3-Hydroxypyridine → 4-(3-Pyridyloxymethyl)2-phenylbenzoic acid methyl ester

HRID 2121164Notes

Reaction equation

HRID 2121164 reaction equation
[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10]Cl)=[CH:6][C:5]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1OCCOCCOCCOCCOCCOC1.[OH:37][C:38]1[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=1.[K]>C1(C)C=CC=CC=1.O>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:37][C:38]2[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=2)=[CH:6][C:5]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1

Participants

7

Reactant 4

HCID 79713-HydroxypyridineHCID 2855718-Crown-6HCID 5462222PotassiumHCID 544945664-Chloromethyl-2-phenylbenzoic acid methyl ester

Product 1

HCID 106870984-(3-Pyridyloxymethyl)2-phenylbenzoic acid methyl esterYield 50.2%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 1140TolueneSolvent

Procedure

To a solution of 11.1 g (42.3 mmol) of 4-chloromethyl-2-phenylbenzoic acid methyl ester, prepared as in Example 187A, in 150 mL of toluene was added 1.7 g (6.4 mmol) of 18-Crown-6, and 8.40 g (63.1 mmol) of 3-hydroxypyridine, potassium salt. The reaction was stirred at ambient temperature for 20 minutes, then heated to reflux under N2. After 3 hours, the mixture was poured into 100 mL of water. The layers were separated, then the aqueous layer was extracted with ethyl acetate (3×100 mL). The combined organic layers were back extracted with 2M aqueous NaOH (2×30 mL), brine (1×100 mL), dried over magnesium sulfate, filtered, and concentrated to an oil which slowly crystallized. The product was recrystallized from 50 mL of 2-propanol to give 6.78 g of a tan solid. The supernatant was concentrated and purified via silica gel chromatography (50:50 hexanes:ethyl acetate) to give another 2.18 g of product, for a total yield of 8.96 g (66%). 1H NMR (300 MHz, d6-DMSO) δ 3.60 (s, 3H), 5.33 (s, 2H), 7.28-7.54 (m, 8H), 7.57 (dd, J=1.5, 9.0 Hz, 1H), 7.78 (d, J=9 Hz, 1H), 8.18 (dd, J=1.0, 5.5 Hz, 1H), 8.38 (d, J=3.0 Hz, 1H).

Workup

  1. temperatureheated
  2. temperatureto reflux under N2
  3. waitAfter 3 hours
  4. customThe layers were separated
  5. extractionthe aqueous layer was extracted with ethyl acetate (3×100 mL)
  6. extractionThe combined organic layers were back extracted with 2M aqueous NaOH (2×30 mL), brine (1×100 mL)
  7. dry with materialdried over magnesium sulfate
  8. filtrationfiltered
  9. concentrationconcentrated to an oil which
  10. customslowly crystallized
  11. customThe product was recrystallized from 50 mL of 2-propanol

Sources & evidence

ORD record
ord-e89e8abce4ca4a0f85b319f2f14615ce
Source dataset
uspto-grants-2004_02
Patent number
US06693123B2

Reaction notes

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