Potassium Phosphate, Tribasic → tert-butyl 4-(2-(isoquinolin-5-yl)-5-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate

HRID 2172288Notes

Reaction equation

HRID 2172288 reaction equation
B1(C2CCN(C(OC(C)(C)C)=O)CC=2)OC(C)(C)C(C)(C)O1.BrC1C=CC(C(F)(F)F)=CC=1I.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:44]1[CH:49]=[CH:48][C:47]([C:50]([F:53])([F:52])[F:51])=[CH:46][C:45]=1[C:54]1[CH2:59][CH2:58][N:57]([C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])[CH2:56][CH:55]=1.[CH:67]1[C:76]2[C:71](=[C:72](B(O)O)[CH:73]=[CH:74][CH:75]=2)[CH:70]=[CH:69][N:68]=1>O1CCOCC1.O.C(OCC)C>[CH:67]1[C:76]2[C:71](=[C:72]([C:44]3[CH:49]=[CH:48][C:47]([C:50]([F:53])([F:52])[F:51])=[CH:46][C:45]=3[C:54]3[CH2:59][CH2:58][N:57]([C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])[CH2:56][CH:55]=3)[CH:73]=[CH:74][CH:75]=2)[CH:70]=[CH:69][N:68]=1

Participants

9

Reactant 5

HCID 62657Potassium Phosphate, TribasicHCID 599474Isoquinoline-5-boronic acidHCID 4642098Tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine-1-carboxylateHCID 467352311-Bromo-2-iodo-4-(trifluoromethyl)benzeneHCID 71259576tert-butyl 4-(2-bromo-5-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate

Product 1

HCID 89813602tert-butyl 4-(2-(isoquinolin-5-yl)-5-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 3283Diethyl EtherSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

A solution of Cl2Pd(dppf)-CH2Cl2 adduct (Strem Chemicals Inc., Newburyport, Mass., 1.157 g, 1.416 mmol), (n-tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (Maybridge Chemicals, Cornwall, UK, 8.76 ml, 28.3 mmol), 1-bromo-2-iodo-4-(trifluoromethyl)benzene (Combi-Blocks, San Diego, Calif., 9.94 g, 28.3 mmol), and potassium phosphate (36.1 g, 170 mmol) in 100 mL dioxane and 40 mL water was heated to 100° C. for 3 hours. LC/MS showed clean conversion to tert-butyl 4-(2-bromo-5-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate. To the resulting mixture was added isoquinolin-5-ylboronic acid (Sigma-Aldrich, St. Louis, Mo., 4.90 g, 28.3 mmol) and Cl2Pd(AmPhos) (Sigma-Aldrich, St. Louis, Mo., 1.003 g, 1.416 mmol). The reaction mixture was again heated to 100° C. an additional hour before the reaction mixture was allowed to cool to room temperature and was diluted with diethyl ether. The organics were washed with water, then brine, dried over MgSO4 and concentrated. Purification of the resulting residue by silica gel column chromatography (0 to 100% EtOAc/heptane) gave tert-butyl 4-(2-(isoquinolin-5-yl)-5-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (9.80 g, 21.56 mmol).

Workup

  1. temperatureto cool to room temperature
  2. washThe organics were washed with water
  3. dry with materialbrine, dried over MgSO4
  4. concentrationconcentrated
  5. customPurification of the resulting residue by silica gel column chromatography (0 to 100% EtOAc/heptane)

Sources & evidence

ORD record
ord-32dc4fd039c74cab9932372758a776e2
Source dataset
uspto-grants-2015_06
Patent number
US09051311B2

Reaction notes

Loading…