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Chemical Structure| 57513-54-9
Chemical Structure| 57513-54-9
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Product Details of [ 57513-54-9 ]

CAS No. :57513-54-9 MDL No. :MFCD00117242
Formula : C13H13NO4 Boiling Point : -
Linear Structure Formula :- InChI Key :IGIHLDXSSGANGR-UHFFFAOYSA-N
M.W : 247.25 Pubchem ID :54682929
Synonyms :

Calculated chemistry of [ 57513-54-9 ]

Physicochemical Properties

Num. heavy atoms : 18
Num. arom. heavy atoms : 10
Fraction Csp3 : 0.23
Num. rotatable bonds : 3
Num. H-bond acceptors : 4.0
Num. H-bond donors : 1.0
Molar Refractivity : 67.58
TPSA : 68.53 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.49 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.93
Log Po/w (XLOGP3) : 1.86
Log Po/w (WLOGP) : 1.42
Log Po/w (MLOGP) : 1.51
Log Po/w (SILICOS-IT) : 1.76
Consensus Log Po/w : 1.69

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 0.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -2.76
Solubility : 0.432 mg/ml ; 0.00175 mol/l
Class : Soluble
Log S (Ali) : -2.92
Solubility : 0.297 mg/ml ; 0.0012 mol/l
Class : Soluble
Log S (SILICOS-IT) : -3.08
Solubility : 0.205 mg/ml ; 0.000828 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 2.16

Safety of [ 57513-54-9 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P280-P301+P312-P302+P352-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 57513-54-9 ]

* 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.

  • Downstream synthetic route of [ 57513-54-9 ]

[ 57513-54-9 ] Synthesis Path-Downstream   1~85

  • 1
  • [ 504-29-0 ]
  • [ 57513-54-9 ]
  • 4-hydroxy-1-methyl-2-oxo-N-(pyridin-2-yl)-1,2-dihydroquinolin-3-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
92% at 150 - 160℃; for 0.166667h;
38% In N,N-dimethyl-formamide at 160℃; for 0.5h; Sealed tube; 9 Example 9 Preparation of 4-hydroxy-1-methyl-2-oxo-N-(pyridin-2-yl)-1,2-dihydroquinolin-3-carboxamide Ethyl 4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylate (124 mg,0.50 mmol) and 2-aminopyridine (71 mg, 0.75 mmol) of Example 7 were added It wasdissolved in DMF (3 mL), put in a sealed tube, heated at 160° C for 30 minutes, and cooled slowly to room temperature. The resulting solid was filtered and washed withethanol to give the target compound (KCNS-SM-35); 56 mg, 38% yield).
  • 2
  • [ 10328-92-4 ]
  • [ 105-53-3 ]
  • [ 57513-54-9 ]
YieldReaction ConditionsOperation in experiment
80% With sodium hydride In N,N-dimethyl-formamide at 120℃; for 2.5h;
78% Stage #1: diethyl malonate With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20 - 90℃; Inert atmosphere; Stage #2: N-Methylisatoic anhydride In N,N-dimethyl-formamide; mineral oil at 120℃; Inert atmosphere; 4.5 Synthesis of ethyl 4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylate (3) A solution of diethyl malonate (51mmol) was added slowly to a suspension of sodium hydride (60% in mineral oil, 56mmol) in dimethylformamide under N2 atmosphere. The mixture was stirred at room temperature until the evolution of hydrogen gas ceased, then heated to 90°C for 30min and cooled to room temperature. A solution of N-methylisatoic anhydride (56mmol) in dimethylformamide was added slowly and the mixture was heated overnight at 120°C. The mixture was then cooled to room temperature, poured into ice water, and acidified by cold 10% HCI. The solids formed were filtered and washed several times by water to afford ethyl 4-hydroxy-1-methyl-2-oxo-1, 2-dihydroquinoline-3-carboxylate as light brown coloured solid with 78% yield.1H NMR (500MHz, CDCl3): δ1.49 (t,J=7.1Hz, 3H, CH3),3.66 (s, 3H, CH3), 4.51 (q, J=7.1Hz, 2H, CH2), 7.27-7.38 (m, 1H, Ar-H), 7.66-7.73 (m, 1H, Ar-H), 8.19 (dd, J=7.9Hz, 1.5Hz, 1H, Ar-H), 14.20 (s, 1H, OH).
78% Stage #1: diethyl malonate With sodium hydride In N,N-dimethyl-formamide; mineral oil at 90℃; for 0.5h; Inert atmosphere; Stage #2: N-Methylisatoic anhydride In N,N-dimethyl-formamide; mineral oil at 120℃; Inert atmosphere; Synthesis of ethyl 4-hydroxy-1-alkyl-2-oxo-1,2-dihydroquinoline-3-carboxylate (4,5) A solution of diethyl malonate (51 mmol) was added slowly to a suspension of sodium hydride (60 percent in mineral oil, 56 mmol) in dimethylformamide under N2 atmosphere. The mixture was stirred at room temperature until the evolution of hydrogen gas ceased, then heated to 90 oC for 30 minutes and cooled to room temperature. A solution of N-alkyl isatoic anhydride (56 mmol) in dimethylformamide was added slowly and the mixture was heated overnight at 120 oC. The mixture was then cooled to room temperature, poured into ice water, and acidified by cold 10% HCl. The solids formed were filtered and washed several times by water to afford ethyl 4-hydroxy-1-methyl-2-oxo-1, 2-dihydroquinoline-3-carboxylate as light brown coloured solid with 78% yield and ethyl 1-ethyl-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylate as light brown coloured solid with 70% yield. 1H NMR of 4-hydroxy-1-methyl-2-oxo-1, 2-dihydroquinoline-3-carboxylate (500 MHz, CDCl3): δ1.49 (t, J = 7.1 Hz, 3H, CH3), 3.66 (s, 3H, CH3), 4.51 (q, J = 7.1 Hz, 2H, CH2), 7.27-7.38 (m, 1H, Ar-H), 7.66-7.73 (m, 1H, Ar-H), 8.19 (dd, J = 7.9 Hz, 1.5 Hz, 1H, Ar-H), 14.20 (s,1H, OH).
78% Stage #1: diethyl malonate With sodium hydride In N,N-dimethyl-formamide; mineral oil at 90℃; for 0.5h; Inert atmosphere; Stage #2: N-Methylisatoic anhydride In N,N-dimethyl-formamide; mineral oil at 120℃; for 16h; Inert atmosphere;
71% With sodium hydride In N,N-dimethyl-formamide for 5h; Reflux; 2 Typical procedure for preparation of compounds 3a-e General procedure: To a suspension of NaH (1 equiv) in DMF at 0 C was slowlyadded diethyl malonate (10 equiv) and a solution of the correspondingisatoic anhydride (1 equiv) in DMF. Then the reactionmixture was heated to reflux. After completion of the reaction (TLC monitoring) the crude mixture was quenched with water andacidified with concentrated hydrochloric acid. The resulting solidwas filtered, washed with water and diethylether and then driedin vacuo to give the desired compound.
