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4-(2-Methoxycarbonyl-ethyl)-3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester (Aldrich, 228 g, 0.9 mol) and 720 mL of 5 N sodium hydroxide were refluxed for one hour. Thin layer chromatography showed the hydrolysis to be complete. The stirred mixture was cooled to 50° C. and hydrochloric acid (10 N, 390 mL) was slowly added to give a pH of 2-3. The oil which separated solidified. The mixture was stirred and cooled to 4° C. The solids were collected by vacuum filtration, washed thoroughly with water and dried under vacuum at 40° C. to give 65.7 g (49percent yield) of 3-(2,4-dimethyl-1H-pyrrol-3-yl)-propionic acid as a reddish solid.
49%
Stage #1: at 50℃; for 1 h; Heating / reflux Stage #2: With hydrogenchloride In water at 4 - 50℃;
[0184] 4-(2-Methoxycarbonyl-ethyl)-3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester (Aldrich, 228 g, 0.9 mol) and 720 mL of 5 N sodium hydroxide were refluxed for one hour. Thin layer chromatography showed the hydrolysis to be complete. The stirred mixture was cooled to 50° C. and hydrochloric acid (10 N, 390 mL) was slowly added to give a pH of 2-3. The oil which separated solidified. The mixture was stirred and cooled to 4° C. The solids were collected by vacuum filtration, washed thoroughly with water and dried under vacuum at 40° C. to give 65.7 g (49percent yield) of 3-(2,4-dimethyl-1H-pyrrol-3-yl)-propionic acid as a reddish solid.
Reference：
[1] Journal of Organic Chemistry, 1988, vol. 53, # 12, p. 2796 - 2802
[2] Patent: US2004/204407, 2004, A1, . Location in patent: Page/Page column 16-17
[3] Patent: US2004/266843, 2004, A1, . Location in patent: Page 12
2
[ 122676-34-0 ]
[ 2386-37-0 ]
Reference：
[1] Journal of Organic Chemistry, 1989, vol. 54, # 20, p. 4801 - 4807
3
[ 13984-53-7 ]
[ 16115-80-3 ]
[ 2386-37-0 ]
Yield
Reaction Conditions
Operation in experiment
28%
for 3.5 h; Heating / reflux
b) Preparation of the Compound of Formula (5): A 4.5 l Keller round-bottomed flask equipped with a reflux condenser, a thermometer, a dropping funnel and an argon conduit is loaded with acetic acid (1.30 l) and refluxed. A solution of a mixture of compound (6) (248.71 g, 1.34 mol) and of dimethyl aminomalonate hydrochloride (367.50 g, 1.74 mol) in acetic acid (0.85 l) is added dropwise to the mixture at reflux, over 1 h. The mixture is again refluxed for 2.5 h. The conversion is followed by HPLC. The reaction mixture is cooled to ambient temperature and the acetic acid is eliminated by distillation under reduced pressure. The dark crude product is triturated with water (4.5 l), which is added slowly, portionwise. The mixture is mechanically stirred for a further 1 h and is then filtered, and the filtration cake is washed with water (1 l). The recrystallization of the dark gray crude product is carried out from ethanol/water (350/350 ml) by refluxing and then cooling to 10° C. The precipitate is isolated by filtration and washed with ethanol/water (4.x.100/100 ml). The product is dried under reduced pressure at ambient temperature, to give the compound (5) (95.00 g, 28percent) in the form of a light purple-colored solid.1H NMR (300 MHz, CDCl3): 1.34 (t, CH3), 2.21 (s, CH3), 2.27 (s, CH3), 2.43 (t, CH2), 2.70 (t, CH2), 3.66 (s, CH3), 4.29 (q, CH2), 8.60 (broad singlet, NH2).
c) Preparation of the Compound of Formula (4): A 2.5 l Keller round-bottomed flask equipped with a reflux condenser/distillation head, a thermometer, a dropping funnel and an argon conduit is loaded with a solution of compound (5) (95.00 g, 0.38 mol) in benzyl alcohol (685 ml) and heated to 120 C., which results in the azeotropic removal of minor amounts of water. The mixture is then heated to 190 C. The dropping funnel is loaded with a separately prepared solution of sodium (3 g) in benzyl alcohol (70 ml). This solution is added in 5 ml portions, which results in a vigorous reflux of the reaction mixture. The resulting methanol and ethanol are removed by semi-continuous distillation. The conversion is followed by HPLC. The reaction mixture is cooled to 150 C. and then transferred into a mixture of methanol (0.85 l), water (0.54 l) and acetic acid (10 ml). At 30 C., crystallization takes place rapidly. The mixture is stirred again at ambient temperature for 1 h. The product is isolated by filtration. The product is dried under reduced pressure, to give the compound (4) (113.30 g, 77%) in the form of an off-white solid.1H NMR (300 MHz, CDCl3): 2.16 (s, CH3), 2.27 (s, CH3), 2.47 (t, CH2), 2.71 (t, CH2), 4.70 (s, CH3), 5.08 (s, CH2), 5.28 (s, CH2), 7.40 (m, 10H), 8.60 (broad singlet, NH2).
