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Structure of 1010422-51-1

Chemical Structure| 1010422-51-1

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Product Details of [ 1010422-51-1 ]

CAS No. :1010422-51-1
Formula : C7H5BrF3N
M.W : 240.02
SMILES Code : CC1=CC(=NC=C1Br)C(F)(F)F
MDL No. :MFCD18257679
InChI Key :MIJYRALTRQVVAF-UHFFFAOYSA-N
Pubchem ID :68471500

Safety of [ 1010422-51-1 ]

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

Computational Chemistry of [ 1010422-51-1 ] Show Less

Physicochemical Properties

Num. heavy atoms 12
Num. arom. heavy atoms 6
Fraction Csp3 0.29
Num. rotatable bonds 1
Num. H-bond acceptors 4.0
Num. H-bond donors 0.0
Molar Refractivity 41.9
TPSA ?

Topological Polar Surface Area: Calculated from
Ertl P. et al. 2000 J. Med. Chem.

12.89 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

2.14
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

2.83
Log Po/w (WLOGP)?

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

4.32
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.

2.64
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

3.48
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

3.08

Water Solubility

Log S (ESOL):?

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

-3.42
Solubility 0.0923 mg/ml ; 0.000385 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.

-2.76
Solubility 0.418 mg/ml ; 0.00174 mol/l
Class?

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

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

-4.16
Solubility 0.0167 mg/ml ; 0.0000697 mol/l
Class?

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

Moderately 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.

-5.75 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

1.0
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)

1.69

Application In Synthesis of [ 1010422-51-1 ]

* 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 [ 1010422-51-1 ]

