CN114605416A - Preparation method of acatinib crystal form I - Google Patents
Preparation method of acatinib crystal form I Download PDFInfo
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- CN114605416A CN114605416A CN202011443766.9A CN202011443766A CN114605416A CN 114605416 A CN114605416 A CN 114605416A CN 202011443766 A CN202011443766 A CN 202011443766A CN 114605416 A CN114605416 A CN 114605416A
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- acatinib
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
- C07C255/02—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms of an acyclic and saturated carbon skeleton
- C07C255/03—Mononitriles
-
- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a preparation method of an acatinib crystal form I. Specifically, the invention provides a preparation method of crystalline form I of acatinib (formula I), which comprises the following steps: (1) providing a first mixed system; wherein the first mixing system is (i) a mixing system of the acatinib acetonitrile compound in the first solvent or (ii) a mixing system of the raw material acatinib in the first solvent and acetonitrile; (2) treating the first mixed system of step (1) to obtain a second mixed system containing the acatinib crystal form I; and (3) separating the second mixed system obtained in step (2), thereby obtaining the crystalline form I of acatinib. The preparation method provided by the invention has high crystallization yield which can reach more than 90%; good impurity removal effect, high product purity of more than 99.8 percent, simple and convenient operation, easy preparation and suitability for industrial mass production.
Description
Technical Field
The invention relates to the field of pharmaceutical chemistry, and in particular relates to a preparation method of an acatinib crystal form I.
Background
Acatinib (acarabutinib, trade name: calsequence) is a new drug approved by FDA in 2017 at 10 months from the drug assikang for the treatment of Mantle Cell Lymphoma (MCL). The acatinib is a second-generation BTK inhibitor, and compared with the first-generation BTK inhibitor, namely Ibrutinib (Ibrutinib), the drug selectivity is higher, and the side effect is lower.
The structural formula of acatinib is shown as follows:
US9796721 in the US hesperidin patent list discloses 8 crystalline forms of acatinib free base and crystalline forms of a plurality of salts of acatinib. The crystal form I in the 8 free base crystal forms is a medicinal crystal form on the market, has good chemical and thermodynamic stability, low hygroscopicity, higher dissolution rate, excellent processability in a pharmaceutical preparation and the like; the crystal form II is a trihydrate, the fluidity is poor, the water content is different under different conditions, and the highest water content can reach 10%; forms III-VIII are all metastable forms. Two methods of preparing form I are reported herein, one being the cooling crystallization method: dissolving amorphous acatinib in a solvent, heating to 60 ℃ at the speed of 5 ℃/hour, preserving heat for 1 hour, cooling to 5 ℃ at the same speed, and separating a solid to obtain a crystal form I; secondly, a pulping method: amorphous acatinib is suspended in a solvent for 3 days and the solid is isolated to give form I, which is too time consuming. It is also reported that form I is difficult to prepare, difficult to precipitate in most solvents, and can only be prepared from a mixture of certain solvents (such as acetone) and n-heptane or ethanol, and only ethanol can be used as a solvent for larger scale preparation, such as 60g scale preparation.
In view of the above, there is a great need in the art to develop a novel preparation method that overcomes the above-mentioned deficiencies of the existing methods for preparing crystalline form I of acatinib.
Disclosure of Invention
The invention aims to provide a novel preparation method of an acatinib crystal form I, which is simple to operate, low in cost and easy for industrial mass production.
In a first aspect of the invention, a preparation method of an acatinib crystal form I is provided, wherein the acatinib is shown as a formula I,
and, the preparation method comprises the steps of:
(1) providing a first mixed system;
wherein the first mixing system is a mixing system of (i) an acatinib acetonitrile compound in a first solvent or (ii) a mixing system of raw material acatinib in the first solvent and acetonitrile;
(2) processing the first mixed system in the step (1) to obtain a second mixed system containing the acatinib crystal form I; and
(3) separating the second mixed system obtained in step (2) to obtain the crystalline form I of acatinib.
In another preferred embodiment, the step (3) further comprises the step of drying the solid separated from the second mixed system.
In another preferred embodiment, the drying temperature is 40-60 ℃.
In another preferred embodiment, the first solvent is selected from the group consisting of: an alcohol solvent, a ketone solvent, an ester solvent, an ether solvent, or a combination thereof.
In another preferred embodiment, the alcohol solvent is an aliphatic alcohol solvent having 1 to 6 carbon atoms, preferably, comprising: methanol, ethanol, isopropanol, n-propanol, n-butanol, or a combination thereof.
In another preferred embodiment, the ketone solvent includes: acetone, methyl ethyl ketone, butanone, MIBK, or a combination thereof; preferably, it is selected from the group consisting of: acetone, methyl ethyl ketone, methyl isobutyl ketone, or a combination thereof.
In another preferred embodiment, the ester solvent includes: ethyl acetate, isopropyl acetate, ethyl formate, methyl acetate, or a combination thereof; preferably, it is selected from the group consisting of: methyl formate, ethyl acetate, isopropyl acetate, or a combination thereof.
In another preferred embodiment, the ethereal solvent includes: tetrahydrofuran, methyl tert-butyl ether, isopropyl ether, anisole, 1, 4-dioxane, or a combination thereof; preferably, it is selected from the group consisting of: tetrahydrofuran, methyl tert-butyl ether, or combinations thereof.
In another preferred embodiment, the first solvent is selected from the group consisting of: methanol, ethanol, isopropanol, n-propanol, n-butanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl formate, ethyl acetate, isopropyl acetate, tetrahydrofuran, methyl tert-butyl ether, or a combination thereof.
In another preferred embodiment, in the first mixed system, the mass-to-volume (g: ml) ratio of the accatinib acetonitrile compound or the raw material accatinib to the first solvent is 1 (1-20); preferably, the ratio is 1 (5-10); more preferably 1 (5-6).
In another preferred embodiment, in the first mixed system, the mass-to-volume (g: ml) ratio of the raw material acatinib to acetonitrile is 1 (0.1-25); preferably, the ratio is 1 (0.5-5); more preferably, 1: 1. + -. 0.5; most preferably 1: 1. + -. 0.1.
In another preferred embodiment, the first mixing system is (i) a mixing system of an acatinib acetonitrile compound in a first solvent, and
in the first mixed system, the mass-volume (g: ml) ratio of the acatinib acetonitrile compound to the first solvent is 1 (1-20); preferably, the ratio is 1 (5-10); more preferably 1 (5-6).
