* 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.
Reference：
[1] Journal of Organic Chemistry, 1998, vol. 63, # 12, p. 4116 - 4119
4
[ 67-56-1 ]
[ 610-71-9 ]
[ 57381-43-8 ]
Yield
Reaction Conditions
Operation in experiment
203.6 g
Reflux
Step 1: To a 2 L round-bottom flask, 2,5-dibromobenzoic acid (250 g, 0.90 mol) in MeOH (2 L) and concentrated H2SO4 (18.4 g, 0.19 mol) were added. The mixture was refluxed overnight before cooled to room temperature. The resulting precipitate was then filtered, washed with cold methanol and dried under vacuum. It yielded 203.6 g methyl 2,5-dibromobenzoate as a yellow solid. To a 2 L round-bottom flask was added 2,5-dibromobenzoate (198.2 g, 0.68 mol) in 1 L dry DMF. CuCN (122 g, 1.36 mol) and NaI (22.8 g, 0.15 mol) were introduced next. The mixture was stirred overnight at 130 °C under nitrogen atmosphere. After the reaction was complete, it was extracted with ethyl acetate (500 mL × 3),washed with water (500 mL) and purified over silica gel (PE/EtOAc = 5/1) to give 95.2 g methyl 2,5-dicyanobenzoate as a brown solid (yield: 75.1 percent).
Reference：
[1] Tetrahedron, 2016, vol. 72, # 24, p. 3454 - 3467
[2] Asian Journal of Chemistry, 2014, vol. 26, # 19, p. 6655 - 6657
5
[ 186581-53-3 ]
[ 610-71-9 ]
[ 57381-43-8 ]
Reference：
[1] Journal of Organic Chemistry, 1977, vol. 42, # 2, p. 257 - 260
6
[ 88-65-3 ]
[ 610-71-9 ]
Yield
Reaction Conditions
Operation in experiment
85.6%
With sodium periodate; sulfuric acid; sodium bromide In water; acetic acid at 30 - 65℃;
First, sodium periodate solution was configured: 4.3 g (19.9 mmol) of sodium periodate was dissolved in 30 ml of water and 18 ml of acetic acid.Then, 10 g (49.7 mmol) of 2-bromobenzoic acid, 5.1 g (49.7 mmol) of sodium bromide, and sodium periodate solution were added to the reaction flask.Heat to 30°C and add 4.4 ml concentrated sulfuric acid slowly at this temperature.After completion of the dropwise addition of concentrated sulfuric acid, the temperature was raised to 50-65°C and reacted at this temperature for 2-3 hours.Thin layer chromatography (TLC) detection reaction is completed, cooled, poured into ice water, solid precipitated, filtered,The filter cake was washed with water several times to obtain 11.9 g of 2,5-dibromobenzoic acid in a yield of 85.6percent.
Reference：
[1] Patent: CN107954852, 2018, A, . Location in patent: Paragraph 0029-0031
[2] Justus Liebigs Annalen der Chemie, 1891, vol. 266, p. 203
[3] Journal of the Indian Chemical Society, 1980, vol. 57, # 6, p. 640 - 642
7
[ 124-38-9 ]
[ 106-37-6 ]
[ 610-71-9 ]
Reference：
[1] European Journal of Organic Chemistry, 2008, # 10, p. 1797 - 1801
8
[ 615-59-8 ]
[ 610-71-9 ]
Reference：
[1] Journal of the Chemical Society, 1892, vol. 61, p. 1029
[2] Chemische Berichte, 1880, vol. 13, p. 963[3] Chemische Berichte, 1881, vol. 14, p. 417
[4] Journal of the American Chemical Society, 1954, vol. 76, p. 5755,5761
[5] Journal of Organic Chemistry, 1977, vol. 42, # 2, p. 257 - 260
Reference：
[1] Chemische Berichte, 1874, vol. 7, p. 1146[2] Chemische Berichte, 1875, vol. 8, p. 1422
[3] Chemische Berichte, 1874, vol. 7, p. 1146[4] Chemische Berichte, 1875, vol. 8, p. 1422
[5] Journal of the American Chemical Society, 1954, vol. 76, p. 5755,5761
11
[ 32937-55-6 ]
[ 610-71-9 ]
Reference：
[1] Journal of the Karnatak University, 1956, vol. 1, p. 36
[2] Journal of Organic Chemistry, 1958, vol. 23, p. 1412,1217
12
[ 552-16-9 ]
[ 610-71-9 ]
[ 603-78-1 ]
Reference：
[1] Chemische Berichte, 1881, vol. 14, p. 1168,1170
[2] Chemische Berichte, 1881, vol. 14, p. 1168,1170
13
[ 65-85-0 ]
[ 610-71-9 ]
[ 585-76-2 ]
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1915, vol. 34, p. 162
14
[ 65-85-0 ]
[ 610-71-9 ]
[ 619-03-4 ]
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1915, vol. 34, p. 162
15
[ 5794-88-7 ]
[ 610-71-9 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1884, vol. 222, p. 113
[2] Chemische Berichte, 1877, vol. 10, p. 1705
[3] Pharmazie, 1982, vol. 37, # 2, p. 115 - 117
16
[ 98-86-2 ]
[ 610-71-9 ]
Reference：
[1] Journal of Organic Chemistry, 1958, vol. 23, p. 1412,1217
17
[ 57381-41-6 ]
[ 610-71-9 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1892, vol. 269, p. 219
[2] Justus Liebigs Annalen der Chemie, 1892, vol. 269, p. 219
18
[ 2840-02-0 ]
[ 610-71-9 ]
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1915, vol. 34, p. 162
19
[ 3638-73-1 ]
[ 610-71-9 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1892, vol. 269, p. 219
20
[ 95-46-5 ]
[ 610-71-9 ]
Reference：
[1] Journal of the Chemical Society, 1892, vol. 61, p. 1029
21
[ 6933-10-4 ]
[ 610-71-9 ]
Reference：
[1] Chemische Berichte, 1880, vol. 13, p. 963[2] Chemische Berichte, 1881, vol. 14, p. 417
22
[ 57381-43-8 ]
[ 610-71-9 ]
Reference：
[1] Journal of Polymer Science, Part A: Polymer Chemistry, 2017, vol. 55, # 15, p. 2494 - 2505
23
[ 7664-93-9 ]
[ 7657-09-2 ]
[ 610-71-9 ]
Reference：
[1] Journal of the American Chemical Society, 1947, vol. 69, p. 2022
24
[ 56-23-5 ]
[ 64-17-5 ]
[ 29798-82-1 ]
[ 610-71-9 ]
[ 611-00-7 ]
Reference：
[1] Journal of the American Chemical Society, 1955, vol. 77, p. 4619,4621
[2] Sci. Rep. Tohoku Univ., Ser. 1: Phys., Chem., Astron., 1952, vol. 36, p. 166,168[3] Proceedings of the Japan Academy, 1953, vol. 29, p. 347,348
