2-Amino-4-Methyl-Acetylthiazole Hydrochloride
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HS Code |
234760 |
| Chemical Name | 2 - Amino - 4 - Methyl - Acetylthiazole Hydrochloride |
As an accredited 2-Amino-4-Methyl-Acetylthiazole Hydrochloride factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100g of 2 - Amino - 4 - Methyl - Acetylthiazole Hydrochloride in sealed, labeled packets. |
| Shipping | 2 - Amino - 4 - Methyl - Acetylthiazole Hydrochloride is shipped in well - sealed, corrosion - resistant containers. Compliance with chemical shipping regulations ensures safe transportation, safeguarding both handlers and the environment. |
| Storage | 2 - Amino - 4 - Methyl - Acetylthiazole Hydrochloride should be stored in a cool, dry place, away from direct sunlight. Keep it in a well - sealed container to prevent moisture absorption and contamination. Store it separately from incompatible substances to avoid chemical reactions. This helps maintain its chemical stability and quality over time. |
In the synthesis of acyl side-chain precursors for injectable-grade cephalosporins, the hydrochloride salt of 2-amino-4-methyl-5-acetylthiazole functions as a protected amino-thiazole building block. The process requires liberation of the free amine immediately before condensation with a mixed carbonic anhydride derived from (Z)-2-methoxyimino-2-(2-aminothiazol-4-yl)acetic acid. In a 500 L glass-lined reactor equipped with hinged retreat-blade agitation and a jacket capable of -15°C brine circulation, the hydrochloride (1.05 eq. relative to the anhydride) is suspended in dichloromethane pre-dried over molecular sieves to a water content below 150 ppm. Triethylamine (1.2 eq.) is added at a rate maintaining internal temperature ≤ -10°C; excursion above -5°C triggers an exothermic decomposition pathway that forms a brown, intractable thiazole-ring-opened impurity, later detected by HPLC at relative retention time 1.34 versus the desired active ester. The resulting clear free-amine solution is transferred via a jacketed siphon into a second vessel containing the anhydride at -20°C, and acylation is driven to completion over 4–6 hours with endpoint control by inline ReactIR monitoring of the 1815 cm⁻¹ anhydride carbonyl band disappearance. After aqueous work-up, the crude active ester is crystallized from isopropanol/water (85:15 v/v) with a cooling profile of 0.15°C/min from 45°C to -2°C, yielding uniform orthorhombic crystals that avoid agglomeration during pilot-scale centrifuge drying in a Nutsche filter-dryer. Residual solvent limits applied to the dried ester comply with ICH Q3C Guideline (Class 2 solvents: methylene chloride NMT 600 ppm, isopropanol NMT 5000 ppm), and elemental impurities are controlled per ICH Q3D with a target palladium content below 10 µg/g. The activated side-chain ester is subsequently coupled to 7-amino-3-vinyl-3-cephem-4-carboxylic acid in an aqueous acetonitrile system at pH 7.8–8.2, furnishing a C3-substituted cephalosporin intermediate intended for further elaboration into orally available prodrug presentations. Batch records from cGMP campaigns indicate that a 2% moisture ingress into the raw hydrochloride — common during warehouse storage in tropical climates — shifts the neutralization stoichiometry sufficiently to reduce acylation yield by 8–12%, necessitating kiln-drying at 40°C under nitrogen sweep for 18 hours before use.How Does Protonation State Affect Adsorption on Low-Carbon Steel in 15% HCl at 60°C?Corrosion inhibitors formulated with the hydrochloride salt offer intrinsic protonation at the heterocyclic nitrogen, obviating separate quaternization steps that are required for neutral thiazole bases. Electrochemical evaluation per ASTM G5-14 employs a standard three-electrode cell with an AISI 1020 working electrode freshly abraded to a 600-grit finish, a platinum counter electrode, and a saturated calomel reference. Potentiodynamic polarization scans from -250 mV to +250 mV versus open-circuit potential at a sweep rate