodium benzoate, sodium acetate, sodium oleate, polyethylene glycol and D, L-leucine. Lubricants are usually added in the last step before compression because they must be present on the surface of the particles. The amount of lubricant in the composition can be about 0.2 to about 5% by weight of the composition, preferably about 0.5 to about 2% by weight, and more preferably about 0.3 to about 1.5% by weight of the composition.

[0107] Glidants are materials that prevent the components of the pharmaceutical composition from agglomerating and improve the flow characteristics of the particles so that the flow is smooth and uniform. Suitable glidants include silicon dioxide and talc. The amount of glidant in the composition can be about 0.1 to about 5% by weight of the final composition, preferably about 0.5 to about 2% by weight.

[0108] Coloring agent is the excipient that provides coloring for composition or dosage form.This excipient can comprise the food grade dye that is adsorbed on suitable adsorbent such as clay or aluminum oxide.The amount of coloring agent can be about 0.1 to about 5 weight % of composition, preferably about 0.1 to about 1 weight %.

[0109] The Letermovir sodium trihydrate of the present invention exhibits an antiviral effect on representatives of the herpesvirus class (herpesviruses), in particular on cytomegalovirus (CMV), in particular on human cytomegalovirus (HCMV). They are thus suitable for use in methods for the treatment and prevention of diseases, in particular viral infections, in particular the viruses mentioned herein and infectious diseases caused by them. The term "viral infection" is understood herein to refer not only to viral infections, but also to diseases caused by viral infections.

[0110] In another aspect, the invention relates to a pharmaceutical composition obtainable by the method described herein.

[0111] In another preferred embodiment, the pharmaceutical composition is obtainable by the method, which further comprises a subsequent step of adding at least one pharmaceutically acceptable carrier, excipient and / or diluent to the crystalline sodium 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetate trihydrate.

[0112] In a preferred embodiment, the pharmaceutical composition comprises crystalline sodium 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetate trihydrate, wherein the crystalline 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetate trihydrate is preferably selected from the group consisting of: The particle size of sodium [4H-quinazolin-4-yl] acetate trihydrate is in the range of 0.3 to 1000 μm, and the particle size distribution is preferably defined by d(0.1) of 1 to 100 μm, d(0.5) of 30 to 250 μm and d(0.9) of 100 to 800 μm, more preferably the particle size distribution is defined by d(0.1) of 2 to 50 μm, d(0.5) of 25 to 100 μm and d(0.9) of 200 to 600 μm.

[0113] The parameter d(0.1) refers to the mesh size of a single notional sieve that allows 10% of the total number of all particles in the sample to pass through. Thus d(0.1)=2-100 μm means that the upper limit of the particle size range defining the 10% smallest particles in the sample is 2 μm to 100 μm. Thus, 10% of the total particles have a particle size not greater than d(0.1), which means that in this case they have a maximum size of 2 μm to 100 μm.

[0114] Correspondingly, the parameter d(0.5) refers to the mesh size of a single notional sieve that allows 50% of the total number of all particles in the sample to pass through. Thus d(0.5)=30-250 μm means that the upper limit of the particle size range defining the notional half of the sample containing smaller particles is 30 μm-250 μm. Thus, 50% of the total number of all particles have a particle size not greater than d(0.5), which means that in this case they have a maximum size of 30 μm to 250 μm.

[0115] Correspondingly, the parameter d(0.9) refers to the mesh size of a single notional sieve that allows 90% of the total number of all particles of the sample to pass (i.e., only 10% of the sample is retained). Thus d(0.9)=100-800 μm means that the lower limit of the particle size range defining the 10% largest particles in the sample is 100 μm to 800 μm. Thus, 90% of all particles have a particle size that does not exceed d(0.9), which means that in this case their maximum size is between 100 μm and 800 μm.

[0116] Preferably, the antiviral agent used in the pharmaceutical composition of the present invention is effective against viruses of the herpes virus group, in particular cytomegalovirus (CMV), especially human cytomegalovirus (HCMV).

