Piperidine
What Is Piperidine
Piperidine is an organic compound with the molecular formula (CH2)5NH. This heterocyclic amine consists of a six-membered ring containing five methylene bridges (–CH2–) and one amine bridge (–NH–). It is a colorless liquid with an odor described as objectionable, typical of amines. The name comes from the genus name Piper, which is the Latin word for pepper. Although piperidine is a common organic compound, it is best known as a representative structure element within many pharmaceuticals and alkaloids.
Advantages of Piperidine
Less dense than water
Piperidine appears as a clear colorless liquid with a pepper-like odor. Less dense than water, but miscible in water. Will float on water.
Important synthetic fragments for designing drugs
Piperidines are among the most important synthetic fragments for designing drugs and play a significant role in the pharmaceutical industry. Their derivatives are present in more than twenty classes of pharmaceuticals, as well as alkaloids.
Used in chemical degradation reactions
Piperidine is also commonly used in chemical degradation reactions, such as the sequencing of dna in the cleavage of particular modified nucleotides. Piperidine is also commonly used as a base for the deprotection of fmoc-amino acids used in solid-phase peptide synthesis.
Great use as a building block in organic synthesis
The piperidine ring have great use as a building block in organic synthesis. Also, piperidine derivatives have a wide variety of clinical applications, either as centrally acting drugs, analgesics, anticancer or antibacterial drugs.
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Properties of Piperidine
Piperidine is an organic compound with the molecular formula C5H11N. It is a heterocyclic amine with a six-membered ring containing five carbon atoms and one nitrogen atom. It is a clear liquid with a pepper-like odor.
The piperidine structural motif is present in numerous natural alkaloids such as piperine and quinine, and is the main active chemical agent in black pepper and relatives (Piper sp.), hence the name. Piperidine is also a structural element of many pharmaceutical drugs such as raloxifene, minoxidil, thioridazine and mesoridazine.
Piperidine is often used as a solvent for its mild basic properties, most notably in Fmoc-strategy solid phase peptide synthesis. The major industrial application of piperidine is for the production of dipiperidinyl dithium tetrasulfide, which is used as a rubber vulcanization accelerator. Piperidine is naturally found in fire ant venom, and is the cause of the burning sensation associated with the bite of these insects.
Conformation of Piperidine and Derivatives
The piperidine structural motif is present in numerous natural alkaloids. These include piperine, which gives black pepper its spicy taste. This gave the compound its name. Other examples are the fire ant toxin solenopsin, the nicotine analog anabasine of tree tobacco (Nicotiana glauca), lobeline of Indian tobacco, and the toxic alkaloid coniine from poison hemlock, which was used to put Socrates to death.
Piperidine prefers a chair conformation, similar to cyclohexane. Unlike cyclohexane, piperidine has two distinguishable chair conformations: one with the N–H bond in an axial position, and the other in an equatorial position.
After much controversy during the 1950s–1970s, the equatorial conformation was found to be more stable by 0.72 kcal/mol in the gas phase. In nonpolar solvents, a range between 0.2 and 0.6 kcal/mol has been estimated, but in polar solvents the axial conformer may be more stable. The two conformers interconvert rapidly through nitrogen inversion; the free energy activation barrier for this process, estimated at 6.1 kcal/mol, is substantially lower than the 10.4 kcal/mol for ring inversion. In the case of N-methylpiperidine, the equatorial conformation is preferred by 3.16 kcal/mol, which is much larger than the preference in methylcyclohexane, 1.74 kcal/mol.
Piperidine is a six-membered heterocycle including one nitrogen atom and five carbon atoms in the sp3-hybridized state. Piperidine-containing compounds represent one of the most important synthetic medicinal blocks for drugs construction, and their synthesis has long been widespread. Today, it can be unequivocally stated that heterocyclic compounds play a significant part in the pharmaceutical industry, and one of the most common in their structure is the piperidine cycle.
Chemists have used hydrogenation reactions since the early 19th century. This fundamental process plays a key role in modern organic synthesis. Over many decades of scientific progress, researchers have developed approaches to the hydrogenation of a wide variety of heterocyclic compounds and their derivatives, including furans, pyrroles, indoles, thiophenes, imidazoles, oxazolones, quinolines, etc. Pyridines are of particular interest for this review, as they are the most common source for obtaining piperidines by this method.
