- NOVEL PROCESS FOR THE PREPARATION OF ACALABRUTINIB AND ITS INTERMEDIATES
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The present invention relates to an improved and industrially viable process for the preparation of Acalabrutinib and its Intermediates. The present invention involves less expensive reagents, solvents and the process conditions can be easily adopted for commercial scale. The present invention relates to process for the preparation Acalabrutinib of formula (1) and process for the preparation of Acalabrutinib key starting material.
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- PROCESS FOR THE PREPARATION OF ACALABRUTINIB AND ITS INTERMEDIATES
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The present invention provides an improved and industrially viable process for the preparation of Acalabrutinib and its intermediates in high yield and eliminating the use of time-consuming purification process. The present invention also relates to the purification of (S)-4-(8-Amino-3-(pyrrolidin-2-yl)imidazo[1,5-alpyrazin-1-yl)-N-(pyridin-2-yl) benzamide, a key intermediate for the preparation of Acalabrutinib. Further present invention relates to new polymorphic form of Acalabrutinib.
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- Method for preparing Acalabrutinib, in particular to method for preparing Acalabrutinib
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The invention relates to the field of chemical synthesis, in particular to a chemical synthesis method for preparing Acalabrutinib. The synthesis method of the compound 3 is optimized, wherein the cyano compound 2 is reduced to obtain the compound 3 by adopting a method of generating borane in situ under the conditions of indium trichloride and sodium borohydride. The method is simple and convenient to operate, a special reaction container and hydrogen are not needed for reduction, a high-risk material catalyst nickel is prevented from being adopted, and large-scale production is facilitated.In the preparation of the compound 15, water is used as a solvent, equivalent hydrogen peroxide is added to react the compound 13 with the compound 14 to prepare the compound 15, so that the method iseconomic and environment-friendly, the post-treatment is simple and convenient, and the reaction liquid is directly subjected to centrifugal operation; in addition, the yield is high and can reach 90% or above; and the compound 15 is high in purity and does not need to be further purified, so that the technology can satisfy the requirements of industrial production.
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- PROCESSES FOR THE PREPARATION OF 4-{8-AMINO-3-[(2S)-1-(BUT-2-YNOYL)-PYRROLIDIN-2-YL]IMIDAZO[1,5-A]-PYRAZIN-1-YL}N-(PYRIDIN-2-YL)-BENZAMIDE
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The present disclosure relates, in general, to improved processes for the preparation of 4-{8-amino-3-[(2S)-1-(but-2-ynoyl)pyrrolidin-2-yl]imidazo[1,5-a]pyrazin-1-yl}-N-(pyridin-2-yl)-benzamide, particularly large-scale processes for manufacturing 4-{8-amino-3-[(2S)-1-(but-2-ynoyl)pyrrolidin-2-yl]imidazo[1,5-a]pyrazin-1-yl}-N-(pyridin-2-yl)benzamide and intermediates used in such processes.
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Paragraph 00225-00228
(2020/03/23)
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- Preparation method capable of acalabrutinib being used for treating leukemia
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The invention relates to a preparation method of acalabrutinib capable of being used for treating leukemia. The synthesis method of the compound 3 is optimized, so that according to the method, the cyano compound 2 is reduced to obtain the compound 3 by adopting a method of generating borane in situ under the conditions of indium trichloride and sodium borohydride. The method is simple and convenient to operate, a special reaction container and hydrogen are not needed for reduction, a high-risk catalyst nickel is prevented from being adopted, and large-scale production is facilitated; in the preparation of the compound 8, under the condition of a catalyst, large-scale preparation is realized by adding an ammonia water closed system, so that a method of introducing ammonia gas at an extremely low temperature is avoided, and large-scale production is facilitated.
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Paragraph 0045-0046
(2020/07/24)
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- SOLID STATE FORMS OF ACALABRUTINIB
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The present disclosure relates to solid state forms of Acalabrutinib, processes for the preparation thereof and pharmaceutical compositions comprising said solid state forms of Acalabrutinib.
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Paragraph 0147; 0150
(2020/10/20)
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- PROCESSES TO PRODUCE ACALABRUTINIB
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The present invention relates to a method for preparing the compound of formula IV, compound of formula XI, and acalabrutinib, a new generation of bruton tyrosine kinase (BTK) inhibitor.
