[ CAS No. 103291-07-2 ] {[proInfo.proName]}

Name: 103291-07-2|4-Bromo-1-fluoro-2-methoxybenzene|97%
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Quality Control of [ 103291-07-2 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 103291-07-2 ]

Product Details of [ 103291-07-2 ]

CAS No. :	103291-07-2	MDL No. :	MFCD01861130
Formula :	C₇H₆BrFO	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	SEVMQEIGENUPIE-UHFFFAOYSA-N
M.W :	205.02	Pubchem ID :	13604909
Synonyms :

Calculated chemistry of [ 103291-07-2 ]

Physicochemical Properties

Num. heavy atoms :	10
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.14
Num. rotatable bonds :	1
Num. H-bond acceptors :	2.0
Num. H-bond donors :	0.0
Molar Refractivity :	40.59
TPSA :	9.23 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.46 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.3
Log Po/w (XLOGP3) :	2.94
Log Po/w (WLOGP) :	3.02
Log Po/w (MLOGP) :	2.99
Log Po/w (SILICOS-IT) :	2.92
Consensus Log Po/w :	2.83

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-3.34
Solubility :	0.0934 mg/ml ; 0.000456 mol/l
Class :	Soluble
Log S (Ali) :	-2.8
Solubility :	0.328 mg/ml ; 0.0016 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.66
Solubility :	0.0446 mg/ml ; 0.000218 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.53

Safety of [ 103291-07-2 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H332-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 103291-07-2 ]

* 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.

Upstream synthesis route of [ 103291-07-2 ]
Downstream synthetic route of [ 103291-07-2 ]

[ 103291-07-2 ] Synthesis Path-Upstream 1~5

1
[ 103291-07-2 ]
[ 112204-58-7 ]

Yield	Reaction Conditions	Operation in experiment
86%	With boron tribromide In dichloromethane at 20℃;	To a stirred solution OF 4-BROMO-1-FLUORO-2-METHOXYBENZENE (1.00 g, 4.88 mmol) in anhydrous CH2CL2 (20 ml) was added dropwise in an ice bath BBR3 (1 M solution in CH2Cl2, 9.75 ml, 9. 75 mmol), and the mixture was stirred at room temperature overnight. The reaction was cooled in an ice bath and quenched by adding MEOH (1.0 ml) dropwise. The solvent was evaporated and the residue purified by flash chromatography eluting with ISOHEXANE/CH2CL2/MEOH (70: 20: 10) to leave 0.802 g (86percent) of the title compound: BH (400 MHz, CDCL3) 5.24 (1 H, s), 6.96 (2 H, m), 7.16 (1 H, DD, J7. 7,2. 0 HZ).

Reference： [1] Patent: WO2004/65388, 2004, A1, . Location in patent: Page 47

2
[ 103291-07-2 ]
[ 854778-31-7 ]

Yield	Reaction Conditions	Operation in experiment
35%	Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.666667 h; Stage #2: With Trimethyl borate In tetrahydrofuran; hexane at -78 - 20℃; for 18 h; Stage #3: With hydrogenchloride In tetrahydrofuran; hexane; water	To a solution of 7B (2.7 g, 13.1 mmol) in THF (25 mL) at -78° C. was added n-BuLi (1.6 M in hexanes, 11.0 mL, 17.7 mmol). The mixture was stirred at -78° C. for 40 min before trimethyl borate (2.7 mL, 24.3 mmol) was added. The reaction was left stirring from -78° C. to rt over 18 h. It was quenched with 1.0 N HCl (40 mL), extracted with EtOAc, washed with brine and dried over Na₂SO₄. After evaporation of the solvent, the crude solid product was triturated with EtOAc/hexanes (1:4). After filtration, 7C (0.75 g, 35percent yield) was collected as a white solid. ¹H NMR (400 MHz, Methanol-d₄) δ ppm 3.86 (s, 3H) 7.03-7.45 (m, 3H).
35%	Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.666667 h; Stage #2: With Trimethyl borate In tetrahydrofuran; hexane at -78 - 20℃; for 18 h; Stage #3: With hydrogenchloride; water In tetrahydrofuran; hexane	To a solution of 69A (2.7 g, 13.1 mmol) in THF (25 mL) at -78° C. was added n-BuLi (1.6 M in hexanes, 11.0 mL, 17.7 mmol). The mixture was stirred at -78° C. for 40 min before trimethyl borate (2.7 mL, 24.3 mmol) was added. The reaction was left stirring from -78° C. to rt over 18 h. It was quenched with 1.0 N HCl (40 mL), extracted with EtOAc, washed with brine and dried over Na₂SO₄. After evaporation of the solvent, the crude solid product was triturated with EtOAc/hexanes (1:4). After filtration, 69B (0.75 g, 35percent yield) was collected as a white solid. ¹H NMR (400 MHz, Methanol-d₄) δ ppm 3.86 (s, 3 H) 7.03-7.45 (m, 3 H).

