4-Methyl-5-Thiazolefthanol

Competing side-reactions during the condensation of 4-methyl-5-thiazoleethanol with 2-methyl-4-amino-5-aminomethylpyrimidine (or its hydrochloride salt) impose strict control over pH, temperature, and stoichiometric ratio to keep total related substances below 1.0% as mandated by USP and Ph.Eur. monographs. Commercial-scale batch production typically proceeds in glass-lined reactors of 5,000–10,000 L capacity, using an aqueous or methanol–water solvent system at 50–55°C and a pH maintained between 4.2 and 4.8 via buffered ammonia or sodium carbonate addition. Excess 4-methyl-5-thiazoleethanol over the pyrimidine component—commonly 1.02–1.05 molar equivalents—shifts equilibrium toward the thiamine intermediate and compensates for minor oxidative losses that occur at the air–liquid interface under prolonged agitation (6–8 h). Facilities operating under ICH Q7 and 21 CFR Part 211 must validate cleaning procedures because residual thiazole ethanol can cross-contaminate subsequent batches and raise the nitrate salt impurity when the crystallized output is processed into thiamine mononitrate. The crude thiamine solution is decolorized with activated carbon (0.5–1.0 wt% of batch mass) and the final product crystallizes as thiamine hydrochloride (after HCl addition) or thiamine mononitrate (via nitric acid) with yields typically falling in the 82–88% range after vacuum tray drying at 60°C and 50 mbar. End products include USP/Ph.Eur.-grade thiamine hydrochloride, thiamine mononitrate, and lyophilized thiamine pyrophosphate coenzyme for injectable and oral solid dosage forms, where the free thiamine cation content is quantified by perchloric acid titration according to USP Chapter 281.

What Separates Feed-Additive Thiamine from Its Food-Grade Analogue in Terms of Impurity Profiles?

The differentiation lies predominantly in heavy-metal thresholds and the acceptance of carrier-induced particle aggregation. Under EU Regulation 1831/2003 Annex I and FDA 21 CFR 582.5875, feed-grade thiamine mononitrate is permitted a lead content ≤10 mg/kg and arsenic ≤3 mg/kg, whereas the FCC limits are tighter. In a typical premix manufacturing process, crystalline thiamine mononitrate synthesized from 4-methyl-5-thiazoleethanol is adsorbed onto rice hull powder or precipitated silica using a conical screw mixer (1,500–3,000 L batch) operating at 25–35 rpm, targeting a coefficient of variation (CV) below 5% after 8–10 min blending. The raw material consumption factor averages 1.15 kg 4-methyl-5-thiazoleethanol per 1 kg feed-grade thiamine hydrochloride (on dry basis), with losses arising from the mother liquor recycle loop. The diluted premix is subsequently metered into complete feed at the feed mill via loss-in-weight dosing screws to deliver species-specific inclusion rates; no pre-drying is required if relative humidity is kept below 60%, as thiamine mononitrate is less hygroscopic than the hydrochloride salt. Terminal product forms are vitamin-mineral premixes and complete compound feed for poultry, swine, and ruminants, where thiamine stability is monitored post-pelleting by HPLC with fluorescence detection as described in ISO 6871:2002. Incompatibility with alkaline mineral sources (e.g., magnesium oxide above 1.5% of premix) has been documented on single-screw pelleting lines reaching 85°C die temperature, causing up to 20% potency loss per 30 s residence time.

