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WO2013013595A1 - Cristal de 17α-acétoxy-11β-(4-n,n-diméthylaminophényl)-19-norprégna-4,9-diène-3,20-dione et procédé de préparation de celui-ci - Google Patents

Cristal de 17α-acétoxy-11β-(4-n,n-diméthylaminophényl)-19-norprégna-4,9-diène-3,20-dione et procédé de préparation de celui-ci Download PDF

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Publication number
WO2013013595A1
WO2013013595A1 PCT/CN2012/078909 CN2012078909W WO2013013595A1 WO 2013013595 A1 WO2013013595 A1 WO 2013013595A1 CN 2012078909 W CN2012078909 W CN 2012078909W WO 2013013595 A1 WO2013013595 A1 WO 2013013595A1
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Prior art keywords
cdb
crystal
spectrum
solvent
raw material
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PCT/CN2012/078909
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English (en)
Chinese (zh)
Inventor
安晓霞
吕峰
申淑匣
Original Assignee
上海希迈医药科技有限公司
江苏希迪制药有限公司
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Application filed by 上海希迈医药科技有限公司, 江苏希迪制药有限公司 filed Critical 上海希迈医药科技有限公司
Publication of WO2013013595A1 publication Critical patent/WO2013013595A1/fr

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Classifications

    • 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
    • C07J41/0077—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 substituted in position 11-beta by a carbon atom, further substituted by a group comprising at least one further carbon atom
    • C07J41/0083—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 substituted in position 11-beta by a carbon atom, further substituted by a group comprising at least one further carbon atom substituted in position 11-beta by an optionally substituted phenyl group not further condensed with other 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 present invention relates to 17 ⁇ -acetoxy-11 ⁇ -(4-indole-indole-dimethylaminophenyl)-19-norpregna-4,9-diene-3,20-dione (CDB-2914) A new type of crystal and a preparation method thereof. Background technique
  • CDB-2914 (Uliprisnil acetate), molecular formula C 3 QH 37 NO4, molecular weight 475.634, CAS number 126784-99-4, chemical name: 17 ⁇ -acetoxy-11 ⁇ -(4- ⁇ , ⁇ -dimethyl Aminophenyl)-19-norpregna-4,9-diene-3,20-dione, its chemical structural formula is as follows:
  • CDB-2914 is an emergency contraceptive drug jointly developed by the National Institute of Child Health and Human Development and the French H A Pharmaceutical Company.
  • CDB-2914 (trade name ELLA) was approved in Europe in May 2009 and first in the UK, Germany and France on October 1. On August 13, 2010, the US Food and Drug Administration (FDA) approved the ELLA listing application.
  • FDA US Food and Drug Administration
  • a crystalline form of CDB-2914 isopropanol hemisolvate (referred to as Form B) and a process for its preparation are disclosed in Chinese Patent No. 1,753,905.
  • the DSC of this isopropanol hemisolvate crystal form showed a characteristic absorption peak at 156 °C.
  • the isocratic characteristic peak of isopropanol hemisolvate crystal form 2 and its corresponding intensity (%) are shown in Table 1: Table 1
  • CN 1753905 also discloses XRD and DSC data for CDB-2914 Form A in US 5,929,262.
  • the DSC plot of this Form A shows a characteristic absorption peak at 189 °C.
  • the 2 ⁇ characteristic peak of Form A and the corresponding intensity (%) are shown in Table 2:
  • the crystalline form ⁇ is a solvate with poor thermal stability; the crystalline form has a low solubility and is not very stable.
  • the crystal of CDB-2914 of the present invention basically has the powder X-ray diffraction pattern shown in Fig. 1. Further, the crystal of CDB-2914 of the present invention basically has a DSC chart shown in Fig. 2, an IR chart shown in Fig. 3, and a TGA spectrum shown in Fig. 4.
  • the crystal of CDB-2914 according to the present invention is subjected to powder X-ray diffraction at 2 ⁇
  • a method for preparing a crystal of the CDB-2914 comprising the steps of:
  • the CDB-2914 starting material is any known crystal form.
  • the ratio of the CDB-2914 raw material to the organic solvent is 5 ⁇ 15 ml of organic solvent for the lg CDB-2914 raw material.
  • the anti-solvent is added in an amount of 2 to 30 ml of lg CDB-2914 starting material.
  • the organic solvent is a common organic solvent such as acetone, methanol, ethanol, n-butanol, isopropanol or ethyl acetate, and is preferably acetone.
  • the anti-solvent is water, n-hexyl hydrazine, n-heptane, isopropyl ether or methyl tert-butyl ether, and is preferably water.
  • the crystal of CDB-2914 of the present invention, the XRD pattern of the crystal comprising 3 or more of the 2 ⁇ values selected from the group consisting of 4.801 ⁇ 0.2. , 6.339 ⁇ 0.2. , 8.294 ⁇ 0.2 °, 9.593 ⁇ 0.2. , 12.691 ⁇ 0.2. , 13.362 ⁇ 0.2. , 18.628 ⁇ 0.2. , 22.476 ⁇ 0.2. And 26.857 ⁇ 0.2. .
  • the differential scanning calorimetry (DSC pattern) of the crystal has a characteristic endothermic peak at 178 to 194 °C.
  • the crystals have substantially the DSC pattern shown in Fig. 2.
  • the crystallized product is prepared as follows, the method comprising the steps of: a) dissolving the CDB-2914 raw material with an organic solvent, and having a dissolution temperature of 30 to 55 ° C;
  • the ratio of the raw material of the CDB-2914 to the organic solvent is 5 to 15 ml of an organic solvent for the lg CDB-2914 raw material;
  • the organic solvent is acetone, methanol, ethanol, n-butanol, isopropanol or Ethyl acetate, preferably acetone;
  • the anti-solvent is water, n-hexyl, n-heptane, isopropyl ether or methyl tert-butyl ether, preferably water.
  • composition comprising:
  • crystal form C has the advantages of good thermal stability (decompression at 140 ° C for 8 hours, crystal form unchanged), stable storage, and good solubility, etc. It is suitable for preparation into a pharmaceutical preparation.
  • the preparation method provided by the invention can obtain crystals of CDB-2914 with high yield (quality yield can reach more than 90%) and high purity (HPLC purity can reach 99.5%), and has simple operation and scale Advantages of implementation.
  • Figure 1 is an XRPD spectrum of the crystal of CDB-2914 of the present invention.
  • Figure 2 is a DSC spectrum of the crystal of CDB-2914 of the present invention.
  • Figure 3 is an IR spectrum of the crystal of CDB-2914 of the present invention.
  • FIG. 4 is a TGA spectrum of the crystal of CDB-2914 of the present invention. detailed description
  • the infrared absorption spectrum (IR) spectrum measured in PE Spectrum RX equipment after tableting with potassium bromide at 24 and 40% humidity is shown in the figure. 3, wherein KBr blank is a blank control, as can be seen from Figure 3:
  • the crystals of CDB-2914 produced are at wave numbers of 1662, 1610, 1560, 1518, 1458, 1438, 1369, 1349, 1255, 1233, There are absorption peaks at 1202, 1169, 1148, 1092, 1062, 1016, 961, 948, 860, 826, 790, 770, 698, 670, 592, 528 and 494 cm- 1 .
  • Example 8 Add 5.0 mL of ethyl acetate to 5.0 g of CDB-2914 (Form A), heat to 30 ° C, stir to completely dissolve the solid; cool down to 20 ° C, slowly add 70 mL of hexamethylene under stirring; then cool down to 5 to 10 ° C, crystals were precipitated, and after crystallization for 2 hours, it was filtered; dried under reduced pressure at 60 ° C for 12 h to obtain 4.65 g of white crystals, mass yield of 93%, HPLC purity of 99.50%.
  • the new crystal (crystal form C) of CDB-2914 of the present invention has a solubility which is twice as high as that of the known crystal form (crystal form A), and has excellent solubility.
  • Example 12 Pharmaceutical Composition

