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 1670570Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 1670570
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

Komponenten

6

Edukt 4

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

Produkt 1

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

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 887MethanolLösungsmittel2×

Reaktionsbedingungen

Temperatur
0 °C

Versuchsvorschrift

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)+.

Aufarbeitung

  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)

Quellen und Nachweise

ORD-Eintrag
ord-32572d1cd6f04582b00b2cb8acbc2c23
Quelldatensatz
uspto-grants-2011_08
Patentnummer
US07994163B2

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