WO2023125418A1 - Cristaux de sel d'acide benzènesulfonique et leur procédé de préparation - Google Patents

Cristaux de sel d'acide benzènesulfonique et leur procédé de préparation Download PDF

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WO2023125418A1
WO2023125418A1 PCT/CN2022/141957 CN2022141957W WO2023125418A1 WO 2023125418 A1 WO2023125418 A1 WO 2023125418A1 CN 2022141957 W CN2022141957 W CN 2022141957W WO 2023125418 A1 WO2023125418 A1 WO 2023125418A1
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solution
crystalline form
isopropanol
solid
purin
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PCT/CN2022/141957
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English (en)
Chinese (zh)
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郭振荣
李学飞
唐恕一
陈志宏
李增刚
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同润生物医药(上海)有限公司
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Priority claimed from CN202210245007.4A external-priority patent/CN116410194A/zh
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Publication of WO2023125418A1 publication Critical patent/WO2023125418A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom
    • C07D473/34—Nitrogen atom attached in position 6, e.g. adenine

Definitions

  • the present invention relates to the field of medicine, in particular to a PI3K ⁇ / ⁇ dual inhibitor compound (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl) Crystallization of besylate salt of 4H-chromen-4-one compound and process for its preparation.
  • Phosphoinositide-3 kinases belong to a class of intracellular lipid kinases that phosphorylate the 3-hydroxyl of the inositol ring of phosphoinositide lipids (PI), thereby generating lipid second messengers. It has been reported in the art that targeted inhibitors of the phosphoinositide-3-kinase (PI3K) pathway can be used as immunomodulators.
  • a major issue in the large-scale production of pharmaceutical compounds is that the active substance should have stable crystalline polymorphs to ensure consistent processing parameters and drug quality. If an unstable crystalline form is used, the crystalline polymorph may change during manufacturing and/or storage, leading to quality control issues and formulation irregularities. Such variations may affect the reproducibility of the manufacturing process, resulting in a final formulation that does not meet the high quality and stringent requirements for formulation of pharmaceutical compositions.
  • any modification of the solid state of a pharmaceutical composition that improves its physical and chemical stability confers a significant advantage in stability relative to less stable forms of the same drug.
  • it is crucial to develop stable production methods that consistently produce active substances The existence of multiple crystalline forms with similar solubility poses a difficult challenge in the large-scale manufacture of pharmaceutical compounds.
  • polymorphism When a compound crystallizes from a solution or slurry, it can crystallize in different spatial lattice arrangements, a property known as "polymorphism.” Each crystal form is called a "polymorph”. Although polymorphs of a given substance have the same chemical composition, they can differ in one or more physical properties such as solubility, degree of dissociation, true density, dissolution, melting point, crystal shape, compaction behavior, flow properties and and/or differ from each other in terms of solid-state stability.
  • polymorphic behavior of drugs can be of great importance in pharmacology. Differences in physical properties exhibited by polymorphs affect practical parameters such as storage stability, compressibility and density (important in formulation and product manufacturing) and dissolution rate (an important factor in determining bioavailability). Changes in chemical reactivity (e.g., differential oxidation, causing color to change more quickly when the dosage form is one polymorph than when the dosage form is another polymorph), mechanical changes (e.g., tablet discoloration after storage) Kinetically favorable polymorphs convert to thermodynamically more stable polymorphs) or both (e.g. tablets of one polymorph disintegrate more easily at high humidity) may lead to loss of stability difference. Additionally, the physical properties of the crystals may be important in processing.
  • one polymorph may be more likely to form solvates, causing aggregation of the solid form and making solid handling more difficult.
  • the particle shape and size distribution of one polymorph relative to another may differ, leading to increased challenges in filtering pharmaceutical actives to remove impurities.
  • WO2014195888A1 patent document discloses (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromene-4-one compound, its structural formula It is formula I, and as a free base, it exhibits dual inhibitory functions of PI3K ⁇ / ⁇ .
  • the invention provides a benzene compound of (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromene-4-one compound
  • a crystalline form of sulfonate characterized in that the crystalline form shows 13.28°, 20.72°, 21.70°, 18.80°, 18.14°, 17.26°, 23.81°, 23.02°, 11.12°, Peaks at diffraction angles 2 ⁇ of 14.00°, 23.44°, 22.14° ( ⁇ 0.2°).
  • the benzenesulfonate crystalline form also includes crystals at 27.25°, 28.31°, 22.43°, 26.47°, 34.51°, 28.84°, 20.32°, 16.52°, 27.97°, 27.251°, 26.91°, 33.14° , 31.07°, 24.96°, 8.94°, 29.31°, 29.65°, 32.60°, 31.32°, 38.81°, 33.51°, 37.77°, 37.09° ( ⁇ 0.2°) at the diffraction angle 2 ⁇ .
  • the crystalline form of besylate salt shows an X-ray diffraction pattern substantially as shown in FIG. 5 .
