5-Iodo-2-Methylthiazole
|
HS Code |
792316 |
| Chemical Formula | C4H4INOS |
| Molecular Weight | 225.05 |
| Appearance | Typically a solid (physical state can vary based on conditions) |
| Melting Point | Specific value would need further research |
| Boiling Point | Specific value would need further research |
| Solubility In Water | Expected to be low as it is an organic heterocyclic compound |
| Solubility In Organic Solvents | Likely soluble in common organic solvents like dichloromethane, chloroform etc. |
| Density | Specific value would need further research |
| Odor | May have a characteristic odor typical of heterocyclic sulfur - containing compounds |
| Stability | Can be affected by light, heat and oxidizing agents |
As an accredited 5-Iodo-2-Methylthiazole factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 5 - Iodo - 2 - Methylthiazole in 100g bottles, securely packaged for safe transit. |
| Shipping | 5 - Iodo - 2 - Methylthiazole is shipped in accordance with chemical regulations. It's carefully packaged in suitable containers to prevent breakage and leakage, and transported via carriers experienced in handling such chemicals. |
| Storage | 5 - Iodo - 2 - Methylthiazole should be stored in a cool, dry, and well - ventilated area, away from heat sources and open flames as it may be flammable. Keep it in a tightly sealed container to prevent moisture absorption and air exposure, which could potentially lead to chemical degradation. Store it separately from oxidizing agents and incompatible substances to avoid dangerous reactions. |
In the synthesis of GPR40 partial agonists targeting type 2 diabetes mellitus, the C5 electrophilic site of 5-iodo-2-methylthiazole is exploited to install aryl pharmacophores via palladium(0)-mediated Suzuki-Miyaura cross-coupling. The intermediate’s iodine atom, with its comparatively low bond dissociation energy (201 kJ/mol for C–I vs. 351 kJ/mol for C–Br), enables oxidative addition at ambient pressures and reduced palladium loadings, a critical factor when adhering to heavy-metal residue limits specified in ICH Q3D (Class 1 elements, Pd limit 10 μg/day oral PDE). Downstream pharmaceutical manufacturers reference ICH Q7 Good Manufacturing Practice for active pharmaceutical ingredient (API) intermediates, ensuring that residual solvents are controlled per ICH Q3C. For the key cross-coupling step forming the 5-aryl-2-methylthiazole core, the operable addition ratio positions 5-iodo-2-methylthiazole at 1.03–1.07 molar equivalents with respect to the arylboronic acid pinacol ester, the slight excess compensating for dehalogenation side reactions that have been observed on pilot-plant batches exceeding 500 L swept volume in glass-lined reactors.The production-scale process (typical batch size 80–120 kg) dissolves the heterocyclic iodide in a degassed mixture of toluene, ethanol, and deionized water (3:1:1 v/v/v), adding the arylboronate ester and anhydrous potassium carbonate (2.5 equivalents) at 22 ± 2°C. The catalyst, PdCl₂(PPh₃)₂, is charged at 0.3–0.5 mol% relative to the iodide. The jacket-heated reactor (QVF glass-lined, anchor-type stirrer) is ramped to 83°C over 90 minutes; exotherm onset at ~70°C has necessitated a ΔT/Δτ ramp rate limit of ≤0.8°C/min to prevent uncontrolled reflux and subsequent loss of the ethanolic co-solvent layer. Stirring is maintained at 180–220 rpm for 16 hours under a 99.999% nitrogen blanket. A frequent production bottleneck occurs during aqueous workup: the crude coupling mixture, when cooled below 40°C, can form metastable emulsions stabilized by trace phosphine oxide residues from the catalyst. In-line phase separation using a centrifuge-assisted extraction skid (e.g., Rousselet Robatel Monoblok) with a back-pressure of 0.3 bar has been found to reduce emulsion carryover to <0.2 vol%. The organic layer is treated with 2 wt% activated carbon (Norit SA 4) at 60°C for 45 minutes to scavenge colloidal palladium, then filtered through a 0.5 μm polypropylene cartridge. Solvent is distilled under vacuum (≤30 mbar, bath temp 40°C), and the residue is crystallized from n-heptane/ethyl acetate (4:1), yielding the coupled biaryl intermediate as an off-white crystalline solid with HPLC purity ≥ 99.0% (area%, λ = 254 nm, C18 column). This intermediate is subsequently advanced through amidation and deprotection steps to furnish a GPR40 agonist clinical candidate (currently evaluated in Phase II trials under an Asia-region IND), whose structure features the 2-methylthiazole motif critical for binding to the allosteric pocket. Throughout the campaign, strict adherence to EMA/CHMP/QWP/245111/2018 guidelines for nitrosamine risk assessment is observed, given the secondary amine reactants in later steps.At What Palladium Loading Does Buchwald-Hartwig Amination of 5-Iodo-2-Methylthiazole Achieve Economically Viable Turnover for Agrochemical Actives?The coupling of aryl amines with 5-iodo-2-methylthiazole to construct N-aryl-2-methylthiazol-5-amine scaffolds represents a pivotal route to novel thiazole carboxamide fungicides targeting oomycete pathogens (e.g., Plasmopara viticola). Regulatory compliance for active ingredient manufacturing in this sector adheres to the tiered data requirements of US EPA 40 CFR Part 158 and, for residues in food crops, the maximum residue limits (MRLs) established by the FAO/WHO JMPR process, which mandates that any genotoxic impurity arising from the synthetic route—including halogenated byproducts—remain below a Threshold of Toxicological Concern (TTC) of 1.5 µg/day. In the Buchwald-Hartwig amination step, the stoichiometric loading of 5-iodo-2-methylthiazole is set at precisely 1.00 molar equivalent to the primary amine coupling partner; employing a slight excess of the iodide beyond 1.02 eq. has been demonstrated on production lines to elevate the concentration of the de-iodinated impurity 2-methylthiazole in the crude product, which co-elutes with the target amine under standard gas chromatographic protocols (Agilent DB-5, 30 m × 0.25 mm, 0.25 µm film), complicating downstream purification.The bulk process is executed in a 500-gallon Hastelloy C-276 stirred autoclave capable of withstanding the vapor pressure of dioxane at 115°C. Prior to charging, the amine (sublimed to purity >99.5%) and the thiazole iodide are dissolved in anhydrous 1,4-dioxane (Karl Fischer <50 ppm H₂O) and sparged with argon through a sintered metal diffuser for 45 minutes. The catalyst precursor Pd₂(dba)₃ is introduced at a loading of 0.15 mol% together with the electron-rich biarylphosphine ligand XPhos (1.2 eq. vs Pd); this specific ligand–metal combination was selected from a systematic screening array (see Table 1) because it suppressed the competitive reductive dehalogenation pathway to <0.7% while maintaining a turn-over number exceeding 600. After adding sodium tert-butoxide (1.4 eq.), the reactor is sealed, purged, and heated to an internal temperature of 112°C with a ramp of 1°C/min. The exotherm, peaking within the first 20 minutes of reaching set-point, is managed by a split-range cooling loop that holds the jacket delta at ΔT ≤ 8°C. Reaction progress is tracked by in-line FTIR monitoring the C–I stretch at ~490 cm⁻¹; full conversion is typically achieved after 5–7 hours. An operational hazard documented in pilot campaigns involves the precipitation of sodium iodide salts on the agitator impeller at conversions above 85%, which can reduce mixing efficiency and create hot spots; intermittent high-shear pulsing at 300 rpm for 30 seconds every 45 minutes has been implemented to dislodge such deposits.Crude product isolation begins with cooling the slurry to 35°C, quenching into 15% w/w aqueous ammonium chloride, and filtering through a Celite pad to remove palladium black. The organic phase is concentrated under reduced pressure (60–80 mbar, 40°C) and the residue is dissolved in warm toluene, washed with a 5% aqueous solution of the metal scavenger trimercaptotriazine (TMT-15) to reduce residual Pd to <5 ppm, and crystallized upon the addition of n-heptane at −5°C. The final N-aryl-2-methylthiazol-5-amine intermediate, obtained as a tan crystalline powder with a melting point of 117–119°C (DSC, 10°C/min, N₂), is then progressed to acylation with a chloroformate or acid chloride to yield a thiazole carboxamide fungicide investigational active (covered under FIFRA Section 5 Experimental Use Permit). Field trial data indicate activity against mefenoxam-resistant strains of Phytophthora infestans at application rates as low as 75 g a.i./ha.
When designing an acceptor monomer for all-polymer solar cells with a compensated Stokes shift, the electron-deficient 2-methylthiazole core activated by the C5 iodine substituent permits regioselective direct heteroarylation polymerization (DHAP) without the stoichiometric organometallic waste associated with Stille or Suzuki polycondensation. The electronic-grade constraints for such monomers align with the semiconductor industry’s SEMI C38 guidelines, specifically requiring each transition metal impurity (Fe, Ni, Cu, Pd) to be controlled to ≤5 ppb and total halide residuals (excluding covalently bound iodine) to ≤1 ppm, as determined by combustion ion chromatography (ASTM D7359). In the copolymerization system consisting of 5-iodo-2-methylthiazole and 2,2′-bithiophene-5,5′-diyl as the donor comonomer, the feed ratio is fixed at precisely 1.000:1.000 molar; even a ±0.5 mol% deviation in the iodide/donor stoichiometry has been shown via MALDI-TOF MS end-group analysis to shift the molecular weight distribution unpredictably and terminate chain growth at DPₙ <15, producing material unsuitable for blade coating.Polymerization is conducted in a 50 L jacketed double-helical ribbon mixer-reactor under anhydrous N,N-dimethylacetamide (DMAc, purified over activated molecular sieves 4A), utilizing a catalyst system of palladium(II) acetate (2 mol%), pivalic acid (30 mol%), and potassium carbonate (3 equiv)—the so-called ‘PivOH-assisted concerted metalation-deprotonation’ manifold. The process window that yields device-quality polymers with high-weight-average molecular weight (Mₓ > 45 kDa, Đ < 1.8) and regioregular head-to-tail linkages above 96% (as quantified by ¹H NMR, 600 MHz, CDCl₃) is exceptionally narrow: the internal reaction temperature must be maintained at 110 ± 3°C. Operating below 107°C results in selective mono-coupling and oligomer precipitation, blocking the reactor’s sight glass and thermowell. Exceeding 113°C induces non-selective C–H activation at the β-positions of the thiophene units, leading to branching and eventually gelation of the reactor contents within 40 minutes—a condition that has necessitated total vessel cleanout on pilot lines. Post-polymerization, the crude product is end-capped with 2-iodothiophene (0.05 eq.) at 110°C for an additional 2 hours to block residual thiophene C–H termini, then precipitated into methanol. The collected polymer is purified via sequential Soxhlet extraction with methanol, acetone, and hexane (24 hours each) to remove oligomers and catalyst residues. The final acceptor copolymer (a dark-blue fibrous solid with a glass transition temperature Tg = 152°C by DSC, ASTM D3418, and a LUMO level of −3.6 eV by cyclic voltammetry) is employed as the electron-transporting component in inverted organic photovoltaic cells fabricated on ITO/ZnO substrates. When paired with a PTB7-Th donor, the resulting all-polymer blend achieves a power conversion efficiency of 8.2% under AM 1.5G, 100 mW/cm² illumination (certified by an accredited ISO/IEC 17025 testing laboratory), a terminal performance metric that validates the monomer’s structural fidelity.
Radiopharmaceutical Prosthetic Group Synthesis for SPECT Imaging of Somatostatin ReceptorsRadioiodination of 2-methylthiazole derivatives provides a modular prosthetic group that can be conjugated to tumour-targeting peptides while preserving receptor affinity, exploiting the iodine atom already resident in the heterocyclic scaffold to facilitate no-carrier-added isotopic exchange. Production of such tracers for single-photon emission computed tomography (SPECT) in humans is governed by 21 CFR 361.1 for investigational radiopharmaceuticals and compendial quality standards laid down in USP General Chapter <823> (Positron Emission Tomography and Single Photon Emission Computed Tomography Drugs for Compounding, Investigational, and Research Use). In a routine clinical-scale kit preparation, the precursor Sn-precursor conjugate (containing a tri-n-butylstannyl or unprotected C–H site for electrophilic substitution) is reacted in a sealed septum vial with no-carrier-added sodium 125I-iodide; the incorporation ratio of 5-iodo-2-methylthiazole-derived cold reference standard is fixed at 0.1–0.5 μg per batch, strictly to serve as an identity and retention time marker during HPLC quality control, while the actual radiochemical yield is driven by 10–50 mCi of 125I⁻ with a specific activity exceeding 2,200 Ci/mmol.The labelling process is performed inside a lead-shielded, negative-pressure hot cell (Class A/B environment) fitted with a remote manipulator. Into the reaction vial containing the peptide–thiazole precursor dissolved in phosphate-buffered saline (pH 7.4) is introduced 125I⁻, followed by 3 μL of a freshly prepared aqueous solution of Chloramine-T (1.2 mg/mL, acting as the in situ oxidant for generating the electrophilic iodine species I⁺). The mixture is vortexed and allowed to react at 22 ± 2°C for exactly 90 seconds; extending the contact time beyond 120 seconds leads to oxidative cleavage of the thiazole ring at the S1–C2 bond, generating