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CAS No. : | 2345-34-8 | MDL No. : | MFCD00002540 |
Formula : | C9H8O4 | Boiling Point : | 325.7°C at 760 mmHg |
Linear Structure Formula : | - | InChI Key : | - |
M.W : | 180.16 g/mol | Pubchem ID : | - |
Synonyms : |
|
Num. heavy atoms : | 13 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.11 |
Num. rotatable bonds : | 3 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 44.9 |
TPSA : | 63.6 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) : | -6.35 cm/s |
Log Po/w (iLOGP) : | 1.49 |
Log Po/w (XLOGP3) : | 1.48 |
Log Po/w (WLOGP) : | 1.31 |
Log Po/w (MLOGP) : | 1.51 |
Log Po/w (SILICOS-IT) : | 1.1 |
Consensus Log Po/w : | 1.38 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | -2.03 |
Solubility : | 1.67 mg/ml ; 0.00927 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.42 |
Solubility : | 0.681 mg/ml ; 0.00378 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -1.85 |
Solubility : | 2.57 mg/ml ; 0.0143 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.26 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
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* 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 |
---|---|---|
80% | Stage #1: at 155 - 160℃; for 5 h; Stage #2: With hydrogenchloride In water |
4-Acetoxy-benzoic acid (0.350 g, 1.95 mmol) and anhydrous AlCl3 (0.800 g, 6.02 mmol) were mixed and heated at 155-160 °C (oil bath temperature) for 5 h (after 1 h a solid, brown foamy mass formed and stirring was no longer possible). After cooling (ice bath), the reaction mixture was treated with 6.5 mL of 2 N HCl. The acidified reaction mixture was extracted with ethyl acetate (3.x.10 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to afford a yellow solid (0.280 g, 80percent), which was used without any further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With oxalyl dichloride at 20℃; for 4h; | 2 Step 2 To a clean dried 100 ml two neck round bottom flask was added [99] (2.0 g, 1 1 . 1 mmol) in addition of oxalyl chloride (3.0 ml, 33.3 mmol). The resulting solution was stirred at RT for 4 hrs. After completion of the reaction, excess oxalyl chloride was evaporated on a rotary evaporator under nitrogen atmosphere to yield the corresponding acid chloride as a brown solid (2. 16 g, 100%) [100]. The resulting brown solid was dissolved in DCM (50 ml) and cooled to 0 °C followed by the addition of a 2.0 M solution of dimethyl amine in THF ( 1 1.2 ml, 24.4 mmol) and DIPEA ( 1.33 ml, 12.2 mmol) and stirred it for 3 hrs at RT. The progress of the reaction was monitored by TLC. The solvent was evaporated under reduced pressure and crude was used as such for further step. ESIMS: 208 (M+ + 1 ) |
100% | With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 4h; | |
100% | With oxalyl dichloride In dichloromethane at 20℃; for 6h; | 2.1 Step 1: 4-(chlorocarbonyl)phenyl acetate (Compound 9) />Hydroxybenzoic acid was reacted with acetic anhydride and triethylamine at 100 °C for 6 h to provide 4-acetoxybenzoic acid. After oven drying, 4-acetoxybenzoic acid was mixed with oxalyl chloride in methylene chloride at room temperature for about 6 hours to give 4-(chlorocarbonyl)phenyl acetate in quantitative yield. |
99% | With thionyl chloride at 79℃; for 4h; Heating / reflux; | 30.1 Example 30; (Formula (1): n=3, A=-Cy-, X=H, Y=H, B=-COO-(E17)); Preparation of (R)-4-(3-ethyl-1-methylpentyloxycarbonyl)phenyl-4-(trans-4-n-propylcyclohexyl)phenylcarboxylate; (1) Synthesis of 4-acetoxybenozic acid chloride 40.0 Grams (222 mmol) of 4-acetoxybenzoic acid and 264 g (2.22 mol) of purified thionyl chloride were placed in a reactor, and the mixture was refluxed under heat (79° C.) for 4 hours. [00130] Then, thionyl chloride was first distilled off under atmospheric pressure, 150 ml of toluene was added, and toluene and thionyl chloride were distilled off under reduced pressure, to give 44 g of 4-acetoxybenzoic acid chloride (yield 99%). |
99% | With thionyl chloride In toluene | 30.1 (1) (1) Synthesis of 4-acetoxybenozic acid chloride 40.0 Grams (222 mmol) of 4-acetoxybenzoic acid and 264 g (2.22 mol) of purified thionyl chloride were placed in a reactor, and the mixture was refluxed under heat (79°C) for 4 hours. Then, thionyl chloride was first distilled off under atmospheric pressure, 150 ml of toluene was added, and toluene and thionyl chloride were distilled off under reduced pressure, to give 44 g of 4-acetoxybenzoic acid chloride (yield 99 %). |
98% | With thionyl chloride In N,N-dimethyl-formamide at 80℃; for 3h; Inert atmosphere; | 1-1 [Example 1-1] Synthesis of diamine (12) Into a three-necked flask, 36.62 g (200 mmol, manufactured by Tokyo Kasei Kogyo Co., Ltd.) of 4-acetoxybenzoic acid and an appropriate amount of thionyl chloride were added, and a few drops of DMF was added as a catalyst, and the mixture was refluxed at 80° C for 3 hours in a nitrogen atmosphere.After the reaction, benzene was added in an appropriate amount, and thionyl chloride was azeotropically distilled off under reduced pressure, followed by vacuum drying at 30° C. for 12 hours to obtain a chlorinated compound represented by the formula (7) as a colorless liquid (yield: 98%). |
92% | With thionyl chloride for 3.5h; Heating / reflux; | 5.1 5.1 Synthesis of 4-(chlorocarbonyl)phenyl acetate (510) Thionyl chloride (11.1 mL, 15.3 mmol) was added to 4-acetoxybenzoic acid (2.50 g, 13.9 mmol), and the reaction was warmed to reflux. The reaction was cooled after heating for 3.5 hours, and concentrated in vacuo to give a colorless oil. Toluene was added to the residue and the mixture was concentrated in vacuo to remove any residual thionyl chloride. This process was repeated twice more to give 510 (2.54 g, 92%) as a colorless oil. This material was used in the next step without additional purification. Data for 510: 1H-NMR (400 MHz, CDCl3) δ 8.18 (d, J=8.9 Hz, 2 H), 7.29 (d, J=8.9 Hz, 2 H), 2.36 (s, 3 H) ppm. |
92% | With thionyl chloride for 3.5h; Reflux; | 1.5.2.1 Thionyl chloride (11.1 mL, 15.3 mmol) was added to 4-acetoxybenzoic acid (2.50 g, 13.9 mmol), and the reaction was warmed to reflux. The reaction was cooled after heating for 3.5 hours, and concentrated in vacuo to give a colorless oil. Toluene was added to the residue and the mixture was concentrated in vacuo to remove any residual thionyl chloride. This process was repeated twice more to give 510 (2.54 g, 92%) as a colorless oil. This material was used in the next step without additional purification.Data for 510: 1H-NMR (400 MHz, CDCl3) δ 8.18 (d, J=8.9 Hz, 2H), 7.29 (d, J=8.9 Hz, 2H), 2.36 (s, 3H) ppm. |
90% | With thionyl chloride for 4h; Heating / reflux; | 3.1 Example 3; (General formula (1): n = 5, X = -Ph-Ph-COO-Ph- (E3)), Preparation of 4-((R)-1-methyl-3-ethylpentyloxycarbonyl)phenyl-4'-((R)-1-methylhexyloxycarbonyl)biphenyl-4-carboxylate; (1) Synthesis of 4-acetoxybenzoyl chloride 100 g (0.555 mol) of 4-acetoxybenzoic acid was added to 400 g (3.36 mol) of thionyl chloride, and a mixture was refluxed under heat for 4 hours. Then, excess thionyl chloride was distilled off, and a remainder was purified by distillation under reduced pressure (4 mmHg, 116°C), to give 99 g (0.498 mol, yield 90 %) of an end compound. |
