Structure of 87-13-8
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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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Quinolone-3-amidoalkanol: A New Class of Potent and Broad-Spectrum Antimicrobial Agent
Dube, Phelelisiwe S. ; Angula, Klaudia T. ; Legoabe, Lesetja J. ; Jordaan, Audrey ; Boitz Zarella, Jan M. ; Warner, Digby F. , et al.
Abstract: Herein, we describe 39 novel quinolone compounds bearing a hydrophilic amine chain and varied substituted benzyloxy units. These compounds demonstrate broad-spectrum activities against acid-fast bacterium, Gram-pos. and -neg. bacteria, fungi, and leishmania parasite. Compound 30 maintained antitubercular activity against moxifloxacin-, isoniazid-, and rifampicin-resistant Mycobacterium tuberculosis, while 37 exhibited low micromolar activities (<1 μg/mL) against World Health Organization (WHO) critical pathogens: Cryptococcus neoformans, Acinetobacter baumannii, and Pseudomonas aeruginosa. Compounds in this study are metabolically robust, demonstrating % remnant of >98% after 30 min in the presence of human, rat, and mouse liver microsomes. Several compounds thus reported here are promising leads for the treatment of diseases caused by infectious agents.
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Investigation of quinolone‐tethered aminoguanidine as novel antibacterial agents
Klaudia T. Angula ; Lesetja J. Legoabe ; Audrey Jordaan ; Digby F. Warner ; Richard M. Beteck ;
Abstract: A recent study identified quinolone-based thiosemicarbazone with an MIC90 value of 2 µM against Mycobacterium tuberculosis (Mtb). Herein, we report further optimization of the previous hit, which led to the discovery of quinolone-tethered aminoguanidine molecules with generally good antitubercular activity. Compounds 7f and 8e emerged as the hits of the series with submicromolar antitubercular activity, exhibiting MIC90 values of 0.49/0.90 and 0.49/0.60 µM, respectively, in the 7H9 CAS GLU Tx medium. This shows a fivefold increase in antitubercular activity compared to the previous study. Target compounds were also screened against ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) pathogens. However, the series generally exhibited poor antibacterial activities, with only compounds 8d and 8e demonstrating >50% growth inhibition of Staphylococcus aureus and Pseudomonas aeruginosa at 32 µg/ml. The compounds displayed selective antitubercular activity as they showed no cytotoxicity effects against two noncancerous human cell lines. In silico studies predict 7f to have good solubility, no inhibitory effect on cytochrome P450 isoenzymes, and to be a non-pan-assay interfering compound.
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Keywords: tuberculosis ; ESKAPE pathogens ; aminoguanidine ; quinolones ; thiosemicarzone
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CAS No. : | 87-13-8 |
Formula : | C10H16O5 |
M.W : | 216.23 |
SMILES Code : | O=C(OCC)/C(C(OCC)=O)=C/OCC |
MDL No. : | MFCD00009148 |
InChI Key : | LTMHNWPUDSTBKD-UHFFFAOYSA-N |
Pubchem ID : | 6871 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 15 |
Num. arom. heavy atoms | 0 |
Fraction Csp3 | 0.6 |
Num. rotatable bonds | 8 |
Num. H-bond acceptors | 5.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 53.36 |
TPSA ? Topological Polar Surface Area: Calculated from |
61.83 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.81 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.49 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.03 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.63 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.28 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.45 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.59 |
Solubility | 5.54 mg/ml ; 0.0256 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.4 |