69% With sodium hydride In N,N-dimethyl-formamide at 130℃; for 2.5h;
67% With sodium hydride
67% Stage #1: diethyl malonate With sodium hydride In N,N-dimethyl acetamide at 20 - 90℃; for 0.5h; Stage #2: N-Methylisatoic anhydride In N,N-dimethyl acetamide at 120℃; 3 Preparation of 4-HYDROXY-1-METHYL-2-OXO-1, 2-DIHYDRO-QUINOLINE-3-CARBOXYLIC ACID ethyl ester (COMPOUND 1) A solution of diethyl malonate (8.16 g, 51 mmol) was added slowly to a suspension of sodium hydride (60% in mineral oil, 2.24 g, 56 mmol) in dimethylacetamide under N2 atmosphere. The mixture was stirred at room temperature until the evolution of hydrogen gas ceased, then heated to 90 C for 30 min. and cooled to room temperature. A solution of N-methylisatoic anhydride (10 g, 56 mmol) in dimethylacetamide was added slowly and the mixture was heated overnight at 120 C. The mixture was then cooled to room temperature, poured into ice water, and acidified by cold 10% HCI. The solids formed were filtered and washed several times by water to yield 8.47 g (67%) of white solids. M. P. 67°C. IH NMR (DMSO-D6) : d 1.30 (t, J= 7.0 Hz, 3H), 3.53 (s, 3H), 4.32 (Q, J = 7. 0 Hz, 2H), 7.30 (t, J= 7.5 Hz, 1H), 7.52 (D, J = 8. 5 Hz, 1H), 7.75 (T, J= 8.4 Hz, 1H), 8. 04 (d, J = 7.8 Hz, 1H), 13.03 (s, 1H). EIMS m/z 248 (M+1), 270 (M+23). Anal. (CL3HL3NO4) C, H, N.
56% With sodium hydride In N,N-dimethyl-formamide at 85℃; for 6h; General synthesis process for compounds 1 and 2. General procedure: The corresponding anhydride (1 equiv) is dissolved in 40 ml of DMF, and the sodium hydride (1.2 equiv) and diethyl malonate (1.2 equiv) are added. Subsequently, it is heated to 85°C for 6 h. After this time has elapsed, the mixture is allowed to cool and acidified with a 1 M HCl solution. When it reaches an acid medium, it precipitates a white solid which, after being filtered, is the pure final compound.
56% With sodium hydride In N,N-dimethyl-formamide at 85℃; for 6h; Ethyl 4-Hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylate (1). General procedure: The corresponding anhydride (1 equiv) is dissolved in 40 ml of DMF, and the sodium hydride (1.2 equiv) and diethyl malonate (1.2 equiv) are added. Subsequently, it is heated to 85° C. for 6 h. Afier this time has elapsed, the mixture is allowed to cool and acidified with a 1 M HC1 solution. When it reaches an acid medium, it precipitates a white solid which, after being filtered, is the pure final compound. Yield 56%. 1H NMR (300 MHz, CDCl3) δ 8.12 (d, J=8.0 Hz, 1H), 7.64 (t, J=7.9 Hz, 1H), 7.36-7.11 (m, 3H), 4.48 (q, J=7.1 Hz, 2H), 3.61 (s, 3H), 1.99 (sa, 1H), 1.46 (t, J=7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 172.8, 171.8, 159.7, 141.4, 134.5, 125.9, 122.0, 115.0, 114.3, 98.1, 62.4, 29.35, 14.44. M.p.=95° C.-96° C. HPLC: Purity>99%. MS (ES): m/z=248, 201, 133. Elementary Analysis (C13H13NO4) Calculated: C, 63.15%; H, 5.30%; N, 5.67%. Found: C, 63.31%; H, 5.08%; N, 5.77%.
41% Stage #1: N-Methylisatoic anhydride; diethyl malonate With sodium hydride In N,N-dimethyl-formamide at 0 - 85℃; for 5h; Stage #2: With hydrogenchloride In water; N,N-dimethyl-formamide 4.4. General method of preparation of compounds 3a-d General procedure: The corresponding anhydride isatoic (1 eq) was suspended in DMF (10 mL) at 0 °C. Sodium hydride (2 eq) and diethyl malonate (5 eq) were added slowly. Then the reaction mixture was heated at 85 °C for 5 h. Then, 10 mL of water were added and the mixture was acidified with concentrated hydrochloric acid. The resulting solid was filtered, washed with water and dried, yielding the desired compound.
41% With sodium hydride In N,N-dimethyl acetamide; mineral oil at 140℃; for 0.25h;
With sodium hydride In N,N-dimethyl-formamide at 120℃; for 2.5h;
With sodium hydride In N,N-dimethyl-formamide at 85℃; for 5h;
Stage #1: diethyl malonate With sodium hydride In N,N-dimethyl-formamide at 20℃; for 0.25h; Inert atmosphere; Stage #2: N-Methylisatoic anhydride In N,N-dimethyl-formamide at 60℃; for 8h; Inert atmosphere; 4.1.2. General procedure A for the synthesis of compounds b1-b3 General procedure: The synthesis of the compounds b1-b3was accomplished by thefollowing two steps. The first step was based on the method proposedby Ukrainets I. V., et al. [35]. At the beginning, the isatoicanhydride (1 equiv) was dissolved in dry DMF (15 mL) and thesodium hydride (1.3 equiv) was gradually added to the solution atthe temperature of 0 C. After 25 min, the halogenated compound(1.2 equiv) was also added. The reaction mixture was stirred at45 C and the stirring lasted for 10 h. Then, dichloromethane(15 mL) and water (15 mL) were added. The organic phase waswashed with brine (15 mL), dried with magnesium sulfate andfiltered. After the solvent was evaporated, the solid was recrystallizedin dichloromethane/hexane to afford the desired isatoic anhydridederivative. The second step of the synthesis was based onthe publication from Coppola G.M. et al. [36]. Diethylmalonate wasadded dropwise to the sodium hydride dissolved in dry DMF(15 mL) under argon atmosphere and stirred for 15 min at roomtemperature. Then, the mixture was added to a round-bottomedflask that contained the isatoic anhydride derivative dissolved inDMF (15 mL) under argon atmosphere. The reaction mixture washeated to 60 C and maintained at 60 C for 8 h. Following that,dichlorometane (30 mL), water (50 mL), and HCl (1 N) were addedin order to adjust the pH of the mixture to 5. The organic layer wasseparated from the aqueous phase and washed with brine (30 mL).It was then dried with dry magnesium sulfate and filtered. Lastly,the solvent was evaporated and the resulting solid was recrystallizedin dichloromethane/hexane, which produced the compound(b1-b3). 4.1.2.1. Ethyl 4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylate (b1). Yield 51.3%, pale yellow solid. ESI-MS (m/z):248.13 [MH]. 1H NMR (500 MHz, DMSO-d6) δ 8.07 (d, J 7.8 Hz,1H), 7.77 (t, J 7.9 Hz, 1H), 7.54 (d, J 8.6 Hz, 1H), 7.33 (t, J 7.7 Hz,1H), 4.36 (q, J 7.2 Hz, 2H), 3.57 (s, 3H), 1.33 (t, J 7.1 Hz, 3H).

