CN106967083B - Preparation process method of gadobutrol epoxy side chain intermediate - Google Patents
Preparation process method of gadobutrol epoxy side chain intermediate Download PDFInfo
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Abstract
The invention discloses a preparation process method of 4, 4-dimethyl-3, 5, 8-trioxabicyclo [5,1,0] octane, namely gadobutrol epoxy side chain intermediate, wherein the preparation process method comprises the steps of adjusting the feeding weight proportion, optimizing the reaction conditions, improving the post-treatment and purification method, and obtaining gadobutrol epoxy side chain intermediate product with low impurity content, and greatly improving the quality of the intermediate product while improving the yield, thereby improving the difficulty of process control in the production process of gadobutrol bulk drug and improving the quality and qualification rate of gadobutrol bulk drug; the preparation process has simple operation method of each step, safe and feasible solvent and process conditions, realizes environment-friendly and green production, and has wide application prospect.
Description
Technical Field
The invention relates to the technical field of synthesis of pharmaceutical intermediates, in particular to a synthesis method of gadobutrol epoxy side chain intermediates.
Background
Magnetic Resonance Imaging (MRI) diagnostic techniques are techniques that reconstruct images using radio frequency radiation in a magnetic field, which are superior to X-rays in visualizing anatomical and soft tissue lesions. However, in the early 80 s, MRI did not show high specificity in observing tissue structure. A magnetic resonance contrast agent is a compound that affects the relaxation times of its surrounding tissues, and thus allows accurate images to be obtained due to the different signal intensities that occur in different tissues.
The central atom of a paramagnetic ion or the outer layer of an ion has unpaired electrons, making it a suitable magnetic resonance contrast agent. The outer layer of gadolinium (Gd) has 7 unpaired electrons and is therefore a powerful paramagnetic ion. The non-complex gadolinium ions are toxic, but the toxic effect of gadolinium can be almost completely eliminated without obvious influence on the paramagnetic effect of gadolinium after the gadolinium ions form a complex with a non-toxic organic chelating agent. Various intravenous chelators of gadolinium have become an integral part of Magnetic Resonance Imaging (MRI) technology.
Gadobutrol injection (Gadavist) is a gadolinium-based nonionic contrast agent, can be injected intravenously and used for nuclear magnetic resonance imaging examination of brain, spinal cord, liver and the like. FDA approved for marketing in 3 months of 2011 for Magnetic Resonance Imaging (MRI) of cns patients, which can provide contrast-enhanced images of the cns to help detect and visualize lesions that disrupt the cellular barrier and abnormal blood supply and circulation in the cns.
The chemical name of the gadobutrol bulk drug is 10- [ (1SR, 2RS) -2, 3-dihydroxy-1- (hydroxymethyl) propyl ] -1, 4, 7, 10-tetraazacyclododecane-1, 4, 7-triacetic acid gadolinium complex, and the structural formula is shown as the following formula:
as an image diagnostic agent, particularly an MRI diagnostic agent, gadobutrol needs higher purity than other common medicinal medicines, so that higher quality standard is provided for gadobutrol, and higher requirements are provided for the synthesis method of gadobutrol in the aspects of improving purity, improving yield and controlling single impurity content so as to meet the requirement of being used as an injection diagnostic agent. In the existing preparation and synthesis methods of gadobutrol, optimization and improvement of the method have been reported in part of researches. However, due to the characteristics of gadobutrol structure, the further improvement of the quality of gadobutrol obtained by using the existing preparation method reaches the bottleneck, and the improvement of the purity of gadobutrol has great limitation.
The epoxy side chain intermediate of gadobutrol is a key intermediate in the preparation method of gadobutrol, the chemical name of the intermediate is 4, 4-dimethyl-3, 5, 8-trioxabicyclo [5,1,0] octane, and the purity and the quality of the epoxy side chain intermediate greatly influence the quality of the final product of gadobutrol. In the existing preparation method, concentrated sulfuric acid is used as a catalyst, green pollution-free promotion mutual benefit cannot be realized in a post-treatment stage, or the preparation method has defects in yield and product purity, or the preparation method has defects in production cost reduction and green industrial production. Therefore, a need exists for developing a preparation process method of the epoxy side chain intermediate of gadobutrol, in particular a production preparation process method which can be used for carrying out workshop amplification and realizing the requirements of environmental protection.
