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CAS No. : | 99-96-7 | MDL No. : | MFCD00002547 |
Formula : | C7H6O3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | FJKROLUGYXJWQN-UHFFFAOYSA-N |
M.W : | 138.12 | Pubchem ID : | 135 |
Synonyms : |
4-Salicyclic Acid;PHBA;p-Salicyclic Acid;4-hydroxybenzoate;para-Hydroxybenzoic acid;p-hydroxybenzoic acid
|
Num. heavy atoms : | 10 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 35.42 |
TPSA : | 57.53 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.02 cm/s |
Log Po/w (iLOGP) : | 0.85 |
Log Po/w (XLOGP3) : | 1.58 |
Log Po/w (WLOGP) : | 1.09 |
Log Po/w (MLOGP) : | 0.99 |
Log Po/w (SILICOS-IT) : | 0.74 |
Consensus Log Po/w : | 1.05 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | -2.07 |
Solubility : | 1.18 mg/ml ; 0.00852 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.4 |
Solubility : | 0.551 mg/ml ; 0.00399 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -1.17 |
Solubility : | 9.4 mg/ml ; 0.0681 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.0 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P273-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335-H412 | 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% | at 98℃; for 3.08333 h; Microwave irradiation | In the three bottles of p-hydroxybenzoic acid, n-propanol and NKC-9-type macroporous resin,The molar ratio of p-hydroxybenzoic acid to n-propanol was 1: 3.5, the amount of NKC-9 macroporous resin was 30percent of the total mass of the reactants,Three bottles of left mouthGrinding mouth plug, the right side of the mouth probe tube (built-in temperature probe), the middle of the mouth connected to the air through the top of the furnace connected to the outside, respectivelyInstall the water separator, water condensing tube, mix evenly, and then into the electromagnetic stirrer, placed in a microwave oven, stirring, stirring speedFor 260r / min, began to react, the reaction process in time to release the separation of water within the water separator, which, microwave microwave radiationPower of 300W, microwave radiation temperature of 98 , microwave irradiation time of 35min; mixed evenly, and then into the electromagnetic stir bar,Placed in a microwave oven, start stirring, start the reaction, the reaction process in time to release the separation of water within the water separator;After the reaction for 2.5h, turn off the power, react the liquid into a clean three-necked bottle and evaporate the excess with water vapor.Propanol, distillate was poured into a clean beaker, cooled and crystallized, washed with 10percent sodium carbonate solution to pH 7.0-8.0,Filtration, rinse the filter cake with distilled water, dry, refined white solid products of p-hydroxybenzoate.The yield of propyl p-hydroxybenzoate was 89percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | at 70℃; for 3.08333 h; Microwave irradiation | In the three bottles of p-hydroxybenzoic acid, n-butanol and 732 macroporous resin, the molar ratio of p-hydroxybenzoic acid to n-butanol was 1: 3.5, 732 macroporous resin was added in an amount of 25percent of the total mass of the reactants. Three mouth bottles on the left side of the mouth plug mouth plug, the right mouth of the mouth probe tube (built-in temperature probe), the middle of the mouth connected to the air through the top of the furnace connected to the outside, respectively, equipped with water separator. Mixed evenly, and then into the electromagnetic stirrer, placed in a microwave oven, stirring, stirring speed of 270r / min. Began to react, the reaction process in time to release the separation of water within the water separator. Wherein, the microwave radiation power of 215W, microwave radiation temperature of 70 °C, microwave irradiation time of 35min; Mixed evenly, and then placed in the electromagnetic stirrer, placed in a microwave oven, start stirring, start the reaction, the reaction process in time to release the separation of water within the water separator; After 2.5h reaction, turn off the power, the reaction liquid into the clean three bottles and steam distillation of excess n-butanol, distilled liquid into a clean beaker, cooling crystallization, washed with 10percent sodium carbonate solution to pH 7.0-8.0, suction filtration, rinse the filter cake with distilled water, dry, refined white solid products of p-hydroxybenzoate. The yield of butyl p-hydroxybenzoate was determined to be 94percent. |
