132794-07-1|4-Chloro-2,5-difluorobenzoic acid| Ambeed

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Quality Control of [ 132794-07-1 ] Purity: 98% SDS Specification

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Product Details of [ 132794-07-1 ]

CAS No. :	132794-07-1
Formula :	C₇H₃ClF₂O₂
M.W :	192.55
SMILES Code :	O=C(O)C1=CC(F)=C(Cl)C=C1F
MDL No. :	MFCD00077480
Boiling Point :	No data available
InChI Key :	PEPCYJSDHYMIFN-UHFFFAOYSA-N
Pubchem ID :	2733274

Safety of [ 132794-07-1 ]

GHS Pictogram:
Signal Word:	Danger
Hazard Statements:	H318
Precautionary Statements:	P280-P305+P351+P338-P403-P501

Computational Chemistry of [ 132794-07-1 ] Show Less

Physicochemical Properties

Num. heavy atoms	12
Num. arom. heavy atoms	6
Fraction Csp3	0.0
Num. rotatable bonds	1
Num. H-bond acceptors	4.0
Num. H-bond donors	1.0
Molar Refractivity	38.33
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	37.3 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.33
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	2.28
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	3.16
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	3.05
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	2.72
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	2.51

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.77
Solubility	0.324 mg/ml ; 0.00168 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-2.7
Solubility	0.384 mg/ml ; 0.00199 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-2.95
Solubility	0.217 mg/ml ; 0.00112 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	Yes
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	No
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	No
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-5.86 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	1.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.56

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	1.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<1.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	1.56

Application In Synthesis of [ 132794-07-1 ]

* 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 [ 132794-07-1 ]

[ 132794-07-1 ] Synthesis Path-Downstream 1~35

1
[ 132794-07-1 ]
[ 64-17-5 ]
[ 879093-03-5 ]

Yield	Reaction Conditions	Operation in experiment
94%	sulfuric acid; for 18h;Heating / reflux;	Sulfuric acid (62.4 ml, 1.13 moles) was added to a solution of <strong>[132794-07-1]2,5-difluoro-4-chloro-benzoic acid</strong> (750.0 g, 3.895 moles) (PLEASE DEFINE THE SOURCE OF THIS REACTANT) in absolute ethanol (3.75 L). The mixture was refluxed for 18 hours. The mixture was concentrated to remove most of ethanol and then cooled to room temperature. The residue was neutralized with 1N aqueous NaOH (2.4 L) and extracted with ethyl acetate (2×1L). The combined extracts were washed with sat. aqueous NaHCO3 and brine, then dried with (MgSO4) and concentrated to dryness. Ethyl 2,5-difluoro-4-chloro-benzoate (806.7 g) was obtained at 94% yield. 1H NMR (in CDCl3): delta7.72 (dd, J=9.1/6.2, 1H), 7.22 (dd, J=9.1/5.6, 1H), 4.39 (q, 3J=7.0, 2H), 1.39 (t, J=7.0, 3H). GC-MS: 161 (M+).
	With sulfuric acid; for 72h;Heating / reflux;	Preparation 1 4-Chloro-2,5-difluoro-benzaldehyde <strong>[132794-07-1]4-Chloro-2,5-difluoro-benzoic acid</strong> (25.0 g, 129.84 mmol), H2SO4 (3.46 mL, 64.92 mmol) and EtOH (300 mL) were combined and heated at reflux for 72 h. The solution was cooled, concentrated, diluted with H2O (1.0 L), and extracted with EtOAc (3500 mL). The combined organic extracts were washed with saturated NaHCO3 (3200 mL), H2O (200 mL), dried (MgSO4), filtered, and concentrated to provide 28.17 g of <strong>[132794-07-1]4-chloro-2,5-difluoro-benzoic acid</strong> ethyl ester as a golden oil.

References: [1]Patent: US2007/21634,2007,A1 .Location in patent: Page/Page column 4; 6.
[2]Patent: US2006/58361,2006,A1 .Location in patent: Page/Page column 32.

