[ CAS No. 367-83-9 ] {[proInfo.proName]}

Name: 367-83-9|2-Fluoro-5-methoxybenzoic acid|98%
Brand: Ambeed
SKU: A277334
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2D 3D

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Quality Control of [ 367-83-9 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 367-83-9 ]

SDS Specification

Alternatived Products of [ 367-83-9 ]

Product Details of [ 367-83-9 ]

CAS No. :	367-83-9	MDL No. :	MFCD00272566
Formula :	C₈H₇FO₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	REDSLTKMNCCQBC-UHFFFAOYSA-N
M.W :	170.14	Pubchem ID :	2774543
Synonyms :

Calculated chemistry of [ 367-83-9 ]

Physicochemical Properties

Num. heavy atoms :	12
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.12
Num. rotatable bonds :	2
Num. H-bond acceptors :	4.0
Num. H-bond donors :	1.0
Molar Refractivity :	39.85
TPSA :	46.53 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.96 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.64
Log Po/w (XLOGP3) :	1.94
Log Po/w (WLOGP) :	1.95
Log Po/w (MLOGP) :	1.75
Log Po/w (SILICOS-IT) :	1.64
Consensus Log Po/w :	1.78

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.56

Water Solubility

Log S (ESOL) :	-2.36
Solubility :	0.751 mg/ml ; 0.00442 mol/l
Class :	Soluble
Log S (Ali) :	-2.54
Solubility :	0.489 mg/ml ; 0.00287 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.17
Solubility :	1.14 mg/ml ; 0.00673 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.48

Safety of [ 367-83-9 ]

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

Application In Synthesis of [ 367-83-9 ]

* 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.

Upstream synthesis route of [ 367-83-9 ]
Downstream synthetic route of [ 367-83-9 ]

[ 367-83-9 ] Synthesis Path-Upstream 1~6

1
[ 7758-19-2 ]
[ 5329-14-6 ]
[ 105728-90-3 ]
[ 1882-69-5 ]
[ 367-83-9 ]

Reference： [1] Patent: US5519133, 1996, A,

2
[ 459-60-9 ]
[ 124-38-9 ]
[ 367-83-9 ]

Yield	Reaction Conditions	Operation in experiment
80%	Stage #1: With N,N,N',N'',N'''-pentamethyldiethylenetriamine; sec.-butyllithium In tetrahydrofuran at -60℃; for 3 h; Inert atmosphere Stage #2: for 1 h;	To a solution of 1 -fluoro-4-methoxy-benzene (5 g, 39.6 mmol, 1.0 eq) and PMDTA (7.56 g, 43.62 mmol, 1.leq) in dry THF (100 mL) at -60 °C under N₂ was added a solution of s- BuLi (1.3 M, 36.6 mL, 47.5 mmol, 1.2 eq) over a period of 1 h. The reaction mixture was stirred at -60 °C for 2h and then C0₂ (gas) was bubbled into the solution for 1 h. The reaction mixture was then warmed to room temperature, acidified by addition of 1M HC1 and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried ( a₂S04), filtered and evaporated in vacuo. The residue was purified by column chromatography (EtOAc:petroleum ether, 0:1 to 1 :1) to give the title compound as a yellow solid (5.4 g, 80 percent).LC-MS : m z 171.1 [M+H]⁺ 193.0 [M+Na1H NMR (400 MHz, DMSO-d₆) ? 13.33 (s, 1H), 7.31 (m, 1H), 7.24 (m, 1H), 7.20 - 7.16 (m, 1H), 3.78 (s, 3H)
40%	Stage #1: With 2,2,6,6-tetramethyl-piperidine; n-butyllithium In tetrahydrofuran; hexanes at -78 - -70℃; for 12 h; Stage #3: With hydrogenchloride In tetrahydrofuran; hexanes; water at 0℃;	To a vigorously stirred mixture [OF 4-FLUORO-3-METHYLANISOLE] (12.0 g, 85.6 mmol) and pyri- dine (41.7 g, 527 mmol) in water (170 mL) at [50°C] was added portion-wise potassium per- manganate (44.65 g, mmol) and then maintained at this temperature for 2 h. The resulting mixture was then allowed to cool to RT and allowed to stand overnight and then heated for a further 5 h at [50°C.] Then the mixture was filtered over celite and then the residue was washed with sulfuric acid (conc. 100 mL). The combined filtrates were then [HALF-EVAPORA-] ted and neutralised with potasssium carbonate. Then the mixture was washed with diethyl ether and then the aqueous layer was acidified with hydrochloric acid (conc.) and the pro- duct extracted with diethyl ether. The combined extracts were then dried over sodium sul- phate. After filtration and evaporation the crude solid was [RECRYSTALLISED] from 1,2,-di- chloroethane to afford the title compound (4.4 g, 30percent) as a light pink solid. MS [M/E =] 168.9 (M-H). Alternatively, a solution of 4-fluoroanisole (500 mg, 4.0 mmol) in THF (10 mL) was added to a cooled [SOLUTION (-78°C) OF 2,] 2,6, 6-tetramethylpiperidine (1.1 g, 7.9 mmol) and BuLi (5 mL, 1.6 M in hexanes, 7.9 mmol) in THF (10 mL) at a slow rate to maintain the tempera- ture [BELOW-70°C.] The mixture was maintained at this temperature for 12 h, and then dry C02 gas was passed into the solution. The resulting mixture was allowed to warm up to 0°C and then HCl (1 M, 10 mL) was added and the product was extracted with diethyl ether. The combined organic extracts were then dried over sodium sulfate, washed with water and brine, filtered and evaporated. The crude solid was then partioned between sodium hydroxide [(1] M, 10 mL) and diethyl ether. The aqueous phase was then acidified with HCl (1 M) and the product extracted with diethyl ether. Evaporation afforded the title compound (268 mg, 40percent) as a white solid. MS m/e = 168.9 (M-H).

