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With 1,1'-carbonyldiimidazole In ISOPROPYLAMIDE at 20 - 90℃; for 4 h;
10 g (68.42 mmoles) of L-glutamine are suspended in 50 ml of dimethyl-acetamide in a 250 ml 5-neck round-bottom flask at room temperature, followed by 10 g (67.6 mmoles) of phthalic anhydride and the mixture is heated to T=80°C. After 6 h the solution is cooled to 30°C and dropped in a round-bottom flask containing 12 g (74 mmoles) of carbonyl-diimidazole dissolved in 20 ml of dimethyl-acetamide at room temperature. The resulting solution is heated to 85-90°C and kept under stirring at this temperature for 4 h, then the solution is poured into a conical flask containing 500 ml of cold water. The precipitated solid is filtered, washed twice with 250 ml of water and taken up in 100 ml of (4/1) water/ethanol. After filtering and drying overnight under vacuum at 40°C a crystalline white solid is obtained (12.5 g; Y=71 percent).
65%
With 1,1'-carbonyldiimidazole In 1-methyl-pyrrolidin-2-one at 20 - 90℃; for 4 h;
10 g (68.42 mmoles) of L-glutamine are suspended in 50 ml of N-methyl-2-pyrrolidone in a 250 ml 5-neck round-bottom flask at room temperature, followed by 10 g (67.60 mmoles) of phthalic anhydride and heated to T=80°C. After 6 h the solution is cooled to 30°C and poured into a round-bottom flask containing 12 g (74 mmoles) of carbonyl-diimidazole dissolved in 30 ml of N-methyl-2-pyrrolidone at room temperature. The solution is heated at 85-90°C and kept under stirring at this temperature for 4 h. The solution is then poured into a conical flask containing 500 ml of cold water. The precipitated solid is filtered, washed twice with 250 ml of water and taken up in 100 ml of (4/1) water/ethanol. After filtration and drying overnight under vacuum at 40°C a crystalline white solid is obtained (11.5 g; 24 mmoles; Y=65percent).
62%
With 1,1'-carbonyldiimidazole In dimethyl sulfoxide at 20 - 90℃; for 4 h;
10 g (68.42 mmoles) of L-glutamine are suspended in 50 ml of DMSO in a 250 ml 5-neck round-bottom flask at room temperature, added with 10 g (67.60 mmoles) of phthalic anhydride and heated to T=80°C. After 6 h the solution is cooled to 20°C, filtered and poured into a round-bottom flask containing 12 g (74 mmoles) of carbonyl-diimidazole in 20 ml of DMSO at 20°C. The resulting solution is heated to 85-90°C and stirred at this temperature for 4 h. The solution is then poured into a conical flask containing 500 ml of cold water (about 5°C) and left under stirring for 2 h at room temperature. The precipitated solid is filtered and washed twice with 250 ml of water. The filtered solid is then suspended in 200 ml of (4/1) water/methanol at 60°C, filtered and dried overnight under vacuum at 40°C, to give a crystalline white product (10.9 g, yield 62percent).
60%
With 1,1'-carbonyldiimidazole In pyridine at 40℃; for 2 h;
L-glutamine (10 g; 68.42 mmoles) is suspended in pyridine (50 ml) at room temperature. Phthalic anhydride (14 g, 94.5 mmoles) is added and the mixture is gradually heated to T=80-85°C. After 6 h, an aliquot of the reaction mixture is distilled off under vacuum and the mixture is cooled to 40°C. Carbonyl-diimidazole (12 g, 74 mmoles) is added in portions, keeping under stirring for 2 h, thereafter the mixture is concentrated under vacuum to about one fifth of the starting volume, cooled to 25°C, then diluted with a cold (approx. 5°C) 4:1 water-ethanol mixture (100 ml). Aqueous hydrochloric acid (37percent) is dropped to adjust the pH to 7.0 +/- 0.5. The mixture is left under stirring for 4 h until it warms up to room temperature, then the precipitated solid is filtered by suction and washed twice with 25 ml of water. The resulting solid is then dried overnight under vacuum at 40°C, to give a white crystalline product (10.6 g; yield: 60percent on glutamine).
58%
With 1,1'-carbonyldiimidazole In pyridine at 20℃; for 4 h;
L-glutamine (10 g; 68.42 mmoles) is suspended in pyridine (50 ml) at 10°C and added with phthaloyl-dichloride (27.8 g; 136.84 mmoles), keeping the temperature below 15°C. After 4 h carbonyl-diimidazole (12 g) is added in portions, keeping under stirring for 4 h at room temperature, then the mixture is concentrated under vacuum and poured in cold water (100 ml; 5°C). (37percent) Aqueous hydrochloric acid is dropped adjusting the pH to 7.0 +- 0.5 and the mixture is left under stirring for 4 h, until room temperature. The precipitate is filtered by suction, washed twice with 25 ml of water and dried overnight under vacuum at 40°C to give thalidomide in 58percent yield.
