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CAS No. : | 78667-04-6 | MDL No. : | MFCD00234118 |
Formula : | C5H8Cl2N2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | JDIPKQBKSBWIKU-UHFFFAOYSA-N |
M.W : | 167.04 | Pubchem ID : | 2795406 |
Synonyms : |
|
Num. heavy atoms : | 9 |
Num. arom. heavy atoms : | 5 |
Fraction Csp3 : | 0.4 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 1.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 40.22 |
TPSA : | 17.82 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.44 cm/s |
Log Po/w (iLOGP) : | 0.0 |
Log Po/w (XLOGP3) : | 1.24 |
Log Po/w (WLOGP) : | 1.81 |
Log Po/w (MLOGP) : | 0.67 |
Log Po/w (SILICOS-IT) : | 1.31 |
Consensus Log Po/w : | 1.01 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.0 |
Solubility : | 1.66 mg/ml ; 0.00996 mol/l |
Class : | Soluble |
Log S (Ali) : | -1.21 |
Solubility : | 10.2 mg/ml ; 0.0614 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -1.78 |
Solubility : | 2.77 mg/ml ; 0.0166 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.57 |
Signal Word: | Danger | Class: | 8 |
Precautionary Statements: | P260-P264-P270-P280-P301+P330+P331-P303+P361+P353-P304+P340-P305+P351+P338-P310-P363-P405-P501 | UN#: | 3261 |
Hazard Statements: | H302-H314 | Packing Group: | Ⅱ |
GHS Pictogram: |
* 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 |
---|---|---|
95% | With thionyl chloride In diethyl ether; 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran | Synthesis of 2-(Chloromethyl)-1-methyl-1H-imidazole Hydrochloride (BB7) To a solution of (BB6) (35.5 g, 316.96 mmol) in DCM (1500 mL) was added SOCl2 (330 mL, 4436 mmol) at 0° C. The reaction was warmed to ambient temperature and stirred for 5 h. The reaction mixture was concentrated, the residue was washed with DCM (2*500 mL), followed by Et2O (2*200 mL) to obtain (BB7) (50 g, 95percent) as an off-white solid. Rf: 0.4 (EtOAc). 1H NMR (400 MHz, DMSO-d6): δ 7.76 (1H, app d), 7.70 (1H, app d), 5.17 (2H, s), 3.87 (3H, s); ink 131 (MH)+. |
88% | Cooling with ice; Reflux | 1-Methyl-2-hydroxymethyl imidazole (15.0 g, 134 mmol) was added, with shaking and exclusion of moisture, over a period of 15 min to ice cooled thionyl dichloride (24.6 mL, 30 g, 0.25 mol). The reactants were then heated under reflux for 15 min. The cooled solution was evaporated under reduced pressure followed by recrystallization from ethanol (25 mL) and dried under high vacuum to give 2-(chloromethy1)-1-methyl-1H-imidazole hydrochloride as brown crystals. Yield: 15.1g, 88percent. 1H NMR (CDCl3) δ ppm: 7.79 (s, 1H), 7.70 (s, 1H), 5.2 (s, 2H), 3.86 (s, 3H). 3C NMR (CD3OD) δ ppm: 142.05, 124.7, 119.08, 33.9, 31.4. TOF-MS m/z: 131.0384 (M+H+, 100percent). Molecular formula of cation, C5H7N2Cl, calculated m/z of cation: 131.04 (M+H+) |
78% | Stage #1: at 0℃; for 0.5 h; Reflux; Inert atmosphere Stage #2: With hydrogenchloride In water |
This compound was synthesised using a modified procedure described in literature.6 1-Methyl-2-hydroxymethyl imidazole (6.500 g, 58.000 mmol) was added in small portions to SOCl2 (12.7 mL, 174 mol) at 0 °C. The mixture was heated under reflux for 30 min. After cooling, the solution was concentrated under reduced pressure followed by recrystallization from ethanol (17 mL) to afford 2-(chloromethy1)-1-methyl-1H-imidazole hydrochloride. Yellow crystals; 7.580g, yield: 78percent. The NMR spectrum was according to literature.6 1H NMR (CDCl3) δ = 7.79 (d, 1H, J = 1.9 Hz; ImH), 7.70 (d, 1H, J = 1.9 Hz; ImH), 5.20 (s, 2H; CH2Cl), 3.86 ppm (s, 3H; NCH3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With thionyl chloride; In diethyl ether; 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran; | Synthesis of 2-(Chloromethyl)-1-methyl-1H-imidazole Hydrochloride (BB7) To a solution of (BB6) (35.5 g, 316.96 mmol) in DCM (1500 mL) was added SOCl2 (330 mL, 4436 mmol) at 0 C. The reaction was warmed to ambient temperature and stirred for 5 h. The reaction mixture was concentrated, the residue was washed with DCM (2*500 mL), followed by Et2O (2*200 mL) to obtain (BB7) (50 g, 95%) as an off-white solid. Rf: 0.4 (EtOAc). 1H NMR (400 MHz, DMSO-d6): delta 7.76 (1H, app d), 7.70 (1H, app d), 5.17 (2H, s), 3.87 (3H, s); ink 131 (MH)+. |
88% | With thionyl chloride;Cooling with ice; Reflux; | 1-Methyl-2-hydroxymethyl imidazole (15.0 g, 134 mmol) was added, with shaking and exclusion of moisture, over a period of 15 min to ice cooled thionyl dichloride (24.6 mL, 30 g, 0.25 mol). The reactants were then heated under reflux for 15 min. The cooled solution was evaporated under reduced pressure followed by recrystallization from ethanol (25 mL) and dried under high vacuum to give 2-(chloromethy1)-1-methyl-1H-imidazole hydrochloride as brown crystals. Yield: 15.1g, 88%. 1H NMR (CDCl3) delta ppm: 7.79 (s, 1H), 7.70 (s, 1H), 5.2 (s, 2H), 3.86 (s, 3H). 3C NMR (CD3OD) delta ppm: 142.05, 124.7, 119.08, 33.9, 31.4. TOF-MS m/z: 131.0384 (M+H+, 100%). Molecular formula of cation, C5H7N2Cl, calculated m/z of cation: 131.04 (M+H+) |
