WO2019020000A1 - 一种米尔贝a4肟晶型a及其制备方法 - Google Patents

一种米尔贝a4肟晶型a及其制备方法 Download PDF

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WO2019020000A1
WO2019020000A1 PCT/CN2018/096777 CN2018096777W WO2019020000A1 WO 2019020000 A1 WO2019020000 A1 WO 2019020000A1 CN 2018096777 W CN2018096777 W CN 2018096777W WO 2019020000 A1 WO2019020000 A1 WO 2019020000A1
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milbe
solvent
milbemycin
twin
controlled
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PCT/CN2018/096777
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English (en)
French (fr)
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滕云
江连清
应雪肖
郑玲辉
白骅
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浙江海正药业股份有限公司
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Priority to CN201880047116.7A priority Critical patent/CN111094296A/zh
Publication of WO2019020000A1 publication Critical patent/WO2019020000A1/zh

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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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/22—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains four or more hetero rings

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  • the invention relates to the field of pharmacy, especially in the field of veterinary medicine. More specifically, the present invention relates to milbe A4 phthalocyanine A and a process for the preparation thereof and the use of the crystal form as an insecticidal acaricide.
  • Milbemycin is a microbial natural product pesticide, and it has been shown to be one of the best acaricides in the world today.
  • the US Environmental Protection Agency identified it as a low-risk pesticide, and the Netherlands approved it as “GNO” (a natural product in crop production). It is an eco-friendly pesticide and is suitable for the comprehensive prevention and control of organic agricultural pests and diseases. It has become a popular insecticide and acaricide in developed countries.
  • Milbemycin is a metabolite with insect resistance activity selected from the fermentation broth of microorganisms by the Japanese Sankyo Company as a test insect (US 3,950,360). After extensive basic research, a mixture of milbemycin A3 and A4 components was used as an acaricide in 1983. Milbemycin semi-synthetic compound Milbemycin oxime A3/A4 (Milbemycin oxime A3/A4) has also been commercialized for veterinary medicine. The commercial Milbemycin is a mixed component of A3 and A4 and is an amorphous powder.
  • the single component crystalline form has many advantages in formulation and pharmacodynamics, such as: stable nature, ease of storage, ease of dissolution, ease of dispersion, ability to form a homogeneous solution, and the like. Since the mixture of A3/A4 is difficult to obtain a crystal form, the present invention has prepared a single component of A4, and obtained Form A.
  • the milbeir A4 twin form A of the present invention uses Cu-K ⁇ radiation, and the X-ray powder diffraction (XRPD) pattern represented by the 2 ⁇ angle has characteristic peaks at the following positions: 8.39 ⁇ 0.20°, 10.12 ⁇ 0.20°, 14.29 ⁇ 0.20°, 15.24 ⁇ 0.20°, 15.71 ⁇ 0.20°, 16.10 ⁇ 0.20°.
  • XRPD X-ray powder diffraction
  • the milbeir A4 twin form A of the present invention also has characteristic peaks at the following 2 ⁇ diffraction angles: 4.02 ⁇ 0.20°, 10.48 ⁇ 0.20°, 10.97 ⁇ 0.20°, 12.26 ⁇ 0.20°, 12.97 ⁇ 0.20°, 14.75. ⁇ 0.20°, 17.18 ⁇ 0.20°, 17.64 ⁇ 0.20°, 19.34 ⁇ 0.20°, 22.94 ⁇ 0.20°.
  • the milbeir A4 twin form A of the present invention also has characteristic peaks at the following 2 ⁇ diffraction angles: 4.02 ⁇ 0.20°, 6.95 ⁇ 0.20°, 7.37 ⁇ 0.20°, 9.26 ⁇ 0.20°, 10.48 ⁇ 0.20°, 10.97. ⁇ 0.20°, 11.41 ⁇ 0.20°, 12.26 ⁇ 0.20°, 12.97 ⁇ 0.20°, 14.75 ⁇ 0.20°, 17.18 ⁇ 0.20°, 17.64 ⁇ 0.20°, 17.89 ⁇ 0.20°, 19.34 ⁇ 0.20°, 19.93 ⁇ 0.20°, 21.53 ⁇ 0.20°, 22.94 ⁇ 0.20°23.52 ⁇ 0.20°, 24.65 ⁇ 0.20°, 26.28 ⁇ 0.20°.