25
[ 401-75-2 ]
[ 7726-95-6 ]
[ 610-71-9 ]
[ 619-03-4 ]
Reference：
[1] Bulletin de la Classe des Sciences, Academie Royale de Belgique, 1922, vol. <5>8, p. 346[2] Bulletin des Societes Chimiques Belges, 1923, vol. 32, p. 104[3] Chem. Zentralbl., 1923, vol. 94, # I, p. 66
26
[ 7732-18-5 ]
[ 7726-95-6 ]
[ 65-85-0 ]
[ 610-71-9 ]
[ 585-76-2 ]
[ 619-03-4 ]
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1915, vol. 34, p. 162
27
[ 552-16-9 ]
[ 7732-18-5 ]
[ 7726-95-6 ]
[ 636-28-2 ]
[ 610-71-9 ]
[ 603-78-1 ]
Reference：
[1] Chemische Berichte, 1881, vol. 14, p. 1168,1170
28
[ 861602-70-2 ]
[ 610-71-9 ]
Reference：
[1] Chem. Zentralbl., 1912, vol. 83, # I, p. 135
29
[ 615-59-8 ]
[ 7697-37-2 ]
[ 610-71-9 ]
Reference：
[1] Chemische Berichte, 1880, vol. 13, p. 963[2] Chemische Berichte, 1881, vol. 14, p. 417
30
[ 610-71-9 ]
[ 19725-82-7 ]
Reference：
[1] Journal of Organic Chemistry, 1998, vol. 63, # 12, p. 4116 - 4119
31
[ 552-16-9 ]
[ 610-71-9 ]
[ 603-78-1 ]
Reference：
[1] Chemische Berichte, 1881, vol. 14, p. 1168,1170
[2] Chemische Berichte, 1881, vol. 14, p. 1168,1170
32
[ 552-16-9 ]
[ 7732-18-5 ]
[ 7726-95-6 ]
[ 636-28-2 ]
[ 610-71-9 ]
[ 603-78-1 ]
Reference：
[1] Chemische Berichte, 1881, vol. 14, p. 1168,1170
33
[ 610-71-9 ]
[ 147034-01-3 ]
Reference：
[1] Journal of Medicinal Chemistry, 2006, vol. 49, # 12, p. 3563 - 3580
[2] Organic Letters, 2018, vol. 20, # 11, p. 3310 - 3313
34
[ 610-71-9 ]
[ 203314-28-7 ]
Reference：
[1] Journal of Medicinal Chemistry, 2006, vol. 49, # 12, p. 3563 - 3580
35
[ 610-71-9 ]
[ 1346574-57-9 ]
Reference：
[1] Synthetic Communications, 2016, vol. 46, # 14, p. 1215 - 1222
[2] Patent: CN105541801, 2016, A,
Part A: Synthesis of 2,5-Dibromobenzoyl Chloride By the general method of Part C of Example 1, the reaction of 50.0 g (0.1786 mol) <strong>[610-71-9]2,5-dibromobenzoic acid</strong> with 150 mL thionyl chloride gave after distillation 40 g of 2,5-dibromobenzoyl chloride.
With thionyl chloride; for 8h;Heating / reflux;
Into a 2 L flask fitted with a reflux condenser and magnetic stir-bar was introduced <strong>[610-71-9]2,5-dibromobenzoic acid</strong> (50.0 g, 0.1786 mol) and thionyl chloride (150 mL, 2. 04 mol). The mixture was refluxed for 8 hours. Most of the thionyl chloride was distilled off followed by removal of the remainder by rotary evaporation. Distillation gave 40 g of 2, 5-dibromobenzoyl chloride. (pot temperature 110 C ; distillation temp 70 C/0. 70MMHG).
With thionyl chloride; In N,N-dimethyl-formamide; toluene; at 0 - 80℃; for 2.25h;
General procedure: 2-bromobenzoic acid derivatives (8 mmol), toluene (40 mL) were added to a 100 mL round-bottom flask. After cooled to 0 oC, DMF (0.1 eq., 0.8 mmol) was added to the mixture. SOCl2 (1.2 eq., 9.6 mmol) was slowly added to the flask with more than 10 min. After performed at 0 oC for 5 min, the reaction was warmed to 23 oC for 10 min. At last the mixture was performed at 80 oC for 2 h. After evaporated the solvent and dried by vacuum pump, the crude product of 2,4-dibromobenzoyl chloride derivatives were provided as a oil. After 2,4-dibromobenzoyl chloride derivative (6 mmol) was added to it, the tube evacuated and recharged with N2 for 3 times. Before the mixture was cooled to -78 oC, THF (20 mL) was added to the tube. MeMgCl (6 mmol) was dropwised to the mixture. The reaction was performed for 1h at -78 oC, 2 h at 0 oC, 5 to 10 h at rt. 20 mL water was added to the tube and the mixture was extracted with Et2O (30 mL x 3),dried by anhydrous Na2SO4. Evaporation of the solvent followed by purification on silica gel provided 1-(2-bromophenyl)ethanone derivative, yield 60-70%.
With sodium periodate; sulfuric acid; sodium bromide; In water; acetic acid; at 30 - 65℃;
First, sodium periodate solution was configured: 4.3 g (19.9 mmol) of sodium periodate was dissolved in 30 ml of water and 18 ml of acetic acid.Then, 10 g (49.7 mmol) of 2-bromobenzoic acid, 5.1 g (49.7 mmol) of sodium bromide, and sodium periodate solution were added to the reaction flask.Heat to 30C and add 4.4 ml concentrated sulfuric acid slowly at this temperature.After completion of the dropwise addition of concentrated sulfuric acid, the temperature was raised to 50-65C and reacted at this temperature for 2-3 hours.Thin layer chromatography (TLC) detection reaction is completed, cooled, poured into ice water, solid precipitated, filtered,The filter cake was washed with water several times to obtain 11.9 g of 2,5-dibromobenzoic acid in a yield of 85.6%.
66.4%
With N-Bromosuccinimide; sulfuric acid; In dichloromethane; at 25 - 30℃; for 2h;
After adding 20.0 g of o-bromobenzoic acid to 40.0 g of sulfuric acid and 80.0 g of DCM in a four-necked flask equipped with a thermometer and a stirrer, 19.8 g of NBS was added to the reaction solution, and stirring was started to control the reaction temperature at 25 to 30 C. The reaction was incubated for 2 h, and a white solid was precipitated in the reaction mixture. After the reaction of the starting material was completed, the reaction mixture was poured into ice water to quench, the reaction solution was dried, filtered, and recrystallized from 60 ml of methanol to obtain 18.5 g of 2,5- Dibromobenzoic acid. The yield was 66.4%, and the purity was 99.0%.
