CN113912659A - Emamectin benzoate crystal and amorphous crystal of emamectin B2a and preparation method thereof - Google Patents
Emamectin benzoate crystal and amorphous crystal of emamectin B2a and preparation method thereof Download PDFInfo
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- CN113912659A CN113912659A CN202111454671.1A CN202111454671A CN113912659A CN 113912659 A CN113912659 A CN 113912659A CN 202111454671 A CN202111454671 A CN 202111454671A CN 113912659 A CN113912659 A CN 113912659A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
- C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
- C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/90—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having two or more relevant hetero rings, condensed among themselves or with a common carbocyclic ring system
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/41—Preparation of salts of carboxylic acids
- C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
- C07C51/43—Separation; Purification; Stabilisation; Use of additives by change of the physical state, e.g. crystallisation
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C63/00—Compounds having carboxyl groups bound to a carbon atoms of six-membered aromatic rings
- C07C63/04—Monocyclic monocarboxylic acids
- C07C63/06—Benzoic acid
- C07C63/08—Salts thereof
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
- C07H1/06—Separation; Purification
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The invention discloses an amorphous crystal of emamectin benzoate B2a, a crystal form A and a preparation method thereof, belonging to the technical field of pesticides, wherein an X-ray powder diffraction spectrogram of the amorphous crystal expressed by a 2 theta +/-0.2 degree diffraction angle is basically consistent with a peak form in a figure 1, and an X-ray powder diffraction spectrogram of the crystal form A expressed by a 2 theta +/-0.2 degree diffraction angle is basically consistent with a peak form in a figure 2. The amorphous emamectin benzoate B2a and emamectin benzoate B2a crystal form A provided by the invention have high stability, the content is basically not reduced after the amorphous emamectin benzoate B2a and the emamectin benzoate B2a are stored for 3 months at 65 ℃, the crystal form is not transformed, and particularly the solubility of the amorphous emamectin benzoate B2a in water is greatly increased.
Description
Technical Field
The invention belongs to the technical field of pesticides, and particularly relates to emamectin benzoate B2a benzoate crystals, non-crystals and a preparation method thereof.
Background
The abamectin is a macrolide compound separated from a streptomyces fermentation product, and has insecticidal and acaricidal activity. The pesticide contains 8 components, but mainly contains B1a and B2a, the total content of the two components is more than 80%, wherein the structure of B1a is modified to obtain emamectin benzoate, so that the toxicity of the emamectin benzoate is reduced, the activity and the stability of the emamectin benzoate are further improved, and the emamectin benzoate is an ultra-efficient, low-toxicity, low-residue and pollution-free biological pesticide. The other main component B2a in abamectin has special effect on underground nematode and pests on animal body surface. With the current progress of the B2a extraction technology, the B2a technical product with the purity of more than 95% can be conveniently obtained, but the market promotion stage is not reached due to the reasons of stability, activity and the like. At present, the research is more carried out by carrying out structural modification on B2a by analogy to B1a so as to improve insecticidal activity, reduce toxicity and improve stability. At present, emamectin benzoate B2a is a case of successfully modifying the structure of B2a, and has the advantages of high activity, low toxicity and good stability.
The existing synthesis method of emamectin benzoate B2a is as follows: firstly, esterifying hydroxyl at the site of abamectin B2a 5 for protection, then carrying out Swern oxidation reaction, and oxidizing hydroxyl at the site of abamectin 4' into carbonyl to obtain an abamectin B2a ketone compound; and then carrying out 4 'site amination and reduction reaction on the abamectin B2a ketone compound, converting 4' site carbonyl into methylamino, removing 5 site protecting group after the reaction is finished, washing, drying and desolventizing to obtain a coarse methylamino abamectin B2a product, dissolving the coarse methylamino abamectin B2a product by using isopropyl acetate, adding benzoic acid to form a salt, adding n-hexane or petroleum ether solvent to crystallize, and obtaining the methylamino abamectin B2a benzoate.
As is well known, the polymorphism of a compound is one of important factors influencing the quality and the application effect of a medicament, and different crystal forms influence the dissolution rate and the bioavailability of the medicament and produce different application effects, so that the compound has very important significance for the research of the crystal forms of the medicament.
