104197-14-0|4-Bromo-2,6-difluoroanisole| Ambeed

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Quality Control of [ 104197-14-0 ] Purity: 98% SDS Specification

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Product Details of [ 104197-14-0 ]

CAS No. :	104197-14-0
Formula :	C₇H₅BrF₂O
M.W :	223.01
SMILES Code :	COC1=C(F)C=C(Br)C=C1F
MDL No. :	MFCD01631351
Boiling Point :	No data available
InChI Key :	CDOQKISJPOWBKC-UHFFFAOYSA-N
Pubchem ID :	2773287

Safety of [ 104197-14-0 ]

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

Computational Chemistry of [ 104197-14-0 ] Show Less

Physicochemical Properties

Num. heavy atoms	11
Num. arom. heavy atoms	6
Fraction Csp3	0.14
Num. rotatable bonds	1
Num. H-bond acceptors	3.0
Num. H-bond donors	0.0
Molar Refractivity	40.55
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	9.23 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.36
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	2.79
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	3.58
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.	3.41
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	3.34
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	3.1

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-3.32
Solubility	0.107 mg/ml ; 0.000481 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.	-2.64
Solubility	0.511 mg/ml ; 0.00229 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	-3.94
Solubility	0.0254 mg/ml ; 0.000114 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.	-5.68 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<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)	1.47

Application In Synthesis of [ 104197-14-0 ]

* 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 [ 104197-14-0 ]
Downstream synthetic route of [ 104197-14-0 ]

[ 104197-14-0 ] Synthesis Path-Upstream 1~1

1
[ 104197-14-0 ]
[ 363-47-3 ]

References: [1] Nature Chemistry, 2017, vol. 9, # 7, p. 681 - 688.

[ 104197-14-0 ] Synthesis Path-Downstream 1~35

1
[ 104197-14-0 ]
3',5'-difluoro-4'-hydroxy-biphenyl-4-carboxylic acid [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2004,vol. 47,p. 355 - 374.

2
[ 104197-14-0 ]
3',5'-difluoro-4'-hydroxy-biphenyl-3-carboxylic acid methyl ester [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2004,vol. 47,p. 355 - 374.

3
[ 104197-14-0 ]
3',5'-difluoro-4'-hydroxy-biphenyl-4-carboxylic acid methyl ester [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2004,vol. 47,p. 355 - 374.

4
[ 104197-14-0 ]
3',5'-difluoro-4'-hydroxy-biphenyl-3-carboxylic acid [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2004,vol. 47,p. 355 - 374.

5
[ 868263-37-0 ]
[ 104197-14-0 ]
[2-(3-tert-butyl-3',5'-difluoro-4'-methoxybiphenyl-4-yloxy)ethyl]-methylamino}-acetic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
30%	With potassium phosphate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,2-dimethoxyethane; at 20℃;Heating / reflux;	Stir a mixture of (12-[2-tert-butyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2- yl) -phenoxy]ethyl}-methylamino)-acetic acid tert-butyl ester prepared essentially as decribed in Preparation 180 (0.4 mg, 0.89 mmol, leq), potassium phosphate (5 eq) and [1,1'bis(diphenylphosphino)ferrocene]dichloropalladium (II) (0.1 eq) in 1,2- dimethoxyethane for 15 min at room temperature under nitrogen and add 4-bromo-2,6- difluoroanisole (1.5 eq) in 1,2-dimethoxyethane. Heat to reflux over night under nitrogen. Add extra <strong>[104197-14-0]4-bromo-2,6-difluoroanisole</strong> (0.75 eq), potassium phosphate (2.5 eq) and [1,1'bis(diphenylphosphino)ferrocene]dichloropalladium (II) (0.05eq) in 1,2- dimethoxyethane (5 mL) and heat for a further 24 h. Cool to room temperature, filter inorganics on Celite washing with methanol and concentrate. Take up residue in methanol and purify (ion exchange chromatography, eluting with 2 M ammonia in methanol, followed by automated Isco chromatography, eluting with solvent gradient 0:100 to 30:70 cyclohexane:ethyl acetate) to give the title compound as a oil (123 mg, 30%). LC-MS: m/z=464.2

References: [1]Patent: WO2005/100301,2005,A1 .Location in patent: Page/Page column 93.

