WO2016061862A1 - 无定型泊沙康唑的制备工艺 - Google Patents

无定型泊沙康唑的制备工艺 Download PDF

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WO2016061862A1
WO2016061862A1 PCT/CN2014/091350 CN2014091350W WO2016061862A1 WO 2016061862 A1 WO2016061862 A1 WO 2016061862A1 CN 2014091350 W CN2014091350 W CN 2014091350W WO 2016061862 A1 WO2016061862 A1 WO 2016061862A1
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posaconazole
mixed solvent
amorphous
added
alcohol
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PCT/CN2014/091350
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French (fr)
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丁尊良
王希林
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江苏恒盛药业有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D307/10—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/16—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing three or more hetero rings

Definitions

  • the invention relates to a preparation process of amorphous posaconazole, and belongs to the technical field of drug preparation.
  • Posaconazole was developed by Schering-Plough and first marketed in Germany in 2005 under the trade name Noxafil. It is a second-generation triazole antifungal drug with the following chemical structure:
  • the object of the present invention is to provide a preparation process of amorphous posaconazole, in particular, to recrystallize posaconazole using an alcohol ester hydrocarbon ternary solvent system to obtain an amorphous posaconazole product.
  • the solvent used in the process is a low toxicity organic solvent
  • the agent has a small amount of use and high product yield, and is suitable for large-scale production of amorphous posaconazole.
  • a preparation process of amorphous posaconazole which is prepared by dissolving posaconazole in a mixed solvent of an alcohol and an ester, and then dropping it into an alkane or an aromatic hydrocarbon to precipitate a jelly-like solid, which is an amorphous polka Conazole.
  • the ratio (mass: volume) of the posaconazole to the mixed solvent is 1:4 to 1:10, and the unit thereof is g/mL; the ratio (volume: volume) of the alcohol and the ester in the mixed solvent is 1:3 to 1:20; the ratio of the mixed solvent to the alkane or aromatic hydrocarbon (volume: volume) is 1:1 to 1:4.
  • the alcohol in the mixed solvent is one of C1-C4 alcohols.
  • the ester in the mixed solvent is one of C1-C4 acetates.
  • the alkane is one of n-pentane, n-hexane, n-heptane or cyclohexane; the aromatic hydrocarbon is one of toluene or xylene.
  • the ratio (mass: volume) of posaconazole to the mixed solvent is preferably 1:4 in units of g/mL.
  • the ratio (volume: volume) of the alcohol and the ester in the mixed solvent is preferably 1:19.
  • the ratio (volume: volume) of the mixed solvent to the alkane or aromatic hydrocarbon is preferably 1:3.
  • the posaconazole was dissolved in a mixed solvent, and the temperature of the mixed solution was controlled to be 55 to 75 °C.
  • a mixed solution of a mixed solvent of posaconazole, an alcohol, and an ester is added to an alkane or an aromatic hydrocarbon, and the temperature of the precipitated material is controlled to be between 0 and 25 °C.
  • the solubility of posaconazole in alcohol and ester mixed solvents is significantly increased with temperature, and the alkane or cycloalkane or aromatic hydrocarbon solvent is the best antisolvent.
  • the alcohol ester mixed solution heated at 55-75 ° C is added dropwise to the alkane or cycloalkane or aromatic hydrocarbon solvent in 5 to 60 minutes, and the crystallization temperature is controlled at 0-25 ° C during the dropwise addition.
  • the solid was quickly precipitated during the period to obtain amorphous posaconazole. It was found in the study that when the temperature of the precipitated crystal during the dropwise addition exceeds 30 ° C, the complete amorphous posaconazole cannot be obtained.
  • the crystallization method of the ternary solvent system studied in this patent is the first report of this patent.
  • the method for preparing amorphous posaconazole according to the present invention is convenient to operate, is advantageous for industrialization, has high product yield, and the mixed solvent of alcohol and ester used, and the alkane or cycloalkane or aromatic hydrocarbon are in an organic solvent.
  • the three types of solvents are low in toxicity, and the amount of solvent used is greatly reduced compared to the currently reported methods, and the amorphous form can be stably obtained.
