WO2017028802A1 - Forme cristalline de dichlorhydrate de 5-[2,6-di(4-morpholinyl)-4-pyrimidinyl]-4-(trifluorométhyl)-2-pyridinamine et son procédé de préparation - Google Patents

Forme cristalline de dichlorhydrate de 5-[2,6-di(4-morpholinyl)-4-pyrimidinyl]-4-(trifluorométhyl)-2-pyridinamine et son procédé de préparation Download PDF

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WO2017028802A1
WO2017028802A1 PCT/CN2016/095944 CN2016095944W WO2017028802A1 WO 2017028802 A1 WO2017028802 A1 WO 2017028802A1 CN 2016095944 W CN2016095944 W CN 2016095944W WO 2017028802 A1 WO2017028802 A1 WO 2017028802A1
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solvent
formula
compound
salt
crystalline
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Chinese (zh)
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陈敏华
张炎锋
刁小娟
张晓宇
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苏州晶云药物科技有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • C07D401/02—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 two hetero rings
    • C07D401/04—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 two hetero rings directly linked by a ring-member-to-ring-member bond

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  • the present invention relates to the field of chemical medicine, in particular to 5-[2,6-bis(4-morpholinyl)-4-pyrimidinyl]-4-(trifluoromethyl)-2-pyridinamine dihydrochloride Crystal form and preparation method thereof.
  • BKM120 Bis(4-morpholinyl)-4-pyrimidinyl]-4-(trifluoromethyl)-2-pyridinamine
  • compound of formula I also known as BKM120 (Buparlisib)
  • BKM120 is New drug for breast cancer developed by Novartis.
  • the drug treatment of metastatic breast cancer is in the phase III clinical and confirmatory I/II clinical stage.
  • BKM120 is a reversible inhibitor of class I phosphoinositide-3 kinase (PI3K).
  • PI3K phosphoinositide-3 kinase
  • Polymorphism is widespread in medicine. Different crystal forms of the same drug have significant differences in solubility, melting point, density, stability, etc., which affect the stability, homogeneity, bioavailability, efficacy and safety of the drug to varying degrees. Therefore, the comprehensive systematic polymorph screening in drug development and the selection of the most suitable crystal form are one of the important research contents that cannot be ignored.
  • Salt formation can improve certain undesirable physicochemical or biopharmaceutical properties of the drug, such as changing the solubility or dissolution of the drug, reducing the wettability, improving the stability, changing the melting point, improving the grinding performance, facilitating the preparation and purification, and improving the permeability. It has been reported that 5-[2,6-bis(4-morpholinyl)-4-pyrimidinyl]-4-(trifluoromethyl)-2-pyridinamine can be stably present as a hydrochloride.
  • Patent CN103140479A discloses crystalline forms of the compounds of formula I and crystalline forms thereof. Specifically, the patent discloses a compound of formula I, a hemihydrate and an anhydride, a monohydrate of the compound of formula I, a monohydrate, an anhydride form A, a form B and a solvate form Sa, a form Sb, a form Sc, Form Sd and form Se.
  • One of the objects of the present invention is to provide a dihydrochloride of 5-[2,6-bis(4-morpholino)-4-pyrimidinyl]-4-(trifluoromethyl)-2-pyridinamine in crystalline form.
  • the salt, the crystalline form of the dihydrochloride salt has good stability and low wettability, and has better solubility than the existing monohydrochloride salt crystal form, and is of great significance for improving the drug effect and reducing the drug load. .
  • the second object of the present invention is to provide a method for preparing the dihydrochloride salt in a crystalline form, and the method for preparing the crystalline form of the dihydrochloride salt of the present invention is simple and low in cost, and is important for optimization and development of the drug in the future. value.
  • the present invention adopts the following technical solutions:
  • This salt is a crystalline salt.
  • the present invention provides a 5-[2,6-bis(4-morpholinyl)-4-pyrimidinyl]-4-(trifluoromethyl)-2-pyridinamine dihalide salt
  • the crystal form of the acid salt designated as Form I, has an X-ray powder diffraction pattern at 25 ° C which is characterized by 2theta values of 24.1 ° ⁇ 0.2 °, 19.1 ° ⁇ 0.2 ° and 19.7 ° ⁇ 0.2 °. peak.