EXAMPLE 1; 5-iodo-2-[[2-2[(dimethylamino)methyl]phenyl]thio]benzyl alcohol (IDAM) and (5-bromo-2-[[2-2[(dimethylamino)methyl]phenyl]thio]benzyl alcohol); The synthesis of 5-iodo-2-[[2-2[(dimethylamino)-methyl]phenyl]thio]benzyl alcohol (IDAM) and its bromo derivative (5-bromo-2-[[2-2[(dimethylamino)methyl]phenyl]thio]benzyl alcohol) was achieved by a reaction sequence outlined in Scheme 1 shown on page 37 of this application. The direct coupling of <strong>[610-71-9]2,5-dibromobenzoic acid</strong> (Frazer, A., J. Clin. Psychiatry. 6:9-25 (1997)) or 2,5-diiodobenzoic acid (Mathis, C. A. et al., J. Nucl. Med. 33:890(1992)) with 2-thio-N,N-dimethylbenzamide (Wong, D. T. et al. Adv. Exp. Med. & Biol., 363:77-95 (1995)) was carried out in N,N-dimethylacetamide (DMAC) with sodium methoxide to give the desired compounds in good yield (59 and 44% for 23 and 28, respectively). Only when 2-thio-N,N-dimethylbenzamide was freshly prepared, was a good coupling yield achieved. This may due to the fact that the free thiol of 22 was not stable upon prolonged standing at room temperature. The bromo compound was converted to the corresponding tri-n-butyltin derivative (Maryanoff. E. M. et al., J. Med. Chem. 33:2793-2797 (1990)) by a tetrakis(triphyenlphosphine)palladium(0)-catalyzed reaction with good yield (66%). The tin derivative was successfully converted to IDAM with excellent yield (97%), or alternatively, 2-((4-iodo-2-carboxyphenyl)thio)N,N-dimethylbenzamide (Mathis, C. A. et al., Eur. J. Pharmacol. 210:103-104 (1992)) was reduced to IDAM with 66% yield.
Under nitrogen, 2 mmol of the halogen-substituted benzoic acid indicated in Table 6 was stirred with a solution of 3 mmol Na2CO3 at 50-75 C. until all of the halogen-substituted benzoic acid was dissolved. Subsequently, 0.02 mmol CuSO4 and 0.04 mmol rac-trans-N,N'-dimethylcyclohexane-1,2-diamine (Ligand F) dissolved in 1 mL deionized water were added and the reaction mixture was heated at 80-100 C. for 4 h. After cooling to ambient temperature the reaction mixtures were carefully acidified with 35% aqueous HCl.In isolation method A, the products were extracted from the aqueous layer twice with ethyl acetate, the ethyl acetate fractions were combined and the crude reaction product was isolated by evaporation of ethyl acetate under vacuum. In isolation method B, the products were isolated by filtration, washed with water and dried under vacuum. The crude reaction product was analyzed by 1H NMR (d6-dmso). The results are summarized in Table 6. TABLE 6 Examples 8~23 Starting material Halogenated Benzoic Acid Isolation CONV SEL Example Benzoic Acid Product T ( C.) Method (%) (%) 8 2,5-dibromo- 2-hydroxy-5- 80 B >99 >99 bromo- 9 2-bromo-5-nitro- 2-hydroxy-5- 80 B >99 >99 nitro- 10 2-bromo-5-nitro- 2-hydroxy-5- 100 A >99 >99 nitro- 11 2-bromo-5-methyl- 2-hydroxy-5- 80 B >99 >99 methyl- 12 2-bromo-5-methyl- 2-hydroxy-5- 100 A >99 >99 methyl- 13 4-bromo- 4-hydroxy- 100 A >99 >99 14 4-chloro- 4-hydroxy- 80 B >99 >99 15 2,4-dichloro- 2-hydroxy-4- 100 A 70 >99 chloro- 16 2,5-dichloro- 2,5-dihydroxy- 80 B 93 >99 17 2-chloro-5-nitro- 2-hydroxy-5- 100 A 74 >99 nitro- 18 2-chloro-3,5-dinitro- 2-hydroxy-3,5- 100 A >99 >99 dinitro- 19 2-chloro-3,5-dinitro- 2-hydroxy-3,5- 80 B >99 >99 dinitro- 20 2-chloro-5-methyl- 2-hydroxy-5- 100 A >99 >99 methyl- 21 2-bromo-5- 2-hydroxy-5- 100 A >99 >99 methoxy- methoxy- 22 2-bromo-5- 2-hydroxy-5- 80 B >99 >99 methoxy- methoxy- 23 2-chloro-5-bromo- 2-hydroxy-5- 80 B 73 >99 bromo
With methanesulfonyl chloride; triethylamine; In dichloromethane; at 0 - 25℃; for 26h;Inert atmosphere; Reflux;
Compound [17] under a nitrogen atmosphere to methylene chloride solution (0.3L) of the crude product of (8.21g), was added triethylamine (10.8mL, 77.2mmol).The reaction solution was cooled to 0 , the addition of methane sulfonic acid chloride (4.78mL, 61.8mmol).After stirring for 16 hours at 25 , the mixture was stirred for 10 hours under further heated to reflux.The reaction solution was cooled to 25 C., the water was added the reaction was stopped and extracted with methylene chloride.The organic layer was washed with water, then was dried over magnesium sulfate, the solvent was evaporated under reduced pressure to obtain a crude product.Silica gel column chromatography (hexane / ethyl acetate = 20/1) using subjected to purification, to give compound [18] (Yield of 8.19 g, yield ratio (two-step) 85%).Compound [18];
50g (0.18mmol) 2,5- dibromo-benzoic acid was added to the concentrated sulfuric acid, in order to make <strong>[610-71-9]2,5-dibromo-benzoic acid</strong> can be evenly distributed, the reaction system was agitated for a period of time, after which a constant voltage funnel 62.5mL of concentrated nitric acid was added slowly to keep temperature below 70 ; after addition of nitric acid, the reaction was rapidly stirred and heated to 100 deg.] C for 5 hours.The reaction system was cooled down and added to 2L of ice, the ice being added after the precipitation of a solid.Producing a Buchner funnel white solid was filtered off and washed with water several times; the solid was dissolved in 150mL glacial acetic acid and recrystallized to give the product 24.24g (41% yield); The other conditions were the same as in Example 1, the reaction temperature was changed to 80 , the yield of the resulting product was 45%
42%
With sulfuric acid; nitric acid; at 100℃; for 5h;Inert atmosphere;
To a vigorously-stirred mixture of <strong>[610-71-9]2,5-dibromobenzoic acid</strong> (25g, 180 mmol) in conc. H2SO4 (100 mL) was added fuming HNO3 (32 mL) at a rate to keep the internal temperature below 70C. After the addition was completed, the reaction mixture was heated at 100C for 5h. The cooled reaction mixture was cautiously poured into crashed ice (~1L), and the resulting precipitate was filtered through a sintered glass funnel. The solid was washed well with water, dried under high vacuum pump, and was further purified via crystallization with acetic acid to give yellow crystals (12.12g, 42% yield). m.p. 225-229C. 1H NMR (CDCl3, 300 MHz): delta 8.65(d, J=2.4 Hz, 1H), 8.74 (d, J=2.4 Hz, 1H), 12.60 (s, 1H); 13C NMR (CDCl3, 75 MHz): delta118.8, 122.9, 131.1, 134.9, 42.1, 152.5, 169.3; HRMS (ESI): m/z calcd. for C7H2Br2NO4 [M-H]+ 321.8356, found 321.8348.
