WO2016061863A1 - 泊沙康唑晶型i的制备工艺 - Google Patents

泊沙康唑晶型i的制备工艺 Download PDF

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WO2016061863A1
WO2016061863A1 PCT/CN2014/091361 CN2014091361W WO2016061863A1 WO 2016061863 A1 WO2016061863 A1 WO 2016061863A1 CN 2014091361 W CN2014091361 W CN 2014091361W WO 2016061863 A1 WO2016061863 A1 WO 2016061863A1
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posaconazole
crystal form
mixed solvent
hours
alcohol
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PCT/CN2014/091361
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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
    • 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
    • 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 a preparation process of posaconazole crystal form I, and belongs to the technical field of medicine preparation.
  • Posaconazole is a broad-spectrum triazole antifungal drug approved by the US FDA on September 15, 2006 for fungal infections caused by refractory diseases or other drug resistance (into aspergillin) , tuberculosis and sickle bacteria, etc.), the drug was developed by Schering-Plough Company of the United States under the trade name Noxafil.
  • the crystal form I of posaconazole is a stable solid state.
  • the preparation process of the crystal form I is disclosed in the patent US Pat. No. 6,958,337 and the Japanese patent No. 6,713,481 B1.
  • the patent discloses three crystal systems, using methanol as a solvent and water as a counter.
  • posaconazole is a solid powder material with strong hygroscopicity, the introduction of water into the crystallization system poses great difficulty for the later dried product, and moisture is a key element to be controlled in the drug substance. After repeated searches, no other patents for the preparation of posaconazole Form I were retrieved on espacenet and Google pat.
  • the object of the present invention is to provide a preparation process of posaconazole crystal form I, specifically, posaconazole is dissolved in a mixed solvent of an alcohol and an ester to be cooled and recrystallized, preferably by adding an alkane or a cycloalkane.
  • a mixed solvent of an alcohol and an ester to be cooled and recrystallized, preferably by adding an alkane or a cycloalkane.
  • posaconazole crystal form I posaconazole is dissolved in a mixed solvent of alcohols and esters, heated, dissolved and then lowered Warm, crystallization, heat preservation, and obtain posaconazole crystal form I.
  • the anti-solvent is added dropwise, and after the addition is completed, the crystal is cooled and crystallized to obtain posaconazole crystal form I.
  • the posaconazole is dissolved in a mixed solvent of an alcohol and an ester, heated to 60 to 70 ° C, dissolved, and then cooled to 15 to 25 ° C in 1 to 4 hours, crystallized, and kept warm to obtain posaconazole.
  • a mixed solvent of an alcohol and an ester heated to 60 to 70 ° C, dissolved, and then cooled to 15 to 25 ° C in 1 to 4 hours, crystallized, and kept warm to obtain posaconazole.
  • the ratio of the posaconazole to the mixed solvent is 1:4 to 1:20, and the unit is g/mL; the ratio of the alcohol to the ester in the mixed solvent (volume: volume) is 1:2. ⁇ 1:30.
  • the alcohol in the mixed solvent is one of C1-C4 alcohols
  • the ester in the mixed solvent is one of C1-C4 acetates.
  • posaconazole crystal form I The preparation process of posaconazole crystal form I, the posaconazole is dissolved in a mixed solvent of alcohols and esters, the temperature is raised to 60-70 ° C, dissolved, and the mixed solution is cooled to 35-45 in 1 to 2 hours. °C, then add anti-solvent within 10 ⁇ 60 minutes, after the addition is completed, then cool to 15 ⁇ 25 ° C, crystallization, heat preservation, to obtain posaconazole crystal form I.
  • the anti-solvent is one of n-pentane, n-hexane, n-heptane or cyclohexane.
  • the holding temperature is between 15 and 25 ° C, and the holding time is between 1 and 4 hours.
  • the ratio (mass: volume) of posaconazole and antisolvent is from 1:4 to 1:40, preferably from 1:5 to 1:10, and the unit is g/mL.
  • the ratio (mass: volume) of posaconazole to the mixed solvent is preferably from 1:5 to 1:10 in units of g/mL.
  • the volume ratio of the alcohol to the ester in the mixed solvent is preferably from 1:4 to 1:9.
  • the anti-solvent alkane or cycloalkane is further added in the crystallization of the alcohol ester mixed solvent, the supersaturation of the posaconazole in the alcohol ester mixed solvent is further lowered, and then the precipitation is continued on the basis of the original precipitated material. More products to achieve lower saturation of the three-phase mixed solvent.
