WO2021184789A1 - 一种爱普列特杂质及其制备方法和应用 - Google Patents

一种爱普列特杂质及其制备方法和应用 Download PDF

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WO2021184789A1
WO2021184789A1 PCT/CN2020/128606 CN2020128606W WO2021184789A1 WO 2021184789 A1 WO2021184789 A1 WO 2021184789A1 CN 2020128606 W CN2020128606 W CN 2020128606W WO 2021184789 A1 WO2021184789 A1 WO 2021184789A1
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impurity
organic solvent
epristeride
preparation
aprilide
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French (fr)
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何秋
俞波
黄坤
赵杰
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江苏联环药业股份有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/0066—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by a carbon atom forming part of an amide group
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/04—Preparation or injection of sample to be analysed
    • G01N30/06—Preparation
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/04—Preparation or injection of sample to be analysed
    • G01N30/06—Preparation
    • G01N2030/067—Preparation by reaction, e.g. derivatising the sample

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  • the present invention belongs to the field of medicinal chemistry, and specifically relates to an impurity of Epride and its preparation method and application.
  • Epristide also known as Epristeride, has a chemical name of 17 ⁇ -(N-tert-butyl-amino-formyl)androsta-3,5-diene-3-carboxylic acid. It is a new selective and non-competitive steroid type II 5a-reductase inhibitor, which can form a ternary complex with 5d-reductase and nicotinamide adenine dinucleotide phosphate (NADP+), thereby inhibiting testosterone
  • the conversion to DHT reduces the content of dihydrotestosterone (DHT) in the prostate, leading to atrophy of the prostatic body that is proliferating, and achieving the purpose of inhibiting benign prostatic hyperplasia.
  • DHT dihydrotestosterone
  • the technical problem to be solved by the present invention is to provide an impurity of eprister; another technical problem to be solved by the present invention is to provide a method for preparing the impurity of eprister; Another technical problem of the company is to provide the application of the impurity of Aprilide as a reference substance for the quality research of the API and its preparation. The purpose is to solve the problem that there is no method for synthesizing the impurity, and its structure cannot be confirmed, so that the impurity reference substance analysis and verification cannot be carried out, and the quality of Aipriide can be effectively controlled.
  • Epglietide An impurity of Epglietide, its chemical name is 17 ⁇ -(N-tert-butyl-amino-formyl)androst-4-en-3-one-5-hydroxyl, and its molecular structure is shown in formula I:
  • the preparation method of the above-mentioned impurity impurity includes the following steps:
  • the synthetic route is as follows:
  • the above-mentioned preparation method of the impurity of Aprilide includes the following steps:
  • the mass-volume ratio of Aipriide, organic solvent I, oxidant, and organic solvent II is 1:10-30:1-4:4-10;
  • the reaction temperature is 10-30°C, and the reaction time is 30-50 hours.
  • the oxidizing agent includes hydrogen peroxide, tert-butyl hydroperoxide, m-chloroperoxybenzoic acid, and peracetic acid; among them, hydrogen peroxide and tert-butyl hydroperoxide are commonly used non-acid peroxides; m-chlorine Peroxybenzoic acid and peroxyacetic acid are commonly used acid peroxides.
  • the oxidizing agent is hydrogen peroxide and tert-butyl hydrogen peroxide.
  • the oxidizing agent is hydrogen peroxide.
  • the oxidant is hydrogen peroxide or tert-butyl hydrogen peroxide, which is commonly used non-acid peroxide, hydrochloric acid or acetic acid is also required.
  • the organic solvent I is selected from at least one of methanol, ethanol, isopropanol, tert-butanol, benzyl alcohol, tetrahydrofuran, and acetonitrile.
  • the organic solvent II used for recrystallization is selected from at least one of ethyl acetate, acetonitrile, acetone, and toluene.
