Preparation method of 4, 4-dimethyl-3, 5, 8-trioxabicyclo [5.1. 0] octane

Abstract

The invention discloses a preparation method of 4, 4-dimethyl-3, 5, 8-trioxabicyclo [5.1. 0] octane, which comprises the following steps: carrying out cyclization reaction on 1, 4-butylene glycol and 2, 2-dimethoxypropane under the catalysis of sulfonic acid type cation exchange resin, and distilling after the reaction to obtain a gadobutrol intermediate; adding a sodium peroxide solution into the toluene solution of the gadobutrol intermediate to carry out epoxidation reaction, after the reaction is finished, standing and layering the reaction solution, and collecting a toluene layer; and washing the toluene layer with a sodium hydroxide solution, then washing with water, and distilling to obtain the high-purity 4, 4-dimethyl-3, 5, 8-trioxabicyclo [5.1. 0] octane. According to the method, 1, 4-butylene glycol and 2, 2-dimethoxypropane are taken as starting raw materials, firstly, the sulfonic acid type cation exchange resin is taken as a catalyst to carry out cyclization reaction, then, the epoxidation reaction is carried out under the action of the sodium peroxide solution, the whole reaction process is mild, few impurities are generated, the use amount of an organic solvent is small, and the energy consumption is low.

Description

Technical Field

[0001] The invention relates to the technical field of organic reactions, and in particular to a method for preparing 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]octane. Background Art

[0002] 4,4-Dimethyl-3,5,8-trioxabicyclo[5.1.0]octane is an intermediate of the contrast agent gadobutrol, also known as gadobutrol epoxy side chain, and is one of Baolong's superior products along with another intermediate, cyclopentane. Gadobutrol is used in contrast-enhanced magnetic resonance imaging of the brain and spinal cord.

[0003] Patents CN106967083, CN112409370, and CN103896885 disclose methods for preparing epoxy side chains of gadobutrol, which mainly include the following technical features: 1,4-butenediol and 2,2-dimethoxypropane are used as starting materials, and the target product of bicyclooctane is prepared by cyclization in the first step and epoxidation in the second step. Among them, concentrated sulfuric acid is used as a catalyst in the first step of cyclization, and meta-chloroperbenzoic acid is used for epoxidation in the second step. The epoxy side chain intermediate prepared by the above method has a low purity, with a total yield of only 53%. The use of concentrated sulfuric acid increases the discharge of waste acid during subsequent treatment, and the benzoic acid byproduct produced after the oxidation of meta-chloroperbenzoic acid also increases the amount of hazardous waste treatment, which is environmentally unfriendly.

[0004] Patent CN115724849 discloses a method for preparing 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]octane, which includes the following technical features: the first step is to mix 1,4-butenediol and 2,2-dimethoxypropane, add p-toluenesulfonic acid, react at 20°C to 30°C, and after the reaction is completed, add an organic base to quench the reaction; then, silica gel is spread to filter the reaction solution, the filter cake is rinsed with solvent I, and the filtrate is concentrated at 50°C to constant weight to obtain intermediate I; the second step is to place intermediate I in solvent II, adjust the solution pH to 8-9 with sodium hydroxide solution, add hydrogen peroxide at 20°C to 30°C, adjust the reaction solution pH to 9-10 with sodium hydroxide solution after the addition is completed, then add solvent III, concentrate in vacuo at 50°C, and distill to obtain the 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]octane. The above method uses p-toluenesulfonic acid to catalyze the cyclization reaction and uses hydrogen peroxide for epoxidation. The presence of the acidic catalyst in the first step seriously affects the subsequent oxidation process, affecting the product yield and purity. In addition, a large amount of organic solvent is used in the reaction, which not only generates a large amount of organic wastewater, but also increases the product preparation cost. Summary of the invention

[0005] The technical problem to be solved by the present invention is: in view of the shortcomings of the prior art, a method for preparing 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]octane is provided. The method uses 1,4-butenediol and 2,2-dimethoxypropane as starting materials, firstly performs a cyclization reaction using a sulfonic acid type cation exchange resin as a catalyst, and then performs an epoxidation reaction under the action of a sodium peroxide solution. The entire reaction process is mild, less impurities are generated, less organic solvent is used, and energy consumption is low.

