Salts of a dihydroquinazoline derivative
RE049897 ยท 2024-04-02
Assignee
Inventors
Cpc classification
C07C309/29
CHEMISTRY; METALLURGY
C07C309/30
CHEMISTRY; METALLURGY
International classification
Abstract
The invention relates to besylate and tosylate salts of {8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl} acetic acid and solvates thereof, to the use thereof in a method of treating and/or preventing virus infections, and to the use thereof to produce drugs for use in treating and/or preventing diseases, in particular use as antiviral agents, in particular against cytomegaloviruses (FIG. 1).
Claims
1. A method for purifying {8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazoline-4-yl}acetic acid using the following steps: 1.) Reacting {8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazoline-4-yl}acetic acid in a solvent with benzenesulfonic acid or toluenesulfonic acid to obtain a crystalline salt, 2.) Isolating the salt obtained in step 1.), 3.) Treating the isolated salt obtained in step 2.) with a buffer solution at a pH in the range of 5 to 7 to release a zwitterionic form of {8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazoline-4-yl}acetic acid, and 4). Isolating the zwitterionic form of {8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazoline-4-yl}acetic acid obtained in step 3.).
2. A method according to claim 1, wherein the zwitterionic form of {8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazoline-4-yl}acetic acid comprises less than 0.1% impurities.
3. A method according to claim 1, wherein the zwitterionic form of {8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazoline-4-yl}acetic acid comprises less than 0.08% impurities.
4. A method according to claim 1, wherein the zwitterionic form of {8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazoline-4-yl}acetic acid comprises less than 0.05% impurities.
5. The method according to claim 1, wherein the zwitterionic form of {8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazoline-4-yl}acetic acid is suitable for preparation of the crystalline besylate salt of {8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazoline-4-yl}acetic acid, the crystalline tosylate salt of {8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazoline-4-yl}acetic acid, or solvates thereof.
6. A method according to claim 5, wherein a salt or solvate prepared from the zwitterionic form of {8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazoline-4-yl}acetic acid, is suitable for use in a method of treatment and/or prophylaxis of human cytomegalovirus (HCMV) infections or infections with another representative of the herpes viridae group.
7. The method according to claim 6, wherein the said infection of the herpes viridae group is human cytomegalovirus (HCMV).
8. A method according to claim 5, wherein a salt or solvate prepared from the zwitterionic form of {8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazoline-4-yl}acetic acid, is suitable for combination with at least one pharmaceutically acceptable excipient for use in a method of treatment and/or prophylaxis of human cytomegalovirus (HCMV) infections or infections with another representative of the herpes viridae group.
9. A method for purifying {8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4- dihydroquinazoline-4-yl}acetic acid using the following steps: 1.) reacting {8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4- dihydroquinazoline-4-yl}acetic acid in a solvent with benzenesulfonic acid or toluenesulfonic acid, 2.) cooling the reaction from step 1) to initiate the crystallization of the salt obtained in step 1.), 3.) treating the isolated salt obtained in step 2.) with a buffer to release a zwitterionic form of {8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazoline-4- yl}acetic acid, and 4). isolating the zwitterionic form of {8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazoline-4-yl}acetic acid obtained in step 3.).
.Iadd.10. The method according to claim 1, wherein the carbon in position 4 of the dihydroquinazoline ring has an (S)-configuration..Iaddend.
.Iadd.11. The method according to claim 2, wherein the carbon in position 4 of the dihydroquinazoline ring has an (S)-configuration..Iaddend.
.Iadd.12. The method according to claim 3, wherein the carbon in position 4 of the dihydroquinazoline ring has an (S)-configuration..Iaddend.
.Iadd.13. The method according to claim 4, wherein the carbon in position 4 of the dihydroquinazoline ring has an (S)-configuration..Iaddend.
.Iadd.14. The method according to claim 5, wherein the carbon in position 4 of the dihydroquinazoline ring has an (S)-configuration..Iaddend.
