4-Bromo-2-Thiazolecarboxylicacid

When the Bromine Atom Dictates Regioselectivity in Suzuki Couplings for Anticoagulant Scaffolds

4-Bromo-2-thiazolecarboxylic acid serves as a regiochemically pure entry point for constructing 4-aryl-thiazole-2-carboxamide pharmacophores recurrent in next-generation oral Factor Xa inhibitors. The C4 bromine enables site-selective palladium-catalysed cross-coupling while preserving the C2 carboxylic acid for a terminal amidation step with chiral trans-cyclohexane-1,4-diamine derivatives. A process-scale complication arises directly from the unprotected carboxylic acid: under standard Suzuki–Miyaura conditions — Pd(PPh₃)₄ at 2 mol%, aqueous K₂CO₃ in dioxane at reflux — the carboxylate anion participates in a parasitic protodecarboxylation pathway that becomes kinetically significant above 85°C, generating 4-arylthiazole as a difficult-to-purge impurity. Simultaneously, palladium carboxylate aggregates precipitate from the reaction mixture, decreasing the effective catalyst concentration and prolonging reaction times to > 24 h. To mitigate these competing events, the acid is quantitatively converted to its methyl ester using thionyl chloride in methanol at 0–5°C over 6 h followed by cautious aqueous bicarbonate work-up that keeps the product below 10°C to avoid chloride displacement at the thiazole C2 position. The resulting methyl 4-bromo-2-thiazolecarboxylate is then submitted to Suzuki coupling with (5-chloro-2-fluorophenyl)boronic acid in a degassed water/1-propanol (1:4 v/v) medium at 75±2°C, catalysed by 0.8 mol% Pd(OAc)₂ and 1.6 mol% SPhos. HPLC monitoring on a C18 column with UV detection at 220 nm reveals protodebromination of the starting material to ≤3% area after 4 h. After extractive work-up and solvent switch to toluene, in-process controls by Karl Fischer titration confirm water content below 200 ppm before saponification with 1.05 eq LiOH in THF/water at 22°C. Precipitation with dilute HCl furnishes the free 4-aryl-thiazole-2-carboxylic acid in 92–95% isolated yield with 99.2% chromatographic purity. Conversion to the acid chloride is executed with oxalyl chloride and catalytic DMF in dichloromethane at 0–10°C under a nitrogen sweep to expel HCl and CO. The acid chloride solution is metered into a pre-cooled slurry of the amine partner and triethylamine in acetonitrile at −15°C; this inverse addition protocol limits racemization at the chiral carbon bearing the amine to ≤0.5% enantiomeric excess loss. Final recrystallisation from ethyl acetate/n-heptane (1:5) at −10°C for 12 h delivers the bulk drug intermediate with a chemical purity > 99.5% and enantiomeric excess of 99.0%. Residual palladium is controlled to <10 ppm consistent with ICH Q3D Option 1 parenteral limits, verified by ICP-MS after microwave digestion.

The following impurity thresholds are enforced at the final API intermediate stage prior to release for toxicology studies:

