2-Mercapto-4-Methyl-5-Thiazoleacetic Acid
|
HS Code |
513304 |
| Chemical Formula | C6H7NO2S2 |
| Molecular Weight | 189.26 g/mol |
| Appearance | White to off - white powder |
| Melting Point | 168 - 172 °C |
| Solubility In Water | Slightly soluble |
| Solubility In Organic Solvents | Soluble in some polar organic solvents like DMSO |
| Acidity | Weakly acidic due to carboxylic acid group |
| Pka Value | ~3 - 4 (estimated for carboxylic acid group) |
| Odor | Faint sulfur - like odor |
| Stability | Stable under normal conditions, but may react with strong oxidizing agents |
As an accredited 2-Mercapto-4-Methyl-5-Thiazoleacetic Acid factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 250 - gram bottle packaging for 2 - Mercapto - 4 - Methyl - 5 - Thiazoleacetic Acid. |
| Shipping | 2 - Mercapto - 4 - methyl - 5 - thiazoleacetic acid is shipped in well - sealed, corrosion - resistant containers. Special care is taken to ensure compliance with chemical transportation regulations to prevent leakage and ensure safety during transit. |
| Storage | 2 - Mercapto - 4 - methyl - 5 - thiazoleacetic acid should be stored in a cool, dry place, away from direct sunlight and heat sources. Keep it in a well - sealed container to prevent moisture absorption and contact with air, which could potentially lead to oxidation or other chemical changes. Store it separately from incompatible substances, following proper chemical storage regulations. |
Absence of a formal title marks the opening scenario. The downstream integration of 2-Mercapto-4-methyl-5-thiazoleacetic acid into the commercial synthesis of Cefditoren pivoxil hinges on the construction of the C3 (Z)-2-(4-methylthiazol-5-yl)ethenyl substituent via a sequential desulfurization–homologation–Wittig cascade. The acid is first suspended in tetrahydrofuran at a molarity of 1.2–1.5 M and treated with Raney nickel catalyst at a loading of 8–12 wt% relative to substrate at 50–55 °C under a hydrogen blanket of 0.4 MPa. This step affords 4-methyl-5-thiazoleacetic acid in typical isolated yields of 78–84% after charcoal decolorization and crystallization from methyl tert-butyl ether. The desulfurized intermediate is esterified with ethanol under Dean–Stark conditions (p-toluenesulfonic acid, 1.0 mol%, reflux, 6 h) and reduced with lithium aluminum hydride in diethyl ether at −10 °C to the corresponding alcohol. Swern oxidation at −60 °C then delivers the aldehyde, which is immediately telescoped into a Wittig olefination with (triphenyl-λ5-phosphanyl)methyl carboxylate ylide at −5 °C, generating the key C3 side-chain precursor with a (Z/E) ratio exceeding 98:2 as determined by HPLC (C18 column, acetonitrile/0.1% trifluoroacetic acid 45:55, 1.0 mL/min, detection at 254 nm). The resulting enantiomerically resolved side-chain acid chloride is coupled with the 7-amino-3-chloromethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester core under Schotten–Baumann conditions (sodium bicarbonate, acetone/water 3:1, 0–3 °C). The entire route is executed in ISO 8 (Class 100,000) cleanrooms under ICH Q7 GMP for active pharmaceutical ingredients, with batch records demonstrating residual nickel below the 5 μg/g threshold specified in the US Pharmacopeia monograph for Cefditoren Pivoxil. Tablet compression of the formulated pivoxil ester (wet granulation with croscarmellose sodium at 3.0% w/w, intragranular) targets a dissolution profile conforming to USP Apparatus 2 at 50 rpm in pH 6.8 phosphate buffer, with Q = 80% dissolved at 45 minutes.When the Thioether Linkage is Bypassed: Cefmatilen Hydrochloride and the Reductive Alkylation RouteAn alternative processing window arises in the production of Cefmatilen hydrochloride, an experimental oral cephalosporin whose C3 4-methylthiazol-5-yl-ethenyl motif is installed without preliminary desulfurization. Here the mercapto group of 2-Mercapto-4-methyl-5-thiazoleacetic acid is retained and exploited in a regioselective S-alkylation with the 3-chloromethyl cephem nucleus. The acid is converted to its sodium salt with 1.05 