CN111909081B

CN111909081B - Method for purifying pyriproxyfen technical, product obtained by method and application of pyriproxyfen technical

Info

Publication number: CN111909081B
Application number: CN201910375684.6A
Authority: CN
Inventors: 罗昌炎; 詹姆斯·T·布里斯托
Original assignee: Jiangsu Rotam Chemical Co Ltd
Current assignee: Jiangsu Rotam Chemical Co Ltd
Priority date: 2019-05-07
Filing date: 2019-05-07
Publication date: 2024-01-09
Anticipated expiration: 2039-05-07
Also published as: CN111909081A

Abstract

The invention relates to a method for purifying a pyriproxyfen raw medicine, a product obtained by the method and application of the pyriproxyfen raw medicine. The purity of the purified pyriproxyfen raw drug obtained by the purification method is more than or equal to 98 percent, and the yield of the purification process is more than or equal to 96 percent.

Description

Method for purifying pyriproxyfen technical, product obtained by method and application of pyriproxyfen technical

Technical Field

The invention relates to the technical field of fine chemical engineering, in particular to a method for purifying pyriproxyfen original drug, a product obtained by the method and application of the product.

Background

Pyriproxyfen is also called pyriproxyfen, is an alkyl pyridine juvenile hormone chitin synthesis inhibitor developed by Sumitomo (Sumitomo Chemical) company in 1983, can be used for preventing and controlling sanitary pests such as houseflies, mosquitoes, termites and the like, can also be used for preventing and controlling agricultural pests such as homoptera, thysanoptera, lepidoptera and the like, and is a high-efficiency, environment-friendly and low-toxicity pesticide. Pyriproxyfen has systemic transfer activity and can affect larvae hidden at the back of leaves.

The molecular formula of pyriproxyfen is as follows:

U.S. patent No. 4751225 discloses a pyriproxyfen crude drug and a synthesis process of the compound, wherein p-phenoxyphenol is reacted with propylene oxide under alkaline conditions to obtain 1- (4-phenoxyphenoxy) -2-propanol, and separation is carried out by a silica gel column chromatography separation method to obtain light yellow liquid pyriproxyfen. CN108276255a discloses a method for preparing pyriproxyfen intermediate ether alcohol, which synthesizes p-phenoxy phenol and propylene oxide into ether alcohol product through heating reaction under the catalysis of magnesium oxide, so that the content of isomer impurities in pyriproxyfen key intermediate ether alcohol can be remarkably reduced.

In the above prior art on the synthesis of pyriproxyfen, reference is made to the key intermediate ether alcohol of pyriproxyfen [ chemical name: 1- (4-phenoxyphenoxy) -2-propanol ], and synthesizing pyriproxyfen by using the same as a raw material. The intermediate is generally prepared by reacting p-phenoxyphenol with propylene oxide under alkaline conditions. Because the epoxypropane has a plurality of reaction sites, the reaction selectivity is difficult to control, and the content of the ether alcohol isomer reaches 10-20%. The specific reaction formula is as follows:

the ether alcohol isomer can be synthesized with the next step to generate pyriproxyfen isomer, and the specific isomer impurity has the structural formula as follows:

from the point of view of structural similarity of the compounds, the physical properties of the two compounds are very similar, and the original medicine and impurities are difficult to separate by a conventional chemical purification method. Even if the purity of the crude drug can be increased to 98% or more by repeated purification, or the pure product can be obtained by separation using column chromatography, it is not cost-effective from the viewpoint of productivity and cost. Furthermore, the application of such high impurity content formulation products to the environment, especially in terms of hygienic administration, would present a risk to humans and animals and the environment.

CN1651414a discloses a method for separating and purifying pyriproxyfen, which comprises dissolving the crude pyriproxyfen with a certain amount of ethyl acetate or toluene, adding alcohol to form a partial mutual solution system of pyriproxyfen and impurities in a mixed solvent, separating to remove impurities, and finally cooling and crystallizing the clear solution to obtain pyriproxyfen. The method of the scheme is difficult to separate isomer impurities from pyriproxyfen well, the content of pyriproxyfen isomer in the purified product is high, and the overall yield is low.