[0006] In order to solve the above technical problems, the technical solution of the present invention is:

[0007] A method for preparing 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]octane comprises the following steps:

[0008] 1,4-Butenediol and 2,2-dimethoxypropane undergo cyclization reaction under the catalysis of sulfonic acid type cation exchange resin, and distillation is performed after the reaction to obtain gadobutrol intermediate (CAS No. 1003-83-4);

[0009] Adding sodium peroxide solution to the toluene solution of the gadobutrol intermediate to carry out epoxidation reaction, after the reaction is completed, the reaction solution is allowed to stand and separate into layers, and the toluene layer is collected;

[0010] The toluene layer was washed with sodium hydroxide solution, then washed with water and distilled to obtain high-purity 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]octane.

[0011] Preferably, the molar ratio of 1,4-butenediol to 2,2-dimethoxypropane is 1:(1-8), and further preferably, 1:(1-3).

[0012] Preferably, the added amount of the sulfonic acid type cation exchange resin is 0.1-20 wt % of the mass of 1,4-butenediol, and further preferably, 10-20 wt %.

[0013] Preferably, the temperature of the cyclization reaction is 50-70°C and the time is 3-12h.

[0014] Preferably, after the cyclization reaction is completed, the catalyst is first filtered out, and then the filtrate is distilled at atmospheric pressure to remove 2,2-dimethoxypropane, and the intermediate is removed at reduced pressure, and the distillation temperature is 80-90°C.

[0015] Preferably, the sodium peroxide solution is prepared by reacting hydrogen peroxide and sodium hydroxide solution.

[0016] Preferably, the concentration of the hydrogen peroxide solution is 20-30wt%, and the concentration of the sodium hydroxide solution is 3-5wt%.

[0017] Preferably, when preparing the sodium peroxide solution, the molar ratio of hydrogen peroxide to sodium hydroxide is controlled to be 1:(0.03-0.1).

[0018] Preferably, in the epoxidation reaction, when the sodium peroxide solution is added, the molar ratio of the gadobutrol intermediate to hydrogen peroxide is controlled to be 1:(1.0-3.0).

[0019] Preferably, the temperature of the epoxidation reaction is 20-50° C., and sampling and analysis are performed during the reaction. When the mass ratio of the gadobutrol intermediate to the target product in the reaction system is less than 2%, the reaction is terminated.

[0020] Preferably, during the epoxidation reaction, the mass of toluene is 3-5 times the mass of the gadobutrol intermediate.

[0021] Due to the adoption of the above technical solution, the beneficial effects of the present invention are:

[0022] 1. The present invention uses 1,4-butenediol and an excess of 2,2-dimethoxypropane as starting materials and a sulfonic acid type cation exchange resin as a catalyst to carry out a cyclization reaction. The catalyst is easy to separate and no neutralization and post-filtration are required, which simplifies the process steps and reduces the use of neutralizers. Moreover, 2,2-dimethoxypropane is both a raw material and a solvent, which avoids the use of additional solvents and reduces energy consumption.

[0023] 2. In the cyclization reaction, sulfonic acid type cation exchange resin is used to replace the strong acid and organic acid in the prior art, which reduces the discharge of waste acid on the one hand and avoids the presence of acid catalyst affecting the subsequent epoxidation reaction on the other hand.

[0024] 3. In the epoxidation reaction, sodium peroxide solution is used instead of hydrogen peroxide, and toluene is used instead of commonly used ethylene dichloride and dichloromethane, so that the epoxidation process is smoother and easier to control, with fewer side reactions and impurities, simple post-processing, and high product purity and yield. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on the provided drawings without paying creative work.

