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Method for preparing avanafil

A technology of avanafil and methoxybenzylamino, which is applied in the field of compound preparation, can solve the problems of yield and manufacturing cost (high cost, difficult to guarantee product quality, difficult curing and purification, etc.), and achieve low cost and easy operation The effect of simplicity, ease of purification and detection

Inactive Publication Date: 2014-06-04
BEIJING AOHE DRUG RES INST +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0010] Two intermediates (4-(3-chloro-4-methoxybenzylamino)-5-ethoxycarbonyl-2 -Methylthiopyrimidine and (S)-4-(3-chloro-4-methoxybenzylamino)-5-ethoxycarbonyl-2-(2-hydroxymethyl-1-pyrrolidinyl)pyrimidine The melting points are 85-86°C and 88-90°C, respectively, and there are defects such as low melting point, difficulty in solidification and purification, and difficulty in product quality assurance; and alkaline hydrolysis after the introduction of chiral fragments in step 3), there is chirality Risk of central racemization, which in turn affects product purity, yield and manufacturing cost (high cost)

Method used

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Examples

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Embodiment 1

[0042] Example 1 Preparation of Avanafil

[0043] The preparation method of avanafil, comprises the steps:

[0044] 1) Preparation of Intermediate 1: Dissolve 4-(3-chloro-4-methoxybenzylamino)-5-ethoxycarbonyl-2-methylthiopyrimidine (5g) in ethanol (15ml), Add purified water (5ml) and sodium hydroxide (1.1g), reflux and stir for 1 hour; after TLC monitors that the raw materials disappear, concentrate the ethanol to dryness under reduced pressure, adjust the pH to 6-7 with concentrated hydrochloric acid, precipitate the solid, and collect the solid by suction filtration After drying, Intermediate 1 (4.2g) was obtained with a yield of 90%;

[0045] 2) Preparation of intermediate 2: at room temperature, 4-(3-chloro-4-methoxybenzylamino)-5-carboxy-2-methylthiopyrimidine (4.0g), 2-aminomethylpyrimidine (2.2g), EDCI (2.8g) and N-hydroxybenzotriazole (1.9g) were added to DMF (40 mL), stirred for 10 hours; after TLC detected that the reaction was complete, the reaction s...

Embodiment 2

[0049] Example 2 Preparation of Avanafil

[0050] The preparation method of avanafil, comprises the steps:

[0051] 1) Preparation of Intermediate 1: Dissolve 4-(3-chloro-4-methoxybenzylamino)-5-ethoxycarbonyl-2-methylthiopyrimidine (4g) in ethanol (12ml), Purified water (4 ml) and potassium hydroxide (1.2 g) were added thereto, followed by stirring at 40°C for 10 hours. After the disappearance of the raw material was monitored by TLC, the ethanol was concentrated under reduced pressure to dryness, and the pH was adjusted to 6-7 with concentrated hydrochloric acid. After the solid was precipitated, it was filtered with suction, and the solid was collected and dried to obtain Intermediate 1 (3.4 g), with a yield of 92%;

[0052] 2) Preparation of Intermediate 2: Add 4-(3-chloro-4-methoxybenzylamino)-5-carboxy-2-methylthiopyrimidine (4.0 g) to thionyl chloride ( 30mL), reflux for 2 hours, concentrate to dryness under reduced pressure, add dichloromethane to the resi...

Embodiment 3

[0055] Example 3 Preparation of Avanafil

[0056] The preparation method of avanafil, comprises the steps:

[0057] 1) Preparation of Intermediate 1: Dissolve 4-(3-chloro-4-methoxybenzylamino)-5-ethoxycarbonyl-2-methylthiopyrimidine (5g) in ethanol (15ml), Purified water (5 ml) and lithium hydroxide (0.6 g) were added, and the mixture was stirred under reflux for 4 hours. After the disappearance of the raw material was monitored by TLC, the ethanol was concentrated under reduced pressure to dryness, and the pH was adjusted to 6-7 with concentrated hydrochloric acid. After the solid was precipitated, it was filtered with suction, and the solid was collected and dried to obtain Intermediate 1 (4.3 g), with a yield of 92%;

[0058] 2) Preparation of intermediate 2: 4-(3-chloro-4-methoxybenzylamino)-5-carboxy-2-methylthiopyrimidine (2.0 g) in dichloromethane (20 mL) at 0 °C ) solution was added triethylamine (0.9g) and ethyl chloroformate (0.96g), stirred at room tem...

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Abstract

The invention relates to a method for preparing avanafil. The method is characterized by comprising the step of enabling 4-(3-chloro-4-methoxybenzylamino)-5-ethoxycarbonyl-2-methylthiopyrimidine to be subjected to hydrolysis, condensation, oxidation and substitution reaction sequentially, thereby preparing avanafil. The method has the advantages of being simple and convenient in operation, easy in product quality control, high in reaction yield, high in product purity, low in cost and applicable to industrial production and the like.

Description

technical field [0001] The invention relates to the technical field of compound preparation, in particular to a preparation method of avanafil. Background technique [0002] Avanafil (Avanafil, the structure is shown in formula I), namely (S)-4-(3-chloro-4-methoxybenzylamino)-2-(2-hydroxymethyl-1-pyrrolidinyl )-N-(2-pyrimidinemethyl)-5-pyrimidinecarboxamide), is an oral, fast-acting and highly selective phosphodiesterase-5 (PDEV) inhibitor, which can inhibit the in vivo metabolism of cyclic guanosine monophosphate, Strengthen the relaxation of smooth muscle, increase the blood flow of the penis, and help erection. It is used to prevent or treat erectile dysfunction (ED), and it is the fastest-acting drug with the least side effects among similar drugs. Avanafil was approved by the US FDA in 2012 under the trade name Stendra. [0003] [0004] and WO0119802A disclose the preparation method of avanafil and its analogues, comprising the following steps: [0005] 1) Ethyl ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/14C07D239/47
CPCC07D239/47C07D403/14
Inventor 程晓峰马良张威王龙霍彩霞黄晓霞张洋
Owner BEIJING AOHE DRUG RES INST
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