130754-19-7|Ethyl 2-(4-Chlorophenyl)-2,2-difluoroacetate| Ambeed

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Quality Control of [ 130754-19-7 ] Purity: 95% SDS Specification

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Product Details of [ 130754-19-7 ]

CAS No. :	130754-19-7
Formula :	C₁₀H₉ClF₂O₂
M.W :	234.63
SMILES Code :	O=C(OCC)C(F)(C1=CC=C(Cl)C=C1)F
MDL No. :	MFCD11007726
InChI Key :	VGULHXRXMXNYHN-UHFFFAOYSA-N
Pubchem ID :	21468011

Safety of [ 130754-19-7 ]

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

Computational Chemistry of [ 130754-19-7 ] Show Less

Physicochemical Properties

Num. heavy atoms	15
Num. arom. heavy atoms	6
Fraction Csp3	0.3
Num. rotatable bonds	4
Num. H-bond acceptors	4.0
Num. H-bond donors	0.0
Molar Refractivity	52.11
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	26.3 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.67
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	3.45
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	3.73
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.	3.39
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	3.32
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	3.31

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-3.5
Solubility	0.0742 mg/ml ; 0.000316 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.	-3.68
Solubility	0.0486 mg/ml ; 0.000207 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	-4.11
Solubility	0.0183 mg/ml ; 0.0000778 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Moderately 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	Yes
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.	-5.28 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	0.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.55

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)	1.82

Application In Synthesis of [ 130754-19-7 ]

* 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 [ 130754-19-7 ]

[ 130754-19-7 ] Synthesis Path-Downstream 1~35

1
[ 14062-24-9 ]
[ 74569-27-0 ]
(4-Chloro-3-fluoro-phenyl)-acetic acid ethyl ester [ No CAS ]
[ 188424-98-8 ]
[ 130754-19-7 ]

References: [1]Journal of Fluorine Chemistry,1990,vol. 49,p. 115 - 126.

2
[ 14062-24-9 ]
[ 74569-27-0 ]
[ 130754-19-7 ]

References: [1]Journal of Fluorine Chemistry,1990,vol. 49,p. 115 - 126.

3
[ 1878-66-6 ]
[ 130754-19-7 ]

References: [1]Journal of Fluorine Chemistry,1990,vol. 49,p. 115 - 126.
[2]Journal of Fluorine Chemistry,1990,vol. 49,p. 115 - 126.

4
[ 130754-19-7 ]
4-chlorophenyl-2,2-difluoroethanoyl chloride [ No CAS ]
α,α-difluoro-N-[6-methyl-2,4-bis(methylthio)-3-pyridinyl]-4-chlorobenzeneacetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium hydroxide; In ethanol; water;	Part 2. Ethyl 4-chlorophenyl-2,2-difluoroacetate (250 mg) and potassium hydroxide (300 mg) were mixed in 27 ml of ethanol and 2.4 ml of water and the reaction mixture was refluxed for four hours. The mixture was then acidified and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous Na2 SO4 and the solvent was removed in vacuo to give a product which was dissolved in 410 mg of oxalyl chloride with catalytic amount of N,N-dimethylformamide. The mixture was stirred for two hours and excess oxalyl chloride was removed in vacuo to give 4-chlorophenyl-2,2-difluoroethanoyl chloride which was used as is for the subsequent step.

References: [1]Patent: US5583147,1996,A .

5
[ 873-77-8 ]
[ 130754-19-7 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; trans-4,4'-diaminostilbene-2,2'-disulfonic acid; In tetrahydrofuran; diethyl ether;	Part 1. To a solution of diethyloxylate (2.94 g, 20.1 mmol) in 3 ml of anhydrous tetrahydrofuran was added 4-chlorophenylmagnesium bromide (30 ml of 0.33M solution in diethyl ether (10 ml) and tetrahydrofuran (20 ml)) dropwise over one hour period at -10. After stirring at -10 for another 30 minutes, 40 ml of 5% HCl was added to quench the reaction. The organic layer was then separated, washed with sat.NH4 Cl, sat.NaHCO3 and brine, dried over anhydrous Na2 SO4 and evaporated the solvent in vacuo to give a crude product (2.63 g). 600 mg of this crude product was then mixed with 0.5 ml of DAST (3.8 mmol). The mixture was warmed to 40 and then cooled to room temperature. After stirring at room temperature for two hours, the reaction mixture was poured on ice and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous Na2 SO4 and removed the solvent in vacuo to give crude product which was purified by flash column chromatography to give 261 mg of pure ethyl 4-chlorophenyl-2,2-difluoroacetate.

