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Quality Control of [ 403-01-0 ] Purity: 98% SDS Specification

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Product Details of [ 403-01-0 ]

CAS No. :	403-01-0
Formula :	C₈H₇FO₃
M.W :	170.14
SMILES Code :	O=C(OC)C1=CC=C(O)C(F)=C1
MDL No. :	MFCD00215838
Boiling Point :	No data available
InChI Key :	IYUSGKSCDUJSKS-UHFFFAOYSA-N
Pubchem ID :	7019368

Safety of [ 403-01-0 ]

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

Computational Chemistry of [ 403-01-0 ] Show Less

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	39.7
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	46.53 ?2

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.89
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	1.52
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.74
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.	1.75
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	1.64
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.71

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.09
Solubility	1.38 mg/ml ; 0.00812 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.	-2.11
Solubility	1.33 mg/ml ; 0.00784 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	-2.17
Solubility	1.14 mg/ml ; 0.00673 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	No
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.	-6.26 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)	1.4

Application In Synthesis of [ 403-01-0 ]

* 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.

Downstream synthetic route of [ 403-01-0 ]

[ 403-01-0 ] Synthesis Path-Downstream 1~30

1
[ 350-29-8 ]
[ 403-01-0 ]

References: [1]Journal of Organic Chemistry,1952,vol. 17,p. 1425,1429.

2
[ 99-76-3 ]
[ 403-01-0 ]

References: [1]Journal of the American Chemical Society,1990,vol. 112,p. 8563 - 8575.
[2]Journal of Fluorine Chemistry,2003,vol. 120,p. 173 - 183.

3
[ 350-29-8 ]
[ 18107-18-1 ]
[ 403-01-0 ]

References: [1]Tetrahedron Letters,1996,vol. 37,p. 7649 - 7652.

4
[ 403-01-0 ]
N-butyl-4-(chloromethyl)benzamide [ No CAS ]
[ 183664-17-7 ]

References: [1]Tetrahedron Letters,1996,vol. 37,p. 7649 - 7652.

5
[ 69420-67-3 ]
[ 403-01-0 ]
3-Fluoro-4-((1S,2S)-2-pyrrolidin-1-yl-cyclohexyloxy)-benzoic acid methyl ester [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,1999,vol. 9,p. 759 - 764.

6
[ 403-01-0 ]
[ 7581-94-4 ]
3-Fluoro-4-((1S,2S)-2-piperidin-1-yl-cyclohexyloxy)-benzoic acid methyl ester [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,1999,vol. 9,p. 759 - 764.

7
[ 99-76-3 ]
[ 403-01-0 ]
[ 170572-47-1 ]

References: [1]Journal of Fluorine Chemistry,2000,vol. 102,p. 169 - 173.

8
[ 403-01-0 ]
[ 39635-02-4 ]

References: [1]Journal of Medicinal Chemistry,2001,vol. 44,p. 3141 - 3149.
[2]Journal of Medicinal Chemistry,2002,vol. 45,p. 5755 - 5775.

9
[ 403-01-0 ]
[ 106-93-4 ]
[ 386213-21-4 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2001,vol. 11,p. 2569 - 2572.

