Water → (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholin-4-yl)pyrimidin-2-yl]}amino-6-cyano-2-ethyl-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester

HRID 506370Notes

Reaction equation

HRID 506370 reaction equation
[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12](OS(C(F)(F)F)(=O)=O)=[CH:13][CH:14]=2)[C@@H:9]([NH:24][C:25]2[N:30]=[C:29]([CH2:31][C:32]3[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[C:34]([C:42]([F:45])([F:44])[F:43])[CH:33]=3)[C:28]([N:46]3[CH2:51][CH2:50][O:49][CH2:48][CH2:47]3)=[CH:27][N:26]=2)[CH2:8][C@H:7]1[CH2:52][CH3:53])=[O:5])[CH3:2].[CH3:54][N:55](C)C=O.O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C-]#N.[Zn+2].[C-]#N.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([C:54]#[N:55])=[CH:13][CH:14]=2)[C@@H:9]([NH:24][C:25]2[N:30]=[C:29]([CH2:31][C:32]3[CH:33]=[C:34]([C:42]([F:45])([F:43])[F:44])[CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=3)[C:28]([N:46]3[CH2:51][CH2:50][O:49][CH2:48][CH2:47]3)=[CH:27][N:26]=2)[CH2:8][C@H:7]1[CH2:52][CH3:53])=[O:5])[CH3:2]

Participants

7

Reactant 3

HCID 962WaterHCID 6228DimethylformamideHCID 86610603(2R,4S)-4-{[3,5-Bis(trifluoromethyl)benzyl]-[5-(morpholin-4-yl)-pyrimidin-2-yl]}amino-2-ethyl-6-trifluoromethanesulfonyloxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester

Product 1

HCID 86610602(2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholin-4-yl)pyrimidin-2-yl]}amino-6-cyano-2-ethyl-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester

Reagents, catalysts & solvents 3

HCID 11186Zinc cyanide (Zn(CN)2)CatalystHCID 178418397HCID 178418397, compoundCatalystHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
95 °C

Procedure

A mixture of (2R,4S)-4-{[3,5-Bis(trifluoromethyl)benzyl]-[5-(morpholin-4-yl)pyrimidin-2-yl]}amino-2-ethyl-6-trifluoromethanesulfonyloxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (732 mg), tetrakis(triphenylphosphine)palladium (catalytic amount), zinc cyanide (142 mg) and N,N-dimethylformamide (10 ml) is stirred at 95° C. under nitrogen flow for 8 hours. After cooling to room temperature, water and ethyl acetate are added to the reaction solution. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; hexane: ethyl acetate=4:1→2:1) to give (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholin-4-yl)pyrimidin-2-yl]}amino-6-cyano-2-ethyl-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (572 mg). MS (m/z): 664 [M+H]+

Workup

  1. temperatureAfter cooling to room temperature
  2. washThe organic layer is washed with a saturated brine
  3. dry with materialdried over magnesium sulfate
  4. concentrationconcentrated under reduced pressure
  5. customThe resulting residue is purified by column chromatography (silica gel; hexane: ethyl acetate=4:1→2:1)

Sources & evidence

ORD record
ord-d3a01daa5160456db67480c92c52cbd5
Source dataset
uspto-grants-2010_08
Patent number
US07781443B2

Reaction notes

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