METHYL-(TETRAHYDRO-PYRAN-4-YL)-AMINE HCL

To a stirred solution of tetrahydro-4H-pyran-4-one (1 g, 10 mmol) in THF (10 mL) was added methylamine (0.62 g, 20 mmol, 2 M solution in THF) dropwise at ambient temperature followed by acetic acid (0.5 mL). A mixture of 5-formyl-1-methyl-1H-pyrrole-3-carboxylic acid (150 mg, 0.98 mmol), HATU (1.391 g, 3.66 mmol) and DIPEA (1.72 mL, 9.85 mmol) were added to a stirred suspension of 5-bromo-2-methoxybenzoic acid (0.752 g, 3.25 mmol) in THF (10 mL) and stirred for 20 min. N-Methyltetrahydro-2H-pyran-4-amine (0.382 g, 3.32 mmol) was added and the reaction mixture left to stir for 18 h. The solvent was removed in vacuo. The reaction mixture was partitioned between DCM (50 mL) and water (50 mL), the aqueous phase was extracted further with DCM (2 x 20 mL) and the organic phase was filtered through a hydrophobic frit and the solvent removed in vacuo. The residue was dissolved in the minimum amount of DCM and purified by silica gel chromatography (120 g) eluting with 0 - 100% ethyl acetate: ethanol (3:1, v/v) in cyclohexane to give the title compound. LCMS (method F): rt = 0.89, [M+H]+ = 328.HATU (1.391 g, 3.66 mmol) and DIPEA (1.72 mL, 9.85 mmol) were added to a stirred suspension of 5-bromo-2-methoxybenzoic acid (0.752 g, 3.25 mmol) in THF (10 mL) and stirred for 20 min. N-Methyltetrahydro-2H-pyran-4-amine (0.382 g, 3.32 mmol) was added and the reaction mixture left to stir for 18 h. The solvent was removed in vacuo. The reaction mixture was partitioned between DCM (50 mL) and water (50 mL), the aqueous phase was extracted further with DCM (2 x 20 mL) and the organic phase was filtered through a hydrophobic frit and the solvent removed in vacuo. The residue was dissolved in the minimum amount of DCM and purified by silica gel chromatography (120 g) eluting with 0 - 100% ethyl acetate: ethanol (3:1, v/v) in cyclohexane to give the title compound. LCMS (method F): rt = 0.89, [M+H]+ = 328.To a solution/suspension of 5-(5-(2-hydroxypropan-2-yl)-2-methyl-7-((3-(1-methyl-1H-imidazol- 2-yl)benzyl)amino)pyrazolo[1, 5-a]pyrimidin-3-yl)-2-methoxybenzoic acid (Intermediate 120, 2.35 g, 4.46 mmol) and DIPEA (1.6 mL, 9.16 mmol) in THF (50 mL) was added HATU (2.35 g, 6.18 mmol). The mixture was stirred at room temperature for 10 min and N-methyltetrahydro- 2H-pyran-4-amine (0.514 g, 4.46 mmol) was added. The mixture was stirred under nitrogen at room temp. for 16 h. The reaction mixture was partitioned between ethyl acetate (100 mL) and sat. aq. sodium bicarbonate solution (100 mL). The aqueous was extracted a second time with ethyl acetate (100 mL). The combined organic phases were washed with brine (100 mL) and passed through a hydrophobic frit. The solvent was removed under reduced pressure. The residue was purified by silica chromatography (340 g). The compound was dissolved in a minimum of DCM (+ few drops of methanol), loaded onto the top of the column by injection, then eluted using 0 - 25% ethanol in ethyl acetate over 6 CV and then held at 25 % ethanol in ethyl acetate for 6 CV. The fractions containing the desired product were combined and concentrated under reduced pressure. Approximately half the