Hydrochloric Acid → 5-amino-N-[5-(5-amino-3,3-difluoro-azepan-1-yl)-1-methyl-pyrazol-4-yl]-2-(2,6-difluoro-4-methoxy-phenyl)thiazole-4-carboxamide

HRID 1915949Notes

Reaction equation

HRID 1915949 reaction equation
C(OC([NH:8][C:9]1[S:13][C:12](Br)=[N:11][C:10]=1[C:15]([NH:17][C:18]1[CH:19]=[N:20][N:21]([CH3:40])[C:22]=1[N:23]1[CH2:29][C:28]([F:31])([F:30])[CH2:27][CH:26]([NH:32]C(=O)OC(C)(C)C)[CH2:25][CH2:24]1)=[O:16])=O)(C)(C)C.[F:41][C:42]1[CH:47]=[C:46]([O:48][CH3:49])[CH:45]=[C:44]([F:50])[C:43]=1B(O)O.ClCCl.C(=O)([O-])[O-].[Na+].[Na+].Cl.O1CCOCC1>COC.CO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[NH2:8][C:9]1[S:13][C:12]([C:43]2[C:42]([F:41])=[CH:47][C:46]([O:48][CH3:49])=[CH:45][C:44]=2[F:50])=[N:11][C:10]=1[C:15]([NH:17][C:18]1[CH:19]=[N:20][N:21]([CH3:40])[C:22]=1[N:23]1[CH2:24][CH2:25][CH:26]([NH2:32])[CH2:27][C:28]([F:30])([F:31])[CH2:29]1)=[O:16]

Participants

11

Reactant 6

HCID 313Hydrochloric AcidHCID 6344DichloromethaneHCID 10340Sodium CarbonateHCID 312751,4-DioxaneHCID 162174242,6-Difluoro-4-methoxybenzeneboronic acidHCID 86680140tert-butyl 1-(4-(5-(tert-butoxycarbonyl-amino)-2-bromothiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-6,6-difluoroazepan-4-ylcarbamate

Product 1

HCID 749832745-amino-N-[5-(5-amino-3,3-difluoro-azepan-1-yl)-1-methyl-pyrazol-4-yl]-2-(2,6-difluoro-4-methoxy-phenyl)thiazole-4-carboxamideYield 6.3%

Reagents, catalysts & solvents 4

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 887MethanolSolventHCID 962WaterSolventHCID 8254Dimethyl EtherSolvent

Conditions

Temperature
120 °C

Procedure

To a solution of tert-butyl 1-(4-(5-(tert-butoxycabonyl-amino)-2-bromothiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-6,6-difluoroazepan-4-ylcarbamate (200 mg, 0.31 mmol) in dimethyl ether (3 mL) was added 2,6-difluoro-4-methoxyphenylboronic acid (101 mg, 0.54 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (50 mg, 0.06 mmol), sodium carbonate (67 mg, 0.63 mmol) and water (1 mL). The mixture was degassed for 5 minutes before being heated in a microwave at 120° C. for 2.5 hour. The mixture was concentrated under reduced pressure and the residue purified via silica gel column chromatography (0-100% EtOAc/isohexane) to give a brown oil. To a solution of this oil in MeOH (10 mL) was added HCl in dioxane (4 M, 10 mL, 40.0 mmol) and the mixture was heated at 40° C. for 3 hr. Purification via preparative HPLC gave 459 as a white solid (10 mg, 6% over two steps). 1H NMR (400 MHz, d6-DMSO) δ 8.82 (s, 1H), 7.54 (s, 1H), 7.43 (s, 2H), 6.99-6.88 (m, 2H), 3.85 (s, 3H), 3.79-3.50 (m, 4H), 3.47-3.33 (m, 1H), 3.29-3.16 (m, 2H), 3.15-3.05 (m, 1H), 2.29-2.09 (m, 2H), 1.90-1.78 (m, 1H), 1.77-1.65 (m, 1H), 1.62 (s, 2H). LCMS (ES+) m/z 514 (M+1)

Workup

  1. customThe mixture was degassed for 5 minutes
  2. concentrationThe mixture was concentrated under reduced pressure
  3. customthe residue purified via silica gel column chromatography (0-100% EtOAc/isohexane)
  4. customto give a brown oil
  5. temperaturethe mixture was heated at 40° C. for 3 hr
  6. customPurification via preparative HPLC

Sources & evidence

ORD record
ord-8a7b662d6f574ff48f3605c3fc2a03b8
Source dataset
uspto-grants-2013_12
Patent number
US08614206B2

Reaction notes

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