175711-83-8|4'-Chloro-2'-fluoroacetophenone| Ambeed

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Quality Control of [ 175711-83-8 ] Purity: 97% SDS Specification

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Product Details of [ 175711-83-8 ]

CAS No. :	175711-83-8
Formula :	C₈H₆ClFO
M.W :	172.58
SMILES Code :	ClC1=CC(=C(C=C1)C(C)=O)F
MDL No. :	MFCD04116328
InChI Key :	OIGMDNONQJGUCF-UHFFFAOYSA-N
Pubchem ID :	15030552

Safety of [ 175711-83-8 ]

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

Computational Chemistry of [ 175711-83-8 ] Show Less

Physicochemical Properties

Num. heavy atoms	11
Num. arom. heavy atoms	6
Fraction Csp3	0.12
Num. rotatable bonds	1
Num. H-bond acceptors	2.0
Num. H-bond donors	0.0
Molar Refractivity	41.6
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	17.07 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.76
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	2.33
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	3.1
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.	2.79
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	3.21
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	2.64

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.72
Solubility	0.332 mg/ml ; 0.00193 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.	-2.33
Solubility	0.812 mg/ml ; 0.0047 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	-3.62
Solubility	0.041 mg/ml ; 0.000238 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.	-5.7 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	2.0
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)	1.4

Application In Synthesis of [ 175711-83-8 ]

* 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 [ 175711-83-8 ]
Downstream synthetic route of [ 175711-83-8 ]

[ 175711-83-8 ] Synthesis Path-Upstream 1~1

1
[ 175711-83-8 ]
[ 1229236-86-5 ]

References: [1] Organic Process Research and Development, 2012, vol. 16, # 1, p. 70 - 81.
[2] Organic Process Research and Development, 2012, vol. 16, # 1, p. 70 - 81.

[ 175711-83-8 ] Synthesis Path-Downstream 1~35

1
[ 198967-23-6 ]
[ 75-16-1 ]
[ 175711-83-8 ]

Yield	Reaction Conditions	Operation in experiment
	In diethyl ether; dichloromethane; at 0 - 20℃; for 2h;	Reference Example 8 : 1- (4-chloro-2-fluorophenyl) ethanone To a solution 4-chloro-2-fluorobenzoic acid (leq) in CH2C12 (1.6 M) was added N, O-dimethylhydroxylamine hydrochloride (1. 5 eq), EDCI (1.5 eq) and triethylamine (4 eq). The reaction mixture was stirred at rt for 16 hrs, concentrated and 0. 5M aqueous citric acid was added. The mixture was extracted with 1: 1 EtOAc: Et20. The combined organic layers were washed with brine, dried over MgS04 and concentrated to give 4-chloro-2-fluoro-N-methoxy-N- methylbenzamide, which was used as such for the next step. To a solution of the above benzamide (leq) in CHsClz (0.5 M) at 0C was added 3M/EtzO MeMgBr (1.25 eq). The reaction mixture was slowly warmed to rt over a 2 hrs period, quenched with 0.5 M aqueous citric acid and extracted with Et20. The combined organic layers were washed with brine, dried over MgS04 and concentrated. The residue was purified by flash chromatography on silica gel eluted with 20% EtOAc/hexane to give the title compound.

References: [1]Patent: WO2005/56527,2005,A1 .Location in patent: Page/Page column 23.