Although the above documents disclose some methods for separating and purifying the crude pyriproxyfen, the problems of high separation cost or high content of isomer impurities and insufficient purity of the separated product still exist, so that the development of a method for purifying the crude pyriproxyfen crude product with simple operation is of great significance.

Disclosure of Invention

The invention aims to provide a method for purifying a pyriproxyfen raw medicine, a product obtained by the method and application of the pyriproxyfen raw medicine. The purity of the purified pyriproxyfen raw drug obtained by the purification method is more than or equal to 98%, such as 98.2%, 98.5%, 98.8%, 99.2%, 99.5% or 99.7%, and the like, and the purification process yield is more than or equal to 96%, such as 96%, 97% or 99%, and the like.

To achieve the purpose, the invention adopts the following technical scheme:

in a first aspect, the present invention provides a method for purifying a pyriproxyfen drug substance, the method comprising the steps of:

(1) Dissolving the crude pyriproxyfen crude product in a solvent to obtain a solution A;

(2) And (3) carrying out fractional cooling crystallization on the solution A obtained in the step (1) to obtain the purified pyriproxyfen technical product.

According to the method for purifying the crude pyriproxyfen technical product, the solution in which the pyriproxyfen is dissolved is obtained after the crude pyriproxyfen technical product is dissolved, and then the purity of the purified pyriproxyfen technical product obtained by purification is obviously improved through graded cooling. The purity of the purified pyriproxyfen raw medicine obtained by the purification method is more than or equal to 98 percent, and the yield of the purification process is more than or equal to 96 percent.

According to the method, the characteristics of low melting point of the pyriproxyfen raw medicine and high similarity of isomer impurities and the raw medicine structure are considered, and the isomer impurities are prevented from being wrapped in particles due to rapid mass precipitation of the main component during rapid cooling by grading cooling, so that the content of the isomer impurities in the purified pyriproxyfen raw medicine obtained by purification is reduced to below 0.5%, for example, 0.1%, 0.2%, 0.3% or 0.4%, and the like, and the purity of the purified pyriproxyfen raw medicine is ensured; meanwhile, the yield of the purification process is further improved.

Preferably, the crude pyriproxyfen product of step (1) has a purity of 85-97%, such as 85%, 88%, 90%, 92%, 95% or 97%, etc.

Preferably, the ratio of the mass of the crude pyriproxyfen crude drug product in step (1) to the volume of the solvent is 0.2-0.8g/mL, for example 0.2g/mL, 0.3g/mL, 0.4g/mL, 0.5g/mL, 0.6g/mL, 0.7g/mL or 0.8g/mL, etc., preferably 0.3-0.6g/mL.

The method controls the volume ratio of the crude pyriproxyfen crude product to the solvent to be 0.2-0.8g/mL, thereby being beneficial to precipitation of pyriproxyfen in the process of graded cooling and further improving the yield in the purification process.

Preferably, the solvent in step (1) includes any one or a mixture of at least two of aromatic hydrocarbons, aliphatic hydrocarbons, alicyclic hydrocarbons, halogenated hydrocarbons, alcohols, ethers, esters, ketones or nitriles, and the mixture includes, for example, a mixture of aromatic hydrocarbons and aliphatic hydrocarbons, a mixture of alicyclic hydrocarbons and halogenated hydrocarbons, a mixture of alcohols and ethers or a mixture of esters, ketones and nitriles, and the like.

Preferably, the aromatic hydrocarbon includes any one or a mixture of at least two of benzene, toluene, or xylene, and the mixture includes, for example, a mixture of benzene and toluene, a mixture of benzene and xylene, or a mixture of toluene and xylene.

Preferably, the aliphatic hydrocarbon includes any one or a mixture of at least two of pentane, hexane or octane, and the mixture includes, for example, a mixture of pentane and hexane, a mixture of hexane and octane, or a mixture of pentane and octane.

