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Chemical Structure| 1209459-88-0 Chemical Structure| 1209459-88-0

Structure of 4-Bromo-N-methylpicolinamide
CAS No.: 1209459-88-0

Chemical Structure| 1209459-88-0

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Product Details of [ 1209459-88-0 ]

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

Safety of [ 1209459-88-0 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H319-H335
Precautionary Statements:P261-P305+P351+P338

Computational Chemistry of [ 1209459-88-0 ] Show Less

Physicochemical Properties

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
Ertl P. et al. 2000 J. Med. Chem.

41.99 Ų

Lipophilicity

Log Po/w (iLOGP)?

iLOGP: in-house physics-based method implemented from
Daina A et al. 2014 J. Chem. Inf. Model.

1.94
Log Po/w (XLOGP3)?

XLOGP3: Atomistic and knowledge-based method calculated by
XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry

1.15
Log Po/w (WLOGP)?

WLOGP: Atomistic method implemented from
Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.

1.2
Log Po/w (MLOGP)?

MLOGP: Topological method implemented from
Moriguchi I. et al. 1992 Chem. Pharm. Bull.
Moriguchi I. et al. 1994 Chem. Pharm. Bull.
Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.

0.68
Log Po/w (SILICOS-IT)?

SILICOS-IT: Hybrid fragmental/topological method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

1.55
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.31

Water Solubility

Log S (ESOL):?

ESOL: Topological method implemented from
Delaney JS. 2004 J. Chem. Inf. Model.

-2.17
Solubility 1.46 mg/ml ; 0.00677 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Soluble
Log S (Ali)?

Ali: Topological method implemented from
Ali J. et al. 2012 J. Chem. Inf. Model.

-1.63
Solubility 5.08 mg/ml ; 0.0236 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Very soluble
Log S (SILICOS-IT)?

SILICOS-IT: Fragmental method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

-3.27
Solubility 0.115 mg/ml ; 0.000535 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Soluble

Pharmacokinetics

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)
and tested on 415 molecules (test set)
10-fold CV: ACC=0.72 / AUC=0.77
External: ACC=0.88 / AUC=0.94

No
CYP1A2 inhibitor?

Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.83 / AUC=0.90
External: ACC=0.84 / AUC=0.91

Yes
CYP2C19 inhibitor?

Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.80 / AUC=0.86
External: ACC=0.80 / AUC=0.87

No
CYP2C9 inhibitor?

Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set)
and tested on 2075 molecules (test set)
10-fold CV: ACC=0.78 / AUC=0.85
External: ACC=0.71 / AUC=0.81

No
CYP2D6 inhibitor?

Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set)
and tested on 1068 molecules (test set)
10-fold CV: ACC=0.79 / AUC=0.85
External: ACC=0.81 / AUC=0.87

No
CYP3A4 inhibitor?

Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set)
and tested on 2579 molecules (test set)
10-fold CV: ACC=0.77 / AUC=0.85
External: ACC=0.78 / AUC=0.86

No
Log Kp (skin permeation)?

Skin permeation: QSPR model implemented from
Potts RO and Guy RH. 1992 Pharm. Res.

-6.8 cm/s

Druglikeness

Lipinski?

Lipinski (Pfizer) filter: implemented from
Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev.
MW ≤ 500
MLOGP ≤ 4.15
N or O ≤ 10
NH or OH ≤ 5

0.0
Ghose?

Ghose filter: implemented from
Ghose AK. et al. 1999 J. Comb. Chem.
160 ≤ MW ≤ 480
-0.4 ≤ WLOGP ≤ 5.6
40 ≤ MR ≤ 130
20 ≤ atoms ≤ 70

None
Veber?

Veber (GSK) filter: implemented from
Veber DF. et al. 2002 J. Med. Chem.
Rotatable bonds ≤ 10
TPSA ≤ 140

0.0
Egan?

Egan (Pharmacia) filter: implemented from
Egan WJ. et al. 2000 J. Med. Chem.
WLOGP ≤ 5.88
TPSA ≤ 131.6

0.0
Muegge?

Muegge (Bayer) filter: implemented from
Muegge I. et al. 2001 J. Med. Chem.
200 ≤ MW ≤ 600
-2 ≤ XLOGP ≤ 5
TPSA ≤ 150
Num. rings ≤ 7
Num. carbon > 4
Num. heteroatoms > 1
Num. rotatable bonds ≤ 15
H-bond acc. ≤ 10
H-bond don. ≤ 5

0.0
Bioavailability Score?

Abbott Bioavailability Score: Probability of F > 10% in rat
implemented from
Martin YC. 2005 J. Med. Chem.

