CN113563216B

CN113563216B - Preparation method of racemized o, o-EDDHA

Info

Publication number: CN113563216B
Application number: CN202110846300.1A
Authority: CN
Inventors: 贾荣荣; 李会卿; 董浩浩; 左兰兰; 李静; 张林杰; 李娟�
Original assignee: Hebei Sanchuan Chemical Co ltd; Hebei Chengxin Co ltd
Current assignee: Hebei Sanchuan Chemical Co ltd; Hebei Chengxin Co ltd
Priority date: 2021-07-26
Filing date: 2021-07-26
Publication date: 2023-05-30
Anticipated expiration: 2041-07-26
Also published as: CN113563216A

Abstract

The invention relates to the technical field of medicine synthesis, in particular to a preparation method of racemized o, o-EDDHA. The preparation method comprises the following steps: preparing an EDDHA sodium salt solution; adding an acidity regulator into the EDDHA sodium salt solution, regulating the pH of the system, and obtaining the racemized o, o-EDDHA product through crystallization, purification and drying. According to the invention, by regulating the pH value of the system to perform fractional crystallization on the EDDHA sodium salt solution, the racemized o, o-EDDHA product with the purity of 70% is obtained.

Description

Preparation method of racemized o, o-EDDHA

Technical Field

The invention relates to the technical field of medicine synthesis, in particular to a preparation method of racemized o, o-EDDHA.

Background

The EDDHA-Fe has super-strong biological activity, has extremely strong stability in the pH value range of 3-10, has the activity of iron, is easily absorbed by plants by 100%, is a trace element fertilizer with excellent effect, has no negative effect on soil after application, can fix beneficial components in the soil, reduces loss of the beneficial components, is beneficial to regulating the acid-base property of the soil, and prevents soil hardening. The EDDHA-Fe also has the characteristics of complete water solubility, rapid dissolution, rapid absorption and utilization by plants, quick response, safety, convenience, large yield increase and the like. The o, p-isomer and o, o-isomer exist in the EDDHA-Fe chelated iron, wherein the o, o-EDDHA chelated iron is the product with the highest bioavailability, and is the top product in the chelated iron, the efficacy of the o, p-isomer and o-isomer is tens of times of that of common organic iron EDTA, and hundreds of times of that of inorganic iron is the most effective iron supplementing product for treating plant iron deficiency, yellow disease and the like in the world at present. The o, o-EDDHA chelated iron can thoroughly and radically treat physiological diseases such as 'yellow mosaic disease', 'lobular disease', 'Bai Shebing', 'top blight' and the like caused by iron deficiency of fruit trees, vegetables, melon beans, flowers, greening plants and crops, can also be used for supplementing iron to normal plants, can enable plants to grow more vigorously, increases the yield by 7-15%, and has obvious improvement effect on soil hardening and fertility decline caused by long-term application of common fertilizers.

Volume Seperation and Charaterization of the Stereoisomers of N, N' -ethylenbis- [2- (o-hydroxyphenyl) ] -glycine ] in nature 1962, 193 mentions for the first time that both meso and racemic isomers are present in o, o-EDDHA and the two isomers are separated by TLC. At present, the proportion of meso isomer and racemic isomer of an o-EDDHA chelated iron product is close to 1:1 under the condition of stable existence, mainly the meso isomer and the racemic isomer are separated by a column chromatography method, the separation process is complex, and the large-scale popularization and application are difficult. Therefore, the development of a novel synthetic route of the racemized o, o-EDDHA product which is simple and convenient to operate, low in preparation cost and high in product purity has very important significance.

Disclosure of Invention

In view of the above, the present application provides a preparation method of racemic o, o-EDDHA, which is simple to operate and controllable in process, and can obtain a high-purity racemic o, o-EDDHA product.

In order to achieve the above purpose, the embodiment of the invention adopts the following technical scheme:

a process for the preparation of racemic o, o-EDDHA, comprising the steps of:

step one: phenol, ethylenediamine, sodium hydroxide and glyoxylic acid are used as raw materials, and an EDDHA sodium salt solution is obtained through Mannich reaction;

adding an acidity regulator into the EDDHA sodium salt solution, regulating the pH value of the system to 6-7, and performing primary crystallization to obtain an o, o-EDDHA crude product;

adding water into the o, o-EDDHA crude product, dropwise adding caustic soda until the caustic soda is dissolved, adding an acidity regulator, regulating the pH value of the system to 6-7, performing secondary crystallization, and filtering to obtain secondary crystallization mother liquor;

adding an acidity regulator into the secondary crystallization mother liquor, regulating the pH value of the system to 4.8-5.2, crystallizing for three times, and filtering to obtain a tertiary crystallization mother liquor;

and fifthly, adding an acidity regulator into the third crystallization mother liquor, regulating the pH value of the system to be less than or equal to 4.5, performing fourth crystallization, and drying to obtain the racemized o, o-EDDHA product.