material was dissolved in DMSO: methanol (1:1 v/v) and applied to a C18cartridge (120 g), pre-conditioned to 5% acetonitrile (containing ammonia) in water (10 mM ammonium bicarbonate containing ammonia), then eluted with a gradient of 5 - 20% acetonitrile (containing ammonia) in water (10 mM ammonium bicarbonate containing ammonia) over 6 CV and then 20 - 60% acetonitrile (containing ammonia) in water (10 mM ammonium bicarbonate containing ammonia) over 6 CV. The gradient was held at 47.5% acetonitrile (containing ammonia) in water (10 mM ammonium bicarbonate containing ammonia) whilst the product eluted. The remainder of the material was purified in a similar manner, using a gradient of 25 - 55% acetonitrile (containing ammonia) in water (10 mM ammonium bicarbonate containing ammonia), bicarbonate/NH3). The gradient was held at 45% acetonitrile (containing ammonia) in water (10 mM ammonium bicarbonate containing ammonia) whilst the product eluted. The fractions containing pure products from both purifications were combined, concentrated under reduced pressure, then dried under vacuum for 24 h to give the title compound. LCMS (method J): rt = 0.65, [M+H]+= 624. deltaH (600 MHz, d6-DMSO) (mixture of rotamers) 8.54-8.49 (m, 1H), 7.77-7.72 (m, 2H), 7.63 (d, J = 1.8 Hz, 0.5H), 7.59-7.54 (m, 1H), 7.53 (d, J = 2.2 Hz, 0.5H), 7.47-7.43 (m, 2H), 7.22 (s, 1H), 7.18-7.13 (m, 1H), 6.94 (s, 1H), 6.43 (s, 1H), 5.17 (s, 1H), 4.69 (d, J = 6.2 Hz, 2H), 4.64-4.58 (m, 0.5H), 3.98-3.91 (m, 1H), 3.90-3.85 (m, 0.5H), 3.82-3.75 (m, 3.5H), 3.70 (s, 3H), 3.57-3.50 (m, 0.5H), 3.43 (t, J = 11.2 Hz, 1H), 3.12 (t, J = 11.2 Hz, 0.5H), 3.00 (t, J = 11.6 Hz, 0.5H), 2.88 (s, 1.5H), 2.69 (s, 1.5H), 2.56 (ap. d, J = 15.8 Hz, 3H), 1.89-1.72 (m, 2H), 1.59-1.51 (m, 1.5H), 1.42 (d, J = 11.4 Hz, 0.5H), 1.39-1.33 (m, 6H) ppm. deltaC(151 MHz, d6-DMSO) (mixture of rotamers) 168.80, 168.77, 168.1, 167.9, 152.50, 152.47, 150.0, 149.9, 146.4, 146.34, 146.26, 145.18, 145.16, 138.6, 130.8, 129.2, 128.9, 128.6, 127.5, 126.89, 126.87, 126.80, 126.7, 126.6, 126.5, 125.9, 123.4, 111.6, 111.4, 104.7, 104.5, 81.4, 81.3, 72.4, 72.3, 66.5, 66.3, 66.2, 55.7, 55.4, 54.9, 54.8, 49.4, 44.4, 34.3, 30.5, 30.3, 30.09, 30.07, 30.0, 29.2, 26.6, 14.5, 14.4 ppm. HRMS (ESI) calcd. for C35H41N7O4+H+ 624.3220, found 624.3294 [M+H]+.General procedure: To a suspension of 9 (26.6 g, 76.3 mmol) in N, N-dimethylformamide (380 mL) was added 1-amino-2-methyl-propan-2-ol (8.16 g, 91.5 mmol) and triethylamine (31.9 mL, 228 mmol) at 0 C. The reaction mixture was stirred at room temperature for 5.5 h. Then the reaction mixture was diluted with cold water (1000 mL) and the mixture was stirred at room temperature for 1 h. The resulting precipitate was collected and washed with water. The precipitate was triturated with a mixture of diethyl ether and diisopropyl ether (1:1, 60 mL) to give the title compound (27.7 g, 83%) as a tan colored powder.

Molecular Weight:115.17
XLogP3:0.2
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:1
Exact Mass:115.099714038
Monoisotopic Mass:115.099714038
Topological Polar Surface Area:21.3
Heavy Atom Count:8
Complexity:59.5
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes