Sodium Carbonate → HCID 86680061, compound

HRID 1915843Notes

Reaction equation

CC12NC(=O)OC1CCN(C1N(C)N=CC=1[N+]([O-])=O)CC2.Br[C:23]1[S:24][C:25]([NH:53][C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])=[C:26]([C:28]([NH:30][C:31]2[CH:32]=[N:33][N:34]([CH3:52])[C:35]=2[N:36]2[CH2:42][C:41]([F:44])([F:43])[CH2:40][N:39]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:38][CH2:37]2)=[O:29])[N:27]=1.C([O-])([O-])=O.[Na+].[Na+].[F:67][C:68]1[CH:73]=[CH:72][C:71]([CH3:74])=[CH:70][C:69]=1B(O)O>COCCOC.O.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]>[C:57]([O:56][C:54]([NH:53][C:25]1[S:24][C:23]([C:69]2[CH:70]=[C:71]([CH3:74])[CH:72]=[CH:73][C:68]=2[F:67])=[N:27][C:26]=1[C:28]([NH:30][C:31]1[CH:32]=[N:33][N:34]([CH3:52])[C:35]=1[N:36]1[CH2:42][C:41]([F:44])([F:43])[CH2:40][N:39]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:38][CH2:37]1)=[O:29])=[O:55])([CH3:60])([CH3:59])[CH3:58].[NH2:53][C:25]1[S:24][C:23]([C:69]2[CH:70]=[C:71]([CH3:74])[CH:72]=[CH:73][C:68]=2[F:67])=[N:27][C:26]=1[C:28]([NH:30][C:31]1[CH:32]=[N:33][N:34]([CH3:52])[C:35]=1[N:36]1[CH2:42][C:41]([F:43])([F:44])[CH2:40][N:39]([C:45]([O:47][C:48]([CH3:50])([CH3:49])[CH3:51])=[O:46])[CH2:38][CH2:37]1)=[O:29]

Participants

Conditions

Temperature: 120 °C

Procedure

A mixture of Intermediate 3, tert-butyl 4-(4-(2-bromo-5-(tert-butoxycarbonylamino)thiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-6,6-difluoro-1,4-diazepane-1-carboxylate (283 mg, 0.44 mmol), Na2CO3 (93 mg, 0.88 mmol) and 2-fluoro-5-methylphenylboronic acid (95 mg, 0.62 mmol) in DME (4.9 mL) and water (1.6 mL) was degassed by gently bubbling nitrogen through the mixture for 10 min. [1,1′-Bis(diphenylphosphino)ferrocene]dichloro-palladium(II) (36 mg, 0.04 mmol) was then added and the mixture degassed for a further 10 min before being heated in a microwave at 120° C. for 1 hr. The solvents were removed under reduced pressure and the residue dissolved in DCM (50 mL) and washed with water (2×20 mL). The organic layer was separated, dried over MgSO4 and the solvent removed under reduced pressure. The residue was purified via silica gel column chromatography (0-80% EtOAc/isohexane) to yield tert-butyl 4-(4-(5-tert-butoxycarbonylamino-2-(2-fluoro-5-methylphenyl)thiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-6,6-difluoro-1,4-diazepane-1-carboxylate (179 mg) and tert-butyl 4-(4-(5-amino-2-(2-fluoro-5-methylphenyl)thiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-6,6-difluoro-1,4-diazepane-1-carboxylate (50 mg). The isolated intermediates were combined and suspended in MeOH (2 mL) and to this was added a solution of HCl in 1,4-dioxane (4 M, 1.7 mL, 6.75 mmol) and stirred at room temperature for 16 hr. The solvent was removed under reduced pressure and the residue dissolved in EtOAc (50 mL) and washed with 1 M NaOH solution (20 mL). The residue was purified via silica gel column chromatography (0-10% MeOH/DCM) to yield 105 as a beige solid (59 mg, 30% over two steps). 1H NMR (400 MHz, CDCl3) δ 8.98 (s, 1H), 7.90 (dd, J=7.0, 2.5 Hz, 1H), 7.80 (s, 1H), 7.16-7.11 (m, 1H), 7.09-7.01 (m, 1H), 6.09 (s, 2H), 3.77 (s, 3H), 3.63 (t, J=13.5 Hz, 2H), 3.46-3.29 (m, 4H), 3.06 (t, J=5.5 Hz, 2H), 2.39 (s, 3H), 1.95 (s, 1H). LCMS (ES+) m/z 466 (M+1).

Workup

additionwas then added
customthe mixture degassed for a further 10 min
customThe solvents were removed under reduced pressure
dissolutionthe residue dissolved in DCM (50 mL)
washwashed with water (2×20 mL)
customThe organic layer was separated
dry with materialdried over MgSO4
customthe solvent removed under reduced pressure
customThe residue was purified via silica gel column chromatography (0-80% EtOAc/isohexane)

Sources & evidence

ORD record: ord-bb761aa6ead24aec8fbacf18faac385e
Source dataset: uspto-grants-2013_12
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08614206B2

Reaction notes

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