反应详情

(R)-ethyl 3-amino-4-(5′-chloro-2′-fluoro-[1,1-biphenyl]-4-yl)butanoate (114 mg, 0.306 mmol), 3-phosphonoproprionic acid (47.2 mg, 0.306 mmol), EDC (58.7 mg, 0.306 mmol) and HOBT (46.9 mg, 0.306 mmol) were mostly dissolved in DMF (1 mL), and DIPEA (0.321 mL, 1.837 mmol) was added. The reaction mixture was stirred and heated at 70° C. approximately 18 hours, then filtered and purified by HPLC: 30-80% ACN/H2O 0.1% TFA, 40 mL/min over 15 min 30×100 Sunfire C18, product elutes approximately 5.5-8 min. A mixed fraction was repurified on a 20-55% gradient over 20 min, and product eluted ˜12.5-13 min. The fractions were evaporated to dryness to afford (R)-(3-((1-(5′-chloro-2′-fluoro-[1,1-biphenyl]-4-yl)-4-ethoxy-4-oxobutan-2-yl)amino)-3-oxopropyl)phosphonic acid (17 mg) LCMS (ES+) C21H24ClFNO6P: Calc.: 471.1; Found: 472.0[M+H]+.

1. temperatureheated at 70° C. approximately 18 hours
2. filtrationfiltered
3. custompurified by HPLC
4. customA mixed fraction was repurified on a 20-55% gradient over 20 min
5. washproduct eluted ˜12.5-13 min
6. customThe fractions were evaporated to dryness