Reference： [1] Journal of Organic Chemistry, 2007, vol. 72, # 4, p. 1271 - 1275
[2] Patent: WO2013/37705, 2013, A2, . Location in patent: Page/Page column 61; 62
[3] Patent: WO2004/14856, 2004, A1, . Location in patent: Page 21
[4] Tetrahedron Letters, 1992, vol. 33, # 49, p. 7495 - 7498

3
[ 2338-54-7 ]
[ 367-83-9 ]

Yield	Reaction Conditions	Operation in experiment
30%	Stage #1: With pyridine; potassium permanganate In water at 20 - 50℃; Stage #2: With sulfuric acid In water	To a vigorously stirred mixture [OF 4-FLUORO-3-METHYLANISOLE] (12.0 g, 85.6 mmol) and pyri- dine (41.7 g, 527 mmol) in water (170 mL) at [50°C] was added portion-wise potassium per- manganate (44.65 g, mmol) and then maintained at this temperature for 2 h. The resulting mixture was then allowed to cool to RT and allowed to stand overnight and then heated for a further 5 h at [50°C.] Then the mixture was filtered over celite and then the residue was washed with sulfuric acid (conc. 100 mL). The combined filtrates were then [HALF-EVAPORA-] ted and neutralised with potasssium carbonate. Then the mixture was washed with diethyl ether and then the aqueous layer was acidified with hydrochloric acid (conc.) and the pro- duct extracted with diethyl ether. The combined extracts were then dried over sodium sul- phate. After filtration and evaporation the crude solid was [RECRYSTALLISED] from 1,2,-di- chloroethane to afford the title compound (4.4 g, 30percent) as a light pink solid. MS [M/E =] 168.9 (M-H). Alternatively, a solution of 4-fluoroanisole (500 mg, 4.0 mmol) in THF (10 mL) was added to a cooled [SOLUTION (-78°C) OF 2,] 2,6, 6-tetramethylpiperidine (1.1 g, 7.9 mmol) and BuLi (5 mL, 1.6 M in hexanes, 7.9 mmol) in THF (10 mL) at a slow rate to maintain the tempera- ture [BELOW-70°C.] The mixture was maintained at this temperature for 12 h, and then dry C02 gas was passed into the solution. The resulting mixture was allowed to warm up to 0°C and then HCl (1 M, 10 mL) was added and the product was extracted with diethyl ether. The combined organic extracts were then dried over sodium sulfate, washed with water and brine, filtered and evaporated. The crude solid was then partioned between sodium hydroxide [(1] M, 10 mL) and diethyl ether. The aqueous phase was then acidified with HCl (1 M) and the product extracted with diethyl ether. Evaporation afforded the title compound (268 mg, 40percent) as a white solid. MS m/e = 168.9 (M-H).

Reference： [1] Journal of Medicinal Chemistry, 1984, vol. 27, # 5, p. 577 - 585
[2] Patent: WO2004/14856, 2004, A1, . Location in patent: Page 21
[3] Journal of Organic Chemistry, 1960, vol. 25, p. 1016 - 1020
[4] Patent: US5523475, 1996, A,

4
[ 7758-19-2 ]
[ 5329-14-6 ]
[ 105728-90-3 ]
[ 1882-69-5 ]
[ 367-83-9 ]

Reference： [1] Patent: US5519133, 1996, A,

5
[ 102-50-1 ]
[ 367-83-9 ]

Reference： [1] Journal of Medicinal Chemistry, 1984, vol. 27, # 5, p. 577 - 585

6
[ 367-83-9 ]
[ 51446-30-1 ]

Reference： [1] Journal of Medicinal Chemistry, 2007, vol. 50, # 4, p. 611 - 626
[2] Patent: US5523475, 1996, A,
[3] Patent: WO2008/57280, 2008, A1, . Location in patent: Page/Page column 34
[4] Patent: WO2005/113494, 2005, A2, . Location in patent: Page/Page column 117

[ 367-83-9 ] Synthesis Path-Downstream 1~51

1
[ 459-60-9 ]
[ 124-38-9 ]
[ 367-83-9 ]

