Ethyl 4-(2-(1,3-dioxoisoindolin-2-yl)ethoxy)-3-oxobutanoate

Synthetic Routes and Reaction Conditions

The synthesis of Ethyl 4-(2-(1,3-dioxoisoindolin-2-yl)ethoxy)-3-oxobutanoate typically involves the condensation of an aromatic primary amine with a maleic anhydride derivative, leading to the formation of the isoindoline-1,3-dione scaffold . Another approach involves the reaction of phthalic anhydride with glycine and acetic acid in the presence of triethylamine in toluene as a solvent .

Industrial Production Methods

Industrial production methods for this compound are not extensively documented, but they likely involve similar synthetic routes with optimization for large-scale production. This includes the use of efficient catalysts and solvent systems to maximize yield and purity.

Types of Reactions

Ethyl 4-(2-(1,3-dioxoisoindolin-2-yl)ethoxy)-3-oxobutanoate undergoes various types of chemical reactions, including:

Oxidation: This compound can be oxidized to introduce additional functional groups.

Reduction: Reduction reactions can modify the isoindoline-1,3-dione moiety.

Substitution: Electrophilic and nucleophilic substitution reactions can occur at various positions on the molecule.

Common Reagents and Conditions

Common reagents used in these reactions include oxidizing agents like potassium permanganate, reducing agents such as lithium aluminum hydride, and various nucleophiles and electrophiles for substitution reactions .

Major Products

The major products formed from these reactions depend on the specific conditions and reagents used. For example, oxidation can lead to the formation of carboxylic acids, while reduction can yield amines or alcohols.

Ethyl 4-(2-(1,3-dioxoisoindolin-2-yl)ethoxy)-3-oxobutanoate has a wide range of scientific research applications:

Chemistry: Used as a building block in organic synthesis to create more complex molecules.

Biology: Investigated for its potential biological activities, including antiviral, anti-inflammatory, and anticancer properties.

Medicine: Explored for its potential as a therapeutic agent due to its ability to interact with various biological targets.

Industry: Utilized in the development of materials with specific properties, such as photochromic materials and polymer additives.

The mechanism of action of Ethyl 4-(2-(1,3-dioxoisoindolin-2-yl)ethoxy)-3-oxobutanoate involves its interaction with specific molecular targets and pathways. The isoindoline-1,3-dione moiety is known to interact with enzymes and receptors, modulating their activity and leading to various biological effects . The exact pathways and targets depend on the specific application and context of use.

Chemical Identity :

• IUPAC Name: Ethyl 4-[2-(1,3-dioxoisoindol-2-yl)ethoxy]-3-oxobutanoate
• CAS Number : 88150-75-8
• Molecular Formula: C₁₆H₁₇NO₆
• Molecular Weight : 319.31 g/mol .
• Synonyms: Ethyl-4(2-Phthalimido Ethoxy)Acetoacetate, 4-(2-Phthalimidoethoxy)acetoacetic Acid Ethyl Ester .

Structural Features: The compound consists of a phthalimide (1,3-dioxoisoindoline) group linked via an ethoxy chain to a 3-oxobutanoate ethyl ester. This structure confers both lipophilic (phthalimide) and reactive (β-keto ester) properties, making it a versatile intermediate in organic synthesis .

Applications :
Primarily used as a synthetic intermediate in pharmaceuticals (e.g., related to Amlodipine impurities) and isotopomer synthesis .

Physical Properties :

• Boiling Point : 479.7 ± 30.0 °C (at 760 mmHg) .
• Storage : Room temperature, dry conditions .

Structural Analogues

(a) Ethyl 3-Oxobutanoate

• Formula : C₆H₁₀O₃
• Molecular Weight : 130.14 g/mol.
• Key Differences : Lacks the phthalimidoethoxy group. Simpler structure with a single β-keto ester functionality.
• Applications: Precursor for synthesizing chlorinated derivatives (e.g., ethyl 2-chloro-3-oxobutanoate) used in isotopomer production .

(b) Ethyl 4-[2-(Dimethylamino)ethoxy]-3-oxobutanoate

• CAS : 84157-65-3
• Formula: C₁₀H₁₉NO₄
• Molecular Weight : 217.26 g/mol.
• Key Differences: Substitutes phthalimide with a dimethylamino group, introducing basicity. This enhances solubility in acidic media but reduces thermal stability compared to the phthalimide analogue .

(c) Ethyl 4-(2,4-Difluorophenyl)-4-oxobutyrate

• CAS : 1041553-00-7
• Formula : C₁₂H₁₂F₂O₃
• Molecular Weight : 242.22 g/mol.
• Key Differences : Contains a fluorinated aromatic ring instead of phthalimide. Fluorine atoms increase electronegativity, improving metabolic stability in pharmaceutical contexts .

Functional Analogues

(a) Ethyl 2-Chloro-3-oxobutanoate

• Formula : C₆H₉ClO₃
• Molecular Weight : 164.59 g/mol.
• Key Differences : Chlorine substituent at the α-position enhances electrophilicity, facilitating nucleophilic substitutions. Used in synthesizing isotopically labeled 1-chloroacetone .

(b) Cetirizine Ethyl Ester

• Structure : Contains a piperazine-ethoxy-acetic acid ethyl ester backbone.
• Key Differences : Piperazine group introduces basic nitrogen atoms, altering pharmacokinetics (e.g., antihistamine activity). The absence of a phthalimide reduces lipophilicity .

Comparative Data Table

Ethyl 4-(2-(1,3-dioxoisoindolin-2-yl)ethoxy)-3-oxobutanoate is a compound with significant potential in medicinal chemistry, particularly in the context of anticancer research. This article explores its biological activity, focusing on its synthesis, cytotoxic effects, and structure-activity relationships.

• Chemical Formula : C$_{16}$H$_{17}$NO$_6$
• Molecular Weight : 319.31 g/mol
• CAS Number : 88150-75-8
• IUPAC Name : Ethyl 4-[2-(1,3-dioxoisoindolin-2-yl)ethoxy]-3-oxobutanoate
• PubChem CID : 9840027

The synthesis of this compound typically involves the reaction of ethyl chloroacetate with various heterocycles. The resulting derivatives are evaluated for their cytotoxic properties against different cancer cell lines, including MCF-7 (breast cancer) and HeLa (cervical cancer) cells. The mechanism of action is believed to involve the inhibition of key growth factors and enzymes that are crucial for cancer cell proliferation.

Cytotoxic Activity

Recent studies have highlighted the cytotoxic activity of this compound, demonstrating its effectiveness against various cancer cell lines. For instance, a study evaluated several derivatives containing phthalimide moieties and reported significant cytotoxic effects:

Table 1: Cytotoxic Activity of Related Compounds

Compound 3d , which contains two phthalimide structures, exhibited the highest cytotoxicity with an IC$_{50}$ value of 29 μM against the HeLa cell line, indicating a strong potential for further development as an anticancer agent .

Structure-Activity Relationship (SAR)

The structure-activity relationship studies indicate that the presence of specific functional groups significantly enhances the biological activity of these compounds. The incorporation of phthalimide moieties appears to increase lipophilicity, which may facilitate better interaction with biological targets .

Key Findings:

• Lipophilicity : Increased lipophilic character correlates with enhanced cytotoxicity.
• Functional Groups : The presence of electron-withdrawing groups often improves potency by stabilizing reactive intermediates.
• Heterocyclic Scaffolds : Five-membered heterocycles are crucial for maintaining biological activity due to their ability to mimic natural substrates.

Case Studies

Research has demonstrated that derivatives of this compound can induce apoptosis in cancer cells through various pathways:

• Apoptosis Induction : Compounds were shown to activate caspase pathways leading to programmed cell death.
• Inhibition of Growth Factors : Studies indicate that these compounds can inhibit key signaling pathways involved in tumor growth and metastasis.

