- Low-cost preparation method of palbociclib
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The invention discloses a low-cost preparation method of palbociclib. The method comprises the steps: taking 4-(6-aminopyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester as an initial raw material, taking large-steric-hindrance alkali as an acid-binding agent, carrying out nucleophilic substitution reaction with a compound represented by a formula 3, carrying out post-treatment, quenching and dealkalizing to obtain a large-particle compound represented by a formula 4; then taking n-butyl alcohol and water as solvents, taking diisopropylethylamine as an acid-binding agent and a protective agent, and under the action of a composite catalyst palladium chloride and cuprous iodide, carrying out a Herk alkylation reaction with n-butyl vinyl ether; and under the protection of an organic alkali, refining with an ester solvent to obtain a high-purity compound represented by a formula 5 with high yield, and hydrolyzing the compound represented by the formula 5 through a mixed solvent of n-butyl alcohol, anisole and water under an acidic condition to obtain a finished product of palbociclib. The method greatly reduces the usage amount of a palladium catalyst, and is simple and convenient to operate, less in environmental pollution, high in yield, high in product quality and more suitable for industrial production.
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Paragraph 0066-0071
(2021/11/26)
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- Preparation method and process of palbociclib
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The invention relates to a preparation method of palbociclib. The preparation method comprises the steps of 1 reacting a compound I with a compound II to obtain an intermediate I; 2 carrying out a coupling reaction on the intermediate I and vinyl n-butyl ether to obtain an intermediate II; 3 removing a protecting group from the intermediate II under the action of an acid reagent to obtain palbociclib silicate; and 4 carrying out alkali replacement on the palbociclib silicate to obtain palbociclib.
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Paragraph 0034-0038
(2021/03/30)
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- A new route for the synthesis of Palbociclib
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Abstract: In this paper, a novel synthetic method for Palbociclib was reported. It was synthesized in eight steps from 2-(methylthio) pyrimidin-4-(3H)-one with approximately 10% overall yield. This protocol started material 2-(methylthio) pyrimidin-4-(3H)-one, involved nucleophilic substitution by thionyl chloride, bromination, nucleophilic substitution by cyclopentylamine, a one pot-two step method (Heck reaction, ring close sequence), oxidation and bromination, cross-coupling reaction, Heck reaction, aqueous workup to afford Palbociclib. This synthetic route used inexpensive raw material and reagents, involved readily controllable reaction conditions and reduced environmental hazards. Graphic abstract: Synthesis of Palbociclib, a small molecule CDK inhibitor, starting from 2-(methylthio) pyrimidin-4-(3H)-one by 8 steps reaction. This method afforded the Palbociclib in 10% yield. [Figure not available: see fulltext.].
- Li, Shu-ting,Chen, Jun-qing,Feng, Cheng-liang,Yang, Wan-feng,Ji, Min
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p. 3043 - 3051
(2019/10/19)
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- Method for synthesizing palbociclib
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The invention discloses a method for synthesizing palbociclib. The method comprises the following steps: 1, carrying out a coupled reaction on a compound as shown in a formula (II) and a compound as shown in a formula (III) under the action of cyclohexylmagnesium chloride to obtain a compound as shown in a formula (IV); 2, reacting the compound as shown in the formula (IV) with magnesium metal toprepare a Grignard reagent, then, carrying out a Grignard reaction on the Grignard reagent and carbon dioxide, and carrying out hydrolysis to prepare a compound as shown in a formula (V); and 3, reacting the compound as shown in the formula (V) with acetic anhydride under the action of alkaline to obtain a crude product, and deprotecting the crude product under the action of an acid to prepare a target product. The method for synthesizing palbociclib, disclosed by the invention, is cheap and available in raw materials, high in synthesis efficiency, few in impurity, easy to control and suitablefor industrial production and provides a new approach for synthesizing palbociclib.