84.9% | at 60℃; for 48 h; | 4-Hydroxyzenzoicacid (2.0 g, 14.5 mmol) and acetyl chloride (200 μl, 2.2 mmol)were dissolved in 1-butanol (39.8 ml), and the reaction mixture was stirred at60°C. After 48 h, the reaction mixture was evaporated to dryness. Theresulting residue was purified by Wakogel C-200 (Φ 3.0 x 25.0 cm), eluted withhexane/ethyl acetate (8:2, v/v), and then recrystallized with hexane to yieldbutyl 4-hydroxybenzoate (1.47 g, 84.9percent). 1H NMR (CD3OD,500 MHz) δ: 1.03 (3H, t, J = 7.4 Hz); 1.52 (2H, sext, J= 7.3 Hz); 1.77 (2H, quin, J = 6.3Hz); 4.30 (2H, t, J = 6.6 Hz); 6.86(2H, d, J = 8.8 Hz); 7.90 (2H, d, J = 8.7 Hz). 13C NMR (CD3OD,500 MHz) δ: 14.10, 20.33, 31.99, 65.49, 116.12, 116.14,116.15, 122.45, 132.68, 163.50, 168.29. ESI-HRMS [M-H]-: calcd. ForC11H13O4: 193.0865, found 209.0870. HPLC: rt9.9 min, 99.5percent purity. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 3 h; | The 4 - hydroxy benzaldehyde (1.00 g, 8.2 mmol) dissolved in 15 ml DMF in, adding 3 - [...] (1.69 g, 9.0 mmol), potassium carbonate (1.35 g, 9.8 mmol), 80 °C reaction 3 hours, adding 15 ml distilled water, extracted with ethyl acetate twice (2 × 20 ml), then saturated sodium chloride solution for washing 1 time, dried with anhydrous sodium sulfate. Concentrated, column chromatography, eluting agent is petroleum ether: ethyl acetate=5:1, to obtain white solid 1.69 g, yield 90.0percent, |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85.2% | With potassium carbonate In 5,5-dimethyl-1,3-cyclohexadiene at 130 - 140℃; for 24 h; Inert atmosphere | Into a 500 ml four-necked flask, nitrogen was added for protection, and 75 g of 1-chloro-4-phenylbutane, 69 g of p-hydroxybenzoic acid, 65 g of potassium carbonate, 175 g of xylene, and 0.75 g of polyethylene glycol were added. After refluxing at 130~140 °C for 24h, after high-performance liquid chromatography (HPLC), the temperature is lowered to room temperature, 1~5percent liquid alkali is added for washing, xylene is concentrated, methanol is added to dissolve, and the reaction temperature is adjusted to be less than At 20 ° C, filtration, partial concentration of methanol, and filtration under reduced temperature gave p-butoxybenzoic acid with a molar yield of 85.2percent and a purity of 98.56percent (detected by high performance liquid chromatography (HPLC)). The synthesis process in the embodiment is simple in steps and convenient in operation, and avoids the production of the highly toxic intermediate phenylbutane bromide and a large amount of waste water in the synthesis process, so that the environment is friendly and the production cost is saved, and the pair obtained by the process is synthesized. Phenylbutoxybenzoic acid has high purity and is suitable for large-scale industrial production |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With dmap; dicyclohexyl-carbodiimide In tetrahydrofuran at 20℃; for 20.5 h; Inert atmosphere | To a solution of 4-hydroxybenzoic acid 33 (4 g, 28.96 mmol), 4-DMAP (176.9 mg, 1.448 mmol) and tert-butanol (100 mL) in dry THF (100 mL) under N2 atmosphere, a solution of DCC in dry THF (40 mL) was added dropwise at room temperature for 30 min. The reaction mixture was stirred at room temperature under N2 atmosphere for 20 h. The residue mixture was filtered and the filtrate was reduced by rotary evaporation to ∼25 mL. The filtrate was washed with 0.3 M Na2CO3 solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The pale yellow crude product was purified by silica gel chromatography (0-30percent EtOAc in hexane) to afford 34 (4.3 g, 76percent) as a white solid. 1H NMR (300 MHz, DMSO-d6): δ 10.21 (s, 1H), 7.74 (d, J = 8.50 Hz, 2H), 6.81 (d, J = 8.50 Hz, 2H), 1.50 (s, 9H); LC-MS (m/z): 195 [M+H]+. |
