| 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 |
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With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 2h; |
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| 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. |
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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. |
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With thionyl chloride In N,N-dimethyl-formamide for 4h; Reflux; |
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With thionyl chloride In dichloromethane Reflux; |
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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. |
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With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 3h; Inert atmosphere; Reflux; |
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With thionyl chloride at 80℃; for 1h; |
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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°. |
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With phosphorus pentachloride |
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With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 0 - 20℃; for 1h; Inert atmosphere; |
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With phosgene |
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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. |
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With thionyl chloride; N,N-dimethyl-formamide In chloroform at 30 - 40℃; for 48h; |
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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]+. |
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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 |
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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. |
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With thionyl chloride for 3h; Reflux; |
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With oxalyl dichloride |
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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. |
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With thionyl chloride; N,N-dimethyl-formamide at 85℃; for 3h; |
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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. |
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