Structure of 22600-77-7
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CAS No. : | 22600-77-7 |
Formula : | C4H9Cl2N3 |
M.W : | 170.04 |
SMILES Code : | Cl.Cl.NCC1=NC=CN1 |
MDL No. : | MFCD06738779 |
InChI Key : | KYUDBQDDNKPSIC-UHFFFAOYSA-N |
Pubchem ID : | 12417863 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
24% | (S)-Methyl 2-(9-((1H-imidazol-2-yl)methyl)-4-chloro-8-oxo-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)acetate; (S)-Dimethyl 2-((7-chloro-4-(chloromethyl)-1H-indazol-5-yl)methyl)succinate (250 mg, 0.63 mmol) and <strong>[22600-77-7](1H-imidazol-2-yl)methanamine dihydrochloride</strong> (170 mg, 1.0 mmol) were combined and suspended in acetonitrile (10 mL). Triethylamine (800 muL, 5.7 mmol) was added to the mixture. Reaction was warmed to reflux for 3 hours. Acetic acid (1.5 mL) was added to the mixture. Reaction was heated at reflux for 20 hours. Mixture was cooled to room temperature then diluted with dichloromethane. Mixture was extracted twice with water. Aqueous layer was concentrated in vacuo. Residue was purified by preparatory HPLC. Water was lyophilized off. Remaining residue was passed through a column of Dowex 1×4-200 ion exchange resin eluting methanol. Title compound was recovered as amber residue in 24% yield. MS m/e (M+H)+=388.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | With triethylamine; In dichloromethane; at 20℃; | To a solution of 3-[8-(2,6-difluorophenyl)-2-(methylsulfnyl)-7-oxo-7,8- dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (50 mg, 0.09 mmol) in DCM (5 niL) was added (lH-imidazol-2-ylmethyl)amine dihydrochloride (75 mg, 0.44 mmol), triethylamine (0.2 mL, 1.44 mmol). The resultant mixture was stirred at room temperature overnight. The mixture was concentrated and purified by etaPLC to give the title product as the major component (20 mg, 37%). LC-MS (ES) m/z 489 (M+eta)+; 1H-NMR(MeOD) delta 2.36 (s, 3H), 4.58 (s, 2H), 6.48 (d, IH), 7.12 (m, IH), 7.21 (m, IH), 7.39 (s, 2H), 7.56 (m, 3H), 8.00 (s, IH), 8.14 (d, IH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
29% | With 1-methyl-pyrrolidin-2-one; triethylamine; at 23 - 100℃; for 16h; | 2-[8-(2,6-Difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-((1H-imidazol-2-ylmethyl)amino)-8H-pyrido[2,3-d]pyrimidin-7-one (1H-Imidazol-2-yl)-methylamine dihydrochloride (184 mg, 1.1 mmol), NMP (1 ML), and triethylamine (0.31 ML, 2.2 mmol) were stirred at 23 10 min.The product of Example 48 (100 mg, 0.22 mmol) was added and the mixture was reacted at 100 for 16 h to give the crude material.Preparative hplc afforded the title compound, 36 mg (29%). LC-MS: 463.2 (MH+, m/z), 1.42 (Rt, min). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; dmap; In dichloromethane; | 2-[6-(4-Iodo-phenyl)-7-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-pyrazolo[3,4-c]pyridin-1-yl]-5-methoxy-benzoic acid (186 mg, 0.334 mmol) was dissolved in dry chloroform (10 mL) to which was added thionyl chloride (243 muL, 3.34 mmol), and the reaction heated to reflux. The solvent was evaporated, and the residue dried under vacuum to give 2-[6-(4-iodo-phenyl)-7-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-pyrazolo[3,4-c]pyridin-1-yl]-5-methoxy-benzoyl chloride as a pale yellow foam. This material was dissolved in dry methylene chloride (10 mL) to which were added pyridine (0.14 mL, 1.67 mmol), N,N-dimethylaminopyridine (4 mg, 0.033 mmol), and lastly <strong>[22600-77-7]C-(1H-imidazol-2-yl)-methylamine bis-hydrochloride</strong> (114 mg, 0.668 mmol). Upon completion of the reaction the solvent was evaporated, and the residue was purified by preparative HPLC to give the title compound (69 mg, 24%) as a colorless solid. MS (ES+) 636.9 (M+H)+(100%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In acetonitrile; for 3h;Heating / reflux; | (S)-Methyl 2-(9-((1H-imidazol-2-yl)methyl)-4-chloro-8-oxo-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)acetate. (S)-Dimethyl 