90% | With thionyl chloride for 8h; Reflux; | 4-Acetoxy benzoyl chloride Into a single necked 100 mL round bottom flask,equipped with reflux condenser, 4-acetoxy benzoicacid (9.00 g, 0.05 mol) was placed. To this flask,thionyl chloride (5 mL, 0.07 mol) was added dropwiseand the reaction mixture refluxed for 8 hr. Theinitial heterogeneous mass was homogenized. Excessthionyl chloride was removed by distillation. Thecrude product was purified by distillation underreduced pressure at 130°C. Yield: 90%; m.p. 29-30°Cand b.p. 132°C; IR (Nujol): 1780 (COCl), 1730 (C=Ostretching) and 1370 cm-1 (-CH, bending); 1H NMR(CDCl3): d 2.1 (s, 3H), 7.1 (d, 2H) and 8.0 (d, 2H). |
90% | With thionyl chloride for 8h; Reflux; | 2.2b 4-Acetoxy benzoyl chloride: 4-Acetoxy benzoicacid (9.0 g, 0.05 mole) was placed in a single necked 100 mLround bottom flask. To this flask, thionyl chloride (5mL, 0.07mole) was added drop wise and refluxed the reaction mixturegently for 8 h. The initial heterogeneous mass was homogenized.Excess thionyl chloride was removed by distillation.The crude acid chloride was purified by double distillationunder reduced pressure. Yield: 90%. M.p.: 29°C. IR (Nujol,cm-1): 1780 (COCl), 1730 (C=O stretching). |
80% | With thionyl chloride for 2.5h; Heating; | |
79% | With thionyl chloride In dichloromethane at 40℃; for 10h; | |
75% | With thionyl chloride In toluene for 3h; Reflux; | |
75% | With thionyl chloride In toluene for 3h; Reflux; | |
71% | With phosphorus pentachloride In diethyl ether at 20℃; for 2h; | |
With tetrachloromethane; phosphorus pentachloride | ||
With thionyl chloride | ||
With thionyl chloride for 3h; Heating; | ||
With thionyl chloride In chloroform for 2h; Heating; | ||
With thionyl chloride for 0.5h; Heating; | ||
With thionyl chloride In benzene Heating; | ||
With thionyl chloride at 60℃; for 6h; | ||
With thionyl chloride In 1,2-dichloro-ethane; acetone | ||
With tetrachloromethane; triphenylphosphine In acetonitrile for 0.333333h; | ||
With thionyl chloride for 3h; Heating; | ||
With thionyl chloride In tetrahydrofuran | ||
With thionyl chloride In chloroform Heating; | ||
With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 0 - 20℃; for 2h; | ||
With thionyl chloride In dichloromethane at 20℃; | ||
With oxalyl dichloride In chloroform at 20℃; for 4h; | ||
With thionyl chloride | ||
With thionyl chloride; N,N-dimethyl-formamide at 50℃; for 5h; | ||
With thionyl chloride; N,N-dimethyl-formamide at 70℃; for 5h; | ||
With pyridine; thionyl chloride In N,N-dimethyl-formamide | ||
With thionyl chloride | ||
With oxalyl dichloride In DMF (N,N-dimethyl-formamide) for 3h; | 7 Reference example 7; 1-(4-acetoxybenzoyl)-2-methyl-1H-indol-4-yl acetic acid benzyl ester Reference example 7 1-(4-acetoxybenzoyl)-2-methyl-1H-indol-4-yl acetic acid benzyl ester Under argon gas, a mixture of 4-acetoxybenzoic acid (516mg), oxalylchloride (0.5ml), and N, N-dimethylformamide (5μl) was stirred for 3 hours.. The mixture was concentrated by vacuum concentration and 4-acetoxybenzoic acid chloride was prepared.. sodium hydroxide (286mg) and tetrabutylammonium chloride (20mg) were added to dichloromethane (7ml) solution containing the compound (400mg) prepared according to reference example 6 at room temperature over stir.. dichloromethane (3ml) solution containing 4-acetoxybenzoic acid chloride prepared by the described above was added to the mixture, which was stirred at room temperature for 1 hour.. The reaction mixture was filtered and the filtrate was concentrated, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate=7:3) to give a title compound (500mg) having the following physical properties. TLC: Rf 0.34 (hexane: ethyl acetate=7:3) NMR (CDCl3): δ 7.76 (d, J = 8.7 Hz, 2H), 7.40-7.20 (m, 7H), 7.08-6.92 (m, 3H), 6.47 (s, 1H), 5.15 (s, 2H), 3.88 (s, 2H), 2.40 (s, 3H), 2.35 (s, 3H). | |
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 1.5h; Heating / reflux; | 42 To a suspension of 4-(acetyloxy)benzoic acid (17) (10.0 g, 55.5 mmol) in dichloromethane (200 ml) oxalyl chloride (15 ml, 172 mmol) and dimethylformamide (0.1 ml) were added. The reaction mixture was stirred at ambient temperature for 30 minutes and at reflux temperature for 1 hour. The volatiles were evaporated in vacuo, the residue was dissolved in benzene (100 ml) and the solvent was evaporated again. The procedure was repeated several times until the poignant smell disappeared after drying in vacuo. The viscous oil was dissolved in tetrahydrofuran (100 ml) and this solution slowly over 10 minutes was added to a prearranged mixture consisting of saturated NaHCO3 solution (100 ml), solid NaHCO3 (11 g), O-benzylhydroxylamine hydrochloride (9.90 g, 62 mmol), and tetrahydrofuran (150 ml). The resulting mixture was stirred at ambient temperature for 1 hour and the volume of the reaction mixture was decreased ca. twice by evaporating the mixture on vacuum rotary evaporator. The residue was extracted with ethyl acetate (3 x 100 ml), the combined organic extracts were successively washed with 2N HCl (100 ml), water (100 ml), brine (100 ml), and dried (Na2SO4). The solvents were evaporated and the residue was crystallized from toluene to give the title compound (14.275 g, 90%) as white crystals, m. p. 120-122°C. 1H NMR (CDCl3, HMDSO) δ: 2.30 (3H, s); 5.02 (2H, s); 7.14 (2H, d, J=8.6 Hz); 7.26-7. 54 (5H, m); 7.69 (2H, d, J=8.6 Hz); 8.56 (1 H, br s). | |
99 g (0.498 mol. yield 90%) | With thionyl chloride | 4.1 (1) (1) Synthesis of 4-acetoxybenzoyl chloride 100 Grams (0.555 mol) of 4-acetoxybenzoic acid was added to 400 g (3.36 mol) of thionyl chloride, and the mixture was refluxed under heat for 4 hours. Then, excess thionyl chloride was distilled off, and then the remainder was purified by distillation under reduced pressure (4 mmHg, 116° C.), to give 99 g (0.498 mol. yield 90%) of an end compound. |
With oxalyl dichloride In chloroform at 20℃; for 1h; | 1.4 Step 4: Production of 4-acetoxybenzoyl chloride To a solution of 4-acetoxybenzoic acid (1.96 g, 10.9 mmol) in chloroform (40 ml) was added oxalyl dichloride (1.42 ml, 16.3 mmol), a catalytic amount of N,N-dimethylformamide was added dropwise, and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure to give 4-acetoxybenzoyl chloride as a crude product. The obtained crude product was used for Step 6 without further purification. | |
With thionyl chloride In N,N-dimethyl-formamide; benzene | 4.i Step i) STR77 Step i) STR77 In a 20 ml-round-bottomed flask, 2.90 g (16.1 mM) of 4-acetoxybenzoic acid and 3.7 ml of thionyl chloride were placed. To the mixture, two drops of N,N-dimethylformamide was added at room temperature under stirring, followed by heat-refluxing for 20 minutes under stirring. After the reaction, dry benzene was added to the reaction mixture, followed by distilling-off of excessive thionyl chloride together with benzene. The above operation was repeated two times to obtain 4-acetoxybenzoic acid chloride. | |
With phosphorus pentachloride In benzene | 43.ii Step ii) STR219 Step ii) STR219 In a 200 ml-reaction vessel, 21.4 g (1.18*10-1 M) of p-acetoxybenzoic acid and 80 ml of dry benzene were placed. To the mixture, 25.0 g (1.20*10-1 M) of phosphorus pentachloride was added in 10 minutes at room temperature, followed by stirring for 3 hours at 50° C. After cooling, the solvent of the reaction mixture was distilled off to provide oily p-acetoxybenzoyl chloride. | |
With thionyl chloride | 58 5-(4-Acetoxyphenyl)carboxyamido-6-amino-3-methyl-1-phenyluracil The obtained 4-acetoxybenzoic acid was reacted with SOCl2 to prepare 4-acetoxybenzoyl chloride. | |
