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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.
3 Example 3
Example 3 A solution of 1 g of ethyl 5-(1-piperazinyl)-benzofuran-2-carboxylate in 50 ml of THF is stirred with 1 g of di-tert-butyl dicarbonate for 3 hours. After customary working up, ethyl 5-(4-tert-butoxycarbonyl-1-piperazinyl)benzofuran-2-carboxylate, m.p. 116°-118°, is obtained.
4 Example 4
Example 4 A solution of 3 g of ethyl 5-(4-tert-butoxycarbonyl-1-piperazinyl)benzofuran-2-carboxylate in 100 ml of N-methylpyrrolidone is stirred for 5 hours with 1 g of formamide and 3 g of sodium alkoxide. After customary working up, 5-(4-tert-butoxycarbonyl-1-piperazinyl)benzofuran-2-carboxamide, m.p. 198°-200°, is obtained.
With sodium methylate; formamide In methanol at 20 - 30℃; for 1h; Large scale;
2 4-Bromo-5-(4-tert-butoxycarbonylpiperazin-1-yl)-benzofuran-2-carboxylic acid ethyl ester
4-Bromo-5-(4-tert-butoxycarbonylpiperazin-1-yl)-benzofuran-2-carboxylic acid ethyl ester Bromine (12 mL, 0.23 mol) was added to a solution of ester (73 g, 0.19 mol) in presence of cat. iron (0.8 g, 14.3 mmol) in dichloromethane (900 mL). The reaction was stirred for 2 days at rt. The bromohydrate was filtrated off and dried under vacuum. The mother liquor was concentrated, the oily residue was taken into iPrOH and triturated with a spatula. The precipitate obtained was filtered off and dried. Combination of both filtrate provided 88 g, 70% of the desired compound. MS (ES+): 454 (M+H).
Stage #1: ethyl 5-chlorobenzo<b>furan-2-carboxylate; 1-t-Butoxycarbonylpiperazine With palladium diacetate; sodium sulfate; sodium t-butanolate; XPhos for 1h; Milling;
Stage #2: In water; ethyl acetate for 0.0333333h; Milling;
2. General Procedure
General procedure: A mixture of substrate 2 (0.5 mmol), 1 (0.6 mmol), Pd(OAc)2 (2 mol%), Xphos (4 mol%), NaOtBu (2.0 equiv.) and Na2SO4 (2.0 g) were added to the 25 mL screw-capped stainless-steel vessel, along with two stainless steel balls ( = 1.4 cm). After that, the vessel was placed in the mixer mill, and the contents were ball milled at 30 Hz for 60 min. At the end of the reaction, small portion (3 mL) ethyl acetate and (3 mL) H2O were added in to the vessel and grinding for another 2 min at 30 Hz. Then, after the washing by brine, the organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give a residue, which was purified by flash column chromatography on silica gel to give the desired product.
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%.
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