* 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.
With boron tribromide In dichloromethane at -40 - 20℃; for 12.33 h;
To a solution of 1-bromo-5-chloro-2 methoxyphenyl 275 (2.5 g, 11 mmol, 1 eq) in DCM (100 mL) was added dropwise BBr3 (1 M solution in DCM, 38.5 mmol, 3.5 eq) over 20 min at -40 C. The solution was warmed to rt and stirred for 12 h. TLC (3:2 Hexane:DCM) showed complete consumption of 275. The solution was quenched with NaHCO3 and stirred until two phases appeared. The organic was separated, washed with brine, dried, filtered and concentrated in vacuo to afford 0.80 g of 276 as a white solid which was used without purification. Yield 32percent
With bromine In dichloromethane at 0 - 20℃; for 16 h;
A solution of 5.03 gm (39.1 mMol) 3-chlorophenol in 20 mL dichloromethane was cooled in an ice bath as 6.25 gm (39.1 mMol) bromine were added dropwise. The reaction mixture was allowed to warm to room temperature and was stirred for 16 hours. The reaction mixture was diluted with water, the phases separated, and the organic phase dried over magnesium sulfate. The residue was subjected to silica gel chromatography, eluting with 3:2 dichloromethane:hexanes. Fractions containing product were combined and concentrated under reduced pressure to provide 2.04 gm (25percent) of 2-bromo-5-chlorophenol. HRMS: Calculated for C4H4OClBr: 205.9134. Found: 205.9125. EA: Calculated for C4H4OClBr: C, 34.74; H, 1.94. Found: C, 34.74; H, 1.76.
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1932, vol. 51, p. 98,109
13
[ 41513-04-6 ]
[ 13659-23-9 ]
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1932, vol. 51, p. 98,109
14
[ 1193-72-2 ]
[ 124-41-4 ]
[ 13659-23-9 ]
[ 120-83-2 ]
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1932, vol. 51, p. 98,109
[2] Recueil des Travaux Chimiques des Pays-Bas, 1932, vol. 51, p. 98,109
15
[ 108-43-0 ]
[ 89284-48-0 ]
[ 13659-23-9 ]
[ 13631-21-5 ]
[ 855836-62-3 ]
Reference：
[1] Journal of Organic Chemistry, 1997, vol. 62, p. 4504 - 4506
[2] Journal of Organic Chemistry, 1997, vol. 62, p. 4504 - 4506
[3] Journal of Organic Chemistry, 1997, vol. 62, p. 4504 - 4506
[4] Tetrahedron, 2007, vol. 63, # 23, p. 4959 - 4967
[5] Tetrahedron, 2007, vol. 63, # 23, p. 4959 - 4967
16
[ 108-43-0 ]
[ 40979-03-1 ]
[ 13659-23-9 ]
[ 13631-21-5 ]
[ 855836-62-3 ]
Reference：
[1] Journal of Organic Chemistry, 1997, vol. 62, p. 4504 - 4506
[2] Tetrahedron, 2007, vol. 63, # 23, p. 4959 - 4967
With tetra-(n-butyl)ammonium iodide; potassium carbonate In N,N-dimethyl-formamide for 2 h;
Preparation Example 27 Synthesis of 1-bromo-4-chloro-3-(4-ethoxybenzyl)-6-methoxybenzene; A suspension of 2-bromo-5-chlorophenol (2.85 g, 13.7 mmol; synthesized in reference to International Patent Publication WO0109122), potassium carbonate (1.89 g, 13.7 mmol), n-BU4NI (50 mg, 0.137 mmol), methyl iodide (1.28 mL, 20.6 mmol) and N,N-dimethylformamide (8.0 mL) was stirred for two hours. An iced water was added and the obtained mixture was extracted with ethyl acetate twice. The combined organic phase was washed with brine and dried with anhydrous magnesium sulfate. After the desiccant was filtered off, the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane:ethyl acetate=95:5) to obtain colorless oily 2-bromo-5-chloroanisole (2.94 g, 97percent). Then, oxalyl chloride (1.23 mL, 15.1 mmol) and N,N-dimethylformamide (2 drops) were added to 