阅读说明：本技术 一种r-(+)-2,2-二甲基-1,3-二氧戊环-4-甲醛的制备方法 (Preparation method of R- (+) -2, 2-dimethyl-1, 3-dioxolane-4-formaldehyde ) 是由 汪东海 赵刘强 程加铭 陈恬 顾学新 张锦涛 于 2021-08-16 设计创作，主要内容包括：本发明涉及一种R-(+)-2,2-二甲基-1,3-二氧戊环-4-甲醛的制备方法,属于药物中间体合成技术领域。为了解决现有的废水污染大和选择性不高的问题,提供一种R-(+)-2,2-二甲基-1,3-二氧戊环-4-甲醛的制备方法,该方法包括催化量的相转移催化剂季铵盐和氧化剂的作用下,所述氧化剂选自PCC或BPCC,在卤代烷烃类溶剂中将底物式Ⅱ化合物双丙酮-D-甘露醇催化氧化反应转化为产物式Ⅰ化合物R-(+)-2,2-二甲基-1,3-二氧戊环-4-甲醛。本发明具有高产物收率和纯度质量的效果,产物收率达到95％以上,纯度达到99.5％以上,也大大减少了大量废水的产生,对环境友好的优点。(The invention relates to a preparation method of R- (+) -2, 2-dimethyl-1, 3-dioxolane-4-formaldehyde, belonging to the technical field of synthesis of drug intermediates. In order to solve the problems of large pollution and low selectivity of the existing waste water, the preparation method of the R- (+) -2, 2-dimethyl-1, 3-dioxolane-4-formaldehyde comprises the steps of carrying out catalytic oxidation reaction on a substrate compound of a formula II, namely diacetone-D-mannitol, in a halogenated alkane solvent to convert the substrate compound of the formula II into the product compound of the formula I, namely R- (+) -2, 2-dimethyl-1, 3-dioxolane-4-formaldehyde under the action of a catalytic amount of a phase transfer catalyst quaternary ammonium salt and an oxidant. The method has the effects of high product yield and purity and quality, the product yield reaches over 95 percent, the purity reaches over 99.5 percent, the generation of a large amount of waste water is greatly reduced, and the method is environment-friendly.)

1. A preparation method of R- (+) -2, 2-dimethyl-1, 3-dioxolane-4-formaldehyde is characterized by comprising the following steps:

under the action of a catalytic amount of phase transfer catalyst quaternary ammonium salt and an oxidant, wherein the oxidant is selected from PCC or BPCC, a substrate compound shown in a formula II is subjected to a diacetone-D-mannitol catalytic oxidation reaction in a halogenated alkane solvent to be converted into a product compound shown in a formula I, namely R- (+) -2, 2-dimethyl-1, 3-dioxolane-4-formaldehyde;

2. the method for preparing R- (+) -2, 2-dimethyl-1, 3-dioxolane-4-carbaldehyde according to claim 1, wherein said quaternary ammonium salt of a phase transfer catalyst is one or more selected from the group consisting of tetrabutylammonium bromide, tetrabutylammonium chloride, tetramethylammonium bromide, tetramethylammonium chloride, a bis-spiro quaternary ammonium salt and hexadecyltrimethylammonium bromide.

3. The method for preparing R- (+) -2, 2-dimethyl-1, 3-dioxolane-4-carbaldehyde according to claim 1, wherein said haloalkane-based solvent is one or more selected from the group consisting of dichloromethane, chloroform and dichloroethane.

4. The method for preparing R- (+) -2, 2-dimethyl-1, 3-dioxolane-4-carbaldehyde according to claim 3, wherein the temperature of said catalytic oxidation reaction is 20 ℃ to 30 ℃.

5. The process for preparing R- (+) -2, 2-dimethyl-1, 3-dioxolane-4-carbaldehyde according to any one of claims 1 to 4, wherein the amount of said quaternary ammonium salt as a phase transfer catalyst is 1.0% to 3.0% of the amount of diacetone-D-mannitol as a compound of formula II.

