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

HRID 1670548Notes

Reaction equation

HRID 1670548 reaction equation
[CH3:1][C:2]1[N:3]=[C:4]([SH:7])[S:5][CH:6]=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>[C:10]([O:14][C:15]([N:17]1[CH2:23][CH2:22][C:21]2[C:24]([CH2:29][S:7][C:4]3[S:5][CH:6]=[C:2]([CH3:1])[N:3]=3)=[C:25]([Cl:28])[CH:26]=[CH:27][C:20]=2[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 597874103-tert-Butoxycarbonyl-7-chloro-6-chloromethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepineHCID 1784319804-methyl-1,3-thiazole-2-thiol

Product 1

HCID 673358963-tert-butoxycarbonyl-7-chloro-6-(4-methyl-thiazol-2-ylthiomethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineYield 80.5%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Procedure

To a solution of 4-methylthiazole-2-thiol (0.32 g, 2.5 mmol) in anhydrous DMF (8.4 mL) add sodium hydride (0.10 g, 2.6 mmol, 60% dispersion in mineral oil) in portions at room temperature. 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 (0.74 g, 2.2 mmol) in anhydrous DMF (5.6 mL). Heat the reaction mixture at 45° C. for 2 h under nitrogen atmosphere, cool to room temperature and stir overnight. Quench the reaction mixture with 10% aqueous NaHCO3 (14 mL) and extract the mixture three times with EtOAc. Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel (40 g) eluting with hexane/EtOAc (1:0 to 85:15 gradient over 30 min; 35 mL/min) to obtain 3-tert-butoxycarbonyl-7-chloro-6-(4-methyl-thiazol-2-ylthiomethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.753 g, 79%) as a white foam.

Workup

  1. temperatureHeat the reaction mixture at 45° C. for 2 h under nitrogen atmosphere
  2. temperaturecool to room temperature
  3. stirringstir overnight
  4. customQuench the reaction mixture with 10% aqueous NaHCO3 (14 mL)
  5. extractionextract the mixture three times with EtOAc
  6. dry with materialDry the combined organic extracts over Na2SO4
  7. filtrationfilter
  8. concentrationconcentrate in vacuo
  9. customPurify the crude mixture by chromatography on silica gel (40 g)
  10. washeluting with hexane/EtOAc (1:0 to 85:15 gradient over 30 min; 35 mL/min)

Sources & evidence

ORD record
ord-4708fd177ad0479aba07061b029b715f
Source dataset
uspto-grants-2011_08
Patent number
US07994163B2

Reaction notes

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