Preparation method of vardenafil

Abstract

The invention discloses a preparation method of vardenafil. The preparation method is characterized by comprising the following process steps: (1), slowly adding chlorosulfonic acid in an organic solution at a temperature of -0.5-10 DEG C, after a reaction system is stabilized, adding SM1, after naturally raising the temperature to room temperature, continuously reacting for 3-12 hours, diluting a reaction solution with icy dichloromethane, slowly pouring in brine ice, separating an organic phase, and drying with anhydrous sodium sulfate; (2), slowly dropping N-ethylpiperazine in a product obtained in the step 1 at a temperature of -0.5-1.5 DEG C, naturally raising the temperature to room temperature, continuously reacting for 3-8 hours, after reaction is ended, processing a reaction solution to obtain a product, and re-crystallizing the product. The preparation method is simple in operation, high in product yield, low in cost and less in consumption of chlorosulfonic acid.

Description

technical field [0001] The invention relates to the field of synthesis of pharmaceutical compounds, in particular to a preparation method of vardenafil, a medicine for treating male erectile dysfunction. Background technique [0002] Vardenafil hydrochloride (Vardenafil hydrochloride), chemical name: 2-[2-ethoxy-5-(4-ethyl-piperazine-1-sulfonyl)-phenyl]-5-methyl-7- Propyl-3H-imidazol[5,1-f][1,2,4]terazin-4-one monohydrochloride, trade name Levitra, was successfully developed by Bayer, Germany, in August 2003 Approved by the US FDA for the treatment of male erectile dysfunction (ED). Its chemical structural formula is as follows: [0003] U.S. Patent US6777551B2 discloses a kind of preparation method of vardenafil hydrochloride, and its synthetic route is: [0004] This route involves 11 steps of reaction, the cycle is long, the comprehensive yield is low, and the production process requires high equipment: [0005] 1. In reaction step 1, since raw material 2 is too activ...

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Problems solved by technology

[0004]This route involves 11 steps of reaction, the cycle is long, the comprehensive yield is low, and the production process requires high equipment:

[0005] 1. In reaction step 1, since raw material 2 is too active, it is easily hydrolyzed in strong alkali sodium hydroxide solution, thereby reducing the yield of product 1;

[0006]2. In reaction step 5, the intermediate product is not only post-processed, but the two-step ring formation is completed by one-pot method, and the yield is low; in addition, in the process of the reaction A by-product produced in the process is not disposed of, and this by-product is colloidal, so it affects the state and purity of product 6, and affects the subsequent reactions;

[0007] 3. In reaction step 6, according to the method in the literature, the product is not easy to precipitate in the water phase, thereby reducing the yield of product 7

[0009] This process uses 2-(2-ethoxyphenyl)-5-methyl-7-propyl-3H-imidazo[5,1-f ][1,2,4]triazin-4-one is used as the starting material, which shortens the process steps, but the process route has the following disadvantages: 1) Using chlorosulfonic acid as the reactant and solvent requires high equipment requirements; 2) The reaction temperature is difficult to control; 3) The reaction time is long; 4) The amount of chlorosulfonic acid used is large, and a large amount of water is required to quench it during post-treatment, which will produce a large amount of waste acid and pollute the environment

Moreover, because the activity of intermediate 1 is too strong, more heat will be generated during the quenching process, which is prone to hydrolysis and reduces the yield of product 1; 5) It is not suitable for large-scale industrial production