  • the solvent is used in a small amount, and it can be dissolved in posaconazole and all.
  • the ratio of the dose is 1:25 (g/mL) to obtain a stable amorphous solid, the amorphous form is stable, and no mixed crystal is produced; the production cycle is short, the yield is high, and the whole process is controlled within 4 hours.
  • the preparation process is advantageous for large-scale recrystallization; the solvent recovery rate is high, and the commonly used alcohols, esters, and alkanes or cycloalkanes or aromatic hydrocarbon solvents have industrially mature recovery methods.
  • Figure 1 is an XRD pattern of the amorphous posaconazole prepared in Example 1;
  • Figure 2 is an XRD pattern of the amorphous posaconazole prepared in Example 2;
  • Figure 3 is an XRD pattern of the amorphous posaconazole prepared in Example 3;
  • Figure 4 is an XRD pattern of the crystalline form obtained in Example 13 dichloromethane n-heptane system
  • Figure 5 is an XRD pattern of the crystalline form obtained in Example 14 at a crystallization temperature exceeding 30 ° C;
  • the abscissa is the 2 Theta angle and the ordinate is the peak intensity.
  • the source of posaconazole is the company's API product, and other solvents are purchased from Sinopharm Group.
  • posaconazole was added to a mixed solvent of 5 mL of methanol and 45 mL of ethyl acetate, and heated to 65 ° C in a 250 mL three-necked flask to dissolve completely dissolved to obtain a clear solution.
  • posaconazole a mixed solvent of 1 mL of methanol and 19 mL of ethyl acetate, and heated to 65 ° C in a 250 mL three-necked flask to dissolve completely dissolved to obtain a clear solution.
  • posaconazole was added to a mixed solvent of 5 mL of ethanol and 25 mL of ethyl acetate, and heated to 70 ° C in a 250 mL three-necked flask to dissolve completely dissolved to obtain a clear solution.
  • n-hexane 100 mL was added to a 250 mL four-necked flask, and the n-hexane was cooled to 15 ° C for mechanical stirring.
  • posaconazole was added to a mixed solvent of 7 mL of ethanol and 23 mL of methyl acetate, and heated to 75 ° C in a 250 mL three-necked flask to dissolve completely dissolved to obtain a clear solution.
  • posaconazole was added to a mixed solvent of 1 mL of n-butanol and 20 mL of butyl acetate, and heated to 65 ° C in a 250 mL three-necked flask to dissolve completely dissolved to obtain a clear solution.
  • the cis-conazole n-butanol butyl acetate clear solution was added dropwise to cyclohexane alkane in 10 minutes to precipitate a jelly-like product, and the crystallization process temperature was controlled at 5-10 ° C. After the addition was completed, the continuation was continued at 5- After stirring at 10 ° C for 30 minutes, filtration and drying, 4.6 g of amorphous posaconazole was obtained in a yield of 92%, and the crystal form of XRD was amorphous.
  • posaconazole was added to a mixed solvent of 1 mL of isopropyl alcohol and 19 mL of ethyl acetate, and heated to 72 ° C in a 250 mL three-necked flask to dissolve completely dissolved to obtain a clear solution.
  • posaconazole was added to a mixed solvent of 5 mL of ethanol and 35 mL of methyl acetate, and heated to 70 ° C in a 250 mL three-necked flask to dissolve completely dissolved to obtain a clear solution.
  • posaconazole was added to a mixed solvent of 5 mL of methanol and 25 mL of methyl acetate, and heated to 63 ° C in a 250 mL three-necked flask to dissolve completely dissolved to obtain a clear solution.
  • posaconazole was added to a mixed solvent of 5 mL of methanol and 20 mL of ethyl acetate, and heated to 65 ° C in a 250 mL three-necked flask to dissolve completely dissolved to obtain a clear solution.
  • posaconazole a mixed solvent of 5 mL of methanol and 35 mL of ethyl acetate, and heated to 65 ° C in a 250 mL three-necked flask to dissolve completely dissolved to obtain a clear solution.
