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[ CAS No. 132-60-5 ] {[proInfo.proName]}

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Chemical Structure| 132-60-5
Chemical Structure| 132-60-5
Structure of 132-60-5 * Storage: {[proInfo.prStorage]}
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Product Details of [ 132-60-5 ]

CAS No. :132-60-5 MDL No. :MFCD00006750
Formula : C16H11NO2 Boiling Point : -
Linear Structure Formula :- InChI Key :YTRMTPPVNRALON-UHFFFAOYSA-N
M.W : 249.26 Pubchem ID :8593
Synonyms :

Calculated chemistry of [ 132-60-5 ]

Physicochemical Properties

Num. heavy atoms : 19
Num. arom. heavy atoms : 16
Fraction Csp3 : 0.0
Num. rotatable bonds : 2
Num. H-bond acceptors : 3.0
Num. H-bond donors : 1.0
Molar Refractivity : 74.14
TPSA : 50.19 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : Yes
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -5.42 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.98
Log Po/w (XLOGP3) : 3.38
Log Po/w (WLOGP) : 3.6
Log Po/w (MLOGP) : 1.62
Log Po/w (SILICOS-IT) : 3.4
Consensus Log Po/w : 2.8

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 0.0
Bioavailability Score : 0.85

Water Solubility

Log S (ESOL) : -4.01
Solubility : 0.0246 mg/ml ; 0.0000986 mol/l
Class : Moderately soluble
Log S (Ali) : -4.11
Solubility : 0.0192 mg/ml ; 0.0000772 mol/l
Class : Moderately soluble
Log S (SILICOS-IT) : -5.6
Solubility : 0.000632 mg/ml ; 0.00000254 mol/l
Class : Moderately soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 2.03

Safety of [ 132-60-5 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P264-P270-P301+P312+P330-P501 UN#:N/A
Hazard Statements:H302 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 132-60-5 ]

* 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 [ 132-60-5 ]

[ 132-60-5 ] Synthesis Path-Downstream   1~35

  • 1
  • [ 64-17-5 ]
  • [ 132-60-5 ]
  • [ 4420-46-6 ]
YieldReaction ConditionsOperation in experiment
94% With sulfuric acid for 0.166667h; microwave irradiation;
89% With sulfuric acid Reflux;
75% With sulfuric acid Reflux; Synthesis of compounds (7a-f) General procedure: A mixture of the appropriate 4-carboxylic acid 6a-f(10 mmol), absolute ethanol (20 mL) and concentrated sulfuric acid (2 mL) was heated under reuxed for 12-18 hr. Excess solvent was removed under reduced pressure; the residue was diluted with water, and then rendered alkaline with concentrated sodium bicarbonate solution. The formed precipitate was ltered off, washed with water and crystallized from ethanol.Ethyl 2-phenylquinoline-4-carboxylate (7a).Yellow oil (75 % yield); (Reported m.p= 51oC)
75% With sulfuric acid for 10h; Reflux; 4.1.2. General procedure for the synthesis of compounds (2a-f) General procedure: A mixture of the appropriate 4-carboxylic acid 1aef (10 mmol),absolute ethanol (20 mL), and concentrated sulfuric acid (2 mL)was refluxed for 10 h. The solution was concentrated under reduced pressure; the mixture was allowed to cool at room temperature,diluted with water then rendered alkaline with a sodium bicarbonate solution. The formed precipitate was filtered off, washed wiith water and crystallized from ethanol.4.1.2.1. Ethyl 2-phenylquinoline-4-carboxylate (2a) [47]. Yellowliquid (0.20g; 75% yield); m.p; reported 51 C.
48% With sulfuric acid Reflux; Ethyl-2-phenylquinoline-4-carboxylate (4) To a solution of 2-phenylquinoline-4-carboxylic acid (3) (0.01 mol) in ethanol (50 ml), 1 ml of concentrated H2SO4 was added, and the reaction mixture was refluxed for 10-12 h. Excess of ethanol was distilled off and the remaining was added to the crushed ice and kept for 2 days after that the solid compound was filtered under vacuum, washed with water, dried, and recrystallized from ethanol. Yield 48%, m.p. 184-186°C; IR (KBr) cm-1: 3098.42 (C-H, Ar), 1748 (C=O), 1494.95 (C=C, Ar), 1347 (C-N), 1292, 1163 (C-O); 1H-NMR (300 MHz, DMSO-d6) δ ppm: 8.744-8.761 (d, 1H, Ar), 8.395 (s, 1H, Ar), 8.208-8.248 (m, 3H, Ar), 7.753-7.783 (t, 1H, Ar), 7.609-7.640 (t, 1H, Ar), 7.537-7.566 (t, 2H, Ar), 7.475-7.505 (t, 1H, Ar), 4.531-4.574 (q, 2H, CH2), 1.271-1.521 (t, 3H, CH3); 13C-NMR (75 MHz, DMSO-d6): 168.2 (1C, C=O), 146.2 (C-8, quinoline), 143.2 (C-1, phenyl), 132.7 (C-3, quinoline), 130.3 (C-2, quinoline), 128.8 (C-6, quinoline), 128.6 (C-3,5, phenyl), 127.2 (C-4, quinoline), 127 (C-2,6, phenyl), 126.8 (C-4, phenyl), 118.7 (C-9, quinoline), 117.1 (C-5, quinoline), 113.4 (C-7, quinoline), 61.7 (1C, CH2), 58.4 (C-1, quinoline), 14.2 (1C, CH3); EI-MS (m/z): 277.10 (M+); Anal. Cal. for C18H17NO2 (279.3): C, 77.40; H, 6.13; N, 5.01. Found: C, 77.32; H, 5.78; N, 4.89.
With hydrogenchloride
With sulfuric acid
Acidic conditions;
With sulfuric acid for 10h; Reflux;
With sulfuric acid for 10h; Reflux; 2.1.2. General procedure for the synthesis of compounds (2a-e) General procedure: A mixture of the appropriate 4-carboxylic acid 1a-e (10 mmol), absolute ethanol (20 mL) and concentrated sulfuric acid (2 mL) was refluxed for 10 h. Excess ethanol was removed under reduced pressure; the mixture was allowed to cool, diluted with water then rendered alkaline with saturated sodium bicarbonate solution. The precipitate was filtered, washed with water and crystallized from ethanol.
88.6 % With sulfuric acid Reflux;
With sulfuric acid Reflux; Inert atmosphere; Schlenk technique;

Reference: [1]El Ashry, El Sayed H.; Ramadan, El Sayed; Hamid, Hamida Abdel; Hagar, Mohamed [Synthetic Communications, 2005, vol. 35, # 17, p. 2243 - 2250]
[2]Verbanac, Donatella; Malik, Ritu; Chand, Mahesh; Kushwaha, Khushbu; Vashist, Monika; Matijašić, Mario; Stepanić, Višnja; Perić, Mihaela; Paljetak, Hana Čipčić; Saso, Luciano; Jain, Subhash C. [Journal of Enzyme Inhibition and Medicinal Chemistry, 2016, vol. 31, p. 104 - 110]
[3]Abbas, Samar H.; Abd El-Hafeez, Amer Ali; Shoman, Mai E.; Montano, Monica M.; Hassan, Heba A. [Bioorganic Chemistry, 2019, vol. 82, p. 360 - 377]
[4]Kaoud, Tamer S.; Mohassab, Aliaa M.; Hassan, Heba A.; Yan, Chunli; Van Ravenstein, Sabrina X.; Abdelhamid, Dalia; Dalby, Kevin N.; Abdel-Aziz, Mohamed [European Journal of Medicinal Chemistry, 2020, vol. 186]
[5]Abdullah, Mohammad Mustqeem; Kumar, Rajnish [Indian Journal of Heterocyclic Chemistry, 2019, vol. 29, # 1, p. 79 - 86]
[6]Pfitzinger [Journal fur praktische Chemie (Leipzig 1954), 1897, vol. <2> 56, p. 292]
[7]Xu, Peng-Fei; Zhang, Zhi-Hui; Hui, Xin-Ping; Zhang, Zi-Yi; Zheng, Rong-Liang [Journal of the Chinese Chemical Society, 2014, vol. 51, # 2, p. 315 - 319]
[8]Jones, Jennifer E.; Jenkins, Robert L.; Hicks, Robin S.; Hallett, Andrew J.; Pope, Simon J. A. [Dalton Transactions, 2012, vol. 41, # 34, p. 10372 - 10381,10]
[9]Mohassab, Aliaa M.; Hassan, Heba A.; Abdelhamid, Dalia; Gouda, Ahmed M.; Youssif, Bahaa G.M.; Tateishi, Hiroshi; Fujita, Mikako; Otsuka, Masami; Abdel-Aziz, Mohamed [Bioorganic Chemistry, 2021, vol. 106]
[10]Abdel-Aziz, Mohamed; Abdelhamid, Dalia; Fujita, Mikako; Gomaa, Hesham A. M.; Gouda, Ahmed M.; Hassan, Heba A.; Mohassab, Aliaa M.; Otsuka, Masami; Radwan, Mohamed O.; Youssif, Bahaa G. M. [Journal of Molecular Structure, 2021, vol. 1244]
[11]Ezelarab, Hend A. A.; Hassan, Heba A.; Abuo-Rahma, Gamal El-Din A.; Abbas, Samar H. [Journal of the Iranian Chemical Society, 2023, vol. 20, # 3, p. 683 - 700]
[12]Shinde, Ganesh H.; Sundén, Henrik [Chemistry - A European Journal, 2023, vol. 29, # 10]
  • 2
  • [ 105-40-8 ]
  • [ 132-60-5 ]
  • methyl-(2-phenyl-quinoline-4-carbonyl)-carbamic acid ethyl ester [ No CAS ]
  • 3
  • [ 132-60-5 ]
  • [ 62-53-3 ]
  • [ 110662-85-6 ]
YieldReaction ConditionsOperation in experiment
90.1% Stage #1: cinchophen; aniline With benzotriazol-1-ol In N,N-dimethyl-formamide for 0.25h; Stage #2: With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 20℃; for 4h; 16 General procedure: Method 1: To a 25 mL round-bottom flask, 2-phenyl-4-quinolinecarboxylic acid 4a-n (1.5 mmol) and substituted aniline(1.5 mmol) were added, dissolved in appropriate DMF and followed by the addition of HOBT (1.5 mmol) with stirring. After 15 min, EDCI (1.5 mmol) and TEA (1.5 mmol) were added and the reaction mixture was stirred for 4 h at room temperature. The reaction solution was poured into water and the product was extracted with EtOAc three times. The combined organic phases were washed with HCl (1 N), NaHCO3 (1 N), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give crude product. The crude compound was then purified by recrystallization to afford compounds 5-9.
56% With trichlorophosphate for 8h; Reflux; Step-2: Synthesis of compound 2-phenyl quinoline-4-carboxamides (5a-j): General procedure: 2-Phenyl quinoline-4-carboxylic acid (0.73 g, 3 mmol) was taken in round bottom flask, to this POCl3 (5 mL) was added slowly. After 2 h of reflux, substituted aromatic primary amines (4a-j) (0.32 g, 3 mmol) were added. Reaction mixture was stirred and heated under reflux for 8 h. The reaction progress was monitored by TLC (silica gel, ethylacetate/petroleum ether 7:3). Upon completion of the reaction crushed ice was added to the reaction mixture slowly; the precipitate obtained was filtered, washed with dil. HCl followed by water and sodium carbonate solution and finally dried (Scheme-I). 2-Phenyl-N-(3-chlorophenyl)-quinoline-4-carboxamide (5a):
With Tetraethyl pyrophosphate; toluene
With Tetraethyl pyrophosphate

  • 4
  • [ 132-60-5 ]
  • [ 59661-86-8 ]
YieldReaction ConditionsOperation in experiment
With thionyl chloride Erhitzen des Hydrochlorids im Vakuum auf 130grad;
With thionyl chloride
With thionyl chloride for 1h; Heating;
With oxalyl dichloride In dichloromethane
With oxalyl dichloride In dichloromethane at 0 - 20℃;
With oxalyl dichloride In dichloromethane at 5 - 20℃;
27 g With thionyl chloride for 0.75h; Heating;
With thionyl chloride at 80℃; for 24h;
With thionyl chloride Reflux;
With thionyl chloride for 2h; Reflux; 4.1.2. General procedure for the synthesis of compounds 1-10 General procedure: Compounds 1, 2, 3, 4 and 5 were commercially available. Compounds 6, 7, 8, 9 and 10 were prepared from the corresponding carboxylic acid (9.18 mmol) and thionyl chloride (30 mL) with heating under reflux for 2 h. The thionyl chloride was removed in vacuo. The resulting acyl chloride was used without further purification.
With thionyl chloride 1 [Production Example 1] N-[5-(2-furyl)-1,3,4-oxadiazol-2-yl]-2-phenyl-4-quinolinecarboxamide (compound Ia-1) 2-phenyl-4-quinolinecarbonyl chloride was synthesized from commercially available 2-phenyl-4-quinolinecarboxylic acid and thionyl chloride according to a routine method. 2-phenyl-4-quinolinecarbonyl chloride (2.00 g, 7.47 mmol) was added in small portions to a pyridine (40 mL) solution of commercially available 2-amino-5-(2-furyl)-1,3,4-oxadiazole (1.69 g, 11.2 mmol), and the mixture was heated with stirring at 60°C for 6 hours. To the reaction solution, methanol was added, and the solvent was distilled off. The obtained residue was triturated by the addition of water. The deposited crystal was collected by filtration, washed with methanol and then with ethyl acetate, and then recrystallized from DMF-methanol to obtain the title compound (1.23 g, 3.22 mmol) as a light brown powder (yield: 43%). 1H-NMR (DMSO-d6) δ: 12.87 (1H, brs), 8.51 (1H, s), 8.37 (2H, d, J = 7.3 Hz), 8.28 (1H, d, J = 8.3 Hz), 8.21 (1H, d, J = 8.5 Hz), 8.09 (1H, t, J = 1.0 Hz), 7.89 (1H, dd, J = 8.3 Hz, 7.1 Hz), 7.72 (1H, dd, J = 8.0 Hz, 7.3 Hz), 7.63-7.54 (3H, m), 7.33 (1H, d, J = 3.7 Hz), 6.83 (1H, dd, J = 3.7 Hz, 1.7 Hz). ES-MS (m/z) : 383 (M + H)+.
With thionyl chloride; N,N-dimethyl-formamide at 40℃; for 3h; 2-Bromo-1-(2-phenyl-4-quinolinyl)ethanone hydrobromide (72). A suspension of 2-phenyl-4-quinolinecarboxylic acid (0.80 g, 3.2 mmol) and DMF (2 drops) in thionyl chloride (15 mL) was stirred at 40 °C for 3 h. Thionyl chloride was evaporated and the residue was dissolved in dry THF (50 mL) and cooled to 0 °C. A solution of TMSCH2N2 in hexanes (2.5 M, 3.2 mL, 8.0 mmol) was added and the mixture was stirred at 0 °C for 5 h. cHBr (5 mL) was added carefully and the mixture stirred at 20 °C for 16 h. The mixture was neutralized with saturated aqueous KHCO3 and then extracted with EtOAc (3 × 50 mL). The combined organic fraction was washed with water (40 mL), washed with brine (40 mL), dried and the solvent evaporated. The residue was purified by column chromatography, eluting with 5% EtOAc/pet. ether, to give bromide 72 (0.50 g, 48%) as an oil:
With oxalyl dichloride In 1,4-dioxane at 50℃; for 4h; Inert atmosphere;
With thionyl chloride at 80℃; for 2h;
With thionyl chloride at 80℃; for 2h;
With thionyl chloride for 1h; Reflux;
With thionyl chloride for 4h; Reflux; General Procedures for the Synthesis of 2-Arylquinoline-4-amides (8 Series) General procedure: A mixture of 2-arylquinoline-4-carboxylic acids 5 (180mg), thionyl chloride (4 mL), was heated to reflux and keptrefluxing for 4h. The thionyl chloride was removed underreduced pressure. To the residue toluene (10 mL), pyridine(6 mL) and substituted anilines (49 mg) were added. Theresulting mixture was kept at 80 oC for 2h. The resultingmixture was evaporated to dryness under reduced pressure.To the residue, methanol (5 mL) was added and ultrasoundedand filtered. The filter cake was washed with water and driedin vacuum to give amides (8) as solids.
With thionyl chloride for 2h; Reflux; General procedure for thesynthesis of heteroaryl acyl chlorides General procedure: The heteroaryl acyl chlorides used in the synthesis of compounds 1b, 2b, 3b, 4b and 5b were commercially available. For compounds 6b, 7b, 8b, 9b and 10b, the chloride derivatives were prepared from the corresponding carboxylic acid (9.18 mmol) nd thionyl chloride (30 mL) with heating under reflux for 2 h. The thionyl chloride was removed in vacuo. The resulting acyl chloride was used without further purification.
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at -5 - 20℃;
With thionyl chloride In toluene Reflux; 5.12 General procedure for preparation of 2-arylquinoline-4-carbonyl chloride (13a-h and 14a-g) General procedure: Various substituted 2-arylquinoline-4-carboxylic acids 11a-h and 12a-g (0.01mol) were added to thionyl chloride (15mL), respectively, and refluxed for 5-7h. The reaction mixture was evaporated to yield corresponding 2-arylquinoline-4-carbonyl chloride 13a-h and 14a-g.
With thionyl chloride In N,N-dimethyl-formamide at 50℃; for 3h; 49 To a solution of 60.0 g (241 mmol) of 2-phenyl-quinoline-4-carboxylic acid in 300 ml (4.135 mol) of thionyl chloride was added at room temperature a catalytic amound of N,N-dimethylformamide (5 drops). Then, the reaction mixture was warmed to 50°C and stirred for 3 h. After completion of the reaction, the reaction mixture was concentrated to dryness. The residue was suspended in 300 ml of DCM, concentrated to dryness and dried under vacuum to give 76 g of a yellow solid corresponding to 2-phenylquinoline-4- carbonyl chloride. The residue was dissolved in 1200 ml of DCM and was added portionwise at 0°C 35.20 g (360.9 mmol) of Weinreb amine hydrochloride and dropwise over 45 min 125 ml (896.8 mmol) of TEA. The reaction mixture was warmed to room temperature and stired overnight. Then, the reaction was quenched between 5-15°C by addition of 60.0 ml of water. The aqueous layer was extracted with DCM. The combinated organic layers were washed with brine, dried over anhydrous Na2S04, filtered and evaporated under vacuum to give 70.6 g (yield = 97%) of a yellow solid corresponding to N-methoxy-N-methyl-2-phenylquinoline-4-carboxamide. This product was carried to the next step without further purification. 1H NMR (400 MHz, CDC13).
With thionyl chloride In chloroform for 16h; Inert atmosphere; Reflux; Schlenk technique;
With thionyl chloride for 1h; Reflux; Schlenk technique; Synthesis of 4. The following reaction was carried out using a Schlenk line with a supply of dry nitrogen gas. 2-Phenyl-4-quinolinecarboxylic acid 1a (3.28 g, 13.2 mmol) was refluxed in thionyl chloride (5 ml, excess) for 1 h. The resulting bright yellow solution was evaporated to dryness under reduced pressure to give carboxylic acid chloride as a bright yellow solid which was used without further purification.
With thionyl chloride Reflux; 1.K Step K2- phenyl quinoline-4-carboxylic acid chloride (E) The 2-phenyl-quinoline-4-carboxylic acid (0.01mol) was dissolved in 15mL thionyl chloride, the reaction was refluxed for 5-7h, evaporated to dryness, the resulting solid was dried in vacuo to save to give the intermediate 2-phenyl-quinolin-4 - carboxylic acid chloride (E).
With thionyl chloride In chloroform for 16h; Inert atmosphere; Reflux; Synthesis of HL1: Thionyl chloride (excess) was added, dropwise,to a stirring suspension of 2-phenyl-4-quinolinecarboxylicacid (0.465 g, 1.869 mmol) in chloroform (10 mL). The reactionwas heated at reflux for 16 h under dinitrogen. The solvent wasthen removed in vacuo and the yellow solid redissolved in chloroform(10 mL) before the selected 1-octylamine (0.219 g,1.699 mmol) was added dropwise to the stirring solution. EtNiPr2(excess) was added dropwise and the mixture was stirred for16 h at room temperature under dinitrogen. The solvent wasremoved in vacuo before being redissolved in dichloromethane(20 mL). The crude mixturewas washed with aqueous NaHCO3 (sat.2 20 mL), water (1 x 20 mL) and brine (1 x 20 mL). The organicphase was collected, dried over MgSO4 and filtered before the solvent was removed in vacuo. Yield 0.434 g (71%).
With thionyl chloride In chloroform for 16h; Reflux; Inert atmosphere; Schlenk technique;
With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 20℃; for 1.5h; Inert atmosphere;
With thionyl chloride Reflux; 3.2.1. General Procedure General procedure: Following a described procedure [24,42,43] with a few modifications, sodium borohydride wasslowly added to a suspension of selenium powder in water at room temperature or in ethanol, N2atmosphere and 0 C, and stirred until the formation of the typical colorless solution of NaHSe. Then,the corresponding aroyl or heteroaroyl chloride was added. Temperature and time of reaction varieddepending on the compounds. Methylation was achieved through the addition of methyl iodide(in excess). Purification was performed by several washings, recrystallization in different solvents orcolumn chromatography. In those cases where the acyl chloride was not available, it was formed bythe reaction of the corresponding carboxylic acid with SOCl2 for 1-8 h at reflux. Solvent was removedunder vacuum by rotatory evaporation, and the product was then washed three times with dry toluene,which was also eliminated by rotatory evaporation.
With thionyl chloride In tetrahydrofuran General procedure: Method 2: To a 25 mL round-bottom flask, 2-phenyl-4-quinoline carboxylic acid (5.0mmol) was added, dissolved in appropriate THF and a few drops of DMF were added. Then the mixture was cooled in an ice bath and sulfoxide chloride was slowly dropped into it with stirring for 30 min. The resulting solution was warmed slowly to 45 °C, stirred at this temperature for 6h and the solvent was evaporated off at low pressure to give a crude residue. Methyl 3-aminothiophene-2-carboxylate (0.31 g, 2.0mmol) and trimethylamine (0.10 g, 1.0mmol) were added to a 25 mL round-bottom flask, dissolved in appropriate THF, and the solution of the above crude residue in THF was added dropwise with stirring in an ice bath. The reaction mixture was stirred at room temperature for 4h. The solvent was evaporated under reduced pressure and the crude product purified by flash column chromatography on silica gel and eluted with a mixture of EtOAc/petroleum ether (1:8, v/v) to afford 5-9.
With thionyl chloride; N,N-dimethyl-formamide In dichloromethane at 40℃; for 2h; General procedure for the preparation of 35-38 General procedure: 2-phenyl quinoline-3-formic acid (0.2 g, 0.8 mmol) reacted withSOCl2 (0.3 ml, 4 mmol) and DMF (2-3 drops) in dichloromethane(10 ml). The reaction mixture was stirred at 40 C for 2 h, The reactionmixture was monitored by TLC and concentrated in vacuo.
With thionyl chloride Reflux;
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 1.5h; Inert atmosphere;
With thionyl chloride at 40℃; for 3h; 1-107 Example 1-107 7V-(3-Methylphenyl)-4-(2-phenyl-4-quinolinyl)-l,3-thiazol-2-amine (194). [0403] 2-Bromo-l-(2-phenyl-4-quinolinyl)ethanone Hydrobromide (193). A suspension of 2-phenyl-4-quinolinecarboxylic acid (0.80 g, 3.2 mmol) and DMF (2 drops) in thionyl chloride (15 mL) was stirred at 40 0C for 3 h. Thionyl chloride was evaporated and the residue was dissolved in dry THF (50 mL) and cooled to 0 0C. A solution of TMSCH2N2 in hexanes (2.5 M, 3.2 mL, 8.0 mmol) was added and the mixture was stirred at 0 0C for 5 h. cHBr (5 mL) was added carefully and the mixture stirred at 20 0C for 16 h. The mixture was neutralized with saturated aqueous KHC O3 and then extracted with EtOAc (3 x 50 mL). The combined organic fraction was washed with water (40 mL), washed with brine (40 mL), dried and the solvent evaporated. The residue was purified by column chromatography, eluting with 5% EtO Ac/pet, ether, to give bromide 193 (0.50 g, 48%) as an oil: 1H NMR (CDCl3) δ 8.30 (dd, J= 8.6, 0.8 Hz, 1 H, H-8'), 8.25 (d, J= 8.5 Hz, 1 H, H- 5'), 8.15-8.19 (m, 2 H, H-2", H-6"), 8.07 (s, 1 H, H-3'), 7.80 (ddd, J= 8.4, 6.9, 1.4 Hz, 1 H, H-7'), 7.64 (ddd, J= 8.4, 6.9, 1.3 Hz, 1 H, H-6'), 7.50-7.59 (m, 3 H, H-3", H-4", H-5"), 4.58 (s, 2 H, H-2); MS m/z 326.5/328.5 (MH+, 100%). The bromide was converted to the hydrobromide salt and used directly.
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 1h;
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; Inert atmosphere;
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 1h; Inert atmosphere; I N-carbamimidoyl-2-phenylquinoline-4-carboxamide (10e) Compound 10e was synthesized through the acid chloride intermediate. Briefly, to a solution of intermediate 9 (1 mmol) in dichloromethane was added four drops of DMF, followed by oxalyl chloride (1.2 mmol). The mixture was stirred at room temperature for 1 hour and the solvent was removed in vacuo. THF was added to dissolve the acid chloride intermediate. In a separate round bottom flask, to a NaOH aqueous solution (15 eq) was added guanidine HCl (15 mmol). After 30 minutes, the acid chloride solution in THF was added dropwise to the aqueous solution of neutralized guanidine. The resulting mixture was stirred at room temperature overnight. THF was removed in vacuo and the resulting solution was extracted with dichloromethane. The DCM layer was separated and acidified with HCl. Final product was purified by flash column chromatography (10-20% CH3OH/CH2Cl2). Yield: 89% (HCl salt). 1H NMR (400 MHz, DMSO-d6) δ 12.92 (s, 1H), 8.92 (br s, 2H), 8.74 (br s, 2H), 8.59 (s, 1H), 8.48-8.37 (m, 2H), 8.31 (dd, J=8.5, 1.2 Hz, 1H), 8.20 (dd, J=8.5, 1.1 Hz, 1H), 7.89 (ddd, J=8.3, 6.8, 1.4 Hz, 1H), 7.73 (ddd, J=8.3, 6.9, 1.3 Hz, 1H), 7.68-7.47 (m, 3H). 13C NMR (101 MHz, DMSO) δ 167.43, 155.83, 155.66, 147.70, 138.25, 137.61, 130.85, 130.33, 129.41, 128.96, 128.16, 127.78, 124.89, 122.53, 119.08. C17H14N4O, HRMS (ESI): m/z (M+H+): 291.1246 (calculated), 291.1239 (found).
With thionyl chloride at 60℃;
With thionyl chloride In dichloromethane at 20℃; Inert atmosphere; Schlenk technique;
With thionyl chloride; N,N-dimethyl-formamide In dichloromethane at 0 - 60℃; Inert atmosphere;

