145689-41-4|2-(2,3-Difluorophenyl)acetic acid| Ambeed

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Quality Control of [ 145689-41-4 ] Purity: 98% SDS Specification

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Product Details of [ 145689-41-4 ]

CAS No. :	145689-41-4
Formula :	C₈H₆F₂O₂
M.W :	172.13
SMILES Code :	O=C(O)CC1=CC=CC(F)=C1F
MDL No. :	MFCD00040968
InChI Key :	UXSQXUSJGPVOKT-UHFFFAOYSA-N
Pubchem ID :	520772

Safety of [ 145689-41-4 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H335
Precautionary Statements:	P261-P305+P351+P338

Computational Chemistry of [ 145689-41-4 ] Show Less

Physicochemical Properties

Num. heavy atoms	12
Num. arom. heavy atoms	6
Fraction Csp3	0.12
Num. rotatable bonds	2
Num. H-bond acceptors	4.0
Num. H-bond donors	1.0
Molar Refractivity	37.9
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.	1.45
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	1.6
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.43
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.	2.52
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	2.39
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	2.08

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.15
Solubility	1.21 mg/ml ; 0.00703 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.	-1.99
Solubility	1.74 mg/ml ; 0.0101 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very 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	-2.73
Solubility	0.321 mg/ml ; 0.00187 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.	-6.21 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	0.0 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)	1.66

Application In Synthesis of [ 145689-41-4 ]

* 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 [ 145689-41-4 ]

[ 145689-41-4 ] Synthesis Path-Downstream 1~35

1
[ 1489-53-8 ]
[ 105-56-6 ]
[ 85068-28-6 ]
[ 145689-41-4 ]

References: [1]Synthesis,1997,p. 1411 - 1414.

2
[ 530-62-1 ]
[ 145689-41-4 ]
2-(2,3-difluoro-phenyl)-1-imidazol-1-yl-ethanone [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 817 - 821.

3
[ 951-87-1 ]
[ 145689-41-4 ]
N-((1R,2S)-2-Amino-1,2-diphenyl-ethyl)-2-(2,3-difluoro-phenyl)-acetamide [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 435 - 438.

4
[ 145689-41-4 ]
(4S,5R)-2-(2,3-Difluoro-benzyl)-4,5-diphenyl-4,5-dihydro-1H-imidazole [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 435 - 438.

5
[ 145689-41-4 ]
[ 797784-36-2 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 817 - 821.

6
[ 145689-41-4 ]
[ 808144-32-3 ]

Yield	Reaction Conditions	Operation in experiment
80%	With thionyl chloride; In dichloromethane; water;	1) Preparation of (2,3-difluorophenyl)acetyl chloride (1) 1.0 mole of <strong>[145689-41-4](2,3-difluorophenyl)acetic acid</strong> is dissolved in dichloromethane and 1.1 mole of thionyl chloride is added. The mixture is heated to 35 C. and stirred for 4 hours. After completion of the reaction, water is added. The resulting compound is extracted with dichloromethane, dried over MgSO4, and filtered. The solvent is evaporated to yield the target compound. (yield 80%) GC mass data: m/z 193 (>99%)
	With oxalyl dichloride;	Example 1 2-(2, 3-DIFLUORO-PHENYL)-1-(LN-PYRROLO [2, 3-B] PYRIDIN-3-Y L)-ETHANONE : Method A: (X =F) [0198] To 7-azaindole (1 g, 8.5 mmol) and AlCl3 (1.2 g, 9.0 mmol) in methlene chloride at 0C was added (2,3-difluorophenyl)-acetyl chloride [prepared by treating (2,3-difluoro-phenyl)-acetic acid (1.5 mg, 8.72 mmol) with oxalyl chloride (0.90 mL) ] in methlene chloride. After stirring at room temperature for 2 hours, the solution was poured into ice water and extracted with methlene chloride, dried (NA2S04), and concentrated to give 300 mg (13% yield) of title compound used without purification. LCMS Rt= 3. 00 minutes, MH 273.1, M-271. 1.

References: [1]Patent: US2005/133762,2005,A1 .
[2]Patent: WO2005/28475,2005,A2 .Location in patent: Page/Page column 117-118.

7
[ 1131604-85-7 ]
[ 145689-41-4 ]
C₁₄H₈BrF₂N₃O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With lithium hexamethyldisilazane; In tetrahydrofuran; at 0℃;	Reagents and Conditions: (a) (i) LHMDS, THF - 78 C, (ii) diethyl oxalate; (b) H2NNH2, (I-PRO) 4TI, CH2CL2 ; (c) NMP, Microwave (250 C, 5 mins. ); (d) LHMDS, 2, 3-DIFLUOROACETIC ACID, THF, 0 C; (e) (i) Bredereck's reagent, THF, reflux, (ii) hydroxylamine hydrochloride, NaOAc, THF, reflux.

