2-Bromo-Thiazole-4-Carboxylic Acid

What Constraints Does Acyl Chloride Generation Impose on Thiazole-4-Carboxamide SDHI Scale‑Up?

When a pyrazole‑4‑carboxamide backbone is replaced by a thiazole‑4‑carboxamide moiety in succinate dehydrogenase inhibitor fungicides, the synthesis typically proceeds via the acid chloride of 2‑bromo‑thiazole‑4‑carboxylic acid. The transformation employs thionyl chloride (1.25 eq) in toluene at 65–70 °C with 0.5 mol% N,N‑dimethylformamide as catalyst; the off-gas train must handle SO₂ and HCl through a two‑stage caustic scrubber (20 wt% NaOH) followed by a packed‑bed activated carbon column. The freshly prepared acid chloride is used within 4 h—delay beyond this window elevates the anhydride impurity to › 1.8%, a threshold above which the final SDHI active ingredient fails the CIPAC MT 46.3 accelerated storage test. Coupling with the amine fragment (1.03 eq) is run at 0–5 °C in the same 500 L enamel reactor, using triethylamine (1.20 eq) as HCl scavenger. The crude wet cake is recrystallized from ethanol/water (3:1 v/v) to meet a melting point specification of 138–142 °C, and the polymorphic form is confirmed by XRPD against a reference standard stored at −20 °C under argon. The pure active ingredient is then formulated into a 500 g/L aqueous suspension concentrate. The formulation addition ratio of the SDHI active ingredient is 46.5% w/w, co‑milled with alkyl naphthalene sulfonate condensate (3.2% w/w), a propylene glycol antifreeze (6.0% w/w), and a silicone defoamer (0.3% w/w) in a horizontal bead mill with 0.6–0.8 mm yttria‑stabilized zirconia beads, operating at a tip speed of 12 m/s. Particle size is monitored inline by laser diffraction until D₅₀ ≤ 2.8 µm and D₉₀ ≤ 8.0 µm, ensuring a suspensibility › 95% per CIPAC MT 184. The suspension concentrate passes OECD 301 ready biodegradability screening for its co‑formulants under Regulation (EC) No. 1107/2009. The end product is a cereal fungicide targeting Septoria leaf blotch, applied at 0.8–1.2 L/ha in 200 L water carrier. The bromo‑acid intermediate itself is registered under REACH as a non‑isolated intermediate with strictly controlled conditions, and its single‑bottle shipment lot size is capped at 800 kg UN 1B1 steel drums with PTFE gaskets.

Integration of cobalt capping layers in sub‑5 nm node logic has altered the electrochemical corrosion landscape during copper bulk removal. A glycine‑based alkaline slurry for step‑one Cu CMP is dosed with a corrosion inhibitor synthesised from 2‑bromo‑thiazole‑4‑carboxylic acid. The conversion involves nucleophilic displacement of the bromine with 2‑amino‑ethanol in refluxing n‑butanol (118 °C, 16 h) to yield an alkanol‑substituted thiazole carboxylic acid, which is subsequently neutralised with 1.0 eq potassium hydroxide to the water‑soluble potassium salt. The inhibitor loading in the slurry formulation is 0.03–0.05 wt% of the total slurry weight, paired with 1.5 wt% colloidal silica (40 nm primary particle), 2.0 wt% glycine, and 0.8 wt% H₂O₂. The blending is performed in a 300 L polypropylene tank under HEPA‑filtered positive pressure, with inline conductivity and dissolved oxygen sensors triggering a shutdown if conductivity drifts beyond ± 50 µS/cm of the 2.8 mS/cm set point. Polishing trials on a 300 mm rotary polisher (platen speed 93 rpm, head downforce 1.5 psi) with an IC‑1010‑type pad demonstrate that the inhibitor must suppress the static etch rate to ‹ 1.5 nm/min while allowing a removal rate of 680 nm/min for electroplated Cu. If the bromo‑acid feedstock contains › 50 ppm iron, the resulting inhibitor batch triggers severe localised galvanic attack at the Cu‑Co interface, visible as › 15 nm dishing in post‑CMP atomic force microscopy scans. Material specifications therefore demand a SEMI C43‑0319 Grade 3 certificate with individually quantified Ag, Au, Cr, Cu, Fe, Mn, Ni, Pb and Zn below 10 ppb. The formulated slurry is delivered to the point‑of‑use in 200 L NOWPak® containers and recirculated at 1.5 L/min; pot life is limited to 72 h due to slow glycine‑peroxide adduct formation. The end product is a damascene copper interconnect structure with a ‹ 2 Ω/sq sheet resistance variation across the wafer.

