Acetonitrile → 2,2-Dimethyl-propionic acid 5-{3-[hydroxy-(3-trifluoromethyl-pyridin-2-yl)-methyl]-phenyl}-3-(2-methoxy-phenyl)-pyrazolo[3,4-b]pyridin-1-ylmethyl ester

HRID 886577Notes

Reaction equation

HRID 886577 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][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])[N:10]=1.Br[C:36]1[CH:37]=[C:38]([CH:42]([C:44]2[C:49]([C:50]([F:53])([F:52])[F:51])=[CH:48][CH:47]=[CH:46][N:45]=2)[OH:43])[CH:39]=[CH:40][CH:41]=1.C(#N)C.C(=O)(O)[O-].[Na+]>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].ClCCl.C1(C)C=CC=CC=1>[OH:43][CH:42]([C:44]1[C:49]([C:50]([F:53])([F:51])[F:52])=[CH:48][CH:47]=[CH:46][N:45]=1)[C:38]1[CH:37]=[C:36]([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][C:29](=[O:34])[C:30]([CH3:31])([CH3:32])[CH3:33])[C:12]3=[N:13][CH:14]=2)[CH:41]=[CH:40][CH:39]=1

Participants

8

Reactant 4

HCID 6342AcetonitrileHCID 516892Sodium Bicarbonate2×HCID 59824996(3-Bromo-phenyl)-(3-trifluoromethyl-pyridin-2-yl)-methanolHCID 598250492,2-Dimethyl-propionic acid 3-(2-methoxy-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazolo[3,4-b]pyridin-1-ylmethyl ester

Product 1

HCID 598250482,2-Dimethyl-propionic acid 5-{3-[hydroxy-(3-trifluoromethyl-pyridin-2-yl)-methyl]-phenyl}-3-(2-methoxy-phenyl)-pyrazolo[3,4-b]pyridin-1-ylmethyl esterYield 66%

Reagents, catalysts & solvents 3

HCID 53485975CID 53485975CatalystHCID 1140TolueneSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
65 °C

Procedure

465 mg (1.00 mmol) of 2,2-dimethyl-propionic acid 3-(2-methoxy-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazolo[3,4-b]pyridin-1-ylmethyl ester, 50 mg (61 μmol) of dichloro[1,1′-bis(diphenyl-phoshino)ferrocene]palladium(II) dichloromethane adduct and 340 mg (1.02 mmol) of (3-bromo-phenyl)-(3-trifluoromethyl-pyridin-2-yl)-methanol were place in a microwave vial. 8 mL of acetonitrile, 3 mL of toluene and 8 mL of a saturated aqueous solution of sodium bicarbonate were added. The vial was sealed and the resulting mixture heated in an oil bath to 65° C. for 22 h. The resulting mixture was distributed between dichloromethane and a saturated aqueous solution of sodium bicarbonate. The aqueous layer was extracted twice with dichloromethane and the combined organic phases were dried over sodium sulfate and evaporated. The resulting residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate in hexanes to afford 388 mg (0.66 mmol, 66%) of 2,2-dimethyl-propionic acid 5-{3-[hydroxy-(3-trifluoromethyl-pyridin-2-yl)-methyl]-phenyl}-3-(2-methoxy-phenyl)-pyrazolo[3,4-b]pyridin-1-ylmethyl ester as a beige solid. 1H NMR (500 MHz, DMSO-d6) α 8.90 (d, 1H), 8.86 (d, 1H), 8.34 (d, 1H), 8.20 (d(d), 1H), 7.81 (s, 1H), 7.67-7.64 (m, 2H), 7.56-7.50 (m, 2H), 7.45 (t, 1H), 7.39 (d, 1H), 7.27 (d, 1H), 7.13 (t, 1H), 6.51 (s, 2H), 6.26 (d, 1H), 6.11 (d, 1H), 3.86 (s, 3H), 1.12 (s, 9H); MS: m/z 591.1 (M+H+), 613.1 (M+Na+).

Workup

  1. customThe vial was sealed
  2. extractionThe aqueous layer was extracted twice with dichloromethane
  3. dry with materialthe combined organic phases were dried over sodium sulfate
  4. customevaporated
  5. customThe resulting residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate in hexanes

Sources & evidence

ORD record
ord-9d94e08a2dc74580bf148291ec2df55c
Source dataset
uspto-grants-2012_08
Patent number
US08242280B2

Reaction notes

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