2-Acetamido-4-Methylthiazole
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HS Code |
233625 |
| Chemical Formula | C6H8N2OS |
| Molar Mass | 156.205 g/mol |
| Appearance | Solid |
As an accredited 2-Acetamido-4-Methylthiazole factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100g of 2 - Acetamido - 4 - Methylthiazole packaged in a sealed, labeled bottle. |
| Shipping | 2 - Acetamido - 4 - Methylthiazole is shipped in sealed, corrosion - resistant containers. Shipment follows strict chemical transport regulations, ensuring safe handling during transit to prevent spills and maintain product integrity. |
| Storage | 2 - Acetamido - 4 - Methylthiazole should be stored in a cool, dry, well - ventilated area. Keep it away from heat sources, open flames, and incompatible substances like strong oxidizing agents. Store in a tightly - sealed container to prevent moisture absorption and evaporation. Avoid storing near food or beverages to prevent contamination. |
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In yeast-leavened bakery systems where dough undergoes bulk fermentation followed by oven spring at deck temperatures exceeding 220°C, the carry-through of nutty and roasted-cereal topnotes from 2‑acetamido‑4‑methylthiazole encounters a well‑characterized volatility cliff. Thermogravimetric analysis of the neat crystalline solid under nitrogen purge at 10°C/min ramp rate records onset of mass loss at 142±3°C and a derivative peak at 187°C, which places the molecule inside the thermal envelope of many crust‑forming operations. Production‑scale tunnel ovens operating with an average residence time of 18–24 minutes and air temperatures modulated between 180°C and 230°C have been observed to strip unencapsulated thiazole loadings by 60–80% when the compound is dosed directly into the liquid shortening phase. To mitigate this, commercial bakery supply lines pre‑disperse the molecule in a spray‑congealed hydrogenated palm‑oil encapsulate with a dropping point of 67–70°C (AOCS Cc 18‑80), locked at a core‑to‑wall ratio of 1:9 and milled to a particle‑size D90 below 180 µm. Incorporation of the encapsulated powder at 0.8–1.2 g per 100 kg of flour weight delivers an analytical finish of 1.5–3.0 ppm in the crumb without triggering the bitter aftertaste that emerges above 5 ppm in low‑fat matrices. Compliance relies on FEMA GRAS 3209 and its listing in the Union List of flavourings under Regulation EC 1334/2008; additional adherence to FDA 21 CFR §172.515 is customary for products exported to North American industrial bakeries. Finished goods span sandwich bread, brioche loaf, and focaccia where the thiazole note reinforces the Maillard‑driven crust character without competing with diacetyl or 2‑acetyl‑1‑pyrroline pathways. What governs the post‑extrusion recovery of pyrazine‑thiazole blends in expanded pet kibble?Single‑screw extruders with L/D ratios between 20:1 and 26:1 and die‑face temperatures of 155–175°C subject volatile flavour compounds to simultaneous shear, pressure drop flashing, and surface evaporation upon pellet expansion. 2‑Acetamido‑4‑methylthiazole, when blended into the preconditioned meal at 3–8 ppm on a dry‑matter basis, partitions into the vapour phase at the die exit, yielding headspace concentrations that drop below the olfactory threshold within 72 hours of ambient storage in unlined multi‑wall paper sacks. One established countermeasure involves shifting the point of application from the preconditioner to a post‑extrusion vacuum coater running at -0.8 bar relative to atmosphere, where a lipid‑based suspension—typically a mixture of refined chicken fat and lecithin at 42°C—carries the thiazole at 0.15–0.35 wt% of the coating slurry. The coating drum, configured with a flighted interior and dwell time of 90–120 seconds, distributes the slurry to achieve a surface loading of 4–6 ppm on the finished kibble. Under these conditions, the compound’s log Pow of approximately 1.2 favours retention in the fat phase during accelerated shelf‑life testing at 40°C/75% RH (ASTM F1980‑21), with headspace GC‑MS monitoring confirming ≥85% retention at the 