[ CAS No. 25118-59-6 ]

Name: 25118-59-6|4-Bromo-3-chlorobenzoic acid|98%
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Quality Control of [ 25118-59-6 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 25118-59-6 ]

CAS No. :	25118-59-6	MDL No. :	MFCD08276864
Formula :	C₇H₄BrClO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	PSKJIHDVFDVNBU-UHFFFAOYSA-N
M.W :	235.46 g/mol	Pubchem ID :	12594302
Synonyms :

Calculated chemistry of [ 25118-59-6 ]

Physicochemical Properties

Num. heavy atoms :	11
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.0
Num. rotatable bonds :	1
Num. H-bond acceptors :	2.0
Num. H-bond donors :	1.0
Molar Refractivity :	46.11
TPSA :	37.3 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) :	-5.24 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.67
Log Po/w (XLOGP3) :	3.52
Log Po/w (WLOGP) :	2.8
Log Po/w (MLOGP) :	2.94
Log Po/w (SILICOS-IT) :	2.54
Consensus Log Po/w :	2.69

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.86
Solubility :	0.0329 mg/ml ; 0.00014 mol/l
Class :	Soluble
Log S (Ali) :	-3.99
Solubility :	0.0243 mg/ml ; 0.000103 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.25
Solubility :	0.134 mg/ml ; 0.000568 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	2.0
Synthetic accessibility :	1.36

Safety of [ 25118-59-6 ]

Signal Word:	Warning	Class:
Precautionary Statements:	P261-P301+P312-P302+P352-P304+P340-P305+P351+P338	UN#:
Hazard Statements:	H302-H315-H319-H335	Packing Group:
GHS Pictogram:

Application In Synthesis of [ 25118-59-6 ]

* 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 [ 25118-59-6 ]
Downstream synthetic route of [ 25118-59-6 ]

[ 25118-59-6 ] Synthesis Path-Upstream 1~14

1
[ 25118-59-6 ]
[ 17518-98-8 ]

Reference： [1] Chemistry - A European Journal, 2015, vol. 21, # 41, p. 14342 - 14346

2
[ 6627-51-6 ]
[ 25118-59-6 ]

Reference： [1] Journal of the Chemical Society, 1904, vol. 85, p. 1269
[2] Journal of the Chemical Society, 1914, vol. 105, p. 1910
[3] Patent: WO2005/32493, 2005, A2, . Location in patent: Page/Page column 47-48
[4] Patent: WO2005/32493, 2005, A2, . Location in patent: Page/Page column 47-48

3
[ 117738-74-6 ]
[ 25118-59-6 ]

Reference： [1] Patent: EP279698, 1990, A3,

4
[ 535-80-8 ]
[ 25118-59-6 ]

Reference： [1] Journal of the Indian Chemical Society, 1980, vol. 57, # 6, p. 640 - 642

5
[ 120077-69-2 ]
[ 25118-59-6 ]

Reference： [1] Journal of the Chemical Society, 1927, p. 25

6
[ 163596-75-6 ]
[ 25118-59-6 ]

Reference： [1] Journal of the Chemical Society, 1927, p. 25

7
[ 1122-91-4 ]
[ 25118-59-6 ]

Reference： [1] Journal of the Chemical Society, 1927, p. 25

8
[ 108-41-8 ]
[ 25118-59-6 ]

Reference： [1] Journal of the Chemical Society, 1914, vol. 105, p. 1910

9
[ 106-38-7 ]
[ 25118-59-6 ]

Reference： [1] Journal of the Chemical Society, 1914, vol. 105, p. 1910

10
[ 615-65-6 ]
[ 25118-59-6 ]

Reference： [1] Journal of the Chemical Society, 1904, vol. 85, p. 1269

11
[ 25118-59-6 ]
[ 120077-69-2 ]

Reference： [1] Journal of Medicinal Chemistry, 2012, vol. 55, # 23, p. 10572 - 10583
[2] Patent: WO2013/75083, 2013, A1,
[3] Patent: WO2014/8223, 2014, A2,
[4] Patent: US9206128, 2015, B2,
[5] Patent: WO2017/84630, 2017, A1,

12
[ 25118-59-6 ]
[ 3114-31-6 ]

Reference： [1] Patent: WO2013/144224, 2013, A1,
[2] Patent: US2016/194290, 2016, A1,

13
[ 25118-59-6 ]
[ 158435-41-7 ]

Reference： [1] Patent: US9206128, 2015, B2,

14
[ 25118-59-6 ]
[ 87427-57-4 ]

Reference： [1] Patent: WO2013/144224, 2013, A1,

[ 25118-59-6 ] Synthesis Path-Downstream 1~58

1
[ 25118-59-6 ]
[ 21900-32-3 ]

