Structure of 53090-43-0
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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
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CAS No. : | 53090-43-0 |
Formula : | C11H10Cl2O3 |
M.W : | 261.10 |
SMILES Code : | CCOC(=O)CC(=O)C1=CC(Cl)=C(Cl)C=C1 |
MDL No. : | MFCD03424830 |
InChI Key : | SIWICBKMMHBCSU-UHFFFAOYSA-N |
Pubchem ID : | 2758176 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 16 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.27 |
Num. rotatable bonds | 5 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 62.36 |
TPSA ? Topological Polar Surface Area: Calculated from |
43.37 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.54 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
3.25 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
3.13 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
2.7 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
3.62 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
3.05 |
Log S (ESOL):? ESOL: Topological method implemented from |
-3.45 |
Solubility | 0.0918 mg/ml ; 0.000352 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-3.83 |
Solubility | 0.0382 mg/ml ; 0.000146 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-4.47 |
Solubility | 0.00891 mg/ml ; 0.0000341 mol/l |
Class? Solubility class: Log S scale |
Moderately soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
Yes |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
Yes |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
Yes |
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 |
-5.59 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 |
1.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<0.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
1.77 |
* 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 sodium hydroxide; sodium chloride; sodium hydrogencarbonate; toluene-4-sulfonic acid; trifluoroacetic acid; In tetrahydrofuran; ethanol; dichloromethane; chloroform; water; | 3-(3,4-Dichlorophenyl)-3-oxo-1-propanol In 2.4 liters of ethanol, 119 g (0.46 mole) of <strong>[53090-43-0]ethyl 3-(3,4-dichlorophenyl)-3-oxopropionate</strong> were dissolved. To the resulting solution, 115 ml (0.68 mole) of ethyl orthoformate and 4.4 g (2.28 mmol) of p-toluenesulfonic acid were added, followed by heating under reflux for 8 hours. The reaction mixture was poured into 1 liter of a saturated aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate (700 ml, three times). The organic layers were combined, washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the residue was dissolved in 800 ml of tetrahydrofuran. The resulting solution was added dropwise to a suspension of 25.9 g (0.68 mole) of lithium aluminum hydride in 4 liters of tetrahydrofuran over 1 hour under ice-cooling. After stirring at 0 C. for 2 hours, 250 ml of water and 125 ml of a 10% aqueous solution of sodium hydroxide were added and the mixture was stirred at room temperature for a further 1 hour. The reaction mixture was filtered through Celite. The filtrate was poured into 1 liter of a saturated aqueous solution of sodium chloride, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. A residue was dissolved in 500 ml of chloroform. Under ice-cooling, 500 ml of 50% trifluoroacetic acid were added dropwise to the resulting solution over 30 minutes and the mixture was stirred for 30 minutes. The reaction mixture was diluted with 300 ml of methylene chloride. The organic layer was washed with water and a saturated aqueous solution of sodium bicarbonate and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column (eluding solvent: n-hexane: ethyl acetate=9:1), whereby 46 g of the title compound were obtained as white crystals. Nuclear magnetic resonance spectrum (270 MHz, CDCl3) delta ppm: 8.05 (1H, d, J=2.0 Hz), 7.79 (1H, dd, J=2.0, 8.1 Hz), 7.57 (1H, d, J=8.1 Hz), 4.04 (2H, m), 3.19 (2H, t, J=5.3 Hz), 2.44 (1H, t, J=6.6 Hz, D2O disappeared). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; sodium chloride; sodium hydrogencarbonate; toluene-4-sulfonic acid; In tetrahydrofuran; ethanol; dichloromethane; chloroform; water; ethyl acetate; | 7(a) 3-(3,4-Dichlorophenyl)-3-oxo-1-propanol 119 g (0.46 mole) of <strong>[53090-43-0]ethyl 3-(3,4-dichlorophenyl)-3-oxopropionate</strong> were dissolved in 2.4 liters of ethanol, and 115 ml (0.68 mole) of ethyl orthoformate and 4.4 g (22.8 mmole) of p-toluenesulfonic acid were added thereto. The mixture was then heated under reflux for 8 hours. At the end of this time, the reaction solution was poured into 1 liter of a saturated aqueous solution of sodium hydrogen-carbonate and extracted three times, each time with 700 ml of ethyl acetate. The organic extracts were combined, washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, and the resulting residue was dissolved in 800 ml of tetrahydrofuran and then added dropwise to 4 liters of a suspension of 25.9 g (0.68 mole) of lithium aluminum hydride in tetrahydrofuran over a period of 1 hour, whilst ice-cooling. The mixture was stirred at 0 C. for 2 hours, and then 250 ml of water and 125 ml of a 10% w/v aqueous solution of sodium hydroxide were added thereto, and the mixture was stirred for a further 1 hour at room temperature. It was then filtered through a Celite (trade mark) filter aid, and the filtrate was poured into 1 liter of a saturated aqueous solution of sodium chloride and then extracted with ethyl acetate. The organic extract was dried over anhydrous sodium sulfate and concentrated by evaporation under reduced pressure. The resulting residue was dissolved in 500 ml of chloroform. 500 ml of 50% v/v aqueous trifluoroacetic acid were added to the resulting solution over a period of 30 minutes, whilst ice-cooling, and the mixture was stirred for a further 30 minutes at the same temperature. At the end of this time, the reaction solution was diluted with 300 ml of methylene chloride, and the organic layer was washed with water and then with a saturated aqueous solution of sodium hydrogencarbonate, after which it was dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by silica gel column chromatography, using a 9:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 46 g of the title compound as white crystals. Nuclear Magnetic Resonance Spectrum (270 MHz, CDCl3) delta ppm: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 4 6-(3,4-Dichlorophenyl)-1,3-dimethyl-2,4(1H,3H)pyrimidinedione (5.27 g) was obtained according to substantially the same manner as that of Example 2 from <strong>[53090-43-0]ethyl 2-(3,4-dichlorobenzoyl)acetate</strong> (10.0 g) and N,N'-dimethylurea (3.71 g). mp: 172-175 C. IR (Nujol): 1695, 1660, 1620 cm-1 NMR (DMSO-d6, delta): 7.83 (1H, d, J=2 Hz), 7.80 (1H, d, J=8 Hz), 7.50 (1H, dd, J=2 Hz, 8 Hz), 5.68 (1H, s), 3.23 (3H, s), 3.10 (3H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | Step A: 2-Cvclopropyl-6-(3.4-dichloro-phenyl)-pyrimidin-4-ol. To a solution consisting of <strong>[53090-43-0]3-(3,4-dichlorophenyl)-3-oxo-propionic acid ethyl