  • the method for preparing posaconazole crystal form I of the invention is convenient to operate, is favorable for industrialization, has high product yield, and the mixed solvent of alcohol and ester used, and the alkane or cycloalkane are low toxicity in organic solvent.
  • the three types of solvents have high solvent recovery rate, have mature recovery methods in the industry, and can stably obtain posaconazole crystal form I, and the obtained product can be quickly dried.
  • Figure 1 is an XRD pattern of the form I of the form of Shaconazole prepared in Example 1;
  • Figure 2 is an XRD pattern of the form I of the form of Shaconazole prepared in Example 2;
  • Figure 3 is an XRD pattern of the form I of the form of Shaconazole prepared in Example 3;
  • Figure 4 is an XRD pattern of Form I of the form of Shaconazole prepared in Example 4.
  • Figure 5 is an XRD pattern of the form I of the form of Shaconazole prepared in Example 5;
  • Figure 6 is a preparation of Example 6 to obtain an XRD pattern of the form of Shaconazole Form I;
  • Figure 7 is a preparation of Example 9 to obtain an XRD pattern of Shaconazole Form I;
  • Figure 8 is an XRD pattern of the preparation of the form of the form of Shaconazole
  • 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 5g was added to a mixed solvent of 45mL of methyl acetate and 5mL of isopropyl alcohol, heated to 65 ° C to dissolve and clarify, then cooled to 20 ° C within 2 hours, crystallization, and continue to stir for 4 hours, pumping After filtration, 4.30 g was obtained in a yield of 86%, and the crystal form of XRD was crystal form I.
  • posaconazole 5 g was added to a mixed solvent of 45 mL of ethyl acetate and 5 mL of n-butanol, heated to 70 ° C to dissolve and clarify, then cooled to 25 ° C in 2 hours, crystallization, and continued to stir for 4 hours, pumping After filtration, 0.85 g was obtained, the yield was 85%, and the crystal form of XRD was crystal form I.
  • posaconazole 5 g was added to a mixed solvent of 38 mL of ethyl acetate and 2 mL of methanol, and the temperature was raised to 70 ° C to dissolve and clarify, then the temperature was lowered to 40 ° C in 2 hours, and 20 mL of n-heptane was added dropwise over 30 minutes.
  • Anti-solvent process temperature control in 35 ⁇ 45 °C, after the completion of the dropwise addition, the temperature was lowered to 20 ° C in 2 hours, and stirring was continued for 2 hours, and 4.8 g was obtained by suction filtration, the yield was 96%, and the crystal form of XRD was crystal form I.
  • posaconazole 5 g was added to a mixed solvent of 38 mL of ethyl acetate and 2 mL of methanol, and the temperature was raised to 70 ° C to dissolve and clarify, and then the temperature was lowered to 40 ° C in 2 hours, and 30 mL of cyclohexane was added dropwise over 30 minutes.
  • Anti-solvent process the temperature is controlled at 35 ⁇ 45 ° C, after the completion of the addition, the temperature is lowered to 20 ° C within 2 hours, and stirring is continued for 2 hours, after suction filtration to obtain 4.8 g, yield 96%, XRD detection crystal form Form I.
  • posaconazole 5 g was added to a mixed solvent of 38 mL of ethyl acetate and 2 mL of isopropyl alcohol, and the temperature was raised to 70 ° C to dissolve and clarify, and then the temperature was lowered to 40 ° C in 2 hours, and 30 mL of n-hexane was added dropwise over 30 minutes.
  • Add anti-solvent process the temperature is controlled at 35 ⁇ 45 ° C, after the addition is completed, the temperature is lowered to 20 ° C in 2 hours, and stirring is continued for 2 hours, and 4.8 g is obtained by suction filtration, the yield is 96%, XRD detection crystal form Is the crystal form I.
  • posaconazole 5 g was added to a mixed solvent of 38 mL of methyl acetate and 2 mL of methanol, and the temperature was raised to 70 ° C to dissolve and clarify.
  • the hot mixed solution of posaconazole was added to 40 mL of antisolvent cyclohexane in 10 minutes.
  • the temperature is controlled at 35-40 ° C.
  • the temperature is lowered to 20 ° C in 2 hours, and stirring is continued for 2 hours. After suction filtration, 4.7 g is obtained, the yield is 94%, and the crystal form is XRD.
  • posaconazole 5 g was added to a mixed solvent of 96 mL of ethyl acetate and 3.2 mL of methanol, and the temperature was raised to 70 ° C to dissolve and clarify, and then the temperature was lowered to 20 ° C in 2 hours, and stirring was continued for 1 hour, and suction filtration was carried out to obtain 4.35. g, yield 87%, XRD detection crystal form is crystal form I.