  • this application provides for the first time a method for the preparation of impurity of Aprilide, simple operation, high efficiency, mild reaction conditions, strong safety, and easy control.
  • the impurity yield of the Epristeride prepared by the method is high, and the purity is as high as 96% or more. It is suitable for controlling the quality of the API and its preparations as a reference substance, and effectively controlling the quality of the related drugs.
  • Figure 1 is an HPLC chart of the impurity of Aprilide prepared according to the method of Example 1 of the present invention
  • Fig. 2 is a 1 H-NMR spectrum of the impurity of Aprilide prepared according to the method of Example 1 of the present invention
  • Fig. 3 is a 13 C-NMR spectrum of the impurity of Aprilide prepared according to the method of Example 1 of the present invention.
  • FIG. 4 is a mass spectrum chart of the impurity of Epristeride prepared according to the method of Example 1 of the present invention.
  • a preparation method of Impurity Impurity including the following steps:
  • step (1) Take step (1) to obtain a yellow oil, add 20 mL of ethyl acetate, heat to reflux, naturally cool and then crystallize, filter with suction, and dry to obtain 4.2 g of white solid, which is the impurity of Epride.
  • the yield is It is 84%, and the purity is over 96%.
  • HPLC liquid chromatograph: Shimadzu LC-20AT; chromatographic column: Insert Sustain C18 column (4.6 ⁇ 250mm, 5 ⁇ m). Take 25mL of glacial acetic acid, 1mL of diethylamine, add water to dissolve and dilute to 1000mL, mix well as mobile phase A, use methanol as mobile phase B, detection wavelength at 260nm, flow rate 1.0mL/min, column temperature 35°C. The injection volume is 10 ⁇ L. The elution is carried out according to the following gradient program:
  • the proton nuclear magnetic resonance spectrum ( 1 H-NMR instrument: BRUKER AV-400 nuclear magnetic resonance instrument) obtained according to Example 1 shows that the CDCl 3 is the solvent of 1 H -In the NMR spectrum, the solvent peak of CDCl 3 is removed, and the molecular structure has the resonance peaks of 37 protons in 12 different environments.
  • the integration ratio of each peak (from low field to high field) is 1:1:4: 15:3:6:1:2:1:1:1:1.
  • the type and number of protons in the tested product are consistent with the characteristics of hydrogen atoms in the impurity molecular structure of Aipriet.
  • the liquid phase mass spectrometry (LC-MS instrument: agilent 6120 LC-MS liquid mass spectrometer) of the impurity of Epgliet obtained according to Example 1 shows that its molecular weight is 387.56.
  • the results are in line with the structural characteristics of the impurity of Epleyt.
  • a preparation method of Impurity Impurity including the following steps:
  • step (2) Take the yellow oil obtained in step (1), add 30 mL of acetonitrile, heat up to reflux, naturally cool, crystallize, filter with suction, and dry to obtain 3.2 g of white solid, which is the impurity of Epride, and the yield is 64 %, the purity is more than 96%.
  • a preparation method of Impurity Impurity including the following steps:
  • step (2) Take the yellow oil obtained in step (1), add 30 mL of toluene, heat to reflux, naturally cool, crystallize, filter with suction, and dry to obtain 3.5 g of white solid, which is the impurity of Epride, and the yield is 70 %, the purity is more than 96%.
  • a preparation method of Impurity Impurity including the following steps:
  • step (2) Take the yellow oil obtained in step (1), add 50 mL of acetone, heat to reflux to dissolve, and distill to about 25 mL at atmospheric pressure. After natural cooling, crystallize, filter with suction, and dry to obtain 4.5 g of white solid. The yield is 90%, and the purity is more than 96%.
  • a preparation method of Impurity Impurity including the following steps:
  • step (2) Take the yellow oil obtained in step (1), add 50 mL of acetone, heat to reflux to dissolve, and distill to about 25 mL at atmospheric pressure. After natural cooling, crystallize, filter with suction, and dry to obtain 3.1 g of white solid. The yield is 62% and the purity is over 96%.

