[ CAS No. 178984-69-5 ] {[proInfo.proName]}

Name: 178984-69-5|Methyl 4-chloroquinoline-7-carboxylate|98%
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Quality Control of [ 178984-69-5 ]

COA NMR CNMR HPLC LC-MS

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Product Details of [ 178984-69-5 ]

CAS No. :	178984-69-5	MDL No. :	MFCD18381419
Formula :	C₁₁H₈ClNO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	QUCTXYQKZCLAPW-UHFFFAOYSA-N
M.W :	221.64	Pubchem ID :	21708520
Synonyms :

Safety of [ 178984-69-5 ]

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:

Application In Synthesis of [ 178984-69-5 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Upstream synthesis route of [ 178984-69-5 ]
Downstream synthetic route of [ 178984-69-5 ]

[ 178984-69-5 ] Synthesis Path-Upstream 1~7

1
[ 863785-96-0 ]
[ 178984-69-5 ]

Yield	Reaction Conditions	Operation in experiment
86%	at 120℃; for 0.5 h;	A part of the residue (0.59 g) was dissolved in N,N-dimethylformamide (20 ml). Triethylamine (4 ml) and 10percent palladium/carbon (0.59 g) were added to the solution, and the mixture was stirred under a hydrogen gas atmosphere at room temperature overnight. The reaction mixture was filtered and was then washed with chloroform. The solvent was removed by distillation under the reduced pressure, and the residue was washed with methanol to give methyl 4-oxo-1,4-dihydro-quinoline-7-carboxylate (187 mg, yield 28percent) (3 steps). Methyl 4-oxo-1,4-dihydro-quinoline-7-carboxylate (650 mg) was suspended in diisopropylethylamine (7 ml), phosphorus oxychloride (1.5 ml) was added to the suspension, and the mixture was stirred at 120°C for 30 min. Water was added to the reaction mixture under ice cooling. The aqueous layer was neutralized with an aqueous sodium hydrogencarbonate solution, and the organic layer was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography with an acetone-chloroform system to give methyl 4-chloro-quinoline-7-carboxylate (609 mg, yield 86percent).

Reference： [1] Patent: EP1724268, 2006, A1, . Location in patent: Page/Page column 76

2
[ 49713-58-8 ]
[ 74-88-4 ]
[ 178984-69-5 ]

Yield	Reaction Conditions	Operation in experiment
61%	With potassium hydroxide In <i>N</i>-methyl-acetamide; methanol	(2) 7-Carboxy-4-chloroquinoline (5 g, 24.0 mmol) was dissolved in a mixed solution of potassium hydroxide (1.49 g, 26.6 mmol) with methanol (150 ml) and stirred at room temperature overnight. The reactant was evaporated to dryness under reduced pressure. The residue was added with dimethylformamide (DMF; 60 ml) and methyl iodide (3.5 g, 24.6 mmol) in the order named and stirred at 80° C. for an hour. The reaction mixture was poured into ice water. The resulting precipitates were collected by filtration, dried over phosphorus pentoxide and recrystallized from ethanol (20 ml) to obtain 3.6 g (61percent) of 7-methoxycarbonyl-4-chloroquinoline. Melting Point: 118°-119° C.; MS m/z: 221 (M⁺); NMR:δ 4.00(3H, s), 7.82(1H, d), 8.26(1H, dd), 8.38(1H, d), 8.73(1H, d), 8.95(1H, d)

Reference： [1] Patent: US5773449, 1998, A,

3
[ 1374258-80-6 ]
[ 178984-69-5 ]
[ 1416801-65-4 ]

Reference： [1] Patent: WO2012/177893, 2012, A2, . Location in patent: Page/Page column 142-143

4
[ 67-56-1 ]
[ 178984-69-5 ]

Reference： [1] Patent: US2004/102450, 2004, A1, . Location in patent: Page/Page column 72

5
[ 1078-30-4 ]
[ 178984-69-5 ]

Reference： [1] Patent: WO2012/177893, 2012, A2,

6
[ 51552-68-2 ]
[ 178984-69-5 ]

Reference： [1] Patent: WO2012/177893, 2012, A2,

7
[ 178984-69-5 ]
[ 49713-58-8 ]
[ 1150618-22-6 ]

Reference： [1] Patent: WO2012/177893, 2012, A2, . Location in patent: Page/Page column 143

[ 178984-69-5 ] Synthesis Path-Downstream 1~19

1
[ 178984-69-5 ]
[ 178984-44-6 ]

Yield	Reaction Conditions	Operation in experiment
	With lithium aluminium tetrahydride; In tetrahydrofuran; diethyl ether; at -45.0℃; for 0.333333h;Cooling with acetone-dry ice;	B. 7-Hydroxymethyl-4-chloroquinoline. <strong>[178984-69-5]7-Methyloxycarbonyl-4-chloroquinoline</strong> (2.1 g, 9.5 mmol) is dissolved in anhydrous THF (25 ML) and anhydrous ether (200 ML).The solution is cooled in a dry ice/acetone bath and treated 1M lithium aluminum hydride in THF (11.0 ML, 11 mmol).The solution is warmed (approximately -45 C.) for 20 minutes and quenched with ethyl acetate.The solution is diluted with ether (100 ML) and treated with water (36 ML), 15% NaOH (36 ML) and water (36 ML) in succession.The mixture is filtered and evaporated to yield the title compound as a residue (2.0 g, 9.7 mmol) which is dried under vacuum and used without further purification. MS m/z: M+=193; 1H NMR (CDCl3, 300 MHz) delta8.65 (d, 1H), 8.15 (d, 1H), 8.0 (d, 1H), 7.6 (d, 1H), 7.45 (d, 1H), 4.8 (s, 2H).
	With sodium hydroxide; In tetrahydrofuran; water;	Part B 7-Hydroxymethyl-4-chloroquinoline <strong>[178984-69-5]7-Methyloxycarbonyl-4-chloroquinoline</strong> (2.1 g, 9.5 mmol) is dissolved in anhydrous THF (25 mL) and anhydrous ether (200 mL). The solution is cooled in a dry ice/acetone bath and treated 1 M lithium aluminum hydride in THF (11.0 mL, 11 mmol). The solution is warmed (approximately -45 C.) for 20 min. and quenched with ethyl acetate. The solution is diluted with ether (100 mL) and treated with water (36 mL), 15% NaOH (36 mL) and water (3*36 mL) in succession. The mixture is filtered and evaporated to yield the title compound as a residue (2.0 g, 9.7 mmol) which is dried under vacuum and used without further purification. MS m/z: M+=193; 1H NMR (CDCl3, 300 MHz) delta0.00, 8.65 (d, 1H), 8.15 (d, 1H), 8.0 (d, 1H), 7.6 (d, 1H), 7.45 (d, 1H), 4.8 (s, 2H).
1.0 g (30%)	In methanol;	(3) 7-Methoxycarbonyl-4-chloroquinoline(3.75 g, 0.017 mol) was dissolved in methanol (200 ml), added under ice-cooling with sodium borohydride (12.9 g, 0.34 mol) and stirred for an hour. The reaction mixture was poured into ice water. The resulting precipitates were collected by filtration, dried over phosphorus pentoxide and recrystallized from chloroform (20 ml) to obtain 1.0 g (30%) of 7-hydroxymethyl-4-chloroquinoline. Melting Point: 138-139 C.; MS m/z: 193 (M+); NMR:delta 4.77(2H, d), 5.50(1H, t), 7.70(2H, m), 8.03(1H, s), 8.16(1H, d), 8.82(1H, d)

Reference： [1]Patent: US2004/102450,2004,A1 .Location in patent: Page/Page column 72
[2]Patent: US6281227,2001,B1
[3]Patent: US5773449,1998,A

2
[ 67-56-1 ]
C₁₀H₅Cl₂NO [ No CAS ]
[ 178984-69-5 ]

Yield	Reaction Conditions	Operation in experiment
	In tetrahydrofuran; dichloromethane; for 0.5h;	4-Chloro-7-trifluoromethylquinoline (5.0 g, 21.6 mmol) in 100 mL 80% H2SO4 is heated to 200 C. for 24 hours in a sealed tube. The solution is cooled, poured into water and neutralized with sodium hydroxide to pH3-4. The precipitated solid is collected, washed with water and dissolved in 2 N sodium hydroxide. The aqueous solution is washed with ethyl acetate then acidified to pH3-4. The precipitate is collected, washed with water and dried in a vacuum oven overnight to yield 7-carboxy-4-chloroquinoline as a solid (5.1 g, 24.6 mmol). A portion of this material (2.0 g, 9.6 mmol) is treated with anhydrous THF (200 mL) and DMF (2 mL) and 2 M oxalyl chloride in methylene chloride (14.5 mL, 29 mmol). The resulting suspension is stirred at room temperature for 2 h then treated with methanol (10 mL). After stirring 30 minutes the solution is concentrated and the residue is taken up in methylene chloride. The solution is washed with saturated sodium bicarbonate and dried (sodium sulfate) and concentrated to yield the title compound as a solid (2.1 g, 9.5 mmol). MS m/z: M+=221; 1H NMR (CDCl3, 300 MHz) delta8.6 (s, 1H), 8.2 (s, 1H), 7.9 (d, 1H), 7.65 (d, 1H), 7.45 (s, 1H), 3.95 (s. 3H)

