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Structure of 53857-57-1

Chemical Structure| 53857-57-1

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Product Details of [ 53857-57-1 ]

CAS No. :53857-57-1
Formula : C7H5BrN2
M.W : 197.03
SMILES Code : BrC1=CC2=C(NN=C2)C=C1
MDL No. :MFCD00839493
InChI Key :STVHMYNPQCLUNJ-UHFFFAOYSA-N
Pubchem ID :761929

Safety of [ 53857-57-1 ]

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

Computational Chemistry of [ 53857-57-1 ] Show Less

Physicochemical Properties

Num. heavy atoms 10
Num. arom. heavy atoms 9
Fraction Csp3 0.0
Num. rotatable bonds 0
Num. H-bond acceptors 1.0
Num. H-bond donors 1.0
Molar Refractivity 43.79
TPSA ?

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

28.68 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

1.32
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

2.38
Log Po/w (WLOGP)?

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

2.33
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.

1.88
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

2.75
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

2.13

Water Solubility

Log S (ESOL):?

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

-3.23
Solubility 0.117 mg/ml ; 0.000593 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.

-2.62
Solubility 0.469 mg/ml ; 0.00238 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

-3.77
Solubility 0.0337 mg/ml ; 0.000171 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.

-5.81 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)

1.47

Application In Synthesis of [ 53857-57-1 ]

* 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 [ 53857-57-1 ]

