* 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.
Stage #1: With lithium aluminium tetrahydride In tetrahydrofuran at 20℃; for 16 h; Stage #2: With hydrogenchloride In tetrahydrofuran; water
Step 3 4-Bromo-2-(hydroxymethyl)phenol: A solution of 5-bromo-2-hydroxybenzoic acid (21.7 g; 100 mmol; 1.00 equiv) in tetrahydrofuran (200 mL) was added to a suspension of lithium aluminum hydride (5.7 g; 150 mmol; 1.50 equiv) in tetrahydrofuran (100 mL). The suspension was virgously stirred for about 16 hours at ambient temperature and then quenched by adding 3M hydrochloric acid (300 mL). Following standard extractive workup with ethyl acetate, the crude residue was re-crystallized from ethyl acetate/hexane (1/10) to give the title product as gray solid (12.4 g; 60percent yield). 1H NMR (400 MHz, CDCl3) 6: 9.68 (s, 1H), 7.39 (s, 1H), 7.19 (dd, J=2.0, 2.0 Hz, 1H), 6.72 (d, J=8.4 Hz, 1H), 5.10 (s, 1H), 4.44 (s, 2H).
Reference：
[1] Patent: US5587392, 1996, A,
[2] Patent: US2010/9950, 2010, A1, . Location in patent: Page/Page column 20
[3] Chemische Berichte, 1906, vol. 39, p. 2938
[4] Journal of Organic Chemistry, 2006, vol. 71, # 9, p. 3646 - 3649
2
[ 89-55-4 ]
[ 98-80-6 ]
[ 323-87-5 ]
Reference：
[1] Doklady Chemistry, 1990, vol. 315, # 4-6, p. 354 - 357[2] Dokl. Akad. Nauk SSSR Ser. Khim., 1990, vol. 315, # 5, p. 1133 - 1136
[3] Dalton Transactions, 2017, vol. 46, # 26, p. 8598 - 8610
[4] Chemistry - A European Journal, 2014, vol. 20, # 11, p. 3050 - 3060
[5] Organic and Biomolecular Chemistry, 2014, vol. 12, # 25, p. 4511 - 4516
[6] Journal of Medicinal Chemistry, 2009, vol. 52, # 21, p. 6539 - 6542
[7] Organic letters, 2001, vol. 3, # 8, p. 1177 - 1180
3
[ 89-55-4 ]
[ 143-66-8 ]
[ 323-87-5 ]
Reference：
[1] Tetrahedron, 1997, vol. 53, # 42, p. 14437 - 14450
[2] Russian Journal of General Chemistry, 1996, vol. 66, # 12, p. 1925 - 1938
[3] Tetrahedron Letters, 2005, vol. 46, # 24, p. 4255 - 4259
4
[ 89-55-4 ]
[ 100-58-3 ]
[ 323-87-5 ]
Reference：
[1] Journal of Organometallic Chemistry, 1997, vol. 532, # 1-2, p. 271 - 273
5
[ 89-55-4 ]
[ 31044-59-4 ]
[ 323-87-5 ]
Reference：
[1] Tetrahedron, 1997, vol. 53, # 42, p. 14437 - 14450
[2] Russian Journal of General Chemistry, 1996, vol. 66, # 12, p. 1925 - 1938
6
[ 89-55-4 ]
[ 21739-92-4 ]
Yield
Reaction Conditions
Operation in experiment
92.1%
With tetrachloromethane; molybdenum hexacarbonyl In dimethyl sulfoxide at 150℃; for 6 h; Autoclave
This example is the preparation of 2-chloro-5-bromo-benzoic acid, and the specific method is as follows:2.14 g of molybdenum hexacarbonyl (0.01 mol) was added to a 1 L autoclave.217.0 g of 2-hydroxy-5-bromobenzoic acid (1.0 mol),185.0 g of carbon tetrachloride (1.2 mol) and 250 mL of dimethyl sulfoxide,Heat to 150 ° C,The reaction was stirred for 6 h.After the end of the controlled reaction in HPLC,Evaporate the solvent under reduced pressure.Then add 250 mL of acetonitrile,Warm up to 70 ° C and stir to dissolve.Then add neutral alumina for hot filtration.The filtrate was cooled to room temperature.A pale yellow solid precipitated.Then, 564 mL of an ethanol/water mixed solvent (volume ratio 1:3) was added.After heating and dissolving,Slowly cool to 60 ° C first,After a small amount of crystals are precipitated,Cooled to 50 ° C for 1 h,Finally, it was slowly cooled to 28 ° C and stirred for 3 h.filter,Collecting white solids,Washed twice in cold water and dried.217.0 g of white solid 2-chloro-5-bromo-benzoic acid were obtained.The yield was 92.1percent and the purity was 99.9percent (HPLC).
Reference：
[1] Patent: CN108250060, 2018, A, . Location in patent: Paragraph 0016; 0059-0062
7
[ 89-55-4 ]
[ 62176-31-2 ]
Reference：
[1] Patent: WO2011/38572, 2011, A1,
[2] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 17, p. 4034 - 4038
[3] Bioorganic and Medicinal Chemistry Letters, 2019, vol. 29, # 2, p. 212 - 215
8
[ 67-56-1 ]
[ 89-55-4 ]
[ 4068-76-2 ]
Yield
Reaction Conditions
Operation in experiment
89%
at 0 - 70℃; for 40 h; Heating / reflux
Intermediate III: 6- (aminomethyl)-2,2-dimethyl-4H-1,3-benzodioxin-4-one; Step a) Formation of methyl-5-bromosalicylate; To a solution of 5-BROMOSALICYLIC acid (200 G, 0.92 mol) in METHANE . (2 L) was added thionylchloride (440 g, 3.7 mol) at 0°C with stirring and then allowed to reflux at 70°C for 40H. Excess solvent was distilled off and to the crude residue was added EtOAc (2 L). The organic layer was washed with 10percent cold aqueous NAHC03 solution (2X1 L), brine and dried. The solvent was removed UNDER vacuum to give the title compound as a low melting point solid (190 g, 89percent). TLC: PetEther/EtOAc, 7:3, Rf: 0.6
89%
at 0 - 70℃; for 40 h; Heating / reflux
To a solution of 5-bromosalicylic acid (200 g, 0.92 mol) in methanol (2 L) was added thionylchloride (440 g, 3.7 mol) at 0°C with stirring and then allowed to reflux at 70°C for 40h. Excess solvent was distilled off and to the crude residue was added EtOAc (2 L). The organic layer was washed with 10percent cold aqueous NaHCO3 solution (2 x 1 L), brine and dried. The solvent was removed under vacuum to give the title compound as a low melting point solid (190 g, 89percent). TLC: PetEther/EtOAc, 7: 3, Rf: 0. 6
81%
for 12 h; Reflux
5-Bromo-2-hydroxybenzoic acid (2.17 g, 10 mmol) was dissolved in methanol (50 ml_) and sulfuric acid (100percent, 1 ml_) and heated at rx for 12 h. After cooling and neutralization (NaHCO3, aq, sat), the white precipitate was filtered off and washed with water and dried, furnishing 1.92 g (81percent) of intermediate I.
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 10, p. 2621 - 2625
[2] Journal of Materials Chemistry, 1996, vol. 6, # 8, p. 1297 - 1307
[3] Organic Letters, 2014, vol. 16, # 19, p. 5140 - 5143
[4] Patent: WO2005/12280, 2005, A1, . Location in patent: Page/Page column 46-47
[5] Patent: WO2005/11685, 2005, A1, . Location in patent: Page/Page column 41
[6] Organic Letters, 2009, vol. 11, # 21, p. 4790 - 4793
[7] Journal of the American Chemical Society, 2001, vol. 123, # 43, p. 10429 - 10435
[8] Patent: WO2009/138758, 2009, A2, . Location in patent: Page/Page column 73
[9] Journal of Fluorine Chemistry, 1995, vol. 74, p. 69 - 76
[10] Gazzetta Chimica Italiana, 1886, vol. 16, p. 402
[11] Journal of Medicinal Chemistry, 1992, vol. 35, # 2, p. 310 - 319
[12] Synthetic Communications, 2000, vol. 30, # 4, p. 689 - 699
[13] Journal of Organic Chemistry, 2007, vol. 72, # 2, p. 583 - 588
[14] Angewandte Chemie, International Edition, 2009, vol. 48, # 23, p. 4226 - 4228
[15] Journal of Medicinal Chemistry, 2011, vol. 54, # 6, p. 1555 - 1564
[16] Medicinal Chemistry Research, 2014, vol. 23, # 7, p. 3274 - 3286
[17] Polyhedron, 2017, vol. 128, p. 18 - 29
[18] Journal of the American Chemical Society, 2018, vol. 140, # 9, p. 3412 - 3422
Reference：
[1] Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1928, vol. 186, p. 1130
11
[ 89-55-4 ]
[ 6329-74-4 ]
Yield
Reaction Conditions
Operation in experiment
82%
Stage #1: With sulfuric acid In butan-1-ol for 48 h; Heating / reflux Stage #2: With ammonia In methanol at 20℃; for 48 h;
A. 5-bromo-2-hydroxybenzamide; 0 OH 0 OH 1. n-butanol, H2SO4, reflux HO X 2. NH3, MeOH H2N 82percent Br Br To a stirred solution of 5-Bromosalicyclic acid (30 g, 135.5 mmol) in n-butylalcohol (60 mL) was added H2SO4 (95.6percent, 289 L, 5.42 mmol) in a 100 ml round bottom flask connected by a Dean-Stark trap/reflux condenser that was filled with 12 ml of n-butylalcohol. After heated to reflux for 2 days, the reaction was cooled down to R. T. and concentrated to give a pale yellow oil. The mixture was added 50 mL MeOH, followed by NH3 in MeOH (7 N, 116 mL). The reaction was stirred at R. T. for another 2 days, monitored by HPLC. After the reaction complete, it was concentrated to give a white solid. The crude solid was washed with small amount of EtOAc and hexane to afford 24 g of the product as a white crystalline solid (82percent yield).
23%
Stage #1: at 80℃; for 4 h; Stage #2: With ammonium hydroxide In tetrahydrofuran at 20℃; for 2 h;
A solution of 5-bromo-2-hydroxybenzoic acid (20 g, 92.16 mmol, 1.00 equiv) in thionyl chloride (50 mE) was stirred at 80° C. for 4 h. The mixture was concentrated under vacuum. Then the residue was added to a solution of ammonia (50 mE) in tetrahydrofuran (50 mE) and stirred at room temperature for 2 h. Ethyl acetate (50 mE) was added to the reaction. The solid was filtered out. The filtrate was concentrated under vacuum and purified by Si02 chromatography eluted with ethyl acetate/petroleum ether (1:5) to afford 4.5 g (23percent) of 5-bromo-2-hydroxybenzamide as a yellow solid. EC-MS: mlz=216 [M+H].
Reference：
[1] Patent: WO2005/95326, 2005, A2, . Location in patent: Page/Page column 253
[2] Patent: US2018/64726, 2018, A1, . Location in patent: Paragraph 0360; 0361
[3] Chemical and Pharmaceutical Bulletin, 1996, vol. 44, # 4, p. 734 - 745
[4] Patent: US2006/14737, 2006, A1, . Location in patent: Page/Page column 25
12
[ 89-55-4 ]
[ 1285515-21-0 ]
Reference：
[1] Patent: WO2011/38572, 2011, A1,
[2] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 17, p. 4034 - 4038
[3] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 17, p. 4034 - 4038
[00347] To a solution of Example 33a (20 g, 92.1 mmol) in DCM (150 mL) was added SOCl2 (13 g, 110.6 mmol) and DMF (1 mL). The mixture was heated to 50C and stirred for 2 h. After cooling to room temperature, the mixture was concentrated. MeOH (100 mL) was added into the mixture, which was stirred for another 30 min. The solvent was removed to give the desired product Example 33b (21 g, yield 100%) as a white solid. LCMS [M+l]+ =231.0/233.0
89%
With thionyl chloride; at 0 - 70℃; for 40h;Heating / reflux;
Intermediate III: 6- (aminomethyl)-2,2-dimethyl-4H-1,3-benzodioxin-4-one; Step a) Formation of methyl-5-bromosalicylate; To a solution of 5-BROMOSALICYLIC acid (200 G, 0.92 mol) in METHANE . (2 L) was added thionylchloride (440 g, 3.7 mol) at 0C with stirring and then allowed to reflux at 70C for 40H. Excess solvent was distilled off and to the crude residue was added EtOAc (2 L). The organic layer was washed with 10% cold aqueous NAHC03 solution (2X1 L), brine and dried. The solvent was removed UNDER vacuum to give the title compound as a low melting point solid (190 g, 89%). TLC: PetEther/EtOAc, 7:3, Rf: 0.6
89%
With thionyl chloride; at 0 - 70℃; for 40h;Heating / reflux;
To a solution of 5-bromosalicylic acid (200 g, 0.92 mol) in methanol (2 L) was added thionylchloride (440 g, 3.7 mol) at 0C with stirring and then allowed to reflux at 70C for 40h. Excess solvent was distilled off and to the crude residue was added EtOAc (2 L). The organic layer was washed with 10% cold aqueous NaHCO3 solution (2 x 1 L), brine and dried. The solvent was removed under vacuum to give the title compound as a low melting point solid (190 g, 89%). TLC: PetEther/EtOAc, 7: 3, Rf: 0. 6
81%
With sulfuric acid; for 12h;Reflux;
5-Bromo-2-hydroxybenzoic acid (2.17 g, 10 mmol) was dissolved in methanol (50 ml_) and sulfuric acid (100%, 1 ml_) and heated at rx for 12 h. After cooling and neutralization (NaHCO3, aq, sat), the white precipitate was filtered off and washed with water and dried, furnishing 1.92 g (81%) of intermediate I.
