* 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.
Step 1 6-Chloro-1H-benzo[d]1,3-oxazine-2,4-dione A 500 mL 3-necked round bottom flask was charged with 2-amino-5-chlorobenzoic acid (17 g, 0.1 mol) and 1,2-dichloroethane (200 mL). To the above was added dropwise a solution of triphosgene (21 g, 0.21 mol) in 1,2-dichloroethane (100 mL) at 80° C. The resulting mixture was heated at 80° C. for further 3 h then cooled in ice-water. The precipitate was collected by filtration and dried to afford 19 g (97percent) of the product as white solid. 1H NMR (300 MHz, DMSO-d6) δ: 11.85 (br, 1H), 7.88 (d, J=2.4 Hz, 1H), 7.78 (dd, J=8.7, 2.4 Hz, 1H), 7.15 (d, J=8.7 Hz, 1H).
97%
at 80℃; for 3 h;
A 500 mL 3-necked round bottom flask was charged with 2-amino-5- chlorobenzoic acid (17 g, 0.1 mol) and 1 ,2-dichloroethane (200 mL). To the above was added dropwise a solution of triphosgene (21 g, 0.21 mol) in 1,2- dichloroethane (100 mL) at 80 °C. The resulting mixture was heated at 80 °C for further 3 h then cooled in ice- water. The precipitate was collected by filtration and dried to afford 19 g (97percent) of the product as white solid. *H NMR (300 MHz, DMSO-d6) δ: 11.85 (br, 1H), 7.88 (d, J = 2.4 Hz, 1H), 7.78 (dd, J = 8.7, 2.4 Hz, 1H), 7.15 (d, J = 8.7 Hz, 1H).
Reference：
[1] Patent: US2010/120741, 2010, A1, . Location in patent: Page/Page column 78
[2] Patent: WO2011/112731, 2011, A2, . Location in patent: Page/Page column 174
[3] Journal of Medicinal Chemistry, 2013, vol. 56, # 16, p. 6434 - 6456
[4] Chemical Biology and Drug Design, 2010, vol. 75, # 5, p. 444 - 454
[5] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 10, p. 2295 - 2299
[6] Tetrahedron Letters, 2014, vol. 55, # 26, p. 3607 - 3609
[7] Biochemistry, 2017, vol. 56, # 49, p. 6491 - 6502
[8] Journal of Organic Chemistry, 2018, vol. 83, # 4, p. 2006 - 2017
[9] Chemical Biology and Drug Design, 2018, vol. 92, # 5, p. 1914 - 1919
2
[ 635-21-2 ]
[ 503-38-8 ]
[ 4743-17-3 ]
Yield
Reaction Conditions
Operation in experiment
92%
at 20℃; for 4 h; Heating / reflux
Trichloromethyl CHLOROFORMATE (4.8 mL, 300 mmol) was added to a stirred solution of Compound 57 (6.84 g, 40 mmol) in dry dioxane at room temperature and the solution was refluxed for 4 h. The solution was cooled in an ice bath and the solids formed were filtered. The solids were washed by ether and dried under vacuum at room temperature to yield 7.3 g (92percent) of white SOLIDS. H NMR (DMSO-D6) : d 7.47 (d, J= 8.6 Hz, 1H), 7.70 (dd, J= 8.6, 1.8 Hz, 1H), 7.82 (d, J= 1.1, 1H), 11.63 (S, 1H).
Reference：
[1] Journal of Organic Chemistry, 2014, vol. 79, # 9, p. 4196 - 4200
4
[ 79-37-8 ]
[ 635-21-2 ]
[ 4743-17-3 ]
Reference：
[1] Journal of Medicinal Chemistry, 2003, vol. 46, # 1, p. 138 - 147
5
[ 75-44-5 ]
[ 635-21-2 ]
[ 4743-17-3 ]
Reference：
[1] European Journal of Medicinal Chemistry, 1983, vol. 18, # 3, p. 241 - 247
6
[ 77287-34-4 ]
[ 635-21-2 ]
[ 16064-14-5 ]
Yield
Reaction Conditions
Operation in experiment
93.3%
at 150℃; for 2 h;
Examples 13 to 21:; The reaction and the post-treatment were carried out in the same manner as in Example 5, for which, however, the type of the anthranilic acid derivative was changed. The results are shown in Table 4.
90%
at 140℃;
General procedure: To a three necked flask, substituted anthranilic acid (1 meq.) was added in excess of formamide (6 meq). The reaction mixture was then heated at 140 °C for 4-6 h. The reaction was monitored with thin layer chromatography and upon completion; ice was added to the reaction mixture. The resultant solid was filtered, washed with water, dissolved in ethyl acetate, dried over MgSO4 and concentrated to obtain the pure desired product. Where product did not precipitate on addition of ice, the reaction mixture was extracted with ethyl acetate, dried over MgSO4 and concentrated to obtain the desired quinazolin-4(3H)-one derivatives 1-9, 11-15, 17-21 and 23-25.The amino derivatives 10, 16 and 22 were prepared using the following general procedure:To a reaction flask, substituted nitroquinazolin-4(3H)-one derivative (0.3 g, 1.56 mmol) was added followed by addition of 6 mL ethyl acetate and SnCl2*2H2O (2.12 g, 9.42 mmol), then reaction mixture was refluxed for 8 h. The reaction mixture was cooled to room temperature and quenched with saturated sodium bicarbonate solution, followed by repeated extraction with ethyl acetate (3 .x. 50 mL). The organic layers were combined, dried over anhydrous MgSO4 and concentrated to obtain the desired amino substituted quinazolin-4(3H)-one derivatives 10, 16 and 22.The substituted anthranilic acid (1 g) was dissolved in excess acetic anhydride (10 mL) and the resulting reaction mixture was stirred at room temperature for 4-7 h. The reaction was monitored for completion using thin layer chromatography. The solvent was evaporated under vacuum and the resultant residue was stirred with ammonia solution for 7 h. Upon completion, the reaction mixture was extracted with ethyl acetate (3 .x. 10 mL), the organic extracts were combined, dried over MgSO4 and evaporated to obtain compounds 26-30, 31a and 32. The 2-methyl-8-nitroquinazolin-4(3H)-one intermediate (31a) was reduced to compound 31 using the same procedure as reported in Scheme 1 for the synthesis of compounds 10, 16 and 22.
Reference：
[1] Patent: EP1997812, 2008, A1, . Location in patent: Page/Page column 8
[2] European Journal of Medicinal Chemistry, 2012, vol. 50, p. 264 - 273
[3] Chemistry and Biodiversity, 2017, vol. 14, # 4,
[4] Molecules, 2006, vol. 11, # 6, p. 383 - 392
[5] Journal of Medicinal Chemistry, 1983, vol. 26, # 3, p. 420 - 425
[6] Journal of the American Chemical Society, 1946, vol. 68, p. 1303
[7] Journal of the Indian Chemical Society, 1959, vol. 36, p. 787,789, 790
[8] Huaxue Xuebao, 1956, vol. 22, p. 335,336[9] Scientia Sinica (English Edition), 1958, vol. 7, p. 1035,1036
[10] Journal of Organic Chemistry, 1952, vol. 17, p. 149,153
[11] Zhurnal Obshchei Khimii, 1938, vol. 8, p. 1797,1801[12] Chem. Zentralbl., 1940, vol. 111, # I, p. 370
[13] Bioorganic and Medicinal Chemistry, 1996, vol. 4, # 8, p. 1203 - 1207
[14] Biochemistry, 2017, vol. 56, # 49, p. 6491 - 6502
[15] Chemistry and Biodiversity, 2018, vol. 15, # 6,
7
[ 6313-33-3 ]
[ 635-21-2 ]
[ 16064-14-5 ]
Reference：
[1] Journal of Medicinal Chemistry, 1999, vol. 42, # 19, p. 3860 - 3873
8
[ 635-21-2 ]
[ 16064-14-5 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 2003, vol. 11, # 3, p. 383 - 391
9
[ 635-21-2 ]
[ 7253-22-7 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 2003, vol. 11, # 3, p. 383 - 391
[2] Bioorganic and Medicinal Chemistry, 1996, vol. 4, # 8, p. 1203 - 1207
[3] Zeitschrift fuer Naturforschung, Teil B: Anorganische Chemie, Organische Chemie, 1982, vol. 37, # 7, p. 907 - 911
[4] Journal of the American Chemical Society, 1946, vol. 68, p. 1303
[5] Journal of the Indian Chemical Society, 1959, vol. 36, p. 787,789, 790
[6] Oriental Journal of Chemistry, 2010, vol. 26, # 4, p. 1401 - 1406
[7] Patent: WO2016/91774, 2016, A1,
10
[ 77287-34-4 ]
[ 635-21-2 ]
[ 7253-22-7 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 1997, vol. 7, # 4, p. 417 - 420
Reference：
[1] Bioorganic and Medicinal Chemistry, 2009, vol. 17, # 1, p. 119 - 132
13
[ 635-21-2 ]
[ 75-05-8 ]
[ 7142-09-8 ]
Reference：
[1] Chemical Communications, 2017, vol. 53, # 31, p. 4362 - 4365
14
[ 635-21-2 ]
[ 7142-09-8 ]
Reference：
[1] Journal of Medicinal Chemistry, 1990, vol. 33, # 6, p. 1721 - 1728
[2] European Journal of Medicinal Chemistry, 2014, vol. 86, p. 613 - 627
[3] Patent: WO2015/19121, 2015, A1,
15
[ 57-13-6 ]
[ 635-21-2 ]
[ 20028-68-6 ]
Yield
Reaction Conditions
Operation in experiment
49.5%
for 1 h; Reflux
5-Chloro-2-aminobenzoic acid (0.429 g, 2.5 mmol), urea (0.33 g, 5.5 mmol), phosphorus pentachloride (3.124 g, 15 mmol) and phosphorus oxychloride (10 mL) were added and the reaction was stopped by heating to reflux for 1 h. Decompression to steam Excess phosphorus oxychloride, the residue was dissolved in methylene chloride, ice water was washed with phosphorus oxychloride and phosphorus pentachloride, the separation of water The organic phase was adjusted to pH 6-7 with saturated sodium bicarbonate and extracted with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate. Concentration column chromatography gave 0.289 g of a light yellow solid, yield: 49.5percent
Reference：
[1] Patent: CN102250075, 2016, B, . Location in patent: Paragraph 0697; 0698
[2] Journal of Heterocyclic Chemistry, 2017, vol. 54, # 5, p. 2755 - 2766
16
[ 635-21-2 ]
[ 20028-68-6 ]
Reference：
[1] Journal of Medicinal Chemistry, 2014, vol. 57, # 12, p. 5141 - 5156
[2] Chemical and Pharmaceutical Bulletin, 2015, vol. 63, # 2, p. 75 - 80
[3] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 24, p. 7717 - 7727
[4] RSC Advances, 2017, vol. 7, # 36, p. 22360 - 22368
[5] Journal of Medicinal Chemistry, 2018, vol. 61, # 1, p. 265 - 285
[6] Molecules, 2018, vol. 23, # 2,
[7] Patent: CN107652273, 2018, A,
17
[ 57-13-6 ]
[ 635-21-2 ]
[ 1640-60-4 ]
Yield
Reaction Conditions
Operation in experiment
94%
at 200℃; for 3 h;
Step 1 6-Chloroquinazoline-2,4(1H,3H)-dione A 250 mL round bottom flask was charged with 2-amino-5-chlorobenzoic acid (17.2 g, 0.1 mol) and urea (30 g, 0.5 mol). The resulting mixture was heated to 200° C. for 3 h. Work up: the reaction mixture was washed by water and filtered. The solid was dried to give 18.5 g (94percent) of the product. MS m/z: 196 (M+H+).
