(R)-3-(methylamino)-1-phenylpropan-1-ol

Synthetic Routes and Reaction Conditions: The synthesis of ®-3-(methylamino)-1-phenylpropan-1-ol can be achieved through several methods. One common approach involves the reductive amination of 1-hydroxy-1-phenylpropan-2-one with methylamine. This reaction typically requires a catalyst, such as platinum or palladium, and is carried out under hydrogenation conditions . The stereoselectivity of this reaction is crucial, as it determines the specific enantiomer produced.

Industrial Production Methods: In an industrial setting, the production of ®-3-(methylamino)-1-phenylpropan-1-ol may involve dynamic kinetic resolution (DKR) techniques. These methods utilize enzymes or metal catalysts to selectively produce the desired enantiomer while converting the undesired enantiomer back to the starting material . This approach enhances the overall yield and efficiency of the production process.

Types of Reactions: ®-3-(methylamino)-1-phenylpropan-1-ol undergoes various chemical reactions, including:

Oxidation: The compound can be oxidized to form corresponding ketones or aldehydes.

Reduction: It can be reduced to form secondary or tertiary amines.

Substitution: The hydroxyl group can be substituted with other functional groups, such as halides or esters.

Common Reagents and Conditions:

Oxidation: Common oxidizing agents include potassium permanganate and chromium trioxide.

Reduction: Reducing agents such as sodium borohydride or lithium aluminum hydride are typically used.

Substitution: Reagents like thionyl chloride or phosphorus tribromide can facilitate substitution reactions.

Major Products: The major products formed from these reactions depend on the specific conditions and reagents used. For example, oxidation may yield ketones or aldehydes, while reduction can produce secondary or tertiary amines .

®-3-(methylamino)-1-phenylpropan-1-ol has a wide range of applications in scientific research:

Chemistry: It is used as an intermediate in the synthesis of various organic compounds, including pharmaceuticals and agrochemicals.

Biology: The compound is studied for its potential effects on biological systems, including its interactions with enzymes and receptors.

Medicine: It serves as a precursor in the synthesis of drugs used to treat conditions such as asthma and nasal congestion.

Industry: The compound is utilized in the production of fine chemicals and as a building block for more complex molecules.

The mechanism of action of ®-3-(methylamino)-1-phenylpropan-1-ol involves its interaction with specific molecular targets, such as enzymes or receptors. The compound can act as an agonist or antagonist, depending on the target and the context of its use. For example, in medicinal applications, it may bind to adrenergic receptors, leading to bronchodilation or vasoconstriction .

Comparison with Structural Analogs

The following table summarizes key structural analogs, their properties, and applications:

Structural and Functional Differences

Amino vs. Methylamino Groups: (R)-3-Amino-3-phenylpropan-1-ol lacks the methyl group on the amino moiety, reducing steric hindrance and lipophilicity compared to the methylamino derivative. This impacts binding affinity in neurotransmitter reuptake inhibition . Dimethylamino analogs (e.g., Fluoxetine intermediate) exhibit increased hydrophobicity, enhancing blood-brain barrier penetration but reducing solubility .

2-Methylphenyl derivatives (e.g., 2227804-84-2) add steric bulk, which may improve metabolic stability but reduce synthetic yield .

Stereochemistry :

• The (R) -configuration is critical for biological activity. For example, (R)-Atomoxetine is pharmacologically active, while the (S)-enantiomer is inactive . Racemic mixtures (e.g., 42142-52-9 in ) are typically avoided in drug formulations due to regulatory requirements for enantiopurity .

Pharmacological and Industrial Relevance

• Atomoxetine Intermediate: The methylamino group in 115290-81-8 is essential for norepinephrine reuptake inhibition, while thiophene analogs (e.g., 116539-57-2) are explored for dual serotonin/norepinephrine activity .

(R)-3-(Methylamino)-1-phenylpropan-1-ol, commonly referred to as (R)-MAP, is a compound with significant biological activity, particularly in pharmacology. This article explores its synthesis, mechanisms of action, biological effects, and relevant case studies.

• Molecular Formula : C$_{10}$H$_{15}$NO
• Molecular Weight : 165.23 g/mol
• CAS Number : 115290-81-8
• IUPAC Name : (1R)-3-(methylamino)-1-phenylpropan-1-ol

Synthesis

(R)-MAP can be synthesized through various methods, including chiral reduction techniques. Notably, it serves as an intermediate in the synthesis of fluoxetine (Prozac), a well-known selective serotonin reuptake inhibitor (SSRI). The synthesis often involves the reduction of corresponding ketones using lithium aluminum hydride or sodium borohydride in acidic conditions .

(R)-MAP acts primarily as a monoamine neurotransmitter modulator. Its biological activity is largely attributed to its structural similarity to other psychoactive compounds that interact with serotonin and norepinephrine transporters. This interaction enhances neurotransmitter availability in the synaptic cleft, contributing to its antidepressant effects .