2-((7-chloro-4-(chloromethyl)-1H-indazol-5-yl)methyl)succinate (250 mg, 0.63 mmol) and <strong>[22600-77-7](1H-imidazol-2-yl)methanamine dihydrochloride</strong> (170 mg, 1.0 mmol) were combined and suspended in acetonitrile (10 mL). Triethylamine (800 muL, 5.7 mmol) was added to the mixture. Reaction was warmed to reflux for 3 hours. Acetic acid (1.5 mL) was added to the mixture. Reaction was heated at reflux for 20 hours. Mixture was cooled to room temperature then diluted with dichloromethane. Mixture was extracted twice with water. Aqueous layer was concentrated in vacuo. Residue was purified by preparatory HPLC. Water was lyophilized off. Remaining residue was passed through a column of Dowex 1×4-200 ion exchange resin eluting methanol. Title compound was recovered as amber residue in 24% yield. MS m/e (M+H)+=388.1. | |
With triethylamine; In acetonitrile; for 3h;Heating / reflux; | (S)-Methyl 2-(9-((1H-imidazol-2-yl)methyl)-4-chloro-8-oxo-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)acetate; (S)-Dimethyl 2-((7-chloro-4-(chloromethyl)-1H-indazol-5-yl)methyl)succinate (250 mg, 0.63 mmol) and <strong>[22600-77-7](1H-imidazol-2-yl)methanamine dihydrochloride</strong> (170 mg, 1.0 mmol) were combined and suspended in acetonitrile (10 mL). Triethylamine (800 muL, 5.7 mmol) was added to the mixture. Reaction was warmed to reflux for 3 hours. Acetic acid (1.5 mL) was added to the mixture. Reaction was heated at reflux for 20 hours. Mixture was cooled to room temperature then diluted with dichloromethane. Mixture was extracted twice with water. Aqueous layer was concentrated in vacuo. Residue was purified by preparatory HPLC. Water was lyophilized off. Remaining residue was passed through a column of Dowex 1×4-200 ion exchange resin eluting methanol. Title compound was recovered as amber residue in 24% yield. MS m/e (M+H)+=388.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; sodium hydrogencarbonate; | Production Example 162 2-[N-(tert-Butoxycarbonyl)aminomethyl]imidazole To an aqueous solution (10 ml) of 0.34 g of <strong>[22600-77-7]2-aminomethylimidazole dihydrochloride</strong> were added 0.32 g of sodium hydroxide and 0.34 g of sodium hydrogencarbonate. Then a tetrahydrofuran solution (10 ml) of 1.05 g of di-tert-butyl dicarbonate was added thereto and the resulting mixture was stirred at room temperature for 16 hours. After adding an aqueous solution of disodium hydrogenphosphate, the resulting mixture was extracted with ethyl acetate. The organic layer was washed successively with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After concentrating under reduced pressure, the residue was purified by silica gel column chromatography (eluted with n-hexane/ethyl acetate) to thereby give 0.20 g of the title compound as a colorless powder. 1H-NMR(CDCl3) delta ppm: 1.43(s, 9H), 4.32(d, J=7 Hz, 2H), 5.43(br.s, 1H), 6.96(s, 2H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; acetic anhydride; In N,N-dimethyl-formamide; | Production Example 160 N-(Imidazol-2-ylmethyl)acetamide 0.34 g of <strong>[22600-77-7]2-aminomethylimidazole dihydrochloride</strong> was added to 20 ml of N,N-dimethylformamide in a nitrogen atmosphere. Under ice-cooling, 0.40 g of sodium hydride (60% oily) was added thereto and the resulting mixture was subjected to ultrasonication for 30 minutes. To the reaction mixture were added 20 ml of pyridine and 10 ml of acetic anhydride and the obtained mixture was stirred at room temperature for 2 days. After concentrating under reduced pressure, the residue was distributed into water and ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. The extract was concentrated under reduced pressure to thereby give 0.24 g of the title compound as a pale brown solid. 