[ 1010422-51-1 ] Synthesis Path-Downstream   1~7

  • 1
  • [ 436799-32-5 ]
  • [ 74-88-4 ]
  • [ 1010422-51-1 ]
YieldReaction ConditionsOperation in experiment
14% In a dried 250 mL 3-neck round bottom flask fitted with a stirrer bar, thermometer, and flushed with nitrogen, was placed anhydrous THF (16 mL, Aldrich, inhibitor free) followed by N, N-diisopropylamine (0.895 g, 8.85 mmol, Aldrich, redistilled 99.95% pure). After cooling the stirred solution to -70 0C, n-butyl lithium (3.54 mL of a 2.5M solution in hexanes, 8.85 mmol) was added dropwise, keeping the reaction temperature less than -60 0C. The resulting solution was stirred at -70 0C for a further 10 min, then warmed to -20 0C, before immediately cooling to -90 0C. A solution of 5-bromo-2-(trifluoromethyl)pyridine (2 g, 8.85 mmol) in anhydrous THF (8 mL, Aldrich, inhibitor free) was added dropwise, keeping the reaction temperature less than -85 0C. The resulting orange solution was stirred at -90 0C for 40 min.In a separate dried 250 mL 3-neck round bottom flask fitted with a stirrer bar, thermometer, and flushed with nitrogen, was placed anhydrous THF (5 mL, <n="47"/>Aldrich, inhibitor free) followed by methyl iodide (5 mL, 80 mmol). The solution was cooled to -90 0C. To this was added (via cannula) the solution of the pre-formed lithiated pyridine, controlling the rate so as to keep the reaction temperature of the receiving flask less than -80 0C. The resulting dark solution was stirred at -90 0C for a further 15 min (LCMS indicated reaction complete). The reaction was quenched with sat aq. NH4CI solution (50 mL), then allowed to slowly warm to room temperature. Organics were extracted with EtOAc (2 x 50 mL), then the combined organic layers washed with water (50 mL), then brine (50 mL), separated, dried over MgSO4, and then filtered. Concentration in vacuo gave 1.68 g of a brown oil which was purified via short-path vacuum distillation (45-46 0C, ca. 5 mmHg) to give 5-bromo-4-methyl-2- (trifluoromethyl)pyridine 1-2 (0.289 g, 14%) as a yellow oil (>97% pure). MS (M + H)+: 241.8, tR = 2.458 min (method 1 ); 1H NMR (CDCI3) delta 8.74 (1 H, s), 7.56 (1 H, s), 2.50 (3H, s).
14% In a dried 250 mL 3-neck round bottom flask fitted with a stirrer bar, thermometer, and flushed with nitrogen, was placed anhydrous THF (16 mL, Aldrich, inhibitor free) followed by N, N-diisopropylamine (0.895 g, 8.85 mmol, Aldrich, redistilled 99.95% pure). After cooling the stirred solution to -70 0C, n-butyl lithium (3.54 mL of a 2.5M solution in hexanes, 8.85 mmol) was added dropwise, keeping the reaction temperature less than -60 0C. The resulting solution was stirred at -70 0C for a further 10 min, then warmed to -20 0C, before immediately cooling to -90 0C. A solution of 5-bromo-2-(trifluoromethyl)pyridine (2 g, 8.85 mmol) in anhydrous THF (8 <n="39"/>ml_, Aldrich, inhibitor free) was added dropwise, keeping the reaction temperature less than -85 0C. The resulting orange solution was stirred at -90 0C for 40 min.In a separate dried 250 ml_ 3-neck round bottom flask fitted with a stirrer bar, thermometer, and flushed with nitrogen, was placed anhydrous THF (5 ml_, Aldrich, inhibitor free) followed by methyl iodide (5 ml_, 80 mmol). The solution was cooled to -90 0C. To this was added (via cannula) the solution of the pre-formed lithiated pyridine, controlling the rate so as to keep the reaction temperature of the receiving flask less than -80 0C. The resulting dark solution was stirred at -90 0C for a further 15 min (LCMS indicated reaction complete). The reaction was quenched with sat aq. NH4CI solution (50 mL), then allowed to slowly warm to rt. Organics were extracted with EtOAc (2 x 50 mL), then the combined organic layers washed with water (50 mL), then brine (50 mL), separated, dried over MgSO4, and then filtered. Concentration in vacuo gave 1.68 g of a brown oil which was purified via short-path vacuum distillation (45-46 0C, ca. 5 mmHg) to give 5-bromo-4-methyl-2- (trifluoromethyl)pyridine 1-2 (0.289 g, 14%) as a yellow oil (>97% pure). MS (M + H)+: 241.8, tR = 2.458 min (method 1); 1H NMR (CDCI3) delta 8.74 (1H, s), 7.56 (1H, s), 2.50 (3H, s).
  • 2
  • [ 39971-65-8 ]
  • [ 3430-22-6 ]
  • [ 1010422-51-1 ]
  • [ 1448776-80-4 ]
  • 3
  • [ 1010422-51-1 ]
  • [ 1612288-95-5 ]
  • 4
  • [ 941294-57-1 ]
  • [ 81290-20-2 ]
  • [ 1010422-51-1 ]
YieldReaction ConditionsOperation in experiment