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- A method for preparing [...] (by machine translation)
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The present invention provides a method for preparing [...], using N - (pyridine - 2 - yl) terephthalic acid (II) and the thiosulfuric amide under the action of the second grade nitrile in alkali, by condensation reaction, with a halo reagent generating halogenated reaction, and [1 - (1 - oxo - 2 - [...] - 1 - yl)] - S - pyrrolidinyl - 2 - carboxamidine hydrochloride (V) generate the cyclization condensation reaction, and 2 - halogenated acetal diol substituted reaction, ammonium salt - ammonia in the presence of chemical and biological [...] (I) ring. The method of the invention the reaction route is short, simple steps, reaction conditions are easy to control, and the cost is low, and yield and high purity, it is suitable for industrial production. (by machine translation)
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- Imidazopyrazines as Selective BTK Inhibitors
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The invention relates to imidazopyrazine compounds as selective Bruton's tyrosine kinase (BTK) inhibitors. In particular, the invention discloses (S)-4-(8-amino-3-(1-(butyl-2-acetylenyl) pyrrolidine-2-yl) imidazo [1, 5-a] pyrazine-1-yl)-N-(pyridine-2-yl) benzamide and a deuterated compound of an optical isomer thereof, or a pharmaceutically acceptable salt or to a pharmaceutical composition containing the compound, and use thereof in the treatment of BTK-mediated diseases.
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Paragraph 0098-0100; 0122-0123; 0180-0183
(2019/12/25)
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- Preparation method of Acalabrutinib
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The invention discloses a synthesis method of Acalabrutinib. The method comprises the following steps: (1) carrying out oxidative amidation through a compound expressed as a formula I and a compound expressed as a formula II to prepare a compound expressed as a formula III; (2) carrying out condensation through the compound expressed as the formula III and ammonia; (3) preparing a Grignard reagentfrom a compound expressed as a formula V and magnesium and carrying out addition through the Grignard reagent and a compound expressed as a formula IV to prepare a compound expressed as a formula VI;(4) carrying out acylation reaction through the compound expressed as the formula VI and a compound expressed as a formula VII to prepare a compound expressed as a formula VIII; (5) carrying out cyclization through the compound expressed as the formula VIII under the action of a catalyst to prepare a compound expressed as a formula IX; and (6) carrying out amination through the compound expressedas the formula IX to prepare a compound expressed as a formula X, wherein the compound is Acalabrutinib. Through the method, expensive 3-chlorine-2-formaldehyde pyrazine is not used; the cost is reduced; in addition, the method is short in route and high in yield; the reaction of each step is relatively mild and is not related to toxic and dangerous chemical reagents; the method is suitable for industrial production; the formulae I, II, III, IV, V, VI, VII, VIII, IX and X are as shown in description.
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- Acalabrutinib and its intermediate synthesis method (by machine translation)
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The invention discloses a method for synthesizing Acalabrutinib, including proline derivatives of formula L - 1 and 2 - chloro - 2 - formyl acetonitrile as the starting material by direct condensation and cyclization of formula 2, after the bromo acetal with low-cost [...] methanol intermediate obtained by reaction of formula 3, followed by hydrolysis, cyclization reaction to obtain the key intermediate of formula 6, then with the borate intermediates of formula 8 to Suzuki coupling, then deprotected and get of formula 10, finally with the final product is obtained butynoic acid condensation Acalabrutinib type 11. The route the operation is simple, not only higher total yield, purity of the obtained products is also high, and suitable for production. (by machine translation)
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- PROCESSES FOR THE PREPARATION OF ACALABRUTINIB AND INTERMEDIATES THEREOF
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The present invention provides processes for the preparation of Acalabrutinib (1), as well as intermediates useful in the preparation thereof. In particular, processes are provided for coupling of a compound of Formula (5) and 2-butynoic acid in the presence of Carbodiimide (8) to afford Acalabrutinib (1).
