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Chemical Structure| 6635-31-0

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Product Details of [ 6635-31-0 ]

CAS No. :6635-31-0
Formula : C6H4N2O5
M.W : 184.11
SMILES Code : O=C(O)C1=CN=C(O)C([N+]([O-])=O)=C1
MDL No. :MFCD02180840
InChI Key :VJMXJGVEVASJOD-UHFFFAOYSA-N
Pubchem ID :243019

Safety of [ 6635-31-0 ]

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

Computational Chemistry of [ 6635-31-0 ] Show Less

Physicochemical Properties

Num. heavy atoms 13
Num. arom. heavy atoms 6
Fraction Csp3 0.0
Num. rotatable bonds 2
Num. H-bond acceptors 6.0
Num. H-bond donors 2.0
Molar Refractivity 42.04
TPSA ?

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

116.24 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

0.32
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

0.74
Log Po/w (WLOGP)?

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

0.39
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.

-2.28
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

-1.81
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

-0.53

Water Solubility

Log S (ESOL):?

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

-1.66
Solubility 4.05 mg/ml ; 0.022 mol/l
Class?

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

Very soluble
Log S (Ali)?

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

-2.76
Solubility 0.32 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

-0.2
Solubility 115.0 mg/ml ; 0.624 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

No
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

No
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.

-6.9 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.

0.56

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

2.0 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)

1.89

Application In Synthesis of [ 6635-31-0 ]

* 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 [ 6635-31-0 ]

