* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Stage #1: With sodium t-butanolate In toluene at 42℃; for 22 h; Inert atmosphere Stage #2: With acetic acid In water; toluene for 0.166667 h;
5-(4-tert-butoxycarbonylpiperazin-1-yl)-2-hydroxybenzaldehyde Toluene (9.7 L) was introduced into a reactor and degassed using vacuum /nitrogen. Under nitrogen at 23°C was palladium acetate (11.0 g, 0.049 mol, 0.01 equiv.) was loaded and the mixture was stirred until complete dissolution of palladium. A solution of tri-tert-butyl-phosphine (10.0 g, 0.049 mol, 0.01 equiv.) in toluene (0.3 L) was then added, followed by the addition of 5-bromo-2-hydroxybenzaldehyde (1000 g, 4.97 mol, 1 equiv.), tert-butyl-1-piperazinecarboxylate (1065.4 g, 5.72 mol, 1.1 equiv.) and sodium-tert-butoxide (1052.4 g, 10.9 mol, 2.2 equiv.). The resulting yellow-orange solution was stirred for 22 h at 42°C. The red-brownish slurry was mixed with a mixture (pH around 5-6) of distilled water (8 L) and glacial acetic acid (800 mL), and stirred for 10 min. The organic phase was separated from the aqueous phase and washed twice with distilled water (2 x 8 L). The organic phase was then dried by addition of sodium sulphate (2.5 kg), stirred for 30 min. and filtered. The resulting dark-orange organic phase was weighed (9.65 kg) and an aliquot (100 g) was taken. The aliquot was concentrated in vacuo to yield a dark-orange oil which was purified by column chromatography (SiO2, h: 30 cm, d: 4 cm, eluant: MTBE/heptane 1:1). The named compound was obtained as yellow crystals (8.9 g). Calculation of the total yield from the aliquot gave 56percent. MS (ES+): 307 (M+H).
Reference:
[1] Patent: EP2110374, 2009, A1, . Location in patent: Page/Page column 30
[2] Bioorganic and Medicinal Chemistry, 2004, vol. 12, # 18, p. 4843 - 4852
2
[ 50-00-0 ]
[ 158985-25-2 ]
[ 343306-50-3 ]
Yield
Reaction Conditions
Operation in experiment
78%
Stage #1: With tin(IV) chloride; triethylamine In dichloromethane; toluene at 20℃; for 0.5 h; Stage #2: at 110℃;
General procedure: To a stirred suspension of 1 (20.0 mmol) in toluene(40 mL), tin tetrachloride (6.0 mmol) (1M solution in CH2Cl2) was added, followed, after 30 min, by TEA(24.0 mmol). The mixture was stirred for 30 min at rt, then paraformaldehyde (40.0 mmol) was charged.The reaction mixture was heated at 110 °C for 7/8 h, then cooled to 80 °C and treated with water (40.0mL) and AcOEt (20 mL). After stirring for 1 h the mixture was filtered through Celite, the organic layerseparated, dried (Na2SO4) and the solvent evaporated. The crude residues were purified by columnchromatography (SiO2, AcOEt/EtOH : 90/10) (2a,b) or by crystallization (2c,d).
With sodium t-butanolate In n-heptane; water; toluene
1) Synthesis of 5-(4-tert-butoxycarbonylpiperazin-1-yl)-2-hydroxybenzaldehyde 0.58 g of bis(dibenzylideneacetone)palladium and 0.16 g of tri-tert-butylphosphine are added under nitrogen to 200 ml of toluene, and the resultant solution, which becomes dark red, is stirred at 20° for 30 minutes. 10 g of 5-bromo-2-hydroxybenzaldehyde, 10.2 g of tert-butyl 1-piperazinecarboxylate and 7.2 g of sodium tert-butoxide are then added. The mixture is stirred at 60° for 24 hours and cooled, 800 ml of water are added, and the mixture is extracted with 2*500 ml of ethyl acetate. The organic phases are combined and washed with 300 ml of water, and the solvent is removed at 30° under reduced pressure. The dark-orange oil which remains (11 g) is purified by chromatography (300 g of silica gel; MTB ether/heptane 5:1; 1.5 litres) leaving 7.8 g of pale-yellow crystals (51percent), m.p. 84-86°; MS 306 (M+), 250 (100percent), 233, 176, 164.