With thionyl chloride | 1.1.2 2) After heating and refluxing 1.4 g (8.0 mmol) of 4-acetoxybenzoic acid and 6 ml of thionyl chloride, surplus thionyl chloride was removed, and 4-acetoxybenzoic acid chloride was obtained. | |
With phosphorus pentachloride In benzene | 14 p-dodecyloxybenzoic acid-p'-thiocarboxylic acid phenyl-S-p"-(2-methylbutyloxy)phenyl STR28 P-acetyloxybenzoic acid (5.56*10-2 mol) was dissolved in 45 ml of benzene, and 11.8 g (5.56*10-2 mol) of PCl5 was added in 6 fractions at an interval of 5 minutes each at room temperature. Then, the mixture was stirred for 20 minutes at room temperature, followed by heat-refluxing under stirring for 5 hours. After distilling off the solvent, 12.7 g of p-acetyloxybenzoic acid chloride was obtained as a pale yellow oily product. | |
With phosphorus pentachloride In benzene | 12 Production of 4-(3-pentyloxybutoxycarbonyl)phenol. Example 12 Production of 4-(3-pentyloxybutoxycarbonyl)phenol. 10 g of p-acetyloxybenzoic acid was added to 45 ml of benzene, and 11.8 g of PCl5 was added little by little under stirring at room temperature. After 8.5 hours of heat-refluxing thereafter, the solvent was distilled off to obtain 11.5 g of p-acetyloxybenzoic acid chloride. | |
With thionyl chloride at 80℃; for 0.5h; | ||
With thionyl chloride at 80℃; for 5h; | ||
With thionyl chloride In chlorobenzene at 80℃; for 1.5h; | 10.1 Example 10 [00349] Step 1 [00350] Acetic acid 4-chlorocarbonyl-phenyl ester. A solution of 4-acetoxybenzoic acid (200 mg, 1.11 mmol), thionyl chloride(1.6 mL), 1 drop of DMF, and 7.5 mL of chlorobenzene was heated to 80° C. for 1.5 hrs. The reaction was then cooled to room temperature and the solvent and excess thionyl chloride were removed in vacuo. Theoretical yield of the title compound was assumed and the residue was used as is. [00351] Step 2 [00352] Methanesulfonic acid 4-[3-(4-hydroxy-benzoyl)-6-methanesulfonyloxy -benzo[b]thiophen-2-yl]-phenyl ester. To a solution of methanesulfonic acid 4-(6-methanesulfonyloxy-benzo[b]thiophen-2-yl)-phenyl ester1(200 mg, 0.5 mmol) in 14 mL of methylene chloride was added the product from Step 1, Example 10 (104 mg, 0.53 mmol) and triflic acid (0.47 mL, 5.3 mmol). The reaction was stirred at reflux for 16 hrs, cooled to room temperature, and poured into saturated sodium bicarbonate solution and was extracted into methylene chloride. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography using 20% Ethyl acetate/ Hexanes to 50% Ethyl acetate/Hexanes as the gradient eluant to obtain 125 mg of the title compound. [00353] Step 3 [00354] Methanesulfonic acid 4-{6-methanesulfonloxy-3-[4-(1-methyl-piperidin-2-ylmethoxy)-benzoyl]-benzo[b]thiophen-2-yl}-phenyl ester. A solution of the product from Step 2, Example 10 (115 mg, 0.22 mmol), (1-methyl-piperidin-2-yl)-methanol (28.7 mg, 0.22 mmol), and triphenylphosphine (75 mg, 0.29 mmol) in 3 mL of THF was cooled to 0° C. and diethyl azodicarboxylate (0.051 mL, 0.26 mmol) was added dropwise. After the addition was complete, the reaction was allowed to warm to room temperature and was stirred for 16 hrs. The THF was evaporated off and the residue was chromatographed on silica gel using 1% MeOH-1% Diethylamine-methylene chloride as the eluant to give 80 mg of the title compound. [00355] Step 4 [00356] [6-Hydroxy-2-(4-hydroxy-phenyl)-benzo[b]thiophen-3-yl]-[4-(1-methyl -piperidin-3-ylmethoxy)-phenyl]-methanone. A solution of the product from Step 3, Example 10 (80 mg, 0.13 mmol) and 0.25 mL of 5N NaOH in 8 ml of ethanol was heated to reflux for 1 hr. The solvent was evaporated and the residue was diluted with water. The reaction was acidified with 3N HCl then made basic with saturated sodium bicarbonate solution. This aqueous solution was extracted with 1:2 MeOH/ methylene chloride. The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated. The crude product was chromatographed on silica gel using 5% MeOH/CHCl3 to 10% MeOH/CHCl3 as the gradient eluant to obtain the title compound. [00357] 1H NMR (MeOH-d4) δ7.70(d, 2H), 7.40(d, 1H), 7.25(d, 1H), 7.15(d, 2H), 6.85(m, 3H), 6.60(d, 2H), 4.05(m, 2H), 2.95(m, 1H), 2.35(s, 3H), 2.30(m, 2H), 1.65(m, 6H).Example 11 | |
With oxalyl dichloride In dichloromethane at 0 - 20℃; | 35.a To a suspension of acetoxybenzoic acid (350 mg, 1.97 mmol) in CH2Cl2 (36 mL) was added oxalyl chloride (0.696 mL, 7.95 mmol) and catalytic amount of DMF at 0° C., and the mixture was stirred for 5 hr at rt. The solvent was evaporated, and the residual oxalyl chloride was removed with azeotropic distillation using toluene under nitrogen atmosphere. The resulting acid chloride was added to a solution of 5-amino-2-(4-methoxyphenylamino)thiazole-4-carboxamide (350 mg, 1.32 mmol) in pyridine (10 mL) at 0° C., and the mixture was stirred for 2 hr at rt. The reaction mixture was quenched by adding of ice-water, and extracted with EtOAc. The organic layer was washed with water twice, dried over Na2SO4 and concentrated. The residue was triturated with 50% EtOAc in Et2O, and the resulting solids were collected by filtration and washed with 50% EtOAc in Et2O to afford the titled compound (382 mg, 68% yield).1H-NMR (400 MHz, DMSO-d6) δ (ppm) 2.32 (s, 3H), 3.73 (s, 3H), 6.89 (d, 2H, J=8.8 Hz), 7.39 (d, 2H, J=8.8 Hz), 7.6-7.7 (m, 3H), 7.84 (br, 1H), 7.94 (d, 2H, J=8.8 Hz), 9.90 (s, 1H), 12.59 (s, 1H). | |
With oxalyl dichloride In dichloromethane at 0 - 20℃; | 97 A solution of 4-acetoxy-benzoic acid acid (108 mg, 0.598 mmoL) in CH2CI2 (5 ml_) was treated with (COCI)2 (0.07 mL, 0.796 mmoL) and 1 drop, a catalytic amount, of DMF at 0°C. The reaction mixture was slowly warmed to room temperature. The CH2CI2 was removed and dried in vacuo. The 4- acetoxy-benzoic acyl chloride in THF (2 mL) was treated with the indole- 8- Methoxy-6,11-dihydro-5-oxa-11-aza-benzo[a]fluorene (100 mg, 0.398 mmoL) followed by Et3N (0.796 mmoL, 0.11 mL) at 0°C. The reaction was slowly warmed to room temperature over 2 hours. THF was removed in vacuo. The residue was partitioned between CH2CI2 and saturated NaHCO3. The aqueous phase was extracted two times with CH2CI2. The organic layers from the two extractions were combined, washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated to yield a brown oil. The crude material (the oil) was then purified by column chromatography (silica gel, hexanes: EtOAc 4:1 as eluent) to yield the title compound as a pale solid. 1H NMR (CDCI3) δ 8.02 ~ 6.75 (m, 11 H), 5.52 (s, 2H), 3.98 (s, 3H), 2.55(s, 3H).MS (m/z): MH+, 414. | |
With oxalyl dichloride In dichloromethane at 0 - 20℃; | 97 A solution of 4-acetoxy-benzoic acid acid (108 mg, 0.598 mmoL) in CH2CI2 (5 ml_) was treated with (COCI)2 (0.07 ml_, 0.796 mmoL) and 1 drop, a catalytic amount, of DMF at 0°C. The reaction mixture was slowly warmed to room temperature. The CH2CI2 was removed and dried in vacuo. The 4- acetoxy-benzoic acyl chloride in THF (2 ml_) was treated with the indole- 8- Methoxy-6,11-dihydro-5-oxa-11 -aza-benzo[a]fluorene (100 mg, 0.398 mmoL) followed by Et3N (0.796 mmoL, 0.11 ml_) at 0°C. The reaction was slowly warmed to room temperature over 2 hours. THF was removed in vacuo. The residue was partitioned between CH2CI2 and saturated NaHCO3. The aqueous phase was extracted two times with CH2CI2. The organic layers from the two extractions were combined, washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated to yield a brown oil. The crude material (the oil) was then purified by column chromatography (silica gel, hexanes: EtOAc 4:1 as eluent) to yield the title compound as a pale solid. 1H NMR (CDCI3) δ 8.02 ~ 6.75 (m, 11 H), 5.52 (s, 2H), 3.98 (s, 3H), 2.55(s, 3H).MS (m/z): MH+, 414. | |
