4-Bromo-N-methylpicolinamide (CAS: 1209459-88-0) can be used in the preparation of Sorafenib (CAS: 284461-73-0). Sorafenib, an oral multikinase inhibitor, is classified as a bi-aryl urea. It acts on cell surface tyrosine kinase receptors and subsequent intracellular kinases involved in tumor cell proliferation and angiogenesis.
Application In Synthesis of [ 1209459-88-0 ]
* 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.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 18h;
A mixture of 4-bromopicolinic acid ( 15 g, 75 mmol), methanamine hydrochloride (1 5 g, 75 mmol), HOBt (10 g, 75 mmol), EDCI (21 g, 75 mmol) and Et3N (41.5 mL, 300 mmol) in DMF(200 mL) was stirred at r.t. for 18 h. Water was added to the reaction mixture and the resulting mixture was filtered to afford 16 g of 78 as solid which was used directly in the next step. LCMS: m/z 215 (M+l )+
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In tetrahydrofuran; water; toluene; for 18h;Inert atmosphere; Reflux;
KOAc (19 g, 194 mmol) and Pd(dppf)Cl2 (5% mol.) were added successively under vigorous stirring to a solution of <strong>[1209459-88-0]4-bromo-N-methylpicolinamide</strong> (16 g, 75 mmol) and methyl 2- (2-chloro-4-(4,4,5,5-tetramethyl- l ,3,2-dioxaborolan-2-yl)phenyl)acetate (25 g, 82 mmol) in toluene (200 ml), THF (200 ml) and water (50 ml) under N2. The reaction mixture was heated to reflux for 18h. The resulting mixture was evaporated to dryness and the solid was extracted with DCM (3x50ml). The combined organic layers were dried by Na2S04, concentrated in vacuo and chromatographed on silica gel eluting with PE:ethyl acetate (1 : 1) to afford 75 (1 1 g, 47%) as pale white solid. LCMS: m/z 319 (M+l)+.
In tetrahydrofuran; at 20℃; for 2h;Cooling with ice;
4.1.14 4-Bromo-N-methylpyridine-2-carboxamide (18) Compound (17) dissolved in anhydrous tetrahydrofuran was added dropwise to methylamine solution (8 mL), after the action was complete, the ice-bath was removed and the reaction was reacted at room temperature for 2 h. The product was extracted with AcOEt (30 mL * 3), washed twice with water and brine, and dried over Na2SO4. After filtration and concentration in vacuo, the residues was purified by silica gel flash chromatography (PE/AcOEt = 3:1) gave (18) (0.87 g, 52%) as white solid.
1.5 g
In tetrahydrofuran; at 0 - 20℃;
To a stirred solution of 5-1 (2.0 g, 9.09 mmol) in THF (20 mL) was added methylamine (2 M in THF) solution at 0C. After being stirred at rt overnight, the mixture was concentrated under reduced pressure. The resulting residue was dissolved in EtOAc and washed with water. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to afford 5-2 (1.5 g, 70% over 2 steps) which was used in the next step without further purification.
(4-aminophenyl)boronic acid hydrochloride[ No CAS ]
[ 1209459-88-0 ]
4-(4-aminophenyl)-N-methylpyridine-2-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
98%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 100℃;Inert atmosphere;
4.1.15 4-(4-Aminophenyl)-N-methylpyridine-2-carboxamide (19) In a 250 mL round bottom flask, compound (18) (0.87 g, 4 mmol), p-amino phenylboronic acid hydrochloride (0.84 g, 4.86 mmol), K2CO3 (1.7 g, 12.2 mmol), Pd(pddf)Cl2 (0.5 g, 0.41 mmol) was dissolved in 1,4-dioxane (90 mL) and water (30 mL), It was then refluxed overnight under nitrogen. The product was extracted with AcOEt (30 mL * 3), washed twice with water and brine, and dried over Na2SO4. After filtration and concentration in vacuo, the residues was purified by silica gel flash chromatography (PE/AcOEt = 1:1) gave (19) (0.96 g, 98%) as white solid.
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4 dimethylcyclohexane; at 80℃; for 3h;
To a stirred solution of 5-2 (600 mg, 1.0 eq.) in 1,4 dioxane (8 mL) were added bis(pinacalato)diboron (1.5 eq.) and KOAc (3.0 eq.). The mixture was degassed for 10 mm, followed by the addition of PdC12(dppf)-DCM (0.1 eq.), and degassed again for 10 mm. After being stirred at 80C for 3h, TLC indicated formation of a new polar spot with complete consumption of starting material. The mixture was cooled to ft and the crude 5-3 was used in the next step without any workup and purification.
