* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With hydrogenchloride; sodium formate In water at 5 - 50℃; for 2.08333 h; Inert atmosphere
Under the nitrogen atmosphere, 20.0 g of 5-hydroxy-1H-imidazole-4-carboxamide hydrochloric acid salt dihydrate prepared according to the method of Reference Example 2 was added to 240 mL of 0.45 mol/L hydrochloric acid and dissolved therein by heating to 50°C. At 50°C, 40 mL aqueous solution containing 14.3 g of sodium formate was added dropwise thereto over 35 minutes. The reaction mixture was cooled and stirred for 90 minutes with the inside temperature of 5°C. The crystal was collected by filtration and then washed with a mixture liquid containing 20 mL of acetone and 40 mL of water followed by 60 mL of acetone to give 12.6 g of 5-hydroxy-1H-imidazole-4-carboxamide·3/4 hydrate as a pale yellow crystal. Water content ratio: 8.6percent (Karl Fischer Method) IR (ATR) 1655, 1619, 1584, 1551 cm-1 [0145] Powder X-ray diffraction pattern is shown in Fig. 8 and Table 3 while the infrared absorption spectrum (ATR method) is shown in Fig. 9.
12.8 g
With sodium formate In water at 50℃; Inert atmosphere
(2) Under a nitrogen atmosphere, 5-hydroxy-1H-imidazole-4-carboxamide hydrochloride dihydrate (20.0 g) was added to 0.45 mol/L hydrochloric acid (240 mL), and dissolved therein by heating the mixture to 50° C. To this solution, a solution of sodium formate (14.3 g) dissolved in water (40 mL) was added dropwise over 33 minutes. The reaction mixture was cooled to 5° C., and the crystals were collected by filtration, washed with a mixture of acetone (20 mL) and water (40 mL), and then washed with acetone (60 mL) to obtain 5-hydroxy-1H-imidazole-4-carboxamide 3/4 hydrate as pale yellow crystals (12.8 g).
Benzene sulfonic acid salt of SM-108 (500 mg; 1.75 mmol) was dissolved into hot water (5 ml). The resulting solution was neutralized with sodium hydrogencarbonate (147 mg; 1.75 mmol) and acetone (40 ml) was added. After stirring, the precipitated colorless crystals were collected by filtration and were dried in vacuo to give SM-108 [2] (218 mg; 1.72 mmol; yield 98percent) as colorless powders
With triethylamine; In N-methyl-acetamide; chloroform;
EXAMPLE 2 To a suspension of 508 mg of 4-carbamoylimidazolium-5-olate and 486 mg of triethylamine in 6 ml of anhydrous dimethylformamide was added 770 mg of p-chlorobenzoyl chloride in 3 ml of anhydrous dimethylformamide at a temperature below 5 C. The mixture was stirred under ice cooling for 4 hours. The insoluble crystals were filtered off, then the filtrate were concentrated to a residue under reduced pressure, and the resulting residue was dissolved in chloroform. The chloroform solution was washed with water, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 5-carbamoyl-1H-imidazol-4-yl p-chlorobenzoate. The crude solid was washed with ethyl acetate to give 340 mg of pure product, m.p. 220 C. (charred).
5-carbamoyl-1H-imidazol-4-yl p-bromobenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In pyridine;
EXAMPLE 10 To a suspension of 5.084 g of 4-carbamoyl-imidazolium-5-olate in 104 ml of dry pyridine was added 11.41 g of p-bromobenzoyl chloride at room temperature. After addition was over, the mixture was stirred at 40-45 C. for 2.5 hours. The separated crystals were filtered off, washed with chloroform and diisopropyl ether, dried under vacuum to give 10.535 g of 5-carbamoyl-1H-imidazol-4-yl p-bromobenzoate, m.p. 232-233 C. (dec.)
EXAMPLE 4 To a mixture of 1.27 g of 4-carbamoylimidazolium-5-olate in 42.4 g of 10% aqueous solution of sodium carbonate was added 7.38 g of 3,4-methylenedioxybenzoylchloride in 20 ml of toluene at room temperature. After addition was over, the mixture was stirred for 4 hours. Then the separated crystals were filtered off, washed with water and toluene, dried in vacuo to give 5-carbamoyl-1H-imidazol-4-yl 3,4-methylenedioxybenzoate, m.p. 206.5-208 C. (dec.).