References: [1]Patent: US5583147,1996,A .

6
[ 130754-19-7 ]
[ 207799-86-8 ]

Yield	Reaction Conditions	Operation in experiment
95%	With sodium tetrahydroborate; ethanol; at 20℃; for 0.5h;	To a stirred solution of ethyl 2(4chiorophenyTh22difluoroacetate (6.7 g, 29 mmoi) in EtOH (1 0 mLj wa added NaBH4 (1 S5 g 41 mmol) at toom temperature The susptnsion was slowly transformed tO a clear solution. After stirring for 30mm at rt. the: ester was consumed. The reaction mixture wa.s quenched with aqueous IN HG under icewater bath cooling The mixturc %JS ttrctcttd with EtOAc [he organic phasts were washed w nh biuie dried O et Na2SO4 aim concentmted to attoid the title compound as s colni less liquid iS S) 95%). 11 NMR (400 MHz C 003) ii 7.46 (d. qi 8 Hz, 2.1:1). 7.42 (d.. J::; 8.8 Hz. 211), 3.95 (tJ 13.1 Hz,ZH).
	With sodium hydroxide; In diethyl ether; water;	Step A Synthesis of 2,2-difluoro-2-(4-chlorophenyl)ethanol as an intermediate Lithium aluminum hydride, 2.4 grams (0.063 mole), is placed in a reaction vessel, and 200 mL of diethyl ether is added dropwise with stirring. To this is added dropwise a solution of 22.8 grams (0.097 mole) of <strong>[130754-19-7]ethyl 4-chlorophenyldifluoroacetate</strong> (prepared by methods taught by W. J. Middleton et al., J. Org. Chem., (1980), 45, 2883-2887) in 100 mL of diethyl ether, while maintaining the reaction mixture temperature at about 25 C. Upon completion of addition, the reaction mixture is stirred at ambient temperature for about 36 hours. The reaction is then quenched by the careful dropwise addition of an aqueous solution of 10% sodium hydroxide. The reaction mixture is slowly made acidic with aqueous 2N hydrochloric acid and then is diluted with 200 mL of water. The organic layer is separated, and the aqueous layer is washed with two 300 mL portions of diethyl ether. The organic layer and the diethyl ether washes are combined and washed with one 250 mL portion of an aqueous solution saturated with sodium chloride. The organic layer is dried with magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure, yielding 2,2-difluoro-2-(4-chlorophenyl)ethanol.

References: [1]Patent: WO2016/44323,2016,A1 .Location in patent: Paragraph 0369.
[2]Patent: US5622954,1997,A .

7
[ 637-87-6 ]
[ 667-27-6 ]
[ 130754-19-7 ]

