Sodium Carbonate → 3-chloro-N-[(R)-1-(7-chloro-4-oxo-3-phenylamino-3,4-dihydro-quinazolin-2-yl)-but-3-ynyl]-N-[3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)propyl]-2-fluoro-benzamide

To a solution of 3-chloro-2-fluoro-benzoic acid (3.2 g, 18.3 mmol) of in acetonitrile (30 ml) was added 2-chloro-1,3-dimethylimidazolium chloride (DMC) (3.3 g, 19.5 mmol), followed by diisopropylethyl amine (6.8 ml, 39 mmol). The resulted solution was stirred at room temperature for 10 min, then transferred into flask containing (R)-2-{3-[1-(7-chloro-4-oxo-3-phenylamino-3,4-dihydro-quinazolin-2-yl)-but-3-ynylamino]-propyl}-isoindole-1,3-dione (6.1 g) in a 2.5M solution of diisopropylethyl amine in acetonitrile (30 ml). The reaction mixture was stirred at room temperature and the reaction progress was monitored by HPLC/MS. Upon completion, a saturated solution of sodium carbonate (100 ml) was added. The organic layers were collected and the aqueous layer was washed with EtOAc (2×50 ml). The combined organic layers were washed with brine (100 ml) and dried over sodium sulfate. The solvent was removed and residue was separated on silica gel column to afford 3-chloro-N-[(R)-1-(7-chloro-4-oxo-3-phenylamino-3,4-dihydro-quinazolin-2-yl)-but-3-ynyl]-N-[3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)propyl]-2-fluoro-benzamide as off-white solid (7.6 g, 96%). M.p. 130-132° C. LCMS: m/e 682 [M+H]. 1H NMR (CDCl3): δ 8.09 (m, 1H), 7.71 (m, 3H), 7.46 (m, 1H), 7.35 (m, 2H), 7.29 (m, 1H), 7.16 (m, 1H), 7.10 (m, 1H), 7.03 (m, 1H), 6.90 (m, 1H), 6.82 (m, 1H), 6.68 (m, 1H), 6.50 (m, 1H), 3.73 (m, 1H), 3.58 (m, 1H), 3.51 (m, 1H), 3.38 (m, 1H), 3.26 (m, 1H), 3.06 (m, 1H), 2.88 (m, 1H), 2.01 (s, 1H), 1.80 (m, 1H), 1.54 (m, 1H).

1. customtransferred into flask
2. stirringThe reaction mixture was stirred at room temperature
3. customThe organic layers were collected
4. washthe aqueous layer was washed with EtOAc (2×50 ml)
5. washThe combined organic layers were washed with brine (100 ml)
6. dry with materialdried over sodium sulfate
7. customThe solvent was removed
8. customresidue was separated on silica gel column

ORD-Eintrag

ord-9f67d1fcb3fb4bec92c0e84130366c1c

Quelldatensatz

uspto-grants-2012_07

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US08232285B2