  • the XRPD pattern of the milbeir A4 twin form A of the present invention is shown in FIG.
  • the milbeir A4 twin form A of the present invention can also be characterized by an infrared absorption spectrum measured by KBr tableting, according to which the characteristic peaks are at the following positions: 3567 cm -1 , 3433 cm -1 , 2963cm -1 , 2923cm -1 , 2872cm -1 , 1746cm -1 , 1727cm -1 , 1714cm -1 , 1676cm -1 , 1654cm -1 , 1629cm -1 , 1560cm -1 , 1541cm -1 , 1507cm -1 , 1452cm - 1 , 1436 cm -1 , 1375 cm -1 , 1335 cm -1 , 1274 cm -1 , 1243 cm -1 , 1178 cm -1 , 1165 cm -1 , 1115 cm -1 , 1103 cm -1 , 1061 cm -1 , 1040 cm -1 , 964 cm -1 .
  • the infrared absorption spectrum of the milbeir A4 crystallization type A of the present invention is still 906 cm -1 , 865 cm -1 , 823 cm -1 , 803 cm -1 , 683 cm -1 , 501 cm -1 , 488 cm -1 and 460 cm -1 . There are characteristic peaks.
  • FIG. 1 The infrared spectrum of the milbeir A4 twin form A of the present invention is shown in FIG.
  • the differential scanning calorimetry map of the milbeir A4 twin form A of the present invention is shown in FIG.
  • the differential scanning calorimetry pattern of the milbeir A4 twin form A of the present invention has an exothermic peak in the range of 190.6 to 200.4 °C.
  • thermogravimetric analysis map of the milbeir A4 twin form A of the present invention is shown in FIG.
  • Another object of the present invention is to provide a process for the preparation of said milbes A4 fluorene form A, which process comprises the steps of:
  • the solvent of the present invention is selected from the group consisting of methanol, ethanol, acetone, DMF, n-propanol, isopropanol, n-butanol or isobutanol, but is not limited to the above solvent capable of dissolving milbemycin A4.
  • the anti-solvent is water or n-heptane.
  • the concentration of milbemycin A4 in the solution in the step (1) is from 50 g/L to 600 g/L, preferably from 200 g/L to 400 g/L.
  • the temperature of the solution obtained in the step (1) is controlled to be 40 ° C to 80 ° C, preferably 50 ° C to 70 ° C.
  • the volume ratio of the anti-solvent to the solvent in the step (1) is 1:1 to 9:1, preferably 7:3 to 4:1.
  • the temperature of the mixed liquid obtained in the step (2) is controlled at 30 ° C to 60 ° C, preferably 40 ° C to 50 ° C.
  • the vacuum drying temperature in the step (3) is controlled at 50 ° C to 80 ° C, preferably 60 ° C to 70 ° C, and the drying time is controlled at 24-60 h, preferably 36-48 h.
  • step (3) the step of adding seed crystals of milbes A4 phthalocyanine A to the mixture obtained in step (2) is further included.
  • the crystallization time in the present invention can be determined and selected by those skilled in the art based on common general knowledge or conventional technical means.
  • Still another object of the present invention is to provide the use of milbemycin A4 phthalocyanine A in the preparation of insecticidal acaricides.
  • Example 1 is an XRPD pattern of the milbeir A4 twin form A obtained in Example 1.
  • DSC differential scanning calorimetry
  • Example 3 is an infrared spectrum of the milbeir A4 twin form A obtained in Example 1.
