* 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.
Stage #1: With n-butyllithium In tetrahydrofuran at -78℃; for 2 h; Inert atmosphere Stage #2: at -78 - 20℃; for 20 h; Inert atmosphere
Step 1 : Synthesis of 5-cyano-2-methylphenylboronic acid First, 9.5 g (50 mmol) of 3-bromo-4-methylbenzonitrile was put into a 500 mL three-neck flask, and the atmosphere in the flask was replaced with nitrogen. Then, 250 mL of tetrahydrofuran (THF) was added, and the mixture was stirred at -78 °C for 30 minutes. Into this mixed solution, 34 mL (55 mmol) of a 1.63M hexane solution of -butyllithium (-BuLi) was dropped, followed by stirring at -78 °C for 1.5 hours. After that, 7.3 mL (65 mmol) of trimethyl borate was added to the mixture and this solution was stirred for 20 hours while the temperature was raised to room temperature. To this solution was added 100 mL of 1M hydrochloric acid and stirring was performed for 30 minutes. The obtained mixture was separated to an aqueous layer and an organic layer, and the aqueous layer was subjected to extraction with ethyl acetate. The organic layer and a solution of the extract were combined, and washed with saturated saline. Anhydrous magnesium sulfate was added to the obtained solution for drying. The obtained mixture was subjected to gravity filtration, and the filtrate was concentrated to give a solid. This solid was washed with toluene and hexane, so that 4.3 g of a white solid was obtained in a yield of 53 percent. The obtained white solid was identified as 5-cyano-2-methylphenylboronic acid by nuclear magnetic resonance ( MR) spectroscopy. The synthesis scheme of Step 1 is shown in (a-10) below.
Reference:
[1] Patent: WO2016/203350, 2016, A1, . Location in patent: Paragraph 1195
[2] Journal of the American Chemical Society, 2002, vol. 124, # 31, p. 9014 - 9015
Step 1 : Synthesis of 5-cyano-2-methylphenylboronic acid First, 9.5 g (50 mmol) of <strong>[42872-74-2]3-bromo-4-methylbenzonitrile</strong> was put into a 500 mL three-neck flask, and the atmosphere in the flask was replaced with nitrogen. Then, 250 mL of tetrahydrofuran (THF) was added, and the mixture was stirred at -78 C for 30 minutes. Into this mixed solution, 34 mL (55 mmol) of a 1.63M hexane solution of -butyllithium (-BuLi) was dropped, followed by stirring at -78 C for 1.5 hours. After that, 7.3 mL (65 mmol) of trimethyl borate was added to the mixture and this solution was stirred for 20 hours while the temperature was raised to room temperature. To this solution was added 100 mL of 1M hydrochloric acid and stirring was performed for 30 minutes. The obtained mixture was separated to an aqueous layer and an organic layer, and the aqueous layer was subjected to extraction with ethyl acetate. The organic layer and a solution of the extract were combined, and washed with saturated saline. Anhydrous magnesium sulfate was added to the obtained solution for drying. The obtained mixture was subjected to gravity filtration, and the filtrate was concentrated to give a solid. This solid was washed with toluene and hexane, so that 4.3 g of a white solid was obtained in a yield of 53 %. The obtained white solid was identified as 5-cyano-2-methylphenylboronic acid by nuclear magnetic resonance ( MR) spectroscopy. The synthesis scheme of Step 1 is shown in (a-10) below.
4-bromo-N-alpha-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-N-[4-(2H-tetrazol-5-yl)phenyl]-L-phenylalaninamide[ No CAS ]
tert-butyl [(trans-4-[(2S)-3-(5'-cyano-2'-methylbiphenyl-4-yl)-1-oxo-1-[4-(2H-tetrazol-5-yl)phenyl]amino}propan-2-yl]carbamoyl}cyclohexyl)methyl]carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
51%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In water; N,N-dimethyl-formamide; at 120℃; for 2h;Inert atmosphere;
Example 40A tert-Butyl [(trans-4-[(2S)-3-(5'-cyano-2'-methylbiphenyl-4-yl)-1-oxo-1-[4-(2H-tetrazol-5-yl)phenyl]amino}propan-2-yl]carbamoyl}cyclohexyl)methyl]carbamate 0.36 ml (0.72 mmol) of a 2M sodium carbonate solution in water was added to a solution of 150 mg (0.24 mmol) of 4-bromo-N-alpha-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-N-[4-(2H-tetrazol-5-yl)phenyl]-L-phenylalaninamide and 87.3 mg (0.36 mmol) of <strong>[867333-43-5](5-cyano-2-methylphenyl)boronic acid</strong> in 2.5 ml DMF, and the mixture was degassed with argon for 5 min 17.5 mg (0.02 mmol) of 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) chloride were added and the mixture was stirred at 120 C. in a preheated oil bath for 2 h. The mixture was filtered through kieselguhr and washed through with ethyl acetate. The filtrate was diluted with ethyl acetate and water, acidified with 10% strength citric acid and once more washed with ethyl acetate. The organic phase of the filtrate was dried over magnesium sulphate and concentrated under reduced pressure. The residue was suspended in dichloromethane, the resulting solid was precipitated and filtered, washed with acetonitrile and dried under high vacuum. 86 mg (51% of theory) of the title compound were obtained. LC-MS (Method 1): Rt=1.11 min; MS (ESIpos): m/z=663 [M+H]+.
