A METHOD OF PRODUCING A CRYSTALLINE FORM OF SODIUM 2-[(4S)-8-FLUORO-2-[4-(3-METHOXYPHENYL)PIPERAZIN-1-YL]-3-[2-METHOXY-5-(TRIFLUOROMETHYL)PHENYL]-4H-QUINAZOLINE-4-YL]ACETATE TRIHYDRATE
20230219899 · 2023-07-13
Assignee
Inventors
- Helmut BUSCHMANN (Aachen, DE)
- Thomas GOLDNER (Velbert, DE)
- Jordi Carles CERON BERTRAN (La Pobla de Montornes, ES)
Cpc classification
International classification
Abstract
The present invention refers to an effective method of preparing a crystalline form of 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy (trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetic acid sodium trihydrate.
Claims
1. A method of producing a crystalline form of sodium 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin yl]acetate trihydrate of formula (I) ##STR00003## the method comprising the 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 a (C.sub.1-C.sub.6) alkyl acetate and a (C.sub.1-C.sub.6) dialkyl ether, wherein the molar ratio of (C.sub.1-C.sub.6) alkyl acetate:(C.sub.1-C.sub.6) dialkyl ether is from 1:1 to 1:3 in a concentration range of from 0.3 M to 0.7 M and wherein the temperature of the solution is preferably in the range of from 30° C. to 60° C.; Step 2) adding 1.0 to 2.0 mole equivalents of an aqueous sodium hydroxide solution based on the 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetic acid content to the solution resulting from step 1 to provide a mixture; Step 3) stirring the mixture resulting from step 2 for at least 30 minutes at a temperature in the range of from 30° C. to 60° C. to obtain a suspension containing a solid compound; Step 4) separating the solid compound from the suspension resulting from step 3; and Step 5) drying the solid compound resulting from step 4 at a temperature in the range of from 30° C. to 60° C. for at least one hour to obtain 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.
2. The method according to claim 1, wherein the concentration of sodium hydroxide in the aqueous sodium hydroxide solution of step 2 is in the range of from 5 M to 30 M and more preferably in the range of from 10 M to 30 M.
3. The method according to claim 1, wherein 1.1 to 1.5 mole equivalents of sodium hydroxide based on the 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)-piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetic acid content are added in step 2 as an aqueous solution at a concentration of sodium hydroxide in the range of from 10 M to 30 M.
4. The method according to claim 1, wherein step 3 further comprises: cooling down the stirred suspension to room temperature at a cooling rate of 60 K per hour or below, filtering the cooled suspension to provide a solid compound, and optionally washing the solid compound with the (C.sub.1-C.sub.6) dialkyl ether, which is the (C.sub.1-C.sub.6) dialkyl ether used in step 1.
5. The method according to claim 1, wherein the (C.sub.1-C.sub.6) alkyl acetate is methyl acetate, propyl acetate, isopropyl acetate or butyl acetate, or a mixture thereof and the (C.sub.1-C.sub.6) dialkyl ether is diisopropyl ether, methoxypentane, or methyl tert-butyl ether, or a mixture thereof, preferably wherein the (C.sub.1-C.sub.6) alkyl acetate is isopropyl acetate and the (C.sub.1-C.sub.6) dialkyl ether is diisopropyl ether, and more preferably, wherein the (C.sub.1-C.sub.6) alkyl acetate is isopropyl acetate and the (C.sub.1-C.sub.6) dialkyl ether is diisopropyl ether and the molar ratio of isopropyl acetate:dialkyl ether is 1:2.
6. The method according to claim 1, 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 between 0.3 M to 0.6 M.
7. The method according to claim 1, wherein in step 5, drying the solid compound is performed under reduced pressure below 10 hPa, preferably at around 2 to 3 hPa at 50° C. for 15 hours.
8. The method according to claim 1, wherein step 2 further comprises: inoculating the solution with seed 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 trihydrate in an amount of from 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.
9. The method according to claim 1 further comprising the additional subsequent step: Step 6) micronizing or nanomiling 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 resulting from step 5 to obtain a pharmaceutical composition comprising the 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 a range of 0.3 to 1000 μm and the particle size distribution is defined by d(0.1) from 1 to 100 μm, d(0.5) from 30 to 250 μm and d(0.9) from 100 to 800 μm.
10. The method according to claim 1 further comprising the additional subsequent step: Step 7) 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.