Yield	Reaction Conditions	Operation in experiment
	With oxalyl dichloride; In dichloromethane; N,N-dimethyl-formamide; at 20℃; for 3h;Cooling with ice;	To an ice-cooled mixture of Compound I (500 mg) and methylene chloride (4.2 mL) were added dropwise DMF (16 muL) and oxalyl chloride (273 muL), and then the mixture was stirred at room temperature for 3 hours, and the reaction mixture was concentrated under reduced pressure. To the resulting residue was added dichloromethane (6.0 mL), and the mixture was ice-cooled, and thereto was added zinc chloride (289 mg). The mixture was stirred for 30 minutes, and then thereto was added dropwise a solution ofN-methylpyrrole (943 muL) in dichloromethane (5.0 mL), and the mixture was stirred at room temperature for 3 days. To the reaction mixture was added water, and the mixture was extracted with chloroform. The organic layer was washed with brine, and then dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate = 100/0 to 80/20) to give Compound II (113 mg).
	With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 0 - 25℃; for 2h;	90.0 q (381.8 mmol) of a benzene compound represented by the above formula (8) was dissolved in 450 ml of dichloromethane and cooled to 0C. 148.8 g (1145.4 mmol) of oxalyl chloride and 4 ml of N,N-dimethylformamide were added dropwise to this solution. After addition, the resulting mixture was heated to 25C and stirred for 2 hours. After a reaction, the solvent and an excess of oxalyl chloride were distilled off under reduced pressure. The obtained residue was dissolved in 450 ml of tetrahydrofuran and cooled to -50C. 172 ml (343.6 mmol) of phenylmagnesium bromide (2.0M diethyl ether solution) was added dropwise to this solution. After addition, the resulting mixture was heated to 25C and stirred for 4 hours. After a reaction, 200 ml of toluene was added, the reaction solution was washed with water, the solvent was removed, and the obtained product was purified by reslurrying with methanol to obtain a benzophenone derivative represented by the following formula (27) as 73.3 g (214.5 mmol, yield of 56 %) of a white solid.
	With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 1h;	To a 100 ml one neck round bottom flask was charged with <strong>[25118-59-6]4-bromo-3-chlorobenzoic acid</strong> (1.00 g, 4.25 mmol) along with CH2Cl2(8 ml) followed by oxalyl dichloride (0.719 ml, 8.49 mmol) . The mixture was stirred while a drop of DMF was added to initiate the reaction and air bubble formed right away. The resulting mixture was then stirred at room temperature for 60 min until no air bubble evolved. The mixtuer was then concentrated and the resulting crude was carried on for next step coupling.

Reference： [1]Journal of the Chemical Society,1904,vol. 85,p. 1269
[2]Bulletin des Societes Chimiques Belges,1968,vol. 77,p. 273 - 285
[3]Journal of Medicinal Chemistry,2009,vol. 52,p. 3563 - 3575
[4]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 5548 - 5551
[5]Patent: EP2612848,2013,A1 .Location in patent: Paragraph 0350; 0351; 0352
[6]Patent: EP2669277,2013,A1 .Location in patent: Paragraph 0212
[7]Chemistry - A European Journal,2015,vol. 21,p. 14342 - 14346
[8]Patent: WO2016/106627,2016,A1 .Location in patent: Page/Page column 54

2
[ 6627-51-6 ]
[ 25118-59-6 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium permanganate; In water;Heating / reflux;	The 4-BROMO-3CHLOROTOLUENE (4. 0G ; 19. 5MOL) was added to A 250MU round bottom flask, followed by 50 ML of water. To the mixture was added 3. 22g of potassium permanganate (23. 4MMOL) and the reaction was refluxed until completion. After cooling, the mixture was filtered through celite. The aqueous layer was acidified and extracted three times with ETHYLACETATE. The organic layers were washed with brine, dried over MGS04. After filtration and evaporation, the resulting white solid was dissolved in 1. 0M HCI in ether and stirred overnight. The METHANOL was removed under vacuum and the residue was dissolved in ETHYLACETATE and washed with saturated sodium bicarbonate. The organic layer was dried over MGSO4, filtered and evaporated to give the desired material as A clear oil (713MG ; 15%).