Reference: [1]Rojahn; Schulten [Archiv der Pharmazie, 1926, p. 350] Rosenmund [Chemische Berichte, 1921, vol. 54, p. 2896] Current Patent Assignee: Chem. Fabr. Schering - DE252643, 1800, C [Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 11, p. 971][Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 11, p. 971]
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  • 5
  • [ 91-56-5 ]
  • [ 98-86-2 ]
  • [ 132-60-5 ]
YieldReaction ConditionsOperation in experiment
95% With potassium hydroxide In ethanol; water for 0.208333h; microwave irradiation;
95% Stage #1: indole-2,3-dione With cetyltrimethylammonium hydroxide In water at 20℃; for 0.166667h; Sonication; Green chemistry; Stage #2: acetophenone In water at 35℃; for 2.5h; Sonication; Green chemistry;
90% With potassium hydroxide In ethanol at 50 - 60℃; for 14h;
87% With sodium hydroxide In water Reflux;
86% With potassium hydroxide In ethanol Reflux; Synthesis of compounds (6a-f) satin (4a) or 5-methoxyisatin (4b) (10 mmol), 33% potassium hydroxide (10 mL), ethanol (20 mL), and appropriate acetophenone derivative (10 mmol) was mixed and heated under reux for 18-24 hr. The reaction mixture was concentrated under reduced pressure; the residue was diluted with water (50 mL) and extracted with diethylether (3 x 50 mL). The aqueous layer was neutralized with 1 M hydrochloric acid. The precipitated solid was ltered, washed with water, dried and crystallized from ethanol.2-Phenylquinoline-4-carboxylic acid (6a).Yellow needles (86 % yield); mp 212-214oC (Reported m.p= 208-210oC).
80% With potassium hydroxide In ethanol Reflux; 4.1.1. General procedure for the synthesis of compounds 1a-f General procedure: A mixture of isatin or 5-methoxyisatin (10 mmol), 33% potassiumhydroxide (10 mL) in ethanol (20 mL), and appropriate acetophenonederivative (10 mmol) was heated under reflux for 9e18 h. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water (50 mL) and extracted with ether (3 50 mL). The aqueous layer was neutralized with 1 M hydrochloric acid. The formed precipitate was filtered off, washed with water, dried, and crystallized fromethanol.4.1.1.1. 2-Phenylquinoline-4-carboxylic acid (1a) [44]. White needles(0.19 g; 80% yield); m.p. 212e214 C; reported 208e210 C
74% With potassium hydroxide In ethanol; water at 80 - 90℃;
64.4% Stage #1: indole-2,3-dione With potassium hydroxide In ethanol for 0.0833333h; Stage #2: acetophenone In ethanol at 100℃; for 0.0166667h; Microwave irradiation; Stage #3: With hydrogenchloride; water
60% Stage #1: indole-2,3-dione With potassium hydroxide In ethanol at 65℃; for 0.25h; Stage #2: acetophenone In ethanol for 48h; Reflux; I Isatin (2.01 g, 13.66mmol) was suspended in 55mL of ethanol and heated to 65°C to dissolve the solid. A solution of potassium hydroxide (33% w/v, 6.7mL) was added and stirred at 65°C for 15 minutes. Acetophenone (1.8mL, 15.4mmol) was added dropwise to heated solution. Upon complete addition, reaction solution was warmed to reflux. After 48 hours, reaction solution was concentrated to a dark brown solid. A solution (~60mL) of 20% acetic acid in water was added slowly to adjust the pH to 5. The precipitate that formed was vacuum filtered and washed with EtOH (~30mL) and hexanes (~30mL). The beige solid was dried via hi h vac to afford 2.02g (60%) of 2-phenylquinoline-4-carboxylic acid.
58% With potassium hydroxide In ethanol
46.5% With potassium hydroxide In ethanol; water at 80℃; 5.11 General procedure for preparation of 2-arylquinoline-4-carboxylic acid (11a-h) General procedure: To a stirring mixtures of indoline-2,3-dione (3.1g, 0.02mol) in 33% potassium hydroxide solution (10mL), various substituted acetophenone (1.1equiv) in ethanol (30mL) was dropped slowly. The resulting reaction mixture was heated to 80°C for 24-72h, and monitored by TLC. The solvent was concentrated in vacuum and the residue was dissolved by water (100mL), which was extracted with diethyl ether (100mL×3), and the aqueous layer was acidified with glacial acetic acid to pH 5. The resulting precipitate was filtered, dried, and recrystallized with ethanol to yield a series of 2-arylquinoline-4-carboxylic acids 11a-h.
46% With potassium hydroxide In water Reflux; 2.1.1. General Procedure for the Synthesis of Target Molecules. General procedure: A mixture of 0.5 g of the appropriate isatin derivative, 30mLof 33% w/v aqueous potassium hydroxide, and equimolar amount of ketone was heated under reflux for 15-24 hours (the reaction progress was monitored by TLC using ethylacetate : hexane mixture (3 : 2) as a mobile phase). After that, the reaction mixture was cooled and diluted with water. The solution was neutralized with 1M hydrochloric acid. The precipitate was filtered, washed with water, dried, and recrystallized from ethanol (Scheme 1).
With potassium hydroxide; water
With potassium hydroxide In ethanol Heating; Yield given;
With potassium hydroxide In ethanol for 0.5h; Heating;
With potassium hydroxide In ethanol Heating;
With potassium hydroxide In ethanol at 80℃;
With potassium hydroxide In ethanol at 80℃;
With potassium hydroxide In ethanol Heating;
With potassium hydroxide In water 8 EXAMPLE 8 EXAMPLE 8 The compound (2,6-dimethoxy-3-chlorosulfonyl-phenyl)-2-phenyl-N-methyl-quinolinium-4-carboxylate fluorosulfonate, which has the following formula: STR34 is synthesizable according to the following scheme: STR35 Acetophenone (29) (120 g, 1 mol) and isatin (30) (147 g, 1 mol) would be refluxed for 10 hours in water and ethanol, with potassium hydroxide (17 g). The 2-phenyl-quinoline-4-carboxylic acid (31) is recovered from ethanol as white needles.
With potassium hydroxide In water 3 EXAMPLE 3 EXAMPLE 3 The compound (2,6-dimethoxy-3-chlorosulfonyl-phenyl)-2-phenyl-N-methyl-quinolinium-4-carboxylate fluorosulfonate, which has the following formula: STR24 is synthesizable according to the following scheme: STR25 Acetophenone (29) (120 g, 1 mol) and isatin (30) (147 g, 1 mol) would be refluxed for 10 hours in water and ethanol, with potassium hydroxide (17 g). The 2-phenyl-quinoline-4-carboxylic acid (31) is recovered from ethanol as white needles.
With potassium hydroxide In ethanol at 80℃;
With potassium hydroxide In ethanol at 80℃; for 48h;
With potassium hydroxide In ethanol for 72.5h; Reflux; General Procedures for the Synthesis of 2-Arylquinoline-4-carboxylic Acids (5 Series) General procedure: A mixture of KOH (2 g), 3 (2 g), and ethanol (60 mL)was heated to reflux and kept refluxing for 0.5h, substitutedacetophenone was added and kept refluxing for 72h. Thereaction mixture was allowed to cool and ethanol was removedunder reduced pressure. The residue was adjustedwith 2M hydrochloric acid to pH=4 and filtered. The filtercake was washed with water and dried in vacuum to give 2-arylquinoline-4-carboxylic acids (5 series) as solids.
With potassium hydroxide In ethanol; water for 18h; Reflux;
With potassium hydroxide In ethanol; water Reflux; 1.J Step J2- phenyl quinoline-4-carboxylic acid (b) The 3g (0.02mol) was dissolved in 2,3-dione 10mL33.3% aqueous potassium hydroxide solution added dropwise with stirring 30mL acetophenone (1.1equiv.) In ethanol was heated to reflux for 24- 72h.The reaction was completed, most of the solvent was distilled off, water was added to dissolve 100mL, 100mL of diethyl ether and washed three times with an aqueous solution of pH 5 with glacial acetic acid, the precipitated solid by suction filtration, dried, recrystallized from ethanol to give the intermediate 2-phenyl-quinoline 4-carboxylic acid.
With sodium hydroxide In water for 6h; Reflux;
With potassium hydroxide In ethanol at 85℃; 6 5.3. General procedure for the synthesis of 2-phenyl-4-quinolinecarboxylic acid (4a-n) General procedure: To a 100 mL round-bottom flask, isatin 3a-d (34.0mmol), substituted acetophenone (40.8 mmol) and KOH (102mmol) in ethanol (40mL) were added with stirring. The resulting mixture was heated to reflux at 85°C for 3 days. After removing the solvent under reduced pressure, the mixture was dissolved in water and washed twice with ether. The aqueous layer was concentrated and adjusted to pH 2 with concentrated HCl to afford an orange solid. This solid was filtered, washed with water until neutral, dried and purified by flash column chromatography on silica gel and eluted with a mixture of EtOAc/petroleum ether (1:1, v/v) to afford 4a-n as orange solids.