11. 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) ##STR00004## having a hexagonal crystal system, a space group of R3, and a unit cell dimension of a=28.22 Å, b=28.22 Å, c=9.97 Å, α=90±3°, β=90±3°, and γ=120±3° which is obtainable by the method as defined in claim 1.
12. 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 according to claim 11 which is essentially free from ethanol.
13. (canceled)
14. A crystalline sodium 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin yl]acetate trihydrate having a hexagonal crystal system, a space group of R3, and a unit cell dimension of a=28.22 Å, b=28.22 Å, c=9.97 Å, α=90±3°, β=90±3°, and γ=120±3°.
15. The crystalline sodium 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin yl]acetate trihydrate according to claim 11, wherein the X-ray diffraction pattern of said 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 comprises 2-theta angle values of 6.2, 9.5, 12.4, 15.6, 18.0, 19.0, 21.0, 22.5 and 26.8 degrees, and said 2-theta angle values have a normal deviation of ±0.1°.
16. A pharmaceutical composition comprising 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 as defined in claim 11.
17. The pharmaceutical composition according to claim 16 which is a dry powder.
18. The pharmaceutical composition according to claim 16, which is essentially free from ethanol.
19. The pharmaceutical composition according to claim 16 that is suitable for intravenous administration.
20. The pharmaceutical composition according to claim 16 that is suitable for oral administration.
21. The pharmaceutical composition according to claim 16 for use in a method of treatment and/or prevention of diseases, in particular of virus infections, preferably human cytomegalovirus (HCMV) infections or infections with another member of the herpes viridae group.
22. A method for the treatment and/or prevention of diseases, in particular of virus infections, preferably human cytomegalovirus (HCMV) infections or infections with another member of the herpes viridae group, comprising administering to a host in need thereof an effective amount of a pharmaceutical composition according to claim 16.
23. A method for treating or preventing virus infections, preferably human cytomegalovirus (HCMV) infections or infections with another member of the herpes viridae group, in humans and animals comprising the step of administering the pharmaceutical composition as defined in claim 16 to a human or an animal who or which requires such a treatment.
Description
DESCRIPTION OF THE FIGURES
[0127]
[0128]
[0129]
[0130]
[0131]
[0132]
[0133] The following examples are included to demonstrate preferred embodiments of the invention. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques discovered by the inventor to function well in the practice of the invention, and thus can be considered to constitute preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention.
[0134] Further modifications and alternative embodiments of various aspects of the invention will be apparent to those skilled in the art in view of this description. Accordingly, this description is to be construed as illustrative only and is for the purpose of teaching those skilled in the art the general manner of carrying out the invention. It is to be understood that the forms of the invention shown and described herein are to be taken as examples of embodiments. Elements and materials may be substituted for those illustrated and described herein, parts and processes may be reversed, and certain features of the invention may be utilized independently, all as would be apparent to one skilled in the art after having the benefit of this description of the invention. Changes may be made in the elements described herein without departing from the spirit and scope of the invention as described in the following claims.
EXAMPLES
[0135] Equipment Used
[0136] Powder X-Ray Diffraction analysis (PXRD): Approximately 20 mg of sample were prepared in standard sample holders using two foils of polyacetate. The samples were analysed as received without further manipulation. Powder diffraction patterns were acquired on a D8 Advance Series 2Theta/Theta powder diffraction system using CuKα1-radiation (1.54060 Å) in transmission geometry at room temperature. The system is equipped with a VANTEC-1 single photon counting PSD, a Germanium monochromator, a ninety positions autochanger sample stage, fixed divergence slits and a radial soller. The generator intensity for the generation of the X-ray beam is set to 40 mA and 40 kV. Programs used: Data collection with DIFFRAC plus XRD Commander V.2.5.1, and evaluation with EVA V.14.0.0.0 (Bruker-AXS 1996-2007). The patterns were collected in thirty minutes measurements in a range from 4 to 40° in 2θ (step size 0.049°).
[0137] Proton nuclear magnetic resonance spectroscopy (1H-NMR): Proton nuclear magnetic resonance analyses were recorded in deuterated DMSO (DMSO-d6) in a Bruker Avance 400 Ultrashield NMR spectrometer. Spectra were acquired solving 8-10 mg of sample in 0.7 mL of deuterated solvent.