With sulfuric acid; for 22h;Reflux;
Into a 250 ml round-bottom flask was charged 5-bromosalicylicacid (20 g, 92.16 mmol), methanol (110 ml) and concentratedH2SO4 (12 ml). The mixture was stirred under reflux for 22 h. Uponcooled to room temperature, the precipitated white solid, viz.methyl 5-bromosalicylate, was filtered by suction, and washedwith cold methanol solvent, which was directly used for the nextstep without further purification (18.0 g, 84.7%).
With thionyl chloride; at 0 - 65℃; for 48.16h;
General procedure: Methyl 4-bromosalicylate (1 mol) was dissolved in methanol(25 mL), and thionyl chloride was added dropwise under ice-cooling,after 10 min, The mixture was stirred at 65 C for 48 h. and monitoredby TLC. After the reaction was completed, excess methanol was evaporated,the residue was extracted with ethyl acetate and aqueous sodiumcarbonate, and the organic phase was added to anhydrous sodiumsulfate and concentrated to obtain intermediate 6a.The compounds 6b-6h were prepared analogously.
With nitric acid; In water; acetic acid; at 20℃; for 2.83333h;Cooling with ice;
A reaction flask was added 20 g 5-bromo-salicylic acid, 100 ml of glacial acetic acid, glacial acetic acid under ice-cooling with stirring until solidification begins. The 7.8 g of 90% fuming nitric acid was mixed with 6 ml of glacial acetic acid, pressure-equalizing dropping funnel was added, the ice bath was removed, the water bath at room temperature slowly dropwise to the reaction flask. About 20 minutes after the addition was complete, Stirring was continued in room temperature water for 150 minutes. Completion of the reaction, the system was poured into 120 ml of crushed ice and stirred for 30 minutes. Filtered, washing the filter cake overnight at 50 C and dried. Crude ethanol - water of crystallization in a bright yellow solid 15.4 g, yield 64.3%
Example 11 Synthesis of 4-bromo-2-hydroxymethylphenol Under ice cooling, the solution of 5-bromosalicylic acid (21.7 g) in ether (200 ml) was slowly added dropwise to the suspension of LiAlH4 (5.7 g) in ether (200 ml). After stirring at room temperature for 30 minutes, the reaction solution was slowly poured into 3N HCl with floating ice for extraction with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The oily residue generated after the evaporation of the solvent under reduced pressure was crystallized from ether-hexane, and the crystal was filtered, to give the title compound (15.5 g; 76.5%).
60%
Step 3 4-Bromo-2-(hydroxymethyl)phenol: A solution of 5-bromo-2-hydroxybenzoic acid (21.7 g; 100 mmol; 1.00 equiv) in tetrahydrofuran (200 mL) was added to a suspension of lithium aluminum hydride (5.7 g; 150 mmol; 1.50 equiv) in tetrahydrofuran (100 mL). The suspension was virgously stirred for about 16 hours at ambient temperature and then quenched by adding 3M hydrochloric acid (300 mL). Following standard extractive workup with ethyl acetate, the crude residue was re-crystallized from ethyl acetate/hexane (1/10) to give the title product as gray solid (12.4 g; 60% yield). 1H NMR (400 MHz, CDCl3) 6: 9.68 (s, 1H), 7.39 (s, 1H), 7.19 (dd, J=2.0, 2.0 Hz, 1H), 6.72 (d, J=8.4 Hz, 1H), 5.10 (s, 1H), 4.44 (s, 2H).
5-Bromosalicylicacid (5 mmol of) was dissolved in 15mL of distilled water, 37 C water bath, adjusted with 30% NaOH solution to pH 10, stirred for 30min, slowly added dropwise 2 mL of dimethyl sulfate, to the reaction the solution becomes pH 7, then 30% NaOH solution was adjusted to pH 10, reaction I h, dimethyl sulfate dropwise slowly again I mL, the reaction solution until the pH becomes 7, and then 30% NaOH solution pH was adjusted to 10, the reaction I h, at 80 C for hydrolysis water bath 15 min, TLC monitoring progress of the reaction (eluent, ethyl acetate: petroleum ether = 1: 1~1: 4), cooled to room temperature, adjusted with 10% HCl a pH of 5, a white precipitate formed, the precipitate was washed with distilled water, and the precipitate was dried in vacuo; the dried precipitate was dissolved in IOmL of dichloromethane, was added two drops of DMF and 0.5mL of thionyl chloride, 40 C oil bath and heated to reflux for 0.5 H, methylene chloride was distilled off under reduced pressure, and thionyl chloride, dissolved in IOmL of acetone, was added 5,6,7-trimethoxy-1 obtained in Example 4 '- hydroxyflavone 80mg, ImL of triethylamine was added dropwise reaction 3 h, filtration, recovery of acetone, purified by silica gel column chromatography, eluent: ethyl acetate: petroleum ether = 1: 1~1: 4, to give compound 4- (trimethyl 5,6,7_ oxo-4 -4H- chromen-2-yl) phenyl 2-methoxy-5-bromo benzoate. As a yellow powder in 50% yield.
With tetrapropylammonium nonabromide In dichloromethane at 23℃; for 0.5h; Inert atmosphere;
Brominations with Pr4NBr9; General Procedure A
General procedure: A round-bottom flask equipped with a magnetic stir bar and a rubber septum was charged with Pr4NBr9 (0.66 mmol, 0.33 mol%) and CH2Cl2 (1 mL). The homogeneous solution was stirred and cooled to 0 °C if not described otherwise (partial precipitation of the nonabromide can occur at this point). The substrate (2.0 mmol, 1.0equiv) was added and the reaction allowed to warm to 23 °C (attention: exothermic reaction) After the reported reaction time the dark-red color of the nonabromide had vanished and TLC control showed completion of the reaction. The reaction was quenched by addition of sat. aq Na2S2O3 (2 mL) and transferred to a separation funnel. H2O was added (15 mL) followed by extraction with Et2O (4 × 20 mL) if not described otherwise. The organic layers were combined, washed with H2O (4 × 15 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to give the crude product.
93.1%
With sodium vanadate; aluminum tri-bromide; tetrabutylammomium bromide; oxygen In 1,4-dioxane; water at 80℃; for 8h;
3 Example 3
This example is the preparation of 2-hydroxy-5-bromo-benzoic acid, and the specific method is as follows:To a 5 L three-necked flask was added 12.2 g of sodium metavanadate (0.1 mol),26.7 g of aluminum tribromide (0.1 mol) and 338.0 g of tetrabutylammonium bromide (1.05 mol),Then fill with oxygen,Then add 138.0 g of salicylic acid (1.0 mol),2 L of 1,4-dioxane and 1.8 g of water (0.1 mol),Heat to 80 ° C and stir the reaction for 8 h.Oxygen is replenished at the appropriate time during the reaction.The end-of-control reaction in HPLC was completed, and the ratio of 2-hydroxy-5-bromo-benzoic acid to 2-hydroxy-3-bromo-benzoic acid was about 24:1.The reaction system was cooled to room temperature, then 1N hydrochloric acid was added, and then extracted with ethyl acetate (1 L×2), organicAfter the layers were combined, the mixture was washed successively with water and saturated brine, and the solvent was evaporated under reduced pressure, and then a solvent mixture of ethanol/tetrahydrofuran (volume ratio 1:5) was added, the mixture was heated to 70 ° C, stirred and dissolved, and finally slowly cooled to room temperature, and stirred for crystallization. Filtration and drying gave 202.0 g of white solid 2-hydroxy-5-bromo-benzoic acid in a yield of 93.1% and a purity of 99.3% (HPLC).
89%
With 1-butyl-3-methylpyridinium tribromide at 20℃; for 1h;
89%
Stage #1: salicylic acid With sulfuric acid In acetonitrile at 20℃; for 0.0833333h;
Stage #2: With N-Bromosuccinimide In acetonitrile at 20℃; for 0.5h; regioselective reaction;
Representative procedure for the preparation of compound 11a
General procedure: To a solution of phenol (470.6 mg, 5 mmol) in MeCN (10 mL) was added con. H2SO4 (285 μL, 1.05 equiv.) at room temperature, the mixture was stirred for 5 min. Then, NBS (934.4 mg, 1.05 equiv.) was added to the mixture. The reaction was monitored using TLC analysis. The mixture was evaporated to dryness. H2O (15 mL) was added to the residue and extracted with CH2Cl2 (3 x 15 mL). The combined organic layers were washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure to afford the crude product. The major product was isolated using silica gel chromatography to obtain the product as light yellow liquid; yield: 79% (0.69 g).
85%
With N-Bromosuccinimide; N-methoxy-n-butylsulfonamide In n-heptane at 25℃; for 6h; Darkness;
82%
With bis(trifluoroacetoxy)iodobencene; trimethylsilyl bromide In dichloromethane at 20℃; Inert atmosphere;
80%
With potassium bromide In acetonitrile at 20℃; for 5h;
79%
With N-benzyl-N,N-dimethyl anilinium peroxodisulfate; potassium bromide In acetonitrile for 6h; Reflux; regioselective reaction;
75%
With N-bromophthalimide; mercury(II) diacetate; acetic acid In water at 20℃;
70%
With benzyltriphenylphosphonium peroxodisulfate; potassium bromide In acetonitrile for 6.5h; Heating;
68%
With potassium hydrogensulfate; potassium bromide; isoquinolinium chlorochromate In water at 20℃; Sonication; regioselective reaction;
General Procedure for Ultrasonically Assisted Halogenation Reactions
General procedure: The general method for ultrasonically assisted brominationreaction is almost similar to conventional reaction as mentionedabove. A centimolar (0.01 mol) organic substrate (phenols,anilines, or acetanilides), 0.001 mol potassium halide(KBr), about 50 mg of dilute KHSO4, and hypervalent Cr(VI) reagent (IQCC or IQDC) were suspended in about30 mL solvent (DCE or ACN) in a previously cleaned roundbottom(R.B) flask placed in a sonicator. The reaction mixtureis sonicated at room temperature about 30-40 min. Progressof the reaction was monitored by TLC technique. Workupprocedure after completion of the reaction mixture is similarto the one described previously.
35%
With potassium bromate In sulfuric acid; water; acetic acid for 0.0833333h; Heating;
34%
With trimethylsilyl bromide; bis(4-chlorophenyl)sulfoxide In acetonitrile at 35℃; for 12h; Inert atmosphere; regioselective reaction;
With bromine; potassium bromide In water at 25℃; pH 4.5; var. pH, pH-rate profile;
With bromine
With carbon disulfide; bromine
With sulfuric acid; bromine; acetic acid
With phosphorus pentabromide Behandeln des Reaktionsprodukts mit Wasser;
With sodium carbonate durch Bromierung;
With hydrogen bromide; dihydrogen peroxide
With bromine; acetic acid
With bromine; acetic acid
With N-Bromosuccinimide In acetonitrile at 30℃; for 0.05h; UV-irradiation;
With potassium bromate; sulfuric acid; potassium bromide In water at 25℃;
With sulfuric acid; bromine at 20 - 60℃; for 1h;
2 Example 2: Preparation of 5-Bromosalicylic Acid
[0131] Salicylic acid (6.0 g, 43.47 mmol) and concentrated sulfuric acid (98%, 21 .5 mL) were charged into a 250 mL three-necked flask equipped with a (0586) temperature probe, heating mantle, overhead stirrer, and an inlet for a Teflon needle/syringe pump to deliver bromine. Stirring was commenced to dissolve the salicylic acid, which was slightly exothermic. Once the mixture reached ambient temperature, the syringe was loaded with a slight excess of bromine to ensure delivery of 0.575 equivalents over 5 minutes. As bromine was added to the rapidly stirred solution, a slight exotherm was observed. Once the addition was complete, the reaction mixture was stirred for an additional five minutes before heating to 60 °C, which required about 15 minutes. The reaction mixture was stirred at 60 °C for a total of 60 minutes, then allowed to cool to ambient temperature. Ice water (about 100 g) was slowly added to the reaction mixture, which caused a white solid to form. During the ice water addition, the temperature rose to about 50 °C to 60 °C. The reaction mixture was cooled in an ice bath to 10°C, then filtered through a sintered glass funnel. The precipitate was washed with 4 x 30 mL of cold water, re-suspending the cake each time before extracting the water wash. The cake was air dried for 30 minutes, then dried in vacuo (55 °C) overnight to afford the title compound as a white solid (8.7 g, 92%). RP-HPLC (315 nm) and 1 H NMR (600 MHz, DMSO-d6) indicated the crude material had the following composition: 5-bromosalicylic acid (96%), 3- bromosalicylic acid (0.4%) and 3,5-dibromosalicylic acid (3.5%). (0587) [0132] Analytical data for 5-bromosalicylic acid: 1 H NMR (600 MHz, DMSO- d6) δ 1 1 .9-10.9, 7.85, 7.65, 6.95. LCMS (ESI) m/z 214.9 (M-H).
Stage #1: salicylic acid With sulfuric acid at 5℃; for 0.5h;
Stage #2: With bromine
1 Example 1
90kg of salicylic acid was dissolved in 900kg of 98% sulfuric acid at 5 ° C, and kept for 30 minutes until dissolved.Add 63.6 kg of bromine to form 5-bromosalicylic acid, raise the temperature to 35 ° C to pass chlorine, synthesize 5-bromo-3-chlorosalicylic acid, add 360 kg of sulfur trioxide, 4.5 kg of iodine, and keep the reaction at 50 ° C for 5 -Bromo-3,6-dichlorosalicylic acid,After the reaction is completed, dilute the fuming sulfuric acid to sulfurThe acid concentration was 30%, washed with water and dried to obtain 5-bromo-3,6-dichlorosalicylic acid. (from salicylic acid to 5-bromo-3,6-dichlorosalicylic acid yield of 75%)
With sulfuric acid; bromine at 5 - 20℃; for 2h;
1; 2; 3; 4
1000g at 5 ° C Put 138g of salicylic acid into 95% sulfuric acid, 80g of bromine was slowly added dropwise, and the temperature was raised to 20 ° C for 2 h after the addition. When the temperature is raised to 45 ° C, chlorine gas is introduced, and when 5-bromo-3-chlorosalicylic acid is formed in the middle, Stop chlorine, slowly add 400g of sulfur trioxide, Add 0.15g of iodine, maintain the temperature at 35 ° C, and start to pass chlorine gas. When all of the intermediate control produced 5-bromo-3,6-dichlorosalicylic acid, the chlorine gas was stopped. Pour the reaction solution into ice water and dilute the sulfuric acid concentration to 30%. Filtration, washing with water to obtain 5-bromo-3,6-dichlorosalicylic acid. The yield was 75.0%, and the purity was 90.2% (calculated as salicylic acid).
With sulfuric acid; hydrogen bromide at 5 - 20℃; for 2h; Large scale;
1-4 Example 2
138 g of salicylic acid was added to 1000 g of 95% sulfuric acid at 5 ° C.Slowly pass 80g of hydrogen bromide, and after warming up, heat up to 20 °C for 2h.When the temperature is raised to 45 ° C, chlorine gas is introduced, and when 5-bromo-3-chlorosalicylic acid is formed in the middle,Stop chlorine,Slowly add 400g of sulfur trioxide, add 0.15g of iodine, maintain the temperature of 35 ° C,When chlorine gas is introduced, and 5-bromo-3,6-dichlorosalicylic acid is formed in the middle,Stop introducing chlorine. Pour the reaction solution into ice water and dilute the sulfuric acid concentration to 30%.Filtration, washing with water to obtain 238.1 g of 5-bromo-3,6-dichlorosalicylic acid.The yield was 75.3% and the purity was 90.1%.
With sulfuric acid; hydrogen bromide at 5 - 20℃; for 2h;
1-6 Example 4
1000g at 5 ° C Put 138g of salicylic acid into 95% sulfuric acid,Slow drop access81.0 g of hydrogen bromide gas was heated to 20 ° C for 2 h after the completion of the reaction.Warming up to 40 ° C, starting to pass chlorine gas,Central control all generatedWhen 5-bromo-3-chlorosalicylic acidStop chlorine,Slowly add 400gSulfur trioxide, added 0.15gIodine, maintaining the temperature at 35 ° C,When chlorine gas is introduced and all of 5-bromo-3,6-dichlorosalicylic acid is produced in the middle,Stop introducing chlorine. Pour the reaction solution into ice water and dilute the sulfuric acid concentration to30%, filtered, washed with water to obtain 238.9 g of 5-bromo-3,6-dichlorosalicylic acid.Yield 75.3%, 5-bromo-3,6-dichlorosalicylic acidThe content is 90.2%.
With sulfuric acid; bromine at 5 - 20℃; for 2h;
1-6 Example 1
138 g of salicylic acid was added to 1000 g of 95% sulfuric acid at 5 ° C.Slowly add 80.0g of bromine,After the addition is completed, the temperature is raised to 20 ° C for 2 h.Warming up to 40 ° C, starting to pass chlorine gas,When all of the control produces 5-bromo-3-chlorosalicylic acid, the chlorine is stopped.Slowly add 400g of sulfur trioxide,Add 0.15g of iodine, maintain the temperature at 35 ° C, and start to pass chlorine gas.When the central control produces all 5-bromo-3,6-dichlorosalicylic acid,Stop introducing chlorine.Pour the reaction solution into ice water, dilute the sulfuric acid concentration to 30%, filter,The mixture was washed with water to obtain 237.8 g of 5-bromo-3,6-dichlorosalicylic acid.The yield was 75.0%, and the 5-bromo-3,6-dichlorosalicylic acid content was 90.2%.
[0133] Salicylic acid was brominated with molecular bromine as described in Example 2 except that the reagent equivalents and heating time and temperature upon completion of bromine addition were varied as indicated in Table 3-A below. Table 3-A also reports the salicylic acid ("SA"), 3-bromosalicylic acid ("3-Br-SA"), 5- bromosalicylic acid ("5-Br-SA), and 3,5-dibromosalicylic acid ("3,5-Br2-SA") present in the resulting crude material as determined by RP-HPLC peak areas (which were adjusted using response factors of the respective analytes below). (0590) Table 3-A (0591) (0592) [0134] Conditions A, B, and C referenced in Table 3-A are more fully described in Table 3-B below. (0593) Table 3-B
With zinc(II) chloride; trichlorophosphate; at 75℃;Microwave irradiation;
General procedure: The synthesis refers to a procedure described in the literature [43]. To a 50-mL flask 8mL phosphorus oxychloride (POCl3) and anhydrous zinc chloride (6.8g, 0.05mol) were added. The suspension was stirred at 70C until ZnCl2 was completely dissolved into phosphorus oxychloride. The mixture was then cooled down to room temperature (r.t.). Afterwards, salicylic acids (1a-i) (l.0mmol) and 1,3,5-trihydroxybenzene (1.1mmol) were added, respectively, and the mixture was heated with microwave reactor with a programmed procedure of 75C for 30min, where the power was 200W. Then the mixture was cooled down to r. t. and pulled into ice water stirring for 20min. The mixed solution was filtered, washed with cold water. The solid residues were collected and purified by flash column liquid chromatography.
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 phosphorous pentoxide p-toluenesulfonic acid; at 80℃; for 1.5h;
3.15 g of phloroglucinol and 6.51 g of 5-bromosalicylic acid were placed in a round bottom flask, and the Eaton reagent was slowly added under stirring, and reacted at 80 C for 90 minutes.After the reaction was completed, it was cooled to room temperature, and the reaction solution was poured into ice water and vigorously stirred for 2 hours.An orange-red solid precipitated. The filtered solid was washed several times with distilled water, dried and purified by silica gel column chromatography.
With potassium carbonate; In water; at 20℃; for 4h;Green chemistry;
General procedure: A 50 mL flask was charged with an aryl halide (1.0 mmol), anaryl boronic acid (1.2 mmol), K2CO3 (2.0 mmol), nanocatalyst(0.05 mol% Pd) and deionized water (5 mL). The reactionwas stirred at room temperature for 4 h. The progress ofthe reaction was monitored by thin-layer chromatography After the reaction was completed, distilled water (25 mL) wasadded to the mixture and dilute 2 mol/L HCl was added dropwiseto pH 3.0-4.0 with stirring, and the mixture was heatedto 100 C for 10 min. The white solid that had formed wasfiltered off and washed with hot water. After drying, it wasdissolved in ether (5 mL) and was rapidly separated using asilica gel column. Elution with ether left behind small amountsof impurities and traces of palladium black to give a crudeproduct. The ether solution was evaporated to 3-5 mL andrecrystallized to obtain a pure product. All the products 3a-uare known compounds and were characterized by comparingtheir melting points and 1H NMR spectra with those preparedrecently by using a water-soluble glycine-based Pd catalyst,PdCl2(NH2CH2CO2H)2.10 The melting points and 1H NMRdata of 3a-u are listed in the supplemental material.
With potassium carbonate; In water; at 20℃; for 4h;Green chemistry;
General procedure: A 50 mL flask was charged with an aryl halide (1.0 mmol), anaryl boronic acid (1.2 mmol), K2CO3 (2.0 mmol), nanocatalyst(0.05 mol% Pd) and deionized water (5 mL). The reactionwas stirred at room temperature for 4 h. The progress ofthe reaction was monitored by thin-layer chromatography After the reaction was completed, distilled water (25 mL) wasadded to the mixture and dilute 2 mol/L HCl was added dropwiseto pH 3.0-4.0 with stirring, and the mixture was heatedto 100 C for 10 min. The white solid that had formed wasfiltered off and washed with hot water. After drying, it wasdissolved in ether (5 mL) and was rapidly separated using asilica gel column. Elution with ether left behind small amountsof impurities and traces of palladium black to give a crudeproduct. The ether solution was evaporated to 3-5 mL andrecrystallized to obtain a pure product. All the products 3a-uare known compounds and were characterized by comparingtheir melting points and 1H NMR spectra with those preparedrecently by using a water-soluble glycine-based Pd catalyst,PdCl2(NH2CH2CO2H)2.10 The melting points and 1H NMRdata of 3a-u are listed in the supplemental material.
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 6h;
Take compound V-1 (1.085 g, 5 mmol)Soluble in N,N-dimethylformamide (27.77 mL, 0.18 M),Potassium carbonate (3.455 g, 25 mmol) was added in that order.Methyl iodide (933 muL, 15 mmol).Stir at room temperature for 6 h,TLC showed the end of the reaction.The reaction solution was poured into ice water (138 mL).Extracted with ethyl acetate (20 mL x 3),Combine the organic phases, wash with water (30mL x 2),Saturated saline solution (30mL x 2),Dry over anhydrous sodium sulfate. Evaporate the solvent under reduced pressure.The residue was subjected to column chromatography ( petroleum ether: ethyl acetate = 30:1)Purification of Compound V-2 (colorless oil, 1.164 g, yield 95%).
With sulfuric acid; bromine; acetic acid; at 30℃; for 2h;
[0133] Salicylic acid was brominated with molecular bromine as described in Example 2 except that the reagent equivalents and heating time and temperature upon completion of bromine addition were varied as indicated in Table 3-A below. Table 3-A also reports the salicylic acid ("SA"), 3-bromosalicylic acid ("3-Br-SA"), 5- bromosalicylic acid ("5-Br-SA), and 3,5-dibromosalicylic acid ("3,5-Br2-SA") present in the resulting crude material as determined by RP-HPLC peak areas (which were adjusted using response factors of the respective analytes below). (0590) Table 3-A (0591) (0592) [0134] Conditions A, B, and C referenced in Table 3-A are more fully described in Table 3-B below. (0593) Table 3-B
With sulfuric acid; bromine; acetic acid; at 30 - 60℃; for 0.5h;
[0133] Salicylic acid was brominated with molecular bromine as described in Example 2 except that the reagent equivalents and heating time and temperature upon completion of bromine addition were varied as indicated in Table 3-A below. Table 3-A also reports the salicylic acid ("SA"), 3-bromosalicylic acid ("3-Br-SA"), 5- bromosalicylic acid ("5-Br-SA), and 3,5-dibromosalicylic acid ("3,5-Br2-SA") present in the resulting crude material as determined by RP-HPLC peak areas (which were adjusted using response factors of the respective analytes below). (0590) Table 3-A (0591) (0592) [0134] Conditions A, B, and C referenced in Table 3-A are more fully described in Table 3-B below. (0593) Table 3-B
1%Chromat.; 96%Chromat.; 3%Chromat.
