* 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.
With magnesia In neat (no solvent) at 70℃; for 0.583333 h; Green chemistry
General procedure: In an oven dried round bottomed flask (50 mL) nano-MgO (5.0 molpercent) were added and then alky/aryl amines (5.0 mmol) and aromatic/aliphatic acid (5.0 mmol) was added. After that it was allowed to stir on a pre heated oil bath at 70 °C under aerobic condition till the required time (the progress of the reaction was judged by TLC). After the completion, the reaction mixture was brought to room temperature and ethyl acetate (3 × 10 mL) was added to it and then centrifuged at 3500 rpm to recover the nano catalyst. Having done this, the reaction mixture was washed with water and brine, dried over anhydrous Na2SO4, concentrated in a rotary evaporator and finally the crude product was charged to column chromatography (ethylacetate:hexane (3:7) as an eluent) for purification and wherever necessary the products were recrystallized from hot ethanol.
Reference：
[1] Synthetic Communications, 2008, vol. 38, # 7, p. 1028 - 1035
[2] Applied Catalysis A: General, 2013, vol. 456, p. 118 - 125
[3] Green Chemistry, 2012, vol. 14, # 3, p. 847 - 854
[4] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2010, vol. 49, # 9, p. 1274 - 1281
[5] Synthetic Communications, 2008, vol. 38, # 17, p. 2929 - 2940
2
[ 108-24-7 ]
[ 150-13-0 ]
[ 556-08-1 ]
Yield
Reaction Conditions
Operation in experiment
99%
Stage #1: at 20℃; for 5 h; Stage #2: With hydrogenchloride In water
General procedure: Ac2O (5.7 mL, 60.3 mmol) was added to the solution of 4-amino-benzoic acid (1) (6.86 g, 50.0 mmol) in pyridine (25 mL). The reaction was stirred at room temperature for 5 h. The solvent was removed in vacuo and the residue dispersed in water (100 mL) and acidified to pH 2-3 with concentrated hydrochloric acid. The resulting precipitate was collected by filtration, washed with water (30 mL) and dried to give 4-acetamido-benzoic acid (3) as a pale yellow powder (7.80 g, 99percent).
99%
at 20℃; for 5 h;
Step 1: Ac20 (5.7 ml, 60.3 mmol) was added to the solution of 4-amino-benzoic acid(6.86 g, 50.0 mmol) in pyridine (25 ml). The reaction was stirred at room temperature for 5 h. The solvent was removed in vacuo, and the residue was dispersed in water (100 ml) and acidified to pH 2-3 with concentrated hydrochloric acid. The resulting precipitate was collected by filtration, washed with water (30 ml) and dried to give 4-acetamido-benzoic acid as a pale yellow powder (7.80 g, 99percent).
96%
at 55℃; for 2.66667 h;
5mol of p-aminobenzoic acid was dissolved in 1.8L mass fraction of 85percent formic acid solution,Control the stirring speed 150rpm, adding 6.5mol of acetic anhydride,Raise the temperature of the solution to 55 ° C,Continue stirring 90min,Distillation under reduced pressure 60kPa 70min,The remaining solution was added 3L mass fraction of 20percent potassium chloride solution,Reduce the temperature of the solution to 15 ° C,Crystal precipitation,filter,With a mass fraction of 15percent sodium bromide solution was washed,The mass fraction of 95percent ether solution was recrystallized,Solid sodium hydroxide dehydration agent dehydration,The final productAcetamidobenzoic acid 859.20g, yield 96percent.
Reference：
[1] Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 18, p. 5352 - 5360
[2] Patent: WO2016/57779, 2016, A2, . Location in patent: Page/Page column 80
[3] Patent: CN106631858, 2017, A, . Location in patent: Paragraph 0006; 0010-0015
[4] Monatshefte fur Chemie, 2007, vol. 138, # 1, p. 95 - 99
[5] Journal of Organic Chemistry, 2012, vol. 77, # 21, p. 9553 - 9561
[6] Journal of Chemical Research, 2010, # 6, p. 354 - 357
[7] Mikrochemie, 1951, vol. 38, p. 358,365
[8] Organic Letters, 2005, vol. 7, # 22, p. 5087 - 5090
[9] Synthesis, 2006, # 19, p. 3316 - 3340
[10] Analytical Biochemistry, 2010, vol. 398, # 2, p. 150 - 160
[11] Journal of the American Society for Mass Spectrometry, 2011, vol. 22, # 9, p. 1515 - 1525
[12] Journal of Molecular Catalysis A: Chemical, 2012, vol. 357, p. 175 - 176
3
[ 60-35-5 ]
[ 150-13-0 ]
[ 556-08-1 ]
Yield
Reaction Conditions
Operation in experiment
71%
at 150℃; for 24 h;
General procedure: In a typical procedure, a mixture of amine (1 mmol), amide (1 mmol) and 50 mg GO was taken in a round-bottom flask (50 mL) and stirred the mixture using a magnetic stirring bar under open air at 150 °C for 24 h. After the reaction was completed, ethyl acetate (5 mL) was added to the reaction mixture and the catalyst was filtered off. The filtered catalyst was further washed with ethyl acetate and the combined organic layer was evaporated to afford nearly pure product. The residue was further purified by passing through a silica gel columnand eluting with ethyl acetate petroleum ether mixture. All products were characterized by spectral data as well as melting points (for solid compounds).