94%
at 200℃; for 3 h;
A 250 mL round bottom flask was charged with 2-amino-5- chlorobenzoic acid (17.2 g, 0.1 mol) and urea (30 g, 0.5 mol). The resulting mixture was heated to 200 °C for 3 h. Work up: the reaction mixture was washed by water and filtered. The solid was dried to give 18.5 g (94percent) of the product. MS m/z: 196 (M+H+)
79%
at 150℃; for 10 h;
General procedure: A mixture of 2-aminobenzoic acid 3a (2.00 g, 14.91 mmol), urea (4.40 g,73.26 mmol) in phenol (6.00 g, 63.76 mmol) was heated at 150 Cunder the reflux for 10 h. The reaction mixture was cooled downto 100 C and ethanol/water (1:1) 10 mL was added drop-wise.The reaction mixture was cooled to rt, filtered, washed with ethanol(5 mL), and dried to afford 4a in 53percent yield (1.26 g).
Reference：
[1] Patent: US2010/120741, 2010, A1, . Location in patent: Page/Page column 24
[2] Patent: WO2011/112731, 2011, A2, . Location in patent: Page/Page column 79
[3] Chemistry Letters, 2005, vol. 34, # 10, p. 1438 - 1439
[4] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 24, p. 7717 - 7727
[5] Journal of Medicinal Chemistry, 2010, vol. 53, # 6, p. 2390 - 2400
[6] Tetrahedron, 2012, vol. 68, # 43, p. 8908 - 8915
[7] Journal of Medicinal Chemistry, 2014, vol. 57, # 12, p. 5141 - 5156
[8] Chemical and Pharmaceutical Bulletin, 2015, vol. 63, # 2, p. 75 - 80
18
[ 917-61-3 ]
[ 635-21-2 ]
[ 1640-60-4 ]
Yield
Reaction Conditions
Operation in experiment
44%
Stage #1: With acetic acid In water at 30℃; for 0.5 h; Stage #2: With sodium hydroxide In water at 30℃; Stage #3: With hydrogenchloride In water
Into a 500-mL 3-necked round-bottom flask, was placed a solution of 2-ammo-5-chlorobenzoic acid (10 g, 58 48 mmol, 1 00 equiv) in water (100 mL), acetic acid (8 g, 133 33 mmol, 2 24 equiv) This was followed by the addition of NaOCN (8 2 g, 126 15 mmol, 2 13 equiv) The mixture was stirred for 30 rains at 3O0C To this was added sodium hydroxide (86 g, 2 15 mol, 37 00 equiv) The resulting solution was stirred overnight at 30cC The solids were collected by filtration The residue was dissolved in water The pH value of the solution was adjusted to 7 with hydrogen chloπde (12 mol/L) The solids were collected by filtration This resulted in 5 g (44percent) of 6 chloroqmnazolme-2,4(lH,3H)-dione as a white solid.
Reference：
[1] Chemistry Letters, 2005, vol. 34, # 10, p. 1438 - 1439
[2] Chinese Chemical Letters, 2012, vol. 23, # 4, p. 431 - 433
[3] Journal of Chemical Research, 2007, # 6, p. 358 - 361
20
[ 635-21-2 ]
[ 1640-60-4 ]
Reference：
[1] Tetrahedron, 1997, vol. 53, # 25, p. 8457 - 8478
[2] Journal of the American Chemical Society, 1947, vol. 69, p. 940
[3] Patent: US5688803, 1997, A,
21
[ 635-21-2 ]
[ 101861-61-4 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1953, vol. 583, p. 150,155
[2] Patent: WO2011/112731, 2011, A2,
22
[ 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
23
[ 635-21-2 ]
[ 719-59-5 ]
Reference：
[1] Chemical Communications, 2018, vol. 54, # 74, p. 10503 - 10506
24
[ 2516-95-2 ]
[ 635-21-2 ]
Yield
Reaction Conditions
Operation in experiment
96%
With hydrogen In ethanol at 20℃;
To a solution of 5-chloro-2-nitrobenzoic acid (20 g, 110 mmol) in ethanol was added freshly activated raney nickel (2 g). The mixture was stirred overnight at room temperature under hydrogen atmosphere. The solution was filtered through celite and evaporated under reduced pressure to yield 16 g (96percent) of white SOLIDS. 1H NMR (DMSO-D6) : d 6.77 (d, J = 8.9 Hz, 1H), 7.24 (DD, J= 2.9, 8.9 Hz, 1H), 7.62 (d, J= 2.9 Hz, 1H), 8.7 (b, 3H); EIMS: 170 (M-H).
Reference：
[1] Collection of Czechoslovak Chemical Communications, 1984, vol. 49, # 1, p. 86 - 109
[2] Patent: WO2004/74218, 2004, A2, . Location in patent: Page 115-116
[3] Bioorganic and Medicinal Chemistry, 1999, vol. 7, # 12, p. 2801 - 2809
[4] Chemical Biology and Drug Design, 2016, p. 710 - 723
[5] Zhurnal Obshchei Khimii, 1938, vol. 8, p. 1797,1801[6] Chem. Zentralbl., 1940, vol. 111, # I, p. 370
[7] Journal of the American Chemical Society, 1954, vol. 76, p. 6336,6337
[8] Bioorganic and Medicinal Chemistry, 2010, vol. 18, # 14, p. 5039 - 5047
[9] Chinese Chemical Letters, 2010, vol. 21, # 9, p. 1015 - 1019
[10] Asian Journal of Chemistry, 2013, vol. 25, # 2, p. 1039 - 1042
Reference：
[1] Journal of Heterocyclic Chemistry, 2010, vol. 47, # 2, p. 415 - 420
32
[ 1446522-64-0 ]
[ 635-21-2 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 15, p. 4670 - 4677
33
[ 54797-19-2 ]
[ 635-21-2 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 15, p. 4670 - 4677
34
[ 535-80-8 ]
[ 635-21-2 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1884, vol. 222, p. 95
[2] Justus Liebigs Annalen der Chemie, 1865, vol. 135, p. 108
[3] Chemische Berichte, 1873, vol. 6, p. 175
35
[ 5202-86-8 ]
[ 635-21-2 ]
Reference：
[1] Patent: DE152484, , ,
[2] Zhurnal Obshchei Khimii, 1937, vol. 7, p. 842,844[3] Chem. Zentralbl., 1939, vol. 110, # I, p. 1366
36
[ 4340-77-6 ]
[ 635-21-2 ]
Reference：
[1] Nippon Kagaku Zasshi, 1959, vol. 80, p. 1038,1039[2] Chem.Abstr., 1961, p. 5510
[3] Nippon Kagaku Zasshi, 1959, vol. 80, p. 1038,1039[4] Chem.Abstr., 1961, p. 5510
37
[ 13191-02-1 ]
[ 635-21-2 ]
Reference：
[1] Nippon Kagaku Zasshi, 1959, vol. 80, p. 1038,1039[2] Chem.Abstr., 1961, p. 5510
38
[ 31354-77-5 ]
[ 635-21-2 ]
Reference：
[1] Zhurnal Obshchei Khimii, 1953, vol. 23, p. 606,609; engl. Ausg. S. 629, 632
39
[ 2719-08-6 ]
[ 635-21-2 ]
Reference：
[1] Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1906, vol. 143, p. 910[2] Bulletin de la Societe Chimique de France, 1907, vol. <4> 1, p. 224
40
[ 5202-87-9 ]
[ 635-21-2 ]
Reference：
[1] Zhurnal Obshchei Khimii, 1937, vol. 7, p. 842,844[2] Chem. Zentralbl., 1939, vol. 110, # I, p. 1366
41
[ 120-66-1 ]
[ 635-21-2 ]
Reference：
[1] Zhurnal Obshchei Khimii, 1937, vol. 7, p. 842,844[2] Chem. Zentralbl., 1939, vol. 110, # I, p. 1366
42
[ 104-12-1 ]
[ 635-21-2 ]
Reference：
[1] Zhurnal Obshchei Khimii, 1953, vol. 23, p. 606,609; engl. Ausg. S. 629, 632
43
[ 6628-86-0 ]
[ 635-21-2 ]
Reference：
[1] Zhurnal Obshchei Khimii, 1938, vol. 8, p. 1797,1801[2] Chem. Zentralbl., 1940, vol. 111, # I, p. 370
44
[ 65-85-0 ]
[ 635-21-2 ]
Reference：
[1] Chemische Berichte, 1873, vol. 6, p. 175
45
[ 5367-28-2 ]
[ 635-21-2 ]
Reference：
[1] Asian Journal of Chemistry, 2013, vol. 25, # 2, p. 1039 - 1042
46
[ 118-92-3 ]
[ 6388-47-2 ]
[ 635-21-2 ]
Reference：
[1] Chemical Science, 2015, vol. 6, # 6, p. 3454 - 3460
Reference：
[1] Chemische Berichte, 1922, vol. 55, p. 221
49
[ 67-56-1 ]
[ 635-21-2 ]
[ 5202-89-1 ]
Yield
Reaction Conditions
Operation in experiment
100%
at 0℃; for 12 h; Reflux
Example 1006-Chloro-3 ,3 -dimethyl-2- (3 -morpholin-4-yl-phenyl)- 1 ,2,3 ,4-tetrahydro-quinoline-8- carboxylic acidTo a stirred solution of 2-amino-5-chloro-benzoic acid (50 g, 291 mmol) in methanol (300 mL) was added thionyl chloride (45 mL, 605 mmol) dropwise at 0 °C. Then the mixture solution was refluxed for 12 hours before cooling to room temperature. Then the reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate (500 mL), washed with saturated aqueous sodium bicarbonate solution (3 x 100 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-amino-5-chloro- benzoic acid methyl ester (54 g, quant.) as a pale-white solid: LC/MS m/e calcd for C8H8C1N02 (M+H)+: 186.61, observed: 185.9.
100%
at 0℃; for 12 h; Reflux
To a stirred solution of 2-amino-5-chloro-benzoic acid (50 g, 291 mmol) in methanol (300 mL) was added thionyl chloride (45 mL, 605 mmol) dropwise at 0° C. Then the mixture solution was refluxed for 12 hours before cooling to room temperature. Then the reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate (500 mL), washed with saturated aqueous sodium bicarbonate solution (3.x.100 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-amino-5-chloro-benzoic acid methyl ester (54 g, quant.) as a pale-white solid: LC/MS m/e calcd for C8H8ClNO2 (M+H)+: 186.61, observed: 185.9.
Reference：
[1] Patent: WO2011/128251, 2011, A1, . Location in patent: Page/Page column 187
[2] Patent: US2011/257151, 2011, A1, . Location in patent: Page/Page column 69
[3] Bioorganic and Medicinal Chemistry, 1999, vol. 7, # 12, p. 2801 - 2809
[4] Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1906, vol. 143, p. 910[5] Bulletin de la Societe Chimique de France, 1907, vol. <4> 1, p. 224
[6] Journal of Medicinal Chemistry, 1996, vol. 39, # 17, p. 3248 - 3255
[7] Scientia Pharmaceutica, 2003, vol. 71, # 4, p. 331 - 356
[8] Tetrahedron Letters, 2006, vol. 47, # 26, p. 4365 - 4368
[9] Chemistry of Heterocyclic Compounds, 2006, vol. 42, # 1, p. 64 - 69
[10] Journal of Heterocyclic Chemistry, 2010, vol. 47, # 2, p. 415 - 420
[11] Journal of Medicinal Chemistry, 2013, vol. 56, # 21, p. 8332 - 8338
[12] Journal of Organic Chemistry, 2015, vol. 80, # 21, p. 11175 - 11183
[13] Advanced Synthesis and Catalysis, 2018, vol. 360, # 10, p. 1919 - 1925
50
[ 635-21-2 ]
[ 5202-89-1 ]
Yield
Reaction Conditions
Operation in experiment
96%
With potassium carbonate In water; acetone
(109-8) 5-Chloroanthranilic acid (15.0 g), (CH3)2SO4 (11.6 g) and K2CO3 (12.7 g) were refluxed in acetone (150 g) for 30 minutes. The mixture was concentrated to about 90 g, and thereto was added water (90 g). The mixture was extracted with toluene (75 g), and the organic layer was concentrated to give methyl 5-chloroanthranilate (15.6 g, 96percent). 1H NMR (CDCl3, 400 MHz) δ 7.83 (d, 1H, J=2.6 Hz), 7.21 (dd, 1H, J=8.5 and 2.6 Hz), 6.61 (d, 1H, J=8.5 Hz), 5.73 (brs, 2H), 3.88 (s, 3H).