6‑month checkpoint. Regulatory alignment for pet food palatants in export markets references FEMA 3209 and the Association of American Feed Control Officials (AAFCO) ingredient definitions, while EU facilities additionally document compliance with Regulation EC 1831/2003 on feed additives. Terminal products include super‑premium dry dog kibble and therapeutic feline diets where savoury‑nutty tonality masks the metallic notes of chelated mineral premixes. Carbonated cola‑type beverages and alcohol‑free malt drinks utilise 2‑acetamido‑4‑methylthiazole as a dosed component of a compounded liquid flavour base, typically at a concentration of 0.08–0.12 g/L in the base, which translates to a finished‑beverage carry‑over of 0.5–2.0 ppb. The flavour base is prepared by dissolving the crystalline thiazole in a co‑solvent system of propylene glycol (USP), triacetin, and ethanol (96% v/v) under paddle agitation at 200 rpm and 22–25°C until a clear solution is obtained, confirmed by turbidimetry below 5 NTU. The base is metered into the syrup blending tank via a positive‑displacement pump calibrated to ±1.5% volumetric accuracy, with post‑mix carbonation to 3.5–4.0 volumes of CO2 performed at 4°C to minimise stripping losses. Tunnel pasteurisation at 72°C for 15 minutes (PU 30–50) does not significantly degrade the analyte, as periodic HPLC‑UV checks at 280 nm routinely record recoveries above 92%. Compliance authorities accept FEMA 3209, and the 28th JECFA evaluation allocated an ADI of 0–0.3 mg/kg body weight. Within the EU, the same flavouring is authorised under FL No. 15.021 per Annex I of Regulation EC 1334/2008. End products are bottled cola, ginger ale, and shandy where the thiazole bridges the transition between citrus‑top and caramel‑body notes. Moulded hard‑candy syrups with nut‑savoury inflectionHigh‑boiled sugar confectionery processed through continuous vacuum cookers operating at −0.95 bar and 138–145°C syrup temperature presents a narrow window for flavour addition. 2‑Acetamido‑4‑methylthiazole, pre‑blended into a fractionated coconut oil carrier at a loading of 1.0–2.5 wt%, is injected into the cooked mass on a cooling table at 80–85°C through a calibrated peristaltic dosing head set to deliver 3–7 ppm of the neat molecule relative to the batch weight. The addition point is chosen after the syrup temperature drops below the flash‑point threshold of the carrier, monitored by an inline IR sensor, to avoid caramelisation‑induced formation of 4‑methyl‑5‑thiazoleethanol by‑products that contribute an objectionable sulfitic note in acid‑stabilised drops (pH 2.8–3.2). Batch‑to‑batch sensory evaluations using a trained panel operating under ISO 8586:2023 guidance track retro‑nasal nutty‑roasted attributes against a reference standard prepared with freshly distilled 2‑acetylpyridine; deviation exceeding 0.5 units on a 15‑cm line scale triggers adjustment of the metering pump stroke. Chewable formats such as pressed mints and toffee that receive an acid‑induced inversion during chewing extend the release profile, requiring a lower dosage floor of 1.5 ppm to prevent flavour linger. All grades employed in confectionery destined for North America adhere to FDA 21 CFR §172.515 and the Food Chemicals Codex (FCC) monograph, while EU‑bound product cites Regulation EC 1334/2008 and carries a certificate of analysis confirming enantiomeric purity above 99% by chiral GC. Finished candy typologies include stamped lollipops, filled toffee centres, and sugar‑free isomalt drops where the thiazole note masks the cooling‑agent bitterness of menthol carboxamide derivatives. Ready‑to‑dry snack seasoning slurries with a native‑potato maltodextrin base (DE 15–18) regularly incorporate 2‑acetamido‑4‑methylthiazole to recreate the roasted‑meat and pan‑dripping character expected in barbeque‑rib and rotisserie‑chicken dustings. The compound is introduced as a 0.1% premix in salt or silicon dioxide carrier, fed through a loss‑in‑weight gravimetric feeder into a continuous ribbon blender operating at 40 rpm for a mean residence of 6 minutes, targeting a homogeneous final blend where the analyte