Reference：
[1] Journal of Organic Chemistry USSR (English Translation), 1980, vol. 16, p. 340 - 342[2] Zhurnal Organicheskoi Khimii, 1980, vol. 16, # 2, p. 381 - 384
[3] Journal of Organic Chemistry, 1989, vol. 54, # 15, p. 3744 - 3747
[4] Kinetics and Catalysis, 2010, vol. 51, # 4, p. 516 - 520
[5] Justus Liebigs Annalen der Chemie, 1921, vol. 423, p. 90,91
[6] Chemische Berichte, 1903, vol. 36, p. 1805
[7] Chemische Berichte, 1885, vol. 18, p. 2942
[8] Chemische Berichte, 1876, vol. 9, p. 1302
[9] Chemische Berichte, 1903, vol. 36, p. 1805
5
[ 122-85-0 ]
[ 556-08-1 ]
Reference：
[1] Journal of Organic Chemistry, 1986, vol. 51, # 4, p. 567 - 569
[2] ChemCatChem, 2018, vol. 10, # 6, p. 1253 - 1257
[3] Angewandte Chemie - International Edition, 2016, vol. 55, # 36, p. 10806 - 10810[4] Angew. Chem., 2016, vol. 128, p. 10964 - 10968,4
[5] Organometallics, 2017, vol. 36, # 21, p. 4095 - 4098
[6] Bulletin of the Chemical Society of Japan, 1995, vol. 68, # 8, p. 2319 - 2326
[7] Journal of Organic Chemistry, 1986, vol. 51, # 25, p. 4764 - 4767
[8] Journal of Chemical Research, Miniprint, 1988, # 1, p. 201 - 223
[9] Journal of Organic Chemistry, 1996, vol. 61, # 4, p. 1310 - 1314
[10] Journal of Chemical Research, Miniprint, 1999, # 8, p. 2052 - 2074
[11] International Journal of Chemical Kinetics, 2000, vol. 32, # 10, p. 615 - 622
[12] Journal of Physical Organic Chemistry, 2001, vol. 14, # 9, p. 650 - 656
[13] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2002, vol. 41, # 4, p. 832 - 838
[14] Journal of Organic Chemistry, 2000, vol. 65, # 11, p. 3322 - 3325
[15] Journal of the Indian Chemical Society, 2007, vol. 84, # 6, p. 582 - 587
[16] Journal of the Indian Chemical Society, 2008, vol. 85, # 12, p. 1281 - 1288
[17] Journal of the Indian Chemical Society, 2009, vol. 86, # 9, p. 927 - 935
[18] Asian Journal of Chemistry, 2011, vol. 23, # 3, p. 1173 - 1178
[19] Journal of the Indian Chemical Society, 2012, vol. 89, # 8, p. 1045 - 1052
Reference：
[1] Advanced Synthesis and Catalysis, 2015, vol. 357, # 9, p. 2022 - 2026
8
[ 108-24-7 ]
[ 150-13-0 ]
[ 64-19-7 ]
[ 556-08-1 ]
Yield
Reaction Conditions
Operation in experiment
90%
for 0.25 h; Reflux
4-aminobenzoic acid (10) (4 g, 29 mmol) was added to a mixture (1:1)of acetic acid and acetic anhydride (20 mL), stirred, and the reaction mixture was refluxed for 15 min.After the completion of the reaction, the mixture was poured into ice-cooled water and a solid residue was obtained after filtration. The crude was washed three times with 100 mL H2O to remove excessacid. The crude was recrystallized in MeOH, yielding (24) (90percent). IR (KBr): 3340 (NH); 2539 (CH); 1700and 1607 (C=O), cm1. 1H-NMR (400 MHz, DMSO-d6) δ ppm: 2.08 (s, 3H, CH3); 7.68 (d, 2H, C6H4);7.87 (d, 2H, C6H4); 10.24 (s, 1H, NH); 12.68 (s, 1H, COOH). Calculated analysis for C9H9NO3: C, 60.33;H, 5.06; N, 7.82. Found: C, 59.80; H, 4.90; N, 7.52.