  • the hot acetonitrile ethyl acetate clarified solution of posaconazole was added dropwise to n-heptane in 15 minutes, and the jelly-like product was quickly precipitated in n-heptane.
  • the dropping process temperature was controlled at 20-25 ° C. After the addition was completed, stirring was continued at 20-25 ° C for 60 minutes, filtered, and dried to obtain 4.34 g of amorphous posaconazole, yield: 87%, and the XRD detection crystal form was amorphous.
  • posaconazole was added to a mixed solvent of 1 mL of isopropyl alcohol and 19 mL of ethyl acetate, and heated to 72 ° C in a 250 mL three-necked flask to dissolve completely dissolved to obtain a clear solution.
  • posaconazole was added to a mixed solvent of 1 mL of isopropyl alcohol and 19 mL of ethyl acetate, and heated to 72 ° C in a 250 mL three-necked flask to dissolve completely dissolved to obtain a clear solution.
  • Example 13 Crystal form obtained from dichloromethane n-heptane system
  • posaconazole 7.05 g was added to 70 mL of dichloromethane, and stirred at room temperature until completely dissolved. 525 mL of n-heptane was added to a 1000 mL four-necked flask and mechanically stirred at 25 °C.
  • the posaconazole solution in dichloromethane was added dropwise to n-heptane over 20 minutes, and the product was rapidly precipitated in n-heptane.
  • the temperature of the dropping process was controlled at 20-25 ° C, and stirring was continued for 30 minutes after the completion of the dropwise addition. After filtration and drying, 6.42 g of amorphous posaconazole was obtained. The yield was 91%.
  • the crystal form of XRD was obviously amorphous and mixed crystal of a certain crystal form.
