Citric Acid → HCID 86610601, compound

HRID 506369Notes

Reaction equation

HRID 506369 reaction equation
[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([OH:16])=[CH:13][CH:14]=2)[C@@H:9]([NH:17][C:18]2[N:23]=[C:22]([CH2:24][C:25]3[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:26]=3)[C:21]([N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)=[CH:20][N:19]=2)[CH2:8][C@H:7]1[CH2:45][CH3:46])=[O:5])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].COC(=O)[C:56](Cl)([F:58])[F:57].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH:56]([F:58])[F:57])=[CH:13][CH:14]=2)[C@@H:9]([NH:17][C:18]2[N:23]=[C:22]([CH2:24][C:25]3[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([C:35]([F:38])([F:36])[F:37])[CH:26]=3)[C:21]([N:39]3[CH2:40][CH2:41][O:42][CH2:43][CH2:44]3)=[CH:20][N:19]=2)[CH2:8][C@H:7]1[CH2:45][CH3:46])=[O:5])[CH3:2]

Participants

7

Reactant 4

HCID 311Citric AcidHCID 10796Cesium carbonateHCID 73935Methyl chlorodifluoroacetateHCID 178473293HCID 178473293, compound

Product 1

HCID 86610601HCID 86610601, compoundYield 93.8%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
75 °C

Procedure

(2R,4S)-4-{[3,5-Bis(trifluoromethyl)benzyl]-[5-(morpholin-4-yl)pyrimidin-2-yl]}amino-2-ethyl-6-hydroxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (100 mg), cesium carbonate (55 mg) and 2-chloro-2,2-difluoroacetic acid methyl ester (44 mg) are dissolved in N,N-dimethylformamide (1 ml) and stirred at 75° C. for 17 hours. The reaction solution is cooled to room temperature, and thereto are added an aqueous citric acid solution and ethyl acetate. 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=9:1→4:1) to give (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholin-4-yl)pyrimidin-2-yl]}amino-6-difluoromethoxy-2-ethyl-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (101 mg). MS (m/z): 705 [M+H]+

Workup

  1. temperatureThe reaction solution is cooled 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=9:1→4:1)

Sources & evidence

ORD record
ord-1c7ca738adb343988c4c86bd85b77fa4
Source dataset
uspto-grants-2010_08
Patent number
US07781443B2

Reaction notes

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