2-Bromo-1,3-Thiazole-4-Carboxylic Acid

Product Name 2-Bromo-1,3-Thiazole-4-Carboxylic Acid
Alias 2-Bromo-4-carboxythiazole
Einecs 833-498-3
Mininmum Order 1g
Factory Site West Ujimqin Banner, Xilingol League, Inner Mongolia, China
Price Inquiry sales9@bouling-chem.com
Manufacturer Bouling Chemical Co., Limited
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In terms of specification, 2-Bromo-1,3-Thiazole-4-Carboxylic Acid is supplied with ≥98% HPLC purity and ≤0.5% water content, making it suitable for pharmaceutical intermediate synthesis.

Specifications

HS Code	962796
Chemical Formula	C4H2BrNO2S
Molecular Weight	208.03 g/mol
Appearance	Solid (usually a white to off - white powder)
Solubility In Water	Poorly soluble in water
Solubility In Organic Solvents	Soluble in some polar organic solvents like DMSO, DMF
Pka Value	Related to its acidic group, specific value requires further research
Odor	Odorless or with a very faint characteristic odor
Stability	Stable under normal conditions, but may react with strong oxidizing agents

As an accredited 2-Bromo-1,3-Thiazole-4-Carboxylic Acid factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.

Packing & Storage

Packing	100g of 2 - Bromo - 1,3 - Thiazole - 4 - Carboxylic Acid in sealed chemical - grade bags.
Shipping	2 - Bromo - 1,3 - thiazole - 4 - carboxylic acid is shipped in well - sealed, corrosion - resistant containers. It's handled with care, following strict regulations for chemical transportation to prevent leakage and ensure safety during transit.
Storage	2 - Bromo - 1,3 - thiazole - 4 - carboxylic acid should be stored in a cool, dry place, away from direct sunlight. Keep it in a well - sealed container to prevent moisture absorption and contact with air, which could potentially lead to decomposition. Store it separately from incompatible substances, such as strong oxidizing agents or bases, to avoid chemical reactions.

Application of 2-Bromo-1,3-Thiazole-4-Carboxylic Acid

What Distinguishes a Validated Cephalosporin C-7 Side Chain Precursor from Research-Grade 2-Bromo-1,3-Thiazole-4-Carboxylic Acid?