Reference： [1]Patent: US2004/102450,2004,A1 .Location in patent: Page/Page column 72

3
[ 49713-58-8 ]
[ 74-88-4 ]
[ 178984-69-5 ]

Yield	Reaction Conditions	Operation in experiment
3.6 g (61%)	With potassium hydroxide; In N-methyl-acetamide; methanol;	(2) 7-Carboxy-4-chloroquinoline (5 g, 24.0 mmol) was dissolved in a mixed solution of potassium hydroxide (1.49 g, 26.6 mmol) with methanol (150 ml) and stirred at room temperature overnight. The reactant was evaporated to dryness under reduced pressure. The residue was added with dimethylformamide (DMF; 60 ml) and methyl iodide (3.5 g, 24.6 mmol) in the order named and stirred at 80 C. for an hour. The reaction mixture was poured into ice water. The resulting precipitates were collected by filtration, dried over phosphorus pentoxide and recrystallized from ethanol (20 ml) to obtain 3.6 g (61%) of 7-methoxycarbonyl-4-chloroquinoline. Melting Point: 118-119 C.; MS m/z: 221 (M+); NMR:delta 4.00(3H, s), 7.82(1H, d), 8.26(1H, dd), 8.38(1H, d), 8.73(1H, d), 8.95(1H, d)

Reference： [1]Patent: US5773449,1998,A

4
[ 178984-69-5 ]
[ 178984-42-4 ]

Yield	Reaction Conditions	Operation in experiment
	With ammonia; water; In methanol; at 40.0℃;	Methyl 4-chloro-quinoline-7-carboxylate (100 mg) was dissolved in methanol (5 ml), 28% aqueous ammonia (5 ml) was added to the solution, and the mixture was stirred at 40C overnight. The solvent was removed by distillation under the reduced pressure. Water was added to the residue, and the mixture was extracted with chloroform. The organic layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue (58.5 mg) as such was used in the next reaction without purification. A part of the residue (55 mg), 5,6-dimethyl-[2,2']bipyridinyl-3-ol (53 mg), and 4-dimethylaminopyridine (98 mg) was dissolved in dimethylsulfoxide (1.5 ml), cesium carbonate (260 mg) was added to the solution, and the mixture was stirred at 130C overnight. The reaction mixture was cooled to room temperature, and water was added thereto. The organic layer was extracted with chloroform, and the chloroform layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography with a methanol-chloroform system to give the title compound (5 mg, yield 3%) (2 steps). 1H-NMR (CDCl3, 400 MHz): delta 2.42 (s, 3H), 2.67 (s, 3H), 6.59 (d, J = 5.4 Hz, 1H), 7.08 (m, 1H), 7.41 (s, 1H), 7.61 (m, 1H), 7.92 (d, J = 8.1 Hz, 1H), 8.13 (d, J = 8.8 Hz, 1H), 8.28 (d, J = 4.1 Hz, 1H), 8.53 (d, J = 8.8 Hz, 1H), 8.64 - 8.68 (m, 2H) Mass spectrometric value (ESI-MS, m/z): 393 (M+Na)+

Reference： [1]Patent: EP1724268,2006,A1 .Location in patent: Page/Page column 81

5
[ 178984-69-5 ]
[ 666735-37-1 ]
methyl 4-(2-phenyl-[1,8]naphthyridin-3-yloxy)-quinoline-7-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%	With dmap; In 1,2-dichloro-benzene; at 130.0℃; for 5.0h;	2-Phenyl-[1,8]naphthyridin-3-ol (100 mg), <strong>[178984-69-5]methyl 4-chloro-quinoline-7-carboxylate</strong> (100 mg), and 4-dimethylaminopyridine (165 mg) were suspended in 1,2-dichlorobenzene (3 ml), and the suspension was stirred at 130C for 5 hr. The reaction mixture was cooled to room temperature, and an aqueous sodium hydrogencarbonate solution was added to the reaction mixture. The organic layer was extracted with chloroform, and the chloroform layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography with a methanol-chloroform system to give the title compound (143 mg, yield 78%). 1H-NMR (CDCl3, 400 MHz): delta 4.03 (s, 3H), 6.56 (d, J = 5.1 Hz, 1H), 7.29 - 7.35 (m, 3H), 7.57 (dd, J = 4.4, 8.3 Hz, 1H), 8.04 (s, 1H), 8.10 (m, 1H), 8.21 (m, 2H), 8.25 (dd, J = 1.7, 8.8 Hz, 1H), 8.46 (d, J = 8.8 Hz, 1H), 8.69 (d, J = 5.4 Hz, 1H), 8.85 (s, 1H), 9.21 (dd, J = 2.0, 4.1 Hz, 1H) Mass spectrometric value (ESI-MS, m/z): 430 (M+Na)+