  • Figure 5 is an XRPD pattern of a milbein A3/A4 hydrazine mixture.
  • Figure 6 is a differential scanning calorimetry map of the Milbe A3/A4 hydrazine mixture.
  • the raw material containing the milbes A4 hydrazine (i.e., the A3/A4 hydrazine mixture) is first prepared according to US 3,950,360, and is prepared according to US Pat. No. 4,545, 520.
  • the X-ray powder diffraction apparatus and test conditions of the present invention are as follows:
  • the infrared spectrometer and the test conditions of the invention are as follows:
  • Infrared spectrophotometer model BRWKER VECTOR 22;
  • the differential scanning calorimetry (DSC) test conditions of the present invention are:
  • the DSC detector model is: PERKIN ELMER DSC8000;
  • Method of operation heating rate 10 ° C / min, temperature range: 20 ° C ⁇ 280 ° C.
  • thermogravimetric analysis (TGA) test conditions of the present invention are:
  • TGA model PerkinElmer TGA400
  • Method of operation heating rate 10 ° C / min, temperature range: 30 ° C ⁇ 300 ° C.
  • the nuclear magnetic resonance conditions involved in the present invention are:
  • the sample was analyzed by nuclear magnetic resonance and the results were as follows:
  • the hydrogen spectrum and carbon spectrum of the obtained product were substantially the same as those of the milbemycin A4 produced by the preparation example, and the product was still Milbe A4 ⁇ . It was confirmed by X-ray powder diffraction, infrared, DSC and TGA that it was Milbe A4 crystal form A, and its X-ray powder diffraction, infrared, DSC and TGA spectra are shown in Figures 1 to 4, respectively.
  • Milbe A4 twin form A was obtained.
  • Milbe A4 twin form A was obtained.
  • Milbe A4 twin form A was obtained.
  • Milbe A4 2.0 g was added to 6 ml of ethanol, and the mixture was heated to reflux with stirring, and the sample was completely dissolved. The solution was added to 50 ml of n-heptane, and the seed crystal of milbeir A4 crystallization type A prepared in Example 2 was added. After the addition, the temperature of the mixture was controlled at 45 ° C, and the wet crystal was filtered to obtain 1.1 g of a crystal, and the crystal was vacuumed at 50 ° C. Dry for 60h. Upon detection, Milbe A4 twin form A was obtained.
  • Milbe A4 2.0 g was added to 5 ml of ethanol, and the mixture was heated to reflux with stirring, and the sample was completely dissolved. The solution was added to 45 ml of water, and the seed crystal of milbes A4 crystallization form A prepared in Example 2 was added. After the addition, the temperature of the mixture was controlled to 60 ° C, and 1.6 g of wet crystals were obtained by filtration, and the crystals were dried under vacuum at 70 ° C for 48 h. Upon detection, Milbe A4 twin form A was obtained.
  • milbemycin A4 1.0 g was added to 5 ml of isopropyl alcohol, and the mixture was heated to 80 ° C with stirring, and the sample was completely dissolved. The solution was added to 15 ml of n-heptane, and the seed crystal of milbeir A4 crystallization type A prepared in Example 2 was added. After the addition, the temperature of the mixture was controlled to 60 ° C, and the wet crystal was filtered to obtain 0.5 g of a crystal, and the crystal was vacuumed at 80 ° C. Dry for 36h. Upon detection, Milbe A4 twin form A was obtained.
  • the A3/A4 hydrazine mixture (as prepared according to US4547520) is present in amorphous form, the typical X-ray powder diffraction pattern is shown in Figure 5, and the DSC absorption spectrum is shown in Figure 6.
  • milbes A4 oxime forms stable crystals under suitable conditions. Comparing the DSC pattern of A4 twin form A (Fig. 2) and the DSC pattern of A3/A4 ⁇ (Fig. 6), it can be found that the thermal stability of A3/A4 ⁇ is much lower than that of A4 twin form A.