Reference: [1]Ismaili, Lhassane; Refouvelet, Bernard; Robert, Jean Francois [Journal of Heterocyclic Chemistry, 1999, vol. 36, # 3, p. 719 - 722]
[2]Banu, Saleha; Bollu, Rajitha; Bantu, Rajashaker; Nagarapu, Lingaiah; Polepalli, Sowjanya; Jain, Nishant; Vangala, Radhika; Manga, Vijjulatha [European Journal of Medicinal Chemistry, 2017, vol. 125, p. 400 - 410]
[3]Banu, Saleha; Bollu, Rajitha; Naseema, Mohammad; Gomedhika, P. Mary; Nagarapu, Lingaiah; Sirisha; Kumar, C. Ganesh; Gundasw, Shravan Kumar [Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 7, p. 1166 - 1170]
[4]Banu, Saleha; Bollu, Rajitha; Nagarapu, Lingaiah; Nanubolu, Jagadeesh Babu; Yogeswari, Perumal; Sriram, Dharmarajan; Gunda, Shravan Kumar; Vardhan, Divyasphoorthi [Chemical Biology and Drug Design, 2018, vol. 92, # 1, p. 1315 - 1323]
[5]Pudlo, Marc; Luzet, Vincent; Ismaili, Lhassane; Tomassoli, Isabelle; Iutzeler, Anne; Refouvelet, Bernard [Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 8, p. 2496 - 2507]
[6]Collin; Robert; Duflos; Wielgosz; Le Baut; Robin-Dubigeon; Grimaud; Lang; Petit [Journal of Pharmacy and Pharmacology, 2001, vol. 53, # 3, p. 417 - 423]
[7]Coppola, Gary M.; Damon, Robert E.; Hardtmann, Goetz E. [Synthesis, 1981, # 5, p. 391 - 392]
[8]Current Patent Assignee: OTSUKA HOLDINGS CO LTD - WO2004/74218, 2004, A2 Location in patent: Page 93
[9]Current Patent Assignee: GOVERNMENT OF SPAIN - EP2769720, 2014, A1 Location in patent: Paragraph 0049
[10]Current Patent Assignee: GOVERNMENT OF SPAIN - US2015/57311, 2015, A1 Location in patent: Paragraph 0134; 0135; 0136
[11]Location in patent: experimental part Tomassoli, Isabelle; Ismaili, Lhassane; Pudlo, Marc; De Los Ríos, Cristóbal; Soriano, Elena; Colmena, Inés; Gandía, Luis; Rivas, Luis; Samadi, Abdelouahid; Marco-Contelles, José; Refouvelet, Bernard [European Journal of Medicinal Chemistry, 2011, vol. 46, # 1, p. 1 - 10]
[12]Tomassoli, Isabelle; Herlem, Guillaume; Picaud, Fabien; Benchekroun, Mohamed; Bautista-Aguilera, Oscar M.; Luzet, Vincent; Jimeno, María-Luisa; Gharbi, Tijani; Refouvelet, Bernard; Ismaili, Lhassane [Monatshefte fur Chemie, 2016, vol. 147, # 6, p. 1069 - 1079]
[13]Shi, Jiandong; Xiao, Zili; Ihnat, Michael A.; Kamat, Chandrashekhar; Pandit, Bulbul; Hu, Zhigen; Li, Pui-Kai [Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 6, p. 1187 - 1189]
[14]Jönsson, Stig; Andersson, Gunnar; Fex, Tomas; Fristedt, Tomas; Hedlund, Gunnar; Jansson, Karl; Abramo, Lisbeth; Fritzson, Ingela; Pekarski, Olga; Runström, Anna; Sandin, Helena; Thuvesson, Ingela; Björk, Anders [Journal of Medicinal Chemistry, 2004, vol. 47, # 8, p. 2075 - 2088]
[15]Xue, Wenjie; Li, Xueyao; Ma, Guixing; Zhang, Hongmin; Chen, Ya; Kirchmair, Johannes; Xia, Jie; Wu, Song [European Journal of Medicinal Chemistry, 2020, vol. 188]
  • 3
  • [ 16526-19-5 ]
  • [ 57513-54-9 ]
  • [ 153334-94-2 ]
  • [ 153334-93-1 ]
YieldReaction ConditionsOperation in experiment
1: 4% 2: 44% With perhydrodibenzo-18-crown-6; potassium carbonate; potassium iodide In acetone for 18h; Heating;
  • 4
  • [ 768-94-5 ]
  • [ 57513-54-9 ]
  • 1'-Adamantyl-4-hydroxy-N-methyl-3-chinolin-2(1H)-on-carbonsaeureamid [ No CAS ]
YieldReaction ConditionsOperation in experiment
64% With ammonium chloride In 1,4-dioxane for 2h; Heating;
  • 5
  • [ 57513-54-9 ]
  • [ 28144-70-9 ]
  • 1-methyl-2-oxo-4-hydroxyquinoline-3-carboxylic acid 2-carbamylanilide [ No CAS ]
YieldReaction ConditionsOperation in experiment
98% at 150℃; for 0.25h;
  • 6
  • [ 57513-54-9 ]
  • [ 106-96-7 ]
  • ethyl 4-(2-propynyl)oxy-1-methyl-3-quinolin-2(1H)-onecarboxylate [ No CAS ]
  • ethyl 3-(2-propynyl)-2,4-dioxo-1,2,3,4-tetrahydro-1-methyl-3-quinolinecarboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
1: 17% 2: 45% With perhydrodibenzo-18-crown-6; potassium carbonate; potassium iodide In acetone for 18h; Heating;
  • 7
  • [ 57513-54-9 ]
  • [ 95-54-5 ]
  • 3-(1H-Benzoimidazol-2-yl)-4-hydroxy-1-methyl-1H-quinolin-2-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
95% at 250℃; for 0.5h;
  • 9
  • [ 57513-54-9 ]
  • [ 1677-46-9 ]
YieldReaction ConditionsOperation in experiment
86% With sodium hydroxide for 3h; Heating;
  • 11
  • [ 57513-54-9 ]
  • [ 75483-04-4 ]
YieldReaction ConditionsOperation in experiment
90% With trichlorophosphate for 0.5h; Inert atmosphere; Reflux;
89% With triethylamine; trichlorophosphate at 60℃; for 3h;
82% With trichlorophosphate for 0.5h; Heating;
78% With trichlorophosphate at 95℃; for 3h;
27% With trichlorophosphate for 1h; Reflux;
With trichlorophosphate for 2h; Heating;
With trichlorophosphate at 60℃; for 3h; Inert atmosphere; Synthesis of ethyl 4-chloro-1-alkyl-2-oxo-1,2-dihydroquinoline-3-carboxylates (6,7) General procedure: To the corresponding carboxylate compounds 3 and 4 (17 mmol), phosphoryl chloride (218 mmoles) was added slowly and the solution was heated to 60 oC for a total of 3h under inert atmosphere. After the completion of reaction, the mixture was poured on to crushed ice which was brought to pH 6 with conc. NaOH solution to afford light brown coloured solid. This was filtered and dried to afford the corresponding chloro compounds 5 and 6 respectively with 78-74% yields. 1H-NMR of ethyl 4-chloro-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylate (400 MHz, CDCl3): δ1.42 (t, J=7.1 Hz, 3H, CH3), 3.73 (s, 3H, CH3), 4.48 (q, J=7.1 Hz, 2H, CH2), 7.33-7.43 (m, 2H, Ar-H), 7.65-7.73 (m,1H, Ar-H), 8.04-8.09 (m,1H, Ar-H).
3.9 g With trichlorophosphate at 110℃; for 0.666667h; Ethyl 4-chloro-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylate In a round bottom flask, ethyl 1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinoline-3- carboxylate (5 g, 20.22 mmol) and phosphorus oxychloride (5 ml, 53.6 mmol) were added. The reaction mixture was heated at 110 °C for 40 minutes. The volatiles were removed at the Rotovap. To the crude residue, 50 mL ice was added in portions over 15 minutes followed by 150 mL water. The mixture was stirred 15 minutes and ethyl acetate 10 was added. The organic portion was extracted with 20 mL portions of 1x water, 3x 1 N aqueous sodium hydroxide, 1x water and 1x brine. The organic portion was dried over magnesium sulfate and the solvent was removed by rotary evaporation. The residue was place under vacuum overnight to give 3.9 g of a pale yellow solid.1H NMR (400 MHz, chloroform-d) ^ 8.09 (dd, J=8.2, 1.1 Hz, 1H), 7.73-7.68 (m, 1H), 7.43 (d, J=8.5 Hz, 1H), 15 7.38 (t, J=7.7 Hz, 1H), 4.49 (q, J=7.0 Hz, 2H), 3.75 (s, 3H), 1.44 (t, J=7.2 Hz, 3H)

  • 12
  • [ 57513-54-9 ]
  • [ 74693-61-1 ]
YieldReaction ConditionsOperation in experiment
98% With hydrazine hydrate In ethanol Ambient temperature;
96% With hydrazine hydrate
64% With hydrazine In methanol at 100℃; for 0.5h; 4.6. General method for compounds 5a-d General procedure: The quinoline-3-carboxylate (1 eq) and its derivatives were suspended in methanol (20 mL). Hydrazine (1.5 eq) was added and the mixture was heated at 100 °C for 30 min. The precipitated compound was collected by filtration and used without further purification.