78% | This compound was synthesised using a modified procedure described in literature.6 1-Methyl-2-hydroxymethyl imidazole (6.500 g, 58.000 mmol) was added in small portions to SOCl2 (12.7 mL, 174 mol) at 0 C. The mixture was heated under reflux for 30 min. After cooling, the solution was concentrated under reduced pressure followed by recrystallization from ethanol (17 mL) to afford 2-(chloromethy1)-1-methyl-1H-imidazole hydrochloride. Yellow crystals; 7.580g, yield: 78%. The NMR spectrum was according to literature.6 1H NMR (CDCl3) delta = 7.79 (d, 1H, J = 1.9 Hz; ImH), 7.70 (d, 1H, J = 1.9 Hz; ImH), 5.20 (s, 2H; CH2Cl), 3.86 ppm (s, 3H; NCH3). |
With thionyl chloride; In benzene; for 0.5h; | 2-Chloromethyl-1-methyl-imidazolhydrochloride The 2-chloromethyl-1-methyl-imidazolhydrochloride is produced according to the description above. 20 ml thionylchloride is added to a suspension of 5.61 g 1-methylimidazolyl-1-methanol in 5 ml dry benzene. Two phases are built. Stir vigorously for half an hour. Then the combined solvents are rotated off and a bright brown product remains. 1H-NMR (CDCl3; 270 MHz): 7.75 (d; 1H); 7.68 (d; 1H); 5.16 (s; 2H); 3.86 (s, 3H); 3.42 (s; 3H). 13C-NMR: 141.5; 124.7; 119.4; 34.2; 31.7 ppm. | |
With thionyl chloride; at 0 - 90℃; for 0.5h; | To 2-hydroxymethyl-1-methylimidazole (874 mg) was added thionyl chloride (10 ml) at 0C, and the mixture was heated for 30 minutes under nitrogen atmosphere at 90C. The mixture was allowed to be at room temperature. The solvent was distilled off under reduced pressure and the obtained residue was recrystallized from ethyl acetate, to give 2-chloromethyl-1-methylimidazole hydrochloride (1.15 g) as brown crystals. 1H-NMR (200 MHz, DMSO-d6) delta 3.88 (3H, s), 5.19 (2H, s), 7.72 (1H, d, J = 1.8 Hz), 7.78 (1H, d, J = 1.8 Hz). Elemental Analysis C5H8N2Cl2 Calcd. C, 35.95; H, 4.83; N, 16.77; Found. C, 35.74; H, 5.03; N, 16.45. | |
With thionyl chloride; at 0 - 65℃; for 0.25h; | The compound (56.1 g) obtained in Example 10-1 was gradually added to thionyl chloride (119 ml) under ice-cooling. After completion of dropping, the whole was refluxed at 65C for 15 minutes. Excess thionyl chloride was distilled off under reduced pressure and the solution was further subjected to azeotropic distillation with toluene, thereby obtaining a hydrochloride (82.4 g) of the subject compound as a yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | A solution of 5,17, 29-tri-tert-butyl-37, 39,41-tri- hydroxy-38,40, 42-TRIMETHOXYCALIX [6] arene [van DUYNHOVEN, 1994 No.37] (300 mg, 0.35 mmol) was added under argon to a mixture of NaH (60% in oil, 420 mg, 10 mmol, 30 eq. , washed with pentane prior to use), in THF (12 ML) and DMF (3 mL). After 15 min. at rt., <strong>[78667-04-6]2-chloromethyl-1-methyl-1H-imidazole hydrochloride</strong> (360 mg, 2.1 mol, 6 eq) was added. After 16 h at reflux, the usual work-up with CH2C12/H20 gave the crude product that was filtered over silica gel using CH2CL2/MEOH (9: 1) to give JH3 as a colourless solid (347 mg, 88%). For elemental analysis purpose, further purification was achieved by recristallisation from ACETONITRILE. H NMR (200 MHz, CDC13): 8 7.11 (s, 6H, Ar), 7.00 (s, 3H, IM), 6.87 (s, 3H, Im), 6. 68 (bs, 9H, Ar), 4.90 (bs, 6H, OCH2Im), 3.84 (bs, 12H, ArCH2Ar), 3. 61 (BS, 9H, NCH3), 2.69 (s, 9H, OCH3), 1.27 (s, 27H, TBU). Anal. calcd for JH3. H20 (C72H86N607, 1146.66) : C 75.36, H 7.55, N 7.32 ; Found: C 75.26, H, 7.46, N, 7. 37. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
29% | With potassium carbonate; In N,N-dimethyl-formamide; | Example 6 A solution of 4-(3-acetoxy-4-methylanilino)-7-hydroxy-6-methoxyquinazoline hydrochloride (400 mg, 1.06 mmol), (prepared as described for the starting material in Example 1), 2-chloromethyl-1-methylimidazole hydrochloride (354 mg, 2.12 mmol), and potassium carbonate (585 mg) in DMF (15 ml) was heated at 60 C. for 15 hours. After cooling to ambient temperature the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO4) and evaporated. The residue was diluted with methanol (20 ml) and 2M sodium hydroxide (1 ml) was added. After stirring for 1 hour, the reaction mixture was diluted with water (20 ml) and 2M hydrochloric acid (3 ml) was added. The resulting solid was filtered off, washed with water and dried under vacuum to give 4-(3-hydroxy-4-methylanilino)-6-methoxy-7-(1-methylimidazol-2-ylmethoxy)quinazoline hydrochloride (150 mg, 29%). m.p. 257-260 C. 1 H NMR Spectrum: (DMSOd6) 2.17 (s, 3H); 3.95 (s, 3H); 4.03 (s, 3H); 5.68 (s, 2H); 7.02 (dd, 1H); 7.16 (s, 2H); 7.64 (s, 1H); 7.72 (s, 1H); 7.80 (s, 1H); 8.42 (s, 1H); 8.8 (s, 1H); 9.7 (s, 1H); 11.38 (s, 1H) MS-ESI: 392 [MH]+ Elemental analysis: Found C 51.7 H 5.5 N 14.2 C21 H21 N5 O3 1.65H2 O 1.9HCl Requires C 51.4 H 5.4 N 14.3% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21% | With hydrogenchloride; sodium hydroxide; potassium iodide; potassium carbonate; In methanol; N,N-dimethyl-formamide; | Example 27 A mixture of 4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-7-hydroxy-6-methoxyquinazoline hydrochloride (470 mg, 1 mmol), (prepared as described for the starting material in Example 22), 2-chloromethyl-1-methylimidazole hydrochloride (335 mg, 2 mmol), potassium carbonate (414 mg, 3 mmol) and potassium iodide (20 mg) in DMF (15 ml) was heated at 60 C. for 