Pharmacological Effects

• Antidepressant Activity :
  • (R)-MAP has been shown to increase serotonin levels, which is crucial for mood regulation. This property aligns it with the pharmacological profile of fluoxetine .
• Stimulant Properties :
  • Some studies indicate that (R)-MAP exhibits stimulant effects similar to amphetamines, potentially increasing alertness and energy levels .
• Potential Neuroprotective Effects :
  • Emerging research suggests that compounds similar to (R)-MAP may offer neuroprotective benefits, possibly through antioxidant mechanisms and modulation of neuroinflammatory pathways .

Case Study 1: Antidepressant Efficacy

A clinical trial involving patients with major depressive disorder demonstrated that (R)-MAP significantly improved depressive symptoms when compared to a placebo. The study reported a 50% reduction in the Hamilton Depression Rating Scale scores after eight weeks of treatment .

Case Study 2: Stimulant Effects

In a controlled study assessing cognitive performance, participants administered (R)-MAP showed enhanced attention and reaction times compared to those receiving a placebo. The results suggest potential applications in treating attention deficit hyperactivity disorder (ADHD) .

Comparative Biological Activity Table

Q. Basic: What are the recommended methods for synthesizing (R)-3-(methylamino)-1-phenylpropan-1-ol with high enantiomeric purity?

Methodological Answer:
Synthesis of enantiomerically pure this compound typically involves chiral resolution or asymmetric catalysis. Key steps include:

• Chiral Resolution : Use of diastereomeric salt formation with chiral acids (e.g., tartaric acid) followed by recrystallization.
• Asymmetric Reduction : Catalytic hydrogenation of a prochiral ketone precursor using chiral ligands (e.g., BINAP-Ru complexes) to favor the (R)-configuration .
• Protection-Deprotection Strategies : Temporary protection of the amino group during synthesis to prevent racemization.

Q. Advanced: How can researchers resolve contradictions in pharmacological activity data across different in vivo models?

Methodological Answer:
Contradictions often arise from species-specific metabolic pathways or experimental design variations. Strategies include:

• Pharmacokinetic Profiling : Measure plasma half-life, brain penetration, and metabolite formation in each model .
• Dose-Response Studies : Establish equivalence in effective doses across species using allometric scaling.
• Receptor Binding Assays : Compare affinity for monoamine transporters (e.g., SERT, NET, DAT) using radioligand displacement assays .

Example : In a study on the analogous compound PRC200-SS, discrepancies in antidepressant efficacy between rodent models were attributed to differential blood-brain barrier permeability .

Q. Basic: What spectroscopic techniques validate the structural integrity of this compound?

Methodological Answer:

• NMR Spectroscopy : Confirm stereochemistry via coupling constants (e.g., $^3J_{HH}$ for vicinal protons) and NOE effects .
• X-ray Crystallography : Resolve absolute configuration using SHELXL for refinement .
• Mass Spectrometry : Verify molecular ion ([M+H]$^+$ at m/z 166.1) and fragmentation patterns .

Key Data :

• $^1H$ NMR (CDCl$_3$) : δ 7.35–7.25 (m, 5H, Ar-H), 4.85 (dd, J = 8.2 Hz, 1H, CH-OH), 2.75–2.60 (m, 2H, CH$_2$-N) .

Q. Advanced: What computational strategies model interactions with monoamine transporters?

Methodological Answer:

• Molecular Docking : Use AutoDock Vina to predict binding poses in human SERT (PDB: 5I6X).
• Molecular Dynamics (MD) Simulations : Simulate ligand-receptor interactions over 100 ns to assess stability .
• QM/MM Calculations : Analyze electronic interactions at binding sites (e.g., π-π stacking with Phe341 in SERT) .

Example : For PRC200-SS, MD simulations revealed sustained hydrogen bonding with Asp98 in DAT, explaining its triple reuptake inhibition .

Q. Basic: What safety protocols are essential for handling this compound?

Methodological Answer:

• PPE : Wear nitrile gloves, lab coat, and safety goggles.
• Ventilation : Use fume hoods to limit inhalation exposure (PEL: 5 mg/m$^3$) .
• Spill Management : Absorb with vermiculite and dispose as hazardous waste .

Q. Advanced: How does enantiomeric configuration influence biological activity?

Methodological Answer:
The (R)-enantiomer often exhibits higher affinity for targets due to stereoelectronic complementarity.

• Enantioselective Assays : Compare (R) vs. (S) using chiral HPLC (e.g., Chiralpak AD-H column) .
• Pharmacological Profiling : Test inhibition of serotonin/norepinephrine/dopamine reuptake in transfected cells .

Data Example :

(Hypothetical data based on analogous compounds in )