6
[ 104197-14-0 ]
[ 73183-34-3 ]
[ 890839-37-9 ]

Yield	Reaction Conditions	Operation in experiment
90%	With potassium acetate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; dichloromethane; at 80℃; for 12.5h;Inert atmosphere;	Intermediate 112 2-(3,5-difluoro-4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxa borolane To a solution of intermediate 111 (2.0 g, 8.968 mmoles) in Dioxan (40 ml), bis(pinacaloto)diboron (2.73 g, 10.76 mmoles) and potassium acetate (2.64 g, 26.90 mmoles) were added and the system is degassed for 30 min Bis(diphenylphosphinoferrocene)dichloro palladium.CH2Cl2 (0.219 g, 0.269 mmoles) was added under nitrogen atmosphere and heated to 80 C. After 12 h, the reaction mixture filtered through celite and concentrated. The crude product was purified by column chromatography with ethyl acetate:petroleum ether to afford the title compound as yellow liquid (2.2 g, 90% yield).). 1H-NMR (delta ppm, DMSO-d6, 400 MHz): delta delta 7.318 (d, J=8.7 Hz, 2H), 4.02 (s, 3H), 1.32 (s, 12H).
24%	With potassium acetate;1,1'-bis-(diphenylphosphino)ferrocene; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; at 80℃; for 16h;	Example VIII2,6-Difluoro-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)anisolTo a solution of <strong>[104197-14-0]4-bromo-2,6-difluoro-anisol</strong> (3.0 g) in dry dioxane (50 mL) and under argon atmosphere is added bis(pinacolato)diboron (5.13 g), potassium acetate (3.94 g), 1 ,1 '- bis(diphenylphosphino)-ferrocene (0.55 g) and 1 ,1'-bis(diphenylphosphino)- ferrocenedichloropalladium (II) (0.82 g). The flask is tightly sealed and heated to 80 0C for 16 h. Then the reaction mixture is concentrated under reduced pressure and the residue is taken up in ethyl acetate. The resulting mixture is washed with water, dried (sodium sulphate) and the solvent is evaporated. The remainder is purified by chromatography on silica gel (cyclohexane/ethyl acetate 1 :0->2:1 ).Yield: 0.88 g (24% of theory)Mass spectrum (ESI+): m/z = 271 [M+H]+
	With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; at 150℃; for 0.333333h;Microwave irradiation;	Preparation 14. 2-r3,5-difluoro-4-(methyloxy)phenylH,4,5,5-tetramethyl-1.3,2- dioxaborolane; A solution of <strong>[104197-14-0]4-bromo-2,6-difluoroanisole</strong> (223mg, 1 mmole), bis(pinacaolato)diboron (275 mg, 1.09 mmole), [1 ,1 '-bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (40 mg) and KOAc (300 mg) in 5 ml of dioxane was heated in the microwave at 150 for 20 minutes. The reaction was diluted with H2O and extracted with Et2O. The extracts were washed with H2O, dried and evaporated. The residue was chromatographed on a Florisil column, and the titled compound was eluted with Et20, 158 mg (58%). 1H NMR (400 MHz, CDCI3) delta 7.32 (d, J=8Hz, 2H), 4.05 (s, 3H), 1.35 (s, 12H).

References: [1]Patent: US2011/118257,2011,A1 .Location in patent: Page/Page column 100.
[2]Patent: WO2008/34859,2008,A1 .Location in patent: Page/Page column 40.
[3]Patent: WO2006/63167,2006,A1 .Location in patent: Page/Page column 33.

7
[ 104197-14-0 ]
6-bromo-2,4-difluoro-3-methoxy-benzoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With n-butyllithium; phosphoric acid; In tetrahydrofuran; methanol; water;	EXAMPLE 197 2,4-Difluoro-3-methoxy-benzoic acid A solution of <strong>[104197-14-0]5-bromo-1,3-difluoro-2-methoxy-benzene</strong> (12.35 g, 55.4 mmole, L. I. Kruse, et al., Biochemistry 1986, 25, 7271-7278) in anhydrous tetrahydrofuran (350 mL) was transferred via canulla into a 1 L flask which had been flame dried. The solution was cooled to -80 C. and a solution of n-butyl lithium (2.5 M in hexanes, 24.35 mL, 60.9 mmol) was added dropwise via syringe pump over a 1 hour period with stirring under a dry nitrogen atmosphere. After stirring 2.5 hours, dry carbon dioxide gas was bubbled into the cold reaction mixture for 0.5 hour. The solution was then poured onto crushed dry ice and strirred for 0.5 hours. The mixture was causiously added to water (600 mL) and acidified with 10% HCl. The organics were extracted with ether. The extracts were combined and washed with brine. After concentrating and standing at room temperature for two days the residue was redissolved in ether and combined with acid treated (2% H3PO4 in methanol) silica gel. The solvent was removed and the adsorbate was flash chromatographed to give the title compound as an off-white solid: mp 191-192 C.: NMR (400 MHz, DMSO-d6); delta13.37 (broad singlet, 1 H), 7.63-7.58 (m, 1 H,), 7.25 - 7.20 (m, 1 H), 3.92(s, 3 H); MS (+FAB): (M+H): 189 (12%), 154 (100%), 136 (75%); Anal. Calc. for C8H6F2O3: C, 51.08; H, 3.21. Found: C, 50.98, H, 3.15. Concentration of less polar fractions gave 6-bromo-2,4-difluoro-3-methoxy-benzoic acid (3.44 g, 23%) as a white solid: mp 92-94 C.: NMR (400MHz, DMSO-d6); delta14.18 (broad singlet, 1 H), 7.65 (dd, J=3, 1 Hz, 1 H), 3.94 (s, 3 H); MS: (+FAB) (M +H: 267/269 (38%), 91 (100%); Anal. calc. for C8H5BrF2O3: C, 35.98, H, 1.89, N, 0.00. Found: C, 36.26, H, 1.79, N 0.03.