ester</strong> (252 mg, <n="100"/>0.967 mmol) and MeOH were added cyclopropylcarbamidine hydrochloride (140 mg, 1.16 mmol) and potassium tert-butoxide (266 mg, 2.37 mmol). The reaction mixture was stirred at rt overnight, then concentrated. Water and CH2Cl2 were added, and the mixture was adjusted to pH 7 with glacial acetic acid. The layers were separated, and the aqueous phase was extracted with EtOAc. The organics were combined, dried (Na2SO4), and concentrated. The crude residue was purified (FCC) to give the title compound as a white solid (133 mg, 49percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With toluene-4-sulfonic acid; In butan-1-ol; for 2h;Reflux; | To a solution of 4-(4-methylthiazol-2-yl)-lH-pyrazol-5-amine (50 mg, 0.27 mmol) in n-BuOH (1.0 mL) was added p-TsOH (4.7 mg, 0.03 mmol) and ethyl 3-(3,4- dichlorophenyl)-3-oxopropanoate (108 mg, 0.41 mmol). The reaction was stirred for 2 h at reflux, then cooled to room temperature and diluted with methanol (1 mL). The solids were collected by filtration and washed with MeOH (3 x 1 mL) to afford 5-(3,4-dichlorophenyl)-3-(4-methylthiazol-2-yl)pyrazolo[l ,5-a]pyrimidin- 7(4H)-one as a white solid (68.9 mg 65%). LCMS (ES, m/z): [M+l] +: 377.0 *H NMR (300 MHz, CD3OD): delta 8.46 (s, 1H), 8.43 (d, / = 2.1 Hz, 1H), 8.11 (dd, J 1= 2.1 Hz, J = 8.4 Hz, 1H), 7.62 (d, / = 8.4 Hz, 1H), 6.97 (s, 1H), 6.38 (s, 1H), 2.45 (s, 3H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | CDI (41.5 g, 290.32 mmol, 3.70 equiv) was added to a solution of 3,4- dichlorobenzoic acid (15 g, 78.53 mmol, 1.00 equiv) in tetrahydrofuran (200 mL), The resulting solution was stirred for 4 h at 25C. Separately, to a solution of potassium 3-ethoxy-3-oxopropanoate (37.7 g, 235 mmol, 3.00 equiv) in CH3CN (400 mL) was added MgCl2 (33.5 g, 353 mmol, 4.5 equiv) and triethylamine (23.8 g, 235 mmol, 3.00 equiv). The two solutions were combined and stirred for 2 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was diluted with 200 mL of water. The pH of the solution was adjusted to pH 5 with HC1 (1M). The resulting solution was extracted with 4x50 mL of ethyl acetate and the organic layers were combined and dried over magnesium sulfate. The organics were concentrated in vacuo and purified by silica gel column chromatography with petroleum ether/ethyl acetate (50: 1). This resulted in 15 g (73%) of ethyl 3-(3,4-dichlorophenyl)-3-oxopropanoate as a colorless oil |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | With toluene-4-sulfonic acid; In butan-1-ol; for 1h;Reflux; | To a solution of 4-(benzo[d]isoxazol-3-yl)-lH-pyrazol-5-amine (50 mg, 0.25 mmol) in n-BuOH (0.2 mL) was added ethyl 3-(3,4-dichlorophenyl)-3- oxopropanoate (100 mg, 0.37 mmol) and p-TsOH (5 mg) at room temperature.After refluxing 1 hour, the solids were collected by filtration and washed with methanol (3 x 2 mL) to afford 3-(benzo[d]isoxazol-3-yl)-5-(3,4- dichlorophenyl)pyrazolo[l,5-a]pyrimidin-7(4H)-one as a yellow solid (42.5 mg, 43%). LCMS (ES, m/z): [M+H]+ 396.9 *H NMR (400 MHz, DMSO+NH3 (saturated D20 solution)) delta 12.3 (brs, IH), 8.72 (s, IH), 8.30-8.28 (m, IH), 8.11 (s, IH), 7.88-7.74 (m, 4H), 7.53-7.49 (m, IH), 6.34 (s, IH) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | With toluene-4-sulfonic acid; In butan-1-ol; for 2h;Reflux; | To a solution of 2-methyl-l'H,2H-3,4'-bipyrazol-5'-amine (50 mg, 0.30 mmol) in n- BuOH (0.2 mL) was added <strong>[53090-43-0]ethyl 3-(3,4-dichlorophenyl)-3-oxopropanoate</strong> (120 mg, 0.45 mmol) and p-TsOH (5 mg) at room