Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

Preparation method of Avanafil

A technology of avanafil and methoxybenzyl, which is applied in the field of preparation of avanafil, can solve problems such as difficult separation, difficulty in realizing industrialization, complex process, etc., and achieve the effect of simple process and favorable industrial production

Active Publication Date: 2013-08-21
迁安华韵知识产权服务中心
View PDF5 Cites 14 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] It can be seen from this that no matter whether methylmercapto-substituted pyrimidine or dichloropyrimidine is used as the starting material, the whole preparation process has defects such as difficult acquisition of raw materials, many synthesis steps, complicated process and difficult separation, especially in ultra-low temperature conditions and carbon dioxide carbonylation. High pressure conditions and anhydrous and oxygen-free conditions for multi-step metal reagent reactions make the entire synthetic route difficult to industrialize

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Preparation method of Avanafil
  • Preparation method of Avanafil
  • Preparation method of Avanafil

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Add cytosine (2.22g, 20mmol), triethylamine (2.0g, 20mmol), potassium iodide (0.2g, 1% eq) and 50mL of absolute ethanol into the three-neck flask, raise the temperature to 50-55°C, and stir until the system dissolves Uniform. 3-Chloro-4-methoxybenzyl bromide (III) (5.60 g, 24 mol) was slowly added dropwise into the reaction liquid. The temperature was raised to 80° C., and the reaction was continued for 3 hours, and the reaction was detected by TLC. Cool down to room temperature, and remove triethylamine hydrobromide by filtration. The filtrate was adjusted to pH 4-5 with hydrochloric acid. Ethanol was recovered under reduced pressure, and the residue was recrystallized from ethyl acetate to obtain 4.78 g of off-white solid N-(3-chloro-4-methoxybenzyl)cytosine (V), with a yield of 90.2%.

Embodiment 2

[0032] Under nitrogen protection, N-(3-chloro-4-methoxybenzyl)cytosine (V) (2.65g, 10mmol), benzotriazol-1-yloxytri(di Methylamino)phosphonium hexafluorophosphate (BOP) (6.63 g, 15 mmol) and acetonitrile 50 mL. Under stirring, 1,8-diazabicyclo[5.4.0]-undec-7-ene (DBU) (2.28 g, 15 mmol) was added dropwise, and the reaction was carried out at room temperature for 12 hours. The temperature was raised to 60° C., and the reaction was continued for 12 hours. The solvent was distilled off under reduced pressure, dissolved in 100 mL of ethyl acetate, and washed with 20 mL of 2M sodium hydroxide. The organic phase was separated, dried and concentrated under reduced pressure. The residue was dissolved in 100 mL of tetrahydrofuran, S-hydroxymethylpyrrolidine (II) (1.31 g, 13 mmol) and sodium hydride (0.32 g, 13 mmol) were added, the temperature was raised to 55°C, and the reaction was stirred for 5 hours, and the reaction was monitored by TLC. The reaction was quenched with saturated ...

Embodiment 3

[0034]Add 4-[(3-chloro-4-methoxybenzyl)amino]-2-[2-(hydroxymethyl)-1-pyrrolidinyl]pyrimidine (VI) (1.74 g, 5mmol), liquid bromine (0.94g, 6mmol) and 25mL of 2.0M sodium hydroxide solution, 200W microwave irradiation for 5 minutes, cooled to room temperature, a white solid precipitated. After filtering and drying, add 25 mL of ethylene glycol dimethyl ether to dissolve and transfer to a three-necked reaction flask. Add nickel acetate tetrahydrate (13 mg, 0.05 mmol), tris(2,4-di-tert-butyl)phenoxyphosphine (32 mg, 0.05 mmol), sodium methoxide (0.54 g, 10 mmol) and N-(2-methyl Pyrimidine) formamide (IV) (2.05 g, 15 mmol), under the protection of nitrogen, the temperature was raised to 120° C., the reaction was stirred for 10 hours, and the reaction was detected by TLC. The reaction solution was poured into 25 mL of saturated ammonium chloride solution, and extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous magnesium sulfate, the sol...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

Abstract

The invention discloses a preparation method of Avanafil (I). Cytosine is taken as a starting material, and substitution, condensation and halogenated addition reactions are sequentially carried out by virtue of 3-chloro-4-methoxybenzyl halogen (III), S-hydroxymethyl pyrrolidine (II) and N-(2-methyl pyrimidine) formamide (IV), thus the target product Avanafil (I) can be obtained. The preparation method has the advantages of available raw materials, simple process, economy and environmental protection and is applicable to the requirement of industrialized production.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis route design and preparation of raw materials and intermediates, and in particular relates to a preparation method of avanafil. Background technique [0002] Avanafil (Avanafil) is authorized by Mitsubishi Tanabe Pharmaceutical Co., Ltd. of Japan and developed by Vivus Pharmaceutical Company of the United States for the treatment of male erectile dysfunction. Avanafil is an oral, fast-acting, highly selective phosphodiesterase-5 (PDE-5) inhibitor, which can inhibit the metabolism of cyclic guanosine monophosphate in the body, thereby enhancing the relaxation of smooth muscle and reducing blood flow in the penis. Increased flow, which in turn aids in an erection. Avanafil was approved by the US FDA on April 27, 2012 to be marketed in the United States under the trade name of Stendra. [0003] Avanafil (Avanafil, I), the chemical name is (S)-4-[(3-chloro-4-methoxybenzyl)amino]-2-[2-(hydr...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/14
Inventor 许学农
Owner 迁安华韵知识产权服务中心
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Patsnap Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Patsnap Eureka Blog
Learn More
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic, Popular Technical Reports.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com