Thionyl Chloride → Tert-butyl 4-({1-[(benzyloxy)carbonyl]azetidin-3-yl}carbonyl)-1,4-diazepane-1-carboxylate

To a stirred solution of benzyl 3-[(4-cyclobutyl-1,4-diazepan-1-yl)carbonyl]azetidine-1-carboxylate (1.0 g, 4.25 mmol) in DCM (20 mL) was added SOCl2 (0.754 g, 0.460 mL, 6.38 mmol) and the resulting mixture was stirred for 2 hours at room temperature. LCMS analysis showed incomplete conversion so a further 1.0 eq of SOCl2 (501 mg, 305 μL) was added and the reaction stirred for a further 19 hours. Volatiles were removed at reduced pressure and the crude acid chloride dissolved in DCM (10 mL) and added dropwise to a solution of tert-butyl 1,4-diazepane-1-carboxylate (0.658 g, 5.10 mmol, 1.2 eq) and DIPEA (1.67 g, 12.75 mmol, 3.0 eq) in DCM (10 mL) at 0° C. The resulting solution was stirred at room temperature for 17 hours and then quenched by addition of NaHCO3 (5 mL). The reaction was diluted with DCM (10 mL) and the phases separated. The organic was washed with brine (5 mL), dried (MgSO4), filtered and concentrated at reduced pressure. Purification by silica FCC (eluting with 98:1.2:0.8 to 97:2.7:0.3 gradient of DCM/MeOH/NH3) gave the title compound (1.54 g, 86%).

1. additionwas added
2. stirringthe reaction stirred for a further 19 hours
3. customVolatiles were removed at reduced pressure
4. dissolutionthe crude acid chloride dissolved in DCM (10 mL)
5. stirringThe resulting solution was stirred at room temperature for 17 hours
6. customquenched by addition of NaHCO3 (5 mL)
7. additionThe reaction was diluted with DCM (10 mL)
8. customthe phases separated
9. washThe organic was washed with brine (5 mL)
10. dry with materialdried (MgSO4)
11. filtrationfiltered
12. concentrationconcentrated at reduced pressure
13. customPurification
14. washby silica FCC (eluting with 98:1.2:0.8 to 97:2.7:0.3 gradient of DCM/MeOH/NH3)

ORD-Eintrag

ord-34fae5604aff42868d7102440a109325

Quelldatensatz

uspto-grants-2014_12

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US08912176B2