Yield	Reaction Conditions	Operation in experiment
80%		To a solution of 1 -fluoro-4-methoxy-benzene (5 g, 39.6 mmol, 1.0 eq) and PMDTA (7.56 g, 43.62 mmol, 1.leq) in dry THF (100 mL) at -60 C under N2 was added a solution of s- BuLi (1.3 M, 36.6 mL, 47.5 mmol, 1.2 eq) over a period of 1 h. The reaction mixture was stirred at -60 C for 2h and then C02 (gas) was bubbled into the solution for 1 h. The reaction mixture was then warmed to room temperature, acidified by addition of 1M HC1 and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried ( a2S04), filtered and evaporated in vacuo. The residue was purified by column chromatography (EtOAc:petroleum ether, 0:1 to 1 :1) to give the title compound as a yellow solid (5.4 g, 80 %).LC-MS : m z 171.1 [M+H]+ 193.0 [M+Na1H NMR (400 MHz, DMSO-d6) ? 13.33 (s, 1H), 7.31 (m, 1H), 7.24 (m, 1H), 7.20 - 7.16 (m, 1H), 3.78 (s, 3H)
40%		To a vigorously stirred mixture [OF 4-FLUORO-3-METHYLANISOLE] (12.0 g, 85.6 mmol) and pyri- dine (41.7 g, 527 mmol) in water (170 mL) at [50C] was added portion-wise potassium per- manganate (44.65 g, mmol) and then maintained at this temperature for 2 h. The resulting mixture was then allowed to cool to RT and allowed to stand overnight and then heated for a further 5 h at [50C.] Then the mixture was filtered over celite and then the residue was washed with sulfuric acid (conc. 100 mL). The combined filtrates were then [HALF-EVAPORA-] ted and neutralised with potasssium carbonate. Then the mixture was washed with diethyl ether and then the aqueous layer was acidified with hydrochloric acid (conc.) and the pro- duct extracted with diethyl ether. The combined extracts were then dried over sodium sul- phate. After filtration and evaporation the crude solid was [RECRYSTALLISED] from 1,2,-di- chloroethane to afford the title compound (4.4 g, 30%) as a light pink solid. MS [M/E =] 168.9 (M-H). Alternatively, a solution of 4-fluoroanisole (500 mg, 4.0 mmol) in THF (10 mL) was added to a cooled [SOLUTION (-78C) OF 2,] 2,6, 6-tetramethylpiperidine (1.1 g, 7.9 mmol) and BuLi (5 mL, 1.6 M in hexanes, 7.9 mmol) in THF (10 mL) at a slow rate to maintain the tempera- ture [BELOW-70C.] The mixture was maintained at this temperature for 12 h, and then dry C02 gas was passed into the solution. The resulting mixture was allowed to warm up to 0C and then HCl (1 M, 10 mL) was added and the product was extracted with diethyl ether. The combined organic extracts were then dried over sodium sulfate, washed with water and brine, filtered and evaporated. The crude solid was then partioned between sodium hydroxide [(1] M, 10 mL) and diethyl ether. The aqueous phase was then acidified with HCl (1 M) and the product extracted with diethyl ether. Evaporation afforded the title compound (268 mg, 40%) as a white solid. MS m/e = 168.9 (M-H).

Reference： [1]Journal of Organic Chemistry,2007,vol. 72,p. 1271 - 1275
[2]Patent: WO2013/37705,2013,A2 .Location in patent: Page/Page column 61; 62
[3]Patent: WO2004/14856,2004,A1 .Location in patent: Page 21
[4]Tetrahedron Letters,1992,vol. 33,p. 7495 - 7498

2
[ 2338-54-7 ]
[ 367-83-9 ]

Yield	Reaction Conditions	Operation in experiment
30%		To a vigorously stirred mixture [OF 4-FLUORO-3-METHYLANISOLE] (12.0 g, 85.6 mmol) and pyri- dine (41.7 g, 527 mmol) in water (170 mL) at [50C] was added portion-wise potassium per- manganate (44.65 g, mmol) and then maintained at this temperature for 2 h. The resulting mixture was then allowed to cool to RT and allowed to stand overnight and then heated for a further 5 h at [50C.] Then the mixture was filtered over celite and then the residue was washed with sulfuric acid (conc. 100 mL). The combined filtrates were then [HALF-EVAPORA-] ted and neutralised with potasssium carbonate. Then the mixture was washed with diethyl ether and then the aqueous layer was acidified with hydrochloric acid (conc.) and the pro- duct extracted with diethyl ether. The combined extracts were then dried over sodium sul- phate. After filtration and evaporation the crude solid was [RECRYSTALLISED] from 1,2,-di- chloroethane to afford the title compound (4.4 g, 30%) as a light pink solid. MS [M/E =] 168.9 (M-H). Alternatively, a solution of 4-fluoroanisole (500 mg, 4.0 mmol) in THF (10 mL) was added to a cooled [SOLUTION (-78C) OF 2,] 2,6, 6-tetramethylpiperidine (1.1 g, 7.9 mmol) and BuLi (5 mL, 1.6 M in hexanes, 7.9 mmol) in THF (10 mL) at a slow rate to maintain the tempera- ture [BELOW-70C.] The mixture was maintained at this temperature for 12 h, and then dry C02 gas was passed into the solution. The resulting mixture was allowed to warm up to 0C and then HCl (1 M, 10 mL) was added and the product was extracted with diethyl ether. The combined organic extracts were then dried over sodium sulfate, washed with water and brine, filtered and evaporated. The crude solid was then partioned between sodium hydroxide [(1] M, 10 mL) and diethyl ether. The aqueous phase was then acidified with HCl (1 M) and the product extracted with diethyl ether. Evaporation afforded the title compound (268 mg, 40%) as a white solid. MS m/e = 168.9 (M-H).
	With potassium permanganate; In pyridine; water;	6-Fluoro-3-methoxybenzoic acid 4-Fluoro-3-methylanisol (1.0 g, 7.1 mmol) was dissolved in a mixture of pyridine (16 mL) and water (32 mL). Potassium permanganate (3.4 g, 21 mmol) was added and the reaction mixture was refluxed for 3 h and then left at room temperature over night. After filtration and extraction with CH2 Cl2 the aqueous phase was acidified with HCl precipitating the product (440 mg). 1 NMR (CD3 OD): delta7.44-7.47 (m, 1H), 7.18-7.16 (m, 2H), 3.86 (s, 3H); 13 C NMR (CD3 OD): delta167.55, 158.35 (d, J=192 Hz), 156.30, 121.65 (d, J=8.7 Hz), 120.63 (d), 118.94 (d, J=24.4 Hz), 117.03, 56.59.