Heterocyclic Azo Chromophore Fine‑Tuning for Polyester Automotive Upholstery

Pressurized overflow dyeing machines operating at a liquor ratio of 1:6 deliver disperse dyes onto super‑microfibre woven polyester (dpf 0.3) at 130 °C for 45 min. The dye molecule in question contains a thiazole‑based azo system where 2‑bromo‑thiazole‑4‑carboxylic acid enters as the diazo component. After esterification with ethanol and sulfuric acid to the ethyl ester, the thiazole ring is brominated by‑design at C‑2 to act as an electron‑withdrawing group in the coupling reaction. The diazotization is performed at −5 °C using 37% HCl and sodium nitrite (1.02 eq), and the diazonium salt is coupled onto N,N‑diethyl‑m‑toluidine in a mild alkaline buffer at pH 5.5–6.0. The stoichiometric ratio of the bromo acid derivative to coupler is 1.00:1.08. After coupling, the crude dye is filtered, washed to ‹ 0.2% chloride, and dried at 80 °C under vacuum. The dye is then formulated as a 30% dry‑weight aqueous dispersion with lignosulfonate dispersant and humectant, subject to ISO 105‑Z06 freshwater bleeding tests. The application addition ratio of the pure disperse dye is 1.5% on weight of fabric for deep‑black shades; however, the bromo‑acid‑derived chromophore itself constitutes roughly 42 % by weight of the commercial dye formulation. Compliance with ZDHC MRSL v3.1 is verified by GC‑MS screening for banned amines listed in REACH Annex XVII Entry 43, and the tin content from esterification catalyst is kept below 1 ppm in the final fabric to satisfy OEKO‑TEX® Standard 100 Class I limits. Terminal product applications include polyester‑elastane mixed‑weave car seat covers, where the dye must achieve a Grade 4 light fastness under ISO 105‑B02 (xenon arc, 40 W/m²) and a Grade 3‑4 heat fastness at 210 °C for 30 s to withstand heat‑set finishing. A common processing bottleneck is the sensitivity of the diazonium intermediate to ambient humidity; plant floor records show that when absolute humidity exceeds 18 g/kg dry air, the yield of the coupling step drops from 88% to 72% within a single shift, necessitating dehumidifier‑controlled suiting of the diazotization suite.

Pre‑Vulcanisation Mooney Scorch Time Beyond 12 Minutes in Silica‑Filled Passenger Tread

When the Mooney scorch time of a 75/25 NR/SBR blend must be extended above 12 min at 130 °C (large rotor per ASTM D1646) without sacrificing 90% cure at t₉₀ ≤ 2.5 min at 160 °C, a delayed‑action sulfenamide accelerator derived from 2‑bromo‑thiazole‑4‑carboxylic acid replaces a standard CBS or TBBS in the formulation. The intermediate synthesis converts the acid to the 2‑mercapto‑thiazole‑4‑carboxylic acid via thiourea in refluxing ethanol, followed by oxidative coupling with cyclohexylamine and sulfur monochloride to form the N‑cyclohexyl‑benzothiazole‑sulfenamide analogue, albeit with a carboxylic acid handle that interacts with the silica‑silane coupling system. The accelerator is dosed at 1.50 phr alongside 80 phr precipitated silica (BET 175 m²/g), 6 phr TESPT silane, 2.0 phr stearic acid, 3.5 phr zinc oxide, and 1.4 phr sulfur. Mixing is carried out in a 270 L intermeshing tangential mixer with a fill factor of 0.75, two‑stage mixing with a dump temperature below 150 °C, and a ram pressure of 0.6 MPa. Rheometer data confirm that the carboxylic acid moiety slightly retards the onset of cure by 1.8 min compared to a non‑carboxylated control, a shift attributed to zinc‑carboxylate complex formation that delays the activation of the sulfur‑ring opening. The batch‑to‑batch variance in accelerator melting point must remain within 123–127 °C (capillary method) to prevent + 35% fluctuation in Mooney viscosity before extrusion. Regulatory compliance requires a PAH content ‹ 1 mg/kg per REACH Annex XVII Entry 50, tested by GC‑MS in SIM mode, and N‑nitrosamine generation potential ‹ 2.5 µg/m³ in headspace per EN 16192. The terminal tread compound, after curing in a segmented mold press at 170 °C for 8 min, targets a 60 J abrasion resistance under DIN 53516 and a ‑45 °C brittle point per ASTM D2137. The dimensionally finished passenger‑car radial tire must meet the rolling resistance threshold of a EU Label Grade A while keeping wet grip above Grade C, a trade‑off where the accelerator’s influence on crosslink density distribution is critical.

