CN108947915B

CN108947915B - Azoxystrobin acetone solvate and preparation method thereof

Info

Publication number: CN108947915B
Application number: CN201810573687.6A
Authority: CN
Inventors: 龚俊波; 杨海燕; 刘裕; 侯宝红; 陈明洋; 贾丽娜
Original assignee: Tianjin University
Current assignee: Tianjin University
Priority date: 2018-06-06
Filing date: 2018-06-06
Publication date: 2021-07-06
Anticipated expiration: 2038-06-06
Also published as: CN108947915A

Abstract

The invention relates to azoxystrobin acetone solvate and a preparation method thereof. Diffraction angles of the crystal form expressed by 2 theta angles have characteristic peaks at 7.32 +/-0.20 degrees, 8.42 +/-0.20 degrees, 13.26 +/-0.20 degrees, 14.16 +/-0.20 degrees, 18.04 +/-0.20 degrees, 18.52 +/-0.20 degrees, 18.90 +/-0.20 degrees, 20.40 +/-0.20 degrees, 21.04 +/-0.20 degrees, 22.36 +/-0.20 degrees, 23.96 +/-0.20 degrees, 24.36 +/-0.20 degrees, 26.46 +/-0.20 degrees, 28.42 +/-0.20 degrees, 30.06 +/-0.20 degrees and the like, wherein 7.32 +/-0.20 degrees is an initial peak, and the relative intensity is 100 percent. The preparation method is a constant-temperature suspension crystal transformation method, is simple to operate, easy to control and good in reproducibility, solves the problems of difficult filtration and low efficiency in production, and is suitable for industrialization.

Description

Azoxystrobin acetone solvate and preparation method thereof

Technical Field

The invention belongs to the field of pharmaceutical chemicals, and particularly relates to azoxystrobin acetone solvate and a preparation method thereof.

Background

The phenomenon of drug solvate is widely existed in the process of drug development, and the solvate can improve the physical and chemical properties of the drug, promote absorption and improve the bioavailability of the drug.

Azoxystrobin (Azoxystrobin) with chemical name of 3- (E) -2- [2- [6- (2-cyanophenoxy) pyrimidin-4-yloxy]-phenyl radical]-3-methoxy-acrylate of formula: c₂₂H₁₇N₃O₅The chemical structural formula is as follows:

the azoxystrobin is a methoxy acrylate bactericide with the largest global sales volume, and is a novel agricultural bactericide with great development potential and market activity after a triazole bactericide in the pesticide field. Has good activity on almost all fungal diseases, and can be used for gardening, agriculture (vegetables and fruits), lawn maintenance and the like. The preparation is mainly suspending agent and water dispersant.

Chinese invention patents CN103012285A and CN101621926A describe the preparation of azoxystrobin A, B crystalline form and amorphous form, the crystalline form being characterized by using XRPD, DSC, TGA and IR, Raman. And 2 theta angle is used for representing the diffraction characteristic peak of X-ray powder with different crystal forms, so that the characteristic peak of the crystal form A is as follows: 6.25 +/-0.20 degrees, 11 +/-0.20 degrees, 13.8 +/-0.20 degrees, 14.4 +/-0.20 degrees, 17.65 +/-0.20 degrees, 19.05 +/-0.20 degrees, 26.4 +/-0.20 degrees and 28.5 +/-0.20 degrees. The DSC curve has an endothermic peak in the range of about 114 ℃ to 117 ℃. The crystal form A has small granularity and uneven distribution, has serious problems in later preparations, and is easy to generate agglomeration and coalescence phenomena. The characteristic peaks of the crystal form B are as follows: 7.5 +/-0.20 degrees, 11.75 +/-0.20 degrees, 13.20 +/-0.20 degrees, 14.15 +/-0.20 degrees, 17.1 +/-0.20 degrees, 19.65 +/-0.20 degrees and 23.6 +/-0.20 degrees, and a DSC curve has an endothermic peak within the range of about 101-105 ℃. The crystal form B has poor stability, can be quickly converted into the stable crystal form A in a solvent, and has low solubility. The amorphous form is extremely unstable, can be converted into the crystal form B at room temperature, cannot be stored and is difficult to apply in actual production

Most of the mixture of crystal forms B and A obtained in actual production has serious coalescence, rough surface, easy crystal form transformation in grinding and solvent and poor stability; small particle size, poor fluidity and slow filtration; the crystal form has low purity, poor crystal property, a plurality of problems in preparation, filtration, separation and the like, low production efficiency and high production cost.

