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CAS No. : | 93-10-7 | MDL No. : | MFCD00006752 |
Formula : | C10H7NO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | LOAUVZALPPNFOQ-UHFFFAOYSA-N |
M.W : | 173.17 | Pubchem ID : | 7124 |
Synonyms : |
|
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) : | -5.49 cm/s |
Log Po/w (iLOGP) : | 1.25 |
Log Po/w (XLOGP3) : | 2.63 |
Log Po/w (WLOGP) : | 1.93 |
Log Po/w (MLOGP) : | 0.23 |
Log Po/w (SILICOS-IT) : | 1.82 |
Consensus Log Po/w : | 1.57 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | -3.07 |
Solubility : | 0.146 mg/ml ; 0.000844 mol/l |
Class : | Soluble |
Log S (Ali) : | -3.33 |
Solubility : | 0.0802 mg/ml ; 0.000463 mol/l |
Class : | 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 : | 1.21 |
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 |
---|---|---|
75% | at 60℃; for 20 h; Schlenk technique | Weighing quinoline-2-carboxylic acid (51.9 mg, 0.3 mmol),Sodium carbonate (64.0 mg, 0.6 mmol), NaBr (17.6 mg, 0.3 mmol), tert-butyl hypochlorite (32 μL, 0.3 mmol) into a 25 mL of Schlenk reaction bottle, Then CH2Br2 (2 mL) was added and placed in a 60 °C oil bath for 20 h. After completion of the reaction, the solvent was removed under reduced pressure and eluted with petroleum ether / ethyl acetate.The solvent was separated on a silica gel column, he yield of 2-bromoquinoline was 75percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 18 h; Inert atmosphere | A mixture of quinaldine acid (5) (2.0 g, 11.55 mmol), dried K2CO3 (3.19 g, 23.10 mmol) and anhydrous DMF (24 mL) was stirred until the reagents had been dissolved under an argon atmosphere. Iodoethane (2.77 mL, 34.65 mmol) was added and stirred for 18 h to 60 °C. A 30percent cooled aqueous solution of HCl (30 mL) was added. The medium was neutralized with a saturated solution of NaHCO3 until the gas formation was ceased. Extraction was carried out with ethyl acetate (3x 60 mL). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography by eluting with hexane/AcOEt (8:2) to furnish ester 6 as a translucent oil in quantitative yield. Rf 0.51 (hexane/AcOEt 7:3). IR (neat) νmax/cm-1: 3061, 2982, 2938, 2904, 1714, 1463, 1368, 1312, 1133, 1103, 1016, 844, 774. 1H NMR (400 MHz, CDCl3) δ 7.96-7.94 (m, 1H), 7.85-7.81 (m, 1H), 7.76-7.73 (m, 1H), 7.42-7.36 (m, 2H), 7.22-7.18 (m, 1H), 4.22-4.17 (m, 2H), 1.14-1.10 (m, 3H). 13C NMR (100 MHz, CDCl3) δ 164.9, 147.9, 147.2, 136.8, 130.3, 129.8, 128.9, 128.1, 127.2, 120.6, 61.7, 14.1. HRMS (ESI+) calcd for C12H11NO2 [M+H]+ 202.0868, found 202.0868. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92.3% | With thionyl chloride; at 0℃; for 8.5h;Reflux; | <strong>[93-10-7]2-quinolinecarboxylic acid</strong> 22(0.50 g, 2.91 mmol)Dissolved in 30 mL of methanol,Slowly dropwise at 0 C(0.69 g, 5.82 mmol) of thionyl chloride,Stir with the same temperature 30min,And then heated to reflux reaction 8h,TLC detection reaction is complete, minusThe solvent was concentrated, filtered, and the filter cake was washed with ethyl acetate to give 0.49 g of a white solid in a yield of 92.3%. The product goes directly to the next stepreaction. |
85% | With hydrogenchloride;Reflux; | General procedure: To a suspension of the appropriate acid 17a-c (1 eq,) in MeOH (1.9 ml*mmol/eq) was added 1, 25 M HCl in MeOH solution (1.9 ml*mmol/eq). The solution was refluxed overnight, then cooled to room temperature and concentrated under vacuum. The residue was partitioned between sat. aq. NaHCO3 solution (30 ml) and EtOAc (3x35 ml). The combined organic extracts were washed with sat. aq. NaHCO3 solution (25 ml) and water (30 ml), dried over MgSO4 and concentrated under vacuum to give the pure title compounds. |
83% | With thionyl chloride;Reflux; | General procedure: Quinoline-2-carboxylic acid (10.0 mmol) was dissolved in dry MeOH and placed in an ice bath. SOCl2 (0.92 mL, 12.0 mmol) was then added dropwise and the mixture was refluxed overnight until the starting material was undetectable by TLC. The suspension was cooled to room temperature and carefully poured into an aqueous, saturated NaHCO3 solution. The resulting mixture was extracted twice with CH2Cl2. The organic extracts were combined, dried over anhydrous Na2SO4, and filtered, and the solvent was then removed by evaporation in vacuum. The resulting residue was purified by column chromatography to obtain the pure ester. Methyl quinoline-2-carboxylate 1 (Yield: 83%). Pale-green solid. 1H NMR (500 MHz, CDCl3) delta 8.32 (d, J=8.5 Hz, 1H), 8.21 (d, J=8.5 Hz, 1H), 7.89 (dd, J=8.0, 1.0 Hz, 1H), 7.80 (ddd, J=8.5, 7.0, 1.5 Hz, 1H), 7.66 (ddd, J=8.0, 7.0, 1.0 Hz, 1H), 4.10 (s, 3H); 13C NMR (125 MHz, CDCl3) delta 166.0, 147.9, 147.6, 137.4, 130.8, 130.4, 129.4, 128.7, 127.6, 121.1, 53.3; ESI-HRMS m/z [M+H]+ calcd for C11H10NO2 188.0712, found 188.0718. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Quinoline-2-carboxylic acid (Aldrich, 10.0 g, 57.7 mmol) was added to ethanol (500 mL) and sulfuric acid (25 mL) and refluxed for 7 hours. The mixture was concentrated under reduced pressure and dichloromethane (400 mL) was added. The organic layer was washed twice with saturated sodium bicarbonate (400 mL), dried with sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound. 1H NMR (300 MHz, DMSO-d6) delta ppm 1.39 (t, J=7.12 Hz, 3H), 4.43 (q, J=7.12 Hz, 2H), 7.76 (ddd, J=8.14, 6.95, 1.19 Hz, 1H), 7.88 (ddd, J=8.48, 6.95, 1.53 Hz, 1H), 8.11 (m, 2H), 8.18 (d, J=8.48 Hz, 1H), 8.58 (d, J=8.48 Hz, 1H). MS (DCI) m/z 202.05 (M+H)+. | ||
With thionyl chloride; | General procedure: To a stirred solution of isoquinoline-1-carboxylic acid (1.732 g, 10 mmol) in 3 mL ethanol was added thionyl chloride (6 mL) dropwise over 15 minutes. Then, the mixture was heated under reflux for 8 h. Ethanol was distilled out and the saturated NaHCO3 solution was added to adjust pH to 7. Extracted with ethyl acetate, and the organic layer was dried over anhydrous Na2SO4, evaporation of the ethyl acetate gave the ester (I) in 92% yield (1.85g) as a light yellow oily compound I. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With polyphosphoric acid; at 160℃; for 24h; | 10 mmol of phenylene diamine was added to a suspension of quinaldic acid (10 mmol) in 1 g of polyphosphoric acid. The mixture was heated at 160 C for 24 h. After completion of the reaction, water was added and the precipitate that formed was filtered, washed with H2O (2 × 50 mL). The residue was suspended in 20 mL of NaOH (5 M), then filtered to afford the desired product. Yield 92%; Yellow solid; M.p.: 85-88 C (Literature 17: 93-95 C); UV-Vis (MeOH,lambdamax/nm): 286, 308, 322, 336, 350; IR (KBr, cm-1): 3047, 1654, 1596, 1566, 1500, 1411, 1319, 1238, 1141, 829, 748;1H NMR (250.13 MHz, CDCl3) delta: 11.21 (s, 1H), 8.64-7.24 (m, 10H). |
84% | With polyphosphoric acid; at 200℃; for 4h;Inert atmosphere; | 2.1.1 Synthesis of 2-(1H-benzimidazol-2-yl)quinoline (L1) <strong>[93-10-7]Quinaldic acid</strong> (10 mmol, 1.731 g) and o-phenylenediamine (10 mmol, 1.081 g) were stirred in polyphosphoric acid (20 mL) for 4 h at 200 C under argon. At the end this time, the green-colored molten fluid was poured into iced water. Then the solution was neutralized with ammonium hydroxide and the obtaining solid was filtered off. Finally, the product was recrystallized by EtOH. Beige solid, 84% yield, m. p.: 238 C. 1H NMR (600 MHz, DMSO-d6, delta ppm): 7.25 (1 H, t, J = 7.52 Hz, -H4); 7.30 (1 H, t, J = 7.70 Hz, -H5); 7.63 (1 H, d, J = 7.70 Hz, -H3); 7.67 (1 H, ddd, J = 8.07, 6.79 and 1.28 Hz, -H13); 7.77 (1 H, d, J = 8.07 Hz, -H6); 7.86 (1 H, ddd, J = 8.44, 6.97 and 1.47 Hz, -H14); 8.06 (1 H, dd, J = 8.07 and 1.47 Hz, -H10); 8.17 (1 H, dd, J = 8.25 and 0.92 Hz, -H9); 8.49 (1 H, d, J = 8.4 Hz, -H12); 8.54 (1 H, d, J = 8.4 Hz, -H15); 13.22 (1H, s, -NH). 13C NMR (150.92 MHz, DMSO-d6, delta ppm): 112.27; 119.20; 119.55; 122.05; 123.58; 127.28; 128.06; 128.22; 128.73; 130.44; 135.18; 137.39; 143.92; 147.18; 148.71 (-C8); 150.70 (-C1). FTIR (upsilon/cm-1): 3482, 3056, 1948, 1930, 1890, 1852, 1810, 1655, 1597, 1564, 1537, 1497, 1444, 1414, 1318, 1105, 830, 741. UV-Vis (nm): 242, 287, 323, 345 (pi?pi* and n?pi*). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With urea hydrogen peroxide adduct; trifluoroacetic anhydride In dichloromethane at 0 - 20℃; for 1.5h; | |
With dihydrogen peroxide; acetic acid | ||
With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 0℃; for 1.16667h; |
With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 0℃; for 1.16667h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sulfuric acid; In ethanol; water; | A) 29.89 g of quinoline-2-carboxylic acid were heated under reflux for 51/2 hours in 450 ml of ethanol with the addition of 3.5 ml of sulfuric acid. The reaction mixture was worked up by evaporating it, taking up the residue in water and extracting the mixture with dichloromethane. The organic phase was washed with aqueous sodium bicarbonate solution and then with water until neutral, dried and evaporated. 32.23 g of crude ethyl quinoline-2-carboxylate were obtained as a green oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | Step A: 1,2,3,4-tetrahydro<strong>[93-10-7]quinoline-2-carboxylic acid</strong> A solution of <strong>[93-10-7]quinoline-2-carboxylic acid</strong> (500 mg, 2.9 mmol) and platinum oxide (32 mg, 0.14 mmol) in MeOH (6 mL) was stirred under hydrogen atmosphere for 2.5 hr. The mixture was filtered and the filtrate was concentrated to afford the crude product as an oil (500 mg, 97% yield). | |
PtO2; In acetic acid; | Step A Synthesis of 1,2,3,4-Tetrahydroquinoline-2-carboxylic Acid A mixture of PtO2 (25 wt. %) and <strong>[93-10-7]2-quinolinecarboxylic acid</strong> (Aldrich) in acetic acid was hydrogenated at RT under 60 Psi overnight. The reaction mixture was stripped to dryness to give the title compound. C10H11NO2 (MW=177.22); mass spectroscopy (MH+) 178. | |
500 mg | With platinum(IV) oxide; hydrogen; In methanol; for 2.5h; | A solution of <strong>[93-10-7]quinoline-2-carboxylic acid</strong> (500 mg, 2.9 mmol) and platinum oxide (32 mg, 0.14 mmol) in MeOH (6 mL) was stirred under hydrogen atmosphere for 2.5 hr. The mixture was filtered and the filtrate was concentrated to afford the crude product as an oil (500 mg, 97% yield). |
With platinum(IV) oxide; hydrogen; In methanol; at 25℃; under 775.743 Torr; for 5h; | A mixture of <strong>[93-10-7]quinoline-2-carboxylic acid</strong> (2.5 g, 14 mmol) and PtO2 (0.2 g) in methanol (50 mL) was stirred under hydrogen (15 psi) at 25 C for 5 h, at which time TLC showed completion of the reaction. The solid was removed by filtration and the filtrate was concentrated under reduced pressure to give the crude title compound (1.5 g, 59% yield) as a yellow solid. LCMS M/Z (M+H) 178. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With thionyl chloride; at 60℃; for 6h; | Compound 26; (R)-3-Benzylsulfanyl-2- [5-quinolin-2-yl-2-(4-trifluoromethylphenyl) oxazole-4- carbonyl]amino}propionic acid ;Step A: Ouinoline-2-carbonyl chloride; Quinoline-2-carboxylic acid (5 g, 28.9 mmol) was suspended in thionyl chloride (6.32 ml, 86.6 mmol). The reaction mixture was heated at 60 C for 6 h. The heterogeneous mixture became a homogeneous solution. The solution was concentrated in vacuo to give the title compound as a yellow powder (5.6 g, 29 mmol, 100% yield). MS 255.1 (M+H)+. |
82% | With pyridine; thionyl chloride; In N,N-dimethyl-formamide; at 0℃; for 11h;Inert atmosphere; Reflux; | Dichlorosulfoxide (12 mmol, 1.428 g) and pyridine (2.0 mL), in turn, were added drop-wise to <strong>[93-10-7]quinoline-2-carboxylic acid</strong> (12 mmol, 2.067 g) in 30 mL N,N-dimethyformamide (DMF) at 0 C and under N2 atmosphere. Then the solution refluxed for 11 h. After removing the solvent under reduced pressure, the crude solid was dried and recrystallized from petroleum to give 1.885 g of white solid of quinoline-2-carbonyl chloride (compound 1) ( Scheme 1 .). (yield, 82%; m.p. 97-98 C). 1H NMR (400 MHz, DMSO?d6) delta (ppm) 8.55 (d, J = 8.4 Hz, 1H, Ar-H), 8.17 (m, 1H, Ar-H), 8.07-8.02 (2H, Ar-H), 7.97-7.74(m, 1H, Ar-H), 7.72 (t, J = 7.5 Hz, 1H, Ar-H). |
With thionyl chloride;N,N-dimethyl-formamide; In toluene; at 80℃; for 0.5h; | To a solution of <strong>[93-10-7]2-quinolinecarboxylic acid</strong> (656 mg, 3.79 mmol) in toluene (3 ml) were added thionyl chloride (0.41 ml, 5.67 mmol) and N,N-dimethylformamide (1 drop), and the mixture was stirred for 30 minutes at 80C. After cooling, the solvent was distilled off under reduced pressure, and the residue was dissolved in N,N-dimethylformamide (6 ml). Methyl 2-amino-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoate (800 mg, 1.89 mmol) and 4-(dimethylamino)pyridine (924 mg, 7.56 mmol) were added thereto, and the mixture was stirred for 1.5 hours at room temperature. The reaction mixture was combined with ice water, and extracted twice with ethyl acetate. The combined organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified with a silica gel column chromatography (hexane/ethyl acetate, 3:1 followed by 2:1), and the obtained crystals were washed with hexane to give the title compound (831 mg, yield 76%). 1H NMR (CDCl3) delta 1.27 (6H, s), 1.30 (6H, s), 1.47 (3H, t, J = 7.0 Hz), 2.34 (2H, s), 2.69 (2H, s), 4.09 (3H, s), 4.20 (2H, q, J = 7.0 Hz), 6.61 (1H, s), 7.21 (1H, dd, J = 8.0, 1.4 Hz), 7.62-7.70 (1H, m), 7.80-7.93 (2H, m), 8.16 (1H, d, J = 8.0 Hz), 8.33-8.35 (3H, m), 9.09 (1H, d, J = 1.8 Hz). |
With thionyl chloride; at 60℃; for 6h; | Step 1: preparation of quinoline-2-carbonyl chloride[00354] Thionyl chloride (1.264 ml, 17.32 mmol) was added to a screwcap vial containing <strong>[93-10-7]quinoline-2-carboxylic acid</strong> (1 g, 5.77 mmol). The reaction was heated at 60 C for 6 hours and became homogeneous and red. After 6 hours, the reaction was concentrated to afford quinoline-2-carbonyl chloride (1.2 g, 6.26 mmol). The product was used in the next step without further purification. 1H NMR (400 MHz, CDC13) delta (ppm): 8.39 (d, 2H), 8.17 (d, 1H), 7.95 (dd, 1H), 7.86 (m, 1H), 7.75 (m, 1H).Step 2: Methyl 2-(5-methyl-4-(quinoline-2-carbonyl)-6H-thieno[2,3-b]pyrrol-6- yl)acetate | |
With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 0.5h; | General procedure: A solution of isonicotinic acid (0.25 mmol) in CH2Cl2 (2 mL) was treated with oxalyl chloride (1 mmol) in the presence of a catalytic amount of DMF at room temperature for 30 min. The mixture was then concentrated in vacuo and a solution of sootepin A (0.06 mmol) and Et3N (5 equiv) in CH2Cl2 (2 mL) was added to the prepared acid chloride. After stirring further for 30 min, the reaction was quenched with 10% NaHCO3 (aq), then extracted with EtOAc. The combined organic layer was concentrated in vacuo and the residue was purified by column chromatography on sililca gel to give 19 (55% yield). | |
With thionyl chloride; In benzene; for 2h;Inert atmosphere; Reflux; | To a solution of quinaldic acid (0.1 g, 0.58 mmol) in benzene (10 mL) was added 1 ml of thionyl chloride and refluxed for 2 h. After further reacting in room temperature for 1 h, the solvent and excess thionyl chloride were removed by rotary evaporator and dried by vacuum. The residue was dissolved in 10 mL CH2Cl2 and slowly added to the solution of 8-amino-<strong>[93-10-7]quinoline-2-carboxylic acid</strong> 6 (0.52 g, 2.6 mmol) in 20 ml CH2Cl2, which is mixed with DIEA (0.5 ml, 2.9 mmol) under 0 C. After reacting overnight at room temperature, the solvent was evaporated and the residue was extracted with CH2Cl2, washed with brine, dried over Na2SO4, and concentrated to give the crude product, and purified by column chromatography using CH2Cl2. The desired product 11 as a yellow solid was obtained (0.15 g, 90%) and used directly.Compound 11 (0.2 g, 0.56 mmol) was dissolved in THF:MeOH=2:1 (15 mL) and added KOH (0.2 g, 3.57 mmol). After reacting at room temperature for 3 h, THF was removed from reaction mixture by rotary evaporator and adjusted ph to 3-4 by 2 M aqueous HCl, and on further cooling in an ice bath gave light yellow precipitate of 8-[(quinoline-2-carbonyl)-amino]-<strong>[93-10-7]quinoline-2-carboxylic acid</strong>. The precipitate was collected, washed with additional cold water, and dried to give 0.15 g light yellow powder product in 80% yield. The 0.1 g (0.29 mmol) of light yellow powder was dissolved in 10 mL benzene with 1 mL of thionyl chloride and refluxed for 1 h. After cooling to room temperature, benzene and excess thionyl chloride were removed by rotary evaporator and further dried by vacuum to give the 8-[(quinoline-2-carbonyl)-amino]-quinoline-2-carbonyl chloride. The residue was dissolved in 10 mL CH2Cl2 and slowly added to the solution of amino polypyrrole amide 12 in 20 ml CH2Cl2, which is mixed with DIEA (0.5 ml, 2.9 mmol) under 0 C. After reacting overnight at room temperature, the solvent was evaporated and the residue was extracted with CH2Cl2, washed with brine, dried over Na2SO4, and concentrated to give the crude product, and purified by column chromatography using CH2Cl2:MeOH=2:1 as elution. The desired product 1 as a yellow solid was obtained (0.07 g, 35%). | |
With thionyl chloride; In benzene; at 0℃; for 0.5h; | General procedure: To the solution of heterocyclic acid (1 mmol) in benzene at 0C was added SOCl2 (1.5 mmol) and reaction mixture was stirred for 30 min. Solvent was evaporated and heterocyclic acid chlorides obtained were used for next step without any purification. | |
With oxalyl dichloride; In dichloromethane; N,N-dimethyl-formamide; at 20℃; for 1h; | <strong>[93-10-7]Quinaldic acid</strong> (24.4 mg, 0.141 mmol) was placed in an 8 mL vial equipped with a stir bar and then DCM (1 mL) and DMF (10 muL) were added. Oxalyl chloride (20.5 muL, 0.235 mmol) was added dropwise via syringe and then the reaction was stirred at rt for 1 h. The solvent was removed under reduced pressure. The resulting acid chloride was dissolved in DCM (5 mL). | |
With oxalyl dichloride; In dichloromethane; at 50℃; for 4h; | Into a 250 mL three-necked flask equipped with a magneticstirringbar, 1.73 g (0.01 mol) of quinaldic acid and 60 mL anhydrous dichloromethane are added. The mixture was stirred at room temperature for 10 min and then 10 mL oxalyl chloride (0.12 mol) was added. After thermostatting at 50C in an oil bath and stirring for 4 h, the reaction flask was cooled. After removing all the solvent under reduced pressure, the mid-product quinaldic acid chloride was obtained. | |
With thionyl chloride;Reflux; | Compound 9a (191 mg, 1 mmol) was refluxed in excess of thionylchloride (3 mL) overnight. Excess of thionyl chloride was evaporatedand the residue was dissolved in CH2Cl2, 3-bromopropylamine hydrobromide (328 mg, 1.5 mmol was addedfollowed by triethylamine (TEA; 0.42 mL, 3 mmol). The reactionmixture was stirred at room temperature. After the reaction wascompleted, the reaction mixture was diluted with CH2Cl2 andsequentially washed with water, 1 N HCl and saturated NaHCO3.The organic layer was dried over MgSO4, filtered and concentrated.The obtained product was purified by column chromatographywith n-hexane/ethyl acetate (EtOAc) = 4:1 to obtain 10a, (236 mg,76%) as white solid. | |
With thionyl chloride;Reflux; Inert atmosphere; | General procedure: Pyridine-2-carboxylic acid (1.23 g, 10.0 mmol) was treated with SOCl2 (15.0 mL) at reflux temperature under a nitrogen atmosphere. Excess SOCl2 was then removed under reduced pressure to give the acid chloride as a white solid (100%). The chloroform solution of crude 2-pyridine carbonyl chloride was slowly added to an aqueous solution of chloroethylamine hydrochloride(2.55 g, 22.0 mmol) and KOH (1.69 g, 30.0 mmol) at 0 C. After 1 h, the aqueous layer was discarded, the organic layer filtered and washed with water. After the solvent was removed under reduced pressure, the crude carboxamide was yielded as a light yellow solid. This solid was dissolved in THF and then added to as uspension of NaH (0.60 g, 60% in mineral oil) in THF at 0 C. The reaction mixture was stirred at room temperature for 24 h, and then quenched with 10% HCl aq. The THF was removed under reduced pressure, and the residue was dissolved in dichloromethane.The resulting organic layer was dried over anhydrous MgSO4. After evaporating the solvent, the product was obtained as a white powder in 60% yield (0.89 g). | |
With oxalyl dichloride; for 2h;Reflux; | As shown in Scheme 1, L was synthesized via a simple procedure.(1H-benzo[d]imidazol-2-yl)methanamine was obtained via the method reported in our previous paper.37 2-Quinolinecarboxylic acid (0.38 g, 2 mmol) was refluxed in oxalyl dichloride (20 mL) for2 h, and then the solvent was removed. The crude quinoline-2-carbonyl chloride was obtained, which was added into (1H-benzo[d]imidazol-2-yl)methanamine (0.29 g, 2 mmol) dichloromethane solution containing 0.3 mL trimethylamine at 0 C in a 0.5 h timescale.The reaction mixture was gradually returned to room temperature and maintained for 4 h, which was evaporated and separated via column chromatography. Pale yellow solid was obtained.Yield: 0.42 g, 70%. | |
With oxalyl dichloride; In dichloromethane; for 5.5h;Cooling with ice; Inert atmosphere; | <strong>[93-10-7]Quinaldic acid</strong> (C1, 0.38 g, 2 mM) was dissolved in dry dichloromethane (20 mL) and added to a 100 mL two-necked flask. Place the magnetic rotor. Oxalyl chloride (2.60 g, 20 mM) was then dissolved in 10 mL of dry methylene chloride. Was added dropwise to the quinaldic acid solution under ice-cooling. Stirred for 30 minutes. Followed by distilling and stirring for 5 hours under a nitrogen atmosphere. Then, the reaction solution was cooled to room temperature. The solvent was removed by rotary evaporation to give the crude quinaldic chloride (abbreviated as C2). The resulting product C2 was then added with 2-aminobenzimidazole (0.27 g, 2 mM) to a mixed solution of 30 mL of dry methylene chloride and 0.1 mL of trimethylamine. The reaction was stirred at 0 C for 5 hours. The solvent was removed by rotary evaporation. Purified by silica gel column chromatography yielding 0.42 g of QLBM yellow solid, yield 73%. | |
With thionyl chloride;Reflux; | General procedure: Compound 28a (191 mg, 1 mmol) was refluxed in excess of thionylchloride (3 mL) overnight. Excess of thionyl chloride was evaporatedand the residue was dissolved in CH2Cl2, 3-bromopropylamine hydrobromide(328 mg, 1.5 mmol was added followed by triethylamine (TEA;0.42 mL, 3 mmol). The reaction mixture was stirred at room temperature.After the reaction was completed, the reaction mixture was dilutedwith CH2Cl2 and sequentially washed with water, 1 N HCl and saturatedNaHCO3. The organic layer was dried over MgSO4, filtered and concentrated.The obtained product was purified by column chromatographywith n-hexane: Ethyl acetate (EtOAc)=4:1 to obtain 29a,(236 mg, 76%) as white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84.1% | With hydrogenchloride; acetic acid for 3h; Heating; | |
Stage #1: quinoline-2-carboxylic acid methyl ester With water; lithium hydroxide In methanol at 20℃; for 2h; Stage #2: With hydrogenchloride In water | 50 Example 50:To a stirred solution of lithium hydroxide (20.0 mg, 0.84 mmol) in water (1 mL), methyl quinoline-2-carboxylate (20.0 mg, 0.1 1 mmol) in methanol (3 mL) was added. The solution was left to stir at room temperature for 2 h. The solution was then concentrated in vacuo. The yellow solid residue was dissolved in water and made acidic with concentrated hydrochloric acid. The organic material was extracted with ethyl acetate. The organic layers were dried with anhydrous sodium sulphate, filtered, and concentrated in vacuo to yield quinoline-2- carboxylic acid as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With pyridine; triphenyl phosphite at 100℃; for 4h; | |
With 1,1'-carbonyldiimidazole In tetrahydrofuran at 20℃; for 7h; | (SS)/(RR)-Q (3) General procedure: Quinoline-2-carboxylic acid (2.16 g, 12.5 mmol) was divided into three portions and added to a solution of di(1H-imidazol-1-yl)methanone (1.56 g, 12.5 mmol) in 30 mL THF every 5 minutes, and then a solution of (1S,2S)/(1R,2R)-1,2-diphenylethane-1,2-diamine (1.06 g, 5 mmol) in 20mL THF was slowly added to the mixture at room temperature. After 7 hours, the mixture was diluted with water (200 mL), and extracted with CH2Cl2 (3 × 40 mL). The combined organic layers were washed with saturated NaCl aqueous solution and evaporated under reduced pressure to obtain the crude product. The residue was purified through column chromatography on silica gel using dichloromethane/hexane (10:1) as eluent to obtain the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Decarboxylation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 98% 2: 82% 3: 1% | With formic acid at 20℃; for 20h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | Stage #1: quinoline-2-carboxylic acid With pyridine; di-<i>tert</i>-butyl dicarbonate In 1,4-dioxane for 0.166667h; Stage #2: With ammonium bicarbonate In 1,4-dioxane at 20℃; for 24h; | |
99% | With pyridine; di-<i>tert</i>-butyl dicarbonate; ammonium bicarbonate In 1,4-dioxane at 25℃; for 24h; | |
88.3% | With ortho-tungstic acid; urea; zinc(II) oxide at 180℃; for 8h; | 18 Example 18 In the reaction kettle, add 17.2g, 0.1mol 2-quinoline carboxylic acid, add 24g, 0.4mol urea, 0.8g, 10mmol zinc oxide, 1.25g, 5mmol tungstic acid, 200ml DMPU, heat up to 180 degrees, stir to react 8 hour. Filtration with suction, and rotary evaporation under reduced pressure to remove the solvent to obtain 18.6 g of a pale yellow crude product of 2-quinolinecarboxamide. The crude product was recrystallized by heating and refluxing with 30 ml of ethanol to obtain 15.1 g of white crystals with a yield of 88.3%. |
86% | Stage #1: quinoline-2-carboxylic acid With pyridine; di-<i>tert</i>-butyl dicarbonate In 1,4-dioxane for 0.166667h; Stage #2: With ammonium bicarbonate In 1,4-dioxane at 20℃; for 24h; | 2.1 (1) Combine quinoline-2-carboxylic acid (3.46g, 20mmol, 1equiv) and (Boc) 2O (5.68 g, 26 mmol, 1.3 equiv) was dissolved in 1,4-dioxane (100 mL), and then pyridine (2 mL) was added. After stirring for 10 min, NH4HCO3 (2.06g, 26mmol, 1.3equiv) was added in batches, and then the reaction mixture was stirred at room temperature for 24h. After the reaction was completed, the solvent was evaporated, and the residue was dissolved in EtOAc (200 mL).The organic phase was washed sequentially with saturated aqueous NaHCO3 (3×80 mL) and water (80 mL), dried over anhydrous Na2SO4, and spin-dried under reduced pressure to obtain quinoline-2-carboxamide. |
86% | With pyridine; di-<i>tert</i>-butyl dicarbonate; ammonium bicarbonate In 1,4-dioxane at 20℃; for 24h; | 2.1 step 1: To quinoline-2-carboxylic acid (3.46g, 20mmol, 1 equiv) and(Boc) 2O (5.68 g, 26 mmol, 1.3 equiv) in 1,4-dioxane (100 mL) solution was added pyridine (2 mL).After stirring for 10 min, NH4HCO3 (2.06 g, 26 mmol, 1.3 equiv) was added in batches, and then stirred at room temperature for 24 hours.After the reaction was completed, the solvent was spin-dried, and the residue was dissolved in EtOAc (200 mL).The organic phase was washed with NaHCO3 (3×80mL) and water (80mL), dried with anhydrous sodium sulfate,Then the solvent is removed and dried to obtain quinoline-2-carboxamide. |
84% | With ammonium chloride; triethylamine at 20℃; for 0.0166667h; | |
79% | With 1H-imidazole; urea for 0.0638889h; microwave irradiation; | |
Multi-step reaction with 2 steps 1: CH2Cl2 / 0.5 h 2: NH3 / CH2Cl2 / 0.05 h | ||
With ammonia at 195℃; for 0.5h; | A Amide Intermediate Preparation Example A General procedure: Into a 1L open reactor was added 500g of carboxylic acid raw material (chemically pure) and stirring was turned on (600 r/min) from the reactorThe bottom is continuously fed with ammonia gas (chemical purity, water content of 5.1% by weight, flow rate of 100 g/min) to the carboxylic acid feed. After the reaction was allowed to proceed for TC hours at the reaction temperature TA, ammonia gas flow was stopped. The contents of the reactor were sampled and subjected to nuclear magnetic proton and elemental analysis to characterize the amide intermediate. Specific reaction conditions and characterization results are shown in Table A-1, Table A-2, Table A-3, Table A-4, Table A-5 and Table A-6. These characterization results show that the amide intermediates obtained have an extremely high purity (above 99%).In this embodiment, the ammonia gas can be directly replaced with waste ammonia gas (from Yangzi Petrochemical Plant, containing approximately50wt% of ammonia gas, the rest were toluene, oxygen, nitrogen, steam, carbon monoxide, and carbon dioxide, and the flow rate of this waste ammonia was 130g/min). | |
Multi-step reaction with 2 steps 1.1: triethylamine / tetrahydrofuran / Reflux 2.1: ammonium hydroxide / tetrahydrofuran; ethanol; water / 4 h / 20 °C 2.2: 0.33 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58.2% | Quinaldichydroxamic acid was made by first preparing fresh hydroxylamine. The fresh hydroxylamine was prepared by combining hydroxylamine hydrochloride (12.0 g, 173 mmol) and potassium hydroxide (11.4 g, 173 mmol) in methanol (200 mL) at 0 C. The solution was stirred for 20 minutes, filtered to remove potassium chloride, and set aside. Meanwhile, quinaldic acid (20.0 g, 116 mmol) and N-methylmorpholine (14.0 mL, 127 mmol) were combined with stirring in dichloromethane (300 mL). This solution was cooled to 0 C, at which time ethylchloro formate (12.1 mL, 127 mmol) was added. This reaction was stirred for 20 minutes, and then filtered. The hydroxylamine solution was added to the filtrate at 0 C. This reaction mixture was allowed to warm to room temperature and was stirred for 1.5 hours. The volume was reduced to about 200 mL en vacuo and water (1 L) was added to induce the precipitation of a white solid. The solid was collected by filtration and triturated with hot dichloromethane (800 mL) to yield quinaldichydroxamic acid (12.7 g, 58.2%) as a white powder. M.p. 146 - 148C. Electrospray ionization-mass spectroscopy (ESI-MS), calc. for [M + H+], C10H9N2O2, 189.1; found 189.1; calc. for [M + Na+], CioH8N2Na02, 211.0; found 211.1. 1H NMR (400 MHz, DMSC ) delta 11.51 (s, 1 H), 9.18 (s, 1 H), 8.53 (d, J = 8.5 Hz, 1 H), 8.09 - 8.04 (m, 3H), 7.84 (m, 1 H), 7.69 (m, 1H). 13C NMR (100 MHz, DMSO-<) delta 161.7, 150.3, 146.0, 137.6, 130.4, 129.2, 128.6, 128.0, 127.9, 118.7. Elem. Anal, calc. (found) for (C10H8N2O2XH2O), C: 58.25 (58.25), H: 4.89 (4.94), N: 13.59 (13.65). UV-vis (MeOH), lambdaomegaalphachi, nm (log epsilon) 207 (4.4), 238 (4.5), 300(br) (3.5). | |
General procedure: A 10 mL test tube was charged with 3-phenylpropanoic acid (1l) (0.300 g, 2.00 mmol) and anhydrous DMSO (2 mL) and placed under an argon atmosphere. CDI (0.486 g, 3.00 mmol) was added and the resulting mixture was stirred at rt for 1 h. DMAP (24.0 mg, 0.200 mmol) and NH2OTMS (0.420 g, 4.00 mmol) was added at rt and stirred at ambient temperature for 18 h. After addition of anhydrous K2CO3 (0.696 g, 5.04 mmol), the resulting mixture was heated to 90 C and stirred at that temperature for 3 h. After cooling of the reaction mixture to rt, 2 M HCl (2 mL) was added and stirred for 1 h. 2 M NaOH (3 mL) was added to the reaction mixture at 0 C and then Z-chloride (0.51 mL, 3.6 mmol) was added. After stirred for 16 h, the mixture was extracted with CH2Cl2 (15 mL× 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/Et2O = 2:1) to yield the pure N-Boc-(2-phenylethyl)amine (3a) (0.180 g, 41%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With diphenylphosphoranyl azide; triethylamine; In N,N-dimethyl-formamide; | To a solution of <strong>[93-10-7]quinoline-2-carboxylic acid</strong> (1 g, 5.7 mmol) in anhydrous DMF (10 mL) was added triethylamine (0.95 mL, 6.8 mmol) followed by diphenyl phosphoryl azide (1.48 mL, 6.8 mmol) and this mixture was stirred overnight. At this time the resulting solution was diluted with ethyl acetate and washed repeatedly with water. The organic layer was washed with brine, separated and dried over sodium sulfate. After filtration the organics were concentrated and the residue purified by silica gel chromatography eluting with a gradient of 0-20% ethyl acetate in hexanes. The title compound (94) was obtained as a white solid following evaporation of fractions (0.77 g, 65%). This material was used directly in the next step. |
General procedure: Under argon, a stirred solution of appropriate carboxylic acid (0.37 mmol, 1.0 eq.) and Et3N (0.48 mmol, 1.3 eq.) in dry THF (7 mL) was cooled to -10 C. Ethyl chloroformate (0.55 mmol, 1.5 eq.) was dropwise added and the resulting mixture was stirred for 2 h. Afterward, a solution of sodium azide (0.63 mmol, 1.7 eq.) in water (2 mL) was added in one portion. After 1 h at -10 C, the reaction was found to be complete (TLC) and was quenched into iced water (5 mL). The mixture was extracted with EtOAc (3 * 10 mL) and the combined organic layers were successively dried over MgSO4, filtered and evaporated under reduced pressure. The crude acyl azide was placed in dry toluene (20 mL) and the mixture heated at reflux for 1 h to give the corresponding crude isocyanate. The latter was dissolved in dry dioxane (7 mL) prior to adding the amine 4 (0.37 mmol, 1.0 eq.). The solution was heated at reflux for 24 h. The reaction mixture was cooled to room temperature and the volatiles were removed to dryness in vacuum at 40 C. The dark residue was purified by silica gel chromatography column (CH2Cl2/MeOH 99/1) to afford the desired valmerins. | ||
With diphenyl phosphoryl azide; triethylamine; In 1-methyl-pyrrolidin-2-one; at 0 - 35℃; for 1h;Schlenk technique; Inert atmosphere; | General procedure: 2-Pyridinecarboxylic, 2-quinolinecarboxylic or 1-isoquinolinecarboxylic acid (1.5 mmol) and NEt3 (1.5 mmol,152 mg, 209 mL) were added to dry NMP (2.1 mL) in a Schlenk flaskunder Ar atmosphere. At 0 C, diphenyl phosphoryl azide(1.6 mmol, 440 mg, 345 mL) was added drop-wise and the reactionmixture was stirred at 35 C for 1 h. N-Oxide (1 mmol) was thenadded in one portion and the reaction mixture was stirred at 70 Cfor 20 h. The mixture was then poured into water (50 mL) andextracted with AcOEt (3 x 20 mL). Combined organic extracts werewashed with brine (5 x 30 mL) dried over anhyd. Na2SO4 andevaporated. Products 2 were purified by column chromatographyon silica gel using hexaneseAcOEt 2:1 or tolueneeAcOEt 2:1, thenAcOEt as eluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Method B: Methyl lithium (1.6M solution in diethyl ether, 1OmL) was added to a solution of quinoline-2-carboxylic acid (1.4Og, 8.1mmol) in THF (4OmL) at O0C under an EPO <DP n="22"/>atmosphere of argon. After 2hr successively chlorotrimethylsilane (1OmL, 79mmol) and then after a period of lOmin dilute hydrochloric acid (IM, 3OmL) were added under vigorous stirring. The aqueous layer was separated, further diluted with water (20OmL) and neutralised with solid NaHCO3. Similar work-up and purification to Method A gave the title compound, delta? (DMSO): 2.80 (3H, s), 7.78 (IH, m), 7.90 (IH, m), 8.07 (IH, d), 8.81 (IH, d), 8.20 (IH, d), 8.57 (IH, d); m/z (ES+) = 172.10 [M+H]+; RT = 3.34 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran; water; | 2-(Trifluoromethyl)-decahydroquinoline 15 g (0.076 mol) of <strong>[347-42-2]2-(Trifluoromethyl)quinoline</strong> [prepared from quinoline-2-carboxylic acid according to M. S. Raasch, J. Org. Chem. 27, 1406 (1962)] were hydrogenated in 100 ml of tetrahydrofuran on 2.5 g of ruthenium on alumina (about 10% RU content) at 180 C. for 8 h at an H2 pressure of 80-100 bar in a 0.3 1 V4A autoclave. After filtration, the THF was stripped off and the crude product was fractionated in a water pump vacuum by means of a microdistillation apparatus. B.p.16 (main fraction): 88 C. Yield: 12.5 g (0.061 mol) (80% of theory) The product was obtained as a diastereomer mixture. 19 F--NMR: delta=+0.65 ppm(d, JH-F =7.1 Hz)(according to integral about 88%) 19 F--NMR: delta=+0.90 ppm(d, JH-F =7.1 Hz)(according to integral about 12%) (against external CF3 COOH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | To an oven dried 250 mL round bottomed flask was weighed quinaldic acid (1.734 g, 10.0 mmol). A magnetic stir bar was added and the flask was put under N2 atmosphere. The flask was charged with DCM (100 mL) and cooled to 0 C. in an ice bath. The flask was then charged with N-methyl morpholine (1.44 mL, 15.0 mmol) and isobutlychloroformate (1.51 mL, 11.5 mmol) via syringe addition. The reaction was allowed to stir at 0 C. for 20 min until the solution became cloudy. At which point freshly distilled ethanolamine (695 uL, 11.5 mmol) was added slowly to the flask via syringe. The reaction mixture was allowed to slowly warm to room temperature to form N-(2-hydroxyethyl)quinoline-2-carboxamide was formed according to the formula The reaction mixture was quenched, after stirring for 2 h at room temperature, with saturated sodium bicarbonate solution (80 mL) and transferred to a reparatory funnel with DCM (2×15 mL). The layers were separated, and the aqueous layer was back extracted with DCM (2×30 mL). The combined organic phases were washed with water (1×70 mL), which was back extracted with DCM (2×25 mL). The combined organic phases were washed with brine (1×100 mL), which was back extracted with DCM (1×25 mL). Combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting mixture was purified by flash chromatography using a mixed solvent system: 70% EtOAc, 19% DCM, 10% Hexanes, and 1% MeOH. The product was isolated (1.95 g, 90% yield) as a colorless solid by recrystallizing by slow evaporation of DCM. The product was confirmed via NMR, IR and HRMS analyses. Measured melting point was 107-109 C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | To an oven dried 250 mL round bottomed flask was weighed quinaldic acid (866 mg, 5.0 mmol). A magnetic stir bar was added and the flask was put under N2 atmosphere. The flask was charged with DCM (50 mL) and cooled to 0 C. in an ice bath. The flask was charged with N-methyl morpholine (720 muL, 7.5 mmol) and isobutlychloroformate (752 muL, 5.75 mmol) via syringe addition. The reaction was allowed to stir at 0 C. for 10 min until the solution became cloudy. At which point 2-methyl-2-aminopropanol (550 uL, 5.75 mmol) was added slowly to the flask via syringe. The reaction mixture was allowed to slowly warm to room temperature. The reaction was quenched after 2 h with 1M HCl solution (30 mL) and transferred to a separatory funnel with DCM (50 mL). The layers were partitioned and the organic phase was washed with H2O (2×30 mL) and brine (1×40 mL). After drying over Na2SO4 and filtration, the mixture was concentrated under reduced pressure. The crude mixture was purified by flash chromatography eluting with a 1:1 mixture of EtOAc and hexanes to afford N-(1-hydroxy-2-methylpropan-2-yl)quinoline-2-carboxamide as a colorless oil in 91% yield (1.112 g, 4.55 mmol) according to the following reaction | |
88% | With benzotriazol-1-ol; dicyclohexyl-carbodiimide; In tetrahydrofuran; at 0 - 20℃;Inert atmosphere; Schlenk technique; | A solution of <strong>[93-10-7]quinoline-2-carboxylic acid</strong> (346 mg, 2.0 mmol), N,N'-dicyclohexylcarbodiimide (870 mg, 4.2 mmol), N-hydroxybenzotriazole (300 mg, 2.2 mmol), and 2-amino-2-methylpropan-1-ol (178 mg, 2.2 mmol) in dry THF was stirred at 0 C for 1 h and then at room temperature for overnight. The reaction was monitored by TLC for a complete conversion. The resulting mixture was filtered through celite, concentrated under reduced pressure, adn purified by silica gel column chromatography to give N-(1-hydroxy-2-methylpropan-2-yl)quinoline-2-carboxamide in 88% yield as a white solid. The amide was dissolved in dry dichloromethane (50 mL) together with 4-dimethylaminopyridine (12 mg, 0.1 mmol) and triethylamine (0.60 mL). The mxiture was coolded in an ice-water bath and methanesulfonyl chloride (230 muL, 3.0 mmol) was added. The mixtrue was stirred at 0 C for 0.5 h, and another portion of triethylamine (2.40 mL) was added. The resulting mixture was warmed to 40 C. The reaction was monitored with TLC for a complete conversio. The reaction mixture was concentrated under reduced pressure, and purified by silica gel column chromatography (pre-neutralized with Et3N) to give 4,4-dimethyl-2-(quinolin-2-yl)-oxazoline (8) in 72% ytield as a white solid, m.p. 75 - 77 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: 4-methyl-morpholine; isobutyl chloroformate / dichloromethane / 0.33 h / 0 °C / Inert atmosphere 1.2: 0 - 20 °C / Inert atmosphere 2.1: dmap; triethylamine; p-toluenesulfonyl chloride / 1,2-dichloro-ethane / 5.58 h / -5 - 85 °C / Inert atmosphere | ||
Multi-step reaction with 3 steps 1: thionyl chloride / Reflux; Inert atmosphere 2: potassium hydroxide / chloroform; water / 1 h / 0 °C / Inert atmosphere 3: sodium hydride / tetrahydrofuran; mineral oil / 24 h / 0 - 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With water-d2; silver carbonate; In dimethyl sulfoxide; at 120℃; for 16h; | 2-quinoline carboxylic acid (1.73 g, 10 mmol) was dissolved in DMSO (50 mL) containing D20 (10 mL). Silver carbonate (0.28 g, 1 mmol) was added and the mixture was heated at 120 deg for 16 hours. The solid was filtered off through a bed of Celite and washed with ethyl acetate (200 mL). The filtrate was washed with water, separated and the organic layer was washed with brine, dried (MgS04), filtered and concentrated to yield 2-2H-quinoline in a 95% yield. |
78.049% | With water-d2; silver carbonate; In dimethyl sulfoxide; at 140℃; for 16h; | A solution of <strong>[93-10-7]quinoline-2-carboxylic acid</strong> (1.5 g, 8.66 mmol), silver(I) carbonate (238.85 mg, 0.87 mmol) and deuteroxide (9 mL) in DMSO (45 m L) was stirred at 140 C. for 16 h. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure to give the crude product as colorless oil, which was purified by FCC (petroleum ether: ethyl acetate=100:0 to petroleum ether/ethyl acetate=0:100) to afford the title compound (0.88 g, 78.049%) as a colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With triethylamine; trichlorophosphate In dichloromethane at 0 - 20℃; for 2.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With sodium methylate In methanol at 20℃; for 5h; | Synthesis of [RuCl(quinto)(p-cymene)] (I) A round-bottom flask was charged with [RuCl2(p-cymene)2]2 (0.1 g, 0.163 mmol), quinaldic acid (0.056 g, 0.326 mmol) and NaOMe (0.02 g, 0.37 mmol).The resulting mixture was stirred in methanol (40 ml) for 5 h at room temperature. The red solution becomes cloudy as the reaction progress and yellow solid appeared. The solid was collected and washed with cold methanol and then with diethyl ether (2 10 ml) and dried under vacuum. Yield 0.129 g (81%); Yellow solid; 1HNMR (CDCl3, δ): 8.59 (d, 1H, J = 8.7), 8.40 (d, 1H, J = 8.3), 8.23 (d, 1H, J = 8.4), 8.02-7.97 (m, 2H), 7.79 (d, 1H, J = 14.7), 5.74 (d, 1H, J = 5.8), 5.54 (d, 2H, J = 6), 5.42 (d, 1H, J = 6), 2.61 (m, 1H), 2.26 (s, 3H), 1.11 (d, 3H, J = 6.9), 1.00 (d, 3H, J = 6.9). |
79% | With triethylamine In acetonitrile at 20℃; for 24h; Inert atmosphere; Schlenk technique; | 4.2 Synthesis and characterization of compounds General procedure: Monometallic complexes M1-3 were prepared from [Ru(p-cymene)Cl2]2 or [IrCl2Cp*]2 with pyrazine-2-carboxylic acid(1), pyridine-2-carboxylic acid (2), quinoline carboxylic acid(3). Acetonitrile (10mL) was used as solvent and reactions were performed in the presence of NEt3 for 24h at room temperature. The yellow solid was filtrated and washed with diethyl ether (20mL). The product was dried under vacuum. The reaction of [RuCl2(p-cymene)]2 and [IrCl2Cp*]2 with imidazole-4,5-dicarboxylic acid gave the bimetallic complexes (Ru4 and Ir4) respectively. The complexes (Ru5, Ir5) were synthesized according to literature [20]. |
With sodium methylate In methanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | To a solution of <strong>[107-35-7]taurine</strong> (13 mg, 0.104 mmol) in dry DMF (1 mL) was added HOBt (28 mg, 0.207 mmol) and the reaction mixture was stirred for 15 min at rt. The reaction mixture was then cooled to 0 C, EDCI (40 mg, 0.209 mmol) was added and continued stirring for 30 min at 0 C. To this mixture was then added compound 8 (18 mg, 0.104 mmol) and the mixture was stirred for 48 h at rt. The pure synthetic stolonine B was purified by RP-HPLC (MeOH, H2O, 0.1% TFA)to obtain 21.8 mg (75% yield); IR (film) numax 3383, 1677, 1201 and 1064 cm-1; 1H (600 MHz, DMSO-d6) and 13C (150 MHz, DMSO-d6) NMR data are summarized in Table 5; (-)-HRESIMS m/z 279.0446 [M - H]- (calcd for [C12H11N2O4S]-, 279.0445, Delta 0.4 ppm). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | Stage #1: 2-nitro-benzaldehyde With hydrogenchloride; iron In ethanol; water Reflux; Stage #2: pyruvic acid methyl ester With potassium hydroxide In ethanol; water at 20℃; for 1.5h; Reflux; | Quinoline-2-carboxylic acid (8) To a solution of o-nitrobenzaldehyde (7, 302 mg, 2 mmol) in ethanol (5 mL) was added iron powder (504 mg, 9 mmol), followed by 0.1 N HCl (2 mL, 0.2 mmol) and the resulting mixture was vigorously stirred under reflux for 45 min. Methyl pyruvate (200 μL, 2 mmol) and powder KOH (135 mg, 2.4 mmol) were added slowly. The reaction mixture was stirred under reflux for 90 min and then cooled to rt. The crude product was purified by RP-HPLC (MeOH, H2O, 0.1% TFA) to yield 8 (190 mg, 55% in two steps); 1H NMR (500 MHz, DMSO-d6) δ 8.56 (1H, d, J = 8.5 Hz), 8.16 (1H, d, J = 8.0 Hz), 8.11 (1H, d, J = 8.5 Hz), 8.09 (1H, d, J = 8.0 Hz), 7.88 (1H, t, J = 8.0 and 7.5 Hz) and 7.74 (1H, t, J = 8.0 and 7.5 Hz); 13C NMR (125 MHz, DMSO-d6) δ 166.2 (COOH), 148.5 (C), 146.6 (C), 137.6 (CH), 130.5 (CH), 129.5 (CH), 128.7 (C), 128.5 (CH), 127.9 (CH) and 120.6 (CH). (+)-LRESIMS m/z 174. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