Preferably, the alicyclic hydrocarbon includes any one or a mixture of at least two of cyclohexane, cyclohexanone or toluene cyclohexanone, and the mixture includes, as an example, a mixture of cyclohexane and cyclohexanone, a mixture of cyclohexane and toluene cyclohexanone, or a mixture of cyclohexanone and toluene cyclohexanone, etc.

Preferably, the halogenated hydrocarbon includes any one or a mixture of at least two of chlorobenzene, dichlorobenzene or dichloromethane, and the mixture includes, for example, a mixture of chlorobenzene and dichlorobenzene, a mixture of chlorobenzene and dichloromethane, a mixture of dichlorobenzene and dichloromethane, or the like.

Preferably, the alcohol includes any one or a mixture of at least two of methanol, ethanol, or isopropanol, and the mixture includes, for example, a mixture of methanol and ethanol, a mixture of methanol and isopropanol, or a mixture of ethanol and isopropanol, etc.

Preferably, the ethers include any one or a mixture of at least two of diethyl ether, propylene oxide or tetrahydrofuran, and the mixture includes, for example, a mixture of diethyl ether and propylene oxide, a mixture of diethyl ether and tetrahydrofuran, or a mixture of propylene oxide and tetrahydrofuran, etc.

Preferably, the esters include any one or a mixture of at least two of methyl acetate, ethyl acetate, or propyl acetate, and the mixture includes, for example, a mixture of methyl acetate and ethyl acetate, a mixture of methyl acetate and propyl acetate, or a mixture of ethyl acetate and propyl acetate, etc.

Preferably, the nitrile comprises acetonitrile.

Preferably, the method of dissolving in step (1) comprises heating to dissolve.

Preferably, the temperature of the heated dissolution is 35 ℃ to the boiling point temperature of the solvent, for example 35 ℃, 40 ℃, 45 ℃, 50 ℃, 55 ℃, 70 ℃, or the like.

Preferably, the method of heating to dissolve comprises heating to reflux.

Preferably, the heating to dissolve further comprises filtering to remove insoluble materials.

Preferably, the method for fractional cooling crystallization comprises the following steps:

(a) Cooling the solution A to 20-30deg.C, such as 20, 25 or 30deg.C, etc.;

(b) And (c) continuously cooling and crystallizing the solution obtained in the step (a) in an ice water bath until crystals are completely separated out.

The method adopts a graded cooling mode, firstly, the solution containing crude pyriproxyfen crude drug is cooled to 20-30 ℃, and at the moment, the solution is maintained in a supersaturated state and crystals are not precipitated because of slow cooling and low melting point (about 47 ℃) of pyriproxyfen. If the temperature is quickly reduced without control, the local temperature of the solution system is low to lead to crystallization in advance, so that a large amount of solid is triggered to be precipitated in a short time to wrap impurities in the particles. In contrast, the saturated solution obtained by graded cooling is continuously cooled and crystallized by ice water bath, and the pyriproxyfen crystal slowly separates out along with the reduction of the temperature with sufficient stirring, and the isomer impurities are always in an unsaturated state and are not separated out, so that the purity of the purified pyriproxyfen technical product and the yield in the purification process are obviously improved.

Preferably, the rate of cooling in step (a) is 1-8 ℃/min, e.g. 1 ℃/min, 2 ℃/min, 3 ℃/min, 4 ℃/min, 5 ℃/min, 6 ℃/min, 7 ℃/min or 8 ℃/min, etc.

Preferably, prior to step (b), seed crystals are added to the product obtained in step (a).

Preferably, the seed crystal comprises a pure product of pyriproxyfen.

Preferably, the purity of the pure pyriproxyfen is greater than or equal to 98.0%, such as 98%, 98.5%, 99%, 99.5%, 99.7% or 99.9%, etc.