[0138] Differential scanning calorimetry analysis (DSC): DSC analyses were recorded in a Mettler Toledo DSC822 with a 56-point Au—AuPd thermopile FRSS sensor. Approximately 2-3 mg of sample were weighed (using a MX5 Mettler Toledo microbalance) into 40 μL aluminium crucibles with a pinhole lid and heated at 10 and/or 20° C./min from 30° C. to 300° C. under nitrogen (50 mL/min). Programs used: Data collection and evaluation with software STARe.
[0139] Thermogravimetric analysis (TGA): Thermogravimetric analyses were recorded in a Mettler Toledo TGA/SDTA851 with a balance MT1 type. Approximately 3-4 mg of sample were weighed (using a MX5 Mettler Toledo microbalance) into 40 μL aluminium crucibles with a pinhole lid and heated under nitrogen (10 mL/min) at 10° C./min from 30° C. to 300° C. Programs used: Data collection and evaluation with software STARe.
[0140] Single Crystal X-Ray Diffraction (SCXRD):
[0141] The measured crystals were prepared under inert conditions immersed in perfluoropolyether as protecting oil for manipulation. Crystal structure determinations were carried out using a Apex DUO Kappa 4-axis goniometer equipped with an APPEX 2 4K CCD area detector, a Microfocus Source E025 IuS using MoK.sub.α radiation (0.71073 Å), Quazar MX multilayer Optics as monochromator and an Oxford Cryosystems low temperature device Cryostream 700 plus (T=−173° C.). Full-sphere data collection was used with ω and φ scans. Programs used: Data collection APEX-2 (Data collection with APEX II v2014.9-0. Bruker (2014). Bruker AXS Inc., Madison, Wis., USA), data reduction Bruker Saint (Data reduction with Bruker SAINT+ version V8.35A. Bruker (2013). Bruker AXS Inc., Madison, Wis., USA) V/.60A and absorption correction SADABS (SADABS: V2014/5 Bruker (2001). Bruker AXS Inc., Madison, Wis., USA. Blessing, Acta Cryst. (1995) A51 33-38).
[0142] Structure Solution and Refinement: Crystal structure solution was achieved using the computer program SHELXT (SHELXT; Sheldrick, G. M. Acta Cryst. 2015 A71, 3-8). Visualization was performed with the program SHELXIe (SHELXIe; C. B. Huebschle, G. M. Sheldrick & B. Dittrich; J.Appl.Cryst. (2011) 44, 1281-1284). Missing atoms were subsequently located from difference Fourier synthesis and added to the atom list. Least-squares refinement on F2 using all measured intensities was carried out using the program SHELXL 2015 (SHELXL; Sheldrick, G. M. Acta Cryst. 2015 C71, 3-8. SHELXT.). All non-hydrogen atoms were refined including anisotropic displacement parameters.
Comparative Example 01: Monosodium Salt of 2-[(4S)-8-fluoro-2-[4-(3-methoxy-phenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetic acid
[0143] (corresponds to Example 1 of US 2015/0038514 A1)
[0144] 333.1 g of 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoro-methyl)phenyl]-4H-quinazolin-4-yl]acetic acid are dissolved in 1300 mL of a mixture of ethanol and diisopropyl ether (1:1) in a 2000 mL three-neck flask. 21.9 g (546.84 mmol) of NaOH are added as a solid to the solution. The mixture is heated for 25 min. to an inner temperature of 50° C., and this yields a clear orange-coloured solution. The solution thus obtained is stirred for 3 hours at this temperature, and a thin suspension is formed already after 1 hour. The reaction mixture is then cooled down for 10 hours at a cooling rate of 3° C./hour to an inner temperature of 20° C. and then stirred for a further 5 hours at this temperature. The total volume of the reaction mixture is reduced under vacuum to approximately 750 mL and the suspension obtained in this way is stirred at 20° C. for 2 hours. Next, 250 mL diisopropyl ether is added over a period of 10 min to the reaction mixture obtained and the mixture is stirred for further 2 hours. The crystalline product which is obtained is vacuumed off by a suction device, washed 2× within each case 250 mL diisopropyl ether, and dried in a vacuum drying cabinet for 20 hours at 20° C. and 160 mbar. The crystalline solid obtained in this way is then dried for 10 min. at 90° C. in an IR dryer and then again for further 16 hours at 60° C. in the vacuum drying cabinet. In this way a total of 274.4 g (86% of the theoretical yield) of the desired crystalline sodium salt is obtained.
