Thalidomide-O-PEG4-Amine - ≥98% , CAS No.2401832-00-4

CAS: 2401832-00-4 Cat. No.: T595106 Fórmula: C₂₃H₃₁N₃O₉ Peso molecular: 493.5

GRADE & PURITY ≥98%

Storage

Store at -20°C

Shipped In

Ice chest + Ice pads

Application

230

Visão geral

E3 ligase ligand-linker conjugate, Thalidomide-O-PEG4-Amine, is synthesized compound that incorporates the Thalidomide based cereblon ligand and 4-unit PEG linker used in PROTAC technology.

Specifications

Especificações e pureza

≥98%

Condições de armazenamento de armazenamento

Store at -20°C

Enviado em

Ice chest + Ice pads

Este produto requer transporte de cadeia fria. Serviços terrestres e outros serviços econômicos não estão disponíveis.

Pureza

≥98%

Nomes e identificadores

• Peso molecular: 493.5

Application Protocols

No item-specific, validated application protocols are provided for this product.

General guidance for preparing stock solutions and performing couplings (non‑validated, for research planning):

• Stock solution: Dissolve in dry DMSO or DMF at 10–50 mM. Vortex and, if needed, sonicate briefly. Filter (0.22 μm PTFE) for sterile‑like handling in cell assays.
• Storage of stocks: Aliquot and freeze at −20°C. Avoid multiple freeze–thaw cycles; thaw on ice and use promptly.
• Typical amide coupling (outline): To a dry solution of your carboxylic acid warhead (1.0 eq) in DMF, add HATU (1.2 eq) and DIPEA (3.0 eq); stir 5–10 min, then add Thalidomide‑O‑PEG4‑Amine (1.2 eq). React at 0–25°C until LC–MS shows completion. Quench with water, extract or precipitate, and purify by RP‑HPLC.
• Analytical QC: Track reactions by LC–MS; PEGylated products exhibit sodium/potassium adducts and +44 Da spacings. Confirm by 1H/13C NMR and HRMS.

For validated, SKU‑specific protocols (e.g., tested reactions, recommended conditions), consult the CoA/Spec Sheet.

Biological Roles

Context (literature/general; not item-specific claims):

• Thalidomide and analogs (e.g., lenalidomide, pomalidomide) are well‑established ligands for the E3 ubiquitin ligase substrate receptor cereblon (CRBN). Binding occurs via the phthalimide/glutarimide pharmacophore, enabling recruitment of CRBN within the CUL4–DDB1–CRBN complex.
• In chemical biology, thalidomide‑based linkers serve as “E3 recruiter” modules in heterobifunctional degraders (PROTACs), bringing targets into proximity with CRBN to promote ubiquitination and proteasomal degradation (when appropriately linked to a target binder).
• PEG4 spacing imparts flexibility and hydrophilicity that can improve ternary complex formation, solubility, and cellular handling compared with shorter linkers; optimal length and exit vector are target‑ and warhead‑dependent.
• The terminal amine facilitates modular assembly, salt formation (enhanced aqueous solubility upon protonation), and conjugation to dyes, resins, or macromolecules for mechanistic or pull‑down studies.

Important notes:

• No medical or therapeutic claims are made for this product; it is provided strictly for research use.
• Specific binding affinity, cellular activity, and degradation profiles depend on overall conjugate structure and are not defined for this standalone linker. Empirical SAR is essential for each target system.

Buffer Applications

This compound is not a classical buffering agent and is not typically used to set or maintain pH. However, practical considerations apply when formulating for biological assays (general guidance):

• Stock preparation: Prepare concentrated stocks in dry DMSO or DMF (e.g., 10–50 mM). For aqueous delivery, dilute into buffer immediately before use to the minimal organic cosolvent fraction (≤0.1–1% v/v), monitoring for precipitation.
• Protonation/salt forms: Converting the terminal amine to a hydrochloride or TFA salt can increase aqueous compatibility. Adjust buffer pH to 6.5–7.5 to balance amine protonation and target assay needs.
• Compatible buffers: PBS, HEPES, or Tris are commonly used for cellular or biochemical studies; avoid high concentrations of strong nucleophiles or strong base that can attack imide carbonyls.

For exact solubility and formulation stability of this specific item, refer to the lot CoA/Spec Sheet; no item‑specific buffer recipes are provided.

Green Alternatives

Sustainable choices can be integrated without compromising performance. The following suggestions are general/literature guidance for assembling conjugates from Thalidomide‑O‑PEG4‑Amine.

Greener solvent options:

• Replace DMF/NMP with MeCN, 2‑MeTHF, or CPME when solubility permits. MeCN is volatile and amenable to recovery; 2‑MeTHF/CPME offer improved EHS profiles and water separations.
• Use ethanol or isopropanol for crystallizations/precipitations instead of chlorinated solvents.

Greener coupling systems (trade‑offs noted):

• DMTMM (in MeCN/EtOAc) as an alternative to HATU/TBTU (less energetic waste, avoids PF6−). May require optimization for sterically hindered partners.
• CDI or EDCI with catalytic DMAP/NHS in MeCN/2‑MeTHF can reduce reliance on azabenzotriazoles.

Process intensification:

• Micellar catalysis or aqueous MeCN with surfactants can enable couplings at lower organic solvent use; check stability of imides under aqueous conditions.
• Flow chemistry for amide formation improves heat/mass transfer and can cut solvent volumes.

Waste minimization:

• Selectively precipitate product by water addition to MeCN or IPA to reduce silica usage.
• Recover MeCN/EtOAc by distillation; avoid DCM where possible due to environmental and safety concerns.

Comparison snapshot (general):

• Traditional: DMF + HATU → high reactivity, PF6− waste.
• Greener: MeCN + DMTMM → good efficiency, easier solvent recovery, lower hazard. Optimization may be needed for difficult couplings.

Always validate greener swaps on small scale; monitor for any imide sensitivity to bases, heat, or prolonged aqueous exposure.

Pharmaceutical Uses

No pharmacopeial or excipient status is provided for this item. It is sold strictly for research use only.

General R&D context (non‑clinical, literature):

• Discovery chemistry: Employed as a modular CRBN‑recruiting linker fragment for assembling screening libraries of heterobifunctional degraders, molecular glues, and conjugates to interrogate E3 ligase biology.
• Preformulation studies: PEG4 spacers can help explore solubility/permeability trade‑offs in medicinal chemistry optimization of degrader series.
• Analytical reference: Useful as a synthetic intermediate or reference material in LC–MS method development for PROTAC quantification.

No claims are made or implied regarding safety or efficacy in humans or animals. For any development beyond basic research, dedicated quality, tox, and regulatory assessments are required and are outside the scope of this catalog item.

Physical Properties

Item-specific values (from Product Data):

• Appearance: Not specified for this item; refer to CoA/Spec Sheet.
• Grade/Purity: Not specified for this item; refer to CoA/Spec Sheet.
• Molecular weight: Not specified for this item; refer to CoA/Spec Sheet.
• Molecular formula: Not specified for this item; refer to CoA/Spec Sheet.
• Melting point, boiling point, density, refractive index, pKa, logP/logD: Not specified for this item; refer to CoA/Spec Sheet.

General/literature guidance (non‑spec):

• Physical state: Typically a white to off‑white solid for PEGylated thalidomide linkers; hygroscopic tendency may be higher than the parent thalidomide due to PEG content (literature/experience).
• Solubility profile: Good solubility anticipated in polar aprotic solvents (DMSO, DMF, NMP) and alcohols; PEG4 often imparts partial aqueous solubility, especially as the protonated ammonium salt under acidic conditions (literature, general behavior of PEG4 amines).
• Ionization: Terminal primary amine is basic; salts with HCl/TFA increase aqueous solubility. Imide protons (if present) are weakly acidic but typically non-ionized under neutral conditions.
• Stability considerations: Imide rings are generally stable under neutral, anhydrous conditions; prolonged exposure to strong base or strong nucleophiles can open imides. Polyether chains resist many conditions but are susceptible to strong oxidizers and very strong acids.

Note: For project-critical parameters (exact MW, UV cutoff, water/peroxide/metal limits), consult the item’s CoA/Spec Sheet; no numerical specifications are provided here.

Quality and Grades

Item-specific quality details (from Product Data):

• Grade/Purity: Not specified for this item; refer to CoA/Spec Sheet.