  • the present invention also compares the degradation stability of A3/A4 ⁇ and A4 ⁇ crystal form A, and the degradation conditions are as follows:
  • the total illuminance requirement of 200 w ⁇ hr/m 2 and 1200 thousand lux ⁇ hr is required for photodegradation. If the illuminance is 600w/m 2 , the ICH requirement is met and the illumination time needs at least 9 hr.
  • HPLC content was determined as follows:
  • A4 twin form A is superior to A3/A4 ⁇ in purity, and the above stability test results show that the stability of A4 crystal form A is significantly better than A3/A4 ⁇ , so it is easier to store.

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Abstract

一种米尔贝A4肟晶型，它可以通过X-射线粉末衍射谱图，红外吸收(IR)谱图，差示扫描量热分析(DSC)，热重分析(TG)等来表征。同时还涉及制备这种米尔贝A4肟晶型的方法以及这种米尔贝A4肟晶型作为杀虫杀螨剂的用途。

Description

一种米尔贝A4肟晶型A及其制备方法 技术领域
本发明涉及制药领域尤其是兽药领域。更具体地，本发明涉及米尔贝A4肟晶型A和该晶型的制备方法以及该晶型作为杀虫杀螨剂的用途。
背景技术
米尔贝霉素是微生物天然产物农药，已有数据表明它是当今世界上最优良的杀螨剂之一。美国环保署认定其为低危险性杀虫剂，荷兰批准其为“GNO”(作物生产中的天然产物)。它属生态友好型农药，适用于有机农业病虫害的综合防治，在发达国家已成为一种受欢迎的杀虫杀螨剂。
米尔贝霉素是日本三共公司以二斑叶螨作为试虫，从微生物的发酵液中筛选出的具有抗虫活性的代谢产物(US3,950,360)。经过大量基础研究，1983年米尔贝霉素(milbemycin)A3和A4组分的混合物被用作杀螨剂。Milbemycin半合成化合物米尔贝肟A3/A4(Milbemycin oxime A3/A4)也已商品化用于兽药。商业化的米尔贝肟为A3、A4的混合组分，为无定型的粉末。
Figure PCTCN2018096777-appb-000001
现有技术中关于米尔贝肟的报道主要集中在米尔贝霉素的发酵和菌种选育方面，而对于米尔贝肟的研究也主要集中在含大约4:1的米尔贝A4肟和米尔贝A3肟的混合物上。目前并没有关于单一组分的米尔贝A4肟晶型的报道。同时现有技术得到的A3/A4肟混合物有析晶的描述，但并没有数据证明得到 的为何种晶体，如专利CN201410606012.9中也未曾提及混合物属于何种晶型。本领域技术人员应知，单一组分的晶型在制剂学和药效学上具有很多优势，例如：性质稳定、便于储存、易溶解、易分散，能够形成均匀的溶液等等。由于A3/A4肟的混合物难以得到晶型，本发明对A4肟的单一组分进行了制备并获得了晶型A。
发明内容
本发明的目的在于提供米尔贝A4肟的新晶型，命名为晶型A。