temperature. After refluxing 2 hours, the solids were collected by filtration and washed with methanol (3 x 2 mL) to afford 5- (3,4-dichlorophenyl)-3-(l-methyl-lH-pyrazol-5-yl)pyrazolo[l,5-a]pyrimidin- 7(4H)-one as an off-white solid (39.5 mg, 37 %). LCMS (ES, m/z): [M+H]+ 360.0 'H-NMR (300 MHz, DMSO) delta 12.46(brs, 1H), 8.10-8.08(m,2H), 7.80(s,2H), 7.51(d, / = 1.8 Hz, 1H), 6.48(s, 1H), 6.18 (s, 1H), 3.80 (s, 3H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With toluene-4-sulfonic acid; In butan-1-ol; for 1h;Reflux; | To a solution of l'H,2H-3,4'-bipyrazol-5'-amine (50 mg, 0.33 mmol) in n-BuOH (0.2 mL) was added <strong>[53090-43-0]ethyl 3-(3,4-dichlorophenyl)-3-oxopropanoate</strong> (130 mg, 0.50 mmol) and p-TsOH (5 mg) at room temperature. After refluxing 1 hour, the solids were collected by filtration and washed with methanol (3 x 2 mL) to afford 5-(3,4- dichlorophenyl)-3-(lH-pyrazol-3-yl)pyrazolo[l,5-a]pyrimidin-7(4H)-one as a white solid (93 mg, 80%). LCMS (ES, m/z): [M+H]+ 345.9 *H NMR (300 MHz, DMSO) delta 8.32-8.28 (d, / =11.7Hz, 1H), 8.17 (s, 1H), 7.88- 7.80 (m, 3H), 6.71-6.70 (d, / = 2.1 Hz, 1H), 6.21 (s, 1H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With toluene-4-sulfonic acid; In butan-1-ol; for 2h;Reflux; | To a solution of 2-ethyl-l'H,2H-3,4'-bipyrazol-5'-amine (50 mg, 0.28 mmol) in n- BuOH (0.2 mL) was added <strong>[53090-43-0]ethyl 3-(3,4-dichlorophenyl)-3-oxopropanoate</strong> (110 mg, 0.42 mmol) and p-TsOH (5 mg) at room temperature. After refluxing 2 hours, the solids were collected by filtration and washed with methanol (3 x 2 mL) to afford 5- (3,4-dichlorophenyl)-3-(l -ethyl- lH-pyrazol-5-yl)pyrazolo[l ,5-a]pyrimidin-7(4H)- one as off-white solid (68.5 mg, 65 ). LCMS (ES, m/z): [M+H]+ 374.0 'H-NMR (300 MHz, DMSO) delta 12.44 (brs, 1H), 8.03-8.01 (m, 2H), 7.79-7.70(m, 2H), 7.51(d, / = 1.8 Hz, 1H), 6.40(d, / = 1.8 Hz, 1H), 6.13(s, 1H), 4.02(q, / = 7.2 Hz, 2H), 2.23(s, 3H), l,24(t, / = 7.2 Hz, 3H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With toluene-4-sulfonic acid; In butan-1-ol; for 2h;Reflux; | To a solution of 4-(5-methylthiazol-2-yl)-lH-pyrazol-5-amine (100 mg, 0.55 mmol) in n-BuOH (0.2 mL) was added <strong>[53090-43-0]ethyl 3-(3,4-dichlorophenyl)-3-oxopropanoate</strong> (220 mg, 0.83 mmol) and p-TsOH (10 mg) at room temperature. After refluxing for 2 hours, the solids were collected by filtration and washed with methanol (3 x 2 mL) to afford 5-(3,4-dichlorophenyl)-3-(5-methylthiazol-2-yl)pyrazolo[l ,5-a]pyrimidin- 7(4H)-one as a yellow solid (115.9 mg, 55 ). LCMS (ES, m/z): [M+H]+ 377.0 'H-NMR (300 MHz, DMSO) delta 8.41-8.39(m,2H), 8.14-8.10 (dd, / = 2.1 Hz, 8.4 Hz, 1H), 7.63(d, / = 8.4 Hz, 1H), 7.35(d, / = 1.2 Hz, 1H), 6.37(s, 1H), 2.54 (s, 3H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With toluene-4-sulfonic acid; In butan-1-ol; at 130℃; for 1h; | A mixture of <strong>[53090-43-0]ethyl 3-(3,4-dichlorophenyl)-3-oxopropanoate</strong> (1.2 g, 4.60 mmol, 1.20 equiv), 5-amino-lH-pyrazole-4-carbonitrile (400 mg, 3.70 mmol, 1.00 equiv), butan-l-ol (1 mL), and TsOH (10 mg, 0.06 mmol, 0.05 equiv) was stirred for 1 h at 130C. The reaction progress was monitored by LCMS. The solids were collected by filtration. The solid was washed with 3x1 mL of methanol. This resulted in 0.8 g (71%) of 5-(3,4-dichlorophenyl)-7-oxo-4H,7H-pyrazolo[l,5-a]pyrimidine-3- carbonitrile as a white solid. *H NMR (300 MHz, DMSO): delta 8.44 (s, 1H), 8.17 (s, 1H), 7.85 (s, 1H), 6.37 (s, 1H) |
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