CN106995405A - 一种贝曲西班马来酸盐无定型物及其制备方法 - Google Patents

一种贝曲西班马来酸盐无定型物及其制备方法 Download PDF

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Publication number
CN106995405A
CN106995405A CN201610046560.XA CN201610046560A CN106995405A CN 106995405 A CN106995405 A CN 106995405A CN 201610046560 A CN201610046560 A CN 201610046560A CN 106995405 A CN106995405 A CN 106995405A
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Prior art keywords
betrixaban maleate
amorphous article
betrixaban
maleate
preparation
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但春燕
王兵
左小勇
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Chongqing Pharmaceutical Research Institute Co Ltd
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Chongqing Pharmaceutical Research Institute Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • 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

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

本发明涉及一种贝曲西班马来酸盐无定型物及其制备方法，该无定型由贝曲西班马来酸盐用甲醇溶清后再将甲醇蒸干而得。该无定型物稳定，适合制剂生产。

Description

一种贝曲西班马来酸盐无定型物及其制备方法
技术领域
本发明属于药物化学领域，具体涉及一种贝曲西班马来酸盐的无定型物及其制备方法。
背景技术
贝曲西班（Betrixaban）马来酸盐，化学名为N-(5-氯代吡啶-2-基)-2-[[4-(N,N-二甲基甲脒基)苯甲酰基]氨基]-5-甲氧基苯甲酰胺，化学结构如式（1）所示，可通过CN1272316或者CN101595092等专利公开的方法制备。
贝曲西班马来酸盐由武田药品工业株式会社原研，之后权利转让给PortolaPharmaceuticals， 后者与李氏大药厂共同开发。贝曲西班马来酸盐是凝血因子Xa抑制剂，目前处于Ⅲ期临床，2016年初公布III期临床结果。
贝曲西班马来酸盐属水难溶性化合物，在制剂中一般以固体形式使用，因此对其晶型的研究具有十分重要的意义。
CN101304971公开了贝曲西班的马来酸盐的盐和结晶多晶型物，也称为晶型形式Ⅰ，
CN103261161公开了贝曲西班的马来酸盐的结晶形式Ⅱ，为无水物，其X 射线粉末衍射图谱在5.0、9.7、10.1、15.3、17.5和19.6°的衍射角(2θ) 处有特征峰。该专利还公开了贝曲西班的马来酸盐的结晶形式Ⅲ，为半水合物，其X 射线粉末衍射图谱在2.2、4.9、10.0、15.1、17.4和22.4°的衍射角(2θ) 处有特征峰。
本发明人在研究贝曲西班马来酸盐晶型的过程中，制备出一种贝曲西班马来酸盐的无定型物，该无定型物化学性质稳定，容易保存，适合制成各种制剂。
发明内容
本发明的目的在于提供一种贝曲西班马来酸盐的无定型物，该无定型物化学稳定性优良，适于用于多种制剂。
在一实施方案中，本发明的贝曲西班马来酸盐无定型，其X-射线粉末衍射具有如图1所示的特征。
本发明的贝曲西班马来酸盐无定型物的X-射线粉末衍射测试是在环境温度及环境湿度下，经日本岛津XRD-6000型X-射线衍射仪的CuKα源(α = 1.5406Å)测定完成的。“环境温度”一般是0～40℃；“环境湿度”一般是30%～80%的相对湿度。
在另一实施方案中，本发明还提供了一种贝曲西班马来酸盐无定型物的制备方法，该方法为将贝曲西班马来酸盐用甲醇溶解溶清后，再将溶剂甲醇快速蒸发至干而得。
在一具体实施方案中，本发明的一种贝曲西班马来酸盐无定型物的制备方法，包括以下步骤：
1） 将贝曲西班马来酸盐用甲醇溶清；
2） 将溶解的贝曲西班马来酸盐溶液快速蒸发至干。
附图说明
图1是贝曲西班马来酸盐无定型物的X-射线衍射图。
具体实施方式
下面将结合实施例对本发明作进一步说明，可以使本领域的技术人员更全面的理解本发明，但不以任何方式限制本发明的范围。
本发明所述的X射线粉末衍射图是在日本岛津XRD-6000型X-射线衍射仪上采集，其参数具体如下：
X射线反射参数：CuKα
CuKα源(α = 1.5406Å)
电压：40千伏特（KV）
电流：30毫安培（mA）
发散狭缝：自动
扫描模式：连续
扫描范围：3～40度
取样步长：0.02度
扫描速度：2度/分钟。
实施例1
贝曲西班马来酸盐无定型的制备
0.3g贝曲西班马来酸盐加入15ml甲醇，超声以及搅拌使其全部溶解至清，40℃减压蒸馏至干，得贝曲西班马来酸盐无定型固体，HPLC:99.54%。测试所得无定型固体的X-射线粉末衍射，结果见图1。

Claims (5)

1.一种贝曲西班马来酸盐无定型物。
2.如权利要求1所述的无定型物，其X射线粉末衍射具有如图1所示的特征。
3.一种制备权利要求1或2的无定型物的方法，包括将贝曲西班马来酸盐用甲醇溶解后,然后将溶剂甲醇快速蒸发至干而得。
4.如权利要求3所述的方法，贝曲西班马来酸盐与甲醇的质量体积比为1:15～1:100g/ml。
5.如权利要求4所述的方法，贝曲西班马来酸盐与甲醇的质量体积比为1:50g/ml。
CN201610046560.XA 2016-01-25 2016-01-25 一种贝曲西班马来酸盐无定型物及其制备方法 Pending CN106995405A (zh)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108570003A (zh) * 2018-06-01 2018-09-25 浙江宏元药业股份有限公司 一种贝曲西班马来酸盐的一水无定形及其制备方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101304971A (zh) * 2005-11-08 2008-11-12 米伦纽姆医药公司 Xa因子抑制剂n-(5-氯-2-吡啶基)-2-[[4-[(二甲氨基)亚氨基甲基]苯甲酰基]氨基]-5-甲氧基-苯甲酰胺的医药盐和多晶型
CN102762538A (zh) * 2009-12-17 2012-10-31 米伦纽姆医药公司 合成Xa因子抑制剂的方法
CN103261161A (zh) * 2010-09-01 2013-08-21 博尔托拉制药公司 凝血因子Xa抑制剂的结晶形式

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101304971A (zh) * 2005-11-08 2008-11-12 米伦纽姆医药公司 Xa因子抑制剂n-(5-氯-2-吡啶基)-2-[[4-[(二甲氨基)亚氨基甲基]苯甲酰基]氨基]-5-甲氧基-苯甲酰胺的医药盐和多晶型
CN102762538A (zh) * 2009-12-17 2012-10-31 米伦纽姆医药公司 合成Xa因子抑制剂的方法
CN103261161A (zh) * 2010-09-01 2013-08-21 博尔托拉制药公司 凝血因子Xa抑制剂的结晶形式

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108570003A (zh) * 2018-06-01 2018-09-25 浙江宏元药业股份有限公司 一种贝曲西班马来酸盐的一水无定形及其制备方法

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Application publication date: 20170801