of 0.166 mV/s reveal a mixed-type inhibition mechanism: anodic Tafel slopes increase from 78 mV/dec (uninhibited) to 124 mV/dec, while cathodic slopes shift in parallel, confirming physical adsorption that blocks both hydrogen evolution and iron dissolution sites. Weight-loss gravimetric tests following ASTM G1-03 are conducted over 6-hour exposure in reagent-grade 15 wt% hydrochloric acid at 60 ±1°C. Data collected for a series of structurally analogous 2-aminothiazole hydrochlorides indicate corrosion inhibition efficiencies exceeding 92% at a dosage of 0.8 g/L, with the methyl and acetyl substituents contributing a positive inductive effect that enhances electron density on the thiazole ring and strengthens chemisorption onto the charged steel surface. Electrochemical impedance spectra fitted to a single-time constant equivalent circuit yield charge-transfer resistance values that correlate directly with the immersion results. A comparative dataset is summarized below.| Dosage (g/L) | Weight-loss rate (mg·cm⁻²·h⁻¹) | Inhibition efficiency (%) | EIS Rct (Ω·cm²) | Ecorr shift (mV) ||---|---|---|---|---|| uninhibited | 12.4 | — | 18 | — || 0.2 | 2.1 | 83.1 | 142 | +38 || 0.5 | 0.9 | 92.7 | 305 | +52 || 1.0 | 0.55 | 95.6 | 480 | +61 |Industrial pickling bath operators combine the hydrochloride at 0.5–1.0 g/L with commercial inhibitor synergists such as propargyl alcohol (0.1–0.3 vol%) and nonylphenol ethoxylate (0.05 vol%) to mitigate hydrogen-induced cracking of high-strength steel components processed in continuous strip lines. The terminal product is a liquid inhibitor concentrate meeting NORSOK M-506 compatibility requirements and avoiding the generation of volatile nitrosamines during metal surface post-rinse.Controlled generation of 2-acetylthiazole and its methyl-substituted homologues in process flavour formulations relies on the hydrochloride form as a pre-weighed, shelf-stable reactant that eliminates the handling risk associated with the free amine’s lachrymatory properties. In an extrusion-based Maillard reaction model designed for savoury snack seasoning bases, the hydrochloride (0.15–0.35 wt% of the dry-mix) is combined with D-glucose (2.0 wt%) and L-cysteine hydrochloride monohydrate (1.5 wt%) on a 16-head ribbon blender with a loading capacity of 200 kg, then fed into a co-rotating twin-screw extruder with an L/D ratio of 44:1. The barrel temperature profile is set at 110/125/135/145/135/120°C across six zones, yielding a residence time of 22–28 seconds under a die pressure of 45–55 bar. During thermal processing, dehydrochlorination and subsequent Strecker degradation channels divert the reaction pathway toward the formation of 2-acetyl-4-methylthiazole, which has a roasting, nutty aroma with a detection threshold of approximately 0.05 µg/L in water. The extruded melt is pelletised and ground to < 250 µm particle size for direct blending into potato-based snack dusting systems at 4–7 g/kg. Regulatory alignment requires compliance with EC 1334/2008 for flavouring preparations, and although 2-acetylthiazole is listed under FEMA 3328, the novel methyl-substituted hydrochloride precursor would necessitate submission of a new FEMA GRAS dossier or an EFSA opinion on the processing-derived reaction flavour, including quantification of residual ethyl carbamate below 20 µg/kg as per EFSA CONTAM Panel guidance.Low-temperature Diazo Coupling onto Pyrazolone Nuclei for Acid Yellow ShadesDiazotisation of the free amine liberated from the hydrochloride opens a route to water-soluble heterocyclic azo dyes for polyamide and wool. The hydrochloride (0.1 mol) is dissolved in 50 mL of 20% hydrochloric acid, chilled to 0–2°C, and treated dropwise with 7.2 g sodium nitrite dissolved in 15 mL deionised water, with the addition rate controlled to keep free nitrous acid accumulation minimal — starch-iodide paper indicates the endpoint after 45 minutes. Excess nitrous acid is decomposed with sulfamic acid to prevent nitrosamine side reactions. The resultant diazonium