阅读说明：本技术 连续流微通道反应器中氧化制备2,3,5-三苄氧基-d-核糖酸-1,4-内酯的方法 (Method for preparing 2,3, 5-tribenzyloxy-D-ribonic acid-1, 4-lactone by oxidation in continuous flow microchannel reactor ) 是由 陈本顺 叶金星 李大伟 张维冰 徐春涛 江涛 张凌怡 慕欣 何义 庞小召 程刚 于 2020-05-18 设计创作，主要内容包括：本发明涉及一种连续流微通道反应器中氧化制备2,3,5-三苄氧基-D-核糖酸-1,4-内酯的方法,在微通道反应器中以2,3,5-三苄氧基-D-核糖次氯酸钠氧化合成2,3,5-三苄氧基-D-核糖酸-1,4-内酯,反应流程如下所示,解决了现有制备方法反应时间长,反应条件要求高,不能连续生产,成本高等问题,具有操作简单、安全、反应时间短、产物转化率高、产物纯度高等优点,反应完成后的物料可以直接进入后处理操作,后处理简单,产物的收率95％以上,纯度99％以上,特别适合工业化大规模生产。<Image he="221" wi="700" file="DDA0002495941600000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention relates to a method for preparing 2,3, 5-tribenzyloxy-D-ribonic acid-1, 4-lactone by oxidation in a continuous flow microchannel reactor, the method is characterized in that 2,3, 5-tribenzyloxy-D-ribose sodium hypochlorite is oxidized to synthesize 2,3, 5-tribenzyloxy-D-ribono acid-1, 4-lactone in a microchannel reactor, the reaction process is shown as follows, the problems of long reaction time, high reaction condition requirement, incapability of continuous production, high cost and the like of the existing preparation method are solved, and the method has the advantages of simplicity and safety in operation, short reaction time, high product conversion rate, high product purity and the like, materials after the reaction can be directly subjected to post-treatment operation, the post-treatment is simple, the yield of the products is more than 95%, the purity is more than 99%, and the method is particularly suitable for industrial large-scale production.)

1. A method for preparing 2,3, 5-tribenzyloxy-D-ribonic acid-1, 4-lactone by oxidation in a continuous flow microchannel reactor is characterized by comprising the following steps:

(1) preparation of material a solution: adding acid and/or alkali into NaClO water solution with the mass concentration of 3-12% at the temperature of below 10 ℃ to adjust the pH value to 8.2-9.2;

(2) preparation of material B solution: dissolving a compound 2,3, 5-tribenzyloxy-D-ribose in a solvent, adding TEMPO or 4-hydroxyl TEMPO, and stirring for dissolving;

(3) preparation of stock C solution: an aqueous solution of KBr;

(4) respectively conveying the material solution A, the material solution B and the material solution C to a microchannel reactor, reacting for 15-120 s at the temperature of 0-20 ℃ and under the pressure of 0.15-0.3 Mpa, carrying out quenching reaction on the reacted materials, and carrying out liquid separation, washing and concentration to obtain a compound 2,3, 5-tribenzyloxy-D-ribonic acid-1, 4-lactone;

the molar ratio of the compound 2,3, 5-tribenzyloxy-D-ribose to the NaClO is 1: 1.4-2.2; the mass of TEMPO or 4-hydroxyl TEMPO is 0.05-0.2% of that of the compound 2,3, 5-tribenzyloxy-D-ribose; the mass ratio of the compound 2,3, 5-tribenzyloxy-D-ribose to the KBr is 1: 0.05-0.15.

2. The method according to claim 1, wherein in steps (1) and (2), the molar ratio of the compound 2,3, 5-tribenzyloxy-D-ribose to the NaClO is 1: 1.8-2.0; the mass concentration of the NaClO aqueous solution is 4-5%, and preferably 5%.

3. The method according to claim 2, wherein in step (1), the acid is one or more of hydrochloric acid, sulfuric acid or acetic acid, preferably hydrochloric acid; the alkali is one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate, and is preferably sodium bicarbonate; more preferably, hydrochloric acid and sodium bicarbonate are added at a temperature below 10 ℃ to adjust the pH to 8.5-9.0.

