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One-pot method for preparing crucial intermediate in oseltamivirphosphate synthesizing reaction

A technology for synthesis reaction and intermediate, which is applied in the field of obtaining key intermediates of Tamiflu synthesis reaction by "one-pot method", can solve the problems of low final yield, long synthesis route, difficult purification, etc., and achieves simple separation and purification and synthesis. The effect of shortened cycle and short reaction route

Inactive Publication Date: 2012-05-23
NANKAI UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These routes all start synthetic reactions from ready-made quinic acid or shikimic acid, which has caused some defects of themselves: 1, insufficient quantity of quinic acid and shikimic acid; 2, long synthetic route; 3, relative final yield lower
However, its four-step synthetic route is still relatively tedious, and the yield of the final product is insufficient, and the purification is difficult, which cannot meet the large-scale and efficient production

Method used

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  • One-pot method for preparing crucial intermediate in oseltamivirphosphate synthesizing reaction
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  • One-pot method for preparing crucial intermediate in oseltamivirphosphate synthesizing reaction

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0006] Example 1: "One-pot method" to obtain the key intermediate of Tamiflu synthesis reaction

[0007] Step 1: Synthesis of ethyl 1-formate-1,4-diene cyclohexane, the chemical formula is as follows

[0008]

[0009] Seal the 1,3-butadiene in the bottle and cool it to -78°C, then directly pour it into a 40ml high-pressure glass flask pre-cooled at -78°C, add 20g of ethyl ethyl propiolate, 2g of hydroquinone and a Magnetic stir bar. The reaction flask was sealed and stirred at 110° C. for 3 days (note: a protective pad should be used when sealing, which is convenient for monitoring the reaction). The reaction mixture should be cooled to -78°C before opening and sealing, and the contents of the bottle are distilled under reduced pressure (benzyl alcohol 90-92°C / 8mm) to obtain clean oily ethyl 1-formate-1,4-dienecyclohexyl The alkane product (26.4 g, 85% yield). 1 H NMR (500MHz, CDCl 3 )δ6.97(m, 1H), 5.78(m, 1H), 5.67(m, 1H), 4.22(q, J=7.0, 2H), 2.90(m, 1H), 1.31(t, J=7.0...

Embodiment 2

[0018] Example 2: "One pot method" to obtain the key intermediate of Tamiflu synthesis reaction

[0019] Step 1: Synthesis of ethyl 1-formate-1,4-diene cyclohexane, the chemical formula is as follows

[0020]

[0021] Seal the 1,3-butadiene in the bottle and cool it to -78°C, then directly pour it into a 40ml high-pressure glass flask pre-cooled at -78°C, add 20g of ethyl ethyl propiolate, 2g of hydroquinone and a Magnetic stir bar. The reaction flask was sealed and stirred at 110° C. for 3 days (note: a protective pad should be used when sealing, which is convenient for monitoring the reaction). The reaction mixture should be cooled to -78°C before opening and sealing, and the contents of the bottle are distilled under reduced pressure (benzyl alcohol 90-92°C / 8mm) to obtain clean oily ethyl 1-formate-1,4-dienecyclohexyl The alkane product (26.4 g, 85% yield). 1 H NMR (500MHz, CDCl 3)δ6.97(m, 1H), 5.78(m, 1H), 5.67(m, 1H), 4.22(q, J=7.0, 2H), 2.90(m, 1H), 1.31(t, J=7.0,...

Embodiment 3

[0030] Example 3: "One pot method" to obtain the key intermediate of Tamiflu synthesis reaction

[0031] Step 1: Synthesis of ethyl 1-formate-1,4-diene cyclohexane, the chemical formula is as follows

[0032]

[0033] Seal the 1,3-butadiene in the bottle and cool it to -78°C, then directly pour it into a 40ml high-pressure glass flask pre-cooled at -78°C, add 20g of ethyl ethyl propiolate, 2g of hydroquinone and a Magnetic stir bar. The reaction flask was sealed and stirred at 110° C. for 3 days (note: a protective pad should be used when sealing, which is convenient for monitoring the reaction). The reaction mixture should be cooled to -78°C before opening and sealing, and the contents of the bottle are distilled under reduced pressure (benzyl alcohol 90-92°C / 8mm) to obtain clean oily ethyl 1-formate-1,4-dienecyclohexyl The alkane product (26.4 g, 85% yield). 1 H NMR (500MHz, CDCl 3 )δ6.97(m, 1H), 5.78(m, 1H), 5.67(m, 1H), 4.22(q, J=7.0, 2H), 2.90(m, 1H), 1.31(t, J=7.0...

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Abstract

The invention discloses a one-pot method for preparing a crucial intermediate in oseltamivirphosphate synthesizing reaction. The method is characterized in that: 1,3-butadiene and ethyl propiolic acid ethyl ester are adopted as raw materials, alcohol and isocyanate / salt are adopted as main reactants, DBU is adopted as a catalyst, and no separation process is required before a finished product is obtained, such that the one-pot method is realized. The method mainly comprises steps that: 1, 1,3-butadiene is cooled to a temperature of -78 DEG C; ethyl propiolic acid ethyl ester and hydroquinone are added to 1,3-butadiene, and the mixture is stirred for 3 days under a temperature of 110 DEG C; the mixture is subject to vacuum distillation, such that 1-ethyl formate-1,4-diene cyclohexane is obtained; 2, I2 is added to a solution of 1-ethyl formate-1,4-diene cyclohexane and AgOCN; the mixture is heated to a temperature of 35-40 DEG C within 4 hours, such that a mixture A is obtained; alcohol and waterless HCl are added to the mixture A, and the mixture is stirred for 6-8 hours under a temperature of 35-40 DEG C, such that a mixture B is obtained; DBU is added to the mixture B, and the mixture is subject to a reaction over night under a temperature of 35-40 DEG C; the mixture is purified, such that the finished product is obtained; or DBU is added to the mixture A, the mixture is subject to a reaction over night under a temperature of 35-40 DEG C, and the mixture is purified, such that the finished product is obtained. Compared to existing technologies, the method is substantially advantaged in that: initial raw materials are cheap and easy to obtain, the reaction route is short, the synthesis period is shortened, the reaction method is improved into a one-pot method, the separation and purification processes are simple, the yield is high, the reaction efficiency is high, and the method has certain potential to be used in large-scaled productions.

Description

Technical field: [0001] The invention relates to a key intermediate in the synthesis reaction of Tamiflu The preparation method is specifically a "one-pot method" in which 1,8-diazacyclo[5,4,0]undecene-7, namely DBU, is used as a multifunctional catalyst. Background technique: [0002] Bird flu may break out on a large scale at any time, which is a problem that the whole world is paying attention to. Historical records show that outbreaks of human and avian influenza have caused widespread death in many countries. Oseltamivir phosphate (ie "Tamiflu") is currently the only drug that can be taken orally effectively for the treatment and prevention of bird flu. According to the World Health Organization, stockpiling Tamiflu is currently the only way to prevent a large outbreak of bird flu. In addition, since some avian influenza virus strains with reduced susceptibility to neuraminidase inhibitors have been found, it is very meaningful to study the synthesis of Tamiflu deri...

Claims

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Application Information

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IPC IPC(8): C07C271/24C07C269/00
Inventor 洪章勇崔琪彭建南胡欢陈泽铭
Owner NANKAI UNIV
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