AV-412

A solution of the amino compound 2a (6.08 g, 13.4 mmol) obtained by the method of Synthetic Example 2, acrylic acid (1.38 mL, 20.1 mmol), triethylamine (2.8 mL, 20.1 mmol) and EDC (3.86 g, 20.1 mmol) in DMF (100 mL) was stirred overnight at room temperature. Acrylic acid (0.46 mL, 6.71 mmol), triethylamine (0.93 mL, 6.71 mmol) and EDC (1.29. g, 6.71 mmol) were added to the reaction mixture and the mixture was further stirred overnight. The reaction mixture was poured into aqueous sodium hydrogen carbonate (300 mL) and the mixture was filtered. The residue was washed with water and water-ethanol and dried. The crudely purified substance was stirred with heating in water-ethanol and cooled to room temperature. The precipitate was collected by filtration and dried to give the objective compound 1a (3.41 g, 50percent). [CHEMMOL-00368] [0158] 1a: 1H NMR (DMSO-d6) δ ppm: 1.44 (s, 6H), 2.15 (s, 3H), 2.35 (br s, 4H), 2.64 (br s, 4H), 5.85 (d, J=10.3 Hz, 1H), 6.33 (d, J=16.9 Hz, 1H), 6.58 (dd, J=10.3, 16.9 Hz, 1H), 7.47 (t, J=9.1 Hz, 1H), 7.84 (br s, 2H), 8.20 (br d, J=6.1 Hz, 1H), 8.64 (s, 1H), 8.69 (s, 1H), 9.88 (s, 1H), 10.01 (s, 1H).Compound C (453 g, 1 mol) is dissolved in THF (2 L) and the solution is cooled to 0 Compound C1 (453 g, 1 mol) is dissolved in THF (2 L) and the solution is cooled to 0 0C. Acrylic acid (93.7 g, 1.3 mol, 1.3 equiv) and acryloyl chloride (108.6 g, 1.2 mol, 1.2 equiv) and triethylamine (253 g, 2.5 mol, 2.5 equiv) are added, and the resulting solution is stirred at 00C for 6 h and then allowed to warm to ambient temperature. Isolation and purification is carried out by solvent removal, trituration with isopropanol/water, and reslurrying acetonitrile. Compound D1 (324 - 350 g, 64 - 69% yield)( 4-[N-Boc-3-chloro-4- fluorophenyl)]-7-[3-methyl-3-(4-methyl- 1 -piperazinyl)- 1 - butynyl]-6-[N-mefhyl acrylatnide] quinazoline is thus isolated in >99% purity. The acid-labile protecting group BOC is removed in near quantitative yield using an organic acid such as toluenesulfonic aicd (TsOH) or methanesulfonic acid in methanol to provide compound D (see example 6).Compound C (453 g, 1 mol) is dissolved in THF (2 L) and the solution is cooled to 0 0C. Acrylic acid (93.7 g, 1.3 mol, 1.3 equiv) and acryloyl chloride (108.6 g, 1.2 mol, 1.2 equiv) and triethylamine (253 g, 2.5 mol, 2.5 equiv) are added, and the resulting solution is stirred at 00C for 6 h and then allowed to warm to ambient temperature. Isolation and purification is carried out by solvent removal, trituration with isopropanol/water, and reslurrying acetonitrile. Compound D (324 - 350 g, 64 - 69% yield)( 4-[N-3-chloro-4-fluorophenyl)]-7- [3-methyl-3-(4-methyl-l-piperazinyl)-l- butynyl]~6-[N-methyl acrylamide] quinazoline is thus isolated in >99% purity.The compound 1a (100 mg) was dissolved in acetone (3 mL) and 0.5N benzenesulfonic acid-acetone solution (0.8 mL) was added dropwise with stirring at room temperature. After stirring overnight at room temperature, the resulting product was collected by filtration and dried under reduced pressure to give the title compound as a white solid (60 mg). [0218] 1a.2PhSO3H: 1H NMR (DMSO-d6) delta ppm: 1.49 (s, 6H), 2.60 (m, 2H), 2.81 (s, 3H), 3.10 (m, 2H), 3.30 (d, 2H) 3.50 (d, 2H), 5.90 (d, 1H), 6.39 (d, 1H), 6.60 (dd, 1H) 7.32 (m, 6H), 7.60 (m, 5H), 7.75 (m, 1H), 7.92 (s, 1H), 8.07 (m, 1H), 8.88 (s, 1H), 8.96 (s, 1H), 9.40 (br, 1H), 10.10 (s, 1H).The compound 1a (100 mg) was dissolved in acetone (2 mL) and 0.5N ethanedisulfonate-acetone solution (0.8 mL) was added dropwise with stirring at room temperature. After stirring overnight at room temperature, the resulting product was collected by filtration and dried under reduced pressure to give the title compound as a white solid (122 mg). [0216] 1a.2CH2SO3H)2: 1H NMR (DMSO-d6) delta ppm: 1.60 (d, J=2.6, 6H), 2.70.