Comparative Example 02: Production of the Trihydrate of the Monosodium Salt of 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoro-methyl)phenyl]-4H-quinazolin-4-yl]cetic acid
[0145] (modification of Example 2 in US 2015/0038514 A1)
[0146] 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 are suspended in 1 mL methanol or ethanol (containing 4% water) and shaken for a week at 25° C. The crystalline obtained is filtered off and the residue is dried at room temperature and ambient humidity for two weeks. The residue obtained corresponds to the title compound as trihydrate.
[0147] The solid obtained is filtered off after shaking in the respective given solvent for one week at 20° C., the following crystals were obtained.
[0148] In case methanol was used as 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 as shown in
[0149] In case ethanol was used as 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 as shown in
[0150] The asymmetric unit contains one anionic molecule, one sodium cation, one water molecule and one ethanol molecule. The water and the ethanol molecule, which are coordinated to the sodium cation, are disordered in two positions (ratio 60:40). This compound crystallizes in the chiral space group R3 but a determination of the absolute structure could not be performed. The structure obtained by using ethanol is isostructural to the structure obtained using methanol. The structure is of high quality with a R1 value of 4.75%.
[0151]
[0152] Said 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 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 yl]acetate ethanol monohydrate, have to be dried at room temperature and ambient humidity for two weeks for transformation 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 as shown in
TABLE-US-00001 TABLE 1 The crystal data and structure refinement for the crystalline of letermovir sodium methanol monohydrate as shown in FIG. 1. Identification code mo_P0770INOHEOHLT_0m Empirical formula C30 H33 F4 N4 Na O6 Formula weight 644.59 Temperature 100(2) K Wavelength 0.71073 Å Crystal system Trigonal Space group R3 Unit cell dimensions a = 28.0775(12) Å α = 90° b = 28.0775(12) Å β = 90° c = 10.0570(4) Å γ = 120° Volume 6866.2(6) Å.sup.3 Z 9 Density (calculated) 1.403 Mg/m.sup.3 Absorption coefficient 0.126 mm.sup.−1 F(000) 3024 Crystal size 0.40 × 0.40 × 0.20 mm.sup.3 Theta range for data collection 1.450 to 30.511°. Index ranges −20 ≤ h ≤ 39, −38 ≤ k ≤ 37, −10 ≤ l ≤ 13 Reflections collected 13982 Independent reflections 6646[R(int) = 0.0381] Completeness to theta = 30.511° 96.3% Absorption correction Multi-scan Max. and min. transmission 0.975 and 0.76 Refinement method Full-matrix least-squares on F.sup.2 Data/restraints/parameters 6646/87/451 Goodness-of-fit on F.sup.2 1.051 Final R indices [I > 2sigma(I)] R1 = 0.0430, wR2 = 0.1104 R indices (all data) R1 = 0.0504, wR2 = 0.1181 Flack parameter x = −0.2(3) Largest diff. peak and hole 0.314 and −0.345 e .Math. Å.sup.−3
TABLE-US-00002 TABLE 2 The crystal data and structure refinement for the crystalline of letermovir sodium ethanol monohydrate as shown in FIG. 2. Identification code mo_P0770INOHEOH_0m Empirical formula C31 H35 F4 N4 Na O6 Formula weight 658.62 Temperature 100(2) K Wavelength 0.71073 Å Crystal system Trigonal Space group R3 Unit cell dimensions a = 28.4046(16) Å α = 90° b = 28.4048(16) Å β = 90° c = 10.0751(5) Å γ = 120° Volume 7039.7(9) Å.sup.3 Z 9 Density (calculated) 1.398 Mg/m.sup.3 Absorption coefficient 0.124 mm.sup.−1 F(000) 3096 Crystal size 0.20 × 0.20 × 0.10 mm.sup.3 Theta range for data collection 2.184 to 30.652°. Index ranges −40 ≤ h ≤ 20, −40 ≤ k ≤ 28, −12 ≤ l ≤ 10 Reflections collected 13091 Independent reflections 7753[R(int) = 0.0182] Completeness to theta = 30.511° 95.3% Absorption correction Multi-scan Max. and min. transmission 0.988 and 0.947 Refinement method Full-matrix least-squares on F.sup.2 Data/restraints/parameters 7753/133/462 Goodness-of-fit on F.sup.2 1.029 Final R indices [I > 2sigma(I)] R1 = 0.0475, wR2 = 0.1192 R indices (all data) R1 = 0.0531, wR2 = 0.1239 Flack parameter x = 0.13(15) Largest diff. peak and hole 0.794 and −0.413 e .Math. Å.sup.−3
Example 01: Direct 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 and Optimization Experiments
[0153] 1. Development, 2 Gram Scale
[0154] The development at a 2 gram scale was performed in reaction tubes. In light of the previous results, NaOH was added as an aqueous, concentrated solution, and the addition of antisolvent was controlled.
