A process for the preparation of r-(+)-2,2-dimethyl-1,3-dioxolane-4-carboxaldehyde

Abstract

The present application relates to a kind of preparation methods of R-(+)-2,2-dimethyl-1,3-dioxolane-4-formaldehyde, belong to the technical field of pharmaceutical intermediates synthesis.In order to solve the existing wastewater pollution and the problem of low selectivity, provide a kind of preparation method of R-(+)-2,2-dimethyl-1,3-dioxolane-4-formaldehyde, the method includes the action of catalytic amount of phase transfer catalyst quaternary ammonium salt and oxidant, the oxidant is selected from PCC or BPCC, in halogenated alkane solvent, substrate formula II compound double ketone-D-mannitol is converted into product formula I compound R-(+)-2,2-dimethyl-1,3-dioxolane-4-formaldehyde by catalytic oxidation reaction.The present application has the effect of high product yield and purity quality, product yield reaches more than 95%, purity reaches more than 99.5%, also greatly reduces the generation of a large amount of wastewater, the advantage of environment-friendly.

Description

Technical Field

[0001] The invention relates to a preparation method of R-(+)-2,2-dimethyl-1,3-dioxolane-4-carboxaldehyde, belonging to the technical field of pharmaceutical intermediate synthesis. Background Art

[0002] Gemcitabine hydrochloride is a cell cycle-specific anti-metabolite drug that mainly acts on tumor cells in the DNA synthesis phase, i.e., S phase cells. Under certain conditions, it can prevent the progression from the G1 phase to the S phase. It is a relatively safe and effective chemotherapy drug for the treatment of advanced non-small cell lung cancer, and its current market application value is also relatively high.

[0003] R-(+)-2,2-dimethyl-1,3-dioxolane-4-carboxaldehyde (also known as R-glyceraldehyde acetone acetonide) is a key intermediate of gemcitabine and a key raw material in its synthesis. Currently, the synthesis of this intermediate is primarily based on diacetone-D-mannitol. For example, diacetone-D-mannitol is oxidized with sodium periodate. However, the sodium periodate used is expensive and difficult to recycle, and the resulting product has low yield and purity, making it unsuitable for industrial production. Alternatively, diacetone-D-mannitol is oxidized with hydrogen peroxide to obtain R-(+)-2,2-dimethyl-1,3-dioxolane-4-carboxaldehyde. However, hydrogen peroxide is a peroxide and is prone to explosion during the reaction, making it highly dangerous and unsuitable for industrial production. Also have take D-mannitol-diacetone as raw material, through potassium permanganate oxidation synthesis corresponding intermediate product, but, because the oxidisability of the potassium permanganate that adopts is extremely strong, the impurity that reaction generates is more, causes obtaining product yield and purity all lower.Also have as the route of the applicant's early stage research as patent application (publication number: CN108610322B) disclosed a kind of R-glyceraldehyde acetone acetone synthesis also take diacetone-D-mannitol as raw material, under the catalytic action of TEMPO and crown ether, react, adopt hypochlorite to carry out oxidation reaction and be converted into corresponding R-glyceraldehyde acetone acetone.But its reaction is carried out under aqueous system, and the hypochlorite of employing can cause a large amount of waste water to pollute environment, is difficult for handling. Summary of the Invention

[0004] The present invention aims to solve the problems existing in the above prior art and provides a method for preparing R-(+)-2,2-dimethyl-1,3-dioxolane-4-carboxaldehyde, which solves the problem of how to reduce pollution, facilitate operation and make the reaction highly selective.

[0005] The object of the present invention is achieved by the following technical solution: a method for preparing R-(+)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde, which comprises the following steps:

[0006] Under the action of a catalytic amount of a phase transfer catalyst quaternary ammonium salt and an oxidant, wherein the oxidant is selected from PCC or BPCC, a substrate compound of formula II, diacetone-D-mannitol, is catalytically oxidized in a halogenated alkane solvent to convert it into a product compound of formula I, R-(+)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde;

[0007]

