Water → (S)-5-benzyloxy-2-(3-tert-butylamino-2-hydroxypropoxy)nicotinonitrile maleate

HRID 1065236Notes

Reaction equation

HRID 1065236 reaction equation
[C:1]1([C@H:7]2[N:11]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:10][CH:9]([CH2:16][OH:17])[O:8]2)C=CC=C[CH:2]=1.[H-].[Na+].[CH2:20]([O:27][C:28]1[CH:29]=[N:30][C:31](Cl)=[C:32]([CH:35]=1)[C:33]#[N:34])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[OH2:37].CN([CH:41]=[O:42])C>>[C:41]([OH:42])(=[O:27])/[CH:2]=[CH:1]\[C:7]([OH:8])=[O:37].[CH2:20]([O:27][C:28]1[CH:29]=[N:30][C:31]([O:17][CH2:16][C@@H:9]([OH:8])[CH2:10][NH:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[C:32]([CH:35]=1)[C:33]#[N:34])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1

Participants

6

Reactant 5

HCID 962WaterHCID 6228Dimethylformamide2×HCID 24758Sodium hydrideHCID 12296652(S)-2-phenyl-3-tert-butyl-5-hydroxymethyloxazolidineHCID 128520215-Benzyloxy-2-chloronicotinonitrile

Product 1

HCID 70533944(S)-5-benzyloxy-2-(3-tert-butylamino-2-hydroxypropoxy)nicotinonitrile maleateYield 70%

Conditions

Temperature
90 °C

Procedure

To a flame dried flask under N2 was placed DMF (100 mL), (S)-2-phenyl-3-tert-butyl-5-hydroxymethyloxazolidine, (2.5 g, 0.01 mol) and NaH (50% oil dispersion, 0.5 g, 0.01 mol). The mixture was heated at 90° C. for 10 minutes, then cooled to 35° C. and a solution of 5-benzyloxy-2-chloronicotinonitrile (2.5 g, 0.01 mol) in DMF (25 mL) was added dropwise and allowed to stir at room temperature overnight. The mixture was poured into H2O and extracted with Et2O (3×). The organic layer was dried, filtered and concentrated. The residue was treated with 1 N HCl (150 mL) and heated on a steam bath. After 15 minutes, the aqueous solution was cooled, extracted with Et2O (2×), poured into saturated Na2CO3 solution and extracted with CH2Cl2 (3×). After concentration, the residue was crystallized as the maleate salt from isoPrOH/Et2O to yield 3.3 g (70%) of (S)-5-benzyloxy-2-(3-tert-butylamino-2-hydroxypropoxy)nicotinonitrile maleate mp 124°-6° C.; 1H NMR (DMSO-d6) δ1.3 (9H, s), 3.1 (2H, m), 4.2 (3H, m), 5.2 (2H, s), 6.05 (2H, s, olefinic protons of maleic acid), 7.4 (5H, bs) 8.1 (1H, d, J=3) and 8.25 (1H, d, J=3).

Workup

  1. customTo a flame dried flask under N2
  2. temperaturecooled to 35° C.
  3. extractionextracted with Et2O (3×)
  4. customThe organic layer was dried
  5. filtrationfiltered
  6. concentrationconcentrated
  7. additionThe residue was treated with 1 N HCl (150 mL)
  8. temperatureheated on a steam bath
  9. waitAfter 15 minutes
  10. temperaturethe aqueous solution was cooled
  11. extractionextracted with Et2O (2×)
  12. additionpoured into saturated Na2CO3 solution
  13. extractionextracted with CH2Cl2 (3×)
  14. concentrationAfter concentration
  15. customthe residue was crystallized as the maleate salt from isoPrOH/Et2O

Sources & evidence

ORD record
ord-16805a8cc1b948edaf12104dba5e9fb6
Source dataset
uspto-grants-1982_05
Patent number
US04329351

Reaction notes

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