1190865-44-1|1-(3,5-Dichloro-4-fluorophenyl)-2,2,2-trifluoroethanone| Ambeed

Structure of 1190865-44-1

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Quality Control of [ 1190865-44-1 ] Purity: 95% SDS Specification

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Product Details of [ 1190865-44-1 ]

CAS No. :	1190865-44-1
Formula :	C₈H₂Cl₂F₄O
M.W :	261.00
SMILES Code :	O=C(C1=CC(Cl)=C(F)C(Cl)=C1)C(F)(F)F
MDL No. :	MFCD23382507
InChI Key :	NSWPERXXSPCRCT-UHFFFAOYSA-N
Pubchem ID :	75530023

Safety of [ 1190865-44-1 ]

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

Computational Chemistry of [ 1190865-44-1 ] Show Less

Physicochemical Properties

Num. heavy atoms	15
Num. arom. heavy atoms	6
Fraction Csp3	0.12
Num. rotatable bonds	2
Num. H-bond acceptors	5.0
Num. H-bond donors	0.0
Molar Refractivity	46.81
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.	1.95
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	4.08
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	5.56
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.	3.78
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	4.49
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	3.97

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-4.19
Solubility	0.0168 mg/ml ; 0.0000642 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Moderately soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-4.14
Solubility	0.0188 mg/ml ; 0.0000719 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Moderately 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	-4.75
Solubility	0.00467 mg/ml ; 0.0000179 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.	-5.0 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.	0.55

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	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)	1.57

Application In Synthesis of [ 1190865-44-1 ]

* 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 [ 1190865-44-1 ]

[ 1190865-44-1 ] Synthesis Path-Downstream 1~35

1
[ 1190865-44-1 ]
[ 1414377-89-1 ]
[ 1414377-96-0 ]

Yield	Reaction Conditions	Operation in experiment
89.3%		I) Synthesis of3-[3-(3,5-Dichloro-4-fluoro-phenyl)-4,4,4-trifluoro-3-hydroxy-butyryl]-5,6- dihydro-4H-cyclopenta[c]thiophene-l-carboxylic acid methyl esterAdd a solution of LiHDMS (1M in THF, 75 mL, 75 mmol) to a suspension of 3-acetyl-5,6-dihydro-4H-cyclopenta[c]thiophene-l-carboxylic acid methyl ester (14.0 g, 62.5 mmol) in dry THF (200 mL) at -78C under N2. After stirring at room temperature for 1.5 h, add l-(3,5-dichloro-4-fluoro-phenyl)-2,2,2-trifluoro-ethanone (17.9 g, 68.7 mmol) in dry THF (100 mL) to the reaction mixture and stir the resultant mixture at the same temperature for additional 2 hours. Quench the reaction with saturated NH4C1 aqueous solution. Extract the aqueous mixture with EtOAc (100 mL><3). The combined organic layers are washed with brine, dried over anhydrous a2S04 and concentrated under vacuum. Purify the residue by silica gel chromatograph (PE:EtOAc 15: 1) to afford 3-[3-(3,5-Dichloro-4-fluoro-phenyl)-4,4,4-trifluoro-3-hydroxy-butyryl]-5,6-dihydro-4H-cyclopenta [c]thiophene-l-carboxylic acid methyl ester as an orange solid (27 g, 89.3%). MS (m/z): 486 (M+l).
89.3%		I) Synthesis of3-[3-(3,5-Dichloro-4-fluoro-phenyl)-4,4,4-trifluoro-3-hydroxy-butyryl]-5,6- dihydro-4H-cyclopenta[c]thiophene-l-carboxylic acid methyl esterAdd a solution of LiHDMS (1M in THF, 75 mL, 75 mmol) to a suspension of 3-acetyl-5,6-dihydro-4H-cyclopenta[c]thiophene-l-carboxylic acid methyl ester (14.0 g, 62.5 mmol) in dry THF (200 mL) at -78C under N2. After stirring at room temperature for 1.5 h, add l-(3,5-dichloro-4-fluoro-phenyl)-2,2,2-trifluoro-ethanone (17.9 g, 68.7 mmol) in dry THF (100 mL) to the reaction mixture and stir the resultant mixture at the same temperature for additional 2 hours. Quench the reaction with saturated NH4C1 aqueous solution. Extract the aqueous mixture with EtOAc (100 mL><3). The combined organic layers are washed with brine, dried over anhydrous a2S04 and concentrated under vacuum. Purify the residue by silica gel chromatograph (PE:EtOAc 15: 1) to afford 3-[3-(3,5-Dichloro-4-fluoro-phenyl)-4,4,4-trifluoro-3-hydroxy-butyryl]-5,6-dihydro-4H-cyclopenta [c]thiophene-l-carboxylic acid methyl ester as an orange solid (27 g, 89.3%). MS (m/z): 486 (M+l).

