[ CAS No. 154093-72-8 ] {[proInfo.proName]}

Name: 154093-72-8|1-Cyclopropyl-6,7-difluoro-8-hydroxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid|97%
Brand: Ambeed
SKU: A143732
Price: 15.0 USD
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Quality Control of [ 154093-72-8 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 154093-72-8 ]

SDS Specification

Alternatived Products of [ 154093-72-8 ]

Product Details of [ 154093-72-8 ]

CAS No. :	154093-72-8	MDL No. :	MFCD25973506
Formula :	C₁₃H₉F₂NO₄	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	NTWOKQCCNHKEIU-UHFFFAOYSA-N
M.W :	281.21	Pubchem ID :	11680737
Synonyms :

Calculated chemistry of [ 154093-72-8 ]

Physicochemical Properties

Num. heavy atoms :	20
Num. arom. heavy atoms :	10
Fraction Csp3 :	0.23
Num. rotatable bonds :	2
Num. H-bond acceptors :	6.0
Num. H-bond donors :	2.0
Molar Refractivity :	65.87
TPSA :	79.53 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.33 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.36
Log Po/w (XLOGP3) :	2.38
Log Po/w (WLOGP) :	2.8
Log Po/w (MLOGP) :	1.49
Log Po/w (SILICOS-IT) :	2.22
Consensus Log Po/w :	2.05

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	0.0
Bioavailability Score :	0.56

Water Solubility

Log S (ESOL) :	-3.32
Solubility :	0.134 mg/ml ; 0.000478 mol/l
Class :	Soluble
Log S (Ali) :	-3.69
Solubility :	0.0573 mg/ml ; 0.000204 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.74
Solubility :	0.515 mg/ml ; 0.00183 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	0.0
Synthetic accessibility :	2.11

Safety of [ 154093-72-8 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H332-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 154093-72-8 ]

* 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 [ 154093-72-8 ]
Downstream synthetic route of [ 154093-72-8 ]

[ 154093-72-8 ] Synthesis Path-Upstream 1~4

1
[ 154093-72-8 ]
[ 77-78-1 ]
[ 141290-02-0 ]
[ 112811-72-0 ]

Reference： [1] Patent: WO2006/4561, 2006, A1, . Location in patent: Page/Page column title page; 4; 12-13

2
[ 112811-72-0 ]
[ 154093-72-8 ]

Yield	Reaction Conditions	Operation in experiment
90%	With hydrogenchloride; calcium chloride In water; dimethyl sulfoxide at -5 - 25℃; for 3.5 h;	A volume of approximately 500 mL of DMSO filtrate after the step of nucleophilic substitution was put into a 1000 mL reactor and, under stirring, CaCl₂ (approximately 33 g) was added. The mixture was cooled under stirring to 0-5°C (-5°C-25°C) in 30 minutes. The pH was adjusted to the value of 4 with a 15percent HC1 aqueous solution and it was stirred for 3 hours under maintaining the temperature between 0 nad 5°C. The precipitated product was filtered, thoroughly washed with acetone and dried. Dry 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-hydroxy-4-oxo-3-quinoline carboxylic acid (approximately 35 g) with a purity over 90percent was isolated.

Reference： [1] Patent: WO2006/4561, 2006, A1, . Location in patent: Page/Page column title page; 4; 12-13
[2] Patent: WO2008/62379, 2008, A2, . Location in patent: Page/Page column 37
[3] Patent: US2010/222302, 2010, A1, . Location in patent: Page/Page column 21
[4] Patent: WO2007/17828, 2007, A2, . Location in patent: Page/Page column 54

3
[ 112811-71-9 ]
[ 154093-72-8 ]

Yield	Reaction Conditions	Operation in experiment
89.6%	at 100℃;	Embodiment 1 Preparation of 1-Cyclopropyl-6,7-difluoro-8-hydroxyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid The preparation comprises dissolving Ethyl 1-cyclopropyl-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylate (10.0g, 30.9mmol) in 40percent HBr aqueous solution (20 mL) and acetic acid (20 mL) to react at 100°C, charging reaction mixture into ice water (500 mL) under fast stirring after the reaction finishes, going on with the stirring for 0.5 h, filtering, and drying obtained filter cake to give 1-cyclopropyl-6,7-difluoro-8-hydroxy-1,4-dihydro-oxoquinoline-3-carboxylic acid (7.8 g, 89.6percent). ¹H NMR(DMSO) δ =1.01-1.27(4H, m), 4.25-4.33(1H, m), 7.67(1H, dd, J=8.1Hz, J=12.6Hz), 8.68(1H, s), 11.64(1H, s), 14.71(1H, br.). MS(m/z): 282(M⁺ +1).

