4-Methyl-5-Acetoxyethyl Thiazole
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HS Code |
591360 |
| Chemical Formula | C8H11NO2S |
| Molecular Weight | 185.24 |
| Appearance | Colorless to pale yellow liquid |
| Odor | Characteristic, pleasant, nutty and roasted odor |
| Boiling Point | Around 208 - 210 °C |
| Flash Point | Relatively low, flammable liquid |
| Solubility In Water | Slightly soluble in water |
| Solubility In Organic Solvents | Soluble in many organic solvents like ethanol, ether |
| Density | Approximately 1.12 - 1.14 g/cm³ |
| Stability | Stable under normal conditions, but may react with strong oxidizing agents |
As an accredited 4-Methyl-5-Acetoxyethyl Thiazole factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100 - gram bottles for 4 - Methyl - 5 - Acetoxyethyl Thiazole, tightly sealed. |
| Shipping | 4 - Methyl - 5 - acetoxyethyl thiazole is shipped in well - sealed, corrosion - resistant containers. Special care is taken to prevent leakage during transit, adhering to strict chemical shipping regulations to ensure safety. |
| Storage | 4 - Methyl - 5 - acetoxyethyl thiazole should be stored in a cool, dry, well - ventilated area. Keep it away from sources of heat, ignition, and direct sunlight. Store in a tightly sealed container to prevent leakage and exposure to air, which could potentially lead to decomposition or changes in its chemical properties. Avoid storing near incompatible substances. |
Acetyl Protection Strategy in Vitamin B1 Thiazole Segment SynthesisThe acetoxyethyl thiazole serves as a critical protected intermediate in the convergent synthesis of thiamine hydrochloride (Vitamin B1), specifically where the hydroxyl group on the thiazole side chain requires masking to prevent unwanted O-acyl migration and oxidative degradation during the subsequent quaternization step with the pyrimidine moiety. In this route, commercially prepared 4-methyl-5-(2-hydroxyethyl)thiazole is acetylated using acetic anhydride in the presence of a catalytic quantity of methanesulfonic acid (0.5–1.2 mol% relative to thiazole alcohol) under nitrogen blanket at 55–65 °C for 3.5–4.5 hours, achieving a conversion rate exceeding 98.5% as monitored by gas chromatography on a DB-WAX column (30 m × 0.32 mm, 0.25 µm film) with flame ionization detection. The batch is then quenched with deionized water, neutralized with 10% aqueous sodium carbonate to pH 7.0–7.4, extracted with cyclohexane, and vacuum distilled at 2–4 mbar and jacket temperature not exceeding 130 °C to yield the ester with purity suitable for the next coupling stage. Industry practice documented in Chinese pharmacopoeial monographs and European Directorate for the Quality of Medicines (EDQM) submissions confirms that the acetoxy protecting group withstands the harsh alkylation conditions where the pyrimidine component bearing a bromomethyl or chloromethyl substituent is reacted with the thiazole ester in dimethylformamide at 80–95 °C for 6–10 hours in the presence of anhydrous sodium iodide. Following successful thiazolium salt formation, the acetyl group is cleaved by hydrolysis with 3N hydrochloric acid at reflux for 2 hours, liberating the target thiamine without generating mutagenic by-products. The entire sequence is governed by ICH Q7 Section 7.3 (Cleaning Validation) and Section 8.3 (In-process Sampling and Controls), as well as ISO 9001:2015 Clause 8.5.1 regarding control of production. Typical mole ratio of acetoxyethyl thiazole to pyrimidine precursor in multi-tonne campaigns ranges from 1.05:1 to 1.12:1, with strict limits on residual pyrimidine in the isolated thiamine hydrochloride set at ≤ 0.10 area% as per Ph. Eur. monograph 0415. Finished organic synthesis output is exclusively thiamine hydrochloride or thiamine mononitrate meeting USP, BP, and FCC grade specifications.At what addition level does the acetoxyethyl thiazole begin to suppress the metallic off-notes in retorted meat analogues?Within the savory flavor segment, 4-methyl-5-acetoxyethyl thiazole (FEMA 3201) is calibrated to attenuate the characteristic “canned” tin-plate metallic note and enhance roasted bone-marrow depth in retorted high-moisture extruded plant protein matrices. The ingredient is pre-diluted to 0.1% w/w in medium-chain triglyceride oil and dosed into the flavor emulsion consisting of hydrolyzed vegetable protein (EKO, 45% solids), caramel color type III, salt, and yeast extract. Addition rate mapped to finished product weight falls between 0.02 and 0.08 ppm for canned vegan stew pieces and 0.08–0.15 ppm for retorted pet food loaves; exceeding 0.18 ppm pushes the profile into an undesirable musty thiophene-like direction that cannot be masked by subsequent grill-type top notes. The emulsion is injected via a high-pressure (40–60 bar) multi-needle brine injector into structured vegetable protein slabs prior to sterilization in a Lagarde autoclave operating with an F0 value of 6.5–8.0 minutes. The ester demonstrates notable thermal stability under these conditions, with residual concentration measured by GC-MS headspace analysis remaining above 78% of initial spike level after a full 121 °C cycle, attributed to the shielding effect of the continuous lipid phase. The entire flavor system must comply with EU Regulation 1334/2008/EC Annex I, with the specific ester designated as FL No. 15.015, and carry an absence declaration for allergens under 1169/2011/EC. A companion compliance path is required for US export: the formulation must appear on the FEMA GRAS 28 list and must be manufactured under FDA 21 CFR 172.515 which permits the ester as a synthetic flavoring substance, with purity confirmed as ≥ 97.0% ester content and total sulfur content within ±0.5% of theoretical via oxidative microcoulometry. Finished products span retort pouches of chunky meat-style toppings, thermostabilized sausage crumbles for dry soup mixes, and high-pressure processed ready meals where the clean-label alternative to the ester is rarely achievable without burnt-hydrolyzed-protein notes.Bakery pre-mix manufacturers routinely incorporate the thiazole acetate as a cocoa-porter enhancer in dark compound coatings where conventional alkalized cocoa powder at 10–12 Dutched level fails to deliver adequate roasted chocolate depth after enrobing and cooling. The ester is dissolved in propylene glycol at 1.5% w/w and metered into the fat phase of the compound coating—typically non-lauric cocoa butter substitute based on fractionated palm kernel oil—during the conching step at 52–55 °C over 16–20 hours. Final concentration clusters tightly between 0.3 and 0.8 ppm relative to coating mass, as panel evaluation according to ISO 8586:2012 sensory assessor protocols reveals that 0.9 ppm introduces an artificial raisin-like overtone detectable by ≥ 60% of trained panelists. The process must avoid any direct contact between the undiluted ester and lecithin-based emulsifiers prior to fat dispersion, because the thiazole ring can coordinate with polyvalent metal traces present in crude lecithin, catalyzing ester hydrolysis and releasing the free alcohol, which has a markedly different sensory threshold (0.01 ppb in water versus 2.5 ppm for the acetate ester). The coated products—cocoa-dusted almonds, filled wafer bars, and dietary high-fiber biscuits—are manufactured under BRC Global Standard for Food Safety Issue 9, with the flavor house holding ISO 22000:2018 certification and providing an extended certificate of analysis that includes headspace impurities (acetaldehyde ≤ 50 ppm relative to ester) and residual solvents (cyclohexane ≤ 0.1 ppm). The ingredient is registered with the EU Reach implementing regulation covering food contact materials, and in the Japanese market conforms to the Japan Flavor & Fragrance Materials Association (JFFMA) listing under the number 1704.When the molecule functions as a delayed-release flavor precursor in textured meat piecesBeyond conventional low-dose approaches, the inherent lability of the ester bond in 4-methyl-5-acetoxyethyl thiazole can be deliberately exploited as a time-temperature release mechanism in semi-moist intermediate-moisture pet foods (water activity 0.55–0.68). Here the compound is not pre-encapsulated but is added directly at 0.15–0.35 ppm to the meat slurry before thermal processing in a continuous steam tunnel at 94–98 °C for 12–18 minutes, where partial hydrolysis generates the free