References: [1]Patent: WO2005/28475,2005,A2 .Location in patent: Page/Page column 232-233.

8
[ 1218764-82-9 ]
[ 145689-41-4 ]
C₁₄H₈F₃N₃O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With lithium hexamethyldisilazane; In tetrahydrofuran; at 0℃;	Reagents and Conditions: (a) (i) LHMDS, THF-78 C, (ii) diethyl oxalate; (b) H2NNH2/ (I-PRO) 4Ti, CH2C12 ; (c) NMP, Microwave (250 C, 5 mins. ); (d) LHMDS, 2, 3-DIFLUOROACETIC ACID, THF, 0 C; (e) (i) Bredereck's reagent, THF, reflux, (ii) hydroxylamine hydrochloride, NaOAc, THF, reflux ; (f) HNRIR2, NMP.

References: [1]Patent: WO2005/28475,2005,A2 .Location in patent: Page/Page column 234-235.

9
[ 851078-65-4 ]
[ 145689-41-4 ]
[ 851078-66-5 ]

Yield	Reaction Conditions	Operation in experiment
		2-(2,3-Difluoro-phenyl)-1-[2-(2,5-dihydro-pyrrole-1-carbonyl)-1H-imidazol-4-yl]-ethanone: To a mixture of 2-(2,5-dihydro-pyrrole-1-carbonyl)-1H-imidazole-4-carboxylic acid ethyl ester (100 mg, 0.43 mmol) and <strong>[145689-41-4](2,3-difluoro-phenyl)acetic acid</strong> (75 mg, 0.44 mmol) in anhydrous THF (5 mL) was added LDMS (1.0M in THF, 1.5 mL, 1.5 mmol) at -78 C. After addition of LDMS, the dry-ice bath was removed and the reaction was stirred at ambient temperature for 6 hours. To this reaction mixture was added 1 mL of sat. NH4Cl solution and EtOAc then the organic layer was separated and dried over MgSO4. After removal of solvent, the residue was washed with water to afford the title compound as a yellow solid. This crude product was used directly for the next step without further purification. MS (ES+): m/e=318.2 (M+H); Rt=3.21 minutes.

References: [1]Patent: US2005/148574,2005,A1 .Location in patent: Page 23.

10
[ 145689-41-4 ]
[ 141428-47-9 ]
[ 875003-88-6 ]

Yield	Reaction Conditions	Operation in experiment
	With sulfuric acid; nitric acid; In water; at -10 - -5℃; for 0.25h;	Step 1: Preparation of (2,3-difluoro-5-nitrophenyl)acetic acid <strong>[145689-41-4](2,3-Difluoro-phenyl)-acetic acid</strong> (5 g, 0.0290 mol) is dissolved in concentrated sulfuric acid (20 ml) and the resulting solution cooled to -10 C. with vigorous stirring. A solution of nitric acid (1.88 ml, 69.3%, 0.0290 mol) and sulfuric acid (2 ml) is added dropwise at a rate such that the temperature remains below -5 C. The thickened slurry is stirred for 15 minutes and then poured on ice. The resulting white precipitate is filtered and dried under vacuum (6.3 g, 99%) and consists of a 50/50 mixture of 5 and 6-NO2 regioisomers suitable for use directly in the next step.
	With sulfuric acid; nitric acid; In concentrated sulfuric acid; at -10 - -5℃; for 0.25h;	Step 1a: Preparation of (2,3-difluoro-5-nitrophenyl)acetic acid (12) <strong>[145689-41-4](2,3-Difluoro-phenyl)-acetic acid</strong> (11, 5 g, 0.0290 mol) is dissolved in concentrated sulfuric acid (20 ml) and the resulting solution cooled to -10 C. with vigorous stirring. A solution of nitric acid (1.88 ml, 69.3%, 0.0290 mol) and sulfuric acid (2 ml) is added dropwise at a rate such that the temperature remains below -5 C. The thickened slurry is stirred for 15 minutes and then poured on ice. The resulting white precipitate is filtered and dried under vacuum (6.3 g, 99%) and consists of a 50/50 mixture of 5 and 6-NO2 regioisomers suitable for use directly in the next step.
	With sulfuric acid; nitric acid; In water; at 0℃; for 0.416667h;	Example 15 Preparation of N-[(5S)-3-(9-fluoro-l-methyl-2-oxo-l,2,4,5-tetrahydro-3,l- benzoxazepin-7-yl)-2-oxo-l,3-oxazolidin-5-yl]methyl}acetamideStep 1: Preparation of {2-[benzyl(methyl)amino] -3 -fluoro-5-nitrophenyl} acetic acid.; To a cold (-100C) solution of <strong>[145689-41-4](2,3-difluorophenyl)acetic acid</strong> (40.0 g, 232 mmol) in concentrated sulfuric acid (120 mL) is added a cold mixture (00C) of nitric acid (21 mL, 70% <n="38"/>aqueous, 0.33 mol) and concentrated sulfuric acid (40 mL) over 5 min. After 20 min, the mixture is poured into ice water (1 L) and extracted with CH2Cl2 (3x300 mL). The combined organic layers are washed by brine, dried (Na2SO4), filtered and concentrated to provide a mixture of (2,3-difluoro-5-nitrophenyl)acetic acid and (2,3-difluoro-6-nitrophenyl)acetic acid (95%). This mixture is directly used in the next step without further purification. To a solution of the above regioisomeric mixture (52 g, 0.24 mol) in DMSO (100 mL) is added N- benzylmethylamine (175 mL, 1.36 mol). The mixture is stirred at 800C for 17 h, cooled to 23C, diluted with aqueous sodium hydroxide (30 g, in 1 L H2O) and extracted with ether (3x300 mL). The aqueous layer is then acidified with 12 M aqueous HCl to pH = 4 and extracted with CH2Cl2 (4x300 mL). The combined CH2Cl2 extracts are washed by brine, dried (Na2SO4), filtered and concentrated to afford the title compound. 1H NMR (300 MHz, CDCl3): 2.64 (s, IH), 2.70 (s, 3H), 3.82 (s, 2H), 4.15 (d, J =1.8 Hz, 2H), 7.27 (m, 5H), 7.90 (dd, J =2.7 Hz, J =11.4 Hz, IH), 7.95 (m, IH).