With sodium hydroxide; water; for 1h;Heating / reflux;
<strong>[2386-37-0]4-(2-Methoxycarbonyl-ethyl)-3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester</strong> (Aldrich, 228 g, 0.9 mol) and 720 mL of 5 N sodium hydroxide were refluxed for one hour. Thin layer chromatography showed the hydrolysis to be complete. The stirred mixture was cooled to 50 C. and hydrochloric acid (10 N, 390 mL) was slowly added to give a pH of 2-3. The oil which separated solidified. The mixture was stirred and cooled to 4 C. The solids were collected by vacuum filtration, washed thoroughly with water and dried under vacuum at 40 C. to give 65.7 g (49% yield) of 3-(2,4-dimethyl-1H-pyrrol-3-yl)-propionic acid as a reddish solid.
49%
[0184] <strong>[2386-37-0]4-(2-Methoxycarbonyl-ethyl)-3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester</strong> (Aldrich, 228 g, 0.9 mol) and 720 mL of 5 N sodium hydroxide were refluxed for one hour. Thin layer chromatography showed the hydrolysis to be complete. The stirred mixture was cooled to 50 C. and hydrochloric acid (10 N, 390 mL) was slowly added to give a pH of 2-3. The oil which separated solidified. The mixture was stirred and cooled to 4 C. The solids were collected by vacuum filtration, washed thoroughly with water and dried under vacuum at 40 C. to give 65.7 g (49% yield) of 3-(2,4-dimethyl-1H-pyrrol-3-yl)-propionic acid as a reddish solid.
Example 1 Preparation of Compound la (1,7- bis (3-methoxy-3-propionyl) -3, 5-ethoxycarbonyl-2,6-dimethyl - dipyrrolium borane),Its associated reaction scheme is as follows: The 20. 3g (80mmol) dipyrrolium ester (Compound 1) was dissolved in 100ml of ethyl acetate. The 12.8g of liquid bromine (1 eq.) was added dropwise within 15min completion, after stirring for 1 hour to precipitate a pale yellow precipitate. The above reaction mixture was spin dried, and the solid was dissolved in 100ml of methanol, was added 2ml HC1 was refluxed for 1 hour, then cooled to 0 C, adjusted with 10% NH3 H20 pEta=7, a large number of solid precipitation. The solid was filtered off, washed with 70: 30 methanol: aqueous recrystallization. It was pure compound (2).
b) Preparation of the Compound of Formula (5): A 4.5 l Keller round-bottomed flask equipped with a reflux condenser, a thermometer, a dropping funnel and an argon conduit is loaded with acetic acid (1.30 l) and refluxed. A solution of a mixture of compound (6) (248.71 g, 1.34 mol) and of dimethyl aminomalonate hydrochloride (367.50 g, 1.74 mol) in acetic acid (0.85 l) is added dropwise to the mixture at reflux, over 1 h. The mixture is again refluxed for 2.5 h. The conversion is followed by HPLC. The reaction mixture is cooled to ambient temperature and the acetic acid is eliminated by distillation under reduced pressure. The dark crude product is triturated with water (4.5 l), which is added slowly, portionwise. The mixture is mechanically stirred for a further 1 h and is then filtered, and the filtration cake is washed with water (1 l). The recrystallization of the dark gray crude product is carried out from ethanol/water (350/350 ml) by refluxing and then cooling to 10 C. The precipitate is isolated by filtration and washed with ethanol/water (4×100/100 ml). The product is dried under reduced pressure at ambient temperature, to give the compound (5) (95.00 g, 28%) in the form of a light purple-colored solid.1H NMR (300 MHz, CDCl3): 1.34 (t, CH3), 2.21 (s, CH3), 2.27 (s, CH3), 2.43 (t, CH2), 2.70 (t, CH2), 3.66 (s, CH3), 4.29 (q, CH2), 8.60 (broad singlet, NH2).
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