3-[[(1,1-Dimethylethoxy)carbonyl]amino]-D-alanine methyl ester

To a solution of (2S)-2-tetrahydropyran-2-yloxypropanal (7.5 g) in MeOH (80 mL) were added glyoxal (4.2 mL) and methyl (2R)-2-amino-3-hydroxy-propanoate (8.0 g) in MeOH (40 mL) at room temperature. After stirring for 10 minutes, ammonium acetate (2.8 g) was added into the reaction mixture, which was stirred for additional 3 days and concentrated in vacuo. The residue was purified with OH-type silica gel column chromatography (10-100% EtOAc in n-hexane) to give the title compound (4.4 g, 30 % yield) as yellow amorphous. MS (ESI) m/z 398 [M+lh] RT = 0.559 min. LCMS condition : B.To a solution of 4-(bromomethyl)-2-fluorobenzoic acid (0.76 g, 3.25 mmol) in CH2C12 (5 mL), was added oxalyl chloride (1.422 mL, 16.25 mmol) followed by a few drops of DMF at room temperature. The reaction was stirred for 1 h at room temperature. The reaction was concentrated under reduced pressure and the resulting residue was dissolved in CH2C12 (5 mL), and then 4-chloro-2-(4-(3, 3, 3-trifluoropropyl)piperazin-1-yl)aniline (1.0 g, 3.25 mmol) and DIEA (0.420 g, 3.25 mmol) were added. The reaction was stirred for 30 min at room temperature. The reaction was washed with water and dried over MgS04. The organic layer was concentrated under reduced pressure and the residue was crystallized in methanol. The precipitate was filtered and dried under reduced pressure to give the title compound (1.45 g, 85%) as a mixture of bromo- and chloro- intermediates. LC/MS (peak 1) m/z = 478.0 [M+H]+, (peak 2) m/z = 523.2 [M+H]+. Intermediate 2 (10 mg, 0.019 mmol), (R)-methyl 2-amino-3-(teri- butoxycarbonylamino)propanoate (4.17 mg, 0.019 mmol), and DIEA (3.34 mu?, 0.019 mmol) were added to a vial with DMF (0.4 mL). The reaction was heated to 80 C and stirred at this temperature for 1 h. After this time, the reaction was complete. The N-Boc protected intermediate was purified by preparative LC/MS (5-70% ACN/H20, 25 min). After lyophilization, the solid was re-dissolved in MeOH (0.4 mL) and TFA (0.1 mL) (to cleave the N-Boc group). The reaction was allowed to stir at room temperature over night. Then, the solvent was removed, the oil was re-dissolved in ACN (0.4 mL) and H20 (0.8 mL), frozen, and lyophilized to give the title compound. LC/MS m/z = 560.4 [M+H]+; lU NMR (400 MHz, DMSO-i ) delta ppm 1.21-1.31 (m, 1H), 2.75-2.91 (m, 3H), 3.05-3.20 (m, 2H), 3.33-3.81 (m, 17H), 7.29 (dd, = 8.84, 2.27 Hz, 1H), 7.36-7.43 (m, 2H), 7.47 (d, = 13.14 Hz, 1H), 7.89 (t, = 8.02 Hz, 1H), 8.30 (d, = 8.08 Hz, 1H), 9.65 (d, = 8.97 Hz, 1H).

Molecular Weight:218.25
XLogP3:-0.1
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:5
Rotatable Bond Count:6
Exact Mass:218.12665706
Monoisotopic Mass:218.12665706
Topological Polar Surface Area:90.6
Heavy Atom Count:15
Complexity:235
Defined Atom Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes