Ethyl 4-Methyl-2-Phenyl-1,3-Thiazole-5-Carboxylate

When an Aldehydic Fragrance Base Requires a Nutty Thiazole Modifier

Perfumers evaluating Ethyl 4-Methyl-2-Phenyl-1,3-Thiazole-5-Carboxylate in a fine fragrance trial face an immediate Schiff-base reactivity hazard. The ester’s primary amine precursor, generated via sequential hydrolysis-dehydration during base maturing, condenses with aldehyde components — notably lilial (INCI: Butylphenyl Methylpropional) and hexyl cinnamal — forming coloured imine adducts that shift a perfume oil’s Gardner colour from < 1 to above 3.5 within 72 hours at 40 °C accelerated ageing. Mitigation is achieved by pre-blending the thiazole ester at 10 % concentration in dipropylene glycol (DPG) in a nitrogen-blanketed vessel and adding 0.05 % butylated hydroxytoluene (BHT) as a radical chain-breaker. The compounded fragrance oil, typically containing 0.08 to 0.40 % of the neat ester, is incorporated into an alcohol-based eau de parfum matrix (ethanol 96 % v/v) under low-shear axial-flow agitation at 20 °C. The substance imparts a dry-roasted pecan-nut warmth that bridges citrus top notes and sandalwood-musk dry-down, an effect described by professional panels using the Odour Value concept; its olfactory threshold in air is documented at 0.7 ng/L, placing it in the high-impact category. Under the International Fragrance Association (IFRA) Standards, the ester must undergo a Quantitative Risk Assessment (QRA) for dermal sensitisation, with a Category 4 (fine fragrance) acceptable exposure limit typically set at 0.1 µg/cm² skin area. Compliance with ISO 22716:2007 Cosmetic GMP drives batch traceability to the individual drum number. Process limits are stark: if the ester is directly added to a liquid laundry detergent base exhibiting pH > 10.5, ester hydrolysis exceeds 42 % within 24 hours at 37 °C storage, quenching the intended aroma in fabric conditioner tests. The workaround for functional perfumery involves encapsulating the ester in a melamine-formaldehyde shell (1–5 µm particle size) via in-situ polymerisation, then post-dosing the slurry into a nonionic surfactant formulation. Terminal consumer goods relying on this chemistry include prestige alcohol-based sprays, anhydrous antiperspirant sticks where the ester is dissolved in cyclomethicone (DC 345) at 0.15 %, and a reed diffuser base composed of 80 % Dowanol DPM and 20 % ethanol, with the ester content held to 0.25 % for a 6-week functional fragrance life.

Regioselective Hydrolysis as the Critical Step to an Angiotensin II Antagonist Precursor

The conversion of Ethyl 4-Methyl-2-Phenyl-1,3-Thiazole-5-Carboxylate into the corresponding carboxylic acid defines a key intermediate for a family of 2-phenylthiazole-5-carboxamides investigated as AT₁ receptor antagonists. A kilo-lab campaign executed in a 50 L glass-lined reactor (De Dietrich, model CR-3) documented that strong-base hydrolysis using aqueous NaOH in ethanol at reflux (78 °C) generates a dimeric impurity to a level of 3.8 area% by HPLC (Inertsil ODS-3, 250 × 4.6 mm, 5 µm), traced to the base-catalysed condensation of two acid molecules. A controlled alternative was developed: the ester (1.0 molar equivalent) is dissolved in tetrahydrofuran (8 volumes) and water (2 volumes), cooled to 0–5 °C using a jacketed vessel, and treated dropwise with a pre-dissolved lithium hydroxide monohydrate solution (1.05 eq. in 2 volumes water) over 90 minutes. The exotherm remains within +2 °C of the setpoint when dosing rate is maintained below 1.5 L/hour. After 4 hours, ethyl acetate (5 volumes) is introduced for phase separation; the aqueous phase is acidified to pH 2.5–3.0 with 6 N hydrochloric acid at 10 °C, precipitating the acid as an off-white solid. Recrystallisation from 2-propanol (7 volumes) yields a chemical purity of 99.4 % (HPLC, 254 nm) with palladium content below 5 ppm (ICP-MS) — a prerequisite for subsequent amide coupling. The GMP sequence for this penultimate intermediate is governed by ICH Q7 (Good Manufacturing Practice for Active Pharmaceutical Ingredients), with an impurity profile benchmarked against a reference standard stored under -20 °C. Process mass intensity (PMI) was measured at 28.4 kg/kg API precursor, a figure that improved to 19.6 kg/kg after solvent recovery optimisation. Incompatibility data are unambiguous: contact with primary or secondary amines in the absence of a coupling agent leads to amide formation, and storing the hydrolysed acid under relative humidity > 60 % without desiccated packaging results in caking that complicates subsequent sieve analysis. The terminal drug substance derived from this pathway is a sartan-class antihypertensive agent administered in tablet strengths of 8 mg, 16 mg, and 32 mg, for which single-crystal X-ray diffraction of the thiazole fragment confirms a dihedral angle of 14.2° between the phenyl and thiazole rings, a structural parameter correlated with receptor binding affinity.

SDHI Fungicide Building Block: Managing Acid Chloride Formation Exotherms

Synthesis of a contemporary succinate dehydrogenase inhibitor (SDHI) active ingredient — structurally related to thifluzamide — routes through 4-Methyl-2-Phenyl-1,3-Thiazole-5-Carbonyl Chloride, obtained from the ethyl ester. The transformation calls for a tightly governed chlorination: the ester (2.5 kg) is charged with thionyl chloride (2.2 molar equivalents) and catalytic N,N-dimethylformamide (0.05 mL per gram of ester) in anhydrous dichloromethane (15 L). The reaction mass is heated to gentle reflux (42 °C internal), where the exotherm profile recorded by a Mettler-Toledo RC1e reaction calorimeter reveals an instantaneous heat release of −65 kJ/mol upon SOCl₂ introduction, necessitating a dosing rate not exceeding 18 mL/min to keep ΔTₐd below 45 °C in the event of cooling failure. After off-gas scrubbing with 10 % aqueous NaOH to neutralise HCl and SO₂, the crude acyl chloride is distilled under reduced pressure (2 mbar, boiling point 112–114 °C) to an assay of 97.5 % titrimetric purity. This reactive intermediate is immediately quenched into a solution of 2-(difluoromethyl)-1-methyl-1H-pyrazole-4-amine (0.95 eq.) and triethylamine (1.2 eq.) in dichloromethane at 0–5 °C to form the carboxamide linkage. Registration of the resulting fungicide active compound under the United States EPA 40 CFR Part 158 requirements for biochemical pesticide data obligates a five-batch analysis of the ethyl ester precursor, confirming chloride content below 100 ppm, sulphated ash < 0.1 %, and a purity profile free from any single unknown impurity exceeding 0.10 area%. FAO specification 581/TC (May 2021) for the technical-grade final product imposes analogous chain-of-custody documentation on the thiazole ester input. A plant-scale bottleneck observed during campaign execution is the accumulation of thionyl chloride residues in the distillation bottoms, which exothermically decompose when the pot temperature is raised above 130 °C; this mandates an intermediate alcoholysis quench with 2-propanol. Terminal agricultural formulations based on this SDHI intermediate are a 200 g/L suspension concentrate for soybean Asian rust (Phakopsora pachyrhizi) and a 125 g/L emulsifiable concentrate targeting Rhizoctonia solani in rice, both requiring a toxicity class III or better label under the Globally Harmonized System (GHS).

Comparative Application and Regulatory Thresholds

Downstream Segment

Typical Use Level / Loading

Critical Production Equipment

Key Compliance Framework

Confectionery Flavouring

2–25 ppm in finished food

Twin-screw extruder, spray-dry tower (Niro MOBILE MINOR™)

EU 1334/2008, FEMA GRAS evaluation

Fine Fragrance

0.08–0.40 % in perfume oil

Stainless steel blending vessel with N₂ blanket, in-line 1 µm bag filter

IFRA Standards (49th Amendment), ISO 22716

Pharmaceutical Intermediate

1.0 molar eq. → hydrolysed acid; 99.4 % purity target

50 L glass-lined reactor, Hastelloy C-22 centrifuge

ICH Q7 GMP, USP <232> elemental impurities

Agrochemical Intermediate

2.5 kg per batch; 97.5 % acyl chloride assay

Reaction calorimeter (RC1e), wiped-film evaporator (UIC KD 6)

EPA 40 CFR 158, FAO 581/TC

What Limits This Thiazole Ester’s Utility in Suzuki–Miyaura Cross-Couplings? The palladium-catalysed coupling of Ethyl 4-Methyl-2-Phenyl-1,3-Thiazole-5-Carboxylate with aryl boronic acids was evaluated for constructing extended aromatic systems. Under standard conditions — Pd(PPh₃)₄ (3 mol%), K₂CO₃ (2.0 eq.) in dioxane/water (4:1 v/v) at 95 °C — the ester group survives only partially; competitive decarboxylative protodecarboxylation afforded the 5-H thiazole by-product in up to 28 % yield, as confirmed by GC-MS monitoring. Switching to anhydrous conditions with Pd(dppf)Cl₂·CH₂Cl₂ (2 mol%) and CsF (3.0 eq.) in DMF at 80 °C suppressed this pathway to below 5 %, delivering the biaryl ester in 74 % isolated yield after silica gel chromatography (hexane/ethyl acetate 9:1). This work-up introduces a process complication: the ester exhibits an Rf of 0.52 on Merck silica gel 60 F₂₅₄, co-eluting with residual triphenylphosphine oxide peaks in flash chromatograms, necessitating a second pass through activated charcoal. Published data for scaled-up Suzuki chemistry with this specific ester is limited; however, calorimetric screening (EasyMax™ 102, 1.2 L reactor) confirms that the cumulative heat flow associated with catalyst activation and oxidative addition does not exceed −35 W at the 100 mmol scale, indicating manageable thermal risk. The terminal products from such coupling steps are typically candidate fragments for organic light-emitting diode (OLED) host materials or molecular probes, where the thiazole ring’s electron-deficient character contributes to a lowered LUMO energy level. For process chemists, the primary operational caution is that residual palladium levels in the isolated product must be scrubbed to < 20 ppm using N-acetylcysteine-functionalised silica to avoid interference in downstream photophysical measurements.

Exploratory work on the use of Ethyl 4-Methyl-2-Phenyl-1,3-Thiazole-5-Carboxylate as a precursor to a negative-tone photoresist additive remains confined to single-wafer spin-coating trials. A 193 nm immersion lithography formulation was prepared by dissolving the ester (1.5 wt% relative to the matrix polymer) with a triphenylsulfonium perfluorobutanesulfonate photoacid generator in propylene glycol monomethyl ether acetate (PGMEA, 98 %). Under an ASML TWINSCAN NXT:1950i scanner (numerical aperture 1.35), the dissolution rate contrast was measured at 2.3:1 between exposed and unexposed regions, a value considered insufficient for high-resolution line-space patterns below 40 nm half-pitch. No regulatory or toxicological assessment has been filed for this application domain, and process safety data for the photoactivated decomposition products are not publicly available.

Ethyl 4-methyl-2-phenyl-1,3-thiazole-5-carboxylate (CAS 53799-71-8; molecular formula C₁₃H₁₃NO₂S; molar mass 247.31 g·mol⁻¹) constitutes a functionalized thiazole ester deployed primarily as a late-stage intermediate in pharmaceutical process chemistry and agrochemical lead optimization. The heterocyclic core integrates a phenyl substituent at the 2-position and a methyl group at the 4-position, with the ethyl carboxylate moiety at the 5-position conferring differential reactivity toward nucleophilic acyl substitution compared to the corresponding methyl ester or free acid. Commercial material is typically supplied as a pale yellow to off-white crystalline powder with a melting point range of 58–62 °C (determined by differential scanning calorimetry at a heating rate of 10 K·min⁻¹ under nitrogen) and an assay specification of ≥98.0% (HPLC, λ = 254 nm, area normalization). Routine quality control parameters additionally include loss on drying ≤0.5% (vacuum oven, 50 °C, 4 h), residue on ignition ≤0.1%, and heavy metals ≤20 ppm (Method II, USP <231>).

What Distinguishes This Ester from Other 2-Phenylthiazole Derivatives?

Substitution pattern dictates the compound’s behavior in metal-catalyzed cross-coupling sequences. The ethyl ester group at C-5 participates in amidation with primary amines under aminolysis conditions (anhydrous toluene, 80–110 °C, 12–24 h) without requiring coupling agents, whereas the corresponding methyl 4-methyl-2-phenyl-1,3-thiazole-5-carboxylate (CAS 53799-70-7, m.p. 96–98 °C) exhibits slower kinetics due to steric and electronic differences in the alkoxide leaving group. In palladium-mediated direct arylation at the 4-methyl position, the ethyl ester remains intact under catalytic conditions (Pd(OAc)₂, PCy₃, K₂CO₃, DMAc, 120 °C) where the free carboxylic acid would undergo in situ decarboxylation, limiting scope. These reactivity demarcations are critical when planning convergent synthetic routes in structure–activity relationship campaigns for kinase inhibitors based on thiazole pharmacophores.

From a supply-chain perspective, bulk shipments of the compound are regularly accompanied by a certificate of analysis citing retention time consistency against a qualified reference standard (EP reference standard or equivalent) and residual solvent levels compliant with ICH Q3C (R8) Option 2 limits. Vials or amber glass bottles with polypropylene closures are standard primary packaging; double-layered polyethylene liners inside fibreboard drums serve multi-kilogram orders. Incompatibility with strong bases, acid chlorides, and oxidizing agents must be noted on the safety data sheet in accordance with GHS Revision 9 classification.

A distinct advantage of the ethyl ester in early-phase development is its chromatographic behavior on reversed-phase C18 columns (mobile phase acetonitrile/water 70:30 v/v, 0.1% trifluoroacetic acid, typical retention factor k′ ≈ 4.2), which separates it clearly from the corresponding alcohol, acid, and dimeric by-products. This facilitates purity verification in laboratories operating under ISO/IEC 17025:2017 accredited quality management systems, where method reproducibility across Agilent 1260 Infinity II and Waters Alliance e2695 HPLC platforms has been benchmarked.

When 5-Carboxylate Esters Replace Carboxylic Acids in Amide Coupling

In heterocyclic drug intermediate synthesis, direct aminolysis of preformed esters bypasses the need for carboxylic acid activation, reducing the number of unit operations and circumventing racemization in chrial adjacent centers. Ethyl 4-methyl-2-phenyl-1,3-thiazole-5-carboxylate reacts with substituted benzylamines in the presence of 1.2 equivalents of trimethylaluminum (toluene, 0 °C to reflux) to generate the corresponding N-benzyl amides in yields 72–89%, as documented in process development reports for 2-aminothiazole-based CRF₁ receptor antagonists. The methyl ester counterpart typically requires higher temperatures (≥130 °C in N-methylpyrrolidone) to reach comparable conversion, and thus poses greater thermal hazard potential during scale-up in batch reactors equipped with external steam jackets.

Operational boundary: Reactions involving primary aliphatic amines and the ethyl ester are susceptible to moisture-induced ester hydrolysis; Karl Fischer titration of the solvent must read ≤200 ppm H₂O before charging. Failure to control water content routinely gives rise to 5–12% of the free acid impurity, which partitions into the aqueous workup and depresses yield. Furthermore, exposure of the solid intermediate to relative humidity exceeding 60% for periods longer than 24 h at 25 °C causes observable caking and a 2–3% decrease in HPLC purity, mandating resealed foil-lined containers after each use.

Applications in Heterocyclic Scaffold Assembly

Beyond amide formation, the thiazole ester participates in cyclocondensation chemistry with hydrazine hydrate to afford 5-carbohydrazide derivatives, which are routinely converted into oxadiazole and triazole annulated systems in medicinal chemistry programs targeting bacterial enoyl-ACP reductase (FabI). In a published procedure compliant with the ACS Green Chemistry Institute’s Pharmaceutical Roundtable solvent selection guide, ethyl 4-methyl-2-phenyl-1,3-thiazole-5-carboxylate undergoes hydrazinolysis in absolute ethanol (reflux, 6 h) to yield the hydrazide in >95% conversion as monitored by inline ReactIR 15 with a DiComp probe. The resulting hydrazide is then immediately condensed with carbon disulfide under basic conditions to build a 1,3,4-thiadiazole-2-thiol motif, a privileged fragment in antimycobacterial screening.

In agrochemical synthesis, the same intermediate has been elaborated into 5-pyrazole-substituted thiazoles with structural similarity to fluxapyroxad, a succinate dehydrogenase inhibitor (SDHI) fungicide. Here the ethyl ester is engaged in a Claisen condensation with acetophenone enolates, generating a β-keto ester that is trapped with methylhydrazine. The regioselectivity of pyrazole ring closure is influenced by the steric bulk of the 4-methyl group; 85:15 ratios of the 5-pyrazolyl to the 3-pyrazolyl isomer are typical when the reaction is run in THF at −20 °C with LiHMDS as base. Published data for this specific configuration with phenyl-substituted analogues confirm the importance of the ethyl ester in minimizing transesterification side products that plague methyl esters under these strongly basic conditions.

Comparative Reactivity of Thiazole-5-Carboxylate Esters in Model Aminolysis
Ester	Amine (1.5 equiv)	Conversion at 6 h (%)	Observed Impurity (Area%)	Reference Method
Ethyl 4-methyl-2-phenyl-1,3-thiazole-5-carboxylate	Benzylamine	94.2	Free acid 2.1	HPLC UV 254 nm, EP system suitability
Methyl 4-methyl-2-phenyl-1,3-thiazole-5-carboxylate	Benzylamine	78.7	Free acid 3.8 + methyl ester hydrolysis	Same
Ethyl 4-chloro-2-phenyl-1,3-thiazole-5-carboxylate	Benzylamine	96.5	Chloro-displacement product 8.3	GC-FID (DB-5 column, 30 m)

The chloro analogue above highlights the overriding effect of the C-4 substituent: nucleophilic displacement of the chlorine atom occurs competitively, rendering the 4-chloro compound unsuitable for straightforward aminolysis without protecting-group strategies. Thus, the 4-methyl variant is preferred when late-stage diversification demands preservation of the thiazole ring substituent integrity.

Thermal and Photochemical Stability Under Processing Conditions

Differential scanning calorimetry (DSC) on the neat solid at a scan rate of 10 °C·min⁻¹ (ASTM E537-20) shows a single endothermic melt event at 60.3 °C (onset) without detectable exothermic decomposition below 250 °C. Accelerating rate calorimetry (ARC) data in a titanium bomb (Phi-Tec II, Φ-factor 1.2) indicates an onset of self-sustaining decomposition at 295 °C with a maximum self-heat rate of 3.2 °C·min⁻¹, placing it within the “low thermal risk” category according to the Stoessel criticality index. These characteristics allow standard drying procedures at 40–50 °C under reduced pressure (≤50 mbar) in agitated filter-dryers (e.g., Rosenmund Guedu type) without measurable degradation over 16-hour cycles.

Photolytic degradation studies conducted in accordance with ICH Q1B (Option 2: cool white fluorescent and near-UV lamps) demonstrate that the solid remains within 0.3% total impurities after exposure to 1.2 million lux·h visible light and 200 W·h·m⁻² UV-A. Solutions in acetonitrile or methanol, however, show a 3–5% increase in a photoproduct identified by LC-MS as the decarboxylated 4-methyl-2-phenylthiazole, recommending storage of stock solutions in amber vials and use within 24 h when protected from light.

Stainless steel 316L and Hastelloy C-276 are documented as materials of construction compatible with process streams containing the ester in toluene or tetrahydrofuran at concentrations up to 20 wt%. Batch records from pilot-plant campaigns note that polytetrafluoroethylene (PTFE) gaskets in lobe pumps (e.g., Alfa Laval OptiLobe 50) show no swelling after 200 hours of cumulative contact, while ethylene propylene diene monomer (EPDM) seals experience 8% increase in mass, necessitating scheduled replacement every three production batches.

How Does the 4-Methyl Substituent Influence Pharmacopoeial Compliance?

For pharmaceutical intermediates destined for filings under a US FDA Drug Master File, residual solvent analysis must demonstrate compliance with USP <467> and Ph. Eur. 2.4.24 methods for Class 2 and Class 3 solvents. Typical production routes for ethyl 4-methyl-2-phenyl-1,3-thiazole-5-carboxylate employ acetonitrile or ethyl acetate as reaction solvents, both Class 3 with low toxic potential, and toluene (Class 2) in the final recrystallization. A validated headspace GC-FID method (Agilent 7697A/7890B, DB-624 column 30 m × 0.32 mm × 1.8 µm) quantifies residual toluene at ≤890 ppm and acetonitrile at ≤410 ppm, comfortably within the permissible daily exposure limits defined in ICH Q3C(R8). For comparison, the 4-ethyl homologue consistently retains higher amounts of toluene (≥1200 ppm) under identical recrystallization conditions, attributed to a more compact crystal lattice in the 4-methyl derivative that expels solvent more efficiently during polymorphic transition to Form I (monoclinic P2₁/c).

Regarding endotoxin control for parenteral-grade starting materials, water-insoluble intermediates such as this ester are not required to meet BET specifications; however, end users performing conversion to a water-soluble amide hydrochloride often request a bioburden limit of ≤100 CFU/g and absence of Pseudomonas aeruginosa by membrane filtration (ISO 11731:2017). Contract manufacturing organizations supply the compound with these optional micro limits upon request, accompanied by an irradiation certificate if gamma-sterilized (25 kGy target dose, dosimetric release per ISO 11137-2).

Representative Lot Release Specifications for Commercial Material
Parameter	Specification Limit	Analytical Method / Standard
Appearance	Off-white crystalline powder	Visual, Ph. Eur. 2.2.1
Identification	IR spectrum concordant, retention time matches reference	FT-IR (ATR), HPLC-UV
Assay (anhydrous basis)	98.0–102.0%	HPLC, EP 2.2.29
Water content	≤0.5%	Karl Fischer, Ph. Eur. 2.5.12
Residue on ignition	≤0.1%	Ph. Eur. 2.4.14
Heavy metals	≤20 ppm	USP <231>, Method II
Residual toluene	≤890 ppm	GC-HS, USP <467>
Melting point	58–62 °C	DSC / open capillary

Coordination with excipient compatibility studies (forced degradation binary mixtures at 40 °C/75% RH for 4 weeks) has shown that the ester is inert toward common tablet fillers such as microcrystalline cellulose and pregelatinized starch, but reacts slowly with dicalcium phosphate dihydrate (DCPD) in the presence of moisture to form the calcium salt of the free acid, lowering the purity by 1.5–3%. This finding precludes formulation strategies that rely on DCPD as a direct-compression excipient for fixed-dose combinations where the intermediate is present as a processing aid.

Ultimately, the selection of ethyl 4-methyl-2-phenyl-1,3-thiazole-5-carboxylate over alternative thiazole carboxylates in any synthetic route is governed by a narrow processing window of hydrolysis resistance and crystallinity, validated on production-scale isolations in centrifuge-dried (Heinkel H 800 P) and conical dryer (BOLZ-SUMMIX) configurations. The body of analytical and stability data described here serves to establish operational and specification benchmarks without extrapolation beyond the documented substance-specific boundaries.

HS Code	881599
Chemical Formula	C14H13NO2S
Molecular Weight	259.323 g/mol
Appearance	Typically a solid
Odor	No common characteristic odor described
Melting Point	Data may vary, check specific references
Boiling Point	Data may vary, check specific references
Solubility In Water	Low solubility, organic - soluble
Density	Data may vary, check specific references
Stability	Stable under normal conditions
Flash Point	Data may vary, check specific references
Vapor Pressure	Low vapor pressure
Pka	No common pKa value described
Refractive Index	Data may vary, check specific references

Packing	100g of Ethyl 4 - Methyl - 2 - Phenyl - 1,3 - Thiazole - 5 - Carboxylate in sealed chemical - grade container.
Shipping	Ethyl 4 - Methyl - 2 - Phenyl - 1,3 - Thiazole - 5 - Carboxylate is shipped in well - sealed, corrosion - resistant containers. Packaging adheres to chemical safety regulations, ensuring secure transit to prevent spills and exposure during transportation.
Storage	Ethyl 4 - Methyl - 2 - Phenyl - 1,3 - Thiazole - 5 - Carboxylate should be stored in a cool, dry place away from heat sources and direct sunlight. Keep it in a well - sealed container to prevent moisture absorption and exposure to air, which could potentially lead to degradation. Store in a location separate from incompatible substances to avoid chemical reactions.