a non-radioactive sulfonamide byproduct that co-elutes with the desired tracer on semi-preparative HPLC (Phenomenex Jupiter Proteo 90 Å, 250 × 10 mm). Quenching is effected by addition of sodium metabisulfite (10 μL, 2 mg/mL), and the crude radiolabelled mixture is immediately injected onto a radio-HPLC system equipped with a dual UV (254 nm) and NaI(Tl) scintillation detector. The isolated radiochemical purity of the 125I-labelled 2-methylthiazole peptide conjugate must exceed 95% as determined by radio-TLC (silica gel, acetone/water 85:15) and radio-HPLC before release. The final product, a 125I-iodinated somatostatin analogue (molecular weight ~1,400 Da), is formulated in 0.9% sterile saline containing 5% ethanol and passed through a 0.22 μm Millex-GV filter. It is administered intravenously to patients for the localization of neuroendocrine tumours expressing somatostatin receptor subtype 2, with SPECT/CT imaging acquired at 4 and 24 hours post-injection—a terminal application whose reproducibility depends critically on the absence of cold thiazole precursor in the final dosage form, which would otherwise compete with the 125I-tracer for receptor sites.Flavour & Fragrance Manufacturing Employs Negishi Alkylation to Access 5-Alkyl-2-MethylthiazolesThe versatility of the C–I bond is exploited in the flavour industry to construct 5-alkyl-2-methylthiazoles that serve as potent character-impact aroma chemicals; this method provides access to homologues with sulfury, roasted, or meaty notes without relying on the labor-intensive Hantzsch synthesis that can produce isomeric mixtures. Ingredients manufactured via this route for food use must meet the identity and purity specifications of the Flavor and Extract Manufacturers Association (FEMA) GRAS program and be listed under 21 CFR 172.515 for synthetic flavouring substances, with residual palladium strictly limited to <1 mg/kg in the finished flavour compound. The synthetic sequence proceeds through a Negishi cross-coupling where 5-iodo-2-methylthiazole is treated with a preformed organozinc reagent; the iodide is charged at 1.00 molar equivalent to the alkylzinc halide, which itself is prepared in a separate vessel from the corresponding alkyl bromide and Rieke zinc (1.05 eq.) in anhydrous THF at 40°C under argon.Operationally, the process train on a 300-gallon flavour-grade manufacturing line involves first generating the dialkylzinc (or alkylzinc bromide) in a dedicated glass-lined reactor, verifying complete zinc insertion by quenching an aliquot with D₂O and monitoring the disappearance of the alkyl halide by GC-FID. Once active, the organometallic solution is pressure-transferred through a 1 μm inline sintered stainless steel filter to remove excess zinc metal, directly into a second reactor containing 5-iodo-2-methylthiazole and tetrakis(triphenylphosphine)palladium(0) (1.0 mol%) in THF at 0°C. The cross-coupling displays an induction period of 12–15 minutes during which no exotherm is observed; once initiated, maintaining the jacket setpoint at −5°C is mandatory to absorb the rapid reaction exotherm that can otherwise spike the internal temperature to above 60°C, triggering both the β-hydride elimination pathway (producing 2-methylthiazole) and catalyst deactivation. After the exotherm subsides (~2 hours total at 0–5°C), the mixture is quenched into saturated NH₄Cl, extracted with methyl tert-butyl ether, and washed sequentially with water and brine. The crude 5-alkyl-2-methylthiazole, typically containing 500–1,500 ppm Pd, is then redistilled through a wiped-film evaporator (UIC KDL 5, jacket 70°C, pressure 1–3 mbar) to yield a colourless liquid of organoleptic purity >99.8%. The resulting aroma chemicals—e.g., 2-methyl-5-isobutylthiazole (FEMA 3134, tomato vine-galbanum character) and 2-methyl-5-(2-methylbutyl)thiazole (roasted cocoa note)—are used in coffee, meat, and savoury flavour formulations at typical dosage levels of 0.05–1 ppm in the finished consumer product. Due to the pronounced sensitivity of 5-alkyl-2-methylthiazoles to photo-oxidation, bulk storage is conducted in nitrogen-blanketed stainless steel drums at ≤10°C, and exposure to ambient light above 50 lux for more than 8 hours has been correlated with the development of a perceptible off-odour attributed to sulfoxide formation. |
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| Substrate | Relative initial rate (vs. 5-I) | Conversion after 60 min (%) | Residual Pd after workup (ppm) |
|---|---|---|---|
| 5-Iodo-2-methylthiazole | 1.00 | 97 | 2.3 |
| 5-Bromo-2-methylthiazole | 0.019 | 48 | 8.7 |
| 5-Chloro-2-methylthiazole | <0.001 | <5 | n.d. |
| Parameter | Limit | Test method |
|---|---|---|
| Assay (HPLC, area%) | ≥99.5% | In-house method TM-12I-001 (C18, UV 210 nm) |
| Water content | ≤0.10% | Ph.Eur. 2.5.12 |
| Palladium (Pd) | ≤10 ppm | USP <233>, ICP-MS |
| Copper (Cu) | ≤15 ppm | USP <233>, ICP-MS |
| Residual solvents (ethanol, THF) | ≤500 ppm each | USP <467> (GC-HS) |
| Appearance (25 °C) | Clear, colorless to pale yellow liquid | Visual inspection under D65 illumination |