Disclosure of Invention
According to the invention, an amorphous crystal and an emamectin benzoate B2a crystal A are respectively obtained by crystallizing emamectin benzoate B2a in an organic solvent and water mixed solvent, and the amorphous crystal has high solubility and stability.
In order to achieve the purpose, the technical scheme provided by the invention is as follows:
an amorphous emamectin benzoate B2a, wherein an X-ray powder diffraction spectrogram of a crystal form of the emamectin benzoate B2a expressed by a 2 theta +/-0.2-degree diffraction angle is basically consistent with a peak form shown in a figure 1.
The preparation method of the amorphous emamectin benzoate B2a comprises the following steps: dissolving emamectin benzoate B2a in a mixed solution of an organic solvent and water, adding benzoic acid, stirring at 50-80 ℃ to form salt, and evaporating the solvent under reduced pressure to obtain an emamectin benzoate B2a amorphous solid.
The technical scheme of the invention is further improved as follows: the organic solvent is alcohols, nitriles or ethers, including ethanol, acetonitrile, tetrahydrofuran or dioxane.
The technical scheme of the invention is further improved as follows: the mixed liquid of the organic solvent and the water has the proportion of 1-20:1, and the addition amount of the benzoic acid is 1-1.2 times of the molar amount of the emamectin benzoate B2 a.
An emamectin benzoate B2a crystal form A has obvious characteristic peaks at 5.87, 7.12, 7.78, 8.51, 9.22, 9.93, 11.49, 11.99, 12.70, 13.50, 14.19, 14.48, 15.48, 15.87, 16.47, 16.95, 17.98, 18.79, 19.85, 20.12, 20.37, 20.83, 21.37, 23.39, 24.34, 26.45 and 28.73 by using an X-ray powder diffraction spectrum expressed by a 2 theta +/-0.2 DEG diffraction angle by using Cu-Ka radiation.
The technical scheme of the invention is further improved as follows: the X-ray powder diffraction spectrogram of the emamectin benzoate B2a expressed by the 2 theta +/-0.2-degree diffraction angle is basically consistent with the peak type shown in the attached figure 2.
The preparation method of the emamectin benzoate B2a benzoate crystal form A comprises the following steps: dissolving emamectin benzoate B2a in a mixed solution of an organic solvent and water, adding benzoic acid, stirring at 50-80 ℃ to form salt, evaporating part of the organic solvent under reduced pressure, slowly cooling to-5-0 ℃ to crystallize to obtain emamectin benzoate B2a crystals, filtering, and drying to obtain emamectin benzoate B2a benzoate crystal form A.
The technical scheme of the invention is further improved as follows: the organic solvent is alcohols, nitriles or ethers, including ethanol, acetonitrile, tetrahydrofuran or dioxane.
The technical scheme of the invention is further improved as follows: the mixed liquid of the organic solvent and the water has the proportion of 1-20:1, and the addition amount of the benzoic acid is 1-1.2 times of the molar amount of the emamectin benzoate B2 a.
The emamectin benzoate B2a benzoate composition has the main medicinal components including emamectin benzoate B2a in crystal form A or amorphous emamectin benzoate B2a, and the composition is in the form of emulsion, emulsion in water, microemulsion, granule or suspension.
The emamectin benzoate B2a composition has the main medicinal effect component including amorphous emamectin benzoate B2a or emamectin benzoate B2a in crystal form A, and is used for resisting underground nematode and animal body surface pest.
Due to the adoption of the technical scheme, the invention has the following technical effects:
compared with the prior art, the amorphous emamectin benzoate B2a and emamectin benzoate B2a crystal form A provided by the invention have high stability, the content is basically not reduced after the amorphous emamectin benzoate B2a and the crystal form is not transformed after the amorphous emamectin benzoate B2a is stored for 3 months at 65 ℃. Especially, the solubility of the amorphous emamectin benzoate B2a in water is greatly increased. The amorphous emamectin benzoate B2a can be used for preparing granules, suspending agents, missible oil and other dosage forms with better activity, and has good application prospect.
Drawings
FIG. 1 is an X-ray powder diffraction pattern of amorphous emamectin benzoate B2 a;
FIG. 2 is an X-ray powder diffraction pattern of emamectin benzoate B2a phenyl hydrochloride crystal A;
fig. 3 is a plot of the amount of dissolved emamectin benzoate B2a, crystalline form a, and emamectin benzoate B2a as a solid in the prior art versus time.
