* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 2, p. 644 - 651
2
[ 2486-70-6 ]
[ 7697-28-1 ]
Yield
Reaction Conditions
Operation in experiment
90%
Stage #1: With hydrogen bromide In water at 25℃; for 1 h; Stage #2: With sodium nitrate In water at -2 - -1℃; for 1.75 h; Stage #3: With hydrogen bromide; copper(I) bromide In water at -2 - 70℃; for 2 h;
Example 1 b:4-Bromo-3-methyl-benzoic acidA suspension of compound of Example 1a (73 g, 0.483 mol) in water (411 mL) and 47percent HBr (486 mL) was stirred at 250C for 1 h and then the reaction mixture was cooled to -20C. A solution of sodium nitrate (32 g, 0.463 mol) in water (10OmL) was added to the reaction mixture over a period of 15 min, maintaining the temperature at -1 0C to -2°C. The reaction mixture was stirred at -1 0C to -20C for 1.5h. The reaction mixture was added slowly to a suspension of copper(l)bromide (73 g, 0.508 mol) in water (73 mL) and aqueous HBr (73 mL). The reaction mixture was stirred at 250C for 1 h and then digested at 70 °C for 1 h. The solid was filtered, washed with water till the pH of the filtrate was 7 and dried to obtain the title compound. Yield: 94 g (90percent); 1H NMR (DMSOd6, 300 MHz): δ 2.37 (s, 3H1 CH3), 7.64 (m, 2H1 Ar)1 7.87 (s, 1 H, Ar); MS: m/e (ES-) 214 (M-1).
Reference：
[1] Patent: WO2006/51477, 2006, A2, . Location in patent: Page/Page column 54
[2] American Chemical Journal, 1881, vol. 3, p. 431
[3] Patent: US5409928, 1995, A,
3
[ 583-70-0 ]
[ 7697-28-1 ]
Reference：
[1] Patent: EP1820799, 2007, A1,
[2] Patent: WO2006/51851, 2006, A1, . Location in patent: Page/Page column 64-65
[3] Journal of Chemical Education, 1938, vol. 15, p. 217
[4] Journal of Organic Chemistry, 1967, vol. 32, p. 134 - 136
Reference：
[1] Journal of Organic Chemistry, 2005, vol. 70, # 4, p. 1501 - 1504
6
[ 146308-26-1 ]
[ 7697-28-1 ]
[ 78881-21-7 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1992, # 24, p. 3439 - 3450
[2] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1992, # 24, p. 3439 - 3450
7
[ 109-72-8 ]
[ 615-59-8 ]
[ 7697-28-1 ]
Reference：
[1] Journal of the American Chemical Society, 1940, vol. 62, p. 2327,2333
8
[ 615-59-8 ]
[ 5156-01-4 ]
[ 7697-28-1 ]
Reference：
[1] Journal of the American Chemical Society, 1940, vol. 62, p. 2327,2333
9
[ 92243-75-9 ]
[ 7697-28-1 ]
Reference：
[1] Chemische Berichte, 1882, vol. 15, p. 40
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1992, # 24, p. 3439 - 3450
[2] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1992, # 24, p. 3439 - 3450
To a solution of 4-Bromo-3-methyl-benzoic acid (3 g, 13.19 mmol) in MeOH (15 ml) was added conc. H2SO4 (0.6 ml). The mixture was refluxed for 14 h, cooled to 0° C., nuetralized with saturated NaHCO3, and filtered to give a solid. This material was purified by column chromatography to give 4-Bromo-3-methyl-benzoic acid methyl ester (3.1 g, 97percent) as a white solid.
93%
Stage #1: for 0.416667 h; Stage #2: for 18 h; Heating / reflux
26d) methyl 4-bromo-3-methylbenzoateAcetyl chloride (20 ml_) was added drop-wise to methanol (100 ml_) during 20 min then the mixture stirred for 5 min. 4-Bromo-3-methylbenzoic acid (16.1 g, 75 mmol) was added and the mixture heated to reflux then stirred for 18 h. The solvent was evaporated and the residue dissolved in EtOAc (300 ml_). This was washed with cold 0.5 M NaOH(aq) (20 ml_), water (10 ml_) then dried (MgSO4), filtered and evaporated under reduced pressure to give an oil which solidified on standing to give the title compound as a white solid (16.0 g, 93percent), mpt: 38-41 0C.
69%
Stage #1: for 4 h; Reflux Stage #2: for 2 h; Reflux
Step 1: Preparation of methyl 4-bromo-3-methylbenzoate A stirred suspension of 4-bromo-3-methylbenzoic acid (2.15 g, 10 mmol) in thionyl chloride (10 mL) was refluxed for 4 h, cooled to rt and concentrated under reduced pressure. The residue was dissolved in MeOH (15 mL) and the reaction mixture was refluxed for 2 h. The mixture was cooled to rt and concentrated under reduced pressure. The residue was dissolved in EA (10 mL), washed with water, dried over MgSO4, filtered and concentrated under reduced pressure to give methyl 4-bromo-3-methylbenzoate (2.07 g; yield 69percent) as a red solid.
Reference：
[1] Patent: US2011/71150, 2011, A1, . Location in patent: Page/Page column 33
[2] Angewandte Chemie - International Edition, 2008, vol. 47, # 44, p. 8482 - 8486
[3] Patent: WO2006/110173, 2006, A2, . Location in patent: Page/Page column 78
[4] Chemical Communications, 2018, vol. 54, # 65, p. 9051 - 9054
[5] Patent: US2013/131016, 2013, A1, . Location in patent: Paragraph 0189
[6] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 24, p. 6707 - 6713
[7] Patent: WO2009/43889, 2009, A2, . Location in patent: Page/Page column 123
[8] Patent: WO2012/58187, 2012, A1, . Location in patent: Page/Page column 112
[9] Patent: WO2014/99836, 2014, A1, . Location in patent: Page/Page column 29; 31
With lithium aluminium tetrahydride In tetrahydrofuran at 0℃; for 0.25 h;
4-Bromo-5-methylbenzylalcohol (2) LiAlH4 (1.75 g, 46 mmol) was added in portions to a stirred solution of 4-bromo-5-methylbenzoic acid (10 g, 46 mmol) in THF (100 mL) at 0° C. After 15 min, H2O (50 mL) was added drop wise to the reaction which was then extracted with EtAOc (100 mL*3). The combined organic layers were washed with brine (200 mL*2), dried (Na2SO4), and concentrated under reduced pressure to yield compound 2 as a light yellow syrup (9.25 g, 46 mmol, 100percent yield). 1H NMR, (400 MHz, CDCl3): δ 7.52 (d, J=8.2 Hz, 1H), 7.25 (d, J=2.4 Hz, 1H), 6.88-7.10 (m, 1H), 4.63 (s, 2H), 2.43 (s, 3H).
98%
Stage #1: With borane-THF In tetrahydrofuran at 0 - 25℃; Stage #2: With methanol; water In tetrahydrofuran
Preparation of (4-bromo-3-methylphenyl)methanol [0163] To a solution of 4-bromo-3-methylbenzoic acid (30 g, 0.14 mol) in THF 300 mL) was added borane (10 M in THF, 70 mL, 0.7 mol) dropwise at 0 °C and the mixture was stirred at room temperature overnight. The reaction was quenched with methanol and water (10 mL). After removal of the solvent by rotary evaporation, the residue was extracted with dichloromethane. The organic layer was washed with brine, dried over Na2S04 and concentrated to give (4-bromo-3- methylphenyl)methanol (27.5 g, 98percent). 1H NMR (400 MHz, CDC13) δ 7.52-7.50 (d, 1H), 7.25 (s, 1H), 7.06-7.04 (d, 1H), 4.63 (s, 2H), 2.41 (s, 3H).
96%
With borane-THF In tetrahydrofuran at 20℃;
General procedure: 4-bromo-3-methylbenzoic acid (9.9 g, 46.04 mmol) was dissolved in THF (200 mL),to this was slowly added BH3.THF (1.0 M solution in THF) (92 mL, 92.07 mmol). Once added the reaction was stirred for 3 hours. The reaction was slowly/carefullyquenched with saturated Na2CO3 (100 mL), extracted with Et2O (2 x 200 mL), theorganic layer was dried over MgSO4, filtered and evaporated to afford colourless liquid. The crude product was purified by distillation at 1.5 mBar, collecting fractionsthat distilled at 90 °C to afford (4-bromo-3-methylphenyl)methanol (8.90 g, 96 percent) as acolourless liquid.
Reference：
[1] Journal of Medicinal Chemistry, 2010, vol. 53, # 10, p. 3973 - 4001
[2] Patent: US2014/51863, 2014, A1, . Location in patent: Paragraph 0208; 0298-0300
[3] Tetrahedron Letters, 2007, vol. 48, # 52, p. 9144 - 9147
[4] Patent: WO2015/42532, 2015, A1, . Location in patent: Paragraph 0163
[5] Journal of Organic Chemistry, 2003, vol. 68, # 19, p. 7204 - 7218
[6] Synlett, 2014, vol. 25, # 1, p. 123 - 127
[7] Bioorganic and Medicinal Chemistry Letters, 1996, vol. 6, # 22, p. 2651 - 2656
[8] Patent: US5596006, 1997, A,
[9] Patent: US2013/131016, 2013, A1,
[10] Organic Letters, 2014, vol. 16, # 9, p. 2318 - 2321
30
[ 7697-28-1 ]
[ 158429-38-0 ]
Reference：
[1] Chemistry - A European Journal, 2004, vol. 10, # 1, p. 92 - 100
31
[ 7697-28-1 ]
[ 73183-34-3 ]
[ 269409-74-7 ]
Yield
Reaction Conditions
Operation in experiment
90%
With potassium acetate In N,N-dimethyl-formamide at 120℃; for 0.25 h; Microwave irradiation
A mixture of 4-bromo-3-methylbenzoic acid (1 g, 4.65 mmol), 4,4,5, 5,41^1, 5',5'- Octamethyl-[2,2']bi[[1 ,3,2]dioxaborolanyl] (1.77 g, 6.97 mmol), [1 ,1'-bis(diphenyl- phosphino)ferrocene]dichloropalladium(ll) complex with dichloromethane (1 :1 ) (379 mg, 0.46 mmol) and potassium acetate (2.3 g, 23.2 mmol) in N,N-dimethyl formamide (23 ml_) was heated in a microwave system ("Initiator sixty" from Biotage.(R).) at 120 0C for 15 minutes. The solvent was evaporated under reduced pressure and the residue suspended in a HCI 2N/ ethyl acetate mixture (40 ml_, 1 :1 v/v). It was filtered through sintered glass and the aqueous phase extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulphate and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica flash, using hexane/ethyl acetate (7/3) as eluents, to yield the title compound 1.1 g, 90percent) as a white solid.H1-NMR δ (CDCI3): 1.36 (s, 12H), 2.59 (s, 3H), 7.85-7.90 (m, 3H).
Reference：
[1] Journal of Medicinal Chemistry, 2009, vol. 52, # 17, p. 5531 - 5545
[2] Patent: WO2007/96072, 2007, A2, . Location in patent: Page/Page column 36
[3] Patent: WO2008/51493, 2008, A2, . Location in patent: Page/Page column 145
1 (1) Preparation of ethyl 3-methyl-4-bromobenzoate:
5 g of 3-methyl-4-bromobenzoic acid was dissolved in 30 ml of ethanol, and 2 ml of thionyl chloride was added thereto.The reaction was refluxed at 83 ° C for 6 hours, the solution was cooled to room temperature, and 30 ml of saturated sodium carbonate solution was added.Stir well, extract 15 ml 3 with ethyl acetate, and wash the organic layer with 10 ml 2 and 10 ml of saturated brine.Dry over anhydrous magnesium sulfate, filter and concentrate under reduced pressure.Obtaining a reddish brown ethyl 2-methyl-4-bromobenzoate,5.42 g, yield 96%.
