Hydrochloric Acid → 5-amino-N-(5-(4-amino-5-fluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide

HRID 1915869Notes

Reaction equation

HRID 1915869 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[S:10][C:11]([NH:38]C(=O)OC(C)(C)C)=[C:12]([C:14](=[O:37])[NH:15][C:16]2[CH:17]=[N:18][N:19]([CH3:36])[C:20]=2[N:21]2[CH2:27][CH2:26][CH:25]([NH:28]C(=O)C(F)(F)F)[CH:24]([F:35])[CH2:23][CH2:22]2)[N:13]=1.Cl.O1CCOCC1>CO>[NH2:38][C:11]1[S:10][C:9]([C:3]2[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=2[F:8])=[N:13][C:12]=1[C:14]([NH:15][C:16]1[CH:17]=[N:18][N:19]([CH3:36])[C:20]=1[N:21]1[CH2:22][CH2:23][CH:24]([F:35])[CH:25]([NH2:28])[CH2:26][CH2:27]1)=[O:37]

Participants

5

Reactant 3

HCID 313Hydrochloric AcidHCID 312751,4-DioxaneHCID 86680075tert-butyl 2-(2,6-difluorophenyl)-4-(5-(4-fluoro-5-(2,2,2-trifluoroacetamido)azepan-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate

Product 1

HCID 767944405-amino-N-(5-(4-amino-5-fluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Conditions

Temperature
60 °C

Procedure

tert-Butyl 2-(2,6-difluorophenyl)-4-(5-(4-fluoro-5-(2,2,2-trifluoroacetamido)azepan-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate was suspended in MeOH (20 mL) in a pressure vessel and to this was added a solution of HCl in 1,4-dioxane (4 M, 20 mL, 80.0 mmol). The vessel was sealed and the mixture heated at 60° C. for 16 hr. The solvent was removed under reduced pressure and the residue was purified via silica gel column chromatography (0-10% 7 N ammonia in MeOH/DCM) to yield 5-amino-N-(5-(4-amino-5-fluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide as a pale brown solid (653 mg, 70% over two steps). The 4-amino and the 5-fluoro groups are cis. 1H NMR (400 M Hz, CDCl3) δ 8.63 (s, 1H), 7.84 (s, 1H), 7.37-7.29 (m, 1H), 7.03 (t, J=8.7 Hz, 2H), 6.13 (s, 2H), 4.48 (dtd, J=47.9, 8.6, 3.6 Hz, 1H), 3.72 (s, 3H), 3.37-3.15 (m, 5H), 2.23-1.92 (m, 3H), 1.75-1.67 (m, 1H). Alkyl NH2 not observed. LCMS (ES+) m/z 466 (M+1). Chiral separation of the racemic mixture by SFC gave 147 as a single enantiomer. 1H NMR (400 MHz, DMSO) δ 9.04 (s, 1H), 7.59 (s, 1H), 7.56-7.43 (m, 3H), 7.26 (dd, J=14.5, 5.9 Hz, 2H), 4.82 (dd, J=47.0, 7.4 Hz, 1H), 3.63 (s, 3H), 3.29-3.15 (m, 4H), 3.08-2.91 (m, 2H), 2.24-2.06 (m, 1H), 1.91-1.76 (m, 2H), 1.74-1.59 (m, 1H). MS (ESI) m/z: 466.1 [M+H+].

Workup

  1. customThe vessel was sealed
  2. customThe solvent was removed under reduced pressure
  3. customthe residue was purified via silica gel column chromatography (0-10% 7 N ammonia in MeOH/DCM)

Sources & evidence

ORD record
ord-cd7bce21fbd7499887a7fc7cf3cc4d48
Source dataset
uspto-grants-2013_12
Patent number
US08614206B2

Reaction notes

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