Structure of 178686-24-3
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CAS No. : | 178686-24-3 |
Formula : | C9H9NO5 |
M.W : | 211.17 |
SMILES Code : | O=CC1=CC([N+]([O-])=O)=C(O)C(OCC)=C1 |
MDL No. : | MFCD00058678 |
InChI Key : | MDWLNBVKBMKTKN-UHFFFAOYSA-N |
Pubchem ID : | 584878 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302 |
Precautionary Statements: | P280-P305+P351+P338 |
Num. heavy atoms | 15 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.22 |
Num. rotatable bonds | 4 |
Num. H-bond acceptors | 5.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 53.97 |
TPSA ? Topological Polar Surface Area: Calculated from |
92.35 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
0.89 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.75 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.51 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
-0.2 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
-0.27 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
0.74 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.28 |
Solubility | 1.1 mg/ml ; 0.0052 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-3.31 |
Solubility | 0.104 mg/ml ; 0.000494 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-1.69 |
Solubility | 4.3 mg/ml ; 0.0204 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 |
No |
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 |
-6.35 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 |
0.0 |
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 |
3.0 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) |
2.27 |
* 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 piperidine; acetic acid; In toluene; at 100 - 115℃; for 15.0h;Heating / reflux; | Charge <strong>[178686-24-3]3-ethoxy-4-hydroxy-5-nitrobenzaldehyde</strong> 20g (0. 0947mole) of the formula 2 where R= ethyl and N, N-diethylamino cyanoacetamide of the formula (3) 14. 6g, (0.1042), acetic acid 3.13g and piperidine 4.45g along with toluene 200ml and heated to reflux temperature of about 100-115 C with continuous removal of water azeotrophically 15 hours. After the reaction is over the reaction mixture is concentrated to a volume of 20-30ml quenched in to dilute hydrochloric acid and chilled water 200ml and stirred for 60 minutes. The precipitated solid was filtered and dried to get 30g (95%), the HPLC purity is 94% (including isomer) of N, N-DIETHYL - 2-CYANO-3- (-3-ETHOXY-4-HYDROXY-5 NITROPHENYL) ACRYLAMIDE. The product is used as such directly to the. next stage. MR = 110.1- 117. 2 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With nitric acid; In water; acetic acid; for 17.0h; | a). 3-Ethoxy-4-hydroxy-5-nitro-benzaldehyde To a solution of 3-ethoxy-4-hydroxybenzaldehyde (5 g) in acetic acid (50 ml) was added nitric acid (1.4 ml) in 2 portions. The resulting suspension was stirred for 17 h. The solid was collected by filtration, washed with water and dried in vacuo.Yield: 5.07 g. | |
With nitric acid; acetic acid; for 17.0h; | Example 14; Propane- 1 -sulfonic acid r5-(3-cvano-2-methyl-5-oxo-7-propyl-l,4,5,6,7,8-hexahvdro- quinolin-4- vD-3 -ethoxy-2-(3 -methoxy-benzyloxy) -phenyll -amide(a). 3-Ethoxy-4-hvdroxy-5-nitro-benzaldehvdeTo a solution of 3-ethoxy-4-hydroxybenzaldehyde (5 g) in acetic acid (50 ml) was added nitric acid (1.4 ml) in 2 portions. The resulting suspension was stirred for 17 h. The solid was collected by filtration, washed with water and dried in vacuo.Yield: 5.07 g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetra-(n-butyl)ammonium iodide; potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 1.5h; | Example 4; 4-r3-Ethoxy-4-(3-methoxy-benzyloxy)-5-nitro-phenyll-2-methyl-5-oxo-7-propyl- 1,4,5, 6,7,8-hexahvdro-quinoline-3-carbonitrile(a). 