[0008] By using the catalytic amount of the quaternary ammonium salt and PCC or BPCC as an oxidant, and carrying out the reaction in an anhydrous halogenated alkane solvent, the reaction can be carried out under anhydrous solid-liquid heterogeneous conditions, so that PCC or BPCC as an oxidant has high selectivity and efficiently oxidizes the alcohol hydroxyl group in the substrate into the corresponding carbonyl group to form the corresponding target product R-(+)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde, with a high product yield and purity, with the yield reaching above 95% and the purity reaching above 99.5%. At the same time, the catalytic amount of the quaternary ammonium salt and PCC or BPCC as an oxidant can promote the reaction to proceed under relatively mild temperature conditions, eliminating the need for high temperature reaction, making the operation process easier to control, and effectively ensuring the high selectivity of the reaction and reducing the generation of impurities, thereby improving the purity and quality of the product, making it more suitable for industrial mass production. In addition, the use of PCC or BPCC as an oxidant is also easier to produce and operate safely. After the reaction is completed, it is only necessary to simply separate the solid quaternary ammonium salt and the oxidant, which greatly reduces the post-processing process and the generation of a large amount of wastewater. It has the advantage of being environmentally friendly. Compared with the expensive price of sodium periodate, it can better reduce production costs.

[0009] In the above-mentioned method for preparing R-(+)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde, the phase transfer catalyst quaternary ammonium salt is preferably selected from one or more of tetrabutylammonium bromide, tetrabutylammonium chloride, tetramethylammonium bromide, tetramethylbutylammonium chloride, a bispirocyclic quaternary ammonium salt, and hexadecyltrimethylammonium bromide. This allows the reaction to proceed more efficiently and improves the reaction activity. In combination with the use of PCC or PBCC as an oxidant, the reaction can achieve high selectivity and thereby achieve a product with high purity and yield.

[0010] In the above-mentioned method for preparing R-(+)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde, the halogenated alkane solvent is preferably selected from one or more of dichloromethane, chloroform, and dichloroethane. These solvents are easily removed and recovered by distillation, simplifying post-processing. The amount of halogenated alkane solvent used can be based on commonly used amounts in the chemical field, preferably within a range of 10 to 15 times the weight of the raw material substrate, diacetone-D-mannitol, compound of Formula II.

[0011] In the above-mentioned method for preparing R-(+)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde, the temperature of the catalytic oxidation reaction is preferably 20° C. to 30° C. Since a catalytic amount of a quaternary ammonium salt is used in conjunction with PCC or BPCC as an oxidant and the reaction is carried out in a halogenated alkane solvent, the reaction can have better reactivity and can be carried out at a relatively mild temperature. This temperature range can also better reduce the defect of byproducts produced due to excessively high temperatures during the reaction process, effectively reduce the generation of impurities, and ensure the purity and quality of the product.

[0012] In the above-mentioned method for preparing R-(+)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde, the amount of the quaternary ammonium salt of the phase transfer catalyst added is preferably 1.0% to 3.0% of the amount of the compound of Formula II, diacetone-D-mannitol. This allows for more efficient solid-liquid reaction in an anhydrous solvent, thereby improving the reaction conversion rate and conversion ratio.

[0013] In the above-mentioned method for preparing R-(+)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde, preferably, the molar ratio of the compound of Formula II, diacetone-D-mannitol, to the oxidant is 1:1.0-1.3, thereby ensuring catalytic oxidation while reducing the waste of raw materials.

[0014] In the above-mentioned method for preparing R-(+)-2,2-dimethyl-1,3-dioxolane-4-carboxaldehyde, preferably, after the catalytic oxidation reaction is completed, a post-treatment is further included. The post-treatment specifically comprises filtering the reaction solution, recovering the solid matter in the reaction solution, and distilling the collected filtrate to remove the solvent to obtain an oily compound of Formula I, R-(+)-2,2-dimethyl-1,3-dioxolane-4-carboxaldehyde. The recovered solid matter mainly comprises the oxidant PCC or BPCC and the quaternary ammonium salt component, which can be recycled and reused, more effectively reducing production costs and environmental pollution. In addition, the reaction system of the present invention eliminates the need for water washing and does not generate a large amount of wastewater, which is more conducive to reducing the impact on environmental pollution. The halogenated alkane solvent recovered by distillation can also be reused.