6. The process for preparing R- (+) -2, 2-dimethyl-1, 3-dioxolane-4-carbaldehyde according to any one of claims 1 to 4, wherein the molar ratio of diacetone-D-mannitol as a compound of formula II to the oxidizing agent is 1: 1.0 to 1.3.

7. The method for preparing R- (+) -2, 2-dimethyl-1, 3-dioxolane-4-carbaldehyde according to any one of claims 1 to 4, wherein the method further comprises a post-treatment after the catalytic oxidation reaction is finished, wherein the post-treatment specifically comprises: and filtering the reaction solution, recovering solids in the reaction solution, and distilling the collected filtrate to remove the solvent to obtain the oily compound R- (+) -2, 2-dimethyl-1, 3-dioxolane-4-formaldehyde with the formula I.

Technical Field

The invention relates to a preparation method of R- (+) -2, 2-dimethyl-1, 3-dioxolane-4-formaldehyde, belonging to the technical field of synthesis of drug intermediates.

Background

Gemcitabine hydrochloride is a cell cycle specific antimetabolite, mainly acts on tumor cells in a DNA synthesis phase, namely S-phase cells, can prevent the progression from the G1 phase to the S phase under certain conditions, is a safe and effective chemotherapeutic drug for treating late-stage non-small cell lung cancer, and has high market application value at present.

R- (+) -2, 2-dimethyl-1, 3-dioxolane-4-formaldehyde (also called R-glyceraldehyde acetonide) is a key intermediate of gemcitabine, and is a key intermediate raw material in the process of gemcitabine synthesis, while for the synthesis of the intermediate, diacetone-D-mannitol is mainly used as a raw material for synthesis at present, for example, diacetone-D-mannitol is oxidized and synthesized by sodium periodate, but the sodium periodate used in the synthesis is expensive and difficult to recycle, and the yield and purity of the obtained product are low, so that the synthesis is not suitable for industrial production. And the R- (+) -2, 2-dimethyl-1, 3-dioxolane-4-formaldehyde is obtained by oxidizing diacetone-D-mannitol with hydrogen peroxide, wherein the hydrogen peroxide belongs to peroxide, is easy to explode in the reaction process, has high danger and is not suitable for industrial production. In addition, D-mannitol-diacetone is used as a raw material and is oxidized by potassium permanganate to synthesize a corresponding intermediate product, but the adopted potassium permanganate has extremely strong oxidability, so that more impurities are generated in the reaction, and the yield and the purity of the obtained product are lower. In addition, as shown in the patent application (publication No. CN 108610322B), the synthesis of R-glyceraldehyde acetonide according to the earlier research route of the applicant also uses diacetone-D-mannitol as raw material, and uses TEMPO and crown ether as catalysts to perform the reaction, and uses hypochlorite to perform the oxidation reaction to convert into the corresponding R-glyceraldehyde acetonide. However, the reaction is carried out in an aqueous system, and the hypochlorite used causes a large amount of waste water to pollute the environment, so that the waste water is not easy to treat.

Disclosure of Invention

Aiming at the problems in the prior art, the invention provides a preparation method of R- (+) -2, 2-dimethyl-1, 3-dioxolane-4-formaldehyde, which solves the problem of how to realize pollution reduction, is easy to operate and ensures that the reaction has high selectivity.

The invention aims to realize the following technical scheme that the preparation method of the R- (+) -2, 2-dimethyl-1, 3-dioxolane-4-formaldehyde comprises the following steps:

under the action of a catalytic amount of phase transfer catalyst quaternary ammonium salt and an oxidant, wherein the oxidant is selected from PCC or BPCC, a substrate compound shown in a formula II is subjected to a diacetone-D-mannitol catalytic oxidation reaction in a halogenated alkane solvent to be converted into a product compound shown in a formula I, namely R- (+) -2, 2-dimethyl-1, 3-dioxolane-4-formaldehyde;