Preferably, the ratio of the adding amount of the seed crystal to the mass of the crude pyriproxyfen crude drug is 1-10%; for example, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9% or 10%, etc., preferably 3 to 6%. The seed crystal is added in one time or in batches under uniform stirring, and the time is controlled within 3-15 minutes.

The method of the invention is beneficial to improving the efficiency of the crystallization process by adding seed crystals to induce crystallization. Meanwhile, the adding amount of the seed crystal can greatly influence the purity of the purified pyriproxyfen crude drug obtained by purification, the ratio of the adding amount of the seed crystal in the purification process to the mass of the pyriproxyfen crude drug in the raw material is controlled to be 1-10%, the precipitation of isomer impurities can be restrained, and the purity of the purified product can be improved.

Preferably, the step (2) further comprises solid-liquid separation and drying of the product after the fractional cooling crystallization.

Preferably, the solid-liquid separation method comprises filtration.

Preferably, the drying method includes drying under reduced pressure.

As a preferred technical solution of the present invention, the method comprises the steps of:

(1) Heating and dissolving crude pyriproxyfen crude product with purity of 85-97% in a solvent to obtain solution A, wherein the heating and dissolving temperature is 35-the boiling point temperature of the solvent; the solvent comprises any one or a mixture of at least two of aromatic hydrocarbon, aliphatic hydrocarbon, alicyclic hydrocarbon, halohydrocarbon, alcohol, ether, ester, ketone or nitrile;

(2) Cooling the solution A to 20-30 ℃ at a cooling rate of 1-8 ℃/min, adding seed crystals, then placing the solution A in ice water bath for continuous cooling and crystallization until crystals are completely separated out, filtering, and drying under reduced pressure to obtain the purified pyriproxyfen original drug.

In a second aspect, the present invention provides a pyriproxyfen prodrug purified by the method of the first aspect, wherein the content of isomer impurities in the pyriproxyfen prodrug purified by the method is less than or equal to 0.5%, such as 0.1%, 0.2%, 0.3%, 0.4% or 0.5%, etc.

In a third aspect, the present invention provides the use of a purified pyriproxyfen prodrug as described in the second aspect for the preparation of an insecticide.

Compared with the prior art, the invention has the following beneficial effects:

(1) According to the method for purifying the crude pyriproxyfen technical product, the crude pyriproxyfen technical product is heated and dissolved to obtain the solution in which pyriproxyfen is dissolved, and then the purified pyriproxyfen technical product is subjected to graded cooling, so that the purity of the purified pyriproxyfen technical product is obviously improved. The purity of the purified pyriproxyfen raw drug obtained by the purification method is more than or equal to 98 percent, and the yield of the purification process is more than or equal to 96 percent;

(2) According to the method, the characteristics of low melting point of the pyriproxyfen raw medicine and high similarity of isomer impurities and the raw medicine structure are considered, and through graded cooling, the precipitation of the isomer impurities is avoided, and the precipitation of the pyriproxyfen raw medicine is facilitated, so that the content of the isomer impurities in the purified pyriproxyfen raw medicine obtained by purification is reduced to below 0.5%, and the purity of the purified pyriproxyfen raw medicine is ensured;

(3) The method is simple to operate and low in cost.

Detailed Description

The technical scheme of the invention is further described by the following specific embodiments. It will be apparent to those skilled in the art that the examples are merely to aid in understanding the invention and are not to be construed as a specific limitation thereof.

Example 1

The purification method of the crude pyriproxyfen crude drug comprises the following steps:

(1) 100g of crude pyriproxyfen with the purity of 87.5% is added into a flask filled with 90mL of dimethylbenzene, 100mL of tetrahydrofuran is added, heating reflux is carried out at 45 ℃, and insoluble impurities are removed by filtration, so as to obtain solution A;

(2) And (3) cooling the solution A obtained in the step (1) to 25 ℃ at a cooling rate of 2 ℃/min, then placing the solution A in an ice water bath for continuous cooling and crystallization until crystals are completely separated out, filtering, and drying under reduced pressure to obtain the purified pyriproxyfen technical.