How to interpret common grades (general guidance):

• Research grade: Suitable for synthetic, screening, or materials R&D; may not include low‑UV, metals, or bioburden specifications.
• ≥95–98% purity (typical for linker building blocks, literature): Adequate for medicinal chemistry and conjugation. For bioconjugation to sensitive biomolecules, ≥98% and detailed impurity profiling are preferred.
• HPLC/LC–MS trace: A CoA with chromatographic purity, identity (1H NMR/HRMS), and residual solvents gives confidence for SAR or PROTAC assembly.

Stabilizer/additives:

• None indicated for this item. If supplied as a TFA/HCl salt of the amine, note potential counterion content; neutralize during workups as needed. Any stabilizer or salt form would be disclosed on the CoA/Spec Sheet.

Recommendations:

• For scale‑up or GxP‑adjacent work, request lot‑specific CoA including assay, water (KF), residual solvents, and identity spectra. If low‑UV or metal content matters (e.g., for photophysical assays or catalysis studies), specify those requirements before ordering.

Reaction and Applications

Primary application domain (general/literature):

• PROTAC and degrader synthesis: Thalidomide derivatives recruit the CRBN E3 ligase. The O‑PEG4‑Amine variant provides a hydrophilic, flexible spacer and a terminal amine for straightforward coupling to a target‑binding warhead or to linkers/spacers.

Common transformations using the terminal amine (general guidance):

• Amide bond formation: With carboxylic acids or activated esters (NHS), using HATU/HOAt, TBTU/HOBt, EDCI/NHS, or DMTMM in DMF/MeCN. Control base (DIPEA/TEA) to limit imide transacylation.
• Urea/carbamate formation: React with isocyanates or activated carbonates (e.g., p‑nitrophenyl carbonate). For carbonate protection, avoid strong base that may open imide rings.
• Reductive amination: With aldehydes/ketones under NaBH3CN or BH3·THF; consider sterics and aqueous compatibility.
• Sulfonamide formation: With sulfonyl chlorides in the presence of base (e.g., pyridine or DIPEA) at 0–25°C.

Conjugation strategy notes:

• O‑ vs N‑linkage on thalidomide: O‑linked analogs typically maintain CRBN affinity while modulating exit vector orientation (literature). Choice affects ternary complex geometry.
• PEG4 spacer: Enhances aqueous compatibility and can improve degrader permeability/solubility balance relative to shorter or bulkier spacers.
• Protecting groups: If orthogonal chemistry is needed, transiently protect the amine (Boc/CBz/Fmoc) prior to multi‑step assembly.

Workflow tips:

• Prepare 10–50 mM DMSO/DMF stocks under inert gas. For couplings, ensure <0.02% water and use freshly opened reagents. Monitor by LC–MS; PEGylated species show characteristic +44 Da spacing in adduct patterns.

Reaction Conditions

General literature guidance for using the terminal amine in coupling/conjugation (optimize per substrate):

Amide coupling:

• Solvent: Anhydrous DMF or MeCN (alternatives: DCM/2‑MeTHF if soluble).
• Reagents: HATU (1.1–1.5 eq) + DIPEA (2–4 eq) or DMTMM (1.2–1.5 eq) without added base.
• Temperature/time: 0–25°C, 1–12 h. Monitor by LC–MS. Quench with water and extract or precipitate in IPA/Et2O.

Urea/carbamate formation:

• Urea: Isocyanate (1.1–1.3 eq) in MeCN/DCM, 0–25°C, 1–4 h.
• Carbamate: p‑Nitrophenyl carbonate or chloroformate (1.1–1.3 eq) with base (1–2 eq) at 0–25°C. Avoid excess strong base to protect imide rings.

Reductive amination:

• Solvent: MeOH/MeCN with 0.5–1% AcOH to form imine.
• Reductant: NaBH3CN (2–3 eq) at 0–25°C, 2–6 h. Work up with aqueous bicarbonate.

Sulfonamide formation:

• Reagents: R–SO2Cl (1.1 eq), base (2–3 eq pyridine or DIPEA) in MeCN or DCM at 0–25°C, 1–3 h.

Workup/purification tips:

• PEGylated products may resist extraction; use brine salting‑out, back‑extractions with MeOH/EtOAc mixtures, or proceed directly to reverse‑phase purification.
• For LC purification, use water/MeCN or water/MeOH gradients with volatile buffers (0.05–0.1% TFA or 5–20 mM ammonium acetate). Slightly elevated column temperature (30–40°C) can sharpen broad PEG peaks.