Optimizing Fungal SDH Target Binding via C4 Thiazole Diversification

In agrochemical lead optimisation, thiazole-2-carboxamides bearing a tailored aryl group at the 4-position have been recognised as potent inhibitors of succinate dehydrogenase (SDH), a validated target shared by commercial carboxamide fungicides such as thifluzamide. 4-Bromo-2-thiazolecarboxylic acid is employed as the diversification cornerstone in parallel synthesis libraries because the bromine atom serves as a universal leaving group for copper-mediated C–O and C–S bond formation. The carboxylic acid is first activated as its morpholine amide via 1,1′-carbonyldiimidazole (CDI) in dichloromethane at 0°C to suppress competing esterification; the morpholine amide withstands the alkaline conditions of the subsequent Ullmann coupling without cleavage. After aqueous work-up and flash chromatography on silica (hexane/ethyl acetate 1:1), the amide is reacted with an electron-deficient phenol — typically a 4-cyano- or 4-nitrophenol — using 10 mol% CuI, 20 mol% 1,10-phenanthroline, and 2.0 eq Cs₂CO₃ in degassed DMF at 110°C for 18–24 h under argon. The dark reaction mixture is diluted with ethyl acetate and washed with 5% aqueous EDTA disodium salt solution (pH 9) to extract copper ions; residual copper is monitored by ICP-OES and must be reduced to <5 ppm in the dried organic phase to avoid phytotoxicity artefacts during in vivo glasshouse screening. The morpholine amide is then cleaved with LiOH in THF/water (3:1) at 50°C over 8 h, releasing the free carboxylic acid. Final amidation with 2-amino-4-methylbenzonitrile or analogous aniline fragments uses EDC·HCl (1.2 eq) and HOBt (1.2 eq) in DMF at 0°C to room temperature. The SDHI candidate is crystallised from 2-propanol/water. A manufacturing constraint emerges from residual bromide originating from the initial 4-bromo precursor: if bromide content exceeds 0.1% by ion chromatography, subsequent hydrogenation steps intended for the nitrile motif generate trace levels of N-ethyl bromo-aniline impurities, which are mutagenic in Ames II assays. Therefore, an aqueous 5% sodium sulfite wash is introduced after the Ullmann step to guarantee bromide below 50 ppm. The entire sequence delivers > 500 mg of each library member with a purity exceeding 97% by qNMR, enabling rapid structure-activity relationship mapping for cereal rust and powdery mildew.

When bridging ligands for metal-organic frameworks are required to bear a post-synthetic modification handle, 4-bromo-2-thiazolecarboxylic acid provides a geometrically rigid, bromine-decorated carboxylate strut. Under modulated solvothermal conditions — 120°C, 72 h, DMF/formic acid (10:1 v/v) — the acid reacts with ZrCl₄ to yield a UiO-66 isoreticular framework of composition Zr₆O₄(OH)₄(Br-TzCOO)₆, crystallising in the cubic Fm-3m space group. Synchrotron powder X-ray diffraction confirms a lattice parameter of 20.71 Å and octahedral cage diameter of approximately 11 Å. The bromine substituents project into the pore windows where they remain sterically accessible for palladium-catalysed Sonogashira replacement. Post-synthetic modification is executed by suspending the degassed framework in anhydrous DMF (<50 ppm H₂O by Karl Fischer) containing 5 mol% Pd(PPh₃)₄ (relative to bromine), 2.5 mol% CuI, and excess ethynylpyridine (5 eq per Br) at 60°C for 24 h under argon. After three DMF wash cycles and Soxhlet extraction with ethanol, EDS analysis indicates 68–78% bromine replacement in the first cycle; a second PSM cycle boosts conversion to 90–95%. Simultaneous thermogravimetric analysis and differential scanning calorimetry (TGA-DSC) under air show framework decomposition onset at 380°C, with the pyridine-grafted material retaining > 85% of its initial mass at that temperature. Nitrogen physisorption at 77 K (ISO 9277 BET method) reveals a surface area decline from 1 150 m² g⁻¹ to 1 010 m² g⁻¹ after pyridine incorporation, consistent with pore filling, while CO₂ uptake at 298 K and 1 bar increases by 48% — from 2.1 mmol g⁻¹ to 3.1 mmol g⁻¹. The enhanced selectivity is attributed to Lewis acid-base interactions between the pyridyl nitrogen lone pair and the CO₂ quadrupole moment. A processing hazard specific to the thiazole ring must be rigorously managed: in the presence of trace water during solvothermal synthesis, the ring undergoes hydrolytic opening to a thioamide-carboxylate species, characterised by an IR stretch at 1 650 cm⁻¹ and a broad S-H band at 2 540 cm⁻¹. Once formed, this defect cannot be repaired post-synthetically and leads to a 30% reduction in BET surface area. Consequently, fresh anhydrous DMF is pre-dried over activated 3 Å molecular sieves for 48 h and the modulator formic acid is distilled from phthalic anhydride immediately before use.