[0117] Preferably, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, excipient and / or diluent.

[0118] The pharmaceutical composition is preferably administered orally or intravenously.

[0119] The sodium 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetate trihydrate according to the invention exhibits an antiviral effect against representatives of the herpesvirus class (herpesviruses), in particular against cytomegalovirus (CMV), in particular against human cytomegalovirus (HCMV). They are therefore suitable for use in methods for the treatment and prevention of diseases, in particular viral infections, in particular the viruses mentioned herein and infectious diseases caused by them. The term "viral infection" is understood here to mean not only viral infections, but also diseases caused by viral infections.

[0120] Therefore, another aspect of the present invention relates to a pharmaceutical composition comprising crystalline sodium 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetate trihydrate, which is used for treating and / or preventing infectious diseases caused and / or related to cytomegalovirus, especially human cytomegalovirus.

[0121] Furthermore, the present invention relates to a pharmaceutical composition comprising crystalline sodium 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetate trihydrate for the preparation of a medicament for the treatment and / or prevention of diseases, in particular viral infections, preferably human cytomegalovirus (HCMV) infections or infections with other members of the Herpesviridae family.

[0122] In addition, the present invention provides a method for treating and / or preventing diseases associated with and / or caused by infection with cytomegalovirus (CMV), in particular human cytomegalovirus (HCMV) or other members of herpes virus, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising crystalline sodium 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetate trihydrate.

[0123] The term "effective amount" refers to that amount of a compound which, when administered to a subject in need of such treatment, is sufficient to:

[0124] (i) treating or preventing a particular disease, condition or disorder;

[0125] (ii) reduce, ameliorate or eliminate one or more symptoms of a particular disease, condition or disorder; or

[0126] (iii) preventing or delaying the onset of one or more symptoms of a particular disease, condition or disorder described herein.

[0127] The amount of sodium 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetate trihydrate corresponding to such an amount will vary depending on factors such as the specific compound, the disease condition and its severity, and the identity (e.g., weight) of the subject needing treatment, but can generally be determined by one skilled in the art.

[0128] abbreviation

[0129] h hour

[0130] DSC Differential Scanning Calorimetry

[0131] HPLC High Pressure Liquid Chromatography

[0132] min

[0133] NMR Nuclear Magnetic Resonance

[0134] PDF Pair Distribution Function

[0135] TGA Thermogravimetric Analysis

[0136] PXRD Powder X-ray Diffraction BRIEF DESCRIPTION OF THE DRAWINGS

[0137] Figure 1 The crystal structure of Letermovir sodium methanol monohydrate is shown.

[0138] Figure 2 The crystal structure of Letermovir sodium ethanol monohydrate is shown.

[0139] Figure 3 Shown is a PXRD comparison of the PXRD patterns of Letermovir sodium methanol monohydrate (water) solvate (red) derived from SCXRD simulations, Letermovir sodium ethanol monohydrate (water) solvate (blue) derived from SCXRD simulations, and the bulk (black).

[0140] Figure 4 Shown is a PXPD comparison of Letermovir sodium trihydrate (black) derived from the present invention, Letermovir sodium ethanol monohydrate (water) solvate after filtration and air drying for 1 hour (blue), and Letermovir sodium trihydrate (red) after filtration and air drying for 2 weeks.

[0141] Figure 5 The crystal structure of Letermovir sodium trihydrate is shown. Thermal ellipsoids are shown with the electron density set at 50% probability level.

[0142] Figure 6 A trimeric complex formed by three Letermovir anions is shown.

[0143] The following examples are included to show the preferred embodiments of the present invention. It will be appreciated by those skilled in the art that the disclosed technology in the following examples represents the technology found by the inventors in order to better practice the present invention, and thus it can be considered that it constitutes the preferred mode for practicing the present invention. However, it will be appreciated by those skilled in the art that multiple changes can be completed in the disclosed specific embodiments and still obtain close or similar results without departing from the spirit and scope of the present invention according to the present invention.

