Borohydride → Racemic 1,1-dimethylethyl ({4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-[2-(7-fluoro-2-oxo-1(2H)-quinoxalinyl)ethyl]-3-piperidinyl}methyl)carbamate

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Reaction Steps

A mixture of racemic 1,1-dimethylethyl ({1-[2-(7-fluoro-2-oxo-1(2H)-quinoxalinyl)ethyl]-4-oxo-3-piperidinyl}methyl)carbamate (1.35 g, 3.23 mmol) and (2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amine (0.54 g, 3.23 mmol, prepared from 2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethanol (for a synthesis see WO2004002490, Example 6(b)) by reaction with diphenylphosphoryl azide and 1,8 diazabicyclo[5.4.0]undec-7-ene in toluene, 0° C.-room temperature, followed by hydrogenation of the resulting azide over 5% palladium/carbon paste in 200:1 ethanol/acetic acid) in dichloromethane (30 mL) and methanol (3 mL) was stirred with 3A molecular sieves for 1 h. Sodium triacetoxyborohydride (2.05 g, 9.69 mmol) was added and stirring continued at room temperature. More borohydride was added after 6 h (0.20 g), and after an overnight period more amine (0.20 g) and borohydride (0.80 g) were added. After stirring for a further 6 h, aqueous sodium bicarbonate was added and the phases were separated. The aqueous phase was extracted twice with 10% methanol/dichloromethane and the organic fractions were dried and evaporated. Chromatography on silica, eluting with 0-20% methanol/dichloromethane, gave firstly a major product (Isomer1, 1.12 g, 61%), followed by a minor product (Isomer 2, 0.10 g, 5% of good purity, plus 0.17 g less pure).

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