- 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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- Preparation method of palbociclib intermediate
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The invention discloses a preparation method of a palbociclib intermediate. The method comprises the following steps: preparing 5-bromine-2-chloro-N-cyclopentylamine pyrimidine-4 amine from 5-bromine-2,4-dichloropyrimidine and cyclopentylamine by taking solvents such as dichloromethane and water as solvents and taking inorganic base as an acid-binding agent; with DIEA as an acid-binding agent, DMF as a solvent and TBAB as a phase transfer catalyst, in the presence of water, catalyzing with a trace amount of palladium, and carrying out normal hexane reflux dehydration; further subjecting the acetic anhydride to dehydration cyclization, such that 2-chloro-8-cyclopentyl-5-methylpyridino[2,3-D]pyrimidine-7-(8H)-ketone is obtained; and reacting the obtained compound with NBS (N-bromosuccinimide) in acetonitrile to obtain the 6-bromo-2-chloro-8-cyclopentyl-5-methylpyridino[2, 3-D]pyrimidine-7(8H)-ketone. The method is mild in reaction, simple and convenient to operate, recyclable in solvent, less in environmental pollution, high in yield, low in cost, high in product quality and suitable for industrial production.
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Paragraph 0035; 0038-0040; 0043; 0046; 0047
(2021/06/06)
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- Preparation method of CDK4/6 kinase inhibitor SHR6390
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The invention relates to a preparation method of a CDK4/6 kinase inhibitor SHR6390. According to the preparation method disclosed by the invention, the SHR6390 can be rapidly and effectively prepared through six steps of chemical reactions. In the first step of reaction, the advantage of high reaction activity of the fourth site of pyrimidine is fully utilized, a target product compound 3 can be well obtained under mild conditions, in the fourth step of reaction, after-treatment of the synthesis reaction of a compound 8 is simple, a good white solid product can be obtained basically through filtration and washing, purification is not needed, and the method is suitable for amplification and process production.
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Paragraph 0056; 0073-0079
(2021/05/12)
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- Discovery of 5-methylpyrimidopyridone analogues as selective antimycobacterial agents
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With the emergence of multidrug-resistant strains of Mycobacterium tuberculosis (MDR-TB) and extensive drug-resistant strains (XDR-TB), there is an urgent need to develop novel drugs for the treatment of tuberculosis. Here, we designed and synthesized a series of 5-methylpyrimidopyridone analogues as potential antitubercular agents. The most potent compound 6q exhibited a MIC value of 4 μM in vitro against Mycobacterium tuberculosis. The antitubercular activities of the synthesized compounds were impacted by the amantadine and 2-chlorophenyl groups, and were enhanced by the presence of 3-methyl(4-dimethylamino)piperidinylphenyl. Molecular modeling and binding studies suggest that PknB is the potential molecular target of 5-methylpyrimidopyridone compounds. This study provides insights for the future development of new antimycobacterial agents with novel mechanisms of action.
- Wu, Yu,Cheung, Chen-Yi,Zhou, Yang,Wang, Zhen,Tu, Zhengchao,Cook, Gregory M.,Lu, Xiaoyun
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- Preparation method of palbociclib intermediate
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The invention relates to the field of medicine synthesis, in particular to a preparation method of a palbociclib intermediate. According to the preparation method, a compound I, namely 2,4-dichloropyrimidine is used as an initial raw material, and is subjected to substitution by cyclopentylamine, amine ester exchange with methyl acetoacetate and catalytic cyclization by boron trifluoride diethyl ether so as to obtain a target compound IV, namely 2-chloro-8-cyclopentyl-5-methyl-8H-pyrido[2,3-D]pyrimidinyl-7-one. The synthesis route designed by the invention avoids the use of a palladium catalyst, has the advantages of mild overall reaction conditions, high reaction yield and low production cost, is suitable for industrial production, and is green and environment-friendly.
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Paragraph 0029; 0038-0041
(2020/07/28)
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- Preparation method of palbociclib parent nucleus structure compound
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The invention provides a preparation method of a palbociclib mother nucleus structure compound. The preparation method comprises the following step: preparing the palbociclib parent nucleus structurecompound as shown in a formula (I) which is described in the specification by taking cytosine or an intermediate 1 or an intermediate 2 as a starting raw material, wherein the intermediate 1 and the intermediate 2 are as described in the specification, and X is selected from halogen. The method is wide in the source of the starting material, simple in operation process, less in side reaction and high in purity, and accords with the concept of modern green industrial production.
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Paragraph 0069-0071; 0082-0085
(2020/07/15)
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- Preparation method of pyridine pyrimidine derivative
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The invention discloses a preparation method of a pyridine pyrimidine derivative. The preparation method comprises following steps: 3-methyl-2-glutaconate diester and cyclopentamine are subjected to amidation condensation to prepare 1-cyclopentyl-4-methylpyridine-2, 6-(1H, 5H)-dione, and one-pot condensation with methylation reagent (N, N-dimethylformamide acetal) and urea is carried out so as toobtain 2-hydroxyl-5-methyl-8-cyclopentyl pyridine [2, 3-d] pyrimidine-8-hydro-7-one; and then chlorination and bromination reaction are carried out to prepare 2-chlor-5-methyl-6-bromo-8-cyclopentyl pyridine [2, 3-d] pyrimidine-8-hydro-7-one. The preparation method possesses following advantages: using of expensive trihalogen pyrimidine, palladium salt catalyst, and 3-borate substituted ethyl crotonate is avoided; the adopted raw materials are cheap and easily available; operation is convenient; reaction yield is stable; less three wastes are generated; reaction atom economical benefit is high;cost is low; and the preparation method is convenient for green industrialized production.