equivalents of sodium hydride in dimethylformamide at 0–5 °C, then alkylated with the cephem chloride in the presence of 0.5 mol% tetrabutylammonium bromide at 35 °C for 18 h. The resulting 3-(4-methyl-5-thiazolyl)thiomethyl intermediate undergoes a peri-selective Pummerer-type rearrangement triggered by 2.0 equivalents of m-chloroperoxybenzoic acid at −20 °C in dichloromethane, eliminating the sulfoxide to yield the desired exocyclic double bond with a typical yield of 61–67% over three steps. This route is particularly sensitive to trace water in dimethylformamide; Karl Fischer titration of the solvent must read below 120 ppm before use, or dialkylation by-products exceed 4.0% by HPLC area. The crystalline hydrochloride salt is isolated by antisolvent precipitation from methanol/acetone 1:4 v/v and dried in a conical vacuum dryer at 45 °C and 5 mbar for 12 h to achieve a residual solvent profile compliant with ICH Q3C Option 2 limits for Class 2 residual solvents. Analytical method transfer follows USP ⟨1225⟩ validation acceptance criteria, with forced degradation in 0.1 M HCl at 80 °C for 2 h confirming stability-indicating capability of the developed HPLC method. Sterile Cefditoren Sodium — Lyophilization Cycle Design and Subvisible Particulate ControlWhen the same 2-Mercapto-4-methyl-5-thiazoleacetic acid-derived side chain is conjugated to a sodium-salt cephem core intended for intravenous administration, the downstream processing shifts from oral solid dosage to aseptic lyophilization. The bulk active pharmaceutical ingredient is dissolved in water for injection at a concentration of 120 mg/mL (calculated as anhydrous free acid) and sterile-filtered through a 0.2 µm polyvinylidene fluoride membrane within an ISO 5 (Class 100) unidirectional airflow station. The filling needle is siliconized with a crosslinked polydimethylsiloxane emulsion to reduce shear-induced aggregation, and the target fill volume of 5.0 mL per 20 mL Type I glass vial is delivered with a peristaltic pump accuracy of ±0.8%. The lyophilization recipe applies a freezing ramp of 0.5 °C/min to −45 °C, held for 240 min, followed by primary drying at −20 °C and 0.15 mbar for 36 h, and secondary drying at 35 °C and 0.05 mbar for 8 h. Reconstitution with 10 mL sterile water for injection must yield a solution with subvisable particulate counts no greater than 10 particles ≥10 µm per container and 2 particles ≥25 µm per container, in accordance with USP ⟨787⟩ Light Obscuration Method. Container closure integrity is verified via helium leak test (leak rate ≤ 1.4 × 10−6 mbar·L/s), while endotoxin content remains below 0.20 EU/mg using the Limulus amebocyte lysate test per USP ⟨85⟩. A deeper cross-contamination concern emerges in multi-purpose facilities where the same 2-Mercapto-4-methyl-5-thiazoleacetic acid is received for both cephem and non-cephalosporin syntheses. The mercapto group acts as a potent chelator of residual nickel and palladium from catalytic steps, and if vessel train cleaning does not include a nitric acid passivation cycle (5% HNO3 at 60 °C for 45 min), inductively coupled plasma mass spectrometry (ICP-MS) analysis of the subsequent batch frequently detects palladium spikes above 10 μg/g, rendering the lot non-compliant under ICH Q3D Class 1 elemental impurity limits for parenteral products. Validated cleaning validation swab limits are set at 0.2 μg/cm² for the thiazoleacetic acid residue, quantified by liquid chromatography–tandem mass spectrometry (LC-MS/MS) in multiple reaction monitoring mode with a transition of m/z 188 → 144.What Dictates the Raney-Nickel Desulfurization Selectivity When Preparing 4-Methyl-5-Thiazoleacetic Acid for Flavouring Applications?Synthesis of 4-methyl-5-thiazoleacetic acid via catalytic desulfurization of 2-Mercapto-4-methyl-5-thiazoleacetic acid supplies a key intermediate for 4-methyl-5-thiazoleethanol (CAS 137-00-8) and its acetate ester, both approved flavouring substances listed under European Union Regulation (EC) No 1334/2008 and recognized as FEMA 3203 and 3205. The