2-(TETRAHYDRO-PYRAN-4-YL)-ETHANOL

2-(4-Oxanyl)ethanol c) To a solution of 425 mg (2.5 mmol) of ethyl 2-(tetrahydro-2H-pyran-4- yl)acetate in 10 mL of dry THF cooled at 0To a mixture of ethyl 2-(tetrahydro-2H-pyran-4-yl)acetate(20 g, 116 mmol) in anhydrous THF (300 mE) was addedlithium aluminum hydride (8.8 g, 232 mmol) portionwise at0° C. The mixture was stirred at 11-13° C. for 18 h. TEC(petroleum ether: ethyl acetate=3: 1) showed no startingmaterial remaining. The mixture was quenched with water(9 mE), 10percent aq. NaOH solution (9 mE) and water (18 mE)successively at 0° C., filtered and concentrated underreduced pressure to give crude 2-(tetrahydro-2H-pyran-4-yl)ethanol (11.7 g, 77percent) as an oil, which was used for thenext step directly without further purification. ‘H NMR(CDC13, 400 MHz): ö 3.86-3.90 (m, 2H), 3.58-3.61 (t, J=6.4Hz, 2H), 3.32-3.35 (t, J=11.6 Hz, 2H), 2.69-2.70 (m, 1H), 1.61-1.63 (m, 3H), 1.54-1.60 (m, 2H), 1.43-1.45 (m, 2H).Lithium aluminum hydride (2M solution in THF, 40.66 ml, 81.3 mmol) was cooled at 0 °C and a solution of ethyl 2-(tetrahydro-2H-pyran-4-yl)acetate (14.0 g, 81.3 mmol) in THF (70 ml) was added dropwise. Ethyl acetate (20 ml) was added to the reaction mixture dropwise at 0 °C and the resulting mixture was allowed to stir for 16 h. The reaction mixture was filtered through Celite and the filtrate was concentrated to give crude compound. The crude material was purified by column chromatography using mobile phase 0-65percent ethyl acetate in hexane to afford the title compound (66.1percent). ‘H NMR (400MHz, CDC13) & 5.71 (s, 1H), 4.18-4.15 (m, 2H), 3.81-3.75 (m, 4H), 3.05-3.02 (m, 2H), 2.37-2.34 (m, 2H), 1.32- 1.31 (m, 3H).To a suspension of 0.55 g of LiAlHS nthesis of Compound D6Step 1: Synthesis of Compound D2To a suspension of 0.55 g of LiAlHTo a solution of 1.61 g of this compound in ethanol (20 ml), 240 mg of 10% palladium-on-carbon catalyst was added and stirred for an hour in hydrogen atmosphere (1atm.). Filtering the catalyst off from the reaction solution, the filtrate was concentrated under reduced pressure. To a solution of so obtained residue in tetrahydrofuran (30 ml), 550 mg of lithium aluminum hydride was added at 0ØC in nitrogen atmosphere, followed by 30 minutes' stirring at the same temperature. Then 5 g of sodium sulfate decahydrate was added to the solution and stirred for 12 hours at room temperature. The insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure to provide 1.20 g of the title compound.To a solution of Intermediate I, 4, 6-dichloro-2-(methylsulfonyl)pyrimidine (113 mg, 0.5 mmol) in THF (5 ml), was added NaH (14 mg, 0.64mmol) and the solution cooled to -78C. 2- (tetrahydro-2H-pyran-4-yl)ethan-1-ol (65mg) was added dropwise as a solution in THF (lml), and the solution stirred for lh at -78C, then quenched with water, extracted with EtOAc, dried (Mg504), filtered, evaporated and purified by silica gel chromatography (hexane / EtOAc) to give 65 mg of 4-(2-(3, 5-dichlorophenoxy)ethyl)tetrahydro-2H-pyran. This was dissolved in DMF (3 ml), NaH (9 mg) was added, followed by 5-(3-methoxyphenyl)-1H-pyrazole (41 mg) and the reaction mixture stirred for lh at RT. Morpholine (21u1) was added, and the reaction stirred overnight at rt, then quenched with water, extracted with EtOAc, dried (Mg504), filtered, evaporated and purified by LC/MS to give 9 mg of 4-(6-(3-(3-methoxyphenyl)-1H-pyrazol-1-yl)- 2-(2-(tetrahydro-2H-pyran-4-yl)ethoxy)pyrimidin-4-yl)morpholine, Compound 3. LC/MS (mobile phase 5-100% ACN in 5 mi, Rt = 4.14 mi (M+H) 466

Molecular Weight:130.18
XLogP3:0.5
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:2
Exact Mass:130.099379685
Monoisotopic Mass:130.099379685
Topological Polar Surface Area:29.5
Heavy Atom Count:9
Complexity:67.3
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes