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CAS No. : | 486-74-8 | MDL No. : | MFCD00006782 |
Formula : | C10H7NO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | VQMSRUREDGBWKT-UHFFFAOYSA-N |
M.W : | 173.17 | Pubchem ID : | 10243 |
Synonyms : |
Cinchoninic acid (6CI,7CI,8CI);4-Carboxyquinoline
|
Chemical Name : | Quinoline-4-carboxylic acid |
Num. heavy atoms : | 13 |
Num. arom. heavy atoms : | 10 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 48.7 |
TPSA : | 50.19 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -7.03 cm/s |
Log Po/w (iLOGP) : | 1.31 |
Log Po/w (XLOGP3) : | 0.46 |
Log Po/w (WLOGP) : | 1.93 |
Log Po/w (MLOGP) : | 0.23 |
Log Po/w (SILICOS-IT) : | 1.82 |
Consensus Log Po/w : | 1.15 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | -1.71 |
Solubility : | 3.4 mg/ml ; 0.0196 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.08 |
Solubility : | 14.3 mg/ml ; 0.0827 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -3.07 |
Solubility : | 0.147 mg/ml ; 0.000851 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.06 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With thionyl chloride; In toluene; for 1h;Heating / reflux; | Example 134A Quinoline-4-carbonyl chloride A solution of 4-quinolinecarboxylic acid (Aldrich, 0.25 g, 1.4 mmol) in 5 mL of thionyl chloride was warmed to reflux and allowed to stir for 1 hour. The mixture was then cooled to ambient temperature and concentrated under reduced pressure. This material was dissolved in 10 mL toluene and concentrated under reduced pressure (3*) to afford the title compound. | |
With thionyl chloride; for 1h;Heating / reflux; | A solution of 4-quinolinecarboxylic acid (Aldrich, 0.25 g, 1.4 mmol) in 5 mL of thionyl chloride was warmed to reflux and allowed to stir for 1 hour. The mixture was then cooled to ambient temperature and concentrated under reduced pressure. This material was dissolved in 10 mL toluene and concentrated under reduced pressure (3X) to afford the title compound | |
With thionyl chloride; N,N-dimethyl-formamide; at 40℃; for 3h; | A suspension of quinoline 4-carboxylic acid (1.13 g, 6.53 mmol) and DMF (3 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 DCM (50 mL) and MeNHOMe*HCl (0.96 g, 9.8 mmol) and Et3N (2.7 mL, 19.6 mmol) was added. The mixture was stirred at 20 °C for 16 h. The resulting solution was diluted with DCM (100 mL) and washed with water (2 .x. 30 mL), washed with brine (30 mL), dried and the solvent evaporated. The residue was purified by column chromatography, eluting with EtOAc, to give amide 69 (1.36 g, 96percent) as soft solid |
With thionyl chloride;N,N-dimethyl-formamide; at 40℃; for 3h;Product distribution / selectivity; | Example 1-106 7V-(3-Methylphenyl)-4-(4-quinolinyl)-l,3-thiazol-2-amine (192). [0398] 7V-Methyl-7V-(methyloxy)-4-quinolinecarboxamide (189). A suspension of quinoline 4-carboxylic acid (1.13 g, 6.53 mmol) and DMF (3 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 DCM (50 mL) and MeNHOMeetaCl (0.96 g, 9.8 mmol) and Et3N (2.7 mL, 19.6 mmol) was added. The mixture was stirred at 20 0C for 16 h. The resulting solution was diluted with DCM (100 mL) and washed with water (2 x 30 mL), washed with brine (30 mL), dried and the solvent evaporated. The residue was purified by column chromatography, eluting with EtOAc, to give amide 189 (1.36 g, 96percent) as soft solid: 1H NMR (CDCl3) delta 8.97 (d, J= 4.3 Hz, 1 H, H-2), 8.16 (d, J= 8.5 Hz, 1 H, H-5), 7.87 (d, J= 8.3 Hz, 1 H, H-8), 7.73-7.78 (m, 1 H, H-7), 7.56-7.62 (m, 1 H, H-6), 7.39 (d, J= 4.3 Hz, 1 H, H-3), 3.47 (s, 3 H, OCH3), 3.41 (s, 3 H, NCH3); MS m/z 216.4 (MH+, 100percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | <strong>[486-74-8]Quinoline-4-carboxylic acid</strong> (580 mg, 3.35 mmol) was dissolved in an aqueous potassium hydroxide solution (1 M, 10 mL). Nickel/aluminum amalgam (3 g) was added in portions over 1.5 hours. The heterogeneous mixture was stirred at room temperature for 48 hours. Upon completion, the reaction was filtered through Celite.(R). and washed with ethyl acetate. The pH of the aqueous layer was adjusted with concentrated hydrochloric acid to 4-5. Solid sodium chloride was added until the aqueous layer was saturated. The ethyl acetate layer was separated. The aqueous phase was extracted with ethyl acetate. The extracts were combined, washed with minimal brine, dried over sodium sulfate, filtered, and concentrated. l,2,3,4-Tetrahydro-quinoline-4-carboxylic acid was used without further purification (389 mg, 66percent). 1H-NMR (CDCl3) delta: 1.95 - 2.08 (m, IH), 2.22 - 2.37 (m, IH), 3.23 - 3.34 (m, IH), 3.39 - 3.49 (m, IH), 3.79 (dd, IH), 6.56 (d, IH), 6.69 (dd, IH), 7.07 (dd, IH), 7.17 (d, IH). MS m/z: 178 (M+l). | |
With hydrogen;nickel; In methanol; at 20℃; under 3102.97 Torr; for 19h; | Example 31; N-(1-benzyl-1,2,3,4-tetrahydroquinolin-4-yl)-N'-1H-indazol-4-ylurea; Example 31A; 4.35 g (25.1 mmol) quinoline-4-carboxylic acid was added to 125 mL methanol and 8.7 g Raney nickel in a Parr shaker. The reactor was sealed and flushed with nitrogen, and then was pressurized with 60-psi hydrogen. The mixture was shaken at ambient temperature for 19 hours. After the reactor was flushed with nitrogen, the Raney nickel was filtered off and washed with methanol, and the filtrate was concentrated to provide 5.25 g of Example 31A. | |
With sodium hydroxide;Raney nickel; In water; | Example 73; rac- 4-(lH-Imidazol-2-ylmethyl)-l,2,3,4-tetrahydro-quinoline; a) rac-1, 2,3,4- Tetrahvdro-quinoline-4-carboxylic acidrac- 1, 2,3,4- Tetrahydro-quinoline-4-carboxylic acid was prepared from quinoline-4- carboxylic acid by treatment with Raney nickel in aqueous sodium hydroxide according to the procedure described in Khimiya Geterotsiklicheskikh Soedinenii 1988, 77-9; brown <n="66"/>crystals; 1H-NMR (CDCl3): 2.04 (IH, m), 2.29 (IH, m), 3.24-3.46 (br m, 3 H, CH2N and NH), 3.77 (IH, t, CHCO2), 6.55 (IH, d, ArH), 6.67 (IH, dd, ArH), 7.04 (IH, dd, ArH), 7.15 (1H, d, ArH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
5.8 g (87%) | With thionyl chloride; In dichloromethane; | (a) 4-Quinolinecarboxylic acid chloride hydrochloride To 4-quinolinecarboxylic acid (5.0 g, 29.1 mmol) at 0° C. under argon was added thionyl chloride (20.0 ml, 0.27 mol). The reaction mixture was slowly warmed to room temperature and stirred for 1 hour. Dichloromethane (100 ml) was added and the reaction mixture was refluxed for 3 hours. The solvents were removed by distillation and the residue was dried at 130° C. in high vacuum to afford 5.8 g (87percent) of 4-quinolinecarboxylic acid chloride hydrochloride as a green crystals, m.p. 249°-251° C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
solid phase synthesis; Yield given. Multistep reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With thionyl chloride; at 0 - 60℃;Inert atmosphere; | [399] Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed quinoline-4-carboxylic acid (1 g, 5.77 mmol, 1.00 equiv), methanol (25 mL), thionyl chloride (1.38 g, 2.00 equiv) was added at 0°C. The resulting solution was stirred overnight at 60 °C. After cooled to room temperature, the resulting mixture was concentrated under vacuum. This resulted in 1 g (93percent) of methyl quinoline-4-carboxylate as yellow oil. MS: (ES, m/z) [M+H]+: 188. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 20℃; for 10h; | To a solution of quinoline-4-carboxylic acid (1.0 g) in methylene chloride (20 ml) were added 1,3- dicyclohexylcarbodiimide (1.2 g), 4-(dimethylamino)pyridine (0.07 g) and morpholinoethyl resorcinol (1.28 g), and stirring was conducted for 10 hrs at room temperature. The reaction solution was filtered, concentrated in a vacuum, and subjected to extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated in a vacuum, followed by purification through silica gel column chromatography to afford the object compound (1.6 g, 73percent).1H NMR(300 MHz, CDCl3) delta 9.01 - 6.54(m, 10H), 4.14(t, 2H), 3.72(t, 4H), 2.83ft 2H), 2.57ft 4H); <n="32"/>MS m/z 378(M+) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 20℃; for 10h; | To a solution of quinoline-4-carboxylic acid (1.0 g) in methylene chloride (20 ml) were added 1,3- dicyclohexylcarbodiimide (1.2 g), 4-(dimethylamino)pyridine (0.07 g) and morpholinoethyl catechol (1.28 g), and stirring was conducted for 10 hrs at room temperature. The reaction solution was filtered, concentrated in a vacuum, and subjected to extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated in a vacuum, followed by purification through silica gel column chromatography to afford the object compound (1.3 g, 59percent).1H NMR(300 MHz, CDCl3) delta 9.12 - 7.05(m, 10H), 4.19(t, 2H), 3.50(t, 4H), 2.71(t, 2H), 2.40(t, 4H);MS m/z 378(M+) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: hydrobromic acid / Heating 2: phosphorus trichloride 3: Heating 4: aq. base |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; HATU; In DMF (N,N-dimethyl-formamide); at 20℃; for 16h; | To a solution OF 4- [ (Z)- (4-BROMOPHENYL) (ethoxyimino) METHYL]-1- (4-METHYL-4- piperidinyl) piperidine (240 mg, 0.59 MMOL), quinoline-4-carboxylic acid (112 mg, 0.64 MMOL) and Et3N (119 mg, 1. 18 MMOL) in DMF (2 mL), HATU (290 mg, 0.76 MMOL) was added at room temperature. After 16 h, the reaction mixture was poured into ice water, and the solid was collected by filtration. Further purification by flash chromatography afforded title compound.'H NMR (DMSO-d6) 8 0.9 (s, 3H), 1. 18 (t, 3H), 1.22-1. 85 (m, 7H), 1. 98-2. 18 (m, 3H), 2.39 (m, 1H), 2.75 (m, 1 H), 2.96 (m, 2H), 3.31 (q, 1 H), 3.50 (q, 1H), 4.04 (q, 2H), 4.26 (m, 1 H), 7.09 (m, 2H), 7.28 (m, 1H), 7.5 (m, 2H), 7.58 (q, 1H), 7.71-7. 85 (m, 2H), 8.13 (d, 1H), 8.92 (d, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; HATU; In DMF (N,N-dimethyl-formamide); at 20℃; for 16h; | To a solution OF 4- [ (4-BROMOPHENYL) (2-PYRIDINYLOXY) METHYL]-1- (4-METHYL-4- piperidinyl) piperidine (220 mg, 0.5 MMOL), quinoline-4-carboxylic acid (110mg, 0.64 MMOL), and Et3N (192 mg, 1.9 MMOL) in DMF (5 mL) was added HATU (260 mg, 0.68 MMOL) at room temperature. After 16 h the reaction mixture was poured into ice water. The solid was collected by filtration, dissolved in CH2CI2, and dried over NA2SO4. Concentration and purification by flash chromatography (CH2CI2-MEOH, 95: 5 to 9: 1) afforded the title compound as a light yellow POWDER. HNMR (CDCI3, 400MHZ) : LC-MS. 598 (M+). H NMR (CDCL3) No. 0.91 (s, 3H), 1.16-2. 14 (m, 11H), 2.74 (m, 1 H), 2.96 (m, 2H), 3.30 (m, 1H), 3.56 (m, 1 H), 4.06 (q, 2H), 4.24 (m, 1H), 5.80 (m, 1H), 6.75 (m, 2H), 7.25 (m, 1H), 7.30 (d, 1H), 7.42 (m, 2H), 7.50-7. 65 (m, 2H), 7.75 (m, 1H), 7.85 (m, 1H), 8. 05 (m, 1H), 8.15 (d, 1H), 8.95 (d, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32% | [0124] To the solution of compound of Example 1 (120 mg, 0.136 mmol), catalytic amount of dimethylaminopyridine and 4-quinolinecarboxylic acid (50 mg, 0.29 mmol) in CH2Cl2 (2 mL) was added 1,3-dicyclohexylcarbodiimide (120 mg, 0.58 mmol). The reaction was stirred at room temperature for 24 h before being diluted with methanol (5 mL) and stirred for another 24 h. The solvent was then removed and the residue was dissolved in ethyl acetate (50 mL). The resulting organic solution was washed with sat. aq. NaHCO3 and brine, and dried over MgSO4, and concentrated. Purification by chromatography (silica gel, 94:6:0.3 dichloromethane/methanol/conc. NH4OH) yielded 43 mg (32percent) of the title compound. MS 993 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | Example 36; Synthesis of l-quinolin-4-yl-ethanone; [0135] Commercially available 4-quinolinecarboxylic acid was converted to the Weinreb amide in 100 percent yield. The Weinreb amide was converted to 4-acetylquinoline by reaction with methylmagnesium iodide in 50 percent yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride;benzotriazol-1-ol; In dichloromethane; for 16h; | A mixture of the appropriate trans-2- (2- (1- (4-amino) cyclohexyl) ethyl)-2, 3,4, 5- tetrahydro-1 H-3-benzazepine (0.35 mmol), the appropriate acid (0.35 mmol), 1- ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.35 mmol), 1- hydroxybenzotriazole (catalytic amount) and dichloromethane (5ml) was shaken for 16h. Saturated sodium bicarbonate (4ml) was then added and the mixture shaken for 0.25h. Chromatography of the organic layer on silica with 50-100percent ethyl acetate in hexane and 0-10percent methanol in ethyl acetate gradient elution gave the title compounds. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; | Example 63 Synthesis of 4-[(4-Quinolinylcarbonyl)amino]-L-phenylalanine on Wang Resin A 250 mL cylindrical glass vessel equipped with a coarse glass frit was charged with <strong>[95753-56-3]4-amino-N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-phenylalanine</strong> (10 g) obtained in Example 62 and a solution prepared from quinoline-4-carboxylic acid (5.2 g, 30 mmol), BOP (13.75 g, 30 mmol) and diisopropylethylamine (6.8 mL) in 70 mL of N-methylpyrrolidinone. The slurry was agitated for 4 hr. The mixture was filtered and washed with dichloromethane (2*100 mL), methanol (2*100 mL) and dimethylformamide (2*100 mL). To the washed resin was added a solution of 25% piperidine in N-methylpyrrolidinone (80 mL), the mixture was agitated at room temperature for 20 minutes and filtered. The process was repeated and the resulting slurry was filtered and washed with dichloromethane (2*100 mL), methanol (2*100 mL) and dimethylformamide (2*100 mL). Filtration afforded 4-[(4-quinolinylcarbonyl)amino]-L-phenylalanine on Wang resin suitable for use in the next step. | |
With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; | Example 37 Synthesis of 4-[[(4-quinolinyl)carbonyl]amino]-L-phenylalanine on Wang resin A 250 mL cylindrical glass vessel equipped with a coarse glass frit was charged with <strong>[95753-56-3]4-amino-N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-phenylalanine</strong> on Wang resin (10 g) obtained in Example 36 and a solution prepared from quinoline-4-carboxylic acid (5.2 g, 30 mmol), BOP (13.75 g, 30 mmol) and diisopropylethylamine (6.8 mL) in 70 mL of NMP. The slurry was agitated for 4 hours. The mixture was filtered and washed with dichloromethane (2*100 mL), methanol (2*100 mL) and dimethylformamide (2*100 mL). To the washed resin was added a solution of 25% piperidine in NMP (80 mL), the mixture was agitated at room temperature for 20 minutes and filtered. The process was repeated and the resulting slurry was filtered and washed with dichloromethane (2*100 mL), methanol (2*100 mL) and dimethylformamide (2*100 mL). Filtration afforded 4-[[(4-quinolinyl)carbonyl]amino]-L-phenylalanine on Wang resin suitable for use in the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With sodium hydroxide; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In methanol; ethanol; water; ethyl acetate; N,N-dimethyl-formamide; | Example 27 Synthesis of N-[(1-Phenylcyclopentyl)carbonyl]-4-[(4-quinolinylcarbonyl)amino]-L-phenylalanine Sodium Salt To a solution of 4-amino-N-[(1-phenylcyclopentyl)carbonyl]-L-phenylalanine methyl ester (81 mg, 0.2 mmol) and 4-quinolinecarboxylic acid (43.3 mg, 0.25 mmol) in 1 nL of DMF was added HBTU (95 mg, 0.25 mmol) and diisopropylethylamine (65 muL, 0.5 mmol) at room temperature. The mixture was then stirred at this temperature for overnight. The reaction was then diluted with 15 mL of ethyl acetate and was washed with water (2 mL), saturated NaHCO3 (2*2 mL) and saturated brine (2*2 mL). The solution was dried (MgSO4) and concentrated. The residue was hydrolyzed with 0.5 mL of 1N NaOH in 5 mL of ethanol at 25° C. overnight. The crude product was purified by passing through an open C-18 column eluding with water (200 mL), 30percent methanol in water (200 mL), 40percent methanol in water (200 mL) and pure methanol (200 mL). The fractions containing product were concentrated and lyophilized to give N-[(1-phenylcyclopentyl)carbonyl]-4-[(4-quinolinylcarbonyl)amino]-L-phenylalanine sodium salt (79.5 mg, 75percent), HR-FABMS: obs. mass, 530.2056. Calcd. mass, 530.2058. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; | EXAMPLE 1 (2R,4S)-N-[1-(3,5-Bis-trifluoromethyl-benzoyl)-2-benzyl-piperidin-4-yl]-quinoline-4-carboxamide 2.95 g (11.6 mmol) of bis(2-oxo-3-oxazolidinyl)phosphinic acid chloride are added at 0 C. to a solution of 4.16 g (9.67 mmol) of (2R,4S)-2-benzyl-1-(3,5-bis-trifluoromethyl-benzoyl)-4-piperidineamine [EP 532 456 A1, Example 38 f], 1.84 g (10.6 mmol) of quinoline4-carboxylic acid and 3 ml (21.3 mmol) of triethylamine in 30 ml of methylene chloride and the ice bath is removed after 10 minutes. The reaction mixture is stirred for 4 hours at room temperature and then diluted with methylene chloride. The organic phase is extracted with aqueous 10% citric acid and with 1 N potassium carbonate solution, washed with brine, dried over magnesium sulfate and concentrated to dryness by evaporation. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98.6% | In ethyl acetate; | Step 1 Method was as described for Example 36, Step 1, but using quinoline-4-carboxylic acid. The crude reaction mixture was chromatographed on silica gel using ethyl acetate as a eluant to obtain quinoline-4-carboxylic acid methylester (28.6 g, 98.6percent) as a oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With nitric acid In sulfuric acid | 8 (1R,5S,6S,8R,2'S,4'S)-2-(2-(4-Carboxyquinol-8-ylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapenem-3-carboxylic Acid Disodium Salt The starting material was prepared as follows: To a suspension of 4-carboxyquinoline (5 g; 28.9 mM) in concentrated sulphuric acid (10 ml) was added, at 65° C., fuming nitric acid (9 ml) and concentrated sulphuric acid (9 ml). After stirring at 75° C for 30 minutes, the mixture was poured onto ice; the pH adjusted to pH3 and the resulting precipitate filtered and dried to give a mixture of 4-carboxy-8-nitroquinoline and 4-carboxy-5-nitroquinoline which was not separated (4.4 g; 70%). NMR (DMSO-d6): 8 7.97-8.03 (m, 2H); 8.37 (d, 1H); 8.47 (d,! H); 9.19 (d, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With potassium carbonate; In water; acetone; | Preparation of Ethyl-N-ethoxycarbonyl-o-aminobenzoate 2 To an ice cooled solution of ethyl-o-aminobenzoate 1 (33 g, 0.2 mole) in acetone (270 ml) was added with stirring an ice cooled solution of potassium carbonate (36.7 g, 0.27 mole) in water (214 ml) followed by addition of ethyl chloroformate (43 g, 0.4 mole). Stirring was continued at 0° C. for 11/2 hour and at 25° C. for 2 hours. The mixture was poured in water (300 ml) and extracted with three 300 ml portions of ether. The combined and dried (MgSO4) ether phases were evaporated in vacuo to give pure 2 (46.7 g, 98percent). The product was recrystallized (EtOH, H2 O) to give colorless crystals, mp <40° C. (Calc. for C12 H15 NO4: C 60.75; H 6.37; N 5.90). (Found C 60.75; H 6.29; N 5.85) 1 H NMR (CDCl3) delta= 1.3 (3H, t, J=7 Hz) 1.4 (3H, t, J=7 Hz) 4.2 (2H, q, J=7 Hz) 4.3 (2H, q, J=7 Hz) 6.9-8.5 (4H, AA'BB'). IR (CCl4): 3300(m), 2980(m), 1735(s), 1690(s), 1600(s), 1510(w), 1450(s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | In acetic acid; | EXPERIMENTAL SECTION A solution of 4-quinoline carboxylic acid (1.5 g., 8.6 mmoles) in acetic acid (30 ml) containing 5percent Rh/Al2 O3 (400 mg) was reduced (4.2 kg, 85° C.) in a steel bomb for 15 hours. After cooling, the catalyst was filtered and the solvent was evaporated to dryness. The residue was triturated with EtOH/Et2 O (50/50), filtered and washed with a minimum of Et2 O to give pure 4-decahydroquinoline carboxylic acid (1.4 g, 90percent) as white crystals, mp >300° C., see Burckhardt, Helferick, L. Wissel, J. Prak. Chim. 39 (1966). An analytical sample of its hydrochloride salt was recrystallized in acetonitrile/water. (Found: C 54.19; H 8.62; N 6.33. Calc. for C10 H18 ClNO2: C 54.66 H 8.26; N 6.38). 1 H NMR 400 MHz (H2 O) delta=1.3-1.5 (4H, m) 1.67-1.76(1H,m) 1.82-2.04 (5H, m) 2.29-2.4 (1H, m) 2.62-2.7 (1H, d t) 3.01-3.17 (1H, m) 3.46-3.57 (2H,m) 7.89 (1H, broad s, exchangeable D2 O) 8.29 (1H broad s, exchangeable D2 O). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | DIEA (51 mul, 0.29 mmol), 4-quinoline carboxylic acid (33 mg, 0.19 mmol) and TBTU (74 mg, 0.23 mmol) were added to a solution of methyl 3-(5-[l,2,3,6- tetrahydropyridin-4-yl]pyridin-2-yl)-N-(2,6-dichlorobenzoyl)-L-alaninate (83 mg, 0.19 o mmol) in DMF (2 ml). The solution was stirred at room temperature for 4 hours. A solution of 2nu LiOH (210 mul, 0.42 mmol) was added. After stirring overnight, the crude mixture was filtered and purified by reverse phase chromatography using a gradient of acetonitrile in water containing ammonium carbonate (4g/l). After evaporation and trituration in methylene chloride/ether, the title compound was obtained as a white solid s (33 mg, 61percent); 1H NMR spectrum fDMSO-d + CD3COOD, 500 MHz): presence of 2 rotamers (nearly 50/50) 2.35 (bs, IH), 2.71 (bs, IH), 3.09 (dd, IH), 3.29 (dd, IH), 3.37 (bs, IH), 3.67-4.60 (bs, 4H), 4.96 (dd, IH), 6.04 (bs, 0.5H), 6.39 (bs, 0.5H), 7.29 (d, IH), 7.34- 7.44 (m, 3H), 7.50-7.59 (m, IH), 7.62-7.89 (m, 4H), 8.10-8.17 (m, IH), 8.56-8.62 (m, IH), 8.97-9.03 (m, IH); Mass spectrum (M+H)+ = 575. |
Yield | Reaction Conditions | Operation in experiment |
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54.9% | 11.5 <strong>[486-74-8]Quinoline-4-carboxylic acid</strong> trans(4-{2[4-(2-chloro-4-fluoro-phenoxy)-piperidin-1-yl]-ethyl}-cyclohexyl)-amide The title compound was prepared as follows. <strong>[486-74-8]Quinoline-4-carboxylic acid</strong> (0.020 g, 0.115 mmol), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyl uronium tetrafluoroborate (0.035 g, 0.106 mmol) and (0.05 mL, 0.318 mmol) of N-ethyldiisopropylamine were stirred in 0.5 mL of dimethylformamide (DMF) for 0.5 h at room temperature and Trans-4-{2-[4-(4-Fluoro-phenoxy)-piperidin-1-yl]-ethyl}-cyclohexylamine; trifluoro-acetic acid salt (0.050 g, 0.106 mmol) was added. The mixture was stirred for 12 hours at room temperature. The mixture was concentrated to dryness and the residue was taken up on methanol and purified with preparative HPLC on reversed phase eluding with acetonitrile/water. The combined product fractions were evaporated under reduced pressure to yield 0.054 g of a off-white solid (0.101 mmol, 54.9percent). MS (m/e): 510.2 (M+H+). |
Yield | Reaction Conditions | Operation in experiment |
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59% | With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; | EXAMPLE 49; 2-[fOuinoline-4-carbonyl)-aminol-indan-2-carboxylic acid ethyl ester (49):To a solution of quinoline-4-carboxylic acid (301mg, 1.74mmol), 2-amino-indan-2-carboxylic acid ethyl ester (357mg, 1.74mmol), HATU (992mg, 2.61mmol) in anhydrous DMF (8mL) is added DIPEA (431muL, 2.61mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (4OmL) and washed with water (1 x 1OmL) and brine (2 x 1OmL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (12Og silica gel, gradient elution: 5-70percent EtOAc in heptane) to give a pure product (49) as a pale yellow solid (370mg, 59percent).1H NMR (CDCl3, 300MHz): delta 1.34(t, 3H), 3.48(d, 2H), 3.82(d, 2H), 4.34(q, 2H), 6.86(s, IH), 7.21-7.29(m, 5H), 7.51-7.56(m, IH), 7.65-7.71(m, IH), 7.98(d, IH), 8.18(d, IH), 8.73(d, IH)73 <n="75"/>LC/MS (ES+) m/z = 361.14 |
Yield | Reaction Conditions | Operation in experiment |
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65% | To a solution of quinoline-4-carboxylic acid (182 mg, 1.05 mmol) in benzene (5 ml) were added diphenylphosphoryl azide (226 mul, 1.05 mmol) and triethylamine (146 mul, 1.05 mmol), and the mixture was refluxed for 3 hours . To this was added a solution of the compound in Example 81 (200 mg, 523 mumol) in N,N-dimethylformamide (1 ml), and the mixture was refluxed further for 2 hours. Ethyl acetate was added to the reaction mixture, which was washed with brine, then dried over anhydrous magnesium sulfate, and solvent was distilled off. The residue obtained was purified by means of silica gel column chromatography [methylene chloride-ethanol [30:1 7:1)] to obtain 188 mg of ethyl 3,4-dihydro-3-oxo-7-((4-(N-(4-quinolyl)carbamoyloxy)methyl)-imidazole-1-yl)-6-trifluoromethylquinoxaline-2-carboxylate as yellow powder. Yield 65percent. To a solution of the ethyl ester (150 mg, 272 mumol) obtained in ethanol (3 ml) were added 1N aqueous solution of lithium hydroxide (950 mul, 950 mumol) and water (3 ml), and the mixture was stirred for 1.5 hours at 50° C. After cooling, ice water was added and the insolubles were filtered off. After dissolved these by adding 3N hydrochloric acid, the insolubles were filtered off. The filtrate was purified with synthetic adsorbent Sepabeads.(R). SP850 [water-acetonitrile (20:1-->5:1)] and recrystallized from water to obtain 10.3 mg of the title compound as light brown powder. Yield 7percent. mp 239-241° C. (decomposition). HR-FAB-:523.0975 (-0.2 mmu). |
Yield | Reaction Conditions | Operation in experiment |
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To a stirred solution of 4- [4- [1- (4-bromophenyl) ethenyl]-4-piperidinyl] 4-methyl-1- piperidinecarboxylic acid, dimethylethyl ester (51 mg, 0.11 MMOL) in CH2CI2 (2 mL) was added TFA (1 mL) at room temperature. After 2 h, the reaction was concentrated in vacuo and dried over vacuum. The crude product was dissolved in DMF (2 mL), then 4-QUINOLINECARBOXYLIC acid (21 mg, 0.12 MMOL), Et3N (22 mg, 0. 22 MMOL), and HATU (55 mg, 0.14 MMOL) was added at room temperature. After 16 h the mixture was poured into ice water (10 mL), and extracted with CH2CI2 (3x10 mL). The organic phase was dried over NA2SO4, and concentrated in vacuo. The crude product was purified by preparative TLC to afford the title compound. MS: 518 (M+). H NMR (CDCl3, 400MHz) 6 0.93 (d, 3H), 1.1-1. 62 (m, 4H), 1.62-1. 9 (m, 3H), 1.98-2. 22 (m, 3H), 2.24-2. 42 (m, 1H), 2.7-2. 88 (m, 1H), 2.9-3. 1 (m, 1H), 3.24-3. 42 (m, 1H), 3.5-3. 7 (m, 1H), 4.17- 4.4 (m, 1H), 5.0-5. 1 (s, 1H), 5.1-5. 22 (s, 1H), 7.14-7. 23 (m, 2H), 7.28-7. 36 (m, 1H), 7.4-7. 48 (m, 2H), 7.54-7. 66 (m, 1H), 7.72-7. 9 (m, 2H), 8.1-8. 2 (d, 1H), 8.9-9. 0 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
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To a stirred solution OF 4- [4- (4-BROMOPHENYL) HYDROXYMETHYL]-1-PIPERIDINYL]-4-METHYL-1- piperidinecarboxylic acid 1, 1-diemthylethyl ester (1.03 g, 2.2 MMOL) in CH2CI2 (10 ML) was added TFA at room temperature. After 2 h the reaction mixture was concentrated in vacuo, and dried under vacuum. The product was dissolved in DMF (10 mL), and quinoline-4-carboxylic acid (450mg, 2. 6MMOL), Et3N (1. 0mL, 7. 2MMOL), and HATU (1. 1G, 2.9 MMOL) was added at room temperature. After 16 h, the reaction mixture was poured into ice water while stirring vigorously. The solid was collected by filtration, and was re-dissolved in CH2CI2 AND dried over NA2SO4. Concentration and purification by flash chromatography (CH2CI2-MEOH, 100: 1 to 100: 2 to 100: 4) afforded the title compound as a brown powder. MS: 523.1 (M++1). TH NMR (CD3) No. 0.92 (s, 3H), 1.27-2. 14 (m, 10H), 2.72-3. 00 (m, 3H), 3.33 (m, 1H), 3.60 (m, 1H), 4.21 (m, 1H), 4.38 (m, 1H), 7.19 (m, 2H), 7.31 (m, 1H), 7. 48 (m, 2H), 7.62 (m, 1H), 7.77-7. 86 (m, 2H), 8.15 (br. d, 1 H), 8.94 (m, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
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68% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 20h; | d) Quinoliotane-4-carboxylic acid ((S)-3-(benzoyl-methyl-amiotano)-4-phenyl-butyl]-amiotade N-((S)-3-Amino-1-benzyl-propyl)-N-methyl-benzamide (100mg, 0.35 mmo.) , quinoline-4- carboxylic acid (74 mg, 0 43 mmol), HOBt (65 mg, 0.43 mmol). EDC x HCI (102 mg, 0.53 mmo.) and tpiethylamine (143 mg, 1.42 mmol) were dissolved in DCM (10 ml) and stirred at rt for 20 h, The mixture was diluted with EtOAc, washed with NaHCO3- and NaCI-soln , dried (Na2SO4), filtered and concentrated The crude product was purified by chromatography (Flashrnaster, DCM to DCM:MeOH 97:3 over 20 mm ) to yield 105 mg (68percent) of the title compound as white solid. [1 H-NMR (DMSO, 600 MHz) 8 97-8.95 (m, 1 H)1 8.78/8 72 (t, 1 H), 8.17-7.02 (m, 14 H), 6.62 (d, 1H), 5 01/3 74 (br s. 1 H), 3 42-3 35/3.15-3 10 (m, 2H). 2 98- 2.72 (m, 2H), 2.99/2.68 (s, 3H), 2 00-1.77 (m, 2H), LCMS Rt6 = 3 007 mm, (M+Hf ~ 438 2] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32% | To a solution of 4-quinolinecarboxylic acid (111 mg, 0.64 mmol) in tetrahydrofuran (5 ml) were added oxalyl chloride (0.11 ml, 1.72 mmol) and N,N-dimethylformamide (0.01 ml), and the mixture was stirred at room temperature for 30 min. The reaction solution was evaporated under reduced pressure. To a solution of the residue in ethyl acetate (5 ml) were added (1RS,2SR)-1-(4-fluorophenyl)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)-2-propylamine hydrochloride (150 mg, 0.43 mmol) and saturated aqueous sodium hydrogen carbonate (5 ml) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (50 ml), and extracted with ethyl acetate (50 ml.x.2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from ethyl acetate-hexane to give the title compound (63 mg, 32percent). mp! 227-228°C IR nu maxKBrcm-1: 1644, 1508, 1331. Anal. Calcd for C26H20F4N2O2*0.5H2O: C, 65.41; H, 4.43; N, 5.87 Found: C, 65.31; H, 4.68; N, 5.61.1H-NMR (CDCl3)delta: 2.76-2.98 (1H, m), 3.00-3.16 (1H, m) , 4.72-4.92 (1H, m), 5.05 (1H, d, J = 4.0 Hz) , 6.60-6.80 (1H, m) , 7.02-7.20 (3H, m), 7.22-7.60 (8H, m), 7.62-7.78 (1H, m), 8.05 (1H, d, J = 8.4 Hz), 8.82 (1H, brs). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 25℃; for 12h;Inert atmosphere; | A mixture of 43 mg (0.15 mmol) of amine 10, 42 mg (0.24 mmol) of quinoline-4-carboxylic acid (18), 56 mg (0.36 mmol) of EDC, and 2 mg (0.02 mmol) of DMAP in 5 mL of dichloromethane was stirred under argon at 25oC for 12 h. The reaction mixture was diluted with 100 mL of dichloromethane, washed with water, and brine, dried (MgSO4), concentrated, and column chromatographed on silica gel using a gradient mixture of hexane and ethyl acetate as eluant to give 43 mg (65percent yield) of compound 8, as a solid. 1H NMR delta 8.82 (d, J = 4.3 Hz, 1 H), 8.16 (d, J = 8.6 Hz, 1 H), 8.08 (d, J = 8.6 Hz, 1 H), 7.73 (t, J = 7.6 Hz, 1 H), 7.57 (t, J = 7.6 Hz, 1 H), 7.34 (d, J = 4.3 Hz, 1 H), 6.72 (br. s, 1 H, NH), 5.97 (s, 1 H), 5.68 (s, 1 H), 5.09 - 4.98 (m, 1 H), 3.63 - 3.52 (m, 1 H), 3.42 - 3.29 (m, 1 H), 2.43 (d, J = 13.3 Hz, 1 H), 2.14 (s, 4 H), 2.06 - 1.90 (m, 1 H), 1.87 - 1.71 (m, 2 H), 1.71 - 1.51 (m, 2 H), 1.43 - 1.11 (m, 1 H), 0.99 (d, J = 6.6 Hz, 1.5 H, CH3) 0.98 (d, J = 6.6 Hz, 1.5 H, CH3) (2 diastereomers at C12); 13C NMR delta 167.7, 163.5, 162.7, 161.8, 149.9, 148.7, 142.4, 132.4, 130.2, 129.9, 127.8, 125.4, 124.6, 118.5, 109.4, 99.9, 97.4, 79.6, 79.4, 43.9, 39.2, 38.8, 38.7, 38.0, 36.9, 32.4, 32.3, 31.1, 28.6, 20.2, 14.5, 14.4; MS (electrospray ionization) m/z 453.3 (M + Na+), 431.1 (M+H+); HRMS calcd for C26H27N2O4+ (M+H+) 431.1971, found 431.1957 (100percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 28h;Inert atmosphere; | General procedure: To a solution of cyanoacetic acid (340 mg, 4.0 mmol) and 1,1-dioxo-1H-1lambda6-benzo[b]thiophen-6-ylamine (362 mg, 2.0 mmol) in 10 mL of CH2Cl2 was added DIPEA (774 mg, 6.0 mmol). HBTU (1.14 g, 3.0 mmol) was added at 0 °C. The resulting mixture was stirred at r.t. for 28 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 = 1/1) to obtain the desired product (400 mg, 81percent) as a yellow solid (mp 207-208 °C). HPLC purity 98.6percent (tR = 10.93 min). 1H NMR (600 MHz, DMSO-d6) delta 10.79 (s, 1H), 8.04 (s, 1H), 7.67-7.69 (m, 1H), 7.60 (d, 1H, J = 7.2 Hz), 7.57 (d, 1H, J = 7.8 Hz), 7.30 (d, 1H, J = 7.2 Hz), 3.98 (s, 2H). 13C NMR (150 MHz, DMSO-d6) delta 162.0, 140.7, 137.3, 132.8, 130.3, 126.7, 126.1, 123.4, 115.6, 111.4, 27.0. HRMS (ESI) calcd for C11H19N2O3S 249.0328 (M + H)+, found 249.0330. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | -A-(2-(2-cyanopyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide Commercially available quinoline-4-carboxylic acid (0.078g, 0.449 mmol) was dissolved in 7 ml of DMF, A/-ethyl-/V-isopropylpropan-2-amine (0.242ml, 1.347 mmol), HOBT (0.069 g, 0.449 mmol) and TBTU (0.144g, 0.449mmol) were added. After 15 min a solution of (S)-1-(2- aminoacetyl)pyrrolidine-2-carbonitrile 2,2,2-trifluoroacetate (0.120 g, 0.449 mmol) (prepared as described under A.1 of the experimental part) in DMF was added. The mixture was stirred overnight at room temperature. The volatiles were evaporated, the residue was dissolved in ethyl - - acetate and extracted with 1 N citric acid, saturated sodium bicarbonate and brine. The solution was dried over sodium sulfate, filtrated and evaporated. It was purified using column chromatography (1 -5 hexane-ethyl acetate). Yield: 66 mg, 38percent 1 H NMR (400 MHz, CDCI3) : (8.5/1 .5 mixture of trans/cis amide rotamers) delta 2.12 - 2.38 (m, 4H), 3.50 - 3.58 (m, 1 H), 3.68-3.74 (m , 1 H), 4.27 (dd, J= 1 7.6, 4.1 Hz, 0.85H), 4.33 (dd, J= 17.3, 4.3 Hz, 0.15H), 4.43 (dd, J= 18.0, 5.0 Hz, 0.85H), 4.60 (dd, J= 17.3, 5.4 Hz, 0.15H), 4.75 - 4.78 (m, 1 H), 7.14 (br s, 1 H), 7.49 (d, J = 6 Hz, 1 H), 7.62 (d tr, J = 7.7 Hz, J= 1 .3 Hz, 1 H), 7.77 (d tr, J = 7.6, 1 .4 Hz, 1 H), 8.15 (d, J= 8.49 Hz, 1 H), 8.28 (dd, J = 8.07, 0.79 Hz, 1 H) , 8.95 (d, J = 4.3 Hz, 1 H) MS (ESI) m/z 331 .1 [M+Na]+ LC-MS (l-B) Rt 9.7 min, m/z 309.0 [M+H]+ (97percent). | |
38% | Commercially available quinoline-4-carboxylic acid (0.078 g, 0.449 mmol) was dissolved in 7 ml of DMF, N-ethyl-N-isopropylpropan-2-amine (0.242 ml, 1.347 mmol), HOBT (0.069 g, 0.449 mmol) and TBTU (0.144 g, 0.449 mmol) were added. After 15 min a solution of (S)-1-(2-aminoacetyl)pyrrolidine-2-carbonitrile 2,2,2-trifluoroacetate (0.120 g, 0.449 mmol) (prepared as described under A.1 of the experimental part) in DMF was added. The mixture was stirred overnight at room temperature. The volatiles were evaporated, the residue was dissolved in ethyl acetate and extracted with 1 N citric acid, saturated sodium bicarbonate and brine. The solution was dried over sodium sulfate, filtrated and evaporated. It was purified using column chromatography (1-5 hexane-ethyl acetate). Yield: 66 mg, 38percent 1H NMR (400 MHz, CDCl3): (8.5/1.5 mixture of trans/cis amide rotamers) delta 2.12-2.38 (m, 4H), 3.50-3.58 (m, 1H), 3.68-3.74 (m, 1H), 4.27 (dd, J=17.6, 4.1 Hz, 0.85H), 4.33 (dd, J=17.3, 4.3 Hz, 0.15H), 4.43 (dd, J=18.0, 5.0 Hz, 0.85H), 4.60 (dd, J=17.3, 5.4 Hz, 0.15H), 4.75-4.78 (m, 1H), 7.14 (br s, 1H), 7.49 (d, J=6 Hz, 1H), 7.62 (d tr, J=7.7 Hz, J=1.3 Hz, 1H), 7.77 (d tr, J=7.6, 1.4 Hz, 1H), 8.15 (d, J=8.49 Hz, 1H), 8.28 (dd, J=8.07, 0.79 Hz, 1H), 8.95 (d, J=4.3 Hz, 1H) MS (ESI) m/z 331.1 [M+Na]+ LC-MS (I-B) Rt 9.7 min, m/z 309.0 [M+H]+ (97percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | 2.2 Synthesis of final products of formula (I), via intermediates (D) and (E), as defined in Scheme 1. -(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide Commercially available quinoline-4-carboxylic acid (0.065 g, 0.377 mmol) was dissolved in 7 ml of DMF, A/-ethyl-/V-isopropylpropan-2-amine (0.210 ml, 1 .168 mmol), HOBT (0.058 g, 0.377 mmol) and TBTU (0.121 g, 0.377mmol) were added. After 15 min a solution of (S)-1 -(2-aminoacetyl)-4,4- difluoropyrrolidine-2-carbonitrile trifluoroacetate (0.085g, 0.377mmol) (prepared as described under A.2 of the experimental part) in DMF was added. The mixture was stirred overnight at room - - temperature. The volatiles were evaporated, the residue was dissolved in ethyl acetate and washed with 1 N citric acid, saturated sodium bicarbonate and brine. The solution was dried over sodium sulfate, filtrated and evaporated. It was purified using column chromatography (1-4 hexane- ethyl acetate). Yield: 64mg, 45percent 1H NMR (400 MHz, CDCI3): (8.5/1.5 mixture of trans/cis amide rotamers) delta 2.72 - 2.83 (m, 2H), 3.91 -4.07 (m, 2H), 4.21 (dd, J= 17.4, 4.2 Hz, 0.85H), 4.33 (dd, J= 17.4, 4.3 Hz, 0.15H), 4.39 (dd, J= 17.4, 5.6 Hz, 0.85H), 4.70 (dd, J= 17.4, 5.7 Hz, 0.15H), 4.92-4.99 (m, 0.85H), 5.15 (d, J = 9 Hz, 0.15H), 7.30 (s, 1 H), 7.49 (dd, J= 10.11 , 4.30 Hz, 1 H), 7.60 (dd, J = 11.22, 4.11 Hz, 1 H), 7.74 (t, J= 7.69 Hz, 1H), 8.12 (d, J= 8.42 Hz, 1H), 8.23 (t, J= 9.99 Hz, 1H), 8.96 - 8.86 (m, 1H). MS (ESI) m/z 345.0 [M+1]+ LC-MS (l-B) Rt10.8 min, m/z 345.0 [M+H]+ (98percent). | |