10
[ 403-01-0 ]
methyl 5-bromo-3-fluoro-4-hydroxybenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95%	With bromine; acetic acid; In dichloromethane; at 20℃;Ice cooled;	Methyl 3-bromo-5-fluoro-4-hydroxybenzoate (T10.2). Bromine (1.60 mL, 31.1 mmol) was added dropwise with stirring over 30 minutes to an ice-cooled solution of T10.1 (4.79 g, 28.1 mmol) in a 1 :1 mixture of DCM (20 mL) and AcOH (20 mL). Upon complete addition, the reaction mixture was allowed to warm to room temperature and monitored with TLC and LC-MS. After stirring at room temperature for 40 hours, the mixture was diluted with EtOAc. The resulting solution was washed twice with aqueous saturated Na2SO3, once with water, and once with brine. After drying over anhydrous MgSO4, filtration, and concentration, the white solid was identified as T10.2 (6.69 g, 95percent yield). 1H NMR (400 MHz, CDCl3) 8.05 (1 H, m), 7.75 (1 H, dd, J=10.6, 2.0 Hz), 6.12 (1 H, s), 3.94 (3 H, s).
95%	With bromine; acetic acid; In dichloromethane; at 20℃;Cooling with ice;	Methyl 3-bromo-5-fluoro-4-hydroxybenzoate (T25.2). Bromine (1.60 mL, 31.1 mmol) was added dropwise with stirring over 30 minutes to an ice-cooled solution of T25.1 (4.79 g, 28.1 mmol) in a 1 : 1 mixture of DCM (20 mL) and acetic acid (20 mL). Upon complete addition, the reaction mixture was allowed to warm to room temperature and monitored with TLC and LC-MS. After stirring at room temperature for 40 hours, the mixture was diluted with EtOAc, and then the resulting solution was washed twice with aqueous saturated Na2SO3, once with water, and once with brine. After drying over anhydrous magnesium sulfate, filtration, and concentration, the white solid T25.2 was obtained 6.69 g, 95percent yield). 1H NMR (400 MHz, CDCl3) delta ppm 8.05 (1 H, m), 7.75 (1 H, dd, J=10.6, 2.0 Hz), 6.12 (1 H, s), 3.94 (3 H, s).
	With N-Bromosuccinimide; In tetrahydrofuran; at 0 - 20℃; for 2h;	b) 3-Bromo-5-fluoro-4-hydroxybenzoic acid methyl ester To a solution of <strong>[403-01-0]3-fluoro-4-hydroxybenzoic acid methyl ester</strong> (1.0 g) in THF (10 mL) was added N-bromosuccinimide (1.26 g) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with ethyl acetate, washed successively with saturated aqueous sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=3:1, v/v) to give the title compound (1.16 g). (In the above, THF is tetrahydrofuran)

30 g

With bromine; In dichloromethane; acetic acid; at 0 - 20℃; for 48.5h;

Intermediate 27: Methyl 3-bromo-5-fluoro-4-hydroxybenzoate _: To a stirred solution of [403-01-0]methyl 3-fluoro-4-hydroxybenzoate (21.0 g, 123 mmol) in DCM (120 mL) and acetic acid (120 mL) was added bromine (8.0 mL, 155 mmol) at 0 °C drop wise within 30 min. The reaction mixture was stirred for 48 h at RT and then diluted with ethyl acetate (500 ml). The mixture was washed with saturated Na2S203 solution (3 x 500 ml), brine solution (3 x 500ml) and dried over anhydrous Na2S04. The solvent was removed under reduced pressure to afford the title compound (30 g) as a yellow solid which was used without further purification. (0326) LCMS Method B: m/z [M-H]+ 247, tR 0.98 min.

References: [1]Patent: WO2010/45258,2010,A2 .Location in patent: Page/Page column 155; 156.
[2]Patent: WO2009/111056,2009,A1 .Location in patent: Page/Page column 228.
[3]Journal of Medicinal Chemistry,2002,vol. 45,p. 3112 - 3129.
[4]Patent: US2006/89392,2006,A1 .Location in patent: Page/Page column 39.
[5]Patent: WO2016/12916,2016,A1 .Location in patent: Page/Page column 40; 41.

11
[ 403-01-0 ]
3-Fluoro-4-hydroxy-benzoic acid [1-(4-hydroxymethyl-naphthalen-1-yl)-meth-(E)-ylidene]-hydrazide [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2002,vol. 45,p. 5755 - 5775.

12
[ 403-01-0 ]
3-Fluoro-4-hydroxybenzoic Acid (4-Hydroxy-1-naphthylmethylene)hydrazide [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2001,vol. 44,p. 3141 - 3149.

13
[ 403-01-0 ]
1-[2-(4-carboxy-2-fluoro-phenoxy)-ethyl]-3-dodecanoyl-1H-indole-2-carboxylic acid [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2001,vol. 11,p. 2569 - 2572.

14
[ 403-01-0 ]
3-dodecanoyl-1-[2-(2-fluoro-4-methoxycarbonyl-phenoxy)-ethyl]-1H-indole-2-carboxylic acid ethyl ester [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2001,vol. 11,p. 2569 - 2572.

15
[ 403-20-3 ]
[ 403-01-0 ]

References: [1]Tetrahedron Letters,1996,vol. 37,p. 7649 - 7652.
[2]Journal of Organic Chemistry,1952,vol. 17,p. 1425,1429.

16
[ 403-01-0 ]
[ 183664-19-9 ]

References: [1]Tetrahedron Letters,1996,vol. 37,p. 7649 - 7652.