With nitric acid; In sulfuric acid; acetic acid;
(i) 2,5-dibromo-3-nitrobenzoic acid The procedure described in R. K. Bentley and F. G. Holliman, J. Chem. Soc. 2447 (1970) was used. A mixture of <strong>[610-71-9]2,5-dibromobenzoic acid</strong> (50 g, 0.18 mol) in concentrated sulfuric acid was vigorously stirred as fuming nitric acid (62.5 mL) was added dropwise at a rate to keep the temperature below 70 C. The reaction mixture was vigorously stirred, heated to 100 C. and then kept at 100 C. for 5 hours. The cooled reaction was, cautiously poured into 2 liters of ice and vigorously stirred, the precipitate was filtered through a sintered glass funnel and the solid was washed well with water. Crystallization was achieved by dissolving the solid in acetic acid (150 mL) and after concentration to a half of the volume, crystals separated (16.72 g); mp 225-229 C. An additional crop of 7.52 g was obtained to give a total yield of 24.24 g (41%).
With nitric acid; In sulfuric acid; acetic acid;
(i) 2,5-dibromo-3-nitrobenzoic Acid The procedure described in R. K. Bentley and F. G. Holliman, J. Chem. Soc. (c), 2447 (1970) was used. A mixture of <strong>[610-71-9]2,5-dibromobenzoic acid</strong> (50 g, 0.18 mol) in concentrated sulfuric acid was vigorously stirred as fuming nitric acid (52.5 mL) was added dropwise at a rate to keep the temperature below 70 C. The reaction mixture was vigorously stirred, heated to 100 C. and then kept at 100 C. for 5 hours. The cooled reaction was cautiously poured into 2 liters of ice and vigorously stirred, the precipitate was filtered through a sintered glass funnel and the solid was washed well with water. Crystallization was achieved by dissolving the solid in acetic acid (150 mL) and after concentration to a half of the volume, crystals separated (16.72 g); mp 225-229 C. An additional crop of 7.52 g was obtained to give a total yield of 24.24 g (41%).
With nitric acid; In sulfuric acid; acetic acid;
(i) 2,5-dibromo-3-nitrobenzoic acid The procedure described in R. K. Bentley and F. G. Holliman, J. Chem. Soc. (c), 2447 (1970) was used. A mixture of <strong>[610-71-9]2,5-dibromobenzoic acid</strong> (50 g, 0.18 mol) in concentrated sulfuric acid was vigorously stirred as fuming nitric acid (62.5 mL) was added dropwise at a rate to keep the temperature below 70 C. The reaction mixture was vigorously stirred, heated to 100 C. and then kept at 100 C. for 5 hours. The cooled reaction was cautiously poured into 2 liters of ice and vigorously stirred, the precipitate was filtered through a sintered glass funnel and the solid was washed well with water. Crystallization was achieved by dissolving the solid in acetic acid (150 mL) and after concentration to a half of the volume, crystals separated (16.72 g); mp 225-229 C. An additional crop of 7.52 g was obtained to give a total yield of 24.24 g (41%).
With nitric acid; In sulfuric acid; acetic acid;
(i) 2,5-dibromo-3-nitrobenzoic acid The procedure described in R. K. Bentley and F. G. Holliman, J. Chem. Soc. (c), 2447 (1970) was used. A mixture of <strong>[610-71-9]2,5-dibromobenzoic acid</strong> (50 g, 0.18 mol) in concentrated sulfuric acid was vigorously stirred as fuming nitric acid (62.5 mL) was added dropwise at a rate to keep the temperature below 70 C. The reaction mixture was vigorously stirred, heated to 100 C. and then kept at 100 C. for 5 hours. The cooled reaction was cautiously poured into 2 liters of ice and vigorously stirred, the precipitate was filtered through a sintered glass funnel and the solid was washed well with water. Crystallization was achieved by dissolving the solid in acetic acid (150 mL) and after concentration to a half of the volume, crystals separated (16.72 g); mp 225-229 C. An additional crop of 7.52 g was obtained to give a total yield of 24.24 g (41%).
With nitric acid; In sulfuric acid; acetic acid;
(i) 2,5-dibromo-3-nitrobenzoic acid The procedure described in R. K. Bentley and F. G. Holliman, J. Chem Soc. (c), 2447 (1970) was used. A mixture of <strong>[610-71-9]2,5-dibromobenzoic acid</strong> (50 g, 0.18 mol) in concentrated sulfuric acid was vigorously stirred as fuming nitric acid (62.5 mL) was added dropwise at a rate to keep the temperature below 70 C. The reaction mixture was vigorously stirred, heated to 100 C. and then kept at 100 C. for 5 hours. The cooled reaction was cautiously poured into 2 liters of ice and vigorously stirred, the precipitate was filtered through a sintered glass funnel and the solid was washed well with water. Crystallization was achieved by dissolving the solid in acetic acid (150 mL) and after concentration to a half of the volume, crystals separated (16.72 g); mp 225-229 C. An additional crop of 7.52 g was obtained to give a total yield of 24.24 g (41%).
With nitric acid; In sulfuric acid; acetic acid;
(i) 2,5-dibromo-3-nitrobenzoic acid The procedure described in R. K. Bentley and F. G. Holliman, J. Chem, Soc. (c), 2447 (1970) was used. A mixture of <strong>[610-71-9]2,5-dibromobenzoic acid</strong> (50 g, 0.18 mol) in concentrated sulfuric acid was vigorously stirred as fuming nitric acid (62.5 mL) was added dropwise at a rate to keep the temperature below 70 C. The reaction mixture was vigorously stirred, heated to 100 C. and then kept at 100 C. for 5 hours. The cooled reaction was cautiously poured into 2 liters of ice and vigorously stirred, the precipitate was filtered through a sintered glass funnel and the solid was washed well with water Crystallization was achieved by dissolving the solid in acetic acid (150 mL) and after concentration to a half of the volume, crystals separated (16.72 g); mp 225-229 C. An additional crop of 7.52 g was obtained to give a total yield of 24.24 g (41%).
