WO2017096690A1 - 一种达芦那韦无定型的制备方法 - Google Patents

一种达芦那韦无定型的制备方法 Download PDF

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WO2017096690A1
WO2017096690A1 PCT/CN2016/070494 CN2016070494W WO2017096690A1 WO 2017096690 A1 WO2017096690 A1 WO 2017096690A1 CN 2016070494 W CN2016070494 W CN 2016070494W WO 2017096690 A1 WO2017096690 A1 WO 2017096690A1
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solvent
darunavir
dissolved
amorphous
amorphous form
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PCT/CN2016/070494
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French (fr)
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徐建康
吴昊
叶美其
叶恺
诸林冰
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浙江九洲药业股份有限公司
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Priority to US15/780,642 priority Critical patent/US10513527B2/en
Publication of WO2017096690A1 publication Critical patent/WO2017096690A1/zh

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    • 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
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems

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  • the invention relates to the technical field of medicinal chemistry, in particular to a preparation method of amorphous form of darunavir.
  • polycrystalline screening and salt-forming screening are the more selected research methods.
  • Polycrystalline screening is the use of certain methods to form compounds into polycrystals in a variety of different solvents.
  • the main methods used in polycrystalline screening are: suspension equilibrium method, solvent heating and cooling method, saturated solution natural evaporation method, and anti-solvent addition method.
  • the salt-forming screening is a reaction between a drug and a different counterion (acid or base) to form a salt, and the drug and the acid-base molecule mainly act as an ionic bond.
  • Daalunavir is a protease inhibitor that was marketed in the United States in July 2006 in the form of its ethanolate under the trade name Prezista. There is a polymorphic form of darunavir, and many manufacturers have researched and developed specific crystalline forms and amorphous forms, and carried out patent application.
  • amorphous form was prepared by evaporation concentration in the patent application WO2011048604 (Applicant: MATRIX LABORATORIES LIMITED, publication date: 2011-4-28). Specifically, it is dissolved in darunavir in a solvent such as ethyl acetate, and the solvent is removed by concentration to form a semi-solid, and then a hydrocarbon-containing solvent such as n-heptane is added to separate and obtain darunavir amorphous.
  • a solvent such as ethyl acetate
  • the use of evaporation and concentration to prepare amorphous has the following disadvantages: First, the material is easy to puff, and if special vacuum equipment is needed in industrial production, the production capacity will be reduced; second, after industrial production, due to the increase in solvent amount, This results in a longer distillation time, which leads to an extended production cycle and a large amount of exhaust gas during vacuum concentration.
  • the present invention provides a method for preparing an amorphous form of darunavir using an anti-solvent, which is different from the patent application WO2011048604 by vacuum concentration to prepare an amorphous form, although as in WO2013114382, it relates to the use of an anti-solvent, but The final form of the crystal form is completely different. In WO2013114382, it is a solvent-free crystalline form of darunavir, and the present invention is an amorphous form.
  • the invention provides a method for preparing an amorphous form of darunavir by using an anti-solvent,
  • the preparation method has the advantages of simple process, no need to use special equipment, short production cycle and large production capacity, and is suitable for industrial production.
  • the preparation method of the amorphous form of darunavir provided by the invention comprises the following steps:
  • the dissolving solvent is a single solvent or a mixed solvent of an ester solvent or a ketone solvent; preferably, the dissolving solvent is an ester solvent.
  • the ester solvent is ethyl formate, ethyl acetate or isopropyl acetate;
  • the ketone solvent is acetone, methyl ethyl ketone, methyl isobutyl ketone or methyl n-butyl ketone.
  • the anti-solvent is a hydrocarbon-containing solvent or an ether solvent; preferably, the anti-solvent is a hydrocarbon-containing solvent.
  • the hydrocarbon-containing solvent is a C5-C12 alkane, an aromatic hydrocarbon solvent or a mixture thereof, wherein the C5-C12 alkane solvent is: n-heptane, hexane, cyclohexane, methylcyclohexane Or a mixture thereof; the aromatic hydrocarbon solvent is toluene or xylene; and the ether solvent is methyl tert-butyl ether or isopropyl ether.
  • the method for preparing amorphous form of darunavir comprises the following steps:
  • the certain temperature is -30 ° C to 30 ° C, and preferably, the certain temperature is -10 ° C to 10 ° C.
  • the method for preparing darunavir amorphous form includes, for example, Next steps:
  • darunavir a. Add darunavir to the dissolved solvent, b. dissolve and dissolve, add to the anti-solvent at a certain temperature, c. separate the darunavir amorphous.
  • the solution in order to dissolve the solution, the solution may be stirred and the temperature raised.
  • the temperature can be raised from room temperature to the boiling point of the solvent.
  • the mass ratio of the darunavir dissolving solvent to the reverse phase solvent may be 1:1 to 50, preferably 1:1 to 20.
  • darunavir is added to a dissolving solvent such as 50 g of isopropyl acetate, b. dissolved and dissolved, and then added to an anti-solvent such as 80 g of n-heptane at -10 ° C to 10 ° C, c. separation
  • a dissolving solvent such as 50 g of isopropyl acetate, b. dissolved and dissolved, and then added to an anti-solvent such as 80 g of n-heptane at -10 ° C to 10 ° C, c. separation
  • an anti-solvent such as 80 g of n-heptane at -10 ° C to 10 ° C, c. separation
  • the release of ruinavir is unchanged.
  • the invention adopts X-ray powder diffraction to detect the prepared amorphous form of darunavir.
  • the present invention provides a method for preparing an amorphous form of darunavir by crystallization of a reverse phase solvent, that is, a solution of darunavir is added to a cooled reversed-phase solvent to separate a precipitate, and then the amorphous form of darunavir is separated.
  • the preparation method has the advantages of simple process, no need to use special equipment, short production cycle and large production capacity, and is suitable for industrial production.
  • the product obtained by the production method of the present invention has good solubility.
  • Example 1 is an XRPD pattern of the amorphous form of darunavir prepared in Example 1;
  • Example 2 is an XRPD pattern of the amorphous form of darunavir prepared in Example 2.
  • Tube pressure 30kV
  • Tube flow 10mA

