1-Hydroxybenzotriazole → 4-[[(R)-1-(benzo[b]thiophene-3-carbonyl)-2-methyl-azetidine-2-carbonyl]-(3-chloro-benzyl)-amino]-butyric acid methyl ester

Temperature

20 °C

To a suspension of benzo[b]thiophene-3-carboxylic acid (7.12 g, 1.2 eq.) in 210 mL of DCM and 210 mL of THF were added HOBt (5.4 g, 1.2 eq.) EDC.HCl (9.6 g, 1.5 eq.) and TEA (18.5 mL, 4 eq.). The reaction was stirred at 20° C. for 15 h, then a solution of 4-[(3-chloro-benzyl)-((R)-2-methyl-azetidine-2-carbonyl)-amino]-butyric acid methyl ester hydrochloride obtained in step i above (12.5 g, 1 eq.) in 105 mL of DCM and 105 mL of THF was added. The reaction was stirred at 20° C. for 4.5 h. The crude was diluted with DCM. A saturated aqueous solution of NaHCO3 was added. The aqueous layer was extracted three times with DCM. The organic layers were combined, dried over MgSO4, filtered and concentrated under reduced pressure. The crude was purified by chromatography on silica gel (elution with heptane/EtOAc: 90/10 to 50/50) to afford 4-[[(R)-1-(benzo[b]thiophene-3-carbonyl)-2-methyl-azetidine-2-carbonyl]-(3-chloro-benzyl)-amino]-butyric acid methyl ester (14.53 g, yield=87%).

1. stirringThe reaction was stirred at 20° C. for 4.5 h
2. extractionThe aqueous layer was extracted three times with DCM
3. dry with materialdried over MgSO4
4. filtrationfiltered
5. concentrationconcentrated under reduced pressure
6. customThe crude was purified by chromatography on silica gel (elution with heptane/EtOAc: 90/10 to 50/50)

ORD record

ord-c0471365e74041c686816c41d600d815

Source dataset

uspto-grants-2014_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08759334B2