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CAS No. : | 37466-90-3 | MDL No. : | MFCD00179337 |
Formula : | C9H12N2O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | NUJBTXFFJUGENN-UHFFFAOYSA-N |
M.W : | 180.20 | Pubchem ID : | 458855 |
Synonyms : |
|
Num. heavy atoms : | 13 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.22 |
Num. rotatable bonds : | 3 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 51.34 |
TPSA : | 78.34 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.82 cm/s |
Log Po/w (iLOGP) : | 1.46 |
Log Po/w (XLOGP3) : | 0.82 |
Log Po/w (WLOGP) : | 1.04 |
Log Po/w (MLOGP) : | 1.06 |
Log Po/w (SILICOS-IT) : | 0.6 |
Consensus Log Po/w : | 1.0 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.62 |
Solubility : | 4.35 mg/ml ; 0.0241 mol/l |
Class : | Very soluble |
Log S (Ali) : | -2.05 |
Solubility : | 1.62 mg/ml ; 0.00897 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -2.16 |
Solubility : | 1.25 mg/ml ; 0.00693 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.53 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P264-P280-P302+P352+P332+P313+P362+P364-P305+P351+P338+P337+P313 | UN#: | N/A |
Hazard Statements: | H315-H319 | 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 |
---|---|---|
With palladium 10% on activated carbon; ammonium formate; In ethanol; for 3h;Reflux; | General procedure: 4-(2-Substituted amino)-3-nitro-ethylbenzoate, 2 (1 mmol), ammonium formate (3 mmol) and Pd/C (50 mg) were mixed in ethanol (10 mL). The reaction mixture was refluxed until completion (solution turned colorless). The reaction mixture was then filtered through Celite 545. The filtrate was evaporated under reduced pressure. It was resuspended in ethyl acetate and washed with water, dried over Na2SO4 and evaporated to dryness to yield 3 (60%). | |
With tin(ll) chloride; In ethanol; for 0.5h;Reflux; | 4-fluoro-3-nitrobenzoic acid (0.05g, 0.27 mmol) was esterified in the presence of catalytic sulfuric acid in ethanol (lOmL) by refluxing at 65 C for 6 hours. Ammonium hydroxide 28% (0.26 mmol) was subsequently added to the solution, stirred for 0.5 hour, treated with tin (II) chloride (190mg, 1 mmol) and stirred for a further 0.5 hour. The resulting mixture was then treated with benzaldehyde (0.3mmol) and sodium bisulfite (57 mg, 0.3 mmol) and left to stir for another 3 hour. The solution was cooled to room temperature and subsequently evaporated under reduced pressure. It was resuspended in ethyl acetate (lOmL), washed with 10% sodium carbonate (2OmL) and water (2OmL x2), dried over sodium sulfate and concentrated under reduced pressure. The crude products were purified by column chromatography(silica gel, 70-230 mesh; CHC13-MeOH 9:1) to obtain the final products (70-90%). The synthetic scheme for this compound is shown in Figure 1. | |
With tin(ll) chloride; In ethanol; at 65℃; for 0.5h; | P reparation of ethyl 2-phenyl-1 H-benzo[d]imidazole-5-carboxylate 4-fluoro-3-nitrobenzoic acid (0.05g, 0.27 mmol) was esterified in the presence of catalytic sulfuric acid in ethanol (10mL) by refluxing at 65 eC for 6 hours. Ammonium hydroxide 28% (0.26 mmol) was subsequently added to the solution, stirred for 0.5 hour, treated with tin (Pi) chloride (190mg, 1 mmol) and stirred for a further 0.5 hour. The resulting mixture was then treated with benzaldehyde (0.3 mmol) and sodium bisulfite (57 mg, 0.3 mmol) and left to stir for another 3 hour. The solution was cooled to room temperature and subsequently evaporated under reduced pressure. It was resuspended in ethyl acetate (10mL), washed with 10% sodium carbonate (20mL) and water (20mL x2), dried over sodium sulfate and concentrated under reduced pressure. The crude products were purified by column chromatography (silica gel, 70- 230 mesh; C HC I3-MeOH 9:1 ) to obtain the final products (70-90%). |
With tin(ll) chloride; In ethanol; for 0.5h;Reflux; | The synthetic scheme of 5 utilized a facile and efficient sequential one-pot protocol (Scheme 1) in mild reaction conditions, similar to the published method in the previous report [7]. One major advantage of this synthesis is that it does not require any purification steps prior to obtaining the final product 5. Apart from that, expensive catalysts were also not needed during the course of the reaction making it highly scalable. Briefly, 4-fluoro-3-nitrobenzoic acid 1, was esterified in the presence of catalytic sulfuric acid in ethanol by refluxing for 6 h to afford ethyl 4-fluoro-3-nitrobenzoate 2. Ammonium formate was subsequently added into the solution, and the mixture stirred at room temperature for 0.5 h. The resultant intermediate, <strong>[76918-64-4]ethyl 4-amino-3-nitrobenzoate</strong> 3, was then reduced to ethyl 3,4-diaminobenzoate 4 using stannous chloride. Cyclization of intermediate 4 with 4-anisaldehyde and catalytic amounts of sodium metabisulfite proceeded in a fast and smooth manner to afford final compound 5 in good yield (90%). Recrystallization of crude product 5 in ethyl acetate yielded light brown crystals, which are suitable for X-ray crystallographic analysis. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | In ethanol; for 2.5h;Reflux; | Step 6-1-1 Ethyl 2,3-dimethylquinoxaline-6-carboxylate <strong>[37466-90-3]Ethyl 3,4-diaminobenzoate</strong> (500 mg, 2.77 mmol) and diacetyl (238 mg, 2.77 mmol) were dissolved in ethanol (20 ml), and the mixture was heated under reflux. One hour after, diacetyl (30 mg) was added thereto, and the mixture was heated under reflux. After the mixture was heated under reflux for 2.5 hours in total, the reaction solution was poured into water, and the precipitate was separated by filtration and washed with water. By through circulation drying for 15 hours, the title compound (650 mg, quantitative) as a light-brown powder was obtained. 1H-NMR (DMSO-d6) delta: 8.52 (d, J=1.5 Hz, 1H), 8.19 (dd, J=1.9, 8.5 Hz, 1H), 8.07 (d, J=8.5 Hz, 1H), 4.40 (q, J=6.9 Hz, 2H), 2.72 (s, 3H), 2.72 (s, 3H) Mass, m/z: 230 (M+), 185 (base) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90.4% | 76 g of 3,4-diaminobenzoic acid (0.5 mol) and 300 mL anhydrous ethyl alcohol were added to a three-necked bottle, to which 6 mL concentrated sulphuric acid was added slowly under stirring at room temperature. After refluxing for 3 h, the reaction was completed. After concentration under reduced pressure, the residual solution was poured into ice water. The resulting mixture was adjusted to pH 7 with saturated sodium carbonate aqueous solution. After sucking filtration and drying, 81.5 g solid was obtained. Yield: 90.4%. MS: 181(M+1). | |
90.4% | With sulfuric acid; for 3h;Reflux; | Example 1: N'-[(2-hydroxy-3,5-di-tert-butyl)phenylmethylene]-1H-benzo[d]imidazole-6-formhydrazid e hydrochloride;Step A: Preparation of 3,4-diaminobenzoic acid ethyl ester 76 g of 3,4-diaminobenzoic acid (0.5 mol) and 300 mL anhydrous ethyl alcohol were added to a three-necked bottle, to which 6 mL concentrated sulphuric acid was added slowly under stirring at room temperature. After refluxing for 3 h, the reaction was completed. After concentration under reduced pressure, the residual solution was poured into ice water. The resulting mixture was adjusted to pH 7 with saturated sodium carbonate aqueous solution. After sucking filtration and drying, 81.5 g solid was obtained. Yield: 90.4%. MS: 181(M+1). |
84% | With sulfuric acid; at 0 - 85℃; for 18h; | To a stirred solution of 3,4-diamino-benzoic acid (500 mg, 3.29 mmol) in ethanol(20 mL) conc. H2S04 (2 mL) was added drop wise at 0 to 5C and the resultingsolution was heated to reflux at 85C for 18 hours. Reaction was monitored byTLC. After completion of reaction ethanol was evaporated, the residue obtainedwas basified with saturated bicarbonate solution, extracted with ethyl acetate, dried over Na2SO4 and concentrated under reduced pressure to obtain 3,4- diamino-benzoic acid ethyl ester i (500 mg, 84 % yield). MS mlz (M+H) 181 .3. |
