WO2018153364A1 - Forme ii du cristal d'osalmide, son procédé de préparation et ses applications - Google Patents

Forme ii du cristal d'osalmide, son procédé de préparation et ses applications Download PDF

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WO2018153364A1
WO2018153364A1 PCT/CN2018/077185 CN2018077185W WO2018153364A1 WO 2018153364 A1 WO2018153364 A1 WO 2018153364A1 CN 2018077185 W CN2018077185 W CN 2018077185W WO 2018153364 A1 WO2018153364 A1 WO 2018153364A1
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mixture
sulphate
solid
toluene
solvent
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PCT/CN2018/077185
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English (en)
Chinese (zh)
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朱维良
徐志建
李波
张勇
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中国科学院上海药物研究所
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Publication of WO2018153364A1 publication Critical patent/WO2018153364A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/58—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/64—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/08—Preparation of carboxylic acid amides from amides by reaction at nitrogen atoms of carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/22—Separation; Purification; Stabilisation; Use of additives
    • C07C231/24—Separation; Purification
    • 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 invention belongs to the technical field of medicinal chemistry, and particularly relates to sulphate crystal form II, a preparation method and application thereof.
  • the drug polymorph refers to the presence of two or more different crystal forms of the active ingredient (API).
  • API active ingredient
  • Crystalline studies include two stages of crystal discovery and crystal form.
  • a variety of crystallization methods such as melting crystallization, solution evaporation, rapid cooling and suspension crystallization, are used to affect the externalization of the drug crystallization by changing the crystallization conditions, solvent, temperature, speed, and ratio of suspended solvent.
  • Factors using a high-throughput sample preparation platform, while preparing hundreds of crystallization tests, using micro-sample preparation techniques and analytical testing methods to prepare and discover new crystal forms.
  • the new crystal form for the new crystal form process amplification and preparation conditions, a variety of solid characterization methods such as X-ray diffraction, solid state nuclear magnetic resonance, Raman spectroscopy, infrared spectroscopy and the like are used for the crystallization of the crystal form.
  • the physicochemical properties of the crystal forms were studied by DSC, TGA, DVS, HPLC, etc., and the hygroscopicity, chemical stability, physical state stability, and processability of different crystal forms were compared.
  • the most preferred solid form is selected for development.
  • Crystal research should include:
  • the invention adopts a new crystallization nucleation mode and crystallization conditions to prepare a new crystal form II of sulphate. It has been found that the crystal form has small hygroscopicity, good stability, and can form a regular crystal form, thereby facilitating the treatment of the drug and the improvement of the physical and chemical properties, and improving the performance of the drug.
  • One of the objects of the present invention is to provide a sulphate crystal form II which has low hygroscopicity, good stability, and regular crystal form.
  • the present invention provides a sulphate crystal form II having an X-ray powder diffraction represented by a 2 ⁇ angle at a diffraction angle of about 7.527 ⁇ 0.2, about 13.653 ⁇ 0.2, and about 14.644 ⁇ 0.2.
  • the sulphate Form II has an X-ray powder diffraction pattern substantially as shown in FIG.
  • the differential scanning calorimetry of the sulphate Form II has a characteristic melting peak at about 176 °C.
  • the thermal weight loss analysis of the sulphate Form II has a decomposition temperature of about 190 ° C and no weight loss prior to the decomposition temperature.
  • the infrared spectrum of the sulphate crystal form II is 3374.66 cm -1 , 1640.52 cm -1 , 1615.38 cm -1 , 1583.52 cm -1 , 1544.62 cm -1 , 1513.66 cm -1 , 1493.09 cm -1 , 1441.37cm -1 , 1370.38cm -1 , 1343.34cm -1 , 1287.37cm -1 , 1273.46cm -1 , 1249.36cm -1 , 1230.73cm -1 , 1164.93cm -1 , 1138.12cm -1 , 1102.16cm -1 , 1036.60cm -1 , 900.35cm -1 , 862.72cm -1 , 820.96cm -1 , 772.89cm -1 , 754.37cm -1 , 694.80cm -1 , 665.45
  • the sulphate Form II is an unsolvate or a non-hydrate.
  • the crystalline form II of the sulphate is in a range of 0 to 95% relative humidity, the crystal form does not change, and the change in hygroscopicity is extremely small, showing almost no hygroscopicity.
  • a second object of the present invention is to provide a process for the preparation of sulphate Form II.
  • the preparation method of the sulphate crystal form II is selected from the following three methods:
  • Preparing salvianol solid adding solvent, mixing and dissolving; slowly volatilizing to dry at 0-65 ° C, preferably 15-30 ° C or 40-65 ° C, collecting solid to obtain sulphate crystal form II;
  • the sulphate solid is stirred at 0 to 50 ° C (preferably 25 to 50 ° C) with a solvent for at least 24 h, then the solution is filtered, and the solid portion is dried in air for 10 to 30 min to obtain sulphate crystal form II; Part of the solvent is evaporated in a vacuum to precipitate a solid to obtain sulphate Form II; or
  • a small glass bottle containing a solvent having a high solubility to sulphonate is used to dissolve the sulphate solid, and then a large glass bottle containing an anti-solvent highly soluble in sulphate is used, and a large bottle set is used.
  • the small glass bottle is placed in the large glass bottle, the large glass bottle is sealed, and the room temperature is allowed to stand for more than 3 days, so that the poor solvent is continuously poured into the solution, and the precipitate is precipitated to obtain the sulphate crystal form II. .
  • the slow volatilization has a volatilization time of 24 hours or more.
  • the solvent is selected from the group consisting of water, methanol, ethanol, isopropanol, isoamyl alcohol, acetone, methyl ethyl ketone, acetonitrile, methyl isobutyl ketone, ethyl acetate, isopropyl acetate, a mixture of toluene, n-hexane, n-heptane, dichloromethane, petroleum ether, chloroform, methyl tert-butyl ether, tetrahydrofuran or a mixture of two or more;
  • the solvent is selected from the group consisting of ethanol, methyl isobutyl ketone and a mixture of water and ethanol, methyl tert-butyl ether and a mixture of water and ethanol, ethanol and toluene.
  • the solvent is selected from the group consisting of methyl isobutyl ketone, isopropyl acetate, a mixture of methanol and water, a mixture of methyl ethyl ketone and water, a mixture of acetonitrile and water, and acetic acid B.