Reference： [1]Journal of Medicinal Chemistry,1984,vol. 27,p. 577 - 585
[2]Patent: WO2004/14856,2004,A1 .Location in patent: Page 21
[3]Journal of Organic Chemistry,1960,vol. 25,p. 1016 - 1020
[4]Patent: US5523475,1996,A

3
[ 367-83-9 ]
[ 659737-56-1 ]

Yield	Reaction Conditions	Operation in experiment
100%	With thionyl chloride; N,N-dimethyl-formamide; at 20℃; for 14h;	b) 2-Fluoro-5-methoxy-benzoyl chloride A mixture of <strong>[367-83-9]2-fluoro-5-methoxy-benzoic acid</strong> (4.3 g, 25 mmol) and thionyl chloride (68 mL, 937 mmol) and DMF [(1] drop) was stirred at RT for 14 hours. The mixture was then evaporated to afford the title compound (4.77 g, 100%) after repeated azeotroping with toluene.
	With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; for 0.25h;	A. (Z)-I -(2-Amino-l,2-dicyanovinyl)-3-(2-fluoro-5-methoxyphenyl)urea.; <strong>[367-83-9]2-Fluoro-5-methoxybenzoic acid</strong> (0.62 g, 3.62 mmol) was dissolved in CH2Cl2 (15 mL) and DMF (0.5 mL). Oxalyl chloride (0.38 mL, 4.32 mmol) was added dropwise. The mixture was stirred for another 15 min. The reaction was concentrated and then taken up in dioxane (10 mL). Sodium azide (0.26 g, 3.96 mmol) in water/dioxane (1 : 1 v/v, 10 mL) was added to the acid chloride at 0 0C. The mixture was stirred for 10 min. The reaction was partitioned between EtOAc and water. The layers were shaken and separated. The organic layer was dried over sodium sulfate, filtered, and concentrated. The crude acyl azide was filtered through a silica gel plug (90% Hexanes in EtOAc. The filtrate was concentrated. The purified acyl azide was dissolved in toluene and stirred at 100 0C for 1 h. The toluene solution was concentrated to afford l-fluoro-2-isocyanato-4-methoxybenzene in quantitative yield. 1 -Fluoro-2-isocyanato-4-methoxybenzene (0.6 g, 3.62 mmol) was reacted with 2,3- diaminomaleonitrile (0.39 g, 3.62 mmol) according to General Procedure A to afford the title compound. MS (ESI) m/z 216 A [M+ 1]+.
	With thionyl chloride; N,N-dimethyl-formamide; In chloroform; at 70℃; for 5.5h;	General procedure: The mixture of 2,6-difluorobenzoic acid (iii) (500 mg, 3.17 mmol), thionyl chloride (11.5mL, 159 mmol) and DMF (19 muL) was heated at 70 C for 2.5 h. After cooling, the volatile materials were removed under the reduced pressure to give benzoyl chloride iv S2) as a yellow oil, which was used to the next reaction without purification.

Reference： [1]Patent: WO2004/14856,2004,A1 .Location in patent: Page 21
[2]Journal of Medicinal Chemistry,1984,vol. 27,p. 577 - 585
[3]Patent: WO2008/51494,2008,A1 .Location in patent: Page/Page column 182
[4]Journal of the American Chemical Society,2009,vol. 131,p. 13860 - 13869
[5]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 524 - 527
[6]Synlett,2013,vol. 24,p. 2575 - 2580

4
[ 367-83-9 ]
[ 51446-30-1 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogen bromide;	6-Fluoro-3-hydroxybenzoic acid <strong>[367-83-9]6-Fluoro-3-methoxybenzoic acid</strong> (500 mg, 2.94 mmol) was mixed with freshly distilled 48% HBr (20 mL) and heated at 100 C. for 14 h. Water and HBr were evaporated and the crude product (462 mg) was used without further purification. 1 H NMR(CD3 OD): delta7.28-7,29 (m, 1H), 6.92-7.12 (m, 2H); 13 C NMR (CD3 OD): delta167.80, 157.26 (d, J=249 Hz), 154.77, 122.52 (d, J=10.4 Hz), 120.49 (d, J=11 Hz), 118.77 (d, J=19 Hz), 118.58.
	With water; hydrogen bromide; acetic acid; at 140℃;	Example 5Synthesis of 2-Fluoro-5-hvdroxybenzoic acidTo <strong>[367-83-9]2-fluoro-5-methoxybenzoic acid</strong> (5.00 g, 29.4 mmol) was added 49 % aqueous HBr (50 mL) and glacial acetic acid (40 mL). The mixture was heated overnight at 140 0C, cooled to RT, diluted with ice water and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated to yield 2-fluoro-5-hydroxybenzoic acid. MS m/z = 157 [M+l]+. Calc'd for C7H5FO3: 156.11.
	With water; hydrogen bromide; acetic acid; at 140℃;	Example 48 Synthesis of 2-Fluoro-5-hydroxybenzoic acid; To <strong>[367-83-9]2-fluoro-5-methoxybenzoic acid</strong> (5.00 g, 29.4 mmol) was added 49 % aqueous HBr (50 mL) and glacial acetic acid (40 mL). The mixture was heated overnight at 140 C, cooled to RT, diluted with ice water and extracted with EtOAc. The organic layer was dried over NazS04, filtered and concentrated to yield 2-fluoro-5-hydroxybenzoic acid. MS m/z 157 [M+1]+. Calc'd for C7H5FO3: 156.11.

