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Synthetic method of 4-(2-aminoethyl) tetrahydropyrane

A tetrahydropyran and synthesis method technology, applied in the field of synthesis of chemical drug intermediates, can solve the problems of unsuitability for industrial production, instability of sodium azide, and easy explosion, and achieve low price, simple post-treatment, and reaction The effect of short steps

Active Publication Date: 2016-11-09
济南川成医药科技开发有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] Method 2.Justus Liebigs Annalen der Chemie, 1938, vol.535, p.37, 45, reported a method for synthesizing 4-(2-aminoethyl)tetrahydropyran, using tetrahydro-2H-pyran -4-propionic acid reacts with sodium azide to generate 4-(2-aminoethyl)tetrahydropyran, in which sodium azide is a highly toxic controlled chemical, which is not easy to purchase, and sodium azide is unstable and cannot be encountered Acid, need to avoid light, low temperature, no impact, easy to explode, not suitable for industrial production

Method used

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Embodiment 1

[0031] Example 1 Synthesis of 4-(2-aminoethyl)tetrahydropyran

[0032] The molar ratio of 4-chlorotetrahydropyran to methyl cyanoacetate is 0.9:1; the hydrogen pressure is 1MPa

[0033] (1) 80.4g (0.67mol) of 4-chlorotetrahydropyran A, 73g (0.74mol) of methyl cyanoacetate, 75g (0.67mol) of potassium tert-butoxide were dissolved in 100ml of toluene, stirred and reacted at 50°C for 12h Afterwards, the temperature was raised to 110°C for 12 hours. After the reaction was completed, the reaction solution was washed 3 times with 300ml of water, and the organic phase was concentrated under reduced pressure to obtain the oily product 2-cyano-2-(tetrahydro-4-pyranyl)acetic acid methyl ester 113.6g (0.62mol);

[0034] (2) Synthesis of (tetrahydro-4-pyranyl)-acetonitrile

[0035] Add 113.6g (0.62mol) of methyl 2-cyano-2-(tetrahydro-4-pyranyl)acetate, 10.8ml of water, 10.8g of sodium chloride, and 540ml of dimethyl sulfoxide into the flask, at 150°C Stir and react for 8 hours, distill,...

Embodiment 2

[0040] Synthesis of 4-(2-Aminoethyl)tetrahydropyran

[0041] The molar ratio of 4-chlorotetrahydropyran and methyl cyanoacetate is 1:1; the hydrogen pressure is 1MPa

[0042](1) 80.4g (0.67mol) of 4-chlorotetrahydropyran A, 66.3g (0.67mol) of methyl cyanoacetate, 75g (0.67mol) of potassium tert-butoxide were dissolved in 100ml of toluene, and the reaction was stirred at 50°C After 12 hours, the temperature was raised to 110°C and reacted for 12 hours. After the reaction was completed, the reaction solution was washed with 300ml water for 3 times, and the organic phase was concentrated under reduced pressure to obtain oily 2-cyano-2-(tetrahydro-4-pyranyl)methyl acetate Esters 110.6g (0.60mol);

[0043] (2) Synthesis of (tetrahydro-4-pyranyl)-acetonitrile

[0044] Add 110.6g (0.60mol) of methyl 2-cyano-2-(tetrahydro-4-pyranyl)acetate, 10.8ml of water, 10.8g of sodium chloride, and 540ml of dimethyl sulfoxide into the flask, at 150°C Stir and react for 8 hours, distill, add 10...

Embodiment 3

[0049] Synthesis of 4-(2-Aminoethyl)tetrahydropyran

[0050] The molar ratio of 4-chlorotetrahydropyran to methyl cyanoacetate is 0.9:1; the hydrogen pressure is 2MPa

[0051] (1) 80.4g (0.67mol) of 4-chlorotetrahydropyran A, 73g (0.74mol) of methyl cyanoacetate, 75g (0.67mol) of potassium tert-butoxide were dissolved in 100ml of toluene, stirred and reacted at 50°C for 12h Afterwards, the temperature was raised to 110°C for 12 hours. After the reaction was completed, the reaction solution was washed 3 times with 300ml of water, and the organic phase was concentrated under reduced pressure to obtain the oily product 2-cyano-2-(tetrahydro-4-pyranyl)acetic acid methyl ester 112.4g (0.61mol);

[0052] (2) Synthesis of (tetrahydro-4-pyranyl)-acetonitrile

[0053] Add 112.4g (0.61mol) of methyl 2-cyano-2-(tetrahydro-4-pyranyl)acetate, 10.8ml of water, 10.8g of sodium chloride, and 540ml of dimethyl sulfoxide into the flask, at 150°C Stir and react for 8 hours, distill, add 1000m...

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Abstract

The invention belongs to the technical field of chemical medicine intermediate synthesis, and particularly relates to a synthetic method of medicine Bevenopran intermediate 4-(2-aminoethyl) tetrahydropyrane. The method comprises the following steps that (1) 4-chloro amylene oxide and methyl cyanoacetate take a reaction to obtain 2-cyano-2-(tetralin-4-pyranyl) methyl acetate; (2) the 2-cyano-2-(tetralin-4-pyranyl) methyl acetate is degreased to obtain (tetralin-4-pyranyl)-acetonitrile; (3) the (tetralin-4-pyranyl)-acetonitrile C takes a hydrogenation reaction to obtain 4-(2- aminoethyl) tetrahydropyrane. The method has the advantages that the 4-chloro amylene oxide and the methyl cyanoacetate are used as raw materials; the reaction time of the method is short; the cost is low; the raw materials are easy to obtain; no rank poison control or unstable chemical raw materials exist; safety and effectiveness are realized; the yield is high; the impurities are few.

Description

technical field [0001] The invention belongs to the technical field of synthesis of chemical drug intermediates, and in particular relates to a synthesis method of 4-(2-aminoethyl)tetrahydropyran, an intermediate of drug bevopram. Background technique [0002] The CAS number of Bevenopran is 676500-67-7, and the molecular formula is C 2 0H 26 N 4 o 4 , with a molecular weight of 386.44 and a chemical name of [2-methoxy-4-[[2-(oxan-4-yl)ethylamino]methyl]phenoxy]pyrazine-2-carboxamide, a drug developed by Cubist Pharmaceuticals for the treatment of chronic Opioid-induced constipation in patients with noncancer pain. The structural formula of Beckhoff Pulan is as follows: [0003] . [0004] Opioids are currently the most important drugs for the treatment of moderate to severe pain, but these drugs can cause many adverse reactions such as nausea, vomiting, and drowsiness. However, the above adverse reactions can usually be tolerated by most patients within one week; e...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D309/04
CPCC07D309/04
Inventor 刘怀振韩立霞白天凯郭明马居良
Owner 济南川成医药科技开发有限公司
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