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WO2025132929A2 - Sels d'avatrombopag - Google Patents

Sels d'avatrombopag Download PDF

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Publication number
WO2025132929A2
WO2025132929A2 PCT/EP2024/087614 EP2024087614W WO2025132929A2 WO 2025132929 A2 WO2025132929 A2 WO 2025132929A2 EP 2024087614 W EP2024087614 W EP 2024087614W WO 2025132929 A2 WO2025132929 A2 WO 2025132929A2
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Prior art keywords
avatrombopag
mixture
theta
degrees
acetone
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Application number
PCT/EP2024/087614
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WO2025132929A3 (fr
WO2025132929A9 (fr
Inventor
Michal HEGEDUS
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Synthon BV
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Synthon BV
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Publication of WO2025132929A3 publication Critical patent/WO2025132929A3/fr
Publication of WO2025132929A9 publication Critical patent/WO2025132929A9/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
    • C07C57/13—Dicarboxylic acids
    • C07C57/145—Maleic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero 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 invention relates to improved process to prepare avatrombopag hydrogenmaleate form C.
  • the invention further relates to the novel salts of avatrombopag and their crystalline forms.
  • Avatrombopag was first disclosed in W02003062233 (Y amanouchi). Avatrombopag is practically insoluble in water below pH 12 and 0.1N hydrochloride. In addition, studies with LLC-PK cells have shown that avatrombopag has low to moderate in vitro permeability.
  • Salt formation is the most common and effective method of increasing solubility and dissolution rates of acidic and basic drugs.
  • the salts can possess improved properties such as solubility or bioavailability that is advantageous in preparation of final formulations. Because of good crystallinity the salts can be also used for purification of avatrombopag.
  • W02004029049 (Y amanouchi) discloses avatrombopag in the form of maleate salt (also called hydrogenmaleate; ratio of free base to maleic acid molecule 1 : 1), that has been proved to have good oral bioavailability.
  • the salt forming reaction is performed in the mixture of water and ethanol solvent.
  • WO2013018362 discloses crystalline forms A, B and C of avatrombopag maleate.
  • forms A and B can be obtained by crystallisation from a mixture of water and an alcohol (methanol, ethanol, 2-propanol and the like), for example 80% ethanol and 20% water.
  • an alcohol methanol, ethanol, 2-propanol and the like
  • form A crystals can morph depending on the scale of production and are therefore not suitable as drug substance for medicines.
  • form B crystals were found to exhibit poor oral absorption even though they can be stably supplied in industrial production.
  • Form C on the other hand was found to be devoid of these drawbacks.
  • Form C of avatrombopag maleate is used in the commercial Doptelet® tablets marketed by Swedish Orphan Biovitrum.
  • Form C crystals of avatrombopag maleate according to WO2013018362 can be obtained by salt preparation/crystallisation in acetone/water mixtures, methyl ethyl ketone/water mixtures or acetonitrile/water mixtures, which also contain dimethyl sulfoxide (DMSO).
  • DMSO dimethyl sulfoxide
  • mixtures of water, acetone and DMSO (2:2:1 V/V/V) are used.
  • DMSO a solvent in preparation of avatrombopag maleate form C is useful as it increases the solubility of avatrombopag.
  • form C can be obtained via simple cooling crystallization. While the process using DMSO as a solvent provides crystals in reasonable yield, the product contains excessive amount of residual DMSO solvent.
  • CN106749226 discloses the preparation of form C of avatrombopag maleate including dissolving avatrombopag maleate in dimethylformamide (DMF) and the addition of methylene chloride as an anti-solvent.
  • DMF dimethylformamide
  • avatrombopag form C can be prepared by treating avatrombopag maleate with a ketone solvent (selected from acetone, methyl ethyl ketone and methyl isobutyl ketone) at 25 ⁇ 5°C and requires long stirring time (14-18 hours).