4-ethoxybenzoic acid (2.28 g, 13.7 mmol) in chloroform (8 mL) and stirred for five hours. The yellow oil obtained by evaporating the solvent under reduced pressure was dissolved in chloroform (5 mL). To this solution, a chloroform solution (10 mL) of 2-bromo-5-chloroanisole (2.94 g, 13.3 mmol) was added and then aluminum chloride (2.07 g, 15.5 mmol) was added portion wise at -10°C over five minutes. After stirred at 5°C for one hour, the reaction mixture was to room temperature and stirred for 13 hours. The reaction mixture was poured into an iced water and extracted with chloroform three times. After washed with 1 M hydrochloric acid, water, brine, the combined organic layer was dried with anhydrous magnesium sulfate. After the desiccant was filtered off, the residue obtained by evaporating the solvent under reduced pressure was purified by NH type silica gel column chromatography (hexane:ethyl acetate=9:1) to obtain (5-bromo-2-chloro-6-methoxyphenyl)(4-ethoxyphenyl)methanone (1.53 g, 31percent) as a colorless crystal. Then, Et3SiH (1.62 mL, 10.1 mmol) and BF3*Et2O (0.772 mL, 6.09 mmol) were added sequentially to a chloroform - acetonitrile (1:1; 16 mL) solution of (5-bromo-2-chloro-6-methoxyphenyl)(4-ethoxyphenyl)methanone (1.50 g, 4.06 mmol) at -5°C. The reaction mixture was warmed to room temperature and stirred for 16 hours. After the reaction mixture was added with a saturated sodium carbonate aqueous solution and extracted with chloroform, the organic layer was washed with brine and dried with anhydrous magnesium sulfate. After the desiccant was filtered off, the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane:ethyl acetate=20:1) to obtain a colorless oily title compound (1.48 g, 99percent). 1H NMR (200 MHz, CHLOROFORM-d) δ ppm 1.40 (t, J=7.0 Hz, 3 H) 3.87 (s, 3 H) 3.93 (s, 2 H) 4.01 (q, J=7.0 Hz, 2 H) 6.77 - 6.87 (m, 2 H) 6.90 (s, 1 H) 7.03 - 7.12 (m, 2 H) 7.29 (s, 1 H). EI 354(M+), 356(M+2), 358(M+4).
Reference：
[1] Patent: EP1845095, 2007, A1, . Location in patent: Page/Page column 41-42
[2] Journal of Medicinal Chemistry, 2010, vol. 53, # 8, p. 3247 - 3261
26
[ 13659-23-9 ]
[ 77-78-1 ]
[ 174913-09-8 ]
Reference：
[1] Angewandte Chemie - International Edition, 2018, vol. 57, # 9, p. 2450 - 2454[2] Angew. Chem., 2018, vol. 130, # 9, p. 2475 - 2479,5
27
[ 13659-23-9 ]
[ 73183-34-3 ]
[ 1377503-12-2 ]
Yield
Reaction Conditions
Operation in experiment
1.22 kg
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate In 1,4-dioxane at 75 - 90℃; for 16 h; Inert atmosphere
To a 30-L reactor was charged 2-bromo-5-chlorophenol (2.0 kg, 9.65 mol), B2Pin2 (2.7 kg,10.6 mol), AcOK (1.9 kg, 19.3 mol) and 1 ,4-dioxane (15 L). The mixture was stirred and purgedwith nitrogen 3 times. PdCI2(dppf)-CH2CI2 (1 OOg, 0.12 mol) was added under nitrogen and themixture was heated to 75°C (the oil bath could be removed in case of strong exotherm). Themixture was heated at 90°C for 16 hours, after which time HPLC analysis showed that the reaction20 was complete. After cooling to 35°C, the mixture was filtered through a pad of Celite. The filtrate 5-chloro-2-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenol (1.22 kg, 4.8 mol) solution was used innext step without further purification. MS m/z 253.1 [M-H]; 1H-NMR: (CDCb, 400 MHz) 8 9.2 (br,1 H), 7.25 (d, J= 8 Hz, 1 H), 6.64 (d, J= 1.6 Hz, 1 H), 6.62 (dd, Jb= 8 Hz, Jb= 1.6 Hz, 1 H), 1.05 (s,12H).
