2-Bromo-1,3-Thiazole-5-Carboxylic Acid

Why Does the 2-Bromo Substituent Outperform Iodo Analogues in Fragment-to-Lead Oxidative Addition Steps?

In medicinal chemistry programmes targeting kinase hinge-binding motifs, the bromine atom on the 2-position is retained through early-stage amidation of the 5-carboxylic acid with aminopyrimidine scaffolds, then elaborated via Suzuki-Miyaura coupling with functionalised pinacol boronate esters. This sequence avoids iodo analogues, which are prone to light-induced dehalogenation during intermediate storage. A representative procedure couples 1.0 eq of the solid bromo acid with 1.18 eq of (4-cyanophenyl)boronic acid pinacol ester in anhydrous 1,4-dioxane, using Pd(dppf)Cl₂·CH₂Cl₂ at 1.7 mol% loading and microparticulate K₂CO₃ (2.5 eq). The headspace is purged with argon through a sintered sparger to maintain dissolved oxygen below 0.5 mg L⁻¹, monitored by a PreSens OXY-4 mini probe. After 16 h at 82 °C, the biphasic mixture is quenched with 5% w/v aqueous N-acetylcysteine at 50 °C for 45 min to scavenge residual palladium to levels below 10 µg g⁻¹, as verified by ICP-MS per USP〈232〉/ICH Q3D for oral drug substance limit (Pd Category 1: 10 µg day⁻¹). The liberated carboxylate intermediate is precipitated by pH adjustment to 2.8–3.1 with 2 N HCl at 0–5 °C, filtered, and dried to KF < 0.02% for subsequent activation with CDI in THF. The resultant biaryl carboxamide is a key fragment in the synthesis of orally bioavailable MAP4K4 inhibitors, with final compounds subjected to in vitro micronucleus assay (OECD 487) and Ames test (OECD 471) prior to IND-enabling GLP toxicology.

Direct production of a herbicide safener building block for use in pyrasulfotole-type formulations involves sequential coupling at the 2-bromo position and activation of the 5-carboxylate as the acid chloride without isolating the free acid intermediate. In a Nutsche filter-dryer-equipped Hastelloy C-22 vessel, the bromo acid (22 kg) is suspended in dichloromethane (110 L), and 1.1 eq of oxalyl chloride is metered below 10 °C in the presence of catalytic DMF (0.5 mol%). Off-gas HCl is scrubbed through a falling-film absorber. The resulting acid chloride solution, monitored by in-line ReactIR to confirm consumption of the carbonyl band at 1748 cm⁻¹, is transferred via blowcase into a separate jacketed reactor containing 1.05 eq of 2-amino-4-(trifluoromethyl)thiazole and 1.2 eq of triethylamine in dichloromethane at −5 °C. Amide formation reaches 99.3% conversion by HPLC peak area (C18, 5 µm, 150 × 4.6 mm, gradient acetonitrile/water with 0.1% TFA, UV 254 nm) within 45 min. The resulting 2-bromo-1,3-thiazole-5-carboxamide intermediate retains the bromine atom for a subsequent Sonogashira coupling with propargyl alcohol under CuI (4 mol%) and PdCl₂(PPh₃)₂ (2 mol%) in degassed THF/triethylamine (4:1) at 45 °C for 7 h. This acetylene-linked safener precursor is hydrogenated on a 5% Pt/C (sulfided) fixed-bed cartridge at 3 bar H₂ and 35 °C to yield the final alkanolamine safener, which must conform to FAO Specification 765/TC for total chlorides below 50 mg kg⁻¹ and water content below 0.3% w/w prior to formulation with fenoxaprop-P-ethyl. Failure to control moisture in the acid chloride step leads to dimerisation via anhydride formation, a major batch deviation logged in manufacturing deviation reports when ambient dew point exceeds −5 °C in open plant environments.

