1483-55-2|2-Bromo-5-(trifluoromethyl)benzonitrile| Ambeed

Structure of 1483-55-2

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Quality Control of [ 1483-55-2 ] Purity: 98% SDS Specification

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Product Details of [ 1483-55-2 ]

CAS No. :	1483-55-2
Formula :	C₈H₃BrF₃N
M.W :	250.02
SMILES Code :	N#CC1=CC(C(F)(F)F)=CC=C1Br
MDL No. :	MFCD03412187
InChI Key :	ICEINTPQBJRYDE-UHFFFAOYSA-N
Pubchem ID :	12223980

Safety of [ 1483-55-2 ]

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

Computational Chemistry of [ 1483-55-2 ] Show Less

Physicochemical Properties

Num. heavy atoms	13
Num. arom. heavy atoms	6
Fraction Csp3	0.12
Num. rotatable bonds	1
Num. H-bond acceptors	4.0
Num. H-bond donors	0.0
Molar Refractivity	43.86
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	23.79 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.11
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	3.22
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	4.49
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.	3.23
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	3.5
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.	-3.69
Solubility	0.0506 mg/ml ; 0.000202 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.	-3.39
Solubility	0.101 mg/ml ; 0.000405 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	-4.23
Solubility	0.0148 mg/ml ; 0.0000593 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.	-5.54 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	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<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)	1.86

Application In Synthesis of [ 1483-55-2 ]

* 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 [ 1483-55-2 ]

[ 1483-55-2 ] Synthesis Path-Downstream 1~35

1
[ 1483-55-2 ]
[ 102684-91-3 ]

Yield	Reaction Conditions	Operation in experiment
76%		Example 108 Preparation of 2-methyl-5-phenyl-8-(trifluoromethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine, L-tartrate salt Step A: To a solution of the 2-bromo-5-trifluoromethyl-benzonitrile (2.6 g, 10.4 mmol) in toluene (20 mL) at -78 C. was added diisobutylaluminium hydride (21 mL, 21 mmol, 1.0 M in toluene) cooled to -78 C. by cannula. The solution was stirred at -78 to -50 C. for 2 hours. Water (5 mL) was added slowly to the reaction and the reaction was allowed to warm up to room temperature. The mixture was adjusted to pH 10 with NaOH. The product was extracted with dichloromethane, washed with saturated sodium bicarbonate and brine, dried over sodium sulfate and concentrated. The residue was purified by flash chromatography (hexanes/ether 90:10) to give the desired aldehyde (2.0 g, 76%) as a dark solid: 1H NMR (CDCl3, 300 MHz) delta 10.38 (s, 1H), 8.18 (s, 1H), 7.68 (d, J=8.7 Hz, 1H), 7.54 (d, J=8.7 Hz, 1H).
		To a solution of <strong>[1483-55-2]2-bromo-5-(trifluoromethyl)benzonitrile</strong> (10.0 g, 40 mmol) in dichloromethane (100 mL) was dropwise added a 1.0 M solution of diisobutylaluminum hydride in hexane (48 mL). The resulting solution was stirred under nitrogen at ambient temperature for 1 h and was then diluted by addition of ether (100 mL). After cooling in an ice bath, a 3 N solution of HCl was carefully added, and the mixture was vigorously stirred at ambient temperature for 15 min. The organic layer was washed with brine, dried (MgSO4) and evaporated. The resulting oil was purified by flash chromatography (5% EtOAc/hexane) affording 5 g of 2-bromo-5-trifluoromethylbenzaldehyde. 1H NMR (CDCl3) delta 10.39 (s, 1H), 8.18 (d, J=2 Hz, 1H), 7.82 (d, J=8.8 Hz, 1H), 7.70 (dd, J=8.5 Hz, 2 Hz, 1H).

References: [1]Journal of Medicinal Chemistry,1986,vol. 29,p. 1442 - 1452.
[2]Patent: US2007/21408,2007,A1 .Location in patent: Page/Page column 130-131.
[3]ACS Medicinal Chemistry Letters,2010,vol. 1,p. 483 - 487.
[4]Patent: US2005/261310,2005,A1 .Location in patent: Page/Page column 24.