[0155] As antisolvent, diisopropyl ether was selected as the main antisolvent in the performed reactions.
[0156] Solvent: As proven in Comparative Example 02 performed according to the prior art (WO 2013/127971), letermovir sodium forms a significant number of solvates, particularly with alcohols such as methanol and ethanol. Thus, use of alcohols and other solvents which may promote the formation of solvates other than sodium trihydrate were excluded in the present development.
[0157] Other Parameters
[0158] The following parameters were modified during the development and optimization: [0159] solvent/antisolvent ratio [0160] addition of antisolvent (rate and moment of addition) [0161] API concentration [0162] NaOH addition (direct or dissolved in water) [0163] water volume [0164] reaction time [0165] reaction temperature [0166] inoculation with crystal seeds
[0167] A summary of the performed experiments is available in Table 3. The results suggest that the reduction in the water volume seems to positively affect the outcome of the reaction. The rate of addition of the antisolvent does not appear to significantly affect the procedure. The obtained yields were, generally, average to low. Whereas diisopropylether was found to be the most reliable antisolvent, all solvents afford comparable results.
[0168] Based on the experimental results depending on the methodology variables, the most critical reaction parameters were selected for a series of optimization experiments.
TABLE-US-00003 TABLE 3 Reactions performed in the crystallization development of letermovir sodium trihydrate (2 gram scale). Solvent Antisolvent Conc (solv) NaOH Temp. Solvent Volume Volume Conc (total) (water) Duration Seeding Yield AET 2 + 2 + 5 mL 0.5 g/mL 0.5 mL 50° C. (2 h) Yes 52% 2 mL 0.18 g/mL (280 mg/mL) r.T. (15 h) AET 4 mL 4 + 8 mL 0.5 g/mL 0.2 mL 50° C. (2 h) Yes 75% 0.13 g/mL (700 mg/mL) r.T. (15 h) MAC 3 mL 5 + 5 + 5 mL 0.7 g/mL 0.2 mL 50° C. (2 h) Yes 72% (syr.pump) 0.11 g/mL (700 mg/mL) r.T. (15 h) MEC 4 mL 4 + 8 mL 0.5 g/mL 0.2 mL 50° C. (2 h) Yes 88% 0.13 g/mL (700 mg/mL) r.T. (15 h) MEC 2 + 8 mL 0.7 g/mL 0.2 mL 50° C. (2 h) Yes 37% 1 mL (syr.pump) 0.18 g/mL (700 mg/mL) r.T. (15 h) MEC 3 mL 5 + 5 + 5 mL 0.7 g/mL 0.2 mL 50° C. (2 h) Yes 30% (syr.pump) 0.11 g/mL (700 mg/mL) r.T. (4 h) AET = ethyl acetate, AIP = isopropyl acetate, MAC = methyl acetate, MEC = methyl ethyl ketone, Antisolvent = diisopropyl ether.
[0169] 2. Further Optimization
[0170] The results of the development experiments outlined the following critical factors: [0171] API concentration [0172] solvent/antisolvent ratio [0173] antisolvent addition [0174] water volume
[0175] The optimization was aimed to obtain a robust methodology which can be easily scaled up. Thus, experiments were performed in a 10 to 20 g scale, using an EasyMax™. Results are available in Table 4. Experiments performed in the EasyMax™ unveiled some issues which had not been observed at smaller scales.