References: [1]Patent: US2006/30609,2006,A1 .Location in patent: Page/Page column 17.
[2]Patent: US2006/229349,2006,A1 .Location in patent: Page/Page column 8-9; 11.
[3]Patent: WO2007/93904,2007,A1 .Location in patent: Page/Page column 36-37.

11
[ 1036273-31-0 ]
[ 145689-41-4 ]

Yield	Reaction Conditions	Operation in experiment
72%		Example 19: 2, 3-Difluorophenylacetic acid 1 (Z = COOCH3, F = 2-F, X = 3-F)10 mL water and 0.8 mL of a 30% sodium hydroxide solution is added to 0.3 g methyl 2,3- difluorophenylacetate and the mixture is stirred at 60 C for an hour. Once the conversion is completed, it is acidified with concentrated hydrochloric acid to pH = 1. The product is isolated by filtration as a white solid in a 0.2 g (72%) amount.1H-NMR (300 MHz, CDCl3): delta (ppm) : 3.75 (s, 2H); 7.01-7.06 (m, 3H) ; 9.4 (bs, IH) .

References: [1]Patent: WO2008/78350,2008,A2 .Location in patent: Page/Page column 23.

12
[ 145689-41-4 ]
[ 1092477-48-9 ]

Yield	Reaction Conditions	Operation in experiment
42%	With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; at 80℃; for 5h;	To a solution of 738 mg of <strong>[145689-41-4](2,3-difluorophenyl)acetic acid</strong> (4.3 mmole, Aldrich) and of 761 mg of NBS in 15 mL of CCI4 in a dry flask under nitrogen were added 208 mg of benzoyl peroxide (0.86 mmole, Fluka) The solution was then stirred at 8O0C for 5 h. The solids were filtered off and the solvent was removed under reduced pressure and the resulting crude was purified on flash chromatography on 25 g silica gel cartridge using a gradient of AcOEt/DCM 0:10 to 8:2 as an eluent. Solvents were removed under reduced pressure to <n="67"/>give the title compound as a yellow solid (460 mg, 42%). 1H-NMR (400 MHz, DMSOd6): delta 6.09 (1 H, s), 7.15-7.18 (1 H, m), 7.23-7.41 (1 H, m), 7.47-7.52 (1 H, m), 14.76 (1 H, br s); UPLC/MS [Acquity UPLC BEH C18, 50x21 mm, 1.7 mum, Gradient: A: H2O +0.1% HCOOH/B: MeCN+0.075% HCOOH: 1% to 6%B in 0.2 min., 6% to 60%B in 1.05 min, 60% to 100%B in 0.5 min., 100%B for 0.2 min, flow rate: 1 mL/min]: Rt = 0.63 min. (65%) m/z (ES): 249 [M-H]".

References: [1]Patent: WO2008/148853,2008,A1 .Location in patent: Page/Page column 64-65.

13
[ 145689-41-4 ]
[ 57852-42-3 ]
[ 1134165-03-9 ]

References: [1]Bioorganic and Medicinal Chemistry,2009,vol. 17,p. 690 - 698.

14
[ 849069-32-5 ]
[ 849069-44-9 ]
[ 145689-41-4 ]
[ 849069-33-6 ]