Bisoprolol

Conventional Synthesis Framework

Historical Context and Initial Methodologies

The foundational synthesis of bisoprolol, as described in BE859425 and US4258062, involves three sequential stages:

• Etherification of 4-hydroxybenzyl alcohol with 2-isopropoxyethanol using protonic acids or cationic resins

• Epoxidation with epichlorohydrin to form 2-[[4-(2-isopropoxyethoxy)methyl]phenoxymethyl]oxirane

• Amination with isopropylamine to yield this compound base, followed by fumarate salt formation

This route suffered from low overall yields (15–27%) due to multiple high-vacuum distillations required to purify liquid intermediates . For instance, the epoxidation step generated 10–15% residual 1-[p-(2-isopropoxyethoxy)methyl]phenoxy]-3-chloro-propan-2-ol, necessitating energy-intensive purification .

Novel Industrial Synthesis Routes

Amberlyst-15 Catalyzed Process (WO2007069266A2)

This patent describes a streamlined method emphasizing impurity control at each stage:

Intermediate I: 4-[(2-Isopropoxyethoxy)methyl]phenol Synthesis

• Reagents : 4-Hydroxybenzyl alcohol, 2-isopropoxyethanol, Amberlyst-15 resin

• Conditions : 0–5°C for 2 h → 15–20°C for 10 h

• Purification : Toluene/water partitioning removes dimer impurities (2–3% → <0.5%)

• Yield : Quantitative (98–99% by HPLC)

Intermediate II: 2-[[4-(2-Isopropoxyethoxy)methyl]phenoxymethyl]oxirane

• Epoxidation : Sodium hydroxide-mediated reaction with epichlorohydrin

• Key Improvement : In-situ monitoring reduces chloro-propanol residuals from 15% to <1%

• Distillation : Eliminated via aqueous extraction (CHCl₃/water)

Final Amination and Salt Formation

• Amination : Reflux with isopropylamine in methanol (3 h)

• Chromatography : Neutral alumina filtration traps 4-[2-hydroxy-3-[(1-methylethyl)amino]propoxy]benzenemethanol

• Fumarate Yield : 82–85% (30–33 kg from 36 kg base)

Oxazolidinone-Based Route (CN103664657A)

Chinese Patent CN103664657A circumvents traditional epoxidation through a novel heterocyclic intermediate:

Intermediate III: 5-[4-(2-Isopropoxyethoxymethyl)-phenoxy]-3-isopropyloxazolidin-2-one

• Coupling Reaction : Toluene-4-sulfonic acid ester + 4-(2-isopropoxyethoxymethyl)phenol

• Catalyst : K₂CO₃ in DMF at 80°C (12 h)

• Yield : 89% after extraction (vs. 72% in conventional method)

Ring-Opening and Salt Formation

• Hydrolysis : HCl/ethanol at 60°C (4 h) releases this compound free base

• Fumarate Crystallization : Ethanol/acetone system achieves 93% yield (Example 8)

Comparative Analysis of Methodologies

Critical Process Optimization Strategies

Catalytic System Design

• Amberlyst-15 vs. Homogeneous Acids : The macroreticular resin enables 98% conversion at 20°C versus 85% with H₂SO₄ at 50°C, minimizing thermal degradation

• Alkali Metal Carbonates : K₂CO₃ in DMF increases coupling reaction rates by 3× compared to NaHCO₃ (TOF 0.42 vs. 0.15 min⁻¹)

Impurity Control Mechanisms

• Dimer Suppression : Toluene/water partitioning reduces 4-hydroxybenzyl alcohol dimers from 2.3% to 0.4%

• Chromatographic Trapping : Neutral alumina beds adsorb 92% of benzenemethanol impurities during amination

• Crystallization Optimization : Acetone-mediated fumarate recrystallization lowers aldehyde content from 0.15% to 0.06%

Bisoprolol unterliegt verschiedenen chemischen Reaktionen, darunter:

Oxidation: this compound kann zu verschiedenen Metaboliten oxidiert werden.

