Sodium hydride → 6-(5-Amino-[1,3,4]thiadiazol-2-ylthiomethyl)-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine

HRID 1670563Notes

Reaction equation

HRID 1670563 reaction equation
[NH2:1][C:2]1[S:6][C:5]([SH:7])=[N:4][N:3]=1.[H-].[Na+].[C:10]([O:14][C:15]([N:17]1[CH2:23][CH2:22][C:21]2[C:24]([CH2:29]Cl)=[C:25]([Cl:28])[CH:26]=[CH:27][C:20]=2[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]>CN(C=O)C>[NH2:1][C:2]1[S:6][C:5]([S:7][CH2:29][C:24]2[C:21]3[CH2:22][CH2:23][N:17]([C:15]([O:14][C:10]([CH3:12])([CH3:11])[CH3:13])=[O:16])[CH2:18][CH2:19][C:20]=3[CH:27]=[CH:26][C:25]=2[Cl:28])=[N:4][N:3]=1

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 597874103-tert-Butoxycarbonyl-7-chloro-6-chloromethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepineHCID 178509208HCID 178509208, compound

Product 1

HCID 598222776-(5-Amino-[1,3,4]thiadiazol-2-ylthiomethyl)-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepineYield 61%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Procedure

To a mixture of 5-amino-1,3,4-thiadiazole-2-thiol (0.33 g, 2.5 mmol) in anhydrous DMF (8.5 mL) at room temperature add sodium hydride (0.1 g, 2.6 mmol, 60% dispersion in mineral oil) in portions. After stirring at room temperature for 10 min, add a solution of 3-tert-butoxycarbonyl-7-chloro-6-chloromethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.75 g, 2.3 mmol) in anhydrous DMF (5.6 mL). Stir at room temperature overnight and quench the reaction mixture with 10% aqueous NaHCO3 (25 mL). Extract the mixture with DCM (100 mL). Dry the organic phase over Na2SO4, filter and concentrate in vacuo. Dissolve the residue in DCM, load the solution on to a RediSep® column (40 g) and purify the crude mixture by preparative liquid chromatography (hexane over 10 min; 100:0 to 50:50 hexane/EtOAc over 23 min; 50:50 to 0:100 hexane/EtOAc over 33 min; 35 mL/min) to obtain an oil. Add EtOAc (16 mL) to precipitate product. After stirring overnight, filter the slurry, wash the solid with EtOAc (10 mL) and dry to obtain the desired intermediate (0.583 g, 61%) as a white solid. MS (ES+) m/z: 427.1 (M+H)+.

Workup

  1. stirringStir at room temperature overnight
  2. customquench the reaction mixture with 10% aqueous NaHCO3 (25 mL)
  3. extractionExtract the mixture with DCM (100 mL)
  4. dry with materialDry the organic phase over Na2SO4
  5. filtrationfilter
  6. concentrationconcentrate in vacuo
  7. dissolutionDissolve the residue in DCM
  8. customload the solution on to a RediSep® column (40 g) and purify the crude mixture by preparative liquid chromatography (hexane over 10 min; 100:0 to 50:50 hexane/EtOAc over 23 min; 50:50 to 0:100 hexane/EtOAc over 33 min; 35 mL/min)
  9. customto obtain an oil
  10. customAdd EtOAc (16 mL) to precipitate product
  11. stirringAfter stirring overnight
  12. filtrationfilter the slurry
  13. washwash the solid with EtOAc (10 mL)
  14. customdry

Sources & evidence

ORD record
ord-e46da08ef1dd433182c7d1b8a433d38c
Source dataset
uspto-grants-2011_08
Patent number
US07994163B2

Reaction notes

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