Disclosure of Invention
In order to solve the problems in the prior art, the invention aims to provide a preparation process method of gadobutrol epoxy side chain intermediate, which has the advantages of high yield, high product purity, less impurities, short reaction period, no use of strong acid, simple and convenient operation, stable quality and suitability for industrial scale-up production.
One aspect of the invention provides a preparation process method of gadobutrol epoxy side chain intermediate (formula A),
the preparation process method comprises the following steps:
step 1, carrying out cyclization reaction on a compound A-1 and a compound A-2 in the presence of a catalyst to obtain a compound A-3;
and 2, reacting the compound A-3 in the presence of a pH buffer reagent, alkali, hydrogen peroxide and a mixed solvent to generate the gadobutrol epoxy side chain intermediate compound (formula A).
The preparation process route is as follows:
according to the preparation process method of gadobutrol epoxy side chain intermediate, in step 1, the catalyst is p-toluenesulfonic acid, p-toluenesulfonic acid hydrate; preferably p-toluenesulfonic acid monohydrate.
According to the preparation process method of the gadobutrol epoxy side-linking intermediate, in the step 1, the weight ratio (g: g) of the A-1 to the A-2 is 1: 1.5-1: 1.9, preferably 1: 1.7-1: 1.8, and more preferably 1: 1.77.
According to the preparation process method of the gadobutrol epoxy side-linked intermediate, in the step 1, the adding amount of the catalyst is 0.2-0.3 percent of the weight (g) of A-1, and the preference is 0.22 percent.
According to the preparation process method of the gadobutrol epoxy side-linking intermediate, in the step 1, the reaction temperature is 70-90 ℃, and the reaction time is 2-3 hours; the reaction temperature is preferably 80 ℃.
According to the preparation process method of the gadobutrol epoxy side-linking intermediate, in the step 1, a methanol byproduct is simultaneously distilled out within 2-3 hours of reaction time, and the weight ratio (g: g) of the distilled amount of the methanol to A-1 is 0.71: 1-0.73: 1.
According to the preparation process method of the gadobutrol epoxy side-linking intermediate, in the step 1, the compound A-3 is purified by adopting a distillation mode, and can be atmospheric distillation or reduced pressure distillation.
According to the preparation process method of the gadobutrol epoxy side-linking intermediate, in the step 1, the purity of the compound A-3 is more than 96%.
According to certain preferred embodiments of the present invention, step 1 embodiments are as follows: reacting the compounds A-1 and A-2 at 70-90 ℃ for 2-3 hours in the presence of p-toluenesulfonic acid monohydrate, and simultaneously evaporating a methanol byproduct within 2-3 hours, wherein the weight ratio (g: g) of the distilled amount of methanol to A-1 is 0.71: 1-0.73: 1; removing excessive A-2 from the reaction solution, and then carrying out reduced pressure distillation to obtain a target compound A-3;
wherein the feeding weight ratio (g: g) of A-1 to A-2 is 1:1.77, and the addition amount of the paratoluenesulfonic acid monohydrate is 0.22 percent of the weight (g) of A-1.
According to the preparation process method of the gadobutrol epoxy side-linking intermediate, in the step 2, the pH buffering agent is phosphate, preferably disodium hydrogen phosphate; the alkali is inorganic alkali, preferably sodium hydroxide; the content of hydrogen peroxide is 27 to 30 percent; the mixed solvent is a mixed solvent of methanol, acetonitrile and water.
According to the preparation process method of the gadobutrol epoxy side-linking intermediate, the reaction in the step 2 is divided into three stages: a compound A-3 feeding stage, an oxidation reaction stage and a post-treatment purification stage.
According to the preparation process method of the gadobutrol epoxy side-linking intermediate, the feeding stage of the compound A-3 in the step 2 comprises the operations of feeding the compound A-3, the pH buffer agent and the mixed solvent and heating.
According to the preparation process method of the gadobutrol epoxy side-linking intermediate, in the feeding stage of the compound A-3 in the step 2, the weight ratio (g: g) of the compound A-3 to the pH buffering agent is 120: 1-140: 1, preferably 126: 1-139: 1; the weight ratio (g: g) of methanol, acetonitrile and water in the mixed solvent is 1 (1.0-1.3): (1.1 to 1.3), preferably 1: (1.0-1.2): (1.22-1.3); more preferably 1:1.2:1.26, 1:1.17:1.22 or 1:1.0: 1.3; the weight ratio (g: g) of the compound A-3 to the total amount of the mixed solvent is 1: 2-1: 4; preferably 1:2 to 1:3, more preferably 1:2.7 to 1: 3; and heating and then entering a subsequent oxidation stage.
