886762-08-9|5-Bromo-2-(trifluoromethoxy)aniline| Ambeed

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Quality Control of [ 886762-08-9 ] Purity: 98% SDS Specification

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Product Details of [ 886762-08-9 ]

CAS No. :	886762-08-9
Formula :	C₇H₅BrF₃NO
M.W :	256.02
SMILES Code :	NC1=CC(Br)=CC=C1OC(F)(F)F
MDL No. :	MFCD04039242
InChI Key :	FOJWHUFRHXEUBA-UHFFFAOYSA-N
Pubchem ID :	2779367

Safety of [ 886762-08-9 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H312-H332-H315-H319-H335
Precautionary Statements:	P261-P280-P305+P351+P338-P304+P340-P405-P501

Computational Chemistry of [ 886762-08-9 ] 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	4.0
Num. H-bond donors	1.0
Molar Refractivity	45.23
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	35.25 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.04
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	3.13
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.	2.37
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	2.38
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	2.82

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-3.61
Solubility	0.063 mg/ml ; 0.000246 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.	-3.54
Solubility	0.0739 mg/ml ; 0.000289 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	-3.52
Solubility	0.077 mg/ml ; 0.000301 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.	-5.64 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	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<0.0
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)	1.81

Application In Synthesis of [ 886762-08-9 ]

* 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 [ 886762-08-9 ]

[ 886762-08-9 ] Synthesis Path-Downstream 1~35

1
[ 886762-08-9 ]
[ 1048963-39-8 ]

Yield	Reaction Conditions	Operation in experiment
50%	With hydrogenchloride; sulfuric acid; sodium nitrite; In ethanol; water; at 0 - 100℃; for 13.5h;	Into a 250-mL 3-necked round-bottom flask, was placed 5-bromo-2- (trifluoromethoxy) aniline (2 g, 7.81 mmol, 1 equiv), ethanol (20 mL), HCl (2 mL). This was followed by the addition of NaN02 (595 mg, 8.62 mmol, 1.10 equiv) dropwise with stirring at 0 C. To this was added water (110 mL), sulfuric acid (5.5 mL). The resulting solution was stirred for 1.5 h at 0 C in a water/ice bath. The resulting solution was allowed to react, with stirring, for an additional 12 h while the temperature was maintained at 100 C in an oil bath. The resulting solution was extracted with 3x100 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3x50 mL of sodium bicarbonate. The mixture was dried over anhydrous sodium sulfate. This resulted in 1 g (50%) of the title compound as an oil. Analytical Data: LC-MS: (ES, m/z): RT =1.715min, LCMS 53: m/z = 257 [M+l].
	With hydrogenchloride; conc. sulphuric acid; sodium nitrite; In ethanol; water;	b) 5-Bromo-2-trifluoromethoxyphenol A solution of 210 mmol of sodium nitrite in 120 ml of water is added dropwise to a suspension of 200 mmol of <strong>[886762-08-9]5-bromo-2-trifluoromethoxyaniline</strong> in 500 ml of ethanol and 50 ml of conc. HCl at 0C. The reaction mixture is stirred at 5C for 1.5 hours. The reaction mixture is slowly added dropwise to a solution of 135 ml of conc. sulphuric acid in 2.8 l of water and stirred under reflux overnight. The reaction mixture is extracted with diethyl ether (3x) - the combined organic phases are washed with water and 1 M sodium bicarbonate solution and then extracted with 2N NaOH (2x). The combined aqueous phases are acidified with conc. HCl and extracted with diethyl ether (3x). The combined organic phases are washed with water, dried with sodium sulphate and evaporated. The crude title compound is obtained from the residue.
		A solution of 210 mmol of sodium nitrite in 120 ml of water is added dropwise to a suspension of 200 mmol of <strong>[886762-08-9]5-bromo-2-trifluoromethoxyaniline</strong> in 500 ml of ethanol and 50 ml of cone. HCI at 00C. The reaction mixture is stirred at 5C for 1.5 hours. The reaction mixture is slowly added dropwise to a solution of 135 ml of cone, sulphuric acid in 2.8 I of water and stirred under reflux overnight. The reaction mixture is extracted with diethyl ether (3x) - the combined organic phases are washed with water and 1 M sodium bicarbonate solution and then extracted with 2N NaOH (2x). The combined aqueous phases are acidified with cone. HCI and extracted with diethyl ether (3x). The combined organic phases are washed with water, dried with sodium sulphate and evaporated. The crude title compound is obtained from the residue.