Solubility | 0.869 mg/ml ; 0.00402 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-1.47 |
Solubility | 7.28 mg/ml ; 0.0337 mol/l |
Class? Solubility class: Log S scale |
Soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
Yes |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
No |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-6.56 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 |
0.56 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
5.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<2.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
2.69 |
* 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 |
---|---|---|
50% | With NaOEt In ethanol | Example 15 ETHYL 2-TRIFLUOROMETHYL-4-HYDROXYPYRIMIDINE-5-CARBOXYLATE A solution of diethyl ethoxymethylenemalonate (35.0 g, 162 mmol), trifluoroacetaridine (18 g, 162 mmol) and NaOEt (11.0 g, 162 mmol) in EtOH (200 mL) was heated at reflux for 6 h. The reaction mixture was concentrated and H2 O (48 naL) was added. The resulting solid was filtered, washed with Et2 O (300 mL) and H2 O (200 mL), and dried to give the title compound (21 g, 50percent yield); m.p.>220° C. (dec.); 1 H NMR (DMSO-d6) δ 8.38, 4.16 (q, 2H), 1.25 (q, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With NaOEt In ethanol | Example 33 ETHYL 2-TRIFLUOROMETHYL-4-HYDROXYPYRIMIDINE-5-CARBOXYLATE A solution of diethyl ethoxymethylenemalonate (35.0 g, 162 mmol), trifluoroacetamidine (18 g, 162 mmol) and NaOEt (11.0 g, 162 mmol) in EtOH (200 mL) was heated at reflux for 6 h. The reaction mixture was concentrated and H2 O (48 mL) was added. The resulting solid was filtered, washed with Et2 O (300 mL) and H2 O (200 mL), and dried to give the title compound (21 g, 50percent yield); m.p. >220° C. (dec.); 1 H-NMR (DMSO-d6) δ 8.38, 4.16 (q, 2H), 1.25 (q, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With ammonia; In ethanol; at 20℃; for 1.0h; | Ammonia was passed through ethanol (200 mL) for 30 minutes. Diethyl 2- (ethoxymethylene) malonate (21.6 g, 0.1 mol, 1.0 eq) was dissolved in an ammonia / ethanol solution and reacted at room temperature for 1 hour. After the reaction was detected by LC-MS and TLC, the reaction was concentrated. The crude product was purified by silica gel column chromatography (100-200 mesh silica gel, PE / EA = 5: 1) to obtain a white solid (18 g, yield: 96%) |
With ammonia; In ethanol; at 20℃; for 1.0h; | 2-Ethoxymethylene-malonic acid diethyl ester (20 ml, 100 mmol) and a 10% soln. of ammonia in EtOH (37 ml, 220 mmol) are stirred at rt for 1 h. The mixture is evaporated and dried in HV to give 2-aminomethylene-malonic acid diethyl ester that is used without further purification. | |
With ammonia; In ethanol; | a Diethyl aminomethylenemalonate To diethyl ethoxymethylenemalonate (50.13 g, 0.232 mmol), cooled to -20 C. under nitrogen, was added a 2.0 M solution of ammonia in ethanol (232 ml, 0.464 mmol) and the resulting solution was stirred at room temperature overnight. The solution was then evaporated in vacuo to give a quantitative yield of the title compound as a cream solid; 1H NMR (360 MHz, CDCl3) 5 1.28 (3H, t, J 7.1 Hz), 1.35 (3H, t, J 7.1 Hz), 4.19 (2H, q, J 7.1 Hz), 4.26 (2H, q, J 7.1 Hz), 5.68 (1H, br s), 8.11 (1H, dd), 8.69 (1H, br s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | at 20 - 80℃; for 41h;Large scale; | A mixture of 2-bromoaniline (502 g, 2918 mmol, 318 mL) and diethyl ethoxymethylene-malonate (631g, 2918 mmol, 584 mL) was stirred at room temperature for 17 h and at 80C for 24 h. In LC-MScomplete conversion of the starting materials towards the corresponding intermediate was observed.Stirring was continued under vacuo (70 mbar) at 200C for 3 h and at temperatures between 210C and230C for 23 h. The reaction mixture was allowed to cool to room temperature. The solid material wassuspended in refluxing ethyl acetate (2 L). The precipitate was filtered off, washed with ethyl acetate(2x 1 L) and dried on air. This material was combined with material that was obtained from previousreactions towards the title compound starting with in total 4993 mmol of 2-bromoaniline. 