3-Ethoxy-4-(3-methoxy-benzyloxy)-5-nitro-benzaldehvdeA mixture of <strong>[178686-24-3]5-nitro-3-ethoxy-4-hydroxybenzaldehyde</strong> (100 mg), 3-methoxybenzyl bromide (73 mul), potassium carbonate (144 mg) and tetrabutylammonium iodide (10 mg) in DMF (5 ml) was stirred at 60 0C for 90 min. The mixture was poured into water and extracted with ethyl acetate. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by chromatography on silicagel in heptane/ethyl acetate 2/1 (v/v) as eluent.Yield: 43 mg. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol; for 17.0h;Heating / reflux; | (b). 4-(3-Ethoxy-4-hvdroxy-5-nitro-phenviy2-methyl-5-oxo-7-propyl-l,4,5, 6,7,8- hexahydro-quinoline-3 -carbonitrileA mixture of <strong>[178686-24-3]3-ethoxy-4-hydroxy-5-nitro-benzaldehyde</strong> (1.5 g), 3-aminocrotonitrile (584 mg) and 5-propylcyclohexane-l,3-dione (1.09 g) in ethanol (60 ml) was heated at reflux for 17 h. The mixture was concentrated in vacuo. The residue was purified by chromatography on silicagel in heptane/ethyl acetate 1/0 - > 0/1 (v/v) as eluent. EPO <DP n="43"/>Yield: 1.3 g. MS-ESI: [M+H]+ = 412.3 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol; for 17.0h;Heating / reflux; | (b). 4-(3-Ethoxy-4-hydroxy-5-nitro-phenyl)-2-methyl-5-oxo-7-propyl-1,4,5,6,7,8-hexahydro-quinoline-3-carbonitrile A mixture of <strong>[178686-24-3]3-ethoxy-4-hydroxy-5-nitro-benzaldehyde</strong> (1.5 g), 3-aminocrotonitrile (584 mg) and 5-propylcyclohexane-1,3-dione (1.09 g) in ethanol (60 ml) was heated at reflux for 17 h. The mixture was concentrated in vacuo. The residue was purified by chromatography on silicagel in heptane/ethyl acetate 1/0?0/1 (v/v) as eluent.Yield: 1.3 g. MS-ESI: [M+H]+=412.3 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
13% | With cycl-isopropylidene malonate; acetic acid;Reflux; | [00159] A mixture of 1,2-diphenylethanone (150 mg, 0.76 mmol), 3-ethoxy-4- hydroxy- 5 -nitrobenzaldehyde (194 mg, 0.92 mmol), meldrum's acid (132 mg, 0.92 mmol) and ammonium acetate (71 mg, 0.92 mmol) in acetic acid (5 mL) was refluxed overnight. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (EtOAc : PE=2: 1) and prep-HPLC (0.1% TFA as additive) to afford Compound 1 as yellow solid (40 mg, yield: 13%). 1H NMR (DMSO- 6 300 MHz): delta 10.20 (s, 1H), 9.60 (s, 1H), 7.47 (d, J = 3.0 Hz, 1H), 7.24-7.18 (m, 6H), 7.01-6.96 (m, 3H), 6.79 (d, J = 8.1 Hz, 2H), 4.06 (q, J = 6.0 Hz, 2H), 3.96 (d, J = 5.1 Hz, 1H), 3.14-3.07 (m, 2H),1.31 (t, J = 1.2 Hz, 3H); MS (ESI): m/z 430.9 [M+H+]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
12% | With cycl-isopropylidene malonate; acetic acid;Reflux; Inert atmosphere; | [00160] A mixture of l-(pyridin-3-yl)-2-(thiophen-3-yl)ethanone (Intermediate 1, seeExample 18 for synthesic description of all intermediates) (230 mg, 1.1 mmol), 3-ethoxy-4- hydroxy- 5 -nitrobenzaldehyde (296 mg, 1.4 mmol), meldrum's acid (202 mg, 1.4 mmol) and AcONH4 (108 mg, 1.4 mmol) in AcOH (3 mL) was refluxed under N2 overnight. The mixture was concentrated under reduced pressure and the residue was purified by prep-HPLC (0.1% TFA as additive) to give Compound 2 (60 mg, 12%). 1H NMR (MeOD 400 MHz): delta 8.70 (d, J = 5.2 Hz, 1H), 8.67 (s, 1H), 8.30 (d, J = 8.0 Hz, 1H), 7.90-7.62 (m, 1H), 7.72-7.60 (m, 1H), 7.27-7.24 (m, 2H), 6.94-6.92 (m, 1H), 6.58 (d, J = 4.8 Hz, 1H), 4.20-4.11 (m, 3H), 3.30-3.25 (m, 1H), 2.79-2.74 (dd, J = 16.2, 3.2 Hz, 1H), 1.45 (t, J = 6.8 Hz, 3H). MS (ESI): m/z 438.3 [M+l]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