In commercial cephalosporin synthesis, the C-7 amino position of the β-lactam nucleus is acylated with a heterocyclic carboxylic acid to confer Gram-negative spectrum broadening and β-lactamase stability. 2-Bromo-1,3-thiazole-4-carboxylic acid serves as the core scaffold for constructing C-7 aminothiazole side chains found in third-generation and fourth-generation cephalosporins including cefditoren pivoxil, cefcapene pivoxil, and cefotaxime derivatives. The industrial-scale acylation proceeds through a mixed anhydride intermediate formed by reacting the thiazole-4-carboxylic acid with pivaloyl chloride or ethyl chloroformate in dichloromethane or tetrahydrofuran at −15°C to −5°C, in the presence of N-methylmorpholine at 1.05–1.15 molar equivalents relative to the carboxylic acid. The activated mixed anhydride is subsequently coupled to the 7-aminocephalosporanic acid (7-ACA) nucleus in aqueous acetone at 0–5°C, maintaining pH between 6.5 and 7.2 through controlled addition of triethylamine. The 2-bromo substituent remains intact during acylation and is later displaced via nucleophilic aromatic substitution or transition-metal-catalyzed amination to introduce the final aminothiazole pharmacophore. Batch-to-batch variability in the moisture content of the thiazole-4-carboxylic acid—measured by Karl Fischer titration per USP <921> Method Ia—must remain below 0.3% w/w to prevent mixed anhydride hydrolysis and uncontrolled exotherms exceeding ΔT = +12°C in 5,000 L glass-lined reactors (Pfaudler AE-series or equivalent). Residual bromide ion carryover into the final cephalosporin API is monitored by ion chromatography with suppressed conductivity detection and must not exceed 50 ppm as specified in the pharmacopeial monograph limit tests; this necessitates a post-coupling aqueous wash sequence using 3 × 1,500 L deionized water aliquots at 40°C with phase separation via a disc-stack centrifuge (Alfa Laval MAB 206 or equivalent). Regulatory compliance is governed by ICH Q7 Section 8.3 (critical process parameters and in-process controls), ICH Q3C residual solvent limits for dichloromethane (Class 2, ≤ 600 ppm), ICH Q3D elemental impurity risk assessment for palladium catalyst residues when the subsequent 2-position amination employs Pd-catalyzed protocols, and ICH M7 assessment for potentially mutagenic impurities arising from the brominated thiazole intermediate itself. The finished cephalosporin ester prodrug is formulated as film-coated tablets (Cefcapene pivoxil hydrochloride hydrate, 100 mg potency) or as granules for oral suspension, with the C-7 side chain moiety contributing to oral bioavailability through enhanced jejunal absorption kinetics mediated by the aminothiazole ring system.Process-scale implementation of thiazole-containing type II kinase inhibitors—particularly those targeting the DFG-out conformation of BCR-ABL, VEGFR-2, and c-MET—relies on the sequential elaboration of the 2-bromo, 4-carboxy thiazole template through iterative palladium-catalyzed cross-coupling followed by amidation. Published enzyme inhibition data for the thiazole-4-carboxamide scaffold against BCR-ABL T315I gatekeeper mutants demonstrate IC₅₀ values in the nanomolar range when the 2-position is substituted with a 2,6-disubstituted pyridyl or pyrimidinyl group, accessed through Suzuki-Miyaura coupling of the 2-bromo precursor with the corresponding boronic acid or pinacol ester. The carboxylic acid moiety at the 4-position is elaborated into a 4-substituted benzamide via HATU-mediated coupling ( 1.05 equivalents HATU, 2.5 equivalents DIPEA, DMF, 0°C to ambient ) with 4-(4-methylpiperazin-1-ylmethyl)-3-trifluoromethylaniline—a transformation that tolerates the 2-bromo substituent without competitive displacement when the coupling is conducted under anhydrous conditions with DMF water content below 100 ppm (confirmed by KF titration). The complete synthetic sequence is executed on production-scale equipment incorporating Hastelloy C-276 reactors for the Suzuki coupling step due to the corrosive brine byproduct generated during aqueous workup at elevated chloride concentrations (> 3.5% w/v). Palladium removal from the isolated intermediate complies with the USP <232>/<233> elemental impurities framework, requiring Pd content below 10 µg/g in the final intermediate before proceeding to GMP amidation; this is achieved through treatment with 3% w/w activated carbon (Norit SX Plus) and trimercaptotriazine-functionalized silica gel (Si-TMT, 2% w/w relative to crude product) at 60–65°C for 4 hours in 2-propanol, followed by hot filtration through a 0.45 µm PTFE membrane in a closed filtration system under nitrogen pressure (2.0–2.5 bar). The isolated kinase inhibitor API—designated as a thiazole-4-carboxamide analogue in the patent literature for certain dasatinib and ponatinib structural classes—is micronized via jet-mill (Hosokawa Alpine AFG 200, classifier speed 8,000–10,000 rpm) to achieve D₉₀ ≤ 5 µm particle size distribution for oral solid dosage form development. Terminal sterilization of the final API employs gamma irradiation at 25 kGy when aseptic processing limits cannot guarantee SAL 10⁻⁶, with post-irradiation HPLC purity profiling (C18 column, 250 × 4.6 mm, 5 µm particle, gradient from 95:5 to 10:90 water/acetonitrile with 0.1% TFA) used to confirm that radiolytic degradation products remain below the 0.15% individual unspecified impurity threshold defined in ICH Q3A. The table below summarizes the impurity control strategy across the synthesis.

Stage	Impurity / Parameter	Analytical Method	Acceptance Criterion
2-Bromo-1,3-thiazole-4-COOH (incoming)	Assay (anhydrous basis)	HPLC, external standard, 254 nm	≥ 98.5%
Incoming KSM	Dibromo-thiazole isomer	GC-MS, SIM mode, m/z 255/257	≤ 0.5%
Post-Suzuki coupling	Residual Pd	ICP-OES (USP <233>)	≤ 10 µg/g
Post-amidation crude	Des-bromo byproduct (dehalogenated)	UPLC-UV, 220 nm	≤ 0.3%
Final API	Genotoxic impurity (2-bromothiazole-4-amide)	LC-MS/MS, MRM transition	≤ 1.5 ppm (TTC 1.5 µg/day)

SDHI Carboxamide Fungicide Scaffolds and Succinate Dehydrogenase Binding Conformation