According to the preparation process method of the gadobutrol epoxy side-linking intermediate, the oxidation reaction stage in the step 2 comprises the feeding of hydrogen peroxide and alkali and the heating operation.
According to the preparation process method of the gadobutrol epoxy side-linking intermediate, in the oxidation reaction stage in the step 2, the weight ratio (g: g) of the feeding amount of hydrogen peroxide to the compound A-3 is 1.1: 1-1.2: 1, preferably 1.16: 1-1.18: 1; the feeding amount of the alkali is 1M aqueous solution, the weight ratio (g: g) of the 1M alkali feeding amount to the compound A-3 is 0.4: 1-0.6: 1, and preferably 0.47: 1-0.52: 1; in the feeding process, the feeding duration of the hydrogen peroxide is 0.5-2 hours, preferably 1-2 hours; the feeding duration of the 1M alkaline water solution is 3-8 hours, preferably 5-6 hours; heating to 60-80 ℃, and keeping the temperature for 6-9 hours, preferably 8-9 hours; and the pH value of the reaction liquid is 7-9.5 in the stages of feeding, heating and heat preservation.
According to the preparation process method of the gadobutrol epoxy side-linking intermediate, the post-treatment purification stage in the step 2 comprises the following operations: adding saturated sodium chloride aqueous solution and dichloromethane for post-treatment; and drying the organic phase, concentrating and removing the solvent to obtain the target compound A.
According to the preparation process method of the gadobutrol epoxy side-linking intermediate, in the post-treatment purification stage in the step 2, the weight ratio (g: g) of the using amount of the saturated sodium chloride aqueous solution to the compound A-3 is 1.5: 1-1.6: 1; the weight ratio of the dichloromethane to the compound A-3 (g: g) is 2.7: 1-3.5: 1.
According to the preparation process method of the gadobutrol epoxy side-linking intermediate, in the post-treatment purification stage in the step 2, the compound A is purified by adopting a reduced pressure distillation mode.
According to the preparation process method of the gadobutrol epoxy side-linking intermediate, in the step 2, the purity of the compound A is more than 99.6%.
According to the preparation process method of the gadobutrol epoxy side-linking intermediate, in the step 2, the purity of the compound A is more than 99.9%.
According to certain preferred embodiments of the present invention, the step 2 embodiment is as follows:
in the first stage, the compound A-3, sodium dihydrogen phosphate and a mixed solvent containing methanol, acetonitrile and water are fed and mixed, and the reaction liquid enters the next stage after being heated; the weight ratio (g: g) of the compound A-3 to the sodium dihydrogen phosphate is 126: 1-139: 1; the weight ratio of methanol, acetonitrile and water in the mixed solvent (g: g) is 1: (1.0-1.2): (1.22-1.3), preferably 1:1.2:1.26, 1:1.17:1.22 or 1:1.0: 1.3; the weight ratio (g: g) of the compound A-3 to the total amount of the mixed solvent is 1: 2.7-1: 3;
feeding hydrogen peroxide and a sodium hydroxide aqueous solution into the reaction liquid obtained in the first stage, and then continuously heating the reaction liquid to 60-80 ℃ and keeping the temperature for 6-9 hours; the weight ratio (g: g) of the feeding amount of the hydrogen peroxide to the compound A-3 is 1.16: 1-1.18: 1; the feeding amount of the sodium hydroxide is 1M aqueous solution, and the weight ratio (g: g) of the 1M sodium hydroxide feeding amount to the compound A-3 is 0.47: 1-0.52: 1; in the feeding process, the feeding duration of the hydrogen peroxide is 1-2 hours; the feeding duration of the sodium hydroxide aqueous solution with the concentration of 1M is 5-6 hours; the pH value of the reaction liquid is 7-9.5 in the stages of feeding, heating and heat preservation;
adding saturated sodium chloride aqueous solution and dichloromethane into the reaction liquid obtained in the second stage for post-treatment; and drying the organic phase, concentrating and removing the solvent to obtain the target compound A. The weight ratio (g: g) of the amount of the saturated sodium chloride aqueous solution to the compound A-3 is 1.5: 1-1.6: 1; the weight ratio of the amount of the dichloromethane to the compound A-3 (g: g) is 2.7: 1-3.5: 1; and purifying the compound A by adopting a reduced pressure distillation mode.
The technical parameter characteristics in the preparation process method can be combined at will.
The preparation process method of gadobutrol epoxy side-linking intermediate is suitable for industrial scale-up production, and the production scale is kilogram or ton or more.
In the above operations, the post-treatment includes, but is not limited to, stirring, liquid or solid transferring, water washing, alkali washing, acid washing, filtering, ultrafiltration, cyclic ultrafiltration, dilution, concentration, drying, freeze-drying, or one or more of stirring, liquid or solid transferring, water washing, alkali washing, acid washing, filtering, ultrafiltration, cyclic ultrafiltration, dilution, concentration, drying, freeze-drying, and the like.
In the field of synthesis of organic compound molecules as pharmaceutical intermediates, the purity of the intermediate compound and the maximum single impurity content thereof greatly affect the quality of the final pharmaceutical product. The chemical synthesis reaction has the characteristics that reaction sites are not single, and the reaction of impurities is carried out simultaneously and is inevitable. Generally, it is very difficult to improve the purity of a pharmaceutical product compound to a higher level on the basis of reaching a certain purity by optimizing a synthesis method and optimizing reaction conditions. On the other hand, in order to reduce the toxic and side effects that may be caused by impurities in pharmaceutical products, pharmaceutical products have extremely high requirements in terms of purity and content, as living individuals to be administered to humans or other animals for the treatment of diseases. Therefore, the method can meet the requirement of industrial scale-up production, improve the purity of the medical product, reduce the maximum single impurity content, improve the production and preparation processes of different medical products on the basis of not reducing the yield, and has no regular cycle or ready experience and inspiration for reference.
Particularly, the purity and the quality of the gadobutrol epoxy side-linking intermediate compound A have great influence on the quality of the gadobutrol as the final product, and the influence of the purity on the purity of the gadobutrol as the final product is further amplified in the subsequent preparation process. Therefore, the compound A is used as a key intermediate of gadobutrol, and has to be subjected to stricter quality control.
Compared with the prior art, the preparation process method of the gadobutrol epoxy side-linking intermediate has the following beneficial effects:
according to the preparation process method of the gadobutrol epoxy side-linking intermediate, in the step 1, the use of the catalyst is optimized and improved, and a strong acid reagent is not used, so that the equipment corrosion prevention grade and the process equipment cost in the production process are reduced, the preparation process method is safe and environment-friendly, and the potential threat grade of life hazard to staff at the production front line is reduced;
in the step 1, the feeding proportion is optimized, the feeding amount of the material A-2 is reduced, and the generation amount of the byproduct methanol is greatly reduced, so that the subsequent evaporation of the methanol is short in use time, and the period of the whole preparation process flow is shortened. Thereby reducing the material cost, the time cost and the process cycle cost in the production of the gadobutrol epoxy side-linking intermediate;
the gadolinium butol epoxy side connecting intermediate compound A prepared by the preparation process of gadolinium butol epoxy side connecting intermediate has few impurities, especially the maximum single impurity content is less than 0.1%, and the purity and the product quality of the intermediate product are greatly improved; the gadobutrol epoxy side-linked intermediate obtained by the preparation process method is used as a key intermediate to produce medical gadobutrol, so that the purity and quality of gadobutrol are improved, and the toxic and side effects of gadobutrol in use are reduced;
the total yield of the gadobutrol epoxy side-linking intermediate compound A prepared by the preparation process method is improved to over 84 percent, the purity is improved to over 99.6 percent, the maximum single impurity content is below 0.1 percent, the intermediate in each step is easy to purify, and the post-treatment is simple, convenient and easy to operate;
the gadobutrol epoxy side-linked intermediate compound A prepared by the preparation process method has good stability, the purity of the gadobutrol epoxy side-linked intermediate compound A is not obviously changed after the gadobutrol epoxy side-linked intermediate compound A is placed under severe conditions, the storage and the transportation are convenient, the introduction of various impurities during the reaction of the gadobutrol key intermediate is greatly reduced, the quality and the purity of the prepared gadobutrol medicine are favorably improved, the medication toxicity of the gadobutrol is reduced, and the medication safety is improved.