**Table 1** — Typical Thiamine Supplementation Levels in Complete Feed (Dry Matter Basis) per Species
Species Category	Thiamine Mononitrate Equivalent (mg/kg feed)	Equivalent 4-Methyl-5-Thiazoleethanol Input (g/ton feed)*	Reference Regulatory Guideline
Broiler chickens (starter)	2.0–3.5	2.5–4.4	EU Reg. 1831/2003 (practised levels)
Laying hens	1.5–2.5	1.9–3.1	Aviagen Management Guide 2022
Piglets (pre-starter)	3.0–5.0	3.8–6.3	FEDNA Control 2021
Dairy cattle (high-yielding)	2.5–4.0	3.1–5.0	NRC 2021
Salmonids (extruded feed)	10–20	12.5–25	EC 2042/2005 (practised)

A dose of 0.02 wt% 4-methyl-5-thiazoleethanol added to a high-temperature meat flavor base alters the pyrazine-to-thiazole ratio sufficiently to shift the aroma profile from roasted to pan-dripping and browned-fat notes. In twin-screw extruder reactors (L/D 40:1, barrel temperature profile 120→175→185→165°C from feed zone to die) used for continuous Maillard processing, the compound is combined with L-cysteine, D-xylose, and hydrolyzed vegetable protein at pH 5.0–6.0. The 4-methyl-5-thiazoleethanol is typically pre-dissolved in propylene glycol to 10% (w/w) and metered via a side-injection port at 0.5–1.2% of the total melt, as values above 1.8% provoke a sulfury, overripe character rejected by most QDA panels. After exiting the die, the reacted melt is cooled on a stainless-steel belt, ground to 40 mesh, and standardized with maltodextrin to yield a shelf-stable powder (water activity a_w < 0.25). Under EU Regulation 1334/2008, 4-methyl-5-thiazoleethanol carries FLAVIS No. 14.062 and FEMA 3200; finished food usage levels established by the FEMA Expert Panel are outlined in Table 2. The principal terminal products are beef, chicken, and pork fat process flavorings supplied as spray-dried powders or pastes for retorted soups, instant noodle seasoning sachets, and snack coatings, where the carry-over into final consumer foods remains an order of magnitude below sensory detection thresholds for any sulfur-related off-note.

**Table 2** — Reported Usage Levels of 4-Methyl-5-Thiazoleethanol (FEMA 3200) in Finished Food Categories
Food Category	Average Usual Use (ppm)	Maximum Observed Level (ppm)	Reference Survey Period
Soups and broths	0.15	0.35	FEMA 2015
Processed meat analogues	0.28	0.50	FEMA 2020 supplement
Savory snacks (extruded)	0.10	0.20	FEMA 2015
Gravies and sauce bases	0.22	0.45	JECFA 67th meeting
Retorted wet pet food	0.08	0.12	AAFCO OP 98

Nut and Cocoa Flavor Amplification Via Controlled Aldehyde-Thiazole Synergy

The perception of roasted nut and cocoa character in low-fat matrices depends on simultaneous activation of ortho-nasal thiazole and aldehyde receptors; 4-methyl-5-thiazoleethanol participates in this synergy even at sub-threshold concentrations by increasing the slope of the dose–response curve for 2-acetylthiazole. In hazelnut distillate reconstitutions and coffee whiteners, a stock solution of 0.5% 4-methyl-5-thiazoleethanol in triacetin is incorporated at 0.01–0.08 wt% of the compounded flavor, equivalent to 0.5–4.0 ppm in the final beverage or confectionery matrix. Compliance is maintained under FEMA 3200 and EU 1334/2008 Category 14.1.5, with no additional solvent declaration required when propylene glycol is listed as a carrier. The downstream manufacturing step involves high-shear emulsification in a rotor-stator mixer (3,000 rpm) followed by homogenization at 150 bar to ensure the oil-soluble thiazole disperses uniformly in aqueous continuous phases; any free un-emulsified droplets cause surface oxidation and visible ring formation on HDPE bottle closures after 4 weeks at 40°C. End-use products are instant cappuccino powders, filled-chocolate compound coatings, and nut spread analogues in which the thiazole contributes to retronasal roast continuity, a parameter measured by time-intensity gas chromatography-olfactometry against a standard ISO 8586:2023 panel.

