Sodium Carbonate → tert-Butyl {(1R,2R)-2-[({4-[6-(difluoromethoxy)pyrazolo[1,5-a]pyrimidin-3-yl]-5-ethylthiophen-2-yl}carbonyl)amino]-3,3-difluorocyclohexyl}carbamate

HRID 1842610Notes

Reaction equation

HRID 1842610 reaction equation
Br[C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[C:9]([O:11][CH:12]([F:14])[F:13])[CH:8]=[N:7][C:6]=12.[C:15]([O:19][C:20](=[O:49])[NH:21][C@@H:22]1[CH2:27][CH2:26][CH2:25][C:24]([F:29])([F:28])[C@@H:23]1[NH:30][C:31]([C:33]1[S:34][C:35]([CH2:47][CH3:48])=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:37]=1)=[O:32])([CH3:18])([CH3:17])[CH3:16].C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C>[C:15]([O:19][C:20](=[O:49])[NH:21][C@@H:22]1[CH2:27][CH2:26][CH2:25][C:24]([F:29])([F:28])[C@@H:23]1[NH:30][C:31]([C:33]1[S:34][C:35]([CH2:47][CH3:48])=[C:36]([C:2]2[CH:3]=[N:4][N:5]3[CH:10]=[C:9]([O:11][CH:12]([F:14])[F:13])[CH:8]=[N:7][C:6]=23)[CH:37]=1)=[O:32])([CH3:18])([CH3:17])[CH3:16]

Participants

6

Reactant 3

HCID 10340Sodium CarbonateHCID 673254323-Bromo-6-(difluoromethoxy)pyrazolo[1,5-a]pyrimidineHCID 89750975tert-Butyl[(1R,2R)-2-({[5-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophen-2-yl]carbonyl}amino)-3,3-difluorocyclohexyl]carbamate

Product 1

HCID 68304376tert-Butyl {(1R,2R)-2-[({4-[6-(difluoromethoxy)pyrazolo[1,5-a]pyrimidin-3-yl]-5-ethylthiophen-2-yl}carbonyl)amino]-3,3-difluorocyclohexyl}carbamateYield 56.1%

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
85 °C

Procedure

3-Bromo-6-(difluoromethoxy)pyrazolo[1,5-a]pyrimidine (0.030 g, 0.114 mmol), tert-butyl[(1R,2R)-2-({[5-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophen-2-yl]carbonyl}amino)-3,3-difluorocyclohexyl]carbamate (0.059 g, 0.115 mmol), Pd(PPh3)4 (6.57 mg, 0.007 mmol), and 2 M Na2CO3 (aq) (0.170 mL, 0.341 mmol) were placed in a sealed tube and DMF (1.14 mL) added. The mixture was purged with N2 for 5 min. The reaction was heated to 85° C. for 16 h. The mixture was cooled to room temperature, diluted with dichloromethane, and washed twice with saturated sodium bicarbonate (aq) and once with brine. The organic layer was dried with sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (0-70% EtOAc/Hex) to give the title compound (0.037 g, 0.064 mmol). LRMS (APCI) calc'd for (C25H29F4N5O4S) [M+H]+, 572.2; found 572.1.

Workup

  1. customThe mixture was purged with N2 for 5 min
  2. temperatureThe mixture was cooled to room temperature
  3. additiondiluted with dichloromethane
  4. washwashed twice with saturated sodium bicarbonate (aq) and once with brine
  5. dry with materialThe organic layer was dried with sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated under reduced pressure
  8. customThe crude product was purified by column chromatography (0-70% EtOAc/Hex)

Sources & evidence

ORD record
ord-9a053bb8a9e34136b024e380d4c5514c
Source dataset
uspto-grants-2015_02
Patent number
US08946237B2

Reaction notes

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