  • a ketone solvent selected from acetone, methyl ethyl ketone and methyl isobutyl ketone
  • CN112409350 discloses form D of avatrombopag maleate and its use in the process to prepare form C of avatrombopag.
  • Form D is obtained by providing a solution of avatrombopag maleate in a mixture of first and second solvent and the following addition of anti-solvent.
  • First solvent is selected from the group comprising N- methylpyrrolidone, dimethyl sulfoxide, N,N -dimethylformamide and the second solvent is selected from the group comprising acetone, methylene chloride and acetonitrile.
  • As an antisolvent water is used.
  • CN116135854 discloses the preparation of form C by mixing avatrombopag free base with solvent selected from acetone and acetonitrile and maleic acid. Similarly to the present invention, form C is obtained in the step of forming avatrombopag salt and requires no additional crystallization. However, the use of acetone as a single solvent results in high overall vapor pressure, which is disadvantageous in terms of safety and handling.
  • the presented invention relates to a method for preparing form C of avatrombopag maleate, the method comprising following steps: a) Avatrombopag free base is suspended in the mixture of acetone and water and stirred; b) Maleic acid is added into suspension and stirred; c) Obtained solid is isolated, washed with acetone and dried.
  • the present invention further relates to novel salts of avatrombopag, their crystalline forms and the preparation thereof.
  • the salts are selected from hydrogenmalonate, fumarate, sulphate, besylate and tosylate.
  • avatrombopag free base and the corresponding acid are dissolved in a solvent or a solvent mixture, at the defined temperature, followed by an isolation step.
  • Figure 1 depicts the X-Ray Powder Diffractogram (XRPD) of form C of avatrombopag maleate, prepared according to Examples 1.
  • XRPD X-Ray Powder Diffractogram
  • Figure 2 depicts the X-Ray Powder Diffractogram (XRPD) of avatrombopag salt with fumaric acid, Form Bl, prepared according to Example 4.
  • Figure 3 depicts the DSC pattern of avatrombopag salt with fumaric acid, Form Bl, prepared according to Example 4.
  • XRPD X-Ray Powder Diffractogram
  • Figure 4 depicts the X-Ray Powder Diffractogram (XRPD) of avatrombopag salt with malonic acid, Form Cl, prepared according to Example 5.
  • XRPD X-Ray Powder Diffractogram
  • Figure 5 depicts the DSC pattern of avatrombopag salt with malonic acid, Form Cl, prepared according to Example 5.
  • the inventors have surprisingly found that from C of avatrombopag maleate can be obtained with good yield and purity from the mixed solvent of acetone and water.
  • the process is relatively fast as form C of avatrombopag maleate is prepared directly from the reaction of avatrombopag free base and maleic acid.
  • the process according to the present invention does not require the use of excessive amount of solvents or high crystallization temperatures.
  • the method of the present invention is more environmentally friendly as the use of water in the mixed solvent can reduce the overall amount of organic solvents (in this case acetone) needed.
  • the presented invention relates to a method for preparing form C of avatrombopag maleate, the method comprising following steps: a) Avatrombopag free base is suspended in the mixture of acetone and water and stirred; b) Maleic acid is added into suspension and stirred; c) Obtained solid is isolated, washed with acetone and dried.
  • the volume ratio between acetone and water can be between 0.8:1 and 1:0.8. Preferably, the volume ratio is 1: 1.
  • the mass volume ratio of avatrombopag free base and acetone, in g/mL, is between 1:10 to 1:30.
  • step b) to the suspension obtained in step a) maleic acid is added and the suspension is stirred.
  • the molar ratio between avatrombopag free base and added maleic acid can be between 1:1.05 and 1:1.25.
  • the suspension is stirred for 1 - 3 hours at the temperature between 20 - 60°C.
  • step c) the solid obtained in step b) is isolated, optionally washed by a portion of acetone and dried.
  • the obtained form C can be isolated by any suitable technique, for example using filtration or centrifuge.
  • the presented invention further relates to a novel avatrombopag salts.