With potassium hydroxide In ethanol at 0 - 80℃; for 24h; General procedure for the preparation of 4 General procedure: Isatin (0.5 g, 3.34 mmol) was added into a stirred solution ofKOH (0.56 g, 10.02 mmol) in ethanol 10 ml at 80 C. The reactionmixture was stirred at 0 C for 24 h. The mixture was added to50 g ice water. The pH was adjusted by the solution of 2 N HCl to4-5. The mixture was cooled overnight and filtered. The residuewas recrystallized by the mixture of petroleum/ethyl acetate(5:1). Compound 4 (0.8 g) was obtained and the yield was 96.87%.
With sodium hydroxide In ethanol for 12h; Reflux; Step-1: Synthesis of compound 2-phenyl quinoline-4-carboxylic acid (3): Isatin (1.47 g, 10.0 mmol) in 33 % alc. NaOH (15 mL), acetophenone (1.2 g, 10.0 mmol), ethanol (15 mL) was taken in a round bottom flask. The reaction mixture was stirred and refluxed for 12 h. The progress of the reaction was monitored by TLC (ethyl acetate:petroleum ether,7:3 v/v). After the completion of the reaction, the reaction mixture was cooled and poured onto ice-water, then acidified with 10 % HCl to achieve pH 2.0-3.0. The precipitate was filtered, washed with water and dried. The acid was recrystallized from ethanol [15].
In ethanol; water Reflux;
With potassium hydroxide In ethanol; water for 5h; Reflux; 5.2.1. General method of preparation of the compound 5 General procedure: To a solution of chloral hydrate (0.54 mol) in 10 mL water, a solutionof sodium sulfate was added (Solution A). On the other hand, to a solutionof aniline (0.5 mol) in 5 mL water concentrated hydrochloric acidwas added (Solution B). Now the solution B was added to solution B andthe reaction mixture could stir at 60-80 C for half an hour. Formation ofisonitrosoacetanilide needle shaped crystals were observed and the reactionwas cooled to room temperature. The product obtained (2) wasfiltered, dried and produced for further reactions without purification[28]. Dry isonitrosoacetanilide (0.46 mol) in a round bottom flask wasadded with 20 mL concentrated sulfuric acid and the reaction mixturewas stirred at 80 C for half an hour. The mixture was cooled to roomtemperature and quenched with crushed ice to obtain a yellow coloredprecipitate. The precipitate was filtered and washed with cold water toremove the excessive sulfuric acid to obtain pure 1H-indole-2,3-dione, 3(yield 70-75%). To a solution of 1H-indole-2,3-dione (4 mmol) inethanol (20 mL), acetophenone (5 mmol), water (10 mL), and anaqueous solution of potassium hydroxide (2.80 g, 50 mmol) were added.The reaction mixture was heated to reflux at 80 C for 5 h. The reactionwas monitored by TLC (80% EtoAc/hexane). After that completion ofthe reaction, crushed ice was added, and the organic solution wasextracted by EtOAc. The combined organic layers were dried over sodiumsulphate, filtered and concentrated to give the crude yellowcolored product, (5) [15], which was purified by column chromatographyusing 80% EtOAC/Hexane. The yield of the compound wasrecorded to be 75-80% and LC MS m/z (M+H) + = 250.2.
With potassium hydroxide In ethanol Reflux; General Method for Synthesis of Compounds (IIIa-j) General procedure: 10 mmol Isatin (1) was added into a stirred solutionof 33% potassium hydroxide (10 mL) and ethanol(20 mL). 10 mmol of appropriate acetophenone derivative(IIa-j) was mixed and heated under reflux for18-24 h. The reaction mixture was poured on crushedice and the pH was adjusted by the solution of 2 N HClto 6-7. The precipitated solid was filtered, washedwith water, dried and crystallized from ethanol whichwas then taken to the next step without any furtherpurification [29, 30].
With potassium hydroxide In ethanol
With potassium hydroxide In ethanol Reflux; 4.1.1 General procedure for the synthesis of 2-phenylquinoline-4-carboxylic acidderivatives (3) General procedure: Isatin (1) (10mmol), 33% potassium hydroxide (10mL), ethanol (20mL), and appropriate acetophenone derivative (10mmol) were mixed and refluxed for 18-24h. The reaction mixture was cooled and concentrated under reduced pressure; the residue was diluted with water (50mL) and extracted with diethylether (3×50mL). The aqueous layer obtained was neutralized with 1M HCl. The precipitate which was then filtered, washed with water, dried andcrystallized from ethanol to get the pure solid (3) with excellent yield.
With potassium hydroxide In ethanol Reflux; 4.1.1 General procedure for the synthesis of 2-phenylquinoline-4-carboxylic acidderivatives (3) General procedure: Isatin (1) (10mmol), 33% potassium hydroxide (10mL), ethanol (20mL), and appropriate acetophenone derivative (10mmol) were mixed and refluxed for 18-24h. The reaction mixture was cooled and concentrated under reduced pressure; the residue was diluted with water (50mL) and extracted with diethylether (3×50mL). The aqueous layer obtained was neutralized with 1M HCl. The precipitate which was then filtered, washed with water, dried andcrystallized from ethanol to get the pure solid (3) with excellent yield.
Stage #1: indole-2,3-dione With sodium hydroxide In ethanol; water Stage #2: acetophenone In ethanol; water for 1.5h; Reflux;
With potassium hydroxide In ethanol at 80℃; 4.3. General procedure for the synthesis of 2-aryl quinoline-4-carboxylic acids (4k-p and 4q-t) General procedure: For the synthesis of compounds 4k-p , a solution of isatin (34.0 mmol), an acetophenone derivative (40.8 mmol), and KOH (102 mmol) in EtOH (40 mL) was refluxed at 80 °C for 48-72 h and workup was performed similar to that of compound 4a mentioned in 4.2. Also compounds 4q-t synthesized by refluxing of an ani- line derivative (1mmol), pyruvic acid (1.5 mmol) and benzaldehyde (1mmol) in ethanol. After the reaction was complete, the cooled mixture was filtered and recrystallized in ethanol.
With water In ethanol at 80℃; for 24h;
92 % With water; potassium hydroxide In ethanol at 80℃; 1.11 Example 1.11: 2-Phenylquinoline-4-carboxylic acid (RS5974). A mixture of isatin (1.000 g, 0.007 mol), 33% KOH aqueous solution (3.4 mL), acetophenone (0.889 g, 0.008 mol) in ethanol (10.2 mL) was heated to 80 °C for 24 h. The solvent was concentrated in vacuum and the residue was dissolved by water, which was extracted with diethyl ether. The aqueous layer was acidified with glacial acid acetic to pH = 5. The resulting precipitate was filtered and dried to obtain RS5974 (1.55 g, 92%), mp 139-141 °C (from ethanol). 1H NMR (DMSO-d6, 300 MHz): δ 4.32 (br s, disappeared after treatment with D2O, 1H), 7.53-7.62 (m, 4H), 7.75-7.80 (m, 1H), 8.08-8.10 (m, 1H), 8.24-8.27 (m, 3H), 8.60-8.62 ppm (m, 1H). IR: v 1652 and 2487 cm-1.
Stage #1: indole-2,3-dione With potassium hydroxide at 20℃; Stage #2: acetophenone In ethanol at 75℃; 1.1 At room temperature, 1 mmol of isatin was added to 33% potassium hydroxide solution to form a reaction system for ring-opening reaction, and the stirring speed was 650 rpm for 0.5 h.After the completion of the reaction was monitored by TLC, 1.1 mmol of acetophenone was dissolved in ethanol to obtain a mixture, and then the above mixture was slowly added dropwise to the above reaction system, and refluxed at 75° C. for 5 h.After the reaction was completed, it was left standing, cooled to dryness, and the reaction product was evaporated to dryness.Then add distilled water to it, make weak acidity with formic acid, the product is washed out continuously, and stand for 0.5h.Use a cup-shaped suction filter funnel to perform suction filtration, and use a cup-shaped suction filter funnel to perform suction filtration under a pressure of 0.1 MPa for 20 minutes to obtain 2-phenylquinoline-4-carboxylic acid
Stage #1: indole-2,3-dione With potassium hydroxide at 20℃; Stage #2: acetophenone In ethanol at 75℃; 1.1 At room temperature, 1 mmol of isatin was added to 33% potassium hydroxide solution to form a reaction system for ring-opening reaction, and the stirring speed was 650 rpm for 0.5 h.After the completion of the reaction was monitored by TLC, 1.1 mmol of acetophenone was dissolved in ethanol to obtain a mixture, and then the above mixture was slowly added dropwise to the above reaction system, and refluxed at 75° C. for 5 h.After the reaction was completed, it was left standing, cooled to dryness, and the reaction product was evaporated to dryness.Then add distilled water to it, make weak acidity with formic acid, the product is washed out continuously, and stand for 0.5h.Use a cup-shaped suction filter funnel to perform suction filtration, and use a cup-shaped suction filter funnel to perform suction filtration under a pressure of 0.1 MPa for 20 minutes to obtain 2-phenylquinoline-4-carboxylic acid
With potassium hydroxide In water at 60℃;
With potassium hydroxide at 130℃;

