Diphenyl chlorophosphate → N8-[4-(tert-Butyl)-1,3-thiazol-2-yl]-2-{3-[(dimethylamino)carbonyl]piperidino}-4-oxo-4H-pyrido[1,2-a]pyrimidine-8-carboxamide

HRID 1828476Notes

Reaction equation

HRID 1828476 reaction equation
[C:1]([C:5]1[N:6]=[C:7]([NH:10][C:11]([C:13]2[CH:24]=[CH:23][N:16]3[C:17](=[O:22])[CH2:18][C:19](=O)[N:20]=[C:15]3[CH:14]=2)=[O:12])[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.P(Cl)(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O.FC(F)(F)C(O)=O.[CH3:58][N:59]([CH3:68])[C:60]([CH:62]1[CH2:67][CH2:66][CH2:65][NH:64][CH2:63]1)=[O:61].C(=O)([O-])O.[Na+]>CN(C)C=O.C(#N)C>[C:1]([C:5]1[N:6]=[C:7]([NH:10][C:11]([C:13]2[CH:24]=[CH:23][N:16]3[C:17](=[O:22])[CH:18]=[C:19]([N:64]4[CH2:65][CH2:66][CH2:67][CH:62]([C:60]([N:59]([CH3:68])[CH3:58])=[O:61])[CH2:63]4)[N:20]=[C:15]3[CH:14]=2)=[O:12])[S:8][CH:9]=1)([CH3:2])([CH3:4])[CH3:3]

Participants

8

Reactant 5

HCID 75654Diphenyl chlorophosphateHCID 81531Diisopropylethylamine2×HCID 516892Sodium BicarbonateHCID 22063754N8-[4-(tert-butyl)-1,3-thiazol-2-yl]-2,4-dioxo-3,4-dihydro-2H-pyrido[1,2-a]pyrimidine-8-carboxamideHCID 229293733-[(Dimethylamino)carbonyl]piperidine trifluoroacetic acid salt

Product 1

HCID 22063610N8-[4-(tert-Butyl)-1,3-thiazol-2-yl]-2-{3-[(dimethylamino)carbonyl]piperidino}-4-oxo-4H-pyrido[1,2-a]pyrimidine-8-carboxamideYield 20.3%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolvent2×HCID 6342AcetonitrileSolvent

Procedure

N8-[4-(tert-butyl)-1,3-thiazol-2-yl]-2,4-dioxo-3,4-dihydro-2 H-pyrido[1,2-a]-pyrimidine-8-carboxamide (301.9 mg, 0.88 mmol) was suspended in dimethylformamide (6 ml) and acetonitrile (12 ml), added dropwise with diisopropylethylamine (1.83 ml, 10.5 mmol) and diphenyl chlorophosphate (545.1 μl, 2.63 mmol) at −10° C. under an argon flow, and stirred at the same temperature for 5 minutes and at room temperature for 15 minutes. The reaction solution was cooled to −10° C. again, added dropwise with a solution of 3-[(dimethylamino)carbonyl]piperidine trifluoroacetic acid salt (1.18 g, 4.38 mmol) in dimethylformamide (5 ml), and stirred at room temperature for 1 hour and at about 80° C. for 2 hours. The reaction solution was heated to about 100° C., heated for 30 minutes with stirring, then added with diisopropylethylamine (1.83 ml, 10.5 mmol), and further heated at 100° C. for 3 hours and 30 minutes with stirring. After cooling, the solution was added with saturated aqueous sodium hydrogencarbonate and extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate and the solvent was evaporated. The residue was purified by silica gel column chromatography (chloroform→chloroform:methanol=50:1→20:1, v/v) and preparative TLC (chloroform:methanol=20:1, v/v) to obtain the title compound (85.9 mg, 20.3%) as yellow orange oil.

Workup

  1. temperatureThe reaction solution was cooled to −10° C. again
  2. stirringstirred at room temperature for 1 hour and at about 80° C. for 2 hours
  3. temperatureThe reaction solution was heated to about 100° C.
  4. temperatureheated for 30 minutes
  5. stirringwith stirring
  6. temperaturefurther heated at 100° C. for 3 hours and 30 minutes
  7. stirringwith stirring
  8. temperatureAfter cooling
  9. extractionextracted with chloroform
  10. washThe organic layer was washed with saturated brine
  11. dry with materialdried over anhydrous sodium sulfate
  12. customthe solvent was evaporated
  13. customThe residue was purified by silica gel column chromatography (chloroform→chloroform:methanol=50:1→20:1, v/v) and preparative TLC (chloroform:methanol=20:1, v/v)

Sources & evidence

ORD record
ord-55e494728cff4d7c95ced7419c13a450
Source dataset
uspto-grants-2006_06
Patent number
US07056917B2

Reaction notes

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