WO2021134943A1 - 一种啶嘧磺隆晶型及其制备方法 - Google Patents
一种啶嘧磺隆晶型及其制备方法 Download PDFInfo
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- C—CHEMISTRY; METALLURGY
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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- C07B2200/13—Crystalline forms, e.g. polymorphs
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- the invention belongs to the technical field of compound crystals, and specifically relates to a flazasulfuron crystal form and a preparation method thereof.
- Flazasulfuron (English generic name Flazasulfuron) is a broad-spectrum sulfonylurea herbicide developed by Ishihara Sangyo Kaisha in Japan in the 1980s (see CN85109761). Flusulfuron-methyl is very effective in selectively suppressing weeds on open ground. It can be weeded by root or leaf absorption, and it can even be sprayed directly in the soil to prevent weeds. It can be used in a variety of ways. The growth of weeds stopped within a few hours after the application of flazasulfuron. Symptoms include leaf discoloration, dryness, necrosis, and eventually death within 20 to 25 days after application.
- Flusulfuron-methyl has a wide range of activities and can inhibit annual and perennial weeds, especially many broad-leaved weeds.
- the existing flazasulfuron has relatively high impurity content, is not easy to separate, and the stability, efficacy and preparation processability all need to be improved.
- the present invention researches and designs a crystal form of flazasulfuron and a preparation method thereof to improve the shortcomings of insufficient purity of traditional amorphous flazasulfuron and insufficient stability.
- the technical means adopted in the present invention are as follows:
- it has an X-ray powder diffraction pattern as shown in FIG. 1.
- the differential scanning calorimetry curve of the crystal form has an endothermic peak at 177-181°C, and an exothermic peak at 181-190°C and 239-282°C.
- a preparation method of flazasulfuron crystal form comprising the following steps:
- S3 The solid-liquid mixture obtained by S2 is subjected to solid-liquid separation to obtain flazasulfuron crystals.
- step S1 the mixture of flazasulfuron and the solvent is heated to reflux, and the heating is stopped after dissolving, and the solvent is acetonitrile; in step S2, the speed of cooling and crystallization is 5°C/10 minutes; In S3, the method of solid-liquid separation is suction filtration and drying.
- the flazasulfuron used is flazasulfuron with a purity of 90%.
- the flazasulfuron crystal form prepared by the present invention uses the same low content of flazasulfuron raw materials, and the product can be better separated from impurities. After forming a crystalline state, the product purity and recovery rate are higher. , It is easier to obtain high-purity APIs. In addition, the thermal stability is good, which is more conducive to the requirements of production, transportation and storage. It has a longer shelf life, better slow-release performance, increased drug efficacy, better formulation processability, improved processing efficiency, and stable production technology, adaptable For industrial production.
- Figure 1 is an X-ray powder diffraction pattern of the crystal form of flazasulfuron in Example 1 of the present invention
- Example 2 is a DSC/TGA chart of the crystal form of flazasulfuron in Example 1 of the present invention
- Figure 3 is an infrared spectrum of the crystal form of flazasulfuron in Example 1 of the present invention.
- Figure 4 is an X-ray powder diffraction pattern of amorphous flazasulfuron in the comparative example of the present invention.
- Figure 5 is the DSC/TGA spectrum of amorphous flazasulfuron in the comparative example of the present invention.
- the testing instrument and method used in the present invention is a measuring instrument and method used in the present invention.
- the present invention uses low-content amorphous flazasulfuron as a raw material and uses organic solvents to recrystallize to obtain crystalline flazasulfuron.
- the structure has the following formula.
- the crystal form has the advantages of high purity and good stability.
- organic solvent used for recrystallization is one or a mixture of acetonitrile and propionitrile.
- the crystalline form of flazasulfuron described in the present invention uses Cu-K ⁇ radiation to obtain an X-ray powder diffraction pattern expressed in 2 ⁇ angles.