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Paragraph 0041-0042; 0055-0056; 0062-0063
(2019/08/07)
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- Synthesis method of key intermediate V of Palbociclib
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The invention discloses a synthesis method of a key intermediate V of Palbociclib. The method comprises the following steps: (1) performing coupling reaction on 5-bromo-2,4-dichloropyrimidine and cyclopentylamine in an organic solvent in the presence of an alkali to obtain compound 5-bromo-2-chloro-6-cyclopentylamine-pyrimidine; (2) in the presence of triethanolamine, using metal palladium or a metal salt thereof as a catalyst, carrying out heck coupling reaction on the 5-bromo-2-chloro-6-cyclopentylamine-pyrimidine and crotonic acid to obtain a compound II; (3) in the presence of an organic solvent, using acetic anhydride as a cyclization reagent for cyclization to obtain target product compound III, 2-chloro-8-cyclopentyl-5-methylpyridino [2,3-D] pyrimidine-7 (8H)-one. The step (2) of the synthesis method of the key intermediate of THE Palbociclib adopts triethanolamine as both an alkali and a solvent. The reaction system is simpler without adding the alkali and an expensive phosphorus-containing ligand and the like. At the same time the triethanolamine is cheap and easily available.
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Paragraph 0006; 0015; 0017; 0018; 0020
(2019/10/04)
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- Preparation method of Palbociclib intermediate
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The invention relates to the field of medicine synthesis, and discloses a preparation method of a Palbociclib intermediate. In the preparation process, 5-bromine-2,4-dichloropyrimidine is used as a starting raw material; through ammoniation substitution reaction, green solvent PEG (polyethylene glycol) promotion palladium catalysis coupled reaction, BTC (triphosgene) promotion cyclization reactionand NBS (N-bromosuccinimide) bromination reaction, a target compound V is finally obtained; through aftertreatment improvement, the HPLC purity of the final product can reach 99 percent or higher. Compared with a traditional process, the preparation method has the main beneficial effects that the reaction conditions are mild; the operation is simple and convenient; the palladium catalyst consumption is low; the yield is high; the cost is low; the three-waste quantity is small; the industrialization is easy; high implementation values and socioeconomic benefits are realized.
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Paragraph 0040; 0051-0055; 0068-0070; 0081-0083; 0094-0096
(2019/04/11)
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- PYRIMIDINE OR PYRIDOPYRIDONE COMPOUND AND APPLICATION THEREOF
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The present invention discloses a pyrimidine or pyridopyridone compound as shown in formula (I) and an application thereof relating to the technical field of medicament preparation. The compound can selectively suppress cyclin-dependent kinases (Cdks) CDK
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Paragraph 0046; 0049
(2018/11/21)
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- Palbociclib intermediate synthesizing method
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The invention discloses a palbociclib intermediate synthesizing method. According to the method, 2,4-dichloro-5-bromopyrimidine is utilized as a starting raw material; firstly, 5-position bromine is replaced by Grignard reaction; then, the starting material reacts with a boryl replacing reagent to generate aryl boric acid; then, the starting raw material couples with methyl 3-iodo crotonate through Suzuki reaction; then, pyrimidine ring subjects substitution reaction with cyclopentylamine under existence of organic alkali; finally, flupirtine exchange ring formation is performed to obtain palbociclib intermediate 2-chloro-8-cyclopentyl-5methyl-8H-pyrido(2,3-d)pyrimidine-7-one. Noble metal palladium on carbon in the palbociclib intermediate synthesizing method disclosed by the invention isfiltered while being heat to be recycled. The palbociclib intermediate synthesizing method has the advantages of simpleness in operation, easiness in obtaining raw materials, high product yield and suitability for industrial production.
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Paragraph 0033
(2018/05/01)
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- Preparation method for pyrido[2,3-d]pyrimidine compounds
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The invention discloses a preparation method for pyrido[2,3-d]pyrimidine compounds. The preparation method comprises a step of reacting a compound 2 with a compound 3 in a water-soluble organic solvent at a temperature of 60 to 85 DEG C under the action o
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Paragraph 0029; 0030, 0031; 0034; 0036; 0037
(2018/08/04)
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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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Paragraph 0174
(2016/10/09)
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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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Paragraph 0141; 0147; 0148
(2016/10/07)
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- A PROCESS FOR THE PREPARATION OF PALBOCICLIB
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The present invention relates to a process for the preparation of palbociclib utilizing a silyl-protected crotonic acid derivative to produce a silyl-protected 5-(1-methyl-3 carboxy-prop-1-en-1-yl)-2-chloro-piperazine followed by intramolecular cyclization of the compound the piperazine intermediate to produce 2-chloro-8-cyclopentyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one which is then converted to palbociclib.
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Page/Page column 9; 10
(2016/03/12)
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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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Page/Page column 31; 32
(2016/03/22)
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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
(2008/06/13)
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