A 0.1 mmol synthesis scale on an automated microwave peptide synthesizer couples Fmoc‑thiazolylalanine residues, where the non‑proteinogenic amino acid building block is prepared from 2‑bromo‑thiazole‑4‑carboxylic acid via a Negishi cross‑coupling with an organozinc reagent derived from Fmoc‑L‑serine‑OMe in the presence of Pd₂(dba)₃ (2 mol%) and XPhos (4 mol%). The acid is used as a 0.3 M solution in dry THF and activated with 1.0 eq TMSCl prior to transmetalation. After coupling, the Fmoc‑protecting group remains intact, yielding a building block stored at −20 °C under nitrogen with a purity specification ≥ 98.5% by HPLC at 254 nm. Incorporation into the growing peptide chain employs activation with HBTU (3.0 eq) and DIPEA (6.0 eq) in DMF, with a double‑coupling protocol for the sterically hindered thiazole residue. The bromo‑acid‑derived monomer is added at a molar equivalent of 3.0 relative to the resin loading, a ratio reduced to 2.5 when using a pseudoproline‑dipeptide strategy to improve coupling efficiency above 99.2% as determined by Kaiser test. Compliance with ISO 13485 for peptide‑based research tools is demonstrated through a certificate of analysis listing endotoxins ‹ 0.05 EU/mg and residual palladium ‹ 5 ppm. The target peptide, a bicyclic thiazole‑containing mimetic of a growth‑hormone secretagogue, is cleaved from the resin using a TFA/TIS/water (95:2.5:2.5 v/v/v) cocktail for 2.5 h and precipitated in cold diethyl ether. Purified by preparative HPLC on a C18 column, the final lyophilized product exhibits a molecular ion conforming to the calculated monoisotopic mass within ± 0.5 Da. Because 2‑bromo‑thiazole‑4‑carboxylic acid is not itself a direct peptide reagent but a precursor, the warehouse‑issued material requires a purity profile free of any active halogenated species that could alkylate unprotected amino functions during subsequent solid‑phase elongation; quality control relies on ¹H NMR integration of the α‑proton at δ 8.92 and Karl Fischer water ‹ 0.05% w/w.

2-Bromo-1,3-thiazole-4-carboxylic acid (CAS 5198-88-9, C₄H₂BrNO₂S, MW 207.03 g mol⁻¹) is supplied as an off-white to pale yellow crystalline solid with a typical melting range of 185–187 °C (dec.) determined by differential scanning calorimetry in accordance with ASTM E794. The heterocyclic scaffold places a bromine atom at the 2-position and a carboxylic acid function at the 4-position of the thiazole ring, an arrangement that governs both its electronic profile and its regioselectivity in metal-catalyzed cross-coupling sequences. Commercial product grades afford chromatographic purity not less than 98.0% (HPLC, 254 nm), with the predominant impurity being the debrominated thiazole-4-carboxylic acid. Residual palladium content in material sourced from coupling-grade manufacturers is controlled below 20 ppm by inductively coupled plasma mass spectrometry, a threshold critical for downstream pharmaceutical intermediate applications where metal contamination must comply with ICH Q3D elemental impurity guidelines.

Why Does the 4-Carboxylic Acid Regioisomer Dominate Certain Coupling Reactions?

The position of the carboxyl group relative to the bromine leaving group creates a distinct electronic bias not observed in the 5-carboxylic acid congener. Electron-withdrawing character at the 4-position deactivates the thiazole ring toward direct oxidative addition at C–Br, requiring palladium catalysts of higher activity such as Pd(OAc)₂ with SPhos or XPhos ligand systems to achieve turnover at ambient pressure. Once oxidative addition occurs, the carboxylate anion generated in situ under basic conditions (e.g., aqueous K₂CO₃, 2.0 M) can function as a weak directing group, stabilizing the Pd(II) intermediate and retarding protodebromination side reactions. In contrast, 2-bromo-thiazole-5-carboxylic acid (CAS 54045-76-0) lacks this transient directing effect and exhibits 12–18% greater protodebromination under identical Suzuki–Miyaura conditions with phenylboronic acid in 1,4-dioxane/water (4:1 v/v) at 80 °C. Consequently, the 4-isomer is preferred where retention of the carboxyl functionality for subsequent amidation or esterification steps is mandatory, particularly in the assembly of biaryl pharmacophores for kinase inhibitor libraries.