With sulfuric acid; bromine; at 3 - 25℃; for 1.5h;
Into a 4-necked 500 mL glass reactor was placed 96% H2SO4 (129 mL), followed by cooling to 3C in an ice bath. Salicylic acid (40 g, 290 mmol, 1.0 equiv.) was added in portions with stirring, followed by dropwise addition of bromine (8.17 mL, 160 mmol, 0.55 equiv) over 30 min with stirring. After slowly warming to 25C over 30 min, the mixture was stirred at 25C for another 30 min. The above reaction mixture was placed under vacuum (25-30 mm Hg) for 1.5 h to remove excess bromine. HPLC: 96% 5-BSA, 3% 3,5-DBSA, and 1.0% 3-BSA. The above mixture was cooled to 3C, and 65% oleum (37 mL) was added dropwise over 50 min while maintaining temperature at less than 10C. After complete addition (now at 2% oleum), the mixture was warmed to 45C and chlorine gas was continuously bubbled into the reaction mixture using a sparging tube for 8.5 h. HPLC: BCSA (85.5%), sulfonic acid 1 (3.7%), 3-BSA (0.2%), 5-BSA (1.7%), 3,5-DBSA (7.5%). The above mixture was cooled to 5C before 65% oleum (89 mL) was added dropwise while maintaining temperature at less than 10C. After complete addition (now at 25% oleum), iodine (551 mg, 2.17 mmol, 0.75 mol%) was added to the mixture and the temperature was raised to 35C. Chlorine gas was continuously bubbled into the mixture for 3.5 h. The mixture was cooled to 5C, and 75% H2SO4 (125 mL) was added slowly dropwise while maintaining <15C temperature. CAUTION: After the addition of ca. 65 mL of 75% sulfuric acid, significant effervescence (HCl) took place. After complete addition, the reaction mixture was filtered, and the filter cake was washed with four 80 mL portions of 75% sulfuric acid. The wet cake was partitioned between ethyl acetate (400 mL) and water (70 mL). The organic layer was washed with water (50 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to afford 68.7 g (84%) of crude BDCSA as a lt. yellow solid: HPLC: BDCSA (84%), sulfonic acid (1.8%), 3,5,6-TCSA (4.6%), 7.0% DBCSA (7.0%), BCSA (2.5%), ester 2 (0.4%). NOTE: The italicized procedure above was conducted to illustrate the yield and purity of BDCSA. In a normal run, the ethyl acetate solution of BDCSA was carried directly into the hydrodebromination below. BDCSA: 1H NMR (DMSO-d6, 600 MHz) d 7.92 (s, 1H). Low resolution MS (ESI-) m/z 282.8 [M-H]- 3-Bromo-6-((3-bromo-2,5-dichloro-6-hydroxybenzoyl)oxy)-2,5-dichlorobenzoic acid (2): 1H NMR (DMSO-d6, 300 MHz) d 8.29 (s, 1H), 8.09 (s, 1H). Low resolution MS (ESI-) m/z 548.7 [M-H]-
With potassium carbonate; In water; at 20℃; for 4h;Green chemistry;
General procedure: A 50 mL flask was charged with an aryl halide (1.0 mmol), anaryl boronic acid (1.2 mmol), K2CO3 (2.0 mmol), nanocatalyst(0.05 mol% Pd) and deionized water (5 mL). The reactionwas stirred at room temperature for 4 h. The progress ofthe reaction was monitored by thin-layer chromatography After the reaction was completed, distilled water (25 mL) wasadded to the mixture and dilute 2 mol/L HCl was added dropwiseto pH 3.0-4.0 with stirring, and the mixture was heatedto 100 C for 10 min. The white solid that had formed wasfiltered off and washed with hot water. After drying, it wasdissolved in ether (5 mL) and was rapidly separated using asilica gel column. Elution with ether left behind small amountsof impurities and traces of palladium black to give a crudeproduct. The ether solution was evaporated to 3-5 mL andrecrystallized to obtain a pure product. All the products 3a-uare known compounds and were characterized by comparingtheir melting points and 1H NMR spectra with those preparedrecently by using a water-soluble glycine-based Pd catalyst,PdCl2(NH2CH2CO2H)2.10 The melting points and 1H NMRdata of 3a-u are listed in the supplemental material.
5-bromo-N-(4-fluoro-benzyl)-2-hydroxybenzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
62%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 0 - 20℃;
General procedure: To a solution of intermediate 7 (0.4 g, 1.63 mmol), HOBt (0.441 g, 3.26 mmol) and Et3N (0.45 mL, 3.26 mmol) in DCM (20 mL) was added EDCI (0.344 g, 1.8 mmol) at 0 C. 4-Fluorobenzylamine (0.20 mL, 1.8 mmol) was then added and the reaction mixture stirred overnight at room temperature. The reaction mixture was extracted with ethyl acetate, washed with dilute hydrochloric acid and sodium bicarbonate solution. The organic layer was further washed with brine and dried over sodium sulfate. The resulting crude was purified by recrystalization with ethyl acetate/hexane to give a yellow solid.
With n-butylstannoic acid; In toluene; at 110℃; for 12h;Dean-Stark;
General procedure: To a 250 mL three-necked reaction flask equipped with an agitator, Dean-Stark trap with a reflux condenser, temperature sensor, added 50 mL toluene, phenylacetic acid (2.5 g, 19.68 mmol), benzylamine (1.96 g, 19.68 mmol) and catalyst (0.82 g, 18 mol %). The mixture was stirred under gentle reflux at 110 C in an oil bath. Water collected in the Dean-Stark trap, and the progress of the reaction was monitored by TLC. After consumption of starting materials, the reaction mixture was concentrated under reduced pressure to recovered 40 mL of toluene. The mixture was cooled to 20-25 C to this added 100 mL hexane and stirred for 2 h. The precipitated solid was filtered. Solid containing product and the catalyst washed with 25 mL NaHCO3 (5%) solution, 25 mL of water and dried in an oven at 60 C for 3 h. Dried solid extracted with acetone or methanol and filtered to separate the catalyst and filtrate containing amide was concentrated under reduced pressure to afford target amide, 2a as white solid, 4.01 gm, yield 97%. Similarly, the scalability of the reaction was assessed, phenylacetic acid 25 gm (183 mmol) with benzylamine 19.68 gm (183 mmol) and 18 mol % of n-butyl stannoic acid (6.9 g, 33 mmol) in 500 mL toluene after 3 h, maximum conversion of amide was observed, and the product was isolated by the procedure mentioned above to give 40.5 gm, yield 98%.
With 2-[5-(4-methylphenyl)isoxazol-3-yl]-5-(5-phenylisoxazol-3-yl)-1,3,4-oxadiazole·2PdCl2; potassium carbonate; In water; N,N-dimethyl-formamide; at 100℃; for 0.0166667h;
General procedure: A 0.01 solution of L1-4·PdCl2 (0.2 mol % Pd) in DMF (0.1-0.2 ml)(or 0.8-4 mg of the respective Pd/Fe composite) was addedto a mixture of aryl(hetaryl)boronic acid (1.20 mmol), aryl-(hetaryl) bromide (1.00 mmol), Bu4NBr (3.2 mg, 0.01 mmol,used in the case of aryl halides that were insoluble in water),and K2CO3 (0.35 g, 2.5 mmol) in 2 (10 ml) (or in 10 mlof 1:1 methanol-water mixture). The reaction mixture wasvigorously stirred at the indicated temperature until fullconversion was obtained. The reaction progress wascontrolled by TLC method (eluent hexane-Et2O, 2:1). In thecase of activated aryl bromides, the reaction was veryexothermic, therefore it was important to use an effectivereflux condenser for larger scale syntheses. In the cases when the reaction products were aryl(hetaryl)benzoic acids, analytically pure samples were obtainedby diluting the reaction mixture with water, heating, filteringin order to remove an insignificant amount (~0.2 mol %) ofpalladium black and the homocoupling product, diluted with10-15% (v/v) of ethanol, heated to ~50C, and slowly,while stirring, acidified with 5% HCl to pH 2-3. Theprecipitate that formed after cooling was easily filtered, andpure compounds were isolated without a need forchromatographic separation. In the case when Pd/Fe wasused, the catalyst was separated after the completion of thereaction with the aid of an external magnet and the reactionmixture was used as described above. The recovered Pd/Fecatalyst could be used again after washing with water andacetone. In the case of biaryls (heterobiaryls) that wereinsoluble in water, the reaction mixture was diluted withsaturated NaCl solution, extracted with Et2O or EtOAc, theextract was dried over Na2SO4 and filtered through a thinsilica gel layer. The solvent was evaporated on a rotaryevaporator, and the residue, as a rule, had a purity of atleast 99%. Analytically pure samples were obtained by recrystallization of biaryls from a minimal amount ofaqueous alcohol (10-20% (v/v) 2) or by converting theamines to hydrochlorides. The residual palladium contentin the target products was in the range from 0.5 to 2.2 ppmaccording to the results of atomic absorption spectroscopy.
98.37%
With potassium carbonate; palladium dichloride; In water; N,N-dimethyl-formamide; at 75℃;Sonication; Cooling;
120ml of distilled water,120ml of N,N-dimethylformamide mixed into the ultrasonic reactor and ultrasonically mixed to form solution A,Add 53.2 mg of PdCl2 (0.03 mmol) in a cold water bath and disperse evenly. Add 7.2 g of 2,4-difluorophenylboronic acid (45 mmol).6.51g 5-bromosalicylic acid (30 mmol) was dissolved and dispersed in a cold water bath.Finally, 3.36 g of K2CO3 (60 mmol) was added to dissolve and disperse.The reaction was carried out in an ultrasonic reactor at a temperature of 75 C and an ultrasonic power of 175 W for 100 min.After the reaction is completed, the liquid filtration catalyst after the reaction isTo the filtrate, a concentration of 1 mol/L of HCl was added and the mixture was shaken until the precipitated flocculent precipitate no longer disappeared, and 2000 ml of distilled water was added to the filtrate, and the mixture was allowed to stand.The flocculent precipitate of fluorophenylsalicylic acid was completely precipitated and filtered to obtain a white cake.The filter cake was dissolved in 200 ml of ethyl acetate, and washed with deionized water for 3 times.The upper organic phase was taken, dried over 45 g of anhydrous sodium sulfate, filtered over anhydrous sodium sulfate, and evaporated under vacuo to give a white solid.Recrystallization temperature 5 C, recrystallization time 10 h,Filtration to obtain a refined product of fluorophenylsalicylic acid,Product yield is 98.37%,The product purity is 99.89%.
97%
With C11H8Cl4N2O3Pd; potassium carbonate; In methanol; water; N,N-dimethyl-formamide; at 100℃; for 0.0833333h;
General procedure: To a mixture of 1.20 mmol of arylboronic acid, 1.00 mmol of aryl(hetaryl) bromide, 3.2 mg (0.01 mmol) of Bu4NBr (for water insoluble aryl halides) and 0.35 g (2.5 mmol) K2CO3 in 5 mL of H2O (or in 5 mL of equal volumes of water and methanol) pre-heated to 80C was added 0.1 mL of a suspension of L1-4PdCl2 complexes (0.1 mol % Pd) in methanol-DMF mixture (0.01 M). The reaction mixture was stirred vigorously at the same temperature (Table 4) to complete conversion. The reaction progress was monitored by TLC (eluent hexane-Et2O, 3 : 1). In the case of activated aryl bromides the reaction was highly exothermic that should be considered at the synthesis scaling. If the reaction products were aryl(hetaryl)benzoic acids, to obtain ananalytically pure sample the reaction mixture was diluted with water, heated, and filtered from mino ramounts (~ 0.1 mol %) of palladium black. Then about 10-15 vol % of alcohol was added, the mixture wa sheated to ~50C and acidified carefully with 10% HCl to adjusting pH = 2-3. As a result, the formed precipitate was filtered off and dried to provide analytically pure samples without the use of chromatographic methods. In the case of water-insoluble biaryls (heterobiaryls), the reaction mixture was diluted with a saturated solution of NaCl, extracted with Et2O or EtOAc, the extract was dried with Na2SO4 and filtered through a bed of silica gel. The solvent was removed to give the target compound with a purity ? 99% .Analytically pure sample was obtained by recrystallization from the minimum amount of aqueous alcohol (about 10-20 vol % of 2), or by conversion of amines to hydrochlorides.
90%
With potassium carbonate; In water; at 20℃; for 6h;Green chemistry;
General procedure: A 50 mL flask was charged with an aryl halide (1.0 mmol), anaryl boronic acid (1.2 mmol), K2CO3 (2.0 mmol), nanocatalyst(0.05 mol% Pd) and deionized water (5 mL). The reactionwas stirred at room temperature for 4 h. The progress ofthe reaction was monitored by thin-layer chromatography After the reaction was completed, distilled water (25 mL) wasadded to the mixture and dilute 2 mol/L HCl was added dropwiseto pH 3.0-4.0 with stirring, and the mixture was heatedto 100 C for 10 min. The white solid that had formed wasfiltered off and washed with hot water. After drying, it wasdissolved in ether (5 mL) and was rapidly separated using asilica gel column. Elution with ether left behind small amountsof impurities and traces of palladium black to give a crudeproduct. The ether solution was evaporated to 3-5 mL andrecrystallized to obtain a pure product. All the products 3a-uare known compounds and were characterized by comparingtheir melting points and 1H NMR spectra with those preparedrecently by using a water-soluble glycine-based Pd catalyst,PdCl2(NH2CH2CO2H)2.10 The melting points and 1H NMRdata of 3a-u are listed in the supplemental material.
