Sodium hydride → 4-Cyano-3-(3-tert. butylamino-2-hydroxypropoxy)-5-methylthioisothiazole hydrogen maleate salt hemihydrate

HRID 426540Notes

Reaction equation

HRID 426540 reaction equation
C([C:3]1[C:4]([OH:10])=[N:5][S:6][C:7]=1[S:8][CH3:9])#N.[H-].[Na+].S(C1C=CC(C)=CC=1)([O-])(=O)=[O:14].O.[C:25]([OH:32])(=[O:31])/[CH:26]=[CH:27]\[C:28]([OH:30])=[O:29].[C:33]([C:35]1[C:36]([O:42][CH2:43][CH:44]([OH:51])[CH2:45][NH:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[N:37][S:38][C:39]=1[S:40][CH3:41])#[N:34].[C:52]([C:54]1[C:55]([O:61][CH2:62][CH:63]([OH:70])[CH2:64][NH:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[N:56][S:57][C:58]=1[S:59][CH3:60])#[N:53].[C:71]([OH:78])(=[O:77])/[CH:72]=[CH:73]\[C:74]([OH:76])=[O:75]>CN(C=O)C.O>[OH2:10].[C:25]([OH:32])(=[O:31])/[CH:26]=[CH:27]\[C:28]([OH:30])=[O:29].[C:33]([C:35]1[C:36]([O:42][CH2:43][CH:44]([OH:51])[CH2:45][NH:46][C:47]([CH3:49])([CH3:48])[CH3:50])=[N:37][S:38][C:39]=1[S:40][CH3:41])#[N:34].[C:52]([C:54]1[C:55]([O:61][CH2:62][CH:63]([OH:70])[CH2:64][NH:65][C:66]([CH3:68])([CH3:67])[CH3:69])=[N:56][S:57][C:58]=1[S:59][CH3:60])#[N:53].[C:71]([OH:78])(=[O:77])/[CH:72]=[CH:73]\[C:74]([OH:76])=[O:75].[C:33]([C:35]1[C:36]([O:42][CH2:43][CH:44]([OH:51])[CH2:45][NH:46][C:47]([CH3:49])([CH3:48])[CH3:50])=[N:37][S:38][C:39]=1[S:40][CH3:41])#[N:34].[OH2:14].[C:25]([OH:32])(=[O:31])/[CH:26]=[CH:27]\[C:28]([OH:30])=[O:29].[CH3:9][S:8][C:7]1[S:6][N:5]=[CH:4][CH:3]=1.[CH3:9][S:8][C:7]1[S:6][N:5]=[CH:4][CH:3]=1.[C:25]([OH:32])(=[O:31])/[CH:26]=[CH:27]\[C:28]([OH:30])=[O:29]

Participants

9

Reactant 4

HCID 24758Sodium hydrideHCID 85570p-ToluenesulfonateHCID 1317112934-Cyano-3-(3-tert. butylamino-2-hydroxypropoxy)-5-methylthioisothiazole hydrogen maleate salt hemihydrateHCID 178503646HCID 178503646, compound

Product 3

HCID 12583768HCID 12583768, compoundHCID 1317112934-Cyano-3-(3-tert. butylamino-2-hydroxypropoxy)-5-methylthioisothiazole hydrogen maleate salt hemihydrateYield 42%HCID 1317112945-Methylthioisothiazole hydrogen maleate salt hemihydrate

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent2×

Procedure

Into a dry flask under N2 is added 4-cyano-3-hydroxy-5-methylthioisothiazole (8.6 g., 0.05 m.), DMF (120 ml.) and NaH (50% mineral oil, 2.5 g., 0.052 m.). After stirring at room temperature for 15 minutes, the tosylate of (S) 2-phenyl-3-tert. butylamino-5-hydroxymethyloxazolidine (0.05 m.) in DMF (80 ml.) is added and the solution heated at 80° C. with stirring. After 15 hours, the solution is cooled to 0°-10°, poured into H2O (600 ml.) and extracted with ether (4×100 ml.). The organic layer is washed with H2O (2×100 ml.) and 1N HCl (3×100 ml.). The acid layer is poured into NaOAc.3H2O (41 g., 0.3 m.) and the solution stirred at room temperature. After 5 hours, the solution is extracted with ether (2×100 ml.). The aqueous layer is neutralized with saturated Na2CO3 and extracted with CHCl3 (4×150 ml.). The organic layer is dried over Na2SO4, filtered and concentrated to dryness. The residue is chromatographed on silica gel 60 and the product eluted with CHCl3 saturated with ammonia. There is obtained 6.3 g. (42%) of (S) 4-cyano-3-(tert.-butylamino-2-hydroxypropoxy)-5-methylthioisothiazole, which on treatment with maleic yields the (S) 4-cyano-3-(3-tert. butylamino-2-hydroxypropoxy(-5-methylthioisothiazole hydrogen maleate salt hemihydrate, m.p. 199°-200° C.

Workup

  1. temperaturethe solution heated at 80° C.
  2. stirringwith stirring
  3. waitAfter 15 hours
  4. temperaturethe solution is cooled to 0°-10°
  5. extractionextracted with ether (4×100 ml.)
  6. washThe organic layer is washed with H2O (2×100 ml.) and 1N HCl (3×100 ml.)
  7. additionThe acid layer is poured into NaOAc.3H2O (41 g., 0.3 m.)
  8. stirringthe solution stirred at room temperature
  9. waitAfter 5 hours
  10. extractionthe solution is extracted with ether (2×100 ml.)
  11. extractionextracted with CHCl3 (4×150 ml.)
  12. dry with materialThe organic layer is dried over Na2SO4
  13. filtrationfiltered
  14. concentrationconcentrated to dryness
  15. customThe residue is chromatographed on silica gel 60
  16. washthe product eluted with CHCl3 saturated with ammonia
  17. customThere is obtained 6.3 g

Sources & evidence

ORD record
ord-c860306af835435cb15632c555ec2a4a
Source dataset
uspto-grants-1979_10
Patent number
US04169835

Reaction notes

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