WO2023103261A1 - 2-氰基-3-氨基-3-苯基丙烯酸乙酯的晶型b、制备方法和应用 - Google Patents

2-氰基-3-氨基-3-苯基丙烯酸乙酯的晶型b、制备方法和应用 Download PDF

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WO2023103261A1
WO2023103261A1 PCT/CN2022/089234 CN2022089234W WO2023103261A1 WO 2023103261 A1 WO2023103261 A1 WO 2023103261A1 CN 2022089234 W CN2022089234 W CN 2022089234W WO 2023103261 A1 WO2023103261 A1 WO 2023103261A1
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crystal form
ethyl
cyano
amino
phenylacrylate
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PCT/CN2022/089234
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English (en)
French (fr)
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马海军
曹杨
万宏剑
曹庆亮
王俊
王宁
谢欣
曹燕蕾
周亚岭
张楠楠
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江苏省农药研究所股份有限公司
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Publication of WO2023103261A1 publication Critical patent/WO2023103261A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
    • C07C255/32—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring
    • C07C255/42—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by singly-bound nitrogen atoms, not being further bound to other hetero atoms
    • 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
    • A01N25/00—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests
    • A01N25/02—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests containing liquids as carriers, diluents or solvents
    • A01N25/04—Dispersions, emulsions, suspoemulsions, suspension concentrates or gels
    • 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
    • A01N25/00—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests
    • A01N25/12—Powders or granules
    • 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
    • A01N25/00—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests
    • A01N25/12—Powders or granules
    • A01N25/14—Powders or granules wettable
    • 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
    • A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
    • A01N37/44—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids containing at least one carboxylic group or a thio analogue, or a derivative thereof, and a nitrogen atom attached to the same carbon skeleton by a single or double bond, this nitrogen atom not being a member of a derivative or of a thio analogue of a carboxylic group, e.g. amino-carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/32—Separation; Purification; Stabilisation; Use of additives
    • C07C253/34—Separation; Purification
    • 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

Definitions

  • the invention relates to the technical field of pesticides, in particular to a crystal form B of ethyl 2-cyano-3-amino-3-phenylacrylate, a preparation method and an application.
  • Different crystalline forms of an active substance may sometimes have different properties, such as in solubility, vapor pressure, dissolution rate, stability against phase change to different crystalline forms, stability during milling, suspension stability, optical and mechanical properties, hygroscopicity, crystal form and size, filterability, density, melting point, decomposition stability, color and sometimes even chemical reactivity or biological activity.
  • the present invention provides crystal form B, preparation method and application of ethyl 2-cyano-3-amino-3-phenylacrylate.
  • the invention provides a stable crystal form of ethyl 2-cyano-3-amino-3-phenylacrylate, which solves the problem of ethyl 2-cyano-3-amino-3-phenylacrylate in the prior art. Problem of irreversible particle size increase of active compound particles in liquid formulations of ester solid particles.
  • the crystal form B of ethyl 2-cyano-3-amino-3-phenylacrylate described in the present invention uses the X-ray powder diffraction method under Cu-K radiation to obtain a powder diffraction pattern at the following 2 ⁇ Angle has diffraction peaks: 8.1° ⁇ 0.2°, 8.6° ⁇ 0.2°, 12.3° ⁇ 0.2°, 17.2° ⁇ 0.2°, 19.1° ⁇ 0.2°, 23.7° ⁇ 0.2°, 24.4° ⁇ 0.2°, 25.1° ⁇ 0.2°, 26.4° ⁇ 0.2°, 41.4° ⁇ 0.2°.
  • the crystal form B of the present invention also includes diffraction peaks at the following 2 ⁇ angles: 13.4° ⁇ 0.2°, 15.7° ⁇ 0.2°, 20.4° ⁇ 0.2°, 21.3° ⁇ 0.2°, 22.3° ⁇ 0.2°.
  • the crystal form B of the present invention has characteristic absorption bands at wavelengths of 3349 cm -1 , 2212 cm -1 , 1668 cm -1 and 1678 cm -1 through Fourier transform infrared spectroscopy.
  • the weight percentage of ethyl 2-cyano-3-amino-3-phenylacrylate is at least 95%.
  • the weight percentage of ethyl 2-cyano-3-amino-3-phenylacrylate in crystal B is greater than 99%.
  • the basic catalyst is 4-dimethylaminopyridine, triethylamine, monomethylamine, dimethylamine, trimethylamine, diethylamine, pyridine, ammonia water, sodium methylate, sodium ethylate, ammonium carbonate, ammonium acetate , ammonium chloride, potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate in one or more.
  • the reaction temperature is 0-50°C.
  • the molar ratio of ethyl benzimide to ethyl cyanoacetate is 0.8-1.5:0.8-1.5.
  • the molar ratio of the basic catalyst to ethyl benzimidate is 0.005-0.05:1.
  • the stirring reaction time is 80-150 hours.
  • the reaction system of crystal B contains an organic solvent as a reaction medium.
  • the method for producing the above-mentioned crystal form B of the present invention comprises the following steps: in an organic solvent, the amorphous 2-cyano-3-amino-3-phenylacrylate ethyl ester, 2-cyano-3-
  • the crystal form A of ethyl amino-3-phenylacrylate or the mixed crystal of ethyl 2-cyano-3-amino-3-phenylacrylate is mixed with one or more kinds, and heated to 80-120°C to make it completely Dissolve, then lower the temperature at a rate of 1-20°C/h, before the solid precipitates, add the seed crystal of crystal form B, drop to 40-50°C, keep stirring for 12-24 hours, and then continue at 1-20°C/h The temperature was lowered to room temperature at a certain speed, filtered, and the product of crystal form B was obtained.
  • a seed crystal of crystal form B is added.
  • the organic solvent includes methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, ethyl acetate, methyl acetate, isopropyl acetate, butyl acetate, dicarbonate Methyl ester, toluene, chlorobenzene, xylene, methyl tert-butyl ether, diethyl ether, tetrahydrofuran, methylene chloride, 1,1-dichloroethane, 1,2-dichloroethane, acetone, ethyl cyanoacetate and one or more of ethyl benzimide.
  • the organic solvent is toluene, ethanol, ethyl cyanoacetate or ethyl benzimidate.
  • the present invention also provides a plant protection agent containing ethyl 2-cyano-3-amino-3-phenylacrylate, including the above crystal form B.
  • a plant protection agent containing ethyl 2-cyano-3-amino-3-phenylacrylate according to the present invention contains at least 95% by weight of 2-cyano-3 -Amino-3-phenylacrylate ethyl ester Form B.
  • the plant protection agent of the present invention includes a single agent containing ethyl 2-cyano-3-amino-3-phenylacrylate crystal form B and a composition containing other active components.
  • the plant protection agent of the present invention is a liquid formulation containing solid particles.
  • the plant protection agent of the present invention contains at least one additive.
  • the additives of the plant protection agent may include one or more of emulsifiers, excipients, carriers, diluents, surfactants, antifreeze agents, colorants, adhesives and plasticizers.
  • the active ingredients of the plant protection agent of the present invention are insecticides, pathogen-killing biological agents, plant nutrients, biostimulants, and plant growth regulators.
  • the plant protection agent of the present invention is in the form of a liquid formulation containing solid particles, including but not limited to granules, powders, wettable powders, water-dispersible granules, suspensions, aqueous emulsions, microemulsions, seed coatings, Sustained release agent, etc.
  • the crystal form B of ethyl 2-cyano-3-amino-3-phenylacrylate of the present invention has better stability than crystal form A, so it can be used and stored for a long time, and it is also have better biological activity.
  • Fig. 1 is the powder X-ray diffraction pattern of crystal form A
  • Fig. 2 is the infrared spectrogram of crystal form A
  • Fig. 3 is the powder X-ray diffraction pattern of crystal form B
  • Fig. 4 is the infrared spectrogram of crystal form B
  • Fig. 5 is the particle size of the 25% suspending agent of crystal form A-1 before thermal storage
  • Fig. 6 is the particle size of the 25% suspending agent of crystal form A-1 after thermal storage
  • Fig. 7 is the particle size of the 25% suspending agent of crystal form A-2 before thermal storage
  • Fig. 8 is the particle size of the 25% suspending agent of crystal form A-2 after thermal storage
  • Fig. 9 is the particle size of the 25% suspending agent of crystal form B-1 before thermal storage
  • Figure 10 is the particle size of the 25% suspending agent of crystal form B-1 after thermal storage
  • Figure 11 is the particle size of the 25% suspending agent of crystal form B-2 before thermal storage
  • Fig. 12 is the particle size of 25% suspension concentrate of crystal form B-2 after thermal storage.