23% With potassium fluoride; copper(l) iodide; In 1-methyl-pyrrolidin-2-one; at 60℃;Inert atmosphere; To a suspension of 5-bromo-2-iodo-4-methylpyridine(1g, 3.36 mmol) in NMP (6mL) with an inert atmosphere of argon, KF (0.585 g, 10.07 mmol), Cul (1.92 g, 10.08 mmol) and CF3SiMe3 (2.49 mL, 15.07 mmol) were added. The resulting solution was stirred overnight at 60C. After cooling, the mixture was poured into 12% aqueous ammonia, and then extracted with Et2O. The organic solutions were combined, dried over MgSO4, filtered and concentrated. Purification of the crude residue by normal phase chromatography (0% to 100%, hexane - diethyl ether) afforded the desired product (23% yield) as a yellow oil.
  • 5
  • [ 1010422-51-1 ]
  • [ 73183-34-3 ]
  • [ 1612287-99-6 ]
YieldReaction ConditionsOperation in experiment
93% With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; at 110℃;Schlenk technique; Inert atmosphere; General procedure: An oven dried resealable Schlenk tube was charged with 5-bromo-2-chloro-1H-pyrrolo[2,3-b]pyridine (Preparation 1c, 0.5 g, 2.07 mmol), (6-methoxy-4-methylpyridin-3-yl)boronic acid (Preparation 2, 0.35 g, 2.08 mmol), cesium carbonate (2.027 g, 6.22 mmol), 5.5 ml dioxane and 5.5 ml water. The Schlenk tube was subjected to three cycles of evacuation-backfilling with argon, and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (0.085 g, 0.10 mmol) was added. After three further cycles of evacuation-backfilling with argon, the Schlenk tube was capped and placed in an oil bath at 100 C. After 6h, the mixture was cooled and the solvent was removed in vacuo. Water was added and product was extracted with dichloromethane and organic layer was dried (Na2SO4). The residue was purified by flash chromatography (10%, dichloromethane-methanol) to give the title compound (0.353 g, 62% yield) as a solid. <strong>[1010422-51-1]5-bromo-4-methyl-2-(trifluoromethyl)pyridine</strong> (Preparation 63a, 0.27mg, 1.13 mmol) was treated with 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (0.57 mg, 2.27 mmol),1,1' bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (56 mg, 0.07 mmol), potassium acetate (0.33 mg, 3.4 mmol) and dioxane (3 mL) as a solvent. The reaction was heated at 110C overnight according to the method described in Preparation 3a under standard conditions. The crude was purified by flash chromatography (10%, dichloromethane-methanol) to give the title compound (0.325 g, 93% yield) as a brown solid. LRMS (m/z): 288 (M+1)+
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 90℃;Inert atmosphere; A mixture of <strong>[1010422-51-1]5-bromo-4-methyl-2-(trifluoromethyl)pyridine</strong> (150 mg, 625 mumol), bis(pinacolato)diboron (189 mg, 729 mumol), Pd(dppf)Cl2 (89 mg, 106 mumol) and potassium acetate (120 mg, 1.25 mmol) in dioxane (1 mL) was stirred under N2 at 90 C. overnight. Aqueous NH4Cl was added and the mixture was extracted with CH2Cl2. The combined organic layers were dried and the volatiles were removed under reduced pressure to yield the desired compound which was used in the next step without further purification.
  • 6
  • [ 1010422-51-1 ]
  • N-(2,6-difluoro-phenyl)-1-methyl-5-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-1H-pyrazole-3-carboxylic acid amide [ No CAS ]
  • 7
  • [ 1010422-51-1 ]
  • cis-1-(cyclobutyl-methyl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one [ No CAS ]
  • cis-1-(cyclobutylmethyl)-8-dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
37% With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 90℃; for 18h;Inert atmosphere; [0338] Cs2CO3 (2g, 6.45 immol) was added to an argon purged solution of CIS- 1 -(cyclobutylmethyl)-8- (dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-987) (1.1 g, 3.225 mmol, 1 equiv.), Xantphos (279 mg, 0.483 mmol, 0.15 equiv.), Pd2(dba)3 (295 mg, 0.322 mmol, 0.1 equiv.) and <strong>[1010422-51-1]5-bromo-4-methyl-2-(trifluoromethyl)pyridine</strong> (774 mg, 3.225 mmol, 1 equiv.) in 1 ,4-dioxane (55 mL). The mixture was purged again with argon for 15 mm. The reaction mixture was stirred at 90C for 18 h, then cooled down to RT, filtered through Celite and washed with EtOAc (80 mL). The filtrate was concentrated under reduced pressure. The resulting residue was purified by flash chromatography (neutral alumina, 0-3% methanol in DCM) to afford 0.6 g (37%) of CIS- 1 -(cyclobutylmethyl)-8-(dimethylamino)-3 -(4-methyl-6-(trifluoromethyl)pyridin-3 -yl)-8-phenyl- 1,3-diazaspiro[4.5]decan-2-one (SC 3103) as an off white solid. (TLC system: 5% MeOH in DCM; Rf: 0.5). ?H NMR (DMSO-d6): 5 8.56 (s, 1H), 7.80 (s, 1H), 7.34-7.24 (m, 5H), 3.71 (s, 2H), 3.17 (d, 2H), 2.70-2.56 (m, 3H), 2.31 (s, 3H), 2.17-2.11 (m, 2H), 2.03-2.00 (m, 8H), 1.82-1.73 (m, 4H), 1.54-1.41 (m, 4H). Mass: mlz 501.3 (M+H).
 

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