反应详情

To a suspension of 2,2′-dimethyl-biphenyl-4-carboxylic acid of Step B (22.4 g, 99.0 mmol) in dry dichloromethane (500 mL) at room temperature under nitrogen was added dry N,N-dimethylformamide (5 mL) followed by the dropwise addition of 2.0 M solution of oxalyl chloride in dichloromethane (60 mL, 120 mmol). The reaction mixture was stirred at room temperature for 2 hours then concentrated in vacuo and the residue redissolved in dry dichloromethane (200 mL). The solution was concentrated in vacuo to afford the crude acid chloride as a brown oil. The acid chloride was dissolved in dichloromethane (500 mL), 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (21.9 g, 119 mmol) was added followed by N,N-diisopropylethylamine (87 mL, 500 mmol) and the reaction mixture stirred at room temperature under nitrogen for 16 hours. The reaction mixture was then washed with 1 M aqueous hydrochloric acid (5×1 L), 10% aqueous sodium hydroxide (1 L) and brine (500 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give a dark foam. Purification by flash chromatography using a solvent gradient of 2.5 to 40% ethyl acetate in hexane gave a tan solid that was recrystallized from ethyl acetate/hexane to afford the title compound (12.4 g) as a pale orange solid. Purification of the mother liquors by flash chromatography yielded additional title compound (11.5 g) as a white solid, m.p. 145-148° C.

1. concentrationthen concentrated in vacuo
2. dissolutionthe residue redissolved in dry dichloromethane (200 mL)
3. concentrationThe solution was concentrated in vacuo
4. customto afford the crude acid chloride as a brown oil
5. stirringthe reaction mixture stirred at room temperature under nitrogen for 16 hours
6. washThe reaction mixture was then washed with 1 M aqueous hydrochloric acid (5×1 L), 10% aqueous sodium hydroxide (1 L) and brine (500 mL)
7. dry with materialdried over anhydrous magnesium sulfate
8. filtrationfiltered
9. concentrationconcentrated in vacuo
10. customto give a dark foam
11. customPurification by flash chromatography
12. customgave a tan solid
13. customthat was recrystallized from ethyl acetate/hexane