Name: 117738-74-6|Methyl 4-bromo-3-chlorobenzoate|98%
Brand: Ambeed
SKU: A783135
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1
sodium metabisulfite [ No CAS ]
copper(ll) sulfate pentahydrate [ No CAS ]
[ 84228-44-4 ]
[ 117738-74-6 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; sodium bromide; sodium nitrite; In water; hydrogen bromide;	ii) A solution of <strong>[84228-44-4]methyl 4-amino-3-chlorobenzoate</strong> (17.0 g) in 48% hydrobromic acid (200 ml) was stirred at 0. Sodium nitrite solution (6.3 g in 25 ml of water) was added dropwise over 45 minutes and the reaction mixture was maintained at 0-5C. The mixture was stirred at 0-5 for 2 hours. A solution of sodium metabisulphite (5.5 g) and sodium hydroxide (3.6 g) in water (40 ml) was added to a hot solution of copper (II) sulphate pentahydrate (25.5 g) and sodium bromide (12.3 g) in water (80 ml). The stirred suspension was maintained at 75 and the cold diazonium salt solution was added. The mixture was stirred for 15 minutes and 48% hydrobromic acid (30 ml) was added. The mixture was cooled to room temperature and extracted with diethyl ether. The ethereal extracts were washed with water and brine and dried over anhydrous magnesium sulphate. The solution was evaporated in vacuo . Methyl 4-bromo-3-chlorobenzoate (20.4 g) was obtained as a crystalline solid and was used without further purification. Gas-liquid chromatography (g.l.c.): OV-210 at 180 produced one peak. Nuclear magnetic resonance spectrum (N.M.R.) was as follows: 1H (p.p.m. from TMS in CDCl3, integral, number of peaks, J Hz): 3.80, 3H, s; 7.50, 2H, m; 7.90, 1H, m.

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

2
[ 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

3
5-Amino-2-methylpyridine [ No CAS ]
[ 117738-74-6 ]
[ 1072930-83-6 ]

Yield	Reaction Conditions	Operation in experiment
100%	With potassium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In toluene at 80℃; for 16h;	115 3-Chloro-4-(6-methyl-pyridin-3-ylamino)-benzoic Acid Methyl Ester 3-Chloro-4-(6-methyl-pyridin-3-ylamino)-benzoic Acid Methyl Ester A suspension of 4-Bromo-3-chloro-benzoic acid methyl ester (7.0 g, 28.1 mmol), 3-amino-6-methylpyridine (3.19 g, 29.5 mmol), rac-BINAP (1.75 g, 2.81 mmol), Pd2(dba)3 (0.629 g, 2.8 mmol) and K2CO3 (19.4 g, 140 mmol) in toluene (250 mL) was heated to 80° C. for 16 h. The mixture was allowed to cool to RT and washed twice with aq. NaHCO3. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to afford crude 3-Chloro-4-(6-methyl-pyridin-3-ylamino)-benzoic acid methyl ester (9.12 g, 100%) which was used without further purification. HPLC (System 1, 0-100% CH3CN): tR=2.867 min, MS (ES+): 277 [M+1]
100%	With potassium carbonate In toluene at 80℃; for 16h;	115 3-Chloro-4-(6-methyl-pyridin-3-ylamino)-benzoic acid methyl esterA suspension of 4-Bromo-3-chloro-benzoic acid methyl ester (7.0 g, 28.1 mmol), 3-amino-6- methylpyridine (3.19 g, 29.5 mmol), rac-BINAP (1.75 g, 2.81 mmol), Pd2(dba)3 (0.629 g, 2.8 mmol) and K2CO3 (19.4 g, 140 mmol) in toluene (250 ml.) was heated to 80 0C for 16 h. The mixture was allowed to cool to RT and washed twice with aq. NaHCO3. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to afford crude 3-Chloro-4-(6- methyl-pyridin-3-ylamino)-benzoic acid methyl ester (9.12 g, 100%) which was used without further purification. HPLC (System 1 , 0-100% CH3CN): tR = 2.867 min, MS (ES+): 277 [M+1]

Reference： [1]Current Patent Assignee: Novartis (w/o Sandoz); NOVARTIS AG; CARCACHE; GLATTHAR - US2009/105266, 2009, A1 Location in patent: Page/Page column 34
[2]Current Patent Assignee: Novartis (w/o Sandoz); NOVARTIS AG; CARCACHE; GLATTHAR - WO2008/128968, 2008, A1 Location in patent: Page/Page column 79

4
[ 117738-74-6 ]
[ 1279107-81-1 ]
[ 1279106-83-0 ]