  • the invention relates to hydrogenmalonate, fumarate, sulphate, besylate and tosylate salts of avatrombopag and the preparation thereof.
  • the invention also relates to solid forms of these salts.
  • the salts of avatrombopag according to the invention are prepared by reacting avatrombopag free base with selected acid in a suitable solvent or a mixture of solvents at defined temperature, followed by an isolation step (precipitation or crystallization, or filtration).
  • the present invention relates to avatrombopag sulphate, the solid form Al and the preparation thereof.
  • the solid form Al of avatrombopag sulphate can be characterized by XRPD pattern values having 20 values 6.7, 13.6, 18.8 and 20.3 degrees 2 theta ( ⁇ 0.2 degrees 2 theta).
  • the solid form Al can also be characterized by xrpd pattern having 6.7, 7.0, 13.6, 18.8, 20.3 and 24.0 degrees 2 theta ( ⁇ 0.2 degrees 2 theta).
  • the solid form can be further characterized by xrpd pattern described in table 1:
  • Form Al of avatrombopag sulphate salt can be prepared by mixing avatrombopag free base with aqueous sulfuric acid in a solvent, heating the mixture, cooling and isolating form 1 of avatrombopag sulphate.
  • concentration of avatrombopag free base in a solvent(s) can be between 50 and 80 mg/ml.
  • the molar ratio of avatrombopag free base and sulfuric acid can be between 1:1 to 1.3.
  • Solvent is preferably selected from acetonitrile, acetone or the mixture of acetone or acetonitrile and water. Most preferably acetonitrile or a mixture of acetone and water is used.
  • Avatrombopag free base in a solvent is heated to 55 to 80°C and aqueous sulfuric acid is added to the mixture.
  • the mixture is subsequently stirred at the temperature of 55 to 80°C for a sufficient amount of time.
  • the mixture is cooled to a temperature between 20°C and 25°C and the obtained solid is fdtered and dried.
  • the solid Form Al can be isolated by any suitable technique, for example using filtration or centrifuge. Obtained solid can be optionally dried.
  • the present invention also relates to fumaric salt of avatrombopag, form Bl of avatrombopag fumarate and their preparation.
  • the solid form Bl of avatrombopag fumarate can be characterized by XRPD pattern values having 20 values 6.9, 7.6 and 20.3 degrees 2 theta ( ⁇ 0.2 degrees 2 theta).
  • the solid form Bl can also be characterized by xrpd pattern having 6.9, 7.6, 13.2, 18.8, 19.4 and 20.3 degrees 2 theta ( ⁇ 0.2 degrees 2 theta).
  • the solid form can be further characterized by xrpd pattern described in table 2: Table 2:
  • the solid form Bl of avatrombopag fumarate can be further characterized by xrpd pattern depicted in figure 2.
  • Form Bl of avatrombopag fumarate salt can be prepared by mixing avatrombopag free base with fumaric acid in a solvent or a mixture of solvents, heating the mixture, cooling and isolating form Bl of avatrombopag fumarate.
  • the concentration of avatrombopag free base in a solvent(s) can be between 50 and 75 mg/ml.
  • the molar ratio of avatrombopag free base and fumaric acid can be between 0.9:1 to 1.3.
  • Solvent is preferably selected from methanol, ethanol or the mixture thereof.
  • the mixture comprising avatrombopag free base and methanol or a mixture or ethanol and methanol is heated to a temperature between 55 to 65°C and to the mixture fumaric acid is added.
  • Fumaric acid is preferably added in the form of solution in ethanol.
  • the mixture is subsequently stirred at the temperature of 55 to 65°C for a sufficient amount of time.
  • the mixture is cooled to a temperature between 20°C and 25°C.
  • the solid Form Bl can be isolated by any suitable technique, for example using filtration or centrifuge.
  • Obtained solid can be optionally dried.
  • the present invention also relates to hydrogenmalonate salt of avatrombopag, form Cl of avatrombopag hydrogenmalonate and the preparation thereof.