Disclosure of Invention

One of the objects of the present invention is: provides a novel azoxystrobin acetone solvate with high crystallinity and larger granularity, and solves the problems of small granularity and serious coalescence of azoxystrobin in the prior art.

The second purpose of the invention is: the preparation method of the azoxystrobin acetone solvate is simple and convenient to prepare, good in reproducibility and good in fluidity, is suitable for industrial production, solves the problems of difficulty in filtration, high cost and low efficiency in production, and fills up the technical blank.

In order to solve the technical problems, the invention is realized by the following technical scheme:

azoxystrobin acetone solvate, characterized in that the crystal form has characteristic peaks at diffraction angles expressed in terms of 2 theta by X-ray powder diffraction measured by Cu-Kalpha ray of 7.32 + -0.20 degrees, 8.42 + -0.20 degrees, 13.26 + -0.20 degrees, 14.16 + -0.20 degrees, 18.04 + -0.20 degrees, 18.52 + -0.20 degrees, 18.90 + -0.20 degrees, 20.40 + -0.20 degrees, 21.04 + -0.20 degrees, 22.36 + -0.20 degrees, 23.96 + -0.20 degrees, 24.36 + -0.20 degrees, 26.46 + -0.20 degrees, 28.42 + -0.20 degrees, 30.06 + -0.20 degrees and the like, wherein 7.32 + -0.20 degrees is an initial peak and the relative intensity is 100%.

The diffraction angle of X-ray powder diffraction of the azoxystrobin acetone solvate measured by using Cu-Kalpha ray and expressed by 2 theta angle has characteristic peaks shown in the following table 1.

TABLE 1X-ray powder diffraction List of azoxystrobin acetone solvate

The azoxystrobin acetone solvate of the invention has a d-value as shown in the table

Preferably, the solvate has a characteristic peak intensity as shown in the above table.

The azoxystrobin acetone solvate is characterized in that an X-ray powder diffraction pattern of the crystal form is shown in figure 1.

The azoxystrobin acetone solvate is characterized in that the crystal form is a monoclinic system, and the space group is P2₁N, unit cell parameter of

α is 90.00 °; β is 98.86(3) °; gamma 90 DEG, unit cell volume of

In the azoxystrobin acetone solvate, the molar ratio of azoxystrobin to acetone molecules is 1:1, and the molecular formula is C₂₂H₁₇N₃O₅·C₃H₆O, there was a weight loss of 13.1% + -0.5% before heating to 80 ℃.

The azoxystrobin acetone solvate has a Differential Scanning Calorimetry (DSC) spectrum with an endothermic peak at 55.0 +/-5 ℃, an endothermic exothermic peak at 104.5 +/-5 ℃ and a characteristic melting peak at 116.6 +/-5 ℃.

According to the invention, the azoxystrobin acetone solvate has an infrared spectrum at 3106, 3037, 2957, 1752, 1711, 1442, 1377, 1301, 1274, 1228, 1098, 941 and 530cm^-1Etc. have characteristic peaks. As shown in particular in fig. 4.

The invention also provides a preparation method of the azoxystrobin acetone solvate, which is prepared by adopting a constant-temperature suspension crystal transformation method, the azoxystrobin is added into acetone, the azoxystrobin is added in one time or in batches, the mass ratio of the azoxystrobin to the solvent acetone is 1: 0.6-4, the constant-temperature suspension crystal transformation temperature is 20-50 ℃, the stirring is carried out for 1-3 h, a white solid is generated, a product is filtered, and the azoxystrobin acetone solvate is obtained after drying.

