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 1828476노트

반응식

HRID 1828476 반응식
[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]

참가 물질

8

반응물 5

HCID 75654Diphenyl chlorophosphateHCID 81531Diisopropylethylamine2회HCID 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

생성물 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-carboxamide수율 20.3%

시약·촉매·용매 2

HCID 6228Dimethylformamide용매2회HCID 6342Acetonitrile용매

실험 절차

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.

후처리

  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)

출처 및 근거

ORD 기록
ord-55e494728cff4d7c95ced7419c13a450
출처 데이터셋
uspto-grants-2006_06
특허 번호
US07056917B2

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