References: [1]Patent: WO2012/155676,2012,A1 .Location in patent: Page/Page column 74.
[2]Patent: WO2012/158396,2012,A1 .Location in patent: Page/Page column 74.

2
[ 1190865-44-1 ]
[ 1357614-53-9 ]
3-{4-[5-(3,5-dichloro-4-fluoro-phenyl)-5-trifluoromethyl-[1,4,2]dioxazol-3-yl]-phenyl}-3-fluoro-azetidine-1-carboxylic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
39.32%		Step 3: Preparation of 3-{4-[5-(3,5-dichloro-4-fluoro-phenyl)-5-trifluoromethyl- [1 ,4,2]dioxazol-3-yl]-phenyl}-3-fluoro-azetidine-1 -carboxylic acid tert-butyl ester To a stirred solution of 3-fluoro-3-[4-(hydroxyimino-methyl)-ph azetidine-1 -carboxylic acid tert-butyl ester (0.5 g, 1 .7 mmol, 1 eq) in DMF (6.5 mL) was added N-chloro succinimide (0.227 g, 1 .7 mmol, 1 eq). Reaction mixture was stirred at 55C for 1 hour . After 1 hour (chloro intermediate formation), 1 -(3,5-dichloro-4-fluoro-phenyl)-2, 2,2-trifluoro-ethanone (0.45 g, 1 .73 mmol, 1 .02 eq) was added followed by addition of sodium bicarbonate (0.146 g, 1 .74 mmol, 1.02 eq) at room temperature. Resulting reaction mixture was stirred at 55C for 3 hours under nitrogen atmosphere. After complete consumption of starting material, reaction mixture was quenched by water (10 mL) and extracted with ethyl acetate (3x50 mL). Combined organic phase was washed with brine solution (20 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure to get brown thick oil (0.6 g, Crude). Crude was purified by Combiflash using 40 g Redisep column. Desired compound was eluted in 25% ethyl acetate in hexane to afford title compound as colorless thick oil (0.37 g, 39.32%). H NMR (400 MHz, CDCI3)8: 1 ,47 (s, 9H), 4.16-4.24 (m, 2H), 4.38-4.47 (m, 2H), 7.59 (d, J= 8.44 Hz, 2H), 7.66 (d, J= 5.88 Hz, 2H), 7.89 (d, J= 8.2 Hz, 2H), LC- MS (m/z): No ionization.

References: [1]Patent: WO2013/169622,2013,A1 .Location in patent: Page/Page column 71.

3
[ 1190865-44-1 ]
[ 1575811-23-2 ]
[ 1575811-25-4 ]

