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CAS No. : | 95233-37-7 | MDL No. : | MFCD00665919 |
Formula : | C13H15ClO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | NXXDIEYTMQYWJU-UHFFFAOYSA-N |
M.W : | 238.71 | Pubchem ID : | 2735792 |
Synonyms : |
|
Num. heavy atoms : | 16 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.46 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 64.92 |
TPSA : | 37.3 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.12 cm/s |
Log Po/w (iLOGP) : | 2.29 |
Log Po/w (XLOGP3) : | 3.71 |
Log Po/w (WLOGP) : | 3.7 |
Log Po/w (MLOGP) : | 3.27 |
Log Po/w (SILICOS-IT) : | 3.22 |
Consensus Log Po/w : | 3.24 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | -3.8 |
Solubility : | 0.0376 mg/ml ; 0.000157 mol/l |
Class : | Soluble |
Log S (Ali) : | -4.18 |
Solubility : | 0.0156 mg/ml ; 0.0000654 mol/l |
Class : | Moderately soluble |
Log S (SILICOS-IT) : | -3.6 |
Solubility : | 0.06 mg/ml ; 0.000251 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 2.0 |
Synthetic accessibility : | 2.36 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H332-H335 | Packing Group: | N/A |
GHS Pictogram: |
* 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 |
---|---|---|
89% | With water; lithium hydroxide In methanol at 20℃; for 5 h; | A mixture of methyl 4-chlorophenylcyclohexylcarboxylate (III)10.08 g (0.04 mol) was added to 250 mlThree bottles, add 80ml of methanol,20mlWater and lithium hydroxide(3.60 g, 0.15 mol) was added and stirred at room temperature5h, with 1N hydrochloric acid to adjust the pH 1, stirring 30min, the precipitation of solid by filtration, filter cake washedTo a pH of 5 to give the crude product which was recrystallized from 60 ml of ethanol to give 8.50 g of a white solid product,Yield 89percent, content 99.17percent |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99.9% | With hydrogenchloride; hydrogen;platinum(IV) oxide; In methanol; at 50℃; under 3750.38 Torr; for 3h; | 2.11.a 4-cyclohexyl-1-cyclohexylcarboxylic acid 0.44 mL conc. hydrochloric acid and 100 mg platinum oxide are added to a solution of 500 mg (2.10 mmol) of 4-(4-chlorophenyl)-cyclohexanecarboxylic acid in 10 mL methanol. The reaction mixture is stirred at 50 C. and 5 bar hydrogen for 3 h. After separation of the catalyst the solvent is eliminated using the rotary evaporator. Yield: 440 mg (99.9% of theory); C13H22O2 (M=210.319); calc.: molar peak (M-H)-: 209 fnd.: molar peak (M-H)-: 209. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
The solid was filtered off, washed with water, dried and recrystallized from ethanol to give 4-(4-chlorophenyl)cyclohexane-1-carboxylic acid, m.p. 254-256 C. | ||
The solid was filtered off, washed with water, dried and recrystallized from ethanol to give 4-(4-chlorophenyl)cyclohexane-1-carboxylic acid, m.p. 254-256 C. | ||
The solid was filtered off, washed with water, dried and recrystallized from ethanol to give 4-(4-chlorophenyl)cyclohex- ane-1-carboxylic acid, m.p. 254-256 C. |
(a) 4-(4-Chlorophenyl)cyclohexane-1-carboxylic Acid Acetyl chloride (30 g) and finely powdered aluminium chloride (60 g) were stirred together in carbon disulphide (120 ml) and then cooled to -50 C., in a CO2 /oxitol bath. Cyclohexene (30 g), previously cooled to -50 C., was added dropwise during 10 minutes while maintaining the temperature of the reaction mixture at below -20 C. The mixture was stirred at -50 C. for a further 60 minutes and the solvent then decanted to leave a gummy orange complex. A little chlorobenzene was added as the material warmed to ambient