1) Synthesis of 5-(4-tert-butoxycarbonylpiperazin-1-yl)benzofuran-2-carboxamide 5 ml of 1-methyl-2-pyrrolidone, 0.16 g of chloroacetamide and 0.25 g of potassium carbonate are added at 20 C. with stirring/under nitrogen to 0.5 g of <strong>[343306-50-3]5-(4-tert-butoxycarbonylpiperazin-1-yl)-2-hydroxybenzaldehyde</strong>. The mixture is stirred at 60 C. for 16 hours, cooled and then filtered, and the solvent is removed under reduced pressure. The residue is taken up in MTB ether, re-filtered and concentrated, and the residue is crystallized from toluene. The isolated yield is 0.34 g (60%).
5-(4-tert-butoxycarbonylpiperazin-1-yl)-2-hydroxybenzaldehyde Toluene (9.7 L) was introduced into a reactor and degassed using vacuum /nitrogen. Under nitrogen at 23C was palladium acetate (11.0 g, 0.049 mol, 0.01 equiv.) was loaded and the mixture was stirred until complete dissolution of palladium. A solution of tri-tert-butyl-phosphine (10.0 g, 0.049 mol, 0.01 equiv.) in toluene (0.3 L) was then added, followed by the addition of 5-bromo-2-hydroxybenzaldehyde (1000 g, 4.97 mol, 1 equiv.), tert-butyl-1-piperazinecarboxylate (1065.4 g, 5.72 mol, 1.1 equiv.) and sodium-tert-butoxide (1052.4 g, 10.9 mol, 2.2 equiv.). The resulting yellow-orange solution was stirred for 22 h at 42C. The red-brownish slurry was mixed with a mixture (pH around 5-6) of distilled water (8 L) and glacial acetic acid (800 mL), and stirred for 10 min. The organic phase was separated from the aqueous phase and washed twice with distilled water (2 x 8 L). The organic phase was then dried by addition of sodium sulphate (2.5 kg), stirred for 30 min. and filtered. The resulting dark-orange organic phase was weighed (9.65 kg) and an aliquot (100 g) was taken. The aliquot was concentrated in vacuo to yield a dark-orange oil which was purified by column chromatography (SiO2, h: 30 cm, d: 4 cm, eluant: MTBE/heptane 1:1). The named compound was obtained as yellow crystals (8.9 g). Calculation of the total yield from the aliquot gave 56%. MS (ES+): 307 (M+H).
With sodium t-butanolate;bis(dibenzylideneacetone)-palladium(0); In n-heptane; water; toluene;
1) Synthesis of 5-(4-tert-butoxycarbonylpiperazin-1-yl)-2-hydroxybenzaldehyde 0.58 g of bis(dibenzylideneacetone)palladium and 0.16 g of tri-tert-butylphosphine are added under nitrogen to 200 ml of toluene, and the resultant solution, which becomes dark red, is stirred at 20 for 30 minutes. 10 g of 5-bromo-2-hydroxybenzaldehyde, 10.2 g of tert-butyl 1-piperazinecarboxylate and 7.2 g of sodium tert-butoxide are then added. The mixture is stirred at 60 for 24 hours and cooled, 800 ml of water are added, and the mixture is extracted with 2*500 ml of ethyl acetate. The organic phases are combined and washed with 300 ml of water, and the solvent is removed at 30 under reduced pressure. The dark-orange oil which remains (11 g) is purified by chromatography (300 g of silica gel; MTB ether/heptane 5:1; 1.5 litres) leaving 7.8 g of pale-yellow crystals (51%), m.p. 84-86; MS 306 (M+), 250 (100%), 233, 176, 164.
ethyl 5-(4-tert-butoxycarbonyl-1-piperazinyl)benzofuran-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70%
With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 110℃; for 4h;
5-(4-tert-butoxycarbonylpiperazin-1-yl)-benzofuran-2-carboxylic acid ethyl ester K2CO3 (250 mg, 1.8 mmol) and Ethyl bromoacetate (0.20 ml, 1.7 mmol) were added to a solution of hydroxybenzaldehyde in NMP (5 mL). The mixture was stirred for 4 h at 110C. The reaction was quenched with H2O, extracted with EtOAc, washed with brine and water. After evaporation of EtOAc, the residue was recrystallized in a mixture of MTB/Heptane 5/1 to give yellow crystals (0.45 g, 70%). MS (ES+): 375 (M+H).
