Diisopropylethylamine → Isoquinolin-3-yl-carbamic acid (S)-3-benzyloxycarbonylamino-2-[3-(2-chloro-3-fluoro-benzyl)-1-methyl-ureido]-propyl ester

HRID 416428Notes

Reaction equation

HRID 416428 reaction equation
[CH2:1]([O:8][C:9]([NH:11][CH2:12][C@H:13]([NH:29][CH3:30])[CH2:14][O:15][C:16](=[O:28])[NH:17][C:18]1[N:19]=[CH:20][C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:31][C:32]1[C:51]([F:52])=[CH:50][CH:49]=[CH:48][C:33]=1[CH2:34][NH:35][C:36](=[O:47])OC1C=CC([N+]([O-])=O)=CC=1.CCN(C(C)C)C(C)C>C1COCC1>[CH2:1]([O:8][C:9]([NH:11][CH2:12][C@H:13]([N:29]([CH3:30])[C:36]([NH:35][CH2:34][C:33]1[CH:48]=[CH:49][CH:50]=[C:51]([F:52])[C:32]=1[Cl:31])=[O:47])[CH2:14][O:15][C:16](=[O:28])[NH:17][C:18]1[N:19]=[CH:20][C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1

Participants

5

Reactant 3

HCID 81531DiisopropylethylamineHCID 57947441Isoquinolin-3-yl-carbamic acid (S)-3-benzyloxycarbonylamino-2-methylamino-propyl esterHCID 579475384-Nitrophenyl 2-chloro-3-fluorobenzylcarbamate

Product 1

HCID 57947695Isoquinolin-3-yl-carbamic acid (S)-3-benzyloxycarbonylamino-2-[3-(2-chloro-3-fluoro-benzyl)-1-methyl-ureido]-propyl esterYield 72.8%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a solution of the crude isoquinolin-3-yl-carbamic acid (S)-3-benzyloxycarbonylamino-2-methylamino-propyl ester (9.0 mmol) in THF (35 mL) were added 4-nitrophenyl 2-chloro-3-fluorobenzylcarbamate (2.85 g, 8.79 mmol) and DIEA (2.3 mL, 13.2 mmol) at RT. The reaction mixture was stirred at RT for 30 min. The solvent was removed and the residue was dissolved in EtOAc (400 mL). The organic mixture was washed with NaOH (1 N, 50 mL×3), HCl (0.5 N, 50 mL), saturated NaHCO3, and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified on silica gel column using a mixture of EtOAC and hexanes to give Isoquinolin-3-yl-carbamic acid (S)-3-benzyloxycarbonylamino-2-[3-(2-chloro-3-fluoro-benzyl)-1-methyl-ureido]-propyl ester (3.8 g, 71% for two steps) as white foam. LRMS (M+H+) m/z 594.2.

Workup

  1. customThe solvent was removed
  2. dissolutionthe residue was dissolved in EtOAc (400 mL)
  3. washThe organic mixture was washed with NaOH (1 N, 50 mL×3), HCl (0.5 N, 50 mL), saturated NaHCO3, and brine
  4. dry with materialdried over Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated under reduced pressure
  7. customThe residue was purified on silica gel column
  8. additiona mixture of EtOAC and hexanes

Sources & evidence

ORD record
ord-2b1dc3c72ac246b0aaea24c5ac678c3c
Source dataset
uspto-grants-2012_01
Patent number
US08088793B2

Reaction notes

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