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 611 - 626
[2]Patent: US5523475,1996,A
[3]Patent: WO2008/57280,2008,A1 .Location in patent: Page/Page column 34
[4]Patent: WO2005/113494,2005,A2 .Location in patent: Page/Page column 117

5
[ 367-83-9 ]
2-fluoro-5-(3-(4-(methylamino)-1,3,5-triazin-2-yl)pyridin-2-yloxy)benzoic acid [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 611 - 626

6
[ 367-83-9 ]
2-fluoro-5-[4-(2-methylamino-pyridin-3-yl)-[1,3,5]triazin-2-yloxy]-benzoic acid [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 611 - 626

7
[ 367-83-9 ]
[ 89106-46-7 ]

Reference： [1]Journal of Medicinal Chemistry,1984,vol. 27,p. 577 - 585

8
[ 367-83-9 ]
[ 89106-43-4 ]

Reference： [1]Journal of Medicinal Chemistry,1984,vol. 27,p. 577 - 585

9
[ 367-83-9 ]
[ 89106-44-5 ]

Reference： [1]Journal of Medicinal Chemistry,1984,vol. 27,p. 577 - 585

10
[ 367-83-9 ]
[ 89106-45-6 ]

Reference： [1]Journal of Medicinal Chemistry,1984,vol. 27,p. 577 - 585

11
[ 102-50-1 ]
[ 367-83-9 ]

Reference： [1]Journal of Medicinal Chemistry,1984,vol. 27,p. 577 - 585

Yield	Reaction Conditions	Operation in experiment
		a 2-Fluoro-5-methoxybenzoic acid The title compound was prepared according to a method reported by Hay and Blanchard [Canad. J. Chem. 43, 1306 (1965)]. In a three-necked round-bottom flask (1000 mL), equipped with a magnetic stirrer, thermometer, reflux condensor and a gas distribution tube, cobalt(II)acetate tetrahydrate (12.6 g; 51 mmol) was dissolved in glacial acetic acid (404 mL) by stirring. Commercial 4-fluoro-3-methylanisole (35.4, 252 mmol) and 33% HBr in acetic acid (10.1 mL; 51 mmol) were added and then the mixture was heated on an oil-bath to 90-95 C. All the time a stream of oxygen was passed through the solution at a rate of about 660 mL/min. After 3 hours the reaction mixture was cooled to room temperature and then rotary evaporated to dryness. The violet colored solid thus obtained was transferred to an Erlen-Meyer flask, dissolved in boiling water (350 mL) containing concentrated hydrochloric acid (5-10 mL) and then allowed to crystallize at a cold place over night. The crude acid was filtered off by suction, washed with small portions of ice-water until the washing were pale yellow, dissolved in 2M NaOH (120 mL) and washed with toluene (2100 mL). The organic extracts were discarded. The aqeous phase was suction filtered, cooled in a beaker on an ice-bath and carefully acidified with concentrated hydrochloric acid until all the acid was precipitated. The contents in the beaker was heated to the boiling point whereby most of the acid dissolved. The solution was cooled at room temperature and finally in the refrigerator. The mother liquor was sucked off. The crystal mass was washed with ice-water (350 mL) and then dried in a vacuum-oven at 40 C. to give 31.5 g of the title compound as a grey-white solid. Mp. 146-148 C.

13
[ 7758-19-2 ]
5-methoxy-2-nitrobezaldehyde [ No CAS ]
[ 5329-14-6 ]
[ 105728-90-3 ]
[ 1882-69-5 ]
[ 367-83-9 ]

Yield	Reaction Conditions	Operation in experiment
	In water; acetone;	EXAMPLE 13 Preparation of 5-Methoxy-2-nitrobenzoic acid STR50 Sulfamic acid (15.73 g, 0.162 mol) is added to a solution of 5-methoxy-2-nitrobezaldehyde (19.6 g, 0.108 mol) in an acetone/water (1:1) mixture. Sodium chlorite (18.31 g, 80% real, 0.162 mol) is then added to the reaction mixture at a rate which maintains the reaction mixture temperature below 40 C. The resultant reaction mixture is stirred at room temperature for 24 hours and poured into water. The aqueous mixture is extracted with ethyl acetate. The organic extracts are combined, washed sequentially with 2N hydrochloric acid and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give the title product as a yellow solid. Using essentially the same procedure, but substituting 2-fluoro-5-methoxybenzaldehyde for 5-methoxy-2-nitrobezaldehyde, 2-fluoro-5-methoxybenzoic acid is obtained as a white solid, mp 144-146 C.

Reference： [1]Patent: US5519133,1996,A

14
[ 54-96-6 ]
[ 367-83-9 ]
C₁₃H₁₀FN₃O [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 5111 - 5114

15
[ 110-91-8 ]
[ 367-83-9 ]
[ 1046468-44-3 ]

Reference： [1]Tetrahedron Letters,2008,vol. 49,p. 4579 - 4581

16
[ 367-83-9 ]
[ 124-40-3 ]
[ 1046468-46-5 ]

Reference： [1]Tetrahedron Letters,2008,vol. 49,p. 4579 - 4581

17
[ 367-83-9 ]
[ 62-53-3 ]
[ 1046468-39-6 ]

Reference： [1]Tetrahedron Letters,2008,vol. 49,p. 4579 - 4581

18
[ 367-83-9 ]
[ 100-46-9 ]
[ 1046468-41-0 ]

Reference： [1]Tetrahedron Letters,2008,vol. 49,p. 4579 - 4581

19
[ 34472-65-6 ]
[ 367-83-9 ]
[ 96826-42-5 ]

Yield	Reaction Conditions	Operation in experiment
97%	In methanol; diethyl ether; dichloromethane; at 0℃; for 0.5h;	To a suspension of <strong>[367-83-9]2-fluoro-5-(methyloxy)benzoic acid</strong> (2.0 g, 1 1.8 mmol) in DCM (20 ml.) and MeOH (2 mL) at 00C, trimethylsilyl diazomethane (2 M in ether, 12.3 mmol, 6.2 mL) was added dropwise. The reaction mixture was allowed to stir for 30 min at 00C and the solvents were removed under reduced pressure. The residue was diluted with EtOAc, adsorbed onto silica gel, and subjected to silica gel chromatography to give 2.1 g (97 %) of the title compound of Step A: 1H NMR (CDCI3, 300 MHz) delta 7.41-7.39 (m, 1 H), 7.07-7.02 (m, 2 H), 3.93 (s, 3 H), and 3.82 (s, 3 H).