[0026] Figure 1 is a chromatogram of the gadobutrol intermediate concentrated solution in Example 1;

[0027] Figure 2 It is the chromatogram of the target product concentrate in Example 1. DETAILED DESCRIPTION

[0028] In order to more clearly understand the above-mentioned objectives, features and advantages of the present invention, the scheme of the present invention will be further described below. It should be noted that the embodiments of the present invention and the features in the embodiments can be combined with each other without conflict.

[0029] In the following description, many specific details are set forth to facilitate a full understanding of the present invention, but the present invention may also be implemented in other ways different from those described herein; it is obvious that the embodiments in the specification are only part of the embodiments of the present invention, rather than all of the embodiments.

[0030] In order to better solve the problems pointed out in the background technology, the present invention discloses the following technical solutions:

[0031] A method for preparing 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]octane comprises the following steps:

[0032] (1) 1,4-Butenediol and 2,2-dimethoxypropane undergo a cyclization reaction under the catalysis of a sulfonic acid type cation exchange resin to obtain a gadobutrol intermediate;

[0033] (2) The gadobutrol intermediate is subjected to epoxidation reaction with a sodium peroxide solution to prepare the target product.

[0034] Regarding step (1):

[0035] In the prior art, sulfuric acid and p-toluenesulfonic acid are often used for catalysis, which will affect the subsequent epoxidation process. The present invention uses sulfonic acid type cation exchange resin as a catalyst, which not only has a good catalytic effect, but is also easy to separate, and is convenient for subsequent epoxidation treatment.

[0036] After the reaction is completed, there is no need for neutralization and washing. The catalyst is recovered by filtration, and then the filtrate is used to remove 2,2-dimethoxypropane, and then the intermediate is obtained by reduced pressure distillation. In addition, in the cyclization process, 2,2-dimethoxypropane is both a raw material and a solvent, avoiding the use of organic solvents, which is economical and environmentally friendly.

[0037] In some embodiments of the present invention, the molar ratio of 1,4-butenediol to 2,2-dimethoxypropane is 1:(1-8), and further preferably 1:(1-3); the amount of 2,2-dimethoxypropane used in this process is excessive, so that the cyclization reaction is more thorough.

[0038] In some embodiments of the present invention, the added amount of the sulfonic acid type cation exchange resin is 0.1-20 wt % of the mass of 1,4-butenediol, and further preferably 10-20 wt %.

[0039] In some embodiments of the present invention, the temperature of the cyclization reaction is 50-70° C. and the time is 3-10 h.

[0040] In some embodiments of the present invention, after the cyclization reaction is completed, the catalyst is first filtered out, and then the filtrate is distilled at atmospheric pressure to remove 2,2-dimethoxypropane, and then distilled at reduced pressure to obtain an intermediate, and the distillation temperature is 80-90°C.

[0041] Regarding step (2):

[0042] In the epoxidation reaction, directly adding hydrogen peroxide to react will cause a violent reaction, produce certain impurities, and reduce the purity of the product. The present invention uses sodium peroxide solution instead of hydrogen peroxide to carry out the epoxidation reaction, the reaction process is mild, easy to control, less impurities are produced, and post-processing is simple.

[0043] The epoxidation reaction of the present invention adopts toluene as the reaction solvent instead of the commonly used ethylene dichloride and methylene dichloride, so that the epoxidation process is more stable.

[0044] After the epoxidation reaction is completed, the reaction mixture is allowed to stand for separation, the toluene layer is collected, the toluene layer is washed with a sodium hydroxide solution of a certain concentration, the reaction mixture is allowed to stand again, the toluene layer is collected, the toluene layer is washed with water, the reaction mixture is allowed to stand, and the collected toluene layer is subjected to reduced pressure distillation to obtain high-purity 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]octane.

[0045] In some embodiments of the present invention, the sodium peroxide solution is prepared by reacting hydrogen peroxide with sodium hydroxide solution. Specifically, the concentration of the hydrogen peroxide is 20-30wt%, and the concentration of the sodium hydroxide solution is 3-5wt%.