17
[ 403-01-0 ]
N-Butyl-4-(4-butylcarbamoyl-benzyloxy)-3-fluoro-benzamide [ No CAS ]

References: [1]Tetrahedron Letters,1996,vol. 37,p. 7649 - 7652.

18
[ 403-01-0 ]
N-Butyl-4-[2-fluoro-4-(piperidine-1-carbonyl)-phenoxymethyl]-benzamide [ No CAS ]

References: [1]Tetrahedron Letters,1996,vol. 37,p. 7649 - 7652.

19
[ 403-01-0 ]
[ 183664-21-3 ]

References: [1]Tetrahedron Letters,1996,vol. 37,p. 7649 - 7652.

20
[ 60-29-7 ]
[ 54550-36-6 ]
[ 403-01-0 ]
[ 584-08-7 ]
[ 117420-32-3 ]

Yield	Reaction Conditions	Operation in experiment
	In dichloromethane; acetonitrile;	PART A -- Preparation of methyl 3-fluoro-4-[2-(2-ethoxyethoxy)-ethoxy]-benzoate. Into a 500-ml, round-bottom flask equipped with a magnetic stirrer, heating mantle and condenser were placed 5.7 g (33.5 mmol) <strong>[403-01-0]methyl 3-fluoro-4-hydroxybenzoate</strong>, 8.5 g (43.2 mmol) 1-bromo-2-(2-ethoxyethoxy)-ethane, 23.2 g of powdered anhydrous potassium carbonate and 350 ml acetonitrile. After stirring the reaction mixture under reflux for four hours, TLC analysis showed that none of the phenolic starting material remained. Three hundred ml of the acetonitrile was then distilled off and 300 ml dichloromethane was added. The reaction mixture was filtered through Celite and the solids were washed thoroughly with dichloromethane. Evaporation of the filtrate yielded product in the form of a yellow oil. Purification by flash chromatography on silica gel with 4percent ethyl ether in dichloromethane, followed by low temperature recrystallization from pentane, yielded 0.55 g of white crystals, 89percent, m.p. 33-36.5°C. The structure was confirmed by infrared, nuclear magnetic resonance and mass spectral analyses.

References: [1]Patent: EP258578,1993,B1 .

21
[ 403-01-0 ]
[ 74-89-5 ]
[ 633317-77-8 ]

Yield	Reaction Conditions	Operation in experiment
		The other compounds of Example 3 were prepared by essentially the same procedure using the corresponding carboxamide and acyl hydrazide. Acetonitrile was used as solvent in the preparation of 3-2. Compound [3-19] was isolated as a byproduct in the synthesis of 3-18. The methyl amides were prepared from their corresponding methyl esters and [METHYLAMINE] using well established protocols. The other amides were conveniently prepared from commercially available carboxylic acids and amines using 1- (dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride as the reagent and published procedures. Preparation of the acyl hydrazides was described in Procedures 3A, 3B, 3C and 3D.

References: [1]Patent: WO2003/104207,2003,A2 .Location in patent: Page 54.

22
(R,S)-1-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-heptan-1-ol [ No CAS ]
[ 403-01-0 ]
[ 871253-41-7 ]

Yield	Reaction Conditions	Operation in experiment
57%	With tributylphosphine; 1,1'-azodicarbonyl-dipiperidine; In toluene; at 0 - 20℃; for 16h;	Example 147; (R,S)-3-(3-Fluoro-4- f 1-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-heptyloxy}- benzoylamino) -propionic acid ;Step A. 3-Fluoro-4-{1-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-heptyloxy}- benzoic acid methyl ester; Combine 1 - [6-(4-trifluoromethyl-phenyl)-pyridin-3 -yl] -heptan- I -ol' (0.050g, 0.15mmol) and <strong>[403-01-0]3-fluoro-4-hydroxy-benzoic acid methyl ester</strong> (0.030g, 0.18mmol) in toluene (0.5mL). Add 1,1'-(diazocarbonyl)dipiperidine (0.057g, 0.23mmol) followed by tributyl-phosphine (0.06mL, 0.23mmol) under inert atmosphere. Stir at room temperature for 16 hours. Dilute reaction with ethyl acetate filter and remove solvent under reduced pressure. Purify on silica gel chromatography (0-40percent ethyl acetate/hexane gradient) to provide 0.04g of title compound (57percent).