4. The process according to claim 1, characterized in that in step (2) the mass of TEMPO or 4-hydroxy TEMPO is 0.06-0.12%, preferably 0.12% of the mass of 2,3, 5-tribenzyloxy-D-ribose of the compound.

5. The method according to claim 1, wherein in the step (2), the mass-to-volume ratio of the compound 2,3, 5-tribenzyloxy-D-ribose to the solvent is 1:4 to 15g/ml, preferably 1:4 to 6 g/ml; the solvent is dichloromethane, trichloromethane, toluene and n-hexane, and toluene or dichloromethane is preferred.

6. The method according to claim 1, wherein in steps (2) and (3), the mass ratio of the compound 2,3, 5-tribenzyloxy-D-ribose to the KBr is 1:0.05 to 0.1, preferably 1: 0.1; the mass volume ratio of KBr to water in the KBr water solution is 1: 12-80 g/ml, preferably 1: 12-25 g/ml, and more preferably 1: 12-22 g/ml.

7. The method of claim 1, wherein in the step (4), the temperature of the microchannel reaction is 5-15 ℃; the time of the microchannel reaction is 80-120 s, preferably 80-103 s.

8. The method according to claim 1, wherein in the step (4), the reacted materials are quenched with sodium thiosulfate or sodium bisulfite; preferably, after quenching the reaction, the reaction mixture is separated, washed with an aqueous solution of sodium thiosulfate or sodium bisulfite, and concentrated.

9. The method according to claim 1, wherein in the step (4), the flow rate of the solution of the material A is 15-55 ml/min; the flow rate of the solution for conveying the material B is 16-65 ml/min; the flow rate of the solution for conveying the material C is 4-55 ml/min.

10. The method of claim 1, wherein the microchannel reactor is a microreactor or a micromixer of a three-feed single-outlet module, and the reaction module of the microchannel reactor has a T-shaped structure, a spherical baffled structure, a drop-shaped structure or a heart-shaped structure.

Technical Field

The invention belongs to the technical field of chemical production, and relates to a method for preparing 2,3, 5-tribenzyloxy-D-ribonic acid-1, 4-lactone by oxidation in a continuous flow microchannel reactor, in particular to a continuous flow preparation method for synthesizing 2,3, 5-tribenzyloxy-D-ribonic acid-1, 4-lactone by oxidizing 2,3, 5-tribenzyloxy-D-ribose in a microchannel continuous flow reactor.

Background

2,3, 5-tribenzyloxy-D-ribonic acid-1, 4-lactone is an important raw material for synthesizing a plurality of medicaments, such as the antiviral medicament Reidesvir.

The method for synthesizing 2,3, 5-tribenzyloxy-D-ribono-1, 4-lactone by using 2,3, 5-tribenzyloxy-D-ribose as a raw material reported in the literature comprises the following steps:

(1) DMSO and acetic anhydride are adopted as oxidants, the reaction time of the method is long and reaches 48 hours, products are not easy to solidify, and dimethyl sulfoxide with good water solubility and high boiling point is directly used, so that a large amount of waste water is generated.

(2) Patent CN 108285438A discloses a method of oxidation with sodium hypochlorite, but the conventional reaction kettle cannot perform continuous production; the product quality is not stable enough, once the reaction can not be completed within 1-2 hours, a large amount of oxidant needs to be supplemented, the effect is not good, the subsequent work is greatly influenced, the reaction time is too long, impurities are generated, and the yield is influenced.

(3) Patent CN 102731445a discloses a method of oxidation with iodine (potassium carbonate addition), the raw material cost is large, and continuous production cannot be carried out.

Disclosure of Invention

The invention aims to provide a method for preparing 2,3, 5-tribenzyloxy-D-ribonic acid-1, 4-lactone by oxidation in a continuous flow microchannel reactor on the basis of the prior art, which is prepared by taking 2,3, 5-tribenzyloxy-D-ribose as a raw material and using sodium hypochlorite for oxidation synthesis in the microchannel reactor, and has the advantages of short reaction time, lower requirement on reaction conditions, continuous production, simple and safe operation, short reaction time, high product conversion rate and high product purity.

