4-bromo-2-(2-methylpyrazolo[1,5-a]pyridin-3-yl)-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)thiazole → 3-[4-(4-Chlorobenzyl)-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-1,3-thiazol-2-yl]-2-methylpyrazolo[1,5-a]pyridine

HRID 2402025Notes

Reaction equation

HRID 2402025 reaction equation
Br[C:2]1[N:3]=[C:4]([C:20]2[C:21]([CH3:29])=[N:22][N:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=23)[S:5][C:6]=1[C:7]1[N:11]=[CH:10][N:9]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[N:8]=1.[Cl-].[Cl:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36][Zn+])=[CH:34][CH:33]=1>O1CCCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[Cl:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36][C:2]2[N:3]=[C:4]([C:20]3[C:21]([CH3:29])=[N:22][N:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=34)[S:5][C:6]=2[C:7]2[N:11]=[CH:10][N:9]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[N:8]=2)=[CH:34][CH:33]=1

Participants

5

Reactant 2

HCID 580948524-bromo-2-(2-methylpyrazolo[1,5-a]pyridin-3-yl)-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)thiazoleHCID 178478120HCID 178478120, compound2×

Product 1

HCID 667494813-[4-(4-Chlorobenzyl)-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-1,3-thiazol-2-yl]-2-methylpyrazolo[1,5-a]pyridineYield 86%

Reagents, catalysts & solvents 2

HCID 178418851HCID 178418851, compoundCatalystHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
60 °C

Procedure

To a solution of 3-[4-bromo-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-1,3-thiazol-2-yl]-2-methylpyrazolo[1,5-a]pyridine (0.200 g, 0.407 mmol) in tetrahydrofuran (2.8 mL) were added 4-chlorobenzylzinc chloride (0.50M solution in tetrahydrofuran, 1.63 mL, 0.814 mmol) and bis(tri-t-butylphosphine)palladium(0) (0.0156 g, 0.0305 mmol) under argon. The solution was stirred at 60° C. for 3 hours. The reaction was incomplete by LCMS, so additional 4-chlorobenzylzinc chloride (0.50M solution in tetrahydrofuran, 1.0 mL, 0.5 mmole) was added then the reaction was stirred at 60° C. for an additional 3 hours. The reaction was cooled to room temperature then the solvent was evaporated in vacuo. The residue was purified by column chromatography (SiO2, elution with EtOAc in hexanes 10-100% gradient) to yield the title compound (0.188 g, 86%). LCMS: (FA) ES+, 538. 1H NMR (400 MHz, d6-DMSO) δ: 8.87 (s, 1H), 8.76-8.72 (m, 1H), 8.28-8.24 (m, 1H), 7.54-7.48 (m, 1H), 7.44-7.40 (m, 2H), 7.35-7.30 (m, 2H), 7.09-7.03 (m, 1H), 5.58 (s, 2H), 4.63 (s, 2H), 3.68-3.62 (m, 2H), 2.66 (s, 3H), 0.91-0.84 (m, 2H), 0.050 (s, 9H).

Workup

  1. additionwas added
  2. stirringthe reaction was stirred at 60° C. for an additional 3 hours
  3. temperatureThe reaction was cooled to room temperature
  4. customthe solvent was evaporated in vacuo
  5. customThe residue was purified by column chromatography (SiO2, elution with EtOAc in hexanes 10-100% gradient)

Sources & evidence

ORD record
ord-2c335265dae74f9ebbfa227dce4ef145
Source dataset
uspto-grants-2014_08
Patent number
US08796271B2

Reaction notes

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