Reference： [1] Patent: EP1767536, 2007, A1, . Location in patent: Page/Page column 8

4
[ 112811-71-9 ]
[ 154093-72-8 ]

Reference： [1] ChemMedChem, 2017, vol. 12, # 20, p. 1687 - 1692

[ 154093-72-8 ] Synthesis Path-Downstream 1~17

1
[ 112811-71-9 ]
[ 154093-72-8 ]

Yield	Reaction Conditions	Operation in experiment
89.6%	With water; hydrogen bromide; acetic acid; at 100℃;	Embodiment 1 Preparation of 1-Cyclopropyl-6,7-difluoro-8-hydroxyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid The preparation comprises dissolving Ethyl 1-cyclopropyl-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylate (10.0g, 30.9mmol) in 40% HBr aqueous solution (20 mL) and acetic acid (20 mL) to react at 100C, charging reaction mixture into ice water (500 mL) under fast stirring after the reaction finishes, going on with the stirring for 0.5 h, filtering, and drying obtained filter cake to give 1-cyclopropyl-6,7-difluoro-8-hydroxy-1,4-dihydro-oxoquinoline-3-carboxylic acid (7.8 g, 89.6%). 1H NMR(DMSO) delta =1.01-1.27(4H, m), 4.25-4.33(1H, m), 7.67(1H, dd, J=8.1Hz, J=12.6Hz), 8.68(1H, s), 11.64(1H, s), 14.71(1H, br.). MS(m/z): 282(M+ +1).

Reference： [1]Patent: EP1767536,2007,A1 .Location in patent: Page/Page column 8

2
[ 154093-72-8 ]
[ 64-17-5 ]
[ 452092-31-8 ]

Yield	Reaction Conditions	Operation in experiment
95%	With sulfuric acid;Heating / reflux;	Embodiment 2 Preparation of Ethyl 1-cyclopropyl-6,7-difluoro-8-hydroxyl-1,4-dihydro-4-oxoquinoline-3-carboxylate The preparation comprises refluxing a mixture of 1-cyclopropyl-6,7-difluoro-8-hydrohyl-4-oxoquinoline- 3-carboxylic acid (target product of embodiment 1, 20.0 g, 71.2 mmol), concentrated sulfuric acid (5 mL) and ethanol (300 mL) to give a clear solution, cooling down to room temperature, filtering, washing obtained filter cake with ethanol, and drying to give 1-cyclopropyl-6,7-difluoro-8-hydroxy-1,4-dihydro-4-oxoquinoline-3-carboxylate (20.9 g, 95.0%). 1H NMR(CDCl3) delta =0.85-1.11(4H, m), 1.42(3H, t, J=6.9Hz), 4.33-4.40(1H, m), 4.42(2H, q, J=6.9Hz), 7.80-7.85(1H, m), 8.68(1H, s). MS(m/z): 310(M+ +1)

Reference： [1]Patent: EP1767536,2007,A1 .Location in patent: Page/Page column 9
[2]ChemMedChem,2017,vol. 12,p. 1687 - 1692

3
[ 154093-72-8 ]
[ 77-78-1 ]
[ 141290-02-0 ]
[ 112811-72-0 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium chloride; In acetone;Heating / reflux;Product distribution / selectivity;	A volume of approximately 500 mL of DMSO filtrate after the step of nucleophilic substitution was put into a 1000 mL reactor and, under stirring, CaCl2 (approximately 33 g) was added. The mixture was cooled under stirring to 0-5C (-5C-25C) in 30 minutes. The pH was adjusted to the value of 4 with a 15% HC1 aqueous solution and it was stirred for 3 hours under maintaining the temperature between 0 nad 5C. The precipitated product was filtered, thoroughly washed with acetone and dried. Dry 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-hydroxy-4-oxo-3-quinoline carboxylic acid (approximately 35 g) with a purity over 90% was isolated.Dry 1 -cyclopropyl-6,7-difluoro-1,4-dihydro-8-hydroxy-4-oxo-3-quinoline carboxylic acid was added to acetone (approximately 160 mL) and potassium chloride (approximately 26 g) and dimethyl sulfate (18 mL) were added. Alternatively, 1,4-dioxan or tetrahydrofuran (THF) could be used as the solvent instead of acetone. The reaction mixture was heated to reflux temperature and was left to reflux until the completion of the reaction. After the completed reaction the suspension was cooled to room temperature and filtered. A mixture (58.4 g) of unreacted salts was isolated, which were added to an aqueous potassium carbonate solution, heated to reflux and the ester bond was hydrolyzed for from 30 minutes to some hours. The solution at reflux was cooled to room temperature and l-cyclopropyl-6,7-difluoro-l,4-dihydro-4-oxo-3-quinoline carboxylic acid formed was isolated. The yield of methylation and hydrolysis was approximately 17%.

