Hydroxyphenylacetic acid → HCID 23369908, compound

HRID 1590228Notes

Reaction equation

HRID 1590228 reaction equation
[CH3:1][C:2]1([CH3:11])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][CH:4]([OH:10])[CH2:3]1.[OH:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20](O)=[O:21])=[CH:15][CH:14]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>O>[OH:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:10][CH:4]2[CH2:3][C:2]([CH3:11])([CH3:1])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5]2)=[O:21])=[CH:15][CH:14]=1

Participants

6

Reactant 4

HCID 127Hydroxyphenylacetic acidHCID 241BenzeneHCID 6101p-Toluenesulfonic acidHCID 758513,3,5,5-Tetramethylcyclohexanol

Product 1

HCID 23369908HCID 23369908, compoundYield 48.2%

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Procedure

3,3,5,5-Tetramethylcyclohexanol (7.81 g, 0.05 mol), 4-hydroxyphenylacetic acid (7.6 g, 0.05 mol), p-toluenesulfonic acid (2 g) and benzene (200 mL) were refluxed with continuous water separation for 8 hours. The reaction mixture was evaporated, the oily residue was dissolved in ethyl acetate (100 mL), washed first with aqueous 5% NaHCO3 solution (100 mL) and then twice with water (200 mL), then dried over anhydrous MgSO4. The solvent was evaporated under reduced pressure to give 3,3,5,5-tetramethylcyclohexyl 4-hydroxyphenylacetate as a solid (7.00 g, 8.20% yield). 3,3,5,5-Tetramethylcyclohexyl 4-hydroxyphenylacetate was taken up in acetone (25 mL), combined with epichlorohydrin (20 mL) with stirring and refluxed for 2 hours in the presence of dBU (1 mL), 0.007 mol). The reaction mixture was evaporated. The oily residue was taken up in acetonitrile (50 mL). Isopropylamine (20 mL, 0.23 mol) was added and the reaction mixture was refluxed for 4 hours, then was evaporated to give the crude free amine base as an oil. The oil was taken up in acetone and an equivalent amount of oxalic acid (5.2 g, 0.05 mol) was added. The acetone solution was concentrated and partitioned between ether (100 mL) and aqueous 1M KOH solution (50 mL). The ether layer was separated and washed with 1M HCl (50 mL). The acidic layer was basified with aqueous 1M KOH solution and extracted with fresh anhydrous ethyl ether. The ether layer was separated, dried over anhydrous MgSO4, filtered and evaporated. The residue was dissolved in acetone (25 mL), an equivalent amount of oxalic acid in acetone was added, and the oxalate salt of 3,3,5,5-tetramethylcyclohexyl 4-(2-hydroxy-3-isopropylamino)-propoxyphenylacetate which separated on cooling was isolated. The product melted at 96°-98° C. The free base has the structure shown in EXAMPLE 8.

Workup

  1. customThe reaction mixture was evaporated
  2. dissolutionthe oily residue was dissolved in ethyl acetate (100 mL)
  3. washwashed first with aqueous 5% NaHCO3 solution (100 mL)
  4. dry with materialtwice with water (200 mL), then dried over anhydrous MgSO4
  5. customThe solvent was evaporated under reduced pressure

Sources & evidence

ORD record
ord-b93707f942384bfb929cefdd12998282
Source dataset
uspto-grants-1993_04
Patent number
US05202347

Reaction notes

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