Compared with the prior art, the preparation method of the racemized o, o-EDDHA provided by the application has the following advantages:

the invention provides a preparation method of racemic o, o-EDDHA, which is characterized in that a method for fractional crystallization of EDDHA sodium salt solution by regulating and controlling the pH value of a system is provided, meso isomer is firstly removed, then a specific pH condition is adopted, the racemic isomer in an o, o-EDDHA product can be separated out independently, other isomers are not added in the crystallization process to separate out, and the racemic o, o-EDDHA product with the purity of more than 70% is obtained, and the method is simple to operate and high in safety, so that the industrial production of the racemic o, o-EDDHA product is realized.

Preferably, in the fifth step, the pH of the system is adjusted to 3.5-4.5.

Preferably, in the fifth step, the pH of the system is adjusted to 4-4.5.

The preferable pH value can separate out the raceme isomer in the crystallization mother liquor, avoid the precipitation of meso isomer products in the fourth crystallization process, and provide a basis for obtaining high-purity raceme o, o-EDDHA products.

Preferably, the acidity regulator is added dropwise, and the dropping speed is 3-4 mL/min.

The preferable adding mode and the speed of the acidity regulator enable the speed of the pH regulation stage to be slow, thereby ensuring that the generated EDDHA crystallization precipitation process can not be wrapped by other isomers to be precipitated, and avoiding the occurrence of the condition of lower purity of the raceme isomer in the obtained target compound.

Preferably, the acidity regulator is hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid or formic acid.

Further preferably, the acidity regulator is hydrochloric acid or sulfuric acid.

Preferably, the concentration of the acidity regulator is 0.2mol/L to 3mol/L.

The preferred concentration range avoids the occurrence of low purity of the target product due to excessive local acidity.

Preferably, in the third step, the adding amount of the water is 10-20 times of the mass of the o, o-EDDHA crude product.

The preferable water addition amount can ensure that the concentration of meso-o, o-EDDHA reaches saturation and precipitation under the specific pH condition, and avoid incomplete precipitation of the meso-o, o-EDDHA caused by over-high concentration, thereby affecting the purity of a target product.

Preferably, in the fifth step, the drying condition is: vacuum drying, wherein the drying temperature is 40-50 ℃.

The preferable drying condition can avoid the conditions of oxidation, deterioration and the like caused by high temperature or in the air, thereby providing guarantee for obtaining the racemized o, o-EDDHA product.

Preferably, the first step is that the aqueous solution of phenol, ethylenediamine and sodium hydroxide is uniformly mixed, and the aqueous solution of glyoxylic acid is added dropwise, and the mixture is reacted for 3 to 4 hours at the temperature of between 50 and 80 ℃, and after the reaction is finished, the mixture is extracted by an organic solvent to obtain the EDDHA sodium salt solution.

Preferably, the molar ratio of the phenol, the ethylenediamine, the glyoxylic acid and the sodium hydroxide is 2-20:1:2:2-2.1.

The preferable preparation conditions of the EDDHA sodium salt solution can ensure that ortho-H of the phenolic hydroxyl groups in the reaction raw material mixture are combined with the glyoxylate, so that the obtained EDDHA sodium salt solution contains higher ortho-value, and a large amount of impurities generated by the participation of the phenolic hydroxyl groups in the reaction are obviously reduced.

Preferably, the organic solvent is chlorinated alkane, benzene, ester or ether.

Further preferably, the organic solvent is dichloroethane or dichloromethane.

The oil-soluble compounds in the reaction system are removed by extraction with an organic solvent, thus providing a basis for fractional crystallization.

Drawings

In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings that are needed in the embodiments will be briefly described below, and it is obvious that the drawings in the following description are only some embodiments of the present invention, and other drawings may be obtained according to these drawings without inventive effort for a person skilled in the art.

FIG. 1 is a liquid chromatogram of an o, o-EDDHA standard;

FIG. 2 is a liquid chromatogram of crude o, o-EDDHA provided in example 1 of the present invention;

FIG. 3 is a liquid chromatogram of racemic o, o-EDDHA provided in example 1 of the present invention;

fig. 4 is a liquid chromatogram of the o, o-EDDHA product provided in comparative example 1 of the present invention.

Detailed Description

The present invention will be described in further detail with reference to the following examples in order to make the objects, technical solutions and advantages of the present invention more apparent. It should be understood that the specific embodiments described herein are for purposes of illustration only and are not intended to limit the scope of the invention.

Example 1

The embodiment provides a preparation method of racemic o, o-EDDHA, which comprises the following steps:

step one: phenol (56.4 g,0.6 mol), ethylenediamine (4.1 mL,0.06 mol) and 31wt% sodium hydroxide aqueous solution (0.12 mol) are added into a four-port bottle, then 30wt% glyoxylate aqueous solution (0.12 mol) is added dropwise, the mixture is reacted for 3.5 hours at 60 ℃ after the dripping is finished, and dichloroethane is added for extraction for 3 times to obtain EDDHA sodium salt solution;

dripping hydrochloric acid with the concentration of 1mol/L into the EDDHA sodium salt solution to adjust the pH of the system to 6.4, slowly stirring for 2 hours, standing for crystallization for 2 hours, carrying out suction filtration, and fully washing with distilled water to obtain a light red o, o-EDDHA crude product;

adding 10 times of water into the o, o-EDDHA crude product, dropwise adding 30wt% of liquid alkali until the liquid alkali is dissolved, dropwise adding 1mol/L of hydrochloric acid to adjust the pH of the system to 6.4, performing secondary crystallization, and filtering to obtain secondary crystallization mother liquor;

step four, dropwise adding 1mol/L hydrochloric acid into the secondary crystallization mother liquor, adjusting the pH of the system to 5, performing tertiary crystallization, and filtering to obtain tertiary crystallization mother liquor;

and fifthly, dropwise adding hydrochloric acid with the concentration of 1mol/L into the three-time crystallization mother liquor to adjust the pH of the system to 4.5, standing for crystallization for 3h, carrying out suction filtration, and drying at 45 ℃ under vacuum condition to obtain 9.45g of the racemized o, o-EDDHA product, wherein the yield is 30.6%, and the purity is 70%.

Example 2

step one: phenol (11.3 g,0.12 mol), ethylenediamine (4.1 mL,0.06 mol) and 32wt% sodium hydroxide aqueous solution (0.126 mol) are added into a four-port bottle, then 30wt% glyoxylate aqueous solution (0.12 mol) is added dropwise, the mixture is reacted for 3 hours at 80 ℃ after the dripping is finished, and after the reaction is finished, dichloromethane is added for extraction, and extraction is carried out for 3 times, thus obtaining EDDHA sodium salt solution;

step two, dropwise adding sulfuric acid with the concentration of 2mol/L into the EDDHA sodium salt solution to adjust the pH of the system to 6, slowly stirring for 2 hours, standing for primary crystallization for 2 hours, carrying out suction filtration, and fully washing with distilled water to obtain a light red o, o-EDDHA crude product;

adding 15 times of water into the o, o-EDDHA crude product, dropwise adding 30wt% of liquid alkali until the liquid alkali is dissolved, dropwise adding 2mol/L of sulfuric acid to adjust the pH of the system to 6, performing secondary crystallization, and filtering to obtain secondary crystallization mother liquor;

step four, dropwise adding sulfuric acid with the concentration of 2mol/L into the secondary crystallization mother liquor to adjust the pH of the system to 5.2, performing tertiary crystallization, and filtering to obtain tertiary crystallization mother liquor;

and fifthly, dropwise adding sulfuric acid with the concentration of 2mol/L into the three-time crystallization mother liquor to adjust the pH of the system to 3.5, standing for crystallization for 3h, carrying out suction filtration, and drying at 40 ℃ under vacuum condition to obtain 8.97g of the racemized o, o-EDDHA product, wherein the yield is 29.1%, and the purity is 70%.