References: [1]Patent: WO2017/181177,2017,A1 .Location in patent: Paragraph 0875-0878.
[2]Patent: EP1958666,2008,A1 .
[3]Patent: WO2006/95020,2006,A1 .Location in patent: Page/Page column 53.

2
[ 886762-08-9 ]
[ 108-24-7 ]
[ 392726-69-1 ]

Yield	Reaction Conditions	Operation in experiment
95%	In ethanol; at 0 - 20℃;	Example 29; 5-(4-Methyl-piperazin-l-yl)-2-trifluoromethoxy-phenylamine trihydrochloride salt; Step 1. N-(5-bromo-2-trifluoromethoxy-phenyl)-acetamide; To a solution of <strong>[886762-08-9]5-bromo-2-trifluoromethoxy-phenylamine</strong> (5.12 g, 20 mmol) inEtOH (50 mL) at 00C was added a solution of acetic anhydride (4.7 mL, 50 mmol) in EtOH (10 mL). The mixture was stirred at room temperature overnight. The solvent was evaporated to drieness and the solid was tritured with diethyl ether and filtered to give 5.64 g (95% yield) of N-(5-bromo-2-trifluoromethoxy-phenyl)-acetamide .1H NMR (400 MHz, DMSO-J6) delta ppm: 2.11 (s, 3 H) 7.39 (m, 2 H) 8.21 (s, 1 H) 9.87(s, 1 H).
95%	In ethanol; at 0 - 20℃;	Example 6; 2-trifluoromethoxy-5-(4-methyl-piperazin-l-yl)-phenylamine trihydrochloride salt and l-(3-iodo-4-trifluoromethoxy-phenyl)-4-methyl-piperazine; Step 1: N-(5-bromo-2-trifluoromethoxy-phenyl)-acetamide; To a solution of <strong>[886762-08-9]2-trifluoromethoxy-5-bromo-phenylamine</strong> (5.12 g, 20 mmol) in EtOH (50 mL) at 00C was added a solution of acetic anhydride (4.7 mL, 50 mmol) in EtOH (10 mL). The mixture was stirred at room temperature overnight. The solvent was evaporated to drieness and the solid was tritured with diethyl ether and filtered to give 5.64 g (95% yield) of N-(5-bromo-2-trifluoromethoxy-phenyl)-acetamide . <n="54"/>1H NMR (400 MHz, DMSO-d6) delta ppm: 2.11 (s, 3 H) 7.39 (m, 2 H) 8.21 (s, 1 H) 9.87 (s,1 H); MS (ESI): 257 [M+H]+.
95%	In ethanol; at 0 - 20℃;	To a solution of <strong>[886762-08-9]2-trifluoromethoxy-5-bromo-phenylamine</strong> (5.12 g, 20 mmol) in EtOH (50 niL) at 00C was added a solution of acetic anhydride (4.7 rnL, 50 mmol) in EtOH (10 mL). The mixture was stirred at room temperature overnight. The solvent was evaporated to drieness and the solid was tritured with diethyl ether and filtered to give 5.64 g (95% yield) of N-(5-bromo-2-trifluoromethoxy-phenyl)-acetamide . 1H NMR (400 MHz, DMSO-d6) delta ppm: 2.11 (s, 3 H) 7.39 (m, 2 H) 8.21 (s, 1 H) 9.87 (s, 1 H); MS (ESI): 257 [M+H]+.

References: [1]Patent: WO2008/74788,2008,A1 .Location in patent: Page/Page column 87.
[2]Patent: WO2009/40399,2009,A1 .Location in patent: Page/Page column 52-53.
[3]Patent: WO2009/71480,2009,A2 .Location in patent: Page/Page column 21-22.

3
[ 109-01-3 ]
[ 886762-08-9 ]
[ 1034618-02-4 ]