Reference：
[1] Molecules, 2017, vol. 22, # 11,
9
[ 201230-82-2 ]
[ 556-08-1 ]
Reference：
[1] Advanced Synthesis and Catalysis, 2018, vol. 360, # 17, p. 3401 - 3405
10
[ 532-32-1 ]
[ 141-78-6 ]
[ 556-08-1 ]
Yield
Reaction Conditions
Operation in experiment
48%
at 75 - 135℃; for 26 h;
p-acetamidobenzoic acid Starting Materials Ethyl Acetate 0.75 mol Sodium p-aminobenzoate 0.25 mol Sodium methoxide (catalyst) 0.25 mol Ethylene Glycol 150 g. Operating Conditions Pressure Atmospheric Temperature/time regime 75° C./8 h.; then 90° C./2 h.; then 110° C./9 h.; then 120-125° C./2.5 h.; then 135° C./4.5 h. Reaction Progress Monitored by TLC Work-up The reaction mass was allowed to cool to 40° C., transferred to a beaker, diluted with water to a total volume of 500 mL, pH adjusted to 2-3 by addition of 51.3 g. concentrated hydrochloric acid, cooled to 10° C., stirred during 30 min at that temperature and filtered. The filter cake was later drained, washed with 100 mL cold water, drained thoroughly and dried at 60-68° C. to constant weight. 21.5 g. of crys- tals (m.p. 258-259° C. (dec.))were obtained (literature 252° C.) Yield 48percent
EXAMPLE 4 STR8 4-Acetylaminobenzoic acid. A mixture of 4-aminobenzoic acid (Aldrich, 50.0 g, 0.365 mol) and anhydrous sodium acetate (35.0 g, 0.427 mol) in glacial acetic acid (150 mL) was heated to reflux for 15 h. The mixture was poured into cold water (1 L). The precipitate was separated by filtration and washed several times with cold water. The cake was dried in oven at 70° C. and recrystallized from 2:1 water:ethanol to give 43.0 g (68percent) of the title compound as off-white flakes, mp 258° C. Analysis: Calculated for C9 H9 NO3: C, 60.32; H, 5.06; N, 7.82 Found: C, 60.51; H, 5.14; N, 7.81
Reference：
[1] Patent: US5602277, 1997, A,
12
[ 119072-55-8 ]
[ 101251-09-6 ]
[ 556-08-1 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2017, vol. 15, # 38, p. 8078 - 8083
13
[ 150-13-0 ]
[ 75-36-5 ]
[ 556-08-1 ]
Reference：
[1] European Journal of Medicinal Chemistry, 1995, vol. 30, # 7-8, p. 561 - 568
[2] Journal of the Indian Chemical Society, 2012, vol. 89, # 2, p. 261 - 268
[3] Journal of the American Chemical Society, 1956, vol. 78, p. 2870
[4] Journal of Organic Chemistry, 2013, vol. 78, # 23, p. 11765 - 11771
14
[ 10602-00-3 ]
[ 556-08-1 ]
Reference：
[1] Advanced Synthesis and Catalysis, 2017, vol. 359, # 22, p. 3968 - 3976
[2] Angewandte Chemie - International Edition, 2013, vol. 52, # 30, p. 7850 - 7854[3] Angew. Chem., 2013, vol. 125, # 30, p. 8004 - 8008
15
[ 150-13-0 ]
[ 507-09-5 ]
[ 556-08-1 ]
Reference：
[1] Journal of Organic Chemistry, 2013, vol. 78, # 11, p. 5550 - 5555
16
[ 15456-83-4 ]
[ 150-13-0 ]
[ 556-08-1 ]
Reference：
[1] Journal of Chemical Research - Part S, 2003, # 3, p. 121 - 123
17
[ 557-34-6 ]
[ 150-13-0 ]
[ 556-08-1 ]
Reference：
[1] Journal of Chemical Research, 2010, # 5, p. 288 - 295
18
[ 64-19-7 ]
[ 62-23-7 ]
[ 556-08-1 ]
Reference：
[1] Chemistry - A European Journal, 2011, vol. 17, # 9, p. 2763 - 2768
19
[ 150-13-0 ]
[ 830-03-5 ]
[ 14609-74-6 ]
[ 556-08-1 ]
Reference：
[1] Journal of the American Chemical Society, 1993, vol. 115, # 20, p. 8980 - 8984
20
[ 150-13-0 ]
[ 72-89-9 ]
[ 556-08-1 ]
Reference：
[1] Food and Chemical Toxicology, 1998, vol. 36, # 9-10, p. 761 - 770
[2] Food and Chemical Toxicology, 1999, vol. 37, # 6, p. 655 - 661
[3] Drug Metabolism and Disposition, 2014, vol. 42, # 3, p. 377 - 383
21
[ 13483-16-4 ]
[ 150-13-0 ]
[ 556-08-1 ]
Reference：
[1] Journal of the Indian Chemical Society, 2009, vol. 86, # 2, p. 179 - 182
22
[ 64-19-7 ]
[ 103-89-9 ]
[ 66047-05-0 ]
[ 122-85-0 ]
[ 556-08-1 ]
Reference：
[1] Russian Journal of Applied Chemistry, 2008, vol. 81, # 7, p. 1198 - 1201
Reference：
[1] Journal of the American Chemical Society, 1921, vol. 43, p. 1323
46
[ 556-08-1 ]
[ 4123-72-2 ]
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1934, vol. 53, p. 7,12
47
[ 556-08-1 ]
[ 16375-88-5 ]
Reference：
[1] Organic Letters, 2004, vol. 6, # 22, p. 4133 - 4136
[2] Journal of Natural Products, 2003, vol. 66, # 1, p. 62 - 66
48
[ 556-08-1 ]
[ 56961-25-2 ]
[ 2486-71-7 ]
Reference：
[1] Journal of Organic Chemistry USSR (English Translation), 1991, vol. 27, # 11.2, p. 2132 - 2142[2] Zhurnal Organicheskoi Khimii, 1991, vol. 27, # 11, p. 2401 - 2412
[3] Journal of Organic Chemistry USSR (English Translation), 1991, vol. 27, # 11.2, p. 2132 - 2142[4] Zhurnal Organicheskoi Khimii, 1991, vol. 27, # 11, p. 2401 - 2412
49