The specific preparation of azoxystrobin acetone solvate is shown in the examples.

The third purpose of the invention is that: provides the application of the azoxystrobin acetone solvate in preparing the solvent-free azoxystrobin compound with good fluidity and larger granularity.

The azoxystrobin acetone solvate provided by the invention is used for preparing an azoxystrobin solvent-free compound with good fluidity and larger granularity. The specific operation method is that the azoxystrobin acetone solvate is dried under the conditions of 30-90 ℃ and 0.08-0.1 MPa to obtain the azoxystrobin pure crystal compound without solvent. The azoxystrobin solvent-free compound obtained by the method can keep the rod-shaped crystal morphology and the crystal granularity of the original azoxystrobin acetone solvate, is the crystal form A reported by the previous patent, has greatly improved fluidity compared with the product sold in the market, and is not easy to agglomerate.

The method adopts a constant-temperature suspension crystallization method, and the selected solvent is three solvents of acetone, so that the toxicity is low, and the method is safe and environment-friendly; compared with the elution crystallization process disclosed in patent CN101621926A, the method is simple and easy to implement, good in reproducibility and easy to control; compared with the method of reflux and quenching after melting described in patent CN101621926A, the method avoids high-temperature operation, is safer, and has lower energy consumption and mild conditions; the crystal product obtained by the method has high crystallinity, is a short rod crystal habit, and has a scanning electron microscope picture shown in figure 5, and a scanning electron microscope picture shown in figure 6 of a commercially available product. The product of the invention has a volume average particle size of 46 μm and an angle of repose of 23 degrees, while the product of the invention has a volume average particle size of 22 μm and an angle of repose of 50 degrees. The comparison of scanning electron micrographs shows that the crystal obtained by the method has smooth surface and no coalescence phenomenon, avoids the impurity occlusion phenomenon in the purification and separation process and ensures that the filtering and drying speed is higher. Moreover, there is a substantial improvement in particle size distribution and flowability. The product of the invention has good stability and is easy to store. The stability of the azoxystrobin acetone solvate is inspected, the azoxystrobin acetone solvate product is placed in a centrifugal tube, the centrifugal tube is sealed and placed in a dryer, the temperature is controlled at 25 ℃, the humidity is 75%, samples are taken at 7 days to carry out XRPD and TGA detection, and the comparison with the result of the day 0 is carried out, so that the result shows that the crystal form of the azoxystrobin acetone solvate does not change, and the stability is good.

The azoxystrobin acetone solvate is not reported, and the obtained crystal product has complete crystal habit, high crystallinity, uniform particle size, difficulty in agglomeration and good fluidity; the preparation method adopts constant-temperature suspension and cooling crystallization, and has the advantages of simple method, easy control of the crystallization process and good reproducibility; and the desolvation of the azoxystrobin can be used for preparing a pure crystal compound without a solvent, the operation is simple and convenient, and a novel, simple, convenient, feasible and economical method for preparing the azoxystrobin pure crystal compound without the solvent is provided in the technical aspect. The product of the invention has the same sterilization effect principle as the A, B crystal form, inhibits mitochondrial respiration by hindering electron transfer among cytochromes, then controls and prevents fungi growing on agricultural and horticultural crops, plays the function of a bactericide, has no cross resistance with other existing bactericides, and has the characteristics of high efficiency, broad spectrum, protection, treatment, eradication, permeation, systemic activity and the like.