EXAMPLE 1 To a suspension of 455 mg of 4-carbamoylimidazolium-5-olate in 5 ml of dry pyridine was added 1.02 g of benzoyl chloride at a temperature below 5 C. After addition was over, the mixture was stirred under ice cooling for 2 hours. Then separated crystals were filtered off, washed with water and ether, dried to give 5-carbamoyl-1H-imidazol-4-yl benzoate, m.p. 204 C. (dec.).
EXAMPLE 5 To a solution of 1-adamantanecarbonylchloride (39.73 g) in pyridine (260 ml) was added 4-carbamoylimidazolium-5-olate (12.71 g) and the reaction temperature was maintained at 41-43 C. for 3.5 hours. Pyridine was removed under reduced pressure. To the residue was added ethylacetate (300 ml) and water (300 ml), and stirred at room temperature for 1 hour. The insoluble solid was filtered and washed with ethyl acetate to give almost pure 5-carbamoyl-1H-imidazol-4-yl 1-adamantanecarboxylate (25.9 g, beta form, m.p. 205-205.5 C. (dec.)). Recrystallization from dimethylformamide-diethylether gave analytically pure sample (beta form m.p. 213.5-216.5 C. (dec.)).
With triethylamine; In N-methyl-acetamide; water; ethyl acetate;
EXAMPLE 6 To a suspension of 4-carbamoylimidazolium-5-olate (1.016 g) in dimethylformamide (20 ml) was added triethylamine (1.942 g) at 0-5 C. and then 1-adamantanecarbonylchloride (3.50 g) in dimethylformamide (20 ml) dropwisely over 24 minutes. The reaction mixture was stirred at 0-5 C. for 23 hours. The solvent was removed under reduced pressure. To the residue was added ethyl acetate (20 ml) and water (20 ml), and stirred at room temperature for 1 hour. The insoluble solid was filtered and washed with ethyl acetate to give almost pure 5-carbamoyl-1H-imidazol-4-yl 1-adamantanecarboxylate (1.5 g, alpha form, m.p. 206.5-207.5 C. (dec.)), which was washed thoroughly with ethyl acetate to give pure product, alpha form, m.p. 211 C. (dec.).
With triethylamine; In N-methyl-acetamide; water; ethyl acetate;
EXAMPLE 9 To a suspension of 4-carbamoylimidazolium-5-olate (4.064 g) in dimethylformamide (80 ml) was added triethylamine (7.768 g) at 0-5 C. and then 1-adamantanecarbonylchloride (14.00 g) in dimethylformamide (80 ml) dropwisely over 22 minutes. The reaction mixture was stirred at 0-5 C. for 15 hours. The solvent was removed under reduced pressure. To the residue was added ethyl acetate (100 ml) and water (100 ml), and stirred at room temperature for 1 hours. The insoluble solid was filtered and washed with ethyl acetate to give almost pure 5-carbamoyl-1H-imidazol-4-yl 1-adamantanecarboxylate (5.67 g, beta form, m.p. 207-210 C. (dec.)).
In pyridine; water; ethyl acetate;
EXAMPLE 7 To a solution of 1-adamantanecarbonylchloride (2.980 g) in pyridine (26 ml) was added 4-carbamoylimidazolium-5-olate (1.271 g) and the reaction temperature was kept at 40-43 C. for 4 hours. Unreacted starting material was recovered by filtration (210 mg). The filtrate was concentrated under reduced pressure. To the residue was added ethyl acetate (30 ml) and water (30 ml), and stirred at room temperature for 1 hour. The insoluble solid was filtered and washed with ethyl acetate to give almost pure 5-carbamoyl-1H-imidazol-4-yl 1-adamantanecarboxylate (1.602 g, alpha form, m.p. 207-209 C. (dec.)).
EXAMPLE 11 To a suspension of 636 mg of 4-carbamoylimidazolium-5-olate in 15 ml of dry pyridine was dropwisely added 1.0 g of o-methylbenzoyl chloride at less than 5 C. in N2 atmosphere. After being stirred for 2 hours at 41-43 C., the reaction mixture was cooled to room temperature and 658 mg of triethylamine was added. Then the reaction mixture was concentrated under reduced pressure. To the residue was added chloroform (about 20 ml) and then separated crystals were filtered off, washed with chloroform, toluene and ether, and dried to give 600 mg of 5-carbamoyl-1H-imidazol-4-yl o-methyl benzoate, m.p. 181.5-182.5 C. Recrystallized was 447 mg of crude material from N,N-dimethylformamide and water. Amount: 416 mg. m.p.: 185-185.5 C. (dec.)