55% | With 1,8-diazabicyclo[5.4.0]undec-7-ene; dicyclohexyl-carbodiimide In dichloromethane for 18 h; | fert-Butyl 4-hydroxybenzoate (SO2-059) (31 ): Hydroxy benzoic acid (1 .50 g, 1 0.86 mmol), ferf-butanol (13.34 g, 18 mmol), DBU (0.1 9 ml, 1 .20 mmol) and DCC (2.5 g, 12.00 mmol) were mixed in DCM (40 ml) and vigorously stirred for 1 8 h. After evaporation to dryness, DCM (50 ml) was added to the residue and the resulting heterogeneous solution was filtered. The solution was washed with sat. K2C03 (2 x 50 ml) and sat. NaCI (50 ml). The solvent was dried (MgS04) and evaporated and purified by column chromatography (EtOAc:hexane gradient elution) to obtain SO2-059 31 as a crystalline white compound. (1 .1 g, 55percent). 1 H NM R (400 MHz, cdcl3) δ 7.89 (d, J = 8.8 Hz, 1 H), 6.84 (d, J = 8.9 Hz, 1 H), 5.29 (s, 1 H), 1 .57 (s, 9H). |
39% | Inert atmosphere | (7a) Tert-butyl 4-hydroxybenzoate Into tert-butyl alcohol (200 mL), 4-hydroxybenzoic acid (10.0 g, 72.4 mmol) and 4-dimethylaminopyridine (354 mg, 2.90 mmol) were dissolved, to which 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (15.3 g, 79.6 mmol) was added, followed by stirring overnight under a nitrogen atmosphere. The resulting reaction liquid was concentrated under reduced pressure, to which ethyl acetate and hexane were added, followed by decantation. The resulting liquid was concentrated under reduced pressure again, and the residue thus obtained was purified by silica gel column chromatography (hexane : ethyl acetate, 100 : 0 - 70 : 30, V/V) to give the desired title compound (5.48 g, yield 39percent). 1H-NMR (CDCl3) δ: 1.59 (9H, s), 6.18 (1H, s), 6.85 (2H, d, J = 8.3 Hz), 7.90 (2H, d, J = 8.3 Hz). MS(ESI) m/z: 193 (M-H)- |
39% | Inert atmosphere | (7a) Tert-butyl 4-hydroxybenzoate Into tert-butyl alcohol (200 mL), 4-hydroxybenzoate (10.0 g, 72.4 mmol) and 4-dimethylaminopyridine (354 mg, 2.90 mmol) were dissolved, to which 1-methyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (15.3 g, 79.6 mmol) was added, followed by stirring overnight under a nitrogen atmosphere. The resulting reaction liquid was concentrated under reduced pressure, to which ethyl acetate and hexane were added, followed by decantation. The resulting liquid was concentrated under reduced pressure again, and the residue thus obtained was purified by silica gel column chromatography (hexane : ethyl acetate, 100 : 0 - 70 : 30, V/V) to give the desired title compound (5.48 g, yield 39percent). 1H-NMR (CDCl3) δ: 1.59 (9H, s), 6.18 (1H, s), 6.85 (2H, d, J = 8.3 Hz), 7.90 (2H, d, J = 8.3 Hz) . |
80 g | With dmap; dicyclohexyl-carbodiimide In tetrahydrofuran for 24 h; | After dissolving about 100 g of Compound 25 (4-hydroxybenzoic acid), about 100 g of N,N'-dicyclohexylcarbodiimide, about 10 g of 4-(dimethylamino)pyridine, and about 20 g of tert-butanol in tetrahydrofuran, the mixture was stirred for about 24 h. Then, the reacted product was extracted with dichloromethane and water, and about 80 g of Compound 26 was obtained by chemically drying the extracted organic layer and refining the same with column chromatography. |
80 g | With dmap; dicyclohexyl-carbodiimide In tetrahydrofuran for 24 h; | Synthesis of Compound 26 (0154) After dissolving about 100 g of Compound 25 (4-hydroxybenzoic acid), about 100 g of N,N′-dicyclohexylcarbodiimide, about 10 g of 4-(dimethylamino)pyridine, and about 20 g of tert-butanol in tetrahydrofuran, the mixture was stirred for about 24 h. Then, the reacted product was extracted with dichloromethane and water, and about 80 g of Compound 26 was obtained by chemically drying the extracted organic layer and refining the same with column chromatography. |