86.97%
With potassium carbonate; In N,N-dimethyl-formamide; at 150℃; for 4h;
The 15mmol2,4-difluorophenyl boronic acid, 10mmol5- bromine salicylic acid, 0.1mmol o-phenylenediamine condensation of benzaldehyde bis Schiff base complexes of palladium catalyst, 20mmol of potassium carbonate were added to 80ml volume percentage of 50% of N, N - dimethylformamide an aqueous solution of, the reaction mixture was stirred at 150 240 minutes, the reaction was stopped, cooled to room temperature, the catalyst was recovered by filtration, to the filtrate was added 800ml of deionized water, boiled for 20 minutes, cooled to room temperature and mass fraction 37.5% of the HCl reaction mixture was adjusted to pH 3 and stirred to precipitate Diflunsial flocculent precipitate completely, filtration, distillation of the reaction solvent recovered in the filtrate, and the filter cake was added diethyl ether mass 5:1 the filter cake was dissolved, together with 50mL of deionized water three times to remove water-soluble impurities, to take the upper organic phase was dried over anhydrous sodium sulfate, anhydrous sodium sulfate was filtered off, the filtrate was evaporated to give the crude product Diflunsial, then in = 3/1 by volume ethanol - aqueous solution at 2 recrystallized from 12 hours to obtain Diflunsial products, by IR, 1 HNMR and HPLC analysis, the yield was Diflunsial to 86.97%.
With potassium carbonate; In water; at 20℃; for 4h;Green chemistry;
General procedure: A 50 mL flask was charged with an aryl halide (1.0 mmol), anaryl boronic acid (1.2 mmol), K2CO3 (2.0 mmol), nanocatalyst(0.05 mol% Pd) and deionized water (5 mL). The reactionwas stirred at room temperature for 4 h. The progress ofthe reaction was monitored by thin-layer chromatography After the reaction was completed, distilled water (25 mL) wasadded to the mixture and dilute 2 mol/L HCl was added dropwiseto pH 3.0-4.0 with stirring, and the mixture was heatedto 100 C for 10 min. The white solid that had formed wasfiltered off and washed with hot water. After drying, it wasdissolved in ether (5 mL) and was rapidly separated using asilica gel column. Elution with ether left behind small amountsof impurities and traces of palladium black to give a crudeproduct. The ether solution was evaporated to 3-5 mL andrecrystallized to obtain a pure product. All the products 3a-uare known compounds and were characterized by comparingtheir melting points and 1H NMR spectra with those preparedrecently by using a water-soluble glycine-based Pd catalyst,PdCl2(NH2CH2CO2H)2.10 The melting points and 1H NMRdata of 3a-u are listed in the supplemental material.
95%
With sodium carbonate;palladium diacetate; In water; at 20℃; for 1h;
Palladium(II)acetate (55mg; 0.23mmol) was added under argon to a mixture of 5-bromosalicylic acid (5.4g; 22.4mmol), sodium carbonate (7.2g; 68.1mmol) and 4-methoxyboronic acid (3.8g; 25mmol) in water (125ml). The reaction mixture was stirred at room temperature for 1h. The resulting slurry was dissolved in hot water (1300ml) and filtered to give a filtrate and a precipitate. The filtrate was acidified with hydrochloric acid. The precipitate was washed with water and dried in vacuo to give 5.3g (95%) of 4-hydroxy-4'-methoxy-3-biphenylcarboxylic acid.
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
Multi-step reaction with 2 steps
1: 87 percent / SOCl2 / tetrahydrofuran / 2 h / 20 °C
2: 90 percent / tetrahydrofuran / 0.17 h / 120 °C / microwave irradiation
With sulfuric acid In ethanol
Ethyl-5-bromosalicylate (Compound 1)
Ethyl-5-bromosalicylate (Compound 1) To 5-bromosalicylic acid (25 g, 115 mmol) in ethyl alcohol (300 mL) was added sulfuric acid (98%, 2 mL). The mixture was refluxed in a Dean-Stark apparatus for 2 days. The reaction mixture was cooled to room temperature. Most of the ethyl alcohol was removed by distillation. The residue was diluted with ethyl acetate, washed with water, aq. Na2CO3 and brine. The organic layer was dried (Na2SO4) and the solvent was removed to afford the title compound as a white solid. 1H NMR (300 MHz, CDCl3): δ 1.41 (t, J=6.9 Hz, 3H), 4.38 (q, J=7.0 Hz, 2H), 6.83 (d, J=8.2 Hz, 1H), 7.48 (d, J=8.2 Hz, 1H), 7.93 (s, 1H), 10.8 (s, 1H).
A. 5-bromo-2-hydroxybenzamide; 0 OH 0 OH 1. n-butanol, H2SO4, reflux HO X 2. NH3, MeOH H2N 82% Br Br To a stirred solution of 5-Bromosalicyclic acid (30 g, 135.5 mmol) in n-butylalcohol (60 mL) was added H2SO4 (95.6%, 289 L, 5.42 mmol) in a 100 ml round bottom flask connected by a Dean-Stark trap/reflux condenser that was filled with 12 ml of n-butylalcohol. After heated to reflux for 2 days, the reaction was cooled down to R. T. and concentrated to give a pale yellow oil. The mixture was added 50 mL MeOH, followed by NH3 in MeOH (7 N, 116 mL). The reaction was stirred at R. T. for another 2 days, monitored by HPLC. After the reaction complete, it was concentrated to give a white solid. The crude solid was washed with small amount of EtOAc and hexane to afford 24 g of the product as a white crystalline solid (82% yield).
23%
A solution of 5-bromo-2-hydroxybenzoic acid (20 g, 92.16 mmol, 1.00 equiv) in thionyl chloride (50 mE) was stirred at 80 C. for 4 h. The mixture was concentrated under vacuum. Then the residue was added to a solution of ammonia (50 mE) in tetrahydrofuran (50 mE) and stirred at room temperature for 2 h. Ethyl acetate (50 mE) was added to the reaction. The solid was filtered out. The filtrate was concentrated under vacuum and purified by Si02 chromatography eluted with ethyl acetate/petroleum ether (1:5) to afford 4.5 g (23%) of 5-bromo-2-hydroxybenzamide as a yellow solid. EC-MS: mlz=216 [M+H].
STEP 1. 5-bromo-2-hydroxybenzamide H2SO4 (95.6%, 289 muL, 5.42 mmol) was added to a stirred solution of 5-bromosalicyclic acid (30 g, 135.5 mmol) in n-butylalcohol (60 mL) in a 100 mL round bottom flask connected by a Dean-Stark trap/reflux condenser that was filled with 12 mL of n-butylalcohol. The reaction was refluxed for two days, then cooled to room temperature and concentrated to produce a pale yellow oil. MeOH (50 mL) was added to the mixture, followed by NH3 in MeOH (7 N, 116 mL). The reaction was stirred at room temperature for another two days, then concentrated to yield a white solid. The crude solid was washed with small amount of ethyl acetate and hexane to yield the product as a white crystalline solid (24 g, 82%). 1H NMR (CDCl3) delta 12.15 (s, 1H), 7.54 (m, 2H), 6.97 (d, J=12 Hz, 1H), 6.00 (broad, 2H).
With sodium hydroxide; sodium carbonate;palladium diacetate; In methanol;
(1) [4'-(Trifluoromethyl)-4-hydroxybiphenyl]-3-carboxylic acid. A mixture of 5-bromosalicylic acid(500mg, 2.30mmol), dihydroxy-4-(trifluoromethyl)phenylborane(488mg, 2.57mmol), palladium acetate(10mg 0.040mmol) and 1M sodium carbonate(7mL) was stirred at 80ØC for 1 hour. The reaction mixture was poured into 2 N hydrochloric acid and extracted with ethyl acetate. After the ethyl acetate layer was washed with water and brine one after another, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. According to the fixed procedure, the obtained residue was methyl-esterified by trimethylsilyldiazomethane and methanol, and purified by column chromatography on silica gel(n-hexane:ethyl acetate=5:1) to give a colourless liquid(563mg). This liquid was dissolved in methanol(10mL). 2 N sodium hydroxide(3mL) was added, and the mixture was stirred at 60ØC for 1 hour. After the reaction mixture was cooled to room temparature, it was poured into 2 N hydrochloric acid and extracted with ethyl acetate. After the ethyl acetate layer was washed with water and saturted brine one after another, dried over MgSO4, the solvent was evaporated under reduced pressure. The obtained residue was suspended and washed with n-hexane-dichloromethane under heating at reflux to give the title compound(458mg, 70.4%) as a white crystal. mp 185ØC(dec). 1H-NMR(DMSO-d6): delta 7.09(1H, d, J=8.8Hz), 7.77(2H, d, J=8.0Hz), 7.85(2H, d, J=8.0Hz), 7.90(1H, dd, J=8.8, 2.0Hz), 8.10(1H, d, J=2.4Hz), 11.80(brs).
70.4%
With sodium carbonate;palladium diacetate; In water; at 80℃; for 1h;
A mixture of 5-bromosalicylic acid(500mg, 2.30mmol), dihydroxy-4-(trifluoromethyl)phenylborane(488mg, 2.57mmol), palladium acetate(10mg, 0.040mmol) and 1M sodium carbonate(7mL) was stirred at 80C for 1 hour. The reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate. After the ethyl acetate layer was washed successively with water and brine, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. According to the fixed procedure, the obtained residue was methyl-esterified by trimethylsilyldiazomethane and methanol, and purified by column chromatography on silica gel(n-hexane:ethyl acetate=5:1) to give a colourless liquid(563mg). This liquid was dissolved in methanol(10mL). 2N Sodium hydroxide(3mL) was added, and the mixture was stirred at 60C for 1 hour. After the reaction mixture was cooled to room temperature, it was poured into 2N hydrochloric acid and extracted with ethyl acetate. After the ethyl acetate layer was washed successively with water and saturted brine, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was suspended and washed with n-hexane-dichloromethane under heating at reflux to give the title compound(458mg, 70.4%) as a white crystal. mp 185C(dec).1H-NMR(DMSO-d6): delta 7.09(1H, d, J=8.8Hz), 7.77(2H, d, J=8.0Hz), 7.85(2H, d, J=8.0Hz), 7.90(1H, dd, J=8.8, 2.0Hz), 8.10(1H, d, J=2.4Hz), 11.80(1H, brs).
70.4%
With sodium carbonate;palladium diacetate; In water; at 80℃; for 1h;
A mixture of 5-bromosalicylic acid(500mg, 2.30mmol), dihydroxy-4-(trifluoromethyl)phenylborane(488mg, 2.57mmol), palladium acetate(10mg, 0.040mmol) and 1M sodium carbonate(7mL) was stirred at 80C for 1 hour. The reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate. After the ethyl acetate layer was washed successively with water and brine, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. According to the fixed procedure, the obtained residue was methyl-esterified by trimethylsilyldiazomethane and methanol, and purified by column chromatography on silica gel(n-hexane:ethyl acetate=5:1) to give a colourless liquid(563mg). This liquid was dissolved in methanol(10mL). 2N Sodium hydroxide(3mL) was added, and the mixture was stirred at 60C for 1 hour. After the reaction mixture was cooled to room temperature, it was poured into 2N hydrochloric acid and extracted with ethyl acetate. After the ethyl acetate layer was washed successively with water and saturted brine, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was suspended and washed with n-hexane-dichloromethane under heating at reflux to give the title compound(458mg, 70.4%) as a white crystal. mp 185C(dec).1H-NMR(DMSO-d6): delta 7.09(1H, d, J=8.8Hz), 7.77(2H, d, J=8.0Hz), 7.85(2H, d, J=8.0Hz), 7.90(1H, dd, J=8.8, 2.0Hz), 8.10(1H, d, J=2.4Hz), 11.80(1H, brs).
