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CN114989062A - Crystal form of BTK kinase inhibitor intermediate and preparation method thereof - Google Patents

Crystal form of BTK kinase inhibitor intermediate and preparation method thereof Download PDF

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CN114989062A
CN114989062A CN202210272263.2A CN202210272263A CN114989062A CN 114989062 A CN114989062 A CN 114989062A CN 202210272263 A CN202210272263 A CN 202210272263A CN 114989062 A CN114989062 A CN 114989062A
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crystal form
pyrrole
tert
phenyl
cyano
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李涛
熊锋
代少先
凌超
彭明敏
李婷
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Shanghai Zaiqi Bio Tech Co ltd
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    • C07ORGANIC CHEMISTRY
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    • C07D207/00Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07BGENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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Abstract

The invention relates to a crystal form of a BTK kinase inhibitor intermediate and a preparation method thereof, belonging to the technical field of medicines. The crystal form is a crystal form IV of (R) -1- (1- (tert-butoxy acyl) pyrrolidine-3-yl) -3-cyano-4- (4- (2, 6-difluorophenoxy) phenyl) -1H-pyrrole-2-ethyl formate. The crystal form IV of the (R) -1- (1- (tert-butoxyacyl) pyrrolidine-3-yl) -3-cyano-4- (4- (2, 6-difluorophenoxy) phenyl) -1H-pyrrole-2-ethyl formate obtained by the invention has good chemical stability and crystal form stability, is favorable for storage and transportation, can highly purify an intermediate to obtain a sample with the purity of over 99.82 percent, and has good stability and stability in the preparation of a crystal form IV of a crystal form of a (R) -1- (1- (tert-butoxyacyl) pyrrolidine-3-yl) -1H-pyrrole-2-carboxylic acid group of a crystal form of a (R, the quality control of the 3-d ] pyridazine-7-one has important significance, meanwhile, the solubility in ethanol is superior to that of other crystal forms, the next-step production is facilitated, the preparation process is simple, and the method is suitable for industrial mass production.

Description

Crystal form of BTK kinase inhibitor intermediate and preparation method thereof
Technical Field
The invention relates to a crystal form of a BTK kinase inhibitor intermediate and a preparation method thereof, in particular to a crystal form IV of (R) -1- (1- (tert-butoxy acyl) pyrrolidine-3-yl) -3-cyano-4- (4- (2, 6-difluorophenoxy) phenyl) -1H-pyrrole-2-ethyl formate and a preparation method thereof, belonging to the technical field of medicines.
Background
Immune cells can be generally divided into two categories, T cells and B cells, wherein the main role of B cells is to secrete various antibodies to help the body resist various foreign invasion. Bruton's tyrosine protein kinase (BTK) is one of the members of the tyrosine protein kinase subfamily, belongs to Tec family kinase, is mainly expressed in hematopoietic cells, and is distributed in the lymphatic system, hematopoietic system and blood system. Bruton's tyrosine protein kinase (BTK) is a key protein kinase in the BCR signaling pathway. Can regulate the maturation and differentiation of normal B cells, and is also closely related to various B cell lymphoid tissue disorder diseases. Thus, the targeted small molecule inhibitor BTK may provide benefits for the treatment of B cell malignancies and autoimmune diseases.
Ibrutinib (Ibrutinib) is the first generation of small molecule BTK inhibitors co-developed by pharmaceuticals and Janssen, first approved by the FDA for the treatment of Mantle Cell Lymphoma (MCL) in 2013 at 11 months, and then approved again for the treatment of Chronic Lymphocytic Leukemia (CLL) in 2014 at 2 months. Ibrutinib can be irreversibly combined with 481 # cysteine of ATP binding region of BTK kinase through Michael receptor, thereby inhibiting transmission of BTK to downstream signals and effectively controlling growth of tumor cells. Ibrutinib transmits signals in BCR signal path and cytokine receptor signal path to mediate migration, chemotaxis and adhesion of B cells. Preclinical studies prove that ibrutinib can inhibit proliferation and survival of malignant B cells.
PCT/US2014/061393 relates to a compound of formula II with a specific structure
Figure BDA0003554055060000011
I.e. (R) -4-amino-1- (1- (but-2-ynoyl) pyrrolidin-3-yl) -3- (4- (2, 6-difluorophenoxy) phenyl) -1, 6-dihydro-7H-pyrrolo [2,3-d]Pyridazine-7-one, which is a novel BTK kinase inhibitor and has improved kinase selectivity, clinical curative effect or indication, safety and the like.
The literature reports that the purification of (R) -4-amino-1- (1- (but-2-alkynoyl) pyrrolidin-3-yl) -3- (4- (2, 6-difluorophenoxy) phenyl) -1, 6-dihydro-7H-pyrrolo [2,3-d ] pyridazin-7-one is realized by silica gel column chromatography and then crystallization purification, the next step is reacted with hydrazine hydrate to dissolve and react at high temperature, a large amount of hydrazine hydrate is volatilized into the air in the heating process to pollute the environment, so that the purification method of the BTK kinase inhibitor is difficult to amplify and is not beneficial to large-scale production, the BTK kinase inhibitor is used as a medicament for human bodies, impurities usually have adverse effects on the human bodies, and thus the high-purity medicament is an important target of medicament development, however, high purity intermediates are critical to obtaining high purity pharmaceutical products.
CN201910614068.1 provides an indication i, and the specific structure is
Figure BDA0003554055060000021
(R) -1- (1- (tert-butoxyacyl) pyrrolidin-3-yl) -3-cyano-4- (4- (2, 6-difluorophenoxy) phenyl) -1H-pyrrole-2-carboxylic acid ethyl ester crystal form II with good stability.
As the BTK kinase inhibitor (R) -4-amino-1- (1- (but-2-ynoyl) pyrrolidin-3-yl) -3- (4- (2, 6-difluorophenoxy) phenyl) -1, 6-dihydro-7H-pyrrolo [2,3-d ] pyridazin-7-one key intermediate (R) -1- (1- (tert-butoxyacyl) pyrrolidin-3-yl) -3-cyano-4- (4- (2, 6-difluorophenoxy) phenyl) -1H-pyrrole-2-carboxylic acid ethyl ester, which is a key intermediate of (R) -1- (1- (tert-butoxyacyl) pyrrolidin-3-yl) -3-cyano-4- (4- (2, 6-difluorophenoxy) phenyl) -1H-pyrrole-2-carboxylic acid, purification of the intermediate by column chromatography is high in cost, low in efficiency and not favorable for industrial production, and therefore, there is an urgent need for development of a purification method by crystallization, a method for purification of (I) ethyl ester, a novel intermediate of (I) and (I) having a novel structure, The intermediate has stable chemical property and is easy to dissolve in ethanol at normal temperature, so that the novel BTK kinase inhibitor (R) -4-amino-1- (1- (butyl-2-alkynoyl) pyrrolidine-3-yl) -3- (4- (2, 6-difluorophenoxy) phenyl) -1, 6-dihydro-7H-pyrrolo [2,3-d ] pyridazine-7-ketone is easier to purify, and the next reaction is easier to perform. Meanwhile, the deep research is necessary to find a new crystal form which has higher crystal form purity, good chemical stability and high solubility in ethanol at normal temperature.
Disclosure of Invention
In order to solve the above technical problem, the present invention provides an equation i: the crystal form IV of (R) -1- (1- (tert-butoxy acyl) pyrrolidine-3-yl) -3-cyano-4- (4- (2, 6-difluorophenoxy) phenyl) -1H-pyrrole-2-ethyl formate has good stability and high solubility in ethanol at normal temperature.