References: [1]Patent: WO2005/118542,2005,A1 .Location in patent: Page/Page column 149-150.

23
[ 67-56-1 ]
[ 350-29-8 ]
[ 403-01-0 ]

Yield	Reaction Conditions	Operation in experiment
87%	With sulfuric acid; at 80℃;Cold solution;	Methyl 3-fluoro-4-hydroxybenzoate (T10.1). To a round bottom flask containing 3-fluoro-4-hydroxybenzoic acid (commercially available from Sigma- Aldrich, St. Louis, MO, USA) (5.03 g, 32.22 mmol) was added a cold solution of MeOH (50.0 mL) and sulfuric acid (2.0 mL). The mixture was heated to 80°C and monitored with TLC. After 20.5 hours, the solvent was removed and the resulting mixture was diluted with diethyl ether. The organic phase was washed carefully two times with saturated aqueous NaHCO3, once with brine, and then dried over anhydrous sodium sulfate. After filtration, the organic solvent was removed in vacuo to afford TlO.1 as a white solid (4.79 g, 87percent yield). 1H NMR (400 MHz, CDCl3) 7.81 (2 H, m), 7.06 (1 H, t, J=8.4 Hz), 5.62 (1 H, d, J=4.3 Hz), 3.91 (3 H, s).
87%	With sulfuric acid; at 80℃; for 20.5h;	Methyl 3-fluoro-4-hydroxybenzoate (T25.1). To a round bottom flask containing 3-fluoro-4-hydroxybenzoic acid (5.03 g, 32.22 mmol)(comrnercially available from Aldrich) was added a cold solution of MeOH (50.0 mL) and sulfuric acid (2.0 mL). The mixture was heated to 80°C and monitored with TLC. After 20.5 hours, the solvent was removed and the mixture was diluted with diethyl ether. The organic phase was washed carefully twice with saturated aqueous NaHCO3 and once with brine. The organic phase was then dried over anhydrous sodium sulfate. After filtration, the organic solvent was removed in vacuo to afford T25.1 as a white solid (4.79 g, 87percent yield). 1H NMR (400 MHz, CDCl3) delta ppm 7.81 (2 H, m), 7.06 (1 H, t, J=8.4 Hz), 5.62 (1 H, d, J=4.3 Hz), 3.91 (3 H, s).
85%	sulfuric acid;Heating / reflux;	Hydroxy -aryl- or hydroxy-heteroaryl-carboxylic acid to methyl ester- General procedure4-hydroxy-benzoic acid (usually 24.0 mmol) was dissolved in MeOH (50 mL) and sulfuric acid (1 mL/g substrate) was added. The mixture was refluxed overnight, after which the solvent was evaporated under reduced pressure; the crude was dissolved in DCM and washed with saturated NaHCO3 to basic pH. The organic phase was dried and evaporated under reduced pressure, and the product was used without further purification. The yields were between 80 and 90percent.; a) 3-Fluoro-4-hydroxy-ben.sum.oic acid methyl ester3-Fluoro-4-hydroxy-benzoic acid (5 g, 32.0 mmol) was dissolved in-MeOH (50 niL) and catalytic quantity of sulfuric acid (1 mL) was added. The mixture was refluxed overnight, after which the solvent was evaporated under reduced pressure; <n="121"/>the crude was dissolved in DCM and washed with saturated NaHCO3 to basic pH. The organic phase was dried and evaporated under reduced pressure, and the residue was used without further purification (yield 85percent).C8H7FO31H-NMR (dmso-d6): 3.78 (3H, s); 7.00-7.02 (IH, m); 7.61-7.64 (2H5 m); 10.89 (l , br s).