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Abstract

本发明公开了一种爱普列特杂质及其制备方法和应用，属于医药化学领域。该爱普列特杂质的化学名称为17β-(N-叔丁基-氨基-甲酰基)雄甾-4-烯-3-酮-5-羟基。其制备方法，包括以下步骤：1)以爱普列特为原料，在有机溶剂I中，与氧化剂搅拌混匀反应，反应完毕后得到爱普列特杂质粗品反应液；爱普列特杂质粗品反应液经后处理后，浓缩得到油状物；2)油状物经有机溶剂II重结晶后得到爱普列特杂质。本发明操作简单高效，反应条件温和，安全性强，易于控制，由该制备方法所制得的爱普列特杂质收率高、纯度高达96％以上，适用于作为对照品研究爱普列特原料药及其制剂的质量，为爱普列特相关药物的质量进行有效控制夯实了基础。

Description

一种爱普列特杂质及其制备方法和应用 技术领域
本发明属于医药化学领域，具体涉及一种爱普列特杂质及其制备方法和应用。
背景技术
爱普列特(Epristeride)，又名依立雄胺，化学名称为17β-(N-叔丁基-氨基-甲酰基)雄甾-3，5-二烯-3-羧酸。是一种新型选择性的和非竞争性的类固醇II型5a-还原酶抑制剂，可与5d-还原酶及尼克酰胺腺嘌呤二核苷酸磷酸(NADP+)形成三元复合物，从而抑制睾酮向DHT转化，使前列腺内的双氢睾酮(DHT)含量降低，导致增生的前列腺体萎缩，达到抑制前列腺增生的目的。
为了爱普列特的用药安全，达到有效控制其质量的目的，对药品中杂质的研究显得尤为重要。目前国际通行的办法是对杂质进行杂质对照品分析验证，因此开展爱普列特中杂质的合成研究具有重要意义。化合物I为爱普列特合成中常见的杂质，且在原料药和制剂中也会降解产生。经检索，目前无合成该杂质的方法，因此合成该杂质并确证其结构，合成该杂质研究其理化性质从而加以控制，并选择合适方法有效去除对于提高爱普列特质量意义重大。
发明内容
针对现有技术存在的上述问题，本发明所要解决的技术问题是提供一种爱普列特杂质；本发明所要解决的另一技术问题是提供爱普列特杂质的制备方法；本发明所要解决的再一技术问题是提供爱普列特杂质在作为爱普列特原料药及其制剂质量研究的对照品中的应用。旨在解决目前无合成该杂质的方法，不能确认其结构，从而不能进行杂质对照品分析验证，有效控制爱普列特质量的问题。
为了解决上述技术问题，本发明所采用的技术方案如下：
一种爱普列特杂质，其化学名称为17β-(N-叔丁基-氨基-甲酰基)雄甾-4-烯-3-酮-5-羟基，其分子结构式如式I所示：
Figure PCTCN2020128606-appb-000001
上述爱普列特杂质的制备方法，包括以下步骤：
1)以爱普列特为原料，在有机溶剂I中，与氧化剂搅拌混匀反应，反应完毕后得到爱普列特杂质粗品反应液；爱普列特杂质粗品反应液经后处理后，浓缩得到油状物；
2)油状物经有机溶剂II重结晶后得到爱普列特杂质；
合成路线如下：
Figure PCTCN2020128606-appb-000002
进一步的，上述爱普列特杂质的制备方法，包括以下步骤：
1)称取爱普列特，加入有机溶剂I和氧化剂，反应完毕后得到爱普列特杂质粗品反应液；在爱普列特杂质粗品反应液中加入硫代硫酸钠溶液搅拌，减压浓缩除去有机溶剂I，二氯甲烷萃取，浓缩萃取液即得爱普列特油状物杂质；
2)爱普列特油状物杂质中加入有机溶剂II，升温至回流溶清，常压蒸馏，自然冷却后析晶，抽滤，干燥得到爱普列特杂质；
其中，爱普列特、有机溶剂I、氧化剂、有机溶剂II的质量体积比为1∶10～30∶1～4∶4～10；
反应温度为10～30℃，反应时间为30～50小时。
进一步的，氧化剂包括过氧化氢、叔丁基过氧化氢、间氯过氧苯甲酸、过氧乙酸；其中，过氧化氢、叔丁基过氧化氢为常用的非酸性过氧化物；间氯过氧苯甲酸、过氧乙酸为常用的酸性过氧化物。
优选的，氧化剂为过氧化氢、叔丁基过氧化氢。
更优选的，氧化剂为过氧化氢。
当所述氧化剂为过氧化氢、叔丁基过氧化氢常用的非酸性过氧化物时，还需加入盐酸或醋酸。
进一步的，有机溶剂I选自甲醇、乙醇、异丙醇、叔丁醇、苯甲醇、四氢呋喃、乙腈中的至少一种。
进一步的，重结晶所用的有机溶剂II选自乙酸乙酯、乙腈、丙酮、甲苯中的至少一种。
上述爱普列特杂质在作为爱普列特原料药及其制剂质量研究的对照品中的应用。
有益效果：相比于现有技术，本发明的优点为：本申请首次提供了爱普列特杂质的制备的方法，操作简单，高效，反应条件温和，安全性强，易于控制，由该制备方法所制得的爱普列特杂质收率高、纯度高达96％以上，适用于作为对照品控制爱普列特原料药及其制剂的质量，为爱普列特相关药物的质量进行有效控制夯实了基础。同时为爱普列特国家质量标准提升提供了技术基础。
附图说明
图1为本发明按实施例1的方法制备得到的爱普列特杂质的HPLC图谱图；
图2为本发明按实施例1的方法制备得到的爱普列特杂质的 1H-NMR谱图；
图3为本发明按实施例1的方法制备得到的爱普列特杂质的 13C-NMR谱图；
图4为本发明按实施例1的方法制备得到的爱普列特杂质的质谱谱图。
具体实施方式
下面结合具体实施例对本发明进一步进行描述。
实施例1
一种爱普列特杂质的制备方法，包括以下步骤：