[0046] In some embodiments of the present invention, when preparing the sodium peroxide solution, the molar ratio of hydrogen peroxide to sodium hydroxide is controlled to be 1:(0.03-0.1); and the molar ratio of the gadobutrol intermediate to hydrogen peroxide is controlled to be 1:(1.0-3.0).

[0047] In some embodiments of the present invention, the temperature of the epoxidation reaction is 20-50° C., and sampling and analysis are performed during the reaction. When the mass ratio of the gadobutrol intermediate to the target product in the reaction system is less than 2%, the reaction is terminated.

[0048] In order to further understand the present invention, preferred embodiments of the present invention are described below in conjunction with examples. However, it should be understood that these descriptions are only for further illustrating the features and advantages of the present invention, rather than limiting the claims of the present invention.

[0049] Unless otherwise specified, the raw materials described in the following examples are all commercially available, and the conditions described are all conventional conditions in the art unless otherwise specified.

[0050] Target product yield (%) = (actual yield of 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]octane / theoretical yield of 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]octane) × 100%.

[0051] Example 1

[0052] 1. Add 150g (1.70mol) of 1,4-butenediol, 520g (4.99mol) of 2,2-dimethoxypropane and 18g of sulfonic acid type cation exchange resin into a 1000ml three-necked flask, raise the temperature of the reaction system to 65-70°C under stirring, and reflux for 10h. During the reflux process, the low-boiling methanol produced during the reaction process gradually refluxes and separates; after the reaction is completed, cool to room temperature and filter out the cation exchange resin; evaporate 280g of 2,2-dimethoxypropane in the reaction system at 80-90°C under normal pressure to obtain 192g of concentrated solution, and then evaporate 171g of gadobutrol intermediate in the reaction system under reduced pressure (vacuum degree 80-85KPa, 80-85°C), with a purity of 99.1% and a yield of 78.5%;

[0053] 2. In a 5000ml three-necked flask, slowly drop 60.8g of 0℃ 5wt% NaOH aqueous solution into 172g of 30wt% hydrogen peroxide precooled to 0℃, controlling the solution temperature not to exceed 5℃ during the process, to obtain a sodium peroxide solution;

[0054] 3. Add 150g (1.17mol) of the intermediate obtained in step 1 into a 2000ml three-necked flask, add 500ml of toluene, and stir the solution until it is clear; add the sodium peroxide solution in step 2 to the above system, and control the temperature below 50°C; after the addition is completed, continue stirring and reacting at 40°C for 4h; during the reaction, take the toluene layer for detection, and when the mass ratio of the intermediate to the target product is less than 2%, the reaction is completed;

[0055] 4. After the reaction, the reaction solution was allowed to stand, the toluene layer was collected, 20 ml of a 5 wt% NaOH solution was added to the toluene layer for washing, the layer was allowed to stand for stratification, and the toluene layer was collected again; water was added to the toluene layer for washing, the layer was allowed to stand again, the organic layer was collected, and the organic layer was concentrated to obtain 165 g of a concentrated solution; the concentrated solution was subjected to reduced pressure distillation (0.095 MPa, 80-90° C.) to obtain 151.72 g of the target product 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]octane with a purity of 99.91% and a yield of 90%.

[0056] Example 2

[0057] 1. Add 150g (1.70mol) of 1,4-butenediol, 520g of 2,2-dimethoxypropane and 25g of sulfonic acid type cation exchange resin into a 1000ml three-necked flask, raise the temperature of the reaction system to 65-70°C under stirring, and reflux for 10h. During the reflux process, the low-boiling methanol produced during the reaction process gradually refluxes and separates. After the reaction is completed, cool to room temperature and filter out the cation exchange resin; evaporate 292g of 2,2-dimethoxypropane in the reaction system at 80-90°C under normal pressure to obtain 198g of concentrated solution, and then evaporate 166g of gadobutrol intermediate in the reaction system under reduced pressure (vacuum degree 80-85KPa, 80-85°C), with a purity of 98.3% and a yield of 76.2%;