temperature; the remainder of the chlorobenzene (total 300 ml) was then added, the so-obtained solution heated at 40 C. for 3 hours with stirring, poured onto a mixture of ice and concentrated hydrochloric acid and the organic layer separated, washed with 2M hydrochloric acid, 2M sodimhydroxide and water, dried over anhydrous sodium sulphate and evaporated to dryness. The product was distilled in vacuo, the fraction boiling at 140- 154 C. (0.1 mm Hg) collected, diluted with an equal volume of petroleum ether (40-60), cooled to -6 C. and a continuous stream of nitrogen gas bubbled through, and the separated colourless solid recovered. Bromine (2.8ml) was added to a solution of sodium hydroxide (6.2 g) in water (42 ml) at 0 C. The above-obtained substituted hexahydroacetophenone (3.1 g) was dissolved in dioxan (15 ml) and the cold hypobromite solution then added, keeping the reaction mixture at below 20 C. The reaction mixture was stirred at ambient temperature for 6 hours then allowed to stand overnight. Sodium metabisulphite was added to destroy excess hypobromite, the mixture cooled and then acidified to give a colourless solid. The solid was filtered off, washed with water, dried and recrystallized from ethanol to give 4-(4-chlorophenyl)cyclohexane-1-carboxylic acid, m.p. 254-256 C. | ||
C. Preparation of 4-(4-Chlorophenyl)cyclohexane-1-carboxylic Acid Acetyl chloride (30 g) and finely powdered aluminium chloride (60 g) were stirred together in carbon disulphide (120 ml) and then cooled to -50 C. in a CO2 /oxitol bath. Cyclohexene (30 g), previously cooled to -50 C., was added dropwise during 10 minutes while maintaining the temperature of the reaction mixture at below -20 C. The mixture was stirred at -50 C. for a further 60 minutes and the solvent then decanted to leave a gummy orange complex. A little chlorobenzene was added as the material warmed to ambient temperature; the remainder of the chlorobenzene (total 300 ml) was then added, the so-obtained solution heated at 40 C. for 3 hours with stirring, poured onto a mixture of ice and concentrated hydrochloric acid and the organic layer separated, washed with 2M hydrochloric acid, 2M sodium hydroxide and water, dried over anhydrous sodium sulphate and evaporated to dryness. The product was distilled in vacuo, the fraction boiling at 140-154 C. (0.1 mm Hg) collected, diluted with an equal volume of petroleum ether (40-60), cooled to -6 C. and a continuous stream of nitrogen gas bubbled through, and the separated colourless solid recovered. Bromine (2.8 ml) was added to a solution of sodium hydroxide (6.2 g) in water (42 ml) at 0 C. The above-obtained substituted hexahydroacetophenone (3.1 g) was dissolved in dioxan (15 ml) and the cold hypobromite solution then added, keeping the reaction mixture at below 20 C. The reaction mixture was stirred at ambient temperature for 6 hours then allowed to stand overnight. Sodium metabisulphite was added to destroy excess hypobromite, the mixture cooled and then acidified to give a colourless solid. The solid was filtered off, washed with water, dried and recrystallized from ethanol to give 4-(4-chlorophenyl)cyclohexane-1-carboxylic acid, m.p. 254-256 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With silver nitrate; In water; acetonitrile; | b) 2-[4-(4-chlorophenyl)cyclohexyl]-3-chloro-1,4-naphthoquinone A mixture of 2-chloro-1,4-naphthoquinone (3.95 g, 0.02 mol), <strong>[95233-37-7]4-(4-chlorophenyl)cyclohexane-1-carboxylic acid</strong> (4.9 g, 0.02 mol) and powdered silver nitrate (1.05 g, 0.0062 mol) was heated to reflux