Example 3

step one: phenol (112.8 g,1.2 mol), ethylenediamine (4.1 mL,0.06 mol) and 32wt% sodium hydroxide aqueous solution (0.12 mol) are added into a four-mouth bottle, then 30wt% glyoxylate aqueous solution (0.12 mol) is added dropwise, the mixture is reacted for 4 hours at 50 ℃ after the dripping is finished, dichloroethane is added for extraction for 3 times, and EDDHA sodium salt solution is obtained;

dripping hydrochloric acid with the concentration of 0.2mol/L into the EDDHA sodium salt solution to adjust the pH of the system to 7, slowly stirring for 2 hours, standing for primary crystallization for 2 hours, carrying out suction filtration, and fully washing with distilled water to obtain a light red o, o-EDDHA crude product;

adding 20 times of water into the o, o-EDDHA crude product, dropwise adding 30wt% of liquid alkali until the liquid alkali is dissolved, dropwise adding 0.2mol/L of hydrochloric acid to adjust the pH of the system to 7, performing secondary crystallization, and filtering to obtain secondary crystallization mother liquor;

step four, dropwise adding hydrochloric acid with the concentration of 0.2mol/L into the secondary crystallization mother liquor to adjust the pH of the system to 4.8, performing tertiary crystallization, and filtering to obtain tertiary crystallization mother liquor;

and fifthly, dropwise adding hydrochloric acid with the concentration of 0.2mol/L into the three-time crystallization mother liquor to adjust the pH of the system to 4, carrying out suction filtration, and drying at 50 ℃ under vacuum condition to obtain 9.15g of the racemized o, o-EDDHA product, wherein the yield is 29.6%, and the purity is 70%.

Example 4

step one: phenol (56.4 g,0.6 mol), ethylenediamine (4.1 mL,0.06 mol) and 31wt% sodium hydroxide aqueous solution (0.12 mol) are added into a four-port bottle, then 30wt% glyoxylate aqueous solution (0.12 mol) is added dropwise, the mixture is reacted for 3.5 hours at 70 ℃ after the dripping is finished, and dichloroethane is added for extraction for 3 times to obtain EDDHA sodium salt solution;

dropwise adding nitric acid with the concentration of 3mol/L into the EDDHA sodium salt solution to adjust the pH of the system to 6.8, slowly stirring for 2 hours, standing for primary crystallization for 2 hours, carrying out suction filtration, and fully washing with distilled water to obtain a light red o, o-EDDHA crude product;

adding 20 times of water into the o, o-EDDHA crude product, dropwise adding 30wt% of liquid alkali until the liquid alkali is dissolved, dropwise adding 3mol/L of nitric acid to adjust the pH of the system to 6.8, performing secondary crystallization, and filtering to obtain secondary crystallization mother liquor;

step four, dropwise adding nitric acid with the concentration of 3mol/L into the secondary crystallization mother liquor to adjust the pH of the system to 5, performing tertiary crystallization, and filtering to obtain tertiary crystallization mother liquor;

and fifthly, dropwise adding nitric acid with the concentration of 3mol/L into the three-time crystallization mother liquor to adjust the pH of the system to 4.2, and drying at 45 ℃ under vacuum condition to obtain 9.5g of the racemized o, o-EDDHA product, wherein the yield is 29.9%, and the purity is 68%.

In order to better illustrate the technical solutions of the present invention, the following is further compared with examples of the present invention.

Comparative example 1

The comparative example provides a method for preparing o, o-EDDHA, comprising the following steps:

step one: phenol (56.4 g,0.6 mol), ethylenediamine (4.1 mL,0.06 mol) and 32wt% sodium hydroxide aqueous solution (0.12 mol) are added into a four-port bottle, then 30wt% glyoxylate aqueous solution (0.12 mol) is added dropwise, the mixture is reacted for 3.5 hours at 60 ℃ after the dripping is finished, and dichloroethane is added for extraction for 3 times to obtain EDDHA sodium salt solution;

and fifthly, dropwise adding 1mol/L hydrochloric acid into the three crystallization mother liquor, regulating the pH of the system to 5, filtering, and drying at 45 ℃ under vacuum condition to obtain 9.72g of o, o-EDDHA product with the yield of 45%.

The structure of the o, o-EDDHA standard is shown as (I), which is purchased from CANADA TRC company under the lot number 7-LXS-88-1, specification: 500mg, purity: 95%.

And (3) drying the o, o-EDDHA crude product prepared in the step II of the example 1 at the temperature of 50 ℃ in vacuum to obtain the o, o-EDDHA.

