Introduction

Phenylephrine, CAS 59-42-7 is a synthetic sympathomimetic amine widely used in medicine as a selective α₁-adrenergic receptor agonist. It uses in pharmacotherapy, particularly in the treatment of nasal congestion, hypotension, and in diagnostic ophthalmology. It is an alternative to ephedrine and pseudoephedrine.

Phenylephrine features a phenethylamine with functional groups that contribute to its biological activity and synthetic accessibility. Its structure includes a phenolic hydroxyl group at the meta-position, a secondary hydroxyl on the ethyl side chain, and a methylated amine, all of which influence its receptor selectivity, solubility, and metabolic profile. The chemical reactivity of phenylephrine enables a range of transformations.

This article explores phenylephrine from a chemical perspective, covering its physical and chemical properties, synthetic methods, reactivity patterns, safety considerations, and broad pharmaceutical applications.

Physical and Chemical Properties of Phenylephrine

Phenylephrine, (1R)-2-(methylamino)-1-phenylethan-1-ol, CAS 59-42-7 is a member of the phenylethanolamines class with molecular formula C₉H₁₃NO₂. It is a white to off-white crystalline powder with a bitter taste. It has a molecular weight of 167.21 g/mol and a melting point in the range of 169-172°C. Phenylephrine is moderately soluble in water and freely soluble in ethanol and chloroform. It possesses a density 1.122 g/cm³. The compound is optically active and typically used in its hydrochloride salt form (phenylephrine hydrochloride) to enhance stability and aqueous solubility.

Chemically, phenylephrine features a phenethylamine core substituted with a hydroxyl group at the para-position and a hydroxymethyl group on the ethylamine side chain. This structural arrangement gives it hydrophilic and lipophilic characteristics, influencing its interaction with biological membranes and adrenergic receptors. The molecule is relatively stable under standard conditions but may undergo oxidative degradation in the presence of light or air.

1. Synthesis of Phenyl ephrine | B. Pharm IV Semester | Medicinal Chemistry – I

Synthesis of Phenylephrine

The synthesis of phenylephrine, CAS 59-42-7 7 is typically synthesized through multi-step organic transformations. The target compound, (R)-3-hydroxy-alpha-((methylamino)methyl)benzene methanol, contains three key functional groups: a phenolic hydroxyl, a secondary alcohol, and a secondary amine. Multiple synthetic routes exist to obtain phenylephrine in high yield.

The first synthetic route involves the nucleophilic substitution of (R)-3-(2-chloro-1-hydroxyethyl)phenol with methylamine (MeNH₂). In this reaction, the chloro group on the side chain acts as a leaving group, allowing the amine to displace it. This route is regioselectivity and is often preferred in enantioselective synthesis, particularly when the (R)-enantiomer is obtained through chiral resolution or asymmetric synthesis.

An alternative and commonly explored route to phenylephrine is through the reduction of 1-(3-hydroxyphenyl)-2-(methylamino)ethanone, which contains a ketone functional group at the β-position relative to the amine. This intermediate can be selectively reduced using a mild reducing agent such as sodium borohydride (NaBH₄) or via catalytic hydrogenation, yielding the desired β-hydroxyethyl side chain. The reaction results in the formation of phenylephrine. This reduction is often performed under cold conditions in solvents in methanol or ethanol, and it avoids over-reduction or side reactions.

Chemical Reactions of Phenylephrine

Phenylephrine, CAS 59-42-7 a phenylethanolamine derivative, participates in several important chemical reactions due to the presence of its phenolic hydroxyl group, secondary alcohol, and secondary amine. These functional groups enable transformations relevant to pharmaceutical formulation, chemical stability, and metabolic conversion.

One of the most common and pharmaceutically significant reactions is the formation of phenylephrine hydrochloride, the salt form used in most commercial drug products. The secondary amine group in phenylephrine reacts readily with hydrochloric acid to yield a water-soluble, stable crystalline salt.

Phenylephrine also yields (3-[2-(methylamino)ethyl]phenol) under reducing conditions. This transformation removes the secondary alcohol group and is typically carried out using reducing agents such as hydrogen in the presence of platinum catalyst or lithium aluminum hydride (LiAlH₄) reductive agent.

