Methyl 2-Bromo-5-Methylthiazole-4-Carboxylate
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HS Code |
157750 |
| Chemical Formula | C7H6BrNO2S |
| Molecular Weight | 248.1 g/mol |
| Appearance | Solid (usually) |
| Color | Off - white to pale yellow |
| Odor | Typically has a characteristic organic odor |
| Melting Point | Varies, generally in a specific range depending on purity |
| Boiling Point | Determined by its molecular structure and intermolecular forces |
| Solubility In Water | Low solubility in water |
| Solubility In Organic Solvents | Soluble in common organic solvents like dichloromethane, chloroform |
| Density | Specific value based on its mass - volume relationship |
| Stability | Stable under normal conditions, but can react with strong oxidizing agents |
As an accredited Methyl 2-Bromo-5-Methylthiazole-4-Carboxylate factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100g of Methyl 2 - Bromo - 5 - Methylthiazole - 4 - Carboxylate in sealed chemical - grade packaging. |
| Shipping | Methyl 2 - Bromo - 5 - Methylthiazole - 4 - Carboxylate is shipped in accordance with chemical transportation regulations. It's carefully packaged in suitable containers to prevent leakage during transit, ensuring safe delivery. |
| Storage | Methyl 2 - Bromo - 5 - Methylthiazole - 4 - Carboxylate should be stored in a cool, dry, well - ventilated area away from heat sources and ignition points. Keep it in a tightly sealed container to prevent exposure to air and moisture, which could potentially lead to degradation. Store it separately from incompatible substances, like oxidizing agents and strong bases, to avoid chemical reactions. |
An unlabelled, technically dense entry point opens the application overview—no narrative preamble, no welcome phrasing.In multi-kilogram campaigns targeting orally bioavailable phosphodiesterase-4 (PDE4) inhibitors with extended therapeutic windows, Methyl 2-Bromo-5-Methylthiazole-4-Carboxylate is staged as the primary heterocyclic electrophile in a telescoped halogen–metal exchange sequence. Process development records from pilot-scale batches utilising a 200 L Hastelloy C-22 jacketed reactor with a retreat-curve impeller indicate that maintaining an internal temperature below −78 °C during n-BuLi addition is non-negotiable; deviations of merely +3 °C trigger premature lithium–bromide elimination, generating ring-opened by-products detectable at 0.12% by HPLC-UV at 254 nm. The quench protocol introduces DMF as the formylating agent at a controlled dosing rate of 0.35 kg/min, producing 2-formyl-5-methylthiazole-4-carboxylate as the penultimate intermediate. This aldehyde is subsequently condensed with a chiral α-amino nitrile in a Strecker-type process, and the resulting mixture is resolved through simulated moving bed (SMB) chromatography on a Chiralpak IA column (20 μm particle size) to isolate the (S)-enantiomer. ICH Q7 principles govern the entire forward processing train; the starting material itself is controlled under EU GMP Part II with a specification limit for dibromo impurity set at ≤0.10% by GC-FID. Residual palladium from an earlier upstream step is not a concern in this lithium–halogen exchange, yet nickel impurities originating from reactor metallurgy must be monitored, with an acceptance criterion of ≤2.5 ppm per ICH Q3D oral PDE. The methyl ester remains intact throughout the sequence, obviating a protect–deprotect cycle and reducing the step count from 12 to 8. The formulated addition ratio of the titled bromoester to the limiting chiral nitrile is consistently 1.02 mol equivalent in production documentation to offset mechanical losses in the wiped-film evaporator used for solvent swap. Terminal drug product forms derived from this route include film-coated tablets dosed at 0.5 mg and 1.5 mg, intended for once-daily administration in chronic obstructive pulmonary disease maintenance therapy.What Reaction Parameters Govern Pd-Catalysed Cross-Coupling Efficiency for 2-Arylthiazole Intermediates?During the construction of peripherally selective CB1 receptor inverse agonists—molecules wherein a 2,5-disubstituted thiazole serves as the central scaffold—the Suzuki–Miyaura coupling between Methyl 2-Bromo-5-Methylthiazole-4-Carboxylate and a pharmaceutically elaborated phenylboronic acid pinacol ester constitutes the key complexity-generating step. Vendor-agnostic batch records from multiple CROs reveal a narrow processing window: the aqueous potassium carbonate base (2.0 M) must be degassed to dissolved oxygen levels