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With potassium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 90℃; for 18h;Inert atmosphere;
Example 11Synthesis of 3-Methoxy-1 -(2-f 4-r°-d -methyl-1 H-F1 ,2,41triazol-3-yl)-phenv?-3.6- dihvdro-2H-pyridin-1 -yl)-2-oxo-ethyl)-pyrrolidine-3-carboxylic acid r3-(6-ethoxy- pyridin-3-yl)-1 H-indazol-5-yll-amide (Example 1) Step 1 : A mixture of <strong>[612845-44-0]6-ethoxypyridine-3-boronic acid</strong> (2.5 g, 14.97 mmol), bromoindazole 3Bl (7.25 g, 14.97 mmol), potassium carbonate (6.2 g, 44.91 mmol), PdCI2(dppf)2.CH2Cl2 (1.22 g, 1.497 mmol), 1 ,4-dioxane (40 ml_) and water (10 rriL), was purged with nitrogen for 15 min at r.t. and then heated at 90 0C for 18 hrs and cooled to r.t. Water (100 ml_) and ethyl acetate (300 ml_) were added. Solids were filtered through Celite. Layers were separated and the separated organic layer was washed with water (100 ml_). The combined organic layers were dried (Na2SO4), filtered and solvents were removed in vacuum. Column purification [Hexanes-ethyl acetate = 9:1 (Wv)] gave Compound 2BU (7 g, 89%).
With triethylamine;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; XPhos; In 1,4-dioxane; at 100℃;Inert atmosphere;
Step 1. In a 100 mL round-bottomed flask, 1-acetyl-6-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (250 mg, 947 mumol, Eq: 1.00), triethylamine (575 mg, 792 mul, 5.68 mmol, Eq: 6) and X-PHOS (181 mg, 379 mumol, Eq: 0.40) were combined with dioxane (25 ml) to give a colorless solution. [1,1'-bis(diphenylphosphino)ferrocene]dichloropaladium(II) (173 mg, 237 mumol, Eq: 0.25) and <strong>[612845-44-0]2-ethoxy-5-pyridineboronic acid</strong> (205 mg, 1.23 mmol, Eq: 1.3) were added and the resultant mixture was degassed for 5 minutes under Nitrogen. The reaction mixture was heated to 100 C. and stirred for O/N h. The reaction mixture was poured into 50 mL H2O and extracted with EtOAc (3×50 mL). The organic layers were dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 40 g, 20% to 30% EtOAc in hexanes) to give 6-(6-ethoxypyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (167 mg, 67%).
2-(6-ethoxy-pyridin-3-yl)-pyrimidine-5-carboxylic acid cyclopropyl-piperidin-4-yl-amide trifluoroacetic acid salt[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Intermediate 62-(6-Ethoxy-pyridin-3-yl)-pyrimidine-5-carboxylic acid cvclopropyl-piperidin-4-yl-annideAqueous Na2CO3 solution (2 M, 1 .05 ml_) and Pd(PPh3)2CI2 (22 mg) are added to a mixture of 4-[(2-chloro-pyrimidine-5-carbonyl)-cyclopropyl-amino]-piperidine-1 - carboxylic acid tert-butyl ester (400 mg) and <strong>[612845-44-0]2-ethoxy-5-pyridineboronic acid</strong> (351 mg) in 1 ,4-dioxane (20 ml_) and methanol (10 ml_) under argon atmosphere. The reaction mixture is stirred over night at 80 C. After cooling to room temperature, the solvents are evaporated and the residue is mixed with dichloromethane and water. The aqueous phase is extracted with dichloromethane and the combined organic phases are dried and concentrated in vacuo. The crude product is dissolved in dichloromethane and trifluoroacetic acid is added. The mixture is stirred for 1 h at room temperature and concentrated in vacuo. The crude product is purified by HPLC (MeOH/H2O/TFA) to give the title compound as trifluoroacetic acid salt. LC (method 4): tR = 0.99 min; Mass spectrum (ESI+): m/z = 368 [M+H]+.
2-(6-Ethoxy-pyridin-3-yl)-pyrimidine-5-carboxylic acid cyclopropyl-piperidin-4-yl-amide Aqueous Na2CO3 solution (2 M, 1.05 mL) and Pd(PPh3)2Cl2 (22 mg) are added to a mixture of 4-[(2-chloro-pyrimidine-5-carbonyl)-cyclopropyl-amino]-piperidine-1-carboxylic acid tert-butyl ester (400 mg) and <strong>[612845-44-0]2-ethoxy-5-pyridineboronic acid</strong> (351 mg) in 1,4-dioxane (20 mL) and methanol (10 mL) under argon atmosphere. The reaction mixture is stirred over night at 80 C. After cooling to room temperature, the solvents are evaporated and the residue is mixed with dichloromethane and water. The aqueous phase is extracted with dichloromethane and the combined organic phases are dried and concentrated in vacuo. The crude product is dissolved in dichloromethane and trifluoroacetic acid is added. The mixture is stirred for 1 h at room temperature and concentrated in vacuo. The crude product is purified by HPLC (MeOH/H2O/TFA) to give the title compound as trifluoroacetic acid salt. LC (method 4): tR=0.99 min; Mass spectrum (ESI+): m/z=368 [M+H]+.
Intermediate 892-(6-Ethoxy-ryridin-3-yl)-ryrimidine-5-carboxylic acid cyclororyl-rireridin-4-yl-amide: Under an argon atmosphere an aqueous solution of Na2003 (2 M, 1 .0 mL) andbis(triphenylphosphine)-palladium(II) chloride (22 mg) are added to a mixture of <strong>[612845-44-0]2-ethoxy-5-pyridineboronic acid</strong> (0.35 g) and 4-[(2-chloro-pyrimidine-5-carbonyl)- cyclopropyl-amino]-piperidine-1-carboxylic acid tert-butyl ester (0.4 g) in 1 ,4-dioxane (20 mL) and methanol (10 mL). The mixture is stirred for 12 h at 80C and concentrated in vacuo. To the residue is added dichloromethane and water. Theorganic phase is separated and the aqueous phase is extracted with dichloromethane. The combined extracts are dried over MgSO4 and concentrated in vacuo and treated with dichloromethane/ trifluoroacetic acid (1:1 +5% H20). The mixture is stirred at room temperature for 1 h, concentrated and purified by HPLC (018 RP Sunfire, MeOH/H20 +0.1% TEA) to give the desired product as atrifluoroacetic acid salt. LC (method 12): tR = 0.99 mm; Mass spectrum (ESI): mlz =368 [M+H]
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