70.4%
With sodium carbonate;palladium diacetate; In water; at 80℃; for 1h;
A mixture of 5-bromosalicylic acid(500mg, 2.30mmol), dihydroxy-4-(trifluoromethyl)phenylborane(488mg, 2.57mmol), palladium acetate(10mg, 0.040mmol) and 1M sodium carbonate(7mL) was stirred at 80C for 1 hour. The reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate. After the ethyl acetate layer was washed successively with water and brine, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. According to the fixed procedure, the obtained residue was methyl-esterified by trimethylsilyldiazomethane and methanol, and purified by column chromatography on silica gel(n-hexane:ethyl acetate=5:1) to give a colourless liquid(563mg). This liquid was dissolved in methanol(10mL). 2N Sodium hydroxide(3mL) was added, and the mixture was stirred at 60C for 1 hour. After the reaction mixture was cooled to room temperature, it was poured into 2N hydrochloric acid and extracted with ethyl acetate. After the ethyl acetate layer was washed successively with water and saturted brine, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was suspended and washed with n-hexane-dichloromethane under heating at reflux to give the title compound(458mg, 70.4%) as a white crystal. mp 185C(dec).1H-NMR(DMSO-d6): delta 7.09(1H, d, J=8.8Hz), 7.77(2H, d, J=8.0Hz), 7.85(2H, d, J=8.0Hz), 7.90(1H, dd, J=8.8, 2.0Hz), 8.10(1H, d, J=2.4Hz), 11.80(1H, brs).
With sodium hydroxide; sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In methanol; 1,2-dimethoxyethane;
(1) 2-Hydroxy-5-(2-thienyl)benzoic acid. <strong>[89-55-4]5-Bromosalicylic acid</strong>(500mg, 2.30mmol) was dissolved in 1,2-dimethoxyethane(5mL). Tetrakis(triphenylphosphine)palladium(80mg, 0.07mmol) was added under argon atmosphere, and the mixture was stirred at room temparature for 10 minutes. Then dihydroxy-2-thienylborane(324mg, 2.53mmol) and 1M sodium carbonate(7mL) were added, and the mixture was refluxed for 2 hours. After the reaction mixture was cooled to room temparature, it was poured into 2 N hydrochloric acid and extracted with ethyl acetate. After the ethyl acetate layer was washed with water and brine one after another, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. According to the fixed procedure, the obtained residue was methyl-esterified by trimethylsilyldiazomethane and methanol, and purified by column chromatography on silica gel(n-hexane:ethyl acetate=5:1) to give a yellow liquid(277mg). This was dissolved in methanol(5mL). 2 N sodium hydroxide(1.5mL) was added, and the mixture was stirred at 60ØC for 1 hour. After the reaction mixture was cooled to room temparature, it was poured into 2 N hydrochloric acid and extracted with ethyl acetate. After the ethyl acetate layer was washed with water and brine one after another, dried over anhydrous magnesium sulfate, the residue obtained by evaporating the solvent under reduced pressure was crystallized from n-hexane-dichloromethane to give the title compound(58mg, 11.5%) as a white crystal. 1H-NMR(DMSO-d6): delta 6.95(1H, d, J=8.8Hz), 7.09(1H, dd, J=4.8, 3.6Hz), 7.37(1H, dd, J=4.0, 1.2Hz), 7.45(1H, dd, J=5.2, 1.2Hz), 7.74(1H, dd, J=8.8, 2.8Hz), 7.96(1H, d, J=2.8Hz).
11.5%
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 20℃; for 2h;Heating / reflux;
<strong>[89-55-4]5-Bromosalicylic acid</strong>(500mg, 2.30mmol) was dissolved in 1,2-dimethoxyethane(5mL). Tetrakis(triphenylphosphine)palladium(80mg, 0.07mmol) was added under argon atmosphere, and the mixture was stirred at room temperature for 10 minutes. Then dihydroxy-2-thienylborane(324mg, 2.53mmol) and 1M sodium carbonate(7mL) were added, and the mixture was refluxed for 2 hours. After the reaction mixture was cooled to room temperature, it was poured into 2N hydrochloric acid and extracted with ethyl acetate. After the ethyl acetate layer was washed successively with water and brine, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. According to the fixed procedure, the obtained residue was methyl-esterified by trimethylsilyldiazomethane and methanol, and purified by column chromatography on silica gel(n-hexane:ethyl acetate=5:1) to give an yellow liquid(277mg). This was dissolved in methanol(5mL). 2N Sodium hydroxide(1.5mL) was added, and the mixture was stirred at 60C for 1 hour. After the reaction mixture was cooled to room temperature, it was poured into 2N hydrochloric acid and extracted with ethyl acetate. After the ethyl acetate layer was washed successively with water and brine, dried over anhydrous magnesium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was crystallized from n-hexane-dichloromethane to give the title compound(58mg, 11.5%) as a white crystal.1H-NMR(DMSO-d6): delta 6.95(1H, d, J=8.8Hz), 7.09(1H, dd, J=4.8, 3.6Hz), 7.37(1H, dd, J=4.0, 1.2Hz), 7.45(1H, dd, J=5.2, 1.2Hz), 7.74(1H, dd, J=8.8, 2.8Hz), 7.96(1H, d, J=2.8Hz).
11.5%
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 20℃; for 2h;Heating / reflux;
<strong>[89-55-4]5-Bromosalicylic acid</strong>(500mg, 2.30mmol) was dissolved in 1,2-dimethoxyethane(5mL). Tetrakis(triphenylphosphine)palladium(80mg, 0.07mmol) was added under argon atmosphere, and the mixture was stirred at room temperature for 10 minutes. Then dihydroxy-2-thienylborane(324mg, 2.53mmol) and 1M sodium carbonate(7mL) were added, and the mixture was refluxed for 2 hours. After the reaction mixture was cooled to room temperature, it was poured into 2N hydrochloric acid and extracted with ethyl acetate. After the ethyl acetate layer was washed successively with water and brine, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. According to the fixed procedure, the obtained residue was methyl-esterified by trimethylsilyldiazomethane and methanol, and purified by column chromatography on silica gel(n-hexane:ethyl acetate=5:1) to give an yellow liquid(277mg). This was dissolved in methanol(5mL). 2N Sodium hydroxide(1.5mL) was added, and the mixture was stirred at 60C for 1 hour. After the reaction mixture was cooled to room temperature, it was poured into 2N hydrochloric acid and extracted with ethyl acetate. After the ethyl acetate layer was washed successively with water and brine, dried over anhydrous magnesium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was crystallized from n-hexane-dichloromethane to give the title compound(58mg, 11.5%) as a white crystal.1H-NMR(DMSO-d6): delta 6.95(1H, d, J=8.8Hz), 7.09(1H, dd, J=4.8, 3.6Hz), 7.37(1H, dd, J=4.0, 1.2Hz), 7.45(1H, dd, J=5.2, 1.2Hz), 7.74(1H, dd, J=8.8, 2.8Hz), 7.96(1H, d, J=2.8Hz).
N-[3,5-bis(trifluoromethyl)phenyl]methyl}-5-bromo-2-hydroxybenzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
55.4%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In tetrahydrofuran; at 20℃; for 1h;
Under argon atmosphere, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (it is abbreviated as WSC · HCl hereafter.; 192mg, 1mmol) was added to a mixture of 5-bromosalicylic acid(217mg, 1mmol), 3,5-bis(trifluoromethyl)benzylamine(243mg, 1mmol), 4-dimethylaminopyridine(12mg, 0.1mmol) and tetrahydrofuran(10mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel(n-hexane:ethyl acetate=4:1) to give the title compound(244.8mg, 55.4%) as a white solid.1H-NMR(DMSO-d6): delta 4.69(2H, d, J=5.7Hz), 6.93(1H, d, J=8.7Hz), 7.56(1H, dd, J=8.7, 2.4Hz), 8.02(1H, d, J=2.4Hz), 8.06(3H, s), 9.41(1H, t, J=5.7Hz), 12.13(1H, s).
55.4%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In tetrahydrofuran; at 20℃; for 1h;
Under argon atmosphere, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (it is abbreviated as WSC · HCl hereafter.; 192mg, 1mmol) was added to a mixture of 5-bromosalicylic acid(217mg, 1mmol), 3,5-bis(trifluoromethyl)benzylamine(243mg, 1mmol), 4-dimethylaminopyridine(12mg, 0.1mmol) and tetrahydrofuran(10mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel(n-hexane:ethyl acetate=4:1) to give the title compound(244.8mg, 55.4%) as a white solid.1H-NMR(DMSO-d6): delta 4.69(2H, d, J=5.7Hz), 6.93(1H, d, J=8.7Hz), 7.56(1H, dd, J=8.7, 2.4Hz), 8.02(1H, d, J=2.4Hz), 8.06(3H, s), 9.41(1H, t, J=5.7Hz), 12.13(1H, s).
55.4%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In tetrahydrofuran; at 20℃; for 1h;
Under argon atmosphere, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (it is abbreviated as WSC · HCl hereafter.; 192mg, 1mmol) was added to a mixture of 5-bromosalicylic acid(217mg, 1mmol), 3,5-bis(trifluoromethyl)benzylamine(243mg, 1mmol), 4-dimethylaminopyridine(12mg, 0.1mmol) and tetrahydrofuran(10mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel(n-hexane:ethyl acetate=4:1) to give the title compound(244.8mg, 55.4%) as a white solid.1H-NMR(DMSO-d6): delta 4.69(2H, d, J=5.7Hz), 6.93(1H, d, J=8.7Hz), 7.56(1H, dd, J=8.7, 2.4Hz), 8.02(1H, d, J=2.4Hz), 8.06(3H, s), 9.41(1H, t, J=5.7Hz), 12.13(1H, s).
55.4%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In tetrahydrofuran; at 20℃; for 1h;
Under argon atmosphere, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (it is abbreviated as WSC · HCl hereafter.; 192mg, 1mmol) was added to a mixture of 5-bromosalicylic acid(217mg, 1mmol), 3,5-bis(trifluoromethyl)benzylamine(243mg, 1mmol), 4-dimethylaminopyridine(12mg, 0.1mmol) and tetrahydrofuran(10mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel(n-hexane:ethyl acetate=4:1) to give the title compound(244.8mg, 55.4%) as a white solid.1H-NMR(DMSO-d6): delta 4.69(2H, d, J=5.7Hz), 6.93(1H, d, J=8.7Hz), 7.56(1H, dd, J=8.7, 2.4Hz), 8.02(1H, d, J=2.4Hz), 8.06(3H, s), 9.41(1H, t, J=5.7Hz), 12.13(1H, s).
13 5-Bromo-2-propoxybenzoic Acid STR29
PREPARATION 13 5-Bromo-2-propoxybenzoic Acid STR29 5-Bromo-2-hydroxy-benzoic acid (26.6 gm) was dissolved in 160 mL DMF containing 125 gm 1-iodopropane and 50.8 gm K2 CO3. The reaction mixture was heated to 50° C. overnight. Ether (250 mL) was added to the cooled reaction mixture and the suspended solids were removed by filtration. The solution was washed with water (2*50 mL). The aqueous extract was extracted with 4*50 mL ether. The combined ether extracts were washed with brine, dried (MgSO4) and concentrated by rotary evaporation to afford 38 gm of a pale yellow liquid. HPLC analysis of this material showed ≥95% of a single component with retention time 4.6 minutes (HPLC conditions: YMC S5 ODS 4.6*50 mm column, 4 minute gradient-0% B to 100% B, 4 mL/min flow, solvent A: 10% MeOH-90% H2 O-0.2% H3 PO4, solvent B: 90% MeOH-10% H2 O-0.2% H3 PO4).
Synthesis of methyl 2-methoxy-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)benzoateStep 1: Preparation of methyl 5-b nzoate; To a mixture of 5-bromo-2-hydroxybenzoic acid (10.0 g, 46.1 mmol) in acetone (100 mL) in a 250 mL round bottom flask was added K2CO3 (15.90 g, 1 15 mmol) and then dimethyl sulfate (10.92 mL, 115 mmol). The resulting reaction mixture was stirred at 50 C for overnight. After completion of reaction, the reaction mixture was filtered and concentrated to get the crude compound, which was then added with water and extracted with diethyl ether (200 mL x 2). The combined organic extracts were washed with 10% aHC03 solution, dried over a2S04, filtered and evaporated to give a colorless liquid. Yield: 11.7 g (77%).¾ NMR (400 MHz, CDC13) delta: 7.90 (s, 1H), 7.57-7.54 (m, 1H), 6.88-6.86 (s, 1H),3.89 (s, 6H).LCMS: (ES+) m/z = 245 (M+H)+ Column: Acquity UPLC BEH C181.7 urn, 2.1x50 mm ColumnMobile (M) phase A: 0.1% TFA in waterMobile (M) phase B: AcetonitrileTime (min) : 0 1 1.6% B : 2% 98%: 98%Retention Time (RT): 0.92 min
With potassium carbonate; In acetone; for 19h;Heating / reflux;
[Example 1-1-1]; Production of 3-N-(4-chlorophenyl)-4-methoxyisophthalamide (compound 1-1-1); Step A; Preparation of methyl 5-bromo-2-methoxybenzoate (CAS registry number: 7120-41-4); 5-Bromo-2-hydroxybenzoic acid (25 g) and 40 g of potassium carbonate were suspended in 300 mL of acetone. Dimethyl sulfate (28 mL) was added to the suspension, and the mixture was stirred for 19 hours under reflux with heating. The reaction mixture was cooled to room temperature, whereafter the insolubles were separated by filtration, and washed with ethyl acetate. The filtrate and the washings were combined, and acetone and ethyl acetate were distilled off under reduced pressure. The resulting residue was dissolved in 300 mL of ethyl acetate. Water (300 mL) was added to the solution, and the organic layer was separated, followed by extracting the aqueous layer with 200 mL of ethyl acetate. After the respective organic layers were combined, the combined organic layer was washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was separated by filtration, and then washed with ethyl acetate. The filtrate and the washings were combined, and ethyl acetate was distilled off under reduced pressure to obtain 30 g of methyl 5-bromo-2-methoxybenzoate. 1H-NMR (400 MHz, CDCl3) delta 3.89 (3H, s), 6.87 (1H, d, J = 8.8 Hz), 7.55 (1H, dd, J = 8.8 Hz, 2.9 Hz), 7.90 (1H, d, J = 2.9 Hz). ESI (LC/MS positive mode) m/z 245, 247 (M+H+); retention time 3.18 min (Condition 1 for high-performance liquid chromatography).
