Methanol → HCID 53469634, compound

HRID 1909931Notes

Reaction equation

HRID 1909931 reaction equation
I[C:2]1[C:3]2[S:11][CH:10]=[C:9]([C:12]3[CH:13]=[C:14]4[C:18](=[CH:19][CH:20]=3)[N:17]([C:21](=[O:29])[CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:16][CH2:15]4)[C:4]=2[C:5]([NH2:8])=[N:6][CH:7]=1.C([N:37]1[CH:41]=[C:40](B2OC(C)(C)C(C)(C)O2)[CH:39]=[N:38]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>[C:23]1([CH2:22][C:21]([N:17]2[C:18]3[C:14](=[CH:13][C:12]([C:9]4[C:4]5[C:5]([NH2:8])=[N:6][CH:7]=[C:2]([C:40]6[CH:41]=[N:37][NH:38][CH:39]=6)[C:3]=5[S:11][CH:10]=4)=[CH:20][CH:19]=3)[CH2:15][CH2:16]2)=[O:29])[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1

Participants

8

Reactant 4

HCID 887MethanolHCID 516892Sodium BicarbonateHCID 16217654tert-butyl 4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylateHCID 66561009HCID 66561009, compound

Product 1

HCID 53469634HCID 53469634, compoundYield 53.3%

Reagents, catalysts & solvents 3

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

Conditions

Temperature
120 °C

Procedure

A mixture of 7-iodo-3-[1-(phenylacetyl)-2,3-dihydro-1H-indol-5-yl]thieno[3,2-c]pyridin-4-amine (101 mg, 0.198 mmol), 1-Boc-pyrazol-4-boronic acid pinacol ester (88 mg, 0.299 mmol), and PdCl2(dppf)-CH2Cl2 adduct (9 mg, 0.011 mmol) in 1,4-Dioxane (2.0 mL) and saturated aqueous sodium bicarbonate (0.6 mL, 0.600 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 water (15 mL), and extracted with ethyl acetate (2×15 mL). The extracts were washed with brine (1×15 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 15 minutes, then EtOAc for 5 minutes, then 0-10% MeOH in EtOAc over 20 minutes) to give 3-[1-(phenylacetyl)-2,3-dihydro-1H-indol-5-yl]-7-(1H-pyrazol-4-yl)thieno[3,2-c]pyridin-4-amine (50 mg, 0.105 mmol, 53.3% yield) as a light gray solid. LC/MS (ES) m/z=452 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 3.24 (t, J=8.34 Hz, 2H), 3.89 (s, 2H), 4.26 (t, J=8.46 Hz, 2H), 5.40 (br. s., 2H), 7.22-7.30 (m, 2H), 7.30-7.40 (m, 5H), 7.48 (s, 1H), 7.95 (br. s., 1H), 8.06 (s, 1H), 8.12-8.21 (m, 2H), 13.10 (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 water (15 mL)
  5. extractionextracted with ethyl acetate (2×15 mL)
  6. washThe extracts were washed with brine (1×15 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 15 minutes
  12. waitEtOAc for 5 minutes

Sources & evidence

ORD record
ord-8fe05940dd6c4f9693c4ef0ca36865e1
Source dataset
uspto-grants-2013_12
Patent number
US08598156B2

Reaction notes

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