96%
With potassium carbonate In water; acetone
(109-8) 5-Chloroanthranilic acid (15.0 g), (CH3)2SO4 (11.6 g) and K2CO3 (12.7 g) were refluxed in acetone (150 g) for 30 minutes. The mixture was concentrated to about 90 g, and thereto was added water (90 g). The mixture was extracted with toluene (75 g), and the organic layer was concentrated to give methyl 5-chloroanthranilate (15.6 g, 96 percent). 1H NMR (CDCl3, 400MHz) δ 7.83 (d, 1H, J=2.6Hz), 7.21 (dd, 1H, J=8.5 and 2.6Hz), 6.61 (d, 1H, J=8.5Hz), 5.73 (brs, 2H), 3.88 (s, 3H).
Reference：
[1] Chemistry - A European Journal, 2013, vol. 19, # 10, p. 3315 - 3318
[2] Chemical Communications, 2018, vol. 54, # 74, p. 10503 - 10506
55
[ 118-92-3 ]
[ 6388-47-2 ]
[ 635-21-2 ]
Reference：
[1] Chemical Science, 2015, vol. 6, # 6, p. 3454 - 3460
56
[ 635-21-2 ]
[ 13421-00-6 ]
Reference：
[1] Collection of Czechoslovak Chemical Communications, 1968, vol. 33, # 6, p. 1852 - 1872
[2] Chemical Communications, 2013, vol. 49, # 31, p. 3254 - 3256
[3] Organic Letters, 2015, vol. 17, # 17, p. 4180 - 4183
[4] Journal of Organic Chemistry, 2017, vol. 82, # 4, p. 2263 - 2268
[5] Organic Letters, 2017, vol. 19, # 7, p. 1578 - 1581
[6] Organic Letters, 2018, vol. 20, # 2, p. 345 - 348
57
[ 635-21-2 ]
[ 20028-53-9 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 19, p. 5810 - 5831
[2] Organic and Biomolecular Chemistry, 2017, vol. 15, # 31, p. 6474 - 6477
58
[ 635-21-2 ]
[ 37585-25-4 ]
Yield
Reaction Conditions
Operation in experiment
93%
With lithium aluminium tetrahydride In tetrahydrofuran at 20℃; for 3.5 h;
General procedure: To a suspension of lithium aluminum hydride (20.4 mmol) in THF (10 mL) was added benzoic acid (8.5 mmol) dissolved in THF (24 mL) dropwise over 20 minutes at room temperature. The reaction continued to stir at room temperature for 3.5 h, and then was quenched at 0 °C with H2O (10 mL). The suspension was filtered through a Celite plug with EtOAc (100 mL), washed with brine (30 mL), dried with MgSO4 and concentrated in vacuo.
88%
Stage #1: With lithium aluminium tetrahydride In diethyl ether at 20℃; Cooling with ice Stage #2: With water; sodium hydroxide In diethyl ether
Preparation of (2-amino-phenyl)-methanols (2) by reduction of 2-amino- benzoic acids (3) - General procedure; [0078] 2-Amino-benzoic acid (14 mmol) in dry diethyl ether (15 ml_) is added dropwise to an ice cooled solution of lithium aluminum hydride (15 mmol) in dry diethyl ether (100 mL) and stirred at room temperature for 2 h. Water (8 ml) is added dropwise, followed by 1M aqueous sodium hydroxide solution (13 mL). The organic layer is collected, dried over sodium sulfate and concentrated under reduced pressure. The crude product is used in the next step without further purification.; (2-Amino-5-chloro-phenyl)-methanol; Yield 88percent; 1H NMR (DMSO): 4.31 (d, 5 Hz, 2H); 5.01 (br s, 2H); 5.11 (t, 5 Hz, 1 H); 6.58 (d, 9 Hz, 1 H); 6.94 (dd, 9 and 2 Hz, 1 H) and 7.07 (d, 2 Hz, 1 H). [0080](2-Amino-3,5-dichloro-phenyl)-methanolYield 98percent; ^1H NMR (DMSO): 4.38 (d, 5 Hz1 2H); 5.22 (br s, 2H); 5.33 (t, 5 Hz, 1 H); 7.12 and 7.23 (both d, 3 Hz, both 1 H).
Reference：
[1] ACS Catalysis, 2013, vol. 3, # 4, p. 622 - 624
[2] Organic Letters, 2017, vol. 19, # 12, p. 3219 - 3222
[3] Tetrahedron Letters, 2017, vol. 58, # 40, p. 3795 - 3799
[4] Patent: WO2010/37533, 2010, A1, . Location in patent: Page/Page column 44
[5] Organic Letters, 2016, vol. 18, # 21, p. 5572 - 5575
[6] Tetrahedron Letters, 1995, vol. 36, # 41, p. 7527 - 7530
[7] Patent: US4164407, 1979, A,
[8] Journal of Organic Chemistry, 2008, vol. 73, # 11, p. 4252 - 4255
[9] Tetrahedron Letters, 2011, vol. 52, # 45, p. 5913 - 5917
[10] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 19, p. 5810 - 5831
[11] Tetrahedron, 2014, vol. 70, # 34, p. 5114 - 5121
[12] Tetrahedron, 2014, vol. 70, # 34, p. 5114 - 5121
[13] Synthesis (Germany), 2014, vol. 46, # 24, p. 3365 - 3373
[14] Organic Letters, 2015, vol. 17, # 19, p. 4750 - 4753
[15] Organic and Biomolecular Chemistry, 2017, vol. 15, # 31, p. 6474 - 6477
[16] Tetrahedron Letters, 2017, vol. 58, # 45, p. 4264 - 4268
[17] Organic Letters, 2018, vol. 20, # 6, p. 1526 - 1529
[18] Organic and Biomolecular Chemistry, 2018, vol. 16, # 12, p. 2039 - 2042
To a solution of 5-chloro-2-nitrobenzoic acid (20 g, 110 mmol) in ethanol was added freshly activated raney nickel (2 g). The mixture was stirred overnight at room temperature under hydrogen atmosphere. The solution was filtered through celite and evaporated under reduced pressure to yield 16 g (96%) of white SOLIDS. 1H NMR (DMSO-D6) : d 6.77 (d, J = 8.9 Hz, 1H), 7.24 (DD, J= 2.9, 8.9 Hz, 1H), 7.62 (d, J= 2.9 Hz, 1H), 8.7 (b, 3H); EIMS: 170 (M-H).
With acetic acid; diethylamine; at 150℃; for 2h;Product distribution / selectivity;
Examples 13 to 21:; The reaction and the post-treatment were carried out in the same manner as in Example 5, for which, however, the type of the anthranilic acid derivative was changed. The results are shown in Table 4.
90%
at 140℃;
General procedure: To a three necked flask, substituted anthranilic acid (1 meq.) was added in excess of formamide (6 meq). The reaction mixture was then heated at 140 C for 4-6 h. The reaction was monitored with thin layer chromatography and upon completion; ice was added to the reaction mixture. The resultant solid was filtered, washed with water, dissolved in ethyl acetate, dried over MgSO4 and concentrated to obtain the pure desired product. Where product did not precipitate on addition of ice, the reaction mixture was extracted with ethyl acetate, dried over MgSO4 and concentrated to obtain the desired quinazolin-4(3H)-one derivatives 1-9, 11-15, 17-21 and 23-25.The amino derivatives 10, 16 and 22 were prepared using the following general procedure:To a reaction flask, substituted nitroquinazolin-4(3H)-one derivative (0.3 g, 1.56 mmol) was added followed by addition of 6 mL ethyl acetate and SnCl2·2H2O (2.12 g, 9.42 mmol), then reaction mixture was refluxed for 8 h. The reaction mixture was cooled to room temperature and quenched with saturated sodium bicarbonate solution, followed by repeated extraction with ethyl acetate (3 × 50 mL). The organic layers were combined, dried over anhydrous MgSO4 and concentrated to obtain the desired amino substituted quinazolin-4(3H)-one derivatives 10, 16 and 22.The substituted anthranilic acid (1 g) was dissolved in excess acetic anhydride (10 mL) and the resulting reaction mixture was stirred at room temperature for 4-7 h. The reaction was monitored for completion using thin layer chromatography. The solvent was evaporated under vacuum and the resultant residue was stirred with ammonia solution for 7 h. Upon completion, the reaction mixture was extracted with ethyl acetate (3 × 10 mL), the organic extracts were combined, dried over MgSO4 and evaporated to obtain compounds 26-30, 31a and 32. The 2-methyl-8-nitroquinazolin-4(3H)-one intermediate (31a) was reduced to compound 31 using the same procedure as reported in Scheme 1 for the synthesis of compounds 10, 16 and 22.
at 130 - 135℃; for 4h;
General procedure: Compound 18 was prepared accordingto the procedure previously reported.39 A mixture of anthranilicacid 11 (0.1 mol) and formamide (18 g, 0.4 mol) was heated at130-135 C. After the mixture had been stirred for 4 h, water(40 mL) was added. The reaction mixture was cooled to 60 C,and water (20 mL) was added to the mixture. After the mixturehad been stirred for 30 min, the precipitated product wasfiltered off with suction. The crude products were recrystallizedwith ethanol to give compound 18 in yields of 80-95%.
(2) 2-(N-carboxymethylamino)-5-chlorobenzoic acid To a solution of <strong>[635-21-2]2-amino-5-chlorobenzoic acid</strong> (2.0 g, 11.6 mmol) in 15 ml of 2 N Na2CO3, a solution of chloroacetic acid (0.69 g, 7.3 mmol) in 7.5 ml of 2 N Na2CO3 was added dropwise. After stirred for 20 hours at 80 C, the reaction mixture was cooled down to room temperature. 50 ml ether and 8 ml of 2 N hydrochloric acid were added to the mixture. The organic phase was separated, and dried with MgSO4. After concentration, a light brown solid was obtained. A white solid (2-(N-carboxymethylamino)-5-chlorobenzoic acid) (1.58 g, yield: 59%; mp: 182-183 C) was obtained through silica gel column chromatography (ethyl acetate/methanol, v/v, 1/1).
59%
(2) 2-(N-carboxymethylamino)-5-chlorobenzoic acid To a solution of <strong>[635-21-2]2-amino-5-chlorobenzoic acid</strong> (2.0 g, 11.6 mmol) in 15 ml of 2 N Na2CO3, a solution of chloroacetic acid (0.69 g, 7.3 mmol) in 7.5 ml of 2 N Na2CO3 was added dropwise. After stirred for 20 hours at 80 C., the reaction mixture was cooled down to room temperature. 50 ml ether and 8 ml of 2 N hydrochloric acid were added to the mixture. The organic phase was separated, and dried with MgSO4. After concentration, a light brown solid was obtained. A white solid (2-(N-carboxymethylamino)-5-chlorobenzoic acid) (1.58 g, yield: 59%; mp: 182-183 C.) was obtained through silica gel column chromatography (ethyl acetate/methanol, v/v, 1/1).