10% With hydrazine In ethanol for 18h; Heating;

  • 14
  • [ 57513-54-9 ]
  • [ 57931-81-4 ]
YieldReaction ConditionsOperation in experiment
89% With hydrogenchloride for 5h; Heating;
56.2% With hydrogenchloride In acetic acid at 60℃; for 10h; Reflux; 4.1.3. General procedure B for the synthesis of compounds c1-c3 General procedure: At first, the concentrated HCl (1.38 mL, 37%) was slowly added tothe acetic anhydride (4.50 mL) at 0 C, which yielded a solution ofapproximately 2.8 M HCl in acetic acid. Subsequently, the preparedsolution (3 mL) of 2.8 M HCl in acetic acid was added to the ester(b1-b3, 1.00 mmol). The reaction mixture was heated to 60 C andrefluxed at that temperature for 10 h. After the reaction mixturewas cooled down to the room temperature, it was mixed with 2-propanol. The end product was obtained by filtering, washedwith 2-propanol and dried in a vacuum. 4.1.3.1. 4-Hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (c1). Yield 56.2%, white solid. ESI-MS (m/z): 218.41[MH]. 1H NMR (500 MHz, DMSO-d6) δ 14.42 (s, 1H), 11.34 (s, 1H),8.19 (d, J 7.9 Hz, 1H), 7.99-7.95 (m, 1H), 7.82 (d, J 8.7 Hz, 1H), 7.55(t, J 7.6 Hz, 1H), 3.74 (s, 3H).
  • 15
  • Potassium; 3-ethoxycarbonyl-1-methyl-2-oxo-1,2-dihydro-quinolin-4-olate [ No CAS ]
  • [ 57513-54-9 ]
YieldReaction ConditionsOperation in experiment
96% With hydrogenchloride for 1h;
  • 16
  • [ 96-50-4 ]
  • [ 57513-54-9 ]
  • 4-hydroxy-1-methyl-2-oxo-N-(thiazol-2-yl)-1,2-dihydroquinoline-3-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
89% In diphenylether at 150 - 160℃; for 0.25h;
39% In N,N-dimethyl-formamide at 160℃; for 0.5h; General procedure to prepare 2-oxo-N-(thiazol-2-yl)-1,2-dihydroquinoline-3-carboxamide (6a, 6c, 6d) General procedure: Thiazol-2-amine (0.388 mmol) was added to the solution of 1,2-dihydroquinoline-3-carboxylate (5a, 5c, 5d) (0.323 mmol) in DMF (3 mL) and the reaction mixture was heated at reflux for 30 min., when TLC shows completion of reaction. The reaction mixture was cooled to room temperature then added crushed ice to it, the precipitate formed was filtered, washed with cold water, dried, and recrystallized from ethanol.
25% In N,N-dimethyl-formamide at 160℃; for 0.5h; Sealed tube; 12 Example 12 Preparation of 4-hydroxy-1-methyl-2-oxo-N-(thiazol-2-yl)-1,2-dihydroquinoline-3-carboxamide Ethyl 4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylate (124 mg, 0.50 mmol) and thiazol-2-amine (75 mg, 0.75 mmol) in Example 7. ) Was dissolved in DMF (3 mL), put in a sealed tube, heated at 160°C for 30 minutes, and cooled slowly to room temperature. The resulting solid was filtered and washed with ethanol to give the target compound (KCNS-SM-38); 38 mg, 25% yield).
  • 17
  • [ 57513-54-9 ]
  • 3-Bromo-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinoline-3-carboxylic acid ethyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
With bromine In chloroform for 0.5h;
  • 18
  • [ 2627-86-3 ]
  • [ 57513-54-9 ]
  • 4-Hydroxy-1-methyl-2-oxo-1,2-dihydro-quinoline-3-carboxylic acid ((S)-1-phenyl-ethyl)-amide [ No CAS ]
YieldReaction ConditionsOperation in experiment
86% In ethanol for 7h; Heating;
  • 19
  • [ 3886-69-9 ]
  • [ 57513-54-9 ]
  • 4-Hydroxy-1-methyl-2-oxo-1,2-dihydro-quinoline-3-carboxylic acid ((R)-1-phenyl-ethyl)-amide [ No CAS ]
YieldReaction ConditionsOperation in experiment
84% In ethanol for 7h; Heating;
  • 20
  • [ 57513-54-9 ]
  • [ 3306-62-5 ]
  • 1-methyl-2-oxo-4-hydroxyquinoline-3-carboxylic acid 2-sulfamylanilide [ No CAS ]
YieldReaction ConditionsOperation in experiment
87% at 180 - 190℃; for 0.166667h;
  • 21
  • [ 57513-54-9 ]
  • 5,9-dimethyl-6,7,8-trioxodiquinolino[3,4-b;3',4'-e]-4H-pyran [ No CAS ]
YieldReaction ConditionsOperation in experiment
96% at 230 - 250℃;
  • 22
  • [ 3731-52-0 ]
  • [ 57513-54-9 ]
  • N-(3-methylpyridinyl)-1,2-dihydro-4-hydroxy-1-methyl-2-oxoquinoline-3-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
88% In xylene for 2h; Heating;
  • 23
  • [ 5407-87-4 ]
  • [ 57513-54-9 ]
  • N-(4,6-dimethylpyridin-2-yl)-1,2-dihydro-4-hydroxy-1-methyl-2-oxoquinoline-3-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
75% In xylene for 2h; Heating;
  • 24
  • [ 5108-51-0 ]
  • [ 57513-54-9 ]
  • 4-hydroxy-1-methyl-2-oxo-1,2-dihydro-quinoline-3-carboxylic acid (1,1-dioxo-1,2-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-ylmethyl)-amide [ No CAS ]
YieldReaction ConditionsOperation in experiment
84% at 170 - 190℃;
  • 25
  • [ 57513-54-9 ]
  • 4-(adamant-1-yl)-2-aminothiazole [ No CAS ]
  • 4-hydroxy-1-methyl-2-oxo-1,2-dihydro-quinoline-3-carboxylic acid (4-adamantan-1-yl-thiazol-2-yl)-amide [ No CAS ]
YieldReaction ConditionsOperation in experiment
97% at 160 - 180℃; for 0.166667h;
  • 26
  • [ 57513-54-9 ]
  • [ 62-53-3 ]
  • [ 84088-17-5 ]
YieldReaction ConditionsOperation in experiment
91% In N,N-dimethyl-formamide Heating;
40% In N,N-dimethyl-formamide at 160℃; for 0.5h; Sealed tube; 7.2 Step 2: Preparation of 4-hydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide Ethyl 4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylate (124 mg, 0.50 mmol) and aniline (47 mg, 1.00 mmol) were dissolved in DMF (3 mL) Placed in a sealed tube, heated at 160 oC for 30 minutes, and cooled slowly to room temperature. The resulting solid was filtered and washed with ethanol to give the target compound (KCNS-SM-33); 60 mg, 40% yield).