  • the present invention also provides a (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromene- Process for the preparation of crystalline forms of besylate salts of 4-keto compounds, characterized in that it comprises the following steps:
  • Step (1) Weigh a certain mass of (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromene-4-
  • the ketone free base compound is added to a certain volume of isopropanol solvent and dissolved in a water bath to obtain solution 1;
  • Step (2) Weigh a certain mass of benzenesulfonic acid ligand, heat it ultrasonically and dissolve it in a certain volume of isopropanol to obtain solution 2;
  • Step (3) adding the solution 2 obtained in step (2) dropwise to the stirred solution 1 obtained in step (1) to obtain solution 3;
  • Step (4) Stir the solution 3 obtained in step (3), and no solid is precipitated, and a certain volume of anti-solvent is added to the solution to precipitate a solid, and the stirring is continued to obtain a suspension;
  • Step (5) filter the suspension obtained in step (4) under reduced pressure, rinse the surface of the filter cake with isopropanol, and vacuum-dry the obtained solid at room temperature to obtain the crystalline form.
  • the anti-solvent in step (4) is selected from n-heptane.
  • the volume ratio of the volume of isopropanol in step (1), step (2) to the antisolvent in step (4) is 2:0.1-0.5:3.
  • the molar ratio of the free base compound in step (1) to the benzenesulfonic acid ligand in step (2) is 1:1.5, preferably 1:1.1.
  • Benzenesulfonate of (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromene-4-one compound of the present invention The crystals have good crystallinity, slightly hygroscopicity, controllable crystal form preparation, and exhibit excellent pharmacokinetics, and can be used as PI3K ⁇ / ⁇ inhibitors.
  • the TGA figure of accompanying drawing 6 besylate crystal form
  • the DSC figure of accompanying drawing 7 besylate crystal form
  • the PLM figure of accompanying drawing 9 besylate crystal form
  • the 1 HNMR figure of accompanying drawing 10 besylate crystal form
  • the crystal form of the samples was analyzed by X-powder diffractometer.
  • the 2 ⁇ scanning angle of the sample is from 3° to 40°, the scanning step is 0.02°, and the scanning time of each step is 0.2s.
  • the light tube voltage and current were 40kV and 40mA, respectively.
  • the samples were analyzed by TA instruments Q200 DSC. Put the weighed sample (0.5mg-5mg) into the sample tray, and raise the sample to the final temperature at a rate of 10°C/min under the protection of nitrogen (50mL/min).
  • the samples were analyzed by TA instruments Q500.
  • the sample was put into a tared platinum crucible, the system automatically weighed, and then the sample was raised to the final temperature at a rate of 10°C/min under the protection of nitrogen (40mL/min).
  • the samples were analyzed using a polarizing microscope, and the morphology and microstructure of the crystals were obtained by adjusting different magnifications.
  • Dynamic moisture adsorption was performed using TA Instruments Q5000 SA. Approximately 1-10 mg of sample is placed in a sample pan and suspended from the sample chamber. The room temperature was maintained at a constant 25 ⁇ 1°C by a water bath. In the step mode, the sample is subjected to a cycle test in the relative humidity of 0%RH-80%RH. Analysis was performed at 10% RH/step. Set the time to maintain each humidity to 90min, so that the sample and the indoor environment can reach equilibrium.
  • the samples were analyzed using Bruker Ascend 500MH, and the solvent was deuterated dimethyl sulfoxide.
  • Step (1) About 200 mg of the free base compound prepared in Example 2.1 was added to 2 mL of isopropanol, and dissolved in a water bath at 60 ° C to obtain solution 1;
  • Step (2) about 94 mg of benzenesulfonic acid was dissolved in 0.4 mL of isopropanol by ultrasonic heating to obtain solution 2;
  • Step (3) adding solution 2 dropwise to solution 1 under stirring to obtain solution 3;
  • Step (4) The solution 3 was stirred for about 1 day without solid precipitation, and 3 mL of n-heptane was added to precipitate a solid, which turned into oil after stirring, and continued stirring for about 2 days to obtain a suspension.
  • Step (5) The suspension was suction-filtered under reduced pressure, the surface of the filter cake was washed with isopropanol, and the obtained solid was vacuum-dried overnight at room temperature to obtain crystalline form 1 of besylate salt (about 200 mg).
  • API represents the free base compound prepared in Example 2.1
  • base represents the free base compound
  • acid represents the benzenesulfonic acid pair ion ligand.
  • Step (1) Weigh about 200 mg of the free base compound prepared in Example 2.1, add 2 mL of isopropanol, and dissolve in a water bath at 60°C to obtain solution 1;
  • Step (2) about 103 mg of citric acid was dissolved in 0.8 mL of isopropanol to obtain solution 2;
  • Step (3) adding solution 2 dropwise to solution 1 under stirring to obtain solution 3;
  • Step (4) Solution 3 was stirred overnight without solid precipitation, and 3 mL of n-heptane was added to solution 3 to precipitate solid, which turned into oil after stirring;
  • Step (5) The supernatant was discarded, and the obtained oil was vacuum-dried at room temperature overnight to obtain an amorphous solid of citrate, whose XRPD is shown in Figure 11 and 1 HNMR is shown in Figure 12 .
  • Step (1) about 200mg of the free base compound prepared in Example 2.1, add 2mL of isopropanol, dissolve in a water bath at 60°C, solution 1;
