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WO2013034087A1 - Cristaux d'hydrate de doripénème et leur procédé de préparation - Google Patents

Cristaux d'hydrate de doripénème et leur procédé de préparation Download PDF

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Publication number
WO2013034087A1
WO2013034087A1 PCT/CN2012/081064 CN2012081064W WO2013034087A1 WO 2013034087 A1 WO2013034087 A1 WO 2013034087A1 CN 2012081064 W CN2012081064 W CN 2012081064W WO 2013034087 A1 WO2013034087 A1 WO 2013034087A1
Authority
WO
WIPO (PCT)
Prior art keywords
crystal
doripenem
hydrate crystal
hydrate
spectrum
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/CN2012/081064
Other languages
English (en)
Chinese (zh)
Inventor
安晓霞
吕峰
胡猛
周吴
王光华
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 DESANO PHARMACEUTICALS CO Ltd
Shanghai Cdymax Pharmaceuticals Co Ltd
Original Assignee
JIANGSU DESANO PHARMACEUTICALS CO Ltd
Shanghai Cdymax Pharmaceuticals 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.)
Filing date
Publication date
Application filed by JIANGSU DESANO PHARMACEUTICALS CO Ltd, Shanghai Cdymax Pharmaceuticals Co Ltd filed Critical JIANGSU DESANO PHARMACEUTICALS CO Ltd
Publication of WO2013034087A1 publication Critical patent/WO2013034087A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
    • C07D477/10—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
    • C07D477/12—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6
    • C07D477/16—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6 with hetero atoms or carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 3
    • C07D477/20—Sulfur atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • the invention relates to a doripene hydrate crystal and a preparation method thereof, and belongs to the field of organic chemistry technology. Background technique
  • Doripenem is a new beta-methyl carbapenem antibiotic developed by Japan's Yanyeyi Pharmaceutical Co., Ltd., which was launched in Japan on September 16, 2005 under the trade name Finibax. Doripenem was approved by the US FDA on October 15, 2007 for the clinical treatment of complex intra-abdominal infections and complex urinary tract infections. By inhibiting cell wall synthesis, it exhibits broad-spectrum, high-efficiency antibacterial activity, and is particularly active against Pseudomonas aeruginosa than existing carbapenem antibiotics.
  • the Chinese patent discloses the preparation method of amorphous doripenem. It is well known that amorphous substances are generally less stable than crystalline substances and are difficult to preserve. To overcome these defects, Japan Yanye Yiyi Pharmaceutical Company has successively disclosed four kinds of doripenem crystals (Form I, Form II, Form III and Form IV) and preparation methods thereof. The specific information of the four crystal compounds is shown in Table 1. .
  • the stability of the three crystal forms I, II and III is not good.
  • Only the crystal form IV is the crystal form with the best stability.
  • the form IV cannot be directly obtained, and the crystal must be obtained first.
  • After the type III it is obtained by drying under reduced pressure, and there are undoubted defects such as complicated preparation process and high preparation cost.
  • the Chinese patent (patent number ZL200610028746. 9) has successively disclosed two kinds of doripenem crystals (crystal form V and crystal form VI) and preparation methods thereof.
  • the specific information of the two kinds of crystal compounds is shown in Table 2. .
  • Patent No. ZL200710127224. 9 discloses another form of Dominican form V containing 2 molecules of water of crystallization.
  • the specific information of the crystalline compound is shown in Table 3.
  • the object of the present invention is to provide a Dominican hydrate crystal having high purity, low residual solvent and good stability, and a method for preparing the crystal which is simple in process, low in preparation cost and suitable for industrial production.
  • the powder has a powder X-ray diffraction spectrum of 3 or more (preferably 3-18, or 5-18, or 7-18, most Good place is 18) 2 selected from the group below
  • the o value is 5%.
  • the powder X-ray diffraction spectrum of the doripenem hydrate crystal of the present invention is basically as shown in FIG. 1, and the measured value of moisture in the crystal is 4.4 to 5.5%, and more preferably O is 4.7 to 5.1%. More preferably 4.8-5.0%.
  • the moisture in the crystal is substantially or entirely crystalline water.
  • the Dominican hydrate crystal 1+ inch body of the present invention further has the DSC spectrum shown in FIG. 2,
  • the doripenem hydrate crystal of the present invention is under 2+ powder X-ray diffraction at 2 ⁇ o
  • a method for preparing a doripenem hydrate crystal according to the present invention comprises the following steps:
  • the method for preparing the doripenem hydrate crystal of the present invention comprises the following steps: a) dissolving the crude doripenem in water at 40 to 70 ° C (preferably 50 to 60 ° C);