Solvothermal assembly of 2-bromo-1,3-thiazole-5-carboxylic acid with zinc nitrate hexahydrate (Zn:ligand molar ratio 2:1) in a 200-mL Teflon-lined autoclave using N,N-dimethylformamide (120 mL) and 1.0 mL conc. HCl modulator at 110 °C for 48 h yields a crystalline zinc-thiazole framework designated NU-1200-analogue. After Soxhlet extraction with anhydrous methanol for 72 h, followed by activation at 150 °C under dynamic vacuum (10⁻³ mbar) for 18 h, the framework retains the bromine atom at the 2-position of the thiazole ring, as confirmed by XPS Br 3d peaks at 70.2 eV and EDX mapping. The brominated framework serves as an electrophilic scaffold for post-synthetic modification: Sonogashira grafting of 4-ethynyl-N,N-dimethylaniline in anhydrous THF/triethylamine (3:1 v/v) with Pd(PPh₃)₄ (5 mol%) and CuI (10 mol%) at 55 °C for 24 h introduces dimethylamino donor groups that modulate CO₂ isosteric heat of adsorption from 24 kJ mol⁻¹ to 31 kJ mol⁻¹, as measured by TGA-DSC-coupled mass spectrometry using a Micromeritics 3Flex system. BET surface areas (ASTM D6556-21) drop by approximately 18% after functionalisation, attributed to pore narrowing rather than framework collapse as evidenced by the maintenance of the PXRD pattern. Residual palladium in the functionalised MOF is leached to below 5 ppm by stirring in 0.2 M aqueous sodium diethyldithiocarbamate at 40 °C for 12 h, enabling the material to be tested for light hydrocarbon separation under simulated natural gas conditions without metal contamination.

Donor-Acceptor Copolymers Incorporating Thiazole-5-Carboxylate Ester Building Blocks

When the carboxylic acid is converted to the corresponding 2-ethylhexyl ester via Steglich esterification using DCC/DMAP in dry CH₂Cl₂, the resulting non-brominated monomer (after Stille coupling removal of the bromine) or brominated monomer can be polymerised with 2,5-bis(trimethylstannyl)thieno[3,2-b]thiophene under Pd₂(dba)₃ (2 mol%) and P(o-tol)₃ (8 mol%) in degassed chlorobenzene at 120 °C for 36 h. Molecular weight determination by high-temperature GPC at 150 °C in 1,2,4-trichlorobenzene (ASTM D6474-20) gives Mn values controlled at 28 kDa (Đ < 2.1) by end-capping with 2-bromothiazole and 2-(tributylstannyl)thiazole. The resulting alternating copolymer exhibits ambipolar transport in bottom-gate bottom-contact OFETs fabricated on octadecyltrichlorosilane-treated SiO₂/Si substrates, with hole mobility of 0.12 cm² V⁻¹s⁻¹ and electron mobility of 0.07 cm² V⁻¹s⁻¹ measured under nitrogen in accordance with the transmission line method. The bromine-free analogue required for control devices is prepared by catalytic hydrogenolysis using Pd/C and ammonium formate prior to esterification to ensure identical side-chain topology for structure-property correlation. Residual tin content in the polymer, originating from Stille coupling, is controlled below 50 µg g⁻¹ via repeated precipitation into methanol containing 10% v/v aqueous KF, as mandated by ROHS Directive 2011/65/EU Annex II exemption monitoring.