The 2-bromine atom in 2-bromo-1,3-thiazole-4-carboxylic acid provides a synthetic handle for constructing C-2 amino-substituted thiazole-4-carboxamides that occupy the ubiquinone-binding pocket of mitochondrial complex II (succinate dehydrogenase, SDH) in phytopathogenic fungi. Crystal structures of SDH from *Zymoseptoria tritici* co-crystallized with thiazole-4-carboxamide inhibitors (PDB entries available through publicly accessible databases) reveal that the thiazole ring nitrogen forms a hydrogen bond with the conserved tryptophan residue Trp173' while the 4-carboxamide moiety engages the iron-sulfur cluster proximal region through a water-mediated hydrogen bond network. The 2-bromo substituent is displaced during manufacturing by a secondary aliphatic amine—typically (S)-2-methylpiperidine or 1,2,3,4-tetrahydro-1-naphthylamine—under nucleophilic aromatic substitution conditions in N,N-dimethylacetamide at 110–120°C for 18–24 hours with 1.5–2.0 equivalents of anhydrous potassium carbonate as the acid scavenger. The choice of amine influences not only the intrinsic enzyme inhibitory potency but also the log P and phloem mobility within the treated plant, which directly affects curative versus protectant activity profiles in the field. The carboxyl group is concurrently converted to the carboxamide during a prior amidation step with 9-(dichloromethylene)-1,2,3,4-tetrahydro-1,4-methanonaphthalen-5-amine or a structurally related lipophilic amine, using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC·HCl, 1.2 equivalents) and 1-hydroxybenzotriazole (HOBt, 0.1 equivalents) in dichloromethane at ambient temperature for 12–16 hours. The target product—a 2-alkylamino-thiazole-4-carboxamide—is registered as a succinate dehydrogenase inhibitor (SDHI) fungicide under FRAC Code 7 and is subject to evaluation by regulatory bodies under Regulation (EC) 1107/2009 with residue definition enforced through Codex Alimentarius CX/PR 21/53/8 and maximum residue limits (MRLs) established via FAO/WHO JMPR evaluations. The manufacturing process generates a technical-grade active ingredient with purity ≥ 96% as determined by CIPAC Method MT 167 reverse-phase HPLC; the product is formulated as a suspension concentrate (SC, 200 g/L), emulsifiable concentrate (EC, 100 g/L), or water-dispersible granule (WG, 50% w/w). Brodifacoum-class anticoagulants are not structurally related to the thiazole pharmacophore and are excluded from this discussion. A critical process control parameter is the residual unreacted 2-bromo intermediate in the final product, quantified by GC-ECD after derivatization with pentafluorobenzyl bromide, with a specification limit of ≤ 0.1% w/w to satisfy the OECD 402 acute dermal toxicity classification threshold for non-genotoxic process-related impurities. Field efficacy trials conducted in compliance with EPPO PP 1/26 (cereal foliar diseases) and PP 1/61 (*Septoria tritici*) demonstrate that the thiazole-4-carboxamide SDHI controls resistant strains carrying the H272Y and SdhC-T79N mutations when combined with a demethylation inhibitor (DMI) triazole partner in a co-formulated product at a ratio of 1:1.5 w/w.The 2-bromo substituent undergoes facile oxidative addition to Pd(0) catalysts at rates superior to the 2-chloro analogue—a property directly attributable to the lower carbon-halogen bond dissociation energy (C–Br: ~285 kJ/mol versus C–Cl: ~350 kJ/mol)—enabling chemoselective Suzuki-Miyaura cross-coupling in the presence of the 4-carboxylic acid functionality without the competitive protodehalogenation that plagues the corresponding iodo derivative under basic aqueous conditions. This reactivity profile permits the sequential construction of 2,4-disubstituted thiazoles where the bromine at C-2 is first coupled with an aryl or heteroaryl boronic acid, and the carboxylic acid at C-4 is subsequently amidated or reduced, without protecting group manipulation. Practical manufacturing-scale Suzuki coupling employs tetrakis(triphenylphosphine)palladium(0) at 0.5–1.0 mol% loading or the air-stable Pd(dppf)Cl₂·CH₂Cl₂ at 0.3–0.8 mol%, with the ligand-to-palladium ratio maintained at 2.0:1 to suppress catalyst deactivation by bromide ion accumulation. The choice of base exerts a measurable effect on the reaction rate; aqueous potassium carbonate (2.0 M, 2.5–3.0 equivalents) in THF:water (4:1 v/v) achieves complete conversion within 3–5 hours at 65°C jacket temperature in a 2,000 L glass-lined reactor under nitrogen atmosphere, whereas cesium carbonate (2.0 equivalents) reduces the reaction time to 1.5–2.5 hours at a cost premium that must be offset against reduced cycle time in multi-product facilities. The heterogeneous biphasic mixture necessitates efficient mechanical agitation; tests on a Chemineer HE-3 axial-flow impeller operating at 85–110 rpm (tip speed 1.8–2.3 m/s) in the specified reactor geometry demonstrate a volumetric mass transfer coefficient (k_La) of 0.04–0.08 s⁻¹ sufficient to prevent mass transfer limitation at the organic-aqueous interface. Post-coupling workup includes a controlled quench with 10% w/w aqueous ammonium chloride to complex residual palladium and maintain the carboxylic acid in its protonated form for extraction into ethyl acetate. The isolated biarylthiazole-4-carboxylic acid intermediate typically exhibits a palladium content of 200–800 ppm prior to purification, which is reduced to below 5 ppm through recrystallization from toluene:heptane (1:3 v/v) with 0.5% w/w activated carbon treatment. The resulting 2-aryl-1,3-thiazole-4-carboxylic acid serves as a versatile building block for medicinal chemistry libraries targeting kinases, GPCRs, and epigenetic reader domains; alternatively, it is advanced directly into peptide coupling with α-amino acid methyl esters using isobutyl chloroformate/N-methylmorpholine activation in THF at −20°C for construction of thiazole-containing depsipeptide natural product analogs.