Reference： [1]Patent: WO2009/32667,2009,A1 .Location in patent: Page/Page column 183

20
[ 367-83-9 ]
[ 74-88-4 ]
[ 870221-15-1 ]

Yield	Reaction Conditions	Operation in experiment
		Step 1. Preparation of 2-fluoro-5-methoxy-4-methylbenzoic acid; Potassium tert-butoxide (7.92 g, 70.5 mmol) was dissolved in THF (150 mL) and cooled to-78 C. 2-Fluoro-5- methoxybenzoic acid (3.00 g, 17.6 mmol) in THF (100 mL) was added followed by n-butyl lithium (2.5 N in hexanes, 28.2 mL, 70.5 mmol). After 40 minutes, iodomethane (2.2 mL, 35.4 mmol) was added and allowed to stir at-78 C for 70 minutes before warming to room temperature. The reaction was quenched with saturated ammonium chloride (100 mL) and extracted with ether. The aqueous layer was acidified using 6 N HCl then extracted with ether. The organic layer was dried over sodium sulfate, filtered and concentrated. The crude material was purified by Gilson reverse-phase HPLC (acidic mobile phase) to yield 2-fluoro-5-methoxy-4- methylbenzoic acid as a white solid. MS m/z = 185 [M+1]+. Calc'd for CgHgF03: 184.20.

Reference： [1]Patent: WO2005/113494,2005,A2 .Location in patent: Page/Page column 119-120

21
[ 1346499-02-2 ]
[ 367-83-9 ]
[ 1346496-31-8 ]

Yield	Reaction Conditions	Operation in experiment
	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; for 6h;	(7-Chlorospiro[benzo[b]pyrrolo[l,2-d] [l,4]oxazine-4,4'-piperidine]- l'-yl)(2-fluoro-5- methoxyphenyl)methanone Chlorospiro[benzo[b]pyrrolo[l,2-d][l,4]oxazine-4,4'-piperidine] (62 mg, 0.20 mmol), 2- fluoro-5-methoxybenzoic acid (34 mg, 0.20 mmol), EDCI (38 mg, 0.20 mmol), and Et3N (56 mu, 0.40 mmol) were combined in DCM (1 mL) and the mixture was stirred for 6 h. The mixture was diluted with DCM and was washed with IN HCl, sat. aq. sodium bicarbonate and brine. The organics were dried over sodium sulfate and were evaporated. The crude material was purified by silica gel chromatography eluting with 0-40% ethyl acetate in hexanes to provide (7-chlorospiro[benzo[b]pyrrolo[l,2-d][l,4]oxazine-4,4'-piperidine]- -yl)(2-fluoro-5- methoxyphenyl)methanone. ESI-MS m/z calc. 426.1, found 427.5 (M+l)+. Retention time: 2.12 minutes (3 min run). 1H NMR (400 MHz, CDC13) delta 7.26 (d, J = 8.4 Hz, 1H), 7.13 - 7.07(m, 2H), 7.05 - 6.96 (m, 2H), 6.94 - 6.85 (m, 2H), 6.33 (t, J = 3.2 Hz, 1H), 6.08 - 5.98 (m, 1H), 4.69 (d, J = 13.1 Hz, 1H), 3.80 (s, 3H), 3.63 - 3.44 (m, 2H), 3.33 (t, J = 12.8 Hz, 1H), 2.19 (d, J = 13.8 Hz, 1H), 2.09 - 1.96 (m, 2H), 1.60 (s, 1H).

Reference： [1]Patent: WO2011/140425,2011,A1 .Location in patent: Page/Page column 337-338

22
[ 367-83-9 ]
[ 1532528-59-8 ]

Reference： [1]Synlett,2013,vol. 24,p. 2575 - 2580

23
[ 367-83-9 ]
[ 1214-20-6 ]