Reference： [1]Journal of the Chemical Society,1904,vol. 85,p. 1269
[2]Patent: WO2005/32493,2005,A2 .Location in patent: Page/Page column 47-48

3
[ 64-17-5 ]
[ 25118-59-6 ]
[ 120077-67-0 ]

Yield	Reaction Conditions	Operation in experiment
97%	With sulfuric acid;Reflux;	A solution of <strong>[25118-59-6]4-bromo-3-chlorobenzoic acid</strong> (24.5 g, 104.05 mmol) and concentrated sulfuric acid (11.09 mL, 208.10 mmol) in EtOH (245 mL) was heated under reflux overnight. The reaction mixture was cooled, and concentrated under reduced pressure. To the residue was added ethyl acetate, and the organic layer was washed with water, aqueous sodium hydrogen carbonate solution and brine. Then, the organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give ethyl 4-bromo-3-chlorobenzoate (26.6 g, 101 mmol, 97%) as a pale orange solid. 1H NMR (300 MHz, CDCl3):delta 1.40(3H,t,J=7.0 Hz), 4.38(2H,q,J=7.2 Hz), 7.59-7.73(1H,m), 7.74-7.87(1H,m), 8.11(1H,d,J=1.5 Hz).
96%	With sulfuric acid; for 4h;Inert atmosphere; Reflux;	Step 1: ethyl 4-bromo-3-chlorobenzoateA solution of <strong>[25118-59-6]4-bromo-3-chlorobenzoic acid</strong> (5 g, 21 .23 mmol) and H2S04 (5 mL) in EtOH (50 mL) was heated under reflux for 4 hr under nitrogen atmosphere. The mixture was cooled down to rt and quenched with water (100 mL). The solution was extracted with EA (150 mL x 3), washed with saturated NaHC03 (500 mL x 3), dried over anhydrous Na2S04 and concentrated in vacuo to afford ethyl 4-bromo-3-chlorobenzoate (5.39 g, 96%) as a colorless oil.
88%	With sulfuric acid; at 0 - 85℃;	Example 5; l-(4-(5-(8-Bromo-6-(trifluoromethyl)imidazo[l,2-fl]pyridin-2-yl)-l,2,4-oxadiazol-3-yl)-3- chlorobenzyl)azetidine-3-carboxylic acid; Ethyl 3-chloro-4-bromo benzoate (34). To a stirred solution of intermediate 33 (10 g, 43 mmol) in EtOH (50 rnL) was added concentrated H2SO4 (20 mL) at 0 0C. After the addition was complete, the reaction was stirred at 85 0C for 4 h. After completion, the reaction mixture was concentrated in vacuo and the residue was dissolved in DCM. The organic layer was washed with water, aqueous sodium bicarbonate solution, and saturated NaCl. The organic layers were combined, dried over Na2SO4, and concentrated in vacuo to afford the title intermediate 34 as an off-white solid (10 g, yield 88%).

	With sulfuric acid; In water; for 60h;Heating / reflux;	Description for D22Ethyl 4-bromo-3-chlorobenzoate (D22) <n="47"/>To a suspension of <strong>[25118-59-6]4-bromo-3-chlorobenzoic acid</strong> (5.00 g, 21.2 mmol) in ethanol (50 ml.) was added sulphuric acid (5 mL) and the resultant mixture heated to reflux for 60 h. The reaction was partitioned between ethyl acetate (50 mL) and water (50 mL). The aqueous layer was extracted with further ethyl acetate and the combined organic fractions dried (phase separator) and concentrated in vacuo to give the title compound as a brown oil/solid (5.09 g, 19.3 mmol). deltaH (d6-DMSO, 400 MHz): 8.06 (1 H, d), 7.96 (1 H, d), 7.80 (1 H, dd), 4.33 (2H, q), 1.33 (3H, t). MS (ES): no mass ion observed.
	With sulfuric acid; for 60h;Heating / reflux;	To a suspension of <strong>[25118-59-6]4-bromo-3-chlorobenzoic acid</strong> (5.00 g, 21.2 mmol) in ethanol (50 ml.) was added sulphuric acid (5 mL) and the resultant mixture heated to reflux for 60 h. The reaction was partitioned between ethyl acetate (50 mL) and water (50 mL). The aqueous layer was extracted with further ethyl acetate and the combined organic fractions dried (phase separator) and concentrated in vacuo to give the title compound as a brown oil/solid (5.09 g, 19.3 mmol). deltaH (d6-DMSO, 400 MHz): 8.06 (1 H, d), 7.96 (1 H, d), 7.80 (1 H, dd), 4.33 (2H, q), 1.33 (3H, t).
	With thionyl chloride; at 0 - 60℃; for 16h;	To a solution of <strong>[25118-59-6]4-bromo-3-chlorobenzoic acid</strong> (21 .23 mmol, 5 g) in dry ethanol (30 ml_) at 05C, thionyl chloride (1 .8 eq. 38.2 mmol. 2.79 ml) was added dropwise. The mixture was stirred at 605C for 16h. Solvent was evaporated and the crude product was dissolved with EtAcO. The solution was washed with saturated NaHC03 aqueous solution, brine, dried over anhydrous MgS04, filtered and concentrated to dryness to afford the title compound which was used in the next step without further purification (5.60 g., Yield: 100%). LC-MS: tR = 2.79 [M+H] + = not ion (method 6)

