CN114163403A

CN114163403A - Novel method for efficiently preparing 3-oxetane

Info

Publication number: CN114163403A
Application number: CN202111147728.3A
Authority: CN
Inventors: 赵文武; 孟纪文; 王可为; 韩建国
Original assignee: China Haohua Dalian Research and Design Institute of Chemical Industry Coltd
Current assignee: China Haohua Dalian Research and Design Institute of Chemical Industry Coltd
Priority date: 2021-09-29
Filing date: 2021-09-29
Publication date: 2022-03-11

Abstract

The invention provides a novel method for efficiently preparing 3-oxetane. Taking short-chain fatty acid and epoxy chloropropane as starting raw materials, and adopting a continuous flow microreactor to respectively carry out ring-opening esterification, hydroxyl protection, ring closure and dehydroxylation protection reactions to prepare the oxetane; the method is different from a commonly adopted kettle type reactor, adopts a continuous flow micro-reactor, enables the reaction to have the characteristics of mildness, controllability, low temperature, high efficiency, good selectivity and the like, greatly improves the yield and index of the product, and is safe, feasible, green and economical in process.

Description

Novel method for efficiently preparing 3-oxetane

Technical Field

The invention belongs to the technical field of organic synthesis, and particularly relates to a novel method for efficiently preparing 3-oxetane.

Background

3-oxetane is an important oxa-tetratomic ring medical small molecule, and an oxa-ring structure has a very special spatial configuration, so that the properties of solubility, lipophilicity, metabolic stability and the like of a medicament can be obviously changed, so that the 3-oxa-cyclobutanol has specific application in a medicament structure, such as the medicaments taxol, otano, otattin and the like which all have an oxa-ring special structure, and the oxa-ring structure such as the alenib and the like can be introduced in the synthesis process of part of medicament intermediates; 3-Oxetanol is an important way to introduce an oxa-ring structure into a drug molecule, and as drugs containing an oxa-ring structure are developed, such an oxa-ring small molecule is increasingly emphasized.

The current preparation process of 3-oxetanol mainly comprises the following steps: CN109305948 uses epichlorohydrin and glacial acetic acid as raw materials, and prepares 3-oxetane through ring opening esterification, hydroxyl protection and ring closing, and then dehydroxylation protection in an organic strong acid environment. The method is carried out in a kettle type reactor, has long reaction time, high reaction temperature and more side reactions, and is not beneficial to large-scale industrial production; CN103554064 uses glycerol as a starting material, and prepares 3-oxetanyl alcohol through condensation, hydroxyl protection, aldehyde ketone removal protection, ring closing and final hydroxyl removal protection. The method has the advantages that the reaction is carried out in a kettle type reactor, the process is long, the post-treatment is complex, the yield is low, and the industrial amplification equipment is complicated; EP751136 uses epichlorohydrin and 2-ethyl butyric acid as raw materials, and prepares 3-oxetanyl alcohol through ring opening, hydroxyl protection, ring closing and dehydroxylation protection. Therefore, how to develop a process route which has mild reaction conditions, short reaction time, convenient operation and easy industrial production has important significance.

Disclosure of Invention

Aiming at the defects of the existing method, the invention provides a novel method for efficiently preparing 3-oxetane, which can efficiently shorten the reaction time and accelerate the reaction speed by utilizing a continuous flow microreactor, is convenient to operate, is miniaturized in equipment, is beneficial to industrial scale production, and specifically comprises the following steps:

step 1, inputting fatty acid dissolved with a ring-opening catalyst and epoxy chloropropane into a continuous flow microreactor by using a metering pump, and reacting for 20-30 min at 20-30 ℃ to obtain a compound I;

step 2, uniformly mixing the catalyst and the compound I, inputting the mixture and a hydroxyl protective agent into a continuous flow microreactor by using a metering pump, and reacting for 20-30 min at 20-30 ℃ to obtain a compound II;

step 3, inputting the compound II and a prepared alkali liquor into a continuous flow microreactor by using a metering pump, reacting for 30-60 min at 40-60 ℃, putting into a liquid separator for liquid separation after the reaction is finished, and then washing with water to obtain a compound III;

step 4, inputting the compound III and methanol dissolved with a catalyst in advance into a continuous flow microreactor by using a metering pump, and controlling the temperature at 20-30 ℃; and (3) the reaction time is 10-30 min, the reaction product is placed in a distillation kettle after the reaction is finished, a small amount of sodium bicarbonate is added for neutralization, the methanol is recovered by normal pressure distillation, and then the 3-oxetanol is obtained by reduced pressure distillation.

