Potassium Carbonate → 3-{3-[(benzyloxy)carbonyl]phenyl}-6-[4-fluoro-3-(methoxycarbonyl)phenyl]-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid

HRID 575000Notes

Reaction equation

HRID 575000 reaction equation
O.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=C(S([O-])(=O)=O)C=2OC)CCCCC1.[Na+].[F:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]2[CH:44]=[C:45]([C:59]([OH:61])=[O:60])[C:46]3[C:51](I)=[N:50][N:49]([CH:53]4[CH2:58][CH2:57][CH2:56][CH2:55][O:54]4)[C:47]=3[N:48]=2)=[CH:39][C:38]=1[C:62]([O:64][CH3:65])=[O:63].CC1(C)C(C)(C)OB([C:74]2[CH:75]=[C:76]([CH:87]=[CH:88][CH:89]=2)[C:77]([O:79][CH2:80][C:81]2[CH:86]=[CH:85][CH:84]=[CH:83][CH:82]=2)=[O:78])O1.C(=O)([O-])[O-].[K+].[K+].C([O-])(O)=O.[Na+]>CN(C=O)C.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]>[CH2:80]([O:79][C:77]([C:76]1[CH:75]=[C:74]([C:51]2[C:46]3[C:45]([C:59]([OH:61])=[O:60])=[CH:44][C:43]([C:40]4[CH:41]=[CH:42][C:37]([F:36])=[C:38]([C:62]([O:64][CH3:65])=[O:63])[CH:39]=4)=[N:48][C:47]=3[N:49]([CH:53]3[CH2:58][CH2:57][CH2:56][CH2:55][O:54]3)[N:50]=2)[CH:89]=[CH:88][CH:87]=1)=[O:78])[C:81]1[CH:82]=[CH:83][CH:84]=[CH:85][CH:86]=1

Participants

8

Reactant 5

HCID 11430Potassium CarbonateHCID 516892Sodium BicarbonateHCID 17750214Benzyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoateHCID 23693092Sodium 2'-(dicyclohexylphosphanyl)-2,6-dimethoxy(1,1'-biphenyl)-3-sulfonate--water (1/1/1)HCID 1177781086-[4-fluoro-3-(methoxycarbonyl)phenyl]-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid

Product 1

HCID 1177779033-{3-[(benzyloxy)carbonyl]phenyl}-6-[4-fluoro-3-(methoxycarbonyl)phenyl]-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acidYield 72%

Reagents, catalysts & solvents 2

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
95 °C

Procedure

The ligand sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′-biphenyl-3-sulphonate hydrate (146 mg/0.3 mmol) and the catalyst PdCl2(dppf) (280 mg/0.36 mmol) are added successively, under argon, to a suspension of 6-[4-fluoro-3-(methoxycarbonyl)phenyl]-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid [described in Step 1.7.] (1.5 g/3 mmol), benzyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate [880157-10-8] (1.16 g/3.4 mmol) and potassium carbonate (828 mg/6.0 mmol) in 9.5 mL of DMF. The reaction mixture is heated at 95° C. for 1 h. It is run into a saturated aqueous solution of NaHCO3 and extracted with EtOAc. The organic phase is washed with water and with a saturated aqueous solution of NaCl, dried over sodium sulphate, filtered and concentrated to dryness. After purification by flash chromatography on silica (DCM/EtOH 0.1% TEA: 100/0 to 90/10), 1.31 g of a yellow solid are obtained (triethylamine salt; yield: 72%).

Workup

  1. extractionextracted with EtOAc
  2. washThe organic phase is washed with water and with a saturated aqueous solution of NaCl
  3. dry with materialdried over sodium sulphate
  4. filtrationfiltered
  5. concentrationconcentrated to dryness
  6. customAfter purification by flash chromatography on silica (DCM/EtOH 0.1% TEA: 100/0 to 90/10), 1.31 g of a yellow solid
  7. customare obtained (triethylamine salt; yield: 72%)

Sources & evidence

ORD record
ord-fe5bc8da9c1a479684750ab93e357bec
Source dataset
uspto-grants-2015_05
Patent number
US09034898B2

Reaction notes

Loading…