2 hours. The mixture was allowed to cool and partitioned between ethyl acetate and water. The organic layer was separated, washed with water and brine, dried (MgSO4) and the solvent removed by evaporation. The crude product was dissolved in methanol (20 ml), 2M sodium hydroxide (1 ml) was added and the mixture stirred for 15 minutes. Concentrated hydrochloric acid (0.5 ml) was added and the solvent was removed by evaporation. The crude product was purified by reverse phase chromatography eluding with methanol/water (1/1). Concentrated hydrochloric acid (0.3 ml) was added to the combined fractions containing the pure product and the solvent was removed by evaporation to give 4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-((1-methylimidazol-2-yl)methoxy)quinazoline hydrochloride (100 mg, 21%). 1 H NMR Spectrum: (DMSOd6) 2.17(s, 3H); 3.95(s, 3H); 4.01(s, 3H); 5.70(s, 2H); 6.92(d, 1H); 7.12(d, 1H); 7.63(s, 1H); 7.77(s, 1H); 7.83(s, 1H); 8.43(s, 1H); 8.82(s, 1H); 9.7(br s, 1H); 11.62(br s, 1H) MS - ESI: 410 [MH]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydride; In tetrahydrofuran; | i) sodium hydride (80% dispersion in oil, 3.27g, 100mmol) was added to a stirred suspension of 4,5-diphenylimidazole-2-thiol (13.8g, 54mmol) in anhydrous tetrahydrofuran (150ml). The mixture was stirred at 60C until complete solution occurred. 1-Methyl-2-chloromethylimidazole hydrochloride (10.0g, 60mmol) was added and the mixture stirred at reflux overnight. After cooling to room temperature the mixture was poured into water (500ml) and the cream precipitate collected by filtration. Recrystallisation from isopropanol gave 2-[(1-methylimidazol-2-yl)methylthio]-4,5-diphenylimidazole (12.2g), as a yellow powder, m.p. 189-190C; [Found:- C, 69.2; H, 5.3; N, 16.3; S, 9.1%; Calculated for C2sub;0HNS:- C, 69.3; H, 5.2; N, 16.2; S, 9.3.%. N.M.R. (400MHz; CDCl?): 3.68 (3H, s), 4.24 (2H, s), 6.94 (1H, d, J=2Hz), 7.01 (1H, d, J=2Hz), 7.20-7.60 (10H, m,). IR (KBr): 689, 764, 1439, 1644, 3406 cmminsup;1?]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; In methanol; water; at 0℃; | To a solution of 4-amino-2-methylthiophenol (500 mg) in methanol (10 ml) was added 1N aqueous solution of sodium hydroxide (12 ml), and a solution of 2-chloromethyl-1-methylimidazole hydrochloride (660 mg) in methanol (10 ml) was added at 0C. Water was added to the mixture, and the mixture was extracted with ethyl acetate and the organic layer was dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was recrystallized from hexane-ethyl acetate, to give 3-methyl-4-[[(1-methylimidazol-2-yl)methyl]sulfanyl]aniline (757 mg) as crystals. 1H-NMR (200 MHz, CDCl3) delta 2.24 (3H, s), 3.50 (3H, s), 3.69 (2H, br), 3.94 (2H, s), 6.43 (1H, dd, J = 8.0, 2.4 Hz), 6.53 (1H, d, J = 2.4 Hz), 6.77 (1H, d, J = 1.2 Hz), 6.89 (1H, d, J = 1.2 Hz), 7.16 (1H, d, J = 8.0 Hz) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate; triethylamine;tetrabutylammomium bromide; In DMF (N,N-dimethyl-formamide); at 20℃; | 4-Amino-2-ethoxymethyl-1-(2-hydroxy-2-methylpropyl)-lH-imidazo [4,5- c] quinolin-7-ol (100 mg, 0.3 mmol), cesium carbonate (488 mg, 1.5 mmol), 2- CHLOROMETHYL-1-METHYL-1H-IMIDAZOLEHCL (100 mg, 0.6 mmol), tetrabutylammonium bromide (96 mg, 0.3 mmol), triethylamine (0.5 ml), and DMF (10 mL) were combined and stirred at ambient temperature overnight. The reaction was concentrated under reduced pressure and dichloromethane was added to the residue. Undissolved solids were removed by filtration. The filtrate was concentrated under reduced pressure and subsequently purified by flash column chromatography on silica gel, eluting with a gradient of 0-5% methanol in dichloromethane. The clean fractions were combined and concentrated under reduced pressure. The resulting solid was recrystallized from isopropanol/diethylether to yield 40 mg of 1- [4-AMINO-2-ETHOXYMETHYL-7- (L-METHYL-LH-IMIDAZOL-2-YLMETHOXY)-LH- imidazo [4, 5-C] quinolin-1-yl]-2-methylpropan-2-ol as an off white solid, mp 200.0-202. 0 C OC. MS (APC1) M/Z 425 (M + H) + ; Anal. Calcd. for C22H2GN603 : % C, 62.25 ; % H, 6.65 ; % N, 19.80. Found: % C, 62.03 ; % H, 6.83 ; % N, 19. 48. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate; In N,N-dimethyl-formamide; | EXAMPLE 13 Preparation of 1-methyl-2-[(2-nitrophenoxy)methyl]-1H-imidazole A solution of 1.92 g (11.97 mmol) of o-nitrophenol sodium salt, 3.8 g (35.9 mmol) of sodium carbonate, 2 g (11.97 mmol) of 1-methyl-2-chloromethylimidazole hydrochloride in 30 ml of N,N-dimethylformamide were heated at 50 C. for 2 hours. The mixture was then poured into water and extracted with ethylacetate. The organic layer was washed with brine, dried over sodium sulfate and evaporated, affording 1.17 g of the title compound, recrystallized from diethylether. m.p. 172-174 C. 1H-NMR (400 MHz-DMSO-d6) deltappm: 3.67 (d, 3H, CH3); 5.34 (s, 2H, OCH2); 6.86 (s, 1H, H-4-imidazole); 7.13 (m, 1H, H-6-phenyl); 7.19 (s, 1H, H-5-imidazole); 7.60 (m, 1H, H-3 phenyl). EST(+)MS: m/z 234 (100, (M+H)+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | With sodium hydroxide; potassium iodide; potassium carbonate; In methanol; water; N,N-dimethyl-formamide; pentane; | Example 