Yield	Reaction Conditions	Operation in experiment
		(3) Anhydrous magnesium chloride (6.7g, 70mmol) and triethylamine (24.2g, 0.24mol) were added to toluene (120ml), and dimethyl malonate (15.8g, 0.12mmol) was added dropwise under cooling with water. After the reaction mixture was stirred at room temperature for 3 hours, a toluene solution of the compound prepared in reference example 6-(2) (about 20g) in toluene (20ml) was added dropwise at about 20 ØC. The resulting mixture was stirred for 14 hours at room temperature. After concentrated hydrochloric acid (20ml) was added to the reaction mixture under cooling with ice, the resulting mixture was added to ice water. The organic layer was separated, and the aqueous layer was further extracted with toluene. The toluene layer was combined with the former organic layer, washed with brine, dried, and then evaporated to give an oil. The oil was added to a mixture of DMSO (80ml) and water (4ml). The mixture was gradually heated, stirred at 140 ØC (the temperature of oil bath) for 2 hours, and further stirred at 180 ØC for 1 hour. After cooling, the reaction mixture was poured into ice water, and extracted with diethyl ether. The extract was washed with brine, dried, and then evaporated. The residue was distilled under reduced pressure to give 4-chloro-2-fluoroacetophenone (14.4g, oil). 1H-NMR(CDCl3) delta 2.63(3H, d, J=5.03Hz), 7.12-7.25(2H, m), 7.84(1H, t, J=9.02Hz). b.p.:100-104 ØC/20mmHg

3
[ 175711-83-8 ]
[ 725743-41-9 ]

Yield	Reaction Conditions	Operation in experiment
95%	With 4-(dimethylamino)pyridine tribromide; In acetic acid; at 20℃; for 24h;	A mixture of <strong>[175711-83-8]4'-chloro-2'-fluoroacetophenone</strong> (17.5 g, 100 mmol), 4-(dimethylamino)pyridine tribromide (40.0 g, 110 mmol) and acetic acid (100 mL) was stirred at room temperature for 24 h. Water (150 mL) was added and after stirring for 30 min the precipitated solid was collected by filtration, washed with water, and dried in vacuo to give the desired bromide intermediate as a white solid (24 g, 95%).
95%	With 4-dimethylaminopyridine tribromide; acetic acid; at 20℃; for 24h;	A mixture of 4?-chloro-2?-fluoroacetophenone (17.5 g, 100 mmol), 4- (dimethylamino)pyridine tribromide (40.0 g, 110 mmol) and acetic acid (100 mL) was stirred room temperature for 24 h. Water (150 mL) was added and after stirring for 30 mm the precipitated solid was collected by filtration, washed with water, and dried in vacuo to give the desired bromide intermediate as a white solid (24 g, 95%).
95%	With 4-(dimethylamino)pyridine tribromide; acetic acid; at 20℃; for 24h;	A mixture of 4?-chloro-2?-fluoroacetophenone (17.5 g, 100 mmol), 4-(dimethylamino)pyridine tribromide (40.0 g, 110 mmol) and acetic acid (100 mE) was stirred at room temperature for 24 h. Water (150 mE) was added and after stirring for 30 mm the precipitated solid was collected by filtration, washed with water, and dried in vacuo to give the desired bromide intermediate as a white solid (24 g, 95%).

85.8%

With pyridinium hydrobromide perbromide; In tetrahydrofuran; at 25℃; for 2h;Green chemistry;

As shown in Figure 2, Tetrahydrofuran (400 mL) and <strong>[175711-83-8]2-fluoro-4-chloroacetophenone</strong> (74.2 g, 1.0 eq) were added to the reaction flask at room temperature, stirred and dissolved completely, and the temperature was controlled at 25 C. A solution of pyridinium tribromide (137.5 g, 1.0 eq) in tetrahydrofuran was added dropwise. The reaction system was stirred at 25 C for 2 hours. after filtration, the filter cake was rinsed with a small amount of tetrahydrofuran to give a yellow solid, dried.Recrystallization from n-hexane (900 ml) and ethyl acetate (100 ml). 92.8 g of yellow was obtained in a yield of 85.8%.

References: [1]Patent: US2009/48311,2009,A1 .Location in patent: Page/Page column 39.
[2]Patent: WO2016/100766,2016,A1 .Location in patent: Paragraph 0399.
[3]Patent: US2018/228158,2018,A1 .Location in patent: Paragraph 0311; 0319.
[4]Patent: CN109651119,2019,A .Location in patent: Paragraph 0036-0039.