本发明的米尔贝A4肟晶型A，使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射(XRPD)图谱在以下位置具有特征峰：8.39±0.20°、10.12±0.20°、14.29±0.20°、15.24±0.20°、15.71±0.20°、16.10±0.20°。
进一步的，本发明的米尔贝A4肟晶型A还在以下2θ衍射角处有特征峰：4.02±0.20°、10.48±0.20°、10.97±0.20°、12.26±0.20°、12.97±0.20°、14.75±0.20°、17.18±0.20°、17.64±0.20°、19.34±0.20°、22.94±0.20°。
进一步的，本发明的米尔贝A4肟晶型A还在以下2θ衍射角处有特征峰：4.02±0.20°、6.95±0.20°、7.37±0.20°、9.26±0.20°、10.48±0.20°、10.97±0.20°、11.41±0.20°、12.26±0.20°、12.97±0.20°、14.75±0.20°、17.18±0.20°、17.64±0.20°、17.89±0.20°、19.34±0.20°、19.93±0.20°、21.53±0.20°、22.94±0.20°23.52±0.20°、24.65±0.20°、26.28±0.20°。
本发明所述的米尔贝A4肟晶型A的2θ角度、d值和相对强度数据如下表1所示：
表1
Figure PCTCN2018096777-appb-000002
Figure PCTCN2018096777-appb-000003
本发明所述米尔贝A4肟晶型A的XRPD图谱如图1所示。
此外，本发明所述的米尔贝A4肟晶型A还可以用KBr压片测得的红外吸收图谱表征，根据所述图谱，其在以下位置处有特征峰：3567cm -1、3433cm -1、2963cm -1、2923cm -1、2872cm -1、1746cm -1、1727cm -1、1714cm -1、1676cm -1、1654cm -1、1629cm -1、1560cm -1、1541cm -1、1507cm -1、1452cm -1、1436cm -1、1375cm -1、1335cm -1、1274cm -1、1243cm -1、1178cm -1、1165cm -1、1115cm -1、1103cm -1、1061cm -1、1040cm -1、964cm -1。
进一步的，本发明的米尔贝A4肟晶型A的红外吸收图谱还在906cm -1、865cm -1、823cm -1、803cm -1、683cm -1、501cm -1、488cm -1和460cm -1处有特征峰。
本发明所述的米尔贝A4肟晶型A的红外谱图如图3所示。
本发明所述的米尔贝A4肟晶型A的差示扫描量热图谱如图2所示。
本发明所述的米尔贝A4肟晶型A的差示扫描量热图谱在190.6至200.4℃的范围内有放热峰。
本发明所述的米尔贝A4肟晶型A的热重分析图谱如图4所示。
本发明的另一个目的是提供制备所述的米尔贝A4肟晶型A的方法，该方法包括如下步骤：
(1)将米尔贝A4肟溶于一种溶剂中，形成一种溶液；
(2)将步骤(1)所得溶液加入一种反溶剂中；
(3)结晶、过滤并真空干燥得到米尔贝A4肟晶体A。
进一步地，本发明所述的溶剂选自甲醇、乙醇，丙酮，DMF，正丙醇，异丙醇，正丁醇或异丁醇，但不仅限于以上可溶解米尔贝A4肟的溶剂，所述反溶剂为水或正庚烷。
更进一步地，步骤(1)中米尔贝A4肟在所述溶液中的浓度为50g/L～600g/L，优选为200g/L～400g/L。
更进一步地，将步骤(1)所得溶液的温度控制在40℃～80℃，优选50℃～70℃。
更进一步地，步骤(1)所得溶液加入反溶剂后，所述反溶剂与步骤(1)所述溶剂的体积比为1:1～9:1，优选为7:3～4:1。
更进一步地，将步骤(2)所得混合液的温度控制在30℃～60℃，优选40℃～50℃。
更进一步地，将步骤(3)中的真空干燥温度控制在50℃～80℃，优选60℃～70℃，干燥时间控制在24-60h，优选36-48h。