65% | 3,4-Diaminobenzoic acid (2.003 g, 13.17 mmol) and triphenylphosphine (4.248 g, 16.20 mmol) were suspended in toluene (20 ml) and tetrahydrofuran (10 ml). Ethanol (2 ml) was then added, diisopropyl azodicarboxylate (2.5 ml, 9.96 mmol) was added dropwise to the obtained light brown suspension, and the mixture was stirred at room temperature for 3.5 hours. Isopropyl azodicarboxylate (1.5 ml, 5.98 mmol) was further added dropwise, the mixture was stirred at room temperature for 1 hour, and the obtained reaction mixture was extracted with 1N hydrochloric acid (100 ml x 2 times), after which the aqueous layer was washed with 50 ml of ethyl acetate. After adding 2N aqueous sodium hydroxide to the aqueous layer to raise the pH to 11 or higher, the precipitate was extracted with ethyl acetate (100 ml x 2 times). The organic layer was washed with saturated brine (50 ml) and dried overnight over anhydrous sodium sulfate. The desiccant was filtered out and the filtrate was concentrated to obtain 3,4-diaminobenzoic acid ethyl ester as a faint yellow solid. The compound was identified by LC-MS. Yield: 1.547 g (65%), Found: ESI/MS m/e 181.1(M+1). | |
59.12% | With sulfuric acid; for 12h;Reflux; | To a suspension of 3,4-diaminobenzoic acid (10g, 65.12 mmol) in ethanol (100 ml), was added catalytic amount of sulfuric acid (2 ml) and reaction mixture was refluxed for 12 hr. After completion of reaction, the reaction mixture was allowed to cool to ambient temp and concentrated under reduced pressure to obtain thick semi solid reaction mixture. Further the reaction mixture was diluted with ethyl acetate and water and quenched with saturated sodium bicarbonate. The organic layer was separated from aqueous layer. The aqueous layer was back extracted with ethyl acetate. Both the organic layer were combined and dried over anhydrous sodium sulfate and concentrated, and the semisolid residue was triturated with n-hexane which leads to the formation of ester (1) as an off white solid. Yield 17g, 59.12%, m.p. 79-80. |
With sulfuric acid; for 20h;Reflux; | Dry H2SO4 (3 mL) treated over dry ethanol (30 mL) until the weight increased 10 % and 3,4-diaminobenzoic acid (1 g) was added into this acid mixture and the mixture was heated under reflux with stirring for 20 h [19]. To this mixture deionized water (30 mL) was added, and then the dark brown solution was neutralized by Na2CO3. The precipate was filtered, recrystallized from water and dried under vacuum overnight. Molecular structure was analyzed by means of FT-IR, 1H NMR, 13C NMR. FT-IR (KBr, numax, cm-1): 1735 (C=O), 1H NMR (400 MHz, ppm in CDCl3): 7.46 (m, 2H), 6.67 (d, 1H), 4.30 (m, 2H), 3.54 (broad s, 4H),1.35 (t, 3H); 13C NMR (100 MHz, ppm in CDCl3): 167.09(C=O), 140.53 (C-NH2),133.32 (C-NH2), 123.47, 121.78,118.59, 115.14, 60.57, 14.62. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogen;palladium/active carbon; In methanol; at 50℃; for 16h; | Five-percent palladium on carbon (0.50 g) was added to a solution of 4.00 g of ethyl 3-amino-4-nitro-benzoate in 100 ml of methanol, and the mixture was stirred in a hydrogen atmosphere at 50 C. for 16 hours.. The solid material was separated through filtration, and the filtrate was concentrated to obtain ethyl 3,4-diaminobenzoate.. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With N-[3-(diethylamino)propyl]-N'-ethylcarbodiimide hydrochloride; benzotriazol-1-ol; In DMF (N,N-dimethyl-formamide); at 20℃; for 15h; | To N,N-dimethylformamide (10 ml) solution of 2,85 g (15.8 mmol) of <strong>[37466-90-3]ethyl 3,4-diaminobenzoate</strong> were added 1.48 g (17.4 mmol) of cyanoacetic acid, 3.64 g (19.0 mmol) of 1-ethyl-3-(3-diethylaminopropyl)carbodiimide hydrochloride and 2.14 g (15.8 mmol) of 1-hydroxybenzotriazole, and the resulting mixture was stirred at room temperature for 15 hours. The reaction mixture was diluted with 100 ml of chloroform, and the solution was washed successively with 30 ml of aqueous saturated sodium bicarbonate solution and 30 ml of brine. The organic layer was taken out, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in 20 ml of acetic acid, and the solution was heated under reflux for 3 hours. After cooling, acetic acid was evaporated under reduced pressure, and the residue was applied to a silica gel column chromatography. This was eluted with a mixed solvent of chloroform/methanol (95/5, v/v) to obtain an acetic acid salt of the entitled compound. This was dissolved in 100 ml of chloroform, and the solution was washed successively with 50 ml of aqueous saturated sodium bicarbonate solution and 30 ml of brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain 2.43 g (67 %) of the entitled compound as a pale brown crystal. MS(EI)m/z:230(M+H)+.1H-NMR(400MHz, CDCl3)delta: 1.41(3H, t, J=7.08Hz), 4.19(2H, s), 4.41(2H, q, J=7.08Hz), 7.30-7.85(1H, m), 8.01(1H, dd, J=1.47, 8.55Hz), 8.15-8.55(1H, m). IR(ATR): 1681, 1623, 1537, 1423, 1369, 1300cm-1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
4-Aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (0.394 g, 1.84 mmol) was dissolved in acetonitrile (3 ml). A solution of thiocarbonyldiimidazole (0.340 g, 1.91 mmol) and imidazole (0.052 g, 0.77 mmol) in acetonitrile (6 ml) was added dropwise over 3 minutes, at 0C. The mixture was stirred at room temperature for 1 hour, <strong>[37466-90-3]3,4-diaminobenzoic acid ethyl ester</strong> (0.371 g, 2.06 mmol) was added to the reaction mixture, and the mixture was stirred at 50C for 5.5 hours. Diisopropylcarbodiimide (0.32 ml) was further added, and the mixture was stirred overnight at 50C. Saturated brine was then added to the obtained reaction mixture, extraction was performed with ethyl acetate (100 ml), and the organic layer was dried overnight over anhydrous sodium sulfate. After filtering out the desiccant and concentrating the filtrate, the obtained light brown oil was'purified by silica gel column chromatography (dichloromethane/methanol = 49/1 ? 19/1) to obtain 2-[(1-tert-butoxycarbonyl-piperidin-4-ylmethyl)-amino]-1H-benzimidazole-5-carboxylic acid ethyl ester as a yellow amorphous solid. Yield: 0.838 g ( %), Found: ESI/MS m/e 403.2(M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58.1% | With sodium hydroxide; In ethanol; water; | EXAMPLE 36 2-[4-(4-Acetyl-3-hydroxy-2-propylphenoxy)butyl]-benzimidazole-5-carboxylic acid A mixture of ethyl 5-(4-acetyl-3-hydroxy-2-propylphenoxy)-pentanimidate hydrochloride (3.0 g) and <strong>[37466-90-3]ethyl 3,4-diaminobenzoate</strong> (1.4 g) in ethanol (40 ml) was stirred at room temperature for 24 hours. To the mixture was added a solution of sodium hydroxide (1.6 g/30 ml of water) and the resulting mixture was refluxed for 40 minutes. After removal of the solvent under reduced pressure, the mixture was poured into ice-water, acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. The extract was evaporated and the resulting residue was purified by silica gel column chromatography, eluding with dichloromethane-ethanol (9:1), to give the title compound (2.0 g, 58.1 %) as amorphous powder, mp 98-100 C. Analysis (%) for C23 H26 N2 O5 Calcd. (Found); C, 67.30 (67.14); H, 6.38 (6.40); N, 6.82 (6.85). Examples 37-39 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With potassium carbonate; triethylamine; In tetrahydrofuran; at 20℃; | Synthesis of 2-Oxo-2,3-dihydro-lH-benzoimidazole-5-carboxylic acid ethyl ester '22a): 3,4-Diamino-benzoic acid ethyl ester (100 mg, 0.56 mmol) was dissolved in 5 mL of IHF and cooled to 00C. Triethyamine (77 muL, 0.56 mmol) was added followed by potassium carbonate (230 mg, 1.68 mmol). Triphosgene (82 mg, 0.28 mmol) was added in one portion, md the reaction mixture was then warmed up to room temperature and quenched with saturated ammonium chloride solution. The mixture was extracted with ethyl acetate. The organic layers were combined, washed with brine and dried over MgSO4. Solvent was then removed and the residue was purified by column chromatography (60% ethyl <n="136"/>acetate/hexanes). The product (92 mg, 80%) was obtained as a white solid. MS (ES) M+H expected = 207.1, found = 207.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | (1 13a) 2-(2,6-Dichloro-phenylamino)-1 H-benzimidazole-5-carboxylic acid A mixture of <strong>[37466-90-3]3,4-diamino-benzoic acid ethyl ester</strong> (5.00 g, 27.8 mmol) and 1 ,3-dichloro-2- isothiocyanato-benzene (5.66 g, 27.8 mmol) in 40 ml. DMF was stirred for 2h under argon. DCC (5.72 g, 27.8 mmol) was added and mixture heated to 800C for 45 min. After stirring the mixture was diluted with water and concentrated /.vac. The residue was diluted with ethanol and 1 M NaOH (aq). The mixture was heated to 1000C and stirred overnight. Then ethanol was evaporated and the aq. phase was cooled, acidified with acetic acid, filtered and the solid washed with water. Yield: 8 g (90%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With AlPO4 supported ethylenediamine-chromium(III)-salen complex nanoparticles; air; In ethanol; at 20℃; for 0.833333h;Green chemistry; | General procedure: A mixture of o-phenylenediamine (1.0 mmol), aryl aldehyde(1.0 mmol) and chromium(III) salen complex nanoparticles supported on AlPO4(2.0 mol%) in ethanol (5 mL) was stirred at room temperature. After completion of the reaction (TLC), the mixture was centrifuged and rinsed with ethanol (3 × 15 mL). The recovered nanocatalyst was dried and stored for another consecutive runs. The solvent was evaporated to give the crude product, which was purified by silica gel column chromatography employing n-hexane/ethyl acetate (8:1) as eluent. |
