Boron tribromide → (R)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,4-difluorophenyl)thiazole-4-carboxamide

HRID 1185304Notes

Reaction equation

HRID 1185304 reaction equation
C(OC(=O)[NH:10][C@@H:11]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]2[N:19]([CH3:47])[N:20]=[CH:21][C:22]=2[NH:23][C:24]([C:26]2[N:27]=[C:28]([C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][C:40]=3[F:46])[S:29][C:30]=2[NH:31]C(OC(C)(C)C)=O)=[O:25])[CH2:13][CH2:12]1)C1C=CC=CC=1.B(Br)(Br)Br>C(Cl)Cl>[NH2:31][C:30]1[S:29][C:28]([C:39]2[CH:44]=[CH:43][C:42]([F:45])=[CH:41][C:40]=2[F:46])=[N:27][C:26]=1[C:24]([NH:23][C:22]1[CH:21]=[N:20][N:19]([CH3:47])[C:18]=1[N:14]1[CH2:15][CH2:16][CH2:17][C@@H:11]([NH2:10])[CH2:12][CH2:13]1)=[O:25]

Participants

4

Reactant 2

HCID 25134Boron tribromide2×HCID 58464864[(R)-1-(4-{[5-tert-butoxycarbonylamino-2-(2,4-difluoro-phenyl)-thiazole-4-carbonyl]-amino}-2-methyl-2H-pyrazol-3-yl)-perhydro-azepin-4-yl]-carbamic acid benzyl ester

Product 1

HCID 53482162(R)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,4-difluorophenyl)thiazole-4-carboxamideYield 42.4%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent3×

Procedure

To a stirred mixture of [(R)-1-(4-{[5-tert-butoxycarbonylamino-2-(2,4-difluoro-phenyl)-thiazole-4-carbonyl]-amino}-2-methyl-2H-pyrazol-3-yl)-perhydro-azepin-4-yl]-carbamic acid benzyl ester (46.0 mg, 0.067 mmol) in anhydrous DCM (4.0 mL) at −10° C. under N2 was added dropwise 1.0 M boron tribromide in DCM (0.22 mL, 0.22 mmol, 3.3 eq.). The reaction mixture was stirred at ambient temperature for 4 h and then cooled to −20° C. Additional 1.0 M Boron tribromide in DCM (0.11 mL, 0.11 mmol, 1.65 eq.) was added dropwise, and the reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was quenched with saturated aq. NaHCO3 solution and then extracted with ethyl acetate (3×50 mL). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified via reverse phase HPLC to afford 200 (12.7 mg, 42.1%) as a white solid. 1H NMR (400 MHz, DMSO) δ 8.93 (s, 1H), 8.39 (s, 1H), 8.33 (dd, J=15.5, 8.8 Hz, 1H), 7.47-7.36 (m, 4H), 7.29 (dd, J=11.6, 5.3 Hz, 1H), 3.66 (s, 3H), 3.26-3.14 (m, 3H), 3.14-3.05 (m, 3H), 2.03-1.89 (m, 2H), 1.88-1.77 (m, 1H), 1.76-1.56 (m, 3H); MS (ESI) m/z: 448.1 [M+H]+

Workup

  1. temperaturecooled to −20° C
  2. stirringthe reaction mixture was stirred at ambient temperature for 16 h
  3. customThe reaction mixture was quenched with saturated aq. NaHCO3 solution
  4. extractionextracted with ethyl acetate (3×50 mL)
  5. washThe combined organic phases were washed with brine
  6. dry with materialdried over Na2SO4
  7. filtrationfiltered
  8. concentrationconcentrated under reduced pressure
  9. customThe crude was purified via reverse phase HPLC

Sources & evidence

ORD record
ord-4ebf750271a14d5096241f12ccbc3e8a
Source dataset
uspto-grants-2014_03
Patent number
US08669361B2

Reaction notes

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