Detailed Description
Example 1
113g (0.1mol) of methylamino abamectin B2a (80%) is taken, 200g of ethanol and 40g of water are added, the mixture is heated and dissolved, 14.6g of benzoic acid is added, the mixture is stirred for 2 hours at 80 ℃, ethanol and water are evaporated out under reduced pressure, and the mixture is dried at 100 ℃ to obtain 125g of methylamino abamectin B2a phenyl hydrochloride crystal with the content of 82.1%. The crystal is irradiated at 25 ℃ by using Cu-Ka, and an X-ray powder diffraction pattern expressed by 2 theta angle is shown in figure 1 and is in an amorphous state.
Example 2
113g (0.1mol) of emamectin benzoate B2a (80%) is taken, 200g of acetonitrile and 10g of water are added, the mixture is heated and dissolved, 13.4g of benzoic acid is added, the mixture is stirred for 2 hours at 80 ℃, 120g of acetonitrile is evaporated out under reduced pressure, the temperature is slowly reduced to-5 ℃, the mixture is stirred for 5 hours, crystals are separated out, the crystals are filtered and dried at 80 ℃, and 64.1g of emamectin benzoate B2a benzoate A crystals with the content of 96% are obtained.
Example 3
113g (0.1mol) of methylamino abamectin B2a (80%) is taken, 200g of ethanol and 40g of water are added, the mixture is heated and dissolved, 12.8g of benzoic acid is added, the mixture is stirred for 2 hours at 80 ℃, 120g of ethanol is evaporated out under reduced pressure, the temperature is slowly reduced to 0 ℃, the mixture is stirred for 5 hours, crystals are separated out, the crystals are filtered and dried at 80 ℃, and the methylamino abamectin B2a phenyl carboxylate crystal A90.8g with the content of 96% is obtained.
An X-ray powder diffraction pattern of the crystal at 25 ℃ by using Cu — Ka radiation and a 2 θ angle is shown in fig. 2, and the crystal has a maximum peak at a 2 θ angle of 11.49, and has a peak height of 100%, and peak diffraction angles of 5.87, 7.12, 7.78, 8.51, 9.22, 9.93, 11.49, 11.99, 12.70, 13.50, 14.19, 14.48, 15.48, 15.87, 16.47, 16.95, 17.98, 18.79, 19.85, 20.12, 20.37, 20.83, 21.37, 23.39, 24.34, 26.45, and 28.73, wherein the peak height is 10% or more. Detailed data of X-ray powder diffraction are shown in Table 1
TABLE 1 XRD data Table of emamectin B2a Phenylate Crystal A
Example 4
53.4g (0.05mol) of methylamino abamectin B2a benzoate (96%) in example 3 is taken, 50g of dioxane and 50g of water are added, the mixture is heated to 60 ℃ and stirred for 2 hours to be dissolved, dioxane and water are evaporated out under reduced pressure, and amorphous methylamino abamectin B2a phenyl carboxylate crystals with the content of 96% are obtained after drying at 100 ℃.
Example 5
113g (0.1mol) of methylamino abamectin B2a (80%) is taken, 100g of methanol and 100g of water are added, the mixture is heated and dissolved, 12.2g of benzoic acid is added, the mixture is stirred for 2 hours at the temperature of 60 ℃, 50g of methanol is evaporated out under reduced pressure, the temperature is slowly reduced to 0 ℃, the mixture is stirred for 5 hours, the mixture is filtered and dried at the temperature of 80 ℃, and 97.2g of methylamino abamectin B2a phenylate A crystal with the content of 95% is obtained.
Example 6
Taking 108g (95 percent, 0.1mol) of the solid emamectin B2a phenyl acid salt crystal in the comparative example 1, adding 200g of ethanol and 40g of water, heating for dissolving, decompressing to evaporate the ethanol and the water, drying at 100 ℃ to obtain 108g of the solid emamectin B2a phenyl acid salt, wherein the content of the solid is 95 percent, and the solid is in an amorphous state through X-ray powder diffraction detection.