2
[ 132794-07-1 ]
[ 5763-61-1 ]
[ 247568-34-9 ]
[ 247570-13-4 ]

Yield	Reaction Conditions	Operation in experiment
		PREPARATION 151 4-Chloro-2,5-difluoro-N-(3,4-dimethoxybenzyl)benzamide (1.66 g) was obtained from <strong>[132794-07-1]4-chloro-2,5-difluorobenzoic acid</strong> (1.05 g) and veratrylamine (0.91 mL) in a in a manner similar to preparation 1. NMR (DMSO-d6, delta): 3.73 (3H, s), 3.74 (3H, s), 4.39 (2H, d, J=6 Hz), 6.81-6.97 (3H, m), 7.67 (1H, dd, J=6, 9 Hz), 7.79 (1H, dd, J=6, 9 Hz), 8.96 (1H, t, J=6 Hz).

References: [1]Patent: US6384080,2002,B1 .

Yield	Reaction Conditions	Operation in experiment
79%		EXAMPLE 2 The above reaction was repeated, cutting down the reflux time to 2 hours instead of 18 hours. The conversion was 79% and the yield of 4-chloro-2,5-difluorobenzoic acid was 83%.

4
potassium hypochlorite [ No CAS ]
[ 655-12-9 ]
[ 132794-07-1 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; potassium hydroxide; In water;	EXAMPLE 1 Preparation of 4-Chloro-2,5-difluorobenzoic Acid A 3.6 liter aqueous solution containing 500 g (5.5 mole) of potassium hypochlorite and 115 g potassium hydroxide, was taken in a 5 liter, 3-necked round-bottomed flask equipped with a Trubore stirrer, a thermometer, an addition funnel and a water condenser. 228.5 g (1.2 mole) of 4'-chloro-2',5'-difluoroacetophenone was dissolved in 550 ml of chloride and the solution was slowly added to the flask via the addition funnel. The temperature was not allowed to exceed 40 C. After the addition was complete, the heterogeneous mixture was stirred vigorously at reflux (40 C.) for 18 hours. The reaction mixture was cooled to room temperature and filtered. The solid was dried and then suspended in 2200 ml of water containing 120 ml of concentrated HCl. It was stirred, filtered, washed with water, and dried in an oven to a constant weight of 177 g. It had a melting point of 154.7 C. The CH2 Cl2 layer was rotovapped to recover 30 g (13%) of the starting ketone, 4'-chloro-2',5'-difluoroacetophenone. The conversion of the ketone into acid was 87%. The yield of 4-chloro-2,5-difluorobenzoic acid was 88%.

References: [1]Patent: US4996355,1991,A .

5
[ 132794-07-1 ]
[ 132794-08-2 ]

Yield	Reaction Conditions	Operation in experiment
	With thionyl chloride;	EXAMPLE 3 Preparation of 4-chloro-2,5-difluorobenzoyl Chloride 38.5 g <strong>[132794-07-1]4-chloro-2,5-difluorobenzoic acid</strong> (0.2 mole) was placed in a 250 mL, 3-necked roundbottom flask equipped with a magnetic stirbar, a thermometer, and a water-cooled condenser. 238 g thionyl chloride was added in one lot. The mixture was stirred and heated on a water bath. At about 58-60 C. the solid dissolved with evolution of gas and formation of foam. The mixture was stirred and maintained at 60 C. until all the solid dissolved - about 30 minutes. It was then heated in a boiling water bath to reflux and held there for 2 hours. The excess thionyl chloride was distilled out. The contents were cooled and then distilled under reduced pressure. The capillary GC analysis showed the distilled product to be 99.6% pure. The yield was 41.1 g, 98%.
	With thionyl chloride; In N,N-dimethyl-formamide; at 70 - 80℃; for 2.5h;	After stirring a mixture of <strong>[132794-07-1]4-chloro-2,5-difluorobenzoic acid</strong>, thionyl chloride and DMF at 70C for one hour and additionally at 80C for 1.5 hours, the solvent was removed under reduced pressure and THF was added. , This reaction solution was added to a mixture of methyl 3-aminothiophene-2-carboxylate, THF and diisopropylethylamine in an MeOH-ice bath and stirred at room temperature for 1.5 days to give methyl 3-[(4-chloro-2,5-difluorobenzoyl)amino]thiophene-2-carboxylate.
	With thionyl chloride; In N,N-dimethyl-formamide; at 80℃;	General procedure: A mixture of 4-bromo-2,5-difluorobenzoic acid (11a, 53.28 g), thionyl chloride (165 mL) and DMF (0.87 mL) was stirred at 80 C for 1.5 h, and cooled down to room temperature. The mixture was evaporated in vacuo, and the resulting residue was dissolved in chloroform (300 mL). To the solution was added dropwise 28 wt % aqueous ammonia (300 mL) at 5 C, and the mixture was stirred at 5 C for 0.5 h. The mixture was extracted with chloroform, and the organic layer was dried. The desiccant was removed by filtration and the filtrate was evaporated in vacuo to obtain a pale yellow solid. The mixture of the obtained solid and phosphoryl chloride (195 mL) was stirred at 80 C for 2 h, and cooled down to room temperature. The mixture was evaporated in vacuo, and the resulting residue was treated with diethyl ether (500 mL) and ice-water (300 mL), then stirred at room temperature for 0.5 h. The mixture was extracted with diethyl ether and the organic layer was washed with saturated aqueous sodium hydrogen carbonate and brine, and then dried. The desiccant was removed by filtration and the filtrate was evaporated in vacuo to obtain 9h (41.57 g, 85%) as a pale yellow solid.