80%
With sulfuric acid In toluene for 1h; Heating;
With hydrogenchloride
With sulfuric acid at 95℃;
29.1
Step 1: 4-Bromo-3-methyl-benzoic acid ethyl ester To 4-bromo-3-methylbenzoic acid (16.27 g, 75.7 mmol) in EtOH (500 mL) was added concentrated sulfuric acid (0.5 mL), and the reaction was stirred at 95° C. overnight. Additional sulfuric acid (2 mL) was added and then the mixture was quenched with the slow addition of sodium carbonate. The mixture was filtered and concentrated, and the residue was diluted and washed with H2O twice, saturated aqueous NaHCO3, brine, and H2O to give the title compound.
With thionyl chloride at 50℃;
34.1
Step 1: 4-Bromo-3-methyl-benzoic acid ethyl ester 4-bromo-3-methylbenzoic acid (3 g, 14 mmol) in EtOH (200 mL) was added thionyl chloride (2 mL, 28 mmol), and the reaction was stirred for 10 minutes. Additional thionyl chloride (3 mL, 35 mmol) was added, and the reaction was stirred overnight at 50° C. After cooling to room temperature, the mixture was quenched with the slow addition of powdered Na2CO3, and then filtered and concentrated. The residue was partitioned between EtOAc and H2O, and the organic layer was dried, filtered, and concentrated to give the title compound.
With sulfuric acid at 95℃;
1.2
Step 2: To 4-bromo-3-methylbenzoic acid (16.27 g, 75.7 mmol) in EtOH (500 mL) was added concentrated sulfuric acid (0.5 mL), and the reaction was stirred at 95° C. overnight. Additional sulfuric acid (2 mL) was added to push the reaction to completion, and then the mixture was quenched with the slow addition of sodium carbonate. The mixture was filtered and concentrated, and the residue was diluted and washed with H2O twice, saturated aqueous NaHCO3, brine, and H2O to give 4-bromo-3-methyl-benzoic acid ethyl ester.
at 0℃; for 6h; Heating / reflux;
1.01
Example 1; 3-[4-(2-Butyl-4-oxo-l, 3-diaza-spiro [4.4] non-l-en-3-ylmethyl)-2-ethoxymethyl-phenyl]- 5-methyl-thiophene-2-sulphonic acid (4, 5-dimethyl-isoxazol-3-yl)-amide; STEPOl: Synthesis of 4-Bromo-3-methyl benzoic acid ethyl ester.; To the cooled (O0C) solution of 4 bromo-3 methyl benzoic acid (25 gm, 0.116 mol) in (100 ml) ethanol was added (8 ml) of concentrated sulphuric acid with stirring. After the completion of the addition, the reaction mixture was refluxed for 6 hrs. The reaction mixture was cooled and then concentrated under vacuum. To the residue was added (50 ml) of cold water, followed by extraction with diethyl ether (100 ml x2). The organic layer was washed with saturated sodium bicarbonate solution, followed by water and brine solution washings. Finally the ether layer was dried over sodium sulphate and evaporated under vacuum to give 26 gm of 4-bromo-3 methyl benzoic acid ethyl ester.
With thionyl chloride for 2h; Reflux;
74.1 Step 1: ethyl 4-bromo-3-methylbenzoate
To a solution of 4-bromo-3-methylbenzoic acid (commercially available) (1.0 eq.) in EtOH (0.3 M) was added thionyl chloride (1.5 eq.) and heated to reflux for 2 hours. The solvent was concentrated en vaccuo, and the residue was diluted in ether and neutralized with saturated aqueous sodium bicarbonate solution. The two phases were separated, and the aqueous layer was extracted with ether. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vaccuo to give ethyl 4-bromo-3-methylbenzoate.
8.5 g
With sulfuric acid In toluene Reflux;
1.1
(1) 3-Methyl-4-bromobenzoic acid (0.093 mol)Dissolved in a mixed solvent of ethanol and toluene (1: 1,560 ml)Add the catalytic amount of concentrated sulfuric acid after reflux reaction overnight,After completion of the reaction, the resulting organic phase was extracted with methylene chloride and neutralized with sodium bicarbonate.dry,After concentration, it was dissolved in carbon tetrachloride (200 ml) and N-bromosuccinimide (6.5 g)After three days of reflux reaction,Cooling filter,The filtrate was concentrated and spin-dried to give 11 g of bromide,Was dissolved in methanol (200 ml)Sodium formate (8.87 g)After the reaction was refluxed for 6 hours,concentrate,Purification by column chromatography gave 8.5 g of intermediate IV;
With thionyl chloride for 2h; Reflux;
74.1
To a solution of 4-bromo-3-methylbenzoic acid (commercially available) (1.0 eq.) inEtOH (0.3 M) was added thionyl chloride (1.5 eq.) and heated to reflux for 2 hours. The solvent was concentrated en vaccuo, and the residue was diluted in ether and neutralized with saturated aqueous sodium bicarbonate solution. The two phases were separated, and the aqueous layer was extracted with ether. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vaccuo to give ethyl 4-bromo-3-methylbenzoate.
Reference Example 50 39% Nitric acid (300 mL) suspension containing <strong>[583-70-0]4-bromo-m-xylene</strong> (50 g, 0.26 mol) was heated under reflux for 24 hours. The reaction solution was cooled on an ice bath and then left in a refrigerator (5C) for 3 days. The precipitated crystals were collected by filtration, washed with distilled water and then with hexane, and dried under reduced pressure, to obtain 4-bromo-3-methylbenzoic acid (33.54 g, 60.0%) as colorless crystals. 1H-NMR(DMSO-d6)delta:2.40(3H,s),7.63-7.75(2H,m)7.90 (1H,dd,J=3.9,5.9Hz),12.75-13.66(1H,br)ppm
Example 1 b:4-Bromo-3-methyl-benzoic acidA suspension of compound of Example 1a (73 g, 0.483 mol) in water (411 mL) and 47% HBr (486 mL) was stirred at 250C for 1 h and then the reaction mixture was cooled to -20C. A solution of sodium nitrate (32 g, 0.463 mol) in water (10OmL) was added to the reaction mixture over a period of 15 min, maintaining the temperature at -1 0C to -2C. The reaction mixture was stirred at -1 0C to -20C for 1.5h. The reaction mixture was added slowly to a suspension of copper(l)bromide (73 g, 0.508 mol) in water (73 mL) and aqueous HBr (73 mL). The reaction mixture was stirred at 250C for 1 h and then digested at 70 C for 1 h. The solid was filtered, washed with water till the pH of the filtrate was 7 and dried to obtain the title compound. Yield: 94 g (90%); 1H NMR (DMSOd6, 300 MHz): delta 2.37 (s, 3H1 CH3), 7.64 (m, 2H1 Ar)1 7.87 (s, 1 H, Ar); MS: m/e (ES-) 214 (M-1).
With hydrogen bromide; sodium nitrite;copper(I) chloride; In water;
(1) Preparation of ethyl 4-bromo-3-methylbenzoate To an aqueous solution of 47% hydrobromic acid (60 ml) and water (60 ml) was added <strong>[2486-70-6]4-amino-3-methylbenzoic acid</strong> (10 g, 0.066 mol), and the mixture was stirred at room temperature for 2 hours. After ice-cooling, a solution obtained by dissolving sodium nitrite (5.3 g, 0.066 mol) in water (25 ml) was added, and the mixture was stirred for 2 hours as it was. To the mixture was added copper(I) chloride (10 g, 0.07 mol) was added, and the mixture was stirred at room temperature for 15 hours. The precipitate was separated by filtration, washed with water, and dried to give 4-bromo-3-methylbenzoic acid. This product was dissolved in ethanol (100 ml), and thereto was added conc.
With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 50℃; for 0.5h;
EXAMPLE 104 3-(4-(5-(3-Cyano-4-(2-methylpropyl)phenyl)-1, 3, 4-thiadiazol-3-yl)-5-methylphenyl)propanoic acid; Step A: 2-Amino-5- (4-bromo-3-methylphenyl)-1, 2,4-thiadiazole; In an oven-dried round bottom flask, 7. 0g of <strong>[7697-28-1]4-bromo-3-methylbenzoic acid</strong> (32.6 mmol) was dissolved in lOmL of dichloromethane, 30 mL of dimethyl formamide was added to the solution and the resulting mixture was treated with 7.0 mL of oxalyl chloride at 50C for 30 min. The reaction mixture was cooled to rt and solvents were removed under reduced pressure. The residual white solids were dissolved in 50 mL of EtOAc and added over 10 minutes to a stirring biphasic system consisting of 150 mL of EtOAc, 150 mL of saturated solution of sodium bicarbonate, and 7.5g of thiosemicarbazide (81. 4mmol). The resulting reaction mixture was allow to stir at rt for 3 h, organic layer was separated and aqueous was extracted with 2 x 250mL of EtOAc. Combined organic extracts were dried over sodium sulfate and concentrated to yield a crude product, contaminated with thiosemicarbazide. This crude material was treated with 25 mL of neat sulfuric acid at rt for 30 minutes. The reaction mixture was diluted with 500 mL of ice-water mixture and basified with solid sodium hydroxide to pH > 13, controlling the isotherm by an external ice-bath. The basic heterogeneous solution was extracted 3 x 300 mL of EtOAc, organic extracts dried over sodium sulfate and concentrated. The crude product was purified by column chromatography using Biotage 40L cartridge (eluant hexanes/EtOAc = 1/1) yielding 3.7g of the title compound : 1H NMR (500 MHZ, CDC13) 8 2.56 (s, 3H), 5.28 (s, 2H), 7.42 (d, J = 6.5, 1H), 7.44 (d, J = 6.5, 1H), 7.49 (s, 1H).
With thionyl chloride; for 2h;Heating / reflux;
A stirred suspension of <strong>[7697-28-1]4-bromo-3-methylbenzoic acid</strong> (15 g, 69.0 mmol) in thionyl chloride (60 mL) was heated at reflux for 2 h and then concentrated under reduced pressure.The residual acyl chloride was dissolved in dichloromethane (300 mL) and added to a stirred solution of lambda/,O-dimethylhydroxylamine hydrochloride (7.2 g, 72.0 mmol) and pyridine(16.8 mL, 207.0 mmol) in dichloromethane (450 mL) at -20 0C. The reaction mixture was allowed to warm to room temperature overnight and then washed with 1 M aqueous potassium carbonate solution. The aqueous solution was extracted with dichloromethane.The organic extracts were concentrated under reduced pressure. The residue was purified by chromatography on silica gel using 50% ethyl acetate/hexanes as eluent to afford the title product as a pale yellow oil (17.81 g, 69.0 mmol, 100% yield).1H NMR (CDCl3): 7.55 (m, 2H), 7.37 (m, IH), 3.54 (s, 3H), 3.34 (s, 3H), 2.42 (s, 3H).
With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 6h;
Oxalyl chloride (15.8 mL, 181 mmol) was added to a stirred suspension of <strong>[7697-28-1]4-bromo-3-methylbenzoic acid</strong> (6.00 g, 27.9 mmol) in anhydrous CH2Cl2 (40 mL), followed by the addition of 2 drops of DMF. The suspension was stirred at room temperature under nitrogen atmosphere for 6 h, then it was concentrated to dryness. To the crude benzoyl chloride suspended in anhydrous chlorobenzene (50 mL) was added 6-benzyloxy-2-(dimethyl-amino)benzo[b]thiophene (6.33 g, 22.3 mmol). The resultant mixture was heated in an oil bath at 110 C. for 2 h. At room temperature, the mixture was diluted with EtOAc (160 mL) before it was cautiously treated with saturated NaHCO3 (50 mL). The organic layer was dried over MgSO4, filtered, concentrated, and chromatographed on silica [gradient 0-5% EtOAc in toluene] to give 7.49 g (70%) of the amino-ketone as a foam. IR (neat) 3450, 1623, 1598 cm-1; FDMS m/e 479 (M+, 79Br) and 481 (M+, 81Br); Anal. Calcd. for C25H22BrNO2S: C, 62.50; H, 4.62; N, 2.92. Found: C, 62.77; H, 4.59; N, 2.87.
