* 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.
General procedure: A mixture of aromatic amine (1.0 mmol), glycerol (3.0 mmol), and Brönsted acidic ionic liquid BAIL (1.5 mmol) in a closed glass vial was heated using a GE model JE635WW microwave oven, at full power (920W) in five 20 s pulses giving 5 s cooling time between the pulses. Then cooled reaction mixture was diluted with water (30 mL), basified with 0.5 M aqueous sodium hydroxide and steam distilled. The distillate was extracted with methylene chloride (3X 6 mL). Combined organic layer was dried and chromatographed on silica, eluting with methylene chloride gave corresponding quinolines.
Reference：
[1] Organic Letters, 2011, vol. 13, # 15, p. 4024 - 4027
[2] Tetrahedron Letters, 2014, vol. 55, # 22, p. 3319 - 3321
[3] RSC Advances, 2014, vol. 4, # 41, p. 21456 - 21464
[4] Bulletin de la Societe Chimique de France, 1930, vol. <4> 47, p. 749
[5] Journal of the Chemical Society, 1943, p. 419
[6] Journal fuer Praktische Chemie (Leipzig), 1893, vol. <2> 48, p. 140
[7] Ing. Chimiste Bruessel, 1936, vol. 20, p. 204,207
Reference：
[1] Journal of the American Chemical Society, 1947, vol. 69, p. 1222
[2] Journal of Fluorescence, 2018, vol. 28, # 5, p. 1121 - 1126
5
[ 56-81-5 ]
[ 88-75-5 ]
[ 148-24-3 ]
[ 130-16-5 ]
Reference：
[1] Bulletin de la Societe Chimique de France, 1947, p. 969
[2] Roczniki Chemii, 1936, vol. 16, p. 519,522[3] Chem. Zentralbl., 1937, vol. 108, # I, p. 3142
6
[ 89-64-5 ]
[ 56-81-5 ]
[ 130-16-5 ]
Reference：
[1] Journal of the Indian Chemical Society, 1952, vol. 29, p. 711
[2] Journal of the Indian Chemical Society, 1952, vol. 29, p. 711
[3] Journal of the Indian Chemical Society, 1945, vol. 22, p. 169
[4] Journal of the Indian Chemical Society, 1952, vol. 29, p. 711
7
[ 144-62-7 ]
[ 5435-44-9 ]
[ 56-81-5 ]
[ 2836-04-6 ]
[ 494-38-2 ]
Reference：
[1] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 3, p. 297
[2] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 3, p. 292
8
[ 6153-56-6 ]
[ 5435-44-9 ]
[ 56-81-5 ]
[ 2836-04-6 ]
[ 494-38-2 ]
[ 82207-69-0 ]
Reference：
[1] Journal of the Chemical Society, 1947, p. 244,247
9
[ 57-50-1 ]
[ 57-48-7 ]
[ 50-99-7 ]
[ 56-81-5 ]
[ 470-69-9 ]
[ 13133-07-8 ]
Reference：
[1] Journal of Agricultural and Food Chemistry, 2008, vol. 56, # 8, p. 2805 - 2809
Reference：
[1] Catalysis Science and Technology, 2014, vol. 4, # 9, p. 3090 - 3098
17
[ 504-29-0 ]
[ 56-81-5 ]
[ 254-60-4 ]
Reference：
[1] ChemMedChem, 2014, vol. 9, # 6, p. 1161 - 1168
[2] Chemical Communications, 2018, vol. 54, # 18, p. 2268 - 2271
[3] Monatshefte fur Chemie, 1996, vol. 127, # 4, p. 391 - 396
18
[ 462-08-8 ]
[ 56-81-5 ]
[ 254-79-5 ]
Yield
Reaction Conditions
Operation in experiment
45%
With sulfuric acid; sodium 3-nitrobenzenesulfonate In water at 150℃; for 2.5 h;
1,5-Naphthyridine (4) A flask was charged withcompound 3 (1 g, 10.63 mmol), m-NO2PhSO3Na (3.59 g, 15.95 mmol),glycerol (3.33 mL, 46.85 mmol), H2SO4 (5.92 mL, 111.53mmol) and 3 mL water. The mixture was heated to 150°C and stirred for 2.5 h,then cooled to room temperature, basified with NaOH (4 M) to pH 8, and extractedwith EA (5×30 mL). The combined extracts were washed with brine, driedover anhydrous Na2SO4, and concentrated in vacuum.Purification by chromatography (PE/EA = 1:1) provided compound 4 (622 mg, 45percent) as a yellow solid. MP:74~75°C (Ref.1 75°C).1H NMR (400 MHz, CDCl3): δ 9.04–8.96 (m, 2H), 8.43 (d, J = 8.4 Hz, 2H), 7.66 (dd, J= 8.4, 4.1 Hz, 2H).
Reference：
[1] Synthetic Communications, 2011, vol. 41, # 12, p. 1843 - 1851
[2] Tetrahedron Letters, 2002, vol. 43, # 20, p. 3747 - 3750
[3] Organic Letters, 2000, vol. 2, # 7, p. 875 - 878
[4] Chemistry - A European Journal, 2017, vol. 23, # 53, p. 13046 - 13050
[5] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 16, p. 3251 - 3255
[6] Crystal Growth and Design, 2017, vol. 17, # 12, p. 6793 - 6800
[7] Chemische Berichte, 1927, vol. 60, p. 1083[8] Chem. Zentralbl., 1928, vol. 99, # I, p. 2093
[9] Journal of the Chemical Society, 1954, p. 1879,1882
[10] Journal of Organic Chemistry, 1950, vol. 15, p. 1224,1231
19
[ 107-15-3 ]
[ 56-81-5 ]
[ 290-37-9 ]
[ 109-08-0 ]
[ 123-32-0 ]
[ 5910-89-4 ]
[ 6705-33-5 ]
[ 108-50-9 ]
[ 5780-66-5 ]
Reference：
[1] Kinetics and Catalysis, 2016, vol. 57, # 5, p. 602 - 609[2] Kinet. Katal., 2016, vol. 57, # 5, p. 607 - 614,8
Reference：
[1] Angewandte Chemie - International Edition, 2010, vol. 49, # 49, p. 9456 - 9459
31
[ 56-81-5 ]
[ 371-40-4 ]
[ 396-30-5 ]
Reference：
[1] RSC Advances, 2014, vol. 4, # 41, p. 21456 - 21464
[2] Journal of the American Chemical Society, 2012, vol. 134, # 41, p. 16967 - 16970,4
[3] Journal of the American Chemical Society, 2012, vol. 134, # 41, p. 16967 - 16970
[4] Journal of Molecular Structure, 2003, vol. 661-662, # 1-3, p. 209 - 218
[5] Patent: WO2009/87649, 2009, A1, . Location in patent: Page/Page column 24
[6] Angewandte Chemie - International Edition, 2016, vol. 55, # 41, p. 12891 - 12894[7] Angew. Chem., 2016, vol. 128, p. 13083 - 13086,4
32
[ 394-70-7 ]
[ 56-81-5 ]
[ 396-30-5 ]
Reference：
[1] Journal of Organic Chemistry, 1951, vol. 16, p. 1450
33
[ 56-81-5 ]
[ 106-40-1 ]
[ 5332-25-2 ]
Yield
Reaction Conditions
Operation in experiment
81%
With tungstic acid functionalized KIT-6 In water at 200℃; for 3 h; Autoclave
General procedure: All the reactions were carried out in a 50 mL stainless steel autoclave (Scheme 1). A mixture of glycerol (1 g, 1 equiv.), aniline (0.58 g, 0.5 equiv.), water (2.5 mL) and W-KIT-6 (100 mg) was charged in to the autoclave simultaneously and finally heated to 200 °C with stirring for 3 h. On completion of the reaction (monitored by TLC), the autoclave was cooled to room temperature and the catalyst was removed by filtration. Ethyl acetate (10 mL) and water (5 mL) were added to the reaction mixture and stirred well for few minutes. The organic layer was dried over anhydrous Na2SO4 and the crude was purified by column chromatography using 60-120 mesh silica with ethylacetate/hexane as eluent to afford the desired product in good yield. The product was analyzed and confirmed with GC-MS and 1H NMR and 13C NMR spectroscopy (Table 1 and Figs S1-S5, Supplementary Data).
42%
With sulfuric acid; sodium 3-nitrobenzenesulfonate In water at 140℃;
Step 1. 6-Bromoquinoline 4-Bromobenzenamine (25 g, 145.32 mmol, 1.00 equiv), sodium 3-nitrobenzenesulfonate (55.5 g, 246.64 mmol, 1.70 equiv), propane-1,2,3-triol (50.8 g, 551.63 mmol, 3.80 equiv), and sulfuric acid (170 mL, 70percent) were placed into a 500-mL round-bottom flask. The resulting solution was stirred overnight at 140° C. The pH value of the solution was adjusted to with 10percent aqueous sodium hydroxide. The resulting solution was extracted with 5*150 mL of ethyl acetate. The organic layers were combined and dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with ethyl acetate/petroleum ether (1:50). This resulted in 17.2 g (42percent) of 6-bromoquinoline as yellow oil.
28.6%
at 100℃; for 20 h; Reflux
Glycerol (60.0mL, 0.82mol), FeSO4·7H2O (7.00g, 0.025mol), p-bromoaniline (34.40g, 0.20mol), and nitrobenzene (12.5mL, 0.13mol) were added to a three-necked round bottom flask with mechanical stirring. H2SO4 (35.0mL, 0.64mol) was added to the system slowly while kept the temperature blow 100°C. The mixture was then heated to reflux for 20h. After cooling to r.t., adjusted pH to 7 with 50percent NaOH aq. solution and extracted with diethyl ether. The extraction was dried over MgSO4 and concentrated in vacuo. The product was isolated by reduced pressure distillation. Fraction was collected at 138–140°C, 16Torr (Ref.[13]. 161–162°C, 22Torr). Light yellow liquid was afforded (11.90g, 28.6percent yield). 1H NMR (300MHz, DMSO-d6) δ (ppm): 9.00 (d, J=4.1Hz, 1H), 8.37 (d, J=8.3Hz, 1H), 8.28 (d, J=1.7Hz, 1H), 8.02 (d, J=9.2Hz, 1H), 7.89 (dd, J1=9.0Hz, J2=2.1Hz, 1H), 7.62 (q, J=8.3Hz, 1H).
Reference：
[1] Indian Journal of Chemistry - Section A Inorganic, Physical, Theoretical and Analytical Chemistry, 2016, vol. 55A, # 8, p. 919 - 928
[2] Patent: US2012/277224, 2012, A1, . Location in patent: Page/Page column 90
[3] Dyes and Pigments, 2013, vol. 99, # 1, p. 240 - 249
[4] Patent: WO2006/2981, 2006, A1, . Location in patent: Page/Page column 96
[5] Chemische Berichte, 1882, vol. 15, p. 559
[6] Patent: CN105837503, 2016, A, . Location in patent: Paragraph 0026-0027
34
[ 56-81-5 ]
[ 591-27-5 ]
[ 580-20-1 ]
Reference：
[1] RSC Advances, 2014, vol. 4, # 41, p. 21456 - 21464
[2] Journal of the Chemical Society, 1947, p. 437,44
35
[ 554-84-7 ]
[ 56-81-5 ]
[ 580-20-1 ]
Reference：
[1] Journal of the Indian Chemical Society, 1952, vol. 29, p. 711
[2] Journal of the Indian Chemical Society, 1952, vol. 29, p. 711
Reference：
[1] Chinese Chemical Letters, 2013, vol. 24, # 8, p. 751 - 754
38
[ 348-54-9 ]
[ 56-81-5 ]
[ 394-68-3 ]
Yield
Reaction Conditions
Operation in experiment
83%
Stage #1: at 130℃; for 1 h; Stage #2: at 130℃; for 18 h;
85percent sulfuric acid (623 g) was added to a 1 L reaction flask, and o-fluoroaniline (133 g, 1.2 mol) was added dropwise. Warm to 130°C and stir for 2 hours. The reaction temperature was controlled at 130°C, and the mixture was dropped with glycerol (121 g, 1.3 mol) and potassium iodide (3 g). The resulting solution was stirred at 130C for 18 hours after the addition was complete. The reaction solution was cooled to room temperature and slowly added to ice water. After the release, an aqueous solution of sodium hydroxide was added dropwise to adjust the pH to 8-9. Extract with methyl tert-butyl ether to concentrate the separated oil layer. The tert-butyl ether was re-distilled under high vacuum through a packed distillation column to obtain high-purity 8-fluoroquinoline (146 g). The rate is 83percent and the gas chromatogram content is 99.7percent.
Reference：
[1] Patent: CN107698503, 2018, A, . Location in patent: Paragraph 0061-0072
[2] Biological and Pharmaceutical Bulletin, 1997, vol. 20, # 6, p. 646 - 650
39
[ 372-19-0 ]
[ 56-81-5 ]
[ 396-32-7 ]
[ 394-69-4 ]
Reference：
[1] Journal of Organic Chemistry, 2006, vol. 71, # 7, p. 2666 - 2676
Sodium nitrobenzene sulfonic acid (3.9 g, 17.3 mmol) and methanesulfonic acid (10 ml) were placed in a 100 ml three-necked flask and stirred. 0.2 g (0.8 mmol) of iron (II) sulfate hydrate, and 3-methoxyaniline (3.09 mL) were added dropwise and the mixture was heated to about 120 ° C.6.3 g of glycerol was added and the reaction was carried out at 135 ° C. for 16 hours. After completion of the reaction, 10Approximately 100 mL of M aqueous NaOH solution was added and extracted with ethyl acetate. The organic layer was collected, dried over anhydrous magnesium sulfate, and the solvent was removed and purified by column chromatography to obtain 4.2 g of RL-0107 (yield: about 48percent).
Reference：
[1] Chemical Communications, 2017, vol. 53, # 31, p. 4339 - 4341
[2] Patent: JP2018/118935, 2018, A, . Location in patent: Paragraph 0098
[3] Angewandte Chemie - International Edition, 2013, vol. 52, # 42, p. 11124 - 11128[4] Angew. Chem., 2013, vol. 125, # 42, p. 11330 - 11334,5
[5] RSC Advances, 2014, vol. 4, # 41, p. 21456 - 21464
[6] Chemische Berichte, 1924, vol. 57, p. 1246
[7] Journal of the Chemical Society, 1947, p. 437,44
[8] Journal of the Chemical Society, 1934, p. 1419,1421
45
[ 91-22-5 ]
[ 56-81-5 ]
[ 1780-17-2 ]
[ 6281-32-9 ]
Reference：
[1] Synlett, 2004, # 5, p. 874 - 876
46
[ 4318-76-7 ]
[ 56-81-5 ]
[ 17965-80-9 ]
Yield
Reaction Conditions
Operation in experiment
41%
With sulfuric acid; sodium 3-nitrobenzenesulfonate In water at 135℃; for 16 h;
b. 1,5-Naphthyridin-2-amine A mixture of pyridine-2,5-diamine (5.2 g, 33.9 mmol), glycerol (15.6 g, 169.5 mmol), sodium 3-nitrobenzenesulphonate (15.2 g, 67.8 mmol), sulfuric acid (20 mL) and water (30 mL) was heated to 135° C. and stirred for 16 h. The mixture was cooled to room temperature and then poured into ice/water (150 g). The pH of the mixture was adjusted to ~9 with saturated aqueous NaOH solution. Then the mixture was extracted with EtOAc (3*100 mL) and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduce pressure to give the crude product, which was purified by silica gel column chromatography (eluting with DCM/MeOH v/v 20:1) to afford the product as a yellow solid (2.0 g, yield 41percent). ESI MS: m/z 146 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 8.50 (dd, J=1.6 Hz, 4.4 Hz, 1H), 7.94 (d, J=8.8 Hz, 1H), 7.82-7.80 (m, 1H), 7.47 (dd, J=4.0 Hz, 8.4 Hz, 1H), 7.00 (d, J=9.2 Hz, 1H), 6.72 (s, 2H).
