161957-56-8|3-Bromo-2-fluorobenzoic acid| Ambeed

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Quality Control of [ 161957-56-8 ] Purity: 98% SDS Specification

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Product Details of [ 161957-56-8 ]

CAS No. :	161957-56-8
Formula :	C₇H₄BrFO₂
M.W :	219.01
SMILES Code :	O=C(O)C1=CC=CC(Br)=C1F
MDL No. :	MFCD00665763
Boiling Point :	No data available
InChI Key :	UVKURTLVTLRSSM-UHFFFAOYSA-N
Pubchem ID :	2736313

Safety of [ 161957-56-8 ]

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

Application In Synthesis of [ 161957-56-8 ]

* 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 [ 161957-56-8 ]
Downstream synthetic route of [ 161957-56-8 ]

[ 161957-56-8 ] Synthesis Path-Upstream 1~2

1
[ 161957-56-8 ]
[ 161957-61-5 ]

References: [1] Patent: US2008/76771, 2008, A1, .

2
[ 161957-56-8 ]
[ 1195768-19-4 ]

References: [1] ACS Medicinal Chemistry Letters, 2013, vol. 4, # 3, p. 358 - 362.

[ 161957-56-8 ] Synthesis Path-Downstream 1~35

1
[ 64-17-5 ]
[ 161957-56-8 ]
[ 334792-76-6 ]

Yield	Reaction Conditions	Operation in experiment
92%	With sulfuric acid; at 20℃; for 24h;Reflux;	To a stirred solution of <strong>[161957-56-8]3-bromo-2-fluorobenzoic acid</strong> 1 (25.0 g, 114.15 mmol) in ethanol (400 mL) was added conc. H2S04 (3 mL) at RT and stirred at reflux temperature for 24 h. The reaction was monitored by LC-MS; after completion of the reaction, the reaction mixture was concentrated to obtain the residue. The residue was diluted with EtOAc (500 mL), washed with water (300 mL), brine (300 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford compound 2 (26.0 g, 92%) as a light yellow liquid. 1H NMR (400 MHz, CDC13): (57.88-7.84 (m, 1H), 7.72-7.69 (m, 1H), 7.08-7.04 (m, 1H), 4.39 (q, J= 7.2 Hz, 2H), 1.39 (t, J= 7.2 Hz, 3H).
92%	With sulfuric acid; for 24h;Reflux;	Step 1: Synthesis of ethyl 3-bromo-2-fluorobenzoate (2’):1003051 To a stirred solution of <strong>[161957-56-8]3-bromo-2-fluorobenzoic acid</strong> 1(25.0 g, 114.15 mmol) in ethanol (400 mL) was added conc. H2S04 (3 mL) at RT and stirred at reflux temperature for 24 h. The reaction was monitored by LC-MS; after completion of the reaction, the reaction mixture was concentrated to obtain the residue. The residue was diluted with EtOAc (500 mL), washed with water (300 mL), brine (300 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford compound 2 (26.0 g, 92%) as a light yellow liquid. 1H NMR (400 MHz, CDC13): (57.88-7.84 (m, 1H), 7.72-7.69 (m, 1H), 7.08-7.04 (m, 1H), 4.39 (q, J= 7.2 Hz, 2H), 1.39 (t, J 7.2 Hz, 3H).
92%	With sulfuric acid; for 24h;Reflux;	Step 5: Synthesis of ethyl 3-bromo-2-fluorobenzoate (A2) To a stirred solution of <strong>[161957-56-8]3-bromo-2-fluorobenzoic acid</strong> A1 (25.0 g, 114.15 mmol) in ethanol (400 mL) was added conc. H2SO4 (3 mL) at RT and stirred at reflux temperature for 24 h. The reaction was monitored by LC-MS; after completion of the reaction, the reaction mixture was concentrated to obtain the residue. The residue was diluted with EtOAc (500 mL), washed with water (300 mL), brine (300 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford compound A2 (26.0 g, 92%) as a light yellow liquid. 1H NMR (400 MHz, CDCl3): δ 7.88-7.84 (m, 1H), 7.72-7.69 (m, 1H), 7.08-7.04 (m, 1H), 4.39 (q, J=7.2 Hz, 2H), 1.39 (t, J=7.2 Hz, 3H).

92%

With sulfuric acid; for 24h;Reflux;

To a stirred solution of <strong>[161957-56-8]3-bromo-2-fluorobenzoic acid</strong> Al (25.0 g, 114.15 mmol)in ethanol (400 mL) was added conc. H2 SO4 (3 mL) at RT and stirred at reflux temperature for 24 h. The reaction was monitored by LC-MS; after completion of the reaction, the reaction mixture was concentrated to obtain the residue. The residue was diluted with EtOAc (500 mL), washed with water (300 mL), brine (300 mL), dried over Na2 SO4, filtered and concentrated under reduced pressure to afford compound A2 (26.0 g, 92%) as a light yellow liquid. 1H NMR (400 MHz, CDC13): ö 7.88-7.84 (m, 1H), 7.72-7.69 (m, 1H), 7.08-7.04 (m, 1H), 4.39 (q, J = 7.2 Hz, 2H), 1.39 (t, I = 7.2 Hz, 3H).

