CN112745255A - Preparation method of BTK kinase inhibitor - Google Patents
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- CN112745255A CN112745255A CN202011156225.8A CN202011156225A CN112745255A CN 112745255 A CN112745255 A CN 112745255A CN 202011156225 A CN202011156225 A CN 202011156225A CN 112745255 A CN112745255 A CN 112745255A
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- C07D207/02—Heterocyclic 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
- C07D207/30—Heterocyclic 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
- C07D207/34—Heterocyclic 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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- 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
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Abstract
The present disclosure relates to a method for preparing a BTK kinase inhibitor. Specifically, the disclosure relates to a crystal form I of a compound shown as a formula (A) and a preparation method thereof, which can be used for preparing pyrrolopyridazinone compounds. The novel crystal form disclosed by the invention has good physicochemical properties, and is more beneficial to preparation of the pyrrolopyridazinone compound.
Description
Technical Field
The disclosure relates to a preparation method of a BTK kinase inhibitor, in particular to a crystal form of a raw material for preparing a pyrrolopyridazinone compound and a preparation method thereof.
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), one of the members of the tyrosine protein kinase subfamily, belongs to Tec family kinases, is expressed primarily in B cells, and is distributed in the lymphatic, hematopoietic, and blood systems. B Cell Receptor (BCR) has been clinically proven to have crucial regulatory effects on the proliferation and survival of various lymphomas including Chronic Lymphocytic Leukemia (CLL) and non-hodgkin's lymphoma (NHL) subtypes, Mantle Cell Lymphoma (MCL), and Diffuse Large B Cell Lymphoma (DLBCL), and in addition, the role of B cells in the pathogenesis of rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, and other immune diseases. 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.
WO2016007185 relates to a compound of formula I, (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 which is a novel BTK kinase inhibitor, having improved kinase selectivity, clinical efficacy or indication, and safety, and having the structure shown below:
in the preparation process for preparing the compound of formula (I), the compound of formula (A) is a very important reaction raw material, and the quality of the product of the raw material directly influences the quality of the compound of formula (I). WO2016007185 and WO2019196915 disclose a method for preparing a compound represented by formula (a). The compound shown in the formula (A) prepared by the currently disclosed preparation method has various problems of uneven product content, overproof solvent residue and the like, and the product quality of the compound shown in the formula (I) is seriously influenced. In addition, the compound of formula (a) prepared by the known method is aggregated into a hard block solid after being left for a while, and accurate weighing is difficult, which affects the accuracy of feeding.
Therefore, it is necessary to improve various properties of the above-mentioned raw materials.
Disclosure of Invention
The purpose of the present disclosure is to provide a novel crystal form of a compound represented by formula (a), which has good stability and can be better applied to clinical applications.
In one aspect, the present disclosure provides a crystalline form I of a compound of formula (a), characterized by: the X-ray powder diffraction pattern has characteristic peaks at 2 theta angles of 9.34, 11.84, 14.41, 14.56, 15.28, 17.20, 18.82 and 19.04.
In certain embodiments, the present disclosure provides a crystalline form I of the compound of formula (a) having an X-ray powder diffraction pattern with peaks at 5.89, 7.27, 8.62, 9.34, 10.03, 11.84, 14.41, 14.56, 15.28, 15.97, 16.53, 17.20, 17.83, 18.45, 18.82, 19.04, 20.18, 20.52, 20.82, 21.37, 21.78, 22.42, 23.12, 23.28, 23.59, 23.85, 24.06, 24.31, 24.68, 25.23, 25.42, 26.09, 27.01, 27.36, 27.57, 27.95, 28.23, 28.93, 29.39, 29.77, 30.20, 30.91, 31.26, 31.68, 32.34, 32.74, 2, 33.44, 38.35, 389, 35.36, 35.35, 35.38, 35.9.9.9, 35, 35.9.9.9.9, 35, 38, 35.9.9.9, 38, and 38.9.82 at an angle 2 θ.
In certain embodiments, the present disclosure provides a crystalline form I of a compound represented by formula (a), characterized in that: the X-ray powder diffraction pattern is shown in figure 1.
The present disclosure further provides a process for preparing crystalline form I of a compound represented by formula (a), the process comprising: mixing the compound shown in the formula (A) with a proper amount of solvent, pulping, filtering and crystallizing, wherein the solvent can be C1～C6Alkyl alcohols, ethers, C5～C8One or more of the alkanes is/are,preferably one or more of ethanol, isopropanol, n-heptane, isopropyl ether.
The crystal form obtained by the present disclosure is subjected to structure determination and crystal form research through X-ray powder diffraction pattern (XRPD) and Differential Scanning Calorimetry (DSC).
The crystallization method of the crystalline form in the present disclosure is conventional, such as volatile crystallization, temperature-reduced crystallization or room temperature crystallization.
The starting materials used in the preparation method of the crystal forms disclosed by the present disclosure may be any form of the compound represented by formula (a), and specific forms include, but are not limited to: amorphous, random crystalline, hydrate, solvate, and the like.
The present disclosure further provides a method of preparing a compound of formula (I) comprising the step of reacting a compound of formula (a) in crystal form I as described in the present disclosure.
For example, the compound can be produced by the method described in CN 106573001A.
In certain embodiments, the method of preparation comprises the step of reacting the compound of formula (A) in form I to prepare the compound of formula (III),
in some embodiments, the compound of formula (a) is dissolved in an organic solvent under heating, hydrazine hydrate is added, the reaction is heated under reflux, the mixture is cooled and concentrated, purified water and dichloromethane are added, the mixture is extracted, organic phases are combined, and the mixture is dried, filtered, washed and concentrated to obtain the compound of formula (III); the organic solvent is selected from alcohols, ethers, ketones, sulfones, sulfoxides, amides or nitriles;
the amide solvent is selected from N, N-dimethylformamide or N, N-dimethylacetamide;
the alcohol solvent is selected from methanol, ethanol, isopropanol or n-amyl alcohol;
the ether solvent is selected from tetrahydrofuran or 1, 4-dioxane;
the ketone solvent is selected from N-methyl pyrrolidone;
the nitrile solvent is selected from acetonitrile or propionitrile;
preferably acetone, tetrahydrofuran, acetonitrile, N-methylpyrrolidone, methanol, ethanol or isopropanol, more preferably ethanol;
in certain embodiments, the method further comprises the step of reacting a compound of formula (III) to produce a compound of formula (II),
in some embodiments, the organic solvent is added into the reaction kettle, the Boc protecting group is removed in an acidic system, the compound shown in the formula (III) is added under stirring, the reaction is stirred at room temperature, and the compound shown in the formula (II) is obtained after concentration and drying. The organic solvent is selected from halogenated hydrocarbon, ester, ether or alcohol; the acid is preferably sulfuric acid, hydrochloric acid, acetic acid or trifluoroacetic acid;
the halogenated hydrocarbon solvent is fine dichloromethane, chloroform or carbon tetrachloride;
the ester solvent is selected from ethyl acetate, dimethyl phthalate or butyl acetate;
the ether solvent is selected from tetrahydrofuran, diethyl ether or dioxane;
the alcohol solvent is selected from methanol or ethanol;
preferably dichloromethane, ethyl acetate, tetrahydrofuran or ethanol, more preferably ethyl acetate or ethanol;
in certain embodiments, the method further comprises the step of reacting a compound of formula (II) to produce a compound of formula (I),
in some embodiments, the compound of formula (II) and 2-butynoic acid undergo condensation reaction under condensing agent conditions, purified water is added to the reaction solution, stirring is performed, the aqueous phase is extracted, the organic phase is washed with purified water, drying, filtering, washing, and the filtrate is concentrated to obtain the compound of formula (Ia); the condensing agent is selected from carbonyldiimidazole, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride/1-hydroxybenzotriazole, 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethylurea hexafluorophosphate, dicyclohexylcarbodiimide/4-N, N-dimethylpyridine, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride or oxalyl chloride; carbonyl diimidazole or 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride is preferred.