With N-benzyl-N,N,N-triethylammonium chloride; potassium iodide; sodium hydroxide; In water; at 30 - 70℃; for 2h;
Add 4.71g of 4-amino-3-fluorophenol, 4.13g of sodium hydroxide, 32.11g of potassium iodide, 22.78g of triethylbenzylammonium chloride, 500ml of water to the reaction flask, and heat to 30 C to stir and dissolve. When the temperature reaches At 70 C, 21.61 g of compound III was added dropwise, and the reaction was stirred for 2 h. After completion of the reaction, the mixture was cooled, washed with a 2% aqueous sodium hydroxide solution, and the mixture was separated. The organic layer was recrystallized from ethanol to give compound IV 25.48 g, product yield 97.5%, purity 99.96%.
The reaction bottle adding compound IV 31.35 g, cesium carbonate 46.33 g, cuprous chloride 2.84 g, 2,2,6,6-tetramethyl-3,5-heptyldiketone (0.0332 muM), 600 ml N,N-dimethyl-pyrrolidone, control in the 50 - 60 C stirring 30 min, then the compound is added V 24.47 g, stirring to reflux 2 h, TLC monitoring the completion of reaction. After the reaction is concentrated under reduced pressure, ethanol or recrystallization, to obtain the solid sorafenib (I) 42.62 g, the product yield is 96.7%, HPLC purity of 99.98%
3,3-difluoro-N-(2-methoxypyrimidin-5-yl)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclobutanecarboxamide[ No CAS ]
4-(4-(3,3-difluoro-1-((2-methoxypyrimidin-5-yl)carbamoyl)cyclobutyl)phenyl)-N-methylpicolinamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Step 3. To a solution of 3,3-difluoro-N-(2-methoxypyrimidin-5-yl)-l -(4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)cyclobutanecarboxamide (0.36 g, 0.82 mmol) in dioxane (10 mL) and saturated aq. NaHC03 (5 mL) was added <strong>[1209459-88-0]4-bromo-N-methylpicolinamide</strong> (0.26 mg, 1.23 mmol). The mixture was sparged with N2 for 5 min before tetrakis(triphenylphosphine) palladium(O) (0.05 g, 0.04 mmol) was added. The reaction was heated at 90 C for 16 h under a nitrogen atmosphere and partitioned between EtOAc and brine. The organic phase was extracted with water (2X), concentrated in vacuo and coevaporated once with EtOAc. The crude material was purified on silica gel eluting with a solvent gradient of 20% to 100% EtOAc in hexanes to afford 4-(4-(3,3-difluoro-l-((2-methoxypyrimidin-5- yl)carbamoyl)cyclobutyl)phenyl)-N-methylpicolinamide. LC-MS: 454 (M+H)+.
methyl 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclobutane-1-carboxylate[ No CAS ]
methyl 1-(4-(2-(methylcarbamoyl)pyridin-4-yl)phenyl)cyclobutane-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
250 mg
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In N,N-dimethyl-formamide; at 150℃; for 0.333333h;Inert atmosphere; Sealed tube;
Step 2. Methyl l-(4-(2-(methylcarbamoyl)pyridin-4-yl)phenyl)cyclobutane-l- carboxylate: Into a 20 mL microwave vial equipped with a magnetic stir bar and under N2 were added <strong>[1209459-88-0]4-bromo-N-methyl-pyridine-2-carboxamide</strong> (204mg, 948.77 muiotatauiotaomicron), methyl l-[4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]cyclobutanecarboxylate (300 mg, 948.77 mupiiotaomicron), tetrakis(triphenylphosphine)palladium(0) (109mg, 94.88 mupiiotaomicron), potassium carbonate (393 mg, 2.85 mmol), MeOH (3 mL) and DMF (6 mL). The vial was sealed and the suspension degassed with nitrogen for 10 minutes and the mixture was heated to 150 C for 10 minutes. The mixture was purified by column chromatography through silica gel eluting with 100:0 to 0: 100 hexanes:EtOAc as a gradient over 25 minutes. The desired fractions were combined, concentrated and further dried under high vacuum O/N to provide a yellow solid (250 mg). LCMS (ESI+) m/z = 325 (M+l).
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
120K+ Compounds
Competitive Price
1-2 Day Shipping
