CN112409370B - Preparation method of epoxy side chain intermediate, epoxy side chain intermediate and gadobutrol - Google Patents
Preparation method of epoxy side chain intermediate, epoxy side chain intermediate and gadobutrol Download PDFInfo
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- CN112409370B CN112409370B CN202011455303.4A CN202011455303A CN112409370B CN 112409370 B CN112409370 B CN 112409370B CN 202011455303 A CN202011455303 A CN 202011455303A CN 112409370 B CN112409370 B CN 112409370B
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Abstract
The invention is applicable to the technical field of synthesis of medical intermediates, and provides a preparation method of an epoxy side chain intermediate, the epoxy side chain intermediate and gadobutrol, wherein the preparation method of the epoxy side chain intermediate comprises the following steps: the method comprises the steps of taking 2-butene-1, 4-diol and 2, 2-dimethoxypropane as raw materials, introducing resin for catalytic cyclization reaction, and introducing hydrogen peroxide for epoxidation reaction after the reaction is finished to obtain an epoxy side chain intermediate. Compared with the prior art, the method has the advantages that the 10 kg-level large-scale production preparation is realized, on one hand, the recyclable cation exchange resin is adopted as the catalyst in the first-step cyclization reaction, the catalytic activity is good, the material economy is high, the extra hazardous waste discharge caused by the organic acid catalyst is reduced, and the production cost is further reduced; on the other hand, the total yield and the product purity are high, the total yield of 10 kg-scale amplification preparation reaches 88 percent, the product purity is 99.83 percent, and the product quality and the yield are superior to those reported in the prior art.
Description
Technical Field
The invention belongs to the technical field of synthesis of medical intermediates, and particularly relates to a preparation method of an epoxy side chain intermediate, the epoxy side chain intermediate and gadobutrol.
Background
Gadobutrol injection is a contrast medium for contrast-enhanced magnetic resonance imaging, can increase the sensitivity of Magnetic Resonance Imaging (MRI) after intravenous injection, and is often used for detecting tumors, inflammation and demyelinating diseases of the central nervous system. The ginbuconazole serving as a novel strong magnetic resonance contrast agent has the advantages of high concentration, high relaxation rate and the like, and has low risk of generating renal systemic fibrosis which is unique in untoward effect of the ginbuconazole-containing contrast agent. The epoxy side chain is an important intermediate in the preparation method of the ginnol, the chemical name of the epoxy side chain is 4, 4-dimethyl-3, 5, 8-trioxabicyclo [5,1,0] octane, and the structure is shown as the formula (I):
the quality of the epoxy side chain obviously influences the quality of the ginnol serving as a final product, and the ginnol serving as a diagnostic agent, particularly an MRI diagnostic agent, has higher requirements on the purity of the raw material medicine of the ginnol. Therefore, the preparation method for developing the epoxy side chain intermediate with good economy, high yield and high purity has better application prospect and practical significance.
The existing synthesis method of the epoxy side chain intermediate takes 2-butene-1, 4-diol, 2-dimethoxypropane and the like as raw materials, and the epoxy side chain intermediate is prepared by a first-step cyclization and a second-step epoxidation. The synthetic route is as follows:
among them, there is a method for preparing an epoxy side chain intermediate by using concentrated sulfuric acid for catalytic cyclization and m-chloroperoxybenzoic acid epoxidation in the prior art. The epoxy side chain intermediate prepared by the method has low purity, the total yield is only 53%, the use of concentrated sulfuric acid increases the discharge of waste acid in the post-treatment stage, and the benzoic acid byproduct generated after the oxidation of m-chloroperoxybenzoic acid also increases the treatment capacity of hazardous waste, so the method is poor in environmental friendliness. In the prior art, p-toluenesulfonic acid catalytic cyclization and hydrogen peroxide epoxidation are adopted to prepare an epoxy side chain intermediate, so that high yield and purity are obtained, but p-toluenesulfonic acid which is difficult to recycle is still adopted as a catalyst in the first step of catalytic cyclization, so that the material economy is low, and the amount of hazardous waste treatment is increased.
In conclusion, the existing synthesis method of the epoxy side chain intermediate has the problems of low purity and yield, or low material economy and increased hazardous waste treatment capacity caused by the fact that a catalytic reagent cannot be recycled.
Disclosure of Invention
The embodiment of the invention aims to provide a preparation method of an epoxy side chain intermediate, and aims to solve the problems of low purity and yield, low material economy and increased hazardous waste treatment capacity caused by the fact that a catalytic reagent cannot be recycled in the conventional synthesis method of the epoxy side chain intermediate.
The embodiment of the invention is realized in such a way that the preparation method of the epoxy side chain intermediate comprises the following steps:
the method comprises the steps of taking 2-butene-1, 4-diol and 2, 2-dimethoxypropane as raw materials, introducing resin for catalytic cyclization reaction, and introducing hydrogen peroxide for epoxidation reaction after the reaction is finished to obtain an epoxy side chain intermediate.
