Water → (s)-3-Benzo[1,2,5]thiadiazol-5-yl-n-[(1r,2r)-2-hydroxy-l-methyl-2-phenyl-ethyl]-2,n-dimethyl-propionamide

HRID 988746Notes

Reaction equation

HRID 988746 reaction equation
O.[Li+].CC([N-]C(C)C)C.[OH:10][C@H:11]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C@H:12]([N:14]([CH3:19])[C:15](=[O:18])[CH2:16][CH3:17])[CH3:13].Br[CH2:27][C:28]1[CH:29]=[CH:30][C:31]2[C:32]([CH:36]=1)=[N:33][S:34][N:35]=2.[NH4+].[Cl-]>C1COCC1.CCOC(C)=O>[N:35]1[S:34][N:33]=[C:32]2[CH:36]=[C:28]([CH2:27][C@H:16]([CH3:17])[C:15]([N:14]([C@H:12]([CH3:13])[C@H:11]([OH:10])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:19])=[O:18])[CH:29]=[CH:30][C:31]=12

Participants

8

Reactant 5

HCID 962WaterHCID 25517Ammonium ChlorideHCID 5910045-(Bromomethyl)-2,1,3-benzothiadiazoleHCID 2724682Lithium diisopropylamideHCID 10799021(1R,2R)-(-)-Pseudoephedrinepropionamide

Product 1

HCID 69710086(s)-3-Benzo[1,2,5]thiadiazol-5-yl-n-[(1r,2r)-2-hydroxy-l-methyl-2-phenyl-ethyl]-2,n-dimethyl-propionamide

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolvent2×HCID 8857Ethyl AcetateSolvent

Procedure

Water free LiCl (59.4 g, 1.4 mol) is carefully dried in vacuo at 600° for 10 minutes and then the vessel purged with Ar. THF (460 ml) is added and cooled to 0°. A solution of LDA (2M in THF/heptane/Et2O, 200 ml, 0.4 mol) is added and cooled to −75°. A solution of N-[(1R,2R)-2-hydroxy-1-methyl-2-phenyl-ethyl]-N-methyl-propionamide (44.4 g, 0.2 mol) in 460 ml THF is added dropwise over 170 minutes while maintaining the internal temperature at −62° to −69°. After stirring for 1 h at −75°, the cooling bath is removed for 30 minutes, during which time the temperature rises to −30°. The mixture is recooled to −75° and then treated with a solution of 5-bromomethyl-benzo[1,2,5]thiadiazole (34.8 g, 0.152 mol) in 260 ml THF during 85 min at −70° to −78°. The mixture is then stirred for 40 h at −78°. A 15% NH4Cl solution (1000 ml) is added and the mixture stirred well. Extraction with EtOAc (2×500 ml), drying (Na2SO4) and evaporation afford crude product. MPLC purification (2 kg silicagel, EtOAc/hexanes 2/1) afford pure product as a orange oil. Diastereomeric ration 92:8 (NMR, 120°). TLC (silicagel, EtOAc/hexanes2:1): rf 0.38.

Workup

  1. customthe vessel purged with Ar
  2. additionTHF (460 ml) is added
  3. temperaturecooled to 0°
  4. temperaturecooled to −75°
  5. temperaturewhile maintaining the internal temperature at −62° to −69°
  6. customthe cooling bath is removed for 30 minutes, during which time the temperature
  7. customrises to −30°
  8. customis recooled to −75°
  9. stirringThe mixture is then stirred for 40 h at −78°
  10. stirringthe mixture stirred well
  11. extractionExtraction with EtOAc (2×500 ml)
  12. customdrying
  13. custom(Na2SO4) and evaporation
  14. customafford crude product
  15. customMPLC purification (2 kg silicagel, EtOAc/hexanes 2/1)
  16. customafford pure product as a orange oil

Sources & evidence

ORD record
ord-10e70618404b46d9ac745c2d0569a362
Source dataset
uspto-grants-2003_10
Patent number
US06635647B2

Reaction notes

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