In certain embodiments, the method of making comprises,
in the description and claims of this application, unless otherwise indicated, scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. However, for a better understanding of the present disclosure, definitions and explanations of some of the relevant terms are provided below. In addition, where the definitions and explanations of terms provided herein are inconsistent with the meanings that would normally be understood by those skilled in the art, the definitions and explanations of terms provided herein shall control.
The term "pulping" as used in the present disclosure refers to a method of purification by utilizing the characteristic that a substance has poor solubility in a solvent, but impurities have good solubility in a solvent, and pulping purification can remove color, change crystal form or remove a small amount of impurities.
The term "X-ray powder diffraction pattern or XRPD" as used in this disclosure refers to the pattern of X-rays according to bragg formula 2d sin θ ═ n λ (where λ is the wavelength of the X-rays,
the order n of diffraction is any positive integer, a first-order diffraction peak is generally taken, n is 1, when X-rays are incident on an atomic plane with a d-lattice plane spacing of a crystal or a part of a crystal sample at a grazing angle theta (complementary angle of incidence, also called Bragg angle), the Bragg equation can be satisfied, and the set of X-ray powder diffraction patterns can be measured.
The "X-ray powder diffraction pattern or XRPD" described in this disclosure is a pattern obtained by using Cu-ka radiation in an X-ray powder diffractometer.
The differential scanning calorimetry or DSC in the present disclosure refers to measuring the temperature difference and heat flow difference between a sample and a reference substance during the temperature rise or constant temperature process of the sample to characterize all the physical changes and chemical changes related to the thermal effect and obtain the phase change information of the sample.
The "2 theta or 2 theta angle" referred to in the present disclosure means the diffraction angle, theta is the bragg angle in degrees or degrees, and the error range of 2 theta is ± 0.3 or ± 0.2 or ± 0.1.
The term "interplanar spacing or interplanar spacing (d value)" as used in this disclosure means that the spatial lattice selects 3 non-parallel unit vectors a, b, c connecting two adjacent lattice points, which divide the lattice into juxtaposed parallelepiped units, called interplanar spacing. The space lattice is divided according to the determined connecting lines of the parallelepiped units to obtain a set of linear grids called space grids or lattices. The lattice and the crystal lattice respectively reflect the periodicity of the crystal structure by using geometrical points and lines, and the surface spacing (namely the distance between two adjacent parallel crystal surfaces) of different crystal surfaces is different; has a unit of
Or angstroms.
Advantageous effects of the invention
The compound shown in the formula (A) prepared by the method has the advantages of high crystal form I purity, good crystal form stability under the conditions of illumination, high temperature and high humidity, small HPLC purity change and high chemical stability, and is more favorable for storage and use of raw materials. In addition, the compound shown in the formula (A) has low moisture and solvent residue of the crystal form I, and is more suitable to be used as a raw material for preparing the compound shown in the formula (A).
Drawings
FIG. 1 is an XRPD pattern for crystalline form I of a compound of formula (A);
FIG. 2 is a DSC of crystalline form I of the compound of formula (A);
FIG. 3 is an amorphous XRPD pattern of a compound of formula (A).
Detailed Description
The present disclosure will be explained in more detail with reference to examples, which are provided only for illustrating the technical solutions of the present disclosure and do not limit the spirit and scope of the present disclosure.
Test conditions of the apparatus used for the test:
1. differential Scanning Calorimeter (DSC)
The instrument model is as follows: mettler Toledo DSC 1STARe System
And (3) purging gas: nitrogen gas
The heating rate is as follows: 10.0 ℃/min
Temperature range: 40-300 deg.C
2. X-ray Diffraction Spectroscopy (XRPD)
The instrument model is as follows: BRUKER D8 Focus 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
According to CN106573001A example 93, amorphous compound of formula (A) is prepared, and its X-ray diffraction pattern is shown in figure 3.
Example 2
First step, synthesis of Compound represented by formula (SM1-1)
Under nitrogen protection, compound SM1-b (20g), tert-butylamine (9.91g), and 4-dimethylaminopyridine (5.17 g) were added to toluene (400mL), the reaction mixture was heated to reflux and stirred for 6 hours, after the reaction was completed, the reaction was stopped, concentrated, and subjected to column chromatography (eluent petroleum ether: ethyl acetate: 5:1) to obtain the objective compound (16.6g, yield 74.5%).
Second step, Synthesis of Compound represented by the formula (SM2-2)
Adding acetic acid (2600mL) and ammonium acetate (411.42g) into a reaction bottle, stirring the mixture to be completely dissolved, adding nitromethane (912.2g) solution of a compound SM2-c (500g), heating the mixture in an oil bath to 90 ℃, preserving the temperature for 5 hours for reaction, stopping the reaction, removing the oil bath, adding water (5.2L), precipitating a solid, stirring the mixture for crystallization for 2 hours, and filtering the mixture to obtain crude product 662 g; isopropanol (2.5L) was added, dissolved to dryness at reflux, cooled to room temperature, stirred overnight, filtered and dried to give the product (443g, 74.9% yield).
Step three, synthesis of Compound represented by formula (E1)
Under the protection of nitrogen, compound SM1-1(2.28g), compound SM3-2(1.88g), compound SM2-2 (2g) and nitromethane (4.4g) were added to toluene (50mL), iron trichloride (234mg) was added, the reaction solution was heated to reflux and stirred for 2 hours, after the reaction was completed, the reaction solution was cooled to room temperature, and column chromatography was performed (eluent petroleum ether: ethyl acetate ═ 2:1) to separate and purify the product (3.4g, yield 69.9%).
Step four, Synthesis of Compound represented by the formula (D1)
Adding a compound E1(30g) and methanol (300mL) into a reaction bottle, stirring, adding palladium hydroxide (9.0g), using a hydrogen replacement system for three times, finally heating the reaction solution to 50 ℃ for hydrogenation, stirring, cooling to room temperature after complete reaction, filtering through kieselguhr, concentrating the filtrate to obtain a crude product 27.0g, and directly using the crude product in the next oxidation reaction.
Fifth step Synthesis of Compound represented by the formula (C1)
Compound D1(27.0g) was added to a reaction flask in dimethyl sulfoxide (270mL), dissolved by stirring, S-IBX (56.5g, IBX content-47%) was added at once, and the reaction was stirred at 40 ℃ for 1 hour, after completion of the reaction, the reaction solution was naturally cooled, methyl t-butyl ether (200mL) was added, the layers were sufficiently stirred, celite was filtered to remove solids, the filtrate was extracted with methyl t-butyl ether (200mL × 3), the organic phases were combined, the organic phase was washed with water (150mL × 3) three times, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the product (26.0g, yield 96.6%).
Sixth step Synthesis of Compound represented by formula (B1)
Compound C1(26.0g), tert-butanol (500mL) and isoamylene (57.6mL) were charged into a reaction flask, and dissolved with stirring, sodium chlorite (20.7g) and sodium dihydrogen phosphate (12.4g) were dissolved in water (100mL), and the solution was dropped into the reaction solution, after completion of the dropping, the reaction was stirred at 20 ℃ to complete the reaction, and after completion of the reaction, most of the tert-butanol was concentrated and removed, water (300mL) was added, followed by extraction with methyl tert-butyl ether (300mL × 3), the organic phases were combined, the organic phase was washed with water (200mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a product (28.3g, yield 105.8%).
Seventh step Synthesis of Compound represented by the formula (A1-1)
Compound B1(28.3g) and dichloromethane (400mL) were added to a reaction flask, trifluoroacetic anhydride (20.4g) was dissolved in dichloromethane (160mL), and the solution was dropped into the above reaction system, after completion of the dropping, the reaction was carried out at room temperature, 200mL of water was added after completion of the reaction, the mixture was sufficiently stirred and separated, the aqueous phase was extracted with dichloromethane (200mL × 2), the organic phases were combined, washed with water to neutrality, dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain a product (25.0g, yield 100%).