Reduktion: Reduktionsreaktionen sind weniger häufig, können aber unter bestimmten Bedingungen auftreten.

Substitution: this compound kann Substitutionsreaktionen eingehen, insbesondere unter Beteiligung seiner phenolischen und Aminogruppen.

Häufig verwendete Reagenzien in diesen Reaktionen sind Oxidationsmittel wie Wasserstoffperoxid und Reduktionsmittel wie Natriumborhydrid. Die Hauptprodukte, die aus diesen Reaktionen entstehen, sind typischerweise Metaboliten, die entweder ausgeschieden oder im Körper weiter verstoffwechselt werden .

Pharmaceutical Applications

1.1 Drug Delivery Systems
The amphiphilic nature of 2-Methylene-beta-alanine allows it to form micelles and liposomes, which are effective in encapsulating hydrophobic drugs. This enhances the solubility and bioavailability of these compounds, making them more effective in therapeutic applications. The ability to modify drug release profiles through the use of this compound can lead to improved patient outcomes in various treatments.

1.2 Antioxidant Properties
While 2-Methylene-beta-alanine itself does not exhibit antioxidant properties, it contributes to increased levels of carnosine in tissues. Carnosine is known for its ability to scavenge reactive oxygen species (ROS), thereby potentially mitigating oxidative stress and enhancing cellular protection against damage caused by free radicals.

Sports Nutrition

2.1 Performance Enhancement
Research indicates that supplementation with beta-alanine can enhance athletic performance by increasing muscle carnosine content. This results in improved buffering capacity during high-intensity exercise, which can delay fatigue and enhance endurance. A study on recreationally trained men demonstrated that a sustained-release formulation of beta-alanine improved performance metrics and reduced symptoms of paraesthesia commonly associated with beta-alanine supplementation .

2.2 Case Study: Equestrian Performance
In a study involving Yili horses participating in speed racing, beta-alanine supplementation resulted in a significant improvement in performance, with test group horses completing races faster than control group horses. The supplementation also led to increased levels of antioxidants in the blood, suggesting a dual benefit of enhanced performance and reduced oxidative stress during exercise .

Biochemical Research

3.1 Modulation of Enzymatic Activity
2-Methylene-beta-alanine has been studied for its potential to modulate the activity of various enzymes, including cytochrome c oxidase. Research indicates that increasing concentrations of this compound can significantly decrease enzyme function, suggesting applications in metabolic disorders where modulation of mitochondrial respiration is desired.

3.2 Biosynthesis of Natural Products
The incorporation of beta-amino acids like 2-Methylene-beta-alanine into natural products is an area of active research. The ability to swap beta-amino acid moieties with different side chains could lead to the development of novel bioactive compounds with therapeutic potential .

Summary Table of Applications

Bisoprolol exerts its effects by selectively blocking beta-1 adrenergic receptors in the heart. This action reduces the heart rate and the force of contraction, leading to a decrease in cardiac output and blood pressure. The molecular targets involved include the beta-1 adrenergic receptors, which are part of the sympathetic nervous system .

Pharmacological Properties

Receptor Selectivity and Molecular Mechanisms

Bisoprolol exhibits >100-fold higher affinity for β₁-adrenoceptors compared to β₂-receptors, minimizing bronchoconstrictive and metabolic side effects . In contrast:

• Atenolol: At 50 mg, shows similar β₁-selectivity to this compound 10 mg but requires higher doses for equivalent β₁-blockade .
• Carvedilol: Non-selective β-blocker with additional α₁-blocking activity, increasing vasodilation but raising hypotension risk .
• Nebivolol : β₁-selective with nitric oxide-mediated vasodilation, offering unique hemodynamic benefits .

Table 1: Receptor Selectivity and Key Mechanisms

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Ion Channel Effects

This contrasts with propranolol, which primarily blocks Na⁺ channels .