1H-NMR(CDCl3) delta ppm: 1.99(s, 3H), 4.44(d, J=7 Hz, 2H), 6.96(s, 2H), 8.25(br.s, 1H), 8.39(br.m, 1H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33% | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; | Example 52; 3-(8-r2.6-difluorophenyl')-2-["alphaH-imidazol-2-ylmethyl)amino1-7-oxo-5,6,7,8- tetrahvdrop yrimido [4,5 -cflp yrimidin-4- yl ) -4-methyl-iV-( 1 -methyleth vPbenzamide; To a solution of compound 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7- oxo-5,6,7,8-tetrahydropyrimido[4,5-c?]pyrimidin-4-yl]-4-methyl-N-(l- methylethyl)benzamide (20 mg, 0.04 mmol) in THF (3 mL) were added (IH- imidazol-2-ylmethyl)amine dihydrochloride (50 mg, 0.52 mmol) and N,N- diisopropylethylamine (0.1 mL, 0.574 mmol). The resultant solution was stirred at room temperature over night. The result mixture was concentrated. CombiFlash chromatography (mobile phase DCM/DCM[90]+MeOH[7]+NH4OH[3]) provided the title compound as a white solid (7 mg, 33%). LC-MS m/z 533 (M + H)+; 1H- NMR (MeOD) delta 1.26 (d, 6H), 2.26 (s, 3H), 4.12 (s, 2 H), 4.23 (m, 1 H), 4.36 (s, 2 H), 6.88 (s, 2 H), 7.10 (t, 2 H), 7.48 (m, 2 H), 7.69 (s, 1 H), 7.85 (d, 1 H). |
33% | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; | To a solution of compound 3-[8-(2,6-difluorophenyl)-2-(methylsulfnyl)-7-oxo- 5,6,7,8-tetrahydropyrimido[4,5-<i]pyrimidin-4-yl]-4-methyl-lambda/-(l-methylethyl)benzamide (20 mg, 0.04 mmol) in TetaF (3 mL) were added (lH-imidazol-2-ylmethyl)amine dihydrochloride (50 mg, 0.52 mmol) and JV,jV-diisopropylethylamine (0.1 mL, 0.574 mmol). The resultant solution was stirred at room temperature over night. The result mixture was concentrated. CombiFlash chromatography (mobile phase DCM/DCM[90]+MeOeta[7]+Neta4Oeta[3]) <n="152"/>provided the title compound as a white solid (7 mg, 33%). LC-MS m/z 533 (M + H) + ;. I 1TH- NMR (MeOD) delta 1.26 (d, 6H), 2.26 (s, 3H), 4.12 (s, 2 H), 4.23 (m, 1 H), 4.36 (s, 2 H), 6.88 (s, 2 H), 7.10 (t, 2 H), 7.48 (m, 2 H), 7.69 (s, 1 H), 7.85 (d, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33% | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; dichloromethane; N,N-dimethyl-formamide; at 40℃; | Example 44; 3-{8-(2.6-difluorophenyl)-2-rflH-imidazol-2-ylmethvDaminol-7-oxo-5.6.7.8- tetrahvdropyriniido|'4,5-tf|pyrimidin-4-yl}-7V-r4-fluorophenvD-4-methylben2amide; To a solution of compound 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7- oxo-5,6,7,8-tetrahydropyrimido[4,5-(f]pyrimidin-4-yl]-iV-(4-fluorophenyl)-4- methylbenzamide (20 mg, 0.036 mmol) in THF(3 mL)/ DMF(3 raL)/ DCM(3 mL) were added (lH-imidazol-2-ylmethyl)amine dihydrochloride (50 mg, 0.52 mmol) and LambdazetaN-diisopropylethylamine (0.1 mL, 0.574 mmol). The resultant solution was stirred at 400C over night. The result mixture was concentrated. CombiFlash chromatography (mobile phase DCM/DCM[90]+MeOH[7]+NH4OH[3]) provided the title compound as a white solid (7 mg, 33 %). LC-MS m/z 585 (M + H)+; 1H- NMR (MeOD) delta 2.33 (s, 3 H), 4.13 (s, 2 H), 4.42 (s, 2 H), 6.92 (m, 2 H), 7.15 (m, 4 H), 7.50 (m, 2 H), 7.72 (m, 2 H), 7.82 (s, 1 H), 7.98 (d, 1 H). |
33% | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; dichloromethane; N,N-dimethyl-formamide; at 40℃; | To a solution of compound 3-[8-(2,6-difluorophenyl)-2-(methylsulfnyl)-7-oxo- 5,6,7,8-tetrahydropyrimido[4,5-(i]pyrimidin-4-yl]-N-(4-fluorophenyl)-4-methylbenzamide (20 mg, 0.036 mmol) in TetaF(3 mL)/ DMF(3 mL)/ DCM(3 mL) were added (lH-imidazol-2- ylmethyl)amine dihydrochloride (50 mg, 0.52 mmol) and JV,jV-diisopropylethylamine (0.1 mL, 0.574 mmol). The resultant solution was stirred at 400C over night. The result mixture was concentrated. CombiFlash chromatography (mobile phase DCM/DCM[90]+MeOeta[7]+Neta4Oeta[3]) provided the title compound as a white solid (7 mg, <n="148"/>33 %). LC-MS m/z 585 (M + H) ++;. I 1TH-NMR (MeOD) delta 2.33 (s, 3 H), 4.13 (s, 2 H), 4.42 (s, 2 H), 6.92 (m, 2 H), 7.15 (m, 4 H), 7.50 (m, 2 H), 7.72 (m, 2 H), 7.82 (s, 1 H), 7.98 (d, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With triethylamine; In dichloromethane; at 20℃; | 79c) 3-{8-r2.6-difluorophenylV2-rdH-imidazol-2-ylniethvnaminol-7-oxo-7J dihydropyrido[23-c?pyrimidin-4-vU-4-niethyl-A/-1.3-thiazol-2-ylbenzamideTo the solution of 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl) -7-oxo-7,8- dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methyl-N-l,3-thiazol-2-ylbenzamide (1.37 g, 2.54 mmol) in DCM (127 niL) were added Et3N (1.78 mL, 12.7 mmol) and (IH- imidazol-2-yl)-methylamine dihydrochloride (0.625 g, 3.81 mmol). The mixture was stirred at room temperature over night and concentrated under vacuum. Flash chromatography [mobile phase DCM/DCM (90)+MeOH(7)+NH4OH(3)] then provided the title compound as a white solid 1.23 g (85 %). MS (ES) m/z 571 (M + H)+; 1H-NMR (MeOD) delta 2.16 (s, 1.5 H), 2.32 (s, 1.5 H), 3.18 (d, J= 4.4 Hz, 0.75 H), 4.11 (d, J= 5.2 Hz, 0.25 H), 4.21 (d, J= 5.0 Hz, 1 H), 4.50 (m, 1 H), 6.37 (d, J = 9.6 Hz, 1 H), 6.85 (s, 2 H), 7.29 (s, 2 H), 7.43 (m, 2 H), 7.57 (m, 3 H), 8.18 (m, 3 H), 11.60 (s, br, 1 H), 12.64 (s, br, 2 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
15% | With triethylamine; In dichloromethane; at 20℃; | 97b) 3-r2-r2-(aniinomethyl)-lH-imidazol-l-yll-8-r2.6-difluorophenylV7-oxo-7.8- dihvdropyrido[2,3-dlpyrimidin-4-yl]-4-methylbenzoic acid trifluoroacetateTo a solution of 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-7,8- dihydropyrido[2,3-J]pyrimidin-4-yl]-4-methylbenzoic acid (50 mg, 0.09 mmol) in DCM (5 mL) was added (lH-imidazol-2-ylmethyl)amine dihydrochloride (75 mg, 0.44 mmol), triethylamine (0.2 mL, 1.44 mmol). The resultant mixture was stirred at room temperature overnight. The mixture was concentrated and purified by HPLC to give the title product as the minor component (8 mg, 15%). LC-MS (ES) m/z 489 (M+H)+; 1H-NMR(MeOD) delta 2.39 (s, 3H), 4.26 (s, 2H), 6.86 (d, IH), 7.08 (s, IH), 7.38 (t, 2H), 7.64 (d, IH), 7.77 (m, 2H), 7.82 (s, IH), 8.11 (s, IH), 8.20 (d, IH). |
15% | With triethylamine; In dichloromethane; at 20℃; | To a solution of 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-7,8- dihydropyrido[2,3-J]pyrimidin-4-yl]-4-methylbenzoic acid (50 mg, 0.09 mmol) in DCM (5 mL) was added (lH-imidazol-2-ylmethyl)amine dihydrochloride (75 mg, 0.44 mmol), triethylamine (0.2 mL, 1.44 mmol). The resultant mixture was stirred at room temperature overnight. The mixture was concentrated and purified by etaPLC to give the title product as the minor component (8 mg, 15%). LC-MS (ES) m/z 489 (M+eta)+; 1H-NMR(MeOD) delta 2.39 (s, 3H), 4.26 (s, 2H), 6.86 (d, IH), 7.08 (s, IH), 7.38 (t, 2H), 7.64 (d, IH), 7.77 (m, 2H), 7.82 (s, IH), 8.11 (s, IH), 8.20 (d, IH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | With triethylamine; In dichloromethane; at 20℃; | Example 98; 3-(8-(2.6-difluorophenylV2-[(lH-imidazol-2-ylmethvDaminol-7-oxo-7.8- dihvdropyrido[2,3-t/]pyrimidin-4-yl|-4-methylbenzoic acid trifluoroacetateTo a solution of 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-7,8- dihydropyrido[2,3-c(]pyrimidm-4-yl]-4-methylbenzoic acid (50 mg, 0.09 mmol) in DCM (5 mL) was added (lH-imidazol-2-ylmethyl)amine dihydrochloride (75 mg, 0.44 mmol), triethylamine (0.2 mL, 1.44 mmol). The resultant mixture was stirred at room temperature overnight. The mixture was concentrated and purified by EtaPLC to give the title product as the major component (20 mg, 37%). LC-MS (ES) m/z 489 (M+Eta)+; 1H-NMR(MeOD) delta 2.36 (s, 3H), 4.58 (s, 2H)5 6.48 (d, IH), 7.12 (m, IH), 7.21 (m, IH), 7.39 (s, 2H), 7.56 (m, 3H), 8.00 (s, IH), 8.14 (d, IH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; at 20℃;Product distribution / selectivity; | 116c) 3- {8-(2,6-difluororhohenvD-2-rdH"-imidazol-2-ylmethyl)amino1-7-oxo-7,8- dihydropyridor2,3-c?pyrimidin-4-yl)-4-methyl-N-(phenylmethyl)benzamide3-[8-(2,6-Difluorophenyl)-2-(methylsulfinyl)-7-oxo-7,8-dihydropyrido[2,3- (i]pyrimidin-4-yl]-4-methyl-7V-(phenylmethyl)benzamide (0.084 g, 0.154 mmol) and (lH"-imidazol-2-ylmethyl)amine dihydrochloride (0.039 g, 0.23 mmol) were dissolved in CH2Cl2 (5 mL) and triethylamine (0.7 mL). The resulting mixture was stirred under argon at room temperature overnight. The solvents were pumped off in vacuo, and the residue taken up in EtOAc and 1 N NaOH. The organic phase was washed with brine, dried over anhydrous Na2SO4 filtered and evaporated. The residue was flash chromatographed on silica gel (20 g) eluted with 6:1 :0.05 CH2Cl2:isopropanol:NH4thetaH. The material isolated was not pure, and was rechromatographed on silica gel (20 g) eluted with 0-5% MeOHZCH2Cl2 to give the title compound as a white amorphous solid, mp (dec) 185-19O0C. LC-MS m/z 578 (M+H)+, 1.76 min (ret time). | |
With triethylamine; In dichloromethane; at 20℃; | 3-[8-(2,6-Difluorophenyl)-2-(methylsulfmyl)-7-oxo-7,8-dihydropyrido[2,3- d]pyrimidin-4-yl]-4-methyl-lambda/-(phenylmethyl)benzamide (0.084 g, 0.154 mmol) and (IH- imidazol-2-ylmethyl)amine dihydrochloride (0.039 g, 0.23 mmol) were dissolved in CH2Cl2 (5 mL) and triethylamine (0.7 mL). The resulting mixture was stirred under argon at room temperature overnight. The solvents were pumped off in vacuo, and the residue taken up in EtOAc and 1 N NaOH. The organic phase was washed with brine, dried over anhydrous Na2SO4 filtered and evaporated. The residue was flash chromatographed on silica gel (20 g) eluted with 6:1 :0.05 CH2Cl2:isopropanol:NH4OH. The material isolated was not pure, and was rechromatographed on silica gel (20 g) eluted with 0-5% MeOH/CH2Cl2 to give the title compound as a white amorphous solid, mp (dec) 185-19O0C. LC-MS m/z 578 (M+H)+, 1.76 min (ret time). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With triethylamine; In N,N-dimethyl-formamide; at 60℃; for 3h; | Example 23; iV-cyclopropyl-3-{8-(2,6-difluorophenyl')-2-[('lH-imidazol-2-ylmethyl)amino]-7- oxo-7,8-dihydropyrido[2,3-6?pyrimidin-4-yl|-4-methylbenzamideN-cyclopropyl-3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-7,8- dihydropyrido[2,3-J]pyrimidin-4-yl]-4-methyIbenzamide (0.1 g, 0.2 mmol) is dissolved in DMF (10 mL) and (lH-imidazol-2-ylmethyl)amine dihydrochloride (0.053 g, 0.4 mmol) is added followed by triethylamine (0.167 mL, 1.2 mmol). The mixture is heated to about 60 0C for about 3 h. The reaction is judged to be complete by LCMS and the crude mixture is purified via reversed-phase HPLC. HPLC indicates 95% pure (254 nm) and the desired product is obtained as a white powder (54 mg, 50%): LC-MS m/z 528 (M+H)+, 1.45 min (ret time). |
50% | With triethylamine; In N,N-dimethyl-formamide; at 60℃; for 3h; | lambda/-cyclopropyl-3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-7,8- dihydropyrido[2,3-J]pyrimidin-4-yl]-4-methylbenzamide (0.1 g, 0.2 mmol) is dissolved in DMF (10 mL) and (lH-imidazol-2-ylmethyl)amine dihydrochloride (0.053 g, 0.4 mmol) is added followed by triethylamine (0.167 mL, 1.2 mmol). The mixture is heated to about 60 0C for about 3 h. The reaction is judged to be complete by LCMS and the crude mixture is purified via reversed-phase etaPLC. etaPLC indicates 95% pure (254 nm) and the desired product is obtained as a white powder (54 mg, 50%): LC-MS m/z 528 (M+eta)+, 1.45 min (ret time). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In ethanol; | EXAMPLE 8 2-(4-Chlorophenyl)-3-(1H-imidazol-2-ylmethyl)-3H-imidazo[4,5-b]pyridine A suspension of 2-chloro-3-nitropyridine (7.74 g, 0.0490 mol) and 2-aminomethyl imidazole dihydrochloride (10.0 g, 0.0588 mol) in absolute ethanol (250 mL) was stirred at room temperature and triethylamine (11.88 g, 0.118 mol) was added. The mixture was heated at reflux for 4 hours, additional triethylamine (5.9 g, 0.0588 mol) was added, and refluxing was continued for 2 additional hours. The solvents were removed under reduced pressure, and the residue was partitioned between ethyl acetate and water. The insoluble solid was collected by filtration and was combined with the product that was obtained by separating the layers of the filtrate followed by washing the ethyl acetate with saturated sodium chloride solution. The product was recrystallized from ethyl acetate/isopropyl ether/light petroleum ether to give 3.10 g of crude N-(1H-imidazol-2-ylmethyl)-3-nitro-2-pyridine. An additional recrystallization of 0.5 g of the solid from ethyl acetate/light petroleum ether gave 0.33 g, mp 144-146 C. Anal. for C9 H9 N5 O2: Calcd: C, 49.31; H, 4.14; N, 31.95. Found: C, 49.36; H, 4.05; N, 31.88. |
Yield | Reaction Conditions | Operation in experiment |
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2.86% | (R/5)-3-(2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)- l,2,4-oxadiazol-3-yl)phenyl)acetamido)propanoic acid (Example 22, 22 mg, 0.044 mmol), (lH-imidazol-2-yl)methanamine-2HCl (1 1.17 mg, 0.066 mmol), 4- methylmorpholine (17.72 mg, 0.175 mmol), and HATU (21.65 mg, 0.057 mmol) were added to DMF (1 mL). This was stirred for 1 h before it was purified by prep HPLC (PHENOMENEX Luna 5u 21.2 x 100mm, gradient elution with Method 1- MeOH / water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 12 min, 20 mL/min, 220 nM, product retention = 13.1 min) to provide (R/S)- N-((lH-imidazol-2-yl)methyl)-3-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-l,2,4-oxadiazol-3-yl)phenyl)acetamido)propanamide- TFA (1 mg, 1.252 muiotaetaomicron, 2.86 % yield): LCMS = 582.3 [M+H]+; XH NMR (400 MHz, methanol-cU) delta ppm 8.15 (2 H, d, J=8.36 Hz), 7.54-7.74 (7 H, m), 7.41 (2 H, s), 5.13 (1 H, s), 4.59 (2 H, s), 3.46-3.69 (2 H, m), 2.44-2.58 (2 H, m); HPLC peak RT = min (Method A). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
19.4% | With 4-methyl-morpholine; HATU; In N,N-dimethyl-formamide; | 2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-l,2,4- oxadiazol-3-yl)phenyl)acetic acid (Int-Va, 30 mg, 0.070 mmol) was dissolved in DMF (1 mL) prior to the addition of 4-methylmorpholine (0.046 mL, 0.417 mmol), C-(lH-imidazol-2-yl)-methylamine-2HCl (13.51 mg, 0.139 mmol), and HATU (52.9 mg, 0.139 mmol). This was stirred overnight and was then purified by preparative HPLC (PHENOMENEX Luna 5u C18 21.2 x 250 mm, gradient elution with Method 1-MeOH / water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 30 min, 15 mL/min, 220 nM, product retention = 29.3 min) to give single enantiomer N-((lH-imidazol-2-yl)methyl)-2-hydroxy-2-(4-(5-(3-phenyl-4- (trifluoromethyl)isoxazol-5-yl)-l,2,4-oxadiazol-3-yl)phenyl)acetamide-TFA (8.8mg, 0.014 mmol, 19.4 % yield): LCMS = 51 1.2 [M+H]+; XH NMR (400 MHz, methanol- cU) delta rhorhoetaiota 8.11-8.24 (2 H, m), 7.43-7.78 (9 H, m), 5.19-5.31 (1 H, m), 4.57-4.77 (2 H, m); HPLC Peak RT = 8.1 min (Analytical Method A). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; phenol; at 130℃; for 5h;Inert atmosphere; | A mixture of <strong>[22600-77-7](1H-imidazol-2-yl)methanamine dihydrochloride</strong> 10 (27, 440 mg, 2.59 mmol), 4,7-dichloroquinoline (615 mg, 3.10 mmol), phenol (1.2 g, 13 mmol) and DIPEA (0.9 ml, 5.18 mmol) was heated for 5 h at 130 C, stirring under N2. After cooling, the mixture was diluted with CH2Cl2 and alkalized with 2 N NaOH until a precipitate was formed. The solid was filtered off, washed in succession with CH2Cl2, 2 N NaOH solution, water and dried overnight in vacuo (over KOH pellets). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70.5% | With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; dimethyl sulfoxide; at 100℃; for 16h; | N,N-Diisopropylethylamine (0.30 mL, 1.726 mmol) was added to 2-chloro-4-((2-fluoro-6-(trifluoromethyl)benzyl)amino)quinazoline-8-carbonitrile 4 (131.4 mg, 0.345 mmol) in 1,4-dioxane (1.6 mL)and dimethyl sulfoxide (1.6 mL) at room temperature, followed by<strong>[22600-77-7](1H-imidazol-2-yl)methanamine dihydrochloride</strong> 5e (88 mg,0.518 mmol) and the solution was heated to 100 C and stirred forsixteen hours. The reaction mixture was poured into ether, washedwith water, dried over magnesium sulfate, filtered, and concentrated.The residue was purified by silica gel chromatography, elutingwith methanol:ethyl acetate (1:32) to give 2-(((1H-imidazol-2-yl)methyl)amino)-4-((2-fluoro-6-(trifluoromethyl)benzyl)amino)quinazoline-8-carbonitrile 6e (113.1 mg, 0.243 mmol, 70.5% yield).1H NMR (400 MHz, CD3SOCD3) d 11.62 (br s, 1H), 8.40-8.26 (m,2H), 7.99 (d, 1H, J = 7 Hz), 7.74-7.34 (m, 4H), 7.16-6.88 (m, 2H),6.78 (br s, 1H), 4.73 (br s, 2H), 4.60 (br s, 2H); LC-MS (LC-ES) M+H = 442. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
143 mg | (1H-Imidazol-2-yl)methanamine dihydrochloride (250 mg, 1.47 mmol) was dissolved in 40 ml of n-butanol. After adding 1-hexyl-3-cyanoguanidine (296 mg, 1.75 mmol), the reaction mixture was refluxed for 24 h. The n-butanol was removed completely under reduced pressure, and the resulting residue was dissolved in dry methanol and cooled to 0 C. An HCl solution in 1,4-dioxane was added, and the reaction was stirred for 20 min at 0 C. The solvent was then removed under reduced pressure. To the residue, dry CH2Cl2 and a few drops of dry methanol were added and cooled overnight in a refrigerator. The resulting salt was filtered and washed with cool dry CH2Cl2 to afford 143 mg (26%) of (N1-hexyl-N5-(1H-imidazol-2-yl)methyl) biguanidine) trihydrochloride. NMR data for structure verification of HIB were 1H NMR (400 MHz, DMSO-d6) delta 14.45 (br s, 1H), 7.81 (br s, 2H), 7.56 (s, 2H), 7.17 (br s, 2H), 5.75 (s, 1H), 4.66 (br s, 2H), 3.10-2.89 (m, 2H), 1.56-142 (m, 2H), 1.38-1.12 (m, 6H), 0.87-0.84 (m, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
4% | With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 72h; | To a 10 mL microwave vial was added sodium 2-(l-((lr,4r)-4- (cyanomethyl)cyclohexyl)- 1, 6-dihydroimidazo[4, 5 -d]pyrrolo[2, 3 -b]pyridin-2-yl)acetate (Intermediate 4, 136 mg, 0.378 mmol) as a solid followed by dissolution into DMF (1.5 mL).PyBOP (304 mg, 0.584 mmol) was added in one portion. The solution was stirred for 15 minutes prior to addition of DIPEA (0.261 mL, 1.51 mmol), followed by (1H-imidazol-2- yl)methanamine dihydrochloride (151 mg, 0.870 mmol) and was stirred at room temperature for 72 h. The reaction was added to saturated NaHCO3 (20 mL), which resulted in a precipitate forming. The solids were collected by filtration. The solids were solubilized in EtOAc, and theaqueous phase was extracted with EtOAc and CH2C12, and the organic phases were combined, dried over anhydrous Na2SO4, and concentrated to dryness. The residue was purified by basic HPLC: Waters Xbridge Prep OBD C18 150 mm x30 mm Sjim, eluent 0-100% aq NH4OHIACN (10 min)to provide the title compound (6 mg, 4% yield). MS (ESI): mass calcd. for C22H24N80, 416.21; m/z found, 418.0 [M+H]t ?H NIVIR (500 MHz, CD3OD): oe 8.54 (s, 1H), 7.48 (d, J 3.5Hz, 1H), 7.09-6.92 (m, 2H), 6.84 (d, J= 3.6 Hz, 1H), 4.74-4.37 (m, 4H), 2.69-2.41 (m, 3H),2.20- 1.97 (m, 5H), 1.55 - 1.38 (m, 2H), 1.38- 1.24 (m, 3H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: Intermediate H (30 - 40 mg, 0.059 - 0.078 mmol) was dissolved in dichloromethane (3 ml) and amine I amine hydrochloride added (0.12 - 0.18 mmol). N,N-Diisopropylethylamine (0.028 - 0.067 ml, 0.15 - 0.36 mmol) was added if an amine hydrochloride was used. Sodium or magnesium sulfate was added and the mixture stirred at room temperature and progress monitored by UPLC-MS. After 0.25 - 20 h sodium triacetoxyborohydride (20 - 29mg, 0.094 - 0.136 mmol) was added and reaction stirred at room temperature, monitoring by UPLC-MS. Extra sodium triacetoxyborohydride (0.094 mmol) was added as required. Once complete, the reaction was poured into saturated sodium bicarbonate and extractedthree times with dichioromethane. The combined organics were dried (sodium sulfate), filtered and evaporated. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