References: [1]Patent: WO2015/48301,2015,A1 .Location in patent: Paragraph 00406.
[2]Patent: WO2015/77503,2015,A1 .Location in patent: Page/Page column 00305; 00343.
[3]Patent: US9051320,2015,B1 .Location in patent: Paragraph 0260.
[4]Patent: WO2016/191427,2016,A1 .Location in patent: Paragraph 00324; 00329.
[5]Bioorganic and Medicinal Chemistry,2006,vol. 14,p. 4158 - 4181.

2
[ 6638-79-5 ]
[ 161957-56-8 ]
[ 680610-73-5 ]

Yield	Reaction Conditions	Operation in experiment
95%		(RS)-4-(3-Bromo-2-fluoro-phenyl)-4-(4-methoxy-3-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine 3-Bromo-2-fluoro-N-methoxy-N-methylbenzamide [680610-73-5] Carbonyldiimidazole (7.76 g) was added portionwise to commercially available <strong>[161957-56-8]3-bromo-2-fluorobenzoic acid</strong> [161957-56-8] (9.53 g) in dichloromethane (100 mL) over 30 min. The mixture was then heated at reflux for 30 min (until gas evolution ceased). The reaction was then cooled to room temperature and triethylamine (6.37 mL) followed by N,O-dimethylhydroxylamine hydrochloride (4.7 g) were added. The reaction was left to stir at room temperature for 16 h before being washed with 10% citric acid (2100 mL) and sat. NaHCO3 (2100 mL), and then dried over sodium sulfate. The solvent was removed by evaporation to yield the product as a brown oil (10.89 g, 95%). 1H NMR (CDCl3): 3.20-3.80 (6H, m, ArCONCH3OCH3), 7.10 (1H, t, Ar), 7.35 (1H, td, Ar), 7.60 (1H, dt, Ar).
73%	With pyridine; carbon tetrabromide; triphenylphosphine; In dichloromethane; at 20℃; for 4h;	3-Bromo-2-fluoro-benzoic acid (0.22 g, 1.0 mmol), O,N-Dimethyl-hydroxylammonium chloride (0.11 g, 1.1 mmol), carbon tetrabromide (0.32 g, 1.1 mmol), triphenylphosphine (0.29 g, 1.1 mmol) and pyridine (87 mg, 1.1 mmol) were all combined in CH2Cl2 (10 mL) and stirred at room temperature for 4 h. The mixture was concentrated and chromatographed to provide 0.19 mg (73%) of the title compound as colorless oil.

References: [1]Patent: US2009/209529,2009,A1 .Location in patent: Page/Page column 34.
[2]Patent: US2008/76771,2008,A1 .Location in patent: Page/Page column 18.

3
[ 161957-56-8 ]
[ 334792-77-7 ]

References: [1]Bioorganic and Medicinal Chemistry,2006,vol. 14,p. 4158 - 4181.

4
[ 161957-56-8 ]
[ 334792-80-2 ]

References: [1]Bioorganic and Medicinal Chemistry,2006,vol. 14,p. 4158 - 4181.

5
[ 161957-56-8 ]
[ 334792-79-9 ]

References: [1]Bioorganic and Medicinal Chemistry,2006,vol. 14,p. 4158 - 4181.

6
[ 161957-56-8 ]
[ 334792-78-8 ]

References: [1]Bioorganic and Medicinal Chemistry,2006,vol. 14,p. 4158 - 4181.

7
[ 161957-56-8 ]
[ 334792-82-4 ]

References: [1]Bioorganic and Medicinal Chemistry,2006,vol. 14,p. 4158 - 4181.

8
[ 161957-56-8 ]
[ 334792-81-3 ]

References: [1]Bioorganic and Medicinal Chemistry,2006,vol. 14,p. 4158 - 4181.

9
[ 161957-56-8 ]
[ 334792-84-6 ]

References: [1]Bioorganic and Medicinal Chemistry,2006,vol. 14,p. 4158 - 4181.

10
[ 161957-56-8 ]
[ 334792-83-5 ]

References: [1]Bioorganic and Medicinal Chemistry,2006,vol. 14,p. 4158 - 4181.

11
[ 161957-56-8 ]
(2S)-benzenesulfonylamino-3-[2-fluoro-3-{4-(1,4,5,6-tetrahydropyrimidin-2-ylamino)piperidin-1-yl}benzoylamino]propionic acid [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry,2006,vol. 14,p. 4158 - 4181.

12
[ 161957-56-8 ]
[ 75-65-0 ]
[ 848440-23-3 ]

