Sodium Bicarbonate → N-[1-amino-1-[4-({(5-chloromethoxy-1-pyrimidin-2-yl-1H-[1,2,4]triazol-3-yl)-[2-fluoro-3-(2-hydroxyethoxy)-5-methoxyphenyl]methyl}amino)phenyl]methylidene]benzamide

HRID 2089664Notes

Reaction equation

HRID 2089664 reaction equation
[NH2:1][C:2](=[N:36][C:37](=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:23]2[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[C:25]([O:31][CH2:32][CH2:33][OH:34])[C:24]=2[F:35])[C:11]2[NH:15][C:14](=[O:16])[N:13]([C:17]3[N:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:12]=2)=[CH:5][CH:4]=1.C(=O)([O-])O.[Na+].S(Cl)(O[CH2:54][Cl:55])(=O)=O>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O.C(OCC)(=O)C.ClCCl.C1COCC1>[NH2:1][C:2](=[N:36][C:37](=[O:44])[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:11]2[N:15]=[C:14]([O:16][CH2:54][Cl:55])[N:13]([C:17]3[N:18]=[CH:19][CH:20]=[CH:21][N:22]=3)[N:12]=2)[C:23]2[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[C:25]([O:31][CH2:32][CH2:33][OH:34])[C:24]=2[F:35])=[CH:5][CH:4]=1

Participants

9

Reactant 3

HCID 516892Sodium BicarbonateHCID 2733556Chloromethyl chlorosulfate2×HCID 136334022N-[1-amino-1-(4-{[[2-fluoro-3-(2-hydroxyethoxy)-5-methoxyphenyl]-(5-oxo-1-pyrimidin-2-yl-4,5-dihydro-1H-[1,2,4]triazol-3-yl)methyl]amino}phenyl)methylidene]benzamide

Product 1

HCID 67470606N-[1-amino-1-[4-({(5-chloromethoxy-1-pyrimidin-2-yl-1H-[1,2,4]triazol-3-yl)-[2-fluoro-3-(2-hydroxyethoxy)-5-methoxyphenyl]methyl}amino)phenyl]methylidene]benzamideYield 34.9%

Reagents, catalysts & solvents 5

HCID 94433Tetrabutylammonium hydrogen sulfateCatalystHCID 962WaterSolvent3×HCID 6344DichloromethaneSolvent4×HCID 8028TetrahydrofuranSolvent2×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
-10 °C

Procedure

To a mixture of dichloromethane (20 mL), THF (20 mL), and water (20 mL), N-[1-amino-1-(4-{[[2-fluoro-3-(2-hydroxyethoxy)-5-methoxyphenyl]-(5-oxo-1-pyrimidin-2-yl-4,5-dihydro-1H-[1,2,4]triazol-3-yl)methyl]amino}phenyl)methylidene]benzamide (Example 1a, 901 mg), sodium hydrogen carbonate (632 mg), and tetrabutylammonium hydrogen sulfate (102 mg) were sequentially added. After cooling the resulting mixture to −10° C., a mixture of chloromethyl chlorosulfate (373 mg) and dichloromethane (5 mL) was added dropwise thereto with stirring, and the resulting mixture was stirred overnight at room temperature. Dichloromethane (10 mL), THF (10 mL), and water (10 mL) were added to the mixture, and the resulting mixture was cooled again to −10° C., after which a mixture of chloromethyl chlorosulfate (373 mg) and dichloromethane (5 mL) was added dropwise thereto with stirring, and the resulting mixture was stirred overnight at room temperature. Ethyl acetate (300 mL) and water (100 mL) were added to the mixture, and the resulting mixture was shaken, after which the organic layer was collected. Ethyl acetate (80 mL) and THF (20 mL) were added to the aqueous layer, and the resulting mixture was shaken again, after which the organic layer was collected. The combined organic layers were dried over anhydrous magnesium sulfate. The mixture was filtered, and the filtrate obtained was concentrated under reduced pressure. The residue obtained was purified by NAM silica gel column chromatography (mixed solvent of heptane-ethyl acetate) to obtain the captioned compound (340 mg).

Workup

  1. additionwere sequentially added
  2. additionwas added dropwise
  3. stirringthe resulting mixture was stirred overnight at room temperature
  4. temperaturethe resulting mixture was cooled again to −10° C.
  5. additionwas added dropwise
  6. stirringwith stirring
  7. stirringthe resulting mixture was stirred overnight at room temperature
  8. stirringthe resulting mixture was shaken
  9. customafter which the organic layer was collected
  10. additionEthyl acetate (80 mL) and THF (20 mL) were added to the aqueous layer
  11. stirringthe resulting mixture was shaken again
  12. customafter which the organic layer was collected
  13. dry with materialThe combined organic layers were dried over anhydrous magnesium sulfate
  14. filtrationThe mixture was filtered
  15. customthe filtrate obtained
  16. concentrationwas concentrated under reduced pressure
  17. customThe residue obtained
  18. customwas purified by NAM silica gel column chromatography (mixed solvent of heptane-ethyl acetate)

Sources & evidence

ORD record
ord-2077e741375c4f389df9fb0737930f30
Source dataset
uspto-grants-2013_05
Patent number
US08436009B2

Reaction notes

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