| 96% |
With sulfuric acid at 0℃; for 1h; Reflux; |
1.B
Step B: will be 3 - aminobenzoic acid (1 a) (1.097 g, 8 mmol) dissolved in 10 ml in methanol, in the 0 °C lower concentrated sulfuric (0 . 098 g, 1 mmol), heated to reflux reaction for 1 hour. After the reaction under reduced pressure to remove the methanol, oil pump pumping the oil of from methyl 3-aminobenzoate (4 a), yield 96%. |
| 95% |
With sulfuric acid Reflux; |
|
| 95% |
With thionyl chloride at 0 - 20℃; |
|
| 94% |
Acidic conditions; Reflux; |
|
| 93% |
With thionyl chloride at 0℃; Reflux; |
60.1 Methyl 3-aminobenzoate
Thionyl chloride (43 g, 361.34 mmol, 5.00 equiv) was added dropwise with stirring at 0° C. to a solution of 3-aminobenzoic acid (10 g, 72.92 mmol, 1.00 equiv) in methanol (100 mL) and allowed to react, with stifling, overnight under reflux. The resulting mixture was concentrated under vacuum and quenched by the addition of 50 mL of water/ice. The resulting solids were collected via vacuum filtration and dried in an oven under reduced pressure, affording 10.3 g (93%) of methyl 3-aminobenzoate as a white solid. |
| 93.8% |
With thionyl chloride at 0 - 40℃; |
1.2 Step 2:
Step 2: To a solution of compound 2 (50 g, 0.365 mol) in methanol (1 L) thionyl chloride (66 mL, 0.91 mol) was added at 0° C. under stirring. Then the reaction mixture was stirred at 40° C. overnight. The reaction was monitored via TLC (petroleum ether/ethyl acetate (PE/EA)=1:1). After the reaction was completed, the mixture was evaporated, and the residue was adjusted to pH 8 by adding Na2CO3 and extracted with ethyl acetate (EA). The organic phase was washed with saturated brine, dried with anhydrous sodium sulfate and concentrated to obtain compound 3 (51.7 g, yield: 93.8%) as a brown solid, which was used directly in the next step without a further purification. |
| 93.8% |
With thionyl chloride at 0 - 40℃; |
1.2; 5.2
To a solution of compound 2 (50 g, 0.365 mol) in methanol (1 L) thionyl chloride (66 mL, 0.91 mol) was added at 0° C. under stirring. Then the reaction mixture was stirred at 40° C. overnight. The reaction was monitored via TLC (petroleum ether/ethyl acetate (PE/EA)=1:1). After the reaction was completed, the mixture was evaporated, and the residue was adjusted to pH 8 by adding Na2CO3 and extracted with ethyl acetate (EA). The organic phase was washed with saturated brine, dried with anhydrous sodium sulfate and concentrated to obtain compound 3 (51.7 g, yield: 93.8%) as a brown solid, which was used directly in the next step without a further purification. |
| 91% |
Stage #1: methanol; meta-aminobenzoic acid With thionyl chloride at 30 - 50℃; Inert atmosphere;
Stage #2: With sodium hydrogencarbonate In water for 0.75h; |
4.2.2 Synthesis of 3-aminobenzoic acid esters (5a-c) and 4-aminobenzoic acid esters (6a-c)
