Methyl 2-Bromo-1,3-Thiazole-4-Carboxylate
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HS Code |
136861 |
| Name | Methyl 2 - Bromo - 1,3 - Thiazole - 4 - Carboxylate |
| Chemical Formula | C5H4BrNO2S |
| Molar Mass | 222.06 g/mol |
| Appearance | Typically a solid (appearance can vary based on purity and preparation) |
| Melting Point | Data may vary, needs specific experimental determination |
| Boiling Point | Data may vary, needs specific experimental determination |
| Solubility In Water | Low solubility, thiazole - based esters are generally hydrophobic |
| Solubility In Organic Solvents | Soluble in common organic solvents like dichloromethane, chloroform, ethyl acetate |
| Density | Data may vary, needs specific experimental determination |
| Flash Point | Data may vary, needs specific experimental determination |
| Reactivity | The bromine atom is reactive towards nucleophilic substitution reactions, and the ester group can undergo hydrolysis, trans - esterification |
As an accredited Methyl 2-Bromo-1,3-Thiazole-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 - 1,3 - Thiazole - 4 - Carboxylate in a sealed chemical - grade bottle. |
| Shipping | Methyl 2 - Bromo - 1,3 - Thiazole - 4 - Carboxylate is shipped in properly sealed containers, following strict chemical shipping regulations. Packaging ensures protection from breakage and leakage during transit. |
| Storage | Methyl 2 - Bromo - 1,3 - Thiazole - 4 - Carboxylate should be stored in a cool, dry, well - ventilated area. Keep it away from heat sources, flames, and oxidizing agents. Store in a tightly sealed container to prevent moisture absorption and potential reactions. Due to its bromine content, handle with care, and ensure the storage location is secure to avoid spills and unauthorized access. |
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In late-stage diversification of Type II kinase inhibitors, where the hinge-binding motif requires a planar heteroaryl carboxylate to achieve extended residence time at the ATP-binding site, Methyl 2-Bromo-1,3-Thiazole-4-Carboxylate is introduced as a crystalline, non-hygroscopic precursor for palladium-catalysed cross-coupling. The compound is charged into a 0.3 M solution in degassed 1,4-dioxane inside an MBraun UNIlab glovebox maintained at <0.1 ppm O₂ and <0.5 ppm H₂O. Coupling with (4-fluorophenyl)boronic acid (1.2 eq.) proceeds under a catalyst system comprising Pd(dba)₂ (0.5 mol%) and tri-tert-butylphosphine tetrafluoroborate (1.0 mol%) with anhydrous potassium carbonate (2.5 eq.) as base. The reaction mass is heated to 82 ± 3 °C under positive argon pressure for 6–8 h. Deviation above 85 °C initiates an unwanted debromination side reaction, detected by in-line ReactIR as a carbonyl shift at 1732 cm⁻¹ shifting to 1715 cm⁻¹ corresponding to the ester hydrolysis product. Upon complete consumption of the heteroaryl bromide (IPC by Agilent 1260 Infinity II HPLC, Zorbax SB-C18 column, 254 nm, tR 4.7 min), the crude mixture is filtered through a pad of Celite, concentrated on a Büchi R-300 rotary evaporator at 40 °C/25 mbar, and purified by automated flash chromatography (Biotage Isolera One, hexane/ethyl acetate gradient 10–50% over 12 column volumes). The isolated biaryl ester is obtained as an off-white solid with a typical purity of >99.2% by quantitative 1H NMR (internal standard 1,3,5-trimethoxybenzene). Residual palladium content is determined by ICP-MS according to USP <233>; a specification of <10 ppm is enforced before advancement to the next synthetic step to comply with ICH Q3D Option 1 intake limits for oral drug products. The ester is subsequently hydrolysed to the corresponding carboxylic acid using LiOH·H₂O (1.5 eq.) in THF/H₂O (3:1 v/v) at 0–5 °C to suppress epimerisation of the adjacent chiral centre in the target inhibitor scaffold. The free acid is activated with HATU (1.1 eq.) and DIPEA (3.0 eq.) in DMF and coupled to a previously elaborated chiral amine fragment to install the final kinase inhibitory pharmacophore. Batch records from kilo-lab campaigns highlight sensitivity to residual water: maintaining the reaction mixture below 200 ppm H₂O (Karl Fischer) during the amide bond-forming step prevents yield erosion from 94% to less than 70%. The thiazole-containing intermediate is subsequently crystallised from methyl tert-butyl ether/n-heptane to afford the API intermediate with a differential scanning calorimetry onset melting endotherm at 156.8 °C and a consistent XRPD pattern (Rigaku MiniFlex 600). Any batch exhibiting a polymorphic shift beyond 0.2° 2θ in the major diffraction peak at 8.7° 2θ is rejected for downstream tableting studies.A comparative screening of cross-coupling methodologies applied to this electron-deficient 2-bromoheterocycle underscores the impact of the catalytic system on process mass intensity. The table below summarises data from a parallel reaction evaluation conducted in an Argonaut Advantage Series 2050 synthesizer with 12 reactor positions.
