Triethylamine → Ethyl 1-(2-chloroquinazolin-4-yl)-5-methoxy-2-methylindolin-3-ylacetate

Participants

Reaction Steps

A mixture of 2,4-dichloroquinazoline (3.2g.), ethyl 5-methoxy-2-methylindolin-3-ylacetate (4.0g.) and triethylamine (2.23ml; dried over potassium hydroxide pellets) in dry 1,2-dimethoxyethane (50ml.) was heated under reflux for 30 mins. The mixture was evaporated in vacuo, and to the residue was added water (100ml.) and ethyl acetate (50ml.). The aqueous layer was separated and extracted with ethyl acetate (2 × 30ml.), and the extracts were washed with water (30ml.), dried(MgSQ 4) and evaporated. The residual syrup slowly crystallised to give ethyl 1-(2-chloroquinazolin-4-yl)-5-methoxy-2-methylindolin-3-ylacetate, m.p. 111°-112° C. This indoline ester (3.6g.) was added to a solution of sodium (0.5g.) in methanol (50ml.; dried over magnesium methoxide), and the resulting solution was heated under reflux for 18 hrs. After removal of methanol in vacuo, the mixture was added to water (50ml.) and acidified with acetic acid to give 1-(2-methoxyquinazolin-4-yl)-5-methoxy-2-methylindolin-3-ylacetic acid hemihydrate, m.p. 115°-120° C. This acid (3.0g.) was dissolved in dry methanol (40ml.) containing concentrated sulphuric acid (0.1ml.), and the mixture was heated under reflux for 5 hrs. Saturated sodium acetate solution (2ml.) was added, and the mixture was evaporated in vacuo. The residue was partitioned between water (50ml.) and ether (40ml.). After separation, the aqueous layer was extracted with ether (2 × 20ml.). The ether extracts were washed successively with saturated sodium hydrogen carbonate solution (20ml.) and water (20ml.), dried (Na2SO4), and evaporated to give methyl 1-(2-methoxyquinazolin-4-yl)-5-methoxy-2-methhylindolin-3-ylacetate as a dark yellow syrup [pure by TLC (system A); NMR: 5--OCH3 at 6.3τ; 2-- OCH3 at 6.15τ ].

Provenance & Evidence