TABLE-US-00004 TABLE 4 Reactions performed in the crystallization development of letermovir sodium trihydrate in 10-20 gram scale. Conc (solv) Solvent Antisolvent Conc NaOH Temp. Scale Solvent Volume Volume (total) (water) Duration Seeding Yield 10 g AET 15 mL 25 + 25 mL 0.7 g/mL 0.7 mL 50° C. (1 hour) Yes 88% (syr.pump) 0.15 g/mL (1 g/mL) 50-20° C. (2 (<0.5%) hour) 20-5° C. (1 hour) 10 g AET 15 mL 15 + 15 mL 0.7 g/mL 0.75 mL 50-35° C. (1 h) Yes 62% 0.22 g/mL (1 g/mL) 35° C. (1 h) (<0.5%) 50° C. (1 h) 50-5° C. (1.5 h) 20 g AET 20 mL 40 mL 1 g/mL 2 mL 50° C. (4 hours) Yes 98% 0.33 g/mL (1 g/mL) 50-20° C. (1 (0.5%) hour) 20 g AIP 20 mL 40 mL 1 g/mL 2 mL 50° C. (4 hours) Yes 99% 0.33 g/mL (1 g/mL) 50-20° C. (1 (0.5%) hour) 10 g MAC 15 mL 15 + 15 mL 0.7 g/mL 0.75 mL 50° C. (4 h) Yes 70% 0.22 g/mL (1 g/mL) 50-20° C. (2 h) (<0.5%) 20 g MAC 20 mL 20 + 20 + 1 g/mL 1.5 mL 50° C. (1 hour) Yes 93% 20 mL 0.25 g/mL (1 g/mL) 50-20° C. (<0.5%) (1 hour) 50° C. (1 hour) 20 g MAC 20 mL 40 mL 1 g/mL 2 mL 50° C. (4 hours) Yes 74% 0.33 g/mL (1 g/mL) 50-20° C. (1 (0.5%) hour) 10 g MEC 15 mL 15 + 15 mL 0.7 g/mL 0.75 mL 50° C. (2 h) Yes ~99% (syr.pump) 0.22 g/mL (1 g/mL) 50-10° C. (2 h) (<0.5%) r.T (15 h) 20 g MEC 20 mL 40 + 10 mL 1 g/mL 2 mL 50° C. (1 hour) Yes ~99% 0.29 g/mL (1 g/mL) 50-20 C. (2 (<0.5%) hour) 20-5° C. (1 hour) 20 g MEC 20 mL 40 mL 1 g/mL 2 mL 50° C. (4 hours) Yes 59% 0.33 g/mL (1 g/mL) 50-20° C. (1 (0.5%) hour) AET = ethyl acetate, AIP = isopropyl acetate, MAC = methyl acetate, MEC = methyl ethyl ketone, Antisolvent = diisopropyl ether.
[0176] The following parameters were optimized: [0177] A more concentrated NaOH solution was used (1 g/mL in water). NaOH was added in excess (1.5 mole equivalents) [0178] More concentrated API solutions were used (ca. 0.33 g/mL) [0179] The stir rate was medium to vigorous (poor stirring may lead to the formation of oils, resins and biphasic systems) [0180] Diisopropyl ether was added at different times and rates, with no visible improvements in the outcome [0181] Reaction was streamlined by dissolving the API in a solvent/antisolvent mixture before NaOH addition [0182] Optionally, in order to better induce letermovir sodium trihydrate precipitation, the initial solution+base was inoculated with a 0.5 wt % of letermovir sodium trihydrate crystal seeds [0183] Isopropyl acetate was found to be the most suitable solvent in the optimized reaction conditions; its use affords highly crystalline letermovir sodium trihydrate in quantitative yields
[0184] Based on the optimized parameters, a general procedure for the preparation of letermovir sodium trihydrate is outlined.
[0185] 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy (trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetic acid (letermovir) is dissolved in a 1:2 mixture of isopropyl acetate and diisopropylether at 50° C. (final API concentration: 0.33 g/mL). Then, 1.5 mole equivalents of NaOH (1 g/mL aqueous solution) are added and the solution is seeded with letermovir sodium trihydrate A (1-0.5% w/w) and allowed to stir for 4 hours at 50° C. The suspension is then cooled down gradually (50° C. to 20° C. in 1 hour). The contents of the reactor are filtered under vacuum, washed thrice with diisopropyl ether and dried under reduced pressure (2-3 hPa) at 50° C. for 15 hours. A white, compact powder (letermovir sodium trihydrate) is obtained.
[0186] The technical features of letermovir sodium ethanol monohydrate (water) and letermovir sodium trihydrate are summarized below.