  • Form A was subjected to Fourier transform infrared testing, and the results are shown in Figure 2, showing characteristic absorption bands at wavelengths of 3352cm -1 , 2214cm -1 , and 1671cm -1 .
  • the X-ray powder diffraction test of Form B at 25°C and Cu-K radiation showed the following reflections given by characteristic 2 ⁇ values: 8.12°, 8.68°, 12.32°, 13.44°, 15.72°, 17.22 °, 19.14°, 20.42°, 21.34°, 22.32°, 23.78°, 24.48°, 25.14°, 26.48°, 41.42°.
  • Form B was subjected to Fourier transform infrared testing, showing characteristic absorption bands at wavelengths of 3349cm -1 , 2212cm -1 , 1668cm -1 and 1678cm -1 .
  • the triethylamine in the reaction system is oxidized with monomethylamine, dimethylamine, trimethylamine, diethylamine, pyridine, ammonia water, sodium methoxide, sodium ethoxide, ammonium carbonate, ammonium acetate, ammonium chloride, potassium hydroxide, hydroxide Sodium, potassium carbonate, sodium carbonate, potassium bicarbonate or sodium bicarbonate are replaced, and other conditions remain unchanged, 2-cyano-3-amino-3-phenylacrylate ethyl ester crystal form B can also be obtained.
  • Embodiment 6 Effect of crystal form on dosage form stability
  • Embodiment 7 Effect of crystal form on biological activity
  • the 25% suspension of crystal form A and crystal form B was diluted step by step with sterile water according to the test design. According to the concentration gradient in Table 2, add the test agent into the PDA medium that has been sterilized and cooled to about 45°C, mix well, and pour 60 mL of medium into 3 plates on average to make a drug-containing plate.