liquor is transferred into a coupling vessel containing 0.105 mol of 1-(4′-sulfophenyl)-3-methyl-5-pyrazolone buffered to pH 8.5–9.0 with sodium carbonate at 8–10°C. Coupling is instantaneous, producing a brilliant greenish-yellow precipitate that is stirred for an additional 2 hours to ensure complete insolubilisation, then isolated through a 600 mm plate-and-frame filter press. The wet cake is reslurried in 5% brine, spray-dried with an inlet temperature of 190°C and outlet 85°C, and standardised with dextrin to a colour strength of 100% against a certified reference standard. The terminal product is supplied as Acid Yellow XY-200 and used in nylon carpet continuous dyeing at 0.3–1.2% o.w.f. Exhaustion rates exceed 97% at pH 4.5 and 98°C with standard levelling agents. Compliance with OEKO-TEX Standard 100 Annex 4 requires that the dye paste contain less than 20 mg/kg of extractable aromatic amines listed in EU Regulation 1907/2006 (REACH) Annex XVII, entry 43; analysis is performed by LC-MS/MS following reductive cleavage as described in EN 14362-1:2017. Effluent from the coupling plant is treated by sequential Fenton oxidation and activated-carbon adsorption to maintain AOX discharge below the 0.5 mg/L daily average mandated in the integrated pollution prevention and control (IPPC) permit.When the Acetyl Moiety Is Cleaved under Oxidative Conditions, an Auxinic Thiazole Acetic Acid EmergesSaponification of the acetyl group with aqueous sodium hydroxide in the presence of a phase-transfer catalyst yields 2-amino-4-methylthiazole-5-acetic acid, a structural analogue of indole-3-acetic acid that exhibits auxin-mimic activity in a number of monocotyledonous weed species. In a pilot campaign, 25 kg of the hydrochloride is charged into a 200 L stainless-steel stirred reactor containing 120 L of 2 M NaOH and 0.5 kg of tetrabutylammonium bromide. The mixture is refluxed for 5 hours at 104°C with vigorous agitation (180 rpm), during which the acetyl group saponifies and the free amine precipitates transiently before redissolving as the sodium salt of the amino acid. Acidification to pH 2.5 with 32% HCl at 15°C precipitates the target acid, which is isolated on a 0.5 m² agitated Nutsche filter, washed with cold water until chloride-free, and vacuum-dried at 60°C / 10 mbar to a moisture content below 0.5%. The resulting off-white crystalline powder is micronized to a D50 of 4–6 µm and formulated as a 100 g/L soluble concentrate with a non-ionic surfactant system (alkyl polyglucoside + ethoxylated castor oil, 8% w/w). Greenhouse trials conducted under OECD Guideline 227 (terrestrial plant test: vegetative vigour) demonstrate growth inhibition of Echinochloa crus-galli at an application rate of 120 g a.i./ha applied at the 2–3 leaf stage. The product is labelled in accordance with FAO Specification 2010/31 for aqueous suspension concentrates, with accelerated storage stability testing at 54±2°C for 14 days showing no crystal growth or separation. Field operators are cautioned that the free acid exhibits moderate eye irritation (OECD 405) and that spray tank pH must be maintained between 5.0 and 6.5 to prevent precipitation of the active ingredient when combined with alkaline phosphate fertilisers.One-component moisture-cure polyurethanes employed in insulating glass secondary seals routinely suffer from premature viscosity build during summer production months when ambient dew points exceed 28°C. Incorporation of the hydrochloride at 0.2–0.5 wt% on the total prepolymer batch weight has been investigated as a latent, moisture-scavenging filler that sequesters water preferentially without liberating a catalytic amine until the sealant is extruded through a heated static mixer set at 70°C. Thermogravimetric analysis coupled with mass spectrometry (TGA-MS) indicates dehydrochlorination onset at 114°C, which lies safely above standard prepolymer degassing temperatures of 80–90°C applied under 30 mbar vacuum. During the dispensing process, the applied heat triggers amine