Yield	Reaction Conditions	Operation in experiment
61%		A suspension of <strong>[161957-56-8]3-bromo-2-fluorobenzoic acid</strong> (21.9 g, 100 mmol), DPPA (33.0 g, 120 mmol), and triethylamine (17 mL, 120 mmol) in toluene (1,000 mL) was stirred at 120C. After the mixture was heated to reflux for 2 hours, t-BuOH was added to the mixture, and the mixture was heated to reflux for further 2 hours. The solvent was removed from the mixture, the residue was purified by silica gel column chromatography using petroleum ether to give tert-butoxy-N-(3-bromo-2-fluorophenyl)carboxamide as colorless oil (17.7 g, yield 61%). 1H-NMR Spectrum (300MHz, CDCl3):δ (ppm): 1.52 (s, 3H), 6.72 (brs, 1H), 6.93-6.99 (m, 1H), 7.12-7.18 (m, 1H), 8.04 (t, J=7.5Hz, 1H)
		Triethylamine (0.6 ml) was added to a stirred solution of <strong>[161957-56-8]3-bromo-2-fluorobenzoic acid</strong> (438 mg, 2MMOL) in tert-butanol (10 ml). Diphenyl phosphoryl azide (1 ml, 4. 6MMOL) was then added and the reaction mixture was heated under reflux overnight. The solution was evaporated to dryness and azeotroped with toluene. The residues were then purified by flash chromatography on silica eluting with ethyl acetate/i-hexane (10/90). Fractions containing the required product were combined and evaporated to give tert-butyl (3-bromo-2-fluorophenyl) carbamate as a white solid (330mg)
	With diphenyl phosphoryl azide; triethylamine; In toluene; at 100℃; for 2h;	To 3-bromo-2-fluorobenzoicacid (10.0 g, 45.7 mmol) in 100 mL of toluene, were added by Et3N(7.7 mL, 54.8 mmol) and DPPA (15.0 g, 54.8 mmol). The mixture was heated to 1000C. When gas evolved, t-BuOH(10 mL) was added and stirring was kept for additional 2 hours. The mixture was cooled down and washedsuccessively by saturated Na2CO3 solution, 10% citric acidand brine. The organic layer was collected, dried over Na2SO4and concentrated to get the N-Bocprotected intermediate, which was used directly for next step.The crudesuspended in 30 mL of DCM, was added by TFA (15 mL). The mixture was thenstirred at rt for 2 hours. The resulting solid was filtered off and 5 M ofHCl/MeOH was added to the filtrate, forming the yellow solid, which wascollected and neutralized by saturated Na2CO3 solution toget free base as brown oil. (6.5 g, 71% yield)

To <strong>[161957-56-8]3-bromo-2-fluorobenzoic acid</strong> (10.0 g, 45.7 mmol) in 100 mL of toluene, were added by Et3N (7.7 mL, 54.8 mmol) and DPPA (15.0 g, 54.8 mmol). The mixture was heated to 100 C. When gas evolved, t-BuOH (10 mL) was added and stirring was kept for additional 2 hours. The mixture was cooled down and washed successively by saturated Na2CO3 solution, 10% citric acid and brine. The organic layer was collected, dried over Na2SO4 and concentrated to get the N-Boc protected intermediate, which was used directly for next step.

References: [1]Patent: EP2987787,2016,A1 .Location in patent: Paragraph 0193.
[2]Patent: WO2005/26150,2005,A1 .Location in patent: Page/Page column 124.
[3]Bioorganic and Medicinal Chemistry,2008,vol. 16,p. 10001 - 10012.
[4]Bioorganic and Medicinal Chemistry,2015,vol. 23,p. 7661 - 7670.
[5]Patent: US10221168,2019,B1 .Location in patent: Page/Page column 20; 21.

13
[ 161957-56-8 ]
[ 98-80-6 ]
[ 177942-40-4 ]

Yield	Reaction Conditions	Operation in experiment
46%	With sodium carbonate;palladium diacetate; In water; at 20℃; for 120h;	a) 2-Fluorobiphenyl-3-carboxylic acid 3-Bromo-2-fluorobenzoic acid (0.50 g, 2.3 mmol), phenylboronic acid (0.28 g, 2.3 mmol), sodium carbonate (0.73 g, 6.9 mmol), and palladium (II) acetate (5 mg, 0.023 mmol) in water (10 mL) were stirred at ambient temperature for 5 days. The reaction mixture was poured into 1 N HCl solution and extracted with ethyl acetate. The ethyl acetate layer was washed with 1 N HC1 (lx), water (lx) and brine (lx), and dried over MgS04. After filtration, the solvent was removed in vacuo to yield 0.53 g of product, which was recrystallized from EtOAc/hexane (1: 1) to yield 2-fluorobiphenyl-3-carboxylic acid (225 mg, 46%) as a white crystalline solid. 1H-NMR (300 MHz, d6-DMSO): 8 13.29 (1H, br s, exchangeable), 7.90- 7. 80 (1H, m), 7. 76-7.66 (1H, m), 7. 59-7. 33 (6H, m).

References: [1]Patent: WO2005/61494,2005,A1 .Location in patent: Page/Page column 15.

14
[ 161957-56-8 ]
[ 374554-41-3 ]

