1-Methylimidazole → HCID 86700559, compound

HRID 712583Notes

Reaction equation

HRID 712583 reaction equation
Cl.[CH2:2]([O:4][C:5](=[O:9])[C@H:6]([CH3:8])[NH2:7])[CH3:3].[P:10](Cl)(Cl)(=[O:18])[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CN1C=CN=C1.[C:27]([O:41][CH2:42][CH3:43])(=[O:40])[CH2:28][CH2:29][NH:30][C:31](=[O:39])[C@@H:32]([C:34]([CH2:37][OH:38])([CH3:36])[CH3:35])[OH:33]>C(Cl)Cl.CO>[CH2:2]([O:4][C:5](=[O:9])[C@@H:6]([NH:7][P:10]([O:38][CH2:37][C:34]([CH3:36])([CH3:35])[C@@H:32]([OH:33])[C:31]([NH:30][CH2:29][CH2:28][C:27]([O:41][CH2:42][CH3:43])=[O:40])=[O:39])([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:18])[CH3:8])[CH3:3]

Participants

7

Reactant 4

HCID 13901-MethylimidazoleHCID 13038Phosphorodichloridic acid, phenyl esterHCID 2724356L-Alanine, ethyl ester, hydrochloride (1:1)HCID 9816328HCID 9816328, compound

Product 1

HCID 86700559HCID 86700559, compound

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 6344DichloromethaneSolvent2×

Procedure

L-Alanine ethyl ester hydrochloride (0.50 g, 3.25 mmol) was suspended in 10 mL of CH2Cl2 and treated with phenyl phosphorodichloridate (0.50 mL, 3.35 mmol) at −10° C. and under an atmosphere of nitrogen. The well-stirred mixture was then treated dropwise with N-methylimidazole (1.0 mL, 12.5 mmol). After 1 hr. and still at −10° C., ethyl pantothenate (0.70 g, 2.8 mmol) in 3 mL of CH2Cl2 was added slowly. This mixture was allowed to warm to room temperature, and after 3 hrs, 2 mL of methanol was added. Extraction was performed sequentially with 1 M HCl, water, 5% NaHCO3, and brine. The organic phase was dried (Na2SO4), and the solvent was evaporated affording 1.11 g of a clear, colorless syrup. This material was purified by flash column chromatography using 30 g of silica gel and eluting with 1:1 EtOAc/hexanes containing 5% EtOH. The process was repeated until 1.1 g of phosphoramidate was obtained. HPLC showed the product, as a 1:1 mixture of disastereomers, having a purity of 97%. 1H NMR (300 MHz, CDCl3): δ 1.08 (s, 3H, CH3), 1.21 (d, 3H, J=2.7 Hz, CH3), 1.27 (m, 6H, CH3), 1.35 (t, 3H, J=6.9 Hz, CH3), 2.53 (q, 2H, J=4.2 Hz, CH2), 3.50 (m, 2H, CH2), 3.60 (m, 1H, CH), 3.78 (d, J=7.5 Hz, CH), 3.9 (m, 2H, CH2), 4.10 (m, 6H, CH2), 4.79 (t, 1H, J=6.5 Hz, CH), 7.15 and 7.40 (2 Ms, 5H, Ph). Expected Mol. Wt. 502.21, Observed Mol. Wt. 503.09 (M+H+]

Workup

  1. waitafter 3 hrs
  2. extractionExtraction
  3. dry with materialThe organic phase was dried (Na2SO4)
  4. customthe solvent was evaporated
  5. customaffording 1.11 g of a clear, colorless syrup
  6. customThis material was purified by flash column chromatography
  7. washeluting with 1:1 EtOAc/hexanes containing 5% EtOH
  8. customwas obtained
  9. additionas a 1:1 mixture of disastereomers

Sources & evidence

ORD record
ord-f321bf706941498e94828fdfebbacbac
Source dataset
uspto-grants-2015_11
Patent number
US09181286B2

Reaction notes

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