In another preferred embodiment, the first mixing system is (ii) a mixing system of raw material acatinib in a first solvent and acetonitrile, and
in the first mixed system, the mass volume (g: ml) ratio of the raw material acatinib to the first solvent is 1 (1-20); preferably, the ratio is 1 (5-10); more preferably 1 (5-6); and/or in the first mixed system, the mass volume (g: ml) ratio of the raw material acatinib to the acetonitrile is 1 (0.5-25); preferably, the ratio is 1 (0.1-5); more preferably, 1: 1. + -. 0.5; most preferably 1: 1. + -. 0.1.
In another preferred example, in the step (2), the processing includes the steps of: heating the first mixed system to T1(ii) temperature; and cooling to T2(ii) temperature; or the processing steps comprise: at T3Agitating the first at temperatureAnd (4) mixing the components.
In another preferred example, in the step (2), the processing includes the steps of: heating the first mixed system to T1(ii) temperature; and cooling to T2And (3) temperature.
In another preferred embodiment, the cooling is carried out to T2Before the temperature, the first mixed system is dissolved and cleared.
In another preferred embodiment, at T1At temperature, the first mixed system dissolves out.
In another preferred embodiment, T2≤T1。
In another preferred embodiment, T140-80 deg.C (preferably, T)150-60 ℃), and/or T2＝5～25℃。
In another preferred embodiment, the first mixed system is heated to T1After the temperature also includes optionally at T1And stirring at the temperature for t1 time.
In another preferred embodiment, the cooling is carried out to T2After the temperature also includes optionally at T2And stirring at the temperature for t2 time.
In another preferred embodiment, t1 is 0.5-5 hours, preferably t1 is 1-3 hours.
In another preferred embodiment, t2 is 0.5-5 hours, preferably t2 is 1-3 hours.
In another preferred embodiment, the preparation method comprises the following steps:
(1) providing a first mixed system;
wherein the first mixing system is a mixing system of (i) an acatinib acetonitrile compound in a first solvent or (ii) a mixing system of raw material acatinib in the first solvent and acetonitrile;
(2) heating the first mixed system of the step (1) to T1At temperature and optionally at T1Stirring at the temperature for t1 time; and cooling to T2At temperature and optionally at T2Stirring for t2 time at temperature to obtain a second mixed system containing the acatinib crystal form I; and
(3) separating the second mixed system obtained in step (2) to obtain the crystalline form I of acatinib.
In another preferred embodiment, the cooling is carried out to T2Before the temperature, the first mixed system is dissolved.
In another preferred example, in the step (2), the processing includes the steps of: at T3Stirring the first mixed system at a temperature.
In another preferred embodiment, T35-80 deg.C (preferably, T)3Preferably, T is 40-80 deg.C3＝50～60℃)。
In another preferred embodiment, at T3The first mixed system includes a solid at temperature.
In another preferred embodiment, at T3The stirring time of stirring the first mixed system at the temperature was t 3.
In another preferred example, t3 is 0.5-8 hours.
In another preferred example, the processing further comprises the steps of: optionally cooling, preferably to 5-25 deg.C.
In another preferred embodiment, the preparation method comprises the following steps:
(1) providing a first mixed system;
wherein the first mixing system is a mixing system of (i) an acatinib acetonitrile compound in a first solvent or (ii) a mixing system of raw material acatinib in the first solvent and acetonitrile;
(2) at T3Stirring the first mixed system at the temperature for t3 time; and
(3) separating the second mixed system obtained in step (2) to obtain the crystalline form I of acatinib.
In another preferred embodiment, in the acatinib acetonitrile compound, the ratio of acatinib molecules to acetonitrile molecules is about 1: 1.
in another preferred embodiment, the acatinib acetonitrile compound is an acatinib acetonitrile compound crystal form.
In another preferred embodiment, the acatinib acetonitrile compound has an X-ray powder diffraction having characteristic peaks at diffraction angles of 8.2 ° ± 0.2 °, 10.6 ° ± 0.2 °, 11.0 ° ± 0.2 °, 22.7 ° ± 0.2 °, and 25.0 ° ± 0.2 ° at the 2 θ value.
In another preferred embodiment, the acatinib acetonitrile compound has an X-ray powder diffraction having characteristic peaks at diffraction angles, under conditions of Cu-ka radiation, of 8.2 ° ± 0.2 °, 10.6 ° ± 0.2 °, 11.0 ° ± 0.2 °, 22.7 ° ± 0.2 °, and 25.0 ° ± 0.2 ° at the 2 θ value.
In another preferred embodiment, the acatinib acetonitrile compound further has an X-ray powder diffraction pattern with characteristic peaks at one or more of 2 Θ values of 6.2 ° ± 0.2 °, 12.7 ° ± 0.2 °, 13.7 ° ± 0.2 °, 14.2 ° ± 0.2 °, 16.3 ° ± 0.2 °, 17.2 ° ± 0.2 °,19.1 ° ± 0.2 °, 19.4 ° ± 0.2 °, 20.4 ° ± 0.2 °, 21.4 ° ± 0.2 °, 23.1 ° ± 0.2 °, 26.1 ° ± 0.2 °, 28.2 ° ± 0.2 °, 29.8 ° ± 0.2 ° under conditions of Cu-ka radiation.
In another preferred embodiment, the acatinib acetonitrile compound has an X-ray powder diffraction pattern with at least one or more (preferably at least 5, more preferably at least 10, more preferably at least 15) peaks at 2-theta values of 6.2 ° ± 0.2 °, 8.2 ° ± 0.2 °, 10.6 ° ± 0.2 °, 11.0 ° ± 0.2 °, 12.7 ° ± 0.2 °, 13.7 ° ± 0.2 °, 14.2 ° ± 0.2 °, 16.3 ° ± 0.2 °, 17.2 ° ± 0.2 °,19.1 ° ± 0.2 °, 19.4 ° ± 0.2 °, 20.4 ° ± 0.2 °, 21.4 ° ± 0.2 °, 22.7 ° ± 0.2 °, 23.1 ° ± 0.2 °, 25.0 ° ± 0.2 °, 26.1 ° ± 0.2 °, 28.2 ° ± 0.2 °, 29.8 ° ± 0.2 ° under conditions of Cu-ka radiation.
In another preferred embodiment, the acatinib acetonitrile compound has an X-ray powder diffraction (PXRD) pattern substantially as shown in fig. 1 under conditions of Cu-ka radiation.
In another preferred embodiment, the Differential Scanning Calorimetry (DSC) of the acatinib acetonitrile compound has an initial (onset) peak at 63.4 + -2 deg.C, 127.8 + -2 deg.C.
In another preferred embodiment, the Differential Scanning Calorimetry (DSC) of the acatinib acetonitrile compound is substantially as shown in figure 2.
In another preferred embodiment, the acatinib acetonitrile compound has an infrared absorption spectrum with absorption peaks at 3480 + -10, 3323 + -10, 3117 + -10, 2974 + -10, 2880 + -10, 2249 + -10, 2213 + -10, 1672 + -10, 1660 + -10, 1629 + -10, 1609 + -10, 1576 + -10, 1521 + -10, 1498 + -10, 1435 + -10, 1416 + -10, 1314 + -10, 784 + -10, 756 + -10 and 734 + -10 cm-1.
In another preferred embodiment, the acatinib acetonitrile compound has an infrared absorption (IR) spectrum substantially as shown in fig. 4.
In another preferred embodiment, the acatinib acetonitrile compound has a thermogravimetric analysis (TGA) with a weight loss of 2.5 ± 0.2% in the range of 0 to 105 ± 3 ℃ and/or a weight loss of 4.5 ± 0.2% in the range of 105 ± 3 ℃ to 155 ± 3 ℃.
In another preferred embodiment, the thermogravimetric analysis (TGA) of the acatinib acetonitrile compound is substantially as shown in figure 5.
In another preferred embodiment, the acatinib acetonitrile compound is prepared by the following method:
i. providing a third mixed system; wherein the third mixed system is a mixed system of raw material acatinib in acetonitrile;
ii.T4(ii) stirring the third mixed system of step (i) at temperature for t4 time to obtain a fourth mixed system containing the acatinib acetonitrile compound;
wherein, T4At 5-80 ℃ and t4 for 0.5-8 hours; and
(iii) isolating the fourth mixed system obtained in step (ii) to obtain the acatinib acetonitrile compound.
In another preferred example, in the third mixed system, the mass volume ratio (g: ml) of the raw material alcatinib to acetonitrile is 1: 3-50; preferably 1:5 to 10.
In another preferred embodiment, in step (ii), T4＝50～60℃。
In another preferred example, in the step (ii), t4 is 1-3 hours.
In another preferred embodiment, in step (ii), T4(ii) after stirring the third mixed system of step (i) at the temperature for t4 time, further comprising the steps of: cooling to T5At a temperature T5Optionally stirred at temperature for t5 time.
In another preferred embodiment, T2＝5～25℃
In another preferred embodiment, t5 is 0.5 to 5 hours, preferably t5 is 1 to 3 hours.
In another preferred example, the starting material acatinib is acatinib free base.
In another preferred example, the raw material acatinib comprises: amorphous or crystalline form III of acatinib.
In another preferred embodiment, the acatinib form III has an X-ray powder diffraction pattern with at least one more peak at 2 Θ values of 6.2 ° ± 0.2 °, 7.5 ° ± 0.2 °, 8.3 ° ± 0.2 °, 10.4 ° ± 0.2 °, 11.3 ° ± 0.2 °, 12.5 ° ± 0.2 °, 13.9 ° ± 0.2 °, 14.5 ° ± 0.2 °, 15.0 ° ± 0.2 °, 16.6 ° ± 0.2 °, 17.7 ° ± 0.2 °, 18.9 ° ± 0.2 °, 20.5 ° ± 0.2 °, 20.8 ° ± 0.2 °, 21.6 ° ± 0.2 °, 23.0 ° ± 0.2 °, 24.2 ° ± 0.2 °, 25.0 ° ± 0.2 °, 25.5 ° ± 0.2.8 ° ± 0.2 °, 21.6 ° ± 0.2 °, 23.0 ° ± 0.2 °, 24.2 ° ± 0.2 °, 25.0 °, 25.5 ° ± 0.2 ° or more preferably at least one more peak at 2 ° ± 2 ° (preferably at least 10 ° ± 2 ° ± 0.2 ° ± 2 ° ± 0.2 °.
In another preferred embodiment, the acatinib form III has an X-ray powder diffraction pattern as shown in fig. 11.
In another preferred embodiment, the amorphous acatinib has an X-ray powder diffraction pattern as shown in fig. 12.
In another preferred embodiment, the acatinib form I has an X-ray powder diffractogram with at least one of the features of at least one of (6.3 ° ± 0.2 °, 8.6 ° ± 0.2 °, 10.5 ° ± 0.2 °, 10.9 ° ± 0.2 °, 11.5 ° ± 0.2 °, 12.7 ° ± 0.2 °, 13.4 ° ± 0.2 °, 14.2 ° ± 0.2 °, 14.8 ° ± 0.2 °, 15.6 ° ± 0.2 °, 16.0 ° ± 0.2 °, 17.2 ° ± 0.2 °, 18.1 ° ± 0.2 °, 19.0 ° ± 0.2 °, 19.4 ° ± 0.2 °, 19.7 ° ± 0.2 °, 20.6 ° ± 0.2 °, 21.1 ° ± 0.2 °, 21.5 ° ± 0.2 °, 21.9 ° ± 0.2 °, 19.4 ° ± 0.2 °, 19.7 ° ± 0.2 °, 20.6 ° ± 0.2 °, 21.1 ° ± 0.2 °, 26 ° ± 0.2 °, 25 ° ± 0.2 ° or more preferably at 2 ° ± 0.2 ° ± 0 ° ± 0.2 ° (preferably at the 2 ° ± 0.2 ° ± 0 ° ± 0.2 ° ± 25 ° ± 0.2 ° ± 0 °.
In another preferred embodiment, the acatinib form I has an X-ray powder diffraction pattern as shown in fig. 6.
In another preferred embodiment, the Differential Scanning Calorimetry (DSC) of said form I of acatinib has an initial (onset) peak of 192.6 ± 2 ℃.
In another preferred embodiment, the DSC spectrum of said acatinib form I is substantially as shown in figure 7.
In another preferred embodiment, the acatinib form I has an H NMR spectrum substantially as shown in fig. 8.
In another preferred embodiment, the form I of acatinib has an IR spectrum substantially as shown in fig. 9.
In another preferred embodiment, the TGA profile of crystalline form I of acatinib is substantially as shown in figure 10.
In a second aspect of the invention, an acatinib acetonitrile compound is provided.
In another preferred embodiment, in the acatinib acetonitrile compound, the ratio of acatinib molecules to acetonitrile molecules is about 1: 1.
in another preferred embodiment, the acatinib acetonitrile compound is an acatinib acetonitrile compound crystal form.
In another preferred embodiment, the acatinib acetonitrile compound has an X-ray powder diffraction having characteristic peaks at diffraction angles of 8.2 ° ± 0.2 °, 10.6 ° ± 0.2 °, 11.0 ° ± 0.2 °, 22.7 ° ± 0.2 °, and 25.0 ° ± 0.2 ° at the 2 θ value.
