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Chemical Structure| 6358-06-1 Chemical Structure| 6358-06-1

Structure of 6358-06-1

Chemical Structure| 6358-06-1

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Product Details of [ 6358-06-1 ]

CAS No. :6358-06-1
Formula : C6H6ClNO
M.W : 143.57
SMILES Code : OC1=CC(N)=CC=C1Cl
English Name :2-Chloro-5-aminophenol
MDL No. :MFCD01707858
InChI Key :JSCNCRWPXOTDDZ-UHFFFAOYSA-N
Pubchem ID :80676

Safety of [ 6358-06-1 ]

Computational Chemistry of [ 6358-06-1 ] Show Less

Physicochemical Properties

Num. heavy atoms 9
Num. arom. heavy atoms 6
Fraction Csp3 0.0
Num. rotatable bonds 0
Num. H-bond acceptors 1.0
Num. H-bond donors 2.0
Molar Refractivity 37.88
TPSA ?

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

46.25 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

1.37
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

1.47
Log Po/w (WLOGP)?

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

1.64
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.

1.41
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

1.31
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.44

Water Solubility

Log S (ESOL):?

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

-2.15
Solubility 1.02 mg/ml ; 0.00709 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.

-2.05
Solubility 1.29 mg/ml ; 0.00896 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

-2.06
Solubility 1.26 mg/ml ; 0.00881 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

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

Yes
Log Kp (skin permeation)?

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

-6.13 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

1.0 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)

1.11

Application In Synthesis of [ 6358-06-1 ]

* 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 [ 6358-06-1 ]