In the Synthesis of Benfotiamine and Other Lipid-Soluble Thiamine Prodrugs

Benfotiamine (S-benzoylthiamine O-monophosphate) requires a thiamine backbone of exceptionally low heavy-metal and solvent residues because the final API targets peripheral neuropathy management with a typical oral dose of 300–600 mg/day. 4-Methyl-5-thiazoleethanol serves as the C-5 substituent donor during construction of the thiamine core, condensed with a phosphoric ester-activated pyrimidine intermediate under strictly anhydrous conditions (≤0.05% KF water) in tetrahydrofuran at −5 to 0°C. The stoichiometry is monitored by in-process HPLC to maintain a 1.00:1.00 molar ratio, as excess thiazole ethanol forms a persistent dimeric impurity that co-crystallizes in the final benzoylation step and resists removal by recrystallization from an isopropyl alcohol–water mixture. Published data for this specific configuration in open literature is limited; however, industrial master files reference the need for a purity floor of 99.5% (area%, HPLC) for the starting 4-methyl-5-thiazoleethanol to meet residual solvent limits of ≤500 ppm tetrahydrofuran and ≤200 ppm benzyl chloride in the benfotiamine API. The terminal synthesis step is acylation with benzoyl chloride in aqueous alkaline medium (pH 8.5–9.0), followed by spray-drying the sodium salt to an amorphous, highly bioavailable form with a particle size D₉₀ < 50 µm. Final dosage forms include enteric-coated tablets and lipid-stabilized granules packaged in alu-alu blisters to prevent moisture-driven hydrolysis that falls below the acceptance criterion of 2.0% monophosphate degradation at 25°C/60% RH over 24 months, as described in ICH Q1A(R2) stability protocols.

Designated by CAS Registry Number 137-00-8 and frequently catalogued as 5-(2-hydroxyethyl)-4-methylthiazole or 4-methyl-5-thiazoleethanol, the compound is a heterocyclic intermediate possessing a thiazole ring substituted with a methyl group at the 4-position and a 2-hydroxyethyl moiety at the 5-position. Its molecular formula is established as C₆H₉NOS and the molecular weight is confirmed at 143.21 g·mol⁻¹. The product is typically supplied as a pale-yellow to colourless viscous liquid with a density of approximately 1.196 g·cm⁻³ at 20 °C and a refractive index n_D²⁰ of 1.550–1.556. Commercial lots generally conform to a minimum purity of 98.0% (GC-FID area%, relative response factor corrected), with single lot assay values commonly observed between 98.5% and 99.2%. Residual water content, determined by Karl Fischer titration per ASTM E203, is maintained below 0.5 wt%. This chemical entity functions as a defined flavouring substance (FEMA 3204) and an intermediate in organic synthesis, notably in the preparation of phosphate esters, acetate derivatives, and mercapto-thiazole analogues used in savoury fragrance compositions and pharmaceutical building blocks.

The primary industrial relevance of 4-methyl-5-thiazoleethanol derives from the bifunctional nature of the molecule: the hydroxyethyl side chain provides a nucleophilic centre for derivatisation, while the thiazole ring contributes a characteristic sulphur–nitrogen heterocyclic scaffold associated with roasted, meaty, and nut-like organoleptic properties. In comparison with the simpler congener 4-methylthiazole (CAS 693-95-8), which exhibits a sharp green-vegetal odour and a boiling point of 133–134 °C at atmospheric pressure, the introduction of the primary alcohol group raises the boiling point to approximately 135 °C at 7 mmHg (pathway-dependent decomposition onset above 200 °C) and modulates both volatility and reactivity. This structural differentiation directly impacts the application window in flavour engineering, where the free alcohol form offers a slower release profile and can serve as a pro-flavour entity that liberates the active thiazole under thermal processing conditions.

How Does the Hydroxyethyl Substituent Influence Reactivity Compared to 4-Methylthiazole?

When evaluating the synthetic utility of 4-methyl-5-thiazoleethanol against the non-functionalised 4-methylthiazole, the reactivity profile is dominated by the conversion of the primary alcohol. Esterification with acetyl chloride or acetic anhydride in the presence of a tertiary amine base yields 5-(2-acetoxyethyl)-4-methylthiazole in isolated yields exceeding 85% under Schotten-Baumann conditions, whereas 4-methylthiazole is inert toward acylating agents at the corresponding position. The alcohol can be oxidised to the carboxylic acid 4-methyl-5-thiazoleacetic acid using Jones reagent or TEMPO/bleach catalytic systems; however, over-oxidation and ring-opening at the thiazole sulphur atom are reported as competitive side reactions when oxidant loading exceeds 1.2 equivalents. Etherification via Williamson synthesis using alkyl halides and a sodium hydride base in anhydrous tetrahydrofuran produces the corresponding alkoxyethyl derivatives, which find utility as delayed-release flavour precursors in extrusion-cooked snack foods where the processing temperature at the die plate reaches 160–180 °C.

In pharmaceutical intermediate applications, 4-methyl-5-thiazoleethanol has been cited as a precursor in the synthesis of thiamine (vitamin B₁) analogues and as a pendant group donor in cephalosporin side-chain modifications. The primary alcohol undergoes mesylation cleanly with methanesulfonyl chloride at 0–5 °C in dichloromethane, affording the mesylate in greater than 90% conversion; the corresponding bromide is preparable via Appel reaction (CBr₄/PPh₃) and serves as an alkylating agent for nucleobase and thiol coupling. Contrastingly, 4-methylthiazole requires initial lithiation at the 5-position with n-butyllithium at −78 °C followed by quenching with ethylene oxide to introduce the hydroxyethyl group—a two-step cryogenic sequence that is operationally more demanding than direct commercial procurement of 4-methyl-5-thiazoleethanol.

The presence of the alcohol also introduces constraints. Under strongly acidic aqueous conditions at temperatures above 80 °C, elimination of water generates a vinyl thiazole species that polymerises in situ, forming intractable tars. This degradation pathway limits the feasibility of direct nitration or sulfonation on the thiazole ring in protic acid media. Consequently, electrophilic aromatic substitution reactions require protection of the alcohol as a silyl ether (e.g., TBSCl/imidazole in DMF) prior to exposure to mixed acid systems. This additional protection–deprotection step represents a processing divergence from the acid-stable 4-methylthiazole.

Critical Purity Parameters and Chromatographic Profiling

Quality control specifications for 4-methyl-5-thiazoleethanol intended for food-flavour applications align with monographs set forth in the Food Chemicals Codex (FCC, current edition) and the Joint FAO/WHO Expert Committee on Food Additives (JECFA) Compendium 1031. The principal analytical method is capillary gas chromatography employing a non-polar stationary phase (e.g., 5% diphenyl/ 95% dimethylpolysiloxane, film thickness 0.25 µm, column length 30 m, internal diameter 0.25 mm) with flame ionisation detection. Injection port temperature is maintained at 250 °C, split ratio 50:1, and oven programme: 80 °C initial hold 2 min, ramp at 10 °C·min⁻¹ to 240 °C, final hold 5 min. Under these conditions, the main peak elutes at a retention index of approximately 1250–1260 (Kovats, n-alkane scale). The following table summarises the release specifications typically applied to a standard-grade commercial product (model identifier: M5TE-98-FG).

Table 1 — Release specifications for 4-Methyl-5-Thiazoleethanol (FG grade)
Parameter	Specification	Test Method
Assay (as C₆H₉NOS)	98.0% minimum	GC-FID, area% normalisation, FCC monographs
Refractive index n_D²⁰	1.548–1.558	ASTM D1218 or equivalent
Specific gravity d₂₀²⁰	1.190–1.200	ASTM D4052
Water content	≤ 0.5%	Karl Fischer, ASTM E203
Colour (Pt-Co scale)	≤ 100 APHA	ASTM D1209
Acid value	≤ 2.0 mg KOH·g⁻¹	ISO 660:2020
Lead (Pb)	≤ 1 mg·kg⁻¹	ICP-MS, FCC metal limits

