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

HRID 1670570Notes

Reaction equation

HRID 1670570 reaction equation
Cl.[C:2]([O:6][C:7]([N:9]1[CH2:15][CH2:14][C:13]2[C:16]([CH2:21][S:22][C:23](=[NH:25])[NH2:24])=[C:17]([Cl:20])[CH:18]=[CH:19][C:12]=2[CH2:11][CH2:10]1)=[O:8])([CH3:5])([CH3:4])[CH3:3].C[O-].[Na+].[C:29]([S-:31])#[N:30].[K+].BrBr>CO>[NH2:30][C:29]1[S:31][N:24]=[C:23]([S:22][CH2:21][C:16]2[C:13]3[CH2:14][CH2:15][N:9]([C:7]([O:6][C:2]([CH3:5])([CH3:3])[CH3:4])=[O:8])[CH2:10][CH2:11][C:12]=3[CH:19]=[CH:18][C:17]=2[Cl:20])[N:25]=1

Participants

6

Reactant 4

HCID 24408BromineHCID 516872Potassium thiocyanateHCID 10942334Sodium MethoxideHCID 673354473-tert-Butoxycarbonyl-6-carbamimidoylthiomethyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine hydrochloride

Product 1

HCID 673359726-(5-amino-[1,2,4]thiadiazol-3-ylthiomethyl)-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepineYield 43%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent2×

Conditions

Temperature
0 °C

Procedure

To a solution of 3-tert-butoxycarbonyl-6-carbamimidoylthiomethyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine hydrochloride (0.510 g, 1.256 mmol) in methanol (12.5 mL) at room temperature add solid sodium methoxide (0.14 g, 2.5 mmol) and then KSCN (0.12 g, 1.3 mmol). After cooling the reaction mixture to 0° C., add a solution of bromine (0.20 g, 1.3 mmol) in methanol (4 mL) dropwise. Stir the reaction mixture at room temperature overnight. Concentrate the reaction mixture in vacuo and partition the residue between DCM (100 mL) and water (50 mL). Extract the aqueous phase with DCM (50 mL). Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo. Dissolve the residue in DCM/methanol, add silica gel (5 g) and concentrate to a powder. Load the powder on to a dry column attached to a RediSep® column (40 g) and purify the crude mixture by preparative liquid chromatography (100:0 to 95:5 DCM/2M ammonia in methanol over 33 min; 95:5 to 80:20 DCM/2M ammonia in methanol over 33 min; 35 mL/min) to afford 6-(5-amino-[1,2,4]thiadiazol-3-ylthiomethyl)-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.229 g, 43%). MS (ES+) m/z: 427.2 (M+H)+.

Workup

  1. concentrationConcentrate the reaction mixture in vacuo
  2. custompartition the residue between DCM (100 mL) and water (50 mL)
  3. extractionExtract the aqueous phase with DCM (50 mL)
  4. dry with materialDry the combined organic extracts over Na2SO4
  5. filtrationfilter
  6. concentrationconcentrate in vacuo
  7. dissolutionDissolve the residue in DCM/methanol
  8. additionadd silica gel (5 g)
  9. concentrationconcentrate to a powder
  10. custompurify the crude mixture by preparative liquid chromatography (100:0 to 95:5 DCM/2M ammonia in methanol over 33 min; 95:5 to 80:20 DCM/2M ammonia in methanol over 33 min; 35 mL/min)

Sources & evidence

ORD record
ord-32572d1cd6f04582b00b2cb8acbc2c23
Source dataset
uspto-grants-2011_08
Patent number
US07994163B2

Reaction notes

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