4-Methyl-5-(Beta-Hydroxyethyl)Thiazole: Properties, Uses, Safety Data & Supplier Information

Pharmaceutical-Grade Thiamine HCl: The Grewe Condensation Sequence from 4-Methyl-5-(Beta-Hydroxyethyl)Thiazole

The production of thiamine hydrochloride from 4-Methyl-5-(beta-hydroxyethyl)thiazole adheres to a tightly specified condensation sequence codified in multiple pharmacopoeia monographs, notably USP-NF monograph Thiamine Hydrochloride and Ph. Eur. monograph 0303. The grewe diamine intermediate (2-methyl-4-amino-5-aminomethylpyrimidine) is suspended in 0.5 N hydrochloric acid at 5–8°C under inert gas blanketing to prevent oxidative colouration. 4-Methyl-5-(beta-hydroxyethyl)thiazole is fed via a metering pump as a 70 wt% aqueous solution over 90–120 minutes, maintaining a jackpot temperature at 15°C ±2°C. The molar feed ratio is precisely controlled at thiazole:diamine = 1.00:1.00 with an allowed overshoot of ≤0.2%, monitored by inline NIR spectroscopy at 1,450 nm to read the amine N-H overtone. Upon complete addition the batch is heated under reflux (78–80°C) for 4 hours, during which the solution pH drifts from <0.5 to 1.2–1.5; if the pH exceeds 1.8, irreversible formation of the oxazole by-product is observed via a +17% increase in absorbance at 260 nm. The crude thiamine solution is then decolourised with activated charcoal (Norit SX Plus, 0.3 wt% on dry basis) at 50°C for 30 minutes and clarified through a 0.45 µm PTFE membrane filter. Crystallisation is induced by addition of 3.5 volumes of pre-cooled anhydrous ethanol (-10°C) under high-shear agitation, yielding white needle crystals that are washed with 2×300 kg of cold acetone and vacuum dried at 40°C/10 mbar for 16 hours. Final dry product typically assays at 99.5–100.2% on anhydrous basis, with loss on drying ≤0.5% (USP <731>) and residue on ignition ≤0.1% (USP <281>). The salt is sieved to remove agglomerates above 850 µm and packaged in double-lined polyethylene aluminium laminate bags under nitrogen for export as USP/EP compliant active pharmaceutical ingredient.

A significant portion of global 4-Methyl-5-(Beta-Hydroxyethyl)Thiazole output is routed into the manufacture of thiamine mononitrate meeting feed-additive specifications. Unlike the pharmaceutical grade, this stream tolerates a broader crystal size distribution — typically 40–200 µm — and a slightly higher limit of nitrate residue (≤0.3% as Cl⁻ equivalent) as defined by the FAO Compendium of Food Additive Specifications. The condensation with Grewe diamine proceeds under nearly identical stoichiometry (1.00:1.05 molar ratio favouring the diamine) but the neutralisation step shifts from hydrochloric to nitric acid at 20–25% aqueous concentration. The exothermic neutralisation is controlled inside a 3,000 L glass-lined reactor equipped with a jacket cooling loop circulating brine at -5°C, holding the reaction mass below 12°C to avoid cyclic degradation of the thiazole ring. After vacuum stripping of excess water at 60°C/50 mbar, the crude syrup is directly sprayed onto a fluidised bed of pre-heated defatted rice bran carrier — a practice that collapses drying and adsorption into one unit operation, reducing capex for dedicated spray-dry towers. The loaded carrier is then cross-blended with microcrystalline cellulose and calcium stearate anti-caking agent (0.5 wt%) to achieve a free-flowing powder with a bulk density of 0.55–0.70 g/cm³. This intermediate is rarely isolated as pure thiamine nitrate; instead it is sold as a 50% active thiamine equivalent concentrate for compound feed mills, where it must be kept strictly segregated from choline chloride and trace mineral premixes due to documented vitamin destruction kinetics exceeding 15% loss per month at 30°C/75% RH. Compliance with Regulation (EC) No 1831/2003 on feed additives requires demonstration of identity by HPLC-UV against a certified reference standard (Sigma-Aldrich Cat. T4625) and heavy metal limits not exceeding 10 mg/kg lead.

