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CAS No. : | 83857-96-9 | MDL No. : | MFCD01934396 |
Formula : | C8H11ClN2O | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | JLVIHQCWASNXCK-UHFFFAOYSA-N |
M.W : | 186.64 | Pubchem ID : | 55176 |
Synonyms : |
|
Num. heavy atoms : | 12 |
Num. arom. heavy atoms : | 5 |
Fraction Csp3 : | 0.5 |
Num. rotatable bonds : | 4 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 48.37 |
TPSA : | 45.75 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.63 cm/s |
Log Po/w (iLOGP) : | 1.49 |
Log Po/w (XLOGP3) : | 2.55 |
Log Po/w (WLOGP) : | 2.22 |
Log Po/w (MLOGP) : | 0.62 |
Log Po/w (SILICOS-IT) : | 3.12 |
Consensus Log Po/w : | 2.0 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.65 |
Solubility : | 0.42 mg/ml ; 0.00225 mol/l |
Class : | Soluble |
Log S (Ali) : | -3.16 |
Solubility : | 0.13 mg/ml ; 0.000695 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.4 |
Solubility : | 0.0738 mg/ml ; 0.000395 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.19 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302 | Packing Group: | N/A |
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 |
---|---|---|
89.9% | With potassium carbonate In N,N-dimethyl acetamide; water; toluene | EXAMPLE 14 2-n-Butyl-4-chloro-1-p-bromobenzyl-1H-imidazole-5-carboxaldehyde A mixture of 2-n-butyl-4-chloro-1H-imidazole-5-carboxaldehyde (0.6 m=111.9 g), p-bromobenzylbromide (0.6 m=153.02 g), anhydrous potassium carbonate (0.75 m=103.5 g), and dry N,N-dimethylacetamide (900 mL) was stirred at room temperature for 4 hours. The mixture was diluted with 1.2L of toluene and 1.8L of water. After mixing for half an hour, the layers were separated. The organic layer was washed two more times with 900 mL portions of water, then dried over magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated. The residual oil was pumped overnight to a weight of 191.71 g (89.9percent yield). |
89.9% | With potassium carbonate In N,N-dimethyl acetamide; water; toluene | EXAMPLE 14 2-n-Butyl-4-chloro-1-p-bromobenzyl-1H-imidazole-5-carboxaldehyde A mixture of 2-n-butyl-4-chloro-1H-imidazole 5-carboxaldehyde (0.6 m=111.9 g), p-bromobenzylbromide (0.6 m=153.02 g), anhydrous potassium carbonate (0.75 m=103.5 g), and dry N,N-dimethylacetamide (900 mL) was stirred at room temperature for 4 hours. The mixture was diluted with 1.2 L of toluene and 1.8 L of water. After mixing for half an hour, the layers were separated. The organic layer was washed two more times with 900 mL portions of water, then dried over magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated. The residual oil was pumped overnight to a weight of 191.71 g (89.9percent yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82.12% | Example 1: Preparation of 2-Butyl-4~chloro-l[(carbomethoxy-phenyl)methyl]-lH-imidazole- 5-carboxaldehydeTo dimethylformamide (400 ml) was added n-Butyl-4-chloro-5-formyl-lH-imidazole (10Og, 0.536 mol) followed by the addition of anhydrous potassium carbonate (55.4 g, 0.4 mol) at a temperature of 25-30C.The contents were stirred at this temperature for 30 minutes, followed by cooling the reaction mixture to 0-50C. To this was added Methyl-4-(bromomethyl) benzoate (129.2 g, 0.564 mol) in four equal lots at intervals of 30 minutes, maintaining the temperature between 0-5C.The reaction mixture was stirred for 8-10 hours below 100C, heated to 28-3O0C for 10-12 hours. After the completion of the reaction, it was poured into water (2000 ml) at 28- 30C,stirred for 1 hour at the same temperature, filtered , washed with water (1 X 200 ml). The product was dried at 50-550C in hot air oven. The product was recrystallised by heating in methanol/water at 50-550C. Mixture was stirred at 20-250C for 2 hours, filtered, washed with methanol and dried at 50-550C to get the desired compound (Dry wt. 147 g, Yield = 82.12 %) . | |
With caesium carbonate; In N,N-dimethyl-formamide; | EXAMPLE 9 2-Butyl-1-(4-carbomethoxybenzyl)-4-chloro-5-formylimidazole (J. Med. Chem. 1991; 34:1514-17). A solution of 17.50 g (0.098 mole) of 2-butyl-4-chloro-5-formylimidazole (U.S. Pat. No. 4,355,040) in 855 mL of DMF is treated with 91.65 g (0.28 mole) of cesium carbonate and the mixture is stirred at room temperature for 10 minutes. A solution of 22.56 g (0.099 mole) of methyl 4-(bromomethyl)benzoate in 270 mL of DMF is added and the mixture is stirred for 4 hours at room temperature. The cesium salts are filtered and the DMF filtrate is concentrated at reduced pressure. The crude product is purified by silica gel chromatography, eluding with methylene chloride, and then 1:7 ethyl acetate/methylene chloride, obtaining 23.16 g (74%) of pure product; mp 96-98 C.; tlc (1:1 hexane-ethyl acetate), 1 spot, Rf 0.7; MS (CI), 335 (M+). | |
With potassium carbonate; In N,N-dimethyl-formamide; at 25 - 70℃; for 12.5h; | Reference Example 1; Step-(a): Potassium carbonate (246.3 gm) and dimethylformamide (960 ml) are added to 2-butyl-4-chloro-1 H-imidazole-5-carbaldehyde (245 gm), the contents are stirred for 30 minutes at 25-300C and then methyl 4-(bromomethyl)benzoate (334 gm) is added to the reaction mass at once at 25-300C. The reaction mass is heated to 700C, stirred for 12 hours and then cooled to 20-250C. Filtered the mass, washed the solid with ethyl acetate (668 ml), to the resulting filtrate added ethyl acetate (668 ml) followed by 10% NaCI solution (260 gm of NaCI in 2627 ml of water) and then stirred for 30 minutes. Separated the layers and collected the ethyl acetate layer. To the aqueous layer added ethyl acetate (668 ml), stirred for 30 minutes, separated the layers, combined the total ethyl acetate layer and then stirred with 10% NaCI solution (69 gm of NaCI in 695 ml of water) for 30 minutes. Separated the layers, combined the total ethyl acetate layer and passed through sodium sulphate (10 gm). The ethyl acetate layer is distilled under vacuum at below 500C and co-distilled with isopropyl alcohol (348 ml). To the resulting mass added isopropyl alcohol (1667 ml) and charcoal (11.7 gm) and then the contents are refluxed for 1 hour. The reaction mass is filtered through hyflow bed, washed the bed with hot isopropyl alcohol (478 ml), the resulting filtrate is initially cooled to 25-300C and latter cooled to 0-50C. The reaction mass is stirred for 2 hours, filtered the mass, washed with chilled isopropyl alcohol (145 ml), suck dried the material and then dried at 700C to give 265 gm of methyl 4-[[2-butyl-4-chloro-5-formyl-1 H-imidazol-1 - yl]methyl]benzoate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With ammonium cerium(IV) nitrate In acetic acid at 25℃; for 3h; | |
690 mg | With 2,2,6,6-tetramethyl-piperidine-N-oxyl; iodine; sodium hydrogencarbonate In water; toluene at 20℃; for 16h; | |
With oxygen In methanol at 60℃; for 6h; |
12.81 g (86%) | With manganese dioxide In dichloromethane | 1.v (v) (v) 2-n-Butyl-4-chloro-5-imidazolecarboxaldehyde A stirred mixture of 2-n-butyl-4-chloro-5-hydroxymethylimidazole (15.00 g, 0.0795 mol) and activated manganese dioxide (40.00 g) in 600 ml of methylene chloride was refluxed for 24 h using a water separator. The mixture was filtered hot through a Celite pad. The Celite pad was washed several times with hot methylene chloride. The washings were combined with the filtrate and concentrated in vacuo to give 12.81 g (86%) of the aldehyde as a white solid; mp 97°-98° C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With potassium carbonate; In N,N-dimethyl-formamide; at 0 - 20℃; for 4h; | 2-Butyl-4-chloroimidazole carboxaldehyde 627 (5.0 g, 26.9 mmol) in DMF was added potassium carbonate (4.08 g, 29.56 mmol) and benzyl bromide (3.15 mL, 26.9 mmol) with stirring at 0 C for 1 h and then at RT for 3 h. The reaction mixture was poured in ice cold water, extracted with ethyl acetate (3 × 25 mL), combined organic extract was dried over anhydrous sodium sulphate and evaporated under vacuum. The crude residue thus obtained was chromatographed over silica gel (hexane/ethyl acetate, 9:1) to give 1-benzyl-2-butyl-4-chloroimidazole carboxaldehyde 7 (6.53 g, 92%) as pale yellow syrup. 1H NMR (300 MHz, CDCl3) delta 9.74(s, 1H), 7.29 (m, 3H), 7.01 (d, J = 8.3 Hz, 2H), 5.53 (s, 2H), 2.59 (t, J = 7.5Hz, 2H), 1.60-1.70 (m, 2H), 1.25-1.37 (m, 2H), 0.88(t, J = 7.5Hz, 3H). MS (ESI) m/z 277 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.154 g | With trichlorophosphate; In toluene; at 60 - 100℃; for 2h;Green chemistry; | Valeronitrile(0.83 g, 10 mmol) and methanol (4 g) were added to the flask, thenacetyl chloride (1.18 g, 15 mmol) was added dropwise at 0 C. After2 h, the valeronitrile was completely reacted. The mixture was to pH= 9 by adding sodium hydroxide solution. The aqueous phase wasextracted with toluene and the organic phases were combined. Then,methanol (4 g), sodium methoxide (0.030 g), glycine (0.825 g) wereadded and the resulting solution was stirred at 0C for 2 h. Afterfiltration of the mixture, the resulting white solid was washed withcold toluene and dried under reduced pressure at 40-50C to giveN-carboxymethyl pentamidine. Then, POCl3 (0.431 g, 2.8 mmol) andDMF (0.219 g, 3 mmol) was added dropwise to a flask containingN-carboxymethyl pentamidine (0.158 g, 1 mmol) and toluene (5 mL).The temperature was maintained below 60oC. After the addition, thereaction mixture was heated to 100oC for 2 h. Then the solution wascooled, and some cool distilled water and sodium hydroxide solutionwas added to adjust the pH to 2. The solution was washed with toluene(20 mL) and the organic phase was combined. Then the solution wasevaporated about 50% and cooled to 0 C. The crystallised solid wasfiltered, washed with cold toluene and dried under reduced pressure at 40-50 C to give 2-butyl-4-chloro-1H-imidazole-5-carbaldehyde (5)(0.154 g, 82%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With sodium tetrahydroborate In methanol at 20℃; for 2h; | |
With hydrogen; magnesium In methanol at 20℃; for 0.583333h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | Example 2; Preparation of BCFI from Methyl Pentanimidate Using a Triflate Catalyst; 50 g (0.666 mol) of glycine was added to freshly prepared methanolic sodium hydroxide solution (sodium hydroxide 26.64 g (0.666 mol) in 250 ml of methanol) at 0 C. and stirred for another 15 min. 80 g (0.70 mol) of the methyl pentanimidate prepared according to example 1 was added over a period of 10-15 min to the above suspension at 0-5 C. and stirring was continued for 16 hrs at room temperature. The solvent was then distilled under vacuum below 50 C.500 ml of toluene was added to the above reaction mass, followed by 0.25 g of Copper(II) trifluoromethanesulfonate. Then 320 g (2.08 mol) of phosphorous oxychloride was added to this reaction mixture in 60 min, followed by 150 g (2.05 mol) N,N-dimethylformamide in 2 hrs. The reaction mixture was heated to 100 C. and stirred for 2 hrs, then cooled to 30 C. and quenched in 260 ml of cooled deionised water (temperature below 25 C.). 30 g of filter aid (hi-flow) was added and the pH adjusted to 1.2 using 440 ml of 30% aqueous sodium hydroxide solution.It was then filtered and washed with 100 ml of toluene, and the layers were separated. The toluene layer was washed twice with deionised water (400 ml each time). 8 g of activated carbon was added to the toluene and the layer was stirred for 30 min at 30-35 C., followed by filtration and washing with 100 ml of toluene. All toluene layers were combined and concentrated to 50 vol% under vacuum below 55 C. The concentrated toluene solution was then cooled to 0-5 C. and stirred for 2 hrs, followed by filtration of the precipitated product and washing with 25 ml of chilled toluene, to yield a wet material, which upon drying at 50-55 C. to constant weight resulted in 89 g (0.47 mol) of crystalline 2-butyl-4-chloro-5-formylimidazole (yield 71%). The analysis of this product by HPLC gave a purity of 99.8%, confirmed by IR. Melting range 95-99 C.; Example 4; Preparation of BFI from Valeronitrile; 58 g (1.2 mol) of valeronitrile was charged in 34 ml of methanol and cooled to -5 to -10 C. Hydrochloric acid gas was slowly passed through for 15-18 hrs. The nitrogen pressure was kept at 1.5 to 2.0 kg/cm2 for 14 hrs at 0-15 C., followed by the addition of 32 ml of methanol while stirring for 60 min.The reaction mass was transferred to a methanolic ammonia solution (12-15 wt % and stirred for 3 hrs at 20-30 C., while keeping the pH at 8.0-9.0. Precipitated material was filtered off and washed with 15 ml of methanol. The filtrate was concentrated by distillation under reduced pressure (650-700 mm Hg) at a temperature not exceeding 90 C., followed by cooling to give pentanimidate.50 g (0.666 mol) of glycine was added to a freshly prepared methanolic sodium hydroxide solution (sodium hydroxide 26.64 g (0.666 mol) in 250 ml of methanol) at 0 C. and stirred for 15 min. The above prepared, 80 g pentanimidate was added at 0-5 C. in 10-15 min and the mixture was stirred for another 16 hrs at room temperature. The solvent was distilled under vacuum while keeping the temperature below 50 C.500 ml of toluene was added to the above reaction mass, followed by 0.25 g of Copper(II) trifluoromethanesulfonate. Then 320 g (2.08 mol) of phosphorous oxychloride and 150 g (2.05 mol) N,N-dimethylformamide were added successively in 60 minutes and 2 hours, respectively. The reaction mixture was heated to 100 C. and stirred for another 2 hrs, then cooled to 30 C. and quenched in 260 ml of cooled water having a temperature below 25 C. 30 g of filter aid (hi-flow) was added and the pH adjusted to 1.2 with 440 ml of 30% aqueous sodium hydroxide solution.It was then filtered and washed with 100 ml of toluene, and the layers were separated. The toluene layer was washed twice with deionised water (400 ml each time), and 8 g of activated carbon was added to the toluene and stirred for 30 min at 30-35 C., followed by filtration and washing with 100 ml of toluene. All toluene layers were combined and concentrated to dryness under vacuum below 55 C. The concentrated mass was cooled to 30 C. The weight of the residue was 96 g.500 ml of methanol and 60 g of triethylamine was added hereto, followed by 4.5 g of 10% palladium on carbon in the autoclave. The hydrogen pressure was kept at 4-5 kg/cm at 20-25 C. for 8-10 hrs, while monitoring the reaction by thin layer chromatography.At the end of the reaction, the mixture was unloaded from the autoclave. The solvent was removed under reduced pressure, thereby keeping the temperature below 50 C. 250 ml of deionised water was added and it was cooled to 25-30 C. The pH was adjusted to 1.2 with diluted hydrochloric acid and the aqueous layer was extracted with 60 ml of dichloromethane to remove traces of the starting material. The pH was then readjusted to 6.8-7.5 using sodium carbonate solution, and the aqueous layer was extracted with 3×160 ml of dichloromethane. The dichloromethane solution was dried with sodium sulfate for 30 min and the so... | |
66.4% | Comparative Example 2; Preparation of BCFI Without Triflate Catalyst; The procedure reported in example 2 was exactly repeated, with the only difference that phosphorous oxychloride was now added in the absence of Copper(II) trifluoromethanesulfonate. All other steps, including reaction times and temperatures, were in accordance with those mentioned in example 2.It resulted in a wet material, which upon drying at 50-55 C. to constant weight resulted in 82.7 g (0.4431 mol) of crystalline 2-butyl-4-chloro-5-formylimidazole (yield 66.4%). The analysis of this product by HPLC showed a purity of 92.5%, based on glycine. The yield and purity were comparable to those mentioned in example 4 of U.S. Pat. No. 5,696,272 (62.0% yield and 85% HPLC purity), using a corresponding synthesis route and the same starting materials.In order to arrive at the purity levels reported in example 2 (preparation of BCFI in the presence of a triflate catalyst), extensive purification, including a charcoal treatment, was required, accompanied by a drop in yield to about 50%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 10h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | COMPOUND 12.1. 14: 4- {2-r (2-BUTYL-4-CHLORO-lH-IMIDAZOL-5- YL)METHYL]-6,7-DIMETHOXY-1,2,3,4-TETRAHYDROISOQUINOLIN-1-YL}- N, N-DIETHYLBENZAMIDE; INTERMEDIATE 5.1. 7 (30 mg, 0.08 mmol) and 4-chloro-2-n-butylimidazole-5- carbaldehyde (45 mg, 0.24 mmol) were dissolved in DCE (2.0 mL). After stirring for 10 min at room temperature, sodium triacetoxyborohydride (76 mg, 0.36 mmol) was added and the mixture was stirred for 18 h at room temperature. Tosylhydrazine scavenger resin (0.20 g, 2.4 mmol/g) was added and the mixture was stirred for another 2 h. DCM and 1 M sodium hydroxide solution were added and the mixture was passed through a Whatman 1PS silicon-treated filter paper. The organic phase was evaporated and the crude product was purified by flash chromatography to yield the product (26 mg, 0.048 mmol, 60%). 1H NMR (500 MHz, CDC13) : 8 0.91 (m, 3 H), 1.16, 1.24 (2 brs, 6 H), 1. 39 (m, 2 H), 1.64 (m, 2 H), 2. 59-2. 70,2. 94,3. 09,3. 50-3. 62 (4 m, 10 H), 3. 28 (brs, 2 H), 3.63, 3.87 (2 s, 6 H), 4.62 (s, 1 H), 6.19, 6.62 (2 s, 2 H), 7.30 (m, 4 H), 9.65 (brs, 1 H). (+) LRESIMS m/z 561, 563 [M+Na] +. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
255 g (91%, corrected for 99.5% purity) | With sodium borohydrid; potassium carbonate; In ISOPROPYLAMIDE; water; | Step B 2-n-butyl-4-chloro-5-hydroxymethyl-1-p-bromobenzyl-1H-imidazole A suspension of 2-n-butyl-4-chloro-1H-imidazole-5-carboxyaldehyde (146.9 g, 0.78 mol) and p-bromobenzyl bromide (195 g, 0.78 mol) in dimethylacetamide (1.0 L) was cooled to 0 C. and potassium carbonate (1.38 g, 1.0 mol) was added. The mixture was aged for three hours at 0 C. and then at 20 to 25 C. or two to four hours. The mixture was diluted with dimethylacetamide (0.15 L) and then filtered. The filter cake was washed with dimethylacetamide (50 ml). The combined filtrates were diluted with methanol (0.66 L) and cooled to 0 C. Sodium borohydride (37.8 g, 1.0 mol) was added as a solid and the mixture was aged with stirring at 20 to 25 C. for two hours. Water (1.56 L) was added slowly to crystallize the product. The filter cake was washed carefully with water (1.56 L) and dried in vacuo at 60 C. The yield was 255 g (91%, corrected for 99.5% purity). |
255 g (91%, corrected for 99.5% purity) | With sodium borohydrid; potassium carbonate; In ISOPROPYLAMIDE; water; | Step B 2-n-butyl-4-chloro-5-hydroxymethyl-1-p-bromobenzyl-1H-imidazole A suspension of 2-n-butyl-4-chloro-1H-imdazole-5-carboxyaldehyde (146.9 g, 0.78 mol) and p-bromobenzyl bromide (195 g, 0.79 mol) in dimethylacetamide (1.0 L) was cooled to 0 C. and potassium carbonate (1.38 g, 1.0 mol) was added. The mixture was aged for three hours at 0 C. and then at 20 to 25 C. or two to four hours. The mixture was diluted with dimethylacetamide (0.15 L) and then filtered. The filter cake was washed with dimethylacetamide (50 ml). The combined filtrates were diluted with methanol (0.66 L) and cooled to 0 C. Sodium borohydride (37.8 g, 1.0 mol) was added as a solid and the mixture was aged with stirring at 20 to 25 C. for two hours. Water (1.56 L) was added slowly to crystallize the product. The filter cake was washed carefully with water (1.56 L) and dried in vacuo at 60 C. The yield was 255 g (91%, corrected for 99.5% purity). |
255 g (91%, corrected for 99.5% purity) | With sodium borohydrid; potassium carbonate; In ISOPROPYLAMIDE; water; | EXAMPLE 18 2-n-butyl-4-chloro-5-hydroxymethyl-1-p-bromobenzyl-1H-imidazole A suspension of 2-n-butyl-4-chloro-1H-imidazole-5-carboxyaldehyde (146.9 g, 0.78 mol) and p-bromobenzyl bromide (195 g, 0.78 mol) in dimethylacetamide (1.0L) was cooled to 0 C. and potassium carbonate (138 g, 1.0 mol) was added. The mixture was aged for three hours at 0 C. and then at 20 to 25 C. for two to four hours. The mixture was diluted with dimethylacetamide (0.15L) and then filtered. The filter cake was washed with dimethylacetamide (50 ml). The combined filtrates were diluted with methanol (0.66L) and cooled to 0 C. Sodium borohydride (37.8 g, 1.0 mol) was added as a solid and the mixture was aged with stirring at 20 to 25 C. for two hours. Water (1.56L) was added slowly to crystallize the product. The filter cake was washed carefully with water (1.56L) and dried in vacuo at 60 C. The yield was 255 g (91%, corrected for 99.5% purity). |
255 g (91%, corrected for 99.5% purity) | With sodium borohydrid; potassium carbonate; In ISOPROPYLAMIDE; water; | Step B 2-n-butyl-4-chloro-5-hydroxymethyl-1-p-bromobenzyl-1H-imidazole A suspension of 2-n-butyl-4-chloro-1H-imdazole-5carboxyaldehyde (146.9 g, 0.78 mol) and p-bromobenzyl bromide (195 g, 0.78 mol) in dimethylacetamide (1.0 L) was cooled to 0 C. and potassium carbonate (1.38 g, 1.0 mol) was added. The mixture was aged for three hours at 0 C. and then at 20 to 25 C. or two to four hours. The mixture was diluted with dimethylacetamide (0.15 L) and then filtered. The filter cake was washed with dimethylacetamide (50 ml). The combined filtrates were diluted with methanol (0.66 L) and cooled to 0 C. Sodium borohydride (37.8 g, 1.0 mol) was added as a solid and the mixture was aged with stirring at 20 to 25 C. for two hours. Water (1.56 L) was added slowly to crystallize the product. The filter cake was washed carefully with water (1.56 L) and dried in vacuo at 60 C. The yield was 255 g (91%, corrected for 99.5% purity). |
255 g (91%, corrected for 99.5% purity) | With sodium borohydrid; potassium carbonate; In ISOPROPYLAMIDE; water; | Step B 2-n-butyl-4-chloro-5-hydroxymethyl-1-p-bromobenzyl-1H-imidazole A suspension of 2-n-butyl-4-chloro-1H-imdazole-5-carboxyaldehyde (146.9 g, 0.78 mol) and p-bromobenzyl bromide (195 g, 0.78 mol) in dimethylacetamide (1.0 L) was cooled to 0 C. and potassium carbonate (1.38 g, 1.0 mol) was added. The mixture was aged for three hours at 0 C. and then at 20 to 25 C. or two to four hours. The mixture was diluted with dimethylacetamide (0.15 L) and then filtered. The filter cake was washed with dimethylacetamide (50 ml). The combined filtrates were diluted with methanol (0.66 L) and cooled to 0 C. Sodium borohydride (37.8 g, 1.0 mol) was added as a solid and the mixture was aged with stirring at 20 to 25 C. for two hours. Water (1.56 L) was added slowly to crystallize the product. The filter cake was washed carefully with water (1.56 L) and dried in vacuo at 60 C. The yield was 255 g (91%, corrected for 99.5% purity). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; sodium hydroxide In methanol | 1 Process for the preparation of 2-n-butyl-4-chloro-5-formylimidazole EXAMPLE 1 Process for the preparation of 2-n-butyl-4-chloro-5-formylimidazole 4.0 g of 2-n-butyl4-chloro-5-hydroxymethylimidazole, 21.5 ml of 1N NaOH and 13.6 ml of methanol were heated to 60° C. to give a solution. 0.6 g of 5% Pt-5% Bi/C (Degussa, comprising 60 percent H2 O) was added. At 60° to 62° C., 4.2 g of 20 percent strength aqueous H2 O2 solution was added dropwise over 60 min. The mixture was then left to react for a further 15 min; it was then filtered, and the catalyst was then washed with 5 ml of methanol. The filtrate was adjusted from pH 12.4 to pH 7.5 using 32 percent strength HCl. 15 ml of H2 O was added, and the mixture was partially evaporated on a rotary evaporator (removal of methanol). The mixture was then allowed to cool with thorough stirring, and the resultant white suspension was filtered at 20° C. The filter cake was then washed with 5 ml of H2 O and dried to give 3.4 g of a white to slightly yellowish substance. According to 1 H NMR, this substance comprised 32.6 mol percent of 2-n-butyl4-chloro-5-hydroxymethylimidazole and 67.3 mol percent of 2-n-butyl4-chloro-5-formylimidazole. 1 H NMR data for 2-n-butyl4-chloro-5-formylimidazole was: | |
With hydrogenchloride; sodium hydroxide In methanol | 2 Process for the preparation of 2-n-butyl 4-chloro-5-formylimidazole EXAMPLE 2 Process for the preparation of 2-n-butyl 4-chloro-5-formylimidazole 4.0 g of 2-n-butyl4-chloro-5-hydroxymethylimidazole, 4 ml of 1N NaOH, 6 ml of H2 O and 12.6 ml of methanol were heated to 60° C. to give a solution. 0.6 g of 5% Pt-5% Bi/C (Degussa, comprising 60 percent H2 O) was added. At 60° to 62° C., 4.2 g of 20 percent strength aqueous H2 O2 solution was added dropwise over 60 min. The mixture was then left to react for a further 15 min; it was then filtered, and the catalyst was then washed with 5 ml of methanol. The filtrate was adjusted from pH 8.4 to pH 7.5 using 32 percent strength HCl. 15 ml of H2 O was added, and the mixture was partially evaporated on a rotary evaporator (removal of methanol). The mixture was then allowed to cool with thorough stirring, and the resultant white suspension was filtered at 20° C. The filter cake was then washed with 5 ml of H2 O and dried to give 3.7 g of a white substance. According to 1 H NMR, this substance comprised 36.9 mol percent of 2-n-butyl4-chloro-5hydroxymethylimidazole and 63.1 mol percent of 2-n-butyl-4-chloro-5-formylimidazole. |
Yield | Reaction Conditions | Operation in experiment |
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With hydrogenchloride; sodium hydroxide In water | 3 Process for the preparation of 2-n-butyl-4-chloro-5-formylimidazole EXAMPLE 3 Process for the preparation of 2-n-butyl-4-chloro-5-formylimidazole 3.0 g of 2-n-butyl4-chloro-5-hydroxymethylimidazole, 1.2 g of 5% Pt-5% Bi/C (Degussa, comprising 60% H2 O), 44 g of methyl isobutyl ketone, 1.3 ml of 1N NaOH solution and 6.8 g of water were heated to 59° C. with stirring. At 60° to 62° C, 4.0 g of 20 percent strength aqueous H2 O2 solution was added over 75 min. The reaction mixture was then allowed to react for a further 15 min; it was then filtered. The filtrate was adjusted from pH 10.4 to pH 7.0 using 10 percent strength HCl. The mixture was then introduced to a separating funnel, and the aqueous phase was separated off and then extracted with 10 ml of methyl isobutyl ketone. The two organic phases were combined and evaporated on a rotary evaporator. The evaporation residue was 3.1 g of white crystals. According to 1 H MNR, 93.5 mol percent of 2-n-butyl-4-chloro-5-formylimidazole and 6.5 mol percent of 2-n-butyl-4-chloro-5-hydroxymethylimidazole were obtained. |
Yield | Reaction Conditions | Operation in experiment |
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99.2% | In a suitable reactor, 92.79 g of 5-[4'-(bromomethyl)-l,l'-bimethyl-2-yl]-2- (triphenylmethyl)-2H-tetrazole, 195 mL of dimethylformamide, 31.06 g of 2-butyl-4-chloro- lH-imidazole-5-carbaldehyde and 27.37 g of potassium carbonate were combined. The resulting suspension was stirred at 20-22 C for 3 hours. Thereafter, 12.68 mL of an aqueous solution of sodium borohydride (20%) was added to the solution over approximately 5 minutes. The suspension was then stirred and heated to 48-52 C for 3 hours. After the reduction, the mixture was cooled to 20-25 C. The mixture was then combined over approximately 20 minutes with 117 mL of ethyl acetate and a previously prepared solution of 390 mL of water and 10.3 mL of acetone. The resulting suspension obtained was stirred for 2 hours. Thereafter the suspension was filtered, and the resulting solid was washed with 40 mL of water.The resulting wet solid was next placed in a suitable reactor with 300 mL of ethyl acetate. The suspension was then heated to reflux temperature until a solution was obtained, and the mixture was cooled to 0-5 C for 2 hours. The suspension was then filtered, and the solid was washed with 15 mL of ethyl acetate to yield 148.05 g of wet (2-butyl-4-chloro-l-[2'-(2-trityl-2H-tetrazol-5yl)biphenyl-4-yl]-methyl}-lH-imidazol-5-yl)methanol (trityl losartan) (estimated dry mass: 109.9 g, yield 99.2%). | |
With potassium carbonate; In N,N-dimethyl acetamide; | EXAMPLE 6 2-n-Butyl-4-chloro-1-[(2'-(2-triphenylmethyl-2H-tetrazol-5-yl)-1,1'-biphenyl-4-yl)methyl]-1H-imidazole-5-carboxaldehyde A mixture of 5-(4'-bromomethyl-1,1'-biphenyl-2-yl)-2-triphenylmethyl-2H-tetrazole (0.102 m=63.1 g), 2-n-butyl-4-chloro-1H-imidazole-5-carboxaldehyde (0.113 m=21.1 g) and anhydrous potassium carbonate (0.135 m=18.6 g) in 251 g of N,N-dimethylacetamide was stirred at 0-5 C. for 8 hours and the temperature of the reaction was raised to 25 C. for an additional 4 hours. Normally the product of this step was not isolated but reduced with sodium borohydride to give 2-n-butyl-4-chloro-1-[(2'-(2-triphenylmethyl-2H-tetrazol-5-yl)-1,1'-biphenyl-4-yl)methyl]-1H-imidazole-5-methanol. | |
With potassium carbonate; In N,N-dimethyl acetamide; | EXAMPLE 6 2-n-Butyl-4-chloro-1-[(2'-(2-triphenylmethyl-2H-tetrazol 5-yl)-1,1'-biphenyl-4-yl)methyl]-1H-imidazole-5-carboxaldehyde A mixture of 5-(4'-bromomethyl-1,1'-biphenyl-2-yl)-2triphenylmethyl-2H-tetrazole (0.102 m=63.1 g), 2-n-butyl-4-chloro-1H-imidazole-5-carboxaldehyde (0.113 m=21.1 g) and anhydrous potassium carbonate (0.135 m=18.6 g) in 251 g of N,N-dimethylacetamide was stirred at 0-5 C. for 8 hours and the temperature of the reaction was raised to 25 C. for an additional 4 hours. Normally the product of this step was not isolated but reduced with sodium borohydride to give 2-n-butyl-4-chloro-1-[(2'-(2-triphenylmethyl-2H-tetrazol-5-yl)-1,1'-biphenyl-4-yl)methyl]-1H-imidazole-5-methanol. |
Yield | Reaction Conditions | Operation in experiment |
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89.9% | With potassium carbonate; In N,N-dimethyl acetamide; water; toluene; | EXAMPLE 14 2-n-Butyl-4-chloro-1-p-bromobenzyl-1H-imidazole-5-carboxaldehyde A mixture of 2-n-butyl-4-chloro-1H-imidazole-5-carboxaldehyde (0.6 m=111.9 g), p-bromobenzylbromide (0.6 m=153.02 g), anhydrous potassium carbonate (0.75 m=103.5 g), and dry N,N-dimethylacetamide (900 mL) was stirred at room temperature for 4 hours. The mixture was diluted with 1.2L of toluene and 1.8L of water. After mixing for half an hour, the layers were separated. The organic layer was washed two more times with 900 mL portions of water, then dried over magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated. The residual oil was pumped overnight to a weight of 191.71 g (89.9% yield). |
89.9% | With potassium carbonate; In N,N-dimethyl acetamide; water; toluene; | EXAMPLE 14 2-n-Butyl-4-chloro-1-p-bromobenzyl-1H-imidazole-5-carboxaldehyde A mixture of 2-n-butyl-4-chloro-1H-imidazole 5-carboxaldehyde (0.6 m=111.9 g), p-bromobenzylbromide (0.6 m=153.02 g), anhydrous potassium carbonate (0.75 m=103.5 g), and dry N,N-dimethylacetamide (900 mL) was stirred at room temperature for 4 hours. The mixture was diluted with 1.2 L of toluene and 1.8 L of water. After mixing for half an hour, the layers were separated. The organic layer was washed two more times with 900 mL portions of water, then dried over magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated. The residual oil was pumped overnight to a weight of 191.71 g (89.9% yield). |
Yield | Reaction Conditions | Operation in experiment |
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With manganese dioxide In tetrahydrofuran; methanol; water; ethyl acetate; N,N-dimethyl-formamide | 11 2-Butyl-4-chloro-5-formyl-imidazole 2-Butyl-4-chloro-5-formyl-imidazole A mixture of 2-butyl-4-chloro-5-hydroxymethyl-imidazole 20 g (0.1 mol) and MnO2 (46.1 g, 0.53 mol) in THF (500 mL) was heated at reflux for 4 hours. The reaction mixture was cooled and filtered through a bed of celite and washed thoroughly with hot THF. The filtrate and the washings were concentrated under reduced pressure to give 18.7 g of a solid. It was chromatographed using CH2 Cl2 /MeOH (2%) as eluant to give 14 g of a solid; mp 95°-96° C. A mixture of the above aldehyde (1.86 g, 0.01 mol) and CS2 CO3 (7.17 g, 0.02 mol) in DMF (20 mL) was stirred for 10 minutes. To this mixture was added a solution of (4-carbethoxy)benzylbromide (2.7 g, 0.011 mol) in DMF (10 mL) and the resulting mixture was stirred for 2 hours. DMF was distilled, the residue was treated with water, and the mixture was extracted with EtOAc. The EtOAc solution was washed with brine, dried, and evaporated. The residue was chromatographed (CH2 Cl2 /EtOAc, 10-15%) to give an oil (2.7 g). MS (CI) 345 (m). Analysis calculated for C18 H21 ClN2 O3: C, 61.98; H, 6.07; N, 8.03. Found: C, 61.65; H, 6.09; N, 7.84. A solution of the above 4-chloro-imidazole derivative (1.18 g) in EtOH (75 mL) containing KOAc (0.33 g) was subjected to catalytic reduction in presence of 5% Pd-C to give the title compound as an oil (0.8 g). MS 314, (m). |
Yield | Reaction Conditions | Operation in experiment |
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92% | With potassium hydroxide; In water; acetic acid; | f 2-n-Butyl-4-chloro-5-formylimidazole 305 ml of a 1M (NH4)2 Ce(NO3)6 solution in H2 O are added slowly at 10-15 C. to 20 g (0.106 mol) of 2-n-butyl-n-4-chloro-5-hydroxymethylimidazole (prepared according to EP-A 253,310) in 350 ml of glacial acetic acid. After 2.5 h at room temperature, the pH is adjusted to 4 using 2N KOH (20 C. during the addition of the base). The mixture is then extracted 4* using 500 ml of CH2 Cl2 each time and the combined organic extracts are washed 3* with 300 ml of saturated aqueous NaHCO3 solution each time, dried with Na2 SO4 and concentrated, the title compound being obtained as a colorless solid (18 g, 92%). M.p.:=90 C. Rf (DIP/MTB 1:1)=0.5 |
In water; acetic acid; | a 2-Butyl-4-chloro-5-formylimidazole 305 ml of a 1M solution of (NH4)2 Ce(NO3)6 in H2 O are added slowly at 10-15 C. to 20 g (0.106 mol) of 2-butyl-4-chloro-5-hydroxymethylimidazole in 350 ml of glacial acetic acid. After 2.5 h at RT, the pH is adjusted to 4 with 2N KOH (20 C. during addition of the base). After extraction 4* with 500 ml of CH2 Cl2 each time the combined organic extracts are washed 3* with 300 ml of saturated aqueous NaHCO3 solution each time, dried with Na2 SO4 and concentrated, resulting in the title compound as a colorless solid (18 g). Melting point was 90 C. |
Yield | Reaction Conditions | Operation in experiment |
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With sodium hydroxide;tetrabutylammomium bromide; In n-Butyl chloride; water; at 25 - 50℃; for 32h; | 5-(4'-Bromomethyl-l,r-biphenyl-2-yl)-l-(triphenylmethyl)-lH-tetrazole (100 g) is suspended in a mixture of 1-chlorobutane (600 ml)and IN sodium hydroxide (400 ml) at EPO <DP n="8"/>temperature of 250C and tetra butyl ammonium bromide (1Og) is added. 2-n-Butyl-4- chloroimidazole-5-carboxaldehyde (35g) is added in small portions to the reaction mass at temperature of 250C to 3O0C and maintained the reaction mass for about 32 hrs at temperature of 250C to 3O0C. Temperature of the reaction mass is raised to 450C to 5O0C and allowed to settle the layers. Organic layer is separated, extracted the aqueous layer with 1-chloro butane (200 ml) and the combined organic layer is washed with water (200ml) at 450C to 50C.The organic layer is cooled and sodium borohydride (7.4 g) is added at 250C to 3O0C under nitrogen atmosphere. Reaction mass temperature is raised to 4O0C to 450C, methanol (50 ml) is added over 45 min and maintained the reaction mass at 4O0C to 450C for 5hrs. Water (100 ml) is added to the reaction mass, allowed to settle and separated the layers at 4O0C to 450C. 1 -Chlorobutane (100 ml) is added to the organic layer, raised the temperature to 6O0C to 650C and washed with water (100 ml). Distilled off the solvent till reaction mass volume becomes around 600 ml. Cooled the reaction mass to 280C. Water (100 ml) is added, cooled the reaction mass to 1O0C over 2 hrs and maintained at 100C to 150C for 4 hrs. Filtered the product and washed with chilled 1- chloro butane (50 ml).The wet cake (130g) is suspended in ethyl acetate (300 ml), raised the temperature to reflux, maintained for 30 min at reflux temperature. Slowly cooled the reaction mass to 150C and maintained at 140C to 160C for 3 hrs. Filtered the product, washed with ethyl acetate (100 ml) and dried at 6O0C - 650C till constant weightThe dry weight of 2-n-Butyl-4-chloro-l-[2Lambda-(2-triphenylmethyl-2H-tetrazole-5-yl)-l,r- birhohenyl-4-yl]methyl}-lH-imidazole-5-methanol is 93.0 g (Yield: 78%) | |
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; | 2-Butyl-5-chloro-3-[2'-(1-trityl-1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-3H-imidazole-4-carbaldehyde (11a): To a DMF (150 mL) solution of 5-(4'-bromomethyl-biphenyl-2-yl)-1-trityl-1H-tetrazole (30 g, 53.8 mmol) was added 2-butyl-5-chloro-3H-imidazole-4-carbaldehyde (10 g, 53.8 mmol) and K2CO3 (7.4 g, 53.8 mmol). The mixture was stirred at room temperature overnight. EtOAc (500 mL) was added and the organic was washed three times with a NaHCO3 solution (200 mL) followed by saturated aqueous NaCl (200 mL). Solvent was removed and purification was achieved by silica gel chromatography (50:50 EtOAc:hexanes) using an isocratic gradient to provide intermediate (11a) a white solid (41 g). MS m/z: [M+H+] calcd for C41H35ClN6O, 663.26; found 663.4. 1H-NMR (d4-MeOH): 0.83 (m, 3H), 1.26 (m, 2H), 1.53 (m, 2H), 2.53 (m, 2H), 5.56 (s, 2H), 6.87-6.96 (m, 8H), 7.05 (m, 2H), 7.25-7.43 (m, 10H), 7.53-7.58 (m, 2H), 7.84 (d, 1H), 9.73 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
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47.2% | With sodium hydroxide; sodium tetrahydroborate; In water; toluene; | Part D Preparation of 1-[(2'-(Triphenylmethyltetrazol-5-yl)biphenyl-4-yl)methyl]-2-butyl-4-chloro-5-hydroxymethylimidazole The organic phase is charged to a 100 mL round bottomed flask equipped with condenser, thermometer, and nitrogen. Also charged to the flask is 2.56 g 2-butyl-4-chloroimidazole-5-carboxaldehyde (0.0137 mole), 9.5 mL water, 2.8 mL 10N NaOH, and 1.2 mL aliquot 336. The two-phase system is stirred overnight at room temperature. To the completed reaction mass is added 0.48 g NaBH4 (0.0127 mole) and the reaction mass is again stirred overnight at room temperature. Upon completion, the reaction mass is washed with 30 mL water and the aqueous phase discarded. The organic phase is entered into a 100 mL round-bottomed flask equipped with thermometer, distillation head-condenser, receiver and addition flask. Methylene chloride and carbon tetrachloride are distilled and reaction volume replaced with 25 mL toluene. Distillation is continued until the pot temperature reaches ~110 C. The reaction mass is cooled to ~40 C. and then diluted with 15 mL ethyl acetate and 20 mL n-heptane. A seed crystal is added and the reaction mass is further cooled to 0-10 C. and stirred for 1.0-2.0 hours. The slurry is filtered through a Buchner funnel, and solids are rinsed with small amount of cold toluene/ethyl acetate. Solids are dried in a vacuum oven overnight to give 5.91 grams; 51.7% yield (based on 2-butyl-4-chloro-imidazole-5-carboxaldehyde or 47.2% yield (based on 2-(triphenylmethyltetrazol-5-yl)-4'-methylbiphenyl. Crude material was recrystallized from 30 mL toluene to give 4.57 grams product (77.33% recovery) with M.P.=161-162.5 C. |
47.2% | With sodium hydroxide; sodium tetrahydroborate; In water; toluene; | Part D: Preparation of 1-[(2'-(Triphenylmethyltetrazol-5-yl)biphenyl-4-yl)methyl]-2-butyl-4-chloro-5-hydroxymethylimidazole The organic phase is charged to a 100 mL round bottomed flask equipped with condenser, thermometer, and nitrogen. Also charged to the flask is 2.56 g 2-butyl-4-chloroimidazole-5-carboxaldehyde (0.0137 mole), 9.5 mL water, 2.8 mL 10 N NaOH, and 1.2 mL aliquot 336. The two-phase system is stirred overnight at room temperature. To the compete reaction mass is added 0.48 g NaBH4 (0.0127 mole) and the reaction mass is again stirred overnight at room temperature. Upon completion, the reaction mass is washed with 30 mL water and the aqueous phase discarded. The organic phase is entered into a 100 mL round-bottomed flask equipped with thermometer, distillation head-condenser, receiver and addition flask. Methylene chloride and carbon tetrachloride are distilled and reaction volume replaced with 25 mL toluene. Distillation is continued until the pot temperature reaches ~11 C. The reaction mass is cooled to ~40 C. and then diluted with 15 mL ethyl acetate and 20 mL n-heptane. A seed crystals is added and the reaction mass is further cooled to 0-10 C. and stirred for 1.0-2.0 hours. The slurry is filtered through a Buchner funnel, and solids are rinsed with small amount of cold toluene/ethyl acetate. Solids are dried in a vacuum oven overnight to give 5.91 grams; 51.7% yield (based on 2-butyl-4-chloro-imidazole-5-carboxaldehyde or 47.2% yield (based on 2-(triphenylmethyltetrazol-5-yl)-4'-methylbiphenyl. Crude material was recrystallized from 30 mL toluene to give 4.57 grams product (77.33% recovery) with M.P. =161-162.5 C. |
Yield | Reaction Conditions | Operation in experiment |
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With NH4Ca(NO3)3; sodium hydroxide In acetic acid | C Preparation of 2-n-Butyl-4-chloroimidazole-5-carboxaldehyde Part C Preparation of 2-n-Butyl-4-chloroimidazole-5-carboxaldehyde 2-n-Butyl-4-chloro-5-hydroxymethylimidazole (50.0 g, 265 mmol, 1 eq.) was dissolved in glacial acetic acid (150 mL). A 1N cerricammonium nitrate (CAN) solution (575.0 mL, 595 mmol, 2.25 eq.) was then added dropwise to the stirred imidazole solution maintaining the temperature at 20°-30° C. After the addition was complete, an additional 10 mL of 1N CAN solution was added so that the mixture remained orange. After 3 hours, the reaction was cooled on ice and 50% NaOH (210 mL) was added to neutralize the acetic acid. The product precipitated. The pH was adjusted to 6 and the solids were filtered, washed with water (3*500 mL) and dried under high vacuum to yield 38.13 g of a white powder; M.P. 92.5°-93.5° C. NMR (200 MHz, CDCl3): δ11.83 (m, 1H); 9.64 (s, 1H); 2.85 (t, 2H, J= 7 Hz); 1.78 (t of t, 2H, J=7,7 Hz); 1.38 (t of q, 2H, J=7,7 Hz); 0.93 (t, 3H, J=7 Hz). Anal. calcd. for C8 H11 ClN2 O: C, 51.48; H, 5.94; Cl, 19.00; N, 15.01. Found: C, 51.75; H, 5.82; Cl, 18.73; N, 14.87. | |
With NH4Ca(NO3)3; sodium hydroxide In acetic acid | C Part C: Part C: Preparation of 2-n-Butyl-4-chloroimidazole-5-carboxaldehyde 2-n-Butyl-4-chloro-5-hydroxymethylimidazole (50.0 g, 265 mmol, 1 eq.) was dissolved in glacial acetic acid (150 mL). A 1 N cerricammonium nitrate (CAN) solution (575.0 mL, 595 mmol, 2.25 eq.) was then added dropwise to the stirred imidazole solution maintaining the temperature at 20°-30° C. After the addition was complete, an additional 10 mL of 1 N CAN solution was added so that the mixture remained orange. After 3 hours, the reaction was cooled on ice and 50% NaOH (210 mL) was added to neutralize the acetic acid. The product precipitated. The pH was adjusted to 6 and the solids were filtered, washed with water (3*500 mL) and dried under high vacuum to yield 38.13 g of a white powder; M.P. 92.5-93.5° C. NMR (200 MHz, CDCl3): δ 11.83 (m, 1H); 9.64 (s, 1H); 2.85 (t, 2 H, J=7Hz); 1.78 (t of t, 2H, J=7,7Hz); 1.38 (t of q, 2H, J=7,7Hz); 0.93 (t, 3H, J=7Hz). Anal. calcd. for C8 H11 ClN2 O: C, 51.48; H, 5.94; Cl, 19.00; N, 15.01. Found: C, 51.75; H, 5.82; Cl, 18.73; N, 14.87. |
Yield | Reaction Conditions | Operation in experiment |
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73.2% | With potassium carbonate; In N,N-dimethyl-formamide; at -10℃; for 12h;Inert atmosphere; | A solution of compound 4 (87.5 mg, 0.47 mmol) and K2CO3 (135 mg, 0.98 mmol) in DMF (10 mL) was treated with compound 5 (200.5 mg, 0.74 mmol), and the mixture was stirred at -10 C under nitrogen for 12 h. The resulting mixture was diluted with water and extracted with ethyl acetate (30 mL * 4). The organic layer was washed with saturated salt water (40 mL * 4) and dried over MgSO4. After filtration, the solvent was removed under reduced pressure. The resulting residue was purified by column chromatography to give 6 (163 mg) as a yellow solid. Yield: 73.2%. 1H NMR (400 MHz, CDCl3, ppm) delta: 9.78 (s, 1H), 7.76-7.43 (m, 6H), 7.18 (d, 2H), 5.62 (s, 2H), 2.68 (t, 2H), 1.71 (m, 2H), 1.36 (m, 2H), 0.89 (t, 3H). MS (ESI): [M+H]+ calcd 378.1; found 378.2. |
With potassium carbonate; In hexane; ethyl acetate; N,N-dimethyl-formamide; | Part A Preparation of 2-n-Butyl-4-chloro-1-[(2'-cyanobiphenyl-4-yl)methyl]imidazole-5-carboxaldehyde 2-n-Butyl-4-chloroimidazole-5-carboxaldehyde (6.34 g, 34.0 mmol, 1 eq.), 4-bromomethyl-2'-cyanobiphenyl (9.25 g, 34.0 mmol, 1 eq.), potassium carbonate (5.17 g, 37.4 mmol, 1.1 eq.) and DMF (100 mL) were mixed and stirred at 25 C. overnight. The solids were filtered and the filtrate evaporated. The residue was chromatographed over silica gel in 9:1 to 1:1 hexane/ethyl acetate and crystallized from methylcyclohexane/n-butyl chloride yielding 9.70 g of a solid; m.p. 96.0-97.0 C. NMR (CDCl3): delta9.78 (s, 1H); 7.83-7.40 (m, 6H); 7.19 (d, 2H, J=9 Hz); 5.63 (s, 2H); 2.71 (t, 2H, J=7 Hz); 1.72 (t of t, 2H, J=7,7 Hz); 1.38 (t of q, 2H, J=7,7 Hz); 0.90 (t, 3 H, J=7 Hz). Anal. calcd. for C22 H20 ClN3 O: C, 69.93; H, 5.34; N, 11.12. Found: C, 69.64; H, 5.37; N, 11.21. | |
With sodium hydroxide;tetrabutylammomium bromide; In water; toluene; at 25 - 30℃; for 28 - 30h;Product distribution / selectivity; | EXAMPLE - I: Preparation of Losartan Potassium. Step (I): Preparation of l-(2'-Cyano biphenyl-4- methyl)-2-butyl-4-chloro-5-formyl imidazole of the formula 5 (Cyano aldehyde)A solution of Benzoyl peroxide (3.6 g) and Carbon tetrachloride (180 ml) was slowly added to a suspension of Ortho tolyl benzonitrile (90 gm, 0.466 M), l,3-Dibromo-5,5- dimethyl hydantoin (66 gm, 0.23M), Carbon tetrachloride (540 ml) at reflux temperature. (Exothermic, stop external heating during the addition of benzoyl peroxide solution). The reaction mixture was stirred for about 4 hours at reflux temperature. TLC Showed the absence of ortho tolyl benzonitrile. The precipitate was filtered, washed with carbon tetrachloride and dried. Solvent is evaporated under reduced pressure for about 3 hours at about 50C to give crude 4'-(Bromomethyl)-2-cyano biphenyl (Bromo OTBN) . The crude 4'-(Bromomethyl)-2-cyano biphenyl (Bromo OTBN) used further without purification to produce cyano aldehyde of the formula 5.To a stirred solution of Demineralised Water (360 ml), and sodium hydroxide flakes (14.4 gm, 0.36 M) was added toluene (900 ML), Tetrabutyl ammonium bromide (TBAB) (7.2 gm), 4'-(Bromomethyl)-2-cyano biphenyl (Bromo OTBN) (90 gm, 0.33 M) prepared as explained above and 2-butyl-4-chloro-5-formyl imidazole (65 gm, 0.34 M) at room temperature (25 - 30C). The solution was stirred at room temperature for 28-30 hours. After the reaction is completed by TLC, the organic layer is separated and the EPO <DP n="17"/>U aqueous layer is extracted with 200 ml of toluene. The combined organic layers were washed with 150 ml of 7% sodium hydroxide solution and then finally washed with 200 ml of water. The Organic layer was concentrated to give a Crude Cyano aldehyde and was then triturated with Isopropyl alcohol to give Cyano aldehyde which is (l-(2'- Cyano biphenyl-4-methyl)-2-butyl-4-chloro-5-formyl imidazole ) of the formula 5 .Yield 83% .Melting point: 107 - 108C.HPLC Purity: > 98%IR. v max (KBR): 2218 ( - CN), 1662.40 ( - CHO ) 1K NMR (CDC13) delta , 0.91 (t, 3H), 1.38 (sext, 2H), 1.73 (quint, 2H), 2.67 ( t, 2H ), 5.61(s, 2H ), 7.16 - 7.77 ( m, 8H), 9.77 ( s, IH).13C NMR (CDC13) delta , 13.51, 22.18, 26.33, 29.04, 47.74, 110.05, 118.36, 124.11,126.59, 127.65, 129.16, 129.81, 132.76, 133.61, 136.01, 137.69, 142.96, 144.33, 154.46,177.73 |
With sodium hydroxide;N-benzyl-N,N,N-triethylammonium chloride; In water; toluene; at 25 - 30℃; for 28 - 30h;Product distribution / selectivity; | To a stirred solution of DM Water (360 ml), sodium hydroxide flakes (14.4 gm, 0.36 M) was added toluene (900 ML), Benzyl triethyl ammonium chloride (TEBAC) (7.2 gm), 4'- (Bromomethyl)-2-cyanobiphenyl (90 gm, 0.33 M) and 2-butyl-4-chloro-5-formyl imidazole (65 gm, 0.34 M) at room temperature (25 - 300C). The solution was stirred at room temperature for 28-30 hours. After TLC completes the reaction, the organic layer is separated and the aqueous layer is extracted with 200 ml of toluene. The combined organic layers were washed with 150 ml of 7% sodium hydroxide solution and then finally washed with 200 ml of water. Toluene layer is proceed further without isolation of cyano aldehyde of the formula 5 . | |
With sodium hydroxide;N-benzyl-N,N,N-triethylammonium chloride; In water; toluene; at 25 - 30℃; for 28 - 30h;Product distribution / selectivity; | Step (I): Preparation of l-(2'-Cyano biphenyl-4-methyl)-2-butyl-4-chloro-5-formyl imidazole of the formula 5 (cyano aldehyde)A solution of Benzoyl peroxide (3.6 g) and Methylene chloride (180 ml) was slowly added to a suspension of Ortho tolyl benzonitrile (90 gm, 0.466 M), l,3-Dibromo-5,5- dimethyl hydantoin (66 gm, 0.23M), Methylene chloride (540 ml) at reflux temperature.(Exothermic, stop external heating during the addition of benzoyl peroxide solution). The EPO <DP n="20"/>reaction mixture was stirred for about 4 hours at reflux temperature. TLC Showed the absence of ortho tolyl benzonitrile. The precipitate was filtered, washed with Methylene chloride and dried . solvent is evaporated under reduced pressure for about 3 hours at about 50C to give crude 4>-(Bromomethyl)-2-cyano biphenyl (Bromo OTBN). The Crude 4'-(Bromomethyl)-2-cyano biphenyl (Bromo OTBN) was used further without purification to produce cyano aldehyde of the formula 5To a stirred solution of Demineralised Water (360 ml), sodium hydroxide flakes (14.4 gm, 0.36 M) was added toluene (900 ML), Benzyl triethyl ammonium chloride (TEBAC) (7.2 gm), 4'-(Bromomethyl)-2-cyano biphenyl (Bromo OTBN) (90 gm, 0.33 M) obtained by the process described above and 2-butyl-4-chloro-5-formyl imidazole (65 gm, 0.34 M) at room temperature (25 - 30C). The solution was stirred at room temperature for 28-30 hours. After TLC completed the reaction, the organic layer was separated and the aqueous layer was extracted with 200 ml of toluene. The combined organic layers were washed with 150 ml of 7% sodium hydroxide solution and then finally washed with 200 ml of water. The Organic layer was concentrated to give a Crude Cyano aldehyde and is then triturated with Isopropyl alcohol to give l-(2'-Cyano biphenyl-4-methyl)-2-butyl-4- chloro-5-formyl imidazole (which is Cyano aldehyde) of the formula 5 . Yield 83% , HPLC Purity: > 98% | |
With sodium hydroxide;tetrabutylammomium bromide; In water; toluene; at 25 - 30℃; for 28 - 30h;Product distribution / selectivity; | To a stirred solution of DM Water (360 ml), sodium hydroxide flakes (14.4 gm, 0.36 M) was added toluene (900 ML), Tetrabutyl ammonium bromide (TBAB) (7.2 gm), 4'- (Bromomethyl)-2-cyanobiphenyl (90 gm, 0.33 M) and 2-butyl-4-chloro-5-formyl imidazole (65 gm, 0.34 M) at room temperature (25 - 30C). The solution was stirred at room temperature for 28-30 hours. After TLC completed the reaction, the organic layer was separated and the aqueous layer was extracted with 200 ml of toluene. The combined organic layers were washed with 150 ml of 7% sodium hydroxide solution and then finally washed with 200 ml of water. Toluene layer was preceded further without isolation of cyano aldehyde of the formula 5 . To the stirred solution of toluene with compound of the formula 5 (approximately 1200 ml) was added sodium borohydride (12.6 gm, 0.33 M) at room temperature (25 - 300C). The reaction temperature was raised to 40 - 45C and methanol was added at 40 - 45C over a period of 1 hour. After the methanol addition, maintained for 3 hours at 40 - 45C. After TLC showed the conversion > 99%, it was cooled to 25 - 300C and 1100 ml of water was added. Further cooled to 10 - 15C. The cooled solution was filtered and washed with water to get 2-n-butyl-4-chloro-l-[2'-(cyanobiphenyl-4-yl)methyl]-5- (hydroxymethyl)-imidazole of the formula of the formula 6 (Yield 86%) Melting point: 154 - 156C. HPLC Purity. > 98% IR. v max (KBR): 3275.27 ( - CH2OH ), 2221 ( - CN), | |
With sodium hydroxide;tetrabutylammomium bromide; In water; toluene; for 24h; | B) To a solution of NaOH (134gm; 3.35mole) in water (2000ml), 2-Butyl4-Chloro-5- formyl Imidazole (BCFI) (313gm; 1.68mole) and Tetra butyl ammonium bromide (5.4gm; 0.59moles) was added. The toluene slurry prepared in part A was added to reaction mixture and stirred for 24 hours. Reaction was monitored by HPLC. After completion of reaction, organic layer was separated and methanol (1100ml) was added. Sodium Borohydride (23.75gm; 0.62mole) was added to the reaction mass. After completion of reaction, water was added to obtain solid, which was filtered and dried. Weight-556.85gm | |
With sodium hydroxide;tetrabutylammomium bromide; In water; toluene; at 25 - 30℃;Product distribution / selectivity; | EXAMPLE-1Preparation of Losartan Potassium; Step (I): Preparation of 2-n-butyl-4-chloro-1-[2'-(cyanobiphenyl-4-yl)methyl]-5-(hydroxymethyl)-imidazole of the formula (6) To a stirred solution of DM Water (360 ml), sodium hydroxide flakes (14.4 gm, 0.36 M) was added toluene (900 ML), Tetrabutyl ammonium bromide (TBAB) (7.2 gm), 4'-(Bromomethyl)-2-cyanobiphenyl (90 gm, 0.33 M) and 2-butyl-4-chloro-5-formyl imidazole (65 gm, 0.34 M) at room temperature (25-30 C.). The solution was stirred at room temperature for 28-30 hours. After TLC completed the reaction, the organic layer was separated and the aqueous layer was extracted with 200 ml of toluene. The combined organic layers were washed with 150 ml of 7% sodium hydroxide solution and then finally washed with 200 ml of water. Toluene layer was preceded further without isolation of cyano aldehyde of the formula 5.To the stirred solution of toluene with compound of the formula 5 (approximately 1200 ml) was added sodium borohydride (12.6 gm, 0.33 M) at room temperature (25-30 C.). The reaction temperature was raised to 40-45 C. and methanol was added at 40-45 C. over a period of 1 hour. After the methanol addition, maintained for 3 hours at 40-45 C. After TLC showed the conversion >99%, it was cooled to 25-30 C. and 1100 ml of water was added. Further cooled to 10-15 C. The cooled solution was filtered and washed with water to get 2-n-butyl-4-chloro-1-[2'-(cyanobiphenyl-4-yl)methyl]-5-(hydroxymethyl)-imidazole of the formula of the formula 6 (Yield 86%)Melting point 154-156 C.HPLC Purity. >98%IR. v max (KBR): 3275.27 (-CH2OH), 2221 (-CN),1H NMR (CDCl3) delta, 0.88 (t, 3H), 1.35 (sext, 2H), 1.69 (quint, 2H), 2.6 (t, 2H), 4.51 (s, 2H), 5.30 (s, 2H), 7.11-7.77 (m, 8H).13C NMR (CDCl3) delta, 13.64, 22.30, 26.63, 29.60, 47.11, 52.85, 111.05, 118.47, 124.99, 126.2, 127.0, 127.7, 129.29, 129.9, 132.8, 133.7, 136.72, 137.65, 144.52, 148.5MS (m/z)=380.2 (M+1). | |
With sodium hydroxide;tetrabutylammomium bromide; In water; toluene; at 25 - 30℃;Product distribution / selectivity; | EXAMPLE-1; Preparation of Losartan Potassium. Step (I): Preparation of 1-(2'-Cyano biphenyl-4-methyl)-2-butyl-4-chloro-5-formyl imidazole of the Formula 5 (Cyano Aldehyde) A solution of Benzoyl peroxide (3.6 g) and Carbon tetrachloride (180 ml) was slowly added to a suspension of Ortho tolyl benzonitrile (90 gm, 0.466 M), 1,3-Dibromo-5,5-dimethyl hydantoin (66 gm, 0.23M), Carbon tetrachloride (540 ml) at reflux temperature. (Exothermic, stop external heating during the addition of benzoyl peroxide solution). The reaction mixture was stirred for about 4 hours at reflux temperature. TLC Showed the absence of ortho tolyl benzonitrile. The precipitate was filtered, washed with carbon tetrachloride and dried. Solvent is evaporated under reduced pressure for about 3 hours at about 50 C. to give crude 4'-(Bromomethyl)-2-cyano biphenyl (Bromo OTBN). The crude 4'-(Bromomethyl)-2-cyano biphenyl (Bromo OTBN) used further without purification to produce cyano aldehyde of the formula 5.To a stirred solution of Demineralised' Water (360 ml), and sodium hydroxide flakes (14.4 gm, 0.36 M) was added toluene (900 mL), Tetrabutyl ammonium bromide (TBAB) (7.2 gm), 4'-(Bromomethyl)-2-cyano biphenyl (Bromo OTBN) (90 gm, 0.33 M) prepared as explained above and 2-butyl-4-chloro-5-formyl imidazole (65 gm, 0.34 M) at room temperature (25-30 C.). The solution was stirred at room temperature for 28-30 hours. After the reaction is completed by TLC, the organic layer is separated and the aqueous layer is extracted with 200 ml of toluene. The combined organic layers were washed with 150 ml of 7% sodium hydroxide solution and then finally washed with 200 ml of water. The Organic layer was concentrated to give a Crude Cyano aldehyde and was then triturated with Isopropyl alcohol to give Cyano aldehyde which is (1-(2'-Cyano biphenyl-4-methyl)-2-butyl-4-chloro-5-formyl imidazole) of the formula 5.Yield 83%.Melting point: 107-108 C.HPLC Purity: >98%IR. nu max (KBR): 2218 (-CN), 1662.40 (-CHO)1H NMR (CDCl3) delta, 0.91 (t, 3H), 1.38 (sext, 2H), 1.73 (quint, 2H), 2.67 (t, 2H), 5.61 (s, 2H), 7.16-7.77 (m, 8H), 9.77 (s, 1H).13C NMR (CDCl3) delta, 13.51, 22.18, 26.33, 29.04, 47.74, 110.05, 118.36, 124.11, 126.59, 127.65, 129.16, 129.81, 132.76, 133.61, 136.01, 137.69, 142.96, 144.33, 154.46, 177.73 | |
With potassium carbonate; In N,N-dimethyl-formamide; at 40℃; for 6h;Green chemistry; | 2-Butyl-4-chloro-1H-imidazole-5-carbaldehyde (0.185g, 1 mmol) and potassium carbonate (0.230 g, 1.67mmol) was added to a solution of 2-cyano-4?-bromomethylbiphenyl(0.299 g, 1.1 mmol) in DMF (5 mL) at room temperature. The resultingmixture was heated to 40C for 6 h. After completion of the reaction,methanol (1.5 g) was added followed by slow, dropwise addition ofsodium borohydride (0.023 g) over 10 min while the temperature wasmaintained at room temperature. After completion of the addition,the mixture was stirred at 40C for 1 h. Distilled water was added toquench the excess sodium borohydride, and the resultant mixture wasstirred for 20 min. The precipitated solid was filtered, washed withwater (2×10 mL) and toluene (2×10 mL) to give 2-butyl-4-chloro-5-hydroxymethyl-1-[(2?-cyano)-[1,1?-biphenyl]-4-yl]-methyl}-1Himidazole(7) (0.369 g, 93%) | |
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 14h; | this aldehyde is obtained by using 2-butyl-5-chloro-4,5-di- hydro-3H-imidazolylaldehyde (1 mmol), 4-(2-cy- anophenyl)benzyl bromide (1.2 mmol), potassium carbonate (2.5 mmol), and DMF (8 ml) as solvent and stirring for about 14 hours at RT. | |
With potassium carbonate; In N,N-dimethyl acetamide; at 20℃; for 5h; | 600 g of 2-butyl-4-chloro-lH-imidazole-5-carboxaldehyde prepared by the method of U.S. patent No. 4,355,040 and 858 g of 4'-bromomethyl-2-biphenylcarbonitrile were added to N,N-dimethylacetamide (4,800 ml) and then 457 g of potassium carbonate was slowly added thereto, followed by stirring the resulting solution at room <n="7"/>temperature for 5 hours. Methanol (1,800 ml) was added thereto and the resulting mixture was cooled to 5C. Then, 47.1 g of sodium borohydride was slowly added thereto while maintaining the temperature of the mixture at under 10C or lower, and then stirred at room temperature for an hour. Water (6,000 ml) was slowly added to the resulting mixture to induce the precipitation of a solid material, which was filtered, washed with a mixed solution of water and methanol, and dried at 40C to obtain 1,110 g of the title compound as a white crystalline powder.[50][51] Melting point: 158C to 161C[52] 1H-NMR (CDCl3, ppm): 7.8 (IH, d), 7.68 (IH, t), 7.5 (4H, m), 7.1 (2H, d), 5.3 (2H, s), 4.6 (2H, s), 2.7 (IH, br), 2.6 (2H, m), 1.7 (2H, m), 1.4 (2H, m), 0.9 (3H, t). | |
With potassium carbonate; In hexane; ethyl acetate; N,N-dimethyl-formamide; | Part A: Preparation of 2-n-Butyl-4-chloro-1-[(2'-cyanobiphenyl-4-yl)methyl]imidazole-5-carboxaldehyde 2-n-Butyl-4-chloroimidazole-5-carboxaldehyde (6.34 g, 34.0 mmol), 1 eq.), 4-bromomethyl-2'-cyanobiphenyl (9.25 g, 34.0 mmol, 1 eq.), potassium carbonate (5.17 g, 37.4 mmol., 1.1 eq.) and DMF (100 mL) were mixed and stirred at 25 C. overnight. The solids were filtered and the filtrate evaporated. The residue wash chromatography over silica gel in 9:1 to 1:1 hexane/ethyl acetate and crystallized from methylcylcohexane/n-butyl chloride yielding 9.70 g of a solid; m.p. 96.0-97.0 C. NMR (CDCl3): delta 9.78 (s, 1H); 7.83-7.40 (m, 6H); 7.19 (d, 2H, J=9Hz); 5.63 (s, 2H); 2.71 (t, 2H, J=7Hz); 1.72 (t of t, 2H, J=7,7Hz); 1.38 (t of q, 2H, J=7,7Hz); 0.90 (t, 3H, J= 7Hz). Anal. calcd. for C22 H20 ClN3 O: C, 69.93; H, 5.34; N, 11.12. Found: C, 69.64; H, 5.37; N, 11.21. | |
With tetraethylammonium bromide; sodium carbonate; In toluene; at 90 - 95℃; | Put 365 g of toluene into the reaction bottle, and add 56 g of compound 1, 33.6 g of sodium carbonate and 5.6 g of tetraethylammonium bromide under slow stirring, speed up the stirring and raise the temperature to 90-95 C.The temperature was controlled at 90-95 C, and 142 g of a toluene solution of 39.2 g of compound 2 was added dropwise. The addition time was controlled for 3-4 hours. After the addition was completed, the reaction was maintained for 4-5 hours.After the reaction was completed, 140 g of water was added and the layers were separated. The toluene layer was added with 1 g of tetraethylammonium bromide and the temperature was controlled at 20-25 C.A mixed solution of sodium borohydride and sodium hydroxide (9g sodium borohydride, 5.6g sodium hydroxide, 24.5g water) prepared in advance was added dropwise. After the dropwise addition, the reaction was held at 20-25 C for 4 hours.The temperature was further raised to 80-85 C, and the reaction was kept warm. After the reaction was completed, 105 g of water was added, and the temperature was stirred at 80-85 C for 10 minutes. The mixture was transferred to a separatory funnel and allowed to stand and separate.The organic layer was transferred to a four-necked flask, and 8.4 g of diethylacetamide was added, stirred and heated to 85-90 C, and the crystals were maintained at a temperature.After the crystallization is completed, the temperature is reduced to 0-5 C, and the obtained crystals are filtered.It was dried under vacuum at 60 C. for 5-6 h to obtain 71.9 g of compound 4 in a yield of 92%. |
Yield | Reaction Conditions | Operation in experiment |
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With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; | 4'-(2-Butyl-4-chloro-5-formylimidazol-1-ylmethyl)biphenyl-2-carboxylic acid t-butyl ester (4a): 2-Butyl-5-chloro-3H-imidazole-4-carbaldehyde (9.9 g, 53.3 mmol), 4'-bromomethylbiphenyl-2-carboxylic acid t-butyl ester (18.5 g, 53.3 mmol), and K2CO3 (7.4 g, 53.3 mmol) were combined in DMF (200 mL) and stirred at room temperature overnight. The reaction was quenched with water, extracted with EtOAc, washed with saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. The crude mixture was purified by flash chromatography (0-40% EtOAc:hexanes) to yield 21.5 g of intermediate (4a). |
Yield | Reaction Conditions | Operation in experiment |
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86% | With potassium carbonate; In N,N-dimethyl-formamide; for 3h; | A solution of 4-bromomethylbenzeneboronic acid (3.63 g) in anhydrous dimethylformamide (9.8 mL) was slowly added (2 h) to a mixture of 2-n-butyl-4-chloro-1H-imidazole-5-carbaldehyde (2 g) and K2CO3 (5.92 g) finely pulverized in anhydrous dimethylformamide (8.0 mL) under inert atmosphere. When the addition was completed, 4-bromomethylbenzeneboronic acid (0.48 g) was further added. The reaction was stirred for 1 h. The mixture was filtered and the solid was washed with ethyl acetate (48 mL). The filtrate and washings were collected and poured on to H2O (60 mL). The aqueous layer was adjusted to neutral pH with 1 M HCI. The organic layer was washed with aqueous NaCl saturated solution (brine, 96 mL x 4) and dried over anhydrous Na2SO4, then filtered and evaporated to dryness. The residue was stirred in a mixture of dichloromethane (34.3 mL) and 1 M HCl (34.3 mL) at 0-5 C for 2 h. The solid was filtered, washed with cold H2O (7 mL) and dried at room temperature giving 2.93 g (86 %). 1H NMR (400 MHz, CDCl3) delta 9.73 (s, 1 H, CHO), 7.70 (d, J = 7.6 Hz, 2 H, H-Ar), 7.01 (d, J = 7.6 Hz, 2 H, H-Ar), 5.55 (s, 2 H, CH2), 2.61 (t, J = 7.8 Hz, 2 H, CH2), 1.64 (m, 2 H, CH2), 1.32 (m, 2 H, CH2), 0.87 (t, J = 7.0 Hz, 3 H, CH3) ppm. 13C NMR (100 MHz, CDCl3) delta 177.9 (CHO), 154.7 (C-imidazole), 142.8 (C-ipso-Ar-B), 137.2 (C), 134.1 (CH), 128.5 (C), 125.3 (CH), 124.1 (C), 48.1 (CH2), 28.9 (CH2), 26.2 (CH2), 20.1 (CH2), 13.3 (CH3) ppm. IR (upsilon): 3402 (OH), 1673 (C=O), 1338 (B-O and C-O), 1193 (B-C) cm-1. MS-ES(+): 321 (M++1) |
Yield | Reaction Conditions | Operation in experiment |
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74 - 81% | Example 3; Preparation of BFI from BCFI; In an autoclave 50 g (0.27 mol) of 2-butyl-4-chloro-5-formylimidazole was brought in 500 ml of methanol and 32 g of triethylamine was added hereto, followed by 2.5 g of 10% palladium on carbon. The hydrogen pressure in the autoclave was kept at 4-5 kg/cm2 at 20-25 C. for 8-10 hrs, while monitoring the reaction by thin layer chromatography.At the end of the reaction, the mixture was taken from the autoclave and the solvent was removed under reduced pressure below 50 C. 250 ml of deionised water was added to the dried mixture and it was cooled to 25-30 C. The pH was adjusted to 1.2 using diluted hydrochloric acid. The aqueous layer was then washed with 50 ml of dichloromethane to remove traces of the starting material. The pH was then readjusted to 6.8-7.5 using a sodium carbonate solution, and the aqueous layer was extracted with 3×150 ml of dichloromethane. Afterwards, the dichloromethane was dried with sodium sulfate for 30 min and then filtered to remove the sodium sulfate. This was followed by evaporation to dryness. 250 ml of hexane was added hereto at a temperature of 45 C., and then cooled to 10-15 C. for 30 min, to obtain 2-butyl-5-formylimidazole.The product was isolated by filtration followed by washing with 100 ml of chilled hexane (10 C.) and dried at 55-60 C. for 6 hrs. The yield of the dried material was 30-33 g (0.20-0.22 mol; 74-81%). The analysis of this product by HPLC gave 99.1% purity, confirmed by IR.; Example 4; Preparation of BFI from Valeronitrile; 58 g (1.2 mol) of valeronitrile was charged in 34 ml of methanol and cooled to -5 to -10 C. Hydrochloric acid gas was slowly passed through for 15-18 hrs. The nitrogen pressure was kept at 1.5 to 2.0 kg/cm2 for 14 hrs at 0-15 C., followed by the addition of 32 ml of methanol while stirring for 60 min.The reaction mass was transferred to a methanolic ammonia solution (12-15 wt % and stirred for 3 hrs at 20-30 C., while keeping the pH at 8.0-9.0. Precipitated material was filtered off and washed with 15 ml of methanol. The filtrate was concentrated by distillation under reduced pressure (650-700 mm Hg) at a temperature not exceeding 90 C., followed by cooling to give pentanimidate.50 g (0.666 mol) of glycine was added to a freshly prepared methanolic sodium hydroxide solution (sodium hydroxide 26.64 g (0.666 mol) in 250 ml of methanol) at 0 C. and stirred for 15 min. The above prepared, 80 g pentanimidate was added at 0-5 C. in 10-15 min and the mixture was stirred for another 16 hrs at room temperature. The solvent was distilled under vacuum while keeping the temperature below 50 C.500 ml of toluene was added to the above reaction mass, followed by 0.25 g of Copper(II) trifluoromethanesulfonate. Then 320 g (2.08 mol) of phosphorous oxychloride and 150 g (2.05 mol) N,N-dimethylformamide were added successively in 60 minutes and 2 hours, respectively. The reaction mixture was heated to 100 C. and stirred for another 2 hrs, then cooled to 30 C. and quenched in 260 ml of cooled water having a temperature below 25 C. 30 g of filter aid (hi-flow) was added and the pH adjusted to 1.2 with 440 ml of 30% aqueous sodium hydroxide solution.It was then filtered and washed with 100 ml of toluene, and the layers were separated. The toluene layer was washed twice with deionised water (400 ml each time), and 8 g of activated carbon was added to the toluene and stirred for 30 min at 30-35 C., followed by filtration and washing with 100 ml of toluene. All toluene layers were combined and concentrated to dryness under vacuum below 55 C. The concentrated mass was cooled to 30 C. The weight of the residue was 96 g.500 ml of methanol and 60 g of triethylamine was added hereto, followed by 4.5 g of 10% palladium on carbon in the autoclave. The hydrogen pressure was kept at 4-5 kg/cm at 20-25 C. for 8-10 hrs, while monitoring the reaction by thin layer chromatography.At the end of the reaction, the mixture was unloaded from the autoclave. The solvent was removed under reduced pressure, thereby keeping the temperature below 50 C. 250 ml of deionised water was added and it was cooled to 25-30 C. The pH was adjusted to 1.2 with diluted hydrochloric acid and the aqueous layer was extracted with 60 ml of dichloromethane to remove traces of the starting material. The pH was then readjusted to 6.8-7.5 using sodium carbonate solution, and the aqueous layer was extracted with 3×160 ml of dichloromethane. The dichloromethane solution was dried with sodium sulfate for 30 min and the sodium sulfate removed by filtering. The filtrate was evaporated to dryness, 300 ml of hexane was added at 45 C., and the mixture was cooled to 10-15 C. and maintained at that temperature for another 30 min, to obtain 2-butyl-5-formylimidazole.The product was isolated by filtration followed by washing with 150 ml of chilled hexane (10 C.) and dried at 55-60 C. for 6 hrs, with a yield of 58 g. Analysis of the product by HPLC showed 99.0% purity. The yield wa... |
Yield | Reaction Conditions | Operation in experiment |
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92% | With potassium carbonate; In acetone; for 2h;Reflux; | 2-Butyl-4-chloro-1H-imidazole-5-carbaldehyde 1 (5.0 g, 27.6 mmol) in acetone (50 mL), K2CO3 (7.5 g, 55.2 mmol), 1-bromo-3-chloro propane (4.3 g, 27.6 mmol) were added and refluxed for 2 h. The reaction mixture was cooled to room temperature, filtered and the filtrate was concentrated under reduced pressure. Crude residue thus obtained was purified over silica gel flash column chromatography to give 2-butyl-4-chloro-1-(3-chloropropyl)-1H-imidazole-5-carbaldehyde. Compound 2 as light yellow syrup (6.4 g), Yield = 92%; 1H NMR (300 MHz, CDCl3) delta 9.71 (s, 1H), 4.38 (t, J = 7.17 Hz, 2H),3.58 (t, J = 7.17 Hz, 2H), 2.74 (t, J = 7.74 Hz, 2H), 2.15-2.24 (m, 2H), 1.72-1.82 (m, 2H), 1.37-1.49 (m, 2H), 0.96 (t, J = 7.36 Hz, 3H). 13C NMR (125 MHz, CDCl3) delta 177.6, 154.0, 143.2, 124.0, 42.8, 41.4, 32.9, 29.5, 26.1, 22.3, 13.6. IR (KBr) 2960, 2932, 2872, 1665, 1516, 1437, 1381, 1275, 1237, 844, 747 cm-1. MS (ESI) m/z 263 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
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[0056] An aqueous solution of sodium hydroxide (15 grams in 700 ml water) was added to a mixture of 2-n-butyl-4-chloro-5-formyl imidazole (54 grams), and tetrabutyl ammonium bromide (14 grams) in toluene (1000 ml), and the resulting reaction mixture was stirred for 20-30 minutes at a temperature of 30-35 C. N-(triphenyl methyl)-5-[4'-(bromomethyl)biphenyl-2-yl]tetrazole) (170 grams) was added to the resulting reaction mixture and stirred for another 33-35 hours. The completion of the reaction was confirmed by Thin Layer Chromatographic (TLC) testing of aliquots withdrawn. The organic layer was separated from the reaction mass and washed with dilute a sodium hydroxide solution (40 ml), and further with water (600 ml). Sodium borohydride (4.0 grams) was added then to the organic layer, and heated to a temperature of 40-45 C., and methanol (40 ml) was added and the temperature maintained for 1½-2 hours. The reaction mass was washed with water (3×200 ml), cooled to a temperature of 0-5 C. and stirred for 1½-2 hours to allow the separation of the solid, which was filtered and dried to afford the desired Trityl Losartan compound (140-145 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium hydroxide In PEG-400 at 40℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88.0% | Example-1 [117] [118] Preparation of 2-n-Butyl-4-chloro-l-[2'-(cyanobiphenyl-4-yl) methyl] -5-(hydroxymethyl)-imidazole (IV); [119] A mixture of 4'-Bromomethyl-2-cyanobiphenyl(II) (125.0 g), l-Methyl-2-pyrrolidinone (NMP) (375.0 ml), anhydrous potassium carbonate (76.0 g) and 2-Butyl-4-chloro-5-formylimidazole (III) (90.0 g) was heated at 7O0C to 750C for about 4-5 hrs. Sodium borohydride (18.0 g) was charged to the reaction mixture at 3O0C. Water (1875.0 ml) was added to it and isopropanol (562.5 ml) was added to the wet cake and heated at 75-8O0C for 1.5 hours. The reaction mixture was cooled at room temperature and filtered. The solid was suck dried and dried in oven to give the title compound (153.0g).[120] Yield: 88.0%[121] Purity (By HPLC): 99.1% | |
With tetrabutylammomium bromide; sodium hydroxide; In water; toluene; at 20℃; | First Step: successively added toluene 200ml, Bromobiphenyl compound 45g, 2-Butyl-4-chloro-5-formylimidazole 30g, 0.5g of tetrabutylammonium bromide; aqueous sodium hydroxide solution was added at room temperature to the reaction starting material the reaction was complete, The layers were separated and washed. The organic layer was added a reducing agent, water crystallization, filtration and drying, to obtain the compound of formula 1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89.6% | 2-Butyl-4-chloro-1H-imidazole-5-carbaldehyde 1 (5.0 g, 26.7 mmol) in DMF (25 mL), NaH (1.28 g, 53.46 mmol) was added at 0 C. After 30 min, CH3I (4.71 g, 32.07 mmol) was added and stirred for 4 h at rt. The reaction mixture was quenched with methanol (3 mL), DMF was evaporated under vacuum, and ice cold H2O/EtOAc 1:1 (30 mL) was added. The ethyl acetate layer was washed with water (25 mL) and brine (25 mL), dried over anhydrous sodium sulphate and evaporated under vacuum. Purification over silica gel flash column chromatography gave 2-butyl-4-chloro-1-methyl-1H-imidazole-5-carbaldehyde 2 (4.79 g, 89.6%) as pale yellow syrup. 1H NMR (300 MHz, CDCl3) delta 9.72 (s, 1H), 3.85 (s, 3H), 2.65 (t, J = 7.5 Hz, 2H), 1.68-1.78 (m, 2H) 1.36-1.46 (m, 2H), 0.97 (t, J = 7.5 Hz, 3H). IR (neat) 2958, 2866, 1668, 1511, 1471, 1367, 1280, 866, 706 cm-1 MS (ESI) m/z 201 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With sodium cyanide; manganese(IV) oxide; acetic acid; at 60℃; for 20h; | To a solution of 7 (3.00 g, 16.07 mmol) in EtOH (120 mL) was added NaCN (4.17 g, 85.2 mmol), AcOH (1.54 g, 25.71 mmol) and MnO2 (29.34 g, 337.47 mmol). The mixture was stirred for 20 h at 60 C. After cooling, the mixture was filtered and the solvent was evaporated under reduced pressure. The residue was dissolved in Et2O (60 mL) and washed with H2O (30 mL). The organic phase was dried (MgSO4), the desiccant was filtered off and the solvent was evaporated under reduced pressure to give 8 as a dark brown oil (3.20 g, 86%): Rf = 0.21 (hexane/AcOEt/MeOH 4:1:0.05); 1H NMR (200 MHz, CDCl3): delta = 10.71 (bs, 1H), 4.34 (q, J = 7.1 Hz, 2H), 2.70 (t, J = 7.6 Hz, 2H), 1.70 (quin, J = 7.5 Hz, 2H), 1.43-1.22 (m, 5H), 0.89 ppm (t, J = 7.3 Hz, 3H); 13C NMR (300 MHz, CD3OD): delta = 160.3, 152.5, 134.9, 118.3, 61.8, 31.4, 28.8, 23.1, 14.6, 13.9 ppm; IR (CHCl3): nu = 3617, 3270, 3019, 2965, 2400, 1682, 1508, 1423, 1215, 1073, 757, 668 cm-1; MS (EI, 70 eV) m/z (%): 230 (8) [M + H]+, 188 (91) [M - 42]+, 142 (100) [M - 88]+; Anal. Calcd for C10H15ClN2O2: C 52.06, H 6.55, N 12.14, found: C 51.99, H 6.59, N 12.23. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With sodium chlorite; sodium dihydrogen phosphate monohydrate; 2-methyl-but-2-ene; In tetrahydrofuran; water; tert-butyl alcohol; at 20℃; for 12h; | A solution of sodium chlorite (2.0 g, 21.6 mmol) and sodium dihydrogen phosphate monohydrate (1.8 g, 12.9 mmol) in water (4.8 ml.) was added to a stirred solution of 4-chloro-2-butyl-1 /-/-imidazole-5-carbaldehyde (0.400 g, 2.1 mmol), 2-methyl-2- butene (13.4 ml. of a 2M solution in THF, 26.8 mmol), and terf-butanol (1.6 ml.) in THF (6.7 ml_). The reaction mixture was stirred at RT for 12h. The aqueous phase was separated and extracted with EtOAc (4 x 40 ml_). The combined extracts were dried (Na2SO4), filtered, concentrated and the residue was triturated with diethyl ether to provide the title compound (0.41 1 g, 95%) as a white solid. 1H NMR (400 MHz, DMSO-d6) delta ppm 12.99 (br. s., 1 H), 12.88, (br. s., 1 H), 2.58 (t, 2 H), 1.59 (quint, 2 H), 1.20 - 1.31 (sex, 2 H), 0.87 (t, 3 H). ES-LCMS: m/z 203.1 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | Example 27 To a mixture (not dissolved) of {2'-[1-(o-methoxybenzyl)-1H-tetrazol-5-yl]biphenyl-4-yl}methanol (compound 4c, 196 mg, 0.525 mmol) and acetonitrile (1.0 mL) was added bromotrimethylsilane (0.140 mL, 162 mg, 1.06 mmol), and the mixture was heated with stirring for 7 hr in a bath at 50-60 C., and allowed to cool to room temperature. Potassium carbonate (74.8 mg, 0.541 mmol), 2-butyl-4-chloro-1H-imidazole-5-carbaldehyde (compound 6, 101 mg, 0.541) and acetonitrile (0.50 mL) were added thereto, and the mixture was heated with stirring for 3 hr in a bath at 50 C. The reaction mixture was allowed to cool to room temperature, ethyl acetate (20 mL) was added thereto, and the mixture was filtered, and the insoluble material was washed with ethyl acetate (10 mL). The obtained ethyl acetate solution was concentrated under reduced pressure, and the residue was purified by thin layer silica gel column chromatography (hexane /ethyl acetate (1:1)) to give the objective compound (compound 7b, 384 mg, 73%).IR (neat): 1664, 1604 cm-1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With potassium carbonate; In ISOPROPYLAMIDE; at -10 - 20℃; for 8h;Inert atmosphere; | Step 1 Under a nitrogen atmosphere, into a 50 mL pear-shaped flask were charged compound 5a (93.0 mg, 0.213 mmol), compound 6 (40.5 mg, 0.217 mmol), DMA (1.00 g) and potassium carbonate (30.3 mg, 0.219 mmol), and the mixture was reacted at -10 C. for 4 hr, and stirred at room temperature for 4 hr. Then, ethyl acetate (10 mL) was added thereto, the mixture was filtered, and the solid was washed with ethyl acetate (5 mL). The filtrate and washing were combined, concentrated, and vacuum-dried at room temperature to give a pale- yellow liquid (0.11 g, yield 95%). The obtained crude product was purified by silica gel column chromatography (ethyl acetate /hexane-1/2) to give compound 7a (0.106 mg, yield 92%) as a colorless solid.1H-NMR (400 MHz, CDCl3) delta=0.90 (3H, t, J=7.2), 1.30-1.42 (2H, m), 1.61-1.73 (2H, m), 2.61 (2H, t, J=7.6), 3.72 (3H, s), 4.74 (2H, s), 5.52 (2H, s), 6.66-6.73 (4H, m), 6.97 (2H, d, J=8.0), 7.09 (2H, d, J=8.0), 7.34 (1H, d, J=7.6), 7.46 (1H, t, J=7.2), 7.53 (1H, d, J=7.6), 7.65 (1H, t, J=7.6), 9.75 (1H, s).13C-NMR (400 MHz, CDCl3) delta=122.64, 124.11, 124.87, 135.35, 138.45, 140.74, 143.03, 153.92, 154.30, 159.52 (10s), 113.98, 126.73, 127.90, 129.07, 129.26, 130.10, 131.07, 131.43, 177.64 (9d), 22.49, 26.60, 29.32, 47.88, 50.54 (5t), 13.83, 55.30 (2q).IR(KBr) nu(cm-1):1664 EIMS (m/z):540(M+-1) melting point: 47.1-48.6 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54.5% | With potassium carbonate; In acetonitrile; at 50℃; for 6h;Inert atmosphere; | To a solution of 7a (2.262 g, 7 mmol), 2-butyl-4-chloro-1H-imidazole-5-carboxaldehyde (1.437 g, 7.7 mmol) and 25 mL of acetonitrile was added potassium carbonate (1.449 g, 10.5 mmol).The mixture was stirred at 50 C under nitrogen for 6 h.The mixture was diluted with ethylacetate.The organic layer was washed with water (30 mL * 3) and brine (30 mL * 3), dried over MgSO4.After filtration, the solvent was removed under reduced pressure. The residue was purified by flash column chromatography with petroleum ether-ethyl acetate (3/1) as eluant to afford a white solid. Yield: 54.5%. 1H NMR(CDCl3, 400 MHz) delta: 9.94(1H, s, C-CHO),7.58(1H, dd, J1 = 9.2 Hz, J2 = 2.8 Hz, Ph-H), 7.32?7.22(4H, m, Ph-H), 7.08(2H, d, J = 8.4 Hz, Ph-H), 5.23(2H, s, Ph-CH2-N), 3.67(3H, s, Ph-COOCH3), 2.67(2H, t, J = 8.0 Hz, CH2CH2CH2CH3), 1.71(2H, m, J = 8.0 Hz, CH2CH2CH2CH3), 1.37(2H, m, J = 8.0 Hz, CH2CH2CH2CH3),0.90(3H, t, J = 8.0 Hz, CH2CH2CH2CH3); 13C NMR (CDCl3, 400 MHz) delta: 182.97, 169.50, 165.32,162.85, 152.70, 143.07, 140.18, 136.69, 135.71, 134.85, 131.63, 128.31, 127.27, 120.87, 119.36, 54.50, 49.22, 32.01, 31.53, 29.86, 24.69, 15.99, 12.31; ESI-MS(m/z): 431.2 [M+1]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34.1% | With potassium carbonate; In acetonitrile; at 50℃; for 6h;Inert atmosphere; Reflux; | General procedure: To a solution of 7a (2.262 g, 7 mmol), 2-butyl-4-chloro-1H-imidazole-5-carboxaldehyde (1.437 g, 7.7 mmol) and 25 mL of acetonitrile was added potassium carbonate (1.449 g, 10.5 mmol).The mixture was stirred at 50 C under nitrogen for 6 h.The mixture was diluted with ethylacetate.The organic layer was washed with water (30 mL * 3) and brine (30 mL * 3), dried over MgSO4.After filtration, the solvent was removed under reduced pressure. The residue was purified by flash column chromatography with petroleum ether-ethyl acetate (3/1) as eluant to afford a white solid. Compound 8b was prepared as the procedure of 8a. Yield: 34.1%. 1H NMR (CDCl3, 400 MHz) delta: 9.92(1H, s, C-CHO), 7.91(1H, dd, J1 = 8.4 Hz, J2 = 5.6 Hz, Ph-H), 7.28(2H, t, J = 8.0 Hz, Ph-H), 7.11(3H, dd, J1 = 11.2 Hz, J2 = 2.4 Hz, Ph-H, Ph-H),7.00(1H, dd, J1 = 9.2 Hz, J2 = 2.4 Hz, Ph-H), 5.23(2H, s, Ph-CH2-N), 3.64(3H, s, Ph-COOCH3), 2.67(2H, t, J = 7.6 Hz, CH2CH2CH2CH3), 1.71(2H, m, J = 7.6 Hz, CH2CH2CH2CH3), 1.37(2H, m, J = 7.6 Hz, CH2CH2CH2CH3), 0.90(3H, t, J = 7.6 Hz, CH2CH2 CH2CH3). ESI-MS(m/z): 431.2 [M+1]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43.2% | With potassium carbonate; In acetonitrile; at 50℃; for 6h;Inert atmosphere; | General procedure: To a solution of 7a (2.262 g, 7 mmol), 2-butyl-4-chloro-1H-imidazole-5-carboxaldehyde (1.437 g, 7.7 mmol) and 25 mL of acetonitrile was added potassium carbonate (1.449 g, 10.5 mmol).The mixture was stirred at 50 C under nitrogen for 6 h.The mixture was diluted with ethylacetate.The organic layer was washed with water (30 mL * 3) and brine (30 mL * 3), dried over MgSO4.After filtration, the solvent was removed under reduced pressure. The residue was purified by flash column chromatography with petroleum ether-ethyl acetate (3/1) as eluant to afford a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76.9% | With potassium carbonate; In acetonitrile; at 80 - 85℃; for 20h; | Example 5-(1)(a) (0376) (0377) A mixture of IAL (0.2 g, 0.11 mmol), BBR (0.48 g, 1.18 mmol), potassium carbonate (0.25 g, 1.82 mmol) and acetonitrile (5 mL, 25 vol) was stirred at 80-85 C. for 20 hr. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the concentrated residue was purified by silica gel column chromatography (18-20% ethyl acetate/hexane) to give LALD (0.4 g, yield 76.9%). (0378) IR (KBr): numax=1665, 1517, 1459, 1275 cm-1; (0379) 1H NMR (CDCl3): delta=9.76 (s, 1H), 7.65-7.61 (m, 1H), 7.53 (dd, J=8.0, 1.2 Hz, 1H), 7.44 (dt, J=7.6, 1.2 Hz, 1H), 7.33 (dd, J=7.6, 1.2 Hz, 1H), 7.24-7.14 (m, 3H) 7.08 (d, J=8.0 Hz, 2H), 6.99 (d, J=8 Hz, 2H), 6.78 (d, J=7.6 Hz, 2H), 5.52 (s, 2H), 4.80 (s, 2H), 2.61 (t, J=7.6 Hz, 2H), 1.72-1.64 (m, 2H), 1.40-1.31 (m, 2H), 0.90 (t, J=7.2 Hz, 3H); (0380) Mass: 511 [M]+. |
74% | With potassium carbonate; In acetonitrile; at 25 - 85℃; for 20h;Inert atmosphere; | Into a 25-mL two-neck flask were sequentially added 2-butyl-4-chloro-1H-imidazole-5-carbaldehyde (5; 0.2 g, 1.11 mmol), bromide3 (0.48 g, 1.18 mmol), K2CO3 (0.25 g, 1.82 mmol) and MeCN(5 mL) under nitrogen atmosphere at 25 C. The reaction mixturewas heated at 80-85 C until completion (20 h). The mixture wascooled to 25 C, then filtered through a sintered funnel and washedwith MeCN (10 mL). The resulting mixture was concentrated underreduced pressure. The obtained crude product was purified usingcolumn chromatography (18-20% EtOAc in hexane) to give 6;yield: 0.419 g (74%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With ammonia In methanol for 18 - 20h; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: potassium carbonate / N,N-dimethyl-formamide / 14 h / 20 °C 2: potassium carbonate / methanol / 9 h / 20 °C | ||
Multi-step reaction with 2 steps 1: potassium carbonate / N,N-dimethyl-formamide / 14 h / 20 °C 2: potassium carbonate |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 14h; | This compound is obtained by using 2-butyl-5-chioro-4,5-dihydro-3H- imidazolylaldehyde (1 mmol), 1 -(bromomethyl)-4-phe- noxybenzene (1.2 mmol), potassium carbonate (2.5 mmol), and DMF (8 ml) as a solvent and stirringabout 14 hours at RT. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With hydrogenchloride; In ethanol;Reflux; | General procedure: A mixture of N-(aryl)-3-oxobutanamides (0.01 mol), 2-butyl-4-chloro-1H-imidazole-5 carbaldehyde (0.01 mol), urea (0.015 mol) and catalytic amount of concentrated hydrochloric acid in ethanol (30 ml) was heated under reflux condition for 20 to 22 hrs. The reaction mixture was kept at room temperature for 24 hrs. The product obtained was isolated and recrystallized from ethanol. 4-(2-butyl-4-chloro-1H-imidazol-5-yl)-6-methyl-2-oxo-N-phenyl-1,2,3,4 tetrahydropyrimidine-5-carboxamide (4a)Yield: 68%; mp = 176-178 C; IR (numax, cm-1, KBr): 3208, 3085, 2972, 2955, 2780, 1715, 1299, 744; 1H NMR (400 MHz, DMSO-d6, delta, ppm): 0.87 (t, 3H, -CH2CH2CH2CH3), 1.33 (m, 2H, -CH2CH2CH2CH3), 1.62 (m, 2H, -CH2CH2CH2CH3), 2.28 (s, 3H, CH3, 1,2,3,4-tetrahydropyrimidine), 2.90 (t, 2H, -CH2CH2CH2CH3), 5.58 (s, 1H, 1,2,3,4-tetrahydropyrimidine) 7.10-7.65 (m, 5H, aromatic ring), 9.65 (s, 1H, -NH of 1,2,3,4-tetrahydropyrimidine), 10.23 (s, 1H, -CONH), 12.73 (s, 1H, -NH of imidazole) ppm. 13C NMR (100 MHz, DMSO-d6, delta, ppm): 14.3, 17.6, 22.5, 27.5, 30.4, 49.0, 108.9, 121.5 (2), 122.6, 127.8, 128.7 (2), 134.4, 137.5, 146.0, 147.7, 150.1, 163.4; LCMS (ESI): m/z = 387.5 [M+]. Anal. Calcd. for C19H22ClN5O2: C, 58.84; H, 5.72; N, 18.06; Found: C, 58.79; H, 5.66; N, 18.17%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With hydrogenchloride; In ethanol;Reflux; | General procedure: A mixture of N-(aryl)-3-oxobutanamides (0.01 mol), 2-butyl-4-chloro-1H-imidazole-5 carbaldehyde (0.01 mol), urea (0.015 mol) and catalytic amount of concentrated hydrochloric acid in ethanol (30 ml) was heated under reflux condition for 20 to 22 hrs. The reaction mixture was kept at room temperature for 24 hrs. The product obtained was isolated and recrystallized from ethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With hydrogenchloride; In ethanol;Reflux; | General procedure: A mixture of N-(aryl)-3-oxobutanamides (0.01 mol), 2-butyl-4-chloro-1H-imidazole-5 carbaldehyde (0.01 mol), urea (0.015 mol) and catalytic amount of concentrated hydrochloric acid in ethanol (30 ml) was heated under reflux condition for 20 to 22 hrs. The reaction mixture was kept at room temperature for 24 hrs. The product obtained was isolated and recrystallized from ethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With hydrogenchloride; In ethanol;Reflux; | General procedure: A mixture of N-(aryl)-3-oxobutanamides (0.01 mol), 2-butyl-4-chloro-1H-imidazole-5 carbaldehyde (0.01 mol), urea (0.015 mol) and catalytic amount of concentrated hydrochloric acid in ethanol (30 ml) was heated under reflux condition for 20 to 22 hrs. The reaction mixture was kept at room temperature for 24 hrs. The product obtained was isolated and recrystallized from ethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With hydrogenchloride; In ethanol;Reflux; | General procedure: A mixture of N-(aryl)-3-oxobutanamides (0.01 mol), 2-butyl-4-chloro-1H-imidazole-5 carbaldehyde (0.01 mol), urea (0.015 mol) and catalytic amount of concentrated hydrochloric acid in ethanol (30 ml) was heated under reflux condition for 20 to 22 hrs. The reaction mixture was kept at room temperature for 24 hrs. The product obtained was isolated and recrystallized from ethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With hydrogenchloride; In ethanol;Reflux; | General procedure: A mixture of N-(aryl)-3-oxobutanamides (0.01 mol), 2-butyl-4-chloro-1H-imidazole-5 carbaldehyde (0.01 mol), urea (0.015 mol) and catalytic amount of concentrated hydrochloric acid in ethanol (30 ml) was heated under reflux condition for 20 to 22 hrs. The reaction mixture was kept at room temperature for 24 hrs. The product obtained was isolated and recrystallized from ethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With hydrogenchloride; In ethanol;Reflux; | General procedure: A mixture of N-(aryl)-3-oxobutanamides (0.01 mol), 2-butyl-4-chloro-1H-imidazole-5 carbaldehyde (0.01 mol), urea (0.015 mol) and catalytic amount of concentrated hydrochloric acid in ethanol (30 ml) was heated under reflux condition for 20 to 22 hrs. The reaction mixture was kept at room temperature for 24 hrs. The product obtained was isolated and recrystallized from ethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With hydrogenchloride In ethanol Reflux; | General procedure for the synthesis of 4-(2-butyl-4-chloro-1H-imidazol-5-yl)-N-(aryl)-6-methyl-2-oxo-1,2,3,4 tetrahydropyrimidine-5-carboxamides (4a-p) General procedure: A mixture of N-(aryl)-3-oxobutanamides (0.01 mol), 2-butyl-4-chloro-1H-imidazole-5 carbaldehyde (0.01 mol), urea (0.015 mol) and catalytic amount of concentrated hydrochloric acid in ethanol (30 ml) was heated under reflux condition for 20 to 22 hrs. The reaction mixture was kept at room temperature for 24 hrs. The product obtained was isolated and recrystallized from ethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With hydrogenchloride; In ethanol;Reflux; | General procedure: A mixture of N-(aryl)-3-oxobutanamides (0.01 mol), 2-butyl-4-chloro-1H-imidazole-5 carbaldehyde (0.01 mol), urea (0.015 mol) and catalytic amount of concentrated hydrochloric acid in ethanol (30 ml) was heated under reflux condition for 20 to 22 hrs. The reaction mixture was kept at room temperature for 24 hrs. The product obtained was isolated and recrystallized from ethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With hydrogenchloride; In ethanol;Reflux; | General procedure: A mixture of N-(aryl)-3-oxobutanamides (0.01 mol), 2-butyl-4-chloro-1H-imidazole-5 carbaldehyde (0.01 mol), urea (0.015 mol) and catalytic amount of concentrated hydrochloric acid in ethanol (30 ml) was heated under reflux condition for 20 to 22 hrs. The reaction mixture was kept at room temperature for 24 hrs. The product obtained was isolated and recrystallized from ethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With L-proline; In ethanol; at 20℃; for 0.166667h; | General procedure: To a stirred solution of 2-butyl-4-chloro-1H-imidazole-5-carbaldehyde derivatives (1a-e) (10 mmol) and L-proline (15 mol %) in ethanol (10 mL), 2-cyanomethylbenzimidazole 2 (10 mmol) was added at rt. Completion of the reaction was monitored by TLC analysis. Separated solid was filtered, washed with cold ethanol (2x10 mL), dried to obtain 3a-e. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
23.5% | General procedure: To a stirred suspension of potassium carbonate (0.166 g, 1.2mmol) in ethanol (8 mL) was added 1H-imidazole (0.068 g,1 mmol). The mixture was stirred at 60 C for 1 h and thencooled to room temperature. Compound 3 (0.232 g, 1 mmol)was added and stirred under 70 C. After the reaction wascompleted (monitored by TLC, chloroform/methanol, 30:1,V/V), the solvent was evaporated and the residue was treatedwith water (15 mL) and extracted with chloroform (315mL). The combined organic phase was dried over anhydroussodium sulfate and concentrated under the reduced pressure.The crude product was purified by silica gel column chromatography(eluent, chloroform/methanol, 50:1-30:1, V/V)to afford the pure compound 4a (0.142 g) as white solid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28.1% | General procedure: To a stirred suspension of potassium carbonate (0.166 g, 1.2mmol) in ethanol (8 mL) was added 1H-imidazole (0.068 g,1 mmol). The mixture was stirred at 60 C for 1 h and thencooled to room temperature. Compound 3 (0.232 g, 1 mmol)was added and stirred under 70 C. After the reaction wascompleted (monitored by TLC, chloroform/methanol, 30:1,V/V), the solvent was evaporated and the residue was treatedwith water (15 mL) and extracted with chloroform (315mL). The combined organic phase was dried over anhydroussodium sulfate and concentrated under the reduced pressure.The crude product was purified by silica gel column chromatography(eluent, chloroform/methanol, 50:1-30:1, V/V)to afford the pure compound 4a (0.142 g) as white solid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | To a 50 mL round bottom flask was added 2-butyl-4-chloro-1H-imidazole-5-aldehyde (0.187 g, 1 mmol) and K2CO3(0.207 g, 1.5 mmol) in acetonitrile (5 mL) as the solvent, stirring at 60 C for 2 to 4 hours, cooling to room temperature, adding intermediate IV (0.338 g, 1 mmol), stirring the reaction to 60 C, The solvent was distilled off under reduced pressure, extracted by column chromatography, and dried to give 0.284 g of compound I-7 in a yield of 64%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | To a 50 mL round bottom flask was added 2-butyl-4-chloro-1H-imidazole-5-aldehyde (0. 187 g, 1mmol) and K2CO3 (0.207 g, 1.5 mmol) in acetonitrile (5 mL) as solvent, stirring at 60 C for 2 to 4 h, cooling to room temperature, adding intermediate III (0.21 g, 0.5 mmol), the reaction was stirred at 60 C until the reaction was completed. The solvent was distilled off under reduced pressure and extracted by column chromatography. The compound II-8 as 0.186 g, yield 55% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89.2% | (1-iminopentyl) glycine tert-butyl ester (1.35 kg, 6.3 mil) was added to 20 L of 10% solution of 1,2-dichloroethane in trifluoroacetic acid,Stirred at room temperature for 24 hours,Reaction is completed,Evaporated,Add toluene 15L,Phosphorus oxychloride (9.64 kg, 63 mol) was heated to 80 C,Stir for 2 hours,Dropping DMF into 4.6 kg,Up to 105 C,Stirring for 7 hours,After completion of the reaction, cool down to 0 C,Poured into aqueous sodium hydroxide solution,Ethyl acetate was added,The organic layer was dried over anhydrous sodium sulfate,Evaporated to dryness, recrystallized from ethyl acetate n-heptane,2-n-butyl-4-chloro-5-formylimidazole, 1.05 kg, purity 99.5%, yield 89.2% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85.1% | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; | 2-Butyl 4-chloro-5-formylimidazole (10.00 g, 53.75 mmol)Was dissolved in N, N-dimethylformamide (100 mL)A solution of 2- (4-chloromethylindole) benzonitrile (15.73 g, 59.12 mmol)And potassium carbonate (14.80 g, 107.50 mmol).The mixture was reacted at room temperature for about 2 to 4 hours,TLC was monitored until the reaction was complete.After the temperature of the reaction solution is lowered to room temperature,The filter cake was washed three times with dichloromethane (20 mL).To the filtrate was added 200 mL of dichloromethane and 200 mL of water,Separation of organic phaseThe aqueous phase was extracted with dichloromethane (150 mL x 3)Combine organic phase.The organic phase was washed with saturated brine (300 mL x 4)Dried over anhydrous magnesium sulfate,Filtered, the filtrate was concentrated under reduced pressure,To give a tan solid.The solid column chromatography was purified to give about 19 g of the off-white solid VIIa-1,The yield is about 85.1%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86.3% | With sodium hydroxide; In ethanol; water; at 20℃; for 24h; | General procedure: To a mixture of acetophenone 5 (0.56 g, 3.0 mmol) and2-butyl-4-chloro-1H-imidazole-5-carbaldehyde (0.56 g, 3.00mmol) in ethanol (25 mL) was added 10% sodium hydrateaqueous (5 mL), the mixture was stirred for 24 h at roomtemperature. The solution was acidified with 1N HCl andfiltered, and the filter cake was recrystallized from ethanolgot 6 as white power (8.25 g). Yield: 86.3%; mp: 187-188C; IR (KBr, cm-1) nu: 3443 (OH), 3053 (Ar-H), 1718(C=O), 1618, 1578 (aromatic frame); 1H NMR (400 MHz,CDCl3) delta: 10.93 (s, 1H, OH), 10.63 (s, 1H, NH), 7.69-7.59(m, 1H, flavone-5-H), 6.96-6.75 (m, 2H, flavone-3,6-2H),6.74-6.64 (m, 1H, flavone-8-H), 2.81-2.66 (m, 2H, CH2),1.84-1.68 (m, 2H, CH2), 1.39 (ddd, J = 29.0, 14.6, 7.5 Hz,2H, CH2), 1.01-0.89 (m, 3H, CH3) ppm; 13C NMR (101MHz, CDCl3) delta: 181.3, 177.0, 167.2, 166.2, 151.9, 144.9,125.7, 114.1, 113.1, 98.8, 97.6, 30.1, 29.7, 29.5, 28.7, 28.6,28.3, 22.2, 22.0, 13.6 ppm; MS (m/z): 319 [M+H]+; HRMS(TOF) calcd for C16H15ClN2O3: [M+H]+, 319.0849; found,319.0847. |