Q. Basic: What are the recommended synthetic routes for Ethyl 4-(2-(1,3-dioxoisoindolin-2-yl)ethoxy)-3-oxobutanoate, and how can purity be optimized?

The compound is synthesized via multicomponent reactions , such as coupling phthalimide derivatives with ethyl acetoacetate intermediates. A key step involves introducing the 1,3-dioxoisoindolin-2-yl ethoxy group through nucleophilic substitution or esterification under anhydrous conditions . To optimize purity:

• Use column chromatography (silica gel, ethyl acetate/hexane eluent) for separation.
• Monitor reaction progress via thin-layer chromatography (TLC) .
• Recrystallize from ethanol or methanol to achieve >95% purity, as reported by suppliers .

Q. Basic: How should researchers handle and store this compound to ensure stability?

Conflicting storage recommendations exist:

• Refrigeration (2–8°C) is advised by Fujifilm Wako to prevent decomposition of the β-ketoester moiety .
• Room temperature (dry conditions) is suggested by other suppliers, assuming short-term stability .
  Methodological guidance :
• Conduct accelerated stability studies (e.g., 40°C/75% RH for 1 week) to determine degradation kinetics.
• Store under inert gas (N₂/Ar) to minimize hydrolysis of the ester group .

Q. Intermediate: What spectroscopic techniques are critical for characterizing this compound?

Essential methods :

• ¹H/¹³C NMR : Confirm the presence of the phthalimide ring (δ 7.8–8.0 ppm for aromatic protons) and β-ketoester (δ 3.5–4.5 ppm for ethoxy groups) .
• FT-IR : Verify ester C=O stretches (~1730 cm⁻¹) and phthalimide C=O (~1770 cm⁻¹) .
• HRMS : Validate molecular weight (C₁₆H₁₇NO₆, [M+H]⁺ = 320.1128) .

Q. Advanced: How can researchers resolve contradictions in reported melting points and boiling points?

reports a boiling point of 479.7±30.0°C but no melting point , while other sources omit thermal data.
Approach :

• Perform differential scanning calorimetry (DSC) to determine decomposition temperature.
• Use thermogravimetric analysis (TGA) to assess volatility under reduced pressure.
• Compare results with computational predictions (e.g., COSMO-RS for boiling point estimation).

Q. Advanced: What mechanistic insights exist for the reactivity of the β-ketoester group in this compound?

The β-ketoester moiety undergoes:

• Knoevenagel condensation with aldehydes, forming α,β-unsaturated esters.
• Michael addition with nucleophiles (e.g., amines), useful for constructing heterocycles .
  Key considerations :
• Stabilize enolate intermediates using Lewis acids (e.g., MgCl₂).
• Monitor pH to avoid hydrolysis of the ester group during reactions .

Q. Advanced: How can computational modeling guide the design of derivatives for biological applications?

Strategies :

• Perform docking studies to evaluate interactions with targets like tyrosyl-DNA phosphodiesterase 1 (TDP1), leveraging its phthalimide scaffold’s DNA-binding affinity .
• Use QSAR models to predict solubility (LogP = 1.2) and bioavailability.
• Simulate metabolic pathways (e.g., esterase-mediated hydrolysis) using ADMET predictors .

Q. Advanced: What are the implications of conflicting purity grades (85% vs. 97%) across suppliers?

Impact : Lower purity (85%) may introduce side products (e.g., hydrolyzed β-ketoester) affecting reaction yields.
Mitigation :

• HPLC-PDA analysis to quantify impurities.
• Pre-purify commercial batches via flash chromatography if purity <95% .

Q. Cross-Disciplinary: How is this compound applied in materials science or catalysis?

• Coordination chemistry : The phthalimide group chelates metals (e.g., Cu²⁺), enabling use in catalytic systems .
• Polymer synthesis : Acts as a monomer in step-growth polymerization for functional polyesters.