Reference： [1]Patent: EP3192791,2017,A1 .Location in patent: Paragraph 0485
[2]Patent: WO2012/67664,2012,A1 .Location in patent: Page/Page column 37
[3]Patent: WO2010/65760,2010,A1 .Location in patent: Page/Page column 118-119
[4]Journal of the Indian Chemical Society,1980,vol. 57,p. 640 - 642
[5]Patent: WO2008/74821,2008,A1 .Location in patent: Page/Page column 44-45
[6]Patent: WO2008/128951,2008,A1 .Location in patent: Page/Page column 42-43
[7]Patent: WO2013/149996,2013,A1 .Location in patent: Page/Page column 96

4
[ 163596-75-6 ]
[ 25118-59-6 ]

Reference： [1]Journal of the Chemical Society,1927,p. 25

5
[ 1122-91-4 ]
[ 25118-59-6 ]

Reference： [1]Journal of the Chemical Society,1927,p. 25

6
[ 108-41-8 ]
[ 25118-59-6 ]

Reference： [1]Journal of the Chemical Society,1914,vol. 105,p. 1910

7
[ 106-38-7 ]
[ 25118-59-6 ]

Reference： [1]Journal of the Chemical Society,1914,vol. 105,p. 1910

8
[ 25118-59-6 ]
4-bromo-3-chloro-benzoic acid menthyl ester [ No CAS ]

Reference： [1]Journal of the Chemical Society,1904,vol. 85,p. 1269

9
[ 615-65-6 ]
[ 25118-59-6 ]

Reference： [1]Journal of the Chemical Society,1904,vol. 85,p. 1269

10
[ 25118-59-6 ]
4-Brom-3-chlor-4'-methyl-benzophenon [ No CAS ]

Reference： [1]Bulletin des Societes Chimiques Belges,1968,vol. 77,p. 273 - 285

11
[ 2127-03-9 ]
[ 25118-59-6 ]
[ 625446-26-6 ]

Yield	Reaction Conditions	Operation in experiment
	With triphenylphosphine; In acetonitrile; at 20℃; for 0.5h;	A mixture of <strong>[25118-59-6]4-bromo-3-chlorobenzoic acid</strong> (5.00 G, 21.24 MMOL), 2, 2 -DITHIODIPYRIDINE (4.68 G, 21.24 MMOL) and triphenylphosphine (5.57 G, 21.24 MMOL) in acetonitrile (150 ML) was stirred at room temperature for 0.5 h. The crystals were filtered and washed with petroleum ether to give the title compound.

Reference： [1]Patent: WO2005/9940,2005,A1 .Location in patent: Page 119

12
[ 109-72-8 ]
[ 624-92-0 ]
[ 25118-59-6 ]
[ 108-18-9 ]
4-bromo-3-chloro-2-methylsulphenylbenzoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; In tetrahydrofuran; hexane;	REFERENCE EXAMPLE 52 n-Butyllithium (2.5M in hexane; 8.8 ml) was added to a stirred cooled solution of di-isopropylamine (2.22 g) in dry tetrahydrofuran, maintaining the temperature below -40 C. The mixture was stirred for 0.5 hours then a solution of <strong>[25118-59-6]4-bromo-3-chlorobenzoic acid</strong> (2.36 g) in dry tetrahydrofuran was added. The mixture was stirred at -40 C. for 6 hours. Dimethyl disulphide (2.82 g) was added and the mixture was stirred at -40 C. for 1 hour and at room temperature overnight. Hydrochloric acid (2M) was added and the layers were separated. The organic layer was washed with water, dried (magnesium sulphate) and filtered. The filtrate was evaporated to dryness and the residue was recrystallized from a mixture of ethyl acetate and hexane to give 4-bromo-3-chloro-2-methylsulphenylbenzoic acid (0.98 g) as a solid, m.p. 128-130 C.

Reference： [1]Patent: US5804532,1998,A

13
[ 117738-74-6 ]
[ 25118-59-6 ]

Yield	Reaction Conditions	Operation in experiment
	In sodium hydroxide;	iii) Methyl 4-bromo-3-chlorobenzoate (20 g) was refluxed, with stirring, in aqueous sodium hydroxide solution (60 ml of 10% solution) for 2 hours. The resulting solution was cooled, diluted with water and acidified with concentrated hydrochloric acid solution. The aqueous mixture was extracted with diethyl ether and the ethereal extracts were dried over anhydrous magnesium sulphate. The solvent was removed in vacuo 4-Bromo-3-chlorobenzoic acid (18 g) was obtained as an off-white solid and was used without further purification. Nuclear magnetic resonance spectrum (N.M.R.) was as follows: 1H (p.p.m. from TMS in CDCl3, integral, number of peaks, J Hz): 7.80,2H, m; 8.10, 1H, m; 10.30, 1H, broad signal.

