Structure of Paracetamol impurity J
CAS No.: 539-03-7
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Synonyms: 4-Chloroacetanilide
4.5
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| CAS No. : | 539-03-7 |
| Formula : | C8H8ClNO |
| M.W : | 169.61 |
| SMILES Code : | CC(NC1=CC=C(Cl)C=C1)=O |
| Synonyms : |
4-Chloroacetanilide
|
| English Name : | N-(4-Chlorophenyl)acetamide |
| MDL No. : | MFCD00000612 |
| InChI Key : | GGUOCFNAWIODMF-UHFFFAOYSA-N |
| Pubchem ID : | 10871 |
* 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 Copper; potassium carbonate at 180℃; Erwaermen des Reaktionsprodukts mit wss. Natronlauge; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| With sulfuric acid at 145℃; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 98% | With N-Bromosuccinimide In acetonitrile for 2h; Irradiation; regioselective reaction; | |
| 95% | With hydrogen bromide; Selectfluor In water at 20℃; for 3.5h; regioselective reaction; | II. Bromination of anilides 1 General procedure: 1a as example: To a stirred suspension of N-(p-tolyl)acetamide 1a (75 mg, 0.5 mmol) and Selectfluor (213 mg, 0.6 mmol) in water (3.0 mL) was added HBr (40% aqueous, 0.08 mL, 0.55 mmol), and the mixture was stirred for 5 min at room temperature. After 1a was consumed, as indicated by TLC, the reaction mixture was quenched with saturated aqueous Na2S2O3 (2.0 mL) and water (20.0 mL), and extracted with CH2Cl2 (10.0 mL) three times. The residue obtained after evaporation of the solvent was purified by column chromatography on silica gel (petroleum ether-ethyl acetate = 6:1, v/v) to afford N-(2-bromo-4-methylphenyl)acetamide 2a as a white solid (108 mg, 95% yield). |
| 88% | With acetic anhydride; copper(II) bis(trifluoromethanesulfonate); N-Fluorobenzenesulfonimide; sodium bromide In acetonitrile at 80℃; for 3h; Inert atmosphere; regioselective reaction; |
| 79% | With N-Bromosuccinimide; cobalt acetylacetonate; trifluoroacetic acid; silver(l) oxide In 1,2-dichloro-ethane at 60℃; for 16h; regioselective reaction; | |
| 75% | With N-Bromosuccinimide; methanesulfonic acid; nickel(II) chloride hexahydrate In water at 20℃; for 5h; Sealed tube; Microwave irradiation; Green chemistry; regioselective reaction; | Procedure B General procedure: A 10 mL microwave vial was charged with an anilide or carbamate derivative (1.0 equiv, 0.5 mmol), NXS (1.2 equiv, 0.6 mmol), Ag2CO3 (10 mol%, 14 mg), MSA (3.0 equiv, 1.5 mmol, 144 mg) and toluene (2.0 mL). The vial was then sealed and stirred at 50 °C, for 8 h. After the reaction time, the mixture was diluted with EtOAc and washed with sodium bicarbonate solution. The organic layer was dried with anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (n-hexane/EtOAc) to give the desired product. |
| 69% | With N-Bromosuccinimide; bis[dichloro(pentamethylcyclopentadienyl)iridium(III)]; Boc-Phe-OH; silver(I) triflimide In 1,2-dichloro-ethane at 20℃; for 4h; Inert atmosphere; Sealed tube; | |
| With perchloric acid; mercury(II) diacetate; N-bromoacetamide In water at 35℃; δE(excit.), ΔH(excit.), ΔS(excit.); further reaction partners: Cl(-), Br(-); | ||
| With hydrogen bromide; nitric acid | ||
| With bromine; sodium acetate; acetic acid at 70℃; | ||
| With water; bromine |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| With sulfuric acid at 180℃; | ||