Yield	Reaction Conditions	Operation in experiment
		Preparation 44: tert-butyl 5'-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)- 1 ,4,2-dioxazol-3-yl)-3' -spiro[azetidine-3, 1 '-isobenzofuran]-1 -carboxylate To a stirred solution of tert-butyl 5'-((hydroxyimino)methyl)-3'H- spiro[azetidine-3,1 '-isobenzofuran]-1 -carboxylate (Preparation 43) (0.5 g, 1 .645 mmol, 1 eq) in DMF (6.5 mL) was added NCS (0.218g, 1 .645mmol, 1 eq). Reaction mixture was stirred at 55C for 1 hour under nitrogen atmosphere. After 1 hour (chloro intermediate formation), 1 -(3,5-dichloro-4-fluoro-phenyl)- 2,2,2-trifluoro-ethanone (0.437g, 1 .678mmol, 1 .02 eq) was added followed by addition of sodium bicarbonate (0.140g, 1 .678mmol, 1 .02 eq) at room temperature. Resulting reaction mixture was stirred at 55C for 3 hours under nitrogen atmosphere. After complete consumption of starting material, reaction mixture was quenched by water (10 mL) and extracted with ethyl acetate (3x50 mL). Combined organic phase was washed with brine solution (20 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure to get brown thick oil (0.6g, crude). Crude compound was purified by Combiflash using 40g Redisep column. Desired compound was eluted in 25% ethyl acetate in hexane to afford title compound as colorless thick oil (0.33g, impure). 1H NMR (400 MHz, CDCI3)5: 1 .46 (s, 9H), 4.1 1 (d, J= 10.04 Hz, 2H), 4.32 (d, J= 9.92 Hz, 2H), 5.15 (s, 2H), 7.56-7.58 (m, 1 H), 7.64-7.68 (m, 3H), 7.86 (d, J= 8.04 Hz, 1 H), 8.02-8.04 (dd, i= 6.12 Hz, J2= 0.64 Hz, 1 H). LC-MS (m/z): No ionization.

References: [1]Patent: WO2014/39489,2014,A1 .Location in patent: Page/Page column 101; 102.

4
[ 1190865-44-1 ]
[ 1398609-81-8 ]
[ 1398610-04-2 ]

Yield	Reaction Conditions	Operation in experiment
80.64%	With caesium carbonate; In toluene; at 110℃; for 16h;	Preparation 6: tert-butyl 5'-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-2- enoyl)-3'H-spiro[azetidi -3,1 '-isobenzofuran]-1 -carboxylate In 100 mL two neck RBF equipped with dean-stark apparatus a stirred solution of tert-butyl 5'-acetyl-3'H-spiro[azetidine-3,1 '-isobenzofuran]-1- carboxylate (Preparation 1 , 4.5g, 14.851 mmol) in toluene (13.5ml_) and trifluorotoluene (13.5ml_) was added 2,2,2-trifluoro-1 -(3,4,5-trichlorophenyl)- ethanone (4.44g, 17.079mmol) and Cs2C03 (0.483g, 1.485mmol) at room temperature. Resulting reaction mixture was heated at 1 10C for 16 hours. After complete consumption of starting material, reaction mixture was diluted with ter-butylmethyl ether (30ml_) and filtered through celite bed. Filtrate was concentrated under vacuum to afford brown sticky oil (9.01 g, crude). Crude compound was purified by column chromatography using silica gel (230-400 mesh). Desired compound was eluted in 20% ethyl acetate in n-hexane to give light yellow solid (6.54g, 80.64%). 1 H NMR (400 MHz, CDCI3)8: 1 .47 (s, 9H), 4.10 (d, J = 9.52 Hz, 2H), 4.32 (d, J = 9.36 Hz, 2H), 5.12 (s, 2 H), 7.20 (d, J = 9.76 Hz, 2H), 7.39 (s, 1 H), 7.56 (d, J = 7.96 Hz, 1 H), 7.67 (s, 1 H), 7.84 (d, J = 7.96 Hz, 1 H). LC-MS (m/z): 374.1 (M+H).
8 g	With caesium carbonate; In toluene; at 110℃; for 6h;Dean-Stark; Inert atmosphere;	Intermediate 4: te/f-butyl 5'-[3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-2- enoyl]-3'H-spiro[azetidine-3 1 '-isobenzofuran]-1-carboxylate The starting materials, te/f-butyl 5'-acetyl-3'H-spiro[azetidine-3, 1'-isobenzofuran]-1- carboxylate (5.5 g, 18.1 mmol), 1-(4-chloro-3,5-difluorophenyl)-2,2,2- trifluoroethanone (5.44 g, 1.15 eq), were dissolved in a solvent mixture of toluene and a,a,a-trifluorotoluene (40 ml_, 1 :1 , vol/vol) in a 100 ml_ three necked round bottom flask equipped with a Dean-Stark head and a condenser on top on one neck and a nitrogen inlet on another. The reaction mixture was heated to 1 10C and cesium carbonate (0.5 g) was added. The reaction mixture was heated for 1 h and then another 0.1 g of cesium carbonate was added and heating was continued for another 1 h under a very slow stream of nitrogen. TLC analysis showed still starting material left and another 0.1 g cesium carbonate was added and heating continued for another 1 h. This process was repeated three more times (total amount of cesium carbonate = 1.0 g, total reaction time = 6 h). The reaction mixture was cooled to room temperature, filtered through a short path of silica gel, rinsed with MTBE, and concentrated. The crude product was purified using flash silica gel column chromatography (330 g RediSep column, eluting with 0 to 20% ethyl acetate in heptanes) to yield 8 g of te/f-butyl 5'-[3-(3,5-dichloro-4-fluorophenyl)-4,4,4- trifluorobut-2-enoyl]-3'H-spiro[azetidine-3, 1'-isobenzofuran]-1-carboxylate. H-NMR (400 MHz, CDCIs) delta ppm 7.86 (d, 1 H, J = 8.0 Hz), 7.69 (s, 1 H), 7.58 (d, 1 H, J = 8.0 Hz), 7.42 (d, 1 H, J = 1.4 Hz), 7.25 (d, 2H, J = 6.1 Hz), 5.14 (s, 2H), 4.34 (d, 2H, J = 9.5 Hz), 4.13 (d, 2H, J = 9.5 Hz), 1.49 (s, 9H).

