Methanol → HCID 53469452, compound

HRID 1909977Notes

Reaction equation

HRID 1909977 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][C:10]([N:12]1[C:20]2[C:15](=[CH:16][C:17]([C:21]3[C:25]4[C:26]([NH2:31])=[N:27][CH:28]=[C:29](I)[C:24]=4[O:23][CH:22]=3)=[CH:18][CH:19]=2)[CH2:14][CH2:13]1)=[O:11].C([N:39]1[CH:43]=[C:42](B2OC(C)(C)C(C)(C)O2)[CH:41]=[N:40]1)(OC(C)(C)C)=O.C(=O)(O)[O-].[Na+].CO>O1CCOCC1.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].C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][C:10]([N:12]1[C:20]2[C:15](=[CH:16][C:17]([C:21]3[C:25]4[C:26]([NH2:31])=[N:27][CH:28]=[C:29]([C:42]5[CH:43]=[N:39][NH:40][CH:41]=5)[C:24]=4[O:23][CH:22]=3)=[CH:18][CH:19]=2)[CH2:14][CH2:13]1)=[O:11]

Participants

8

Reactant 4

HCID 887MethanolHCID 516892Sodium BicarbonateHCID 16217654tert-butyl 4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylateHCID 66823738HCID 66823738, compound

Product 1

HCID 53469452HCID 53469452, compoundYield 91.4%

Reagents, catalysts & solvents 3

HCID 178418807HCID 178418807, compoundCatalystHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
120 °C

Procedure

A mixture of 3-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7-iodofuro[3,2-c]pyridin-4-amine (142 mg, 0.267 mmol), 1-Boc-pyrazol-4-boronic acid pinacol ester (118 mg, 0.401 mmol), and PdCl2(dppf)-CH2Cl2 adduct (13 mg, 0.016 mmol) in 1,4-Dioxane (3 mL) and saturated aqueous sodium bicarbonate (0.80 mL, 0.800 mmol) was degassed with Nitrogen for 10 minutes in a microwave vial. The vial was then capped and the mixture was stirred at 120° C. in the microwave for 30 min. LCMS showed complete conversion to the de-Boc product. The mixture was cooled, poured into half-saturated aqueous NaHCO3 (25 mL), and extracted with ethyl acetate (2×25 mL). The extracts were washed with brine (1×25 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography (Analogix, 24 g SiO2, 50%-100% EtOAc in hexanes gradient over 10 minutes, then EtOAc for 5 minutes, then 0-10% MeOH in EtOAc over 20 minutes) to give 3-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7-(1H-pyrazol-4-yl)furo[3,2-c]pyridin-4-amine (121 mg, 0.244 mmol, 91% yield) as a white solid. LC/MS (ES) m/z=472 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 3.29 (t, J=8.34 Hz, 2H), 3.97 (s, 2H), 4.31 (t, J=8.46 Hz, 2H), 5.49 (s, 2H), 7.15-7.30 (m, 3H), 7.33 (d, J=8.08 Hz, 1H), 7.44 (s, 1H), 7.99-8.10 (m, 2H), 8.13 (d, J=8.08 Hz, 1H), 8.17-8.29 (m, 2H), 13.01 (br. s., 1H).

Workup

  1. customwas degassed with Nitrogen for 10 minutes in a microwave vial
  2. customThe vial was then capped
  3. temperatureThe mixture was cooled
  4. additionpoured into half-saturated aqueous NaHCO3 (25 mL)
  5. extractionextracted with ethyl acetate (2×25 mL)
  6. washThe extracts were washed with brine (1×25 mL)
  7. dry with materialdried (Na2SO4)
  8. filtrationfiltered
  9. concentrationconcentrated in vacuo
  10. customThe residue was purified by flash chromatography (Analogix, 24 g SiO2, 50%-100% EtOAc in hexanes
  11. waitgradient over 10 minutes
  12. waitEtOAc for 5 minutes

Sources & evidence

ORD record
ord-afa410a20f0647978d6ed1976844d264
Source dataset
uspto-grants-2013_12
Patent number
US08598156B2

Reaction notes

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