Pharmacokinetic Profile

Metabolism and Elimination

• This compound : Hepatic metabolism (CYP3A4) and renal excretion (50% unchanged). Half-life: 10–12 hours , enabling once-daily dosing .
• Metoprolol : Metabolized by CYP2D6, leading to variability in poor metabolizers .
• Carvedilol : CYP2D6/2C9-dependent metabolism; shorter half-life (6–8 hours) necessitates twice-daily dosing .

Table 2: Pharmacokinetic Comparison

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Genetic Polymorphisms

In contrast, metoprolol’s efficacy is highly dependent on CYP2D6 status .

Clinical Efficacy Comparison

Hypertension

• This compound vs. Metoprolol CR/ZOK: In the CREATIVE study, this compound provided superior HR reduction (ΔHR: −11.2 vs. −8.5 bpm) and non-inferior BP control .
• This compound vs. Nifedipine : Comparable BP reduction, but this compound showed more consistent 24-hour control .

Heart Failure (HF)

• CIBIS-II Trial : this compound reduced all-cause mortality by 34% in HF patients vs. placebo .
• CARNEBI Trial : this compound, carvedilol, and nebivolol showed similar improvements in ejection fraction, but carvedilol had higher hypotension rates .

Table 3: Clinical Outcomes in Key Trials

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Bisoprolol is a selective beta-1 adrenergic antagonist primarily used in the management of hypertension and heart failure. Its pharmacological properties, mechanisms of action, and clinical efficacy have been extensively studied, revealing significant insights into its biological activity. This article delves into the biological activity of this compound, supported by data tables, case studies, and detailed research findings.

This compound exhibits its therapeutic effects through competitive inhibition of beta-1 adrenergic receptors located predominantly in the heart. By blocking these receptors, this compound reduces cardiac output and lowers heart rate, which decreases myocardial oxygen demand. Additionally, it is believed to lower renin secretion from the kidneys, further contributing to its antihypertensive effects .

Pharmacokinetics

The pharmacokinetics of this compound are characterized by moderate lipophilicity and high bioavailability. It is primarily metabolized in the liver via cytochrome P450 enzymes, particularly CYP2D6 and CYP3A4. Variations in these enzymes due to genetic polymorphisms can influence this compound's plasma concentrations and therapeutic outcomes .

Heart Failure

The Cardiac Insufficiency this compound Study II (CIBIS-II) demonstrated that this compound significantly reduces mortality in patients with chronic heart failure. Key findings include:

• All-Cause Mortality : A relative reduction of 29.3% compared to placebo (hazard ratio 0.66; 95% CI 0.54–0.81) was observed .
• Sudden Death : Fewer sudden deaths occurred in the this compound group (3.6% vs. 6.3% in placebo) with a hazard ratio of 0.56 .

Table 1: Summary of CIBIS-II Findings

Hypertension

In patients with mild to moderate hypertension, this compound has shown significant reductions in blood pressure and heart rate:

• Blood Pressure Reduction : After six weeks of treatment, systolic blood pressure decreased by an average of 14.3 mmHg and diastolic by 8.4 mmHg .
• Heart Rate Reduction : The average reduction in heart rate was noted to be approximately 6 BPM .

BISOCOR Observational Study

This study evaluated the long-term effects of this compound on patients with heart failure over nine months:

• Ejection Fraction Improvement : An increase of 0.06 in ejection fraction was recorded.
• Adverse Effects : Approximately 10% of patients discontinued due to adverse effects, indicating a need for careful monitoring during treatment .

This compound in COPD Study (BICS)

A recent randomized clinical trial assessed this compound's efficacy in patients with chronic obstructive pulmonary disease (COPD):

• Study Design : Patients were randomized to receive either this compound or placebo.
• Findings : While initial results indicated potential benefits, further analysis is ongoing to confirm efficacy in this population .