Reference：
[1] Patent: US2012/178748, 2012, A1, . Location in patent: Page/Page column 47
[2] Yakugaku Zasshi, 1942, vol. 62, p. 257,265; dtsch. Ref. S. 66[3] Chem.Abstr., 1951, p. 2950
[4] Patent: WO2011/150156, 2011, A2, . Location in patent: Page/Page column 133
Reference：
[1] Journal of the Chemical Society, 1949, p. 1157,1159
[2] Journal of the Chemical Society, 1956, p. 212
[3] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 17, p. 2445
49
[ 99-99-0 ]
[ 56-81-5 ]
[ 91-62-3 ]
[ 19655-46-0 ]
Reference：
[1] Roczniki Chemii, 1936, vol. 16, p. 519,522[2] Chem. Zentralbl., 1937, vol. 108, # I, p. 3142
50
[ 56-81-5 ]
[ 615-65-6 ]
[ 19655-46-0 ]
Reference：
[1] Journal of the Chemical Society, 1950, p. 2207,2209
51
[ 7647-01-0 ]
[ 99-99-0 ]
[ 56-81-5 ]
[ 91-62-3 ]
[ 19655-46-0 ]
Reference：
[1] Roczniki Chemii, 1936, vol. 16, p. 519,522[2] Chem. Zentralbl., 1937, vol. 108, # I, p. 3142
52
[ 33630-99-8 ]
[ 56-81-5 ]
[ 67967-11-7 ]
Reference：
[1] Journal of the Chemical Society, 1952, p. 4985,4990
53
[ 5439-04-3 ]
[ 56-81-5 ]
[ 33216-52-3 ]
Reference：
[1] Journal of the Chemical Society, 1905, vol. 87, p. 801[2] Journal of the Chemical Society, 1908, vol. 93, p. 1993
54
[ 56-81-5 ]
[ 501-30-4 ]
Reference：
[1] Atti della Accademia Nazionale dei Lincei, Classe di Scienze Fisiche, Matematiche e Naturali, Rendiconti, 1921, vol. <5> 30 II, p. 325[2] Gazzetta Chimica Italiana, 1921, vol. 51 II, p. 274
[3] Atti della Accademia Nazionale dei Lincei, Classe di Scienze Fisiche, Matematiche e Naturali, Rendiconti, 1921, vol. <5> 30 II, p. 325[4] Gazzetta Chimica Italiana, 1921, vol. 51 II, p. 274
Reference：
[1] Chemistry - A European Journal, 2014, vol. 20, # 21, p. 6358 - 6365
[2] Journal of the Chemical Society, 1955, p. 4391
[3] Journal fuer Praktische Chemie (Leipzig), 1981, vol. 323, # 6, p. 979 - 984
[4] Journal of Fluorescence, 2018, vol. 28, # 5, p. 1121 - 1126
57
[ 52671-64-4 ]
[ 56-81-5 ]
[ 18119-24-9 ]
Yield
Reaction Conditions
Operation in experiment
77%
Stage #1: With sulfuric acid; boric acid; iron(II) sulfate In nitrobenzene at 120 - 150℃; for 22 h; Stage #2: With potassium carbonate In water; nitrobenzene
Step 4: 8-Chloro-6-hydroxyquinoline In a 500 mL 3-necked flask equipped with a mechanical stirrer, a reflux condenser, were added in order ferrous sulfate (2.0 g), 4-amino-3-chlorophenol hydrochloride (6.4 g, commercially available), nitrobenzene (2.9 mL) and a solution of boric acid (3.0 g) in glycerol (16 g). Then concentrated sulfuric acid (9 mL) was added drop by drop with cooling. The ice bath was removed and replaced by an oil bath and the mixture was heated cautiously to 120° C. for 2 hours, then at 150° C. and kept stirring under this temperature for 20 hours. After cooling, the reaction was poured on crushed ice and the resulting solution was neutralized with K2CO3. The product separated as a light brown solid that was filtered off, washed with water and hexanes and dried in a vacuum oven (35° C.) overnight giving 7 g (77percent) of the desired product. MS (ES) m/z (relative intensity): 180 (M++-H, 100).
77%
Stage #1: at 0 - 150℃; for 22 h; Stage #2: With potassium carbonate In water
In a 500 ml 3-necked flask equipped with a mechanical stirrer, a reflux condenser, were added in order ferrous sulfate (2.0 g), 4-amino-3-chlorophenol hydrochloride (6.4 g, commercially available), nitrobenzene (2.9 mL) and a solution of boric acid (3.0 g) in glycerol (16 g). Then concentrated sulfuric acid (9 mL) was added drop by drop with cooling. The ice bath was removed and replaced by an oil bath and the mixture was heated cautiously to 120° C. for 2 hours, then at 150° C. and kept stirring under this temperature for 20 hours. After cooling, the reaction was poured on crushed ice and the resulting solution was neutralized with K2CO3. The product separated as a light brown solid that was filtered off, washed with water and hexanes and dried in a vacuum oven (35° C.) overnight giving 7 g (77percent) of the desired product. MS (ES) m/z (relative intensity): 180 (M++-H, 100).
Reference：
[1] Patent: US2007/299083, 2007, A1, . Location in patent: Page/Page column 14
[2] Journal of Medicinal Chemistry, 2010, vol. 53, # 10, p. 4066 - 4084
[3] Patent: US2007/27160, 2007, A1, . Location in patent: Page/Page column 43
58
[ 17609-80-2 ]
[ 56-81-5 ]
[ 18119-24-9 ]
Yield
Reaction Conditions
Operation in experiment
77%
Stage #1: With sulfuric acid; boric acid; iron(II) sulfate; nitrobenzene In water at 0 - 150℃; for 22 h; Stage #2: With potassium carbonate In water
Example 10 Intermediate 10-8-chloro-6-hydroxy-quinoline In a 500 ml 3-necked flask equipped with a mechanical stirrer and a reflux condenser, added in order were 2.0 g ferrous sulfate, 6.4 g 4-amino, 3-chloro-phenol (generated from 9.0 g of the corresponding commercially available HCl salt), 2.9 m nitrobenzene and a cold solution of 3.0 g boric acid in 16 g of glycerol. Then, 9 ml of concentrated sulfuric acid was added drop by drop with cooling. The ice bath was removed and replaced by an oil bath and the mixture was heated cautiously to 120° C. for 2 hrs, then at 150° C. and kept stirring under this temperature for 20 hrs. The mixture was then cooled and poured on crushed ice and the resulting solution was neutralized to with K2CO3 (saturated solution in water) till exactly pH 5. The product separated as a light brown solid which was filtered off, washed with water and hexane and dried in a vacuum oven (35° C.) overnight. The product was purified by dissolving it in a minimal amount of THF, and the solution poured in 20* volume of hexane, giving 7 g (77percent) of the desired product.
77%
With sulfuric acid; boric acid; iron(II) sulfate In water; nitrobenzene at 120 - 150℃; for 22 h;
In a 500 ml 3-necked flask equipped with a mechanical stirrer and a reflux condenser, added in order were 2.0 g ferrous sulfate, 6.4 g 4-amino, 3-chloro-phenol (generated from 9.0 g of the corresponding commercially available HC1 salt), 2.9 m nitrobenzene and a cold solution of 3.0 g boric acid in 16 g of glycerol. Then, 9 ml of concentrated sulfuric acid was added drop by drop with cooling. The ice bath was removed and replaced by an oil bath and the mixture was heated cautiously to 120°C for 2 hrs, then at 150°C and kept stirring under this temperature for 20 hrs. The mixture was then cooled and poured on crushed ice and the resulting solution was neutralized to with K2C03 (saturated solution in water) till exactly pH 5. The product separated as a light brown solid which was filtered off, washed with water and hexane and dried in a vacuum oven (35°C) overnight. The product was purified by dissolving it in a minimal amount OF THF, and the solution poured in 20X volume of hexane, giving 7 g (77 percent) of the desired product.
Reference：
[1] Angewandte Chemie - International Edition, 2013, vol. 52, # 42, p. 11124 - 11128[2] Angew. Chem., 2013, vol. 125, # 42, p. 11330 - 11334,5
[3] Journal fuer Praktische Chemie (Leipzig), 1895, vol. <2> 51, p. 415
60
[ 626-40-4 ]
[ 56-81-5 ]
[ 34522-69-5 ]
Yield
Reaction Conditions
Operation in experiment
56%
Stage #1: at 120℃; Stage #2: at 130℃;
Step 1: A 100 mL flask was charged with 3,5-dibromoaniline (5.00 g, 19.9 mmol), sodium 3-nitrobenzenesulfonate (987 mg, 4.39 mmol), iron(ll)sulfate heptahydrate (63.2 mg, 0.658 mmol), and methanesulfonic acid (20 mL). A reflux condenser was added, and the reaction was heated in a 120 °C aluminum block.Glycerol (0.64 mL, 8.8 mmol) was added through the condenser, and the aluminum block temperature was then increased to 130 °C. Heating was continued overnight. After cooling to rt, the reaction mixture was diluted with DCM and water, cooled in an ice/water bath, and rendered alkaline by addition of a 50percent aqueous solution of NaOH. The resulting mixture was filtered over Celite® and extracted with DCM. The organicphase was dried over Na2SO4 and concentrated to a brown solid. Purification by chromatography (80 g Si gel, 0—40percent EtOAc in heptane gradient over 17 CV and then held at 40percent) afforded 5,7-dibromoquinoline as a tan solid (3.19 g, 56percent). 1H NMR (400 MHz, CDCI3) O 7.53 (dd, 1 H), 7.96 (d, 1 H), 8.29 (d, 1 H), 8.50 (d, 1 H), 8.93 (dd, 1 H). LCMS (ESI) m/z: 285.9 [M+H] (95percent). LCMS data were acquired from the reactionmixture immediately prior to workup.
Reference：
[1] Chemistry of Natural Compounds, 1982, vol. 18, p. 604 - 605[2] Khimiya Prirodnykh Soedinenii, 1982, vol. 18, # 5, p. 638 - 640
[3] Chemistry of Natural Compounds, 1982, vol. 18, p. 604 - 605[4] Khimiya Prirodnykh Soedinenii, 1982, vol. 18, # 5, p. 638 - 640
62
[ 150-13-0 ]
[ 56-81-5 ]
[ 10349-57-2 ]
Yield
Reaction Conditions
Operation in experiment
95%
at 140℃;
Step 1. Quinoline-6-carboxylic acid Into a 500-mL 3-necked round-bottom flask, was placed 4-aminobenzoic acid (13.7 g, 100.00 mmol, 1.00 equiv), 4-nitrobenzoic acid (10.7 g, 64.07 mmol, 0.64 equiv), boric acid (5.9 g), FeSO4.7H2O (6.4 g), glycerol (38 mL), and concentrated sulfuric acid (18 mL). The resulting solution was stirred overnight at 140° C. The reaction mixture was cooled. The pH value of the solution was adjusted to 10 with sodium hydroxide (10percent). The resulting solution was extracted with 2*100 mL of ethyl acetate and the aqueous layers were combined. The pH value of the aqueous layers was adjusted to pH 6 with conc. hydrochloric acid. The solids were collected by filtration. The resulting solution was diluted with 200 mL of methanol and the resulting solids were collected by filtration. The solid was dried to afford 17.3 g (95percent) of quinoline-6-carboxylic acid as a dark-grey solid. LC-MS: (ES, m/z):174 [M+H]+
56%
Stage #1: at 135℃; for 48 h; Stage #2: at 0℃;
Step 1: Quinoline-6-carboxylic acid To a mixture of 4-aminobenzoic acid (175 g, 1.28 mol), 4-nitrophenol (88.75 g, 0.64 mol) and sulphuric acid (1.2 lit.), glycerol (234.8 g, 2.55 mol) was added dropwise at 135° C. After 48 h, the reaction mixture was cooled to 0° C. and the pH adjusted to 3-5 with 10percent sodium hydroxide solution. The resulting precipitate was collected by filtration and washed with water and dried under vacuum to afford the title compound as a black solid (125 g, 56percent).
56%
at 135℃; for 48 h;
To a mixture of 4-aminobenzoic acid (175 g, 1.28 mol), 4-nitrophenol (88.75 g, 0.64 mol) and sulphuric acid (1.2 lit.), glycerol (234.8 g, 2.55 mol) was added dropwise at 135°C. After 48h, the reaction mixture was cooled to 0°C and the pH adjusted to 3-5 with 10percent sodium hydroxide solution. The resulting precipitate was collected by filtration and washed with water and dried under vacuum to afford the title compound as a black solid (125 g, 56percent).
56%
at 135℃; for 48 h;
[252] Intermediates Intermediate 1: Quinolin-6-ylmethanamine: Stepl : Quinoline-6-carboxylic acid: To a mixture of 4-aminobenzoic acid: (175 g, 1.28 mol), 4-nitrophenol (88.75 g, 0.64 mol) and sulphuric acid (1.2 lit.), glycerol (234.8 g, 2.55 mol) was added drop wise at 135°C. After 48h, the reaction mixture was cooled to 0°C and the pH adjusted to 3-5 with 10percent sodium hydroxide solution. The resulting precipitate was collected by filtration and washed with water and dried under vacuum to afford the title compound as a black solid (125 g, 56percent).
56%
Stage #1: at 135℃; for 48 h; Stage #2: With sodium hydroxide In water at 0℃;
Step 1: Quinoline-6-carboxylic acid To a mixture of 4-aminobenzoic acid: (175 g, 1.28 mol), 4-nitrophenol (88.75 g, 0.64 mol) and sulphuric acid (1.2 lit.), glycerol (234.8 g, 2.55 mol) was added drop wise at 135° C. After 48 h, the reaction mixture was cooled to 0° C. and the pH adjusted to 3-5 with 10percent sodium hydroxide solution. The resulting precipitate was collected by filtration and washed with water and dried under vacuum to afford the title compound as a black solid (125 g, 56percent).