  • the volume ratio thereof is not limited; for example, when the solvent is a mixture of two solvents, the volume ratio may be 2:1, 1:1; When the solvent is a mixture of three solvents, the volume ratio thereof may be 1:1:1, 2:1:1, 2:2:1 or the like.
  • the solvent is selected from one or a mixture of two or more of toluene, n-heptane, n-hexane, dichloromethane, chloroform, petroleum ether, water, methyl t-butyl ether.
  • a mixture of an ether and petroleum ether is selected from one or a mixture of two or more of toluene, n-heptane, n-hexane, dichloromethane, chloroform, petroleum ether, water, a mixture of methyl tert-butyl ether and n-hexane, a mixture of
  • the volume ratio thereof is not limited; for example, when the solvent is a mixture of two solvents, the volume ratio may be 2:1, 1:1; When the solvent is a mixture of three solvents, the volume ratio thereof may be 1:1:1, 2:1:1, 2:2:1 or the like.
  • the combination of the solvent and the anti-solvent is selected from the group consisting of a combination of isoamyl alcohol and n-hexane, a combination of ethyl acetate and n-hexane, a combination of methyl isobutyl ketone and n-hexane, and an acetic acid A combination of propyl ester and n-hexane, a combination of isopropanol and petroleum ether, a combination of isoamyl alcohol and petroleum ether, a combination of ethyl acetate and petroleum ether, a combination of methyl isobutyl ketone and petroleum ether.
  • a third object of the present invention is to provide the use of the sulphate Form II for the preparation of a medicament for the treatment and/or prevention of cholecystitis, cholangiitis, cholelithiasis, tumor, hepatitis B, and whitening cosmetics.
  • the method for preparing the sulphate crystal form II and the preparation method thereof provided by the invention has the advantages of simple operation, small crystal form hygroscopicity, good stability, and formation of a regular crystal form, thereby facilitating the processing of the drug. And the improvement of physical and chemical properties, improve the performance of the drug.
  • the raw material sulphate solid in the examples was purchased from Shanghai Titan Technology Co., Ltd.
  • the slow volatilization described in the examples is that the command time is above 24h.
  • Phenol Form II is an off-white crystal.
  • Phenol Form II is an off-white crystal.
  • the drug substance was dissolved in 200 ml of methyl isobutyl ketone in a small glass bottle, and then the small glass bottle was placed in a large glass bottle containing 6 L of n-hexane, sealed, and allowed to stand at room temperature for one week to collect the precipitated solid.
  • the sulphate crystalline form II is obtained as an off-white crystal.
  • Approximately 3 g of the drug substance in a small glass bottle was dissolved in 200 ml of isopropyl acetate, and then the small glass bottle was placed in a large glass bottle containing 6 L of n-hexane, sealed, allowed to stand at room temperature for one week, and the precipitated solid was collected to obtain a willow.
  • the amine phenol crystal form II is an off-white crystal.
  • Phenol Form II is an off-white crystal.
  • Phenol Form II is an off-white crystal.
  • Phenol Form II is an off-white crystal.
  • the sulphate crystal form II single crystals obtained in Examples 1-1 to 1-63 are colorless and transparent cuboids, and the basic information is as follows:
  • the crystal structure of the sulphate crystal form II single crystal is as follows:
  • the crystal structure of the sulphate crystal form II single crystal is as follows:
  • Example 1-1 About 20 mg of the sulphate Form II prepared in Example 1-1 was taken and stirred at 25 ° C with 1 mL of deionized water for at least 24 h, and then the solution was separately filtered. The liquid portion was evaporated in vacuo to determine the approximate solubility of the drug substance in the solvent by gravimetric analysis. Gravimetric analysis: Accurately take a certain volume (usually 0.5mL) of the filtrate into a dry and weighed container. The weight of the empty container is recorded as M0mg. After the solvent is evaporated in a vacuum, the total weight is accurately weighed.
  • the solubility of the sulphate Form II in deionized water was found to be 0.323 mg/mL.
  • Example 3 XRPD, TG, DSC, IR, Raman, DVS, dissolution curve, etc.
  • XRPD X-ray powder diffraction
  • TG thermogravimetric analysis
  • XD-ray powder diffraction XRPD
  • TG thermogravimetric analysis
  • TG thermogravimetric analysis
  • TG differential scanning calorimetry of the sulphate crystal form II prepared in Example 1-1 of the present invention.
  • DSC infrared spectroscopy
  • IR infrared spectroscopy
  • Raman spectroscopy Raman spectroscopy
  • DVDS hygroscopicity analysis
  • Polarized photo It was tested by XPV-400E polarized light microscope of Shanghai Changfang Optical Instrument Co., Ltd., and the test magnification was 5 times. The analysis results are shown in Figure 1. The polarized photograph shows that the crystalline form II of the sulphate prepared in the above Example 1-1 is an off-white crystal having good morphological characteristics.
  • the diffraction pattern obtained from a particular crystal form is often characteristic. Due to differences in crystallization conditions, particle size, relative content of the mixture, and other test conditions, the diffraction pattern may produce a preferred orientation effect, resulting in a change in the relative intensity of certain bands (especially at low angles) in the spectrum. Therefore, the relative intensities of the diffraction peaks are not characteristic for the crystals that are targeted, and it is more important to note the position of the peaks rather than their relative intensities when determining whether they are the same as the known crystal forms.
  • Humidity is an important physical property of raw materials, which directly affects the storage stability, processability and process preparation of the drug.
  • a dynamic water adsorption instrument (DVS) was used to investigate the adsorption and desorption experiments of water at 0 ° to 95% relative humidity at 25 ° C to determine the wettability of various crystal forms.
  • the following table is the definition and range of the wettability of the Chinese Pharmacopoeia 2015 edition for the drug at 25 ° C, 80% RH balance.
  • the intrinsic dissolution test was carried out using a ⁇ Diss (Pion Inc.) drug dissolution absorption test system using a hydrochloric acid-glycine solution having a pH of 2.0 as a dissolution medium.
  • the correlation coefficient is 0.998 and the linearity is good.
  • the dissolution rate was 0.105 ⁇ g/mL/min, and the dissolution rate of sulphate crystal form II in a hydrochloric acid-glycine solution having a pH of 2.0 was determined according to the following formula:

