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

Temperature

45 °C

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.

1. customThe reaction mixture was then quenched with CH2Cl2 (4 mL) and water (4 mL)
2. washthe organic portion further washed with a 1 N aqueous hydrochloric acid solution (2×3 mL)
3. dry with materialThe organic layer was then dried over MgSO4
4. filtrationfiltered
5. customevaporated 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%)
6. customThe reaction was then evaporated
7. customthe resulting oil triturated with water (3×2 mL)
8. dissolutionthen dissolved in EtOAc (2 mL)
9. dry with materialdried over MgSO4
10. filtrationfiltered
11. customevaporated
12. dissolutionThe crude oil product was then dissolved in diethyl ether (2 mL)
13. additiontreated with a 4 N solution of hydrogen chloride in 1,4,-dioxane
14. customto precipitate product as a colorless solid
15. filtrationThe solid was filtered with the aid of diethyl ether and air
16. customdried

ORD record

ord-91baccb5d6d04c71a0b0f60ff8723b5f

Source dataset

uspto-grants-2015_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09029397B2