Reference：
[1] Patent: US2012/277224, 2012, A1, . Location in patent: Page/Page column 82
[2] Patent: US2011/281865, 2011, A1, . Location in patent: Page/Page column 83
[3] Patent: WO2011/145035, 2011, A1, . Location in patent: Page/Page column 107-108
[4] Patent: WO2013/144737, 2013, A2, . Location in patent: Paragraph 252
[5] Patent: US2015/57309, 2015, A1, . Location in patent: Paragraph 0504
[6] Journal of the American Chemical Society, 1946, vol. 68, p. 2721
63
[ 150-13-0 ]
[ 56-81-5 ]
[ 62-23-7 ]
[ 10349-57-2 ]
Reference：
[1] Monatshefte fuer Chemie, 1891, vol. 12, p. 309
[2] Monatshefte fuer Chemie, 1881, vol. 2, p. 519
64
[ 7664-93-9 ]
[ 150-13-0 ]
[ 56-81-5 ]
[ 62-23-7 ]
[ 10349-57-2 ]
Reference：
[1] Monatshefte fuer Chemie, 1881, vol. 2, p. 519
65
[ 40925-68-6 ]
[ 56-81-5 ]
[ 1198-14-7 ]
Reference：
[1] Journal fuer Praktische Chemie (Leipzig), 1891, vol. <2> 44, p. 439,442
[2] Journal of Fluorescence, 2018, vol. 28, # 5, p. 1121 - 1126
66
[ 88-74-4 ]
[ 56-81-5 ]
[ 607-35-2 ]
Yield
Reaction Conditions
Operation in experiment
72%
With sulfuric acid In water for 4 h; Reflux
8-Nitroquinoline (3). Concentrated sulfuric avid,385 mL, was slowly added to a suspension of 165.6 g(1.2 mol) of 2-nitroaniline (1) in 265 mL of water, themixture was heated to the boil, and 125 mL (1.71 mol)of glycerol (2) was slowly added. The resulting mixturewas refluxed under stirring for 4 h, cooled, dilutedwith equal volume of water, and neutralized with a25percent ammonia solution. The precipitate that formedwas filtered off, washed with water, dried, dissolved inbenzene, and chromatographed on alumina (Brockmannactivity II) with benzene as eluent. The eluatewas reduced in a minimal volume, 8-nitroquinolinewas precipitated with methanol, filtered off, and driedat 70° in air. Yield 75.6 g (72percent).
Reference：
[1] Russian Journal of General Chemistry, 2016, vol. 86, # 9, p. 2232 - 2235[2] Zh. Obshch. Khim., 2014, vol. 58, # 5-6, p. 85 - 89,5
[3] Chemische Berichte, 1883, vol. 16, p. 673
[4] Chemische Berichte, 1896, vol. 29, p. 708
[5] Arzneimittel-Forschung/Drug Research, 2011, vol. 61, # 7, p. 373 - 378
67
[ 7664-93-9 ]
[ 7778-39-4 ]
[ 88-74-4 ]
[ 56-81-5 ]
[ 607-35-2 ]
Reference：
[1] Chemische Berichte, 1896, vol. 29, p. 708
68
[ 7664-93-9 ]
[ 98-95-3 ]
[ 88-74-4 ]
[ 56-81-5 ]
[ 607-35-2 ]
Reference：
[1] Chemische Berichte, 1883, vol. 16, p. 673
Reference：
[1] Journal of the Chemical Society - Perkin Transactions 1, 1999, # 13, p. 1839 - 1845
[2] Chemische Berichte, 1883, vol. 16, p. 673
[3] Chemische Berichte, 1896, vol. 29, p. 708
[4] Journal of the Chemical Society, 1943, p. 413,416
[5] RSC Advances, 2014, vol. 4, # 41, p. 21456 - 21464
72
[ 104-04-1 ]
[ 56-81-5 ]
[ 613-50-3 ]
Reference：
[1] Journal of Organic Chemistry, 1947, vol. 12, p. 435[2] Journal of Organic Chemistry, 1948, vol. 13, p. 937
Stage #1: at 150℃; for 7 h; Stage #2: for 12 h; Reflux
Synthesis of methyl quinoline-5-carboxylate (intermediate-97):A 500mL RB flask fitted with magnetic stirrer was charged with Starting Material-32 (60g,435mmo1), Starting material-33 (168g, 1824mmo1), 3-nitrobenzoic acid (30g, i79mmol) in9OmL of conc.H2S04. Then reaction mixture was heated at 150 CC for 7 h. After reactioncooled to RT and added MeOH (600 mL) and refluxed for 12 hours. Then cooled to 0 °C quenched with ice and concentrated. Crude reaction mixture was basif led with NaHCO3, extracted with DCM and concentrated. Resulted crude material was purified by silica gel column chromatography eluting with Petroleum ether (60-80), ethyl acetate and 0.5percent of triethylamine as eluent. The product (intermediate-97) was obtained as a brown liquid (21g).
21 g
Stage #1: at 150℃; for 7 h; Reflux Stage #2: at 20℃; for 12 h; Reflux
Synthesis of methyl quinoline-5-carboxylate (intermediate-97) [0751] A 500 mL RB flask fitted with magnetic stirrer was charged with Starting Material-32 (60 g, 435 mmol), Starting material-33 (168 g, 1824 mmol), 3-nitrobenzoic acid (30 g, 179 mmol) in 90 mL of conc.H2SO4. Then reaction mixture was heated at 150° C. for 7 h. After reaction cooled to RT and added MeOH (600 mL) and refluxed for 12 hours. Then cooled to 0° C. quenched with ice and concentrated. Crude reaction mixture was basified with NaHCO3, extracted with DCM and concentrated. Resulted crude material was purified by silica gel column chromatography eluting with Petroleum ether (60-80), ethyl acetate and 0.5percent of triethylamine as eluent. The product (intermediate-97) was obtained as a brown liquid (21 g).
Stage #1: With sulfuric acid; iron(II) sulfate In nitrobenzene at 200℃; for 5 h; Stage #2: With sodium hydroxide In water; nitrobenzene
N-((4-chloro-2-methylp yl)quinolin-6-yl)acetamidea) 2-(quinolin-6-yl)acetic acidA mixture of / aminophenylacetic acid (20 g, 0.132 mol), FeSC>4 (4.9 g, 0.032 mol), glycerol (51 g, 0.555 mol), PhN02 (10.5 g, 0.086 mol), and concentrated H2S04 (23 mL) was heated to 200 °C for 5 h. The reaction mixture was treated with 4 N aq. NaOH to adjust the pH to -10. The reaction mixture was filtered and the clear filtrate was acidified with AcOH to pH~5. The resultant precipitate was collected by filtration to afford the title compound (12.5 g, 51percent) as a brown solid. TLC: 20percent MeOH/CH2Cl2, Rf= 0.2.H NMR (300 MHz, DMSO-d6) 8 ppm 8.85 (m, 1H), 8.31 - 8.28 (m, 1H), 7.96 (d, J= 8.3 Hz, 1H), 7.82 (m, 1H), 7.67 - 7.64 (m, 1H), 7.50 - 7.49 (m, 1H), 3.78 (s, 2H).
17.8%
Stage #1: With sulfuric acid; iron(II) sulfate In nitrobenzene for 5 h; Heating / reflux Stage #2: With sodium hydroxide In water; nitrobenzene
A mixture of compound 1 (276 g, 1.8 mol), ferrous sulfate (63.6 g, 0.22 mol), glycerol (696 g, 7.56 mol), nitrobenzene (138 g, 1.12 mol) and cone, sulfuric acid (324 mL) was heated gently. After the first vigorous reaction, the mixture was refluxed for five hours and then was treated with aq. sodium hydroxide solution (2 N, 1320 mL), stirred with kieselguhr, and filtered. The filtrate was basified with aq. sodium hydroxide solution to pH 5~6, and a dark brown precipitate formed. The precipitate was filtered, washed with water, taken up with aq. sodium hydroxide solution (0.82 N, 3000 mL), then boiled with carbon (150 g). The mixture was filtered and the filtrate was treated with glacial acetic acid (240 mL), and the mixture was left standing overnight during which time dark-brown crystalline precipitate formed. The precipitate was collected and dried in vacuo to give crude compound 2 (60 g, 17.8percent).
Reference：
[1] Patent: WO2013/19682, 2013, A1, . Location in patent: Page/Page column 117
[2] Journal of Medicinal Chemistry, 2013, vol. 56, # 17, p. 6651 - 6665
[3] Patent: WO2007/138472, 2007, A2, . Location in patent: Page/Page column 28
[4] Journal of the American Chemical Society, 1948, vol. 70, p. 2843,2945
[5] Patent: WO2009/137404, 2009, A1, . Location in patent: Page/Page column 60
81
[ 5925-93-9 ]
[ 56-81-5 ]
[ 55706-57-5 ]
Reference：
[1] J. Annamalai Univ., 1933, vol. 2, p. 227,236
82
[ 2941-78-8 ]
[ 56-81-5 ]
[ 55706-57-5 ]
Reference：
[1] Journal of Organic Chemistry, 2013, vol. 78, # 17, p. 8217 - 8231
83
[ 98-16-8 ]
[ 56-81-5 ]
[ 325-14-4 ]
Yield
Reaction Conditions
Operation in experiment
69%
Stage #1: at 70 - 85℃; for 0.666667 h; Stage #2: With iodine; potassium iodide In water at 135℃; for 4 h;
H2SO4 (13.7 g, 0.14 mol) was slowly added to glycerol (8.63 g, 0.094 mol).The temperature must not exceed 70 ° C,Then add m-trifluoromethylaniline (5.00 g, 0.031 mol),The temperature was raised to 85 ° C and the reaction was carried out for 40 min.Add potassium iodide (0.30 g, 1.80 mmol),(0.34 g, 1.34 mmol) of iodine,Water (1.50 mL), warmed to 135 ° C, and reacted for 4 h.After cooling to room temperature, it was poured into ice to quench the reaction and suction filtered over Celite. The filtrate was adjusted to pH 7 with aqueous ammonia, suction filtered, and the filtrate was extracted with ethyl acetate.The organic phase is dried over anhydrous sodium sulfate and concentrated.The residue was subjected to column chromatography to give 7-trifluoromethylquinoline (3.50 g, 69percent).
22.13%
at 80 - 170℃; for 4 h;
Conc. sulfuric acid (4.56 g; 1.5 equiv.) was added dropwise to a mixture of 3-(trifluoromethyl)aniline (5 g; 1 equiv.), glycerol (5.14 g; 1.8 equiv.) and iodine (150 mg). The resulting reaction mixture was stirred for 1 hour at 80-90° C. and for 3 hours at 160-170° C. When the conversion was complete, the reaction mixture was diluted at room temperature with 100 ml of water, neutralised with sodium carbonate and extracted 4.x. with 200 ml of dichloromethane. The combined organic phases were dried over sodium sulfate, the solvent was removed under reduced pressure and the crude product was purified by column chromatography (silica gel, 10percent EtOAc/hexane). 7-(Trifluoromethyl)quinoline (1.35 g; 22.13percent) was obtained in the form of a white crystalline solid.
Reference：
[1] Patent: CN108409649, 2018, A, . Location in patent: Paragraph 0042; 0043; 0044
[2] Patent: US2010/234340, 2010, A1, . Location in patent: Page/Page column 21
84
[ 98-16-8 ]
[ 56-81-5 ]
[ 325-14-4 ]
[ 342-30-3 ]
Reference：
[1] Experientia, 1947, vol. 3, p. 28
[2] Journal of the American Chemical Society, 1943, vol. 65, p. 2467
[3] Journal of the Chemical Society, 1954, p. 3846,3849
85
[ 7664-93-9 ]
[ 98-16-8 ]
[ 7778-39-4 ]
[ 56-81-5 ]
[ 325-14-4 ]
[ 342-30-3 ]
Reference：
[1] Journal of the American Chemical Society, 1943, vol. 65, p. 2467
86
[ 536-25-4 ]
[ 56-81-5 ]
[ 5852-78-8 ]
Reference：
[1] Chemische Berichte, 1916, vol. 49, p. 16
87
[ 2840-29-1 ]
[ 56-81-5 ]
[ 204782-96-7 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1887, vol. 237, p. 323
[2] Justus Liebigs Annalen der Chemie, 1887, vol. 237, p. 323
88
[ 139399-67-0 ]
[ 56-81-5 ]
[ 66127-01-3 ]
Reference：
[1] Journal of Organic Chemistry, 1951, vol. 16, p. 941,945
89
[ 57339-57-8 ]
[ 56-81-5 ]
[ 40000-20-2 ]
Reference：
[1] Journal of the American Chemical Society, 1944, vol. 66, p. 396
90
[ 53472-18-7 ]
[ 56-81-5 ]
[ 40000-20-2 ]
Reference：
[1] Journal of the Chemical Society, 1946, p. 155
91
[ 875-51-4 ]
[ 56-81-5 ]
[ 68527-67-3 ]
Yield
Reaction Conditions
Operation in experiment
46%
at 150℃; for 0.75 h; Inert atmosphere
General procedure: To glycerol (4.7 mL, 62.0 mmol) preheated to 160 C for 1 hour, and cooled down to 110 C, 4-bromo-2-nitroaniline (5.00 g, 23.0 mmol) and sodium iodide (0.07 g, 0.48 mmol) were added. The mixture was vigorously stirred, heated to 150 C and sulfuric acid 95-98percent (2.8 ml, 53.0 mmol) was added drop wise. After 45 minutes at 150 C, the mixture was allowed to reach room temperature, and then distributed in DCM and water. The organic layer was separated, washed with water, brine solution, dried over Na2SO4 and evaporated. The crude product was purified through column chromatography to give 21 compound (2.6 g, 46percent); 1H NMR (300 MHz, DMSO-d6): δ 9.06 (d, J = 4.3 Hz, 1H), 8.52-8.66 (m, 3H), 7.79 (dd, J = 8.4, 4.2 Hz, 1H); LCMS (m/z) = 253 [M+1]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 5, p. 1100 - 1103
[2] Monatshefte fuer Chemie, 1994, vol. 125, # 6/7, p. 723 - 730
Reference：
[1] Chemistry - A European Journal, 2017, vol. 23, # 42, p. 9996 - 10000
94
[ 56-81-5 ]
[ 99-57-0 ]
[ 4008-48-4 ]
Reference：
[1] Archiv der Pharmazie (Weinheim, Germany), 1958, vol. 291, p. 168,175
95
[ 56-81-5 ]
[ 442-51-3 ]
Reference：
[1] Journal of the Chemical Society, 1919, vol. 115, p. 939
96
[ 42606-38-2 ]
[ 56-81-5 ]
[ 4199-88-6 ]
Reference：
[1] Journal of the Chemical Society, 1946, p. 155
97
[ 53981-25-2 ]
[ 56-81-5 ]
[ 35048-10-3 ]
Yield
Reaction Conditions
Operation in experiment
59%
With sulfuric acid In nitrobenzene at 140℃; for 6 h; Sealed tube; Inert atmosphere
To a solution of 2-amino-6-fluoro-phenol (2000 mg, 15.73 mmol) and nitrobenene (10 ml) in a sealable reaction pressure vessel was added in portions sulfuric acid (2 mL, 37.52 mmol). Glycerol (4.8 mL, 65.15 mmol) was added in one portion, and the solution turned to dark brown. The vessel was flushed with nitrogen, sealed and heated to 140 °C for 6 hours. The reaction mixture was cooled to ambient, diluted with (30 mL) ice/water mixture, extracted (2 X 200 mL) methyl tert-butyl ether. The aqueous phase was neutralized to pH~6-7 by slow addition of 6N sodium hydroxide. The resulting black precipitate was collected by filtration and the water solution was extracted with ethyl acetate 3 times. The organic extracts were combined with the black precipitate, concentrated in vacuo, and purified by automated normal-phase chromatography using 0-10percent methanol/dichloromethane as an eluent. The title compound was isolated as a solid (1.56 g, 59percent yield). MS (ES+) m/z 164.9 [M+H]+. 1H NMR (400 MHz, DMSO-^6) δ ppm 7.43 - 7.49 (m, 1 H) 7.50 - 7.57 (m, 2 H) 8.37 (dd, J=8.21, 1.64 Hz, 1 H) 8.90 (dd, J=4.17, 1.64 Hz, 1 H) 10.26 (br. s., 1 H).