With sodium hydroxide; dimethyl sulfate; In dichloromethane; water;
The starting material is prepared as follows: The solution of 110 g of 5-bromosalicylic acid in 900 ml of water and 48 g of sodium hydroxide is stirred while 60 ml of dimethyl sulfate are added. The mixture is stirred at 70 for 3 hours, whereupon 50 ml of 50% aqueous sodium hydroxide are added, followed slowly by 60 ml of dimethyl sulfate. After stirring at 70 for 6 hours the last step is repeated and the mixture warmed 17 hours longer. It is cooled in an ice bath, filtered, the filtrate stirred with methylene chloride and neutralized with cold 5 N aqueous hydrochloric acid. The organic phase is separated, dried and evaporated to yield the 5-bromo-2-methoxybenzoic acid melting at 115-117. The solution of 62.5 g thereof in 120 ml of thionyl chloride is refluxed for 2 hours and the residue dissolved in 300 ml of methylene chloride.
2,4-Diamino-6-(5-bromo-2-methoxyphenyl)-1,3,5-triazine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In ethanol;
EXAMPLE 8 2,4-diamino-6-(3-bromo-6-methoxyphenyl)-s-triazine 5.0 g of 2-methoxy-5-bromobenzoic acid methylester (oil) prepared from 5-bromosalicylic acid and 3.0 g of biguanide are refluxed in 50 ml of ethanol with stirring for 8 hours. After cooling, the separated crystals are collected and recrystallized from aqueous dimethylsulfoxide. Melting point: 294-297 C.; yield: 3.2 g.
N-(3,5-bis(trifluoromethyl)phenyl)-5-bromo-2-hydroxybenzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
88.5%
Example 52 N-[3,5-Bis(trifluoromethyl)phenyl]-5-bromo-2-hydroxybenzamide (Comopund No. 51). Using 5-bromosalicylic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound. Yield: 88.5%. 1H-NMR(DMSO-d6): delta 6.98(1H, d, J=8.8Hz), 7.59(1H, dd, J=8.8, 2.8Hz), 7.83(1H, s), 7.98(1H, d, J=2.8Hz), 8.43(2H, s), 10.82(1H, s), 11.37(1H, s).
83%
With phosphorus trichloride; In chlorobenzene;Microwave irradiation;
General procedure: All salicylanilides(1a-8d) were synthesized via a previously described microwave assisted (MicroSYNTH Milestone) method.25 Briefly,the appropriately substituted salicylic acid (1 eq) and the substituted aniline (1 eq) were suspended or dissolved in chlorobenzene(1 mL/0.15 mmol of acid). Phosphorus trichloride (PCl3) was added(0.5 eq) and the mixture was stirred (600 rpm) and radiated(530 W) for 30-60 min. The mixture was filtrated while hot and was let cool, initially at r.t. and overnight at 4 C. The formed pre-cipitate was filtered and recrystallized with ethanol or mixture of hexane/AcOEt in order to afford the final compounds with yields of 41-83%.
14%
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; 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-bromo-N-(2,5-bis(trifluoromethyl)phenyl)-2-hydroxybenzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
24.0%
Example 101 N-[2,5-Bis(trifluoromethyl)phenyl]-5-bromo-2-hydroxybenzamide (Comopund No. 101). Using 5-bromosalicylic acid and <strong>[328-93-8]2,5-bis(trifluoromethyl)aniline</strong> as the raw materials, the same operation as the example 16 gave the title compound. Yield: 24.0percent. 1H-NMR(DMSO-d6): 6 7.03(1H, d, J=8.7Hz), 7.65(1H, dd, J=8.7, 2.7Hz), 7.76(1H, d, J=8.4Hz), 8.03(1H, d, J=8.1Hz), 8.11(1H, d, J=2.7Hz), 8.74(1H, s), 11.02(1H, s), 12.34(1H, s).
2-(5-bromo-2-hydroxybenzoyl)amino-4-phenylthiazole-5-carboxylic acid ethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
28.6%
210 Example 210
Example 210 2-(5-Bromo-2-hydroxybenzoyl)amino-4-phenylthiazole-5-carboxylic acid ethyl ester (Comopund No. 210). Using 5-bromosalicylic acid and 2-amino-4-phenylthiazole-5-carboxylic acid ethyl ester as the raw materials, the same operation as the example 195(3) gave the title compound. Yield: 28.6%. mp 197-199ØC. 1H-NMR(DMSO-d6): δ 1.21(3H, t, J=6.8Hz), 4.20(2H, q, J=6.8Hz), 7.01(1H, d, J=8.8Hz), 7.43-7.48(3H, m), 7.63(1H, dd, J=8.8, 2.4Hz), 7.70-7.72(2H, m), 8.04(1H, d, J=2.4Hz), 12.33(1H, brs).
5-bromo-2-hydroxy-N-[3-methoxy-5-(trifluoromethyl)phenyl]benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
58.8%
Example 122 5-Bromo-2-hydroxy-N-[3-methoxy-5-(trifluoromethyl)phenyl]benzamide (Comopund No. 122). Using 5-bromosalicylic acid and 3-methoxy-5-(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound. Yield: 58.8%. 1H-NMR(DMSO-d6): delta 3.85(3H, s), 6.98(1H, d, J=8.7Hz), 7.03(1H, s), 7.57-7.61(2H, m), 7.77(1H, s), 8.00(1H, d, J=2.4Hz), 10.57(1H, s), 11.56(1H, s).
5-Bromo-N-(4,5-diphenylthiazol-2-yl)-2-hydroxybenzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Example 204 5-Bromo-N-(4,5-diphenylthiazol-2-yl)-2-hydroxybenzamide (Comopund No. 204). Using 5-bromosalicylic acid and <strong>[6318-74-7]2-amino-4,5-diphenylthiazole</strong> as the raw materials, the same operation as the example 195(3) gave the title compound. (2-Amino-4,5-diphenylthiazole: refer to Nihon Kagaku Zasshi, 1962, 83, 209.) Yield: 25.9%. mp 262-263ØC. 1H-NMR(DMSO-d6): delta 7.02(1H, d, J=8.1Hz), 7.34-7.47(10H, m), 7.63(1H, d, J=6.9Hz), 8.08(1H, d, J=2.4Hz), 11.88(1H, brs), 12.08(1H, brs).
5-bromo-2-hydroxy-N-[2-methoxy-5-(trifluoromethyl)phenyl]benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
71.3%
Example 123 5-Bromo-2-hydroxy-N-(2-methoxy-5-(trifluoromethyl)phenyl]benzamide (Comopund No. 123). Using 5-bromosalicylic acid and 2-methoxy-5-(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound. Yield: 71.3%. 1H-NMR(DMSO-d6): delta 3.99(3H, s), 7.03(1H, d, J=9.0Hz), 7.30(1H, d, J=8.7Hz), 7.47-7.51(111, m), 7.61(1H, dd, J=9.0, 2.4Hz), 8.10(1H, d, J=2.4Hz), 8.82(1H, d, J=2.1Hz), 11.03(1H, s), 12.19(1H, s).
5-Bromo-N-[5-bromo-4-(trifluoromethyl)thiazol-2-yl]-2-hydroxybenzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
22.4%
Example 183 5-Bromo-N-[5-bromo-4-(trifluoromethyl)thiazol-2-yl]-2-hydroxybenzamide (Comopund No. 182). Using 5-bromosalicylic acid and <strong>[136411-21-7]2-amino-5-bromo-4-(trifluoromethyl)thiazole</strong> as the raw materials, the same operation as the example 16 gave the title compound. (2-Amino-5-bromo-4-(trifluoromethyl)thiazole: refer to J. Heterocycl. Chem., 1991, 28, 1017.) Yield: 22.4%. mp 215ØC (dec.). 1H-NMR(DMSO-d6): delta 7.00(1H, d, J=8.8Hz), 7.61(1H, dd, J=8.8, 2.8Hz), 7.97(1H, d, J=2.4Hz).
5-Bromo-N-(4,5-dimethylthiazol-2-yl)-2-hydroxybenzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
14.4%
Example 187 5-Bromo-N-(4,5-dimethylthiazol-2-yl)-2-hydroxybenzamide (Comopund No.187). Using 5-bromosalicylic acid and <strong>[2289-75-0]2-amino-4,5-dimethylthiazole</strong> as the raw materials, the same operation as the example 16 gave the title compound. Yield: 14.4%. 1H-NMR(DMSO-d6): delta 2.18(3H, s), 2.22(3H, s), 6.89(1H, d, J=8.8Hz), 7.51(1H, d, J=6.8Hz), 8.02(1H, d, J=2.8Hz), 13.23(1H, brs).
5-Bromo-2-hydroxy-N-[2-morpholino-5-(trifluoromethyl)phenyl]benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
65.9%
127 Example 127
Example 127 5-Bromo-2-hydroxy-N-[2-morpholino-5-(trifluoromethyl)phenyl]benzamide (Comopund No. 127). Using 5-bromosalicylic acid and 2-morpholino-5-(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound. Yield: 65.9%. 1H-NMR(DMSO-d6): δ 2.90(4H, dd, J=4.5, 4.2Hz), 3.84(4H, dd, J=4.8, 4.2Hz), 7.09(1H, d, J=8.4Hz), 7.48(2H, s), 7.61(1H, dd, J=8.4, 2.7Hz), 8.13(1H, d, J=2.7Hz), 8.90(1H, s), 11.21(1H, s), 12.04(1H, s).
2-(5-bromo-2-hydroxybenzoyl)amino-4-(trifluoromethyl)thiazol-5-carboxylic acid ethylester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
88.7%
Example 216 2-(5-Bromo-2-hydroxybenzoyl)amino-4-(trifluoromethyl)thiazole-5-carboxylic acid ethyl ester (Comopund No. 216). Using 5-bromosalicylic acid and <strong>[344-72-9]2-amino-4-(trifluoromethyl)thiazole-5-carboxylic acid ethyl ester</strong> as the raw materials, the same operation as the example 195(3) gave the title compound. Yield: 88.7%. 1H-NMR(DMSO-d6): delta 1.32(3H, t, J=7.2Hz), 4.33(2H, q, J=7.2Hz), 7.01(1H, d, J=8.7Hz), 7.63(1H, dd, J=8.7, 2.7Hz), 7.98(1H, d, J=2.4Hz), 12.64(1H, br).
5-Bromo-N-(5-methyl-4-phenylthiazol-2-yl)-2-hydroxybenzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
27.7%
Example 188 5-Bromo-N-(5-methyl-4-phenylthiazol-2-yl)-2-hydroxybenzamide (Comopund No. 188). Using 5-bromosalicylic acid and <strong>[30709-67-2]2-amino-5-methyl-4-phenylthiazole</strong> as the raw materials, the same operation as the example 16 gave the title compound. (2-Amino-5-methyl-4-phenylthiazole: refer to Yakugaku Zasshi, 1961, 81, 1456.) Yield: 27.7%. mp 243-244ØC. 1H-NMR(CD3OD): δ 2.47(3H, s), 6.92(1H, d, J=8.7Hz), 7.36-7.41(1H, m), 7.44-7.50(2H, m), 7.53(1H, dd, J=9.0, 2.7Hz), 7.57-7.61(2H, m), 8.16(1H, d, J=2.7Hz).
5-bromo-N-[2-chloro-4-(trifluoromethyl)phenyl]-2-hydroxybenzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
34.9%
Example 129 5-Bromo-N-[2-chloro-4-(trifluoromethyl)phenyl]-2-hydroxybenzamide (Comopund No. 129). Using 5-bromosalicylic acid and <strong>[39885-50-2]2-chloro-4-(trifluoromethyl)aniline</strong> as the raw materials, the same operation as the example 16 gave the title compound. Yield: 34.9percent. 1H-NMR(DMSO-d6): delta 7.04(1H, d, J=8.7Hz), 7.64(1H, dd, J=8.7, 2.7Hz), 7.79(1H, dd, J=9.0, 2.1Hz), 7.99(1H, d, J=2.1Hz), 8.11(1H, d, J=2.4Hz), 8.73(1H, d, J=9.0Hz), 11.15(1H, s), 12.42(1H, s).
