Dichloromethane → [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]carbamic acid 2,2-dimethylpropyl ester

HRID 2089627Notes

Reaction equation

HRID 2089627 reaction equation
[CH3:1][C:2]([CH3:44])([CH3:43])[CH2:3][O:4][C:5](=[O:42])[N:6]=[C:7]([NH2:41])[C:8]1[CH:13]=[CH:12][C:11]([NH:14][CH:15]([C:28]2[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[C:30]([O:36][CH2:37][CH2:38][OH:39])[C:29]=2[F:40])[C:16]2[NH:20][C:19](=[O:21])[N:18]([C:22]3[N:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[N:17]=2)=[CH:10][CH:9]=1.[Cl:45][CH2:46]Cl.C(=O)([O-])O.[Na+].S(Cl)(OCCl)(=O)=O>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl.C1COCC1.O.C1COCC1.C(OCC)(=O)C.C1COCC1>[CH3:1][C:2]([CH3:44])([CH3:43])[CH2:3][O:4][C:5](=[O:42])[N:6]=[C:7]([NH2:41])[C:8]1[CH:9]=[CH:10][C:11]([NH:14][CH:15]([C:16]2[N:20]=[C:19]([O:21][CH2:46][Cl:45])[N:18]([C:22]3[N:23]=[CH:24][CH:25]=[CH:26][N:27]=3)[N:17]=2)[C:28]2[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[C:30]([O:36][CH2:37][CH2:38][OH:39])[C:29]=2[F:40])=[CH:12][CH:13]=1

Participants

10

Reactant 4

HCID 6344DichloromethaneHCID 516892Sodium BicarbonateHCID 2733556Chloromethyl chlorosulfateHCID 136334024HCID 136334024, compound

Product 1

HCID 67470504[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]carbamic acid 2,2-dimethylpropyl ester

Reagents, catalysts & solvents 5

HCID 94433Tetrabutylammonium hydrogen sulfateCatalystHCID 962WaterSolvent2×HCID 8028TetrahydrofuranSolventHCID 21919333Tetrahydrofurane dichloromethaneSolventHCID 21939870Tetrahydrofuran ethyl acetateSolvent

Procedure

To a mixture of [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]carbamic acid 2,2-dimethylpropyl ester (4 g) and dichloromethane (80 mL), sodium hydrogen carbonate (6.63 g) and tetrabutylammonium hydrogen sulfate (447 mg) were added at low temperature (−10° C.˜5° C.). To the resulting mixture, THF (80 mL) and water (80 mL) were added. To the resulting mixture, chloromethyl chlorosulfate (3.26 g) in dichloromethane/THF (1:1) mixture (10 mL) was added dropwise at −5° C., and the resulting mixture was stirred overnight at room temperature. Under ice-cooling, THF/ethyl acetate (1:4) mixture (500 mL) was added to the mixture, and the resulting mixture was filtered. To the filtrate obtained, water (300 mL) was added, and the resulting mixture was shaken, after which the organic layer was collected. The organic layer was washed with saturated aqueous sodium chloride solution (150 mL). An aqueous layer was extracted with THF/ethyl acetate (1:4) mixture (250 mL, twice). The organic layers were combined and washed with saturated aqueous sodium chloride solution (150 mL). All the organic layers were combined and dried over anhydrous sodium sulfate and anhydrous magnesium sulfate. The resulting 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 methanol-ethyl acetate) to obtain the captioned compound (1.56 g).

Workup

  1. additionwere added at low temperature (−10° C.˜5° C.)
  2. temperatureUnder ice-cooling
  3. filtrationthe resulting mixture was filtered
  4. customTo the filtrate obtained
  5. stirringthe resulting mixture was shaken
  6. customafter which the organic layer was collected
  7. washThe organic layer was washed with saturated aqueous sodium chloride solution (150 mL)
  8. extractionAn aqueous layer was extracted with THF/ethyl acetate (1:4) mixture (250 mL
  9. washwashed with saturated aqueous sodium chloride solution (150 mL)
  10. dry with materialdried over anhydrous sodium sulfate and anhydrous magnesium sulfate
  11. filtrationThe resulting mixture was filtered
  12. customthe filtrate obtained
  13. concentrationwas concentrated under reduced pressure
  14. customThe residue obtained
  15. customwas purified by NAM silica gel column chromatography (mixed solvent of methanol-ethyl acetate)

Sources & evidence

ORD record
ord-2abc6ea166fa4094a767ed1c89ed68c3
Source dataset
uspto-grants-2013_05
Patent number
US08436009B2

Reaction notes

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