The research finds that: the compound of formula I is crystallized under different crystallization conditions, and the obtained crystallized product is subjected to X-diffraction and DSC detection, and the crystal forms with the same good stability are obtained under the crystallization conditions of the invention and are called as crystal form IV. The DSC spectrum of the crystal form IV crystal in the application shows that the crystal form IV crystal has a melting endothermic peak near 93.57 ℃, and an X-ray powder diffraction spectrum expressed by 2theta angles and interplanar spacings is obtained by using Cu-Ka radiation, wherein the characteristic peaks at the 2theta position comprise: 5.66,10.28,13.02,14.42,20.39,21.79 and 26.73.
Further, in a specific embodiment, crystalline form iv of ethyl (R) -1- (1- (tert-butoxyacyl) pyrrolidin-3-yl) -3-cyano-4- (4- (2, 6-difluorophenoxy) phenyl) -1H-pyrrole-2-carboxylate has an XRD pattern with characteristic peaks expressed in 2 Θ comprising: 5.66,9.30,10.01,10.28,13.02,13.32,14.42,18.38,20.39,20.76,21.79,22.71,22.84,26.73 and 27.62.
A typical spectrum of the crystalline form IV of ethyl (R) -1- (1- (tert-butoxycarbonyl) pyrrolidin-3-yl) -3-cyano-4- (4- (2, 6-difluorophenoxy) phenyl) -1H-pyrrole-2-carboxylate obtained during the preparation of examples 4-6 is shown in FIG. 7.
Further, in the technical scheme, the differential scanning calorimetry curve of the crystal form IV has an endothermic peak at 54.52-93.62 ℃. Specifically, the obtained crystal forms are determined to be crystal form IV by adopting grinding treatment and tabletting treatment, and the DSC absorption peak positions are 93.53 ℃ and 93.62 ℃ respectively.
Further, in the technical scheme, the purity of the crystal form IV is more than 99.0%.
Definitions of terms "comprising" or "including" are open-ended expressions that include what is specified in the present invention, but do not exclude other aspects.
The crystal form is used for describing the existence state of a solid compound and describing a plurality of parameter aggregates of ion, atom or molecule composition, symmetrical property and periodic arrangement rule in the crystal.
"relative intensity" refers to the ratio of the intensity of the first strong peak to the intensity of the other peaks when the intensity of the first strong peak in a set of diffraction peaks assigned to a certain crystal form is defined as 100%.
In the context of the present invention, the 2 θ (also called 2theta or diffraction peak) values in the X-ray powder diffraction pattern are all in degrees (°).
When referring to a map and/or data in a map, a "diffraction peak" refers to a characteristic peak that one skilled in the art would not ascribe to background noise.
The X-ray powder diffraction peak of the crystal form has experimental error in the measurement of 2theta or diffraction peak of the X-ray powder diffraction pattern between one instrument and another instrument and between one sample and another sample.
The measurements of the 2theta or diffraction peaks of the X-ray powder diffraction patterns may differ slightly, and the experimental error or difference may be of a value of +/-0.20 units or +/-0.1 units or +/-0.05 units, so that the values of the 2theta or diffraction peaks cannot be considered absolute.
The Differential Scanning Calorimetry (DSC) curve of the crystal form has experimental errors, the position and peak value of the endothermic peak may slightly differ between one instrument and another instrument and between one sample and another sample, and the numerical value of the experimental errors or differences may be 5 ℃ or less, 4 ℃ or less, 3 ℃ or less, 2 ℃ or less or 1 ℃ or less, so the peak position or peak value of the DSC endothermic peak cannot be regarded as absolute.
In the context of the present invention, all numbers disclosed herein are approximate values, regardless of whether the word "about" or "approximately" is used. The numerical value of each number may be different by 1%, 2% or 5%.
By room temperature is meant a temperature of about 15 ℃ to 32 ℃ or about 20 ℃ to 30 ℃ or about 23 ℃ to 28 ℃ or about 25 ℃.