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[18]Giardina, Giuseppe A. M.; Raveglia, Luca F.; Grugni, Mario; Sarau, Henry M.; Farina, Carlo; Medhurst, Andrew D.; Graziani, Davide; Schmidt, Dulcie B.; Rigolio, Roberto; Luttmann, Mark; Cavagnera, Stefano; Foley, James J.; Vecchietti, Vittorio; Hay, Douglas W. P. [Journal of Medicinal Chemistry, 1999, vol. 42, # 6, p. 1053 - 1065]
[19]Yu, Xiang Y.; Hill, Jason M.; Yu, Guixue; Yang, Yifeng; Kluge, Arthur F.; Keith, Dennis; Finn, John; Gallant, Paul; Silverman, Jared; Lim, Audrey [Bioorganic and Medicinal Chemistry Letters, 2001, vol. 11, # 4, p. 541 - 544]
[20]Current Patent Assignee: LONDON DIAGONOSTICS - US5284951, 1994, A
[21]Current Patent Assignee: LONDON DIAGONOSTICS - US5284952, 1994, A
[22]Location in patent: experimental part Dahal, Upendra P.; Joswig-Jones, Carolyn; Jones, Jeffrey P. [Journal of Medicinal Chemistry, 2012, vol. 55, # 1, p. 280 - 290]
[23]Location in patent: experimental part Dahal, Upendra P.; Jones, Jeffrey P.; Davis, John A.; Rock, Dan A. [Drug Metabolism and Disposition, 2011, vol. 39, # 12, p. 2355 - 2360]
[24]Shi, Zhi-Bing; Zhang, Lei; Bin, Zheng-Yang; Cao, Xiang-Rong; Gong, Zhu-Nan; Li, Jian-Xin [Letters in drug design and discovery, 2013, vol. 10, # 5, p. 420 - 426]
[25]Bonacorso, Helio G.; Nogara, Pablo A.; Silva, Fernanda D'A.; Rosa, Wilian C.; Wiethan, Carson W.; Zanatta, Nilo; Martins, Marcos A.P.; Rocha, João B.T. [Journal of Fluorine Chemistry, 2016, vol. 190, p. 31 - 40]
[26]Current Patent Assignee: SHENYANG PHARMACEUTICAL UNIVERSITY - CN103965107, 2016, B Location in patent: Paragraph 0177; 0178
[27]Kaushik, Reena; Kushwaha, Khushbu; Chand, Mahesh; Vashist, Monika; Jain, Subhash C. [Journal of Heterocyclic Chemistry, 2017, vol. 54, # 2, p. 1042 - 1047]
[28]Zhu, Li; Luo, Kaixiu; Li, Ke; Jin, Yi; Lin, Jun [Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 21, p. 5939 - 5951]
[29]Liao, Chen; Liu, Yan; Liu, Chunxia; Zhou, Jiaqi; Li, Huilan; Wang, Nasi; Li, Jieming; Liu, Taiyu; Ghaleb, Hesham; Huang, Wenlong; Qian, Hai [Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 4, p. 845 - 854]
[30]Shetty, P. Raghurama; Shivaraja; Krishnaswamy; Pruthviraj; Mohan, Vivek Chandra; Sreenivasa [Asian Journal of Chemistry, 2020, vol. 32, # 5, p. 1151 - 1157]
[31]Mohassab, Aliaa M.; Hassan, Heba A.; Abdelhamid, Dalia; Gouda, Ahmed M.; Youssif, Bahaa G.M.; Tateishi, Hiroshi; Fujita, Mikako; Otsuka, Masami; Abdel-Aziz, Mohamed [Bioorganic Chemistry, 2021, vol. 106]
[32]Singh, Anju; Kalamuddin, Md; Maqbool, Mudasir; Mohmmed, Asif; Malhotra, Pawan; Hoda, Nasimul [Bioorganic Chemistry, 2021, vol. 108]
[33]Shaikh, Sarfaraz F.; Dhavan, Pratik P.; Singh, Pinky R.; Vaidya; Jadhav; Ramana [Russian Journal of Bioorganic Chemistry, 2021, vol. 47, # 2, p. 572 - 583][Bioorg. Khim.]
[34]Abdel-Aziz, Mohamed; Abdelhamid, Dalia; Fujita, Mikako; Gomaa, Hesham A. M.; Gouda, Ahmed M.; Hassan, Heba A.; Mohassab, Aliaa M.; Otsuka, Masami; Radwan, Mohamed O.; Youssif, Bahaa G. M. [Journal of Molecular Structure, 2021, vol. 1244]
[35]Swain, Baijayantimala; Sahoo, Santosh Kumar; Singh, Priti; Angeli, Andrea; Yaddanapudi, Venkata Madhavi; Supuran, Claudiu T.; Arifuddin, Mohammed [European Journal of Medicinal Chemistry, 2022, vol. 234]
[36]Swain, Baijayantimala; Sahoo, Santosh Kumar; Singh, Priti; Angeli, Andrea; Yaddanapudi, Venkata Madhavi; Supuran, Claudiu T.; Arifuddin, Mohammed [European Journal of Medicinal Chemistry, 2022, vol. 234]
[37]Kumar Sahoo, Santosh; Naiyaz Ahmad, Mohammad; Kaul, Grace; Nanduri, Srinivas; Dasgupta, Arunava; Chopra, Sidharth; Madhavi Yaddanapudi, Venkata [Chemistry and biodiversity, 2022, vol. 19, # 7]
[38]Omidkhah, Negar; Hadizadeh, Farzin; Abnous, Khalil; Ghodsi, Razieh [Journal of Molecular Structure, 2022, vol. 1267]
[39]Wang, Yedong; Wu, Yixin; Liu, Chang; Zhang, Jingli; Yan, Xiaoyu [Chemistry - An Asian Journal, 2022, vol. 17, # 18]
[40]Current Patent Assignee: UNIVERSITA DEGLI STUDI DI ROMA LA SAPIENZA; ISTITUTO EUROPEO DI ONCOLOGIA SRL; UNIVERSITY OF TRENTO - EP4089077, 2022, A1 Location in patent: Paragraph 0063
[41]Current Patent Assignee: ZHENGZHOU UNIVERSITY - CN114890947, 2022, A Location in patent: Paragraph 0045-0048
[42]Current Patent Assignee: ZHENGZHOU UNIVERSITY - CN114890947, 2022, A Location in patent: Paragraph 0045-0048
[43]Shinde, Abhijit D.; Nandurkar, Yogesh M.; Bhalekar, Swapnil; Walunj, Yogesh S.; Ugale, Sandip; Ahmad, Iqrar; Patel, Harun; Chavan, Abhijit P.; Mhaske, Pravin C. [Journal of Biomolecular Structure and Dynamics, 2023]
[44]Soni, Jay Prakash; Devi, Priyanka; Chemitikanti, Sowjanya; Sharma, Anamika; Swamy, Chintha Venkata Dinesh; Phanindranath, Regur; Sathish, Manda; Nagesh, Narayana; Godugu, Chandraiah; Shankaraiah, Nagula [Journal of Molecular Structure, 2023, vol. 1291]
  • 6
  • [ 100-52-7 ]
  • [ 127-17-3 ]
  • [ 62-53-3 ]
  • [ 132-60-5 ]
YieldReaction ConditionsOperation in experiment
89% With toluene-4-sulfonic acid; glacial acetic acid In 1,2-dichloro-benzene; butan-1-ol
80% With toluene-4-sulfonic acid In ethanol for 0.05h; Microwave irradiation; Green chemistry;
72% With ytterbium perfluorooctanoate In lithium hydroxide monohydrate for 3h; Reflux;
51% In ethanol for 3h; Reflux;
43% Stage #1: benzaldehyde; aniline With borane-THF In acetonitrile at 65℃; for 0.166667h; Stage #2: 2-oxo-propionic acid In acetonitrile for 24h; Stage #3: With lithium hydroxide monohydrate In acetonitrile A3 Example A3
Production of 2-phenylquinoline-4-carboxylic acid To a solution of aniline (0.952 g, 10.2 mmol) in acetonitrile (5.7 mL), benzaldehyde (1.21 g, 11.4 mmol) and boron trifluoride-tetrahydrofuran complex (313 μL, 2.84 mmol) were added, and the mixture was heated to 65° C. 10 minutes later, a solution of pyruvic acid (0.500 g, 5.68 mmol) in acetonitrile (9.5 mL) was added dropwise thereto over 3 hours. 21 hours later, the reaction solution was cooled to room temperature, and water was added thereto, followed by extraction with toluene. The obtained organic layer was washed with water, followed by extraction with a 1 mol/L sodium hydroxide aqueous solution. The obtained aqueous layer was adjusted to pH 1 or lower by the addition of concentrated hydrochloric acid, and saturated aqueous sodium chloride solution was then added thereto, followed by extraction with tetrahydrofuran. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then filtered, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (0.614 g, yield: 43%) as a pale yellow solid. 1H-NMR (400 MHz, DMSO-D6) δ: 14.0 (1H, s), 8.67 (1H, d, J=8.5 Hz), 8.47 (1H, s), 8.32-8.30 (2H, m), 8.18 (1H, d, J=7.9 Hz), 7.89-7.85 (1H, m), 7.74-7.70 (1H, m), 7.61-7.53 (3H, m) ESI-MS (m/z): 250 (M+H)+
12% for 0.0666667h; microwave irradiation;
With ethanol
In ethanol for 3h; Reflux;