| With sulfuric acid at 140 - 170℃; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 70% | With C20H25Cl2CoN3; sodium triethylborohydride; In 1,2-dimethoxyethane; at 100℃; for 6h;Inert atmosphere; | Under an inert atmosphere, the substrate 4-chloroacetanilide (170 mg, 1 mmol), polymethylhydrosiloxane (668 μL, 3 mmol), Co-2 catalyst (9.0 mg, 0.02 mmol), sodium triethylborohydride (40 μL, 0.04 mmol)were sequentially added to the reaction tube and ethylene glycol dimethyl ether (2 mL), and the resulting mixture was stirred well.The reaction was carried out in an oil bath at 100C for 6 hours. The reaction system was cooled to room temperature, diluted and quenched by adding ethyl acetate, and concentrated. The crude product was subjected to flash silica gel column chromatography to obtain 109 mg of light yellow oily liquid, yield: 70%. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| (i) P2S5, (ii) K3<Fe(CN)6>; Multistep reaction; | ||
| Multi-step reaction with 2 steps 1: xylene; P2S5; K2S 2: K3<Fe(CN)6>; aqueous NaOH | ||
| Multi-step reaction with 2 steps 1: Lawessons reagent / 1,4-dioxane / 110 °C 2: sodium hydroxide; potassium hexacyanoferrate(III) / ethanol; water / 0.5 h / 80 °C |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 99% | With cetyltrimethylammonim bromide In water at 25℃; Irradiation; Micellar solution; Inert atmosphere; regioselective reaction; | |
| 52% | With zirconium(IV) oxychloride at 160 - 180℃; for 0.5h; | |
| 32% | With ytterbium trifluoromethanesulfonate; lithium perchlorate In nitromethane at 100℃; for 8h; |
| 20 %Spectr. | In acetonitrile at 20℃; for 20h; Inert atmosphere; UV-irradiation; |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 68% | With aluminium trichloride In 1,2-dichloro-ethane for 16h; | |
| 41% | With H-ZSM-5 zeolite In 1,2-dichloro-ethane Heating; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 88% | With sodium dodecyl-sulfate; trichlorophosphate In acetonitrile for 1.5h; Heating; | |
| 65% | With trichlorophosphate In 1,2-dichloro-ethane at 40℃; for 1h; ultrasound irradiation; | |
| 45% | With trichlorophosphate at 85℃; for 24h; |
| 36% | With trichlorophosphate at 80 - 90℃; for 16h; | |
| 36% | Stage #1: N,N-dimethyl-formamide With trichlorophosphate at 0 - 5℃; for 1h; Stage #2: 4-Chloroacetanilide at 0 - 80℃; Inert atmosphere; | 1.1 General procedure for synthesis of 2-chloroquinoline-3-carbaldehydes (13-18) General procedure: A round bottom flask charged with N, N-dimethylformamide (7.0 mol) was placed on an ice bath and the temperature kept at 0-5 °C. To this flask, phosphorus oxychloride (12.0 mol) was added dropwise and the reaction mixture was stirred for 1 h at 0-5 °C. The appropriate N-phenylacetamide (1.0 mol) was then added and stirred for a further 30 min followed by heating under reflux for 5-4 h under N2 atmosphere. After the reaction was completed (TLC monitoring), the mixture was poured into 200 g of crushed ice under constant stirring. The precipitate obtained was vacuum filtered, washed with water (2 × 30 mL), air-dried and recrystallised from EtOAc to give the relevant compounds in 36-84% yields. |
| With trichlorophosphate 1.) 0 deg C, 0.5 h, 2.) 70 deg C, 16 h; Multistep reaction; | ||
| With trichlorophosphate at 5 - 75℃; for 4h; | 25 2,6-Dichloroquinoline-3-carbaldehyde POCl3 (31.1 g, 210 mmol) was added to DMF (6.5 g, 90 mmol) while keeping the temperature below 5° C. 4-Chloroacetanilide (5.07 g, 30 mmol) was added in one portion and the reaction mixture was heated to 75° C. for 4 hours. The reaction mixture was cooled to room temperature and poured onto ice. The separated crystals were filtered and dried. Yield 220 mg. M.p. 188-190° C. | |