The installation of a terminal alkyne handle onto a protein-reactive scaffold is a standard strategy for bioconjugation via copper-catalysed azide-alkyne cycloaddition (CuAAC). Starting from 4-bromo-2-thiazolecarboxylic acid, the sequence requires transient protection of the carboxylic acid as the tert-butyl ester. Treatment with Boc anhydride (1.5 eq) and DMAP (0.1 eq) in t-BuOH at 40°C for 8 h followed by chilled aqueous work-up furnishes the ester in 88% yield. The ester is then submitted to a Sonogashira coupling with trimethylsilylacetylene using PdCl₂(PPh₃)₂ (3 mol%), CuI (6 mol%), and triethylamine in rigorously degassed THF at 50°C for 16 h. After filtration through a short silica plug to remove palladium residues, the TMS group is cleaved with tetrabutylammonium fluoride (1.1 eq) in THF at 0°C — the internal temperature must not exceed 5°C to prevent premature ester solvolysis. The liberated alkyne is obtained in 82% yield over the two steps after aqueous EDTA extraction and drying over Na₂SO₄. tert-Butyl ester deprotection proceeds smoothly with 20% trifluoroacetic acid in dichloromethane at room temperature over 2 h; the product precipitates upon addition of n-heptane and is collected by filtration in 95% yield. The free acid is immediately activated with N,N′-disuccinimidyl carbonate (1.3 eq) and triethylamine (1.5 eq) in acetonitrile at 4°C to form the NHS ester, which is isolated by rapid silica filtration to avoid hydrolysis. For antibody labelling, the NHS ester is added at 5 eq relative to the monoclonal antibody (mAb) in phosphate-buffered saline at pH 8.0, 4°C, and the reaction is quenched after 4 h with Tris buffer (50 mM, pH 7.5). The degree of labelling (DOL) is determined by intact mass analysis on an ESI-TOF instrument; a DOL of 2.0–3.5 is routinely achieved. Subsequent CuAAC conjugation with an azido-fluorophore in the presence of THPTA ligand and sodium ascorbate proceeds without detectable protein aggregation as confirmed by dynamic light scattering (hydrodynamic radius remains < 6 nm). The critical purification step is the exhaustive removal of residual copper originating from the Sonogashira reaction; ICP-MS analysis of the final mAb conjugate must show copper < 0.5 ppb to prevent copper-catalysed generation of hydroxyl radicals during cellular imaging. Accelerated stability testing of the thiazole-carboxamide linkage at 37°C and pH 7.4 over 24 h shows no ring hydrolysis or retro-amide cleavage, demonstrating the biocompatibility of this heterocyclic scaffold under physiological conditions.

Interfacial Dipole Tuning in n-i-p Perovskite Devices Using 4-Bromo-2-Thiazolecarboxylate SAMs