  • Example 14 Crystal form obtained by crystallization temperature exceeding 30 ° C
  • posaconazole was added to a mixed solvent of 1 mL of ethanol and 19 mL of ethyl acetate, and heated to 72 ° C in a 250 mL three-necked flask to dissolve completely dissolved to obtain a clear solution.

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Abstract

一种无定型泊沙康唑的制备工艺，将泊沙康唑溶于醇类和酯类的混合溶剂中，然后加到烷烃或环烷烃或芳香烃中，析出果冻状固体，即为无定型泊沙康唑；泊沙康唑与混合溶剂的质量体积比（g/mL）为1:4~1:10；所述混合溶剂中醇类和酯类的体积比为1:3~1:20；所述混合溶剂和烷烃或芳香烃的体积比为1:1~1:4。

Description

无定型泊沙康唑的制备工艺 技术领域
本发明涉及一种无定型泊沙康唑的制备工艺，属药物制备技术领域。
背景技术
泊沙康唑是由Schering-Plough研发，2005年首次在德国上市，商品名为Noxafil，是第二代三唑类抗真菌药物，化学结构式如下：
Figure PCTCN2014091350-appb-000001
中文化学名：4-[4-[4-[4-[[(3R,5R)-5-(2,4-二氟苯基)-5-(1,2,4-三唑-1-基甲基)氧杂戊环-3-基]甲氧基]苯基]哌嗪-1-基]苯基]-2-[(2S,3S)-2-羟基戊-3-基]-1,2,4-三唑-3-酮，CAS号：171228-49-2。主要适用于多种对两性霉素不能耐受或难治性成人侵袭性真菌感染的治疗；对高危患者预防用药，用于13岁以上、免疫功能低下的患者，特别是患有移植物抗宿主病(graft versus host disease，GVHD)的造血干细胞移植者、白血病患者和由于化疗而长期白细胞减少的患者。
关于泊沙康唑的合成工艺国内外做了大量研究工作，其中首次在世界专利WO9517407中报道。原料药的晶型对药物制剂具有重要的影响，不同晶型的同一种药制成的制剂可能会在人体内的溶出度和药物吸收度有不同的影响，进而可能对药物的临床应用和安全性产生严重的后果，特别是对于一些难溶性固体制剂，原料药晶型的影响至关重要。
迄今为止，对于泊沙康唑的不同晶型的制备已经有大量的专利进行了报道，其中在美国专利US200420443中报道了泊沙康唑晶型I、晶型II和晶型III的制备方法，美国专利US2011065722中报道了泊沙康唑晶型IV的制备方法，世界专利WO2011158248中报道了泊沙康唑晶型V的制备方法，另外对于无定型泊沙康唑的制备在目前公开文献中报道极少，根据专利检索，在世界专利WO2013042138中报道过用泊沙康唑的二氯甲烷溶液加入到大量的正庚烷中析出无定型固体，在实际操作中由于原料和溶剂比例太过于悬殊，在其优选范围的实施例子中可见其泊沙康唑的质量与二氯甲烷的使用量比为1:10(单位g/mL)，泊沙康唑的质量和正庚烷的使用量比为1：75(单位g/mL)，使用溶剂量太大，不适合大规模生产，并且在实际的实验过程中发现容易产生少量混晶。
发明内容
本发明的目的是提供一种无定型泊沙康唑的制备工艺，具体来说，是利用醇类酯类烃类三元溶剂体系重结晶泊沙康唑得到无定型的泊沙康唑产品，本工艺所用溶剂为低毒性有机溶 剂，且使用量少，产品收率高，适合大规模生产制备无定型泊沙康唑。
本发明采用的技术方案为：
一种无定型泊沙康唑的制备工艺，将泊沙康唑溶于醇类和酯类的混合溶剂中，然后滴加到烷烃或芳香烃中，析出果冻状固体，即为无定型泊沙康唑。
