Acetic Acid → 2-(3,4-Dimethoxy-phenyl)-5-[6-(4-methyl-piperazin-1-yl)-5-trifluoromethyl-pyridin-3-yl]-imidazo[2,1-b][1,3,4]thiadiazole

HRID 2409560Notes

Reaction equation

HRID 2409560 reaction equation
[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[S:15][C:14]3=[N:16][CH:17]=[C:18]([C:19]4[CH:20]=[N:21][C:22]([N:29]5[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]5)=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=4)[N:13]3[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:35]CN(CC)CC.C=O.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[S:15][C:14]3=[N:16][CH:17]=[C:18]([C:19]4[CH:20]=[N:21][C:22]([N:29]5[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]5)=[C:23]([C:25]([F:27])([F:28])[F:26])[CH:24]=4)[N:13]3[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]

Participants

7

Reactant 5

HCID 176Acetic AcidHCID 712FormaldehydeHCID 8471TriethylamineHCID 5003444Sodium cyanoborohydrideHCID 667169522-(3,4-Dimethoxy-phenyl)-5-(6-piperazin-1-yl-5-trifluoromethyl-pyridin-3-yl)-imidazo[2,1-b][1,3,4]thiadiazole

Product 1

HCID 667169812-(3,4-Dimethoxy-phenyl)-5-[6-(4-methyl-piperazin-1-yl)-5-trifluoromethyl-pyridin-3-yl]-imidazo[2,1-b][1,3,4]thiadiazoleYield 50%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Procedure

To a mixture of 2-(3,4-Dimethoxy-phenyl)-5-(6-piperazin-1-yl-5-trifluoromethyl-pyridin-3-yl)-imidazo[2,1-b][1,3,4]thiadiazole (105 mg, 0.199 mmol, 1 eq), Et3N (0.056 mL, 0.399 mmol, 2 eq), formaldehyde (0.180 mL, 2.39 mmol, 12 eq) and acetic acid (0.02 mL, 0.239 mmol, 1.2 eq) in MeOH (4 mL) was added Sodium cyanoborohydride (0.175 g, 2.79 mmol, 14 eq). The reaction mixture was stirred at rt for 2 h. Solvents were evaporated to dryness and the residue was dissolved in sat NaHCO3/EtOAc. Layers were separated and the aqueous layer was extracted once with EtOAc. The combined organic layers were dried, filtered and evaporated. The residue was purified on silica gel (isolute flash Si II, 10 g, 96:4 DCM/7N NH3 in MeOH) to give the desired product (50 mg, 50%). HPLC-MS: (5-100% B in 8 min, 0.8 mL/min, 50° C.): tR=3.47 min, [M+H]+ m/z 505.3; 1H NMR (300 MHz, CDCl3) δ 8.92 (s, 1H), 8.49 (d, J=1.9 Hz, 1H), 7.52 (s, 1H), 7.42 (d, J=1.7 Hz, 1H), 7.36 (dd, J=8.3, 2.0 Hz, 1H), 6.90 (d, J=8.4 Hz, 1H), 3.94 (s, 3H), 3.88 (s, 3H), 3.41 (m, 4H), 2.57 (m, 4H), 2.34 (s, 3H).

Workup

  1. customSolvents were evaporated to dryness
  2. dissolutionthe residue was dissolved in sat NaHCO3/EtOAc
  3. customLayers were separated
  4. extractionthe aqueous layer was extracted once with EtOAc
  5. customThe combined organic layers were dried
  6. filtrationfiltered
  7. customevaporated
  8. customThe residue was purified on silica gel (isolute flash Si II, 10 g, 96:4 DCM/7N NH3 in MeOH)

Sources & evidence

ORD record
ord-4bb1b2355f9849cdbea039877918f2cf
Source dataset
uspto-grants-2014_08
Patent number
US08815918B2

Reaction notes

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