Reference： [1] Patent: US2010/227894, 2010, A1, . Location in patent: Page/Page column 28
[2] Patent: US2007/3539, 2007, A1, . Location in patent: Page/Page column 71

3
[ 112204-58-7 ]
[ 74-88-4 ]
[ 103291-07-2 ]

Yield	Reaction Conditions	Operation in experiment
100%	With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 65 h;	Reference Example-13 Potassium carbonate (18.8 g, 136 mmol) and methyl iodide (19.3 g, 136 mmol) were added to a solution of 5-bromo-2-fluorophenol (13.0 g, 68.1 mmol) in DMF (120 mL), followed by stirring at room temperature for 65 hours. After the reaction was completed, water (150 mL) was added to the reaction solution, and the resultant product was extracted with ethyl acetate (100 mL1, 50 mL2). The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure, whereby a pale yellow oily crude product (29.0 g) was obtained. This was purified by silica gel column chromatography (hexane:ethyl acetate=10:1), whereby 5-bromo-2-fluoroanisole (14.2 g, yield: quantitative) was obtained as a colorless oily material. ¹H-NMR (400 MHz, CDCl₃): δ3.88 (s, 3H), 6.95 (dd, J=8.6 and 10.8 Hz, 1H), 7.02 (ddd, J=2.2, 4.2 and 8.6 Hz, 1H), 7.08 (dd, J=2.2 and 7.6 Hz, 1H). ¹⁹F-NMR (376 MHz, CDCl₃): δ-137 (s, 1F).
77%	With potassium carbonate In N,N-dimethyl-formamide at 20 - 40℃; for 2 h;	100204] To a solution of 23 A (3.3 g, 17.3 mmol) and K₂CO₃ (4.78 g, 34.6 mmol) in DMF (20 mL) was added methyl iodide (1.46 niL, 23.4 mmol) at rt. The mixture was heated at 40⁰C for 2.0 h. After cooling to rt, it was diluted with diethyl ether, washed with water and brine, dried over MgS O4. The crude residue was purified by flash column chromatography (EtOAc:hexanes = 1 : 6) to give 2.74 g(77percent) of 23B as a viscous oil. ¹H NMR (400 MHz, CDCl₃) δ ppm 3.89 (s, 3 H), 6.95 - 7.00 (m, 3 H).
77%	With potassium carbonate In N,N-dimethyl-formamide at 20 - 40℃;	To a solution of 7A (3.3 g, 17.3 mmol) and K₂CO₃(4.78 g, 34.6 mmol) in DMF (20 mL) was added methyl iodide (1.46 mL, 23.4 mmol) at rt. The mixture was heated at 40° C. for 2.0 h. After cooling to rt, it was diluted with diethyl ether, washed with water and brine, dried over MgSO₄. The crude residue was purified by flash column chromatography (EtOAc:hexanes=1:6) to give 2.74 g (77percent) of 7B as a viscous oil. ¹H NMR (400 MHz, CDCl₃) δ ppm 3.89 (s, 3H), 6.95-7.00 (m, 3H).

77%

With potassium carbonate In N,N-dimethyl-formamide at 40℃; for 2 h;

To a solution of 64A (3.3 g, 17.3 mmol) and K₂CO₃(4.78 g, 34.6 mmol) in DMF (20 mL) was added methyl iodide (1.46 mL, 23.4 mmol) at rt. The mixture was heated at 40° C. for 2.0 h. After cooled to rt, it-was diluted with ether, washed with water and brine, dried over MgSO₄. The crude residue was purified by flash column chromatography (EtOAc:hexanes=1:6) to give 2.74 g (77percent) of 69A as viscous oil. ¹H NMR (400 MHz, CDCl₃) δ ppm 3.89 (s, 3 H), 6.95-7.00 (m, 3 H).

Reference： [1] Patent: US2016/24110, 2016, A1, . Location in patent: Paragraph 0452; 0453
[2] Patent: WO2006/76246, 2006, A2, . Location in patent: Page/Page column 87
[3] Patent: US2010/227894, 2010, A1, . Location in patent: Page/Page column 28
[4] Patent: US2007/3539, 2007, A1, . Location in patent: Page/Page column 71

4
[ 64465-53-8 ]
[ 103291-07-2 ]

Yield	Reaction Conditions	Operation in experiment
70%	Stage #1: With hydrogen bromide; sodium nitrite In water at 0 - 5℃; for 0.25 h; Stage #2: With hydrogen bromide; copper(I) bromide In water at 20 - 75℃; for 16 h;	Aqueous hydrobromic acid (48percent, 2.41 mL) was added to 4-fluoro-3-methoxyaniline (1.0 g, 7.1 mmol) in water (10 mL) and the resulting mixture was cooled to 0 °C in an ice bath. A solution of sodium nitrite (538 mg, 7.8 mmol) in water (5 mL) was added dropwise during 15 min while maintaining the temperature between 0-5 ⁰C. The resulting diazoniumsalt solution was added to a suspension of copper(I) bromide (1.12 g, 7.8 mmol) in water (5 mL) which had been pre-heated to 75 °C. The mixture was shaken thoroughly, aqueous hydrobromic acid (48percent, 12.07 mL) was added and the solution was stirred at ambient temperature for 16 h. Excess water was added and the product was extracted with diethyl ether and the combined organic extracts were washed with aqueous saturated sodium chloride, dried over magnesium sulfate, filtered and the solvent was evaporated in vacuo to give 1.02 g (70percent yield) of the title compound.: ¹H-NMR (DMSO-J₆): δ 7.36 (dd, J= 7.78, 2.26 Hz, 1 H), 7.23-7.17 (m, 1 H), 7.14-7.09 (m, 1 H), 3.86 (s, 3 H); MS (EI) (m/z, percent) 204,206 (100), 189,191 (23), 161,163 (45)

