Tetrahydrofuran → Ethyl 2-(3-carbamoyl-2-(3-chloro-4-fluorophenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-5-carboxamido)-2-methylpropanoate

Temperatur

85 °C

To a stirred solution of 3-ethoxy-2,2-dimethyl-3-oxopropanoic acid (543 mg, 3.39 mmol) in toluene (25 mL) at RT under nitrogen was added TEA (1.182 mL, 8.48 mmol), DPPA (0.731 mL, 3.39 mmol) and the reaction mixture was heated to 85° C. and stirred for 1 h. The reaction mass was cooled to RT and in to it was added a solution of Intermediate 185B (500 mg, 1.697 mmol) in THF (4 mL) and stirred at RT for 12 h. The reaction mass was concentrated and the residue was extracted with ethyl acetate (3×10 mL) The combined organic layer was washed with water, brine, dried over Na2SO4, filtered and the filtrate concentrated. The crude product was triturated with diethyl ether to afford Intermediate 213A as an off-white solid (550 mg, 70% yield). MS(ES): m/z=452 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ ppm 7.85 (dd, J=7.2, 2.3 Hz, 1H), 7.68 (s, 1H), 7.51-7.42 (m, 1H), 7.40-7.32 (m, 1H), 7.25-7.14 (m, 1H), 7.06 (s, 1H), 4.73 (s, 2H), 4.17-4.09 (m, 2H), 4.01 (q, J=7.2 Hz, 2H), 3.89-3.79 (m, 2H), 1.37 (s, 6H), 1.09 (t, J=7.0 Hz, 3H).

1. temperatureThe reaction mass was cooled to RT and in to it
2. stirringstirred at RT for 12 h
3. concentrationThe reaction mass was concentrated
4. extractionthe residue was extracted with ethyl acetate (3×10 mL) The combined organic layer
5. washwas washed with water, brine
6. dry with materialdried over Na2SO4
7. filtrationfiltered
8. concentrationthe filtrate concentrated
9. customThe crude product was triturated with diethyl ether

ORD-Eintrag

ord-0e05ec8c8eef467d8e17628906b5875a

Quelldatensatz

uspto-grants-2016_03

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US09273058B2