The invention also provides a preparation method of the crystal form IV of the compound shown in the formula I, which comprises the following steps:
1. adding any crystal form or amorphous (R) -1- (1- (tert-butoxy acyl) pyrrolidine-3-yl) -3-cyano-4- (4- (2, 6-difluoro phenoxy) phenyl) -1H-pyrrole-2-ethyl formate solid into a solvent, heating to dissolve, and then cooling for crystallization;
2. filtering and drying to obtain the (R) -1- (1- (tert-butoxy acyl) pyrrolidine-3-yl) -3-cyano-4- (4- (2, 6-difluoro phenoxy) phenyl) -1H-pyrrole-2-ethyl formate crystal form IV.
In step 1), the solvent is selected from acetonitrile or a mixed solvent of acetonitrile and water. Acetonitrile is preferred.
The method of recrystallization is not particularly limited, and the recrystallization can be carried out by a usual recrystallization operation method. For example, the compound of formula (I) as a starting material is dissolved in an organic solvent under heating, then crystallized by stirring under slow cooling, and after completion of the crystallization, the desired crystals can be obtained by filtration and drying. In particular, the filtered crystals are usually dried under reduced pressure under heating at about 30 to 40 ℃ in vacuum, whereby the recrystallization solvent can be removed.
The crystal form of the obtained crystal is researched by differential scanning thermal analysis (DSC) and X diffraction (XRD) pattern measurement, and the solvent residue of the obtained crystal is detected.
Researches show that the crystal form IV crystal of the compound shown in the formula (I) has better stability than the crystal form II crystal under the conditions of illumination and high temperature, the crystal form stability is good under the conditions of grinding, pressure and the like, the requirements of production, transportation and storage can be met, the solubility in ethanol at normal temperature is obviously better than that of other crystal forms, the production process is stable, repeatable and controllable, and the crystal form IV crystal can be suitable for industrial production.
Drawings
FIG. 1 is an XRD pattern of crystalline form I of the compound of formula (1) of example 1;
FIG. 2 is a DSC of crystalline form I of compound of formula (1) of example 1;
FIG. 3 is an XRD pattern of crystalline form II of the compound of formula (1) of example 2;
FIG. 4 is a DSC of example 2 of compound of formula (1) in crystalline form II;
figure 5 is an XRD pattern of crystalline form III of the compound of formula (1) of example 3;
FIG. 6 is a DSC of example 3 of compound of formula (1) in crystalline form III;
FIG. 7 is an XRD pattern of crystalline form IV of the compound of formula (1) of example 4;
FIG. 8 is a DSC of crystalline form IV of the compound of formula (1) of example 4;
Detailed Description
The present invention will be explained in more detail with reference to examples, which are provided only for illustrating the technical solutions of the present invention and are not intended to limit the spirit and scope of the present invention.
Test instrument for experiments
1. DSC spectrum
The instrument model is as follows: mettler Toledo DSC 1Staree System
And (3) purging gas: nitrogen gas
The heating rate is as follows: 10.0 ℃/min
Temperature range: 20-150 deg.C
2. X-ray diffraction spectrum
The instrument model is as follows: bruker D8Focus X-ray powder diffractometer
Ray: monochromatic Cu-ka radiation (λ ═ 1.5406)
The scanning mode is as follows: θ/2 θ, scan range: 2-40 °
Voltage: 40KV, current: 40mA
Example 1
Preparation of ethyl (R) -1- (1- (tert-butoxyacyl) pyrrolidin-3-yl) -3-cyano-4- (4- (2, 6-difluorophenoxy) phenyl) -1H-pyrrole-2-carboxylate