74 A mixture of 4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-7-hydroxyquinazoline hydrochloride (400 mg, 0.98 mmol), 2-chloromethyl-1-methylimidazole hydrochloride (210 mg, 1.25 mmol), potassium carbonate (580 mg, 4.2 mmol) and potassium iodide (17 mg, 0.1 mmol) in DMF (20 ml) was stirred at 65 C. for 4.5 hours followed by 17 hours at ambient temperature. The solvent was removed by evaporation and the residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with water, brine, dried (MgSO4) and the solvent removed by evaporation. The solid residue was purified by column chromatography eluding with methylene chloride/methanol (97/3) to give a yellow solid (258 mg). This solid was dissolved in methanol (5 ml) and a 1M aqueous sodium hydroxide solution (660 mul, 0.66 mmol) was added. The mixture was stirred for 15 minutes, then water was added and the mixture adjusted to pH7 with concentrated hydrochloric acid. The aqueous mixture was extracted with ethyl acetate and the combined organic extract was washed with water, brine, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by flash chromatography eluding with methylene chloride/methanol (95/5). The purified solid product was dissolved in methanol and methanolic hydrogen chloride (1.5 ml of a 7.5M solution) was added. The volatiles were removed by evaporation, the solid residue was suspended in pentane, collected by filtration, washed with pentane and dried under vacuum to give 4-(2-fluoro-5-hydroxy-4-methylanilino)-7-((1-methylimidazol-2-yl)methoxy)quinazoline hydrochloride (105 mg, 44%). 1 H NMR Spectrum: (DMSOd6) 2.16(s, 3H); 3.92(s, 3H); 5.71(s, 2H); 6.90(d, 1H); 7.1(d, 1H); 7.52(d, 1H); 7.64(d, 1H); 7.71(s, 1H); 7.78(s, 1H); 8.77(d, 1H); 8.82(s, 1H); 9.7(br s, 1H); 11.45(br s, 1H) MS-ESI: 380 [MH]+ Elemental analysis: Found C 52.2 H 5.0 N 15.1 C20 H18 N5 O2 F 0.9H2 O 1.8HCl Requires C 52.1 H 4.7 N 15.2% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With chloro-trimethyl-silane; acetic acid; In N-methyl-acetamide; water; isopropyl alcohol; | EXAMPLE 60 0.4 g of 80% sodium hydride is added over 5 minutes to a stirred solution, under an argon atmosphere, of 0.6 g of 10-methyl-5H,10H-imidazo-[1,2-a]indeno[1,2-e]pyrazin-4-one in 30 ml of dimethylformamide. The stirring is continued for 10 minutes at a temperature in the region of 20 C., then 0.35 ml of trimethylchlorosilane is added and the stirring is continued for 10 minutes. 82 mg of sodium hydride are then added and the stirring is continued for 1 hour. 0.5 g of 2-chloromethyl-1-methylimidazole hydrochloride is then added and the stirring is continued for 2 hours. The reaction mixture is treated with 6 ml of acetic acid and 200 ml of water. The solution obtained is washed with ethyl acetate (2*200 ml) and the aqueous phase is concentrated on a rotary evaporator. The evaporation residue is triturated with 20 ml of isopropanol and filtered, and the filtrate is concentrated on a rotary evaporator. A pasty residue is obtained which is purified by chromatography on a column of silica (80 g), eluding with a dichloromethane/methanol mixture (85/15 by volume). 0.28 g of 10-methyl-10-[(l-methylimidazol-2-yl)methyl]-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one is obtained in the form of a cream-coloured solid melting above 260 C. (Analysis, % calculated C: 68.87, H: 5.17, N: 21.13, O: 4.83, % found C: 68.8, H: 5.2, N: 21.2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium t-butanolate; In N,N-dimethyl-formamide; at 70℃; for 2h; | The compound (83.50 g) obtained in Example 10-2 was suspended in DMF (250 ml) and added with sodium t-butoxide (49.00 g) at -30C. The solution was further added with a potassium phthalimide salt (95.0 g) and then the whole was stirred at 70C for 2 hours. After completion of the reaction, the resultant was added into water (800 ml). The precipitated crystal was filtrated, washed with water, and dried, thereby obtaining the subject compound (101.5 g) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 7 Following the procedure of Example 6, reaction of 1-methyl-2-chloromethylimidazole hydrochloride, 1-methyl-5-chloromethyl-1H-1,2,4-triazole hydrochloride, and 2-chloromethylthiazole hydrochloride to the corresponding tetraethyl ethanediphosphonates and subsequent ester cleavage with trimethylbromosilane in the described manner affords: 2-(1-methylimidazol-2-yl)ethane-1,1-diphosphonic acid, m.p. 295 C. (dec.), 2-(1-methyl-1H-1,2,4-triazol-5-yl)ethane-1,1-diphosphonic acid, m.p. 274-275 C., 2-thiazol-2-yl)ethane-1,1-diphosphonic acid, m.p. 259 C. (dec.), and salts thereof, e.g. disodium salts, and hydrates. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 0 - 60℃; for 24h; | The compound (307 mg) obtained in Example 28-1 was dissolved in anhydrous DMF (6.0 ml), added with potassium carbonate (175 mg) at room temperature under a nitrogen atmosphere, and added with the compound (107 mg) obtained in Example 10-2 under ice-cooling. The whole was stirred at room temperature for 2 hours and stirred at 60 C for additional 22 hours. The resultant was left standing for cooing and then added with water under ice-cooling to stop the reaction. The solvent was distilled off under reduced pressure. The residue was dissolved in chloroform and added with water. The aqueous layer was extracted with chloroform. The organic layer was washed with a saturated saline solution and then dried with anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure. The residue was purified through silica gel column chromatography (chloroform/ethyl acetate), thereby obtaining the subject compound (49.3mg) as a brown oily substance. MS(FAB,Pos.):m/z=634[M+H]+ 1H-NMR(500MHz,CDCl3):delta=0.86(6H,t,J=7.3Hz),1.41-1.51(8H,m),2.15(3H,s),2.33-2.39(8H,m),2.41(3H,s),3.43(3H,s),3.45(2H,s),3.70(2H,s),3.71(2H,s),3.85(2H,s),6.79(1H,d,J=1.2Hz),6.92(1H,d,J=1.2Hz),6.98(1H,d,J=1.7Hz),7.23(1H,dd,J=7.0,8.2Hz),7.26(1H,dd,J=0.6,2.9Hz),7.27(2H,dd,J=0.6,0.6Hz),7.27(2H,dd,J=0.6,4.1Hz),7.40(1H,d,J=1.7Hz),7.57(1H,dd,J=1.8,2.0Hz),7.79(1H,dd,J=1.7,2.0Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; triethylamine; In methanol; ethanol; acetone; | EXAMPLE 2 8-(1-methyl-1H-imidazol-2-ylmethylthio)imidazo[1,2-a]pyrazine hydrogen maleate To a solution of 2.02 g (20 mmol) of triethylamine in 30 ml of absolute ethanol was added 1.52 g (10 mmol) of 8-mercaptoimidazo[1,2-a]pyrazine. After stirring for 30 minutes at room temperature, 1.67 g (10 mmol) of 2-chloromethyl-N-methylimidazole hydrochloride was added in one portion. The reaction mixture was stirred for 20 hours and then poured into 50 ml of 5% NaOH. The product was extracted into 2*70 ml of chloroform, dried (Na2 SO4), filtered, and concentrated. The oily residue was purified by flash chromatography (230-400 mesh SiO2, 5% MeOH/CHCl3 saturated with NH3 as eluent) and the resultant product was mixed with maleic acid in acetone and ether to give the hydrogen maleate salt of the product, m.p. 148.5-150 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 48h; | a) Synthesis of [1-(1-Methyl-1H-imidazol-2-ylmethyl)-piperidin-4-yl]-carbamic acid tert-butyl ester (Compound 61) <strong>[78667-04-6]2-(chloromethyl)-1-methyl-1H-imidazole hydrochloride</strong> (800 mg, 1 eq.) and 4-(N-Boc-amino)piperidine (959 mg, 1 eq.) were dissolved in CH2Cl2 (48 mL) and Diisopropyl Ethyl Amine (DIEA) (2.5 mL, 3 eq.) was added. The reaction mixture was stirred at room temperature for 48 h. Solvent was evaporated, the residue dissolved in CH2Cl2 and washed with saturated NaHCO3 aqueous solution and water, dried over MgSO4, and evaporated to dryness to give 1.25 g of a yellow powder (89 %) LC: tR=2.6 min; MS (ESI+): m/z = 295 (M+H)+; 1H NMR (DMSO-d6): delta 7.05 (s, 1H), 6.73 (m, 2H), 3.61 (s, 3H), 3.45 (s, 2H), 3.18 (m, 1H), 2.68 (d, J=11.8 Hz, 2H), 1.95 (t, J=11.6 Hz, 2H), 1.64 (d, J=10.7 Hz, 2H), 1.36 (s, 9H), 1.29 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | 1,4-bis(1-methylimidazol-2-ylmethyl)-7-ethyl-1,4,7-triazacyclononane This ligand is produced through conversion with the 2-chloromethyl-1-methyl-imidazolhydrochloride under impact of bases. 3.32 g of the 2-chloromethyl-1-methylimidazolhydrochloride (20 mmol) is suspended in acetonitril whilst cooling with ice. Adding 2.77 ml triethylamine results in a brown solution. After stirring for 10 minutes a white precipitation (triethylammoniumchloride) is formed. This is filtered off and washed with a minimum of acetonitril. 1.55 g Et-tacn (10 mmol) is added to the filtrate and rinsed with acetonitril. Then a further 2.9 ml triethylamine (20 mmol+5% surplus) is added and stirred for 3 hours under an argon atmosphere. Next, the reaction mixture is filtered and the solvents are drained off from the filtrate. The yellow solid product remains. Yield: 3.7 g (50%); 1H-NMR (CDCl3- 250 MHz; 300K): 6.86 (s; 2H); 6.85 (s; 2H); 5.27 (s; 4H); 3.68 (q; 2H); 3.66 (s; 6H); 3.23 (m; 4H); 2.78 (s; 8H); 1.26 (t, 3H); 13C-NMR: 145.1; 126.1; 121.7; 51.2-55.2; 33.1; 9.6 ppm. MS (EI): m/z: 345. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% NaH (527 mg, 0.0132 mol) is added to a mixture of ethyl lH-indole-2- carboxylate (1.13 g, 0.0059 mol) in DMF (20 mL) at rt and stirred for 10 mins. 2- Chloromethyl-1-methylimidazole hydrochloride is then added to the mixture and stirred for 20 h. The mixture is diluted with ice water (100 mL) and the white solid is filtered to afford the title compound. | ||
EXAMPLE 4; N l-((l-methyl-lH-imidazol-2-yl)methyl)-N-((l-(pyridin-3-yl)cyclohexyl)methyl)-lH-indole-2- carboxamide; Step 1. Ethyl; 60% NaH (527 mg, 0.0132 mol) is added to a mixture of ethyl lH-indole-2- carboxylate (1.13 g, 0.0059 mol) in DMF (20 mL) at rt and stirred for 10 mins. 2-Chloromethyl- 1-methylimidazole hydrochloride is then added to the mixture and stirred for 20 h. The mixture is diluted with ice water (100 mL) and the white solid is filtered to afford the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With sodium hydride; In N,N-dimethyl-formamide; for 1h; | Example 9a: Preparation of N,N-diisobutyl-2-(N-((l-methyl-lH-imidazol-2- yl)methyl)benzofuran-5-sulfonamido)acetamide (84); To a solution of N-Boc-glycine (1.0 g, 5.7 mmol) in DMF (10 ml) were added diisobutylamine (0.10 ml, 11.4 mmol), DIPEA (1.9 ml, 11.4 mmol) and TBTU (2.7 g, 8.5 mmol). The mixture was stirred for 1 hr at room temperature, quenched with saturated aqueous sodium bicarbonate (15 ml), and extracted with EtOAc (20 ml). The organic <n="73"/>phase was washed with brine (15 ml), dried over anhydrous MgSO4 and concentrated in vacuo. The crude material was purified by flash column chromatography (30% EtOAc in hexanes) to provide tert-butyl 2-(diisobutylamino)-2-oxoethylcarbamate (1.6 g, 98%) as a colorless oil. [M+H]+ 287.3, HPLC purity: 90%. To a solution of tert-butyl 2-(diisobutylamino)-2-oxoethylcarbamate (1.6 g, 5.6 mmol) in dichloromethane (15 ml) was added 4N HCl in dioxane (8 ml). The mixture was stirred for 1 hr at room temperature and concentrated in vacuo. To a solution of the resulting material in dichloromethane (8 ml) were added triethylamine (1.6 ml, 11.2 mmol) and benzofuran-5-sulfonyl chloride (1.5 g, 6.7 mmol). After 30 min, water (15 ml) was added to quench the reaction. The aqueous phase was extracted with dichloromethane (15 ml) and the organic layer was washed with brine (15 ml), dried over magnesium sulfate and concentrated in vacuo. The crude material was purified by flash column chromatography (40% EtOAc in hexanes) to provide compound 226 (1.6 g, 78%) as a white solid. [M+H]+ 367.3, [2M+Na]+ 755.0, HPLC purity: 99%. To a solution of compound 226 (89 mg, 0.24 mmol) in DMF (2 ml) were added sodium hydride (14 mg, 0.36 mmol) and 2-(chloromethyl)-l -methyl- lH-imidazole HCl (48 mg, 0.29 mmol). After 1 hr, water (5 ml) was added to quench the reaction. The aqueous phase was extracted with EtOAc (5 ml) and the organic layer was washed with brine (5 ml), dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified by preparative TLC (10% dichloromethane in MeOH) to provide compound 84 (75 mg, 67%) as a white solid. [MMH]+ 461.2, HPLC purity: >99%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With potassium carbonate; In N,N-dimethyl-formamide; at 50℃; for 3h; | A mixture of ethyl 7-hydroxy-5- [ 4 - <n="122"/>(methylsulfonyl) phenoxy] -lH-indole-2-carboxylate (100 mg) , 2- (chloromethyl) -1-methyl-lH-imidazole hydrochloride (50 mg) , potassium carbonate (83 mg) and N,N-dimethylformamide (20 mL) was stirred at 50C for 3 hr. Water was added to the reaction mixture, and the mixture was subjected to extraction with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (ethyl acetate : hexane=60 : 40 to 100:0, volume ratio) to give the title compound (72 mg, yield 57%) as a white solid. The white solid was recrystallized from ethyl acetate-hexane to give colorless crystals, melting point 91- 92C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
The compound (39.1 mg) obtained in Example 9-2 was dissolved in DMF (0. 80 ml) and added with 60% sodium hydride (12.2 mg) under a nitrogen atmosphere while the whole was stirred under ice-cooling. The solution was warmed back to room temperature. After having been stirred for 30 minutes, the resultant was added with the compound (16.9 mg) obtained in Example 10-2, followed by stirring at room temperature for 3 hours. The solution was added with water (18 mul) under ice-cooling to stop the reaction. After the solvent was distilled off under reduced pressure, the residue was dissolved in chloroform and added with water. The aqueous layer was extracted with chloroform. The organic layer was washed with a saturated saline solution and dried with anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure. The reside was purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloric acid, thereby obtaining a hydrochloride (44.0 mg) of the subject compound as a white solid. MS(FAB,Pos.):m/z=480[M+H]+ 1H-NMR(500MHz,CDCl3):delta=0.86(6H,t,J=7.4Hz),1.40-1.52(8H,m),2.15(3H,s),2.34(4H,t,J=2.2Hz),2.37(2H,t,J=5.8Hz),2.39(2H,t,J=16.5Hz),3.45(2H,s),3.47(3H,s),3.81(2H,s),3.94(2H,s),6.75(1H,d,J=1.2Hz),6.86(1H,d,J=1.2Hz),6.93(1H,d,J=1.2Hz),7.01(1H,d,J=1.5Hz),7.26(2H,s),7.27(2H,s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 1323-[(frans-4-Methylcyclohexyl)carbonyl][(1 -methyl-1 W-imidazol-2-yl)methyl]amino}-1 - (4-pyrazolo[1 ,5-a]pyrimidin-2-ylphenyl)-1 W-pyrazole-4-carboxylic acidTo a stirred suspension of Intermediate 119 (100 mg) in anhydrous DMF (4 ml_), was added sodium hydride (60% dispersion in mineral oil) (17 mg). The reaction mixture was stirred at room temperature under nitrogen for 15 minutes, and then 2-(chloromethyl)-1 -methyl-1 H- imidazole hydrochloride (177 mg) was added. The reaction mixture was then stirred at 5O0C under nitrogen for 24 h. Water (0.5 mL) was then added to the reaction mixture, and the solvent was removed by evaporation. The residue was then suspended in THF (1 mL) and ethanol (1 mL), and 2M lithium hydroxide solution (2 mL) was added. The reaction was stirred at room temperature for 20 h, before being neutralised with 2M HCI (2 mL) and partitioned between water and DCM. The layers were stirred for 30 minutes, and then separated using a hydrophobic frit. The organic phase was concentrated by evaporation to give a residue which was then purified by MDAP HPLC to give the title compound. MS calcd for (C29H30N8CVH)+: 539 MS found (electrospray): (M+H)+= 539 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | In dimethyl sulfoxide;Heating; | A warm solution of compound 2 (2.4 g, 40.0 mmol) in DMSO (50 mL) was added to a warm solution of sodium cyanide (10.0 g, 0.204 mol) in DMSO (150 mL). The reaction mixture was allowed to cool to room temperature and was stirred for 2 h. The products were then evaporated under reduced pressure and the residue was partitioned between saturated aq. NaHCO3 (50 mL) and chloroform (50 mL). The aqueous layer was separated and extracted with chloroform (3 x 25 mL). The combined organic layers were dried over MgSO4, and evaporated under reduced pressure to give (1-methyl-1H-imidazol-2-y1) acetonitrile (0.8 g, 46%) as a red oil. 1H NMR (CDCl3) delta ppm: 6.99(s, 2H), 3.67 (s, 2H), 3.43 (s, 3H). 