Example 1006-Chloro-3 ,3 -dimethyl-2- (3 -morpholin-4-yl-phenyl)- 1 ,2,3 ,4-tetrahydro-quinoline-8- carboxylic acidTo a stirred solution of 2-amino-5-chloro-benzoic acid (50 g, 291 mmol) in methanol (300 mL) was added thionyl chloride (45 mL, 605 mmol) dropwise at 0 C. Then the mixture solution was refluxed for 12 hours before cooling to room temperature. Then the reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate (500 mL), washed with saturated aqueous sodium bicarbonate solution (3 x 100 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-amino-5-chloro- benzoic acid methyl ester (54 g, quant.) as a pale-white solid: LC/MS m/e calcd for C8H8C1N02 (M+H)+: 186.61, observed: 185.9.
100%
With thionyl chloride; at 0℃; for 12h;Reflux;
To a stirred solution of 2-amino-5-chloro-benzoic acid (50 g, 291 mmol) in methanol (300 mL) was added thionyl chloride (45 mL, 605 mmol) dropwise at 0 C. Then the mixture solution was refluxed for 12 hours before cooling to room temperature. Then the reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate (500 mL), washed with saturated aqueous sodium bicarbonate solution (3×100 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-amino-5-chloro-benzoic acid methyl ester (54 g, quant.) as a pale-white solid: LC/MS m/e calcd for C8H8ClNO2 (M+H)+: 186.61, observed: 185.9.
94%
With sulfuric acid; at 60℃; for 72h;Inert atmosphere;
A solution of 2-amino-5-chlorobenzoic acid (5.00 g, 29.1 mmol) in methanol (75 ml_) was treated with concentrated sulfuric acid (7.5 ml_) and heated at 60 C under a nitrogen atmosphere for 72 h. After this time, the reaction mixture was concentrated under reduced pressure to remove the volatiles. The resulting residue was carefully treated with saturated aqueous sodium bicarbonate (150 ml_) and extracted with ethyl acetate (3 c 100 ml_). The combined organics were dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide methyl 2-amino-5- chlorobenzoate (5.10 g, 94%) as a brown solid: 1H NMR (500 MHz, DMSO-d6) d 7.63 (d, J = 2.5 Hz, 1H), 7.28 (dd, J = 8.5, 2.5 Hz, 1H), 6.81 (d, J = 8.5 Hz, 1H), 6.77 (br s, 2H), 3.80 (s, 3H).
To a solution of 200 g (1.05 mol) of 2-amino-5-chlorobenzoic acid in 3.4 L of HOAc at 15C was added dropwise 184 g (1.15 mol) of Br2. The mixture was stirred at 15C for 4 hrs, quenched slowly into 8 L of water, and extracted with 2 X 2 L of t-BuOMe. The combined extract was washed with water, dried over MgSO4 and concentrated. The crude product was treated with hot hexane, filtered and dried to give 210 g (80%) of 2-amino-3-bromo-5-chlorobenzoic acid as white solid. Mp. 225-228C. 1H NMR (DMSO-d6): delta 7.70 (d, J = 2.6 Hz, 1 H), 7.69 (d, J = 2.6 Hz, 1 H), 6.8 (bs, 2 H). 13C NMR (DMSO-d6): delta 168.16, 147.06, 136.25, 130.19, 118.22, 112.35, 110.34. IR: 3480 (m), 3350 (m), 2920 (s), 1670 (s) cm-1. Analysis calcd. for C7H5BrClNO2: C, 33.53, H, 2.00, N, 5.59; Found: C, 33.63, H, 2.12, N, 5.70.
With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 20℃; for 10h;
To a mixture of 1.7g of 2-amino-5-chlorobenzoic acid and 100 ml of N, N-dimethylformamide was added 1.8g of N-bromosuccinimide at room temperature, and the mixture was stirred at room temperature for 10 hours. Water was poured into the reaction mixture, and a deposited precipitate was collected by filtration to obtain l.lg of 2-amino-3-bromo-5- chlorobenzoic acid of the formula: 2-Amino-3-bromo-5-chlorobenzoic acid1H-NMR (DMSO-d6 ,TMS) delta (ppm) : 6.87 (2H, brs), 7.74 (IH, d, J=2Hz), 7.76 (IH, d, J=2Hz) .
With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 20℃; for 14h;
Step 1 : Synthesis of 2-amino-3-bromo-5-chlorobenzoic acid (Compound 19a) Compound 19a [0283] A mixture of 2-amino-5-chlorobenzoic acid (5 g, 29 mmol, Ark Pharm Inc, AK- 26989) and N-bromosuccinimide (5.4 g, 30 mmol) in N,N-dimethylformamide (100 mL) was stirred at room temperature for 14 hours. The reaction mixture was poured into water (400 mL) and product was extracted with diethylether (400 mL). The organic phase was washed with brine (200 mL), dried over sodium sulfate, filtered and concentrated down under reduced pressure to afford the title compound 19a. LCMS (m/z) 250.0 [M+H], Tr = 4.05 min (LCMS method 1 ).
With bromine; In acetic acid; at 0 - 15℃;
Its preparation method:Using 5-chloroanthranilic acid (compound 1a) as a starting material,Intermediate 3-bromo-5-chloroanthranilic acid 2a prepared under the action of bromine,The reaction temperature is 0-15 C, and the reaction solvent is AcOH;
With N-iodo-succinimide In N,N-dimethyl-formamide at 20℃; for 24h;
57-(1)
To a mixture of 1.5 g of 2-amino-5-chlorobenzoic acid and EPO 100 ml of N,N-dimethylforrnamide was added 2.7 g of N-iodosuccinimide at room temperature, and the mixture was stirred at room temperature for 24 hours. After 30 ml of water was poured into the reaction mixture, the mixture was extracted with ethyl acetate three times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 1.2 g of 2-amino-5-chloro-3-iodobenzoic acid of the formula:2-Ammo-5-chloro-3-iodobenzoic acid1H-NMR (DMSO-d6 ,TMS) δ (ppm) : 6.76 (2H, brs), 7.75 (IH, d,J=IHz), 7.87 (IH, d, J=IHz) .
With sodium carbonate; In tetrahydrofuran; for 16h;
Benzoyl chloride (5.3 mL, 45 mmol) was added dropwise to a suspension of Na2CO3 (3.8 g, 36 mmol) and <strong>[635-21-2]2-amino-5-chloro-benzoic acid</strong> (3.1 g, 18 mmol) in THF (60 mL). The mixture was allowed to stir for 16 h and then H2O (200 mL) was added. The resulting precipitate was collected by filtration, washed with MeOH/H2O (1/1, 100 mL) and then dried in vacuo to provide 6-chloro-2-phenyl-benzo[d][1,3]oxazin-4-one (4.3 g, 92%).
19%
With pyridine; sodium hydrogencarbonate;Cooling with ice;
5-Chloroanthranilic acid (1.72 g, 10.0 mmol) was dissolved in pyridine (4.0 mL),Under ice cooling, benzoyl chloride (0.63 g, 4.5 mmol) was added dropwise.Add saturated sodium bicarbonate solution to the reaction solution,The precipitate was collected by filtration and washed with water.Silica gel column chromatography (hexane: ethyl acetate = 9: 1 to 4: 1 gradient) gave 0.51 g (19%),
With pyridine; at 0 - 20℃;
General procedure: 0.05mol of benzoyl chloride was added to a solution of equimolaranthranilic acid in 25 mL of pyridine drop-wise with thetemperature maintained between 0-5 C for 1 h. The stirringwas continued for another 2 h at room temperature to get asolid product. Upon neutralization of the above reactionmixture with sodium bicarbonate solution yields pale yellowsolid crude product (compound 1). This separated product canbe filtered, washed with water and then recrystallized fromethanol [12]. m.f.: C 21 H 16 N 2 O, m.w.: 223, Colour and Appea-rance: cream colour crystals, m.p.: 120 C, yield: 78 %, R fvalue: 0.70 [toluene:chloroform (8:2)], UV lambda max (methanol)313 nm, IR (KBr, nu max , cm -1 ): 3030 (C-H, Ar-H), 1764 (C=O),1614 (C=N), 1254 (C-O).
With sodium carbonate; In tetrahydrofuran; at 0 - 20℃;
General procedure: To a mixture of concentrated anthranilic acid (10 mmol), Na2CO3(20 mmol) in THF (20 mL), benzoyl chloride was added drop wise at0C. After 10 min, the cold-bath was removed, and the mixture wasstirred at room temperature overnight. After the reaction wascomplete, water (20 mL) was added, and the mixture was stirred for10 min prior to ltration. After removal of the solvent, the solid waswashed with water and 50% aqueous MeOH respectively to get thedesired product 1 (1a-1p).
8-chloro-10-oxo-10H-pyridazino(6,1-b)quinazoline-2-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With pyridine; In acetic acid;
EXAMPLE 2 8-chloro-10-oxo-10H-pyridazino(6,1-b)quinazoline-2-carboxylic acid. A mixture of 5-chloroanthranilic acid (5.4 g, 31.6 mmol) and <strong>[5096-73-1]6-chloropyridazine-3-carboxylic acid</strong> (5.0 g, 31.6 mmol) is heated at reflux in acetic acid (50 ml) for 80 hrs. The mixture is cooled and the precipitate which formes is collected to give 4.73 g of crude product, m.p. 253-300 C. (dec.). Recrystallization of this material from pyridine gives the analytical material, m.p. 260-262 C.
With lithium aluminium tetrahydride; In tetrahydrofuran; at 20℃; for 3.5h;
General procedure: To a suspension of lithium aluminum hydride (20.4 mmol) in THF (10 mL) was added benzoic acid (8.5 mmol) dissolved in THF (24 mL) dropwise over 20 minutes at room temperature. The reaction continued to stir at room temperature for 3.5 h, and then was quenched at 0 C with H2O (10 mL). The suspension was filtered through a Celite plug with EtOAc (100 mL), washed with brine (30 mL), dried with MgSO4 and concentrated in vacuo.
89%
With lithium aluminium tetrahydride; In tetrahydrofuran; at 20℃; for 2h;Inert atmosphere;
Under nitrogen protection conditions,To 26.5 g (0.7 mol) of lithium tetrahydrogenate andAdd a mixture of dry tetrahydrofuran (800 mL)A solution of 100 g (0.58 mol) of 5-chloro-2-aminobenzoic acid and dry tetrahydrofuran (300 mL) was added, and the mixture was stirred at room temperature for 2 hr.A solution of 20 grams of sodium hydroxide and 100 mL of water was added. Filtration, the filtrate was extracted with EtOAc.The concentrate was crystallized from ethyl acetate/petroleum ether to give2-1.7 g of 2-amino-5-chloro-benzyl alcohol (yield: 89%).
88%
Preparation of (2-amino-phenyl)-methanols (2) by reduction of 2-amino- benzoic acids (3) - General procedure; [0078] 2-Amino-benzoic acid (14 mmol) in dry diethyl ether (15 ml_) is added dropwise to an ice cooled solution of lithium aluminum hydride (15 mmol) in dry diethyl ether (100 mL) and stirred at room temperature for 2 h. Water (8 ml) is added dropwise, followed by 1M aqueous sodium hydroxide solution (13 mL). The organic layer is collected, dried over sodium sulfate and concentrated under reduced pressure. The crude product is used in the next step without further purification.; (2-Amino-5-chloro-phenyl)-methanol; Yield 88%; 1H NMR (DMSO): 4.31 (d, 5 Hz, 2H); 5.01 (br s, 2H); 5.11 (t, 5 Hz, 1 H); 6.58 (d, 9 Hz, 1 H); 6.94 (dd, 9 and 2 Hz, 1 H) and 7.07 (d, 2 Hz, 1 H). [0080](2-Amino-3,5-dichloro-phenyl)-methanolYield 98%; ^1H NMR (DMSO): 4.38 (d, 5 Hz1 2H); 5.22 (br s, 2H); 5.33 (t, 5 Hz, 1 H); 7.12 and 7.23 (both d, 3 Hz, both 1 H).
