| 92% |
With thionyl chloride for 1.5h; Reflux; |
1 4-amino-N-(4-methoxyphenyl)benzamide (IV-1)
4-Aminobenzoic acid (1) (6.9 g, 50.3 mmol) was dissolved in thionyl chloride (30 mL).The mixture was heated to reflux for 1.5 hours, and excess thionyl chloride was evaporated under reduced pressure to give 4-aminobenzoic acid chloride (7.2 g).Yield 92.0% as a yellow oil. |
| 91.5% |
With thionyl chloride Heating; |
4.1.1 General procedure A for the synthesis of compound I-1∼I-9
A mixture of 4-aminobenzoic acid 1 (6.86g, 50.02mmol) and sulfurous dichloride (36.31mL, 50.02mmol) was heated to 70°C for 1.5h, solvent was removed under reduced pressure gave 2 as yellow oil (7.12g, 91.5% yield). To a solution of the intermediate 2 (5.00g, 32.14mmol) in anhydrous dichloromethane (20mL) was added a suspension of 3a-3i (32.14mmol) in anhydrous dichloromethane (20mL) and triethylamine (5.34mL, 38.57mmol) at 0°C, the reaction mixture was stirred at ambient temperature overnight. After completion of the reaction, the mixture was extracted with dichloromethane twice, the combined organic phases were washed with water and aqueous sodium chloride respectively, dried over anhydrous Na2SO4 and purified by silica gel column chromatography (PE: EA=5:1) to give 4a-4i. 4a, Light grey solid, 85.8% yield. m.p.: 106-108°C. 1H NMR (300MHz, DMSO-d6) δ (ppm): 10.47 (1H, s, CONH), 8.99 (1H, d, J=3.0Hz, ArH), 8.75 (1H, d, J=6.9Hz, ArH), 8.46 (1H, d, J=7.8Hz, ArH), 8.04 (1H, s, ArH), 7.83-7.59 (4H, m, ArH), 6.72 (2H, d, J=8.4Hz, ArH). |
| 91.5% |
With thionyl chloride Heating; |
4.1.1 General procedure A for the synthesis of compound I-1∼I-9
A mixture of 4-aminobenzoic acid 1 (6.86g, 50.02mmol) and sulfurous dichloride (36.31mL, 50.02mmol) was heated to 70°C for 1.5h, solvent was removed under reduced pressure gave 2 as yellow oil (7.12g, 91.5% yield). To a solution of the intermediate 2 (5.00g, 32.14mmol) in anhydrous dichloromethane (20mL) was added a suspension of 3a-3i (32.14mmol) in anhydrous dichloromethane (20mL) and triethylamine (5.34mL, 38.57mmol) at 0°C, the reaction mixture was stirred at ambient temperature overnight. After completion of the reaction, the mixture was extracted with dichloromethane twice, the combined organic phases were washed with water and aqueous sodium chloride respectively, dried over anhydrous Na2SO4 and purified by silica gel column chromatography (PE: EA=5:1) to give 4a-4i. 4a, Light grey solid, 85.8% yield. m.p.: 106-108°C. 1H NMR (300MHz, DMSO-d6) δ (ppm): 10.47 (1H, s, CONH), 8.99 (1H, d, J=3.0Hz, ArH), 8.75 (1H, d, J=6.9Hz, ArH), 8.46 (1H, d, J=7.8Hz, ArH), 8.04 (1H, s, ArH), 7.83-7.59 (4H, m, ArH), 6.72 (2H, d, J=8.4Hz, ArH). |
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With thionyl chloride for 4h; Heating; |
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With oxalyl dichloride; N,N-dimethyl-formamide In benzene Ambient temperature; |
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With phosphorus(V) chloride Ambient temperature; |
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With thionyl chloride |
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With thionyl chloride In dichloromethane; N,N-dimethyl-formamide at 20℃; for 20h; |
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With thionyl chloride for 2h; Reflux; |
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With thionyl chloride |
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Stage #1: 4-amino-benzoic acid With oxalyl dichloride In dichloromethane at 0 - 20℃;
Stage #2: With pyridine In dichloromethane at 0℃; for 0.833333h; |