With sodium hydrogensulfite; In ethanol; for 3h;Reflux; | 4-fluoro-3-nitrobenzoic acid (0.05g, 0.27 mmol) was esterified in the presence of catalytic sulfuric acid in ethanol (lOmL) by refluxing at 65 C for 6 hours. Ammonium hydroxide 28% (0.26 mmol) was subsequently added to the solution, stirred for 0.5 hour, treated with tin (II) chloride (190mg, 1 mmol) and stirred for a further 0.5 hour. The resulting mixture was then treated with benzaldehyde (0.3mmol) and sodium bisulfite (57 mg, 0.3 mmol) and left to stir for another 3 hour. The solution was cooled to room temperature and subsequently evaporated under reduced pressure. It was resuspended in ethyl acetate (lOmL), washed with 10% sodium carbonate (2OmL) and water (2OmL x2), dried over sodium sulfate and concentrated under reduced pressure. The crude products were purified by column chromatography(silica gel, 70-230 mesh; CHC13-MeOH 9:1) to obtain the final products (70-90%). The synthetic scheme for this compound is shown in Figure 1. | |
With sodium hydrogensulfite; In ethanol; at 65℃; for 3h; | Preparation of ethyl 2-phenyl-1 H-benzo[d]imidazole-5-carboxylate 4-fluoro-3-nitrobenzoic acid (0.05g, 0.27 mmol) was esterified in the presence of catalytic sulfuric acid in ethanol (10mL) by refluxing at 65 eC for 6 hours. Ammonium hydroxide 28% (0.26 mmol) was subsequently added to the solution, stirred for 0.5 hour, treated with tin (Pi) chloride (190mg, 1 mmol) and stirred for a further 0.5 hour. The resulting mixture was then treated with benzaldehyde (0.3 mmol) and sodium bisulfite (57 mg, 0.3 mmol) and left to stir for another 3 hour. The solution was cooled to room temperature and subsequently evaporated under reduced pressure. It was resuspended in ethyl acetate (10mL), washed with 10% sodium carbonate (20mL) and water (20mL x2), dried over sodium sulfate and concentrated under reduced pressure. The crude products were purified by column chromatography (silica gel, 70- 230 mesh; C HC I3-MeOH 9:1 ) to obtain the final products (70-90%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70.2% | 40 g of <strong>[37466-90-3]3,4-diaminobenzoic acid ethyl ester</strong> (0.22 mol) and 200 mL formic acid were added to a three-necked bottle. After refluxing for 7 h, the reaction was completed. After concentration under reduced pressure, the ice water was poured into the residual solution. The resulting mixture was adjusted to pH 7 with sodium hydroxide. After sucking filtration, the filtrate was extracted with dichloromethane thrice, dried with anhydrous sodium sulfate, and decolored with active charcoal. Then the solution was concentrated under reduced pressure to get a white solid (29.6 g). Yield: 70.2%. MS: 191 (M+1) | |
70.2% | Step B: Preparation of 1H-benzo[d]imidazole-6-carboxylic acid ethyl ester 40 g of <strong>[37466-90-3]3,4-diaminobenzoic acid ethyl ester</strong> (0.22 mol) and 200 mL formic acid were added to a three-necked bottle. After refluxing for 7 h, the reaction was completed. After concentration under reduced pressure, the ice water was poured into the residual solution. The resulting mixture was adjusted to pH 7 with sodium hydroxide. After sucking filtration, the filtrate was extracted with dichloromethane thrice, dried with anhydrous sodium sulfate, and decolored with active charcoal. Then the solution was concentrated under reduced pressure to get a white solid (29.6g). Yield: 70.2%. MS: 191 (M+1) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Intermediates 1-a and 1-b ((I-la) and (I-lb))(l-1 a) (l-1 b) <strong>[37466-90-3]Ethyl 3,4-diaminobenzoate</strong> (15 g, 83.24 mmol) was dissolved in CH3COOH (170 mL) and H20 (145 mL) was added. Then, pyruvic acid (6.94 mL, 99.88 mmol) was added dropwise to the solution. The mixture was stirred at r.t. for 7 h, then neutralized with NaOH in pellets (ca. 100 g) and extracted with DCM. The organic solvent was dried (Na2S04), filtered, and concentrated under vacuum to give a mixture of intermediates I-la and I-lb around 60% pure (13.5 g) that was used as such in the next reaction step. C12H12N2O3. LCMS: Rt 1.51 (I-la), 1.45 (I-lb), m/z 233 [M + H]+ (method 2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With sodium metabisulfite; In ethanol; water; for 4h; | General procedure: To a mixture of 2-pyridine aldehyde (5a, 107 mg, 1mmol) and 1,2-diaminobenzene (6a, 108 mg, 1 mmol) in ethanol (25 mL)was added an aqueous solution of sodium pyrosulfite (1.52g, 8 mmol, 5 mL) and refluxed for 4 to 6 h, until the TLC indicated that reaction was completed. The reaction mixture was concentrated under vacuum and the residue was dissolved in CHCl3 (2 x15 mL) and washed with water. The combined organic phases were dried over anhydrousNa2SO4, filtered and the solvent was removed under vacuumand purified by column chromatography (70% EtOAc-hexane) to afford compound 7a as a brown solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | In ethanol; for 4h;Reflux; | To a solution of compound 1 (1.2 g, 6.67 mmol) in dry EtOH (15 ml) was added ethyl 2-oxoacetate (816 mg, 8.0 mmol). The reaction was stirred at reflux for 4 hours, cooled to r.t., and crystallized from EtOH to afford the desired product, compound 2 (1.3 g, 89%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | In ethanol; at 20℃; for 1h; | Step 1: To a solution of <strong>[37466-90-3]ethyl 3,4-diaminobenzoate</strong> (5g, 0.027 mol) in EtOH (5 ml ) was added ethyl 2-oxoacetate (3.4 g, 0.033 mol), which was then stirred at r.t. for 1 hour. The mixture was concentrated and recrystallized with EtOH to obtain the target compound as a white solid (4.8g, 80%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | In N,N-dimethyl-formamide; at 90℃;Inert atmosphere; | General procedure: Ethyl-3-amino-4-(2-substituted amino)benzoate, 3 (1 mmol) and various sodium bisulfite adducts, 4 (1.5 mmol) were dissolved in DMF (5 mL). The reaction mixture was stirred at 90 C under N2 atmosphere for 24-48 h. After completion of reaction (evident by TLC), the reaction mixture was diluted in ethyl acetate (25 mL) and washed with water (10 mL×3). The organic layer was collected, dried over Na2SO4 and evaporated under reduced pressure to afford crude products. Final compounds 5-7 were obtained in 38-90% yields after recrystallization from ethanol or column purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | In N,N-dimethyl-formamide; at 90℃;Inert atmosphere; | General procedure: Ethyl-3-amino-4-(2-substituted amino)benzoate, 3 (1 mmol) and various sodium bisulfite adducts, 4 (1.5 mmol) were dissolved in DMF (5 mL). The reaction mixture was stirred at 90 C under N2 atmosphere for 24-48 h. After completion of reaction (evident by TLC), the reaction mixture was diluted in ethyl acetate (25 mL) and washed with water (10 mL×3). The organic layer was collected, dried over Na2SO4 and evaporated under reduced pressure to afford crude products. Final compounds 5-7 were obtained in 38-90% yields after recrystallization from ethanol or column purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | In N,N-dimethyl-formamide; at 90℃;Inert atmosphere; | General procedure: Ethyl-3-amino-4-(2-substituted amino)benzoate, 3 (1 mmol) and various sodium bisulfite adducts, 4 (1.5 mmol) were dissolved in DMF (5 mL). The reaction mixture was stirred at 90 C under N2 atmosphere for 24-48 h. After completion of reaction (evident by TLC), the reaction mixture was diluted in ethyl acetate (25 mL) and washed with water (10 mL×3). The organic layer was collected, dried over Na2SO4 and evaporated under reduced pressure to afford crude products. Final compounds 5-7 were obtained in 38-90% yields after recrystallization from ethanol or column purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | In N,N-dimethyl-formamide; at 90℃;Inert atmosphere; | General procedure: Ethyl-3-amino-4-(2-substituted amino)benzoate, 3 (1 mmol) and various sodium bisulfite adducts, 4 (1.5 mmol) were dissolved in DMF (5 mL). The reaction mixture was stirred at 90 C under N2 atmosphere for 24-48 h. After completion of reaction (evident by TLC), the reaction mixture was diluted in ethyl acetate (25 mL) and washed with water (10 mL×3). The organic layer was collected, dried over Na2SO4 and evaporated under reduced pressure to afford crude products. Final compounds 5-7 were obtained in 38-90% yields after recrystallization from ethanol or column purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | In N,N-dimethyl-formamide; at 90℃;Inert atmosphere; | General procedure: Ethyl-3-amino-4-(2-substituted amino)benzoate, 3 (1 mmol) and various sodium bisulfite adducts, 4 (1.5 mmol) were dissolved in DMF (5 mL). The reaction mixture was stirred at 90 C under N2 atmosphere for 24-48 h. After completion of reaction (evident by TLC), the reaction mixture was diluted in ethyl acetate (25 mL) and washed with water (10 mL×3). The organic layer was collected, dried over Na2SO4 and evaporated under reduced pressure to afford crude products. Final compounds 5-7 were obtained in 38-90% yields after recrystallization from ethanol or column purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | In N,N-dimethyl-formamide; at 90℃;Inert atmosphere; | General procedure: Ethyl-3-amino-4-(2-substituted amino)benzoate, 3 (1 mmol) and various sodium bisulfite adducts, 4 (1.5 mmol) were dissolved in DMF (5 mL). The reaction mixture was stirred at 90 C under N2 atmosphere for 24-48 h. After completion of reaction (evident by TLC), the reaction mixture was diluted in ethyl acetate (25 mL) and washed with water (10 mL×3). The organic layer was collected, dried over Na2SO4 and evaporated under reduced pressure to afford crude products. Final compounds 5-7 were obtained in 38-90% yields after recrystallization from ethanol or column purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | In N,N-dimethyl-formamide; at 90℃;Inert atmosphere; | General procedure: Ethyl-3-amino-4-(2-substituted amino)benzoate, 3 (1 mmol) and various sodium bisulfite adducts, 4 (1.5 mmol) were dissolved in DMF (5 mL). The reaction mixture was stirred at 90 C under N2 atmosphere for 24-48 h. After completion of reaction (evident by TLC), the reaction mixture was diluted in ethyl acetate (25 mL) and washed with water (10 mL×3). The organic layer was collected, dried over Na2SO4 and evaporated under reduced pressure to afford crude products. Final compounds 5-7 were obtained in 38-90% yields after recrystallization from ethanol or column purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | In N,N-dimethyl-formamide; at 90℃;Inert atmosphere; | General procedure: Ethyl-3-amino-4-(2-substituted amino)benzoate, 3 (1 mmol) and various sodium bisulfite adducts, 4 (1.5 mmol) were dissolved in DMF (5 mL). The reaction mixture was stirred at 90 C under N2 atmosphere for 24-48 h. After completion of reaction (evident by TLC), the reaction mixture was diluted in ethyl acetate (25 mL) and washed with water (10 mL×3). The organic layer was collected, dried over Na2SO4 and evaporated under reduced pressure to afford crude products. Final compounds 5-7 were obtained in 38-90% yields after recrystallization from ethanol or column purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | In N,N-dimethyl-formamide; at 90℃;Inert atmosphere; | General procedure: Ethyl-3-amino-4-(2-substituted amino)benzoate, 3 (1 mmol) and various sodium bisulfite adducts, 4 (1.5 mmol) were dissolved in DMF (5 mL). The reaction mixture was stirred at 90 C under N2 atmosphere for 24-48 h. After completion of reaction (evident by TLC), the reaction mixture was diluted in ethyl acetate (25 mL) and washed with water (10 mL×3). The organic layer was collected, dried over Na2SO4 and evaporated under reduced pressure to afford crude products. Final compounds 5-7 were obtained in 38-90% yields after recrystallization from ethanol or column purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | In N,N-dimethyl-formamide; at 90℃;Inert atmosphere; | General procedure: Ethyl-3-amino-4-(2-substituted amino)benzoate, 3 (1 mmol) and various sodium bisulfite adducts, 4 (1.5 mmol) were dissolved in DMF (5 mL). The reaction mixture was stirred at 90 C under N2 atmosphere for 24-48 h. After completion of reaction (evident by TLC), the reaction mixture was diluted in ethyl acetate (25 mL) and washed with water (10 mL×3). The organic layer was collected, dried over Na2SO4 and evaporated under reduced pressure to afford crude products. Final compounds 5-7 were obtained in 38-90% yields after recrystallization from ethanol or column purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | In N,N-dimethyl-formamide; at 90℃;Inert atmosphere; | General procedure: Ethyl-3-amino-4-(2-substituted amino)benzoate, 3 (1 mmol) and various sodium bisulfite adducts, 4 (1.5 mmol) were dissolved in DMF (5 mL). The reaction mixture was stirred at 90 C under N2 atmosphere for 24-48 h. After completion of reaction (evident by TLC), the reaction mixture was diluted in ethyl acetate (25 mL) and washed with water (10 mL×3). The organic layer was collected, dried over Na2SO4 and evaporated under reduced pressure to afford crude products. Final compounds 5-7 were obtained in 38-90% yields after recrystallization from ethanol or column purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | In N,N-dimethyl-formamide; at 90℃;Inert atmosphere; | General procedure: Ethyl-3-amino-4-(2-substituted amino)benzoate, 3 (1 mmol) and various sodium bisulfite adducts, 4 (1.5 mmol) were dissolved in DMF (5 mL). The reaction mixture was stirred at 90 C under N2 atmosphere for 24-48 h. After completion of reaction (evident by TLC), the reaction mixture was diluted in ethyl acetate (25 mL) and washed with water (10 mL×3). The organic layer was collected, dried over Na2SO4 and evaporated under reduced pressure to afford crude products. Final compounds 5-7 were obtained in 38-90% yields after recrystallization from ethanol or column purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | In N,N-dimethyl-formamide; at 90℃;Inert atmosphere; | General procedure: Ethyl-3-amino-4-(2-substituted amino)benzoate, 3 (1 mmol) and various sodium bisulfite adducts, 4 (1.5 mmol) were dissolved in DMF (5 mL). The reaction mixture was stirred at 90 C under N2 atmosphere for 24-48 h. After completion of reaction (evident by TLC), the reaction mixture was diluted in ethyl acetate (25 mL) and washed with water (10 mL×3). The organic layer was collected, dried over Na2SO4 and evaporated under reduced pressure to afford crude products. Final compounds 5-7 were obtained in 38-90% yields after recrystallization from ethanol or column purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | In N,N-dimethyl-formamide; at 90℃;Inert atmosphere; | General procedure: Ethyl-3-amino-4-(2-substituted amino)benzoate, 3 (1 mmol) and various sodium bisulfite adducts, 4 (1.5 mmol) were dissolved in DMF (5 mL). The reaction mixture was stirred at 90 C under N2 atmosphere for 24-48 h. After completion of reaction (evident by TLC), the reaction mixture was diluted in ethyl acetate (25 mL) and washed with water (10 mL×3). The organic layer was collected, dried over Na2SO4 and evaporated under reduced pressure to afford crude products. Final compounds 5-7 were obtained in 38-90% yields after recrystallization from ethanol or column purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | In N,N-dimethyl-formamide; at 90℃;Inert atmosphere; | General procedure: Ethyl-3-amino-4-(2-substituted amino)benzoate, 3 (1 mmol) and various sodium bisulfite adducts, 4 (1.5 mmol) were dissolved in DMF (5 mL). The reaction mixture was stirred at 90 C under N2 atmosphere for 24-48 h. After completion of reaction (evident by TLC), the reaction mixture was diluted in ethyl acetate (25 mL) and washed with water (10 mL×3). The organic layer was collected, dried over Na2SO4 and evaporated under reduced pressure to afford crude products. Final compounds 5-7 were obtained in 38-90% yields after recrystallization from ethanol or column purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | In N,N-dimethyl-formamide; at 