[0144] In view of this specification, it will be clear to those skilled in the art that other modifications and alternative embodiments of various aspects of the present invention. Therefore, this specification is only interpreted as illustrative and is for the purpose of teaching the general mode of implementing the present invention to those skilled in the art. It should be understood that the form of the present invention shown and described herein will be regarded as an example of an embodiment. Elements and materials can replace the elements and materials shown and described herein, parts and processes can be reversed, and the specific features of the present invention can be used independently, all of which will be apparent to those skilled in the art after benefiting from the specification of the present invention. Without departing from the spirit and scope of the present invention described in the appended claims, the elements described herein may be changed. DETAILED DESCRIPTION

[0145] Equipment used

[0146] Powder X-ray Diffraction Analysis (PXRD): About 20 mg of sample was prepared using two polyacetate foils in a standard sample holder. The sample was analyzed directly as received without further processing. CuKα1 radiation was used on a D8 Advance series 2θ / θ powder diffraction system. Powder diffraction patterns were obtained in transmission geometry at room temperature. The system was equipped with Single photon counting PSD, germanium monochromator, ninety position autochanger sample stage, fixed divergence slit and radial soller. The generator intensity for generating the X-ray beam was set to 40 mA and 40 kV. Programs used: Data were collected using DIFFRAC and XRD Commander V.2.5.1 and evaluated using EVA V.14.0.0.0 (Bruker-AXS 1996-2007). Patterns were collected in the 2θ range of 4 to 40° within 30 minutes of measurement time (step size 0.049°).

[0147] Proton Nuclear Magnetic Resonance Spectra (1H-NMR): Proton nuclear magnetic resonance analysis was recorded in deuterated DMSO (DMSO-d6) on a Bruker Avance 400 Ultrashield NMR spectrometer. Spectra were obtained by dissolving 8-10 mg of sample in 0.7 mL of deuterated solvent.

[0148] Differential Scanning Calorimetry (DSC): DSC analysis was recorded in a Mettler Toledo DSC822 with a 56-point Au-AuPd thermopile FRS5 sensor. Approximately 2-3 mg of sample was weighed (using an MX5 Mettler Toledo microbalance) into a 40 μL aluminum crucible with a pinhole cover and heated from 30°C to 300°C under nitrogen (50 mL / min) at a rate of 10 and / or 20°C / min. Program used: Data acquisition and evaluation were performed using the software STARe.

[0149] Thermogravimetric analysis (TGA): Thermogravimetric analysis was recorded in a Mettler Toledo TGA / SDTA851 with a model MT1 balance. About 3-4 mg of sample was weighed (using an MX5 Mettler Toledo microbalance) into a 40 μL aluminum crucible with a pinhole cover and heated at 10°C / min from 30°C to 300°C under nitrogen (10 mL / min). Program used: Data acquisition and evaluation were performed using the software STARe.

[0150] Single Crystal X-ray Diffraction (SCXRD):

[0151] The crystals for measurement were prepared under inert conditions immersed in perfluoropolyether as a processing protection oil. The crystals were measured using an APPEX 2 4K CCD area detector with MoK α radiation The crystal structure was determined using a Microfocus Source E025IuS from Oxford Cryosystems, a Quazar MX multilayer Optics as a monochromator, and an Apex DUO Kappa 4-axis goniometer on a Cryostream 700plus (T = -173°C) cryosystem from Oxford Cryosystems. Scans were collected globally. The programs used were: data acquisition APEX-2 (using APEX II v2014.9-0 Bruker (2014). Bruker AXS Inc., Madison, Wisconsin, USA) for data acquisition, data reduction Bruker Saint (using Bruker SAINT+ version V8.35A. Bruker (2013). Bruker AXS Inc., Madison, Wisconsin, USA) for data reduction, V / .60A and absorption correction SADABS (SADABS: V2014 / 5 Bruker (2001). Bruker AXS Inc., Madison, Wisconsin, USA. Blessing, Acta Cryst. (1995) A51 33-38).