80 g | With dmap; dicyclohexyl-carbodiimide In tetrahydrofuran for 24 h; | About 100 g of compound 25 (4-hydroxybenzoic acid)About 100 g of N, N'-dicyclohexylcarbodiimide,About 10 g of 4- (dimethylamino) pyridine,And about 20 g of t-butanol were dissolved in tetrahydrofuran,The mixture was stirred for about 24 hours.then,The reaction product was extracted with dichloromethane and water,And the extracted organic layer was chemically dried and subjected to column chromatography to obtain about 80 g of compound 26. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | at 80℃; for 1.25 h; Molecular sieve | 4-Hydroxy-benzoic acid (3 g, 21.7 mmol) was stirred in toluene (35 ml, dried over mol. sieves). The solution was heated to 80 °C under N2, and λ/,λ/-dimethylformamide di-tert- butyl acetal (10.42 ml_, 43.4 mmol) was added over ca. 5 min. The mixture was stirred at 80 °C for 1 h 10 min., and cooled to rt. The solution was washed with water, twice with sat. NaHCO3 and sat. NaCI (15 ml. each), dried over MgSO4, and concentrated to yield a yellow oil (2.77 g). The product was purified by flash chromatography (380 g silica, eluant: 4:6 AcOEt/heptane (2 L) and 1 :1 AcOEt/heptane 700 mL) to yield white crystals (2.07g, 49percent yield).HPLC-MS m/z: 217 (M+23).1H-NMR (CDCI3, 400 MHz) 7.90 (d, 2H), 6.85 (d, 2H), 6.10 (s, 1 H), 1.59 (s, 9H). |
23% | for 1 h; Heating / reflux | Intermediate 39; 4-Hydroxy-benzoic acid tert-butyl ester; 4-Hydroxybenzoic acid (5.29 g, 38.3 mmol) (Aldrich) was suspended in dry benzene (200 mL) and the mixture was heated to reflux. N,N'-Dimethylformamide di-t-butyl acetal (36.7 mL, 0.15 mol) (Aldrich) was added dropwise and the mixture was heated at reflux for a further 1 hour. The cooled solution was washed with water, saturated aqueous sodium bicarbonate solution and brine. After drying (magnesium sulfate) and filtering, the solvent was evaporated. The residue was purified by flash chromatography eluting with 25percent hexanes in dichloromethane and 10percent ethyl acetate in dichloromethane to give 4-hydroxy-benzoic acid tert-butyl ester. (Yield 1.72 g, 23percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Y: 10% | With sulfuric acid In 1,4-dioxane; dichloromethane | EXAMPLE 43 4-Hydroxybenzoic acid tert-butyl ester (XXVIIIa) STR45 To a solution of 4-hydroxybenzoic acid (2.00 g, 14.5 mmol) in 1,4-dioxane (10.0 mL) saturated with isobutylene at -78° C. in a metal bomb was added concentrated sulfuric acid (0.150 mL). The bomb was sealed and warmed to room temperature. After 72 hours at room temperature, the reaction mixture was cooled to -78° C., poured into saturated sodium bicarbonate (30.0 mL) and extracted with diethyl ether (2*50.0 mL). The combined organic phases were concentrated and the residue chromatographed on silica gel (eluted with 5percent methanol in methylene chloride to give 290 mg (Y: 10percent) of the title product; 1 H-NMR (CDCl3): δ7.89 (d, J=8.8 Hz, 2H), 6.83 (d, J=8.8 Hz, 2H), 1.57 (s, 9H). |
Y: 10% | With sulfuric acid In 1,4-dioxane; dichloromethane | EXAMPLE 43 4-Hydroxybenzoic acid tert-butyl ester (XXVIIIa) STR45 To a solution of 4-hydroxybenzoic acid (2.00 g, 14.5 mmol) in 1,4-dioxane (10.0 mL) saturated with isobutylene at -78° C. in a metal bomb was added concentrated sulfuric acid (0.150 mL). The bomb was sealed and warmed to room temperature. After 72 hours at room temperature, the reaction mixture was cooled to -78° C., poured into saturated sodium bicarbonate (30.0 mL) and extracted with diethyl ether (2*50.0 mL). The combined organic phases were concentrated and the residue chromatographed on silica gel (eluted with 5percent