  • the solid form Cl of avatrombopag hydrogenmalonate can be characterized by XRPD pattern values having 20 values 19.1, 20.6 and 23.9 degrees 2 theta ( ⁇ 0.2 degrees 2 theta).
  • the solid form Cl can also be characterized by xrpd pattern having 12.8, 19.1, 19.4, 20.6, 23.9 and 25.2 degrees 2 theta ( ⁇ 0.2 degrees 2 theta).
  • the solid form can be further characterized by xrpd pattern described in table 3:
  • the solid form Cl of avatrombopag hydrogenmalonate can be further characterized by xrpd pattern depicted in figure 4.
  • Form Cl can be prepared by mixing avatrombopag free base with malonic acid in a solvent or a mixture of solvents, heating the mixture, cooling and isolating form Cl of avatrombopag hydrogenmalonate.
  • the concentration of avatrombopag free base in a solvent(s) can be between 50 and 75 mg/ml.
  • the molar ratio of avatrombopag free base and malonic acid can be between 1: 1 to 1.3.
  • Solvent is preferably selected from methanol or the mixture of methanol and water.
  • the mixture comprising avatrombopag free base and methanol is heated to a temperature between 55 to 65°C and to the mixture malonic acid is added.
  • Malonic acid is preferably added in the form of solution in ethanol.
  • the mixture is subsequently stirred at the temperature of 55 to 65°C for a sufficient amount of time.
  • the mixture is cooled to a temperature between 20°C and 25°C.
  • the solid Form Cl can be isolated by any suitable technique, for example using filtration or centrifuge. Obtained solid can be optionally dried.
  • the present invention further relates to besylate salt of avatrombopag, form D 1 of avatrombopag besylate and the preparation thereof.
  • the solid form DI of avatrombopag besylate was identified as a DMSO solvate.
  • Form DI can be characterized by XRPD pattern values having 20 values 16.6, 19.9 and 21.8 degrees 2 theta ( ⁇ 0.2 degrees 2 theta).
  • the solid form DI can also be characterized by xrpd pattern having 8.3, 10.6, 13.7, 16.6, 19.9 and 21.8 degrees 2 theta ( ⁇ 0.2 degrees 2 theta).
  • the solid form can be further characterized by xrpd pattern described in table 4:
  • Form DI can be prepared by mixing avatrombopag free base with benzenesulfonic acid in a mixture of solvents comprising DMSO, acetone and water, heating the mixture, cooling and isolating form DI of avatrombopag besylate.
  • the concentration of avatrombopag free base in a mixture of solvents can be between 10 and 20 mg/ml.
  • the molar ratio of avatrombopag free base and benzene sulfonic acid can be between 1 : 1 to 1.3.
  • the molar ration between DMSO, acetone and water is preferably around 1: 1:0.5.
  • the mixture comprising avatrombopag free base and the solvent mixture is heated to a temperature between 55 to 75°C and to the mixture solid benzene sulfonic acid is added.
  • the mixture is subsequently stirred at the temperature of 55 to 75°C for a 10 - 60 minutes.
  • the mixture is cooled to a temperature between 2°C and 10°C.
  • the solid Form DI can be isolated by any suitable technique, for example using filtration or centrifuge. Obtained solid can be optionally dried.
  • the present invention also relates to tosylate salt of avatrombopag, form El of avatrombopag tosylate and the preparation thereof.
  • the solid form El of avatrombopag tosylate has been identified as DMSO solvate.
  • Form El can be characterized by XRPD pattern values having 20 values 9.6, 20.5 and 21.3 degrees 2 theta ( ⁇ 0.2 degrees 2 theta).
  • the solid form El can also be characterized by xrpd pattern having 9.6, 10.2, 13.6, 14.5, 20.5 and 21.3 degrees 2 theta ( ⁇ 0.2 degrees 2 theta).
