Hydrochloric Acid → HCID 178509477, compound

HRID 2401725Notes

Reaction equation

HRID 2401725 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:29])[C:9]2[CH:10]=[C:11]([B-](F)(F)F)[S:12][C:13]=2[C:14]2[N:18]=[CH:17][N:16](C3CCCCO3)[N:15]=2)=[CH:4][CH:3]=1.[K+].Br[C:32]1[CH:37]=[CH:36][N:35]=[C:34]([C:38]#[N:39])[CH:33]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC(C)C)=CC=CC=2OC(C)C)CCCCC1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C.O1CCOCC1.C(O)(C)(C)C.Cl>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:29])[C:9]2[CH:10]=[C:11]([C:32]3[CH:37]=[CH:36][N:35]=[C:34]([C:38]#[N:39])[CH:33]=3)[S:12][C:13]=2[C:14]2[NH:18][CH:17]=[N:16][N:15]=2)=[CH:6][CH:7]=1

Participants

10

Reactant 8

HCID 313Hydrochloric AcidHCID 702EthanolHCID 6386tert-ButanolHCID 10340Sodium CarbonateHCID 312751,4-Dioxane2×HCID 6932834-Bromo-2-cyanopyridineHCID 162179852-Dicyclohexylphosphino-2',6'-diisopropoxybiphenylHCID 87134396potassium (4-((4-chlorophenyl)(hydroxy)methyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)thiophen-2-yl)trifluoroborate

Product 1

HCID 178509477HCID 178509477, compoundYield 11.4%

Reagents, catalysts & solvents 1

HCID 167845palladium(II) acetateCatalyst

Conditions

Temperature
85 °C

Procedure

A mixture of potassium (4-((4-chlorophenyl)(hydroxy)methyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)thiophen-2-yl)trifluoroborate (0.133 g, 0.276 mmol), 4-bromo-pyridine-2-carbonitrile (60.6 mg, 0.331 mmol), 2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl (24.8 mg, 0.0533 mmol), palladium acetate (4.6 mg, 0.020 mmol) and sodium carbonate (77 mg, 0.73 mmol) in ethanol (6.2 mL, 110 mmol) was degassed with argon and then heated at 85° C. for 13 h. The mixture was absorbed on silica gel and purified by chromatography to afford an intermediate. LCMS: (AA) ES+ 478.1, 480.0. This intermediate in 1,4-dioxane (2.0 mL, 26 mmol), tert-butyl alcohol (2.0 mL, 21 mmol) and 4.00 M HCl in dioxane (3.0 mL, 14 mmol) was heated at 60° C. for 1 h. The mixture was evaporated to dryness and then purified by HPLC to afford 4-(4-((4-chlorophenyl)(hydroxy)methyl)-5-(4H-1,2,4-triazol-3-yl)thiophen-2-yl)picolinonitrile (12.4 mg, 11.4%). LCMS: (FA) ES+ 394.3, 396.1. 1H NMR (400 MHz, d6-DMSO) δ: 14.69-13.48 (br, 1H), 8.69 (d, J=6.79 Hz, 2H), 8.45 (s, 1H), 8.08-7.88 (m, 2H), 7.56 (d, J=8.39 Hz, 2H), 7.35 (d, J=8.40 Hz, 2H), 6.79 (s, 1H).

Workup

  1. customwas degassed with argon
  2. customThe mixture was absorbed on silica gel
  3. custompurified by chromatography
  4. customto afford an intermediate
  5. customThe mixture was evaporated to dryness
  6. custompurified by HPLC

Sources & evidence

ORD record
ord-e57ad7bf2cfa468ca3f229ace0dcc750
Source dataset
uspto-grants-2014_08
Patent number
US08796268B2

Reaction notes

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