Ethyl Tetrahydropyran-4-Carboxylate

1. 1. Ethyl tetrahydro-2H-pyran-4-carboxylate (5.0 g, 34.7 mmol) was added to a stirred solution of LiAlH4 (4.0 g, 104 mmol) in THF (100 mE) at 0 C. and the reaction mixture was stirred for 1 h. Ethyl acetate (20 mE) was added dropwise to the reaction mixture followed by addition of 10% aq.NaOH and the resulting mixture was stirred for additional 30 mm. Reaction mass was filtered through Celite and the filtrate was concentrated under reduced pressure to give (tetrahydro-2H-pyran-4-yl)methanol (9) as a colorless oil. Yield (3.9 g, 96%); 'H NMR (400 MHz, DMSO-d5) delta 4.46 (bs, 1H), 3.82 (dd, J=i0.8, 8.0 Hz, 2H), 3.25-3.22 (m, 4H), 1.62-1.52 (m, 3H), 1.18-1.04 (m, 1H).Method USynthesis of (S)-l-(Tetrahvdro-pyran-4-ylmethyl)-azepane-2-carboxylic acid (5-tert- butyl-isoxazol-3-yl)-amide (Example 172)Step 1: Synthesis of (Tetrahydro-pyran-4-yl)-methanolLiAlH4 (IM in THF) (100.0 mL, mmol) is added at 00C to a solution of tetrahydro-pyran-4- carboxylic acid ethyl ester (25.0 g, 173.6 mmol) is THF (500.0 mL). The reaction mixture is warmed up to room temperature and stirred under reflux for five hours. The reaction mixture is cooled to room temperature and then 5.0 mL of water, 5.0 mL of 5N NaOH and 20.0 mL of water are added and the precipitated salts are filtered through a celite pad and washed with 1:1 Et2O: MeOH. The filtrate is concentrated under reduced pressure to afford the title productExample 235 - Preparation of Intermediate 57 The synthesis of Intermediate 57 followed the procedure of General Procedure 7 following: Intermediate 57 To a cooled solution (0C) of tetrahydro-2H-pyran-4-carboxylic acid (10 g, 76 mmol) in Ethanol (100 mL) was added thionyl chloride (17.1 mL, 230 mmol). After stirring at this temperature for 3 hours, the mixture was concentrated under reduced pressure. The mixture was diluted with saturated NaHCO3 (20 mL) and extracted into Diethyl ether (3 x 100 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give ethyl tetrahydro-2H-pyran-4- carboxylate (Intermediate 57, 11 g, yield: 91%) as an oily residue that was used without further purification into the next step. m/z 145.03 [M+H]+; TLC System: 30% Ethyl acetate in hexane; Rf-0.7.Step 1: ethyl 4-(but-3-en-1-yl)tetrahydro-2H-pyran-4-carboxylate To a solution of diisopropylamine (3.19 mL, 22.8 mmol) in dry tetrahydrofuran (20 mL) under nitrogen atmosphere at -78 C was added n-butyllithium in hexanes (2.5 M, 7.28 mL, 18.2 mmol). This mixture was stirred for 45 minutes at -78 C, then

Molecular Weight:158.19
XLogP3:0.8
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:3
Exact Mass:158.094294304
Monoisotopic Mass:158.094294304
Topological Polar Surface Area:35.5
Heavy Atom Count:11
Complexity:127
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes