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Structure of 822-36-6
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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
4.5
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Surveying the scope of aromatic decarboxylations catalyzed by prenylated-flavin dependent enzymes
Anushree Mondal ; Pronay Roy ; Jaclyn Carrannatto ; Prathamesh M. Datar ; Daniel J. DiRocco ; Katherine Huntera and E. Neil G. Marsh
Abstract: The prenylated-flavin mononucleotide-dependent decarboxylases (also known as UbiD-like enzymes) are the most recently discovered family of decarboxylases. The modified flavin facilitates the decarboxylation of unsaturated carboxylic acids through a novel mechanism involving 1,3-dipolar cyclo-addition chemistry. UbiD-like enzymes have attracted considerable interest for biocatalysis applications due to their ability to catalyse (de)carboxylation reactions on a broad range of aromatic substrates at otherwise unreactive carbon centres. There are now ∼35[thin space (1/6-em)]000 protein sequences annotated as hypothetical UbiD-like enzymes. Sequence similarity network analyses of the UbiD protein family suggests that there are likely dozens of distinct decarboxylase enzymes represented within this family. Furthermore, many of the enzymes so far characterized can decarboxylate a broad range of substrates. Here we describe a strategy to identify potential substrates of UbiD-like enzymes based on detecting enzyme-catalysed solvent deuterium exchange into potential substrates. Using ferulic acid decarboxylase (FDC) as a model system, we tested a diverse range of aromatic and heterocyclic molecules for their ability to undergo enzyme-catalysed H/D exchange in deuterated buffer. We found that FDC catalyses H/D exchange, albeit at generally very low levels, into a wide range of small, aromatic molecules that have little resemblance to its physiological substrate. In contrast, the sub-set of aromatic carboxylic acids that are substrates for FDC-catalysed decarboxylation is much smaller. We discuss the implications of these findings for screening uncharacterized UbiD-like enzymes for novel (de)carboxylase activity.
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Purchased from AmBeed: 27916-43-4 ; 2438-05-3 ; 501-89-3 ; 42287-94-5 ; 776-79-4 ; 53473-36-2 ; 7251-61-8 ; 42287-97-8 ; 1621-91-6 ; 37718-11-9 ; 288-13-1 ; 86-73-7 ; 104-53-0 ; 2018-90-8 ; 87-66-1 ; 135-19-3 ; 1664-57-9 ; 289-80-5 ; 693-95-8 ; 55-22-1 ; 102-93-2 ; 1477-50-5 ; 1632-76-4 ; 4780-79-4 ; 16642-79-8 ; 3581-89-3 ; 501-97-3 ; 771-50-6 ; 98-98-6 ; 619-64-7 ; 100-51-6 ; 402-45-9 ; 59-67-6 ; 93-60-7 ; 273-53-0 ; 2084-13-1 ; 51-17-2 ; 2459-09-8 ; 2459-07-6 ; 95-16-9 ; 459-31-4 ; 90-05-1 ; 150-76-5 ; 103-25-3 ; 271-44-3 ; 6293-56-7 ; 2550-26-7 ; 288-32-4 ; 501-52-0 ; 2001-32-3 ; 1592-38-7 ; 95-15-8 ; 91-19-0 ; 1122-61-8 ; 3724-19-4 ; 20173-24-4 ; 118-31-0 ; 6125-24-2 ; 60-12-8 ; 90-15-3 ; 120-72-9 ; 822-36-6 ; 288-47-1 ; 288-42-6 ; 2038-57-5 ; 38628-51-2 ; 1929-29-9 ; 15009-91-3 ; 1505-50-6 ; 581-40-8 ; 616-47-7 ; 1571-33-1
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CAS No. : | 822-36-6 |
Formula : | C4H6N2 |
M.W : | 82.10 |
SMILES Code : | CC1=CNC=N1 |
MDL No. : | MFCD00005201 |
InChI Key : | XLSZMDLNRCVEIJ-UHFFFAOYSA-N |
Pubchem ID : | 13195 |
GHS Pictogram: |
![]() ![]() ![]() |
Signal Word: | Danger |
Hazard Statements: | H302-H314-H351 |
Precautionary Statements: | P501-P260-P270-P202-P201-P264-P280-P308+P313-P303+P361+P353-P301+P330+P331-P363-P301+P312+P330-P304+P340+P310-P305+P351+P338+P310-P405 |
Class: | 8 |
UN#: | 3263 |
Packing Group: | Ⅲ |
Num. heavy atoms | 6 |
Num. arom. heavy atoms | 5 |
Fraction Csp3 | 0.25 |
Num. rotatable bonds | 0 |
Num. H-bond acceptors | 1.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 23.55 |
TPSA ? Topological Polar Surface Area: Calculated from |
28.68 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
0.77 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
0.46 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
0.72 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
-0.47 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.56 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
0.61 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.26 |
Solubility | 4.56 mg/ml ; 0.0555 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-0.63 |
Solubility | 19.2 mg/ml ; 0.234 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-1.51 |
Solubility | 2.55 mg/ml ; 0.0311 mol/l |
Class? Solubility class: Log S scale |
Soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
Yes |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
No |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-6.47 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
2.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
0.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
1.0 |
* 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 |
---|---|---|
99% | With N-Bromosuccinimide In tetrahydrofuran at 20℃; for 1 h; | [0229] To a solution of 3-1 (3.4 g, 40 mmol) in THF (50 mL) at r.t. was added NBS ( 14 g, 80 mmol). The mixture was stirred for 1 h. The solvent were removed under reduced pressure. Purification by column chromatography on silica gel (PE:EA=2: 1 ) provided 3-2 as white solid (9.6 g, 99percent). +E SI-MS: m/z 239.0 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With trans-N,N'-dimethyl-1,2-cyclohexyldiamine; potassium phosphate; copper(l) iodide In 1,4-dioxane at 115℃; for 72 h; Molecular sieve | Coupling reaction: A reaction flask was charged with 3-bromo-5-trifluoromethylbenzoic acid (compound 2, 2.7 g, 0.01 mol), 4-methyl-1H- imidazole (1.64 g, 1), trans- N, N'-dimethylcyclohexanediamine (0.28 g, 0.002 mol), 1,4-dioxane (10 vol./g), anhydrous potassium phosphate , 0.03mol) and 4A molecular sieves (0. lg / g), to form a mixed system; the mixed system is purged with nitrogen to have an oxygen content of 500ppm, finally adding cuprous iodide (0.38g, 0.002mol) The system was heated to 115 ° C, the reaction was stirred for 72 hours, TLC showed compound 2 disappeared to give the product system; and then the system was cooled to room temperature, transferred to 2M hydrochloric acid quenched, concentrated filtered without fraction To be purified solution. Adding n-butanol, extracting and separating the organic phase, extracting with n-butanol twice, and combining the organic phases; concentrating the organic phase to remove n-butanol to obtain 3- (4-methyl- -5- (trifluoromethyl) benzoic acid (Compound 3) crude. Recrystallization from methanol (4: 1 ./g) gave 1.76 g of a khaki-colored solid in 65percent yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With paraformaldehyde; In hydrogenchloride; ethanol; | EXAMPLE 1 42.0 Parts of 97.5% pure 4-methylimidazole, 56.8 parts of cysteamine hydrochloride and 18.0 parts of paraformaldehyde are dissolved in 207 parts of 37% strength aqueous hydrochloric acid, whilst cooling so that the temperature does not exceed 30 C. The mixture is heated in a closed glass-lined kettle for 5 hours at 110-120 C. and for a further 10 hours at 120 C. The hydrochloric acid is then distilled off under reduced pressure from a water-pump, at not more than 80 C., until the residue has almost been reduced to dryness, after which the latter is dissolved in 237 parts of boiling ethanol. The solution is cooled to 20 C. and the precipitate which forms is filtered off and dried. 81.9 Parts (constituting the 1st fraction) of 4-methyl-5-[(2-aminoethyl)-thiomethyl]-imidazole dihydrochloride, of melting point 179-180 C., are obtained. The filtrate is evaporated to about half its volume and is cooled to 20 C., and the precipitate is filtered off. After drying, a further 12.7 parts (constituting the 2nd fraction) of melting point 149-154 C. are obtained. Fractions 1 and 2 are combined and recrystallized from 315 parts of glacial acetic acid. After drying at 10 mm Hg and 90 C., 82.4 parts (67.5%) of 4-methyl-5-[(2-aminoethyl)-thiomethyl]-imidazole dihydrochloride of melting point 190-191 C. are obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78.2% | With isoquinolin-8-ol; copper(l) iodide; potassium carbonate; triethylamine; In N,N-dimethyl-formamide; at 100 - 140℃; for 5h; | 13.5 g of <strong>[630125-49-4]3-bromo-5-nitro-trifluorotoluene</strong> (13.5 g, 0.05 mol), 5.0 g of 4-methyl-1H-imidazole (5.0 g, 0.06 mol), 1.42 g of cuprous iodide (1.42 g, 7.5 mmol), 2.2 g of 8-hydroxyisoquinoline (2.2 g, 7.5 mmol), 7.6 g of potassium carbonate (0.055 mol) and 50 mL of N,N-dimethylformamide were added to a 250 mL three-necked bottle, heated to 100 C., stirred to dissolve. Added with 0.75 g of triethylamine (0.75 g, 7.5 mmol), continued to heat to 140 C., reacted for 5 hours, to complete the reaction detected by TLC. Cooled down to 50-60 C., filtered, and the filter cake was washed with ethyl acetate, the filter liquor was washed with saline water and water, concentrated, then recrystallized by ethyl acetate and n-hexane (1:1), to get 10.6 g of yellow solid 3-(4-methyl-1H-imidazol-1-yl)-5-nitro-trifluorotoluene, with a yield of 78.2%, melting point 118-120 C., MS-ESI (m/z): 272(M+H), 1H NMR (400 MHz, CDCl3) delta 8.45(s, 2H), 7.95(s, 1H), 7.93(s, 1H), 7.16(s, 1H), 2.33(s, 3H). |
53.3% | Example 13 4-Methyl-1 -(3-nitro-5-tiotaf luoromethyl-phenyl)-1 H-imidazole (IX) (by aromatic substitution)4-Methylimidazole (10.5 g, 125.5 mmol) and potassium carbonate (12.0 g, 119.6 mmol) is suspended in Lambda/,Lambda/-dimethylformamide (80 mL) and stirred at 1000C for 1 hour. A solution of 1-fluoro-3-nitro-5-trifluoromethyl-benzene (12.5 g, 59.8 mmol) in EPO <DP n="26"/>ty/V-dimethylformamide (20 mL) is added over 10 minutes. The mixture is stirred at 1080C internal temperature for 3 hours. HPLC analysis shows complete consumption of the fluoride starting material. The mixture is cooled down to about 200C and water (200 mL) is added over 1 hour. The resulting suspension is filtered to give 17.5 g of wet solid (HPLC: 88.8 area% desired isomer, 8.9 area% undesired isomer/byproduct). A suspension of this material in water (100 mL) is stirred for 1 hour at room temperature. The solid is filtered, washed with water (100 mL) and dried at 50C under reduced pressure to give the crude product. HPLC analysis shows more than 90 area% of the desired product. Re-crystallization: A solution of above crude product (9.5 g) in ethyl acetate (50 mL) is treated for 2 hours at 700C with activated carbon (1 g) and filter aid (1 g) and, thereafter, is filtered, and the filtrate is evaporated to dryness to give 11.1 g of a residue. This material is dissolved in ethyl acetate (3.25 g) and heptane (50 mL) under reflux. The solution is seeded at 65C with 4-methyl-1-(3-nitro-5-trifluoromethyl-phenyl)-1H-imidazole and allowed to cool down to room temperature over night and afterwards stirred at 00C for 3 hours. The solid formed is filtered, washed with heptane (20 mL) and dried at 500C under reduced pressure to give 4-methyl-1-(3-nitro-5-trifluoromethyl-phenyl)-1 /-/-imidazole as a solid. Yield overall: 53.3% (HPLC purity: 98.2 area%), Melting point: 117-118C | |
21.1% | With copper(l) iodide; potassium carbonate; ethylenediamine; In N,N-dimethyl-formamide; at 110℃; for 23h;Product distribution / selectivity; | Example 10 4-Methyl-1-(3-nitro-5-trifluoromethyl-phenyl)-1H-imidazole (IX) (by catalyzed coupling)To a stirred suspension of <strong>[630125-49-4]1-bromo-3-nitro-5-trifluoromethyl-benzene</strong> (4.05 g, 15 mmol), 4-methyl-1 W-imidazole (2.01 g, 24 mmol, 98%) and potassium carbonate (3.73 g, 27 mmol) in Lambda/,Lambda/-dimethylformamide (10 mL) are added ethylenediamine (0.141 mL, 2.1 mmol) and copper(l) iodide (0.204 g, 1.05 mmol). The vigorously stirred mixture is heated to 110 0C for 23 hours. After that, most of the 1-bromo-3-nitro-5-trifluoromethyl- benzene is converted, and the suspension is allowed to cool down to room temperature. The mixture is diluted with terf-butyl methyl ether (30 mL) and 5% aqueous NaCI solution (30 mL) and isopropyl acetate (15 mL) are added. The aqueous layer is separated and extracted with a mixture of tert-buty methyl ether (10 mL) and isopropyl acetate (5 mL). The organic layers are combined and filtered. The filtrate is washed with water (10 mL), treated for 5 minutes with ethylenediamine (0.303 mL), washed with water (10 mL), 5% aqueous sodium EPO <DP n="24"/>metabisulfite solution (10 mL) and water (10 ml.) before it is treated with activated carbon (1.2 g) at room temperature for 1 hour. The suspension is filtered using filter aid, and the filtrate is evaporated to dryness under reduced pressure to give a clear, red-brown oil which solidifies upon standing at room temperature. The obtained solid is purified by column chromatography on silica gel eluting with a 4:5 mixture of ethyl acetate and hexane (in the presence of 0.5 volume% of triethylamine) to afford mainly 4-methyl-1-(3-nitro- 5-trifluoromethyl-phenyl)-1 /-/-imidazole as a pale yellow solid. Yield: 21.1% (HPLC purity: 96.7 area%) Melting point: 118-119C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With potassium carbonate; In dimethyl sulfoxide; at 125℃; for 16h;Autoclave; Inert atmosphere; | 2-Fluoro-5-nitroanisole (50 g, 0.29 mol) was added to a solution of 4-methyl-lH- imidazole (36.0 g, 0.44 mol) and K2C03 (40.38 g, 0.29 mol) in DMSO (150 ml) in a stainless steel autoclave under a N2 atmosphere. The vessel was closed and the r.m. was heated at 125 °C for 16 h. Subsequently, the mixture was cooled and the solvent was evaporated under reduced pressure. H20 (q.s.) was added to the residue and the precipitated product was collected by filtration. This solid was then triturated with DIPE and collected by filtration to yield a light-brown solid. Yield: 53.8 g of intermediate 40(79 percent). |
79% | With potassium carbonate; In dimethyl sulfoxide; at 125℃; for 16h;Inert atmosphere; | 2-Fluoro-5-nitroanisole (50 g, 0.29 mol) was added to a solution of 4-methyl-lH- imidazole (36.0 g, 0.44 mol) and K2C03 (40.38 g, 0.29 mol) in DMSO (150 ml) in a stainless steel autoclave under a N2 atmosphere. The vessel was closed and the r.m. was heated at 125 °C for 16 h. Subsequently, the mixture was cooled and the solvent was evaporated under reduced pressure. H20 (q.s.) was added to the residue and the precipitated product was collected by filtration. This solid was then triturated with DIPE and collected by filtration to yield a light-brown solid. Yield: 53.8 g of intermediate 40 (79 percent). |
79% | With potassium carbonate; In dimethyl sulfoxide; at 125℃; for 16h;Inert atmosphere; | 2-Fluoro-5-nitroanisole (50 g, 0.29 mol) was added to a solution of 4-methyl-1H-imidazole (36.0 g, 0.44 mol) and K2CO3 (40.38 g, 0.29 mol) in DMSO (150 ml) in a stainless steel autoclave under a N2 atmosphere. The vessel was closed and the r.m. was heated at 125° C. for 16 h. Subsequently, the mixture was cooled and the solvent was evaporated under reduced pressure. H2O (q.s.) was added to the residue and the precipitated product was collected by filtration. This solid was then triturated with DIPE and collected by filtration to yield a light-brown solid. Yield: 53.8 g of intermediate 40 (79percent). |
78.9% | With potassium carbonate; In dimethyl sulfoxide; at 125℃; for 16h;Inert atmosphere; Autoclave; | Example A2 a) Preparation of intermediate 3. (NOTE: this reaction was carried out in 4 batches of 50 g of <strong>[454-16-0]2-fluoro-5-nitroanisole</strong>). A mixture of <strong>[454-16-0]2-fluoro-5-nitroanisole</strong> (200 g, 1.17 mol), 4-methyl- IH- imidazole (143.9 g, 1.75 mol) and K2CO3 (161.5 g, 1.17 mol) in DMSO (600 ml) was prepared in a stainless steel autoclave under a N2 atmosphere. The vessel was closed and the r.m. heated at 125 0C for 16 h. The contents were allowed to cool and the solvent was evaporated under reduced pressure. H2O (q.s.) was added to the residue and the precipitated product was collected by filtration. This solid was then triturated with DIPE and collected by filtration to yield a light-brown solid. Yield: 215 g ofintermediate 3 (78.9 percent). |
With potassium carbonate; In acetonitrile; at 20℃; | Step C:; Two equivalent of 4-methylimidazole, 1 equivalent of 3-methoxy-4-fluoro- nitrobenzene and 5 eq. of K2CO3 were stirred in CH3CN at room temperature over night. The reaction mixture was filtered and concentrated under reduced pressure. The crude product was recrystalized with EtOAc to give desired product 5.1 d. | |
With potassium carbonate; In acetonitrile; at 20℃; | Step F: Two equivalent of 4-methylimidazofe, 1 equivalent of 3-rnethoxy-4-fluoro- nitrobenzene and 5 eq. of K2CO3 were stirred in CH3CN at room temperature over night. The reaction mixture was filtered and concentrated under reduced pressure. The crude product was recrystalized with EtOAc to give desired product E1i. | |
With potassium carbonate; In acetonitrile; at 20℃; | 4-methylimidazole (2.0 mmol), <strong>[454-16-0]3-methoxy-4-fluoro-nitrobenzene</strong> (1.0 mmol) and K2CO3 (5 mmol) were stirred in CH3CN (10 mL) at room temperature over night. The reaction mixture was filtered and concentrated under reduced pressure. The crude product was recrystallized with EtOAc to give desired product 1a. | |
With potassium carbonate; In acetonitrile; at 20℃; | EXAMPLE 1Step A: 4-methylimidazole (2.0 mmol), <strong>[454-16-0]3-methoxy-4-fluoro-nitrobenzene</strong> (1.0 mmol) and K2CO3 (5 mmoi) were stirred in CH3CN (10 mL) at room temperature over night. The reaction mixture was filtered and concentrated under reduced pressure. The crude product was recrystalized with EtOAc to give desired product 1a. | |
With potassium carbonate; In N,N-dimethyl-formamide; at 85℃;Sealed tube; | Example 34 a. 3-methoxy-4-(5-methyl-lH-imidazol-l-yl)anilineA mixture of 4-methyl imidazole (500 mg, 6.1 mmol), 2-fluoro-5-nitro anisole (1.02 g, 5.9 mmol) and potassium carbonate (1.68 g, 12 mmol) in DMF (15 mL) was heated overnight at 85°C in a sealed tube. The reaction mixture was cooled, transferred into a round bottom flask using ethyl acetate and concentrated under high vacuum to 5 mL volume. The residue was suspended in water and extracted with dichloromethane. The organic extracts were combined, washed with brine, dried over anhydrous MgSO4, filtered and concentrated. The residue was dissolved in dichloromethane (10 mL) and diluted with hexane until the solution became slightly turbid. The turbid solution was left at room temperature. The separated solid was filtered, washed with hexane to give l-(2-methoxy-4-nitro-phenyl)-4- methyl-lH-imidazole. The mother liquor was purified by preparative HPLC giving 0.20 g of l-(2-methoxy-4-nitro-phenyl)-5-methyl-lH-imidazole.10 percent Pd/C (0.28 g, 2.6 mmol) was added to a solution of l-(2-methoxy-4-nitro-phenyl)-5- methyl-lH-imidazole (0.61 g, 2.6 mmol) in ethyl acetate (20 mL). The mixture was hydrogenated at 35 psi over night. The mixture was filtrated through celite and concentrated to about 10 mL. Diethylether (50 mL) was added and the solution was cooled to 00C. 4M HCl in dioxane (2 mL) was added and the solution was stirred for 15 min then warmed up to rt and stirred for 30 min. The excess solvent was decanted off and more diethylether was added and the mixture stirred for 15 min. This was repeated once more with a large amount of diehtylether. The wet solid was dried under vacuum giving 0.60 g of the title compound (16 percent Yield).1H NMR (400 MHz, METHANOL-d4) ppm 2.15 (s, 3 H), 3.92 (s, 3 H), 7.07 (dd, 1 H), 7.19 (d, 1 H), 7.49 (s, 1 H), 7.59 (d, 1 H), 9.03 (d, 1 H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | With potassium hydroxide; In N,N-dimethyl-formamide; at 20.0℃; for 16.0h; | 4-methoxy-2-(4-methyl-1H-imidazol-1-yl)-3-nitropyridine To a mixture of <strong>[6980-09-2]2-chloro-3-nitro-4-methoxypyridine</strong> (2.0 g, 10.6 mmol) and 4-methylimidazole (1.3 g, 15.9 mmol) in 20 mL of DMF was added freshly powdered KOH (0.9 g, 15 mmol). The resulting mixture was stirred at rt for 16 h. The reaction was poured into water and extracted with ethyl acetate (3*). Standard work-up followed by column chromatography using 50% ethyl acetate in hexane provided the product (0.65 g, 28% yield). MS (ESI) 235.0 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 85℃; | A mixture of 4-methyl imidazole (500 mg, 6 mmol), 2-fluoro-5-nitro anisole (1.02 g, 5.9 mmol) and potassium carbonate (1.68 g, 12 mmol) in DMF (15 mL) was heated overnight at 850C in a sealed tube. The reaction mixture was cooled, transferred into a round bottom flask using ethyl acetate and concentrated under high vacuum to 5 mL volume. The residue was suspended in water and extracted with dichloromethane (3 x 25 mL). The organic extracts were combined, washed with brine, dried over anhydrous MgSO4, filtered and concentrated to give an orange solid. The solid was dissolved in dichloromethane (10 mL) and diluted with hexane until the solution became slightly turbid. The turbid solution was left at room temperature. The separated orange solid was filtered, washed with hexane to give l-(2-methoxy-4-nitro-phenyl)-4-methyl-lH-imidazole and l-(2-methoxy-4-nitro- phenyl)-5 -methyl- lH-imidazole (577 mg, 43 percent).1H NMR (400 MHz, methanol- d4) delta ppm 2.25 (s, 3 H) 4.02 (s, 3 H) 7.21 (s, 1 H) 7.62 (d, 1 H) 7.92 - 8.02 (m, 2 H) 8.04 (s, 1 H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | Example 1 Synthesis of 1-[3-Bromo-5-(trifluoromethyl)phenyl]-4-methyl-1H- imidazole (XXVI)Scheme 12(XXVI)A 2 L, 4-neck, round-bottom flask equipped with a mechanical stirrer, a digital thermometer, heatingZcooling capacity, an addition funnel, and a nitrogen inlet/outlet is EPO <DP n="16"/>charged 1-methyl-2-pyrrolidinone (113 g) and sodium hydride (8.0 g, 60% in oil) under nitrogen purge. The mixture is stirred at 20-250C for 15 minutes. A solution of 4-methylimidazole (17.6 g) and 1-methyl-2-pyrrolidinone (181 g) is slowly added to the mixture over 30 minutes, maintaining the batch temperature between 20-25C. After the addition, the mixture is stirred at 20-250C for 2 hours. A solution of 3-bromo-5- fluorobenzotrifluoride (XXV) (40 g) and 1-methyl-2-pyrrolidinone (76 g) is slowly added into the mixture over 10 minutes, maintaining the batch temperature between 20-250C. After the addition, the mixture is stirred at 20-250C for 16 hours.Water (720 g) is slowly added to the mixture over 3 hours, maintaining the batch temperature between 20-250C. After the addition, the mixture is stirred at 20-25C for 1 hour. Any solid is isolated by filtration, rinsed with a solution of 1-methyl-2-pyrrolidinone (41 g) and water (100 g), and then rinsed with water (100 g). The solid is air-dried in the funnel for 1 hour.A 2 L, 4-neck , round-bottom flask under nitrogen purge is charged with the solid (~50 g) and ethyl acetate (361 g). The mixture is stirred for 5 minutes at 20-25C until a solution is obtained. The solution is washed with water (2 x 100 g). The organic layer is distilled at 100 mm Hg at 400C until a residual volume of 100 ml_ is reached. Heptane (342 g) is added, and the mixture is distilled at 400 mm Hg at 60C until a residual volume of 300 ml. is reached. This operation is repeated one more time. The residue is cooled from 55C to 200C over 5 hours, and stirred for an additional 1 hour at 200C. The mixture is cooled to 5C over 1 hour and stirred for an additional 1 hour at 5C. Any solid is isolated by filtration and rinsed with cold (50C) heptane (68 g). The cake is dried at 5 mm Hg/20-25C for 4 hours to yield (XXVI) (24.3 g, 48% yield) as a white solid:1H NMR 300 MHz, DMSOd6), delta 8.45 (s, 1 H), 8.30 (s, 1H), 8.10 (s, 1H), 7.90 (s, 1H), 7.70 (s, 1 H), 2.10 (s, 3H). EPO <DP n="17"/> |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With silver trifluoromethanesulfonate; In toluene; at 70℃;Inert atmosphere; | General procedure: Imidazole 3 (1.0 mmol, 2.0 equiv) and AgOTf (0.025 mmol, 5 mol %) were added to a mixture of 2-alkynylbenzaldehyde 1 (0.5 mmol) and amine 2 (0.5 mmol, 1.0 equiv) in toluene (2.0 mL). The reaction mixture was stirred at 70 C vigorously until completion of the reaction. Subsequently, the mixture was diluted with ethyl acetate (5.0 mL), and quenched with water (5.0 mL). The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel to provide the desired product I. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With silver trifluoromethanesulfonate; In toluene; at 70℃;Inert atmosphere; | General procedure: Imidazole 3 (1.0 mmol, 2.0 equiv) and AgOTf (0.025 mmol, 5 mol %) were added to a mixture of 2-alkynylbenzaldehyde 1 (0.5 mmol) and amine 2 (0.5 mmol, 1.0 equiv) in toluene (2.0 mL). The reaction mixture was stirred at 70 C vigorously until completion of the reaction. Subsequently, the mixture was diluted with ethyl acetate (5.0 mL), and quenched with water (5.0 mL). The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel to provide the desired product I. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | With potassium phosphate;copper(l) iodide; trans-1,2-Diaminocyclohexane; In 1,4-dioxane; for 0.5h;Inert atmosphere; Reflux; | Step 1 . Synthesis of 5-bromo-3-methoxy-2-(4-methyl-1 /-/-imidazol-1 - yl)pyrazine (C11 ). A solution of <strong>[476622-89-6]5-bromo-2-iodo-3-methoxypyrazine</strong> (which may be prepared according to Garg, N . K. et al., J. Am. Chem. Soc. 2002, 124, 13179- 13184) (92 g, 0.29 mol), 4-methyl-1 H-imidazole (38.5 g, 0.47 mol), K3P04 (157 g, 0.74 mol) and trans- ,2-diaminocyclohexane (15 mL, 0.12 mol) in dioxane (300 mL) was heated at reflux under a stream of argon for 15 minutes. Copper(l) iodide (5.5 g, 29 mmol) was added, and the reaction mixture was heated at reflux for an additional 30 minutes. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (1 .0 L) and chromatographed on silica (Gradient: 0% to 16% methanol in ethyl acetate) to provide the title compound. Yield: 21.7 g, 0.081 mol, 28%. 1 H N MR (400 MHz, CDCI3) delta 2.28 (s, 3H), 4.15 (s, 3H), 7.53 (s, 1 H), 8.08 (s, 1 H), 8.38 (s, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66.3% | With 2-di-tertbutylphosphino-3,4,5,6-tetramethyl-2',4',6'-triisopropyl-1,1'-biphenyl; potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); In toluene; at 120℃; for 5h; | An oven-dried vial was charged with Pd2(dba)3 (0.12 g, 0.14 mmol) and MeriBuXPhos (0.067 g, 0.14 mmol). The vial was sealed, then evacuated and backfilled with argon (three times in total). Anhydrous toluene (5 mL) was added, and the resulting premixed catalyst solution was stirred at 120C for 5 minutes. A second vial was charged with 4-methyl- 1H-imidazole (1.37 g, 16.74 mmol), K3PO4 (5.91 g, 27.90 mmol) and <strong>[618-89-3]methyl 3-bromobenzoate</strong> (3.0 g, 13.95 mmol), then the premixed catalyst solution was added by syringe to the second vial, followed by the addition of toluene (25 mL) and 1,4- dioxane (5 mL) (total 30 mL solvent). The reaction mixture was heated at 120C for 5 h, then cooled to room temperature and diluted with EtOAc. The organic layer was separated and washed with brine, then dried over anhydrous Na2SO4 and concentrated in vacuo. The crude residue was purified by flash chromatography to afford the title compound (2 g, 66.3%). dH (400 MHz, DMSO-d6) 8.22 (s, 1H), 8.06 (s, 1H), 7.89 (br s, 2H), 7.65 (br t, 1H), 7.53 (s, 1H), 3.89 (s, 3H), 2.17 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | In acetonitrile; at 100℃; for 16h; | 4-Methylimidazole (6.14 g, 73.3 mmol) was added to a sol. of 2-chloro-5-nitro-6- picoline (4.3 g, 24.42 mmol) in CH3CN (64.5 mL). The r.m. was stirred at 100 °C in a pressure tube for 16 h. The r.m. was cooled to r.t. and the solvents evaporated in vacuo. The residue was washed with water and extracted with DCM. The o.l. was separated, dried (MgSC^), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; eluent: DCM/MeOH from 100/0 to 95/5). The product fractions were collected and the solvent evaporated in vacuo. The product was precipitated from DIPE, filtered off and dried in vacuo. Yield: 4.4 g of intermediate 20 (82percent yield) as a pale yellow solid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With copper acetylacetonate; [bis(acetoxy)iodo]benzene; dihydrogen peroxide; oxygen; nickel diethyldithiocarbamate; ferric nitrate; In ethanol; at 70℃; under 760.051 Torr; for 1.5h; | Dissolve 4-methylimidazole in ethanol, concentration is 5g/L. Add oxidant iodobenzene diacetate, hydrogen peroxide, and catalyst mixture of cupric acetylacetonate, ferric nitrate, and nickel diethyldithiocarbamate where in the molar ratio of cupric acetylacetonate, ferric nitrate, and nickel diethyldithiocarbamate is 3:5:1. Stir completely. Heat to 70C at normal pressure. Introduce oxygen at a rate of 100mL/min. Reflux reaction for 90min. After reaction, add acetone and shock extract. Vacuum concentration. Vacuum distill the solvent. After, obtain the crude product. Recrystallize to obtain the desired product 1H-imidazolo-4-carboxylic acid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63 g | In N,N-dimethyl acetamide; at 80 - 85℃; for 12h; | Example 18: Preparation of 3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl benzoic acid : In 3 lit four necked round bottom flask equipped with mechanical stirrer, thermometer, reflux condenser and an addition funnel, <strong>[161622-05-5]3-fluoro-5-(trifluoromethyl)benzoic acid</strong> (80 g), 4-methylimidazole (47.2 g) and dimethylacetamide (400 ml) was added, heated to 80-85C and stirred for 12 hrs at the same temperature. The reaction mass was cooled to room temperature, diluted with water (500 ml) and extracted with ethyl acetate (1000 ml). The solvent from organic layer was distilled off under vacuum and th obtained residue was titrated with water to get the title compound. Yield: 63 g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A mixture of 7-butyl 3-(iodomethyl)- azetidine-l-carboxylate (419 mg, 1.41 mmol), 4-methyl- 1 //-imidazole (97 mg, 1.18 mmol) and Cs2C03 (769 mg, 2.36 mol) in acetonitrile (10 mL) was stirred at 80 C for 3 h. The mixture was diluted with water (30 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over anhydrous Na2S04 and then concentrated in vacuo. The residue was purified by column chromatography on silica gel (PE : EtOAc =10 : l to 1 : l) to give a mixture of 2063-A and 2063-A1 (231 mg, 78%) as a yellow oil. MS 239.7 [M + H]+. Synthesis of 2063-B and 2063-B1. To a solution of 2063-A and 2063-A1 (201 mg, 0.80 mmol) in DCM (6 mL) was added TFA (2 mL) dropwise at 0 C. Then the solution was stirred at room temperature for 1 h. The solution was concentrated in vacuo to give a mixture of 2063-B and 2063-B1 as a crude product which was directly used in the next step. MS 151.1 [M + H]+.Synthesis of 2063-B and 2063-B1. To a solution of 2063-A and 2063-A1 (201 mg, 0.80 mmol) in DCM (6 mL) was added TFA (2 mL) dropwise at 0 C. Then the solution was stirred at room temperature for 1 h. The solution was concentrated in vacuo to give a mixture of 2063-B and 2063-B1 as a crude product which was directly used in the next step. MS 151.1 [M + H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate; In acetonitrile; at 80℃; for 3h; | A mixture of 7-butyl 3-(iodomethyl)- azetidine-l-carboxylate (419 mg, 1.41 mmol), 4-methyl- 1 //-imidazole (97 mg, 1.18 mmol) and Cs2C03 (769 mg, 2.36 mol) in acetonitrile (10 mL) was stirred at 80 C for 3 h. The mixture was diluted with water (30 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over anhydrous Na2S04 and then concentrated in vacuo. The residue was purified by column chromatography on silica gel (PE : EtOAc =10 : l to 1 : l) to give a mixture of 2063-A and 2063-A1 (231 mg, 78%) as a yellow oil. MS 239.7 [M + H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A mixture of 7-butyl 3-(iodomethyl)- azetidine-l-carboxylate (419 mg, 1.41 mmol), 4-methyl- 1 //-imidazole (97 mg, 1.18 mmol) and Cs2C03 (769 mg, 2.36 mol) in acetonitrile (10 mL) was stirred at 80 C for 3 h. The mixture was diluted with water (30 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over anhydrous Na2S04 and then concentrated in vacuo. The residue was purified by column chromatography on silica gel (PE : EtOAc =10 : l to 1 : l) to give a mixture of 2063-A and 2063-A1 (231 mg, 78%) as a yellow oil. MS 239.7 [M + H]+. Synthesis of 2063-B and 2063-B1. To a solution of 2063-A and 2063-A1 (201 mg, 0.80 mmol) in DCM (6 mL) was added TFA (2 mL) dropwise at 0 C. Then the solution was stirred at room temperature for 1 h. The solution was concentrated in vacuo to give a mixture of 2063-B and 2063-B1 as a crude product which was directly used in the next step. MS 151.1 [M + H]+.Synthesis of 2063-B and 2063-B1. To a solution of 2063-A and 2063-A1 (201 mg, 0.80 mmol) in DCM (6 mL) was added TFA (2 mL) dropwise at 0 C. Then the solution was stirred at room temperature for 1 h. The solution was concentrated in vacuo to give a mixture of 2063-B and 2063-B1 as a crude product which was directly used in the next step. MS 151.1 [M + H]+. Synthesis of 2063-C and 2061-C1. A mixture of 2063-B and 2063-B1 (0.80 mmol, crude product from previous step), 1949-B (216 mg, 0.44 mmol) in DMSO (6 mL) was stirred at room temperature for 10 min, then Na2C03 (471 mg, 4.44 mmol) was added into above mixture and stirred at room temperature for 2 h. The mixture was diluted with water (20 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over anhydrous Na2S04 and then concentrated in vacuo. The residue was purified by Prep-TLC (DCM : MeOH = 45 : 1) to give a mixture of 2063-C and 2063-C1 (109 mg, 58%) as a yellow solid. MS 429.1 [M + H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40 mg; 25 mg | A mixture of 7-butyl 3-(iodomethyl)- azetidine-l-carboxylate (419 mg, 1.41 mmol), 4-methyl- 1 //-imidazole (97 mg, 1.18 mmol) and Cs2C03 (769 mg, 2.36 mol) in acetonitrile (10 mL) was stirred at 80 C for 3 h. The mixture was diluted with water (30 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over anhydrous Na2S04 and then concentrated in vacuo. The residue was purified by column chromatography on silica gel (PE : EtOAc =10 : l to 1 : l) to give a mixture of 2063-A and 2063-A1 (231 mg, 78%) as a yellow oil. MS 239.7 [M + H]+. Synthesis of 2063-B and 2063-B1. To a solution of 2063-A and 2063-A1 (201 mg, 0.80 mmol) in DCM (6 mL) was added TFA (2 mL) dropwise at 0 C. Then the solution was stirred at room temperature for 1 h. The solution was concentrated in vacuo to give a mixture of 2063-B and 2063-B1 as a crude product which was directly used in the next step. MS 151.1 [M + H]+.Synthesis of 2063-B and 2063-B1. To a solution of 2063-A and 2063-A1 (201 mg, 0.80 mmol) in DCM (6 mL) was added TFA (2 mL) dropwise at 0 C. Then the solution was stirred at room temperature for 1 h. The solution was concentrated in vacuo to give a mixture of 2063-B and 2063-B1 as a crude product which was directly used in the next step. MS 151.1 [M + H]+. Synthesis of 2063-C and 2061-C1. A mixture of 2063-B and 2063-B1 (0.80 mmol, crude product from previous step), 1949-B (216 mg, 0.44 mmol) in DMSO (6 mL) was stirred at room temperature for 10 min, then Na2C03 (471 mg, 4.44 mmol) was added into above mixture and stirred at room temperature for 2 h. The mixture was diluted with water (20 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over anhydrous Na2S04 and then concentrated in vacuo. The residue was purified by Prep-TLC (DCM : MeOH = 45 : 1) to give a mixture of 2063-C and 2063-C1 (109 mg, 58%) as a yellow solid. MS 429.1 [M + H]+.Synthesis of 51 and 52. A mixture of 2063-C and 2063-C1 (124 mg, 0.29 mmol), Pd/C (124 mg) in MeOH/EtOAc (5 mL/5 mL) was stirred at room temperature for 2 h under H2 atmosphere. Pd/C was removed by filtration through a pad of Celite. The filtrate was concentrated in vacuo and the residue was purified by Prep-TLC (DCM : MeOH = 25 : 1) to give a mixture of 51 and 52 (90 mg, 78%) as a white solid. MS 399.1 [M + H]+ .Separation of 51 and 52. The mixture of 51 and 52 (90 mg, 0.23 mmol) was separated by using SFC (Column: Chiralcel OJ-3; Solvent: EtOH (0.3%DEA); Flow rate: 2 mL/min; RT51 = 1.138 min, RT52 = 1.920 min) to give 51 (40 mg, 44%) as a white solid (MS 399.1 [M+H]+) and 52 (25 mg, 28%) as a white solid. MS 399.1 [M+H]+. |
Tags: 822-36-6 synthesis path| 822-36-6 SDS| 822-36-6 COA| 822-36-6 purity| 822-36-6 application| 822-36-6 NMR| 822-36-6 COA| 822-36-6 structure
A131658 [53316-51-1]
4,5-Dimethyl-1H-imidazole hydrochloride
Similarity: 0.83
A241837 [66247-84-5]
(1H-Imidazol-4-yl)methanamine hydrochloride
Similarity: 0.83
A100134 [38585-61-4]
4-(Chloromethyl)-1H-imidazole hydrochloride
Similarity: 0.81
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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 |
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The concentration of the dissolution solution you need to prepare is mg/mL