  • the crude doripenem may be either amorphous or known in any crystal form.
  • the HPLC purity of the crude doripenem is preferably 95%.
  • the mass ratio of the crude product of doripenem to water in the step a) is preferably 1:10 to 1:30.
  • the organic solvent is preferably any one of a C 4 lower alcohol (e.g., methanol, ethanol, isopropanol, n-butanol, etc.), tetrahydrofuran, acetone, and acetonitrile; preferably isopropanol.
  • a C 4 lower alcohol e.g., methanol, ethanol, isopropanol, n-butanol, etc.
  • tetrahydrofuran acetone
  • acetonitrile preferably isopropanol.
  • the ratio of the volume ratio of the organic solvent to the water used in the step a) is preferably 0.1:1 to 3:1; preferably 0.44:1 ⁇
  • the invention also provides a pharmaceutical composition comprising:
  • the invention also provides the use of the novel doripene hydrate crystal of the invention in preparing an antibacterial medicament, in particular for preparing an antibacterial agent for inhibiting Pseudomonas aeruginosa.
  • the doripenem hydrate crystal provided by the invention has the following advantages: high purity (HPLC purity greater than 99.8%); low residual solvent (isopropanol residual amount not exceeding 500 ppm, generally lower than 300ppm), far below the ICH limit for isopropyl alcohol solvent residue not exceeding 5000ppm, which greatly guarantees the safety of docepinan preparation; good stability, at 40 ° C and relative humidity of 75% After being placed in the environment for 6 months, there was no significant change in the traits, contents, related substances and moisture of the samples examined.
  • the preparation method of the doripene hydrate crystal provided by the invention has the advantages of simple process, low preparation cost, and suitable for industrial production.
  • Figure 1 is a powder X-ray diffraction spectrum of the doripenem hydrate crystal of the present invention
  • Figure 2 is a DSC spectrum of the doripenem hydrate crystal of the present invention.
  • Figure 3 is a TG spectrum of the doripenem hydrate crystal of the present invention.
  • Figure 4 is an infrared (IR) spectrum of the doripenem hydrate crystal of the present invention. detailed description
  • the present invention will be further described in detail below with reference to the accompanying drawings and embodiments. It is to be understood that the examples are merely illustrative of the invention and are not intended to limit the scope of the invention.
  • the experimental methods in which the specific conditions are not specified in the following examples are usually carried out according to conventional conditions or according to the conditions recommended by the manufacturer. Unless otherwise stated, the percentages and parts are percentages by weight and parts by weight.
  • the crude doripenem used in the examples may be either amorphous or known in any form, preferably 95% by HPLC.
  • For the preparation method refer to ZL92111069. 3, ZL95104834. 1, ZL95193672. 7 , ZL01810309. X , ZL200610028746. 9, ZL200710127224. 9 and other documents.
  • the measurement of the powder X-ray diffraction spectrum is: 1. 5460 angstroms (A) of the wavelength ⁇ 1 , 1. 54439 angstroms ( ⁇ ) of the wavelength of i 2 radiation source, the intensity ratio ⁇ 1 / (1 2 is 0.5 Dedye-Scherrer INEL CPS-120 with a voltage of 40 kV and a current of 30 mA.
  • the measurement error of the diffraction angle 2 ⁇ is approximately ⁇ 0.2.
  • DSC measurement conditions In a closed vessel, a nitrogen flow of 50 ml/min was used, and the heating rate was 10 ° C/min at 20 to 320 ° C, using a DSC Q 2000 (TA company, USA) equipment.
  • TGA measurement conditions In a closed vessel, a nitrogen flow of 100 ml/min was used, and the heating rate was 10 ° C/min at 20 to 320 ° C, using an SDT Q600 (TA company, USA) equipment.
  • HPLC purity of the obtained crystal was measured by the method described in “Journal of Chromatography B, 853 (2007), 123 ⁇ 126”; the test was carried out by the method described in “Chinese Journal of Antibiotics, 3 (31), 2006, 187 ⁇ 189". The residual amount of isopropanol in the crystal.
  • the crystal purity of the crystal obtained in this example was 99.85%, and the residual amount of isopropyl alcohol was 219 ppm.
  • the water content in the crystal was determined by Karl Fischer (KF) method to be 4.83%.
  • Fig. 1 The powder X-ray diffraction spectrum of the crystal obtained in this example is shown in Fig. 1: at 2 ⁇ , 6.43°, 13.02°, 14.96°, 15.27°, 15.85°, 16.60°, 17.46°, 20.60°, 21.04°, 22.18°. , 23.88°, 25.35°, 26.04°, 28.19°, 29.00°, 31.65. , 34.09. , 34.90. There is a main peak; at 2 ⁇ , it is 10.86°, 11.22°, 18.05°, 18.43°, 18.92°, 19.62°, 23.10°, 23.40°, 33.34. , 36.44. , 37.21° , 38.04. , 39.77° , 41.22° , 45.22° There are secondary peaks.
  • the DSC spectrum of the crystal obtained in this example is shown in Fig. 2: There is an endothermic peak at 110 ⁇ 160 °C, the Onset value (starting temperature) is 137.17 ° C; there is an exothermic peak at 170 ⁇ 200 ° C, Onset The value (starting temperature) was 179.02 °C.
  • the TG spectrum of the crystal obtained in this example is shown in Fig. 3: The measured value of the thermogravimetric analysis is 4.86%.