1707 g (5447mmol; 68% of theory, based on 7911 mmol) of the title compound were obtained.LC-MS (Method 1): R = 1.69 mm; mlz = 296/298 (M+H)?H NMR (400 MHz, DMSO-d6) 11.65 (s, 1H), 8.46 (s, 1H), 8.18 (m, 1H), 8.05 (m, 1H), 7.37 (t, J=7.9 Hz, 1H), 4.24 (q, J= 7.1 Hz, 2H), 1.29 (t, J= 7.1 Hz, 3H). |
Preparation Example 1 3-Carbethoxy-4-hydroxy-8-bromoquinoline A mixture of 50 g (0.291 mol) of 2-bromoaniline and 63 g (0.291 mol) of diethyl ethoxymethylenemalonate was heated at 100 C. under a reduced pressure for 3 hours, followed by heating at 200 C. for further 12 hours. After the completion of the reaction, the solid matter in the resulting reaction mixture was washed with ethyl acetate, and the crystals were collected by filtration and dried, to give 50 g of the title compound. 1H-NMR (DMSO-d6) delta (ppm) 1.26 (3H, t, J=7.2 Hz), 4.21 (2H, Q, J=7.2 Hz), 7.34 (1H, t, J=7.6 Hz), 8.03 (1H, dd, J=1.6 Hz, 7.6 Hz), 8.15 (1H, dd, J=1.6 Hz, 7.6 Hz), 8.43 (1H, s), 11.56 (1H, s). | ||
Production Example 3b 3-Carbethoxy-4-hydroxy-8-bromoquinoline A mixture of 50 g (0.291 mol) of 2-bromoaniline and 63 g (0.291 mol) of diethylethoxymethylene malonate was heated at100C under reduced pressure for 3 hours and further at 200C for 12 hours. After the reaction was completed, the reaction mixture solid was washed with ethyl acetate and the crystals were collected by filtration and dried, to give 50 g of the title compound. 1H-NMR(DMSO-d6) delta (ppm):1.26(3H, t, J=7.2Hz), 4.21(2H, q, J=7.2Hz), 7.34(1H, t, J=7.6Hz), 8.03(1H, dd, J=1.6Hz, 7.6Hz), 8.15(1H, dd, J=1.6Hz, 7.6Hz), 8.43(1H, s), 11.56(1H, s). |
PRODUCTION EXAMPLE 3b 3-Carbethoxy-4-hydroxy-8-bromoquinoline A mixture of 50 g (0.291 mol) of 2-bromoaniline and 63 g (0.291 mol) of diethylethoxymethylene malonate was heated at 100 C. under reduced pressure for 3 hours and further at 200 C. for 12 hours. After the reaction was completed, the reaction mixture solid was washed with ethyl acetate and the crystals were collected by filtration and dried, to give 50 g of the title compound. 1H-NMR(DMSO-d6) delta (ppm): 1.26(3H, t, J=7.2 Hz), 4.21(2H, q, J=7.2 Hz), 7.34(1H, t, J=7.6 Hz), 8.03(1H, dd, J=1.6 Hz, 7.6 Hz), 8.15(1H, dd, J=1.6 Hz, 7.6 Hz), 8.43(1H, s), 11.56(1H, s). | ||
3.5 g | In diphenylether; at 100℃; for 5h;Inert atmosphere; | A solution of 2-bromoaniline (2.5 g, 14.62 mmol) and ethyl ethoxymethylenemalonate (3.16 g, 14.62 mmol) was heated at 100 C. for 3 h. Then the volatiles were removed by passing a stream of nitrogen and the molten mass was added slowly onto boiling diphenyl ether (10 mL) and the mixture was heated at reflux for 2 h. Then petroleum ether was added to the reaction mixture at rt and the precipitated solid was collected by filtration and dried to afford 3.5 g of the title product. 1H NMR (300 MHz, DMSO d6): delta 11.65 (br s, 1H), 8.45 (s, 1H), 8.17 (d, J=7.8 Hz, 1H), 8.05 (d, J=7.8 Hz, 1H), 7.39-7.34 (t, J=7.8 Hz, 1H), 4.26-4.19 (q, J=7.2, 14.1 Hz, 2H), 1.30-1.26 (t, J=6.9 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | In diphenylether; at 60 - 250℃; for 2.75h; | A mixture of <strong>[5369-19-7]3-tert-butylaniline</strong> (5.30 g, 35.5 mmol) and diethyl ethoxymethylenemalonate (10.2 g, 47.30 mmol) were heated at 60 0C for 15 min. then 1 hour at 120 0C. After the generated ethanol was evaporated in vacuo, the crude oil was added dropwise to boiling diphenylether (150 ml) at 200-2500C and the mixture was stirred at 25O0C for 90 min. After cooling to room temperature, the mixture was diluted with hexane (ca. 200 ml) and the precipitate solid was collected to give (4.55 g, 47 percent) of the title compound as a slightly yellow solid. The compound was used for the next step without the determination of NMR, MS for hard solids. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In toluene; at 100℃; | A mixture of <strong>[59702-07-7]1-<strong>[59702-07-7]methylpiperazin-2-one</strong></strong> (183 g, 1.6 mol) and diethyl ethoxymethylenemalonate (346 g, 1.6 mol) in toluene (12 L) was heated at 100 °C overnight. The resultant mixture was concentrated under vacuum. The residue was dissolved in anhydrous THF (8 L), brought to reflux under an atmosphere of nitrogen, and treated with a solution of lithium bis (trimethylsilyl)amide in THF (1 M, 1.05 eq). The reaction mixture was allowed to cool to room temperature and concentrated under vacuum. The residue was partitioned between methylene chloride and dilute aqueous HCI. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was triturated with ethyl acetate, cooled to -20 °C, and the solid precipitated was filtered to provide the title compound. 1H NMR (400 MHz, DMSO-d6) 8 8.50 (s, 1H), 7.33 (s, 1H), 4.18 (q, J = 7.1 Hz, 2H), 4.11 (t, J = 5.5 Hz, 2H), 3.59 (t, J = 5.5 Hz, 2H), 2.92 (s, 3H), 1.24 (t, J = 7.1 Hz, 3H). ES MS M+l = 239 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In ethanol; for 3h;Heating / reflux; | A suspension of <strong>[60481-51-8]3,4-dimethylphenylhydrazine hydrochloride</strong> (2.0 g; 0.012 mol.) and potassium carbonate (3.2 g; 0.023 mol.) in anhydrous ethanol (40.0 mL) was treated dropwise with diethyl(ethoxymethylene)malonate (2.5 g; 0.012 mol.) and the mixture stirred and heated under reflux for 3 h. After cooling the mixture was evaporated and the residue suspended in water and acid;ified to pH 2 followed by extraction with ethyl acetate. After drying and evaporation the resulting intermediate 1-(3,4-dimethyl-phenyl)-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxylic acid; ethyl ester was dissolved in methanol (10.0 mL) and 10percent aqueous sodium hydroxide (10.0 mL) and stirred at room temperature for 3 h and then heated under reflux to effect hydrolysis. The solution was cooled and acid;ified to pH 4 with 3M aqu. hydrochloric acid; and stirred at room temperature for 2 h to effect decarboxylation. The mixture was extracted with ethyl acetate, dried and evaporated to give the title compound (87percent) as a yellow solid. 1H NMR (300 MHz, CDCl3) delta 7.61 (d, J=2.3 Hz, 1H), 7.55 (dd, J=8.2 and 2.3 Hz, 1H), 7.48 (t, J=1.3 Hz, 1H), 1.16 (d, J=8.2 Hz, 1H), 3.50 (d, J=1.3 Hz, 2H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
at 130℃; for 2.5h; | 4-lodo-3-methylaniline (5.75 g) was suspended in diethyl ETHOXYMETHYLENEMALONATE (5.5 mL). The mixture was heated at 130oC for 2.5 h. After cooling to-90oC, hexane was added and the mixture stirred while cooling to room temperature. The product crystallised out, and was filtered off, washing well with more hexane. The solid was dried in vacuo to yield the title compound as a pale grey powder (7.947 g) ; 1 H NMR 8 (CDCI3) 1.33 (3H, t), 1.38 (3H, t), 2.43 (3H, s), 4.25 (2H, q), 4.3 (2H, q), 6.69 (1 H, dd), 7.01 (1 H, d), 7.75 (1 H, d), 8.46 (1 H, d), and 10.95 (1 H, br d). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step 4: Ethyl 8-hydroxy-2-methyl-l-oxo-l,2,3,4-tetrahydropyrrolo[l,2-alpha]-pyrazine-7-carboxylate; -A mixture of l-<strong>[59702-07-7]methylpiperazin-2-one</strong> (183 g, 1.6mol) and diethyl ethoxymethylenemalonate (346 g, 1.6 mol) in toluene (12 L) was heated at 100 0C overnight. The resultant mixture was concentrated under vacuum. The residue was dissolved in anhydrous THF (8 L), brought to reflux under an atmosphere of nitrogen, and treated with a solution of lithium bis(trimethylsilyl)amide in THF (I M, 1.05 eq). The reaction mixture was allowed to cool to room temperature and concentrated under vacuum. The residue was partitioned between methylene chloride and dilute aqueous HCl. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was triturated with ethyl acetate, cooled to -20 0C, and the solid precipitated was filtered to provide the title compound. lH NMR (400 MHz,DMSO-d6) delta 8.50 (s, IH), 7.33 (s, IH), 4.18 (q, J= 7.1 Hz, 2H), 4.11 (t, J= 5.5 Hz, 2H), 3.59 (t, J= 5.5Hz, 2H), 2.92 (s, 3H), 1.24 (t, J= 7.1 Hz, 3H). ES MS M+l = 239. | ||