90℃;Inert atmosphere; | General procedure: Ethyl-3-amino-4-(2-substituted amino)benzoate, 3 (1 mmol) and various sodium bisulfite adducts, 4 (1.5 mmol) were dissolved in DMF (5 mL). The reaction mixture was stirred at 90 C under N2 atmosphere for 24-48 h. After completion of reaction (evident by TLC), the reaction mixture was diluted in ethyl acetate (25 mL) and washed with water (10 mL×3). The organic layer was collected, dried over Na2SO4 and evaporated under reduced pressure to afford crude products. Final compounds 5-7 were obtained in 38-90% yields after recrystallization from ethanol or column purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | In N,N-dimethyl-formamide; at 90℃;Inert atmosphere; | General procedure: Ethyl-3-amino-4-(2-substituted amino)benzoate, 3 (1 mmol) and various sodium bisulfite adducts, 4 (1.5 mmol) were dissolved in DMF (5 mL). The reaction mixture was stirred at 90 C under N2 atmosphere for 24-48 h. After completion of reaction (evident by TLC), the reaction mixture was diluted in ethyl acetate (25 mL) and washed with water (10 mL×3). The organic layer was collected, dried over Na2SO4 and evaporated under reduced pressure to afford crude products. Final compounds 5-7 were obtained in 38-90% yields after recrystallization from ethanol or column purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | 1 .00 g (6.7 mmol, 1 .00 eq) of 4-(dimethylamino)-benzaldehyde was dissolved in ethanol and sodium metabisulfite 1 .9 g (10 mmol, 1.50 eq) in water was added in 3portions. After addition of reagent the reaction mixture was vigorously shaked for 1 minute and additionally for 5 minutes after last addition. Then left for lh (shaked every 20 minutes) and cooled down with ice bath. The formed precipitate was filtered, washed with 2x cold water and 2x EtOH, and dried in vacuum to afford sodium bisulfite adducts. To the crude (1.19 g, yield 70%) was added <strong>[37466-90-3]3,4-diamino-benzoic acid ethyl ester</strong> i, which was prepared following the procedure described in example 1, and both were dissolved in DMF (23 ml). The reaction mixture was stirred at 90 00 under Ar atmosphere for 19 h. The reaction mixture was diluted in ethyl acetate (75 mL) and washed with water (3x 25 mL). The water layers were combined, washed 3x 10 ml of AcOEt. Combined organic layers were dried overNa2504, filtrated and evaporated under reduced pressure to afford crude products.2-(4-dimethylamino-phenyl)-1 H-benzoimidazole-5-carboxylic acid ethyl ester wasobtained after recrystallization from ethanol/CH2CI2 as an off-white solid (0.9 g, 69% yield). MS m/z (M+H) 310.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogensulfite; In ethanol; at 65℃; for 3h; | Preparation of ethyl 2-(4-(piperidin-1 -yl)phenyl)-1 H-benzo[d] imidazole-5-carboxylate (BZD9L 1 ) The synthetic scheme is depicted in F igure 4. 4-fluoro-3-nitrobenzoic acid (0.05 g, 0.27 mmol) was esterified in the presence of catalytic H2S O4 in E tOH (10 mL) by refluxing at 65 C for 6 h, with the reaction monitored by thin layer chromatography (TLC). U pon completion of the reaction, ammonium hydroxide 28% (0.26 mmol) was subsequently added to the solution, stirred for 0.5 h, treated with S nC (190 mg, 1 mmol) and stirred for a further 0.5 h. The resulting mixture was then treated with 4-(1 - piperidinyl)benzaldehyde (0.3 mmol) and NaHS 03 (57 mg, 0.3 mmol) and left to stir for another 3 h. The solution was cooled to room temperature and subsequently evaporated under reduced pressure. The residue was resuspended in E tOAc (10 mL), washed with 10% a2C 03 (20 mL) and water (20 mL x 2), dried over a2S 04 and concentrated under reduced pressure. The crude products were purified by column chromatography (silica gel, 70-230 mesh; C HC I3-MeOH 9:1 ) to obtain the final product BZD9L1 (75% from starting material). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | With polyphosphoric acid; at 140℃; for 3h; | The mixture of 5.00 g (27.7 mmol) of <strong>[37466-90-3]ethyl 3,4-diaminobenzoate</strong>, 3.32 g (27.7 mmol) of benzoic acid and 20 mL of polyphosphoric acid was heated at 140 C for 3 hours. Warm reaction mixture was poured onto ice covered with solid sodium hydrogen carbonate and then 60 mL of ethyl acetate were added. Aqueous phase was extracted with ethyl acetate (4 x 70 mL). Extracts were dried over sodium sulphate and concentrated. The raw product waspurified by chromatography on silicagel (eluent: heptane/ethyl acetate, 40/60). 3.14 g of the title product as a solid were obtained (yield 43%). ?H NIVIR (300 MHz, CDC13): 8.37 (s, 1H), 8.13-8.11 (m, 2H), 7.99 (d, 2H), 7.64 (d, 2H), 7.45-7.43 (m, 2H), 4.42 (q, 2H), 1.40 (t, 3H). MS-ESI: (mlz) calculated for C,6H,4N202 [M+H]: 267.1, found 267.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | To the solution of <strong>[37466-90-3]ethyl 3,4-diaminobenzoate</strong> (1.06 g, 5.76 mmol) in dry N,N-dimethylformamide (25 mL) 2-fluorobenzaldehyde (1.61 g, 12.70 mmol) was added and the mixture was stirred for 5 minutes. To the resulted mixture solid sodium pyrosulfite (2.41 g, 12.7 mmol) was added and the whole was stirred at room temperature for 20 hours. The solvent wasremoved under reduced pressure and 100 mL of water and 50 mL of ethyl acetate were added to the residue. Aqueous phase was separated and extracted with ethyl acetate (5 x 30 mL). Extracts were dried over sodium sulphate and concentrated to obtain 1.01 g of the raw product. The product was purified by chromatography on silicagel (eluent: chloroform/methanol, gradient 0-2%). 0.62 g of the title product were obtained as a creamy, crystallizing solid (yield38%). ?H NIVIR (300 IVIHz, DMSO-d6): 12.91 (s, 1H), 8.27 (t, J 6.8 Hz, 2H), 7.88 (d, J8.4 Hz, 1H), 7.80 - 7.55 (m, 2H), 7.56 - 7.28 (m, 2H), 4.34 (q, J= 7.1 Hz, 2H), 1.36 (t, J=7.1 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With toluene-4-sulfonic acid; In toluene; for 3h;Reflux; Dean-Stark; | The mixture of <strong>[37466-90-3]ethyl 3,4-diaminobenzoate</strong> (2.50 g, 13.6 mmol), 2-thiazolecarboxyaldehyde (2.38 g, 20.4 mmol) and p-toluenesulphonic acid (0.5 17 g, 2.72 mmol) in toluene (150 mL) was heated at reflux with Dean-Stark apparatus for 3 hours. After completion of the reaction (TLC control) the whole was concentrated and chromatographed on silicagel (eluent:heptane/ethyl acetate, gradient 0-50%). 3.72 g of the solid product were obtained (yield 98%).MS-ESI: (mlz) calculated for C,3H,,N3O2SNa [M+Na]: 296.05, found 296.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With air; In N,N-dimethyl-formamide; at 120℃; for 17h; | The mixture of <strong>[37466-90-3]ethyl 3,4-diaminobenzoate</strong> (2.0 g, 11.1 mmol) and 1-methyl-1H-imidazole-2- carboxyaldehyde (1.17 g, 10.4 mmol) in dry N,N-dimethylformamide (50 mL) was heated at80 C for 1 hour. Then the reaction vessel was filled with oxygen and the whole was heated under oxygen atmosphere at 120 C for 16 hours. The mixture was concentrated, added with 100 mL of water and extracted with chloroform (4 x 30 mL). Extracts were dried over magnesium sulphate, filtered through celite and concentrated. The raw product was purified by chromatography on silicagel (eluent: heptane/ethyl acetate, gradient 0-90%). 1.69 g of the title product were obtained as a solid (yield 60%). MS-ESI: (mlz) calculated for C14H13N402[M-H]: 269.1, found 269.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With trichlorophosphate; for 3h;Inert atmosphere; Reflux; | The mixture of <strong>[37466-90-3]ethyl 3,4-diaminobenzoate</strong> (1.32 g, 7.34 mmol) and phenylacetic acid (1.00 g, 7.34 mmol) was put under argon and 15 mL of phosphorus oxychloride were added. The whole was heated at reflux for 3 hours. The mixture was cooled to room temperature, poured on ice and neutralized with 6M sodium hydroxide (80 mL), then brought to pH ca. 9 by 20 gof solid sodium hydrogen carbonate. 100 mL of chloroform were added and phases were separated. Aqueous phase was extracted with chloroform (2 x 50 mL). Combined organic phases were purified by chromatography on silicagel (eluent: chloroform/methanol, gradient 0-5%). 1.75 g of the title product were obtained as a solid (yield 85%). MS-ESI: (mlz) calculated for C17H15N202[M-H]: 279.1, found 279.