85%
With lithium aluminium tetrahydride; In tetrahydrofuran; at 20℃; for 2h;Inert atmosphere;
Lithium tetrahydroaluminum (10.6g, 279.8mmol) under nitrogen protectionAnd dry tetrahydrofuran (250 mL)2-amino-5-chlorobenzoic acid (40.0 g, 233.1 mmol)And dry tetrahydrofuran (300 mL) solution,Stir at room temperature for 2 hours and add 15 mL dropwiseQuenched with water, then added sodium hydroxide (10g) and water (100mL)The solution.Filtered, the filtrate was extracted with ethyl acetate, the organic phases were combined,It was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.The concentrate was crystallized from ethyl acetate / petroleum ether to obtain Inter-3 (31.2 g, yield 85%).
With sodium hydroxide; In tetrahydrofuran; water;
Step A, 2-hydroxymethyl-4-chloroaniline STR16 10.6 g (0.26 M) of lithium aluminum hydride are added slowly to 500 ml of tetrahydrofuran freshly dried over molecular sieve. At a temperature of 50 to 60 34.4 g (0.2 M) of 5-chloroanthranilic acid is added in small portions every 5 to 10 minutes over a period of 3 hours. The temperature of the mixture is then allowed to decrease to room temperture and is then stirred for 16 hrs. The reaction mixture is then cooled to 0 to 5 and 12 ml. of water slowly added at 0 to 5. 12 ml of 20% ag. sodium hydroxide are then added slowly at 0 to 5. The resulting mixture is then stirred for 1/2 hr. at 0 to 5. 18 ml of water are then added slowly, the mixture stirred for 1/2 hr, and then filtered. The recovered solids are slurried in 200 ml of tetrahydrofuran, the mixture heated to reflux and filtered. The filtrates are concentrated by evaporating off solvent. The residue is crystallized from toluene to yield 2-hydroxymethyl-4-chloroaniline m.p. 104-106.
With borane-THF; In tetrahydrofuran; at 0 - 30℃; for 1.66667h;Inert atmosphere;
General procedure: To a solution of 6-chloroanthranilic acid (1.5 g, 8.74 mmol) in THF (5 mL) was added dropwise 1.08 M borane-tetrahydrofuran complex in THF (24.3 mL, 26.2 mmol) at 0 C under an Ar atmosphere for 10 min. After 1.5 h with stirring at 30 C, the solution was cooled at 0 C, added aqueous THF (THF/H2O = 1:1, 60 mL) and potassium carbonate, and extracted with diethyl ether three times. The combined organic extracts were washed with brine, dried over Na2SO4, and evaporated in vacuo. The residue was crystallized from AcOEt to give 1a (1.2 g, 88%) as a white needle crystal. Mp 76-78 C. IR (KBr): 3388, 3107, 1451, 1004, 780 cm-1. 1H NMR (300 MHz, CDCl3) delta: 4.29 (2H, br s), 4.86 (2H, s), 6.57 (1H, dd, J = 0.9, 8.1 Hz), 6.77 (1H, dd, J = 0.9, 7.8 Hz), 7.00 (1H, t, J = 8.1 Hz), a proton (OH) was not observed. 13C NMR (75 MHz, CDCl3) delta: 59.4, 114.6, 119.1, 122.0, 129.6, 134.1, 147.9. HRMS (EI) Calcd for C7H8ClNO [M]+: 157.0294. Found: 157.0293.
With lithium aluminium tetrahydride; In tetrahydrofuran; at 20℃; for 2h;Cooling with ice;
General procedure: To a stirred solution of anthranilic acid (15 mmol) in tetrahydrofuran (1 M, 15 mL) was slowly added Lithium aluminum hydride solution 1M in THF (30mL, 30 mmol, 2 eq.) in an ice bath. Upon completion of the addition, the ice bath was taken away, and stirring was continued for 2 hours at the room temperature. The reaction was quenched with water and a 5% solution of NaOH in water. The inorganic solid residue was filtered under vacuum, washed with ethyl acetate and the filtrate was transferred to a separatory funnel. The two layers were separated, and the product was extracted with ethyl acetate (x3). The organic phase was washed with brine (x1), dried over sodium sulfate, concentrated under reduced pressure and used in the next step without further purification.
With lithium aluminium tetrahydride; In tetrahydrofuran; at 0 - 20℃; for 2h;Inert atmosphere;
General procedure: A solution of the LiAlH4 (1.5 equiv) in anhydrous THF (50 mL) was stirred at 0 C, while 2-amino-benzoic acid (1.0 equiv) in THF was added dropwise. Then the mixture was warmed to room temperature and stirred for 2 hours. After complete consumption of the acid, the mixture was quenched with 10 % NaOH. The resulting suspension was filtered and extracted with ethyl acetate. The combined organic collection was evaporated. The residue was purified by column chromatography to give the product S1 as a white solid or off-white solid.
2-Amino-5-chlorobenzoic acid (1-1, 5.0 g, 29.1 mmol) was dissolved in 50 mL of dry tetrahydrofuran, and triphosgene (2.9 g, 9.9 mmol) was added with stirring, and the temperature was raised to 65 C. for 16 h. TLC monitored the reaction to completion. The temperature was reduced to room temperature, the solvent was distilled off under reduced pressure, 1N ammonia water (233 mL) was added, the temperature was raised to 65C for 1 hour, and the temperature was reduced to 0C to precipitate a white solid. The reaction was completed by TLC. Reduce to room temperature, filter with suction and wash the filter cake with water (10mL×3). The filter cake is dried to constant weight to obtain 4.23g of white powdery solid with a yield of 85%.
With ammonium chloride; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 20℃; for 15h;
General procedure: The syntheses of compounds 3a-3x were mainly referred to literature method [35]. A mixture of 1a-1q, 1w, 1x (2mmol), EDC?HCl (575mg, 3mmol), HOBt (446mg, 3.3mmol), NH4Cl (348mg, 6.5mmol) and DIPEA (2.3mL, 13mmol) in DMSO (7mL) was stirred at room temperature for 15h. The mixture was extracted with EtOAc three times, and the combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford 3a-3q, 3w, 3x. A mixture of 2r-2v (2mmol) and NH3·H2O (25-28wt%, 80mmol) in sealed tube was heated at 100C for 12h. The mixture was cooled to room temperature and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford 3r-3v.
Step 1 6-Chloroquinazoline-2,4(1H,3H)-dione A 250 mL round bottom flask was charged with 2-amino-5-chlorobenzoic acid (17.2 g, 0.1 mol) and urea (30 g, 0.5 mol). The resulting mixture was heated to 200 C. for 3 h. Work up: the reaction mixture was washed by water and filtered. The solid was dried to give 18.5 g (94%) of the product. MS m/z: 196 (M+H+).
94%
at 200℃; for 3h;
A 250 mL round bottom flask was charged with 2-amino-5- chlorobenzoic acid (17.2 g, 0.1 mol) and urea (30 g, 0.5 mol). The resulting mixture was heated to 200 C for 3 h. Work up: the reaction mixture was washed by water and filtered. The solid was dried to give 18.5 g (94%) of the product. MS m/z: 196 (M+H+)
79%
In phenol; at 150℃; for 10h;
General procedure: A mixture of 2-aminobenzoic acid 3a (2.00 g, 14.91 mmol), urea (4.40 g,73.26 mmol) in phenol (6.00 g, 63.76 mmol) was heated at 150 Cunder the reflux for 10 h. The reaction mixture was cooled downto 100 C and ethanol/water (1:1) 10 mL was added drop-wise.The reaction mixture was cooled to rt, filtered, washed with ethanol(5 mL), and dried to afford 4a in 53% yield (1.26 g).
In neat (no solvent); at 150℃; for 12h;
General procedure: The typical procedure to aromatic fused pyrimidine-2,4(1H,3H)-diones (2) is as follows. Aromatic-3-amine-2-carboxylic acid (0.1 mol) and urea (2 mol) were both mixed in a flask and then heated at 150 C for 12 h. When the mixture was cooled down to 100 C, 40 mL of water was added and the resultant mixture was stirred for another 10 min to dissolve the unreacted urea. After the reaction mixture was cooled down to room temperature, it was filtered and 400 mL, 1 mol/L NaOH aqueous solution was then added. Another 1 h later 55 mL of acetic acid was dropwise added for acidification and the resultant light yellow or white precipitates were filtered and dried to give the desired product 2 in a yield of 80-95%.
4.5 g
at 160℃; for 6h;
2-Amino-5-chlorobenzoic acid (5.0 g, 29.14 mmol, CAS RN 635-21-2) and urea (17.5 g, 291.41 mmol, CAS RN 57-13-6) were stirred at 160C for 6 h. The reaction mixture was cooled to 100C and 0 was added while stirring for 5 min. The precipitate was filtered off and washed with 0 to yield a solid cake that was suspended in a solution of 0.5 N NaOH and heated to boil for 5-10 min. The mixture was cooled down and the pH adjusted to 2 with a cone. HC1 solution; the solids were filtered off. The filter cake was dried under reduced pressure to provide an off-white solid (4.5 g, 22. 9 mmol). NMR (400 MHz, DMSO- e) delta 7.78 (s, 1H), 7.62 (d, J= 8.7 Hz, 1H), 7.19 (d, J= 8.8 Hz, 1H). MS (EI): m/z = 197.1 [M+H]+.
With sodium azide; acetic acid at 0 - 20℃; for 19h;
With sodium azide; acetic acid at 0 - 20℃;
1 Step 1 : 5 -Chloro-2-Π H-tetrazol- l-yl)benzoic acid.
Step 1 : 5 -Chloro-2-Π H-tetrazol- l-yl)benzoic acid. A suspension of 2-amino-5-chlorobenzoic acid (5.0 g, 29.1 mmol) and sodium azide (5.41 g, 83 mmol) in trimethyl orthoformate (9.12 ml, 83 mmol) was cooled to 0 °C. Acetic acid (100 mL) was added, and the mixture was stirred at 0 °C for 3 hours. The reaction was warmed to room temperature and then stirred at room temperature overnight. The mixture was concentrated in vacuo, and the residue was partitioned between ethyl acetate and 3 N HC1. The organic phase was dried over MgS04, filtered and the solvent was evaporated under reduced pressure to give 5-chloro-2-(lH-tetrazol-l-yl)benzoic acid.
400 mg
With sodium azide In acetic acid at 20℃; for 17h; Cooling with ice;
Preparation of intermediate 3
In an ice-water bath, compound 13 (867 mg, 8.18 mmol) was slowly added to a solution of compound 12 (500 mg, 2.92 mmol) and sodium azide (537 mg, 8.18 mmol) in acetic acid (10 mL). After stirring for 1 hour, it was raised to Stir at room temperature for 16 hours, concentrate under reduced pressure, add aqueous hydrochloric acid solution (20mL, 3N), and extract with ethyl acetate (10mL × 3).The organic phase was dried over anhydrous sodium sulfate, filtered,Concentrated under reduced pressure to give Intermediate 3 (400 mg) as a white solid.