With tetra-(n-butyl)ammonium iodide; potassium carbonate; In N,N-dimethyl-formamide; for 2h;
Preparation Example 27 Synthesis of 1-bromo-4-chloro-3-(4-ethoxybenzyl)-6-methoxybenzene; A suspension of <strong>[13659-23-9]2-bromo-5-chlorophenol</strong> (2.85 g, 13.7 mmol; synthesized in reference to International Patent Publication WO0109122), potassium carbonate (1.89 g, 13.7 mmol), n-BU4NI (50 mg, 0.137 mmol), methyl iodide (1.28 mL, 20.6 mmol) and N,N-dimethylformamide (8.0 mL) was stirred for two hours. An iced water was added and the obtained mixture was extracted with ethyl acetate twice. The combined organic phase was washed with brine and dried with anhydrous magnesium sulfate. After the desiccant was filtered off, the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane:ethyl acetate=95:5) to obtain colorless oily 2-bromo-5-chloroanisole (2.94 g, 97%). Then, oxalyl chloride (1.23 mL, 15.1 mmol) and N,N-dimethylformamide (2 drops) were added to 4-ethoxybenzoic acid (2.28 g, 13.7 mmol) in chloroform (8 mL) and stirred for five hours. The yellow oil obtained by evaporating the solvent under reduced pressure was dissolved in chloroform (5 mL). To this solution, a chloroform solution (10 mL) of 2-bromo-5-chloroanisole (2.94 g, 13.3 mmol) was added and then aluminum chloride (2.07 g, 15.5 mmol) was added portion wise at -10C over five minutes. After stirred at 5C for one hour, the reaction mixture was to room temperature and stirred for 13 hours. The reaction mixture was poured into an iced water and extracted with chloroform three times. After washed with 1 M hydrochloric acid, water, brine, the combined organic layer was dried with anhydrous magnesium sulfate. After the desiccant was filtered off, the residue obtained by evaporating the solvent under reduced pressure was purified by NH type silica gel column chromatography (hexane:ethyl acetate=9:1) to obtain (5-bromo-2-chloro-6-methoxyphenyl)(4-ethoxyphenyl)methanone (1.53 g, 31%) as a colorless crystal. Then, Et3SiH (1.62 mL, 10.1 mmol) and BF3·Et2O (0.772 mL, 6.09 mmol) were added sequentially to a chloroform - acetonitrile (1:1; 16 mL) solution of (5-bromo-2-chloro-6-methoxyphenyl)(4-ethoxyphenyl)methanone (1.50 g, 4.06 mmol) at -5C. The reaction mixture was warmed to room temperature and stirred for 16 hours. After the reaction mixture was added with a saturated sodium carbonate aqueous solution and extracted with chloroform, the organic layer was washed with brine and dried with anhydrous magnesium sulfate. After the desiccant was filtered off, the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane:ethyl acetate=20:1) to obtain a colorless oily title compound (1.48 g, 99%). 1H NMR (200 MHz, CHLOROFORM-d) delta ppm 1.40 (t, J=7.0 Hz, 3 H) 3.87 (s, 3 H) 3.93 (s, 2 H) 4.01 (q, J=7.0 Hz, 2 H) 6.77 - 6.87 (m, 2 H) 6.90 (s, 1 H) 7.03 - 7.12 (m, 2 H) 7.29 (s, 1 H). EI 354(M+), 356(M+2), 358(M+4).
With boron tribromide; In dichloromethane; at -40 - 20℃; for 12.33h;
To a solution of 1-bromo-5-chloro-2 methoxyphenyl 275 (2.5 g, 11 mmol, 1 eq) in DCM (100 mL) was added dropwise BBr3 (1 M solution in DCM, 38.5 mmol, 3.5 eq) over 20 min at -40 C. The solution was warmed to rt and stirred for 12 h. TLC (3:2 Hexane:DCM) showed complete consumption of 275. The solution was quenched with NaHCO3 and stirred until two phases appeared. The organic was separated, washed with brine, dried, filtered and concentrated in vacuo to afford 0.80 g of 276 as a white solid which was used without purification. Yield 32%
2-Bromo-5-chloroanisole (461 mg, 2.08 mmol) was dissolved in anhydrous dichloromethane (5 mL) and cooled to 0 C. To the cooled solution was added boron tribromide solution (1M in dichloromethane, 2 eq). The reaction mixture was stirred at 0 C. for 5 minutes, warmed to room temperature and stirred at room temperature for 2 hours. The reaction mixture was then poured into ice-water and extracted with ethyl acetate (3×). The combined organic layer was then dried over sodium sulfate, filtered and concentrated to get the crude phenol which was used in the next step without further purification.