6% | With cycl-isopropylidene malonate; acetic acid;Reflux; Inert atmosphere; | [00162] A mixture of l-(l-methyl-lH-pyrazol-4-yl)-2-(thiophen-3-yl)ethanone(Intermediate 3) (150 mg, 0.73 mmol), <strong>[178686-24-3]3-ethoxy-4-hydroxy-5-nitrobenzaldehyde</strong> (185 mg, 0.87 mmol), meldrum's acid (125 mg, 0.87 mmol) and AcONH4 (84 mg, 1.1 mmol) in AcOH (3 mL) was refluxed under N2 overnight. The mixture was concentrated under reduced pressure and the residue was purified by prep-HPLC (0.1% TFA as additive) to giveCompound 4 as yellow solid (20 mg, 6%). 1H NMR (DMSO- 6, 400 MHz): delta 10.20 (s, 1H), 9.43 (s, 1H), 7.62 (s, 1H), 7.42-7.36 (m, 2H), 7.19-7.11 (m, 1H), 7.06 (s, 2H), 6.70-6.68 (m, 1H), 4.11-4.03 (m, 2H), 3.95-3.92 (m, 1H), 3.77 (s, 3H), 3.08 (dd, J = 16.4, 7.6 Hz, 1H), 2.60-2.52 (m, 1H), 1.34 (t, J = 6.8 Hz, 3H). MS (ESI): m/z 440.9 [M+l]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With hydrogenchloride; In ethanol; water;Reflux; | 00161] A mixture of 2-phenyl-l-p-tolylethanone (65 mg, 0.31 mmol), 3-ethoxy-4- hydroxy-5-nitrobenzaldehyde (54 mg, 0.26 mmol), urea (56 mg, 0.93 mmol), andconcentrated HC1 solution (0.03 mL, 0.31 mmol) in EtOH (5 mL) was refluxed overnight. The mixture was evaporated in vacuo and the residue was purified by preparative HPLC to give compound 16 (455.19 mg, yield 40%). 1H NMR (DMSO- d6 400 MHz): delta 10.28 (s, 1H), 8.64 (s, 1H), 7.51 (s, 1H), 7.42 (s, 1H), 7.17 (s, 1H), 7.08-6.96 (m, 7H), 6.80 (d, J = 6.8 Hz, 2H), 5.14 (d, J = 2.4 Hz, 1H), 4.05-3.98 (m, 2H), 2.23 (s, 3H), 1.31 (t, J = 6.8 Hz, 3H); MS (ESI): m/z 446.2 [M+l]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
13% | With hydrogenchloride; In ethanol; water;Reflux; | 00177] A mixture of l-(3-fluorophenyl)-2-phenylethanone (100 mg, 0.47 mmol), 3- ethoxy-4-hydroxy-5-nitrobenzaldehyde (82 mg, 0.39 mmol), urea (70 mg, 1.17 mmol), and concentrated HC1 solution (0.03 mL, 0.39 mmol) in EtOH (5 mL) was refluxed overnight. The mixture was evaporated in vacuo and purified by preparative HPLC to give Compound 32 (22.35 mg, yield 13%) as a yellow solid. 1H NMR (DMSO-d6 400 MHz): delta 10.28 (s, IH), 8.79 (s, IH), 7.56 (s, IH), 7.42 (s, IH), 7.30-7.25 (m, IH), 7.16 (s, IH), 7.12-6.99 (m, 6H), 6.86 (d, J = 1.6 Hz, 2H), 5.23 (d, J = 2.4 Hz, IH), 4.04 (q, J = 7.2 Hz, 2H), 1.33 (t, J = 1.2 Hz, 3H); MS (ESI): m/z 450.0 [M+l]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With hydrogenchloride; In ethanol; water;Reflux; | [00184] A mixture of l-(3-fluoro-4-methoxyphenyl)-2-phenylethanone (100 mg, 0.41 mmol), <strong>[178686-24-3]3-ethoxy-4-hydroxy-5-nitrobenzaldehyde</strong> (72 mg, 0.34 mmol), urea (61 mg, 1.02 mmol), and concentrated HCl solution (0.03 mL, 0.34 mmol) in EtOH (5 mL) was refluxed overnight. The mixture was evaporated in vacuo, and the residue was purified by preparative HPLC to give Compound 39 (78 mg, yield 48%). 1H NMR (DMSO- 6 400 MHz): delta 10.28 (s, 1H), 8.71 (s, 1H), 7.53 (s, 1H), 7.42 (s, 1H), 7.17 (s, 1H), 7.10-7.01 (m, 5H), 6.95 (d, J = 92 Hz, 1H), 6.85 (d, J = 6.8 Hz, 2H), 5.18 (s, 1H), 4.08-4.01 (m, 2H), 3.79 (s, 3H), 1.33 (t, J = 7.2 Hz, 3H); MS (ESI): m/z 480.0 [M+l]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