51.7%
Stage #1: With sulfuric acid In nitrobenzene at 140℃; for 6 h; Stage #2: With sodium hydroxide In water
To a solution of 2-amino-6-fluorophenol (4.0 g, 31.6 mmol) and nitrobenzene (20 mL) in a sealable reaction vessel was added in portions sulfuric acid (4.0 mL). Glycerol (12.0 g, 126 mmol) was added in one portion, and the solution turned to dark brown. The vessel was flushed with nitrogen, sealed and heated to 140 °C for 6 h. The reaction mixture was cooled to rt, diluted with 30 mL ice/water mixture, and washed 3 times with methyl -butyl ether (removes most of the nitrobenzene). The aqueous phase was neutralized to pH=6-7 by slow addition of 6N NaOH. The resulting black precipitate was collected and the water solution was extracted with ethyl acetate 3 times. The organic extracts were combined with the black precipitate, concentrated in vacuo, and purified on silica gel column with 0-10percent MeOH/DCM to give 2.67 g (51.7percent) of 7-fluoro-8-quinolinol as an off-white solid.
Reference：
[1] Chemical Communications, 2006, # 18, p. 1941 - 1943
99
[ 56-81-5 ]
[ 635-21-2 ]
[ 6456-78-6 ]
Yield
Reaction Conditions
Operation in experiment
68.91%
Stage #1: at 65 - 140℃; for 5.5 - 7.5 h; Stage #2: at 0℃;
Example-2; 6-Chloro-l ,2,3,4-tetrahydro-quinoline-8-carboxylic acid (4-/er/-butyl-benzyl)-[2-(4- fluoro-phenyl)-ethyl]-amide, hydrochloride salt a) Concentrated sulfuric acid (73.83 g, 0.80 mol) was added dropwise to a vigorously stirred mixture of 2-amino-5-chloro-benzoic acid (90 g, 0.524 mol), I2 (1.65g, 6.4 mmol) in glycerol within 30 minutes, wherein the temperature of the mixture rises to 65-70 0C. The mixture was then heated to 135-140 0C for 5-7 hrs giving a dark brown foaming mixture. The reaction mixture was cooled to room temperature and poured into 1500 ml of ice water. The pH of the mixture was adjusted to 6.5 by adding 25-30 percent ammonia solution. The precipitated compound was filtered, washed with cold water and dried over P2O5 to get brown solid. of 6-chloro- quinoline-8-carboxylic acid (75 g) (Yield=68.91 percent).
68.91%
Stage #1: at 20 - 140℃; Stage #2: With ammonia In water; glycerol
Concentrated sulfuric acid (73.83 g, 0.80 mol) was added dropwise to a vigorously stirred mixture of 2-amino-5-chloro-benzoic acid (90 g, 0.524 mol), I2 (1.65 g, 6.4 mmol) in glycerol within 30 minutes, wherein the temperature of the mixture rises to 65-70° C. The mixture was then heated to 135-140° C. for 5-7 hrs giving a dark brown foaming mixture. The reaction mixture was cooled to room temperature and poured into 1500 ml of ice water. The pH of the mixture was adjusted to 6.5 by adding 25-30percent ammonia solution. The precipitated compound was filtered, washed with cold water and dried over P2O5 to get brown solid of 6-chloro-quinoline-8-carboxylic acid (75 g) (Yield=68.91percent).
7.9%
at 65 - 140℃; for 6.5 h;
1.01 g of 5-chloroanthranilic acid and 26.6 mg of iodine were mixed with 0.7 6 g of glycerol, and the mixture was vigorously stirred,0.44 ml of concentrated sulfuric acid was added dropwise at 65 ° C. to 70 ° C. over a period of 30 minutes and the reaction was carried out at 140 ° C. for 6 hours. Then,17 mL of water at 0 ° C. was added and the pH6.5 was filtered, the solid was washed with cold water and then dried. The obtained residue was dissolved in chloroform,Insolubles were removed by filtration, activated carbon was added to adsorb impurities, and the activated carbon was removed by filtration.The solvent was distilled off, and the residue obtained was recrystallized in a mixed solution of chloroform and ethyl acetate, and the obtained crystals were washed with ethyl acetate.The solvent was distilled off to obtain 96.2 mg (yield 7.9percent) of the compoundWas obtained. For this compound, NMR, mass spectrum,The melting point was measured, and the compound 2 having the structure of the general formula 3(6-chloroquinoline-8-carboxylic acid) was confirmed.
Reference：
[1] Patent: WO2008/59513, 2008, A2, . Location in patent: Page/Page column 14
[2] Patent: US2009/171091, 2009, A1, . Location in patent: Page/Page column 6
[3] Patent: JP2018/52866, 2018, A, . Location in patent: Paragraph 0046
100
[ 107-15-3 ]
[ 56-81-5 ]
[ 290-37-9 ]
[ 109-08-0 ]
[ 123-32-0 ]
[ 5910-89-4 ]
[ 6705-33-5 ]
[ 108-50-9 ]
[ 5780-66-5 ]
Reference：
[1] Kinetics and Catalysis, 2016, vol. 57, # 5, p. 602 - 609[2] Kinet. Katal., 2016, vol. 57, # 5, p. 607 - 614,8
Stage #1: With sulfuric acid; sodium 3-nitrobenzenesulfonate In water at 135℃; for 16 h; Stage #2: With sodium hydroxide In water
a. 1,7-Naphthyridin-8-amine A mixture of pyridine-2,3-diamine (5.0 g, 45.9 mmol), glycerol (21.1 g, 229 mmol), sodium 3-nitrobenzenesulphonate (20.6 g, 91.7 mmol), sulfuric acid (20 mL) and water (30 mL) was heated to 135° C. and stirred for 16 h. The mixture was cooled to room temperature and then poured into ice/water (150 g). The mixture was adjusted to pH ~9 with saturated NaOH aqueous solution. Then the mixture was extracted with EtOAc (3*100 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduce pressure to give the crude product, which was purified by silica gel column (eluting with PE/EtOAc v/v 2:1) to give 1,7-naphthyridin-8-amine as a yellow solid (2.6 g, yield 39percent). ESI MS: m/z 146.1 [M+H]+.
22%
With sulfuric acid; sodium 3-nitrobenzenesulfonate In water at 135℃; for 144 h;
To a mixture of pyridine-2 , 3-diamine (10.0 g, 91.74 mmol) , sodium 3-nitrobenzenesulfonate (41.3 g, 183.5 mmol) and glycerol (33.5 mL, 458.7 mmol) were added water (60 mL) and sulfuric acid (40 mL) . The reaction mixture was heated at 135°C for 6 days. The product formation was confirmed by TLC. The mixture was cooled to room temperature, and poured into ice-cold water. The pH of the mixture was adjusted to 8-9 with saturated NaOH solution (aq. ) . The aqueous layer was extracted with ethyl acetate (3 x 100 mL) . The combined organic layers were washed with brine (100 mL) and dried over sodium sulfate. The organic layer was evaporated under vacuo, then the crude material was purified by column chromatography using 5-10 percent methanol in DCM as a mobile phase to give the title compound (3.0 g, 22 percent) . MS(EI)m/z: 145.8 (M+l); XH NMR (400 MHz, DMSO-d6) : δ 6.90 - 6.92 (m, 3H) , 7.67 (dd, J = 3.6 & 8.0 Hz, 1H) , 7.86 (d, J = 6.0 Hz, 1H) , 8.16 (dd, J= 2.0 & 8.4 Hz, 1H) , 8.78 (dd, J = I.2, 4.0 Hz, 1H) .
Reference：
[1] JAOCS, Journal of the American Oil Chemists' Society, 2000, vol. 77, # 11, p. 1139 - 1145
[2] Journal of Agricultural and Food Chemistry, 2003, vol. 51, # 7, p. 2096 - 2099
[3] Agricultural and Biological Chemistry, 1987, vol. 51, # 8, p. 2153 - 2160
[4] Journal fuer Praktische Chemie (Leipzig), 1933, vol. <2>136, p. 309
[5] Ann.Chim.applic., vol. 25, p. 322[6] Chem. Zentralbl., 1935, vol. 106, # II, p. 3084
[7] Biochemische Zeitschrift, 1926, vol. 177, p. 166[8] Proceedings of the Imperial Academy (Tokyo), vol. 2, p. 343[9] Chem. Zentralbl., 1926, vol. 97, # II, p. 2451
[10] Gazzetta Chimica Italiana, 1912, vol. 42 II, p. 291
[11] Recueil des Travaux Chimiques des Pays-Bas, 1899, vol. 18, p. 193
[12] Industrial and Engineering Chemistry, 1929, vol. 21, p. 953[13] Chem. Zentralbl., 1930, vol. 101, # I, p. 3840
[14] Journal of the Chemical Society, 1934, p. 670[15] Journal of the Chemical Society, 1948, p. 987
[16] Chemistry and Physics of Lipids, 1995, vol. 77, # 2, p. 155 - 171
111
[ 56-81-5 ]
[ 112-76-5 ]
[ 555-43-1 ]
Reference：
[1] Journal of the American Oil Chemists' Society, 1958, vol. 35, p. 416
[2] Journal of the American Chemical Society, 1938, vol. 60, p. 2604
[3] Journal of the American Chemical Society, 1938, vol. 60, p. 2604
[4] Proceedings of the Royal Society of London, Series A: Mathematical, Physical and Engineering Sciences, 1942, vol. 181, p. 31
112
[ 57-11-4 ]
[ 56-81-5 ]
[ 555-43-1 ]
[ 22610-63-5 ]
[ 51063-97-9 ]
[ 621-61-4 ]
[ 504-40-5 ]
Reference：
[1] Magnetic Resonance in Chemistry, 2012, vol. 50, # 6, p. 424 - 428
113
[ 112-61-8 ]
[ 56-81-5 ]
[ 555-43-1 ]
[ 22610-63-5 ]
[ 51063-97-9 ]
[ 621-61-4 ]
[ 504-40-5 ]
Reference：
[1] JAOCS, Journal of the American Oil Chemists' Society, 1998, vol. 75, # 6, p. 755 - 756
[2] Asian Journal of Chemistry, 2015, vol. 27, # 2, p. 458 - 462
114
[ 334-48-5 ]
[ 56-81-5 ]
[ 60514-49-0 ]
[ 2277-23-8 ]
[ 17598-93-5 ]
[ 172588-12-4 ]
Reference：
[1] Journal of Molecular Catalysis B: Enzymatic, 2014, vol. 100, p. 7 - 18
115
[ 334-48-5 ]
[ 56-81-5 ]
[ 60514-49-0 ]
[ 621-71-6 ]
[ 2277-23-8 ]
[ 17598-93-5 ]
[ 172588-12-4 ]
Reference：
[1] Journal of Molecular Catalysis B: Enzymatic, 2014, vol. 100, p. 7 - 18
116
[ 110-42-9 ]
[ 56-81-5 ]
[ 2277-23-8 ]
[ 17863-69-3 ]
[ 17598-93-5 ]
Reference：
[1] Green Chemistry, 2013, vol. 15, # 3, p. 786 - 797
Reference：
[1] Green Chemistry, 2017, vol. 19, # 2, p. 390 - 396
119
[ 334-48-5 ]
[ 56-81-5 ]
[ 621-71-6 ]
[ 2277-23-8 ]
[ 17863-69-3 ]
[ 17598-93-5 ]
Reference：
[1] JAOCS, Journal of the American Oil Chemists' Society, 1999, vol. 76, # 7, p. 839 - 843
120
[ 334-48-5 ]
[ 56-81-5 ]
[ 621-71-6 ]
[ 2277-23-8 ]
[ 17598-93-5 ]
Reference：
[1] JAOCS, Journal of the American Oil Chemists' Society, 1996, vol. 73, # 11, p. 1521 - 1525
[2] JAOCS, Journal of the American Oil Chemists' Society, 2014, vol. 91, # 2, p. 261 - 270
121
[ 110-38-3 ]
[ 56-81-5 ]
[ 621-71-6 ]
[ 2277-23-8 ]
[ 3376-48-5 ]
[ 17863-69-3 ]
[ 17598-93-5 ]
Reference：
[1] JAOCS, Journal of the American Oil Chemists' Society, 1996, vol. 73, # 11, p. 1489 - 1495
Reference：
[1] Monatshefte fuer Chemie, 1890, vol. 11, p. 87
137
[ 7664-93-9 ]
[ 10035-10-6 ]
[ 56-81-5 ]
[ 194033-79-9 ]
[ 26944-17-2 ]
Reference：
[1] Monatshefte fuer Chemie, 1890, vol. 11, p. 87
[2] Journal of the American Chemical Society, 1935, vol. 57, p. 1282
138
[ 95-48-7 ]
[ 56-81-5 ]
[ 59-47-2 ]
Reference：
[1] Yakugaku Zasshi, 1954, vol. 74, p. 1273[2] Chem.Abstr., 1955, p. 14668
[3] Monatshefte fuer Chemie, 1908, vol. 29, p. 953
[4] Xenobiotica, 2000, vol. 30, # 5, p. 469 - 483
[5] Xenobiotica, 2000, vol. 30, # 5, p. 485 - 502
[6] Green Chemistry, 2013, vol. 15, # 3, p. 625 - 628
139
[ 120287-30-1 ]
[ 56-81-5 ]
[ 13296-94-1 ]
Reference：
[1] Chinese Chemical Letters, 2011, vol. 22, # 3, p. 253 - 255
140
[ 18162-48-6 ]
[ 56-81-5 ]
[ 102191-92-4 ]
Reference：
[1] European Journal of Organic Chemistry, 2014, vol. 2014, # 25, p. 5549 - 5556
141
[ 51792-34-8 ]
[ 56-81-5 ]
[ 146796-02-3 ]
Yield
Reaction Conditions
Operation in experiment
55%
With toluene-4-sulfonic acid; hydroquinone In diethylene glycol dimethyl ether at 140℃; for 10 h; Inert atmosphere
152 g (1.05 mol) of 3,4-dimethoxythiophene, 775 g (8.42 mol) of glycerin, 19.9 g (0.105 mol) of p-toluenesulfonic acid monohydrate, 11.5 g (0.105 mol ) of Hydroquinone and 3.68 L of diglyme were added to a reactor, and then the inside of the reaction system was sufficiently purged with argon gas. The oxygen concentration in the reaction vessel gas atmosphere was 0.3 vol percent. Thereafter, the mixture was heated to 140 ° C and stirred for 10 hours. After cooling to room temperature, the reaction solution was analyzed by gas chromatography and the formation rate of the target product (2) was 75percent and the formation rate of the by-product (4) was 0.5percent (molar ratio 99.3 : 0.7). 1.68 L of a 10percent sodium hydroxide aqueous solution was added and the mixture was allowed to stand for 12 hours. The solvent was distilled off and extracted three times with a toluene / saturated aqueous sodium chloride solution. The toluene layer was concentrated and dried and dissolved in 3.7 L of a mixed solvent of toluene / ethyl acetate = 4/1, and the insoluble matter was filtered off. The solvent was distilled off and dissolved in 220 g of toluene, then 220 g of hexane was further added, and the mixture was allowed to stand at about 10 ° C for 2 hours. The obtained crystals were filtered, then washed with hexane and dried under vacuum to obtain 100 g of the desired product (2) as a white precipitate (yield: 55percent). By gas chromatography, 0.5percent of the by-product (4) was contaminated, and the purity of the target product (2) was 99.5percent.