The resulting 25.0g of crude product was dissolved in methyl tert-butyl ether (200mL), tert-butylamine (6.2mL) was diluted in methyl tert-butyl ether (50mL) and slowly added dropwise to the system, stirred at room temperature to slowly precipitate a solid, stirred for 5h, filtered under suction, the filter cake washed with methyl tert-butyl ether and dried under vacuum to give the product (21.5g, 75% yield, 94.1% purity).
Eighth step Synthesis of Compound represented by formula (A)
Tert-butylamine salt of compound a1-1 (21.5g), potassium carbonate (15.3g) and N, N-dimethylformamide (200mL) were charged to a reaction flask, the mixture was cooled with ice water, iodoethane (8.8mL) was added thereto, after completion of dropwise addition, the ice bath was removed, the reaction was carried out at 30 ℃ until the starting material was completely consumed, water (200mL) was added, extraction was carried out with methyl tert-butyl ether (200mL × 3), the organic phases were combined, the organic phase was washed with water (100mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the product, compound represented by formula (a) (18.5g, yield 91%), which was determined to be amorphous.
Example 3
The compound represented by the formula (B1) (276g) in example 2 was dissolved in tetrahydrofuran (2.76L), and potassium carbonate (130.8g) and diethyl sulfate (109.3g) were added. Stirring, heating and refluxing for 10 hours, stopping the reaction, cooling the reaction solution to room temperature, concentrating to dryness, and separating and purifying by column chromatography (ethyl acetate: petroleum ether: 1:5) to obtain the compound shown as the formula (B1-1) with the purity of 97.96%.
MS m/z(LC-MS):612.47[M+1]
The compound represented by the formula (B1-1) obtained in the above step was added to methylene chloride (1.7L), and a solution of trifluoroacetic anhydride (165.7g) in methylene chloride (500mL) was slowly added at 0 ℃. After dropping, the temperature was slowly raised to room temperature and the reaction was stirred for 5 hours, and the reaction was stopped. The reaction mixture was quenched by adding methanol (200mL), washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue of the compound represented by the formula (A) in 92% yield and 96.2% purity, which was determined to be amorphous.
Example 4
Placing amorphous 20mg of the compound shown in the formula (A) into a reaction bottle, adding 600 mu l of absolute ethyl alcohol, pulping for 36h, filtering, and drying at 40 ℃ to obtain the crystal form I of the compound shown in the formula (A). The X-ray diffraction pattern is shown in figure 1, the DSC pattern is shown in figure 2, and the characteristic peak positions are shown in the following table:
example 5
Placing amorphous 20mg of the compound shown in the formula (A) into a reaction bottle, adding 600 mu l of isopropanol, pulping for 36h, filtering, and drying at 40 ℃ to obtain the crystal form I of the compound shown in the formula (A).
Example 6
The compound I crystal form and amorphous form of the formula (A) are examined for stability. The detection method comprises the following steps: agilent 1200 high performance liquid chromatography system with detection column water symmetry C18, (250 × 4.6mm,5 μm), mobile phase: potassium dihydrogen phosphate/ACN/H2O, detection wavelength: 210 nm.
As can be seen from the table, the crystal form I has good physical and chemical stability after long-term storage; whereas the amorphous form is poorly stable under light conditions.
In addition, we have found that after the amorphous and crystal form I of the compound of formula (a) are left to stand for a period of time, especially when a large batch (more than 1 kg) of the compound of formula (a) is left to stand in a concentrated manner, amorphous raw materials are aggregated into a massive solid to form a hard whole, and the taking and weighing are very difficult, which greatly affects the subsequent product preparation. And the crystal form I product still presents a powdery solid after being placed for a long time, has good fluidity and is easy to accurately weigh.