In toluene for 4h; Heating;
  • 28
  • [ 105-53-3 ]
  • 2-methylamino-benzoic acid benzotriazol-1-yl ester [ No CAS ]
  • [ 57513-54-9 ]
YieldReaction ConditionsOperation in experiment
1.5 g With sodium hydride In tetrahydrofuran at 20℃; for 2.5h;
  • 29
  • [ 10328-92-4 ]
  • [ 1099-45-2 ]
  • C17H19NO6 [ No CAS ]
  • [ 57513-54-9 ]
YieldReaction ConditionsOperation in experiment
1: 44% 2: 30% With benzoic acid In ethyl acetate for 48h; Heating;
  • 30
  • [ 57513-54-9 ]
  • 4-amino-1-methyl-2-oxoquinoline-3-carboxylic acid ethyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: POCl3 / 2 h / Heating 2: Et3N / ethanol / 5 h / Heating 3: 2.04 g / aq. HCl / 0.03 h / 100 °C
  • 31
  • [ 119-68-6 ]
  • [ 57513-54-9 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: N,N'-dicyclohexylcarbodiimide / tetrahydrofuran / 3 - 5 °C 2: 1.5 g / NaH / tetrahydrofuran / 2.5 h / 20 °C
  • 32
  • [ 118-48-9 ]
  • [ 57513-54-9 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: NaH / dimethylformamide / 5 h / 20 °C 2: NaH / dimethylformamide / 5 h / 85 °C
Multi-step reaction with 2 steps 1.1: sodium hydride / mineral oil; N,N-dimethyl-formamide / 0.17 h 1.2: 5 h / 0 - 20 °C 2.1: sodium hydride / mineral oil; N,N-dimethyl-formamide / 20 - 90 °C / Inert atmosphere 2.2: 120 °C / Inert atmosphere
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl acetamide / 3 h / Reflux 2: sodium hydride / N,N-dimethyl acetamide; mineral oil / 0.25 h / 140 °C
Multi-step reaction with 2 steps 1.1: sodium hydride / N,N-dimethyl-formamide / 0.17 h 1.2: 5 h / 0 - 20 °C 2.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 0.5 h / 90 °C / Inert atmosphere 2.2: 120 °C / Inert atmosphere
Multi-step reaction with 2 steps 1.1: sodium hydride / N,N-dimethyl-formamide / 0.17 h 1.2: 5 h / 0 - 20 °C 2.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 0.5 h / 90 °C / Inert atmosphere 2.2: 16 h / 120 °C / Inert atmosphere
Multi-step reaction with 2 steps 1.1: sodium hydride / N,N-dimethyl-formamide / 0.42 h / 0 °C 1.2: 10 h / 45 °C 2.1: sodium hydride / N,N-dimethyl-formamide / 0.25 h / 20 °C / Inert atmosphere 2.2: 8 h / 60 °C / Inert atmosphere

  • 33
  • [ 118-92-3 ]
  • [ 57513-54-9 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: dioxane / 1 h / 20 °C 2: NaH / dimethylformamide / 5 h / 20 °C 3: NaH / dimethylformamide / 5 h / 85 °C
  • 34
  • [ 57513-54-9 ]
  • 1-methyl-2-oxo-3-(2H-1,2,4-benzothiadiazine-1,1-dioxid-3-yl)-4-hydroxyquinoline [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: 87 percent / 0.17 h / 180 - 190 °C 2: 96 percent / 10 percent KOH / H2O / 5 h / Heating
  • 35
  • [ 57513-54-9 ]
  • 5-methyl-1,2,4,5-tetrahydropyrazolo<4,3-c>quinoline-3,4-dione [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: 82 percent / POCl3 / 0.5 h / Heating 2: 52 percent / hydrazine / 2-ethoxy-ethanol / 2 h / Heating
Multi-step reaction with 2 steps 1: 98 percent / hydrazine hydrate / ethanol / Ambient temperature 2: 86 percent / 0.5 h
Multi-step reaction with 2 steps 1: trichlorophosphate / 1 h / Reflux 2: hydrazine hydrate / 2-ethoxy-ethanol / Reflux
  • 36
  • [ 57513-54-9 ]
  • 2,5-dimethyl-1,2,4,5-tetrahydropyrazolo<4,3-c>quinoline-3,4-dione [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: 82 percent / POCl3 / 0.5 h / Heating 2: 58 percent / 2-ethoxy-ethanol / 2 h / Heating
  • 37
  • [ 57513-54-9 ]
  • 5-methyl-2-phenyl-1,2,4,5-tetrahydropyrazolo<4,3-c>quinoline-3,4-dione [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: 82 percent / POCl3 / 0.5 h / Heating 2: 46 percent / 2-ethoxy-ethanol / 2 h / Heating
  • 38
  • [ 57513-54-9 ]
  • [ 213181-38-5 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: 89 percent / POCl3, Et3N / 3 h / 60 °C 2: 77 percent / NaN3 / dimethylformamide / 1 h / 80 °C 3: 81 percent / various solvent(s) / 0.5 h / Heating
  • 39
  • [ 57513-54-9 ]
  • 4-Ethoxy-5-methyl-5H-isoxazolo[4,3-c]quinolin-3-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: 89 percent / POCl3, Et3N / 3 h / 60 °C 2: 77 percent / NaN3 / dimethylformamide / 1 h / 80 °C 3: 196 - 226 °C / ΔH
  • 40
  • [ 57513-54-9 ]
  • [ 213181-31-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: 89 percent / POCl3, Et3N / 3 h / 60 °C 2: 77 percent / NaN3 / dimethylformamide / 1 h / 80 °C
Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / 3 h 2: sodium azide / N,N-dimethyl-formamide / 12 h / 80 °C
  • 41
  • [ 57513-54-9 ]
  • [ 90061-40-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: Br2 / CHCl3 / 0.5 h 2: H2O / Heating
  • 43
  • [ 57513-54-9 ]
  • 1-methyl-4-hydroxy-2-quinolone-3-carboxylic acid 2-chloroacetylaminoanilide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: 94 percent / 0.5 h / 150 °C 2: 89 percent / triethylamine / dioxane / 5 h
  • 44
  • [ 57513-54-9 ]
  • [ 79966-24-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: 78 percent / POCl3 / 3 h / 95 °C 2: 65 percent / methanol / 24 h / Heating
  • 45
  • [ 57513-54-9 ]
  • [ 79966-22-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: 78 percent / POCl3 / 3 h / 95 °C 2: 67 percent / toluene / 18 h / Heating
Multi-step reaction with 2 steps 1: trichlorophosphate / 1 h / Reflux 2: 2-ethoxy-ethanol / Reflux
  • 46
  • [ 57513-54-9 ]
  • [ 79966-21-5 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: 78 percent / POCl3 / 3 h / 95 °C 2: 73 percent / dimethylformamide / 4 h / Heating
  • 47
  • [ 57513-54-9 ]
  • [ 79966-14-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: 78 percent / POCl3 / 3 h / 95 °C 2: 68 percent / toluene / 18 h / 60 °C / Heating; steel vessel
  • 48
  • [ 57513-54-9 ]
  • [ 79966-16-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: 78 percent / POCl3 / 3 h / 95 °C 2: 79 percent / toluene / 8 h / Heating
  • 49
  • [ 57513-54-9 ]
  • [ 79966-23-7 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: 78 percent / POCl3 / 3 h / 95 °C 2: 37 percent / NaH / N,N-dimethyl-acetamide / 1.5 h / 85 °C
  • 50
  • [ 57513-54-9 ]
  • [ 79966-15-7 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: 78 percent / POCl3 / 3 h / 95 °C 2: 50 percent / toluene / 8 h / Heating
  • 51
  • [ 57513-54-9 ]
  • [ 79966-17-9 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: 78 percent / POCl3 / 3 h / 95 °C 2: 70 percent / toluene / 8 h / Heating
  • 52
  • [ 57513-54-9 ]
  • [ 79966-18-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: 78 percent / POCl3 / 3 h / 95 °C 2: 63 percent / toluene / 8 h / Heating
  • 53
  • [ 57513-54-9 ]
  • [ 79791-13-2 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: 78 percent / POCl3 / 3 h / 95 °C 2: 39 percent / toluene / 8 h / Heating
  • 54
  • [ 108-91-8 ]
  • [ 57513-54-9 ]
  • 4-hydroxy-1-methyl-2-oxo-1,2-dihydro-quinoline-3-carboxylic acid cyclohexylamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
70% In toluene for 4h; Heating / reflux; 3 PREPARATION OF 4-HYD-METHYL-2-OXO-12-DIHYDRO-QUINOLINE-3-CARBOXYLIC ACID CYCLOHEXYLAMIDE (Compound 2) Cyclohexylamine (2.0 mL, 18.20 mmol) was added to a solution of Compound 1 (2.25 g, 9.1 mmol) in toluene (20 mL) and refluxed for 4 h. The solution was cooled and the solvent was evaporated under vacuum. The residue obtained was suspended in water, briefly sonicated, and filtered to yield 1.9 g (70%) of white solids. M. P. 145 C. 1H NMR (DMSO-D6) : d 1.26 (m, 1H), 1.38 (m, 4H), 1.54 (m, 1H), 1.68 (m, 2H), 1. 86 (m, 2H), 3.62 (s, 3H), 3. 87 (m, 1H), 7. 37 (t, J = 7.5 Hz, 1H), 7.63 (d, J= 8.5 Hz, 1H), 7.80 (t, J= 8.4 Hz, 1H), 8.09 (d, J= 7.8 Hz, 1H), 10. 46 (s, 1H), 17.46 (s, 1H),. EIMS M/Z 301 (M+1), 323 (M+23). Anal. (CL7H2ON203) C, H, N.