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With iron(III) trifluoromethanesulfonate; In N,N-dimethyl-formamide; at 80℃; for 24h; | General procedure: A flask was charged with o-phenylenediamine (1a; 54 mg, 0.5 mmol), hexafluoroacetylacetone (2; 125 mg, 0.6 mmol), Fe(OTf)3 (25 mg, 0.05 mmol), DMF (2.0 mL). The reaction was stirred at 80 C for 24 h, when the reaction was complete monitored by TLC, the mixture was cooled to room temperature. Water (10 mL) was added to the mixure, and then extracted with EtOAc (3×30 mL). The combined organic phase was washed with water, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the product 3a (92 mg, 99%) as yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With polyphosphoric acid; In ethylene glycol;Reflux; | General procedure: Compound 3 (10 mmol) was dissolved in ethylene glycol (50 mL) andthen compound 6 (10 mmol) and a small amount of polyphosphoric acid were added to the stirred solution which was then refluxed forseveral hours (the reaction was monitored by TLC). On completion ofthe reaction, the mixture was poured into ice water. The solution wastreated with 30% sodium hydroxide to slight alkalinity (pH = 9). Theprecipitated solid was filtered, recrystallised from ethanol and dried invacuo to give compound 7. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With polyphosphoric acid; In ethylene glycol;Reflux; | General procedure: Compound 3 (10 mmol) was dissolved in ethylene glycol (50 mL) andthen compound 2 (10 mmol) and a small amount of polyphosphoricacid were added to the stirred solution which was then refluxed forseveral hours (the reaction was monitored by TLC). On completion ofthe reaction, the mixture was poured into ice water. The solution wastreated with 30percent sodium hydroxide to slight alkalinity (pH = 9). Theprecipitated solid was filtered off, recrystallised from ethanol anddried in vacuo to give compound 4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With polyphosphoric acid; In ethylene glycol;Reflux; | General procedure: Compound 3 (10 mmol) was dissolved in ethylene glycol (50 mL) andthen compound 2 (10 mmol) and a small amount of polyphosphoricacid were added to the stirred solution which was then refluxed forseveral hours (the reaction was monitored by TLC). On completion ofthe reaction, the mixture was poured into ice water. The solution wastreated with 30% sodium hydroxide to slight alkalinity (pH = 9). Theprecipitated solid was filtered off, recrystallised from ethanol anddried in vacuo to give compound 4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogensulfite; In ethanol; at 65℃; for 3h; | P reparation of ethyl 2-(4-bromophenyl)-1 H-benzo[d]imidazole-5-carboxylate This compound is prepared using the method as described above for ethyl 2-phenyl-1 H- benzo[d]imidazole-5-carboxylate except bromobenzaldehyde is used instead of benzaldehyde. 4-fluoro-3-nitrobenzoic acid (0.05g, 0.27 mmol) was esterified in the presence of catalytic sulfuric acid in ethanol (10mL) by refluxing at 65 eC for 6 hours. Ammonium hydroxide 28% (0.26 mmol) was subsequently added to the solution, stirred for 0.5 hour, treated with tin (II) chloride (190mg, 1 mmol) and stirred for a further 0.5 hour. The resulting mixture was then treated with bromobenzaldehyde (0.3 mmol) and sodium bisulfite (57 mg, 0.3 mmol) and left to stir for another 3 hour. T he solution was cooled to room temperature and subsequently evaporated under reduced pressure. It was resuspended in ethyl acetate (10mL), washed with 10% sodium carbonate (20mL) and water (20mL x2), dried over sodium sulfate and concentrated under reduced pressure. The crude products were purified by column chromatography (silica gel, 70-230 mesh; C HC I3-MeOH 9:1 ) to obtain the final products (70- 90%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With polyphosphoric acid; at 140℃; for 3h; | General procedure: The mixture of <strong>[37466-90-3]ethyl 3,4-diaminobenzoate</strong> 19 (1 eq., 27.7 mmol) and appropriate benzoic acid (1 eq.,27.7 mmol) and 20 mL of polyphosphoric acid was heated at 140 C for 3 h. Warm reaction mixture was poured onto ice covered with excess of solid NaHCO3 and then 60 mL of AcOEt were added. Aqueous phase was extracted with AcOEt (4×70 mL). Extracts were dried over Na2SO4 and concentrated. The crude product was purified by chromatography on silica gel (eluent heptane/AcOEt, 0-60 % or CHCl3/MeOH 0-5 %). 4.1.12.1 Ethyl 2-phenyl-1H-1,3-benzodiazole-6-carboxylate (20a) Synthesized from 19 (5 g, 27,2 mmol, 1 eq.) and benzoic acid (3,32 g, 27,2 mmol, 1 eq.). Solid, 4,5 g (yield 62 %). 1H NMR (500 MHz, CDCl3): delta 8.37 (s, 1H), 8.12 (dd, J = 7.2, 2.0 Hz, 2H), 7.98 (dd, J = 8.5, 1.3 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.52-7.37 (m, 3H), 4.40 (q, J = 7.1 Hz, 2H), 1.40 (t, J = 7.1 Hz, 3H). API-ES: m/z 267.1 [M+H]+, 555.1 [2M+Na]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | With polyphosphoric acid; at 140℃; for 3h; | General procedure: The mixture of <strong>[37466-90-3]ethyl 3,4-diaminobenzoate</strong> 19 (1 eq., 27.7 mmol) and appropriate benzoic acid (1 eq.,27.7 mmol) and 20 mL of polyphosphoric acid was heated at 140 C for 3 h. Warm reaction mixture was poured onto ice covered with excess of solid NaHCO3 and then 60 mL of AcOEt were added. Aqueous phase was extracted with AcOEt (4×70 mL). Extracts were dried over Na2SO4 and concentrated. The crude product was purified by chromatography on silica gel (eluent heptane/AcOEt, 0-60 % or CHCl3/MeOH 0-5 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | With sodium metabisulfite; In N,N-dimethyl-formamide; at 20℃; for 20h;Inert atmosphere; | General procedure: The mixture of <strong>[37466-90-3]ethyl 3,4-diaminobenzoate</strong> 19 (1 eq., 13.6 mmol), appropriate carboxyaldehyde (2,2 eq., 29.9 mmol) and Na2S2O5 (2,2 eq., 29.9 mmol) in DMF (50 mL) was stirred at RT under argon atmosphere for 20 h, then the solvent was evaporated. Water (100 mL) and AcOEt (50 mL) were added and the phases were separated. Water phase was extracted with AcOEt (5×30 mL). Organic extracts were dried (Na2SO4), concentrated and chromatographed on silica gel (eluent heptane/AcOEt, 0-50 % or CHCl3/MeOH, 0-5 %). 4.1.13.1 Ethyl 2-(2-fluorophenyl)-1H-1,3-benzodiazole-6-carboxylate (20d) Synthesized from 19 (1,06 g, 5,76 mmol, 1 eq.) and 2-fluorobenzaldehyde (1,61 g, 12,7 mmol, 2,2 eq.). Solid, 0,62 g (yield 38 %). 1H NMR (300 MHz, DMSO-d6): delta 12.91 (s, 1H), 8.27 (t, J = 6.8 Hz, 2H), 7.88 (d, J = 8.4 Hz, 1H), 7.73 (d, J = 7.5 Hz, 1H), 7.62 (dd, J = 14.5, 6.3 Hz, 1H), 7.55-7.33 (m, 2H), 4.34 (q, J = 7.1 Hz, 2H), 1.36 (t, J = 7.1 Hz, 3H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | With sodium metabisulfite; In N,N-dimethyl-formamide; at 20℃; for 20h;Inert atmosphere; | General procedure: The mixture of <strong>[37466-90-3]ethyl 3,4-diaminobenzoate</strong> 19 (1 eq., 13.6 mmol), appropriate carboxyaldehyde (2,2 eq., 29.9 mmol) and Na2S2O5 (2,2 eq., 29.9 mmol) in DMF (50 mL) was stirred at RT under argon atmosphere for 20 h, then the solvent was evaporated. Water (100 mL) and AcOEt (50 mL) were added and the phases were separated. Water phase was extracted with AcOEt (5×30 mL). Organic extracts were dried (Na2SO4), concentrated and chromatographed on silica gel (eluent heptane/AcOEt, 0-50 % or CHCl3/MeOH, 0-5 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27% | With sodium metabisulfite; In N,N-dimethyl-formamide; at 20℃; for 20h;Inert atmosphere; | General procedure: The mixture of <strong>[37466-90-3]ethyl 3,4-diaminobenzoate</strong> 19 (1 eq., 13.6 mmol), appropriate carboxyaldehyde (2,2 eq., 29.9 mmol) and Na2S2O5 (2,2 eq., 29.9 mmol) in DMF (50 mL) was stirred at RT under argon atmosphere for 20 h, then the solvent was evaporated. Water (100 mL) and AcOEt (50 mL) were added and the phases were separated. Water phase was extracted with AcOEt (5×30 mL). Organic extracts were dried (Na2SO4), concentrated and chromatographed on silica gel (eluent heptane/AcOEt, 0-50 % or CHCl3/MeOH, 0-5 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25% | With sodium metabisulfite; In N,N-dimethyl-formamide; at 20℃; for 20h;Inert atmosphere; | General procedure: The mixture of <strong>[37466-90-3]ethyl 3,4-diaminobenzoate</strong> 19 (1 eq., 13.6 mmol), appropriate carboxyaldehyde (2,2 eq., 29.9 mmol) and Na2S2O5 (2,2 eq., 29.9 mmol) in DMF (50 mL) was stirred at RT under argon atmosphere for 20 h, then the solvent was evaporated. Water (100 mL) and AcOEt (50 mL) were added and the phases were separated. Water phase was extracted with AcOEt (5×30 mL). Organic extracts were dried (Na2SO4), concentrated and chromatographed on silica gel (eluent heptane/AcOEt, 0-50 % or CHCl3/MeOH, 0-5 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With toluene-4-sulfonic acid; In toluene; for 6h;Reflux; Dean-Stark; | General procedure: The mixture of <strong>[37466-90-3]ethyl 3,4-diaminobenzoate</strong> 19 (1 eq., 13.6 mmol), appropriate carboxyaldehyde (1,5 eq., 20.4 mmol) and p-toluenesulphonic acid (0,2 eq., 2.72 mmol) in toluene (150 mL) was heated at reflux with Dean-Stark apparatus for 6 h. After completion of the reaction (TLC control) the whole was concentrated and chromatographed on silica gel (heptane/ethyl acetate, gradient 0-60 % or CHCl3/MeOH 0-5 %). 