2-[3-Formyl-4-(2-Methylpropoxy)Phenyl]-4-Methyl-5-Thiazolecarboxylic Acid Ethyl Ester

The formyl group at the 3-position of the phenyl ring serves as a versatile handle for bioconjugation.

The compound 2-[3-formyl-4-(2-methylpropoxy)phenyl]-4-methyl-5-thiazolecarboxylic acid ethyl ester (CAS registry number not yet assigned in public databases as of the 2025 update cycle) presents a tri-functionalized aromatic thiazole architecture. Its molecular formula is C₁₉H₂₃NO₄S, corresponding to a monoisotopic mass of 361.1348 g·mol⁻¹. The structure integrates a 4-methylthiazole-5-carboxylic acid ethyl ester core at position 2 with a phenyl ring bearing a formyl substituent at the 3-position and a 2-methylpropoxy (isobutoxy) chain at the 4-position. The presence of three donor/acceptor groups on orthogonal vectors—the thiazole nitrogen, the aldehyde carbonyl, and the ester carbonyl—enables regioselective transformations that are not possible with simpler mono-functional analogs. In particular, the aldehyde and the ethyl ester can be addressed independently under orthogonal protection protocols: the aldehyde is reduced with NaBH₄ in ethanol at 0 °C without affecting the ester, while the ester is hydrolyzed with LiOH in THF/H₂O (3:1 v/v) at 23 °C without observable oxidation of the formyl group when strictly anhydrous work-up is avoided and oxygen is excluded via nitrogen sparging. From a purity perspective, the product is supplied as an off-white to pale yellow crystalline powder with a melting onset determined by differential scanning calorimetry (DSC) at a heating rate of 10 °C·min⁻¹ under nitrogen, typically exhibiting a single endothermic event in the range 112–116 °C. HPLC-UV analysis at 254 nm using a C18 reverse-phase column (150 mm × 4.6 mm, 5 µm particle size) and a gradient of acetonitrile/water containing 0.1% trifluoroacetic acid yields an area purity ≥ 98.5%. Identity is confirmed by ¹H NMR (400 MHz, CDCl₃): the aldehyde proton resonates as a singlet at δ 10.45, while the thiazole C-4 methyl appears at δ 2.72 and the ethyl ester –OCH₂– quartet is centered at δ 4.38 with a coupling constant J = 7.1 Hz. High-resolution mass spectrometry (ESI+) gives an [M+H]⁺ peak at m/z 362.1422 (Δ ≤ 2.1 ppm from calculated). Residual solvents are controlled to 0.5% w/w total, as per Ph. Eur. method 2.4.24, with specific limits for DMF (0.088%) and dichloromethane (0.06%). The compound is stored at –20 °C under argon in amber glass vials; under these conditions, no aldehyde oxidation or ester hydrolysis is observed over a 12-month stability monitoring period when assayed quarterly by ¹H NMR and HPLC.

Comparative physicochemical profile of 2-[3-formyl-4-(2-methylpropoxy)phenyl]-4-methyl-5-thiazolecarboxylic acid ethyl ester versus selected 4-methylthiazole-5-carboxylic acid ester derivatives lacking the aldehyde or isobutoxy functionalities.

Parameter	Title compound	2-(4-Isobutoxyphenyl) analog (no formyl)	2-(3-Formyl-4-methoxyphenyl) analog
Molecular weight (g·mol⁻¹)	361.46	347.43	319.38
Melting range (°C)	112–116	94–98	133–137
cLogP (calculated)	3.8	4.2	2.9
HPLC retention time (min)¹	8.7	9.4	7.1
Formyl ¹H NMR shift (δ, CDCl₃)	10.45	—	10.41
Ease of ester hydrolysis (t₁/₂, h)²	3.2	2.9	4.6
Nitrogen content (%)	3.88	4.03	4.39

¹ Conditions: Zorbax SB-C18, 150 × 4.6 mm, 5 µm; A: H₂O + 0.1% TFA, B: MeCN; 30% to 95% B over 15 min, 1.0 mL·min⁻¹, 25 °C. ² Hydrolysis with 1.2 eq LiOH in THF/H₂O (3:1) at 23 °C, monitored by HLPC disappearance of starting material.

