Hydrochloric Acid → (S)-N-(2-amino-1-(3-chlorophenyl)ethyl)-4-(3-amino-6-(4,4-difluorocyclohexyl)pyrazin-2-yl)-2-fluorobenzamide

HRID 596053Notes

Reaction equation

HRID 596053 reaction equation
[NH2:1][C:2]1[C:3]([C:16]2[CH:41]=[CH:40][C:19]([C:20]([NH:22][C@@H:23]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[CH:34]=3)[CH2:24][NH:25]C(=O)OC(C)(C)C)=[O:21])=[C:18]([F:42])[CH:17]=2)=[N:4][C:5]([CH:8]2[CH2:13][CH2:12][C:11]([F:15])([F:14])[CH2:10][CH2:9]2)=[CH:6][N:7]=1.Cl.O1CCOCC1>>[NH2:25][CH2:24][C@@H:23]([NH:22][C:20](=[O:21])[C:19]1[CH:40]=[CH:41][C:16]([C:3]2[C:2]([NH2:1])=[N:7][CH:6]=[C:5]([CH:8]3[CH2:9][CH2:10][C:11]([F:14])([F:15])[CH2:12][CH2:13]3)[N:4]=2)=[CH:17][C:18]=1[F:42])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[CH:34]=1

Participants

4

Reactant 3

HCID 313Hydrochloric AcidHCID 312751,4-DioxaneHCID 118054654(S)-tert-butyl (2-(4-(3-amino-6-(4,4-difluorocyclohexyl)pyrazin-2-yl)-2-fluorobenzamido)-2-(3-chlorophenyl)ethyl)carbamate

Product 1

HCID 118046335(S)-N-(2-amino-1-(3-chlorophenyl)ethyl)-4-(3-amino-6-(4,4-difluorocyclohexyl)pyrazin-2-yl)-2-fluorobenzamideYield 41.9%

Procedure

To (S)-tert-butyl (2-(4-(3-amino-6-(4,4-difluorocyclohexyl)pyrazin-2-yl)-2-fluorobenzamido)-2-(3-chlorophenyl)ethyl)carbamate (11 mg, 0.018 mmol) was added HCl 4M in dioxane (1 mL, 4.00 mmol). The reaction was stirred for 1 h at room temperature. The solvent was removed and concentrated to residue, which was dissolved in 1:1 acetonitrile/water, filtered and lyophilized to HCl salt. The crude salt residue was dissolved in 1 mL of DMSO, purified by prep HPLC and lyophilized to give 3.8 mg of the desired product (S)—N-(2-amino-1-(3-chlorophenyl)ethyl)-4-(3-amino-6-(4,4-difluorocyclohexyl)pyrazin-2-yl)-2-fluorobenzamide as a TFA salt (33%). LCMS (m/z): 504.2 (MH+), 0.74 min; 1H NMR (CD3OD) δ ppm 7.85-7.73 (m, 2H), 7.62 (dd, J=8.0, 1.4 Hz, 1H), 7.54 (dd, J=12.1, 1.2 Hz, 1H), 7.46 (s, 1H), 7.38-7.28 (m, 3H), 5.39 (dd, J=9.0, 5.9 Hz, 1H), 3.40-3.33 (m, 2H), 2.72 (br. s., 1H), 2.12-1.98 (m, 2H), 1.96-1.73 (m, 6H).

Workup

  1. customThe solvent was removed
  2. concentrationconcentrated to residue, which
  3. dissolutionwas dissolved in 1:1 acetonitrile/water
  4. filtrationfiltered
  5. dissolutionThe crude salt residue was dissolved in 1 mL of DMSO
  6. custompurified by prep HPLC

Sources & evidence

ORD record
ord-3b51aaeaf0184437b196d9aed8d8f05d
Source dataset
uspto-grants-2016_01
Patent number
US09242996B2

Reaction notes

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