Reference： [1] Patent: WO2007/58602, 2007, A2, . Location in patent: Page/Page column 141
[2] Patent: US4593037, 1986, A,
[3] Patent: WO2007/145568, 2007, A1,
[4] Patent: WO2007/145569, 2007, A1,

5
[ 77-78-1 ]
[ 112204-58-7 ]
[ 103291-07-2 ]

Reference： [1] Angewandte Chemie - International Edition, 2018, vol. 57, # 9, p. 2450 - 2454[2] Angew. Chem., 2018, vol. 130, # 9, p. 2475 - 2479,5

[ 103291-07-2 ] Synthesis Path-Downstream 1~88

1
Br^(1-)*C₇H₆FN₂O⁽¹⁺⁾ [ No CAS ]
[ 103291-07-2 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogen bromide; copper(I) bromide; In water; at 20 - 75℃; for 16h;	Aqueous hydrobromic acid (48%, 2.41 mL) was added to 4-fluoro-3-methoxyaniline (1.0 g, 7.1 mmol) in water (10 mL) and the resulting mixture was cooled to 0 C. in an ice bath. A solution of sodium nitrite (538 mg, 7.8 mmol) in water (5 mL) was added drop wise during 15 min while maintaining the temperature between 0 and 5 C. The resulting diazoniumsalt solution was added to a suspension of copper(I) bromide (1.12 g, 7.8 mmol) in water (5 mL) which had been pre-heated to 75 C. The mixture was shaken thoroughly, aqueous hydrobromic acid (48%, 12.07 mL) was added and the solution was stirred at ambient temperature for 16 h. Excess water was added and the product was extracted with diethyl ether and the combined organic extracts were washed with aqueous saturated sodium chloride, dried over magnesium sulfate, filtered and the solvent was evaporated in vacuo to give 1.02 g (70% yield) of the title compound: 1H-NMR (DMSO-d6): delta 7.36 (dd, J=7.78, 2.26 Hz, 1H), 7.23-7.17 (m, 1H), 7.14-7.09 (m, 1H), 3.86 (s, 3H); MS (EI) m/z 204, 206 [M+].
		Example 1; 4-Bromo- 1 -fluoro-2-methoxybenzene; Aqueous hydrobromic acid (48%, 2.41 mL) was added to 4-fluoro-3-methoxyaniline (1.0 g, 7.1 mmol) in water (10 mL) and the resulting mixture was cooled to 0 0C in an ice bath. A solution of sodium nitrite (538 mg, 7.8 mmol) in water (5 mL) was added drop wise during 15 min while maintaining the temperature between 0-5 0C. The resulting diazoniumsalt solution was added to a suspension of copper (I) bromide (1.12 g, 7.8 mmol) in water (5 mL) which had been pre-heated to 75 C. The mixture was shaken thoroughly, aqueous hydrobromic acid (48%, 12.07 mL) was added and the solution was stirred at ambient temperature for 16 h. Excess water was added and the product was extracted with <n="48"/>diethyl ether and the combined organic extracts were washed with aqueous saturated sodium chloride, dried over magnesium sulfate, filtered and the solvent was evaporated in vacuo to give 1.02 g (70% yield) of the title compound: 1H-NMR (DMSO-afo): delta 7.36 (dd, J = 7.78, 2.26 Hz, 1 H), 7.23 - 7.17 (m, 1 H), 7.14 - 7.09 (m, 1 H), 3.86 (s, 3 H); MS (EI) m/z 204, 206 [M+«]
		Example 1; 4-Bromo- 1 -fluoro-2-methoxvbenzeneF; Aqueous hydrobromic acid (48%, 2.41 mL) was added to 4-fluoro-3-methoxyaniline (1.0 g, 7.1 mmol) in water (10 mL) and the resulting mixture was cooled to 0 0C in an ice bath. A solution of sodium nitrite (538 mg, 7.8 mmol) in water (5 mL) was added dropwise during 15 min while maintaining the temperature between 0 - 5 0C. The resulting diazoniumsalt solution was added to a suspension of copper(I) bromide (1.12 g, 7.8 mmol) in water (5 mL) which had been pre-heated to 75 0C. The mixture was shaken thoroughly, aqueous hydrobromic acid (48%, 12.07 mL) was added and the solution was stirred at ambient temperature for 16 h. Excess water was added and the product was extracted with diethyl ether and the combined organic extracts were washed with aqueous saturated sodium chloride, dried over magnesium sulfate, filtered and the solvent was evaporated in vacuo to give 1.02 g (70% yield) of the title compound: 1H-NMR (DMSO-d«j): delta 7.36 (dd, J = 7.78, 2.26 Hz, 1 H), 7.23 - 7.17 (m, 1 H), 7.14 - 7.09 (m, 1 H), 3.86 (s, 3 H); MS (EI) 0 >«/z 204, 206 [M+»].

Reference： [1]Patent: US2007/299087,2007,A1 .Location in patent: Page/Page column 15
[2]Patent: WO2007/145568,2007,A1 .Location in patent: Page/Page column 46-47
[3]Patent: WO2007/145569,2007,A1 .Location in patent: Page/Page column 45

2
[ 73183-34-3 ]
[ 103291-07-2 ]
2-(4-fluoro-3-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%		A mixture OF 4-BROMO-1-FLUORO-2-METHOXYBENZENE (5.0 g, 24.4 mmol), potassium acetate (4.79 g, 48.8 mmol), bis (pinacolato) diboron (7.12 g, 28.0 mmol) and dichloro [1, 1'-BIS (diphenylphosphino) ferrocene] palladium (II) dichloromethane adduct (1.00 g, 1.22 mmol) in 1, 4-dioxan (50 ML) containing 4. 5 ml of dimethylsulphoxide was degassed with nitrogen for 45 min and then heated at 90C for 16 h. The reaction was allowed to cool to ambient temperature and the solid removed from the reaction by filtration. The filtration cake was washed with diethyl ether (100 ML) AND then the filtrates were combined and concentrated in vacuo. The residue was stirred with 2N sodium hydroxide solution (500 ml) for 45 min and the solid removed by filtration. The aqueous component was cooled (0C) and treated with 36% hydrochloric acid in a dropwise manner to pH 5 over a 15 min period. The precipitate was allowed to stand at 0C for 2 h and then filtered. The resulting solid was washed with ice-cold water (100 ml) and dried at 40C under high vacuum to give the title compound (5.52 g, 90%): ON (400 MHz, CDC13) 1.34 (12H, s), 3.92 (3H, s), 7.03-7. 09 (1H, M), 7.37- 7.39 (2H, M).
	With potassium acetate; tricyclohexylphosphine;tris-(dibenzylideneacetone)dipalladium(0); In 1,2-dimethoxyethane; at 150℃; for 1h;Microwave;	Anhydrous 1,2-dimethoxyethane (12 mL) was added to 4-bromo-l-fluoro-2- methoxybenzene (1.02 g, 5.0 mmol), tris(dibenzylideneaceton)dipalladium (0) (228 mg, 0.25 mmol), tricyclohexylphosphine (209 mg, 0.75 mmol), potassium acetate (732 mg, 7.5 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-l,3,2-dioxaborolane (1.14 g, 4.5 mmol), and the mixture was irradiated under an atmosphere of argon in a microwave at 150 0C for 1 h. When cooled to ambient temperature the mixture was filtered and the solvent was evaporated in vacuo to give the title compound as an oil: MS (EI) (m/z, %) 252 (81), 237 (44), 166 (78), 152 (100)
	With potassium acetate;tris-(dibenzylideneacetone)dipalladium(0); tricyclohexylphosphine; In 1,2-dimethoxyethane; at 150℃; for 1h;	Anhydrous 1,2-dimethoxyethane (12 mL) was added to <strong>[103291-07-2]4-bromo-1-fluoro-2-methoxybenzene</strong> (1.02 g, 5.0 mmol), tris(dibenzylideneaceton)dipalladium (0) (228 mg, 0.25 mmol), tricyclohexylphosphine (209 mg, 0.75 mmol), potassium acetate (732 mg, 7.5 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane (1.14 g, 4.5 mmol) and the resulting mixture was irradiated in a microwave at 150 C. for 1 h. When cooled to ambient temperature the mixture was filtered and the solvent was evaporated in vacuo to give the crude product: MS (EI) m/z 252 [M+].

	With potassium acetate;tris-(dibenzylideneacetone)dipalladium(0); tricyclohexylphosphine; In 1,2-dimethoxyethane; at 150℃; for 1h;Microwave irradiation;	Example 2 2-(4-Fluoro-3-methoxyphenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane; Anhydrous 1,2-dimethoxy ethane (12 mL) was added to 4-bromo-l-fiuoro-2- methoxybenzene (1.02 g, 5.0 mmol), tris(dibenzylideneaceton)dipalladium (0) (228 mg, 0.25 mmol), tricyclohexylphosphine (209 mg, 0.75 mmol), potassium acetate (732 mg, 7.5 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-l,3,2-dioxaborolane (1.14 g, 4.5 mmol) and the resulting mixture was irradiated in a microwave at 150 C for 1 h. When cooled to ambient temperature the mixture was filtered and the solvent was evaporated in vacuo to give the crude product: MS (EI) m/z 252 [M+»]
	With potassium acetate;tris-(dibenzylideneacetone)dipalladium(0); tricyclohexylphosphine; In 1,2-dimethoxyethane; at 150℃; for 1h;Microwave irradiation;	Example 2; 2-(4-Fluoro-3-methoxvphenvlV4,4,5.5-tetramethvl-1.3,2-dioxaborolane; <n="47"/>Anhydrous 1,2-dimethoxy ethane (12 mL) was added to 4-bromo-l-fluoro-2- methoxybenzene (1.02 g, 5.0 mmol), tris(dibenzylideneaceton)dipalladium (0) (228 mg, 0.25 mmol), tricyclohexylphosphine (209 mg, 0.75 mmol), potassium acetate (732 mg, 7.5 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-l,3,2-dioxaborolane (1.14 g, 4.5 mmol) and 5 the resulting mixture was irradiated in a microwave at 150 C for 1 h. When cooled to ambient temperature the mixture was filtered and the solvent was evaporated in vacuo to give the crude product: MS (EI) m/z 252 [M+*].

