Formaldehyde → (R)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylenepentanoic acid

Temperature

50 °C

Under N2, LDA (25 mL, 1.0 M in tetrahydrofuran, 25 mmol) is added to the mixture of (S)-2-Biphenyl-4-ylmethyl-5-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (3a, R1=t-butoxycarbonyl) (3.51 g, 10 mmol) in 20 mL dry tetrahydrofuran is added to the reaction mixture at −10° C., the resulting mixture is then stirred for 30 min at −10° C. benzoyl chloride (1.55 g, 11 mmol) is added to the reaction mixture at −10° C., after about 1 hour at −10° C., the reaction mixture is diluted with 15 mL saturated aqueous ammonium chloride solution and stirred for 15 min, stop stirring, and remove the lower aqueous layer. Formaldehyde (37% in water, 2.43 g, 0.03 mol), K2CO3 aqueous solution (2.76 g in 10 mL water, 0.02 mol) and tetrabutyl-ammonium-hydroxide solution (40% in water, 0.13 g, 0.5 mmol) are added to the remaining organic phase, and heated to 50° C., and stirred for 2 hours. Then the reaction mixture is diluted with 15 mL brine and stirred for 15 min, stop stirring, and remove the lower aqueous layer. Lithium hydroxide monohydrate solution (1.5 g in 10 mL water, 0.036 mol) and tetrabutylammonium bromide (32 mg, 0.1 mmol) are added to the remaining organic phase, stirred at r.t. for 2 hours. Then, about 5 g of phosphoric acid 85% is added in order to set the pH to 3.0-4.0. then 15 mL toluene and 15 mL brine is added. After phase separation and concentrated under vacuo. The residue is dissolved in 20 mL acetonitrile at 80° C., filtered hot (80° C.) to remove inorganic salt and cooled to 0° C., whereas crystallization occurs and standing for 3 hours, crystals are collected by filtration, washed with 5 mL acetonitrile and died under vacuum at 50° C. to afford (R)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylenepentanoic acid. The ratio of intermediate (3S,5S-4, R1=t-butoxycarbonyl, R4=phenyl) to (3R,5S-4, R1=t-butoxycarbonyl, R4=phenyl) is 70:30 as determined by HPLC. Spectroscopic data as Example 35, Method 1.

1. additionis added to the reaction mixture at −10° C.
2. additionis added to the reaction mixture at −10° C., after about 1 hour at −10° C.
3. stirringstop stirring
4. customremove the lower aqueous layer
5. stirringstirred for 2 hours
6. stirringstirred for 15 min
7. stirringstop stirring
8. customremove the lower aqueous layer
9. stirringstirred at r.t. for 2 hours
10. customAfter phase separation
11. concentrationconcentrated under vacuo
12. dissolutionThe residue is dissolved in 20 mL acetonitrile at 80° C.
13. filtrationfiltered hot (80° C.)
14. customto remove inorganic salt
15. temperaturecooled to 0° C., whereas crystallization
16. waitstanding for 3 hours
17. filtrationcrystals are collected by filtration
18. washwashed with 5 mL acetonitrile
19. customdied under vacuum at 50° C.

ORD record

ord-f64c94de8e7d4a78b591f1ee4d216220

Source dataset

uspto-grants-2016_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09278908B2