Triethylamine → 9H-fluoren-9-ylmethyl N-[(E)-3-[(6aS)-3-[3-[[(6aS)-2-methoxy-8-[4-(4-methylpiperazin-1-yl)phenyl]-6,11-dioxo-5-(2-trimethylsilylethoxymethyl)-6a,7-dihydropyrrolo[2,1-c][1,4]benzodiazepin-3-yl]oxy]propoxy]-2-methoxy-6,11-dioxo-5-(2-trimethylsilylethoxymethyl)-6a,7-dihydropyrrolo[2,1-c][1,4]benzodiazepin-8-yl]prop-2-enyl]carbamate

Mono triflate 13 (0.100 g, 0.0802 mmol, 1.0 eq.), (4-methylpiperazin-1-yl)phenylboronic acid, pinacol ester (0.023 g, 0.0762, 0.95 eq.) and triethylamine (0.051 mL, 0.369 mmol, 4.6 eq.) were solubilised in a mixture of Toluene/Ethanol/H2O [6:3:1] (4 mL) under a nitrogen atmosphere. The reaction was flushed with nitrogen for 5 minutes and palladium-tetrakistriphenylphosphine (0.9 mg, 0.000802 mmol, 0.01 eq.) was added. The reaction was then subjected to microwave irradiation at 80° C. for 5 minutes. The above reaction was repeated 3 times on 0.100 g scale. The combined reaction mixtures were concentrated under reduced pressure, and the solid residue was partitioned between H2O (180 mL) and ethyl acetate (180 mL). The aqueous layer was extracted with ethyl acetate (2×180 mL) before the combined organics were washed with brine (180 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The resulting crude mixture was purified by flash chromatography (silica gel, 40:1 v/v DCM/MeOH to 20:1 v/v DCM/MeOH) to afford the desired product as a yellow solid (0.220 g, 54%). LC/MS (2.833 min (ES+)), m/z: 1272.53 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.77 (d, 2H, J=7.5 Hz), 7.60 (d, 2H, J=7.3 Hz), 7.43-7.39 (m, 3H), 7.35-7.30 (m, 6H), 6.95 (m, 1H), 6.90-6.87 (m, 1H), 6.34 (d, 1H, J=15.7 Hz), 5.67-5.57 (m, 1H), 5.50 (dd, 2H, J=10.1, 3.3 Hz), 4.86 (m, 1H), 4.75 (dd, 2H, J=10.1, 5.6 Hz), 4.54 (m, 2H), 4.44 (d, 2H, J=6.8 Hz), 4.31-4.21 (m, 6H), 3.96-3.87 (m, 9H), 3.81-3.73 (m, 3H), 3.71-3.62 (m, 3H), 3.31-3.20 (m, 5H), 3.10 (m, 1H), 2.87 (m, 1H), 2.58 (m, 4H), 2.43 (m, 2H), 2.36 (s, 3H), 0.97 (m, 4H), 0.01 (s, 18H).

1. customThe reaction was flushed with nitrogen for 5 minutes
2. customirradiation at 80° C. for 5 minutes
3. customThe above reaction
4. customThe combined reaction mixtures
5. concentrationwere concentrated under reduced pressure
6. customthe solid residue was partitioned between H2O (180 mL) and ethyl acetate (180 mL)
7. extractionThe aqueous layer was extracted with ethyl acetate (2×180 mL) before the combined
8. washorganics were washed with brine (180 mL)
9. dry with materialdried over MgSO4
10. filtrationfiltered
11. concentrationconcentrated under reduced pressure
12. customThe resulting crude mixture was purified by flash chromatography (silica gel, 40:1 v/v DCM/MeOH to 20:1 v/v DCM/MeOH)

ORDレコード

ord-7018258254554ae59b4f493bdc6b6ddb

出典データセット

uspto-grants-2016_07

DOI

10.6084/m9.figshare.5104873.v1

特許番号

US09399073B2