[ 6358-06-1 ] Synthesis Path-Downstream   1~14

  • 1
  • [ 136927-64-5 ]
  • [ 6358-06-1 ]
  • [ 918340-62-2 ]
YieldReaction ConditionsOperation in experiment
With hydrogenchloride In ethanol; water at 90℃;
  • 2
  • [ 918340-51-9 ]
  • [ 6358-06-1 ]
  • [ 918340-57-5 ]
  • 3
  • [ 918340-55-3 ]
  • [ 6358-06-1 ]
  • [ 918340-63-3 ]
YieldReaction ConditionsOperation in experiment
With hydrogenchloride In ethanol; water at 90℃;
  • 4
  • [ 6358-06-1 ]
  • [ 357263-41-3 ]
  • [ 918340-60-0 ]
YieldReaction ConditionsOperation in experiment
With hydrogenchloride In ethanol; water at 90℃;
  • 5
  • [ 6358-06-1 ]
  • [ 28443-52-9 ]
  • [ 1187477-80-0 ]
YieldReaction ConditionsOperation in experiment
With acetic anhydride In 1,4-dioxane Preparation of 2-chloro-5-acetaminophenol Preparation of 2-chloro-5-acetaminophenol 0.05 Mole (7.17 grams) of 2-chloro-5-aminophenol is dissolved in 21 cc of dioxane at 75°C. There is then added, with agitation, 0.05 mole (5.1 grams) of acetic anhydride. At the end of this addition, the reaction medium is maintained for 10 minutes at 70°C and then cooled. The raw product which has crystallized in then filtered and recrystallized in a hydroalcoholic medium. It exhibits a melting point of 212°C. 2-fluoro-5-acetamino phenol is prepared in a similar manner.
  • 6
  • [ 6358-06-1 ]
  • [ 76464-54-5 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: acetic acid / 0.08 h / Reflux 2: caesium carbonate / N,N-dimethyl-formamide / 18 h / Reflux 3: ethanol; potassium hydroxide / water / 8 h / Reflux
  • 7
  • [ 6358-06-1 ]
  • [ 108-24-7 ]
  • [ 28443-52-9 ]
YieldReaction ConditionsOperation in experiment
93% With acetic acid for 0.0833333h; Reflux;
93% In acetic acid for 0.0833333h; Reflux; 26 N-(4-chloro-3-hydroxyphenyl)acetamide (17a) Acetic anhydride (3.0 mL, 42.0 mmol) was added to a solution of 4-chloro-3-hydroxy aniline (4.0 g, 28 mmol) in acetic acid (20 mL), and the reaction was refluxed for 5 mins. The reaction mixture was cooled to room temperature and the product was solidified. It was filtered off and washed with water (10 mL) and dried to obtain the product 17a in 93% yield (4.8 g) as a creamy white solid. There was no need for further purification. [0160] 1H NMR (400 MHz, Acetone) δ 9.26 (br s, 1H), 9.01 (s, 1H), 7.72 (d, J=2.4 Hz, 1H), 7.20 (d, J=8.6 Hz, 1H), 6.93 (dd, J=8.6, 2.4 Hz, 1H), 2.09 (s, 3H). [0161] 13C NMR (101 MHz, Acetone) δ 169.66, 154.05, 140.20, 130.49, 115.18, 112.16, 108.56, 24.35. HRMS (ESI) calculated for C8H8ClNO2 [M+Na]+: 208.0136. Found: 208.0144.
With acetic acid for 0.0833333h; Reflux;
  • 8
  • [ 6358-06-1 ]
  • [ 75-26-3 ]
  • [ 76464-54-5 ]
YieldReaction ConditionsOperation in experiment
100% With potassium carbonate In acetonitrile Reflux; 11 INTERMEDIATE PREPARATION 114-chloro- -[(1-methylethyl)oxy]anilineA mixture of 5-amino-2-chlorophenol (2.87 g, 20 mmol), 2-bromopropane (4.92 g, 40.0 mmol), and potassium carbonate (5.53 g, 40.0 mmol) in acetonitrile (50.00 mL) was heated to reflux over the weekend. The reaction mixture was filtered, and the solids were washed with ethyl acetate. The filtrate concentrated in vacuo and the residue was purified via column chromatography (ISCO, 0-40% ethyl acetate/hexanes) to afford 4-chloro-3-[(1- methylethyl)oxy]aniline (3.7 g, 100% yield).
87% With potassium carbonate In acetonitrile at 20℃; for 24h; Reflux; 14.1 Step-i: 4-Chloro-3-isopropoxyaniline ] A mixture of 5-amino-2-chlorophenol (20 g, 139mmol) and 2-bromopropane (26 mE, 278 mmol) and K2C03(38.4 g, 278 mmol) in CH3CN (300 mE) was refluxed for 24h. The reaction mixture was cooled to room temperature, filtered and the solid was washed with ethyl acetate (150 mE). The filtrate was concentrated and the residue was purified by ISCO (Si02: Flex/EtOAc 0 to 40%) to give the title compound (22.6 g, 87%)
58% With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 2.5h; 4-Chloro-3-ethoxyaniline (21a) To a mixture of 5-amino-2-chlorophenol (148 mg, 1.03 mmol) and K2CO3 (296 mg, 2.14 mmol) in DMF (2.0 mL) was added EtI (100 μL, 1.25 mmol). The whole was stirred at 60°C for 2.5 h and then diluted with AcOEt. The organic layer was washed with water and brine, dried and concentrated. Column chromatography (n-hexane : AcOEt=3 : 1) of the residue gave the title compound (88.5 mg, 0.515 mmol, 50%) as a pale yellow paste.
47% With potassium carbonate In acetonitrile at 80℃; for 16h; 73.1 Step-1: Synthesis of 4-chloro-3-isopropoxyaniline To a stirred solution 5-amino-2-chlorophenol (5 g, 34.8 mmol, 1.0 eq.) and 2-bromopropane (8.5 g, 69.6 mmol, 2.0 eq.) in ACN (30 mL) was added K2CO3 (9.6 g, 69.6 mmol, 2 eq.) The resulting mixture heated at 80° C. for 16 h. Following this, reaction was allowed to cool to RT and filtered through celite pad, the celite pad washed with ethyl acetate and water. The aqueous layer was separated extracted using ethyl acetate (3*30 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum to get the solid residue. The crude was purified by normal phase silica-gel column provided title compound (3.0 g, 47%). LCMS: 186.0 [M+1]+.