  • the mycelium growth rate method was used. In the center of the drug-containing plate, pick up a fungus dish of Fusarium graminearum, with the mycelium facing down. Cultivate at 25°C until the blank control colonies cover more than 2/3 of the culture dish, then measure the colony diameter of each treatment. Each colony was measured twice by the cross method, and the average number represented the diameter of the colony. Calculate the inhibition of the drug on the growth rate of the bacteria.

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Abstract

本发明公开了一种2-氰基-3-氨基-3-苯基丙烯酸乙酯的晶型B、制备方法和应用。本发明的2-氰基-3-氨基-3-苯基丙烯酸乙酯的晶型B具有相比晶型A具有更优的稳定性，从而能够用与长期地保存，且其还具有更理想的生物活性。

Description

2-氰基-3-氨基-3-苯基丙烯酸乙酯的晶型B、制备方法和应用 技术领域
本发明涉及农药技术领域，特别涉及一种2-氰基-3-氨基-3-苯基丙烯酸乙酯的晶型B、制备方法和应用。
背景技术
2-氰基-3-氨基-3-苯基丙烯酸乙酯最早由Haller报道于Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences,1900,vol.130,p.1592。专利CN1160318C将其用于农作物病害的防治。Journal of the Chemical Society,1943,p.388、Pharmazie,1985,vol.40,#11,p.799–80以及CN101417962均报道了其制备的方法。这些方法产生的化合物呈无定型或者混合晶型状态。
在实际生产过程中，按照CN101417962报道的制备方法制备的2-氰基-3-氨基-3-苯基丙烯酸乙酯原药，用于含固体颗粒型液体制剂生产时，在一定的时间后，尤其在升高的温度下储存时，存在分散的活性化合物颗粒的不可逆粒度增加，这对产品质量具有显著的不利影响。
为了以工业规模生产活性物质并为了活性物质的配制，在许多情况下，关于活性物质的晶型(也描述为晶型或多晶型物)或溶剂化物的可能存在的知识、该类晶型或溶剂化物的特定性能及其制备方法的知识，均具有决定性的重要性。一些活性物质可能以数种不同的晶型存在，但也以无定型存在。多晶现象是用于这些情况的术语。多晶型物是化合物的固体晶相，其特征在于在该固体中分子的特定均匀堆积和排列。尽管全球顶尖科研小组正进行努力，活性物质晶型的存在可能性或性质仍是不可预测的并因此不可预见。一种活性物质的不同晶型有时可能具有不同性能，例如在溶解性、蒸气压、溶解速率、对相变成不同晶型的稳定性、研磨过程中的稳定性、悬浮稳定性、光学和机械性能、吸湿性、晶体形式和尺寸、过滤性、密度、熔点、分解稳定性、颜色以及有时甚至还有化学反应性或生物活性上表现出不同。
发明内容
发明目的：本发明提供了2-氰基-3-氨基-3-苯基丙烯酸乙酯的晶型B、制备方法和应用。本发明提供了一种稳定的2-氰基-3-氨基-3-苯基丙烯酸乙酯的晶型，解决了现有技术中含2-氰基-3-氨基-3-苯基丙烯酸乙酯固体颗粒的液体制剂中，活性化合物颗粒的 不可逆粒度增加的问题。
技术方案：本发明所述的2-氰基-3-氨基-3-苯基丙烯酸乙酯的晶型B，使用Cu-K辐射下的X-射线粉末衍射方法得到的粉末衍射图在如下2θ角有衍射峰：8.1°±0.2°、8.6°±0.2°、12.3°±0.2°、17.2°±0.2°、19.1°±0.2°、23.7°±0.2°、24.4°±0.2°、25.1°±0.2°、26.4°±0.2°、41.4°±0.2°。
本发明所述的晶型B，还包括在如下2θ角有衍射峰：13.4°±0.2°、15.7°±0.2°、20.4°±0.2°、21.3°±0.2°、22.3°±0.2°。
本发明所述的晶型B通过傅立叶变换红外光谱在波长3349cm -1、2212cm -1、1668cm -1和1678cm -1处的特性吸收带。
本发明所述的晶型B，2-氰基-3-氨基-3-苯基丙烯酸乙酯的重量百分含量为至少95％。
进一步地，本发明所述的晶型B，2-氰基-3-氨基-3-苯基丙烯酸乙酯在晶体B中的重量百分含量大于99％。