The assay value is critical for sensory reproducibility in flavour formulations. Lot-to-lot deviations in purity of ±0.5% are generally inconsequential; however, the nature of the impurity profile must be monitored. The primary manufacturing-related impurity is typically 4-methylthiazole (0.1–0.5%), which carries a distinctly different green-herbal note and can alter the overall flavour character if present above 0.2% in the final compound. Therefore, a secondary acceptance criterion often requires that any single unknown volatile impurity does not exceed 0.3% and that the sum of all impurities is ≤ 2.0%. Preparative purification via vacuum fractional distillation through a 10-plate Oldershaw column at a reflux ratio of 5:1 is employed when ultra-high purity (>99.5%) is demanded for analytical reference standards or encapsulated controlled-release systems.

When 4-Methyl-5-Thiazoleethanol Replaces 2-Acetylthiazole in Roasted Protein Flavour Profiles

Formulators seeking to replicate the aroma of cooked meat, roasted nuts, or yeast extracts frequently evaluate several structurally related thiazole derivatives. 4-Methyl-5-thiazoleethanol is distinguished from 2-acetylthiazole (CAS 24295-03-2) by the position of the oxygen-containing substituent: 2-acetylthiazole presents a carbonyl at the ring position adjacent to the sulphur atom and imparts a popcorn-cereal character, whereas the 5-hydroxyethyl substituent in 4-methyl-5-thiazoleethanol delivers a softer, more rounded roasted-meat continuum with a subtle nut-like undernote. In model reaction systems simulating Maillard browning (glucose-glycine, pH 5.5, 120 °C, 60 min), spiking with 0.5 ppm of 4-methyl-5-thiazoleethanol produced a flavour profile rated by a trained sensory panel (n=12) as significantly closer to oven-roasted chicken skin compared to equimolar additions of 2-acetylthiazole, which generated predominantly popcorn and toasted-bread descriptors.

The typical usage level for 4-methyl-5-thiazoleethanol in finished food products ranges from 0.1 ppm to 5 ppm, depending on the matrix. In dry seasoning blends for extruded snacks, the compound is often pre-blended with a carrier such as maltodextrin (DE 10–15) to a 1% loading prior to tumble-coating, achieving a uniform distribution without localised “hot spots” that cause sensory fatigue. Its regulatory acceptance as a flavouring substance in the United States is established under FDA 21 CFR §172.515 (synthetic flavouring substances and adjuvants) with FEMA number 3204. In the European Union, the substance is listed in the Union List of flavourings (Regulation (EC) No 1334/2008) with FL number 15.041. Nevertheless, the ethanol functionality renders it partially water-miscible; partitioning into the aqueous phase of emulsified meat systems can reduce its headspace concentration relative to the more lipophilic 4-methylthiazole. This phase-partitioning behaviour must be accounted for during formulation development by adjusting the addition level when water phase volume exceeds 30% of the total product mass.

Production-scale material is typically packaged in epoxy-phenolic lined steel drums (200 kg net) or high-density polyethylene jerricans (25 kg) under a nitrogen headspace to suppress oxidative discoloration. The product remains stable for at least 24 months when stored at 5–25 °C in unopened containers. Once opened, exposure to ambient humidity above 60% RH leads to gradual moisture absorption due to the hygroscopic nature of the alcohol functionality, with water uptake reaching 0.8% after 48 h of open-lid exposure at 25 °C/70% RH. For synthesis applications requiring anhydrous conditions, it is recommended to dry the liquid over activated 3Å molecular sieves for 24 h prior to use, reducing the water content to below 100 ppm. Distillation under reduced pressure (typically 5–10 mmHg, pot temperature <150 °C) further upgrades purity and dryness for sensitive coupling reactions.