[ 556-08-1 ]
[ 56961-25-2 ]
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1959, vol. 78, p. 534,540
50
[ 556-08-1 ]
[ 56961-25-2 ]
[ 2486-71-7 ]
Reference：
[1] Journal of Organic Chemistry USSR (English Translation), 1991, vol. 27, # 11.2, p. 2132 - 2142[2] Zhurnal Organicheskoi Khimii, 1991, vol. 27, # 11, p. 2401 - 2412
[3] Journal of Organic Chemistry USSR (English Translation), 1991, vol. 27, # 11.2, p. 2132 - 2142[4] Zhurnal Organicheskoi Khimii, 1991, vol. 27, # 11, p. 2401 - 2412
51
[ 556-08-1 ]
[ 95-54-5 ]
[ 112522-64-2 ]
Yield
Reaction Conditions
Operation in experiment
66%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 16 h;
To the extent possible, the procedure set forth in Thomas, M. et al., Bioorganic & Medicinal Chemistry 2008, 16, 8109-8116, was followed as described herein. To a stirred solution of 4-acetamido benzoic acid 7.4 (2.5 g, 13.95 mmol, 1.0 eq.) in N,N-dimethylformamide (50 mL) was added o-phenyldiamine 7.7 (4.53 g, 41.9 mmol, 3.0 eq.), followed by N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (3.48 g, 18.14 mmol, 1.3 eq.) and catalytic 4-(dimethylamino)pyridine (0.18 g, 1.47 mmol, 0.1 eq.). The reaction mixture was stirred at room temperature for 16 hours. The solvents were removed under reduced pressure at 58° C. The crude residue was diluted with dichloromethane (100 mL) and kept in the refrigerator overnight. The resulting precipitate was filtered, washed with hot dichloromethane (100 mL), and dried under vacuum to afford 4-acetamido-N-(2-aminophenyl)benzamide 7.6 as an off-white solid. Yield 7.6=2.48 g (66percent).
Reference：
[1] Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 17, p. 8109 - 8116
[2] Patent: US2013/102677, 2013, A1, . Location in patent: Paragraph 0149; 0150
[3] Journal of Medicinal Chemistry, 2007, vol. 50, # 23, p. 5543 - 5546
[4] Patent: WO2012/3413, 2012, A1, . Location in patent: Page/Page column 40
Stage #1: acetic anhydride; 4-amino-benzoic acid With pyridine at 20℃; for 5h;
Stage #2: With hydrogenchloride In water
Stage #3: In water
4.1.1.2. 4-Acetamido-benzoic acid (3)
General procedure: Ac2O (5.7 mL, 60.3 mmol) was added to the solution of 4-amino-benzoic acid (1) (6.86 g, 50.0 mmol) in pyridine (25 mL). The reaction was stirred at room temperature for 5 h. The solvent was removed in vacuo and the residue dispersed in water (100 mL) and acidified to pH 2-3 with concentrated hydrochloric acid. The resulting precipitate was collected by filtration, washed with water (30 mL) and dried to give 4-acetamido-benzoic acid (3) as a pale yellow powder (7.80 g, 99%).
99%
With pyridine at 20℃; for 5h;
16.1
Step 1: Ac20 (5.7 ml, 60.3 mmol) was added to the solution of 4-amino-benzoic acid(6.86 g, 50.0 mmol) in pyridine (25 ml). The reaction was stirred at room temperature for 5 h. The solvent was removed in vacuo, and the residue was dispersed in water (100 ml) and acidified to pH 2-3 with concentrated hydrochloric acid. The resulting precipitate was collected by filtration, washed with water (30 ml) and dried to give 4-acetamido-benzoic acid as a pale yellow powder (7.80 g, 99%).
96%
With formic acid at 55℃; for 2.66667h;
3 Example 3:
5mol of p-aminobenzoic acid was dissolved in 1.8L mass fraction of 85% formic acid solution,Control the stirring speed 150rpm, adding 6.5mol of acetic anhydride,Raise the temperature of the solution to 55 ° C,Continue stirring 90min,Distillation under reduced pressure 60kPa 70min,The remaining solution was added 3L mass fraction of 20% potassium chloride solution,Reduce the temperature of the solution to 15 ° C,Crystal precipitation,filter,With a mass fraction of 15% sodium bromide solution was washed,The mass fraction of 95% ether solution was recrystallized,Solid sodium hydroxide dehydration agent dehydration,The final productAcetamidobenzoic acid 859.20g, yield 96%.
90%
at 20℃;
88.41%
In water at 80℃; for 0.5h;
1-4 Example 4
In a 100mL four-necked flask equipped with a thermometer and a spherical condenser, add 1g (7.3mmol) of p-aminobenzoic acid, 30mL of distilled water, and heat and stir to about 80. When the p-aminobenzoic acid is completely dissolved, take 1.5g ( 14.6mmol) Acetic anhydride was slowly added dropwise in the dropping funnel. After the dropping was completed, the reaction was stopped for 0.5h.The final reaction solution was poured into cold water, cooled, filtered, washed, and dried to obtain the product with a purity of 99.5% by HPLC and a yield of 88.41%.