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Paragraph 0014; 0021-0022
(2019/07/11)
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- Preparation method and product of palbociclib
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The invention discloses a preparation method of palbociclib. The preparation method comprises the following steps: 1) dissolving 4-(6-aminopyridine-3-yl)-piperazine-1-tertiary butyl carboxylate into asolvent A, adding an alkali reagent, activating at 0-20 DEG C, adding 6-bromine-2-chlorine-8-cyclopentyl-5-methyl-pyridino-[2,3-D]-pyrimidine-7(8H)-ketone, adjusting the solution to acid after a reaction is completed, cooling and filtering, taking filter cakes, and drying the filter cakes to obtain an intermediate I; 2) in the presence of an inert atmosphere, dissolving the intermediate I and butyl vinyl ether into a solvent B, catalyzing with a catalyst at 95-105 DEG C, cooling and separating a crystal after the reaction is completed, filtering, and taking the filter cakes, and drying the filter cakes to obtain an intermediate II; 3) dissolving the intermediate II into a solvent C, adding an acid, adjusting the solution to acid after the reaction is completed, filtering, and taking and centrifuging filtrate to obtain a target product, namely palbociclib. By adjusting reaction parameters and optimizing preparation process procedures, the preparation method is high in product yield, good in purity, simple and mild in process conditions and applicable to industrial large-scale production.
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Paragraph 0038; 0039; 0040; 0043; 0044; 0045
(2019/02/27)
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- Potent and Preferential Degradation of CDK6 via Proteolysis Targeting Chimera Degraders
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A focused PROTAC library hijacking cancer therapeutic target CDK6 was developed. A design principle as "match/mismatch" was proposed for understanding the degradation profile differences in these PROTACs. Notably, potent PROTACs with specific and remarkable CDK6 degradation potential were generated by linking CDK6 inhibitor palbociclib and E3 ligase CRBN recruiter pomalidomide. The PROTAC strongly inhibited proliferation of hematopoietic cancer cells including multiple myeloma and robustly degraded copy-amplified/mutated forms of CDK6, indicating future potential clinical applications.
- Su, Shang,Yang, Zimo,Gao, Hongying,Yang, Haiyan,Zhu, Songbiao,An, Zixuan,Wang, Juanjuan,Li, Qing,Chandarlapaty, Sarat,Deng, Haiteng,Wu, Wei,Rao, Yu
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supporting information
p. 7575 - 7582
(2019/08/20)
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- POLYMORPHIC FORMS OF PALBOCICLIB
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The present invention relates to polymorphic forms of palbociclib and processes for preparation thereof,to pharmaceutical compositions comprising palbociclib,and to the use of such compositions for the treatment of cancer.
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Page/Page column 21; 22
(2018/05/15)
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- Protection of renal tissues from ischemia through inhibition of the proliferative kinases CDK4 and CDK6
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The presently disclosed subject matter relates to methods and compositions for protecting cells and or tissues from damage due to ischemia. In particular, the presently disclosed subject matter relates to the protective action of cyclin dependent kinase 4/6 (CDK4/6) inhibitors administered to subjects that have been exposed to, or that are at risk of, ischemia.
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- Novel synthetic method of Palbociclib
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The invention provides a novel synthetic method of Palbociclib, comprising the following steps: 1) under the action of alkali and a solvent, an intermediate V and an intermediate B1 undergo a condensation reaction to obtain a compound VI; 2) the compound VI undergoes exchange with a Grignard reagent, and then the exchange reaction product reacts with an acylation reagent to obtain a compound VII; when X is acetyl, the compound VI is the compound VII; 3) the compound VII undergoes deprotection reaction under the action of hydroxyethanesulphonic acid and finally salification is conducted so as to obtain the finished product Palbociclib X. the synthetic method has a simple process route, is low-cost, and is suitable for industrial production. The synthetic route is as shown in the specification.
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- Deuterated palbociclib derivative and preparation method and application thereof
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The invention belongs to the technical field of pharmaceutical compounds and particularly relates to a deuterated palbociclib derivative and preparation method and application thereof; the deuterated palbociclib derivative has a structure shown as in formula (I); by selectively deuterating active metabolic sites of palbociclib, the metabolic nature of a pharmaceutical is improved, and the therapeutic effect, safety and durability of the pharmaceutical are improved accordingly; through the synthesis of the deuterated palbociclib derivative, a novel compound is provided for synthesizing a novel antitumor pharmaceutical; this compound is applicable to the inhibitor pharmaceutical aspect to inhibit cyclin dependent kinase 4 and/or 6, and the aspect of pharmaceuticals for treating breast cancer, ovarian cancer, liver cancer or acute lymphoblastic leukemia.