Further, the ring-opening catalyst in the step 1 is selected from ferric trichloride, ferric tribromide, aluminum trichloride, zinc chloride and the like, and preferably ferric trichloride; the short chain fatty acid is selected from acetic acid, propionic acid, butyric acid and the like, preferably acetic acid; furthermore, the molar ratio of the acetic acid to the epichlorohydrin to the ferric trichloride is 1:1.05: 0.005.

Further, the catalyst in the step 2 is selected from p-toluenesulfonic acid, methanesulfonic acid, pyridinium p-toluenesulfonate and the like, preferably p-toluenesulfonic acid; the hydroxyl protective agent is vinyl ethyl ether, vinyl butyl ether, allyl methyl ether and the like, preferably vinyl ethyl ether; furthermore, the molar ratio of the compound I, vinyl ethyl ether and the catalyst is 1:1.05: 0.005.

Further, the alkali liquor in the step 3 is a sodium hydroxide aqueous solution, the molar ratio of sodium hydroxide to the compound II is 1: 2.5-3.5, and the concentration of the alkali liquor is 20-30%; the reaction temperature is 40-60 ℃; the reaction time is 30-60 min.

Further, the deprotection reaction catalyst in the step 4 is p-toluenesulfonic acid, methanesulfonic acid, diluted hydrochloric acid, diluted sulfuric acid, etc., preferably p-toluenesulfonic acid; the temperature is 20-30 ℃; the reaction time is 10-30 min.

[ description of the drawings ]

FIG. 1 is a schematic process flow of a novel process for the preparation of 3-oxetane using a continuous-flow microreactor.

[ detailed description ] embodiments

The present invention will be described in detail with reference to the following examples, which are provided for better illustration of the present invention and are not intended to limit the present invention.

Example 1

Step 1, dissolving 0.76g of ferric trichloride in 60g of glacial acetic acid, and respectively using 97g of epoxy chloropropane to set flow rate by using a feed pump, simultaneously inputting the flow rate and the epoxy chloropropane into a continuous flow microreactor, and reacting for 20min at 25 ℃ to obtain 157g of a brownish red compound I;

step 2, adding 0.85g of catalyst p-toluenesulfonic acid into the compound I, respectively setting the flow rate of the p-toluenesulfonic acid and 75g of vinyl ether by using a feeding pump, simultaneously inputting the p-toluenesulfonic acid and the 75g of vinyl ether into a continuous flow microreactor, and reacting for 20min at 25 ℃ to obtain 230g of light yellow compound II;

step 3, respectively setting the flow rate of a prepared 400g of sodium hydroxide solution (25%) and the compound II by using a feeding pump, simultaneously inputting the sodium hydroxide solution and the compound II into a continuous flow microreactor, reacting for 30min at 50 ℃, putting the continuous flow microreactor into a liquid separator, separating liquid after cooling, collecting upper-layer brown liquid, and washing the upper-layer brown liquid with water to obtain 112g of light yellow liquid III;

and 4, adding 1g of prepared dilute hydrochloric acid (10%) into 200g of methanol, reacting the compound III and the dilute hydrochloric acid with a feeding pump at a set flow rate in a continuous flow microreactor for 30min at 30 ℃, putting the mixture into a distillation flask, adding a small amount of sodium bicarbonate for neutralization, distilling the methanol at normal pressure, and distilling under reduced pressure to obtain 45g of 3-oxetanol.

Example 2

Step 1, dissolving 1.5g of ferric tribromide in 74g of propionic acid, and 97g of epoxy chloropropane respectively using a feed pump, setting the flow rate, simultaneously inputting the flow rate and the epoxy chloropropane into a continuous flow microreactor, and reacting for 20min at 30 ℃ to obtain 171g of a brownish red compound I;

step 2, adding 0.85g of catalyst p-toluenesulfonic acid into the compound I, respectively setting the flow rate of the p-toluenesulfonic acid and 78g of allyl methyl ether by using a feeding pump, simultaneously inputting the p-toluenesulfonic acid and the allyl methyl ether into a continuous flow microreactor, and reacting for 30min at 25 ℃ to obtain 249g of a light yellow compound II;

