3-Chloro-4-trifluoromethoxyphenol

Cat.NO.:A109845 Purity:98%

Product Details of [ 1000339-94-5 ]

CAS No. :	1000339-94-5
Formula :	C₇H₄ClF₃O₂
M.W :	212.55
SMILES Code :	ClC1=C(C=CC(=C1)O)OC(F)(F)F
MDL No. :	MFCD04972754
Boiling Point :	No data available
InChI Key :	ZDKAPCMMTRJKTR-UHFFFAOYSA-N
Pubchem ID :	40427108

Safety of [ 1000339-94-5 ]

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

Computational Chemistry of [ 1000339-94-5 ] Show Less

Physicochemical Properties

Num. heavy atoms	13
Num. arom. heavy atoms	6
Fraction Csp3	0.14
Num. rotatable bonds	2
Num. H-bond acceptors	5.0
Num. H-bond donors	1.0
Molar Refractivity	40.16
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	29.46 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.87
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	3.57
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	4.2
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.	2.22
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	2.58
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	2.89

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-3.62
Solubility	0.0514 mg/ml ; 0.000242 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.	-3.87
Solubility	0.0284 mg/ml ; 0.000134 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	-3.07
Solubility	0.18 mg/ml ; 0.000847 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	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.	-5.06 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<2.0
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)	1.75

Application In Synthesis of [ 1000339-94-5 ]

* 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 [ 1000339-94-5 ]

[ 1000339-94-5 ] Synthesis Path-Downstream 1~21

1
[ 1000339-94-5 ]
[ 77-78-1 ]
[ 1034669-92-5 ]

Yield	Reaction Conditions	Operation in experiment
73%	With sodium hydroxide; tetrabutylammonium sulfate; In dichloromethane; water; at 20℃; for 18.0h;	Example 30; 2-Chloro-4-methoxy-l-(trifluoromethoxy)benzene; A mixture of <strong>[1000339-94-5]3-chloro-4-(trifluoromethoxy)phenol</strong> (1.00 g, 4.71 mmol), dimethylsulfate (490 muL, 5.18 mmol), tetrabutylammonium sulfate, 2 M aqueous sodium hydroxide (2.59 mL, 5.18 mmol) and dichloromethane (25 mL) was vigorously stirred at room temperature for 18 h. The mixture was diluted with dichloromethane, washed with water, dried over sodium sulfate and concentrated in vacuo to give 780 mg (73% yield) of the title compound: 1H NMR (CDCl3) delta 7.22 – 7.26 (m, 1 H), 6.99 (d, J= 2.8 Hz, 1 H), 6.81 (dd, J = 9.1, 3.0 Hz, 1 H), 3.82 (s, 3 H).
73%	With sodium hydroxide; tetrabutylammonium sulfate; In dichloromethane; water; at 20℃; for 18.0h;	A mixture of 3-chloro-4~(trifluoromethoxy)phenol (1.00 g, 4.71 mmol), dimethylsulfate (490 muL, 5.18 mmol), tetrabutylammonium sulfate, 2 M aqueous sodium hydroxide (2.59 mL, 5.18 mmol) and dichloromethane (25 mL) was vigorously stirred at room temperature for 18 h. The mixture was diluted with dichloromethane, washed with water, dried over sodium sulfate and concentrated in vacuo to give 780 mg (73% yield) of the title compound: 1HNMR (CDCl3) 5 7.22 – 7.26 (m, 1 H), 6.99 (d, J= 2.8 Hz, 1 H), 6.81 (dd, J = 9.1, 3.0 Hz, 1 H), 3.82 (s, 3 H).

References: [1]Patent: WO2008/76043,2008,A1 .Location in patent: Page/Page column 70.
[2]Patent: WO2008/76046,2008,A1 .Location in patent: Page/Page column 208-209.

2
[ 1000339-94-5 ]
[ 1354955-46-6 ]

References: [1]Patent: US2012/10207,2012,A1 .

3
[ 1000339-94-5 ]
[ 1354962-93-8 ]

References: [1]Patent: US2012/10207,2012,A1 .
[2]Patent: WO2014/8458,2014,A2 .