General procedure: Acid 2 or 3 (1.5 g, 10.94 mmol) was dissolved in the corresponding alcohol (150 mL) at temperature about 50 °C. Then the solution was cooled to rt and thionyl chloride (15 mL, 206.77 mmol) was added. The reaction mixture was heated at 30 °C (MeOH), 50 °C (EtOH), or 65 °C (BuOH). The reaction course was monitored by TLC (toluene/EtOAc/formic acid 25:25:1). When the starting acid was consumed (4-10 h), water (20 mL) was added. The reaction mixture was stirred for 30 min and concentrated. The resulting residue was stirred with satd NaHCO3 (30 mL) for 45 min and extracted with EtOAc (3 × 30 mL). The organic extracts were pooled, dried (Na2SO4), and concentrated to obtain esters 5a,43 5b,32,44 5c,32 6a,45 6b,32,46,47 and 6c32 as an oil. All esters were used in the next step without purification. Analytical data (HRMS) and yields are in Table 1 (Supplementary data). 1H and 13C NMR data for 5f and 6f are in Table 2 (Supplementary data). |
| 90% |
With thionyl chloride at 0℃; for 16h; |
3
Example 3. Synthesis of methyl 3-aminobenzoate. Thionyl chloride (0.37 mL, 3.27 mmol) was slowly added to a solution of 3-aminobenzoic acid (0.3 g, 2.18 mmol) in dry MeOH (3.26 mL) at 0°C. The reaction was stirred for 16 hours and then hydrolyzed with a saturated aqueous solution of NaHCO3. The crude product was extracted with CH2Cl2, dried on Na2SO4 and concentrated under reduced pressure. The product was used in the following phases without purification (yield: 90%). |
| 90% |
With thionyl chloride Cooling with ice; |
22 2.2.22 Methyl-3-aminobenzoate (35)
3-Aminobenzoic acid (5.48g, 40mmol) was dissolved in 60mL methanol and 4.36mL thionyl chloride (60mmol) were added dropwise with stirring and cooling on ice. When the reaction had stopped, the methanol was evaporated and the remaining residue was neutralized with saturated NaHCO3 solution and extensively extracted with ethyl acetate. After evaporation of the ethyl acetate, a reddish oil remained which was distilled under vacuum over a 20cm Vigreux column. The pure product passed over at 118°C (0.3Torr) and crystalized by cooling to give 5.46g of a white powder (yield 90%). mp: 31-32°C; H NMR (500MHz, CDCl3) δ 3.82 (br s, 2H, NH); 3.87 (s, 3H, 1’-H); 6.84 (d, 1H, 3J=8.4Hz, 4-H); 7.19 (m, 1H, 5-H); 7.34 (s, 1H, 2-H); 7.40 (d, 1H, 3J=7.5Hz, 6-H); C NMR (100MHz, CDCl3) δ 51.9 (C1’); 115.6 (C2); 119.3 (C4); 119.5 (C6); 129.1 (C5); 131.0 (C1); 146.5 (C3); 167.2 (C7); EI-MS (70eV): m/z (rel. int.)=151 [M+] (100), 120 (72), 92 (45), 65 (13). |
| 89% |
With sulfuric acid at 0℃; for 18h; Reflux; |
Methyl 3-aminobenzoate3 (14):
Sulfuric acid (98%, 5.5 mL) was added slowly to a solution of 3-aminobenzoic acid (6.17 g, 45.0 mmol) in methanol (110 mL) at 0 C. The solution was subsequently heated to reflux for 18 h, then cooled to r.t. and concentrated under reduced pressure. Water (80 mL) and NaOH (1 M) was added until pH6 was reached. This solution was extracted with EtOAc (3 100 mL), and the combined organic extracts were washed with NaHCO3 (50 mL), dried (MgSO4), filtered, and the filtrate concentrated under reduced pressure. The resulting residue was purified by flash chromatography (40-60% EtOAc in hexane) affording the title compound as a yellow oil (6.05 g, 89%); |
| 88% |
With acetyl chloride for 1h; Heating; |
|
| 85% |
With sulfuric acid Reflux; |
Methyl 3-amino-4-(2-(4-(benzyloxy)phenyl)acetamido)benzoate (43)