(1)称取爱普列特5g，加入甲醇50mL，30％过氧化氢10mL，醋酸10mL，于20～30℃反应36小时，反应完毕，反应液中加入硫代硫酸钠溶液搅拌，减压浓缩除去甲醇，二氯甲烷100mL萃取，浓缩萃取液即得黄色爱普列特油状物杂质。
(2)取步骤(1)得到黄色油状物，加入乙酸乙酯20mL，升温至回流，自然冷却后析晶，抽滤，干燥得到白色固体4.2g，即得爱普列特杂质，其收率为84％，纯度为96％以上。
HPLC：液相色谱仪：Shimadzu LC-20AT；色谱柱：Inert Sustain C18柱(4.6×250mm，5μm)。以冰醋酸25mL，二乙胺1mL，加水溶解并稀释至1000mL，混匀为流动相A，以甲醇作为流动相B，检测波长为260nm，流速1.0mL/min，柱温35℃。进样量为10μL。按如下梯度程序进行洗脱：
时间(min) 流动相A(％) 流动相B(％)
0 30 70
30 30 70
30.1 17 83
50 17 83
取爱普列特及爱普列特杂质适量，称重，用稀释液超声溶解，配制成每1mL中约含爱普列特2.5mg和爱普列特杂质均为2.5μg的混合溶液作为系统适用性溶液。按上述条件进行高效液相分析，记录色谱图，如图1所示，出峰顺序依次为爱普列特杂质、爱普列特及其他杂质，在上述色谱条件下，爱普列特的杂质与爱普列特分离度好，各杂质理论板数均不低于已4000，满足中国药典的要求。
如图2所示，根据实施例1得到的爱普列特杂质的核磁共振氢谱( 1H-NMR仪器为：BRUKER AV-400型核磁共振仪)分析可知，在CDCl 3为溶剂的 1H-NMR谱中，除去CDCl 3的溶剂峰，测得分子结构中有12种不同环境的37个质子的共振峰，各峰积分比(由低场向高场)为：1∶1∶4∶15∶3∶6∶1∶2∶1∶1∶1∶1。测得供试品中质子的类型和数目与爱普列特杂质分子结构中氢原子特征相符。
如图3所示，根据实施例1得到的爱普列特杂质的碳谱( 13C-NMR仪器为：BRUKER AV-400型核磁共振仪)分析可知，在CDCl 3为溶剂的 13C-NMR谱中，除去CDCl 3的共振峰(图中δ c77.35，77.03，76.71，72.99)，具有化学位移从大到小21种不同环境的24个碳的共振峰。测得供试品中碳核的类型和数目与爱普列特杂质分子结构中的碳原子特征相符。
如图4所示，根据实施例1得到的爱普列特杂质的液相质谱(LC-MS仪器：agilent6120 LC-MS液质联用仪)显示其分子量为387.56。结果符合对爱普列特杂质的结构特征。
实施例2
一种爱普列特杂质的制备方法，包括以下步骤：
(1)称取爱普列特5g，加入乙醇60mL，叔丁基过氧化氢5mL，盐酸5mL，于20～30℃反应30小时，反应完毕，反应液中加入硫代硫酸钠溶液搅拌，减压浓缩除去乙醇，二氯甲烷 100mL萃取，浓缩萃取液即得黄色爱普列特油状物杂质。
(2)取步骤(1)得到黄色油状物，加入乙腈30mL，升温至回流，自然冷却后析晶，抽滤，干燥得到白色固体3.2g，即得爱普列特杂质，其收率为64％，纯度为96％以上。
实施例3
一种爱普列特杂质的制备方法，包括以下步骤：
(1)称取爱普列特5g，加入异丙醇100mL，间氯过氧苯甲酸6.5g，于10～20℃反应48小时，反应完毕，反应液中加入硫代硫酸钠溶液搅拌，减压浓缩除去异丙醇，二氯甲烷100mL萃取，浓缩萃取液即得黄色爱普列特油状物杂质。
(2)取步骤(1)得到黄色油状物，加入甲苯30mL，升温至回流，自然冷却后析晶，抽滤，干燥得到白色固体3.5g，即得爱普列特杂质，其收率为70％，纯度为96％以上。
实施例4
一种爱普列特杂质的制备方法，包括以下步骤：
(1)称取爱普列特5g，加入四氢呋喃100mL，35％过氧乙酸20mL，于10～20℃反应48小时，反应完毕，反应液中加入硫代硫酸钠溶液搅拌，减压浓缩除去四氢呋喃，二氯甲烷100mL萃取，浓缩萃取液即得黄色爱普列特油状物杂质。
(2)取步骤(1)得到黄色油状物，加入丙酮50mL，升温至回流溶清，常压蒸馏至25mL左右，自然冷却后析晶，抽滤，干燥得到白色固体4.5g，即得爱普列特杂质，其收率为90％，纯度为96％以上。
实施例5
一种爱普列特杂质的制备方法，包括以下步骤：
(1)称取爱普列特5g，加入叔丁醇150mL，叔丁基过氧化氢20mL，醋酸20mL，于20～30℃反应36小时，反应完毕，反应液中加入硫代硫酸钠溶液搅拌，减压浓缩除去叔丁醇，二氯甲烷100mL萃取，浓缩萃取液即得黄色爱普列特油状物杂质。
(2)取步骤(1)得到黄色油状物，加入丙酮50mL，升温至回流溶清，常压蒸馏至25mL左右，自然冷却后析晶，抽滤，干燥得到白色固体3.1g，即得爱普列特杂质，其收率为62％，纯度为96％以上。
上述实施例为本发明较佳的实施方式，但本发明的实施方式并不受所述实施例的限制，本申请中的实施例及实施例中的特征在不冲突的情况下，可以相互任意组合。其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化，均应为等效的置换方式，都包含在本发明的保护范围之内。除此之外，本说明书中未详细说明的技术细节属于本领域技术人员的公知技术，因此本说明书不在赘述。