Drawings

FIG. 1 is an X-ray powder diffraction (XRPD) pattern of azoxystrobin acetone solvate provided by the present invention;

FIG. 2 is a thermogravimetric analysis (TG) plot of azoxystrobin acetone solvate provided by the present invention;

FIG. 3 is a Differential Scanning Calorimetry (DSC) plot of azoxystrobin acetone solvate provided in the present invention;

FIG. 4 is an infrared spectrum (IR) plot of azoxystrobin acetone solvate provided by the present invention;

FIG. 5 is a Scanning Electron Microscope (SEM) image of azoxystrobin acetone solvate provided by the invention

FIG. 6 is a Scanning Electron Microscope (SEM) image of commercially available azoxystrobin

FIG. 7 is an XRPD pattern for azoxystrobin feedstock used in example 1 of the present invention

Figure 8 is an XRPD pattern of azoxystrobin solventless compounds prepared after desolvation of azoxystrobin acetone solvate in example 8 of the present invention.

Detailed Description

The present invention will be described in further detail below with reference to the drawings and examples. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention. Any modifications and variations made on the basis of the present invention are still within the scope of the present invention.

Example 1

Adding 20g of acetone into a crystallizer, stirring at 20 ℃, adding 5g of azoxystrobin raw material into the crystallizer in 2 batches, carrying out suspension crystallization, continuing stirring the solution for 1h after the raw material is added, filtering the solid, and drying to obtain the product. The X-ray powder diffraction pattern of the product is shown in figure 1, and is at 7.32 +/-0.20 degrees, 8.42 +/-0.20 degrees, 13.26 +/-0.20 degrees, 14.16 +/-0.20 degrees, 18.04 +/-0.20 degrees, 18.52 +/-0.20 degrees, 18.90 +/-0.20 degrees, 20.40 +/-0.20 degrees, 21.04 +/-0.20 degrees, 22.36 +/-0.20 degrees, 23.96 +/-0.20 degrees and 24 degrees.The peak values at 36 plus or minus 0.20 degrees, 26.46 plus or minus 0.20 degrees, 28.42 plus or minus 0.20 degrees, 30.06 plus or minus 0.20 degrees and the like have characteristic peaks, wherein 7.32 plus or minus 0.20 degrees is an initial peak, and the relative intensity is 100 percent. The TGA results are shown in FIG. 2, with a weight loss of 13.1% + -0.5% before heating to 80 ℃. The DSC result is shown in FIG. 3, which shows an endothermic peak at 55.0 + -5 deg.C, an endothermic exothermic peak at 104.5 + -5 deg.C, and a characteristic melting peak at 116.6 + -5 deg.C. The IR results are shown in FIG. 4 at 3106, 3037, 2957, 1752, 1711, 1442, 1377, 1301, 1274, 1228, 1098, 941, 530cm^-1Etc. have characteristic peaks. The crystal shape is rod-like as shown in fig. 5. The volume average particle size is 40 μm, the angle of repose is 26 degrees, no coalescence is caused, and the fluidity is good. The azoxystrobin raw material crystal form XRPD is shown as a crystal form A in figure 7.

Example 2

Adding 25g of acetone into a crystallizer, stirring at 25 ℃, adding 6g of azoxystrobin raw material into the crystallizer in 3 batches for suspension crystallization, continuing stirring the solution for 1.5h after the raw material is added, filtering the solid, and drying to obtain the product. The X-ray powder diffraction pattern of the product is shown in figure 1. The TGA and DSC curves are shown in figure 2 and figure 3. Its infrared spectrum (IR) is shown in FIG. 4. The crystal shape is similar to that of fig. 5 as a rod. Indicating that azoxystrobin acetone solvate was obtained. The volume average particle size is 40 μm, the angle of repose is 26 degrees, no coalescence is caused, and the fluidity is good. The azoxystrobin raw material crystal form XRPD is shown as a crystal form A in figure 7.

Example 3

Adding 30g of acetone into a crystallizer, stirring at 30 ℃, adding 8g of azoxystrobin raw material into the crystallizer in 2 batches, carrying out suspension crystallization, continuing stirring the solution for 2 hours after the raw material is added, filtering the solid, and drying to obtain the product. The X-ray powder diffraction pattern of the product is shown in figure 1. The TGA and DSC curves are shown in figure 2 and figure 3. Its infrared spectrum (IR) is shown in FIG. 4. The crystal shape is similar to that of fig. 5 as a rod. Indicating that azoxystrobin acetone solvate was obtained. The volume average particle size is 40 μm, the angle of repose is 22 degrees, no coalescence is caused, and the fluidity is good. The azoxystrobin raw material crystal form XRPD is shown as a crystal form A in figure 7.