With nitric acid; In sulfuric acid; acetic acid;
(i) 2,5-dibromo-3-nitrobenzoic acid The procedure described in R. K. Bentley and F. G. Holliman, J. Chem. Soc. (c), 2447 (1970) was used. A mixture of <strong>[610-71-9]2,5-dibromobenzoic acid</strong> (50 g, 0.18 mol) in concentrated sulfuric acid was vigorously stirred as fuming nitric acid (62.5 mL) was added dropwise at a rate to keep the temperature below 70 C. The reaction mixture was vigorously stirred, heated to 100 C. and then kept at 100 C. for 5 hours. The cooled reaction was cautiously poured into 2 liters of ice and vigorously stirred, the precipitate was filtered through a sintered glass funnel and the solid was washed well with water. Crystallization was achieved by dissolving the solid in acetic acid (150 mL) and after concentration to a half of the volume, crystals separated (16.72 g); mp 225-229 C. An additional crop of 7.52 g was obtained to give a total yield of 24.24 g (41%).
With nitric acid; In sulfuric acid; acetic acid;
(i) 2,5-dibromo-3-nitrobenzoic acid The procedure described in R. K. Bentley and F. G. Holliman, J. Chem. Soc. (c), 2447 (1970) was used. A mixture of <strong>[610-71-9]2,5-dibromobenzoic acid</strong> (50 g, 0.18 mol) in concentrated sulfuric acid was vigorously stirred as fuming nitric acid (62.5 mL) was added dropwise at a rate to keep the temperature below 70 C. The reaction mixture was vigorously stirred, heated to 100 C. and then kept at 100 C. for 5 hours. The cooled reaction was cautiously poured into 2 liters of ice and vigorously stirred, the precipitate was filtered through a sintered glass funnel and the solid was washed well with water. Crystallization was achieved by dissolving the solid in acetic acid (150 mL) and after concentration to a half of the volume, crystals separated (16.72 g); mp 225-229 C. An additional crop of 7.52 g was obtained to give a total yield of 24.24 g (41%).
With nitric acid; In sulfuric acid; acetic acid;
(i) 2,5-dibromo-3-nitrobenzoic acid The proceudre described in R. K. Bentley and F. G. Holliman, J. Chem. Soc. (c), 2447 (1970) was used. A mixture of <strong>[610-71-9]2,5-dibromobenzoic acid</strong> (50 g, 0.18 mol) in concentrated sulfuric acid was vigorously stirred as fuming nitric acid (62.5 mL) was added dropwise at a rate to keep the temperature below 70 C. The reaction mixture was vigorously stirred, heated to 100 C. and then kept at 100 C. for 5 hours. The cooled reaction was cautiously poured into 2 liters of ice and vigorously stirred, the precipitate was filtered through a sintered glass funnel and the solid was washed well with water. Crystallization was achieved by dissolving the solid in acetic acid (150 mL) and after concentration to a half of the volume, crystals separated (16.72 g); mp 225-229 C. An additional crop of 7.52 g was obtained to give a total yield of 24.24 g (41%).
With nitric acid; In sulfuric acid; acetic acid;
(i) 2,5-dibromo-3-nitrobenzoic acid The procedure described in R. K. Bentley and F. G. Holliman, J. Chem. Soc. (c), 2447 (1970) was used. A mixture of <strong>[610-71-9]2,5-dibromobenzoic acid</strong> (50 g, 0.18 mol) in concentrated sulfuric acid was vigorously stirred as fuming nitric acid (62.5 mL) was added dropwise at a rate to keep the temperature below 70 C. The reaction mixture was vigorously stirred, heated to 100 C. and then kept at 100 C. for 5 hours. The cooled reaction was cautiously poured into 2 liters of ice and vigorously stirred, the precipitate was filtered through a sintered glass funnel and the solid was washed well with water. Crystallization was achieved by dissolving the solid in acetic acid (150 mL) and after concentration to a half of the volume, crystals separated (16.72 g); mp 225-229 C. An additional crop of 7.52 g was obtained to give a total yield of 24.24 g (41%).
(a) A mixture of 2,5-dibromobenzoic acid (25 g, 0.09 mol), DMF (200 ml), 5-amino-1-ethylpyrazole (10 g, 0.09 mol), Cu(OAc)2 (1 g) and K2 CO3 (12.3 g, 0.09 mol) is heated at reflux for about 2 days. The reaction mixture is poured into water, acidified with acetic acid, and the precipitate which forms is collected by filtration to afford 12.6 g of N-(1-ethylpyrazol-5-yl)-5-bromoanthranilic acid.
Cu(OAc)2; In N,N-dimethyl-formamide;
(a) A mixture of 2,5-dibromobenzoic acid (25 g, 0.09 mol), DMF (200 ml), 5-amino-1-ethylpyrazole (10 g, 0.09 mol), Cu(OAc)2 (1 g) and K2 CO3 (12.3 g, 0.09 mol) was heated at reflux for about 2 days. The reaction mixture was poured into water, acidified with acetic acid and the precipitate which formed was collected by filtration to afford 12.6 g of N-(1-ethylpyrazol-5-yl)-5-bromoanthranilic acid.
N-(1-ethylpyrazol-5-yl)-3-bromoanthranilic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Cu(OAc)2; In N,N-dimethyl-formamide;
(a) A mixture of 5-amino-1-ethylpyrazole (33.7 g, 0.3 mol), 2,5-dibromobenzoic acid (84 g, 0.3 mol), K2 CO3 (41.4 g, 0.3 mol), Cu(OAc)2 (1 g) and DMF (500 ml) is refluxed overnight. The reaction mixture is poured into ice water (4 L), and is then acidified with acetic acid. The solid which forms is collected by filtration and dried to afford 35 g of a mixture of N-(1-ethylpyrazol-5-yl)-3-bromoanthranilic acid and N-(1-ethylpyrazol-5-yl)-5-bromoanthranilic acid.
