Hydrochloric Acid → (S)-N-(3-(5-(2-(2-aminopropylamino)pyrimidin-4-yl)-2-cyclopropyl-1H-imidazol-4-yl)-2-chlorophenyl)propane-1-sulfonamide

HRID 885765Notes

Reaction equation

HRID 885765 reaction equation
[Cl:1][C:2]1[C:7]([NH:8][S:9]([CH2:12][CH2:13][CH3:14])(=[O:11])=[O:10])=[CH:6][CH:5]=[CH:4][C:3]=1[C:15]1[N:16]=[C:17]([CH:46]2[CH2:48][CH2:47]2)[N:18](COCC[Si](C)(C)C)[C:19]=1[C:20]1[CH:25]=[CH:24][N:23]=[C:22]([NH:26][CH2:27][C@@H:28]([NH:30]C(=O)OC(C)(C)C)[CH3:29])[N:21]=1.Cl>CCO>[NH2:30][C@@H:28]([CH3:29])[CH2:27][NH:26][C:22]1[N:21]=[C:20]([C:19]2[NH:18][C:17]([CH:46]3[CH2:48][CH2:47]3)=[N:16][C:15]=2[C:3]2[C:2]([Cl:1])=[C:7]([NH:8][S:9]([CH2:12][CH2:13][CH3:14])(=[O:11])=[O:10])[CH:6]=[CH:5][CH:4]=2)[CH:25]=[CH:24][N:23]=1

Participants

4

Reactant 2

HCID 313Hydrochloric Acid2×HCID 69811403(S)-tert-butyl 1-(4-(4-(2-chloro-3-(propylsulfonamido)phenyl)-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate

Product 1

HCID 69809521(S)-N-(3-(5-(2-(2-aminopropylamino)pyrimidin-4-yl)-2-cyclopropyl-1H-imidazol-4-yl)-2-chlorophenyl)propane-1-sulfonamideYield 107.1%

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent

Conditions

Temperature
60 °C

Procedure

A solution of (S)-tert-butyl 1-(4-(4-(2-chloro-3-(propylsulfonamido)phenyl)-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate (116 mg, 0.14 mmol) in EtOH (2 mL) was treated with aqueous 6.0 N HCl solution (0.8 mL, 4.8 mmol) and the resulting reaction was heated to 60° C. for 30 minutes, then at room temperature for 40 minutes. The reaction was allowed to cool to room temperature and the volatiles were removed in vacuo. Further drying under high vacuum afforded (S)—N-(3-(5-(2-(2-aminopropylamino)pyrimidin-4-yl)-2-cyclopropyl-1H-imidazol-4-yl)-2-chlorophenyl)propane-1-sulfonamide (80 mg, 0.15 mmol) as the HCl salt (4A-2) which was used without further purification: LCMS(m/z) 490.2 (MH+), tR=0.48 minute. 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 lypholized 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. customthe resulting reaction
  2. temperatureto cool to room temperature
  3. customthe volatiles were removed in vacuo
  4. customFurther drying under high vacuum

Sources & evidence

ORD record
ord-dda570ceeb69400c9e9d86ea6b4bf5a2
Source dataset
uspto-grants-2012_08
Patent number
US08242260B2

Reaction notes

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