  • the X-ray powder diffraction pattern of Form I provided by the present invention has characteristic peaks at 2theta values of 9.9 ° ⁇ 0.2 °, 8.8 ° ⁇ 0.2 °, and 17.9 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of Form I provided by the present invention has a characteristic peak at 2theta values of 22.2° ⁇ 0.2°, 16.8° ⁇ 0.2°, and 11.6° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form I is also 2theta values of 9.9 ° ⁇ 0.2 °, 8.8 ° ⁇ 0.2 °, 17.9 ° ⁇ 0.2 °, 22.2 ° ⁇ 0.2 °, 16.8 ° There are characteristic peaks at both ⁇ 0.2° and 11.6° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form I is substantially as shown in FIG.
  • the crystalline form I provided by the present invention begins to exhibit an endothermic peak near heating to 72 ° C, 167 ° C, and 214 ° C, and the differential scanning calorimetry chart is substantially as shown in FIG. 2 .
  • the crystalline form I provided by the present invention has a weight loss gradient of about 21% when heated to 222 ° C, and the thermogravimetric analysis chart is substantially as shown in FIG.
  • the molar ratio of the compound of the formula I in the crystalline form I of the compound of the formula I to hydrochloric acid is from 1:1.89 to 2.10. That is, Form I is the dihydrochloride salt of a compound of Formula I.
  • the present invention provides a 5-[2,6-bis(4-morpholinyl)-4-pyrimidinyl]-4-(trifluoromethyl)-2-pyridinamine II
  • the crystal form of the hydrochloride salt was designated as Form II, and the X-ray powder diffraction pattern of Form II had characteristic peaks at 2theta values of 22.9 ° ⁇ 0.2 °, 10.1 ⁇ 0.2 °, and 24.1 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of Form II provided by the present invention has a characteristic peak at a 2theta value of 26.3° ⁇ 0.2°, 20.5° ⁇ 0.2°, and 17.1° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form II provided by the present invention has a characteristic peak at 2theta values of 22.7° ⁇ 0.2°, 18.0° ⁇ 0.2°, and 18.8° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form II provided by the present invention is also 2theta value of 26.3° ⁇ 0.2°, 20.5 ° ⁇ 0.2 °, 17.1 ° ⁇ 0.2 °, 22.7 ° ⁇ 0.2 There are characteristic peaks at °, 18.0 ° ⁇ 0.2 °, and 18.8 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of Form II is substantially as shown in FIG.
  • the Form II is heated to 118 ° C, and an endothermic peak begins to appear near 196 ° C.
  • the differential scanning calorimetry chart is substantially as shown in FIG. 9 .
  • Form II has a weight loss gradient of about 14% when heated to 175 ° C, and the thermogravimetric analysis chart is substantially as shown in FIG.
  • the molar ratio of the compound of the formula I in the dihydrochloride salt form II of the compound of the formula I to hydrochloric acid is from 1: 1.95 to 2.10. That is, Form II is the dihydrochloride salt of a compound of Formula I.
  • Another object of the present invention is to provide a process for the preparation of Form I, which is obtained by the following method:
  • cyclic ether solvent is preferably 1,4 dioxane.
  • the positive solvent is preferably a C1-C4 alcohol, that is, the positive solvent is methanol, ethanol, propanol, butanol, more preferably ethanol.
  • the anti-solvent is preferably an alkyl ether solvent, more preferably methyl tert-butyl ether.
  • a third object of the present invention is to provide a process for the preparation of Form II which is obtained by the following method:
  • a hydrochloride of a compound of the formula I is obtained by stirring and crystallization in a ketone solvent, an ester solvent, a cyclic ether solvent or a mixed solvent system with water; or
  • cyclic ether solvent does not include 1,4 dioxane.
  • the ketone solvent includes, but is not limited to, one or two of acetone and 4-methyl-2-pentanone; and the ester solvent includes, but not limited to, ethyl acetate and isopropyl acetate.
  • the cyclic ether solvent includes, but is not limited to, 2-methyltetrahydrofuran, tetrahydrofuran.
  • the compound of formula (I) in the present invention may be in the form of a solid, semi-solid, wax or oil of the compound of formula (I).
  • a fourth object of the present invention is to provide a pharmaceutical composition comprising an effective amount of 5-[2,6-bis(4-morpholinyl)-4-pyrimidinyl]-4- (Trifluoromethyl)-2-pyridinamine dihydrochloride and a pharmaceutically acceptable adjuvant. That is, the active ingredient in the pharmaceutical composition may be 5-[2,6-bis(4-morpholinyl)-4-pyrimidinyl]-4-(trifluoromethyl)-2-pyridine in any crystalline form.