A mixture of l-<strong>[59702-07-7]methylpiperazin-2-one</strong> (183 g, 1-6mol) and diethyl ethoxymethylenemalonate (346 g, 1.6 mol) in toluene (12 L) was heated at 100 °C ovemight. The resultant mixture was concentrated under vacuum. The residue was dissolved in anhydrous THF (8 L), brought to reflux under an atmosphere of nitrogen, and treated with a solution of lithium bis (trimethylsilyl) amide in THF (1 M, 1.05 eq). The reaction mixture was allowed to cool to rt and concentrated under vacuum. The residue was partitioned between methylene chloride and dilute aqueous HC1. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was triturated with ethyl acetate, cooled to-20 °C, and the solid precipitated was filtered to provide the title compound. 1H NMR (400 MHz, DMSO-d6) S 8.50 (s, 1H), 7.33 (s, 1H), 4.18 (q, J = 7.1 Hz, 2H), 4.11 (t, J = 5.5 Hz, 2H), 3.59 (t, J = 5.5 Hz, 2H), 2.92 (s, 3H), 1.24 (t, J = 7.1 Hz, 3H). ES MS M+1 = 239 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
17.9 g (95%) | In dichloromethane; | Preparation 42 Diethyl 2-(((2-Chloro-6-methyl-3-pyridinyl)amino)methylene) malonate [BT.2] A mixture of 2-chloro-6-methyl-3-pyridinylamine (8.5 g) and diethyl ethoxy-methylenemalonate (22.0 mL) is heated at 140° C. for 18 hours. The mixture is cooled to room temperature and the resulting solids are recrystallized from a mixture of heptane (400 mL) and CH2Cl2 (2 mL) to obtain 17.9 g (95percent) of the title compound as a pale red solid. Physical characteristics: MS (ESI+) m/z 313 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With PPA; In water; toluene; | EXAMPLE 3 A mixture of 606 kg of diethyl ethoxymethylenemalonate and 400 kg of 6-fluorotetrahydroquinaldine was stirred and heated at about 125 C. for 5 hours. The mixture was cooled to about 95 C. and evaporated. To the stirred reaction mixture was added 450 liters of toluene, then 908 kg of polyphosphoric acid at a rate to maintain a reaction temperature of 90 to 100 C. The mixture was then heated at reflux for fourteen hours. To this mixture was added 950 liters of water over five hours. The ester was saponified by heating for 13 hours at 110 to 115 C. while removing the toluene via the toluene-water azeotrope. The solid product flumequine was separated by filtration, washed thrice with hot water, then with N,N-dimethylformamide. Recrystallization form N,N-dimethylformamide gave white solid flumequine. | |
In sodium hydroxide; toluene; | EXAMPLE 2 6-Fluorotetrahydroquinaldine (12.05 kg containing 10% of toluene) and diethyl ethoxymethylene malonate (16.2 kg) were charged to a 225 liter Pfaudler reactor and heated at 125 C. under vacuum for 4 hours. Ethanol (3.1 kg) was recovered. The product was cooled, diluted with toluene (35 liters) and tetraphosphoric acid (35 kg), reheated to reflux for 2 hours, cooled to 80 C., diluted with water (128 liters) and refluxed for 6 hours to complete the hydrolysis. The crude flumequine was collected, washed acid free with water and rinsed with methanol. The damp cake was dissolved in sodium hydroxide solution (2.94 kg/59 liters) filtered hot through a cartridge filter heated to 90 C. and acidified with hydrochloric acid (6.64 liters). The product was collected, washed acid free, rinsed with methanol and dried in a vacuum oven. The yield of flumequine was 15.4 kg (90.8%). The dry solid was dissolved in N,N-dimethylformamide (70 liters) at 125 C., allowed to cool with stirring to 100 C. then cooled to 7 C. with cold water. The product was collected, washed with methanol and dried as before. The yield of recrystallized flumequine was 14.4 kg (82.3%) overall. | |