With potassium carbonate; In water;
1) Synthesis of ethyl 5-(4-tert-butoxycarbonylpiperazin-1-yl)benzofuran-2-carboxylate 520 mg of <strong>[343306-50-3]5-(4-tert-butoxycarbonylpiperazin-1-yl)-2-hydroxybenzaldehyde</strong> are added at 20 under nitrogen with stirring to 5 ml of NMP, and 0.25 g of potassium carbonate and 0.2 ml of ethyl bromoacetate are added to the solution. The mixture is stirred at 105 for 3 hours and then cooled to 25. The batch is added to 30 ml of water (10) with stirring, the aqueous phase is extracted at 10 with 3 times 30 ml of ethyl acetate, and the combined organic phases are washed with 30 ml of saturated NaCl solution and with 30 ml of water and then freed from solvent under reduced pressure (0.6 g of orange oil with crystal components). After chromatography on 30 g of silica gel (MTB ether/heptane 5:1), 0.45 g of pale-yellow crystals can be isolated (70%), m.p. 116-117; MS 374 (M+), 318 (100%), 244, 232.
EXAMPLE 23.5 g of 5-(4-tert-butoxycarbonylpiperazin-l-yl)-2-hydroxybenzaldehyde are dissolved in 15 ml of dimethylformamide at 20 C. with stirring. 2.1 g of potassium carbonate are added and stirred for 15 min. 2.8 g of 2-bromomalonic acid monoethyl ester monoamide are subsequently metered in. The mixture is stirred at room temperature for 2 hrs., then stirred at 120 C. for 5 hrs. After cooling to 20 C., the solid component is filtered off; the filter residue is washed with 20 ml of dimethylformamide and discarded. The combined filtrates are slowly diluted with 150 ml of water with stirring and stirred at 20 C. for 1 hr. The solid product formed is filtered off, the filter residue is washed with water and dried. The solid formed is recrystallised from tolueneln-heptane.
General procedure: To a stirred suspension of 1 (20.0 mmol) in toluene(40 mL), tin tetrachloride (6.0 mmol) (1M solution in CH2Cl2) was added, followed, after 30 min, by TEA(24.0 mmol). The mixture was stirred for 30 min at rt, then paraformaldehyde (40.0 mmol) was charged.The reaction mixture was heated at 110 C for 7/8 h, then cooled to 80 C and treated with water (40.0mL) and AcOEt (20 mL). After stirring for 1 h the mixture was filtered through Celite, the organic layerseparated, dried (Na2SO4) and the solvent evaporated. The crude residues were purified by columnchromatography (SiO2, AcOEt/EtOH : 90/10) (2a,b) or by crystallization (2c,d).
Take compound B 13.0mg (0.0457mmol, 1.0eq), 4- (3-formyl-4-hydroxyphenyl) piperazine-1-carboxylic acid tert-butyl ester 25.0mg (0.178mmol, 3.9eq), dissolved in 4mL In a mixed solution of methanol and 4 mL of ether, stir at 60 C for 4 h.At the end of the reaction, light yellow solid particles precipitated.Return to room temperature and centrifuge to obtain a light yellow solid.It was washed twice with 0.5 mL of anhydrous methanol, 0.5 mL of dichloromethane, and 0.5 mL of petroleum ether to obtain 28.3 mg of a pure product as a pale yellow powdery solid.The yield was 60.1%.
With potassium carbonate In ethanol; N,N-dimethyl-formamide at 50 - 130℃; for 3h; Inert atmosphere;
1.4-2.4 Step 4: Synthesis of ethyl 5-(4-N-tert-butoxycarbonylpiperazin-1-yl)benzofuran-2-carboxylate (II)
Under the protection of nitrogen, add compound VI (9.2g, 0.03mol), potassium carbonate (6.2g, 0.045mol), absolute ethanol (2.8g, 0.06mol) and DMF (46mL) into the reaction flask, and heat to 50. Diethyl 2-bromomalonate was added dropwise to it, and after completion, it was stirred at this temperature for 1 hour. After the conversion of compound VI was detected by HPLC, the reaction system was heated to 120-130°C and stirred for 2 hours. HPLC showed that the intermediate was less than 3%, after cooling to less than 35, filter, and wash the filter cake with DMF (24mL), slowly add water (104mL) to the filtrate and keep the temperature below 35, stir for 1 hour, filter, and rinse the filter cake with water (18mL) The crude compound II was obtained.The crude product was dissolved in ethyl acetate (40mL) and added with 26% sodium chloride aqueous solution (10mL) for separation. The organic layer was added with activated carbon (1g) and refluxed for 0.5 hours, filtered while hot and rinsed with ethyl acetate (20mL). The filtrate Combine and distill to 35mL under reduced pressure. After heating to 70°C, add n-heptane (50mL) and stir for 0.5 hour. Cool to 20°C and stir for 1 hour to filter. Wash the filter cake with n-heptane (14mL) and dry under reduced pressure. 9.1g compound II, yield: 82%.