23.B Preparation of 5-(2,4-difluorophenyl)-salicylic acid from 2,4-difluorophenylboronic acid and palladium tetrakis(triphenylphosphine)
B) A mixture of 5-bromosalicylic acid (3 g; 13.8 mmoles), ethanol (2.3 ml), a 2M aqueous sodium carbonate solution (21 ml) and palladium tetrakis(triphenylphosphine) (0.073 g; 0.063 mmoles), prepared from PdCl2 (Fluka) and triphenylphosphine (Fluka), was heated at 80°C. In 10 minutes, a solution of 2,4-difluorophenylboronic acid (2.75 g; titre 94%; 16.4 mmoles), prepared as described in example 20, in ethanol (3.2 ml) was added. At the end of the addition, the reaction mixture was kept under stirring at 80°C for 3 hours. The resultant suspension was filtered obtaining 5-(2,4-difluorophenyl)-salicylic acid (2.8 g; titre 86%; 70% yield).
(1) [4-Hydroxy-4'-(trifluoromethyl)biphenyl]-3-carboxylic acid. A mixture of 5-bromosalicylic acid(500mg, 2.30mmol), dihydroxy-4-(trifluoromethyl)phenylborane(488mg, 2.57mmol), palladium acetate(10mg, 0.040mmol) and 1M sodium carbonate(7mL) was stirred at 80C for 1 hour. The reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate. After the ethyl acetate layer was washed successively with water and brine, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. According to the fixed procedure, the obtained residue was methyl-esterified by trimethylsilyldiazomethane and methanol, and purified by column chromatography on silica gel(n-hexane:ethyl acetate=5:1) to give a colourless liquid(563mg). This liquid was dissolved in methanol(10mL). 2N Sodium hydroxide(3mL) was added, and the mixture was stirred at 60C for 1 hour. After the reaction mixture was cooled to room temperature, it was poured into 2N hydrochloric acid and extracted with ethyl acetate. After the ethyl acetate layer was washed successively with water and saturted brine, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was suspended and washed with n-hexane-dichloromethane under heating at reflux to give the title compound(458mg, 70.4%) as a white crystal. mp 185C(dec). 1H-NMR(DMSO-d6): delta 7.09(1H, d, J=8.8Hz), 7.77(2H, d, J=8.0Hz), 7.85(2H, d, J=8.0Hz), 7.90(1H, dd, J=8.8, 2.0Hz), 8.10(1H, d, J=2.4Hz), 11.80(1H, brs).
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.
With potassium carbonate; In acetone; at 70℃;
Neat 1-(bromomethyl)-2-fluorobenzene (1533 mg, 8.11 mmol) was added over 1 min to a stirred suspension of 5~bromo-2-hydroxybenzoic acid (800 mg, 3.69 mmol) and potassium carbonate (1274 mg, 9.22 mmol) in acetone (60 ml) in air at roomtemperature. The reaction mixture was stirred at 70 C overnight. The reaction mixture was filtered. The filtrate was evaporated and the residue was dissolved in diethyl ether (30 ml) and evaporated again. The residue was dried in vacuo to yield the title compound as a white solid. 1.74 g.MS (electrospray): m/z [M+H]+ = 433, [M+Na]+ =4 55
With potassium carbonate In acetone at 55℃; for 16h; Inert atmosphere;
2.1 2-Chlorobenzyl 5-bromo-2-(2-chlorobenzyloxy)benzoate(10a)
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.
With potassium carbonate In acetone at 55℃; for 16h; Inert atmosphere;
27
1-(Bromomethyl)-2-chlorobenzene (833 mg, 4.05 mmol) was added dropwise to a stirred suspension of 5-bromo-2-hydroxybenzoic acid (400 mg, 1.84 mmol) and potassium carbonate (509 mg, 3,69 mmol) in acetone (50 ml) over 1 min under nitrogen. The reaction mixture was stirred at 55 °C for 16 h. The organic phase was evaporated and the residue was washed with water (25 ml), extracted by ethyl acetate (3 x 30 ml) and evaporated in vacuo to yield the title compound as a light yellow solid. 520 mg.MS (electrospray): m/z [M+Na]+ = 487, 489, 491 , 493
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane Reflux;
4.3. General procedure for synthesis of target compounds 5a-5y
General procedure: Compounds 5a-5y were synthesized by coupling substituted 2-amino-1,3,4-thi- adiazoles with substituted carboxylic acids, using 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCl) and N-hydroxybenzotriazole (HOBt) as condensing agent. The mixture was refluxed in anhydrous CH2Cl2 for 8-10 h. The products were extracted with ethyl acetate. The extract was washed successively with 10% HCl, saturated NaHCO3 and water, respectively, then dried over anhydrous Na2SO4, filtered and evaporated. The residue was purified by column chromatography using petroleum ether and ethyl acetate (3:1).
4-bromo-2-propionylphenylmethylphenylcarbamate[ No CAS ]
[ 5827-78-1 ]
[ 89-55-4 ]
[ 17764-93-1 ]
Yield
Reaction Conditions
Operation in experiment
60%; 43%
With water; sodium hydride; In tetrahydrofuran; for 24h;Reflux;
General procedure: To a solution of the O-carbamoylatedphenol (1 eq.) in reagent grade tetrahydrofuran (0.2 M) was added sodiumhydride (2.5 eq.) and the resulting solution was heated at reflux for 24 hours.The mixture was allowed to cool and acidified with hydrochloric acid solution(1 M). The product was extracted with ethyl acetate (2×) and the combinedorganic layers were washed with distilled water (2×), brine, dried (MgSO4),filtered and the solvent evaporated in vacuo to afford the crude residue which was purified by flashcolumn chromatography.
N-(4-benzoylphenyl)-5-bromo-2-hydroxybenzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
26%
With phosphorus trichloride In chlorobenzene at 120℃; for 0.366667h; Microwave irradiation;
1 Synthesis of salicylanilides 2
General procedure: Salicylanilides 2 were prepared by the reaction of the appropriatesubstituted salicylic acids (5 mmol) and the substituted anilines(5 mmol) in the presence of phosphorus trichloride(2.5 mmol) in chlorobenzene [19]. The reaction was carried outwith vigorously stirring in a microwave reactor (MicroSYNTH MLSETHOS 1600 URM) for 22 min to reflux. The reaction mixture wasfiltered while hot, let stand at 20 C and then at 4 C for 24 h. Thecrude productwas filtered off and once or more times recrystallizedfrom aqueous ethanol to obtain the pure product. The mother liquorwas partly evaporated to the crystallization to obtain thesecond portion of crude product.
5-bromo-N-(6-bromo-1,3-benzothiazol-2-yl)-2-hydroxy-N-methylbenzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
9%
General procedure: A mixture of salicylic acid (72 mg, 0.52 mmol, 1.0 eq.) and PCl3(23 µL, 0.26 mmol, 0.5 eq.) in chlorobenzene was heated at reflux temperature during 15 minutes. After cooling at room temperature, 6-bromo-1,3-benzothiazol-2-amine (120 mg, 0.52 mmol, 1.0 eq.) was added and the reaction was stirred at reflux temperature during 3 hours. The mixture was diluted with ethanol, filtered and the solid residue was triturated with methyltert-butylether to afford26fas an off-white solid (70 mg, 39 %).
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; Inert atmosphere;
General procedure for peptidic coupling of anthranilic and salicylic acid derivatives :
General procedure: In a round bottom flask, 1.0 equiv. of allyl benzylamine was placed in DCM (C = 0.067mol/L) under argon. Then 1.2 equiv. of the desired tosyl/boc anthranilic acid or salicylic acid were added, followed successively by 1.2 equiv. of EDC.HCl and 1.2 equiv. of HOBt. The clear solution was stirred at room temperature or reflux until starting material was totally consumed (monitored by TLC). The reaction mixture was then quenched with water. The aqueous layer was extracted with DCM (3 times). The combined organic phases were then dried with MgSO4, filtrated and the solvent was removed under vacuum. The crude residue was purified by silica gel flash chromatography using pentane/Et2O as eluent (9:1 to 1:1).
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).
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).
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).
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).
In a 500 mL glass vessel equipped with a stirrer, a thermometer, a heating jacket and a nitrogen gas pipe was added diethyl ether 25. 0. g, 1-bromododecane 97. 38 g, metallic lithium 3. 47 g, reacted at -10 C for 2 h, followed by addition of cuprous iodide 23. 81 g l l C reaction lh. The mixture was washed with water and the layers were removed by addition of 5-bromosalicylic acid, 27 g of water Keep at 60 C 12h. After the completion of the reaction, the mixture was washed with water and the water and ether were distilled off to give a reddish-brown liquid as an alkyl salicylic acid. nuclear The magnetic analysis product contained 5-docosyl salicylic acid 97. 93%.
Multi-step reaction with 3 steps
1.1: sulfuric acid / 12 h / 109.84 °C
2.1: cesium fluoride; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / 1,4-dioxane; water / 14 h / 90 °C
3.1: boron tribromide / dichloromethane / -78 - 20 °C
3.2: 24 h / 49.84 °C
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 14h;
1-Ethyl-3-(3- dimethylaminopropyl)carbodiimide (5.20 g, 27.64 mmol, 2 eq.) was added to a stirred solution of 83 (3.0 g, 13.82 mmol, 1 eq.), <strong>[32372-82-0]isoindoline hydrochloride</strong> (3.22 g, 20.73 mmol, 1.5 eq.), 1- hydroxybenzotriazole (3.73 g, 27.64 mmol, 2 eq.) N,N-diisopropylethylamine (4.81 mL, 27.64 mmol, 2 eq.) in dichloromethane (150 mL) at 0 C. The resulting solution was stirred at rt for 14 h before quenching with saturated sodium bicarbonate solution (120 mL). The organic layer was washed with 1 M hydrochloric acid solution (120 mL) and saturated sodium chloride solution (120 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (Si02, 1 :4 hexanes/ethyl acetate) to afford 84 (3.24 g,77.9 %) as a white amorphous solid. 1H NMR (400 MHz, CDC13) delta 10.92 (s, 1H), 7.73 (d, J= 2.2 Hz, 1H), 7.48 (dd, J= 8.8, 2.4 Hz, 1H), 7.34 (s, 4H), 6.94 (d, J= 8.8 Hz, 1H), 5.10 (s, 4H).13C NMR (100MHz, CDCI3) delta 169.4, 159.4, 136.1 (2), 134.8, 130.5, 128.2 (2), 122.8 (2), 120.2, 118.7 110.2, 55.8, 53.3. HRMS (ESI+) m/z [M + H+] calcd for C15H13BrN02, 318.0130, found 318.0119.
Multi-step reaction with 3 steps
1.1: thionyl chloride / N,N-dimethyl-formamide; dichloromethane / 2 h / 50 °C
1.2: 0.5 h
2.1: potassium carbonate / N,N-dimethyl-formamide / 16 h / 20 °C
3.1: lithium hydroxide monohydrate / methanol; water / 3 h / 20 °C
Stage #1: (2,4-difluorophenyl)magnesium bromide With titanium (IV) ethoxide In tetrahydrofuran for 0.5h; Inert atmosphere;
Stage #2: 5-bromosalicyclic acid With iron(III) chloride; N,N,N,N,-tetramethylethylenediamine In tetrahydrofuran; toluene Inert atmosphere; Reflux;
2 Example 1. Preparation of diflunisal
In an argon atmosphere,Ti (OEt) 4 (456 mg, 2 mmol) and 2 mL of THF were added to a 25 mL three-necked flask, and 17 mL of a 2,4-difluorophenylmagnesium bromide tetrahydrofuran solution was added dropwise at room temperature.(From 2,4-difluorobromobenzene according to literature methods [Osborne, C.A .; Endean, T.B.D .; Jarvo.E.R.Org.Lett., 2015, 17,5340.]; 1M in THF, 17mmol),After dripping, stirring was continued for 30 min, and the resulting mixture was set aside.Take another three-necked flask, add 5-iodosalicylic acid (1.32g, 5mmol) and 5mL THF under argon atmosphere, stir for a while,Add FeCl3 (81.2mg, 0.5mmol),TMEDA (232mg, 2.0mmol) and 8mL toluene (THF / toluene 3: 1),After stirring for about 10 minutes,Slowly add the prepared titanium reagent, and stir and reflux for 6 to 8 hours.The reaction was completed (TLC tracking). Dilute hydrochloric acid was added until the reaction was clear.The product was extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate, rotary evaporated, and separated by column chromatography to obtain 1.1 g of the product. Yield: 85%.
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