.Iadd.15. The method according to claim 6, wherein the carbon in position 4 of the dihydroquinazoline ring has an (S)-configuration..Iaddend.
.Iadd.16. The method according to claim 7, wherein the carbon in position 4 of the dihydroquinazoline ring has an (S)-configuration..Iaddend.
.Iadd.17. The method according to claim 8, wherein the carbon in position 4 of the dihydroquinazoline ring has an (S)-configuration..Iaddend.
.Iadd.18. The method according to claim 9, wherein the carbon in position 4 of the dihydroquinazoline ring has an (S)-configuration..Iaddend.
Description
BRIEF DESCRIPTION OF THE FIGURES
(1)
(2)
(3)
(4)
(5)
(6)
(7) Unless indicated otherwise, the percentages given in the following tests and examples are weight percentages, parts are weight proportions. Solvent ratios, dilution ratios and concentrations of liquid solutions relate, in each case, to the volume.
List of Abbreviations
(8) ACN Acetonitrile
(9) API active pharmaceutical ingredient
(10) API-ES-pos. Atmospheric pressure ionization, electrospray, positive (in MS)
(11) API-ES-neg. Atmospheric pressure ionization, electrospray, negative (in MS)
(12) ca. circa
(13) CI, NH.sub.3 chemical ionization (with ammonia)
(14) DBU 1,8-Diazabicyclo[5.4.0]undec-7-en
(15) DMAP 4-(Dimethylamino)pyridine
(16) DMSO Dimethyl sulfoxide
(17) ESTD external standardization
(18) h hour(s)
(19) HPLC high pressure liquid chromatography
(20) cone. concentrated
(21) min. minutes
(22) MS mass spectroscopy
(23) MTBE Methyl tert-butylether
(24) NMR nuclear magnetic resonance spectroscopy
(25) R.sub.T retention time (in HPLC)
(26) VTS vacuum drying cabinet
(27) General HPLC Methods:
(28) Method 1 (HPLC): Instrument: HP 1050 with variable wavelength detection; column: Phenomenex Prodigy ODS (3) 100 A, 150 mm?3 mm, 3 ?m; Eluent A: (1.0 g KH2PO4+1.0 ml H3PO4)/1 water, Eluent B: acetonitrile; gradient: 0 min 10% B, 25 min 80% B, 35 min 80% B; flow: 0.5 ml/min; temp.: 45? C.; UV detection: 210 nm.
(29) Method 2 (HPLC): Instrument: HP 1050 with variable wavelength detection; column: Chiral AD-H, 250 mm?4.6 mm, 5 m; Eluent A: n-heptane+0.2% diethylamine, Eluent B: isopropanol+0.2% diethylamine; gradient: 0 min 12.5% B, 30 min 12.5% B; flow: 1 ml/min; temp.: 25? C.; UV detection: 250 nm.
(30) Method 3 (HPLC): Instrument: HP 1050 with variable wavelength detection; column: Chiral AD-H, 250 mm?4.6 mm, 5 ?m; Eluent A: n-heptane+0.2% diethylamine, Eluent B: isopropanol+0.2% diethylamine; gradient: 0 min 25% B, 15 min 25% B; flow: 1 ml/min; temp.: 30? C.; UV detection: 250 nm.
EXAMPLES
A.) Production of {8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazoline-4-yl}acetic acid
Example 1A
N-(2-fluorophenyl)-N-[2-methoxy-5-(trifluoromethyl)phenyl]urea
(31) ##STR00008##
(32) 2-methoxy-5-trifluoromethylphenyl isocyanate (78 kg) is melted at approx. 35? C. and dissolved in acetonitrile (a total of approx. 270 l), then 2-fluoroaniline (39.9 kg) is added and rinsed with acetonitrile (approx. 25 l). The resulting clear solution is agitated for 4 h at reflux and then cooled to approx. 75? C. Once this temperature is reached, the solution is inoculated with seed crystals of the desired end product (200 g), agitated for an additional 15 min., and then cooled to 0? C. over the course of 3 h. The resulting crystalline product is isolated by centrifugation, washed with cold acetonitrile (twice using approx. 13 l), and dried at 45? C. in the VTS under purging with nitrogen (approx. 3.5 h). A total of 101.5 kg of N-(2-fluorophenyl)-N-[2-methoxy-5-(trifluormethyl)phenyl]urea is thus obtained as a solid, corresponding to 85.9% of theory.
