* 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.
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 1996, vol. 6, # 2, p. 185 - 188
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[ 76055-09-9 ]
[ 360-97-4 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1980, p. 2316 - 2321
3
[ 2627-69-2 ]
[ 532-20-7 ]
[ 360-97-4 ]
Reference：
[1] Journal of Organic Chemistry, 1987, vol. 52, # 14, p. 3113 - 3119
4
[ 85622-95-3 ]
[ 360-97-4 ]
Reference：
[1] Journal of Medicinal Chemistry, 2002, vol. 45, # 25, p. 5458 - 5470
5
[ 479071-08-4 ]
[ 360-97-4 ]
Reference：
[1] Journal of Medicinal Chemistry, 2002, vol. 45, # 25, p. 5458 - 5470
6
[ 37842-62-9 ]
[ 360-97-4 ]
Reference：
[1] Journal of the Chemical Society, 1959, p. 1648,1652
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[ 85622-95-3 ]
[ 360-97-4 ]
[ 28177-14-2 ]
[ 107-07-3 ]
Reference：
[1] Journal of Medicinal Chemistry, 1984, vol. 27, # 2, p. 196 - 201
[2] Journal of Medicinal Chemistry, 1984, vol. 27, # 2, p. 196 - 201
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[ 100191-43-3 ]
[ 360-97-4 ]
Reference：
[1] Journal of Biological Chemistry, 1949, vol. 181, p. 89,91
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[ 85622-93-1 ]
[ 53952-42-4 ]
[ 813-78-5 ]
[ 1455-13-6 ]
[ 53952-43-5 ]
[ 360-97-4 ]
Reference：
[1] Journal of the Chemical Society, Chemical Communications, 1993, # 15, p. 1177 - 1178
10
[ 6313-33-3 ]
[ 6719-21-7 ]
[ 360-97-4 ]
Reference：
[1] Journal of the Chemical Society, 1949, p. 1440
11
[ 82647-13-0 ]
[ 371-62-0 ]
[ 624-72-6 ]
[ 360-97-4 ]
[ 75-07-0 ]
Reference：
[1] Canadian Journal of Chemistry, 1981, vol. 59, # 9, p. 1347 - 1356
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[ 7664-93-9 ]
[ 68-94-0 ]
[ 360-97-4 ]
Reference：
[1] Res.Rep.Nagoya ind.Sci.Res.Inst., 1957, # 9, p. 83[2] Chem.Abstr., 1957, p. 12074
13
[ 360-97-4 ]
[ 21190-16-9 ]
Yield
Reaction Conditions
Operation in experiment
45%
Stage #1: With methanesulfonic acid In ethanol for 288 h; Heating / reflux Stage #2: With sodium hydroxide; water In water at 0℃;
Example C.30 4-Trifluoromethyl-2-(4-trifluoromethyl-phenyl)-imidazo[1,5-a]pyrimidine-8-carboxylic acid; 1) A stirred solution of commercially available 5-amino-1H-imidazole-4-carboxamide (25 g, 198 mmol) in methanesulfonic acid (107 ml) and ethanol (400 ml) was stirred at reflux conditions for 12d, evaporated and water (300 ml) was added. While stirring and cooling (ice/water) sodium hydroxide solution (32percent) was added until pH=6 was reached. The water layer was saturated with sodium chloride and extracted with ethyl acetate (3.x.200 ml). The combined organic layers were dried (MgSO4), evaporated and the crude product purified crystallization (ethyl acetate/ethanol) to yield 5-amino-1H-imidazole-4-carboxylic acid ethyl ester (13.7 g, 45percent) as a light brown solid. MS (EI) 155.1 [(M)+]; mp 178° C. 2) A mixture of 4,4,4-trifluoro-1-(4-trifluoromethyl-phenyl)-butane-1,3-dione (10.0 g, 35.2 mmol) and 5-amino-1H-imidazole-4-carboxylic acid ethyl ester (5.0 g, 32.2 mmol) in acetic acid (120 ml) was refluxed for 24 h and evaporated. The crude product was further purified by column chromatography on silica gel (ethyl acetate/heptane) and crystallization (diethyl acetate/hexane) to yield 4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-imidazo[1,5-a]pyrimidine-8-carboxylic acid