  • Step (2) about 73mg L-malic acid was dissolved in 0.8mL isopropanol to obtain solution 2;
  • Step (3) adding solution 2 dropwise to solution 1 under stirring to obtain solution 3;
  • Step (4) Solution 3 was stirred overnight without solid precipitation, and 3 mL of n-heptane was added to Solution 3, and oil was precipitated after stirring for about 2 days;
  • Step (5) The supernatant was discarded, and the obtained oil was vacuum-dried overnight at room temperature to obtain an amorphous solid of L-malate, whose XRPD is shown in Figure 13 and 1 HNMR is shown in Figure 14 .
  • Step (1) About 200 mg of the free base compound prepared in Example 2.1 was added to 2 mL of isopropanol, and dissolved in a water bath at 60°C to obtain solution 1;
  • Step (2) About 55 mg of sulfuric acid was dissolved in 0.4 mL of isopropanol to obtain solution 2;
  • Step (3) adding solution 2 dropwise to solution 1 under stirring to obtain solution 3;
  • Step (4) Solids were precipitated from solution 3 immediately, dissolved after stirring for about 1 day, and 4 mL of n-heptane was added, solids were precipitated, and oil was formed after stirring for about 2 days;
  • Step (5) The supernatant was discarded, and the obtained oil was vacuum-dried overnight at room temperature to obtain an amorphous sulfate sulfate solid, whose XRPD is shown in Figure 15 .
  • Step (1) about 200mg of the free base compound prepared in Example 2.1, add 2mL of isopropanol, dissolve in a water bath at 60°C, solution 1;
  • Step (2) about 80mg L-tartaric acid was dissolved in 0.8mL isopropanol to obtain solution 2;
  • Step (3) adding solution 2 dropwise to solution 1 under stirring to obtain solution 3;
  • Step (4) The solution 3 was slightly turbid, and a large amount of solids did not precipitate out after stirring overnight. Add 3mL of n-heptane, the solids precipitated, and stirred for about 2 days to form an oil;
  • Step (5) The supernatant was discarded, and the obtained oil was vacuum-dried at room temperature overnight to obtain an amorphous solid of L-tartrate salt, whose XRPD is shown in Figure 16 and 1 HNMR is shown in Figure 17 .
  • Step (1) About 200 mg of the free base compound prepared in Example 2.1 was added to 2 mL of isopropanol, and dissolved in a water bath at 60 ° C to obtain solution 1;
  • Step (2) about 93 mg of p-toluenesulfonic acid was dissolved in 0.4 mL of isopropanol to obtain solution 2;
  • Step (3) adding solution 2 dropwise to solution 1 under stirring to obtain solution 3;
  • Step (4) Solution 3 was stirred for about 1 day without solid precipitation, added 3 mL of n-heptane, solid was precipitated, and stirred for about 2 days to form an oil;
  • Step (5) The supernatant was discarded, and the obtained oil was vacuum-dried overnight at room temperature to obtain an amorphous solid of p-toluenesulfonate, whose XRPD is shown in Figure 18 and 1 HNMR is shown in Figure 19 .
  • Step (1) About 200 mg of the free base compound prepared in Example 2.1 was added to 2 mL of isopropanol, and dissolved in a water bath at 60 ° C to obtain solution 1;
  • Step (2) about 44 ⁇ L of hydrochloric acid was dissolved in 0.4 mL of isopropanol to obtain solution 2;
  • Step (3) adding solution 2 dropwise to solution 1 under stirring to obtain solution 3;
  • Step (4) Solution 3 was stirred for about 1 day without precipitation of solids, and 3 mL of n-heptane was added to precipitate solids, and stirred for about 2 days to form an oil;
  • Step (5) The supernatant was discarded, and the obtained oil was vacuum-dried at room temperature overnight to obtain an amorphous hydrochloride solid, and its XRPD is shown in Figure 20.
  • Step (1) About 200 mg of the free base compound prepared in Example 2.1 was added to 2 mL of isopropanol, and dissolved in a water bath at 60 ° C to obtain solution 1;
  • Step (2) About 62 mg of maleic acid was dissolved in 0.4 mL of isopropanol to obtain solution 2;
  • Step (3) adding solution 2 dropwise to solution 1 under stirring to obtain solution 3;
  • Step (4) Solution 3 was stirred for about 1 day without solid precipitation, added 3 mL of n-heptane, solid was precipitated, and stirred for about 2 days to form an oil;
  • Step (5) The supernatant was discarded, and the obtained oil was vacuum-dried overnight at room temperature to obtain an amorphous maleate salt, whose XRPD is shown in Figure 21 and 1 HNMR is shown in Figure 22 .
  • Step (1) About 200 mg of the free base compound prepared in Example 2.1 was added to 2 mL of isopropanol, and dissolved in a water bath at 60 ° C to obtain solution 1;
  • Step (2) about 53 mg of methanesulfonic acid was dissolved in 0.4 mL of isopropanol to obtain solution 2;
  • Step (3) adding solution 2 dropwise to solution 1 under stirring to obtain solution 3;
  • Step (4) Solution 3 was stirred for about 1 day without solid precipitation, added 3 mL of n-heptane, solid was precipitated, and stirred for about 2 days to form an oil;
  • Step (5) The supernatant was discarded, and the obtained oil was vacuum-dried overnight at room temperature to obtain an amorphous solid of mesylate salt, whose XRPD is shown in Figure 23 and 1 HNMR is shown in Figure 24 .
  • the present invention also studies (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophenyl)-4H-chromen-4-one free base and benzene
  • Animal blood collection points are before and after administration and 0.25, 0.5, 1, 2, 4, 8 and 24 hours.
  • Jugular vein blood collection the blood collection volume of each blood collection point is about 150 ⁇ L, EDTA-K2 anticoagulant, within 15 minutes after sampling 4 Centrifuge at 2000g for 5min, and analyze by LCMSMS-28 (Triple Quad 6500+).

