Methyl bromoacetate → (6R,7aS)-[6-(4-bromobenzyloxy)-2-(3,5-dichlorophenyl)-1,3-dioxo-tetrahydro-pyrrolo[1,2-c]imidazol-7a-yl]-acetic Acid Methyl Ester

Temperature

-65 °C

The compound of formula (Io), wherein Z is methoxycarbonylmethyl and the bonds depicted as wavy bonds define the 7aS,6R stereoisomer, was prepared as follows. 1.65 mL of a solution of LDA (1 M) in THF (1.5 eq.) was added to a solution of (7aR,6R)-2-(3,5-dichloro-phenyl)-6-(4-bromobenzyloxy)-tetrahydro-pyrrolo[1,2-c]imidazole-1,3-dione (500 mg) (1.1 mmol) (Ex. 6) in 5 mL of dry THF cooled to −65° C. under nitrogen. The reaction mixture was stirred for 1 h then treated with a solution of methyl bromoacetate (340 mg) (2 eq.) in 3 mL of THF. After 1 h at −65° C., the reaction mixture was allowed to warm to −20° C., stirred for 2 h, and then poured in a mixture of water/EtOAc (1:1, 20 mL). The organic layer was washed with water, dried over MgSO4, and evaporated under reduced pressure. The resulting oily residue was purified over SiO2 column (25 g) (eluent: EtOAc/cyclohexane 3/7) to afford the above-titled compound (28.8 mg) as a foam. NMR (CDCl3, 200 MHz): 7.43 (2H, d), 7.35 (1H, m), 7.15-7.0 (4H, m), 4.4-4.2 (3H, dd+m), 4.15 (1H, m), 3.7 (3H, s), 3.2-3.0 (2H, dd+d), 2.75 (1H, d), 2.52 (1H, dd), 2.05 (1H, dd).

1. customwas prepared
2. waitAfter 1 h at −65° C.
3. temperatureto warm to −20° C.
4. stirringstirred for 2 h
5. washThe organic layer was washed with water
6. dry with materialdried over MgSO4
7. customevaporated under reduced pressure
8. customThe resulting oily residue was purified over SiO2 column (25 g) (eluent: EtOAc/cyclohexane 3/7)

ORD record

ord-a5f3a5cea68b47a88d3720449dc20e63

Source dataset

uspto-grants-2004_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06710064B2