General procedure: Step 1: To a solution of 4-hydroxyphenylacetic acid (400 mg, 2.628 mmol) in MeOH (3 mL), H2SO4 (500 µL) was added and refluxed for 2 h. The excess of MeOH was evaporated and diluted with water. The pH was neutralized with NaHCO3. Then it was extracted with ethyl acetate. The combined organic layer was combined, dried and evaporated to give methyl 2-(4-hydroxyphenyl)acetate (320 mg, 73% yield). CAS 14199-15-6. Step 2: To a solution of methyl 2-(4-hydroxyphenyl)acetate (346 mg, 2.084 mmol, 1 eq) in DMF (3 mL), K2CO3 (622.24 mg, 4.502 mmol, 2.16 eq) was added at 0°C and the resulting mixture was stirred for 30 min. Then benzyl bromide (248.78 µL, 2.084 mmol, 1 eq) was added onto that and stirred for 20 min. The reaction was taken into room temperature and stirred for 3 h. After completion, it was quenched with distilled water, the precipitated product was filtered to give methyl 2-(4-(benzyloxy)phenyl)acetate (508 mg, 95% yield). CAS 68641-16-7. Step 3: To a solution of methyl 2-(4-(benzyloxy)phenyl) acetate (429 mg, 1.662 mmol, 1 eq) in THF: H2O (5: 5 mL), LiOH.H2O (174.4 mg, 4.155 mmol, 2.5 eq) was added. The resulting mixture was refluxed for 4 h. The excess of solvent was evaporated and diluted with water. The pH was acidified with conc. HCl and then the precipitated product was filtered to give 2-(4-(benzyloxy)phenyl)acetic acid (90% yield). CAS 6547-53-1. Step 4: To a solution of methyl 3,4-diaminobenzoate (1.2 eq) in DCM (6 mL), DMAP (0.2 eq) was added and stirred for 10 min at room temperature under inert atmosphere. After 2-(4-(benzyloxy) phenyl)acetic acid (1 eq) was added and stirred for another 10 min, EDC.HCl (1.2 eq) was added and left to stir overnight at room temperature under inert atmosphere. After complication, it was partition between DCM and water. The combined organic phase was dried, filtered and evaporated to give the crude which was washed with hexane/EtOAc, filtered. It was used in the next step. |
| 85% |
With sulfuric acid Reflux; |
Methyl 3-amino-4-(2-(4-(benzyloxy)phenyl)acetamido)benzoate (43)
General procedure: Step 1: To a solution of 4-hydroxyphenylacetic acid (400 mg, 2.628 mmol) in MeOH (3 mL), H2SO4 (500 µL) was added and refluxed for 2 h. The excess of MeOH was evaporated and diluted with water. The pH was neutralized with NaHCO3. Then it was extracted with ethyl acetate. The combined organic layer was combined, dried and evaporated to give methyl 2-(4-hydroxyphenyl)acetate (320 mg, 73% yield). CAS 14199-15-6. Step 2: To a solution of methyl 2-(4-hydroxyphenyl)acetate (346 mg, 2.084 mmol, 1 eq) in DMF (3 mL), K2CO3 (622.24 mg, 4.502 mmol, 2.16 eq) was added at 0°C and the resulting mixture was stirred for 30 min. Then benzyl bromide (248.78 µL, 2.084 mmol, 1 eq) was added onto that and stirred for 20 min. The reaction was taken into room temperature and stirred for 3 h. After completion, it was quenched with distilled water, the precipitated product was filtered to give methyl 2-(4-(benzyloxy)phenyl)acetate (508 mg, 95% yield). CAS 68641-16-7. Step 3: To a solution of methyl 2-(4-(benzyloxy)phenyl) acetate (429 mg, 1.662 mmol, 1 eq) in THF: H2O (5: 5 mL), LiOH.H2O (174.4 mg, 4.155 mmol, 2.5 eq) was added. The resulting mixture was refluxed for 4 h. The excess of solvent was evaporated and diluted with water. The pH was acidified with conc. HCl and then the precipitated product was filtered to give 2-(4-(benzyloxy)phenyl)acetic acid (90% yield). CAS 6547-53-1. Step 4: To a solution of methyl 3,4-diaminobenzoate (1.2 eq) in DCM (6 mL), DMAP (0.2 eq) was added and stirred for 10 min at room temperature under inert atmosphere. After 2-(4-(benzyloxy) phenyl)acetic acid (1 eq) was added and stirred for another 10 min, EDC.HCl (1.2 eq) was added and left to stir overnight at room temperature under inert atmosphere. After complication, it was partition between DCM and water. The combined organic phase was dried, filtered and evaporated to give the crude which was washed with hexane/EtOAc, filtered. It was used in the next step. |
