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A kind of preparation method of avanafil intermediate

A technology for avanafil and intermediates, which is applied in the field of preparation of pharmaceutical intermediates, can solve the problems of low yield and large pollution, and achieves the effects of high yield, lower production cost and lower pollution degree.

Inactive Publication Date: 2019-02-15
HEBEI UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The purpose of the present invention is to provide a preparation method of avanafil intermediate, to solve the problems of large pollution and low yield in the existing preparation method

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0018] Weigh 2g of ethyl 4-hydroxy-2-methylthio-5-pyrimidinecarboxylate and add it to the reaction flask, add 10mL of DMF, place the reaction flask in a low-temperature bath at -10°C, weigh 0.94g of potassium carbonate and add it to the reaction flask bottle; weigh 1.18g of methanesulfonyl chloride, dissolve it in DMF, and slowly add the solution dropwise to the reaction flask under stirring. hours, the reaction is complete, slowly add water to the reaction solution, add ethyl acetate, extract and separate the liquid, add anhydrous sodium sulfate to the organic phase, dry, and concentrate under reduced pressure to obtain 4-methylsulfonate-2-methylthio - 2.05 g of ethyl 5-pyrimidinecarboxylate, yield: 75%, purity: 99% (HPLC, area normalized). 1 H NMR (d 6 -DMSO): δ 1.41 (t, J = 6.0 Hz, 3H), 2.62 (s, 3H), 3.54 (s, 3H), 4.41 (q, J = 6.0 Hz, 2H), 9.06 (s, 1H).

[0019] Weigh 1.90g of ethyl 4-methylsulfonate-2-methylthio-5-pyrimidinecarboxylate and add it to the reaction flask, a...

Embodiment 2

[0021] Weigh 2g of ethyl 4-hydroxy-2-methylthio-5-pyrimidinecarboxylate and add it to the reaction flask, add 10mL of DMF, place the reaction flask in a low-temperature bath at -10°C, weigh 0.94g of potassium carbonate and add it to the reaction flask bottle; weigh 1.60g of methanesulfonyl chloride, dissolve it in DMF, slowly add the solution dropwise to the reaction bottle under stirring, after the dropwise addition, raise the reaction temperature to 0°C, and stir at 0°C for 4 hours, the reaction is complete, slowly add water to the reaction solution, add ethyl acetate, extract and separate the liquid, add anhydrous sodium sulfate to the organic phase, dry, and concentrate under reduced pressure to obtain 4-methylsulfonate-2-methylthio - 2.05 g of ethyl 5-pyrimidinecarboxylate, yield: 75%, purity: 99% (HPLC, area normalization).

[0022] Weigh 1.90g of ethyl 4-methylsulfonate-2-methylthio-5-pyrimidinecarboxylate into the reaction flask, add 10mL of DMF, weigh 1.33g of (3-chlo...

Embodiment 3

[0024] Weigh 2g of ethyl 4-hydroxy-2-methylthio-5-pyrimidinecarboxylate and add it to the reaction flask, add 10mL of DMF, place the reaction flask in a low-temperature bath at -10°C, weigh 0.94g of potassium carbonate and add it to the reaction flask bottle; weigh 3.21g of methanesulfonyl chloride, dissolve it in DMF, slowly add the solution dropwise to the reaction bottle under stirring, after the dropwise addition, raise the reaction temperature to 0°C, and stir at 0°C for 4 hours, the reaction is complete, slowly add water to the reaction solution, add ethyl acetate, extract and separate the liquid, add anhydrous sodium sulfate to the organic phase, dry, and concentrate under reduced pressure to obtain 4-methylsulfonate-2-methylthio - 2.05 g of ethyl 5-pyrimidinecarboxylate, yield: 75%, purity: 99% (HPLC, area normalization).

[0025] Weigh 1.90g of ethyl 4-methylsulfonate-2-methylthio-5-pyrimidinecarboxylate into the reaction flask, add 10mL of DMF, weigh 2.65g of (3-chlo...

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PUM

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Abstract

The invention provides a preparation method of an Avanafil intermediate. The preparation method comprises the following steps: dissolving 4-hydroxy-2-methylthio-ethyl 5-pyrimidinecarboxylate and potassium carbonate in DMF to obtain a mixed solution, adding methanesulfonyl chloride into the mixed solution under the stirring condition, continuously stirring after addition until a reaction is ended, adding water and ethyl acetate into a reaction solution, carrying out extraction and liquid separation, carrying out vacuum concentration on an organic phase to prepare 4-methanesulfonic sulfonic ester-2-methylthio-ethyl 5-pyrimidinecarboxylate; dissolving the obtained 4-methanesulfonic sulfonic ester-2-methylthio-ethyl 5-pyrimidinecarboxylate into DMF, adding a (3-chloro-4-methoxy)Benzylamine hydrochloride to obtain mixed liquor, adding triethylamine into the mixed liquor under the stirring condition, continuously stirring after addition until a reaction is ended, adding water and ethyl acetate, carrying out extraction and liquid separation, carrying out vacuum concentration on an organic phase, and recrystallizing to prepare 4-(3-chloro-4-methoxybenzylamino)-5- ethyloxycarbonyl-2-methylthiopyrimidine. The invention has advantages of less environmental pollution, high product yield, safe post-processing and simple operation.

Description

technical field [0001] The invention relates to a preparation method of a pharmaceutical intermediate, in particular to a preparation method of an avanafil intermediate. Background technique [0002] 4-(3-chloro-4-methoxybenzylamino)-5-ethoxycarbonyl-2-methylthiopyrimidine is the key intermediate for the preparation of avanafil, and its traditional preparation method is: with 4- Hydroxy-2-methylthio-5-pyrimidinecarboxylic acid ethyl ester is raw material, first generates 4-chloro-2-methylthio-5-pyrimidinecarboxylic acid ethyl ester through chlorination reaction, and then with (3-chloro-4-methyl Oxygen) benzylamine takes place amino substitution reaction, obtains product 4-(3-chloro-4-methoxybenzylamino)-5-ethoxycarbonyl-2-methylthiopyrimidine, and the reaction formula is: [0003] . [0004] The chlorination reaction in this method is the key link of the whole preparation process, and it uses highly corrosive phosphorus oxychloride as the chlorination reagent, in order t...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D239/47
CPCC07D239/47
Inventor 李玮胥稳智徐志栋杨瑜涛
Owner HEBEI UNIVERSITY
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