  • 55
  • [ 57513-54-9 ]
  • 4-methoxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbaldehyde [ No CAS ]
YieldReaction ConditionsOperation in experiment
34 Preparation of 1-Methyl-3-Formyl-4-Methoxy-2(1H)-Quinolinone (Formula 1.27) EXAMPLE 34 Preparation of 1-Methyl-3-Formyl-4-Methoxy-2(1H)-Quinolinone (Formula 1.27) Starting with 1-methyl-3-ethoxycarbonyl-4-hydroxy-2(1 H)-quinolinone (J. Org. Chem. 829 (1976), the disclosure of which is incorporated herein by reference thereto) and following the procedure set forth in Example 29, the title compound was obtained. That the expected product was obtained was confirmed by the spectral data: MS (EI): m/e 217 (M+); NMR (CDCl3): δ3.70 (s, 3H, NHCH3), 4.15 (s, 3H, OCH3), 10.50 (s, 1H, CHO).
  • 56
  • [ 57513-54-9 ]
  • [ 84088-17-5 ]
YieldReaction ConditionsOperation in experiment
With pyridine; aniline 1 EXAMPLE 1 EXAMPLE 1 A mixture of 1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxylic acid ethyl ester (10 parts), aniline (4 parts), and pyridine (40 parts) is heated at 125° C. for 3 h. The ethanol formed is distilled off continuously. The product, N-phenyl-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide (1), precipitates on cooling to room temperature and is filtered off and recrystallized from pyridine. M. p. 199°-200° C.
  • 57
  • [ 57513-54-9 ]
  • [ 106-40-1 ]
  • 4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid 4-bromoanilide [ No CAS ]
YieldReaction ConditionsOperation in experiment
94% In N,N-dimethyl-formamide at 170℃;
  • 58
  • [ 446-24-2 ]
  • [ 57513-54-9 ]
  • [ 331963-42-9 ]
YieldReaction ConditionsOperation in experiment
91% In N,N-dimethyl-formamide at 160℃;
  • 60
  • [ 57513-54-9 ]
  • [ 3619-22-5 ]
  • [ 1185758-28-4 ]
YieldReaction ConditionsOperation in experiment
90% In N,N-dimethyl-formamide at 160℃;
  • 61
  • [ 57513-54-9 ]
  • [ 5933-32-4 ]
  • [ 331963-52-1 ]
YieldReaction ConditionsOperation in experiment
90% In N,N-dimethyl-formamide at 160℃;
  • 62
  • [ 43002-14-8 ]
  • [ 57513-54-9 ]
  • [ 300590-43-6 ]
YieldReaction ConditionsOperation in experiment
89% In N,N-dimethyl-formamide for 1h; Reflux;
  • 63
  • [ 57513-54-9 ]
  • [ 111-40-0 ]
  • [ 1263357-34-1 ]
YieldReaction ConditionsOperation in experiment
89% In 5,5-dimethyl-1,3-cyclohexadiene for 2h; Reflux; 4.5. General method for compounds 4a-d General procedure: The corresponding amine (2.4 eq) was suspended in xylene (20 mL), then the corresponding quinoline (1 eq) was added. The resulting mixture was heated at reflux for 2 h and then was allowed to cool to room temperature. The compound was filtered and washed with ether.
  • 64
  • [ 57513-54-9 ]
  • [ 112-24-3 ]
  • [ 1263357-36-3 ]
YieldReaction ConditionsOperation in experiment
10% In 5,5-dimethyl-1,3-cyclohexadiene for 2h; Reflux; 4.5. General method for compounds 4a-d General procedure: The corresponding amine (2.4 eq) was suspended in xylene (20 mL), then the corresponding quinoline (1 eq) was added. The resulting mixture was heated at reflux for 2 h and then was allowed to cool to room temperature. The compound was filtered and washed with ether.
  • 65
  • [ 934-32-7 ]
  • [ 57513-54-9 ]
  • [ 371126-42-0 ]
YieldReaction ConditionsOperation in experiment
91% Heating;
50.3% In N,N-dimethyl-formamide at 160℃; for 0.5h; General procedure to prepare N-(1H-benzo[d]imidazol-2-yl)-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxamide (8a ~ 8d) General procedure: 1-H-benzo[d]imidazol-2-amine (0.053 g, 0.404 mmol) was added to the solution of ethyl 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylate (5a ~ 5d) (0.404 mmol) in DMF (3 mL) and the reaction mixture was heated at reflux for 30 min., when TLC shows completion of reaction. The reaction mixture was cooled to room temperature then added crushed ice to it, the precipitate formed was filtered, washed with cold water, dried, and recrystallized from ethanol.
  • 66
  • [ 106-49-0 ]
  • [ 57513-54-9 ]
  • [ 75483-05-5 ]
YieldReaction ConditionsOperation in experiment
74% In n-heptane at 100℃; for 8h; Sealed vial; N- (4-methylphenyl ) -1 , 2 -dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3- carboxamideNot according to invention. Prepared as precursor for acylation reactions . A solution of ethyl 1 , 2-dihydro-4-hydroxy-l-methyl-2-oxo-quinoline- 3-carboxylate (247 mg, 1.00 mmol) and 4-Me-aniline (133 mg, 1.25 mmol) in heptane (20 mL) was stirred at 100 °C for 8 h in a sealed vial, with occasional opening letting formed EtOH to evaporate.After cooling the product crystallized from the solution and was collected by filtration. Recrystallization from heptane gave the title compound (229 mg, 74 %) .XH NMR: 2.35 (s, 3H) , 3.74 (s, 3H) , 7.19 (d, 2H) , 7.34 (t, 1H) , 7.40 (d, 1H) , 7.57 (d, 2H) , 7.72 (ddd, 1H) , 8.26 (dd, 1H) , 12.43 (s, 1H) , 16.86 (S, 1H) .
  • 67
  • [ 57513-54-9 ]
  • [ 356094-10-5 ]
  • [ 1373260-61-7 ]
YieldReaction ConditionsOperation in experiment
73% In n-heptane at 110℃; for 6h; Inert atmosphere; 117 N- (2, 4-dimethoxybenzyl) -N-phenyl-1, 2-dihydro-4-hydroxy-l-methyl-2- oxo-quinoline-3-carboxamide A solution of ethyl 1 , 2-dihydro-4-hydroxy-l-methyl-2-oxo-quinoline- 3-carboxylate (9.25 g, 37.4 mmol) and N- ( 2 , 4-dimethoxybenzyl ) - aniline (9.10 g, 37.4 mmol) in heptane (200 mL) was stirred at 110 °C under a flow of N2 for 6 h letting the EtOH evaporate from the reaction mixture. The product started to precipitate and some extra heptane was added. The reaction mixture was then stirred at 100 °C overnight, still under a gentle flow of N2. The product (12.21 g, 73 %) crystallized from the reaction mixture and was collected by filtration while still warm (ca 50 °C) .¾ NMR: 3.30 (bs, 3H) , 3.69 (s, 3H) , 3.77 (s, 3H) , 5.09 (s, 2H) , 6.39 (d, 1H) , 6.46 (bd, 1H) , 7.07-7.19 (m, 5H) , 7.20 (bd, 1H) , 7.24 (t, 1H) , 7.47 (bs, 1H) , 7.59 (ddd, 1H) , 8.12 (dd, 1H) , 12.09 (bs, 1H) .