Reference：
[1] Patent: JP2018/65778, 2018, A, . Location in patent: Paragraph 0044-0081
Reference：
[1] Chemical Communications, 2006, # 18, p. 1941 - 1943
144
[ 56-81-5 ]
[ 289686-70-0 ]
Reference：
[1] Patent: CN105523916, 2016, A, . Location in patent: Paragraph 0036; 0033; 0034; 0037
145
[ 656-65-5 ]
[ 56-81-5 ]
[ 127827-52-5 ]
Yield
Reaction Conditions
Operation in experiment
85.8%
With sulfuric acid; sodium 3-nitrobenzenesulfonate In water at 120 - 140℃;
The starting material, 3-fluoro-4-bromoaniline (20 g, 0.105 mol) And catalyst sodium 3-nitrobenzenesulfonate (28 g, 0.124 mol, 1.2 eq) was added to a mixed solution of concentrated sulfuric acid (60 ml) and water (24 ml), heated to an internal temperature of 120 ° C, Glycerol (29 g, 0.315 mol, 3 eq) was added slowly and the reaction was warmed to 130-140 ° C overnight after the addition was complete and allowed to cool. The reaction solution was poured into crushed ice, concentrated ammonia to pH 8, extracted with dichloromethane, washed with water, After drying, column chromatography purified to give a yellow solid 20.3g, yield 85.8percent.
81%
With sulfuric acid; sodium 3-nitrobenzenesulfonate In water at 110 - 140℃;
4-Bromo-3-fluoroaniline (D-1, 5.0 g, 26.3 mmol) and sodium 3-nitrobenzenesulfonate (7.1 g, 31.6 mmol)were added to the mixture of H2SO4 (20ml) and H2O (10ml). When the mixture was heated to 110C, Glycerin (7.27 g,78.9 mmol) was added slowly, then the reactionwas stirred at 140C overnight. After cooled to rt, the mixture was poured to alarge amount of ice water, concentrated ammonia water was added to adjust topH=8, then extracted with EtOAc, washed with brine and dried over anhydrous Na2SO4,then purified by flash column chromatography to afford6-bromo-7-fluoroquinoline as white solid (D-2,4.8 g, 81percent yield). LC-MS (ESI): [M+H]+=226. 1H NMR (400MHz, CDCl3) δ 8.93 (dd, J1=4.4Hz, J2=1.6 Hz, 1H),8.12-8.02 (m, 2H), 7.81 (d, J=9.6 Hz, 1H), 7.41 (dd, J1=8.4 Hz, J2=4.4 Hz, 1H).
51.9%
Stage #1: With sulfuric acid; iron(II) sulfate In nitrobenzene at 130℃; for 14 h; Stage #2: With ammonia; water In nitrobenzene at 20℃;
Step 1: A mixture of compound A (90 g, 0.60 mol), glycerol (1800 g, 1.9 mol), ferrous sulfate (27 g, 0.0954 mol), nitrobenzene (99 mL, 0.95 mol) and concentrated sulfuric acid (261 mL, 4.77 mol) was heated at 130° C. for 14 h. The reaction mixture was allowed to cool to room temperature and basified to pH about 8 by 28percent NH3 solution. The resulting mixture was extracted with CH2Cl2 (1000 mL.x.3). The combined organic phases was evaporated and the residue was dried in vacuo to afford crude compound B, which was purified by column chromatography (silica gel, EtOAc/Petroleum ether=1:10) to yield compound B (56 g, 51.9percent) as a yellow solid.
44%
at 140℃; for 12 h;
Intermediate 2: (7-fluoroquinolin-6-yl)methanamine Step 1 : 6-Bromo-7-fluoroquinoline: To a mixture of 4-bromo-2-fluoroaniline (10 g, 52.62 mmol), ferrous sulphate (3.33 g, 11.97 mmol) and glycerol (15.78 ml) con. sulphuric acid (9.15 ml) was added slowly and the reaction mixture was heated to 140°C. After 12h, the reaction mixture was cooled to 0°C and the pH adjusted to 10-12 with 10percent sodium hydroxide solution. The reaction mixture was filtered through celite, washed with ethyl acetate and layers were separated. The organic layer was washed with brine solution, dried over sodium sulphate and concentrated. The crude product was purified by column chromatography with ethyl acetate: petroleum ether to afford the title compound as a white solid (4.9 g, 44percent). 'H- NMR (δ ppm, CDC13, 400 MHz): δ 8.96 (dd, J = 4.3, 2.7 Hz, 1H), 8.15 (m, 2H), 7.81 (d, J = 9.5 Hz, 1H), 7.42 (dd, J = 8.3,4.3 Hz, 1H).
44%
Stage #1: at 140℃; for 12 h; Stage #2: With sodium hydroxide In water at 0℃;
Step 1: 6-Bromo-7-fluoroquinoline To a mixture of 4-bromo-2-fluoroaniline (10 g, 52.62 mmol), ferrous sulphate (3.33 g, 11.97 mmol) and glycerol (15.78 ml) con. sulphuric acid (9.15 ml) was added slowly and the reaction mixture was heated to 140° C. After 12 h, the reaction mixture was cooled to 0° C. and the pH adjusted to 10-12 with 10percent sodium hydroxide solution. The reaction mixture was filtered through celite, washed with ethyl acetate and layers were separated. The organic layer was washed with brine solution, dried over sodium sulphate and concentrated. The crude product was purified by column chromatography with ethyl acetate: petroleum ether to afford the title compound as a white solid (4.9 g, 44percent). 1H-NMR (δ ppm, CDCl3, 400 MHz): δ 8.96 (dd, J=4.3, 2.7 Hz, 1H), 8.15 (m, 2H), 7.81 (d, J=9.5 Hz, 1H), 7.42 (dd, J=8.3, 4.3 Hz, 1H).
42.5%
With iron(III) sulfate; sulfuric acid In nitrobenzene for 7 h; Heating / reflux
Intermediate 2: 6-Bromo-7-fluoro-quinoline; [0302] A mixture of 4-bromo-3-fluoroaniline (2.85 g, 15 mmol), ferric sulfate (0.95 g, 6.25 mmol), glycerol (5.66 g, 61 mmol), nitrobenzene (0.93 mL, 9.1 mmol), and concentrated sulfuric acid (2.61ml) was heated gently. After the first vigorous reaction, the mixture was boiled for 7h. Nitrobenzene was then evaporated in vacuo. The aqueous solution was acidified with glacial acetic acid, and a dark brown precipitate separated, which was collected and purified by flash chromatography (silica gel, petroleum/ethyl acetate= 8/1) to give 1.44 g of 6-bromo-7-fluoro-quinoline as white crystals (42.5percent yield).
42.5%
With sulfuric acid; iron(II) sulfate In nitrobenzene for 7 h; Heating / reflux
A mixture of 4-bromo-3-fluoro-phenylamine (2.85 g, 15 m mole), ferrous sulfate (0.95 g), glycerol (5.658 g, 4.5 ml), nitrobenzene (1.125 g, 0.93 ml) and concentrated sulfuric acid (2.61 mL) were heated gently. After the first vigorous reaction, the mixture was heated to reflux for 7 hours. Nitrobenzene was evaporated in vacuo. The aqueous solution was acidified with glacial acetic acid and dark brown precipitate separated, which was purified by flash chromatography (silica gel, petroleum: ethyl acetate= 8:1) to return compound title as white crystals (1.44 g, 42.5percent).
39%
Stage #1: at 130℃; for 14 h; Stage #2: With ammonium hydroxide In waterCooling with ice
Intermediate E and F 7-Fluoro-quinoline-6-carbaldehyde and 7-(7-Fluoro-quinolin-6-yl)-methylamine 6-bromo-7-fluoro quinoline (i) To a suspension of 4-bromo-3-fluoro-phenylamine (100 g, 526 mmol) in concentrated sulfuric acid (290 ml.) was added glycerol (220 g, 2.39 mol, 4.5 eq.) followed by ferrous sulfate (30 g, 0.2 eq.). The reaction mixture was heated at 130 0C for 14 h, cooled to rt and poured into ice-water. The solution was neutralized with saturated aqueous ammonium hydroxide to pH 8 and extracted with DCM (2 L x 3). The combined organic layers were washed with brine (1 L x 3), dried over sodium sulfate and concentrated under reduced pressure to afford the crude product as a brown solid, which was purified by column chromatography (Petroleum:Ethyl acetate=10:1 ) to give 6-bromo-7-fluoro quinoline as a white solid (45 g, 39percent). 1H-NMR (400MHz, DMSO-Cf6) δ ppm 8.86 (s, 1 H), 8.56 (m, 1 H), 8.45 (m, 1 H), 7.90 (d, 1 H), 7.71 (m, 1 H).
Reference：
[1] Patent: CN105968115, 2016, A, . Location in patent: Paragraph 0560-0562
[2] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 18, p. 4281 - 4290
[3] Patent: US2007/265272, 2007, A1, . Location in patent: Page/Page column 31-32
[4] Patent: WO2013/144737, 2013, A2, . Location in patent: Paragraph 252
[5] Patent: US2015/57309, 2015, A1, . Location in patent: Paragraph 0509
[6] Patent: WO2008/51808, 2008, A2, . Location in patent: Page/Page column 79
[7] Patent: WO2008/144767, 2008, A1, . Location in patent: Page/Page column 107
[8] Patent: WO2011/18454, 2011, A1, . Location in patent: Page/Page column 57
[9] Patent: WO2011/20861, 2011, A1, . Location in patent: Page/Page column 61
[10] Patent: US2011/281865, 2011, A1, . Location in patent: Page/Page column 84
[11] European Journal of Medicinal Chemistry, 2017, vol. 134, p. 147 - 158
146
[ 367-24-8 ]
[ 56-81-5 ]
[ 127827-52-5 ]
Yield
Reaction Conditions
Operation in experiment
44%
at 140℃; for 12 h;
To a mixture of 4-bromo-2-fluoroaniline (10 g, 52.62 mmol), ferrous sulphate (3.33 g, 11.97 mmol) and glycerol (15.78 ml), con.sulphuric acid (9.15 ml) was added slowly and the reaction mixture was heated to 140°C. After 12h, the reaction mixture was cooled to 0°C and the pH adjusted to 10-12 with 10percent sodium hydroxide solution. The reaction mixture was filtered through celite, washed with ethyl acetate and layers were separated. The organic layer was washed with brine solution, dried over sodium sulphate and concentrated. The crude product was purified by column chromatography with ethyl acetate: petroleum ether to afford the title compound as a white solid (4.9 g, 44percent). 'H-NMR (δ ppm, CDC13, 400 MHz): 8.96 (dd, J = 4.3, 2.7 Hz, 1H), 8.15 (m, 2H), 7.81 (d, J = 9.5 Hz, 1H), 7.42 (dd, J = 8.3,4.3 Hz, 1H).
With sulfuric acid; sodium 3-nitrobenzenesulfonate In water at 120 - 130℃; for 1.5 h;
The raw materials 3,5-difluoroaniline G-1 (5.6 g, 27 mmol) and sodium 3-nitrobenzenesulfonate (7.2 g, 32 mmol) Was added to a mixed solution of concentrated sulfuric acid (15 mL) and water (6 mL) After heating to an internal temperature of 120 ° C, glycerol (7.4 g, 80 mmol) After the addition was completed, the temperature was raised to 130 ° C and reacted for 1.5h, then cooled. The reaction was poured into crushed ice, concentrated ammonia water to adjust the pH to 5 ~ 6, the precipitated solid was filtered off, washed with water, After drying, column chromatography gave 3.82 g of white solid compound G-2 in 58percent yield. A mixture of 6-bromo-7-methylquinoline (I-2) and 6-bromo-5-methylquinoline (J-1) was synthesized. Then separated by supercritical preparative chromatography (SFC), IC-H column, mobile phase: isopropanol / carbon dioxide = 18/82, detection wavelength: 254nm. The first fraction was collected as 6-bromo-7-methylquinoline (I-2) as a white solid, yield: 25percent. The second fraction was collected as a 6-bromo-5-methylquinoline (J-1) white solid in a yield of 20percent
Reference：
[1] Patent: CN105968115, 2016, A, . Location in patent: Paragraph 0492; 0518-0520
[2] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 18, p. 4281 - 4290
149
[ 6933-10-4 ]
[ 56-81-5 ]
[ 122759-89-1 ]
Yield
Reaction Conditions
Operation in experiment
31%
Stage #1: With iron(III) sulfate; sulfuric acid In nitrobenzene for 3 h; Heating / reflux Stage #2: With water; sodium hydrogencarbonate In nitrobenzene
Intermediate 4: 6-Bromo-7-methyl-quinoline; [0304] A mixture of 4-bromo-3-methylaniline (20 g, 107.5 mmol), ferric sulfate (6.6 g, 43.4 mmol), glycerol (40.8 g, 440 mmol), nitrobenzene (8.12 g, 66 mmol), and concentrated EPO <DP n="81"/>sulfuric acid (23 ml) was heated gently. After the first vigorous reaction, the mixture was boiled for 3h and then evaporated to remove the excess nitrobenzene. The solution was added a saturated aqueous solution of sodium bicarbonate until pH=7-8, then the solution was filtered and extracted with dichloromethane. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The solid was purified by flash column chromatography to give a yellow solid, which was further washed with petroleum ether to give 7.5 g of 6-bromo-7-methyl-quinoline (31percent yield): 1H NMR (CDCl3): 2.60 (s, 3H), 7.36 (m, IH), 7.96 (s, IH), 8.04 (m, 2H), 8.89 (m, IH).