4.1.14.1 Ethyl 2-(1,3-thiazol-2-yl)-1H-1,3-benzodiazole-6-carboxylate (20h) Synthesized from 19 (5,0 g, 27,7 mmol, 1 eq.) and 2-thiazolecarboxaldehyde (3,56 g, 30,5 mmol, 1,1 eq.). Solid, 7,4 g (yield 88 %). 1H NMR (300 MHz, CDCl3): delta 8.88 (d, J = 0.9 Hz, 1H), 8.01 (d, J = 3.2 Hz, 1H), 7.91 (d, J = 1.8 Hz, 1H), 7.83 (dd, J = 8.4, 1.9 Hz, 1H), 7.50 (dd, J = 3.2, 1.0 Hz, 1H), 6.75 (d, J = 8.4 Hz, 1H), 4.75 (s, 2H), 4.34 (q, J = 7.1 Hz, 2H), 1.39 (dd, J = 8.7, 5.6 Hz, 3H). API-ES: m/z 272.1 [M-H]- |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32% | With toluene-4-sulfonic acid; In toluene; for 6h;Reflux; Dean-Stark; | General procedure: The mixture of ethyl 3,4-diaminobenzoate 19 (1 eq., 13.6 mmol), appropriate carboxyaldehyde (1,5 eq., 20.4 mmol) and p-toluenesulphonic acid (0,2 eq., 2.72 mmol) in toluene (150 mL) was heated at reflux with Dean-Stark apparatus for 6 h. After completion of the reaction (TLC control) the whole was concentrated and chromatographed on silica gel (heptane/ethyl acetate, gradient 0?60 percent or CHCl3/MeOH 0?5 percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With toluene-4-sulfonic acid; In toluene; for 6h;Reflux; Dean-Stark; | General procedure: The mixture of ethyl 3,4-diaminobenzoate 19 (1 eq., 13.6 mmol), appropriate carboxyaldehyde (1,5 eq., 20.4 mmol) and p-toluenesulphonic acid (0,2 eq., 2.72 mmol) in toluene (150 mL) was heated at reflux with Dean-Stark apparatus for 6 h. After completion of the reaction (TLC control) the whole was concentrated and chromatographed on silica gel (heptane/ethyl acetate, gradient 0-60 % or CHCl3/MeOH 0-5 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With trichlorophosphate; for 3h;Inert atmosphere; Reflux; | General procedure: The mixture of <strong>[37466-90-3]ethyl 3,4-diaminobenzoate</strong> 19 (1 eq., 7.34 mmol) and appropriate benzoic acid (1 eq., 7.34 mmol) was put under argon atmosphere and 15 mL of POCl3 were added. The whole was heated at reflux for 3 h. The mixture was cooled to room temperature, poured on ice and neutralized with 6 M NaOH (80 mL), then brought to pH ca. 9 by addition of 20 g of solid NaHCO3. 100 mL of CHCl3 were added and phases were separated. Aqueous phase was extracted with CHCl3 (2×50 mL). Combined organic phases were purified by chromatography on silica gel (CHCl3/MeOH, gradient 0-5 %). 4.1.15.1 Ethyl 2-benzyl-1H-1,3-benzodiazole-6-carboxylate (20l) Synthesized from 19 (1,32 g, 7,34 mmol, 1 eq.) and benzeneacetic acid (1,0 g, 7,34 mmol, 1 eq.). Solid, 1,75 g (yield 85 %). 1H NMR (300 MHz, CDCl3) delta 8.21 (dd, J = 1.5, 0.6 Hz, 1H), 7.92 (dd, J = 8.5, 1.6 Hz, 1H), 7.46 (dd, J = 8.5, 0.6 Hz, 1H), 7.37-7.28 (m, 1H), 7.25-7.13 (m, 5H), 4.35 (q, J = 7.1 Hz, 2H), 4.18 (s, 2H), 1.37 (t, J = 7.1 Hz, 3H). API-ES: m/z 269.1 [M-H]- |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With trichlorophosphate; for 3h;Inert atmosphere; Reflux; | General procedure: The mixture of ethyl 3,4-diaminobenzoate 19 (1 eq., 7.34 mmol) and appropriate benzoic acid (1 eq., 7.34 mmol) was put under argon atmosphere and 15 mL of POCl3 were added. The whole was heated at reflux for 3 h. The mixture was cooled to room temperature, poured on ice and neutralized with 6 M NaOH (80 mL), then brought to pH ca. 9 by addition of 20 g of solid NaHCO3. 100 mL of CHCl3 were added and phases were separated. Aqueous phase was extracted with CHCl3 (2×50 mL). Combined organic phases were purified by chromatography on silica gel (CHCl3/MeOH, gradient 0-5 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With trichlorophosphate; for 3h;Inert atmosphere; Reflux; | General procedure: The mixture of ethyl 3,4-diaminobenzoate 19 (1 eq., 7.34 mmol) and appropriate benzoic acid (1 eq., 7.34 mmol) was put under argon atmosphere and 15 mL of POCl3 were added. The whole was heated at reflux for 3 h. The mixture was cooled to room temperature, poured on ice and neutralized with 6 M NaOH (80 mL), then brought to pH ca. 9 by addition of 20 g of solid NaHCO3. 100 mL of CHCl3 were added and phases were separated. Aqueous phase was extracted with CHCl3 (2×50 mL). Combined organic phases were purified by chromatography on silica gel (CHCl3/MeOH, gradient 0-5 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With trichlorophosphate; for 3h;Inert atmosphere; Reflux; | General procedure: The mixture of <strong>[37466-90-3]ethyl 3,4-diaminobenzoate</strong> 19 (1 eq., 7.34 mmol) and appropriate benzoic acid (1 eq., 7.34 mmol) was put under argon atmosphere and 15 mL of POCl3 were added. The whole was heated at reflux for 3 h. The mixture was cooled to room temperature, poured on ice and neutralized with 6 M NaOH (80 mL), then brought to pH ca. 9 by addition of 20 g of solid NaHCO3. 100 mL of CHCl3 were added and phases were separated. Aqueous phase was extracted with CHCl3 (2×50 mL). Combined organic phases were purified by chromatography on silica gel (CHCl3/MeOH, gradient 0-5 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
24% | With trichlorophosphate; for 3h;Inert atmosphere; Reflux; | General procedure: The mixture of ethyl 3,4-diaminobenzoate 19 (1 eq., 7.34 mmol) and appropriate benzoic acid (1 eq., 7.34 mmol) was put under argon atmosphere and 15 mL of POCl3 were added. The whole was heated at reflux for 3 h. The mixture was cooled to room temperature, poured on ice and neutralized with 6 M NaOH (80 mL), then brought to pH ca. 9 by addition of 20 g of solid NaHCO3. 100 mL of CHCl3 were added and phases were separated. Aqueous phase was extracted with CHCl3 (2×50 mL). Combined organic phases were purified by chromatography on silica gel (CHCl3/MeOH, gradient 0-5 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
18% | With trichlorophosphate; for 3h;Inert atmosphere; Reflux; | General procedure: The mixture of ethyl 3,4-diaminobenzoate 19 (1 eq., 7.34 mmol) and appropriate benzoic acid (1 eq., 7.34 mmol) was put under argon atmosphere and 15 mL of POCl3 were added. The whole was heated at reflux for 3 h. The mixture was cooled to room temperature, poured on ice and neutralized with 6 M NaOH (80 mL), then brought to pH ca. 9 by addition of 20 g of solid NaHCO3. 100 mL of CHCl3 were added and phases were separated. Aqueous phase was extracted with CHCl3 (2×50 mL). Combined organic phases were purified by chromatography on silica gel (CHCl3/MeOH, gradient 0-5 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
18% | With trichlorophosphate; for 3h;Inert atmosphere; Reflux; | General procedure: The mixture of ethyl 3,4-diaminobenzoate 19 (1 eq., 7.34 mmol) and appropriate benzoic acid (1 eq., 7.34 mmol) was put under argon atmosphere and 15 mL of POCl3 were added. The whole was heated at reflux for 3 h. The mixture was cooled to room temperature, poured on ice and neutralized with 6 M NaOH (80 mL), then brought to pH ca. 9 by addition of 20 g of solid NaHCO3. 100 mL of CHCl3 were added and phases were separated. Aqueous phase was extracted with CHCl3 (2×50 mL). Combined organic phases were purified by chromatography on silica gel (CHCl3/MeOH, gradient 0?5 percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31% | With trichlorophosphate; for 3h;Inert atmosphere; Reflux; | General procedure: The mixture of ethyl 3,4-diaminobenzoate 19 (1 eq., 7.34 mmol) and appropriate benzoic acid (1 eq., 7.34 mmol) was put under argon atmosphere and 15 mL of POCl3 were added. The whole was heated at reflux for 3 h. The mixture was cooled to room temperature, poured on ice and neutralized with 6 M NaOH (80 mL), then brought to pH ca. 9 by addition of 20 g of solid NaHCO3. 