EXAMPLE 2 Following a procedure similar to that of Example 1 but using 0.636 g. of 4-carbamoylimidazolium-5-olate and 0.880 g. of 2-thiophenecarbonyl chloride there was obtained 0.993 g. of 5-carbamoyl-1H-imidazole-4-yl thiophene-2'-carboxylate, m.p. 198.5-199 C. Recrystallized was crude material from N,N-dimethylformamide and water. m.p.: 199-199.5 C.
5-carbamoyl-1H-imidazole-4-yl furan-3'-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With pyridine; triethylamine; In chloroform; N,N-dimethyl-formamide; acetonitrile;
EXAMPLE 7 To a stirred solution of 12.5 ml of N,N-dimethylformamide in 7.5 ml of acetonitrile was added slowly a solution of 0.9 ml of oxalyl chloride in 10 ml of acetonitrile at -20 C. and reaction temperature was raised to 20 C. from -15 C. over a period of 30 minutes. To the reaction mixture was slowly added 1.77 g. of furan-3-carboxylic acid at -25 C. and stirring was continued for 16 hours at room temperature. To the reaction mixture were slowly added 1.272 g. of 4-carbamoylimidazolium-5-olate and 5 ml of pyridine at 0 C. and stirring was continued for four hours at room temperature. After 3.8 ml of triethylamine was added to the reaction mixture, separated precipitates were filered off. To the filtrate was added 170 ml of chloroform, then separated crystals were filtered off and dried to give 1.55 g. of 5-carbamoyl-1H-imidazole-4-yl furan-3' -carboxylate. m.p. 173 C. (dec.) Recrystallized was crude material from methanol and water. m.p.: 198 C. (dec.)
5-carbamoyl-1H-imidazole-4-yl N-methylpyrrole-2'-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With pyridine; triethylamine; In chloroform; N,N-dimethyl-formamide; acetonitrile;
EXAMPLE 6 To a stirred solution of 12.5 ml of N,N-dimethylformamide in 7.5 ml of acetonitrile was added slowly 0.9 ml of oxalyl chloride in 10 ml of acetonitrile at -20 C. and stirring was continued for twenty minutes at -15 C. To the reaction mixture was slowly added 1.50 g. of N-methylpyrrole-2-carboxylic acid at -15 C. and stirring was continued for forty-five minutes at 0 C. To the reaction mixture were slowly added 1.272 g. of 4-carbamoylimidazolium-5-olate and 10 ml of pyridine at -20 C. and stirring was continued for ninety minutes at room temperature. After 200 ml of chloroform was added to the reaction mixture, separated precipitates were filtered off and the filtrate was concentrated under reduced pressure. To the residue were added 30 ml of pyridine and 3.8 ml of triethylamine and separated precipitates were filtered off and the filtrate was concentrated under reduced pressure to give 1.17 g. of 5-carbamoyl-1H-imidazole-4-yl N-methylpyrrole-2'-carboxylate, m.p. 174 C. (dec.), which was recrystallized from ethanol, m.p. 189.5 C. (dec.).
5-carbamoyl-1H-imidazole-4-yl o-benzyloxycarbonylbenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With pyridine; triethylamine; In N,N-dimethyl-formamide; acetonitrile;
EXAMPLE 22 To a stirred solution of 6.3 ml of N,N-dimethylformamide in 14 ml of acetonitrile was added slowly 0.45 ml of oxalyl chloride at -20 C. and the reaction mixture was heated up to room temperature. To the reaction mixture was added 1.33 g of o-benzyloxycarbonylbenzoic acid at -25 C. and the reaction mixture was heated up to room temperature. To the reaction mixture were added 0.636 g of 4-carbamoylimidazolium-5-olate and 2.5 ml of dry pyridine over an ice bath in N2 atmosphere and stirring was continued for 30 minutes at room temperature. To the residue was added 1.9 ml of triethylamine over an ice bath and separated precipitates were filtered off and the filtrate was concentrated under reduced pressure to give 0.78 g of 5-carbamoyl-1H-imidazole-4-yl o-benzyloxycarbonylbenzoate. m.p.: 122-124 C.