Another object of an embodiment of the present invention is an epoxy side chain intermediate prepared by the method of preparing the epoxy side chain intermediate.
Another object of an embodiment of the invention is gadobutrol obtained from the further conversion of said epoxy side chain intermediate.
According to the preparation method of the epoxy side chain intermediate provided by the embodiment of the invention, 2-butene-1, 4-diol and 2, 2-dimethoxypropane are taken as raw materials, resin is introduced for catalytic cyclization reaction, and after the reaction is finished, hydrogen peroxide is introduced for epoxidation reaction to prepare the epoxy side chain intermediate. Compared with the prior art, the method has the advantages that the 10 kg-level large-scale production preparation is realized, on one hand, the recyclable cation exchange resin is adopted as the catalyst in the first-step cyclization reaction, the catalytic activity is good, the material economy is high, the extra hazardous waste discharge caused by the organic acid catalyst is reduced, and the production cost is further reduced; on the other hand, the total yield and the product purity are high, the total yield of 10 kg-scale amplification preparation reaches 88 percent, the product purity is 99.83 percent, and the product quality and the yield are superior to those reported in the prior art.
Drawings
FIG. 1 is a GC spectrum of a reaction solution of intermediate 1 prepared in example 1 of the present invention;
FIG. 2 is a GC spectrum of the reaction solution of intermediate 1 prepared in comparative example 1 of the present invention;
FIG. 3 is a GC spectrum of the reaction solution of intermediate 1 prepared in comparative example 2 of the present invention;
FIG. 4 is a GC spectrum of the reaction solution of intermediate 1 prepared in comparative example 3 of the present invention;
FIG. 5 is a GC spectrum of the reaction solution of intermediate 1 prepared in comparative example 4 of the present invention;
FIG. 6 is a GC spectrum of the reaction solution of intermediate 1 prepared in comparative example 5 of the present invention;
FIG. 7 is a GC spectrum of the reaction solution of intermediate 1 prepared in comparative example 6 of the present invention;
FIG. 8 is a GC spectrum of intermediate 1 prepared in example 2 of the present invention;
FIG. 9 is a GC spectrum of the product epoxy side chain intermediate prepared in example 2 of the present invention;
FIG. 10 is a GC spectrum of intermediate 1 prepared in example 3 of the present invention;
FIG. 11 is a GC spectrum of the product epoxy side chain intermediate prepared in example 3 of the present invention.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is described in further detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
The embodiment of the invention provides a preparation method of an epoxy side chain intermediate, aiming at solving the problems of low purity and yield, or low material economy and increased hazardous waste treatment capacity caused by the fact that a catalytic reagent cannot be recycled in the existing synthesis method of the epoxy side chain intermediate, wherein 2-butylene-1, 4-diol and 2, 2-dimethoxypropane are taken as raw materials, resin is introduced for catalytic cyclization reaction, and after the reaction is finished, hydrogen peroxide is introduced for epoxidation reaction to prepare the epoxy side chain intermediate. Compared with the prior art, the method has the advantages that the 10 kg-level large-scale production preparation is realized, on one hand, the recyclable cation exchange resin is adopted as the catalyst in the first-step cyclization reaction, the catalytic activity is good, the material economy is high, the extra hazardous waste discharge caused by the organic acid catalyst is reduced, and the production cost is further reduced; on the other hand, the total yield and the product purity are high, the total yield of 10 kg-scale amplification preparation reaches 88 percent, the product purity is 99.83 percent, and the product quality and the yield are superior to those reported in the prior art.
In the embodiment of the invention, 2-butene-1, 4-diol and 2, 2-dimethoxypropane are used as raw materials, and an epoxy side chain intermediate is prepared through the first step of resin catalytic cyclization and the second step of hydrogen peroxide epoxidation. The synthetic route is as follows:
wherein, the materials involved in the process route are as follows:
2-butene-1, 4-diol, starting material 1 (II):
2, 2-dimethoxypropane as starting material 2 (iii):
intermediate 1 (iv):
epoxy side chain (i):
in the embodiment of the present invention, the preparation method of the epoxy side chain intermediate specifically includes the following steps:
in the step S101, 2-butene-1, 4-diol, 2-dimethoxypropane and resin are added into a reaction container, the temperature is increased to 70-85 ℃ for reaction, and after the reaction is finished, the intermediate 1 is obtained through cooling and distillation treatment.
In an embodiment of the present invention, the resin is a sulfonic acid type cation exchange resin.
In the embodiment of the invention, the molar weight ratio of the 2-butene-1, 4-diol to the 2, 2-dimethoxypropane is 1: 1.3-1.6; the weight ratio of the 2-butene-1, 4-diol to the resin is 1: 0.10-0.16.
In a preferred embodiment of the invention, the molar weight ratio of 2-butene-1, 4-diol to 2, 2-dimethoxypropane is preferably 1: 1.4; the weight ratio of 2-butene-1, 4-diol to resin is preferably 1: 0.14.
In a preferred embodiment of the present invention, the step 101 includes:
in step S201, 2-butene-1, 4-diol, 2-dimethoxypropane and resin are added into a reaction vessel, the temperature is raised to 75-80 ℃ for reaction, a byproduct methanol is evaporated while the reaction is carried out, and the reaction lasts for 3 hours.
In step S202, after the reaction is finished, the temperature of the reaction liquid is cooled to 25-30 ℃, vacuum distillation is started under the condition of maintaining 0.090-0.093MPa, and the target fraction at 73-82 ℃ is collected to obtain an intermediate 1.
In the step S102, a mixed solvent is added into the intermediate 1, the pH value is adjusted to 7-10, the temperature is adjusted to 10-25 ℃, hydrogen peroxide is dropwise added for heat preservation reaction, and after the reaction is finished, liquid separation, washing, drying and distillation treatment are carried out to obtain the epoxy side chain intermediate.
In the embodiment of the invention, the weight ratio of the intermediate 1 to the mixed solvent is 1: 3.1; the weight ratio of the components of the mixed solvent is methanol, acetonitrile and water is 1:1: 1.1.
In the embodiment of the invention, the molar weight ratio of the intermediate 1 to hydrogen peroxide is 1: 1.3-1.7.
In a preferred embodiment of the invention, the molar weight ratio of the intermediate 1 to hydrogen peroxide is 1: 1.5.
In a preferred embodiment of the present invention, the step 102 includes:
in the step S301, a mixed solvent is added into the intermediate 1, after the temperature is reduced to 10-15 ℃, a 5% sodium hydroxide solution is added to adjust the pH of the system to 7.5-9.5, the temperature is kept at 10-15 ℃, hydrogen peroxide with the concentration of 30% is slowly dripped, the temperature of the system is kept at 10-15 ℃ in the process, the sodium hydroxide solution is continuously replenished to keep the pH of the system at 7.5-9.5, and the temperature is kept at 15-20 ℃ for reaction for 4 hours after the hydrogen peroxide is added.
In step S302, after the reaction is finished, adding saturated saline solution and dichloromethane, stirring, separating liquid, washing a water phase by using dichloromethane, combining organic phases, drying by using anhydrous magnesium sulfate, filtering, evaporating the dichloromethane at normal pressure, then opening vacuum of 0.091-0.093MPa, and collecting target fractions at 109-117 ℃ to obtain the epoxy side chain intermediate.
The embodiment of the invention also provides an epoxy side chain intermediate, which is prepared by the preparation method of the epoxy side chain intermediate.
The embodiment of the invention also provides gadobutrol which is obtained by further converting the epoxy side chain intermediate.
In the embodiment of the present invention, the method for the conversion synthesis of gadobutrol from the epoxy side chain intermediate can be realized by referring to the prior art, for example, obtained by alkylating the epoxy side chain intermediate with chloroacetic acid and then reacting the obtained product with gadolinium oxide.
Examples of certain embodiments of the invention are given below, which are not intended to limit the scope of the invention.
In addition, it should be noted that the numerical values given in the following examples are as precise as possible, but those skilled in the art will understand that each numerical value should be understood as a divisor rather than an absolutely exact numerical value due to measurement errors and experimental operational problems that cannot be avoided. For example, due to errors in weighing apparatus, it should be understood that the weight values of the respective raw materials for preparing the epoxy side chain intermediate for the respective examples may have errors of ± 2% or ± 1%.
Example 1: preparation of intermediate 1 (IV) reaction solution
15.0g of 2-butene-1, 4-diol (raw material 1), 23.2g of 2, 2-dimethoxypropane (raw material 2), 2.2g of sulfonic acid type cation exchange resin were added to a reaction flask, the temperature was raised to 80 to 85 ℃ for reaction, while the reaction was continued, by-product methanol was distilled off, the reaction was carried out for 4 hours, and samples were taken for examination.
FIG. 1 is a GC spectrum of the reaction solution of intermediate 1 prepared in example 1 of the present invention: the retention time of intermediate 1 was 7.312min, and the peak area content was 95.47%. The retention time of the raw material 1 was 7.961min, and the peak area content was 1.85%.
Comparative example 1: preparation of intermediate 1 (IV) reaction solution
The catalyst in example 1 was replaced with a carboxylic acid type cation exchange resin, and the other reaction conditions and operation were the same.