| With trichlorophosphate | ||
| With trichlorophosphate at 0 - 75℃; for 6h; | ||
| With trichlorophosphate | ||
| With trichlorophosphate | ||
| Stage #1: N,N-dimethyl-formamide With trichlorophosphate Stage #2: 4-Chloroacetanilide | ||
| With trichlorophosphate Heating; | ||
| With trichlorophosphate at 0℃; Reflux; | General procedure for the synthesis of 6-substituted-2-chloroquinoline-3-carbaldehydes 2a-d (Meth-Cohnet al., 1981) General procedure: Dimethylformamide 9.6 mL (0.125 mol)was cooled to 0 C, and phosphoryl chloride 32.2 mL(0.35 mol) was added drop-wise with stirring. To thissolution was added substituted acetanilide 1a-d (0.05 mol)and the reaction mixture was refluxed for 16-17 h. Reactioncompletion was monitored by TLC. The reactionmixture was poured into ice water (300 mL) and stirred for30 min at 0-10 °C. The resulting suspension was filteredand washed with water to give the intermediates 2a-d. | |
| With trichlorophosphate at 80 - 100℃; | Step II Preparation of 2-chloro-3-formylquinoline CFQ 8, 9 General procedure: To a s o l u t i o n o f a c e t a n i l i d e(N-phenylacetamide) (5 mmoles) in dry DMF (15mmoles) at 0-5oC POCl3 (60 mmoles) was addeddropwise with stirring and the mixture was thenstirred at 80 - 100oC for time ranging between 4-16hr. The mixture was poured on to crush ice, stirredfor 5 minutes and the resulting solid fltered, washedwell with water and dried. The compounds wererecrystallized from ethyl acetate. Phosphoryl chloride(commonly called phosphorus oxychloride) is acolorless liquid with the formula POCl3. It hydrolysesin moist air to phosphoric acid to release choking fumes of hydrogen chloride. It is manufacturedindustrially on a large scale from phosphorustrichloride and oxygen or phosphorus pentoxide. Itis mainly used to make phospha (Table 1). | |
| With trichlorophosphate | ||
| Stage #1: N,N-dimethyl-formamide With trichlorophosphate at 0℃; Stage #2: 4-Chloroacetanilide at 80℃; for 18h; | ||
| With trichlorophosphate at 0 - 82℃; for 24h; Inert atmosphere; | ||
| With trichlorophosphate for 24h; Heating; | ||
| With trichlorophosphate at 80 - 90℃; | ||
| With trichlorophosphate at 0℃; for 16h; Reflux; | 2.3.1 General procedure for the synthesis of 6/7/8-substituted-2-chloro quinoline-3-carbaldehydes (2) General procedure: Dimethyl formamide (9.13g, 9.9ml, and 0.125mole)wasfrozento 0°C in a flask along with a drying tube and phosphoryl chloride (53.7g, 32.2ml. 0.35mole) was mixed drop wise with stirring. The substituted acetanilide (1) (6.55g, 0.05mole) was added to the mixture and the mixture was heated under reflux for 16h. The product obtained was added into ice cold water and stirred for 30min at 0-10°C. 6/7/8-Substituted-2-chloro quinoline-3-carbaldehyde (2) separated as yellow precipitate. It was filtered, washed with water and recrystallized from ethyl acetate. | |
| With trichlorophosphate at 70 - 80℃; for 16h; | Preparation of 2-chloroquinolin-3-carbaldehyde (6c-i) General procedure: Vilsmeir-Haack adduct was prepared by adding phosphorous oxychloride (0.35 mol) drop wise to the cold solution of DMF (0.125 mol) with constant stirring. To this adduct, substituted acetanilide (0.05 mol) was added slowly and stirred well for 15-20 min. The mixture was then refluxed for 16 h at 70-80°C. After completion of the reaction, the contents were poured into ice water and stirred for 30 min. The 2-chloroquinoline-3-carbaldehyde 6c-i precipitated out was filtered and washed well with water. Dried and recrystallized from ethyl acetate. | |