  • 68
  • [ 141-52-6 ]
  • [ 85-91-6 ]
  • [ 1663-67-8 ]
  • [ 57513-54-9 ]
YieldReaction ConditionsOperation in experiment
71% Stage #1: Methyl N-methylanthranilate; malonoyl dichloride With dmap; triethylamine In dichloromethane at 0 - 20℃; for 5h; Inert atmosphere; Stage #2: sodium ethanolate With hydrogenchloride In ethanol; water at 20℃; Reflux; Inert atmosphere;
  • 69
  • [ 50541-93-0 ]
  • [ 57513-54-9 ]
  • [ 1601219-58-2 ]
YieldReaction ConditionsOperation in experiment
63% In 5,5-dimethyl-1,3-cyclohexadiene for 3h; Reflux; 3 Typical procedure for preparation of compounds 5a-i General procedure: Method A: Compounds 5a-f: Quinolinone ester 3a-c (1 equiv)was added to a solution of the amine (1.1 equiv) in xylene and themixture was refluxed. After completion of the reaction (TLC monitoring),solvent was removed in vacuo and products were obtainedby precipitation, column chromatography and/or recrystallization.
  • 70
  • [ 88915-26-8 ]
  • [ 57513-54-9 ]
  • [ 1601219-61-7 ]
YieldReaction ConditionsOperation in experiment
63% In 5,5-dimethyl-1,3-cyclohexadiene for 3h; Reflux; 4 Typical procedure for preparation of compounds 5a-i General procedure: Method A: Compounds 5a-f: Quinolinone ester 3a-c (1 equiv)was added to a solution of the amine (1.1 equiv) in xylene and themixture was refluxed. After completion of the reaction (TLC monitoring),solvent was removed in vacuo and products were obtainedby precipitation, column chromatography and/or recrystallization.
  • 72
  • [ 6304-39-8 ]
  • [ 57513-54-9 ]
  • [ 300704-86-3 ]
YieldReaction ConditionsOperation in experiment
99% In N,N-dimethyl-formamide; at 160℃; for 0.05h; General procedure: 1 equivalent of 1 or 2, as specified in each case, the corresponding hydrazide (1 equiv) and 0.2 ml of DMF are placed in a flask, and heated to 160C for 3 min. It is allowed to cool, MeOH is carefully added, and a white solid precipitates, which is filtered and purified by means of MeOH washings.
99% In N,N-dimethyl-formamide; at 160℃; for 0.05h; General procedure: 1 equivalent of 1 or 2, as specified in each case, the corresponding hydrazide (1 equiv) and 0.2 ml of DMF are placed in a flask, and heated to 160 C. for 3 min. It is allowed to cool, MeOH is carefully added, and a white solid precipitates, which is filtered and purified by means of MeOH washings. Reagents: Compound 1 and <strong>[6304-39-8]octanoyl hydrazide</strong>. Yield 99%. ?H NMR (300 MHz, CDC13) oe 15.49 (s,1H), 12.46 (d, J=5.6 Hz, 1H), 8.28 (d, J=5.7 Hz, 1H), 8.18 (dd,J=8. 1, 1.5 Hz, 1H), 7.71 (t, J=7.9 Hz, 1H), 7.44-7.27 (m, 2H),3.69 (s, 3H), 2.44-2.20 (t, J=7.6 Hz, 2H), 1.90-1.56 (m, 2H),1.45-1.18 (m, 8H), 0.88 (t, J=6.8 Hz, 3H). ?3C NMR (75MHz, CDC13) oe 172.4, 171.4, 166.9, 162.4, 140.2, 134.8,126.2, 129.9, 115.8, 115.1, 96.1, 34.4, 31.8, 31.3, 29.6, 29.4,25.4, 22.7, 14.1. M.p.=157 C.-158 C. HPLC: Purity>99%.MS (ES): mlz=360, 234. ElementaryAnalysis (C,9H25N304)Calculated: C, 63.49%; H, 7.01%; N, 11.69%. Found: C,63.76%; H, 6.94%; N, 11.65%.
  • 73
  • [ 6279-86-3 ]
  • [ 100-61-8 ]
  • [ 57513-54-9 ]
YieldReaction ConditionsOperation in experiment
40% at 215℃; General procedure: Aniline (4a ~ 4d) was added dropwise with stirring to triethyl methanetricarboxylate (1 eq.), and heated to 215C, at such a rate that the temperature of the reaction mixture was maintained within ±5C of the initial temperature. The ethanol eliminated during the reaction was distilled through a suitable still-head. After adding all the aniline the reaction mixture was maintained at the same temperature for 10-15 min, andt was cooled to rt. The solid ester (5a ~ 5d) was filtered off, washed with water, and dried, which was used for next step without any further purification.
35% Microwave irradiation; Heating; General procedure: 4.1.1.1 Ethyl 1-hexyl-1,2-dihydro-4-hydroxy-2-oxo-quinoline-3-carboxylate (2a); A mixture of N-hexylaniline (0.88g, 5mmol) and triethyl methanetricarboxylate 3 (3.48g, 15mmol) was irradiated with microwaves at the fixed power of 250 Watt (max temp 250C) for 20min in open vessel conditions. The crude mixture was directly purified by flash chromatography (PE/AcOEt 4:1) giving compound 2a as a yellow oil. (0.856g, 54% yield). 4.1.1.5 Ethyl 1-methyl-1,2-dihydro-4-hydroxy-2-oxo-quinoline-3-carboxylate (2e) Yield: 35%. 1H NMR: (200 MHz, CDCl3): delta 12.64 (bs, 1H), 7.30-7.26 (m, 4H), 4.35 (q, 2H, J = 7.3 Hz), 3.62 (s, 3H), 1.19 (t, 3H, J = 7.3 Hz). ES-MS: 270 [M+Na]+.
640 mg at 230℃; for 0.5h; N-methylaniline (1.43 g, 13.4 mmol) and triethyl methane tricarboxylate (3.1 g, 13.4 mmol) were heated at 230 C. for 30 minutes. The resulting compound was cooled to room temperature, filtered using ethyl acetate (50 mL) and MeOH (30 mL), and the organics were concentrated and column chromatography (ethylacetate: methanol = 49: 1) was used.To ethyl 4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylate (640 mg, 2.6 mmol).
  • 74
  • [ 94-12-2 ]
  • [ 57513-54-9 ]
  • propyl 4-(1-methyl-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-carboxamido)benzoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
42% In toluene at 250℃; Microwave irradiation; 3.8 4.1.3. General procedure for the synthesis of 4-hydroxy quinolones 1 and 8-27 General procedure: 4.1.3.1 Propyl 4-(1-hexyl-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-carboxamido)benzoate (GSA-10, 1) A mixture of 2a (0.63 g 2 mmol) and propyl 4-aminobenzoate (0.394 g, 2.2 mmol) in toluene (4 mL) was submitted to MW irradiation at 250 Watt (max temperature set 250 °C) for 1 h (two times of 30 min each) in open vessel conditions. After cooling, the crude mixture was purified by flash chromatography eluting with PE/AcOEt: 6/1 to give 1 (0.630 g, 70% yield). 4.1.3.8 Propyl 4-(1-methyl-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-carboxamido)benzoate (14) Yield: 42%. 1H NMR: (400 MHz, CDCl3): δ 16.52 (bs, 1H), 12.81 (bs, 1H), 8.24 (d, 1H, J = 8 Hz), 7.85 (d, 2H, J = 8.4 Hz), 7.76 (d, 2H, J = 8.4 Hz), 7.71 (t, 1H, J = 8 Hz), 7.38 (d, 1H, J = 7.6 Hz), 7.32 (t, 1H, J = 8 Hz), 4.26 (t, 2H, J = 6.4 Hz), 3.71 (s, 3H), 1.78 (q, 2H, J = 7.2 Hz), 1.02 (t, 3H, J = 7.2 Hz). 13C NMR: (100 MHz, CDCl3): δ 173.23, 164.25, 141.32, 133.81, 130.30, 125.28, 123.06, 119.89, 113.94, 66.03, 31.51, 22.26, 13.67. ES-MS: 403 [M+Na]+. LC/MS: RT 5.62 min; 481 [M+H]+. Purity: 98%. Anal calcd for C21H20N2O5 C, H, N: C 66.31, H 5.30, N 7.36, O 21.03; found C 66.29, H 5.31, N 7.32.