80%
With 4-butylazobenzyl-4′-triazologlucuronic acid sodium salt In water at 20℃; Irradiation;
80%
With 7% w/w Pd/C In water for 0.25h; Reflux; Green chemistry;
General procedure for the N-acetylation of arylamines catalyzed by Pd/C
General procedure: To the synthesis of N-phenylacetamide (acetanilide) as a representative example, a mixture of aniline (1 mmol, 0.093 g) and H2O (2 mL) was prepared in around-bottom flask (15 mL), which equipped with a magnetic stirrer. Then, Pd/C(24 mg) was added into the reaction environment, and the resulting mixture was stirred at reflux. Next, Ac2O (1 mmol, 0.102 g) was added to the prepared mixture followed by stirring for 2 min at reflux. After completion of the acetylation reaction (monitored by TLC using n-hexane:EtOAc (5:1) as an eluent), the mixture was cooled to room temperature, and the Pd/C catalyst was separated by filtration. Then, the reaction mixture was extracted with DCM (3 × 5 mL) and then dried over Na2SO4. Finally, evaporation of the solvent under reduced pressure afforded the pure acetanilide in 88% yield.
78%
at 130℃; for 3h;
With hydrogenchloride
0.1689 g
In tetrahydrofuran; water for 0.5h;
169 mg
In tetrahydrofuran; water for 0.5h;
In dichloromethane
With pyridine In tetrahydrofuran at 20℃; for 1h;
With platinum nanoparticles supported on zirconia In methanol at 20℃; for 0.5h;
With sulfuric acid; nitric acid; at 0 - 20℃; for 0.666667h;
4-acetamidobenzoic acid (24) (2.5 g, 14 mmol) was addedslowly to a mixture (1:1) of HNO3 and conc. H2SO4 (40 mL) with stirring for 10 min at 0 C. After,the mixture was stirred for 30 min at room temperature. The reaction mixture was poured into icewater and neutralized by adding 15 mL of 5% Na2CO3. The product was obtained by filtration andwashed with an excess of H2O. The crude was purified by recrystallization with ethanol, yielding (17)(84%). IR (KBr): 3324 (NH); 2912 (CH); 1717 and 1672 (C=O); 773 (NO2) cm1. 1H-NMR (400 MHz,DMSO-d6) δ ppm: 2.1 (s, 3H, CH3); 7.8 (s, 1H, C6H3NO2); 8.1 (s, 1H, C6H3NO2); 8.3 (s, 1H, C6H3NO2);10.2 (s, 1H, NH); 12.6 (s, 1H, COOH). Calculated analysis for C9H8N2O5: C, 48.22; H, 3.60; N, 12.50.Found: C, 47.90; H, 3.30; N, 12.20.
With pepsin immobilized on terephthalaldehyde functionalized chitosan magnetic nanoparticle In acetonitrile at 20℃; for 48h;
Deacetylation of Amides
General procedure: To a solution of an amide (1 mmol) in 10 mL of acetonitrile and 10 mLof citrate buffer (pH = 2.0) was added the catalyst (100 mg). The reactionmixture was stirred at rt, and the progress of the reaction was monitored byTLC using ethyl acetate/n-hexane 50:50 as the eluent. After 48 h, the catalystswere removed and washed with HCl (0.01M). The crude residue was purifiedby preparative silica gel plate chromatography using ethyl acetate/n-hexane 50:50 as the eluent. The recovered catalyst was used for the next reaction cycleby the same procedure described above.
81%
With ammonium bromide; ethylenediamine at 70℃; for 5h; Microwave irradiation; Inert atmosphere; neat (no solvent);
With 4,4'-dimethoxyphenyl disulfide; iridium(lll) bis[2-(2,4-difluorophenyl)-5-methylpyridine-N,C20]-4,40-di-tert-butyl-2,20-bipyridine hexafluorophosphate; triphenylphosphine In toluene for 24h; Irradiation;
91%
With palladium(II) acetylacetonate; hydrogen; 2,2-dimethylpropanoic anhydride; dicyclohexylphenylphosphine In tetrahydrofuran at 80℃; for 20h; Inert atmosphere;
69%
With potassium phosphate; sodium hypophosphite; 2,2-dimethylpropanoic anhydride In tetrahydrofuran at 60℃; for 16h;
With glycerol-3-Phosphate Dehydrogenase; D-glucose; NADP<SUP>+</SUP>; Nocardia PPTase; Segniliparus CAR; ATP; coenzyme A; magnesium chloride In dimethyl sulfoxide at 35℃; for 16h; Enzymatic reaction;
2.4. Standard reduction procedure
General procedure: The His-CAR (1.5 mg) was incubated with His-PPTase (295 g) in the presence of CoA (1 mM) as a cofactor for 1 h at 28°C in a final volume of 600 L of sodium phosphate buffer (100 mM, pH 7.5) containing 10 mM of MgCl2. The resulting enzyme mixture (holo-CAR, 50 g) was mixed with NADP+ (0.9 mM), GDH (1 U, one unitcorresponds to the amount of enzyme which could reduce 1 molNADP+ to NADPH per minute), glucose (60 mM), MgCl2 (10 mM), substrate (5 or 10 mM, from 1 M stock solution in DMSO), and ATP (15 mM) in Tris-HCl buffer (100 mM, pH 9) with a nal volume of 1 mL. The reaction mixture was incubated at 100 rpm in a rotaryshaker at 35C for 16 h, and extracted with 1 mL of ethyl acetateafter the pH was adjusted to 2-3 with 1 M HCl solution. The organicextracts were dried over anhydrous sodium sulfate and analyzedby gas chromatography (GC) and gas chromatography-mass spec-trometry (GC-MS) to determine the amount of substrate (a) andproducts (aldehyde b, alcohol c) in the mixture. All experimentswere conducted in triplicate.