In another preferred embodiment, the acatinib acetonitrile compound has an X-ray powder diffraction having characteristic peaks at diffraction angles, under conditions of Cu-ka radiation, of 8.2 ° ± 0.2 °, 10.6 ° ± 0.2 °, 11.0 ° ± 0.2 °, 22.7 ° ± 0.2 °, and 25.0 ° ± 0.2 ° at the 2 θ value.
In another preferred embodiment, the acatinib acetonitrile compound further has an X-ray powder diffraction pattern with characteristic peaks at one or more of 2 Θ values of 6.2 ° ± 0.2 °, 12.7 ° ± 0.2 °, 13.7 ° ± 0.2 °, 14.2 ° ± 0.2 °, 16.3 ° ± 0.2 °, 17.2 ° ± 0.2 °,19.1 ° ± 0.2 °, 19.4 ° ± 0.2 °, 20.4 ° ± 0.2 °, 21.4 ° ± 0.2 °, 23.1 ° ± 0.2 °, 26.1 ° ± 0.2 °, 28.2 ° ± 0.2 °, 29.8 ° ± 0.2 ° under conditions of Cu-ka radiation.
In another preferred embodiment, the acatinib acetonitrile compound has an X-ray powder diffraction pattern with at least one or more (preferably at least 5, more preferably at least 10, more preferably at least 15) peaks at 2-theta values of 6.2 ° ± 0.2 °, 8.2 ° ± 0.2 °, 10.6 ° ± 0.2 °, 11.0 ° ± 0.2 °, 12.7 ° ± 0.2 °, 13.7 ° ± 0.2 °, 14.2 ° ± 0.2 °, 16.3 ° ± 0.2 °, 17.2 ° ± 0.2 °,19.1 ° ± 0.2 °, 19.4 ° ± 0.2 °, 20.4 ° ± 0.2 °, 21.4 ° ± 0.2 °, 22.7 ° ± 0.2 °, 23.1 ° ± 0.2 °, 25.0 ° ± 0.2 °, 26.1 ° ± 0.2 °, 28.2 ° ± 0.2 °, 29.8 ° ± 0.2 ° under conditions of Cu-ka radiation.
In another preferred embodiment, the acatinib acetonitrile compound has an X-ray powder diffraction (PXRD) pattern substantially as shown in fig. 1 under conditions of Cu-ka radiation.
In another preferred embodiment, the Differential Scanning Calorimetry (DSC) of the acatinib acetonitrile compound has an initial (onset) peak at 63.4 + -2 deg.C, 127.8 + -2 deg.C.
In another preferred embodiment, the Differential Scanning Calorimetry (DSC) of the acatinib acetonitrile compound is substantially as shown in figure 2.
In another preferred embodiment, the acatinib acetonitrile compound has an infrared absorption spectrum with absorption peaks at 3480 + -10, 3323 + -10, 3117 + -10, 2974 + -10, 2880 + -10, 2249 + -10, 2213 + -10, 1672 + -10, 1660 + -10, 1629 + -10, 1609 + -10, 1576 + -10, 1521 + -10, 1498 + -10, 1435 + -10, 1416 + -10, 1314 + -10, 784 + -10, 756 + -10 and 734 + -10 cm-1.
In another preferred embodiment, the acatinib acetonitrile compound has an infrared absorption (IR) spectrum substantially as shown in fig. 4.
In another preferred embodiment, the acatinib acetonitrile compound has a thermogravimetric analysis (TGA) with a weight loss of 2.5 ± 0.2% in the range of 0 to 105 ± 3 ℃ and/or a weight loss of 4.5 ± 0.2% in the range of 105 ± 3 ℃ to 155 ± 3 ℃.
In another preferred embodiment, the thermogravimetric analysis (TGA) of the acatinib acetonitrile compound is substantially as shown in figure 5.
In a third aspect of the present invention, there is provided a process for the preparation of the acatinib acetonitrile compound according to the second aspect, comprising the steps of:
i. providing a third mixed system; wherein the third mixed system is a mixed system of raw material acatinib in acetonitrile;
ii.T4(ii) stirring the third mixed system of step (i) at temperature for t4 time to obtain a fourth mixed system containing the acatinib acetonitrile compound;
wherein, T4At 5-80 ℃ and t4 for 0.5-8 hours; and
(iii) isolating the fourth mixed system obtained in step (ii) to obtain the acatinib acetonitrile compound.
In another preferred embodiment, in the third mixed system, the mass-to-volume ratio (g: ml) of the raw material acatinib to acetonitrile is 1: 3-50; preferably 1:5 to 10.
In another preferred embodiment, in step (ii), T4＝50～60℃。
In another preferred example, in the step (ii), t4 is 1-3 hours.
In another preferred embodiment, in step (ii), T4(ii) after stirring the third mixed system of step (i) at the temperature for t4 time, further comprising the steps of: cooling to T5At a temperature T5Optionally stirred at temperature for t5 time.
In another preferred embodiment, T2＝5～25℃
In another preferred embodiment, t5 is 0.5-5 hours, preferably t5 is 1-3 hours.
In another preferred example, the starting material acatinib is acatinib free base.
In another preferred example, the raw material acatinib comprises: amorphous or crystalline form III of acatinib.
In another preferred embodiment, the acatinib form III has an X-ray powder diffraction pattern with at least one more peak at 2 Θ values of 6.2 ° ± 0.2 °, 7.5 ° ± 0.2 °, 8.3 ° ± 0.2 °, 10.4 ° ± 0.2 °, 11.3 ° ± 0.2 °, 12.5 ° ± 0.2 °, 13.9 ° ± 0.2 °, 14.5 ° ± 0.2 °, 15.0 ° ± 0.2 °, 16.6 ° ± 0.2 °, 17.7 ° ± 0.2 °, 18.9 ° ± 0.2 °, 20.5 ° ± 0.2 °, 20.8 ° ± 0.2 °, 21.6 ° ± 0.2 °, 23.0 ° ± 0.2 °, 24.2 ° ± 0.2 °, 25.0 ° ± 0.2 °, 25.5 ° ± 0.2.8 ° ± 0.2 °, 21.6 ° ± 0.2 °, 23.0 ° ± 0.2 °, 24.2 ° ± 0.2 °, 25.0 °, 25.5 ° ± 0.2 ° or more preferably at least one more peak at 2 ° ± 2 ° (preferably at least 10 ° ± 2 ° ± 0.2 ° ± 2 ° ± 0.2 °.
In another preferred embodiment, the acatinib form III has an X-ray powder diffraction pattern as shown in fig. 11.
In another preferred embodiment, the amorphous acatinib has an X-ray powder diffraction pattern as shown in fig. 12.
