Study On Synthesis Of Entacapone And Determination Of Related Solubility

At present time, there are many people disturbed by the Parkinson disease(PD). This paper designed a synthetic route of entacapone on the base of many references, which was used to treat PD. The technology of this route was easy to operate and the raw material was cheap and easy to obtain, with high yield.This essay synthesized 5-nitrovanillin through nitration with vanillin as raw material, then 3,4-Dihydroxy-5-nitrobenzaldehyde was obtained by demethylation from 5-nitrovanillin. The final compound E-entacapone was obtained by Knoevengel condensation reaction of 3,4-Dihydroxy-5-nitrobenzaldehyde and N,N-diethyl cyanoacetamide . The optimal condition was determined for each condition as fallows. Nitration: the mole ratio of nitric acid whose mass fraction was 65% and vanillin is 1.2: 1; the addition velocity of the nitic acid was 20 mL/h; the reaction was carried at 25℃. The yield of this step is 90.00%. Demethylation: Dichloromethane as the solvent, the condition was moderate, and its mole ratio: 5-nitrovanillin was 31:1; Aluminium Chloride: 5-nitrovanillin was 1.25:1; Pyridine : 5-nitrovanillin was 4:1; the phase transfer catalytist TEBA with which the reaction time was reduced to only 16 h is 0.12 times of 5-nitrovanillin. The yield of this step was 85.00%. Knoevengel condensation: In isopropanol, piperidine acetic acid salt or Hexamethylenetetramine used as catalyst, 3,4-Dihydroxy-5-nitrobenzaldehyde was reacted with N,N-diethyl cyanoacetamide and the (E)-entacapone was obtained. In this step, the ratio between piperdine acetic acid salt and 3,4-Dihydroxy-5-nitrobenzaldehyde was 0.45:1, The concentrated hydrochloric acid was 19 times of raw material . And the yield is 75.60%. It was found that Hexamethylenetetramine(HMTA) as the catalyst was less better than the piperdine acetic acid salt. The overall yield of the entacapone synthesized in this paper is 57.83%. The structures of the compounds were characterized by melt points, HLPC, ¹H NMR and ESI-MS.As the base data of industry process, solubility is very important in the purity and recrystallization of the products. The main methods to determine solubility are static and synthetic method. This paper set up a laser monitor system which was studied actively, and improved the system compared to the references with burette instead of syringe. HMTA as the catalyst of the entacapone synthesis is widely used in chemical engineering, medicine indurstry,whose solubility were reported rarely. So this paper determined the solubility of HMTA in some solvents.The solubility of HMTA in water determined in this paper was close to the references. This indicated that the system and process of this paper was right and feasible. Then the solubility of HMTA in methanol, acetic acid, the mixture of water and ethanol with the weight fraction of ethanol from w₁=0.20174 to w₁=0.79070 were determined with temperature ranging from (299.38 to 340.35) K at atmospheric pressure. The results were correlated by a semiempirical Apelblat equation. The ADD was in 2% and the rmsd in 0.1%, which indicated that Apelblat equation is appropriate to describe the temperature dependence of the solubility of HMTA.