Reference： [1]Patent: WO2004/43930,2004,A1 .Location in patent: Page 27-28
[2]Patent: WO2007/58602,2007,A2 .Location in patent: Page/Page column 142
[3]Patent: US2007/299087,2007,A1 .Location in patent: Page/Page column 15
[4]Patent: WO2007/145568,2007,A1 .Location in patent: Page/Page column 47
[5]Patent: WO2007/145569,2007,A1 .Location in patent: Page/Page column 45-46

3
[ 103291-07-2 ]
[ 112204-58-7 ]

Yield	Reaction Conditions	Operation in experiment
86%	With boron tribromide; In dichloromethane; at 20℃;	To a stirred solution OF 4-BROMO-1-FLUORO-2-METHOXYBENZENE (1.00 g, 4.88 mmol) in anhydrous CH2CL2 (20 ml) was added dropwise in an ice bath BBR3 (1 M solution in CH2Cl2, 9.75 ml, 9. 75 mmol), and the mixture was stirred at room temperature overnight. The reaction was cooled in an ice bath and quenched by adding MEOH (1.0 ml) dropwise. The solvent was evaporated and the residue purified by flash chromatography eluting with ISOHEXANE/CH2CL2/MEOH (70: 20: 10) to leave 0.802 g (86%) of the title compound: BH (400 MHz, CDCL3) 5.24 (1 H, s), 6.96 (2 H, m), 7.16 (1 H, DD, J7. 7,2. 0 HZ).

Reference： [1]Patent: WO2004/65388,2004,A1 .Location in patent: Page 47

4
[ 112204-58-7 ]
[ 74-88-4 ]
[ 103291-07-2 ]

Yield	Reaction Conditions	Operation in experiment
100%	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 65h;	Reference Example-13 Potassium carbonate (18.8 g, 136 mmol) and methyl iodide (19.3 g, 136 mmol) were added to a solution of 5-bromo-2-fluorophenol (13.0 g, 68.1 mmol) in DMF (120 mL), followed by stirring at room temperature for 65 hours. After the reaction was completed, water (150 mL) was added to the reaction solution, and the resultant product was extracted with ethyl acetate (100 mL1, 50 mL2). The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure, whereby a pale yellow oily crude product (29.0 g) was obtained. This was purified by silica gel column chromatography (hexane:ethyl acetate=10:1), whereby 5-bromo-2-fluoroanisole (14.2 g, yield: quantitative) was obtained as a colorless oily material. 1H-NMR (400 MHz, CDCl3): delta3.88 (s, 3H), 6.95 (dd, J=8.6 and 10.8 Hz, 1H), 7.02 (ddd, J=2.2, 4.2 and 8.6 Hz, 1H), 7.08 (dd, J=2.2 and 7.6 Hz, 1H). 19F-NMR (376 MHz, CDCl3): delta-137 (s, 1F).
77%	With potassium carbonate; In N,N-dimethyl-formamide; at 20 - 40℃; for 2h;	100204] To a solution of 23 A (3.3 g, 17.3 mmol) and K2CO3 (4.78 g, 34.6 mmol) in DMF (20 mL) was added methyl iodide (1.46 niL, 23.4 mmol) at rt. The mixture was heated at 400C for 2.0 h. After cooling to rt, it was diluted with diethyl ether, washed with water and brine, dried over MgS O4. The crude residue was purified by flash column chromatography (EtOAc:hexanes = 1 : 6) to give 2.74 g(77%) of 23B as a viscous oil. 1H NMR (400 MHz, CDCl3) delta ppm 3.89 (s, 3 H), 6.95 - 7.00 (m, 3 H).
77%	With potassium carbonate; In N,N-dimethyl-formamide; at 20 - 40℃;	To a solution of 7A (3.3 g, 17.3 mmol) and K2CO3 (4.78 g, 34.6 mmol) in DMF (20 mL) was added methyl iodide (1.46 mL, 23.4 mmol) at rt. The mixture was heated at 40 C. for 2.0 h. After cooling to rt, it was diluted with diethyl ether, washed with water and brine, dried over MgSO4. The crude residue was purified by flash column chromatography (EtOAc:hexanes=1:6) to give 2.74 g (77%) of 7B as a viscous oil. 1H NMR (400 MHz, CDCl3) delta ppm 3.89 (s, 3H), 6.95-7.00 (m, 3H).

77%

With potassium carbonate; In N,N-dimethyl-formamide; at 40℃; for 2h;

To a solution of 64A (3.3 g, 17.3 mmol) and K2CO3 (4.78 g, 34.6 mmol) in DMF (20 mL) was added methyl iodide (1.46 mL, 23.4 mmol) at rt. The mixture was heated at 40 C. for 2.0 h. After cooled to rt, it-was diluted with ether, washed with water and brine, dried over MgSO4. The crude residue was purified by flash column chromatography (EtOAc:hexanes=1:6) to give 2.74 g (77%) of 69A as viscous oil. 1H NMR (400 MHz, CDCl3) delta ppm 3.89 (s, 3 H), 6.95-7.00 (m, 3 H).

