He Juan, Chang Junbiao, Chen Rongfeng, Wang Limin
(Institute of Chemistry, Academy of Science of Henan Province, Zhengzhou 450002, China)

Received Dec.6, 2001; Supported by the National New Drug Foundation of China

Abstract 5-Methoxy-2-methyl benzofuran, which was isolated from the root of Pimpinella thellungiana Wolff, is a new compound with antihypertensive activity. According to the structure effect relationship, we synthesized the compound 5-(3-(4-(2-methoxyphenyl)-1-piperazinyl) propionyl) benzofuran and confirmed that it has higher antihypertensive activity. The present paper first reported the synthesis of 5-(3-(4-(2-Methoxyphenyl)-1-piperazinyl) propionyl) benzofuran with salicyladehyde and diethyl bromomalonate as the starting material via five step reactions. Its structure is confirmed by UV, IR, MS, ¹H NMR and elemental analysis.
Keywords Pimpinella thellungiana Wolff., antihypertensive activity, 5-(3-(4-(2-Methoxyphenyl)-1-piperazinyl) propionyl benzofuran

1 INTRODUCTION
The number of hypertensive disease is increasing in the world, more and more antihypertensive drugs have been synthesized. But these drugs have a common property, that is the patients must eat the drug continually to maintain the normal blood pressure. 5-Methoxy-2-methyl benzofuran was isolated from the root of Pimpinella thellungiana Wolff. and its structure was identified by UV, IR, MS, ¹H NMR, DEPT, ¹H-¹HCOSY and ¹H-¹³CCOSY. It is a new compound with antihypertensive activity. According to the structure effect relationship, we designed the compound 5-(3-(4-(2-Methoxyphenyl)-1-piperazinyl) propionyl) benzofuran (6), and expected that it might have higher antihypertensive activity. The present paper reports the synthesis of 5-(3-(4-(2-Methoxyphenyl)-1-piperazinyl) propionyl) benzofuran (6) with salicyladehyde and diethyl bromomalonate as the starting material via five steps of reactions for the first time. Its structure is confirmed by UV, IR, MS, ¹H NMR and elemental analysis. The modern pharmacology showed it had the higher antihypertensive activity.

2 EXPERIMENTAL     
Melting points were obtained on a XT-4 microscope and uncorrected. Infrared spectra were recorded on a Shimadzu 8700 spectrophotometer in KBr. ¹H NMR spectra data were obtained on a Bruker AV 300 spectrometer in CDCl₃ with TMS as the internal standard. Mass spectra were recorded on a Shimadzu QP-5000 spectrometer. Elemental analyses were carried out on an Elementar Vario EL elemental analyzer. UV spectra were recorded on Shimadzu UV-2100 spectrophotometer. Sillica gel GF₂₅₄ were used for TLC.
   5-(3-(4-(2-Methoxyphenyl)-1-piperazinyl) propionyl) benzofuran was synthesized with salicylaldehyde and diethyl bromomalonate as the starting material via five steps of reaction. (Scheme 1).

Scheme 1. The synthesis route of 5-(3-(4-(2-Methoxyphenyl)-1-piperazinyl) propionyl) benzofuran

Reagents: a) diethyl bromomalonate, K₂CO₃, DMF; b) CH₃COCl, AlCl₃; c) NaOH, EtOH/H₂O; d) Cu, quinoline; e) 1N HCl, EtOH, 1-(2-methoxyphenyl)-1-piperazinyl, paraformaldehyde.