With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 20℃;
Step 1: 4-Bromo-3-methyl-benzoyl chlorideTo <strong>[7697-28-1]4-bromo-3-methylbenzoic acid</strong> (8.6 g, 40.0 mmol) in CH2Cl2 was added DMF (0.4 mL), followed by oxalyl chloride (3.7 mL, 42 mmol) slowly over 10 minutes by syringe. The reaction was stirred for 1 hour at room temperature, and then concentrated to give the title compound.
With thionyl chloride;N,N-dimethyl-formamide; In toluene; at 20℃;Reflux;
To a suspension of <strong>[7697-28-1]3-methyl-4-bromobenzoic acid</strong> 24-1 (2.15 g, 10 mmol) in toluene (15 niL, anhydrous) were added SOCl2 (1.4 rnL, -1.9 eq) and 3 drops of DMF at room temperature. The mixture was refluxed 2 hours with stirring. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in THF (25 mL, anhydrous) and then at 0 0C NEt3 (2.2 mL) and TMSCHN2 (8.2 mLx2.0 M in hexanes) were added. After 12 hours of stirring the mixture was poured into saturated NaHCO3 solution (60 mL) and extracted with ethyl acetate (3x60 mL). The combined extracts were washed with brine, dried over Na2SO4 and evaporated to give the crude intermediate 24-3. This crude intermediate was added in small portions to a refluxed solution of NEt3 (4.2 mL), PhCO2Ag (0.70 g) in t-butanol (50 mL) and toluene (20 mL) with stirring. After 1 hour of refluxing, the reaction mixture was cooled to room temperature. Activated carbon powder was added to the reaction mixture which was then filtered through Celite. The filtrate was diluted with ethyl acetate (100 mL) and washed with brine. After dried over Na2SO4, the resulting solution was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with DCM-EtOAc (30:1) as eluent to afford the t-butyl ester 24-4.
With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 3h;Inert atmosphere;
To a suspension of commercially available <strong>[7697-28-1]4-bromo-3-methyl benzoic acid</strong> (S1) in dichloromethane (130mL) was added a catalytic amount of DMF (4-5 drops) and 70mL oxalyl chloride (2.0M, 140 mmol) in dichloromethane slowly over 5 minutes via addition funnel. The reaction was stirred at room temperature under a nitrogen atmosphere for 3 hours then the reaction was placed in a warm water bath for 30 minutes until the reaction appeared homogeneous. The reaction was allowed to stir at room temperature under a nitrogen atmosphere overnight. Volatiles were removed from the reaction in vacuuo using a rotary evaporator and the reaction residue was dissolved in anhydrous THF (150mL) and cooled to 0C under a nitrogen atmosphere. Potassium tert-butoxide (13.86g, 123.5 mmol) in THF (150mL) was added slowly to the reaction via cannula. Upon complete otassium tert-butoxide addition, the ice bath was removed and the reaction was allowed to warm to room temperature and stir for 2.5 hours. The reaction was concentrated in vacuuo using a rotary evaporator and water was added to the reaction. The mixture was extracted with ethyl acetate. The organic extracts were combined and washed sequentially with water and brine. The organic extract was dried over magnesium sulfate and 2.5g of activated charcoal added to the mixture. The organic extract was filtered through a bed of celite and solvent removed from the filtrate in vacuuo using a rotary evaporator to yield 31.36g of product as a red oil.1H NMR (300 MHz, CHLOROFORM-d) delta 7.84 (d, J=1.46 Hz, 1H), 7.62-7.68 (m, 1H), 7.54-7.60 (m, 1H), 2.44 (s, 3H), 1.59 (s, 9H)HPLC retention time: 1.76 min.
With thionyl chloride; In toluene; at 80℃; for 4h;Inert atmosphere;
Example 8: compound (65) in table I <strong>[7697-28-1]4-bromo-3-methylbenzoic acid</strong> (9.92 g, 40 mmoles, 1 eq.) was placed in toluene (40 mL) under an inert atmosphere of argon. Thionyl chloride (6 mL, 80 mmoles, 2 eq.) was slowly added. The reaction mixture was heated at 80C and stirred for 4 hours. Upon cooling to room temperature, the reaction mixture was concentrated under reduced pressure. 3-Methyl-1-butanamine (1.393 mL, 12 mmoles, 2 eq.) was placed in a 3N NaOH aqueous solution (8 mL) and dichloromethane (4 mL) was added to the solution. The reaction mixture was cooled down to 0C with an ice bath and a solution of the 4-bromo-3-methyl benzoyl chloride residue (6 mmoles, 1 eq.) in dichloromethane (26 mL) was added dropwise. The reaction mixture was then stirred at room temperature for 18 hours under an inert atmosphere of argon. Upon decantation, the organic phase was washed with water, dried over MgSO4, filtered and concentrated under reduced pressure to afford 4-bromo-3-methyl-N-(3-methylbutyl)benzamide (1.44 g, 84%). 1H NMR (300 MHz, CDCl3) delta 7.64 (s, 1H), 7.58 (d, J = 8.2 Hz, 1H), 7.40 (d, J = 8.2 Hz, 1H), 6.02 (s, 1H), 3.47 (q, J = 7.0 Hz, 2H), 2.45 (s, 3H), 1.69 (heptuplet, J = 6.6 Hz, 1H), 1.51 (q, J = 7.0 Hz, 2H), 0.96 (d, J = 6.6 Hz, 6H).
1.1 g
With thionyl chloride; for 1h;Reflux;
bromo-3-methyl-benzoyl chloride lg <strong>[7697-28-1]4-bromo-3-methyl-benzoic acid</strong> in 20 g thionylchloride was refluxed lh. The reaction was evaporated to give l . lg desired product.
1.1 g
With thionyl chloride;Reflux;
6.01.23.01 4-bromo-3-methyl-benzoyl chloride 1 g <strong>[7697-28-1]4-bromo-3-methyl-benzoic acid</strong> in 20 g thionylchloride was refluxed 1 h. The reaction was evaporated to give 1.1 g desired product.
With thionyl chloride;
Synthesis of 4-bromo-3-methylbenzoyl chloride A mixture of <strong>[7697-28-1]4-bromo-3-methylbenzoic acid</strong> (5.0 g, 23.25 mmol) and thionylchloride (50 ml) was refluxed for 5 hours. After removal of thionyl chloride, the residue was dried under high vacuum and used in next step without further purification.
With thionyl chloride; In dichloromethane; N,N-dimethyl-formamide; at 20℃;Inert atmosphere;
General procedure: Under inert atmosphere, a mixture of carboxylic acid 21-31 ( Scheme 1 ) (1 equiv), thionyl chloride (1.5 equiv) and DMF (3-5 drops) in dichloromethane was stirred at rt until the complete consumption of the carboxylic acid (1H NMR control). The pale yellow solution was concentrated in vacuo to give the crude acid chloride 32-42 ( Scheme 1 ) as a yellow pale solid in quantitative yield
With thionyl chloride;N,N-dimethyl-formamide; at 70℃; for 1h;
Step 15; Suspend 4-bromo-3-mettiylbenzotepsilon acid (39 mg, 0,18 mmol) in thionyf chloride (600 muL) and add DMF (10 muL) Stir for about 1 h at TQ0C, Evaporate the votatiles, then co-evaporate with DCE, To the rematrting residue,, add Sa12 (20 mg, 0,0? mmol) fn DCE and add pyridine (25 muL, 0.31 mmol). Heat to 1S0C for 15 min in a microwave. Diiyte with THF and treat with polystyrene-trisamine for about 2 h at RT. Filter the solids, collect the filtrate and concentrate. Add DMSO (1 mL) and S N NaOH (aqueous, 0.15 mL) and stir at RT for about 3 h. Acidify with excess AcOH. Purification and fyophilizatto? of the voiatifes affords 2022.
With thionyl chloride; for 2h;Heating / reflux;
Preparation of ^[S-CS^-dichloropheny^^.S-dihydro-l-methyl-S-Ctrifluoromethyl)- lH-pyrazol-3-yl]-2-methyl-lambdaT-(2-pyridinylmethyl)benzamide; Step A: Preparation of 4-bromo-7V-methoxy-lambda^,3-dimethylbenzamide; A stirred suspension of 4-bromo-3-rnethylbenzoic acid (15 g, 69.0 mmol) in thionyl chloride (60 mL) was heated at reflux for 2 h and then concentrated in vacuo. The residual acyl chloride was dissolved in dichloromethane (300 mJL) and added to a stirred solution of iV.O-dirnethylhydroxylamine hydrochloride (7.2 g, 72.0 mmol) and pyridine (16.8 mL, 207.0 <n="31"/>mmol) in dichloromethane (450 mL) at -20 0C. The reaction mixture was allowed to warm to room temperature overnight and then washed with 1 M aqueous potassium carbonate solution. The aqueous solution was extracted with dichloromethane. The organic extracts were concentrated under reduced pressure. The residue was purified by chromatography on silica gel using 50% hexanes/ethyl acetate as eluent to afford the title product as a pale yellow oil (17.81 g, 69.0 mmol, 100% yield). 1H NMR (CDCl3): 7.55 (m, 2H), 7.37 (m, IH), 3.54 (s, 3H), 3.34 (s, 3H), 2.42 (s, 3H).
With lithium aluminium tetrahydride; In tetrahydrofuran; at 0℃; for 0.25h;
4-Bromo-5-methylbenzylalcohol (2) LiAlH4 (1.75 g, 46 mmol) was added in portions to a stirred solution of 4-bromo-5-methylbenzoic acid (10 g, 46 mmol) in THF (100 mL) at 0 C. After 15 min, H2O (50 mL) was added drop wise to the reaction which was then extracted with EtAOc (100 mL*3). The combined organic layers were washed with brine (200 mL*2), dried (Na2SO4), and concentrated under reduced pressure to yield compound 2 as a light yellow syrup (9.25 g, 46 mmol, 100% yield). 1H NMR, (400 MHz, CDCl3): delta 7.52 (d, J=8.2 Hz, 1H), 7.25 (d, J=2.4 Hz, 1H), 6.88-7.10 (m, 1H), 4.63 (s, 2H), 2.43 (s, 3H).
98%
Preparation of (4-bromo-3-methylphenyl)methanol [0163] To a solution of 4-bromo-3-methylbenzoic acid (30 g, 0.14 mol) in THF 300 mL) was added borane (10 M in THF, 70 mL, 0.7 mol) dropwise at 0 C and the mixture was stirred at room temperature overnight. The reaction was quenched with methanol and water (10 mL). After removal of the solvent by rotary evaporation, the residue was extracted with dichloromethane. The organic layer was washed with brine, dried over Na2S04 and concentrated to give (4-bromo-3- methylphenyl)methanol (27.5 g, 98%). 1H NMR (400 MHz, CDC13) delta 7.52-7.50 (d, 1H), 7.25 (s, 1H), 7.06-7.04 (d, 1H), 4.63 (s, 2H), 2.41 (s, 3H).
96%
With borane-THF; In tetrahydrofuran; at 20℃;
General procedure: 4-bromo-3-methylbenzoic acid (9.9 g, 46.04 mmol) was dissolved in THF (200 mL),to this was slowly added BH3.THF (1.0 M solution in THF) (92 mL, 92.07 mmol). Once added the reaction was stirred for 3 hours. The reaction was slowly/carefullyquenched with saturated Na2CO3 (100 mL), extracted with Et2O (2 x 200 mL), theorganic layer was dried over MgSO4, filtered and evaporated to afford colourless liquid. The crude product was purified by distillation at 1.5 mBar, collecting fractionsthat distilled at 90 C to afford (4-bromo-3-methylphenyl)methanol (8.90 g, 96 %) as acolourless liquid.