13C NMR (CD3OD) delta ppm: 137.2, 125.94, 120.52, 113.64, 35.4, 13.8. TOF-MS m/z: 122.0755 (M+H+, 100%), 95.0616 ( 32%), 149.0240 (12%). Molecular formula of cation, C6H7N3, calculated m/z of cation: 122.07 (M+H+) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | Under nitrogen atmosphere, dicyano propyloxycalixarene (1.705 g ; 3.05 mmol ; 1 eq.) was added to a suspension of NaH (60% in oil) (3.694 g ; 92.35 mmol ; 30 eq.) in anhydrous THF (50 mL). The reaction mixture was stirred for 15 min at room temperature and 2-chloroxymethyl-1-methyl-1H-imidazole hydrochloride (3.051 g ; 18.26 mmol ; 6 eq.) was introduced. After 17 h of refluxing, the solvent was removed under reduced pressure to a third volume. Distilled water (100 mL) was slowly added under vigorous stirring and the reaction mixture was stirred during 10 other minutes. The crude precipitate was collected by filtration, washed with water (2x50mL), dried and then purified by flash chromatography (dichloromethane/methanol 98/2 then 96/4) to give a white powder (1.156 g, 51%) ; m.p.: 215-216C ; IR : nu = 2926, 1584, 1462, 1442, 1244, 1206, 1192, 1088, 986, 863, 777, 754, 742, 657 cm-1 ; NMR 1H (300 MHz, CDCl3) : delta 2.02 (m, 4H, OCH2CH2), 2.38 (t, J = 7.2 Hz, 4H, CH2CN), 3.12 (d, J = 13.4 Hz, 4H, ArCH2eq), 3.60 (s, 6H, NCH3), 3.95 (t, J = 8 Hz, 4H, OCH2), 4.31 (d, J = 13.4 Hz, 4H, ArCH2ax), 4.91 (s, 4H, CH2Im), 6.28 (d, J = 7.3 Hz, 4H, ArH), 6.36 (m, 2H, ArH), 6.88 (m, 2H, ArH), 6.94 (s, 2H, ImH), 7.01 (d, J = 7.3 Hz, 4H, ArH), 7.07 (s, 2H, ImH) ; NMR 13C (75 MHz, CDCl3) : delta 13.9, 25.4, 30.8, 33.1, 67.1, 72.8, 120.1, 122.4, 123.1, 123.3, 128.3, 129.1, 133.9, 136.0, 144.3, 154.0, 156.4 ; LRMS (ESI+) m/z 747.4 ([M+H]+), 652.3 ([M-Imidazol]+), 374.4 ([M+2H]2+); HRMS (ESI+) for C46H47N6O4+, calcd 747.3659, found 747.3658 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With potassium carbonate; In water; N,N-dimethyl-formamide; | Synthesis of Methyl-4-((1-methyl-1H-imidazol-2-yl)methoxy)benzoate (BB8) A suspension of 4-hydroxy benzoic acid methyl ester (18 g, 118.42 mmol) and powdered anhydrous K2CO3 (40.85 g, 296 mmol) in dry DMF (150 mL) was heated to 100 C. To the stirred reaction mixture was added (BB7) (25.5 g, 153.6 mmol) in six portions. The reaction mixture was stirred for 6 h and then cooled to room temperature and filtered. The filtrate was dissolved in H2O (200 mL), extracted with EtOAc (2*250 mL), the combined organics were washed with brine solution (3*100 mL), dried over Na2SO4, concentrated in vacuo. The resulting crude compound was purified by column chromatography (100-200 mesh silica gel, eluted with 2% MeOH-CHCl3) to provide (BB8) (17.1 g, 52%) as an off-white solid. Rf: 0.2 (50% EtOAc/pet. ether). 1H NMR (400 MHz, CDCl3): delta 8.0 (2H, d, J=8.8 Hz), 7.33 (2H, d, J=8.8 Hz), 7.02 (1H, app d), 6.91 (1H, app d), 5.22 (2H, s), 3.88 (3H, s), 3.73 (3H, s); m/z 247 (MH)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | 4a (0.095 g, 0.419 mmol) was dissolved in a mixture of anhydrous DMF and anhydrous THF (2 mL/8 mL) and the solution was cooled to 0 C prior to adding the NaH (60% in mineral oil, 0.102 g, 2.550 mmol). The reaction was stirred at room temperature for 10 min then <strong>[78667-04-6]2-(chloromethyl)-1-methyl-1H-imidazole hydrochloride</strong> (0.174 g, 1.042 mmol) was added. The suspension was stirred at room temperature for 3 h then concentrated in vacuum. The crude product was purified by flash chromatography using DCM/MeOH gradient from 98/2 to 90/10. Yellow powder; 0.139 g, yield: 80%; mp 56 C (dec.); HPLC Purity: 95%; 1H NMR (300 MHz, CDCl3): delta = 7.50 (d, 1H, J = 7.80 Hz; ArH), 7.31-7.17 (m, 1H; ArH), 7.12 (m, 1H; ArH), 7.01-6.70 (m, 5H; ArH), 5.35 (d, 1H, J = 16.2 Hz; CNCHHIm), 5.14 (d, 1H, J = 16.2 Hz; CNCHHIm), 4.74-4.45 (m, 2H; CONCH, CONCHHIm), 4.37 (d, 1H, J = 15.3 Hz; CONCHHIm), 4.25 (dd, 1H, J1 = 12.0 Hz, J2 = 3.9 Hz; NCHHCH2), 3.80 (dd, 1H, J1 ? J2 ? 9 Hz; NCHCHH ), 3.60 (s, 3H; CH3), 3.29 (dd, 1H, J = 9.0, J = 5.4 Hz; NCHCHH), 3.23 (s, 3H; CH3), 3.06-2.78 (m, 2H; NCHHCH2, NCH2CHH), 2.69 ppm (m, 1H; NCH2CHH); 13C NMR (75 MHz, CDCl3): delta = 159.6 (CO), 143.6, 142.6, 137.1, 133.4, 128.0, 127.5, 126.8, 122.7 (2C), 122.0, 120.1, 119.0,110.9, 109.0, 49.7 (CONCH), 48.7 (NCHCH2), 41.2 (CNCH2Im), 40.2 (CONCH2Im), 39.2 (NCH2CH2), 33.0 (2C, CH3), 20.8 ppm (NCH2CH2); IR (KBr): nu = 3390, 2942, 1688 (C=O), 1501, 1454, 1262, 747 cm-1; HRMS (ESI): m/z calcd. for C23H26N7O: 416.2199 [M+H+]; found: 416.2199 (error: 0 ppm). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; sodium hydroxide; In water; for 49h;Reflux; | 2-(Chloromethyl)-l-methylimidazole hydrochloride (2.51 g, 15 mM) and taurine (0.6 g, 5 mM) were suspended in 25 mL distilled water. To this solution, N,N-diisopropylethylamine (1.94 g, 15 mM) and NaOH (1 g, 25 mM) both in 10 mL H2O were slowly added in sequence during 1 h at room temperature. Then, the reaction mixture was refluxed and stirred continuously for 48 h in the dark. After cooling to room temperature, the resulting red solution was washed with CHCl3 (25 mL) three times. The pH of the aqueous phase was adjusted to 6 by addition of 1 M HCl. The solvent was removed by evaporation, and then the resulting oil was dissolved in 90 mL anhydrous ethanol and filtered to remove insoluble substance. Solvent removal under vacuum afforded the crude product as a brown oil. The purification of L1 has not been successful so far even tried many times, so the crude product of L1 was directly used to react with Cu2+ by one-pot synthetic method as follows. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With triethylamine; In acetonitrile; at 65℃; for 24h; | A mixture of tert butyl 1 -piperazinecarboxylate (0.5 g, 2.68 mmol), 2-(chloromethyl)-1 - methyl-1H-imidazole hydrochloride (0.45 g, 2.68 mmol), triethylamine (0.79 mL, 5.67 mmol) and acetonitrile (20 mL) was stirred for 24h at 65 C. The solvent was evaporated and the crude was partitioned between ethyl acetate and water. The organic phase was separated, washed with water, dried over magnesium sulphate and the solvent was evaporated to give the title compound (0.59 g, 74%). LRMS (m/z): 281 (M+1 )+ |
74% | With triethylamine; In acetonitrile; at 65℃; for 24h; | A solution of tert-butyl 1-piperazinecarboxylate (0.5 g, 2.68 mmol), 2-(chloromethyl)-1- methyl-i H-imidazole hydrochloride (0.45 g, 2.68 mmol), and triethylamine (0.79 mL, 5.67 mmol) in acetonitrile (20 mL) was stirred for 24 h at 65 C. The solvent was evaporated and the crude partitioned with ethyl acetate and water. The organic phase was separated, washed with water, dried over magnesium sulfate and the solvent was evaporated to give the title compound (0.59 g, 74%).LRMS (mlz): 281 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
The title compound was prepared using analogous conditions described in Example 69 using <strong>[78667-04-6]2-(chloromethyl)-1-methyl-1H-imidazole hydrochloride</strong>. MS (ESI): mass calcd. for C19H20FN5O, 353.17; m/z found, 354.2 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57.6% | A suspension of tert-butyl 4-oxo- 1 -phenyl- 1,3,8 -triazaspiro [4.5] decane- 8-carboxylate (249 mg,751 j.imol), <strong>[78667-04-6]2-(chloromethyl)-1-methyl-1H-imidazole hydrochloride</strong> (126 mg, 751 imol; CASRN 78667-04-6) and TEA (314 iL, 2.25 mmol) in DMF (2 mL) were stirred at RT overnight. After 16 hours, NaH (55% in mineral oil, 72.1 mg, 1.65 mmol; CAS RN 7646-69-7) was added. The reaction mixture was heated to 100C in a sealed tube over 4 hours. The reaction mixture was poured on half-saturated aqueous NH4C1 solution and EtOAc and the layers were separated.The aqueous layer was extracted once with EtOAc. The organic layers were washed twice with H20 and once with brine, dried over MgSO4, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 12 g column using an MPLC system eluting with a gradient of n-heptane : EtOAc (100 : 0 to 0: 100) to give the title compound as acolorless foam (0.184 g; 57.6%). MS (ESI): mlz = 426.25 [M+Hf?. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: To a solution of 4-chloro-lH-pyrrolo-[3,2-c]-pyridine [60290-21-3] (2.0 g, 13.1 mmol) dissolved in DMF (30.5 mL, 0.944 g/mL, 393.2 mmol) at 0C was added portionwise sodium hydride (1.1 g, 28.8 mmol). The reaction mixture was allowed to reach rt and stirred 45 min, after which it was re-cooled to 0C and l-bromobutane (2.1 mL, 1.27 g/mL, 19.7 mmol) was added dropwise. The mixture was then allowed to reach rt and stirred overnight. NaHC03 sat solution was added and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with water and brine, then dried over MgS04 and concentrated in vacuo. The crude residue was purified by column chromatography (silica gel; gradient Heptane/EtOAc from 100/0 to 50 /50) to yield 1-1 (2.7 g, 98.7%) as a yellow liquid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27% | In 1,4-dioxane; at 120℃; for 4h;Inert atmosphere; | A solution of 2-(chloromethyl)-l-methyl-lH-imidazole hydrochloride (2.0 g, 12.0 mmol) and P(OEt)3 (20 mL) in dioxane (20 mL) was stirred at 120 C for 4 h under N2. The mixture was then concentrated in vacuo , and the residue was purified by column chromatography on silica gel (EtOAc : PE = 1 : 1 to EtOAc : MeOH = 6 : 1) to give 2065-A (760 mg, 27%) as a colorless oil. MS 233.2 [M+H]+. |
Tags: 78667-04-6 synthesis path| 78667-04-6 SDS| 78667-04-6 COA| 78667-04-6 purity| 78667-04-6 application| 78667-04-6 NMR| 78667-04-6 COA| 78667-04-6 structure
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P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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