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 16h;
To the extent possible, the procedure set forth in Thomas, M. et al., Bioorganic & Medicinal Chemistry 2008, 16, 8109-8116, was followed as described herein. To a stirred solution of 4-acetamido benzoic acid 7.4 (2.5 g, 13.95 mmol, 1.0 eq.) in N,N-dimethylformamide (50 mL) was added o-phenyldiamine 7.7 (4.53 g, 41.9 mmol, 3.0 eq.), followed by N-(3-dimethylaminopropyl)-N?-ethylcarbodiimide hydrochloride (3.48 g, 18.14 mmol, 1.3 eq.) and catalytic 4-(dimethylamino)pyridine (0.18 g, 1.47 mmol, 0.1 eq.). The reaction mixture was stirred at room temperature for 16 hours. The solvents were removed under reduced pressure at 58 C. The crude residue was diluted with dichloromethane (100 mL) and kept in the refrigerator overnight. The resulting precipitate was filtered, washed with hot dichloromethane (100 mL), and dried under vacuum to afford 4-acetamido-N-(2-aminophenyl)benzamide 7.6 as an off-white solid. Yield 7.6=2.48 g (66%).
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 16h;
To the extent possible, the procedure set forth in Thomas, M. et al., Bioorganic & Medicinal Chemistry 2008, 16, 8109-8116, was followed as described herein. To a stirred solution of 4-acetamido benzoic acid 7.4 (2.5 g, 13.95 mmol, 1.0 eq.) in N,N-dimethylformamide (50 mL) was added o-phenyldiamine 7.7 (4.53 g, 41.9 mmol, 3.0 eq.), followed by N-(3- dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (3.48 g, 18.14 mmol, 1.3 eq.) and catalytic 4-(dimethylamino)pyridine (0.18g, 1.47 mmol, 0.1 eq.). The reaction mixture was stirred at room temperature for 16 hours. The solvents were removed under reduced pressure at 58 C. The crude residue was diluted with dichloromethane (100 mL) and kept in the refrigerator overnight. The resulting precipitate was filtered, washed with hot dichloromethane (100 mL), and dried under vacuum to afford 4-acetamido-N-(2-aminophenyl)benzamide 7.6 as an off-white solid. Yield 7.6 = 2.48g (66%).
The suspension of compounds 330A0 (4-acetamidobenzoic acid, a para-aminobonzoic acid derivative) and 330B0 (dimethylaminoisopropanol) in water is stirred for 2 hours at 50 C. The solvent is evaporated under vacuum. The residue is taken up and evaporated three times in acetonitrile. The residue is taken up in cold acetonitrile, crystallization is observed. The solid is filtered and dried under vacuum. Compound 330A1 (salt) is obtained as a white solid (approximately 6g.) The yield is approximately 76% the purity of compound 330A1 is controlled by RMN 1H and is approximately greater than 95%. See FIG. 1 for quantities and for chemical structures.
With 1,1'-carbonyldiimidazole; In tetrahydrofuran;
(1) Carbonyldiimidazole (12.9 g, 79.9 mmol) was added to a suspension of 4-acetylaminobenzoic acid (13 g, 72.6 mmol) in tetrahydrofuran (100 ml) at room temperature. After stirred at room temperature for 6 hours, a magnesium salt of malonic acid monoethyl ester (12.5 g, 43.6 mmol) was added to this mixture. The reaction mixture was stirred at 60 C. for 2 hours. This was diluted with ethyl acetate (100 ml), washed with an aqueous saturated ammonium chloride solution 2 times, dried with sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography [eluent: hexane-ethyl acetate (1:1)] to obtain ethyl 3-(4-acetylaminophenyl)-3-oxopropionate (14.77 g, 59.3 mmol, 82%) as colorless plates. mp.93-94 C. IR numax (KBr) cm-1: 3483 (NH), 1743, 1714, 1674 (C=O). 1H-NMR (CDCl3) delta: 1.260 ({fraction (9/10)}*3H, t, J=7.4 Hz), 1.333 ({fraction (1/10)}*3H, t, J=7.4 Hz), 2.214 (3H, s), 3.962 ({fraction (9/10)}*2H, s), 4.127 ({fraction (1/10)}*2H, q, J=7.4 Hz), 4.214 ({fraction (9/10)}, *2H, q, J=7.4 Hz), 5.617 ({fraction (1/10)}*1H, s), 7.632 (2H, d, J=8.8 Hz), 7.740 ({fraction (1/10)}*2H, d, J=8.8 Hz), 7.78-7.84 (1H, br), 7.905 ({fraction (9/10)}*2H, d, J=8.8 Hz). Elemental analysis (C13H15NO4.0.3H2O) Cal'd: C, 61.31; H, 6.17; N, 5.50 Found: C, 61.49; H, 6.10; N, 5.55.
