* 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.
Preparation of methyl 5-fluorosalicylate (compound 2a):10 g (0.064 mol) of 5-fluorosalicylic acid was dissolved into 60 mL methanol in a 250 mL round-bottom flask with a magnetic stirrer. 5 mL of concentrated sulfuric acid was added dropwise under the ice bath. Upon addition, the mixture was heated under reflux condensation overnight in an oil bath at 80°C. On the next day the reaction mixture was cooled to room temperature and methanol was removed under reduced pressure by rotary evaporator. 60 mL of ethyl acetate was added to the residue and the organic layer was washed with 50 mL of saturated sodium bicarbonate solution and 50 mL of saturated sodium chloride solution in turn. Then the organic layer was dried on anhydrous sodium sulfate and evaporated to dryness. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate = 150:1) to afford 10.0 g product as a light color oil in 92percent yield. Then the oil solidified to be strip crystal when pumping to dryness by oil pump. 1HNMR (300 MHz, CDCl3) δ 10.51 (s, 1H), 7.50 (dd, J= 3.3, 8.7 Hz, 1H), 7.22-7.15 (m, 1H), 6.94 (q, J= 4.5Hz, 1H), 3.96 (s, 3H); MS (EI) M+: m/z (percent) 170 (50).
92%
at 80℃; Cooling with ice
Preparation of methyl 5-fluorosalicylate (compound 2a)10 g (0.064 mol) of 5-fluorosalicylic acid was dissolved into 60 mL methanol in a 250 mL round-bottom flask with a magnetic stirrer. 5 mL of concentrated sulfuric acid was added dropwise under the ice bath. Upon addition, the mixture was heated under reflux condensation overnight in an oil bath at 80□.On the next day the reaction mixture was cooled to room temperature and methanol was removed under reduced pressure by rotary evaporator. 60 mL of ethyl acetate was added to the residue and the organic layer was washed with 50 mL of saturated sodium bicarbonate solution and 50 mL of saturated sodium chloride solution in turn. Then the organic layer was dried on anhydrous sodium sulfate and evaporated to dryness. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=150:1) to afford 10.0 g product as a light color oil in 92percent yield. Then the oil solidified to be strip crystal when pumping to dryness by oil pump. 1HNMR (300 MHz, CDCl3) δ 10.51 (s, 1H), 7.50 (dd, J=3.3, 8.7 Hz, 1H), 7.22-7.15 (m, 1H), 6.94 (q, J=4.5 Hz, 1H), 3.96 (s, 3H); MS (EI) M+: m/z (percent) 170 (50).
83%
at 0℃; for 48 h; Reflux
To a stirred solution of 5-fluoro salicylic acid (25 g, 160 mmol) in MeOH (250 mL), cone, sulfuric acid (20 mL) was added slowly at 0°C. The resulting reaction mixture was refluxed for 48 h then was concentrated under reduced pressure and the resulting crude was basified to pH 8.0 with sat. NaHC03. Then it was neutralized by 1 .5 N HCI solution and extracted with EtOAc. The organic layer was dried over anhydrous Na2S04 and concentrated to afford methyl 5-fluoro-2-hydroxybenzoate as a light brown liquid (22.8 g, 83percent). GCMS: (AcqMethod HP-1 MS.M) 1 70.1 (M). 1 H NMR (400 MHz, DMSO-d6): δ ppm 1 0.29 (s, 1 H), 7.51 -7.49 (m, 1 H), 7.42-7.41 (m, 1 H), 57.03-7.01 (m, 1 H), 3.89 (s, 3H).
83%
at 0℃; for 48 h; Reflux
To a stirred solution of 5-fluoro salicylic acid (25 g, 160 mmol)inMeOH (250 mL), conc. sulfuric acid (20 mL)was added slowly at 0°C.The resulting reaction mixture was refluxed for 48 h then was concentrated under reduced pressure and the resulting crude was basified to pH 8.0 with sat. NaHCO3. The mixture was neutralized by 1 .5 N HCI solution and extracted with EtOAc. The organic layer wasdried over anhydrous Na2504 and concentrated to afford methyl 5-fluoro-2-hydroxybenzoate as a light brown liquid (22.8 g, 83percent yleld). GC-MS (AcqMethod HP-1MS.M) 170.1 (M). 1H NMR (400 MHz, DMSO-d6) 6 ppm 10.29 (5, 1H), 7.51-7.49 (m, 1H), 7.42-7.41 (m, 1H), 7.03-7.01 (m, 1H), 3.89 (5, 3H).
76%
Reflux
Step 1 : To a solution of compound 114 (2.5 g, 16 mmol) in methanol (32 mL) was added sulfuric acid (2.0 mL, 21 mmol). The solution was heated at reflux overnight, cooled to room temperature and concentrated. The residue was dissolved in EtOAc, washed with saturated NaHC03 (3x), brine, dried (MgS04), filtered and concentrated to give compound 115 as to a cream solid (2.1 g, 76percent yield). 1H NMR (400 MHz, DMSO-d6) δ 3.89 (s, 3 H), 7.01 (dd, J = 9.1 , 4.5 Hz, 1 H), 7.40 (td, J = 8.6, 3.2 Hz, 1 H), 7.45 - 7.54 (m, 1 H), 10.28 (s, 1 H).
Reference：
[1] Patent: EP2813495, 2014, A1, . Location in patent: Paragraph 0016
[2] Patent: US2015/18542, 2015, A1, . Location in patent: Paragraph 0063; 0064; 0065
[3] Journal of Medicinal Chemistry, 2014, vol. 57, # 13, p. 5579 - 5601
[4] Patent: WO2016/96686, 2016, A1, . Location in patent: Page/Page column 83
[5] Patent: WO2017/211759, 2017, A1, . Location in patent: Page/Page column 46
[6] Patent: WO2013/132376, 2013, A1, . Location in patent: Page/Page column 181
[7] Journal of Medicinal Chemistry, 2014, vol. 57, # 11, p. 4720 - 4744
[8] Journal of Medicinal Chemistry, 1992, vol. 35, # 2, p. 310 - 319
[9] Patent: WO2006/46916, 2006, A1, . Location in patent: Page/Page column 55
[10] Patent: US2014/275172, 2014, A1, . Location in patent: Paragraph 0400
2
[ 67-56-1 ]
[ 345-16-4 ]
[ 149-73-5 ]
[ 391-92-4 ]
Yield
Reaction Conditions
Operation in experiment
90%
Stage #1: for 4 h; Heating / reflux Stage #2: at 66℃; for 16 h;
Example 5 Synthesis of 5-fluorosalicylic acid methyl ester (7) 5-Fluorosalicylic acid (272.6 g, 1.74 mol) was dissolved in methanol (1.3 L) to form a clear solution. Concentrated sulfuric acid (50 ml) was slowly added to the methanol solution with vigorous stirring. The solution was heated to reflux for 4 hours. Trimethyl orthoformate (200 ml) was added slowly to the reaction solution. 300 ml of solvents (methyl formate and methanol) was distilled off. The remaining reaction solution was heated at 66° C. (refluxing temperature) for 16 hours. HPLC analysis indicated that the reaction was complete. Reaction solution was cooled to ambient temperature. Solvent was removed under reduced pressure. The residue was partitioned between water (140 ml) and methylene chloride (220 ml). Organic layer was separated. Aqueous layer was extracted with methylene chloride (3*220 ml). The combined organic layer was washed with water (270 ml), brine (270 ml) and dried with MgSO4. The organic solution was concentrated to dryness to afford crude product (293.8 g). This crude material was used in the next step without further purification. 1H NMR (300 MHz, CDCl3) δ 3.96(s, 3H), 6.94(dd, 1H, J=4.5 Hz and J=9.0 Hz), 7.19(m, 1H), 7.50(dd, 1H, J=3.3 Hz and J=8.7 Hz), 10.508(s, 1H).