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Paragraph 0050; 0052
(2017/08/29)
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- Crystal form of deuteration Palbociclib and preparation method thereof and application
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The invention relates to a compound crystal form, a preparation method thereof and an application, and particularly relates to a crystal form of deuteration Palbociclib and preparation method thereof and an application. The crystal form of deuteration Palbociclib is represented by 2 theta angle diffracted by X-ray powder, and includes 9.98+/-0.2 degrees, 10.19+/-0.2 degrees, 11.45+/-0.2 degrees, 13.97+/-0.2 degrees, 17.03+/-0.2 degrees, 19.62+/-0.2 degrees, 20.09+/-0.2 degrees, 22.43+/-0.2 degrees, and 22.93+/-0.2 degrees; the crystal form has the featured diffraction peak. The crystal form is good in stability, stable in treatment effect and others, and can be applied to prepare CDK4/6 inhibitor drug. The invention further discloses a preparation method of the deuteration Palbociclib crystal matter; the crystal form acquired by the preparation method has high structural uniformity, crystal form purity, and high yield.
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Paragraph 0040; 0041; 0043
(2017/08/31)
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- A deuterium generation Palbociclib derivatives, preparation method and application
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The invention discloses a deuterated palbociclib derivative, and a preparation method and an application thereof. A structural formula of the deuterated palbociclib derivative is as shown in a formula (I), a formula (II), a formula (III) or a formula (IV). According to the deuterated palbociclib derivative disclosed by the invention, through selective deuteration of palbociclib, the pharmacokinetic property of the medicine is improved, thus the curative effect, the safety and the tolerance of the medicine are improved. According to the deuterated palbociclib salt disclosed by the invention, the solubility and the dissolution rate of the medicine are improved; a new compound is provided for synthesis of a novel anti-tumor medicine through synthesis of the deuterated palbociclib derivative; and the deuterated palbociclib derivative has similar biologic activity to the palbociclib, and has a good medicine application prospect.
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- Palbociclib Commercial Manufacturing Process Development. Part I: Control of Regioselectivity in a Grignard-Mediated SNAr Coupling
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This is the first in a series of three papers describing commercial manufacturing process development for palbociclib (1). This manuscript focuses on the SNAr coupling between aminopyridine 3 and chloropyrimidine 7. The regioselectivity of the SNAr coupling was studied from a synthetic and mechanistic perspective. Grignard bases were identified as the preferred class of bases for this reaction, allowing for a simplified process and reduced usage factor for aminopyridine 3. The development of this SNAr reaction into a scalable commercial manufacturing process is also described.
- Duan, Shengquan,Place, David,Perfect, Hahdi H.,Ide, Nathan D.,Maloney, Mark,Sutherland, Karen,Price Wiglesworth, Kristin E.,Wang, Ke,Olivier, Mark,Kong, Fangming,Leeman, Kyle,Blunt, Jon,Draper, John,McAuliffe, Marie,O'Sullivan, Maria,Lynch, Denis
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p. 1191 - 1202
(2016/07/23)
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- CYCLIN DEPENDENT KINASE INHIBITORS AND METHODS OF USE
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The presently disclosed subject matter relates to methods and compositions for protecting healthy cells from damage due to DNA damaging agents. In particular, the presently disclosed subject matter relates to the protective action of selective cyclin dependent kinase 4/6 (CDK4/6) inhibitors administered to subjects that have been exposed to or that are at risk of exposure to DNA damage.
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- Pyrimidine or pyridine pyridine ketone compound and its preparation method and application (by machine translation)
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The invention discloses a kind of type I of the pyrimidine or pyridine pyridine ketone compound and its preparation and application, which belongs to the technical field of pharmaceutical preparation. The compounds have high-efficient and selectively inhibit the cell cycle dependent kinases (Cdks) CDK4 and CDK6 active, and then by inhibiting CDK4/CDK6 prevent tumor cell division. Therefore, the compounds of this invention can be used for CDK4 and CDK6 the involved in cell cycle control disorders result in various diseases, especially suitable for the treatment of malignant tumors. (by machine translation)
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- METHOD OF PRODUCING PALBOCICLIB AND PHARMACEUTICAL COMPOSITIONS COMPRISING THE SAME
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The present invention relates to a method of producing palbociclib and to pharmaceutical compositions comprising the same.
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- Preparation method of Palbociclib isethionate
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The invention belongs to the field of chemical medicine synthesis technology, and more specifically relates to a preparation method of Palbociclib isethionate. The method comprises four steps and is used for preparing Palbociclib, that is 2-(pyridin-2-ylamino)-pyrido[2,3-d]pyrimidin-7-one isethionate. The method has the advantages of mild process conditions, simple post-treatment, high purity, low reaction cost, and easy industrial production.