The o, o-EDDHA standard, the o, o-EDDHA obtained in example 1, the racemic o, o-EDDHA product prepared in example 1, and the o, o-EDDHA product prepared in comparative example 1 were subjected to liquid chromatography, and the results are shown in fig. 1-4, wherein the liquid chromatography detection conditions are chromatographic conditions commonly used in the art.

As can be seen from fig. 1, the o, o-EDDHA standard includes both meso and racemic isomers, and the ratio of the racemic isomer to the meso isomer is close to 1:1, wherein the off-peak time of the racemate is 17.064min, the off-peak time of the meso is 22.511min, and the specific chromatographic peak data are shown in table 1 below.

TABLE 1

	Time	Peak area	Peak height	Peak width	Symmetry factor	Peak area%
							Racemization	17.064	11480.5	597.8	0.2881	0.658	49.328
Meso form	22.511	11793.2	437.4	0.4006	0.573	50.672

As can be seen from fig. 2, the crude o, o-EDDHA product prepared in example 1 of the present application also includes two isomers of meso and racemic, wherein the peak time of the racemization is 17.055min, the peak time of the meso is 22.499min, and the specific chromatographic peak data are shown in the following table 2, so that the ratio of the racemic isomer to the meso isomer in the o, o-EDDHA sodium salt prepared in the present application is similar to the ratio in the o, o-EDDHA standard.

TABLE 2

As can be seen from fig. 3, the purity of the racemic o, o-EDDHA obtained by the preparation method provided by the present application is about 70%, and as can be seen from fig. 4, if the pH of the system is adjusted to about 5, the ratio of meso isomer to racemic isomer in the obtained product is 45:55. Therefore, the method for fractional crystallization of the EDDHA sodium salt solution by regulating the pH value of the system can obtain the high-purity racemic o, o-EDDHA product.

The results of the liquid chromatography detection of the target products prepared in examples 2 to 4 are consistent with the spectrum of example 1.

As long as the addition amount of the organic solvent, the acidity regulator, the water and the pH value of the system are all within the preferred ranges of the invention, the same or corresponding technical effects in the embodiments 1 to 4 of the invention can be achieved.

The foregoing description of the preferred embodiments of the invention is not intended to be limiting, but rather is intended to cover all modifications, equivalents, or alternatives falling within the spirit and principles of the invention.

Claims

1. A preparation method of racemized o, o-EDDHA is characterized by comprising the following steps: the preparation method comprises the following steps:

step one: phenol, ethylenediamine, sodium hydroxide and glyoxylic acid are used as raw materials, and after the reaction is finished, the raw materials are extracted by an organic solvent to obtain an EDDHA sodium salt solution; the organic solvent is dichloromethane or dichloroethane;

adding an acidity regulator into the EDDHA sodium salt solution, regulating the pH value of the system to 6-7, and performing primary crystallization to obtain an o, o-EDDHA crude product; the acidity regulator is hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid or formic acid; the acidity regulator is added dropwise, and the dropping speed is 3-4 mL/min;

2. A process for the preparation of racemic o, o-EDDHA according to claim 1, characterized in that: and step five, regulating the pH of the system to 3.5-4.5.

3. A process for the preparation of racemic o, o-EDDHA according to claim 2, characterized in that: and step five, regulating the pH value of the system to 4-4.5.

4. A process for the preparation of racemic o, o-EDDHA according to claim 1, characterized in that: the concentration of the acidity regulator is 0.2 mol/L-3 mol/L.

5. A process for the preparation of racemic o, o-EDDHA according to claim 1, characterized in that: in the third step, the adding amount of the water is 10-20 times of the mass of the o, o-EDDHA crude product.

6. A process for the preparation of racemic o, o-EDDHA according to claim 1, characterized in that: in the fifth step, the drying conditions are as follows: vacuum drying, wherein the drying temperature is 40-50 ℃.

7. A process for the preparation of racemic o, o-EDDHA according to claim 1, characterized in that: the first step is as follows: and uniformly mixing the aqueous solution of phenol, ethylenediamine and sodium hydroxide, dropwise adding the aqueous solution of glyoxylic acid, reacting for 3-4 hours at 50-80 ℃, and extracting by an organic solvent after the reaction is finished to obtain the EDDHA sodium salt solution.

8. A process for the preparation of racemic o, o-EDDHA according to claim 7, characterized in that: the molar ratio of the phenol, the ethylenediamine, the glyoxylic acid and the sodium hydroxide is 2-20:1:2:2-2.1.