by adopting the catalytic amount of quaternary ammonium salt and taking PCC or BPCC as an oxidant to act together, and enabling the reaction to be carried out in an anhydrous halogenated alkane solvent, which is equivalent to the reaction to be carried out under the anhydrous solid-liquid heterogeneous condition, the PCC or BPCC as the oxidant has high selectivity, and the alcoholic hydroxyl in the substrate is efficiently oxidized into a corresponding carbonyl to form a corresponding target product R- (+) -2, 2-dimethyl-1, 3-dioxolane-4-formaldehyde, so that the yield and the purity quality are high, the yield is more than 95%, and the purity is more than 99.5%; meanwhile, the catalytic amount of quaternary ammonium salt and the PCC or BPCC as the oxidant coact, so that the reaction can be promoted to be carried out under a mild temperature condition, high temperature is not required for the reaction, the operation process is easier to control, the high selectivity of the reaction can be effectively ensured, the generation of impurities can be reduced, the purity and the quality of the product can be improved, and the method is more suitable for industrial mass production. In addition, the PCC or BPCC is adopted as the oxidant, so that safe production and operation are easier, only the solid quaternary ammonium salt and the oxidant need to be simply separated after the reaction is finished, the post-treatment process is greatly reduced, the generation of a large amount of waste water is reduced, the method has the advantage of environmental friendliness, and compared with sodium periodate, the method is expensive in price, and the production cost can be better reduced.

In the above method for preparing R- (+) -2, 2-dimethyl-1, 3-dioxolane-4-carbaldehyde, preferably, the quaternary ammonium salt of the phase transfer catalyst is one or more selected from tetrabutylammonium bromide, tetrabutylammonium chloride, tetramethylammonium bromide, tetramethylammonium chloride, a bis-spiro quaternary ammonium salt and hexadecyltrimethylammonium bromide. The reaction can be carried out more effectively, the activity of the reaction can be improved better, and the high-efficiency selectivity of the reaction can be better realized by combining with the PCC or PBCC as an oxidant, so that the effect that the product has high purity and yield can be better realized.

In the above process for producing R- (+) -2, 2-dimethyl-1, 3-dioxolane-4-carbaldehyde, preferably, the haloalkane-based solvent is one or more selected from the group consisting of dichloromethane, chloroform and dichloroethane. The use of the above solvent has the advantages of easy removal and recovery by distillation and simplified post-treatment. The dosage of the halogenated alkane solvent can be generally used according to the chemical field, and the dosage of the halogenated alkane solvent is preferably within the range of 10-15 times of the weight of the raw material substrate, namely the compound diacetone-D-mannitol of the formula II.

In the above method for producing R- (+) -2, 2-dimethyl-1, 3-dioxolane-4-carbaldehyde, the temperature of the catalytic oxidation reaction is preferably 20 to 30 ℃. Due to the combined action of the quaternary ammonium salt with the catalytic amount and the PCC or BPCC as the oxidant and the reaction in the halogenated alkane solvent, the reaction has better reaction activity, the reaction can be carried out at a milder temperature, the defect of by-products generated due to overhigh temperature in the reaction process can be better reduced within the temperature range, the generation of impurities is effectively reduced, and the purity and the quality of the product are ensured.

In the preparation method of the R- (+) -2, 2-dimethyl-1, 3-dioxolane-4-formaldehyde, the addition amount of the quaternary ammonium salt of the phase transfer catalyst is preferably 1.0-3.0% of the addition amount of the diacetone-D-mannitol which is a compound of the formula II. The method can be carried out more efficiently in a solid-liquid system in an anhydrous solvent, and the conversion rate of the reaction are improved.

In the above process for producing R- (+) -2, 2-dimethyl-1, 3-dioxolane-4-carbaldehyde, preferably, the molar ratio of diacetone-D-mannitol as the compound of formula ii to the oxidizing agent is 1: 1.0 to 1.3. The waste of raw materials can be reduced while the catalytic oxidation effect is ensured.