[0058] 2. In a 5000ml three-necked flask, slowly drop 36.5g of 0℃ 5wt% NaOH aqueous solution into 172g of 30wt% hydrogen peroxide precooled to 0℃, controlling the solution temperature not to exceed 5℃ during the process, to obtain a sodium peroxide solution;

[0059] 3. Add 150g of the gadobutrol intermediate obtained in step 1 to a 2000ml three-necked flask, add 500ml of toluene, and stir the solution until it becomes clear; add the sodium peroxide solution in step 2 to the above system, and control the temperature to be below 50°C; after the addition is completed, continue stirring and reacting at 40°C for 4h; during the reaction, take the toluene layer for detection, and when the mass ratio of the intermediate to the target product is less than 2%, the reaction is terminated;

[0060] 4. After the reaction, the reaction solution was allowed to stand, the toluene layer was collected, 20 ml of a 5 wt% NaOH solution was added to the toluene layer for washing, the layer was allowed to stand for stratification, and the toluene layer was collected again; water was added to the toluene layer for washing, the layer was allowed to stand again, the organic layer was collected, and the organic layer was concentrated to obtain 148 g of a concentrated solution; the concentrated solution was subjected to reduced pressure distillation (0.095 MPa, 80-90° C.) to obtain 152.06 g of the target product 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]octane with a purity of 99.92% and a yield of 90.2%.

[0061] Example 3

[0062] 1. Add 150g 1,4-butenediol, 520g 2,2-dimethoxypropane and 15g sulfonic acid type cation exchange resin into a 1000ml three-necked flask, raise the temperature of the reaction system to 70°C under stirring, and reflux for 10h. During the reflux process, the low-boiling methanol produced during the reaction is gradually refluxed and separated. After the reaction is completed, cool to room temperature and filter out the cation exchange resin; evaporate 306g 2,2-dimethoxypropane in the reaction system at 80-90°C under normal pressure to obtain 186g concentrated solution, and then evaporate 168g of gadobutrol intermediate in the reaction system under reduced pressure, with a purity of 98.5% and a yield of 77.1%;

[0063] 2. In a 5000ml three-necked flask, slowly drop 85.1g of 0℃ 5wt% NaOH aqueous solution into 172g of 30wt% hydrogen peroxide precooled to 0℃, controlling the solution temperature not to exceed 5℃ during the process, to obtain a sodium peroxide solution;

[0064] 3. Add 150g of the gadobutrol intermediate obtained in step 1 to a 2000ml three-necked flask, add 500ml of toluene, and stir the solution until it becomes clear; add the sodium peroxide solution in step 2 to the above system, and control the temperature to be below 50°C; after the addition is completed, continue stirring and reacting at 40°C for 4h; during the reaction, take the toluene layer for detection, and when the mass ratio of the intermediate to the target product is less than 2%, the reaction is terminated;

[0065] 4. After the reaction, the reaction solution was allowed to stand, the toluene layer was collected, 20 ml of a 5 wt% NaOH solution was added to the toluene layer for washing, the mixture was allowed to stand for stratification, and the toluene layer was collected again; water was added to the toluene layer for washing, the mixture was allowed to stand again, the organic layer was collected, and the organic layer was concentrated to obtain 169 g of a concentrated solution; the concentrated solution was subjected to reduced pressure distillation (0.095 MPa, 80-90° C.) to obtain 153.4 g of the target product 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]octane with a purity of 99.91% and a yield of 91%.

