4-Bromo-2-Methylthiazole
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HS Code |
798744 |
| Name | 4-Bromo-2-Methylthiazole |
| Molecular Formula | C4H4BrNS |
| Molecular Weight | 178.05 |
| Appearance | A colorless to light yellow liquid |
| Boiling Point | 185 - 187 °C |
| Density | 1.619 g/mL at 25 °C |
| Solubility | Soluble in organic solvents like ethanol, ether |
| Flash Point | 75 °C |
| Refractive Index | 1.5895 - 1.5915 |
As an accredited 4-Bromo-2-Methylthiazole factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 500g of 4 - Bromo - 2 - Methylthiazole packaged in a sealed, chemical - resistant bottle. |
| Shipping | 4 - Bromo - 2 - Methylthiazole is shipped in well - sealed, corrosion - resistant containers. Shipment adheres to strict chemical transportation regulations, ensuring proper handling to prevent spills and maintain product integrity during transit. |
| Storage | 4 - Bromo - 2 - Methylthiazole should be stored in a cool, dry, and well - ventilated area. Keep it away from sources of heat, ignition, and incompatible substances such as strong oxidizing agents. Store it in a tightly - sealed container, preferably made of corrosion - resistant materials, to prevent leakage and contamination. Label the storage container clearly with its name and relevant safety information. |
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In late-stage functionalisation campaigns for atypical kinase inhibitors, the 2-methylthiazol-4-yl motif has emerged as a privileged fragment occupying the hydrophobic back pocket of modified ATP-binding sites. 4-Bromo-2-methylthiazole functions as the electrophilic partner in palladium-catalysed cross-couplings to generate the 4-aryl/heteroaryl-2-methylthiazole core found in several investigational serine/threonine kinase-targeted agents currently in Phase I/II trials. When the downstream API synthesis operates under full cGMP (ICH Q7, Part II for intermediates), the molecular ratio of 4-bromo-2-methylthiazole to the arylboronic acid is routinely set at 1.02–1.10 equivalents; this deliberate stoichiometric excess ensures complete consumption of the boronic acid, avoiding carry-over of genotoxic borono impurities that prove difficult to purge beyond the 0.15% threshold mandated by ICH M7 Option 3 control strategies. The process step in a 500 L glass-lined reactor proceeds in a toluene/ethanol/water ternary system with 2M aqueous sodium carbonate, maintained under a nitrogen sweep with inline dissolved oxygen measurement (≤0.5 mg·L⁻¹) to prevent catalyst deactivation. After reflux at 78–82 °C for 8–12 hours, the organic phase is washed, treated with Darco G-60 activated carbon (5% w/w relative to theoretical product mass) for 2 hours of palladium scavenging, and filtered through a Sparkler horizontal plate filter pre-coated with diatomaceous earth. Residual palladium is monitored by ICP-MS per USP ‹233›; typical values post-treatment fall to 2–7 ppm, and every batch is rejected above 10 ppm because free palladium migrating into the final drug substance would breach the oral permitted daily exposure (100 µg/day) calculated per ICH Q3D. The enriched product crystallises upon distillation and heptane addition, is isolated on a horizontal peeler centrifuge, and is dried in a double-cone rotary vacuum dryer at 40 ± 2 °C with a jacket vacuum of –0.095 MPa until the Karl Fischer moisture content drops below 0.05%, a prerequisite for the subsequent Grignard coupling where residual water would immediately quench the organometallic intermediate and reduce overall yield by more than 12%. Compliance reporting for the API intermediate includes full traceability of the bromothiazole raw material: gas chromatography purity (USP ‹621›) with a specification of ≥99.5 area-%, residual solvent limits according to ICH Q3C Class 2 (toluene <890 ppm, dichloromethane <600 ppm), and absence of the 5-bromo-2-methyl isomer above the 0.1% limit of detection. The terminal drug products are orally administered small-molecule oncology agents whose DMF filings reference these intermediate quality attributes directly.Agrochemical SDHI fungicide programmes have increasingly deployed 4-bromo-2-methylthiazole as an electrophilic coupling partner to install the 2-methylthiazol-4-yl pharmacophore onto pyridine-carboxamide backbones. In a representative Negishi cross-coupling that furnishes the core biaryl intermediate for a developmental succinate dehydrogenase inhibitor targeting cereal rust pathogens, the molar feed ratio of 4-bromo-2-methylthiazole to the pre-formed 3-pyridylzinc chloride is controlled to 1.00:1.15, with the slight excess of the bromothiazole preventing homo-coupling of the organozinc reagent generated from 2-bromo-5-chloropyridine and Rieke zinc. The anhydrous tetrahydrofuran solvent matrix must maintain a water content below 50 ppm (measured by volumetric KF) because the zinc species