  • the solid form can be further characterized by xrpd pattern described in table 5 :
  • Form El can be prepared by mixing avatrombopag free base with p-Toluenosulfonic acid in a mixture of solvents comprising DMSO, acetone and water, heating the mixture, cooling and isolating form DI of avatrombopag besylate.
  • concentration of avatrombopag free base in a mixture of solvents can be between 10 and 20 mg/ml.
  • the molar ratio of avatrombopag free base and p-Toluenosulfonic acid can be between 1: 1 to 1.3.
  • the molar ratio between DMSO, acetone and water is preferably around 1: 1:0.5.
  • the mixture comprising avatrombopag free base and the solvent mixture is heated to a temperature between 55 to 75°C and to the mixture solid p-Toluenosulfonic acid is added.
  • the mixture is subsequently stirred at the temperature of 55 to 75°C for a 10 - 60 minutes.
  • the mixture is cooled to a temperature between 20°C and 25°C.
  • the solid Form El can be isolated by any suitable technique, for example using filtration or centrifuge. Obtained solid can be optionally dried.
  • DCS patterns were obtained using the following conditions: 10°C/min -> 350°C
  • Example 1 Avatrombopag maleate form C
  • Avatrombopag free base (24.950 g, 38.4 mmol) form A was suspended into the mixture of 375 ml of acetone and 375 ml of water at ambient temperature. The suspension was stirred at 25°C for one hour at 300 RPM (mechanical stirrer, PTFE). To the suspension, solid maleic acid was added (4.46 g,
  • Example 2 Avatrombopag maleate form C Avatrombopag free base form A (5 g, 7.70 mmol) was suspended into the mixture of acetone
  • Example 3 Avatrombopag sulphate tetrahydrate, form Al
  • Avatrombopag free base 250 mg, 0.385 mmol was placed into 5 mL vial and to this, 2 mL of acetonitrile were added. The suspension was stirred and heated to 65 °C for 10 minutes.
  • Crystalline form Al proved to be stable when placed in open dish for 1 month at 40°C, 75% relative humidity and at 55°C, 90% relative humidity.
  • Avatrombopag free base 250 mg, 0.396 mmol was placed into 5 mL glass vial. To the vial, 2 mL of methanol was added and the mixture was ultrasonicated for 5 minutes and then stirred and heated to 65 °C. After 5 minutes, fumaric acid (leq,45.9 mg, 0.396 mmol) in 2.2mL of 10% aqueous ethanol was added and the mixture was stirred overnight at 65 °C. The solid was filtered off next day and dried freely in air for 24 hours. Yield: 75%.
  • Crystalline form Bl proved to be stable when placed in open dish for 1 month at 40°C, 75% relative humidity and at 55°C, 90% relative humidity.
  • Avatrombopag 250 mg, 0.396 mmol was placed into 5 mL glass vial. To the vial, 2 mL of methanol was added and the mixture was ultrasonicated for 5 minutes and then stirred and heated to 65 °C. After 5 minutes, malonic acid (41.2 mg, 0.396 mrnol) in 2 rnL of water was added and the mixture was stirred overnight at 65 °C. The solid was fdtered off next day and dried freely in air for 24 hours. Crystalline form Cl proved to be stable when placed in open dish for 1 month at 40°C, 75% relative humidity and at 55°C, 90% relative humidity.
  • Example 6 Avatrombopag besylate DMSO solvate, Form DI
  • Avatrombopag free base 250 mg, 0.396 mmol was placed into 25 mL round-bottom flask. To the flask a mixture of DMSO/acetone/water (1: 1:0.5) was added (16 mL). The mixture was ultrasonicated for 5 minutes and then stirred (500RPM) and heated to 70 °C. After 5 minutes, solid benzenesulfonic acid (62.6 mg, 0.396 mmol) was added. Dissolution of solid was observed in seconds. Clear yellowish solution was obtained. This were stirred and heated for another 30 min and then laced into refrigerator (6 °C). Highly crystalline beige solid was filtrated off next day and dried freely in air. Yield: 62%.