76.9% | With sodium hydroxide; In ethanol; at 20℃; for 24h; | To a solution of compound IV-1 (0.93 g, 5.0 mmol)2-Butyl-4-chloro-5-imidazol aldehyde(0.93 g, 5.0 mmol) and an appropriate amount of ethanol (15 mL) was added dropwise 10% NaOH (7 mL) and the reaction was stirred at room temperature for 24 h. Thin layer chromatographyTracing to the end of the reaction, with 1mol / L of dilute hydrochloric acid to pH = 7, and then recrystallized and dried to give 1.22g compoundMaterial III-9, yield 76.9%.Compound III-9: yellow powder; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.9% | With potassium carbonate; In N,N-dimethyl-formamide; at 20 - 25℃; for 10h; | 55.0 g of methyl p-chloromethylbenzoate and 52.7 g of imidazole aldehyde were dissolved in 400 ml of DMF, and 58.4 g of potassium carbonate was added thereto, and the reaction was stirred at 20 to 25 C for about 10 hours, and the reaction liquid was determined by HPLC to confirm that the reaction was substantially complete. Potassium carbonate was removed by suction filtration, 400 ml of water was added to the filtrate, and the mixture was stirred at room temperature for 3 hours, filtered to dryness, and dried under vacuum to a constant weight to obtain 86.8 g of a yellow aryl imidazole aldehyde solid, yield 91.9%, purity 97.3%, N The isomer impurity was 0.2%, and the dimer impurity was 0.03%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55.2% | Add 2-butyl-4-chloro-5-formylimidazole(0.20 g, 1.86 mmol) to a 50 mL round bottom flaskPotassium carbonate (0.77 g, 5.58 mmol) was stirred in acetonitrile (20 mL) at room temperature for 1 hour.Intermediate IX (0.60 g, 1.86 mmol) was then added to the reaction mixture.Stirring was carried out at 80 C for 12 hours under reflux. Thin layer chromatography was followed until the end of the reaction.The solvent is distilled off under reduced pressure, and then concentrated, extracted, and separated by column chromatography.After drying and the like, the compound III-3 (440 mg) was obtained in a yield of 55.2%.White solid, melting point > 250 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | In ethanol; at 78℃; for 4h; | The ligand synthesized by formerly reported process [33], to a10 mL ethanolic solution of 2-butyl-4-chloro-1H-imidazole-5-carbaldehyde (0.01 mol; 1.87 gm), was added N-methylhydrazinecarbothioamide (0.01 mol; 1.06 gm) under vigorous stirring andrefluxed for about 4 h at 78 C. The progress of reaction has monitoredby TLC technique (Ethyl acetate: hexane - 6:4, Rf - 0.72). Theobtained precipitate has filtered and recrystallized in ethanol.Scheme 1 shows the synthesis procedure of L. The colour of thesolid: white, yield: 83%. Elemental analysis (%) for C10H16N5SCl:calc. C, 43.87; H, 5.89; N, 25.58; found. C, 43.72, H, 5.81, N, 25.46;HRMS [M+H]+: 274 [C10H16N5SCl]+ion. IR (cm-1): 3167 s, (nuNH);1605 s, nu(C=N), 1244m & 815 s, nu(C=S); NMR spectrum (Bruker,400 MHz, DMSO- d 6, ppm): 1H NMR; delta= 0.89 (3H, t, CH3),1.31-1.33 (2H, m, CH2), 1.62-1.65 (2H, m, CH2), 2.49-2.51 (2H, m,CH2), 3.06 (3H, m, CH2), 7.84 (1H, s, NCH), 8.31 (1H, s, NH), 11.53(1H, s, NH), 12.31 (1H, s, NH); 13C NMR; delta= 30.9 (C1), 178.1(C2),129.9 (C3), 128.9 (C4), 122 (C5), 150.4 (C6), 28.2 (C7), 30.2 (C8), 22.1(C9), 14.0 (C10). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | In methanol at 80℃; for 0.5h; | General procedure for the synthesis of compounds (12-43). General procedure: First, 0.5 g of 2-hydrazinoadenosine (11) and different aralkyl or alkylaldehyde compounds (1.1 equivalent) were combined in methanol(30 ml) and heated by microwave at 80 °C for 30 min. The crudeproducts (12-13, 17, 19, 21-32, and 35-39) were precipitated frommethanol, and the other products (14-16, 18, 20, 33-34, and 40-43) were purified from the reaction mixture using silica gel column chromatography. All the crude products were further purified by MPLC on reverse phase C18 material to yield the products(12-43). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68.5% | With acetic acid; In ethanol; at 80℃; for 15h; | In a 100 mL round bottom flask was added intermediate IV (400 mg, 1.47 mmol), 2-butyl-4-chloro-1H-imidazole-5-carbaldehyde (275.2 mg, 1.47 mmol), glacial acetic acid (6 mL, 104 mmol), and ethanol (30mL) as solvent, reflux at 80 for 15h,TLC traced to the end of the reaction.The reaction solution was poured into ice water, filtered, washed with ice water, and subjected to post-treatment such as column chromatography separation and drying to obtain compound I-1 (444mg), yield: 68.5%; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | General procedure: A mixture of 2-butyl-4-chloro-1H-imidazole-5-carbaldehyde(1.87 g, 0.01 mol) and potassium carbonate (1.38 g,0.01 mol) in acetonitrile (5 mL) was stirred at 60C for 1 h.After the mixture was cooled to room temperature, compound1a (2.44 g, 0.02 mol) was added and refluxed for 10 h(monitored by TLC, eluent, ethyl acetate/petroleum, 1:1,v/v). After the solvent was evaporated under reduced pressure,and the resulting residue was extracted with ethyl acetate(3×20 mL), the organic layers were combined, driedover anhydrous sodium sulfate, and concentrated under reducedpressure. The crude product was purified by silica gelcolumn chromatography eluting with ethyl acetate/petroleum(1:2, v/v) to afford the target compound 2a (1.06 g) as whitesolid. Yield: 46.2%; mp: 102-103C. 1H NMR (400 MHz,DMSO-d6) delta: 9.61 (s, 1H, CHO), 4.01-3.95 (m, 2H, N-CH2),2.70-2.63 (m, 2H, imidazole-CH2), 1.65 (m, J = 10.5, 7.3Hz, 4H, N-CH2CH2, imidazole-CH2CH2CH2), 1.32 (dd, J =15.1, 7.3 Hz, 2H, imidazole-CH2CH2CH2), 0.91 (t, J = 7.3Hz, 3H, CH3), 0.86 (t, J = 7.3 Hz, 3H, CH3) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46.2% | General procedure: A mixture of 2-butyl-4-chloro-1H-imidazole-5-carbaldehyde(1.87 g, 0.01 mol) and potassium carbonate (1.38 g,0.01 mol) in acetonitrile (5 mL) was stirred at 60C for 1 h.After the mixture was cooled to room temperature, compound1a (2.44 g, 0.02 mol) was added and refluxed for 10 h(monitored by TLC, eluent, ethyl acetate/petroleum, 1:1,v/v). After the solvent was evaporated under reduced pressure,and the resulting residue was extracted with ethyl acetate(3×20 mL), the organic layers were combined, driedover anhydrous sodium sulfate, and concentrated under reducedpressure. The crude product was purified by silica gelcolumn chromatography eluting with ethyl acetate/petroleum(1:2, v/v) to afford the target compound 2a (1.06 g) as whitesolid. Yield: 46.2%; mp: 102-103C. 1H NMR (400 MHz,DMSO-d6) delta: 9.61 (s, 1H, CHO), 4.01-3.95 (m, 2H, N-CH2),2.70-2.63 (m, 2H, imidazole-CH2), 1.65 (m, J = 10.5, 7.3Hz, 4H, N-CH2CH2, imidazole-CH2CH2CH2), 1.32 (dd, J =15.1, 7.3 Hz, 2H, imidazole-CH2CH2CH2), 0.91 (t, J = 7.3Hz, 3H, CH3), 0.86 (t, J = 7.3 Hz, 3H, CH3) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51.5% | General procedure: A mixture of 2-butyl-4-chloro-1H-imidazole-5-carbaldehyde(1.87 g, 0.01 mol) and potassium carbonate (1.38 g,0.01 mol) in acetonitrile (5 mL) was stirred at 60C for 1 h.After the mixture was cooled to room temperature, compound1a (2.44 g, 0.02 mol) was added and refluxed for 10 h(monitored by TLC, eluent, ethyl acetate/petroleum, 1:1,v/v). After the solvent was evaporated under reduced pressure,and the resulting residue was extracted with ethyl acetate(3×20 mL), the organic layers were combined, driedover anhydrous sodium sulfate, and concentrated under reducedpressure. The crude product was purified by silica gelcolumn chromatography eluting with ethyl acetate/petroleum(1:2, v/v) to afford the target compound 2a (1.06 g) as whitesolid. Yield: 46.2%; mp: 102-103C. 1H NMR (400 MHz,DMSO-d6) delta: 9.61 (s, 1H, CHO), 4.01-3.95 (m, 2H, N-CH2),2.70-2.63 (m, 2H, imidazole-CH2), 1.65 (m, J = 10.5, 7.3Hz, 4H, N-CH2CH2, imidazole-CH2CH2CH2), 1.32 (dd, J =15.1, 7.3 Hz, 2H, imidazole-CH2CH2CH2), 0.91 (t, J = 7.3Hz, 3H, CH3), 0.86 (t, J = 7.3 Hz, 3H, CH3) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53.6% | General procedure: A mixture of 2-butyl-4-chloro-1H-imidazole-5-carbaldehyde(1.87 g, 0.01 mol) and potassium carbonate (1.38 g,0.01 mol) in acetonitrile (5 mL) was stirred at 60C for 1 h.After the mixture was cooled to room temperature, compound1a (2.44 g, 0.02 mol) was added and refluxed for 10 h(monitored by TLC, eluent, ethyl acetate/petroleum, 1:1,v/v). After the solvent was evaporated under reduced pressure,and the resulting residue was extracted with ethyl acetate(3×20 mL), the organic layers were combined, driedover anhydrous sodium sulfate, and concentrated under reducedpressure. The crude product was purified by silica gelcolumn chromatography eluting with ethyl acetate/petroleum(1:2, v/v) to afford the target compound 2a (1.06 g) as whitesolid. Yield: 46.2%; mp: 102-103C. 1H NMR (400 MHz,DMSO-d6) delta: 9.61 (s, 1H, CHO), 4.01-3.95 (m, 2H, N-CH2),2.70-2.63 (m, 2H, imidazole-CH2), 1.65 (m, J = 10.5, 7.3Hz, 4H, N-CH2CH2, imidazole-CH2CH2CH2), 1.32 (dd, J =15.1, 7.3 Hz, 2H, imidazole-CH2CH2CH2), 0.91 (t, J = 7.3Hz, 3H, CH3), 0.86 (t, J = 7.3 Hz, 3H, CH3) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44.2% | General procedure: A mixture of 2-butyl-4-chloro-1H-imidazole-5-carbaldehyde(1.87 g, 0.01 mol) and potassium carbonate (1.38 g,0.01 mol) in acetonitrile (5 mL) was stirred at 60C for 1 h.After the mixture was cooled to room temperature, compound1a (2.44 g, 0.02 mol) was added and refluxed for 10 h(monitored by TLC, eluent, ethyl acetate/petroleum, 1:1,v/v). After the solvent was evaporated under reduced pressure,and the resulting residue was extracted with ethyl acetate(3×20 mL), the organic layers were combined, driedover anhydrous sodium sulfate, and concentrated under reducedpressure. The crude product was purified by silica gelcolumn chromatography eluting with ethyl acetate/petroleum(1:2, v/v) to afford the target compound 2a (1.06 g) as whitesolid. Yield: 46.2%; mp: 102-103C. 1H NMR (400 MHz,DMSO-d6) delta: 9.61 (s, 1H, CHO), 4.01-3.95 (m, 2H, N-CH2),2.70-2.63 (m, 2H, imidazole-CH2), 1.65 (m, J = 10.5, 7.3Hz, 4H, N-CH2CH2, imidazole-CH2CH2CH2), 1.32 (dd, J =15.1, 7.3 Hz, 2H, imidazole-CH2CH2CH2), 0.91 (t, J = 7.3Hz, 3H, CH3), 0.86 (t, J = 7.3 Hz, 3H, CH3) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51.2% | General procedure: A mixture of 2-butyl-4-chloro-1H-imidazole-5-carbaldehyde(1.87 g, 0.01 mol) and potassium carbonate (1.38 g,0.01 mol) in acetonitrile (5 mL) was stirred at 60C for 1 h.After the mixture was cooled to room temperature, compound1a (2.44 g, 0.02 mol) was added and refluxed for 10 h(monitored by TLC, eluent, ethyl acetate/petroleum, 1:1,v/v). After the solvent was evaporated under reduced pressure,and the resulting residue was extracted with ethyl acetate(3×20 mL), the organic layers were combined, driedover anhydrous sodium sulfate, and concentrated under reducedpressure. The crude product was purified by silica gelcolumn chromatography eluting with ethyl acetate/petroleum(1:2, v/v) to afford the target compound 2a (1.06 g) as whitesolid. Yield: 46.2%; mp: 102-103C. 1H NMR (400 MHz,DMSO-d6) delta: 9.61 (s, 1H, CHO), 4.01-3.95 (m, 2H, N-CH2),2.70-2.63 (m, 2H, imidazole-CH2), 1.65 (m, J = 10.5, 7.3Hz, 4H, N-CH2CH2, imidazole-CH2CH2CH2), 1.32 (dd, J =15.1, 7.3 Hz, 2H, imidazole-CH2CH2CH2), 0.91 (t, J = 7.3Hz, 3H, CH3), 0.86 (t, J = 7.3 Hz, 3H, CH3) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52.3% | General procedure: A mixture of 2-butyl-4-chloro-1H-imidazole-5-carbaldehyde(1.87 g, 0.01 mol) and potassium carbonate (1.38 g,0.01 mol) in acetonitrile (5 mL) was stirred at 60C for 1 h.After the mixture was cooled to room temperature, compound1a (2.44 g, 0.02 mol) was added and refluxed for 10 h(monitored by TLC, eluent, ethyl acetate/petroleum, 1:1,v/v). After the solvent was evaporated under reduced pressure,and the resulting residue was extracted with ethyl acetate(3×20 mL), the organic layers were combined, driedover anhydrous sodium sulfate, and concentrated under reducedpressure. The crude product was purified by silica gelcolumn chromatography eluting with ethyl acetate/petroleum(1:2, v/v) to afford the target compound 2a (1.06 g) as whitesolid. Yield: 46.2%; mp: 102-103C. 1H NMR (400 MHz,DMSO-d6) delta: 9.61 (s, 1H, CHO), 4.01-3.95 (m, 2H, N-CH2),2.70-2.63 (m, 2H, imidazole-CH2), 1.65 (m, J = 10.5, 7.3Hz, 4H, N-CH2CH2, imidazole-CH2CH2CH2), 1.32 (dd, J =15.1, 7.3 Hz, 2H, imidazole-CH2CH2CH2), 0.91 (t, J = 7.3Hz, 3H, CH3), 0.86 (t, J = 7.3 Hz, 3H, CH3) ppm. |
Tags: 83857-96-9 synthesis path| 83857-96-9 SDS| 83857-96-9 COA| 83857-96-9 purity| 83857-96-9 application| 83857-96-9 NMR| 83857-96-9 COA| 83857-96-9 structure
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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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