With caesium carbonate; In water; N,N-dimethyl-formamide; at 100℃; for 4h;
To a solution of <strong>[13659-23-9]2-bromo-5-chlorophenol</strong> (1 g, 4.8 mmol) in DMF/water (45 mL/5 mL) was added sodium chlorodifluoroacetate (1.95 g, 12.0 mmol) and cesium carbonate (3.14 g, 9.64 mmol), and the reaction mixture was heated to 100 C. for 4 hours. The reaction mixture was cooled and diluted with TBME (20 mL) and water (20 mL). The organic layer was collected, washed with saturated aqueous NaHCO3 solution, brine, dried over Na2SO4 and concentrated in vacuo to afford the title compound (1.21 g, 98%), which was used without further purification.
With caesium carbonate; In water; N,N-dimethyl-formamide; at 100℃; for 3h;
Sodium chlorodifluoroacetate (2.5 eq.) and cesium carbonate (1.5 eq.) were added to a solution of <strong>[13659-23-9]2-bromo-5-chlorophenol</strong> in DMF containing 10 volume % water, and the reaction mixture was heated for 3h at 100 C. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water (3×), then with brine (1×). The organic layer was dried over sodium sulfate and concentrated to obtain the crude product which was used in the next step without further purification.
With caesium carbonate; In water; N,N-dimethyl-formamide; at 100℃; for 16h;
To a solution of <strong>[13659-23-9]2-bromo-5-chlorophenol</strong> (4.34 g, 20.92 mmol, Ark Pharm) in N,N-dimethylformamide (21.79 ml, 20.92 mmol) was added sodium chlorodifluoroacetate (7.34 g, 48.1 mmol), cesium carbonate (9.54 g, 29.3 mmol), and water (2.179 ml, 20.92 mmol). The reaction was heated at 100 C for 16 h. After 16 h, the reaction was partitioned between EtOAc (100 mL) and water (50 mL). The aqueous layer was extracted with EtOAc (2x70mL). The organic portions were combined and washed with water (2x50 mL), 10% aq citric acid (1x30 mL), and brine, dried over MgS04, filtered, and concentrated to provide 1- bromo-4-chloro-2-(difluoromethoxy)benzene (4.35 g, 16.90 mmol, 81 % yield) as a colorless oil. The material was used without further purification.
With potassium carbonate; In acetone; for 3h;Heating / reflux;
A mixture OF 2-BROMO-5-CHLOROPHENOF (3. 93G, 18. 94MMOL), benzyl bromide (3. 42G, 20MMOL) and potassium carbonate (10g, 72. 46MMOL) in acetone (80MUT) was stirred and REFLUXED for 3 hours then cooled, evaporated and dissolved in ETHER/WATER. The organic phase was dried (magnesium sulphate) evaporated and purified by chromatography on silica eluting with ethyl ACETATE/ISO-HEXANE (1: 99) to give 5. 51G of white solid. 1H NMR (CDCL3) delta: 5.13 (2H, s), 6.84 (1H, dd, J=8HZ, 2Hz), 6.93 (1H, d, J=2Hz), 7.34-7. 48 (6H, m).
With bromine; In dichloromethane; at 0 - 20℃; for 16h;
A solution of 5.03 gm (39.1 mMol) 3-chlorophenol in 20 mL dichloromethane was cooled in an ice bath as 6.25 gm (39.1 mMol) bromine were added dropwise. The reaction mixture was allowed to warm to room temperature and was stirred for 16 hours. The reaction mixture was diluted with water, the phases separated, and the organic phase dried over magnesium sulfate. The residue was subjected to silica gel chromatography, eluting with 3:2 dichloromethane:hexanes. Fractions containing product were combined and concentrated under reduced pressure to provide 2.04 gm (25%) of 2-bromo-5-chlorophenol. HRMS: Calculated for C4H4OClBr: 205.9134. Found: 205.9125. EA: Calculated for C4H4OClBr: C, 34.74; H, 1.94. Found: C, 34.74; H, 1.76.
The requisite 4-(4-chloro-2-(R,S)-methylsulfinylphenyl)piperidine was prepared according to the procedures described in Example 2 except 3-chlorophenol was used in place of 3-methoxyphenol. The oxidation of the thiomethyl adduct was carried out according to the procedure described in Example 16, sub-part (e). 3-Chlorophenol (24.28 g) was reacted with bromine (29.78 g) to give 6.15 g of 2-bromo-5-chlorophenol (minor isomer) and 24.60 g 4-bromo-3-chlorophenol (major isomer) after purification by column chromatography (10:1 hexane:EtOAc); minor isomer-1H NMR (CDCl3) delta 7.37 (d, 1H), 7.04 (d, 1H), 6.82 (dd, 1H), 5.55 (s, 1H).
9 ml of boron tribromide is added dropwise to a solution containing 20 g of 5-bromo 2-chloro anisole in 200 ml of methylene chloride. Agitation is carried out for 10 minutes at 0 C., then for 24 hours at 20 C. and the reaction medium is poured into a water and ice mixture. The resultant suspension is agitated for 30 minutes, extraction is carried out with methylene chloride, followed by saturation with sodium chloride and extraction twice with methylene chloride. The organic phases are collected, dried over magnesium sulphate, evaporated under reduced pressure and 18.5 g of 5-chloro 2-bromophenol is obtained. M.p.=56 C.
2-(2-Bromo-5-chlorophenoxy)-N,N-dimethylpropionamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In 4-methyl-2-pentanone;
EXAMPLE 3 2-(2-Bromo-5-chlorophenoxy)-N,N-dimethylpropionamide (Compound no. 11) <strong>[13659-23-9]2-Bromo-5-chlorophenol</strong> (8 g), 2-bromo-N,N-dimethylpropionamide (6.66 g) and anhydrous potassium carbonate (2.6 g) in methyl iso-butyl ketone (100 ml) were refluxed with stirring overnight. The mixture was cooled to 50 and washed with 5% sodium hydroxide (2*20 ml) and then water (2*50 ml). The organic solution was dried and evaporated under reduced pressure to yield a pale red oil, which solidified on cooling. Recrystallisation from 50% aqueous ethanol gave the title compound, m.p. 76-77. Compounds 2, 9, 10 to 13, 17 and 21 were made by a similar procedure.
To a solution of MgCl2 (powder 325 mesh, 0.734 g, 7.71 mmol, 2 eq), paraformaldehyde (0.347 g, 11.57 mmol, 3 eq) and Et3N (1.08 mL, 7.71 mmol, 2 eq) in THF (20 mL) was added 276 (0.800 g, 3.68 mmol, 1 eq), heated in the microwave at 160 C for 15 min. TLC (3:2 Hexane:DCM) showed complete consumption of 3. THF was evaporated and the reaction mixture was taken up in EtOAc, washed with brine, dried, filtered and concentrated in vacuo to afford 0.52 g of 277 which was used without purification. Yield 47%
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; for 16.3333h;
A: 4- { [(2-bromo-4-chlorophenyl)oxy]methyl} - 1 -(phenylmethyl)- 1 ,2,3,6- tetrahydropyridineTriphenylphosphine (6.9 g, 26.3 mmol) was dissolved in THF (175 niL) and the solution cooled to 0 0C in an ice bath under nitrogen. Diisopropyl azodicarboxylate (5.3 g, 26.2 mmol) was then added dropwise and the mixture stirred at 0 0C for 20 minutes, during which a white ppt was seen to form. <strong>[13659-23-9]2-Bromo-5-chlorophenol</strong> (4.4 g, 21 mmol) was then added as a solid followed by [1 -(phenylmethyl)- 1,2,3, 6- tetrahydro-4-pyridinyl]methanol (4.3 g, 21 mmol). The mixture was allowed to warm to ambient temperature overnight. The reaction was evaporated to a residue after 16 hours and then purified by FCC on the ISCO (0% to 25% EtOAc/Hex). Fractions containing product were concentrated to give a colorless oil (6.14g, 74%). MS (ES) m/e 393.8 [M+H]+.
