[ CAS No. 220844-73-5 ]

Name: 220844-73-5|6-Fluoroquinoline-4-carboxylic acid|98%
Brand: Ambeed
SKU: A393667
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Quality Control of [ 220844-73-5 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 220844-73-5 ]

Product Details of [ 220844-73-5 ]

CAS No. :	220844-73-5	MDL No. :	MFCD09259934
Formula :	C₁₀H₆FNO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	FNGWSJQERDIOJO-UHFFFAOYSA-N
M.W :	191.16	Pubchem ID :	18475525
Synonyms :

Calculated chemistry of [ 220844-73-5 ]

Physicochemical Properties

Num. heavy atoms :	14
Num. arom. heavy atoms :	10
Fraction Csp3 :	0.0
Num. rotatable bonds :	1
Num. H-bond acceptors :	4.0
Num. H-bond donors :	1.0
Molar Refractivity :	48.66
TPSA :	50.19 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.17 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.4
Log Po/w (XLOGP3) :	1.82
Log Po/w (WLOGP) :	2.49
Log Po/w (MLOGP) :	0.65
Log Po/w (SILICOS-IT) :	2.21
Consensus Log Po/w :	1.72

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.85

Water Solubility

Log S (ESOL) :	-2.63
Solubility :	0.444 mg/ml ; 0.00232 mol/l
Class :	Soluble
Log S (Ali) :	-2.49
Solubility :	0.613 mg/ml ; 0.00321 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.36
Solubility :	0.0842 mg/ml ; 0.000441 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.38

Safety of [ 220844-73-5 ]

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

Application In Synthesis of [ 220844-73-5 ]

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

Downstream synthetic route of [ 220844-73-5 ]

[ 220844-73-5 ] Synthesis Path-Downstream 1~25

1
[ 220844-72-4 ]
[ 220844-73-5 ]

Yield	Reaction Conditions	Operation in experiment
98%	In water at 200℃; for 3h; Sealed tube;	53 Synthesis of 6-fluoroquinoline-4-carboxylic acid (53B) 53A (0.30g, 1.28mmol) was dissolved in water (8mL), the tube was sealed at 200°C for 3h, the pH was adjusted to 3-4 with dilute hydrochloric acid, and then filtered with suction to obtain 0.24g of dark brown solid with a yield of 98%.
90%	In water at 200℃; for 4h;	9.2 Step 2: 6-Fluoroquinoline-4- carboxylic acid Step 2: 6-Fluoroquinoline-4- carboxylic acid. 6-Fluoroquinoline-2,4- dicarboxylic acid (0.103 g, 0.437 mmol) was transferred in a pressure tube, 6 mL water was added. The closed tube was heated to 200 for 4h. After slow cooling of the tube, the resulting precipitate was filtered and washed with water to yield white crystals Yield: 0.076 g, 90% 1 H NMR (400 MHz, DMSO-d6) : δ 7.79 (ddd, J = 9.24, 8.20, 2.94 Hz, 1 H), 8.03 (d, J = 4.31 Hz, 1 H), 8.21 (dd, J = 5.86 Hz, J' = 9.27 Hz, 1 H), 8.52 (dd, J = 1 1 .19, 2.90 Hz, 1 H), 9.05 (d, J = 4.38 Hz, 1 H). MS (ESI) m/z 192.1 [M+H]+, 189.9 [M-H]
90%	In water at 200℃; for 4h; Sealed tube;	9.2 Step 2: 6-Fluoroquinolin-4-carboxylic acid 6-Fluoroquinoline-2,4-dicarboxylic acid (0.103 g, 0.437 mmol) was transferred in a pressure tube, 6 mL water was added. The closed tube was heated to 200° C. for 4 h. After slow cooling of the tube, the resulting precipitate was filtered and washed with water to yield white crystals Yield: 0.076 g, 90% 1H NMR (400 MHz, DMSO-d6): δ 7.79 (ddd, J=9.24, 8.20, 2.94 Hz, 1H), 8.03 (d, J=4.31 Hz, 1H), 8.21 (dd, J=5.86 Hz, J=9.27 Hz, 1H), 8.52 (dd, J=11.19, 2.90 Hz, 1H), 9.05 (d, J=4.38 Hz, 1H). MS (ESI) m/z 192.1 [M+H]+, 189.9 [M-H].