with vigorous stirring in 40 ml of acetonitrile. A solution of ammonium persulphate (12.0 g, 0.0525 mol) in 50 ml of water was added dropwise over 1 hour. The mixture was refluxed for 3 hours then cooled in ice for 30 mins, after which it was filtered, and the residual sticky solid extracted twice with boiling chloroform to remove inorganic material. The chloroform was removed by evaporation to leave a yellow-brown solid (ca 2.7 g). This was dissolved in 40 ml of boiling acetonitrile; a little insoluble material was removed by filtration. | |
With silver nitrate; In water; acetonitrile; | b 2-[4-(4-chlorophenyl)cyclohexyl]-3-chloro-1,4-naphthoquinone A mixture of 2-chloro-1,4-naphthoquinone (3.95 g, 0.02 mol), <strong>[95233-37-7]4-(4-chlorophenyl)cyclohexane-1-carboxylic acid</strong> (4.9 g, 0.02 mol) and powdered silver nitrate (1.05 g, 0.0062 mol) was heated to reflux with vigorous stirring in 40 ml of acetonitrile. A solution of ammonium persulphate (12.0 g, 0.0525 mol) in 50 ml of water was added dropwise over 1 hour. The mixture was refluxed for 3 hours then cooled in ice for 30 mins, after which it was filtered, and the residual sticky solid extracted twice with boiling chloroform to remove inorganic material. The chloroform was removed by evaporation to leave a yellow-brown solid (ca 2.7 g). This was dissolved in 40 nl of boiling acetonitrile; a little insoluble material was removed by filtration. | |
With silver nitrate; In water; acetonitrile; | b) 2-[4-(4-chlorophenyl)cyclohexyl]-3-chloro-1,4-naphthoquinone A mixture of 2-chloro-1,4-naphthoquinone (3.95g, 0.02 mol), <strong>[95233-37-7]4-(4-chlorophenyl)cyclohexane-1-carboxylic acid</strong> (4.9g, 0.02 mol) and powdered silver nitrate (1.05g, 0.0062 mol) was heated to reflux with vigorous stirring in 40 ml of acetonitrile. A solution of ammonium persulphate (12.0g, 0.0525 mol) in 50 ml of water was added dropwise over 1 hour. The mixture was refluxed for 3 hours then cooled in ice for 30 mins, after which it was filtered, and the residual sticky solid extracted twice with boiling chloroform to remove inorganic material. The chloroform was removed by evaporation to leave a yellow-brown solid (ca 2.7g). This was dissolved in 40 ml of boiling acetonitrile; a little insoluble material was removed by filtration. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With thionyl chloride; In tetrachloromethane; | Then, <strong>[95233-37-7]trans-4-(p-chlorophenyl)cyclohexane carboxylic acid</strong> (160 g, 0.67 mole) was stirred together with 100 ml of thionyl chloride and 500 ml of carbon tetrachloride at a reflux temperature for one day and a night. Then the solvent was distilled off by an evaporator. The residue was distilled under reduced pressure, whereby <strong>[95233-37-7]trans-4-(p-chlorophenyl)cyclohexane carboxylic acid</strong> chloride was obtained as a yellow liquid. | |
With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 14.5h; | To a solution of <strong>[95233-37-7]4-(4-chlorophenyl)cyclohexanecarboxylic acid</strong> (2.50 g, 10.5 mmol) in CH2CI2 (30.0 mL) were added DMF (23.0 mg, 314.2 muiotaetaomicron) and oxalyl dichloride (2.79 g, 22.0 mmol) at room temperature. The mixture was stirred at room temperature for 14.5 h. The reaction mixture was concentrated under reduced pressure to give 4-(4- chlorophenyl)cyclohexanecarbonyl chloride (2.69 g). A solution of crude acid chloride (2.69 g) in CH2CI2 (10 mL) was added to a solution of 2,2-dimethyl-l,3-dioxane-4,6-dione (1.66 g, 11.6 mmol) and pyridine (1.66 g, 21.0 mmol) in CH2CI2 (20 mL) at 0 C. The