methanol in methylene chloride to give 290 mg (Y: 10percent) of the title product; 1 H-NMR (CDCl3): δ 7.89 (d, J=8.8 Hz, 2H), 6.83 (d, J=8.8 Hz, 2H), 1.57 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | at 40 - 60℃; Microwave irradiation | (1) in 500 ml in the reaction bottle, to join the hydroxy benzoic acid 138g (1 µM), adding methanol 160g (5 µM), solid acid 50g, stirring to a solid uniform. In putting into ultrasonic reactor, and is additionally provided with a return device, the reaction temperature is 40 - 60 °C, ultrasonic power 500W, reaction 1 - 3h, reaction solution gradually changed from white to yellow, and then into orange red. HPLC tracking the conversion rate of the reaction, the reaction to the hydroxy benzoic acid is less than 5percent the following calculating the reaction is complete, stopping the reaction, filtering of the solid acid catalyst, the catalyst can be applied to the next reaction; the filter placed about 5 - 10 °C crystalline 6 - 10h, the crystal filter, 50 - 60 °C drying 6h, HPLC detection, impurities less than 0.1percent, to obtain the intermediate 4 - hydroxy - 3, 5 - dimethyl benzoic acid 141g, yield is 85percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | Stage #1: With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 17 h; Stage #2: With potassium hydroxide In methanol at 20℃; for 3 h; Stage #3: With hydrogenchloride In water |
4-Hydroxybenzoic acid (2.00 g, 14.5 mmol) was suspended in dichloromethane (50 mL), and the suspension was added with diisopropylethylamine (10.1 mL, 57.9 mmol) and chloromethyl methylether (2.20 mL, 29.0 mmol) under ice-cooling. Then, the reaction mixture was warmed to room temperature, followed by stirring for 2.5 hours. The reaction mixture was added with chloromethyl methylether (1.10 mL, 14.5 mmol) under ice-cooling, followed by stirring at room temperature for 17 hours. The solvent was evaporated under reduced pressure, then the reaction mixture was added with methanol (50 mL) and 4 mol/L aqueous potassium hydroxide solution (50 mL) followed by stirring at room temperature for 3 hours. The solvent was evaporated under reduced pressure, and the residue was added with 4 mol/L hydrochloric acid and water, followed by extracting with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 4-methoxymethoxybenzoic acid (2.63 g, yield 100percent). ESI-MS m/z: 181 [M-H]-; 1H-NMR (CDCl3)δ(ppm) : 3.37 (s, 3H), 5.26 (s, 2H), 7.00-7.16 (m, 2H), 7.80-7.96 (m, 2H), 12.65 (br s, 1H). |
110 g | Stage #1: With N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃; for 24 h; Stage #2: With potassium hydroxide In methanol; water for 3 h; Reflux |
After dissolving 100 g of Compound 25 (4-hydroxybenzoic acid) and about 400 g of N,N-diisopropylethylamine in dichloromethane, about 200 g of methylchloromethylether was slowly added thereto dropwise at about 0 °C. After stirring the mixture for about 24 h, the product was washed with about 500 ml of ammonium chloride and extracted with dichloromethane and water. The extracted organic layer was chemically dried and the solvent was eliminated therefrom. The product obtained in this way and a potassium hydroxide aqueous solution were put in methanol and the solution was refluxed and stirred for about 3 h. The product was extracted by adding 6N hydrochloric acid thereto and then the solvent was eliminated therefrom by filtering the same. Then, about 110 g of Compound 36 was obtained by eliminating extra foreign substances therefrom by using hexane, and drying the same for about 48 h. |