	In water at 190 - 200℃; for 0.0833333h; Microwave irradiation;
	In water at 205℃; for 2h; Autoclave;
	In 1-methyl-pyrrolidin-2-one at 210℃; for 8h;	22.2 Step 2: Compound P-22-B (13 g, 55.28 mmol) was added to 100 ml of N-methylpyrrolidone, and the mixture was heated to 210 ° C for 8 hours, and the reaction was confirmed by LC-MS.The reaction solution was directly subjected to the next step without any operation.

Reference： [1]Current Patent Assignee: CHINA PHARMACEUTICAL UNIVERSITY; NANJING ZHONGAO CONVERSION MEDICINE RES INSTITUTE - CN113061098, 2021, A Location in patent: Paragraph 0417; 0418; 0421; 0422
[2]Current Patent Assignee: FOX CHASE CANCER CENTER; UNIVERSITY OF ANTWERP - WO2013/107820, 2013, A1 Location in patent: Page/Page column 52
[3]Current Patent Assignee: FOX CHASE CANCER CENTER; UNIVERSITY OF ANTWERP - US2014/357650, 2014, A1 Location in patent: Paragraph 0365; 0366; 0367; 0368
[4]Location in patent: experimental part Zhu, Hui; Yang, Ri Fang; Yun, Liu Hong; Li, Jin [Chinese Chemical Letters, 2010, vol. 21, # 1, p. 35 - 38]
[5]Jansen, Koen; Heirbaut, Leen; Cheng, Jonathan D.; Joossens, Jurgen; Ryabtsova, Oxana; Cos, Paul; Maes, Louis; Lambeir, Anne-Marie; De Meester, Ingrid; Augustyns, Koen; Van Der Veken, Pieter [ACS Medicinal Chemistry Letters, 2013, vol. 4, # 5, p. 491 - 496]
[6]Current Patent Assignee: YANGTZE RIVER PHARMACEUTICAL GROUP CO LTD - CN110105275, 2019, A Location in patent: Paragraph 0234; 0235; 0237

2
[ 443-69-6 ]
[ 113-24-6 ]
[ 220844-73-5 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 5-fluoro-1H-indole-2,3-dione; sodium pyruvate With water; sodium hydroxide at 110℃; for 0.166667h; Microwave irradiation; Stage #2: In water at 190 - 200℃; for 0.0833333h; Microwave irradiation;

Reference： [1]Location in patent: experimental part Zhu, Hui; Yang, Ri Fang; Yun, Liu Hong; Li, Jin [Chinese Chemical Letters, 2010, vol. 21, # 1, p. 35 - 38]

3
[ 443-69-6 ]
[ 220844-73-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: sodium hydroxide / water / Reflux 2: water / 2 h / 205 °C / Autoclave
	Multi-step reaction with 2 steps 1: sodium hydroxide / 4 h / 110 °C 2: water / 4 h / 200 °C / Sealed tube
	Multi-step reaction with 2 steps 1: sodium hydroxide / 6 h / 110 °C 2: 1-methyl-pyrrolidin-2-one / 8 h / 210 °C

Multi-step reaction with 2 steps 1: sodium hydroxide / water / 5 h / Reflux 2: water / 3 h / 200 °C / Sealed tube

Reference： [1]Jansen, Koen; Heirbaut, Leen; Cheng, Jonathan D.; Joossens, Jurgen; Ryabtsova, Oxana; Cos, Paul; Maes, Louis; Lambeir, Anne-Marie; De Meester, Ingrid; Augustyns, Koen; Van Der Veken, Pieter [ACS Medicinal Chemistry Letters, 2013, vol. 4, # 5, p. 491 - 496]
[2]Current Patent Assignee: FOX CHASE CANCER CENTER; UNIVERSITY OF ANTWERP - US2014/357650, 2014, A1
[3]Current Patent Assignee: YANGTZE RIVER PHARMACEUTICAL GROUP CO LTD - CN110105275, 2019, A
[4]Current Patent Assignee: CHINA PHARMACEUTICAL UNIVERSITY; NANJING ZHONGAO CONVERSION MEDICINE RES INSTITUTE - CN113061098, 2021, A

4
[ 1145966-18-2 ]
[ 220844-73-5 ]
[ 1428264-69-0 ]