[ 53857-57-1 ] Synthesis Path-Downstream   1~6

  • 1
  • [ 53857-57-1 ]
  • [ 74-88-4 ]
  • [ 465529-56-0 ]
  • [ 465529-57-1 ]
YieldReaction ConditionsOperation in experiment
36%; 52% With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium hydride; In tetrahydrofuran; at 20℃; for 3h; The A14-1 (590mg, 2.99mmol) was dissolved in tetrahydrofuran (10mL), was added NaH in the case of an ice bath with stirring (180mg80%, 6.00mmol),After stirring for 30 minutes was added CH3I (468mg, 3.30mmol), stirring was continued for 3 hours, raised to room temperature, water (20 mL), ethyl acetate (20mL × 3)Extraction, the organic phase was washed with saturated brine (50mL × 3), dried over anhydrous sodium sulfate, and spin dry solvent, the residue was purified by column chromatography (petroleum ether: ethyl acetate= 10:1-3:1) to give A14-2 (230mg, 36%) and A14-3 (330mg, 52%).A14-2: off-white solid. 1HNMR (400MHz, DMSO) delta8.33 (s, 1H), 7.96-7.95 (m, 1H), 7.57 (d, J = 9.2Hz,1H), 7.31-7.28 (m, 1H), 4.16 (s, 3H).A14-3: white solid.
29%; 42.5% 5-Bromo-1-methyl-1 H-indazole (ii) and 5-Bromo-2-methyl-2H-indazole (iii)To a solution of 5-bromo-1 H-indazole (0.19 g, 0.94 mmol) in 3 mL THF at 0 0C was added NaH (0.04 g, 1.03 mmol). The reaction solution was stirred at this temperature for 1 hour before methyl iodide (0.09 mL, 1.41 mmol) was added at 0 0C. The reaction was allowed to warm to room temperature slowly and stirred for 2 hours, quenched with water and concentrated in vacuo. The residue was diluted with water and extracted with DCM twice. The organic layers were combined, dried over Na2SO4 and concentrated. The crude product was purified by flash chromatography (hexane:EtOAc = 10:1 ) to give the title compound ii (88.7 mg, 42.5 %) and iii (60.9 mg, 29 %) as two white solids, ii: 1H-NMR (400MHz, DMSO- Cf6) delta ppm 8.02 (d, 1 H), 7.99 (d, 1 H), 7.64 (d, 1 H), 7.50 (dd, 1 H), 4.04 (s, 3H). LCMS(method A): [MH]+ = 21 1/213, tR = 5.19 min. iii: 1H-NMR (400MHz, DMSO-Cf6) delta ppm 8.33 (s, 1 H), 7.95 (d, 1 H), 7.57 (d, 1 H), 7.30 (dd, 1 H), 4.16 (s, 3H). LCMS (method A): [MH]+ = 21 1/213, tR = 4.95 min.
29%; 42.5% To a solution of 5-bromo-1 H-indazole (0.19 g, 0.94 mmol) in 3 ml_ of THF at 0 QC was added NaH (0.04 g, 1 .03 mmol). The reaction mixture was stirred at this temperature for 1 h before the addition of methyl iodide (0.09 ml_, 1 .41 mmol) at 0 QC. The reaction was allowed to warm to rt slowly and stirred for 2 h, quenched with water and concentrated in vacuo. The residue was diluted with water and extracted with DCM twice. The organic layers were combined, dried over Na2SO4 and concentrated. The crude products were purified by flash chromatography (hexane:EtOAc = 10:1 ) to give the title compound ii (88.7 mg, 42.5 %) and iii (60.9 mg, 29 %) as white solid, ii: 1H-NMR (400MHz, DMSO-d6) Dppm 8.02 (d, 1 H), 7.99 (d, 1 H), 7.64 (d, 1 H), 7.50 (dd, 1 H), 4.04 (s, 3H). LCMS (method A): [MH]+ = 21 1/213, tR = 5.19 min. iii: 1H-NMR (400MHz, DMSO-Cf6) deltappm 8.33 (s, 1 H), 7.95 (d, 1 H), 7.57 (d, 1 H),7.30 (dd, 1 H), 4.16 (s, 3H). LCMS (method A): [MH]+ = 21 1/213, tR = 4.95 min.
Scheme 5:F G R Me HI R Et JK R Pr LM R iPr N Sodium hydride (60% in oil, 1.5 g, 37.5 mmol, 1.2 equiv) was added to a solution of 5- bromoindazole F (6 g, 30.6 mmol, 1 equiv) in DMF (60 mL) at RT. After stirring for 30 min, methyl iodide (2.83 mL, 45.9 mmol, 1.5 equiv) was added and the reaction stirred for another 2 h at RT. The reaction was quenched with sat. NaHC03, extracted with EtOAc (lx), dried over MgS04, filtered, and concentrated under reduced pressure to give a mixture of JV-l and N-2 methylated 5-bromoindazoles G and H, which were separated by silica-gel chromatography using 0?30 % EtOAc/hexanes as eluent. The Nl -alkylated regioisomer G elutes first, followed by the N2-methyl regioisomer H. Other N-l -alkylated 5-bromoindazoles (I, , M) were prepared by the same procedure, substituting the appropriate electrophile for methyl iodide (ethyl iodide, i-propyl iodide, n-propyi iodide).
[000842] To a solution of 5-bromo-lH-indazole, 202A, (4.92 g, 25.0 mmol) in THF (300 mL) at 0 C was added NaH (1.10 g, 27.5 mmol). The reaction solution was stirred at this temperature for 1 hour before methyl iodide (5.32 g, 37.5 mmol) was added at 0 C. The reaction was allowed to warm to room temperature slowly, stirred for 2 hours, and quenched with water and concentrated in vacuo. The residue was diluted with water and extracted with dichloromethane (80 mL x 2). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 10% v/v) to give Compound 202B and Compound 202C.
[000791j To a solution of Compound 125A (4.92 g, 25.0 mmol) in THF (300 mL) was added NaH (1.10 g, 27.5 mmol) at 0 C. The reaction solution was stirred at this temperature for 1 h before methyl iodide (5.32 g, 37.5 mmol) was added at 0 C. The reaction was allowed to warm to room temperature slowly, stirred for 2 h, and quenched with water and concentrated in vacuo. The residue was diluted with water and extracted with dichloromethane (80 mL x 2). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 10% v/v) to give Compound 125B and Compound 125C. For Compound 125B: LC-MS (ESI) mlz: 211 [M+H] ?H-NMR (CDC13, 400 MHz): (5(ppm) 4.06 (s, 3H), 7.26-7.28 (m, 1H), 7.44-7.48 (m, 1H), 7.86-7.87 (m, 1H), 7.91 (s, 1H). For Compound 125C: LC-MS (ESI) mlz: 211 [M+H] ?H-NMR (CDC13, 400 MHz) (5(ppm) 4.20 (s, 3H), 7.3 1-7.34 (m, 1H), 7.56-7.58 (m, 1H), 7.79-7.80 (m,1H), 7.84 (s, 1H).
Sodium hydride (60% in oil, 1.5 g, 37.5 mmol) was added to a solution of 5-bromoindazole D (6 g, 30.6 mmol) in DMF (60 mL) at RT. After stirring for 30 min, methyl iodide (2.83 mL, 45.9 mmol) was added and the reaction stirred for another 2 h at RT. The reaction was quenched with sat. NaHCO3 (aq), extracted with EtOAc (1×), dried over MgSO4, filtered, and concentrated under reduced pressure to give a mixture of N-1 and N-2 methylated 5-bromoindazoles E and F, which were separated by silica-gel chromatography using 0?30% EtOAc/hexanes.