Stage #1: With sulfuric acid; sodium 3-nitrobenzenesulfonate In water at 110℃; Stage #2: at 95 - 140℃; Stage #3: With ammonia In water
A solution of concentrated sulphuric acid (63 ml, 820 mmol) in water (49.4 ml) was treated with sodium 3-nitro-benzenesulfonate (commercially available, for example, from Aldrich) (47.9 g, 213 mmol) and glycerol (commercially available, for example, from Fluka) (52 ml, 720 mmol) to give a thick grey suspension. This was heated to 110 0C. 4-Bromo-2- fluoroaniline (commercially available, for example, from Fluorochem) (38 g, 200 mmol) was added portion wise over 10 min, during which the temperature rose to 95 0C. The reaction was heated to 140 0C and stirred overnight. The reaction mixture was cooled and then poured into water (1000 ml) and basified to pH 7 with aqueous ammonia (0.88 s.g., 190 ml). The brown precipitated that formed was collected by filtration and partially dried. This solid <n="50"/>(63 g) was loaded onto a Silica column (1500 ml) and eluted with EtOAc to give the title compound (43.8 g, 96.9percent) LCMS RT = 2.87 min, ES+ve m/z 226/228 [M+H]+.
88%
With sulfuric acid; sodium 3-nitrobenzenesulfonate In water at 95 - 140℃;
A solution of concentrated H2504 (0.63 ml, ii .82 mmoi) in H20 (0.48 ml, 26.6 mmoi) was treated with 3-Nitrohenzenesulfonic acid, sodium salt ( 0.48g. 2.132 nrniol) and glycerol (0.516 ml. 706 mmoi) to give a thick grey suspension, the mixture was heated to 110 °C. 4-Bromo2fluoroaniline was added portion wise over 10 mm, during which the temperature rose to 95 °C. The reaction was heated to 140 °C and stirred overnight. The reaction mixture was cooled and then poured into water and basified to pH 7 with aqueous ammonia. The brown precipitated that formed was collected by filtration and partially dried. This solid (0.63 g) was purified by flash column chromatography givethe 6-bromo-8-fluoroquinohne (04 g, 1770 mmoi, 88 percent yield) compound.
81.2%
With sulfuric acid; sodium 3-nitrobenzenesulfonate In water at 110 - 140℃;
Glycerol (14.5 g, 158 mmol) And the catalyst sodium 3-nitrobenzenesulfonate (14.2 g, 63 mmol) were added to the sulfuric acid Aqueous solution (20 mL of concentrated sulfuric acid + 15 mL of water), The mixture was heated to 110 ° C and 2-fluoro-4-bromoaniline C-1 (10 g, 52.6 mmol) was added slowly and stirred at 140 ° C overnight. After dropping to room temperature, pour into crushed ice, adjust the pH to about 8 with concentrated aqueous ammonia, extract with ethyl acetate, wash with water, Washed with saturated saline, dried over anhydrous sodium sulfate, filtered and evaporated to dryness. The crude product was purified by column chromatography to obtain 9.65 g of white solid compound C-2, yield 81.2percent
60%
Stage #1: With sulfuric acid; sodium 3-nitrobenzenesulfonate In water at 135℃; Stage #2: With sodium hydroxide In waterCooling with ice
5.00 g (26.3 mmol) of 4-bromo-2-fluoroaniline, 5.31 g (57.89 mmol) glycerol and 9.89 g (43.94 mmol) of 3-nitrophenylsulfonic acid-sodium salt were prepared and homogenized. Then 25 ml of 70percent sulfuric acid was added dropwise. The mixture was stirred overnight at 135°C. The cooled black reaction mixture was made alkaline, cautiously and with ice cooling, with 50percent sodium hydroxide solution, and then filtered on a large bed of silica gel and kieselguhr. It was washed again with water and ethyl acetate. The phases collected were combined, then the organic phase was separated. The aqueous phase that remained was then extracted with ethyl acetate (2x). Then the organic phases thus obtained and the phase already separated previously were combined. It was dried over magnesium sulfate and the volatile components were removed in a rotary evaporator. The residue was finally purified by MPLC (Puriflash Analogix: 4OM: isohexane / ethyl acetate = 4 / 1). We obtained 3.56 g (60percent of theor.) of the target compound. IH-NMR (400 MHz, DMSO-D6): δ [ppm] = 7.70 (dd, 2H), 7.89 (dd, IH), 8.17 (s, IH), 8.44 (d, IH), 9.00 (d, IH).
Reference：
[1] Patent: WO2009/50204, 2009, A1, . Location in patent: Page/Page column 15; 48-49
[2] Patent: WO2018/116072, 2018, A1, . Location in patent: Page/Page column 97; 98
[3] Patent: CN105968115, 2016, A, . Location in patent: Paragraph 0449-0451
[4] Patent: WO2010/20363, 2010, A1, . Location in patent: Page/Page column 131-132
[5] Journal of Medicinal Chemistry, 2010, vol. 53, # 10, p. 4066 - 4084
Stage #1: at 120℃; for 4 h; Stage #2: With water; sodium hydroxide In ethanol; ethyl acetate; nitrobenzene at 20℃;
To a mixture of 5-bromo-2-(trifluoromethyl)aniline (3.0g, 12.6mmol), glycerol (4.64g, 50.0mmol), and ferrous sulfate (0.56 g, 2.0mmol) was added cone, sulfuric acid (2.2mL) dropwise. The reaction mixture was heated at 120 0C for 4hr. After cooled to RT, the reaction was diluted with ethyl acetate (15OmL), and 2N aq. NaOH was introduced to adjust pH about 13. The organic layer was separated and washed with brine and dried over Na2SO4 and evaporated to give the crude product, which was purified with flash column chromatography to give 5-bromo- 8-(trifluoromethyl)quinoline (1.2g, 48percent).
Reference：
[1] Patent: WO2010/91310, 2010, A1, . Location in patent: Page/Page column 101
[2] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 18, p. 5521 - 5527
With methanesulfonic acid; ferrous sulfate hydrate; sodium 3-nitrobenzenesulfonate; at 120 - 135℃; for 16h;
Sodium nitrobenzene sulfonic acid (3.9 g, 17.3 mmol) and methanesulfonic acid (10 ml) were placed in a 100 ml three-necked flask and stirred. 0.2 g (0.8 mmol) of iron (II) sulfate hydrate, and 3-methoxyaniline (3.09 mL) were added dropwise and the mixture was heated to about 120 C.6.3 g of glycerol was added and the reaction was carried out at 135 C. for 16 hours. After completion of the reaction, 10Approximately 100 mL of M aqueous NaOH solution was added and extracted with ethyl acetate. The organic layer was collected, dried over anhydrous magnesium sulfate, and the solvent was removed and purified by column chromatography to obtain 4.2 g of RL-0107 (yield: about 48%).
With sulfuric acid; nitrobenzene; at 0 - 160℃; for 3h;
To a 0 °C solution of glycerol (46 g, 0.5 mol), reagent 1 (12.3 g, 0.10mol) and nitrobenzene (12.3 g, 0.10 mol) was concentrated sulfuric acid (39.2 g, 0.4 mmol). The mixture was then stirred at 160 °C for 3 hours. The resulting solution was cooled to the room temperature and diluted with water (100 mL). It was then neutralized with saturated aqueous NaHCO3 solution to adjust pH = 7, and the resulting mixture was extracted with EtOAc (300mL x 3). The organic layers were combined, washed with brine (100 mL) and dried over Na2SO4. The Na2SO4 was removed by filtration, and the volatiles were removed under reduced pressure. The resulting residue was purified by flash chromatography using a mixture of hexane and ethyl acetate to obtain the pure product 2 (6.5 g, 41percent) as a yellow solid. LCMS(M+Hj m/z: cacld. 160.18, found 160.10; ?H-NMR (CDC13): 8.74(dd, 1H),8.9 (dd, 1H), 7.33 - 7.38 (m, 2H), 7.26 (d, 1H), 2.48(s, 3H).
With methanesulfonic acid; In toluene; at 120℃; for 2.5h;Large scale;
Add 10 kg of glycerol and 13.26 kg of benzoic acid to the reaction kettle.Methane sulfonic acid catalyst was added 0.05 kg of toluene and the agent with 2kg,The reaction was completed at 120 oC for 150 min.The catalyst was extracted and recovered by water, and the raw material was removed by distillation under reduced pressure to give an intermediate glycerol mono benzoate, yield 97.5%, purity 99%.
99%Chromat.
With poly(ethylene glycol) 1000 based dicationic acidic ionic liquid; In toluene; at 80℃; for 1h;Ionic liquid;
General procedure: Aromatic acids (2 mmol) and alcohols (3 mmol) were added into a 10 mL tube reactor preloaded with PEG1000-DAIL (2 mL) and toluene (2 mL). The reaction mixture was stirred thoroughly at 80C for 1 h. After the completion of reaction, the mixture separated into two phases at room temperature, the upper phase was decanted for analysis and the below phase was reused for the next time directly or after removing water under vacuum at 80C for 1 h.
With Amberlyst 15 resin acid catalyst; at 100℃; for 5.0h;Large scale; Green chemistry;
1000 g of glycerin (analytical grade) was taken, added to a 1000 mL three-necked flask, and the temperature was raised to 100 C, and 260-400 g of paraformaldehyde was added in portions.After all the paraformaldehyde was dissolved, 20% of the A15 resin acid catalyst (based on the mass of glycerin) was added.Keep the three-necked bottle open,The reaction was continued for five hours while maintaining 100 C.After cooling to 40 C, it was suction filtered with a Buchner funnel.Sodium carbonate was added to the flask to neutralize to pH 7, and the solid impurities were removed after standing.The filtrate was separated by a rotary evaporator. Remove the water before 40-50C, then heat to 70-80C to distill off the first fraction (by-product), then slowly increase to 130-150C to collect the second fraction, ie, glycerol formal (colorless, transparent, liquid with a certain viscosity) ) 1118 grams,The yield is over 95% (calculated as glycerol).
With sulfuric acid; sodium 3-nitrobenzenesulfonate sulfuric acid; In water; at 140℃;
To the solution of concentrated sulfuric acid (18 mL) diluted with water (6 mL), was added <strong>[367-34-0]2,4,5-trifluoroaniline</strong> (3.68 g, 25 mmol), glycerol (4.60 g, 50 mmol) and sodium 3-nitrobenzenesulfonate (6.75 g, 30 mmol) in sequence. The resulting suspension was stirred at 140°C overnight. The reaction mixture was cooled to room temperature and added saturated NaHCC>3 aqueous solution to adjust pH to 7, extracted with dichloromethane (200 mL x 2). The combined organic layer was evaporated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 3/1) to give the desired product (3.5 g, 76percent) as a yellow solid. H NMR (400 MHz, CDC13) delta 8.99 (s, IH), 8.46- 8.44 (m, IH), 7.61-7.56 (m, IH), 7.38-7.31 (m, IH).
85percent sulfuric acid (623 g) was added to a 1 L reaction flask, and o-fluoroaniline (133 g, 1.2 mol) was added dropwise. Warm to 130°C and stir for 2 hours. The reaction temperature was controlled at 130°C, and the mixture was dropped with glycerol (121 g, 1.3 mol) and potassium iodide (3 g). The resulting solution was stirred at 130C for 18 hours after the addition was complete. The reaction solution was cooled to room temperature and slowly added to ice water. After the release, an aqueous solution of sodium hydroxide was added dropwise to adjust the pH to 8-9. Extract with methyl tert-butyl ether to concentrate the separated oil layer. The tert-butyl ether was re-distilled under high vacuum through a packed distillation column to obtain high-purity 8-fluoroquinoline (146 g). The rate is 83percent and the gas chromatogram content is 99.7percent.
Concentrated sulfuric acid (3 eq) was added dropwise to a vigorously stirred mixture of 4-fluoro aniline (1 eq), I2 (0.1 eq), in glycerol (1.5 eq) within 0.5 h, wherein the temperature of the mixture rises to 65-70 C. The mixture was then heated to 135-140 0C for 10-12 h giving dark brown forming mixture. The mixture was cooled to room temperature and quenched in ice cooled water. pH of the solution was adjusted to 8 to 9 by adding 25-30percent ammonia solution. Aqueous layer was extracted with EtOAc. Organic layer was washed with brine, dried over sodium sulfate and evaporated in vacuo to get crude product. Purification of the crude product thus obtained by the way of flash column chromatography (SiO2, 8:2 (v/v) hexane:: EtOAc) to afforded title compound as dark red liquid.
9.71 grams of glycerin was placed into a 100-ml round bottom flask with 4.69 grams of 36% hydrochloric acid. A distillation apparatus was connected to the round bottom flask. The temperature was set at 120 C. Over a period of 30 minutes 47.29 grams of cysteine hydrochloride was added. When the temperature reached 100 C., all of the cysteine hydrochloride was in solution. The reaction ran until there was no further removal of water. Glycerin (50%) is then added to product. Reaction time: four hours Water removed: 9.1 grams Color: amber
8-Methylquinoline-7-carboxylic acid (19): A mixture of <strong>[52130-17-3]3-amino-2-methylbenzoic acid</strong> (18) (6.1 g, 39.7 mmol), arsenic acid (7.4 g, 52.3 mmol), and glycerol (5.8 mL, 79.4 mmol) in sulfuric acid (9 mL) was heated at 160 0C for 5 hours. The reaction mixture was cooled to room temperature and diluted with water. The mixture was filtered through a bed of celite and the filtrate was adjusted with 2 M NaOH to pH ~ 6. The aqueous layer was extracted numerous times with chloroform/isopropanol. The pooled organic layers were removed under vacuum. The solid residue was triturated with chloroform. The mixture was filtered, and the solid was washed with hexane and dried under high vacuum to give 8- methylquinoline-7-carboxylic acid (19) 3.86 g (20.6 mmol, 52% yield).