TABLE-US-00005 TABLE 5 Ethanol/Water Solvate Trihydrate Preparation Reaction crystallization in an Reaction crystallization in an isopropyl method ethanol/diisopropylether mixture acetate/diisopropyl ether mixture Macroscopic White Powder White Powder aspect of the solid Optical Crystalline solid Crystalline solid microscopy PXRD Similar crystalline phases; peaks are slightly shifted, some clear differences SCXRD 1 Letermovir molecule 1 Letermovir molecule 1 Sodium atom 1 Sodium atom 1 Ethanol molecule 3 Water molecules 1 Water molecule TGA 1.6% loss of mass between 30 and 100° C. 3.8% loss of mass between 30 and 100° C. 6.3% loss of mass between 100 and 150° C. 3.8% loss of mass between 100 and 150° C. Decomposition occurs at ca. 250° C. Decomposition occurs at ca. 250° C. DSC Weak endotherm between 30 and 80° C. Weak endotherm between 75 and 105° C. Strong endotherm between 100 and 150° C. Strong endotherm (or two overlapping endotherms) between 105 and 140° C. Hygroscopicity 3.2% water adsorption (10-90% RH) 8.6% water adsorption (10-90% RH) (DVS) 5.3% water adsorption (10-80% RH) 4.1% water adsorption (10-80% RH) PXRD after experiment: trihydrate No PXRD changes after experiment Additional info The solid turns into the amorphous The solid turns into the amorphous form in a drying process (>60° C.). form in a drying process (>60° C.) The trihydrated form cannot be obtained in a drying process
Example 02. Preparation of Sodium 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)pi-perazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetate trihydrate in 500 g Scale
[0187] 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 are dissolved in a 1:2 mixture of isopropyl acetate and diisopropyl ether at 50° C. (0.75 L/1.5 L), followed by addition of ca. 1.5 equivalents of NaOH (aqueous solution, 1 g/mL, 50 mL) and the solution is 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 with respect to the base). The suspension is stirred for 4 hours at 50° C. (stir rate: 150 rpm, glass anchor shaft). Abundant white solid precipitates within the first hour. The reactor is gradually cooled down (50° C. to 20° C. in 1 hour) and its contents are filtered under vacuum and washed thrice with diisopropyl ether. The obtained white solid is dried under reduced pressure (2-3 mBar) at 50° C. for 15 hours.
[0188] 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]acetic acid trihydrate have been obtained.
Example 03. Preparation of Single Crystal of Letermovir Sodium Trihydrate
[0189] The crystal was obtained via partial evaporation of a concentrated Letermovir Sodium solution in an isopropyl acetate/diisopropyl ether mixture.
[0190] The asymmetric unit contains one molecule of Letermovir in anionic form, a sodium cation and three molecules of water. The content of the asymmetric unit is represented in
TABLE-US-00006 TABLE 6 Crystal data Identification code mo_P0821002_0m Empirical formula C.sub.29H.sub.27F.sub.4N.sub.4Na.sub.1O.sub.4 .Math. 3 × H.sub.2O Formula weight 648.58 Temperature 100(2) K Wavelength 0.71073 Å Crystal system Trigonal Space group R3:H Unit cell dimensions a = 28.2198(15) Å □ = 90° b = 28.2198(15) Å □ = 90° c = 9.9699(6) Å □ = 120° Volume 6875.9(8) Å.sup.3 Z 9 Density (calculated) 1.410 mg/m.sup.3 Absorption coefficient 0.115 mm.sup.−1 F(000) 3042 Crystal size 0.50 × 0.40 × 0.20 mm3 Theta range for data collection 2.206 to 32.514° Index ranges −42 ≤ h ≤ 40, −40 ≤ k ≤ 42, −9 ≤ l ≤ 14 Reflections collected 44772 Independent reflections 8331[R(int) = 0.0255] Completeness to theta = 32.514° 95.50% Absorption correction Multi-scan Max. and min. transmission 0.74 and 0.69 Refinement method Full-matrix least-squares on F.sup.2 Data/restraints/parameters 8331/231/511 Goodness-of-fit on F2 1.044 Final R indices [I > 2sigma(I)] R.sub.1 = 0.0460, wR.sub.2 = 0.1083 R indices (all data) R.sub.1 = 0.0483, wR.sub.2 = 0.1102 Flack parameter x = 0.05(7) Largest diff. peak and hole 0.563 and −0.589 e .Math. Å.sup.−3