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Abstract

本发明涉及医药化学技术领域，具体涉及一种达芦那韦无定型的制备方法，见公式（Ｉ）。本发明达芦那韦无定型的制备属于晶型制备筛选中的反溶剂法，现有技术中虽已有使用反溶剂来筛选晶型，但最终制备获得的是达芦那韦的具体晶型形式，而非无定型，如WO2013114382。本发明提供的是不同于现有技术，产能高，适合于工业化生产的制备方法。

Description

一种达芦那韦无定型的制备方法 技术领域
本发明涉及医药化学技术领域，具体涉及达芦那韦无定型的制备方法。
背景技术
在药物晶型研究开发中，多晶筛选和成盐筛选是较多的被选择的研究方式。多晶筛选是采用一定的方法使化合物在各种不同溶剂中形成多晶。多晶筛选主要运用的方法有：混悬平衡法，溶剂加热冷却法，饱和溶液自然蒸发法，反溶剂加入法。成盐筛选是药物和不同的反离子(酸或碱)反应生成盐，药物与酸碱分子之间主要以离子键形式发生作用。
达芦那韦，化学名称为[(1R,5S,6R)-2,8-二氧双环[3.3.0]-癸烷-6-基]-N-[(2S,3R)-4-[(4-氨基苯基)磺酰基-(2-甲基丙基)氨基]-3-羟基-1-苯基-丁烷-2-基]氨基甲酸酯，结构式如下：
Figure PCTCN2016070494-appb-000001
达芦那韦是一种蛋白酶抑制剂，于2006年7月在美国以其乙醇合物的形式上市，商品名为Prezista。达芦那韦存在多晶型形式，很多厂家对具体晶型形式和无定型形式进行了研究开发，并对其进行了 专利申请。
如专利申请WO2011048604(申请人：MATRIX LABORATORIES LIMITED，公开日：2011-4-28)中采用蒸发浓缩的方式制备得到了无定型。具体为溶解达芦那韦在溶剂如乙酸乙酯中，通过浓缩除去溶剂形成半固体后，加入含碳氢化合物的溶剂如正庚烷，分离即能得到达芦那韦无定型。通常，采用蒸发浓缩的方式去制备无定型存在如下缺点：一是物料易膨化，工业化生产时如需要特殊的真空设备，会导致产能降低；二是，工业化生产后，由于溶剂量的增加，会导致蒸馏时间变长，从而导致其生产周期延长，并且真空浓缩的过程中，也会产生大量的废气。
如WO2013114382中，(申请人：MYLAN LABORATORIES LTD，公开日：2013-8-8)采用将达芦那韦溶解在溶剂如乙酸乙酯中，后在其中加入反溶剂如正庚烷，制备得到了不含溶剂的达芦那韦晶型。虽然，该专利申请中采用的是反溶剂加入法，不存在真空浓缩工艺的缺点，但最终制备得到的是不含溶剂的达芦那韦晶型，而并非其无定型。
本发明提供了一种使用反溶剂去制备达芦那韦无定型的方法，不同于专利申请WO2011048604中使用真空浓缩的方式去制备无定型，虽然与WO2013114382中一样，均涉及到使用反溶剂，但是，最终制备得到的晶型形式却截然不同，WO2013114382中为不含溶剂的达芦那韦晶型形式，本发明为无定型形式。
发明内容
本发明提供了一种使用反溶剂，制备达芦那韦无定型的方法，该 制备方法工艺简单，无需使用特殊设备，生产周期短，产能大，适合工业化生产。
为实现本发明的技术目的，本发明采用的技术方案如下：
本发明提供的达芦那韦无定型的制备方法，包括如下步骤：
a.将达芦那韦加入到溶解溶剂中，b.溶解后，加入到反溶剂中，c.分离出达芦那韦无定型。
其中，所述溶解溶剂为酯类溶剂或酮类溶剂的单一溶剂或混合溶剂；优选地，所述溶解溶剂为酯类溶剂。所述酯类溶剂为甲酸乙酯，乙酸乙酯或醋酸异丙酯等；所述酮类溶剂为丙酮，甲基乙基酮，甲基异丁基酮或甲基正丁基酮。