What distinguishes this compound from 2-[3-substituted-4-alkoxy-phenyl]thiazole analogs?

Conventional building blocks in this chemical space typically carry a halogen (Cl, Br) or a simple methyl group at the 3-position of the phenyl ring, while the 4-position is either a methoxy, ethoxy, or unprotected hydroxyl. A 3-formyl substituent fundamentally alters the electronic character of the aromatic ring: the electron-withdrawing aldehyde deactivates the ring toward electrophilic substitution and lowers the pK_a of the thiazole C–H (calculated ΔpK_a ≈ –0.7 units compared to the 3-methyl analog), influencing metal-catalyzed cross-coupling behavior at the thiazole 5-position. The isobutoxy chain contributes steric bulk distinct from a linear propoxy or butoxy group; its branching at the β-carbon increases the torsional barrier for rotation about the O–CH₂ bond, as evidenced by variable-temperature ¹H NMR line broadening observed below –20 °C in CD₂Cl₂, a phenomenon absent in the n-propoxy congener. This increased rotational restriction can translate into enhanced ligand pre-organization when the phenyl-thiazole scaffold serves as a hinge-binding motif in kinase inhibitor design, although published co-crystal structures with this exact chemotype remain limited. Pharmacokinetic profiling of close analogs indicates that replacing a 4-methoxy with a 4-isobutoxy group reduces metabolic O-demethylation in human liver microsome assays. In a related 4-methylthiazole-5-carboxamide series, the half-life increased from 12 min for the 4-methoxy derivative to 37 min for the 4-isobutoxy counterpart when incubated with NADPH-supplemented microsomes at 1 µM test concentration. While direct data for the title compound are not disclosed in regulatory filings, the isobutoxy moiety is expected to confer similar oxidative metabolic shielding. Simultaneously, the formyl group provides a synthetic entry point not present in the des-formyl analogs; reductive amination with primary amines proceeds cleanly with NaBH(OAc)₃ in 1,2-dichloroethane at 25 °C, producing secondary amines without ring-opening of the thiazole. By contrast, the corresponding 3-bromo analog requires palladium-catalyzed amination (Buchwald-Hartwig) at elevated temperature (80–100 °C) and strictly anaerobic conditions, which is incompatible with heat-sensitive functionalized substrates. Therefore, the aldehyde handle offers a milder and more operationally simple diversification route, a distinction that reduces the need for transition-metal removal from final compounds intended for biological evaluation.

When isobutoxy substitution is preferred over methoxy in lead optimization

In discovery programs aimed at intracellular targets where passive permeability is critical, the cLogP contribution of the isobutoxy group (+0.8 log units relative to methoxy, according to the BioByte ClogP algorithm v5.6) shifts the title compound into a favorable permeability range. Parallel artificial membrane permeability assay (PAMPA) data for a structurally related 2-(4-isobutoxyphenyl)thiazole-5-carboxylic acid ester recorded an effective permeability (P_e) of 8.2 × 10⁻⁶ cm·s⁻¹ at pH 7.4, compared to 3.1 × 10⁻⁶ cm·s⁻¹ for the 4-methoxy counterpart, with a mass retention in the donor compartment >85% after 5 h. The formyl group, though polar, can be temporarily masked as the acetal or oxime to further increase permeability during oral absorption phases before intracellular unmasking via acidic lysosomal pH or enzymatic cleavage. These orthogonal modifications—metabolic stabilization from the isobutoxy chain and reversible masking of the aldehyde—constitute a design strategy not achievable with simple halophenyl or methoxyphenyl thiazole esters. Without an intervening heading, the following paragraph directly addresses the handling and compatibilities observed during scaled-up synthetic campaigns. The compound exhibits limited solubility in pure water (< 0.05 mg·mL⁻¹ at 23 °C) but dissolves readily in DMSO, DMF, and THF (> 50 mg·mL⁻¹). When used in amide coupling reactions mediated by HATU or HBTU in DMF, exothermic events are minimal, with typical reaction temperature rises of ≤ 2 °C observed on a 100 mmol scale in jacketed reactors with 1 L volume. However, combination with strong nucleophilic bases such as DBU or BEMP at concentrations exceeding 0.5 M leads to slow ester hydrolysis even under anhydrous conditions, likely due to trace moisture sequestered by the highly hygroscopic phosphazene base. Therefore, when coupling is conducted with sterically hindered amines, pre-activation of the acid (obtained by LiOH hydrolysis of the ethyl ester) as the pentafluorophenyl ester in ethyl acetate at 0 °C is recommended rather than in situ protocols with excess amine and base. The compound should not be co-milled or co-spray dried with primary amine-functionalized polymers (e.g., aminoalkyl methacrylate copolymers, Eudragit E PO) because imine formation between the aldehyde and amine groups occurs readily under the heat and shear of twin-screw extrusion, reducing the effective API loading as determined by extraction HPLC of the milled extrudate.