In conclusion, the preparation process method disclosed by the invention is used for preparing the gadobutrol epoxy side-linked intermediate without using a strong acid reagent; the material feeding proportion is reduced; the feeding weight proportion and the reaction condition are optimized and adjusted, the post-treatment and purification method is improved, the obtained gadobutrol epoxy side-linked intermediate product has low impurity content, the yield is improved, and the purity and the quality of the intermediate product are greatly improved, so that the difficulty of process control in the production process of gadobutrol bulk drug is improved, and the quality and the qualification rate of the gadobutrol bulk drug are improved; the method has the advantages of simple and easy steps, safe and cheap solvent and process conditions, environmental-friendly and green industrial production realization, and wide application prospect.
Drawings
FIG. 1 is a GC spectrum of compound A-3 in exemplary example 2 according to the present invention;
FIG. 2 is a GC spectrum of Compound A in exemplary example 2 according to the present invention;
the abscissa of the GC plot is time in minutes; the ordinate is the current value in pico amperes.
Detailed Description
All of the features disclosed in this specification, or all of the steps in any method or process so disclosed, may be combined in any combination, except combinations of features and/or steps that are mutually exclusive.
Any feature disclosed in this specification may be replaced by alternative features serving equivalent or similar purposes, unless expressly stated otherwise. That is, unless expressly stated otherwise, each feature is only an example of a generic series of equivalent or similar features.
The preparation process of gadobutrol epoxy side chain intermediate of the present invention will be further detailed in turn.
According to an exemplary embodiment of the invention, the preparation process of the gadobutrol epoxy side chain intermediate comprises the following steps:
heating the compounds A-1 and A-2 to 80 ℃ in the presence of p-toluenesulfonic acid monohydrate, reacting for 2-3 hours to obtain a reaction solution, and simultaneously evaporating a methanol byproduct within 2-3 hours of reaction time, wherein the weight ratio (g: g) of the distilled amount of methanol to A-1 is 0.71: 1-0.73: 1; wherein the feeding weight ratio (g: g) of A-1 to A-2 is 1:1.77, and the addition amount of the paratoluenesulfonic acid monohydrate is 0.22 percent of the weight (g) of A-1;
removing excessive A-2 from the reaction solution, and then carrying out reduced pressure distillation to obtain a target compound A-3;
the compound A-3, sodium dihydrogen phosphate and a mixed solvent containing methanol, acetonitrile and water are fed and mixed, and the temperature of the reaction solution is raised. The weight ratio (g: g) of the compound A-3 to the sodium dihydrogen phosphate is 126: 1-139: 1; the weight ratio of methanol, acetonitrile and water in the mixed solvent (g: g) is 1:1.2:1.26, 1:1.17:1.22 or 1:1.0: 1.3; the weight ratio (g: g) of the compound A-3 to the total amount of the mixed solvent is 1: 2.7-1: 3;
feeding hydrogen peroxide and a sodium hydroxide aqueous solution into the heated reaction solution, and then continuously heating the reaction solution to 60-80 ℃ and keeping the temperature for 6-9 hours; the weight ratio (g: g) of the feeding amount of the hydrogen peroxide to the compound A-3 is 1.16: 1-1.18: 1; the feeding amount of the sodium hydroxide is 1M aqueous solution, and the weight ratio (g: g) of the 1M sodium hydroxide feeding amount to the compound A-3 is 0.47: 1-0.52: 1; in the feeding process, the feeding duration of the hydrogen peroxide is 1-2 hours; the feeding duration of the sodium hydroxide aqueous solution with the concentration of 1M is 5-6 hours; the pH value of the reaction liquid is 7-9.5 in the stages of feeding, heating and heat preservation;
and cooling the reaction liquid obtained in the previous stage, adding a saturated sodium chloride aqueous solution and dichloromethane, separating out an organic phase, drying, filtering, concentrating and removing the solvent to obtain the target compound A. The weight ratio (g: g) of the amount of the saturated sodium chloride aqueous solution to the compound A-3 is 1.5: 1-1.6: 1; the weight ratio of the dichloromethane to the compound A-3 (g: g) is 2.7: 1-3.5: 1.
The compound A is further purified by reduced pressure distillation.