Reference：
[1] Tetrahedron, 1996, vol. 52, # 1, p. 23 - 36
[2] Journal of Fluorine Chemistry, 1991, vol. 51, # 2, p. 299 - 304
11
[ 445-93-2 ]
[ 345-16-4 ]
Reference：
[1] Journal of the American Chemical Society, 1939, vol. 61, p. 2317
12
[ 371-41-5 ]
[ 345-16-4 ]
Reference：
[1] European Journal of Organic Chemistry, 2001, # 15, p. 2911 - 2915
13
[ 141362-06-3 ]
[ 345-16-4 ]
Reference：
[1] European Journal of Organic Chemistry, 2001, # 15, p. 2911 - 2915
14
[ 394-04-7 ]
[ 345-16-4 ]
Reference：
[1] Journal of Organic Chemistry, 1954, vol. 19, p. 1617,1621[2] Bulletin de la Societe Chimique de France, 1956, p. 629,632
[3] Bulletin de l'Academie Polonaise des Sciences, Serie des Sciences Chimiques, 1960, vol. 8, p. 591 - 597
15
[ 394-32-1 ]
[ 345-16-4 ]
Reference：
[1] Journal of Organic Chemistry, 1960, vol. 25, p. 1016 - 1020
16
[ 459-60-9 ]
[ 345-16-4 ]
Reference：
[1] Journal of Organic Chemistry, 1954, vol. 19, p. 1617,1621[2] Bulletin de la Societe Chimique de France, 1956, p. 629,632
17
[ 445-82-9 ]
[ 345-16-4 ]
Reference：
[1] Journal of Organic Chemistry, 1954, vol. 19, p. 1617,1621[2] Bulletin de la Societe Chimique de France, 1956, p. 629,632
18
[ 452-71-1 ]
[ 345-16-4 ]
Reference：
[1] Bulletin de l'Academie Polonaise des Sciences, Serie des Sciences Chimiques, 1960, vol. 8, p. 591 - 597
19
[ 452-72-2 ]
[ 345-16-4 ]
Reference：
[1] Bulletin de l'Academie Polonaise des Sciences, Serie des Sciences Chimiques, 1960, vol. 8, p. 591 - 597
20
[ 399-54-2 ]
[ 345-16-4 ]
Reference：
[1] Bulletin de l'Academie Polonaise des Sciences, Serie des Sciences Chimiques, 1960, vol. 8, p. 591 - 597
In a 250 mL round bottom flask 5.00 g (32.0 mmol, 1.00 eq) <strong>[345-16-4]5-fluoro-2-hydroxybenzoic acid</strong> and 6.55 g (64.0 mmol, 6.05 mL, 2.00 eq) acetic acid anhydride were mixed. To this suspension a catalytic amount (6 drops) of concentrated sulphuric acid was added at 35C whereupon the temperature of the mixture rose to 45 C. After 14 hours, 67.0 mL water were added. The precipitate was filtered off, washed with 250 mL water. The title compound was obtained as a colourless solid in 5.49 g (27.7 mmol, 86 %).
85%
With sulfuric acid; for 0.333333h;
General procedure: 5-Halogenated salicylic acids (46 mmol) were stirred with acetic anhydride (20 mL) and 80 muL of concd H2SO4 was then added. After a few (20) min the reaction mixture solidified and was poured into cold water. The solid so obtained was filtered and extracted with ethyl acetate, washed with brine and dried over Na2SO4. The solvent was evaporated under reduced pressure to obtain a crude solid which was recrystalized from ethyl acetate/hexane to afford white crystals (5a-5c).
Preparation of methyl 5-fluorosalicylate (compound 2a):10 g (0.064 mol) of 5-fluorosalicylic acid was dissolved into 60 mL methanol in a 250 mL round-bottom flask with a magnetic stirrer. 5 mL of concentrated sulfuric acid was added dropwise under the ice bath. Upon addition, the mixture was heated under reflux condensation overnight in an oil bath at 80C. On the next day the reaction mixture was cooled to room temperature and methanol was removed under reduced pressure by rotary evaporator. 60 mL of ethyl acetate was added to the residue and the organic layer was washed with 50 mL of saturated sodium bicarbonate solution and 50 mL of saturated sodium chloride solution in turn. Then the organic layer was dried on anhydrous sodium sulfate and evaporated to dryness. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate = 150:1) to afford 10.0 g product as a light color oil in 92% yield. Then the oil solidified to be strip crystal when pumping to dryness by oil pump. 1HNMR (300 MHz, CDCl3) delta 10.51 (s, 1H), 7.50 (dd, J= 3.3, 8.7 Hz, 1H), 7.22-7.15 (m, 1H), 6.94 (q, J= 4.5Hz, 1H), 3.96 (s, 3H); MS (EI) M+: m/z (%) 170 (50).
92%
With sulfuric acid; at 80℃;Cooling with ice;
Preparation of methyl 5-fluorosalicylate (compound 2a)10 g (0.064 mol) of 5-fluorosalicylic acid was dissolved into 60 mL methanol in a 250 mL round-bottom flask with a magnetic stirrer. 5 mL of concentrated sulfuric acid was added dropwise under the ice bath. Upon addition, the mixture was heated under reflux condensation overnight in an oil bath at 80?.On the next day the reaction mixture was cooled to room temperature and methanol was removed under reduced pressure by rotary evaporator. 60 mL of ethyl acetate was added to the residue and the organic layer was washed with 50 mL of saturated sodium bicarbonate solution and 50 mL of saturated sodium chloride solution in turn. Then the organic layer was dried on anhydrous sodium sulfate and evaporated to dryness. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=150:1) to afford 10.0 g product as a light color oil in 92% yield. Then the oil solidified to be strip crystal when pumping to dryness by oil pump. 1HNMR (300 MHz, CDCl3) delta 10.51 (s, 1H), 7.50 (dd, J=3.3, 8.7 Hz, 1H), 7.22-7.15 (m, 1H), 6.94 (q, J=4.5 Hz, 1H), 3.96 (s, 3H); MS (EI) M+: m/z (%) 170 (50).
83%
With sulfuric acid; at 0℃; for 48h;Reflux;
To a stirred solution of 5-fluoro salicylic acid (25 g, 160 mmol) in MeOH (250 mL), cone, sulfuric acid (20 mL) was added slowly at 0C. The resulting reaction mixture was refluxed for 48 h then was concentrated under reduced pressure and the resulting crude was basified to pH 8.0 with sat. NaHC03. Then it was neutralized by 1 .5 N HCI solution and extracted with EtOAc. The organic layer was dried over anhydrous Na2S04 and concentrated to afford methyl 5-fluoro-2-hydroxybenzoate as a light brown liquid (22.8 g, 83%). GCMS: (AcqMethod HP-1 MS.M) 1 70.1 (M). 1 H NMR (400 MHz, DMSO-d6): delta ppm 1 0.29 (s, 1 H), 7.51 -7.49 (m, 1 H), 7.42-7.41 (m, 1 H), 57.03-7.01 (m, 1 H), 3.89 (s, 3H).
83%
With sulfuric acid; at 0℃; for 48h;Reflux;
To a stirred solution of 5-fluoro salicylic acid (25 g, 160 mmol)inMeOH (250 mL), conc. sulfuric acid (20 mL)was added slowly at 0C.The resulting reaction mixture was refluxed for 48 h then was concentrated under reduced pressure and the resulting crude was basified to pH 8.0 with sat. NaHCO3. The mixture was neutralized by 1 .5 N HCI solution and extracted with EtOAc. The organic layer wasdried over anhydrous Na2504 and concentrated to afford methyl 5-fluoro-2-hydroxybenzoate as a light brown liquid (22.8 g, 83% yleld). GC-MS (AcqMethod HP-1MS.M) 170.1 (M). 1H NMR (400 MHz, DMSO-d6) 6 ppm 10.29 (5, 1H), 7.51-7.49 (m, 1H), 7.42-7.41 (m, 1H), 7.03-7.01 (m, 1H), 3.89 (5, 3H).
76%
With sulfuric acid;Reflux;
Step 1 : To a solution of compound 114 (2.5 g, 16 mmol) in methanol (32 mL) was added sulfuric acid (2.0 mL, 21 mmol). The solution was heated at reflux overnight, cooled to room temperature and concentrated. The residue was dissolved in EtOAc, washed with saturated NaHC03 (3x), brine, dried (MgS04), filtered and concentrated to give compound 115 as to a cream solid (2.1 g, 76% yield). 1H NMR (400 MHz, DMSO-d6) delta 3.89 (s, 3 H), 7.01 (dd, J = 9.1 , 4.5 Hz, 1 H), 7.40 (td, J = 8.6, 3.2 Hz, 1 H), 7.45 - 7.54 (m, 1 H), 10.28 (s, 1 H).
Methyl 5-fluoro-2-hydroxybenzoate5-Fluoro-2-hydroxybenzoic acid (468mg, 3 mmole) was refluxed in methanol (20 mL +6 drops of cone H2SO4) overnight followed by evaporation to dryness. The product was used in next step without further purification.
With sulfuric acid; at 80℃;
a) Methyl 5-fluoro-2-hydroxybenzoate Into a 1-L round-bottom flask was placed 5-fluoro-2-hydroxybenzoic acid (20 g, 128.11 mmol), methanol (250 mL) and sulfuric acid (20 mL). The resulting solution was stirred overnight at 80 C. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with ethyl acetate (300 mL). The resulting mixture was washed with sodium bicarbonate (3*100 mL). The resulting residue was dried over anhydrous sodium sulfate. The resulting residue was purified on a silica gel column with ethyl acetate/petroleum ether (95:5) to yield methyl 5-fluoro-2-hydroxybenzoate as a white solid. Mass spectrum (ESI, m/z): Calculated for C8H7FO3, 172 (M+H). found 172.
With sulfuric acid; at 70℃; for 12h;Inert atmosphere;
Step 1 Methyl 5-fluoro-2-hydroxybenzoate 5-Fluoro-2-hydroxybenzoic acid (2.50 g, 16.01 mmol) was dissolved in methanol (25.00 mL), added with sulfuric acid (78.51 mg, 800.50 umol), and then stirred at 70° C. for 12 hours under nitrogen atmosphere. After the reaction mixture was concentrated, the residue was dissolved in ethyl acetate (20.00 mL). The organic phase was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give methyl 5-fluoro-2-hydroxybenzoate (a yellow oil, 2.0 g, crude product). 1H NMR (400 MHz, CDCl3) 10.51 (s, 1H), 7.49 (dd, J=3.1, 8.7 Hz, 1H), 7.24-7.10 (m, 1H), 6.94 (dd, J=4.5, 9.0 Hz, 1H), 3.95 (s, 3H).
With thionyl chloride; In tetrahydrofuran; for 3h;Reflux;
General procedure: To a solution of 5-halogen-substituted salicylic acid (10 mmol) in THF (50 mL) thionyl chloride (2.5 mL, 34 mmol) was added dropwise with stirring and refluxed for 3h. The reaction temperature was raised to 110C to remove the excess thionyl chloride and solvent with a Dean-Stark trap, and the produced 2-hydroxy-5-halogen-substituted benzoyl chloride was collected. This benzoyl chloride residue was directly refluxed with 4-halogen-2-fluoro benzenamine (10 mmol) in THF (50 mL) for 12 h. The mixture was concentrated in vacuo and extracted with ethyl acetate. The organic layer was dried over MgSO4, and the solvent was concentrated in vacuo. The crude product was washed with warm dichloromethane to give the desired compound as a white powder.
With thionyl chloride; N,N-dimethyl-formamide; In dichloromethane; at 25℃; for 12h;
General procedure: Thionyl chloride (1.46 mL, 20.0 mmol) was added to a suspension of salicylic acid (4.0 mmol) in DCM (20 mL), followed by a catalytic amount of DMF (0.80 mmol). The reaction mixture was stirred overnight at room temperature. The solvent and residual thionyl chloride were removed under reduced pressure and the crude residue was used immediately without further purification. The crude was resuspended in DCM (20 mL), 4-aminobenzonitrile (945 mg, 8.0 mmol) was added and the reaction mixture was stirred overnight at room temperature. The mixture was diluted with DCM, washed with 1M HCl solution, brine, dried (MgSO4) and evaporated to dryness under reduced pressure. Chromatography (hexanes in ethyl acetate 0-100%) afford the salicylamides.
Compound D was prepared by adding a solution of 0.39 g (2.5 mmol) of 5-fluorosalicylic acid, 1.63 g (2.5 mmol) of PyBop, 0.40 g (2.5 mmol) of HOBt, and 0.50 g (5 mmol) of NMM in 25 mL of DMF to 2.5 g of consensus peptide-2. The reaction mixture was shaken overnight. The solvent was removed from the resin and the resin subsequently washed with DMF (3×20 mL), isopropyl alcohol (3×20 mL), and CH2Cl2 (3×20 mL). All the side chain protecting groups were removed by treatment with TFA:H2O:TIS (95:2.5:2.5) for 2 h at ambient temperature. The peptide-nonpeptide conjugates were cleaved from the disulfide-containing resin with 10 mM DTT in 50 mM Tris, pH 7.5 (3×10 mL for 3 h each), and the resultant crude solution was purified by RP-HPLC. ESI-MS (m/z) calculated for C67H92N20O16S2 (M+) 1497.70, found 1498.17.
With caesium carbonate; In DMF (N,N-dimethyl-formamide); at 20 - 80℃; for 2h;
Benzyl bromide (0.86 mL, 7.2 mmol) and cesium carbonate (2.6 g, 8 mmol) were added to a solution of 2-hydroxy-5-fluoro-benzoic acid (0.5 g, 3.2 mmol) in anhydrous DMF (8 mL) at room temperature. The reaction was heated to 80 C. for two hours, cooled and diluted with water (50 mL). The mixture was extracted with ethyl acetate (3×40 mL) and the combined organic layers were washed with water (1×50 mL) and brine (1×50 mL), dried (Na2SO4), filtered and concentrated to afford 1.02 g of the title compound as a colorless oil (93%). MS: 337 (M+H)+. 1H NMR (400 MHz, CDCl3) delta 7.55 (dd, 1H, J=8.7, 3.1 Hz); 7.35 (m, 10OH); 7.1 (m, 1H); 6.97 (dd, 1H, J=9.1, 4.3 Hz); 5.3 (s, 2H); 5.1 (s, 2H).