Yield	Reaction Conditions	Operation in experiment
	N,N-dimethyl-formamide; In oxalyl dichloride; dichloromethane;	REFERENCE EXAMPLE 24 To a solution of <strong>[161957-56-8]3-bromo-2-fluorobenzoic acid</strong> (2.3 g) in dichloromethane (20 ml) were added in turn oxalyl chloride (1.83 ml) and a catalytic amount of N,N-dimethylformamide (2 drops) at ambient temperature. After stirring at ambient temperature for an hour, the reaction mixture was evaporated in vacuo to give 3-bromo-2-fluorobenzoyl chloride.
	With thionyl chloride; for 2h;Heating / reflux;	Example A.5; a) Preparation of intermediate (15); A mixture of 3-bromo-2-fluoro-benzoic acid (22 mmol) and thionyl chloride (20 mL) was stirred and refluxed for 2 hours. The reaction mixture was concentrated in vacuo, and co-evaporated twice with toluene (40 mL), yielding intermediate (15), which was used as such in the next step.
	With thionyl chloride; In dichloromethane; for 6h;Reflux;	To a stirred solution of <strong>[161957-56-8]3-bromo-2-fluorobenzoic acid</strong> (24.3 g, 111 mmol) in CH2Cl2 (100 mL) was added SOCl2 (12.2 mL, 166 mmol). The mixture was stirred under reflux for 6 h until the solution is colorless. CH2Cl2 was removed under vacuum. Then the residue was dissolved in ethyl acetate (200 mL) and then added dropwise to NH3H2O (80 mL). The organic layer was washed with H2O (50 mL*2), brine and dried over Na2SO4, filtered and concentrated to give 23.8 g of the title compound as a white solid (98% yield).

	With thionyl chloride; In dichloromethane; for 6h;Reflux;	Example 20 3-Bromo-2-fluorobenzamide To a stirred solution of <strong>[161957-56-8]3-bromo-2-fluorobenzoic acid</strong> (24.3 g, 111 mmol) in CH2Cl2 (100 mL) was added SOCl2 (12.2 mL, 166 mmol). The mixture was stirred under reflux for 6 h until the solution is colorless. CH2Cl2 was removed under vacuum, the residue was dissolved in ethyl acetate (200 mL), then was added dropwise to NH3H2O (80 mL). The organic layer was wash with H2O (50 mL*2), brine and dried Na2SO4, filtered and concentrated to give 23.8 g of the title compound as a white solid (98% yield).
	With thionyl chloride;N,N-dimethyl-formamide; at 85℃; for 3h;	Example 7; 9-(pyrrolidin-1-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine dihydrochloride; (1) N-benzyl-3-bromo-2-fluoro-N-(2-hydroxyethyl)benzamide; A solution of <strong>[161957-56-8]3-bromo-2-fluorobenzoic acid</strong> (10.0 g, 45.9 mmol) and N,N-dimethylformamide (0.100 ml) in thionylchloride (10 ml) was stirred for 3 hr at 85C, and the solvent was evaporated under reduced pressure. The residue was added to a solution of N-benzylethanolamine (6.94 g, 45.8 mmol) and triethylamine (9.60 ml, 68.9 mmol) in tetrahydrofuran (140 ml) under ice-cooling, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the desired product (11.5 g, 68.9%) as an oil. 1H-NMR (CDCl3) δ; 1.58 (0.3H, t, J = 6.0 Hz), 2.71 (0.7H, t, J = 5.1 Hz), 3.27-3.31 (0.6H, m), 3.57-3.68 (2H, m), 3.78-3.83 (1.4H, m), 4.50 (1.4H, s), 4.90 (0.6H, s), 7.04-7.14 (2H, m), 7.28-7.40 (5H, m), 7.56-7.62 (1H, m).
	With thionyl chloride; In dichloromethane; for 6h;Reflux;	Example 17 3-Bromo-2-fhiorobenzamideTo a stirred solution of <strong>[161957-56-8]3-bromo-2-fluorobenzoic acid</strong> (24.3 g, 111 mmol) in CH2Cl2 (100 mL) was added SOCl2 (12.2 mL, 166 mmol). The mixture was stirred under reflux for 6 h until the solution is colorless. CH2Cl2 was removed under vacuum. Then the residue was dissolved in ethyl acetate (200 mL) and then added dropwise to NH3H2O (80 mL). The organic layer was washed with H2O (50 mL x 2), brine and dried over Na2SOzI, filtered and concentrated to give 23.8 g of the title compound as a white solid (98% yield).
	With thionyl chloride;Reflux;	General procedure: A mixture of benzoic acid 8 (10 mmol) in sulfinyl dichloride (SOCl2, 20-50 mmol) was stirred under reflux condition for 3-8 h, and then the solvent was removed under reduced pressure to afford crude chlorides 9. Ammonium thiocyanate (15 mmol) and PEG-400 (0.18 g) were added to the solution of benzoyl chloride 9 (10 mmol) in dichloromethane (25 mL). The mixture was stirred at room temperature for 1 h. Then the precipitate was filtered off, the filtrate containing compounds 10 was collected to be used in next step directly.
	With thionyl chloride; triethylamine; In tetrahydrofuran; for 1h;	To a solution of <strong>[161957-56-8]3-bromo-2-fluorobenzoic acid</strong> (3.77 g, 17.2 mmol) in dry tetrahydrofuran (200 ml) was added triethylamine (4.77 ml, 34.4 mmol) and thionyl chloride (1.69 ml, 21.5 mmol). The reaction mixture was stirred for 1 h and then quenched with ammonia in methanol (10 ml, saturated). After an additional hour of stirring the mixture was evaporated and the crude product was purified by flash column chromatography (ethyl acetate/isooctane 1:1) to give the title compund (1.76 g). MS m/z (rel. intensity, 70 eV) 219 (M+, 26), 217 (M+, 26), 203 (62), 201 (70), 94 (bp).
	With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 0 - 25℃; for 2h;Inert atmosphere;	Synthesis of (3b) To a solution of <strong>[161957-56-8]3-bromo-2-fluorobenzoic acid</strong> (3a) (2.5 g, 11.42 mmol) in DCM (10 mL) were added DMF (83.44 mg, 1.14 mmol, 87.83 uL) and oxalyl dichloride (2.90 g, 22.83 mmol, 2.00 mL) at 0 C. under N2. After addition, the mixture was stirred at 25 C. under N2 for 2 hrs. The reaction mixture was concentrated under reduced pressure to give 3-bromo-2-fluorobenzoyl chloride (3b) which was used directly in the next step.
	With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 4h;	A suspension of 3-bromo-2-fiuorobenzoic acid (1 g, 4.6 mmol) in DC (15 mL) at 0 C was treated with oxaiyl chloride (474 mI_, 5.5 mmol) dropwise over 2 minutes. DMF (2 drops) was added and the reaction mixture was stirred at room temperature for 4 h. Solvent was removed under reduced pressure to give crude 3-bromo-2-fluorobenzoyl chloride, which was used immediately without further purification.

