4-Toluenesulfonyl chloride → tert-Butyl (E)-3-[8-[(E)-2-(4-isopropyl-1,3-thiazol-2-yl)-1-ethenyl]-2-{[(4-methyl-phenyl)sulfonyl]oxy)-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl]-2-propenoate

HRID 1828484Notes

Reaction equation

HRID 1828484 reaction equation
[CH:1]([C:4]1[N:5]=[C:6](/[CH:9]=[CH:10]/[C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[CH:12]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2].[C:18](OC1C=CC(Cl)=C(Cl)C=1Cl)(=O)[CH2:19][C:20]([O-])=O.P(Cl)(Cl)(Cl)=[O:35].[C:39](=[O:42])([O-])O.[Na+].[C:44]([O:48][C:49]([CH:51]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:50])([CH3:47])([CH3:46])[CH3:45].[C:71]1([CH3:81])[CH:76]=[CH:75][C:74]([S:77](Cl)(=[O:79])=[O:78])=[CH:73][CH:72]=1>C1(C)C(C)=CC=CC=1.ClCCl.CN(C)C=O.CN(C)C1C=CN=CC=1.O.CCCCCC>[CH:1]([C:4]1[N:5]=[C:6](/[CH:9]=[CH:10]/[C:11]2[CH:16]=[CH:15][N:14]3[C:39](=[O:42])[C:19](/[CH:20]=[CH:51]/[C:49]([O:48][C:44]([CH3:45])([CH3:46])[CH3:47])=[O:50])=[C:18]([O:78][S:77]([C:74]4[CH:75]=[CH:76][C:71]([CH3:81])=[CH:72][CH:73]=4)(=[O:35])=[O:79])[N:17]=[C:13]3[CH:12]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2]

Participants

13

Reactant 6

HCID 73974-Toluenesulfonyl chlorideHCID 24813Phosphorus oxychlorideHCID 256127tert-Butyl (triphenylphosphoranylidene) acetateHCID 516892Sodium BicarbonateHCID 220635144-[(E)-2-(4-Isopropyl-1,3-thiazol-2-yl)-1-ethenyl]-2-pyridinamineHCID 22063717Trichlorophenyl malonate

Product 1

HCID 86588115tert-Butyl (E)-3-[8-[(E)-2-(4-isopropyl-1,3-thiazol-2-yl)-1-ethenyl]-2-{[(4-methyl-phenyl)sulfonyl]oxy)-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl]-2-propenoateYield 3.7%

Reagents, catalysts & solvents 6

HCID 142844-(Dimethylamino)pyridineCatalystHCID 962WaterSolventHCID 6228DimethylformamideSolvent2×HCID 6344DichloromethaneSolventHCID 7237O-XyleneSolventHCID 8058HexaneSolvent

Procedure

4-[(E)-2-(4-Isopropyl-1,3-thiazol-2-yl)-1-ethenyl]-2-pyridinamine (100 mg, 0.408 mmol) was dissolved in xylene (1.2 ml), added with trichlorophenyl malonate (208 mg, 0.448 mmol), and then the mixture was refluxed by heating for 1.3 hours. The reaction mixture was added with n-hexane, and the deposited solid was collected by filtration. Dimethylformamide (110 μl) was added with phosphorus oxychloride (190 μl, 2.04 mmol) under ice cooling and stirred at room temperature for 30 minutes. The mixture was added with the solid dissolved in dichloromethane (3.0 ml) under ice cooling, and stirred at room temperature for 1.5 hours. The reaction mixture was added with saturated aqueous sodium hydrogencarbonate and extracted with chloroform. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was suspended in anhydrous tetrahydrofuran (4.0 ml), added with (tert-butoxycarbonylmethylene)triphenylphosphorane (460 mg, 1.22 mmol), and stirred at 80° C. for 5 days. The reaction solution was concentrated, and then the residue was purified by silica gel column chromatography (chloroform:methanol=100:0→100:10, v/v) and thin layer chromatography (chloroform:methanol=10:1, v/v). The resulting compound was dissolved in anhydrous tetrahydrofuran (600 μl) and dimethylformamide (600 μl), added with 4-dimethylaminopyridine (10.2 mg, 0.0831 mmol) and p-toluenesulfonyl chloride (13.4 mg, 0.0703 mmol), and stirred at room temperature for 2 hours. The reaction mixture was added with water and extracted with chloroform. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by thin layer chromatography (n-hexane:ethyl acetate=2:1, v/v) to obtain the title compound (9.0 mg, 3.7%).

Workup

  1. temperaturethe mixture was refluxed
  2. temperatureby heating for 1.3 hours
  3. filtrationthe deposited solid was collected by filtration
  4. additionThe mixture was added with the solid
  5. stirringstirred at room temperature for 1.5 hours
  6. extractionextracted with chloroform
  7. dry with materialThe organic layer was dried over magnesium sulfate
  8. customthe solvent was evaporated under reduced pressure
  9. stirringstirred at 80° C. for 5 days
  10. concentrationThe reaction solution was concentrated
  11. customthe residue was purified by silica gel column chromatography (chloroform
  12. dissolutionThe resulting compound was dissolved in anhydrous tetrahydrofuran (600 μl)
  13. stirringstirred at room temperature for 2 hours
  14. extractionextracted with chloroform
  15. dry with materialThe organic layer was dried over magnesium sulfate
  16. customthe solvent was evaporated under reduced pressure
  17. customThe residue was purified by thin layer chromatography (n-hexane

Sources & evidence

ORD record
ord-f8e44a91e89c4c748d216ca6ac440357
Source dataset
uspto-grants-2006_06
Patent number
US07056917B2

Reaction notes

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