4
[ 1160097-36-8 ]
[ 175711-83-8 ]
[ 1159913-05-9 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 2252 - 2257.

5
[ 175711-83-8 ]
2-chloro-1-(4-chloro-2-fluorophenyl)ethan-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	With sulfuryl dichloride; In methanol; n-heptane; at 0℃; for 3.5h;Inert atmosphere;Product distribution / selectivity;	PREPARATION 2 2-Chloro-<strong>[175711-83-8]1-(4-chloro-2-fluorophenyl)ethanone</strong> In a 1 L round bottom flask combine <strong>[175711-83-8]4'-chloro-2'-fluoroacetophenone</strong> (40 g, 231.8 mmol), heptane (120 mL), and methanol (16 mL). Cool to 0 C. and place under nitrogen. Dissolve sulfuryl chloride (21.5 mL, 1.15 equiv.) in heptane (120 mL) and charge to an addition funnel Add drop-wise to the reaction over 60 min. Stir for 2.5 h at 0 C.; a white precipitate forms during this time. Charge the addition funnel with 1 M sodium bicarbonate (400 mL) then add to the reaction drop-wise. After all gas evolution stops, filter the biphasic suspension to collect the title compound (38.18 g, 80%) as white needles. 1H NMR (DMSO-d6) delta 5.00 (d, 2H, J=2.5 Hz), 7.43 (m, 1H), 7.63 (m, 1H), 7.89 (t, 1H, J=8.4 Hz).
57%	With sulfuryl dichloride; In methanol; dichloromethane; at 0 - 20℃; for 24h;Inert atmosphere;	Intermediate P6: 2-Chloro- 1 -(4-chloro-2-fluorophenyl)ethanone To the mixture of 1 -(4-chloro-2-fluorophenyl)ethanone (4.00 g, 23.2 mmol), dichloromethane (12 mL) and methanol (1 .6 mL) cooled to 0 C under argon atmosphere sulfuryl chloride (2.35 mL, 29.0 mmol) solution in dichloromethane (5 mL) was added during 10 minutes. The reaction mixture was stirred for 24 hours at room temperature. Then, the reaction mixture was cooled to 0 C and 14% aqueous solution of sodium hydroxide (20 mL) was added. The mixture was extracted with dichloromethane (2 chi 20 mL). Organic layers were combined, washed with brine, dried (Na2S04) and evaporated under reduced pressure. Remaining solid was dissolved in boiling ethyl acetate and heptane was added to crystallize crystals. White crystals were filtered and washed with heptane to obtain title product with the yield of 57% (2.74 g, 13.2 mmol). 1 H NMR (500 MHz, CDCl3) delta 7.93 (t, J=8.1 Hz, 1 H), 7.29 (dd, J=9.0 Hz, 1 .2 Hz, 1 H), 7.23 (dd, J=10.8 Hz, 1 .9 Hz, 1 H), 4.70 (d, J=2.9 Hz, 2H ). 13C NMR ( 125 MHz, CDCl3) delta 188. 1 , 162.6, 141 ,5, 132.2 (d, J=3.7 Hz), 125.6 (d, J=3.2 Hz), 121 .1 , 1 17.3 (d, J=27.2 Hz), 49.8 (d, J=1 1 .5 Hz).

References: [1]Organic Process Research and Development,2012,vol. 16,p. 70 - 81.
[2]Patent: US2010/152181,2010,A1 .Location in patent: Page/Page column 2.
[3]Patent: WO2014/20531,2014,A1 .Location in patent: Page/Page column 16.
[4]Journal of Medicinal Chemistry,2014,vol. 57,p. 5702 - 5713.

6
[ 175711-83-8 ]
[ 1229236-81-0 ]

References: [1]Organic Process Research and Development,2012,vol. 16,p. 70 - 81.

7
[ 175711-83-8 ]
[ 1229236-81-0 ]
C₃₂H₁₈Cl₂FN₅O₅ [ No CAS ]

References: [1]Organic Process Research and Development,2012,vol. 16,p. 70 - 81.