-3.00 (m, 13H), 3.20 (m. 2H), 3.60 (m, 4H), 5.40 (d, 1H), 6.60 (dd, 1H), 7.60 (t, 1H), 7.70 (m, 1H), 8.00 (s, 1H), 8.10(d, 1H), 8.92 (s, 1H), 9.00 (s, 1H), 9.80 (br, 1H), 10.20 (s, 1H).The compound 1a (100 mg) was dissolved in acetone (4 mL), and 0.5N ethanedisulfonate-acetone solution (0.4 mL) was added dropwise with stirring at room temperature. After stirring overnight at room temperature, the resulting product was collected by filtration and dried under reduced pressure to give the title compound as a white solid (89 mg). [0214] 1a.CH2SO3H)2: 1H NMR (DMSO-d6). delta ppm: 1.46 (s, 6H), 2.60 (m, 2H), 2.70-2.90 (m, 7H), 2.90-3.80 (m, 6H), 5.90 (d, 1H), 6.38 (d, 1H), 6.60 (dd, 1H), 7.50 (t, 1H), 7.86 (m, 1H), 7.97 (s, 1H), 8.12 (m, 1H), 8.76 (s, 2H), 9.40 (br, 1H), 10.03 (s, 1H), 10.50 (br, 1H).Ethyl acetate (80 mL) was added to la (1.08 g, 2.14 mmol) for dissolution and a solution (6.42 mL, 3.21 mmol), wherein ethyl acetate had been added to concentrated sulfuric acid (0.68 ml L, 12.5 mmol) to the total amount of 25 mL, was added thereto. The mixture was stirred at room temperature for 18 hrs. The precipitated crystals were collected by filtration, and the crystals were washed with ethyl acetate and dried under reduced pressure at 70 C. for 3 hrs to give yellow crude crystals (1.34 g, 95.9%). To this crude crystal (889 mg, 1.36 mmol) was added methanol (44.4 mL), and the mixture was heated under reflux to allow dissolution. After stirring at room temperature for 3 hrs, the mixture was allowed to cool to room temperature. The precipitated crystals were collected by filtration and the obtained crystals were washed with methanol and dried under reduced pressure at 70 C. for 2 hrs to give yellow crystals (604 mg, 68.0%). [0243] 1H NMR (270 MHz, DMSO-d6) delta ppm: 1.42 (s, 6H), 2.46-2.64 (m, 2H), 2.80 (s, 3H), 2.95-3.11 (m, 2H), 3.16-3.34 (m, 2H), 3.40-3.54 (m, 2H), 5.89 (dd, 1H), 6.36 (dd, 1H), 6.61 (dd, 1H), 7.52 (t, 1H), 7.73-7.79 (m, 1H), 7.94 (s, 1H), 8.10 (dd, 1H), 8.80 (s, 2H), 10.04 (s, 1H), 10.75 (br s, 1H). [0244] Elemental analysis: (calcd. for 1a.1.5H2SO4.H2O) C, 48.25; H, 4.95; N, 12.50; S, 7.16; (analyzed value) C, 48.47; H, 4.95; N, 12.56; S, 7.11.Ethyl acetate (80 mL) was added to 1a (1.09 g, 2.15 mmol) for dissolution and a solution (4.31 mL, 2.15 mmol), wherein ethyl acetate had been added to concentrated sulfuric acid (0.68 ml L, 12.5 mmol) to the total amount of 25 mL, was added thereto. The mixture was stirred at room temperature for 15 hrs. The precipitated crystals were collected by filtration, and the crystals were washed with ethyl acetate and dried in vacuo at 60 C. for 4 hrs to give pale-yellow crude crystals (1.27 g, 97.8%) [0241] 1H NMR (270 MHz, DMSO-d6) delta ppm: 1.45 (s, 6H), 2.79 (s, 3H), 2.90-3.50 (m, 8H), 5.86 (dd, 1H), 6.34 (dd, 1H), 6.59 (dd, 1H), 7.46 (t, 1H), 7.80-7.86 (m, 1H), 7.92 (s, 1H), 8.18 (dd, 1H), 8.63 (s, 1H), 8.69 (s, 1H), 9.95 (s, 1H), 10.01 (br s, 1H).Toluene (3.0 mL) was added to compound 1a (150 mg) and the suspension was stirred at room temperature for 69 hrs. The suspension was filtered and the filtration residue was washed with toluene and dried under reduced pressure at 60 C. for 6 hrs to give the title compound as pale-yellowish white crystals (131 mg, 87%). The XRD pattern of this crystal showed a type A crystal form.Acetone (126 mL) was added to compound 1a (9.00 g) and the mixture was stirred with heating at an inner temperature of 53 C. After complete dissolution of the solid, the solution was cooled to an inner temperature of 24 C. over 7 hrs with stirring. The precipitate was collected by filtration, and the filtration residue was washed with acetone and dried under reduced pressure at 80 