Nitrogen → HCID 86731020, compound

HRID 1852486Notes

Reaction equation

HRID 1852486 reaction equation
[NH2:1][C:2]1[C:6]([C:7](=[O:9])[NH2:8])=[CH:5][N:4]([CH:10]2[CH2:15][CH2:14][CH:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH:11]2[C:23]#[N:24])[N:3]=1.Br[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1.CC([O-])=O.[K+].C(Cl)(Cl)Cl.CC(C1C=C(C(C)C)C(C2C(P(C(C)(C)C)C(C)(C)C)=CC=CC=2)=C(C(C)C)C=1)C.N#N>C(O)(C)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:7]([C:6]1[C:2]([NH:1][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)=[N:3][N:4]([CH:10]2[CH2:15][CH2:14][CH:13]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[CH2:12][CH:11]2[C:23]#[N:24])[CH:5]=1)(=[O:9])[NH2:8]

Participants

9

Reactant 6

HCID 947NitrogenHCID 6212ChloroformHCID 7806p-BromochlorobenzeneHCID 517044Potassium AcetateHCID 11618717Di-tert-butyl(2',4',6'-tris(propan-2-yl)-(1,1'-biphenyl)-2-yl)phosphaneHCID 86731021HCID 86731021, compound

Product 1

HCID 86731020HCID 86731020, compound

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 3776IsopropanolSolvent

Conditions

Temperature
85 °C

Procedure

A solution of (1S,3S,4S and 1R,3R,4R)-t-butyl 4-(3-amino-4-carbamoyl-1H-pyrazol-1-yl)-3-cyanocyclohexane-1-carboxylate (Intermediate #47-4, 11 g, 33 mmol), 1-bromo-4-chlorobenzene (9.2 g, 48 mmol), KOAc (9.4 g, 96 mmol), Pd2(dba)3.CHCl3 (4.9 g, 5.0 mmol) and t-Butyl X-Phos (4.1 g, 10 mmol) in iso-propanol (100 mL) was degassed with bubbling N2 gas for 15 minutes and then stirred at 85° C. under nitrogen for 16 hours, and then concentrated in vacuo. The crude residue was purified by MPLC on Silica gel (eluting with 1-2% MeOH/DCM). Desired fractions were identified, combined, and concentrated in vacuo. The residue was further purified by reverse-phase preparative HPLC (using a gradient elution of 40-60% MeCN/water with 0.5% ammonia in 20) to afford the title compound. 1H NMR (400 MHz, CD3OD) δ 8.13 (s, 1H), 7.54 (d, J=9.2 Hz, 2H), 7.24 (d, J=8.8 Hz, 2H), 4.32-4.30 (m, 1H), 3.49-3.42 (m, 1H), 2.51-2.47 (m, 2H), 2.20-2.13 (m, 3H), 1.95-1.82 (m, 1H), 1.66-1.59 (m, 1H), 1.50 (s, 9H). MS ESI: [M+H]+ m/z 444.

Workup

  1. concentrationconcentrated in vacuo
  2. customThe crude residue was purified by MPLC on Silica gel (eluting with 1-2% MeOH/DCM)
  3. concentrationconcentrated in vacuo
  4. customThe residue was further purified by reverse-phase preparative HPLC (
  5. washa gradient elution of 40-60% MeCN/water with 0.5% ammonia in 20)

Sources & evidence

ORD record
ord-73593cd4e1214cf4a98079e869e41f87
Source dataset
uspto-grants-2015_02
Patent number
US08962608B2

Reaction notes

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