Reference： [1]Synlett,2013,vol. 24,p. 2575 - 2580

24
[ 367-83-9 ]
(S)-2-amino-N-(4-fluoro-2-methoxyphenyl)-5-methylhexanamide [ No CAS ]
C₂₂H₂₆F₂N₂O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of EDCI?HCl (264.5 mg, 1.38 mmol) in DMF (3.5 mL) and CH2Cl2 (3.5 mL) were successively added OxymaPure (196.1 mg, 1.28 mmol) and <strong>[367-83-9]2-fluoro-5-methoxybenzoic acid</strong> (234.9 mg, 1.38 mmol) at room temperature. After the mixture was stirred for 5 min, S2 (370.5 mg, 1.38 mmol) and DIPEA (299 muL, 2.07 mmol) were added, the reaction mixture was stirred for 10 h. The volatiles were removed under reduced pressure. The residue was diluted with ethyl acetate and 1 N HCl aq. was added. The resulting mixture was extracted with ethyl acetate twice, the combined organic layers were washed with aqueous saturated NaHCO3 twice, H2O, brine and dried over Na2SO4. After filtration, the residue was concentrated under reduced pressure, dried in vacuo to give crude diamide as a brown oil. To the diamide in CH2Cl2 (6.9 mL) was added BBr3 (1.0 M in CH2Cl2, 6.9 mL, 6.9 mmol) over 5 min at 0 C. After stirring for 24 h, the reaction was quenched with i-PrOH at the same temperature, and then water was added. The resulting mixture was extracted with CHCl3 twice and the combined organic layers were washed with aqueous saturated NaHCO3, H2O, brine, and dried over Na2SO4. After filtration, the residue was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography (acetone/n-hexane = 8/92 to 66/34) to give 1b (275.4 mg, 701.8 mumol, 51% over 2 steps) as a white amorphous.White amorphous; [alpha]D27 -5.8 (c 0.16, CH3OH); 1H NMR (400 MHz, CD3OD) delta 7.73 (dd, J = 8.8 , 6.2 Hz, 1H), 7.15 (dd, J = 5.7, 3.1 Hz, 1H), 7.05 (dd, J = 10.4, 8.9 Hz, 1H), 6.92 (ddd, J = 8.9, 4.0, 3.1 Hz, 1H), 6.60 (dd, J = 10.0, 2.9 Hz, 1H), 6.55 (ddd, J = 8.8, 8.4, 2.9 Hz, 1H), 4.69 (dd, J = 8.0, 5.5 Hz, 1H), 2.07-1.98 (m, 1H), 1.90-1.80 (m, 1H), 1.67-1.57 (m, 1H), 1.44-1.33 (m, 2H), 0.94 (d, J = 6.6 Hz, 3H), 0.94 (d, J = 6.6 Hz, 3H); 13C NMR (100 MHz, CD3OD) delta 172.6, 166.7 (d, J = 2.2 Hz), 161.7 (d, J = 240.6 Hz), 155.1 (d, J = 1.5 Hz), 155.0 (d, J = 238.4 Hz), 151.3 (d, J = 10.9 Hz), 124.8 (d, J = 10.2 Hz), 123.8 (d, J = 15.3 Hz), 123.0 (d, J = 2.9 Hz), 120.7 (d, J = 8.0 Hz), 117.9 (d, J = 24.8 Hz), 117.0 (d, J = 1.5 Hz), 106.5 (d, J = 22.6 Hz), 103.8 (d, J = 25.5 Hz), 56.1, 35.9, 31.1, 29.0, 23.0, 22.8; 19F NMR (376 MHz, CD3OD) delta -118.1, -128.2; IR (KBr) nu 3247, 2962, 1649, 1618, 1538, 1501, 1452, 1317, 1228, 1143 cm-1; HRMS (ESI) calcd. for C20H22N2O4F2Na m/z 415.1440 [M+Na]+, found 415.1421.

Reference： [1]Tetrahedron,2017,vol. 73,p. 1517 - 1521

25
[ 367-83-9 ]
C₁₄H₂₁FN₂O₂*C₂HF₃O₂ [ No CAS ]
(S)-2-fluoro-N-(1-((4-fluoro-2-methoxyphenyl)amino)-4,4-dimethyl-1-oxopentan-2-yl)-5-methoxybenzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1.16 g		To a solution of S4 (1.22 g, 3.31 mmol) in CH2Cl2 (12 mL) was added TFA (6 mL). The reaction mixture was stirred at room temperature for 2 h and concentrated. Toluene was added to the residue and the volatiles were removed under reduced pressure, which was repeated twice. The resulting residue was dried in vacuo to give crude amine?TFA salt as a white solid. To a solution of EDCI?HCl (634.5 mg, 3.31 mmol) in DMF (8.3 mL) and CH2Cl2 (8.3 mL) were successively added OxymaPure (470.4 mg, 3.31 mmol) and <strong>[367-83-9]2-fluoro-5-methoxybenzoic acid</strong> (563.2 mg, 3.31 mmol) at room temperature. After stirring for 5 min, the crude amine?TFA salt and DIPEA (717 muL, 4.97 mmol) were added, and then the resulting mixture was stirred for 9 h at the same temperature. The volatiles were removed under reduced pressure. The residue was diluted with ethyl acetate and 1 N HCl aq. was added. The resulting mixture was extracted with ethyl acetate twice, the combined organic layers were washed with aqueous saturated NaHCO3 twice, H2O, brine and dried over Na2SO4. After filtration, the residue was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography (ethyl acetate/n-hexane = 8/92 to 66/34) to give S5 (1.16 g, 2.76 mmol, 84% over 2 steps) as a colorless amorphous.Colorless amorphous; [alpha]D26 -38.3 (c 1.12, CHCl3); 1H NMR (400 MHz, CD3OD) delta 7.96 (dd, J = 8.8, 6.1 Hz, 1H), 7.24 (dd, J = 5.6, 3.2 Hz, 1H), 7.17 (dd, J = 10.0, 9.0 Hz, 1H), 7.10 (ddd, J = 9.0, 3.9, 3.2 Hz, 1H), 6.84 (dd, J = 10.5, 2.7 Hz, 1H), 6.66 (ddd, J = 8.6, 8.6, 2.7 Hz, 1H), 4.81 (dd, J = 9.1, 3.4 Hz, 1H), 3.86 (s, 3H), 3.82 (s, 3H), 2.00 (dd, J = 14.4, 3.4 Hz, 1H), 1.76 (dd, J = 14.4, 9.1 Hz, 1H), 1.04 (s, 9H); 13C NMR (100 MHz, CD3OD) delta 172.9, 166.5 (d, J = 1.5 Hz), 161.5 (d, J = 241.3 Hz), 157.4 (d, J = 2.2 Hz), 155.6 (d, J = 240.6 Hz), 152.7 (d, J = 10.2 Hz), 124.2 (d, J = 1.5 Hz), 124.1 (d, J = 10.9 Hz), 123.7 (d, J = 9.5 Hz), 119.7 (d, J = 8.8 Hz), 118.1 (d, J = 25.5 Hz), 115.4 (d, J = 2.9 Hz), 107.1 (d, J = 21.9 Hz), 100.3 (d, J = 27.0 Hz), 56.7, 56.4, 53.7, 46.0, 31.5, 30.1 (3C); 19F NMR (376 MHz, CD3OD) delta -116.9, -126.5; IR (neat) nu 3019, 1686, 1656, 1531, 1492, 1216, 1216, 1036, 757, 689 cm-1; HRMS (ESI) calcd. for C22H26N2O4F2Na m/z 443.1753 [M+Na]+, found 443.1744.