Example 7
113g (0.1mol) of methylamino abamectin B2a (80%) is taken, 200g of tetrahydrofuran and 40g of water are added, the mixture is heated and dissolved, 12.2g of benzoic acid is added, the mixture is stirred for 2 hours at 80 ℃, 100g of tetrahydrofuran is evaporated out under reduced pressure, the temperature is slowly reduced to 0 ℃, the mixture is stirred for 5 hours, the mixture is filtered and dried at 80 ℃, and 88.5g of methylamino abamectin B2a phenyl hydrochloride crystal A with the content of 96% is obtained.
Example 8
Preparing methylamino abamectin benzoate missible oil: and (2) taking 640g of S-150 solvent oil and 298g of amorphous emamectin benzoate B2a benzoate solid, stirring, and adding 60g of emulsifier glycerol stearate and 2g of antioxidant BHT with the content of 29.8%.
Example 9
Preparing an emamectin benzoate aqueous emulsion: 199g of S-150 solvent oil and 2g of methylamino abamectin B2a benzoate A solid are taken, 50g of emulsifier glycerol stearate and 2g of antioxidant BHT are added, and an oil phase is obtained after stirring and dissolving; and sequentially adding 30g of antifreeze ethylene glycol and 399g of deionized water, and stirring at a high speed for 2 hours to obtain the emamectin benzoate aqueous emulsion with the content of 0.2 percent.
Comparative example 1 (preparation method in the prior art)
113g (0.1mol) of methylamino abamectin B2a (80%) is taken, 200g of isopropyl acetate is added, the mixture is heated and dissolved, 12.2g of benzoic acid is added, 200g of n-hexane is added, the temperature is slowly reduced to 20 ℃, the mixture is stirred for 5 hours, the mixture is filtered, and the mixture is dried at 80 ℃ to obtain 95.1g of methylamino abamectin B2a phenyl acid salt solid with the content of 95%.
Physical and chemical stability
The content of the amorphous emamectin benzoate B2a obtained in example 1, the crystal A obtained in example 3 and the emamectin benzoate B2a solid obtained in comparative example 1 are all 95.0% by HPLC detection. The three powders are respectively placed in ovens at 25 ℃, 45 ℃ and 65 ℃, and are stored for 3 months, and the crystal form and the content of the powder after three months are detected, and the results are shown in the following table 2.
TABLE 2 Emamectin B2a benzoate Heat storage test data
As can be seen from Table 2, the emamectin benzoate B2a in the crystal form A and the solid and amorphous forms in the comparative example 1 have good stability at the test temperature, and the content reduction is not obvious. The powder X-ray diffraction pattern expressed by the angle of 2 theta has no obvious change and no change of crystal form by using Cu-Ka radiation at 25 ℃.
Determination of solubility in Water
Taking 1kg of water, keeping the temperature to 25 ℃, adding emamectin benzoate B2a benzoate A crystal form solid, stirring and timing to keep insoluble solid, sampling at different times, detecting the content of emamectin benzoate B2a by using a high performance liquid chromatography, calculating the dissolved amount, and calculating the solubility in the water after the content of emamectin benzoate B2a in the water is not increased any more. The solubility of the comparative solid and the amorphous solid were determined in the same manner. The solubility data for the three solids in water are shown in table 3, and the amount of dissolution as a function of time is shown in figure 3.
TABLE 3 solubility of emamectin benzoate B2a solid
From table 3, it can be seen that the solubility of the amorphous emamectin benzoate B2a in water is higher, which is significantly higher than that of the emamectin benzoate B2a obtained by the prior art preparation method and the crystal form a.
From fig. 3, it can be seen that the solubility of the amorphous emamectin benzoate B2a in water is increased, and the dissolution rate is faster. Is obviously superior to the solid prepared by the method of the crystal form A and the comparative example 1.
Claims (10)
1. An amorphous emamectin benzoate B2a, which is characterized in that: the X-ray powder diffraction spectrogram of the emamectin benzoate B2a expressed by the 2 theta +/-0.2-degree diffraction angle is basically consistent with the peak type shown in the figure 1.
2. The amorphous emamectin benzoate B2a according to claim 1, which is prepared by the following steps: dissolving emamectin benzoate B2a in a mixed solution of an organic solvent and water, adding benzoic acid, heating to 50-80 ℃, stirring to form salt, and evaporating the solvent under reduced pressure to obtain an emamectin benzoate B2a amorphous solid.