Now, there are many ways to achieve N-heteroaromatic compounds hydrogenation. Usually, the reactions take place under transition metal catalysis and harsh conditions (high temperature, great pressure, long reaction time), which makes them more expensive than the use of the other methods. Moreover, in order to meet modern pharmaceutical standards, in most cases, it is necessary to obtain a specific isomer. Thus, the reaction must be stereoselective, which is difficult in view of the aforementioned conditions. However, despite all the obvious problems of this approach, in the last decade, scientists offered various methods for overcoming them.
Along with ruthenium and cobalt, iridium is an effective transition metal for stereoselective catalytic hydrogenation. Thus, Qu et al. reported the successful asymmetric hydrogenation of 2-substituted pyridinium salts using an iridium(I) catalyst containing a P,N-ligand. The authors suggested that the reaction proceeds through the outer-sphere dissociative mechanism, which is known for this type of hydrogenation. The reactant undergoes a series of successive protonations. The product configuration is determined by the stereoselective enamine protonation. This approach is also suitable for high-volume synthesis. Thus, the authors performed the large-scale enantioselective reduction of 2,3-disubstituted indenopyridine as part of the synthesis of a biologically active substance—11β-hydroxysteroid dehydrogenase type 1 inhibitor (11β-HSD1) . 11β-HSD1 is used for treating diseases associated with cortisol abnormalities.
Rhodium and palladium are befitting for pyridine hydrogenation as well. First, the authors used rhodium(I) complex and pinacol borane to achieve highly diastereoselective products through the dearomatization/hydrogenation process (Scheme 4A). As a result, a wide range of substituted fluoropiperidines have been obtained, including fluorinated analogs of commercially available and biologically active substances, including Melperone, Diphenidol, Dyclonine, Eperisone, and Cycrimine. The work represents a major advance in the underdeveloped field of fluoropiperidine derivatives acquirement.
However, the method has its limitations in the pyridine moieties range (products with hydroxy, aryl, ester, and amide groups were not affordable) and moisture sensitivity. The method is based on palladium-catalyzed hydrogenation (Scheme 4B). The developed approach was suitable for most substrates that were inaccessible by rhodium catalysis and was effective in the presence of air and moisture. It is worth noting that the axial-position for fluorine atoms was prevalent in the majority of experiments.
The interruption of palladium-catalyzed hydrogenation by water led to piperidinones. The method allows for the furthering of the one-pot functionalization of unsaturated intermediates, which usually requires multiple steps. Moreover, the reaction possessed great selectivity, high yields, and a broad substrate scope.
Piperidine Derivatives: Recent Advances in Synthesis and Pharmacological Applications
Piperidine is a six-membered heterocycle including one nitrogen atom and five carbon atoms in the sp3-hybridized state.
Piperidine-containing compounds represent one of the most important synthetic medicinal blocks for drugs construction, and their synthesis has long been widespread. Today, it can be unequivocally stated that heterocyclic compounds play a significant part in the pharmaceutical industry, and one of the most common in their structure is the piperidine cycle.
Piperidine Derivatives as Anticancer Agents
Cancer, uncontrolled cell growth, is a worldwide health matter that impacts a major proportion of the human population. These three malignant properties of cancer differentiate them from benign tumors, which are self-limited, do not invade or metastasize. Cancer treatments have developed through recent years. Cancer treatments now include surgery, chemotherapy, radiotherapy, and modern approaches, namely interventional radiology, hormone therapy, and immunotherapy. Anticancer medicines are categorized into groups according to their mechanism of action into alkylating agents, antimetabolites, anti-tumor antibiotics, topoisomerase inhibitors, and microtubule binding agents. There are more than one hundred medically approved chemotherapeutic medications. However, the toxicological data of most anticancer drugs have restrained their medicinal application as antiproliferative agents. In spite of the great achievements made in chemotherapy in recent years, resistance to conventional chemotherapeutic drugs and new targeted therapeutic agents is still a significant issue in cancer treatments and the cause of most recurrences. Therefore, research of new anticancer agents with new mechanisms of action, high potency and low side effects is essential for chemists. To diminish anticancer drugs' adverse effects upon normal cells, targeted cancer therapies are favored nowadays. Targeted drugs block the growth and proliferation of cancer by interfering with specific molecules that are involved in the rise, advancement, and expansion of cancer without affecting normal cells. Some chemotherapeutic agents have piperidine moiety within their structure, foremost among them, vinblastine and raloxifene.