References: [1]Patent: US2003/176454,2003,A1 .
[2]Patent: WO2009/71631,2009,A2 .Location in patent: Page/Page column 18.
[3]Patent: US2009/203657,2009,A1 .Location in patent: Page/Page column 47.
[4]Patent: US2009/197871,2009,A1 .Location in patent: Page/Page column 40.
[5]Patent: EP2123644,2009,A1 .Location in patent: Page/Page column 47-48.
[6]Journal of Medicinal Chemistry,2010,vol. 53,p. 7011 - 7020.
[7]Patent: WO2009/100169,2009,A1 .Location in patent: Page/Page column 125.
[8]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 2641 - 2644.
[9]Patent: WO2005/121087,2005,A1 .Location in patent: Page/Page column 66.
[10]Patent: US2019/315767,2019,A1 .Location in patent: Paragraph 0399; 0402.
[11]Patent: WO2020/257632,2020,A1 .Location in patent: Page/Page column 62; 71.

15
[ 124-38-9 ]
[ 161957-56-8 ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of 1-bromo-2-fluorobenzene (6.0 g, 34.3 mmol) in dry tetrahydrofuran (50 ml) under nitrogen, at-78 C was added lithium diisopropylamide (2.5 M in hexane, 18.8 ml, 37.7 mmol). The mixture was stirred for 50 minutes and then poured onto crushed solid carbon dioxide. The reaction mixture was brought to ambient temperature and aqueous sodium carbonate (10%, 50 ml) was added. The aqueous phase was washed with diethyl ether (2x100 ml), and then made acidic by addition of aqueous hydrochloric acid. The acidified aqueous phase was extracted with ethyl acetate (2x50 ml) and the combined organic phases was dried (MgS04) and evaporated to dryness to give the title compound (4.24 g).

References: [1]Patent: WO2005/121087,2005,A1 .Location in patent: Page/Page column 66.

16
[ 333792-46-4 ]
[ 79-37-8 ]
[ 161957-56-8 ]
[ 374554-93-5 ]

Yield	Reaction Conditions	Operation in experiment
	With ammonium chloride; sodium hydrogencarbonate; triethylamine; In methanol; dichloromethane; N,N-dimethyl-formamide;	REFERENCE EXAMPLE 79 To a suspension of <strong>[161957-56-8]3-bromo-2-fluorobenzoic acid</strong> (1.16 g) in dichloromethane (10 ml) were added oxalyl chloride (1.34 g) and N,N-dimethylformamide (1 drop) under stirring at ambient temperature. After stirring for 2 hours, the reaction mixture was evaporated in vacuo, and the residue was taken up into dichloromethane (5 ml) to give a solution of a crude acid chloride. To a solution of 3-(1,2-dimethyl-1H-imidazol-5-yl)aniline (900 mg) and triethylamine (971 mg) in dichloromethane (10 ml) was added the solution of the acid chloride dropwise under stirring at ambient temperature. After stirring for 14 hours, the reaction mixture was evaporated. The residue was diluted with water (100 ml) and extracted with ethyl acetate (50 ml2). The combined extracts were washed with an aqueous saturated solution of ammonium chloride (50 ml2), an aqueous saturated solution of sodium hydrogencarbonate (50 ml*2) and brine (50 ml). The organic layer was dried over magnesium sulfate and filtered. After evaporation, the residue was chromatographed on silica gel diluting with a mixture of dichloromethane and methanol to give 3-bromo-N-[3-(1,2-dimethyl-1H-imidazol-5-yl)phenyl]-2-fluorobenzamide (1.66 g) as crystals. Mass: 388,390 (1:1 ratio, Br isotopes, m/z, (M+H)+) NMR(DMSO-d6, δ): 2.35 (3H, s), 3.55 (3H, s), 6.87 (1H, s), 7.19 (1H, d, J=7.8 Hz), 7.31 (1H, t, J=7.8 Hz), 7.44 (1H, t, J=7.8 Hz), 7.6-7.8 (3H, m), 7.8-8.0 (1H, m).

References: [1]Patent: US2003/176454,2003,A1 .