0.55

Medicinal Chemistry

PAINS?

Pan Assay Interference Structures: implemented from
Baell JB. & Holloway GA. 2010 J. Med. Chem.

0.0 alert
Brenk?

Structural Alert: implemented from
Brenk R. et al. 2008 ChemMedChem

0.0 alert: heavy_metal
Leadlikeness?

Leadlikeness: implemented from
Teague SJ. 1999 Angew. Chem. Int. Ed.
250 ≤ MW ≤ 350
XLOGP ≤ 3.5
Num. rotatable bonds ≤ 7

No; 1 violation:MW<1.0
Synthetic accessibility?

Synthetic accessibility score: from 1 (very easy) to 10 (very difficult)
based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties,
trained on 12'782'590 molecules and tested on 40 external molecules (r2 = 0.94)

1.58

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.

  • Downstream synthetic route of [ 1209459-88-0 ]

[ 1209459-88-0 ] Synthesis Path-Downstream   1~17

  • 1
  • [ 593-51-1 ]
  • [ 30766-03-1 ]
  • [ 1209459-88-0 ]
YieldReaction ConditionsOperation 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 )+
  • 2
  • [ 1209459-88-0 ]
  • [ 1428760-94-4 ]
  • 3
  • [ 1209459-88-0 ]
  • [ 1428759-62-9 ]
  • 4
  • [ 849934-95-8 ]
  • [ 1209459-88-0 ]
  • [ 1428760-95-5 ]
YieldReaction ConditionsOperation 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)+.
  • 5
  • [ 22282-99-1 ]
  • [ 1209459-88-0 ]
  • 6
  • [ 74-89-5 ]
  • [ 64197-01-9 ]
  • [ 1209459-88-0 ]
YieldReaction ConditionsOperation 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.
  • 7
  • [ 1209459-88-0 ]
  • 4-{4-[([4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}-N-methylpyridine-2-carboxamide [ No CAS ]
  • 8
  • [ 1209459-88-0 ]
  • 4-{4-[([3,5-bis(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}-N-methylpyridine-2-carboxamide [ No CAS ]
  • 9
  • (4-aminophenyl)boronic acid hydrochloride [ No CAS ]
  • [ 1209459-88-0 ]
  • 4-(4-aminophenyl)-N-methylpyridine-2-carboxamide [ No CAS ]
YieldReaction ConditionsOperation 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.
  • 11
  • [ 1209459-88-0 ]
  • [ 73183-34-3 ]
  • [ 1313738-91-8 ]
YieldReaction ConditionsOperation 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.
  • 12
  • [ 1209459-88-0 ]
  • [ 399-95-1 ]
  • [ 757251-39-1 ]
YieldReaction ConditionsOperation 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%.
  • 13
  • [ 1129683-83-5 ]
  • [ 1209459-88-0 ]
  • [ 284461-73-0 ]
YieldReaction ConditionsOperation 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%
  • 14
  • [ 1209459-88-0 ]
  • 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 ]
YieldReaction ConditionsOperation 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)+.
  • 15
  • [ 1209459-88-0 ]
  • 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 ]
YieldReaction ConditionsOperation 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).
  • 16
  • [ 1209459-88-0 ]
  • 1-(5-bromopyridin-2-yl)-N-(2-methoxypyrimidin-5-yl)cyclobutanecarboxamide [ No CAS ]
  • 6-(1-((2-methoxypyrimidin-5-yl)carbamoyl)cyclobutyl)-N-methyl-[3,4’-bipyridine]-2’-carboxamide [ No CAS ]
YieldReaction ConditionsOperation 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)+.
  • 17
  • [ 1209459-88-0 ]
  • 1-(5-bromopyridin-2-yl)-N-(5-chloropyrimidin-2-yl)cyclobutanecarboxamide [ No CAS ]
  • 6-(1-((5-chloropyrimidin-2-yl)carbamoyl)cyclobutyl)-N-methyl-[3,4'-bipyridine]-2'-carboxamide [ No CAS ]
YieldReaction ConditionsOperation 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)+.
 

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