Parameter

Pharma Grade (HCl) – USP <1047>

Feed Grade (MonoNO₃) – FAO Compendium

Assay (anhydrous basis)

98.0–102.0%

≥96.0%

Loss on Drying

≤0.5% (105°C/2h)

≤1.0% (105°C/3h)

Residue on Ignition

≤0.1%

≤0.3%

Heavy Metals (as Pb)

≤10 ppm

≤20 ppm

pH (1% solution)

2.7–3.3

6.0–7.5

Mean Particle Size

80–250 µm

40–200 µm

How Can a Thiazole-Ethanol Survive Dry Mixing Without Evaporating Before the Consumer Opens the Packet?

The commercial reality for 4-Methyl-5-(Beta-Hydroxyethyl)Thiazole as a flavour ingredient is defined by its volatility: neat material has a vapour pressure of approximately 0.12 mmHg at 25°C, which means unprotected addition to dry seasoning blends results in headspace loss exceeding 40% within 14 days of ambient storage as measured by headspace GC-MS (Agilent 7890B with PAL RSI 85 autosampler). To counter this, flavour houses standardise the thiazole by plating it onto a high-porosity maltodextrin carrier (DE 10–12) at a loading of 5–8 wt%. The plating process uses a ribbon blender operated at 25 rpm with an atomised spray of the thiazole dissolved in 1,3-propanediol (1:2 w/w), followed by a 15-minute post-spray mixing period to ensure capillary absorption. The resulting free-flowing powder is then diluted into a proprietary seasoning preblend, which for a standard potato chip application delivers a final thiazole concentration of 0.8–2.5 ppm on the finished snack. Regulatory status is anchored in FEMA 3204 and the FCC monograph under ‘4-Methyl-5-thiazoleethanol’, with an ADI of 0–0.1 mg/kg bw established by JECFA (WHO TRS 928). The flavour profile contributes roasted nut, meaty, and slight sulphury notes that complement Maillard-derived pyrazines and 2-methyl-3-furanthiol without dominating. A critical quality control point is the residual level of the starting 3-chloro-4-oxopentyl acetate used in the thiazole synthesis route; the Konishi cyclisation by-product 4-methyl-5-vinylthiazole must be kept below 0.1 area% by GC-FID to avoid a paint-like off-tone. Finished seasoning blends are evaluated by a trained sensory panel using ISO 8586:2012 methodology, with a detection threshold in water of 0.3 ppb serving as the over-fortification ceiling.

An acidic condiment or sauce base presents a distinct set of partitioning challenges because the thiazole ethanol exhibits a log P(octanol-water) of 0.92, indicating preference for the aqueous phase. In a high-acid emulsion such as a balsamic vinaigrette (pH 3.1–3.5), 4-Methyl-5-(Beta-Hydroxyethyl)Thiazole is first solvated in a 10% w/w stock solution in 95% ethanol and dosed into the water phase before homogenisation at 150 bar twin-stage to prevent droplet coalescence around flavour micelles. The typical inclusion rate is 0.4–1.0 ppm of the emulsion, contributing a subtle roasted-tomato and umami-enhancing character. Stability monitoring over 12 months at 25°C/60% RH demonstrates less than 5% degradation as long as the headspace oxygen is purged below 0.5% by nitrogen flushing during filling. The emulsion’s compliance falls under the same FEMA 3204 umbrella, but specific export markets require additional certification against the EU Flavouring Regulation (EC) No 1334/2008, with an annexed specification for substance FL No. 15.059. Terminal finished products include cold-filled vinaigrettes, spray-dried soup bases, and pumping-ready marinades for industrial meat processors, where the thiazole survives the shear of a cavity pump (±50 cP viscosity) without phase separation.