所述反溶剂为含碳氢化合物的溶剂或醚类溶剂；优选地，所述反溶剂为含碳氢化合物的溶剂。所述含碳氢化合物的溶剂为C5～C12的烷烃，芳香烃溶剂或其混合物，其中，所述C5～C12的烷烃溶剂为：正庚烷，已烷，环己烷，甲基环己烷或其混合物；所述芳香烃类溶剂为甲苯或二甲苯；所述醚类溶剂为甲基叔丁基醚或异丙醚。
进一步地，本发明提供的达芦那韦无定型的制备方法，包括如下步骤：
a.将达芦那韦加入到溶解溶剂中，b.溶解后，加入到一定温度下的反溶剂中，c.分离出达芦那韦无定型。
其中，所述一定温度为-30℃～30℃，优选地，所述一定温度为-10℃～10℃。
更进一步地，本发明提供的达芦那韦无定型的制备方法，包括如 下步骤：
a.将达芦那韦加入到溶解溶剂中，b.溶解并溶清后，加入到一定温度下的反溶剂中，c.分离出达芦那韦无定型。
其中，为使溶液溶清，可以搅拌溶液并升高温度。所述温度可以从室温升高到所述溶剂的沸点。
本发明的技术方案中，所述达芦那韦溶解溶剂与反相溶剂的质量比可以为1:1～50，优选地为1:1～20。
本发明比较具体的一种实施方式为：
a.将10g达芦那韦加入到溶解溶剂如50g醋酸异丙酯中，b.溶解并溶清后，加入到-10℃～10℃下的反溶剂如80g正庚烷中，c.分离出达芦那韦无定型。
本发明采用X射线粉末衍射对制备得到的达芦那韦无定型进行了检测。
本发明提供了一种使用反相溶剂结晶制备达芦那韦无定型的方法，即将达芦那韦溶液加入到已冷却的反相溶剂中析料，再分离出达芦那韦无定型。制备方法工艺简单，无需使用特殊设备，生产周期短，产能大，适于工业化生产。采用本发明的制备方法获得的产品溶解性好。
附图说明
图1为实施例1中制备得到的达芦那韦无定型的XRPD图谱；
图2为实施例2中制备得到的达芦那韦无定型的XRPD图谱。
具体实施方式
为了更好的理解本发明的内容，下面结合具体实施例来做进一步的说明，但具体的实施方式并不是对本发明的内容所做的限制。
本发明所使用的检测条件：
仪器：Bruker D2Phaser X-衍射粉末衍射仪；
X射线靶材：Cu Kα(1.54184A)；
管压：30kV；
管流：10mA；
2θ扫描范围：2°—40°；
扫描速率(步时)：0.2s/step；
步长：0.02°。
实施例1：
在250ml四口瓶中加入50g醋酸异丙酯和10g达芦那韦，搅拌，升温至50-60℃；溶液溶清后，将溶液滴加至0～5℃正庚烷中，加毕后继续保温1-3小时。抽滤，正庚烷淋洗。湿品于60℃真空烘箱干燥。得到达芦那韦无定型9.3g，纯度100.0％，收率为93.0％。其XRPD如图1所示。
实施例2：
在250ml四口瓶中加入4g丙酮和1g达芦那韦，搅拌，升温至50-60℃；溶液溶清后，将溶液滴加至0～5℃正庚烷中，加毕后继续保温1-3小时。抽滤，正庚烷淋洗。湿品于60℃真空烘箱干燥。得到达芦那韦无定型0.95g，纯度99.9％，收率95.0％。其XRPD如图2所示。
实施例3：
在250ml四口瓶中加入50g醋酸异丙酯和10g达芦那韦，搅拌，升温 至50-60℃；溶液溶清后，将溶液滴加至-10～0℃正庚烷中，抽滤，正庚烷淋洗。湿品于60℃真空烘箱干燥。得到达芦那韦无定型9.3g，纯度100.0％，收率为93.0％。
实施例4：
在250ml四口瓶中加入50g醋酸异丙酯和10g达芦那韦，搅拌，升温至50-60℃；溶液溶清后，在5～10℃下，将溶液滴加至正庚烷中，抽滤，正庚烷淋洗。湿品于60℃真空烘箱干燥。得到达芦那韦无定型9.3g，纯度100.0％，收率为93.0％。