  • 7
  • [ 132-60-5 ]
  • [ 57591-61-4 ]
  • [ 189815-93-8 ]
  • 8
  • [ 132-60-5 ]
  • [ 7732-18-5 ]
  • [ 7722-84-1 ]
  • [ 64-19-7 ]
  • [ 579-93-1 ]
  • [ 20389-12-2 ]
  • 9
  • [ 20174-68-9 ]
  • [ 132-60-5 ]
  • 5-methyl-3-(2-phenylquinoline-4-yl)-1,2,4-triazolo[3,4-b]benzothiazole [ No CAS ]
  • 10
  • [ 67-56-1 ]
  • [ 132-60-5 ]
  • [ 4546-48-9 ]
YieldReaction ConditionsOperation in experiment
100% With sulfuric acid Reflux; 20 methyl 2-phenyl-quinoline-4-carboxylate To a solution of 2 g (8 mmol) of commercially available 2-phenyl-4-quinolinecarboxylic acid in 20 ml of methanol was added 0.5 ml of concentrated H2S04 and the mixture was heated overnight under reflux. The reaction mixture was concentrated, treated with a mixture of ethyl acetate and water, and then the organic layer was washed with a saturated NaHC03 aqueous solution, dried over MgS04, filtered and concentrated to give 2.1 g (quantitative yield) of yellow oil corresponding to methyl 2-phenyl-quinoline-4- carboxylate. 1H NMR (300 MHz, CDC13).
99% With dicyclohexyl-carbodiimide In dichloromethane at 0 - 20℃; for 13h;
84.9% With thionyl chloride at 0℃; Reflux;
71% With sulfuric acid at 130℃; for 0.2h; Sealed tube; Microwave irradiation;
50% Stage #1: methanol; cinchophen With sulfuric acid for 2h; Reflux; Stage #2: With sodium carbonate for 1h;
With thionyl chloride for 4h; Reflux; Synthesis of 2-Arylquinoline-4-esters (7a and 7b) General procedure: A mixture of 2-arylquinoline-4-carboxylic acids 5 (400mg), thionyl chloride (2 mL), and methanol (10 mL) washeated to reflux and kept refluxing for 4h. The resulting mixturewas evaporated to dryness under reduced pressure. Tothe residue methanol (5 mL) was added and ultrasoundedand filtered. The filter cake was washed with water and driedin vacuum to give esters (7a, 7b) as solids.
1.44 g With sulfuric acid for 24h; Inert atmosphere; Reflux;
With sulfuric acid for 16h; Reflux;
With sulfuric acid Reflux;