[0152] Structure solution and refinement: Crystal structure solution was achieved using the computer program SHELXT (SHELXT; Sheldrick, G.M.ActaCryst. 2015 A71, 3-8). Visualization was performed using the program SHELXle (SHELXle; CB Huebschle, G.M.Sheldrick & B. Dittrich; J. Appl. Cryst. (2011) 44, 1281-1284). Missing atoms were subsequently located from the differential Fourier synthesis and added to the atom list. The program SHELXL 2015 (SHELXL; Sheldrick, G.M.Acta Cryst. 2015 C71, 3-8. SHELXT.) was used to perform least squares refinement of F2 using all measured intensities. All non-hydrogen atoms were refined, including anisotropic displacement parameters.

[0153] Comparative Example 01: Monosodium salt of 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetic acid

[0154] (Corresponding to Example 1 of US 2015 / 0038514 A1)

[0155] 333.1 g of 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetic acid were dissolved in 1300 mL of a mixture of ethanol and diisopropyl ether (1:1) in a 2000 mL three-necked flask. 21.9 g (546.84 mmol) of NaOH solid were added to the solution. The mixture was heated for 25 minutes to an internal temperature of 50° C., which resulted in a transparent orange solution. The solution thus obtained was stirred at this temperature for 3 hours, and a dilute suspension had formed after 1 hour. The reaction mixture was then cooled to an internal temperature of 20° C. within 10 hours at a cooling rate of 3° C. / hour, and then stirred at this temperature for a further 5 hours. The total volume of the reaction mixture was reduced to about 750 mL under vacuum, and the suspension obtained in this way was stirred at 20° C. for 2 hours. Next, 250 mL of diisopropyl ether was added to the resulting reaction mixture over a period of 10 minutes, and the mixture was stirred for a further 2 hours. The resulting crystalline product was evacuated by suction, washed twice (each time with 250 mL of diisopropyl ether), and dried in a vacuum drying oven at 20° C. and 160 mbar for 20 hours. The crystalline solid obtained in this way was then dried in an IR dryer at 90° C. for 10 minutes, and then dried in a vacuum drying oven at 60° C. for another 16 hours. A total of 274.4 g (86% of theoretical yield) of the desired crystalline sodium salt were obtained in this way.

[0156] Comparative Example 02: Preparation of the trihydrate of the monosodium salt of 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetic acid

[0157] (Variation of Example 2 in US 2015 / 0038514 A1)

[0158] About 300 mg of the sodium salt of 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetic acid obtained from Comparative Example 1 was suspended in 1 mL of methanol or ethanol (containing 4% water) and shaken at 25° C. for one week. The resulting crystals were filtered off and the residue was dried at room temperature and ambient humidity for two weeks. The resulting residue corresponds to the title compound as a trihydrate.

[0159] After shaking at 20°C for one week in the respective given solvents, the obtained solid was filtered off to obtain the following crystals.

[0160] In the case of using methanol as a solvent, crystals of sodium 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetate methanol monohydrate were obtained, such as Figure 1 Table 1 lists the X-ray structural data of the crystalline Letermovir sodium methanol monohydrate.

[0161] When ethanol was used as the solvent, crystals of sodium 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetate ethanol monohydrate were obtained, such as Figure 2 Table 2 lists the X-ray structural data of the crystalline Letermovir sodium ethanol monohydrate.

[0162] The asymmetric unit contains an anion molecule, a sodium cation, a water molecule and an ethanol molecule. The water and ethanol molecules coordinated to the sodium cation are disordered in two positions (ratio 60:40). The compound crystallized in chiral space group R3, but absolute structural determination was not possible. The structure obtained using ethanol is isostructural to that obtained using methanol. The structure has a high quality with an R1 value of 4.75%.