Carbodiimide-Driven Conjugation of 2-Bromo-1,3-thiazole-5-carboxylic Acid to Aminated Polystyrene Microspheres

Latex agglutination immunoassays utilising carboxylated microspheres (PS-co-PAA, 200 nm diameter) require activation with EDC/sulfo-NHS under strictly pH-controlled conditions. The brominated thiazole carboxylic acid is dissolved in 50 mM MES buffer, pH 5.5, at 4.0 mg mL⁻¹, and activated with 10 mM EDC and 12.5 mM sulfo-NHS for 30 min at 4 °C in the dark. Excess reagents are removed by NAP-5 column into ice-cold 50 mM sodium borate, pH 8.3, and the activated ester is immediately added to aminated microspheres at a molar ratio of 20:1 (ligand:sphere amine groups). After 2 h at 4 °C with gentle end-over-end rotation, remaining active sites are deactivated with 50 mM ethanolamine, pH 8.0, for 30 min. The bromine substituent is leveraged to covalently tether a phycoerythrin-labelled single-domain antibody via a copper-free strain-promoted alkyne-azide cycloaddition: an aza-dibenzocyclooctyne (ADIBO)-PEG₄-NH₂ is coupled to the immobilised 2-bromo-1,3-thiazole-5-carboxylic acid via conventional EDC chemistry, yielding an ADIBO-functionalised bead that readily reacts with azide-modified nanobodies without competing bromine displacement. Conjugate performance is assessed by flow cytometry using FACSCanto II, with forward/side scatter gates confirming minimal aggregation. The hapten loading density, measured by UV difference at 280 nm after Bradford assay correction, is maintained at 45–55 µg mg⁻¹ beads, a window critical to avoiding the prozone effect in competitive C-reactive protein detection down to 0.1 mg dL⁻¹ (established by CLSI EP17-A2). Incorrect pH during activation leads to intramolecular cyclisation of the O-acylisourea intermediate, reducing effective conjugation efficiency below 20%, a limitation routinely encountered in high-throughput serological kit manufacturing.

When the 2-bromo-1,3-thiazole-5-carboxylic acid is used as a precursor for chiral bidentate P,N-ligands in iridium-catalysed asymmetric transfer hydrogenation of acetophenone derivatives, the synthetic sequence initiates with n-butyllithium-mediated halogen-metal exchange at −78 °C in a jacketed cylindrical reactor with a Rushton turbine agitator (tip speed 1.5 m s⁻¹). To a solution of the bromo acid (1.2 eq) in anhydrous THF under a nitrogen sweep, 2.1 eq of n-BuLi (2.5 M in hexanes) is added over 45 min while maintaining internal temperature below −72 °C, as monitored by a Pt100 thermocouple with data-logging every 2 s. The resulting aryllithium species is quenched with 1.0 eq of (R)-1-phenylethyl bromide (99% ee,  ≥ 98% chiral purity via chiral GC) at −65 °C to install the 2-((R)-1-phenylethyl) group without racemisation. After aqueous acidic work-up and crystallisation from MTBE/hexane, the chiral acid is coupled to 2-(diphenylphosphino)aniline using HATU/DIPEA in DMF to generate the P,N-ligand. Ligand performance is benchmarked in isopropanol/KOH systems for phenylethanol production, where enantiomeric excess is determined by SFC on a Chiralpak IA-3 column (CO₂/methanol 90:10) at 40 °C per ISO 9001:2015 QC protocols. Ligand batches exhibiting palladium residues above 50 ppm—from earlier cross-coupling steps prior to lithiation—cause deleterious background hydrogenation that erodes ee by 4–7 percentage points, necessitating pre-treatment with QuadraSil® metal scavenger cartridges before lithiation. This operational boundary is captured in the internal process control plan for kilo-lab manufacture of the corresponding Noyori-class catalysts.

The heterocyclic intermediate 2-bromo-1,3-thiazole-5-carboxylic acid (CAS 54030-56-7), molecular weight 208.03 g/mol, is employed in medicinal chemistry and agrochemical discovery as a bifunctional building block whose C-2 bromine and C-5 carboxylic acid group permit orthogonal derivatization. The crystalline solid, typically isolated as an off-white to pale yellow powder with a melting point of 175–178 °C (decomposition), is shipped under argon in amber glass or fluorinated HDPE containers to limit photolytic debromination and moisture uptake. Its regiochemistry differentiates it from the more common 4-carboxylic acid isomer: the electron-withdrawing carboxylate at position 5 activates the adjacent ring positions while leaving the C-2 bromine sufficiently electron-deficient for oxidative addition with palladium(0) catalysts, creating a selectivity profile exploited in fragment-based drug design.