The technical scheme of the invention is as follows:

a method for preparing 2,3, 5-tribenzyloxy-D-ribonic acid-1, 4-lactone by oxidation in a continuous flow microchannel reactor comprises the following steps:

(1) preparation of material a solution: adding acid and/or alkali into NaClO water solution with the mass concentration of 3-12% at the temperature of below 10 ℃ to adjust the pH value to 8.2-9.2;

(2) preparation of material B solution: dissolving a compound 2,3, 5-tribenzyloxy-D-ribose in a solvent, adding TEMPO or 4-hydroxyl TEMPO, and stirring for dissolving;

(3) preparation of stock C solution: an aqueous solution of KBr;

(4) respectively conveying the material solution A, the material solution B and the material solution C to a microchannel reactor, reacting for 15-120 s at the temperature of 0-20 ℃ and under the pressure of 0.15-0.3 Mpa, carrying out quenching reaction on the reacted materials, and carrying out liquid separation, washing and concentration to obtain a compound 2,3, 5-tribenzyloxy-D-ribonic acid-1, 4-lactone;

the molar ratio of the compound 2,3, 5-tribenzyloxy-D-ribose to the NaClO is 1: 1.4-2.2; the mass of TEMPO or 4-hydroxyl TEMPO is 0.05-0.2% of that of the compound 2,3, 5-tribenzyloxy-D-ribose; the mass ratio of the compound 2,3, 5-tribenzyloxy-D-ribose to the KBr is 1: 0.05-0.15.

The preparation method adopts the microchannel reactor to carry out continuous flow type reaction, the materials staying in the microchannel reactor are few, the reaction materials are fully mixed, the reaction time is short, the reaction time and the reaction temperature can be accurately controlled, the generation of a large number of byproducts caused by local overheating or prolonged reaction time is avoided, the problems of long reaction time, more byproducts, tedious post-treatment, low yield and purity and the like in each reaction step in the prior art are avoided, and under the coordination of other conditions, the preparation method can accurately control the feeding proportion of the reaction materials, greatly shortens the reaction time, and is high in safety, low in cost, simple in post-treatment, high in yield of the product and high in purity, more than 99%, and particularly suitable for industrial large-scale production.

The method has the advantages that the microchannel reactor is adopted to produce the target intermediate 2,3, 5-tribenzyloxy-D-ribonic acid-1, 4-lactone, the feeding proportion of reaction materials can be accurately controlled, the reactants are fully mixed, the pH, the reaction temperature and the reaction time of the reaction materials can be accurately controlled, impurities are reduced, raw materials can be saved, the cost is reduced, the reaction time is greatly shortened, and the safety is high.

In one scheme, the material A solution and the material B solution prepared in the steps (1) and (2) have a molar ratio of the compound 2,3, 5-tribenzyloxy-D-ribose to NaClO of 1: 1.8-2.0, and preferably have a molar ratio of 2,3, 5-tribenzyloxy-D-ribose to NaClO of 1: 2.0.

Further, the mass concentration of the NaClO aqueous solution is 4-5%, preferably 5%.

In step (1) of the present invention, the pH of the solution may be adjusted using an acid or a base commonly used in the art. For example, the acid may be, but is not limited to, one or more of hydrochloric acid, sulfuric acid, or acetic acid, and is preferably hydrochloric acid.

The alkali can be one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate, and is preferably sodium bicarbonate.

In a preferable scheme, water is added into a sodium hypochlorite aqueous solution to dilute the sodium hypochlorite aqueous solution to a NaClO aqueous solution with the mass concentration of 4-5%, and hydrochloric acid and sodium bicarbonate are added at the temperature of below 10 ℃ to adjust the pH value to 8.5-9.0.

In the step (2), the adopted catalyst is TEMPO or 4-hydroxy TEMPO, wherein the mass of the TEMPO or 4-hydroxy TEMPO is 0.06-0.12%, preferably 0.12% of that of the compound 2,3, 5-tribenzyloxy-D-ribose.

In the step (2), a compound 2,3, 5-tribenzyloxy-D-ribose is firstly dissolved in a solvent, then TEMPO or 4-hydroxy TEMPO is added and stirred to be dissolved, and a material B solution is prepared, wherein the mass-volume ratio of the compound 2,3, 5-tribenzyloxy-D-ribose to the solvent is 1: 4-15 g/ml, and preferably 1: 4-6 g/ml.