Yield	Reaction Conditions	Operation in experiment
64%	With lithium hexamethyldisilazane;tris-(dibenzylideneacetone)dipalladium(0); DavePhos; In tetrahydrofuran; for 1h;Heating / reflux;	Example 35; N-[5-(4-Methyl-piperazin-l-yl)-2-trifluoromethoxy-phenyl]-guanidine; Step 1. 5-(4-Methyl-piperazin-l-yl)-2-trifluoromethoxy-phenylamine; Tris(dibenzilideneacetone)dipalladium, Pd2(dba)3 (1.1 g, 1.2 mmol), 2- dicyclohexylphosphino-2'-(N,N-dimethylamino)-biphenyl (0.94 g, 2.4 mmol), 5- bromo-2-trifluoromethoxy-phenylamine (30.7 g, 120 mmol) in THF (50 mL) were charged in a round-bottom flask flushed with argon. The flask was evacuated and backfilled with argon. LiN(TMS)2 solution (IM in THF, 288 mL) and N- methylpiperazine (26.7 mL, 194 mmol) were added and the reaction refluxed for 1 h. The reaction mixture was then allowed to cool to room temperature and filtered through a pad of celite. The organic phase was concentrated, the residue dissolved inDCM (200 ml) and washed with water (1 x 100 ml). The organic phases were dried over anhydrous Na2SO4, the solvent evaporated in vacuo and the crude solid was purified by flash chromatography on silica gel (eluant: DCM/EtOH 90/10) to afford 21.1 g of 5-(4-methyl-piperazin- 1 -yl)-2-trifluoromethoxy-phenylamine (64% yield) as a light brown powder.1H NMR (400 MHz, DMSO-J6) delta ppm 2.23 (s, 3 H) 2.42 - 2.47 (m, 4 H) 3.02 - 3.08 (m, 4 H) 5.10 (s, 2 H) 6.16 (dd, J=8.90, 2.93 Hz, 1 H) 6.33 (d, J=2.93 Hz, 1 H) 6.90 (dd, J=8.90, 1.46 Hz, I H).

References: [1]Patent: WO2008/74788,2008,A1 .Location in patent: Page/Page column 93.
[2]Bulletin of the Korean Chemical Society,2014,vol. 35,p. 1929 - 1930.

4
[ 886762-08-9 ]
[ 420-04-2 ]
[ 1034617-98-5 ]

Yield	Reaction Conditions	Operation in experiment
89%	With hydrogenchloride; In ethanol; water; for 72h;Heating / reflux;	Example 34; N-(5-Bromo-2-trifluoromethoxy-phenyl)-guanidine; <n="94"/>To a suspension of <strong>[886762-08-9]5-bromo-2-trifluoromethoxy-phenylamine</strong> (5.0 g, 19.5 mmol) in EtOH (15 mL), cyanamide (1.64 g, 39 mmol) dissolved in 5 mL of EtOH and 1 mL H2O, and HCl 37% (3.25 mL) diluted in 10 mL EtOH were added drop wise into the mixture under stirring. The mixture was refluxed for 72 h. The mixture was cooled down to room temperature, concentrated then diluted with water; NaOH IN was added to basic pH and extracted several times with ethyl acetate, dried over sodium sulfate and concentrated to afford 5.2 g of the title compound (89% yield). 1H NMR (400 MHz, DMSO-J6) delta ppm 5.40 (s, 4 H) 6.98 (dd, J=8.72, 2.38 Hz, 1 H) 7.05 (d, J=I.83 Hz, 1 H) 7.11 (m, 1 H).

References: [1]Patent: WO2008/74788,2008,A1 .Location in patent: Page/Page column 92-93.

5
[ 454482-11-2 ]
[ 886762-08-9 ]
[ 1034618-10-4 ]

Yield	Reaction Conditions	Operation in experiment
65%	With caesium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In N,N-dimethyl-formamide; at 80℃; for 3h;	Example 43; 5-(l-Methyl-piperidin-4-yl)-2-trifluoromethoxy-phenylamine; Step 1. 5-(l-Methyl-l,2,3,6-tetrahydro-pyridin-4-yl)-2-trifluoromethoxy- phenylamine; 5-Bromo-2-trifluoromethoxy-phenylamine (0.43 g, 1.68 mmol), cesium carbonate (1.65 g, 5.06 mmol), 1 , r-bis(diphenylphosphino)ferrocenepalladium(ii) dichloride, complex with dichloromethane (1 :1) (0.08g, 0.1 mmol) in dry DMF (20 mL) were charged in a round-bottom flask flushed with argon. The flask was evacuated and backfilled with argon. A solution of l-methyl-4-(4,4,5,5-tetramethyl- [l,3,2]dioxaborolan-2-yl)-l,2,3,6-tetrahydro-pyridine (0.45 g, 2.01 mmol) in dry DMF (10 mL) were added to the suspension and the reaction mixture warmed at 80 0C for 3 hours. The reaction mixture was then allowed to cool to room temperature, diluted with water (100 mL) and extracted with DCM (2 x 50 mL) and the combined <n="102"/>organic phases were extracted with IN HCl solution (50 rnL). The aqueous layer was basifed by addition of sodium bicarbonate and extracted with EtOAc (2 x 50 mL). The combined organic phases were dried over anhydrous Na2SO4, the solvent removed under reduced pressure and the crude solid purified by flash chromatography on silica gel (eluant: DCM/MeOH 90/10) to afford the intermediate as a light brown solid (0.3 g, 65 percent yield)1H NMR (400 MHz, DMSO-J6) delta ppm 2.29 (s, 3 H) 2.38 - 2.44 (m, 2 H) 2.58 (t, J=5.55 Hz, 2 H) 3.02 (d, J=2.32 Hz, 2 H) 5.29 (s, 2 H) 6.03 (t, J=3.48 Hz, 1 H) 6.64 (dd, J=8.54, 2.19 Hz, 1 H) 6.86 (d, J=2.32 Hz, 1 H) 7.03 (dd, J=8.54, 1.34 Hz, 1 H).