96.3%
With dimethylsulfide borane complex; In tetrahydrofuran; at 0 - 40℃; for 5h;Inert atmosphere;
A solution of 4-bromo-3-methyl-benzoic acid (50.0 g, 232 mmol) in THF (500 mL) was cooled to 0 C. and borane dimethyl sulfide complex (35.0 mL, 350 mmol, 10M in THF) was added under nitrogen. The reaction mixture was allowed to reach ambient temperature and stirred for 2 hours followed by stirring at 40 C. for 3 hours. The mixture was cooled to 0 C. and was quenched with water (200 mL). The mixture was extracted with ethyl acetate (300 mL) and the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated give (4-bromo-3-methyl-phenyl)methanol (45.0 g, 96.3% yield) as a brown oil. 1H NMR (CDCl3, 400 MHz) delta ppm 7.51 (d, J=8.2 Hz, 1H), 7.25 (d, J=1.6 Hz, 1H), 7.05 (dd, J=1.6, 8.2 Hz, 1H), 4.63 (s, 2H), 2.41 (s, 3H).
In tetrahydrofuran; water; ethyl acetate;
EXAMPLE XI 4-Bromo-3-methylbenzyl alcohol STR21 93 ml of a 1M solution of borane-tetrahydrofuran complex in tetrahydrofuran are added dropwise to a solution of 10 g (46.5 mmol) of 4-bromo-3-methyl-benzoic acid in 100 ml of tetrahydrofuran at 0 C. under argon. After the reaction mixture has been heated to 20 C., it is stirred at this temperature for 16 hours. The excess borane complex is then destroyed by careful addition of water (end of the evolution of hydrogen), the mixture is extracted twice with in each case 250 ml of ethyl acetate and the combined organic phases are washed twice with in each case 100 ml of saturated sodium bicarbonate solution, water and saturated sodium chloride solution, dried over sodium sulphate and concentrated. The compound is reacted further without purification. Yield: 8 g (crude, 86% of theory) Rf: 0.5 (petroleum ether/ethyl acetate=2:1)
25 g (116 mmol) of <strong>[7697-28-1]4-bromo-3-methylbenzoic acid</strong> are dissolved in 250 mL of dichloromethane and the mixture is then cooled to 0 C. 10.1 mL (116 mmol) of oxalyl chloride are added slowly, followed by a few drops of dimethylformamide and 16 mL (116 mmol) of triethylamine. After 30 minutes, 12.5 g (128 mmol) of N,O-dimethylhydroxylamine hydrochloride are added slowly, followed by 35.5 mL (255 mmol) of triethylamine. The medium is stirred for 14 hours and then treated with ammonium chloride solution and extracted with dichloromethane. The crude residue is then taken up in ethyl ether and rinsed with IN sodium hydroxide solution, and then dried and concentrated. The intermediate amide obtained is dissolved in 300 mL of anhydrous THF and cooled to =78 C. 40 mL (120 mmol) of 3.0M ethylmagnesium bromide are added slowly and the reaction medium is warmed to 0 C. and then stirred for 18 hours. After the usual treatment and chromatography on silica gel (9 heptane/1 ethyl acetate), the desired product is obtained in the form of thick colourless oil (m=17 g; Y=64%).
[0108] 4-Bromo-3-methylbenzoic acid (3.5 g, 16.27 mmol) was suspendedin anhydrous dichloromethane (25 mL) under argon. DMF (0.5 mL) was added andfollowed by addition of oxalyl chloride (1.7 mL) at room temperature. The reactionmixture was stirred at room temperature for 20 min. and oxalyl chloride (0.5 mL) wasadded dropwise. The mixture was then stirred at room temperature for further 2 h. Solventwas evaporated. The residue was dissolved in anhydrous THF (25 mL) and cooled in anice-bath. A solution of potassium terf-butoxide (3.65 g, 32.52 mmol) in anhydrous THF(20 mL) was added dropwise at 0 C. The reaction mixture was stirred at roomtemperature for 1 h, and water (100 mL) was added. The mixture was extracted withEtOAc and organic phase was washed with brine and water, and dried over anhydrousMgSC>4. After evaporation of solvent, brown oil was obtained (3.78 g, 86%). MS (ESI)272.76 (M + H+).
With disodium hydrogenphosphate; disodium bis(2-aminopyrimidine-4,6-diolate)palladium acetate; In water; at 50 - 120℃; for 0.166667h;Microwave irradiation;
In a 35 mL microwave reaction vessel, commercially available 4-bromo-3- methylbenzoic acid (0.25 g, 1.16 mmol), phenylboronic acid (0.17 g, 1.4 mmol) and Na2HPO4 (0.83 g, 5.8 mmol) were sequentially added. H20 (10 mL) was added and the mixture stirred at 50 C to dissolve most of the materials. Bis-(disodium 2-aminopyrimidine-4,6-diolate) palladium acetate [prepared as described in I Am. Chem. Soc. 2009, 131, 16346-1 6347] (0.01 M in Pd(II),1.50 mL, 0.0 15 mmol) was added to the reaction and the tube was heated to 120 C under microwave irradiation for 10 mm, under vigorous stirring. After cooling to r.t., the reaction was partitioned between 1.0 M HC1 solution (100 mL) and EtOAc (100 mL). The organic layer was separated, dried over Na2SO4, and filtered through a short pad of silica gel and Celite. The collected organic phase was concentrated under reduced pressure affording the title compound(0.29 g, quant.) as a white solid, which was used in the next step without any further purification.R= 2.04 mm. MS (ESI) m/z: 213 [M-H]. MS (ESI) m/z: 211 [M-H]. ?H NMR (DMSO-d6): oe12.88 (s, 1H), 7.90-7.86 (m, 1H), 7.84-7.76 (m, 1H), 7.50-7.44 (m, 2H), 7.43-7.29 (m, 4H), 2.28(s, 3H).
With potassium fluoride;palladium diacetate; XPhos; In tetrahydrofuran; for 1h;Heating / reflux;
Example 14: 4-[5-(2-Methyl-biphenyl-4-yl)-[1 ,2,4]oxadiazol-3-yl]-benzylamine; a) 2-Methyl-biphenyl-4-carboxylic acid; To a solution of <strong>[7697-28-1]4-bromo-3-methyl-benzoic acid</strong> (2.5g, 11.6mmol) in THF (150ml) is added under inert atmosphere phenylboronic acid (2.94g, 23.4mmol), dicyclohexylphosphino-2,4,6- thisopropylbiphenyl (570mg, 1.16mmol), KF (2.7g, 60mmol) and finally Pd(OAc)2 (133mg,0.6mmol). The reaction mixture is then stirred under reflux for 1 hour. The reaction mixture is cooled and concentrated to dryness. Purification using flash chromatography afford the title compound. m/z = 211 (M-H)-
With caesium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In N,N-dimethyl-formamide; at 80℃; for 16h;
Reference Example 28 (Syn. X) 4-phenyl-3-methylbenzoic acid To an N,N-dimethylformamide solution (4.0 mL) of phenylboronic acid (36.6 mg, manufactured by Tokyo Chemical Industry Co., Ltd.) and <strong>[7697-28-1]4-bromo-3-methylbenzoic acid</strong> (43.0 mg, manufactured by Wako Pure Chemical Industries, Ltd.), [1,1'-bis(diphenylphosphino)ferrocene]dichloro palladium, dichloromethane complex (1:1) (49.0 mg, manufactured by Aldrich), cesium carbonate (163 mg, manufactured by Wako Pure Chemical Industries, Ltd.) were added. The resultant mixture was stirred for 16 hours at 80 C. After the stirring was ended, the reaction solution was concentrated, 1NHCl aqueous solution (manufactured by Wako Pure Chemical Industries, Ltd.) was added thereto, extraction was performed by using ethyl acetate, and an organic layer was dried by using magnesium sulfate. For the obtained residue, flash chromatography (as an elution solution, 2:1 (v/v) of hexane/ethyl acetate was used) was performed, so that the titled compound (14.9 mg) was obtained. ESI-MS: 211.2 (M-H), RTime 4.53 min.
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 110℃; for 5h;Inert atmosphere;
General procedure: Under an argon atmosphere, substituted 4-bromobenzoic acid(1 equiv), benzoic acid (1.1 equiv), K2CO3 (2 equiv), Pd[P(Ph)3]4 (0.1equiv) were added to dioxane/H2O (10:1). The mixture was stirredin an 110 C oil bath for 5 h. The reaction mixture was cooled toroom temperature, and the solvent was removed by rotary evaporation.The residue was dissolved in water, and the solution wasacidified with 3 N HCl until the product precipitated. The precipitatewas filtered to afford compounds 8a-n.
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; for 6h;Inert atmosphere; Reflux;
General procedure: Underan argonatmosphere, 4-bromobenzoic acid (1 equiv.), substituted boronic acid (1.2equiv.) and Pd[P(C6H5)3]4(1 mol%) weredissolved in a mixed solution ofdioxane/H2O (10:1). K2CO3(2 equiv.) was added and the mixture was heated under reflux for 6 h.Thereaction mixture was cooled to room temperatureand the dioxane was removed byrotary evaporation. H2O was added and the solution was adjusted to pH=1-3 with 2 N HCl.The whitesolid precipitate was collected by filtration and dried to give the desiredcompound.
In N-methyl-acetamide; methanol; dichloromethane; water;
EXAMPLE 21 N- (3, 4-Dimethyl-5-isoxazolyl) -2'-›(formylamino)[methyl]-4'-(2-oxazolyl)›1,1'-[biphenyl]-2-sulfonamide STR48 A. 4-Bromo-3-methylbenzamide To a solution of 10 g (46.5 mmol) of 4-bromo-3-methyl benzoic acid in 200 mL of dichloromethane under argon, 30 mL of 2M solution of oxalyl chloride in dichloromethane w as added. Four drops of dimethylformamide was then added and the mixture was stirred at room temperature for 1 hour. The soltion was evaporated and dried in vacuo. The residue was dissolved in 100 mL of methanol, and 25 mL of 28% aqueous ammonium hydroxide was added to the mixture. The solution was stirred at room temperature for 3 hours, and then diluted with 500 mL of water. The resulting white solid was filtered, washed with water and dried to afford 8.9g (89%) of compound A.
With potassium acetate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In N,N-dimethyl-formamide; at 120℃; for 0.25h;Microwave irradiation;
A mixture of 4-bromo-3-methylbenzoic acid (1 g, 4.65 mmol), 4,4,5, 5,41^1, 5',5'- Octamethyl-[2,2']bi[[1 ,3,2]dioxaborolanyl] (1.77 g, 6.97 mmol), [1 ,1'-bis(diphenyl- phosphino)ferrocene]dichloropalladium(ll) complex with dichloromethane (1 :1 ) (379 mg, 0.46 mmol) and potassium acetate (2.3 g, 23.2 mmol) in N,N-dimethyl formamide (23 ml_) was heated in a microwave system ("Initiator sixty" from Biotage) at 120 0C for 15 minutes. The solvent was evaporated under reduced pressure and the residue suspended in a HCI 2N/ ethyl acetate mixture (40 ml_, 1 :1 v/v). It was filtered through sintered glass and the aqueous phase extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulphate and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica flash, using hexane/ethyl acetate (7/3) as eluents, to yield the title compound 1.1 g, 90%) as a white solid.H1-NMR delta (CDCI3): 1.36 (s, 12H), 2.59 (s, 3H), 7.85-7.90 (m, 3H).
With triethylamine;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; at 20 - 80℃;
A. 3-Methyl-4-(4,4,5,5-tetramethyI-l,3,2-dioxaborolan-2-yl)benzoic acid.Bis (pinacolato)diboron (3.07 g, 12.09 mmol), dichloro[l,l '-bis(diphenylphosphino) ferrocene] palladium (II) dichloromethane (1 14 mg, 0.14 mmol) and triethylamine (1.95 mL, 13.95 mmol) were successively added to a solution of 4-bromo-3-methyl-benzoic acid (1.0 g, 4.65 mmol) in dioxane (15 ml). The resulting reaction mixture was allowed to stir at rt for 20 min, before being heated at 80 C in a sealed tube. The volatiles were removed under reduced pressure, and the residual oil was partitioned between water and ethyl acetate. The aqueous phase was extracted with ethyl acetate (2x). The combined organic fractions were dried over magnesium sulfate, filtered and concentrated. The crude product was used without further purification. MS (ESI) m/z 263.2 [M+ 1]+.