10% | General procedure: To a solutionof the corresponding aldehyde (1.2 eq.; unless stated otherwise) in DMF (2 inL per 0.3 mmol of aldehyde; unless stated otherwise) was added the corresponding amine (2.5 eq.; unless stated otherwise) and the resulting solution was stirred at 25 C to form the corresponding inline. Then, the corresponding isocyano(tosyl)methyl)arene reagent (1 eq.; unless stated otherwise) and K2CO3 (1.5 eq.; unless stated otherwise*) were added and the reaction mixture was stirred at 25 C (unless stated otherwise). The reaction was stopped after the time indicated for each particular reaction. The reaction progress was monitored by TLC. (0083) A saturated aqueous solution of NH4CI (10 mL per 1 mmol of aldehyde) was added to the reaction mixture, which was then extracted with EtOAc (2 x 30 mL per 1 mmol of aldehyde). The combined organic extracts were washed with H2O (2 x 25 mL per 1 mmol of aldehyde), dried over MgSCC, filtered, and the solvent was evaporated in vacuo to provide the crude product. The residue obtained after the workup was purified using column chromatography or preparative TLC (unless stated otherwise). (0084) * note: in cases when the amine was used as HC1 salt, 4 eq. of K2CO3 were used |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | General procedure: An oven dried pW reactor was charged with 2,4,6-Trichloropyrido[3,4-c/]pyrimidine (Intermediate F) (234 mg, 1 mmol, 1 equiv.) sealed with a septum and purged with Ar atmosphere (3 cycles Ar/vacuum). Then, EtOAc (7 mL. 0.14 M) and N,N- diisopropylethylamine (0.51 mL, 2.9 mmol, 2.9 equiv.) were added and the mixture was homogenized by stirring for 5 min. The corresponding amine or alcohol (RXH) (1.05 mmol, 1.05 equiv.) was added. The resulting mixture was stirred at 22C until complete conversion of the Intermediate F was achieved (2-20 h). The corresponding amine (R3R2NH) (1.5-10.3 mmol, 1.5-10.3 equiv.) was added. The mixture was homogenized by stirring and submitted to reaction under microwave irradiation at 120C for 15-30 min (Energy Power: 60 W). The progress of the reaction was confirmed by TLC (EtOAc:MeOH). The crude mixture was transferred to a round bottom flask by addition of EtOAc and volatiles were removed under reduced pressure. The residue was dissolved in EtOAc (70 ml.) and transferred to a separating funnel. The organic phase was washed with water (3 x 30 ml.) and saturated NaCI solution (1 x 30 ml_). The organic phase was dried over anhyd. Na2S04 and filtered through a pad of Na2S04 with a filter plate. The solvent was removed under reduced pressure giving the crude mixture, which was purified by automated flash chromatography (EtOAc:MeOH) yielding the corresponding products (Examples 1-38 and 68-99). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
300 mg | With dmap; triethylamine; In dichloromethane; at 20 - 50℃; for 52.8h; | <strong>[22600-77-7]1H-imidazol-2-ylmethanamine dihydrochloride</strong> (300mg, 1.76mmol) was suspended in DCM(10mL), treated with N,N-dimethylpyridin-4-amine (76mg, 0.62mmol), triethylamine (1.35mL,9.7mmol) and finally with di-tert-butyl dicarbonate (1.156g, 5.29mmol). The reaction was stirredat room temperature for 20min, heated at 50C for 5hrs, cooled and stored at room temperaturefor 48hrs. The reaction was diluted with DCM and washed with brine. The organic layer wasevaporated, the residue dissolved in DCM/MeCN/TF A and stirred at room temperature for onenight. The reaction was basified with NaHC03 (sat. solution) then the organic layer was separatedgiving after evaporation tert-butyl [(1H-imidazol-2-yl)methyl]carbamate (300mg, 1.76mmol) asyellowish oil. |
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