85%	With sulfuric acid;Reflux;	Hydroxy-aryl- or hydroxy-heteroaryl-carboxylic acid to methyl ester - General procedure; [0157] 4-hydroxy-benzoic acid (usually 24.0 mmol) was dissolved in MeOH (50 mL) and sulfuric acid (1 mL/g substrate) was added. The mixture was re fluxed overnight, after which the solvent was evaporated under reduced pressure; the crude was dissolved in DCM and washed with saturated NaHCO3 to basic pH. The organic phase was dried and evaporated under reduced pressure, and the product was used without further purification. The yields were between 80 and 90percent.
82%	With sulfuric acid; for 48h;Heating / reflux;	A solution of 3-fluoro-4-hydroxybenzoic acid (5.00 g, 32.0 mmol) in 15percent methanolic sulfuric acid solution (50 mL) was heated at reflux over 48 h, then poured upon ice and extracted with ethyl acetate. The organic layer was washed with 1 M aq. sodium carbonate solution and brine, dried (MgSO4), and evaporated to afford 4-fluoro-3-trifluoromethyl-benzoic acid methyl ester (4.48 g, 82percent). Off-white solid, MS (ISP)=169.1 (M-H)-.
	With thionyl chloride; at 0℃; for 2h;Heating / reflux;	Production Example 8-1: Methyl 3-fluoro-4-hydroxybenzenecarboxylate: A commercial product, 3-fluoro-4-hydroxybenzoic acid hydrate (1.1 g) was dissolved in methanol (11 mL), and in an ice bath, thionyl chloride (0.77 mL) was added thereto, and heated under reflux for 2 hours. After the reaction, the reaction liquid was entirely concentrated to obtain the entitled compound (1.1 g).
	With sulfuric acid; for 10h;Heating / reflux;	Into a 100 mL round-bottomed was added 4-hydroxy-3-fluorobenzoic acid (1 g), methanol (10 mL), and concentrated sulfuric acid (98percent, 0.1 mL). The mixture was heated to reflux for 10 hr. After the reaction was completed, the mixture was poured into 100 mL of ice water, and filtered to yield product A (1 g) as a white solid.
	With thionyl chloride; at 20℃; for 2h;Heating / reflux;	To a solution of 3-fluoro-4-hydroxybenzoic acid (1.17 g) in methanol (10 mL), thionyl chloride (602 muL) was added at room temperature, and the mixture was refluxed for 2 hours. The reaction mixture was concentrated under reduced pressure. Water (10 mL) and chloroform (10 mL) were added to the residue for phase separation. The aqueous layer was extracted with chloroform (2 x 10 mL). The organic layers were combined and dried over sodium sulfate anhydrate. The filtrate was concentrated under reduced pressure, whereby the title compound (1.19 g) was yielded. 1H-NMR (CDCl3)delta: 3.90(3H,s),5.85(1H,s),7.04(1H,t,J=8.3Hz),7.79-7.75(2H,m).
	With sulfuric acid; for 5h;Heating / reflux;	a) 3-Fluoro-4-hydroxybenzoic acid methyl ester To a solution of 3-fluoro-4-hydroxybenzoic acid (3.0 g) in methanol (30 mL) was added conc. sulfuric acid (3 mL), and the mixture was heated for 5 hours under reflux. The reaction solution was allowed to stand for cooling down to room temperature, and then concentrated in vacuo. The residue was diluted with ethyl acetate, washed successively with water, saturated aqueous sodium bicarbonate, water, and saturated brine, dried over anhydrous sodium sulfate, and concentrated to give the title compound (2.99 g).
21 g	With thionyl chloride; at 0 - 65℃; for 18h;	Intermediate 26: methyl 3-fluoro-4-hydroxybenzoate To a stirred solution of 3-fluoro-4-hydroxybenzoic acid (25 g, 160 mmol, Combiblocks) in methanol (250 mL), was added SOCI2 (25 ml, 343 mmol) at 0 °C and the mixture stirred at 65 °C for 18 h. The solvent was removed under reduced pressure and the residue diluted with diethyl ether (500 ml). The mixture was washed with cold saturated NaHC03 solution (3 x 500 ml), brine solution (2 x 500 ml), dried over anhydrous Na2S04 and the solvent removed under reduced pressure to give the title compound as a brown solid (21 g) which was used in the next step without further purification. (0324) LCMS Method B: m/z [M-H]" 169, tR 0.73 min
	With sulfuric acid; at 50℃;	3-Fluoro-4-hydroxybenzoic acid (0201-14) (1.0 g, 6.41 mmol, 1.0 equiv)Dissolved in 50 ml of methanol,Concentrated sulfuric acid (3 ml) was slowly added dropwise.The mixture was stirred at 50°C overnight.After the reaction was completed, the solvent was removed, the residue was added to ice water, extracted with ethyl acetate, washed twice with saturated brine, and dried over anhydrous sodium sulfate.Concentration afforded methyl 3-fluoro-4-hydroxybenzoate (1.25 g, crude) as an off-white solid.