Reference： [1]Patent: EP279698,1990,A3

14
[ 25118-59-6 ]
[ 36805-97-7 ]
[ 570407-88-4 ]

Yield	Reaction Conditions	Operation in experiment
	In toluene; at 115℃; for 16h;	Intermediate 16 4-Carboxymethylsulfanyl-3-chloro-benzoic acid tert-butyl ester a) 3-Chloro-4-fluoro-benzoic acid tert-butyl ester4-Bromo-3-chloro-benzoic acid (1.3 g) was slurried in toluene (3 mL) and (di-tert- butoxymethyl)dimethylamine (9 mL) was added. The reaction mixture was heated to 115 0C for 16 h. The mixture was evaporated, the residue was partitioned between sodium bicarbonate solution and ethyl acetate, the organic phase was dried and evaporated to give the subtitle compound (1.3 g). LC-MS std RT 2.85 <n="34"/>1HNMR delta(cDCB) 1.60 (9H3 s), 7.17 (IH, t), 7.85 - 7.93 (IH3 m), 8.01 - 8.07 (IH, m).

Reference： [1]Patent: WO2007/102767,2007,A1 .Location in patent: Page/Page column 32-33

15
[ 25118-59-6 ]
[ 55899-42-8 ]
[ 1072930-35-8 ]

Yield	Reaction Conditions	Operation in experiment
71%		2-(4-Bromo-3-chloro-phenyl)-1-propyl-1H-benzoimidazole A mixture of <strong>[25118-59-6]4-bromo-3-chloro-benzoic acid</strong> (10 g, 41.2 mmol) and N-propyl-benzene-1,2-diamine (7.43 g, 49.5 mmol) in PPA (100 ml) was heated to 150 C. for 18 h. The mixture was poured onto ice/water. The pH was adjusted to 10 with a 30% aq. soln. of NaOH, filtered and extracted twice with EtOAc. The combined org layers were dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography (Hex/EtOAc 100:0 to 30:70) provided the desired product (10.17 g, 71%). HPLC (System 3, 30-100% CH3CN): tR=2.263 min, MS (LC-MS): 350 [M+1].
71%	With PPA; Polyphosphoric acid (PPA); at 150℃; for 18h;	2-(4-Bromo-3-chloro-phenyl)-1 -propyl-1 H-benzoimidazoleA mixture of <strong>[25118-59-6]4-bromo-3-chloro-benzoic acid</strong> (10 g, 41.2 mmol) and N-propyl-benzene-1 ,2- diamine (7.43 g, 49.5 mmol) in PPA (100 ml) was heated to 150 0C for 18 h. The mixture was poured onto ice/water. The pH was adjusted to 10 with a 30% aq. soln. of NaOH, filtered and extracted twice with EtOAc. The combined org layers were dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography (Hex/EtOAc 100:0 to 30:70) provided the desired product (10.17 g, 71 %). HPLC (System 3, 30-100% CH3CN): tR = 2.263 min, MS (LC-MS): 350 [M+1].

Reference： [1]Patent: US2009/105266,2009,A1 .Location in patent: Page/Page column 31
[2]Patent: WO2008/128968,2008,A1 .Location in patent: Page/Page column 72

16
[ 1039985-78-8 ]
[ 25118-59-6 ]
[ 1072930-39-2 ]

Yield	Reaction Conditions	Operation in experiment
70%		2-(4-Bromo-3-chloro-phenyl)-7-chloro-1-propyl-1H-benzoimidazole A mixture of <strong>[25118-59-6]4-bromo-3-chloro-benzoic acid</strong> (10 g, 41.2 mmol) and 3-Chloro-2N-propyl-benzene-1,2-diamine (9.13 g, 49.4 mmol) in PPA (100 ml) was heated to 150 C. for 18 h. The mixture was poured onto ice/water. The pH was adjusted to 10 with a 30% aq. soln. of NaOH, filtered and extracted twice with EtOAc. The combined org layers were dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography (Hex/EtOAc 100:0 to 20:80) provided the desired product (11.1 g, 70%). HPLC (System 3, 30-100% CH3CN): tR=3.591 min, MS (LC-MS): 358 [M+1].
70%	With PPA; Polyphosphoric acid (PPA); at 150℃; for 18h;	2-(4-Bromo-3-chloro-phenyl)-7-chloro-1 -propyl-1 H-benzoimidazoleA mixture of <strong>[25118-59-6]4-bromo-3-chloro-benzoic acid</strong> (10 g, 41.2 mmol) and 3-Chloro-2N-propyl- benzene-1 ,2-diamine (9.13 g, 49.4 mmol) in PPA (100 ml) was heated to 150 0C for 18 h. The mixture was poured onto ice/water. The pH was adjusted to 10 with a 30% aq. soln. of NaOH, filtered and extracted twice with EtOAc. The combined org layers were dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography (Hex/EtOAc 100:0 to 20:80) provided the desired product (1 1.1 g, 70%). HPLC (System 3, 30-100% CH3CN): tR = 3.591 min, MS (LC-MS): 358 [M+1].