FIG. 2 is a GC spectrum of the reaction solution of intermediate 1 prepared in comparative example 1 of the present invention: the retention time of the intermediate 1 was 7.325min, and the peak area content was 78.15%. The retention time of the raw material 1 was 8.045min, and the peak area content was 10.10%.
Comparative example 2: preparation of intermediate 1 (IV) reaction solution
The catalyst in example 1 was replaced with p-toluenesulfonic acid monohydrate in an amount of 3.2g (0.1eq.) and the other reaction conditions and operations were the same.
FIG. 3 is a GC spectrum of the reaction solution of intermediate 1 prepared in comparative example 2 of the present invention: the retention time of the intermediate 1 was 6.946min, and the peak area content was 92.76%. The retention time of the raw material 1 was 7.464min, and the peak area content was 2.22%.
Comparative example 3: preparation of intermediate 1 (IV) reaction solution
The catalyst in example 1 was replaced with formic acid in an amount of 0.78g (0.1eq.) and the other reaction conditions and operation were the same.
FIG. 4 is a GC spectrum of the reaction solution of intermediate 1 prepared in comparative example 3 of the present invention: the retention time of intermediate 1 was 7.317min, and the peak area content was 84.01%. The retention time of the raw material 1 was 8.012min, and the peak area content was 6.54%.
Comparative example 4: preparation of intermediate 1 (IV) reaction solution
No catalyst was added to the reaction mixture in example 1, and the reaction conditions and operation were otherwise the same.
FIG. 5 is a GC spectrum of the reaction solution of intermediate 1 prepared in comparative example 4 of the present invention: the retention time of intermediate 1 was 7.311min, and the peak area content was 73.72%. The retention time of the raw material 1 was 8.069min, and the peak area content was 25.17%.
Comparative example 5: preparation of intermediate 1 (IV) reaction solution
An experiment was conducted under the reaction conditions and operation of example 1 using the resin used in example 1 regenerated with an acid as a catalyst.
FIG. 6 is a GC spectrum of the reaction solution of intermediate 1 prepared in comparative example 5 of the present invention: the retention time of the intermediate 1 was 7.324min, and the peak area content was 94.39%. The retention time of the raw material 1 was 8.014min, and the peak area content was 0.08%.
Comparative example 6: preparation of intermediate 1 (IV) reaction solution
The resin used in comparative example 5 was regenerated with an acid and used as a catalyst, and an experiment was conducted in accordance with the reaction conditions and operation of example 1.
FIG. 7 is a GC spectrum of the reaction solution of intermediate 1 prepared in comparative example 6 of the present invention: the retention time of the intermediate 1 was 7.311min, and the peak area content was 94.36%. The retention time of the raw material 1 was 7.974min, and the peak area content was 0.89%.
The purity of intermediate 1 and SM1 remained in the reaction solutions prepared in example 1 and comparative examples 1 to 6, as shown in table 1.
TABLE 1
| Experimental group | Catalyst and process for preparing same | Reaction solution intermediate 1 purity | SM1 residual |
| Example 1 | Sulfonic acid type cation exchange resin | 95.47％ | 1.85％ |
| Comparative example 1 | Cation exchange resin of carboxylic acid type | 78.15％ | 10.10％ |
| Comparative example 2 | P-toluenesulfonic acid monohydrate | 92.76％ | 2.22％ |
| Comparative example 3 | Formic acid | 84.01％ | 6.54％ |
| Comparative example 4 | Without catalyst | 73.72％ | 25.17％ |
| Comparative example 5 | EXAMPLE 1 resin regeneration | 94.39％ | 0.08％ |
| Comparative example 6 | Comparative example 5 resin regeneration | 94.36％ | 0.89％ |
In summary, as can be seen from the comparison of the data in Table 1, the experimental groups using the sulfonic acid type cation exchange resin and the organic acid as the catalyst were improved in reactivity to different degrees, compared to the experimental groups without the catalyst and the carboxylic acid type cation exchange resin. The best performance is sulfonic acid type cation exchange resin, the purity of the intermediate 1 of the reaction liquid reaches 95.47 percent, and the catalyst is recycled twice without obvious reduction of activity.
Example 2: hectogram scale-up preparation
Step (1), preparation of intermediate 1 (IV)
300g of 2-butene-1, 4-diol (raw material 1), 496g of 2, 2-dimethoxypropane (raw material 2, 42g of sulfonic acid type cation exchange resin) were added into a reaction flask, and the temperature was raised to 75 to 80 ℃ for reaction, while the by-product methanol was distilled off, the reaction was carried out for 3 hours. After the reaction, the temperature of the reaction solution was cooled to 25-30 ℃, vacuum distillation was started under 0.090-0.093MPa, and the target fraction at 73-82 ℃ was collected to obtain intermediate 1, 406g in weight, and 99.40% purity.