In the above method for preparing R- (+) -2, 2-dimethyl-1, 3-dioxolane-4-carbaldehyde, preferably, after the catalytic oxidation reaction is completed, the method further comprises a post-treatment, wherein the post-treatment specifically comprises: and filtering the reaction solution, recovering solids in the reaction solution, and distilling the collected filtrate to remove the solvent to obtain the oily compound R- (+) -2, 2-dimethyl-1, 3-dioxolane-4-formaldehyde with the formula I. The recovered solid is mainly the oxidant PCC or BPCC and the quaternary ammonium salt component, can be recycled, more effectively reduce the production cost and the pollution to the environment, and the reaction system of the invention does not need to adopt water washing, does not generate a large amount of waste water, is more favorable for reducing the influence on the environmental pollution, and the halogenated alkane solvent recovered by distillation can be reused.

The preparation method of the R- (+) -2, 2-dimethyl-1, 3-dioxolane-4-formaldehyde can be represented by the following chemical reaction equation:

in summary, compared with the prior art, the invention has the following advantages:

1. the invention adopts the above-mentioned quaternary ammonium salt of catalytic amount and takes PCC or BPCC as oxidizing agent coaction, and make the reaction go on in anhydrous halogenated alkane solvent, can make the reaction go on under the anhydrous solid-liquid heterogeneous condition, make PCC or BPCC have high selectivity as oxidizing agent, oxidize alcoholic hydroxyl group into corresponding carbonyl with high efficiency and form corresponding product R- (+) -2, 2-dimethyl-1, 3-dioxolane-4-formaldehyde, have the effects of high yield and purity quality, the yield reaches more than 95%, the purity reaches more than 99.5%.

2. The reaction of the invention is easier to produce and operate safely, and only needs to separate out the solid simply after the reaction is finished, thus greatly reducing the post-treatment process, greatly reducing the generation of a large amount of waste water, having the advantage of environmental protection, and being more expensive than sodium periodate, and being capable of reducing the production cost better.

Detailed Description

The technical solution of the present invention is further specifically described below by way of specific examples, but the present invention is not limited to these examples.

Example 1

Adding 200g of dioxymethane into a clean reactor, adding 20g of diacetone-D-mannitol under the stirring state, controlling the temperature to be 20-25 ℃, stirring and fully dissolving, then adding 0.2g of tetrabutylammonium bromide and 17.9g of oxidant PCC, controlling the temperature to be 20-25 ℃, preserving the temperature and reacting for 3 hours, after the reaction is finished, carrying out suction filtration, recovering solids in reaction liquid, and carrying out reduced pressure distillation on collected filter to recover the solvent, thereby obtaining 19.5g of oily product R- (+) -2, 2-dimethyl-1, 3-dioxolane-4-formaldehyde, wherein the yield of the product is 98.4%, and the purity content is 99.7%.

Example 2

Adding 200g of dioxymethane into a clean reactor, adding 20g of diacetone-D-mannitol under the stirring state, controlling the temperature to be 20-25 ℃, stirring and fully dissolving, then adding 0.2g of tetrabutylammonium bromide and 24.4g of oxidant BPCC, controlling the temperature to be 20-25 ℃, preserving the temperature and reacting for 3 hours, after the reaction is finished, carrying out suction filtration, recovering solid matters in reaction liquid, and carrying out reduced pressure distillation on collected filter to recover solvent to obtain an oily product R- (+) -2, 2-dimethyl-1, 3-dioxolane-4-formaldehyde with the yield of 98.0% and the purity content of 99.8%.

Example 3

Adding 200g of dioxymethane into a clean reactor, adding 20g of diacetone-D-mannitol under the stirring state, controlling the temperature to be 20-25 ℃, stirring and fully dissolving, then adding 0.2g of tetrabutylammonium chloride and 19.6g of oxidant PCC, controlling the temperature to be 20-25 ℃, preserving the temperature and reacting for 3 hours, after the reaction is finished, carrying out suction filtration, recovering solid matters in reaction liquid, and carrying out reduced pressure distillation on collected filter to recover the solvent, thereby obtaining 19.2g of oily R- (+) -2, 2-dimethyl-1, 3-dioxolane-4-formaldehyde, wherein the yield of the product is 97.0%, and the purity content is 99.5%.