References: [1]Patent: WO2014/39489,2014,A1 .Location in patent: Page/Page column 57; 58.
[2]Patent: WO2016/115315,2016,A1 .Location in patent: Paragraph 31; 32.

5
[ 1190865-44-1 ]
methyl 5-acetyl-3-(trifluoromethyl)thiophene-2-carboxylate [ No CAS ]
methyl 5-[3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluoro-but-2-enoyl]-3-(trifluoromethyl)thiophene-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
38%	With potassium carbonate; triethylamine; In 1,2-dichloro-ethane; at 100℃;	Step 3: Methyl 5-[3-(3,5-d ichloro-4-fluoro-phenyl)-4 ,4 ,4-trifluoro-but-2-enoyl]-3-(trifl uoromethyl)-thiophene-2-carboxylateA solution of the product of step 2 (3.3 g) in a 1 ,2-dichloroethane (?DOE?, 100 mL) was treated with 1 -(3,5-d ichloro-4-fluoro-phenyl)-2,2,2-trifluoro-ethanone (5.2 g, CAS 1190865-44-1), K2003 (1 .8 g), triethylamine (0.9 mL). The reaction was stirred over-night at 10000. Then, the mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried (Na2504), filtered and concentrated to give a residue which was purified by flash chromatography on silica gel (ethyl acetate/petroleum ether) to afford the title product (2.4 g, 38%).1H NMR (400 MHz, 0D013): 8.19 (s, 1H), 7.78-7.72 (m, 1H), 7.47 (m, 2H), 3.95 (s,3H).

References: [1]Patent: WO2014/206909,2014,A1 .Location in patent: Page/Page column 211.

6
[ 1190865-44-1 ]
tert-butyl 4-acetyl-2-chloro-benzoate [ No CAS ]
tert-butyl 2-chloro-4-[3-(3,5-dichloro-4-fluoro-phenyl)-4,4,4-trifluoro-3-hydroxy-butanoyl]benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
63%	With triethylamine; In n-heptane; at 70℃;	A solution of the product of step 1 (30 g) and the product of step 2 (23.4 g) in a mixture of triethylamine (10 ml.) and heptane (300 ml.) was stirred at 70 C overnight. Then, the mixture was concentrated. The residue was purified by flash chromatography on silica gel to afford the product (37.5 g, 63%). H NMR (400 MHz, CDCI3): delta 7.9 (s, 1 H), 7.8 (m, 2H), 7.5 (m, 2H), 5.5 (s, 1 H), 3.7 (d, 1 H), 3.6 (d, 1 H), 1.6 (s, 9H).

References: [1]Patent: WO2014/206911,2014,A1 .Location in patent: Page/Page column 146.

