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WO2015180549A1 - Cristal de type i de trifluoroacétate d'ester de l-alanine-(14-oridonine) et son procédé de préparation - Google Patents

Cristal de type i de trifluoroacétate d'ester de l-alanine-(14-oridonine) et son procédé de préparation Download PDF

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Publication number
WO2015180549A1
WO2015180549A1 PCT/CN2015/077620 CN2015077620W WO2015180549A1 WO 2015180549 A1 WO2015180549 A1 WO 2015180549A1 CN 2015077620 W CN2015077620 W CN 2015077620W WO 2015180549 A1 WO2015180549 A1 WO 2015180549A1
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WIPO (PCT)
Prior art keywords
alanine
ester
crystal
cancer
ester trifluoroacetate
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2015/077620
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English (en)
Chinese (zh)
Inventor
孙飘扬
武乖利
邱振均
陈永江
沈灵佳
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Jiangsu Hengrui Medicine Co Ltd
Original Assignee
Jiangsu Hengrui Medicine Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Application filed by Jiangsu Hengrui Medicine Co Ltd filed Critical Jiangsu Hengrui Medicine Co Ltd
Priority to HK16111954.3A priority Critical patent/HK1223618B/xx
Priority to CN201580002233.8A priority patent/CN105636964B/zh
Publication of WO2015180549A1 publication Critical patent/WO2015180549A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • 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
    • C07D493/08—Bridged systems