  • 2
  • [ 53857-57-1 ]
  • [ 420-37-1 ]
  • [ 465529-56-0 ]
YieldReaction ConditionsOperation in experiment
70% Preparation 1 Synthesis of 5-bromo-2-methyl-2H-indazole Add at room temperature under nitrogen, trimethyloxonium tetrafluoroborate (229.34 g, 1.52 mol) portion wise to a mixture of 5-bromo-1H-indazole (199.6 g, 1.01 mol) in ethyl acetate (3.04 L, 31.06 mol), stir 2.5 h and filter to give a white solid. Wash the recovered solid twice with ethyl acetate (500 mL) and then add it portion wise to a cooled aqueous solution of 2 M sodium hydroxide (3.80 L, 7.60 mol) in an ice bath. Stir the mixture for 1 h, sonicate for 15 min., filter and wash the recovered solid twice with water (200 mL). Dry the solid overnight under vacuum, slurry in dichloromethane (1 L) and filter. Concentrate the filtrate and purify by silica gel chromatography eluding with dichloromethane to give the title compound as a yellow solid (149.77 g, 70%). MS (m/z): 211, 213 (M+1).
  • 3
  • [ 53857-57-1 ]
  • [ 1211537-09-5 ]
YieldReaction ConditionsOperation in experiment
50% With acetic acid; Selectfluor; In acetonitrile; at 80℃; for 12h; Step-1: Synthesis of 5-bromo-3-fluoro-1H-indazole Into a 500-mL round-bottom flask was placed 5-bromo-1H-indazole (20 g, 101.51 mmol, 1.00 equiv), selectfluor (71.6 g, 2.00 equiv), AcOH (30 mL), and CH3CN (300 mL). The resulting solution was stirred at 80 C. in an oil bath until completion. The reaction was then quenched by the addition of 100 mL of water. The resulting solution was extracted with 3*100 mL of ethyl acetate and the organic layers combined. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:4). The collected fractions were combined and concentrated under vacuum to deliver the title compound in 11 g (50%) as a white solid. LCMS: 215.1 [M+H]+.
33% With acetic acid; Selectfluor; In acetonitrile; at 80℃; for 16h; Into a 5-L 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed 5-bromo-1H-indazole (200 g, 1.0204mol, 1.00 equiv), CH3CN (3.5L), acetic acid (120 mL), and selectfluoro (544 g, 1.5367mol, 1.51 equiv). The resulting solution was stirred at 80oC until completion. The reaction progress was monitored by LCMS. The resulting solution was diluted with 8 L of ethyl acetate and washed with 3x4000 mL of H2O. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (0:100-15:85). The collected fractions were combined and concentrated under vacuum to deliver the title compound in 72 g (33%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) delta 12.77 (s, 1H), 8.03-7.90 (m, 1H), 7.59-7.48 (m, 2H). LCMS: 215 [M+H]+.
9 g With Selectfluor; In N,N-dimethyl acetamide; at 60℃; for 18h;Inert atmosphere; Selectfluor (72 g, 203 mmol) was added to a solution of 5-bromo-lH-indazole (20.0 g, 102 mmol) and N,N-dimethylacetamide (500 mL) under N2. The mixture was heated at 60 C for 18 h, allowed to cool to rt, diluted with ethyl acetate ( 1.5 L), and washed with water (150 mL x The organic layer was dried (Na2S04), filtered, concentrated, and purified by silica gel chromatography (1 : 10; ethyl acetate :petroleum ether) to give 10.8 g of an impure product. Repurification by silica gel chromatography (1 :20; ethyl acetate:petroleum ether) gave 9 g of 5-bromo-3-fluoro-1H-indazole as a light yellow solid. 1H NMR (400 MHz; DMSO-d6): delta 12.77 (s 1H), 7.96 (s, 1H), 7.54 (d, IH), 7.48 (d, 1H).
  • 4
  • [ 313545-34-5 ]
  • [ 53857-57-1 ]
  • [ 1613505-02-4 ]
  • 5
  • [ 74-83-9 ]
  • [ 53857-57-1 ]
  • [ 465529-56-0 ]
  • [ 465529-57-1 ]
YieldReaction ConditionsOperation in experiment
69%; 77% General procedure: NaH (6.1 mmol, 1.2 equiv) was slowly added to a solution of 5-bromoindole/indazole (5.1 mmol,1 equiv) in DMF (10 mL) at 0 C. The mixture was stirred at 0 C for 10 min then the alkylhalide (6.1 mmol, 1.2 equiv) was added at the same temperature. The reaction mixture wascontinued to stir at rt for 2 h. When the reaction was complete [TLC (EtOAc/hexane 1:5)], themixture was extracted with EtOAc (2 × 20 mL) and washed with water (2 × 20 mL). The organiclayer was separated, dried over anhydrous Na2SO4 and the solvent removed under reducedpressure. The residue obtained was purified by flash column chromatography [silica gel (230-400 mesh; Merck), EtOAc/hexane 1:5].
  • 6
  • [ 5722-11-2 ]
  • [ 53857-57-1 ]
  • 1-(1H-indazol-5-yl)-2,2-dimethylcyclopropane-1-carbonitrile [ No CAS ]
 

Historical Records

Technical Information

Categories

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[ 53857-57-1 ]

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[ 53857-57-1 ]

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