163.A
Step A: Preparation of 4-amino-N-(2,6-dimethyl-phenyl)-benzamide. Oxalyl chloride (1.9 mL, 22 mmol) was added dropwise to a solution of DMF (1.7 mL, 22 mmol) and DCM (22 mL) that was kept at 0° C. The resulting foamy white suspension was stirred for 30 min and allowed to warm to room temperature, then cooled again to 0° C. 4-Aminobenzoic acid (1.50 g, 10.9 mmol) was added and the reaction mixture was stirred at room temperature for 1 h. The flask was again cooled to 0° C. and DCM (11 mL) and pyridine (2.6 mL, 33 mmol) were added. Stirring was continued for 50 min and 2,6-dimethyl-phenylamine (1.33 g, 10.9 mmol) was then added. The reaction mixture was stirred at room temperature for 1.5 h and concentrated to dryness. The residue was dissolved in ethanol (30 mL) and 1,2-ethylenediamine (3.3 mL, 49 mmol) was added. The reaction mixture was heated at reflux for 2 h, allowed to cool to room temperature, stirred for 2 d, and concentrated. Water (50 mL) was added to the residue and the precipitate was collected, rinsed well with water, and dried to yield the titled compound (1.904 g, 70% yield). MS (ESI/Cl): mass calcd. for C15H16N2O, 240.1; m/z found, 241.1 [M+H]+. 1H NMR (400 MHz, CD3OD): 7.76 (d, J=8.8 Hz, 2H), 7.10 (s, 3H), 6.72 (d, J=8.8 Hz, 2H), 2.24 (s, 6H). |
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With thionyl chloride for 0.5h; Reflux; |
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With thionyl chloride at 90℃; |
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With pyridine; thionyl chloride at 20 - 70℃; Inert atmosphere; |
General procedure: Firstly, benzoyl chloride intermediates 1b, 2b, 3b, 4b, 5b and 6b were synthesized by reacting respective benzoic acids (1a-5a, Scheme 1) or picolinic acid (6a, Scheme 1) with thionyl chloride. In general, 1 g of benzoic acid compounds 1a, 2a, 3a, 4a, 5a or picolinic acid (6a) was added to thionyl chloride (12 mL) and then stirred with addition of 50 µL pyridine as a catalyst. The resulting mixture was refluxed until no gas overflowed. Then the excess thionyl chloride was removed off in vacuo, and the residue was directly used for the next step synthesis. |
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With thionyl chloride for 2h; Reflux; |
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With thionyl chloride In chloroform for 8h; Reflux; |
General procedure for the synthesis of amides (1a-n)
General procedure: To a solution of an appropriate substituted carboxylic acid (10 mmol) in CHCl3 (50 mL) was added thionyl chloride (3.6 mL, 50 mmol), dropwise over 10 min. The resulting solution was refluxed for 8 h and then concentrated in vacuo. The residual light brown oil was dissolved in THF (50 mL), diluted with a solution of 30% NH4OH (6 mL), and stirred at room temperature for an additional 2 h. At that point, saturated aqueous NaHCO3 (10 mL) was added and the reaction mixture was extracted with EtOAc (3 × 30 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The crude amide was carried directly to the next step without further purification. |
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With thionyl chloride In dichloromethane at 20℃; for 2h; |
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With thionyl chloride at 25℃; for 2h; Reflux; Inert atmosphere; |
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With thionyl chloride at 80℃; for 4h; |
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With thionyl chloride for 2h; Reflux; Inert atmosphere; |
b General Procedure b (t-butyl protection of salicylic acid).