45% | Commercially available quinoline-4-carboxylic acid (0.065 g, 0.377 mmol) was dissolved in 7 ml of DMF, N-ethyl-N-isopropylpropan-2-amine (0.210 ml, 1.168 mmol), HOBT (0.058 g, 0.377 mmol) and TBTU (0.121 g, 0.377 mmol) were added. After 15 min a solution of (S)-1-(2-aminoacetyl)-4,4-difluoropyrrolidine-2-carbonitrile trifluoroacetate (0.085 g, 0.377 mmol) (prepared as described under A.2 of the experimental part) in DMF was added. The mixture was stirred overnight at room temperature. The volatiles were evaporated, the residue was dissolved in ethyl acetate and washed with 1 N citric acid, saturated sodium bicarbonate and brine. The solution was dried over sodium sulfate, filtrated and evaporated. It was purified using column chromatography (1-4 hexane-ethyl acetate). Yield: 64 mg, 45percent 1H NMR (400 MHz, CDCl3): (8.5/1.5 mixture of trans/cis amide rotamers) delta 2.72-2.83 (m, 2H), 3.91-4.07 (m, 2H), 4.21 (dd, J=17.4, 4.2 Hz, 0.85H), 4.33 (dd, J=17.4, 4.3 Hz, 0.15H), 4.39 (dd, J=17.4, 5.6 Hz, 0.85H), 4.70 (dd, J=17.4, 5.7 Hz, 0.15H), 4.92-4.99 (m, 0.85H), 5.15 (d, J=9 Hz, 0.15H), 7.30 (s, 1H), 7.49 (dd, J=10.11, 4.30 Hz, 1H), 7.60 (dd, J=11.22, 4.11 Hz, 1H), 7.74 (t, J=7.69 Hz, 1H), 8.12 (d, J=8.42 Hz, 1H), 8.23 (t, J=9.99 Hz, 1H), 8.96-8.86 (m, 1H). MS (ESI) m/z 345.0 [M+1]+ LC-MS (I-B) Rt 10.8 min, m/z 345.0 [M+H]+ (98percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
177 mg | With triethylamine; In acetonitrile; at 20℃; for 72h; | General procedure: Methyl iodide (570 mg, 4 mmol) was added to a stirred solution of 14 (320 mg, 1 mmol) dissolved in dry MeCN (2 mL) and dry THF (2 mL) at rt. The volatiles were removed under reduced pressure after 24 h, the residue was dissolved in dry MeCN (4 mL), and Et3N (101 mg, 1 mmol) and the appropriate carboxylic acid (1 mmol) were added. The solution was allowed to stir at rt for 12?120 h before the volatiles were removed under reduced pressure. The residue was purified by flash chromatography (silica gel, mixtures of CH2Cl2 and MeOH?40:1, 20:1 or 9:1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
15% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; | <strong>[486-74-8]Quinoline-4-carboxylic acid</strong> (361 mg, 1.74 mmol) was dissolved in methylene chloride (10 ml), and mixed with EDCI (397 mg, 2.08 mmol) and HOBt (281 mg, 2.08 mmol) for min and then with 9b-amino-6-ethyl-4b-hydroxy-4bH-benzo[d]indeno[1,2-b]furan-10(9bH)-one (500 mg, 1.74 mmol) overnight at room temperature while stirring. After extraction with CH2Cl2 and water, the organic layer was dried over MgSO4 and concentrated in a vacuum. Purification by column chromatography (EA:Hex=1:1) afforded the title compound as a white solid. 112 mg (15percent). [0982] 1H-NMR (500 MHz, CDCl3) delta 6.86 (d, J=8.6 Hz, 1H ArH), 7.19 (s, 1H, NH), 7.277.29 (m, 1H, ArH), 7.43 (d, J=2.1 Hz, 1H, ArH), 7.53 (d, J=4.2 Hz, 1H, ArH), 7.60-7.65 (m, 2H, ArH), 7.78 (t, J=7.9 Hz, 1H, ArH), 7.87-7.91 (m, 2H, ArH), 8.06-8.11 (m, 2H, ArH), 8.16 (d, J=8.1 Hz, 1H, ArH), 8.98 (d, J=4.2 Hz, 1H, ArH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
15% | With trimethylsilyl polyphosphate; In 1,2-dichloro-benzene; at 180℃; for 9h; | Precursor: 2-Quinolin-4-ylnaphtho[1,2-d]oxazole-4,7-disulfonic acid disodium salt 1 g of 4-amino-3-hydroxynaphthalene-2,7-disulfonic acid disodium salt, 480 mg of quinoline-4-carboxylic acid and 4.0 g of trimethylsilyl polyphosphate are heated in 6 ml of 1,2-dichlorobenzene to 180 C. for 9 hours. Cooling is followed by suspending with 20 ml of dichloromethane and neutralizing by admixture of 40 ml of 1N NaOH solution. The aqueous phase is separated off and purified via RP chromatography. Yield: 205 mg (15%) (C20H10N2O7S2Na2, 500.42 g/mol) MS ESI-(m/z): 227 (base, [M]2-) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
10% | With trimethylsilyl polyphosphate; In 1,2-dichloro-benzene; at 180℃; for 12h; | Precursor: 2-Quinolin-4-yl-naphtho[1,2-d]oxazole-5-sulfonic acid sodium salt 700 mg of 1-amino-2-naphthol-4-sulfonic acid sodium salt, 500 mg of quinoline-4-carboxylic acid and 2 g of trimethylsilyl polyphosphate are heated in 7 ml of 1,2-dichlorobenzene to 180 C. for 12 hours. Cooling is followed by suspending with 20 ml of dichloromethane and neutralizing by admixture of 20 ml of 1N NaOH solution. This is followed by treatment in an ultrasonication bath until the tacky precipitate has substantially dissolved. The aqueous phase is separated off and purified via RP chromatography. [0184] Yield: 115 mg (10%) (C20H11N2O4SNa, 398.38 g/mol) [0185] MS ESI-(m/z): 375 (base, [M]-) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | With N-ethyl-N,N-diisopropylamine; In 1,2-dichloro-benzene; at 180℃; for 6h; | Precursor 1: 2-Quinolin-4-ylbenzooxazol-6-ol 0.933 g of 4-aminoresorcinol hydrochloride, 1.0 g of 4-quinolinecarboxylic acid and 4 g of trimethylsilyl polyphosphate are heated in 10 ml of 1,2-dichlorobenzene and 0.99 ml of ethyldiisopropylamine to 180 C. for 6 hours. Cooling is followed by suspending with 70 ml of dichloromethane and neutralizing by admixture of 40 ml of 1N NaOH solution. This is followed by treatment in an ultrasonication bath until there is a pale gray fine precipitate, which is filtered, washed with a little water and a little dichloromethane and dried. Yield: 595 mg (39%) (C16H10N2O2, 262.27 g/mol) MS ESI-(m/z): 261 (base, [M-H]-) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: sulfuric acid; sulfur trioxide / 2 h / 200 °C / Sealed tube 2.1: potassium hydroxide / water 2.2: 300 °C 3.1: thionyl chloride / 2 h / 0 - 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
29% | Example 7. (3 -(5 -Methyl- Gamma 1 ,2,41triazolor 1 ,5-a1pyrimidin-7-yl)piperidin- 1 - yl)(quinolin-4-yl)methanone To a 1 dram screw cap vial was added quinoline-4-carboxylic acid (0.1 1 mmol), HATU (0.2 mL of a 0.55 M solution in DMF, 0.1 1 mmol) and DIPEA (20 mu, 0.1 1 mmol). The mixture was stirred at rt for 30 min then 5-methyl-7-(piperidin-3-yl)-[ l ,2,4]triazolo[l ,5- a]pyrimidine (0.109 mmol, 0.6 mL of a 0.1817 M solution in DIPEA and DMF) was added. The vial was sealed and shaken at rt overnight. The mixture was filtered, a 5mu aliquot taken and diluted with 200 DMF and an analytical reverse-phase-UPLC was taken. The desired product mass was observed. Subsequently, based on the retention time of the desired product from the analytical UPLC, a corresponding PREP-HPLC gradient was recommended and the compound was purified. Obtained was the title compound (15 mg, 29percent) as the TFA salt. [M+H] = 373.