Dimethyl Sulfoxide → 2-(R)-(3-(R)-Formyl-4-(S)-phenylpyrrolidin-1-yl)-3-(cyclobutyl)propionic acid, benzyl ester

Temperature

0 °C

A solution of 1.29 mL (14.8 mmol) of oxalyl chloride in 15 mL of CH2Cl2 at −78° C. was treated with 2.10 mL (29.7 mmol) of DMSO maintaining the temperature at less than −60° C. The resulting mixture was stirred cold for 5 min. A solution of 2.33 g (5.9 mmol) of 2-(R)-(3-(R)-(hydroxymethyl)4-(S)-phenylpyrrolidin-1-yl)-3-(cyclobutyl)propionic acid, benzyl ester (from Step B) in 10 mL of CH2Cl2 was added maintaining the temperature at less than −60° C. The resulting mixture was stirred cold for 30 min. The mixture was treated with 10.3 mL (59.3 mmol) of DIEA maintaining the temperature at less than −60° C. The reaction was warmed to 0° C., stirred for 20 min and quenched with H2O. The mixture was partitioned between 250 mL of CH2Cl2 and 100 mL of H2O and the layers were separated. The aqueous layer was extracted with 250 mL of CH2Cl2. The combined organic phases were dried over Na2SO4 and concentrated. Flash chromatography on 100 g of silica gel using 4:1 v/v hexanes/ether as the eluant afforded 2.30 g (97%) of the title compound: 1H NMR (300 MHz) δ 1.54-2.08 (m, 8H), 2.31 (m, 1H), 2.75 (t, J=8.6 Hz, 1H), 2.96 (m, 1H), 3.11-3.35 (m, 4H), 3.56 (q, J=7.9 Hz, 1H), 5.16 (s, 2H), 7.19-7.39 (m, 10H), 9.63 (d, J=2.2 Hz, 1H).

1. temperaturemaintaining the temperature at less than −60° C
2. stirringThe resulting mixture was stirred cold for 30 min
3. stirringstirred for 20 min
4. customquenched with H2O
5. customThe mixture was partitioned between 250 mL of CH2Cl2 and 100 mL of H2O
6. customthe layers were separated
7. extractionThe aqueous layer was extracted with 250 mL of CH2Cl2
8. dry with materialThe combined organic phases were dried over Na2SO4
9. concentrationconcentrated

ORD record

ord-ec1ec93ae4ef457caeaa684b4f94f5be

Source dataset

uspto-grants-2002_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06498161B1