Example 4

Adding 200g of dioxymethane into a clean reactor, adding 20g (0.08mol) of diacetone-D-mannitol under the stirring state, controlling the temperature to be 20-22 ℃, stirring and fully dissolving, then adding 0.2g of tetrabutylammonium chloride and 26.6g of oxidant BPCC, controlling the temperature to be 20-22 ℃, preserving the temperature for 4 hours, after the reaction is finished, carrying out suction filtration, recovering solids in reaction liquid, collecting filtered solution, carrying out reduced pressure distillation and recovering solvent to obtain 19.0g of oily R- (+) -2, 2-dimethyl-1, 3-dioxolane-4-formaldehyde, wherein the yield of the product is 96.0%, and the purity content is 99.6%.

Example 5

Adding 300g of chloroform into a clean reactor, adding 20g of diacetone-D-mannitol under the stirring state, controlling the temperature to be 28-30 ℃, stirring and fully dissolving, then adding 0.6g of tetramethylammonium bromide and 30.4g of oxidant BPCC, controlling the temperature to be 28-30 ℃, preserving the temperature and reacting for 3 hours, after the reaction is finished, carrying out suction filtration, recovering solid matters in reaction liquid, collecting the filtrate, carrying out reduced pressure distillation and recovering solvent to obtain 19.2g of oily R- (+) -2, 2-dimethyl-1, 3-dioxolane-4-formaldehyde, wherein the yield of the product is 97%, and the purity content is 99.7%.

Example 6

Adding 250g of dichloromethane into a clean reactor, adding 20g of diacetone-D-mannitol under the stirring state, controlling the temperature to be 25-28 ℃, stirring and fully dissolving, then adding 0.4g of tetrabutylammonium bromide and 20.7g of oxidant PCC, controlling the temperature to be 25-38 ℃, preserving the temperature and reacting for 3.5 hours, after the reaction is finished, carrying out suction filtration, recovering solid matters in reaction liquid, and carrying out reduced pressure distillation on collected filter to recover the solvent to obtain 19.1g of oily R- (+) -2, 2-dimethyl-1, 3-dioxolane-4-formaldehyde, wherein the yield of the product is 96.5%, and the purity content is 99.5%.

Example 7

Adding 200g of dioxymethane into a clean reactor, adding 20g of diacetone-D-mannitol under the stirring state, controlling the temperature to be fully dissolved at 25 ℃, then adding 0.3g of double-spiro quaternary ammonium salt and 25.7g of oxidant BPCC, controlling the temperature to be kept at 25 ℃, carrying out heat preservation reaction for 3 hours, carrying out suction filtration after the reaction is finished, recovering solid matters in reaction liquid, carrying out reduced pressure distillation on the collected filter to recover solvent, and obtaining an oily product R- (+) -2, 2-dimethyl-1, 3-dioxolane-4-formaldehyde, wherein the yield of the product is 97.5%, and the purity content is 99.6%.

Example 8

This example shows that the solid matter recovered in the post-treatment process of example 6 (recovered oxidizing agent and quaternary ammonium salt) can be recovered and reused as a catalyst and an oxidizing agent, and is specifically carried out as follows.

Adding 200g of dioxymethane into a clean reactor, adding 20g of diacetone-D-mannitol under the stirring state, controlling the temperature to be fully stirred and dissolved at 25 ℃, then adding the solid (containing an oxidant PCC and quaternary ammonium salt tetrabutyl ammonium bromide) recovered in the example 6 into a reaction system, controlling the temperature to be kept at 25 ℃ for reaction for 4 hours, after the reaction is finished, carrying out suction filtration, recovering the solid in the reaction liquid, carrying out reduced pressure distillation on the collected filter to recover the solvent, obtaining 18.9g of oily product R- (+) -2, 2-dimethyl-1, 3-dioxolane-4-formaldehyde, wherein the yield of the product is 95.6%, the purity content was 99.5%.

The specific embodiments described herein are merely illustrative of the spirit of the invention. Various modifications or additions may be made to the described embodiments or alternatives may be employed by those skilled in the art without departing from the spirit or ambit of the invention as defined in the appended claims.

While the invention has been described in detail and with reference to specific embodiments thereof, it will be apparent to one skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope thereof.