Definitions

  • the present invention relates to a type I crystal of L-alanine-(14-Rhoxantine) ester trifluoroacetate, a preparation method thereof and use thereof.
  • the compound of formula (I) is L-alanine-(14-Rhoxedron A) ester trifluoroacetate, which is
  • L-alanine-(14-Rhoxantine) ester trifluoroacetate can obtain a crystal form with good stability under conventional crystallization conditions, which we call type I crystal.
  • the DSC pattern of the type I crystal in the present application shows a melting endotherm peak near 234 ° C, and the X-ray powder diffraction pattern is shown in Fig.
  • the X-ray powder diffraction pattern is represented by 6.85 (12.89), 8.09 (10.92), 11.30 (7.82), 13.71 (6.45), 14.08 (6.29), 14.35 (6.17), 16.40 (5.40), 17.41 (5.09).
  • the form of use which can be used as a raw material is not particularly limited, and any crystal form or amorphous solid can be used, and L-alanine-(14-Rhoxedron A) ester of the present invention can be used.
  • the preparation method of the trifluoroacetate type I crystal is:
  • a certain polar organic solvent preferably a polar organic solvent such as an alcohol, a ketone, an ester or a halogenated hydrocarbon having a small number of carbon atoms and capable of volatilization and being used as a crystallization solvent, or a mixed solution thereof;
  • a polar organic solvent such as an alcohol, a ketone, an ester or a halogenated hydrocarbon having a small number of carbon atoms and capable of volatilization and being used as a crystallization solvent, or a mixed solution thereof
  • Preferred is acetone, ethyl acetate, methanol, ethanol, isopropanol, diisopropyl ether or a mixture thereof as a recrystallization solvent of L-alanine-(14-Rhoxantine) ester and trifluoroacetate .
  • a single solvent may be used for crystallization, or a mixed solvent selected from the above organic solvents may be used.
  • the method for preparing L-alanine-(14-Rhoxantine) ester trifluoroacetate Form I crystal comprises the following steps:
  • N-Boc-L-alanine-(14-Rhoxedron A) ester with trifluoroacetic acid, or L-alanine-(14-Rhoxedron A) ester trifluoroethyl The acid salt solid is dissolved in an appropriate amount of an organic solvent, and stirred and crystallized; or an anti-solvent is added, and the crystal is stirred and stirred;
  • the organic solvent is one or more selected from the group consisting of an alcohol having a carbon number of 3 or less, a halogenated hydrocarbon, a ketone, and an ester, or an alcohol selected from the group consisting of carbon atoms of 3 or less;
  • the organic solvent is selected from one or more of ketones, alcohols, and esters having a carbon number of 3 or less, or is selected from the group consisting of ketones, alcohols, and esters. Any one or more mixed solvents with ethers.
  • the most preferred single solvent is ethyl acetate.
  • a preferred mixed organic solvent is acetone/isopropyl ether, and the ratio of the two is not particularly limited. In a preferred embodiment of the present invention, the volume ratio of the two is 1:2.
  • the method of recrystallization is not particularly limited and can be carried out by a usual recrystallization operation method.
  • the raw material L-alanine-(14-Rhoxedron A) ester trifluoroacetate can be stirred and dissolved in an organic solvent, and then stirred and crystallized at room temperature. After the crystallization is completed, it can be obtained by filtration and drying. The crystals required. The crystals collected are usually vacuumed under reduced pressure at normal temperature. Drying can achieve the effect of removing the recrystallization solvent.
  • the crystal form of the obtained L-alanine-(14-Erymentum A) ester trifluoroacetate crystal was studied by differential scanning calorimetry (DSC) and X-ray diffraction spectrometry. The residual solvent of the crystal was examined.
  • the L-alanine-(14-Rhoxantine) ester trifluoroacetate salt prepared according to the method of the present invention contains no or only a low content of residual solvent, and is in compliance with the relevant Pharmacopoeia regulations.
  • the solvent is required to be limited, and thus the crystal of the present invention can be preferably used as a pharmaceutically active ingredient.
  • Figure 1 is an X-ray powder diffraction pattern of Form I crystal of L-alanine-(14-Rhoxedron A) trifluoroacetate.
  • Figure 2 is a DSC chart of Form I crystal of L-alanine-(14-Rhoxedron A) trifluoroacetate.
  • Figure 3 is an X-ray powder diffraction pattern of an amorphous solid of L-alanine-(14-Rhoxedron A) trifluoroacetate.
  • Figure 4 is a DSC chart of an amorphous solid of L-alanine-(14-Rhoxedron A) trifluoroacetate.
  • the above white powder was added with 600 g of isopropyl ether, and the mixture was stirred and beaten for 2 hours, filtered, and the filter cake was washed with isopropyl ether (60 g), and blast dried at 25 ° C for 4 h to obtain a white powder of 110-137 g, yield 50-62%. .
  • Example 2 Determination of the crystal form of the sample of Example 1.
  • the X-ray powder diffraction pattern of the solid sample prepared in Example 1 is shown in Fig. 3, showing the characteristic peak of the amorphous form, the DSC spectrum is 4, and the melting characteristic absorption peak is not observed below 300 ° C, and the product is determined to be amorphous. solid.
  • the crystals are at about 6.85 (12.89), 8.09 (10.92), 11.30 (7.82), 13.71 (6.45), 14.08 (6.29), 14.35 (6.17), 16.40 (5.40), 17.41 (5.09), 18.19 (4.87), 18.44. (4.81), 20.12 (4.41), 21.17 (4.19), 23.38 (3.80), 23.88 (3.72), 24.42 (3.64), 24.84 (3.58), 25.72 (3.46), 26.46 (3.37), 27.22 (3.27), 28.40 (3.14), characteristic peaks at 29.38 (3.04), 31.26 (2.86), and 31.79 (2.81).
  • the DSC spectrum is shown in Figure 2. There is a sharp melting endotherm peak of 232.59 ° C. This crystal form is defined as the I crystal form.
  • N-Boc-L-alanine-(14-anthracycline) ester 500 mg was dissolved in 1.5 ml of dichloromethane and cooled to 0 ° C in an ice water bath. 8 ml of a trifluoroacetic acid/dichloromethane (1:1) mixed solution was slowly added dropwise at less than 5 ° C, and the addition was completed within 15 min. Stir under ice water, and the reaction was complete by TLC. 20 ml of isopropyl ether was slowly added to the reaction solution.
  • Example 3 The sample of the Form I obtained in Example 3 and the sample of the amorphous L-alanine-(14-Rhoxedron A) trifluoroacetate obtained in Example 1 were separately placed in an open position and examined.
  • the L-alanine-(14-Rhoxedron A) trifluoroacetate type I crystal obtained by the method of Example 1 was subjected to special stability studies such as grinding, pressure and heat, and the results showed that the crystal form was stable.
  • special stability studies such as grinding, pressure and heat, and the results showed that the crystal form was stable.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un cristal de type I de trifluoroacétate d'ester de L-alanine-(14-oridonine) et son procédé de préparation. Le procédé de préparation comprend la cristallisation d'un solide trifluoroacétate d'ester de L-alanine-(14-oridonine) en une quelconque forme cristalline ou forme amorphe dans un solvant organique unique ou un solvant organique mixte de celui-ci pour obtenir le cristal de type I de trifluoroacétate d'ester de L-alanine-(14-oridonine). Le cristal de type I de trifluoroacétate d'ester de L-alanine-(14-oridonine) obtenu dans la présente invention possède de bonnes stabilité de forme cristalline et stabilité chimique, et utilise un solvant de cristallisation qui présente une faible toxicité et teneur en résidus, et peut mieux être utilisé dans les traitements cliniques.
PCT/CN2015/077620 2014-05-30 2015-04-28 Cristal de type i de trifluoroacétate d'ester de l-alanine-(14-oridonine) et son procédé de préparation Ceased WO2015180549A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
HK16111954.3A HK1223618B (en) 2014-05-30 2015-04-28 I-type crystal of l-alanine-(14-oridonin) ester trifluoroacetate and preparation method therefor
CN201580002233.8A CN105636964B (zh) 2014-05-30 2015-04-28 L‑丙氨酸‑(14‑冬凌草甲素)酯三氟乙酸盐的i型结晶及制备方法