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Steroid Compounds (AREA)

Abstract

La présente invention concerne un cristal de 17α-acétoxy-11β-(4-N,N-diméthylaminophényl)-19-norprégna-4,9-diène-3,20-dione, et le procédé de préparation de celui-ci. Le cristal a sensiblement le profil de diffraction des rayons X sur poudre représenté sur la figure 1. Le procédé de préparation du cristal comprend la fourniture d'une solution de solvant organique d'une matière première de CDB-2914, la température de la solution étant de 30 à 55 °C ; la réduction de la température à 20 à 30 °C, et l'ajout d'un antisolvant ; et ensuite la réduction de la température à 0 à 10 °C et la cristallisation pendant 2 à 7 heures.
PCT/CN2012/078909 2011-07-22 2012-07-20 Cristal de 17α-acétoxy-11β-(4-n,n-diméthylaminophényl)-19-norprégna-4,9-diène-3,20-dione et procédé de préparation de celui-ci WO2013013595A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201110207825.7 2011-07-22
CN 201110207825 CN102344478B (zh) 2011-07-22 2011-07-22 一种17α-乙酰氧基-11β-(4-N,N-二甲氨基苯基)-19-去甲孕甾-4,9-二烯-3,20-二酮的结晶物及其制备方法

Publications (1)

Publication Number Publication Date
WO2013013595A1 true WO2013013595A1 (fr) 2013-01-31

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CN (1) CN102344478B (fr)
WO (1) WO2013013595A1 (fr)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102344478B (zh) * 2011-07-22 2013-08-07 上海希迈医药科技有限公司 一种17α-乙酰氧基-11β-(4-N,N-二甲氨基苯基)-19-去甲孕甾-4,9-二烯-3,20-二酮的结晶物及其制备方法
CN102675395B (zh) * 2012-04-17 2014-04-30 常州市第四制药厂有限公司 醋酸乌利司他的多晶型及其制备方法
CN103755765B (zh) * 2012-04-17 2018-01-02 常州市第四制药厂有限公司 醋酸乌利司他的多晶型及其制备方法
JP2015532263A (ja) * 2012-09-28 2015-11-09 あすか製薬株式会社 ウリプリスタール酢酸エステルの結晶多形

Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4954490A (en) * 1988-06-23 1990-09-04 Research Triangle Institute 11 β-substituted progesterone analogs
US5929262A (en) * 1995-03-30 1999-07-27 The United States Of America As Represented By The Department Of Health And Human Services Method for preparing 17α-acetoxy-11β-(4-N, N-dimethylaminophyl)-19-Norpregna-4,9-diene-3, 20-dione, intermediates useful in the method, and methods for the preparation of such intermediates
CN1753905A (zh) * 2003-01-22 2006-03-29 克利斯托制药股份有限公司 获得17α－乙酰氧基－11β－(4－N,N－二甲氨基苯基)－19－去甲孕甾－4,9－二烯－3,20－二酮的方法
US20060111577A1 (en) * 2003-02-28 2006-05-25 Kim Hyun K Method for preparing 17 alpha-acetoxy-11beta-(4-n,n-dimethylaminophenyl)-19-norpregna-4,9-diene-3,20-dione, intermediates thereof, and methods for the preparation of such intermediates
CN101466723A (zh) * 2006-06-14 2009-06-24 吉瑞工厂 用于合成17α-乙酰氧基-11β-[4-(N,N-二甲基-氨基)-苯基]-19-去甲孕甾-4,9-二烯-3,20-二酮的工业生产方法和用于所述方法的新的中间体
CN102241722A (zh) * 2010-05-12 2011-11-16 杭州容立医药科技有限公司 一种合成孕酮受体调节剂优力司特的纯化方法
CN102295674A (zh) * 2011-07-14 2011-12-28 四川大学 获得高纯度17α-乙酰氧基-11β-（4-N,N-二甲氨基苯基）-19-去甲孕甾-4,9-二烯-3,20-二酮的方法
CN102344478A (zh) * 2011-07-22 2012-02-08 上海希迈医药科技有限公司 一种17α-乙酰氧基-11β-（4-N,N-二甲氨基苯基）-19-去甲孕甾-4，9-二烯-3,20-二酮的结晶物及其制备方法
CN102372760A (zh) * 2010-08-12 2012-03-14 杭州容立医药科技有限公司 一种合成孕酮受体调节剂优力司特的合成方法
CN102675395A (zh) * 2012-04-17 2012-09-19 常州市第四制药厂有限公司 醋酸乌利司他的多晶型及其制备方法

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4954490A (en) * 1988-06-23 1990-09-04 Research Triangle Institute 11 β-substituted progesterone analogs
US5929262A (en) * 1995-03-30 1999-07-27 The United States Of America As Represented By The Department Of Health And Human Services Method for preparing 17α-acetoxy-11β-(4-N, N-dimethylaminophyl)-19-Norpregna-4,9-diene-3, 20-dione, intermediates useful in the method, and methods for the preparation of such intermediates
CN1753905A (zh) * 2003-01-22 2006-03-29 克利斯托制药股份有限公司 获得17α－乙酰氧基－11β－(4－N,N－二甲氨基苯基)－19－去甲孕甾－4,9－二烯－3,20－二酮的方法
US20060111577A1 (en) * 2003-02-28 2006-05-25 Kim Hyun K Method for preparing 17 alpha-acetoxy-11beta-(4-n,n-dimethylaminophenyl)-19-norpregna-4,9-diene-3,20-dione, intermediates thereof, and methods for the preparation of such intermediates
CN101466723A (zh) * 2006-06-14 2009-06-24 吉瑞工厂 用于合成17α-乙酰氧基-11β-[4-(N,N-二甲基-氨基)-苯基]-19-去甲孕甾-4,9-二烯-3,20-二酮的工业生产方法和用于所述方法的新的中间体
CN102241722A (zh) * 2010-05-12 2011-11-16 杭州容立医药科技有限公司 一种合成孕酮受体调节剂优力司特的纯化方法
CN102372760A (zh) * 2010-08-12 2012-03-14 杭州容立医药科技有限公司 一种合成孕酮受体调节剂优力司特的合成方法
CN102295674A (zh) * 2011-07-14 2011-12-28 四川大学 获得高纯度17α-乙酰氧基-11β-（4-N,N-二甲氨基苯基）-19-去甲孕甾-4,9-二烯-3,20-二酮的方法
CN102344478A (zh) * 2011-07-22 2012-02-08 上海希迈医药科技有限公司 一种17α-乙酰氧基-11β-（4-N,N-二甲氨基苯基）-19-去甲孕甾-4，9-二烯-3,20-二酮的结晶物及其制备方法
CN102675395A (zh) * 2012-04-17 2012-09-19 常州市第四制药厂有限公司 醋酸乌利司他的多晶型及其制备方法

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