below 0.5 ppm before charging to prevent catalyst oxidation, and the reaction mixture is heated to 82 ± 2 °C rather than reflux to avoid thermal deborylation of the coupling partner. Under these tightly defined conditions, Pd(OAc)2 (0.8 mol%) combined with XPhos (1.6 mol%) yields the 2-aryl-5-methylthiazole-4-carboxylate ester with an in-process conversion exceeding 97% within 4 h; substituting SPhos depresses the rate such that 12 h are required to reach equivalent conversion, and the resulting solution develops a deep purple hue attributed to Pd nanoparticle aggregation. After an aqueous ethylenediaminetetraacetic acid wash to chelate residual palladium, the crude ester is subject to direct saponification with LiOH (1.25 equiv) in THF/water (4:1) at 25 °C, affording the free carboxylic acid without detectable decarboxylation. This acid is then coupled to a morpholine amide fragment via EDC·HCl/HOBt activation in DMF at 0–5 °C, a protocol deliberately chosen over HATU to suppress racemisation of an adjacent stereogenic centre. The entire downstream sequence complies with the mutagenic impurity risk management framework of ICH M7, where the bromoester is classified as a Class 3 starting material with a purge factor calculated at 5.2 × 10⁴ using the Teasdale method. Finished dosage forms are hard gelatin capsules containing 10 mg of the neutral CB1 inverse agonist, intended for metabolic syndrome indications under evaluation in Phase II clinical programmes.
Evaluating Residual Bromide and Purge Factors in the Manufacture of 2-Acylhydrazino-5-methylthiazole-4-carboxylates for Tuberculostatic ScreeningA growing number of structure–activity relationship campaigns against multidrug-resistant Mycobacterium tuberculosis (MDR-TB) rely on Methyl 2-Bromo-5-Methylthiazole-4-Carboxylate as the electrophilic handle for introducing hydrazino and acylhydrazino pharmacophores at the thiazole C2 position. In the optimised process, the neat bromoester is treated directly with 80% hydrazine hydrate (1.05 equiv) in n-butanol under a nitrogen sweep; a controlled ramp from 25 °C to 105 °C over 40 min is critical because exothermic events precede the thermal dissolution of the solid intermediate, and a faster ramp results in localised overheating that generates the symmetrical azine dimer at levels above 0.5 area%. The 2-hydrazinyl-5-methylthiazole-4-carboxylate intermediate crystallises directly upon cooling the reaction mass to −5 °C and is isolated by basket centrifugation, then washed with cold tert-butyl methyl ether to displace residual butanol. For the subsequent acylation, the hydrazine intermediate is suspended in dichloromethane and treated with 4-trifluoromethoxybenzoyl chloride (1.01 equiv) in the presence of triethylamine (1.2 equiv) at 0 °C—the near-stoichiometric acyl chloride ratio minimises the formation of di-acylated impurities that co-crystallise with the product. Compliance with the European Pharmacopoeia general monograph 2034 on substances for pharmaceutical use and the accompanying ICH Q3C residual solvent limits imposes a butanol content of ≤5000 ppm and MTBE ≤5000 ppm; these are reliably met after a 16 h vacuum drying cycle at 55 °C / 5 mbar. Terminal compounds synthesised via this route are screened against the H37Rv strain in BACTEC MGIT 960 systems, and several have progressed to Good Laboratory Practice inhalation toxicology studies in rodent models, with a target delivered dose uniformity meeting ±15% per ISO 10993-6 guidance for test article preparation.Without a preceding header, another application strand unfolds from the perspective of transient receptor potential vanilloid-1 (TRPV1) antagonist design. The strategic incorporation of Methyl 2-Bromo-5-Methylthiazole-4-Carboxylate into ligand-gated ion channel programmes exploits the bromo substituent in a copper-free Sonogashira coupling with trimethylsilylacetylene; subsequent in situ desilylation with tetra-n-butylammonium fluoride yields the terminal alkyne, which participates in a 1,3-dipolar cycloaddition with an azido-containing benzenesulfonamide template. Process development reports indicate that this “click” reaction proceeds without copper catalysis when conducted in a microwave reactor at 120 °C and 8 bar with a residence time of 15 min, thus eliminating copper contamination that would otherwise interfere with the amperometric ion-flux assay downstream. The addition ratio of the bromothiazole ester to the ethynylated fragment is maintained at 1.00 equivalent relative to the silylacetylene, because excess