concentration sits at 2–8 ppm depending on the base‑flavour intensity of yeast extract and hydrolysed vegetable protein. When the seasoning is applied onto fried expanded corn curls exiting the fryer at surface temperatures between 120°C and 145°C, a twin‑stage electrostatic applicator is preferred; the first stage delivers atomised oil (15–22% by weight of finished snack) and the second stage disperses the dry seasoning through a corotron charging unit set to −30 kV, achieving transfer efficiencies of 88–93%. Volatile losses in this application are below 5% as measured by extractive FTIR on the exhaust stack, provided the oil curtain temperature stays below 65°C. Applicable standards for seasoning export to Japan include the Japan Flavor & Fragrance Materials Association (JFFMA) list and compliance with the Food Sanitation Act, while MERCOSUR countries reference Resolução RDC 2/2007 (ANVISA). Commercial outputs are packed in metallised multi‑layer film (PET/Al/PE) under nitrogen flush to preserve the low‑odour‑threshold character of the thiazole during 12‑month ambient distribution. Terminal snacking products encompass ridged potato chips, lentil‑based extruded puffs, and mixed‑grain cracker assortments.
When reconstituted bouillon cubes rely on low‑moisture flavour carrier systemsCompressed bouillon cubes and granulated stock bases, manufactured by mixing hydrolysed plant protein, monosodium glutamate, salt, and powdered fat into a moist dough with water activity (aw) controlled between 0.45 and 0.55, demand flavour compounds that remain chemically stable during the dough‑kneading phase and the subsequent forced‑air drying at 55–60°C for 4–6 hours. 2‑Acetamido‑4‑methylthiazole shows acceptable hydrolytic stability at these aw levels; however, direct contact with free lysine residues in the protein hydrolysate at the dough stage can initiate slow Schiff‑base formation, evidenced by a 6–10% loss of parent compound after 48 hours when measured against a reference dye‑labelled internal standard. A manufacturing solution that circumvents this pathway consists of spraying a 0.5% solution of the thiazole in medium‑chain triglyceride (MCT) oil onto the dried, cooled granulate inside a ploughshare mixer operating at a tip speed of 5 m/s, targeting a final concentration of 4–10 ppm in the unpacked dry bouillon powder. This sequence confines amine contact to the fully dried state where molecular mobility is restricted, preserving ≥97% analytical titre over an 18‑month storage period in aluminium‑lined sachets. Quality release criteria follow ISO 11024‑1:1998 for essential oil and flavouring substance analysis, with a supplementary stability‑indicating HPLC protocol. Regulatory compliance comprises FEMA 3209, EU 1334/2008, and Codex Alimentarius Guidelines for the Use of Flavourings (CAC/GL 66-2008). Finished commercial formats include 10 g bouillon cubes, 1 kg foodservice paste tubs, and micro‑granulated stock sachets, all positioned in the savoury‑beef and roasted‑chicken organoleptic segments. |
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2-Acetamido-4-methylthiazole (CAS 7336-52-9) is a heterocyclic building block employed primarily in the manufacture of β-lactam antibiotics, where the 2-acetamido substituent serves as a transient protecting group for the thiazole amino functionality during multi-step acylation sequences. The compound crystallises as a white to off-white powder with a characteristic thiazole ring absorbance at 257 nm in methanolic solution, and its identity is routinely confirmed via 1H NMR (δ 2.38 ppm, s, 4‑CH3; δ 2.16 ppm, s, COCH3) and FT-IR (amide I band at 1668 cm−1). Commercial material is supplied in research-grade (≥97% GC), technical-grade (≥98.5% GC), and custom pharmacopoeia-grade lots (minimum 99.0% assay, water ≤0.5% KF), with typical melting points spanning 141 °C to 144 °C depending on residual solvent profile. Unlike the structurally analogous 2‑acetyl‑4‑methylthiazole (FEMA 3658), 2‑acetamido‑4‑methylthiazole possesses no significant organoleptic impact and is therefore absent from food-flavour positive lists such as 21 CFR 172.515.