Reference： [1]Tetrahedron,2017,vol. 73,p. 1517 - 1521

26
[ 367-83-9 ]
C₁₂H₁₃FN₂O₂ [ No CAS ]
(S)-2-fluoro-N-(1-((4-fluoro-2-methoxyphenyl)amino)-1-oxopent-4-yn-2-yl)-5-methoxybenzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1.36 g		To a solution of EDCI?HCl (1.08 g, 5.63 mmol) in DMF (14 mL) and CH2Cl2 (14 mL) were successively added OxymaPure (800.1 mg, 5.63 mmol) and S6 (1.20 g, 5.63 mmol) at room temperature. After stirring the reaction mixture for 5 min, 4-fluoro-2-methoxyaniline (884.6 mg, 5.63 mmol) and DIPEA (1.06 mL, 7.32 mmol) were added, and the reaction mixture was stirred for 5 h at the same temperature. The volatiles were removed under reduced pressure. The residue was diluted with ethyl acetate and 1 N HCl aq. was added. The resulting mixture was extracted with ethyl acetate twice, the combined organic layers were washed with aqueous saturated NaHCO3 twice, H2O, brine and dried over Na2SO4. After filtration, the residue was concentrated under reduced pressure and dried in vacuo to give crude amide as a brown oil. To the crude amide in CH2Cl2 (20 mL) was added TFA (10 mL). The reaction mixture was stirred at room temperature for 5 h and concentrated. Toluene was added to the residue and the volatiles were removed under reduced pressure, which was repeated twice. The resulting residue was dried in vacuo to give crude amine S10 as a brown oil. To a solution of EDCI?HCl (1.08 g, 5.63 mmol) in DMF (14 mL) and CH2Cl2 (14 mL) were successively added OxymaPure (800.0 mg, 5.63 mmol) and <strong>[367-83-9]2-fluoro-5-methoxybenzoic acid</strong> (958.0 mg, 5.63 mmol) at room temperature. After stirring the reaction mixture for 5 min, the crude amine S10 in DMF (1 mL) and DIPEA (1.22 mL, 8.45 mmol) were added, and the resulting mixture was stirred for 12 h at the same temperature. The volatiles were removed under reduced pressure. The residue was diluted with ethyl acetate and 1 N HCl aq. was added. The resulting mixture was extracted with ethyl acetate twice, the combined organic layers were washed with aqueous saturated NaHCO3 twice, H2O, brine, and dried over Na2SO4. After filtration, the residue was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography (ethyl acetate/n-hexane = 8/92 to 66/34) to give S11 (1.36 g, 3.57 mmol, 62% over 3 steps) as a white solid.White solid; m.p. 130-132 C; [alpha]D26 -17.6 (c 1.66, CHCl3); 1H NMR (400 MHz, CD3OD) delta 7.97 (dd, J = 8.8, 6.1 Hz, 1H), 7.34 (dd, J = 5.6, 3.2 Hz, 1H), 7.18 (dd, J = 10.3, 9.0 Hz, 1H), 7.11 (ddd, J = 9.0, 4.0, 3.2 Hz, 1H), 6.84 (dd, J = 10.5, 2.7 Hz, 1H), 6.67 (ddd, J = 8.8, 8.4, 2.7 Hz, 1H), 4.93 (dd, J = 7.1, 6.1 Hz, 1H), 3.88 (s, 3H), 3.83 (s, 3H), 2.91 (ddd, J = 16.9, 6.1, 2.7 Hz, 1H), 2.83 (ddd, J = 16.9, 7.1, 2.7 Hz, 1H), 2.45 (t, J = 2.7 Hz, 1H); 13C NMR (100 MHz, CDCl3) delta 167.3, 163.3 (d, J = 3.7 Hz), 159.5 (d, J = 242.1 Hz), 156.0 (d, J = 1.5 Hz), 155.3 (d, J = 239.9 Hz), 149.4 (d, J = 10.2 Hz), 123.2 (d, J = 3.7 Hz), 120.9 (d, J = 9.5 Hz), 120.4 (d, J = 8.8 Hz), 120.3 (d, J = 13.1 Hz), 117.1 (d, J = 27.0 Hz), 114.6 (d, J = 2.2 Hz), 106.7 (d, J = 21.9 Hz), 98.8 (d, J = 27.0 Hz), 79.0, 72.1, 56.0, 55.9, 52.9, 22.0; 19F NMR (376 MHz, CDCl3) delta -115.6, -123.1; IR (KBr) nu 3413, 3307, 3019, 1658, 1493, 1216, 758, 668 cm-1; HRMS (ESI) calcd. for C20H18N2O4F2Na m/z 411.1127 [M+Na]+, found 411.1123.

Reference： [1]Tetrahedron,2017,vol. 73,p. 1517 - 1521

27
[ 367-83-9 ]
[ 161643-29-4 ]

Reference： [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 1417 - 1431

28
[ 367-83-9 ]
[ 91319-42-5 ]

Reference： [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 1417 - 1431

29
[ 367-83-9 ]
2-((2S,4S)-1-(4-(3-(2-fluoro-5-methoxybenzyl)-2-methylphenoxy)phenyl)-4-(trifluoromethyl)pyrrolidin-2-yl)acetonitrile [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 1417 - 1431

30
[ 367-83-9 ]
2-((2S,4S)-1-(4-(3-(2-fluoro-5-methoxybenzyl)-2-methylphenoxy)phenyl)-4-(trifluoromethyl)pyrrolidin-2-yl)acetic acid trifluoroacetic acid salt [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 1417 - 1431

31
[ 53220-41-0 ]
[ 367-83-9 ]
(4-(4-chlorobenzoyl)piperidin-1-yl)(2-fluoro-5-methoxyphenyl)methanone [ No CAS ]