thiazole alcohol in a controlled gradient. The chemico-kinetic data derived from real-time FTIR monitoring of the carbonyl stretch at 1740 cm⁻¹ indicates that under pH 5.8–6.3 buffered by sodium tripolyphosphate, the pseudo-first-order rate constant kobs at 95 °C is 1.8 × 10⁻⁴ s⁻¹, yielding 8–12% conversion during tunnel residence and a further 4–6% during ambient storage over 12 months as the product headspace equilibrates. This staged release profile delivers an initial savory note upon opening the pouch followed by a sustained nutty undercurrent that pet food sensory panels (using descriptive analysis per ISO 11035:1994) distinguish from unreacted ester profiles. The addition protocol demands strict segregation from liquid smoke condensate and amine-containing Maillard reaction intermediates, as previously noted, due to the risk of Schiff base formation precipitating a dark insoluble sludge that clogs injection nozzles. The regulatory framework for this application embeds the ester within AAFCO feed ingredient definitions and FDA 21 CFR 582.60 for synthetic flavoring substances in animal feed, with pre-market approval in export target markets such as Japan requiring submission of residue studies compliant with the MAFF Agricultural Production Bureau guidelines. The final product formats consist of pillow pouches of lamb-and-vegetable kibble enhancer, sausage-shaped semi-moist rolls, and retorted jerky strips where the ester functions synergistically with 2-methyl-3-furanthiol.
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Introduced into industrial flavour portfolios as a high-boiling, esterified thiazole derivative, 4-Methyl-5-acetoxyethyl thiazole (CAS 656-53-1, FEMA 3277) functions primarily as a controlled-release precursor of the potent sulfur–meaty odorant 4-methyl-5-thiazoleethanol. The acetate moiety masks the free hydroxyl group, suppressing the immediate sulfury impact characteristic of the parent alcohol and imparting a cleaner roasted-nut, braised-meat, and cocoa-like aroma profile upon thermal de-esterification. Commercial grades are typically offered as pale yellow to amber liquids with a specified assay of ≥98% (GC, sum of isomers) and a residual acid value not exceeding 1.0 mg KOH/g. Distillation at scale—commonly conducted in wiped-film evaporators operating at 1–5 mbar and jacket temperatures between 110 °C and 130 °C—removes sulfurous process impurities that otherwise depress organoleptic brightness. This material differs markedly from the analogous 4-methyl-5-vinylthiazole (FEMA 3313), which delivers a raw peanut-skin and burnt character, and from the free alcohol sulfurol (FEMA 3200), whose immediate aggressive thiamine-degradation note limits its dosage window in dry-blended seasonings.
Thermal processing of savoury reaction flavours—extrusion-expanded pet foods, retorted gravies, and UHT-processed bouillons—imposes a kinetic demand that the free alcohol cannot satisfy without generating mercaptan off-odours. In a standard Clextral BC-45 twin-screw extruder (L/D 32:1, barrel temperature profile 90→145→155 °C), addition of 4-methyl-5-thiazoleethanol at levels as low as 0.05 wt% relative to the dry mix results in a measurable spike in hydrogen sulfide liberation above 140 °C, detected by headspace GC-SCD as a 3.2-fold increase versus the acetate-protected analogue under identical screw speed (350 rpm) and moisture (18%) conditions. The acetate ester, by contrast, remains substantially intact during the dwell time of 45–60 s, undergoing controlled retro-esterification only when the expanded kibble contacts the acidified meat slurry or salivary enzymes post-processing. This staged release is evidenced by GC-olfactometry time-intensity curves: while sulfurol exhibits an immediate, sharp roasted-meat peak that decays within 15 s, the acetate generates a slower-developing, sustained savory background spanning 90 s, closely matching the temporal profile of long-simmered bone broth. The operational boundary is defined by moisture content; below 12 wt% in the melt, cleavage of the acetate group is retarded to the point that desired roast character fails to develop even after 12 weeks of product shelf life at 35 °C.