5-carbamoyl-1H-imidazole-4-yl 2',6'-dimethylbenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine; In pyridine;
EXAMPLE 1 To a suspension of 0.636 g. of 4-carbamoylimidazolium-5-olate in 15 ml of dry pyridine was dropwise added 1.2 g of 2,6-dimethylbenzoyl chloride at a temperature below 5 C. in N2 atmosphere. After being stirred for two hours at 41-43 C., the reaction mixture was cooled to room temperature and 0.8 g of triethylamine was added, and separated crystals were filtered off. Then the filtrate was concentrated under reduced pressure, and separated crystals were filtered off, washed with toluene and ether and dried to give 0.689 g of 5-carbamoyl-1H-imidazole-4-yl 2',6'-dimethylbenzoate, m.p. 176-177 C. Crude material was recrystallized from N,N-dimethylformamide and water. m.p.: 180-180.5 C.
EXAMPLE 4 Following a procedure similar to that of Example 3 but using 0.636 g. of 4-carbamoylimidazolium-5-olate and 1.068 g. of isonicotinoyl chloride hydrochloride there was obtained 1.16 g. of 5-carbamoyl-1H-imidazole-4-yl isonicotinate, m.p. 186 C. (charred). Recrystallized was crude material from dimethylsulfoxide and water. m.p.: 192.5 C. (charred).
5-carbamoyl-1H-imidazole-4-yl isonicotinate hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In pyridine;
EXAMPLE 5 To a suspension of 0.636 g. of 4-carbamoylimidazolium-5-olate in 15 ml of dry pyridine was slowly added 1.068 g. of isonicotinoyl chloride hydrochloride at a temperature below 5 C. in N2 atmosphere. After being stirred for an hour at 41-43 C., the reaction mixture was cooled to room temperature. Then separated crystals was filtered off, washed with pyridine, chloroform, ethyl acetate and diethyl ether, and dried to give 1.194 g. of 5-carbamoyl-1H-imidazole-4-yl isonicotinate hydrochloride.
5-carbamoyl-1H-imidazole-4-yl nicotinate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine;
EXAMPLE 3 Following a procedure similar to that of Example 1 but using 0.636 g. of 4-carbamoylimidazolium-5-olate, 1.157 g. of nicotinoyl chloride hydrochloride and 1.315 g. of triethylamine there was obtained 0.988 g. of 5-carbamoyl-1H-imidazole-4-yl nicotinate, m.p. 183.5 C. (charred).
5-carbamoyl-1H-imidazole-4-yl p-benzyloxybenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
EXAMPLE 17 Following a procedure similar to that of Example 1 but using 2.544 g of 4-carbamoylimidazolium-5-olate and 5.922 g of p-benzyloxybenzoyl chloride, there was obtained 5-carbamoyl-1H-imidazole-4-yl p-benzyloxybenzoate. Crude material was recrystallized from dimethylsulfoxide and water. m.p.: 215-218 C. (dec.)
5-carbamoyl-1H-imidazole-4-yl 3',4'-dimethoxybenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
EXAMPLE 2 Following a procedure similar to that of Example 1 but using 0.636 g of 4-carbamoylimidazolium-5-olate and 1.30 g of 3,4-dimethoxybenzoyl chloride there was obtained 1.353 g of 5-carbamoyl-1H-imidazole-4-yl 3',4'-dimethoxybenzoate. m.p.: 209.5 C. (dec.) Crude material was recrystallized from N,N-dimethylformamide and water. m.p.: 216.5 C.
5-carbamoyl-1H-imidazole-4-yl 5'-methylthiophene-2'-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In pyridine; water; N,N-dimethyl-formamide;
EXAMPLE 8 To a stirred suspension of 0.636 g. of 4-carbamoylimidazolium-5-olate in 15 ml of dry pyridine was added 0.883 g. of 5-methyl-2-thiophenecarbonyl chloride at a temperature below 5 C. in N2 atmosphere. After being stirred for two hours at 41-43 C., the reaction mixture was cooled to room temperature and then separated crystals were filtered off and dried to give 1.44 g. of white crystals. Recrystallized was 0.815 g. of crude material from N,N-dimethylformamide and water to give 0.513 g. of 5-carbamoyl-1H-imidazole-4-yl 5'-methylthiophene-2'-carboxylate, m.p. 189.5 C. (charred).