mixture was stirred at 0 C for 10 min and at room temperature for 1.5 h. The reaction mixture was partitioned between CH2CI2 and IN HC1 aqueous solution. The organic layer was washed with brine, dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, hexane/EtOAc) to give a mixture contained 5-[4-(4-chlorophenyl)cyclohexanecarbonyl]-2,2-dimethyl-l,3- dioxane-4,6-dione (2.71 g). The mixture of 5-[4-(4-chlorophenyl)cyclohexanecarbonyl]-2,2- dimethyl-l,3-dioxane-4,6-dione (2.70 g) and tert-butyl carbamate (1.04 g, 8.88 mmol) in acetonitrile (50.0 mL) was stirred at 90 C for 35 min. The reaction mixture was (0251) concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, hexane/EtOAc) to give a mixture contained tert-butyl N-[3-[4-(4- chlorophenyl)cyclohexyl]-3-oxo-propanoyl]carbamate (1.82 g) as a white solid. This product was used next step without further purification. TFA (5.0 mL) was added to a solution of tert-butyl N-[3-[4-(4-chlorophenyl)cyclohexyl]-3-oxo-propanoyl]carbamate (1.81 g) in CH2CI2 (30.0 mL) at room temperature. The reaction mixture was stirred at room temperature for 14.5 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (basic silica gel, C^Ch/MeOH) and by washed with ethyl acetate and IPE to give 3-[4-(4-chlorophenyl)cyclohexyl]-3-oxo- propanamide (330.0 mg, 1.18 mmol, 25% yield) as white solid. NMR (500 MHz, Chloroform- delta 7.26 (tt, J= 3.0, 1.3 Hz, 2H), 7.14 - 7.10 (m, 2H), 6.99 (s, 1H), 5.45 (s, 1H), 3.50 (s, 2H), 2.50 (dtd, J= 14.9, 11.2, 3.4 Hz, 2H), 2.09 - 1.97 (m, 4H), 1.53 - 1.44 (m, 4H), CO2H was not detected. MS m/z: 280 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With sodium hydroxide; bromine; In 1,4-dioxane; | Then, an aqueous sodium hypobromite solution obtained by dropwise addition of bromine (385 g, 2.41 moles) to 1 l of an aqueous solution of sodium hydroxide (264 g, 8.6 moles), was dropwise added to 800 ml of a dioxane solution of trans-4-(p-chlorophenyl)-1-acetylcyclohexane (165 g, 0.70 mole). After the dropwise addition, the mixture was stirred for 2 hours at room temperature, and then the neutral organic substances were removed by extraction with ether. The aqueous layer was acidified with hydrochloric acid, whereby colorless crystals were obtained. The crystals were collected by filtration, washed with water and dried, whereupon 160 g of trans-4-(p-chlorophenyl)cyclohexane carboxylic acid was obtained. The yield was 96%, and the melting point was 235 C. (decomposed). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 44 4-(4-Chlorophenyl)cyclohexanecarboxylic Acid {4-[3-(acetylmethylamino)-pyrrolidin-1-yl]phenyl}amide N-[1-(4-Aminophenyl)pyrrolidin-3-yl]-N-methylacetamide was reacted with <strong>[95233-37-7]4-(4-chlorophenyl)cyclohexanecarboxylic acid</strong> by method E. This resulted in the product with the molecular weight of 454.02 (C26H32ClN3O2); MS (ESI): 454 (M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With 4-methyl-morpholine; (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 2h; | 4-Methylmorpholine (28 muL, 0.25 mol) was added to a mixture of <strong>[95233-37-7]4-(4-chlorophenyl)cyclohexanecarboxylic acid</strong> (20.0 mg, 0.0838 mmol), [(1R,4S)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl]methanesulfonic acid-(1R)-3H-spiro[2-benzofuran-1,3'-pyrrolidin]-3-one (1:1) (37.1 mg, 0.0880 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (41 mg, 0.092 mmol) in N,N-dimethylformamide (0.5 mL). The mixture was stirred at RT for 2 h, and then was diluted with methanol (1.3 mL) and adjusted with TFA to PH=2. The resulting solution was purified by prep-HPLC (pH=2 conditions) to give a TFA salt of (1R)-1'-[4-(4-chlorophenyl)cyclohexyl]carbonyl-3H-spiro[2-benzofuran-1,3'-pyrrolidin]-3-one (20.4 mg, 60%). LCMS: (M+H)+=410.1/412.