Example 7
The moisture and solvent residues of the crystal form I and the amorphous form were measured and the results are shown in the following table. The detection method comprises the following steps: agilent 7890B gas chromatograph with 6% cyanopropylphenyl-94% dimethylpolysiloxane detection column.
As can be seen from the table, both the moisture and solvent residues of form I are low; the amorphous product is easy to wrap solvent and moisture, and the product quality is influenced.
Example 8
According to the method of WO2019196915, 16.0kg of the compound I crystal form of the formula (A) is thrown in, and 8.26kg of the compound of the formula (I) is finally obtained, wherein the HPLC purity is 99.75%, and the water content is 0.2%.
Claims (7)
1. A crystal form I of a compound shown as a formula (A) has an X-ray powder diffraction pattern which has characteristic peaks at 2 theta angles of 9.34, 11.84, 14.41, 14.56, 15.28, 17.20, 18.82 and 19.04,
2. a crystalline form I of the compound of formula (a) according to claim 1, characterised by an X-ray powder diffraction pattern having peaks at 5.89, 7.27, 8.62, 9.34, 10.03, 11.84, 14.41, 14.56, 15.28, 15.97, 16.53, 17.20, 17.83, 18.45, 18.82, 19.04, 20.18, 20.52, 20.82, 21.37, 21.78, 22.42, 23.12, 23.28, 23.59, 23.85, 24.06, 24.31, 24.68, 25.23, 25.42, 26.09, 27.01, 27.36, 27.57, 27.95, 28.23, 28.93, 29.39, 29.77, 30.20, 30.91, 31.26, 31.68, 32.34, 32.74, 2, 33.44, 34.82, 3936, 38735, 3935, 35.38, 3936, 3899.35, 35, 35.9.9.9.9.9.9, 18, 3.9.9, 3, 3.9.9.9, 3, 3.9.9, 3, 3.9.9.9.36, 3, 3.36, 3, 3.6.
3. The crystalline form I of the compound of formula (a) according to claim 1, characterized by the X-ray powder diffraction pattern as shown in figure 1.
4. A crystalline form I of the compound of formula (a) according to any one of claims 1 to 3, characterized in that: the error range of the 2 theta angle is +/-0.2.
5. A process for preparing a crystalline form I of the compound of formula (a) as claimed in any one of claims 1 to 4, which process comprises: mixing the compound shown in the formula (A) with a proper amount of solvent, pulping, filtering and crystallizing, wherein the solvent is selected from C1～C6Alkyl alcohols, ethers, C5～C8One or more alkanes, preferably one or more of ethanol, isopropanol, n-heptane, isopropyl ether.
6. A process for the preparation of a compound of formula (I) comprising the step of carrying out a reaction using the crystalline form I of a compound of formula (A) according to any one of claims 1 to 4,
7. the method of making according to claim 6, comprising:
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN114751850A (en) * | 2022-06-06 | 2022-07-15 | 上海再启生物技术有限公司 | Preparation method of key intermediate of BTK kinase inhibitor |
| CN114989062A (en) * | 2022-07-04 | 2022-09-02 | 上海再启生物技术有限公司 | Crystal form of BTK kinase inhibitor intermediate and preparation method thereof |
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| CN107406453B (en) * | 2016-01-05 | 2018-12-28 | 江苏恒瑞医药股份有限公司 | A kind of crystal form and preparation method thereof of BTK kinase inhibitor |
| 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 |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN114751850A (en) * | 2022-06-06 | 2022-07-15 | 上海再启生物技术有限公司 | Preparation method of key intermediate of BTK kinase inhibitor |
| CN114751850B (en) * | 2022-06-06 | 2023-08-25 | 上海再启生物技术有限公司 | Preparation method of key intermediate of BTK kinase inhibitor |
| CN114989062A (en) * | 2022-07-04 | 2022-09-02 | 上海再启生物技术有限公司 | Crystal form of BTK kinase inhibitor intermediate and preparation method thereof |
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