In another preferred embodiment, the acatinib form I has an X-ray powder diffractogram with at least one of the features of at least one of (6.3 ° ± 0.2 °, 8.6 ° ± 0.2 °, 10.5 ° ± 0.2 °, 10.9 ° ± 0.2 °, 11.5 ° ± 0.2 °, 12.7 ° ± 0.2 °, 13.4 ° ± 0.2 °, 14.2 ° ± 0.2 °, 14.8 ° ± 0.2 °, 15.6 ° ± 0.2 °, 16.0 ° ± 0.2 °, 17.2 ° ± 0.2 °, 18.1 ° ± 0.2 °, 19.0 ° ± 0.2 °, 19.4 ° ± 0.2 °, 19.7 ° ± 0.2 °, 20.6 ° ± 0.2 °, 21.1 ° ± 0.2 °, 21.5 ° ± 0.2 °, 21.9 ° ± 0.2 °, 19.4 ° ± 0.2 °, 19.7 ° ± 0.2 °, 20.6 ° ± 0.2 °, 21.1 ° ± 0.2 °, 26 ° ± 0.2 °, 25 ° ± 0.2 ° or more preferably at 2 ° ± 0.2 ° ± 0 ° ± 0.2 ° (preferably at the 2 ° ± 0.2 ° ± 0 ° ± 0.2 ° ± 25 ° ± 0.2 ° ± 0 °.
In another preferred embodiment, the acatinib form I has an X-ray powder diffraction pattern as shown in fig. 6.
In another preferred embodiment, the Differential Scanning Calorimetry (DSC) profile of form I of the acatinib has an initial (onset) peak of 192.6 ± 2 ℃.
In another preferred embodiment, the DSC spectrum of said acatinib form I is substantially as shown in figure 7.
In another preferred embodiment, the alcatinib form I has an H NMR spectrum substantially as shown in fig. 8.
In another preferred embodiment, the form I of acatinib has an IR spectrum substantially as shown in fig. 9.
In another preferred embodiment, the TGA profile of crystalline form I of acatinib is substantially as shown in figure 10.
In a fourth aspect of the invention there is provided the use of an acartinib acetonitrile compound according to the second aspect for the preparation of form I of acartinib; wherein the crystalline form I of acatinib is as defined in the first aspect.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.
Drawings
FIG. 1 shows a PXRD pattern for a typical example of an acatinib acetonitrile compound of the present invention;
FIG. 2 shows a DSC spectrum of an acatinib acetonitrile compound of the present invention;
FIG. 3 shows a HNMR map of an accatinib acetonitrile compound of the present invention;
FIG. 4 shows an IR spectrum of an acatinib acetonitrile compound of the invention;
FIG. 5 shows a TGA profile of an acatinib acetonitrile compound of the present invention;
FIG. 6 shows a PXRD pattern of form I obtained in an example of the present invention;
FIG. 7 shows a DSC profile of form I obtained in an example of the present invention;
FIG. 8 shows HNMR spectra of form I obtained in examples of the present invention;
FIG. 9 shows an IR spectrum of crystalline form I obtained by an example of the present invention;
figure 10 shows a TGA profile of crystalline form I obtained by an example of the present invention.
Figure 11 shows an X-ray powder diffraction pattern of crystalline form III of acatinib used in the examples of the present invention.
FIG. 12 shows the X-ray powder diffraction pattern of the amorphous form of acatinib used in the examples of the present invention.
Detailed Description
The inventor has long and deeply studied and unexpectedly found that the crystal form I of the accatinib can be easily obtained without additionally adding the crystal form I of the accatinib as a seed crystal by adding acetonitrile into a system for preparing the crystal form I of the accatinib or using an accatinib acetonitrile compound as a raw material. The crystal form I formed in the system is easy to separate, and the obtained crystal form I has high purity, low single impurity content in the formula A and high yield; furthermore, the process is less time consuming. Based on this, the inventors have completed the present invention.
Term(s) for
Herein, unless otherwise specified, "form I" or "acatinib form I" may be used interchangeably to refer to the acatinib free base form I disclosed in US 9796721.
Herein, unless otherwise specified, "form III" or "acatinib form III" may be used interchangeably to refer to the acatinib free base form III disclosed in US 9796721.
Herein, unless otherwise specified, each abbreviation has the conventional meaning well known to those skilled in the art, for example, MIBK means methyl isobutyl ketone, TGA means thermogravimetric analysis, PXRD means X-ray powder diffraction, DSC means differential scanning calorimetry, and IR means infrared spectroscopy.
Preparation method of acatinib crystal form I
Although processes for the preparation of form I of acatinib have been provided in the prior art (e.g. US9796721), the inventors have found, when trying to prepare form I by processes of the prior art (e.g. cooling crystallization), that either a sticky solid is obtained (difficult to separate) or no solid can be precipitated when preparing form I of acatinib by adjusting the ratio of acetone or dichloromethane to n-heptane; when ethanol is used as a solvent, if crystal form I seed crystals are not added, a solid cannot be separated out, and the solid is obtained after the crystal form I is added, but the purity is not ideal, the content of impurity A is high, and the purification effect is poor. Impurity a has the following structural formula:
in order to solve the defects of preparing the acatinib crystal form I in the prior art, the invention provides a novel preparation method of the crystal form I.
Typically, the preparation method of the crystalline form I of acatinib provided by the invention comprises the following steps:
(1) providing a first mixed system;
wherein the first mixing system is a mixing system of (i) an acatinib acetonitrile compound in a first solvent or (ii) a mixing system of raw material acatinib in the first solvent and acetonitrile;
(2) treating the first mixed system of step (1) to obtain a second mixed system containing the acatinib crystal form I; and
(3) separating the second mixed system obtained in step (2) to obtain the crystalline form I of acatinib.
In a preferred embodiment, the steps are as previously defined.
In a specific embodiment, the preparation method of the acatinib crystalline form I provided by the invention comprises the following steps:
1) suspending an acatinib acetonitrile compound in a first solvent to obtain a first mixed system; (ii) a
2) Heating the first mixed system to 40-80 ℃, and then cooling to 5-25 ℃ to obtain a second mixed system; and
3) separating to obtain crystal form I.
Preferably, the first solvent is selected from an alcohol (aliphatic alcohol having 1 to 6 carbon atoms) solvent, a ketone (acetone, methyl ethyl ketone, MIBK) solvent, an ester (ethyl acetate, isopropyl acetate, ethyl formate, methyl acetate) solvent, an ether (tetrahydrofuran, methyl tert-butyl ether, isopropyl ether, anisole, 1, 4-dioxane) solvent, or a mixture of any two or more thereof. Wherein the alcohol solvent is preferably methanol, ethanol, isopropanol, n-propanol or n-butanol; the ketone solvent is preferably acetone, methyl ethyl ketone or methyl isobutyl ketone; the ester solvent is preferably methyl formate, ethyl acetate or isopropyl acetate; the ether solvent is preferably tetrahydrofuran or methyl tert-butyl ether.