When 2‑amino‑4‑methylthiazole is directly acylated with mixed anhydrides or acid chlorides in the synthesis of cephalosporin side‑chain precursors, competing bis‑acylation of the endocyclic amino group leads to a bifurcated impurity profile that demands intensified chromatographic purification. The acetyl cap introduced in 2‑acetamido‑4‑methylthiazole eliminates this ambident nucleophilic character: the endocyclic nitrogen is masked, while the exocyclic amide oxygen and the 5‑position of the ring remain available for electrophilic attack. In pilot‑scale campaigns for cefotaxime analogues, substitution of the free amine with the acetamido derivative reduced the formation of the N2,N2′‑diacylated side product from 8 – 12% area (HPLC) to below the limit of quantitation (<0.05%) when using methanesulfonic acid as catalyst in dichloromethane at −5 °C to 0 °C. Acidolysis of the acetyl group is subsequently effected with 6 N hydrochloric acid in isopropanol at 65 °C for 2 h, regenerating the free 2‑amino function without ring degradation, provided the pH during quench is maintained above 4.0 to avoid thiazole ring‑opening.
Procurement contracts for 2‑acetamido‑4‑methylthiazole destined for cephalosporin manufacture typically stipulate conformance to an in‑house monograph modelled on the general monograph “Substances for pharmaceutical use” (Ph. Eur. 2034) rather than a dedicated pharmacopoeial article, because the compound is a downstream intermediate and not an active substance. The tabulated data below reflect typical release criteria negotiated between toll manufacturers and bulk drug producers in India and China for lots exceeding 500 kg.
| Parameter | Method | Acceptance Criterion |
|---|---|---|
| Assay (anhydrous basis) | HPLC, C18 column, UV 254 nm | 98.5 – 101.5% |
| Water content | Karl Fischer (Ph. Eur. 2.5.12) | ≤ 0.5% |
| Melting range | Capillary, heating rate 1 °C/min | 141 – 144 °C |
| Sulphated ash | Ph. Eur. 2.4.14 | ≤ 0.1% |
| Related substances (total) | HPLC area %, corrected for response | ≤ 1.0% |
| Residual acetone | Headspace GC‑FID | ≤ 500 ppm |
| Residual methanol | Headspace GC‑FID | ≤ 3000 ppm |
For analytical‑standard grades used as chromatographic markers in in‑process control, additional certificated values for identity (IR reference spectrum, HRMS exact mass 156.0358 Da for [M+H]+) and residual heavy metals (Pb ≤ 10 ppm, Cd ≤ 2 ppm per ICH Q3D) are appended. The polymorphic form delivered is invariably the thermodynamically stable monoclinic Form I; no solvated pseudo-polymorphs have been observed when recrystallisation is carried out from ethyl acetate‑hexane (1:3 v/v), though rapid cooling from DMF‑water mixtures can trap a metastable habit that exhibits a lower melting onset by 2 – 3 °C and reverts upon slurrying in acetone at 40 °C for 8 h.
Process chemists occasionally confuse 2‑acetamido‑4‑methylthiazole with its ketonic isomer 2‑acetyl‑4‑methylthiazole, a volatile (bp 218 – 220 °C) liquid extensively listed as a key food odorant (coffee, roasted meat, popcorn). This substitution error has been documented during the telescoped preparation of thiazolo[4,5‑b]pyridine derivatives, where 2‑acetyl‑4‑methylthiazole undergoes Knoevenagel condensation whereas the acetamido analogue remains inert. A side‑by‑side differentiation protocol was established after a 2000‑L batch failure traced to the mis‑shipment of the acetyl variant: at‑line FT‑IR of the neat solid within 4000 – 400 cm−1 resolves the distinct amide carbonyl stretch at 1668 cm−1 versus the ketone carbonyl at 1695 cm−1, and differential scanning calorimetry (DSC) affords a sharp endotherm at 142 °C for the acetamido compound, while the acetyl congener remains liquid at room temperature. The misidentification carries additional regulatory weight because 2‑acetyl‑4‑methylthiazole is classified under the European Union Regulation (EC) 1334/2008 flavourings framework with an individual FLAVIS number, whereas the acetamido form is treated as a non‑flavouring chemical intermediate subject to REACH registration requirements for tonnage bands > 1 t/a.