The total yield of the preparation process method of the gadobutrol epoxy side-linking intermediate compound A is more than 84%, the purity is more than 99.6%, and the maximum single impurity content is less than 0.1%.
The largest single impurity is the impurity of the single component with the highest content in the medical product, and in the medical synthesis preparation process method, the largest single impurity is the key quality control index of the medical product.
The preparation process of gadobutrol epoxy side chain intermediate of the present invention will be further illustrated with reference to the specific examples.
The preparation process route of the embodiment of the invention is as follows:
example 1 preparation Process of gadobutrol epoxy side chain intermediate
Step 1:
(1) 300g of Compound A-1 was added to the reaction flask;
(2) then 450g of compound A-2 is added;
(3) 0.9g of p-toluenesulfonic acid monohydrate was added;
(4) stirring and heating to 70 ℃, distilling 219g of methanol out, heating and distilling methanol out simultaneously for 3 hours;
(5) heating to 120 ℃, and distilling to separate excessive compound A-2;
(6) heating to 170 ℃, distilling under normal pressure to separate front fraction impurities, and collecting distillation range of 80-142 ℃;
(7) compound A-3 was collected with a distillation range of 142-147 deg.C (354g, purity 96.2%).
Step 2:
(1) 338g of Compound A-3, 315g of acetonitrile, 270g of methanol and 330g of water were added to a reaction flask, and 2.4g of disodium hydrogen phosphate was further added;
(2) stirring and heating the reaction solution;
(3) adding 398g of 30% hydrogen peroxide and 159g of 1M sodium hydroxide solution into a reaction bottle at the temperature of 60-80 ℃, continuously adding the hydrogen peroxide for 0.5-1 hour, continuously adding the sodium hydroxide solution for 5 hours, and controlling the pH value of the reaction solution in the adding process to be 7-9.5;
(4) stirring the reaction solution in the reaction bottle for 6-8 hours, and cooling to room temperature;
(5) 540g of saturated saline and 998g of dichloromethane are sequentially added into a reaction bottle, stirred and an organic phase is separated;
(6) adding 911g of 1.7M sodium sulfite solution into the organic phase, stirring, separating out the organic phase, and drying with sodium sulfate;
(7) filtering the dried organic phase, and evaporating the solvent at 40 ℃ under reduced pressure to obtain a crude compound A;
(8) the crude compound A was distilled under reduced pressure to give the product compound A (333g, 85.8% overall yield).
The purity of the obtained compound a was determined to be 99.6% or more.
Example 2 preparation method of gadobutrol epoxy side chain intermediate
Step 1:
(1) adding 180g of compound A-1 into a reaction bottle;
(2) 319g of Compound A-2 are then added;
(3) 0.4g of p-toluenesulfonic acid monohydrate was added;
(4) stirring and heating to 70 ℃, distilling 128g of methanol out, and heating and distilling methanol out simultaneously for 2 hours;
(5) heating to 120 ℃, and distilling to separate excessive compound A-2;
(6) heating to 170 ℃, and distilling under normal pressure to separate front fraction impurities;
(7) compound A-3 was collected with a distillation range of 142-147 deg.C (212g, 96.3% purity).
Step 2:
(1) a reaction flask was charged with 180g of Compound A-3, 190g of acetonitrile, 157g of methanol and 198g of water; then 1.4g of disodium hydrogen phosphate is added;
(2) stirring and heating the reaction solution;
(3) dropwise adding 210g of 30% hydrogen peroxide, simultaneously dropwise adding 94g of 1M sodium hydroxide solution, controlling the temperature to be 60-80 ℃, continuously adding 0.5-1 hour of hydrogen peroxide, continuously adding 3-5 hours of sodium hydroxide solution, and controlling the pH value of reaction liquid in the dropwise adding process to be 7-9.5;
(4) stirring the reaction solution in the reaction bottle for 6-8 hours, and cooling to room temperature;
(5) adding 300g of saturated saline and 599g of dichloromethane into a reaction bottle in sequence, stirring and separating an organic phase;
(6) 438g of 1.7M sodium sulfite solution was added to the organic phase, stirred and the organic phase was separated and dried over sodium sulfate;
(7) filtering the dried organic phase, and evaporating the solvent at 40 ℃ under reduced pressure to obtain a crude compound A;
(8) the crude compound A was distilled under reduced pressure to give the product compound A (178g, 86% overall yield).
