| 20% |
In toluene; for 24h;Reflux; |
2-cyano phenyl boronic acid and 1,3 propanediol was solubilized in anhydrous toluene. The reaction mixture was refluxed in a flask equipped with a Dean-Stark apparatus. After 24 h, the reaction was concentrated under reduced pressure to give colorless oil. The crude product was purified on silica gel (DCM) to give 2-[1-3]dioxaborinan-2-yl-benzonitrile; yield: 20percent; 1H NMR (300 MHz, CDCl3) delta ppm 2.08 (t, J = 5.4 Hz, 2H), 4.21 (q, J = 5.4 Hz, 4H), 5.31 (ls, 2H), 7.45 (td, J1 = 7.5 Hz, J2 = 1.5 Hz, 1H), 7.53 (td, J1 = 7.5 Hz, J2 = 1.5 Hz, 1H), 7.65 (d, J = 7.5 Hz, 1H), 7.85 (d, J = 7.5 Hz, 1H). The 2-[1-3]dioxaborinan-2-yl-benzonitrile was readily solubilized in toluene (0.2 M). To this solution, compound 3e (1eq), PdCl2(dppf) (2percent) and K3PO4 (2 eq) were added. The mixture was refluxed during 2 h, then was concentrated under reduced pressure. The obtained crude product was dissolved in ethyl acetate and washed by HCl 1N. The organic layer was concentrated under reduced pressure and purified by flash chromatography on silica gel with cyclohexane/ethyl acetate (70/30) to give 9 as a yellow powder; purity 99percent; yield: 83percent; mp: 169-170 °C; 1H NMR (300 MHz, CDCl3) delta ppm 1.29 (t, J = 6.9 Hz, 3H), 2.10 (s, 3H), 4.23 (q, J = 6.9 Hz, 2H), 7.61 (td, J1 = 7.8 Hz, J2 = 1.2 Hz, 1H), 7.69 (dd, J1 = 7.8 Hz, J2 = 0.9 Hz, 1H), 7.75 (d, J = 8.7 Hz, 2H), 7.82 (td, J1 = 7.8 Hz, J2 = 1.2 Hz, 1H), 7.82 (dd, J1 = 7.8 Hz, J2 = 0.9 Hz, 1H), 7.82 (d, J = 8.7 Hz, 2H), 9.13 (s, 1H), 9.95 (sl, 1H); 13C NMR (75 MHz, CDCl3) delta ppm 15.0, 23.9, 60.8, 110.2, 110.9, 119.3, 119.5, 129.3, 130.1, 130.2, 132.7, 134.5, 134.8, 137.1, 139.6, 144.2, 148.4, 162.7, 169.6; LCMS (EI (+)) m/z = 389 [M + H] +. HRMS (EI) calcd for C21H18N4O2 [M + H]+ 375.14517. Found 375.14454. |
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In tetrahydrofuran; hexane; at 20℃; for 2h;Product distribution / selectivity; |
Example 3; The organic phase obtained in Example 2 was charged with 77 ml of 1,3-propanediol, and the resulting solution was stirred at room temperature for 2 hours. The free aqueous layer was separated, and then the solvent was removed by distillation using an evaporator. The residual oily substance was dissolved in 700 ml of dichloromethane, and the resulting solution was washed with 153 ml of water. The obtained organic phase was then dried with anhydrous magnesium sulfate, and turned into a solid by drying under reduced pressure using an evaporator. While stirring with a magnetic stirrer, 450 ml of hexane was slowly added dropwise to the oily residue under ice cooling to cause crystals to precipitate. The obtained crystals were washed with 500 of chilled hexane, and dried for 12 hours under reduced pressure at room temperature to obtain 184 g of the 1,3-propanediol ester of 2-cyanophenylboronic acid (2-(1,3,2-dioxaborinan-2-yl)benzonitrile). The purity was 99.4percent, and these crystals contained 0.45 mol percent of 1-phenyl-1-(2,2,6,6-tetramethylpiperidin-1-yl)methyl imine. |
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In tetrahydrofuran; Isopropyl acetate; toluene; at 20 - 25℃; for 2h; |