To a solution of 4-Bromo-3-methyl-benzoic acid (3 g, 13.19 mmol) in MeOH (15 ml) was added conc. H2SO4 (0.6 ml). The mixture was refluxed for 14 h, cooled to 0 C., nuetralized with saturated NaHCO3, and filtered to give a solid. This material was purified by column chromatography to give 4-Bromo-3-methyl-benzoic acid methyl ester (3.1 g, 97%) as a white solid.
93%
26d) methyl 4-bromo-3-methylbenzoateAcetyl chloride (20 ml_) was added drop-wise to methanol (100 ml_) during 20 min then the mixture stirred for 5 min. 4-Bromo-3-methylbenzoic acid (16.1 g, 75 mmol) was added and the mixture heated to reflux then stirred for 18 h. The solvent was evaporated and the residue dissolved in EtOAc (300 ml_). This was washed with cold 0.5 M NaOH(aq) (20 ml_), water (10 ml_) then dried (MgSO4), filtered and evaporated under reduced pressure to give an oil which solidified on standing to give the title compound as a white solid (16.0 g, 93%), mpt: 38-41 0C.
69%
Step 1: Preparation of methyl 4-bromo-3-methylbenzoate A stirred suspension of <strong>[7697-28-1]4-bromo-3-methylbenzoic acid</strong> (2.15 g, 10 mmol) in thionyl chloride (10 mL) was refluxed for 4 h, cooled to rt and concentrated under reduced pressure. The residue was dissolved in MeOH (15 mL) and the reaction mixture was refluxed for 2 h. The mixture was cooled to rt and concentrated under reduced pressure. The residue was dissolved in EA (10 mL), washed with water, dried over MgSO4, filtered and concentrated under reduced pressure to give methyl 4-bromo-3-methylbenzoate (2.07 g; yield 69%) as a red solid.
With thionyl chloride; at 20℃; for 12h;
To a solution of <strong>[7697-28-1]4-bromo-3-methylbenzoic acid</strong> (Aldrich 532819, 30 g; 139.5 mmol) in MeOH (600 mL), under N2 was added dropwise thionyl chloride (40.5 mL; 558.0 mmol) over 10 min. The reaction mixture was stirred at RT for 12 hours. The solvents were concentrated and the crude residue was dissolved in EtOAc (700 mL). The organic layer was washed with a saturated aqueous solution of NaHCtheta3 (200 mL), water (200 mL), brine (200 mL), dried over MgSO4 and concentrated affording the title compound as an orange solid (31 .3 g, 98%). 1H NMR (DMSO-d6, 300 MHz) delta 7.96-7.95 (m, 1 H), 7.79-7.69 (m, 2H), 3.89 (s, 3H), 2.45 (s, 3H). HPLC (Method A) Rt 4.37 min (Purity: 96.4%).
With thionyl chloride; at 10℃; for 5h;Reflux;
Into a 10,000-mL 4-necked round-bottom flask was placed a solution of 4-bromo-3- methylbenzoic acid (500 g, 2.33 mol, 1.00 equiv) in methanol (5000 mL). This was followed by the addition of SOCl2 (556 g, 4.67 mol, 2.00 equiv) dropwise with stirring at <10C over 120 min. The resulting solution was heated to reflux for 5 h in an oil bath. The resulting mixture was cooled and concentrated under vacuum. This resulted in 535 g (crude) of methyl 4-bromo-3- methylbenzoate as a dark red solid.
With thionyl chloride; at 10℃; for 7h;
Part B, Step 1: Into a 10000-mL 4-necked round-bottom flask was placed asolution of <strong>[7697-28-1]4-bromo-3-methylbenzoic acid</strong> (500 g, 2.33 mol) in methanol (5000 mL). This was5 followed by the addition ofthionyl chloride (556 g, 4.67 mol) dropwise with stirring at <10 Cover 120 min. The resulting solution was heated to reflux for 5 h in an oil bath. The resultingmixture was cooled and concentrated under vacuum.
Reference Example 39 3'-Chloro-2'-fluoro-2-methylbiphenyl-4-carboxylic acid To DMF solution (38 mL) comprising 4-bromo-3-methylbenzoic acid (821 mg, manufactured by Wako Pure Chemical Industries, Ltd.), <strong>[352535-82-1]3-chloro-2-fluorophenylboronic acid</strong> (1.0 g, manufactured by Aldrich Company), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium-dichloromethane complex (1:1) (619 mg, manufactured by Aldrich Company), and cesium carbonate (1.87 g, manufactured by Kanto Chemical Co., Inc.) were added, followed by stirring at 120 C. for fifteen hours. Upon the completion of stirring, the reaction solution was filtered using Celite, and the filtrate was concentrated under reduced pressure. To thus obtained residues 1N hydrochloric acid solution (manufactured by Wako Pure Chemical Industries, Ltd.) was added, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and the solids were removed. Thus obtained residues were subjected to flash column chromatography (using 10:1 (v/v) to 3:1 (v/v) hexane/ethyl acetate as an eluent) to obtain the title compound (717 mg) MASS: 263.2 (M-H), RT: 1.77 min.
With disodium hydrogenphosphate; disodium bis(2-aminopyrimidine-4,6-diolate)palladium acetate; In water; at 50 - 120℃; for 0.166667h;Microwave irradiation;
In a 35 mL microwave reaction vessel, commercially available 4-bromo-3- methylbenzoic acid (0.2 g, 0.93 mmol), o-tolylboronic acid (0.151 g, 1.12 mmol) and Na2HPO4 (0.66 g, 4.65 mmol) were sequentially added. H20 (6.0 mL) was added and the mixture stirred at 50 C to dissolve most of the materials. Bis-(disodium 2-aminopyrimidine-4,6-diolate) palladium acetate [prepared as described in I Am. Chem. Soc. 2009, 131, 16346-1 6347] (0.01 M in Pd(II),1.50 mL, 0.0 15 mmol) was added to the reaction and the tube was heated to 120 C under microwave irradiation for 10 mm, under vigorous stirring. After cooling to r.t., the reaction was partitioned between 1.0 M HC1 solution (100 mL) and EtOAc (100 mL). The organic layer was separated, dried over Na2504, filtered and concentrated affording a solid residue (0.304 g). Purification by typical silica gel flash chromatography (CH2C12) afforded the pure titlecompound (0. 20 g, 95%) as a white wax. R= 2.20 mm. MS (ESI) m/z: 225 [M-Hf. ?H NMR (DMSO-d6): oe 12.90 (s, 1H), 7.90 (d, 1H, J= 1.0 hz), 7.80 (dd, 1H, J= 7.9, 1.6 Hz), 7.35-7.23 (m, 3H), 7.19 (d, 1H, J= 7.9 Hz), 7.07 (dd, 1H, J= 7.5, 1.4 Hz), 2.04 (s, 3H), 1.99 (s, 3H).
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; triphenylphosphine; In water; N,N-dimethyl-formamide; at 90℃; for 24h;
4-Bromo-3-methylbenzoic acid (0.389 g, 1.81 mmol), 4-carboxybenzeneboronic acid (0.300 g, 1.81 mmol), PPh3 (0.047 g, 0.18 mmol), Pd(PPh3)4 (0.105 g, 0.095 mmol) and 2M K2CO3 aqueous solution (3 ml) were dissolved in DMF (10 ml). The mixture was stirred at 90 for 1 day. The mixture was then cooled to room temperature and diluted with water. The solution was washed with ethyl acetate and 2 N HCl aqueous solution was added to give white precipitates. The precipitates were filtered, wash with water and dried under vacuum. The product was white solid (0.418 g, 91%).
Step 7-1 : Synthesis of 4-cyano-3-methylbenzoic acid[0179] 4-Bromo-3-methylbenzoic acid (3.0 g) was dissolved in N,N-dimethylformamide (20 ml). The resulting solution was subjected to deaeration three times under argon atmosphere (i.e., the reaction solution was de-pressurized to 20 mmHg, and then brought back to atmospheric pressure under argon atmosphere). To the solution, zinc cyanide (1.6 g) and tetrakis(triphenylphosphine) palladium (0) (1.6 g) were added and the mixture was stirred under heating at 900C for 6 hours under argon atmosphere. After adjusting to room temperature, precipitates were filtered off. The filtrate was diluted with water, added with lithium hydroxide monohydrate (2.9 g) and washed twice with tert-butyl methyl ether. The aqueous phase was acidified with 2N hydrochloric acid and extracted twice with ethyl acetate. The organic phases were combined, washed with brine and dried over magnesium sulfate. After filtering off the drying agent, the solvent was distilled off under reduced pressure to obtain 4-cyano-3- methylbenzoic acid as a crude product (1.9 g). Without further purification, the crude product was used for the next reaction.
With potassium carbonate; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; In tetrahydrofuran; at 20℃; for 14h;
Intermediate Example Int30.014-bromo-N-(2-fluoroethyl)-3-methylbenzamideTo a stirred solution of 4-bromo-3-methylbenzoic acid (1.25 g) in THF (50 mL) was added Hiinig Base (1.82 g), <strong>[460-08-2]2-fluoroethylamine hydrochloride</strong> (0.93 g) and TBTU (2.35 g). The mixture was stirred at r.t. for 14 h. A half-saturated solution of sodium bicarbonate was added and the mixture was extracted with ethyl acetate. The organic phase was washed with aqueous ammonium chloride solution and with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Silica gel chromatography gave 1.45 g of the title compound. H-NMR (400 MHz, DMSO-d6): delta [ppm] = 2.39 (s, 26H), 3.52 (q, 1H), 3.58 (q, 1H),.47 (t, 1H), 4.59 (t, 1H), 7.56 - 7.64 (m, 1H), 7.66 - 7.72 (m, 1H), 7.84 (d,H), 8.73 (t, 1H).
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; for 14h;
Intermediate Example Int30.014-bromo-N-(2-fluoroethyl)-3-methylbenzamide To a stirred solution of 4-bromo-3-methylbenzoic acid (1.25 g) in THF (50 mL) was added Hiinig Base (1.82 g), <strong>[460-08-2]2-fluoroethylamine hydrochloride</strong> (0.93 g) and TBTU (2.35 g). The mixture was stirred at r.t. for 14 h. A half-saturated solution of sodium bicarbonate was added and the mixture was extracted with ethyl acetate. The organic phase was washed with aqueous ammonium chloride solution and with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Silica gel chromatography gave 1.45 g of the title compound.1H-NMR (400 MHz, DMSO-d6): delta [ppm] = 2.39 (s, 26H), 3.52 (q, 1 H), 3.58 (q, 1 H), 4.47 (t, 1 H), 4.59 (t, 1 H), 7.56 - 7.64 (m, 1 H), 7.66 - 7.72 (m, 1 H), 7.84 (d, 1 H), 8.73 (t, 1 H).
Intermediate Example Int23.014-bromo-3-methylphenyl)(2-oxa-6-azaspiro[3.3]hept-6-yl)methanoneTo a stirred solution of 4-bromo-3-methylbenzoic acid (1.5 g) in DMF (55 mL) was added molecular sives (1.9 g) and the mixture was stirred for 1 h. TBTU (4.0 g) was added and the mixture was stirred for 30 minutes. Potassium carbonate (4.8 g) and <strong>[1159599-99-1]2-oxa-6-azaspiro[3.3]heptane ethanedioate</strong> (2:1 ) (1.5 g) were added and the mixture was stirred at r.t. for 16 h. Water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Aminophase-silica-gel chromatography gave 1.77 g of the title compound.