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ammonium peroxydisulfate; silver nitrate; In water; acetonitrile; at 75 - 80℃; for 3h;Heating / reflux;Product distribution / selectivity; | 10 g (57 mmoles) of 2-hydroxy-l,4-naphthoquinone, 20.5 g (85.9 mmoles) of 4-(4-chlorophenyl)-cyclohexanecarboxylic acid and 6 g (35 mmoles) of silver nitrate are added to 150 ml of acetonitrile and 150 ml of water. The mixture is heated to reflux temperature (75-800C) and a solution of 18 g (79 mmoles) of ammonium persulfate in 100 ml of deionised water is then added dropwise in approximately 1 hour. At the end of the dripping, it is left under agitation for 2 hours at reflux temperature. The reaction mixture is sampled and the HPLC analysis highlights a very low conversion (5-10%) with significant formation of by-products. A further 9 g of ammonium persulfate and 3 g of silver nitrate are added and left at reflux for a further 4 hours. The mixture is sampled again but the HPLC analysis does not highlight any substantial change in the previous situation: conversion approximately 10% and presence of byproducts. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100 g (0.46 moles) of 2-acetoxy-l,4-naphthoquinone and 88.4 g (0.37 moles) of 4-(4-chloropheny l)-cy clohexanecarboxy lie acid are added to 560 ml of acetonitrile. The mixture is left under agitation at 20-250C for 10 minutes. A solution of 20.4 g (0.12 moles) of silver nitrate in 133 ml of deionised water is <n="9"/>added. The mixture is heated to reflux temperature (78-800C); a solution of 179 g (0.8 moles) of ammonium persulfate in 600 ml of deionised water is added dropwise in approximately 1 hour. At the end of the dripping, the mixture is left under agitation for 2 hours at reflux temperature. It is cooled to 700C, 1000 ml of toluene are added and the mixture is left under agitation at 60-700C for 10 minutes. The phases are separated and the organic phase is washed three times with 500 ml of water for each wash. The organic phase is filtered and concentrated to 1/3 of the initial volume by distillation of the toluene at reduced pressure. It is cooled to 20-250C and left under agitation for 12-14 hours; the temperature is then brought to 0-50C and maintained for 1 hour. The solid is filtered and washed with 20 ml of toluene pre-cooled to +50C and then with 20 ml of acetone. The damp product is dried at 400C for 6- 8 hours, providing 44 g of acetyl-atovaquone mainly in the CIS configuration (melting point 197-2000C). 400 ml of acetone are added to the crystallisation mother liquor and the mixture is left under agitation at 20-250C for 16 hours. It is cooled to 0-50C and left at said temperature for 2 hours. The solid is filtered and washed with 10 ml of acetone pre-cooled to 5C. The damp product is dried at 400C for 6-8 hours providing 19 g of acetyl-atovaquone mainly in the TRANS configuration (melting point 150-1550C). The two dried solids are re-combined to give 63 g of CIS/TRANS acetyl-atovaquone (yield 41.7%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