- the crystal includes the 2 ⁇ values of 4.6°, 6.9°, 8.3°, 9.2 °, 11.5°, 13.4°, 13.8°, 14.7°, 15.2°, 15.4°, 16.7°, 17.4°, 17.8°, 18.4°, 19.6°, 20.6°, 21.4°, 21.8°, 22.9°, 23.4°, 24.1°, 24.5°, 25.1°, 25.9°, 26.4°, 27.1°, 27.9°, 28.1°, 28.5°, 29.6°, 29.9°, 30.7°, 31.3°, 32.5°, 33.3°, 33.9°, 34.5° , 34.9°, 35.7°, 36.2°, 36.8°, 37.3° and 38.2°.
- the error range of the above-mentioned 2 ⁇ angle values is ⁇ 0.2°.
- the above crystal form of flazasulfuron has an X-ray powder diffraction pattern as shown in Fig. 1; the differential scanning calorimetry curve of this crystal form has an endothermic peak at 177-181°C, and at 181-190°C And there is an exothermic peak at 239-282°C; the infrared absorption spectrum of this crystal form is at 3093cm -1 , 2945cm -1 , 1737cm -1 , 1622cm -1 , 1578cm -1 , 1512cm -1 , 1495cm -1 , 1452cm -1 , 1417cm -1, 1362cm -1, 1268cm -1, 1233cm -1, 1199cm -1, 1169cm -1, 1156cm -1, 1127cm -1, 1037cm -1, 1012cm -1, 987cm -1, 916cm -1, 894cm -1, 827c
- the method for preparing the above-mentioned flazasulfuron crystal form includes the following steps: S1: mixing flazasulfuron with a solvent, heating to 70-100°C, and stopping heating after dissolving, the solvent is acetonitrile and propionitrile Or a mixture of acetonitrile and propionitrile; S2: cooling and crystallization at a speed of 5-10°C/10 minutes, and then keeping it at room temperature and stirring for more than 0.5h; S3: separating the solid-liquid mixture obtained by S2 to obtain pyridine Suimesulfuron crystals.
- step S1 the mixture of flazasulfuron and the solvent is preferably heated to reflux, and the heating is stopped after dissolving.
- the solvent is acetonitrile; in step S2, the preferred rate of cooling and crystallization is 5°C/10 minutes;
- the method of solid-liquid separation is suction filtration and drying.