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; at 75 - 90℃; for 16h;Inert atmosphere;
To a 30-L reactor was charged <strong>[13659-23-9]2-bromo-5-chlorophenol</strong> (2.0 kg, 9.65 mol), B2Pin2 (2.7 kg,10.6 mol), AcOK (1.9 kg, 19.3 mol) and 1 ,4-dioxane (15 L). The mixture was stirred and purgedwith nitrogen 3 times. PdCI2(dppf)-CH2CI2 (1 OOg, 0.12 mol) was added under nitrogen and themixture was heated to 75C (the oil bath could be removed in case of strong exotherm). Themixture was heated at 90C for 16 hours, after which time HPLC analysis showed that the reaction20 was complete. After cooling to 35C, the mixture was filtered through a pad of Celite. The filtrate 5-chloro-2-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenol (1.22 kg, 4.8 mol) solution was used innext step without further purification. MS m/z 253.1 [M-H]; 1H-NMR: (CDCb, 400 MHz) 8 9.2 (br,1 H), 7.25 (d, J= 8 Hz, 1 H), 6.64 (d, J= 1.6 Hz, 1 H), 6.62 (dd, Jb= 8 Hz, Jb= 1.6 Hz, 1 H), 1.05 (s,12H).
Step 1: l-bromo-2-(2-bromoethoxy)-4-chlorobenzene [00186] To a suspension of <strong>[13659-23-9]2-bromo-5-chloro-phenol</strong> (2.58 g, 12.44 mmol) in water (8 mL) was added sodium hydroxide (995 mg, 24.88 mmol) and the solution heated to reflux for 1 h and then allowed to cool to room temperature. 1,2-dibromoethane (4.67 g, 24.88 mmol) was added and the mixture heated at reflux for 25h. The solution was allowed to cool to room temperature and partitioned between EtAOc and water. The aqueous was washed with saturated sodium hydrogen carbonate, water and brine and then dried (MgS04) and concentrated. Material was purified using an ISCO (0-5% EtOAc/hexanes) to afford l-bromo-2-(2-bromoethoxy)-4-chlorobenzene as a white solid (1.30 g, 33 %). NMR (500 MHz, d6-DMSO) delta 7.62 (1H, d), 7.26 (1H, s), 7.02 (1H, d), 4.46 (2H, t), 3.83 (2H, t).
2-bromo-5-chlorophenyl tert-butyl carbonate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
94.6%
With dmap; In dichloromethane; at 20℃; for 24h;
To a solution of compound 36A (5 g, 24.1 mol) and Boc20 (6.61 g, 31.33 mol) in DCM (50 mL) at rt was added DMAP (0.147 g, 1.205mol).The mixture was stirred at rt for 24 h and concentrated to dryness. The crude product was purified by silica gel chromatography to afford compound 36B (7 g, 94.6%).
37.41 g
With dmap; In dichloromethane; at 20℃; for 25h;
To a mixture of <strong>[13659-23-9]2-bromo-5-chlorophenol</strong> (23.236 g, 121.6 mmol) and Boc2O (33.475 g, 153.4 mmol) in DCM (300 mL) was added DMAP (0.962 g, 7.87 mmol) at room temperature. The reaction mixture was stirred at room temperature for 25 h. After the solvent was evaporated under reduced pressure, the residue was purified by flash chromatography on silica gel (340 g column) eluted with 0 to 20% ethyl acetate/hexanes to afford 37.41 g (100%) of 2-bromo-5-chlorophenyl tert- butyl carbonate. ESI-MS m/z 292.0, 293.9 (M-15)+, 251.0, 253.0 (M-56)+.
2-(4,8-dimethoxy-naphthalen-1-yl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane[ No CAS ]
C18H15ClO3[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In tetrahydrofuran; water; at 70℃; for 15h;
11.5 g of Intermediate 1-4 and 8 g of <strong>[13659-23-9]2-bromo-5-chlorophenol</strong> were diluted with 300 ml of tetrahydrofuran and 150 ml of water. Then, 2.1 g of Pd(PPh3)4and 15 g of potassium carbonate were added thereto, and the mixture was refluxed while stirring at 70 C. After maintaining the reaction mixture for 15 hours, the reaction mixture was cooled to ambient temperature, and an organic layer was separated by using ethyl acetate. The separated organic layer was dried using anhydrous magnesium sulfate and concentrated under a reduced pressure, and the residue was separately purified using silica gel column chromatography to obtain 9.8 g of Intermediate 1-4 (Yield: 85%).