Reference: [1]Current Patent Assignee: GENOSCIENCE PHARMA - WO2014/147611, 2014, A1 Location in patent: Page/Page column 101; 102
[2]Lautens, Mark; Tayama, Eiji; Herse, Christelle [Journal of the American Chemical Society, 2005, vol. 127, # 1, p. 72 - 73]
[3]Location in patent: experimental part DasGupta, Shirshendu; Murumkar, Prashant R.; Giridhar, Rajani; Yadav, Mange Ram [Bioorganic and Medicinal Chemistry, 2009, vol. 17, # 10, p. 3604 - 3617]
[4]Serpier, Fabien; Pan, Fei; Ham, Won Seok; Jacq, Jérôme; Genicot, Christophe; Ritter, Tobias [Angewandte Chemie - International Edition, 2018, vol. 57, # 33, p. 10697 - 10701][Angew. Chem., 2018, vol. 130, # 33, p. 10857 - 10861,5]
[5]Location in patent: experimental part Saeed; Elhadi [Synthetic Communications, 2011, vol. 41, # 10, p. 1435 - 1443]
[6]Shi, Zhi-Bing; Zhang, Lei; Bin, Zheng-Yang; Cao, Xiang-Rong; Gong, Zhu-Nan; Li, Jian-Xin [Letters in drug design and discovery, 2013, vol. 10, # 5, p. 420 - 426]
[7]Tang, Tommy Siu-Ming; Leung, Kam-Keung; Louie, Man-Wai; Liu, Hua-Wei; Cheng, Shuk Han; Lo, Kenneth Kam-Wing [Dalton Transactions, 2015, vol. 44, # 11, p. 4945 - 4956]
[8]Bonacorso, Helio G.; Nogara, Pablo A.; Silva, Fernanda D'A.; Rosa, Wilian C.; Wiethan, Carson W.; Zanatta, Nilo; Martins, Marcos A.P.; Rocha, João B.T. [Journal of Fluorine Chemistry, 2016, vol. 190, p. 31 - 40]
[9]Khan, Bilal Ahmad; Hamdani, Syeda Shamila; Jalil, Saquib; Ejaz, Syeda Abida; Iqbal, Jamshed; Shawky, Ahmed M.; Alqahtani, Alaa M.; Gabr, Gamal A.; Ibrahim, Mahmoud A. A.; Sidhom, Peter A. [Pharmaceuticals, 2023, vol. 16, # 1]
  • 11
  • [ 5319-77-7 ]
  • [ 132-60-5 ]
  • 2-phenyl-quinoline-4-carboxylic acid (5-methylsulfanyl-[1,3,4]thiadiazol-2-yl)-amide [ No CAS ]
  • 12
  • (6S,8R)-N-{(1R)-1-[(3AS,4S,6S 7AR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-ylpropyl]-8-amino-8-methyl-4-oxo-3-[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxamide [ No CAS ]
  • [ 132-60-5 ]
  • [ 148893-10-1 ]
  • [ 437758-43-5 ]
YieldReaction ConditionsOperation in experiment
5.6 mg (32%) With triethanolamine; In tetrahydrofuran; dichloromethane; N,N-dimethyl-formamide; acetonitrile; Example 15 N-((6S,8R)-6-[({(1R)-1-[(3aS,4S,6S,7aR)-Hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]propyl}amino)carbonyl]-8-methyl-4-oxo-3-[3-(trifluoromethyl)benzyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidin-8-yl)-2-phenyl-4-quinolinecarboxamide To a solution of 13a (10.0 mg, 0.0166 mmol) and 2-phenyl-4-quinolinecarboxylic acid (4.6 mg, 0.018 mmol) in 1:1 THF/CH2Cl2 (1 mL) and 200 muL DMF, was added TEA (2.8 muL, 0.020 mmol) and HAtU (7.6 mg, 0.020 mmol). The mixture was stirred at rt for 2 h, then was diluted with EtOAc. The organic phase was washed with H2O, NaHCO3, and brine, dried (Na2SO4), and concentrated. The crude product was purified by flash chromatography (55% EtOAc/hexanes), followed by preparative HPLC (gradient, 50 to 100% CH3CN/H2O+0.1% TFA) to afford 5.6 mg (32%) of Example 15 as the diTFA salt. MS (ESI) 833.6 (M+H+) 855.6 (M+Na+); 831.6 (M-H+); MS (HR-ESI) calculated for C46H49BF3N6O5 (M+H+), found 833.3828.
  • 13
  • [ 132-60-5 ]
  • [ 121148-00-3 ]
  • [ 919094-66-9 ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine; ((3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)oxy)tri(pyrrolidin-1-yl)phosphonium hexafluorophosphate(V); In acetonitrile; at 20℃; To a solution of Fmoc(2S,4R)-4-amino-1-Boc-pyrrolidine-2-carboxylic acid (300 mg, 0.663 mmol) in DMF (5 mL), cesium carbonate (475 mg, 1.459 mmol) and methyl iodide (0.1 mL, 1.658 mmol) were added. The reaction mixture was stirred at room temperature for overnight. Then it was treated with water and extracted with ethyl acetate. The organic layer was separated, washed with brine and dried over MgSO4. Evaporation of solvent gave a colorless thick oil. It was then dissolved in acetonitrile (5 mL) and pyrrolidine (1 mL) was added. The reaction mixture was stirred at room temperature for 3 hours. LC/MS shown completion of deprotection of Fmoc. It was then concentrated and put on high vacuum to pump out excess pyrrolidine. Then it was redissolved in acetonitrile (5 mL). PyAOP (519 mg, 0.995 mmol), 2-phenyl-4-quinolinecarboxylic acid (198 mg, 0.796 mmol) and DIEA (0.17 mL, 0.995 mmol) were added. This reaction mixture was stirred at room temperature for overnight. It was then concentrated down, washed with water and extracted with ethyl acetate. The organic layer was separated, washed with brine and dried over MgSO4, and filtered. Evaporation of solvent gave yellowish oil as crude product. It was then purified by flash column chromatography (silica gel, 2:1 ethyl acetate:hexanes) to provide a light yellow solid (0.22 g, 70percent yield). (48110-177 48110-178): 1H NMR(CDCl3, 300 MHz) delta:8.07-8.26 (m, 4H), 7.87 (s, 1H), 7.77 (t, J=8.1 Hz, 1H), 7.44-7.65 (m, 4H), 6.30(m, br, 1H), 4.88 (m, 1H), 4.44 (m, 1H), 3.98 (m, 1H), 3.78 (s, 3H), 3.54 (m, 1H), 2.35-2.50 (m, 2H), 1.34-1.5 (m, 9H). LC-MS (retention time: 1.530 minutes.), MS m/z 476(MH+).
  • 14
  • [ 919093-81-5 ]
  • [ 132-60-5 ]
  • [ 919093-82-6 ]
YieldReaction ConditionsOperation in experiment
56% With N-ethyl-N,N-diisopropylamine; ((3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)oxy)tri(pyrrolidin-1-yl)phosphonium hexafluorophosphate(V) In acetonitrile at 20℃; B.23 To a solution of Compound 8 (20 mg, 0.03 mmol) in 5 mL of CH3CN was added 2-phenyl-4-quinolinecarboxylic acid (11.1 mg, 0.04 mmol), DIEA (0.01 mL, 0.05 mmol) and the coupling reagent PyAOP (29.1 mg, 0.05 mmol). The solution was stirred at room temperature for overnight. It was then concentrated, washed with water and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The crude product was purified by preparative HPLC column to yield a yellow oil as 1:1 diatereomers (Compound 9)(18 mg, 56% yield). (Compound 9, 48110-164): 1H NMR(CD3OD, 500 MHz) δ:8.26-8.34 (m, 3H), 8.18 (m, 2H), 7.99(m, 1H), 7.81 (m, 1H), 7.66(m, 3H), 5.74 (m, 1H), 5.32 (m, 1H), 5.14 (m, 1H), 4.88 (m, 1H), 4.57 (m, 1H), 4.48 (m, 1H), 4.23(m, 1H), 4.11 (m, 1H), 2.95 (m, 1H), 2.46 (m, 1H), 2.21-2.38 (m, 2H), 2.02 (m, 2H), 1.90 (dd, J=8.2 Hz, 5.5 Hz, 0.5H), 1.82 (dd, J=8.2 Hz, 5.2 Hz, 0.5H), 1.38-1.46 (m, 1H), 1.00-1.23(m, 13H), 0.79 (m, 1H), 0.37 (m, 2H), 0.06 (m, 2H). LC-MS (retention time: 1.673 minutes.), MS m/z 769 (MH+).
  • 15
  • [ 4530-20-5 ]
  • [ 5336-90-3 ]
  • [ 132-60-5 ]
  • [ 108-24-7 ]
  • [ 176486-63-8 ]
  • [ 1029683-82-6 ]
  • 16
  • [ 4530-20-5 ]
  • [ 5336-90-3 ]
  • [ 132-60-5 ]
  • [ 108-24-7 ]
  • [ 176486-63-8 ]
  • [ 1029683-86-0 ]
  • 17
  • [ 4530-20-5 ]
  • [ 132-60-5 ]
  • [ 6284-80-6 ]
  • [ 108-24-7 ]
  • [ 176486-63-8 ]
  • [ 1029683-83-7 ]
  • 18
  • [ 4530-20-5 ]
  • [ 132-60-5 ]
  • [ 6284-80-6 ]
  • [ 108-24-7 ]
  • [ 176486-63-8 ]
  • [ 1029683-87-1 ]
  • 19
  • [ 4530-20-5 ]
  • [ 132-60-5 ]
  • [ 4361-00-6 ]
  • [ 108-24-7 ]
  • [ 176486-63-8 ]
  • [ 1029683-81-5 ]
  • 20
  • [ 4530-20-5 ]
  • [ 132-60-5 ]
  • [ 4361-00-6 ]
  • [ 108-24-7 ]
  • [ 176486-63-8 ]
  • [ 1029683-85-9 ]
  • 21
  • [ 5467-57-2 ]
  • [ 98-80-6 ]
  • [ 132-60-5 ]
  • 22
  • [ 27049-71-4 ]
  • [ 132-60-5 ]
  • [ 865287-85-0 ]
  • 23
  • [ 52838-39-8 ]
  • [ 132-60-5 ]
  • [ 1236056-67-9 ]
  • 25
  • [ 5467-57-2 ]
  • [ 960-16-7 ]
  • [ 132-60-5 ]
  • 26
  • [ 132-60-5 ]
  • [ 166168-16-7 ]
  • [ 1165797-17-0 ]
YieldReaction ConditionsOperation in experiment
65% With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; triethylamine In dichloromethane at 20℃; for 15h; Inert atmosphere; 4.1.1. tert-Butyl [trans-4-([(2-phenylquinolin-4-yl)carbonyl]-amino}methyl)cyclohexyl]methyl}carbamate (17) 2-Phenyl-quinoline-4-carboxylic acid (200 mg, 0.80 mmol) was dissolved in CH2Cl2 (8 mL) and tert-butyl [trans-4-(aminomethyl)-cyclohexyl]methyl}carbamate (4, 204 mg, 0.84 mmol), TBTU (283 mg, 0.88 mmol) and Et3N (0.45 mL, 3.2 mmol) were added and the reaction mixture was stirred at rt for 15 h. The reaction mixture was concentrated in vacuo to leave a residue, which was dissolved in DMSO and purified by HPLC, using a gradient of 40-100% mobile phase A (100% CH3CN) over 30 min (mobile phase B = 5% CH3CN + 95% 0.1 M NH4OAc) to give the title compound as a white solid (247 mg, 65%). 1H NMR (400 MHz, DMSO-d6) δ 8.77 (t, J = 5.6 Hz, 1H), 8.29-8.23 (m, 2H), 8.14-8.04 (m, 3H), 7.81-7.75 (m, 1H), 7.64-7.46 (m, 5H), 3.19 (t, J = 6.1 Hz, 2H), 2.74 (t, J = 6.2 Hz, 2H), 1.80 (d, J = 11.1 Hz, 2H), 1.68 (d, J = 11.5 Hz, 2H), 1.57-1.45 (m, 1H), 1.33 (s, 9H), 1.32-1.22 (m, 1H), 1.00-0.76 (m, 4H); HRMS (ESI) m/z calcd for C29H36 N3O3 [M+H]+ 474.2757; found 474.2773.
  • 27
  • [ 132-60-5 ]
  • [ 2627-86-3 ]
  • [ 174635-49-5 ]
YieldReaction ConditionsOperation in experiment
94% With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 3h; Inert atmosphere; 3 4.1.3
(S)-2-Phenylquinoline-4-carboxylic acid (1-phenylethyl)amide (8)
