3,4-dihydro-2H-pyran → 6-[4-fluoro-3-(methoxycarbonyl)phenyl]-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid

HRID 574997Notes

Reaction equation

HRID 574997 reaction equation
[O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.C([N:14]1[C:18]2[N:19]=[C:20]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[C:28]([C:33]([O:35][CH3:36])=[O:34])[CH:27]=3)[CH:21]=[C:22]([C:23]([OH:25])=[O:24])[C:17]=2[C:16]([I:37])=[N:15]1)C1C=CC=CC=1.OS([O-])(=O)=O.[K+].C(N(CC)CC)C>C(Cl)Cl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[F:32][C:29]1[CH:30]=[CH:31][C:26]([C:20]2[CH:21]=[C:22]([C:23]([OH:25])=[O:24])[C:17]3[C:16]([I:37])=[N:15][N:14]([CH:6]4[CH2:5][CH2:4][CH2:3][CH2:2][O:1]4)[C:18]=3[N:19]=2)=[CH:27][C:28]=1[C:33]([O:35][CH3:36])=[O:34]

Participants

7

Reactant 4

HCID 80803,4-dihydro-2H-pyranHCID 8471TriethylamineHCID 516920Potassium bisulfateHCID 1177779471-benzyl-6-[4-fluoro-3-(methoxycarbonyl)phenyl]-3-iodo-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid

Product 1

HCID 1177781086-[4-fluoro-3-(methoxycarbonyl)phenyl]-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acidYield 82%

Reagents, catalysts & solvents 2

HCID 6101p-Toluenesulfonic acidCatalystHCID 6344DichloromethaneSolvent3×

Procedure

para-Toluenesulphonic acid (38 mg/0.20 mmol) and 3,4-dihydro-2H-pyran (2.75 mL/30.1 mmol) are added successively to a solution of 1-benzyl-6-[4-fluoro-3-(methoxycarbonyl)phenyl]-3-iodo-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (4.43 g/10.0 mmol) in 50 mL of DCM. The solution is stirred at ambient temperature for 12 hours. The reaction medium is run into a solution of KHSO4 (1 M) 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. The brown gum obtained is dissolved in 75 mL of DCM and added to the TEA scavenger resin (FL-TEA, Polymerlab, Variant, 3.53 mmol/g) (3.3 g/11 mmol). After stirring at ambient temperature for 2 h, the resin is filtered and washed with DCM. After drying under vacuum, the resin is then stirred for 20 minutes in a solution of triethylamine (2.6 mL/18 mmol) in 90 mL of DCM and then filtered and rinsed with DCM. The filtrate is acidified with a solution of KHSO4 (1 M). After extraction 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 to give 4.3 g of an orange powder (yield: 82%).

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. customThe brown gum obtained
  7. stirringAfter stirring at ambient temperature for 2 h
  8. filtrationthe resin is filtered
  9. washwashed with DCM
  10. customAfter drying under vacuum
  11. filtrationfiltered
  12. washrinsed with DCM
  13. extractionAfter extraction with EtOAc
  14. washthe organic phase is washed with water and with a saturated aqueous solution of NaCl
  15. dry with materialdried over sodium sulphate
  16. filtrationfiltered
  17. concentrationconcentrated to dryness

Sources & evidence

ORD record
ord-a1ceeefcb00d484f932b8dc8ffd15875
Source dataset
uspto-grants-2015_05
Patent number
US09034898B2

Reaction notes

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