| Stage #1: N,N-dimethyl-formamide With trichlorophosphate at 0℃; for 0.25h; Stage #2: 4-Chloroacetanilide at 80℃; for 8h; | ||
| With trichlorophosphate for 6h; Reflux; | ||
| With trichlorophosphate at 0℃; Reflux; Heating; | General procedure for the synthesis of N’-substituted-2-chloroquinoline-3-carbaldehydes2(a-e) and N’-substituted-2-methoxyquinoline-3-carbaldehydes 5(a-e) General procedure: Dimethylformamide 9.6 mL (0.125 mol) was takenin round bottom flask equipped with drying tube and phosphorus oxychloride 32.2 mL (0.35 mol) was added drop wise with continuous stirring at 0°C. To above solution different aryl acetanilide 1(a-e) (0.05 mol) were added and after 5 min the solution is heated under reflux for 16-17 h. The completion of the reaction was monitored by TLC, reaction contents were decanted into crushed ice with constant stirring. The settled solid was sieved, washed with water, dried and purified by recrystallization using ethyl acetate to afford final pure product 2(a-e) in good yield. | |
| With trichlorophosphate at 0 - 90℃; | General procedure for the synthesis of 6-substituted-2-chloro-3-formyl quinolines, 2 General procedure: To a solution of substituted acetanilide (5 mmol) indry dimethyl formamide (15 mmol) at 0-5°C withstirring POCl3 (60 mmol) was added drop-wise andthe mixture stirred at 80-90°C for time rangingbetween 4-16 h. The product obtained was pouredinto crushed ice, stirred for 5 min and the resultingsolid mass was filtered, washed well with water anddried. The compounds were recrystallized from ethylacetate. | |
| With trichlorophosphate at 80 - 90℃; | Synthesis of substituted quinoline-3-carbaldehydes (1a, b) General procedure: 6-substituted-2-chloro-quinoline-3-carbaldehydes (1a-b) were prepared by Vilsmeier-Haack reaction from substituted acetanilide using DMF and POCl3 as per the reported protocol. The reported melting points of compounds 1a and 1b are 146-148°C and 188-192°C, respectively, and the observed melting points of these intermediates were found to be 146-150°C and 188-190°C, respectively. | |
| With trichlorophosphate at 0℃; Reflux; | ||
| With trichlorophosphate at 0 - 90℃; | 4.2.2. General procedure for synthesis of compound 3 General procedure: DMF (42 mmol) was added dropwise to a solution of compound 2(16.7 mmol) in POCl3 (116.7 mmol) at 0 C, after completion, the icewaterbath was removed, the solution was heated to 90 C and stirredfor 6 h (monitored by TLC, VEA/VPE = 1/2). The solution was allowed tocool to room temperature, poured into ice water (200 mL) and theresulting mixture was stirred for 30 min. The precipitate was filtered andwashed with saturated sodium bicarbonate solution and afforded 3 as ayellow solid. Yield 40 % ~ 70 %. The crude 3 was used directly in thenext step without further purification. | |
| With trichlorophosphate at 0 - 90℃; | 4.2.2. General procedure for synthesis of compound 3 General procedure: DMF (42 mmol) was added dropwise to a solution of compound 2(16.7 mmol) in POCl3 (116.7 mmol) at 0 C, after completion, the icewaterbath was removed, the solution was heated to 90 C and stirredfor 6 h (monitored by TLC, VEA/VPE = 1/2). The solution was allowed tocool to room temperature, poured into ice water (200 mL) and theresulting mixture was stirred for 30 min. The precipitate was filtered andwashed with saturated sodium bicarbonate solution and afforded 3 as ayellow solid. Yield 40 % ~ 70 %. The crude 3 was used directly in thenext step without further purification. | |