[0066] Example 4

[0067] 1. Add 150g of 1,4-butenediol, 520g of 2,2-dimethoxypropane and 30g of sulfonic acid type cation exchange resin into a 1000ml three-necked flask, raise the temperature of the reaction system to 70°C under stirring, and reflux for 8h. During the reflux process, the low-boiling point methanol produced during the reaction is gradually refluxed and separated. After the reaction is completed, cool to room temperature and filter out the cation exchange resin; evaporate the 2,2-dimethoxypropane in the reaction system at 80-90°C under normal pressure to obtain 201g of concentrated solution, and then evaporate 163g of gadobutrol intermediate in the reaction system under reduced pressure, with a purity of 98.2% and a yield of 74.8%;

[0068] 2. In a 5000ml three-necked flask, slowly drop 109.4g of 0℃ 5wt% NaOH aqueous solution into 172g of 30wt% hydrogen peroxide precooled to 0℃, controlling the solution temperature not to exceed 5℃ during the process, to obtain a sodium peroxide solution;

[0069] 3. Add 150g of the gadobutrol intermediate obtained in step 1 to a 2000ml three-necked flask, add 500ml of toluene, and stir the solution until it becomes clear; add the sodium peroxide solution in step 2 to the above system, and control the temperature to be below 50°C; after the addition is completed, continue stirring and reacting at 40°C for 4h; during the reaction, take the toluene layer for detection, and when the mass ratio of the intermediate to the target product is less than 2%, the reaction is terminated;

[0070] 4. After the reaction, the reaction solution was allowed to stand, the toluene layer was collected, 20 ml of a 5 wt% NaOH solution was added to the toluene layer for washing, the layer was allowed to stand for stratification, and the toluene layer was collected again; water was added to the toluene layer for washing, the layer was allowed to stand again, the organic layer was collected, and the organic layer was concentrated to obtain 165 g of a concentrated solution; the concentrated solution was subjected to reduced pressure distillation (0.095 MPa, 80-90° C.) to obtain 151.9 g of the target product 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]octane with a purity of 99.92% and a yield of 90.12%.

[0071] Comparative Example 1

[0072] Compared with Example 1, the difference is that the addition amount of sulfonic acid cation exchange resin is 30wt% of the mass of 1,4-butene diol, and other conditions are the same as Example 1, and 152.56g of the target product 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]octane is obtained with a purity of 99.92% and a yield of 90.05%.

[0073] Comparative Example 2

[0074] Compared with Example 1, the difference is that during the cyclization reaction, an equal amount of p-toluenesulfonic acid is used instead of the sulfonic acid type cation exchange resin as a catalyst, and other conditions are the same as those in Example 1, and 104 g of the target product 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]octane is obtained with a purity of 98.8% and a yield of 61.7%.

[0075] Comparative Example 3

[0076] Compared with Example 1, the difference is that during the cyclization reaction, an equal amount of sulfuric acid is used instead of the sulfonic acid type cation exchange resin as a catalyst, and the other conditions are the same as those in Example 1, and 89 g of the target product 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]octane is obtained with a purity of 98.5% and a yield of 52.8%.

[0077] Comparative Example 4

[0078] Compared with Example 1, the difference is that during the epoxidation reaction, hydrogen peroxide and sodium hydroxide solution are simultaneously added to the toluene solution of the intermediate, the concentration and amount of hydrogen peroxide and sodium hydroxide solution are the same as those in Example 1, and other conditions are the same as those in Example 1, and 121g of the target product 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]octane is obtained with a purity of 99% and a yield of 71.7%.

[0079] Comparative Example 5

[0080] Compared with Example 1, the difference is that during the epoxidation reaction, sodium hydroxide solution is first added to the toluene solution of the intermediate, and hydrogen peroxide is added after the sodium hydroxide solution is added dropwise. The concentrations and amounts of hydrogen peroxide and sodium hydroxide solution are the same as those in Example 1, and other conditions are the same as those in Example 1. 117 g of the target product 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]octane is obtained with a purity of 99.1% and a yield of 69.4%.