References: [1]Patent: US6110962,2000,A .

Yield	Reaction Conditions	Operation in experiment
		PREPARATION EXAMPLE 17 Preparation of Compound (17) 2,6-Difluorophenol is brominated and then reacted with methyl iodide, etc. to obtain 4-bromo-2,6-difluoroanisole, which is led to compound (17) in the same manner as in Preparation Example 13.
		A phenol derivative of formula (P22): STR100 is obtained using the resulting 4-bromo-2,6-difluoroanisole, which is then led to compound (35) in the same manner as in Preparation Example 31.

9
[ 104197-14-0 ]
[ 57260-71-6 ]
[ 909418-83-3 ]

Yield	Reaction Conditions	Operation in experiment
90%	With palladium diacetate; johnphos; sodium t-butanolate; In toluene; at 90℃; for 16h;	A mixture of <strong>[104197-14-0]4-bromo-2,6-difluorophenyl methyl ether</strong> (5.Og), 1 ,1-dimethylethyl 1- piperazinecarboxylate (5.Og), 2-biphenylyl[bis(1 ,1-dimethylethyl)]phosphane (0.666g), palladium acetate (0.246g), sodium tert-butoxide (3.01 g) in toluene(30ml) was heated at 9O0C for 16 hours. After cooling ,The reaction mixture was diluted with diethyl ether, filtered through a pad of celite. Then concentrated in vacuo to give a black oil. The desired product was isolated by column chromatography on silica eluting with a gradient of 5 to 100% ethyl acetate in pentane. The title compound was obtained as a solid, (90% yield), LC/MS (ESI) Found 229 (M-BOC+1 ).

References: [1]Patent: WO2006/94842,2006,A1 .Location in patent: Page/Page column 59-60.

10
[ 544-92-3 ]
[ 104197-14-0 ]
[ 104197-15-1 ]

Yield	Reaction Conditions	Operation in experiment
	In N,N-dimethyl-formamide; at 120℃; for 48h;	(iii) 3 ,5-Difluoro-4-methoxybenzonitrileA mixture of 4-bromo-2,6-difluororhohenyl methyl ether (11.5 g, 0.0516 mol; see step (ii) above) and CuCN (6.92 g, 0.0774 mol) in dry DMF (15 mL) was stirred at 120C for two days under nitrogen atmosphere. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine and dried over sodium sulfate. Solvent evaporation under reduced pressure followed by column chromatography over silica gel, using 2% ethyl acetate in petroleum ether as eluent, yielded 2.7 g of the sub-title compound as a pale yellow solid.

References: [1]Patent: WO2006/135316,2006,A1 .Location in patent: Page/Page column 55.

11
5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside [ No CAS ]
[ 104197-14-0 ]
[ 910649-09-1 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In methanol; 1,2-dimethoxyethane; dichloromethane; water; at 130℃; for 0.5h;Microwave reaction;	EXAMPLE 145 5-(3,5-difluoro-4-methoxyphenyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-beta-D-xylopyranoside 0.334 g (1.5 mM) of <strong>[104197-14-0]4-bromo-2,6-difluoroanisole</strong>, 12 ml of DME, 0.569 g (2.25 mM) of bispinacolborane, 0.036 g (0.045 mM) of [1,1'-bis(diphenyl-phosphino)ferrocene]dichloropalladium(II) dichloromethane and 0.441 g (4.5 mM) of potassium acetate are mixed in a reactor adapted for microwaves. The reactor is heated at 110 C. for 30 minutes by microwaves. After cooling, the reaction mixture is filtered and 0.672 g (1.8 mM) of 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-beta-D-xylopyranoside, 1.122 g (0.12 mM) of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane and a solution of 0.196 g (1.8 mM) of sodium carbonate in 1.5 ml of water are then added to the filtrate. The mixture is heated at 130 C. for 30 minutes by microwaves. Water is added to the cooled reaction mixture and extraction is carried out with ethyl acetate. The organic phase is washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The evaporation residue is purified by chromatography on silica gel using a dichloromethane/methanol mixture (99/1; v/v) as the eluent. The product obtained is recrystallized from ether and filtered off to give the desired product in the form of a white powder with a yield of 64%. M.p.=203 C. [alpha]d29=-18 (c=0.30; DMSO).