8
[ 175711-83-8 ]
C₂₃H₁₃Cl₂FN₄O₃ [ No CAS ]

References: [1]Organic Process Research and Development,2012,vol. 16,p. 70 - 81.
[2]Organic Process Research and Development,2012,vol. 16,p. 70 - 81.

9
[ 175711-83-8 ]
C₁₅H₁₁Cl₂FN₄O*ClH [ No CAS ]

References: [1]Organic Process Research and Development,2012,vol. 16,p. 70 - 81.
[2]Organic Process Research and Development,2012,vol. 16,p. 70 - 81.

10
[ 175711-83-8 ]
C₁₅H₁₃Cl₂FN₄O [ No CAS ]

References: [1]Organic Process Research and Development,2012,vol. 16,p. 70 - 81.
[2]Organic Process Research and Development,2012,vol. 16,p. 70 - 81.

11
[ 175711-83-8 ]
[ 1229236-84-3 ]

References: [1]Organic Process Research and Development,2012,vol. 16,p. 70 - 81.
[2]Organic Process Research and Development,2012,vol. 16,p. 70 - 81.

12
[ 175711-83-8 ]
[ 1229236-88-7 ]

References: [1]Organic Process Research and Development,2012,vol. 16,p. 70 - 81.
[2]Organic Process Research and Development,2012,vol. 16,p. 70 - 81.

13
[ 175711-83-8 ]
[ 1229236-85-4 ]

References: [1]Organic Process Research and Development,2012,vol. 16,p. 70 - 81.

14
[ 175711-83-8 ]
C₃₁H₃₃ClFN₇O₂ [ No CAS ]
C₄₃H₄₇FN₁₀O₃ [ No CAS ]

References: [1]Organic Process Research and Development,2012,vol. 16,p. 70 - 81.

15
[ 175711-83-8 ]
[ 1229236-86-5 ]

References: [1]Organic Process Research and Development,2012,vol. 16,p. 70 - 81.
[2]Organic Process Research and Development,2012,vol. 16,p. 70 - 81.

16
[ 175711-83-8 ]
[ 1229236-83-2 ]
C₁₉H₁₇Cl₂FN₄O₂ [ No CAS ]

References: [1]Organic Process Research and Development,2012,vol. 16,p. 70 - 81.

17
[ 175711-83-8 ]
[ 1346221-91-7 ]
C₃₅H₄₇FN₁₀O [ No CAS ]

References: [1]Organic Process Research and Development,2012,vol. 16,p. 70 - 81.

18
[ 175711-83-8 ]
[ 1229236-80-9 ]

References: [1]Organic Process Research and Development,2012,vol. 16,p. 70 - 81.

19
[ 175711-83-8 ]
[ 2365-48-2 ]
[ 1415968-74-9 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; for 5h;	j00392j To a solution of 1-(4-chloro-2-fluoro-phenyl)ethanone (7.0 g, 4lmmol) and potassium carbonate (11 g, 81 mmol) in dimethyl formamide (50 mL) at 25 C was added methyl thioglycolate (7.3 g, 69 mmol). The mixture was stirred for 5 hours, then diluted with water (50 mL) and extracted with ethyl acetate (3 x 40 mL). The combined organic phases were concentrated in vauo to give compound B-60(8 g, crude) as a yellow solid.

References: [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 15 - 30.
[2]Patent: WO2017/69980,2017,A1 .Location in patent: Paragraph 00391; 00392.

20
[ 175711-83-8 ]
[ 1415968-56-7 ]

References: [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 15 - 30.

21
[ 175711-83-8 ]
[ 1415968-57-8 ]

References: [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 15 - 30.

22
[ 175711-83-8 ]
[ 66490-32-2 ]

References: [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 15 - 30.
[2]Patent: WO2016/145153,2016,A1 .
[3]Patent: WO2017/69980,2017,A1 .

23
[ 175711-83-8 ]
[ 856562-68-0 ]