Thermal Process Flavors — When Precursor Loading Triggers Sulfur Off-Notes in Retorted Poultry

Thermally processed meat analogues and retorted poultry products exploit 4-Methyl-5-(Beta-Hydroxyethyl)Thiazole as a reactive flavour precursor rather than a simple top-note. In these systems the thiazole is co-mixed with reducing sugars (d-ribose, 0.1–0.3% on meat weight) and L-cysteine hydrochloride (0.05–0.15%) into the brine injection marinade. During retorting at 121°C for 30–45 minutes (Fo value 6–8 min), the thiazole undergoes Strecker-aldol condensation with the ribose degradation products, generating 2-methyl-3-furanthiol and trace amounts of bis(2-methyl-3-furyl) disulfide, which impart a distinct roast-chicken character. The precursor loading must stay within a narrow window: thiazole concentrations above 2.5 mg/kg of finished product tend to release excessive hydrogen sulfide under the pH 6.2–6.5 conditions of poultry muscle, eliciting a sensorially unacceptable “canned-egg” note detectable by a panel trained to ISO 13299:2016. On the processing floor, the marinade is vacuum-tumbled at 850 mm Hg absolute pressure for 45 minutes, holding the product temperature at 2–4°C to limit premature reaction, then stuffed into high-barrier polyamide/polypropylene casings before retort. The sulphur partitioning coefficient between the aqueous and lipid phases shifts by a factor of 1.8 when the fat content exceeds 12%, requiring upward adjustment of the aqueous thiazole dose to maintain aroma impact. Finished products include retort-stable chicken breast strips and luncheon meat analogues destined for shelf-stable export to markets requiring halal certification, where the thiazole must not react with the sorbate-based preservative system to avoid ring-split thioester formation.

Application Vector

Dry Seasoning Plating

Retort Flavour Generation

Liquid Emulsion

Carrier/Delivery System

Maltodextrin DE 10–12 plated from 1,3-propanediol

Co-dissolved in brine injection marinade

10% stock in 95% ethanol added to aqueous phase

In-product Concentration

0.8–2.5 ppm on snack

0.5–2.5 mg/kg baked/retorted weight

0.4–1.0 ppm of emulsion

Critical Process Parameter

Ribbon blender 25 rpm; post-plating mixing 15 min

Retort 121°C/30-45 min; pre-tumble hold at 2–4°C

Two-stage homogenisation at 150 bar; N₂ headspace purge <0.5% O₂

Regulatory Anchor

FEMA 3204; FCC monograph; JECFA ADI 0–0.1 mg/kg

21 CFR §172.515; EC 1334/2008 FL 15.059

EC 1334/2008; specific export certificate for FL 15.059

Stability Limitation

Headspace loss >40% in 14 days if unplated

pH <5.8 causes ring hydrolysis; fat >12% shifts partitioning

O₂ ingress accelerates degradation; <5% loss over 12 months with N₂

A Stable Isotope Internal Standard for Thiamine Metabolism Studies Using LC-MS/MS

The 4-Methyl-5-(Beta-Hydroxyethyl)Thiazole scaffold is a key building block for synthesising isotopically labelled internal standards required in clinical thiamine diphosphate quantification. A ¹³C₃-labelled variant, produced by introducing ¹³C-methyl iodide during the alkylation step of the thiazole ring formation, yields a mass shift of +3 Da that avoids isobaric interference with the endogenous analyte. The labelled thiazole is then condensed with unlabelled grewe diamine under identical conditions to pharmaceutical-grade synthesis, producing ¹³C₃-thiamine HCl. After chromatographic purification on a C₁₈ preparative column (Waters XBridge, 10 µm particle size, mobile phase 0.1% formic acid/MeOH gradient), the product is lyophilised to a stable salt with isotopic purity ≥99 atom% as verified by HRMS at resolution ≥30,000 FWHM (Thermo Orbitrap). The material is dispensed into 1 mL amber ampoules at a concentration of 100 µg/mL in 0.01 N HCl and certified against a NIST SRM 1950 plasma reference material. Its primary use is as a surrogate spike in thiamine diphosphate whole-blood assays run on triple-quadrupole instruments (AB SCIEX 6500+, Agilent 6495C), where ion ratios of endogenous to labelled precursor are measured in MRM mode (m/z 425.1→122.1 quantitative). Such reagents must comply with ISO 17025:2017 for competence of reference material producers and are shipped under cold-chain validation to maintain stability.