A mixture of an aminobenzoic acid (1 eq.), a 2-fluoronitrobenezene (3 eq.) and CS2CO3 (3 eq.) in DMF was heated to 1400C for 1 hour, and then allowed to obtain room temperature. The mixture was diluted with water and washed with EtOAc (2 x).[0143] EtOH and Na2S2O4 (5 eq.) was added to the aqueous phase and the resulting mixture was stirred for 1 h. Aqueous HCl (2 M) was added to the mixture and then the aqueous phase was extracted with EtOAc (3 x) and the combined organic phases were concentrated.[0144] The residue was taken up in CH2Cl2 and l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (3 eq.) was added and the resulting mixture was stirred at room temperature for 1 h, and then concentrated. The residue was diluted with EtOAc, washed with aqueous NaOH (2 M) and concentrated.[0145] The residue was taken up in dioxane and added to a mixture of TiCU (1.1 eq., 1 M in toluene) and piperazine (5 eq.) in dioxane at 500C. The resulting mixture was <n="52"/>stirred at 1000C over night, and then allowed to obtain room temperature. Aqueous HCl (2 M) was added to the mixture until the solution became acidic and then the aqueous phase was extracted with EtOAc (2 x). Aqueous NaOH (2 M) was added to the aqueous phase until a basic solution was obtained and the resulting suspension was extracted with EtOAc (3 x). The combined organic phases were concentrated and purified by HPLC; 4-Chloro-2-fluoronitrobenzene (263 mg, 1.5 mmol) and 2-amino-5- chlorobenzoic acid (86 mg, 0.5 mmol) were reacted according to GPl to give 6.1 mg of the title compound (166 JO85F1). MS (ESI) 347 (MH+). Purity for MH+ (UV/MS) 100/85.
a) A mixture of 2.0 g (11.6 mmol) of 2-amino-5-chlorobenzoic acid and 3.48 g (58 mmol) of urea was heated to 160 C. for 2 hrs. and at 180 C. for a further 2 hrs. The resulting brown mass was triturated with 200 ml of methanol, filtered off and dried in a vacuum. There were obtained: 1.48 g (65%) of 6-chloro-1,2,3,4-tetrahydroquinazoline-2,4-dione as white crystals.
With caesium carbonate; In DMF (N,N-dimethyl-formamide); at 140℃; for 1h;
A mixture of an aminobenzoic acid (1 eq. ), a 2-fluoronitrobenezene (3 eq. ) and Cs2CO3 (3 eq. ) in DMF was heated to 140C for 1 hour, and then allowed to obtain room temperature. The mixture was diluted with water and washed with EtOAc (2 x). [0141] EtOH and Na2S204 (5 eq. ) was added to the aqueous phase and the resulting mixture was stirred for 1 h. Aqueous HC1 (2 M) was added to the mixture and then the aqueous phase was extracted with EtOAc (3 x) and the combined organic phases were concentrated. [0142] The residue was taken up in CH2C12 and 1-ethyl-3- (3- dimethylaminopropyl) carbodiimide hydrochloride (3 eq. ) was added and the resulting mixture was stirred at room temperature for 1 h, and then concentrated. The residue was diluted with EtOAc, washed with aqueous NaOH (2 M) and concentrated. [0143] The residue was taken up in dioxane and added to a mixture of TiCl4 (1.1 eq. , 1 M in toluene) and piperazine (5 eq. ) in dioxane at 50C. The resulting mixture was stirred at 100C over night, and then allowed to obtain room temperature. Aqueous HCl (2 M) was added to the mixture until the solution became acidic and then the aqueous phase was extracted with EtOAc (2 x). Aqueous NaOH (2 M) was added to the aqueous phase until a basic solution was obtained and the resulting suspension was extracted with EtOAc (3 x). The combined organic phases were concentrated and purified by HPLC.; Example 2; -2, 7-Dichloro-11- (pierazin-1-yl)-SH dibenzo [b, e] [1, 4] diazepine (166J085F1) [0144] 4-Chloro-2-fluoronitrobenzene (263 mg, 1.5 mmol) and 2-amino-5- chlorobenzoic acid (86 mg, 0.5 mmol) were reacted according to GP1 to give 6.1 mg of the title compound (166 J085F1). MS (ESI) 347 (MH+). Purity for MH+ (UV/MS) 100/85.
(109-8) 5-Chloroanthranilic acid (15.0 g), (CH3)2SO4 (11.6 g) and K2CO3 (12.7 g) were refluxed in acetone (150 g) for 30 minutes. The mixture was concentrated to about 90 g, and thereto was added water (90 g). The mixture was extracted with toluene (75 g), and the organic layer was concentrated to give methyl 5-chloroanthranilate (15.6 g, 96%). 1H NMR (CDCl3, 400 MHz) delta 7.83 (d, 1H, J=2.6 Hz), 7.21 (dd, 1H, J=8.5 and 2.6 Hz), 6.61 (d, 1H, J=8.5 Hz), 5.73 (brs, 2H), 3.88 (s, 3H).
96%
With potassium carbonate; In water; acetone;
(109-8) 5-Chloroanthranilic acid (15.0 g), (CH3)2SO4 (11.6 g) and K2CO3 (12.7 g) were refluxed in acetone (150 g) for 30 minutes. The mixture was concentrated to about 90 g, and thereto was added water (90 g). The mixture was extracted with toluene (75 g), and the organic layer was concentrated to give methyl 5-chloroanthranilate (15.6 g, 96 %). 1H NMR (CDCl3, 400MHz) delta 7.83 (d, 1H, J=2.6Hz), 7.21 (dd, 1H, J=8.5 and 2.6Hz), 6.61 (d, 1H, J=8.5Hz), 5.73 (brs, 2H), 3.88 (s, 3H).
With sodium hydroxide; benzotriazol-1-ol In dichloromethane
R.33 Preparation of 4-[{(N-(2-Amino-5-chlorobenzoyl)glycyl)amino}methyl]-1-(tert-butoxycarbonyl)piperidine
Reference Example 33 Preparation of 4-[{(N-(2-Amino-5-chlorobenzoyl)glycyl)amino}methyl]-1-(tert-butoxycarbonyl)piperidine A solution of 4-{(glycylamino)methyl}-1-(tert-butoxycarbonyl)piperidine (1.33 g, 4.90 mmol) in CH2Cl2 (25 mL) was treated with EtN (0.75 mL, 5.4 mmol), 2-amino-5-chlorobenzoic acid (840 mg, 4.9 mmol), EDCI (940 mg, 4.9 mmol) and HOBt (660 mg, 4.9 mmol). After the reaction mixture was stirred at room temperature for 3 h, 2 N aqueous NaOH solution (20 mL) was added. The organic layer was separated, and the aqueous layer was extracted with dichloromethane (20 mL*3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography (SiO2, ethyl acetate) afforded the desired 4-[{(N-(2-amino-5-chlorobenzoyl)glycyl)amino}methyl]-1-(tert-butoxycarbonyl)piperidine (1.63 g, 78%) as a solid.
With caesium carbonate; In N,N-dimethyl-formamide; at 140℃; for 1h;
A mixture of an aminobenzoic acid (1 eq.), a 2-fluoronitrobenezene (3 eq.) and Cs2CO3 (3 eq.) in DMF was heated to 1400C for 1 hour, and then allowed to obtain room temperature. The mixture was diluted with water and washed with EtOAc (2 x). EPO <DP n="66"/>[0178] EtOH and Na2S2O4 (5 eq.) was added to the aqueous phase and the resulting mixture was stirred for 1 h. Aqueous HCl (2 M) was added to the mixture and then the aqueous phase was extracted with EtOAc (3 x) and the combined organic phases were concentrated.[0179] The residue was taken up in CH2Cl2 and l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (3 eq.) was added and the resulting mixture was stirred at room temperature for 1 h, and then concentrated. The residue was diluted with EtOAc, washed with aqueous NaOH (2 M) and concentrated.[0180] The residue was taken up in dioxane and added to a mixture of TiCl4 (1.1 eq., 1 M in toluene) and piperazine (5 eq.) in dioxane at 500C. The resulting mixture was stirred at 1000C over night, and then allowed to obtain room temperature. Aqueous HCl (2 M) was added to the mixture until the solution became acidic and then the aqueous phase was extracted with EtOAc (2 x). Aqueous NaOH (2 M) was added to the aqueous phase until a basic solution was obtained and the resulting suspension was extracted with EtOAc (3 x). The combined organic phases were concentrated and purified by HPLC.; Example 2 - 2.7-Dichloro-l l-f°iperazin-l-ylV5H-dibenzorZ>,eiri.41diazepine (1661085Fl)[0181] 4-Chloro-2-fluoronitrobenzene (263 mg, 1.5 mmol) and 2-amino-5- chlorobenzoic acid (86 mg, 0.5 mmol) were reacted according to GPl to give 6.1 mg of the title compound (166 JO85F1). MS (ESI) 347 (MH4). Purity for MH+ (UV/MS) 100/85.
General procedure: 2-Amino benzoic acid (0.1 mol), HCl (20 ml) and H2O (20 ml) were added to a beaker and the mixture was cooled at 0 C. An aqueous solution of sodium nitrite (0.11 mol) (30%) was added slowly added and the reaction mixture was stirred for 30 min. The mixture was then poured into an aqueous solution of disodium diselenide (0.05 mol) and the resulting solution was stirred at room temperature for another 3 h before the pH was adjusted with aqueous HCl (10%) to a value of 2-3. Precipitation occurred and the final products were obtained by filtration.
General procedure: Compound 4 was prepared according to the reported procedure.3 2-amino benzoic acid 3 (0.1 mol), HCl (20 mL) and H2O (20 mL) were added to a beaker, and the mixture was cooled at 0C. An aqueous solution of sodium nitrite (0.11 mol) (30%) was added slowly, and the reaction mixture was stirred for 30 min. The mixture was then slowly added into an aqueous solution of disodium diselenide (0.05 mol), and the resulting solution was stirred at 50C for another 2.5 h. After cooling, the pH was adjusted with aqueous HCl to a value of 2O. The crude solid was dissolved in saturated NaHCO3 and was stirred at 100C for 1 h. After cooling, the pH was adjusted with aqueous HCl to a value of
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.
Example 37a: (2-AMINO-5-CHLOROPHENYL .-PERIDIN-2-EL-METHANONE To a cooled solution (-40 C) OF 2-BROMOPYRIDINE (1.68 mL, 17.6 mmol) in tetrahydrofuran (THF) (30 mL) was added n-butyllithium (nBuLi) (9.7 mL, 19 mmol, 2M in pentane) in a dropwise fashion and the resulting mixture was stirred for 30 min. 2- amino-5-chlorobenzoic acid (0.7 g, 4 mmol) was added and stirring was continued at 0 C. After 2 h, the mixture was quenched with trimethylchlorosilane (TMSCl) (10 mL), and hydrolyzed with 1N HC1 (30 mL). The aqueous layer was separated from the organic phase, neutralized with 3N aq. sodium hydroxide, and extracted with ether (3 X 100 mL). The combined ether extracts were dried (NA2SO4), filtered, concentrated and purified by flash chromatography on silica gel [hexanes: ethyl acetate (7: 3) ] to give (2-amino-5- chlorophenyl) -pyridin-2-yl-methanone (0.71 g, 76 %).