Example 4

Adding 30g of acetone into a crystallizer, stirring at 35 ℃, adding 10g of azoxystrobin raw material into the crystallizer in 2 batches, carrying out suspension crystallization, continuing stirring the solution for 2.5h after the raw material is added, filtering the solid, and drying to obtain the product. The X-ray powder diffraction pattern of the product is shown in figure 1. The TGA and DSC curves are shown in figure 2 and figure 3. Its infrared spectrum (IR) is shown in FIG. 4. The crystal shape is similar to that of fig. 5 as a rod. Indicating that azoxystrobin acetone solvate was obtained. The volume average particle size is 44 μm, the angle of repose is 26 degrees, no coalescence is caused, and the fluidity is good. The azoxystrobin raw material crystal form XRPD is shown as a crystal form A in figure 7.

Example 5

Adding 30g of acetone into a crystallizer, stirring at 40 ℃, adding 12g of azoxystrobin raw material into the crystallizer in 2 batches, carrying out suspension crystallization, continuing stirring the solution for 3 hours after the raw material is added, filtering the solid, and drying to obtain the product. The X-ray powder diffraction pattern of the product is shown in figure 1. The TGA and DSC curves are shown in figure 2 and figure 3. Its infrared spectrum (IR) is shown in FIG. 4. The crystal shape is similar to that of fig. 5 as a rod. Indicating that azoxystrobin acetone solvate was obtained. The volume average particle size is 40 μm, the angle of repose is 24 degrees, no coalescence is caused, and the fluidity is good. The azoxystrobin raw material crystal form XRPD is shown as a crystal form A in figure 7.

Example 6

Adding 20g of acetone into a crystallizer, stirring at 50 ℃, adding 10g of azoxystrobin raw material into the crystallizer at one time for suspension crystallization, continuing stirring the solution for 3 hours after the raw material is added, filtering the solid, and drying to obtain the product. The X-ray powder diffraction pattern of the product is shown in figure 1. The TGA and DSC curves are shown in figure 2 and figure 3. Its infrared spectrum (IR) is shown in FIG. 4. The crystal shape is similar to that of fig. 5 as a rod. Indicating that azoxystrobin acetone solvate was obtained. The volume average particle size is 46 mu m, the angle of repose is 26 degrees, no coalescence is caused, and the fluidity is good. The azoxystrobin raw material crystal form XRPD is shown as a crystal form A in figure 7.

Example 7

1.0g of the product in example 1 is taken and placed in a drying oven at 50 ℃, the vacuum degree is kept at about 0.09MPa, the product is dried for 24 hours, the XRPD pattern of the solid product analysis is as shown in figure 8, the XRPD pattern is consistent with that of figure 7, the same peak spectrum position and shape are obtained, and after TGA thermogravimetric analysis, the dried sample has no weight loss before the decomposition temperature, which indicates that the azoxystrobin acetone solvate is converted into a solvent-free compound. The obtained azoxystrobin solvent-free compound can keep the rod-like crystal morphology and the crystal granularity of the original azoxystrobin acetone solvate, and compared with a commercially available product, the obtained azoxystrobin solvent-free compound has greatly improved fluidity and is not easy to agglomerate.

Example 8

2.0g of the product in example 6 is placed in a drying oven at 80 ℃, the vacuum degree is kept at about 0.08MPa, the product is dried for 12 hours, the XRPD pattern of the solid product analysis is consistent with the XRPD pattern in figure 7, the same peak spectrum position and shape are obtained, after TG thermogravimetric analysis, the dried sample has no weight loss before the decomposition temperature, and the azoxystrobin acetone solvate is converted into a solvent-free compound. The obtained azoxystrobin solvent-free compound can keep the rod-like crystal morphology and the crystal granularity of the original azoxystrobin acetone solvate, and compared with a commercially available product, the obtained azoxystrobin solvent-free compound has greatly improved fluidity and is not easy to agglomerate.