5-chloro-2-(1-(difluoromethyl)-1H-pyrazol-4-yl)phenol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 80℃; for 3h;Inert atmosphere;
1-(difluoromethyl)-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (282 mg, 1.157 mmol), 2-bromo-5- chlorophenol (200 mg, 0.964 mmol) and 1,1'-bis(diphenylphosphino)ferrocene- palladium(II)dichloride dichloromethane complex (79 mg, 0.096 mmol) were mixed in a pressure release vial, degassed and backfilled with nitrogen (3x). Dioxane (6 mL) and potassium phosphate tribasic (3M aqueous) (1 mL) were added subsequently. The reaction mixture was stirred at 80 C for 3 h. It was cooled to rt and purified by flash column chromatography on silica gel (eluting with 50% ethyl acetate in hexane) to give the title compound. MS (ES+) m/z: 245 (M+H).
ethyl 2-(2-bromo-5-chlorophenoxy)-3-oxobutanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
54%
n a solution of <strong>[13659-23-9]2-bromo-5-chlorophenol</strong> (1.4958, 7.211111101) in ethanol (1311 ^), cesium carbonate(2.58 g, 7.92 mmo 1) in ethanol (33 mL) was added and the mixture was stirred at room temperature for half an hour,Ethyl 2-chloroacetoacetate (1.4 g, 8.43 mmo 1) was added and stirred at 50 C.The mixture was cooled to room temperature,Column chromatography (petroleum ether / ethyl acetate = 60: 1) gave 1.4 g of colorless oil, yield 54%
(2-(2-bromo-5-chlorophenoxy)ethoxy)(dimethyl)(2-methyl-2-propanyl)silane[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83.5%
With potassium carbonate; potassium iodide; In 1-methyl-pyrrolidin-2-one; at 90℃; for 5h;
To a solution of<strong>[13659-23-9]2-bromo-5-chlorophenol</strong> (50 g, 241 rnmol) in NJVIP (500mL) wa. added K?C03 (66.51 g, 482 mmol), (2-bromoethoxy)-tert-butyl-25 dimethylsilane (56 8 mL 265.1 mmol) and catalytic amount of KJ (800 mg, 4.80mmol), and the suspension was heated to 90 oc for 5 h. On completion, thesuspension vas cooled to room temperature and diluted vvith water (500 mL).Aqueous phase was extracted with ethyl acetate (3 x 250 mL). Combined organic layer was washed ·with water (500 mL), brine (500 mL) and dried over sodiumsulphate. Solvent was removed tmder reduced pressure to afford crude materialwhich v.·as purified by column chromatography (1 00-200 mesh size silica gel,eluting with a gradient of 100();6 hexanes to 5% ethyl acetate in hexanes) affording5 pure (2-(2-bromo-5-chlorophenoxy)ethoxy)(dimethyl)(2-methyl-2-propanyl)silane(72 g, 83.5%) as light yellov oiL Rr: 0.8 in 5() Ethyl acetate in hexane.
With p-nitrobenzenesulfonic acid; cis-dichlorobis(triphenylphosphine)molybdenum; 1-ethyl-3-methylimidazolium tetrafluoroborate; bis-[(trifluoroacetoxy)iodo]benzene; 4,4'-di-tert-butyl-2,2'-bipyridine; In N,N-dimethyl-formamide; at 85℃; for 11h;Inert atmosphere;
At room temperature, In the appropriate amount of the organic solvent (A mixture of N, N-dimethylformamide (DMF) and 1-ethylethyl ether-3- in a mass ratio of 5: 1, 100 mmol of the compound of formula (I), 70 mmol of the compound of the formula (II), 4 mmol of catalyst cis-dichlorobis (triphenylphosphine) molybdenum,12 mmol of organic ligand L1,140 mmol of oxidant bis(trifluoroacetate) iodobenzene and 7 mmol of auxiliary p-nitrobenzene sulfonic acid, then purged with nitrogen, until the reaction atmosphere is a nitrogen atmosphere, and stirred heated to 85 C, the reaction was stirred at this temperature for 11 hours;After completion of the reaction, the reaction system was cooled to room temperature, pH adjusted to neutral, and then washed thoroughly with saturated saline, the mixture was further extracted with ethyl acetate for 2-3 times, organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, resulting residue was subjected to silica gel column chromatography, an equal volume ratio of acetone and petroleum ether mixture was rinsed, Thus, the compound of the above formula (III) was obtained in a yield of 96.1%.
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