5-carbamoyl-1H-imidazole-4-yl 1'-methylcyclopropane-1'-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine; In pyridine;
EXAMPLE 16 To a stirred suspension of 2.358 g. of 4-carbamoylimidazolium-5-olate in 60 ml of dry pyridine was dropwise added 2.2 g. of 1-methylcyclopropanecarbonyl chloride at a temperature below 5 C. in N2 atmosphere. After being stirred for two hours at 41-43 C., 2.07 g. of triethylamine was added to the reaction mixture. Separated salts were filtered off and the filtrate was concentrated under reduced pressure. 2.89 g. of 5-carbamoyl-1H-imidazole-4-yl 1'-methylcyclopropane-1'-carboxylate was obtained. Purified was crude material by silica gel column chromatography. m.p.: 173.5-174 C.
EXAMPLE 4 Following a procedure similar to that of Example 1 but using 0.508 g of 4-carbamoylimidazolium-5-olate and 1.83 g of 3,4-bisbenzyloxybenzoyl chloride there was obtained 1.548 g of 5-carbamoyl-1H-imidazole-4yl 3',4'-bisbenzyloxybenzoate. m.p.: 189.5-191.5 C. Crude material was recrystallized from N,N-dimethylformamide and water. m.p.: 191.5-192.5 C.
5-carbamoyl-1H-imidazole-4-yl 2',2'-dichloro-1'-methylcyclopropane-1'-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With pyridine; triethylamine;
EXAMPLE 17 Following a procedure similar to that of Example 16 but using 0.636 g. of 4-carbamoylimidazolium-5-olate, 15 ml of dry pyridine, 1.03 g. of 2,2-dichloro-1-methylcyclopropanecarbonyl chloride and 0.612 g. of triethylamine there was obtained 1.123 g. of 5-carbamoyl-1H-imidazole-4-yl 2',2'-dichloro-1'-methylcyclopropane-1'-carboxylate, m.p. 169-172 C. (charred).
5-carbamoyl-1H-imidazole-4-yl 2',4',6'-trimethoxybenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
EXAMPLE 3 Following a procedure similar to that of Example 1 but using 0.636 g of 4-carbamoylimidazolium-5-olate and 2.0 g of 2,4,6-trimethoxybenzoyl chloride there was obtained 0.699 g of 5-carbamoyl-1H-imidazole-4-yl 2',4',6'-trimethoxybenzoate. m.p.: 174 C. (charred) Crude material was recrystallized from N,N-dimethylformamide and water. m.p.: 184.5 C. (charred)
5-carbamoyl-1H-imidazole-4-yl 1'-methylcyclohexane-1'-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In pyridine; water;
EXAMPLE 15 To a stirred suspension of 0.636 g. of 4-carbamoylimidazolium-5-olate in 15 ml of dry pyridine was dropwise added 1.61 g. of 1-methylcyclohexanecarbonyl chloride at a temperature below 5 C. in N2 atmosphere. After being stirred for 3.5 hours at 41-43 C., the reaction mixture was concentrated under reduced pressure. To the residue was added water and then separated crystals were filtered off, washed with diisopropyl ether and dried to give 1.06 g. of 5-carbamoyl-1H-imidazole-4-yl 1'-methylcyclohexane-1'-carboxylate, m.p. 197.5-198 C. Recrystallized was crude material from ethyl acetate. m.p.: 202.5-203 C.
5-carbamoyl-1H-imidazole-4-yl furan-2'-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine; In pyridine; chloroform;
EXAMPLE 1 To a suspension of 0.636 g. of 4-carbamoylimidazolium-5-olate in 15 ml. of dry pyridine was dropwise added 0.848 g. of 2-furoyl chloride at a temperature below 5 C. in N2 atmosphere. After being stirred for two hours at 41-43 C., the reaction mixture was cooled to room temperature and 0.658 g. of triethylamine was added. Then the reaction mixture was concentrated under reduced pressure. To the residue was added chloroform and then separated crystals were filtered off, washed with chloroform, toluene and diethyl ether, and dried to give 0.789 g. of 5-carbamoyl-1H-imidazole-4-yl furan-2'-carboxylate, m.p. 161-163 C. (dec.). Recrystallized was crude material from N,N-dimethylformamide and diisopropyl ether after washing with a small quantity of water. m.p.: 186.5 C. (dec.)