17
[ 161957-56-8 ]
[ 149-73-5 ]
[ 206551-41-9 ]

Yield	Reaction Conditions	Operation in experiment
	With toluene-4-sulfonic acid; In methanol;	EXAMPLE 120 3-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-2-fluoro-benzonitrile A solution of 3-bromo-2-fluorobenzoic acid (0.219 g, 1 mmol) in dry methanol (5 mL) under nitrogen was treated with trimethylorthoformate (0.22 mL, 2 mmol) and p-toluenesulfonic acid (catalytic amount), and then heated under reflux. After 16 h, the mixture was evaporated and the residue partitioned between water and Et2O. the organic layer was washed with sat. sodium hydrogen carbonate solution, water, brine, dried (MgSO4) and evaporated to give methyl 3-bromo-2-fluorobenzoate (0.195 g, 0.84 mmol, 84percent): 1H-NMR (CDCl3) delta7.90-7.85 (m, 1H), 7.71-7.65 (m, 1H), 7.10 (dt, 1H, J=8.0, 1.0 Hz), 3.94 (s, 3H): MS (EI) 232 (M+).
	With toluene-4-sulfonic acid; In methanol;	EXAMPLE 68 2-fluoro-3-(1',2'-Dihydro-2'-oxospiro[cyclohexane-1,3'-[3H]indol-5'-yl)benzaldehyde oxime A solution of 3-bromo-2-fluorobenzoic acid (0.219 g, 1 mmol) in dry methanol (5 ml) under nitrogen was treated with trimethylorthoformate (0.22 ml, 2 mmol) and p-toluenesulfonic acid (catalytic amount), and then heated under reflux. After 16 h, the mixture was evaporated and the residue partitioned between water and Et2O. The organic layer was washed with sat. sodium hydrogen carbonate solution, water, brine, dried (MgSO4) and evaporated to give methyl 3-bromo-2-fluorobenzoate (0.195 g, 0.84 mmol, 84percent): 1H NMR (CDCl3) delta7.90-7.85 (m, 1H), 7.71-7.65 (m, 1H), 7.10 (dt, 1H, J=8.0, 1.0 Hz) and 3.94 (s, 3H): MS (EI) 232 (M+).
	With toluene-4-sulfonic acid; In methanol;	EXAMPLE 120 3-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-2fluoro-benzonitrile A solution of 3-bromo-2-fluorobenzoic acid (0.219 g, 1 mmol) in dry methanol (5 mL) under nitrogen was treated with trimethylorthoformate (0.22 mL, 2 mmol) and p-toluenesulfonic acid (catalytic amount), and then heated under reflux. After 16 h, the mixture was evaporated and the residue partitioned between water and Et2O. the organic layer was washed with sat. sodium hydrogen carbonate solution, water, brine, dried (MgSO4) and evaporated to give methyl 3-bromo-2-fluorobenzoate (0.195 g, 0.84 mmol, 84percent): 1H-NMR (CDCl3) delta7.90-7.85 (m, 1H), 7.71-7.65 (m, 1H), 7.10 (dt, 1H, J=8.0, 1.0 Hz), 3.94 (s, 3H): MS (EI) 232 (M+).

With toluene-4-sulfonic acid; In methanol;

EXAMPLE 68 2-Fluoro-3-(1',2'-dihydro-2'-oxospiro[cyclohexane-1,3'-[3H]indol]-5-yl) A solution of 3-bromo-2-fluorobenzoic acid (0.219 g, 1 mmol) in dry methanol 5 ml) under nitrogen was treated with trimethylorthoformate (0.22 ml, 2 mmol) and p-toluenesulfonic acid (catalytic amount), and then heated under reflux. After 16 h, the mixture was evaporated and the residue partitioned between water and Et2O. The organic layer was washed with sat. sodium hydrogen carbonate solution, water, brine, dried (MgSO4) and evaporated to give methyl 3-bromo-2-fluorobenzoate (0.195 g, 0.84 mmol, 84percent): 1H NMR (CDCl3) delta 7.90-7.85 (m, 1H), 7.71-7.65 (m, 1H), 7.10 (dt, 1H, J=8.0, 1.0 Hz) and 3.94 (s, 3H): MS (EI) 232 (M+).

References: [1]Patent: US2002/49204,2002,A1 .
[2]Patent: US6391907,2002,B1 .
[3]Patent: US6444668,2002,B1 .
[4]Patent: US6462032,2002,B1 .

18
[ 1072-85-1 ]
[ 29786-93-4 ]
[ 161957-56-8 ]

Yield	Reaction Conditions	Operation in experiment
57%	With lithium; diisopropylamine; In tetrahydrofuran; water;	Intermediate 38: 3-Bromo-2-fluorobenzoic acid Tetrahydrofuran (60 ml) was added to diisopropylamine (9.6 ml, 68 mmol) in an argon atmosphere. n-Butyllithium (hexane solution, 1.5 M, 38 ml, 57 mmol) was added dropwise thereto at -10C, and the mixture was stirred for one hr. Separately, 55 ml of tetrahydrofuran was added to 1-bromo-2-fluorobenzene (10 g, 57 mmol) to prepare a solution which was then added dropwise to the lithium reagent solution at -78C. The mixture was stirred for 2 hr and was then stirred for additional 30 min while blowing carbon dioxide thereinto. The temperature of the reaction mixture was returned to room temperature, and the reaction mixture was concentrated under the reduced pressure. Water (200 ml) was added to the residue to prepare a solution, and the solution was washed twice with 100 ml of diethyl ether.The aqueous layer was adjusted to pH 1 by the addition of 1.0 M hydrochloric acid, was extracted twice with 300 ml of methylene chloride, was dried over anhydrous magnesium sulfate, and was concentrated under the reduced pressure to give the title compound (7.1 g, 57%). Physicochemical properties of intermediate 38

References: [1]Patent: EP1229024,2002,A1 .