References: [1]Patent: US4996355,1991,A .
[2]Patent: EP1806347,2007,A1 .Location in patent: Page/Page column 9.
[3]Bioorganic and Medicinal Chemistry,2012,vol. 20,p. 5235 - 5246.

6
4-chloro-2,5-difluoro-α,α-dichloroacetophenone [ No CAS ]
sodium bissulfite [ No CAS ]
[ 132794-07-1 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; In sodium hypobromide; water;	EXAMPLE 14 4-Chloro-2,5-difluoro-benzoic acid 124 g of 4-chloro-2,5-difluoro-alpha,alpha-dichloroacetophenone from Example 13 are added dropwise with stirring at 30 C. in the course of 1 h to 1258 g of sodium hypobromite solution (9.5% strength). The mixture is subsequently stirred at 30 C. for 45 min and then at 50 C. for 3 h. After diluting with 1500 ml of water, the mixture is brought to pH 6 using 70 ml of hydrochloric acid (32% with the addition of sodium disulphite and the organic phase is separated off. The benzoic acid is then precipitated to pH 1 using 50 ml of hydrochloric acid (32%) with the addition of sodium disulphite. In this manner, 77.3 g of 4-chloro-2,5-difluorobenzoic acid are obtained, which corresponds to 80.3% of theory, relative to 0.5 mol of 1-chloro-2,5-difluorobenzene employed in Example 13.

References: [1]Patent: US5093529,1992,A .

7
[ 109-99-9 ]
[ 132794-07-1 ]
[ 121-43-7 ]
(4-chloro-2,5-difluoro-phenyl)-methanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		(4-Chloro-2,5-difluoro-phenyl)-methanol To a mixture of <strong>[132794-07-1]4-chloro-2,5-difluoro-benzoic acid</strong> (15 g, 78 mmol) tetrahydrofuran (THF) (75 mL) and trimethylborate (26 mL, 230 mmol) was added borane-methylsulfide complex (86 mL, 86 mmol, 10 M solution in DMS), and the mixture was stirred for 18 hours at ambient temperature. Additional borane-methylsulfide complex (2.47 mL, 24.7 mmol) was added to drive the reaction to completion. The mixture was poured into 1M aqueous NaOH, extracted 3* with ether, and the combined organic layers were dried over anhydrous MgSO4, filtered and concentrated in vacuo. Trituration of the solid residue with ether-hexane afforded 14 g of (4-chloro-2,5-difluoro-phenyl)-methanol as a colorless solid. 1H NMR (400 MHz, CDCl3) delta7.26 (dd, 1H, J=6, 8.8 Hz), 7.11 (dd, 1H, J=6, 9.2 Hz), 4.71 (d, 2H, J=6.0 Hz), 1.80 (t, 1H, J=6.0 Hz) ppm.

References: [1]Patent: US6235764,2001,B1 .