Example 2Synthesis of 2-(i ,3,2-dioxaborinane-2-yl)benzoni- trile?Effect of the Temperature in step a) on molaryield and chemical purity 10062] Into a previously dried flask, equipped with a thermometer, condenser and dropping thnnel, under nitrogen flow, 100.0 g (1.00 equiv.) of 2-bromobenzonitrile and 750 ml (7.5 V) of anhydrous Toluene are charged. The mixture is cooled at ?22/?18° C. and 519.0 g (1.30 equiv.) of Isopropylmagnesium chloride/lithium chloride complex 1.3 M (about 20percent wt/wt) in THF are added keeping the Tat ?22/?18° C., over about 1.5 h. The reaction is stirred at ?22/?18° C. for additional 4 hthen the conversion in checked by HPLC. When the reaction is complete, 125.6 g (2.20 equiv.) oftrimethylborate are added keeping the Tat ?22/?18° C. over about 0.5 h. Once the addition is complete, cooling is removed and the reaction is warmed to 20-25° C. and stirred for about 0.5 h. The conversion is checked by HPLC. When the reaction is complete, the mixture is cooled to 0-5°C. and a solution of 0.1 M hydrochloric acid, prepared by mixing 10 ml of 32percent hydrochloric acid (10.17 M) and 990 ml (9.9 V) of purified water, is added at 0-20° C. Afier stirring 0.25 h at 20-25° C. the pH is modified to 3-4 with appropriate amount of 32percent hydrochloric acid. The layers are then separated. The aqueous phase is extracted again with 500 ml (5 V) of Toluene. The organic phases are recombined and washed with 500 ml (5 V) of a saturated sodium chloride solution. The organic layer is extracted at 20-25° C. with 0.1 M sodium hydroxide solution, prepared by mixing 5 ml (0.05 V) of 30percent sodium hydroxide solution and 495 ml (4.95 V) of purified water (the product passes into the aqueous phase). Before performing layer separation the pH is modified to 10-11 with the appropriate amount of 30percent sodium hydroxide solution. Layers are separated and the organic layer is extracted twice with 0.1 M sodium hydroxide solution, prepared by mixing 5 ml (0.05 V) of 30percent sodium hydroxide solution and 495 ml (4.95 V) of purified water. The pH is corrected to 10-11 if needed before each layer separation. The aqueous phases are recombined and are washed with 2x300 ml (2x3 V) of Isopropyl acetate. The organic phase is discarded. The pH of the aqueous phase (containing the reaction product) is corrected with hydrochlonc acid to a final pH of 3-4. The aqueous phase is extracted with 2x500 ml (2x5 V) of Isopropyl acetate. The product passes into the organic phase. 46.0 g (1.1 equiv.) of 1,3- propanediol are then added to the organic solution and the mixture stirred at 20-25° C. for 2 h. The conversion in checked by TLC. When the reaction is complete, the aqueous phase is separated (water is generated during the reaction) and the organic layer is concentrated to residue at T bath 3 5-40° C. The residue is dissolved with 500 ml (5 V) of Dichloromethane and the organic phase is washed with 100 ml (1.0 V) of purified watet Layers are separated and the organic phase is concentrated to small volume in T bath 35-40°C. 100 ml (1.0 V) of n-Heptane are added keeping boiling under vacuum at T bath 35-40° C. and the mixture is concentrated to small volume. Then, 5 ml of Isopropanol and 300 ml (3.0 V) of n-Heptane are slowly added under vigorous stirring. The product crystallizes out. The slurry is stirred at 20-25° C. for 0.5 hand then at 0-5° C. for at least 2 h. The mixture is filtered and washed with 100 ml (1.0 V) of n-Heptane pre-cooled to 0-5° C. Afier vacuum drying at 20-25° C. for at least 8 h 75.1g of 2-(1,3,2-dioxaborinane-2-yl)benzonitrile equal to amolar yield from 2-bromo benzonitrile of 73percent. HPLC purity(AlA percent 99.9percent). |
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