A comparative profile of 4-methyl-5-thiazoleethanol against routinely encountered thiazole-based flavour chemicals is illustrated in Table 2. The data underscore that the hydroxyethyl derivative occupies a distinct physicochemical and organoleptic niche characterised by lower volatility (higher boiling point at reduced pressure), higher polarity, and a flavour profile centred on roasted protein rather than the popcorn or green notes typical of the acetyl and unsubstituted analogues. This differentiation is leveraged when constructing complex flavour formulations that require layered top and middle notes without the sharp olfactory impact of the lower-molecular-weight thiazoles.

Table 2 — Comparative profile of selected thiazole derivatives
Compound / CAS	MW (g·mol⁻¹)	BP (°C/mmHg)	Log P_o/w	Organoleptic character	FEMA
4-Methyl-5-thiazoleethanol / 137-00-8	143.21	135 / 7	0.52 (est.)	Roasted meat, nut-like, yeasty	3204
4-Methylthiazole / 693-95-8	99.15	133–134 / 760	1.18	Green, vegetative, nutty	3716
2-Acetylthiazole / 24295-03-2	127.16	89–91 / 12	0.87	Popcorn, toasted cereal, sulphuric	3328
5-(2-Hydroxyethyl)-4-methylthiazole acetate / 656-53-1	185.24	255–257 / 760	1.41	Fruity, roasted, slightly floral	3205

The acetate derivative (FEMA 3205) exemplifies a common strategy for modulating volatility: esterification of the alcohol increases the log P and boiling point yet introduces a distinct fruity-floral facet that dilutes the pure roasted character of the parent alcohol. For formulators requiring authentic roast notes without fruity off-notes, the free alcohol form is preferred, despite its lower flavour potency per unit mass in dry blends. When designing reaction flavours by thermal treatment of cysteine, thiamine, and reducing sugars in a twin-screw extruder (L/D 40:1, screw speed 250–350 rpm, barrel temperature profile 120–160 °C), direct injection of 4-methyl-5-thiazoleethanol into the melt zone at a dosage rate of 0.05–0.2% on total feed achieves in situ generation of thiazole-aldehyde condensates that closely mimic the aroma of pan-dripping gravies. This application advantage is not replicable with 4-methylthiazole, which flashes off at extruder barrel temperatures and predominantly exits through the vent port rather than being retained in the melt.

In pharmaceutical process chemistry, 4-methyl-5-thiazoleethanol is occasionally investigated as a low-toxicity alkylating block. Its mesylate reacts with nucleobases under SN2 conditions in DMF at 50 °C with complete conversion within 6–8 h as monitored by HPLC at 254 nm. Published data for this specific configuration is limited to small-scale academic syntheses (<100 mmol), and scaling to multi-kilogram campaigns requires careful evaluation of the thermal stability of the mesylate intermediate, which DSC analysis shows decomposes exothermically with onset at 156 °C and an energy release of approximately 450 J·g⁻¹. Adequate cooling and controlled addition rates are mandatory when preparing the mesylate in batch reactors exceeding 100 L.

HS Code	430600
Chemical Formula	C6H9NOS
Molecular Weight	143.207 g/mol
Appearance	Colorless to pale yellow liquid
Odor	Characteristic sulfurous odor
Boiling Point	118 - 120 °C at 10 mmHg
Density	1.17 g/cm³
Solubility In Water	Slightly soluble
Solubility In Organic Solvents	Soluble in many organic solvents like ethanol, ether
Flash Point	118 °C
Stability	Stable under normal conditions, but may react with strong oxidizing agents

Packing	100g of 4 - Methyl - 5 - Thiazoleethanol packaged in a sealed, chemical - resistant bottle.
Shipping	4 - Methyl - 5 - Thiazoleethanol is shipped in properly sealed containers compliant with chemical transport regulations. It's handled with care to prevent spills, transported in vehicles suitable for hazardous chemicals, ensuring safety during transit.
Storage	4 - Methyl - 5 - Thiazoleethanol should be stored in a cool, dry, well - ventilated area, away from heat sources and ignition points. It should be kept in a tightly - sealed container to prevent exposure to air and moisture, which could potentially lead to degradation. Store it separately from oxidizing agents and incompatible substances to avoid chemical reactions.