100 g | With N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃; for 24 h; | Synthesis of Compound 36 (0232) After dissolving 100 g of Compound 25 (4-hydroxybenzoic acid) and about 400 g of N,N-diisopropylethylamine in dichloromethane, about 200 g of methylchloromethylether was slowly added thereto dropwise at about 0° C. After stirring the mixture for about 24 h, the product was washed with about 500 ml of ammonium chloride and extracted with dichloromethane and water. The extracted organic layer was chemically dried and the solvent was eliminated therefrom. The product obtained in this way and a potassium hydroxide aqueous solution were put in methanol and the solution was refluxed and stirred for about 3 h. The product was extracted by adding 6N hydrochloric acid thereto and then the solvent was eliminated therefrom by filtering the same. Then, about 110 g of Compound 36 was obtained by eliminating extra foreign substances therefrom by using hexane, and drying the same for about 48 h. |
110 g | With N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃; for 24 h; | After 100 g of compound 25 (4-hydroxybenzoic acid) and about 400 g of N, N-diisopropylethylamine were dissolved in dichloromethane,About 200 g of methyl chloromethyl ether was slowly added dropwise at about 0 ° C.After stirring the mixture for about 24 hours,The product was washed with about 500 ml of ammonium chloride,And extracted with dichloromethane and water.and,The extracted organic layer was chemically dried,And removing the solvent therefrom.The product thus obtained and the aqueous potassium hydroxide solution were placed in methanol,And the solution was stirred at reflux for about 3 hours.6N hydrochloric acid was added to extract the product,The solvent is then removed by filtration.after that,The excess foreign material was removed from it and dried for about 48 hours to give about 110 g of compound 36. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63.5% | With hydrogenchloride; dihydrogen peroxide In water | 10 mLof 33percent hydrogen peroxide was added to a suspension of 3.5 g (0.025 mol) of 4-hydroxybenzoic acid I in10 mL of hydrochloric acid and 20 mL of water. The formed white precipitate was filtered off, washed with hot water, and recrystallized from ethanol. Yield 3.19 g (63.5percent), white crystals, mp 265°C. 1H NMR spectrum, , ppm: 7.84 s (2H, H2,6). Found, percent: C40.64; H 1.87; Cl 34.34. C7H4Cl2O2. Calculated, percent: C40.58; H 1.93; Cl 34.30. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | at 0℃; Reflux; Inert atmosphere | General procedure: Thionyl chloride (1.16 g, 1.5 equiv) was added drop-wise to a solution of acid (1.0 g, 1.0 equiv) in the corresponding alcohol (15 ml) at 0&d eg;C. The solution was refluxed under a nitrogen atmosphere until all starting material was consumed (TLC monitoring). Then the solvent was removed under vacuo and the residue was purified by silica gel column chromatography eluting with ethyl acetate/n-hexane to afford the corresponding carboxylic esters.#10; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
13% | at 80℃; for 21 h; Inert atmosphere | 4-Hydroxybenzamide (0.2743 g, 2 mmol) was dissolved in acetic acid (4 mL), and to the stirringsolution was added amyl nitrite (1.20 mL, 6 mmol). The reaction was placed under N2 atmosphere andheated to 80 °C. At specified time points (15 min., 30 min., 1 hr, 2 hr, 4 hr, 6 hr, 8 hr, 12 hr, and 24 hr)a 100 μL aliquot of the solution was syringed out of the reaction and quenched by mixing with 1 mLsolution of 5percent Et3N in MeOH. Each aliquot was then condensed and dried in vacuum before beinganalysed via 1H-NMR |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | Stage #1: With copper(I) oxide In trifluoroacetic acid for 5 h; Reflux Stage #2: With hydrogenchloride In water at 20℃; for 1 h; |
General procedure: To a solution of substrates (1a–1q, 0.15 mmol) in trifluoroacetic acid (5 ml), hexamethylenetetramine (0.3 mmol) and cuprous oxide (0.15 mmol) were added. The reaction mixture was refluxed for about 5 h, cooled to room temperature, followed by addition of hydrochloric acid (3 N, 5 ml). After stirring for another 1 h, the solution was concentrated under reduced pressure. The products were purified by silica gel column chromatography (200–300 mesh). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