reaction is conducted in deionized water with powdered Raney nickel (W-2 grade, pre-washed to pH 8.5) at a substrate-to-catalyst ratio of 1:0.15 w/w and refluxed at 98–102 °C for 90 min. Hydrogen evolution is monitored until cessation; the pH of the slurry drifts from an initial 4.2 to 5.8 over the course of the reaction. Over-reduction to 4-methyl-5-thiazoleethane is suppressed by terminating agitation precisely 5 min after the bubbling rate drops below 0.5 mL/min as measured by a wet-test meter on the off-gas line. The filtered solution is acidified to pH 1.5 with concentrated hydrochloric acid and extracted with ethyl acetate (3 × 200 mL per mole of theoretical product). After drying over anhydrous magnesium sulfate and solvent recovery, the crude 4-methyl-5-thiazoleacetic acid is rectified by vacuum distillation (boiling point 142–145 °C at 6 mmHg) to a purity exceeding 99.5% by GC-FID (DB-WAX column, 30 m × 0.25 mm × 0.25 µm, split ratio 75:1). Sensory panel evaluation for the downstream ethanol derivative requires compliance with the Joint FAO/WHO Expert Committee on Food Additives (JECFA) specifications, particularly a sulfide odor threshold not exceeding 10 ppb in aqueous solution, a parameter directly traceable to residual sulfur from incomplete thiol removal. Any batch exhibiting > 0.05% sulfur by microcoulometric analysis (ASTM D5453-19e1) is rejected for flavour use and redirected to technical-grade cephem side-chain synthesis, creating an economically advantageous cascade utilization stream. A dense technical paragraph, unheralded by a header, delineates the niche in-scale use as a ligand precursor for heterogeneous asymmetric catalysis. 2-Mercapto-4-methyl-5-thiazoleacetic acid is grafted onto chloropropyl-functionalized silica gel (pore size 60 Å, particle size 40–63 μm) via its thiol group in refluxing toluene with 1.1 equivalents of triethylamine. The immobilization density reaches 0.48 mmol/g as determined by elemental sulfur analysis. The resulting tethered thioether ligand is treated with palladium(II) acetate (0.05 mmol Pd/g support) to generate a recoverable catalyst that mediates Suzuki–Miyaura cross-coupling of 4-bromoanisole and phenylboronic acid in ethanol/water at 80 °C with a turnover frequency of 320 h−1 and only 3 ppb palladium leaching into the product phase, as verified by ICP-MS. Published data for this specific configuration is limited to laboratory-scale demonstrations (50 mmol scale), and no long-term catalyst robustness data under continuous-flow conditions have been reported in the open literature. Process safety during immobilization mandates strict exclusion of moisture to prevent silane gelation, and the mercaptan off-gas must be scrubbed through a 10% sodium hypochlorite solution before venting. |
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A white to off-white crystalline powder supplied under the designation 2‑Mercapto‑4‑Methyl‑5‑Thiazoleacetic Acid (abbreviated MTAA in compounding and synthesis literature) possesses a molecular weight of 189.27 g/mol and a melting point of 178–182°C (capillary method, uncorrected). The mass spectrum exhibits a molecular ion peak at m/z = 189 with fragmentation ions at 144 (loss of COOH) and 100 (loss of CH₂COOH and SH). The molecule, containing both a reactive thiol moiety at the 2‑position and a pendent acetic acid group at the 5‑position of the thiazole ring, displays ambident nucleophilicity exploited in divergent reaction manifolds: thiolate attack on allylic chlorides in cephalosporin synthesis and sulfur‑crosslink formation in diene‑rubber vulcanization. In anhydrous form the acid dissociation constants for the carboxylic acid proton and the thiol proton are pKa 3.28±0.06 and 7.12±0.08, respectively, determined by potentiometric titration at 25 °C in aqueous ethanol (1:1 v/v). The product is supplied under supplier‑specific catalog grades that correspond directly to the end‑use purity level; the following specification matrix quantifies the typical product attributes for three industrial streams.