4
[ 1000339-94-5 ]
[ 1354960-64-7 ]
[ 1354963-01-1 ]

Yield	Reaction Conditions	Operation in experiment
47%	With potassium carbonate; In dimethyl sulfoxide; at 20℃; for 3.0h;	4-Methylphenyl-5-chloro-2,4-difluorobenzoate (Preparation 10, 133 mg, 0.47 mmol) was added to a mixture of potassium carbonate (84 mg, 0.61 mmol), <strong>[1000339-94-5]3-chloro-4-(trifluoromethoxy)phenol</strong> (100 mg, 0.47 mmol) in dimethylsulfoxide (1.0 mL) and the reaction stirred at room temperature for 3 hours. The reaction was diluted by addition of water (2.0 mL) and ethyl acetate (3.0 mL) and the mixture partitioned. The aqueous was further extracted with ethyl acetate (3.0 mL), the organics combined, dried with magnesium sulfate, filtered and evaporated to give a white solid. Purification was accomplished by column chromatography on silica, eluting with ethyl acetate:heptanes (3:97) to provide the title compound as a white solid (106 mg, 47%).LCMS Rt=6.15 minutes, no mass ion.1H-NMR (400 MHz, CDCl3): delta 2.37 (s, 3H), 6.75 (d, 1H), 7.01 (dd, 1H), 7.00 (d, 2H), 7.23-7.21 (m, 3H), 7.38 (d, 1H), 8.42 (d, 1H)19F-NMR (400 MHz, CDCl3): 6-58.1, -104.9

References: [1]Patent: US2012/10207,2012,A1 .Location in patent: Page/Page column 58.

5
[ 1000339-94-5 ]
[ 1354961-13-9 ]
[ 1354962-92-7 ]

Yield	Reaction Conditions	Operation in experiment
97%	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 19.0h;	To a mixture of tert-butyl 5-chloro-2,4-difluorobenzoate (WO2012007883A1, 1.17 g, 4.72 mmol) and <strong>[1000339-94-5]3-chloro-4-(trifluoromethoxy)phenol</strong> (1.02 g, 4.80 mmol) in anhydrous N,N-dimethylformamide (10 mL) was added potassium carbonate (1.31 g, 9.45 mmol). The mixture was stirred at ambient temperature for 19 h. The reaction mixture was then diluted with diethyl ether (200 mL), washed with saturated aqueous sodium bicarbonate (2 chi 200 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness to afford the title compound as a white solid (2.02 g, 97%): FontWeight=”Bold” FontSize=”10″ H NMR (300 MHz, CDC13) delta 7.98 (d, J= 13 Hz, 1H), 7.34-7.31 (m, 1H), 7.12 (d, J= 2.9 Hz, 1H), 6.93 (dd, J= 2.9, 9.0 Hz, 1H), 6.68 (d, J= 10.8 Hz, 1H), 1.57 (s, 9H); MS (ES+) m/z 440.9, 441.9 (M + 1).
75%	With potassium carbonate; In dimethyl sulfoxide; at 20℃; for 18.0h;	<strong>[1000339-94-5]3-chloro-4-(trifluoromethoxy)phenol</strong> (22.6 g, 0.106 mol) and tert-butyl 5-chloro-2,4-difluorobenzoate (Preparation 51, 26.4 g, 0.106 mol) were dissolved in dimethlysulfoxide (105 mL). Then potassium carbonate (29.4 g, 0.213 mol) was added portionwise to the mixture, which was stirred at room temperature for 18 hours. The reaction mixture was dropped into iced water (500 mL) and stirred vigorously for 4 hours. The resulting solid was collected by filtration then taken up in isopropanol (75 mL) and water (15 mL). The reaction was heated to 55 C., then cooled down to room temperature. The resulting solid was collected by filtration to yield the title compound as an off-white white solid (35.3 g, 75%).1H NMR (400 MHz; CDCl3): delta 1.62 (s, 9H), 6.72 (d, 1H), 6.97 (dd, 1H), 7.16 (d, 1H), 7.35-7.38 (m, 1H), 8.02 (d, 1H)LC Rt=8.637 minutes.

References: [1]Patent: WO2014/8458,2014,A2 .Location in patent: Paragraph 0300-0301.
[2]Patent: US2012/10207,2012,A1 .Location in patent: Page/Page column 56.