23% | With hydrogenchloride; sodium hydroxide; sodium hydrogensulfite In chloroform; water | EXAMPLE 36 3-Formyl-4-hydroxybenzoic acid 140 g (1.01 mol) of 4-hydroxybenzoic acid were added to a hot solution of 250 g (6.25 mol) of sodium hydroxide in 500 mL H2 O. 150 mL of CHCl3 were cautiously added to the hot solution, and after the foaming had ceased, the reaction mixture was stirred overnight at room temperature. The reaction mixture was then diluted to 4 L with H2 O, acidified to pH 1 by addition of about 300 mL of concentrated HCl, and extracted two times with 2 L and then three times with 1 L ethyl ether. The ether extracts were combined and a solution of 750 g sodium bisulfite in 3 L H2 O was added. This mixture was stirred thoroughly for 2 minutes, then the layers were separated and the aqueous layer was extracted two times with 500 ml ethyl ether. The aqueous layer was acidified by slow addition of a solution of 230 mL concentrated H2 SO4 in 230 mL H2 O. Vigorous SO2 evolution was noted. The solution was then heated on a steam bath, and a stream of N2 was blown through the hot solution for about 15 minutes until a large amount of crystals formed. The mixture was allowed to stand at room temperature overnight, then cooled to -10° C. for 1/20 hour, then filtered. The crystals were washed two times with H2 O and then dried under vacuum to yield 38.46 g of the title product as a tan powder. 23percent yield. 1 H NMR (300 m Hz, DMSO-d6): δ10.3 (s, 1H). MS (Cl, NH3): 183 M+17, 166 (M+), 165 Base. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97.6% | With sodium hydroxide In water; xylene at 90℃; | EXAMPLE I 15 g (0.108 mole) of 4-hydroxybenzoic acid and 54.4 g (0.353 mole) of diethylsulfate were introduced into a glass flask containing xylene (75 ml). The mixture was heated to 90° C. The pH of mass was checked by a calibrated pH electrode immersed in the mass. The pH was maintained between 8-10 by drop wise addition under stirring of a 35percent aqueous NaOH solution [13.6 g (0.326 mole) NaOH flakes in 25 ml water] in 90 minutes. The mass is further stirred for 15 minutes after addition of NaOH. Then the mass was cooled to ambient temperature and 75 ml water was added. The upper organic phase containing the formed product was separated from the lower aqueous phase, washed with 2percent NaOH aqueous solution (75 ml) and finally with water. Evaporation of solvent gave 20.5 g (97.6percent) of p-ethoxy ethylbenzoate having purity 98.6percent by HPLC. |
71.4% | With sodium hydroxide In water; xylene at 90℃; for 0.25 - 1.75 h; | Example I15 g (0.108 mole) of 4-hydroxybenzoic acid and 54.4 g (0.353 mole) of diethylsulfate were introduced into a glass flask containing xylene (75 ml). The mixture was heated to 90 C. The pH of mass was checked by a calibrated pH electrode immersed in the mass. The pH was maintained between 8-10 by drop wise addition under stirring of a 35percent aqueous NaOH solution [13.6 g (0.326 mole) NaOH flakes in 25 ml water] in 90 minutes. The mass is further stirred for 15 minutes after addition of NaOH. Then the mass was cooled to ambient temperature and 75 ml water was added. The upper organic phase containing the formed product was separated from the lower aqueous phase, washed with <n="5"/>2percent NaOH aqueous solution (75 ml) and finally with water. Evaporation of solvent gave 20.5 g (97.6percent) of p-ethoxy ethylbenzoate having purity 98.6percent by HPLC; Comparative Experiment A15 g (0.108 mole) of 4-hydroxybenzoic acid and 54.4 g (0.353 mole) of diethylsulfate were introduced into a glass flask containing xylene (75 ml). The mixture was heated to 90 C. The pH of mass was checked by a calibrated pH electrode immersed in the mass. The pH was