  • the infrared (IR) spectrum of the crystal obtained in this example is shown in Fig. 4:
  • the test has a HPLC purity of 99.86%, wherein the residual amount of isopropanol is 205 ppm, and the moisture measured by the Karl Fischer (KF) method is 4.79%;
  • the powder X-ray diffraction spectrum shown, the DSC spectrum shown in Fig. 2, the TG spectrum shown in Fig. 3, and the infrared (IR) spectrum characteristics shown in Fig. 4 are shown.
  • Example 3
  • the test has a purity of 99. 83%, the residual amount of isopropyl alcohol is 259 ppm, and the moisture measured by the Karl Fischer (KF) method is 4.81%;
  • the powder X-ray diffraction spectrum shown, the DSC spectrum shown in Fig. 2, the TG spectrum shown in Fig. 3, and the infrared (IR) spectrum characteristics shown in Fig. 4 are shown.
  • Example 4
  • Example 1 The lg obtained in Example 1 was added.
  • the lg obtained in Example 1 was added to the mixture obtained in Example 1.
  • the lg obtained in Example 1 was added.
  • the crystal is used as a seed crystal, and a solid precipitates.
  • 200 ml of isopropanol is added dropwise, and the mixture is cooled to 10 to 15 ° C.
  • After stirring for 2 hours, it is filtered with suction, and the filter cake is washed with isopropyl alcohol/water 4:1.
  • lg crystals were obtained by drying at 40 to 50 ° C, 5 mmHg for 3 hours.
  • the sample has a HPLC purity of 99. 84%, wherein the residual amount of isopropyl alcohol is 235 ppm, and the moisture measured by the Karl Fischer (KF) method is 4.76%;
  • the powder X-ray diffraction spectrum shown, the DSC spectrum shown in Fig. 2, the TG spectrum shown in Fig. 3, and the infrared (IR) spectrum characteristics shown in Fig. 4 are shown.
  • Example 5
  • the test has a HPLC purity of 99. 87%, wherein the residual amount of isopropanol is 165 ppm, and the moisture measured by the Karl Fischer (KF) method is 4.78%;
  • the powder X-ray diffraction spectrum shown, the DSC spectrum shown in Fig. 2, the TG spectrum shown in Fig. 3, and the infrared (IR) spectrum characteristics shown in Fig. 4 are shown.
  • Example 6
  • the detection of the crystals of the present example has a purity of 99.88%, wherein the residual amount of isopropanol is 265 ppm, the moisture measured by the Karl Fischer (KF) method is 5.01%; and has the powder X-ray diffraction spectrum shown in FIG. 1, the DSC spectrum shown in FIG. 2, and the TG spectrum shown in FIG.
  • the infrared (IR) spectrum features shown in Figure 4 and Figure 4.
  • the test has a HPLC purity of 99. 82%, wherein the residual amount of isopropyl alcohol is 275 ppm, and the moisture measured by the Karl Fischer (KF) method is 4.87%;
  • the powder X-ray diffraction spectrum shown, the DSC spectrum shown in Fig. 2, the TG spectrum shown in Fig. 3, and the infrared (IR) spectrum characteristics shown in Fig. 4 are shown.
  • Example 8
  • the test has a HPLC purity of 99. 73%, wherein the residual amount of tetrahydrofuran is 175 ppm, and the moisture measured by the Karl Fischer (KF) method is 4.78%;
  • Example 10 The powder X-ray diffraction spectrum, the DSC spectrum shown in Fig. 2, the TG spectrum shown in Fig. 3, and the infrared (IR) spectrum characteristics shown in Fig. 4.
  • HPLC purity of the crystal obtained in this example was 99.59%, and the residual amount of acetonitrile was
  • the moisture measured by the Karl Fischer (KF) method is 4.95%; and has the powder X-ray diffraction spectrum shown in Fig. 1, the DSC spectrum shown in Fig. 2, and the TG spectrum shown in Fig. 3.
  • the infrared (IR) spectrum features shown in Figure 4 and Figure 4.
  • the obtained doripene hydrate crystal of the present invention is placed in a drier having a relative humidity of 75%, and placed in a constant temperature drying oven at 40 ° C, respectively Samples were taken after 0, 1, 2, 3, and 6 months to analyze the traits, contents, related substances, and moisture of the analyzed samples. The results are shown in Table 4.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Oncology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Communicable Diseases (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des cristaux d'hydrate de doripénème et leur procédé de préparation. Le spectrogramme de diffraction des rayons X de la poudre cristalline est dans le principe tel que représenté sur la figure 1, et la teneur en eau mesurée est de 4,4 à 5,5 %. Les cristaux d'hydrate de doripénème de la présente invention possèdent une pureté élevée, un faible teneur en solvant résiduel, une bonne stabilité et une sécurité d'application. De plus, le procédé de préparation des cristaux d'hydrate de doripénème de la présente invention présente des techniques simples et un faible coût de préparation, et est approprié pour une production industrielle.
PCT/CN2012/081064 2011-09-08 2012-09-06 Cristaux d'hydrate de doripénème et leur procédé de préparation Ceased WO2013034087A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201110266374.4 2011-09-08
CN201110266374A CN102285988B (zh) 2011-09-08 2011-09-08 一种多尼培南水合物晶体及其制备方法