85%
With potassium carbonate; In acetone; at 55℃; for 16h;Inert atmosphere;
General procedure: To a suspension of 5-bromo-2-hydroxybenzoic acid (400 mg, 1.843 mmol) and potassiumcarbonate (509 mg, 3.69 mmol) in acetone (50 mL) under nitrogen at 20 C was added 1-(bromomethyl)-2-chlorobenzene (833 mg, 4.05 mmol) dropwise. The mixture was stirred at55 C for 16 hours. The organic phase was evaporated and the residue was dissolved in water (25mL), extracted with ethyl acetate (30*3 mL). The organic layer was concentrated to give the titlecompound 10a (520 mg, 60.5 % yield) as a light yellow solid.
In N-methyl-acetamide;
The starting material used in B 23 was prepared starting from <strong>[345-16-4]5-fluoro-2-hydroxy-benzoic acid</strong> by reaction with benzyl bromide in dimethylformamide to give benzyl 2-benzyloxy-5-fluoro-benzoate, basic hydrolysis and esterification with acetone oxime.
With potassium carbonate; In acetone; for 5h;Heating / reflux;
Step 1: benzyl 2-(benzyloxy)-5-fluorobenzoate ("3-DTo a suspension of 10.5g (67.3 mmol) <strong>[345-16-4]5-fluoro-2-hydroxybenzoic acid</strong> and 37.1g (269 mmol) fine mesh K2CO3 in 250 mL of acetone was added 18.0 mL (151.2 mmol) benzyl bromide and the resulting mixture was refluxed for 5 h. After cooling to room temperature, the solids were filtered off, the filtrate was concentrated, loaded onto a silica gel column, and eluted with EtOAc/hexanes to provide M as a white solid. Data for 3A: 1HNMR (500 MHz, CDCl3) delta 7.55 (m, IH), 7.4 - 7.3 (m, 10H), 7.1 (m, IH), 6.95 (m, IH), 5.35 (s, 2H), 5.1 (s, 2H) ppm.
With potassium carbonate; In acetone; at 50℃;
A suspension of <strong>[345-16-4]5-fluoro-2-hydroxybenzoic acid</strong> (468 mg, 3 mmol), potassium carbonate (1037 mg, 7.50 mmol) and (bromomethyl)benzene (1283 mg, 7.50 mmol) in acetone (60 ml) was stirred at 50C overnight. The mixture was cooled and filtered. The filtrate was concentrated and the crude product was purified by silica gel chromatography, eluting with hexane: ethyl acetate (10:1 ) to yield the title compound as a colourless oil. 860 mg. MS (electrospray): m/z [M+Na]+ = 359
N-[3,5-bis(trifluoromethyl)phenyl]-5-fluoro-2-hydroxybenzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
58.7%
Example 50 N-[3,5-Bis(trifluoromethyl)phenyl]-5-fluoro-2-hydroxybenzamide (Comopund No. 49). Using 5-fluorosalicylic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound. Yield: 58.7%. 1H-NMR(DMSO-d6):delta 7.04(1H, ddd, J=9.0, 4.5, 1.2Hz), 7.30-7.37(1H, m), 7.66(1H, ddd, J=9.0, 3.3, 1.2Hz), 7.84(1H, s), 8.46(2H, s), 10.85(1H, s), 11.21(1H, brs).
58.7%
With phosphorus trichloride; In chlorobenzene; for 3h;Heating / reflux;
A mixture of 5-fluorosalicylic acid(156mg, 1mmol), 3,5-bis(trifluoromethyl)aniline(229mg, 1mmol), phosphorus trichloride(44 mu L, 0.5mmol) and monochlorobenzene(5mL) was refluxed for 3 hours under argon atmosphere. After the reaction mixture was cooled to room temperature, it was diluted with ethyl acetate(50mL). After the ethyl acetate layer was washed successively with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel(n-hexane:ethyl acetate=6:1) to give the title compound(215mg, 58.7%) as a white solid.1H-NMR(DMSO-d6):delta 7.04(1H, ddd, J=9.0, 4.5, 1.2Hz), 7.30-7.37(1H, m), 7.66(1H, ddd, J=9.0, 3.3, 1.2Hz), 7.84(1H, s), 8.46(2H, s), 10.85(1H, s), 11.21(1H, brs).
58.7%
With phosphorus trichloride; In chlorobenzene; for 3h;Heating / reflux;
A mixture of 5-fluorosalicylic acid(156mg, 1mmol), 3,5-bis(trifluoromethyl)aniline(229mg, 1mmol), phosphorus trichloride(44 mu L, 0.5mmol) and monochlorobenzene(5mL) was refluxed for 3 hours under argon atmosphere. After the reaction mixture was cooled to room temperature, it was diluted with ethyl acetate(50mL). After the ethyl acetate layer was washed successively with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel(n-hexane:ethyl acetate=6:1) to give the title compound(215mg, 58.7%) as a white solid.1H-NMR(DMSO-d6):delta 7.04(1H, ddd, J=9.0, 4.5, 1.2Hz), 7.30-7.37(1H, m), 7.66(1H, ddd, J=9.0, 3.3, 1.2Hz), 7.84(1H, s), 8.46(2H, s), 10.85(1H, s), 11.21(1H, brs).
48%
With pyridine; phosphorus trichloride; In toluene;Inert atmosphere; Reflux;
General procedure: Phosphorus trichloride (0.13ml, 1.5mmol) was added to a stirred solution of 3,5-bis(trifluoromethyl)aniline (0.47ml, 3mmol), a catalytic amount of pyridine and 5-chloro salicylic acid (621.3mg, 3.6mmol) in anhydrous toluene (10ml) in in a Radley?s Carousel reaction tube under an argon atmosphere. After the reaction mixture was refluxed for overnight, it was cooled to room temperature and aq. sodium bicarbonate was added dropwise until PH=6 - 7. After extracting with ethyl acetate, the organic layers was dried, dried (MgSO4) and concentrated in vacuo. After chromatography (EA-Hex, 1:10) of the crude product, and followed by recrystalization from EtOAc/hexane provided 2a as a white solid (320mg, 28%).
With pyridine; thionyl chloride; In 5,5-dimethyl-1,3-cyclohexadiene; ethanol;
a) 6-Fluoro-2-(5-fluoro-2-hydroxyphenyl)benz[e][1,3]oxazin4-one: 4.3 g of 5-fluoro-salicylamide and 4.7 g of 5-fluorosalicylic acid are boiled under reflux in 50 ml of xylene after addition of 0.3 ml of pyridine. 4.4 ml of thionyl chloride are added in the course of 2 h, the mixture is stirred for a further 1 h and the solvent is then distilled off under reduced pressure. The residue is suspended in 30 ml of ethanol, filtered off and washed with ethanol. After drying, 6-fluoro-2-(5-fluoro-2-hydroxyphenyl)benz[e][1,3]oxazin-4-one is obtained as slightly yellow crystals of m.p. 250-252 C.
