Structure of 4-Bromo-N-methylpicolinamide
CAS No.: 1209459-88-0
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CAS No. : | 1209459-88-0 |
Formula : | C7H7BrN2O |
M.W : | 215.05 |
SMILES Code : | O=C(C1=NC=CC(Br)=C1)NC |
MDL No. : | MFCD14702606 |
InChI Key : | MCICFBBFLFBLJW-UHFFFAOYSA-N |
Pubchem ID : | 72219227 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 11 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.14 |
Num. rotatable bonds | 2 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 44.93 |
TPSA ? Topological Polar Surface Area: Calculated from |
41.99 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.94 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.15 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.2 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.68 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.55 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.31 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.17 |
Solubility | 1.46 mg/ml ; 0.00677 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-1.63 |
Solubility | 5.08 mg/ml ; 0.0236 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-3.27 |
Solubility | 0.115 mg/ml ; 0.000535 mol/l |
Class? Solubility class: Log S scale |
Soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
Yes |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
Yes |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-6.8 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
0.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
0.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
1.58 |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
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 )+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | 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)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | 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. |
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. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
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. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97.5% | 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%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96.7% | 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% |
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)+. |
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). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.063 g | Step 4: 6-(l-((2-methoxypyrimidin-5-yl)carbamoyl)cyclobutyl)-N-methyl-[3,4'- bipyridine]-2'-carboxamide: l-(5-Bromopyridin-2-yl)-N-(2-methoxypyrimidin-5- yl)cyclobutanecarboxamide (0.28 g, 0.77 mmol), bis(pinacolato)diboron (0.236 g, 0.93 mmol), and potassium acetate (0.226 g, 2.31 mmol) were combined in dioxane (10 mL) and the mixture was bubbled with nitrogen for 5 min at RT. Pd(dppf)C12 complex with DCM (0.03 lg, 0.038 mmol) was then added, and the mixture was warmed to 100C, stirred for 2 hrs, then cooled to RT and diluted with EtOAc (20 mL). The mixture was filtered through celite and concentrated to dryness. The residue was redissolved in dioxane (6 mL) and 4-bromo-N-methylpyridine-2- carboxamide (0.200 g, 0.93 mmol) was added, followed by saturated aqueous sodium bicarbonate (2 mL). The mixture was again bubbled with nitrogen for 5 min, after which time Pd(dppf)C12 complex with DCM (0.03 lg, 0.038 mmol) was added. The mixture was warmed to 75C, stirred for 2 hrs, then cooled to RT and diluted with EtOAc (50 mL) and water (20 mL). The aqueous layer was separated and discarded, and the organic layer was dried over MgS04, filtered, and concentrated to dryness. The crude residue was purified by silica gel column chromatography, eluting with 0% to 20% EtOAc in hexanes to afford 6-(l-((2- methoxypyrimidin-5-yl)carbamoyl)cyclobutyl)-N-methyl-[3,4'-bipyridine]-2'-carboxamide (0.063 g) as a tan solid. LC-MS: 419 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.49 g | Step 3 : 6-(l-((5-chloropyrimidin-2-yl)carbamoyl)cyclobutyl)-N-methyl-[3,4'- bipyridine]-2'-carboxamide: l-(5-Bromopyridin-2-yl)-N-(5-chloropyrimidin-2- yl)cyclobutanecarboxamide (0.55 g, 1.5 mmol), bis(pinacolato)diboron (0.495 g, 1.95 mmol), and potassium acetate (0.441 g, 4.5 mmol) were combined in dioxane (20 mL) and the mixture was bubbled with nitrogen for 5 min at RT. Pd(dppf)C12 complex with DCM (0.060g, 0.074 mmol) was then added, and the mixture was warmed to 100C, stirred for 2 hrs, then cooled to RT and <strong>[1209459-88-0]4-bromo-N-methylpyridine-2-carboxamide</strong> (0.39 g, 1.8 mmol) was added, followed by saturated aqueous sodium bicarbonate (4 mL). The mixture was again bubbled with nitrogen for 5 min, after which time additional Pd(dppf)C12 complex with DCM (0.030 g, 0.037 mmol) was added. The mixture was warmed to 85C, stirred O/N, then cooled to RT and diluted with EtOAc (100 mL) and water (30 mL). The aqueous layer was separated and discarded, and the organic layer was dried over MgS04, filtered, and concentrated to dryness. The crude residue was purified by reversed-phase column chromatography, eluting with 5% to 100% ACN (modified with 0.5% formic acid) in water (modified with 0.5% formic acid). Product- containing fractions were then combined in a separatory funnel and partitioned with EtOAc (100 mL) and saturated aqueous sodium bicarbonate (20 mL). The aqueous layer was drained and discarded, and the organic layer was dried over MgS04, filtered, and concentrated to dryness to afford 6-(l-((5-chloropyrimidin-2-yl)carbamoyl)cyclobutyl)-N-methyl-[3,4'-bipyridine]-2'- carboxamide (0.49 g) as a tan solid. LC-MS: 423 (M+H)+. |