FIG. 8 is a GC spectrum of intermediate 1 prepared in example 2 of the present invention: the retention time of the intermediate 1 was 6.957min, and the peak area content was 99.40%. The retention time of the raw material 1 was 7.435min, and the peak area content was 0.16%.
Step (2), preparation of epoxy side chain (I)
Adding 406g of the intermediate 1 and a mixed solvent into a reaction bottle, wherein the weight ratio of the intermediate 1 to the mixed solvent is 1:3.1, the weight ratio of the components of the mixed solvent is methanol to acetonitrile to water is 1:1:1.1, and cooling to 10-15 ℃. Adding a 5% sodium hydroxide solution to adjust the pH of the system to 8.5-9.0, keeping the temperature at 10-15 ℃, slowly adding 540g of 30% hydrogen peroxide dropwise, keeping the temperature of the system at 10-15 ℃ in the process, and continuously supplementing the sodium hydroxide solution to keep the pH of the system at 8.5-9.0. After the hydrogen peroxide is added, the temperature is kept at 15-20 ℃ for 4 hours. After completion of the reaction, 600g of saturated saline and 1000g of dichloromethane were added to the reaction flask, followed by stirring and liquid separation, the aqueous phase was washed with 405g of dichloromethane, and the organic phases were combined, dried over anhydrous magnesium sulfate and filtered. After the dichloromethane is distilled off under normal pressure, the vacuum is opened at 0.091-0.093MPa, and the target fraction with the temperature of 109-.
FIG. 9 is a GC spectrum of the product epoxy side chain intermediate prepared in example 2 of the present invention: the retention time of the intermediate 1 was 10.040min, and the peak area content was 99.79%. The retention time of the maximum single impurity is 4.345min, and the peak area content is 0.08%.
Example 3: preparation of ten kilogram scale amplification
Step (1), preparation of intermediate 1 (IV)
10.52Kg 2-butene-1, 4-diol, i.e., the raw material 1, 17.39Kg2, 2-dimethoxypropane, i.e., the raw material 2, 1.47Kg of sulfonic acid type cation exchange resin, was added to a reaction flask, and the temperature was raised to 75 to 80 ℃ for reaction, while the by-product methanol was distilled off, the reaction was carried out for 3 hours. After the reaction, the temperature of the reaction solution is cooled to 25-30 ℃, the vacuum is maintained at 0.090-0.093MPa, reduced pressure distillation is started, and the target fraction with the temperature of 73-82 ℃ is collected to obtain 14.31Kg of intermediate 1 with the weight of 99.57 percent.
FIG. 10 is a GC spectrum of intermediate 1 prepared in example 3 of the present invention: the retention time of the intermediate 1 was 6.952min, and the peak area content was 99.57%. The retention time of the raw material 1 was 7.434min, and the peak area content was 0.09%.
Step (2), preparation of epoxy side chain (I)
Adding 14.31Kg of the intermediate 1 and a mixed solvent into a reaction bottle, wherein the weight ratio of the intermediate 1 to the mixed solvent is 1:3.1, the weight ratio of the components of the mixed solvent is methanol to acetonitrile to water is 1:1:1.1, and the temperature is reduced to 10-15 ℃. Adding a 5% sodium hydroxide solution to adjust the pH of the system to 8.5-9.0, keeping the temperature at 10-15 ℃, slowly adding 19.10Kg of 30% hydrogen peroxide dropwise, keeping the temperature of the system at 10-15 ℃ in the process, and continuously supplementing the sodium hydroxide solution to keep the pH of the system at 8.5-9.0. After the hydrogen peroxide is added, the temperature is kept at 15-20 ℃ for 4 hours. After the reaction, 21.5Kg of saturated saline and 35.8Kg of dichloromethane were added to the reaction flask, followed by stirring and liquid separation, the aqueous phase was washed with 14.3Kg of dichloromethane, and the organic phases were combined, dried over anhydrous magnesium sulfate, and filtered. After the dichloromethane is distilled off under normal pressure, the vacuum is opened to 0.090-0.093MPa, and the target fraction with the temperature of 110-119 ℃ is collected to obtain the product, namely the epoxy side chain intermediate with the weight of 15.13Kg, the purity of 99.83 percent and the total yield of 88 percent.
FIG. 11 is a GC spectrum of the product epoxy side chain intermediate prepared in example 3 of the present invention: the retention time of the intermediate 1 was 10.047min, and the peak area content was 99.83%. The retention time of the maximum single impurity is 6.385min, and the peak area content is 0.18%.
In the embodiment of the invention, relevant optimization experiment design is carried out on each process parameter of the preparation method of the epoxy side chain intermediate in the early development process, wherein the types of the catalysts in the preparation process of the intermediate 1 (specifically, see example 1 and comparative examples 1 to 4), the molar weight ratio of 2-butene-1, 4-diol to 2, 2-dimethoxypropane, the weight ratio of 2-butene-1, 4-diol to resin and the reaction temperature are specifically seen in the following experimental groups 1 to 14.