Yield	Reaction Conditions	Operation in experiment
20%	Stage #1: 6-fluoroquinoline-4-carboxylic acid With 1-chloro-1-(dimethylamino)-2-methyl-1-propene In tetrahydrofuran; dichloromethane at 20℃; for 0.5h; Stage #2: (S)-1-(2-aminoacetyl)-pyrrolidine-2-carbonitrile trifluoroacetic acid salt With triethylamine In tetrahydrofuran; dichloromethane for 2h;	9.3 Step 3: (-A^(2-(2-Cyanopyrrolidin-1-yl)-2-oxoethyl)-6-fluoroquinoline-4-carboxamide Step 3: (-A^(2-(2-Cyanopyrrolidin-1-yl)-2-oxoethyl)-6-fluoroquinoline-4-carboxamide 6-Fluoroquinoline-4- carboxylic acid (17) (0.054 g, 0.282 mmol) was dissolved in a 1 :1 mixture of dry DCM and THF (5 m L). 1 -chloro-/V,/V,2-trimethylprop-1 -en-1 -amine (0.052 mL, 0.395 mmol) was added to this solution, and the mixture was stirred for 30minut.es at rt. Then, a solution of (S)-1 -(2- aminoacetyl)pyrrolidine-2-carbonitril 2,2,2-trifluoroacetate (0.075 g, 0.282 mmol) prepared as described in general procedure B and triethylamine (80 iL, 0.571 mmol) in 3 m L dry THF was added, and the mixture was stirred for 2h. After evaporation of volatiles, the residue was dissolved in DCM (15 m L), washed with saturated sodium bicarbonate and brine. The organic layer was dried over sodium sulfate, filtrated and purified using flash chromatography (95-5 ethyl acetate - methanol) to yield white crystals Yield: 0.019g, 20% 1 H NMR (400 MHz, CDCI3) (9/1 mixture of trans/cis amide rotamers) 62.21 - 2.41 (m, 4H), 3.57 (m, 1 H), 3.73 (m , 1 H), 4.27 (dd, J = 17.81 , 3.90 Hz, 1 H), 4.42 (dd, J = 17.86, 4.81 Hz, 1 H), 4.73 (d, J = 8.8 Hz, 0.1 H), 4.81 (m , 0.9H), 7.06 (br_s, 1 H), 7.51 - 7.56 (m , 1 H), 7.56 - 7.59 (m , 1 H), 8.01 (dd, J = 10.00, 2.81 Hz, 1 H), 8.17 (dd, J = 9.25, 5.45 Hz, 1 H), 8.95 (d, J = 4.36 Hz, 1 H). UPLC I (ESI) Rt 1 .29 min, m/z 325.3 [M-H]+ (100%). - - MS (ESI) m/z 327.2 [M+H]+.
20%	Stage #1: 6-fluoroquinoline-4-carboxylic acid With 1-chloro-1-(dimethylamino)-2-methyl-1-propene In tetrahydrofuran; dichloromethane at 20℃; for 0.5h; Stage #2: (S)-1-(2-aminoacetyl)-pyrrolidine-2-carbonitrile trifluoroacetic acid salt With triethylamine In tetrahydrofuran; dichloromethane for 2h;	9.3 Step 3: (S)-N-(2-(2-Cyanopyrrolidine-1-yl)-2-oxoethyl)-6-fluoroquinoline-4-carboxamide 6-Fluoroquinoline-4-carboxylic acid (17) (0.054 g, 0.282 mmol) was dissolved in a 1:1 mixture of dry DCM and THF (5 mL). 1-chloro-N,N,2-trimethylprop-1-en-1-amine (0.052 mL, 0.395 mmol) was added to this solution, and the mixture was stirred for 30 minutes at rt. Then, a solution of (S)-1-(2-aminoacetyl)pyrrolidine-2-carbonitrile 2,2,2-trifluoroacetate (0.075 g, 0.282 mmol) prepared as described in general procedure B and triethylamine (80 μL, 0.571 mmol) in 3 mL dry THF was added, and the mixture was stirred for 2 h. After evaporation of volatiles, the residue was dissolved in DCM (15 mL), washed with saturated sodium bicarbonate and brine. The organic layer was dried over sodium sulfate, filtrated and purified using flash chromatography (95-5 ethyl acetate-methanol) to yield white crystals Yield: 0.019 g, 20% 1H NMR (400 MHz, CDCl3) (9/1 mixture of trans/cis amide rotamers) δ 2.21-2.41 (m, 4H), 3.57 (m, 1H), 3.73 (m, 1H), 4.27 (dd, J=17.81, 3.90 Hz, 1H), 4.42 (dd, J=17.86, 4.81 Hz, 1H), 4.73 (d, J=8.8 Hz, 0.1H), 4.81 (m, 0.9H), 7.06 (br_s, 1H), 7.51-7.56 (m, 1H), 7.56-7.59 (m, 1H), 8.01 (dd, J=10.00, 2.81 Hz, 1H), 8.17 (dd, J=9.25, 5.45 Hz, 1H), 8.95 (d, J=4.36 Hz, 1H). UPLC I (ESI) Rt 1.29 min, m/z 325.3 [M-H]+ (100%). MS (ESI) m/z 327.2 [M+H]+.