在优选的实施方案中，在步骤(3)之前，还包括在步骤(2)所得的混合液中加入米尔贝A4肟晶型A的晶种的步骤。
本发明中结晶时间是本领域技术人员根据公知常识或常规技术手段能够确定和选择的。
本发明又一个目的是提供米尔贝A4肟晶型A在制备杀虫杀螨剂中的用途。
应当强调的是，本发明技术方案中所涉及的数值或数值端点，其含义或意在保护的范围并不局限于该数字本身。本领域技术人员能够理解，它们包含了那些已被本领域广为接受的可允许的误差范围，例如：实验误差、测量误差、 统计误差和随机误差等，而这些误差范围均包含在本发明的范围之内。
附图说明
图1为实施例1所得米尔贝A4肟晶型A的XRPD图谱。
图2为实施例1所得米尔贝A4肟晶型A的差示扫描量热(DSC)图谱。
图3为实施例1所得米尔贝A4肟晶型A的红外谱图。
图4为实施例1所得米尔贝A4肟晶型A的热重分析(TG)图谱。
图5为米尔贝A3/A4肟混合物的XRPD图谱。
图6为米尔贝A3/A4肟混合物的差示扫描量热图谱。
具体实施方式
下列实施例进一步详细说明本发明，但是，它们并不构成对本发明范围的限制或限定。
本发明含有米尔贝A4肟的原料(即A3/A4肟混合物)是按照US3950360首先制备了含有米尔贝A3/A4霉素的原料，然后按照专利US4547520制备得到的。
本发明所涉及的X-射线粉末衍射仪器及测试条件为：
X-衍射仪器型号Rigaku D/max-2200Cu靶；
操作方法：扫描速度4°/min，扫描步宽0.01°，X射线Cu(40kV，40mA)，I(cps)＝332。用于计算晶格间距
Figure PCTCN2018096777-appb-000004
(CU/K-alpha1)。
本发明所涉及的红外分光广度仪及测试条件为：
红外分光光度仪型号：BRWKER VECTOR 22；
操作方法：采用KBr压片法，扫描范围400～4000cm-1。
本发明涉及的差示扫描量热(DSC)测试条件为：
DSC检测仪型号为：PERKIN ELMER DSC8000；
操作方法：升温速率10℃/min，温度范围：20℃～280℃。
本发明涉及的热重分析(TGA)测试条件为：
TGA型号：PerkinElmer TGA400；
操作方法：升温速率10℃/min，温度范围：30℃～300℃。
本发明涉及的核磁共振条件为：
仪器型号：BRUKER公司400兆NMR仪；
测定条件：CDCl 3溶剂，TMS作内标。
制备实施例
米尔贝A4肟的制备
将溶解有10.0g含有米尔贝A4肟的原料的甲醇溶液(10mL)加样至制备液相(购自创新通恒)，采用ODS键合硅胶反相填料，洗脱液为甲醇：水＝85:15，收集米尔贝A4肟组分，60℃浓缩，冷却后加水沉淀，过滤得米尔贝A4肟样品。样品经核磁共振分析，结果如下:
Figure PCTCN2018096777-appb-000005
表2：A4肟质子核磁共振化学位移
Figure PCTCN2018096777-appb-000006
Figure PCTCN2018096777-appb-000007
表3：A4肟核磁共振碳谱的化学位移
Figure PCTCN2018096777-appb-000008
Figure PCTCN2018096777-appb-000009
米尔贝A4肟晶型A的制备
实施例1：
将1.5g米尔贝A4肟加入5ml甲醇中，搅拌加热至50℃，样品全部溶解。将溶液加至15ml水中，加完后控制混合液温度40℃，过滤得湿晶体1.2g，晶体70℃真空干燥48h。
经核磁共振分析，所得产物氢谱、碳谱与制备实施例所制得米尔贝A4肟实质相同，产物仍为米尔贝A4肟。经X-射线粉末衍射、红外、DSC以及TGA测定，确认为米尔贝A4肟晶型A，其X-射线粉末衍射、红外、DSC以及TGA图谱分别如图1至4所示。
