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With triethylamine; In toluene; at 0 - 20℃; for 2.25h; |
66.0 g (436 mmol) of 2-(5-ethylpyridin-2-yl)ethanol was dissolved in 500 mL of toluene. 72.5 mL (523 mmol) of triethylamine was added to this solution, at room temperature. The resulting solution was cooled between 0 and 10C, after which 34.0 mL (438 mmol) of methanesulphonyl chloride was added dropwise during 75 minutes. When addition was completed, it was stirred for 1 hour at room temperature. Next, the organic phase was washed with a saturated solution of sodium bicarbonate (400 mL) and with water (400 mL), and was dried over sodium sulphate, obtaining a toluene solution of 2-(5-ethylpyridin-2-yl)ethyl methanesulphonate, a compound of formula (III) in which Z = OMs. The said solution in toluene (equivalent to 436 mmol) was added to a mixture containing 120 g (425 mmol) of the compound obtained in stage 1.A, 64.5 g (467 mmol) of potassium carbonate and 2.7 g (8.4 mmol) of tetrabutylammonium bromide. An additional 700 mL of toluene was added, and the resulting suspension was stirred at 70C. After 8 hours, a further 110 mL of the aforementioned solution in toluene (equivalent to 93 mmol) and 14.0 g (191 mmol) of potassium carbonate were added to the reaction mixture, stirring of which continued at 70C. After 30 hours, 2.7 g (8.4 mmol) of tetrabutylammonium bromide was added. Once reaction was completed (40 hours), the suspension obtained was used directly, without purification, in the next stage. 1360 mL of 2N HCl was added to the suspension obtained in the preceding stage. The resulting mixture was stirred for 1 hour at 70C. The phases were decanted and the aqueous phase was extracted, discarding the toluene phase. The aqueous phase was returned to the reactor and was alkalized by addition of aqueous solution of NaOH at 50%. After alkalization, the resulting solution was stirred for 2 hours at 70C. After cooling, the aqueous phase was washed with toluene (2 x 250 mL) and was neutralized with concentrated HCl to pH 5, with precipitation of a solid of a pale yellow colour that was filtered in a Buchner funnel. The filtered solid was digested in 825 mL of water and was recrystallized from methanol, obtaining (+/-)-2-amino-3-[4-[2-(5-ethylpyridin-2-yl)ethoxy]phenyl]propionic acid, compound (IV) (83.9 g, 62.8% overall yield from L-tyrosine) in the form of a solid of a pale yellow colour. It was demonstrated by chiral HPLC and by experiments of optical rotatory dispersion that the product is obtained in the form of a racemic mixture. The compound is very slightly soluble in the usual solvents for NMR. To record its 1H and 13C spectra, an aliquot in 1M HCl is dissolved in MeOH (anhydrous), followed by solvent evaporation at reduced pressure. Consequently, the NMR spectra recorded correspond to the double hydrochloride of compound (IV). The spectral data are as follows: 1H-NMR (CD3OD, 400 MHz) delta (ppm): 8.68 (s, 1 H, H6 pyridine), 8.48 (d, 3JH3-H4 = 7.8 Hz, 1 H, H4 pyridine), 8.05 (d, 3JH3-H4 = 7.8 Hz, 1 H, H3 pyridine), 7.22 (d, 3JH2-H3 = 8.6 Hz, 2 H, H3 benzene), 6.93 (d, 3JH2-H3 = 8.6 Hz, 2 H, H2 benzene), 4.42 (t, 3JH-H = 5.6 Hz, 2 H, pyr-CH2-CH2O-), 4.21 (dd, 3JHb-H = 7.2 Hz, 3JHa-H = 6.0 Hz, 1 H, -CH-COOH), 3.54 (t, 3JH-H = 5.6 Hz, 2 H, pyr-CH2-CH2O-) , 3.23 (dd, 2JHa-Hb = 14.4 Hz, 3JHa-H = 6.0 Hz, 1 H, Ha benzyl), 3.13 (dd, 2JHa-Hb = 14.4 Hz, 3JHb-H = 7.2 Hz, 1 H, Hb benzyl), 2 . 89 (q, 3JH-H = 7 . 4 Hz, 2 H, pyr-CH2-CH3) , 1.33 (t, 3JH-H = 7 . 4 Hz, 3H, pyr-CH2-CH3) . 13C-NMR (CD3OD, 100 MHz) delta (ppm): 171 . 11 (-COOH), 159.18 (C2 pyridine), 153.15 (C1 benzene), 147 . 73 (C4 pyridine), 143.83 (C5 pyridine), 140.95 (C6 pyridine), 131.76 (C3 benzene), 128.82 (C3 pyridine), 128.19 (C4 benzene), 116.17 (C2 benzene), 66.89 (pyr-CH2-CH2O-), 55.16 (-CH-COOH), 36.36 (CH2 benzyl), 34.15 (pyr-CH2-CH2O-), 26.30 (pyr-CH2-CH3), 14.85 (pyr-CH2-CH3). |
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With triethylamine; In dichloromethane; at 0 - 20℃;Inert atmosphere; |
To a solution of 2-(5-ethyI~pyrdne-2-yiDCM (130 mL) at 0 0C under nitrogen was added methane sulfonyl chloride (15.56 ml), then the reaction mixture was allowed to warm to room temperature and stirred overnight. A further portion of methane sulfonyl chloride (3.88 ml) was added and the reaction stirred for 30 min. The reaction was diluted with DCM and washed with H2O and brine. The organic layer was dried (MgSO4) and the solution concentrated to give the title compound as a oil (38.24 g). 1H NMR (400 MHz, CDCI3 ): delta 8.39 (d, J = 2.2 Hz, 1 H), 7.47 (dd, J = ' 7.7, 2.3Hz, 1 H), 7.14 (d, J? 7.7 Hz, 1 H), 4.64 (t, J = 6.5 Hz, 2H), 3.19 (t, J = 6.5 Hz, 2H)1 2.9C (s, 3H), 2.64 (q, J = 7.6 Hz, 2 H), 1.25 (t, J = 7.6 Hz, 3H). |
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