Experimental groups 1-5: the molar weight ratios of 2-butene-1, 4-diol to 2, 2-dimethoxypropane were 1:1.2, 1:1.3, 1:1.4, 1:1.5, and 1:1.6, respectively, with the corresponding purity of reaction mixture intermediate 1 and SM1 remaining, as shown in table 2.
The specific experimental process is as follows: adding 2-butene-1, 4-diol which is raw material 1, 2-dimethoxypropane which is raw material 2 and sulfonic acid type cation exchange resin into a reaction bottle, wherein the molar weight ratio of the five experimental raw materials 1 to 2 is 1:1.2, 1:1.3, 1:1.4, 1:1.5 and 1:1.6 respectively, the weight ratio of the raw material 1 to the resin is 1:0.15, heating to 80-85 ℃ for reaction, evaporating by-product methanol while reacting, reacting for 3-4 hours to obtain intermediate 1 reaction liquid, and sampling and inspecting.
TABLE 2
| Experimental group | Molar weight ratio of |
Reaction solution intermediate 1 purity | SM1 residual |
| 1 | 1:1.2 | 90.67％ | 7.33％ |
| 2 | 1:1.3 | 93.52％ | 2.63％ |
| 3 | 1:1.4 | 96.29％ | 2.72％ |
| 4 | 1:1.5 | 96.25％ | 2.55％ |
| 5 | 1:1.6 | 96.18％ | 2.68％ |
From Table 2, it is clear that reactivity is not significantly different when the molar weight ratio is more than 1:1.4, and 1:1.4 is preferable in view of material economy.
Experimental groups 6-10: the purity of the reaction mixture intermediate 1 and the SM1 remained when the weight ratio of 2-butene-1, 4-diol to resin was 1:0.08, 1:0.10, 1:0.12, 1:0.14, and 1:0.16, respectively, as shown in table 3.
The specific experimental process is as follows: adding 2-butene-1, 4-diol which is raw material 1, 2-dimethoxypropane which is raw material 2 and sulfonic acid type cation exchange resin into a reaction bottle, wherein the molar weight ratio of the raw material 1 to the raw material 2 is 1:1.4, the weight ratio of the five experimental raw materials 1 to the resin is 1:0.08, 1:0.10, 1:0.12, 1:0.14 and 1:0.16 respectively, heating to 80-85 ℃ for reaction, evaporating by-product methanol while reacting, reacting for 3 hours to obtain intermediate 1 reaction liquid, and sampling and inspecting.
TABLE 3
| Experimental group | Weight ratio of |
Reaction solution intermediate 1 purity | SM1 residual |
| 6 | 1:0.08 | 89.75％ | 8.23％ |
| 7 | 1:0.10 | 92.82％ | 4.85％ |
| 8 | 1:0.12 | 93.47％ | 2.49％ |
| 9 | 1:0.14 | 96.83％ | 2.14％ |
| 10 | 1:0.16 | 96.82％ | 2.11％ |
Experimental groups 11-14: the purity of intermediate 1 and SM1 remained in the reaction mixture at 70 ℃, 75 ℃, 80 ℃ and 85 ℃ respectively, as shown in Table 4.
The specific experimental process is as follows: adding 2-butene-1, 4-diol which is raw material 1, 2-dimethoxypropane which is raw material 2 and sulfonic acid type cation exchange resin into a reaction bottle, wherein the molar weight ratio of the raw material 1 to the raw material 2 is 1:1.4, the weight ratio of the raw material 1 to the resin is 1:0.14, the four groups of reaction temperatures are respectively 70 ℃, 75 ℃, 80 ℃ and 85 ℃, and by-product methanol is distilled out while reaction is carried out, the reaction is carried out for 3 hours, thus obtaining reaction liquid of an intermediate 1, and sampling and inspecting.
TABLE 4
| Experimental group | Reaction temperature | Reaction solution intermediate 1 purity | SM1 residual |
| 11 | 70℃ | 92.73％ | 5.80％ |
| 12 | 75℃ | 96.34％ | 2.60％ |
| 13 | 80℃ | 96.60％ | 0.27％ |
| 14 | 85℃ | 93.39％ | 2.75％ |
Wherein, the pH value of a reaction system, the molar weight ratio of the intermediate 1 to hydrogen peroxide and the reaction temperature in the preparation process of the epoxy side chain intermediate are optimized, and the reaction temperature is specifically shown in the following experimental groups 15-29.
Experimental groups 15-20: the pH of the reaction system is 7.0-7.5, 7.5-8.0, 8.0-8.5, 8.5-9.0, 9.0-9.5, 9.5-10.0, respectively, corresponding to the purity of the reaction solution of the epoxy side chain product and the residue of the intermediate 1, as shown in Table 5.