In another embodiment, the present invention provides a process for preparing crystalline form I of acatinib, comprising the steps of:
1) adding raw material acatinib such as amorphous form or crystal form III thereof into a first solvent, and adding acetonitrile with the volume of 0.1-25 to obtain a first mixed system;
2) stirring the first mixed system at 5-80 ℃ for 0.5-8 hours, and optionally cooling to 5-25 ℃ to obtain a second mixed system;
3) and separating to obtain the acatinib crystal form I.
Preferably, the first solvent is selected from an alcohol (aliphatic alcohol having 1 to 6 carbon atoms) solvent, a ketone (acetone, methyl ethyl ketone, MIBK) solvent, an ester (ethyl acetate, isopropyl acetate, ethyl formate, methyl acetate) solvent, an ether (tetrahydrofuran, methyl tert-butyl ether, isopropyl ether, anisole, 1, 4-dioxane) solvent, or a mixture of any two or more thereof. Wherein the alcohol solvent is preferably methanol, ethanol, isopropanol, n-propanol or n-butanol; the ketone solvent is preferably acetone, methyl ethyl ketone or methyl isobutyl ketone; the ester solvent is preferably methyl formate, ethyl acetate or isopropyl acetate; the ether solvent is preferably tetrahydrofuran or methyl tert-butyl ether.
Further, in the step 1), the weight-to-volume (g/ml) ratio of the raw material acatinib such as amorphous or crystalline form III thereof to the first solvent is preferably 5-10 volumes;
further, in the step 1), the weight-to-volume (g/ml) ratio of the raw material acatinib such as amorphous or crystalline form III thereof to acetonitrile is preferably 0.5-2 by volume;
further, in the step 2), the stirring temperature is preferably 50-60 ℃, and the stirring time is preferably 1-3 hours.
Acatinib acetonitrile compound and preparation method thereof
The invention also provides an acatinib acetonitrile compound which is very suitable for preparing the acatinib crystal form I.
Typically, the present invention provides a novel acatinib acetonitrile compound having X-ray powder diffraction characteristic peaks at diffraction angle 2 θ values of 8.2 ° ± 0.2 °, 10.6 ° ± 0.2 °, 11.0 ° ± 0.2 °, 22.7 ° ± 0.2 °, 25.0 ° ± 0.2 ° using Cu-K α radiation.
Furthermore, the invention provides a crystal form of an acatinib acetonitrile compound, which has an X-ray powder diffraction pattern having characteristic peaks at one or more positions with 2 theta values of 6.2 degrees +/-0.2 degrees, 8.2 degrees +/-0.2 degrees, 10.6 degrees +/-0.2 degrees, 11.0 degrees +/-0.2 degrees, 12.7 degrees +/-0.2 degrees, 13.7 degrees +/-0.2 degrees, 14.2 degrees +/-0.2 degrees, 16.3 degrees +/-0.2 degrees, 17.2 degrees +/-0.2 degrees, 19.1 degrees +/-0.2 degrees, 19.4 degrees +/-0.2 degrees, 20.4 degrees +/-0.2 degrees, 21.4 degrees +/-0.2 degrees, 22.7 degrees +/-0.2 degrees, 23.1 degrees +/-0.2 degrees, 25.0 degrees +/-0.2 degrees, 26.1 degrees +/-0.2 degrees, 28.2 degrees +/-0.2 degrees, 29.8 degrees 0.2 degrees.
Furthermore, the crystal form of the acatinib acetonitrile compound provided by the invention has an X-ray powder diffraction pattern with characteristic peaks at one or more 2 theta positions with 2 theta values shown in table 1
TABLE 1
| NO. | 2θ(°) | Relative Strength (%) |
| 1 | 6.2±0.2° | 3.2％ |
| 2 | 8.2±0.2° | 21.8％ |
| 3 | 10.6±0.2° | 68.3％ |
| 4 | 11.0±0.2° | 72.2％ |
| 5 | 12.7±0.2° | 39.5％ |
| 6 | 13.7±0.2° | 30.2％ |
| 7 | 14.2±0.2° | 6.5％ |
| 8 | 16.3±0.2° | 15.3％ |
| 9 | 17.2±0.2° | 16.0％ |
| 10 | 19.1±0.2° | 22.0％ |
| 11 | 19.4±0.2° | 10.3％ |
| 12 | 20.4±0.2° | 20.2％ |
| 13 | 21.4±0.2° | 10.1％ |
| 14 | 22.7±0.2° | 100.0％ |
| 15 | 23.1±0.2° | 14.9％ |
| 16 | 25.0±0.2° | 53.0％ |
| 17 | 26.1±0.2° | 8.1％ |
| 18 | 28.2±0.2° | 11.7％ |
| 19 | 29.8±0.2° | 9.3％ |
Furthermore, the X-ray powder diffraction pattern of the crystal form of the acatinib acetonitrile compound provided by the invention is basically shown in figure 1.
Furthermore, the crystal form of the acatinib acetonitrile compound provided by the invention has the onset peak values of 63.4 +/-2 ℃ and 127.8 +/-2 ℃, and the Differential Scanning Calorimetry (DSC) diagram is basically shown in figure 2.
Furthermore, the crystal form of the acatinib acetonitrile compound provided by the invention has an infrared absorption spectrum with absorption peaks at 3480 +/-10, 3323 +/-10, 3117 +/-10, 2974 +/-10, 2880 +/-10, 2249 +/-10, 2213 +/-10, 1672 +/-10, 1660 +/-10, 1629 +/-10, 1609 +/-10, 1576 +/-10, 1521 +/-10, 1498 +/-10, 1435 +/-10, 1416 +/-10, 1314 +/-10, 784 +/-10, 756 +/-10 and 734 +/-10 cm < -1 >.
Furthermore, the infrared absorption spectrum of the crystal form of the acatinib acetonitrile compound provided by the invention is basically shown in figure 4.
Furthermore, the crystal form of the acatinib acetonitrile compound provided by the invention has a weight loss of 2.5 +/-0.2% within a temperature range of 0-105 +/-3 ℃, and/or has a weight loss of 4.5 +/-0.2% within a temperature range of 105 +/-3 ℃ to 155 +/-3 ℃. The thermogravimetric analysis (TGA) profile is substantially as shown in figure 5.