With oxalyl dichloride In dichloromethane at 0 - 20℃; | 2.A A slurry of 4-acetoxybenzoic acid (100 g, 555.1 mmol) in CH2Cl2 (50 mL) was treated with a catalytic amount of DMF (0.5 mL) and cooled in ice bath. The reaction was stirred as neat oxalyl chloride (51 mL, 582.82 mmol, 1.05 equiv.) was added dropwise. The reaction was allowed to warm to ambient temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure to give 4-(chlorocarbonyl)phenyl acetate (110 g, 100% th.; 110% pract.), which was used in the next step without further purification; 1H NMR (CDCl3) δ 8.09 (d, 2H), 7.20 (d, 2H), 2.28 (s, 3H) ppm. | |
With thionyl chloride Reflux; | 5.1.5. General procedures for benzoyl chloride (6a-6m) General procedure: The selected acid was refluxed in thionyl chloride for 2-3 h, and then the solution was cooled to room temperature, and the remaining thionyl chloride was evaporated to afford the acyl chloride, which was used without further purification. | |
With thionyl chloride In N,N-dimethyl-formamide at 80℃; for 1h; Inert atmosphere; | ||
With oxalyl dichloride In toluene for 3h; Reflux; Inert atmosphere; | ||
With thionyl chloride Reflux; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 8h; Inert atmosphere; | ||
With thionyl chloride for 2h; Reflux; | General Procedure: The carboxylic acid (1equiv) was refluxed with excess of thionyl chloride for 2 h. The excess of thionyl chloride was evaporated at reduce pressure. The residue was dissolved in toluene (5 mL) and evaporated at reduce pressure until dryness two times. The crude acid chloride was dissolved in acetone. This solution was treated at 0 °C with (+)-6-aminopenicillanic acid (6-APA, 1.5 equiv) dissolved into a 2% NaHCO3/water solution (50 ml), diluted with acetone (40 ml). After stirring at room temperature for 2-4 h, the reaction mixture was washed with ethyl acetate (25 ml). The aqueous layer was poured into ethyl acetate (50 ml) and acidified with a 0.1M HCl/water solution to pH 2-3. The organic phase was washed three times with water and dried with anhydrous Na2SO4. The organic layer was concentrated by evaporating the solvent at reduced pressure and triturated with petroleum ether and ethyl acetate or dichloromethane to give the title compounds. | |
With thionyl chloride; N,N-dimethyl-formamide for 0.5h; Inert atmosphere; | ||
With oxalyl dichloride; N,N-dimethyl-formamide at 20℃; for 1h; | ||
With thionyl chloride In tetrahydrofuran | ||
With thionyl chloride | ||
With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 20℃; for 1h; Inert atmosphere; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0℃; | ||
With thionyl chloride for 8h; Reflux; | ||
With thionyl chloride In benzene for 2h; Reflux; | ||
With thionyl chloride for 3h; Reflux; | ||
With thionyl chloride; N,N-dimethyl-formamide | ||
With oxalyl dichloride In dichloromethane at 20℃; | ||
With thionyl chloride at 81.84℃; for 5h; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In acetonitrile at 20℃; for 1h; | 33 Preparation of 4-(4-(trifluoromethyl)pyridin-2-ylcarbamoyl)phenyl acetate (500-2) To a suspension of 4-acetoxybenzoic acid (500-1) (1.6 g, 8.9 mmol) in anhydrous acetonitrile (10 mL) was added 1 drop of DMF before introducing (COCF)2 (2 mL, 21 mmol). The resulting mixture was stirred at room temperature for 1 hr. The solvent was evaporated. The freshly generated acid chloride was dissolved in anhydrous DCM (3 mL) and the solution was introduced to a solution of 4- (trifluoromethyl)pyridin-2-amine (700 mg, 4.3 mmol) in DCM (3 mL). The reaction mixture was stirred at room temperature for 1 hr before being quenched with MeOH (5 mL). Solvents were removed and the residue was purified by column chromatography (silica gel, 0 to 30% ethyl acetate in petroleum ether) to give 4-(4-(trifluoromethyl)pyridin-2-ylcarbamoyl)phenyl acetate (500-2) (697 mg, 50%) as a solid. LC- MS (ESI): mlz (M+l) 325.2. | |
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 3h; Inert atmosphere; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane | 1 10086] 40 g of 4-acetoxybenzoic acid (222 mmol) was added to a 500 ml round bottom flask and was then dissolved in methylene chloride. Subsequently, 31 g of oxalyl chloride (244 mmol) and ito 5 drops of DMF were added thereto and then reacted for 3 hours or more. Reaction termination was confirmed using thin layer chromatography (TLC). When the reaction was finished, a material, in which a hydroxyl group of 4-acetoxybenzoic acid was chlorinated, was obtained by evaporation. | |
88.1 g | With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; | 1.1 (1) Preparation of 4-acetoxy-benzoyl chloride 4-acetoxy-benzoic acid 80g, and then the turbid solution made by diluting 2.2 eq. In methylene chloride (MC) solvent was added as a catalyst in dimethylformamide was stirred at room temperature for 1 to 3 drops. Chloride at room temperature 58.92g, 2.3 eq oxalyl while stirring Slowly added in and stirred for a few hours; To remove residual oxalyl chloride and the methylene chloride solvent through a rotary evaporator under reduced pressure acetone was synthesized 4-benzoyl chloride 88.1g of the liquid phase. |
With thionyl chloride at 80℃; for 5h; | ||
With thionyl chloride In N,N-dimethyl-formamide; toluene at 60℃; for 2h; Inert atmosphere; | 1 225 g of toluene, three drops of DMF, and 90.0 g of p-acetoxybenzoic acid (AcPOB) were put into 1000 ml four mouth flask purged with nitrogen, and dssolved by stirring. Subsequently, 89.2 g of thionyl chloride was added and stirred at 60 degrees C for 120 minutes, and toluene was distilled off under reduced pressire to obtain p-acetoxybenzoyl chloride. 68 ml of allyl alcohol previously dissolved in 100 ml of N-methyl-2-pyrrolidone was added dropwise to this p-acetoxybenzoyl chloride at 0 degree C and stirred at room temperature for 1 hour. The reaction mixture was transferred to the separating funnel containing ethyl acetate. A saturated sodium bicarbonate aqueous solution was added to this reaction mixture and the mixture was separated. Further, a saturation sodium chloride aqueous solution was added and the liquids were separated. The unreacted carboxylic acid, the raw material, and the inorganic component were removed by discarding the aqueous layer. Sodium sulfate was added to the obtained ethyl acetate layer, dehydrated by stirring, filtered and the filtrate was concentrated under reduced pressure to obtain 107.2 g of yellow liquid. | |
88.1 g | With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide | 1 (1) Preparation of 4-acetoxybenzoyl chloride 72.72 g of 4-acetoxybenzoic acid, 2 equivalents, was diluted in methylene chloride (MC) solvent to make a cloudy solution, and then dimethylformamide 1 to 3 drops were added as a catalyst and stirred at room temperature. At the same time as stirring, 51.23 g of oxalyl chloride, 2 equivalents, And the mixture was stirred for 1 to 2 hours. The residual oxalyl chloride and methylene chloride The rye solvent was removed to obtain 88.1 g of liquid 4-acetone benzoyl chloride |
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 2h; | ||