5-(3-bromophenyl)-1-(2,4,6-trimethylphenyl)-3-methyl-1H-1,2,4-triazole[ No CAS ]
5-(5'-cyano-2'-methyl-1,1'-biphenyl-3-yl)-3-methyl-1-(2,4,6-trimethylphenyl)-1H-1,2,4-triazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
78%
With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; potassium phosphate; bis(dibenzylideneacetone)-palladium(0); In water; toluene; at 90℃; for 3.5h;Inert atmosphere;
Step 2: Synthesis of 5-(5'-cyano-2'-methyl- 1 , 1 '-biphenyl-3 -yl)-3 -methyl- 1 -(2,4,6-trimethylphenyl)- H- 1 ,2,4- triazole (abbreviation: HMm3CN5btzl-tmp) Into a 300 mL three-neck flask were put 7.6 g (21 mmol) of 5-(3-bromophenyl)-l-(2,4,6-trimethylphenyl)-3-methyl-lH-l,2,4-triazole obtained in Step 1, 4.12 g (26 mmol) of <strong>[867333-43-5]5-cyano-2-methylphenylboronic acid</strong>, 16 g (77 mmol) of potassium phosphate, 130 mL of toluene, and 13 mL of water. The atmosphere in the flask was replaced with nitrogen. To this mixture were added 0.84 g (2.1 mmol) of bis(dibenzylideneacetone)palladium(0) and 0.59 g (1.0 mmol) of 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (S-phos), and the mixture was heated and stirred at 90 C for 3.5 hours to be reacted. After the reaction, an organic layer and an aqueous layer of the obtained reacted solution were separated, and the aqueous layer was subjected to extraction with toluene. The solution of the extract and the organic layer were combined and washed with water and saturated saline. Anhydrous magnesium sulfate was added to the obtained solution for drying. The obtained mixture was subjected to gravity filtration, and the filtrate was concentrated to give an oily substance. This oily substance was purified by flash column chromatography. As a developing solvent, a mixed solvent of toluene and ethyl acetate in a ratio of 5: 1 (v:v) was used. The obtained fraction was concentrated to give 6.5 g of a yellow oily substance in a yield of 78 %. The obtained yellow oily substance was identified as HMm3CN5btzl-tmp by nuclear magnetic resonance ( MR) spectroscopy. The synthesis scheme of Step 2 is shown in (b-10) below.
5,6-bis(3,5-dimethylphenyl)pyrazin-2-yl trifluoromethanesulfonic acid[ No CAS ]
5-(5-cyano-2-methylphenyl)-2,3-bis(3,5-dimethylphenyl)pyrazine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
96%
With potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); tris(2,6-dimethoxyphenyl)phosphine; In water; toluene; for 8h;Inert atmosphere; Reflux;
First, 1.83 g of 5,6-bis(3,5-dimethylphenyl)pyrazin-2-yltrifluoromethanesulfonate, 0.79 g of 5-cyano-2-methylphe-nylboronic acid, 3.17 g of tripotassium phosphate, 33 mL oftoluene, and 3.3 mL of water were put into a three-neck flask, and the air in the flask was replaced with nitrogen. The mixture in the flask was degassed by being stirred under reduced pressure, 0.038 g of tris(dibenzylideneacetone)dipalladium(0) and 0.075 g of tris(2,6-dimethoxyphenyl)phos-phine were added thereto, and the mixture was refluxed for 8 hours. After the reaction, extraction was performed with toluene. Then, purification by flash column chromatography using hexane: ethyl acetate=5: 1 as a developing solvent was performed, so that the target pyrazine derivative Hdmdpprm5CP (abbreviation) was obtained as a white solid in a yield of 96%. A synthesis scheme of Step 1 is shown in (b-i).