The reaction mixture was stirred with ethyl (R) -1- (1- (tert-butoxycarbonyl) pyrrolidin-3-yl) -3-cyano-4-bromo-1H-pyrrole-2-carboxylate (1.98g,4.8mmol), I 2 (1.60g,4.8mmol) and K 3 PO 4 ·3H 2 O (1.88g,7.2mmol) in 1, 4-dioxane/water (60mL/6mL) was degassed with nitrogen and Pd was added under nitrogen protection 2 (dba) 3 (220mg,0.24mmol) and P (Cy) 3 (140mg,0.48mmol) followed by heating to reflux for 16 h. After the reaction was complete, it was cooled to room temperature, the solid was filtered off and the filtrate was concentrated. The residue was purified by silica gel chromatography (eluent: dichloromethane) and rotary evaporated under reduced pressure to give 0.57g of (R) -1- (1- (tert-butoxyacyl) pyrrolidin-3-yl) -3-cyano-4- (4- (2, 6-difluorophenoxy) phenyl) -1H-pyrrole-2-carboxylic acid ethyl ester as an off-white solid. HPLC: 99.31%, max monohetero: 0.21 percent. 1 H NMR(400MHz,DMSO-d 6 ):7.69(d,1H),7.61-7.66(d,2H),7.39-7.29(m,3H),7.02-7.04(d,2H),5.57-5.60(s,1H),4.35-4.30(dd,2H),3.77-3.74(m,1H),3.50-3.44(m,2H),3.40-3.44(m,1H),2.31-2.36(m,2H),1.37-1.36(s,9H),1.33-1.30(t,3H).MS(ESI):m/z=538[M+H] + . The X-ray diffraction spectrogram of the solid sample shows an amorphous characteristic absorption peak, and the spectrogram is shown as figure 1; the product was identified as amorphous solid I by the DSC spectrum of FIG. 2 with a sharp melting endotherm of 58.7 ℃.
Example 2
1.0g of the compound of formula (I) (crude product prepared as in example 1) was added to a 25mL single-neck flask, 2mL of anhydrous ethanol was added, heated to reflux for clarification, heating was stopped, cooling for crystallization, suction filtered the next day, and dried under reduced pressure to give 715mg of a white solid with a yield of 71.5%. HPLC: 99.73%, maximum single hetero: 0.04 percent. The X-ray diffraction pattern of the crystal sample is shown in FIG. 3. The X-ray powder diffraction pattern has characteristic peaks at 2 θ values of about 5.52,8.62,9.34,11.85,14.36,14.52,15.25,17.16,18.79,19.02,20.02,20.18,20.49,20.79,22.44,23.79,24.02,24.29 and 28.18, with characteristic peak positions as shown in table 1 below and in fig. 3. The DSC spectrum is shown in figure 4, and has a sharp melting endothermic peak of 97.92 ℃, and the crystal form is defined as the crystal form II. The crystal form II at least contains more than 97 percent of crystal form II.
TABLE 1 characteristic peaks of form II
Figure BDA0003554055060000061
Figure BDA0003554055060000071
Example 3:
1.0g of the compound of formula (I) (crude as prepared in example 1 of the present application) was taken and placed in a 25mL single-neck flask, 3mL of a mixed solvent of methanol/water (1/1 vol.%) was added, the mixture was heated under reflux to dissolve it, heating was stopped, the mixture was cooled to crystallize, the next day of filtration was carried out, and the mixture was dried under reduced pressure to obtain 304mg of a white solid with a yield of 30.4%. HPLC: 99.64%, max monohetero: 0.17 percent. The X-ray diffraction pattern of the crystal sample is shown in FIG. 5. An X-ray powder diffraction pattern having characteristic peaks at 2 Θ values of about 8.66,9.39,11.89,14.42,14.60,15.34,15.59,17.22,18.88,19.08,20.20,20.56,20.87,21.40,21.83,22.48,23.15,23.15,23.31,23.64,23.89,24.11,24.35,27.04,28.27, and 33.47, with characteristic peak positions as shown in table 2 below. The DSC spectrum is shown in figure 6, and has a sharp melting endothermic peak of 104.71 ℃, and the crystal form is defined as the crystal form III. The crystal form II at least contains more than 97 percent of crystal form III.