ethyl ester (5.65 g, 43percent) as a yellow solid. MS (EI) 403.1 [(M)+]; mp 243° C. 3) A mixture of 4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-imidazo[1,5-a]pyrimidine-8-carboxylic acid ethyl ester (5.6 g, 13.9 mmol), 2M potassium hydroxide solution (111 ml) and water (55 ml) was stirred at room temperature for 5h, cooled (ice-water), and acetic acid (30 ml) was added. The mixture was evaporated, acetic acid (150 ml) was added and the stirred solution was heated under reflux conditions for 20 min. The reaction mixture was evaporated, water (150 ml) was added followed by extraction with ethyl acetate (2.x.300 ml). The combined organic layers were washed with brine (2.x.150 ml), dried (MgSO4) and evaporated. The crude product was further purified by cholumn chromatography on silica gel (ethyl acetate/heptane 1:1) to yield 4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-imidazo[1,5-a]pyrimidine-8-carboxylic acid (1.93 g, 37percent) as a yellow solid. MS (ISN) 374.3 [(M-H)-]; mp 231° C.
A mixture of 5-amino-1H-imidazole-4-carboxamide (30.0 g, 238 mmol) and sulfuric acid (70.0 g, 714 mmol) in ethanol (300 mL) was heated to 120 °C in a sealed tube for 24 h. The reaction mixture was cooled to room temp, and the solvent was removed in vacuo. The residue was purified via silica gel column chromatography to give ethyl 5-amino-1H-imidazole-4-carboxylate (20.0 g, 54percent). MS (ESI) calcd for C6H9N3O2: 155.07
54%
at 120℃; for 24 h; Sealed tube
A mixture of 5-amino-1H-imidazole-4-carboxamide (30.0 g, 238 mmol) and sulfuric acid (70.0 g, 714 mmol) in ethanol (300 mL) was heated to 120 °C in a sealed tube for 24 h. The reaction mixture was cooled to room temp, and the solvent was removed in vacuo. The residue was purified via silica gel column chromatography to give ethyl 5-amino-1H-imidazole-4-carboxylate (20.0 g, 54percent). MS (ESI) calcd for C6H9N3O2: 155.07
45%
for 48 h; Reflux
A solution of 5-amino-1H-imidazole-4-carboxamide (35 g, 277 mmol) in MeSO3H (150 mL) and EtOH (560 mL) was stirred at reflux conditions for 2 days, and then concentrated in vacuo. To the resulting residue, water (400 mL) was added and while stirring and cooling (ice/water) sodium hydroxide solution (32 percent) was added until pH = 7 was reached. The water layer was saturated with sodium chloride and extracted with DCM (200 mL x 3). The combined organic layers were dried (MgSO4), and filtered. The filtrate was concentrated in vacuo to afford ethyl 5-amino-1H-imidazole-4-carboxylate (13.7 g, 45percent) as a white solid.
(e) 4-[(6-Butoxypyridin-2-yl)methyl]amino}-lH-imidazole-5-carboxamide; 5 <strong>[360-97-4]5-Aminoimidazole-4-carboxamide</strong> (0.30 g, 2.4 mmol) was added to the solution of 6- butoxypyridine-2-carbaldehyde (0.43 mg, 2.4 mmol, obtained from Example 17(d)) in anhydrous ethanol (30 mL) and the reaction mixture was refluxed. After 2 h, the reaction mixture was concentrated in vacuo. The light pink solid was suspended in anhydrous ethanol (25 mL), and acetic acid (0.27 mL, 4.8 mmol) was added. After 1.5 h, sodium 0 cyanoborohydride (0.30 g, 4.8 mmol) was added to the mixture. After stirring o.n. at ambient temperature, the reaction mixture was concentrated in vacuo. The resulting 1.2 g <n="77"/>of crude title compound was used in the next step without further purification. MS (ESI) m/z 290 (M+l).