[ 6635-31-0 ] Synthesis Path-Downstream   1~1

  • 1
  • [ 67-56-1 ]
  • [ 6635-31-0 ]
  • [ 59237-53-5 ]
YieldReaction ConditionsOperation in experiment
90% DMF (0.15 eq) was added to a solution of beta-hydroxy-S-nitronicotinic acid (1 eq) in SOCl2 (4.7 eq). The mixture was heated at reflux for 8 h then concentrated in vacuo. The residue was taken up in CH2Cl2, cooled to -400C, and MeOH (1.4 eq) added while maintaining the internal temperature below -300C. Aqueous NaHCO3 (1 eq) was added and the mixture allowed to warm to room temperature. The organic phase was separated and concentrated in vacuo. The crude residue was crystallized from EtOH to give methyl 6-chloro-5-nitronicotinate (90 percent yield)
76% A 250 ml. round-bottorned flask was charged with 6-hydroxy-5-nitronicotinicacid (2.72 g, 14.8 mmol) and thionyl chloride (6.6 mL, 90 mmol), purged with N2, DMF(0.11 mL, 1.42 mmol) was added then heated to reflux with stirring overnight. The reaction was cooled to roorn ternperature and concentrated in vacuo. The residue was dissolved in CH2C12 (70 mL), cooled to 0°C, then rnethanol (10 mL, 247 mmol) was added, allowed to gradually warrn to roorn ternperature as bath warrned, and stirredovernight. The reaction mixture was concentrated. The resulting solid was recrystalized frorn hot EtOH, cooled in ice, the solid collected by filtration, washed with cold EtOH, and air dried to afford the product (rnethyl 6-chloro-5-nitronicotinate (2.433 g, 76 percent)) as atan solid: ?H NMR (400 MHz, CDC13) oe 9.18 (d, J=2.0 Hz, 1 H), 8.77 (d, J=2.2 Hz, 1 H), 4.03 (s, 3 H).
75% a)Methyl 6-chloro-5-nitronicotinateN,N'-Dimethylformamide (0.4 mL) was added to a suspension of 6-hydroxy-5-nitronicotinic acid (10.0 g, 50 mmol) in thionyl chloride (50 mL) and the mixture was stirred and heated to 60 °C.After gas evolution had ceased, the mixture was heated to 80 °C and stirred overnight.The mixture was concentrated in vacuo and then co-evaporated with toluene three times.The residue was taken up in dichloromethane (20 mL), cooled to 0 °C and methanol (12 mL) was added dropwise with stirring.The mixture was stirred for 1 hour then evaporated.The residue was partitioned between ethyl acetate and water and the organic layer was separated, dried (MgSO4 and evaporated to give the title compound (8.83 g, 75percent) as a pale yellow solid.LRMS (m/z): 217 (M+1)+.1H NMR delta (300 MHz, CDCl3): 4.03 (s, 3H), 8.77 (d, 1H), 9.18 (d, 1H).
75% 5-(Difluoromethyl)-2-methoxypyridin-3 -amine a) Methyl 6-chloro-5-nitronicotinateLambda/,Lambda/'-Dimethylformamide (0.4 mL) was added to a suspension of 6-hydroxy-5- nitronicotinic acid (10.0 g, 50 mmol) in thionyl chloride (50 mL) and the mixture was stirred and heated to 60 °C. After gas evolution had ceased, the mixture was heated to 80 °C and stirred overnight. The mixture was concentrated in vacuo and then co- evaporated with toluene three times. The residue was taken up in dichloromethane (20 mL), cooled to 0 °C and methanol (12 mL) was added dropwise with stirring. The mixture was stirred for 1 hour then evaporated. The residue was partitioned between ethyl acetate and water and the organic layer was separated, dried (MgS04) and evaporated to give the title compound (8.83 g, 75percent) as a pale yellow solid.LRMS (m/z): 217 (M+1 )+.1H NMR delta (300 MHz, CDCI3): 4.03 (s, 3H), 8.77 (d, 1 H), 9.18 (d, 1 H).
54% To a solution of phosphoryl pentachloride (12.98 g, 62.3 mmol) in phosphoryl chloride (18 mL), was added 3 (4.00 g, 21.7 mmol), and the mixture was stirred for 3 h at 100 oC equipped with condenser. Then, the excess amount of phosphoryl chloride was removed in vacuo at 50 oC, and the residue was dissolved in MeOH (30 mL) at 0 oC and further stirred for 30 min. Excess amount of MeOH was removed in vacuo and the residue was dissolved in AcOEt. This organic layer was washed with water, brine and dried over anhydrous Na2SO4. After the solvent was removed in vacuo, the resultant residue was purified by column chromatography on silica gel using hexane/AcOEt (6:1) as an eluant to give 4 as pale yellow needles (2.54 g, 54percent); 1H NMR (300 MHz, CD3OD) 4.00 (s, 3H), 8.52 (d, J = 2.1Hz, 1H), 9.14 (d, J = 2.1 Hz, 1H); HRMS (ES+): m/z 217.0006 (M+H+) (calcd for C7H6N2O4Cl: 217.0016).
52% A. 6-Chloro-5-nitro-nicotinic acid methyl ester; To a suspension of 49.0 g (0.27 mol) 6-hydroxy-5-nitro-nicotinic acid in thionyl chloride (240 ml) is added DMF (2 ml). This mixture is stirred at 60°C and after gassing stops it is stirred at 80°C for further 18 h. The thionyl chloride is removed under vacuo and the residue is coevaporated with toluene three times. Subsequently this reaction mixture is dissolved in dichloromethane (100 mi) and cooled to 0°C before methanol (55.5 ml) is dropwise added. The precipitated solid is filtered off and dried under vacuo at 50°C to give 27.6 g (13.7 mmol/52 percent) of the titled compound as a light yellow solid with a melting point of 78°C (dichloromethane/methanol).
18.2 g Compound 2 (20.0 g) and N,N-dimethylformamide (8.44 mL, 0.109 mmol) were added to a 500 mL recovery flask in an argon gas stream, and thionyl chloride (158.3 mL, 2.18 mmol) was added while cooling by ice bath. After the entire amount of thionyl chloride had been added, the flask was returned to room temperature. It was then gradually heated using an oil bath, and stirring was conducted for 16 hours at 80° C. After stopping heating and allowing to cool to room temperature, the reaction solution was concentrated under reduced pressure. Dichloromethane (50 mL) was added to the residue obtained, which was again concentrated, and the remaining thionyl chloride was distilled off azeotropically. After concentration, the residue obtained was cooled by an ice bath, and methanol (50 mL) was added. Compound 3 (18.2 g, 0.084 mmol) was obtained by concentration and drying under reduced pressure. 1H NMR (300 MHz, CD3OD) 4.00 (s, 3H), 8.52 (d, J=2.1 Hz, 1H), 9.14 (d, J=2.1 Hz, 1H); HRMS (ES+): m/z 217.0006 (M+H)+ (calcd for C7H8N2O4Cl: 217.0016).

 

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Technical Information

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