References: [1]Patent: WO2008/74788,2008,A1 .Location in patent: Page/Page column 100-101.

6
[ 886762-08-9 ]
[ 1137468-13-3 ]
[ 1137467-60-7 ]

Yield	Reaction Conditions	Operation in experiment
52%	With potassium carbonate;palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In N,N-dimethyl-formamide; at 80℃; for 3h;	Step (d'). 5-[2-(5-bromo-2-trifluoromethoxy-phenylamino)-pyrimidin-4-yl]-l- methyl-lH-pyrrole-3-carboxylic acid ethyl ester (AlBlClMl); Palladium acetate [Pd(OAc)2] (0.12 g, 0.55 mmol), (+)-BINAP (0.34 g, 0.55 mmol) and dimethylformamide (60 mL) were charged to a round-bottom flask flushed with argon. The flask was evacuated and backfilled with argon. The mixture was stirred under argon for 30 minutes and added to a mixture of 5-bromo-2-trifluoromethoxy aniline (2.0 g, 5.60 mmol), 5 -(2-iodo-pyrimidin-4-yl)-l -methyl- lH-pyrrole-3-carboxylic acid ethyl ester (1.44 g, 5.60 mmol), and potassium carbonate (7.70 g, 55.80 mmol) in <n="40"/>dimethylformamide (90 niL). The resulting mixture was stirred at 800C for 3 hours under argon. After cooling to room temperature, the reaction mixture was filtered on a pad of celite. The solvent was concentrated, the crude solid was purified by flash chromatography on silica gel (eluant: hexane/ethyl acetate 70/30) to afford 1.41 g (52%) of the title compound as white solid.1H NMR (400 MHz, DMSO-J6) delta ppm 1.27 (t, J=7.07 Hz, 3 H) 3.92 (s, 3 H) 4.20 (q, J=7.07 Hz, 2 H) 7.29 (d, J=5.37 Hz, 1 H) 7.28 (d, J=I.83 Hz, 1 H) 7.35 - 7.38 (m, 1 H) 7.38 - 7.42 (m, 1 H) 7.66 (d, J=I.71 Hz, 1 H) 8.15 (d, J=2.20 Hz, 1 H) 8.40 (d, J=5.37 Hz, 1 H) 9.20 (s, 1 H); MS (ESI): 485 [M+H]+.

References: [1]Patent: WO2009/40399,2009,A1 .Location in patent: Page/Page column 38-39.
[2]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 96 - 101.

7
[ 109-01-3 ]
[ 886762-08-9 ]
[ 1034732-96-1 ]

