866084-31-3

Basic information

• Product Name: tert-butyl 4-(6-(8-cyclopentyl-5-Methyl-7-oxo-6-(1-propoxyvinyl)-7,8-dihydropyrido[2,3-d]pyriMidin-2-ylaMino)pyridin-3-yl)piperazine-1-carboxylate
• Synonyms: tert-butyl 4-(6-(8-cyclopentyl-5-Methyl-7-oxo-6-(1-propoxyvinyl)-7,8-dihydropyrido[2,3-d]pyriMidin-2-ylaMino)pyridin-3-yl)piperazine-1-carboxylate;Palbociclib INT;tert-butyl 4-(6-((6-(1-butoxyvinyl)-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-1-carboxylate;4-[6-[[6-(1-Butoxyvinyl)-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino]pyridin-3-yl]piperazine-1-carboxylic acid tert-butyl ester;2-Methyl-2-propanyl 4-(6-{[8-cyclopentyl-5-methyl-7-oxo-6-(1-prop oxyvinyl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}-3-pyridin yl)-1-piperazinecarboxylate
• CAS NO: 866084-31-3
• Molecular Formula: C32H43N7O4
• Molecular Weight: 589.72832
• Product Categories: Anticancer
• Mol File: 866084-31-3.mol

Chemical Properties

• Boiling Point: 764.2±70.0 °C(Predicted)
• Appearance: /
• Density: 1.224±0.06 g/cm3(Predicted)
• Storage Temp.: 2-8°C(protect from light)
• PKA: 5.24±0.10(Predicted)
• CAS DataBase Reference: tert-butyl 4-(6-(8-cyclopentyl-5-Methyl-7-oxo-6-(1-propoxyvinyl)-7,8-dihydropyrido[2,3-d]pyriMidin-2-ylaMino)pyridin-3-yl)piperazine-1-carboxylate(CAS DataBase Reference)
• NIST Chemistry Reference: tert-butyl 4-(6-(8-cyclopentyl-5-Methyl-7-oxo-6-(1-propoxyvinyl)-7,8-dihydropyrido[2,3-d]pyriMidin-2-ylaMino)pyridin-3-yl)piperazine-1-carboxylate(866084-31-3)
• EPA Substance Registry System: tert-butyl 4-(6-(8-cyclopentyl-5-Methyl-7-oxo-6-(1-propoxyvinyl)-7,8-dihydropyrido[2,3-d]pyriMidin-2-ylaMino)pyridin-3-yl)piperazine-1-carboxylate(866084-31-3)

Safety Data

• Hazardous Substances Data: 866084-31-3(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
tert-butyl 4-(6-(8-cyclopentyl-5-Methyl-7-oxo-6-(1-propoxyvinyl)-7,8-dihydropyrido[2,3-d]pyriMidin-2-ylaMino)pyridin-3-yl)piperazine-1-carboxylate is used as a key intermediate in the synthesis of palbociclib, a highly selective reversible inhibitor of CDK 4/6. This application is significant because palbociclib has been shown to be effective in the treatment of breast cancer, particularly in cases where the cancer cells have specific hormonal receptor profiles.
The development of palbociclib as a targeted therapy represents a significant advancement in cancer treatment, as it offers a more precise approach to addressing the molecular drivers of breast cancer growth. By inhibiting the CDK 4/6 proteins, palbociclib can effectively halt the cell cycle in cancer cells, thereby preventing their proliferation and contributing to tumor regression.

