2-Methylpiperazine: Key Cyclic Diamine Building Block

2-Methylpiperazine is a cyclic diamine that serves as a critical building block in the synthesis of a wide array of pharmaceutical compounds and specialty chemicals. Its structural features, including a chiral center and two nitrogen atoms with differing basicity, impart unique chemical properties that are leveraged in drug design and complex organic synthesis.

2-Methylpiperazine derivatives as potent CCR5 antagonists

Acquired immunodeficiency syndrome (AIDS), caused by human immunodeficiency virus (HIV), is one of the fatal diseases threatening human. Although highly active antiretroviral therapy (HAART), a combination of drugs targeting HIV-1 protease and reverse transcriptase, has been successful in reducing HIV-1-associated mortality and morbidity, many patients are still suffered from long term toxicity, incomplete efficacy, and the eventual emergence of resistance. The chemokine receptor 5 (CCR5), a member of the seven-transmembrane G-protein coupled receptor family, serves a critical role for the entrance of R5-tropic HIV-1 into host cells. In our previous work, we designed a series of novel piperazinederivatives. Among them was a CCR5 antagonist containing a 4-cyanophenylpiperazin moiety with an IC50 value of 6.29 μM. In order to further explore the structure–activity relationship between 2-methylpiperazine derivatives and potential CCR5 antagonists that may have therapeutic potential, TAK220 was chosen as our lead compound; we subsequently designed three series of target compounds. First, we replaced the substituent (R1) at the 4-position of the 2-methylpiperazine ring in TAK220 with a variety of aromatic rings. Then, we focused on modifying the terminal group tethered to the amide moiety (R4). Finally, the 2-methylpiperazine moiety was replaced with a heptatomic ring and bridged ring. Herein, we report the synthesis and biological evaluation of these novel 2-methylpiperazin derivatives.[1]

N-alkylation of the 2-methylpiperazine with a substituted benzyl chloride in the presence of potassium carbonate afforded the 1-benzyl-3-methylpiperazine analogues. In contrast, treatment of 2-methylpiperazine with 4-fluorobenzoyl chloride or 4-fluorobenzenesulfonyl chloride resulted in the generation of the benzamide and sulfonamide, respectively. Moreover, reacting 4-fluorobenzaldehyde with homopiperazine, (R)-2-methylpiperazine, (S)-2-methylpiperazine or (1S,4S)-2,5-diazabicyclo[2.2.1]heptanes in the presence of sodium triacetoxyborohydride led to the formation of other compounds. In summary, three series of novel 2-methylpiperazine derivatives were designed and synthesized by using a fragment-assembly strategy. The CCR5 antagonistic activities of the target compounds were evaluated based on a calcium mobilization assay. Several compounds showed promising activities, with IC50 values ranging from 3.0 to 11.7 nM. Among them, six compounds showed better activity in comparison with that of the positive control, maraviroc. The most potent compounds, as identified by the calcium mobilization assay, were selected for further antiviral evaluation. As a result, four compounds showed potent efficacy at the nanomolar level. Additionally, the four compounds chosen for additional study  showed no cytotoxicity at a concentration of 10 μM by the CCK-8 assay. We believe that the results of this research will provide a foundation that will prove useful in the further design and optimization of novel small molecular CCR5 antagonists.

Thermodynamic and Kinetic Modeling of Piperazine/2-Methylpiperazine

Concentrated piperazine (PZ) has emerged as a solvent of interest due to its multiple advantages over monoethanolamine, such as higher resistance to degradation, higher kinetic rates, and higher capacity. PZ precipitation can be mitigated by blending PZ with another amine. This paper looks at 4 m PZ blended with 4 m 2-methylpiperazine (2MPZ), a moderately hindered secondary amine. There are no prior open-literature models of 2MPZ/PZ. There are prior models of the subsystems. For 2-methylpiperazine there is a thermodynamic and corresponding kinetic model. For concentrated PZ, there is an Aspen Plus® model and a proprietary model (Independence) developed by the University of Texas.[2]

The equimolar 4 m 2MPZ/4 m PZ was modeled in Aspen Plus® using the eNRTL thermodynamic framework. 109 data points for VLE, density, and viscosity were regressed using twenty-six parameters. The resulting thermodynamic model correctly predicts the CO2 equilibrium partial pressure at absorber and stripper temperatures. The average differential heat of absorption is close to the 70 kJ/mol CO2. The predicted speciation and stoichiometry reveal that the 2-methylpiperazine carbamate species is less prevalent than the PZ carbamate species, though the 2MPZ zwitterion is more prevalent than its PZ counterpart. The viscosity normalized capacity is the same as that of 8 m PZ at 0.78 mol CO2/kg amine+H2O. The kinetic model used ten different reactions to capture the rate behavior across the range of lean to rich loadings as well as from 40 100°C. The rate predictions are worst at the temperature extremes as well as at the rich loading. The SSE for the kinetic model was 2.39. The formation of PZ dicarbamate catalyzed by 2MPZ carbamate is negligible. The dominant reaction at lean loading is the formation of 2-methylpiperazine carbamate catalazyed by PZ, while at rich conditions the formation of PZ dicarbamate catalyzed by PZ carbamate becomes dominant. Taken as a whole, this thermodynamic and kinetic model can be used for techno-economic assessments, pilot plant data reconciliation, and process modeling.

References

[1]Hu, S., Wang, Z., Hou, T., Ma, X., Li, J., Liu, T., Xie, X., & Hu, Y. (2015). Design, synthesis, and biological evaluation of novel 2-methylpiperazine derivatives as potent CCR5 antagonists. Bioorganic & Medicinal Chemistry, 23(5), 1157–1168.

[2]Sherman, B., Frailie, P. T., Li, L., Salta, N., & Rochelle, G. T. (2014). Thermodynamic and kinetic modeling of piperazine/2-methylpiperazine. Energy Procedia, 63, 1243–1255.

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