Reference： [1]Patent: US2016/24110,2016,A1 .Location in patent: Paragraph 0452; 0453
[2]Patent: WO2006/76246,2006,A2 .Location in patent: Page/Page column 87
[3]Patent: US2010/227894,2010,A1 .Location in patent: Page/Page column 28
[4]Patent: US2007/3539,2007,A1 .Location in patent: Page/Page column 71

5
[ 626-55-1 ]
(4-fluoro-3-methoxyphenyl)magnesium bromide [ No CAS ]
[ 103291-07-2 ]
3-(4-fluoro-3-methoxyphenyl)pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
12.3 g (79%)	With hydrogenchloride; potassium carbonate;tetrakis(triphenylphosphine)palladium (0); In tetrahydrofuran; water;	PREPARATION 12 3-(4-Fluoro-3-methoxyphenyl)pyridine A solution of 15.6 g (76.1 mmole) of <strong>[103291-07-2]1-bromo-4-fluoro-3-methoxybenzene</strong> in 67 ml of tetrahydrofuran was added dropwise, with stirring, under nitrogen, to 1.92 g (79.1 mmole) of dried magnesium turnings. Stirring was continued for 1 hour and then the supernatant liquid was removed to give a solution of 4-fluoro-3-methoxyphenylmagnesium bromide. In a separate flask, 7.3 ml (76.1 mmole) of 3-bromopyridine was dissolved in 23 ml of tetrahydrofuran and 880 mg (0.76 mmole) of tetrakis-triphenylphosphine palladium was added. This latter mixture was heated to reflux, and the above Grignard solution was added dropwise, during 10 minutes, with stirring. The resulting mixture was refluxed for 1 hour and then it was stirred overnight at room temperature. The reaction mixture was diluted with 100 ml of water, followed by 100 ml of 10% hydrochloric acid, and the resulting solution was washed with dichloromethane. The aqueous phase was basified with sodium bicarbonate and then it was extracted with dichloromethane. The combined extracts were dried using potassium carbonate and evaporated in vacuo to give 12.3 g (79%) of the title compound as a reddish oil.

Reference： [1]Patent: US4593037,1986,A

6
[ 64465-53-8 ]
[ 103291-07-2 ]

Yield	Reaction Conditions	Operation in experiment
70%		Aqueous hydrobromic acid (48%, 2.41 mL) was added to 4-fluoro-3-methoxyaniline (1.0 g, 7.1 mmol) in water (10 mL) and the resulting mixture was cooled to 0 C in an ice bath. A solution of sodium nitrite (538 mg, 7.8 mmol) in water (5 mL) was added dropwise during 15 min while maintaining the temperature between 0-5 0C. The resulting diazoniumsalt solution was added to a suspension of copper(I) bromide (1.12 g, 7.8 mmol) in water (5 mL) which had been pre-heated to 75 C. The mixture was shaken thoroughly, aqueous hydrobromic acid (48%, 12.07 mL) was added and the solution was stirred at ambient temperature for 16 h. Excess water was added and the product was extracted with diethyl ether and the combined organic extracts were washed with aqueous saturated sodium chloride, dried over magnesium sulfate, filtered and the solvent was evaporated in vacuo to give 1.02 g (70% yield) of the title compound.: 1H-NMR (DMSO-J6): delta 7.36 (dd, J= 7.78, 2.26 Hz, 1 H), 7.23-7.17 (m, 1 H), 7.14-7.09 (m, 1 H), 3.86 (s, 3 H); MS (EI) (m/z, %) 204,206 (100), 189,191 (23), 161,163 (45)
	With hydrogen bromide; copper(I) bromide; sodium nitrite; In water;	PREPARATION 13 1-Bromo-4-fluoro-3-methoxybenzene To a stirred suspension of 20.8 g (0.147 mole) of 4-fluoro-3-methoxyaniline (Mulvey et al., Tetrahedron Letters, 16, 1419 [1978]) in 200 ml of water was added 50.2 ml of 48% hydrobromic acid. The resulting mixture was cooled to 0 C., and a solution of 11.2 g (0.162 mole) of sodium nitrite in 100 ml of water was added dropwise during 1 hour, with stirring, maintaining the temperature between 0 and 5 C. The solution of the diazonium salt thus obtained was then added to a suspension of 23.2 g (0.162 mole) of cuprous bromide in 100 ml of water which had been preheated to 75 C. The mixture was shaken thoroughly and then 251 ml of 48% hydrobromic acid was added. The resulting mixture was stirred overnight at room temperature and then it was diluted with an excess of water. The product was extracted into diethyl ether, and the extract was washed with saturated sodium chloride solution and dried (MgSO4). Evaporation of the dried ethereal solution in vacuo afforded a black liquid, which was distilled under reduced pressure. This afforded 23 g of the title compound as a yellow liquid, b.p. 82-85 C. (8 mm of Hg).