- the melting point and decomposition point data of the DSC test show that the melting point and decomposition point of the flazasulfuron crystal form prepared by the present invention are significantly higher than the flazasulfuron in the amorphous state, and its stability is significantly better than that of the amorphous sample.
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Abstract
本发明公开了一种啶嘧磺隆晶型及其制备方法,属于化合物晶体技术领域。所述晶型使用Cu-Kα辐射的X-射线粉末衍射图谱如图1所示。本发明使用相同低含量的啶嘧磺隆原料,产品可以和杂质更好的分离,形成结晶状态后,产品纯度与回收率更高,更易获得高纯度的原料药。另外,热稳定性好,更有利于生产运输储存的要求,保质期更长,具有较好的缓释性能,增加药效,具有更好的制剂加工性,提高加工效率,且生产工艺稳定,适应于工业化生产。
Description
本发明属于化合物晶体技术领域,具体涉及一种啶嘧磺隆晶型及其制备方法。
啶嘧磺隆(英文通用名称Flazasulfuron)是由日本石原产业株式会社(Ishihara Sangyo Kaisha)在上世纪80年代开发的磺酰脲类广谱除草剂(参见CN85109761)。啶嘧磺隆对于选择性抑制开阔地上的杂草非常有效,可以通过根系或者叶片吸收的方式进行除草,甚至可以直接喷洒在土壤中对杂草进行预防,使用方式灵活多样。啶嘧磺隆施用后数小时内杂草生长停止,症状包括叶片变色,干燥,坏死,最终在施用后20至25天内死亡。啶嘧磺隆具有广泛的活性,可以抑制一年生和多年生杂草,特别是许多阔叶杂草。现有啶嘧磺隆杂质含量较高,不易分离,稳定性、药效和制剂加工性均有待于提高。
发明内容
本发明针对以上问题的提出,而研究设计一种啶嘧磺隆晶型及其制备方法,来改善传统无定型啶嘧磺隆纯度不够高、稳定性不够好的缺点。本发明采用的技术手段如下:
一种啶嘧磺隆晶型,使用Cu-Kα辐射的X-射线粉末衍射图谱包括在2θ值为4.6°±0.2°、6.9°±0.2°、8.3°±0.2°、9.2°±0.2°、11.5°±0.2°、13.4°±0.2°、13.8°±0.2°、14.7°±0.2°、15.2°±0.2°、15.4°±0.2°、16.7°±0.2°、17.4°±0.2°、17.8°±0.2°、18.4°±0.2°、19.6°±0.2°、20.6°±0.2°、21.4°±0.2°、21.8°±0.2°、22.9°±0.2°、23.4°±0.2°、24.1°±0.2°、24.5°±0.2°、25.1°±0.2°、25.9°±0.2°、26.4°±0.2°、27.1°±0.2°、27.9°±0.2°、28.1°±0.2°、28.5°±0.2°、29.6°±0.2°、29.9°±0.2°、30.7°±0.2°、31.3°±0.2°、32.5°±0.2°、33.3°±0.2°、33.9°±0.2°、34.5°±0.2°、34.9°±0.2°、35.7°±0.2°、36.2°±0.2°、36.8°±0.2°、37.3°±0.2°和38.2°±0.2°处的特征峰。
优选地,其具有如图1所示的X-射线粉末衍射图谱。
优选地,所述晶型的差示扫描量热曲线在177-181℃处具有吸热峰,在 181-190℃及239-282℃处有放热峰。
优选地,所述晶型的红外吸收光谱在3093cm
-1、2945cm
-1、1737cm
-1、1622cm
-1、1578cm
-1、1512cm
-1、1495cm
-1、1452cm
-1、1417cm
-1、1362cm
-1、1268cm
-1、1233cm
-1、1199cm
-1、1169cm
-1、1156cm
-1、1127cm
-1、1037cm
-1、1012cm
-1、987cm
-1、916cm
-1、894cm
-1、827cm
-1、815cm
-1、799cm
-1、759cm
-1、745cm
-1、703cm
-1、631cm
-1、582cm
-1、530cm
-1和513cm
-1处有吸收峰。
一种啶嘧磺隆晶型的制备方法,包括以下步骤:
S1:将啶嘧磺隆与溶剂混合,加热至80-85℃,至溶清后停止加热,所述溶剂为乙腈、丙腈或乙腈与丙腈的混合物;
S2:以5-10℃/10分钟的速度降温析晶,降至室温后保温搅拌0.5h以上;
S3:将S2得到的固液混合物进行固液分离,得到啶嘧磺隆晶体。