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  • Plural Heterocyclic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

本发明涉及一种泊沙康唑晶型I的制备工艺，将泊沙康唑溶于醇类和酯类的混合溶剂中，升温至60~70℃，溶解，然后在1~4小时内降温到15~25℃，析晶，保温，得到泊沙康唑晶型I；泊沙康唑与混合溶剂的质量体积比为1:4~1:20，混合溶剂中醇类和酯类的体积比为1:2~1:30。在降温过程中，先在1~2h内将混合溶液降温至35~45℃，然后在10~60分钟内滴加反溶剂，滴加完毕后，降温至15~25℃。该工艺操作方便，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类是属于有机溶剂中低毒性的溶剂，溶剂回收率高，且能够稳定地得到泊沙康唑晶型I，所得产品能够快速干燥。

Description

泊沙康唑晶型I的制备工艺 技术领域
本发明涉及一种泊沙康唑晶型I的制备工艺，属药物制备技术领域。
背景技术
泊沙康唑(Posaconazole)是2006年9月15日由美国FDA批准的一种广谱三唑类抗真菌药，用于难治性疾病或其他药物耐药引起的真菌感染(入曲霉菌素、结核菌病和镰刀细菌等)，该药物有美国Schering-Plough公司研制上市，商品名为Noxafil。
泊沙康唑中文化学名：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。
其化学结构式如下：
Figure PCTCN2014091361-appb-000001
泊沙康唑的具体分子专利在专利US5703079中报道，并在专利WO9517407中报道具体的合成工艺路线。原料药的晶型状态是药物制剂的关键因素，不同晶型的同一种药制成的制剂在人体内具有不同的生物利用度，药物晶型对用药安全性具有重要的研究价值。
泊沙康唑的晶型I是一种稳定的固体存在状态，在专利US6958337以及同族专利US6713481B1公开了晶型I的制备工艺，该专利报道了三种结晶体系，用甲醇为溶剂，水为反溶剂的结晶体系，用异丙醇为溶剂，水为反溶剂的结晶体系和单独以乙腈为溶剂的结晶体系，其中以乙腈重结晶的收率为78％。由于泊沙康唑是一种具有较强吸湿性的固体粉末物料，在结晶体系中引入水对后期干燥产品带来较大困难，而水分在原料药中是一个需要控制的关键要素。经过反复检索，在espacenet和Google pat上均没有检索到其他制备泊沙康唑晶型I的专利。
发明内容
本发明的目的是提供一种泊沙康唑晶型I的制备工艺，具体来说，是将泊沙康唑溶于醇类和酯类的混合溶剂中冷却重结晶，优选加入烷烃或环烷烃等反溶剂，然后析晶，本工艺产品收率高，采用低毒性的有机溶剂，适合大规模生产制备泊沙康唑晶型I。
本发明采用的技术方案为：
泊沙康唑晶型I的制备工艺，将泊沙康唑溶于醇类和酯类的混合溶剂中，升温，溶解后降 温，析晶，保温，得到泊沙康唑晶型I。
优选的，在降温过程中，滴加反溶剂，滴加完毕后，再降温析晶，得到泊沙康唑晶型I。
将泊沙康唑溶于醇类和酯类的混合溶剂中，升温至60～70℃，溶解，然后在1～4小时内降温到15～25℃，析晶，保温，得到泊沙康唑晶型I。
其中泊沙康唑与混合溶剂的比例(质量：体积)为1:4～1：20，其单位为g/mL；混合溶剂中醇类和酯类的比例(体积：体积)为1：2～1:30。
所述混合溶剂中醇类为C1-C4的醇类中的一种；
所述混合溶剂中酯类为C1-C4的乙酸酯类中的一种。
泊沙康唑晶型I的制备工艺，将泊沙康唑溶于醇类和酯类的混合溶剂中，升温至60～70℃，溶解，在1～2h内将混合溶液降温至35～45℃，然后在10～60分钟内滴加反溶剂，滴加完毕后，再降温至15～25℃，析晶，保温，得到泊沙康唑晶型I。
所述反溶剂为正戊烷、正己烷、正庚烷或环己烷中的一种。
保温温度为15～25℃之间，保温时间为1～4小时。
泊沙康唑和反溶剂的比例(质量：体积)为1:4～1：40，优选为1:5～1：10，其单位为g/mL。
泊沙康唑与混合溶剂的比例(质量：体积)优选为1:5～1:10，其单位为g/mL。
混合溶剂中醇类和酯类的体积比优选为1:4～1：9。
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降低而显著降低的性质，本专利研究的醇类酯类冷却结晶体系和烷烃环烷烃类反溶剂结晶方法均为本专利首次报道。
在醇类酯类混合溶剂结晶时进一步加入反溶剂烷烃类或环烷烃类后，使得醇类酯类混合溶剂中的泊沙康唑的过饱和度进一步降低，继而在原有析出物料基础上继续析出更多的产品以达到三相混合溶剂的更低饱和度。