Reference： [1]Patent: US2009/105266,2009,A1 .Location in patent: Page/Page column 32
[2]Patent: WO2008/128968,2008,A1 .Location in patent: Page/Page column 72

17
[ 25118-59-6 ]
(4-bromo-3-chlorophenyl)methanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
99%	With borane-THF; In tetrahydrofuran; at 0 - 20℃; for 2h;Inert atmosphere;	Under nitrogen, <strong>[25118-59-6]4-bromo-3-chlorobenzoic acid</strong> (1.5 g, 6.37 mmol) was placed in a 250 mL round bottom flask and taken up in tetrahydrofuran (THF) (15 mL), and then cooled to 0 C in an ice bath. Added dropwise via an addition funnel was borane-tetrahydrofuran complex (1M solution, 15 mL, 15 mmol). The solution was stirred for 2 h, slowly allowing the ice bath to warm to room temperature. Added to the flask was 4 mL of 1 : 1 THF:H20 followed by water (2 mL). The entire solution was concentrated in vacuo. The residue was taken up in ethyl acetate (50 mL) and water (50 mL) and the layers were separated. The aqueous layer was extracted with ethyl acetate (3 x 20 mL). The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to afford the title compound (1.4 g, 99%). 1H NMR (400 MHz, CHLOROFORM-d) d ppm 4.67 (s, 2 H) 7.14 (d, J=2.27 Hz, 1 H) 7.40 - 7.53 (m, 1 H) 7.61 (d, J=8.08 Hz, 1 H).
97%	With borane-THF; In tetrahydrofuran; at 20℃;	General procedure: 4-Bromo-3-chlorobenzoic acid (9.9 g, 42.04 mmol) was dissolved in THF (150 ml) tothis was (30 minutes) slowly added borane-THF (88 ml, 88.29 mmol) and the reaction was stirred for 2 hours. The reaction was very carefully quenched with methanol (50 mL), once the addition was complete, the mixture was quenched with water (75 mL), extracted with Et2O (2 x 150 mL), the organic layer was dried overMgSO4, filtered and evaporated to afford (4-bromo-3-chlorophenyl)methanol (9.00 g,97 %) as a colourless liquid.
92.1%	With borane-THF; at 0℃; for 10h;	Borane-THF complex (31.85 mL, 31.85 mmol) was added to 4-bromo-3- chlorobenzoic acid (1.5 g, 6.37 mmol) at 0 C, and stirred at 0 C for 10 h. The reaction wasquenched by methanol (50 mL) and concentrated under reduced pressure to give (4-bromo-3- chlorophenyl)methanol (1.3 g, 5.8696 mmol, 92.1% yield) as a light yellow oil.