Yield	Reaction Conditions	Operation in experiment
41%	With caesium carbonate In 1,4-dioxane at 100℃; for 4h; Inert atmosphere;	88 methyl ester: A solution of 1-benzenesulfonyl-2-(2,6-difluoro-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole (200 mg, 0.40 mmol) and 4-bromo-3-chloro-benzoic acid methyl ester (82 mg, 0.60 mmol) in 1,4-dioxane (5 mL) was purged with nitrogen (10 min), then Cs2CO3 (263 mg, 0.80 mmol) and Pd(dppf)Cl2 (33 mg, 0.040 mmol) were added, and purged with nitrogen again (5 min). The reaction mixture was stirred at 100° C. for 4 h. After the completion of reaction it was filtered through Celite and the filtrate was diluted with water and extracted with EtOAc. The organic phase was washed with brine, dried over Na2SO4 and concentrated. The crude compound was purified by CombiFlash column chromatography to give 4-[1-benzenesulfonyl-2-(2,6-difluoro-phenyl)-1H-indol-5-yl]-3-chloro-benzoic acid methyl ester (90 mg, 41%).

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - US2011/71150, 2011, A1 Location in patent: Page/Page column 75-76

5
[ 117738-74-6 ]
[ 1279107-81-1 ]
[ 1279104-25-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: caesium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / 1,4-dioxane / 4 h / 100 °C / Inert atmosphere 2: methanol; caesium carbonate / tetrahydrofuran / 24 h / 25 °C

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - US2011/71150, 2011, A1

6
[ 117738-74-6 ]
[ 1608148-00-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: zinc dibromide / tetrahydrofuran; cyclohexane / 0.5 h / -78 - 20 °C / Inert atmosphere 1.2: 2 h / -78 - 20 °C / Inert atmosphere 2.1: potassium hydroxide; water / 1,4-dioxane / Reflux

Reference： [1]Current Patent Assignee: AKAAL PHARMA - WO2014/63199, 2014, A1

7
[ 117738-74-6 ]
[ 1608148-02-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: zinc dibromide / tetrahydrofuran; cyclohexane / 0.5 h / -78 - 20 °C / Inert atmosphere 1.2: 2 h / -78 - 20 °C / Inert atmosphere 2.1: potassium hydroxide; water / 1,4-dioxane / Reflux 3.1: oxalyl dichloride / N,N-dimethyl-formamide; dichloromethane / 1 h / 20 °C 4.1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 2 h / 0 - 20 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: AKAAL PHARMA - WO2014/63199, 2014, A1

8
[ 117738-74-6 ]
[ 54256-44-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: zinc dibromide / tetrahydrofuran; cyclohexane / 0.5 h / -78 - 20 °C / Inert atmosphere 1.2: 2 h / -78 - 20 °C / Inert atmosphere 2.1: potassium hydroxide; water / 1,4-dioxane / Reflux 3.1: oxalyl dichloride / N,N-dimethyl-formamide; dichloromethane / 1 h / 20 °C

Reference： [1]Current Patent Assignee: AKAAL PHARMA - WO2014/63199, 2014, A1

9
[ 29786-93-4 ]
[ 117738-74-6 ]
[ 1608147-96-1 ]
[ 1608147-98-3 ]

Yield	Reaction Conditions	Operation in experiment
1: 57% 2: 21%	Stage #1: n-butyllithium With zinc dibromide In tetrahydrofuran; cyclohexane at -78 - 20℃; for 0.5h; Inert atmosphere; Stage #2: methyl 4-bromo-3-chlorobenzoate With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide In tetrahydrofuran; cyclohexane at -78 - 20℃; for 2h; Inert atmosphere;	56.B Step B: Methyl 4-n-butyl-3-chlorobenzoate: ZnBr2 (0.56 g; 2.49 mmol) was kept in vacuo at 1 10°C for 1 h. After cooling to room temperature under N2, anhydrous THF (4 ml) was added to it with stirring and the resulting solution was cooled to -78°C. To it 2N nBuLi in cyclohexane was added and the resulting mixture was stirred at room temperature for 30 min, cooled back to -78°C. To it the product of Step A (0.75 g; 3 mmol) was added under N2 with stirring, followed by CIPd(PPh3)2 (0.12 g) and Cul (0.05 g). The mixture was allowed to warm up to room temperature and stirred for 2 h. To it MeOH (4 ml) was added and solvents were removed under reduced pressure. The residue was partitioned between EtOAc (50 ml) and 5% NH4CI (10 ml). The organic phase was washed with brine, dried over anhydrous MgS04, filtered and filtrate evaporated to dryness. The residue was purified by FCC (Si02; CH2CI2/hexane 1 :1 ) to give the title compound (0.39 g; 57%), as creamy solid). 1H-NMR (CDCI3) 7.99 (d, 1 H, J = 1 .7 Hz); 7.81 (dd, 1 H, J = 1 .7; 8 Hz); 7.26 (d, 1 H, J = 8 Hz); 3.89 (s, 3H); 2.75 (tr, 2H, J = 7.6 Hz) ; 1 .54 - 1 .64 (m, 2H); 1 .31 - 1 .45 (m, 2H); 0.93 (tr, 3H, J = 7.3 Hz). In addition n- butyl 4-nbutyl-3-chlorobenzoate (0.17 g; 21 %) was isolated, as colourless oil). 1 H-NMR (CDCIg) 7.98 (d, 1 H, J = 1 .7 Hz); 7.82 (dd, 1 H, J = 1 .7; 8 Hz) ; 7.25 (d, 1 H, J = 8 Hz); 4.3 (tr, 2H, J = 6.6 Hz) ; 2.76 (tr, 2H, J = 7.6 Hz); 1 .36 - 1 .78 (m, 8H, + H20); 0.93 - 0.98 (m, 6H).