在0-60℃，苯甲亚胺酸乙酯和氰乙酸乙酯在碱性催化剂存在的条件下，搅拌反应，直到析出大量固体，分离得到晶型B：
Figure PCTCN2022089234-appb-000001
优选地，所述碱性催化剂为4-二甲氨基吡啶、三乙胺、一甲胺、二甲胺、三甲胺、二乙胺、吡啶、氨水、甲醇钠、乙醇钠、碳酸铵、乙酸铵、氯化铵、氢氧化钾、氢氧化钠、碳酸钾、碳酸钠、碳酸氢钾、碳酸氢钠中的一种或者多种。
优选地，所述反应温度为0-50℃。
优选地，苯甲亚胺酸乙酯与氰乙酸乙酯的摩尔比为0.8-1.5:0.8-1.5。
优选地，碱性催化剂与苯甲亚胺酸乙酯的摩尔比为0.005-0.05:1。
优选地，搅拌反应的时间为80-150小时。
作为一种可选的实施方式，晶体B的反应体系中含有作为反应介质的有机溶剂。
本发明所述的生产上述的晶型B的方法，包括以下步骤：在有机溶剂中，将无定型2-氰基-3-氨基-3-苯基丙烯酸乙酯、2-氰基-3-氨基-3-苯基丙烯酸乙酯的晶型A或者2-氰基-3-氨基-3-苯基丙烯酸乙酯的混晶一种或者多种混合，加热到80-120℃，使其完全溶解， 然后以1-20℃/h的速度降温，在固体析出前，加入晶型B的晶种，降到40-50℃，保温搅拌12-24小时，然后继续以1-20℃/h的速度降温到室温，过滤，得到晶型B的产品。
作为本发明的一种可选实施方式，在50℃-60℃时，加入晶型B的晶种。
上述的制备方法中，所述有机溶剂包括甲醇、乙醇、正丙醇、异丙醇、正丁醇、叔丁醇、乙酸乙酯、乙酸甲酯、乙酸异丙酯、乙酸丁酯、碳酸二甲酯、甲苯、氯苯、二甲苯、甲基叔丁基醚、乙醚、四氢呋喃、二氯甲烷、1,1－二氯乙烷、1,2－二氯乙烷、丙酮、氰乙酸乙酯和苯甲亚胺酸乙酯中的一种或多种。
优选地，所述有机溶剂为甲苯、乙醇、氰乙酸乙酯或者苯甲亚胺酸乙酯。
本发明还提供了含有2-氰基-3-氨基-3-苯基丙烯酸乙酯的植物保护剂，包含了上述的晶型B。
优选地，本发明所述的一种含有2-氰基-3-氨基-3-苯基丙烯酸乙酯的植物保护剂，所述植物保护剂至少含有重量百分比为95％2-氰基-3-氨基-3-苯基丙烯酸乙酯晶型B。
本发明所述的植物保护剂，包含了含有2-氰基-3-氨基-3-苯基丙烯酸乙酯晶型B的单剂以及含有其他活性组分的组合物。
本发明所述的植物保护剂为含固体颗粒的液体制剂。
本发明所述的植物保护剂，至少包含了一种添加剂。
优选地，所述植物保护剂的添加剂可以包括乳化剂、赋形剂、载体、稀释剂、表面活性剂、防冻剂、着色剂、粘合剂以及增塑剂中的一种或多种。
本发明所述的植物保护剂的活性成分杀虫剂、杀病原生物剂、植物营养物质、生物刺激素、植物生长调节物质。
本发明所述的植物保护剂，其呈含固体颗粒的液体制剂形式，包括但不限于粒剂、粉剂、可湿性粉剂、水分散粒剂、悬浮剂、水乳剂、微乳剂、种衣剂、缓释剂等。
有益效果：本发明的2-氰基-3-氨基-3-苯基丙烯酸乙酯的晶型B具有相比晶型A具有更优的稳定性，从而能够用与长期地保存，且其还具有更理想的生物活性。
附图说明
图1为晶型A的粉末X-射线衍射图；
图2为晶型A的红外光谱图；
图3为晶型B的粉末X-射线衍射图；
图4为晶型B的红外光谱图；
图5为晶型A-1的25％悬浮剂热储前粒径；
图6为晶型A-1的25％悬浮剂热储后粒径；
图7为晶型A-2的25％悬浮剂热储前粒径；
图8为晶型A-2的25％悬浮剂热储后粒径；
图9为晶型B-1的25％悬浮剂热储前粒径；
图10为晶型B-1的25％悬浮剂热储后粒径；
图11为晶型B-2的25％悬浮剂热储前粒径；
图12为晶型B-2的25％悬浮剂热储后粒径。
具体实施方式
下列实施例用于说明本发明,但不限制本发明。
对照例1：(参见CN 101417962)
将220g氰乙酸乙酯溶于300mL乙醇的反应瓶中，将该反应瓶内温度控制在5～10℃，加入395g苯甲亚氨酸乙酯盐酸盐，在此温度下滴入适量的三乙胺，将反应液的pH值调到8～9，随后升温回流，回流5～6小时，缓慢冷却至室温，用冰浴冷至0～5℃，保持1小时，将固体滤出，得产品397g，含量97.3％，收率为89.0％。熔点是122～124℃。经X-射线衍射检测，为2-氰基-3-氨基-3-苯基丙烯酸乙酯晶型A(晶型A)。
将晶型A在25℃和Cu-K辐射下的X-射线粉末衍射测试，结果显示出特征的2θ值给出的下列反射，结果如图1所示：8.18°、11.92°、14.46°、16.40°、17.16°、18.70°、19.34°、23.28°、24.70°、26.60°、27.56°、28.40°、41.76°。