19
[ 161957-56-8 ]
[ 871353-25-2 ]

Yield	Reaction Conditions	Operation in experiment
98%		Example 17 3-Bromo-2-fluorobenzamide To a stirred solution of <strong>[161957-56-8]3-bromo-2-fluorobenzoic acid</strong> (24.3 g, 111 mmol) in CH2Cl2 (100 mL) was added SOCl2 (12.2 mL, 166 mmol). The mixture was stirred under reflux for 6 h until the solution is colorless. CH2Cl2 was removed under vacuum. Then the residue was dissolved in ethyl acetate (200 mL) and then added dropwise to NH3H2O (80 mL). The organic layer was washed with H2O (50 mL*2), brine and dried over Na2SO4, filtered and concentrated to give 23.8 g of the title compound as a white solid (98% yield).
85.38%		To a solution of compound 36.1 (1.0g, 4.56mmol, 1.0eq) in dichloromethane (15mL) was added thionyl chloride (3.28mL, 45.6mmol, 10.0eq) at 0C with catalytic dimethylformamide (0.5mL). Reaction mixture was stirred at 70C for 2h. After completion of reaction, reaction mixture was concentrated under reduced pressure to obtain crude material. To this crude material was added 20ml ethyl acetate followed by 20mL aqeous ammonia solution and stirred at room temperature for 1h. The organic layer was separated, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to obtain crude material. This was further purified by column chromatography using 30% ethyl acetate in hexane to obtain 36.2. (0.850g, Yield: 85.38%), MS (ES): m/z 218.95 [M+H]+.
75%		A mixture of <strong>[161957-56-8]3-bromo-2-fluorobenzoic acid</strong> (2-79, 400 mg, 1.83 mmol) and SOd2 (4.39 mg, 3.66 mmol) in DCM (5 mL) was stirred at r.t for 1 h, and then NH3H20 (1 mL) was added. The resulting mixture was then stirred at r.t for 2 h. Upon reaction completion, the resulting mixture was washed with water and extracted with ethyl acetate (150 ml. x 3). The combined organic phases were concentrated under reduced pressure and the resulting residue was purified via silica gel chromatography (Pet Ether/ethyl acetate =1/1) to obtain intermediate-2-80 (white solid, 300 mg, 75% yield). LCMS (m/z): 218 [M + Hj.

64%

To a solution of 2-fluoro-3-bromobenzoic acid (1.36 g) in N, N-dimethylformamide (5 inL) were added l-ethyl-3- (3- dimethylaminopropyl) carbodiimide hydrochloride (1.80 g) and ammonium 1-hydroxybenzotriazole (1.43 g) , and the mixture was stirred overnight at room temperature. The mixture was diluted with ethyl acetate, saturated aqueous sodium hydrogen carbonate, washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound (867 mg, yield 64%) as colorless oil.1H NMR (300 MHz, CDCl3) δ ppm 5.85 (1 H, br. s.) 6.61 (1 H, br. s.) 7.10 - 7.23 (1 H, m) 7.64 - 7.81 (1 H, m) 7.99 - 8.17 (1 H, m)

References: [1]Patent: US2009/203677,2009,A1 .Location in patent: Page/Page column 50.
[2]Patent: WO2020/112937,2020,A1 .Location in patent: Paragraph 00548.
[3]Patent: WO2016/161145,2016,A1 .Location in patent: Paragraph 00752.
[4]Patent: WO2008/156757,2008,A1 .Location in patent: Page/Page column 138.
[5]Patent: WO2005/121087,2005,A1 .
[6]Patent: WO2009/100169,2009,A1 .

20
[ 67-56-1 ]
[ 161957-56-8 ]
[ 206551-41-9 ]