17% | With hydrogenchloride; In ethanol; water; for 48.0h;Reflux; | 00192] To a solution of l-(3,4-dichlorophenyl)-2-phenylethanone (Intermediate 19)(100 mg, 0.38 mmol), <strong>[178686-24-3]3-ethoxy-4-hydroxy-5-nitrobenzaldehyde</strong> (74.4 mg, 0.38 mmol), and urea (68.5 mg, 1.14 mmol) in 5 mL of ethanol was added 0.2 mL of concentrated HC1 solution, and the mixture was refluxed for 2 days. After the solvent was removed under reduced pressure, the residue was purified by reverse-phase preparatory HPLC (26-53% acetonitrile + 0.1% trifluoroacetic acid in water + 0.1% trifluoroacetic acid, over 15 min.) to give Compound 47 (32 mg, yield 17.0%). 1H NMR (DMSO- 6 300 MHz) delta 10.28 (s, 1H), 8.85 (s, 1H), 7.58 (s, 1H), 7.48 (t, J = 1.5 Hz, 2H), 7.41 (d, J = 1.8 Hz, 1H), 7.13-7.05 (m, 5H), 6.88 (t, J = 1.8 Hz, 2H), 5.25 (d, J = 2.1 Hz, 1H), 4.02 (m, 2H), 1.32 (t, J = 6.9 Hz, 3H); MS(ESI): m/z 499.9 [M+l]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38.3% | With hydrogenchloride; In ethanol; water; at 79℃; for 80h; | 00222] A mixture of l-phenyl-2-(pyridin-4-yl)ethanone (Intermediate 36) (100 mg,0.507 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (107 mg, 0.507 mmol), urea (91.3 mg, 4.587 mmol), and concentrated hydrochloric acid (0.3 mL) in ethanol (1 mL) was refluxed at 79C for 80 h. After being cooled down to room temperature, the mixture was evaporated, and purified by preparative HPLC to give Compound 74 (80.1 mg, yield 38.3%). 1H NMR (DMSO- 6 400MHz): delta 10.41 (s, IH), 9.57 (s, IH), 8.34 (d, J = 6.4 Hz, 2H), 8.02 (s, IH), 7.50-7.42 (m, 4H), 7.39 (d, J = 1.2 Hz, 2H), 7.34 (d, J = 1.6 Hz, IH), 7.06 (d, J = 6.4 Hz, 2H), 5.39 (d, J = 3.2 Hz, IH), 4.15-4.10 (m, 2H), 1.38-1.35 (m, 3H); MS (ESI): m/z 433.0 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43.7% | With hydrogenchloride; In ethanol; water; at 78℃; for 70.0h; | [00233] A mixture of l-phenyl-2-(pyridin-3-yl)ethanone (Intermediate 42) (200 mg,1.01 mmol), <strong>[178686-24-3]3-ethoxy-4-hydroxy-5-nitrobenzaldehyde</strong> (213.3 mg, 1.01 mmol), urea (181.8 mg, 3.03 mmol), and concentrated hydrochloric acid solution (0.5 mL) in ethanol (2 mL) was refluxed at 78C for 70 h. After being cooled down to room temperature, the reaction mixture was evaporated, and the residue was purified by preparative HPLC to giveCompound 84 (191.1 mg, yield 43.7%). 1H NMR (DMSO- 6 400MHz): delta 10.34 (s, 1H), 9.06 (s, 1H), 8.35-8.33 (m, 1H), 8.10 (d, J = 2.0 Hz, 1H), 7.72 (s, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.45-7.39 (m, 2H), 7.33-7.23 (m, 6H), 5.39 (d, J = 2.8 Hz, 1H), 4.11-4.06 (m, 2H), 1.36-1.33 (m, 3H); MS (ESI): m/z 433.0 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.5% | With hydrogenchloride; In ethanol; water; for 96.0h;Reflux; | 00168] To a solution of 2-(3-methoxyphenyl)-l-phenylethanone (400 mg, 1.77 mmol), <strong>[178686-24-3]3-ethoxy-4-hydroxy-5-nitrobenzaldehyde</strong> (374 mg, 1.77 mmol) and urea (244 mg, 5.31 mmol) in 20 mL of ethanol was added 0.2 mL of concentrated HCl, then the mixture was stirred at reflux for 4 days. After the solvent was removed under reduced pressure, the residue was purified by HPLC (35-65% acetonitrile + 0.1% trifluoroacetic acid in water, over 15 min.) and then purified by thin layer chromatography (PE:EtOAc=l :2) further to give Compound 23 (20 mg, yield 2.5%). 1H NMR (CD3OD 400 MHz): delta 7.43 (s, IH), 7.17 (s, 5H), 6.86-6.82 (m, 2H), 6.48 (d, J=6.4 Hz, IH), 6.40 (d, J=8.0 Hz, IH), 6.30 (s, IH), 5.03 (s, IH), 3.91-3.89 (m, 2H), 3.37 (s, 3H), 1.30 (t, J=7.2 Hz, 3H); MS (ESI): mJz 462.3 [M+l]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