[0163] Figure 3 A comparison of the PXRD patterns of the two solvates (derived from SCXRD simulations) and the bulk is shown. The three samples have very similar patterns (isostructural).

[0164] The crystals obtained, i.e., crystalline sodium 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetate methanol monohydrate or crystalline sodium 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetate ethanol monohydrate, must be dried at room temperature and ambient humidity for two weeks to be converted into Figure 4 Shown is crystalline sodium 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetate trihydrate.

[0165] Table 1. Figure 1 Crystal data and structural refinement of crystalline Letermovir sodium methanol monohydrate shown

[0166]

[0167]

[0168] Table 2. Figure 2 Crystal data and structural refinement of crystalline Letermovir sodium ethanol monohydrate shown

[0169]

[0170]

[0171] Example 01: Direct preparation and optimization experiment of crystalline sodium 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetate trihydrate

[0172] 1. Development, 2g scale

[0173] Development was performed on a 2 gram scale in a reaction tube. NaOH was added as a concentrated aqueous solution and the addition of antisolvent was controlled according to previous results.

[0174] As antisolvent, diisopropyl ether was selected as the main antisolvent in the conducted reaction.

[0175] Solvent: As demonstrated in Comparative Example 02 according to the prior art (WO 2013 / 127971), Letermovir sodium forms a large number of solvates, particularly with alcohols such as methanol and ethanol. Thus, the use of alcohols and other solvents that can promote the formation of solvates other than sodium trihydrate was excluded in the present development.

[0176] Other parameters

[0177] The following parameters were modified during development and optimization:

[0178] -Solvent / Antisolvent Ratio

[0179] - Addition of antisolvent (addition rate and time)

[0180] -API concentration

[0181] -NaOH addition (directly or dissolved in water)

[0182] - Volume of water

[0183] - Reaction time

[0184] - Reaction temperature

[0185] - Inoculation with seed crystals

[0186] A summary of the experiments performed is provided in Table 3. The results indicate that a reduction in the volume of water appears to have a positive effect on the reaction outcome. The rate of addition of the antisolvent does not appear to have a significant effect on the procedure. The yields obtained are generally average to low. Although diisopropyl ether was found to be the most reliable antisolvent, all solvents provided roughly comparable results.

[0187] Based on the experimental results depending on the methodological variables, the most critical reaction parameters were selected for a series of optimization experiments.

[0188] Table 3: Reactions performed in the crystallization development of Letermovir sodium trihydrate (2 g scale).

[0189]

[0190] AET = ethyl acetate, AIP = isopropyl acetate, MAC = methyl acetate, MEC = methyl ethyl ketone, antisolvent = diisopropyl ether.

[0191] 2. Further optimization

[0192] The results of the development experiments outlined the following key factors:

[0193] -API concentration

[0194] -Solvent / Antisolvent Ratio

[0195] - Addition of anti-solvent

[0196] - Volume of water

[0197] The optimization aims to obtain a robust method that can be easily scaled up. Therefore, using EasyMax TM The experiments were conducted on a 10 to 20 g scale. The results are shown in Table 4. TM The experiments conducted in the study revealed some problems that were not observed on a smaller scale.

[0198] Table 4: Reactions performed in the crystal development of Letermovir sodium trihydrate on a 10-20 g scale

[0199]

[0200] AET = ethyl acetate, AIP = isopropyl acetate, MAC = methyl acetate, MEC = methyl ethyl ketone, antisolvent = diisopropyl ether.