Purity measurement of the compound A-3 obtained in step 1 revealed that the compound A-3 had a purity of 96.28% and the spectrum was as shown in FIG. 1.
The purity of the final product compound a obtained in step 2 was determined, and the purity of compound a was 99.86%, and the spectrum is shown in fig. 2.
Example 3 workshop amplification preparation Process of gadobutrol epoxy side chain intermediate
Step 1:
(1) 186kg of compound A-1 is added into a reaction kettle;
(2) then 330kg of compound A-2 was added;
(3) 372g of p-toluenesulfonic acid monohydrate was added;
(4) stirring and heating to 80 ℃, and distilling off methanol; heating and separating out methanol while continuing for 3 hours;
(5) heating to 120 ℃, and distilling out excessive compound A-2 to obtain a crude compound A-3;
(6) the crude compound A-3 was distilled under reduced pressure to give compound A-3(216kg, 96.2% purity).
Step 2:
(1) 215kg of compound A-3, 208kg of acetonitrile, 178kg of methanol and 217kg of water are added into a reaction kettle, and 1.6kg of disodium hydrogen phosphate is added;
(2) stirring and heating the reaction solution;
(3) 257kg of 27% hydrogen peroxide and 103kg of 1M sodium hydroxide aqueous solution are added into a reaction kettle, and the temperature is controlled to be 60-80 ℃; adding hydrogen peroxide for 1-2 hours, adding a sodium hydroxide aqueous solution for 5-6 hours, and dropwise adding a reaction solution in the process to control the pH value to be 7-9.5;
(4) stirring the reaction liquid in the reaction kettle for 8-9 hours, and cooling to room temperature;
(5) 345kg of saturated salt water and 593kg of dichloromethane are sequentially added into the reaction kettle, stirred and an organic phase is separated;
(6) 481kg of 1.7M sodium sulfite solution is added into the organic phase, the organic phase is stirred and separated, and the sodium sulfate is dried;
(7) filtering the dried organic phase, and evaporating the solvent at 40 ℃ under reduced pressure to obtain a crude compound A;
(8) the crude compound A was distilled under reduced pressure to give the product compound A (209kg, 84.4% overall yield). Purity determination of the obtained compound a showed that the purity of the compound a was 99.64%.
The 1H-NMR analysis of the compound A obtained gave the following results:
1H-NMR(400MHz,CDCl3)：3.93～4.03(m，4H)，3.15～3.17(m，2H)，1.28(s，3H)，1.33(s，3H)。
example 4 workshop amplification preparation of gadobutrol epoxy side chain intermediate
Step 1:
(1) 1550kg of compound A-1 is added into a reaction kettle;
(2) 2940kg of Compound A-2 were then added
(3) Then 3350g of p-toluenesulfonic acid monohydrate was added;
(4) stirring and heating to 80 ℃, and distilling off 1120kg of methanol;
(5) heating to 120 ℃, and distilling out excessive compound A-2 to obtain a crude compound A-3;
(6) the crude compound A-3 was distilled under reduced pressure to give compound A-3(1820kg, 96.28% pure). Step 2:
(1) 1810kg of compound A-3, 1730kg of acetonitrile, 1480kg of methanol and 1920kg of water are added into a reaction kettle, and then 15.1kg of disodium hydrogen phosphate is added;
(2) stirring and heating the reaction solution;
(3) 1990kg of 27% hydrogen peroxide and 1086kg of 1M sodium hydroxide aqueous solution are added into a reaction kettle, and the temperature is controlled to be 60-80 ℃; controlling the pH value of the reaction liquid to be 7-9.5 in the feeding process;
(4) continuously stirring the reaction liquid in the reaction kettle for 8-9 hours, and cooling to room temperature;
(5) 2880kg of saturated saline water and 6335kg of dichloromethane are sequentially added into a reaction kettle, stirred and an organic phase is separated;
(6) adding 1.7M sodium sulfite solution 4010kg into the organic phase, stirring, separating out the organic phase, and drying with sodium sulfate;
(7) filtering the dried organic phase, and evaporating the solvent at 40 ℃ under reduced pressure to obtain a crude compound A;
(8) the crude compound A was distilled under reduced pressure to give the product compound A (1820kg, 85.2% overall yield).
The purity of the obtained compound a was determined to be 99.6% or more.