With sodium chloride; sulfuric acid; potassium carbonate; sodium sulfate; In tetrahydrofuran; methanol; N,N-dimethyl-formamide;
EXAMPLE 3 Production of 5-fluoro-2-(2-phenylethoxy]benzyl Alcohol To a solution of 4.99 g of 5-fluorosalicylic acid in 30 ml of methanol, was added 2 ml of conc. sulfuric acid and the mixture was heated under reflux for 18 hours. Then the reaction mixture was ice-cooled and the crystals thus precipitated were collected by filtration and thoroughly washed with cold methanol. The crystals were dried and then dissolved in 50 ml of N,N-dimethylformamide. After adding 16.54 ml of (2-bromoethyl)benzene and 16.73 g of anhydrous potassium carbonate, the mixture was stirred at room temperature for a day. Then the reaction mixture was concentrated under reduced pressure, poured into water and extracted with ethyl acetate. The organic layer was successively washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and then filtered. The solvent was evaporated under reduced pressure. The residue was dissolved in 50 ml of tetrahydrofuran and 1.15 g of aluminum lithium hydride was added thereto in portions under ice-cooling. After stirring for additional 1 hour under ice-cooling, a saturated aqueous solution of sodium sulfate was added dropwise thereto until no hydrogen gas evolved any more. The solid matters thus precipitated were separated by filtration and the residue was subjected to silica gel column chromatography (developing solvent; n-hexane:acetone=20:1-10:1) to give 7.07 g of 5-fluoro-2-(2-phenylethoxy)benzyl alcohol. NMR (CDCl3) delta (ppm); 2.20 (1H, t, J=6.3 Hz, exchangeable with D2 O), 3.08 (2H, t, J=6.8 Hz), 4.18 (2H, t, J=6.8 Hz), 4.53 (2H, d, J=6.3 Hz), 6.75 (1H, dd, J=5.0, 10.0 Hz), 6.83-7.00 (2H, m), 7.19-7.38 (5H, m). MS m/e; 246 (M+).
(a) 5-Fluoro-3-nitro-salicylic acid 6.24 g (40 mmol) of <strong>[345-16-4]5-fluoro-salicylic acid</strong> is dissolved in 62.4 ml of acetonitrile with warming, the solution is cooled to 0 C. and, with this temperature being maintained a solution of 2.96 ml (44 mmol) of 65% HNO3 in 14.8 ml of acetonitrile is instilled. The reaction mixture is stirred for 24 hours at 0 C., then filtered over 7.5 g of silica gel 60 and evaporated to dryness 6.1 g =75.8% of the theoretical yield is obtained of the crude product, which is used in the next reaction without purification.
With sulfuric acid; nitric acid; In water; at 0 - 5℃;
Example 115 A5-fluoro-2-hydroxy-3-nitrobenzoic acid; To a mixture of <strong>[345-16-4]5-fluoro-2-hydroxybenzoic acid</strong> (3.08 g, 19.76 mmol) in concentrated H2SO4 (30 mL) below 0 C. was added dropwise a mixture of concentrated HNO3 (2.11 g, 21.74 mmol) and concentrated H2SO4 (6 mL) with stirring below 5 C. After the addition, the mixture was stirred at this temperature for 2 hr. The reaction mixture was poured onto crash ice and the precipitate was collected, then the precipitate was dissolved in ethyl acetate (100 mL), washed with water (50 mL×2), brine (30 mL), dried over anhydrous sodium sulfate and concentrated to give 5-fluoro-2-hydroxy-3-nitrobenzoic acid (3.8 g) as a brown solid. LC-MS (ESI) m/z 202 [M+1]+.
With thionyl chloride; In ethyl acetate; N,N-dimethyl-aniline; benzene;
EXAMPLE 9 SPC18 Preparation of 3',5'-dichloro-2,4'-dihydroxy-5-fluorobenzanilide 5Fluorosalicylic acid (5.15 g.) and <strong>[5930-28-9]4-amino-2,6-dichlorophenol</strong> (5.88 g.) were well mixed to which was added benzene (10 ml.) and N,N-dimethylaniline (4.35 ml.). Then with stirring thionyl chloride (3.3 ml.) was added and refluxed 30 minutes. The resulting solution was evaporated and the residue was dissolved in ethyl acetate and subjected to decolorization with activated charcoal followed by washing with 2 N hydrochloric acid and 2.5percent sodium bicarbonate solution. The ethyl acetate was then extracted several times with 2 N sodium carbonate solution and the aqueous extracts were combined and brought to pH 1-2 with hydrochloric acid to give a precipitate which was recrystallized from aqueous acetone to give white needle-like crystals (5.7 g.) of 3',5'-dichloro-2,4'-dihydroxy-5-fluorobenzanilide. Yield: 55percent. Melting point: 227°-229° C.
With potassium carbonate; In N,N-dimethyl-formamide;
Preparation 66 To a mixture of <strong>[345-16-4]5-fluoro-2-hydroxybenzoic acid</strong> (2.0g), potassium carbonate (4.42g), and N,N-dimethylformamide (25ml) was added at room temperature methyl iodide (3.98ml). Stirred at room temperature for four hours. Diluted with ethyl acetate (100ml), washed with water (twice, 100ml each time), brine (twice, 100ml each time), dried over Magnesium sulfate, filtered, and evaporated to give 5-fluoro-2-methoxymethylbenzoate (2.23g) as a yellow liquid. MS:185(M+1), 153(M-CH3OH+1) NMR(DMSO, delta):3.79(3H,s), 3.81(3H,s), 7.18(1H,dd,J=8.7Hz,4.2Hz), 7.35-7.48 (2H,m).
N-(3,5-dichlorophenyl)-5-fluoro-2-hydroxybenzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
33.3%
Example 147 N-(3,5-Dichlorophenyl)-5-fluoro-2-hydroxybenzamide (Comopund No. 146). Using 5-fluorosalicylic acid and 3,5-dichloroaniline as the raw materials, the same operation as the example 16 gave the title compound. Yield: 33.3%. mp 258-260ØC. 1H-NMR(DMSO-d6): delta 7.00-7.05(1H, m), 7.28-7.37(2H, m), 7.63(1H, dd, J=9.3, 3.3Hz), 7.84(2H, d, J=2.1Hz), 10.56(1H, s), 11.23(1H, s).
With potassium carbonate; In ISOPROPYLAMIDE; at 80℃; for 17h;
A suspension of 5-fluorosalicylic acid (2.96 g), potassium carbonate (7.90 g) and iodoethane (4.6 mL) in dimethylacetamide (20 mL) was heated at 80C for 17 hours. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over sodium sulfate and concentrated and dried under reduced pressure to obtain 4.62 g of a yellow oil. This yellow oil (4.62 g) was heated under reflux in 1N sodium hydroxide (30 mL) aqueous solution and tetrahydrofuran (90 mL) for 3.5 hours. The organic solvent was removed under reduced pressure and 1N hydrochloric acid (40 mL) was added to the mixture. The deposited precipitate was collected by filtration, recrystallized from isopropyl ether/hexane again and 1.79 g (51 %) of the title compound was obtained as a white solid.