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | General procedure: To a suspension of the acid(0.25 mmol, 1.00 equiv) and N,N,N0 ,N0-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (HBTU) (0.25 mmol,1.00 equiv) in CH2Cl2 (2.5 mL), under an air atmosphere, at ambienttemperature, was added diisopropylethylamine (0.1 mL,0.58 mmol, 2.34 equiv) and the mixture was stirred for 25 min.2-((5-(Trifluoromethyl)pyridin-2-yl)sulfonyl)ethan-1-aminiumchloride(14) (0.26 mmol, 1.05 equiv) and CH2Cl2 (5 mL) were thenadded and the mixture was stirred for 48 h. The reaction wasquenched with aqueous HCl (1 M, 2 mL), followed by H2O(10 mL) and EtOAc (20 mL). The mixture was transferred to a separatoryfunnel and the flask rinsed with EtOAc (10 mL). The organicphase was separated, washed with saturated aqueous NaHCO3(15 mL) and dried over anhydrous Na2SO4. The solvent was thenremoved under reduced pressure, at or below 40 C, to afford thecrude product. Purification was performed as indicated for eachcompound below 5.3.6.15 N-(2-((5-(Trifluoromethyl)pyridin-2-yl)sulfonyl)ethyl)quinoline-4-carboxamide (45) The title compound was prepared from quinoline-4-carboxylic acid (97percent, 0.045 g, 0.25 mmol). The crude product was purified by flash chromatography on silica gel (0:100-2:98/CH3OH:CH2Cl2) affording a colourless solid (0.075 g, 0.18 mmol, 73percent). 1H NMR (600 MHz, DMSO-d6) delta 9.21 (m, 1H), 8.94 (d, J = 4.3 Hz, 1H), 8.91 (t, J = 5.6 Hz, 1H), 8.58 (dd, J = 8.2, 2.2 Hz, 1H), 8.31 (d, J = 8.2 Hz, 1H), 8.16 (br dd, J = 8.4, 1.3 Hz, 1H), 8.06 (br d, J = 8.3 Hz, 1H), 7.81 (ddd, J = 8.4, 6.8, 1.4 Hz, 1H), 7.66 (ddd, J = 8.3, 6.9, 1.3 Hz, 1H), 7.38 (d, J = 4.3 Hz, 1H), 3.93 (t, J = 6.5 Hz, 2H), 3.75 (q, J = 6.2 Hz, 2H). 13C NMR13C NMR (151 MHz, DMSO-d6) delta 166.6, 159.9 (q, J = 1.4 Hz), 150.0, 147.9, 147.4 (q, J = 3.9 Hz), 141.0, 137.1 (q, J = 3.5 Hz), 129.8, 129.3, 128.5 (q, J = 33.0 Hz), 127.3, 125.5, 123.9, 122.7 (q, J = 273.3 Hz), 122.4, 119.0, 50.4, 33.4. HRMS (ESI) Calcd for C18H14F3N3NaO3S [M+Na]+: 432.0600; found 432.0607 (-1.6 ppm). HPLC (CH3OH:H2O/50:50, 1 mL/min, 254 nm) tr(major) 11.68 min (>99percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 12h; | <strong>[486-74-8]Quinoline-4-carboxylic acid</strong> (72 mg, 0.41 mmol)and 1-(2-chloro-4-nitrophenyl)piperazine (72 mg, 0.41 mmol) in dimethylformamide (2 mL) It is dissolved in triethylamine (0.14 mL, 1.03 mmol) to the reaction mixture dry high-profile and (propylphosphonic anhydride, 0.37 mL, 0.62 mmol) It was added and Stirring for 12 hours the reaction mixture at room temperature, concentrating it under reduced pressure extracted. And then being washed with brine saturation of at said extract, the drying in the form of tetrabutylammonium sodium. Dried reaction mixture solids of a dark brown comes concentrated under the reduced pressure obtained. Said obtained mixture column chromatography (ethyl acetate/n = 2:3-hexanediol) for purifying the yellow solid thereby, a desired compound (120 mg, 75percent) is obtained. |
75% | With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine; for 12h; | <strong>[486-74-8]Quinoline-4-carboxylic acid</strong>(72 mg,0.41mmol) and 1-(2-chloro-4-nitro phenyl)piperazine( 72 mg , 0.41 mmol ), the dimethiconeDissolved in butyl formamide (2 mL). The reaction mixture triethylamine ( 0.14 mL , 1.03 mmol ) was added ( propylphosphonic anhydride , 0.37 mL , 0.62 mmol ) . the reaction mixture was stirred for 12 hours and then concentrated under reduced pressure and was extracted twice with ethyl acetate. The extract saturated salt Washed , dried with sodium sulfate and water. The dried reaction mixture was concentrated under reduced pressure to give a dark brown solid .The mixture thus obtained was purified by column chromatography ( ethyl acetate / n- hexane = 2 : 3) to obtain the target compound as a yellow solid ( 120 mg , 75 percent ). |
75% | With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 12h; | quinoline-4-carboxylic acid (72 mg, 0.41 mmol) and 1 - (2-chloro-4-nitro-phenyl) piperazine (72 mg, 0.41 mmol) to dimethylformamide (2 mL) to dissolve thereby. The reaction mixture triethylamine (0.14 mL, 1.03 mmol) was added to the profile, and a high dry-c phosphonic sulphonic not de (propylphosphonic anhydride, 0.37 mL, 0.62 mmol). Stirring for 12 hours the reaction mixture at room temperature, and concentrated under reduced pressure and extracted two times with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate. The dried reaction mixture was concentrated under reduced pressure to give a dark brown solid thus obtained and the mixture was purified by column chromatography (ethyl acetate / n- hexane = 2: 3) to give the target compound as a yellow solid (120 mg, 75percent) a obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
11% | With pyridine; trichlorophosphate; at 80℃; for 1h; | Quinoline-4-carboxylic acid (36.4 mg, 0.226 mmol),3-chloro-5-(methylthio)benzene amine (50.0 mg, 0.205 mmol)and POCl3 (34.6 mg, 0.226 mmol)Dissolved in pyridine (1 mL)and stirred at 80°C for 1 hour. Thin film chromatography (TLC) in verifying, new spot the system is moved, and adding water to the composition, a reaction mixture of a, die chloro methane at extracted times 2. The organic layer extracted are dried, using magnesium sulfate, after, concentrating it under reduced pressure, organic for extract of moisture MgSO4removal of filtering the concentrate and a thin silica gel fraction is concentrated to after chromatography (preparative TLC, n/ethyl acetate = 1/1-hexanediol) for purifying the white solid thereby, a desired compound (11percent) is obtained. |
11% | With pyridine; trichlorophosphate; at 80℃; for 1h; | quinoline-4-carboxylic acid ( 36.4 mg , 0.226 mmol ) ,6-chloro-2-(methylsulfanyl)pyrimidin-4-amine( 50.0 mg , 0.205 mmol ) and POCl3 ( 34.6 mg , 0.226 mmol ) in pyridine (1 mL) and stirred at 80°C for 1 hour. When the thin film check chromatography (TLC), when a new spot is confirmed , water was added to the reaction mixture twice with dichloromethane It was extracted . The extracted organic layer was dried using magnesium sulfate, and then concentrated under reduced pressure , the water content of the organic extractAfter removing MgSO4 by filtration and then concentrated by preparative silica gel thin layer chromatography ( preparative TLC , ethyl acetate/ N- hexane = 1/ 1) to obtain the title compound ( 11percent) as a white solid |