45%
With 1H-imidazole; thionyl chloride In pyridine at 5 - 85℃; for 4 h;
5 g (34.21 mmoles) of L-glutamine are suspended in 25 ml of pyridine in a 100 ml 5-neck round-bottom flask at room temperature, followed by addition of 5 g (33.80 mmoles) of phthalic anhydride and the mixture is heated to T=80-85°C. 6 hrs later an aliquot of the reaction mixture is distilled under vacuum, then cooled to 40°C. 3.1 g (45.5 mmoles) of imidazole are loaded in the flask, which is then cooled to 5-10°C, then 1.6 ml (22 mmoles) of thionyl chloride are dropped in with caution. The mixture is stirred at room temperature for 1 h, heated to 85°C and kept under stirring at this temperature for 3 h, then distilled to one fifth of the starting volume. The residue is cooled to 25°C and 100 ml of a cold (ca. 5°C) (4/1) water/absolute ethanol mixture are added. The mixture is acidified with 37percent HCl to pH=7.0 +/- 0.5 and left under stirring for 4 h until room temperature, then the precipitated solid is filtered by suction and washed twice with 25 ml of water. The resulting solid is then dried overnight under vacuum at 40°C to give a white crystalline product (3.9 g, yield 45percent).
41%
at 5 - 20℃; for 3 h;
5 g (34.21 mmoles) of L-glutamine are suspended in 25 ml of pyridine in a 100 ml 5-neck round-bottom flask at room temperature, followed by 5 g (33.80 mmoles) of phthalic anhydride. The mixture is heated to T=80°C for 6 hrs, then the solution is cooled to 5-10°C. 2.60 ml (4.2 g; 35.3 mmoles) of thionyl chloride are dropped with caution in the reaction flask, then the mixture is cooled to room temperature. After 3 h a pyridine volume of about 80-85percent of the starting volume is distilled off and the residue is cooled to 30-35°C, then 100 ml of a (4/1) water/absolute ethanol mixture are added. The mixture is cooled to 8-10°C with an ice bath and acidified with 37percent HCl 37percent to pH=7-5. The mixture is left under stirring for 4 h until room temperature; the precipitated solid is filtered by suction and washed twice with 25 ml of water. The resulting solid is then dried overnight under vacuum at 40°C to give a crystalline white solid (3.6 g, yield 41 percent).
With 1,1'-carbonyldiimidazole; In ISOPROPYLAMIDE; at 20 - 90℃; for 4h;Product distribution / selectivity;
10 g (68.42 mmoles) of L-glutamine are suspended in 50 ml of dimethyl-acetamide in a 250 ml 5-neck round-bottom flask at room temperature, followed by 10 g (67.6 mmoles) of phthalic anhydride and the mixture is heated to T=80C. After 6 h the solution is cooled to 30C and dropped in a round-bottom flask containing 12 g (74 mmoles) of carbonyl-diimidazole dissolved in 20 ml of dimethyl-acetamide at room temperature. The resulting solution is heated to 85-90C and kept under stirring at this temperature for 4 h, then the solution is poured into a conical flask containing 500 ml of cold water. The precipitated solid is filtered, washed twice with 250 ml of water and taken up in 100 ml of (4/1) water/ethanol. After filtering and drying overnight under vacuum at 40C a crystalline white solid is obtained (12.5 g; Y=71 %).
65%
With 1,1'-carbonyldiimidazole; In 1-methyl-pyrrolidin-2-one; at 20 - 90℃; for 4h;Product distribution / selectivity;
10 g (68.42 mmoles) of L-glutamine are suspended in 50 ml of N-methyl-2-pyrrolidone in a 250 ml 5-neck round-bottom flask at room temperature, followed by 10 g (67.60 mmoles) of phthalic anhydride and heated to T=80C. After 6 h the solution is cooled to 30C and poured into a round-bottom flask containing 12 g (74 mmoles) of carbonyl-diimidazole dissolved in 30 ml of N-methyl-2-pyrrolidone at room temperature. The solution is heated at 85-90C and kept under stirring at this temperature for 4 h. The solution is then poured into a conical flask containing 500 ml of cold water. The precipitated solid is filtered, washed twice with 250 ml of water and taken up in 100 ml of (4/1) water/ethanol. After filtration and drying overnight under vacuum at 40C a crystalline white solid is obtained (11.5 g; 24 mmoles; Y=65%).