TABLE 2 characteristic peaks of form III
Figure BDA0003554055060000072
Figure BDA0003554055060000081
Example 4
1.0g of the compound of formula (I) (crude product prepared as in example 1) was added to a 25mL single-necked flask, 3mL of acetonitrile was added, heated to reflux for elution, the heating was stopped, cooled for crystallization, filtered the next day, and dried to obtain 928mg of a white solid with a yield of 92.8%. The X-ray diffraction pattern and the DSC pattern of the crystal sample are compared through research, and the product is determined to be a crystal form IV. HPLC: 99.82%, max monohetero: 0.09 percent. The X-ray diffraction pattern of the crystal sample is shown in FIG. 7. The X-ray powder diffraction pattern had characteristic peaks at 2 θ values of 5.66,9.30,10.01,10.28,13.02,13.32,14.42,18.38,20.39,20.76,21.79,22.71,22.84,26.73 and 27.62, with characteristic peak positions as shown in table 3 below. The DSC spectrum is shown in figure 8, and a sharp melting endothermic peak of 93.57 ℃ is formed, and the crystal form is defined as a crystal form IV. The crystal form IV at least contains more than 97 percent of crystal form IV.
TABLE 3 characteristic peaks of form IV
Figure BDA0003554055060000082
Example 5
1.0g of the compound of formula (I) (crude product prepared as in example 1) was added to a 25mL single-necked flask, 5mL of acetonitrile was added, heated to reflux for elution, the heating was stopped, cooled for crystallization, filtered the next day, and dried to obtain 911mg of a white solid with a yield of 91.1%. The X-ray diffraction pattern and the DSC pattern of the crystal sample are compared through research, and the product is determined to be a crystal form IV.
Example 6
1.0g of the compound of formula (I) (crude product prepared as in example 1) was added to a 25mL single-necked flask, 3mL of acetonitrile and 0.4mL of water were added, heated under reflux to dissolve the crystals, the heating was stopped, the crystals were cooled and crystallized, filtered the next day, and dried to yield 934mg of a white solid, which was 93.4%. The X-ray diffraction pattern and the DSC pattern of the crystallization sample are compared through research, and the product is determined to be a crystal form IV.
Example 7
The stability of the crystal forms obtained in examples 1 and 2 to 4 were compared, and the data are shown in Table 4.
Table 4, comparison of the crystalline stabilities of form I to form IV of compounds of formula (I):
Figure BDA0003554055060000091
the stability examination result shows that: the stability of the amorphous I, crystal II, crystal III and crystal IV samples is found to be remarkably better than that of the amorphous samples under the conditions of illumination, high temperature and high humidity by comparing the stability of the amorphous I, crystal II, crystal III and crystal IV samples under the condition of open placement under the conditions of illumination and high temperature.
Example 8
The iv form of the compound of formula (I) prepared as in example 4 was ground, heated and tabletted to show a stable form, and the detailed experimental data are shown in table 5 below.
TABLE 5 study of the particular stability of the IV form of the Compound of formula (I)
Figure BDA0003554055060000101
Example 9
Adding 5mL of ethanol solvent into a 10mL test tube, respectively adding 100mg of the compound of the formula (I), continuously shaking, sealing with a membrane, placing into an ultra-constant temperature water tank at a certain temperature (the temperature control range is 0.1 ℃), standing for 1 hour, taking out a supernatant, diluting, analyzing by HPLC, obtaining the content of the compound of the formula (I), and calculating the solubility at the temperature.
Taking different crystal forms II, III and IV of the compound of the formula (I), measuring the content at 265nm at 22 ℃, 25 ℃,28 ℃, 31 ℃, 34 ℃ and 37 ℃ respectively, and calculating the solubility data, see Table 6.
TABLE 6 determination of the solubility of 3 crystal forms of the compound of the formula (I) in ethanol at different temperatures
Crystal form 22℃ 25℃ 28℃ 31℃ 34℃ 37℃
Crystal form II 2.83 3.20 3.48 3.82 4.16 4.47
Crystal form III 1.41 1.72 1.90 2.15 2.21 2.15
Crystal form IV 3.71 4.13 4.39 4.80 5.22 5.64
Example 10
The crystal forms obtained in the above examples 1 and 2 to 4 are used for accelerated stability experiments, aiming at investigating the change rule of the product along with time under the influence of temperature, humidity and light and providing scientific basis for the production, packaging and transportation conditions of the product.
