Methyl chloroformate → (S)-methyl 1-(4-(4-(2-chloro-3-(propylsulfonamido)phenyl)-2-cyclopropyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate

HRID 1043748Notes

Reaction equation

HRID 1043748 reaction equation
[NH2:1][C@@H:2]([CH3:33])[CH2:3][NH:4][C:5]1[N:10]=[C:9]([C:11]2[NH:15][C:14]([CH:16]3[CH2:18][CH2:17]3)=[N:13][C:12]=2[C:19]2[C:20]([Cl:32])=[C:21]([NH:25][S:26]([CH2:29][CH2:30][CH3:31])(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:8]=[CH:7][N:6]=1.C([O-])(O)=O.[Na+].Cl[C:40]([O:42][CH3:43])=[O:41]>C1COCC1.O.O>[Cl:32][C:20]1[C:21]([NH:25][S:26]([CH2:29][CH2:30][CH3:31])(=[O:28])=[O:27])=[CH:22][CH:23]=[CH:24][C:19]=1[C:12]1[N:13]=[C:14]([CH:16]2[CH2:18][CH2:17]2)[NH:15][C:11]=1[C:9]1[CH:8]=[CH:7][N:6]=[C:5]([NH:4][CH2:3][C@@H:2]([NH:1][C:40](=[O:41])[O:42][CH3:43])[CH3:33])[N:10]=1

Participants

6

Reactant 3

HCID 6586Methyl chloroformateHCID 516892Sodium BicarbonateHCID 69809521(S)-N-(3-(5-(2-(2-aminopropylamino)pyrimidin-4-yl)-2-cyclopropyl-1H-imidazol-4-yl)-2-chlorophenyl)propane-1-sulfonamide

Product 1

HCID 58164470(S)-methyl 1-(4-(4-(2-chloro-3-(propylsulfonamido)phenyl)-2-cyclopropyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 21881883Oxolane--water (1/1)Solvent

Procedure

To a mixture of (S)—N-(3-(5-(2-(2-aminopropylamino)pyrimidin-4-yl)-2-cyclopropyl-1H-imidazol-4-yl)-2-chlorophenyl)propane-1-sulfonamide in THF-water (1:1, 2 mL) at 0° C. was added solid NaHCO3 (137 mg, 1.6 mmol) and the resulting mixture was stirred for 5 minutes. Methyl chloroformate (14 μL, 0.18 mmol) was added and the reaction mixture was stirred at 0° C. for 15 minutes. The reaction was diluted with water and extracted with EtOAc (2×). The combined organic portions were washed with water, brine, dried (Na2SO4), and concentrated. The resulting residue was dissolved in DMSO and purified by reverse phase HPLC. Product fractions were combined and lyophilized to give (S)-methyl 1-(4-(4-(2-chloro-3-(propylsulfonamido)phenyl)-2-cyclopropyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate (19.9 mg) as the TFA salt (4A-3): LCMS (m/z) 548.0 (MH+), tR=0.61 minute, 1H NMR (400 MHz, CD3OD) δ 1.04 (t, J=7.4 Hz, 3H) 1.14 (d, J=6.6 Hz, 3H) 1.27 (t, J=4.5 Hz, 2H) 1.34-1.44 (m, 2H) 1.80-1.95 (m, 2H) 3.14-3.21 (m, 2H) 3.67 (br s, 3H) 3.97 (br s, 1H) 6.40 (br s, 1H) 7.45 (d, 7.0 Hz, 1H) 7.54 (m, 1H) 7.84 (d, J=7.4 Hz, 1H) 8.13 (d, J=5.1 Hz, 1H).

Workup

  1. stirringthe reaction mixture was stirred at 0° C. for 15 minutes
  2. extractionextracted with EtOAc (2×)
  3. washThe combined organic portions were washed with water, brine
  4. dry with materialdried (Na2SO4)
  5. concentrationconcentrated
  6. dissolutionThe resulting residue was dissolved in DMSO
  7. custompurified by reverse phase HPLC

Sources & evidence

ORD record
ord-b96d38475a644f0dad1a71e24e5278da
Source dataset
uspto-grants-2013_10
Patent number
US08563553B2

Reaction notes

Loading…