With PPA; In water; toluene; | EXAMPLE 4 A mixture of 606 kg of diethyl ethoxymethylenemalonate and 400 kg of 6-fluorotetrahydroquinaldine was stirred and heated at about 125 C. for 5 hours. The mixture was cooled to about 95 C. and evaporated. To the stirred reaction mixture was added 450 liters of toluene, then 908 kg of polyphosphoric acid at a rate to maintain a reaction temperature of 90 to 100 C. The mixture was then heated at reflux for fourteen hours. To this mixture was added 950 liters of water over five hours. The ester was saponified by heating for 13 hours at 110 to 115 C. while removing the toluene via the toluene-water ezeotrope. The solid product flumequine was separated by filtration, washed thrice with hot water, then with N,N-dimethylformamide. Recrystallization form N,N-dimethylformamide gave white solid flumequine. |
In sodium hydroxide; toluene; | EXAMPLE 3 6-Fluorotetrahydroquinaldine (12.05 kg containing 10% of toluene) and diethyl ethoxymethylene malonate (16.2 kg) were charged to a 225 liter Pfaudler reactor and heated at 125 C. under vacuum for 4 hours. Ethanol (3.1 kg) was recovered. The product was cooled, diluted with toluene (35 liters) and tetraphosphoric acid (35 kg), reheated to reflux for 2 hours, cooled to 80 C., diluted with water (128 liters) and refluxed for 6 hours to complete the hydrolysis. The crude flumequine was collected, washed acid free with water and rinsed with methanol. The damp cake was dissolved in sodium hydroxide solution (2.94 kg/59 liters) filtered hot through a cartridge filter heated to 90 C. and acidified with hydrochloric acid (6.64 liters). The product was collected, washed acid free, rinsed with methanol and dried in a vacuum oven. The yield of flumequine was 15.4 kg (90.8%). The dry solid was dissolved in N,N-dimethylformamide (70 liters) at 125 C., allowed to cool with stirring to 100 C. then cooled to 7 C. with cold water. The product was collected, washed with methanol and dried as before. The yield of recrystallized flumequine was 14.4 kg (82.3%) overall. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In diphenylether; | A mixture of 3-t-butylaniline (67.6 g.) and diethyl ethoxymethylenemalonate was heated on the steam bath for 3 hours, the ethanol formed being collected by distillation. The resulting yellow oil was dissolved in diphenyl ether (200 ml.) and added during 0.5 hour to stirred diphenyl ether (800 ml.) at 250°-260°, the ethanol formed being collected by distillation. The mixture was stirred at 250°-260° for 0.5 hour, then allowed to cool to room temperature and diluted with an equal volume of petroleum ether (b.p. 60°-80°). The precipitate was collected by filtration to give the novel compound ethyl 7-t-butyl-4-hydroxyquinoline-3-carboxylate, m.p. 279°-281°. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32% | To a suspension solution of 6-fluoroquinolin-4-ol (3.67 g, 22.5 mmol) (synthesized in overall yield of 32percent starting from 4-fluoroaniline and diethyl ethoxymethylenemalonate according to a literature procedure (see Price et al., Organic Syntheses, Coll. Vol. 3, p. 272; Vol. 28, p. 38), triphenylphosphine (6.56 g, 25 mmol), and 3-bromo-1-propanol (2.3 mL, 25 mmol) in dry tetrahydrofuran (30 mL) was added diisopropyl azodicarboxylate (4.9 mL, 25 mmol) at 25° C. over 30 minutes under nitrogen and the reaction mixture was left stirring for one hour. Hydrobromic acid (2.8 mL of 48percent aqueous solution, 25 mmol) was added, resulting in precipitation of the titled compound. The product was collected by suction filtration and washed with THF, acetone and ether to give a light yellow crystalline solid (4.17 g, 51percent). 1H NMR (400 MHz, DMSO-d6): 2.45 (2H, m), 3.82 (2H, t, J=6.5 Hz), 4.61 (2H, t, J=5.7 Hz), 7.64 (1H, d, J=6.6 Hz), 8.40 (1H, dt, J=8.5, 2.7 Hz), 7.90 (m, 1H), 8.27 (1H, dd, J=9.4, 4.8 Hz), 9.24 (1H, d, J=6.6 Hz). | |