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

Abstract

La présente invention concerne des cristaux d'un sel d'acide benzènesulfonique d'un composé (S)-2-(1-(9H-purin-6-ylamino)propyl)-3-(3-fluorophényl)-4H-chroméne-one composé inhibiteur double de PI3Kδ/γ et son procédé de préparation. Une forme cristalline selon la présente invention a d'excellentes propriétés physiques et pharmacodynamiques/pharmacocinétiques.
PCT/CN2022/141957 2021-12-31 2022-12-26 Cristaux de sel d'acide benzènesulfonique et leur procédé de préparation WO2023125418A1 (fr)

Applications Claiming Priority (4)

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CN202111679211.9 2021-12-31
CN202111679211 2021-12-31
CN202210245007.4 2022-03-11
CN202210245007.4A CN116410194A (zh) 2021-12-31 2022-03-11 一种苯磺酸盐结晶及其制备方法

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105358560A (zh) * 2013-06-07 2016-02-24 理森制药股份公司 双重选择性PI3δ和γ激酶抑制剂
CN106279170A (zh) * 2015-05-12 2017-01-04 苏州晶云药物科技有限公司 5-氟-3-苯基-2-((1s)-1-(9h-嘌呤-6-基氨基)丙基)-3h-喹唑啉-4-酮的无水晶型及其制备方法

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105358560A (zh) * 2013-06-07 2016-02-24 理森制药股份公司 双重选择性PI3δ和γ激酶抑制剂
CN106279170A (zh) * 2015-05-12 2017-01-04 苏州晶云药物科技有限公司 5-氟-3-苯基-2-((1s)-1-(9h-嘌呤-6-基氨基)丙基)-3h-喹唑啉-4-酮的无水晶型及其制备方法

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