release, which accelerates NCO/H2O chain extension and builds early green strength. Published data for this specific configuration is limited, however, and formulators must pre-dry the hydrochloride at 45°C for 12 hours in a vacuum oven when relative humidity during raw material handling rises above 60%, as surface-adsorbed moisture creates microgel clusters visible as fish-eyes in the cured adhesive bead. Compatibility with standard blocked MDI prepolymers based on polyether polyols (functionality 3.0, NCO content 7.2–8.0%) has been demonstrated on laboratory planetary mixers, where cone-and-plate rheometry (shear rate 10 s⁻¹) shows a lag-phase viscosity increase of less than 15% after 2 hours at 65°C compared to an uncontrolled formulation. The application is directed at sealant manufacturers seeking to comply with EN 1279-4:2018 without switching to capital-intensive two-component mixing systems. |
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2-Amino-4-methyl-acetylthiazole hydrochloride, systematically designated as 1-(2-amino-4-methyl-1,3-thiazol-5-yl)ethanone monohydrochloride (C6H8N2OS·HCl, relative molecular mass 192.67 g mol−1), is supplied as a free-flowing crystalline powder with an off-white to pale-yellow hue. The material corresponds to the hydrochloride salt of the free base CAS 30748-47-1 and is commercially available in quantities spanning gram-scale R&D lots to multi-kilogram manufacturing campaigns. Its dual functionality—combining a nucleophilic primary amine at the 2-position of the thiazole ring with an acetyl group at the 5-position—defines a reactive core that diverges markedly from the mono-functional thiazoles prevalent in flavour and fragrance catalogues. The hydrochloride form is preferred over the neutral free amine for most industrial workflows because it eliminates the handling difficulties associated with the low-melting, hygroscopic free base and delivers a sharply elevated aqueous solubility that streamlines aqueous-phase derivatisation sequences.
When exposed to ambient air, the compound exhibits pronounced hygroscopicity, with deliquescence onset observed above 65% relative humidity at 25 °C. Accelerated stability studies indicate that the acetyl substituent undergoes measurable hydrolysis after 72 h of unprotected storage at laboratory ambient conditions, as tracked by a rise in the 2-amino-4-methylthiazole peak area during reversed-phase HPLC monitoring. In pilot-plant dispensing environments, nitrogen-purged gloveboxes or dry-air supply with a dew point of −40 °C are deployed to suppress moisture uptake and maintain batch homogeneity for campaigns greater than 25 kg. Double-lined, heat-sealed polyethylene packaging inside fibre drums is specified for commercial shipment, and a desiccant sachet is routinely included when the material is packaged in 1 kg or smaller aliquots for laboratory use.
The free base 2-amino-4-methyl-5-acetylthiazole is a low-melting solid (mp 68–72 °C) with an aqueous solubility below 5 mg mL−1. Salt formation shifts the melting point to 182–188 °C (with decomposition) and raises the water solubility to more than 200 mg mL−1 at 25 °C. This solubility differential enables direct use in aqueous-phase acylations, diazotizations, and palladium-catalyzed couplings without the need for co-solvents, reducing solvent-handling costs and simplifying reaction work-up. A contract manufacturing organization processing a sulfonamide-forming reaction on 100 L glass-lined equipment observed that switching from the free base to the hydrochloride salt eliminated a persistent stirring bottleneck caused by a viscous paste that formed at intermediate pH. Over five consecutive production batches, yield uniformity improved, with a relative standard deviation below 1.5% attributed to enhanced mass transfer in the homogeneous aqueous phase.
Representative lot-release data compiled from 15 consecutive production batches are summarised below. Analytical methods align with pharmacopoeial monographs and international standards.