45%
To a solution of 2-bromopyridine (5 MI, 52 MMOL) in Et20 (60 ml) was added 40 ml of a n-butyllithium (1.6M in hexane, 64 MMOL) drop wise AT-40C over 30 min under a nitrogen atmosphere. The resulting yellow solution was stirred for a further 1 hr AT-50C TO-30C. In a separate flask, a solution of 2-AMINO-5-CHLOROBENZOIC acid (2.05 g, 12 MMOL) in dry THF (90 ML), under nitrogen atmosphere and with ice-cooling, was added in one portion to the solution prepared as described above. The reaction mixture was stirred for 2 hrs at 0C and then CHLOROTRIMETHYLSILANE (30 ml) was added at 0C with stirring. The reaction mixture was allowed to warm to room temperature and 1 N HCI aq (100 ml) was added. The resulting two-phase system was separated. The aqueous phase was adjusted to PH12 with 6N NAOH solution and extracted with ethyl acetate (2X150 ML). The combined organic extractions were dried over NA2SO4. After removal of solvent, the residue was purified by the flash chromatography using ethyl acetate/hexane (1: 4) as eluent. Crystallization of the product from Et20/hexane mixture gave 1.26 g (45 %) of desired product as yellow SOLID. 1H-NMR (DMSO-D6, 500 MHz): B 6.90 (1 H, d, J= 9 Hz), 7.31 (1 H, dd, J= 9 and 2.5 Hz), 7.40 (2H, br), 7.53 (1H, d, J= 2. 5 HZ), 7.61 (1H, m), 7.79 (1H, d, J= 8 HZ), 8.03 (1H, m), 8.69 (1H, m). MS: (ESI+) : 233.2 (M+1).
With pyridine; methanesulfonyl chloride In acetonitrile at 20℃; Cooling with ice;
1
EXAMPLE 1 Preparation (1) of methyl (E)-3-(6-chloro-4-oxo-4H-benzo[d][1,3]oxazin-2-yl)acrylate A mixed solution comprising 1.49 g of methanesulfonyl chloride and 10 ml of acetonitrile was cooled with ice, and 10 ml of an acetonitrile solution comprising 1.3 g of monomethyl maleate and 1.34 g of pyridine was dropwise added thereto under cooling with ice over a period of 5 minutes, followed by stirring for 5 minutes at the same temperature. 10 ml of an acetonitrile solution comprising 1.72 g of 5-chloroanthranilic acid and 2.77 g of pyridine was added under cooling with ice over a period of 2 minutes, followed by rinsing with 5 ml of acetonitrile and stirring for 20 minutes at the same temperature. 1.49 g of methanesulfonyl chloride was added over a period of 2 minutes under cooling with ice, followed by rinsing with 2 ml of acetonitrile and stirring for 30 minutes, and then the temperature was returned to room temperature, followed by reaction for 4 hours. The reaction liquid was poured to 20 ml of water, followed by stirring for 30 minutes. The resulting crystals were collected by filtration, washed with water and a mixed liquid of acetonitrile: water (2:1), and dried to obtain 1.82 g of the brown desired product (melting point: 162 to 164°C). 1H-NMR(400MHz,CDCl3) δ:8.20(dd,1H),7.77(dd,1H),7.51(dd,1H),7.23(d,1H),7.01(d,1H), 3.84(s,3H)
To suspension of <strong>[635-21-2]5-chloroanthranilic acid</strong> (1000 mg; 5.828 rnmol) in 1 ,2-dichloroethane (5 mL) triphosgene (692 mg; 2.331 mmol) in 1 ,2-dichloroethane solution (10 mL) was added and the mixture was heated to reflux for 4 hours. After cooling down to room temperature the precipitate was filtered, washed with cold DCM and dried to afford a white solid (1.128 g; 5.709 mmol; 98% yield).
97%
In 1,2-dichloro-ethane; at 80℃;
Step 1 6-Chloro-1H-benzo[d]1,3-oxazine-2,4-dione A 500 mL 3-necked round bottom flask was charged with <strong>[635-21-2]2-amino-5-chlorobenzoic acid</strong> (17 g, 0.1 mol) and 1,2-dichloroethane (200 mL). To the above was added dropwise a solution of triphosgene (21 g, 0.21 mol) in 1,2-dichloroethane (100 mL) at 80 C. The resulting mixture was heated at 80 C. for further 3 h then cooled in ice-water. The precipitate was collected by filtration and dried to afford 19 g (97%) of the product as white solid. 1H NMR (300 MHz, DMSO-d6) delta: 11.85 (br, 1H), 7.88 (d, J=2.4 Hz, 1H), 7.78 (dd, J=8.7, 2.4 Hz, 1H), 7.15 (d, J=8.7 Hz, 1H).
97%
In 1,2-dichloro-ethane; at 80℃; for 3h;
A 500 mL 3-necked round bottom flask was charged with 2-amino-5- chlorobenzoic acid (17 g, 0.1 mol) and 1 ,2-dichloroethane (200 mL). To the above was added dropwise a solution of triphosgene (21 g, 0.21 mol) in 1,2- dichloroethane (100 mL) at 80 C. The resulting mixture was heated at 80 C for further 3 h then cooled in ice- water. The precipitate was collected by filtration and dried to afford 19 g (97%) of the product as white solid. *H NMR (300 MHz, DMSO-d6) delta: 11.85 (br, 1H), 7.88 (d, J = 2.4 Hz, 1H), 7.78 (dd, J = 8.7, 2.4 Hz, 1H), 7.15 (d, J = 8.7 Hz, 1H).
70%
In 1,4-dioxane; for 2h;Reflux;
Triphosgene (285 mg, 0.96 mmol) was added to a <strong>[635-21-2]2-amino-5-chlorobenzoic acid</strong> (500 mg, 2.0 mmol) solution dissolved in 1,4-dioxane (5 ml), and the solution was refluxed for 2 hours. The reaction mixture was cooled in an ice bath. The solid was washed with hexane and dried in vacuo to give 400 mg (70%) of the pure compound as a brown solid.
70%
In 1,4-dioxane; at 100℃;
To the solution of <strong>[635-21-2]2-amino-5-chlorobenzoic acid</strong> (500 mg, 2.0 mmol) dissolved in 1,4-dioxane (5 ml), triphosgene (285 mg, 0.96 mmol) was added and the solution was refluxed for 2 hours. The reaction mixture was cooled in an ice container. The solid was washed and was under vacuum drying to obtain a pure compound of 400 mg (70%) as a brown solid. 1H NMR (300 MHz, DMSO-d6) delta 11.88 (s, 1H), 7.89 (d, J=2.4 Hz, 1H), 7.80 (dd, J=8.7, 2.5 Hz, 1H), 7.19 (d, J=8.7 Hz, 1H).
In tetrahydrofuran; at 20℃; for 4h;
General procedure: To a solution of different substituted 2-aminobenzoic acid (3 mmol) in 15 mL of THF was added triphosgene (0.30 g, 1 mmol). The mixture was stirred at room temperature and monitored with TLC. After more than 4 h, the solvent was evaporated and the residue was dissolved in 15 mL of EtOH. The hydrazine hydrate (80 %) (0.94 g, 15 mmol) was added to this mixture dropwise. After 2 h, the reaction was completed, 30 mL of ethyl acetate was added. The solution was washed with 1 mol/L hydrochloric acid solution, saturated sodium bicarbonate solution, and brine. The ethyl acetate solution was dried and evaporated, and the residue was applied to a flash column chromatography by eluting with ethyl acetate to give the compounds 1a-f.
Reflux; Inert atmosphere;
General procedure: To the solution of appropriate 2-aminobenzoic acid in dried THF or 1,4- dioxane was added triphosgene (0.35 eq). The mixture was stirred under reflux for 4-8 hrs. Then the solvent was removed in vacuo to give the isotaic anhydride as a solid in theoretical yield. 1H NMR indicated the product was of sufficient purity and was used in the next step without further purification.
General procedure: Compound 12 was prepared according tothe procedure previously reported.36 A mixture of anthranilicacid 11 (50 mmol) and tetrahydrofuran (THF, 100 mL) wasstirred at -10 C for 30 min. Then, a solution of triphosgene(BTC, 50 mmol) in THF (30 mL) was added dropwise to themixture described above. After that, the mixture was stirred for1 h at -10 C, followed by 18-24 h at 20-25 C. The solventwas removed under reduced pressure, and anhydrous ether(150 mL) was added to the obtained residue while the mixturewas being vigorously stirred. The precipitate was collected byfiltration, washed with anhydrous ether, and dried to givecompound 12 in yields of 80-90%.
In tetrahydrofuran; at -5 - 20℃; for 15h;
General procedure: A mixture of anthranilic acid (40 mmol) and tetrahydrofuran (THF, 100 mL) was stirred at -5 C for 30 min. Then, triphosgene (40 mmol) was dissolved in THF (20 mL) and added dropwise to the above mixture. After that, the mixture was stirred for 5 h at -5C, followed by 10 h at room temperature. The solvent was removed under reduced pressure, and the residue was washed with ether, and dried to afford compound 2 in yield of 85-95%.
In tetrahydrofuran; at 20℃;
(3) Add 3 g (1 mmol) of the raw material 4 to a 100 ml three-necked flask with tetrahydrofuran as a solvent,Stir at room temperature, add 4.32 g (1 mmol) triphosgene in portions,TLC followed the reaction. After the basic reaction of the raw materials was completed, the reaction was stopped, desolved, filtered with suction, washed with n-hexane multiple times, intermediate 5
Into a 500-mL 3-necked round-bottom flask, was placed a solution of 2-ammo-5-chlorobenzoic acid (10 g, 58 48 mmol, 1 00 equiv) in water (100 mL), acetic acid (8 g, 133 33 mmol, 2 24 equiv) This was followed by the addition of NaOCN (8 2 g, 126 15 mmol, 2 13 equiv) The mixture was stirred for 30 rains at 3O0C To this was added sodium hydroxide (86 g, 2 15 mol, 37 00 equiv) The resulting solution was stirred overnight at 30cC The solids were collected by filtration The residue was dissolved in water The pH value of the solution was adjusted to 7 with hydrogen chlo?de (12 mol/L) The solids were collected by filtration This resulted in 5 g (44%) of 6 chloroqmnazolme-2,4(lH,3H)-dione as a white solid.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 7h;
2-Amino-5-chlorobenzoic acid (10 g, 58.1 mmol), N,O-dimethylhydroxylamine hydrochloride (10 g, 103 mmol), EDCI (14 g, 71.5 mmol) and 1-hydroxybenzotriazole (9.2 g, 68 mmol) were dissolved in DMF (150 mL), and DIPEA (23.6 g, 183 mmol) was added. The mixture was stirred at room temperature for 7 h until TLC indicated that the reaction was completed. The reaction mixture was diluted with 1 N aq. NaOH solution and extracted with DCM. The organic layer was washed with water for three times, dried and concentrated. The residue was purified through silica gel column chromatography to obtain 2-amino-5-chloro-N-methoxy-N-methylbenzamide (compound 20a, 7.2 g, yield 72%).
68%
To a solution of <strong>[635-21-2]2-amino-5-chlorobenzoic acid</strong> (17.1 g, 0.1 mol) in THF (170 ml_) was added 1,1 '-carbonyldiimidazole (16.2 g, 0.1 mol) and the mixture was stirred at room temperature under a nitrogen atmosphere. After 2 hours, a suspension of N1O- dimethylhydroxylamine hydrochloride (10.7 g, 0.11 mol) and Et3N (15.3 ml_, 0.11 mol) in THF (170 ml_) was added and the resulting mixture was stirred at room temperature overnight and evaporated to dryness. The residue was triturated with 1N sodium hydroxide, extracted with EtOAc, washed with brine, dried over Na2SO4, filtered and evaporated to give the title compound as a yellow oil (14.6 g, 68%). LC/MS: m/z 215 (M+H)+, Rt: 2.28 min.
Q; 63
A mixture of 2-amino-5-chlorobenzoic acid (leq) and cyclic ketone (leq) was treated with POCl3 (5eq) at 0 °C. The mixture was heated at reflux for 7 h and at rt for 16 h. After this time the reaction was poured into ice water and extracted with DCM. The crude residue was purified by flash column chromatography to give the desired quinoline.; 7,9-Dichloro-2,3-dihydro-1H-cyclopenta[b]quinolinePrepared according to procedure Q using 2-amino-5-chlorobenzoic acid (5.15 g, 30 mmol) and propane (2.7 rnL, 30 mmol) in POCI3 (25 mL). The crude product was purified by column chromatography on silica (using a gradient of DCM:MeOH:NH4OH, 90:9:1 as eluent) to give 7,9-dichloro-2,3-dihydro-1H- cyclopenta[b]quinoline. Mass Spectrum (ESI) m/e = 239 (M + 1).