[0201] The following parameters have been optimized:

[0202] - A more concentrated NaOH solution was used (1 g / mL in water). Excess NaOH was added (1.5 molar equivalents)

[0203] - Use a more concentrated API solution (approximately 0.33 g / mL)

[0204] - Moderate to vigorous stirring (poor stirring may result in the formation of oils, resins and biphasic systems)

[0205] - Adding diisopropyl ether at different times and rates did not significantly improve the results

[0206] -Simplify the reaction by dissolving the API in the solvent / antisolvent mixture before adding NaOH

[0207] - Optionally, in order to better induce the precipitation of Letermovir sodium trihydrate, the initial solution + base is seeded with 0.5% by weight of Letermovir sodium trihydrate seeds

[0208] - Under the optimized reaction conditions, isopropyl acetate was found to be the most suitable solvent; its use provided highly crystalline Letermovir sodium trihydrate in quantitative yield.

[0209] Based on the optimized parameters, the general procedure for the preparation of Letermovir sodium trihydrate was outlined.

[0210] 2-[(4S)-8-Fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetic acid (Letermovir) was dissolved in a 1:2 mixture of isopropyl acetate and diisopropyl ether at 50°C (final API concentration: 0.33 g / mL). Then, 1.5 molar equivalents of NaOH (1 g / mL in water) were added, and the solution was seeded with Letermovir sodium trihydrate A (1-0.5% w / w) and stirred at 50°C for 4 hours. The suspension was then gradually cooled (from 50°C to 20°C in 1 hour). The reactor contents were vacuum filtered, washed three times with diisopropyl ether, and dried at 50°C under reduced pressure (2-3 hPa) for 15 hours. A white compact powder (Letermovir sodium trihydrate) was obtained.

[0211] The technical features of Letermovir sodium ethanol monohydrate (water) and Letermovir sodium trihydrate are summarized as follows.

[0212] Table 5.

[0213]

[0214] Example 02. Preparation of sodium 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetate trihydrate on a 500 g scale

[0215] 499 g of 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetic acid were dissolved in a mixture of isopropyl acetate and diisopropyl ether in a ratio of 1:2 (0.75 L / 1.5 L) at 50° C., then about 1.5 equivalents of NaOH (aqueous solution, 1 g / mL, 50 mL) were added and the solution was seeded with sodium 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetate trihydrate (0.5-1% w / w relative to substrate). The suspension was stirred at 50° C. for 4 hours (stirring rate: 150 rpm, glass anchor). A large amount of white solid precipitated within the first hour. The reactor was gradually cooled (from 50°C to 20°C in 1 hour) and its contents were filtered under vacuum and washed three times with diisopropyl ether. The resulting white solid was dried at 50°C for 15 hours under reduced pressure (2-3 mBar).

[0216] 510 g of sodium 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetate trihydrate were obtained.

[0217] Example 03. Preparation of Letermovir Sodium Trihydrate Single Crystal

[0218] Crystals were obtained by partial evaporation of a concentrated solution of Letermovir sodium in an isopropyl acetate / diisopropyl ether mixture.

[0219] The asymmetric unit contains one Letermovir molecule in anionic form, one sodium cation and three water molecules. The contents of the asymmetric unit are shown in Figure 5 (disordered atoms have been avoided). The water molecules are each disordered in two positions, with ratios of 77:23, 67:33 and 63:37. The CF3 group is also disordered in two orientations with a ratio of 63:37. The trihydrate crystallizes in the highly symmetric trigonal space group R3 to form a trimer complex in which the three Letermovir anions form a channel containing sodium cations and water molecules ( Figure 6 ). The negatively charged carboxylates are inside the channel and interact with the sodium cations.