In N,N-dimethyl-formamide; at 20℃; for 17.5h;
Intermediate Example Int23.014-bromo-3-methylphenyl)(2-oxa-6-azaspiro[3.3]hept-6-yl)methanoneTo a stirred solution of 4-bromo-3-methylbenzoic acid (1.5 g) in DMF (55 mL) was added molecular sives (1.9 g) and the mixture was stirred for 1 h. TBTU (4.0 g) was added and the mixture was stirred for 30 min. Potassium carbonate (4.8 g) and <strong>[1159599-99-1]2-oxa-6-azaspiro[3.3]heptane ethanedioate</strong> (2:1 ) (1.5 g) were added and the mixture was stirred at r.t. for 16 h. Water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Aminophase-silica-gel chromatography gave 1.77 g of the title compound.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In tetrahydrofuran; dichloromethane; at 20℃; for 16h;
A mixture of <strong>[7697-28-1]4-bromo-3-methylbenzoic acid</strong> (5, 5.00 g, 23.3 mmol), dimethylamine (2 M in THF, 17.4 mL, 34.9 mmol), 1-hydroxybenzotriazole (3.15 g, 23.3 mmol), and triethylamine (7.06 g, 69.9 mmol) in dichloromethane (200 mL) was treated with 1-(3-(dimethylamino)propyl)-3-ethyl carbodiimide hydrochloride (5.82 g, 30.3 mmol). The mixture was stirred at room temperature for 16 h. After diluting with EtOAc (300 mL), the mixture was washed with water (100 mL) and brine (100 mL), dried (Na2SO4), filtered, and concentrated. The residue was purified by silica gel chromatography eluting with 0-20% EtOAc in hexanes to afford the title compound (4.67 g, 83%) as a yellow oil: 1H NMR (300 MHz, CDCl3) delta 7.55 (d, J=8.1 Hz, 1H), 7.30 (d, J=1.6 Hz, 1H), 7.08 (dd, J=1.9, 8.1 Hz, 1H), 3.09 (s, 3H), 2.97 (s, 3H), 2.41 (s, 3H); Multimode MS m/z 242 [M+H]+
65%
With 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride; In ethanol; water; at 20℃; for 24h;
4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride n-hydrate (n = about 2.7) (2.42 g, 7.53 mmol) was added to a mixture of <strong>[7697-28-1]4-bromo-3-methylbenzoic acid</strong> (1.58 g, 7.37 mmol), EtOH (26 ml) and a 40% aqueous dimethylamine solution (0.75 ml, 7.4 mmol), and the mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was then dissolved in ethyl acetate. The organic layer was washed with water, and then dried over MgSO4 and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 2/1) to give 4-bromo-3,N,N-trimethyl-benzamide as a colorless solid (1.16 g, 65%). 1H-NMR (300 MHz) (CDCl3) delta 2.42 (3H, s), 2.98 (3H, br s), 3.10 (3H, br s), 7.08 (1H, dd, J = 8.4 and 2.1 Hz), 7.30 (1H, d, J = 2.1 Hz), 7.55 (1H, d, J = 8.4 Hz). MS (ESI) m/z = 243 (M+H)+.
4-(l-Hydroxy-l-methyl-ethyl)-3-methyl-benzoic acid[00390] 4-Bromo-3-methyl-benzoic acid (3.96 g, 18.4 mmol) was dissolved in tetrahydrofuran (100 mL) and the solution was cooled to -78 C. n-Butyllithium in hexanes (16.2 mL of 2.5 M, 41 mmol) was added dropwise over 20 minutes. The reaction mixture was allowed to stir for 30 minutes at -78 C and then acetone (1.35 mL, 18.4 mmol) was added in a drop-wise manner. The reaction mixture was allowed to stir for 30 minutes at -78 C, and then it was allowed to warm to room temperature. The reaction mixture was then diluted with 100 mL of 1M aqueous sodium hydroxide. The organic layer was discarded and then the aqueous layer was made acidic with 4M aqueous hydrochloric acid. The aqueous layer was then extracted 3 times with ethyl acetate. The combined extracts were dried over sodium sulfate and then evaporated to dryness. The crude material was further purified on silica gel utilizing a gradient of 0-10% methanol in dichloromethane to give 4-(l -hydroxy- l-methyl-ethyl)-3-methyl- benzoic acid (1.51 g, 42%). 1H MR (400 MHz, DMSO) delta 12.74 (s, 1H), 7.68 (dd, J = 3.9, 2.5 Hz, 2H), 7.55 (d, J = 8.7 Hz, 1H), 5.06 (s, 1H), 2.56 (s, 3H), 1.51 (s, 6H).
42%
[00394] Preparation of 4-(l-Hydroxy-l-methyl-ethyl)-3-methyl-benzoic acid[00395] 4-Bromo-3-methylbenzoic acid (3.96 g, 18.4 mmol) was dissolved in tetrahydrofuran (100 mL) and the solution was cooled to -78 C. n-Butyllithium in hexanes (16.2 mL of 2.5 M, 41 mmol) was added dropwise over 20 minutes. The reaction mixture was allowed to stir for 30 minutes at -78 C and then acetone (1.35 mL, 18.4 mmol) was added in a dropwise manner. The reaction mixture was allowed to stir for 30 minutes at -78 C, and then allowed to warm to room temperature. The reaction mixture was then diluted with 1M aqueous sodium hydroxide (100 mL). The organic layer was discarded and then the aqueous layer was acidified with 4M aqueous hydrochloric acid. The aqueous layer was then extracted 3 times with ethyl acetate. The combined extracts were dried over sodium sulfate and then concentrated in vacuo. The crude material was purified by silica gel column chromatography using a gradient of 0-10% methanol in dichloromethane to give 4-(l -hydroxy- l-methyl-ethyl)-3 -methyl - benzoic acid (1.51 g, 42%). 1H NMR (400 MHz, DMSO) delta 12.74 (s, 1H), 7.68 (dd, J = 3.9, 2.5 Hz, 2H), 7.55 (d, J - 8.7 Hz, 1H), 5.06 (s, 1H), 2.56 (s, 3H), 1.51 (s, 6H).
42%
4-Bromo-3-methyl-benzoic acid (3.96 g, 18.4 mmol) was dissolved in tetrahydrofuran (100 mL) and the solution was cooled to -78 C. n-Butyllithium in hexanes (16.2 mL of 2.5 M, 41 mmol) was added dropwise over 20 minutes. The reaction mixture was allowed to stir for 30 minutes at -78 C. and then acetone (1.35 mL, 18.4 mmol) was added in a drop-wise manner. The reaction mixture was allowed to stir for 30 minutes at -78 C., and then it was allowed to warm to room temperature. The reaction mixture was then diluted with 100 mL of 1M aqueous sodium hydroxide. The organic layer was discarded and then the aqueous layer was made acidic with 4M aqueous hydrochloric acid. The aqueous layer was then extracted 3 times with ethyl acetate. The combined extracts were dried over sodium sulfate and then evaporated to dryness. The crude material was further purified on silica gel utilizing a gradient of 0-10% methanol in dichloromethane to give 4-(1-hydroxy-1-methyl-ethyl)-3-methyl-benzoic acid (1.51 g, 42%). 1H NMR (400 MHz, DMSO) delta 12.74 (s, 1H), 7.68 (dd, J=3.9, 2.5 Hz, 2H), 7.55 (d, J=8.7 Hz, 1H), 5.06 (s, 1H), 2.56 (s, 3H), 1.51 (s, 6H).
42%
4-Bromo-3-methylbenzoic acid (3.96 g, 18.4 mmol) was dissolved in tetrahydrofuran (100 mL) and the solution was cooled to -78 C. n-Butyllithium in hexanes (16.2 mL of 2.5 M, 41 mmol) was added dropwise over 20 minutes. The reaction mixture was allowed to stir for 30 minutes at -78 C and then acetone (1.35 mL, 18.4 mmol) was added in a drop-wise manner. The reaction mixture was allowed to stir for 30 minutes at -78 C, and then it was allowed to warm to room temperature. The reaction mixture was then diluted with 100 mL of 1M aqueous sodium hydroxide. The organic layer was discarded and then the aqueous layer was made acidic with 4M aqueous hydrochloric acid. The aqueous layer was then extracted 3 times with ethyl acetate. The combined extracts were dried over sodium sulfate and then evaporated to dryness. The crude material was further purified on silica gel utilizing a gradient of 0-10% methanol in dichloromethane to give 4-(1-hydroxy-1-methylethyl)-3-methylbenzoic acid (1.51 g, 42%). 1H NMR (400 MHz, DMSO) delta 12.74 (s, 1H), 7.68 (dd, J= 3.9, 2.5 Hz, 2H), 7.55 (d, J= 8.7 Hz, 1H), 5.06 (s, 1H), 2.56 (s, 3H), 1.51 (s, 6H).
Stage #1: 4-bromo-3-methylbenzoic acid With n-butyllithium In tetrahydrofuran at -78℃; for 0.5h;
Stage #2: diisopropyl sulfide In tetrahydrofuran at -78 - 20℃; for 1h;
[00413] Preparation of 4-(Isopropylsulfonyl)-3-methylbenzoic acid[00414] Step l:[00415] Butyllithium (16 mL of 1.6 M, 25.6 mmol) was added dropwise to a mixture of 4-bromo-3-methyl-benzoic acid (2.5 g, 1 1.6 mmol) and THF (63 mL) at -78 °C. The reaction mixture was allowed to stir at -78 °C for 30 minutes before a solution of 2-isopropyldisulfanylpropane (1.7 g, 11.6 mmol) in THF (2 mL) was added dropwise. The mixture was allowed to stir at -78 °C for 30 minutes, then 30 minutes at room temperature. The reaction mixture was then diluted with 1 M aqueous sodium hydroxide (100 mL). The organic layer was discarded and the aqueous layer was acidified with 4M aqueous hydrochloric acid. The aqueous layer was then extracted 3 times with ethyl acetate. The combined extracts were dried over sodium sulfate and concentrated in vacuo. The crude material was purified by silica gel columnchromatography using a gradient of 0-5% MeOH in dichloromethane to give 4- (isopropylthio)-3-methylbenzoic acid (873 mg, 18 %). MS m/z calc. 210.3, found 211.2 (M+l)+. Retention time: 2.32 minutes (3 min run).
Stage #1: 4-bromo-3-methylbenzoic acid With n-butyllithium In tetrahydrofuran at -78℃; for 0.5h;
Stage #2: diisopropyl sulfide In tetrahydrofuran at -78 - 20℃; for 1h;
1 4-(Isopropylsulfonyl)-3-methylbenzoic acid Step 1:
Butyllithium (16 mL of 1.6 M, 26 mmol) was added drop-wise to a mixture of 4-bromo-3-methyl-benzoic acid (2.5 g, 12 mmol) and THF (63 mL) at -78° C. The mixture was allowed to stir at -78° C. for 30 minutes before a solution of 2-isopropyldisulfanylpropane (1.7 g, 12 mmol) in THF (2 mL) was added drop-wise. The mixture was allowed to stir at -78° C. for 30 min, then 30 min at rt. The reaction mixture was then diluted with 100 mL of 1M aqueous sodium hydroxide. The organic layer was discarded and the aqueous layer was made acidic with 4M aqueous hydrochloric acid. The aqueous layer was then extracted 3 times with ethyl acetate. The combined extracts were dried over sodium sulfate and then evaporated to dryness. The crude material was purified by column chromatography using a gradient of 0-5% MeOH in dichloromethane to give 4-(isopropylthio)-3-methylbenzoic acid (870 mg, 18%). MS m/z calc. 210.3. found 211.2 (M+1) +. Retention time: 2.32 minutes (3 min run).