7
1,3-dichloro-2-fluoro-5-iodo-benzene [ No CAS ]
[ 104863-67-4 ]
[ 1190865-44-1 ]

Yield	Reaction Conditions	Operation in experiment
53%	With n-butyllithium; In tetrahydrofuran; hexane; at -78℃; for 0.333333h;	To a solution of 1 ,3-dichloro-2-fluoro-5-iodo-benzene (CAS 133307-08-1 , 50 g) and 2,2,2-trifluoro-/S/-methoxy-/S/-methyl-acetamide (40.5 g) in THF (800 ml.) at -78C was added n-BuLi (82.5 ml_, 2.5 M in hexanes). The reaction was stirred for 20 min, then quenched by saturated aqueous NH4CI solution and extracted with ethyl acetate. The organic layer was dried (Na2S04), filtered, and concentrated. The residue was purified by flash chromatography on silica gel to afford the product (24 g, 53%). H NMR (400 MHz, CDC ): delta 8.0 (m, 2H).

References: [1]Patent: WO2014/206911,2014,A1 .Location in patent: Page/Page column 145; 146.

8
[ 1190865-44-1 ]
tert-butyl 2-chloro-4-[3-(3,5-dichloro-4-fluoro-phenyl)-4,4,4-trifluoro-but-2-enoyl]benzoate [ No CAS ]

References: [1]Patent: WO2014/206911,2014,A1 .

9
[ 1190865-44-1 ]
tert-butyl 2-chloro-4-[3-(3,5-dichloro-4-fluoro-phenyl)-4,4,4-trifluoro-3-sulfanyl-butanoyl]benzoate [ No CAS ]

References: [1]Patent: WO2014/206911,2014,A1 .

10
[ 1190865-44-1 ]
tert-butyl 2-chloro-4-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]benzoate [ No CAS ]

References: [1]Patent: WO2014/206911,2014,A1 .

11
[ 1190865-44-1 ]
2-chloro-4-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]benzoic acid [ No CAS ]

References: [1]Patent: WO2014/206911,2014,A1 .

12
[ 1190865-44-1 ]
[2-chloro-4-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]phenyl]-(4,4-difluoro-1-piperidyl)methanone [ No CAS ]

References: [1]Patent: WO2014/206911,2014,A1 .

13
[ 1190865-44-1 ]
methyl 7-acetylindane-4-carboxylate [ No CAS ]
methyl 7-[(3-(3,5-dichloro-4-fluoro-phenyl)-4,4,4-trifluoro-but-2-enoyl)]indane-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
74%	With potassium carbonate; triethylamine; In 1,2-dichloro-ethane;Reflux;	Step 2: Methyl 7-[(3-(3,5-d ichloro-4-fluoro-phenyl)-4 ,4 ,4-trifluoro-but-2-enoyl]indane-4- carboxylateTo a solution of the product of step 1(12 g) and <strong>[1190865-44-1]1-(3,5-dichloro-4-fluoro-phenyl)-2,2,2-trifluoro-ethanone</strong> (28.7 g, CAS 1190865-44-1) in DCE (100 mL) was added K2C03(7.6 g) and triethylamine (7.6 mL). The reaction was stirred at reflux overnight. Then, the mixture was cooled to r.t., filtered and concentrated to give a residue, which was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate) to afford the product (18.75 g, 74%).1H NMR (400 MHz, CDCI3): 7.8 (m, 1H), 7.5 (m, 1H), 7.3 (m, 1H), 7.2 (m, 2H), 3.9 (s,3H), 3.2 (m, 2H), 3.1 (m, 2H), 2.0 (m, 2H).
74%	With potassium carbonate; triethylamine; In 1,2-dichloro-ethane;Reflux;	To a solution of the product of step 1(12 g) and <strong>[1190865-44-1]1-(3,5-dichloro-4-fluoro-phenyl)-2,2,2-trifluoro-ethanone</strong> (28.7 g, CAS 1190865-44-1) in DCE (100 mL) was added K2C03(7.6 g) and triethylamine (7.6 mL). The reaction was stirred at reflux overnight. Then,the mixture was cooled to r.t., filtered and concentrated to give a residue, which waspurified by flash chromatography on silica gel (petroleum ether/ethyl acetate) to affordthe product (18.75 g, 74%).1H NMR (400 MHz, CDCI3): 7.8 (m, 1H), 7.5 (m, 1H), 7.3 (m, 1H), 7.2 (m, 2H), 3.9 (s,3H), 3.2 (m, 2H), 3.1 (m, 2H), 2.0 (m, 2H).
63%	With potassium carbonate; triethylamine; In 1,2-dichloro-ethane;Reflux;	To a solution of the product of step 1 (10 g) and 1 -(3,5-dichloro-4-fluoro-phenyl)-2,2,2- trifluoro-ethanone (33 g, CAS 1190865-44-1) in 1,2-dichloroethane (?DOE?, 500 mL) was added K2003 (6.7 g) and triethylamine (5 g). The reaction was stirred at reflux overnight. Then, to the mixture was added water and 0H2012. The organic layer wasseparated, dried (Na2SO4), filtered and concentrated to give a residue, which was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate) to afford the product (14 g, 63%).1H NMR (400 MHz, 0D013): 7.8 (m, 1H), 7.5 (m, 1H), 7.3 (m, 1H), 7.2 (m, 2H), 3.9 (s,3H), 3.2 (m, 2H), 3.1 (m, 2H), 2.0 (m, 2H).