  • 75
  • [ 57513-54-9 ]
  • l,2-dihydro-4-hydroxy-l-methyl-2-oxo-3-quinoline carboxylic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
86% With hydrogenchloride; acetic acid In water at 80 - 85℃; for 6h; 4.6 Synthesis of 4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (4) 1,2-Dihydro-4-hydroxy-l-methyl-2-oxo-3-quinoline carboxylic acid methyl ester (3.61mmol) was added to glacial acetic acid (88.6mmol) at 25-30°C followed by the addition of hydrochloric acid (54.5mmol) and then heated to 80-85°C. The reaction mixture was stirred at 80-85°C for 6h. The resulting mass was cooled to 10-15°C followed by the addition of ethanol (10mL). The resulting solid was filtered and washed with ethanol (10mL) and then dried to get l,2-dihydro-4-hydroxy-l-methyl-2-oxo-3- quinoline carboxylic acid as white coloured solid with 86% yield. 1H NMR (500MHz, CDCl3): δ3.77 (s, 3H, CH3), 7.38-7.54 (m, 2H, Ar-H), 7.77-7.87 (m, 1H,Ar-H), 8.27 (dd,, J=8.0Hz, 1.2Hz, 1H, Ar-H), 14.55 (s, 1H, COOH), 15.60 (s, 1H,OH).
  • 76
  • [ 57513-54-9 ]
  • 5-methyl-1-phenyl-1,2-dihydro-3H-pyrazolo[4,3-c]quinoline-3,4(5H)-dione [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: trichlorophosphate / 1 h / Reflux 2: 2-ethoxy-ethanol / Reflux
  • 77
  • [ 57513-54-9 ]
  • N-(3,5-bis(trifluoromethyl)benzyl)-4-chloro-N,1-dimethyl-2-oxo-1,2-dihydroquinoline-3-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: toluene / 12 h / 120 °C 2: trichlorophosphate / acetonitrile / 3 h / 90 °C
Multi-step reaction with 2 steps 1: toluene / 12 h / 120 °C 2: trichlorophosphate / acetonitrile / 3 h / 90 °C
  • 78
  • [ 57513-54-9 ]
  • tert-butyl 4-(3-((3-((3,5-bis(trifluoromethyl)benzyl)(methyl) carbamoyl)-1-methyl-2-oxo-1,2-dihydroquinolin-4-yl)oxy)propyl) piperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: toluene / 12 h / 120 °C 2: potassium carbonate / N,N-dimethyl-formamide / 80 °C
Multi-step reaction with 2 steps 1: toluene / 12 h / 120 °C 2: potassium carbonate / N,N-dimethyl-formamide / 60 °C / Inert atmosphere
  • 79
  • [ 57513-54-9 ]
  • N-(3,5-bis(trifluoromethyl)benzyl)-N,1-dimethyl-2-oxo-4- (pyrrolidin-1-yl)-1,2-dihydroquinoline-3-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: toluene / 12 h / 120 °C 2: trichlorophosphate / acetonitrile / 3 h / 90 °C 3: triethylamine / dimethyl sulfoxide / 80 °C
Multi-step reaction with 3 steps 1: toluene / 12 h / 120 °C 2: trichlorophosphate / acetonitrile / 3 h / 90 °C 3: triethylamine / dimethyl sulfoxide / 80 °C
  • 80
  • [ 57513-54-9 ]
  • [ 159820-24-3 ]
  • N-(3,5-bis(trifluoromethyl)benzyl)-4-hydroxy-N,1-dimethyl-2-oxo-1,2-dihydroquinoline-3-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
76% In toluene at 120℃; for 12h; 2.1.2 N-(3,5-bis(trifluoromethyl)benzyl)-4-hydroxy-N,1-dimethyl-2-oxo-1,2-dihydroquinoline-3-carboxamide (6) To a mixture of 4 (1.0g, 4.0mmol) in toluene (20ml) was added commercially available 5 (1.0g, 4.0mmol) at rt. The mixture was stirred at 120°C for 12h. The mixture was neutralized with aqueous 1M HCl at 0°C and extracted with AcOEt. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 30%-100% AcOEt in hexane). The residue was crystallized from AcOEt-IPE to give 6 (1.4g, 76%) as a colorless solid. 1H NMR (300MHz, CDCl3) δ 3.05 (3H, s), 3.68 (3H, s), 4.86 (2H, brs), 7.27-7.37 (2H, m), 7.58-7.73 (1H, m), 7.77-7.95 (3H, m), 8.05-8.19 (1H, m), 12.11 (1H, brs). LCMS (ESI+) m/z 459.2.
76% In toluene at 120℃; for 12h; 5.1.1. N-(3,5-Bis(trifluoromethyl)benzyl)-4-hydroxy-N,1-dimethyl-2-oxo1,2-dihydroquinoline-3-carboxamide (6) To a mixture of 1 (1.0 g, 4.0 mmol) in toluene (20 ml) was added 2 (1.0 g, 4.0 mmol) at rt. The mixture was stirred at 120 °C for 12 h. The mixture was neutralized with aqueous 1 M HCl at 0 °C and extracted with AcOEt. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 30-100% AcOEt in hexane). The residue was crystallized from AcOEt-IPE to give 6 (1.4 g, 76%) as a colorless solid. 1 H NMR (300 MHz, CDCl3) δ 3.05 (3H, s), 3.68 (3H, s), 4.86 (2H, brs), 7.27-7.37 (2H, m), 7.58-7.73 (1H, m), 7.77-7.95 (3H, m), 8.05-8.19 (1H, m), 12.11 (1H, brs). LCMS (ESI+) m/z 459.2.
  • 81
  • [ 2619-88-7 ]
  • [ 57513-54-9 ]
  • 4-hydroxy-1-methyl-N'-palmitoyl-2-oxo-1,2-dihydroquinoline-3-carbohydrazide [ No CAS ]
YieldReaction ConditionsOperation in experiment
94% In N,N-dimethyl-formamide at 160℃; for 0.05h;
  • 82
  • [ 57513-54-9 ]
  • [ 1068-57-1 ]
  • N'-acetyl-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbohydrazide [ No CAS ]
YieldReaction ConditionsOperation in experiment
89% In N,N-dimethyl-formamide at 160℃; for 0.05h;
  • 83
  • [ 57513-54-9 ]
  • [ 937-39-3 ]
  • 4-hydroxy-1-methyl-2-oxo-N'-(2-phenylacetyl)-1,2-dihydroquinoline-3-carbohydrazide [ No CAS ]
YieldReaction ConditionsOperation in experiment
80% In N,N-dimethyl-formamide at 160℃; for 0.05h;
  • 84
  • [ 20401-90-5 ]
  • [ 57513-54-9 ]
  • N'-3-(indol-3-yl)propanoyl-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbohydrazide [ No CAS ]
YieldReaction ConditionsOperation in experiment
45% In N,N-dimethyl-formamide at 160℃; for 0.05h;
  • 85
  • [ 1738-82-5 ]
  • [ 57513-54-9 ]
  • N-(2-((2-(benzyloxy)-2-oxoethyl)amino)-2-oxoethyl)-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
17% In ethanol for 5h; Reflux;
Same Skeleton Products
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