| Parameter | Technical Grade | Refined Grade | Pharma Intermediate Grade |
|---|---|---|---|
| Assay (HPLC, area‑%, dried basis) | ≥97.5 | ≥99.0 | ≥99.5 |
| Heavy metals (as Pb, ppm) | ≤20 | ≤10 | ≤5 |
| Loss on drying (105 °C, 2 h, %) | ≤0.5 | ≤0.3 | ≤0.2 |
| Residue on ignition (sulfated ash, %) | ≤0.3 | ≤0.15 | ≤0.1 |
| Particle size D50 (µm) | 35–65 | 25–45 | 10–30 |
| Particle size D90 (µm) | ≤150 | ≤100 | ≤60 |
The bulk density of the Technical Grade material ranges from 0.55 to 0.65 g/cm³, with an angle of repose of 38–42°; flowability in dense‑phase conveying is rated as borderline according to ISO 4324, and hopper vibration or aeration is mandated for automated feeding. The powder is hygroscopic above 60% relative humidity, picking up 0.8–1.2% moisture within 24 h at 25 °C and 75% RH. Pre‑drying in a vacuum tray drier at 50 °C for at least 4 h is required if the moisture content exceeds 0.3% before compounding. Exposure to strong oxidizing agents (hydrogen peroxide, peracetic acid) initiates rapid and exothermic decomposition, generating SO₂ and forming a dark resinous mass. Amine‑based rubber additives—particularly secondary aliphatic amines such as dibenzylamine—must be excluded from co‑storage because they catalyse premature thiol oxidation and cause caking of the powder within 48 h under ambient conditions. The compound remains stable when stored in sealed HDPE containers at temperatures below 30 °C for at least 24 months; after this period the assay typically declines by <0.5%.
In highly dispersible silica‑filled natural rubber compounds (BET surface area 160 m²/g, silane coupling agent TESPT at 6.4 phr), the introduction of MTAA as a secondary accelerator alongside sulfenamide (CBS) shifts the entire cure curve to longer times without proportionally reducing the maximum torque. The delay is attributed to two concurrent molecular events: steric shielding of the active sulfurating complex by the methyl group at the 4‑position, which retards the rate of sulfur insertion into the rubber backbone, and reversible chelation of zinc ions by the acetic acid side chain, temporarily decreasing the concentration of zinc‑accelerator complexes during the induction period. Oscillating disc rheometer data obtained per ASTM D5289 at 160 °C and an arc of 0.5° for a model NR/BR (70/30) tread formulation loaded with 2.0 phr insoluble sulfur are summarized in the table below; the values represent the mean of three independent lab‑scale batches compounded on a two‑roll mill (friction ratio 1:1.12, nip gap 0.5 mm).
| Accelerator System | ts2 (min) | t90 (min) | ML (dN·m) | MH (dN·m) | Hardness (Shore A) | Tensile Strength (MPa) | Elongation at Break (%) |
|---|---|---|---|---|---|---|---|
| MBT 0.5 phr | 2.8 | 7.5 | 1.4 | 12.3 | 68 | 23.5 | 480 |
| MTAA 0.6 phr | 4.2 | 11.3 | 1.4 | 10.8 | 64 | 21.8 | 520 |
Mooney scorch measurements per ASTM D1646 (large rotor, 125 °C, preheat 1 min) confirm the extension of the processing safety window: the time to a 5‑unit rise above the minimum viscosity (t5) rises from 14.5 min for the MBT control to 22.8 min for the MTAA‑containing compound. The 12% reduction in MH observed with MTAA is partially recovered by the addition of 0.3 phr diphenylguanidine (DPG), which raises MH to 11.9 dN·m while preserving the scorch delay. The lower crosslink density of the MTAA‑only stock is reflected in a decrease in Shore A hardness and a corresponding increase in elongation, a property profile that can be favourable for fatigue‑resistant sidewall compounds requiring high crack‑growth resistance measured per ASTM D813. No significant change in compression set (22 h at 70 °C) was noted between the two accelerator systems, both recording final values below 18%.