With magnesia In neat (no solvent) at 70℃; for 0.583333h; Green chemistry; chemoselective reaction;
General procedure for the synthesis of amides
General procedure: In an oven dried round bottomed flask (50 mL) nano-MgO (5.0 mol%) were added and then alky/aryl amines (5.0 mmol) and aromatic/aliphatic acid (5.0 mmol) was added. After that it was allowed to stir on a pre heated oil bath at 70 °C under aerobic condition till the required time (the progress of the reaction was judged by TLC). After the completion, the reaction mixture was brought to room temperature and ethyl acetate (3 × 10 mL) was added to it and then centrifuged at 3500 rpm to recover the nano catalyst. Having done this, the reaction mixture was washed with water and brine, dried over anhydrous Na2SO4, concentrated in a rotary evaporator and finally the crude product was charged to column chromatography (ethylacetate:hexane (3:7) as an eluent) for purification and wherever necessary the products were recrystallized from hot ethanol.
88%
With aluminum oxide at 70℃; for 0.5h; Neat (no solvent);
81%
With zinc(II) acetate dihydrate for 0.1h; Microwave irradiation; Sealed tube; chemoselective reaction;
With sodium hydride; sodium hydrogencarbonate; potassium carbonate; (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; trifluoroacetic acid;Pd(PPh3)4; palladium; In 1,2-dimethoxyethane; ethanol; dichloromethane; water;
Synthesis of 4-acetamido-N-(2-amino-5-phenethylphenyl)benzamide (BRD-7050) To a stirred solution of <strong>[5228-61-5]5-bromo-2-nitroaniline</strong> (4.0 g, 18.43 mmol, 1.0 eq), 4-acetamidobenzoic acid (4.95 g, 27.6 mmol, 1.5 eq) and BOP (10.60 g, 23.96 mmol, 1.3 eq) was added sodium hydride (2.96 g, 123.0 mmol, 6.7 eq) portion-wise at 0 C. The reaction mixture was allowed to warm to room temperature and stir for 60 h. The solvents were evaporated under reduced pressure. The residue was diluted with a saturated solution of sodium bicarbonate. The obtained precipitate was filtered. The product was purified by column chromatography (silica gel, 25% EtOAc/CH2Cl2) to afford the desired product (3.31 g, 40% yield). A mixture of tert-butyl 2-(4-acetamidobenzamido)-4-bromophenylcarbamate (0.50 g, 1.11 mmol, 1.0 eq), (E)-styrylboronic acid (0.33 g, 2.23 mmol, 2.0 eq), potassium carbonate (0.46 g, 3.335 mmol, 3.0 eq), Pd(PPh3)4 (0.09 g, 0.08 mmol, 0.07 eq) and tritolyl phosphine (0.10 g, 0.33 mmol, 0.3 eq) in DME/H2O (30 mL) was heated to reflux for 20 h. The reaction mixture was diluted with water. The obtained solid was filtered. The crude product was purified by column chromatography (silica gel, 2% MeOH/CH2Cl2) to obtain pure product (0.30 g, 57% yield). To a solution of (E)-tert-butyl 2-(4-acetamidobenzamido)-4-styrylphenylcarbamate (0.15 g, 0.32 mmol, 1.0 eq) in ethanol (10 mL) was added palladium on carbon (0.02 g, 0.23 mmol, 0.7 eq). The reaction mixture was stirred under H2 atmosphere for 20 h. The reaction mixture was filtered through celite, the solids were washed with methanol. The reaction was then concentrated under reduced pressure to afford an off white solid (0.14 g, 93% crude yield) which was used in the next step without further purification. To a solution of tert-butyl 2-(4-acetamidobenzamido)-4-phenethylphenylcarbamate (0.14 g, 0.29 mmol) in CH2Cl2 (3 mL) at 0 C. was added TFA (2 mL) dropwise. The reaction mixture was slowly warmed to room temperature and stirred for 2 h. The solvent was removed by evaporation under reduced pressure. The crude residue was diluted with water and quenched with a saturated aqueous solution of sodium bicarbonate. The obtained solid was filtered, washed with water and dried under vacuum to afford the desired product (0.08 h, 68% yield). ESI+ MS: m/z (rel intensity) 374 (95.0, M+H).
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.