2
[ 454-79-5 ]
[ 143-33-9 ]
[ 1483-55-2 ]

References: [1]Collection of Czechoslovak Chemical Communications,1975,vol. 40,p. 1940 - 1959.
[2]Arzneimittel-Forschung/Drug Research,1963,vol. 13,p. 802 - 804.

3
[ 1483-55-2 ]
phenylmagnesium bromide [ No CAS ]
[ 16190-19-5 ]

References: [1]Arzneimittel-Forschung/Drug Research,1963,vol. 13,p. 802 - 804.

Yield	Reaction Conditions	Operation in experiment
		Specific examples of the trifluoromethylbenzonitrile include 2-trifluoromethylbenzonitrile, 3-trifluoromethylbenzonitrile, 4-trifluoromethylbenzonitrile, 2-bromo-5-trifluoromethylbenzonitrile, 2-chloro-5-trifluoromethylbenzonitrile, 2-fluoro-5-trifluoromethylbenzonitrile, 4-iodo-2-trifluoromethylbenzonitrile, 4-iodo-3-trifluoromethylbenzonitrile, 2-methoxy-5-trifluoromethylbenzonitrile, ...
		Specific examples of the trifluoromethylbenzonitrile include 2-trifluoromethylbenzonitrile, 8-trifluoromethylbenzonitrile, 4-trifluoromethylbenzonitrile, 2-bromo-5-trifluoromethylbenzonitrile, 2-chloro 5-trifluoromethylbenzonitrile, 2-fluoro-5-trifluoromethylbenzonitrile, 4-iodo-2-trifluoromethylbenzonitrile, 4-iodo 3-trifluoromethylbenzonitrile, 2-methoxy-5-trifluoromethylbenzonitrile, 3-methoxy-4-trifluoromethylbenzonitrile, ...

5
magnesium sulfate-charcoal [ No CAS ]
[ 1483-55-2 ]
[ 102684-91-3 ]

Yield	Reaction Conditions	Operation in experiment
	With diisobutylaluminium hydride; In hydrogenchloride; dichloromethane;	(a) 2-(8-Phenyloctyl)-5-trifluoromethyl benzaldehyde To a solution of <strong>[1483-55-2]2-bromo-5-trifluoromethyl benzonitrile</strong> (20.16 mmoles) in methylene chloride (50 ml), under argon at room temperature, was added diisobutylaluminum hydride (25 mmoles, 25 ml hexane) dropwise and the resulting solution was stirred for 30 minutes. The reaction mixture was diluted with ether (50 ml), cooled in ice and quenched by the careful addition of hydrochloric acid (50 ml, 3N). The ice bath was removed and the mixture was stirred vigorously for 15 minutes. The organic layer was washed with brine (50 ml), treated with magnesium sulfate-charcoal and evaporated. The resulting oil was purified by distillation to give 2-bromo-5-trifluoromethyl benzaldehyde, bp 50-55 C. at 0.05 mm Hq.
	With diisobutylaluminium hydride; In hydrogenchloride; dichloromethane;	(a) 2-(8-Phenyloctyl)-5-trifluoromethyl benzaldehyde To a solution of <strong>[1483-55-2]2-bromo-5-trifluoromethyl benzonitrile</strong> (20.16 mmoles) in methylene chloride (50 ml), under argon at room temperature, was added diisobutylaluminum hydride (25 mmoles, 25 ml hexane) dropwise and the resulting solution was stirred for 30 minutes. The reaction mixture was diluted with ether (50 ml), cooled in ice and quenched by the careful addition of hydrochloric acid (50 ml, 3 N). The ice bath was removed and the mixture was stirred vigorously for 15 minutes. The organic layer was washed with brine (50 ml), treated with magnesium sulfate-charcoal and evaporated. The resulting oil was purified by distillation to give 2-bromo-5-trifluoromethyl benzaldehyde, bp 50-55 C. at 0.05 mm Hg.
	With diisobutylaluminium hydride; In hydrogenchloride; dichloromethane;	(a) 2-(8-Phenyloctyl)-5-trifluoromethyl benzaldehyde To a solution of <strong>[1483-55-2]2-bromo-5-trifluoromethyl benzonitrile</strong> (20.16 mmoles) in methylene chloride (50 ml), under argon at room temperature, was added diisobutylaluminum hydride (25 mmoles, 25 ml hexane) dropwise and the resulting solution was stirred for 30 minutes. The reaction mixture was diluted with ether (50 ml), cooled in ice and quenched by the careful addition of hydrochloric acid (50 ml, 3N). The ice bath was removed and the mixture was stirred vigorously for 15 minutes. The organic layer was washed with brine (50 ml), treated with magnesium sulfate-charcoal and evaporated. The resulting oil was purified by distillation to give 2-bromo-5-trifluoromethyl benzaldehyde, bp 50-55 C. at 0.05 mm Hg.