2-carboethoxy benzofuran 2
    A mixture of salicyladehyde (32g , 0.25mol) , diethyl bromomalonate (86g , 0.36mol) and potassium carbonate in 200 ml of dimethyl formamide was refluxed with vigorous stirring for 3 hours under nitrogen. The mixture was cooled to room temperature , diluted with water and extracted with two 50 ml portions of ethyl acetate. The organic extracts were washed with water and dried over magnesium sulfate, and then concentrated by means of rotary evaporator. The residue was purified by chromatography on silicagel using hexane/ethyl acetate as the eluent to afford 2 as a pale yellow oil,yield 65%; ¹H NMR (CDCl₃): d (ppm) 7.69-7.27 (m , 5H , Ar-H) , 4.49-4.40 (dd , 2H , -CH₂- ) , 1.46-1.40 (t , 3H , -CH₃); Anal. Calcd for C₁₁H₁₀O₃: C 69.47, H 5.26; found C 69.62, H 5.18.
5-acetyl-2-carboethoxy benzofuran 3
    A solution of compound 2 (10g , 52.6 mmol) and acetyl chloride (7.5ml , 0.106 mol) was added over 30 min to a stirred suspension of aluminium chloride (18.1g , 0.136 mol) in dichloromethane at 0°C. The reaction mixture was stirred for 1h at room temperature and then it was heated at reflux with stirring for 30 hours. After cooling the contents of the flask poured onto 150g of crashed ice. Most of CH₂Cl₂ was removed from the mixture by distillation using a rotary evaporator. The solid product is collected by filtration , washed with water , and dried over MgSO₄. The solvent was removed under reduced pressure and the residue was purified by chromatography on silicagel using hexane/ethyl acetate to afford 3 as a crystalline solid, yield 82%, m.p. 104-106°C; ¹H NMR (CDCl₃): d (ppm) 8.29-7.60 (m , 4H , Ar-H) , 4.49-4.45 (dd , 2H , -CH₂-) , 2.69 (s , 3H , CH₃CO-) , 1.47-1.41(t , 3H , -CH₃) . Anal. Calcd for C₁₃H₁₂O₄: C 67.24, H 5.17; found C 67.36, H 5.12
5-acetyl-2-carboxyl benzofuran 4 
    A mixture of Compound 3 (4.0g , 17.2 mmol) and sodium hydroxide (0.5g , 14.3 mmol) in 30 ml of 50% ethanol was refluxed with stirring for 3 hours under nitrogen. The mixture was cooled to room temperature and most of the ethanol was removed by means of rotary evaporator. After addition of 20 ml of water to the residue and added 25 ml of 2N HCl with stirring on a oil bath at 70°C. The resulting crystalline product was filtered and washed with water and then dried in vacuum to give 4 as a crystalline solid, yield 98%, m.p. 235-240°C; ¹H NMR (CDCl₃): d (ppm) 6.92-6.46 (m , 4H , Ar-H) , 2.64 (s , 3H , CH₃CO-). Anal. Calcd for C₁₁H₈O₄: C 64.71, H 3.92; found C 64.85, H 3.81.
5-acetyl benzofuran 5
    A mixture of compound 4 (2.9g , 14.3 mmol) and copper (0.1g) in 10 ml of quinoline was stirred at 220°C for 2 hours. After cooling , ethyl acetate was added to the mixture followed by washing three times with 50% HCl and brine. The solution was dried over MgSO₄ and removed under reduced pressure. The residue was purified by chromatography on silicagel to afford 5 as a colorless plate, yield 37%, m.p. 39-40°C; ¹H NMR (CDCl₃): d (ppm) 8.51-7.12 (m , 5H , Ar-H) , 2.80 (s , 3H , CH₃CO-). Anal. Calcd for C₁₀H₈O₂: C 75.00, H 5.00; found C 74.83, H 4.92.
5-(3- (4-(2-methoxyphenyl)-1-piperazinyl) propionyl) benzofuran 6         
    5ml of 1N HCl was added to a solution of 1-(2-methoxyphenyl) piperazine (1.7g , 8.8 mmol) in ethanol. After stirring at room temperature for 1h, the solution was removed under reduced pressure. Paraformaldehyde (600 mg) , 0.02 ml of 1N HCl and a solution of 5 (1.08g, 6.8 mmol) in 95% ethanol was added to the residue . After the solvent was evaporated , the residue was diluted with 1N NaOH , extracted with ethyl acetate and washed with brine. After dring over MgSO₄ , the solvent was removed under reduced pressure. The residue was purified by silicagel chromatography to afford 6 as a white solid, yield 46%, m.p. 132-133°C; UV(EtOH)l_max: 230, 209 nm; ¹H NMR (CDCl₃, 300MHz ): d (ppm) 8.38-6.86 (m ,9H , Ar-H) , 3.87 (s , 3H , CH₃O-), 3.84-2.74 (m , 12H , -CH₂-CH₂-); IR (KBr) l:3140,3113,2816,1678,1632,1585,1504,1415,9/33,771,740cm^-1; MS (70 eV) m/z: 364(M⁺), Anal. Calcd for C₂₂H₂₄N₂O₃: C 72.53, H 6.59,N 7.69; found C 72.28, H 6.48, N 7.74

3 RESULTS AND DISCUSSION           
The synthetic method of benzofuran and its derivatives have been reported^[1-4] . 5-Acetyl-2-carboxyl benzofuran (4) was prepared according to the literature reference. During the synthesis of 5-acetyl benzofuran (5), the temperature of the reaction should be controlled tightly to ensure completion of the reaction. At the last step, because it is three molecule reaction, the ratio of the reaction compounds influences the yield. Thus, the yield of the target compound is low.

REFERENCES
[1] Ausar M, Ebrik S, Alcoum A, Mouhoub R et al. J. Med. Chem., 1996, 31 (6): 449.
[2] Deshparde A R, Paradkar M V. Indian J. Chem., Sect. B. , 1992, 31B (8): 526.
[3] Debaert M, Berthelot P, Vaccher Clande. Eur. Pat. Appl. EP 463,969 (Cl. C07D307/81), 02 Jan 1992 FR Appl. 90/8, 093,27 Jun 1990; 32.
[4] Danzonne D, Gillardin J M, Lepage F. J. Med. Chem. 1995, 30 (1): 53-59.

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