29% | With hydrogenchloride; In ethanol; water;Reflux; | [00217] A mixture of 2-(2-oxo-2-phenylethyl)benzonitrile (Intermediate 33) (100 mg,0.45 mmol), <strong>[178686-24-3]3-ethoxy-4-hydroxy-5-nitrobenzaldehyde</strong> (87 mg, 0.41 mmol), urea (81 mg, 1.36 mmol), and concentrated HC1 solution (0.03 mL, 0.41 mmol) in EtOH (5 mL) was refluxed overnight. The mixture was concentrated, and purified by preparative HPLC to give Compound 70 (54.26 mg, yield 29%) as a yellow solid. 1H NMR (DMSO- 6 300 MHz): (510.24 (s, 1H), 8.91 (s, 1H), 7.61(s, 1H), 7.51-7.44 (m, 2H), 7.31 (s, 1H), 7.24-7.16 (m, 4H), 7.13-7.08 (m, 3H), 5.37 (s, 1H), 3.99-3.93 (m, 2H), 1.31 (t, J = 6.8 Hz, 3H); MS (ESI): m/z 456.8 [M+l]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
16.5% | With hydrogenchloride; In ethanol; water; for 72.0h;Reflux; | [00170] To a solution of 2-(4-bromophenyl)-l-phenylethanone (Intermediate 8) (140 mg, 0.5 mmol), <strong>[178686-24-3]3-ethoxy-4-hydroxy-5-nitrobenzaldehyde</strong> (108 mg, 0.5 mmol), and urea (69 mg, 1.5 mmol) in 20 mL of ethanol was added 0.2 mL of concentrated HCl, the mixture was stirred at reflux for 3 days. After the solvent was removed under reduced pressure, the residue was purified by HPLC (46-76% acetonitrile + 0.1% trifluoroacetic acid in water, over 15 min.) to give Compound 25 (43 mg, yield 16.5%). 1H NMR (CD3OD 400 MHz): delta 7.52 (s, 1H), 7.20-7.17 (m, 5H), 7.11-7.08 (m, 3H), 6.69 (d, J = 8.4 Hz, 2H), 5.23 (s, 1H), 3.40- 3.95 (m, 2H), 1.30 (t, J = 6.8 Hz, 3H); MS (ESI): mJz 510.2 [M+l]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | With hydrogenchloride; In ethanol; water;Reflux; | 00183] A mixture of l-(3,4-dimethoxyphenyl)-2-phenylethanone (180 mg, 0.7 mmol),<strong>[178686-24-3]3-ethoxy-4-hydroxy-5-nitrobenzaldehyde</strong> (124 mg, 0.59 mmol), urea (105 mg, 1.8 mmol), and concentrated HC1 solution (0.05 mL, 0.59 mmol) in EtOH (5 mL) was refluxed overnight. The mixture was evaporated in vacuo, and the residue was purified by preparative HPLC to give Compound 38 (100 mg, yield 35%) as a yellow solid. 1H NMR (CD3OD 400 MHz): delta 7.63 (d, J = 1.2 Hz, 1H), 7.19 (s, 1H), 7.13-7.06 (m, 3H), 6.93-6.85 (m, 4H), 6.73 (s, 1H), 5.34 (s, 1H), 4.11-4.02 (m, 2H), 3.80 (s, 3H), 3.57 (s, 3H), 1.41 (t, J = 6.8 Hz, 3H); MS (ESI): m/z 492.0 [M+l]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | With hydrogenchloride; In ethanol; water;Reflux; | [00266] A mixture of 2-phenyl-l-(4-(trifluoromethyl)phenyl)ethanone (commercially available) (200 mg, 0.76 mmol), <strong>[178686-24-3]3-ethoxy-4-hydroxy-5-nitrobenzaldehyde</strong> (145 mg, 0.69 mmol), urea (124 mg, 2.06 mmol), cone. HC1 (0.06 mL, 0.69 mmol) in EtOH (5 mL) was refluxed overnight. Followed a standard aqueous/EtOAc workup, then purified by preparative HPLC to give Compound 113 (135.34 mg, yield 39%). 1H NMR (DMSO- 6 400 MHz): delta 8.83 (d, J = 1.6 Hz, 1H), 7.60-7.56 (m, 3H), 7.40-7.39 (m, 3H), 7.13 (s, 1H), 7.06-7.00 (m, 3H), 6.83-6.80 (m, 2H), 5.23 (d, J = 2.4 Hz, 1H), 4.06-3.97 (m, 2H), 1.30 (t, J = 7.2 Hz, 3H); MS (ESI): m/z 500.0 [M+l]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34% | With hydrogenchloride; In ethanol; water;Reflux; | 00178] A mixture of l-(4-bromophenyl)-2-phenylethanone (100 mg, 0.36 mmol), 3- ethoxy-4-hydroxy-5-nitrobenzaldehyde (64 mg, 0.30 mmol), urea (55 mg, 0.91 mmol), and concentrated HC1 solution (0.03 mL, 0.36 mmol) in EtOH (5 mL) was refluxed overnight. The mixture was evaporated in vacuo, and purified by preparative HPLC to give Compound 33 (52.12 mg, yield 34%). 1H NMR (DMSO- 6 400 MHz): delta 10.29 (s, 1H), 8.78 (s, 1H), 7.56 (s, 1H), 7.46-7.42 (m, 3H), 7.15-7.13 (m, 3H), 7.09-7.03 (m, 3H), 6.84 (d, J = 6.8 Hz, 2H), 5.21 (d, J = 2.0 Hz, 1H), 4.07-3.99 (m, 2H), 2.23 (s, 3H), 1.33 (t, J = 6.8 Hz, 3H); MS (ESI): m/z 511.9 [M+l]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