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201410240920.0 2014-05-30
CN201410240920.0A CN105131009A (zh) 2014-05-30 2014-05-30 L-丙氨酸-(14-冬凌草甲素)酯三氟乙酸盐的i型结晶及制备方法

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WO2015180549A1 true WO2015180549A1 (fr) 2015-12-03

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110407848B (zh) * 2019-06-25 2021-10-22 郑州大学 L-氨基酸-14-(7-醚-柔茎香茶菜甲素)酯三氟乙酸盐类化合物及其制备方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101139350A (zh) * 2007-10-15 2008-03-12 中国药科大学 冬凌草甲素类衍生物、其制备方法及用途
WO2013107429A1 (fr) * 2012-01-21 2013-07-25 杭州本生药业有限公司 Dérivé d'oridonine acylé en position 14 par monooxoacylation, son procédé de préparation et son application
CN103467474A (zh) * 2013-09-17 2013-12-25 中国药科大学 1,6,7,14-位取代的冬凌草甲素衍生物、制备方法及用途
CN104017000A (zh) * 2013-03-01 2014-09-03 江苏恒瑞医药股份有限公司 L-丙氨酸-(14-冬凌草甲素)酯三氟乙酸盐及其制备方法和用途

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102058566A (zh) * 2010-12-24 2011-05-18 中国药科大学 一种冬凌草甲素类成分干粉吸入剂及其制备方法和用途

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101139350A (zh) * 2007-10-15 2008-03-12 中国药科大学 冬凌草甲素类衍生物、其制备方法及用途
WO2013107429A1 (fr) * 2012-01-21 2013-07-25 杭州本生药业有限公司 Dérivé d'oridonine acylé en position 14 par monooxoacylation, son procédé de préparation et son application
CN104017000A (zh) * 2013-03-01 2014-09-03 江苏恒瑞医药股份有限公司 L-丙氨酸-(14-冬凌草甲素)酯三氟乙酸盐及其制备方法和用途
CN103467474A (zh) * 2013-09-17 2013-12-25 中国药科大学 1,6,7,14-位取代的冬凌草甲素衍生物、制备方法及用途

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CN105131009A (zh) 2015-12-09
CN105636964B (zh) 2017-04-12
CN105636964A (zh) 2016-06-01

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