[0015] The preparation method of R-(+)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde of the present invention can be represented by the following chemical reaction equation:

[0016]

[0017] In summary, compared with the prior art, the present invention has the following advantages:

[0018] 1. The present invention adopts the above-mentioned catalytic amount of quaternary ammonium salt and PCC or BPCC as an oxidant to act together, and the reaction is carried out in an anhydrous halogenated alkane solvent, which can enable the reaction to be carried out under anhydrous solid-liquid heterogeneous conditions. PCC or BPCC as an oxidant has high selectivity and efficiently oxidizes the alcohol hydroxyl group to the corresponding carbonyl group to form the corresponding product R-(+)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde, with the effects of high product yield and purity quality, with the yield reaching more than 95% and the purity reaching more than 99.5%.

[0019] 2. The reaction of the present invention is easier to produce and operate safely, and after the reaction is completed, only the solid needs to be simply separated, which greatly reduces the post-processing process and also greatly reduces the generation of a large amount of wastewater, which is environmentally friendly. Compared with the expensive price of sodium periodate, it can better reduce production costs. DETAILED DESCRIPTION

[0020] The technical solution of the present invention is further specifically described below through specific embodiments, but the present invention is not limited to these embodiments.

[0021] Example 1

[0022] 200 g of dichloromethane was added to a clean reactor, 20 g of diacetone-D-mannitol was added under stirring, the temperature was controlled at 20° C. to 25° C., and stirring was performed to fully dissolve the mixture. Then, 0.2 g of tetrabutylammonium bromide and 17.9 g of oxidant PCC were added, and the temperature was controlled at 20° C. to 25° C. to keep the reaction for 3 hours. After the reaction was completed, the reaction solution was filtered to recover the solid matter in the reaction solution. The collected filtrate was subjected to reduced pressure distillation to recover the solvent to obtain 19.5 g of R-(+)-2,2-dimethyl-1,3-dioxolane-4-carboxaldehyde as an oily product. The product yield was 98.4% and the purity was 99.7%.

[0023] Example 2

[0024] 200 g of dichloromethane was added to a clean reactor, 20 g of diacetone-D-mannitol was added under stirring, and the temperature was controlled at 20° C. to 25° C. to stir until fully dissolved. Then, 0.2 g of tetrabutylammonium bromide and 24.4 g of oxidant BPCC were added, and the temperature was controlled at 20° C. to 25° C. to keep the reaction for 3 hours. After the reaction was completed, the reaction solution was filtered to recover the solid matter in the reaction solution. The collected filtrate was subjected to reduced pressure distillation to recover the solvent to obtain 19.4 g of R-(+)-2,2-dimethyl-1,3-dioxolane-4-carboxaldehyde as an oily product, with a product yield of 98.0% and a purity of 99.8%.

[0025] Example 3

[0026] 200 g of dichloromethane was added to a clean reactor, 20 g of diacetone-D-mannitol was added under stirring, the temperature was controlled at 20° C. to 25° C., and stirring was performed to fully dissolve the mixture. Then, 0.2 g of tetrabutylammonium chloride and 19.6 g of an oxidant PCC were added, and the temperature was controlled at 20° C. to 25° C. for 3 hours. After the reaction was completed, the reaction solution was filtered to recover the solid matter in the reaction solution. The collected filtrate was subjected to reduced pressure distillation to recover the solvent to obtain 19.2 g of R-(+)-2,2-dimethyl-1,3-dioxolane-4-carboxaldehyde as an oil, with a product yield of 97.0% and a purity of 99.5%.

[0027] Example 4

[0028] 200 g of dichloromethane was added to a clean reactor, and 20 g (0.08 mol) of diacetone-D-mannitol was added under stirring. The temperature was controlled at 20° C. to 22° C. and stirred to fully dissolve. Then, 0.2 g of tetrabutylammonium chloride and 26.6 g of oxidant BPCC were added. The temperature was controlled at 20° C. to 22° C. and the reaction was kept warm for 4 hours. After the reaction was completed, the reaction solution was filtered to recover the solid matter in the reaction solution. The collected filtrate was subjected to reduced pressure distillation to recover the solvent to obtain 19.0 g of R-(+)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde as an oil, with a product yield of 96.0% and a purity of 99.6%.

[0029] Example 5

[0030] 300 g of chloroform was added to a clean reactor, and 20 g of diacetone-D-mannitol was added under stirring. The temperature was controlled at 28° C. to 30° C. and stirred to fully dissolve. Then, 0.6 g of tetramethylammonium bromide and 30.4 g of oxidant BPCC were added. The temperature was controlled at 28° C. to 30° C. and the reaction was kept warm for 3 hours. After the reaction was completed, the reaction solution was filtered to recover the solid matter in the reaction solution. The collected filtrate was subjected to reduced pressure distillation to recover the solvent to obtain 19.2 g of R-(+)-2,2-dimethyl-1,3-dioxolane-4-carboxaldehyde as an oil, with a product yield of 97% and a purity of 99.7%.