88.1 g | With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; | 1.1 (1) Preparation of 4-acetoxybenzoyl chloride The mixture was diluted with a solvent to prepare a cloudy solution. One to three drops of dimethylformamide were added thereto as a catalyst, and the mixture was stirred at room temperature.Simultaneously with stirring, 58.92 g of oxalyl chloride,2.3 equivalents were added slowly at room temperature and stirred for 1-2 hours.The residual oxalyl chloride and methylene chloride solvent were removed through a rotary evaporator to obtain a liquid88.1 g of 4-acetone benzoyl chloride was synthesized. |
With thionyl chloride at 80℃; for 5h; | 2.2. General Procedure for Sulfonamide Derivatives General procedure: Secondary sulfonamides were synthesized using naturally available 4-hydroxy and3,4,5-trihydroxy benzoic acids (gallic acid) in various plants and fruits, which were reacted with aceticanhydride to obtain 4-acetoxy and 3,4,5-triacetoxy benzoic acids for the protection of hydroxyl groups.Then, they were converted to their corresponding chloride derivatives by treating with thionyl chlorideto produce benzoyl chlorides, which underwent reactions with secondary sulfonamides having thiazole, pyrimidine, pyridine, isoxazole and thiadiazole groups to obtain secondary sulfonamidederivatives of acetoxybenzamides and triacetoxybenzamides as one part of target compounds.Deacetylation under acidic conditions gave the other part of our targeted sulfonamide derivatives [28].The reaction scheme is given in Figure 1. | |
With thionyl chloride In N,N-dimethyl-formamide for 4h; Reflux; | ||
With thionyl chloride In dichloromethane Reflux; | ||
With thionyl chloride at 60℃; for 5h; Inert atmosphere; | 1-3 (Example 1-3) Preparation of a compound represented by the formula (C-2B) Under a nitrogen atmosphere, 10.0 g of a compound represented by the formula (C-2B-2)50 mL of thionyl chloride was added and the mixture was heated and stirred at 60 ° C. for 5 hours.Thionyl chloride was distilled off to obtain an acid chloride of the compound represented by the formula (C-2B-2).Under a nitrogen atmosphere, 6.9 g of the compound represented by the formula (C-2B-1), 60 mL of dichloromethane and 5.3 g of pyridine were added to the reaction vessel.A solution of the acid chloride of the compound represented by the formula (C-2B-2) dissolved in 20 mL of dichloromethane was added dropwise while cooling with ice, and the mixture was stirred at room temperature for 5 hours.The reaction solution was washed with 5% hydrochloric acid, water and brine.By distilling off the solvent and drying, 15.1 g of a compound represented by the formula (C-2B-3) was obtained. | |
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 3h; Inert atmosphere; Reflux; | ||
With thionyl chloride at 80℃; for 1h; | ||
With thionyl chloride | 6.b (b) (b) 4-Hydroxy-[2-(endobicyclo[3.1.0]hex-6-yl)ethyl]phenyl urea A solution (20 ml.) of thionyl chloride containing 3.0 g of 4-acetoxybenzoic acid (Preparation 5) is refluxed for 3 hours. After evaporation of excess thionyl chloride, 4-acetoxybenzoyl chloride is obtained and dissolved in 15 ml. THF and 15 ml. acetone at 5°. | |
With phosphorus pentachloride | ||
With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 0 - 20℃; for 1h; Inert atmosphere; | ||
With phosgene | ||
With thionyl chloride In tetrahydrofuran for 2h; Inert atmosphere; Reflux; | 1 Reference Example 1 (Synthesis of 4-hydroxybenzoic acid methallyl ester) mixer,90.1 g (0.5 mol) of 4-acetoxybenzoic acid in a 1000 mL four-necked flask equipped with a temperature sensor and a reflux condenser,65.4 g (0.55 mol) of thionyl chloride and 360.3 g of tetrahydrofuran were added, and under nitrogen stream,The temperature was raised to reflux while stirring,The mixture was stirred at the same temperature for 2 hours. Then,After cooling down to 18 ° CEvaporate the solvent by reduced pressure,A liquid of 4-acetoxybenzoic acid chloride was obtained. | |
With thionyl chloride; N,N-dimethyl-formamide In chloroform at 30 - 40℃; for 48h; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 22℃; for 2h; Inert atmosphere; | 2.a a) [4- [ [4- [4- (2-Pyridyl)piperazin- 1 - yl] phenyl] carb amoyl] phenyl] acetate 4-Acetoxybenzoic acid (1.59 g, 8.8 mmol) was dissolved at 22 °C in DCM (65 ml) un der an inert atmosphere. Oxalyl chloride (1.68 g, 1.16 ml, 13.2 mmol) was added at 22 °C followed by DMF (32.2 mg, 34.1 m, 440 m mol) and the reaction mixture was stirred at 22 °C for 2 h. The mixture was evaporated at 40 °C and the resulting acid chloride was dissolved in DCM (32.3 ml) and added dropwise (5 min) at 22 °C to a solution of 4-(4-(pyridin-2-yl)pi- perazin-l-yl)aniline (Intermediate l.b) (2.24 g, 8.8 mmol) and DIPEA(4.55 g, 6.15 ml, 35.2 mmol) in DCM (80 ml) keeping the internal temperature below 20 °C (ice-bath). Stirring was continued at 22 °C for 30 min. The reaction was stopped by adding at 22 °C MeOH (5.64 g, 7.12 ml, 176 mmol). Stirring was continued for 1 h before filtering through a membrane-fil ter. Solids were washed with DCM (2 x 35 ml) and the cake was dried for 2 min (air dried by suction). Then the cake was washed with H20 (2 x 35 ml) and dried in HV to give the title compound (3.20 g, 87%) as white solid. LC-MS: m/z = 417.3 [M+H]+. | |
With thionyl chloride at 80℃; for 1h; Inert atmosphere; | 30 The mixture of compound 26.1 (216 mg, 1 .2 mmol, 1.0 eq) in thionyl chloride (2 iiiL) was stirred at 80 °C for 1 h under nitrogen atmosphere. The reaction was monitored by TLC. Then the mixture was quenched with methanol. The residue was dried over sodium sulfate and concentrated under reduced pressure to obtain compound 26.2 (245 mg, crude) as a light yellow oil, which was used directly in the next step without further purification | |
With thionyl chloride at 78℃; for 4h; | 5.1.4. General procedure for the synthesis of compounds 5a-c, 7a General procedure: 3,4,5-triacetoxybenzoic acid 4a (2000 mg, 6.756 mmol) wasdissolved in SOCl2 (8000 mg, 67.244 mmol). The solution was thenheated under reflux at 78 °C for 4 h. The solvent was removed usinga rotary evaporator under reduced pressure to yield white solid.Yielding 99% compound 5a (2100 mg) as a white solid. Compounds5b-c and 7a were synthesized following the procedure of preparation5a. | |
With thionyl chloride for 3h; Reflux; | ||
With oxalyl dichloride | ||
With thionyl chloride In dichloromethane at 20℃; for 2h; | To a solution of 4-acetoxybenzoic acid (1.0 g, 5.6 mmol) in driedDCM (10 mL), thionyl chloride (660 mg, 5.6 mmol) was added dropwise,and the reaction mixture was stirred for 2 h at room temperature.After completion of the reaction, the mixture was concentrated undervacuo to give 4-(chlorocarbonyl)phenyl acetate (4), which was usedfurther without purification. | |
