Picolinic acid → Diethyl 2-(3-(6-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyridin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)malonate

HRID 1775063Notes

Reaction equation

HRID 1775063 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[C:28]4[C:23](=[CH:24][N:25]=[C:26](Br)[CH:27]=4)[N:22]([CH:30]4[CH2:35][CH2:34][CH2:33][CH2:32][O:31]4)[N:21]=3)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:36]([O:42][CH2:43][CH3:44])(=[O:41])[CH2:37][C:38]([O-:40])=[O:39].C(=O)([O-])[O-].[Cs+].[Cs+].N1C=CC=[CH:53][C:52]=1C(O)=O>O1CCOCC1.[Cu]I>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]=[C:16]([C:20]3[C:28]4[C:23](=[CH:24][N:25]=[C:26]([CH:37]([C:38]([O:40][CH2:52][CH3:53])=[O:39])[C:36]([O:42][CH2:43][CH3:44])=[O:41])[CH:27]=4)[N:22]([CH:30]4[CH2:35][CH2:34][CH2:33][CH2:32][O:31]4)[N:21]=3)[CH:17]=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]

Participants

7

Reactant 4

HCID 1018Picolinic acidHCID 10796Cesium carbonateHCID 3595298Propanedioic acid, monoethyl esterHCID 866766914-{6-[5-bromo-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl]-pyridin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester

Product 1

HCID 71253905Diethyl 2-(3-(6-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyridin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)malonateYield 47%

Reagents, catalysts & solvents 2

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of 218 mg (0.40 mmol) of 4-{6-[5-Bromo-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl]-pyridin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester, 1.22 mL (8.02 mmol) of Ethyl malonate, 76 mg (0.40 mmol) of copper(I) iodide, 654 mg (2.006 mmol) of cesium carbonate and 99 mg (0.80 mmol) of picolinic acid in 4.0 ml of 1,4-dioxane was degassed and then heated for 24 hours at 100° C. The mixture was filtered and the filtrate concentrated in vacuum. The residue was partitioned between ethyl acetate and water, the organic extracts were washed consequently with saturated aqueous NaHCO3, 5% aqueous citric acid, water, brine, dried over MgSO4 and concentrated. The residue was purified via silica gel chromatography using a gradient of ethyl acetate in heptane to afford 117 mg (47%) of Diethyl 2-(3-(6-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyridin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)malonate. ESI MS m/z 623.3 (M+1).

Workup

  1. customwas degassed
  2. filtrationThe mixture was filtered
  3. concentrationthe filtrate concentrated in vacuum
  4. customThe residue was partitioned between ethyl acetate and water
  5. washthe organic extracts were washed consequently with saturated aqueous NaHCO3, 5% aqueous citric acid, water, brine
  6. dry with materialdried over MgSO4
  7. concentrationconcentrated
  8. customThe residue was purified via silica gel chromatography

Sources & evidence

ORD record
ord-e6fcd5686e344782b651a3383c889695
Source dataset
uspto-grants-2016_02
Patent number
US09260425B2

Reaction notes

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