With diisobutylaluminium hydride; In hydrogenchloride; dichloromethane;

(a) 2-(8-Phenyloctyl)-5-trifluoromethyl benzaldehyde To a solution of <strong>[1483-55-2]2-bromo-5-trifluoromethyl benzonitrile</strong> (20.16 mmoles) in methylene chloride (50 ml), under argon at room temperature, was added diisobutylaluminum hydride (25 mmoles, 25 ml hexane) dropwise and the resulting solution was stirred for 30 minutes. The reaction mixture was diluted with ether (50 ml), cooled in ice and quenched by the careful addition of hydrochloric acid (50 ml, 3N). The ice bath was removed and the mixture was stirred vigorously for 15 minutes. The organic layer was washed with brine (50 ml), treated with magnesium sulfate-charcoal and evaporated. The resulting oil was purified by distillation to give 2-bromo-5-trifluoromethyl benzaldehyde, bp 50-55 C. at 0.05 mm Hg.

References: [1]Patent: US4937253,1990,A .
[2]Patent: US4730005,1988,A .
[3]Patent: US4871771,1989,A .
[4]Patent: US4874792,1989,A .

6
magnesium sulfate-charcoal [ No CAS ]
diisobutylaluminum hydride [ No CAS ]
[ 1483-55-2 ]
[ 102684-91-3 ]

Yield	Reaction Conditions	Operation in experiment
	In hydrogenchloride; dichloromethane;	(a) 2-(8-Phenyloctyl)-5-trifluoromethyl benzaldehyde To a solution of <strong>[1483-55-2]2-bromo-5-trifluoromethyl benzonitrile</strong> (20.16 mmoles) in methylene chloride (50 ml), under argon at room temperature, was added diisobutyl-aluminum hydride (25 mmoles, 25 ml hexane) dropwise and the resulting solution was stirred for 30 minutes. The reaction mixture was diluted with ether (50 ml), cooled in ice and quenched by the careful addition of hydrochloric acid (50 ml, 3N). The ice bath was removed and the mixture was stirred vigorously for 15 minutes. The organic layer was washed with brine (50 ml), treated with magnesium sulfate-charcoal and evaporated. The resulting oil was purified by distillation to give 2-bromo-5-trifluoromethyl benzaldehyde, bp 50-55 C. at 0.05 mm Hg.

References: [1]Patent: US4820719,1989,A .

7
[ 1483-55-2 ]
[ 1483-56-3 ]

References: [1]Journal of the American Chemical Society,2008,vol. 130,p. 810 - 811.
[2]Tetrahedron,2010,vol. 66,p. 4668 - 4686.