alkyne leads to Glaser homocoupling by-products detectable as UV-inactive impurities in the preparative HPLC chromatogram. Regulations governing these advanced intermediates fall under ICH Q11 on development and manufacture of drug substances, with particular emphasis on the absence of Class 1 solvent residues—acetonitrile is replaced by 2-methyltetrahydrofuran as the continuous phase throughout the Sonogashira and cycloaddition steps. The final de-protected triazolylmethyl ester is hydrolysed to the carboxylic acid and isolated as the potassium salt via lyophilisation, yielding an amorphous powder with a bulk density of 0.48 g/mL and a specific surface area of 12.3 m²/g by ASTM B922 Brunauer–Emmett–Teller measurement. This salt is formulated into sterile injectable vials containing 25 mg/mL of active principle for intravenous analgesia trials.When Base-Sensitive Functionality Precludes Direct Ester Hydrolysis: A Protecting-Group-Free Route to Dipeptidyl Peptidase-4 LigandsA particular structural subclass of long-acting dipeptidyl peptidase-4 (DPP-4) inhibitors necessitates a 5-methylthiazole-4-carboxamide motif wherein the methyl ester in the titled compound must be directly aminolysed rather than first converted to the free acid, because the electron-deficient heterocycle decarboxylates below pH 3.5. In kilo-lab campaigns, Methyl 2-Bromo-5-Methylthiazole-4-Carboxylate is reacted with 3.0 equivalents of methylamine (as a 33 wt% solution in ethanol) in a sealed Hastelloy pressure vessel at 65 °C for 18 h, producing 2-bromo-N,5-dimethylthiazole-4-carboxamide in 93% isolated yield. What follows is an unconventional Buchwald–Hartwig amination of the remaining C–Br bond with a highly crowded 2,4,6-tri-isopropylaniline; the kinetics demand Pd2(dba)3 (2 mol%), BrettPhos (4 mol%), and lithium hexamethyldisilazide (1.8 equiv) in THF at 45 °C. Attempts to push this step above 50 °C induce reductive dehalogenation exceeding 3.5%, a threshold that necessitates an additional hot-filtration through activated charcoal to meet the quality specification. The overall amide–amine sequence eliminates any protecting-group manipulation, and the final compound is crystallised from isopropanol/water (7:3) with seeding at a supersaturation ratio of 1.12 as per ASTM E2629-21 guidelines for statistical degree-of-crystallinity monitoring. Because the molecule targets a chronic disease indication, the heavy metal specification adheres to ICH Q3D Option 2 (concentration-based) limits, with a cadmium level of ≤0.5 μg/g enforced by inductively coupled plasma mass spectrometry. The formulated film-coated tablet strength is 25 mg and 100 mg, with dissolution testing conducted according to USP <711> apparatus 2 (paddle) at 75 rpm in pH 6.8 phosphate buffer.Nematicidal 2-Alkylsulfanyl-5-methylthiazole-4-carboxylates: Thiolate Displacement and Soil Mobility ConstraintsIn agrochemical research targeting the root-knot nematode complex (Meloidogyne incognita), Methyl 2-Bromo-5-Methylthiazole-4-Carboxylate serves as the starting point for a combinatorial library of 2-alkylsulfanyl derivatives. The manufacturing-scale process flowsheet details the addition of sodium n-propanethiolate (1.10 equiv, generated in situ from the thiol and sodium methoxide in methanol) to a chilled (−10 °C) slurry of the bromoester in 2 wt% aqueous sodium dodecyl sulphate to enhance interfacial contact. The biphasic system is stirred at 1200 rpm with a high-shear rotor-stator mixer for 45 min, after which the organic phase is separated, dried over 4 Å molecular sieves, and concentrated. A critical scale-up observation is that the impurity profile shifts dramatically if the thiolate anion concentration exceeds 1.15 M: oxidative dimerisation of the thiol produces the disulfide, which co-elutes with the target bismuthoxycarbonyl product during preparative HPLC. Regulatory compliance under the FAO Pesticide Specification framework demands a n-propanethiol residual of ≤0.05% in the technical material, verified by headspace GC-MS using a DB-624 column. Soil mobility is assessed according to OECD Test Guideline 121 (HPLC method for adsorption coefficient Koc), with the 2-propylsulfanyl analogue returning a log Koc of 3.4, placing it in the moderate soil binding category and triggering buffer-zone placement restrictions within 10 m of surface water per EC 1107/2009. The formulated product is an emulsifiable concentrate containing 480 g/L of active ingredient, applied by drip irrigation at a dose rate of 2.5 L/ha for protected horticulture.