Yields: Highly substrate‑dependent; 50–90% is typical for clean amide couplings under optimized conditions (literature ranges).

Safety and Handling

GHS/SDS information (from Product Data):

• Signal word: Not specified for this item; refer to SDS.
• Hazard statements, pictograms, classification: Not specified for this item; refer to SDS.

General laboratory safety (guidance only; defer to SDS):

• PPE: Use lab coat, appropriate chemical‑resistant gloves (e.g., nitrile), and safety glasses or face shield. Work in a chemical fume hood to avoid inhalation of dust or solvent vapors.
• Avoid: Contact with strong bases (risk of imide ring opening), strong oxidizers (polyether oxidation), and strong acids for prolonged times (PEG degradation). Prevent moisture ingress to limit hydrolysis.
• Handling: Minimize dust generation. For weighing, allow the sealed container to warm to room temperature before opening to reduce condensation. If form is supplied as a TFA/HCl salt, avoid aerosolization and handle with care due to corrosivity of acid residues in dust.
• First aid (overview): Inhalation—move to fresh air; Skin/Eye—rinse with water for at least 15 minutes; Ingestion—rinse mouth and seek medical attention. Remove contaminated clothing and wash before reuse.
• Spill response: Collect solids by gentle sweeping; for solutions, absorb on inert material. Dispose according to institutional/municipal regulations.
• Transport/storage risks: Protect from light and heat. Avoid repeated freeze–thaw of solutions. Although thalidomide analogs are research chemicals, handle with heightened caution and prevent environmental release. Always consult the product SDS for authoritative hazard and exposure guidance.

Solvent Selection

Compound class perspective: Thalidomide‑O‑PEG4‑Amine is an amphiphilic small molecule with a PEG4 chain and a basic primary amine; it typically displays excellent solubility in polar aprotic media and enhanced miscibility with aqueous buffers when protonated.

Practical solvent choices (general/literature):

• High solubility: DMSO, DMF, NMP. Ideal for stock solutions (10–100 mM) used in conjugation or screening. Degas and dry if moisture‑sensitive couplings are planned.
• Moderate to good: Methanol, ethanol, isopropanol, acetonitrile. Often usable for precipitation‑driven purifications.
• Aqueous buffers: Improved upon salt formation (e.g., HCl/TFA). For biological assays, prepare concentrated DMSO stocks and dilute into buffer to ≤0.1–1% DMSO v/v, monitoring for turbidity.
• Poorer solvents: Nonpolar hydrocarbons (hexanes, toluene) due to PEG polarity; chlorinated solvents (DCM/CHCl3) may dissolve but are less ideal for amide couplings compared with DMF or MeCN.

Selection tips:

• For amide couplings, anhydrous DMF or MeCN balances solubility and reactivity; 0–10% DIPEA/TEA can assist amine deprotonation.
• For preparative chromatography, MeOH/CH3CN with water and 0.1% TFA/NH4OAc modulates retention of PEGylated species.

Mini comparison (general):

• DMSO: Maximum solubilization; harder to remove; excellent for bioassays.
• DMF: Coupling workhorse; dry easily; toxic—use hood.
• MeCN: Volatile, LC‑friendly; may limit solubility at high loadings.

Always confirm solvent compatibility with your reaction and consult the CoA for any item-specific solubility notes.

Storage and Reconstitution

Item-specific storage and shipping (from Product Data):

• Storage conditions: Store at −20°C.
• Shipped in: Ice chest + Ice pads.
• Research use note: For research use only.

General handling and solution guidance (non‑spec):

• Protect from moisture and light. Store tightly capped in the original container or in a desiccator. Allow vial to equilibrate to room temperature while sealed before opening to prevent condensation.
• Solid stability: Under dry, inert conditions at −20°C, PEGylated thalidomide linkers are typically stable for many months. Always follow the retest date on the label/CoA.
• Reconstitution: For stock solutions, dissolve in dry DMSO or DMF to 10–50 mM. If higher aqueous compatibility is required, prepare an HCl or TFA salt of the amine or dilute DMSO stocks slowly into buffer with vigorous mixing.
• Aliquoting: Divide solutions into single‑use portions to avoid freeze–thaw. Store aliquots at −20°C (or below) in inert‑gas‑flushed vials when possible.
• In‑use stability: Minimize exposure to strong bases and oxidants; avoid extended heating. Check for precipitation upon dilution into aqueous media and re‑clarify by gentle warming or additional cosolvent if needed.