In retort pouch wet pet food (F0 ≥ 5.5 min, 121.1 °C cone temperature), the conversion efficiency of the acetate to the active odorant is strongly pH-dependent. At product pH above 6.2, hydrolysis proceeds to ≥85% completion within 20 min of thermal processing, affording a roast note equivalent to that of a directly added alcohol dose without the risk of pre-reaction during mixing. At pH below 5.0, however, the acetate undergoes premature acid-catalyzed scission in the slurry holding tank (60 °C hold, residence time 30 min), leading to flavour intensity loss prior to thermal processing. Compensating for this loss by overdosing typically produces an acidic, burnt-tallow defect that correlates with a headspace methyl mercaptan concentration exceeding 150 µg/kg. The mitigation strategy adopted by commercial flavour houses involves microencapsulation in hydrogenated vegetable fat (droplet size Dv,90 < 50 µm, melt point 65 °C) which delays release until the retort hold phase.
| Parameter | Specification | Method |
|---|---|---|
| Assay (sum of isomers) | ≥98.0% | GC-FID, internal standard, ASTM E202 equivalent |
| Refractive index nD20 | 1.495–1.502 | ISO 280:1998 |
| Specific gravity d2020 | 1.130–1.140 | ISO 279:1998 |
| Acid value | ≤ 1.0 mg KOH/g | ISO 660:2020 |
| Water content | ≤ 0.1% | Karl Fischer, ISO 760 |
| Free 4-methyl-5-thiazoleethanol | ≤ 0.5% | GC-MS quantitation, SIM mode |
| Volatile sulfur impurities (as H2S equivalents) | ≤ 0.2 µg/g | Headspace GC-SCD |
Batch-to-batch consistency monitoring in flavour production environments demands rapid identity confirmation. A validated FTIR-ATR method, correlated against the JECFA primary GC assay (r2 = 0.998), identifies the characteristic ester carbonyl stretch at 1740 cm⁻¹ and the thiazole ring C=N vibration at 1555 cm⁻¹. Accept-shipment limits for a fragrance-grade variant are tightened to ≥99.0% purity with a free alcohol ceiling of 0.2%, because even trace sulfurol causes a perceptible burnt-rubber off-note in fine-fragrance alcoholic solutions stored under daylight at 25 °C for 28 days.
In the Asia-Pacific manufacturing region, certain producers offer a “flavour-stable” grade containing 50–100 ppm of tert-butylhydroquinone (TBHQ) to retard peroxide-induced oxidation of the thiazole ring during storage in partially empty drums. While effective—peroxide value remains below 2 meq/kg after 12 months at 25 °C versus 8 meq/kg for unstabilized material—this addition must be declared for customers subject to EU regulation (EC) No 1333/2008 on food additives, as the TBHQ carryover may trigger additive labelling obligations distinct from the flavouring substance category.
Aqueous beverage systems represent the most chemically hostile environment for the acetoxyethyl thiazole ester: acid-catalyzed ester hydrolysis proceeds with pseudo-first-order kinetics (kobs = 1.3 × 10⁻³ min⁻¹ at pH 3.0, 25 °C) yielding a half-life of approximately 9 h, rendering direct addition of the neat ester impractical for still drinks or clear functional waters. Spray-dried encapsulation in modified starch (OSA-starch, wall thickness 0.8–1.2 µm) with a core loading of 20% extends the detectable roast character shelf life to 6 months at 22 °C in a model beverage at pH 3.2. Particle size distribution (Dv,50 12–15 µm) remains below the sensory gritty perception threshold, and sensory panel data (n = 18, triangle test, ISO 4120) confirm no metallic or astringent carryover from the encapsulating matrix at use levels up to 40 ppm of encapsulated powder.
A technologically distinct route involves pH-triggered liposomal delivery using lecithin-cholesterol bilayers (melt extrusion at 60 °C). Bench-scale comparative data show that liposome-protected acetate maintains ≥92% chemical integrity after 14-day accelerated storage at 35 °C/pH 3.0, whereas unprotected ester drops to 18% under identical conditions. The principal barrier to commercial adoption is the cost of liposome hydration and homogenization steps, which add approximately €12.50 per kg of finished flavour above standard spray-dry encap costs, a differential tolerated primarily in premium meal-replacement shakes positioned on clean-deck label claims.
No reported organoleptic interference occurs when 4-methyl-5-acetoxyethyl thiazole is co-encapsulated with 2-acetylthiazole (popcorn note) or 2-isobutylthiazole (tomato-vine character), though physical blending of multiple loaded capsules must be conducted under nitrogen sweep to avoid electrostatic segregation caused by triboelectric charge differentials between starch-coated and maltodextrin-coated powders.
