| 83.4% |
|
[0150] In a 5L three-necked flask, 320 g (1.453 mol) of cyclopentylmandelic acid racemate, 2670 mL of acetonitrile and 211 mL of water were added, stirred and heated for dissolution. The temperature of the reaction mixture was 40-45 C, at which time the solid was completely dissolved. 141.53g (0.725 mol) of D-tyrosine methyl ester was added at this temperature to precipitate a solid. A heating was performed until the reaction mixture was refluxed and the solid was completely dissolved so that a clear and transparent solution is obtained. The heating was stopped, the reaction mixture was cooled to 0 C in an ice bath, and the reaction was continued with stirring for 4 hours to precipitate a large amount of crystals. The solid was collected by filtration, washed with acetonitrile three times (3150 mL), and dried to obtain 230.69 g of R-cyclopentylmandelic acid D-tyrosine methyl ester salt with a yield of 76.6%. [0151] 230.69 g of the above R-cyclopentylmandelic acid D-tyrosine methyl ester salt was added to a 5L three-necked flask, and 2000 mL of toluene and 1000 mL of water were added. 66 mL of concentrated hydrochloric acid was added with stirring, heated to 40 C in an water bath until the solid was completely dissolved, and cooled. The aqueous phase and organic phase were separated with a separatory funnel. 20 mL of concentrated hydrochloric acid was added to the aqueous phase and extracted twice (2250 mL) with toluene. The organic phases were combined and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, the solvent was removed under reduced pressure, and the residue was added with 500 mL of n-hexane and stirred to produce a large amount of solid. The solid was filtered and dried at 45 C for 3 hours to obtain 134.4 g of R-cyclopentylmandelic acid white solid with a yield of 83.4%. |
| 33.3 - 37.6% |
|
(-)-Strychnine (6.10 g) in 50 ml of methanol (suspension) was added to racemic cyclopentylmandelic acid 1, (3.96 g) in methanol (20 ml) at room temperature. The reaction solution was let to stand for overnight. The crystals were removed by filtration and crystallized again with hot methanol. The second crop of crystals was collected by filtration and treated with sodium hydroxide solution. The basic solution was extracted with methylene chloride twice (methylene chloride solution discarded), and then acidified with hydrochloric acid to recover the resolved cyclopentylmandelic acid. To this resolved acid (20.6 mg in 0.1 ml of ethyl acetate), 13 muL of (+)-alpha-phenylethylamine was added. The precipitate which formed was washed with hexane three times and dried under vacuum. The precipitate was identified by NMR as optically pure cyclopentylmandelic acid, R(-)1, (1.49 g, 37.6%). M.p.: 121-122 C. [alpha]25D=-22.5 (c=1 g/100 ml, CHCl3). 1H NMR(CDCl3, 500 MHz): 1.28-1.39, 1.42-1.50, 1.51-1.61, 1.64-1.73 [8H, m, (CH2)4], 2.93 [1H, p, CHC(OH)], 7.25-7.28, 7.32-7.35, 7.64-7.65(5H, m, Ph) ppm. ; (-)-Strychnine (11.4 g) in 100 ml of methanol (suspension) was added to racemic cyclopentylmandelic acid 1 (7.5 g) in methanol (20 ml) at room temperature. The reaction solution was allowed to stand overnight. The crystals were filtered and crystallized again with hot methanol. The second crop of crystals was collected by filtration and treated with sodium hydroxide solution. The basic solution was extracted with methylene chloride twice (methylene chloride solution discarded), and then acidified with hydrochloric acid to recover the resolved cyclopentylmandelic acid. To this resolved acid (20.6 mg in 0.1 ml of ethyl acetate), 13 muL of (+)-alpha-phenylethylamine was added. The precipitate which formed was washed with hexane three times and dried under vacuum. The precipitate was identified by NMR as optically pure cyclopentylmandelic acid, R(-)1, (2.5 g, 33.3%). M.p.: 121-122 C. [alpha]25D=-22.5 (c=1 g/100 ml, CHCl3). 1H NMR(CDCl3, 300 MHz): 1.28-1.39, 1.42-1.50, 1.51-1.61, 1.64-1.73 [8H, m, (CH2)4], 2.93 [1H, p, CHC(OH)], 7.25-7.28, 7.32-7.35, 7.64-7.65(5H, m, Ph) ppm. |
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