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- Synthesis method of BTK inhibitor Acalabrutinib for treating chronic lymphocytic leukemia
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A synthesis method of a BTK inhibitor Acalabrutinib for treating chronic lymphocytic leukemia comprises the steps as follows: preparing (S)-2-(8-aminoimidazo[1,5-a]pyrazine-3-yl)-1-pyrrolidinecarboxylic aci benzyl ester; preparing (S)-2-(8-tert-butoxycarbonylaminoimidazo[1,5-a]pyrazine-3-yl)-1-pyrrolidinecarboxylic acid benzyl ester; preparing (S)-2-(8-tert-butoxycarbonylamino-1-bromoimidazo[1,5-a]pyrazine-3-yl)-1-pyrrolidinecarboxylic acid benzyl ester; preparing (S)-2-(8-tert-butoxycarbonylamino-1-[4-(2-pyridylcarbamoyl)phenyl]imidazo[1,5-a]pyrazine-3-yl)-1-pyrrolidinecarboxylic acid benzyl ester; preparing (S)-2-(8-tert-butoxycarbonylamino-1-[4-(2-pyridylcarbamoyl)phenyl]imidazo[1,5-a]pyrazine-3-yl)pyrrolidine; preparing (S)-2-(8-tert-butoxycarbonylamino-1-[4-(2-pyridylcarbamoyl)phenyl]imidazo[1,5-a]pyrazine-3-yl)-1-(2-butynoyl)pyrrolidine; preparing Acalabrutinib. The yield is high, the process is simplified, and the synthesis method is green and environmentally friendly.
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Paragraph 0048; 0049; 0050; 0064; 0065; 0079; 0080
(2018/01/19)
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- Preparation method of acalabrutinib
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The invention discloses a preparation method of a new drug acalabrutinib applicable to treatment of leukemia. The preparation method comprises the steps of condensation, acylation, cyclization, amination and other reactions by using 3-chloro-2-formylpyrazine as the raw material, thereby obtaining the acalabrutinib. The preparation method of acalabrutinib has the advantages of accessible raw materials, simple technique and the like, is economical and environment-friendly, and is suitable for large-scale industrial production.
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- BTK INHIBITORS TO TREAT SOLID TUMORS THROUGH MODULATION OF THE TUMOR MICROENVIRONMENT
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In certain embodiments, the invention includes therapeutic methods of using a BTK inhibitor to treat solid tumor cancers by modulation of the tumor microenvironment, including macrophages, monocytes, mast cells, helper T cells, cytotoxic T cells, regulatory T cells, natural killer cells, myeloid-derived suppressor cells, regulatory B cells, neutrophils, dendritic cells, and fibroblasts.
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- THERAPEUTIC COMBINATIONS OF A BTK INHIBITOR, A PI3K INHIBITOR, A JAK-2 INHIBITOR AND/OR A CDK 4/6 INHIBITOR
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Therapeutic combinations of a phosphoinositide 3-kinase (PI3K) inhibitor, including PI3K inhibitors selective for the γ- and δ-isoforms and selective for both γ- and δ-isoforms (PI3K-γ,δ, PI3K-γ, and PI3K-δ, a Janus kinase-2 (JAK-2) inhibitor, a cyclin-dependent kinase- 4/6 (CDK4/6) inhibitor, and/or a Bruton's tyrosine kinase (BTK) inhibitor are described. In certain embodiments, the invention includes therapeutic combinations of a cyclin-dependent kinase-4/6 (CDK4/6) inhibitor and a BTK inhibitor, a PI3K-δ inhibitor and a BTK inhibitor, a JAK-2 and a BTK inhibitor, and a JAK-2, PI3K-δ, and BTK inhibitor.
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- THERAPEUTIC COMBINATIONS OF A BTK INHIBITOR, A PI3K INHIBITOR, A JAK-2 INHIBITOR, AND/OR A BCL-2 INHIBITOR
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Therapeutic combinations of a phosphoinositide 3-kinase (PI3K) inhibitor, including PI3K inhibitors selective for the γ- and δ-isoforms and selective for both γ- and δ-isoforms (PI3K-γ,δ, PI3K-γ, and PI3K-δ), a Janus kinase-2 (JAK-2) inhibitor, a Bruton's tyrosine kinase (BTK) inhibitor, and/or a B-cell lymphoma-2 (BCL-2) inhibitor are described. In some embodiments, the invention provides therapeutic combinations of a PI3K-δ inhibitor and a BTK inhibitor, a JAK-2 and a BTK inhibitor, and a BCL-2 and BTK inhibitor.
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- 4 - IMIDAZOPYRIDAZIN- 1 -YL-BENZAMIDES AND 4 - IMIDAZOTRIAZIN- 1 - YL - BENZAMIDES AS BTK- INHIBITORS
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The present invention relates to 6-5 membered fused pyridine ring compounds according to formula (I) or a pharmaceutically acceptable salt thereof or to pharmaceutical compositions comprising these compounds and to their use in therapy. In particular, the present invention relates to the use of 6-5 membered fused pyridine ring compounds according to formula I in the treatment of Brutons Tyrosine Kinase (Btk) mediated disorders.
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Page/Page column 35-36
(2013/03/26)
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