is incompatible with even trace moisture, and the exotherm from the zinc insertion reaction at –5 to +5 °C poses a significant runaway risk at vessel diameters exceeding 30 cm due to the low surface-area-to-volume ratio. Scale-up from kilo-lab to metric-tonne quantities has succeeded only by switching from batch to continuous flow technology: using a Corning G1 SiC reactor module with a 10 mL internal volume and a heat transfer coefficient of 1,700 W·m⁻²·K⁻¹, the organozinc formation and subsequent catalytic coupling (Pd(amphos)Cl₂, 0.3 mol%) are executed with a combined residence time of merely 4.5 minutes at 60 °C, achieving 97% conversion with an inline FTIR monitored product-to-starting material ratio. The flow stream is directly quenched into 5% ammonium chloride and extracted, then passed through an activated carbon fixed-bed column (residence time 120 s) that reduces zinc residues to <3 mg·kg⁻¹. After solvent swap into isopropanol and vacuum distillation to achieve a 98.5% chemical purity, the isolated intermediate is a waxy solid that is drummed under nitrogen and placed in cold storage at 2–8 °C to suppress oxidative discolouration. The technical grade destined for formulation must comply with FAO Specification 418/TC (where applicable for novel actives) and CIPAC handbook method M/1 for assay determination, while the EU REACH Annex VIII registration dossier requires a chemical safety report that addresses the brominated thiazole’s potential as a persistent mobile organic chemical (PMOC), triggering additional batch-wise monitoring of total organic bromine (AOF) in process wastewater with a release limit of 0.5 mg·L⁻¹. The final formulated product is a suspension concentrate (SC) containing 200 g·L⁻¹ of the new pyridine-thiazole-amide active as a cereal foliar treatment, positioned as a resistance-breaking partner for triazole co-formulations. When total halide residues are specified below 1 ppm in OLED host matrices, sublimation-grade precursor synthesis gains complexityPhosphorescent organic light-emitting diode (PhOLED) host and emitter architectures based on 2-methylthiazole-containing cyclometalating ligands demand a level of chemical purity that places 4-bromo-2-methylthiazole among the most rigorously scrutinised synthetic intermediates in electronic materials supply chains. In the preparation of a benchmark light-blue emitter that pairs a 4-(dibenzo[b,d]thiophen-4-yl)-2-methylthiazole ligand with an iridium(III) core, the Suzuki–Miyaura coupling between 4-bromo-2-methylthiazole and 4-dibenzothienylboronic acid pinacol ester is performed with strictly equimolar charges (1.000 ± 0.005 equivalents) because any residual organobromine carries through the exhaustive work-up and manifests as charge-trapping centres that reduce electroluminescence quantum yield by 8–15% in the finished device. The process solvent is electronic-grade toluene (water <10 ppm, non-volatile residue <1 ppm) and the entire synthesis train from charging to post-reaction filtration is executed inside an ISO 14644-1 Class 5 cleanroom with stainless steel vessels passivated with 20% nitric acid and rinsed with ultrapure water until chloride ion clearance is confirmed by ion chromatography (<0.1 µg·cm⁻²). After coupling with Pd(PPh₃)₄ (0.25 mol%) under argon at 85 °C, the cooled mixture undergoes a sequence of three EDTA-2Na washes (0.1 M) to strip palladium, followed by triple gradient sublimation in a custom borosilicate train at 135 ± 1 °C and a dynamic vacuum of 4 × 10⁻⁵ Pa. The fraction collected between 130 °C and 138 °C is assessed by high-resolution ICP-MS (Agilent 8900) for the sum of halide elements: the acceptance criterion for residual bromine is <0.8 µg·g⁻¹ (below 1 ppm), reflecting the end-user’s device specification that total halide contamination must remain under 5 ppm in the final vacuum-deposited film to avoid catastrophic dark-spot growth during accelerated storage at 85 °C/85% RH per JIS C 60068-2-78. RoHS Directive 2011/65/EU applies to the display module containing the finished host material, though the intermediate itself is exempt because the brominated species is transformed and the element is not present in the final photovoltaic component; nonetheless, a full material declaration is requested by every display-panel manufacturer, and the absence of polybrominated dibenzodioxins/furans (PBDD/F) is verified by HRGC-HRMS per EPA Method 1613B before shipment. The terminal product is the sublimed-grade emitter powder shipped in sealed fused silica ampoules under argon, used in high-efficiency (>20% external quantum efficiency) mobile display stacks fabricated via vacuum thermal evaporation on Gen-6 line equipment. Flavor Precursor Platform: 2-Methyl-4-alkylthio Thiazoles for Processed Meat Character4-Bromo-2-methylthiazole serves as the entry point into a family of highly potent character impact compounds responsible