To create a hole-selective contact in inverted perovskite solar cells, self-assembled monolayers (SAMs) based on thiazole-2-carboxylic acid anchor groups are investigated because the electron-deficient thiazole ring lowers the highest occupied molecular orbital energy relative to purely aromatic carboxylates. The 4-bromo substituent serves as a temporary placeholder that is displaced by a 4-(diphenylamino)phenyl donor group via Suzuki coupling to generate a donor-π-acceptor chromophore. The coupling is performed on methyl 4-bromo-2-thiazolecarboxylate with the corresponding arylboronic acid using 2 mol% Pd(dppf)Cl₂, 3 eq K₃PO₄ in toluene/water (5:1) at 90°C for 12 h under argon. After silica gel chromatography (hexane/ethyl acetate gradient), the methyl ester is isolated in 79% yield and hydrolysed with 1.2 eq KOH in methanol/water at 60°C for 4 h to give the free SAM precursor acid. Indium tin oxide (ITO) substrates are cleaned by sequential ultrasonic treatment in detergent, deionised water, acetone, and isopropanol, followed by UV-ozone irradiation for 20 min. SAM deposition is performed by immersing the substrate in a 0.5 mM solution of the thiazole-carboxylic acid in anhydrous toluene for 16 h under an argon atmosphere in the dark. After deposition, substrates are sonicated in fresh toluene (5 min) and blown dry with nitrogen. Static water contact angle increases from <10° (bare ITO) to 68°, and Kelvin probe force microscopy measures a work function decrease of 0.38 eV, confirming the formation of a uniform monolayer. When integrated into a device stack ITO/SAM/FA₀.₈₅Cs₀.₁₅PbI₃/PC₆₁BM/BCP/Ag, encapsulated and measured under simulated AM1.5G illumination (IEC 60904-3), the champion device yields an open-circuit voltage of 1.12 V, a short-circuit current density of 22.8 mA cm⁻², and a fill factor of 78.3%, representing a 7% absolute improvement in fill factor over the bare ITO control. Electrochemical impedance spectroscopy (EIS) at 0.9 V forward bias reveals a recombination resistance (R_rec) of 4.2 kΩ cm² compared to 1.1 kΩ cm² for the control, consistent with reduced interfacial charge recombination. A key durability concern is the chemical stability of the thiazole ring under operational conditions: XPS S 2p spectra of the SAM after 500 h continuous light soaking at 60°C and 40% relative humidity show a small peak at 168.5 eV attributed to sulfone formation; this degradation pathway can be suppressed by encapsulating the device with a glass cover and an epoxy edge seal under nitrogen. Devices assembled with the unsubstituted 4‑bromo‑thiazole‑carboxylate SAM exhibit severe J‑V hysteresis (hysteresis index > 25%), demonstrating that the C4 donor group is mechanistically essential for efficient hole extraction and trap passivation at the buried interface.

In the search for selective adenosine receptor modulators, 4-bromo-2-thiazolecarboxylic acid is harnessed as a bifunctional core for iterative amidation and Buchwald-Hartwig amination sequences in hit-to-lead programs targeting the A₁ and A₂A receptor subtypes. The carboxylic acid is first activated with HATU (1.2 eq) and DIPEA (3.0 eq) in dry DMF at 0°C and then treated with a panel of chiral amines — including (S)-pyrrolidin-3-ylamine hydrochloride and 2-(aminomethyl)pyridine — to generate a focused library of 4-bromo-thiazole-2-carboxamides in 60–95% isolated yield after automated mass-directed flash purification on C18 cartridges (eluent: acetonitrile/water with 0.1% formic acid). Each isolated amide is subsequently submitted to Buchwald-Hartwig coupling with an electron-deficient aniline: typically 4-cyanoaniline (1.2 eq), Pd₂(dba)₃ (5 mol%), Xantphos (10 mol%), and NaO^tBu (2.0 eq) in degassed toluene at 100°C for 12 h under argon. The crude products are treated with a trimercaptotriazine (TMT) silica scavenger (2 eq relative to initial Pd, 2 h stirring in THF) to sequester residual palladium; after filtration and concentration, the final compounds exhibit palladium levels <1 ppm by ICP-MS, qualifying them for radioligand binding assays. Competitive displacement assays are conducted using [³H]DPCPX for A₁ receptors and [³H]ZM241385 for A₂A receptors expressed in CHO cell membranes. Hits demonstrating Kᵢ values below 50 nM are progressed to functional cAMP assays in HEK293 cells to distinguish agonists from antagonists. A metabolic stability screen in human liver microsomes (0.5 µM test compound, 1 mg mL⁻¹ microsomal protein, NADPH regeneration system at 37°C) reveals that the parent thiazole-carboxamide remains > 70% after 60 min, although a minor 4-debromination metabolite (<5%) is detected by LC–MS/MS when the bromine has not been fully substituted. This observation places an absolute requirement on confirming the absence of unreacted bromo intermediate in the library amides before scaling for in vivo pharmacokinetic studies, as 4-debromo impurities can give false-positive metabolic turnover readouts. The thiazole core demonstrates negligible CYP3A4 and CYP2D6 inhibition (IC₅₀ > 30 µM), reinforcing the scaffold’s attractiveness for CNS-penetrant adenosine antagonist development.