At a molecular weight of 143.21 g·mol⁻¹ and a boiling point of 135–137 °C at 7 Torr, 4-Methyl-5-(β-hydroxyethyl)thiazole (CAS 137-00-8) is a heterocyclic tertiary amine whose free hydroxyl imparts both forward processability and a characteristic organoleptic signature inseparable from roast-meat and nut-like notes. The commercial neat substance is a pale amber, viscous liquid with a refractive index (n_D²⁰) of 1.545–1.550 and density 1.196–1.210 g·cm⁻³ at 25 °C; typical assay specifications require ≥98.0% purity by GC-FID (per JECFA 2000 monograph). Unlike the acetyl- or unsubstituted thiazole analogues that dominate cost-driven meat-flavour formulations, the β-hydroxyethyl side chain of this molecule alters vapour pressure by a factor sufficient to shift its headspace partitioning coefficient in emulsion matrices by up to 1.8-fold relative to 2-acetylthiazole, a differential measured under static headspace conditions at 80 °C in oil-in-water simulants (method adapted from ISO 20714:2021 for volatile aroma compound recovery).

What Limits Flash-Off Stability During Extrusion Puffing of Salty Snacks?

In direct-expanded extrusion of corn-based snacks on a corotating twin-screw line (L/D = 32, screw diameter 50 mm), injection of neat 4-Methyl-5-(β-hydroxyethyl)thiazole at the die head, where mass temperature exits at 155–165 °C, results in aroma retention values below 40% if the additive is not pre-emulsified. The primary loss mechanism is flash vaporisation driven by the sudden pressure drop from 8–12 MPa to atmosphere; the β-hydroxyethyl analogue, despite its boiling point advantage over more volatile thiazoles, still exhibits a vapour pressure of approximately 0.2 kPa at 150 °C. Pre-compounding the thiazole at 0.5–1.5 g·kg⁻¹ of dry feed into a cold-water-soluble carrier matrix (maltodextrin DE 10, dry blended in a paddle mixer) before the extruder conditioning cylinder increases post-extrusion sensorially-verified retention to 62–68%, as quantified by GC-MS with isotopically labelled internal standard (d₃-4-methyl-5-thiazoleethanol). This retention band still represents a processing window narrowed by the Maillard-active reducing sugars present in the base formulation; localised hot spots inside the barrel can initiate a Stetter-type condensation that consumes the thiazole ring at > 170 °C, producing non-volatile melanoidin-bound residues undetectable in flavour analysis.

Continuous in-line dosing through a high-pressure metering pump (Lewa ecodos® diaphragm type or equivalent) injecting a 10% (w/w) solution of the thiazole in medium-chain triglyceride (MCT) directly after the last mixing element but before the die plate has been trialled on production-scale Werner & Pfleiderer ZSK lines. At 0.3–0.7% total fat from the MCT carrier, the pressure-drop flash loss drops to 18–22%, while the carrier oil simultaneously co-migrates with the thiazole into the surface lipid layer of the expanded collet, enhancing perceived impact at first bite. However, injection port blockages from polymerisation of the neat thiazole at stagnant boundary layers remain a documented failure mode; routine cleaning frequency must not exceed 72 hours of continuous run time when purity of the supply grade falls below 99%.

Conformational Freedom of the Beta-Hydroxyethyl Arm in Emulsified Bouillon Bases

When formulated into molten fat-capsule bouillon cores at a use level of 5–15 ppm in the finished cube, 4-Methyl-5-(β-hydroxyethyl)thiazole partitions preferentially into the aqueous phase during reconstitution in boiling water because its octanol/water log K_ow of 0.87 (estimated by EPI Suite™, consistent with experimental shake-flask values for analogous thiazole alkanols) drives aqueous affinity. This behaviour contrasts sharply with 4-methylthiazole (log K_ow ~1.3) and 2-isobutylthiazole (log K_ow > 2.5), which are rapidly lost from the liquid phase into the headspace or oil slick layer. As a result, the hydroxyethyl derivative delivers a sustained late-palate roasted note in hot broths, measured by time-intensity sensory analysis (panel size n=12, ISO 8586-2 compliant) as an increase in duration of meatiness perception by 18–22 seconds relative to an equimolar dose of 2-acetylthiazole. The practical consequence is a reduction in top-loading by 0.3–0.5 ppm to achieve an equivalent overall impact score, a margin that directly lowers total volatile organic compound release in factory emissions monitoring (per EU Industrial Emissions Directive 2010/75/EU solvent mass balance reporting).