[0220] Table 6. Crystal data

[0221]

[0222]

Claims

1. A method for producing sodium 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetate trihydrate represented by formula (I) in crystalline form, The method comprises the following steps: Step 1) providing a solution of 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetic acid in a mixture of (C1-C6) alkyl acetate and (C1-C6) dialkyl ether with a concentration of 0.3M to 0.7M, wherein the molar ratio of (C1-C6) alkyl acetate: (C1-C6) dialkyl ether is 1:1 to 1:3; step 2) adding 1.0 to 2.0 molar equivalents of an aqueous sodium hydroxide solution based on the content of the 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetic acid to the solution obtained in step 1 to provide a mixture; Step 3) stirring the mixture obtained in step 2 at a temperature ranging from 30° C. to 60° C. for at least 30 minutes to obtain a suspension containing a solid compound; Step 4) separating the solid compound from the suspension obtained in step 3; and Step 5) drying the solid compound obtained in step 4 at a temperature ranging from 30° C. to 60° C. for at least 1 hour to obtain crystalline sodium 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetate trihydrate; wherein the X-ray diffraction pattern of the crystalline sodium 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy]-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetate trihydrate includes 2θ angle values ​​of 6.2, 9.5, 12.4, 15.6, 18.0, 19.0, 21.0, 22.5 and 26.8°, and the standard deviation of the 2θ angle values ​​is ±0.1°.

2. The method according to claim 1, wherein the temperature of the solution in step 1 is preferably in the range of 30°C to 60°C.

3. The method according to claim 1 or 2, wherein the concentration of sodium hydroxide in the sodium hydroxide aqueous solution of step 2 is in the range of 5M to 30M.

4. The method according to claim 3, wherein the concentration of sodium hydroxide in the sodium hydroxide aqueous solution of step 2 is in the range of 10M to 30M.

5. The method according to claim 1 or 2, wherein in step 2, 1.1 to 1.5 molar equivalents of sodium hydroxide based on the content of 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetic acid is added, and the sodium hydroxide is in the form of an aqueous solution with a sodium hydroxide concentration in the range of 10M to 30M.

6. The method according to claim 1 or 2, wherein step 3 further comprises: Cooling the stirred suspension to room temperature at a cooling rate of 60 K / hour or less; The cooled suspension is filtered to provide a solid compound; and Optionally, the solid compound is washed with the (C1-C6)dialkyl ether, which is the same as the (C1-C6)dialkyl ether used in step 1.

7. The method according to claim 1 or 2, wherein the (C1-C6) alkyl acetate is methyl acetate, propyl acetate, isopropyl acetate or butyl acetate or a mixture thereof, and the (C1-C6) dialkyl ether is diisopropyl ether, methoxypentane or methyl tert-butyl ether or a mixture thereof.

8. The method according to claim 7, wherein the (C1-C6) alkyl acetate is isopropyl acetate and the (C1-C6) dialkyl ether is diisopropyl ether.

9. The method according to claim 8, wherein the molar ratio of isopropyl acetate:dialkyl ether is 1:

2.

10. The method according to claim 1 or 2, wherein in step 1, the concentration of the solution of 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetic acid is 0.3M to 0.6M.

11. The method according to claim 1 or 2, wherein in step 5, the drying of the solid compound is carried out under reduced pressure conditions below 10 hPa. 12 . The method according to claim 11 , wherein in step 5 , the solid compound is dried under a reduced pressure condition of 2 hPa to 3 hPa at 50° C. for 15 hours.

13. The method according to claim 1 or 2, wherein step 2 further comprises: The solution was seeded with sodium 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetate trihydrate seeds in an amount of 0.5 to 1 wt % based on the total weight of 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetic acid provided in step 1.

14. The method according to claim 1 or 2, further comprising an additional subsequent step: Step 6) micronizing or nano-milling the crystalline sodium 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetate trihydrate obtained in step 5) to obtain a pharmaceutical composition comprising micronized crystalline sodium 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetate trihydrate; wherein the particle size is in the range of 0.3 μm to 1000 μm, and the particle size distribution is defined by d(0.1) from 1 μm to 100 μm, d(0.5) from 30 μm to 250 μm, and d(0.9) from 100 μm to 800 μm.

15. The method according to claim 1 or 2, further comprising an additional subsequent step of: Step 7) adding at least one pharmaceutically acceptable carrier, excipient and / or diluent to the crystalline 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetate sodium trihydrate.

Images