EXAMPLE 1 To a suspension of 0.98 g. of 4-carbamoylimidazolium-5-olate in 20 ml. of dry pyridine was added 2.17 g. of 3-fluoroadamantane-1-carbonylchloride and the reaction mixture was stirred for an hour at 40-45 C. Then the reaction mixture was concentrated under reduced pressure. To the residue was added ethylacetate and water and then separated crystals were filtered off, washed with ethyl acetate and dried to give 2.07 g. of 5-carbamoyl-1H-imidazole-4-yl 3'-fluoroadamantane-1'-carboxylate. The crude material was recrystallized from methanol and water. m.p.: 199 C. (dec.).
EXAMPLE 2 Following a procedure similar to that of Example 1 but using 0.89 g. of 4-carbamoylimidazolium-5-olate, 18 ml. of dry pyridine and 1.96 g. of 3-chloroadamantane-1-carbonyl chloride there was obtained 1.7 g. of 5-carbamoyl-1H-imidazole-4-yl 3'-chloroadamantane-1'-carboxylate. The crude material was recrystallized from N,N-dimethylformamide and water. m.p.: 192.5 C. (dec.).
EXAMPLE 3 Following a procedure similar to that of Example 1 but using 0.83 g. of 4-carbamoylimidazolium-5-olate, 17 ml. of dry pyridine and 2.17 g. of 3-bromoadamantane-1-carbonyl chloride there was obtained 1.5 g. of 5-carbamoyl-1H-imidazole-4-yl 3'-bromoadamantane-1'-carboxylate. The crude material was recrystallized from N,N-dimethylformamide and water. m.p.: 187.5 C. (dec.).
EXAMPLE 4 Following a procedure similar to that of Example 1 but using 0.89 g. of 4-carbamoylimidazolium-5-olate, 18 ml. of dry pyridine and 2.31 g. of 3-phenyladamantane-1-carbonyl chloride there was obtained 2.5 g. of 5-carbamoyl-1H-imidazole-4-yl 3'-phenyladamantane-1'-carboxylate. The crude material was recrystallized from N,N-dimethylformamide and water. m.p.: 190 C. (char.).
EXAMPLE 6 To a suspension of 0.636 g. of 4-carbamoylimidazolium-5-olate in 20 ml. of dry pyridine was added 1.445 g. of 3,5,7-trimethyladamantane-1-carbonyl chloride at room temperature. After being stirred for two hours at 40-45 C., the reaction mixture was cooled to room temperature and 0.93 ml. of triethylamine was added. After being stirred for half an hour, separated crystals were filtered off and the filtrate was concentrated under reduced pressure. To the residue was added dry diethyl ether and then separated crystals were filtered off and dried to give 1.506 g. of 5-carbamoyl-1H-imidazole-4-yl 3',5',7'-trimethyladamantane-1'-carboxylate. The crude material was purified by silica gel column chromatography and subjected to recrystallization from dimethylsulfoxide and diethyl ether. m.p.: 206-207 C.
EXAMPLE 14 To a stirred suspension of 0.636 g. of 4-carbamoylimidazolium-5-olate in 15 ml of dry pyridine was dropwise added 1.61 g. of 1-(p-chlorophenyl)-1-cyclopropanecarbonyl chloride at a temperature below 5 C. in N2 atmosphere. After being stirred for two hours at 41-43 C., the reaction mixture was cooled to room temperature and 0.83 g. of triethylamine was added. Then the reaction mixture was concentrated under reduced pressure. To the residue was added diethyl ether and then separated crystals were filtered off, washed with diethyl ether, water and diisopropyl ether and dried to give 1.176 g. of 5-carbamoyl-1H-imidazole-4-yl 1'-(p-chlorophenyl)cyclopropane-1'-carboxylate, m.p. 190 C. (charred). Recrystallized was crude material from N,N-dimethylformamide and water. m.p.: 190-191 C.
EXAMPLE 15 Following a procedure similar to that of Example 1 but using 4-carbamoyl-imidazolium-5-olate and 2,3,4,6-tetra-O-acetyl-alpha-D-glucopyranosyl bromide there was obtained 4-(2,3,4,6-tetra-O-acetyl-beta-D-glucopyranosyl)oxy-1H-imidazole-5-carboxamide. This product was identified to be same as that obtained in Example 2.