With thionyl chloride; N,N-dimethyl-formamide at 85℃; for 3h; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 1h; Inert atmosphere; | 1 4-(6-Methoxy-2-(4-methoxyphenyl)benzo[b]thiophene-3-carbonyl)phenyl acetate (0309) (50) Oxalyl chloride (9.70 mL, 120 mmol, 3.0 eq) was added dropwise under N2 to a solution of 4-acetoxybenzoic acid (49) (7.206 g, 40 mmol, 1.0 eq) in anhydrous DCM (80 mL) at 0 °C. Then several drops of DMF were added. The solution was warmed to rt and stirred for 1 h. The solution was concentrated and dried to obtain the acyl chloride as a white solid. This intermediate was dissolved in anhydrous DCM (150 mL), then 6- methoxy-2-(4-methoxyphenyl)- benzo[b]thiophene (8.65 g, 32 mmol, 0.8 eq) was added followed by addition of AICI3 (8.00 g, 60 mmol, 1.5 eq) in three portions over a period of 5 min with vigorous stirring at 0 °C under N2. The mixture was warmed to rt and stirred for lh. The reaction was quenched by slow addition of ice-ILO followed by IN HC1 (aq). The layers were separated and the aqueous layer was extracted twice with DCM. The combined organic layer was dried over anhydrous Na2SC>4. After filtration and concentration, the residue was purified on a silica gel flash column with hexane: DCM (100:1-1:100) to afford the intermediate (50) as a yellow solid (5.517 g, 40% yield). 'H NMR (CDCI3, 400 MHz) d (ppm) 7.81 (d , J = 8.8 Hz, 2H), 7.61 (d , J = 8.8 Hz, 1H), 7.32-7.29 (m, 3H), 7.02-6.99 (m, 3H), 6.74 (d, J= 8.8 Hz, 2H), 3.86 (s, 3H), 3.73 (s, 3H), 2.25 (s, 3H); 13C NMR (CDCI3, 100 MHz) d (ppm) 193.15, 168.63, 159.99, 157.78, 154.38, 144.16, 140.10, 135.03, 133.76, 131.52, 130.48, 130.02, 125.76, 124.16, 121.54, 114.99, 114.13, 104.54, 55.65, 55.28, 21.16; UPLC-MS (ESP) calc, for C25H21O5S [M+l]+: 433.11, found 433.37. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | 4-Acetoxy-benzoic acid (0.350 g, 1.95 mmol) and anhydrous AlCl3 (0.800 g, 6.02 mmol) were mixed and heated at 155-160 °C (oil bath temperature) for 5 h (after 1 h a solid, brown foamy mass formed and stirring was no longer possible). After cooling (ice bath), the reaction mixture was treated with 6.5 mL of 2 N HCl. The acidified reaction mixture was extracted with ethyl acetate (3.x.10 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to afford a yellow solid (0.280 g, 80percent), which was used without any further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98.6% | With pyridine In tetrahydrofuran for 1h; Cooling with ice; | 3 In a dry 50 ml round bottom flask was added 5 g (0.036 mol) of p-hydroxybenzoic acid (PHB)25 mL of anhydrous tetrahydrofuran, Stirring the solution into a uniform and transparent,After the addition of 4.04 ml (0.06 mol) of pyridine,After the reaction was completed, the reaction mixture was washed twice with deionized water and suction-filtered to give the desired product, acetoxybenzoic acid, which was naturally air-dried and then dried in vacuo. The oven was dried for 24 h to give 6. 346 g of the desired product in 98.6% yield. |
97% | In cyclohexane at 30 - 40℃; for 2h; | 1.1 Example 1 To 100 ml of cyclohexane was added 51.8 g (0.375 mol) of p-hydroxybenzoic acid,35.30 g (0.45 mol) of acetyl chloride was added dropwise at 30 to 35 ° C,Dropwise at 35 ~ 40° C reaction was incubated 2h. Atmospheric distillation to recover excess acetyl chloride and solvent cyclohexane,Recrystallization from ethanol gave 65.5 g of p-acetoxybenzoic acid in 97% yield; |
82.3% | In pyridine at 0 - 20℃; for 1.58333h; | 41 To a mixture of 4-hydroxybenzoic acid (16) (20.0 g, 144.8 mmol) and pyridine (60 ml, 742 mmol) at 0°C was added acetyl chloride (12 ml, 169 mol) over 5 minutes. The resulting mixture was stirred at ice bath temperature for 30 minutes and for 1 hour at room temperature. The mixture was poured into ice water (500 ml) and the pH of the medium was brought to 1-2 by adding conc. HCl (ca. 40 ml). The precipitate was filtered, washed with water (100 ml), and dried (Na2S04). The obtained solid material was crystallized from methanol-water (1 : 1) (200 ml) affording the title compound (21.485 g, 82. 3%) as white crystals, m. p. 181-183°C. 1H NMR (CDCl3, HMDSO) δ: 2.32 (3H, s); 7.22 (2H, d, J=8. 2 Hz) ; 8.16 (2H, d, J=8. 2 Hz) ; 10.50 (1 H, br s). |
In benzene Heating; | ||
With triethylamine | ||
With pyridine at 0 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With Oxone; 2-iodo-3,4,5,6-tetramethylbenzoic acid In water; acetonitrile for 19h; | |
80% | With tert.-butylhydroperoxide In water at 50℃; for 12h; Sealed tube; Green chemistry; | |
75% | With Oxone In N,N-dimethyl-formamide at 25℃; for 3h; |
30% | With ammonium thiocyanate; oxygen In acetic acid at 25℃; for 8h; | General procedure for the preparation of compound 3 General procedure: Themixture of styrene (2.0 mmol) and ammonium thiocyanate (1.0 mmol) in HOAc (3mL) was stirred in oxygen atmosphere at 25 oC for 8 h. After removalof solvent under reduced pressure, the residue waspurified by flash silica-gel column chromatography (eluted with petroleum ether/ acetone from 50/1 to 8/1 (v:v)) and afforded the desired phenacylthiocyanate 3. 4.3.5 4′-Acetoxybenzoic acid (3h)11 (0013) Yellow oil (54mg, 30% yield). 1H NMR (400MHz, CDCl3): δ 9.99 (s, 1H), 7.92 (d, J=8.0Hz, 2H), 7.28 (d, J=8.0Hz, 2H), 2.34 (s, 3H). 13C NMR (150MHz, CDCl3): δ 190.9, 168.7, 155.3, 134.0, 131.2, 122.4, 21.2. MS (ESI-TOF) m/z: (M+H)+ calcd for C9H9O4 181.0, found 181.0 |
With 1,2-dibutoxyethane; oxygen at 110℃; for 12h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; In pyridine; at 20℃; | Step 1: Acetic acid 4-(2-TERT-BUTOXYCARBONYLAMINO-5-THIOPHEN-2-YL-PHENYLCARBAMOYL)-PHENYL ester (183) [0346] TERTBUTYL 2-AMINO-4-(THIOPHEN-2-YL) PHENYLCARBAMATE 178 (0.198g, 0.68 MMOL), BENZOTRIAZOL-1-YLOXY-TRIS (DIMETHYLAMINO) PHOSPHONIUM HEXAFLUOROPHOSPHATE (BOP) (0.302g, 0.68 MMOL) and 4-acetoxybenzoic acid (182) (0. 123G, 0.68 MMOL) were stirred in pyridine at rt overnight then solvent evaporated and purified by flash chromatography (35% ethyl acetate in hexanes) to provide 183 (O. 11g, 36%). 1H NMR: (DMSO) 5 (ppm): 400 MHz, (DMSO) d (ppm): 9.91 (s, 1H), 8.72 (s, 1H), 8.01 (d, J= 8.8 Hz, 2H), 7.78 (d, J= 1.8 Hz, 1H), 7.63 (d, J= 8. 4 Hz, 1H), 7.51 (dd, J= 4.9, 0.98 Hz, 2H), 7.44 (dd, J= 3.7, 0.98 Hz, 1H), 7.30 (d, J= 8.6 Hz, 1H), 7.11 (dd, J= 5.1 Hz, 1H), 2.32 (s, 3H), 1.46 (s, 9H). MS: (CALC.) 452.14 ; (obt. ) 475 (M+Na). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70.8% | With pyridine; thionyl chloride In 1,4-dioxane; (2S)-N-methyl-1-phenylpropan-2-amine hydrate; N,N-dimethyl-formamide; benzene | 1 EXAMPLE 1 STR78 In a 20 ml round-bottom flask, 2.90 g (16.1 m mole) of 4-acetoxybenzoic acid and 3.7 ml of thionyl chloride were placed. To the mixture two drops of N,N-dimethylformamide was added at room temperature under stirring followed by refluxing and stirring for 20 minutes. After the reaction, dry benzene was added into the reaction mixture. Excessive thionyl chloride was distilled off under reduced pressure, followed by distilling-off thereof with benzene. This operation was repeated twice. In a 100 ml round-bottom flask, the resultant 4-acetoxybenzoic chloride, 3.10 g (15.1 m mole) of 2-amino-4-octylphenol and 40 ml of dioxane were placed and heated to keep inner temperature 85 to 88.5° C. To the mixture, 5.5 ml of pyridine was added dropwise under stirring, followed by heating and stirring for 20 minutes at 85 to 88.5° C. After the reaction, the reaction mixture was cooled with ice and poured into ca. 200 ml of ice water to precipitate a crystal. The crystal was filtered, washed and recrystallized from methanol to obtain 4.10 g of 2-(4-acetoxybenzoylamino)-4-octylphenol (Yield: 70.8%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogen bromide; acetic anhydride; acetic acid; In titanium-clad; | EXAMPLE IV One hundred and sixty-six (166) g (0.933 mole) of p-acetoxyacetophenone, 100 g (0.98 mole) of acetic anhydride, 250 g (4.17 moles) of acetic acid, 1.2 g (0.0048 mole) of Co(OAc)2.4H2 O, 1.2 g (0.0049 mole) of Mn(OAc)2.4H2 O, and 1.6 g (0.01 mole) of 48% HBr were combined in a two-liter titanium-clad autoclave. The mixture was heated to 300 F. and pressurized to 300 psi. Air was introduced at a rate of 0.75 scf/min for the first fifteen minutes and then lowered to 0.63 scf/min for the remainder of the reaction. During the oxidation, a mixture of 140 g (1.37 moles) of acetic anhydride and 35 g (0.58 mole) of acetic acid was added through a pump. The oxidation ran for 31 minutes. The reaction solution was cooled and evaporated from 678 g to 579 g. The precipitated p-acetoxybenzoic acid was filtered and dried to yield 106 g with a purity of 96.4 mole % (61 mole % yield). Analysis of the filtrate showed: p-acetoxybenzoic acid, 18.2 mole %, p-acetoxyacetophenone, 2.4 mole %, p-hydroxybenzoic acid, 1.3 mole %. Analysis of the reactor wash showed p-acetoxybenzoic acid, 2.2 mole %. Total reaction yield of p-acetoxybenzoic acid was 81.4 mole %. | |