What Controls Selectivity During Suzuki-Miyaura Cross-Coupling on a Heterocyclic Bromide Adjacent to an Ester Function?Field development of novel succinate dehydrogenase inhibitor (SDHI) fungicides has drawn substantial synthetic effort toward 2-aryl-1,3-thiazole-4-carboxylate templates as key intermediates. Methyl 2-Bromo-1,3-Thiazole-4-Carboxylate undergoes chemoselective coupling with 3,5-bis(trifluoromethyl)phenylboronic acid under biphasic conditions that minimise protodebromination. A dedicated process window utilises Pd(OAc)₂ (0.8 mol%) and sodium 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl-3-sulfonate (sSPhos, 1.6 mol%) in a toluene/water mixture (5:2 v/v) containing Aliquat 336 (2.5 vol%). Potassium phosphate tribasic (2.2 eq.) is preferred over carbonate bases to prevent saponification of the methyl ester during the prolonged 10 h hold at 78–80 °C. A rigorous stirring rate of 500–650 rpm in a jacketed baffled reactor ensures the dispersed aqueous phase droplet size remains at a Sauter mean diameter of 35–50 µm, measured by a Malvern Mastersizer 3000 with an in-line probe. Phase separation after quenching with a 5 wt% aqueous NaCl solution is performed at 55 °C to avoid emulsification. The organic layer is dried by azeotropic distillation under reduced pressure (200 mbar) until a water content below 150 ppm is achieved. The resulting 2-(3,5-bis(trifluoromethyl)phenyl)-1,3-thiazole-4-carboxylic acid methyl ester is saponified without isolation, and the free acid is converted to the corresponding acyl chloride using SOCl₂ in chlorobenzene with DMF as catalyst (0.05 eq.), then condensed with 2-amino-4,6-dimethylpyrimidine to form the target amide, which exhibits broad-spectrum activity against Rhizoctonia solani in vitro. The technical material is milled in a Netzsch MiniCer bead mill with a 0.3 mm yttria-stabilised zirconia grinding media to achieve a particle size distribution where D₉₀ < 4.0 µm (CIPAC MT 187, wet-sieving and laser diffraction). The resulting aqueous suspension concentrate (SC, 250 g/L) is formulated with an alkyl polyglucoside wetter (3.0 wt%) and a xanthan gum rheology modifier (0.15 wt%) to obtain a viscosity of 450–650 mPa·s at 20 s⁻¹ shear rate, ensuring pourability per CIPAC MT 148.1. Photodegradation was assessed following US EPA OCSPP 835.6100 (Tier 1 aqueous photolysis); the half-life under simulated sunlight (xenon arc, 300–800 nm) at 25 ± 2 °C in a sterilised buffer at pH 7.0 was determined to be 8.4 days, which warrants the inclusion of a benzotriazole UV absorber (1.0 wt%) in the formulation to maintain biological efficacy during field exposure. A 14-day storage stability test at 54 ± 2 °C (CIPAC MT 46.1.3) revealed no crystal growth beyond 1.0 µm and less than 3% relative loss in active ingredient content by HPLC dose verification, satisfying FAO specification 285/SC/S/F for systemic cereal fungicides. Conversion of the electron-deficient thiazole ring to a diazo component introduces intense bathochromic shifts suitable for high-washfastness azo disperse dyes for polyester textiles. The synthetic sequence begins with a controlled chemoselective reduction of the 2-bromo substituent while preserving the methyl ester. Catalytic transfer hydrogenation using ammonium formate (5.0 eq.) and 10% Pd/C (5 wt%, dry basis) in THF at 45 °C yields 2-amino-1,3-thiazole-4-carboxylic acid methyl ester in ± 91% yield. The amine is diazotised in a jacketed continuous-flow microreactor (Chemtrix Labtrix S1, glass microchip with 19.5 µL internal volume) by feeding an ice-cold solution of the amine hydrochloride (0.5 M) and sodium nitrite (1.02 eq., 0.55 M aqueous) at 0–2 °C with a residence time of 12 seconds, minimising diazonium decomposition. The resulting diazonium salt stream is immediately reacted with a 0.55 M solution of N,N-diethyl-m-toluidine in methanol/acetic acid (10:1 v/v) at a flow rate ratio of 1:1.2, producing a bright-red azo chromophore