86g of white crystals are obtained by purification in the example, and the purity of the obtained purified pyriproxyfen raw material is 98.7% and the yield in the purification process is 97% by high performance liquid chromatography quantitative analysis.

Example 2

(1) 100g of crude pyriproxyfen with 93% purity is added into a flask filled with 90mL of normal hexane, 100mL of methanol is added, heating reflux is carried out at 45 ℃, and insoluble impurities are removed by filtration, thus obtaining solution A;

(2) And (3) cooling the solution A obtained in the step (1) to 25 ℃ at a cooling rate of 3 ℃/min, adding 3g of pure pyriproxyfen, then placing the pure pyriproxyfen in an ice water bath for continuous cooling and crystallization until crystals are completely separated out, filtering, and drying under reduced pressure to obtain the purified pyriproxyfen technical.

92.4g of white crystals are obtained by purification in the example, and the purity of the obtained purified pyriproxyfen raw drug is 99.2% and the yield in the purification process is 98.5% by high performance liquid chromatography quantitative analysis.

Example 3

In this example, the cooling rate in step (2) in example 1 was replaced with 3.5 ℃/min, and the other conditions were identical to those in example 1.

Example 4

In this example, the cooling rate in step (2) in example 1 was replaced with 4.5 ℃/min, and the other conditions were identical to those in example 1.

Example 5

In this example, the cooling rate in step (2) in example 1 was replaced with 5.5 ℃/min, and the other conditions were identical to those in example 1.

Example 6

In this example, the cooling rate in step (2) in example 1 was replaced with 8 ℃/min, and the other conditions were identical to those in example 1.

Example 7

This example differs from example 1 in that in step (2), after cooling to 25 ℃, 1g of seed crystal was added, and then the seed crystal was placed in an ice-water bath to continue cooling crystallization, and the other conditions were exactly the same as in example 1.

Example 8

In this example, the amount of seed crystal added in example 7 was replaced with 3g, and the other conditions were the same as those in example 7.

Example 9

In this example, the amount of seed crystal added in example 7 was replaced with 6g, and the other conditions were the same as those in example 7.

Example 10

In this example, the amount of seed crystal added in example 7 was replaced with 8g, and the other conditions were the same as those in example 7.

Example 11

In this example, the amount of seed crystal added in example 7 was replaced with 10g, and the other conditions were the same as those in example 7.

Comparative example 1

In this comparative example, the step (2) was carried out by directly cooling and crystallizing the solution A in an ice-water bath without subjecting to the step cooling as in example 1, and the other conditions were exactly the same as those in example 1.

The purity of the purified pyriproxyfen crude drugs obtained in examples 1 to 11 and comparative example 1 was analyzed by high performance liquid chromatography quantitative analysis, and the purity and purification process yield of the purified pyriproxyfen crude drugs obtained in examples 1 to 11 and comparative example 1 were measured as shown in table 1:

TABLE 1

As can be seen from the table, when the cooling rate is controlled to be 1-8 ℃, the purity of the purified product is more than or equal to 98.1%, and the purity of the product is reduced along with the increase of the cooling rate, the yield is slightly increased, and the purity is more than or equal to 96.2%; in contrast to comparative example 1, the purity of the purified product and the yield of the purification process are obviously reduced without stage cooling.

As can be seen from comparative example 1 and examples 7 to 11, the addition amount of seed crystals has an effect on the purity of the purified product and the yield of the purification process, and the ratio of the optimal addition amount of seed crystals to the crude pyriproxyfen product is 3 to 6% by mass, and the purity and the purification yield of the purified product are remarkably improved in the above addition amount range compared with the purification process without seed crystals. When the seed crystal is added in an amount of more than 6% of the crude pyriproxyfen crude product, the purity of the purified product is reduced, but the yield is increased.

