Potassium Carbonate → 6-((5-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazole

HRID 1847985Notes

Reaction equation

HRID 1847985 reaction equation
Cl[CH2:2][C:3]1[CH:13]=[CH:12][C:6]2[N:7]=[C:8]([S:10][CH3:11])[S:9][C:5]=2[CH:4]=1.[NH:14]1[CH:18]=[C:17]([C:19]2[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=2)[N:16]=[CH:15]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:24][N:22]1[CH:23]=[C:19]([C:17]2[N:16]([CH2:2][C:3]3[CH:13]=[CH:12][C:6]4[N:7]=[C:8]([S:10][CH3:11])[S:9][C:5]=4[CH:4]=3)[CH:15]=[N:14][CH:18]=2)[CH:20]=[N:21]1.[CH3:24][N:22]1[CH:23]=[C:19]([C:17]2[N:16]=[CH:15][N:14]([CH2:2][C:3]3[CH:13]=[CH:12][C:6]4[N:7]=[C:8]([S:10][CH3:11])[S:9][C:5]=4[CH:4]=3)[CH:18]=2)[CH:20]=[N:21]1

Participants

6

Reactant 3

HCID 11430Potassium CarbonateHCID 866809946-(Chloromethyl)-2-(methylthio)benzo[d]thiazoleHCID 178480105HCID 178480105, compound

Product 2

HCID 894986026-((5-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazoleHCID 894987006-((4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazole

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
80 °C

Procedure

To a stirred mixture of 6-(chloromethyl)-2-(methylthio)benzo[d]thiazole (209 mg, 0.9 mmol) from Step 4 of Example 36 and 4-(1H-imidazol-4-yl)-1-methyl-1H-pyrazole (248 mg, 1.0 mmol) from Step 3 of this Example, in anhydrous DMF (3.0 mL) was added K2CO3 (700 mg, 5 mmol). After stirring for 3 h at 80° C., the reaction mixture was cooled to rt and partitioned between EtOAc (150 mL) and water (50 mL). The EtOAc layer was separated, washed with brine (50 ml), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified via silica gel flash chromatography (eluting isocratically with 1% MeOH in CH2Cl2) to afford separately 6-((5-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazole and 6-((4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazole as white solids. The first eluting regioisomer is referred to as regioisomer 1 (55 mg, 16%) and the second eluting regioisomer is referred to as regioisomer 2 (142 mg, 42%). The regiochemistry of the alkylation was examined by 2-dimensional nuclear Overhauser effect (NOE) experiment but was inconclusive. Regioisomer 1: 1H NMR (300 MHz, CDCl3) δ 7.81 (d, J=8.3 Hz, 1H), 7.60 (s, 1H), 7.37 (s, 1H), 7.31 (s, 1H), 7.19 (s, 1H), 7.08-7.14 (m, 2H), 5.23 (s, 2H), 3.85 (s, 3H), 2.78 (s, 3H). LCMS (ESI) m/z 342 (M+H)+. Regioisomer 2: 1H NMR (300 MHz, CDCl3) δ 7.81 (d, J=8.3 Hz, 1H), 7.60-7.71 (m, 2H), 7.47-7.56 (m, 2H), 7.22 (dd, J=1.6, 8.4 Hz, 1H), 6.94 (s, 1H), 5.15 (s, 2H), 3.87 (s, 3H), 2.76 (s, 3H). LCMS (ESI) m/z 342 (M+H)+.

Workup

  1. temperaturethe reaction mixture was cooled to rt
  2. custompartitioned between EtOAc (150 mL) and water (50 mL)
  3. customThe EtOAc layer was separated
  4. washwashed with brine (50 ml)
  5. dry with materialdried over Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated under reduced pressure
  8. customThe residue was purified via silica gel flash chromatography (
  9. washeluting isocratically with 1% MeOH in CH2Cl2)

Sources & evidence

ORD record
ord-1bab1ed016f74652a18edafb93c6ee4c
Source dataset
uspto-grants-2015_02
Patent number
US08952058B2

Reaction notes

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