| 31 - 72% |
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EXAMPLE1; Allyl bromide (48 ml, 0.556 mol) was added to a solution of anhydrous sodium thiosulfate (88.2 grams, 0.558 mol) in water (189.6 ml), and about one minute thereafter the solution turned yellow. The resulting mixture was then stirred overnight at room temperature and was kept in the cold room (at about 4 0C) for storage. The solution was filtered before usage to remove mechanical impurities. Then, part of this solution (197 ml, 0.4 mol) was transferred to another flask and was mixed with a 0.5 M disodium hydrogen orthophosphate solution (34 ml).In a separate flask, a homogeneous <strong>[62571-86-2]captopril</strong> (CPSH) solution was prepared by dissolving <strong>[62571-86-2]captopril</strong> (21.7 grams, 0.1 mol) in a 0.5 M disodium hydrogen orthophosphate solution (170 ml) while heating the mixture in a water bath under nitrogen atmosphere. The <strong>[62571-86-2]captopril</strong> solution was added to the flask containing the previously prepared allyl thiosulfate solution and stirring was continued under nitrogen atmosphere for 2 hours at room temperature, followed by cooling in an ice bath (to about 5 0C). 4M HCl (15.9 ml) was added to the cooled mixture, so as to acidify the mixture to a final pH of about 3, and a precipitation of a white solid was observed. The mixture was then placed in a cold room (at about 4 C) for 5 days, and <n="23"/>was monitored on a daily basis by HPLC. After 5 days, the precipitate was washed with water, and the crude product was twice slurried in water and filtered. The precipitate was thereafter dried in the air, followed by additional drying in a dessicator over P2O5 under vacuum. The product was then slurried in hexane, and filtered. After drying in a dessicator, pure allyl mercapto<strong>[62571-86-2]captopril</strong> (CPSSA) was obtained (20.87 grams, 0.086 mol, 72 % yield).The purity of the final product, as determined by HPLC, was 99.46 %.1H-NMR (CDCl3): delta = 1.18 (d, 3H), 2.20 (m, 4H), 2.64 (m, IH), 3.03 (m, 2H), 3.29 (d, 2H), 3.64 (t, 2H), 4.55 (m, IH), 5.15 (m, 2H, allyl), 5.80 (m, IH, allyl) ppm. melting point: 44 0C.IR: v = 2968, 1604, 1329, 1187, 924 cm'1.UV-VIS: lambda max = 211 nmThe same experiment was repeated using 128 ml (0.26 mol) of the allyl thiosulfate solution, also obtaining a high purity product (98.74% purity, 17.33 grams, 0.071 mol, 60 % yield).; EXAMPLE 2; Allyl bromide (17.3 ml, 0.2 mol) was added to a solution of sodium thiosulfate pentahydrate (49.6 grams, 0.2 mol) in water (50 ml) and the resulting mixture was stirred at room temperature for 15 hours until the initial two phases disappeared and the reaction mixture became homogeneous. Disodium hydrogen orthophosphate (50 ml of a 0.5 M aqueous solution having a pH of about 8.0) was added and the resulting allyl thiosulfate solution was cooled in an ice bath. A <strong>[62571-86-2]captopril</strong> (CPSH) solution was prepared by dissolving <strong>[62571-86-2]captopril</strong> (32 grams, 0.147 mol) in a 0.5 M disodium hydrogen orthophosphate solution (250 ml) under nitrogen atmosphere. The <strong>[62571-86-2]captopril</strong> solution was added, under stirring and bubbling of nitrogen, to the allyl thiosulfate solution, while maintaining the pH of the reaction mixture at about 8.0. Stirring was continued for 1 hour at 00C and for another hour at room temperature. The reaction mixture was thereafter cooled again in an ice bath, and 4M HCl (35 ml) was added, under nitrogen atmosphere, so as to acidify the mixture to a final pH in the range of 2-3. The mixture was then placed in a <n="24"/>refrigerator (+4 0C) for 4 days, until precipitation of a white solid was observed. The precipitate was filtered, carefully washed with water, and dried under vacuum. The crude product (23 grams) was treated with n-hexane (100 ml) for 1 hour and the white solid was thereafter filtered and dried in vacuum to give pure CPSSA (21 grams, 0.086 mol, 59 % yield).The purity of the final product, as determined by HPLC, was 96 %.1H NMR (CDCl3): delta = 1.18 (d, 3H), 2.20(m, 4H), 2.64(m, IH), 3.03 (m, 2H)5 3.29 (d, 2H), 3.64 (t, 2H), 4.55(m, IH), 5.15(m, 2H allyl), 5.80 (m, IH allyl) ppm. melting point: 44 C. IR: v = 2968, 1604, 1329, 1187, 924 cm"1.UV-vis lambda max = 211 nm.; EXAMPLE 3; Allyl bromide (17.3 ml, 0.2 mol) was added to a solution of sodium thiosulfate pentahydrate (49.6 grams, 0.2 mol) in water (50 ml), and the mixture was stirred at room temperature for 5 hours until the initial two phases disappeared and the reaction mixture became homogeneous. The reaction mixture was then cooled and stirred in an ice bath. A <strong>[62571-86-2]captopril</strong> (CPSH) solution was prepared by dissolving <strong>[62571-86-2]captopril</strong> (32 grams, 0.147 mol) in a 0.5 M disodium hydrogen orthophosphate solution (300 ml) under nitrogen atmosphere. The <strong>[62571-86-2]captopril</strong> solution was added to the reaction mixture, under stirring and bubbling of nitrogen, while maintaining the pH of the reaction mixture at about 8.0 and monitoring the reaction progress by HPLC. Stirring was continued for 30 minutes at 0 0C and the temperature was then raised to room temperature. 4M HCl (35 ml) was added, under nitrogen atmosphere, so as to acidify the mixture to a final pH ... |
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In water; at 0℃; for 0.5 - 0.666667h;pH ~ 8.0;0.5 M disodium hydrogen orthophosphate solution;Product distribution / selectivity; |
EXAMPLE 4; Allyl bromide (0.173 ml, 2 mmol) was added to a solution of sodium thiosulfate pentahydrate (500 mg, 2 mmol) in water (5 ml), and the resulting mixture was stirred at room temperature for 15 hours until the initial two phases disappeared and the reaction mixture became homogeneous. The reaction mixture was then cooled and stirred in an ice bath. A <strong>[62571-86-2]captopril</strong> (CPSH) solution was prepared by dissolving <strong>[62571-86-2]captopril</strong> (432 mg, 2 mmol) in 3 ml of a 0.5 M disodium hydrogen orthophosphate solution under nitrogen atmosphere. The <strong>[62571-86-2]captopril</strong> solution was added, under stirring and bubbling of nitrogen, to the allyl thiosulfate mixture, while maintaining the mixture pH at about 8.0. Stirring was continued while monitoring the reaction progress by HPLC. After 30 minutes of stirring at 0 C the reaction mixture contained 70 % of CPSSA and 15 % of unreacted <strong>[62571-86-2]captopril</strong>, as determined by HPLC.; EXAMPLE 5; Allyl chloride (0.144 ml, 2 mmol) was added to sodium thiosulfate pentahydrate (500 mg, 2 mmol) in 5 ml of water, and the mixture was stirred at room temperature for 3 hours until the initial two phases disappeared and the reaction mixture became homogeneous. The reaction mixture was then cooled and stirred in an ice bath. A <strong>[62571-86-2]captopril</strong> (CPSH) solution was prepared by dissolving <strong>[62571-86-2]captopril</strong> (432 mg, 2 mmol) in a 0.5 M disodium hydrogen orthophosphate solution (3 ml) under nitrogen atmosphere. The <strong>[62571-86-2]captopril</strong> solution was added, under stirring and bubbling of nitrogen, to the reaction mixture, while maintaining the pH of the reaction mixture at about 8.0. Stirring was continues while monitoring the reaction progress by HPLC. <n="26"/>After 40 minutes of stirring at 0 0C, the reaction mixture contained 30 % of CPSSA and 20 % unreacted <strong>[62571-86-2]captopril</strong>, as well as other products, as determined by HPLC.; EXAMPLE 6; AHyI chloride (0.720 ml, 10 mmol) was added to a solution of sodium thiosulfate pentahydrate (2.48 grams, 10 mmol) in water (15 ml), and the resulting mixture was stirred at room temperature for 15 hours until the initial two phases disappeared and the reaction mixture became homogeneous. The water was thereafter evaporated in vacuum and the precipitated white solid (1.76 grams) was washed with ethyl alcohol, dried and re-dissolved in a 0.5 M disodium hydrogen orthophosphate buffer (10 ml). The mixture was cooled and stirred in ice bath. A <strong>[62571-86-2]captopril</strong> (CPSH) solution was prepared by dissolving <strong>[62571-86-2]captopril</strong> (920 mg, 4.2 mmol) in a 0.5 M disodium hydrogen orthophosphate solution (3 ml) under nitrogen atmosphere. The <strong>[62571-86-2]captopril</strong> solution was added, under stirring and bubbling of nitrogen, to the allyl thiosulfate mixture, while maintaining the pH of the reaction mixture at about 8.0. Stirring was continues while monitoring the reaction progress by HPLC. After 30 minutes of stirring at 0 C, the reaction mixture contained 38 % of CPSSA and 43 % unreacted <strong>[62571-86-2]captopril</strong>, as determined by HPLC. |
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