The azoxystrobin acetone solvate provided by the invention can be used for controlling and preventing fungi growing on agricultural and horticultural crops, has the same action mechanism as the reported A, B crystal form, and has a disclosed action, so the bactericidal action of the azoxystrobin acetone solvate is not repeated herein.

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

1. An azoxystrobin acetone solvate, characterized in that the azoxystrobin acetone solvate has characteristic peaks at diffraction angles, expressed as 2 theta angles, of 7.32 + -0.20 °, 8.42 + -0.20 °, 13.26 + -0.20 °, 14.16 + -0.20 °, 18.04 + -0.20 °, 18.52 + -0.20 °, 18.90 + -0.20 °, 20.40 + -0.20 °, 21.04 + -0.20 °, 22.36 + -0.20 °, 23.96 + -0.20 °, 24.36 + -0.20 °, 26.46 + -0.20 °, 28.42 + -0.20 ° and 30.06 + -0.20 ° in its crystalline form measured using Cu-Kalpha radiation, wherein 7.32 + -0.20 ° is the initial peak and the relative intensity is 100%;

the azoxystrobin acetone solvate is prepared by adopting a constant-temperature suspension crystal transformation method, and the specific method comprises the following steps:

adding an azoxystrobin raw material into acetone, wherein the azoxystrobin raw material is added in one time or in batches for multiple times, the mass ratio of the azoxystrobin raw material to solvent acetone is 1: 0.6-4, the constant-temperature suspension crystal transition temperature is 20-50 ℃, stirring is carried out for 1-3 h, a white solid is generated, and filtering and drying are carried out to obtain the azoxystrobin acetone solvate; the azoxystrobin raw material is of a crystal form A, and XRPD of the azoxystrobin raw material is shown in figure 7;

the molar ratio of the azoxystrobin to the acetone molecule is 1:1, and the molecular formula is C₂₂H₁₇N₃O₅·C₃H₆O, there was a weight loss of 13.1% + -0.5% before heating to 80 ℃.

2. The solvate according to claim 1, wherein the azoxystrobin acetone solvate has a monoclinic crystal form and a space group of P2₁N, unit cell parameter of

α is 90.00 °; β is 98.86(3) °; gamma 90 DEG, unit cell volume of

3. The solvate of claim 1, wherein the azoxystrobin acetone solvate has a Differential Scanning Calorimetry (DSC) profile with an endothermic peak at 55.0 ± 5 ℃, an endothermic exothermic peak at 104.5 ± 5 ℃ and a characteristic melting peak at 116.6 ± 5 ℃.

4. The solvate according to claim 1, having an infrared spectrum at 3106, 3037, 2957, 1752, 1711, 1442, 1377, 1301, 1274, 1228, 1098, 941, 530cm^-1Has characteristic peaks.

5. The preparation method of the azoxystrobin acetone solvate according to any one of claims 1 to 4, which is characterized in that the azoxystrobin is added into acetone by a constant-temperature suspension crystal transformation method, the azoxystrobin is added in one time or in batches for many times, the mass ratio of the azoxystrobin to the solvent acetone is 1: 0.6-4, the constant-temperature suspension crystal transformation temperature is 20-50 ℃, the stirring is carried out for 1-3 h, a white solid is generated, and the azoxystrobin acetone solvate is obtained by filtering and drying; the azoxystrobin raw material is of a crystal form A, and XRPD of the azoxystrobin raw material is shown in figure 7.

6. Use of azoxystrobin acetone solvate according to claim 1 for the preparation of azoxystrobin solventless compounds.

7. The use as claimed in claim 6, wherein the process for the preparation of azoxystrobin solvent-free compounds is: drying the azoxystrobin acetone solvate of claim 1 at 30-90 ℃ and 0.08-0.1 MPa to obtain the azoxystrobin solvent-free compound.