With trichlorophosphate; In toluene; for 6h;Reflux;
A mixture of 5-fluorosalicylic acid (5.07 g, 32.5 mmol), POCl3 (6.5 mL, 65 mmol) and toluene (12 mL) was heated under reflux for 6 h. After cooling the reaction mixture, the crystals deposited were separated by filtration and washed with aq NaHCO3. The crystalline solid was collected to give a crude mixture of tetrasalicylide (1e) and hexasalicylide (2e). Yield 2.75 g. The resultant mixture was recrystallized from N-methyl-pyrrolidone (100 mL) to give 1:4 inclusion crystals of 2e with N-methyl-pyrrolidone (1.05 g) after two days. Upon heating the inclusion crystals at 200 C for 3 h, free host 2e (0.67 g) was obtained. The filtrate left after separation of the 1:4 inclusion crystals was kept at room temperature for three days to afford the crystals of 1e as colourless prisms (0.90 g). Tetrasalicylide (1e): yield 20%; mp 276-278 C; IR (KCl) 1743 cm-1 (C=O); 1H NMR (CDCl3, 400 MHz) delta 7.96-7.99 (m, 4H, Ar), 7.30-7.35 (m, 4H, Ar), 7.16-7.19 (m, 4H, Ar); 13C NMR (CDCl3, 100 MHz) delta 161.6, 161.3, 158.8, 146.9, 146.8, 125.7, 125.6, 123.2, 123.1, 122.0, 121.8, 119.2, 119.0. MS (ESI) m/z: 559.11 [M+Li]; 575.11 [M+Na]; 591.11 [M+K]; Anal. Calcd for C28H12F4O8: C 60.88, H 2.19; found: C 60.63, H 2.01. Hexasalicylide (2e): yield 15%; mp >300 C; IR (KCl) 1751 cm-1 (C=O); 1H NMR (CDCl3, 400 MHz) delta 8.30-8.34 (m, 6H, Ar), 7.08-7.13 (m, 6H, Ar), 6.93-6.96 (m, 6H, Ar); 13C NMR (CDCl3, 100 MHz) delta 161.3, 161.2, 158.7, 146.6, 146.5, 125.6, 123.2, 123.1, 122.0, 121.7, 119.4, 119.2; MS (ESI) m/z: 835.14 [M+Li]; 851.13 [M+Na]; 867.13 [M+K]; Anal. Calcd for C42H18F6O12: C 60.88, H 2.19; Found: C 60.71, H 2.03.
Example 5 Synthesis of 5-fluorosalicylic acid methyl ester (7) 5-Fluorosalicylic acid (272.6 g, 1.74 mol) was dissolved in methanol (1.3 L) to form a clear solution. Concentrated sulfuric acid (50 ml) was slowly added to the methanol solution with vigorous stirring. The solution was heated to reflux for 4 hours. Trimethyl orthoformate (200 ml) was added slowly to the reaction solution. 300 ml of solvents (methyl formate and methanol) was distilled off. The remaining reaction solution was heated at 66° C. (refluxing temperature) for 16 hours. HPLC analysis indicated that the reaction was complete. Reaction solution was cooled to ambient temperature. Solvent was removed under reduced pressure. The residue was partitioned between water (140 ml) and methylene chloride (220 ml). Organic layer was separated. Aqueous layer was extracted with methylene chloride (3*220 ml). The combined organic layer was washed with water (270 ml), brine (270 ml) and dried with MgSO4. The organic solution was concentrated to dryness to afford crude product (293.8 g). This crude material was used in the next step without further purification. 1H NMR (300 MHz, CDCl3) delta 3.96(s, 3H), 6.94(dd, 1H, J=4.5 Hz and J=9.0 Hz), 7.19(m, 1H), 7.50(dd, 1H, J=3.3 Hz and J=8.7 Hz), 10.508(s, 1H).
With N-Bromosuccinimide; acetic acid; at 80℃; for 24h;
A mixture of 37A (5.1 g, 33 mmol, 1.0 eq) and NBS (6.4 g, 36 mmol, (0957) 1.1 eq) in AcOH (25 mL) was stirred at 80 C for 24 hours. The reaction was monitored by TLC. The mixture was concentrated in vacuo and the residue was purified by column chromatography (PE/EA = 2: 1 to 1 : 1 ) to give 37B (6.5 g, 85%). ESI-MS: [M-H]": 233,235
With phosphorus trichloride; In chlorobenzene; at 20 - 130℃; for 3.5h;Inert atmosphere;
Synthesis of methyl 4-(5-fluoro-2-hydroxybenzamido)-2-(2-fluoro-4-methylphenyl)thiophene-3-carboxylate (385): Under an atmosphere of argon, PCl3 (8.2 muL, 13 mg, 94 mumol) was added to amine 375 (50 mg, 188 mumol) and acid 384 (29.4 mg, 188 mumol) in chlorobenzene (0.9 mL) at room temperature. The reaction was heated to 130 C. and stirred for 3.5 h. The mixture was cooled and quenched with a saturated solution of NaHCO3 (1 mL) extracted with dichloromethane (3×5 mL) and combined extracts were washed with 2 M HCl (2 mL), brine (2 mL), dried over Na2SO4 and concentrated under reduced pressure. Flash chromatography (ISCO system, silica, 0-50% ethyl acetate in hexane) provided 385 (61 mg, 80%) as a solid: LRESIMS m/z 404.0 [M+H]+, calcd. for C20H16F2N1O4S1 404.1.
Methyl 5-fluorosalicylate (17)A solution of 5-fluorosalicylic acid (10. lg, 64.7mmol) in methanol (250ml) was treated portionwise with acetyl chloride (10ml, 140mmol) and heated at reflux for 4 d. The reaction solvent was removed under vacuum, the residue taken into DCM and washed with water and brine. The organics were dried and reduced under vacuum to give the title compound (12.2g,64.2mmol).NMR (CDCI3) delta 10.55 (1H, s), 7.54 (1H, dd, J 9.2, 3.2), 7.22 (1H, m), 6.97 (1H, dd, J 9.2, 4.1), 3.99 (3H, s)
With phosphorus pentoxide-methanesulfonic acid; at 80℃; for 3h;
General procedure: To a mixture of commercially available phloroglucinol (1.2 equiv) and an appropriate substituted salicylic acid (1 equiv), 20 mL of Eaton's reagent (P2O5-CH3SO3H) was added slowly. The mixture was stirred for 3 h at 80 C, cooled to rt, and poured onto ice. After vigorous stirring at rt for 2 h, a brown solid was precipitated. The solid was collected by filtration, washed with water (pH ? 6), and dried at 60 C. In most instances, this intermediate 1,3-dihydroxy-9H-xanthen-9-one was used without further purification.
With phosphorus pentoxide-methanesulfonic acid; at 80℃; for 2h;
General procedure: 2,6-dihydroxybenzoic acid (5.0 g, 32.4 mmol) andphloroglucinol (4.09 g, 32.4 mmol) were added to Eaton?s reagent (20 mL) and heated on an 80 Coil bath for 2 h. After cooling to r.t., the dark-brown solution was transferred slowly to crushedice while being vigorously stirred. The mixture was filtered and the filter cake was washed withwater, dried, and purified by flash column chromatography to afford xanthone 3 as a yellow solid(2.3 g, yield: 29%).
N-(2-bromo-5-(trifluoromethyl)phenyl)-5-chloro-2-hydroxybenzamide[ No CAS ]
[ 345-16-4 ]
N-[3,5-bis(trifluoromethyl)phenyl]-5-fluoro-2-hydroxybenzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With pyridine; phosphorus trichloride; In toluene;Inert atmosphere; Reflux;
General procedure: The salicylic acid (1.2 equiv) was added to a mixture of toluene (0.3 M), aniline (1.0 equiv), phosphorus trichloride (1.1 equiv), and pyridine (0.05 equiv) in a Radley?s Carousel reaction tube (modified from Itai et al.20). The mixture was refluxed under nitrogen for 12 h then cooled to room temperature. Aqueous sodium bicarbonate was added dropwise to attain pH 6-7. The resultant mixture was extracted with EtOAc. The organic extracts were combined, dried (MgSO4), and concentrated under vacuum. After chromatography (1:10 EtOAc:Hex) compounds were recrystallized (EtOAc/Hex).