4-(2,3,4,6-tetra-O-acetyl-α-D-mannopyranosyl)oxy-1H-imidazole-5-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
EXAMPLE 16 Following a procedure similar to that of Example 1 but using 4-carbamoyl-imidazolium-5-olate and 2,3,4,6-tetra-O-acetyl-alpha-D-mannopyranosyl chloride there was obtained 4-(2,3,4,6-tetra-O-acetyl-alpha-D-mannopyranosyl)oxy-1H-imidazole-5-carboxamide. m.p. 148-154 C. (92 C. sintering)
EXAMPLE 17 Following a procedure similar to that of Example 1 but using 4-carbamoyl-imidazolium-5-olate and 3,4,6-tri-O-acetyl-2-deoxy-2-phthalimido-beta-D-glucopyranosyl chloride there was obtained 4-(3,4,6-tri-O-acetyl-2-deoxy-2-phthalimido-beta-D-glucopyranosyl)oxy-1H-imidazole-5-carboxamide. m.p. 202-208 C.
With formic acid; In ethanol; at 80℃;sealed tube;Product distribution / selectivity;
2-Aminomalonamide (99.2 mg; 0.847 mmol), formamidine acetate (88.6 mg; 0.851 mmol), and formic acid (128 mul) were dissolved into dry ethanol (3.8 ml) and were introduced into a sealed tube. The air in the tube was evacuated, sealed, and then heated at 80C for 1 hour. After opening the tube, into the reaction mixture was added a small portion of formic acid, and then the volatiles were removed in vacuo azeotropically with toluene. The resulting light blue solid was filtered and washed with small amount of cold water. The powder obtained was dissolved in formic acid again and the solvent removed in vacuo with toluene to give nearly white SM-108 (65.5 mg; 0.515 mmol). 1H-NMR (400 MHz, DMSO-d6): delta 7.83 (1H, s), 7.03 (1H, brs), 6.64 (1H, brs). 13C--NMR (100 MHz, DMSO-d6): delta 161.9 (1C), 156.5 (1C), 125.8 (1C), 99. 6 (1C). melting point: 185.7C
To SM-108 (165.5 mg; 0.515 mmol) obtained in Example 1, benzenesulfonic acid monohydrate (331 mg; 1.88 mmol) was added and dissolved in a small amount of water. Toluene was added and the volatiles were evaporated azeotropically under reduced pressure. The residue was washed with ethyl acetate to give benzensulfonic acid salt of SM-108 [5] (109.8 mg; 0.362 mmol; yield 43%) as colorless fine scales. 1H-NMR (400 MHz, DMSO-d6): delta 8.24 (1H, brs), 7.58 (2H, m), 7.33-7.28 (3H, m). melting point: 238.2C (decomposition)
With sodium hydrogencarbonate; In water; acetone;Product distribution / selectivity;
Benzene sulfonic acid salt of SM-108 (500 mg; 1.75 mmol) was dissolved into hot water (5 ml). The resulting solution was neutralized with sodium hydrogencarbonate (147 mg; 1.75 mmol) and acetone (40 ml) was added. After stirring, the precipitated colorless crystals were collected by filtration and were dried in vacuo to give SM-108 [2] (218 mg; 1.72 mmol; yield 98%) as colorless powders
With hydrogenchloride; sodium formate; In water; at 5 - 50℃; for 2.08333h;Inert atmosphere;
Under the nitrogen atmosphere, 20.0 g of 5-hydroxy-1H-imidazole-4-carboxamide hydrochloric acid salt dihydrate prepared according to the method of Reference Example 2 was added to 240 mL of 0.45 mol/L hydrochloric acid and dissolved therein by heating to 50C. At 50C, 40 mL aqueous solution containing 14.3 g of sodium formate was added dropwise thereto over 35 minutes. The reaction mixture was cooled and stirred for 90 minutes with the inside temperature of 5C. The crystal was collected by filtration and then washed with a mixture liquid containing 20 mL of acetone and 40 mL of water followed by 60 mL of acetone to give 12.6 g of 5-hydroxy-1H-imidazole-4-carboxamide·3/4 hydrate as a pale yellow crystal. Water content ratio: 8.6% (Karl Fischer Method) IR (ATR) 1655, 1619, 1584, 1551 cm-1 [0145] Powder X-ray diffraction pattern is shown in Fig. 8 and Table 3 while the infrared absorption spectrum (ATR method) is shown in Fig. 9.