62%
With 1,1'-carbonyldiimidazole; In dimethyl sulfoxide; at 20 - 90℃; for 4h;Product distribution / selectivity;
10 g (68.42 mmoles) of L-glutamine are suspended in 50 ml of DMSO in a 250 ml 5-neck round-bottom flask at room temperature, added with 10 g (67.60 mmoles) of phthalic anhydride and heated to T=80C. After 6 h the solution is cooled to 20C, filtered and poured into a round-bottom flask containing 12 g (74 mmoles) of carbonyl-diimidazole in 20 ml of DMSO at 20C. The resulting solution is heated to 85-90C and stirred at this temperature for 4 h. The solution is then poured into a conical flask containing 500 ml of cold water (about 5C) and left under stirring for 2 h at room temperature. The precipitated solid is filtered and washed twice with 250 ml of water. The filtered solid is then suspended in 200 ml of (4/1) water/methanol at 60C, filtered and dried overnight under vacuum at 40C, to give a crystalline white product (10.9 g, yield 62%).
60%
With 1,1'-carbonyldiimidazole; In pyridine; at 40℃; for 2h;Product distribution / selectivity;
L-glutamine (10 g; 68.42 mmoles) is suspended in pyridine (50 ml) at room temperature. Phthalic anhydride (14 g, 94.5 mmoles) is added and the mixture is gradually heated to T=80-85C. After 6 h, an aliquot of the reaction mixture is distilled off under vacuum and the mixture is cooled to 40C. Carbonyl-diimidazole (12 g, 74 mmoles) is added in portions, keeping under stirring for 2 h, thereafter the mixture is concentrated under vacuum to about one fifth of the starting volume, cooled to 25C, then diluted with a cold (approx. 5C) 4:1 water-ethanol mixture (100 ml). Aqueous hydrochloric acid (37%) is dropped to adjust the pH to 7.0 +/- 0.5. The mixture is left under stirring for 4 h until it warms up to room temperature, then the precipitated solid is filtered by suction and washed twice with 25 ml of water. The resulting solid is then dried overnight under vacuum at 40C, to give a white crystalline product (10.6 g; yield: 60% on glutamine).
58%
With 1,1'-carbonyldiimidazole; In pyridine; at 20℃; for 4h;Product distribution / selectivity;
L-glutamine (10 g; 68.42 mmoles) is suspended in pyridine (50 ml) at 10C and added with phthaloyl-dichloride (27.8 g; 136.84 mmoles), keeping the temperature below 15C. After 4 h carbonyl-diimidazole (12 g) is added in portions, keeping under stirring for 4 h at room temperature, then the mixture is concentrated under vacuum and poured in cold water (100 ml; 5C). (37%) Aqueous hydrochloric acid is dropped adjusting the pH to 7.0 +- 0.5 and the mixture is left under stirring for 4 h, until room temperature. The precipitate is filtered by suction, washed twice with 25 ml of water and dried overnight under vacuum at 40C to give thalidomide in 58% yield.
45%
With 1H-imidazole; thionyl chloride; In pyridine; at 5 - 85℃; for 4h;Product distribution / selectivity;
5 g (34.21 mmoles) of L-glutamine are suspended in 25 ml of pyridine in a 100 ml 5-neck round-bottom flask at room temperature, followed by addition of 5 g (33.80 mmoles) of phthalic anhydride and the mixture is heated to T=80-85C. 6 hrs later an aliquot of the reaction mixture is distilled under vacuum, then cooled to 40C. 3.1 g (45.5 mmoles) of imidazole are loaded in the flask, which is then cooled to 5-10C, then 1.6 ml (22 mmoles) of thionyl chloride are dropped in with caution. The mixture is stirred at room temperature for 1 h, heated to 85C and kept under stirring at this temperature for 3 h, then distilled to one fifth of the starting volume. The residue is cooled to 25C and 100 ml of a cold (ca. 5C) (4/1) water/absolute ethanol mixture are added. The mixture is acidified with 37% HCl to pH=7.0 +/- 0.5 and left under stirring for 4 h until room temperature, then the precipitated solid is filtered by suction and washed twice with 25 ml of water. The resulting solid is then dried overnight under vacuum at 40C to give a white crystalline product (3.9 g, yield 45%).
41%
With pyridine; thionyl chloride; at 5 - 20℃; for 3h;Product distribution / selectivity;
5 g (34.21 mmoles) of L-glutamine are suspended in 25 ml of pyridine in a 100 ml 5-neck round-bottom flask at room temperature, followed by 5 g (33.80 mmoles) of phthalic anhydride. The mixture is heated to T=80C for 6 hrs, then the solution is cooled to 5-10C. 2.60 ml (4.2 g; 35.3 mmoles) of thionyl chloride are dropped with caution in the reaction flask, then the mixture is cooled to room temperature. After 3 h a pyridine volume of about 80-85% of the starting volume is distilled off and the residue is cooled to 30-35C, then 100 ml of a (4/1) water/absolute ethanol mixture are added. The mixture is cooled to 8-10C with an ice bath and acidified with 37% HCl 37% to pH=7-5. The mixture is left under stirring for 4 h until room temperature; the precipitated solid is filtered by suction and washed twice with 25 ml of water. The resulting solid is then dried overnight under vacuum at 40C to give a crystalline white solid (3.6 g, yield 41 %).
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