In another embodiment, the present invention also provides a method for preparing an acatinib acetonitrile compound, comprising the following steps:
i) adding the raw material acatinib into 3-50 volumes of acetonitrile to obtain a third mixed system;
ii) stirring for 0.5-8 hours at 5-80 ℃ to obtain a fourth mixed system;
iii) separating to obtain the acatinib acetonitrile compound.
The weight volume ratio of the raw material acatinib to acetonitrile in the step i is preferably 5-10 volume; in the step ii, the reaction temperature is preferably 50-60 ℃, and the stirring time is preferably 1-3 hours.
The main advantages of the invention include:
(1) the crystallization yield is high and can reach more than 90 percent;
(2) good impurity removal effect and can efficiently remove the impurity A. The purity of the product is as high as more than 99.8 percent.
(3) The method is simple and convenient to operate, the crystal form I is easy to prepare, and the method is suitable for industrial mass production.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are percentages and parts by weight.
Unless otherwise indicated, reagents or starting materials for use herein may be obtained commercially or by methods well known in the art, and the experimental procedures used in the present invention are all those routinely practiced in the art and may be performed by conventional methods.
Raw materials and general procedure:
1. raw materials
In the examples, the raw material used is amorphous or crystalline form III of acatinib
The crystal form III is prepared by referring to US9290504 and US9796721, the purity of the crystal form III is 97.2%, and the content of impurity A is 0.62%.
The crystal form III is dissolved by methanol/dichloromethane (10vol./2vol.) and then concentrated to be dried to obtain amorphous form of the acatinib.
XRPD pattern determination method
X-ray powder diffraction instrument: BRUKER AXS D2 PHASER X-ray powder diffractometer; radiation source:
the intensity ratio α 1/α 2 was 0.5; generator (Generator) kv: 30.0 kv; generator (Generator) mA: 10.0 mA; initial 2 θ:2.000 degrees and the scanning range is 2.0000-40.000 degrees.
Example 1:
the preparation method comprises the following steps:
adding raw material of the crystal form III (60.0g) of the acatinib into 500mL of acetonitrile, heating to 50-60 ℃, stirring for 1.5 hours under the condition of heat preservation, separating out a large amount of solid in the system, cooling to room temperature, and stirring for 1 hour under the condition of heat preservation. Filtering, and vacuum drying the filter cake at 40 ℃ to obtain 56.9g of the acatinib acetonitrile compound solid, wherein the purity of the acatinib acetonitrile compound solid is 99.78 percent by HPLC analysis, and the impurity A is 0.03 percent.
The obtained acatinib acetonitrile solid is subjected to XRPD test, the X-ray powder diffraction data of the solid is shown in Table 1, and the X-ray powder diffraction pattern of the solid is shown in figure 1; performing DSC test, and the spectrum is shown in figure 2; performing H NMR test, wherein the spectrogram is shown in figure 3; performing an IR test, wherein the spectrogram is shown in FIG. 4; TGA testing was performed and the spectrum is shown in figure 5.
Example 2:
a process for preparing form I of acatinib:
adding 50.0g of the acatinib acetonitrile compound obtained in the example 1 into 300mL of ethanol, heating to 50-60 ℃, preserving the temperature for 0.5 hour, and cooling to room temperature, wherein a large amount of solid (the solid is transformed into a crystal form I by detection) exists in the system. Filtering, and vacuum drying the filter cake at 40 ℃ to obtain 47.6g of the acatinib solid, wherein the purity of the acatinib solid is 99.85% by HPLC analysis, and the impurity A is 0.02%. The resulting solid was subjected to XRPD testing, and its X-ray powder diffraction pattern is shown in fig. 6; performing DSC test, and the spectrum is shown in figure 7; h NMR measurement is carried out, and the spectrum is shown in figure 8; performing an IR test, wherein the spectrum is shown in FIG. 9; TGA testing was performed and the spectrum is shown in figure 10 as acatinib form I.
Example 3:
taking 0.3g of the accatinib acetonitrile compound obtained in example 1, adding 1.5mL of the solvents listed in the following table, heating to 50-60 ℃ until the system is clear, keeping the temperature at 50-60 ℃ for 1 hour, cooling to room temperature, keeping the temperature at room temperature, and stirring for 1 hour. And (3) performing suction filtration, leaching a filter cake by using the same solvent, and performing vacuum drying at 40 ℃ to obtain the crystalline form I of the acatinib, wherein the yield, the HPLC purity and the content of the impurity A are shown in the following table:
example 4:
taking 0.3g of raw acatinib (amorphous or crystal form III), adding 1.5mL of solvents listed in the following table, adding 0.3mL of acetonitrile, heating to 50-60 ℃ until the system is clear, preserving heat at 50-60 ℃ for 1 hour, cooling to room temperature, preserving heat at room temperature, and stirring for 1 hour. And (4) carrying out suction filtration, leaching a filter cake by using the same solvent, and carrying out vacuum drying at 40 ℃ to obtain the crystal form I of the acatinib.
Wherein, when the acatinib is used as the crystal form III as the raw material, the yield, the HPLC purity and the content of the impurity A of the obtained crystal form I are shown in the following table:
comparative example 1:
taking 0.3g of the raw material (amorphous or crystal form III) of the acatinib, adding 1.5mL of the solvents listed in the following table, heating to 50-60 ℃ until the system is clear, keeping the temperature at 50-60 ℃ for 1 hour, cooling to room temperature, keeping the temperature at room temperature, and stirring for 1 hour. The results of the experiments are shown in the following table (phenomena observed for amorphous and crystalline form III are essentially identical):
comparative example 2:
taking 0.3g of raw acatinib (crystal form III or amorphous), adding 1.5mL of the solvents listed in the following table, heating to 50-60 ℃ until the system is clear, adding 1% of the crystal form I obtained in example 2 as a seed crystal, keeping the temperature at 50-60 ℃ for 1 hour, cooling to room temperature, keeping the temperature at room temperature, and stirring for 1 hour. And leaching the filter cake with the same solvent, and drying in vacuum at 40 ℃ to obtain the crystal form I of the acatinib.
Wherein, when the raw material of the acatinib is the crystal form III of the acatinib, the yield, the HPLC purity and the content of the impurity A of the crystal form I are shown in the following table:
all documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.
Claims (10)
1. A preparation method of an acatinib crystal form I is characterized in that the acatinib is shown as a formula I,
and, the preparation method comprises the steps of:
(1) providing a first mixed system;
wherein the first mixing system is a mixing system of (i) an acatinib acetonitrile compound in a first solvent or (ii) a mixing system of raw material acatinib in the first solvent and acetonitrile;
(2) processing the first mixed system in the step (1) to obtain a second mixed system containing the acatinib crystal form I; and
(3) separating the second mixed system obtained in step (2) to obtain the crystalline form I of acatinib.