(b) tert-Butyl {2-[(5-carbamoyl-lH-irnidazol-4-yl)amno]-l-methylethyl}comega'bamate; To a stirred solution tert-butyl (l-methyl-2-oxoethyl-carbamate (0.82 g, 4.8 mmol, obtained from Example 29(a)) in ethanol (10 mL) was added 5-aminoimidazole-4- carboxamide (9.4 mL, 67 mmol). After 1 h, glacial acetic acid (0.28 mL, 4.0 mmol) was added. After another 1 h, sodium cyanoborohydride (0.48 g, 4.0 mmol) was added. After 20 h, the solvent was removed in vacuo. The product was purified by silica gel column chromatography (dichloromethane / methanol, 95:5 then 90:10) to give the title compound (0.95 g, 66% yield) as a solid.1H NMR (CDCl3) delta ppm 7.17 (IH), 6.51 (IH), 4.71 (IH), 3.57-3.46 (IH), 3.40 (IH)5 3.06- 2.96 (IH)5 1.48 (9H)5 1.25 (3H); MS (ESI) m/z 284 (M+l).
With sodium cyanoborohydride; acetic acid; In methanol; at 20℃; for 1h;
(c) 4-f(2-Meth.yl-2-propoxypropyl)amino]--lH-imidazole-5-carboxamide; The reaction mixture of 2-methyl-2-propoxypropanal, which was obtained from Example 2(b), (1.0 g, 8.3 mmol), 5-amino-4-irnidazolecarboxamide (0.5 g, 4.0 mmol), sodium cyanoborohydride (0.25 g, 4.0 mmol) and acetic acid (0.45 mL, 7.9 mmol) in 10 mL of methanol was stirred at ambient temperature for 1 h. The solvent was removed in vacuo. Water (20 mL) and ethyl acetate (20 mL) were added. The organic phase was separated and the solvent was removed in vacuo. Purification by ISCO flash (EtOAc:Heptane, gradient elution 1:1 to 100% EtOAc) gave 0.19 g (20 %) of the title compound. 1R NMR (CDCl3) delta ppm 6.98 (s, IH), 6.39 (br s, IH), 3.40 (t, 2H, J=6.7 Hz), 3.14 (d, 2H, J=4.3 Hz), 1.56-1.65 (m, 2H), 1.22 (s, 6H), 0.95 (t, 3H, J=7.5 Hz); MS (ESI) m/z 241 (M+l).
With N-ethyl-N,N-diisopropylamine; In chloroform; N,N-dimethyl-formamide; at 0 - 20℃;
2.53 g of 4-amino-5-imidazolecarboxamide was dissolved in 30 mL chloroform and 30 mL dimethylformamide. To this solution was added at 0C 3.02 mL of 3-chlorobenzoylchloride, followed by 5.4 mL di-isopropylethylamine. The reaction mixture was allowed to warm to room temperature and maintained at room temperature overnight. The reaction mixture was diluted with chloroform and washed with water, 10% aqueous sodium carbonate solution and brine. The organic layer was dried over anhydrous sodium sulfate and filtered. The crude residue obtained after concentration was taken up in the minimal amount of chloroform and chromatographed on silica gel, using ethyl acetate, 5% methanol to give 4.81 g of compound of formula (I)
1-(m-cyanobenzyl)-5-aminoimidazole-4-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In methanol; acetone;
EXAMPLE 3 Preparation of 1-(m-cyanobenzyl)-<strong>[360-97-4]5-aminoimidazole-4-carboxamide</strong> A mixture of <strong>[360-97-4]5-aminoimidazole-4-carboxamide</strong> (5.00 g), potassium carbonate (12.0 g), and alpha-bromo-m-tolunitrile (9.80 g) were refluxed in acetone (300 ml) for 24 hours under a nitrogen atmosphere. The mixture was cooled to room temperature and filtered. The solid residue was washed with acetone and the combined filtrates were evaporated to dryness. The residual solid was dissolved in acetone (50 ml), concentrated to a volume of 20 ml in vacuo, and diluted with diethyl ether (100 ml) to provide a gum. The solvent was decanted from the residue