With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 0 - 20℃; for 12h;Inert atmosphere;
General procedure: An experimental procedure previously described, that employs HATU as the coupling reagent [8] was used for the reaction between the four different amino purine derivatives (3, 9, 10 and 16) with several aryl carboxylic acids (both commercially available 4a-e or compounds 4f-i). The corresponding amino purine derivative (50 mg scale) was dissolved in 3 mL of anhydrous DMF or CH2Cl2 under argon, and the corresponding commercial or previously synthesized arylcarboxilic acid (1.15 equiv) and HATU (1.2 equiv) were added. The mixture was cooled at 0 C (ice/water bath) and DIPEA (1.2 equiv) was added dropwise via a syringe. The reaction mixture was allowed to reach room temperature, and the reaction was already complete after 3 h. The crude product was concentrated in vacuo and redissolved in EtOAc. It was washed twice with saturated aqueous NH4Cl and once with brine. The organic phase was dried over anhydrous MgSO4. The solids were filtered off and the solvent was removed in vacuo. This crude material was purified by column chromatography over silica gel, using EtOH/CH2Cl2 mixtures (0%-3% ethanol) as eluent, giving the desired products in high yields (71-99%).
With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 0 - 20℃; for 3h;Inert atmosphere;
General procedure: An experimental procedure previously described, that employs HATU as the coupling reagent [8] was used for the reaction between the four different amino purine derivatives (3, 9, 10 and 16) with several aryl carboxylic acids (both commercially available 4a-e or compounds 4f-i). The corresponding amino purine derivative (50 mg scale) was dissolved in 3 mL of anhydrous DMF or CH2Cl2 under argon, and the corresponding commercial or previously synthesized arylcarboxilic acid (1.15 equiv) and HATU (1.2 equiv) were added. The mixture was cooled at 0 C (ice/water bath) and DIPEA (1.2 equiv) was added dropwise via a syringe. The reaction mixture was allowed to reach room temperature, and the reaction was already complete after 3 h. The crude product was concentrated in vacuo and redissolved in EtOAc. It was washed twice with saturated aqueous NH4Cl and once with brine. The organic phase was dried over anhydrous MgSO4. The solids were filtered off and the solvent was removed in vacuo. This crude material was purified by column chromatography over silica gel, using EtOH/CH2Cl2 mixtures (0%-3% ethanol) as eluent, giving the desired products in high yields (71-99%).
With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 0 - 20℃; for 3h;Inert atmosphere;
General procedure: An experimental procedure previously described, that employs HATU as the coupling reagent [8] was used for the reaction between the four different amino purine derivatives (3, 9, 10 and 16) with several aryl carboxylic acids (both commercially available 4a-e or compounds 4f-i). The corresponding amino purine derivative (50 mg scale) was dissolved in 3 mL of anhydrous DMF or CH2Cl2 under argon, and the corresponding commercial or previously synthesized arylcarboxilic acid (1.15 equiv) and HATU (1.2 equiv) were added. The mixture was cooled at 0 C (ice/water bath) and DIPEA (1.2 equiv) was added dropwise via a syringe. The reaction mixture was allowed to reach room temperature, and the reaction was already complete after 3 h. The crude product was concentrated in vacuo and redissolved in EtOAc. It was washed twice with saturated aqueous NH4Cl and once with brine. The organic phase was dried over anhydrous MgSO4. The solids were filtered off and the solvent was removed in vacuo. This crude material was purified by column chromatography over silica gel, using EtOH/CH2Cl2 mixtures (0%-3% ethanol) as eluent, giving the desired products in high yields (71-99%).
4-Bromo-3-methylbenzoic acid (740 mg, 3.44 mmol, 1 eq.), (Boc)20 (1 .92 g, 8.78 mmol, 2.5 eq.) and DMAP (93 mg, 0.764 mmol, 1 eq.) were dissolved in dry THF (10 ml) and refluxed overnight. After cooling to room temperature and evaporating the solvent, the residue was dissolved in Et20 and washed with saturated NaHC03 aqueous solution, water and brine, dried over Na2S04, filtered and evaporated. The resulting crude was purified by silica gel column chromatography (n-hexane/EtOAc = 95/5) to obtain tert- butyl 4-bromo-3-methylbenzoate as a pale yellow liquid. (647 mg, 87%)1H NMR (400 MHz, CDCl3) delta 7.83 (d, 1 H, J = 1 .7 Hz), 7.64 (dd, 1 H, J = 8.9, 1 .6 Hz), 7.56 (d, 1 H, J = 8.8 Hz), 2.43 (s, 3 H), 1 .59 (s, 9 H).13C NMR (100 MHz, CDCl3) delta 165.3, 138.0, 132.3, 131 .6, 131 .1 , 129.8, 128.2, 81 .4, 28.2, 22.9.
87%
With dmap; In tetrahydrofuran;Reflux;
A.7 tert-butyl 4-bromo-3-methylbenzoate5c 4-Bromo-3-methylbenzoic acid (740 mg, 3.44 mmol, 1 eq.), (Boc)2O (1.92 g, 8.78 mmol, 2.5 eq.) and DMAP (93 mg, 0.764 mmol, 1 eq.) were dissolved in dry THF (10 ml) and refluxed overnight. After cooling to room temperature and evaporating the solvent, the residue was dissolved in Et2O and washed with saturated NaHCO3 aqueous solution, water and brine, dried over Na2SO4, filtered and evaporated. The resulting crude was purified by silica gel column chromatography (n-hexane/EtOAc=95/5) to obtain tert-butyl 4-bromo-3-methylbenzoate as a pale yellow liquid. (647 mg, 87%) [0130] 1H NMR (400 MHz, CDCl3) delta 7.83 (d, 1H, J=1.7 Hz), 7.64 (dd, 1H, J=8.9, 1.6 Hz), 7.56 (d, 1H, J=8.8 Hz), 2.43 (s, 3H), 1.59 (s, 9H). [0131] 13C NMR (100 MHz, CDCl3) delta 165.3, 138.0, 132.3, 131.6, 131.1, 129.8, 128.2, 81.4, 28.2, 22.9.
70%
tert-Butyl 4-bromo-3-methylbenzoate (FIG. 22, compound 3) was synthesized as follows. To a stirred suspension of <strong>[7697-28-1]4-bromo-3-methylbenzoic acid</strong> (20 g, 93 mmol) and DMAP (17 g, 140 mmol) in 200 mL of tBuOH:THF, 1:1, was carefully added Boc2O (40.6 g, 186 mmol) with evolution of gas. Once gas evolution had ceased, the reaction mixture was warmed to 70 C. TLC (5% EtOAc/hexanes) showed complete consumption of starting material after 12 h. The solvent was removed under reduced pressure. To remove residual Boc2O (Basel and Hassner, Synthesis. 2001, 2001:0550- 0552), the crude reaction mixture was re-dissolved in 150 mL EtOH, imidazole (15 g, 220 mmol) was added, and the solution was stirred at ambient temperature for 3 h. EtOH was removed under reduced pressure, and the residual solid was re-suspended in 200 mL EtOAc and washed sequentially with 10% aq K2C03 (1 x 200 mL), H20 (1 x 200 mL), 1 M HC1 (2 x 200 mL), and brine (1 x 200 mL). The organic layer was dried over anhydrous Mg504 and concentrated under reduced pressure. Purification by silica column chromatography (4% EtOAc/hexanes) afforded compound 3 as a colorless liquid (17.7 g, 70% yield). ?H NMR (400 MHz, CDC13) 7.82 (d, J= 2.0 Hz, 1H), 7.63 (dd, J= 8.3, 2.1 Hz, 1H), 7.55 (d, J= 8.3 Hz, 1H), 2.42 (s, 3H), 1.58 (s, 9H); ?3C NMR (151 MHz, CDC13) 165.2, 137.9, 132.2, 131.5, 131.1,129.8, 128.1, 81.3, 28.1, 22.8; LRMS calcd. for C,2H,5BrO2 (M) 270.03, found 270.
69%
With dmap; In tert-butyl alcohol; at 60℃;
DMAP (0.170 g, 1.395 mmol) and Boc-anhydride(1.02 g, 4.65 mmol) were added to a stirred suspension of 8 (1.00 g, 4.65 mmol) in t-BuOH (23mL). The suspension was heated to 60 C, upon which all starting materials were solubilized andthe evolution of gas was observed. After being stirred overnight the reaction was cooled to roomtemperature. The reaction was diluted with water and extracted three times withdichloromethane. The organic fractions were combined, dried (MgSO4) and the solvents wereremoved by rotatory evaporation to give a clear colorless oil. Purification by flash columnchromatography (pentane/dichloromethane, 9:1) afforded 9 (0.870 g, 69%) as a colorless oil.Product structure and purity were verified by HRMS, 1H, 19F and 13C NMR, and the data werefound to be in accord with what has previously been reported for this compound.
7.2 g
With dmap; In tert-butyl alcohol; at 70℃;
Step 1 To a 250 mL RBF was added <strong>[7697-28-1]4-bromo-3-methylbenzoic acid</strong> (10 g, 46.5 mmol), DMAP (8.52 g, 69.8 mmol) and tert-butyl alcohol (100 mL). Di-tert-butyl dicarbonate (12.96 mL, 55.8 mmol) was added via a syringe to the solution, which caused vigorous bubbling, foaming and the loss of some material. The remaining reaction mixture was heated at 70 C. overnight. The reaction was cooled to room temperature and the volatiles were removed under reduced pressure. Crude material was diluted with ethyl acetate:hexanes (1:4, 200 mL) and was washed sequentially with 5% aqueous KOH (200 mL) and saturated aqueous ammonium chloride (2*100 mL). The organics were dried over sodium sulfate, filtered and concentrated before purification by column chromatography. tert-Butyl 4-bromo-3-methylbenzoate was isolated as a colorless oil (7.2 g, 26.6 mmol). 1H NMR (500 MHz, CDCl3) delta 7.87 (s, 1H), 7.67 (d, J=8.3 Hz, 1H), 7.60 (d, J=8.2 Hz, 1H), 2.47 (s, 3H), 1.62 (s, 9H).
7.2 g
With dmap; In tert-butyl alcohol; at 70℃;
Step A: tert-Butyl 4-bromo-3-methylbenzoate: To a 250 mL round bottomed flask was added 4- bromo-3-methylbenzoic acid (lOg, 46.5 mmol), DMAP (8.52 g, 69.8 mmol) and tert-butyl alcohol (100 mL). Di-tert-butyl dicarbonate (12.96 mL, 55.8 mmol) was added via a syringe to the solution, which caused vigorous bubbling, foaming and the loss of some material. Theremaining reaction mixture was heated at 70C overnight. The reaction was cooled to room temperature and the volatiles were removed under reduced pressure. The crude material was diluted with ethyl acetate:hexanes (1:4, 200 mL), then washed sequentially with 5% aqueous KOH (200 mL) and saturated aqueous ammonium chloride (2 x 100 mL). The organics were dried over sodium sulfate, filtered and the filtrate concentrated before purification by columnchromatography. tert-Butyl 4-bromo-3 -methylbenzoate was isolated as a colorless oil (7.2 g,26.6 mmol). ?H NMR (500 MHz, CDC13) 7.87 (s, 1H), 7.67 (d, J=8.3 Hz, 1H), 7.60 (d, J8.2Hz, 1H), 2.47 (s, 3H), 1.62 (s, 9H).
With dmap; In tert-butyl alcohol; at 70℃;
Step 1: To a 250 mL RBF was added <strong>[7697-28-1]4-bromo-3-methylbenzoic acid</strong> (1 Og, 46.5mmol), DMAP (8.52 g, 69.8 mmol) and tert-butyl alcohol (100 mL). Di-tert-butyl dicarbonate(12.96 mL, 55.8 mmol) was added via a syringe to the solution, which caused vigorous bubbling,25 foaming and the loss of some material. The remaining reaction mixture was heated at 70 C overnight. The reaction was cooled to room temperature and the volatiles were removed underreduced pressure. Crude material was diluted with ethyl acetate:hexanes (1 :4, 200 mL) and waswashed sequentially with 5% aqueous KOH (200 mL) and saturated aqueous ammoniumchloride (2 x 100 mL ). The organics were dried over sodium sulfate, filtered and concentrated5 before purification by column chromatography. tert-Butyl4-bromo-3-methylbenzoate wasisolated as a colorless oil. 1H NMR (500 MHz, CDCh) 8 7.87 (s, 1H), 7.67 (d, J = 8.3 Hz, 1H),7.60 (d, J = 8.2 Hz, 1H), 2.47 (s, 3H), 1.62 (s, 9H).