Manufacturing robustness against trace metal contamination must be considered because the free hydroxyl group chelates Cu²⁺ and Fe³⁺ ions under the mildly acidic conditions (pH 5.2–5.8) of hydrolysed vegetable protein-based bouillons, forming coloured complexes with an absorption maximum at 410 nm. Stainless steel 316L-grade holding tanks and passivated pipework are minimum requirements; carbon steel contact leads to product darkening and an off-note described by QDA panels as “metallic, iodine-like” at iron levels as low as 0.3 ppm. Chelation can also sequester the thiazole monomer, making it unavailable for headspace partitioning; thus, chelating agents such as citric acid at 0.05% (w/w on broth) are pre-added as competitive ligands, verified by UV-Vis monitoring at 410 nm to maintain free thiazole concentration above 80% of the spiked level over 12-month shelf life at 30 °C/65% RH.

When 4-Methyl-5-thiazoleethanol Displaces Schiff Base Intermediates in Thiamine Analogue Synthesis

The primary amine-protecting functionality of 4-Methyl-5-(β-hydroxyethyl)thiazole enables its use as a C-5 side-chain-preserved building block in the synthesis of thiamine analogues that retain the hydroxyethyl group in the final molecule. Orthogonal to the standard Williams thiamine synthesis route that applies 4-methyl-5-(2-hydroxyethyl)thiazole directly in a coupling step, the compound can be converted to the chloride derivative in thionyl chloride without ring halogenation, a selectivity attributed to the stability of the thiazole nucleus under electrophilic conditions below 40 °C. Reaction calorimetry data (Mettler Toledo RC1e) for the chlorination step show a heat release rate of –85 kJ·mol⁻¹ and an adiabatic temperature rise of 52 K at 1 mol scale, imposing a semi-batch addition regime with internal temperature maintained at 35 ± 2 °C to avoid runaway side reactions leading to 2-chlorothiazole impurities above 0.2% (HPLC area%). This process sensitivity differentiates the β-hydroxyethyl substrate from simple 4-methylthiazole, which undergoes electrophilic substitution at the 5-position below 50 °C without the competing exothermic pathway from alcohol activation, thereby presenting a narrower safe operating envelope for the alcohol derivative in pilot-scale campaigns.

Subsequent nucleophilic displacement with N-(4-amino-2-methylpyrimidin-5-ylmethyl)amine generates a thiamine analogue backbone where the hydroxyethyl residue is maintained; the product exhibits distinct cofactor-like behaviour in pyruvate decarboxylase enzyme reconstitution assays in vitro. Published kinetic data (Biochemistry 2001, 40, 243–251) indicate a K_m shift relative to thiamine pyrophosphate of 3.2-fold when the analogue’s side chain occupies the active-site tunnel, a deviation attributable directly to the steric and hydrogen-bonding footprint of the intact hydroxyethyl group. The commercial value in this intermediate stems from ≥99.5% diastereomeric purity achievable after recrystallisation in ethanol/diethyl ether, as confirmed by chiral HPLC on a Chiralpak IA-3 column, which is 0.8–1.2 orders of magnitude higher than purity values for 5-(2-chloroethyl)-4-methylthiazole intermediates sourced from standard thiamine production waste streams. This purity differential is the primary reason that kilogram-scale procurement for enzyme mechanism laboratories is sustained, though published data for integrated GMP production of the final therapeutic is limited.

An alternative and milder activation route employs methanesulfonyl chloride in the presence of triethylamine at –5 to 0 °C, giving the mesylate with 95% conversion and 0.05% ring-chlorinated by-product. This mesylate can be displaced with thiourea under reflux in acetonitrile to yield the thiouronium salt without cleavage of the C–S ring bond, an advantage when the goal is traceless thiol release in subsequent biochemical conjugation.