11% | With pyridine; trichlorophosphate; at 80℃; for 1h; | Quinoline-4-carboxylic acid (36.4 mg, 0.226 mmol),3-chloro-5 - (methylthio) benzene amine (50.0 mg, 0.205 mmol) and POCl3 (34.6 mg, 0.226 mmol), pyridine (1 mL) was dissolved in, 80 was stirred for 1 hour dongan. When thin layer chromatography (TLC) check when, a new spot is confirmed, water was added to the reaction mixture, and extracted twice with dichloromethane. And the extracted organic layer was dried using magnesium sulfate, vacuum concentrated and, after the water was removed by filtration of the organic extract over MgSO4 and concentrated by silica gel preparative thin layer chromatography (preparative TLC, ethyl acetate / n- hexane = l / l ) to give to give the title compound (11percent) of a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 12h; | quinoline-4-carboxylic acid (72 mg, 0.41 mmol) and 1 - (2-chloro-4-nitro-phenyl) piperazine (72 mg, 0.41 mmol) to dimethylformamide (2 mL) to dissolve thereby. The reaction mixture triethylamine (0.14 mL, 1.03 mmol) was added to the profile, and a high dry-c phosphonic sulphonic not de (propylphosphonic anhydride, 0.37 mL, 0.62 mmol). Stirring for 12 hours the reaction mixture at room temperature, and concentrated under reduced pressure and extracted two times with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate. The dried reaction mixture was concentrated under reduced pressure to give a dark brown solid thus obtained and the mixture was purified by column chromatography (ethyl acetate / n- hexane = 2: 3) to give the target compound as a yellow solid (120 mg, 75percent) a obtained. Instead of using one equivalent of quinolin-4-carboxylic acid in Example 29, using quinoline-4-carboxylic acid, and using 2 equivalents of 1- (2-chloro-4-nitro phenyl) piperazine but using 2- (methylthio) -6-phenyl-pyrimidin-4-amine in place of and performs in the same manner as in example 29 to give the title compound (30percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
11% | With pyridine; trichlorophosphate; at 80℃; for 1h; | Quinoline-4-carboxylic acid (36.4 mg, 0.226 mmol),3-chloro-5 - (methylthio) benzene amine (50.0 mg, 0.205 mmol) and POCl3 (34.6 mg, 0.226 mmol), pyridine (1 mL) was dissolved in, 80 was stirred for 1 hour dongan. When thin layer chromatography (TLC) check when, a new spot is confirmed, water was added to the reaction mixture, and extracted twice with dichloromethane. And the extracted organic layer was dried using magnesium sulfate, vacuum concentrated and, after the water was removed by filtration of the organic extract over MgSO4 and concentrated by silica gel preparative thin layer chromatography (preparative TLC, ethyl acetate / n- hexane = l / l ) to give to give the title compound (11%) of a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a stirred solution of quinoline-4-carboxylic acid (12.00 g, 69.30 mmol) in anhydrous dichloromethane (50 ml) was added 2-(3H-[l,2,3]triazolo[4,5-b]pyridin-3-yl)- 1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (39.52 g, 103.95 mmol). The mixture solution was stirred for 15 minutes at room temperature (15 °C), and then N-ethyl-N- isopropylpropan-2-amine (26.87 g, 207.89 mmol) and Nu,Omicron-dimethylhydroxylamine hydrochloride (8.1 g, 83.16 mmol) were slowly added to the reaction solution. The reaction solution was stirred for 12 hr at room temperature. The reaction solution was quenched by addition of water (50 ml) and concentrated. The aqueous solution was extracted with ethyl acetate (50 mL x 3). The combined organics layer was dried over sodium sulfate, filtered and concentrated to afford the crude N-methoxy-N-methylquinoline-4-carboxamide (14.98 g). It was used in next step directly. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | Under nitrogen protection conditions,17.3 g (100 mmol) of quinoline-4-carboxylic acid was dissolved in 100 mL of tetrahydrofuran.Mix with 157 mL (220 mmoL) sec-butyl lithium (1.4 M) at -40 ° C to remove the freezer.The reaction solution was allowed to stand in the water bath at room temperature for 60 minutes.Stir for 2 hours, cool at -78 ° C,100 mL of tetrahydrofuran mixed with 14.4 g (150 mmol) of methanesulfonic acid was added dropwise.Remove the cold sink,The mixture was allowed to stand at room temperature for 30 minutes in a water bath, and refluxed at 60 ° C for 5 hours.After the reaction was stopped, it was washed with saturated sodium chloride and then 2N aqueous HCl solution and stirred for 30 min. The water in the organic layer was removed with anhydrous magnesium sulfate, and the mixture was filtered with suction.Intermediate TM-1 6.2 g (40percent) was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54.39% | With lithium aluminium tetrahydride; In tetrahydrofuran; at 0℃; for 3h; | To a stirred solution of quinoline-4-carboxylic acid (1 g, 5.77 mmol, 1 equiv.) in THF (15 mL) was added LiAlH4(0.3 g, 8.66 mmol, 1.5 equiv). The resulting mixture was stirred for 3 h at 0 degrees Celsius. The resulting mixture was concentrated under reduced pressure. This resulted in quinolin-4-ylmethanol(500 mg, 54.39%) as a yellow solid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.8 g | After adding quinoline-4-carboxylic acid (2.2 g, 12.8 mmol), HATU (5.8 g, 15.3 mmol) and DIPEA (6.7 mL, 38.4 mmol) to dichloromethane (25 mL), the result was stirred for 30 minutes. To the reaction solution, an N,O-dimethylhydroxylamine salt (1.9 g, 19.2 mmol) was introduced, and the result was stirred for 12 hours at room temperature. After terminating the reaction, the reaction solution was removed, and ethyl acetate was added thereto. The result was washed with water and saline, then dried using anhydrous magnesium sulfate, and filtered. The filtrate was concentrated and purified using column chromatography to obtain a target compound (2.8 g). 1H NMR spectrum (300 MHz, CDCl3) delta 8.96(d, 1H), 8.15(d, 1H), 7.86(d, 1H), 7.76(t, 1H), 7.59(t, 1H), 7.39(d, 1H), 3.48-3.40(m, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27 mg | With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; at 20℃; for 0.333333h; | To the crude compound 11 (30 mg, 0.072 mmol) were added dichloromethane (1.5 mL), quinoline-4-carboxylic acid (14.9 mg, 0.086 mmol), HATU (32.7 mg, 0.086 mmol), triethylamine (0.060 mL, 0.430 mmol). The mixture was stirred at room temperature for 20 minutes. To the reaction mixture was added saturated aqueous solution of sodium hydrogen carbonate. The mixture was extracted with ethyl acetate. The organic layer was washed by saturated aqueous solution of sodium hydrogen carbonate, water, brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol) to give a compound I-053 (27 mg, yield 75percent).1H-NMR (CDCl3) delta: 1.14-1.41 (m, 5H), 1.51-1.56 (m, 2H), 1.87-1.91 (m, 2H), 2.18-2.22 (m, 2H), 2.56-2.60 (m, 2H), 2.71-2.80 (m, 4H), 3.47 (s, 2H), 4.01-4.13 (m, 1H), 4.54 (td, J=13.1, 4.1 Hz, 2H), 5.83 (d, J=8.2 Hz, 1H), 6.12 (tt, J=55.1, 4.1 Hz, 1H), 7.43 (d, J=4.3 Hz, 1H), 7.62 (t, J=7.7 Hz, 1H), 7.77 (t, J=7.7 Hz, 1H), 8.14 (d, J=8.5 Hz, 1H), 8.21 (d, J=8.5 Hz, 1H), 8.94 (d, J=4.3 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; at 20℃; for 0.333333h; | To compound 11 (30 mg, 0.072 mmol) of the crude product, methylene chloride (1.5 mL), quinoline-4-carboxylic acid (14.9 mg, 0.086 mmol), HATU (32.7 mg, 0.086 mmol), and triethylamine (0.060 mL, 0.430 mmol) and stirred at room temperature for 20 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, water, and saturated brine, and then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain compound I-053 (27 mg, yield 75%). |
[ 816448-09-6 ]
8-Methylquinoline-4-carboxylic acid
Similarity: 0.87
[ 1092287-30-3 ]
2-Chloroquinoline-5-carboxylic acid
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[ 31009-04-8 ]
7-Bromoquinoline-4-carboxylic acid
Similarity: 0.86
[ 816448-09-6 ]
8-Methylquinoline-4-carboxylic acid
Similarity: 0.87
[ 1092287-30-3 ]
2-Chloroquinoline-5-carboxylic acid
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[ 31009-04-8 ]
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H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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