Reference： [1]Current Patent Assignee: AKAAL PHARMA - WO2014/63199, 2014, A1 Location in patent: Page/Page column 87

10
[ 75-77-4 ]
[ 25118-59-6 ]
[ 117738-74-6 ]

Yield	Reaction Conditions	Operation in experiment
93%	In methanol; at 20℃;	To a suspension of 4-bromo-3- chlorobenzoic acid (1 .2 g; 5.18 mmol) in MeOH (HPLC grade; 10 ml) chlorotrimethylsilane (2 ml) was added and the resulting mixture was stirred over a weekend at room temperature. After evaporation of solvents under reduced pressure the residue was diluted to 60 ml with EtOAc, washed with 5% NaHC03 (2 x 10 ml), brine (20 ml), dried over anhydrous MgS04, filtered and filtrate evaporated to dryness to give a title compound (1 .2 g; 93%), as creamy solid. 1H-NMR (CDCI3) 8.09 (d, 1 H, J = 1 .4 Hz); 7.75 (dd, 1 H, J = 1 .4; 8.3 Hz); 6.68 (d, 1 H), J = 8.3 Hz); 3.91 (s, 3H).

Reference： [1]Patent: WO2014/63199,2014,A1 .Location in patent: Page/Page column 87

11
[ 117738-74-6 ]
3-chloro-4-cyanobenzoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: tetrakis(triphenylphosphine) palladium⁽⁰⁾ / N,N-dimethyl-formamide / 100 °C 2: lithium hydroxide; water / tetrahydrofuran / 3 h / 10 - 35 °C

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP2975031, 2016, A1

12
[ 117738-74-6 ]
3-chloro-4-cyano-N-(4-((1,3-diethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-6-yl)amino)-2-isopropyl-4-oxobutyl)benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: tetrakis(triphenylphosphine) palladium⁽⁰⁾ / N,N-dimethyl-formamide / 100 °C 2: lithium hydroxide; water / tetrahydrofuran / 3 h / 10 - 35 °C 3: N-ethyl-N,N-diisopropylamine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide / ethyl acetate / 70 °C

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP2975031, 2016, A1

13
[ 117738-74-6 ]
copper(l) cyanide [ No CAS ]
[ 214759-66-7 ]

Yield	Reaction Conditions	Operation in experiment
43.7%	With tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 100℃;	(Step 3) (0896) A mixture of methyl 4-bromo-3-chlorobenzoate (5.84 g, 23.41 mmol), tetrakis(triphenylphosphine)palladium (1.352 g, 1.17 mmol), copper(I) cyanide (1.484 mL, 23.41 mmol) and DMF (50 mL) was stirred at 100C overnight. The reaction mixture was allowed to be cooled to room temperature, saturated brine was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 5?50% ethyl acetate/hexane) to give methyl 3-chloro-4-cyanobenzoate (2.0 g, 10.22 mmol, 43.7%) as a colorless solid. 1H-NMR(300MHz,CDCl3):delta4.01(3H,s),7.92(1H,d,J=8.7Hz),8.38(1H,dd,J=8 .1,1.7Hz),8.46(1H,d,J=1.5Hz).

Reference： [1]Patent: EP2975031,2016,A1 .Location in patent: Paragraph 0896

14
[ 117738-74-6 ]
methyl 3-chloro-4-(1-phenoxyethyl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: tetrakis(triphenylphosphine) palladium⁽⁰⁾ / 1,4-dioxane / 6.67 h / 100 °C / Inert atmosphere 2: hydrogenchloride / water / 2 h / 20 °C 3: sodium tetrahydroborate; methanol / 1 h / 0 - 20 °C 4: zinc tetraphenylporphyrin; diethylazodicarboxylate / tetrahydrofuran / 12.33 h / 0 - 20 °C