Under acid-catalyzed conditions, phenylephrine may undergo cleavage and rearrangement of its side chain, resulting in the formation of (3-hydroxyphenyl)acetaldehyde, particularly under conditions of hydrolytic or oxidative stress. Leaving the reaction going for too long or too low of a pH will likely cause problems. Once formed the aldehyde might start to undergo aldol polymerization since it partially exists as its enol form. Aldehydes (and also phenols) are somewhat unstable in air so the reaction might have to be performed under nitrogen.

Applications of Phenylephrine

Phenylephrine, CAS 59-42-7 is widely used in medicine due to its potent vasoconstrictive and decongestant properties, primarily mediated through selective stimulation of α₁-adrenergic receptors. One of its most common applications is as a nasal decongestant, where it is administered orally or intranasally to relieve congestion associated with colds, allergies, or sinusitis. By constricting blood vessels in the nasal mucosa, phenylephrine reduces swelling and promotes easier breathing. Over-the-counter products such as Sudafed PE and Neo-Synephrine nasal sprays are typical examples of its use in this context.

Another major application is in ophthalmology, where phenylephrine eye drops are used to induce mydriasis (pupil dilation) for diagnostic procedures such as retinal examination and cataract surgery. Concentrations ranging from 2.5% to 10% are used depending on the desired duration and extent of dilation.

Phenylephrine also uses in anesthesiology and emergency medicine as a vasopressor agent.

Health Effects of Phenylephrine

Phenylephrine, CAS 59-42-7 while widely regarded as safe when used as directed in therapeutic contexts, can cause a range of physiological effects due to its action as an α₁-adrenergic receptor agonist. By inducing vasoconstriction, phenylephrine increases peripheral vascular resistance, leading to elevated blood pressure and reduced nasal or conjunctival swelling. In standard doses, this mechanism is beneficial for relieving nasal congestion or maintaining blood pressure during anesthesia. However, excessive or inappropriate use may result in adverse cardiovascular responses, such as hypertension, reflex bradycardia, palpitations, and, in rare cases, arrhythmias or ischemia in susceptible individuals.

Central nervous system (CNS) effects are also possible, especially when phenylephrine is used in high doses or over long periods. Some users report nervousness, restlessness, insomnia. These symptoms are typically mild and transient, but they can be more pronounced in individuals sensitive to sympathomimetic agents. In pediatric and geriatric populations, caution is advised, as these groups may be more vulnerable to central and peripheral side effects. Additionally, when used as an ophthalmic agent, phenylephrine may cause stinging, blurred vision, or sensitivity to light, although these effects are usually short-lived.

Prolonged use, particularly of topical nasal decongestants, can lead to rebound congestion (rhinitis medicamentosa), where the nasal passages become more congested once the drug’s effect wears off. This condition often leads to a cycle of repeated use, dependency, and worsening symptoms. To prevent this, clinical guidelines recommend limiting topical use to no more than three consecutive days. Systemically, phenylephrine is generally well-tolerated, but individuals with hypertension, cardiovascular disease, hyperthyroidism, or glaucoma are advised to use it only under medical supervision due to the risk of exacerbating these conditions.

While phenylephrine is effective and widely used, its health effects depend strongly on the dose, route of administration, duration of use, and the individual’s health status.

Safety Precautions

Handling phenylephrine, CAS 59-42-7 requires safety precautions due to its bioactive properties and potential health risks. As a sympathomimetic agent, phenylephrine can exert significant physiological effects even in small quantities if absorbed through the skin, inhaled, or ingested. Therefore, personal protective equipment (PPE) is essential during all stages of its handling. Laboratory personnel must wear lab coats, chemical-resistant gloves, safety goggles, and, when working with powders or solutions, respiratory protection or work in a fume hood to prevent inhalation of dust or aerosols.

Phenylephrine should be stored in a cool, dry place away from light and incompatible substances, such as strong oxidizers, acids, or bases. Due to its sensitivity to light and air, containers should be tightly sealed and, if possible, flushed with inert gas for long-term storage.

Conclusion

In conclusion, phenylephrine, CAS 59-42-7 is a sympathomimetic compound with pharmacological and chemical properties. It is widely used as a decongestant, vasopressor, and mydriatic agent in both over-the-counter and clinical formulations. Phenylephrine’s chemical structure, featuring a phenolic hydroxyl group, secondary alcohol, and secondary amine, allows for various chemical transformations and influences its physical behavior and reactivity. Its synthesis can be achieved through several efficient methods, including substitution and reduction reactions. Overall, the properties, reactions, and applications of phenylephrine make it an important compound in pharmaceutical chemistry.

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