When the 2-Bromo Substituent Outperforms Alternative Halogens in Palladium-Catalyzed Cross-Coupling

The selection between 2-bromo, 2-chloro, and 2-iodo-1,3-thiazole-4-carboxylic acid as the starting material for a given synthetic sequence hinges on three interlocking process parameters: oxidative addition kinetics, functional group tolerance during aqueous workup, and palladium removal efficiency from the isolated product stream. The 2-iodo derivative undergoes oxidative addition approximately 3- to 5-fold faster than the 2-bromo compound at 60°C in a toluene-ethanol-water ternary solvent system (kinetic data derived from in situ ReactIR monitoring of the Pd(PPh₃)₄-catalyzed coupling with 4-fluorophenylboronic acid, monitoring the disappearance of the C–X stretching band), yet the iodo intermediate consistently generates 0.8–2.5% of the protodehalogenated des-halo byproduct—which cannot be removed from the desired product by fractional crystallization due to near-identical solubility parameters in the ethyl acetate/n-heptane recrystallization system (Hansen solubility parameter difference Δδ < 0.5 MPa^½). The 2-chloro analogue, while less expensive to manufacture, requires catalyst loadings of 2.0–5.0 mol% Pd and elevated temperatures of 90–110°C to achieve comparable conversion, conditions under which the 4-carboxylic acid undergoes partial decarboxylation ( 2–7% ) in the presence of catalytic quantities of copper(I) iodide or other transition-metal contaminants commonly present in technical-grade potassium carbonate. The 2-bromo substrate occupies the optimal position in this reactivity continuum: oxidation addition proceeds to completion within 2–4 hours at 60–75°C using 0.5–1.0 mol% Pd(PPh₃)₄, the des-bromo byproduct is formed at levels below 0.3%, and decarboxylation is not observed under standard coupling conditions (verified by headspace GC analysis for CO₂ evolution with a detection limit of 0.05 mL per gram of substrate). Table 2 compiles the comparative performance data across halogen variants.

Parameter	2-Bromo-Thiazole-4-COOH	2-Chloro Analogue	2-Iodo Analogue
Oxidative addition t₉₀ at 60°C (Pd(PPh₃)₄ 1 mol%)	2.5–3.5 hours	> 24 hours (incomplete)	0.5–1.0 hours
Optimal catalyst loading	0.5–1.0 mol%	3.0–5.0 mol%	0.3–0.8 mol%
Protodehalogenation byproduct	≤ 0.3%	≤ 0.1%	0.8–2.5%
Decarboxylation under coupling conditions	Not detected (< 0.05 mL CO₂/g)	2–7% (at 100°C)	Not detected
Residual Pd after EtOAc extraction	200–800 ppm	500–2,000 ppm (due to ligand decomposition at elevated T)	100–400 ppm
Pd after carbon treatment + recrystallization	≤ 5 ppm	10–25 ppm	≤ 5 ppm