References: [1]Patent: WO2010/45258,2010,A2 .Location in patent: Page/Page column 155.
[2]Patent: WO2009/111056,2009,A1 .Location in patent: Page/Page column 227-228.
[3]Patent: WO2008/87529,2008,A1 .Location in patent: Page/Page column 42; 43; 119-120.
[4]Patent: WO2010/9290,2010,A1 .Location in patent: Page/Page column 58.
[5]Patent: US2007/191603,2007,A1 .Location in patent: Page/Page column 35.
[6]Molecular Crystals and Liquid Crystals,2011,vol. 542,p. 123 - 131.
[7]Patent: EP1748048,2007,A1 .Location in patent: Page/Page column 37.
[8]Patent: US2008/132458,2008,A1 .Location in patent: Page/Page column 26.
[9]Patent: EP2017263,2009,A1 .Location in patent: Page/Page column 227.
[10]Patent: US2006/89392,2006,A1 .Location in patent: Page/Page column 39.
[11]Patent: WO2016/12916,2016,A1 .Location in patent: Page/Page column 40.
[12]Patent: CN107383024,2017,A .Location in patent: Paragraph 0140.

Yield	Reaction Conditions	Operation in experiment
17%		EXAMPLE 7 Fluorination of Methyl 4-hydroxybenzoate By the method outlined in Example 1, methyl 4-hydroxybenzoate was fluorinated to give methyl 3-fluoro-4-hydroxybenzoate (deltaF -133.2 ppm d6 -Me2[CO], yield 30percent) and methyl 3,5-difluoro-4-hydroxybenzoate (deltaF -129.1 ppm d6 -Me2[CO], yield 17percent). Conversion 100percent.

25
[ 350-29-8 ]
[ 107-06-2 ]
[ 403-01-0 ]

Yield	Reaction Conditions	Operation in experiment
91.6%	With sulfuric acid; sodium hydrogencarbonate; In methanol; hexane;	Step i) Production of methyl 3-fluoro-4-hydroxybenzoate 10.0 g (64.1 mM) of 3-fluoro-4-hydroxybenzoic acid, 150 ml of 1,2-dichloroethane, 80 ml of methanol and 10 ml of concentrated sulfuric acid were mixed, followed by refluxing for 5.5 hours under stirring and further stirring for 12 hours at room temperature. After the reaction, a solution of salt was added to the reaction mixture, followed by sufficient shaking to separate the reaction mixture. The organic layer was recovered from the reaction mixture and the water layer was subjected to extraction with methylene chloride to be added thereto. The resultant organic layer was washed with a 5percent-aqueous solution of sodium hydrogencarbonate in a solution of salt and further washed with a solution of salt, followed by drying with anhydrous sodium sulfate. The sodium sulfate was recovered by filtration and the filtrate was condensed into a solid. Hexane was added to the solid and subjected to filtration to obtain 9.98 g of methyl 3-fluoro-4-hydroxybenzoate (Yield: 91.6percent).

References: [1]Patent: US5200109,1993,A .

26
80%-hydrazine hydrate [ No CAS ]
[ 403-01-0 ]
[ 39635-02-4 ]

Yield	Reaction Conditions	Operation in experiment
92.6%	With hydrogenchloride; In methanol; water;	Step ii) Production of 3-fluoro-4-hydroxybenzohydrazide 10.00 g (58.8 mM) of <strong>[403-01-0]methyl 3-fluoro-4-hydroxybenzoate</strong> and 17.5 ml of 80percent-hydrazine hydrate were mixed and stirred for 1 hour and 20 minutes at 100° C., followed by cooling to room temperature. The resultant mixture was poured into 150 ml of iced water and 16.8 ml of concentrated hydrochloric acid was added thereto (pH=about 8), followed by addition of common salt and stirring at room temperature to precipitate a crystal. The crystal was recovered by filtration and stirred in methanol at room temperature. The resultant crystal was recovered from the above mixture by filtration to obtain 9.26 g of 3-fluoro-4-hydroxybenzohydrazide (Yield: 92.6percent).

References: [1]Patent: US5200109,1993,A .