将晶型A进行傅立叶变换红外测试，结果如图2所示，显示在波长3352cm -1、2214cm -1、1671cm -1处的特性吸收带。
实施例1：2-氰基-3-氨基-3-苯基丙烯酸乙酯晶型B的制备
将苯甲亚氨酸乙酯149g(1mol)、氰乙酸乙酯169.5g(1.5mol)、4-二甲氨基吡啶1g加入到四口瓶中，控制反应温度0℃，搅拌反应48小时，有固体逐渐析出，继续搅拌反应150小时，过滤，用50mL乙醇洗涤，烘干，得到白色砂状颗粒产品158g，含量99％，收率73.1％。经X-射线衍射检测，为晶型B。
将晶型B在25℃和Cu-K辐射下的X-射线粉末衍射测试，结果显示出特征的2θ值给出的下列反射：8.12°、8.68°、12.32°、13.44°、15.72°、17.22°、19.14°、20.42°、21.34°、22.32°、23.78°、24.48°、25.14°、26.48°、41.42°。
将晶型B进行傅立叶变换红外测试，显示在波长3349cm -1、2212cm -1、1668cm -1和1678cm -1处的特性吸收带。
实施例2：2-氰基-3-氨基-3-苯基丙烯酸乙酯晶型B的制备
将苯甲亚氨酸乙酯223.5g(1.5mol)、氰乙酸乙酯113g(1mol)、5g三乙胺加入到四口瓶中，控制反应温度30℃，搅拌反应15小时，有固体逐渐析出，继续搅拌反应100小时，过滤，用50mL乙醇洗涤，烘干，得到白色砂状颗粒产品141g，含量99％，收率65.3％。经X-射线衍射检测，为2-氰基-3-氨基-3-苯基丙烯酸乙酯晶型B(晶型B)。
实施例3：2-氰基-3-氨基-3-苯基丙烯酸乙酯晶型B的制备
将苯甲亚氨酸乙酯149g(1mol)、氰乙酸乙酯113g(1mol)、5g三乙胺、50mL乙醇加入到四口瓶中，控制反应温度50℃，搅拌反应10小时，有固体逐渐析出，继续搅拌反应36小时，过滤，用50mL乙醇洗涤，烘干，得到白色砂状颗粒产品142g，含量99％，收率65.7％。经X-射线衍射检测，为晶型B。
将反应体系中的三乙胺用一甲胺、二甲胺、三甲胺、二乙胺、吡啶、氨水、甲醇钠、乙醇钠、碳酸铵、乙酸铵、氯化铵、氢氧化钾、氢氧化钠、碳酸钾、碳酸钠、碳酸氢钾或碳酸氢钠代替，其他条件不变，同样可以制得2-氰基-3-氨基-3-苯基丙烯酸乙酯晶型B。
实施例4：2-氰基-3-氨基-3-苯基丙烯酸乙酯晶型B的制备
将晶型A或混晶的2-氰基-3-氨基-3-苯基丙烯酸乙酯产品150g和300mL乙醇加入到1000mL四口瓶，搅拌，加热到80℃，固体完全溶解。然后按照10℃/h的速度降温，当液温到达60℃时，加入3g的晶型B产品作为晶种，继续降温到50℃，在此温度保温搅拌12小时，然后继续按照10℃/h的速度降温到室温。过滤，50mL乙醇洗涤，烘干，得到108g白色固体。经X-射线衍射检测，为晶型B。
实施例5：2-氰基-3-氨基-3-苯基丙烯酸乙酯晶型B的制备
将晶型A或混晶的2-氰基-3-氨基-3-苯基丙烯酸乙酯产品150g和400mL甲苯加入到1000mL四口瓶，搅拌，加热到110℃，固体完全溶解。然后按照5℃/h的速度降温，当液温到达60℃时，加入3g的晶型B产品作为晶种，继续按照5℃/h降温到40℃，在此温度保温搅拌12小时，然后继续按照5℃/h的速度降温到室温。过滤，50mL甲苯洗涤，烘干，得到115g白色固体。经X-射线衍射检测，为晶型B。
实施例6：晶型对剂型稳定性的影响
按照以下组分制备25％悬浮剂：2-氰基-3-氨基-3-苯基丙烯酸乙酯25重量份(晶型A 或者实施例3制备的晶型B)、润湿剂对甲基脂肪酰胺基苯磺酸钠6重量份、分散剂烷基酚聚氧乙烯醚甲醛缩合物2重量份、增稠剂羧甲基纤维素纳6重量份、防腐剂水杨酸钠1重量份、防冻剂丙二醇2重量份、消泡剂硅油1重量份，水57重量份，按悬浮剂加工工艺进行加工，分别制备成25％晶型A的悬浮剂和25％晶型B的悬浮剂，加工结束后，用粒度仪进行颗粒粒度检测，其中，每种晶型选取两个不同批次的样品进行对比实验。
将样品按照《GB/T 19136-2003农药热贮稳定性测定方法》在54±2℃条件下，进行热贮14天，然后再次用用粒度仪进行颗粒粒度检测。
检测结果如下：
表1 25％晶型A悬浮剂与25％晶型B悬浮剂热贮结果