Reference： [1]Patent: WO2006/4561,2006,A1 .Location in patent: Page/Page column title page; 4; 12-13

4
[ 112811-72-0 ]
[ 154093-72-8 ]

Yield	Reaction Conditions	Operation in experiment
90%	With hydrogenchloride; calcium chloride; In water; dimethyl sulfoxide; at -5 - 25℃; for 3.5h;pH 4;	A volume of approximately 500 mL of DMSO filtrate after the step of nucleophilic substitution was put into a 1000 mL reactor and, under stirring, CaCl2 (approximately 33 g) was added. The mixture was cooled under stirring to 0-5C (-5C-25C) in 30 minutes. The pH was adjusted to the value of 4 with a 15% HC1 aqueous solution and it was stirred for 3 hours under maintaining the temperature between 0 nad 5C. The precipitated product was filtered, thoroughly washed with acetone and dried. Dry 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-hydroxy-4-oxo-3-quinoline carboxylic acid (approximately 35 g) with a purity over 90% was isolated.
	With hydrogen bromide; acetic acid; at 100℃; for 24h;	Example 1: (/iS^tfSH-cyclopropyl^-fluoro-l-beta-fluoro- 4-((R)-5-hydroxymethyl-2-oxo-oxazolidin-3-yl)-phenoxym ethyl] - 16-hydroxy-4-oxo- 1,4,13, 15,16,17-hexahydro-12H-ll-oxa-l,14-diaza-cyclopenta[a]phenanthrene- 3-carboxylic acid:l; .i. l-cyclopropyl-6, 7-difluoro-8-hydroxy-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid:; A solution of l-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-l,4-dihydro-quinoline- 3-carboxylic acid (13.02 g) in HBr in AcOH (33%; 100 ml) was stirred at 1000C for 1 day. The reaction mixture was cooled to 00C and diluted with water (400 ml). The resulting crystals were collected by filtration, affording, after drying, 12.4 g of a colourless material. 1H NMR (DMSOd6; delta ppm): 1.09-1.23 (4H, m); 4.32 (IH, m); 7.70 (dd, IH, J = 8 and J = 10); 8.75 (IH, s); 11.66 (IH, broad); 14.78 (IH, s).
		A solution of 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (13.02 g) in HBr in AcOH (33%; 100 ml) was stirred at 100 C. for 1 day. The reaction mixture was cooled to 0 C. and diluted with water (400 ml). The resulting crystals were collected by filtration affording after drying 12.4 g of colourless material.1H NMR (DMSOd6; delta ppm): 1.09-1.23 (4H, m); 4.32 (1H, m); 7.70 (dd, 1H, J=8 and J=10); 8.75 (1H, s); 11.66 (1H, broad); 14.78 (1H, s).

With hydrogen bromide; acetic acid; at 100℃; for 24h;

A solution of l-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-l,4-dihydro-quinoline- 3-carboxylic acid (13.02 g) in HBr in AcOH (33%; 100 ml) was stirred at 100C for 1 day. The reaction mixture was cooled to 0C and diluted with water (400 ml). The resulting crystals were collected by filtration affording after drying 12.4 g of colourless material.1H NuMR (DMSOd6; delta ppm): 1.09-1.23 (4H, m); 4.32 (lH,m); 7.70 (dd, IH, J = 8 and J = 10); 8.75 (IH, s); 11.66 (IH, broad); 14.78 (IH, s).

Reference： [1]Patent: WO2006/4561,2006,A1 .Location in patent: Page/Page column title page; 4; 12-13
[2]Patent: WO2008/62379,2008,A2 .Location in patent: Page/Page column 37
[3]Patent: US2010/222302,2010,A1 .Location in patent: Page/Page column 21
[4]Patent: WO2007/17828,2007,A2 .Location in patent: Page/Page column 54

5
[ 154093-72-8 ]
[ 100-39-0 ]
[ 926279-21-2 ]

Yield	Reaction Conditions	Operation in experiment
		l.ii. 8-benzyloxy-l-cyclopropyl-6, 7-difluoro-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid:; A solution of intermediate l.i (1 g) in DMF (15 ml) was treated with N NaOH (3.56 ml). After stirring for 15 min, the yellow solution was treated with BnBr (486 mul). The reaction mixture was stirred at rt for 1 h, diluted with water (50 ml) and the resulting colourless crystals were filtered, affording, after drying, 1.2 g of a solid.MS: 372.1.
		A solution of intermediate 1.B.i (1 g) in DMF (15 ml) was treated with 1N NaOH (3.56 ml). After stirring for 15 min, the yellow solution was treated with BnBr (486 mul). The reaction mixture was stirred at rt for 1 h, diluted with water (50 ml) and the resulting colourless crystals were filtered affording after drying 1.2 g of solid.MS (ESI+): 372.1 (M+H)+.
		A solution of intermediate l.B.i (1 g) in DMF (15 ml) was treated with IN NaOH (3.56 ml). After stirring for 15 min, the yellow solution was treated with BnBr (486 mul). The reaction mixture was stirred at rt for 1 h, diluted with water (50 ml) and the resulting colourless crystals were filtered affording after drying 1.2 g of solid. MS(ESI^): 372.1 (M+H)+.

Reference： [1]Patent: WO2008/62379,2008,A2 .Location in patent: Page/Page column 37
[2]Patent: US2010/222302,2010,A1 .Location in patent: Page/Page column 21
[3]Patent: WO2007/17828,2007,A2 .Location in patent: Page/Page column 55

6
[ 112811-71-9 ]
[ 154093-72-8 ]
C₁₂H₉F₂NO₂ [ No CAS ]