51%
With sulfuric acid; orthoarsenic acid; at 160℃; for 5h;
A mixture of <strong>[52130-17-3]3-amino-2-methylbenzoic acid</strong> (Intermediate M1) (6.06 g, 39.6 mmol) (commercially available from Aldrich) and arsenic acid (H5As3O10) 7.43 g (commercially available from VWR/ALFA) in glycerol (5.8 mL, 79.2 mmol), and sulfuric acid (9 mL) was heated to 160 C. for 5 h. The mixture was cooled to rt, diluted with water and filtered through a bed of diatomaceous earth. The pH was adjusted to pH 6-7 with 2 M NaOH. The aqueous layer was exhaustively extracted with CHCl3:MeOH (3:1). The organic fractions were pooled and evaporated under vacuum to give a solid. This solid was titurated with CHCl3, and collected on a glass frit. The solid material was washed with hexanes and dried under high vacuum to give a pure solid, 8-methylquinoline-7-carboxylic acid (Intermediate M2) 3.86 g (51%). A solution of 8-methylquinoline-7-carboxylic acid (Intermediate M2) (3.86 g, 20.6 mmol) in thionyl chloride (15 mL) was heated to reflux for 1 h. The mixture was cooled to rt and concentrated under vacuum. The material was diluted in CH2Cl2 and decanted into a clean flask. The mixture was treated with N,O-dimethylhydroxylamine-HCl (3.0 g, 30.1 mmol) and triethylamine (10.6 mL, 76 mmol) at 0 C. The mixture was stirred at rt for several h. After a typical aqueous work-up, the residue was purified by chromatography on silica gel with 50 to 60% EtOAc:hexane to give N-methoxy-N-8-dimethylquinoline-7-carboxamide (Intermediate M3) 3.91 g (82% over two steps) as in Method L. N-methoxy-N-8-dimethylquinoline-7-carboxamide (Intermediate M3) (3.91 g, 17 mmol) was subjected to the appropriate process steps in Method L to produce (8-methylquinolin-7-yl)(1-trityl-1H-imidazol-4-yl)methanone (Intermediate M4) 3.59 g (44%). A solution of (8-methylquinolin-7-yl)(1-trityl-1H-imidazol-4-yl)methanone (Intermediate M4) (3.59 g, 7.49 mmol) in THF (100 mL) at 0 C. was treated with MeMgBr (5.0 mL, 3M in ether) for 16 h. The reaction mixture was quenched with NH4Cl (aq) and extracted with EtOAc. The layers were separated and dried over MgSO4, filtered, evaporated and purified by column chromatography on silica gel with 3 to 4% NH3-MeOH. The alcohol in CH2Cl2 (100 mL) was treated with Et3N (8.4 mL, 60.3 mmol) and methane sulfonyl chloride (1.75 mL, 22.6 mmol) at 0 C. for 3 h. The mixture was quenched with water and extracted with CH2Cl2. The organic layers were pooled and evaporated to give 8-methyl-7-[1-(1-trityl-1H-imidazol-4-yl)vinyl]quinoline (Intermediate M5) 2.14 g (60% over two steps). This material was used in the next step without further purification. A solution of 8-methyl-7-[1-(1-trityl-1H-imidazol-4-yl)vinyl]quinoline (Intermediate M5) (2.14 g, 4.49 mmol) in TFA (40 mL) was reduced by action of 10% Pd/C (0.51 g) under H2 (45-50 psi) for 16 h at rt. The mixture was filtered through celite and the solvent was removed under vacuum. The residue was purified by chromatography on silica gel with 2-4% NH3-MeOH:CH2Cl2 to give 7-[1-(1H-imidazol-4-yl)ethyl]-8-methylquinoline (Intermediate M6) 834 mg, (79%). 7-[1-(1H-Imidazol-4-yl)ethyl]-8-methylquinoline (Intermediate M6) was subjected to the appropriate process steps in Method A to produce 4-[1-(8-methyl-quinolin-7-yl)-ethyl]-1,3-dihydro-imidazole-2-thione (Compound 18). 1H NMR (300 MHz, CD3OD): delta 11.91 (brs, 1H), 11.77 (brs, 1H), 8.92 (dd, J=4.2, 1.8 Hz, 1H), 8.28 (dd, J=8.4, 1.8 Hz, 1H), 7.76 (d, J=8.7 Hz, 1H), 7.49 (dd, J=8.1, 4.2 Hz, 1H), 7.36 (d, J=8.4 Hz, 1H), 6.69 (s, 1H), 4.44 (q, J=7.2 Hz, 1H), 2.82 (s, 3H), 1.49 (d, J=7.2 Hz, 3H).
Intermediate 2: 8-Methyl-7-quinolinecarbox lic acidTo a solution of concentrated sulfuric acid (21 .74 ml) in water (16ml), was added 3- amino-2-methylbenzoic acid (5g; supplier Acros), 1 ,2,3-propanetriol (2.437 ml) and sodium iodide (0.104 g). The reaction mixture was heated to reflux for 2 hours at 150C. Further 1 ,2,3-propanetriol (2.437 ml) was added and reaction mixture was refluxed for another two hours. The pH of the reaction mixture was adjusted to pH 3 by adding sodium hydroxide (12.5 M, 32.6 ml) then the mixture was filtered and the solid discarded. The aqueous phase was extracted with ethyl acetate and then the organic solvent was removed under vacuum to give crude product. This was dissolved in 1 :1 DMSO & MeOH and purified by reverse phase chromatography and relevent fractions were combined and concentrated to afford the title compound (750 mg) as a white solid.LCMS (low pH) RT 0.45 min, m/z (ES) 188 [M+H]+
750 mg
With sulfuric acid; sodium iodide; In water; at 150℃; for 4h;
Intermediate 2: 8-Methyl-7-quinolinecarboxylic acid[0174][0175]To a solution of concentrated sulfuric acid (21.74 ml) in water (16 ml), was added <strong>[52130-17-3]3-amino-2-methylbenzoic acid</strong> (5 g; supplier Acros), 1,2,3-propanetriol (2.437 ml) and sodium iodide (0.104 g). The reaction mixture was heated to reflux for 2 hours at 150 C. Further 1,2,3-propanetriol (2.437 ml) was added and reaction mixture was refluxed for another two hours. The pH of the reaction mixture was adjusted to pH 3 by adding sodium hydroxide (12.5 M, 32.6 ml) then the mixture was filtered and the solid discarded. The aqueous phase was extracted with ethyl acetate and then the organic solvent was removed under vacuum to give crude product. This was dissolved in 1:1 DMSO & MeOH and purified by reverse phase chromatography and relevant fractions were combined and concentrated to afford the title compound (750 mg) as a white solid.[0176]LCMS (low pH) RT 0.45 min, m/z (ES) 188 [M+H]+
Example-2; 6-Chloro-l ,2,3,4-tetrahydro-quinoline-8-carboxylic acid (4-/er/-butyl-benzyl)-[2-(4- fluoro-phenyl)-ethyl]-amide, hydrochloride salt a) Concentrated sulfuric acid (73.83 g, 0.80 mol) was added dropwise to a vigorously stirred mixture of 2-amino-5-chloro-benzoic acid (90 g, 0.524 mol), I2 (1.65g, 6.4 mmol) in glycerol within 30 minutes, wherein the temperature of the mixture rises to 65-70 0C. The mixture was then heated to 135-140 0C for 5-7 hrs giving a dark brown foaming mixture. The reaction mixture was cooled to room temperature and poured into 1500 ml of ice water. The pH of the mixture was adjusted to 6.5 by adding 25-30 percent ammonia solution. The precipitated compound was filtered, washed with cold water and dried over P2O5 to get brown solid. of 6-chloro- quinoline-8-carboxylic acid (75 g) (Yield=68.91 percent).
68.91%
Concentrated sulfuric acid (73.83 g, 0.80 mol) was added dropwise to a vigorously stirred mixture of 2-amino-5-chloro-benzoic acid (90 g, 0.524 mol), I2 (1.65 g, 6.4 mmol) in glycerol within 30 minutes, wherein the temperature of the mixture rises to 65-70° C. The mixture was then heated to 135-140° C. for 5-7 hrs giving a dark brown foaming mixture. The reaction mixture was cooled to room temperature and poured into 1500 ml of ice water. The pH of the mixture was adjusted to 6.5 by adding 25-30percent ammonia solution. The precipitated compound was filtered, washed with cold water and dried over P2O5 to get brown solid of 6-chloro-quinoline-8-carboxylic acid (75 g) (Yield=68.91percent).
7.9%
With sulfuric acid; iodine; at 65 - 140℃; for 6.5h;
1.01 g of 5-chloroanthranilic acid and 26.6 mg of iodine were mixed with 0.7 6 g of glycerol, and the mixture was vigorously stirred,0.44 ml of concentrated sulfuric acid was added dropwise at 65 ° C. to 70 ° C. over a period of 30 minutes and the reaction was carried out at 140 ° C. for 6 hours. Then,17 mL of water at 0 ° C. was added and the pH6.5 was filtered, the solid was washed with cold water and then dried. The obtained residue was dissolved in chloroform,Insolubles were removed by filtration, activated carbon was added to adsorb impurities, and the activated carbon was removed by filtration.The solvent was distilled off, and the residue obtained was recrystallized in a mixed solution of chloroform and ethyl acetate, and the obtained crystals were washed with ethyl acetate.The solvent was distilled off to obtain 96.2 mg (yield 7.9percent) of the compoundWas obtained. For this compound, NMR, mass spectrum,The melting point was measured, and the compound 2 having the structure of the general formula 3(6-chloroquinoline-8-carboxylic acid) was confirmed.
Ethyl 8-chloro-6-quinolinecarboxylate. A solution of <strong>[2486-71-7]4-amino-3-chlorobenzoic acid</strong> (12.8 g; 0.069 mol.), glycerol (29.1 g; 0.316 mol.), sodium 3-nitrobenzenesulfonate (29.8 g; 0.132mol.) and 75% aq. sulfuric acid (110 ml_) was stirred and heated at 100 0C for 3 h then at 140 0C for 1 h. The mixture was allowed to cool to 60 then ethanol was added and the solution stirred and heated at 60 overnight. The solution was evaporated and the residue poured into a ice-water mixture then basified with sat. aq. ammonium hydroxide. The mixture was then diluted with ethyl acetate (1 L), filtered to remove charred material, then the organic layer separated, dried and evaporated. The residue was purified by chromatography (silica gel, 50% ethyl acetate in hexanes) to give the title compound (5.7 g; 35%) as a yellow solid. 1 H NMR (400 MHz, DMSO-Qf6) delta ppm 1.38 (t, J=7.07 Hz, 3 H) 4.40 (q, J=7.07 Hz, 2 H) 7.75 (dd, J=8.34, 4.29 Hz, 1 H) 8.27 (d, J=1.77 Hz, 1 H) 8.66 (d, J=1.77 Hz, 1 H) 8.68 (dd, J=8.46, 1.64 Hz, 1 H) 9.13 (dd, J=4.04, 1.77 Hz, 1 H).
With rabbit 3-hydroxyhexobarbital dehydrogenase (AKR1C29); NADPH; In aq. phosphate buffer; ethyl acetate; at 37℃; for 0.5h;pH 7.4;Enzymatic reaction;Catalytic behavior; Kinetics;
General procedure: The reaction was conducted at 37°C in a 2.0-mL reaction mixture, containing coenzyme (1-mM NADP+ or 0.1-mM NADPH), substrate (0.05?0.1mM), enzyme (0.1?0.3mg), and 0.1-M potassium phosphate, pH 7.4. The substrate and products were extracted into 4-mL ethyl acetate 30min after the reaction was started at 37°C. The products of oxidoreduction of steroids [25] and reduction of PGD2 [28], farnesal [29] and 4-oxo-2-nonenal [18] were analyzed by TLC, as described. The reduced products of TBE were identified by the HPLC methods [23]. The products of 3HB oxidation, 3OB reduction, 5beta-androstane-3alpha,17beta-diol oxidation and 5beta-androstan-3alpha-ol-17-one reduction were analyzed by the liquid chromatography?electrospray ionization-mass spectrometry (LC?ESI-MS) using a Hewlett-Packard HP 1100 Series LC/MSD system attached with a diode array detector and a column (Mightysil RP-18 GP 5mum, 4.6mm×250mm, Kanto Chemical Co., Tokyo, Japan). Separations were carried out at a flow rate of 0.5mL/min and 40°C using the following mobile phases: 25percent acetonitrile aqueous solution containing 0.1percent formic acid for 3OB and alpha/beta-3HBs, and 80percent acetonitrile aqueous solution containing 0.1percent formic acid for the two steroids. 3OB, alpha-3HB, beta-3HB, 5beta-androstan-3alpha-ol-17-one and 5beta-androstane-3alpha,17beta-diol were detected by monitoring their total ions (m/z 249.1, 251.1, 251.1, 289.4 and 291.4, respectively) in the negative ESI mode, and eluted at the retention times of 20.1, 17.6, 16.8, 14.9 and 12.7min, respectively. The detection limits of 3OB, alpha/beta-3HBs and the two steroids were 0.1, 0.1 and 1nmol, respectively.
platinum on carbon; In water; for 3h;Direct aqueous phase reforming;
Direct aqueous phase reforming (APR) experiments were conducted in 100-ml stirred reactors with draft-tube gas-induction impeller (Parr Series 4590). Reaction tests for direct bio-based feedstock aqueous phase reforming (APR) entailed filling the reactor with 60-grams of solvent (deionized water, or a mixture of DI water and isopropanol (IPA), and 3-3.5 grams of bio-based feedstock comprising biomass (bagasse, or pine sawdust)). One (1) gram of acetic acid was optionally charged to facilitate biomass hydrolysis.[0098] Bagasse was milled via a 1-mm grate. Dry, debarked Loblolly pine was ground via blender (Thomas Scientific of Swedesboro, NJ) and sieved to less than 30 mesh. Dry solids fraction was determined by vacuum drying at 80 °C to 82 °C. One gram of aqueous phase reforming catalyst (reduced 5percent Pt/C catalyst at 50percent moisture, or powdered 1.9percent Pt/A1203) was charged to the reactor, which was charged with 4200 kPa of hydrogen or nitrogen. To minimize degradation of hydrolysate to heavy ends, each reactor was typically heated with a staged temperature sequence of one hour at, 160 °C, 190 °C, 225 °C, and finally 250 °C, before leaving overnight at the final setpoint.[0099] Comparison tests were also conducted with glucose or sorbitol fed directly to the reaction in place of biomass, to simulate and quantify conversion of model hydrolysate to APR intermediates. Glucose is one of the sugars readily leached from biomass in hot water, while sorbitol is readily formed via hydrogenation of glucose, where platinum or other catalysts capable of hydrogenation are present.[00100] A batch reaction time of 20 hours under these conditions corresponds to a weight hourly space velocity (g-feed/g-catalyst/h) of about 3, for a comparable continuous flow reactor. A 0.5-micron sintered metal filter attached to a dip tube allowed liquid samples to be taken throughout the course of reaction, without loss of biomass or catalyst. Samples were analyzed by an HPLC method based on combined size and ion exclusionchromatography, to determine unreacted sorbitol, and amount of C3 and smaller polyols formed: glycerol (Gly), ethylene glycol (EG), and 1,2-propylene glycol (PG). Additional GC analysis via a moderate polarity DB-5 column were conducted to assess formation of C6 and lighter oxygenates (e.g., ketones, aldehydes, alcohols), as well as alkane and alkene products. A separate GC equipped with thermal conductivity and flame ionization (FID) detectors for refinery gas analysis, were used for detection of H2, C02, and light alkanes C1-C5. GC-mass spec was used to characterize select APR reaction product mixtures. Examples 1-3[00101] Batch APR reactions with sugar cane bagasse as biomass feed, and with a comparison of 25percent sorbitol as feed, were performed as described above. 1.7percent acetic acid was added to simulate catalysis of hydrolysis by recycle acid. Products formed from this concentration of acetic acid were subtracted from total product formation, to calculate the net production of liquid fuels from bagasse. This result shown in Table 1 shows the critical importance of concerted APR reaction with hydrolysis of biomass. In the absence of concerted aqueous phase reforming, the hydrolysate undergoes irreversible degradation (presumably to heavy ends), and cannot be reverted to liquid fuels upon subsequent APR and condensation. Converted reaction may be effected by direct inclusion of APR catalyst in the hydrolysis reactor, or via a pump around loop to recirculate liquid between a biomass contactor, and an APR catalytic reactor. Table 1: Direct APR of Biomass
With arsenic pentoxide; sulfuric acid; at 100 - 160℃; for 2.0h;
To a mixture of 3-methoxy-4-nitro-phenylamine (13.4 g, 80.0 mmol), arsenic pentoxide (11.0 g, 48.0 mmol) and glycerol (33 mL, 216.0 mmol) at 100 C., was added, dropwise, concentrated sulfuric acid (4.7 mL, 88.0 mmol). The reaction mixture was then heated at a temperature ranging between 150 and 160 C. for 2 hours and then was cooled. Water (200 mL) was added and the resulting mixture was extracted four times with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude residue was purified by flash chromatography (EtOAc) to give 9.00 g (61% yield) of 7-methoxy-6-nitro-quinoline as an orange solid.