19.9% | With hydrogenchloride; In ethanol; water; for 48.0h;Reflux; | [00191] To a solution of l-(3,5-difluorophenyl)-2-phenylethanone (Intermediate 18)(100 mg, 0.43 mmol), <strong>[178686-24-3]3-ethoxy-4-hydroxy-5-nitrobenzaldehyde</strong> (84.9 mg, 0.43 mmol), and urea (78.6 mg, 1.29 mmol) in 5 mL of ethanol was added 0.2 mL of concentrated HC1, and the mixture was refluxed for 2 days. After the solvent was removed under reduced pressure, the residue was purified by reverse-phase preparatory HPLC (26-53% acetonitrile + 0.1% trifluoroacetic acid in water + 0.1% trifluoro acetic acid, over 15 min.) to give Compound 46 (40 mg, yield 19.9%). 1H NMR (DMSO- 6 400 MHz) delta 10.27 (s, 1H), 8.81 (s, 1H), 7.56 (s, 1H), 7.41 ( s, 1H), 7.31 (m, 2H), 7.14 (s, 1H), 7.11-6.99 (m, 4H), 6.86 (d, J = 7.2 Hz, 2H), 5.24 (s, 1H), 4.04 (m, 2H), 1.32 (t, J = 12 Hz, 3H); MS(ESI): mJz 468.0 [M+l]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
8.6% | With hydrogenchloride; In ethanol; water;Reflux; | [00182] A mixture of l-(3-chlorophenyl)-2-phenylethanone (450 mg, 1.95 mmol), 3- ethoxy-4-hydroxy-5-nitrobenzaldehyde (411 mg, 1.95 mmol), and urea (350 mg, 5.83 mmol) in anhydrous EtOH (15 mL) was added concentrated HC1 solution (0.5 mL), the reaction mixture was refluxed overnight. TLC (EtOAc:MeOH=10: l) showed that about 30% of starting materials were consumed, and the reaction mixture was concentrated. The residue was purified by column chromatography (EtOAc:MeOH=40: l) and preparative HPLC to afford Compound 37 as a yellow solid (78.1 mg, yield: 8.6%). 1H NMR (DMSO- 6 400 MHz): delta 10.30 (s, 1H), 8.81 (s, 1H), 7.56 (s, 1H), 7.42 (d, J = 1.2 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 7.20-7.25 (m, 2H), 7.02-7.7.13 (m, 5H), 6.85 (d, J = 6.8 Hz, 2H), 5.25 (d, J = 2.8 Hz, 1H), 4.00-4.10 (m, 2H), 1.33 (t, J = 6.8 Hz, 3H); MS (ESI): m/z 466.0 [M+l]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
14.5% | With hydrogenchloride; In ethanol; water; for 48.0h;Reflux; | [00190] To a solution of l-(3,4-difluorophenyl)-2-phenylethanone (120 mg, 0.52 mmol), <strong>[178686-24-3]3-ethoxy-4-hydroxy-5-nitrobenzaldehyde</strong> (101.8 mg, 0.52 mmol), and urea (95.1 mg, 1.56 mmol) in 5 mL of ethanol was added 0.2 mL of concentrated HC1 solution, and the mixture was refluxed for 2 days. After the solvent was removed under reduced pressure, the residue was purified by reverse-phase preparatory HPLC (26-53% acetonitrile + 0.1% trifluoroacetic acid in water + 0.1% trifluoroacetic acid, over 15 min.) to give Compound 45 (35 mg, yield 14.5%). 1H NMR (DMSO- 6 400 MHz TMS): delta 10.27 (s, IH), 8.81 (s, IH), 7.56 (s, IH), 7.41 (s, IH), 7.31 (m, 2H), 7.14 (s, IH), 7.11-6.99 (m, 3H), 6.87 (m, IH), 6.86 (d, J = 12 Hz, 2H), 5.24 (d, J = 2.0 Hz, IH), 4.04 (m, 2H), 1.32 (t, J = 7.2 Hz, 3H); MS(ESI): m/z 468.0[M+1]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
9.8% | With hydrogenchloride; In ethanol; water; for 96.0h;Reflux; | [00169] To a solution of 2-(3,4-dimethoxyphenyl)- l-phenylethanone (Intermediate 7)(130 mg, 0.5 mmol), <strong>[178686-24-3]3-ethoxy-4-hydroxy-5-nitrobenzaldehyde</strong>(106 mg, 0.5 mmol) and urea (69 mg, 1.5 mmol) in 20 mL of ethanol was added 0.2 mL of concentrated HC1, then the mixture was stirred at reflux for 4 days. After the solvent was removed under reduced pressure, the residue was purified by thin layer chromatography (PE : EtOAc = 1 :2) to give Compound 24 (24.3 mg, yield 9.8%). 