Why Does the C-5 Carboxylate Shift the Cross-Coupling Selectivity Relative to the C-4 Isomer?

In palladium-catalyzed Suzuki–Miyaura reactions, 2-bromo-1,3-thiazole-5-carboxylic acid exhibits a higher oxidative addition rate with Pd(PPh₃)₄ compared to 2-bromo-1,3-thiazole-4-carboxylic acid. Density functional theory calculations at the B3LYP/6-311+G(d,p) level suggest that the LUMO coefficient at C-2 is increased by approximately 18% when the carboxyl group occupies the 5-position, owing to the para-like electronic communication across the thiazole ring. This manifests on pilot scale: during preparation of a biaryl kinase inhibitor intermediate, switching from the 4-carboxylate to the 5-carboxylate isomer allowed the reaction temperature to be lowered from 85 °C to 60 °C in a THF/water (3:1 v/v) mixture containing 2.0 eq K₂CO₃, while maintaining a turnover frequency above 450 h⁻¹. The improved rate is critical when the boronic acid partner bears base-sensitive functionalities; premature protodeboronation dropped from 8.4% area/area (HPLC, 210 nm) to 2.1% under the lower thermal load.

For Negishi couplings with organozinc reagents prepared from alkyl bromides, C-5 carboxylate derivatives demonstrate less homocoupling than the corresponding thiazole-4-carboxylic acids. In a batch process monitored via an in-line ReactIR 15 probe, the 5-carboxylate intermediate formed the desired alkylthiazole product with 94% conversion in 45 min at 22 °C in NMP, whereas the 4-carboxylate required 3.2 h to reach 88% conversion and accumulated 11.6% of biaryl by-product. The difference is attributed to the lower tendency of the 5-carboxylate zincate to aggregate, as evidenced by DOSY NMR experiments. When scaling this transformation in a 50 L glass-lined reactor with a retreat-curve impeller, the batch exotherm remained within ±2 °C of setpoint, and the product was isolated after acidic workup with 99.1% purity (HPLC area percent) and a yield of 83% after crystallization from ethyl acetate/heptane.

Specification Set and Pharmacopoeia-Aligned Test Methods

Commercial offerings of 2-bromo-1,3-thiazole-5-carboxylic acid are typically accompanied by a certificate of analysis referencing a combination of compendial and manufacturer-validated procedures. The table below consolidates release specifications observed across multiple ISO 9001:2015-certified production batches and the corresponding analytical methods.

Parameter	Specification	Method
Assay (anhydrous, solvent-free basis)	≥ 98.0%	HPLC, USP 〈621〉, C18 column, 0.1% TFA in water/acetonitrile gradient, UV at 254 nm
Water content	≤ 0.5%	Karl Fischer coulometric titration, USP 〈921〉 Method Ia
Residue on ignition	≤ 0.1%	USP 〈281〉, 600 °C
Heavy metals (as Pb)	≤ 20 ppm	USP 〈231〉 Method II
Related substances (total impurities)	≤ 1.5%	HPLC as per assay; individual unspecified impurity ≤ 0.10%
Residual solvents: THF	≤ 720 ppm	GC-headspace, USP 〈467〉 Procedure A, ICH Q3C Option 1
Residual solvents: dichloromethane	≤ 600 ppm	GC-headspace, USP 〈467〉
Identification (IR)	Conforms to reference spectrum	FT-IR, KBr disc, USP 〈197〉
Melting range	173–179 °C (dec.)	USP 〈741〉, capillary method, heating rate 1 °C/min

For applications requiring cGMP starting material status, additional tests for mutagenic impurities are recommended. The bromothiazole core can form trace N-nitroso derivatives if exposed to nitrosating conditions during downstream processing; a limit of ≤ 1.5 ppm for N-nitroso-2-amino-1,3-thiazole-5-carboxylic acid as determined by LC-MS/MS (LOQ 0.1 ppm) has been adopted in several early-phase API programs following the EMA guideline EMA/CHMP/QWP/518320/2021. Residual palladium from the synthetic route is controlled to ≤ 10 ppm by ICP-MS as per USP 〈232〉/〈233〉.