Yield	Reaction Conditions	Operation in experiment
70%	With lithium hexamethyldisilazane; DavePhos;tris-(dibenzylideneacetone)dipalladium(0); In tetrahydrofuran; for 1h;Inert atmosphere; Reflux;	Preparation F-(4-Methyl-piperazin-1-yl)-2-trifluoromethoxy-phenylamine.Pd2(dba)3 (1.1 g, 1.2 mmol), 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)-biphenyl (0.94 g, 2.4 mmol), 5- bromo-2-trifluoromethoxy-phenylamine (30.7 g, 120 mmol) in THF (50 mL) were charged in a round-bottom flask flushed with argon. The flask was evacuated and backfilled with argon. LiN(TMS)2 solution (1 M in THF, 288 mL) and N-methylpiperazine (26.7 mL, 194 mmol) were added and the reaction refluxed for 1 hours. The reaction mixture was then allowed to cool to room temperature and filtered through a pad of celite. The organic phase was concentrated, the residue dissolved in DCM (200 mL) and washed with H2O (1 x 100 mL). The organic phases were dried over anhydrous Na2S04, the solvent evaporated in vacuo and the crude solid was purified by flash chromatography on silica gel (eluant: DCM/EtOH 90/10) to afford 23 g of 4-(4-methyl-piperazin-1-yl)-2- trifluoromethoxy-phenylamine (70% yield) as a light brown powder.1H NMR (401 MHz, DMSO-d6) delta ppm 2.22 (s, 3H), 2.44 (t, J=4.88 Hz, 4H), 2.94 (t, J=4.88 Hz, 4 H) 4.77 (br.s., 2 H) 6.66-6.69 (m, 1 H) 6.73 - 6.80 (m, 2 H);MS calc: 276.1318; MS found: 276.1320
70%	With lithium hexamethyldisilazane;tris-(dibenzylideneacetone)dipalladium(0); DavePhos; In tetrahydrofuran; for 1h;Inert atmosphere; Reflux;	Preparation 7; 4-(4-Methyl-piperazin-1-yl)-2-trifluoromethoxy-phenylamine; Tris(dibenzilideneacetone)dipalladium, Pd2(dba)3(1.1 g, 1.2 mmol), 2-dicyclohexylphosphino-2'-(N,N- dimethylamino)-biphenyl (0.94 g, 2.4 mmol), <strong>[886762-08-9]5-bromo-2-trifluoromethoxy-phenylamine</strong> (30.7 g, 120 mmol) in THF (50 mL) were charged in a round-bottom flask flushed with argon. The flask was evacuated and backfilled with argon. LiN(TMS)2 solution (1 M in THF, 288 mL) and N-methylpiperazine (26.7 mL, 194 mmol) were added and the reaction refluxed for 1 h. The reaction mixture was then allowed to cool to room temperature and filtered through a pad of celite. The organic phase was concentrated, the residue dissolved in DCM (200 mL) and washed with water (1 x 100 mL). The organic phases were dried over anhydrous Na2SU4, the solvent evaporated in vacuo and the crude solid was purified by flash chromatography on silica gel (eluant: DCM/EtOH 90/10) to afford 23 g of 4-(4- methyl-piperazin-1-yl)-2-trifluoromethoxy-phenylamine (70% yield) as a light brown powder. MS calc: 276.1318; MS found: 276.1320

References: [1]Patent: WO2012/13557,2012,A1 .Location in patent: Page/Page column 33.
[2]Patent: WO2009/156315,2009,A1 .Location in patent: Page/Page column 61.

8
[ 802537-20-8 ]
[ 886762-08-9 ]
[ 1034614-87-3 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 6489 - 6494.
[2]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 2969 - 2974.

9
[ 886762-08-9 ]
[ 154065-33-5 ]

Yield	Reaction Conditions	Operation in experiment
52%	With copper(l) iodide; tert.-butylnitrite; In acetonitrile; at 60℃; for 1h;	10.74 g (93.75 mmol) of tert-butyl nitrite and 28.5 g (150 mmol) of copper iodide are suspended in 270 ml of acetonitrile and heated to 60 C. A solution of 15 g (62.5 mmol) of <strong>[886762-08-9]5-bromo-2-trifluoromethoxyaniline</strong> in 130 ml of acetonitrile is slowly added dropwise to this suspension and the mixture is left to stir at 60 C. for another hour. The reaction solution is then poured on to a mixture of 250 ml of 2 N aqueous HCl and 250 ml of ethyl acetate. The organic phase is washed twice more with aqueous NaCl solution, filtered through a little silica gel and concentrated. The residue is separated by chromatography on silica gel (ethyl acetate/n-heptane=1/18). This affords 12.2 g (52% yield) of product 96 as a colorless oil.

References: [1]Patent: US2011/59910,2011,A1 .Location in patent: Page/Page column 55.

10
[ 886762-08-9 ]
[ 1181682-10-9 ]

References: [1]Patent: US2011/59910,2011,A1 .

11
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[ 1181682-12-1 ]

References: [1]Patent: US2011/59910,2011,A1 .

12
[ 886762-08-9 ]
[ 1304581-32-5 ]
C₁₉H₁₉BrF₃NO₆S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; for 16h;	General Procedure: Methyl 2-[4-(chlorosulfonyl)-2,3-dimethylphenyl]oxy}propanoate (7) (4 g, 13.0 mmol) was dissolved in pyridine (10 mL). After 5 min, 3-bromo-2-chloroaniline (3.22 g, 15.6 mmol) was added. The reaction was complete within a few hours. The reaction mixture was then extracted using diethyl ether. The combined organic phases were washed with 1N HCl and brine, dried over sodium sulfate, filtered, and concentrated in vacuo to afford the title compound which was used without further purification.

References: [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 2345 - 2350.

13
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[ 1034616-36-8 ]