6
[ 1000339-94-5 ]
[ 1445862-81-6 ]
[ 1445862-80-5 ]

Yield	Reaction Conditions	Operation in experiment
98%	With potassium carbonate; at 90℃; for 18.0h;	A suspension of 3-(2-ethoxypyridin-3-yl)-4-fluorobenzaldehyde (Preparation 8, 346 mg, 1 .41 mmol), <strong>[1000339-94-5]3-chloro-4-(trifluoromethoxy)phenol</strong> (300 mg, 1 .41 mmol), and potassium carbonate (585 mg, 4.23 mmol) was stirred for 18 hours at 90 C. The reaction mixture was partitioned between water (50 mL) and ethyl acetate (50 mL). The organic layer was separated, washed with water (4 x 50 mL), dried over sodium sulfate, filtered and concentrated in vacuo to afford the title compound as a brown oil (604 mg, 98%). 1H NMR (400MHz, Acetone-D6): delta ppm 1 .22 (m, 3H), 4.32 (m, 2H), 6.92 (m, 2H), 7.10 (m, 2H), 7.25 (m, 1 H), 7.54 (m, 1 H), 7.89 (m, 1 H), 7.92 (m, 1 H), 8.16 (m, 1 H), 10.00 (s, 1 H). 19F NMR (400MHz, Acetone-D6): delta ppm -58.3 LCMS Rt = 3.92 minutes MS m/z 438 [MH]+

References: [1]Patent: WO2013/93688,2013,A1 .Location in patent: Page/Page column 42-43.

7
[ 1000339-94-5 ]
[ 1445862-81-6 ]
[ 1445862-60-1 ]

References: [1]Patent: WO2013/93688,2013,A1 .

8
[ 1000339-94-5 ]
[ 1445862-86-1 ]
[ 1445862-90-7 ]

Yield	Reaction Conditions	Operation in experiment
96%	With potassium carbonate; In dimethyl sulfoxide; at 20℃; for 48.0h;	To a solution of terf-butyl 2,4-difluoro-5-iodobenzoate (Preparation 16, 579 mg, 1 .70 mmol) and <strong>[1000339-94-5]3-chloro-4-(trifluoromethoxy)phenol</strong> (362 mg, 1 .70 mmol) in DMSO (15 mL) was added potassium carbonate (706 mg, 5.1 1 mmol) and the mixture stirred at room temperature for two days. The mixture was poured onto water (20 mL) and extracted with EtOAc (2 x 30 mL), washed with water (3 x 30 mL), dried over MgSO4 and filtered. The solvent was removed under reduced pressure to afford the title compound as a colourless oil (870 mg, 96%). LCMS Rt = 4.1 1 minutes, no mass ion observed

References: [1]Patent: WO2013/93688,2013,A1 .Location in patent: Page/Page column 50.

9
[ 1000339-94-5 ]
[ 1533431-19-4 ]

References: [1]Patent: WO2014/8458,2014,A2 .

10
[ 1000339-94-5 ]
tert-butyl N-[6-(bromomethyl)-5-chloro-1,2-benzoxazol-3-yl]-N-[(tert-butoxy)carbonyl]carbamate [ No CAS ]
tert-butyl N-[(tert-butoxy)carbonyl]-N-{5-chloro-6-[3-chloro-4-(trifluoromethoxy)phenoxymethyl]-1,2-benzoxazol-3-yl}carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 25℃; for 16.0h;	A solution of tert-butyl N-[6-(bromomethyl)-5-chloro-l,2-benzoxazol-3-yl]-N-[(tert-butoxy)carbonyl]carbamate (100 mg, 0.22 mmol) in DMF (2 mL) was added <strong>[1000339-94-5]3-chloro-4-(trifluoromethoxy)phenol</strong> (55 mg, 0.26 mmol) and potassiumm carbonate (61 mg, 0.44 mmol). After stirring at 25C for 16 h, the mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to afford tert-butyl N-[(tert-butoxy)carbonyl]-N-{5-chloro-6-[3-chloro-4-(trifluoromethoxy)phenoxymethyl]-1,2-benzoxazol-3-yl} carbamate (100 mg, crude) as an oil which was used in the next step without further purification. LCMS (ESI) m/z: 437.0 [M-156+H]+

References: [1]Patent: WO2014/144545,2014,A2 .Location in patent: Page/Page column 64; 66.

11
[ 1000339-94-5 ]
C₉H₈Br₂FNO₃S [ No CAS ]
C₁₆H₁₁BrClF₄NO₄S [ No CAS ]

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