  • the mixing of one or more of the amine dihydrochloride species may, in particular, be Form I, Form II or a mixture of the two.
  • a therapeutically effective amount of 5-[2,6-bis(4-morpholinyl)-4-pyrimidinyl]-4-(trifluoromethyl)-2-pyridinamine dihydrochloride is generally used.
  • the crystalline salt is mixed or contacted with one or more pharmaceutical excipients to form a pharmaceutical composition or formulation which is prepared in a manner well known in the pharmaceutical art.
  • composition of the present invention can be used for the treatment of metastatic breast cancer.
  • a fifth object of the present invention is to provide a crystalline form of 5-[2,6-bis(4-morpholinyl)-4-pyrimidinyl]-4-(trifluoromethyl)-2-pyridinamine II.
  • hydrochloride for the preparation of a pharmaceutical preparation for the treatment of metastatic breast cancer.
  • a sixth object of the present invention is to provide a crystalline form of 5-[2,6-bis(4-morpholinyl)-4-pyrimidinyl]-4-(trifluoromethyl)-2-pyridinamine II. Use of hydrochloride in the treatment of metastatic breast cancer.
  • the dihydrochloride salt crystal salt provided by the invention has good stability, can well avoid the occurrence of crystal transformation during drug storage and development, thereby avoiding bioavailability and drug effect change.
  • the crystal form provided by the invention has higher solubility, and is of great significance for improving the drug effect and reducing the drug load.
  • the crystal form provided by the invention has low wettability, is not easily affected by high humidity and deliquesces, and is convenient for long-term storage and placement of the medicine.
  • the crystalline crystal provided by the invention has complete morphology, high crystallinity and moderate particle size, and is favorable for filtration drying in the subsequent industrial production process.
  • the crystal form provided by the invention has simple preparation operation and low cost, and is valuable for the optimization and development of the drug in the future.
  • Example 1 is an XRPD pattern of Form I prepared in Example 1;
  • Example 2 is a DSC chart of Form I prepared in Example 1;
  • FIG. 5 is a comparison diagram of the stability XRPD of Form I prepared in Example 2 at a temperature of 4 ° C for 90 days (the XRPD pattern of the former Form I before the top view, and the XRPD diagram of the Form I after the placement) ;
  • FIG. 6 is a comparison diagram of the stability XRPD of Form I prepared in Example 2 under the condition of 25° C./60% relative humidity for 90 days (the XRPD pattern of the former Form I is placed in the above figure, and the figure below shows the crystal form after standing. I XRPD map);
  • Figure 7 is a comparison diagram of the stability XRPD of the Form I prepared in Example 2 under the condition of 40 ° C / 75% relative humidity for 90 days (the XRPD pattern of the former Form I is placed in the above figure, and the figure below shows the crystal form after placement) I XRPD map);
  • Figure 8 is an XRPD pattern of Form II prepared in Example 3.
  • Figure 9 is a DSC chart of Form II prepared in Example 3.
  • Figure 10 is a TGA diagram of Form II prepared in Example 3.
  • Figure 11 is a PLM diagram of Form II prepared in Example 3.
  • Figure 12 is a DVS diagram of Form II prepared in Example 3.
  • Figure 13 is an XRPD pattern of Form II before and after standing for 90 days at 25 ° C / 60% relative humidity (the XRPD pattern of the former Form II is placed in the above figure, and the XRPD pattern of Form II is placed in the figure below);
  • Figure 14 is an XRPD pattern of Form II before and after leaving for 90 days at 40 ° C / 75% relative humidity (the XRPD pattern of the former Form II is placed in the above figure, and the XRPD pattern of Form II is placed in the figure below).
  • test methods are generally carried out according to conventional conditions or conditions recommended by the manufacturer; the 5-[2,6-bis(4-morpholinyl)-4-pyrimidinyl]-4-
  • the starting material of (trifluoromethyl)-2-pyridinamine hydrochloride or the free base is obtained by a commercially available method.
  • the X-ray powder diffraction pattern of the present invention was collected on a Panalytical Empyrean X-ray powder diffractometer at a temperature of about 25 °C.
  • the method parameters of the X-ray powder diffraction described in the present invention are as follows:
  • Scan range: from 3.0 to 40.0 degrees
  • the differential scanning calorimetry (DSC) map of the present invention was acquired on a TA Q2000.
