Sodium Carbonate → tert-butyl N-[2-(2-fluoro-4-pyridyl)-4-[[1-methyl-5-[(4S)-4-[(2,2,2-trifluoroacetyl)amino]azepan-1-yl]pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate

HRID 1915937Notes

Reaction equation

HRID 1915937 reaction equation
Br[C:2]1[S:3][C:4]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[C:5]([C:7](=[O:29])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:28])[C:13]=2[N:14]2[CH2:20][CH2:19][CH2:18][C@H:17]([NH:21][C:22](=[O:27])[C:23]([F:26])([F:25])[F:24])[CH2:16][CH2:15]2)[N:6]=1.[F:38][C:39]1[CH:44]=[C:43](B2OC(C)(C)C(C)(C)O2)[CH:42]=[CH:41][N:40]=1.CC([O-])=O.[K+].C([O-])([O-])=O.[Na+].[Na+]>C(#N)C.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Fe]>[F:38][C:39]1[CH:44]=[C:43]([C:2]2[S:3][C:4]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[C:5]([C:7](=[O:29])[NH:8][C:9]3[CH:10]=[N:11][N:12]([CH3:28])[C:13]=3[N:14]3[CH2:20][CH2:19][CH2:18][C@H:17]([NH:21][C:22](=[O:27])[C:23]([F:26])([F:25])[F:24])[CH2:16][CH2:15]3)[N:6]=2)[CH:42]=[CH:41][N:40]=1

Participants

7

Reactant 4

HCID 10340Sodium CarbonateHCID 517044Potassium AcetateHCID 120601642-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridineHCID 86680137tert-butyl N-[2-bromo-4-[[1-methyl-5-[(4S)-4-[(2,2,2-trifluoroacetyl)amino]azepan-1-yl]pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate

Product 1

HCID 86680136tert-butyl N-[2-(2-fluoro-4-pyridyl)-4-[[1-methyl-5-[(4S)-4-[(2,2,2-trifluoroacetyl)amino]azepan-1-yl]pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamateYield 59.8%

Reagents, catalysts & solvents 2

HCID 178477754HCID 178477754, compoundCatalystHCID 6342AcetonitrileSolvent

Procedure

In a microwave reaction vial, tert-butyl N-[2-bromo-4-[[1-methyl-5-[(4S)-4-[(2,2,2-trifluoroacetyl)amino]azepan-1-yl]pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate (100 mg, 0.16 mmol), 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (110 mg, 0.49 mmol) and PD(DPPF)CL2 (12 mg, 0.016 mmol) were dissolved in acetonitrile (3 mL). 1.0M KOAc (0.25 mL, 0.25 mmol) and 1.0M Na2CO3 (0.25 mL, 0.25 mmol) were added and the reaction was irradiated with microwave at 120° C. for 30 min. The mixture was cooled, filtered through Celite, concentrated and purified via flash chromatography, EA/heptane 0% to 100% to afford tert-butyl N-[2-(2-fluoro-4-pyridyl)-4-[[1-methyl-5-[(4S)-4-[(2,2,2-trifluoroacetyl)amino]azepan-1-yl]pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate (60 mg, 58%). This compound was stirred with 4N HCl in dioxane (3 mL, 12 mmol) and methanol (2 mL) at room temperature for 3 h. Solvent was removed under reduced pressure. The residue was dissolved in methanol (3 mL) and water (1 mL), potassium carbonate (67 mg, 0.48 mmol) was added and the mixture was heated at 60° C. for 1.5 h. After cooling to room temperature, the reaction mixture was diluted with water and extracted with EA 3×. The combined organic layers were dried over MgSO4 and the solvent removed under reduced pressure and the residue purified by preparative HPLC to afford 417. 1H NMR (400 MHz, DMSO) δ 9.04 (s, 1H), 8.29 (d, J=5.3 Hz, 1H), 7.74 (d, J=5.3 Hz, 3H), 7.59 (s, 1H), 7.42 (s, 1H), 3.66 (s, 3H), 3.24-3.01 (m, 5H), 1.94-1.73 (m, 3H), 1.67-1.48 (m, 3H). LCMS (ES+) m/z 431 (M+1)

Workup

  1. customIn a microwave reaction vial
  2. customthe reaction was irradiated with microwave at 120° C. for 30 min
  3. temperatureThe mixture was cooled
  4. filtrationfiltered through Celite
  5. concentrationconcentrated
  6. custompurified via flash chromatography, EA/heptane 0% to 100%

Sources & evidence

ORD record
ord-dd4c1bf91ffc43a6a2846841b1bd50d4
Source dataset
uspto-grants-2013_12
Patent number
US08614206B2

Reaction notes

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