Dichloromethane → HCID 71254287, compound

HRID 1775058Notes

Reaction equation

HRID 1775058 reaction equation
Cl[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([C:17]4[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=4)[CH:15]=3)[N:10]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][O:24]3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:37]2[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][CH:38]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+].ClCCl>CCOC(C)=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].CN(C)C=O>[CH3:22][N:20]1[CH:21]=[C:17]([C:14]2[CH:15]=[C:16]3[C:8]([C:6]4[N:7]=[C:2]([C:37]5[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][CH:38]=5)[CH:3]=[CH:4][CH:5]=4)=[N:9][N:10]([CH:23]4[CH2:28][CH2:27][CH2:26][CH2:25][O:24]4)[C:11]3=[CH:12][N:13]=2)[CH:18]=[N:19]1

Participants

8

Reactant 4

HCID 6344DichloromethaneHCID 10796Cesium carbonateHCID 4642098Tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine-1-carboxylateHCID 86676693HCID 86676693, compound

Product 1

HCID 71254287HCID 71254287, compoundYield 35%

Reagents, catalysts & solvents 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
90 °C

Procedure

In a high-pressure vial was placed 3-(6-chloropyridin-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine ((84.1 mg, 0.21 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (197.5 mg, 0.64 mmol), cesium carbonate (346.979 mg, 1.06494 mmol;), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloro-methane (1:1) (17.4 mg, 0.021 mmol), and N,N-Dimethylformamide (2.5 mL). Nitrogen was passed through the mixture for 15 minutes and the vessel was sealed. The reaction mixture was stirred at 90° C. under N2 for 4 days, cooled to RT, and diluted with EtOAc. The reaction mixture was filtered through a pad of Celite®. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and evaporated in vacuo. The crude product was purified using both flash chromatography (Si-PPC gradient elution, solvent: 0-20% methanol in ethyl acetate) and reverse phase HPLC purification to give tert-butyl 4-(6-(5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate as an oil (40.4 mg, 35.0%). 1H NMR (400 MHz, CDCl3) δ 9.12 (s, 1H), 8.72 (s, 1H), 8.08 (d, J=7.8 Hz, 1H), 7.98 (s, 1H), 7.93 (s, 1H), 7.75 (t, J=7.8 Hz, 1H), 7.39 (d, J=7.7 Hz, 1H), 6.79 (s, 1H), 5.87 (dd, J=8.5, 2.0 Hz, 1H), 4.23 (d, J=2.6 Hz, 2H), 4.07-3.96 (m, 1H), 3.98 (s, 3H), 3.85-3.72 (m, 3H), 2.87 (s, 2H), 2.66-2.52 (m, 1H), 2.17 (d, J=9.2 Hz, 2H), 1.90-1.67 (m, 3H), 1.52 (s, 9H). LC/MS: m/z 542.4 [M+1].

Workup

  1. customthe vessel was sealed
  2. temperaturecooled to RT
  3. filtrationThe reaction mixture was filtered through a pad of Celite®
  4. washThe organic layer was washed with water and brine
  5. dry with materialdried over Na2SO4
  6. filtrationfiltered
  7. customevaporated in vacuo
  8. customThe crude product was purified
  9. washboth flash chromatography (Si-PPC gradient elution, solvent: 0-20% methanol in ethyl acetate)
  10. customphase HPLC purification

Sources & evidence

ORD record
ord-5934837272134e07a8376d6bd71d69bd
Source dataset
uspto-grants-2016_02
Patent number
US09260425B2

Reaction notes

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