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Chemical Structure| 3970-35-2 Chemical Structure| 3970-35-2

Structure of Mesalazine EP Impurity Q
CAS No.: 3970-35-2

Chemical Structure| 3970-35-2

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Product Details of [ 3970-35-2 ]

CAS No. :3970-35-2
Formula : C7H4ClNO4
M.W : 201.56
SMILES Code : C1=C(C(=C([N+](=O)[O-])C=C1)Cl)C(O)=O
MDL No. :MFCD00007069
InChI Key :JRQDVRIQJJPHEQ-UHFFFAOYSA-N
Pubchem ID :19870

Safety of [ 3970-35-2 ]

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

Computational Chemistry of [ 3970-35-2 ] 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 4.0
Num. H-bond donors 1.0
Molar Refractivity 47.23
TPSA ?

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

83.12 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

0.88
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

1.85
Log Po/w (WLOGP)?

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

1.95
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.

1.11
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

-0.26
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.1

Water Solubility

Log S (ESOL):?

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

-2.46
Solubility 0.691 mg/ml ; 0.00343 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.

-3.22
Solubility 0.122 mg/ml ; 0.000607 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

-1.77
Solubility 3.4 mg/ml ; 0.0169 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.

-6.22 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.

0.56

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)

1.76

Application In Synthesis of [ 3970-35-2 ]

* 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 [ 3970-35-2 ]

[ 3970-35-2 ] Synthesis Path-Downstream   1~6

  • 1
  • [ 34662-24-3 ]
  • [ 3970-35-2 ]
  • 2
  • [ 3970-35-2 ]
  • [ 89639-98-5 ]
YieldReaction ConditionsOperation in experiment
99% Intermediate 1 2-Chloro-3-nitrobenzyIbromide2-Chloro-3-nitrobenzoic acid (0.30 g, 1.5 mmol) was added to BH3 (IM, 4.0 mL, 4.0 mmol). The reaction was refluxed for 3 hours and then cooled to room temperature. The reaction was quenched with water and extracted with diethyl ether (3x15 mL). Purification on silica (100% dichloromethane) gave 0.28g, (99% yield) of the 2-chloro-3- nitrobenzylalcohol.
98% Step 1. (2-Chloro-3-nitrophenyl)methanol; A 500-mL 3-necked round-bottom flask was charged with a solution of NaBH4 (4 g, 105.26 mmol, 2.10 equiv) in THF (100 mL). To this was added a solution of 2-chloro-3-nitrobenzoic acid (10 g, 49.75 mmol) in THF (100 mL) at 0 C. After 10 minutes, BF3.Et2O (15 mL) in THF (50 mL) was added dropwise over 10 minutes. The resulting solution was stirred at room temperature overnight. The reaction progress was monitored by TLC (DCM: MeOH=5:1). Upon completion, the reaction was quenched with water (500 mL) and extracted with ethyl acetate (3×300 mL). Combined organic layers were dried over anhydrous sodium sulfate, filtered off and concentrated on a rotary evaporator affording (2-chloro-3-nitrophenyl)methanol as light yellow solid (9 g, 98%).
84% In tetrahydrofuran; water; Example 132 Synthesis of (2-chloro-3-nitrophenyl)methanol A borane-tetrahydrofuran complex (1.0 M, 20 ml) was added dropwise to a solution of 2-chloro-3-nitrobenzoic acid (5.0 g) in anhydrous tetrahydrofuran (30 ml) in a nitrogen atmosphere and the mixture was heated under reflux for 16 h. Water was added to the reaction mixture which was extracted with ethyl acetate; the organic layer was washed successively with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, dried with anhydrous-sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=5:2) to give 3.5 g of the titled compound (yield, 84%). 1H-NMR(CDCl3) δ: 2.04(1H, t, J=5.9 Hz), 4.88(2H, d, J=5.9 Hz), 7.45(1H, dd, J=7.9, 7.9 Hz), 7.72-7.82(2H,m)
61% The following procedure for the synthesis of the intermediate 7-nitro-benzo[b]thiophene-2-carboxylic acid is a modification of the procedure in the chemical literature (L. K. A. Rahaman and R. M. Scrowston, J. Chem. Soc. Perkin Trans. I, 19, 1984, 385). 3-Nitro-2-chlorobenzoic acid (25.51 g, 126.56 mmol) was dissolved in anhydrous THF (400 mL) under a nitrogen atmosphere. The solution was cooled to -70 C. (internal temperature) under N2 flush. DIBAL-H (260 mL, 1.0M in hexanes) was added dropwise over about 11/2 h (internal temperature was maintained below -65 C.). The reaction was allowed to slowly warm to room temperature and was stirred 12 h. The reaction was cooled to -70 C. and 50 mL of MeOH was added dropwise. The reaction mixture was placed in an H2O/ice bath and a 1M Rochelle's salt solution was slowly added in. This solution was stirred for 1 h at room temperature, then filtered through diatomaceous earth. The THF was concentrated in vacuo and the remaining aqueous solution was extracted 3 times with EtOAc. The combined organic layers were washed with brine, dried with MgSO4, filtered, and evaporated to obtain 14.4 g (61%) of the desired 3-nitro-2-chlorobenzyl alcohol as a yellow solid.
43% In tetrahydrofuran; hydrogenchloride; hexane; EXAMPLE 9 2-Chloro-3-nitrobenzenemethanol A solution of 2-chloro-3-nitrobenzoic acid (1.0 g, 5.0 mmol) in tetrahydrofuran (10 mL) is cooled to 0 C. under an argon atmosphere. Boranetetrahydrofuran complex (6.4 mL of a 1.0 M solution) is added dropwise, maintaining a reaction temperature of less than 5 C. After the addition is complete, the reaction mixture is stirred for 6 hours at room temperature. It is then cooled in an ice bath and quenched by the addition of 10 mL of 1.0 N HCl. The reaction mixture is heated at reflux for 30 minutes and concentrated by distilling the THF. The remaining aqueous solution is extracted with methylene chloride, and the organic layer is washed with saturated aqueous bicarbonate and brine. Evaporation of the organic layer followed by recrystallization of the residue from hexane gives 2-chloro-3-nitrobenzenemethanol (0.4 g, 43%), mp=69-70 C.
With dimethylsulfide borane complex; triethylamine; In tetrahydrofuran; at 0℃; for 3h;Reflux; General procedure: Triethylamine (94.3 g, 0.932 mol) and 10 N BH3·SMe2 in DMS (281 mL, 2.81 mol) were added to 2-bromo-4-nitro-benzoic acid 17 (230 g, 0.935 mol, sourced commercially) in THF (1.5 L) at 0 C, then the reaction mixture was heated at reflux for 3 h. The reaction mixture was allowed to cool to rt, then slowly quenched with water (100 mL) and acidified with concd aq HCl to pH=1, heated at reflux for 30 min, then allowed to cool to rt. The mixture was extracted three times with DCM (3*500 mL), and the combined organic layers were evaporated and purified by flash chromatography, eluting with 17-33% EtOAc in petroleum ether, to afford the title compound (135.1 g, 62%) as a yellow solid;