(33) .sup.1H NMR (300 MHz, d.sub.6-DMSO): ?=8.93 (s, 1H), 8.84 (s, 1H), 8.52 (d, .sup.3J=2, 3, 2H), 7.55 (d, .sup.2J=7.7, 1H), 7.38-7.26 (m, 3H), 7.22 (d, .sup.2J=8.5, 11H), 4.00 (s, 3H) ppm;
(34) MS (API-ES-pos.): m/z=409 [(M+H).sup.+, 100%];
(35) HPLC (Method 1): R.sub.T=22.4 and 30.6 min.
Example 2A
Methyl-(2Z)-3-[3-fluoro-2-({[2-methoxy-5-(trifluoromethyl)phenyl]carbamoyl}amino)-phenyl]acrylate
(36) ##STR00009##
(37) N-(2-fluorophenyl)-N-[2-methoxy-5-(trifluoromethyl)phenyl] urea (51 kg) is dissolved in acetic acid (approx. 430 l) in one reactor in a nitrogen atmosphere. Methyl acrylate (20.1 kg) is added to the resulting solution and the resulting suspension is agitated until further use. Acetic acid (950 l) is placed in a second reactor, oleum (57 kg) is carefully added and palladium (II) acetate (7 kg) is dissolved in the mixture. The suspension formed in the first reactor is then added to the mixture contained in the second reactor over the course of approx. 2 h; the reaction mixture is overflowed with a mixture of 96% nitrogen and 4% oxygen and the resulting reaction mixture is agitated for approx. 18 h at room temperature. Part of the acetic acid (approx. 900 l) is then distilled off; water (approx. 500 l) is added to the remaining reaction mixture over the course of approx. 1 h and the resulting suspension is agitated for 1 h. The resulting particulate matter is filtered off, washed once with a mixture of acetic acid and water (1:1) and twice with water, and finally dried at approx. 30 mbar and 50? C. A total of 44.8 kg of methyl-(2Z)-3-[3-fluoro-2-({[2-methoxy-5-(trifluoromethyl)phenyl]carbamoyl}amino)phenyl]acrylate is thus obtained as a solid, corresponding to 65.0% of theory.
(38) .sup.1H NMR (300 MHz, d.sub.6-DMSO): ?=9.16 (s, 1H), 8.84 (s, 1H), 8.45 (d, 1.7 Hz, 1H), 7.73 (m, 2H), 7.33 (m, 3H), 7.22 (d, 8.6 Hz, 1H), 6.70 (d, 16 Hz, 1H), 3.99 (s, 3H), 3.71 (s, 3H) ppm;
(39) MS (API-ES-pos.): m/z=429.9 [(M+NH.sub.4).sup.+]; 412.9 [(M+H).sup.+]
(40) HPLC: R.sub.T=46.4 min.
(41) Instrument: HP 1100 with variable wavelength detection; column: Phenomenex Prodigy ODS (3) 100 A, 150 mm?3 mm, 3 ?m; Eluent A: (1.36 g KH.sub.2PO.sub.4+0.7 ml H.sub.3PO.sub.4)/1 of water, Eluent B: acetonitrile; gradient: 0 min 20% B, 40 min 45% B, 50 min 80% B, 65 min 80% B; flow: 0.5 ml/min; temp.: 55? C.; UV detection: 210 nm.