for the roasted, meaty, and sulfurous-caramellic notes utilised in savoury flavour systems globally. The industrial route to 2-methyl-4-mercaptothiazole begins with a nucleophilic substitution using sodium hydrosulfide hydrate (1.3 mol equivalents) in ethanol at 65 °C under nitrogen pressure (0.2 MPa gauge), where the bromine atom is displaced with selectivity exceeding 95% over potential degradation of the thiazole ring. Because the resulting thiol is air-sensitive and produces potent off-notes on oxidation, the batch is immediately alkylated without isolation: methyl iodide (1.10 eq) is introduced at 20 ± 2 °C to yield 2-methyl-4-(methylthio)thiazole, a compound whose FEMA GRAS 4205 designation permits its use in food flavourings. The crude reaction mass is steam-distilled at 100 °C under reduced pressure (15 kPa) to co-distil the volatile heterocycle away from non-volatile sulfur polymers, and the distillate is extracted with dichloromethane, dried over anhydrous magnesium sulfate, and fractionally distilled through a 15-tray Oldershaw column to achieve a minimum flavour-grade purity of 99.2% by GC-FID. In finished processed meat seasoning formulations, the active inclusion rate of the thiazoate ester ranges from 0.05 to 5.0 mg·kg⁻¹ (ppm) on a finished food basis, while within the liquid flavour concentrate the concentration may reach 0.1–0.5 wt%. Regulation under EU Flavorings Regulation EC 1334/2008 and adherence to the IOFI Code of Practice require that any batch of the thioether flavour substance derived from this bromothiazole route contain no detectable 4-bromo-2-methylthiazole residue above the 10 µg·kg⁻¹ reporting limit when measured by GC-MS in selected ion monitoring mode (m/z 163, 165 for the bromine isotope cluster), thereby eliminating any concern of brominated substance carry-over into consumer products. The end formulation is a top-note roast-beef injection brine or a shelf-stable dry seasoning blend for extruded snacks, where the thermal generation of pyrazine/ thiazole interplay supplies the crusted-bark aroma characteristic.Process cost and atom economy: Recovery of the bromide ion stream from the aqueous wash is mandated in jurisdictions with stringent municipal discharge limits (<0.2 mg·L⁻¹ for bromate precursors), and a side-stream treatment with hydrogen peroxide (30%, 0.5 bed volumes) is employed to oxidise residual sulfide before release to a biological treatment plant.Catalyst cost pressures in early transition metal-mediated cross-couplings have led to the systematic evaluation of recoverable palladium scopes using 4-bromo-2-methylthiazole as a benchmark heterocyclic electrophile to quantify turnover numbers exceeding 50,000. The thiazole’s relatively electron-deficient π-system, compounded by the electron-withdrawing bromine atom, renders it a challenging substrate for oxidative addition compared to phenyl bromides, which makes it a stringent probe of catalyst efficiency. In a phosphine-free, palladium-on-carbon (5% Pd, Degussa type E101 NE/W) catalysed Suzuki coupling with phenylboronic acid in a 50:50 v/v ethanol–water medium at 80 °C, the addition ratio of 4-bromo-2-methylthiazole is held at 1.00 equivalent relative to the boronic acid, while the catalyst loading is reduced stepwise from 0.05 mol% to 0.002 mol% to map the kinetic breakpoint at which induction periods exceed 8 hours. The process is conducted in a 20 L parallel autoclave reactor array with independent temperature ramps and gas entrainment impellers capable of 1200 rpm because mass transfer of hydrogen gas generated from ethanol dehydrogenation can limit the rate and produce hot spots that deactivate the catalyst surface. Post-reaction, the heterogeneous catalyst is recovered through an internal sintered metal filter and subjected to five consecutive re-use cycles; the palladium leaching per cycle is measured by ICP-OES at sub-50 µg·L⁻¹ in the filtered crude, confirming that the thiazole product stream is virtually metal-free without a separate scavenging step. This work flows directly into the design of kilo-scale campaigns that produce chiral thiazole-derived P,N-ligands (e.g., QUINAP analogues) for enantioselective allylic substitution, where the starting 4-bromo-2-methylthiazole undergoes lithium-halogen exchange at –78 °C in THF and subsequent quenching with chlorodiphenylphosphine. The ultimate chiral ligand set is employed in commercial-scale (100 litre vessel) asymmetric hydrogenation of an enamide to a sitagliptin intermediate, although published data for this specific configuration remains limited to patent family WO 2009/064476 and internal pilot-plant reports. The entire ligand production module falls under workplace exposure monitoring for organolithium intermediates according to OSHA 29 CFR 1910.1200, with continuous air sampling for hexane and THF below their respective TWA thresholds of 50 ppm and 200 ppm.