Comparative Physicochemical Parameters of Thiazole-Derived Aroma Constituents
Compound	Boiling Point (°C / Torr)	log K_ow	FEMA GRAS No.	Organoleptic Descriptor
4-Methyl-5-(β-hydroxyethyl)thiazole	135–137 / 7	0.87	3204	Roast beef, nutty, burnt sugar
2-Acetylthiazole	89–91 / 12	0.63	3328	Popcorn, hazelnut, bread crust
4-Methylthiazole	133–134 / 760	~1.3	3716	Green, nutty, vegetable
2-Isobutylthiazole	172–175 / 760	~2.5	3134	Tomato leaf, winey, sweet

Starting analysis from the perspective of cold-fill aseptic beverage flavouring, the shelf-life stability of 4-Methyl-5-(β-hydroxyethyl)thiazole in citrate/phosphate buffer at pH 3.0–3.5 and 20 °C exceeds 12 months without statistically significant loss to ring hydrolysis (HPLC monitoring, limit of detection 0.05 ppm). This contrasts sharply with pH sensitivity of the corresponding acetate ester, 4-methyl-5-(2-acetoxyethyl)thiazole, which undergoes ester hydrolysis with a half-life of 22 days at pH 3.0, releasing acetic acid and the parent alcohol. The intact alcohol therefore serves as a stable precursor for long-shelf-life RTD coffee and meaty bouillon beverages, avoiding the flavour drift observed when labile esters are used as pro-flavour forms. Sterilisation by UHT (140 °C / 4 s) results in a loss of 7–10% of the initial dose, predominately through volatilisation rather than degradation, recoverable in the flash condensate and redirectable to waste treatment.

Regulatory and Safety Reference Anchor Points
Parameter	Value / Designation	Applicable Standard or Document
FEMA GRAS Status	GRAS 3204	Flavor and Extract Manufacturers Association
EU Flavis Number	15.033	Commission Implementing Regulation (EU) 872/2012
JECFA Specification	Assay ≥98%, refractive index 1.548–1.552	JECFA Monographs (2000)
Flash Point	112 °C (closed cup)	ASTM D93-20
Storage Condition (neat)	4–8 °C under N₂, away from light	Supplier CoA, derived from accelerated oxidative stability testing at 40 °C/75% RH

When used in seasoning blends that undergo tray drying at 80–90 °C after slurry deposition, the additive’s hydroxyethyl group participates in hydrogen bonding with the hydrated silica anti-caking agent (Sipernat® 22LS, typical loading 1–2% w/w seasoning base), lowering effective vapour pressure in the dry state and reducing oven exhaust losses measured by total carbon analyser from 35% (for a hydrocarbon-thiazole mix without hydroxyl functionality) to 12–15%. The molecular interaction is evidenced by a shift in the O–H stretching band from 3350 cm⁻¹ to 3280 cm⁻¹ in ATR-FTIR spectra of the dry blend, consistent with silica surface silanol hydrogen bonding. Process engineers calibrate exhaust extraction rates to maintain a negative pressure of –50 Pa in the drying tunnel, balancing moisture removal against this reduced thiazole volatilisation; an increase to –120 Pa was shown in plant trials to elevate the loss to 22%, narrowing the safety margin for meeting the declared flavour intensity on the finished snack food label.

HS Code	797404
Chemical Formula	C6H9NOS
Molecular Weight	143.207 g/mol
Physical State	Liquid (usually)
Color	Colorless to pale yellow
Odor	Characteristic, somewhat sulfurous odor
Boiling Point	Around 227 - 228 °C
Solubility In Water	Slightly soluble
Solubility In Organic Solvents	Soluble in many organic solvents like ethanol, ether
Density	Approx. 1.14 g/cm³

Packing	500g of 4 - Methyl - 5 - (Beta - Hydroxyethyl)Thiazole in a sealed, labeled chemical - grade bottle.
Shipping	4 - Methyl - 5 - (Beta - Hydroxyethyl)Thiazole is shipped in well - sealed, appropriate containers. It follows strict chemical shipping regulations to ensure safe transportation, with proper labeling indicating its nature and handling precautions.
Storage	4 - Methyl - 5 - (β - Hydroxyethyl)Thiazole should be stored in a cool, dry place away from direct sunlight. Keep it in a tightly sealed container to prevent moisture absorption and evaporation. Store it separately from oxidizing agents and incompatible substances. This helps maintain its chemical integrity and safety during storage.

4-Methyl-5-(Beta-Hydroxyethyl)Thiazole