3-oxetanone synthesis method

A technology for oxetanone and a synthesis method, which is applied in the production of bulk chemicals, organic chemistry, etc., can solve problems such as unstable yield, achieve the effects of being environmentally friendly, saving purification steps, and avoiding the use of dangerous chemicals

Pending Publication Date: 2019-04-16
柳州丰康泰科技有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] Method 1 uses 1,3-dichloroacetone as a starting material. Although its total yield reaches 50%, 1,3-dichloroacetone is a highly toxic drug, and there are great risks in purchasing and using it; and in the When deprotecting with HCl in the second step, the yield is unstable because 3-oxetanone is unstable under acidic conditions

Method used

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  • 3-oxetanone synthesis method

Examples

Experimental program
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Effect test

Embodiment 1

[0035](1) Add 140g of intermediate (purity 95%) and 280mL of methanol into a 500mL reaction flask, and slowly add the methanol solution of p-toluenesulfonic acid dropwise at 0°C (the methanol solution of p-toluenesulfonic acid is 0.46 g p-toluenesulfonic acid was dissolved in 5mL methanol), heated to 20°C, stirred for 1 hour, added sodium bicarbonate to neutralize to a pH value of 7.0-8.0, continued to stir for 1 hour, and then distilled off the solvent methanol to obtain The crude product of 3-oxetanol was 75.3g; the mass content of organic solvent I methanol in the crude product of 3-oxetanol was less than 1%; the mass content of 3-oxetanol was 81.5%.

[0036] (2) Add 425g of dichloromethane, 140g of NCS, 101g of sodium bicarbonate, 14g of tetrabutylammonium bromide and 7g of TEMPO into a 1L dry three-necked flask, and then add 75.3g of crude 3-oxetanol dropwise. After the dropwise addition was completed, stirring was continued at 30-40° C. for 2 hours. After the reaction m...

Embodiment 2

[0038] (1) Add 140g of the intermediate (purity 95%) and 280mL of ether into a 500mL reaction flask, and slowly add the ether solution of p-toluenesulfonic acid dropwise at 0°C (the ether solution of p-toluenesulfonic acid is 0.46 g p-toluenesulfonic acid was dissolved in 5mL ether), heated to 20°C, stirred and reacted for 1 hour, added potassium bicarbonate to neutralize to pH 7.0-8.0, continued to stir for 1 hour, and then distilled off the solvent ether to obtain 78.5 g of crude 3-oxetanol. The mass content of the organic solvent I methanol in the crude product of 3-oxetanol was less than 1%; the mass content of 3-oxetanol was 77.3%.

[0039] (2) Add 430g of dichloromethane, 350g of NBS, 121g of potassium bicarbonate, 7g of sodium bromide and 7g of TEMPO into a 1L dry three-necked flask, and then add 78.5g of crude 3-oxetanol dropwise. After the dropwise addition was completed, stirring was continued at 30-40° C. for 2 hours. After filtering the reaction mixture, it was d...

preparation example 1

[0045] (1) Add 139g of epichlorohydrin and 90g of glacial acetic acid into a 500mL reaction bottle, then add 0.6g of ferric chloride, raise the temperature to 70°C, and stir for 7 hours.

[0046] (2) Add 1.0g of p-toluenesulfonic acid to the reaction solution, slowly add 80g of vinyl ethyl ether dropwise, and control the dropping temperature at 40°C. After the dropwise addition, continue to stir and react at 40°C for 2 hours, then cool down to 0 0.9 g of p-toluenesulfonic acid was added, and the reaction was stirred at 40° C. for 4 hours to obtain a reaction solution.

[0047] (3) Add 345g of 50% NaOH solution into another 1000mL reaction bottle, raise the temperature to 110°C, slowly add the reaction liquid obtained in step (2) dropwise, and control the temperature during the dropping process at 110°C. Stir the reaction at 110°C for 7 hours, lower the temperature to 20°C, add 145g of water, 383g of dichloromethane, and 190g of saturated saline into the reaction bottle, stir a...

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Abstract

The invention provides a 3-oxetanone synthesis method, which comprises: removing the protection group from an intermediate in an organic solvent I by using an organic strong acid, neutralizing with aweak alkali to achieve an alkaline pH value, carrying out concentration distillation on the solvent to obtain a oxetan-3-ol crude product, oxidizing the oxetan-3-ol with an oxidizing agent in the presence of a catalyst I, a halide and an alkali, and carrying out separating purification to obtain the 3-oxetanone product, wherein the intermediate preparation method comprises: carrying out a ring opening reaction by using epichlorohydrin and glacial acetic acid as raw materials under the catalysis of a catalyst II, adding ethyl vinyl ether under an organic strong acid condition, carrying out a protection group forming reaction, and carrying out a ring formation reaction under a strong alkali condition so as to obtain the key intermediate solution. According to the present invention, the oxetan-3-ol preparation process is combined without the purifying of oxetan-3-ol so as to eliminate the oxetan-3-ol purifying step; and the method has characteristics of inexpensive raw materials, short route, no use of dangerous reagents and the like.

Description

technical field [0001] The present invention relates to a kind of synthetic method of 3-oxetanone. Background technique [0002] In the research and development of small drug molecules, because certain positions of small drug molecules are easily biodegraded and lead to loss of activity, a disubstituted methyl group is usually introduced at these positions to avoid biodegradation of active small drug molecules. However, the introduction of a disubstituted methyl group will greatly increase the lipophilicity of the active drug molecule, which may make the small drug molecule more easily metabolized. Therefore, finding a more stable small group that does not change its lipophilicity to replace the disubstituted methyl group has become a very important and urgent goal in the development of small drug molecules. Eric Carreira et al found that the introduction of 3-oxetane on the small drug molecule can reduce its lipophilicity, increase its solubility, prevent the molecule from...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D305/10
CPCC07D305/10Y02P20/55
Inventor 杨琛陆承棣蒋薇薇欧韦福欧阳葭
Owner 柳州丰康泰科技有限公司
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