  • 9
  • [ 6358-06-1 ]
  • [ 3032-81-3 ]
  • [ 1333950-06-3 ]
  • 10
  • [ 6358-06-1 ]
  • [ 3032-81-3 ]
  • [ 1333950-36-9 ]
  • 11
  • [ 6358-06-1 ]
  • [ 704-91-6 ]
  • N-(4-chloro-3-hydroxyphenyl)-1H-indazole-6-carboxamide [ No CAS ]
  • 12
  • [ 6358-06-1 ]
  • [ 51071-75-1 ]
  • [ 2003264-25-1 ]
YieldReaction ConditionsOperation in experiment
91.5% With sodium acetate In ethanol for 3h; Reflux; 2.2.1 General procedure for the synthesis of the betaine dyes General procedure: The preparation was carried out by modifications in the procedure [26] to that reported by Kessler and Wolfbeis. A mixture of 2,4,6-triphenylpyrylium hydrogen sulfate (2mmol), aminophenol or aminonaphthol derivative (2mmol), and anhydrous sodium acetate (6mmol) were added to 5mL of ethanol. The mixture was refluxed for 3h and cooled. Next, 10mL of a 5% aqueous sodium hydroxide solution was added, and the mixture was stirred for another 5min. Then, 100mL of water was added to the reaction mixture, which was then extracted with DCM (2×50mL). The combined organic layers were dried over anhydrous Na2SO4. The solvent was removed under reduced pressure. The resulting red crystals were recrystallized from aqueous ethanol and dried over P2O5 under vacuum for 24h.
  • 13
  • [ 6358-06-1 ]
  • [ 69045-84-7 ]
  • [ 87170-48-7 ]
YieldReaction ConditionsOperation in experiment
98.2% With potassium carbonate; 3-butyl-1-methyl-1H-imidazol-3-ium hexafluorophosphate In toluene at 60℃; for 1h; 1.2 2) Preparation of 4-chloro 3-(3-chloro-5-trifluoromethylpyridinyloxy)aniline 87 g (0.42 mol) 2,3 dichloro-5-trifluoromethylpyridine, 65.3 g (0.45 mol) 2-chloro-5-aminophenol, 70 g (0.5 mol) potassium carbonate, 5 mmol 1-butyl-3- Methylimidazolium hexafluorophosphate ionic liquid catalyst and 250 mL toluene solvent were put into the reaction flask,The temperature was raised to 60 ° C under stirring, the reaction was incubated for 1 hour, the solvent was distilled off, 250 mL of water was added to precipitate the solid, which was filtered, and the filter cake was washed with water to give Intermediate II as a solid, yield 98.2%;
98.6 % Stage #1: 5-amino-2-chlorophenol With tetrabutyl-ammonium chloride; potassium carbonate In N,N-dimethyl-formamide at 20℃; Large scale; Stage #2: 2,3-dichloro-5-trifluoromethylpyridine In N,N-dimethyl-formamide at 50 - 100℃; Inert atmosphere; Enzymatic reaction; Large scale; 1.1.1-1.1.4 The first step: 2-chloro-5-aminophenol reacts with 2,3-dichloro-5-trifluoromethylpyridine to generate formula 1) In a dry 2000L stainless steel reactor, add 933kg solvent DMF and 197kg2-chloro-5-aminophenol, stir and dissolve at room temperature, then add 208kg anhydrous potassium carbonate and catalyst (tetrabutylammonium chloride) 1.47kg, stir In 30 minutes, 294kg of trifluoromethylpyridine was quickly added dropwise through the overhead tank, the dropping time was controlled within 1-2 hours, the dropping temperature did not exceed 50°C, and the system was protected by nitrogen. After the dropwise addition was completed, the stainless steel reactor was heated to an inner temperature of 100° C. and kept stirring for reaction. (2) Insulate and stir for 3 hours, track the raw material aminophenol (developing agent, petroleum ether: ethyl acetate = 4:1, raw material Rf = 0.3, product Rf = 0.5, trifluoromethylpyridine Rf = 0.9). (3) After the reaction of the raw materials is completed, after the temperature of the stainless steel reactor is cooled, the solvent DMF is evaporated under reduced pressure, and the internal temperature of the distillation temperature is controlled below 80°C. After the distillation is completed, the solvent DMF evaporates about 800kg. After the stainless steel reactor is emptied, 1333kg of water is added through the head tank, stirred and cooled to 5°C, solids are precipitated, and 476kg of dark brown crude solids are obtained by centrifugation. (4) Purification: Add 600 kg of n-heptane to 477 kg of crude solid, heat to reflux to dissolve, cool and crystallize after reflux for 1 hour, control the crystallization temperature at 10-20 ° C, and filter to obtain 435 kg of dark gray solid, namely formula I. Theoretically obtained 441kg, the yield is 98.6%, and the n-heptane mother liquor is applied mechanically to the next batch.
96% With potassium carbonate In N,N-dimethyl-formamide at 80 - 105℃; 1 Example- 1: Preparation of compound of formula (IV) In round bottom flask (RBF), N, A-dimethyl formamide (DMF, 3-6 Vol), 5-amino-2- chlorophenol (1.0 eq), potassium carbonate (1-1.5 eq) was added at 25°C to 35°C. To the reaction mixture 2,3-dichloro-5(trifluromethyl) pyridine (1-1.2 eq) was added and further heated at 80°C to 105 °C for 3-5 hrs. The completion of reaction was monitored by HPLC. After completion, the reaction mixture was cooled to 25°C to 35°C, water (10-20 Vol) added and stirred for 3 hrs. The reaction mixture was filtered and washed with water. The compound was treated with water at 45°C to 65°C to obtain compound of formula (IV, with 96% yield and HPLC purity 98.5%, and dipyridine impurity of formula (1) is 0.2% as determined by HPLC method 1).
 

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