maintained between 6-7.5 by drop wise addition under stirring of a 35percent aqueous NaOH solution [13.6 g(0.326 mole) NaOH flakes in 25 ml water] in 30 minutes. The mass is further stirred for 15 minutes after addition of NaOH. Then the mass was cooled to ambient temperature and 75 ml water was added. The upper organic phase containing the formed product was separated from the lower aqueous phase, washed with 2percent NaOH aqueous solution (75 ml) and finally with water.Evaporation of solvent gave 15.3 g (72.8 percent) of p-ethoxy ethylbenzoate having purity 99.2 percent by HPLC.It appears that the lower pH causes the yield to drop with respect to the working Examples, where the pH was kept between 8 and 10.; Comparative Experiment B15 g (0.108 mole) of 4-hydroxybenzoic acid and 54.4 g (0.353 mole) of diethylsulfate were introduced into a glass flask containing xylene (75 ml). The mixture was heated to 90 C. The pH of mass was checked by a calibrated pH electrode immersed in the mass. The pH was maintained between 10.5 and 12 by drop wise addition of a 35percent aqueous NaOH solution [13.6 g (0.326 mole) NaOH flakes in 25 ml water]. The mass is further stirred for 15 minutes and cooled to ambient temperature. The mass was diluted by addition of 75 ml water. The upper organic phase containing the formed product was separated from the lower aqueous phase, washed with 2percent NaOH aqueous solution (75 ml) and finally with water. Evaporation of solvent gave 15.0 g (yield: 71.4percent) of p-ethoxy ethylbenzoate having purity 96.57percent by HPLC.It appears that the higher pH causes the yield to drop with respect to the working Examples, where the pH was kept between 8 and 10. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | at 120℃; for 4 h; | General procedure: In a 50 mL two-necked round-bottomed flask equipped with a magnetic stirring bar, a reflux condenser and a calcium chloride drying tube was placed nicotinic acid (1 g, 8.1 mmol) suspended in boron trifluoride etherate (10 mL). The reaction mixture was stirred and heated to 120 °C overnight during which the creamy reaction mixture changed into a brownish solution. Thin layer chromatography (hexane/ethyl acetate 3:1) revealed complete reaction. The cooled reaction mixture was diluted with water (25 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic extract was washed to the end of effervescence with a saturated solution of NaHCO3. The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo giving a crude yield of 1.11 g (92percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78.16% | at 50 - 130℃; for 4.5 h; Inert atmosphere | The acylating agent was 0.11 mol of p-hydroxybenzoic acid and 0.1 mol of pyrogallic acid,Concentrated sulfuric acid 0.015 mol was mixed in a reactor,Into the inert gas 10min,When the system temperature rose to 70-80 ,Closed reactorAt 110-130 ,Pressure 0.1-5MPa,Closed reaction 3h,The reaction was cooled to 50-60 ° C,Insulation 1.5h,Add 20percent ethanol 200ml,Crystallization at 0-5 ,Filter drying,To get the product.The molar yield of the product was 78.16percentHPLC ≥ 98.5percent. |
78.5% | With aluminum (III) chloride In i-Amyl alcohol at 90 - 130℃; for 6 h; Inert atmosphere | The acylation reagent p-hydroxybenzoic acid 0.11mol, pyrogallic acid 0.1mol,0.015 mol of aluminum trichloride and 500 ml of isoamyl alcohol were mixed in the reactor, an inert gas was introduced,When the system temperature was raised to 90-100 , stop the access, continue to heat the reaction at 110-130 for 6h, TLC trace to the end of the reaction, the reaction temperature was cooled to 50-60 , incubated for 1h,Water (100 ml) was added and the layers were separated. The organic layer was crystallized at 0-5 ° C, filtered and dried to give the product.Product molar yield of 78.50percent, HPLC ≥ 98.5percent. |
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