4- aminobenzoic acid was suspended in SOCI2 (2.0 eq.) at 25 °C. The suspension was refluxed for 2h. SOCI2 was removed under reduced pressure, the last traces by azeotrope with CHCI3 (x3). The resulting acid chloride was dissolved in CH2CI2 and a solution of i-butanol in CH2CI2 was added to the stirred solution which was cooled to 0 °C. A solid white precipitate was formed - the hydrochloride salt was quenched with 1.0M KOH and extracted with EtOAC (x4).; Tert-butyl 4-aminobenzoate (1a). Derivative 1a synthesized according to general procedure b on (83%): 1 H NMR (400 MHz, DMSO-cfe) δ 1.06 - 1 .19 (m, 7H), 1.39 (s, 1 H). 1.46 (s, 16H), 1.52 (d, J = 3.6 Hz, 3H), 1.88 (s, 1 H), 1.96 (s, 6H), 4.00 (q, J = 7.1 Hz, 4H), 5.82 (d, J = 15.3 Hz, 4H), 6.47 - 6.55 (m, 4H), 7.50 - 7.59 (m, 4H), 7.79 - 7.98 (m, 2H). 13C NMR (101 MHz, DMSO-d6) δ 28.16, 28.30 , 79.14 , 1 12.80 , 1 17.95 , 119.36 , 1 19.66 , 129.89 , 131.18 , 153.37 , 165.58 . LRMS (ESI+) calculated for CiiHi6N02 [M + H]+ 194.1 1 , found 194.15. |
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With thionyl chloride at 80℃; Inert atmosphere; |
6.1.1. Preparation of acid chlorides
General procedure: Using a typical scale of 2.0 mmol, the appropriate aryl carboxylicacid (2.0 mmol) was added to a small round-bottomed flask, which was flushed with N2(g). SOCl2 (3 mL, 41.4 mmol) was added afterwhich the reaction mixture was refluxed, with stirring, at 80 °C andleft overnight to ensure complete conversion. The reaction mixturewas cooled and excess SOCl2 was completely removed underreduced pressure. The crude acid chloride was then used as a reagentfor subsequent reactions. |
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With thionyl chloride at 50 - 60℃; |
8 Example 8.
p-Aminobenzoic acid (700 g, 1.0 eq.) and thionyl chloride (4 L, 13 eq.) were charged into a 20 L reactor and stirred overnight at 50-60 °C, then concentrated under vacuum at 50 °C to provide the crude acid chloride which was used without further purification. Pyrrolidine (1300 g, 5 eq.) and dichloromethane (3.5 L, 5V) were charged into a 20 L reactor and the mixture was cooled to 0 °C. The acid chloride in dichloromethane (3.5 L, 5 V) was added dropwise to the reactor at 0-5 °C. Once the reaction was determined to be complete by HPLC, water (7 L) was added, and the mixture was filtered. The filter cake was washed with dichloromethane (1.4 L) and water (2.8 L). The aqueous phase was separated and extracted with dichloromethane (7 L), and the organic layers were combined, then washed with brine (3.5 L) and dried over anhydrous sodium sulfate, then concentrated under vacuum at 50 °C to give the crude product. The crude was stirred overnight in n-heptane:dichloromethane (5: 1, 3.5 L) overnight at room temperature, then the solids collected by filtration. The filter cake was washed with dichloromethane (1.4 L) and water (2.8 L) and both filter cakes were combined, then stirred with dichloromethane (2.8 L) overnight at 35-40 °C, then cooled to 15 °C and stirred for 4 hours. The solids were collected by filtration and dried under vacuum at 50 °C to constant weight to provide the desired product (660 g, 99% purity). Deuterated analogs (i.e. those where Y and or Z is D) were prepared by the same procedure using the corresponding deuterated pyrrolidine. |
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With thionyl chloride; N,N-dimethyl-formamide In neat liquid for 1h; Reflux; |
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With pyridine; thionyl chloride at 20℃; for 3h; |
1 Example 1
chloride was added to a pyridine solution of 4-aminobenzoic acid (2.74 g, 0.02 mol). After thionyl chloride was added, the content of the flask was stirred at room temperature for three hours to obtain 4-aminobenzoyl chloride. To the obtained 4-aminobenzoyl chloride, 9,9′-bis(4-aminophenyl)fluorene (3.48 g, 0.01 mol) dissolved in N-methyl-2-pyrrolidone (NMP) was added, and the obtained product was stirred for five hours. The obtained reaction solution was poured little by little into ice water at 0 to 5° C., stirred at a constant speed, followed by solid-liquid separation. In order to remove unreacted 4-aminobenzoic acid, the separated wet product was washed with a sodium hydrogen carbonate aqueous solution having a concentration of 10% by mass four times. Then, the wet product was washed with anhydrous methanol, and then dried at 80° C. to obtain 9,9′-bis(4-(4-aminobenzoylamino)phenyl)fluorene at the yield of 58%. |
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With thionyl chloride at 75℃; for 2h; |
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