Dimethylamine → (3-Dimethylaminomethyl-piperidin-1-yl)-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophen-2-yl]-methanone, hydrochloride

Participants

Reaction Conditions

Reaction Steps

A solution of (3-Hydroxymethyl-piperidin-1-yl)-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophen-2-yl]-methanone (Example 46, 170 mg, 0.454 mmol) and triethylamine (111 μL, 0.795 mmol) in CH2Cl2 (4 mL) at −10 to −5° C., was treated with methanesulfonyl chloride (53 μL, 0.681 mmol) and allowed to stir for 1 hr. The reaction mixture was then quenched with CH2Cl2 (4 mL) and water (4 mL), and the organic portion further washed with a 1 N aqueous hydrochloric acid solution (2×3 mL) followed by a saturated aqueous NaHCO3 solution (2×3 mL) and brine (3 mL). The organic layer was then dried over MgSO4, filtered, and evaporated to the Methanesulfonic acid 1-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carbonyl]-piperidin-3-ylmethyl ester intermediate as an oil (180 mg, 88%). A solution of the intermediate sulfonate (60 mg, 0.1326 mmol) in acetonitrile (2 mL) was treated with a 2 N THF solution of dimethylamine (265 μL, 0.5304 mmol) and heated at 45° C. in a sealed tube for 2 weeks. The reaction was then evaporated and the resulting oil triturated with water (3×2 mL) then dissolved in EtOAc (2 mL), dried over MgSO4, filtered, and evaporated. The crude oil product was then dissolved in diethyl ether (2 mL) and treated with a 4 N solution of hydrogen chloride in 1,4,-dioxane to precipitate product as a colorless solid. The solid was filtered with the aid of diethyl ether and air dried to afford product as a colorless solid (30 mg, 52%). 1H NMR (CDCl3) 1.12-1.29 (m, 1H), 1.44-1.58 (m, 1H), 1.67-1.79 (m, 2H), 1.80-1.90 (m, 1H), 2.05-2.15 (m, 8H), 2.29 (d, J=1.3, 3H), 2.70 (br s, 1H), 3.00 (br s, 1H), 4.10-4.40 (br m, 2H), 7.28 (d, J=3.5, 1H), 7.38 (d, J=3.5, 1H). 13C NMR 7.9, 25.2, 29.7, 34.9, 46.1, 63.3, 114.7, 118.8 (q, J=271), 128.0, 129.1, 131.0, 140.8, 155.1 (q, J=40), 158.0, 162.8. 19F NMR −63.1. LC/MS 4.52 min, [M+1]+ 402.

Provenance & Evidence