Example 3A
{8-fluoro-3-[2-methoxy-5-(trifluoromethyl)phenyl]-2-oxo-1,2,3,4-tetrahydroquinazoline-4-yl} methyl acetate
(42) ##STR00010##
(43) The compound in Example 2A (75 kg) is suspended in acetone (1600 l), and DBU (5.7 kg) is added. The resulting suspension is heated to reflux and agitated for 4 h at reflux. The resulting solution is cooled to a jacket temperature of 55? C. and filter through kieselguhr. Part of the solvent (approx. 1125 l) is removed by distillation and the remaining residue is cooled for 2 h to 0? C. The resulting solid is separated out by centrifugation, washed twice using cold acetone (approx. 15 l), and dried overnight at 45? C. under reduced pressure and under purging with nitrogen to constant mass. A total of 58.3 kg of {8-fluoro-3-[2-methoxy-5-(trifluoromethyl)phenyl]-2-oxo-1,2,3,4-tetrahydroquinazoline-4-yl} methyl acetate is thus obtained as a solid, corresponding to 84.1% of theory.
(44) HPLC (Method 1): R.sub.T=19.4 min.
Example 4A
(2S,3S)-2,3-bis[(4-methylbenzoyl)oxy] succinic acid-{(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazoline-4-yl}methyl acetate (1:1 salt) chlorination/amination/crystallization
(45) ##STR00011##
(46) A solution of {8-fluoro-3-[2-methoxy-5-(trifluoromethyl)phenyl]-2-oxo-1,2,3,4-tetrahydroquinazoline-4-yl}methyl acetate (Example 3A, 129.2 kg) in chlorobenzene (800 l) is heated to reflux and azeotropically dried. Phosphorous oxychloride (144 kg) is added, and the reaction mixture is agitated for 3 h at reflux. Then, DBU (95 kg) and chlorobenzene (45 l) are added and agitated for additional 9 h at reflux. The reaction mixture is cooled to room temperature, hydrolyzed by adding water, diluted with chlorobenzene (80 l), and neutralized with an aqueous solution of ammonia (25%). The phases are separated, the organic phase is washed with water and the solvent is distilled off. The remaining residue is dissolved in dioxane (170 l). 3-methoxyphenylpiperazine (66 kg), DBU (52 kg), and an additional 90 l of dioxane are added and the reaction mixture is heated for 4 h at reflux. The reaction mixture is cooled to room temperature, added to ethyl acetate (1300 l), washed once with water, 3 times with 0.2 N HCl, and once with an aqueous solution of NaCl, and the solvent is distilled off. The resulting residue is dissolved in ethyl acetate (800 l) and added to a solution of (2S,3S)-2,3-bis[(4-methylbenzoyl)oxy] succinic acid (121 kg) in ethyl acetate (600 l). The resulting mixture is agitated for approx. 60 min. at room temperature and then inoculated with (2S,3S)-2,3-bis[(4-methylbenzoyl)oxy]-succinic acid-{(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)-phenyl]-3,4-dihydroquinazoline-4-yl}methyl acetate and agitated for 3 days at room temperature. It is then cooled to 0-5? C. and agitated for an additional 3 h. The suspension is filtered and the remaining solid is rewashed in batches with ethyl acetate. A total of about 141 kg (calculated as dry weight) of the salt is thus obtained as a solid, corresponding to around 46.2% of theory, in three stages (chlorination, amination and crystallization) compared to the racemate).
(47) .sup.1H NMR (300 MHz, d.sub.6-DMSO): ?=7.90 (d, .sup.2J=7.8, 4H), 7.56 (d, .sup.2J=8.3, 1H), 7.40 (d, 2J=7.8, 4H), 7.28-7.05 (m, 4H), 6.91-6.86 (m, 2H), 6.45 (d, 2J=8.3, 1H), 6.39-6.36 (m, 2H), 5.82 (s, 2H), 4.94 (m, 1H), 4.03 (q, .sup.2J=7.1, 2H), 3.83 (brs, 3H), 3.69 (s, 3H), 3.64 (s, 3H), 3.47-3.36 (m, 8H and water, 2H), 2.98-2.81 (m, 5H), 2.58-2.52 (m, 1H), 2.41 (s, 6H), 1.99 (s, 3H), 1.18 (t, .sup.2J=7.2, 3H) ppm;
(48) HPLC (Method 1): R.sub.T=16.6 and 18.5 min.
Example 5A
(2S,3S)-2,3-bis[(4-methylbenzoyl)oxy] succinic acid-{(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazoline-4-yl}methyl acetate (1:1 salt)/recrystallization
(49) (2S,3S)-2,3-bis[(4-methylbenzoyl)oxy] succinic acid(S) {(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazoline-4-yl}acetic acid methyl ester (1:1 salt) (141 kg, calculated as dry weight) is suspended in ethyl acetate (1400 l) and dissolved by heating to reflux (77? C.). The solution is filtered and slowly cooled to room temperature, which results in spontaneous crystallization. The suspension is agitated for 16 h at RT, and then cooled to 0-5? C. and agitated for additional 3 h. The suspension is filtered and the remaining solid is rewashed with cold ethyl acetate. The crystals are dried for 16 h in a vacuum at around 40? C. A total of 131.2 kg of the salt is obtained as a solid, corresponding to 93.0% of theory.
(50) HPLC (Method 1): R.sub.T=16.9 and 18.8 min.;
(51) HPLC (Method 3): 99.9% e.e.
Example 6A
(S)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-(2-methoxy-5-trifluoromethyl-phenyl)-3,4-dihydroquinazoline-4-yl}acetic acid
(52) ##STR00012##
(53) A mixture of (2S,3S)-2,3-bis[(4-methylbenzoyl)oxy]succinic acid-{(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazoline-4-yl}acetic acid methyl ester (1:1 salt) (30.8 kg), sodium bicarbonate (16.4 kg), and water (315 l) is mixed with MTBE (160 l). The phases are separated and the organic phase is treated with 35 l of an approximately seven-percent aqueous solution of sodium bicarbonate. The phases are separated and the organic phase is added to 125 l of an approximately four-percent aqueous solution of sodium hydroxide. The reaction mixture is heated to reflux, the solution is evaporated to dryness, and the reactor contents are then agitated for an additional 5 h at 55-60? C. The reaction mixture is then added at approx. 22? C. to MTBE (160 l) and water (65 l) and agitated. The phases are separated and the organic phase is extracted with an approximately six-percent aqueous solution of sodium chloride (30 l). The combined aqueous phases are mixed with water (25 l) and MTBE (160 l) and the pH value is adjusted to approx. 6.5 with approx. 1 N of hydrochloric acid. The organic phase is separated, the solvent is evaporated to dryness, and the residue is dissolved in acetone (approx. 75 l). The solvent is changed to acetone (6 distillations with approx. 130 l each). The final product is then precipitated by adding water, isolated through centrifugation, and dried in a vacuum dryer. A total of 16.5 kg of (S)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-(2-methoxy-5-trifluoromethylphenyl)-3,4-dihydroquinazoline-4-yl}acetic acid is thus obtained as an amorphous solid, corresponding to 96.4% of theory.
(54) .sup.1H NMR (300 MHz, d.sub.6-DMSO): ?=7.53 (d, .sup.2J=8.4, 1H), 7.41 (brs, 1H), 7.22 (d, .sup.2J=8.5, 1H), 7.09-7.01 (m, 2H), 6.86 (m, 2H), 6.45 (dd, .sup.2J=8.2, .sup.3J=1.8, 1H), 6.39-6.34 (m, 2H), 4.87 (t, .sup.2J=7.3, 1 H), 3.79 (brs, 3H), 3.68 (s, 3H), 3.50-3.38 (m, 4H), 2.96-2.75 (m, 5H), 2.45-2.40 (m, 1H) ppm;
(55) MS (API-ES-neg.): m/z=571 [(M+H), 100%];
(56) HPLC (Method 1): R.sub.T=15.1 min;
(57) HPLC (Method 2): 99.8% e.e.; Pd (ICP): <1 ppm.
B.) Exemplary Embodiments
Crystallization Experiments
(58) Crystallization experiments to find a suitable crystalline salt of {8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazoline-4-yl}acetic acid were conducted. The crystallization experiments were based on (S)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazoline-4-yl}acetic acid and the respective acid either by slurrification in the individually specified solvent for one week at 20? C. or by crystallization through cooling/evaporation of a solution that was kept at 50? C. for 4 hours, followed by slow cooling to 20? C. at a ratio of 3? C./hour.
(59) The results of the crystallization experiments are given in Table 1 below where the abbreviation API denotes (S)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazoline-4-yl}acetic acid.
(60) API is the acronym for active pharmaceutical ingredient.
(61) TABLE-US-00001 TABLE 1 Crystallization experiments using acid counterions Ratio API: Coun- Result Counterions terions Method Solvent (XRPD) HCl 1:2 Cooling Acetone, Acetonitrile, amorphous Methanol, THF Slurrifica- Water, Acetonitrile, tion Methanol and Ethanol Citric acid 1:1 Cooling Acetone, Acetonitrile, amorphous Methanol, THF Slurrifica- Water, Acetonitrile tion Methanol and Ethanol Phosphoric 1:1 Cooling Acetone, Acetonitrile, amorphous acid Methanol, THF Slurrifica- Water, Acetonitrile, tion Methanol and Ethanol Gluconic 1:1 Cooling Acetone, Acetonitrile, amorphous acid Methanol, THF Slurrifica- Water, Acetonitrile tion Methanol and Ethanol Lactic acid 1:1 Cooling Acetone, Acetonitrile, amorphous Methanol, THF Slurrifica- Water, Acetonitrile tion Methanol and Ethanol Maleic acid 1:1 Cooling Acetone, Acetonitrile, amorphous Methanol, THF Slurrifica- Water, Acetonitrile tion Methanol and Ethanol Succinic acid 1:1 Cooling Acetone, Acetonitrile, amorphous Methanol, THF Slurrifica- Water, Acetonitrile tion Methanol and Ethanol Sulfuric acid 1:1 Cooling Acetone, Acetonitrile, amorphous Methanol, THF Slurrifica- Water, Acetonitrile tion Methanol and Ethanol Tartaric acid 1:1 Cooling Acetone, Acetonitrile, amorphous Methanol, THF Slurrifica- Water, Acetonitrile tion Methanol and Ethanol Benzoic acid 1:1 Cooling Acetone, Acetonitrile, amorphous Methanol, THF Slurrifica- Water, Acetonitrile tion Methanol and Ethanol Fumaric acid 1:1 Cooling Acetone, Acetonitrile, amorphous Methanol, THF Slurrifica- Water, Acetonitrile tion Methanol and Ethanol Maleic acid 1:1 Cooling Acetone, Acetonitrile, amorphous Methanol, THF Slurrifica- Water, Acetonitrile tion Methanol and Ethanol Methanesul- 1:1 Cooling Acetone, Acetonitrile, amorphous fonic acid Methanol, THF Slurrifica- Water, Acetonitrile tion Methanol and Ethanol
(62) Noticeable in these experiments was the extreme difficulty to produce crystalline acid salts from (S)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoro-methyl)phenyl]-3,4-dihydroquinazoline-4-yl}acetic acid, where the first crystallization attempts failed altogether. In the course of further research it has been found, however, that it was possible to obtain crystalline salts both with benzenesulfonic acid and toluenesulfonic acid. The besylate and tosylate salts obtained proved to be easily producible and with a high level of purity. Furthermore, the X-ray diffractograms revealed that these salts crystallize without incorporating solvent molecules.
Exemplary Embodiments
Example 1
(63) Besylate salt of (S)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazoline-4-yl}acetic acid 235.00 g (0.41 mol) of (S)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazoline-4-yl}acetic acid (Example 6A) are dissolved in 1645 ml of acetone and 16.45 ml of water is added to the resulting mixture. The resulting yellowish solution is filtered and 64.92 g (0.41 mol) of benzenesulfonic acid as a solid is added portion by portion. The resulting solution is heated to about 40? C. and suitable seed crystals are added at this temperature. The resulting solution is cooled down to room temperature under stirring and the resulting suspension is cooled to 0-5? C. and stirred for an additional 2 hours at that temperature. The resulting solid is filtered, washed 2? with acetone (100 ml, 0? C.) and dried at 60? C. to constant weight. This process yields a total of 243.87 g (81.4% of the theoretic quantity) of the target compound.
(64) From the crystalline solid obtained in Example 1, an X-ray powder diffractogram (XRD) was recorded with a Siemens Powder Diffractometer D5000 that is shown in
(65) The peak lists for the salt obtained in Example 1 as well as for the salt obtained in Example 2 are shown in Table 2.
(66) Measuring Conditions
(67) Copper anode (wavelength 1.5418 ?)
(68) Voltage: 4000 V, Current: 30 mA
(69) Secondary graphite monochromator,
(70) variable (theta-dependent) divergence and anti-diffusion shield
(71) Detector aperture: 0.2 mm
(72) 6?10 mm effective sample surface
(73) Scanning 0.02? (2 theta), 2 sec.
Example 2
Tosylate salt of (S)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazoline-4-yl}acetic acid
(74) 235.00 g (0.41 mol) of (S)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazoline-4-yl}acetic acid (Example 6A) are dissolved in 1645 ml of acetone and 16.45 ml of water is added to the solution. The resulting yellowish solution is filtered and 78.07 g (0.41 mol) of solid p-toluenesulfonic acid monohydrate are added portion by portion at about 36? C. The solution is cooled down to room temperature under stirring and the resulting suspension is then cooled to 0-5? C. and stirred for an additional 2 hours at that temperature. The solid material is separated, washed 2? with acetone (100 ml, 0? C.) and dried at 60? C. to constant weight. This process yielded a total of 248.11 g (79.3% of the theoretic quantity) of the desired final product.
(75) From the crystalline solid material obtained in Example 2 an X-ray powder diffractogram (XRD), shown in
(76) TABLE-US-00002 TABLE 2 2 theta Example 1 Example 2 6.9 6.2 8.6 6.9 9.1 8.8 10.1 11.7 10.6 13.3 10.9 14.8 11.4 15.3 11.7 16.5 12.6 17.0 12.9 17.2 13.9 17.9 14.2 18.1 14.9 18.7 15.5 19.6 15.8 19.8 16.9 20.2 17.3 20.7 18.2 21.0 18.6 21.4 18.8 21.8 19.1 22.5 20.2 23.0 21.0 23.2 21.3 23.7 21.9 24.0 22.2 24.8 22.8 25.6 23.1 26.2 23.6 26.4 23.9 26.7 24.2 27.7 24.7 28.3 25.5 28.6 25.9 29.4 26.2 30.0 26.5 31.8 26.9 34.8 27.2 36.3 27.9 36.7 28.2 38.9 28.6 39.8 29.0 29.4 29.9 30.6 31.1 31.5 32.6 33.1 33.7 34.4 34.9 36.6 37.5 38.1 38.9
C.) Exemplary Embodiments
(77) Purity
(78) The compounds according to the invention of S(+)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazoline-4-yl}acetic acid besylate and S(+)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazoline-4-yl}acetic acid tosylate were analyzed for chemical purity by means of HPLC (Method 4) described below.
(79) In the context of the present invention the term chemical purity describes the amount-of-substance fraction of the above-mentioned salts relative to the total mixture of substances. The undesirable substances are called impurities.
Example aa)
(80) Synthesis of S(+)-{-8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazoline-4-yl}acetic acid besylate: 235 g (0.41 mol) of said besylate were dissolved in 1645 ml of acetone and 16.45 ml of water. The resulting yellowish solution was filtered and treated portion by portion with 64.92 g (0.41 mol) solid benzenesulfonic acid at about 40? C. The resulting clear solution was cooled down to room temperature under stirring. The suspension thus obtained was further cooled to 0? C.-5? C. under stirring for two hours. The solid portion thereof was isolated, washed twice with acetone (100 ml at 0? C. each) and dried at 60? C. in order to obtain 243.87 g (0.334 mol, 81.4%) crystalline S(+)-{-8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazoline-4-yl}acetic acid besylate for the purpose of determining the degree of purity.
Example bb)
(81) Synthesis of S(+)-{-8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazoline-4-yl}acetic acid tosylate: 235 g (0.41 mol) of said tosylate were dissolved in 1645 ml of acetone and 16.45 ml of water.
(82) The resulting yellowish solution was filtered and treated portion by portion with 78.07 g (0.41 mol) solid p-toluenesulfonic acid monohydrate at about 36? C. The resulting solution was cooled down to room temperature under stirring. The suspension thus obtained was further cooled to 0? C.-5? C. under stirring for two hours. The solid portion thereof was separated, washed twice with acetone (100 ml at 0? C. each) and dried at 60? C. in order to obtain 248.11 g (0.325 mol, 79.3%) crystalline S(+)-{-8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazoline-4-yl}acetic acid tosylate for the purpose of determining the degree of purity.
(83) Purity Determination
(84) Method 4 (HPLC): Instrument: HP 1050 with UV detection; Column: Phenomenex-Prodigy ODS (3) 100 A, 150 mm?3 mm, 3 ?m; Eluent A: (1.36 g KH.sub.2PO.sub.4+0.7 ml H.sub.3PO.sub.4; 85%)/1 water; Eluent B: Acetonitrile; Gradient: 0 min 20% B, 40 min 45% B, 50 min 80% B; 50 min 80% B, 65 min 80% B, 75 min 20% B; Flow: 0.5 ml/min; Temp.: 55? C.; Injection volume 3 ?l, UV detection: 210 nm/BW: 4 nm; Temperature auto-sampler 5? C.
(85) 22 mg each of the respective test substances of the salts obtained according to Example aa), Example bb) were dissolved in 50 ml of acetonitrile (c=approx. 0.44 mg/ml). As equivalent reference solutions 22 mg each of S(+)-{-8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazoline-4-yl}acetic acid were dissolved in 50 ml acetonitrile (c=approx. 0.44 mg/ml).
(86) As reference solutions of the known impurities 5 mg each of di-p-toluoyl-D-tartaric acid and/or S-quinazoline piperazine, quinazoline ethyl ester and quinazoline dipiperazine were mixed separately with acetonitrile to 50 ml. 1 ml each of the reference solutions for known impurities was then dissolved separately in 10 ml of acetonitrile (c=approx. 0.44 mg/ml).
(87) Furthermore, 10 ml each of the reference solutions of S(+)-{-8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazoline-4-yl}acetic acid were mixed with 1 ml each of the reference solution for the above-mentioned impurities.
(88) The evaluation of the HPLC analysis was conducted based on the so-called relative area percent method which takes the respective response factors (RF) (RF=1.02 for quinazoline piperazine and 0.81 for quinazoline dipiperazine) into account.
(89) The results for S(+)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazoline-4-yl}acetic acid besylate are shown in
D.) Pharmaceutical Composition
(90) Tablet:
(91) Composition:
(92) 128 mg of the salt from Example 1 (corresponding to 100 mg of the active ingredient), 50 mg lactose (monohydrate), 50 mg corn starch (native), 10 mg polyvinylpyrrolidone (PVP 25) (BASF, Ludwigshafen, Germany) and 2 mg magnesium stearate.
(93) Tablet weight 212 mg. Diameter 8 mm, radius of curvature 12 mm.
(94) Production:
(95) The mixture consisting of active ingredient, lactose and starch is granulated with a 5% solution (m/m) of PVP in water. After drying, the granulate is mixed with the magnesium stearate for 5 min. and the resulting mixture is pressed with a conventional tablet press (see tablet format above). A pressing force of 15 kN is used as reference value for the pressing process.