Sodium Bicarbonate → N-cyclohexyl-N-(2-(2-(5-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)ethylamino)ethyl)-3-(3-(1-methyl-1H-pyrazol-4-yl)phenethoxy)propanamide

Participants

Reaction Conditions

Reaction Steps

p-Toluenesulfonic acid monohydrate (5.31 g) was added in one portion to N-cyclohexyl-N-(2,2-dimethoxyethyl)-3-(3-(1-methyl-1H-pyrazol-4-yl)phenethoxy)propanamide (7.74 g, prepared as in Example 2a, Step ii)) in tetrahydrofuran (60 mL). The resulting solution was stirred at 20° C. for 30 min. This solution was added to a stirred mixture of 8-(2-aminoethyl)-5-hydroxy-2H-benzo[b][1,4]oxazin-3(4H)-one hydrochloride (4.27 g), sodium bicarbonate (4.40 g), water (6 mL) and NMP (60 mL). The mixture was stirred for 10 min. and sodium triacetoxyborohydride (9.25 g) and acetic acid (1 mL) were added. The mixture was stirred for 3 h. The reaction mixture was neutralised with saturated sodium hydrogen carbonate (100 mL) and extracted into ethyl actate (5×100 mL). Methanol (50 mL) was added and the organic was washed with a 1:1 mixture of water and saturated brine (2×70 mL). The organic was dried over magnesium sulfate, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 50 to 100% isohexane in ethyl acetate, then elution gradient 2 to 10% methanol in dichloromethane to afford N-cyclohexyl-N-(2-(2-(5-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)ethylamino)ethyl)-3-(3-(1-methyl-1H-pyrazol-4-yl)phenethoxy)propanamide (5.38 g) as a gum.

Provenance & Evidence