Tri-o-tolylphosphine → (E)-tert-butyl 6-(3-oxo-3-(pyrrolidin-1-yl) prop-1-en-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

Temperatur

110 °C

DIPEA (1.44 ml, 8.36 mmol) was added to a solution of 125a (650 mg, 2.09 mmol), 125b (287 mg, 2.29 mmol), Pd-(OAc)2 (46 mg, 0.21 mmol) and P(o-tol)3 (127 mg, 0.42 mmol) in propionitrile/DMF (8 ml/2 ml) and the reaction mixture was purged with nitrogen for 10 minutes, then was heated at 110° C. for 16 h. The progress of the reaction was monitored by TLC. After 16 h of stirring, the mixture was cooled to 20-35° C. and filtered on celite. The filtrate was concentrated and resultant residue diluted with water (30 ml) and extracted with ethyl acetate (2×30 ml). The combined organic layers were washed with brine (30 ml), followed by drying over anhydrous Na2SO4 and filtering. The filtrate was rotary evaporated to get residue which was purified by column chromatography using a mixture of 50% ethyl acetate/pet ether as an eluent to get the desired compound as an off-white solid (400 mg, 54%). 1H NMR (400 MHz, DMSO-d6) δ 7.50 (d, J=6.8 Hz, 2H), 7.41 (d, J=15.7 Hz, 1H), 7.20 (d, J=8.3 Hz, 1H), 6.94 (d, J=15.7 Hz, 1H), 4.56-4.46 (m, 2H), 3.63 (t, J=6.6 Hz, is 2H), 3.55 (t, J=5.9 Hz, 2H), 3.41-3.34 (m, 2H), 2.79 (t, J=5.9 Hz, 2H), 1.96-1.88 (m, 2H); 1.87-1.76 (m, 2H), 1.43 (s, 9H).

1. customthe reaction mixture was purged with nitrogen for 10 minutes
2. temperaturethe mixture was cooled to 20-35° C.
3. filtrationfiltered on celite
4. concentrationThe filtrate was concentrated
5. additionresultant residue diluted with water (30 ml)
6. extractionextracted with ethyl acetate (2×30 ml)
7. washThe combined organic layers were washed with brine (30 ml)
8. dry with materialby drying over anhydrous Na2SO4
9. filtrationfiltering
10. customThe filtrate was rotary evaporated
11. customto get residue which
12. customwas purified by column chromatography
13. additiona mixture of 50% ethyl acetate/pet ether as an eluent

ORD-Eintrag

ord-869ff5d9f521402e960701d25c3abf24

Quelldatensatz

uspto-grants-2015_06

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US09062002B2