and deposited crystals of crude product on standing. The gum was triturated twice with acetone, and the acetone layers were combined with the above crystals, and evaporated to provide 5.9 g of a dark gum. The gum was dissolved in methanol (100 ml), filtered, added to 100 ml. E. Merck 7734 silica gel, and evaporated to dryness in vacuo. The product on silica gel was placed on top of a column of 1200 ml E. Merck 7734 silica gel and eluted with 9:1 v/v methylene chloride/methanol. After a forerun of 1.0 l, 400 ml fractions were collected and fractions 8-11 and 12-15 were combined separately and evaporated to dryness. The solid product from fractions 8-11 was triturated with a small volume of acetone and filtered. The filtrate was combined separately with the product from fractions 12-15 and evaporated to dryness. The product was recrystallized from methanol to provide 320 mg of 1-(m-cyanobenzyl)-<strong>[360-97-4]5-aminoimidazole-4-carboxamide</strong>, m.p. 246-247 C.
Example C.30 4-Trifluoromethyl-2-(4-trifluoromethyl-phenyl)-imidazo[1,5-a]pyrimidine-8-carboxylic acid; 1) A stirred solution of commercially available 5-amino-1H-imidazole-4-carboxamide (25 g, 198 mmol) in methanesulfonic acid (107 ml) and ethanol (400 ml) was stirred at reflux conditions for 12d, evaporated and water (300 ml) was added. While stirring and cooling (ice/water) sodium hydroxide solution (32%) was added until pH=6 was reached. The water layer was saturated with sodium chloride and extracted with ethyl acetate (3×200 ml). The combined organic layers were dried (MgSO4), evaporated and the crude product purified crystallization (ethyl acetate/ethanol) to yield 5-amino-1H-imidazole-4-carboxylic acid ethyl ester (13.7 g, 45%) as a light brown solid. MS (EI) 155.1 [(M)+]; mp 178 C. 2) A mixture of 4,4,4-trifluoro-1-(4-trifluoromethyl-phenyl)-butane-1,3-dione (10.0 g, 35.2 mmol) and 5-amino-1H-imidazole-4-carboxylic acid ethyl ester (5.0 g, 32.2 mmol) in acetic acid (120 ml) was refluxed for 24 h and evaporated. The crude product was further purified by column chromatography on silica gel (ethyl acetate/heptane) and crystallization (diethyl acetate/hexane) to yield 4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-imidazo[1,5-a]pyrimidine-8-carboxylic acid ethyl ester (5.65 g, 43%) as a yellow solid. MS (EI) 403.1 [(M)+]; mp 243 C. 3) A mixture of 4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-imidazo[1,5-a]pyrimidine-8-carboxylic acid ethyl ester (5.6 g, 13.9 mmol), 2M potassium hydroxide solution (111 ml) and water (55 ml) was stirred at room temperature for 5h, cooled (ice-water), and acetic acid (30 ml) was added. The mixture was evaporated, acetic acid (150 ml) was added and the stirred solution was heated under reflux conditions for 20 min. The reaction mixture was evaporated, water (150 ml) was added followed by extraction with ethyl acetate (2×300 ml). The combined organic layers were washed with brine (2×150 ml), dried (MgSO4) and evaporated. The crude product was further purified by cholumn chromatography on silica gel (ethyl acetate/heptane 1:1) to yield 4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-imidazo[1,5-a]pyrimidine-8-carboxylic acid (1.93 g, 37%) as a yellow solid. MS (ISN) 374.3 [(M-H)-]; mp 231 C.