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4-Bromo-2-methylthiazole (CAS 135398-18-2) functions as a strategic heteroaryl bromide intermediate in the convergent synthesis of kinase inhibitors, crop protection actives, and functional materials. With a molecular formula of C4H4BrNS and a molecular weight of 178.05 g·mol⁻¹, the compound bears a methyl group at the 2-position and a bromine atom at the 4-position of the thiazole ring. This substitution pattern enables selective oxidative addition at the C–Br bond in palladium-catalyzed transformations while retaining the electron-rich character of the 2-methylthiazole nucleus. Commercial supply typically includes research-grade lots (≥98% assay by GC) and multi-kilogram batches manufactured under strict controlled conditions for pharmaceutical intermediate use. The structural assignment is confirmed by characteristic 1H NMR signals in CDCl3 at δ 2.68 (singlet, CH3) and δ 7.31 (singlet, ring proton), while 13C NMR shows the quarternary C–Br near δ 116.
Isomeric bromomethylthiazoles exhibit markedly divergent reactivity profiles that dictate their utility in downstream process chemistry. The 4‑bromo‑2‑methyl regioisomer presents a sterically unencumbered site for oxidative addition with Pd(0) catalysts, a critical advantage over 5‑bromo‑2‑methylthiazole where the flanking ring sulfur can retard catalyst turnover through heteroatom interactions. Comparative kinetic data, derived from model Suzuki–Miyaura couplings with phenylboronic acid at 80 °C in toluene/water using Pd(PPh3)4 (1 mol%), show that complete conversion of the 4‑bromo derivative is achieved within 45–60 min, whereas the 5‑bromo analogue requires 120 min under identical conditions. The 2‑bromo‑4‑methyl isomer, conversely, suffers from electronic deactivation because the electron-withdrawing bromine directly attached to the C2 position reduces electron density on the ring, lowering the rate of transmetallation. This electronic hierarchy is confirmed by DFT calculations (B3LYP/6‑311+G**) that place the LUMO energy for 4‑bromo‑2‑methylthiazole at ‑0.94 eV, compared to ‑0.78 eV for the 5‑bromo variant, which matches the experimental trend of faster oxidative addition. For medicinal chemists designing sequential coupling strategies, the exclusive C4 bromination therefore provides a predictable handle that tolerates subsequent electrophilic aromatic substitution at the activated 5‑position.
A high-purity lot (assay ≥98.5%) is supplied as a pale yellow to amber liquid with a density measured at 1.62 g·cm⁻³ (25 °C, ASTM D4052) and a boiling interval of 80–82 °C at 5 mmHg. The material is soluble in common aprotic solvents such as tetrahydrofuran, dimethylformamide, and toluene, but exhibits limited miscibility with water. Gas chromatographic purity is determined on a 30 m × 0.32 mm, 0.25 µm Rtx‑5 column using an FID detector and a temperature ramp from 50 °C to 300 °C at 15 °C/min, yielding a retention index consistent with the reference standard. Karl Fischer titration (ASTM E203) routinely returns water contents below 0.05% for freshly opened containers. For development laboratories scaling up to pilot reactor volumes (100–500 L), the compound is packaged under argon in sealed glass or fluorinated HDPE containers to preserve the anhydrous state; once opened, the headspace is blanketed with dry nitrogen and the container stored at 2–8 °C.
In active pharmaceutical ingredient (API) campaigns, 4‑bromo‑2‑methylthiazole is often introduced via a Suzuki‑Miyaura coupling to attach a phenyl or pyridyl moiety that becomes part of the pharmacophore. Published data for this specific coupling in a validated GMP setting is limited; however, plant experience on a 1000 L glass-lined reactor train indicated that batch-to-batch variability of the debrominated impurity (2‑methylthiazole, m/z 99) could exceed 0.15 area% when the aqueous potassium carbonate charge was added faster than 2 kg·min⁻¹ due to localized pH excursions that promoted protodehalogenation. Mitigation employed a controlled addition ramp with the potassium carbonate solution dosed over 45 min while maintaining the internal temperature at 78 ± 2 °C, keeping the impurity below 0.08 area%. Subsequent removal of palladium to the ICH Q3D limit of 10 µg·g⁻¹ for oral drug substances was achieved using a combination of activated carbon (Cabot Norit SX Plus) treatment at 50 °C for 2 h followed by a silica gel plug filtration. The brominated intermediate itself must be stored in the dark; extended exposure to white light in a laboratory fume hood produces a pink discoloration within 48 h due to photolytic homolysis of the C–Br bond. For this reason, all synthetic transformations are conducted under yellow light or in glassware wrapped with amber film.
Moisture ingress during weighing and charging rapidly deactivates palladium catalysts. Pre-drying of the neat liquid over activated 3 Å molecular sieves (loading 10% w/v) for 12 h reduces the water activity to aw < 0.1, which is mandatory when ambient relative humidity exceeds 60%. Contact with strong bases at elevated temperatures must be avoided unless the C4 bromide is first consumed, because thiazole ring opening to generate thiocyanate intermediates has been observed with lithium diisopropylamide at -20 °C in tetrahydrofuran. Additionally, formulations containing primary or secondary amines should not be heated in the presence of the neat bromide without a cosolvent such as N-methylpyrrolidone, as nucleophilic aromatic substitution at the 4‑position can generate mutagenic 4‑amino‑2‑methylthiazole derivatives at temperatures above 80 °C.
Industrial sourcing of 4‑bromo‑2‑methylthiazole typically relies on the following specification set, verified against independent reference standards traceable to NIST where applicable.
| Parameter | Specification | Method |
|---|---|---|
| Assay (GC) | ≥ 98.0% | In‑house GC‑FID, internal standard |
| Isomeric impurity (5‑bromo‑2‑methylthiazole) | ≤ 0.5% | GC‑MS, RT comparison |
| Debrominated impurity (2‑methylthiazole) | ≤ 0.2% | GC‑FID, RRF = 1.05 |
| Water (KF) | ≤ 0.05% | ASTM E203 |
| Appearance | Pale yellow to amber liquid, free of particulates | Visual in cuvette, path length 10 mm |
| Density (25 °C) | 1.61–1.64 g·cm⁻³ | ASTM D4052 |
| Refractive index (nD20) | 1.558–1.564 | Abbé refractometer |
Selection of the correct bromothiazole is guided by systematic evaluation of coupling efficiency and side-product formation. The following table collates experimental benchmarks obtained on a common Suzuki‑Miyaura platform (phenylboronic acid, Pd(dppf)Cl2 1 mol%, K2CO3, dioxane/water, 80 °C).
| Property | 4‑Bromo‑2‑methylthiazole | 5‑Bromo‑2‑methylthiazole | 2‑Bromo‑4‑methylthiazole |
|---|---|---|---|
| Time to >98% conversion (min) | 40–50 | 100–120 | 180–240 |
| Major side product | 2‑methylthiazole (protodehalogenation) | Biphenyl (home‑coupling) | No conversion below 100 °C |
| Catalyst loading to reach 90% yield | 0.5 mol% | 2 mol% | 5 mol% (elevated T) |
| Melting point (°C) | Liquid at ambient | 28–30 | Liquid at ambient |
| Preferred handling condition | Store under nitrogen at 2–8 °C | Store under nitrogen at ambient | Store under nitrogen at 2–8 °C |
| Key advantage | Fast oxidative addition, lowest debromination | Higher selectivity in Sonogashira couplings | Low cost, but requires high‑temperature Ullmann conditions |
In a pilot plant evaluation of a fungicide intermediate synthesis that paired 4‑bromo‑2‑methylthiazole with a pyridylboronic acid, a 2000 L vessel equipped with a retreat‑curve impeller achieved a 91% isolated yield after recrystallization from isopropanol, compared with 63% for the 5‑bromo isomer under the same protocol. Off‑gassing of carbon dioxide from the carbonate base was managed by a vapor‑tight charging lance and a nitrogen sweep of 15 L·min⁻¹ through the condenser to prevent oxygen ingress. The exothermic coupling profile exhibited a peak heat release of 340 W·kg⁻¹, requiring jacket fluid chilled to ‑10 °C during the first 20 min of base addition. Post‑reaction, the organic layer was washed with 10% w/v aqueous sodium metabisulfite to reduce color bodies attributed to elemental bromine traces, demonstrating a practical method to meet APHA color specifications of <200 for the final crystalline product. Stability of the brominated precursor under these processing conditions was confirmed by IPC sampling; after 12 h circulation through a 5 µm polypropylene filter loop, no increase in dibrominated species was detected by LC‑MS, supporting the robustness of the C4 bromide under neutral pH and light‑free conditions.
