Preparation of 4-(4-hydroxyphenyl)butyric acid_Kain Industrial Additives

Background

4-(4-Hydroxyphenyl)butyric acid is an organic synthesis intermediate and pharmaceutical intermediate that can be used in laboratory research and development processes and chemical and pharmaceutical synthesis processes.

Preparation^[1-2]

Method 1,

Step 1

4-(3-Chloro-4-methoxyphenyl)-4-oxobutyric acid (131): AlCl₃ (7.78g, 57.4mmol) was dissolved in CH₂Cl₂ (47 mL) was cooled to 0°C and 2-chloroanisole (5.00 g, 35.0 mmol) in nitromethane was added dropwise over 15 minutes. (3.2mL) was dropped into the above system, the solution was heated to room temperature, and treated with succinic anhydride (2.34g, 23.3mmol) in batches within 0.5 hours. Heat the reaction mixture under reflux for 8 hours, remove HCl (g), cool to room temperature, pour in rapidly stirring ice (25g), 2N H₃PO₄ (250mL) Quench with CH₂Cl₂ (250 mL) mixture. A precipitate forms and the suspension is stirred for 6 hours. The precipitate is dissolved and the aqueous mixture is extracted with CH₂ Cl ₂, washed with water, brine and dried (MgSO₄), filtered and concentrated under reduced pressure. Purification by column chromatography on SiO₂ (1:19, MeOH:CH₂Cl₂) gave 5.27 g (93%) 131, a white solid: Rf = 0.27 (10:90, MeOH: CH₂Cl₂); melting point 184°C (CH₂Cl ₂).

Step 2

4-(4-Methoxyphenyl)butyric acid (132): Treat a hydrogenator vessel containing 3% Pd/C (983 mg, 0.278 mmol) with a mixture of THF (5 mL) and water (5 mL) to A suspension is formed. Add acid 131 (5.27g, 22mmol) to the suspension, evacuate the container, add H₂ (2x), pressurize with H₂ to 40p.s.i and Shake for 24 hours. The reaction mixture was depressurized, filtered through a plug of Celite, diluted with EtOAc (50 mL), washed with water, brine, dried (Na₂SO₄), filtered and reduced to Pressure concentration. Purification by column chromatography on SiO₂ (1:19, MeOH:CH₂Cl₂) gave 3.20 g (76%) 132.

Step 3

4-(4-Hydroxyphenyl)butyric acid (133): Dissolve 132 (2.55g, 13.1mmol) in CH₂Cl₂ (187mL) The solution was cooled to -78°C and treated with 1.0 M BBr₃ solution dropwise over 10 minutes. CH₂Cl₂ (59 mL, 59 mmol) was stirred at -78°C and room temperature for 3 h and continued for 2 h. Pour the reaction mixture into a saturated ice mixture. Stir NH₄Cl and CH₂Cl₂ for 0.5 hours, and use CH₂Cl₂ (2x) extraction. The combined organic extracts were washed with brine, dried (MgSO₄), filtered and concentrated under reduced pressure. Purification by column chromatography on SiO2 (1:3, hexane:EtOAc) afforded 1.89 g (80%) of 133 as a white solid.

Method 2,

Dissolve 4-(4-methoxyphenyl)butyric acid (25g, 129mmol) in 48% HBr (125ml) and AcOH (125ml). The resulting solutionHeat at 150°C overnight. The resulting mixture was concentrated in vacuo and the residue was taken up in EtOAc (500 ml). The solution was washed with water (500 ml), dried (MgSO₄) and concentrated to give 4-(4-hydroxy-phenyl)-butyric acid as a brown solid.

Main reference materials

[1] Englund, Erika ElaineFrom 289 pp.; 2008

[2] PCT Int. Appl., 2011050325, 28 Apr 2011