优选地,步骤S1中,将啶嘧磺隆与溶剂的混合物加热至回流,至溶清后停止加热,所述溶剂为乙腈;步骤S2中,降温析晶的速度为5℃/10分钟;步骤S3中,固液分离的方法为抽滤和烘干。
优选地,步骤S1中,使用的啶嘧磺隆为纯度90%的啶嘧磺隆。
与现有技术比较,本发明所制备的啶嘧磺隆晶型,使用相同低含量的啶嘧磺隆原料,产品可以和杂质更好的分离,形成结晶状态后,产品纯度与回收率更高,更易获得高纯度的原料药。另外,热稳定性好,更有利于生产运输储存的要求,保质期更长,具有较好的缓释性能,增加药效,具有更好的制剂加工性,提高加工效率,且生产工艺稳定,适应于工业化生产。
图1是本发明实施例1中啶嘧磺隆晶型的X射线粉末衍射图谱;
图2是本发明实施例1中啶嘧磺隆晶型的DSC/TGA图谱;
图3是本发明实施例1中啶嘧磺隆晶型的红外光谱图谱;
图4是本发明对比例中无定型啶嘧磺隆的X射线粉末衍射图谱;
图5是本发明对比例中无定型啶嘧磺隆的DSC/TGA图谱。
本发明所用的测试仪器及方法:
1、X-射线衍射谱
仪器型号:Bruker D8Focus X-射线粉末衍射仪
射线:单色Cu-Kα射线(λ=1.5406)
扫描方式:θ/2θ,扫描范围:2-40°
电压:40KV,电流:40mA
2、DSC谱
仪器型号:Mettler Toledo DSC 1Staree System
吹扫气:氮气
升温速率:10.0℃/min
温度范围:30-350℃
3、红外光谱
仪器型号:Thermo-Nocilet IR200
样品制备:KBr压片
本发明以低含量的无定型啶嘧磺隆为原料,使用有机溶剂重结晶获得结晶的啶嘧磺隆,结构如下式,该晶型具有纯度高,稳定性好的优点。
进一步的,重结晶使用的有机溶剂为乙腈和丙腈中的一种或两种混合。
本发明所述的一种啶嘧磺隆晶型,使用Cu-Kα辐射,得到以2θ角度表示的X-射线粉末衍射图谱,该结晶包括在2θ值为4.6°、6.9°、8.3°、9.2°、11.5°、13.4°、13.8°、14.7°、15.2°、15.4°、16.7°、17.4°、17.8°、18.4°、19.6°、20.6°、21.4°、21.8°、22.9°、23.4°、24.1°、24.5°、25.1°、25.9°、26.4°、27.1°、27.9°、28.1°、28.5°、29.6°、29.9°、30.7°、31.3°、32.5°、33.3°、33.9°、34.5°、34.9°、35.7°、36.2°、36.8°、37.3°和38.2°处的特征峰。上述各2θ角度值的误差范围为±0.2°,因此在误差范围内包含相应特征峰的晶型均应在本发明要求保护的范围内。
进一步地,上述啶嘧磺隆晶型具有如图1所示的X-射线粉末衍射图谱;该晶型的差示扫描量热曲线在177-181℃处具有吸热峰,在181-190℃及239-282℃处有放热峰;该晶型的红外吸收光谱在3093cm
-1、2945cm
-1、1737cm
-1、1622cm
-1、1578cm
-1、1512cm
-1、1495cm
-1、1452cm
-1、1417cm
-1、1362cm
-1、1268cm
-1、1233cm
-1、1199cm
-1、1169cm
-1、1156cm
-1、1127cm
-1、1037cm
-1、1012cm
-1、987cm
-1、916cm
-1、894cm
-1、827cm
-1、815cm
-1、799cm
-1、759cm
-1、 745cm
-1、703cm
-1、631cm
-1、582cm
-1、530cm
-1和513cm
-1处有吸收峰。
上述一种啶嘧磺隆晶型的制备方法,包括以下步骤:S1:将啶嘧磺隆与溶剂混合,加热至70-100℃,至溶清后停止加热,所述溶剂为乙腈、丙腈或乙腈与丙腈的混合物;S2:以5-10℃/10分钟的速度降温析晶,降至室温后保温搅拌0.5h以上;S3:将S2得到的固液混合物进行固液分离,得到啶嘧磺隆晶体。步骤S1中,优选将啶嘧磺隆与溶剂的混合物加热至回流,至溶清后停止加热,所述溶剂为乙腈;步骤S2中,优选的降温析晶的速度为5℃/10分钟;步骤S3中,固液分离的方法为抽滤和烘干。
实施例1:
向2.5g纯度为90%的啶嘧磺隆样品中,加入25g乙腈,加热至回流,保温并搅拌,至溶清后停止加热,再按照5℃/10分钟的速度缓慢降温析晶,待样品温度降至室温后继续保温搅拌0.5h,再经抽滤、减压烘干得2.0g白色固体,回收率为80%,HPLC法测得结晶样品的纯度为99.6%。该结晶样品的X-射线衍射图谱如图1,其中X-射线粉末衍射图谱在2-40°衍射角下的衍射峰数据如下表1所示。该结晶样品的DSC/TGA图谱如图2,红外光谱图谱如图3。