1H NMR (CD3OD 400 MHz): delta 7.62 (d, J = 1.6 Hz, IH), 7.30 (s, 5H), 7.17 (s, IH), 6.68 (d, J = 8.0 Hz, IH), 6.51 (dd, J = 2.0 Hz, 8.0 Hz, IH), 6.38 (d, J = 2.0 Hz, IH), 5.30 (s, IH), 4.09-4.06 (m, 2H), 3.71 (s, 3H), 3.41 (s, 3H), 1.40 (t, J = 7.2 Hz, 3H); MS (ESI): mJz 492.3 [M+l]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.4% | With hydrogenchloride; In ethanol; water; for 96.0h;Reflux; | [00167] To a solution of 2-(3,4-dichlorophenyl)-l-phenylethanone (Intermediate 6)(400 mg, 1.5 mmol), <strong>[178686-24-3]3-ethoxy-4-hydroxy-5-nitrobenzaldehyde</strong> (317 mg, 1.5 mmol), and urea (207 mg, 4.5 mmol) in 20 mL of ethanol was added 0.2 mL of concentrated HCl, the mixture was stirred at reflux for 4 days. After the solvent was removed under reduced pressure, the residue was purified by HPLC (48-78% acetonitrile + 0.1% trifluoroacetic acid in water, over 15 min.) and thin layer chromatography (PE:EtOAc=l:2) to give Compound 22 (17.8 mg, yield 2.4%). 1H NMR (CD3OD 400 MHz): delta 7.64 (s, 1H), 7.35-7.31 (m, 5H), 7.23-7.19 (m, 2H), 7.03 (s, 1H), 6.79 (d, J = 8.0 Hz, 1H), 5.37 (s, 1H), 4.12 (m, 2H), 1.43 (t, J = 6.8 Hz, 3H); MS (ESI): m/z 500.2 [M+l]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
9% | [00335] A mixture of urea (150 mg, 2.5 mmol), 3-ethoxy-4-hydroxy-5- nitrobenzaldehyde (104 mg, 0.49 mmol), CuCl (99 mg, 1.0 mmol), BF3-Et20 (142 mg, 1.0 mmol) and AcOH (0.2 mL) in anhydrous THF (10 mL) was stirred under refluxing under N2 atmosphere for 0.5 hour. Then 2-cyclohexyl- l-phenylethanone (Intermediate 96) (100 mg, 0.49 mmol) in anhydrous THF (0.5 mL) was added and the reaction mixture was refluxed overnight. Followed a standard aqueous/EtOAc workup and purified by prep-HPLC (0.1 % TFA as additive) to give Compound 177 (20 mg, yield 9%). 1H NMR (CD3OD 400 MHz): delta 7.74 (d, J = 2.0 Hz, 1H), 7.53-7.38 (m, 6H), 7.39 (d, J = 2.0 Hz, 1H), 4.99 (s, 1H), 4.21 (q, J = 7.2 Hz, 1H), 2.35-2.28 (m, 1H), 1.69 (m, 1H), 1.64 (m, 1H), 1.55-1.47 (m, 7H), 1.05-0.92 (m, 3H), 0.85-0.79 (m, 1H). MS (ESI): mJz 438.3 [M+l]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
14.9% | With hydrogenchloride; In ethanol; water; for 48.0h;Reflux; | [00159] To a solution of l-phenyl-2-p-tolylethanone (70 mg, 0.33 mmol), 3-ethoxy-4- hydroxy- 5 -nitrobenzaldehyde (65 mg, 0.33 mmol) and urea (60 mg, 1.0 mmol) in 20 mL of ethanol was added 0.2 mL of concentrated HC1, the mixture was stirred at reflux for 2 days. After the solvent was removed under reduced pressure, the residue was purified by reverse- phase preparatory HPLC (26-53% acetonitrile + 0.1% trifluoroacetic acid in water + 0.1% trifluoroacetic acid, over 15 min.) to give Compound 14 (21 mg, yield 14.9%). 1H NMR (DMSO- 6 400 MHz TMS): delta 10.30 (s, IH), 8.67 (s, IH), 7.52 (s, IH), 7.44 (s, IH), 7.26- 7.19 (m, 6H), 6.85-6.70 (m, 4H), 5.16 (s, IH), 4.05 (s, 2H), 2.12 (s, 3H), 1.33 (t, J = 6.4 Hz, 3H); MS (ESI): mJz 446.0 [M+l]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
23% | With hydrogenchloride; In ethanol; water;Reflux; | 00226] A mixture of 2-phenyl-l-(thiophen-2-yl)ethanone (Intermediate 38) (100 mg,0.49 mmol), <strong>[178686-24-3]3-ethoxy-4-hydroxy-5-nitrobenzaldehyde</strong> (95 mg, 0.45 mmol), urea (81 mg, 1.35 mmol), and concentrated HC1 solution (0.04 mL, 0.45 mmol) in EtOH (5 mL) was refluxed overnight. The mixture was diluted with water, and extracted with EtOAc. The organic layer was separated, and the aqueous layer was extracted with EtOAc. The combined organic layer was dried over Na2S04, evaporated in vacuo, and purified by preparative HPLC to give Compound 78 (45 mg, yield 23%). 1H NMR (DMSO- 6 300 MHz): delta 10.22 (s, IH), 8.61 (s, IH), 7.47 (s, IH), 7.34-7.29 (m, 2H), 7.15-7.13 (m, IH), 7.09-7.06 (m, 3H), 6.99 (s, IH), 6.87-6.83 (m, 3H), 5.02 (d, J = 2.4 Hz, IH), 3.92 (q, J = 1.2 Hz, 2H), 1.22 (t, J = 1.2 Hz, 3H); MS (ESI): m/z 438.0[M+1]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