所述泊沙康唑与混合溶剂的比例(质量：体积)为1:4～1：10，其单位为g/mL；所述混合溶剂中醇类和酯类的比例(体积：体积)为1：3～1:20；所述的混合溶剂和烷烃或芳香烃的比例(体积：体积)为1:1～1:4。
所述混合溶剂中醇类为C1-C4醇类中的一种。
所述混合溶剂中酯类为C1-C4的乙酸酯类中的一种。
所述烷烃为正戊烷、正己烷、正庚烷或者环己烷中的一种；所述芳香烃为甲苯或者二甲苯中的一种。
泊沙康唑与混合溶剂的比例(质量：体积)优选为1:4，其单位为g/mL。
所述混合溶剂中醇类和酯类的比例(体积：体积)优选为1:19。
所述混合溶剂和烷烃或芳香烃的比例(体积：体积)优选为1:3。
将泊沙康唑溶于混合溶剂中，控制混合溶液的温度在55～75℃。
将泊沙康唑、醇类、酯类的混合溶剂组成的混合溶液加到烷烃或芳香烃的过程中，析出物料的温度控制在0～25℃之间。
在本专利中主要了利用泊沙康唑在醇类和酯类混合溶剂中的溶解度随着温度变化的显著上升且烷烃类或环烷烃或芳香烃类溶剂是其最佳的反溶剂的特点，将其加热在55-75℃的醇类酯类混合溶液在5-60分钟滴加到烷烃类或环烷烃类或芳香烃类溶剂中，滴加过程中析晶温度控制在0-25℃，期间快速析出固体，得到无定型泊沙康唑。在研究中发现当滴加过程中的析出晶体温度超过30℃时，则无法得到完整的无定型泊沙康唑。本专利研究的三元溶剂体系结晶方法为本专利首次报道。
在本专利中实施例中，也对此前报道的制备无定型泊沙康唑的工艺条件进行了相关的晶型比较研究，通过实施例和附图中的详细的晶型对比可以说明本专利的晶型研究得到了一种稳定的重复性极高的无定型泊沙康唑，晶型图谱与现有公开的无定型泊沙康唑的晶型图谱比对一致。
有益效果：本发明制备无定型泊沙康唑的方法操作方便，有利于工业化，产品收率高，所使用的醇类和酯类混合溶剂以及烷烃或环烷烃或芳香烃类是属于有机溶剂中低毒性的三类溶剂，而且溶剂使用量相比目前报道的方法大大减少，而且能够稳定地得到无定型晶型。
比较目前公开报道的技术上还具有以下优势：溶剂使用量少，可以在泊沙康唑和所有溶 剂量的比值为1:25(g/mL)内制备得到稳定的无定型固体，所得无定型稳定，不会产生混晶；生产周期短，收率高，前后整个过程基本控制在4小时以内，制备过程有利于规模化重结晶；溶剂回收率高，常用的醇类、酯类溶和烷烃或环烷烃或芳香烃类溶剂在工业上具有成熟的回收方法。
附图说明
图1实施例1制备得到的无定型泊沙康唑的XRD图；
图2实施例2制备得到的无定型泊沙康唑的XRD图；
图3实施例3制备得到的无定型泊沙康唑的XRD图；
图4实施例13二氯甲烷正庚烷体系所得的晶型的XRD图；
图5实施例14结晶温度超过30℃所得的晶型的XRD图；
其中横坐标是2Theta角，纵坐标是峰强度。
具体实施方式
泊沙康唑的来源为本公司API产品，其他溶剂购买自国药集团。
实施例1
将5.02g泊沙康唑加入到5mL甲醇和45mL乙酸乙酯的混合溶剂中，在250mL三口烧瓶中加热至65℃溶解完全溶解得到澄清溶液。
将100mL正庚烷加入到250mL四口烧瓶中，在20℃下机械搅拌。
将泊沙康唑的热的甲醇乙酸乙酯澄清溶液在五分钟内滴加到到正庚烷中，在正庚烷中快速析出果冻状产品，滴加完毕后温度控制在20-25℃，继续搅拌30分钟，过滤，干燥后得到4.81g无定型泊沙康唑，收率：96％，XRD检测晶型为无定型。
实施例2
将5.00g泊沙康唑加入到1mL甲醇和19mL乙酸乙酯的混合溶剂中，在250mL三口烧瓶中加热至65℃溶解完全溶解得到澄清溶液。
将60mL环己烷加入到250mL四口烧瓶中，在20℃下机械搅拌。
将泊沙康唑的甲醇乙酸乙酯澄清溶液在10分钟内滴加到环己烷中，在环己烷中快速析出果冻状产品，滴加完毕后，温度控制在20-25℃，继续搅拌30分钟，过滤，干燥后得到4.75g无定型泊沙康唑，收率：95％，XRD检测晶型为无定型。
实施例3
将5.04g泊沙康唑加入到5mL乙醇和25mL乙酸乙酯的混合溶剂中，在250mL三口烧瓶中加热至70℃溶解完全溶解得到澄清溶液。