Cu(OAc)2; In N,N-dimethyl-formamide;
(a) A mixture of 5-amino-1-ethylpyrazole (33.7 g, 0.3 mol), 2,5-dibromobenzoic acid (84 g, 0.3 mol), K2 CO3 (41.4 g, 0.3 mol), Cu(OAc)2 (1 g) and DMF (500 mL) was refluxed overnight. The reaction mixture was poured into ice-water (4 L) and was then acidified with acetic acid. The solid which formed was collected by filtration and dried to afford 35 g of a mixture of N-(1-ethylpyrazol-5-yl)-3-bromoanthranilic acid and N-(1-ethylpyrazol-5-yl)-5-bromoanthranilic acid.
Butyllithium (97.2 ml of 1.47 M solution in hexane, 143 mmol) was added dropwise to a solution of <strong>[610-71-9]2,5-Dibromo-benzoic acid</strong> (20 g, 72 mmol) in dry THF (300 ml) at -78 C. over a period of 3.5 h under a nitrogen atmosphere. The reaction mixture was stirred at -78 C. for 2 h. A solution of N-methyl piperidone (11.31 g, 99 mmol) in hexane (40 mL) was added dropwise during 30 min to the reaction mixture at 78 C. The reaction mixture was allowed to come to room temperature and stirring was continued for overnight. The reaction mixture was added to a mixture of water (500 ml) and ether (300 mL). The aqueous layer was extracted with ether (5×150 mL) and acidified with concentrated HCl (to pH 2-3) and extracted with ether (2×150 ml).The acidic solution was boiled for 1 h and then cooled to 0-5 C. and made alkaline (to pH 9-10) with aqueous NaOH. The cold solution was rapidly extracted with chloroform (5×300 mL). The combined chloroform extracts were washed with water (150 ml), dried over sodium sulfate and evaporated under reduced pressure. The residue was purified was purified by silica gel (100-200) column chromatography eluting with methanol in dichloromethane (0.5% to 2.5%) to afford 1 (4.2 g, 20%). 1H-NMR (400 MHz, CDCl3): delta 1.71 (d, J=14.2 Hz, 2H), 2.15-2.24 (m, 2H), 2.37 (s, 3H), 2.45-2.52 (m, 2H), 2.83-2.87 (m, 2H), 7.26 (d, J=8.25 Hz, 1H), 7.75 (dd, J 7.8, 1.7 Hz, 1H). 13C-NMR (100 MHz, CDCl3): delta 35.95, 46.05, 51.42, 84.00, 122.54, 122.97, 127.52, 128.64, 137.06, 152.24, 167.77.
Step A rZ1-Ethyl 2-f2.5-dibromobenzoyl1-3-(dimethylamino1acrylate [00543] To a solution of 2,5-dibromobenzoic acid (1033 g, 36 90 mmol) and oxalyl chloride (4 0 mL, 45 82 mmol) in DCM (100 mL) was added DMF (0 5 mL) The reaction mixture was stirred at rt for 40 mm and concentrated under reduced pressure The crude material was dissolved m THF (100 mL) and added <strong>[924-99-2]ethyl 3-(dimethylamino)acrylate</strong> (5 80 g, 40 51 mmol) and TEA (10 5 mL, 75 33 mmol) The mixture was heated at reflux over night, diluted with EtOAc (250 mL) and washed with H2O (2x100 mL) The organic layer was dried over Na2SO4 and concentrated Purification on silica gel column gave the desired product as a yellow oil ( 1032 g) NMR (CDC13) delta 7 89 (s, 1H), 748 (d, 1H), 743 (s, 04H), 741 (s, 06H), 735(d, 06H), 732 (d, 04H), 3 96 (q, 2H), 3 39 (br s, 3H), 3 03 (br s, 3H), 091 (t, 3H)
With caesium carbonate;copper(I) trifluoromethanesolfonate toluene complex; In ethyl acetate; toluene; at 90℃; for 4h;
Example 5 Synthesis of 7-bromo-4-fluoro-2-methoxy-9H-xanthen-9-oneStep 1 : A dry 100 L glass jacketed reactor equipped with an addition funnel, reflux condenser, solids addition system and temperature probe was charged with 2,5- dibromobenzoic acid (2685 g, 9.6 mol) and copper (I) triflate toluene complex (2:1, 50.0 g, 0.2 mol). Toluene (30 L) and EtOAc (20 mL) were then added to the reactor, followed by <strong>[450-93-1]2-methoxy-4-fluorophenol</strong> (1500 g, 10.6 mol). With vigorous stirring cesium carbonate (6258 g, 19.2 mol) was added to the mixture in portions. The mixture was heated to 90 C for 4 hours. The mixture was cooled to 35 C and water (15 L) was added. After 15 minutes of stirring the phases were sping and the aqueous phase was washed with toluene (7.5 L). With stirring, EtOAc (15.0 L) was added to the mixture, followed by 6 M HC1 (5.6 L) keeping the internal temperature below 30 C. The layers were separated and the organics were dried over MgS04. Filtration through a pad of celite and concentration provided a solid that was reslurried in 915 mL of EtOAc and 9.2 L of heptanes. Stirring was continued for 1 hour before the solids were filtered and washed with heptanes. The solids were dried to provide 2560 g of 5-bromo-2-(2-fluoro- 4-methoxyphenoxy)benzoic acid as a cream colored solid.
2560 g
With copper(I) trifluoromethanesulfonate toluene adduct (1/1); caesium carbonate; In ethyl acetate; toluene; at 90℃; for 4h;
Step 1 : A dry 100 L glass jacketed reactor equipped with an addition funnel, reflux condenser, solids addition system and temperature probe was charged with 2,5- dibromobenzoic acid (2685 g, 9.6 mol) and copper (I) triflate toluene complex (2:1, 50.0 g, 0.2 mol). Toluene (30 L) and EtOAc (20 mL) were then charged, followed by 2- methoxy-4-fluorophenol (1500 g, 10.6 mol). Cesium carbonate (6258 g, 19.2 mol) was added in portions while stirring vigorously. The mixture was heated to 90 C for 4 hours. The mixture was cooled to 35 C and water (15 L) was added. After 15 minutes of stirring the phases were separated and the aqueous phase was washed with toluene (7.5 L). With stirring, EtOAc (15.0 L) was added to the aqueous phase, followed by 6 M HC1 (5.6 L) keeping the internal temperature below 30 C. The layers were separated and the organics were dried over magnesium sulfate. Filtration through a pad of celite and concentration provided a solid that was reslurried in 915 mL of EtAOc and 9.2 L of heptanes. Stirring was continued for 1 hour before the solids were filtered and washed with heptanes. Drying provided 2560 g of 5-bromo-2-(2-fluoro-4- methoxyphenoxy)benzoic acid as a cream colored solid.