Reference： [1]Current Patent Assignee: FOX CHASE CANCER CENTER; UNIVERSITY OF ANTWERP - WO2013/107820, 2013, A1 Location in patent: Page/Page column 52; 53
[2]Current Patent Assignee: FOX CHASE CANCER CENTER; UNIVERSITY OF ANTWERP - US2014/357650, 2014, A1 Location in patent: Paragraph 0369; 0370; 0371; 0372; 0373

5
[ 220844-73-5 ]
[ 590-17-0 ]
C₁₂H₇FN₂O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
10 g	With sodium hydrogencarbonate In 1-methyl-pyrrolidin-2-one at 0 - 20℃; for 4h;	22.3 Step 3: The compound P-22-C (13.25 g, 69.31 mmol) in N-methylpyrrolidone was cooled to 0 ° C, and the compound 2-bromoacetonitrile (12.47 g, 103.97 mmol) was added with stirring, followed by NaHCO3(11.65g, 138.63mmol),The reaction solution was heated to 20 ° C and stirred for 4 hours. The reaction was completely detected by LC-MS.The reaction liquid was slowly added to 1 L of water, stirred while being added, and a large amount of solid was precipitated, and the compound P-22-D was obtained by filtration. (10 g, purity: 95.52%, yield: 62.67%).

Reference： [1]Current Patent Assignee: YANGTZE RIVER PHARMACEUTICAL GROUP CO LTD - CN110105275, 2019, A Location in patent: Paragraph 0234; 0235; 0238

6
[ 220844-73-5 ]
C₁₄H₁₂FNO₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: sodium hydrogencarbonate / 1-methyl-pyrrolidin-2-one / 4 h / 0 - 20 °C 2: titanium(IV) isopropylate / diethyl ether / 5 h / 0 - 25 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: YANGTZE RIVER PHARMACEUTICAL GROUP CO LTD - CN110105275, 2019, A

7
[ 220844-73-5 ]
C₁₄H₁₄FNO₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: sodium hydrogencarbonate / 1-methyl-pyrrolidin-2-one / 4 h / 0 - 20 °C 2: titanium(IV) isopropylate / diethyl ether / 5 h / 0 - 25 °C / Inert atmosphere 3: trifluoroacetic acid; triethylsilane / 20 - 25 °C

Reference： [1]Current Patent Assignee: YANGTZE RIVER PHARMACEUTICAL GROUP CO LTD - CN110105275, 2019, A

8
[ 220844-73-5 ]
C₁₅H₁₆FNO₄S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: sodium hydrogencarbonate / 1-methyl-pyrrolidin-2-one / 4 h / 0 - 20 °C 2: titanium(IV) isopropylate / diethyl ether / 5 h / 0 - 25 °C / Inert atmosphere 3: trifluoroacetic acid; triethylsilane / 20 - 25 °C 4: N-ethyl-N,N-diisopropylamine / dichloromethane / 1 h / 0 °C

Reference： [1]Current Patent Assignee: YANGTZE RIVER PHARMACEUTICAL GROUP CO LTD - CN110105275, 2019, A

9
[ 220844-73-5 ]
C₁₅H₁₃FN₂O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: sodium hydrogencarbonate / 1-methyl-pyrrolidin-2-one / 4 h / 0 - 20 °C 2: titanium(IV) isopropylate / diethyl ether / 5 h / 0 - 25 °C / Inert atmosphere 3: trifluoroacetic acid; triethylsilane / 20 - 25 °C 4: N-ethyl-N,N-diisopropylamine / dichloromethane / 1 h / 0 °C 5: potassium carbonate / acetonitrile / 2 h / 120 °C / Microwave irradiation; Inert atmosphere