2. The method of claim 1, wherein the method has one or more of the following characteristics:
(a) the first solvent is selected from the group consisting of: an alcohol solvent, a ketone solvent, an ester solvent, an ether solvent, or a combination thereof; preferably, the first solvent is selected from the group consisting of: methanol, ethanol, isopropanol, n-propanol, n-butanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl formate, ethyl acetate, isopropyl acetate, tetrahydrofuran, methyl tert-butyl ether, or a combination thereof;
(b) in the first mixed system, the mass volume (g: ml) ratio of the alcanib acetonitrile compound or the raw material alcanib to the first solvent is 1 (1-20); preferably, the ratio is 1 (5-10); more preferably 1 (5-6);
(c) in the first mixed system, the mass volume (g: ml) ratio of the raw material acatinib to acetonitrile is 1 (0.1-25); preferably, the ratio is 1 (0.5-5); more preferably, 1: 1. + -. 0.5; most preferably 1: 1. + -. 0.1.
3. The method of claim 1, wherein in step (2), said processing comprises the steps of: heating the first mixed system to T1(ii) temperature; and cooling to T2(ii) temperature; or, the processing comprises the steps of: at T3Stirring the first mixed system at a temperature.
4. The method of claim 3, wherein the method further has one or more of the following features:
(d)T140-80 deg.C (preferably, T)150-60 ℃), and/or T2＝5～25℃；
(e) t1 is 0.5-5 hours, preferably t1 is 1-3 hours;
(f) t2 is 0.5-5 hours, preferably t2 is 1-3 hours;
(g)T3＝5～80℃；
(h) at T3Stirring the first mixed system at the temperature for t3, wherein t3 is 0.5-8 hours.
5. The method of claim 1, wherein the acatinib acetonitrile compound has one or more of the following characteristics:
(a) in the alcatinib acetonitrile compound, the ratio of alcatinib molecules to acetonitrile molecules is about 1: 1;
(b) the X-ray powder diffraction of the acatinib acetonitrile compound has characteristic peaks at diffraction angles of 8.2 degrees +/-0.2 degrees, 10.6 degrees +/-0.2 degrees, 11.0 degrees +/-0.2 degrees, 22.7 degrees +/-0.2 degrees and 25.0 degrees +/-0.2 degrees;
(c) (ii) the Differential Scanning Calorimetry (DSC) of said accatinib acetonitrile compound has an onset (° nset) peak at 63.4 ± 2 ℃, 127.8 ± 2 ℃;
(d) the infrared absorption spectrum of the acatinib acetonitrile compound has absorption peaks at 3480 +/-10, 3323 +/-10, 3117 +/-10, 2974 +/-10, 2880 +/-10, 2249 +/-10, 2213 +/-10, 1672 +/-10, 1660 +/-10, 1629 +/-10, 1609 +/-10, 1576 +/-10, 1521 +/-10, 1498 +/-10, 1435 +/-10, 1416 +/-10, 1314 +/-10, 784 +/-10, 756 +/-10 and 734 +/-10 cm < -1 >;
(e) the alcatinib acetonitrile compound has a thermogravimetric analysis (TGA) with a weight loss of 2.5 ± 0.2% in the range of 0 to 105 ± 3 ℃ and/or a weight loss of 4.5 ± 0.2% in the range of 105 ± 3 ℃ to 155 ± 3 ℃.
6. The method of claim 5, wherein the acatinib acetonitrile compound further has one or more of the following characteristics:
(f) under the condition of Cu-Kalpha radiation, the acatinib acetonitrile compound has an X-ray powder diffraction pattern which also has characteristic peaks at one or more of the 2 theta values of 6.2 +/-0.2 degrees, 12.7 +/-0.2 degrees, 13.7 +/-0.2 degrees, 14.2 +/-0.2 degrees, 16.3 +/-0.2 degrees, 17.2 +/-0.2 degrees, 19.1 +/-0.2 degrees, 19.4 +/-0.2 degrees, 20.4 +/-0.2 degrees, 21.4 +/-0.2 degrees, 23.1 +/-0.2 degrees, 26.1 +/-0.2 degrees, 28.2 +/-0.2 degrees, 29.8 +/-0.2 degrees;
(g) an X-ray powder diffraction (PXRD) pattern of the acatinib acetonitrile compound under Cu-ka radiation is substantially as shown in figure 1;
(h) a Differential Scanning Calorimetry (DSC) profile of the accatinib acetonitrile compound is substantially as shown in figure 2;
(i) an infrared absorption (IR) spectrum of the acatinib acetonitrile compound is substantially as shown in FIG. 4;
(j) the thermogravimetric analysis (TGA) of the accatinib acetonitrile compound is substantially as shown in figure 5.
7. The solvate of the acatinib is characterized by being an acatinib acetonitrile compound.
8. A process for the preparation of the acatinib acetonitrile compound according to claim 7, comprising the steps of:
i. providing a third mixed system; wherein the third mixed system is a mixed system of raw material acatinib in acetonitrile;
ii.T4(ii) stirring the third mixed system of step (i) at a temperature and for a time t4 to obtain a fourth mixed system containing the accatinib acetonitrile compound; wherein, T4At 5-80 ℃ and t4 for 0.5-8 hours; and
(iii) isolating the fourth mixed system obtained in step (ii) to obtain the acatinib acetonitrile compound.
9. The method of claim 8, wherein the method has one or more of the following characteristics:
(a) in the third mixed system, the mass-to-volume ratio (g: ml) of the raw material acatinib to acetonitrile is 1: 3-50; preferably, the ratio is 1: 5-10;
(b) in step (ii), T4＝50～60℃；
(c) In the step (ii), t4 is 1-3 hours;
(d) in step (ii), T4(ii) after stirring the third mixed system of step (i) at the temperature for t4 time, further comprising the steps of: cooling to T5At a temperature of T5Optionally stirring at temperature for t5 time;
(e)T5＝5～25℃；
(f) t5 is 0.5-5 hours, preferably t5 is 1-3 hours;
(g) the raw material acatinib is acatinib free alkali;
(h) the raw material acatinib comprises: amorphous or crystalline form III of acatinib.
10. Use of the acatinib acetonitrile compound according to claim 6 for preparing form I of acatinib; wherein the crystalline form I of acatinib is as defined in claim 1.
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| WO2021135346A1 (en) * | 2019-12-31 | 2021-07-08 | 苏州科睿思制药有限公司 | New crystal form of acalabrutinib, preparation method therefor and use thereof |
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