15.3% | 2.6.a. 4-(4-chloro-phenyl)-cyclohexanecarboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide Prepared according to general working method I from 4-(4-chloro-phenyl)-cyclohexanecarboxylic acid (239 mg, 1.0 mmol) and 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine (204 mg, 1.0 mmol). Yield: 65 mg (15.3% of theory); C26H33ClN2O (M=425.019); calc.: molar peak (M+H)+: 425/427 fnd.: molar peak (M+H)+: 425/427; Rf value: 0.3 (silica gel, ethyl acetate/methanol/NH3 9:1:0.1). General Working Method I (TBTU Coupling): [0528] Triethylamine (1.5 eq.) and TBTU (1.0 eq.) are added successively to a solution of carboxylic acid (1.0 eq.) in THF or DMF. Depending on the carboxylic acid the mixture is stirred for 10 min to 12 h between ambient temperature and 40 C. before the amine (1.0 eq.) is added. The reaction is stirred for 30 min to 2 h between ambient temperature and 40 C., before semisaturated NaHCO3 solution is added. After extraction of the aqueous phase with a suitable solvent (e.g. ethyl acetate) the organic phase is dried over magnesium sulphate. The solvent is removed using the rotary evaporator; further purification is carried out by column chromatography or HPLC. The reaction may also be carried out in a Chemspeed automatic synthesiser. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33% | Example 2 4- (4-CHLOROPHENYL)-N-5-QUINOLINYLCYCLOHEXANECARBOXAMIDE (E2) To a solution OF 4- (4-CHLOROPHENYL) CYCLOHEXANECARBOXYLIC acid (11.9 mg, 0.05 MMOL) in N, N-dimethylacetamide (1 ML) was added thionyl chloride (2.0 M solution in DCM (25 JJI., 0.05 MMOL) and the resultant solution stirred for 30 min. 5-Aminoquinoline (7.2 mg, 0.05 MMOL) and diisopropylethylamine (19 ILL, 0.15 MMOL) in N, N-dimethylacetamide (0.5 mL) were added. The mixture stirred for 16 h and then EVAPORATED IN VACUO. Purification of the residue by reverse phase HPLC gave the title compound as a white solid (6.0 mg, 33%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ammonium peroxydisulfate; silver nitrate; In water; acetonitrile; at 75 - 80℃; for 3h; | Example 7ComparativePreparation of the 2-[4-(p-chlorophenyl)-cyclohexyl]-3-hydroxy-1,4-naphthoquinone (cis/trans atovaquone) starting from the 2-hydroxy-1,4-naphthoquinone10 g (57 mmoles) of 2-hydroxy-1,4-naphthoquinone, 20.5 g (85.9 mmoles) of 4-(4-chlorophenyl)-cyclohexanecarboxylic acid and 6 g (35 mmoles) of silver nitrate are added to 150 ml of acetonitrile and 150 ml of water. The mixture is heated to reflux temperature (75-80 C.) and a solution of 18 g (79 mmoles) of ammonium persulfate in 100 ml of deionised water is then added dropwise in approximately 1 hour. At the end of the dripping, it is left under agitation for 2 hours at reflux temperature. The reaction mixture is sampled and the HPLC analysis highlights a very low conversion (5-10%) with significant formation of by-products. A further 9 g of ammonium persulfate and 3 g of silver nitrate are added and left at reflux for a further 4 hours. The mixture is sampled again but the HPLC analysis does not highlight any substantial change in the previous situation: conversion approximately 10% and presence of by-products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ammonium peroxydisulfate; silver nitrate; In water; acetonitrile; at 20 - 80℃; | Example 2 Preparation of the 2-[4-(p-chlorophenyl)-cyclohexyl]-3-acetoxy-1,4-naphthoquinone (CIS/TRANS acetyl-atovaquone). 