Reference： [1]Patent: WO2007/58602,2007,A2 .Location in patent: Page/Page column 141
[2]Patent: US4593037,1986,A
[3]Patent: WO2007/145568,2007,A1
[4]Patent: WO2007/145569,2007,A1

7
[ 103291-07-2 ]
[ 854778-31-7 ]

Yield	Reaction Conditions	Operation in experiment
35%		To a solution of 7B (2.7 g, 13.1 mmol) in THF (25 mL) at -78 C. was added n-BuLi (1.6 M in hexanes, 11.0 mL, 17.7 mmol). The mixture was stirred at -78 C. for 40 min before trimethyl borate (2.7 mL, 24.3 mmol) was added. The reaction was left stirring from -78 C. to rt over 18 h. It was quenched with 1.0 N HCl (40 mL), extracted with EtOAc, washed with brine and dried over Na2SO4. After evaporation of the solvent, the crude solid product was triturated with EtOAc/hexanes (1:4). After filtration, 7C (0.75 g, 35% yield) was collected as a white solid. 1H NMR (400 MHz, Methanol-d4) delta ppm 3.86 (s, 3H) 7.03-7.45 (m, 3H).
35%		To a solution of 69A (2.7 g, 13.1 mmol) in THF (25 mL) at -78 C. was added n-BuLi (1.6 M in hexanes, 11.0 mL, 17.7 mmol). The mixture was stirred at -78 C. for 40 min before trimethyl borate (2.7 mL, 24.3 mmol) was added. The reaction was left stirring from -78 C. to rt over 18 h. It was quenched with 1.0 N HCl (40 mL), extracted with EtOAc, washed with brine and dried over Na2SO4. After evaporation of the solvent, the crude solid product was triturated with EtOAc/hexanes (1:4). After filtration, 69B (0.75 g, 35% yield) was collected as a white solid. 1H NMR (400 MHz, Methanol-d4) delta ppm 3.86 (s, 3 H) 7.03-7.45 (m, 3 H).

Reference： [1]Patent: US2010/227894,2010,A1 .Location in patent: Page/Page column 28
[2]Patent: US2007/3539,2007,A1 .Location in patent: Page/Page column 71

8
[ 14394-70-8 ]
[ 103291-07-2 ]
[ 936092-73-8 ]

Yield	Reaction Conditions	Operation in experiment
14%	With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; for 5h;Heating / reflux;	[0413] A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (1.2 g, 8.1 mmol), 4-bromo- l-fluoro-2-methoxy-benzene (1.8 g, 8.9 mmol), Pd2(dba)3 (0.74 g, 0.81 mmol), Xaniphos (0.93 g, 1.6 mmol) and cesium carbonate (7.88 g, 24.2 mmol) were suspended in dioxane (60 mL) and heated at reflux under the argon atmosphere for 5 h. The reaction mixture was cooled to room temperature and diluted with DCM (30 mL). The mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by flash chromatography on silica gel to afford the title compound (0.3 g, 14%) as a beige solid.

Reference： [1]Patent: WO2007/53452,2007,A1 .Location in patent: Page/Page column 196

9
[ 141699-55-0 ]
[ 103291-07-2 ]
[ 1035219-86-3 ]

Yield	Reaction Conditions	Operation in experiment
46%		Add sodium hydride (2.77 g, 60% w/w, 69.2 mmol) to a solution of 3-hydroxy- azetidine-1-carboxylic acid tert-butyl ester (10.9 g, 62.9 mmol) in dimethyl sulfoxide (100 mL). Stir the mixture for 30 min and then add 3-bromo-6-fluoroanisole (15.5 g, 75.5 mmol). Heat the mixture to 65 0C overnight. Cool the mixture to room temperature and then dilute the solution with saturated ammonium chloride and brine and extract with ethyl acetate. Wash the organics five times with brine, then dry over sodium sulfate and filter. Concentrate and purify via silica gel chromatography using a 0-45% gradient of ethyl acetate/hexane to give 10.4 g (46%) of the title compound as a clear oil.

Reference： [1]Patent: WO2008/76562,2008,A1 .Location in patent: Page/Page column 50

10
[ 1227162-95-9 ]
[ 103291-07-2 ]
[ 1227163-14-5 ]

Yield	Reaction Conditions	Operation in experiment
93%		Example 41i 1-(3-Bromophenyl)-4-fluoro-1-(4-fluoro-3-methoxyphenyl)-1H-isoindol-3-amine tert-Butyllithium (3.68 mL, 5.89 mmol) was added dropwise to THF (10 mL) at -100 C. under an argon atmosphere. A solution of <strong>[103291-07-2]4-bromo-1-fluoro-2-methoxybenzene</strong> (0.604 g, 2.95 mmol) in THF (5 ml) was added dropwise followed by the addition of (E)-N-((3-bromophenyl)(2-cyano-3-fluorophenyl)methylene)-2-methylpropane-2-sulfinamide (1 g, 2.46 mmol) in THF (5 ml). The resulting reaction mixture was left on the thawing cooling bath for 30 min then the cooling bath was removed and the mixture was stirred at r.t. for 1 h. Hydrogen chloride-methanol solution (11.78 mL, 14.73 mmol) was added and the resulting mixture was stirred at r.t. for 1 h. The mixture was concentrated and purified on a silica gel column eluding with 0-10% 0.1 M NH3 in MeOH in DCM to afford 0.98 g (93%) of the title compound. MS (ES+) m/z 429, 431 (M+H)+

Reference： [1]Patent: US2010/125082,2010,A1 .Location in patent: Page/Page column 27; 28

11
[ 31469-15-5 ]
[ 103291-07-2 ]
[ 1239963-89-3 ]