27
[ 403-01-0 ]
[ 141-43-5 ]
[ 98054-13-8 ]

Yield	Reaction Conditions	Operation in experiment
41%		(a) 4,5-Dihydro-2-(3-fluoro-4-hydroxyphenyl)oxazole [XVI; R2, R4 ', R5 ' and R6 '=H, R1 =3-F, oxazole at 4-position] was prepared by reacting <strong>[403-01-0]methyl 3-fluoro-4-hydroxybenzoate</strong> with ethanolamine, and treating the resulting N-(2-hydroxyethyl)-3-fluoro-4-hydroxybenzamide with thionyl chloride, according to the procedures of Example 9, parts (a) and (b), and was obtained in 41percent yield as a colorless solid, m.p. 201°-203° C., when recrystallized from tetrahydrofuran.

References: [1]Patent: US4843087,1989,A .

28
[ 5292-43-3 ]
[ 403-01-0 ]
4-tert-butoxycarbonylmethoxy-3-fluoro-benzoic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	With Ki; In 1,2-dimethoxyethane;	EXAMPLE 187 4-tert-Butoxycarbonylmethoxy-3-fluoro-benzoic acid methyl ester A mixture of <strong>[403-01-0]3-fluoro-4-hydroxy-benzoic acid methyl ester</strong> (2.5 g, 14.7 mmol), NaH suspension in oil (55percent) (641 mg, 14.7 mmol), KI (244 mg, 14.7 mmol, 0.1 eq.) and tert.butyl bromoacetate (3.44 g, 17.6 mmol 1.2 eq.) in dimethoxyethane (20 ml) was heated to 70° C. for 16 hrs. After evaporation of the solvent the residue was chromatographed over 120 g SiO2 (Merck 230-400 mesh) with EtOAc/nHexane 7:93, affording the title compound (3.53 g, 85percent yield) as a colorless liquid. MS: m/e=284 (M+).

References: [1]Patent: US6265426,2001,B1 .

29
[ 403-01-0 ]
[ 75-03-6 ]
3-Fluoro-4-ethoxy benzoic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
101%	With potassium carbonate; In N,N-dimethyl-formamide;	EXAMPLE 183 3-Fluoro-4-ethoxy benzoic acid methyl ester A solution of <strong>[403-01-0]3-fluoro-4-hydroxy-benzoic acid methyl ester</strong> (1.5 g, 8.82 mmol), K2CO3 (2.43 g, 17.6 mmol) and ethyliodide (2.75 g, 17.6 mmol) in DMF (15 ml) was heated to 80° C. for 2 hrs. Addition of excess Na2CO3 and extraction with EtOAc followed by washing with satd. NaCl, then drying with Na2SO4 and evaporation afforded the title compound (1.76 g, 101percent yield) as an orange oil. MS: m/e=170 (M+).

References: [1]Patent: US6265426,2001,B1 .

30
[ 403-01-0 ]
methyl 4-(difluoromethoxy)-3-fluorobenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83%	With potassium carbonate; In Chlorodifluoromethane;	EXAMPLE 184 4-Difluoromethoxy-3-fluoro-benzoic acid methyl ester A solution of <strong>[403-01-0]3-fluoro-4-hydroxy-benzoic acid methyl ester</strong> (2 g, 11.75 mmol), chlorodifluoromethane (10.6 g, 122.6 mmol, 10.4 eq.) and K2CO3 (1.94 g, 14.1 mmol) was heated in an autoclave for 6 hrs. at 160° C. After cooling the mixture was treated with excess Na2CO3 and extracted with EtOAc. The organic phase was washed twice with satd. NaCl then dried and evaporated to afford the title compound (2.14 g, 83percent yield) as an orange oil. MS: m/e=220 (M+).

References: [1]Patent: US6265426,2001,B1 .

Historical Records

Technical Information

? Acidity of Phenols ? Acyl Group Substitution ? Alkyl Halide Occurrence ? Bouveault-Blanc Reduction ? Catalytic Hydrogenation ? Chan-Lam Coupling Reaction ? Complex Metal Hydride Reductions ? Electrophilic Substitution of the Phenol Aromatic Ring ? Ester Cleavage ? Etherification Reaction of Phenolic Hydroxyl Group ? Halogenation of Phenols ? Oxidation of Phenols ? Pechmann Coumarin Synthesis ? Preparation of Aldehydes and Ketones ? Reactions of Benzene and Substituted Benzenes ? Reactions with Organometallic Reagents ? Reimer-Tiemann Reaction ? Specialized Acylation Reagents-Carbodiimides and Related Reagents

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