5-Amino-imidazole-4-carboxamide, monohydrochloride (0.0133 mol) was dissolved in pyridine (15 ml), and lambda/,lambda/-dimethyl-4-pyridinamine (0.030 g) was added. Afterwards, 4-fluorobenzoyl chloride (0.0110 mol) was added dropwise while stirring. The reaction mixture was stirred for 5 hours at 70 0C. The reaction mixture was poured into water. The precipitate was filtered off, washed with water and dried. Yield: 2.560 g of intermediate 30 (77 %).
With caesium carbonate; In N,N-dimethyl-formamide; at 80℃; for 16h;
A solution of delta-amino-I H-imidazole^-carboxamide (1.4 g, 11 mmol), toluene- 4-sulfonic acid 1 -(tert-butoxycarbonyl-isopropyl-amino)-propyl ester (5 g, 13 mmol) previously prepared (cf. Llauger et al., "Evaluation of 8-Arylsulfanyl, 8- Arylsulfoxyl, and 8-Arylsulfonyl Adenine Derivatives as Inhibitors of the Heat Shock Protein 90", J. Med. Chem. 2005, vol. 48, p. 2892), and Cs2CO3 (3.6 g, 11 mmol) in 40 ml_ of DM F was stirred at 8O0C for 16 h. Removal of the solvent and purification by chromatography on silica (CHCI3/MeOH, 5%) yielded ^-(delta-Amino^-carbamoyl-imidazol-i-yO-propyll-isopropyl-carbamic acid tert-butyl ester (1.45 g, 40%) as a viscous oil . 1H-NMR [CDCI3, delta, ppm]: 7.12 (s, 1 H), 3.37 (m, 2H), 3.32 (m, 1 H), 3.07 (m, 2H), 1.92 (m, 2H), 1.40 (s, 9H), 1.07-1.06 (2s, 6H).
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 0 - 25℃; for 17h;
EXAMPLE 1 Synthesis of Carbamoyl AICA 200 g of base AICA as is (K. F. 11 %) corresponding to 178 g of 100% base AICA and 1000 ml of acetonitrile are charged in a 2-liter reactor. The mixture is stirred at room temperature (about 20 C.) and 267 g of N-Succinimidyl-N'-methyl carbamate and 191.7 g of diisopropylethylamine (DIPEA) are added to the suspension. The temperature of the mixture is kept at 25+2 C. for 16 hours, then the mixture is cooled at 0÷5 C., held for an hour and the suspension is filtered on a Buchner, by washing with 2*200 ml of deionised water. 313.0 g of wet product are discharged, which is then dried on a rotavapor for 5 hours at 50 C. with vacuum line. 212 g of Carbamoyl AICA (96.9% HPLC purity) are obtained, with 0.13% K. F. 88% yield.
Example 1 Preparation of 5-diazo-5H-imidazole-4 carboxamide 47 g of sodium nitrite was dissolved in 1.2 litres of water and the solution cooled to 0 C. 100 g of 5-aminoimidazole-4 carboxamide was dissolved in a solution of hydrochloric acid (80 ml of 36% HCL in 720 ml water) with stirring, and the resultant 5-aminoimidazole-4 carboxamide hydrochloride solution was added slowly, drop-wise over a period of 20-30 minutes at 0-5 C. After the addition was completed, the reaction mixture was stirred for 10 minutes and filtered. The solid obtained was suspended in 400 ml DM water and stirred for 15 minutes. The suspension was filtered and suction dried for 15 mins. The obtained solid was suspended in 500 ml of THF and stirred for 15 minutes. The suspension was filtered and suction dried for 15 minutes. Finally, the solid was dried at 45 C. to afford 60 gms of the title compound. Purity: 96.4% by HPLC.
Briefly, <strong>[360-97-4]5-aminoimidazole-4-carboxamide</strong> was treated with NaNO2 and the resulting product reacted with 2-chloroethylisocyanate in ethyl acetate to provide MTZ.
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