  • 3
  • [ 3970-35-2 ]
  • [ 34662-24-3 ]
  • 4
  • iodine borohydride [ No CAS ]
  • [ 541-41-3 ]
  • [ 3970-35-2 ]
  • [ 89639-98-5 ]
YieldReaction ConditionsOperation in experiment
1.5 g (80%) With triethylamine; In tetrahydrofuran; water; ethyl acetate; 1-A. 2-Chloro-3-nitrobenzyl alcohol A mixture of 2-chloro-3-nitrobenzoic acid (2.01 g, 0.01 mol) and ethyl chloroformate (1.08 g, 0.01 mol) in 25 ml of dry tetrahydrofuran under argon at room temperature was treated with triethylamine (1.01 g, 0.01 mol) in 10 ml of tetrahydrofuran over a period of 15 minutes. After stirring for 1 hour, the solids were removed by filtration and the filtrate was treated dropwise with a solution of iodine borohydride (0.5 g, 0.013 mol) in 3 ml of water. Slight warming and copious gas evolution were noted. Solvent was removed in vacuo and the residue, dissolved in ethyl acetate, was washed with water, dilute sodium bicarbonate, water, 1N hydrochloric acid, water and saturated brine. The dried (magnesium sulfate) organic solution was concentrated in vacuo to give 1.69 g of crude solid product. Hexane trituration gave 1.5 g (80%) of product, melting point 67-70. Analysis for C7 H6 C1NO3:
  • 6
  • [ 3970-35-2 ]
  • [ 170791-09-0 ]
 

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