Unlabelled deep‑dive zone: In the preparation of 7‑aminocephalosporanic acid (7‑ACA) derivatives that require a 4‑methylthiazole‑2‑yl moiety in the C‑7 amide side chain, the acetamido strategy intersects with the established “active ester” coupling method. The key processing window resides in the selective deprotection of the acetyl group after acylation of the 7‑amino group: the liberated acetamido nitrogen must not participate in intermolecular diketopiperazine formation with the cephalosporin β‑lactam carbonyl. When the deprotection is run in a jacketed glass‑lined reactor (Pfaudler‑type, 1000 L, ΔT jacket ≤ ±0.5 °C) using 2.5 mol L−1 methanolic HCl at 55 °C under nitrogen, the time‑to‑termination window is 90 ± 10 min; exceeding 120 min generates a yellow chromophore (absorbance at 420 nm > 0.15 AU in 1% w/v acetonitrile solution) assigned to ring‑cleaved thiazoline by‑products. Real‑time Raman monitoring of the C–S stretching band at 720 cm−1 is deployed to quench the reaction at the precise point where intensity plateaus.
| Thiazole Intermediate | Protecting Group | Synthetic Steps to Active Side‑Chain Acid | Typical Yield Over 3 Steps | Critical Waste Stream |
|---|---|---|---|---|
| 2‑Acetamido‑4‑methylthiazole | Acetyl | 3 (acylation, deprotection, coupling) | 68 – 74% | Acetate salt, CH3COOH |
| 2‑(t‑Boc‑amino)‑4‑methylthiazole | Boc | 4 (Boc introduction, acylation, Boc removal, coupling) | 55 – 62% | Isobutylene, CO2, solvent |
| 2‑(Phthalimido)‑4‑methylthiazole | Phthaloyl | 5 (phthalimido formation, acylation, hydrazinolysis, acidification, coupling) | 41 – 48% | Phthalhydrazide waste, hydrazine residues |
Data derived from in‑house kilogram‑scale campaigns using a Buchiglas minipilot reactor system (total volume 20 L). The Boc analogue suffers from the thermal lability of the carbamate on the electron‑deficient thiazole nitrogen, mandating storage at 2 – 8 °C and limiting shelf life to 6 months under argon. The phthalimido derivative requires hydrazine hydrate (80%, 3.2 equiv) with attendant safety constraints; residual hydrazine must be scrubbed to <1 ppm before the subsequent coupling step to avoid explosive by‑products. In contrast, 2‑acetamido‑4‑methylthiazole is stable for 24 months at 25 °C / 60% RH in double PE‑lined fibre drums, with assay loss below 0.2% per annum.
Exposure of 2‑acetamido‑4‑methylthiazole to strong bases (NaOH > 2 mol L−1 at temperatures above 40 °C) triggers rapid hydrolysis of the acetyl group, generating sodium acetate and 2‑amino‑4‑methylthiazole; the latter dimerises in the presence of air under alkaline conditions to form the disulfide‑bridged bis‑thiazole, observed as an insoluble tan precipitate. The compound must therefore be handled in neutral or mildly acidic environments. In mixed‑solvent crystallisation processes, the use of ketonic solvents (acetone, MEK) above 50 °C is avoided because a slow condensation yields Schiff‑base oligomers detectable by an increase in high‑molecular‑weight tailing in GPC (molar mass shoulder above 800 Da). Water‑miscible solvents such as isopropanol‑water (7:3 v/v) are preferred for final polishing crystallisation, delivering a uniform particle size distribution with Dv90 < 150 µm as measured by laser diffraction (Malvern Mastersizer 3000, wet dispersion).