8
[ 132794-07-1 ]
[ 79-37-8 ]
4-chloro-2-cyclopropylamino-5-fluoro-benzoic acid ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In diethyl ether; ethanol; dichloromethane; ethyl acetate; N,N-dimethyl-formamide; acetonitrile;	EXAMPLE B-3 4-Chloro-2-cyclopropylamino-5-fluoro-benzoic Acid Ethyl Ester A mixture of <strong>[132794-07-1]4-chloro-2,5-difluorobenzoic acid</strong> (5.0 g, 26 mmol) and dichloromethane (150 mL) was reacted with oxalyl chloride (6.0 mL, 69 mmol) and one drop of DMF. The mixture was stirred for 1.5 hours, then concentrated. The residue was then dissolved in dichloromethane (200 mL) and reacted with ethanol (40 mL). After 30 minutes, the mixture was diluted with diethyl ether and washed with 1.0 N NaOH. The organic layer was then dried with sodium sulfate and the solvent concentrated. The residue was then taken up in acetonitrile (40 mL) and heated with an excess of cyclopropyl amine (20 mL) for 48 hours at 80 C. The mixture was cooled to ambient temperature and the solvent concentrated. The residue was then taken up in diethyl ether and washed with water. The organic layer was dried with sodium sulfate and concentrated. The resulting residue was purified by column chromatography (silica gel, gradient dilution of hexanes to 20% ethyl acetate/hexanes) to provide a 4.16 g of the title compound as a solid.

References: [1]Patent: US6331538,2001,B1 .

9
[ 132794-07-1 ]
[ 74-89-5 ]
N-methyl 2,5-difluoro-4-chloro-benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82.7%	With 1,1'-carbonyldiimidazole; In tetrahydrofuran; water; at 20℃; for 1.16667h;Product distribution / selectivity;	40% Methylamine in water (54 ml, 624 mmoles) was added dropwise to a mixture of <strong>[132794-07-1]2.5-difluoro-4-chloro-benzoic acid</strong> (PLEASE DEFINE THE SOURCE OF THIS REACTANT) (30.0 g, 155.8 mmoles) and 1,1'-carbonyldiimidazole (27.6 g, 170 mmoles) in THF (300 ml). The mixture vas stirred at room temperature for 40 minutes. Water (1.8L) was added to the reaction mixture. The slurry was stirred at room temperature for 30 minutes and filtered. The cake was washed with water and dried in a vacuum oven at 40 C. for 18 hours. N-methyl 2,5-difluoro-4-chloro-benzamide (26.5 g) was obtained at 82.7% yield. Mp: 127.5-127.6 C. 1H NMR (in CDCl3): delta7.88 (dd, J=9.5/7.0, 1H), 7.20 (dd, J=10.4/5.4, 1H), 6.67 (brs, 1H), 3.00 (d, J=4.5, 3H). GC-MS: 205 (M+).

References: [1]Patent: US2007/21634,2007,A1 .Location in patent: Page/Page column 4; 6.

10
[ 132794-07-1 ]
[ 1187890-09-0 ]
[ 1187889-53-7 ]

Yield	Reaction Conditions	Operation in experiment
23%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 10 - 20℃;	Example 4 Synthesis of N-Biphenyl-4-yl-3-[4-(4-chloro-2,5-difluoro-benzoyl)-piperazin-1-yl]-3-oxo-propionamide HOBt (34 mg, 0.25 mmol) and DIPEA (67.9 mg, 0.51 mmol) were added to a stirred solution of <strong>[132794-07-1]4-chloro-2,5-difluoro-benzoic acid</strong> (40 mg, 0.21 mmol) in DMF (1 mL). The reaction mixture was cooled to 10 C. and EDCI.HCl (48 mg, 0.25 mmol) followed by N-biphenyl-4-yl-3-oxo-3-piperazin-1-yl-propionamide.hydrochloride (75 mg, 0.2 mmol) were added. The mixture was stirred at room temperature overnight then diluted with water. The resulting precipitate was filtered then purified by column chromatography using silica gel 60-120 mesh and 60% ethyl acetate in hexane to afford 24 mg (23%) of N-biphenyl-4-yl-3-[4-(4-chloro-2,5-difluoro-benzoyl)-piperazin-1-yl]-3-oxo-propionamide. LCMS: 498.18 (M+1)+, 97.0%. 1H NMR: (CDCl3): delta 9.6 (d, 1H), 7.52 (m, 6H), 7.49 (t, 2H), 7.35 (t, 1H), 7.25 (t, 1H), 3.7 (m, 3H), 3.56 (d, 3H), 3.55 (d, 2H), 3.4 (m, 2H).

References: [1]Patent: US2009/239848,2009,A1 .Location in patent: Page/Page column 15.

11
[ 132794-07-1 ]
[ 764648-58-0 ]