With hydrogenchloride; sodium hydroxide; In diphenylether; hexane; water; | (a) 6-Fluoro-4-hydroxyquinoline A mixture of 216 ml of diethyl ethoxymethylenemalonate, 95 ml of 4-fluoroaniline, and 800 ml of diphenyl ether was stirred and slowly heated to 185° with distillation of the ethanol formed. The reaction mixture was then heated to 245° for 1.5 hr. The total amount of ethanol collected was 105 ml. The reaction mixture was allowed to cool to 60° at which time 250 ml of hexane was added. After it had stood overnight, the product was collected, washed with hexane and dried to give 223 g of solid mp 305°-309°. A mixture of the above solid, 600 ml of 3N sodium hydroxide, and 250 ml of water was stirred and heated under reflux for 2 hr. To the hot brown cloudy mixture was slowly added 600 ml of 3N hydrochloric acid to precipitate the product, 6-fluoro-4-hydroxyquinoline-3-carboxylic acid. This product was filtered from the cooled reaction mixture. This damp solid and 600 ml of diphenyl ether was slowly heated to 250° while water was allowed to distill out. The reaction mixture was held at this temperature for 20 min. and then allowed to cool to 100°. Then 500 ml of hexane was added, and the mixture was stirred for 1 hr. The product 6-fluoro-4-hydroxyquinoline, was collected and washed with hexane to give 144 g, mp 209°-212°. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With acetic acid; at 120℃; for 3h; | General procedure: A solution of aminotriazole 11a?m (3.1mmol), glacial acetic acid (5mL), and diethyl ethoxymethylenemalonate (4.6mmol) was refluxed for 3h. After cooling to room temperature, the resulting precipitate was collected by filtration, washed with cold water and dried. The residue was stirred with cold ethyl ether (20mL) and filtered to afford the desired product. Following general procedure C, compound 12c was isolated as a white solid. Yield 67percent, mp>300°C. 1H NMR (200MHz, DMSO-d6) delta: 14.00 (br s, 1H); 8.64 (s, 1H); 8.14?8.10 (m, 2H); 7.55 (m, 3H); 4.26 (q, J=7.0Hz, 2H); 1.28 (t, J=6.8Hz, 3H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With acetic acid; for 20.0h;Reflux; | To the solution of <strong>[1203705-55-8]5-amino-3-bromo-1H-pyrazole</strong> II (20.0 g, 121 mmol) in acetic acid (200 mL) diethyl ethoxymethylenemalonate III (25.9 mL, 127 mmol) was added. Reaction mixture was heated at reflux with stirring for 20 hours. Then the mixture was cooled to room temperature, precipitated solid was filtered, washed with ethanol and diethyl ether. Product was obtained as a creamy solid (27.9 g, 97.4 mmol), with the yield 81%. MS-ESI: (m/z) calculated for C9H7BrN303 [M-H]-= 284.0, found 284.0. 1H NMR (300 MHz, DMSO-d6) delta 8.37 (s, 1H), 6.15 (s, 1H), 4.50 (bs, 1H), 4.14 (q, J=7.1 Hz, 2H), 1.24 (t, 3=1.1 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With ethanol; sodium ethanolate; at 90℃; for 17h; | A mixture of diethyl 2-(ethoxymethylene)malonate (5 g, 23.2 mmol), <strong>[1903-91-9]2-methoxyacetimidamide hydrochloride</strong> (2.88 g, 23.2 mmol) and sodium ethoxide (3.15 g, 46.3 mmol) in anhydrous ethanol (200 mL) was stirred at 90 C for 17 h. The reaction mixture was concentrated, to give ethyl 4-hydroxy-2-(methoxymethyl)pyrimidine-5-carboxylate (4 g, 18.8 mmol, 81 %) as a white solid. LCMS (ESI) m/z: 213.1 [M+H]+ |
Tags: 87-13-8 synthesis path| 87-13-8 SDS| 87-13-8 COA| 87-13-8 purity| 87-13-8 application| 87-13-8 NMR| 87-13-8 COA| 87-13-8 structure
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