cis-3,5-Dimethylpiperazine-1-carboxylic acid tert-butyl ester
[CAS# 129779-30-2]

Identification

• Classification: Organic raw materials >> Carboxylic compounds and derivatives >> Carboxylic esters and their derivatives
• Name: cis-3,5-Dimethylpiperazine-1-carboxylic acid tert-butyl ester
• Molecular Formula: C₁₁H₂₂N₂O₂
• Molecular Weight: 214.30
• CAS Registry Number: 129779-30-2 (1152111-14-2)
• EC Number: 825-251-0
• SMILES: C[C@@H]1CN(C[C@@H](N1)C)C(=O)OC(C)(C)C

Properties

• Density: 1.0±0.1 g/cm³ Calc.^*
• Melting point: 70 - 71 ºC (Expl.)
• Boiling point: 279.7±15.0 ºC 760 mmHg (Calc.)^*, 336.8 - 340.2 ºC (Expl.)
• Flash point: 123.0±20.4 ºC (Calc.)^*
• Solubility: water: Slightly soluble (8.8 g/L) (25 ºC), Calc.
• Index of refraction: 1.452 (Calc.)^*

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

Safety Data

• Hazard Symbols: GHS07 Warning
• Hazard Statements: H302-H312-H315-H319-H335
• Precautionary Statements: P261-P264-P264+P265-P270-P271-P280-P301+P317-P302+P352-P304+P340-P305+P351+P338-P317-P319-P321-P330-P332+P317-P337+P317-P362+P364-P403+P233-P405-P501

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Specific target organ toxicity - single exposure	STOT SE	3	H335
Eye irritation	Eye Irrit.	2A	H319
Acute toxicity	Acute Tox.	4	H312
Skin irritation	Skin Irrit.	2	H315
Acute toxicity	Acute Tox.	4	H302

Discovory and Applicatios

cis-3,5-Dimethylpiperazine-1-carboxylic acid tert-butyl ester (tert-butyl 3,5-dimethylpiperazine-1-carboxylate) is a protected piperazine derivative widely used as a synthetic intermediate in medicinal chemistry. Its molecular formula is C₁₁H₂₂N₂O₂ and molecular weight is approximately 214.30 g/mol. This compound features a piperazine ring substituted at the 3 and 5 positions with methyl groups, while the nitrogen at position 1 is protected with a tert-butoxycarbonyl (Boc) group. The Boc protection stabilizes the nitrogen during synthetic transformations and can be selectively removed under mild acidic conditions to yield the free amine for subsequent reactions.

The compound originated from chemical strategies focused on modifying piperazine cores for the development of biologically active molecules. Researchers initially synthesized cis-3,5-dimethylpiperazine by stereoselective methods starting from cyclic diamines and then introduced the Boc protecting group by reaction with di-tert-butyl dicarbonate in an organic solvent such as dichloromethane. The reaction proceeds with high efficiency, typically producing the tert-butyl carbamate as a yellow oil suitable for further chemical manipulation without extensive purification. The stereochemistry of the cis-3,5-dimethylpiperazine core is important because it constrains the piperazine ring conformation, which can influence the binding properties and selectivity of derivatives derived from it.

One of the main applications of tert-butyl 3,5-dimethylpiperazine-1-carboxylate is in the design of HIV-1 entry inhibitors. Medicinal chemists use this intermediate to attach pharmacophoric groups to the piperazine core, producing molecules capable of interfering with virus-host interactions. The Boc-protected nitrogen allows selective functionalization at the other nitrogen or at the carbon positions of the piperazine ring. For instance, benzoylation at position 4 can be performed while the nitrogen remains protected, producing derivatives with improved pharmacokinetic properties and enhanced antiviral activity once the protecting group is removed.

Beyond antiviral drug design, this compound is a versatile building block in the synthesis of small molecules for various therapeutic targets. Its chemical stability and predictable reactivity make it a common choice in multi-step synthesis pathways. Protected piperazine derivatives are frequently used to explore structure-activity relationships, where small modifications on the ring can lead to significant changes in biological activity. The tert-butyl ester group is particularly useful because it can be cleaved under controlled conditions, allowing chemists to introduce other functional groups without affecting other parts of the molecule.

In practical laboratory use, tert-butyl 3,5-dimethylpiperazine-1-carboxylate is often employed in solution-phase chemistry. Typical reactions include amide bond formation, acylation, and other nitrogen-directed functionalizations. The compound’s solubility in common organic solvents and its solid-state stability make it convenient for storage and handling. Additionally, the cis configuration of the methyl groups has been shown to favor certain conformations, which can influence the orientation of substituents in downstream molecules, enhancing the ability to target specific biological sites.

Overall, cis-3,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester is not an active drug itself, but its role as a stereochemically defined, Boc-protected piperazine intermediate is critical in medicinal chemistry. It supports the synthesis of biologically active molecules, especially in antiviral research, and facilitates the exploration of structure-activity relationships. Its combination of chemical stability, stereochemical control, and ease of deprotection makes it a standard tool in modern organic synthesis.

References

Karadsheh R, Zhang J, Boross P, et al (2020) Composition and Orientation of the Core Region of Novel Diarylpyrimidine HIV-1 Inhibitors. *Molecules* 25 1430 DOI: 10.3390/molecules25061430

Salubi CA, Rey A, Ndahi MF, et al (2024) Medicinal chemistry perspectives on the development of piperazine-containing HIV-1 entry inhibitors. *Future Medicinal Chemistry* (review) DOI: 10.2174/1872312810666240328131855

Wang T, Joshi P, Karadsheh R, et al (2021) Innovation in the discovery of the HIV-1 attachment inhibitor temsavir: synthesis, structure-activity relationship, and mechanism. *Journal of Molecular Microbiology and Biotechnology* DOI: 10.1007/s00044-021-02787-6