Yield	Reaction Conditions	Operation in experiment
46%	With copper; In dimethyl sulfoxide; at 80℃; for 20h;	To a stirred solutIon of I-chioro-4-iodobenzene (15.0 g, 63 mmo) and ethyl 2-bromo- 2,2-ditluoroacetate (12.8g. 63 mmo1 in DMS() (300 mL) was added Cu powder (8.0g. 126 nimol). i?he mixture was heated to 80 C, and stirred for 20 hrs. The mixture was cooled to it, and poured into an aqueous solution of K2HPO4.3N20 (1 1.0 g) in water (1.5 L) under sdrring After stirring for 30 mm at rt, the mixture was filtered through a pad of celite. The filter cake was extracted with ether.The conibned organic phases were washed with waler and brine, dried over Na2SO4 and concentrated, The concentrate was purified column chromatography over silica gel (eluent: hexane) to afford the title compound as a colorless oil (6.8 g, 46%). K NMR. (400 MHz, CDCI3) 67.55 jd, ,J 8.4 Hz, 211), 7.44 (d, .1 8.4 Hz, 2K), 4.30 (q, J 7.1 Hz,2H), 1.31 (t,J7.l Hz,3H).
	With copper; In dimethyl sulfoxide; at 80℃; for 20h;	To a solution of l-chloro-4-iodobenzene (5.9 g, 25 mmol) in DMSO (100 mL) was added ethyl bromo(difluoro)acetate (5.0 g, 25 mmol) and copper powder (3.1 g, 49 mmol) and the mixture was heated at 8O0C. After 20 hours, the reaction mixture was poured into a solution of dibasic potassium hydrogen phosphate, trihydrate (56 g, 250 mmol) in water (500 mL) with vigorous stirring. The suspension was filtered and the solid was rinsed with ether. The filtrate was added to brine and extracted with ether (2x). The combined organics were washed with brine, dried over sodium sulfate, filtered, and concentrated. The resulting oil was dissolved in methanol (100 mL) and treated with 50% aqueous KOEta (250 mL) at room temperature. After 2 hours, the reaction mixture was concentrated, dissolved in CHCl3 and extracted with IM HCl. The aqueous layer was basified with NaOH and extracted with CHCl3. The combined organics were dried over sodium sulfate, filtered, and concentrated to yield the title compound (3.5 g) as a waxy solid.
500 mg	With copper; In dimethyl sulfoxide;	50mL reaction flask, adding 360mg (5.6mmol) copper powder, vacuuming for three times, then injecting 10mL dimethyl sulfoxide, 477mg (2mmol) p-chloroiodobenzene, 609mg (3mmol) ethyl bromodifluoroacetate, 80 C The reaction was carried out overnight, and the temperature was reduced to room temperature, and extracted with 50 mL of ethyl acetate, washed with saturated sodium chloride and dried over anhydrous sodium sulfate.Rotary evaporation to remove the solvent A mixture of ethyl 2-(4-chlorophenyl)-2,2-difluoroacetate, a yellow liquid, 500 mg. Used directly in the next step of the reaction.

References: [1]Patent: WO2016/44323,2016,A1 .Location in patent: Paragraph 0368.
[2]Chemical Communications,2016,vol. 52,p. 1598 - 1601.
[3]European Journal of Organic Chemistry,2016,vol. 2016,p. 5529 - 5538.
[4]Patent: WO2006/113471,2006,A2 .Location in patent: Page/Page column 26; 48.
[5]Patent: CN105085433,2019,B .Location in patent: Paragraph 0355-0358.

8
[ 130754-19-7 ]
2-(4-chlorophenyl)-2,2-difluoroacetic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With methanol; potassium hydroxide; water; at 20℃; for 2h;	To a solution of l-chloro-4-iodobenzene (5.9 g, 25 mmol) in DMSO (100 mL) was added ethyl bromo(difluoro)acetate (5.0 g, 25 mmol) and copper powder (3.1 g, 49 mmol) and the mixture was heated at 8O0C. After 20 hours, the reaction mixture was poured into a solution of dibasic potassium hydrogen phosphate, trihydrate (56 g, 250 mmol) in water (500 mL) with vigorous stirring. The suspension was filtered and the solid was rinsed with ether. The filtrate was added to brine and extracted with ether (2x). The combined organics were washed with brine, dried over sodium sulfate, filtered, and concentrated. The resulting oil was dissolved in methanol (100 mL) and treated with 50% aqueous KOEta (250 mL) at room temperature. After 2 hours, the reaction mixture was concentrated, dissolved in CHCl3 and extracted with IM HCl. The aqueous layer was basified with NaOH and extracted with CHCl3. The combined organics were dried over sodium sulfate, filtered, and concentrated to yield the title compound (3.5 g) as a waxy solid.
270 mg	With potassium hydroxide; In methanol; water; at 20℃; for 2h;	500 mg of <strong>[130754-19-7]ethyl 2-(4-chlorophenyl)-2,2-difluoroacetate</strong>, adding 10 mL of methanol, 10 mL of water, 560 mg (10 mmol) of potassium hydroxide, stirring at room temperature for two hours, then evaporating methanol to remove water by rotary evaporation The layer was adjusted to pH 5 with hydrochloric acid to precipitate a white solid. Filtration in vacuo gave 270 mg of 2-(4-chlorophenyl)-2,2-difluoroacetic acid white powder. Used directly in the next step of the reaction.

References: [1]European Journal of Organic Chemistry,2016,vol. 2016,p. 5529 - 5538.
[2]Patent: WO2006/113471,2006,A2 .Location in patent: Page/Page column 26; 48.
[3]Patent: CN105085433,2019,B .Location in patent: Paragraph 0355; 0359-0361.

9
[ 130754-19-7 ]
[ 1292820-74-6 ]