References: [1]Patent: US2008/293768,2008,A1 .Location in patent: Page/Page column 23-24.

12
[ 1107620-19-8 ]
[ 104197-14-0 ]
[ 1107618-97-2 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine;copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); In tetrahydrofuran; at 80℃; for 2h;	A mixture of Compound 1c (50 mg, 0.206 mmol), <strong>[104197-14-0]4-bromo-2,6-difluoroanisole</strong> (45.9 mL, 0.206 mmol), bis(triphenylphosphine)palladium(II)dichloride (7.23 mg, 0.012 mmol), CuI (3.92 mg, 0.206 mmol) in anhydrous and degassed triethylamine (3 mL) was heated at 80 C. under a nitrogen atmosphere for 2 h in a sealed vessel. The reaction mixture was cooled, filtered on Celite, poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried on Na2SO4 and evaporated to dryness in vacuo to afford a residue, which was purified by flash chromatography (EtOAc-Petroleum Ether 10:90) affording the title product (22 mg).MS: [M+H]+=386.52

References: [1]Patent: US2009/42841,2009,A1 .Location in patent: Page/Page column 64.

13
[ 1198109-66-8 ]
[ 104197-14-0 ]
[ 1198109-27-1 ]

Yield	Reaction Conditions	Operation in experiment
8%	With copper(l) iodide; 1,10-Phenanthroline; caesium carbonate; In N,N-dimethyl-formamide; at 130℃;Microwave irradiation; Inert atmosphere;	Example 27; Dicyclopropylmethyl [9-(3,5-difluoro-4-methoxyphenyl)-2,8-dimethyl-9H-purin-6-yl]-amine Dicyclopropylmethyl-^, 8-dimethyl-9H-purin-6-yl)-amine (0.05Og , 0.194 mmol), 4-bromo-2,6- difluoroanisole (0.087g , 0.388 mmol), Copper(l) Iodide (0.055g , 0.291 mmol), Cesium carbonate (0.158g , 0.485 mmol) and 1 ,10-Phenanthroline (0.070 g , 0.388 mmol) was dissolved in 2.0 ml of anhydrous DMF in a microwave vial with a septum cap. It was degassed alternatively with vacuum and nitrogen 3 times and then heated at 13O0C overnight in an oil bath. The crude was partitioned between 2 ml of water and 3 x 2 ml of DCM through a phase separating cartridge. Combined organics were dried under reduced pressure to yield a dark liquid which was purified by flash column chromatography in the ISCO system with 12g silica cartridge and a gradient of 0 to 40% EtOAc in heptane with sample loading in DCM. Fractions bearing product were combined to yield a transparent oil which was further purified by preparative HPLC method c. Fractions combined to yield the title compound as a solid (6.4mg, 8%).1H NMR (400MHz, CDCI3) delta = 0.39-0.60 (m, 8H), 1.07 (m, 2H), 2.47 (s, 3H), 3.52 (s, 3H), 4.90 (s, 3H),6.99 (d, 2H).LCMS (System 4): 2.90 mins m/z (APCI) = 401 [MH+], m/z (ES) = 401 [MH+]

References: [1]Patent: WO2009/144632,2009,A1 .Location in patent: Page/Page column 44.

14
[ 68-12-2 ]
[ 104197-14-0 ]
2,5-difluoro-4-methoxybenzaldehyde [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Preparation 4 2.5-Difluoro-4-methoxy-benzaldehyde A mixture of <strong>[104197-14-0]4-bromo-2,6-difluoroanisole</strong> (4.46 g, 20.0 mmol), toluene (200 mL), and THF (10 mL) was cooled to -78 C. To the mixture was added n-BuLi (8.00 mL of a 2.5 M solution in hexanes, 20 mmol). After stirring at -78 C. for 1 h, DMF (3.10 ml, 40.0 mmol) was added. The mixture was stirred at -78 C. for 2 h and then H2O (100 mL) was added. After warming to rt, the mixture was extracted with EtOAc (2*75 mL). The combined extracts were dried (MgSO4), filtered and concentrated to provide 3.00 g of 2,5-difluoro-4-methoxy-benzaldehyde as a solid. 1H NMR (400 MHz, CDCl3): delta 10.18 (d, 1, J=2.9), 7.54 (dd, 1, J=10.6, 6.4), 6.72 (dd, 1, J=11.4, 6.4), 3.95 (s, 3).

References: [1]Patent: US2006/58361,2006,A1 .Location in patent: Page/Page column 33.

15
[ 104197-14-0 ]
[ 1287685-44-2 ]

References: [1]Patent: WO2011/44001,2011,A1 .
[2]Patent: WO2011/44001,2011,A1 .

16
[ 104197-14-0 ]
[ 1287686-22-9 ]