[0081] Comparative Example 6

[0082] Compared with Example 1, the difference is that during the epoxidation reaction, hydrogen peroxide is first added to the toluene solution of the intermediate, and then sodium hydroxide solution is added after the hydrogen peroxide addition is completed. The concentration and amount of hydrogen peroxide and sodium hydroxide solution are the same as those in Example 1, and other conditions are the same as those in Example 1. 118g of the target product 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]octane is obtained with a purity of 99.1% and a yield of 70%.

[0083] In summary, compared with the comparative example, the present invention adopts sulfonic acid type cation exchange resin as a catalyst to catalyze the cyclization reaction, avoiding the use of strong acid and organic acid, and facilitating the subsequent epoxidation reaction; during the epoxidation reaction, the present invention adopts sodium peroxide solution as an oxidizing agent, so that the epoxidation process proceeds smoothly, with less impurities, and the obtained target product has high purity and high yield.

[0084] Specific examples are used herein to illustrate the principles and implementation methods of the present invention. The description of the above embodiments is only used to help understand the method of the present invention and its core ideas, including the best mode, and also enable any technician in the field to practice the present invention, including making and using any device or system, and implementing any combined method. It should be pointed out that for ordinary technicians in this technical field, without departing from the principle of the present invention, the present invention can also be improved and modified, and these improvements and modifications also fall within the scope of protection of the claims of the present invention. The scope of patent protection of the present invention is defined by the claims and may include other embodiments that can be thought of by those skilled in the art. If these other embodiments have structural elements similar to the literal expression of the claims, or if they include equivalent structural elements that are not substantially different from the literal expression of the claims, then these other embodiments should also be included in the scope of the claims.

Claims

1. A method for preparing 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]octane, characterized in that: The following steps are involved: 1,4-Butenediol and 2,2-dimethoxypropane undergo cyclization reaction under the catalysis of sulfonic acid type cation exchange resin, and distillation is performed after the reaction to obtain gadobutrol intermediate; Adding sodium peroxide solution to the toluene solution of the gadobutrol intermediate to carry out epoxidation reaction, after the reaction is completed, the reaction solution is allowed to stand and separate into layers, and the toluene layer is collected; The toluene layer was washed with sodium hydroxide solution, then washed with water and distilled to obtain high-purity 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]octane.

2. The method for preparing 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]octane according to claim 1, characterized in that: The molar ratio of 1,4-butenediol to 2,2-dimethoxypropane is 1:(1-8).

3. The method for preparing 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]octane according to claim 1, characterized in that: The addition amount of the sulfonic acid type cation exchange resin is 0.1-20wt% of the mass of 1,4-butenediol.

4. The method for preparing 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]octane according to claim 1, characterized in that: The temperature of the cyclization reaction is 50-70° C. and the time is 3-12 hours.

5. The method for preparing 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]octane according to claim 1, characterized in that: After the cyclization reaction is completed, the catalyst is first filtered out and then the filtrate is distilled under reduced pressure at a distillation temperature of 70-90°C.

6. The method for preparing 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]octane according to claim 1, characterized in that: The sodium peroxide solution is prepared by the reaction of hydrogen peroxide and sodium hydroxide solution.

7. The method for preparing 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]octane according to claim 6, characterized in that: The concentration of the hydrogen peroxide solution is 20-30 wt %, and the concentration of the sodium hydroxide solution is 3-5 wt %.

8. The method for preparing 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]octane according to claim 6, characterized in that: When preparing the sodium peroxide solution, the molar ratio of hydrogen peroxide to sodium hydroxide is controlled to be 1:(0.03-0.1).

9. The method for preparing 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]octane according to claim 1, characterized in that: In the epoxidation reaction, when the sodium peroxide solution is added, the molar ratio of the gadobutrol intermediate to hydrogen peroxide is controlled to be 1:(1.0-3.0).

10. The method for preparing 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]octane according to claim 1, characterized in that: The temperature of the epoxidation reaction is 20-50° C. Sampling and analysis are performed during the reaction. When the mass ratio of the gadobutrol intermediate to the target product in the reaction system is less than 2%, the reaction is terminated.

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