  • the method parameters of the differential scanning calorimetry (DSC) described in the present invention are as follows:
  • thermogravimetric analysis (TGA) map of the present invention was taken on a TA Q5000.
  • the method parameters of the thermogravimetric analysis (TGA) described in the present invention are as follows:
  • the dynamic moisture adsorption (DVS) pattern of the present invention was collected on an Intrinsic dynamic moisture adsorber manufactured by SMS Corporation (Surface Measurement Systems Ltd.).
  • the method parameters of the dynamic moisture adsorber are as follows:
  • Relative humidity range 0%RH-95%RH
  • the X-ray powder diffraction data of Form I obtained in this example is shown in Table 1. Its XRPD diagram is shown in Figure 1. Considering various factors such as d value, low angle, intensity, characteristic line and peak shape integrity, the diffraction peaks at 2theta values of 24.13°, 19.14° and 19.74° are characteristic peaks, and the 2theta values are 9.93° and 8.81°. The diffraction peak at 17.91° is an important peak, and the diffraction peak at 2theta values of 22.15°, 16.75°, and 11.62° is the second most important peak.
  • the DSC of Form I is as shown in Figure 2, and an endothermic peak begins to appear near 72 ° C, 167 ° C, and 214 ° C.
  • the TGA pattern of Form I is shown in Figure 3 and has a weight loss gradient of about 20.86% when heated to 222 °C.
  • the X-ray powder diffraction data of Form I obtained in this example is shown in Table 3. Considering various factors such as d value, low angle, intensity, characteristic line and peak shape integrity, the diffraction peaks at 2theta values of 24.16°, 19.14° and 19.74° are characteristic peaks, and the 2theta values are 9.93° and 8.81°.
  • the diffraction peak at 17.91° is an important peak, and the diffraction peak at 2theta values of 22.16°, 16.75°, and 11.62° is the second most important peak.
  • the X-ray powder diffraction data of Form II obtained in this example is shown in Table 4. Its XRPD diagram is shown in Figure 8. Considering various factors such as d value, low angle, intensity, characteristic line and peak shape integrity, the diffraction peaks at 2theta values of 22.92°, 10.13° and 24.13° are characteristic peaks, and the 2theta values are 26.35° and 20.52°. The diffraction peak at 17.06° is an important peak, and the diffraction peak at 2theta values of 22.69°, 17.99°, and 18.78° is the second most important peak.
  • the DSC pattern of Form II is shown in Figure 9.
  • the endothermic peak begins to appear near 118 ° C and around 196 ° C.
  • the TGA pattern of Form II is shown in Figure 10. When heated to 175 ° C, it has a weight loss gradient of about 14%.
  • Form I is added to a suitable solvent, stirred at room temperature (25 ⁇ 3 ° C) for 6 h, and filtered to give a crystalline solid. See Table 6 for detailed solvents and amounts. The experimental results show that the stirring of Form I under a specific solvent is converted to Form II.
  • Form I was kept at a temperature of 4 ° C, 25 ° C / 60% relative humidity and 40 ° C / 75% relative humidity, leaving the crystal form unchanged for 90 days.
  • the above test results show that Form I has good stability.
  • Form II remained unchanged at 25 ° C / 60% relative humidity and 40 ° C / 75% relative humidity for 90 days.
  • the above test results show that Form II has good stability.
  • the crystal form I prepared in Example 1 of the present invention and the crystal form II obtained in Example 3 were about 10 mg, and the wettability was measured by a dynamic moisture adsorption (DVS) instrument.
  • the experimental results are shown in Table 9.
  • the DVS diagram of the wettability experiment is shown in Figures 4 and 12.
  • the wetting weight gain is not less than 15%
  • Humidity Wet weight gain is less than 15% but not less than 2%
  • wetting gain is less than 2% but not less than 0.2%
  • wetting gain is less than 0.2%
  • Form I prepared in Example 1 of the present invention, Form II obtained in Example 3, and Monohydrochloride Form A in Patent CN103140479 were respectively used at pH 5.0 FeSSIF (simulated intestinal juice in simulated feeding state), pH 6 .5FaSSIF (simulated artificial intestinal juice in the fasting state) was prepared as a saturated solution, and the content of the sample in the saturated solution was determined by high performance liquid chromatography after 4 hours and 24 hours.
  • the experimental results are shown in Table 10.