100 g (0.46 moles) of 2-acetoxy-1,4-naphthoquinone and 88.4 g (0.37 moles) of 4-(4-chlorophenyl)-cyclohexanecarboxylic acid are added to 560 ml of acetonitrile. The mixture is left under agitation at 20-25 C. for 10 minutes. A solution of 20.4 g (0.12 moles) of silver nitrate in 133 ml of deionised water is added. The mixture is heated to reflux temperature (78-80 C.); a solution of 179 g (0.8 moles) of ammonium persulfate in 600 ml of deionised water is added dropwise in approximately 1 hour. At the end of the dripping, the mixture is left under agitation for 2 hours at reflux temperature. It is cooled to 70 C., 1000 ml of toluene are added and the mixture is left under agitation at 60-70 C. for 10 minutes. The phases are separated and the organic phase is washed three times with 500 ml of water for each wash. The organic phase is filtered and concentrated to 1/3 of the initial volume by distillation of the toluene at reduced pressure. It is cooled to 20-25 C. and left under agitation for 12-14 hours; the temperature is then brought to 0-5 C. and maintained for 1 hour. The solid is filtered and washed with 20 ml of toluene pre-cooled to +5 C. and then with 20 ml of acetone. The damp product is dried at 40 C. for 6-8 hours, providing 44 g of acetyl-atovaquone mainly in the CIS configuration (melting point 197-200 C.). 400 ml of acetone are added to the crystallisation mother liquor and the mixture is left under agitation at 20-25 C. for 16 hours. It is cooled to 0-5 C. and left at said temperature for 2 hours. The solid is filtered and washed with 10 ml of acetone pre-cooled to 5 C. The damp product is dried at 40 C. for 6-8 hours providing 19 g of acetyl-atovaquone mainly in the TRANS configuration (melting point 150-155 C.). The two dried solids are re-combined to give 63 g of CIS/TRANS acetyl-atovaquone (yield 41.7%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With sulfuric acid; for 10h;Reflux; | To a solution of compound 1 (2 g, 8.4 mmol) in methanol (20 mL ) was added sulphuric acid (0.1 mL) and refluxed for 10 h. After completion of the reaction, methanol was evaporated under reduced pressure and the obtained residue was taken in ethyl acetate (30 mL,), washed with 10 % aq. NaHCO3 solution (2 × 10 mL) followed by water and brine solution. The organic layer was separated, dried over Na2SO4, filtered and evaporated to afford compound 2. Yellow oily liquid, Yield: 2 g, 94 %; 1H NMR (400 MHz, DMSO-d6): delta 7.32 (d, J = 12.0 Hz, 2H), 7.24 (d, J = 12.0 Hz, 2H), 3.61 (s,3H), 2.51-2,42 (m, 1H), 2.39-2.35 (m, 1H), 1.97 (d, J = 12Hz, 2H), 1.82 (d, J = 12 Hz, 2H), 1.82 (d, J = 12 Hz, 2H),1.54-1.40 (m, 4H). |
94% | With sulfuric acid; for 10h;Reflux; Inert atmosphere; | To a solution of compound 1 (2 g, 8.4 mmol) in methanol (20 mL) was added sulphuric acid (0.1 mL) and refluxed for 10 h. After completion of the reaction, methanol was evaporated under reduced pressure and the obtained residue was taken in ethyl acetate (30 mL), washed with 10% aq. NaHCO3 solution (2 × 10 mL) followed by water and brines olution. The organic layer was separated, dried over anhyd. Na2SO4, filtered and the solvent evaporated to afford compound 2. Yellow oily liquid. Yield 2.0 g, 94%. 1H NMR (400 MHz, DMSO-d6): 7.32 (d,J = 12.0 Hz, 2H), 7.24 (d, J = 12.0 Hz, 2H), 3.61 (s,3H), 2.51-2,42 (m, 1H), 2.39-2.35 (m, 1H), 1.97 (d,J = 12 Hz, 2H), 1.82 (d, J = 12 Hz, 2H), 1.82 (d,J = 12 Hz, 2H), 1.54-1.40 (m, 4H). |
With sulfuric acid; at 20℃; | Preparation 27A: Methy -(4-chlorophenyl)cyclohexanecarboxylate[00340] To a stirred solution of the <strong>[95233-37-7]4-(4-chlorophenyl)cyclohexanecarboxylic acid</strong> (0.5 g, 2.095 mmol) in methanol (10 mL) was added one drop of cone, sulfuric acid. After stirring overnight at room temperature, the reaction mixture was extracted with ethyl acetate and washed with water, saturated sodium bicarbonate and brine. It was then dried over anhyd. magnesium sulfate, concentrated and dried in vacuo to yield methyl 4-(4- chlorophenyl)cyclohexanecarboxylate a white solid. XH NMR (400 