The solvent adopted by the invention is dichloromethane, trichloromethane, toluene or n-hexane, and toluene or dichloromethane is preferred.

In one embodiment, in steps (2) and (3), the mass ratio of the compound 2,3, 5-tribenzyloxy-D-ribose to the KBr is 1: 0.05-0.1, preferably 1: 0.1.

When the material C solution is prepared, the concentration of KBr in the KBr aqueous solution can be adjusted according to actual needs, for example, the mass-to-volume ratio of KBr to water in the KBr aqueous solution is 1: 12-80 g/ml, preferably 1: 12-25 g/ml, and more preferably 1: 12-22 g/ml.

When the microchannel reaction is carried out in the step (4), the microchannel reactor is a micro-reactor or a micro-mixer of a three-feeding single-discharging module and can be connected in series according to requirements, and the reaction module of the microchannel reactor has a T-shaped structure, a spherical structure with a baffle, a water drop-shaped structure or a heart-shaped structure. For example, the microchannel reactor model is WH-IND-152 or WH-LAB-SS 2101.

When the 2,3, 5-tribenzyloxy-D-ribonic acid-1, 4-lactone is synthesized by oxidation in a continuous flow microchannel reactor, the reaction temperature is accurately controlled by an external heat exchanger, for example, the temperature of the microchannel reactor is 0-15 ℃.

Furthermore, the time of the microchannel reaction is 80-120 s, preferably 80-103 s. For example 80s, 85s, 90s, 100s, 103s or 120 s.

In a preferred embodiment, in step (4), the reaction mass is quenched with sodium thiosulfate or sodium bisulfite. In a more preferred embodiment, after the quenching reaction with sodium thiosulfate, the reaction mixture is separated, washed with an aqueous solution of sodium thiosulfate or sodium bisulfite, and concentrated.

In the prior art, sodium hypochlorite serving as an oxidant is quenched by a sodium thiosulfate aqueous solution, and after liquid separation, an organic phase is concentrated to obtain a crude product of 2,3, 5-tribenzyloxy-D-ribose. In contrast, in the invention, when the materials after the reaction in the microchannel are subjected to post-treatment, sodium thiosulfate or sodium bisulfite is firstly adopted for quenching reaction, then standing and liquid separation are carried out, and the separated organic phase is washed by sodium thiosulfate or sodium bisulfite aqueous solution, so that the use amount of sodium thiosulfate can be greatly reduced, the wastewater discharge is reduced, and the cost is saved.

In one scheme, during the quenching reaction in the step (4), the mass ratio of NaClO to sodium thiosulfate or sodium bisulfite is 1: 0.2-4.5; preferably 1: 0.5-3.

Furthermore, the mass volume ratio of the sodium thiosulfate to the water in the sodium thiosulfate solution is 1: 5-1: 20g/ml, and preferably 1: 6-1: 14 g/ml.

Furthermore, the mass volume ratio of the sodium bisulfite to the water in the sodium bisulfite solution is 1: 5-1: 20g/ml, preferably 1: 6-1: 14 g/ml.

In one scheme, in the step (4), the flow rate of the solution of the material A is 15-55 ml/min; the flow rate of the solution of the material B to be conveyed is 15-70 ml/min; the flow rate of the solution for conveying the material C is 4-55 ml/min.

By adopting the technical scheme of the invention, the advantages are as follows:

the invention provides a method for preparing 2,3, 5-tribenzyloxy-D-ribonic acid-1, 4-lactone by oxidizing 2,3, 5-tribenzyloxy-D-ribose sodium hypochlorite by using a microchannel reactor. The preparation method of the invention can be used for continuous production, the materials after the reaction can be directly subjected to post-treatment operation, the post-treatment is simple, the yield of the product is more than 95%, the purity is more than 99%, and the preparation method is particularly suitable for industrial large-scale production, so that the chemical production is more economical and environment-friendly.

The micro-channel reactor adopted by the invention is acid and alkali resistant, can be conveniently assembled and disassembled, and can be adjusted according to actual requirements.

Detailed Description

The process for the oxidative preparation of 2,3, 5-tribenzyloxy-D-ribono-1, 4-lactone according to the invention is further illustrated by the following examples, which are not intended to limit the invention in any way.