12.8 g
With sodium formate; In water; at 50℃;Inert atmosphere;
(2) Under a nitrogen atmosphere, 5-hydroxy-1H-imidazole-4-carboxamide hydrochloride dihydrate (20.0 g) was added to 0.45 mol/L hydrochloric acid (240 mL), and dissolved therein by heating the mixture to 50 C. To this solution, a solution of sodium formate (14.3 g) dissolved in water (40 mL) was added dropwise over 33 minutes. The reaction mixture was cooled to 5 C., and the crystals were collected by filtration, washed with a mixture of acetone (20 mL) and water (40 mL), and then washed with acetone (60 mL) to obtain 5-hydroxy-1H-imidazole-4-carboxamide 3/4 hydrate as pale yellow crystals (12.8 g).
5-hydroxy-1H-imidazole-4-carboxamide hydrochloride[ No CAS ]
[ 56973-26-3 ]
Yield
Reaction Conditions
Operation in experiment
12.8 g
With hydrogenchloride; sodium formate; In water; at 5 - 50℃;Inert atmosphere;
(2) Under a nitrogen atmosphere, 5-hydroxy-1H-imidazole-4-carboxamide hydrochloride dihydrate (20.0 g) was added to 0.45 mol/L hydrochloric acid (240 mL), and dissolved therein by heating the mixture to 50 C. To this solution, a solution of sodium formate (14.3 g) dissolved in water (40 mL) was added dropwise over 33 minutes. The reaction mixture was cooled to 5 C., and the crystals were collected by filtration, washed with a mixture of acetone (20 mL) and water (40 mL), and then washed with acetone (60 mL) to obtain 5-hydroxy-1H-imidazole-4-carboxamide 3/4 hydrate as pale yellow crystals (12.8 g).
12.8 g
With hydrogenchloride; sodium formate; In water; at 50℃; for 0.55h;Inert atmosphere;
(2) Under a nitrogen atmosphere, 5-hydroxy-1H-imidazole-4-carboxamide hydrochloride dihydrate (20.0 g) was added to 0.45 mol/L hydrochloric acid (240 mL), and dissolved by heating the mixture to 50 C. To this solution, a solution of sodium formate (14.3 g) in water (40 mL) was added dropwise over 33 minutes. The reaction mixture was cooled to 5 C., and the crystals were collected by filtration, washed with a mixture of acetone (20 mL) and water (40 mL), and then washed with acetone (60 mL) to obtain 5-hydroxy-1H-imidazole-4-carboxamide 3/4 hydrate as pale yellow crystals (12.8 g).
5-hydroxy-1H-imidazole-4-carboxamide sulfate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1.8 g
To <strong>[56973-26-3]5-hydroxy-1H-imidazole-4-carboxamide</strong> 3/4 hydrate (1.5 g), water (30 mL) and concentrated sulfuric acid (625 muL) were added, the mixture was heated to 50 to 55 C., then water (45 mL) was further added to dissolve the compound, and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was gradually cooled to room temperature. After the deposition of crystals was confirmed, the mixture was cooled on ice, and the crystals were collected by filtration. The crystals were washed with water and air-dried to obtain alpha-form crystals (1.8 g).
To <strong>[56973-26-3]5-hydroxy-1H-imidazole-4-carboxamide</strong> 3/4 hydrate (1.4 g), water (30 mL) and methanesulfonic acid (1.0 g) were added, the mixture was heated at 50 C. to dissolve the compounds, and then the solution was stirred at the same temperature for 30 minutes. After the reaction mixture was cooled to room temperature, toluene was added, water was removed by azeotropy under reduced pressure, and the precipitated solid was collected by filtration. The solid was washed with ethyl acetate and air-dried to obtain methanesulfonate of <strong>[56973-26-3]5-hydroxy-1H-imidazole-4-carboxamide</strong> (1.7 g). (0084) The moisture content of the methanesulfonate of <strong>[56973-26-3]5-hydroxy-1H-imidazole-4-carboxamide</strong> was 7.8%.
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