[0031] Example 6

[0032] 250 g of dichloromethane was added to a clean reactor, and 20 g of diacetone-D-mannitol was added under stirring. The temperature was controlled at 25° C. to 28° C. and stirred to fully dissolve. Then, 0.4 g of tetrabutylammonium bromide and 20.7 g of the oxidant PCC were added. The temperature was controlled at 25° C. to 38° C. and the reaction was kept warm for 3.5 hours. After the reaction was completed, the reaction solution was filtered to recover the solid matter in the reaction solution. The collected filtrate was subjected to reduced pressure distillation to recover the solvent to obtain 19.1 g of R-(+)-2,2-dimethyl-1,3-dioxolane-4-carboxaldehyde as an oil, with a product yield of 96.5% and a purity of 99.5%.

[0033] Example 7

[0034] 200 g of dichloromethane was added to a clean reactor, 20 g of diacetone-D-mannitol was added under stirring, the temperature was controlled at 25 ° C. and stirred to fully dissolve, then 0.3 g of a dispirocyclic quaternary ammonium salt and 25.7 g of an oxidant BPCC were added, and the temperature was controlled at 25 ° C. and kept warm for 3 hours. After the reaction was completed, suction filtration was performed to recover the solid matter in the reaction solution, and the collected filtrate was subjected to reduced pressure distillation to recover the solvent to obtain an oily product R-(+)-2,2-dimethyl-1,3-dioxolane-4-carboxaldehyde R-(+)-2,2-dimethyl-1,3-dioxolane-4-carboxaldehyde 19.3 g, the product yield was 97.5%, and the purity content was 99.6%.

[0035] The specific embodiments described herein are merely illustrative of the spirit of the present invention. Persons skilled in the art may make various modifications, additions, or substitutions to the described embodiments without departing from the spirit of the present invention or exceeding the scope of the appended claims.

[0036] Although the present invention has been described in detail and certain specific embodiments have been cited, it will be apparent to those skilled in the art that various changes and modifications can be made without departing from the spirit and scope of the invention.

Claims

1. A method for preparing R-(+)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde, characterized in that: The method comprises the following steps: Under the action of a catalytic amount of a phase transfer catalyst quaternary ammonium salt and an oxidant, wherein the oxidant is selected from PCC or BPCC, a substrate compound of formula II, diacetone-D-mannitol, is catalytically oxidized in a halogenated alkane solvent to convert it into a product compound of formula I, R-(+)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde; 2. The method for preparing R-(+)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde according to claim 1, characterized in that: The phase transfer catalyst quaternary ammonium salt is selected from one or more of tetrabutylammonium bromide, tetrabutylammonium chloride, tetramethylammonium bromide, tetramethylammonium chloride and hexadecyltrimethylammonium bromide.

3. The method for preparing R-(+)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde according to claim 1, characterized in that: The halogenated alkane solvent is selected from one or more of dichloromethane, chloroform and dichloroethane.

4. The method for preparing R-(+)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde according to claim 3, characterized in that: The temperature of the catalytic oxidation reaction is 20°C to 30°C.

5. The method for preparing R-(+)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde according to any one of claims 1 to 4, characterized in that: The added amount of the phase transfer catalyst quaternary ammonium salt is 1.0% to 3.0% of the added amount of the compound of formula II, diacetone-D-mannitol.

6. The method for preparing R-(+)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde according to any one of claims 1 to 4, characterized in that: The molar ratio of the compound of formula II, diacetone-D-mannitol, to the oxidant is 1:1.0-1.

3.

7. The method for preparing R-(+)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde according to any one of claims 1 to 4, characterized in that: After the catalytic oxidation reaction is completed, post-processing is further included. The post-processing specifically includes: filtering the reaction liquid, recovering the solid matter in the reaction liquid, and distilling the collected filtrate to remove the solvent to obtain an oily compound of formula I, R-(+)-2,2-dimethyl-1,3-dioxolane-4-carboxaldehyde.

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