Reference： [1]Current Patent Assignee: YANGTZE RIVER PHARMACEUTICAL GROUP CO LTD - CN110105275, 2019, A

10
[ 220844-73-5 ]
C₁₅H₁₄FNO₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: sodium hydrogencarbonate / 1-methyl-pyrrolidin-2-one / 4 h / 0 - 20 °C 2.1: titanium(IV) isopropylate / diethyl ether / 5 h / 0 - 25 °C / Inert atmosphere 3.1: trifluoroacetic acid; triethylsilane / 20 - 25 °C 4.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 1 h / 0 °C 5.1: potassium carbonate / acetonitrile / 2 h / 120 °C / Microwave irradiation; Inert atmosphere 6.1: diisobutylaluminium hydride / dichloromethane / 2 h / -78 - -50 °C / Inert atmosphere 6.2: 0.5 h / 20 - 25 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: YANGTZE RIVER PHARMACEUTICAL GROUP CO LTD - CN110105275, 2019, A

11
[ 220844-73-5 ]
C₂₃H₂₁FN₄O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1.1: sodium hydrogencarbonate / 1-methyl-pyrrolidin-2-one / 4 h / 0 - 20 °C 2.1: titanium(IV) isopropylate / diethyl ether / 5 h / 0 - 25 °C / Inert atmosphere 3.1: trifluoroacetic acid; triethylsilane / 20 - 25 °C 4.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 1 h / 0 °C 5.1: potassium carbonate / acetonitrile / 2 h / 120 °C / Microwave irradiation; Inert atmosphere 6.1: diisobutylaluminium hydride / dichloromethane / 2 h / -78 - -50 °C / Inert atmosphere 6.2: 0.5 h / 20 - 25 °C / Inert atmosphere 7.1: methanol / 1 h / 20 - 25 °C 7.2: 2 h / 20 - 25 °C

Reference： [1]Current Patent Assignee: YANGTZE RIVER PHARMACEUTICAL GROUP CO LTD - CN110105275, 2019, A

12
[ 220844-73-5 ]
4-cyano-N'-ethyl-N'-((6-(6-fluoroquinolin-4-yl)-tetrahydro-2H-pyran-3-yl)methyl)benzoyl hydrazide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 8 steps 1.1: sodium hydrogencarbonate / 1-methyl-pyrrolidin-2-one / 4 h / 0 - 20 °C 2.1: titanium(IV) isopropylate / diethyl ether / 5 h / 0 - 25 °C / Inert atmosphere 3.1: trifluoroacetic acid; triethylsilane / 20 - 25 °C 4.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 1 h / 0 °C 5.1: potassium carbonate / acetonitrile / 2 h / 120 °C / Microwave irradiation; Inert atmosphere 6.1: diisobutylaluminium hydride / dichloromethane / 2 h / -78 - -50 °C / Inert atmosphere 6.2: 0.5 h / 20 - 25 °C / Inert atmosphere 7.1: methanol / 1 h / 20 - 25 °C 7.2: 2 h / 20 - 25 °C 8.1: methanol; sodium cyanoborohydride / 2 h / 0 °C

Reference： [1]Current Patent Assignee: YANGTZE RIVER PHARMACEUTICAL GROUP CO LTD - CN110105275, 2019, A

Yield	Reaction Conditions	Operation in experiment
83.3%	In water at 210℃; Microwave irradiation;	2.2 Step 2: Preparation of 6-bromoquinoline-4-carboxylic acid A-1 General procedure: Intermediate 1a (0.4g, 1.35mmol) was added to a 10mL microwave reaction flask, 4mL water was added, and the reaction was carried out under microwave conditions. The reaction tube was placed in a Biotage microwave reactor (Model: Biotage Initiator+), At 210, the internal pressure does not exceed 20bar, Reaction for 10-15min. LC-MS detects the completion of the reaction of the raw materials. After the reaction solution is cooled to room temperature, the obtained solid is filtered and washed with water. The crude product is recrystallized with hot water and filtered. The intermediate A-1 was obtained by infrared drying, 0.29 g of gray solid, and the yield was 85.3%.

14
[ 443-69-6 ]
[ 127-17-3 ]
[ 220844-73-5 ]