With trichlorophosphate for 3h; Cooling with ice; Reflux;
4.4. General procedure for the synthesis of compounds 7
General procedure: POCl3 (25 mL) was added to a mixture of anthranilic acid derivative 5 (23 mmol) and cycloketones derivative 6 (25 mmol) in an ice bath. The mixture was heated at reflux for 3 h. Then, it was cooled to room temperature and concentrated to give slurry. The residue was diluted with ethyl acetate, neutralized with aqueous K2CO3, the organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum affording a pale brown solid which was purified by flash chromatography on silica gel using petroleum ether/ethyl acetate (9:1) to give 7 in 80-90% yield.
65
2,2-Dimethylcyclopentanone (1.12 g, 10 mmol) and 2-amino-5-chlorobenzoic acid (1.72 g, 10 mmol) were stirred at rt for 10 minutes followed by the addition OfPOCl3 (10 mL). The resulting mixture was heated to 100°C for 5 h and overnight at rt. After this time the reaction mixture was poured into ice water and extracted with EtOAc. The solvent was evaporated in vacuo and flash column chromatography on silica (using a gradient of EtOAc/ hexane, 0-100% eluent) gave 7,9-dichloro-3,3-dimethyl-2,3-dihydro-1H-cyclopenta[b]quinoline. Mass Spectrum (ESI) m/e = 267 (M + 1).
Stage #1: 5-chloroanthranilic acid With 1,1'-carbonyldiimidazole In tetrahydrofuran at 20℃; Inert atmosphere;
Stage #2: methylamine In tetrahydrofuran for 3h;
5-chloro-2-(1,3-dioxo-1,3-dihydroisobenzofuran-5-carboxamido)benzoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95%
In dichloromethane; at 20℃;
General procedure: A mixture of trimellitic anhydride chloride (2.15 g, 0.01 mol) and the appropriate anthranilic acid (0.01 mol) in dichloromethane(50 ml) was stirred at room temperature for 4-6 h. The obtained solid was filtered off, washed with dichloromethane and dried.
With sodium azide; trimethyl orthoformate at 0 - 20℃;
1 Step 1: 5-Chloro-2-(1 H-tetrazol-1 -yl)benzoic acid
A suspension of 2-amino-5-chlorobenzoic acid (5.0 g, 29.1 mmol) and sodium azide (5.41 g, 83 mmol) in trim- ethyl orthoformate (9.12 ml, 83 mmol) was cooled to 00 C. Acetic acid (100 mE) was added, and the mixture was stirred at 00 C. for 3 hours. The reaction was warmed to room temperature and then stirred at room temperature overnight. The mixture was concentrated in vacuo, and the residue was partitioned between ethyl acetate and 3 N Rd. The organic phase was dried over Mg504, filtered and the solvent was evaporated under reduced pressure to give 6.28 g (100%) of 5-chloro-2-(1 R-tetrazol- 1 -yl)benzoic acid as a light yellow solid.
Multi-step reaction with 3 steps
1: lithium aluminium tetrahydride / tetrahydrofuran / 3 h / 20 °C
2: manganese(IV) oxide / dichloromethane / 24 h / 20 °C
3: water / 48 h / 70 °C
With phosphorus pentachloride; trichlorophosphate; for 1h;Reflux;
5-Chloro-2-aminobenzoic acid (0.429 g, 2.5 mmol), urea (0.33 g, 5.5 mmol), phosphorus pentachloride (3.124 g, 15 mmol) and phosphorus oxychloride (10 mL) were added and the reaction was stopped by heating to reflux for 1 h. Decompression to steam Excess phosphorus oxychloride, the residue was dissolved in methylene chloride, ice water was washed with phosphorus oxychloride and phosphorus pentachloride, the separation of water The organic phase was adjusted to pH 6-7 with saturated sodium bicarbonate and extracted with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate. Concentration column chromatography gave 0.289 g of a light yellow solid, yield: 49.5%
6-chloro-2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-4H-benzo[d][1,3]oxazin-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
(1) Add 0.5 g of 5-chloro-5-(trifluoromethyl)picolinic acid to a 25 ml three-necked flask,0.7g pyridine and 5ml acetonitrile, ice bath cooling to -5 C,Subsequently, 0.51 g of methanesulfonyl chloride was slowly added dropwise to the system using a constant pressure dropping funnel.After stirring for 10 minutes after addition, add 0.5 g to the system at one time2-amino-3,5-difluorobenzoic acid, After stirring for 10min, add 0.70g pyridine slowly with constant pressure dropping funnel. The dropping process should keep the temperature lower than 0C. Continue stirring for 15min after the addition is complete, then slowly add 0.51g slowly with the constant pressure dropping funnel. The sulfonyl chloride was stirred for 1 h after the addition was complete. The ice salt bath was removed. The reaction temperature was slowly raised to room temperature. After 12 h of reaction, water and dichloromethane were added for extraction. The organic layer was passed through the column (petroleum ether:ethyl acetate=10: 1) Obtain intermediates6-Chloro-2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-4H-benzo[d][1,3]oxazin-4-one.
first step:To a 25 mL three-necked flask was added 0.5 g (2.22 mmol) of3-chloro-5- (trifluoromethyl) picolinic acid, 0.7 g (8.87 mmol) of pyridine and 5 mL of acetonitrile,The ice-salt bath is cooled to -5 C,Subsequently, 0.51 g (4.43 mmol) was slowly added dropwise to the system using a constant pressure dropping funnel.Methanesulfonyl chloride,After stirring for 5 minutes,Add 0.38g (2.22mmol) to the system in one portion2-amino-5-chlorobenzoic acid and stir for 10min,0.70 g (8.87 mmol) of pyridine was slowly added dropwise using a constant pressure dropping funnel. The dropping temperature should be kept below 0 C. Stirring was continued for 15 minutes after the addition, and then 0.51 g (4.43) was slowly added slowly using a constant pressure dropping funnel. mmol) of methanesulfonyl chloride, continue to stir for 1 h, remove the ice-salt bath,After the reaction temperature slowly rises to room temperature, the reaction is continued for 12 hours.Water and dichloromethane were added for extraction, and the organic layer was passed through a column (petroleum ether: ethyl acetate = 10: 1).Get intermediate6-chloro-2- (3-chloro-5- (trifluoromethyl) pyridin-2-yl) -4H-benzo [d] [1,3] oxazin-4-one.
General procedure: General procedure for preparing intermediates 3. As shown in scheme 1, to a solution of 3-chloro-5-(trifluoromethyl)picolinicacid 1 (0.5 g, 2.22 mmol) in 5 mL ofacetonitrile, pyridine (0.7 g, 8.87 mmol) and methanesulphonyl chloride (0.51 g,4.43 mmol) was slowly added at -5 0C, and was left to stir at -5 0Cfor 10 min. The corresponding substituted 2-amino-benzoic acid (2.22 mmol) wasadded and left to stir for further 10 min. Pyridine (0.7 g, 8.87 mmol) and methanesulphonylchloride (0.51 g, 4.43 mmol) were slowly added again below 0 0C. Theresulting mixture was stirred at room temperature for 10 h and monitored byTLC. After the completion of reaction above, water (5 mL) was added to themixture to afford a crystalline solid (intermediate 3) via filter and recrystallization from ethanol.
6-chloro-3-(4-aminosulphonylphenyl)-2-mercapto-3H-quinazolin-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
69%
With triethylamine; In ethanol; for 3h;Inert atmosphere; Reflux;
General procedure: A suspention of anthranilic acid A1-A17 (0.001mol), a catalytic amount of triethylamine and <strong>[51908-29-3]4-isothiocyanato-benzenesulfonamide</strong> B17b (0.169g, 0.001mol) in absolute ethanol (25ml) was refluxed for 3. The reaction mixture was filtered while hot, left to cool and the solvent was removed under reduced pressure. The obtained residue was triturated from diethyl ether, filtered and dried under vacuo to obtain titled compound C: 1-17 as a whitish solid.
With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide
6-chloro-2-(4-isopropylphenyl)-4H-3,1-benzoxazin-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
41%
With pyridine In tetrahydrofuran at 20℃; for 3h; Cooling with ice;
2 Synthesis of 6-chloro-2- (4-isopropylphenyl) -4H-3,1-benzoxazin-4-one (Compound No. 18)
4-Isopropylbenzoyl chloride dissolved in a mixture of tetrahydrofuran (2.0 mL) and pyridine (1.5 mL) with 5-chloroanthranilic acid (0.43 g, 2.50 mmol) and dissolved in THF (1.0 mL) with ice cooling (0.68 g, 3.75 mmol) was added dropwise. After stirring for 1 hour under ice-cooling and 2 hours at room temperature, water was added and the mixture was stirred for 0.5 hour at room temperature. The precipitate was collected by filtration and washed with water and hexane.Rikagel column chromatography (hexane: ethyl acetate = 9: 1 to 17: 3 gradient)By0.31 g (41%),
4-(6-chloro-2-methyl-4-oxoquinazolin-3(4H)-yl)-N-(4-methylpyrimidin-2-yl)benzenesulfonamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
71%
General procedure: Anthranilic acid (0.001M) and acetic anhydride were refluxed under anhydrous condition for 4h. Excess of acetic anhydride was distilled of under reduced pressure. To the mixture obtained, amine (0.001M) in glacial acetic acid was added and refluxed for 4h, and the obtained reaction mixture was poured into crushed ice and kept overnight. The solid which separated out was filtered, thoroughly washed with cold distilled water, dried and recrystallized [15]. The purity of molecules was controlled with Thin Layer Chromatography in developing system benzene/acetone (6:4). The newly synthesized compounds were characterized by elemental analysis and FT-IR, 1H-NMR and MS spectroscopic methods.
4-(6-chloro-2-methyl-4-oxoquinazolin-3(4H)-yl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzenesulfonamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
69%
General procedure: Anthranilic acid (0.001M) and acetic anhydride were refluxed under anhydrous condition for 4h. Excess of acetic anhydride was distilled of under reduced pressure. To the mixture obtained, amine (0.001M) in glacial acetic acid was added and refluxed for 4h, and the obtained reaction mixture was poured into crushed ice and kept overnight. The solid which separated out was filtered, thoroughly washed with cold distilled water, dried and recrystallized [15]. The purity of molecules was controlled with Thin Layer Chromatography in developing system benzene/acetone (6:4). The newly synthesized compounds were characterized by elemental analysis and FT-IR, 1H-NMR and MS spectroscopic methods.
With sodium azide; phosphorus pentoxide at 130℃; for 3h;
142 Synthesis of 5-chloro-2-(1H-tetrazol-1-yl)benzoic Acid
Synthesis of 5-chloro-2-(1H-tetrazol-1-yl)benzoic Acid To a mixture of 2-amino-5-chlorobenzoic acid (100 mg, 0.58 mmol) and NaN3 (38 mg, 0.58 mmol) in triethoxymethane (3 mL) was added P2O5 (16 mg, 0.12 mmol). The reaction mixture was stirred at 130° C. for 3 h and then cooled to RT. Water (20 mL) was added and the mixture was extracted with i-PrOH/CHCl3 (1/3, 20 mL*3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by recrystallization from DCM to give 5-chloro-2-(1H-tetrazol-1-yl)benzoic acid (55 mg, yield: 42%) as a yellow solid. ESI-MS [M+H]+: 225.1.
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