General procedure: To a solution of 2-phenyl-quinoline-4-carboxylic acid (249 mg, 1.0 mmol) and l(-)-α-methylbenzylamine (127 mg, 1.05 mmol) in 10 mL of CH2Cl2 was added DIPEA (388 mg, 3.0 mmol). HBTU (569 mg, 1.5 mmol) was added at 0 °C. The resulting mixture was stirred at r.t. for 3 h. The reaction mixture was diluted with CH2Cl2 (80 mL) and washed with water (20 mL). The organic layer was separated and dried with anhydrous Na2SO4. The solution was concentrated to give a crude product, which was purified with silica gel column (EtOAc/hexane = 1/3) to obtain 8 (330 mg, 94%) as a white solid (mp 157-158 °C). HPLC purity 99.8% (tR = 17.22 min). 1H NMR (600 MHz, CDCl3) δ 8.03-8.07 (m, 3H), 7.97 (d, 1H, J = 8.4 Hz), 7.71 (s, 1H), 7.67 (t, 1H, J = 7.2 Hz), 7.28-7.48 (m, 9H), 6.78 (d, 1H, J = 7.2 Hz), 5.38-5.43 (m, 1H), 1.66 (d, 3H, J = 6.6 Hz). 13C NMR (150 MHz, CDCl3) δ 166.9, 156.9, 148.7, 143.0, 142.6, 138.9, 130.3, 130.2, 129.8, 129.0, 127.8, 127.6, 127.4, 126.4, 125.0, 123.4, 116.4, 49.8, 21.9. HRMS (ESI) calcd for C24H21N2O 353.1648 (M + H)+, found 353.1653.
  • 28
  • [ 132-60-5 ]
  • [ 20503-40-6 ]
  • [ 1430420-02-2 ]
YieldReaction ConditionsOperation in experiment
39% With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 48h;Inert atmosphere; To a solution of 2-phenylquinoline-4-carboxylic acid (249 mg, 1.0 mmol) and 1,1-dioxo-1H-1lambda6-benzo[b]thiophen-6-ylamine (181 mg, 1.0 mmol) in 10 mL of CH2Cl2 was added DIPEA (387 mg, 3.0 mmol). HBTU (759 mg, 2.0 mmol) was added at 0 C. The resulting mixture was stirred at r.t. for 48 h. The reaction mixture was diluted with EtOAc (300 mL) and washed with water (50 mL). The organic layer was separated and dried with anhydrous Na2SO4. The solution was concentrated to give a crude product, which was further purified with short silica gel column (EtOAc/hexane = 1/1 to 4/1) to obtain the desired product (160 mg, 39%) as a pale yellow solid (mp 277-278 C). HPLC purity 99.2% (tR = 32.39 min). 1H NMR (600 MHz, DMSO-d6) delta 11.29 (s, 1H), 8.44 (s, 1H), 8.38 (d, 2H, J = 7.2 Hz), 8.34 (s, 1H), 8.20 (dd, 2H, J = 5.4 Hz, 13.8 Hz), 7.98 (d, 1H, J = 7.8 Hz), 7.88 (t, 1H, J = 7.2 Hz), 7.54-7.70 (m, 6H), 7.34 (d, 1H, J = 6.6 Hz). 13C NMR (150 MHz, DMSO-d6) delta 165.8, 155.8, 147.9, 142.2, 141.2, 138.0, 137.2, 132.9, 130.5, 130.4, 130.0, 129.7, 129.0, 127.6, 127.3, 126.6, 126.3, 125.1, 124.2, 123.0, 117.1, 117.1, 112.3, 112.3. HRMS (ESI) calcd for C24H17N2O3S 413.0954 (M + H)+, found 413.0959.
39% With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 52h; [00137] To a solution of 2-phenyl-quinoline-4-carboxylic acid (249 mg, 1.0mmol) and 1,1-dioxo-1H-IA6-benzo[b]thiophen-6-ylamine (181 mg, 1.0 mmol) in 10 mL ofDCM was added DIPEA (388 mg, 3.0 mmol). HBTU (569 mg, 1.5 mmol) was added at 0 C.The resulting mixture was stirred at r.t. for 28 h. An additional amount of HBTU (190 mg,0.5 mmol) was added to the solution at 0 C, and the resulting mixture was stirred at r.t. for24 h. A white suspension formed during the reaction. The precipitate was dissolved in DMF(10 mL). The solution was added to the stirring water dropwise. A yellow solid was formed.The solid was filtered and washed with H20. 160 mg of the desired product was obtained as ayellow solid (39% yield). 1H NMR (600 MHz, DMSO-d6) o 11.29 (s, 1H), 8.44 (s, 1H), 8.38(d, 2H, J= 7.2 Hz), 8.34 (s, 1H), 8.20 (dd, 2H, J= 5.4 Hz, 13.8 Hz), 7.98 (d, 1H, J= 7.8 Hz),7.88 (t, 1H, J= 7.2 Hz), 7.54-7.70 (m, 6H), 7.34 (d, 1H, J= 6.6 Hz). 13C NMR (150 MHz,DMSO-d6) o 165.8, 155.8, 147.9, 142.2, 141.2, 138.0, 137.2, 132.9, 130.5, 130.4, 130.0,129.7, 129.0, 127.6, 127.3, 126.6, 126.3, 125.1, 124.2, 123.0, 117.1, 117.1, 112.3, 112.3
  • 29
  • [ 132-60-5 ]
  • [ 20503-40-6 ]
  • [ 1620390-54-6 ]
  • 30
  • [ 132-60-5 ]
  • [ 2627-86-3 ]
  • [ 174635-50-8 ]
YieldReaction ConditionsOperation in experiment
94% With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 3h; 1 2-Phenyl-guinoline-4-carboxylic acid {1-phenyl-ethyl)amide (HJC-1-28) [00138] To a solution of 2-phenyl-quinoline-4-carboxylic acid (249 mg, 1.0mmol) and L(-)-a-methylbenzylamine (127 mg, 1.05 mmol) in 10 mL of DCM was added DIPEA (388 mg, 3.0 mmol). HBTU (569 mg, 1.5 mmol) was added at 0 °C. The resultingmixture was stirred at r.t. for 3 h. The reaction mixture was diluted with DCM (80 mL) andwashed with water (20 mL ). The organic layer was separated and dried with anhydrousNa2S04. The solution was concentrated to give a crude product, which was purified withsilica gel column (EtOAc/hexane = 1/3) to obtain HJC-1-28 (330 mg, 94%) as a white solid.1H NMR (600 MHz, DMSO-d6) o 8.03-8.07 (m, 3H), 7.97 (d, 1H, J = 8.4 Hz), 7.71 (s, 1H),7.67 (t, 1H, J= 7.2 Hz), 7.28-7.48 (m, 9H), 6.78 (d, 1H, J= 7.2 Hz), 5.38-5.43 (m, 1H), 1.66(d, 3H, J = 6.6 Hz). 13C NMR (150 MHz, DMSO-d6) o 166.8, 156.7, 148.6, 142.9, 142.7,138.8, 130.1, 130.0, 130.0, 129.8, 128.9, 127.8, 127.6, 127.3, 126.4, 125.0, 125.0, 123.4,116.4, 116.3, 49.7, 22.0.
  • 31
  • [ 132-60-5 ]
  • [ 143300-64-5 ]
  • 4-[4-(N,N-diethylamino)piperidin-1-ylcarbonyl]-2-phenylquinoline [ No CAS ]
YieldReaction ConditionsOperation in experiment
31% With dmap; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃; 18 4-[4-(N,N-diethylamino)piperidin-l-ylcarbonyl1-2-phenyl-quinoline To 500 mg (2 mmol) of commercially available 2-phenyl-4-quinolinecarboxylic acid in 10 ml of dichloromethane were added 376 mg (2.41 mmol) of 4-diethylamino-piperidine, 335 μ (2.41 mmo) of triethylamine, 462 mg of (2.41 mmol) of l-ethyl-3-(3- dimethylaminopropyl)carbodiimide and 325 mg (2.41 mmol) of hydroxybenzotriazole. The mixture was stirred overnight at room temperature and diluted with dichloromethane. The organic layer was washed with water, dried over MgS04, filtered and concentrated to give 1.11 g of yellow oil. This compound was purified by silica gel column chromatography (20 g dichloromethane then dichloromethane / ethyl acetate 1 : 1 then ethyl acetate 100%) to give 692 mg of impure sticky white foam. This product was additionally purified by silica CI 8 reversed-phase column Biotage (100 g -water / methanol 1: 1) to give 565 mg of still impure pale yellow oil. This oil was solubilized in ethyl acetate and the solution was extracted with a IN HCl aqueous solution. The aqueous layer was basified with IN NaOH aqueous solution and the solution was extracted with ethyl acetate. The organic layer was dried over MgS04, filtered and concentrated to give 241 mg (yield 31 ) of clear sticky solid corresponding to 4-[4-(N,N- diethylamino)piperidin- 1 -ylcarbonyl] -2-phenyl-quinoline. HPLC-MS: conditions D: tT = 5.24 min, (ES+) C25H29N30 requires 387; found 388 [M + H], purity 99 %. 1H NMR (300 MHz, CDC13).
  • 32
  • [ 132-60-5 ]
  • [ 143300-64-5 ]
  • 4-[4-(N,N-diethylamino)piperidin-1-ylcarbonyl]-2-phenylquinoline dihydrochloride [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: dmap; benzotriazol-1-ol; triethylamine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 20 °C 2: hydrogenchloride / dichloromethane; diethyl ether / 2 h / 20 °C / Inert atmosphere
  • 33
  • [ 132-60-5 ]
  • [ 97-50-7 ]
  • N-(5-chloro-2, 4-dimethoxyphenyl)-2-phenylquinoline-4-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
General procedure: Method 1: To a 25 mL round-bottom flask, 2-phenyl-4-quinolinecarboxylic acid 4a-n (1.5 mmol) and substituted aniline(1.5 mmol) were added, dissolved in appropriate DMF and followed by the addition of HOBT (1.5 mmol) with stirring. After 15 min, EDCI (1.5 mmol) and TEA (1.5 mmol) were added and the reaction mixture was stirred for 4 h at room temperature. The reaction solution was poured into water and the product was extracted with EtOAc three times. The combined organic phases were washed with HCl (1 N), NaHCO3 (1 N), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give crude product. The crude compound was then purified by recrystallization to afford compounds 5-9.
  • 34
  • [ 132-60-5 ]
  • [ 108-00-9 ]
  • [ 124340-46-1 ]
YieldReaction ConditionsOperation in experiment
93% With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃;
93% Stage #1: cinchophen With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide for 0.0333333h; Inert atmosphere; Stage #2: N,N-dimethylethylenediamine In N,N-dimethyl-formamide at 20℃; Inert atmosphere; I General Procedure of Amide Coupling. General procedure: To a DMF solution of carboxylic acid (1 mmol) was added HATU (1 mmol) and DIEA (1.2 mmol). After stirring for 2 minutes, amine (1 mmol) was added. The resulting solution was stirred overnight at room temperature. The reaction was diluted with dichloromethane and extracted with aqueous NaHCO3 solution, followed by brine. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (1-10% CH3OH/CH2Cl2) to give the final product.
  • 35
  • [ 108-01-0 ]
  • [ 132-60-5 ]
  • [ 740757-60-2 ]
YieldReaction ConditionsOperation in experiment
75.1% With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; Inert atmosphere; 1.1.3 General procedures for the synthesis of compounds 5 by HATU coupling General procedure: To a solution of quinoline 4-carboxylic acid (3) (1 equiv) in DMF was added amine (1 equiv) and DIEA (1 equiv). Then HATU (1 equiv) was added in one portion and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane and extracted with aqueous NaHCO3 solution and brine. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The mixture was then purified by silica gel flash column chromatography (0-10% CH3OH/CH2Cl2) to give the final product.
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