Claims (10)

  1. 一种达芦那韦无定型的制备方法，其特征在于，包括如下步骤：
    a.将达芦那韦加入到溶解溶剂中；
    b.溶解后，加入到反溶剂中；
    c.分离出达芦那韦无定型。
  2. 根据权利要求1所述的达芦那韦无定型的制备方法，其特征在于，包括如下步骤：
    a.将达芦那韦加入到溶解溶剂中；
    b.溶解后，加入到一定温度下的反溶剂中；
    c.分离出达芦那韦无定型。
  3. 根据权利要求1或2所述的达芦那韦无定型的制备方法，其特征在于，包括如下步骤：
    a.将达芦那韦加入到溶解溶剂中；
    b.溶解并溶清后，加入到一定温度下的反溶剂中；
    c.分离出达芦那韦无定型。
  4. 根据权利要求1，2或3所述的制备方法，其特征在于，包括如下步骤：
    a.将达芦那韦加入到溶解溶剂中；
    b.在室温到溶解溶剂沸点下溶解并溶清后，加入到一定温度下的反溶剂中；
    c.分离出达芦那韦无定型。
  5. 根据权利要求1，2，3或4所述的制备方法，其特征在于，所述 溶解溶剂为酯类溶剂或酮类溶剂的单一溶剂或混合溶剂；所述反溶剂为含碳氢化合物的溶剂或醚类溶剂。
  6. 根据权利要求5所述的制备方法，其特征在于，所述酯类溶剂为甲酸乙酯，乙酸乙酯或醋酸异丙酯；所述酮类溶剂为丙酮，甲基乙基酮，甲基异丁基酮或甲基正丁基酮。
  7. 根据权利要求5所述的制备方法，其特征在于，所述含碳氢化合物的溶剂为C5～C12的烷烃，芳香烃溶剂或其混合物；所述醚类溶剂为甲基叔丁基醚或异丙醚。
  8. 根据权利要求7所述的制备方法，其特征在于，所述C5～C12的烷烃溶剂为正庚烷，已烷，环己烷，甲基环己烷或其混合物；所述芳香烃类溶剂为甲苯或二甲苯。
  9. 根据权利要求2，3或4所述的制备方法，其特征在于，所述温度为-30℃～30℃。
  10. 根据权利要求1，2，3或4所述的制备方法，其特征在于，所述达芦那韦溶解溶剂与反相溶剂的质量比为1:1～50。
PCT/CN2016/070494 2015-12-08 2016-01-08 一种达芦那韦无定型的制备方法 WO2017096690A1 (zh)

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CN108794498A (zh) * 2017-05-03 2018-11-13 江苏瑞科医药科技有限公司 一种达芦那韦无定型的制备方法
CN111821309B (zh) * 2020-04-30 2021-08-24 深圳市新阳唯康科技有限公司 一种具有改良溶出速度的达芦那韦组合物

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