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Paragraph 0059; 0060; 0061; 0062
(2016/10/10)
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- Industrial preparation method of high-purity palbociclib
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The invention relates to an industrial preparation method of high-purity palbociclib. According to the method, nucleophilic reaction, Heck reaction, rearrangement and protecting group removal are performed in sequence to obtain palbociclib free alkali. The preparation method of the palbociclib has the advantages of extremely high safety, low cost and low environmental pollution, and is favorable for industrial production; the quality of a product meets the requirement of a medicinal preparation on a raw material medicine and meets the high requirement of ICH on the raw material medicine; the content of all individual impurities is 0.1 percent or lower.
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Paragraph 0043; 0050; 0057; 0064; 0070; 0071
(2017/08/23)
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- SOLID FORMS OF A SELECTIVE CDK4/6 INHIBITOR
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This invention relates to the crystalline free base of acetyl-8- cyclopentyl-5-methyl-2-(5-piperazin-l-yl-pyridin-2-ylamino)-8H- pyrido[2,3-d]pyrimidin-7-one, formula (1) having improved properties, to pharmaceutical compositions and dosage forms comprising the free base, and to methods for making and using such compounds, compositions and dosage forms in the treatment of cell proliferative diseases, such as cancer.
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- SYNTHESIS OF 2-(PYRIDIN-2-YLAMINO)-PYRIDO[2,3-D]PYRIMIDIN-7-ONES
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The present invention provides methods of preparing substituted 2-(pyridin-2-ylamino)-pirido[2,3- d]pyrimidin-7-ones (formula 1 ), useful in treating cell proliferative disorders, or a pharmaceutically acceptable salt thereof.
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Page/Page column 26-27
(2008/06/13)
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- Discovery of a potent and selective inhibitor of cyclin-dependent kinase 4/6
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A pharmacological approach to inhibition of cyclin-dependent kinases 4 and 6 (Cdk4/6) using highly selective small molecule inhibitors has the potential to provide novel cancer therapies for clinical use. Achieving high levels of selectivity for Cdk4/6, versus other ATP-dependent kinases, presents a significant challenge. The pyrido[2,3-d]pyrimidin-7-one template provides an effective platform for the inhibition of a broad cross-section of kinases, including Cdks. It is now demonstrated that the modification of pyrido[2,3-d]pyrimidin-7-ones to include a 2-aminopyridine side chain at the C2-position provides inhibitors with exquisite selectivity for Cdk4/6 in vitro. This selectivity profile is recapitulated in cells where the most selective inhibitors create a G1 block at concentrations up to 100-fold the IC50 for cell proliferation. On the basis of its selectivity profile and pharmacokinetic profile, compound 43 (PD 0332991) was identified as a drug candidate for the treatment of cancer.
- Toogood, Peter L.,Harvey, Patricia J.,Repine, Joseph T.,Sheehan, Derek J.,VanderWel, Scott N.,Zhou, Hairong,Keller, Paul R.,McNamara, Dennis J.,Sherry, Debra,Zhu, Tong,Brodfuehrer, Joanne,Choi, Chung,Barvian, Mark R.,Fry, David W.
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p. 2388 - 2406
(2007/10/03)
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- ISETHIONATE SALT OF A SELECTIVE CDK4 INHIBITOR
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Disclosed are polymorphs of the isethionate salt of 6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one, which is a selective cyclin-dependent kinase 4 (CDK4) inhibitor useful for treating inflammation and cell proliferative diseases such as cancer and restenosis.
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Page/Page column 21
(2008/06/13)
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- Combinations of signal transduction inhibitors
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The present invention relates to methods for treating cancer comprising utilizing a combination of signal transduction inhibitors. More specifically, the present invention relates to combinations of so called cell cycle inhibitors with mitogen stimulated kinase signal transduction inhibitors, more specifically combinations of CDK inhibitors with mitogen stimulated kinase signal transduction inhibitors, more preferably MEK inhibitors. Other embodiments of the invention relate to additional combinations of the aforesaid combinations with standard anti-cancer agents such as cytotoxic agents, palliatives and antiangiogenics. Most specifically this invention relates to combinations of 6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one including salt forms, which is a selective cyclin-dependent kinase 4 (CDK4) inhibitor, in combination with one or more MEK inhibitors, most preferably N-[(R)-2,3-dihydroxy-propoxy]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. The aforementioned combinations are useful for treating inflammation and cell proliferative diseases such as cancer and restenosis.
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Page/Page column 26
(2010/02/14)
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