4-Methylmorpholine → N2-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[2-(4-fluorophenyl)-2-hydroxyethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}-L-glutaminyl-D-tyrosine

N2-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[2-(4-fluorophenyl)-2-hydroxyethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}-L-glutamine (22 mg, 0.0359 mmol), tert-butyl D-tyrosinate hydrochloride (10 mg, 0.0421 mmol) and N-methylmorpholine (14 mg, 0.138 mmol) were dissolved in methylene chloride (0.5 ml). TBTU (14 mg, 0.0436 mmol) was added and the mixture was stirred overnight at room temperature. The solvent was evaporated and the residue was dissolved in formic acid (1 ml). The mixture was stirred at 45-50° C. for 4 h and was then evaporated under reduced pressure. Methanol (10 ml) was added and evaporated. The residue was dissolved in methanol (2 ml). Three drops of TEA were added and the mixture was stirred overnight at room temperature. The solvent was evaporated and the residue was purified by preparative HPLC using acetonitrile/ammonium acetate buffer (40:60) as eluent. After freeze-drying 15 mg (54%) of the title compound was obtained. 1H-NMR, 300 MHz, DMSO): 1.60-2.00 (m, 4H), 2.69-3.0 (m, 4H), 4.09-4.18 (m, 1H), 4.22-4.35 (m, 3H), 4.49 (s, 2H), 4.65-4.78 (m, 1H), 4.97-5.08 (m, 1H), 6.56 (d, 2H), 6.70 (s, 1H), 6.86-7.40 (m, 18H), 7.77-7.91 (m, 1H), 8.12 (d, 1H), 9.10 (bs, 1H).

1. customThe solvent was evaporated
2. dissolutionthe residue was dissolved in formic acid (1 ml)
3. stirringThe mixture was stirred at 45-50° C. for 4 h
4. customwas then evaporated under reduced pressure
5. additionMethanol (10 ml) was added
6. customevaporated
7. dissolutionThe residue was dissolved in methanol (2 ml)
8. additionThree drops of TEA were added
9. stirringthe mixture was stirred overnight at room temperature
10. customThe solvent was evaporated
11. customthe residue was purified by preparative HPLC
12. dry with materialAfter freeze-drying 15 mg (54%) of the title compound
13. customwas obtained

ORDレコード

ord-39f76b1008274dbca10474778b49ab3a

出典データセット

uspto-grants-2011_01

DOI

10.6084/m9.figshare.5104873.v1

特許番号

US07871998B2