8
[ 1483-55-2 ]
[ 57260-71-6 ]
[ 847971-82-8 ]

Yield	Reaction Conditions	Operation in experiment
15%	With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 85℃; for 1h;	Example 192: 4-Chloro-6-(2-piperazin-l-yl-5-trifluoromethyl-benzylamino)-2H- phthalazin-1-one; 4-(2-Cyano-4-tfluoromethyl-phenyl)-piperazine-l-carboxylic acid tert-butyl ester; A mixture of Boc-piperazine (573mg, (3.08 mmol), 2-bromo-5- trifluoromethylbenzonitrile (700mg, 2.80mmol), Pd2(dba)3 (256mg, 0.28 mmol), xantphos (486mg, 0.84mmol), sodium t-butoxide (660mg, 7.0mmol) in degassed anhydrous dioxane (1OmL) was heated at 85C for Ih. The mixture was allowed to cool and filtered through celite. The filtrate was concentrated and purified by chromatography (EtOAc/hexanes) to yield the title compound (150mg, 15%). m/z (M+ 1) 356.37.

References: [1]Patent: WO2008/61108,2008,A2 .Location in patent: Page/Page column 145-146.

9
[ 1070892-35-1 ]
[ 1483-55-2 ]
[ 1070890-04-8 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 95℃; for 16h;	A mixture of 4-chloro-N-[2-(3-hydroxy-propoxy)-6-methyl-phenyl]-N- methyl-3-(4A5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-benzamide (206 mg, 0.45 mmol), <strong>[1483-55-2]2-bromo-5-(trifluoromethyl)-benzonitrile</strong> (75 mg, 0.3 mmol), Pd(PPh3)4 (34.7 mg, 0.03 mmol), Na2CO3 (190.8 mg, 1.8 mmol) in dioxane/water (9/1 , 1.5 ml_), was heated at 95 0C for approximately 16 hrs after degassing of the solvent with a stream of nitrogen. The reaction was allowed to cool to room temperature. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was further washed with brine and dried with MgSO4. The filtrate was evaporated and the residue purified by preparative TLC [eluent: 40% acetone in hexane] to afford 4-chloro-3-(2- cyano^-trifluoromethyl-phenyO-N-^^S-hydroxy-propoxyJ-theta-methyl-phenyll-N-methyl- benzamide 10-1 (120 mg). MS [M+H]+: 502.9; tR= 8.15 min. (method 2)

References: [1]Patent: WO2008/124610,2008,A1 .Location in patent: Page/Page column 73.

10
[ 1483-55-2 ]
[ 1066-54-2 ]
C₁₃H₁₂F₃NSi [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With copper(l) iodide; triethylamine;tetrakis(triphenylphosphine) palladium(0); at 80℃; for 4h;Inert atmosphere;	<strong>[1483-55-2]2-Bromo-5-trifluoromethyl-benzonitrile</strong> (10Og, 0.40 mol) was dissolved in triethylamine (600 mL), and the solution was sparged with Ar for 20 min. CuI(I) (2.5 g, 0.013 mol), Pd(PPh3)4 (450 mg, 0.38 mmol), and TM S -acetylene (50 g, 0.51 mol) were added, and the reaction was stirred at 80 0C for 1 h. A small amount of precipitate developed, and additional CuI(I) (1 g), Pd(PPh3)4 (1.5 g), and TMS-acetylene (15 mL) were added. The reaction was stirred at 80 0C for 3 h more. The reaction mixture was diluted with 1.5 L of hexanes and filtered through celite. The solvents were removed to give tan crystals. These crystals were dissolved in methanol (250 mL) and potassium carbonate (Ig) was added. The mixture was stirred at RT for 2 h. The reaction mixture was then partitioned between ether (500 mL) and water (150 mL). The organic layer was washed with water until it was no longer basic by pH paper (about 10 times). The organic layer was washed with brine, dried over sodium sulfate, and concentrated then purified via silica gel chromatography using EtOAc in hexanes (2-10%). The 2-ethynyl-5-trifluoromethyl-benzonitrile was collected as a tan solid (62.5 g). H1 NMR (CDCl3): £(ppm) 7.93-7.92 (m, 1 H), 7.84-7.80 (m, 1 H), 7.76-7.74 (d, 1 H), 3.64 (s, 1 H).

References: [1]Patent: WO2010/81149,2010,A1 .Location in patent: Page/Page column 28.