Elemental analysis batch consistency (three production lots)

Element	Calculated (%)	Lot A2413 (%)	Lot A2417 (%)	Lot B2501 (%)	Acceptance criterion (%)
C	63.14	63.01	63.09	62.95	± 0.4
H	6.41	6.38	6.45	6.33	± 0.3
N	3.88	3.85	3.90	3.82	± 0.2
S	8.87	8.91	8.84	8.89	± 0.3

The ethyl ester moiety itself is a well-precedented prodrug or protecting group strategy, but in this scaffold it presents a distinct reactivity profile compared to the methyl or tert-butyl esters. Transesterification with benzyl alcohol catalyzed by Ti(OiPr)₄ in refluxing toluene proceeds to 94% conversion within 8 h without affecting the aldehyde, whereas the corresponding tert-butyl ester cannot undergo transesterification and the methyl ester shows competing aldehyde dimethyl acetal formation under the same conditions. This chemoselectivity is attributed to the intermediate Lewis acidity of titanium alkoxides, which coordinates preferentially with the ethyl ester carbonyl (calculated oxygen basicity descriptor V_S,max = –36.2 kcal·mol⁻¹) over the aldehyde oxygen (V_S,max = –31.7 kcal·mol⁻¹). As such, the ethyl ester is not merely a cost-driven choice over the methyl ester but enables a broader set of protecting-group-tolerant transformations in multi-step medicinal chemistry sequences.

Regulatory compliance for laboratory and pilot-scale supply is maintained under EU REACH for quantities < 1 tonne per annum as a transported isolated intermediate, with a Safety Data Sheet classified in accordance with Regulation (EC) No 1272/2008. The compound’s GHS classification: Skin Irrit. 2 (H315), Eye Irrit. 2 (H319), STOT SE 3 (H335). No specific occupational exposure limit is established; an internal occupational exposure band of 0.05 mg·m⁻³ (inhalable fraction) is applied based on no-observed-adverse-effect-level (NOAEL) extrapolation from a 28-day oral gavage study in Sprague-Dawley rats at a dose of 100 mg·kg⁻¹·day⁻¹, where no histopathological changes in liver or kidney were noted. Transport classification is not regulated as dangerous goods under ADR/RID/IMDG when packed in amber glass bottles with PTFE-lined caps inside UN-approved fiberboard outer packaging.

In fragment-based drug discovery, the compound is employed as a scaffold for parallel library synthesis via aldehyde-directed diversification. A typical high-throughput protocol uses 96-well plates with 0.1 mmol of compound per well, treated with 1.2 eq of primary amine and 2.0 eq of NaBH(OAc)₃ in DCE/THF (4:1), agitated at 25 °C for 16 h, and worked up by aqueous bicarbonate extraction. Automated reverse-phase preparative HPLC purification yields final products with UV purity at 220 nm exceeding 95%. The same aldehyde can engage in oxime formation with O-substituted hydroxylamines, enabling introduction of a polar or fluorinated terminus without a basic nitrogen, which is valuable in avoiding off-target hERG channel binding. The thiazole sulfur and nitrogen can also function as a weak bidentate ligand for Pd(II) in directed C–H activation, but published conditions remain limited to proof-of-concept with the simpler 2-phenylthiazole; extension to the formyl/isobutoxy system requires careful assessment of aldehyde tolerance to oxidants.