表1、结晶样品X-射线衍射谱图特征峰
对比例:
啶嘧磺隆无定型粉末提纯:向2.5g纯度为90%的啶嘧磺隆样品中,加入30g氯仿溶清后,经硅胶色谱法(淋洗剂:氯仿)纯化,减压旋蒸得到1.8g白色固体,HPLC法测得纯度为98.9%,回收率为72%。该白色固体样品的X-射线衍射谱图如图4,显示无晶型特征吸收峰,据此确定产物为无定型。该白色固体样品的DSC/TGA谱图如图5。
将上述实施例1得到的啶嘧磺隆晶型和对比例得到的无定型啶嘧磺隆的DSC数据进行比较,数据如表2所示。
表2、啶嘧磺隆结晶及无定型状态的DSC数据比较:
熔点起始/℃ | 熔点峰值/℃ | 分解点起始/℃ | 分解峰值/℃ | |
本晶型 | 177.15 | 179.04 | 181.53 | 183.57 |
无定型 | 154 | 160.92 | 164.14 | 167.58 |
DSC测试的熔点及分解点数据表明:本发明制备的啶嘧磺隆晶型的熔点及分解点明显高于无定型状态的啶嘧磺隆,其稳定性显著优于无定型样品。
以上所述的实施例仅仅是对本发明的优选实施方式进行描述,并非对本发明的范围进行限定,在不脱离本发明设计精神的前提下,本领域普通技术人员对本发明的技术方案做出的各种变形和改进,均应落入本发明权利要求书确定的保护范围内。
Claims (7)
- 一种啶嘧磺隆晶型,其特征在于:使用Cu-Kα辐射的X-射线粉末衍射图谱包括在2θ值为4.6°±0.2°、6.9°±0.2°、8.3°±0.2°、9.2°±0.2°、11.5°±0.2°、13.4°±0.2°、13.8°±0.2°、14.7°±0.2°、15.2°±0.2°、15.4°±0.2°、16.7°±0.2°、17.4°±0.2°、17.8°±0.2°、18.4°±0.2°、19.6°±0.2°、20.6°±0.2°、21.4°±0.2°、21.8°±0.2°、22.9°±0.2°、23.4°±0.2°、24.1°±0.2°、24.5°±0.2°、25.1°±0.2°、25.9°±0.2°、26.4°±0.2°、27.1°±0.2°、27.9°±0.2°、28.1°±0.2°、28.5°±0.2°、29.6°±0.2°、29.9°±0.2°、30.7°±0.2°、31.3°±0.2°、32.5°±0.2°、33.3°±0.2°、33.9°±0.2°、34.5°±0.2°、34.9°±0.2°、35.7°±0.2°、36.2°±0.2°、36.8°±0.2°、37.3°±0.2°和38.2°±0.2°处的特征峰。
- 根据权利要求1所述的啶嘧磺隆晶型,其特征在于:其具有如图1所示的X-射线粉末衍射图谱。
- 根据权利要求1所述的啶嘧磺隆晶型,其特征在于:所述晶型的差示扫描量热曲线在177-181℃处具有吸热峰,在181-190℃及239-282℃处有放热峰。
- 根据权利要求1所述的啶嘧磺隆晶型,其特征在于:所述晶型的红外吸收光谱在3093cm -1、2945cm -1、1737cm -1、1622cm -1、1578cm -1、1512cm -1、1495cm -1、1452cm -1、1417cm -1、1362cm -1、1268cm -1、1233cm -1、1199cm -1、1169cm -1、1156cm -1、1127cm -1、1037cm -1、1012cm -1、987cm -1、916cm -1、894cm -1、827cm -1、815cm -1、799cm -1、759cm -1、745cm -1、703cm -1、631cm -1、582cm -1、530cm -1和513cm -1处有吸收峰。
- 一种啶嘧磺隆晶型的制备方法,其特征在于:包括以下步骤:S1:将啶嘧磺隆与溶剂混合,加热至80-85℃,至溶清后停止加热,所述溶剂为乙腈、丙腈或乙腈与丙腈的混合物;S2:以5-10℃/10分钟的速度降温析晶,降至室温后保温搅拌0.5h以上;S3:将S2得到的固液混合物进行固液分离,得到啶嘧磺隆晶体。
- 根据权利要求5所述的啶嘧磺隆晶型的制备方法,其特征在于:步骤S1中,将啶嘧磺隆与溶剂的混合物加热至回流,至溶清后停止加热,所述溶剂为乙腈;步骤S2中,降温析晶的速度为5℃/10分钟;步骤S3中,固液分离的方法为抽滤和烘干。
- 根据权利要求5或6所述的啶嘧磺隆晶型的制备方法,其特征在于:步骤S1中,使用的啶嘧磺隆为纯度90%的啶嘧磺隆。
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