Step 2.Preparation of 6-methoxy-7-methylquinoline (3B): To 4-methoxy-3- methylaniline (6.7 g) was added concentrated H2S04 (12.4 mL), followed by glycerin (21.1 g), m-nitrobenzenesulfonic acid (6.53 g), H3B03 (3.4 g) and FeS04»7H20 (3.2 g). The mixture was stirred at 140 C for 1 h. The reaction was cooled to 25 C, quenched with ice- water and neutralized with 30% KOH. The mixture was extracted with DCM (2x), and the combined extracts dried with Na2S04 and concentrated in vacuo. The crude product was purified by column chromatography (EtOAc) to give 6-methoxy-7- methylquinoline (4.3 g) LCMS-ESf (m/z): 174.1 (M+H)+.
With ferrous(II) sulfate heptahydrate; sulfuric acid; boric acid; 3-Nitrobenzenesulfonic acid; at 140℃; for 1h;
Preparation of 6-methoxy-7-methylquinoline: To <strong>[136-90-3]4-methoxy-3-methylaniline</strong> (6.7 g) was added concentrated H2S04 (12.4 mL), followed by glycerin (21.1 g), m- nitrobenzenesulfonic acid (6.53 g), H3B03 (3.4 g) and FeS04*7H20 (3.2 g). The mixture was stirred at 140 C for 1 h. The reaction was cooled to 25 C, quenched with ice-water and neutralized with 30% KOH. The mixture was extracted with DCM (2x), and the combined extracts dried with Na2S04 and concentrated in vacuo. The crude product was purified by column chromatography (EtOAc) to give 6-methoxy-7-methylquinoline LCMS-ESI+ (m/z): 174.1 (M+H)+.
With sulfuric acid; sodium 3-nitrobenzenesulfonate; In water; at 137℃; for 2h;
A 250 mL round bottom flask equipped with a stirbar and condenser was charged with <strong>[56131-46-5]3-bromo-2-chloroaniline</strong> (0.867 g, 4.20 mmol), 3-nitrobenzenesulfonate sodium salt (1.686 g, 7.49 mmol), and propane-1,2,3-triol (1.083 g, 11.76 mmol). The mixture was then taken up in water (0.737 mL) and then carefully treated with concentrated sulfuricacid (1.363 mL). The reaction mixture was then heated to i37 °C with stirring for 2 h. The reaction mixture was then cooled to room temperature and the flask fitted with an ice bath. The mixture was then carefully adjusted to basic pH with saturated aq sodium bicarbonate. The mixture was then allowed to stir for 20 mm and then diluted with water (200 mL) and dichloromethane (200 mL). The entire mixture was then transferred to a iseparatory funnel. The organic layer was isolated and the aqueous re-extracted with an additional quantity of dichloromethane (~100 mL). The organics were then pooled, dried over sodium sulfate, filtered, and concentrated to afford the title compound as a dark brown solid (1.081 g, 4.01 mmol, 96percent yield). MS(ES)+ m/e 242.1 [M+H]+.
With lipozyme; In 1,4-dioxane; at 55℃; for 48h;Enzymatic reaction;
To a 1,4-dioxane solution (200 mL) containing glycerol(18.4 g, 0.20 mol) and vinyl benzoate (29.6 g, 0.20 mol),Lipozyme (30 g) was added, and the mixture was stirred for48 h at 55C. After removal of the enzyme by filtration, thereaction mixture was evaporated under reduced pressure andthe residue was partitioned between saturated brine and dichloromethane(100 mL each), and extracted with dichloromethane(3 60 mL). The combined organic layer waswashed with saturated brine, and dried over anhydrousNa2SO4. The extract was washed with hexane to removeunreacted vinyl benzoate. Subsequently, the extract was vacuumdried, affording 36 g of (±)-1 (75% yield) as a colorlessoil. IR (KBr), cm-1: 3600 - 3100, 3050, 1700, 1300, 690; 1HNMR (200 MHz, CDCl3) 3.64-3.86 (2H, m, C3H2), 4.04-4.14 (1H, m, C2H), 4.39-4.57 (2H, m, C1H2), 7.40-7.52 (2H,m, 2C7H), 7.56 (1H, m, C8H), 8.02-8.13 (2H, m, 2C6H); 13CNMR (CDCl3, 200MHz) 63.8 (C3), 65.5 (C1), 70.6 (C2),128.6 (2C7), 129.4 (2C6), 130.7 (C5), 133.1 (C8), 166.5(C4). EI-LR-MS, m/z, M+: 196.
75%
With Mucor miehei lipase (lipozyme); In 1,4-dioxane; at 55℃; for 48h;Enzymatic reaction;
To a 1,4-dioxane solution (200 mL) containing glycerol(18.4 g, 0.20 mol) and vinyl benzoate (29.6 g, 0.20 mol),Lipozyme (30 g) was added, and the mixture was stirred for48 h at 55C. After removal of the enzyme by filtration, thereaction mixture was evaporated under reduced pressure andthe residue was partitioned between saturated brine and dichloromethane(100 mL each), and extracted with dichloromethane(3 60 mL). The combined organic layer waswashed with saturated brine, and dried over anhydrousNa2SO4. The extract was washed with hexane to removeunreacted vinyl benzoate. Subsequently, the extract was vacuumdried, affording 36 g of (±)-1 (75% yield) as a colorlessoil. IR (KBr), cm-1: 3600 - 3100, 3050, 1700, 1300, 690; 1HNMR (200 MHz, CDCl3) 3.64-3.86 (2H, m, C3H2), 4.04-4.14 (1H, m, C2H), 4.39-4.57 (2H, m, C1H2), 7.40-7.52 (2H,m, 2C7H), 7.56 (1H, m, C8H), 8.02-8.13 (2H, m, 2C6H); 13CNMR (CDCl3, 200MHz) 63.8 (C3), 65.5 (C1), 70.6 (C2),128.6 (2C7), 129.4 (2C6), 130.7 (C5), 133.1 (C8), 166.5(C4). EI-LR-MS, m/z, M+: 196.
With tetrabutylammonium benzoate; In acetonitrile; at 40℃;Green chemistry;
General procedure: Diols and polyol reactants (100 mg) were allowed to react with benzoic anhydride (1.1 equiv) in acetonitrile (1 mL) at 40C for 8-12 h in the presence of TBAOBz (0.2 equiv). The reaction mixture was directly purified by flash column chromatography (hexanes/EtOAc=2:1 to 1:1), affording the pure selectively protected derivatives.
2,3-dihydroxy-propyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
93%
at 160℃; for 24h;Dean-Stark; Inert atmosphere;
j0116] To a 1 L reactor fitted with a Deane-Stark trap was added 153.1 g (550 mmol, 1.0 eq) of 3-(3,5-di-tert-butyl-4- hydroxyphenyl)propionic acid and 506.55 g (5.50 mol, 10 eq) of glycerol. Reaction mixture was stirred under a weak nitrogen stream while heated at 160 C. for 24 hours. Product was diluted with water, and then extracted with ethyl acetate and then the organic phase was dried with sodium sulfate. The organic phase was filtered off drying agent and the ethyl acetate was removed by rotary evaporation to reveal clear amber viscous liquid (93% yield bymass).
7-(((3-(3,5-di-tert-butyl-4-hydroxyphenyl)propanoyl)oxy)methyl)-3-(hydroxymethyl)-1,4,6,9-tetraoxa-5-boraspiro[4.4]nonan-1-ium-5-ide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
To a 10 mL round bottom flask was added and 0.9322 g (10.0 mmol, 2.0 eq) of glycerol and 0.313 g (5.0 mmol, 1.0 eq) of boric acid. The reaction mixture was stirred under a weak nitrogen stream while being heated at 90 C. for 15 mm. The water was removed by distillation and the mixture was heated to 190 C. and 1.4 g (5.029 mmol, 1.0 eq) of 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionic acid was added and allowed to stir for 7 hat 190 C. and cooled to room temperature to obtain product.
With ferrous(II) sulfate heptahydrate; sulfuric acid; boric acid; sodium 3-nitrobenzenesulfonate; In water; at 50 - 135℃;Cooling with ice; Reflux;
Ice bath under conditions of 250 mLOf the three bottles by adding concentrated H2SO441 g (22 mL),Stir by addingSodium nitrobenzene sulfonate17.5 g (78 mmol),Boric acid2.4 g (39 mmol),FeSO4 · 7H2O 1.4 g (5 mmol)Glycerol 12.5 mL,2-amino-6-methylpyridine (4.3 g, 40 mmol)Mixed evenly after adding 22.5mL 50 warm water,in135 ° CUnder reflux2-3h,After cooling; with 50percent NaOH solution transferred to alkaline, filter,The aqueous solution was extracted three times with chloroform and the organic layer was dried over anhydrous MgSO4,The solvent was removed by rotary distillation to give the crude product which was recrystallized from cyclohexane to give 2-methylnaphthyridine,Ie probe reagent;The concentrated sulfuric acid concentration is 95-98percent;
propane-1,2,3-triyl tris(3,4-bis(benzyloxy)-5-bromobenzoate)[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
General procedure: The intermediate 3a-d (1.0 mmol) was dissolved in dichloromethane (10.0 mL), which has been dried through refluxing, under nitrogen atmosphere. Then, DMAP (1.5 mmol), EDCI (1.25mmol) were added to it in order. Then, ethylene glycol (0.5 mmol), glycerin (0.3 mmol), ribose (0.25 mmol) or xylose (0.25 mmol) was added. After stirring for 24 h at room temperature, the mixture was poured into water and washed with 1 mol/L HCl. The CH2Cl2 layer was concentrated, and the residue was purified using flash chromatography (ethyl acetate: Petroleum ether, 1:100-1:20) to obtain 4-6a, 4-7c or 4-7d. Compound 6-7a, 4-7b, 6d were used directly in the next step without purification and structural characterization.
With ferrous(II) sulfate heptahydrate; sulfuric acid; at 120℃; for 4h;
To a solution of 5-bromo-2-chloroaniline (2.06 g, 9.88minol) in propane-1,2,3-triol (4.23 g, 45.90 minol) was added FeSO4.7H20 (520 mg, 1.87 minol) and sulfuric acid (3 g, 29.67 minol) at room temperature. The resultingminxture was stirred for 4 h at 120 °C. After cooling to room temperature, the reactionminxture was adJusted to pH 13 using sodium hydroxide solution (2 M). The resultingminxture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in hexane (0percent to 94percent gradient) to yield 5-bromo-8-chloroquinoline as yellow solid (760 mg, 32percent). MS: m/z = 243.8 [M+Hj.
With toluene-4-sulfonic acid; hydroquinone; In diethylene glycol dimethyl ether; at 140℃; for 10h;Inert atmosphere;
152 g (1.05 mol) of <strong>[51792-34-8]3,4-dimethoxythiophene</strong>, 775 g (8.42 mol) of glycerin, 19.9 g (0.105 mol) of p-toluenesulfonic acid monohydrate, 11.5 g (0.105 mol ) of Hydroquinone and 3.68 L of diglyme were added to a reactor, and then the inside of the reaction system was sufficiently purged with argon gas. The oxygen concentration in the reaction vessel gas atmosphere was 0.3 vol percent. Thereafter, the mixture was heated to 140 ° C and stirred for 10 hours. After cooling to room temperature, the reaction solution was analyzed by gas chromatography and the formation rate of the target product (2) was 75percent and the formation rate of the by-product (4) was 0.5percent (molar ratio 99.3 : 0.7). 1.68 L of a 10percent sodium hydroxide aqueous solution was added and the mixture was allowed to stand for 12 hours. The solvent was distilled off and extracted three times with a toluene / saturated aqueous sodium chloride solution. The toluene layer was concentrated and dried and dissolved in 3.7 L of a mixed solvent of toluene / ethyl acetate = 4/1, and the insoluble matter was filtered off. The solvent was distilled off and dissolved in 220 g of toluene, then 220 g of hexane was further added, and the mixture was allowed to stand at about 10 ° C for 2 hours. The obtained crystals were filtered, then washed with hexane and dried under vacuum to obtain 100 g of the desired product (2) as a white precipitate (yield: 55percent). By gas chromatography, 0.5percent of the by-product (4) was contaminated, and the purity of the target product (2) was 99.5percent.
With sulfuric acid; sodium 3-nitrobenzenesulfonate sulfuric acid; at 130℃;
To the solution of concentrated sulfuric acid (30 mL) diluted with water (20 mL), was added pyridin-4-amine (3.76 g, 40.0 mmol), glycerol (12.52 g, 136 mmol) and sodium 3-nitrobenzenesulfonate (19.8 g, 88.0 mmol) in sequence. The resulting suspension was stirred at 130°C overnight. The reaction mixture was cooled to roomtemperature and added saturated NaOH aqueous solution to adjust pH to 10, extracted with dichloromethane (200 mL x 2). The combined organic layer was evaporated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/1) to give the desired product (900 mg, 69percent) as a white solid. H NMR (400 MHz, CDC13) delta 9.30 (s,lH), 9.12 (s,lH), 8.78 (d, / = 5.2 Hz, 1H), 8.32 (d, / = 8.0 Hz, 1H), 7.94 (d, / = 5.2 Hz, 1H), 7.62-7.48 (m, 1H).
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
110K+ Compounds
Competitive Price
1-2 Day Shipping
