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Method for preparing avanafil

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

Inactive Publication Date: 2013-08-28
江苏兰亭市政园林有限公司
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  • 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

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  • Method for preparing avanafil
  • Method for preparing avanafil
  • Method for preparing 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] Add N-(3-chloro-4-methoxybenzyl)cytosine (V) (2.56g, 10mmol), iodine (3.04g, 12mmol) and 50mL of 2.0M sodium hydroxide solution into a microwave reactor, 300W Microwave irradiated for 5 minutes, cooled to room temperature, and a white solid precipitated out. After filtering and drying, add 50 mL of ethylene glycol dimethyl ether to dissolve and transfer to a three-necked reaction flask. Add nickel acetate tetrahydrate (25 mg, 0.1 mmol), tris(2,4-di-tert-butyl)phenoxyphosphine (64 mg, 0.1 mmol), sodium methoxide (1.08 g, 20 mmol) and N-(2-methyl Pyrimidine) formamide (IV) (4.11 g, 30 mmol), under nitrogen protection, was added and the temperature was raised to 110° C., stirred for 10 hours, and the reaction was detected by TLC. The reaction solution was poured into 50 mL saturated ammonium chloride solution, and extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous magnesium sulfate, the solvent was recovered under reduced pre...

Embodiment 3

[0034]Under nitrogen protection, add 6-(3-chloro-4-methoxybenzylamino)-1,2-dihydropyrimidin-2-one-5-(N-2-pyrimidinylmethyl) into the three-necked flask Formamide (VI) (2.0 g, 5 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) (3.31 g, 7.5 mmol) and acetonitrile 25 mL. Under stirring, 1,8-diazabicyclo[5.4.0]-undec-7-ene (DBU) (1.15 g, 7.5 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 50 mL of ethyl acetate, and washed with 10 mL of 2M sodium hydroxide. The organic phase was separated, dried and concentrated under reduced pressure. The residue was dissolved in 50 mL of tetrahydrofuran, S-hydroxymethylpyrrolidine (II) (0.61 g, 6 mmol) and sodium hydride (0.16 g, 6 mmol) were added, the temperature was raised to 65°C, and the reaction was stirred for ...

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Abstract

The invention discloses a method for preparing avanafil (Avanafil, I). The method comprises the steps of taking cytosine as an initial material; and orderly carrying out replacement, halogen addition and condensation reaction on a side chain 3-chlorine-4-methoxy benzyl halide (III), N-(2-methylpyrimidine) formamide (IV) and S-hydroxymethyl pyrrolidine (II), so as to obtain a target product avanafil (I). The preparation method is available in material, concise in technology, economic and environment-friendly, and suitable for the demands of industrial amplification.

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

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Application Information

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IPC IPC(8): C07D403/14
Inventor 许学农
Owner 江苏兰亭市政园林有限公司
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