| 24 g | Stage #1: N,N-dimethyl-formamide With trichlorophosphate at 0 - 20℃; Stage #2: 4-Chloroacetanilide at 0 - 90℃; | 76 Preparation 76.2,6-Dichloroquinoline-3-carbaldehyde (P1.71) A solution of POCl3(150 mL, 1.59 mol, 9.0 eq) in DMF (28 mL) was stirred at 0°C for 10 min and then at rt for 15 min. To the solution was added N-(4-chlorophenyl)acetamide (30 g, 177.48 mmol, 1.0 eq) at 0 °C in one portion. After the solution was stirred at 90°C overnight, the reaction mixture was diluted with H2O (200 mL) and extracted with ethyl acetate (200 mL x 3). The organic layers were washed with brine solution, dried over MgSO4, filtered, and concentrated to give P1.71 as a brown solid (24 g) which was used for the next step without further purification.1H NMR (400 MHz, CDCl3), δ: 10.52 (s, 1H), 8.67 (s, 1H), 8.03- 8.00 (m, 1H), 7.96 (d, J = 2.4 Hz, 1H), 7.83-7.78 (m, 1H). |
| 24 g | Stage #1: N,N-dimethyl-formamide With trichlorophosphate at 0 - 20℃; Stage #2: 4-Chloroacetanilide at 0 - 90℃; | 76 Preparation 76.2,6-Dichloroquinoline-3-carbaldehyde (P1.71) A solution of POCl3(150 mL, 1.59 mol, 9.0 eq) in DMF (28 mL) was stirred at 0°C for 10 min and then at rt for 15 min. To the solution was added N-(4-chlorophenyl)acetamide (30 g, 177.48 mmol, 1.0 eq) at 0 °C in one portion. After the solution was stirred at 90°C overnight, the reaction mixture was diluted with H2O (200 mL) and extracted with ethyl acetate (200 mL x 3). The organic layers were washed with brine solution, dried over MgSO4, filtered, and concentrated to give P1.71 as a brown solid (24 g) which was used for the next step without further purification.1H NMR (400 MHz, CDCl3), δ: 10.52 (s, 1H), 8.67 (s, 1H), 8.03- 8.00 (m, 1H), 7.96 (d, J = 2.4 Hz, 1H), 7.83-7.78 (m, 1H). |
| 65 % | Stage #1: N,N-dimethyl-formamide With trichlorophosphate at 0℃; Stage #2: 4-Chloroacetanilide at 70℃; | General procedure for the synthesis of 2-chloro-3-formylquinoline (4 a-b) General procedure: To N, N-dimethylformamide (4.55 mL, 58.0 mmol, 4equiv.), phosphorous oxychloride (13 mL 0.000147 mmol,10 Equiv.) was added dropwise and stirred at 0 °C for30 min to get Vilsmeier reagent. The substituted acetanilide(2 g, 14.7 mmol, 1 equiv.) was added in the in situ preparedVilsmeier reagent at 70 °C. After completion of the reaction,the reaction mixture was cooled and poured overcrushed ice. Precipitate was filtered, washed with water, anddried to get a yellow crude product. The desired productwas isolated with column chromatography (100-200 meshsize silica) in 10% ethyl acetate in hexane as amobile phase. |
| With trichlorophosphate at 70℃; for 12h; | ||
| Stage #1: N,N-dimethyl-formamide With trichlorophosphate at 0℃; for 0.166667h; Inert atmosphere; Stage #2: 4-Chloroacetanilide for 8h; Inert atmosphere; | ||
| With trichlorophosphate at 85℃; for 18h; | ||
| With trichlorophosphate at 0℃; |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 90% | In 1,2-dichloro-ethane; toluene at -30 - 65℃; for 48h; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| With triethylamine In tetrahydrofuran Heating; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 95% | With potassium phosphate; tert-butyl XPhos In toluene at 100℃; for 20h; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 2 steps 1: water; nitric acid 2: arsenic acid; concentrated sulfuric acid |

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