Reference： [1]Patent: EP1724268,2006,A1 .Location in patent: Page/Page column 76

6
[ 863785-96-0 ]
[ 178984-69-5 ]

Yield	Reaction Conditions	Operation in experiment
86%	With N-ethyl-N,N-diisopropylamine; trichlorophosphate; at 120.0℃; for 0.5h;	A part of the residue (0.59 g) was dissolved in N,N-dimethylformamide (20 ml). Triethylamine (4 ml) and 10% palladium/carbon (0.59 g) were added to the solution, and the mixture was stirred under a hydrogen gas atmosphere at room temperature overnight. The reaction mixture was filtered and was then washed with chloroform. The solvent was removed by distillation under the reduced pressure, and the residue was washed with methanol to give methyl 4-oxo-1,4-dihydro-quinoline-7-carboxylate (187 mg, yield 28%) (3 steps). Methyl 4-oxo-1,4-dihydro-quinoline-7-carboxylate (650 mg) was suspended in diisopropylethylamine (7 ml), phosphorus oxychloride (1.5 ml) was added to the suspension, and the mixture was stirred at 120C for 30 min. Water was added to the reaction mixture under ice cooling. The aqueous layer was neutralized with an aqueous sodium hydrogencarbonate solution, and the organic layer was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography with an acetone-chloroform system to give methyl 4-chloro-quinoline-7-carboxylate (609 mg, yield 86%).

Reference： [1]Patent: EP1724268,2006,A1 .Location in patent: Page/Page column 76

7
[ 178984-69-5 ]
[ 49713-58-8 ]
[ 1150618-22-6 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; water; In tetrahydrofuran; at 60.0℃; for 22.0h;	Step 4a. 4-Hydroxyquinoline-7-carboxylic acid (58) and 4-chloroquinoline-7- carboxylic acid (59)A solution of <strong>[178984-69-5]methyl 4-chloroquinoline-7-carboxylate</strong> (110 mg, 0.496 mmol) in THF/5 N aqueous HC1 (1 :1, 2 mL) was heated to 60 C in a heating block or 22 h. LCMS showed formation of product (40% peak area) with the mass of 4-hydroxyquinoline-7-carboxylic acid (m/z (M+H) = 189.9). Additional product 20% peak area corresponding to the mass of 4-chloroquinoline-7- carboxylic acid (m/z (M+H) = 207.9). The reaction was concentrated and used in the subsequent amide coupling steps without further purification.

Reference： [1]Patent: WO2012/177893,2012,A2 .Location in patent: Page/Page column 143

8
[ 1078-30-4 ]
[ 178984-69-5 ]

Reference： [1]Patent: WO2012/177893,2012,A2

9
[ 51552-68-2 ]
[ 178984-69-5 ]

Reference： [1]Patent: WO2012/177893,2012,A2

10
[ 1374258-80-6 ]
[ 178984-69-5 ]
[ 1416801-65-4 ]

Yield	Reaction Conditions	Operation in experiment
	With trichlorophosphate; at 20.0℃; for 2.0h;Inert atmosphere;	Step 3. Methyl 4-chloroquinoline-7-carboxylate and methyl 2-chloro- quinoline-7-carboxylateTo the N-oxide from above was added phosphoryl trichloride (10 mL, 109 mmol). The resulting reaction mixture was stirred at rt under N2 or 2 h. The reaction was then quenched by slowly adding it to an ice cold solution of saturated aqueous NaHC03 (100 mL) in an ice bath with rapid stirring. The aqueous solution was extracted with EtOAc (3 x 50 mL), the organic layers combined, washed with saturated aqueous NaHC03 (25 mL), H20 (25 mL), dried (MgSC^), and concentrated. Purification by ISCO (40 g Si02, 0-50% EtOAc/hexanes) gave methyl 4-chloroquinoline-7-carboxylate as a white solid and methyl 2-chloro- quinoline-7-carboxylate as a white solid.

Reference： [1]Patent: WO2012/177893,2012,A2 .Location in patent: Page/Page column 142-143

11
[ 178984-69-5 ]
[ 7580-85-0 ]
C₁₇H₂₁NO₄ [ No CAS ]