Yield	Reaction Conditions	Operation in experiment
	sulfuric acid; for 1h;Inert atmosphere; Reflux;	To a 100 mL round bottom flask was added 3-bromo-2-fluorobenzoiotac acid (10 4 g, 10 47 5 mmol), MeOH (100 mL, 2472 mmol) and sulfuric acid (6 mL, 113 mmol) The reaction mixture was refluxed for 1 hr After cooling to rt, the MeOH was removed under reduced pressure and the acidic residue was poured into cold water and EtOAc, the layers were separated and the aqueous layer was extracted with EtOAc The organic layers were combined, washed with brine, dried over sodium sulfate and 15 concentrated under reduced pressure to afford 10 02 g of methyl 3-bromo-2- fluorobenzoate 1H-NMR (400 MHz, DMSO-ds) delta 7 95 (ddd, J = 8 1 , 6 4, and 1 7 Hz, 1 H), 7 82 - 7 87 (m, 1 H), 7 26 (t, J =7 9 Hz, 1 H), and 3 86 (s, 3 H)
	With sulfuric acid; for 1h;Inert atmosphere; Reflux;	To a 100 mL round bottom flask was added 3-bromo-2-fluorobenzoic acid (10.4 g, 47.5 mmol), MeOH (100 mL, 2472 mmol) and sulfuric acid (6 mL, 1 13 mmol). The reaction mixture was refluxed for 1 hr. After cooling to rt, the MeOH was removed under reduced pressure and the acidic residue was poured into cold water and EtOAc, the layers were separated and the aqueous layer was extracted with EtOAc. The organic layers were combined, washed with brine, dried over NaSO and concentrated under reduced pressure to afford methyl 3-bromo-2-fluorobenzoate. 10.02 g. 1H-NMR (400 MHz, DMSO-de) delta 7.95 (ddd, J = 8.1 , 6.4, and 1 .7 Hz, 1 H), 7.82 - 7.87 (m, 1 H), 7.26 (t, J =7.9 Hz, 1 H), and 3.86 (s, 3 H).
	With sulfuric acid; at 20℃; for 18h;	3-Bromo-2-fluorobenzoic acid was transformed to intermediate 4 using the same procedure reported in example intermediate 2 to afford the corresponding amine as pale yellow oil.

With sulfuric acid; for 1h;Reflux;

Intermediate 15: N-{3-[(2-Chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide; Step A: Methyl 3-bromo-2-fluorobenzoate; To a 100 mL round bottom flask was added 3-bromo-2-fluorobenzoic acid (10.4 g, 47.5 mmol), MeOH (100 mL, 2472 mmol) and sulfuric acid (6 mL, 113 mmol). The reaction mixture was refluxed for 1 hr. After cooling to rt, the MeOH was removed under reduced pressure and the acidic residue was poured into cold water and EtOAc, the layers were separated and the aqueous layer was extracted with EtOAc. The organic layers were combined, washed with brine, dried over NaSO4 and concentrated under reduced pressure to afford 10.02 g of methyl 3-bromo-2-fluorobenzoate. 1H-NMR (400 MHz, DMSO-d6) delta 7.95 (ddd, J=8.1, 6.4, and 1.7 Hz, 1H), 7.82-7.87 (m, 1H), 7.26 (t, J=7.9 Hz, 1H), and 3.86 (s, 3H).

References: [1]Patent: WO2010/104899,2010,A1 .Location in patent: Page/Page column 162.
[2]Patent: WO2011/59610,2011,A1 .Location in patent: Page/Page column 86.
[3]ACS Medicinal Chemistry Letters,2013,vol. 4,p. 358 - 362.
[4]Patent: US9126993,2015,B2 .Location in patent: Page/Page column 51.
[5]Patent: US2009/298815,2009,A1 .Location in patent: Page/Page column 52-53.

21
[ 27329-70-0 ]
[ 161957-56-8 ]
[ 1190223-47-2 ]

References: [1]Journal of Medicinal Chemistry,2009,vol. 52,p. 7631 - 7639.
[2]Journal of Medicinal Chemistry,2011,vol. 54,p. 572 - 579.

22
[ 161957-56-8 ]
[ 1336963-98-4 ]

Yield	Reaction Conditions	Operation in experiment
45%		DPPA (75.4 g, 274 mmol) and Et3N (38.2 mL, 274 mmol) were added to a solution of <strong>[161957-56-8]3-bromo-2-fluorobenzoic acid</strong> (50 g, 228 mmol) in toluene (2 L). After heating at reflux for 2 h, f-BuOH was added and the mixture was heated at reflux for 2 additional hours. The solvent was removed and the residue was stirred in 5N HCI/1 ,4-dioxane (500 mL) for 18 h at room temperature. The mixture was filtered and the filter cake was washed with diethyl ether and dried to afford 3-bromo-2-fluoroaniline hydrochloride (27 g, 45% yield) as a white solid.

References: [1]Patent: WO2011/119704,2011,A1 .Location in patent: Page/Page column 40.

23
[ 161957-56-8 ]
[ 1389287-37-9 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 4502 - 4505.
[2]Patent: US2012/220572,2012,A1 .

24
[ 161957-56-8 ]
[ 74-88-4 ]
[ 206551-41-9 ]

Yield	Reaction Conditions	Operation in experiment
	In N,N-dimethyl-formamide; at 50℃; for 24h;	To a solution of 3-bromo-2-fluorobenzoic acid (10 g, 0.045 mol) in N,N-dimethylformamide (50 mL) was added iodomethane (5 mL) dropwise. The reaction was heated to 50° C. for 24 hours. After the reaction was cooled and diluted with water (500 mL), ethyl acetate (200 mL) was added. The organic phase was separated, dried over MgSO4, filtered, and concentrated to provide the title compound

References: [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 4502 - 4505.
[2]Patent: US2012/220572,2012,A1 .Location in patent: Page/Page column 85.
[3]Organic Letters,2017,vol. 19,p. 1112 - 1115.

25
[ 161957-56-8 ]
[ 1195768-18-3 ]

References: [1]Patent: WO2011/59610,2011,A1 .
[2]ACS Medicinal Chemistry Letters,2013,vol. 4,p. 358 - 362.
[3]Patent: US2009/298815,2009,A1 .

26
[ 161957-56-8 ]
[ 1195768-27-4 ]