- Preparation method of palbociclib intermediate
-
The invention discloses a preparation method of a palbociclib intermediate, which comprises the following steps: by using 2-chlorine-8-cyclopentyl-5-methylpyrido [2, 3-D] pyrimidine -7 (8H) -ketone as a raw material, carrying out NBS bromination and cooling crystallization centrifugation under the catalysis of oxalic acid and acetic anhydride to obtain 6-bromine-2-chlorine-8-cyclopentyl-5-methylpyrido [2, 3-D] pyrimidine -7 (8H) -ketone; meanwhile, waste liquid generated in the preparation process is fully reutilized, three wastes are reduced, and the preparation method which is high in quality, low in cost, environmentally friendly and suitable for industrial production is provided.
- -
-
Paragraph 0032-0047
(2021/04/17)
-
- Preparation method of compound containing chlorobromopyrrole pyrimidinone structure
-
The invention provides a preparation method of a compound containing a chlorobromopyrrole pyrimidinone structure. The invention relates to the field of chemical synthesis, in particular to an industrial preparation method of a 6-bromo-2-chloro-8-cyclopentyl--5methyl-pyrido[2,3-d]pyrimidine-7(8H) ketone Palbociclib intermediate with a structure as shown in a formula (I) which is described in the specification. According to the method, a compound shown as a formula (II) is used as a raw material, reacts under the conditions of a specific bromination reagent and acid, and is treated by an aqueoussolution of a reducing inorganic salt to obtain a compound shown as a formula (I). Moreover, compared with a traditional process, the preparation method disclosed by the invention is simple and convenient to operate, high in product yield, high in product purity and suitable for industrial production, and has a great implementation value and social and economic benefits.
- -
-
Paragraph 0037-0054
(2021/03/11)
-
- Preparation method of palbociclib intermediate
-
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.
- -
-
Paragraph 0035; 0041-0043; 0048; 0049
(2021/06/06)
-
- Preparation method of CDK4/6 kinase inhibitor SHR6390
-
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.
- -
-
Paragraph 0056; 0080-0087
(2021/05/12)
-
- Discovery of 5-methylpyrimidopyridone analogues as selective antimycobacterial agents
-
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
-
-
- Preparation method of palbociclib parent nucleus structure compound
-
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.
- -
-
Paragraph 0072-0074; 0086-0089
(2020/07/15)
-
- Preparation method of pyridine pyrimidine derivative
-
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.
- -
-
Paragraph 0043-0044; 0057-0058; 0064-0065
(2019/08/07)
-
- PYRIMIDINE OR PYRIDOPYRIDONE COMPOUND AND APPLICATION THEREOF
-
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
- -
-
-
- Preparation method of Palbociclib intermediate
-
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.
- -
-
Paragraph 0056-0058; 0071-0073; 0084-0086; 0097-0099
(2019/04/11)
-
- Novel synthetic method of Palbociclib
-
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.
- -
-
-
- Pyrimidine or pyridine pyridine ketone compound and its preparation method and application (by machine translation)
-
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)
- -
-
-
- A deuterium generation Palbociclib derivatives, preparation method and application
-
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.
- -
-
-
- Palbociclib Commercial Manufacturing Process Development. Part I: Control of Regioselectivity in a Grignard-Mediated SNAr Coupling
-
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
-
p. 1191 - 1202
(2016/07/23)
-
- METHOD OF PRODUCING PALBOCICLIB AND PHARMACEUTICAL COMPOSITIONS COMPRISING THE SAME
-
The present invention relates to a method of producing palbociclib and to pharmaceutical compositions comprising the same.
- -
-
Page/Page column 32; 33
(2016/03/22)
-
- SOLID FORMS OF A SELECTIVE CDK4/6 INHIBITOR
-
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.
- -
-
Page/Page column 35
(2014/09/03)
-
- SYNTHESIS OF 2-(PYRIDIN-2-YLAMINO)-PYRIDO[2,3-D]PYRIMIDIN-7-ONES
-
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.
- -
-
Page/Page column 26-27
(2008/06/13)
-