Claims (10)

  1. 一种爱普列特杂质，其特征在于，其化学名称为17β-(N-叔丁基-氨基-甲酰基)雄甾-4-烯-3-酮-5-羟基，其分子结构式如式I所示：
    Figure PCTCN2020128606-appb-100001
  2. 权利要求1所述的爱普列特杂质的制备方法，其特征在于，包括以下步骤：
    1)以爱普列特为原料，在有机溶剂I中，与氧化剂搅拌混匀反应，反应完毕后得到爱普列特杂质粗品反应液；爱普列特杂质粗品反应液经后处理后，浓缩得到油状物；
    2)油状物经有机溶剂II重结晶后得到爱普列特杂质。
  3. 根据权利要求2所述的爱普列特杂质的制备方法，其特征在于，包括以下步骤：
    1)以爱普列特为原料，在有机溶剂I中，与氧化剂搅拌混匀反应，反应完毕后得到爱普列特杂质粗品反应液；在爱普列特杂质粗品反应液中加入硫代硫酸钠溶液搅拌，减压浓缩除去有机溶剂I，二氯甲烷萃取，浓缩萃取液即得爱普列特油状物杂质；
    2)爱普列特油状物杂质中加入有机溶剂II，升温至回流溶清，常压蒸馏，自然冷却后析晶，抽滤，干燥得到爱普列特杂质；
    所述爱普列特、有机溶剂I、氧化剂、有机溶剂II的质量体积比为1∶10～30∶1～4∶4～10；
    所述反应温度为10～30℃，反应时间为30～50小时。
  4. 根据权利要求2所述的爱普列特杂质的制备方法，其特征在于，步骤1)中，所述氧化剂包括过氧化氢、叔丁基过氧化氢、间氯过氧苯甲酸、过氧乙酸。
  5. 根据权利要求4所述的爱普列特杂质的制备方法，其特征在于，步骤1)中，所述氧化剂为过氧化氢、叔丁基过氧化氢。
  6. 根据权利要求5所述的爱普列特杂质的制备方法，其特征在于，步骤1)中，所述氧化剂为过氧化氢。
  7. 根据权利要求5所述的爱普列特杂质的制备方法，其特征在于，步骤1)中，当所述氧化剂为过氧化氢、叔丁基过氧化氢时，还需加入盐酸或醋酸。
  8. 根据权利要求2所述的爱普列特杂质的制备方法，其特征在于，步骤1)中，所述有机溶剂I选自甲醇、乙醇、异丙醇、叔丁醇、苯甲醇、四氢呋喃、乙腈中的至少一种。
  9. 根据权利要求2所述的爱普列特杂质的制备方法，其特征在于，步骤2)中，所述重结晶所用的有机溶剂II选自乙酸乙酯、乙腈、丙酮、甲苯中的至少一种。
  10. 权利要求1～9中任一项所述的爱普列特杂质在作为爱普列特原料药及其制剂质量研究的对照品中的应用。
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