Figure PCTCN2022089234-appb-000002
从表1和图5-图12测试结果显示，晶型B制备的悬浮剂，稳定性明显高于晶型A制备的悬浮剂。
实施例7：晶型对生物活性的影响
7.1试验剂量设计
表2 测试药剂用量
编号 药剂 浓度(mg/L)
1 晶型A 25％悬浮剂 0.01、0.1、0.5、1、10、50
2 晶型B 25％悬浮剂 0.01、0.1、0.5、1、10、50
7.2试验方法
晶型A和晶型B的25％的悬浮剂，根据试验设计用无菌水逐级稀释。将测试药剂按照表2的的浓度梯度，分别加入经灭菌并冷却至45℃左右的PDA培养基中混匀，每瓶培养基60mL，平均倒入3个平皿，制成含药平板。
采用菌丝长速率法。在含药平板中央接一小麦赤霉病菌[Fusarium graminearum]菌碟，菌丝朝下。25℃培养至空白对照菌落布满培养皿2/3以上时，测量各处理的菌落直 径。每个菌落按十字交叉法测量2次，以其平均数代表菌落直径的大小。计算药剂对菌体生长率的抑制。
Figure PCTCN2022089234-appb-000003
7.3试验结果
表3 晶型A、晶型B 25％悬浮剂对小麦赤霉病的毒力测定
Figure PCTCN2022089234-appb-000004
从表3的试验结果可以看出，晶型B制成的25％悬浮剂，在活性表现上，要优于晶型A制成的25％悬浮剂。

Claims (10)

  1. 一种2-氰基-3-氨基-3-苯基丙烯酸乙酯的晶型B，其特征在于，使用Cu-K辐射下的X-射线粉末衍射方法得到的粉末衍射图在如下2θ角有衍射峰：8.1°±0.2°、8.6°±0.2°、12.3°±0.2°、17.2°±0.2°、19.1°±0.2°、23.7°±0.2°、24.4°±0.2°、25.1°±0.2°、26.4°±0.2°、41.4°±0.2°。
  2. 根据权利要求1所述的晶型B，其特征在于，还包括在如下2θ角有衍射峰：13.4°±0.2°、15.7°±0.2°、20.4°±0.2°、21.3°±0.2°、22.3°±0.2°。
  3. 根据权利要求1所述的晶型B，其特征在于，通过傅立叶变换红外光谱在波长3349cm -1、2212cm -1、1668cm -1和1678cm -1处的特性吸收带。
  4. 根据权利要求1所述的晶型B，其特征在于，2-氰基-3-氨基-3-苯基丙烯酸乙酯的重量百分含量至少为95％。
  5. 根据权利要求1-4任一所述的晶型B的制备方法，其特征在于，在0-60℃，苯甲亚胺酸乙酯和氰乙酸乙酯在碱性催化剂存在的条件下，搅拌反应，直到析出大量固体，分离得到晶型B：
    Figure PCTCN2022089234-appb-100001
  6. 根据权利要求5所述的晶型B的制备方法，其特征在于，所述碱性催化剂为4-二甲氨基吡啶、三乙胺、一甲胺、二甲胺、三甲胺、二乙胺、吡啶、氨水、甲醇钠、乙醇钠、碳酸铵、乙酸铵、氯化铵、氢氧化钾、氢氧化钠、碳酸钾、碳酸钠、碳酸氢钾、碳酸氢钠中的一种或者多种。
  7. 一种如权利要求1-4任一所述的晶型B的制备方法，其特征在于，包括以下步骤：在有机溶剂中，将无定型2-氰基-3-氨基-3-苯基丙烯酸乙酯、2-氰基-3-氨基-3-苯基丙烯酸乙酯的晶型A或者2-氰基-3-氨基-3-苯基丙烯酸乙酯的混晶中的一种或者多种混合，加热到80-120℃，使其完全溶解，然后以1-20℃/h的速度降温，在固体析出前，加入晶型B的晶种，降到40-50℃，保温搅拌12-24小时，然后继续以1-20℃/h的速度降温到室温，过滤，得到晶型B的产品。
  8. 根据权利要求7所述的晶型B的制备方法，其特征在于，所述有机溶剂为甲醇、乙醇、正丙醇、异丙醇、正丁醇、叔丁醇、乙酸乙酯、乙酸甲酯、乙酸异丙酯、乙酸丁 酯、碳酸二甲酯、甲苯、氯苯、二甲苯、甲基叔丁基醚、乙醚、四氢呋喃、二氯甲烷、1,1－二氯乙烷、1,2－二氯乙烷、丙酮、氰乙酸乙酯和苯甲亚胺酸乙酯中的一种或多种。
  9. 一种含有2-氰基-3-氨基-3-苯基丙烯酸乙酯的植物保护剂，其特征在于，包含如权利要求1所述的晶型B。
  10. 根据权利要求9所述的植物保护剂，其特征在于，所述植物保护剂为含固体颗粒的液体制剂。
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