29% | With copper(II) chloride monohydrate; dihydrogen peroxide; oxygen; potassium carbonate; calcium chloride at 80℃; for 15h; Sealed tube; Green chemistry; | Methyl Esters; General Procedure General procedure: Carboxylic acid (0.5 mmol, 1.0 equiv), K2CO3 (0.5 mmol, 1.0 equiv),and CaCl2 powder (0.5 mmol, 1.0 equiv) were added to a 25-mL tube.10% CuCl2·2 H2O in DMSO (2.0 mL) was added, followed by the dropwise addition of 30% aq H2O2 (1.5 mmol, 3.0 equiv). The tube was sealed with a Teflon-lined cap and the mixture was stirred at 80 °C under O2 for 15 h. The mixture cooled and water (10 mL) was added; the mixture was extracted with EtOAc (3 × 10 mL). After evaporationof the solvent, the residue was purified by column chromatography(silica gel) to obtain the product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With dmap; dicyclohexyl-carbodiimide In dichloromethane at 25℃; Inert atmosphere; Schlenk technique; | 2 4.2 Synthesis of chiral ligands L3-L8 General procedure: To a solution of L1 or its enantiomer (0.35mmol) in dry CH2Cl2 (6mL), dicyclohexylcarbodiimide (0.39mmol), carboxylic acid or N-protected amino acid (0.44mmol) and DMAP (0.11mmol) were added, respectively. Then the reaction mixture was stirred at 25°C under N2 atmosphere for 2-6h (monitoring by TLC). After the reaction was completed, the solvent was removed under reduced pressure and the residue was purified by a flash column chromatography on silica gel to afford the amidophosphine compounds. (0016) For preparing ligands L5-L7, a mixture of 1:1 CH2Cl2/TFA (12mL) was added to the N-Boc amidophosphine, and the solution was stirred at 25°C for 3h under N2 atmosphere. Then the reaction mixture was neutralized with aqueous NaHCO3 to pH ca. 9, and it was extracted with CH2Cl2 (3×10mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by a flash column chromatography on silica gel to afford the deprotected products |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52.9% | General procedure: A mixture of acid 10-13 (10 mmol) and CDI (10 mmol) in acetonitrile (100 mL) or DMF (100 mL)was stirred for 1 h at room temperature. Then the appropriate polyamine (a-d) (6 mmol) was addedand stirring was continued for additional 2 h, then the mixture was filtered. The solvent was removedunder reduced pressure and 20 mL of H2O was added to the residue and left for 24 h at 5 C(for compounds 11a-d, 13a-d, 14a-d. Then the solid was filtered off, washed with H2O and crystallizedfrom DMF/H2O. In case of compounds 12a-d the residues were purified by column chromatographyover silica gel (CHCl3/MeOH, 100:1, 10:1, v/v). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 18h;Inert atmosphere; | A mixture of quinaldine acid (5) (2.0 g, 11.55 mmol), dried K2CO3 (3.19 g, 23.10 mmol) and anhydrous DMF (24 mL) was stirred until the reagents had been dissolved under an argon atmosphere. Iodoethane (2.77 mL, 34.65 mmol) was added and stirred for 18 h to 60 C. A 30% cooled aqueous solution of HCl (30 mL) was added. The medium was neutralized with a saturated solution of NaHCO3 until the gas formation was ceased. Extraction was carried out with ethyl acetate (3x 60 mL). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography by eluting with hexane/AcOEt (8:2) to furnish ester 6 as a translucent oil in quantitative yield. Rf 0.51 (hexane/AcOEt 7:3). IR (neat) numax/cm-1: 3061, 2982, 2938, 2904, 1714, 1463, 1368, 1312, 1133, 1103, 1016, 844, 774. 1H NMR (400 MHz, CDCl3) delta 7.96-7.94 (m, 1H), 7.85-7.81 (m, 1H), 7.76-7.73 (m, 1H), 7.42-7.36 (m, 2H), 7.22-7.18 (m, 1H), 4.22-4.17 (m, 2H), 1.14-1.10 (m, 3H). 13C NMR (100 MHz, CDCl3) delta 164.9, 147.9, 147.2, 136.8, 130.3, 129.8, 128.9, 128.1, 127.2, 120.6, 61.7, 14.1. HRMS (ESI+) calcd for C12H11NO2 [M+H]+ 202.0868, found 202.0868. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 4h; | 43.43a Step 43a: 2-quinolinecarboxylic acid (compound 0802-133)preparation: The compound 2-quinoline carboxylic acid (0801-133) (1.0 g, 5.77 mmol, 1.0 equiv) andPotassium carbonate (1.59 g, 11.54 mmol, 2.0 equiv)Add 30 ml of DMF,Then add methyl iodide (0.98 g, 6.93 mmol, 1.2the amount),The mixture was stirred at room temperature for 4 hours.After the reaction was completed, 100 ml of water was added and extracted with ethyl acetate.The phases were washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the target product methyl 2-quinolinecarboxylate (0.80 g, crude) as a white solid. | |
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 24h; | 6 Example 6: Synthesis of 7a The specific synthesis operation is as follows: Synthesis of 1. Quinoline-2-carboxylic acid (23.10mmol) in 30ml of N,N-dimethylformamide, adding anhydrous potassium carbonate (23.10mmol) and methyl iodide (46.20) mmol), react at room temperature for 24h. Then it was poured into 300ml water, filtered with suction to obtain a solid, dried and dissolved in 40ml anhydrous methanol, added hydrazine hydrate (92.40mmol), and reacted at 66°C for 8h. After the reaction was completed, the solid was obtained by suction filtration, washed with water, dried, and recrystallized with anhydrous methanol to obtain a white solid product 1, with a yield of 68%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate In N,N-dimethyl-formamide at 20℃; for 1h; | 2.7. General procedure for the synthesis of pyrimidine scaffoldbenzamide derivatives (9 a-k) General procedure: The final target compounds were synthesized from 6-methyl-N-(4-(pyridin-3-yl) pyrimidin-2-yl) benzene-1,3-diamine 8(2 mmol), DMF (10 mL), and DIPEA (4 mmol) followed by substituted aromatic acid (2 mmol) was added and stirred at room temperature for 1 h. After completion of the reaction mixture was poured into ice-cold water. The obtained yellow precipitate washed with water and dried to get target titled product pyrimidine scaffold benzamide derivatives (9 a-k). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; In water; | The ethyl ester of quinoline-2-carboxylate obtained in the step (3) is hydrolyzed by an aqueous solution of hydrochloric acid to obtain quinoline-2-carboxylic acid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With tert-butylhypochlorite; sodium carbonate; sodium bromide; at 60℃; for 20h;Schlenk technique; | Weighing quinoline-2-carboxylic acid (51.9 mg, 0.3 mmol),Sodium carbonate (64.0 mg, 0.6 mmol), NaBr (17.6 mg, 0.3 mmol), tert-butyl hypochlorite (32 muL, 0.3 mmol) into a 25 mL of Schlenk reaction bottle, Then CH2Br2 (2 mL) was added and placed in a 60 C oil bath for 20 h. After completion of the reaction, the solvent was removed under reduced pressure and eluted with petroleum ether / ethyl acetate.The solvent was separated on a silica gel column, he yield of 2-bromoquinoline was 75%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With tert-butylhypochlorite; dichloromethane; sodium hydrogencarbonate at 60℃; for 20h; Green chemistry; | |