将100mL正己烷加入到250mL四口烧瓶中，把正己烷降温至15℃下机械搅拌。
将泊沙康唑的乙醇乙酸乙酯澄清溶液在7分钟内到正己烷中，析出果冻状产品，析晶过程中温度控制在15-20℃，滴加完毕后在15-20℃下继续搅拌30分钟，过滤，干燥后得到4.7g无定型泊沙康唑，收率：94％，XRD检测晶型为无定型。
实施例4
将5.11g泊沙康唑加入到7mL乙醇和23mL乙酸甲酯的混合溶剂中，在250mL三口烧瓶中加热至75℃溶解完全溶解得到澄清溶液。
将70mL正己烷加入到250mL四口烧瓶中，降温到10℃下机械搅拌。
将泊沙康唑的乙醇乙酸甲酯澄清溶液在5分钟内滴加到正己烷中，析出果冻状产品，析晶过程温度控制在10-15℃，加料完毕后再续在10-15℃下继续搅拌60分钟，过滤，干燥后得到4.7g无定型泊沙康唑，收率：94％，XRD检测晶型为无定型。
实施例5
将5.08g泊沙康唑加入到1mL正丁醇和20mL乙酸丁酯的混合溶剂中，在250mL三口烧瓶中加热至65℃溶解完全溶解得到澄清溶液。
将100mL环己烷加入到250mL四口烧瓶中，降温到5℃下机械搅拌。
将泊沙康唑的正丁醇乙酸丁酯澄清溶液在10分钟内滴加到环己烷烷中，析出果冻状产品，析晶过程温度控制在5-10℃，加料完毕后继续在5-10℃下搅拌30分钟，过滤，干燥后得到4.6g无定型泊沙康唑，收率：92％，XRD检测晶型为无定型。
实施例6
将5.05g泊沙康唑加入到1mL异丙醇和19mL乙酸乙酯的混合溶剂中，在250mL三口烧瓶中加热至72℃溶解完全溶解得到澄清溶液。
将80mL戊烷加入到250mL四口烧瓶中，降温到5℃下机械搅拌。
将泊沙康唑的异丙醇乙酸乙酯澄清溶液在10分钟内滴加到正戊烷中，析出果冻状产品，析晶过程温度控制在5-10℃，滴加完毕后在5-10℃继续搅拌90分钟，过滤，干燥后得到4.5g无定型泊沙康唑，收率：90％，XRD检测晶型为无定型。
实施例7
将5.07g泊沙康唑加入到5mL乙醇和35mL乙酸甲酯的混合溶剂中，在250mL三口烧瓶中加热至70℃溶解完全溶解得到澄清溶液。
将80mL正戊烷加入到250mL四口烧瓶中，降温至0℃下机械搅拌。
将泊沙康唑的乙醇乙酸甲酯澄清溶液在15分钟内滴加滴加到正戊烷中，析出果冻状物料，析料过程温度控制在0-10℃，滴加完毕后继续在10℃下搅拌75分钟，过滤，干燥后得到4.5g无定型泊沙康唑，收率：90％，XRD检测晶型为无定型。
实施例8
将5.05g泊沙康唑加入到5mL甲醇和25mL乙酸甲酯的混合溶剂中，在250mL三口烧瓶中加热至63℃溶解完全溶解得到澄清溶液。
将70mL环己烷加入到250mL四口烧瓶中，降温到15℃下机械搅拌。
将泊沙康唑的甲醇乙酸甲酯澄清溶液在13分钟内滴加滴加到环己烷中，在环己烷中快速析出果冻状产品，滴加过程温度控制在15-20℃，滴加完毕后继续在20℃搅拌45分钟，过滤，干燥后得到4.5g无定型泊沙康唑，收率：90％，XRD检测晶型为无定型。
实施例9
将5.01g泊沙康唑加入到5mL甲醇和20mL乙酸乙酯的混合溶剂中，在250mL三口烧瓶中加热至65℃溶解完全溶解得到澄清溶液。
将50mL正庚烷加入到250mL四口烧瓶中，降温到5℃下机械搅拌。
将泊沙康唑的热的甲醇乙酸乙酯澄清溶液在五分钟内滴加到到正庚烷中，在正庚烷中快速析出果冻状产品，滴加过程控制温度在5-10℃，滴加完毕后在10℃下继续搅拌30分钟，过滤，干燥后得到4.30g无定型泊沙康唑，收率：86％，XRD检测晶型为无定型。
实施例10
将5.00g泊沙康唑加入到5mL甲醇和35mL乙酸乙酯的混合溶剂中，在250mL三口烧瓶中加热至65℃溶解完全溶解得到澄清溶液。
将70mL正庚烷加入到250mL四口烧瓶中，在20℃下机械搅拌。
将泊沙康唑的热的甲醇乙酸乙酯澄清溶液在15分钟内滴加到到正庚烷中，在正庚烷中快速析出果冻状产品，滴加过程温度控制在20-25℃，滴加完毕后继续在20-25℃继续搅拌60分钟，过滤，干燥后得到4.34g无定型泊沙康唑，收率：87％，XRD检测晶型为无定型。
