Citric Acid → 3-chloro-2-hydroxy-5-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-benzoic acid

HRID 1865625Notes

Reaction equation

HRID 1865625 reaction equation
[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15](B3OC(C)(C)C(C)(C)O3)[CH:16]=2)[N:11]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[N:10]=1.C[O:36][C:37](=[O:47])[C:38]1[CH:43]=[C:42](Br)[CH:41]=[C:40]([Cl:45])[C:39]=1[OH:46].C(=O)(O)[O-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe].C(OCC)(=O)C.C(#N)C>[Cl:45][C:40]1[C:39]([OH:46])=[C:38]([CH:43]=[C:42]([C:15]2[CH:16]=[C:17]3[C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])=[N:10][N:11]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:32])([CH3:34])[CH3:33])[C:12]3=[N:13][CH:14]=2)[CH:41]=1)[C:37]([OH:36])=[O:47]

Participants

8

Reactant 4

HCID 311Citric AcidHCID 257466Methyl 5-bromo-3-chloro-2-hydroxybenzoateHCID 516892Sodium BicarbonateHCID 598360923-(2-methoxy-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(2-trimethylsilanyl-ethoxy-methyl)-1H-pyrazolo[3,4-b]pyridine

Product 1

HCID 579757203-chloro-2-hydroxy-5-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-benzoic acidYield 55.4%

Reagents, catalysts & solvents 3

HCID 53485975CID 53485975CatalystHCID 6342AcetonitrileSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
75 °C

Procedure

400 mg (0.83 mmol) of 3-(2-methoxy-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridine, 265 mg (1.00 mmol) of 5-bromo-3-chloro-2-hydroxy-benzoic acid methyl ester and 34 mg (41 μmol) of dichloro[1,1′-bis(diphenylphoshino)ferrocene]palladium(II) dichloromethane adduct were placed in a vial. 8 mL of acetonitrile and 8 mL of a saturated aqueous solution of sodium bicarbonate were added. The vial was closed and the mixture heated to 75° C. for 17 h. The crude mixture was distributed between ethyl acetate and 10% aqueous citric acid. The aqueous layer was extracted twice with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate and evaporated. The crude was purified by flash chromatography on silica gel using a gradient of ethyl acetate containing 15% of methanol in hexanes to afford 241 mg (0.46 mmol, 55%) of 3-chloro-2-hydroxy-5-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-benzoic acid as a brown oil. 1H NMR (500 MHz, DMSO-d6) δ 8.89 (d, 1H), 8.36 (d, 1H), 8.12 (d, 1H), 8.07 (d, 1H), 7.64 (dd, 1H), 7.50 (ddd, 1H), 7.24 (d(d), 1H), 7.11 (ddd, 1H), 5.85 (s, 2H), 3.84 (s, 3H), 3.70 (t, 2H), 0.86 (t, 2H), −0.08 (s, 9H), MS: m/z 526.1 (M+H+), 548.1 (M+Na+).

Workup

  1. customThe vial was closed
  2. extractionThe aqueous layer was extracted twice with ethyl acetate
  3. washThe combined organic phases were washed with brine
  4. dry with materialdried over sodium sulfate
  5. customevaporated
  6. customThe crude was purified by flash chromatography on silica gel using a gradient of ethyl acetate containing 15% of methanol in hexanes

Sources & evidence

ORD record
ord-ac81cc78375944ed8a256b064d904b10
Source dataset
uspto-grants-2009_12
Patent number
US07626021B2

Reaction notes

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