Upstream product

• 571188-59-5 tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate 
• 1016636-76-2 2-chloro-5-methyl-6-bromo-8-cyclopentylpyridine[2,3-d]pyrimidin-8-hydro-7-one 
• 111-34-2 -butyl vinyl ether 
• 733039-23-1 5?bromo?N?cyclopentyl?2?(methylthio)pyrimidin?4?amine 
• 362656-23-3 8?cyclopentyl?5?methyl?2?(methylthio)pyrido[2,3?d]pyrimidin?7(8H)?one 
• 571188-81-3 6?bromo?8?cyclopentyl?5?methyl?2?(methylsulfinyl)pyrido[2,3?d]pyrimidin?7(8H)?one 
• 571189-16-7 4-(6-nitropyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester 
• 57260-71-6 1-t-Butoxycarbonylpiperazine 
• 39856-50-3 5-bromo2-nitropyridine 
• 1013916-37-4 2-chloro-5-methyl-8-cyclopentylpyridin[2,3-d]pyrimidin-8-hydro-7-one 
• 733039-20-8 5-bromo-2-chloro-N-cyclopentylaminopyrimidine-4-amine 
• 1003-03-8 Cyclopentamine 
• 571188-82-4 tert?butyl 4?(6?((6?bromo?8?cyclopentyl?5?methyl?7?oxo?7,8?dihydropyrido[2,3?d]pyrimidin?2?yl)amino)pyridin?3?yl)piperazine?1?carboxylate 

Downstream Products

• 571190-30-2 PD 0332991 
• 1651214-74-2 4-[6-(6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-ylamino)pyridine-3-yl]piperazine-1-carboxylic acid tert-butyl ester 
• 827022-33-3 6-acetyl-8-cyclopentyl-5-methyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one isethionate 
• 827022-33-3 C₂₄H₂₉N₇O₂*2C₂H₆O₄S 
• 827022-33-3 PD 0332991 isethionate 

Relevant articles and documents

Palbociclib Commercial Manufacturing Process Development. Part II: Regioselective Heck Coupling with Polymorph Control for Processability

A three-step commercial manufacturing route has been developed for palbociclib, a highly selective, reversible inhibitor of CDK 4/6. The second step, which utilizes a Heck coupling to install the enol ether side chain, is described. A highly regioselective catalyst was identified for this transformation along with reaction conditions that ensure robustness upon scale-up. Effective removal of palladium was accomplished via filtration of insoluble metal and an extractive chelation step. Finally, efficient isolation of coupled product 3 was achieved through careful polymorph control via seeding and an optimized cooling protocol that avoids nucleation of a kinetically favored, slow-filtering polymorph.

Preparation method and process of palbociclib

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.

A new route for the synthesis of Palbociclib

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.].

Preparation method and product of palbociclib

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.

Potent and Preferential Degradation of CDK6 via Proteolysis Targeting Chimera Degraders

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.

A PROCESS FOR MAKING PALBOCICLIB

The presented invention relates to a process for preparation of compound of formula (1) or a salt thereof (i.e.) palbociclib: The invention also relates to a solid crystalline form of intermediate of formula (2) used in the process:

Preparation method for palbociclib key intermediate

The invention discloses a preparation method for a palbociclib key intermediate 4-{6-[6-(1-butoxy-vinyl)-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino(2,3-d) pyrimidine-2-yl-amino]-pyridine-3-yl} piperazine-1-tert-butyl formate. The preparation method comprises the step of performing pressurized stuffy-tank reaction on 4-{6-[6-bromine-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyridino(2,3-d) pyrimidine-2-yl-amino]-pyridine-3-yl}-piperazine-1-tert-butyl formate and butyl-ethylene ether perform, so that the reaction temperature is increased, reaction time is shortened, generation of impuritiesis controlled, and purity of the product is improved. The preparation method adopts the stuffy-tank reaction, is beneficial for enabling liable-to-volatilize butyl-ethylene ether to sufficiently takepart in reaction, and increases the reaction yield. A product prepared by the preparation method is high in purity, is high in yield, is good in reproducibility, is liable to realize, and is suitablefor industrial production.

PROCESS FOR PREPARATION OF PALBOCICLIB

The present application relates to a process for the preparation of crystalline form A of palbociclib having specific surface area more than 2m2/g comprising one-pot process for the preparation of compound of formula (IV). The present application further relates to the preparation of acid-addition salts of palbociclib and their use for the synthesis of crystalline form A of palbociclib having specific surface area more than 2 m2/g.

POLYMORPHIC FORMS OF PALBOCICLIB

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.

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.