Sodium Carbonate → tert-butyl 4-(7-(4-amino-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate

Temperatur

100 °C

A round-bottomed flask was charged with 3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)aniline (Example 6, Step A, 200.0 mg, 0.518), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -5,6-dihydropyridine-1(2H)-carboxylate (160.1 mg, 0.518 mmol), tetrakis(triphenylphosphine)palladium (119.7 mg, 0.104 mmol), Na2CO3 (1.30 ml, 2.59 mmol) and DME (50 mL). The reaction mixture was stirred under nitrogen at 100° C. until the starting material had been consumed (4 hours). Then the reaction mixture was cooled to room temperature and partitioned between EtOAc (100 mL) and H2O (100 mL). The phases were separated and the aqueous phase was re-extracted with EtOAc (3×100 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude product. The crude product was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 50/1 to 10/1, v/v) to give product (183.4 mg, 80%). LRMS (APCI pos): m/e 442 (M+1). 1H NMR (400 MHz, CD3OD) δ 8.41 (d, 1H), 7.36 (s, 1H), 7.03 (t, 1H), 6.54 (dd, 1H), 6.47 (m, 2H), 6.30 (m, 1H), 4.13 (m, 2H), 3.83 (br s, 2H), 3.68 (m, 2H), 2.64 (m, 2H), 1.50 (s, 9H).

1. customhad been consumed (4 hours)
2. temperatureThen the reaction mixture was cooled to room temperature
3. custompartitioned between EtOAc (100 mL) and H2O (100 mL)
4. customThe phases were separated
5. extractionthe aqueous phase was re-extracted with EtOAc (3×100 mL)
6. dry with materialThe combined organic layers were dried (Na2SO4)
7. filtrationfiltered
8. concentrationconcentrated
9. customto yield a crude product
10. customThe crude product was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 50/1 to 10/1

ORD-Eintrag

ord-653ba112f32545a7add85c1b8cb4ae26

Quelldatensatz

uspto-grants-2011_08

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US08003662B2