有益效果：本发明制备泊沙康唑晶型I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类是属于有机溶剂中低毒性的三类溶剂，溶剂回收率高，在工业上具有成熟的回收方法，且能够稳定地得到泊沙康唑晶型I，所得产品能够快速干燥。
附图说明
图1实施例1制备得到沙康唑晶型I的XRD图；
图2实施例2制备得到沙康唑晶型I的XRD图；
图3实施例3制备得到沙康唑晶型I的XRD图；
图4实施例4制备得到沙康唑晶型I的XRD图；
图5实施例5制备得到沙康唑晶型I的XRD图；
图6实施例6制备得到沙康唑晶型I的XRD图；
图7实施例9制备得到沙康唑晶型I的XRD图；
图8实施例10制备得到沙康唑晶型I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1g泊沙康唑加入到9mL乙酸乙酯和1mL甲醇的混合溶剂中，升温到65℃溶解澄清，然后在2小时内降温到25℃，析晶，25℃保温搅拌4小时，抽滤后得到0.85g，收率85％，XRD检测晶型为晶型I。
实施例2
将5g泊沙康唑加入到45mL乙酸甲酯和5mL乙醇的混合溶剂中，升温到65℃溶解澄清，然后在2小时内降温到20℃，析晶，20℃保温保持搅拌4小时，抽滤后得到4.30g，收率86％，XRD检测晶型为晶型I。
实施例3
将5g泊沙康唑加入到45mL乙酸甲酯和5mL异丙醇的混合溶剂中，升温到65℃溶解澄清，然后在2小时内降温到20℃，析晶，并继续保持搅拌4小时，抽滤后得到4.30g，收率86％，XRD检测晶型为晶型I。
实施例4
将5g泊沙康唑加入到45mL乙酸乙酯和5mL正丁醇的混合溶剂中，升温到70℃溶解澄清，然后在2小时内降温到25℃，析晶，并继续保持搅拌4小时，抽滤后得到0.85g，收率85％，XRD检测晶型为晶型I。
实施例5
将1g泊沙康唑加入到9mL乙酸丁酯和1mL甲醇的混合溶剂中，升温到70℃溶解澄清，然后在2小时内降温到15℃，析晶，并继续保持搅拌4小时，抽滤后得到0.86g，收率86％，XRD检测晶型为晶型I。
实施例6
将5g泊沙康唑加入到38mL乙酸乙酯和2mL甲醇的混合溶剂中，升温到70℃溶解澄清，然后在2小时内降温到40℃，在30分钟内滴加20mL正庚烷，滴加反溶剂过程，温度控制在35～45 ℃，滴加完毕后，在2小时内降温到20℃，并继续保持搅拌2小时，抽滤后得到4.8g，收率96％，XRD检测晶型为晶型I。
实施例7
将5g泊沙康唑加入到38mL乙酸乙酯和2mL甲醇的混合溶剂中，升温到70℃溶解澄清，然后在2小时内降温到40℃，在30分钟内滴加30mL环己烷，滴加反溶剂过程，温度控制在35～45℃，滴加完毕后，在2小时内降温到20℃，并继续保持搅拌2小时，抽滤后得到4.8g，收率96％，XRD检测晶型为晶型I。
实施例8
将5g泊沙康唑加入到38mL乙酸乙酯和2mL异丙醇的混合溶剂中，升温到70℃溶解澄清，然后在2小时内降温到40℃，在30分钟内滴加30mL正己烷，滴加反溶剂过程，温度控制在35～45℃，滴加完毕后，在2小时内降温到20℃，并继续保持搅拌2小时，抽滤后得到4.8g，收率96％，XRD检测晶型为晶型I。
实施例9
将5g泊沙康唑加入到38mL乙酸甲酯和2mL甲醇的混合溶剂中，升温到70℃溶解澄清，然后在2小时内降温到40℃，在30分钟内滴加40mL环己烷，滴加反溶剂过程中温度控制在35～45℃，滴加完毕后，在2小时内降温到20℃，并继续保持搅拌2小时，抽滤后得到4.8g，收率96％，XRD检测晶型为晶型I。
实施例10
将5g泊沙康唑加入到38mL乙酸甲酯和2mL甲醇的混合溶剂中，升温到70℃溶解澄清，将泊沙康唑的热混合溶液在10分钟内加入到40mL反溶剂环己烷中，加料过程中温度控制在35～40℃，加料完毕后，在2小时内降温到20℃，并继续保持搅拌2小时，抽滤后得到4.7g，收率94％，XRD检测晶型为晶型I。
实施例11
将5g泊沙康唑加入到14mL乙酸甲酯和7mL甲醇的混合溶剂中，升温到70℃溶解澄清，然后在2小时内降温到15℃，并继续保持搅拌1小时，抽滤后得到4.25g，收率85％，XRD检测晶型为晶型I。
实施例12
将5g泊沙康唑加入到96mL乙酸乙酯和3.2mL甲醇的混合溶剂中，升温到70℃溶解澄清，然后在2小时内降温到20℃，并继续保持搅拌1小时，抽滤后得到4.35g，收率87％，XRD检测晶型为晶型I。
实施例13
将5g泊沙康唑加入到20mL乙酸乙酯和5mL甲醇的混合溶剂中，升温到70℃溶解澄清，然后在2小时内降温到20℃，并继续保持搅拌2小时，抽滤后得到4.2g，收率84％，XRD检测晶型为晶型I。