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Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102285988B (zh) * 2011-09-08 2012-09-05 上海希迈医药科技有限公司 一种多尼培南水合物晶体及其制备方法
CN102702201B (zh) * 2012-03-26 2013-12-25 深圳市海滨制药有限公司 一种多尼培南中间体化合物、其制备方法和用途以及多尼培南的制备方法
CN104072497B (zh) * 2013-03-29 2017-10-03 石药集团中奇制药技术（石家庄）有限公司 一种多尼培南新结晶及其制备方法
US9840506B2 (en) 2014-04-28 2017-12-12 Jw Pharmaceutical Corporation Crystal of doripenem, and preparation method therefor
KR20160109904A (ko) * 2015-03-13 2016-09-21 주식회사 대웅제약 결정형 도리페넴의 제조방법

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1432016A (zh) * 2000-03-31 2003-07-23 盐野义制药株式会社 吡咯烷硫卡培南衍生物的新型结晶
CN101100468A (zh) * 2006-07-07 2008-01-09 上海医药工业研究院 多利培南水合物结晶及其制备方法
CN102285988A (zh) * 2011-09-08 2011-12-21 上海希迈医药科技有限公司 一种多尼培南水合物晶体及其制备方法

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2183874T3 (es) * 1994-05-02 2003-04-01 Shionogi & Co Cristal derivado de pirrolidylthiocarbapenem, preparado liofilizado conteniendo dicho cristal y procedimiento para su produccion.
CN101100469B (zh) * 2006-07-03 2011-05-11 成都地奥九泓制药厂 多尼培南的新结晶及其制备方法和用途
EP2275424A1 (fr) * 2009-07-17 2011-01-19 Sandoz AG Procédé de cristallisation du doripénème

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1432016A (zh) * 2000-03-31 2003-07-23 盐野义制药株式会社 吡咯烷硫卡培南衍生物的新型结晶
CN101100468A (zh) * 2006-07-07 2008-01-09 上海医药工业研究院 多利培南水合物结晶及其制备方法
CN102285988A (zh) * 2011-09-08 2011-12-21 上海希迈医药科技有限公司 一种多尼培南水合物晶体及其制备方法

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