实施例2：
将2.0g米尔贝A4肟加入5ml甲醇中，搅拌加热至回流，样品全部溶解。将溶液加至15ml水中，加完后控制混合液温度60℃，过滤得湿晶体1.3g，晶体65℃真空干燥48h。经检测，得到米尔贝A4肟晶型A。
实施例3：
将1.5g米尔贝A4肟加入5ml乙醇中，搅拌加热至70℃，样品全部溶解。将溶液加至15ml水中，加完后控制混合液温度40℃，过滤得湿晶体0.7g，晶体60℃真空干燥48h。经检测，得到米尔贝A4肟晶型A。
实施例4：
将1.0g米尔贝A4肟加入5ml甲醇中，搅拌加热至回流，样品全部溶解。将溶液加至20ml水中，加完后控制混合液温度50℃，过滤得湿晶体0.5g，晶 体80℃真空干燥36h。经检测，得到米尔贝A4肟晶型A。
实施例5：
将2.0g米尔贝A4肟加入6ml丙酮中，搅拌加热至80℃，样品全部溶解。将溶液加至18ml水中，加完后控制混合液温度60℃，过滤得湿晶体1.3g，晶体70℃真空干燥48h。经检测，得到米尔贝A4肟晶型A。
实施例6：
将2.0g米尔贝A4肟加入5ml丙酮中，搅拌加热至60℃，样品全部溶解。将溶液加至18ml正庚烷中，加完后控制混合液温度35℃，过滤得湿晶体0.9g，晶体80℃真空干燥36h。经检测，得到米尔贝A4肟晶型A。
实施例7：
将1.0g米尔贝A4肟加入5ml DMF中，搅拌加热至70℃，样品全部溶解。将溶液加至25ml水中，加完后控制混合液温度45℃，过滤得湿晶体0.8g，晶体60℃真空干燥48h。经检测，得到米尔贝A4肟晶型A。
实施例8：
将2.0g米尔贝A4肟加入6ml乙醇中，搅拌加热至回流，样品全部溶解。将溶液加至50ml正庚烷中，并加入实施例2制得的米尔贝A4肟晶型A的晶种，加完后控制混合液温度45℃，过滤得湿晶体1.1g，晶体50℃真空干燥60h。经检测，得到米尔贝A4肟晶型A。
实施例9：
将2.0g米尔贝A4肟加入5ml乙醇中，搅拌加热至回流，样品全部溶解。将溶液加至45ml水中，并加入实施例2制得的米尔贝A4肟晶型A的晶种，加完后控制混合液温度60℃，过滤得湿晶体1.6g，晶体70℃真空干燥48h。经检测，得到米尔贝A4肟晶型A。
实施例10：
将1.0g米尔贝A4肟加入5ml异丙醇中，搅拌加热至80℃，样品全部溶解。将溶液加至15ml正庚烷中，并加入实施例2制得的米尔贝A4肟晶型A的晶种，加完后控制混合液温度60℃，过滤得湿晶体0.5g，晶体80℃真空干燥36h。经检测，得到米尔贝A4肟晶型A。
稳定性试验
在通常情况下，A3/A4肟混合物(如按US4547520所制备的)以无定型的形式存在，其典型X-射线粉末衍射图谱见图5，其DSC吸收图谱见图6。
在制备米尔贝A4肟的过程中，本发明的发明人发现在合适的条件下米尔贝A4肟可形成稳定的晶体。比较A4肟晶型A的DSC图谱(图2)和A3/A4肟的DSC图谱(图6)可以发现，A3/A4肟的热稳定性远低于A4肟晶型A。
同时，本发明还对A3/A4肟和A4肟晶型A的降解稳定性进行了对比，降解条件如下：
1)氧化降解
精密称取样品50mg至100.0ml容量瓶中，加10ml甲醇溶解，加入1.0ml 30％双氧水放置24小时后，用甲醇稀释至刻度。
2)光降解
根据ICH的要求，对于光降解需要同时满足200w·hr/m 2和1200千lux·hr的总照度要求。若光照度为600w/m 2，则达到ICH的要求，光照时间至少需要9hr。
称取样品约600mg，平摊于称量瓶中，置于光照度为600w/m 2的光照箱内光照24hr后，取出，置于干燥器中冷却至室温，测定干燥失重。
3)避光
称取样品约600mg，平摊于称量瓶中，将装有样品的称量瓶放入一黑色PE袋内，再在PE袋外加一铝箔袋包装，置于光照度为600w/m2的光照箱内光照18hr后，取出，置于干燥器中冷却至室温，测定干燥失重。
HPLC含量测定条件如下：