The specific experimental process is as follows: adding the intermediate 1 and a mixed solvent into a reaction bottle, wherein the weight ratio of the intermediate 1 to the mixed solvent is 1:3.1, the weight ratio of the components of the mixed solvent is methanol, acetonitrile and water is 1:1:1.1, and cooling to 10-15 ℃. Adding a 5% sodium hydroxide solution to adjust the pH of the system, wherein the pH of six experimental groups is 7.0-7.5, 7.5-8.0, 8.0-8.5, 8.5-9.0, 9.0-9.5 and 9.5-10.0 respectively, keeping the temperature at 10-15 ℃, slowly dripping 30% hydrogen peroxide, keeping the molar weight ratio of the intermediate 1 to the hydrogen peroxide at 1:1.4, keeping the temperature of the system at 10-15 ℃ in the process, and continuously adding the sodium hydroxide solution to keep the pH of the system. After the hydrogen peroxide is added, the temperature is kept at 10-15 ℃ for reaction for 3-4 hours to obtain epoxy side chain product reaction liquid, and the epoxy side chain product reaction liquid is sampled and inspected.
TABLE 5
| Experimental group | pH of the reaction System | Purity of reaction | Intermediate | 1 |
| 15 | 7.0～7.5 | 97.06％ | / | |
| 16 | 7.5～8.0 | 97.13％ | 0.20％ | |
| 17 | 8.0～8.5 | 97.77％ | 0.49％ | |
| 18 | 8.5～9.0 | 98.33％ | 0.50％ | |
| 19 | 9.0～9.5 | 97.62％ | 1.37％ | |
| 20 | 9.5～10.0 | 95.94％ | 3.04％ |
Experimental groups 21-25: the molar weight ratios of intermediate 1 to hydrogen peroxide were 1:1.3, 1:1.4, 1:1.5, 1:1.6, and 1:1.7, respectively, corresponding to the purity of the reaction solution of the epoxy side chain product and the residue of intermediate 1, as shown in table 6.
The specific experimental process is as follows: adding the intermediate 1 and a mixed solvent into a reaction bottle, wherein the weight ratio of the intermediate 1 to the mixed solvent is 1:3.1, the weight ratio of the components of the mixed solvent is methanol, acetonitrile and water is 1:1:1.1, and cooling to 10-15 ℃. Adding a 5% sodium hydroxide solution to adjust the pH of the system to 9.0-9.5, keeping the temperature at 10-15 ℃, slowly adding 30% hydrogen peroxide dropwise, keeping the molar weight ratio of the five experimental intermediates 1 to the hydrogen peroxide to be 1:1.3, 1:1.4, 1:1.5, 1:1.6 and 1:1.7, keeping the temperature of the system at 10-15 ℃ in the process, and continuously adding the sodium hydroxide solution to keep the pH of the system. After the hydrogen peroxide is added, the temperature is kept at 10-15 ℃ for reaction for 3-4 hours to obtain epoxy side chain product reaction liquid, and the epoxy side chain product reaction liquid is sampled and inspected.
TABLE 6
Experimental groups 26-29: the reaction temperature was 10 ℃, 15 ℃, 20 ℃ and 25 ℃ respectively, the purity of the reaction solution of the epoxy side chain product and the residue of the intermediate 1 were as shown in table 7.
The specific experimental process is as follows: adding the intermediate 1 and a mixed solvent into a reaction bottle, wherein the weight ratio of the intermediate 1 to the mixed solvent is 1:3.1, the weight ratio of the components of the mixed solvent is methanol, acetonitrile and water is 1:1:1.1, and cooling to 10-15 ℃. Adding a 5% sodium hydroxide solution to adjust the pH of the system to 8.5-9.0, keeping the temperature at 10-15 ℃, slowly adding 30% hydrogen peroxide dropwise, keeping the molar weight ratio of the intermediate 1 to the hydrogen peroxide at 1:1.5, keeping the temperature of the system at 10-15 ℃ in the process, and continuously adding the sodium hydroxide solution to keep the pH of the system. After the addition of hydrogen peroxide is finished, four groups of experiments are respectively subjected to heat preservation at 10 ℃, 15 ℃, 20 ℃ and 25 ℃ for reaction for 4 hours to obtain reaction liquid of the epoxy side chain product, and a sample is taken for inspection.