The applicant declares that the above is only a specific embodiment of the present invention, but the scope of the present invention is not limited thereto, and it should be apparent to those skilled in the art that any changes or substitutions that are easily conceivable within the technical scope of the present invention disclosed by the present invention fall within the scope of the present invention and the disclosure.

Claims

1. A method for purifying a pyriproxyfen prodrug, comprising the steps of:

(2) Cooling the solution A obtained in the step (1) to 20-30 ℃ at a cooling rate of 1-3 ℃/min, adding seed crystals, and then placing the seed crystals in an ice water bath for continuous cooling and crystallization until crystals are completely separated out, thus obtaining a purified pyriproxyfen original drug;

the ratio of the adding amount of the seed crystal to the mass of the crude pyriproxyfen crude product is 3-5%;

the solvent is a combination of aromatic hydrocarbon and alcohol, a combination of aromatic hydrocarbon and ether, a combination of aliphatic hydrocarbon and alcohol, a combination of aliphatic hydrocarbon and ether, a combination of alicyclic hydrocarbon and alcohol, or a combination of alicyclic hydrocarbon and ether.

2. The purification process of claim 1, wherein the crude pyriproxyfen in step (1) has a purity of 85 to 97%.

3. The purification process of claim 1, wherein the crude pyriproxyfen product of step (1) has a mass to solvent volume ratio of 0.2 to 0.8g/mL.

4. The purification process of claim 3, wherein the crude pyriproxyfen product of step (1) has a mass to solvent volume ratio of 0.3 to 0.6g/mL.

5. The purification method of claim 1, wherein the aromatic hydrocarbon is any one or a combination of at least two of benzene, toluene, or xylene.

6. The purification process of claim 1, wherein the aliphatic hydrocarbon is any one or a mixture of at least two of pentane, hexane, or octane.

7. The purification process of claim 1, wherein the cycloaliphatic hydrocarbon is any one or a mixture of at least two of cyclohexane, cyclohexanone, or toluene cyclohexanone.

8. The purification method of claim 1, wherein the alcohol is any one or a mixture of at least two of methanol, ethanol, or isopropanol.

9. The purification method of claim 1, wherein the ether is any one or a mixture of at least two of diethyl ether, propylene oxide, or tetrahydrofuran.

10. The purification method of claim 1, wherein the dissolving method of step (1) comprises heating to dissolve.

11. The purification process of claim 10, wherein the temperature of the heated dissolution is from 35 ℃ to the boiling temperature of the solvent.

12. The purification method of claim 10, wherein the method of heating to dissolve comprises heating to reflux.

13. The method of purifying as recited in claim 10, wherein the heating to dissolve further comprises filtering to remove insoluble materials.

14. The purification process of claim 1, wherein the seed crystals comprise pure pyriproxyfen.

15. The purification process of claim 1, wherein the step (2) of crystallization after fractional cooling further comprises solid-liquid separation of the product and drying.

16. The purification process of claim 15, wherein the solid-liquid separation process comprises filtration.

17. The purification method of claim 15, wherein the drying method comprises drying under reduced pressure.

18. The purification method of claim 1, wherein the purification method comprises the steps of:

(1) Heating and dissolving crude pyriproxyfen crude product with purity of 85-97% in a solvent to obtain solution A, wherein the heating and dissolving temperature is 35-the boiling point temperature of the solvent; the solvent is a combination of aromatic hydrocarbon and alcohol, a combination of aromatic hydrocarbon and ether, a combination of aliphatic hydrocarbon and alcohol, a combination of aliphatic hydrocarbon and ether, a combination of alicyclic hydrocarbon and alcohol or a combination of alicyclic hydrocarbon and ether;

(2) Cooling the solution A to 20-30 ℃ at a cooling rate of 1-3 ℃/min, adding seed crystals, then placing the solution A in ice water bath for continuous cooling and crystallization until crystals are completely separated out, filtering, and drying under reduced pressure to obtain purified pyriproxyfen raw medicine;

the ratio of the adding amount of the seed crystal to the mass of the crude pyriproxyfen technical product is 3-5%.