| 82% |
With sulfuric acid for 8h; Reflux; |
|
| 80% |
With thionyl chloride for 10h; Ambient temperature; |
|
| 79% |
With thionyl chloride |
|
| 78% |
With hydrogenchloride for 3h; Heating; |
|
| 78% |
With thionyl chloride at 0℃; for 3h; Reflux; |
|
| 40% |
With thionyl chloride at 20℃; for 3h; |
|
| 33% |
In water Reflux; |
57.1
Step 1 Synthesis of 3-Amino-benzoic acid methyl ester Concentrated H2SO4 (3 mL) was added to solution of 3-Amino-benzoic acid (7.5 g, 54.74 mmol) in MeOH (200 mL) and refluxed overnight. The reaction mixture was concentrated under reduced pressure to afford the residue. The residue was diluted with water, basified, extracted with ethyl acetate, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to afford 2.7 g (33%) of 3-Amino-benzoic acid methyl ester. LCMS Purity: 98.9%. |
|
With hydrogenchloride |
|
|
With sulfuric acid for 5h; Heating; |
|
| 1.03 g |
With thionyl chloride at 20℃; for 0.25h; |
|
|
With thionyl chloride at 0 - 20℃; |
|
|
With sulfuric acid Heating; |
|
|
With sulfuric acid Reflux; |
|
|
With sulfuric acid |
|
|
With thionyl chloride |
|
|
With thionyl chloride at 0 - 90℃; for 4h; |
|
|
With sulfuric acid |
|
|
With sulfuric acid Reflux; |
|
|
With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; |
|
|
With thionyl chloride at 0℃; for 1h; Reflux; |
|
|
With sulfuric acid at 80℃; |
|
| 2.07 g |
With oxalyl dichloride at 20 - 70℃; for 24.5h; Cooling with ice; |
|
| 2.07 g |
With oxalyl dichloride at 70℃; for 24h; Reflux; |
General Procedure for the Synthesis of Methyl Benzoates Intermediates (5a, b)
3-Aminobenzoic acid (1, 2.0 g, 14.58 mmol) was dissolved in methanol (20 mL) and cooled down in the ice bath. The solution was treated with oxalyl chloride (2, 2.5 mL, 29mmol) stirred at room temperature for 20-30 minutes, and refluxed for 24 hours at 60-70°C. The reaction mixture was then evaporated and neutralized by 3M potassium carbonate. Extraction by chloroform (4 x 20 mL) was carried out four times . The organic layer was dried with sodium sulfate anhydrous followed by evaporation to get 2.07 g of pure 3-aminobenzoic acid methyl ester (3). Afterward, 3-aminobenzoic acid methyl ester (3, 2.0 g, 13.2 mmol) was dissolved in (20 mL) dichloromethane. |
|
With thionyl chloride at 0 - 65℃; for 15h; Inert atmosphere; |
11 Example 11. Preparation of (R)-3-(acetamido-2,2,2-d3)-N-(7-amino-l-(2,6-difluoro- phenoxy)-2-oxoheptan-3-yI)beiizamide (10)
[0254] To a solution of compound 10.7 (10.00 g, 72.92 mmol, 1.00 eq) in MeOH (100.00 mL) was added SOCl2 (17.35 g, 145.84 mmol, 10.58 mL, 2.00 eq) in one portion at 0°C under N2. The mixture was stirred at 65°C for 15 hours. The reaction mixture was poured into H2O (20mL), and the aqueous phase was extracted with EtOAc (3 x lOmL). The combined organic phase was washed with brine (5 mL), dried with anliydrous Na2SC>4, filtered, and concentrated under vacuum to afford compound 10.6 (13.10 g, crude) as a white solid. (0675) LCMS (ESI): m/z: [M + H] calcd for C8H9N02: 152.1 ; found 152.2; RT=1.191 min. NMR (400 MHz, methanol- |