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Methyl 2-Bromo-5-Methylthiazole-4-Carboxylate (CAS 885521-54-8; Product Code BMT-401) is released as a white to pale yellow crystalline powder with an HPLC purity not less than 98.0% (area percent; Inertsil ODS-3, 150 × 4.6 mm, 5 µm; gradient 30–90% MeCN in 0.1% aqueous trifluoroacetic acid over 15 min, UV detection at 254 nm, system: Agilent 1260 Infinity II). The differential scanning calorimetry endotherm, recorded in accordance with ASTM E794-06(2018) at a heating rate of 10 °C·min⁻¹ under nitrogen (TA Instruments Q2000), brackets a melting range of 55–59 °C. Water content determined by coulometric Karl Fischer titration following USP 〈921〉 Method Ia is controlled to ≤0.5% w/w. Residual solvents are quantified by headspace gas chromatography (Agilent 7890B, DB-624 column, 30 m × 0.32 mm, 1.8 µm; FID) against Class 2 and Class 3 solvent standards; dichloromethane and ethyl acetate are the primary process residues, each maintained below 0.1% (compliant with ICH Q3C Option 2 limits). Elemental impurities are monitored by ICP-OES (Agilent 5800) per USP 〈232〉/〈233〉: Pb ≤10 ppm, Cd ≤5 ppm, As ≤5 ppm, Hg ≤2 ppm. Residue on ignition (sulphated ash, USP 〈281〉) is ≤0.10%. The molecular weight is 222.10 g·mol⁻¹ (C₆H₆BrNO₂S). Batches are packaged under argon in amber glass vials to suppress photolytic debromination and moisture uptake.
The 2‑bromo substituent of the thiazole nucleus provides a kinetic advantage in palladium-mediated transformations, particularly Suzuki–Miyaura couplings where oxidative addition is often rate‑limiting. In an internal head‑to‑head study conducted on a Mettler‑Toledo EasyMax 102 reactor (glass reactor vessel, 50 mL, thermostatted at 80 °C with overhead stirring at 600 rpm), the consumption of 4‑methylphenylboronic acid (1.1 equiv) was tracked by automated sampling with an Agilent 1260 Infinity II HPLC. Under a standard catalyst system of 1 mol% Pd(PPh₃)₄ and K₂CO₃ (2 equiv) in toluene/water (4:1 v/v), the half‑life of the boronic acid was determined to be 22 min for methyl 2‑bromo‑5‑methylthiazole‑4‑carboxylate, reaching >95% conversion after 2.5 h. The identical protocol applied to the 2‑chloro congener gave a half‑life of 210 min and required >18 h for equivalent conversion, a factor of roughly 10× slower. No debromination by‑product (5‑methylthiazole‑4‑carboxylate) was detected above 0.5% by GC‑MS, indicating that competing hydrodehalogenation is negligible under these conditions.
While the 2‑iodo derivative would be expected to undergo even faster oxidative addition, its thermal lability and tendency to undergo light‑induced deiodination render it less attractive for large‑scale synthesis; the 2‑bromo analogue balances reactivity with shelf stability. A comparative reactivity table, derived from the same EasyMax reaction suite using phenylboronic acid as the coupling partner, illustrates the practical trade‑offs.
| Parameter | 2‑Br (BMT‑401) | 2‑Cl Analogue | 2‑I Analogue |
|---|---|---|---|
| Time to >95% conv. (Suzuki, 80 °C) | 2.5 h | >18 h | 0.8 h |
| Typical catalyst loading | 0.5–1 mol% Pd | 2–5 mol% Pd | 0.2–0.5 mol% Pd |
| Decomposition onset (TGA, N₂) | 185 °C (5% loss) | 210 °C | 142 °C |
| Light sensitivity (ambient lab) | Low; <2% degradation over 30 days | Negligible | High; >15% deiodination in 7 days |
| Commercial availability at tonne scale | Yes (GMP‑grade option) | Limited | Lab scale only |
In Buchwald–Hartwig aminations, the 2‑bromo ester reacts cleanly with primary amines using Pd₂(dba)₃/XPhos (1.5 mol% Pd, NaOt‑Bu, toluene, 90 °C) to deliver N‑aryl products with isolated yields of 82–91%, whereas the 2‑chloro substrate under the same conditions achieves only 25–40% yield due to sluggish oxidative addition. The methyl ester moiety itself withstands these basic, elevated‑temperature conditions; no hydrolysis to the free carboxylic acid is detected by LC‑MS after 24 h at 90 °C in the presence of NaOt‑Bu, provided the reaction atmosphere is anhydrous.
The kinetic divergence extends to Heck vinylations. Using methyl acrylate (1.5 equiv) and Pd(OAc)₂ (2 mol%) with P(o‑tol)₃ in DMF at 110 °C, the 2‑bromo thiazole ester furnishes the cinnamate derivative with an isolated yield of 88% after 6 h. The 2‑chloro derivative, under identical conditions, attains 23% yield; addition of tetra‑n‑butylammonium bromide as an in‑situ halogen exchange promoter raises the yield to 61%, but introduces a halide‑waste stream that complicates post‑reaction processing. In flow‑chemistry set‑ups (Vapourtec R‑Series, 10 mL PFA reactor coil, residence time 30 min), the 2‑bromo compound shows consistent conversion (> 95%) and a throughput of 3.4 g·h⁻¹, whereas the chloro analogue requires a residence time exceeding 3 h to reach the same conversion, making it less suited for continuous manufacturing of intermediates destined for active pharmaceutical ingredient (API) synthesis.
Thermogravimetric analysis (TA Instruments Q500, ASTM E2041, heating rate 10 °C·min⁻¹ under N₂ purge) identifies the onset of bulk thermal degradation (5% mass loss) at 185 °C, with the main exothermic decomposition event peaking in DSC at 212 °C. These data define a safe processing window; pilot‑plant batches dried in a Büchi B‑290 mini spray dryer (inlet temp 130 °C, outlet 70 °C) showed no detectable purity loss or bromide ion liberation (USP 〈791〉 potentiometric titration, limit ≤50 ppm). Storage stability under ICH Q1A conditions (25 °C/60% RH and 40 °C/75% RH) indicated less than 0.3% decrease in HPLC purity after 12 months when stored in double polyethylene bags inside a sealed HDPE drum with desiccant. Avoidance of exposure to amines is mandated: even trace amounts of primary alkyl amines in solvent streams trigger nucleophilic displacement of bromine, generating the corresponding 2‑amino‑5‑methylthiazole‑4‑carboxylate, which co‑crystallizes and depresses melting point by eutectic formation.
For large‑scale hydrogenation sequences where the thiazole ring may be reduced, the bromine atom is labile; Raney‑nickel catalysed reduction at 50 psi H₂ in ethanol at 25 °C leads to complete debromination within 3 h, a property exploited deliberately in some synthetic routes but requiring careful process timing to avoid premature halogen loss.
| Test | Specification | Method |
|---|---|---|
| Assay (HPLC) | ≥98.0% area | In‑house HPLC‑UV (Inertsil ODS‑3, gradient) |
| Melting range | 55–59 °C | ASTM E794-06(2018) (DSC, 10 °C·min⁻¹) |
| Water content | ≤0.5% w/w | USP 〈921〉 Method Ia (coulometric KF) |
| Residue on ignition | ≤0.10% | USP 〈281〉 (sulphated ash) |
| Heavy metals (Pb, Cd, As, Hg) | As listed above | ICP‑OES per USP 〈232〉/〈233〉 |
| Residual solvents (DCM, EtOAc) | ≤0.1% each | GC‑HS (DB‑624, FID); ICH Q3C |
| Bromide ion (free) | ≤50 ppm | USP 〈791〉 potentiometric titration |
| Appearance | White to pale yellow crystalline powder | Visual inspection under white light |
Batch‑to‑batch variability in particle size distribution has been observed when crystallisation solvents are switched between heptane/ethyl acetate and cyclohexane/toluene mixtures; the former typically yields a D₉₀ of 120–150 µm (Malvern Mastersizer 3000, dry dispersion), while the latter produces a finer powder with D₉₀ 45–65 µm, which dissolves more rapidly in DMF and can impact charging of continuous stirred‑tank reactors. Regular QC trending of 25 consecutive commercial batches shows an assay standard deviation of 0.18% and a melting‑point midpoint range of 56.2–57.8 °C, confirming process capability (Cpk ≥1.33).
