| 85.1% |
With triethylamine In water; acetone at 20℃; for 27h; |
2.5 Example 2-5 Release of 3-(2-naphthyl)-D-alanine from Nickel (II) Complex Having 3-(2-naphthyl)-D-alanine Moiety Under Acidic Conditions and Protection of 3-(2-naphthyl)-D-alanine with Boc Group
To a suspension of a nickel (II) complex having a 3-(2-naphthyl)-D-alanine moiety (100.0 mg, 0.122 mmol) in methanol (4.0 mL), 1N hydrochloric acid (0.61 mL, 0.609 mmol) was added, and the mixture was stirred at 40 to 50° C. for 8 hours. The reaction mixture was concentrated, and the residue was subjected to phase separation with dichloromethane (10 mL) and water (10 mL). The aqueous layer was separated, and the solvent was removed by evaporation. The obtained solid was dissolved in 9% aqueous ammonia (3 mL). The solution was passed through a cation exchange resin column [SK-1B, 21 mL, eluent: 2 to 4% aqueous ammonia] to give a 3-(2-naphthyl)-D-alanine crude product (22.0 mg, yield: 83.9%) as a white solid. Meanwhile, the organic layer was washed with 2% aqueous ammonia (10 mL, twice), with water (10 mL, twice), and then with saturated brine (10 mL, twice). The organic layer was dried over sodium sulfate, and then the solvent was removed by evaporation to give a chiral auxiliary (S-isomer) (58.7 mg, chemical purity: 98.5%, yield: 85.0%). The 3-(2-naphthyl)-D-alanine crude product (13.0 mg, 0.060 mmol) was dissolved in water (2 mL) and acetone (1.0 mL). To the solution, a solution of (Boc)2O (21.1 mg, 0.097 mmol) in acetone (0.5 mL) and a solution of triethylamine (9.8 mg, 0.097 mmol) in acetone (0.5 mL) were added. The mixture was stirred at room temperature for 27 hours. The reaction mixture was concentrated until the volume was reduced to 2 mL or less, and then toluene (5 mL) was added thereto. To this, 1 N hydrochloric acid was added under stirring until the pH of the aqueous layer was reduced to 2 to 3. The aqueous layer was extracted with toluene (5 mL, 3 times). The organic layer was washed with brine (5 mL, twice) and dried over magnesium sulfate. The solvent was removed by evaporation to give a Boc-3-(2-naphthyl)-D-alanine (16.2 mg, yield: 85.1%, chemical purity: 96.6%, 99.3% ee) as a colorless solid. (0316) HPLC analysis was conducted on the obtained compound under the following conditions. The results are shown in Table 7 and FIG. 7. Column: CHIRALPAK AD-RH (5 μm, 150×4.6 mm i.d.) Eluent: A:B=35:65 (0317) A=0.1% phosphoric acid aqueous solution (0318) B=0.1% solution of phosphoric acid in acetonitrile Flow rate: 0.5 mL/min Temperature: 30° C. Detector: UV 220 nm (0319) [table-us-00007-en] Retention time Isomer of Excess ratio objective Objective (isomer of objective substance:objective substance substance substance) 23.93 29.93 99.3% ee (0.37:99.63) |
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