Step 1 : A mixture of 2, 5-dibromobenzoic acid (1244 g, 4.44 mol), 5-hydroxy-2- chloropyridine (663.3 g, 5.12 mol) and cesium carbonate (2893.3 g, 8.88 mol) was stirred for 20 minutes under a nitrogen atmosphere. To this slurry were added copper (I) trifloromethanesulfonate toluene complex (59.7 g, 0.115 mol), toluene (9 L) and EtOAc (39 mL). The resulting suspension was heated to 105 C and stirred for 2 h before being cooled to RT. The toluene was decanted, and water (8 L) and EtOAc (8 L) were added. The resulting mixture was stirred until the solid was completely dissolved. The EtOAc layer was separated and the pH of the aqueous layer was adjusted to pH 2 ~ 3 with 6N HC1. The aqueous layer was extracted with EtOAc (3 X 5 L). The combined organic layers were dried over Na2S04, filtered and concentrated to give 1.28 Kg of 5-bromo-2- (6-chloropyridin-3-yloxy)benzoic acid as brown solid. This material was used in next step without further purification.
Step 1 : A RBF was charged with 2, 5-dibromobenzoic acid (1244 g, 4.44 mol), 5- hydroxy-2-chloropyridine (663.3 g, 5.12 mol) and cesium carbonate (2893.3 g, 8.88 mol). The resulting mixture was stirred for 20 minutes under nitrogen atmosphere at which time copper (I) trifloromethanesulfonate toluene complex (59.7 g, 0.115 mol), toluene (9 L) and EtOAc (39 mL) were added in sequence. The resulting suspension was heated to 105 C for 2 h and cooled to RT. The toluene was decanted and water (8 L) and EtOAc (8 L) were added to the residue. The mixture was stirred until the solids were completely dissolved. The organic layer was separated and the pH of the aqueous layer was adjusted to pH 2 ~ 3 with 6N HC1. This mixture was then extracted with EtOAc (3 X 5 L). The combined organic layers were dried over Na2S04, filtered and concentrated to give 1.28 kg of 5-bromo-2-(6-chloropyridin-3-yloxy)benzoic acid as brown solid, which was used in next step without further purification.
Step 1 : A mixture of 2,5-dibromobenzoic acid (1244 g, 4.44 mol), 5-hydroxy-2- chloropyridine (663.3 g, 5.12 mol) and cesium carbonate (2893.3 g, 8.88 mol) was stirred for 20 minutes under a nitrogen atmosphere. To this slurry were added copper (I) trifloromethanesulfonate toluene complex (59.7 g, 0.115 mol), toluene (9 L) and EtOAc (39 mL). The resulting suspension was heated to 105 C and stirred for 2 h before being cooled to RT. The toluene was decanted, and water (8 L) and EtOAc (8 L) were added. The resulting mixture was stirred until the solid was completely dissolved. The EtOAc layer was separated and the pH of the aqueous layer was adjusted to pH 2 ~ 3 with 6N HCl. The aqueous layer was extracted with EtOAc (3 X 5 L). The combined organic layers were dried over Na2S04, filtered and concentrated to give 1.28 Kg of 5-bromo-2- (6-chloropyridin-3-yloxy)benzoic acid as brown solid. This material was used in next step without further purification.
Step 1 : A dry 100 L glass jacketed reactor equipped with an addition funnel, reflux condenser, solids addition system and temperature probe was charged with 2,5- dibromobenzoic acid (2685 g, 9.6 mol) and copper (I) triflate toluene complex (2:1, 50.0 g, 0.2 mol). Toluene (30 L) and EtOAc (20 mL) were then charged, followed by 2- methoxy-4-fluorophenol (1500 g, 10.6 mol). With vigorous stirring cesium carbonate (6258 g, 19.2 mol) was added in portions. The mixture was heated to 90 C for 4 hours. The mixture was cooled to 35 C and water (15 L) was added. After 15 minutes of stirring the phases were separated and the aqueous phase was washed with toluene (7.5 L). With stirring, EtOAc (15.0 L) was added to the aqueous phase, followed by 6 M HC1 (5.6 L) keeping the internal temperature below 30 C. The layers were separated and the organics were dried over magnesium sulfate. Filtration through a pad of celite and concentration provided a solid that was reslurried in 915 mL of EtAOc and 9.2 L of heptanes. Stirring was continued for 1 hour before the solids were filtered and washed with heptanes. Drying provided 2560 g of 5-bromo-2-(2-fluoro-4- methoxyphenoxy)benzoic acid as a cream colored solid.
A dry 100 L glass jacketed reactor equipped with an addition funnel, reflux condenser, solids addition system and temperature probe was charged with 2,5- dibromobenzoic acid (2685 g, 9.6 mol) and copper (I) triflate toluene complex (2:1, 50.0 g, 0.2 mol). Toluene (30 L) and EtOAc (20 mL) were then charged, followed by 2- methoxy-4-fluorophenol (1500 g, 10.6 mol). With vigorous stirring cesium carbonate (6258 g, 19.2 mol) was added in portions. The mixture was heated to 90 C for 4 hours. The mixture was cooled to 35 C and water (15 L) was added. After 15 minutes of stirring the phases were sping and the aqueous phase was washed with toluene (7.5 L). With stirring, EtOAc (15.0 L) was added to the rich aqueous phase, followed by 6 M HCl (5.6 L) keeping the internal temperature below 30 C. The layers were separated and the organic layers were dried over magnesium sulfate, filtered through a pad of celite and concentration to provide a solid that was re-slurried in 915 mL of EtOAc and 9.2 L of heptanes. Stirring was continued for 1 hour before the solids were filtered and washed with heptanes. The resulting solids were dired to provide 2560 g of 5-bromo-2-(2-fluoro- 4-methoxyphenoxy)benzoic acid as a cream colored solid.
With copper(I) trifluoromethanesolfonate toluene complex; caesium carbonate; In toluene; at 120℃; for 2h;Inert atmosphere;
A 500 mL RBF was charged with <strong>[174669-74-0]2-fluoro-3-hydroxypyridine</strong> (3487 mg, 30.8 mmol), 2,5-dibromobenzoic acid (8630 mg, 30.8 mmol), copper (I) trifluoromethane- sulfonate toluene complex (2:1) (399 mg, 0.771 mmol) and cesium carbonate (2.01E+04 mg, 61.7 mmol). To this was added 100 mL of toluene and the mixture was azeotroped to remove about 20 mL of toluene under reduced pressure. Reaction mixture was then flushed with N2 and was heated to 120 C for 2 hours. LC-MS analysis showed formation of the desired product along wth significant impurities. The reaction mixture was cooled to RT and concentrated to give a gummy residue. The residue was taken up in ethyl acetate (100 mL) and water (75 mL). The aqueous layer was neutralized with IN HC1 to pH ~ 2.0-3.0. The aqueous layer was extracted with ethyl acetate (2 x 150 mL), separated, dried over anhydrous sodium sulfate, and concentrated to yield the crude product as a brown solid which was used directly in the next step.
