| 95% |
With triethylamine; In acetonitrile; at 20℃; |
A solution of [(4R,6R)-6-(2-Amino-ethyl)-2,2-dimethyl-[1,3]dioxan-4-yl]-acetic acid tert-butyl ester (26.3 g; 96 mmol) and bromo-(4-fluoro-phenyl)-acetic acid methyl ester (22.6 g; 92 mmol) in acetonitrile (200 mL) was treated with triethylamine (18.5 g; 182 mmol). After 30 minutes a considerable precipitate was noted. The reaction was allowed to stir at rt overnight then filtered to remove the precipitate. The filtrate was concentrated to dryness. The residue was dissolved in EtOAc, washed with H2O and brine, dried (MgSO4), and concentrated to give a crude oil. The oil was triturated with hexanes to give a white solid which was collected by vacuum filtration and air dried; yield: 38.1 g (95percent); Low resolution mass spectroscopy (APCI) m/z 440 [M+H]+. |
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With triethylamine; In acetonitrile; at 20℃; for 16h; |
Example 5; To a dry MEOH solution (50 ML) containing 4-FLUOROPHENYLACETIC acid 5A (5 g, 0.0324 mole) was added a catalytic amount of 4-toluene sulfonicacid (0.324 mmole, 61 mg). The solution was refluxed for 4 h. The resultant solution was concentrated under reduced pressure to give pale-yellow syrup. The material was diluted with EtOAc (100 mL), and neutralized with NAHCO3 (1M, 5 mL). The organic layer was then washed with H20 (10 mLx2), followed by brine (10 mL), dried over MGS04 and filtered. The filtrate was concentrated to give a pale-yellow liquid. (5.33 g, 31.75 mmole, 98 percent, MS M+H = 169 found: 169, 1H NMR structure confirmed). The methyl ester (2. 0g, 11.9 mmole) was then added to a CCL4 solution (100 mL) containing NBS (2.33 g, 13.09 mmole). The reaction mixture was refluxed at 80 °C for 3 h to yield the brominated methyl ester 5b. The cooled solution was filtered through a pad of silica gel to remove excess SUCCINIMIDE, the filtrate was evaporated under reduced pressure, and the resultant material was transferred to the next reaction without further purification. To an acetonitrile solution containing the amine (TBIA, 2.44 g (8.94 mmole) /15 mL ACN) was added the compound 5B (ca. 2 g). While the reaction mixture was stirred triethylamine was added dropwise (1.70 ML, 12.2 mmole 1.5 equiv. ). The reaction mixture was stirred at ambient temperature for 16 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and diluted with EtOAc (25 mL). The organic layer was treated with H2O, dried over MGS04, and filtered. The filtrate was then concentrated under reduced pressure to give the compound 5c, 3.29 g. Isobutyryl chloride (0.53 ML, 4.99 mmole in 5 mL DCM) was added dropwise to a chilled DCM solution (10 mL) containing the compound 5C (2.0 g, 4.54 mmole). While the reaction mixture was stirred, a triethylamine solution (1.27 ML, 2 equiv. in 5 mL DCM) was added dropwise. The reaction mixture was agitated as it was warmed to room temperature for 2 h. After completion of the reaction, the reaction mixture was treated with IN HCL (20 mL), followed by sat. NAHC03 (3 mL). The organic layer was then washed with water and brine, dried over MGS04, and filtered. The filtrate was concentrated under reduced pressure to give pale-yellow syrup. This was purified by a column chromatography using a gradient of EtOAc-Hexane mixture (from 0 to 25 percent of EtOAc). The isolated yield of the methyl ester was 2.10 g, 4.13 mmole, 90.9 percent. The methyl ester (250 mg, 0.50 mmole) was dissolved in a LIOH solution (1M, THF : water (5: 1) mixture), and vigorously stirred for 3 h. The reaction mixture was neutralized to pH 7 by titrating it with 1N HCL solution. The desired product was then extracted with EtOAc (20 mL). The organic layer was washed with H2O and brine, dried over MgS04, and filtered. The filtrate was then evaporated under reduced pressure to give a white amorphous material 5 (200 mg, 0.40 mmole, 80 percent, MS M+H = 496 found: 496, LU NMR structure confirmed).; Intermediate 3; Solution of 44.87 g (0.164 mol) of amine (TBIA) in 180 ml of acetonitrile was treated with a solution of 36.89 g (0.149 mol) of intermediate 2 in 90 ml of acetonitrile. Mixture was treated with 31.2 ml (0.224 mol) of triethylamine dropwise and stirred overnight at room temperature. Reaction was concentrated and the residue taken up in ethyl acetate and washed with water (2x). Organics were dried over sodium sulfate, filtered, and concentrated to yield approximately 69 g of a thick oil. MS APCI+ 440.2 (M+1). |
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