6-Bromo-2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one
[CAS# 1016636-76-2]

Identification

• Classification: Pharmaceutical intermediate >> API intermediate
• Name: 6-Bromo-2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one
• Molecular Formula: C₁₃H₁₃BrClN₃O
• Molecular Weight: 342.62
• CAS Registry Number: 1016636-76-2
• EC Number: 800-433-2
• SMILES: CC1=C(C(=O)N(C2=NC(=NC=C12)Cl)C3CCCC3)Br

Properties

• Solubility: Practically insoluble (0.048 g/L) (25 °C), Calc.^*
• Density: 1.645±0.06 g/cm³ (20 °C 760 Torr), Calc.^*
• Boiling point: 468.4±45.0 °C 760 mmHg (Calc.)^*
• Flash point: 237.1±28.7 °C (Calc.)^*
• Index of refraction: 1.655 (Calc.)^*

^* Calculated using Advanced Chemistry Development (ACD/Labs) Software.

Safety Data

• Hazard Symbols: GHS06;GHS07;GHS08 Danger
• Risk Statements: H301-H302-H315-H319-H334-H335-H373
• Safety Statements: P233-P260-P261-P264-P264+P265-P270-P271-P280-P284-P301+P316-P301+P317-P302+P352-P304+P340-P305+P351+P338-P319-P321-P330-P332+P317-P337+P317-P342+P316-P362+P364-P403-P403+P233-P405-P501

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Acute toxicity	Acute Tox.	4	H302
Specific target organ toxicity - single exposure	STOT SE	3	H335
Eye irritation	Eye Irrit.	2	H319
Respiratory sensitization	Resp. Sens.	1	H334
Skin irritation	Skin Irrit.	2	H315
Specific target organ toxicity - repeated exposure	STOT RE	2	H373

Discovery and Applications

6-Bromo-2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one is a complex heterocyclic compound that has been studied primarily within the context of medicinal chemistry research. Its discovery is linked to systematic efforts to design and synthesize pyridopyrimidine derivatives, a class of compounds known for their biological activity. Researchers have historically explored fused pyridine and pyrimidine systems because of their prevalence in bioactive molecules, particularly in pharmaceuticals targeting kinases and other enzyme classes. The incorporation of functional groups such as bromine, chlorine, and alkyl chains like the cyclopentyl group was guided by structure-activity relationship studies to enhance binding affinity, solubility, and metabolic stability.

The preparation of 6-bromo-2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one typically involves multi-step synthetic routes. These often start from simpler pyridine derivatives, which undergo selective halogenation, alkylation, and cyclization reactions. Introduction of the cyclopentyl group at the 8-position is usually achieved through alkylation strategies either at an early stage or by late-stage functionalization depending on the desired synthetic efficiency. The bromine and chlorine atoms are introduced through controlled halogenation steps using reagents such as N-bromosuccinimide and thionyl chloride respectively. Final purification and crystallization allow for the isolation of the target compound with confirmed structure by methods such as NMR spectroscopy and mass spectrometry.

In terms of applications, 6-bromo-2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one has been evaluated as an intermediate in the development of pharmaceutical agents. Its structure lends itself well to modifications that can generate libraries of derivatives for screening against biological targets. Specifically, the pyridopyrimidinone core is a privileged structure in the design of kinase inhibitors, which are key in the treatment of various cancers and inflammatory diseases. By varying substituents at different positions on the heterocyclic ring, researchers have been able to optimize binding to ATP-binding sites of kinases, thereby improving potency and selectivity.

Furthermore, the bromo and chloro substituents serve as functional handles for further chemical derivatization. Through cross-coupling reactions such as Suzuki or Buchwald-Hartwig couplings, a wide array of aryl or amine substituents can be introduced at the bromine or chlorine positions. This synthetic flexibility expands the utility of 6-bromo-2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one as a versatile scaffold in medicinal chemistry programs focused on generating novel drug candidates.

Although there is no current evidence of 6-bromo-2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one being developed into a marketed drug, its role in the early-stage research pipeline has been well-documented. Its value lies in providing a foundation for the exploration of structure-activity relationships and the identification of lead compounds with desirable pharmacological profiles.

Overall, 6-bromo-2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one exemplifies how rational design, rooted in a deep understanding of medicinal chemistry principles, can yield chemical entities that significantly contribute to the discovery and optimization of new therapeutic agents.

References

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DOI: 10.1055/s-0035-1562570

2016. Synthesis of Palbociclib. Synfacts, 12(11).
DOI: 10.1055/s-0036-1589195

2023. Development of novel palbociclib-based CDK4/6 inhibitors exploring the back pocket behind the gatekeeper. Investigational New Drugs, 41(5).
DOI: 10.1007/s10637-023-01385-0