Sodium Bicarbonate → 2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)-N-((S)-2-(3,5-difluorophenyl)-1-(6-(3-hydroxy-3-methylazetidin-1-yl)-3-(1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)pyridin-2-yl)ethyl)acetamide

HRID 2170380Notes

Reaction equation

HRID 2170380 reaction equation
Br[C:2]1[C:3]([C@@H:14]([NH:24][C:25](=[O:41])[CH2:26][N:27]2[C:31]3[C:32]([F:37])([F:36])[C@@H:33]4[CH2:35][C@@H:34]4[C:30]=3[C:29]([CH:38]([F:40])[F:39])=[N:28]2)[CH2:15][C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=2)=[N:4][C:5]([N:8]2[CH2:11][C:10]([OH:13])([CH3:12])[CH2:9]2)=[CH:6][CH:7]=1.[CH3:42][N:43]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][C:50]=2B2OC(C)(C)C(C)(C)O2)[C:45]([NH:61][S:62]([CH3:65])(=[O:64])=[O:63])=[N:44]1.C(=O)(O)[O-].[Na+]>C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.Cl[Pd]Cl.O1CCOCC1>[F:40][CH:38]([F:39])[C:29]1[C:30]2[C@H:34]3[CH2:35][C@H:33]3[C:32]([F:37])([F:36])[C:31]=2[N:27]([CH2:26][C:25]([NH:24][C@H:14]([C:3]2[C:2]([C:50]3[CH:49]=[CH:48][CH:47]=[C:46]4[C:51]=3[N:43]([CH3:42])[N:44]=[C:45]4[NH:61][S:62]([CH3:65])(=[O:64])=[O:63])=[CH:7][CH:6]=[C:5]([N:8]3[CH2:9][C:10]([OH:13])([CH3:12])[CH2:11]3)[N:4]=2)[CH2:15][C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=2)=[O:41])[N:28]=1

Participants

6

Reactant 3

HCID 516892Sodium BicarbonateHCID 90281188N-((S)-1-(3-bromo-6-(3-hydroxy-3-methylazetidin-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamideHCID 90281195N-(1-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-3-yl)methanesulfonamide

Product 1

HCID 902814162-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)-N-((S)-2-(3,5-difluorophenyl)-1-(6-(3-hydroxy-3-methylazetidin-1-yl)-3-(1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)pyridin-2-yl)ethyl)acetamide

Reagents, catalysts & solvents 2

HCID 11050900Dichlorobis(tricyclohexylphosphine)pallium (II)CatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
150 °C

Procedure

In a microwave tube were charged with of N—((S)-1-(3-bromo-6-(3-hydroxy-3-methylazetidin-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide (45 mg, 0.07 mmol), N-(1-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-3-yl)methanesulfonamide (36 mg, 0.1 mmol) and PdCl2[P(Cy)3]2 (5 mg, 0.007 mmol). To the mixture was added 1.4 mL of 1,4-dioxane and 0.2 mL of sodium bicarbonate aqueous solution (1M). The system was purged with argon and then the microwave tube was sealed and the reaction mixture was heated up in a microwave synthesizer at 150° C. for 20 min. After cooled down to room temperature, it was partitioned between EtOAc and water. The organic layer was separated and washed with brine, then dried over MgSO4, filtered and concentrated. The residue was purified by reverse phase HPLC eluting with acetonitrile and water (with 0.1% TFA) to afford the title product. 1H NMR (400 MHz, methanol-d4) δ 7.79 (dd, 1H), 7.51 (dd, 1H), 7.29-6.45 (m, 5H), 6.48-6.24 (m, 2H), 4.85 (m, 3H), 4.19-3.91 (m, 4H), 3.58-2.75 (m, 8H), 2.49 (m, 2H), 1.61 (d, J=2.2 Hz, 3H), 1.41 (q, J=7.0 Hz, 1H), 1.20-0.83 (m, 1H). MS (m/z) 789.11 [M+H]+.

Workup

  1. customThe system was purged with argon
  2. customthe microwave tube was sealed
  3. temperatureAfter cooled down to room temperature
  4. customit was partitioned between EtOAc and water
  5. customThe organic layer was separated
  6. washwashed with brine
  7. dry with materialdried over MgSO4
  8. filtrationfiltered
  9. concentrationconcentrated
  10. customThe residue was purified by reverse phase HPLC
  11. washeluting with acetonitrile and water (with 0.1% TFA)

Sources & evidence

ORD record
ord-ef0ba380fa89414ca98c0965fbfd08b0
Source dataset
uspto-grants-2015_06
Patent number
US09050344B2

Reaction notes

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