For any item‑specific shelf life, exact solubility, or stability data, refer to the lot CoA/Spec Sheet.

Structure and Identity

Brief description: Thalidomide‑O‑PEG4‑Amine is a heterobifunctional small‑molecule linker that combines a thalidomide (phthalimide–glutarimide) E3-ligase binder with a hydrophilic tetraethylene glycol (PEG4) spacer terminating in a primary amine. It is widely used as a CRBN‑recruiting linker handle in targeted protein degradation (PROTAC) and conjugate chemistry.

Item-specific identifiers (from Product Data):

• CAS: 2401832-00-4
• SMILES: Not specified for this item; refer to CoA/Spec Sheet.
• InChIKey: Not specified for this item; refer to CoA/Spec Sheet.
• Molecular formula: Not specified for this item; refer to CoA/Spec Sheet.
• Molecular weight: Not specified for this item; refer to CoA/Spec Sheet.

Structural features (general/interpretive):

• Core: Thalidomide scaffold comprising a substituted phthalimide fused through an imide linkage to a glutarimide ring (two cyclic imides).
• Linkage: O‑linkage from the thalidomide phthaloyl ring (phenoxy/alkoxy attachment) to a PEG4 chain (–O–CH2CH2–O–CH2CH2–O–CH2CH2–O–CH2CH2–), providing ~4 ethylene glycol units (literature, typical for PEG4).
• Terminus: Primary amine at the distal PEG end (–NH2) for conjugation (e.g., amide formation with activated acids or NHS esters).
• Functionality: Multiple carbonyl imides (H‑bond acceptors), ether oxygens (H‑bond acceptors), terminal amine (nucleophilic, cationic under acidic conditions).
• 2D depiction in words: Aromatic phthalimide ring bearing an O‑(PEG4) substituent; PEG4 chain as a zig‑zag polyether terminating in –NH2; the glutarimide ring attached to the phthalimide completes the thalidomide core. No stereocenter is implied by the “O‑PEG4‑Amine” designation (literature note: thalidomide can be chiral at C3 of glutarimide in some derivatives, but configuration for this item is not specified).

Synthetic Utility

Functional group portfolio and reactivity (general):

• Terminal primary amine: Nucleophilic handle for amide, urea, carbamate, sulfonamide, and reductive amination chemistry. Salt formation (HCl/TFA) enhances handling and aqueous compatibility.
• PEG4 chain: Provides conformational flexibility and solvation; improves coupling in less polar media relative to shorter PEGs.
• Thalidomide core: Two imide carbonyls (electrophilic under forcing/basic conditions) and an aromatic phthalimide ring. The O‑linked exit vector preserves CRBN‑binding motif while projecting the linker orthogonally from the ring plane (literature design principle).

Retrosynthetic value:

• Break at the terminal amine: Plan final amide/urea coupling late in the sequence to avoid PEG fouling and to simplify purification.
• Protecting group tactics: Temporary Boc/CBz on the amine allows orthogonal introduction of additional linkers or warheads. Avoid strong base (>pH 11) and prolonged heating to protect the imide rings.

Named/standard operations:

• Amide couplings (HATU/TBTU/EDCI/DMTMM), carbamate formation via chloroformates/carbonates, urea formation via isocyanates or CDI.
• Purification tactics: Reverse‑phase LC with water/MeCN and volatile additives (0.1% TFA/NH4HCO3). PEGylated materials often elute late; gradient and temperature help sharpen peaks.

Use cases:

• Assembly of CRBN‑targeting PROTACs, tracer conjugates, affinity resins, and fluorescent probes where hydrophilic spacing is desired.

Target Specificity

Item-specific target data are not provided for this product.

From literature (general note, not item-specific):

• Thalidomide derivatives are widely used as cereblon (CRBN) ligands in E3 ubiquitin ligase recruitment. However, exact affinity, kinetics, and ternary complex behavior depend on the overall conjugate (warhead, linker length/orientation) and are not specified for this item.

For any target-binding specifications, assay validations, or application testing of this SKU, please refer to the product’s CoA/Spec Sheet or contact Technical Support.