With hydrogen bromide; acetic anhydride; acetic acid; In titanium-clad; | EXAMPLE V One hundred and sixty-six (166) g (0.933 mole) of p-acetoxyacetophenone, 100 g (0.98 mole) of acetic anhydride, 250 g (4.17 moles) of acetic acid, 0.35 g (0.0014 mole) of Co(OAc)2.4H2 O, 0.35 g (0.0014 mole) of Mn(OAc)2.4H2 O, and 0.47 g (0.0028 mole) of 48% HBr were combined in a two-liter titanium-clad autoclave. The mixture was heated to 300 F. and pressurized to 300 psi. Air was introduced at a rate of 0.75 scf/min for 15 minutes and then lowered to 0.61 scf/min for the remainder of the reaction. During the run, a solution of 150 g (1.47 moles) of acetic anhydride and 38 g (0.63 mole) of acetic acid was added through a pump. The run time was 31 minutes. The reaction solution was concentrated by evaporating acetic acid from 696 g to 660 g. The precipitated p-acetoxybenzoic acid was isolated by filtration and dried to give 81.3 g of 97.6 mole % purity (47.2 mole % yield). Analysis of the filtrate showed: p-acetoxybenzoic acid, 32 mole %, p-hydroxybenzoic acid, 0.3 mole %, and p-acetoxyacetophenone, 3.2 mole %. Analysis of the reactor wash showed p-acetoxyacetophenone, 2.1 mole %. Total reaction yield of p-acetoxybenzoic acid was 81.3 mole %. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogen bromide; acetic anhydride; acetic acid; In titanium-clad; | EXAMPLE VI One hundred and sixty-six (166) g (0.933 mole) of p-acetoxyacetophenone, 100 g (0.98 mole) of acetic anhydride, 250 g (4.17 moles) of acetic acid, 3.5 g (0.0014 mole) of Co(OAc)2.4H2 O, 3.5 g (0.0014 mole) of Mn(OAc)2.4H2 O, and 4.7 g (0.0028 mole) of 48% HBr were combined in a two-liter titanium-clad autoclave. The reaction mixture was heated to 300 F. and pressurized to 300 psi. Air was introduced at a rate of 0.75 scf/min. During the run, a solution of 54 g (0.53 mole) of acetic anhydride and 13 g (0.217 mole) of acetic acid was added through a pump. The run time was 25 minutes. Analyses of the total reactor effluent and wash showed: p-acetoxybenzoic acid, 87 mole % yield, p-hydroxybenzoic acid, 1.2 mole % yield, and p-acetoxyacetophenone, 3.5 mole % yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With acetic anhydride; acetic acid; | EXAMPLE II The oxidation of p-acetoxyacetophenone proceeded as in Example I, except that the reaction was run for 30 minutes and a total of 150 g (1.47 moles) of acetic anhydride and 37 g (0.62 mole) of acetic acid was added through the pump. The reaction mixture was concentrated from 772 g to 413 g by evaporation of acetic acid. The slurry was filtered to remove precipitated p-acetoxybenzoic acid. After drying, 128.2 g of p-acetoxybenzoic acid of 95 mole % purity (73% yield) were obtained. Remaining in the filtrate were: p-acetoxybenzoic acid, 8.5 mole % yield, p-acetoxyacetophenone, 1.8 mole % yield, p-hydroxybenzoic acid, 0.6 mole % yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogen bromide; acetic anhydride; acetic acid; | EXAMPLE VII Seventeen and one-tenth (17.1) g (0.096 mole) of p-acetoxyacetophenone, 17.1 g (0.17 mole) of acetic anhydride, 65 g (1.08 moles) of acetic acid, 0.51 g (0.002 mole) of Co(OAc)2.4H2 O, 0.50 g (0.002 mole) of Mn(OAc)2.4H2 O, and 0.68 g (0.004 mole) of 48% HBr were combined in a glass reactor and heated to 100 C. Air was introduced at a rate of 50 ml/min. After 164 hours of reaction time, the oxidation ceased. Analysis of the reaction solution showed 3.4 wt % p-acetoxyacetophenone and 2.7 wt % p-hydroxyacetophenone. In addition, p-acetoxybenzoic acid and p-hydroxybenzoic acid were present in substantial amounts. An additional 30 g (0.294 mole) of acetic anhydride were added and the oxidation reaction continued. Final reaction time was 240 hours. Analysis of the final reaction mixture showed 41 mole % yield of p-acetoxybenzoic acid, 3.9 mole % yield of p-hydroxybenzoic acid, and 1.0 mole % yield unreacted p-acetoxyacetophenone. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride;AlCl3; In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; 1,2,4-Trichlorobenzene; | a 3-Acetyl-4-hydroxybenzoic Acid 36.6 g (0.274 mol) of AlCl3 are suspended in 50 ml of 1,2,4-trichloro-benzene and treated with 9 g (50 mmol) of 4-acetoxybenzoic acid. After dropwise addition of 7.84 g (0.1 mol) of acetyl chloride, the reaction mixture is heated to 130-140° C., the evolution of HCl gas occurring from approximately 60° C. The mixture is stirred for approximately 1 hour at 130° C. and then allowed to cool to 60-70° C., and the mixture is poured cautiously into stirred ice water. It is extracted several times with ethyl acetate, then the combined organic phases are extracted with saturated aqueous sodium bicarbonate solution and the combined aqueous phases are adjusted carefully to pH<1 using concentrated HCl, the 3-acetyl-4-hydroxybenzoic acid separating as sparingly soluble material. Colorless crystalline substance, melting point 228-233° C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | Stage #1: 4-acetyloxy-benzoic acid With borane-THF In tetrahydrofuran at 10 - 22℃; Stage #2: With water In tetrahydrofuran | -(Hvdroxymethyl)phenylacetate4- Acetoxy benzoic acid (1 g, 5.55 mmol) was dried at 0.01 mbar for 30 min and afterwards dissolved in THF (7.5 ml) and cooled down to 10°C. BH3*THF complex (1 M, 12.07 ml, 12.07 mmol) in THF was added dropwise over 10 min time period. The reaction mixture was stirred over night at 22 °C. Further, water (4.34 ml) was slowly added to stop the reaction and the all volatiles were removed. Colorless product obtained was extracted using water, ethyl acetate mixture. The organic phase was washed with water (3 x 30 ml), saturated NaCI solution (3 x 70ml) and dried over Na2S04. After removing the solvent, the product was purified by using column chromatography on silica gel and CH2CI2 / ethyl acetate / triethylamine (10:4:0.5, v/v/v) mixture as an eluent. The product is crystalline, colorless solid. Yield was 0.42 g, 2.53 mmol (46 %): TLC-analysis on silica plates: Rf = 0.41 in (CH2CI2 / ethyl acetate / triethylamine (10:4:0.5, v/v/v)). |