实施例11
将5.05g泊沙康唑加入到1mL异丙醇和19mL乙酸乙酯的混合溶剂中，在250mL三口烧瓶中加热至72℃溶解完全溶解得到澄清溶液。
将80mL甲苯加入到250mL四口烧瓶中，降温到5℃下机械搅拌。
将泊沙康唑的异丙醇乙酸乙酯澄清溶液在20分钟内滴加到甲苯中，析出果冻状产品，析晶过程温度控制在5-10℃，滴加完毕后在5-10℃继续搅拌60分钟，过滤，干燥后得到4.5g无定型泊沙康唑，收率：90％，XRD检测晶型为无定型。
实施例12
将5.05g泊沙康唑加入到1mL异丙醇和19mL乙酸乙酯的混合溶剂中，在250mL三口烧瓶中加热至72℃溶解完全溶解得到澄清溶液。
将100mL二甲苯加入到250mL四口烧瓶中，降温到5℃下机械搅拌。
将泊沙康唑的异丙醇乙酸乙酯澄清溶液在16分钟内滴加到二甲苯中，析出果冻状产品，析晶过程温度控制在5-10℃，滴加完毕后在5-10℃继续搅拌45分钟，过滤，干燥后得到4.5g无定型泊沙康唑，收率：91％，XRD检测晶型为无定型。
实施例13二氯甲烷正庚烷体系所得晶型
将7.05g泊沙康唑加入到70mL二氯甲烷中，室温搅拌至溶解完全，将525mL正庚烷加入到1000mL四口烧瓶中，在25℃下机械搅拌。
将泊沙康唑的二氯甲烷溶液在20分钟内滴加到正庚烷中，在正庚烷中快速析出产品，滴加过程温度控制在20-25℃，滴加完毕后继续搅拌30分钟，过滤，干燥后得到6.42g无定型泊沙康唑，收率：91％，XRD检测晶型明显为无定型和某种晶型的混晶。
实施例14结晶温度超过30℃所得晶型
将5.05g泊沙康唑加入到1mL乙醇和19mL乙酸乙酯的混合溶剂中，在250mL三口烧瓶中加热至72℃溶解完全溶解得到澄清溶液。
将80mL正己烷加入到250mL四口烧瓶中，降温到5℃下机械搅拌。
将泊沙康唑的乙醇乙酸乙酯澄清溶液在16分钟内滴加到正己烷中，析出白色固体，析晶过程温度控制在28-33℃，滴加完毕后在30-35℃继续搅拌45分钟，过滤，干燥后得到4.6g泊沙康唑，收率：91％，XRD检测晶型为无定型和某种晶型的混晶。

Claims (9)

  1. 无定型泊沙康唑的制备工艺，其特征在于：将泊沙康唑溶于醇类和酯类的混合溶剂中，然后滴加到烷烃或芳香烃中，析出果冻状固体，即为无定型泊沙康唑；
    其中，泊沙康唑与混合溶剂的质量体积比为1:4～1：10，其单位为g/mL；，所述混合溶剂中醇类和酯类的体积比为1：3～1:20；所述的混合溶剂和烷烃或芳香烃的体积比为1:1～1:4。
  2. 根据权利要求1所述的无定型泊沙康唑的制备工艺，其特征在于：所述混合溶剂中醇类为C1-C4醇类中的一种。
  3. 根据权利要求1所述的无定型泊沙康唑的制备工艺，其特征在于：所述混合溶剂中酯类为C1-C4的乙酸酯类中的一种。
  4. 根据权利要求1所述的无定型泊沙康唑的制备工艺，其特征在于：所述烷烃为正戊烷、正己烷、正庚烷或者环己烷中的一种；所述芳香烃为甲苯或者二甲苯中的一种。
  5. 根据权利要求1所述的无定型泊沙康唑的制备工艺，其特征在于：泊沙康唑与混合溶剂的质量体积比为1:4，其单位为g/mL。
  6. 根据权利要求1所述的无定型泊沙康唑的制备工艺，其特征在于：所述混合溶剂中醇类和酯类的体积比为1:19。
  7. 根据权利要求1所述的无定型泊沙康唑的制备工艺，其特征在于：所述混合溶剂和烷烃或芳香烃的体积比为1:3。
  8. 根据权利要求1所述的无定型泊沙康唑的制备工艺，其特征在于：泊沙康唑溶于混合溶剂中，控制混合溶液的温度在55～75℃。
  9. 根据权利要求1所述的无定型泊沙康唑的制备工艺，其特征在于：将泊沙康唑、醇类、酯类的混合溶剂组成的混合溶液滴加到烷烃或芳香烃的过程中，析出物料的温度控制在0～25℃之间。
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