|
With sulfuric acid for 8h; Reflux; |
4.2 General procedure for the synthesis of compounds 2a-2q
General procedure: The substituted benzoic acid 11q (1 eq.) in methanol was refluxed for 8h. The reactions were completed monitored by TLC (PE/EA=3:1). Then cooling to rt, the solution was adjusted to pH=7 with NaOH. The mixture was extracted with ethyl acetate and washed with brine to give the crude product. |
|
With thionyl chloride at 0 - 80℃; for 6h; |
12 Example 12 Synthesis of methyl 3-(3-(1,2,5-trimethyl-1H-indol-3-yl)propionamido)benzoate (Compound 13)
Take a 50mL single-necked flask, add 502.3mg (3.66mmol) of 3-aminobenzoic acid, 2.5mL thionyl chloride, and 3.5mL methanol at 0C, then transfer the entire reaction system to an oil bath at 80C. The reaction was refluxed in the environment for 6 hours, the reaction was stopped, and the solvent was removed. The residue was washed with a large amount of ethyl acetate, filtered, the filtrate was retained, and the solvent was removed. The residue was placed in a vacuum drying oven and dried overnight to obtain a yellow oily compound. Crude product of methyl 3-aminobenzoate. Take a 25mL single-mouth bottle and add compound 7 (1,2,5-trimethyl-1H-indol-3-yl)propionic acid 99.0mg (0.43mmol), HATU 162.6mg (0.42mmol) at room temperature, DIPEA 74.5μL (0.43mmol), and then 3mL DMF was added to react for 2h, after 2h, 64mg (0.42mmol) of methyl 3-aminobenzoate was added to react for 24h, after thin layer chromatography (V (petroleum ether): V (ethyl acetate) Ester) = 1:1) test, observe whether the reaction of compound 7 is complete, stop the reaction immediately after the complete reaction, extract with ethyl acetate and water, leave the organic layer treated with anhydrous MgSO4 for 2h to remove residual water, filter, and save the filtrate After removing the solvent, the crude product was first eluted with eluent (V (ethyl acetate): V (petroleum ether) = 1: 2), and then with (V (ethyl acetate) V: (methanol): V( Dichloromethane) = 1:1:40) elution, after elution, the solvent is removed, and the residue is placed in a vacuum drying oven for vacuum drying overnight to obtain a pale yellow solid, yield: 57.1%, melting point: 130-131. |
|
With oxalyl dichloride at 60 - 70℃; for 24h; Cooling with ice; |
2.2.1. Synthesis of methyl 3-aminobenzoate (3)
3-Aminobenzoic acid (4 g, 29.2 mmol) was dissolved in150 mL methanol (CH3OH) and placed in the ice water withgradual addition of the oxalyl chloride, (COCl)2, (5 mL 58.3mmol) and refluxing of the prepared solution for 24 hours.The solvent employed has been consequently evaporated,and the generated white product was neutralized to pH-7 via30 mL of 3M potassium carbonate (K2CO3) solution andthen extracted utilizing chloroform (CHCl3, 100 mL) anddistilled water (70 mL). Then, 6 g of anhydrous sodium sulfate(Na2SO4) was added to the organic filtrate. Finally, suctionfiltration was done to get rid of Na2SO4 and the solutionwas evaporated. |
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