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Abstract

L'invention concerne un sel en cristaux de dichlorhydrate de 5- [2,6-di(4-morpholinyl)-4-pyrimidinyl]-4-(trifluorométhyl)-2-pyridinamine et son procédé de préparation, et, plus particulièrement, du dichlorhydrate ayant une forme cristalline I ou une forme cristalline II. Les formes cristallines ont une stabilité favorable, une plus grande solubilité et une hygroscopie plus faible, possédant une valeur significative dans le développement de médicaments futurs et leur optimisation.
PCT/CN2016/095944 2014-11-24 2016-08-19 Forme cristalline de dichlorhydrate de 5-[2,6-di(4-morpholinyl)-4-pyrimidinyl]-4-(trifluorométhyl)-2-pyridinamine et son procédé de préparation WO2017028802A1 (fr)

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CN201510511102.4A CN105085476B (zh) 2014-11-24 2015-08-19 5‑[2,6‑二(4‑吗啉基)‑4‑嘧啶基]‑4‑(三氟甲基)‑2‑吡啶胺二盐酸盐的晶型及其制备方法
CN201510511102.4 2015-08-19

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111454318A (zh) * 2019-01-20 2020-07-28 浙江易众化工有限公司 抗抑郁药物sage-217的晶型及其制备方法

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Publication number Priority date Publication date Assignee Title
CN105085476B (zh) * 2014-11-24 2018-03-09 苏州晶云药物科技有限公司 5‑[2,6‑二(4‑吗啉基)‑4‑嘧啶基]‑4‑(三氟甲基)‑2‑吡啶胺二盐酸盐的晶型及其制备方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007084786A1 (fr) * 2006-01-20 2007-07-26 Novartis Ag Derives de pyrimidine utilises en tant qu’inhibiteurs de kinase pi-3
WO2012044727A2 (fr) * 2010-10-01 2012-04-05 Novartis Ag Procédé de fabrication de dérivés de pyrimidine
WO2014064058A1 (fr) * 2012-10-23 2014-05-01 Novartis Ag Procédé amélioré pour la fabrication de 5-(2,6-di-4-morpholinyl-4-pyrimidinyl)-4-trifluorométhylpyridin-2-amine
CN105085476A (zh) * 2014-11-24 2015-11-25 苏州晶云药物科技有限公司 5-[2,6-二(4-吗啉基)-4-嘧啶基]-4-(三氟甲基)-2-吡啶胺二盐酸盐的晶型及其制备方法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007084786A1 (fr) * 2006-01-20 2007-07-26 Novartis Ag Derives de pyrimidine utilises en tant qu’inhibiteurs de kinase pi-3
WO2012044727A2 (fr) * 2010-10-01 2012-04-05 Novartis Ag Procédé de fabrication de dérivés de pyrimidine
WO2014064058A1 (fr) * 2012-10-23 2014-05-01 Novartis Ag Procédé amélioré pour la fabrication de 5-(2,6-di-4-morpholinyl-4-pyrimidinyl)-4-trifluorométhylpyridin-2-amine
CN105085476A (zh) * 2014-11-24 2015-11-25 苏州晶云药物科技有限公司 5-[2,6-二(4-吗啉基)-4-嘧啶基]-4-(三氟甲基)-2-吡啶胺二盐酸盐的晶型及其制备方法

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111454318A (zh) * 2019-01-20 2020-07-28 浙江易众化工有限公司 抗抑郁药物sage-217的晶型及其制备方法

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