step 3, respectively using a feeding pump to set the flow rate of 360g of sodium hydroxide solution (30%) prepared in advance and the compound II, simultaneously inputting the sodium hydroxide solution and the compound II into a continuous flow microreactor, reacting for 30min at 50 ℃, putting the microreactor into a liquid separator, cooling, separating liquid, collecting upper-layer brown liquid, and washing with water to obtain 125g of a light yellow compound III;

and 4, adding 1g of prepared dilute hydrochloric acid (10%) into 200g of methanol, reacting the compound III and the dilute hydrochloric acid with a feeding pump at a set flow rate in a continuous flow microreactor for 30min at 30 ℃, putting the mixture into a distillation flask, adding a small amount of sodium bicarbonate for neutralization, distilling the methanol at normal pressure, and distilling the methanol at reduced pressure to obtain 51g of 3-oxetanyl alcohol.

Claims

1. The molecular structure of the 3-oxetane provided by the invention is as follows:

。

2. the invention provides a novel method for efficiently preparing 3-oxetane, which is characterized by comprising the following steps:

step 1, carrying out ring-opening esterification reaction by taking short-chain fatty acid and epoxy chloropropane as starting raw materials to obtain a compound I;

step 2, carrying out hydroxyl protection reaction on the compound I obtained in the step 1 to obtain a compound II;

step 3, carrying out a ring-closing reaction on the compound II obtained in the step 2 in excessive alkali liquor to obtain a compound III;

and 4, carrying out dehydroxylation protection reaction on the compound III obtained in the step 3 to obtain the 3-epoxy cyclobutanol.

3. The novel process of claim 2, wherein the reaction steps are all carried out in a continuous-flow microreactor.

4. The novel process according to claim 2, characterized in that the short-chain fatty acid and epichlorohydrin from step 2 are reacted in a continuous-flow microreactor under the catalysis of Lewis acids at a controlled temperature to give compound I.

5. The novel process of claim 4 wherein the short chain fatty acids are acetic acid, propionic acid, butyric acid, and the like, but are not limited thereto; the Lewis acid refers to ferric trichloride, ferric tribromide, aluminum trichloride and the like, but is not limited thereto; the molar ratio of the fatty acid to the epichlorohydrin to the catalyst is 1:1.05: 0.005-0.01; the reaction temperature is 20-30 ℃; the reaction time is 20-30 min.

6. The new method of claim 2, wherein the hydroxyl protection reaction in step 2 is performed by reacting compound I with an ether-type protecting agent in a continuous-flow microreactor under the catalysis of a catalyst and controlling the temperature to obtain compound II.

7. The method of claim 6, wherein the ether-type protecting agent is vinyl ethyl ether, vinyl butyl ether, allyl methyl ether, etc., but is not limited thereto; the catalyst is p-toluenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid pyridinium salt and the like, but is not limited to the catalyst; the molar ratio of the compound II to the protective agent to the catalyst is 1:1.1: 0.005-0.01, the reaction temperature is 20-30 ℃, and the reaction time is 20-30 min.

8. The method of claim 2, wherein the compound II of step 3 is reacted with an alkaline solution prepared from sodium hydroxide in a continuous flow microreactor, and after the reaction, the solution is separated in a liquid separator, and the organic layer is washed with water to neutrality to obtain the compound III.

9. The novel method of claim 8, wherein the molar ratio of the sodium hydroxide to the compound II is 1: 2.5-3.5, and the concentration of the alkali solution is 20-30%; the reaction temperature is 40-60 ℃; the reaction time is 30-60 min.

10. The method of claim 2, wherein the compound III of step 4 is subjected to deprotection reaction in an alcohol solvent under the catalytic action of a deprotection catalyst to obtain a methanol solution of oxetane, neutralized with sodium bicarbonate, subjected to atmospheric distillation to recover methanol, and then subjected to reduced pressure distillation to obtain an oxetane product.

11. The novel process of claim 10 wherein the deprotection reaction catalyst is p-toluenesulfonic acid, methanesulfonic acid, dilute hydrochloric acid, dilute sulfuric acid, or the like; the amount of the methanol is 1.5-2 times of the mass of the compound III; the reaction temperature is 20-30 ℃; the reaction time is 10-30 min.