82% | With tert-butylhypochlorite; sodium carbonate; sodium chloride In dichloromethane at 60℃; for 5h; Schlenk technique; | 1 Example 1: Synthesis of 2-chloroquinoline (2a) Weighing quinoline-2-carboxylic acid (51.9 mg, 0.3 mmol), sodium carbonate (16.0 mg, 0.15 mmol), NaCl (26.3 mg, 0.45 mmol), tert-butyl hypochlorite (102 μL, 0.9 mmol) into a 25 mL of Schlenk reaction bottle, then, CH2Cl2 (2 mL) was added and placed in a 60 °C oil bath for 5 h. After completion of the reaction, the solvent was removed under reduced pressure and eluted with petroleum ether / ethyl acetate.The solvent was separated on a silica gel column, and the yield of 2-chloroquinoline was 82%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With triethylamine; In tetrahydrofuran;Reflux; | The following procedure was scaled up from a previously reportedsynthesis of 2-quinolinyl(acylbenzotriazole) [13]. Quinaldic acid(4.53 g, 26.2 mmol) and 1-(methanesulfonyl)benzotriazole (5.16 g,26.2 mmol) were fully dissolved in 130 mL THF, resulting in a colorlesssolution. Triethylamine (5.12 mL, 36.7 mmol) was added dropwise tothe THF solution, resulting in a cloudy white mixture, and refluxedovernight. After several hours, the solution turned deep red/pink.Upon, cooling the solvent was then removed in vacuo and the resultingred solid was redissolved in 260 mL CHCl3. The orange/red solutionwas then washed once with deionized water and then 3M brine (3 x200 mL), the organic layer was dried over anhydrous Na2SO4, andCHCl3 was evaporated to yield an orange solid. This solid was recrystallizedvia dissolution into a small amount of near boiling CHCl3(25 mL), addition of 30 mL hexanes, and storage in a -20 C freezerovernight, to yield a pink fluffy solid. The solid was isolated via vacuumfiltration and dried for 6 h in a vacuum oven (3.96 g, 55% yield). 1HNMR (400 MHz, CDCl3) delta (ppm): 8.43 (dd, J=8.6, 2.0 Hz, 2H), 8.27(d, J=8.5 Hz, 1H), 8.20 (dt, J=8.3, 0.8 Hz, 1H), 8.10 (d, J=8.5 Hz,1H), 7.96 (dd, J=8.3, 1.5 Hz, 1H), 7.84 (ddd, J=8.5, 6.8, 1.5 Hz, 1H),7.74 (m, 2H), 7.59 (m, 1H). The 1H NMR spectrum matched that previouslypublished so the product was used without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In tetrahydrofuran; water; | EXAMPLE 55 Preparation of N-(1-carbamoyl-1,2-dimethylpropyl)quinaldamide STR203 To a solution of quinaldic acid (20 g, 0.116 mol) in tetrahydrofuran (500 ml) cooled to -9 C. is added methyl chloroformate (8.92 ml, 0.116 mol) followed by triethylamine (18.4 ml, 0.139 mol). After 20 minutes <strong>[40963-14-2]2-amino-2,3-dimethylbutyramide</strong> (15.1 g, 0.116 mol) is added and the mixture stirred overnight at room temperature. Water is added and the solution is reduced to 200 ml of a rotorvap. A white solid separates and is filtered off, water washed and dried. Recrystallization from absolute ethanol gives the product mp 179-180 C., 26.86 g (87%). Anal. calcd. for C16 H19 N3 O2: C, 67.34; H, 6.73; N, 14.72. Found: C, 67.14; H, 6.17; N, 14.72. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36 %Chromat. | With dipotassium peroxodisulfate; bismuth (III) nitrate pentahydrate In acetonitrile at 130℃; for 24h; Sealed tube; | 4.1. General procedure A for decarboxylative nitration of arylcarboxylic acid General procedure: An oven dried resealable screw cap standard reaction tube containinga magnetic stir bar was charged with potassium persulfate(1.75 mmol, 472.5 mg), bismuth nitrate (1.0 mmol, 486 mg). Thenaryl carboxylic (0.5 mmol) was introduced in this mixture followedby acetonitrile (3 mL) was added in it. The tube was placed in apreheated oil bath at 130 °C and the reaction mixture was stirredvigorously for 24 h in air atmosphere. The reaction mixture wascooled to room temperature, diluted with 2 mL ethyl acetate andfiltered through celite, eluting with additional 10 mL of ethyl acetate.The filtrate was concentrated and the resulting residue waspurified by column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With polyphosphoric acid at 170℃; for 48h; Inert atmosphere; | 2.2. Synthesis According to the literature [4,5], 3.3 mmol quinaldic acid (1),1.5 mmol 3,3′-diamino- diphenylamine (2) and 25 mL polyphosphoricacid (PPA) were added into a round bottom flask, stirring 48 h at 170 °Cunder the atmosphere of N2. After the reaction was stopped and cooledto room temperature, the dark green mixture was obtained by addingwater and regulating pH to the range of 9-10 with sodium hydroxide.Then, the product was purified by column chromatography on silica gelwith gradient eluents of petroleum ether and ethyl acetate. 2,2′-Di(quinolin-2-yl)-3H,3′H-5,5′-bibenzo[d]imidazole (3), 0.63 g,yield 86%; yellow solid, m.p. 183.3-185.1 °C; 1H NMR (DMSO-d6-TMS,400 MHz), δ, ppm: 7.55-7.75 (6H, m), 7.80-7.89 (4H, m), 8.07 (2H, d,J=8.0 Hz), 8.15 (1H, s), 8.18 (1H, s), 8.49 (2H, d, J=8.0 Hz), 8.56(2H, d, J=8.0 Hz), 13.27 (2H, b); IR (film), ν, cm-1: 3493, 3048, 1662,1595, 1422, 1407, 1298, 1100, 1052, 836, 798, 758; ESI-MS, m/z (%):Calcd for C32H21N6+ ([M+H]+): 489.17 (100), Found: 489.21 (100);Anal. Calcd for C32H20N6: C 78.66, H 4.14, N 17.20, Found: C 78.59, H4.13, N 17. |
84.9% | With polyphosphoric acid at 165℃; for 50h; | 1.1-3.1 Example 2: (1) 2.39g (13.8mmol) of quinalic acid, 1.29g (6mmol) of 3,3'-diaminobenzidine and 36mL of polyphosphoric acid (PPA) were added to a 100mL three-necked flask, stirred and mixed uniformly, heated to 165C The reaction was stirred for 50 hours, heating was stopped, and 36 mL of deionized water was added after cooling to room temperature. Adjust the mixed solution to pH=10 with sodium hydroxide solution, and filter to obtain a brown solid. It was recrystallized three times with anhydrous ethanol and dried to obtain probe L. The yield: 84.9%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 24h;Inert atmosphere; | General procedure: DIPEA (10 eq), HBTU (3 eq) and quinoline-2-carboxylic acid (3 eq) were dissolved in anhydrous DCM under a nitrogen atmosphere and cooled to 0C. The amine derivative was added in small portions and the mixture was allowed to reach rt and stirred for 24h. The solution was washed with H2O and brine, twice each, dried and concentrated. The residue was subjected to flash column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83.6% | With polyphosphate at 160℃; for 48h; | The synthesis route of BAQ (2,2′-di(quinolin-2-yl)-1H,1′H-5,5′-bibenzo[d]imidazole) isshown in Scheme 1.14 Briefly, 0.0132 mol of quinoline-2-carboxylic acid and 0.006 mol of biphenyl-3,4,3',4'--tetraamine were dissolved in polyphosphate (25 mL), The mixture was refluxed for 48 h at160 °C, the reaction was stopped by adding distilled water, and then cooled to room temperature. Then, the pH value of the solution was adjusted to 9-10 with sodium hydroxide. Thebrown powder was collected by vacuum filtration, further purification was accomplished byrecrystallization from anhydrous ethanol, melting point 183-185 °C (yield: 83.6 %). |
With PPA at 170℃; for 48h; |
Tags: 93-10-7 synthesis path| 93-10-7 SDS| 93-10-7 COA| 93-10-7 purity| 93-10-7 application| 93-10-7 NMR| 93-10-7 COA| 93-10-7 structure
[ 1214363-66-2 ]
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