Influence factor test: the method comprises the steps of placing the sample under three conditions, wherein the high temperature of the sample is 40 +/-2 ℃, the high humidity test is carried out at 25 ℃ and RH 90%, the sample is placed under 5000Lx illumination, the sample is taken in 1 month and 2 months respectively, and all indexes are measured. The results are shown in Table 7.
TABLE 7 sample influence factor test results
Figure BDA0003554055060000111
The influence factor experimental results of table 4 show that: the crystal form II, the crystal form III and the crystal form IV of the compound shown in the formula (I) are placed for 10 days under the conditions of illumination, temperature of 30 ℃ and 40 ℃, high humidity of 75% RH and 90% RH, the purity of the compound is not obviously changed, and the chemical stability is good; the crystal form IV sample after the influence factor experiment is retested, the crystal form is not transformed, and the physical property is stable; the results of the solubility experiments shown in table 6 show that: the solubility of the crystal form IV in ethanol is superior to that of the crystal form II and the crystal form III; the data results in table 7 show that: according to the influence factor test results, the total impurity content and the single impurity content of the crystal form II and the crystal form IV do not change greatly under the conditions of high humidity, high temperature and illumination, but the single impurity content of the crystal form II before the experiment is higher, the single impurity content has an over-limit risk after the experiment is finished, and the total impurity content and the single impurity content of the amorphous form I are increased quickly under the conditions of high temperature, high humidity and illumination. The crystal form IV sample has relatively stable total impurity content and single impurity content under the conditions of high temperature, high humidity and illumination, and has low application risk.

Claims (7)

  1. Ethyl (R) -1- (1- (tert-butoxyacyl) pyrrolidin-3-yl) -3-cyano-4- (4- (2, 6-difluorophenoxy) phenyl) -1H-pyrrole-2-carboxylate in crystalline form iv characterized by: the characteristic peaks of the powder X-ray diffraction pattern expressed by 2theta +/-0.20 comprise: 5.66,10.28,13.02,14.42,20.39,21.79 and 26.73.
  2. 2. Crystalline form of ethyl (R) -1- (1- (tert-butoxyacyl) pyrrolidin-3-yl) -3-cyano-4- (4- (2, 6-difluorophenoxy) phenyl) -1H-pyrrole-2-carboxylate according to claim 1 characterized in that its powder X-ray diffraction pattern has characteristic peaks expressed in 2 Θ ± 0.20 comprising: 5.66,9.30,10.01,10.28,13.02,13.32,14.42,18.38,20.39,20.76,21.79,22.71,22.84,26.73 and 27.62.
  3. 3. The crystalline form of ethyl (R) -1- (1- (tert-butoxyacyl) pyrrolidin-3-yl) -3-cyano-4- (4- (2, 6-difluorophenoxy) phenyl) -1H-pyrrole-2-carboxylate according to claim 1 characterized in that: the powder X-ray diffraction pattern is shown as spectrogram 7.
  4. 4. The crystalline form of ethyl (R) -1- (1- (tert-butoxyacyl) pyrrolidin-3-yl) -3-cyano-4- (4- (2, 6-difluorophenoxy) phenyl) -1H-pyrrole-2-carboxylate according to claim 1 characterized by: the differential scanning calorimetry curve of the crystal form IV has an endothermic peak at 54.52-93.62 ℃.
  5. 5. The crystalline form of ethyl (R) -1- (1- (tert-butoxyacyl) pyrrolidin-3-yl) -3-cyano-4- (4- (2, 6-difluorophenoxy) phenyl) -1H-pyrrole-2-carboxylate according to claim 1 characterized in that: the purity of the crystal form IV is more than 99.0%.