References: [1]Patent: WO2015/128358,2015,A1 .Location in patent: Page/Page column 145; 146.
[2]Patent: WO2016/102488,2016,A1 .Location in patent: Page/Page column 90.
[3]Patent: WO2014/206910,2014,A1 .Location in patent: Page/Page column 196; 197.

14
[ 1190865-44-1 ]
methyl 8-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]tetralin-5-carboxylate [ No CAS ]

References: [1]Patent: WO2014/206910,2014,A1 .

15
[ 1190865-44-1 ]
8-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]tetralin-5-carboxylic acid [ No CAS ]

References: [1]Patent: WO2014/206910,2014,A1 .

16
[ 1190865-44-1 ]
8-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]-N-(pyrimidin-2-ylmethyl)tetralin-5-carboxamide [ No CAS ]

References: [1]Patent: WO2014/206910,2014,A1 .

17
[ 1190865-44-1 ]
methyl 8-[3-(3,5-dichloro-4-fluoro-phenyl)-4,4,4-trifluoro-3-sulfanyl-butanoyl]tetralin-5-carboxylate [ No CAS ]

References: [1]Patent: WO2014/206910,2014,A1 .

18
[ 1190865-44-1 ]
methyl 8-acetyltetralin-5-carboxylate [ No CAS ]
methyl 8-[3-(3,5-dichloro-4-fluoro-phenyl)-4,4,4-trifluoro-but-2-enoyl]tetralin-5-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%	With potassium carbonate; triethylamine; In 1,2-dichloro-ethane; at 100℃;	Step 6: Methyl 8-[3-(3,5-d ichloro-4-fluoro-phenyl)-4 ,4 ,4-trifluoro-but-2-enoyl]tetralin-5- carboxylateTo a solution of the product of step 5 (20 g) and 1-(3,5-dichloro-4-fluoro-phenyl)-2,2,2- trifluoro-ethanone (20 g, CAS 1190865-44-1) in 1,2-dichloroethane (?DOE?, 500 mL) was added K2003 (9 g) and Et3N (2 g). The reaction was stirred at 100C overnight. Then, to the mixture was added water and CH2CI2. The organic layer was separated, dried (Na2504), filtered and concentrated to give a residue, which was purified by flashchromatography on silica gel (petroleum ether/ethyl acetate) to afford the product (20 g, 65%). 1H NMR (400 MHz, CDCI3): 7.57 (m, 1 H), 7.29-7.25 (m, 1 H), 7.20 (s, 1 H), 7.11 (m,2H), 3.92 (s, 3H), 2.99 (m, 2H), 2.83-2.77 (m, 2H), 1.78-1.70 (m, 4H).

References: [1]Patent: WO2014/206910,2014,A1 .Location in patent: Page/Page column 201; 202.

19
[ 1190865-44-1 ]
C₁₉H₁₄Cl₂F₄N₂S*ClH [ No CAS ]