The utility of MTAA in semisynthetic cephalosporin manufacture stems from the mild and orthogonal reactivity of its thiol group toward electrophilic carbon centres. Condensation of MTAA with a 3‑chloromethyl‑ or 3‑acetoxymethyl‑cephem intermediate under phase‑transfer conditions (tetrabutylammonium bromide in dichloromethane‑water, pH 7.5–8.0) yields the corresponding 3‑[(4‑methyl‑5‑carboxymethylthiazol‑2‑yl)thio]methyl cephem in isolated yields exceeding 85%. The carboxylic acid at C‑5 is often esterified prior to coupling—typically as the p‑methoxybenzyl or diphenylmethyl ester—to enhance solubility in the organic phase, then deprotection is accomplished with trifluoroacetic acid/anisole without ring‑opening of the β‑lactam. The methyl group at C‑4 provides sufficient steric bulk to suppress dimerisation via disulfide bond formation during aerial oxidation of the thiol, a persistent side reaction encountered with unsubstituted 2‑mercaptothiazole. This suppression permits the coupling reaction to proceed under a simple nitrogen blanket rather than requiring rigorous exclusion of oxygen by three freeze‑pump‑thaw cycles. Residual solvents are controlled to meet ICH Q3C option‑2 limits: dichloromethane ≤600 ppm, triethylamine ≤320 ppm, and the finished ester intermediate is routinely analysed by USP <621> chromatographic purity protocols. Importantly, the MTAA‑derived side chain introduces a polar carboxylate anchoring point, improving the crystallinity of the final sodium salt and facilitating the isolation of a solvent‑free product with polymorphic consistency verified by XRPD.
Conventional 2‑mercaptobenzothiazole (MBT) remains a workhorse accelerator; however, residual secondary amines formed during MBT synthesis or generated during vulcanization can be nitrosated by atmospheric NOₓ to yield N‑nitrosamines, a class of compounds regulated under European Directive 93/11/EEC and the German TRGS 552. Compliance often necessitates co‑addition of nitrosamine scavengers such as phthalic anhydride or sterically hindered amines. MTAA contains no secondary amine nitrogen in its molecular framework; the sole nitrogen atom resides in the thiazole ring and is not susceptible to nitrosation under typical curing conditions (140–170 °C). Analysis of vulcanizate extracts by GC‑TEA (thermal energy analysis) following ISO 29941 has shown total volatile N‑nitrosamines below the detection limit of 0.5 µg/kg for MTAA‑cured stocks, whereas MBT‑based controls without scavengers frequently report 2–8 µg/kg of N‑nitrosodibenzylamine. This eliminates the need for dedicated nitrosamine‑reducing additives and simplifies the ingredient list for articles destined for infant feeding (e.g., teats, soothers) subject to EN 12868. Additionally, the carboxylic acid group enhances solubility in polar process oils (isooctyl tallate, DOS), reducing bloom tendency at loadings up to 1.2 phr, while MBT is known to exude at levels above 0.5 phr in non‑polar EPDM compounds, causing surface tack and impairing adhesion during co‑vulcanization with textile reinforcement.
In continuous extrusion and injection moulding environments the wider Mooney scorch window of MTAA‑accelerated compounds provides tolerance against short‑term temperature excursions. On a Ø 90 mm cold‑feed extruder with an L/D ratio of 16:1 and a head pressure of 120 bar, a compound containing 0.6 phr MTAA survived a 2‑minute unscheduled shutdown at 105 °C barrel temperature without any scorch particle formation in the die, whereas the MBT‑containing reference developed 1–2 mm scorch pellets after 45 s. This process robustness translates into reduced scrap rates during start‑up, especially on multi‑cavity injection moulding tools where residence time distribution in the hot runner is difficult to homogenise. Dispersion quality, quantified by optical microscopy on microtomed sections and analysed per ISO 11345 (dispersion index method), improved from an average 2.5 to 1.7 on the six‑point scale when MTAA replaced MBT at equimolar sulfur donor concentration, attributed to the surfactant‑like character of the acetic acid moiety in the presence of silane coupling agents on silica surfaces.