The isolated coupling product—a 2-aryl-1,3-thiazole-4-carboxylic acid—is stored under nitrogen blanket at 2–8°C to prevent slow aerial oxidation of the thiazole sulfur to the sulfoxide (detected at levels of 0.05–0.2% after 12 months at 25°C/60% RH in the absence of inert gas protection). Long-term stability studies conducted per ICH Q1A(R2) guidelines at 40°C/75% RH for 6 months in double polyethylene bags contained within fiber drums indicate no significant change in assay, water content, or impurity profile when the nitrogen overlay is maintained. These intermediates are supplied to contract development and manufacturing organizations (CDMOs) operating under FDA 21 CFR Part 210/211 or EudraLex Volume 4 Part II for conversion to active pharmaceutical ingredients destined for clinical trials or commercial distribution.Veterinary antiparasitic drug discovery has adopted 2-aminothiazole-4-carboxamide derivatives as structural replacements for benzimidazole anthelmintics following the widespread emergence of fenbendazole- and albendazole-resistant haemonchosis in sheep and cattle across Oceania and South America. The replacement pharmacophore retains the planar aromatic geometry required for β-tubulin colchicine-site binding while introducing a hydrogen bond donor-acceptor pair (the thiazole nitrogen and the 4-carboxamide NH) that compensates for the binding affinity lost by the absence of the benzimidazole imidazole ring system. Synthesis of the anthelmintic candidate from 2-bromo-1,3-thiazole-4-carboxylic acid follows a two-step telescoped sequence: carbodiimide-mediated coupling with 3,4-dichloroaniline to form the 4-carboxamide, followed by CuI-catalyzed Ullmann-type amination at the 2-position with 4-methoxybenzylamine ( 1.3 equivalents , CuI 10 mol% , N,N′-dimethylethylenediamine 20 mol% , potassium phosphate tribasic 2.5 equivalents , DMF, 105°C , 18 hours ). The telescoped process avoids isolation of the intermediate 2-bromo-N-(3,4-dichlorophenyl)thiazole-4-carboxamide, reducing solvent consumption by approximately 35% compared to a stepwise protocol and eliminating worker exposure to a solid intermediate with moderate dermal sensitization potential (LLNA EC3 value reported in published literature for structurally analogous bromothiazoles: 5–15% ). The crude anthelmintic is purified by flash chromatography on a production-scale Simulated Moving Bed (SMB) system (Novasep Licosep 8-450 or equivalent) using ethyl acetate:n-heptane (60:40 v/v) as the mobile phase, achieving 99.2% purity with 92% recovery. The purified product is formulated as an oral drench suspension containing 25 mg/mL active ingredient in a vehicle of propylene glycol, polysorbate 80, and purified water, preserved with benzyl alcohol 1.5% v/v. Regulatory approval under VICH GL 52 (Bioequivalence) and the EMA/CVMP/EWP/005/2000 guideline on pharmacokinetic studies in target animal species mandates demonstration of equivalent systemic exposure (AUC₀–ₜ and Cmax within the 80–125% confidence interval) relative to the reference benzimidazole product in a parallel-group study design with ≥ 40 animals per treatment arm. Residue depletion studies in edible tissues (muscle, liver, kidney, fat) conducted according to 21 CFR 556 Subpart B and Commission Regulation (EU) 37/2010 establish a withdrawal period of 14 days in cattle and 7 days in sheep, with the marker residue defined as the parent thiazole-4-carboxamide compound in liver quantified by LC-MS/MS (LOQ 10 µg/kg). The commercial product addresses a documented therapeutic gap in regions where the Glu198Ala single nucleotide polymorphism in the β-tubulin isotype-1 gene of Haemonchus contortus confers high-level benzimidazole resistance (resistance ratios exceeding 50-fold relative to susceptible isolates in egg hatch assays performed per WAAVP guidelines).

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Certification & Compliance

2-Bromo-1,3-Thiazole-4-Carboxylic Acid is manufactured under an ISO 9001 quality system and complies with relevant regulatory requirements.
COA, SDS/MSDS, and related certificates are available upon request. For certificate requests or inquiries, contact: sales9@bouling-chem.com.

More Introduction

What Distinguishes the 2-Bromo-Thiazole Scaffold in Palladium-Mediated Couplings?