11
[ 75-75-2 ]
[ 1483-55-2 ]
[ 949089-74-1 ]

Yield	Reaction Conditions	Operation in experiment
71%		Step A: Preparation of 2: 2-Bromo-5-trifluoromethyl-benzylamine methanesulfonic acid salt Sodium borohydride (NaBH4) (225 g, 5.96 mol) was charged to a 22 L flask followed by THF (6.8 L, anhyd). The mixture was cooled in an ice-water bath. Trifluoroacetic acid (TFA) (518 ml) was added to THF (1.4 L) and this solution was also cooled in an ice-water bath. The TFA solution was added to the NaBH4 suspension over 2.5 hours. The ice-water bath was removed and the resulting mixture was stirred at ambient temperature for 2 hours. <strong>[1483-55-2]2-Bromo-5-trifluoromethyl-benzonitrile</strong> (678 g, 2.71 mol) was dissolved in THF (1.2 L). The TFA/NaBH4 mixture was again cooled in an ice-water bath and the nitrile solution was added over 1.5 hours. The mixture was allowed to reach ambient temperature while stirring for 16 hours. LC analysis of an aliquot revealed complete reaction. The mixture was cooled in an ice bath and methanol (2 L) was added over 1 hour. Volatiles were removed in vacuo and ethylacetate (4 L) was added. This mixture was washed with water (3 L) containing sodium-potassium tartarate (1 Kg). The aqueous layer was washed with ethylacetate (2 L) and the combined organics were washed with brine (2 L), dried over sodium sulfate, filtered, and concentrated. The residue was dissolved in THF (3 L) and cooled in an icewater bath. Methanesulfonic acid (195 ml) was added and the mixture was stirred for 2 hours. The resulting solid was filtered and dried in vacuo (676 g, 71% yield). 1H-NMR (CD3OD) 7.92 (d, 8.3 Hz, 1H), 7.87 (s, 1H), 7.65 (d, 8.3 Hz, 1H), 4.34 (s, 2H), 2.66 (s, 3H). Mass Spec (ESI): M+1=255.9
71%		Step A: Preparation of 2: 2-Bromo-5-trifluoromethyl-benzylamine methanesulfonic acid salt Sodium borohydride (NaBH4) (225 g, 5.96 mol) was charged to a 22 L flask followed by THF (6.8 L, anhyd). The mixture was cooled in an ice-water bath. Trifluoroacetic acid (TFA) (518 ml) was added to THF (1.4 L) and this solution was also cooled in an ice-water bath. The TFA solution was added to the NaBH4 suspension over 2.5 hours. The ice-water bath was removed and the resulting mixture was stirred at ambient temperature for 2 hours. <strong>[1483-55-2]2-Bromo-5-trifluoromethyl-benzonitrile</strong> (678 g, 2.71 mol) was dissolved in THF (1.2 L). The TFA/NaBH4 mixture was again cooled in an ice-water bath and the nitrile solution was added over 1.5 hours. The mixture was allowed to reach ambient temperature while stirring for 16 hours. LC analysis of an aliquot revealed complete reaction. The mixture was cooled in an ice bath and methanol (2 L) was added over 1 hour. Volatiles were removed in vacuo and ethylacetate (4 L) was added. This mixture was washed with water (3 L) containing sodium-potassium tartarate (1 Kg). The aqueous layer was washed with ethylacetate (2 L) and the combined organics were washed with brine (2 L), dried over sodium sulfate, filtered, and concentrated. The residue was dissolved in THF (3 L) and cooled in an icewater bath. Methanesulfonic acid (195 ml) was added and the mixture was stirred for 2 hours. The resulting solid was filtered and dried in vacuo (676 g, 71% yield). 1H-NMR (CD3OD) delta 7.92 (d, 8.3 Hz, 1H), 7.87 (s, 1H), 7.65 (d, 8.3 Hz, 1H), 4.34 (s, 2H), 2.66 (s, 3H). Mass Spec (ESI): M+1=255.9

References: [1]Patent: US2007/213314,2007,A1 .Location in patent: Page/Page column 115.
[2]Patent: US2007/213371,2007,A1 .Location in patent: Page/Page column 97.

12
[ 1483-55-2 ]
[ 869725-53-1 ]