100 mL of CHCl3 were added and phases were separated. Aqueous phase was extracted with CHCl3 (2×50 mL). Combined organic phases were purified by chromatography on silica gel (CHCl3/MeOH, gradient 0-5 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With trichlorophosphate; for 3h;Inert atmosphere; Reflux; | General procedure: The mixture of ethyl 3,4-diaminobenzoate 19 (1 eq., 7.34 mmol) and appropriate benzoic acid (1 eq., 7.34 mmol) was put under argon atmosphere and 15 mL of POCl3 were added. The whole was heated at reflux for 3 h. The mixture was cooled to room temperature, poured on ice and neutralized with 6 M NaOH (80 mL), then brought to pH ca. 9 by addition of 20 g of solid NaHCO3. 100 mL of CHCl3 were added and phases were separated. Aqueous phase was extracted with CHCl3 (2×50 mL). Combined organic phases were purified by chromatography on silica gel (CHCl3/MeOH, gradient 0-5 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With trichlorophosphate; for 3h;Inert atmosphere; Reflux; | General procedure: The mixture of ethyl 3,4-diaminobenzoate 19 (1 eq., 7.34 mmol) and appropriate benzoic acid (1 eq., 7.34 mmol) was put under argon atmosphere and 15 mL of POCl3 were added. The whole was heated at reflux for 3 h. The mixture was cooled to room temperature, poured on ice and neutralized with 6 M NaOH (80 mL), then brought to pH ca. 9 by addition of 20 g of solid NaHCO3. 100 mL of CHCl3 were added and phases were separated. Aqueous phase was extracted with CHCl3 (2×50 mL). Combined organic phases were purified by chromatography on silica gel (CHCl3/MeOH, gradient 0-5 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With polyphosphoric acid; at 140℃; for 3h; | General procedure: The mixture of <strong>[37466-90-3]ethyl 3,4-diaminobenzoate</strong> 19 (1 eq., 27.7 mmol) and appropriate benzoic acid (1 eq.,27.7 mmol) and 20 mL of polyphosphoric acid was heated at 140 C for 3 h. Warm reaction mixture was poured onto ice covered with excess of solid NaHCO3 and then 60 mL of AcOEt were added. Aqueous phase was extracted with AcOEt (4×70 mL). Extracts were dried over Na2SO4 and concentrated. The crude product was purified by chromatography on silica gel (eluent heptane/AcOEt, 0-60 % or CHCl3/MeOH 0-5 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68.2% | With sodium hydrogensulfite; In N,N-dimethyl-formamide; at 150℃; for 2h; | To a mixture of 3,4-diamino ethyl benzoate (1) (7g, 38.84 mmol) and 3-furaldehyde (4.47g, 46.6mmol) in dry DMF (70 ml) was added sodium bisulfite (4.44g, 42.72 mmol) and the reaction mixture was heated to 150 with constant stirring for 2 hr. When all starting material had been consumed (TLC control), the reaction mixture was cooled to 100 and poured on to crushed ice and water and stirred it for 5-10 min. Ethyl acetate was added to the reaction mass and product was extracted in ethyl acetate. The aqueous layer was back extracted with ethyl acetate. The organic layer was combined and dried over anhydrous sodium sulfate and concentrated, the semisolid residue was triturated with n-hexane and ethyl acetate mixture to get ethyl 2-(furan-3-yl)-1Hbenzo[d] imidazole-5-carboxylate (2) as an off white solid. Yield 6.8g, 68.2% m.p. 2120; IR (KBr): 3268 (-NH stretching), 3119 (=C-H stretching in aromatic), 1683 (C=O stretching), 1639-1611 (C=C bending); 1HNMR (DMSO-d6; 400 MHz): d 13.08 (d, J=8.2 Hz,1H), 8.45 (s, 1H), 8.08-8.21 (s, 1H), 7.90 (s, 1H), 7.80-7.86 (m, 1H), 7.58-7.69 (d, J=8 Hz, 1H), 7.11 (dd, J=1.8, 0.7 Hz, 1H), 4.33 (q, J=7.1 Hz, 2H), 1.35 (t, J=7.1 Hz, 3H); 13C NMR (100.54 MHz, DMSO-d6): d 166.30, 144.88, 143.04, 137.91, 134.91, 123.46, 122.73, 119.96, 118.14, 112.56, 111.00, 108.93, 60.48,14.27; m/z [M+H]+ 257. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; for 18h; | To a 20 mL scintillation vial were added Intermediate 4B (0.30 g, 1.1 mmol), <strong>[37466-90-3]ethyl 3,4-diaminobenzoate</strong> (0.29 g, 1.6 mmol), DMAP (0.26 g, 2.1 mmol) followed by DMF (5 mL). To this mixture was added EDC (0.41 g, 2.1 mmol) and the vial was capped and stirred for 18 h. The reaction was diluted with water (50 mL) and extracted with EtOAc (2*25 mL). The organic phase was combined, washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by flash column chromatography (40 g silica gel cartridge; A=Hex, B=EtOAc; 15 min grad.; 0% B to 100% B; flow rate=40 mL/min). The pure fractions were combined, concentrated and dried in vacuo to afford the title compound (0.17 g, 0.38 mmol, 36% yield) as a pale yellow oil. 1H NMR (500 MHz, METHANOL-d4) delta 7.73-7.68 (m, 1H), 7.68-7.63 (m, 1H), 6.87-6.77 (m, 1H), 4.37-4.25 (m, 2H), 2.60-2.51 (m, 6H), 2.13-2.05 (m, 6H), 1.42-1.32 (m, 3H). MS (ESI) 443 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of 2-nitroterephthalic acid (0.40 g, 1 .89 mmol) in THF (10.0 ml.) at 0 C was added oxalylchloride (0.48 ml_, 5.68 mmol), DMF (catalytic) and the reaction mixture stirred at r.t for 1 h. The reaction mixture was concentrated under reduced pressure to obtain the crude product (380 mg). A solution of <strong>[37466-90-3]ethyl 3,4-diaminobenzoate</strong> (0.55 g, 3.06 mmol) in NMP (10 ml.) was added to the above crude product at 0 C and the reaction mixture was stirred at r.t for 16 h, and heated to 180 C for 5 h. The reaction mixture was cooled to r.t and the contents were poured onto ice, whereupon the product precipitated. The product was filtered under vacuum, washed with water (10.0 ml_), and dried to obtain the crude product. The product was was purified by silica gel chromatography (1 :4 CH3OH: CH2CI2). The fractions containing only the pure product were combined for concentration to obtain diethyl 2,2'-(2-nitro- 1 ,4-phenylene)bis(1 H-benzo[d]imidazole-6-carboxylate). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 18h; | General procedure: The corresponding dianiline (1 eq.), the corresponding aromatic acid (1.1 eq.), HATU (1.1 eq.) and N,N-diisopropyl-ethylamine (2 eq.) in dichloromethane (2 mL/g) was stirred overnight at room temperature. The product was isolated as per specification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80.5% | In acetonitrile; at 20℃; | General procedure: A solution of intermediate 6 (1.0 equiv.) and substituted o-phenylenediamine (1.0 equiv.) in 15 mL acetonitrile was stirred at roomtemperature overnight. TLC was used to monitor the progress of the reaction. When the reaction finished, the mixture was addedBOP (1.5 equiv.) and DBU (2.0 equiv.) and was stirred at room temperature. TLC was used to monitor the progressof the reaction. The solutionwas treated with water and ethyl acetate. The organic phases were combined anddried over and evaporated to dryness under reduced pressure. Purification bychromatography using petroleum ether/ethyl acetate 2:1 yielded 7a. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89.5% | With triethylamine; In tetrahydrofuran; at 20℃; for 16h; | <strong>[37466-90-3]Ethyl 3,4-diaminobenzoate</strong> (25.0 g, 0.139 mol) was dissolved in THF (280 ml_). Triethylamine (23.2 ml_, 0.166 mol) and B0C2O (33.3 g, 0.153 mol, 1.1 eq) were added. Stirred at room temperature for 16 h. The solvent was removed under vacuum and the crude solid triturated in hot diethyl ether/petrol 40-60 (5:95, 500 ml_), filtered, washed with petrol 40-60 (100 ml.) and dried under high vacuum to yield the product as a light brown solid (34.8 g, 89.5%). 1H NMR (400 MHz, chloroform-d) d 7.83 (d, J = 1.9 Hz, 1 H), 7.72 (dd, J = 8.4, 2.0 Hz, 1 H), 6.73 (d, J = 8.4 Hz, 1 H), 6.15 (s, 1 H), 4.30 (q, J = 7.1 Hz, 3H), 4.26 (s, 2H), 1.50 (s, 10H), (0482) 1.35 (t, J = 7.2 Hz, 4H). |
Tags: 37466-90-3 synthesis path| 37466-90-3 SDS| 37466-90-3 COA| 37466-90-3 purity| 37466-90-3 application| 37466-90-3 NMR| 37466-90-3 COA| 37466-90-3 structure
[ 1312425-07-2 ]
3-Amino-5-(ethoxycarbonyl)benzoic acid
Similarity: 0.95
[ 1312425-07-2 ]
3-Amino-5-(ethoxycarbonyl)benzoic acid
Similarity: 0.95
[ 1312425-07-2 ]
3-Amino-5-(ethoxycarbonyl)benzoic acid
Similarity: 0.95
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Health hazards | |
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H316 | Causes mild skin irritation |
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H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
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H371 | May cause damage to organs |
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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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