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To a solution of methyl-4-(l-hydroxyethyl)benzoate (2.00 g, 11.10 mmol) in a mixture of THF (20 mL) and MeOH (10 mL) was added 1 M KOH (13.32 mL, 13.32 mmol). After stirring at room temperature overnight, the solution was diluted with 2 N HCl and extracted with EtOAc (4x). The combined organic layers were dried (MgSO4) and evaporated to give 4-(l-hydroxyethyl)benzoic acid as a colorless solid. 1H NMR (DMSO-dzeta, 600 MHz) delta 7.86 (d, J = 8.6 Hz, 2H), 7.43 (d, J = 8.3 Hz, 2H), 4.75 (q, J = 6.5 Hz, IH), 1.30 (d, J = 6.6 Hz, 3H). MS: cal'd 167 (MH+), exp 167 (MH+).
EXAMPLE 33 1.8 g (10 mmol) of (+)-methyl 4-(1-hydroxyethyl)benzoate (V-1) obtained in Example 1 was dissolved in 30 ml of dimethylformamide and then cooled to 10 C. 0.3 g (13 mmol) of sodium hydride was added thereto and stirred at a temperature of 30-35 C. for a hour. Then, 4.8 g (14 mmol) of n-dodecyl tosylate was added at a temperature of 20-25 C., and thereafter stirred at 40 C. for 3 hours. After completion of the reaction, the reaction mixture was poured into ice-water and then subjected to extraction-treatment with 100 ml of ether. The organic layer was water-washed and then concentrated in vacuo. The residue was then purified through a column chromatography to obtain 3.08 g of (+)-methyl 4-(1dodecyloxyethyl)benzoate (VII-33). Yield: 88.5%, nD20 =1.4762, [alpha]D20 +29.6 (c=1, CHCl3).
EXAMPLE 2 A solution of 3.6 g (0.02 mol) of V-1 obtained in Example 1 in 30 ml of N-methylpyrrolidone was cooled to 5 C., followed by addition of 0.95 g (0.04 mol) of sodium hydride. The mixture was maintained at 30-35 C. for one hour, then added with 7.1 g (0.05 mol) of methyl iodide at 15-20 C. and reacted at 20-30 C. for 2 hours and further at 40-50 C. for additional 2 hours. The resulting reaction mixture was poured into ice-water and extracted with 60 ml of ethyl acetate. The extract was further treated according to Example 1 to obtain 3.59 g (92.5% yield) of (+)-methyl 4-(1-methoxyethyl)benzoate (VII-2). ([alpha]D20 =+75.9 (c=1, CHCl3), nD20 =1.4996).
(+)-methyl 4-(1-ω-ethoxypropoxyethyl)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
In tetrahydrofuran; N-methyl-acetamide;
EXAMPLE 4 3.6 g (0.02 mol) of V-1 obtained in Example 1 was dissolved in a solution of 20 ml of dimethylformamide and 10 ml of tetrahydrofuran and cooled to 10 C. Then 0.62 g (0.026 mol) of sodium hydride was added and the mixture was maintained at 30-35 C. for one hour. This mixture was further added with 8.26 g (0.032 mol) of omega-ethoxypropyl tosylate and reacted at 50-60 C. for 5 hours. The reaction mixture was treated according to Example 1 to give 4.79 g (90% yield) of (+)-methyl 4-(1-omega-ethoxypropoxyethyl)benzoate (VII-4). ([alpha]D20 =+46.5 (c=1, CHCl3), nD20 =1.4933).
EXAMPLE 3 A solution consisting of 3.6 g (0.02 mol) of V-1 obtained in Example 1 and 30 ml of dimethylformamide was cooled to 10 C., then added with 0.62 g (0.026 mol) of sodium hydride and kept at 30-35 C. for one hour. The mixture was further added with 7.69 g (0.03 mol) of n-hexyl tosylate at 20-25 C. and reacted at 40-50 C. for 5 hours. The reaction mixture was treated according to Example 1 to obtain 4.60 g (92% yield) of (+)-methyl 4-(1-hexyloxyethyl)benzoate (VII-3). ([alpha]D20 =+60.6 (c=1, CHCl3), nD20 =1.4922).
With sodium cyanoborohydride; In methanol; chloroform; water;
(a) Methyl 4-(1-bromoethyl)benzoate was obtained as follows: 2 M Methanolic hydrochloric acid was added in portions to a stirred suspension of 3.6 g. of methyl 4-acetylbenzoate (obtained as a solid, m.p. 90-92 C., by conventional esterification of the corresponding acid) and 1.4 g. of sodium cyanoborohydride in methanol containing a single crystal of the indicator methyl orange, so that a red colour persisted. After 4 hours a further 173 mg. of sodium cyanoborohydride was added and the red colour again maintained by addition of 2 M methanolic hydrochloric acid. One hour after the final addition of reagents the solvents were evaporated and the residue was dissolved in water. The solution obtained was extracted with ether. The extracts were then dried (Na2 SO4) and evaporated. The residue was purified by chromatography on silica using 3:97 v/v ether and chloroform as eluant to give 2.9 g. (80%) methyl 4-(1-hydroxyethyl)benzoate as a yellow oil; partial NMR: 1.50 (d,3H,CH3), 3.91 (s,3H, OCH3), 4.94 (q, 1H,CH.OH).
3.6 g (0.02 mol) of V-1 was dissolved in 30 ml of dimethylformamide and cooled to 10° C. Then 0.62 g (0.026 mol) of sodium hydride was added and the mixture was maintained at 30°-35° C. for one hour. Then the solution was further added with 6.0 g (0.028 mol) of n-propyl tosylate at 20°-25° C. and reacted at 40° C. for 5 hours. The reaction mixture was poured into ice-water and extracted with 50 ml of ethyl acetate. The organic layer was washed with water and concentrated under reduced pressure, and the concentrated residue was purified by column chromatography to obtain 4.0 g (90percent yield) of (+)-methyl 4-(1-propoxyethyl)benzoate (VII-1). ([alpha]D20 =+63.4° (c=1, CHCl3), nD20 =1.4928).
72.0 g (0.324 mol) of IV-1 was mixed with 400 ml of a 0.3M phosphate buffer (pH 7.5) and 4.8 g of Amano Lipase P and stirred vigorously at 40-45 C. for 40 hours. The resulting reaction mixture was extracted with 600 ml of methyl isobutyl ketone. The organic layer was concentrated under reduced pressure and the residue was purified by column chromatography using a 12:1 mixed solution of hexane and ethyl acetate as an eluding solvent to obtain 25.52 g of (+)-methyl 4-(1-hydroxyethyl)benzoate (V-1) ([alpha]D20 =+42.3 (c=1, CHCl3), 99.4% ee, m.p.=52-53 C.) and 39.6 g of unreacted ester.
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