Test example 1:
and (3) performing stability determination on the gadobutrol epoxy side chain intermediate compound A prepared in the above embodiment, sealing and placing a sample at normal temperature for six months, sampling, observing appearance and detecting purity, wherein the purity of the compound A is more than 99.6%.
Compared with the sample before placement, the compound A sample has no obvious change in appearance after being placed for 6 months, and has no obvious reduction in purity. The gadobutrol epoxy side chain intermediate compound A prepared by the preparation process method has good stability and is beneficial to storage and transportation.
The above examples and experimental examples show that the purity of the gadobutrol epoxy side chain intermediate compound A prepared by the preparation process method is more than 96%, the total yield of the process method is more than 84%, and the product stability is good. The method has the advantages of simple and convenient operation of each step, easy purification, simple and convenient post-treatment, environmental protection, easy operation, safe and feasible solvent and conditions, contribution to environmental protection, industrial amplification production and wide application prospect.
The invention is not limited to the foregoing embodiments. The invention extends to any novel feature or any novel combination of features disclosed in this specification and any novel method or process steps or any novel combination of features disclosed.
Claims (1)
1. A preparation process method of gadobutrol epoxy side chain intermediate is characterized by comprising the following preparation process routes and steps:
the gadobutrol epoxy side chain intermediate is shown as a formula A:
the total yield of the preparation process method of the gadobutrol epoxy side chain intermediate is more than 84 percent;
according to the preparation process method of the gadobutrol epoxy side chain intermediate, the purity of the obtained gadobutrol epoxy side chain intermediate is more than 99.6 percent, and the maximum single impurity content is less than 0.1 percent;
the preparation process route is as follows:
step 1, reacting compounds A-1 and A-2 at 80 ℃ for 2-3 hours in the presence of p-toluenesulfonic acid monohydrate, and simultaneously evaporating a methanol byproduct within 2-3 hours, wherein the weight ratio of the distilled amount of methanol to A-1 is 0.71: 1-0.73: 1; removing excessive A-2 from the reaction solution, and then carrying out reduced pressure distillation to obtain a target compound A-3; wherein the feeding weight ratio of A-1 to A-2 is 1:1.77, and the addition amount of the paratoluenesulfonic acid monohydrate is 0.22 percent of the weight of A-1;
step 2,
In the first stage, the compound A-3, sodium dihydrogen phosphate and a mixed solvent containing methanol, acetonitrile and water are fed and mixed, and the reaction liquid is heated to 50 ℃ and then enters the next stage; the weight ratio of the compound A-3 to the sodium dihydrogen phosphate is 126: 1-139: 1; the weight ratio of methanol to acetonitrile to water in the mixed solvent is 1: (1.0-1.2): (1.22-1.3); the weight ratio of the compound A-3 to the total amount of the mixed solvent is 1: 2.7-1: 3;
in the second stage, feeding hydrogen peroxide and a sodium hydroxide aqueous solution into the reaction liquid obtained in the first stage, and then continuously heating the reaction liquid to 60-80 ℃ and keeping the temperature for 6-9 hours; the weight ratio of the feed amount of hydrogen peroxide to the compound A-3 is 1.16: 1-1.18: 1; the feeding amount of the sodium hydroxide is 1M aqueous solution, and the weight ratio of the 1M sodium hydroxide feeding amount to the compound A-3 is 0.47: 1-0.52: 1; in the feeding process, the feeding duration of the hydrogen peroxide is 1-2 hours; the feeding duration of the sodium hydroxide aqueous solution with the concentration of 1M is 5-6 hours; the pH value of the reaction liquid is 7-9.5 in the stages of feeding, heating and heat preservation;
adding saturated sodium chloride aqueous solution and dichloromethane into the reaction solution obtained in the second stage, separating out an organic phase, drying, filtering, concentrating and removing the solvent to obtain a target compound A; the weight ratio of the using amount of the saturated sodium chloride aqueous solution to the compound A-3 is 1.5: 1-1.6: 1; the weight ratio of the using amount of the dichloromethane to the compound A-3 is 2.7: 1-3.5: 1; and purifying the compound A by adopting a reduced pressure distillation mode.
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| CN103613557A (en) * | 2013-10-18 | 2014-03-05 | 武汉利宝瑞医药科技有限公司 | Preparation method for magnetic resonance imaging contrast medium gadobutrol |
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