  • Crystalline form DI proved to be stable when placed in open dish at accelerated conditions (40°C, 75% relative humidity) for 1 month.
  • Avatrombopag free base 250 mg, 0.396 mmol was placed into 25 mL round-bottom flask. To the flask a mixture of DMSO/acetone/water (1: 1:0.5) was added (16 mL). The mixture was ultrasonicated for 5 minutes and then stirred (500RPM) and heated to 70°C. After 5 minutes, solid p- Toluene sulfonic acid (75 mg, 0.396 rnmol) was added. Clear yellowish solution was obtained. This were stirred and heated for another 30 min and then slowly cooled down to room temperature. Yellowish product was then filtered off and dried at 40 °C under vacuum (100 mbar) in nitrogen bleed for 6 hours. Yield: 51 %.
  • Crystalline form El proved to be stable when placed in open dish at accelerated conditions (40°C, 75% relative humidity) for 1 month.

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Abstract

L'invention concerne un procédé amélioré de préparation de la forme C d'hydrogénomaléate d'avatrombopag à partir d'un mélange d'acétone et d'eau, ainsi que les nouveaux sels d'avatrombopag, leurs formes cristallines et leur préparation. Les sels sont choisis parmi les sels d'hydrogénomaléate, de fumarate, de sulfate, de bésylate et de tosylate.
PCT/EP2024/087614 2023-12-19 2024-12-19 Sels d'avatrombopag Pending WO2025132929A2 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP23218326.9 2023-12-19
EP23218326 2023-12-19
EP23219403.5 2023-12-21
EP23219403 2023-12-21

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WO2025132929A2 true WO2025132929A2 (fr) 2025-06-26
WO2025132929A3 WO2025132929A3 (fr) 2025-09-12
WO2025132929A9 WO2025132929A9 (fr) 2025-11-13

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003062233A1 (fr) 2002-01-18 2003-07-31 Yamanouchi Pharmaceutical Co., Ltd. Derive de 2-acylaminothiazole et son sel
WO2004029049A1 (fr) 2002-09-30 2004-04-08 Yamanouchi Pharmaceutical Co., Ltd. Nouveau sel d'un derive de 2-acylaminothiazole
WO2013018362A1 (fr) 2011-08-03 2013-02-07 Astellas Pharma Inc. Cristaux de composé de 2-acylaminothiazole
CN106749226A (zh) 2017-03-15 2017-05-31 广东赛拓医药科技有限公司 一种avatrombopag马来酸盐晶型C的制备方法
CN112409350A (zh) 2020-11-27 2021-02-26 上海迪赛诺生物医药有限公司 一种马来酸阿伐曲泊帕晶型c的制备方法
CN116135854A (zh) 2021-11-16 2023-05-19 四川科伦药物研究院有限公司 2-酰基氨基噻唑衍生物马来酸盐晶型的制备方法

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003062233A1 (fr) 2002-01-18 2003-07-31 Yamanouchi Pharmaceutical Co., Ltd. Derive de 2-acylaminothiazole et son sel
WO2004029049A1 (fr) 2002-09-30 2004-04-08 Yamanouchi Pharmaceutical Co., Ltd. Nouveau sel d'un derive de 2-acylaminothiazole
WO2013018362A1 (fr) 2011-08-03 2013-02-07 Astellas Pharma Inc. Cristaux de composé de 2-acylaminothiazole
CN106749226A (zh) 2017-03-15 2017-05-31 广东赛拓医药科技有限公司 一种avatrombopag马来酸盐晶型C的制备方法
CN112409350A (zh) 2020-11-27 2021-02-26 上海迪赛诺生物医药有限公司 一种马来酸阿伐曲泊帕晶型c的制备方法
CN116135854A (zh) 2021-11-16 2023-05-19 四川科伦药物研究院有限公司 2-酰基氨基噻唑衍生物马来酸盐晶型的制备方法

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WO2025132929A9 (fr) 2025-11-13

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