Perfumery application demands careful management of the thiazole ring’s susceptibility to photo-oxidative opening under UV-A radiation. In an accelerated light-box test (xenon-arc, 765 W/m², 25 °C, 48 h, equivalent to 18 months indirect daylight behind window glass), 4-methyl-5-acetoxyethyl thiazole at 0.5 wt% in a model simple chypre accord (ethanol 80 vol%, water 20 vol%) develops a musty, dimethyl sulfide-like off-note linked to a relative area increase of the GC-MS peak assigned to 4-methylthiazole-5-carboxaldehyde (+4.3% area). Addition of 0.05 wt% of the UV absorber butyl methoxydibenzoylmethane (INCI avobenzone) reduces the aldehyde formation to +0.8% area, but compatibility testing in clear glass flacons is mandatory to confirm that the absorber does not induce colour shifts above the ΔE* value of 2.5 units (CIELAB) after 6-month north-facing window storage.
While the acetate ester exhibits excellent solubility in dipropylene glycol and triethyl citrate (≥ 500 g/kg at 20 °C), its incorporation into water-based microemulsions for room mist diffusers is limited by the surfactant composition. Ethoxylated castor oil (EO 35) at the typical 3:1 surfactant-to-fragrant ratio solubilizes the ester effectively, but subsequent microbiological challenge tests (EN 1276) reveal that the acetate moiety can serve as a carbon source supporting Pseudomonas growth when the free-water activity exceeds 0.92. The inclusion of 0.15% phenoxyethanol is required as a preservative unless the product is manufactured under GMP conditions that guarantee a ≤ 0.6 aw specification.
A comparison of key odorants structurally related to 4-methyl-5-acetoxyethyl thiazole is summarized below to illustrate differences in performance envelope:
| Compound | FEMA | Odor Threshold (µg/m³ in air) | Half-Life at pH 3.0, 25°C (hrs) | Dominant Note |
|---|---|---|---|---|
| 4-Methyl-5-acetoxyethyl thiazole | 3277 | 5–8 | 9 | Roasted meat, cocoa, nut |
| 4-Methyl-5-thiazoleethanol (Sulfurol) | 3200 | 0.2–0.5 | stable* | Sulfury, beefy, burnt |
| 4-Methyl-5-vinylthiazole | 3313 | 10–15 | n/a (polymerizes) | Peanut skin, roasted nut |
| 2-Isobutylthiazole | 3135 | 3–5 | stable* | Tomato leaf, green vine |
*No significant hydrolytic degradation under aqueous acidic conditions; stability limited by volatility and oxidation.
Registration for food use transcends a simple FEMA GRAS declaration; the substance must satisfy the purity criteria of the JECFA Combined Compendium of Food Additive Specifications (monograph 1031) and be listed in an official positive list for each target jurisdiction. In the United States, 21 CFR 172.515 (Synthetic flavoring substances and adjuvants) permits the substance subject to GMP and a defined maximum use level in non-alcoholic beverages of 1.0 ppm as consumed. The EU Flavouring Regulation (EC) No 1334/2008 does not include FEMA 3277 explicitly but has historically permitted it through the “natural-identical” interpretation prior to the Union List establishment; post-Union List, notification under Article 9 for substances not in the list is required, and certain member states require additional approval for use in meat-flavoured snack coatings. In Japan, the substance appears in the List of Existing Food Additives (Notification No. 120) and is subject to the specifications laid out in Japan’s Specifications and Standards for Food Additives, eighth edition, requiring separate heavy metal testing (As ≤ 2 µg/g, Pb ≤ 5 µg/g). Australia-New Zealand Standard 1.3.1 (Food Additives) permits the use as a flavouring substance at quantum satis, but labelling must declare “flavour” only, not the specific chemical name, unless it is added directly as a separate preparation. Exporters should request certificates of analysis that include residual solvent profiles (ethyl acetate ≤ 150 ppm, cyclohexane ≤ 10 ppm per ICH Q3C options) when shipping into regions with residual solvent regulation harmonization.
