Propionamide → 2-(hydroxymethyl)-N-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-6-propionamidoisonicotinamide

HRID 623634Notes

Reaction equation

HRID 623634 reaction equation
Cl[C:2]1[CH:3]=[C:4]([CH:23]=[C:24]([CH2:26][OH:27])[N:25]=1)[C:5]([NH:7][CH:8]([C:10]1[CH:11]=[N:12][C:13]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])=[C:14]([CH3:16])[CH:15]=1)[CH3:9])=[O:6].[C:28]([NH2:32])(=[O:31])[CH2:29][CH3:30].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[OH:27][CH2:26][C:24]1[CH:23]=[C:4]([CH:3]=[C:2]([NH:32][C:28](=[O:31])[CH2:29][CH3:30])[N:25]=1)[C:5]([NH:7][CH:8]([C:10]1[CH:11]=[N:12][C:13]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])=[C:14]([CH3:16])[CH:15]=1)[CH3:9])=[O:6]

Participants

7

Reactant 4

HCID 6578PropionamideHCID 62657Potassium Phosphate, TribasicHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 874274592-chloro-6-(hydroxymethyl)-N-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)isonicotinamide

Product 1

HCID 675089232-(hydroxymethyl)-N-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-6-propionamidoisonicotinamideYield 25%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
150 °C

Procedure

A mixture of 2-chloro-6-(hydroxymethyl)-N-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)isonicotinamide (17 mg, 0.04 mmol, Step-3, single enantiomer), propionamide (6 mg, 0.08 mmol), tris(dibenzylideneacetone)dipalladium(0) (1 mg, 0.8 microM), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (1.5 mg, 2.5 microM), tripotassium phosphate (11 mg, 0.05 mmol) and 1,4-dioxane (1 mL) is heated by microwave irradiation at 150° C. for 1 hour. After cooling to room temperature, the mixture is filtered through a pad of celite. The filtrate is concentrated under reduced pressure and the residue is diluted with methanol (4 mL) and applied onto a strong cation exchange cartridge (BondElute(registered trademark) SCX, 1 g/6 mL, Varian Inc.), and the solid phase matrix is rinsed with methanol (5 mL). The crude mixture is eluted with 1M ammonia in methanol (5 mL) and concentrated under reduced pressure and then by preparative LC-MS to give 4.4 mg (24% yield) of the title compound.

Workup

  1. temperatureAfter cooling to room temperature
  2. filtrationthe mixture is filtered through a pad of celite
  3. concentrationThe filtrate is concentrated under reduced pressure
  4. additionthe residue is diluted with methanol (4 mL)
  5. wash), and the solid phase matrix is rinsed with methanol (5 mL)
  6. washThe crude mixture is eluted with 1M ammonia in methanol (5 mL)
  7. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-99d3da0c434b495d998b05ce4d175db6
Source dataset
uspto-grants-2016_04
Patent number
US09302991B2

Reaction notes

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