10.8% | With hydrogenchloride; In ethanol; water; for 96.0h;Reflux; | [00164] To a solution of 2-(4-methoxyphenyl)-l-phenylethanone (100 mg, 0.44 mmol), <strong>[178686-24-3]3-ethoxy-4-hydroxy-5-nitrobenzaldehyde</strong> (93 mg, 0.44 mmol), and urea (60 mg, 1.32 mmol) in 20 mL of ethanol was added 0.2 mL of concentrated HCl, the mixture was stirred at reflux for 4 days. After the solvent was removed under reduced pressure, the residue was purified by thin layer chromatography (PE : EtOAc=l :2) to give Compound 19 (22 mg, yield 10.8%). 1H NMR (CD3OD 400 MHz): delta 7.55 (s, 1H), 7.20 (s, 5H), 7.12 (s, 1H), 6.73 (d, J = 8.4 Hz, 2H), 6.57 (d, J = 8.8 Hz, 2H), 5.25 (s, 1H), 4.05-4.00 (m, 2H), 3.61 (s, 3H), 1.35 (t, J = 6.8 Hz, 3H); MS (ESI): m/z 462.2 [M+l]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3.4% | With hydrogenchloride; In ethanol; water; for 72.0h;Reflux; | [00157] To a mixture of l-phenyl-2-(thiazol-2-yl)ethanone (Intermediate 3) (170 mg,0.84 mmol), <strong>[178686-24-3]3-ethoxy-4-hydroxy-5-nitrobenzaldehyde</strong> (212 mg, 1.00 mmol), and urea (151 mg, 2.52 mmol) in anhydrous EtOH (20 mL) was added concentrated HCl solution (0.1 mL), and the reaction mixture was refluxed for three days. When TLC (EtOAc:MeOH=10: l) showed that about 30% of the starting materials were consumed, the reaction mixture was concentrated, and the crude product was purified by column chromatography and preparative HPLC to afford Compound 12 as a yellow solid (12.5 mg, yield: 3.4%). 1H NMR (DMSO- 6 400 MHz TMS): delta 10.25 (s, 1H), 9.25 (s, 1H), 7.82 (s, 1H), 7.50-7.56 (m, 4H), 7.48 (s, 1H), 7.36-7.40 (m, 3H), 7.22 (d, J = 3.6 Hz, 1H), 5.68 (d, J = 3.6 Hz, 1H), 4.10(q, J = 6.0Hz, 2H), 1.35 (t, J = 7.2 Hz, 3H); MS (ESI): m/z 439.1 [M+l]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
29% | With hydrogenchloride; In ethanol; water;Reflux; | Example 35: Compound 35, 4-(3-ethoxy-4-hydroxy-5-nitrophenyl)-6-(4-fluorophenyl)- 5-phenyl-3,4-dihydropyrimidin-2(lH)-one[00180] A mixture of l-(4-fluorophenyl)-2-phenylethanone (200 mg, 0.93 mmol), 3- ethoxy-4-hydroxy-5-nitrobenzaldehyde (164 mg, 0.78 mmol), urea (140 mg, 2.3 mmol), and concentrated HCl solution (0.08 mL, 0.93 mmol) in EtOH (5 mL) was refluxed overnight. The mixture was evaporated in vacuo, and the residue was purified by preparative HPLC to give Compound 35 (120 mg, yield 29%). 1H NMR (DMSO- 6 300 MHz): delta 10.28 (s, 1H), 8.76 (s, 1H), 7.54 (s, 1H), 7.42 (s, 1H), 7.25-7.21 (m, 2H), 7.16 (s, 1H), 7.11-6.97 (m, 5H), 6.81 (d, J = 1.5 Hz, 2H), 5.19 (s, 1H), 4.08-3.99 (m, 2H), 1.32 (t, J = 6.6 Hz, 3H); MS (ESI): m/z 450.0 [M+l]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | With hydrogenchloride; In ethanol; water; for 72.0h;Reflux; | 00146] To a mixture of compound 1,2-diphenylethanone (557 mg, 2.8 mmol), 3- ethoxy-4-hydroxy-5-nitrobenzaldehyde (500 mg, 2.4 mmol), and urea (427 mg, 7.1 mmol) in EtOH (50 mL) was added concentrated HCl (0.24 mL), and the reaction mixture was heated at reflux for three days. TLC (EtOAc: MeOH=10: l) showed that the starting materials were consumed. The reaction mixture was concentrated and purified by column chromatography (EtOAc: MeOH=30: l) to afford Compound 1 as a yellow solid (500 mg, yield: 49.0%). 1H NMR (DMSO- 6 400 MHz): delta 10.25 (s, 1H), 8.70 (s, 1H), 7.50 (s, 1H), 7.42 (d, J = 2.0 Hz, 1H), 7.15-7.25 (m, 6H), 6.95-7.05 (m, 3H), 6.80 (d, J = 6.4 Hz, 2H), 5.15 (d, J = 2.8 Hz, 1H), 4.05 (m, 2H), 1.30 (t, J = 6.8 Hz, 3H); MS (ESI): m/z 432.2 [M+l]+. |
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