  6. 6. A process for the preparation of crystalline form IV of ethyl (R) -1- (1- (tert-butoxyacyl) pyrrolidin-3-yl) -3-cyano-4- (4- (2, 6-difluorophenoxy) phenyl) -1H-pyrrole-2-carboxylate according to any one of claims 1 to 5, characterized in that it comprises the following steps:
    A. adding any crystal form or amorphous (R) -1- (1- (tert-butoxy acyl) pyrrolidine-3-yl) -3-cyano-4- (4- (2, 6-difluoro phenoxy) phenyl) -1H-pyrrole-2-ethyl formate solid into a solvent, heating to dissolve, and then cooling for crystallization;
    B. filtering and drying to obtain the (R) -1- (1- (tert-butoxy acyl) pyrrolidine-3-yl) -3-cyano-4- (4- (2, 6-difluoro phenoxy) phenyl) -1H-pyrrole-2-ethyl formate crystal form IV.
  7. 7. A process for the preparation of crystalline form iv of ethyl (R) -1- (1- (tert-butoxyacyl) pyrrolidin-3-yl) -3-cyano-4- (4- (2, 6-difluorophenoxy) phenyl) -1H-pyrrole-2-carboxylate according to claim 6 characterized in that: in step a, the solvent is acetonitrile or acetonitrile/water.
CN202210272263.2A 2022-07-04 2022-07-04 Crystal form of BTK kinase inhibitor intermediate and preparation method thereof Pending CN114989062A (en)

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106573001A (en) * 2014-07-07 2017-04-19 永恒生物科技公司 Aminopyridazinone compounds as protein kinase inhibitors
WO2017118277A1 (en) * 2016-01-05 2017-07-13 江苏恒瑞医药股份有限公司 Crystalline form of btk kinase inhibitor and preparation method thereof
WO2019196915A1 (en) * 2018-04-13 2019-10-17 江苏恒瑞医药股份有限公司 Method for preparing pyrroloaminopyridazinone compound and intermediates thereof
CN110372562A (en) * 2019-07-09 2019-10-25 上海再启生物技术有限公司 A kind of crystal form and preparation method thereof of BTK kinase inhibitor key intermediate
WO2020038405A1 (en) * 2018-08-22 2020-02-27 江苏恒瑞医药股份有限公司 Preparation method of pyrrolo-amino-pyridazinone compound and intermediate thereof
WO2021057998A1 (en) * 2019-09-29 2021-04-01 上海森辉医药有限公司 Preparation method for pyrroloaminopyridazinone compound
CN112745255A (en) * 2019-10-30 2021-05-04 江苏恒瑞医药股份有限公司 Preparation method of BTK kinase inhibitor

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106573001A (en) * 2014-07-07 2017-04-19 永恒生物科技公司 Aminopyridazinone compounds as protein kinase inhibitors
WO2017118277A1 (en) * 2016-01-05 2017-07-13 江苏恒瑞医药股份有限公司 Crystalline form of btk kinase inhibitor and preparation method thereof
WO2019196915A1 (en) * 2018-04-13 2019-10-17 江苏恒瑞医药股份有限公司 Method for preparing pyrroloaminopyridazinone compound and intermediates thereof
WO2020038405A1 (en) * 2018-08-22 2020-02-27 江苏恒瑞医药股份有限公司 Preparation method of pyrrolo-amino-pyridazinone compound and intermediate thereof
CN110372562A (en) * 2019-07-09 2019-10-25 上海再启生物技术有限公司 A kind of crystal form and preparation method thereof of BTK kinase inhibitor key intermediate
WO2021057998A1 (en) * 2019-09-29 2021-04-01 上海森辉医药有限公司 Preparation method for pyrroloaminopyridazinone compound
CN112745255A (en) * 2019-10-30 2021-05-04 江苏恒瑞医药股份有限公司 Preparation method of BTK kinase inhibitor

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