41% | With borane-THF In tetrahydrofuran at 22℃; for 36h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 4-acetyloxy-benzoic acid With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 0.0833333h; Stage #2: 1,8-dihydroxy-3-hydroxymethyl-9,10-anthracenedione In dichloromethane at 20℃; | General procedure for synthesis of ester derivatives of aloe-emodin General procedure: Substituted benzoic acids or cinnamic acids (0.1 mmol) in dry CH2Cl2 (0.2 mL) were treated with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI, 20.6 mg, 0.1 mmol) and DMAP (1.0 mg, 0.006 mmol). The mixtures were stirred at room temperature for 5 min. Aloe-emodin (2, 5.4 mg, 0.02 mmol) was added, and stirring was continued at room temperature until the starting compound was consumed. The resulting solution was diluted with EtOAc (10 mL) and concentrated on a rotary evaporator. The final benzoate and cinnamate derivatives of aloe-emodin were purifiedby using preparative TLC (silica gel, 500 m; hexane/EtOAc, 4:1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: oxalyl dichloride / 4 h / 20 °C 2: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 3 h / 20 °C 3: potassium carbonate / methanol / 5 h / 20 °C | ||
Multi-step reaction with 3 steps 1: N,N-dimethyl-formamide; oxalyl dichloride / dichloromethane / 4 h / 20 °C 2: N-ethyl-N,N-diisopropylamine / tetrahydrofuran; dichloromethane / 3 h / 20 °C 3: potassium carbonate / methanol / 5 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 6.0h; | General procedure: A solution of <strong>[883535-89-5]2-(2-methyl-1H-indol-1-yl)ethanamine</strong> (4a) (65 mg, 0.373 mmol) and 4-(piperidin-1-yl)benzoic acid (5) (76 mg, 1 eq.), and dimethylaminopyridine (catalytic, ?5 mg) in dichloromethane (6 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide.hydrochloride (EDCI) (92 mg, 1.3 eq.) at room temperature. The resulting reaction mixture was stirred for 6h. At the conclusion of the reaction (TLC), water (15 mL) was added to quench the reaction. The product was extracted with ethyl acetate (20mL×3). Organics were washed with dilute HCl (10 mL), saturated NaHCO3 solution (10 mL), water (10 mL) and brine solution (10 mL) and dried over Na2SO4 and concentrated. The resulting crude product was subjected to silica gel chromatography eluting with 0-40% ethyl acetate in hexane to furnish 7k (TG7-152) (100mg, 74% yield). 1H NMR (CDCl3): delta 7.52 (d, J=5.6Hz, 1H), 7.49 (d, J=8.8Hz, 2H), 7.30 (d, J=8Hz, 1H), 7.07 (m, 2H), 6.80 (d, J=8.2Hz, 2H), 6.23 (s, 1H), 5.98 (t, J=5.4Hz, 1H), 4.33 (t, J=6Hz, 2H), 3.76 (q, J=6Hz, 2H), 3.25 (t, J=4.8Hz, 4H), 2.37 (s, 3H), 1.6 (m, 6H). LCMS (ESI): >97% purity at lambda 254, MS; m/z, 362 [M+H]+. Anal. Calcd. for C23H27N3O: C, 76.42; H, 7.53; N, 11.62; found; C, 76.48; H, 7.55; N, 11.59. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; dmap / dichloromethane / 46 h / 0 - 20 °C 2: ammonium acetate; water / methanol / 76 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 20℃; for 46h; | 3 Example 3: 2-(prop-2-yn-1-yl)pent-4-yn-1-yl 4-hydroxybenzoate [41 1] Example 3: 2-(Pro -yl 4-hydroxybenzoate [412] To a solution of 2-(prop-2-yn-1-yl)pent-4-yn-1 -ol (J. Org. Chem. 2002, 67, 2778) (380 mg, 3.1 1 mmol), 4-acetoxybenzoic acid (619 mg, 3.43 mmol) and DMAP (36.9 mg, 0.30 mmol) in DCM at 0°C was added EDC HCI (663 mg, 3.46 mmol) and the resulting solution stirred at 0°C for 1h before allowing to warm to rt. The mixture was stirred for an additional 21 h before further EDC HCI (652 mg, 3.40 mmol) was added. The resultant mixture was stirred at rt for an additional 24h before Et20 and H20 were added. The product was extracted (Et20), washed (H20, then brine), dried (Na2S04), filtered and concentrated under reduced pressure. Flash chromatography (0 - 100% EtOAc / petrol gradient elution) gave 2-(prop-2-yn-1-yl)pent-4-yn-1-yl 4-acetoxybenzoate (427 mg, 1.50 mmol, 48%) as a colourless oil. 2-(prop-2-yn-1-yl)pent-4-yn-1-yl 4-acetoxybenzoate (423.3 mg, 1.49 mmol) was dissolved in a 3:1 mixture of MeOH:H20 (16 mL) before NH4OAc (583.6 mg, 7.57 mmol) was added. The resultant mixture was stirred at rt for 76 h before EtOAc and H20 were added. The product was extracted (EtOAc), washed (H20, then brine), dried (Na2S04), filtered and concentrated under reduced pressure. Flash chromatography (0 - 100% EtOAc / petrol gradient elution) gave the title compound (295.1 mg, 1.22 mmol, 82%) as a white solid. ESI-MS: m/z 243 ([M+Hf). 1H NMR (400 MHz CDCI3): δ 7.95 (m, 2H), 6.86 (m, 2H), 4.38 (d, J = 6.1 Hz, 2H), 2.47 (dd, J = 6.2, 2.7 Hz, 4H), 2.28 (m, 1 H), 2.03 (t, J = 2.7 Hz, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With oxygen In water; <i>tert</i>-butyl alcohol at 120℃; for 0.533333h; Flow reactor; Green chemistry; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; dicyclohexyl-carbodiimide; In dichloromethane; | A solution of 4-acetoxybenzoic acid (524.8 g, 2.91 mol), propyl 4-hydroxybenzoate (500 g, 2.78 mol), N, N-dimethylaminopyridine (DMAP) (20.34 g, 0.17 mmol) in dichloromethane (2.51 ml) was added dropwise a solution of N, N-dicyclohexylcarbodiimide (DCC) (601.3 g, 2.91 mol) in dichloromethane (601.3 g). After completion of the dropwise addition, the mixture was stirred overnight, the precipitate was filtered, and the solvent was distilled off. Methanol (3.4 L) was added to and dissolved in the resulting oil, and then a solution of potassium carbonate (446.1 g, 3.23 mol) in water (1.7 L) was slowly added dropwise under cooling. The reaction mixture was stirred for 1 hour, then neutralized with 35% hydrochloric acid (325 mL), the precipitated crystals were filtered and the crude product was dried to give 4-propoxycarbonylphenyl 4-hydroxybenzoate in two steps 72 .9% (602.17 g, 2.00 mol). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42.9 g | 42.9 g of 4-acetoxybenzoic acid and 0.2 g of pyridine were added to 430 mL of toluene and stirring was performed under a nitrogen atmosphere at 60 C. 34.0 g of thionyl chloride was added dropwise thereto. After dropwise addition, stirring was performed at 60 C. for 4 hours. Toluene was distilled off under a reduced pressure. The obtained residue was added to 230 mL of toluene and stirred while cooling under a nitrogen atmosphere. A 200 mL toluene solution in which 20.0 g of methyl 2,5-dihydroxybenzoate and 33.7 g of triethylamine were dissolved was added dropwise thereto. After dropwise addition, stirring was performed for 4 hours at room temperature. Water was added to the stirred solution and an organic layer was extracted. Next, the organic layer was washed with water and dried with anhydrous magnesium sulfate. Toluene was distilled off under a reduced pressure, and the residue was purified through column chromatography and recrystallization was performed with a mixture (v/v=1/4) of ethyl acetate and heptane to obtain 42.9 g of a compound (ex-1). Here, the packing of the chromatography column was silica gel. Here, the eluent was a mixture (v/v=9/1) of toluene and ethyl acetate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: hydrogenchloride / AlCl3 / (2S)-N-methyl-1-phenylpropan-2-amine hydrate; 1,2,4-Trichlorobenzene 2: hydrogenchloride / water; acetone; acetonitrile |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; | 4.1.6. Procedure for the synthesis of compounds 13a-13t General procedure: The mixture of 6c (1 equiv, 0.83 mmol), various acids (1 equiv,0.83 mmol), EDCI (1.2 equiv, 1.0 mmol), and DMAP (catalyticamount) were stirred in DCM (20 mL) at room temperature for2e18 h. 20 mL DCM was added after the completion of the reaction,the organic layer was washed with water (20 mL) and brine(20 mL), dried over Na2SO4, and concentrated to afford crudeproducts which were purified by flash chromatography (DCM/MeOH, 40:1) to provide 13a-13t as white solids (83e98%). |
Tags: 2345-34-8 synthesis path| 2345-34-8 SDS| 2345-34-8 COA| 2345-34-8 purity| 2345-34-8 application| 2345-34-8 NMR| 2345-34-8 COA| 2345-34-8 structure
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