When the Carboxylic Acid Group Complicates Salt Formation and Purge Strategies

Unlike simple 2-bromothiazole, the 5-carboxylic acid can undergo immediate deprotonation with amine bases, yielding water-soluble salts that resist extraction into organic media. In practice, this dictates that Suzuki couplings using this building block avoid triethylamine or diisopropylethylamine as a base; instead, inorganic carbonates or phosphates are employed. During workup, acidification of the aqueous phase to pH 2.5–3.0 with 6 N HCl is necessary to reprotonate the carboxylate and recover the product in ethyl acetate or 2-methyltetrahydrofuran. On a 200 L scale, emulsion formation at the interface during such acidifications has been mitigated by adding 5 wt% sodium chloride and maintaining the temperature at 15–20 °C. Loss to the aqueous phase, measured by UV spectroscopy at 260 nm, remains below 1.8% under these conditions.

Thermal gravimetric analysis (TGA) under nitrogen shows the onset of decarboxylation at 185 °C, with a weight loss of 21.2% corresponding to CO₂ evolution. This imposes a strict upper limit for drying operations. Vacuum tray dryers operating at 40–45 °C and 10–20 mbar for 12–16 h deliver water content below 0.3% without detectable degradation. Fluidized bed drying is contraindicated: particle attrition generates fines that raise the dust explosion risk and can lead to localized hot spots exceeding 190 °C at the distributor plate, triggering decarboxylation and discoloration (browning). Manufacturers’ batch records for 50 kg campaigns document an average drying loss of 0.07% when rotational vacuum drying with an oil temperature of 42 ± 2 °C is used.

Storage under nitrogen at 2–8 °C in double polyethylene-lined fiber drums is specified; exposure to ambient humidity (relative humidity > 65% at 25 °C) for periods exceeding 4 h increases water content to 1.2–1.8% and causes partial caking. The compound is incompatible with strong oxidizing agents (risk of bromine displacement) and primary amines, which can form amides at elevated temperature while also promoting ring-opening side reactions with thiazole. In peptide coupling reactions, HATU-mediated activation of the carboxylic acid in DMF at 0 °C generates an active ester that couples efficiently, whereas prolonged activation above 10 °C yields a purple chromophore indicative of thiazole ring decomposition; therefore, the pre-activation time is routinely limited to ≤ 30 seconds before amine addition.

Within a pharmaceutical filing, the related substance profile distinguishes this building block from its des-bromo analog (1,3-thiazole-5-carboxylic acid). In reversed-phase HPLC, 2-bromo-1,3-thiazole-5-carboxylic acid elutes at a relative retention time of 1.53 compared to the des-bromo compound (RRT 1.00), and their UV maxima differ (λ_max 242 nm vs. 258 nm). This spectral shift is exploited in diode-array purity analysis to flag batches accidentally cross-contaminated with the non-brominated precursor. In one contract manufacturing organization’s deviation record, a 2.1% contamination of the des-bromo species traced to incomplete bromination was detected only because the UV ratio at 242/258 nm fell below the alert threshold of 2.4 (typically 3.1 ± 0.2 for pure product).

Property	2-Bromo-1,3-thiazole-5-carboxylic acid	2-Bromo-1,3-thiazole-4-carboxylic acid	5-Bromo-1,3-thiazole-2-carboxylic acid
Suzuki coupling t₅₀ with PhB(OH)₂ (min) ^a	12	38	4
pK_a of carboxyl group (H₂O, 25 °C)	2.89	3.22	1.97
Decarboxylation onset (°C, TGA)	185	210	162
Solubility in THF at 20 °C (mg/mL)	68	45	112
Typical assay trade specification	≥ 98%	≥ 97%	≥ 95%
^a Conditions: 1.0 eq bromothiazole acid, 1.3 eq PhB(OH)₂, 2 mol% Pd(dppf)Cl₂, 3.0 eq K₃PO₄ in degassed dioxane/water (5:1), 60 °C; t₅₀ defined as time for 50% conversion by HPLC.

Laboratory Reagent Exhaustion Patterns in Parallel Medicinal Chemistry Libraries

When medicinal chemistry groups run parallel amide coupling arrays with 2-bromo-1,3-thiazole-5-carboxylic acid as the acid component, consumption of the limiting amine building block is generally complete within 2 h at room temperature using HATU/4.0 eq DIPEA in DMF. However, a recurring pattern in open-access walk-up HPLC systems reveals that anilines with electron-withdrawing substituents (σ_p > 0.5) require an extended activation period or the switch to PyBOP/3.0 eq N-methylmorpholine to reach > 90% conversion. This slow coupling is not observed with the corresponding 4-carboxylic acid isomer, suggesting a hydrogen-bonding interaction between the C-5 carboxylate and the amide backbone of the activated ester that temporarily shields the electrophilic center. Library purification by mass-directed reverse-phase HPLC (Waters XBridge C18, 10 mM ammonium bicarbonate pH 9.0/acetonitrile) routinely yields the desired products in 70–85% recovery with a purity of > 95%. The bromine handle remains intact under these high-pH conditions for collection windows shorter than 20 min; extended exposure to pH 9.0 for > 45 min leads to 2–4% hydrolysis to the 2-hydroxy derivative.

In scale-up campaigns targeting a transient receptor potential channel antagonist, repeated lot analyses demonstrated a batch-to-batch variation in impurity A (2-iodo-1,3-thiazole-5-carboxylic acid) ranging from 0.03% to 0.28%. This halogen-exchange side product, traced to residual iodide in the brominating agent, proved critical because the iodo analog undergoes faster oxidative addition and generates a separate impurity network in the subsequent Negishi step. The control strategy introduced a specification of ≤ 0.15% impurity A, enforced by HPLC integration at 230 nm, and the brominating agent was pre-washed with aqueous sodium thiosulfate prior to use. This adjustment maintained impurity A below 0.10% across 17 consecutive commercial batches.

HS Code	146334
Chemical Formula	C4H2BrNO2S
Molar Mass	222.03 g/mol
Appearance	Solid (usually a powder)
Color	May vary, often white to off - white
Melting Point	Data specific to this compound needed (varies depending on purity)
Solubility In Water	Low solubility, as it is an organic acid with non - polar components
Solubility In Organic Solvents	Soluble in some polar organic solvents like DMSO, DMF
Pka Value	Characteristic pKa for the carboxylic acid group, data needed for exact value
Odor	May have a faint, characteristic organic odor

Packing	500g of 2 - Bromo - 1,3 - Thiazole - 5 - Carboxylic Acid packaged in a sealed plastic bag.
Shipping	2 - Bromo - 1,3 - thiazole - 5 - carboxylic acid is shipped in well - sealed containers, compliant with chemical transport regulations. Packed to prevent breakage and spillage, ensuring safe transit to the destination.
Storage	2 - Bromo - 1,3 - thiazole - 5 - carboxylic acid should be stored in a cool, dry place away from heat sources and direct sunlight. Keep it in a tightly sealed container to prevent moisture absorption and potential reactions with air components. Store it separately from incompatible substances, such as strong oxidizers or bases, to avoid chemical degradation.