Vinblastine is a plant alkaloid which is extracted from Vinca Rosea. This drug is an antineoplastic agent. It is thought that the mechanism of action of Vinblastine is inhibition of mitosis at metaphase leading to mitotic arrest or cell death.
Raloxifene is second-generation selective estrogen receptor modulator (SERM). It is used for reducing the risk of invasive breast carcinoma in postmenopausal women by acting as estrogen blocker.
Evodiamine which is a quinolone alkaloid isolated from Evodia rutaecarpa was found to show anticancer effects in vivo and in vitro by induction of apoptosis or cell cycle arrest therefore preventing metastasis and angiogenesis.
Khairia et al. synthesized two piperidine analogues. These analogues were evaluated for their chemo preventive effect. Compound was found to be the most potent chemo-preventive agent and could successfully decrease the number of cancer cells.
Suvankar et al. studied a series of twenty-five piperidine derivatives as free radical scavengers. These compounds exhibited a potent anticancer effect. It was found to be the most potent antitumor agent. The mechanism of action was found to be binding to ctDNA via intercalation.
Pharmacological Applications of Piperidine Derivatives
1.Cancer therapy
Cancer is one of the biggest health problems worldwide, with nearly 10 million deaths reported in 2020 according to who. A lot of resources are spent on the development of new drugs for fighting cancer, but despite all efforts, innate and acquired resistance mechanisms are often observed. Therefore, screening for new developments and breakthroughs in this area is very important and relevant. Piperidine moieties are often used in anticancer drug construction. The resulting product showed slightly better cytotoxicity and apoptosis induction in the fadu hypopharyngeal tumor cells model than the reference drug bleomycin. The authors followed the “escape from flatland” approach, which was popularized throughout recent years and was successfully used in the development of anti-cancer agents. This approach suggests that more saturated and three-dimensional structures will interact better with binding sites of proteins. Therefore, the authors reasoned that the spirocyclic structure played a key role in the biological activity.
2.Alzheimer disease therapy
Alzheimer disease is one of the most lethal and burdening illnesses of the last century. It has no definite treatment other than symptomatic treatment and results in death 6 years after diagnosis, on average. The oldest theory of alzheimer’s disease is the cholinergic hypothesis, which suggests that the illness is caused by the loss of cholinergic innervation. The neurotransmitter acetylcholine is one of many vital components for normal brain function. Deficiency of the cholinergic system has been observed in the brains of alzheimer’s disease patients, leading to the pathophysiology of learning and memory impairment. The main goal of modern therapy is to maintain the level of acetylcholine through the inhibition of cholinesterases: Acetylcholinesterase (ache) and butyrylcholinesterase (buche). Currently, the leading drug among acetylcholinesterase inhibitors is donepezil, a piperidine derivative.
3.Biocides
Biocides are chemical compounds designed to neutralize, suppress, or prevent the action of harmful organisms, namely, pathogenic bacteria, fungi, viruses, parasites, etc. As noted earlier, piperidine derivatives find use in this class of pharmaceuticals. In recent years, a number of works on the topic can be noted. However, due to the wide variety of human pathogens, it is not possible to point out one template structure for all types of activities.
4.Neuropathic pain therapy
Neuropathic pain occurs as a result of the pathological excitation of neurons in the peripheral or central nervous system, which is caused by neurological diseases with damage to peripheral fibers and central neurons. The modern approach to the treatment of neuropathic pain includes three lines of pharmacotherapy. Most of the piperidine derivatives are part of opioids, which are the second and, in some cases, the third line of treatment.
Opioid receptors are divided into four similar types: μ-opioid (mor), δ-opioid (dor), κ-opioid (kor), and nociceptin/orphanin fq peptide receptor (nop). Mor and dor are the main targets of opioid agonists. Mor agonists cause euphoria and help with coping with stress; however, their use causes serious side effects and physical dependence, leading to overdose. One of the main synthetic piperidine-containing opioids is fentanyl.