Yield	Reaction Conditions	Operation in experiment
	With zinc(II) fluoride; tri-tert-butyl phosphine;bis(dibenzylideneacetone)-palladium(0); In N,N-dimethyl-formamide; at 80 - 90℃; for 5h;Inert atmosphere;	To a solution <strong>[103291-07-2]5-bromo-2-fluoroanisole</strong> (109 g, 0.54 mol), ZnF2 (2.52 g, 24.39 mmol), Pd(dba)2 (3.08 g, 5.35 mmol), and PT^ (5.2 mL of a 50% solution in toluene, 11 mmol) in DMF (1 L) was added trimethylsilyl methyl ketene acetal (121 g, 0.7 mol). The reaction mixture was stirred at 80-90 C for 5 h under nitrogen atmosphere and then was allowed to cool to room temperature and diluted with EtOAc. The reaction mixture was filtered through Celite. The filtrate was washed with H20 (2 L) and the aqueous layer was extracted with EtOAc (2.5 L). The combined extracts were washed with brine (2 L x 2), dried over MgSC^, and concentrated at reduced pressure to give methyl 2-(4-fluoro-3- methoxyphenyl)-2-methylpropanoate (151 g), which was used for the next step without further purification. 1H NMR (400MHz, CDC13): delta 7.04-6.98 (m, 1H), 6.95-6.92 (dd, 1H), 6.88-6.85 (m, 1H), 3.89 (s, 3H), 3.67 (s, 3H), 1.57 (s, 6H).
	With zinc(II) fluoride;tri-tert-butyl phosphine; bis(dibenzylideneacetone)-palladium(0); In N,N-dimethyl-formamide; toluene; at 80 - 90℃; for 5h;Inert atmosphere;	To a solution <strong>[103291-07-2]5-bromo-2-fluoroanisole</strong> (109 g, 0.54 mol), ZnF2 (2.52 g, 24.39 mmol), Pd(dba)2 (3.08 g, 5.35 mmol), and P^Bu3 (5.2 mL of a 50% solution in toluene, 11 mmol) in DMF (1 L) was added trimethylsilyl methyl ketene acetal (121 g, 0.7 mol). The reaction mixture was stirred at 80-90 0C for 5 h under nitrogen atmosphere and then was allowed to cool to room temperature and diluted with EtOAc. The reaction mixture was filtered through Celite. The filtrate was washed with H2O (2 L) and the aqueous layer was extracted with EtOAc (2.5 L). The combined extracts were washed with brine (2 L x 2), dried over MgSO4, and concentrated at reduced pressure to give methyl 2-(4-fluoro-3- methoxyphenyl)-2-methylpropanoate (151 g), which was used for the next step without further purification. 1U NMR (400MHz, CDCl3): delta 7.04-6.98 (m, IH), 6.95-6.92 (dd, IH), 6.88-6.85 (m, IH), 3.89 (s, 3H), 3.67 (s, 3H), 1.57 (s, 6H).

Reference： [1]Patent: WO2011/71565,2011,A1 .Location in patent: Page/Page column 152
[2]Patent: WO2010/93845,2010,A1 .Location in patent: Page/Page column 141

12
[ 103291-07-2 ]
[ 1239963-90-6 ]

Reference： [1]Patent: WO2011/71565,2011,A1
[2]Patent: WO2010/93845,2010,A1

13
[ 103291-07-2 ]
[ 1239963-91-7 ]

Reference： [1]Patent: WO2011/71565,2011,A1
[2]Patent: WO2010/93845,2010,A1

14
[ 103291-07-2 ]
[ 1239963-92-8 ]

Reference： [1]Patent: WO2011/71565,2011,A1
[2]Patent: WO2010/93845,2010,A1

15
[ 103291-07-2 ]
[ 1239963-93-9 ]

Reference： [1]Patent: WO2011/71565,2011,A1
[2]Patent: WO2010/93845,2010,A1

16
[ 103291-07-2 ]
[ 1239963-94-0 ]

Reference： [1]Patent: WO2011/71565,2011,A1
[2]Patent: WO2010/93845,2010,A1

17
[ 103291-07-2 ]
[ 1239963-95-1 ]

Reference： [1]Patent: WO2011/71565,2011,A1
[2]Patent: WO2010/93845,2010,A1

18
[ 103291-07-2 ]
[ 1239963-96-2 ]

Reference： [1]Patent: WO2011/71565,2011,A1
[2]Patent: WO2010/93845,2010,A1

19
[ 103291-07-2 ]
[ 1239963-97-3 ]

Reference： [1]Patent: WO2011/71565,2011,A1
[2]Patent: WO2010/93845,2010,A1

20
[ 31181-90-5 ]
[ 103291-07-2 ]
[ 1357563-99-5 ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of <strong>[103291-07-2]5-bromo-2-fluoroanisole</strong> (1.00 g, 4.88 mmol, 1 equiv) in anhydrous THF was added granules of magnesium (125 mg, 5.12 mmol, 1.05 equiv) under nitrogen. The mixture was heated to 60 C for 2 h. After cooling to room temperature, 5-bromo-2-formylpyridine (1.09 g, 5.86 mmol, 1.2 equiv) was added and the reaction mixture was stirred at 80 C overnight. The reaction was cooled to room temperature, quenched with brine and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated to dryness under vacuum. The product was used in the next step without further purification. C13H11BrFNO2; MW 312.

Reference： [1]Journal of Medicinal Chemistry,2016,vol. 59,p. 10719 - 10737
[2]European Journal of Medicinal Chemistry,2012,vol. 47,p. 1 - 17

21
[ 34160-40-2 ]
[ 103291-07-2 ]
[ 1357564-25-0 ]