Example 4Synthesis of 7-Bromo-3-chloro-l-fluoro-5H-chromeno[2,3-c]pyridin-5-one; Step 1 : A 500 mL RBF was charged with <strong>[174669-74-0]2-fluoro-3-hydroxypyridine</strong> (3487 mg, 30.8 mmol), 2,5-dibromobenzoic acid (8630 mg, 30.8 mmol), copper (I) trifluoromethane- sulfonate toluene complex (2:1) (399 mg, 0.771 mmol) and cesium carbonate (2.01E+04 mg, 61.7 mmol). To this was added 100 mL of toluene and the mixture was azeotroped to remove about 20 mL of toluene under reduced pressure. Reaction mixture was then flushed with N2 and was heated to 120 C for 2 hours. LC-MS analysis showed formation of the desired product along wth significant impurities. The reaction mixture was cooled to RT and concentrated to give a gummy residue. The residue was taken up in ethyl acetate (100 mL) and water (75 mL). The aqueous layer was neutralized with IN HC1 to H ~ 2.0-3.0. The aqueous layer was extracted with ethyl acetate (2 x 150 n L), separated, dried over anhydrous sodium sulfate, and concentrated to yield the crude product as a brown solid which was used directly in the next step.
Example 4Synthesis of 7-Bromo-3-chloro-l-fluoro-5H-chromeno[2,3-c]pyridin-5-oneStep 1 : A 500 mL RBF was charged with <strong>[174669-74-0]2-fluoro-3-hydroxypyridine</strong> (3487 mg, 30.8 mmol), 2,5-dibromobenzoic acid (8630 mg, 30.8 mmol), copper (I) trifluoromethane- sulfonate toluene complex (2:1) (399 mg, 0.771 mmol) and cesium carbonate (2.01E+04 mg, 61.7 mmol). To this was added 100 mL of toluene and the mixture was azeotroped to remove about 20 mL of toluene under reduced pressure. Reaction mixture was then flushed with N2 and was heated to 120 C for 2 hours. LC-MS analysis showed formation of the desired product along wth significant impurities. The reaction mixture was cooled to RT and concentrated to give a gummy residue. The residue was taken up in ethyl acetate (100 mL) and water (75 mL). The aqueous layer was neutralized with IN HC1 to pH ~ 2.0-3.0. The aqueous layer was extracted with EtOAc (2 x 150 mL), separated, dried over anhydrous sodium sulfate, and concentrated to yield the crude product as a brown solid which was used directly in the next step
A 500 mL RBF was charged with <strong>[174669-74-0]2-fluoro-3-hydroxypyridine</strong> (3487 mg, 30.8 mmol), 2,5-dibromobenzoic acid (8630 mg, 30.8 mmol), copper (I) trifluoromethane- sulfonate toluene complex (2:1) (399 mg, 0.771 mmol) and cesium carbonate (2.01E+04 mg, 61.7 mmol). To this was added 100 mL of toluene and the mixture was azeotroped to remove about 20 mL of toluene under reduced pressure. Reaction mixture was then flushed with N2 and was heated to 120 C for 2 hours. LC-MS analysis showed formation of the desired product along wth significant impurities. The reaction mixture was cooled to RT and concentrated to give a gummy residue. The residue was taken up in ethyl acetate (100 mL) and water (75 mL). The aqueous layer was neutralized with IN HC1 to pH ~ 2.0-3.0. The aqueous layer was extracted with ethyl acetate (2 x 150 mL), separated, dried over anhydrous sodium sulfate, and concentrated to yield the crude product as a brown solid which was used directly in the next step.
General procedure: 4.2.1. General procedures I for the synthesis of starting materials 1 a-n. Compounds 1a-g, i-n were synthesized according to general procedures I. Compound 1h was commercially available. Method A:16, 17 A two-necked round-bottomed flask equipped with a reflux condenser and a magnetic stir bar was charged withthe 2-bromobenzoic acid (20 mmol) and freshly distilled methanol(25 mL). The solution was heated in a hot water bath, conc. H2SO4(8 mmol) was added slowly and the reaction mixture was refluxed for 24 h. After cooling to room temperature around half of theamount of the solvent was removed in vacuo and the residue was partitioned between water (50 mL) and diethyl ether (70 mL). The organic layer was separated and washed with saturated NaHCO3(250 mL), water (50 mL) and brine (50 mL), dried over anhydrous MgSO4 and the volatiles were removed under reduced pressure.The crude product thus obtained was purified by flash chromatographyon silica gel to afford the alkyl-2-halobenzoate.In a two-necked round-bottomed flask equipped with a reflux condenser and a magnetic stir bar the alkyl 2-halobenzoate(22.5 mmol) was dissolved in freshly distilled dry THF (30 mL) under argon. The solution was cooled to 0 °C using an ice bath and NaH (60percent in mineral oil, 15 mmol) was added portion wise. After stirring for 15 min a solution of the alkyl acetate (15 mmol) in dry THF (30 mL) was added dropwise to the reaction mixture at 0 °C.The mixture was warmed up, stirred at room temperature for 2 h and heated under reflux for 24 h. After cooling to room temperature around half of the amount of the solvent was removed in vacuo and the reaction mixture was diluted with toluene (50 mL). The resulting mixture was washed with 2N HCl (50 mL), saturated NH4Cl (50 mL), dried over anhydrous MgSO4 and the volatiles were removed under reduced pressure. The crude product was purifiedby flash column chromatography on silica gel to afford the alkyl 3-(20-halophenyl)-3-oxo-propanoate 1.
203.6 g
With sulfuric acid;Reflux;
Step 1: To a 2 L round-bottom flask, 2,5-dibromobenzoic acid (250 g, 0.90 mol) in MeOH (2 L) and concentrated H2SO4 (18.4 g, 0.19 mol) were added. The mixture was refluxed overnight before cooled to room temperature. The resulting precipitate was then filtered, washed with cold methanol and dried under vacuum. It yielded 203.6 g methyl 2,5-dibromobenzoate as a yellow solid. To a 2 L round-bottom flask was added 2,5-dibromobenzoate (198.2 g, 0.68 mol) in 1 L dry DMF. CuCN (122 g, 1.36 mol) and NaI (22.8 g, 0.15 mol) were introduced next. The mixture was stirred overnight at 130 °C under nitrogen atmosphere. After the reaction was complete, it was extracted with ethyl acetate (500 mL × 3),washed with water (500 mL) and purified over silica gel (PE/EtOAc = 5/1) to give 95.2 g methyl 2,5-dicyanobenzoate as a brown solid (yield: 75.1 percent).
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