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

HRID 2401798Notes

Reaction equation

HRID 2401798 reaction equation
Br[C:2]1[N:3]=[C:4]([C:20]2[C:21]([CH3:36])=[N:22][N:23]3[CH:28]=[CH:27][C:26]([CH:29]([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])=[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:38][C:39]1[CH:46]=[CH:45][C:42]([CH2:43][Zn+])=[CH:41][CH:40]=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:38][C:39]1[CH:46]=[CH:45][C:42]([CH2:43][C:2]2[N:3]=[C:4]([C:20]3[C:21]([CH3:36])=[N:22][N:23]4[CH:28]=[CH:27][C:26]([CH:29]([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])=[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:41][CH:40]=1

Participants

5

Reactant 3

HCID 8028TetrahydrofuranHCID 667494563-[4-Bromo-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-1,3-thiazol-2-yl]-5-(diethoxymethyl)-2-methylpyrazolo[1,5-a]pyridineHCID 178478120HCID 178478120, compound

Product 1

HCID 667491933-[4-(4-Chlorobenzyl)-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-1,3-thiazol-2-yl]-5-(diethoxymethyl)-2-methylpyrazolo[1,5-a]pyridineYield 70.5%

Reagents, catalysts & solvents 1

HCID 178418851HCID 178418851, compoundCatalyst

Conditions

Temperature
60 °C

Procedure

A mixture of 3-[4-bromo-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-1,3-thiazol-2-yl]-5-(diethoxymethyl)-2-methylpyrazolo[1,5-a]pyridine (0.907 g, 1.53 mmol) and bis(tri-t-butylphosphine)palladium(0) (39.0 mg, 0.0764 mmol) in a 40 mL vial was evacuated under low vacuum and backfilled with nitrogen four times. 4-Chlorobenzylzinc chloride in tetrahydrofuran (0.50 M, 7.0 mL, 3.5 mmol) was added and the solution was again evacuated under low vacuum and backfilled with nitrogen twice. The solution was heated to 60° C. for 4 hours. The reaction mixture was cooled to rt, quenched with water, adjusted to ˜pH 6 with acetic acid, and extracted with EtOAc (2×). The organic layers were combined, washed with water, brine, dried over Na2SO4, filtered and evaporated to give a crude residue which was purified by column chromatography on silica gel column using EtOAc/hexane (0/100 to 40/60) as an eluant to give a solid product (0.806 g, 85% pure by 1H-NMR, yield 70.5%). LCMS: (FA) ES+ 639, 641. 1H NMR of pure fraction (400 MHz, CDCl3) δ: 8.36-8.39 (m, 2H), 8.27 (s, 1H), 7.45-7.47 (m, 2H), 7.23-7.25 (m, 2H), 6.99-7.01 (m, 1H), 5.54 (s, 2H, 5.50 (s, 1H), 4.67 (s, 2H), 3.66-3.74 (m, 4H), 3.57-3.62 (m, 2H), 2.74 (s, 3H), 1.26-1.30 (m, 6H), 0.95-0.99 (m, 2H), 0.00 (s, 9H).

Workup

  1. customwas evacuated under low vacuum
  2. customthe solution was again evacuated under low vacuum
  3. temperatureThe reaction mixture was cooled to rt
  4. customquenched with water
  5. extractionextracted with EtOAc (2×)
  6. washwashed with water, brine
  7. dry with materialdried over Na2SO4
  8. filtrationfiltered
  9. customevaporated

Sources & evidence

ORD record
ord-a23f559edaf24e4fb18fe000595bf2eb
Source dataset
uspto-grants-2014_08
Patent number
US08796268B2

Reaction notes

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