91%	With borane-THF; In tetrahydrofuran; at 0 - 40℃;	(4-bromo-3-chlorophenyl)methanol. A solution of BH3 (34 mL, 1M in tetrahydrofuran) was added dropwise to the solution of <strong>[25118-59-6]4-bromo-3-chlorobenzoic acid</strong> (2.5 g, 11.4 mmol) in tetrahydrofuran at 0C. The mixture was stirred at 40C overnight. Acetic acid (5 mL) was added dropwise to the reaction mixture. The mixture was concentrated to give a residue. The residue was purified by column chromatography (silica gel, petroleum ethe/ ethyl acetate = 1 : 1) to give (4-bromo-3-chlorophenyl)methanol as a white solid (4.47 g, 91%). 1H NMR (300 MHz, /-DMSO): 7.69 (d, J=8.1,1H), delta 7.53 (d, J=0.9,1H), 7.19 (dd, Ji=8.1,lH J 2=0.9, 1H), 5.38 (s, 1H), delta 4.48 (s, 2H).
91%	With acetic acid; diborane; In tetrahydrofuran; at 0 - 40℃;	A solution of BH3 (34 mL, IM in tetrahydrofuran) was added dropwise to the solution of <strong>[25118-59-6]4-bromo-3-chlorobenzoic acid</strong> (2.5 g, 11.4 mmol) in tetrahydrofuran at 0 C. The mixture was stirred at 40 C. overnight. Acetic acid (5 mL) was added dropwise to the reaction mixture. The mixture was concentrated to give a residue. The residue was purified by column chromatography (silica gel, petroleum ethe/ethyl acetate=1:1) to give (4-bromo-3-chlorophenyl)methanol as a white solid (4.47 g, 91%). 1H NMR (300 MHz, d6-DMSO): 7.69 (d, J=8.1, 1H), delta 7.53 (d, J=0.9, 1H), 7.19 (dd, J1=8.1, 1H J2=0.9, 1H), 5.38 (s, 1H), delta 4.48 (s, 2H).
81%	With sodium tetrahydroborate; boron trifluoride diethyl etherate; In tetrahydrofuran; at 20℃; for 16h;Inert atmosphere;	Step A: Preparation of (4-bromo-3-chlorophenyl)methanol: A round bottom flask equipped with a stirbar and nitrogen inlet was charged with dry THF (72 mL), and sodium borohydride (1.09 g, 28.9 mmol). This suspension was chilled to 0 C and boron trifluoride etherate (8.20 g, 57.8 mmol) was then added and the mixture stirred at 0 C for 15 minutes. To this was added <strong>[25118-59-6]4-bromo-3-chlorobenzoic acid</strong> (3.40 g, 14.4 mmol) in one portion (gas evoluiton observed). The reaction mixture was allowed to warm to ambient temperature and stirred for 16 hours. The reaction mixture was then carefully quenched with methanol until gas evolution had ceased. The mixture was concentrated under reduced pressure and the resulting crude material was taken up in 100 mL of 20% aqueous NaOH and stirred at ambient temperature for 1 hour. The mixture was extracted 2 times with DCM, extracts dried over sodium sulfate and concentrated under reduced pressure to give (4-bromo- 3-chlorophenyl)methanol (2.59 g, 81%) as an oil.
	With borane-THF; In tetrahydrofuran; at 0 - 20℃; for 2h;	Preparation of 4-bromo-3-chloro-benzaldehyde (prep a lull); IM Borane/THF solution (150 mL, 150 mmol) was added to a solution of 4-bromo-3- chlorobenzoic acid (15 g, 63.7 mmol) in THF (150 mL) at 0 0C dropwisely. The reaction was allowed to warm to room temperature and stirred at room temperature for two hours. The reaction was quenched by dropwise addition of a mixture of THF and water (20 mL, 1: 1), followed by addition of water (20 mL). The reaction was extracted with EtOAc (100 mL) three times. The organic layer was combined and washed with brine, dried with anhydrous sodium sulfate and concentrated to yield solid intermediate. LCMS (Method b) R, = 1.96 min; m/z: 221 (M+H)+.

Reference： [1]Patent: WO2014/8223,2014,A2 .Location in patent: Page/Page column 97
[2]Synlett,2014,vol. 25,p. 123 - 127
[3]Patent: WO2017/84630,2017,A1 .Location in patent: Paragraph 00694
[4]Patent: WO2013/75083,2013,A1 .Location in patent: Paragraph 00409; 00410
[5]Patent: US9206128,2015,B2 .Location in patent: Page/Page column 194; 195
[6]Patent: WO2014/78331,2014,A1 .Location in patent: Paragraph 00638
[7]Patent: WO2009/11850,2009,A2 .Location in patent: Page/Page column 172
[8]Patent: WO2012/67664,2012,A1
[9]Journal of Medicinal Chemistry,2012,vol. 55,p. 10572 - 10583
[10]Journal of Medicinal Chemistry,2017,vol. 60,p. 7146 - 7165

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[ 1117-97-1 ]
[ 1235711-34-8 ]