With pyridine; phosphorus trichloride; In toluene; for 12h;Inert atmosphere; Reflux;
General procedure: The salicylic acid (1.2 equiv) was added to a mixture of toluene (0.3 M), aniline (1.0 equiv), phosphorus trichloride (1.1 equiv), and pyridine (0.05 equiv) in a Radley?s Carousel reaction tube (modified from Itai et al.20). The mixture was refluxed under nitrogen for 12 h then cooled to room temperature. Aqueous sodium bicarbonate was added dropwise to attain pH 6-7. The resultant mixture was extracted with EtOAc. The organic extracts were combined, dried (MgSO4), and concentrated under vacuum. After chromatography (1:10 EtOAc:Hex) compounds were recrystallized (EtOAc/Hex).
With pyridine; phosphorus trichloride; In toluene; for 12h;Inert atmosphere; Reflux;
General procedure: The salicylic acid (1.2 equiv) was added to a mixture of toluene (0.3 M), aniline (1.0 equiv), phosphorus trichloride (1.1 equiv), and pyridine (0.05 equiv) in a Radley?s Carousel reaction tube (modified from Itai et al.20). The mixture was refluxed under nitrogen for 12 h then cooled to room temperature. Aqueous sodium bicarbonate was added dropwise to attain pH 6-7. The resultant mixture was extracted with EtOAc. The organic extracts were combined, dried (MgSO4), and concentrated under vacuum. After chromatography (1:10 EtOAc:Hex) compounds were recrystallized (EtOAc/Hex).
General procedure: The salicylic acid (1.2 equiv) was added to a mixture of toluene (0.3 M), aniline (1.0 equiv), phosphorus trichloride (1.1 equiv), and pyridine (0.05 equiv) in a Radley?s Carousel reaction tube (modified from Itai et al.20). The mixture was refluxed under nitrogen for 12 h then cooled to room temperature. Aqueous sodium bicarbonate was added dropwise to attain pH 6-7. The resultant mixture was extracted with EtOAc. The organic extracts were combined, dried (MgSO4), and concentrated under vacuum. After chromatography (1:10 EtOAc:Hex) compounds were recrystallized (EtOAc/Hex).
With pyridine; phosphorus trichloride; In toluene; for 12h;Inert atmosphere; Reflux;
General procedure: The salicylic acid (1.2 equiv) was added to a mixture of toluene (0.3 M), aniline (1.0 equiv), phosphorus trichloride (1.1 equiv), and pyridine (0.05 equiv) in a Radley?s Carousel reaction tube (modified from Itai et al.20). The mixture was refluxed under nitrogen for 12 h then cooled to room temperature. Aqueous sodium bicarbonate was added dropwise to attain pH 6-7. The resultant mixture was extracted with EtOAc. The organic extracts were combined, dried (MgSO4), and concentrated under vacuum. After chromatography (1:10 EtOAc:Hex) compounds were recrystallized (EtOAc/Hex).
With pyridine; phosphorus trichloride; In toluene; for 12h;Inert atmosphere; Reflux;
General procedure: The salicylic acid (1.2 equiv) was added to a mixture of toluene (0.3 M), aniline (1.0 equiv), phosphorus trichloride (1.1 equiv), and pyridine (0.05 equiv) in a Radley?s Carousel reaction tube (modified from Itai et al.20). The mixture was refluxed under nitrogen for 12 h then cooled to room temperature. Aqueous sodium bicarbonate was added dropwise to attain pH 6-7. The resultant mixture was extracted with EtOAc. The organic extracts were combined, dried (MgSO4), and concentrated under vacuum. After chromatography (1:10 EtOAc:Hex) compounds were recrystallized (EtOAc/Hex).
5-fluoro-2-hydroxy-N-(4-(trifluoromethyl)phenyl)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
General procedure: The salicylic acid (1.2 equiv) was added to a mixture of toluene (0.3 M), aniline (1.0 equiv), phosphorus trichloride (1.1 equiv), and pyridine (0.05 equiv) in a Radley?s Carousel reaction tube (modified from Itai et al.20). The mixture was refluxed under nitrogen for 12 h then cooled to room temperature. Aqueous sodium bicarbonate was added dropwise to attain pH 6-7. The resultant mixture was extracted with EtOAc. The organic extracts were combined, dried (MgSO4), and concentrated under vacuum. After chromatography (1:10 EtOAc:Hex) compounds were recrystallized (EtOAc/Hex).
With oxygen; potassium acetate; palladium diacetate; p-benzoquinone; In N,N-dimethyl acetamide; at 115℃; for 15h;Schlenk technique;
General procedure: A 50 mL Schlenk-type tube (with a Teflon high-pressure valveand side arm) was charged with m-toluic acid (68.0 mg, 0.50mmol), benzoquinone (54.0 mg, 0.50 mmol), KOAc (98.0 mg,1.00 mmol), Pd(OAc)2 (11.2 mg, 0.050 mmol), and N,N-dimethylacetamide(1.5 mL). The reaction tube was evacuated and backfilledwith O2 (3×, ballon). After the reaction mixture wasstirred at 115 C for 15 h, it was allowed to cool down to r.t. Thereaction mixture was diluted with EtOAc (10 mL) and then filteredthrough a pad of Celite. The filtrate was concentrated invacuo to yield crude 2-hydroxylbenzoic acid. A mixture of thecrude product, Cu2O (3.6 mg, 0.025 mmol), and 1,10-phenanthroline(9.0 mg, 0.050 mmol) in a solution of NMP (1.5 mL) andquinoline (0.5 mL) was heated under an atmosphere of N2 at220 C for 12 h. The reaction mixture was quenched by additionof 0.2 M aq HCl (10 mL), diluted with EtOAc (10 mL), and thenfiltered through a pad of Celite. The filtrate was washed withbrine (10 mL), dried over Na2SO4, and concentrated in vacuo.The residue was purified by silica gel preparative TLC to give pcresol.
With quinoline; copper(I) oxide; 1,10-Phenanthroline; In 1-methyl-pyrrolidin-2-one; at 220℃; for 12h;Schlenk technique; Inert atmosphere;
General procedure: A 50 mL Schlenk-type tube (with a Teflon high-pressure valveand side arm) was charged with m-toluic acid (68.0 mg, 0.50mmol), benzoquinone (54.0 mg, 0.50 mmol), KOAc (98.0 mg,1.00 mmol), Pd(OAc)2 (11.2 mg, 0.050 mmol), and N,N-dimethylacetamide(1.5 mL). The reaction tube was evacuated and backfilledwith O2 (3×, ballon). After the reaction mixture wasstirred at 115 C for 15 h, it was allowed to cool down to r.t. Thereaction mixture was diluted with EtOAc (10 mL) and then filteredthrough a pad of Celite. The filtrate was concentrated invacuo to yield crude 2-hydroxylbenzoic acid. A mixture of thecrude product, Cu2O (3.6 mg, 0.025 mmol), and 1,10-phenanthroline(9.0 mg, 0.050 mmol) in a solution of NMP (1.5 mL) andquinoline (0.5 mL) was heated under an atmosphere of N2 at220 C for 12 h. The reaction mixture was quenched by additionof 0.2 M aq HCl (10 mL), diluted with EtOAc (10 mL), and thenfiltered through a pad of Celite. The filtrate was washed withbrine (10 mL), dried over Na2SO4, and concentrated in vacuo.The residue was purified by silica gel preparative TLC to give pcresol.1H NMR (400 MHz, CDCl3): delta = 7.05 (d, J = 8.3 Hz, 2 H),6.75 (d, J = 8.3 Hz, 2 H), 4.95 (br, 1 H), 2.29 (s, 3 H). 13C NMR (100MHz, CDCl3): delta = 153.18, 130.03, 129.92, 115.06, 20.43. HRMS(ESI-TOF): m/z calcd for C7H9O+: 109.0648 [M + H]+; found:109.0657.