that precipitates upon drowning into ice water. After filtration and reslurry washing with demineralised water until a conductivity of <50 µS/cm is achieved, the presscake is dried in a vacuum oven at 55 °C/20 mbar. Milling is performed on an Alpine AFG 200 jet mill with a classifier speed of 6000 rpm, yielding a powder with a particle size D₅₀ of 0.8–1.2 µm. The product is standardised to a strength of 200% with a sulfonated lignin dispersant (Reax 88A, 30 wt%) and applied to polyester fabric in a Mathis Labomat high-temperature dyeing machine at 130 °C for 45 minutes at a liquor ratio of 10:1, yielding a build-up of 3.0% on weight of fibre. Fastness testing according to ISO 105-C06 (C2S wash) records a shade change of grade 4–5 and cross-staining on multifibre witness fabric of grade 4 for polyamide and acetate. Sublimation fastness per ISO 105-P01 at 210 °C/30 s is grade 3–4, which meets the thermomigration resistance required for automotive interior textiles. The structure is free of restricted arylamines listed in Annex XVII of REACH (entry 43) and the final dyestuff carries an OEKO-TEX Standard 100 certification class II compliance. Screening Electron-Deficient Comonomer Ratios for n-Type Semi-Conducting CopolymersDual-acceptor architectures for organic field-effect transistors (OFETs) exploit the low-lying LUMO of thiazole-4-carboxylate units to lower electron injection barriers. Methyl 2-Bromo-1,3-Thiazole-4-Carboxylate participates in Stille polycondensation with 5,5′-bis(trimethylstannyl)-2,2′-bithiophene (1.00 eq.) and a small fraction of 2,5-bis(trimethylstannyl)thienopyrroledione (0.15 eq.) to tune the frontier orbital alignment. A catalyst system composed of Pd₂(dba)₃ (1.5 mol%) and tris(2-methoxyphenyl)phosphine (6.0 mol%) in anhydrous chlorobenzene (0.15 M total monomer concentration) is subjected to microwave irradiation in a Biotage Initiator+ reactor at 160 °C for 40 minutes, followed by a second cycle at 180 °C for 20 minutes. The resultant polymer is precipitated into methanol, filtered, and purified by sequential Soxhlet extraction with methanol (low molecular weight fraction removal), acetone (oligomer removal), and hexane (residual monomer removal). The highest molecular weight fraction is collected by dissolution in hot dichlorobenzene and re-precipitated into vigorously stirred ethyl acetate. Gel permeation chromatography at 150 °C in 1,2,4-trichlorobenzene against narrow-dispersity polystyrene standards (Varian PLgel MIXED-B columns) yields a number-average molecular weight (Mn) of 21.4 kg mol⁻¹ with a dispersity (Đ) of 2.3, confirming the target degree of polymerisation > 50. Moisture content of the polymer flakes is determined to be <80 ppm by ASTM D5630 for thermogravimetric Karl Fischer coulometry. Top-contact bottom-gate OFET devices are fabricated on heavily doped p-type silicon wafers serving as the gate electrode, with a thermally grown SiO₂ dielectric (300 nm, capacitance 11.5 nF cm⁻²). The substrate is treated with hexamethyldisilazane (HMDS) vapour at 120 °C for 1 h before spin-coating a 7 mg mL⁻¹ solution of the copolymer in chloroform at 1500 rpm for 60 s, then annealed at 200 °C in a nitrogen-filled glovebox for 30 minutes. Gold source/drain contacts (50 nm) are evaporated through a shadow mask defining a channel length of 50 µm and width of 1000 µm. Transistor characterisation is performed inside an MBraun LABmaster glovebox (<0.1 ppm O₂, <0.1 ppm H₂O) using a Keithley 4200-SCS parameter analyser. The saturated electron mobilities extracted from the transfer curve in the accumulation regime according to the gradual channel approximation yield an average of 0.27 cm² V⁻¹ s⁻¹ with a threshold voltage of +12.4 V and an on/off current ratio exceeding 10⁴. Bias stress stability was tested under IEEE 1620-2019 methodology; the drain current decay remained below 8% after 3600 s continuous biasing at VGS = 40 V, indicating suitability for solution-processed flexible display backplanes where electron-transport layers must withstand repeated gate pulsing. Transmetalation Intermediates in Phosphine-Thiazole Hybrid Ligand SystemsEnantioselective palladium-catalysed allylic alkylation relies on conformationally biased P,N-chelates where the thiazole nitrogen exhibits a reduced donor strength that favours rapid reductive elimination of the desired chiral product. Methyl 2-Bromo-1,3-Thiazole-4-Carboxylate is converted to a phosphine-thiazole hybrid ligand through lithium-bromine exchange. A flame-dried Schlenk tube is charged with the bromide (1.0 eq.) dissolved in anhydrous THF (0.2 M) and cooled to −78 °C using an acetone/dry ice bath under an argon atmosphere. A solution of n-butyllithium in hexanes (1.05 eq., 2.5 M) is added dropwise over 15 minutes, maintaining the internal temperature below −73 °C as monitored by a type-K thermocouple. The anion formation is accompanied by a distinct colour change from pale yellow to deep orange. After stirring for 45 minutes at −78 °C, chlorodiphenylphosphine (1.03 eq.) is introduced via a Hamilton gas-tight syringe over 5 minutes. The cooling bath is removed, and the mixture is allowed to warm gradually to 0 °C over 2 h, then quenched with degassed, deionised water (2 mL). The product is extracted with diethyl ether (3 × 20 mL), dried over anhydrous Na₂SO₄, and concentrated in vacuo. The crude oil is purified on a Biotage KP-Sil column under argon pressure, eluting with degassed, peroxide-free toluene/ethyl acetate (20:1) to deliver methyl 2-(diphenylphosphino)-1,3-thiazole-4-carboxylate as a viscous, air-sensitive yellow oil in 74% yield after solvent stripping. 31P NMR (162 MHz, CDCl₃) reveals a single resonance at δ −4.2 ppm, indicative of the diarylphosphine environment. The ligand (2.2 eq.) is stored as a 0.05 M stock solution in toluene inside a nitrogen-purged refrigerator at −20 °C to retard phosphine oxidation that otherwise manifests as a phosphine oxide impurity at δ +27.1 ppm within 48 h in ambient air. The active palladium catalyst is generated in situ by mixing Pd₂(dba)₃ (1.0 mol% Pd) with the ligand and allyl acetate substrate in dichloromethane at room temperature before addition of the sodium dimethyl malonate nucleophile. The catalytic run is monitored by withdrawing aliquots at timed intervals under positive nitrogen; each aliquot is quenched with 0.1 M aqueous EDTA and extracted into hexane for chiral GC analysis on an Agilent CycloSil-B column (30 m × 0.25 mm, 0.25 µm film). The major (R)-enantiomer elutes at 12.7 min with an enantiomeric excess of 92% at full conversion, a value sensitive to the stirring rate: magnetic stirring at 1200 rpm versus 400 rpm shifts the ee from 92% to 78%, attributed to micro-heat zones accelerating the racemic background reaction according to a microkinetic model. No regulatory triggers established under the U.S. Toxic Substances Control Act 40 CFR Part 704 currently apply to this intermediate, though all material safety handling must follow laboratory fume hood practice meeting ANSI/ASHRAE 110-2016 containment benchmarks. The allylated malonate product serves as a versatile intermediate for the synthesis of enantioenriched β-chiral amines and carboxylic acids found in medicinal chemistry programs concerning ion channel modulators. |
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| Parameter | Limit | Method |
|---|---|---|
| Assay (anhydrous, solvent‑free) | 98.0–102.0 % | HPLC, area‑%, 220 nm; C18, 5 µm, MeCN/water 60:40 |
| Melting range | 33.0–35.0 °C | ASTM E324‑79(2023), capillary, heating rate 1 °C·min⁻¹ |
| Water content (KF) | ≤0.3 % | ISO 760:1978, coulometric |
| Residual solvents | Ethyl acetate ≤0.1 %; MeOH ≤0.05 % | GC‑FID, headspace, USP <467> |
| Sulphated ash | ≤0.1 % | Ph.Eur. 2.4.14 |
| 5‑bromo isomer (GC or HPLC) | ≤0.5 % | HPLC, same conditions, RRT ~1.12 |
| Heavy metals | ≤10 ppm | Ph.Eur. 2.4.8, Method A |