Yield	Reaction Conditions	Operation in experiment
91%		PREPARATION B : 4-bromo-3-chloro-N-methoxy-N-methyl-benzamide; [Show Image] Under argon, a 10 mL one-necked round bottomed flask was charged with <strong>[25118-59-6]4-bromo-3-chlorobenzoic acid</strong> (1.74 g, 7.18 mmol) in dry dimethylformamide (10 mL), followed by hydroxybenzotriazole (1.09 g, 7.90 mmol) and after 5 minutes stirring at ambient temperature, N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide (1.54 g, 7.90 mmol). The reaction mixture was stirred at ambient temperature during 30 minutes. Then, at 0C, N,O-dimethylhydroxylamine (0.80 g, 7.90 mmol) was poured. The reaction mixture was stirred at ambient temperature during 16 hours. The reaction mixture was co-evaporated with toluene in vacuo. The residue was diluted with sodium hydrogenocarbonate (40 mL) and the aqueous layer was extracted with ethyl acetate (3 x 40 mL). The organic layer was washed with water (2 x 30 mL), brine (30 mL), dried over anhydrous magnesium sulfate and evaporated in vacuo. The product was dried under high vacuum yielding 4-bromo-3-chloro-N-methoxy-N-methyl-benzamide (1.81 g, 91 %) as a yellow solid. 1H NMR (300 MHz, DMSO-d6): delta 7.85 (AB system, 1H, J=8.3 Hz), 7.80 (d, 1H, J=1.9 Hz), 7.48 (dd, 1H, J=1.9 Hz, 8.3 Hz), 3.55 (s, 3H), 3.26 (s, 3H).
5.91 g	With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃;	To a stirred solution of <strong>[25118-59-6]4-bromo-3-chloro-benzoic acid</strong> (5.0 g, 21 .2 mmol) in dichloromethane (50 ml) was added /V-methoxymethylamine (1 .43 g, 23.34 mmol), 1 -ethyl-3-(3- dimethylaminopropyl)carbodiimide (4.16 g, 25.48 mmol), 7-aza-1 -hydroxybenzotriazole (590 mg, 4.25 mmol)and /V-ethyldiisopropylamine (7.42 ml, 42.5 mmol). The mixture was then allowed to react overnight at room temperature. 100 ml of ethyl acetate as well as 100 ml of water were added. The organic phase was washed once with a saturated solution of sodium bicarbonate (50 ml). The organic phase was then concentrated under reduced pressure. The crude product was purified by flash chromatography to provide 5.91 g of 4-bromo-3-chloro-/V- methoxy-/V-methyl-benzamide

Reference： [1]Patent: EP2208725,2010,A1 .Location in patent: Page/Page column 12
[2]Patent: WO2013/144224,2013,A1 .Location in patent: Page/Page column 32

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[ 25118-59-6 ]
[ 1228826-41-2 ]

Yield	Reaction Conditions	Operation in experiment
100%		To a suspension of <strong>[25118-59-6]4-bromo-3-chlorobenzoic acid</strong> (2.00 g, 8.49 mmol) in toluene (10 mL) at ambient temperature was added thionyl chloride (1.85 mL, 25.4 mmol). The reaction mixture was heated at reflux for 20.5 hours, then distilled for 1 hour, collecting 9 mL of distillate. Toluene (10 mL) was added and the reaction was distilled for 30 minutes, collecting 10 mL of distillate. The reaction mixture was cooled to ambient temperature resulting in a suspension. Toluene (10 mL) saturated with ammonia gas was added to the reaction mixture followed by bubbling ammonia gas through the reaction for 10 minutes. The reaction was stirred at ambient temperature for 1 hour. Heptane (10 mL) was added, and the reaction stirred at ambient temperature for 15 minutes, then 0 C for 1 hour. The solids were collected by vacuum filtration, rinsed with excess heptane, and dried to afford 4-bromo-3- chlorobenzamide (2.327 g, 116.8%) as a white solid which was carried on without further purification.

Reference： [1]Patent: WO2011/29027,2011,A1 .Location in patent: Page/Page column 72; 73

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[ 1370257-32-1 ]

Reference： [1]Patent: WO2012/42007,2012,A1

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[ 1370257-47-8 ]

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[ 1370257-48-9 ]

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[ 1370257-50-3 ]

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[ 1370257-51-4 ]

Reference： [1]Patent: WO2012/42007,2012,A1

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[ 25118-59-6 ]
[ 1370257-46-7 ]

Yield	Reaction Conditions	Operation in experiment
100%		Step 1 : Synthesis of 4-bromo-3-chloro-N-trimethylsilanylmethyl-benzamide To a suspension of <strong>[25118-59-6]4-bromo-3-chlorobenzoic acid</strong> (25.00 g, 106.2 mmol) in CH2CI2 (320 ml.) was added Nu,Nu-dimethyl aminopyridine (1 .95 g), followed by N-ethyl-N- dimethylamine propylcarbodiimide hydrochloride (22.39 g) in small portions. After 30 min at room temperature, aminomethyl trimethylsilane (1 1 .2 g, 7.87 ml_, 108 mmol) was added while maintaining the temperature at 20C. After stirring over night, water was added and the organic layer was separated. The aqueous layer was extracted twice with CH2CI2 and the combined organic phases were dried and evaporated in vacuum. The residue was purified by flash chromatography on silica gel to give the title compound (34.00 g, 100%). Characterization by 1 H-N M R (400 MHz, CDCI3):delta [delta] = 0.15 (s, 9H), 2.96 (m, 2H), 6.07 (br. s, 1 H), 7.50 (m, 1 H), 7.69 (m, 1 H), 7.86 (m, 1 H) ppm.

Reference： [1]Patent: WO2012/42007,2012,A1 .Location in patent: Page/Page column 204

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[ 68120-44-5 ]