Claims (10)

  1. 泊沙康唑晶型I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，升温至60～70℃，溶解，然后在1～4小时内降温到15～25℃，析晶，保温，得到泊沙康唑晶型I；
    其中泊沙康唑与混合溶剂的质量体积比为1:4～1：20，其单位为g/mL；混合溶剂中醇类和酯类的体积比为1：2～1:30。
  2. 根据权利要求1所述的泊沙康唑晶型I的制备工艺，其特征在于：在降温过程中，先在1～2h内将混合溶液降温至35～45℃，然后在10～60分钟内滴加反溶剂，滴加完毕后，降温至15～25℃。
  3. 根据权利要求1或2所述的泊沙康唑晶型I的制备工艺，其特征在于：所述混合溶剂中醇类为C1-C4的醇类中的一种。
  4. 根据权利要求1或2所述的泊沙康唑晶型I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。
  5. 根据权利要求1所述的泊沙康唑晶型I的制备工艺，其特征在于：保温温度为15～25℃之间，保温时间为1～4小时。
  6. 根据权利要求1所述的泊沙康唑晶型I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1:5～1:10，其单位为g/mL。
  7. 根据权利要求1所述的泊沙康唑晶型I的制备工艺，其特征在于：混合溶剂中醇类和酯类的体积比为1:4～1：9。
  8. 根据权利要求2所述的泊沙康唑晶型I的制备工艺，其特征在于：所述反溶剂为正戊烷、正己烷、正庚烷或环己烷中的一种。
  9. 根据权利要求2所述的泊沙康唑晶型I的制备工艺，其特征在于：泊沙康唑和反溶剂的质量体积比为1:4～1：40，其单位为g/mL。
  10. 根据权利要求9所述的泊沙康唑晶型I的制备工艺，其特征在于：泊沙康唑和反溶剂的质量体积比为1:5～1：10，其单位为g/mL。
PCT/CN2014/091361 2014-10-21 2014-11-18 泊沙康唑晶型i的制备工艺 WO2016061863A1 (zh)

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CN116789656A (zh) * 2023-06-25 2023-09-22 山东济坤生物制药有限公司 一种泊沙康唑杂质的制备方法

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WO2009141837A2 (en) * 2008-05-21 2009-11-26 Ind-Swift Laboratories Limited Process for preparing posaconazole and intermediates thereof

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CN1281449A (zh) * 1997-10-07 2001-01-24 先灵公司 结晶抗真菌多晶型物
WO2009141837A2 (en) * 2008-05-21 2009-11-26 Ind-Swift Laboratories Limited Process for preparing posaconazole and intermediates thereof

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116789656A (zh) * 2023-06-25 2023-09-22 山东济坤生物制药有限公司 一种泊沙康唑杂质的制备方法

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