TABLE 7
| Experimental group | Reaction temperature | Purity of reaction | Intermediate | 1 |
| 26 | 10℃ | 97.72％ | 1.38％ | |
| 27 | 15℃ | 98.05％ | 1.24％ | |
| 28 | 20℃ | 98.68％ | / | |
| 29 | 25℃ | 97.21％ | / |
In summary, in the preparation method of the epoxy side chain intermediate provided by the embodiment of the present invention, 2-butene-1, 4-diol and 2, 2-dimethoxypropane are used as raw materials, resin is introduced to perform a catalytic cyclization reaction, and after the reaction is finished, hydrogen peroxide is introduced to perform an epoxidation reaction, so as to prepare the epoxy side chain intermediate. Compared with the prior art, the method has the advantages that the 10 kg-level large-scale production preparation is realized, on one hand, the recyclable cation exchange resin is adopted as the catalyst in the first-step cyclization reaction, the catalytic activity is good, the material economy is high, the extra hazardous waste discharge caused by the organic acid catalyst is reduced, and the production cost is further reduced; on the other hand, the total yield and the product purity are high, the total yield of 10 kg-scale amplification preparation reaches 88 percent, the product purity is 99.83 percent, and the product quality and the yield are superior to those reported in the prior art.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the present invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included within the scope of the present invention.
Claims (6)
1. A method for preparing an epoxy side chain intermediate, comprising:
adding 2-butene-1, 4-diol, 2-dimethoxypropane and resin into a reaction container, heating to 70-85 ℃ for reaction, and after the reaction is finished, cooling and distilling to obtain an intermediate 1; the molar weight ratio of the 2-butene-1, 4-diol to the 2, 2-dimethoxypropane is 1: 1.3-1.6; the weight ratio of the 2-butene-1, 4-diol to the resin is 1: 0.10-0.16; the resin is sulfonic acid type cation exchange resin;
adding a mixed solvent into the intermediate 1, adjusting the pH to 7-10 and the temperature to 10-25 ℃, dropwise adding hydrogen peroxide to perform heat preservation reaction, and after the reaction is finished, performing liquid separation, washing, drying and distillation treatment to obtain an epoxy side chain intermediate; the molar weight ratio of the intermediate 1 to hydrogen peroxide is 1: 1.3-1.7.
2. The process for the preparation of an epoxy side chain intermediate according to claim 1, wherein the molar weight ratio of 2-butene-1, 4-diol to 2, 2-dimethoxypropane is 1: 1.4; the weight ratio of the 2-butene-1, 4-diol to the resin was 1: 0.14.
3. The method for preparing the epoxy side chain intermediate according to claim 1, wherein the step of adding 2-butene-1, 4-diol, 2-dimethoxypropane and resin into a reaction vessel, heating to 70-85 ℃ for reaction, cooling after the reaction is finished, and distilling to obtain the intermediate 1 comprises the following steps:
adding 2-butene-1, 4-diol, 2-dimethoxypropane and resin into a reaction vessel, heating to 75-80 ℃ for reaction, evaporating a byproduct methanol while reacting, and reacting for 3 hours;
after the reaction is finished, cooling the temperature of the reaction liquid to 25-30 ℃, maintaining the vacuum of 0.090-0.093MPa, starting reduced pressure distillation, and collecting the target fraction at 73-82 ℃ to obtain an intermediate 1.
4. The preparation method of the epoxy side chain intermediate as claimed in claim 1, wherein the molar weight ratio of the intermediate 1 to hydrogen peroxide is 1: 1.5.
5. The method for producing an epoxy side chain intermediate according to claim 1, wherein the weight ratio of the intermediate 1 to the mixed solvent is 1: 3.1; the weight ratio of the components of the mixed solvent is methanol, acetonitrile and water is 1:1: 1.1.
6. The preparation method of the epoxy side chain intermediate according to claim 1, wherein the step of adding a mixed solvent into the intermediate 1, adjusting the pH to 7-10 and the temperature to 10-25 ℃, dropwise adding hydrogen peroxide to perform a heat preservation reaction, and after the reaction is finished, performing liquid separation, washing, drying and distillation treatment to obtain the epoxy side chain intermediate comprises the following steps:
adding a mixed solvent into the intermediate 1, cooling to 10-15 ℃, adding a 5% concentration sodium hydroxide solution to adjust the pH of the system to 7.5-9.5, keeping the temperature at 10-15 ℃, slowly dropwise adding 30% concentration hydrogen peroxide, keeping the temperature of the system at 10-15 ℃ in the process, continuously adding the sodium hydroxide solution to keep the pH of the system at 7.5-9.5, and keeping the temperature at 15-20 ℃ for reaction for 4 hours after the hydrogen peroxide is added;
after the reaction is finished, adding saturated salt water and dichloromethane, stirring, separating liquid, washing a water phase by using dichloromethane, combining organic phases, drying by using anhydrous magnesium sulfate, filtering, evaporating the dichloromethane at normal pressure, starting vacuum of 0.091-0.093MPa, and collecting target fraction at 109-117 ℃ to obtain the epoxy side chain intermediate.
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