(1) Synthesis of methyl 2-methoxy-5-fluorobenzoate Solution of 5-fluorosalicylic acid (0.6g, 4mmol), methyl iodide (2.4g, 16mmol) and potassium carbonate (2.2g, 16mmol) in 40mL DMF was reacted in a sealed tube at 100 deg. C overnight. The reaction system was cooled, quenched with saturated ammonium chloride solution, then diluted with ethyl acetate. The organic phase was successively washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent distilled off under reduced pressure to give the product, methyl 2-methoxy-5-fluorobenzoate (0.7 g of, 99% yield).
66%
With potassium carbonate; In acetone; at 50℃; for 16h;
Step 1. Methyl 5-fluoro-2-methoxybenzoate (0540) To a solution of <strong>[345-16-4]5-fluoro-2-hydroxybenzoic acid</strong> (100 g, 641 mmol) in acetone (1000 mL) was added K2CO3 (190 g, 1380 mmol) and MeI (268.3 g, 1890 mmol). The mixture was stirred at 50 C for 16 h. The mixture was filtered and concentrated under reduced pressure. The residue was mixed with EtOAc (500 mL) and washed with H2O (3 × 300 mL). The organic layer was then dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column (0541) chromatography on silica gel eluting with petroleum ether:ethyl acetate = 20:1 to afford methyl 5-fluoro-2-methoxybenzoate.Yield: 78 g (66%). 1H NMR (CDCl3): delta 7.50 (dd, J = 3.6 Hz, 8.8 Hz, 1H), 7.17-7.18 (m, 1H), 6.92 (dd, J = 4.0 Hz, 8.8 Hz 1H), 3.89 (s, 3H), 3.88 (s, 3H).
With potassium carbonate; In acetone; at 40℃; for 12h;
Compound 47 (1.0 eq.), methyl iodide (3.0 eq.), potassium carbonate (3.0 eq.) was dissolved in a certain amount of acetone solution, stirred at 40 C for 12 h, the solvent was evaporated, ethyl acetate was extracted and saturated Sodium hydrogen,After the crude product is dried,Purification by silica gel column chromatography gave Intermediate 48.48 (1.0 eq.) dissolved in ultra dry toluene,Acetonitrile (3.0 eq.) was added, then sodium hydride (3.0 eq.) was added, a balloon was added, and the mixture was heated to 90 C for 3 h. The solvent was dried, the ethyl acetate was extracted and saturated sodium bicarbonate was added.Purification by silica gel column chromatography gave Intermediate 49.49 (1.0 eq.)It is dissolved in ethanol with hydrazine monohydrate (1.2 eq.), and then glacial acetic acid (6.0 eq.) is added. After heating at 50 C for 3 h, the solvent is evaporated, ethyl acetate is extracted and saturated sodium bicarbonate is added. Purification by silica gel column chromatography gave Intermediate 50.50 was added to the DMF solvent in one-to-one equivalents with different types of carboxylic acids, and HATU (1.5 eq.) and DIPEA (1.5 eq.) were added.After reacting at 70 C for 12 h, the crude product was extracted with ethyl acetate and dried.Purification by silica gel column chromatography gave Intermediate 51.51 or 50 (1 eq.) was dissolved in ultra-dry DCM, boron tribromide (8 eq.) was added at 0 C, the reaction was stirred at room temperature for 12 h, the solvent was evaporated, ethyl acetate was evaporated, and saturated sodium hydrogen carbonate was added and dried. Thereafter, purification by silica gel column chromatography gave the final product BRM2-160-174.
<strong>[345-16-4]5-fluoro-2-hydroxybenzoic acid</strong> (500 mg, 3.2 mmol) methanol (20 ml) solution of the was added dropwise concentrated sulfuric acid (300 mul). Under an argon atmosphere, and stirred under reflux conditions overnight. After completion of the reaction, concentrated to dryness. Saturated brine, saturated aqueous sodium hydrogen carbonate solution was added, followed by extraction with ethyl acetate. Dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.DMF (8 ml) solution to the residue,Cesium carbonate (1.25 g, 3.80 mmol),(Bromomethyl) benzene (837 mul, 7.00 mmol) was added at room temperature. And heated under 70 argon atmosphere was stirred for 2 hours. After completion of the reaction, saturated brine, saturated aqueous sodium hydrogen carbonate solution was added, followed by extraction with ethyl acetate. Dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (631 mg, 76%).
5-fluoro-2-hydroxy-<i>N</i>-pyridin-3-yl-benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide;
General procedure: To a solution of 5-bromo-2-hydroxybenzoic acid (2 g, 9.22 mmol) in DMF (15 mL) was addedDIPEA (3.22 mL, 18.43 mmol), 3-aminopyridine (1.128 g, 11.98 mmol), HOBT (1.694 g, 11.06mmol) and EDC (3.53 g, 18.43mmol). The reaction was stirred overnight, water was added andthe solid was filtered to give the title compound 12 (346 mg, 12% yield).
2-fluoro-12H-benzo[e]benzo[4,5]imidazo[2,1-b][1,3]oxazine-12-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
50%
With pyridine; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; copper(I) bromide; In para-xylene; at 120℃; for 36h;Schlenk technique; Green chemistry;
CuBr 6 mg (0.04 mmol), TEMPO 5 mg (0.03 mmol), compounded in a 25 mL Schlenk reaction tubeBenzimidazole 47 mg (0.4 mmol),5-fluorosalicylic acid 32 mg (0.2 mmol), p-xylene (0.5 mL), followed by pyridine 33 muL (0.4 mmol), and the reaction was stirred at 120C for 36 hours under reflux.Cool to room temperature, transfer all to a 25 mL flask, spin off the solvent on a rotary evaporator, add an appropriate amount of silica gel to spin dry, and then use a 300-400 mesh silica gel column. The developing solvent used is petroleum ether:ethyl acetate=16: 1 to 6:1, namely compound III-17 25mg, yield 50%; white solid
In tetrahydrofuran; for 24h;Inert atmosphere; Reflux;
<strong>[345-16-4]5-Fluorosalicylic acid</strong> (10.5 g, 66.9 mmol) in THF (110 mL) under Ar was heated to reflux. N,N-Dimethylformamide di-tert-butyl acetal (50.0 mL, 208 mmol) was added through the condenser in three portions every 30 min. The reaction mixture was stirred at reflux for an additional 23 h. The reaction was diluted with water and extracted two times with DCM. The combined organic layers were washed with water and brine, dried over Na2SO4, filtered, and concentrated. Column chromatography (0-70% DCM/Hexane) afforded the title compound (10.1 g, 71%). ESI-MS m/z 213 (MH)+.
7-fluoro-1-hydroxy-3-methyl-9H-xanthen-9-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
58%
With methanesulfonic acid; phosphorus pentoxide; at 90℃;
General procedure: A mixture of phosphorus pentoxide (0.36 g, 2.5 mmol) and methanesulfonic acid(10 ml) was heated at 110 C until a clear solution was obtained. The temperature wasthen lowered to 90 C and a mixture of 3,5-dihydroxytoluene (0.13 g, 1.0 mmol) andsubstituted salicylic acid (1.0 mmol) was added. Heating was then continued for severalhours. The reaction progress was monitored by thin-layer chromatography (TLC)until the reaction was balanced, then the reaction mixture was poured into icedwater.The crude product was collected by filtration or extracted with ethyl acetate,washed with water, dried, and purified by medium pressure preparative chromatographywith ethyl acetate/petroleum ether to afford the target xanthone.
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
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