3. The emamectin benzoate B2a benzoate crystal form A is characterized in that: the emamectin benzoate B2a crystal form has an X-ray powder diffraction spectrum expressed by a 2 theta +/-0.2 DEG diffraction angle and has obvious characteristic peaks at 5.87, 7.12, 7.78, 8.51, 9.22, 9.93, 11.49, 11.99, 12.70, 13.50, 14.19, 14.48, 15.48, 15.87, 16.47, 16.95, 17.98, 18.79, 19.85, 20.12, 20.37, 20.83, 21.37, 23.39, 24.34, 26.45 and 28.73 by using Cu-Ka radiation.
4. The emamectin benzoate crystal form a of claim 3, wherein the emamectin benzoate crystal form a is characterized in that: the X-ray powder diffraction spectrogram of the emamectin benzoate B2a crystal form A expressed by the diffraction angle of 2 theta +/-0.2 degrees is basically consistent with the peak form shown in the attached figure 2.
5. The emamectin benzoate B2a crystal form A according to claim 3, which is prepared by the following steps: dissolving emamectin benzoate B2a in a mixed solution of an organic solvent and water, adding benzoic acid, heating to 50-80 ℃, stirring to form salt, decompressing to evaporate part of the organic solvent, slowly cooling to-5-0 ℃, crystallizing to obtain emamectin benzoate B2a crystal, filtering, and drying to obtain emamectin benzoate B2a crystal form A.
6. An amorphous emamectin benzoate B2a in accordance with claim 2, wherein: the organic solvent is any one of alcohols, nitriles and ethers.
7. The preparation method of the amorphous emamectin benzoate B2a according to claim 6, wherein the preparation method comprises the following steps: the mixed liquid of the organic solvent and water, wherein the ratio of the organic solvent to the water is 1-20: 1; the adding amount of the benzoic acid is 1 to 1.2 times of the molar amount of the emamectin benzoate B2 a.
8. The emamectin benzoate crystal form A of claim 5, wherein the emamectin benzoate B2a is characterized in that: the organic solvent is any one of alcohols, nitriles and ethers.
9. The emamectin benzoate crystal form a of claim 8, wherein the emamectin benzoate crystal form a is characterized in that: the mixed liquid of the organic solvent and water, wherein the ratio of the organic solvent to the water is 1-20: 1; the adding amount of the benzoic acid is 1 to 1.2 times of the molar amount of the emamectin benzoate B2 a.
10. An emamectin benzoate B2a benzoate composition, which is characterized in that: the main active ingredients of the composition comprise emamectin benzoate B2a benzoate crystal form A or amorphous emamectin benzoate B2a, and the composition is in the form of any one of missible oil, aqueous emulsion, microemulsion, granules or suspending agent.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108484702A (en) * | 2018-01-27 | 2018-09-04 | 湖北荆洪生物科技股份有限公司 | A kind of synthetic method of emamection benaoate |
| CN108840893A (en) * | 2018-07-01 | 2018-11-20 | 李万强 | A kind of novel crystal forms of emamectin-benzoate and preparation method thereof |
| CN111748009A (en) * | 2020-07-22 | 2020-10-09 | 齐鲁晟华制药有限公司 | Emamectin benzoate hydrate crystal form and preparation method thereof |
| CN112707939A (en) * | 2020-12-25 | 2021-04-27 | 河北威远生物化工有限公司 | Purification method of 4' -(s) -emamectin benzoate B2a |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108484702A (en) * | 2018-01-27 | 2018-09-04 | 湖北荆洪生物科技股份有限公司 | A kind of synthetic method of emamection benaoate |
| CN108840893A (en) * | 2018-07-01 | 2018-11-20 | 李万强 | A kind of novel crystal forms of emamectin-benzoate and preparation method thereof |
| CN111748009A (en) * | 2020-07-22 | 2020-10-09 | 齐鲁晟华制药有限公司 | Emamectin benzoate hydrate crystal form and preparation method thereof |
| CN112707939A (en) * | 2020-12-25 | 2021-04-27 | 河北威远生物化工有限公司 | Purification method of 4' -(s) -emamectin benzoate B2a |
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| 杨红梅主编: "《药剂学》", 31 July 2020, 天津：天津科学技术出版社 * |
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