N'-(4-(2-(acridin-9-yl)hydrazinecarbonyl)phenyl)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
68.92%
Stage #1: p-(acetylamino)benzoic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In tetrahydrofuran Cooling with ice;
Stage #2: (acridin-9-yl)hydrazine With triethylamine In tetrahydrofuran Cooling with ice;
General procedure for the synthesis of substituted benzoic acid N'-acridin-9-yl hydrazide (AA-11 to AA-112)
General procedure: 1.5 equivalents of substituted carboxylic acid was added totetrahydrofuran (THF) and allowed to stir till complete dissolution. To it was added 1.5 equivalent of hydroxy-O-benzotriazole (HOBt) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide*HCl (EDC*HCl) and stirred for 15-20 min at ice-cold condition. To this solution were added triethylamine (TEA) and 1.5 equivalent of 9-hydrazinylacridine. The reaction was run at ice-cold condition till completion and worked up with dichloromethane (DCM), washed with dil. HCl and sodium bicarbonate (NaHCO3). DCM layer was collected, and solvent was evaporated under reduced pressure. The final solid product was crystallized. The characterization details are given below:
5-[(R)-2-(5,6-diethylindan-2-yl-amino)-1-hydroxyethyl]-8-benzyloxy-(1H)-quinolin-2-one 4-acetamidobenzoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80.4%
Stage #1: (R)-5-(2-oxiranyl)-8-benzyloxy-2(1H)-quinolinone; 5,6-diethyl-2,3-dihydro-1H-inden-2-amine at 100℃; for 5h;
Stage #2: p-(acetylamino)benzoic acid In ethanol at 60℃; for 0.0833333h;
4 Example 4: 5-[(R)-2-(5,6-Diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-benzyloxy-(1H)-quinoline Preparation of olin-2-one 4-acetylaminobenzoate
8-Benzyloxy-5-(R)-oxiranyl-(1H)-quinolin-2-one (32.02 g, 110 mmoL) dissolved in 160 mLIn 2-isobutyl ketone, 2-amino-(5,6-diethyl)-indane (18.92 g, 100 mmoL) was added and the reaction was stirred at 100° C. for 5 hours. TLC showed that the reaction was complete.The resulting brown solution was cooled to 60° C., 140 mL of ethanol was added and maintained at 60° C., and then a pre-prepared solution of 62.65 g (350 mmoL) of 4-acetylaminobenzoic acid in 140 mL of ethanol was added and the reaction was stirred for 5 minutes and cooled to approximately At 40°C, seed crystals were added and placed in an ice bath to cool.5-[(R)-2-(5,6-Diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-benzyloxy-(1H)-quinoline- 2-Keto-4-acetylaminobenzoate, crude 56.1 g,Recrystallization from ethanol gave 53.2 g of 5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-benzyloxy-( 1H)-quinolin-2-one 4-acetylaminobenzoate pure product,White crystalline powder (total yield 80.4%, purity 97.96%).
N-(4-(2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carbonyl)phenyl)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
14.2%
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃;
To a solution of l,3,8-triazaspiro[4 5]decane-2,4-dione (36 rng, 213 gmol, eq. 1) and 4- acetamidobenzoic acid (CAS 556-08-1, 40 mg, 223 gmol, eq. 1.05) in A V-dimethylformamide (1 ml) were added DIPEA (110 mg, 149 m, 851 gmol, eq. 4) and HATH (121 nig, 319 gmol, eq. 1.5). The reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into ethyl acetate/tetrahydrofuran (1 : 1) and extracted with water followed with brine. The organic layer was dried over NaiSCri and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 4 g, 0% to 10% methanol in dichloromethane) to afford N-(4-(2,4- dioxo-l ,3,8-triazaspiro[4.5]decane-8-carbonyl)phenyl)acetamide (10 mg, 30 3 gmol, 14.2 %) as a white solid. MS (ISP): 331.1 {I M 1 1 | }.
1 <Example 1> Preparation of edoxaban acetamidobenzoate of the present invention
To 1.0 g of edoxaban free base, 30 mL of acetonitrile was added and suspended. After adding 0.34 g of 4-acetamidobenzoic acid, the temperature was raised to 60°C and stirred for 2 hours. It was cooled to room temperature and stirred for 3 hours. The resulting solid was filtered and dried under vacuum at an internal temperature of 50° C. overnight to obtain 1.28 g (97%) of the title compound.
Stage #1: p-(acetylamino)benzoic acid With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 0℃; for 0.5h;
Stage #2: With hydrazine hydrate In N,N-dimethyl-formamide
7 Synthesis of Intermediate 69
1.0 g (5.6 mmol) of intermediate 68 was dissolved in 10 ml of N,N-dimethylformamide, added with 2.34 ml (16.8 mmol) of triethylamine, cooled to 0° C., then added with 2.51 g (6.16 mmol) of N,N,N′,N′-tetramethyl-o-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate, and stirred for 30 min. The resulting solution was added dropwise to a solution of 2.8 g (56 mmol) of hydrazine hydrate in 10 ml of N,N-dimethylformamide and reacted overnight. The reaction was monitored by TLC. After the reaction was completed, the reaction solution was rotary evaporated to dryness, added with 10 ml of saturated sodium bicarbonate solution and 10 ml of dichloromethane, and separated into layers. The aqueous phase was extracted with dichloromethane. The organic phases were combined, dried and rotary evaporated to dryness to give a crude product, which was purified with silica gel column (eluent: DCM/MeOH=10/1, v/v) to give a product (0.24 g) as a white solid. Yield: 22.18%. LC-MS: 194 [M+1]+, tR=1.435 min.
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