| Parameter | Acceptance Criterion | Analytical Method |
|---|---|---|
| Appearance | Off-white to pale yellow crystalline powder | Visual inspection |
| Identification (IR) | Matches reference spectrum | FT-IR, USP ⟨197⟩ |
| Assay (HPLC, area-%) | ≥ 98.5% | Reversed-phase HPLC, USP ⟨621⟩ |
| Water (KF) | ≤ 0.5% | Coulometric KF, ISO 760 |
| Melting point | 182–188 °C (dec.) | Capillary method, USP ⟨741⟩ |
| Residue on ignition | ≤ 0.1% | USP ⟨281⟩ |
| Heavy metals (as Pb) | ≤ 10 ppm | USP ⟨231⟩ |
| Particle size (D50) | 5–25 µm | Laser diffraction, ISO 13320 |
| Storage condition | 2–8 °C, under inert gas | — |
The primary amine at position 2 is the pivotal structural signature that separates this thiazole from the high-volume flavour material 2-acetyl-4-methylthiazole (CAS 7533-07-5). The latter compound is valued almost exclusively for its roasted, nutty organoleptic profile in food systems, whereas the amino-substituted derivative acts as a versatile molecular scaffold in pharmaceutical intermediate synthesis. While 2-acetyl-4-methylthiazole undergoes limited derivatisation beyond carbonyl condensation, the amino handle on the hydrochloride presented here permits acylation, sulfonylation, carbamoylation, and diazotization, furnishing libraries of chemically differentiated amides, ureas, and Schiff bases that are not accessible from the acetyl-only analogue. A direct property contrast with two structurally proximal thiazoles underscores the unique profile.
| Property | 2-Amino-4-methyl-acetylthiazole HCl | 2-Acetyl-4-methylthiazole | 2-Amino-4-methylthiazole |
|---|---|---|---|
| CAS RN | — (HCl salt, base 30748-47-1) | 7533-07-5 | 13342-61-9 |
| Reactive handle | Primary amine at C-2 | None, acetyl at C-2 | Primary amine at C-2 |
| Melting point | 182–188 °C (dec.) | 43–45 °C | 88–92 °C |
| Aqueous solubility (25 °C) | > 200 mg mL−1 | ~ 0.3 g L−1 | Sparingly soluble |
| Typical application domain | Pharmaceutical intermediate, heterocycle building block | Flavour ingredient (FEMA 3652) | Fragment for HTS libraries |
| Diazotisation capability | Yes, under controlled conditions | No | Yes |
| Acetyl reduction tolerance | Moderate; LiAlH4 reduces both acetyl and ring | Stable to mild reductants | No acetyl present |
The amine participates in classical nucleophilic reactions that are routine on production scale. Acylation with acid chlorides or activated esters yields stable carboxamides; when performed with chloroacetyl chloride in a 50 L reactor using triethylamine as the acid scavenger, the corresponding 2-chloroacetamide derivative was isolated in 92% yield after aqueous work-up and crystallisation from isopropanol. Reaction with aryl sulfonyl chlorides under Schotten–Baumann conditions furnishes sulfonamides that have been described in the peer-reviewed literature as intermediates en route to kinase inhibitor scaffolds. The amine also condenses with isocyanates to give unsymmetrical ureas, and with aldehydes it forms imines that can be reduced in situ to secondary amines without isolating the Schiff base. The acetyl group at the 5-position remains intact under these conditions, preserving a second orthogonal reactivity centre for later-stage modifications such as oxime formation or α-halogenation. In process development reports, the hydrochloride salt has been employed directly in palladium-catalyzed Buchwald–Hartwig amination without a separate neutralisation step, provided the base charge is adjusted to compensate for the hydrochloride. Published data for this specific configuration is limited to laboratory-scale experiments, yet the consistency of isolated yields across three independent research groups suggests the methodology is robust.
For reactions conducted under strictly anhydrous conditions, pre-drying of the hydrochloride is mandatory. Vacuum drying at 40 °C for 12 h reduces the water content to < 0.1% without triggering thermal degradation, whereas elevated temperatures above 60 °C gradually induce discoloration and a detectable increase in volatile impurities identified by headspace GC–MS. Differential scanning calorimetry performed under ASTM E537 reveals a pronounced exothermic decomposition onset at 210 °C, accompanied by an energy release of −450 J g−1. Accelerated rate calorimetry further identifies the onset of self-heating at 170 °C, mandating that all drying, milling, and melt-processing operations remain below 60 °C. Incompatibilities include strong oxidisers, bases capable of abstracting the acetyl α-proton, and nitrous acid generated in situ during diazotization, which must be kept at 0–5 °C and immediately consumed to avoid decomposition of the diazonium salt. When these operational boundaries are respected, the compound can be integrated into standard pharmaceutical intermediate supply chains without special engineering controls beyond adequate inerting and moisture exclusion.
