Study On The Synthetic Route Of Propiverine Hydrochloride

Propiverine hydrochloride belongs to anti-cholinergic drugs, which has a good treatment of urinary frequency, pollakiuria and urinary incontinence. It has significant therapeutic effect, less adverse effect than other kinds of drugs. Nowadays, the number of patients of urinary incontinence in our country has increased gradually, however,there are many problems such as defective process, smaller product scale, lower yield of product, and a relatively higher production costs. So it has been unable to meet the clinical needs. Therefore, a suitable synthesis route of propiverine hydrochloride to be explored and optimized has been of great significance.Based on the reported literature, the synthetic route of this article was established. Propiverine hydrochloride was synthesized from 2,2-diphenyl-2-hydroxyacetic acid-1-methyl-4-piperidinyl ester, which was prepared from 2,2-diphenyl-2-hydroxy-acetate. Raw material of 2,2-diphenyl-2-hydroxyacetate through the reaction of esterification and transesterification to preparation the intermediate 2,2-diphenyl-2-hydr-oxyacetic acid-l-methyl-4-piperidinyl ester, and then by chlorination and etherification reaction to get the target product of propiverine hydrochloride.The synthetic process of intermediate 2,2-diphenyl-2-hydroxyacetic acid-]-methyl-4-piperidinyl ester was first investigated in this paper. In this process, the react-ion mass ratio and reaction time which affected product yield were studied to find the best reaction conditions. When the radio of sodium,2,2-diphenyl-2-hydroxy-acetate and 1-methyl-4-piperidineol was 1:4:4.8, under the conditions of temperature from 60℃to 65℃and the reaction time was 5h, and then under reduced pressure concentrated 3h. concentrated to near dry residue by adding appropriate amount of toluene and water and cooling the mixture, the compound of 2,2-diphenyl-2-hydr-oxyacetic acid-1-methyl-4-piperidinyl ester could be directly precipitated and the product obtained from this process had a higher yielded and purity.In the process of the preparation of 2,2-diphenyl-2-chlorideactic acid-1-methyl-4 piperidinyl ester, when the molar ratio of 2,2-diphenyl-2-hydroxyacetic acid-1-methyl-4-piperidinyl ester and SOCl2 was 1:3.5, the reaction time was 5h at reflux temperature, the product yield had a relatively higher yield.In the process of the preparation of propiverine hydrochloride, when the reaction time of 2,2-diphenyl-2-chlorideactic-l-methyl-4-piperidinyl ester and propanol increased to 7h and the crude product used alcohol recrystallization, the product yield improved and the purity reached the pharmacopoeia standard. In this article,2,2-diphenyl-2-hydroxyacetate, the raw material, through four-step chemical reaction, had been transformed into the target product of propiverine hydrochloride. The overall yield of product was up to 75% and the purity (HPLC) of the sample was higher than 99.0%. The synthetic route was optimized, the consumption of raw material was reduced and the yield was increased, which marked this synthetic route for industrial production has a certain leading significance.