C. for 4 hrs to give the title compound as pale-yellow crystals (7.32 g, 81%). [0220] The XRD pattern of this crystal is shown in FIG. 1, and this crystal is taken as type A crystal form. The characteristic peaks shown in FIG. 1 are as follows. characteristic peak (2theta, +/-0.2) [0221] 7.1, 10.6, 11.9, 12.2, 13.8, 17.3, 18.4IR (KBr) nu cm-1: 3376, 2809, 1676, 1628, 1562, 1535, 1497, 1421, 1213, 1177. melting point: 131-133 C. Elemental analysis: (calcd. for C27H28ClFN6O.1/2H2O) C, 62.85; H, 5.66; N, 16.29; (analyzed value) C, 62.68; H, 5.58; N, 16.14.Ethyl acetate (2.0 mL) was added to compound 1a (200 mg) and the mixture was heated to an inner temperature of about 70 C. After complete dissolution of the solid, heptane (3.0 mL) was gradually added dropwise with stirring, and the solution was cooled to room temperature. The precipitate was collected by filtration, and the filtration residue was washed with ethyl acetate-heptane (1:2) and dried under reduced pressure at 60 C. for 6 hrs to give the title compound as pale-yellowish white crystals (119 mg, 79%). The XRD pattern of this crystal showed a type A crystal form.THF (1.0 mL) was added to compound 1a (150 mg) and the mixture was heated to an inner temperature of about 70 C. After complete dissolution of the solid, heptane (1.3 mL) was gradually added dropwise with stirring, and the solution was cooled to room temperature. The precipitate was collected by filtration, and the filtration residue was washed with THF-heptane (1:2) and dried under reduced pressure at 60 C. for 6 hrs to give the title compound as pale-yellowish white crystals (90.5 mg, 59% The XRD pattern of this crystal showed a type A crystal form. [0224] Elemental analysis: (calcd. for C27H28ClFN60.1/2H2O) C, 62.85; H, 5.66; N, 16.29; (analyzed value) C, 62.68; H, 5.58; N, 16.14.Example 34 1a.hydrochloride (1a.HCl) The compound 1a (150 mg) was added to THF (3 ML) and the resulting solution was ice-cooled. 4N hydrochloric acid-ethyl acetate solution (81 muL) was added dropwise with stirring.After stirring overnight at room temperature, the resulting product was collected by filtration and dried under reduced pressure to give the title compound as a white solid (140 mg). 1a.HCl: 1H NMR (DMSO-d6) delta ppm: 1.45 (s, 6H), 2.78 (s, 3H), 2.61 (m, 2H), 3.02 (m, 2H), 3.10-3.75 (m, 4H), 5.85 (dd, 1H), 6.39 (dd, 1H), 6.70 (dd, 1H), 7.58 (t, 1H), 6.80 (m, 1H), 7.92 (s, 1H), 8.20 (m, 1H), 8.65 (s, 1H), 8.70(s, 1H), 10.10 (br. 3H).Example 33 1a.dihydrochloride (1a.2HCl) The compound 1a (1.27 g) was added to and dissolved in THF (38 ML), and 4N hydrochloric acid-ethyl acetate solution (1.28 ML) was added dropwise with stirring.The mixture was stirred overnight at room temperature and collected by filtration.Drying gave the title compound as a white solid (1.17 g).This crude crystal (0.16 g) was suspended in isopropanol (IPA)-THF (1:1, 10 ML) and stirred in an oil bath at 70 C. The reaction mixture was allowed to stand to cool, and the product was collected by filtration and dried under reduced pressure to give the title compound as a crystalline powder (78 mg). 1a.2HCl: 1H NMR (DMSO-d6) delta ppm: 1.55 (s, 6H), 2.80 (s, 3H), 2.90-3.80 (m, 8H), 5.90 (dd, 1H), 6.39 (dd, 1H), 6.70 (dd, 1H), 7.55 (t, 1H), 7.75 (m, 1H), 8.05 (dd, 1H), 8.08 (s, 1H), 8.91 (s, 2H), 10.30 (s, 1H).Elemental analysis: (Calcd. for C27H30Cl3FN6O.1.2IPA.0.5H2O) C, 55.11; H, 5.39; Cl, 17.88; N, 14.13; (analyzed value) C, 55.26; H, 5.19; Cl, 17.72; N, 14.12.

Molecular Weight:507.0
XLogP3:4.5
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:7
Rotatable Bond Count:7
Exact Mass:506.1997154
Monoisotopic Mass:506.1997154
Topological Polar Surface Area:73.4
Heavy Atom Count:36
Complexity:850
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes