4-Methylmorpholine → N-{[4-((2R,3R)-1-(4-Fluorophenyl)-3-{[2-(4-fluorophenyl)-2-oxoethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycylglycine

A solution of [4-((2R,3R)-1-(4-fluorophenyl)-3-{[2-(4-fluorophenyl)-2-oxoethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetic acid (0.200 g, 0.414 mmol), glycylglycine methyl ester hydrochloride (0.090 g, 0.493 mmol) and N-methylmorpholine (0.150 ml) in DCM (5 ml) was stirred for 10 min. TBTU (0.170 g) was added and the mixture was stirred for 20 h. The formation of the ester was confirmed. M/z: 612.0. The solvent was removed under reduced pressure. The residue was dissolved in a mixture of MeOH (5 ml), water (1 ml) and Et3N (0.5 ml). The solution was stirred at 50° C. for 18 h. DBN (0.050 ml, 0.405 mmol) was added and the mixture was stirred for 2 h at 50° C. Ammonium acetate buffer (0.1 M, 3 ml) was added and the mixture was concentrated. The residue was purified by preparative HPLC, using a gradient of 20-50% MeCN in 0.1M ammonium acetate buffer as eluent. After freeze-drying, the title product (0.094 g, 38% yield) was obtained as a white solid. M/z: 598.2. 1H NMR (DMSO, 400 MHz): 3.50 (d, 2H), 3.75 (d, 2H), 4.32 (d, 1H), 4.35 (ABq, 2H), 4.46-4.53 (m, 2H), 5.15 (d, 1H), 6.94-7.00 (m, 2H), 7.10-7.25 (m, 4H), 7.29-7.39 (m, 4H), 7.68-7.81 (m, 1H), 7.98-8.04 (m, 2H), 8.30-8.36 (m, 1).

1. customThe solvent was removed under reduced pressure
2. dissolutionThe residue was dissolved in a mixture of MeOH (5 ml), water (1 ml) and Et3N (0.5 ml)
3. stirringThe solution was stirred at 50° C. for 18 h
4. stirringthe mixture was stirred for 2 h at 50° C
5. concentrationthe mixture was concentrated
6. customThe residue was purified by preparative HPLC
7. customAfter freeze-drying

ORDレコード

ord-a926c66c234046b0b06cfe4cdcaae2c6

出典データセット

uspto-grants-2011_01

DOI

10.6084/m9.figshare.5104873.v1

特許番号

US07871998B2