Tert-butoxycarbonylalanine → HCID 178462193, compound

HRID 243081Notes

Reaction equation

HRID 243081 reaction equation
[CH2:1]([O:8][C@@H:9]1[CH2:12][C@H:11]([NH:13][C:14]2[C:15]([NH2:21])=[CH:16][CH:17]=[C:18]([F:20])[CH:19]=2)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([O:26][C:27]([NH:29][C@@H:30]([CH3:34])[C:31](O)=O)=[O:28])([CH3:25])([CH3:24])[CH3:23].C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:22]([O:26][C:27](=[O:28])[NH:29][C@H:30]([C:31]1[N:13]([C@H:11]2[CH2:12][C@@H:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:10]2)[C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[N:21]=1)[CH3:34])([CH3:25])([CH3:24])[CH3:23]

Participants

6

Reactant 4

HCID 85082Tert-butoxycarbonylalanineHCID 181649HOAtHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 178507656HCID 178507656, compound

Product 1

HCID 178462193HCID 178462193, compound

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
0 °C

Procedure

A mixture of N2-(cis-3-benzyloxycyclobutyl)-4-fluorobenzene-1,2-diamine (1.13 g, 3.95 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (0.83 g, 4.35 mmol) and HOAt (0.59 g, 4.35 mmol) in DCM (20 mL) was cooled to 0° C. under nitrogen atmosphere. To this mixture N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (0.83 g, 4.35 mmol) was added portion wise and the reaction mixture stirred at RT for 1 h. The reaction mixture allowed to warm to RT then partitioned between DCM and a 10% aq. citric acid. The organic fraction was washed with brine (20 mL), dried (MgSO4), concentrated in vacuo and the resulting dark brown residue purified by column chromatography (Si—PCC, gradient 0-40% EtOAc in cyclohexane) to afford the title compound as a yellow gum, which solidified on standing (1.93 g, 93%). 1H NMR (CDCl3, 400 MHz): δ 7.46 (1H, s, br), 7.36-7.30 (5H, m), 7.11 (1H, q, J=14.8 Hz, 2.5 Hz), 6.37 (1H, dt, J=19.5 Hz, 2.8 Hz), 6.25 (1H, dd, J=14 Hz, 2.82 Hz), 4.94 (1H, d, J=5.83 Hz), 4.43 (2H, s), 4.23-4.07 (1H, m), 3.93-3.81 (1H, m), 3.47-3.35 (1H, m), 2.88-2.75 (1H, m), 2.03-1.85 (1H, m), 1.45 (3H, d, J=2.46 Hz), 1.43 (9H, s). LCMS (Method B): RT 3.88 min [M+H]+ 458. 110183151. The compound thus obtained (1 g, 2.19 mmol) was dissolved in AcOH (15 mL) and heated at 70° C. for 18 h. After cooling to RT, the volatiles were evaporated under reduced pressure and the residue partitioned between DCM (40 mL) and a saturated solution of NaHCO3 (20 mL). The organic fraction was washed with brine (20 mL), dried (MgSO4) and concentrated in vacuo. The resulting dark yellow residue was purified by column chromatography (Si—PCC, gradient 0-50% EtOAc in cyclohexane) to afford the title compound as pale red gum (570 mg, 60%). LCMS (Method B): RT 3.61 min [M+H]+ 440.0. 1H NMR (CDCl3, 400 MHz): δ 7.70-7.60 (2H, m), 7.44-7.37 (5H, m), 7.05-6.96 (1H, m), 5.38-5.26 (1H, m), 5.20-5.05 (1H, m), 4.82-4.68 (1H, m), 4.55 (2H, s), 4.10-3.97 (1H, m), 3.02-2.77 (4H, m), 1.47 (3H, d, J=2.44 Hz), 1.44 (9H, s).

Workup

  1. temperatureto warm to RT
  2. customthen partitioned between DCM
  3. washThe organic fraction was washed with brine (20 mL)
  4. dry with materialdried (MgSO4)
  5. concentrationconcentrated in vacuo
  6. customthe resulting dark brown residue purified by column chromatography (Si—PCC, gradient 0-40% EtOAc in cyclohexane)

Sources & evidence

ORD record
ord-f9306f8b17c34e7eacad75c6464bbd2e
Source dataset
uspto-grants-2014_02
Patent number
US08653089B2

Reaction notes

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