| 82% |
With bromine; In water; acetic acid; at 10 - 15℃; for 2h; |
TMEDA (99.5%), 3-methylthiophene (98%) and KOtBu (95%) were obtained from Aldrich and used without further purification. 2.5M n-BuLi in hexanes was obtained from Aldrich and Acros and the exact molarity of each lot was determined via titration prior to use. MTBE used was from EMScience (spectrophotometric grade). A 50 L glass reactor equipped with overhead stirrer and connected to a chiller was purged with nitrogen (20 min.). To the reactor was charged MTBE 20 (20.8 L), TMEDA (2.08 L) and KOtBu (94.8 g). The reactor was closed and the stirred mixture was cooled down to -8 C. under a steady stream of nitrogen. The temperature was monitored via thermocouple and chart recorder. To the reactor was slowly charged a pre-cooled 2.5 M solution of n-BuLi in hexanes (3.38 L) from an addition funnel. The reaction temperature was kept below -5 C. during the addition. Following complete addition, the reaction was stirred an additional 3 hours at -8 C. 3-Methylthiophene 13 (830 g) was slowly charged to the reactor via an addition funnel. Following complete addition, the reaction was stirred an additional 1 hour at -8 C. Dry carbon dioxide gas was introduced into the reaction mixture for 1 hour while keeping the reactor temperature below +15 C. Deionized water (12 L) was carefully added to the reactor with continued stirring. Following complete addition, the chiller was removed and the biphasic mixture was agitated vigorously via overhead stirring. After separation of layers, the lower aqueous layer was drained and set aside. 1N NaOH (5 L) was added to the reactor and the biphasic mixture was agitated vigorously via overhead stirring. After separation of layers, the lower aqueous layer was drained and set aside. This operation was repeated one more time with 1N NaOH (10 L). After the last aqueous phase had been drained from the reactor and set aside, the remaining upper organic layer was drained and discarded. The reactor was given a quick rinse with water and acetone and was allowed to dry. All aqueous layers were recharged to the reactor and stirring was resumed. Concentrated HCl (4 L) was added via addition funnel until pH 1-2 was achieved. MTBE (10 L) was charged to the reactor and the biphasic mixture was agitated vigorously via overhead stirring. After separation of layers, the upper organic phase layer was transferred via vacuum line from the reactor to a separate receptacle. This operation was repeated two more times with 5 L portions each of MTBE. The combined MTBE layers were dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give the product as a grayish solid. The product was dried in a vacuum oven overnight at 30 C. The dried product was milled to a free-flowing powder (if necessary) to afford 4-methylthiophene-2-carboxylic acid 12 as a lavender-colored solid ( 85% yield, 95:5 ratio of regioisomers). [0130] 4-Methylthiophene-2-carboxylic acid 12 (541 g) was dissolved in 4.59 L glacial acetic acid and then cooled to an internal temperature of 10-15 C. Then, a solution of bromine in acetic acid (prepared by dissolving 195 mL of bromine in 2.8 L glacial acetic acid) was added over 1.5 hours while stirring vigorously to the vigorously stirred solution of 2a/2b in acetic acid. After 30 minutes, the reaction mixture is quenched over 30-40 minutes into 19 L of water (at room temperature) with vigorous stirring providing a fine precipitate. The resulting precipitate was collected by vacuum filtration (over a couple of hours) and rinsed with 2 L of water. As much of the excess water as possible was pressed from the filter cake by placing a latex rubber dam over the stainless steel, lowform Buchner funnel for 2-3 hours. The resulting filter cake, still containing about 600 mL of water, was then broken up into chunks in a Pyrex dish/tray and dried in vacuo (with a slight air bleed) at 65-70 C. for 1.5-3 days. This afforded 5-bromo-3-methylthiophene-2-carboxylic acid 11 (692 g, 82% yield) as single regioisomer (determined by 1H NMR) as a cement-gray solid. [0131] 5-Bromo-4-methylthiophene-2-carboxylic acid 11 (690 g) and absolute ethanol (7.4 L) were combined and stirred. Once all of the solids had dissolved, concentrated sulfuric acid (270 mL) was added carefully. The solution was then heated to gentle reflux, under a calcium sulfate drying tube or slight positive pressure of nitrogen (with a bubbler), for 18 hours. The reaction was monitored for disappearance of starting material by 1H NMR or other appropriate analytical method. In the case of an incomplete reaction, a further 0.2 to 0.3 equivalents of concentrated sulfuric acid and 1 L of absolute ethanol was added to the reaction and reflux was continued for another 3 to 4 hours. Upon complete reaction, the reaction was cooled to room temperature and carefully quenched, to a pH of 8, by portion-wise addition of an excess of solid sodium bicarbonate to the vigorously stirred solution (initial induction period between the addition of th... |
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