Structure of 6358-06-1
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| 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 |
| 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 |
46.25 Ų |
| Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.37 |
| Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.47 |
| Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.64 |
| Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.41 |
| Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.31 |
| Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.44 |
| Log S (ESOL):? ESOL: Topological method implemented from |
-2.15 |
| Solubility | 1.02 mg/ml ; 0.00709 mol/l |
| Class? Solubility class: Log S scale |
Soluble |
| Log S (Ali)? Ali: Topological method implemented from |
-2.05 |
| Solubility | 1.29 mg/ml ; 0.00896 mol/l |
| Class? Solubility class: Log S scale |
Soluble |
| Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.06 |
| Solubility | 1.26 mg/ml ; 0.00881 mol/l |
| Class? Solubility class: Log S scale |
Soluble |
| 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) |
No |
| CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
No |
| CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
| CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
| CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
| CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
Yes |
| Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-6.13 cm/s |
| Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
| Ghose? Ghose filter: implemented from |
None |
| Veber? Veber (GSK) filter: implemented from |
0.0 |
| Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
| Muegge? Muegge (Bayer) filter: implemented from |
1.0 |
| Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
| PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
| Brenk? Structural Alert: implemented from |
1.0 alert: heavy_metal |
| Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
| Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
1.11 |
* 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.

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| With hydrogenchloride In ethanol; water at 90℃; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| With hydrogenchloride In ethanol; water at 90℃; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| With hydrogenchloride In ethanol; water at 90℃; |
| Yield | Reaction Conditions | Operation 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. |
| Yield | Reaction Conditions | Operation 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 |
| Yield | Reaction Conditions | Operation 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; |
| Yield | Reaction Conditions | Operation 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]+. |

| Yield | Reaction Conditions | Operation 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. |
| Yield | Reaction Conditions | Operation 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). |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 100% | With sodium tris(acetoxy)borohydride; acetic acid In 1,2-dichloro-ethane |