With dmap; In tert-butyl alcohol; at 70℃;
Step 1 : To a 250 mL RBF was added <strong>[7697-28-1]4-bromo-3-methylbenzoic acid</strong> (lOg, 46.5 mmol), DMAP (8.52 g, 69.8 mmol) and tert-butyl alcohol (100 mL). Di-tert-butyl dicarbonate (12.96 mL, 55.8 mmol) was added via syringe to the solution, which caused vigorous bubbling, foaming and the loss of some material. The remaining reaction mixture was heated at 70 C overnight. The reaction was cooled to room temperature and the volatiles were removed under reduced pressure. Crude material was diluted with ethyl acetate:hexanes (1 :4, 200 mL) and was washed sequentially with 5% aqueous KOH (200 mL) and saturated aqueous ammonium chloride (2 x 100 mL). The organics were dried over sodium sulfate, filtered and concentrated before purification by column chromatography to yield tert-Butyl 4-bromo-3-methylbenzoate. 1H NMR (500 MHz, CDC13) delta 7.87 (s, 1H), 7.67 (d, J = 8.3 Hz, 1H), 7.60 (d, J = 8.2 Hz, 1H), 2.47 (s, 3H), 1.62 (s, 9H).
4-bromo-3-methyl-N-(3-(8-nitroquinolin-4-yl)phenyl)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92%
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 0 - 20℃;
General procedure: A mixture of compound 9 or 10 (0.11 mmol), O-(7-aza-1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.21mmol), and N,N-diisopropylethylamine (0.54 mmol) in dry DMF (1.5 mL) was stirred at 0 C for 30 min. The appropriate acid (0.16 mmol) was then added. After stirring at room temperature for 1-4 h, the reaction mixture was diluted with saturated aqueous NaHCO3, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with EtOAc-hexane (1:1 to 1:3) to afford the corresponding compounds 11a-o and 12a-c.
With n-butyllithium In tetrahydrofuran; hexane at -78 - 25℃; for 2h; Inert atmosphere;
18 Intermediate compound 18: 4-formyl-3-methylbenzoic acid
A solution of 4-bromo-3-methylbenzoic acid (2.32 mmol, 500 mg) in dry THF (12 mL) was purged with argon. The solution was cooled at -785C, BuLi (2.5M in hexane, 7.5 mmol, 3 mL), and DMF (5.16 mmol, 0.4 mL) was added and the reaction was stirred for 1 h at -785C and then warmed to 255C and allowed to react for an additional hour. The reaction was quenched with aqueous 1 N HCI and extracted with EtAcO. The organic layer was extracted with aqueous 1 N NaOH and the aqueous layer was separated and the pH adjusted with aqueous 1 N HCI. The aqueous was extracted with EtAcO then washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting crude was purified by precipitation with hexane (90 mg. Yield: 23%) 1 H NMR (400 MHz, DMSO-d6) δ 13.25 (1 H,s), 10.32 (1 H, s), 7.92 (2H, m), 7.89 (1 H, s), 2.67 (3H, s). LC-MS: tR = 2.53 [M-H]" = 163 (method 3).
Stage #1: 4-bromo-3-methylbenzoic acid With sodium hydride In tetrahydrofuran; mineral oil at 0 - 20℃; for 0.333333h; Inert atmosphere;
Stage #2: With n-butyllithium In tetrahydrofuran; N,N-dimethyl-formamide at -78 - 20℃; for 2.5h;
3
4-Bromo-3-methylbenzoic acid (10 g, 46.5 mmol) was suspended in dry THF (400 mL), purged with N2, and cooled to 0°C. NaH (60% in oil) (1.95 g, 48.8 mmol) was added, and the resulting mixture was stirred at room temperature for 20 mi Afterward, the mixture was cooled to -78°C. tert-Butyllithium (1.7 M in pentane, 64 mL, 97.7 mmol) was thenadded at a rate that allowed the internal temperature to be maintained at less than -74°C. After the addition was complete, dry DMF (7.2 mL, 93 mmol) was added. The resulting mixture was stirred at -78 °C for 1 hr and then allowed to warm up to room temperature. After 1.5 hr, the excess base was quenched using 1 M HC1 aqueous solution until the mixture had an acidic pH. The mixture was then extracted with EtOAc (3 x 200 mL), andthe combined organic extracts were dried over Mg504, filtered, and concentrated under reduced pressure to afford 4-formyl-3-methyl benzoic acid. The acid was dissolved in DMF (30 mL), and MeNH2-HC1 (4.08 g, 60.5 mmol) and HOBt (6.91 g, 51.2 mmol) were added. The resulting mixture was cooled to 0°C, and then Et3N (26 mL, 0.19 mol) was added, followed by EDC-HC1 (11.6 g, 60.5 mmol). The mixture was stirred at roomtemperature for 16 hr, and then filtered on a silica gel pad, which was subsequently rinsed with EtOAc. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel flash column chromatography (Hex/EtOAc 1:1 to 1:2) to provide the title compound (4.5 g, 55%) as a solid. ‘H NMR (300 MHz, CDC13) ö 2.43 (s, 3H), 3.00 (d, J 4.9 Hz, 3H), 6.12 (m, 1H), 7.39 (dd, J 8.2, 2.3 Hz, 1H), 7.57 (d, J= 8.2 Hz, 1H),7.64 (d, J 2.1 Hz, 1H).
Multi-step reaction with 3 steps
1: toluene / 40 h / 20 - 80 °C
2: n-butyllithium / tetrahydrofuran; hexane / 1.5 h / -78 - 20 °C
3: trifluoroacetic acid / dichloromethane / 1 h / 20 °C
Multi-step reaction with 3 steps
1.1: toluene / 40 h / 20 - 80 °C
2.1: n-butyllithium / tetrahydrofuran; hexane / -78 °C
2.2: -78 - 20 °C
3.1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C
With disodium hydrogenphosphate; disodium bis(2-aminopyrimidine-4,6-diolate)palladium acetate; In water; at 50 - 120℃; for 0.166667h;Microwave irradiation;
In a 35 mL microwave reaction vessel, commercially available 4-bromo-3- methylbenzoic acid (0.250 g, 1.16 mmol), m-tolylboronic acid (0.188 g, 1.40 mmol) and Na2HPO4 (0.826 g, 5.81 mmol) were sequentially added. H20 (10 mL) was added and the mixture stirred at 50 C to dissolve most of the materials. Bis-(disodium 2-aminopyrimidine-4,6-diolate) palladium acetate [prepared as described in J Am. Chem. Soc. 2009, 131, 1 6346-1 6347] (0.01 M in Pd(II), 1.50 mL, 0.0 15 mmol) was added to the reaction and the tube was heated to 120 C under microwave irradiation for 10 mm, under vigorous stirring. After cooling to r.t., the reaction was partitioned between 1.0 M HC1 solution (100 mL) and EtOAc (100 mL). The organic layer was separated, dried over Na2SO4, filtered and concentrated affording a cruderesidue (0.39 g). Purification by typical silica gel flash chromatography (CH2C12) afforded the pure title compound (0. 275 g, quant.) as a white solid. R= 2.22 mm. MS (ESI) m/z: 225 [M-Hf. ?H NMR (DMSO-d6): oe 12.86 (s, 1H), 7.87 (s, 1H), 7.83-7.78 (m, 1H), 7.35 (t, 1H, J= 7.5 Hz), 7.29 (d, 1H, J= 7.9 Hz), 7.23-7.12 (m, 3H), 2.36 (s, 3H), 2.27 (s, 3H).
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃;
A solution of <strong>[7697-28-1]4-bromo-3-methylbenzoic acid</strong> (2.0 g, 9.3 mmol) and cyclobutylamine (0.87 ml, 10.2 mmol) in DMF (60 ml) was treated with N, N-diisopropylamine (3.6 ml, 20.5 mmol) and a solution of HATU (4.24 g, 11.2 mmol) in DMF (30 ml) was added thereto.The reaction mixture was stirred at RT overnight (ca. 16 h).The solvent was removed at high vacuum and the residue was added, stirred and sucked with water.The residue was washed thoroughly with water and dried under high vacuum.This gave 2:35 g (94% d. Th.) Of the title compound.
1-bromo-4-(3-methanesulfonylpropoxy)-2-methylbenzene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1.27 g
With potassium carbonate; In N,N-dimethyl-formamide; at 95℃; for 2h;Inert atmosphere;
A mixture of crude 3-(methylsulfonyl)propyl-p-toluenesulfonate 24b (1.87 g, 6.42 mmol), 4-bromo-3-methylbenzoic acid (1.0 g, 5.34 mmol) and potassium carbonate (1.47g, 10.68 mmol) was dissolved in 20 mL of N, N-dimethylformamide, heated to 95 C and stirred for 2 hours. The aqueous phase was extracted with ethyl acetate (30 mL of X2) and the organic phases were combined, washed sequentially with water (30 mL of X3), saturated sodium chloride solution (30 mL), and the mixture was extracted with ethyl acetate (50 mL) and stirred for 30 min. Dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using eluent system B to give the title product bromo-2-methyl-4-(3-(methylsulfonyl)propoxy)benzene 24c (1.27 g, yellow solid), yield: 77.4%.
To a vial was added <strong>[7697-28-1]4-bromo-3-methylbenzoic acid</strong> (1.0 g, 4.65 mmol), dichloromethane (10 mL) and DMF (0.1 mL, 4.65 mmol). Oxalyl chloride (1.2 mL, 13.95 mmol) was added drop-wise. The mixture was stirred at room temperature for 2 hours. The reaction was concentrated in vacuo and re-dissolved in dichloromethane (10 mL). Methylamine (30% in ethanol, 10 mL) was added and stirred at room temperature for 30 minutes. The mixture was concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate, 1:1 to 0:100) to get 4-bromo-N,3-dimethyl-benzamide (1 g, 94% yield) as a white solid. LCMS (ESI) [M+H]+=228.0.
(4-bromo-3-methylphenyl)(4-phenylindolin-1-yl)methanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90.2%
At room temperature,4-phenylporphyrin (0.09 g, 0.46 mmol),<strong>[7697-28-1]4-bromo-3-methylbenzoic acid</strong> (0.1 g, 0.47 mmol),HATU (0.26 g, 0.68 mmol) was dissolved in anhydrous DMF (5 mL).After stirring uniformly, DIPEA (0.11 g, 0.92 mmol) was added, and the mixture was reacted at room temperature for 2 hours.The reaction solution was poured into cold water, stirred for 15 minutes, and filtered to give a white solid (0.16 g).The yield was 90.2%.
87%
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 3h;
General procedure: To a solution of intermediate 14a (1g, 5.13mmol), 3-formylbenzoic acid (0.85g, 5.64mmol), and HATU (2.92g, 7.69mmol) in DMF (15mL) was added DIPEA (3.31g, 25.63mmol). The mixture was stirred at room temperature for 3h. After that time, the solution was poured into water. The precipitate was filtered off to give a residue, which was triturated with ether to give compound 15a (1.37g, 81.7%).
4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)indoline[ No CAS ]
C24H20BrNO3[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85.5%
At room temperature,4-(2,3-Dihydrobenzo[b][1,4]dioxo-6-yl)porphyrin (0.9 g, 3.56 mmol),<strong>[7697-28-1]4-bromo-3-methylbenzoic acid</strong> (0.76 g, 3.56 mmol),HATU (2.03 g, 5.33 mmol) was dissolved in anhydrous DMF (10 mL).After stirring, DIPEA (0.92 g, 7.12 mmol) was added.The reaction was carried out for 3 hours at room temperature.The reaction solution was poured into cold water, stirred for 15 minutes, and filtered to give a white solid, 1.37 g, yield: 85.5%.
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