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une forme II du cristal d'osalmide, son procédé de préparation et ses applications. Selon l'invention, une XRPD indiquée par un angle 2θ, de la forme cristalline a des pics caractéristiques aux angles de diffraction 7,527±0,2, 13,653±0,2, 14,644±0,2, 15,037±0,2, 19,62±0,2, 20,092±0,2, 20,454±0,2, 22,618±0,2, 24,45±0,2, 25,226±0,2, 26,288±0,2, 26,638±0,2, 28,516±0,2, 29,373±0,2, 29,723±0,2, 31,605±0,2, 35,794±0,2 et 38,104±0,2. La forme cristalline a d'excellentes propriétés physicochimiques et une excellente performance de formation de médicament, présente un procédé de préparation simple, une basse hygroscopicité de forme cristalline, une bonne stabilité et une bonne reproductibilité.
PCT/CN2018/077185 2017-02-27 2018-02-26 Forme ii du cristal d'osalmide, son procédé de préparation et ses applications WO2018153364A1 (fr)

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CN112442062B (zh) * 2019-09-05 2022-03-04 中国科学院上海药物研究所 一种柳胺酚有机硅化合物及抗肿瘤用途

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CN109942630B (zh) * 2019-02-28 2021-04-16 上海市第十人民医院 基于柳胺酚和紫檀芪的天然活性分子偶联化合物及其用途

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