2-(4-(Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ol → (2R,3 S,5R)-5-((6-chloro-5-(4'-(2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-yl)-1H-imidazo[4,5-b]pyridin-2-yl)oxy)-2-(hydroxymethyl)tetrahydro-2H-pyran-3-ol

HRID 1050260Notes

Reaction equation

HRID 1050260 reaction equation
CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([C:15]([OH:18])([CH3:17])[CH3:16])=[CH:11][CH:10]=2)O1.Br[C:21]1[CH:26]=[CH:25][C:24]([C:27]2[N:32]=[C:31]3[N:33]=[C:34]([O:36][C@H:37]4[CH2:42][O:41][C@H:40]([CH2:43][OH:44])[C@@H:39]([OH:45])[CH2:38]4)[NH:35][C:30]3=[CH:29][C:28]=2[Cl:46])=[CH:23][CH:22]=1>O1CCOCC1.O.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]>[Cl:46][C:28]1[CH:29]=[C:30]2[NH:35][C:34]([O:36][C@H:37]3[CH2:42][O:41][C@H:40]([CH2:43][OH:44])[C@@H:39]([OH:45])[CH2:38]3)=[N:33][C:31]2=[N:32][C:27]=1[C:24]1[CH:25]=[CH:26][C:21]([C:9]2[CH:10]=[CH:11][C:12]([C:15]([OH:18])([CH3:16])[CH3:17])=[CH:13][CH:14]=2)=[CH:22][CH:23]=1

Participants

7

Reactant 2

HCID 591660132-(4-(Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-olHCID 90044340(2R,3 S,5R)-5-((5-(4-bromophenyl)-6-chloro-1H-imidazo[4,5-b]pyridin-2-yl)oxy)-2-(hydroxymethyl)-tetrahydro-2H-pyran-3-ol

Product 1

HCID 73332558(2R,3 S,5R)-5-((6-chloro-5-(4'-(2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-yl)-1H-imidazo[4,5-b]pyridin-2-yl)oxy)-2-(hydroxymethyl)tetrahydro-2H-pyran-3-ol

Reagents, catalysts & solvents 4

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 962WaterSolvent2×HCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
80 °C

Procedure

2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ol (50.4 mg, 0.192 mmol) and (2R,3 S,5R)-5-((5-(4-bromophenyl)-6-chloro-1H-imidazo[4,5-b]pyridin-2-yl)oxy)-2-(hydroxymethyl)-tetrahydro-2H-pyran-3-ol (70 mg, 0.154 mmol) were dissolved in dioxane (600 μl) and water (600 μl). The reaction mixture was sparged with N2 with 15 min and then [1,1′-Bis(Diphenylphosphino)-Ferrocene]Dichloropalladium (II) (22.53 mg, 0.031 mmol) was added. After stirring 3 h at 80° C., the reaction mixture was diluted with water and EtOAc. The aqueous phase was extracted with EtOAc (×2); and the combined extracts were washed with brine, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by mass directed reverse phase HPLC eluted with acetonitrile in water containing 0.1% formic acid. The desired fractions were combined and lyophilized to give the title compound as a white solid. LC-MS: calculated for C27H28ClN3O5 509.17 observed m/e: 509.87 (M+H)+ (Rt 1.12/2 min); 1H NMR δ (ppm) (CD3OD): 7.82 (s, 1H), 7.72 (s, 4H), 7.66 (d, 2H), 7.59 (d, 2H), 5.11 (septet, 1H), 4.34 (dd, 1H), 3.88 (dd, 1H), 3.66-3.59 (m, 2H), 3.37 (t, 1H), 3.18-3.15 (m, 1H), 2.76-2.74 (m, 1H), 1.68 (q, 1H), 1.58 (s, 6H).

Workup

  1. customThe reaction mixture was sparged with N2 with 15 min
  2. extractionThe aqueous phase was extracted with EtOAc (×2)
  3. washand the combined extracts were washed with brine
  4. dry with materialdried over Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe resulting residue was purified by mass
  8. washeluted with acetonitrile in water containing 0.1% formic acid

Sources & evidence

ORD record
ord-ec60823b1ccc407ea96067378c603a92
Source dataset
uspto-grants-2016_07
Patent number
US09382243B2

Reaction notes

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