MHz, CDCI3) delta ppm 7.23-7.30 (2 H, m), 7.10-7.17 (2 H, m), 3.70 (3 H, s), 2.44-2.56 (1 H, m), 2.36 (1 H, tt, J=12.13, 3.60 Hz), 2.07-2.16 (2 H, m), 1.92-2.01 (2 H, m), 1.38-1.67 (4 H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22% | To a solution of <strong>[95233-37-7]4-(4-chlorophenyl)cyclohexanecarboxylic acid</strong> (40 mg) in dichloromethane at0 C was added oxalyl chloride (250 mul), and then dimethylformamide (50 mul). The reaction was warmed to room temperature and stirred for 2 h at this temperature. The solution was concentrated and then co-concentrated with toluene. The solid was redissolved in dichloromethane, and 4-(5-cyano-7-isopropyl-l,3-benzoxazol-2-yl)-N-(piperidin-4- ylmethyl)benzamide (20 mg, INTERMEDIATE 15) and diisopropylethylamine (100 Dl) were added. The solution was stirred at room temperature for 4 h, and then was concentrated. The residue was purified by reverse-phase HPLC on a Biotage Parallex Flex, Kromasil Cl 8 21 x 100 mm column, eluting at 15 ml/min with 90% water (0.1% TFA) to 95% acetonitrile (0.1% TFA) over 10 min, hold for 2 min, then back to 90% water over 0.5 min, hold for 0.5 min, to provide the title compound (10 mg, 22%). Mass spectrum (ESI) 623.3 (M+l). 1H NMR signals are doubled and broadened because of restricted rotation about the amide C-N bond. IH NMR (500 MHz, CDC13): delta 8.36 (d, J= 8.5 Hz, 2H), 7.99 (d, J = 8.5 Hz, 2H), 7.96 (app d, J = 1.5 Hz, IH), 7.55 (app d, J = 1.5 Hz, IH), 7.27-7.29 (m, 3H), 7.15 (m, 2H), 6.64 (app t, IH), 6.38-6.43 (m, 3H), 4.71-4.74 (m, IH), 4.05-4.07 (m, IH), 3.48-3.58 (m, 2H), 3.38 (m, IH), 3.145 (app tm IH), 2.77 (s, 3H), 2.54-2.66 (m, 4H), 1.99-2.05 (m, 5H), 1.90 (m, 4H), 1.76 (m, 3H), 1.49 (d, J = 7 Hz, 6H), 1.45-1.52 (m, 3H), 1.30 (m, 4H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ammonium peroxydisulfate; silver nitrate; In acetonitrile; for 4h;Reflux; | (1) silver nitrate in the presence of a catalyst to 2-ethoxy-1,4-naphthoquinone and 4- (4-chlorophenyl) cyclohexyl-1-carboxylic acid as the starting material, the reaction was dissolved in acetonitrile, where, ratio of 2-ethoxy-1,4-naphthoquinone, 4- (4-chlorophenyl) cyclohexyl-1-carboxylic acid and the number of moles of silver nitrate was 1: 1: 0.3;(2) Start the reaction, was heated to reflux with stirring, at reflux was added dropwise an aqueous solution of ammonium persulfate, ammonium persulfate in an amount of 5 times the number of 2-ethoxy-1,4-naphthoquinone mole;(3) reaction of 4 hours, cooling and crystallization, filtration, dissolve the crystalline product with chloroform, insoluble substance was filtered, evaporated to dryness under reduced pressure to burn methylene;(4) recrystallized from acetonitrile to give atovaquone yellow needles. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With water; lithium hydroxide; In methanol; at 20℃; for 5h; | A mixture of methyl 4-chlorophenylcyclohexylcarboxylate (III)10.08 g (0.04 mol) was added to 250 mlThree bottles, add 80ml of methanol,20mlWater and lithium hydroxide(3.60 g, 0.15 mol) was added and stirred at room temperature5h, with 1N hydrochloric acid to adjust the pH 1, stirring 30min, the precipitation of solid by filtration, filter cake washedTo a pH of 5 to give the crude product which was recrystallized from 60 ml of ethanol to give 8.50 g of a white solid product,Yield 89%, content 99.17% |
Tags: 95233-37-7 synthesis path| 95233-37-7 SDS| 95233-37-7 COA| 95233-37-7 purity| 95233-37-7 application| 95233-37-7 NMR| 95233-37-7 COA| 95233-37-7 structure
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