The compound is utilized as an electrophilic partner in Suzuki-Miyaura, Stille, and Negishi cross-couplings, where the C-2 bromine atom undergoes oxidative addition with Pd(0) species at rates significantly exceeding those of the corresponding C-2 chloro analogue. Comparative kinetic profiling under standardized conditions—using Pd(PPh₃)₄ (2 mol%) in THF/water at 338 K—shows that the bromo derivative reaches full conversion with phenylboronic acid in 45–60 min, whereas the 2-chloro-1,3-thiazole-4-carboxylic acid requires >12 h and elevated temperatures (373 K) with stronger σ-donor ligands. This reactivity gap is critical when constructing advanced intermediates for kinase inhibitors, where late-stage functionalization demands mild conditions to preserve acid-labile protecting groups. The electron-withdrawing carboxylic acid at C-4 further polarizes the thiazole ring, lowering the LUMO energy at C-2 and accelerating oxidative addition; density functional theory calculations (B3LYP/6-31+G*) indicate a reduction in activation barrier of approximately 8–10 kcal/mol relative to the unsubstituted 2-bromothiazole. Manufacturers employing continuous-flow reactors report consistent space-time yields of the biphenyl carboxylic acid product exceeding 0.4 kg L⁻¹ h⁻¹ when using corrugated plate heat exchangers to manage the exotherm (ΔH_rxn ≈ −120 kJ/mol). The bromo substituent also facilitates sequential chemoselective couplings: the carboxylic acid moiety can be converted to an amide or ester prior to the cross-coupling step without competing side reactions, a pathway that often fails with the iodo analogue due to premature oxidative addition at ambient temperature. A consistent finding across pilot-plant campaigns is that catalytic protodehalogenation becomes problematic when the reaction mixture’s pH drops below 4.0. In aqueous organic media, the presence of free HBr—generated from the hydrolysis of Pd–Br intermediates—accelerates reductive dehalogenation, forming 1,3-thiazole-4-carboxylic acid as an impurity. This side pathway is suppressed by the addition of 1.2 equivalents of K₃PO₄ or by switching to anhydrous dioxane with Cs₂CO₃, maintaining a pH >9.5 throughout the catalytic cycle. Published data from kilogram-scale Suzuki processes (operating in 100 L glass-lined reactors) confirm that the bromo heterocycle can be coupled with a range of arylboronic acids carrying electron-donating or mildly electron-withdrawing substituents without detectable debromination (<0.3% by HPLC), a robustness not uniformly observed with the iodo congener.

Moisture Sensitivity and Pre-Processing Conditioning: Why Storage Under Argon Is Not Optional

The solid-state hygroscopicity of 2-bromo-1,3-thiazole-4-carboxylic acid is moderate, but exposure to relative humidity (RH) above 60% at 25 °C leads to water uptake of 0.8–1.2% w/w within 4 h. The absorbed moisture promotes decarboxylation during thermal processing, particularly when the compound is heated above 130 °C for extended periods. In automated solid-dispensing systems used for parallel synthesis, the compound is therefore supplied in septum-capped vials under argon, with a recommended maximum ambient handling time of 30 min prior to dissolution. Differential scanning calorimetry (DSC) traces exhibit a sharp endotherm at 141 °C (onset) corresponding to melting with decomposition; the decomposition exotherm begins at 157 °C and releases CO₂, HBr, and sulfur-containing volatiles. Users operating in tropical climates (RH > 80%) are advised to dry the material in a vacuum oven at 40 °C (<10 mbar) for 12 h before weighing to avoid deviations in stoichiometry. Photolytic lability is an additional handling constraint. Ambient laboratory lighting accelerates the homolytic cleavage of the C–Br bond under aerobic conditions, generating bromine radicals that can brominate the thiazole core at the electronically activated 5-position. Extended exposure (>48 h on an open bench) results in the formation of a dibromo impurity exceeding 2% (LCMS, m/z 286/288). Consequently, all large-scale operations employ amber glassware and low-energy fluorescent lighting fitted with UV-filtering sleeves. Long-term stability studies at −20 °C under argon show <0.1% degradation over 24 months, confirming that the compound can be stored without significant loss of purity when packaged in double-laminated aluminum pouches with desiccant inserts.

Comparative Reactivity of Halogen-Substituted 1,3-Thiazole-4-Carboxylic Acids in Suzuki Coupling with Phenylboronic Acid
Property	2-Chloro	2-Bromo	2-Iodo
C–X bond dissociation energy (kJ mol⁻¹)	399 ± 5	297 ± 5	218 ± 5
Optimal catalyst loading (Pd(PPh₃)₄, mol%)	5–10	1–2	0.5–1
Reaction temperature for >95% conversion (K)	373	333–343	298–313
Competitive protodehalogenation risk	Negligible	Moderate (pH-dependent)	High
Typical isolated yield (lab scale, 10 mmol)	82%	94%	78% (due to debromination)
Shelf-life at −20°C under argon (months)	>36	24	12

2-Bromo-1,3-thiazole-4-carboxylic acid (CAS 5198-87-7) is released for industrial use as a fine crystalline powder with an assay specification of ≥98.0% (HPLC, area normalization at 254 nm). The molecular formula is C₄H₂BrNO₂S, with a relative molecular mass of 208.03 g mol⁻¹. The material conforms to the purity requirements of REACH-registered intermediates when the residual solvent content complies with the limits defined in ICH Q3C: residual toluene <890 ppm, dichloromethane <600 ppm, and heptane <5000 ppm. Heavy metals by ICP-MS are controlled below 10 ppm for Pd, 5 ppm for Fe, and 2 ppm for Ni, ensuring compatibility with downstream cGMP steps where elemental impurity limits of USP <232> and ICH Q3D apply. The melting range is consistently quoted as 140–144 °C (decomposition) when measured by capillary method at a ramp rate of 2 K min⁻¹. Suppliers routinely provide a certificate of analysis detailing the water content (Karl Fischer, ≤0.5%) and the level of the corresponding carboxylic acid dimer (anhydride) which is maintained at <0.3%. When this intermediate is positioned within a synthetic route targeting SGLT2 inhibitors or histone deacetylase (HDAC) modulators, the primary technical differentiation from the 2-chloro analogue lies in the ability to achieve efficient C–C bond formation without employing sterically hindered, electron-rich phosphine ligands. The 2-bromo compound couples successfully with boronic acids bearing ortho substituents under mild microwave irradiation (100 W, 120 °C, 20 min), whereas the chloro counterpart necessitates the use of XPhos or SPhos ligands and longer hold times (> 2 h). This difference directly translates into reduced palladium scavenging costs in the downstream processing; the palladium content in the crude product after a standard aqueous sodium bisulfite wash is typically <50 ppm for the bromo path, versus 200–500 ppm for the chloro route. The 2-iodo analogue, while more reactive, introduces a significant risk of photolytic deiodination and often generates a violet iodine-charge transfer complex that fouls reactor walls, increasing cleaning cycle frequency by a factor of three in multi-product plants. Direct comparison with 2-chloro-1,3-thiazole-4-carboxylic acid’s performance in amide coupling sequences highlights another practical facet. With HATU/DIEA activation in DMF, both acids couple near-quantitatively with primary amines, but the bromo acid shows a 15% lower exotherm peak temperature (reaction calorimetry, Mettler-Toledo RC1) due to the higher molecular polarizability of the C–Br bond, which moderates the reactive species’ concentration. This characteristic permits the addition of the amine in a single portion at 0 °C without temperature overshoot beyond 5 °C, eliminating the need for syringe-pump controlled dosing and shortening batch cycle times on a 50 L scale by approximately 45 min. No such thermal smoothing is observed with the chloro or iodo analogues; with the iodo acid, an abrupt 8–10 °C spike is repeatedly recorded upon base addition, necessitating active cooling.

When Decarboxylative Functionalization Becomes the Preferred Disconnection

Beyond the bromine as a leaving handle, the carboxylic acid group itself serves as a traceless directing element. In protodecarboxylation protocols using Cu₂O in quinoline at 160 °C, 2-bromo-1,3-thiazole-4-carboxylic acid affords 2-bromothiazole in 85% isolated yield after distillation. This transformation is considerably cleaner than that of its 2-chloro counterpart, which requires silver(I) carbonate and yields a mixture of dechlorinated byproducts. The bromo acid thus becomes a strategic precursor for 2-bromothiazole when a supplier’s batch of the latter fails the peroxide specification (<0.1%). In a typical campaign, decarboxylation is completed within 4 h in a 30 L glass-lined vessel, with the evolved CO₂ volume (110 L at STP per mole) being quantitatively measured to track end-of-reaction. The resulting 2-bromothiazole is directly amenable to Grignard exchange or lithium-halogen exchange, applications that would be compromised by the acidity of the free carboxylic acid. Application notes from kilo-lab transfers stress the incompatibility of the acid with lithium aluminium hydride or borane reagents, which reduce both the bromine and the carboxyl group simultaneously. Selective reduction to the alcohol is instead executed via borane-dimethyl sulfide complex at 0 °C after activation with ethyl chloroformate, a sequence that delivers the hydroxymethyl derivative without detectable debromination. Published comparative data with the 2-chloro analogue indicate a lower reduction selectivity: the chloro alcohol is contaminated with 5–7% of the dechlorinated alcohol under identical conditions, likely because the weaker C–Cl bond cleavage competes with hydride delivery. Therefore, the bromo compound is preferred when the hydroxymethyl thiazole intermediate is required with an isomeric purity above 98% for subsequent Mitsunobu displacements. The compound’s performance in solid-phase peptide synthesis has been evaluated for the construction of thiazole-containing depsipeptide mimics. Coupling to Wang resin via the carboxyl function proceeds with a loading efficiency of 0.6 mmol g⁻¹, and the on-resin Suzuki reaction with Fmoc-protected boronic acids achieves 93% conversion (determined by cleavage and HPLC). No cross-reactivity with unprotected amide backbones is observed, a limitation that has curtailed the use of the iodo analogue in similar contexts. This feature positions the bromo acid as a reliable building block for combinatorial libraries generated by microwave-assisted parallel synthesizers, where 96-well plates are processed in under 2 h total cycle time.

Regulatory and Quality Compliance Framework for Supply of 2-Bromo-1,3-Thiazole-4-Carboxylic Acid
Standard/Regulation	Applicable Clause/Method	Specification Criterion
REACH Regulation (EC) 1907/2006	Annex VII–X (registration dossier)	Full substance identification; PBT/vPvB assessment concluded negative
USP <232> / ICH Q3D	Elemental Impurity Analysis by ICP-MS	Class 1 elements (As, Cd, Hg, Pb) individually ≤ 2 ppm
FDA 21 CFR 211.170	Reserve sample retention	Retained lot samples stored at −20 °C for 5 years
ISO 9001:2015	Clause 8.5 Production and Service Provision	Batch release based on validated HPLC method (R² ≥ 0.999 over range 80–120% of nominal)
OECD 423 (Acute Oral Toxicity)	Fixed dose procedure	No classification as acutely toxic; LD₅₀ > 2000 mg kg⁻¹ (rat)

The granularity of supply specifications differentiates this product from generic alternative sources. The Certificate of Analysis includes residual solvent profile according to Ph. Eur. 2.4.24 with a validated headspace GC-FID method that resolves 12 common process solvents simultaneously. The detection limit for methyltetrahydrofuran—a solvent frequently retained in 2-bromothiazole intermediates—is set at 50 ppm. For users operating under ICH M7 guidelines for mutagenic impurities, a dedicated LC-MS/MS method monitors a potential genotoxic impurity, 2-bromothiazole (Alert Structure: halo-unsaturated heterocycle), with a reporting threshold of 1.5 µg g⁻¹, well below the staged TTC of 15 µg day⁻¹. No other thiazole building block available at commercial scale is accompanied by such a comprehensive impurity fingerprint, reducing the analytical development burden for pharmaceutical manufacturers. In parallel medicinal chemistry laboratories, the 2-bromo derivative’s solubility profile in aqueous buffers (≤0.2 mg mL⁻¹ at pH 7.4) necessitates the use of co-solvent systems for biological assay preparation. DMSO stock solutions at 100 mM are stable for 6 months at −20 °C when protected from moisture, with no detectable hydrolysis to 2-hydroxy-1,3-thiazole-4-carboxylic acid. This hydrolytic stability contrasts sharply with the iodo analogue, which undergoes hydrolysis at measurable rates even in dry DMSO (t₉₀ 14 days at 25 °C). Consequently, the bromo compound is recommended for structure-activity relationship programmes where stock solution longevity directly impacts data reproducibility across multiple screening campaigns. The thermal hazard profile under process conditions must be considered for scale-up. Accelerating rate calorimetry (ARC) tests performed on the neat substance at a phi-factor of 1.2 indicate an onset temperature for exothermic decomposition of 150 °C, with a maximum self-heat rate of 3.5 K min⁻¹ and a pressure rise of 1.2 bar min⁻¹. The Time to Maximum Rate at 120 °C is >24 h, placing the compound in a safe processing window for typical solution-phase amidation and esterification operations conducted below 80 °C. However, when exposed to strong bases in dipolar aprotic solvents at temperatures above 100 °C, an accelerated decomposition pathway evolves HBr gas, mandating the use of scrubbed vent systems rated for acidic vapours. These process safety parameters, which are not catalogued for the 2-chloro or 2-iodo versions by most bulk chemical suppliers, form part of the technical dossier provided with each lot. The material’s optical properties also carry practical implications for in-line process analytical technology (PAT). UV-Vis monitoring at 300 nm allows real-time tracking of the 2-bromothiazole-4-carboxylate anion in aqueous process streams; the extinction coefficient (ε ≈ 4200 L mol⁻¹ cm⁻¹) is approximately three times that of the 2-chloro analogue, improving signal-to-noise ratios in fiber-optic flow cells. This feature supports the implementation of feedback-controlled continuous extraction and wash cycles, reducing downstream processing variability to <2% relative standard deviation across a campaign of 30 batches. Chemical engineers configuring modular API synthesis platforms reliably select the bromo intermediate when UV-guided automation is a design requirement, because the 2-iodo congener exhibits baseline drift from iodine leaching and the 2-chloro species requires higher cell pathlengths that increase backpressure beyond 5 bar in microreactor setups.