Figure PCTCN2018096777-appb-000010
Figure PCTCN2018096777-appb-000011
A3/A4肟(按US4547520制备)和A4肟晶型A(按实施例1制备)的降解稳定性结果见表4。
表4：A3/A4肟和A4肟晶型A的降解稳定性
Figure PCTCN2018096777-appb-000012
A4肟晶型A在纯度上要优于A3/A4肟，且上述稳定性试验结果表明A4肟晶型A的稳定性要明显优于A3/A4肟，因此更便于储存。

Claims (12)

  1. 一种米尔贝A4肟晶型A，其特征在于，使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射图谱在以下位置具有特征峰：8.39±0.20°、10.12±0.20°、14.29±0.20°、15.24±0.20°、15.71±0.20°、16.10±0.20°。
  2. 根据权利要求1所述的米尔贝A4肟晶型A，其特征在于，所述X-射线粉末衍射图谱还在以下位置具有特征峰：4.02±0.20°、10.48±0.20°、10.97±0.20°、12.26±0.20°、12.97±0.20°、14.75±0.20°、17.18±0.20°、17.64±0.20°、19.34±0.20°、22.94±0.20°。
  3. 根据权利要求1所述的米尔贝A4肟晶型A，其特征在于，所述X-射线粉末衍射图谱还在以下位置具有特征峰：4.02±0.20°、6.95±0.20°、7.37±0.20°、9.26±0.20°、10.48±0.20°、10.97±0.20°、11.41±0.20°、12.26±0.20°、12.97±0.20°、14.75±0.20°、17.18±0.20°、17.64±0.20°、17.89±0.20°、19.34±0.20°、19.93±0.2°、21.53±0.20°、22.94±0.20°23.52±0.20°、24.65±0.20°、26.28±0.2°。
  4. 一种制备根据权利要求1-3中任一项所述的米尔贝A4肟晶型A的方法，其特征在于，所述方法包括如下步骤：
    (1)将米尔贝A4肟溶于一种溶剂中，形成一种溶液；
    (2)将步骤(1)所得溶液加入一种反溶剂中；
    (3)结晶、过滤并真空干燥得到米尔贝A4肟晶体A。
  5. 根据权利要求4所述的方法，其特征在于，所述溶剂为选自甲醇、乙醇，丙酮，乙腈，DMF，正丙醇，异丙醇，正丁醇或异丁醇，所述反溶剂为水或正庚烷。
  6. 根据权利要求4或5所述的方法，其特征在于，步骤(1)中米尔贝A4肟在所述溶液中的浓度为50g/L～600g/L，优选为200g/L～400g/L。
  7. 根据权利要求4-6中任一项所述的方法，其特征在于，将步骤(1)所得溶液的温度控制在40℃～80℃，优选50℃～70℃。
  8. 根据权利要求4-7中任一项所述的方法，其特征在于，步骤(1)所得溶液加入反溶剂后，所述反溶剂与步骤(1)所述溶剂的体积比为1:1～9:1，优选为7:3～4:1。
  9. 根据权利要求4-8中任一项所述的方法，其特征在于，将步骤(2)所得混合液的温度控制在30℃～60℃，优选40℃～50℃。
  10. 根据权利要求4-9中任一项所述的方法，其特征在于，在步骤(3)之前，还包括在步骤(2)所得的混合液中加入米尔贝A4肟晶型A的晶种的步骤。
  11. 根据权利要求4-10中任一项所述的方法，其特征在于，将步骤(3)中的真空干燥温度控制在50℃～80℃，优选60℃～70℃，干燥时间控制在24-60h，优选36-48h。
  12. 权利要求1-11中任一项所述的米尔贝A4肟晶型A在制备杀虫杀螨剂中的用途。
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