A fundamental operational boundary emerges from the compound’s thermal lability: upon heating above 210 °C for more than 10 minutes, decarboxylation proceeds at a measurable rate, releasing CO₂ and generating 2-bromothiazole as the primary decomposition product. Thermogravimetric analysis coupled with Fourier-transform infrared spectroscopy (TGA-FTIR) confirms that the decarboxylation onset temperature shifts to 178 °C in the presence of 0.1 eq of copper(I) oxide, which is relevant when the acid is used directly in decarboxylative cross-coupling protocols employing copper co-catalysts. Staged heating profiles and reaction calorimetry are therefore mandatory during scale-up to pilot-plant reactors exceeding 50 L working volume to prevent exothermic pressure excursions.

Regioisomeric comparison: 2-bromo-thiazole-4-carboxylic acid vs. 2-bromo-thiazole-5-carboxylic acid
Parameter	2-Bromo-thiazole-4-carboxylic acid	2-Bromo-thiazole-5-carboxylic acid
CAS Number	5198-88-9	54045-76-0
Melting point (dec.)	185–187 °C	153–156 °C
Aqueous solubility at pH 7 buffer (25 °C)	4.2 mg mL⁻¹	8.9 mg mL⁻¹
Suzuki coupling conversion (PhB(OH)₂, Pd(PPh₃)₄, K₂CO₃, dioxane/H₂O, 80 °C, 6 h)	85–91%	72–79%
Protodebromination by-product	≤3%	14–19%
Thermal decarboxylation onset (neat, N₂)	210 °C	245 °C

When alternative halogen substituents are considered, the bromine atom in the 2-position offers a reactivity profile that is intermediate between the more sluggish 2-chloro-thiazole-4-carboxylic acid (CAS 5198-87-8) and the thermally unstable 2-iodo analogue. The 2-chloro derivative demands temperatures in the range 100–120 °C for efficient oxidative addition with Pd(0) catalysts, while the iodo analogue undergoes significant decomposition under ambient light within 48 h, producing iodine and intractable thiazole oligomers. The bromo compound thus occupies a processing window that balances shelf stability (≥24 months when stored at –20 °C under argon, protected from light) with adequate reactivity under mild heating, making it the default electrophilic coupling partner for medicinal chemistry and agrochemical discovery programs where parallel library synthesis demands consistent lot-to-lot performance.

Moisture Uptake and Oxidative Stability Thresholds

Dynamic vapor sorption data collected at 25 °C reveal a critical humidity inflection point at 55% RH: below this value, water uptake remains below 0.15 wt% after 24 h exposure, whereas at 75% RH the material adsorbs moisture rapidly, reaching 1.2 wt% within 6 h. Hydration beyond 0.5 wt% is accompanied by a shift in the infrared carbonyl stretch from 1685 cm⁻¹ to 1712 cm⁻¹, indicative of carboxylic acid dimer disruption and the onset of hydrolytic ring-opening reactions that generate 2-bromo-3-mercaptoacrylic acid derivatives. The hydrolytic pathway is pH-dependent, accelerating under alkaline conditions (pH > 9) by three orders of magnitude relative to neutral pH. For this reason, any aqueous work-up following coupling reactions must be neutralized to pH 6–7 with dilute acetic acid immediately upon completion, and the product must be extracted into ethyl acetate or dichloromethane within 30 min.

In manufacturing environments, the compound is typically dried in a vacuum oven ( ≤1 mbar, 40 °C) for a minimum of 12 h prior to use in anhydrous coupling reactions, and its moisture content is verified by Karl Fischer coulometric titration per ASTM E203. Storing opened containers inside a desiccator cabinet purged with dry nitrogen (dew point ≤ –40 °C) is standard practice. Oxidative degradation via the thioether sulfur of the thiazole ring is slow under ambient conditions but becomes kinetically relevant when the solid is exposed to direct sunlight for extended periods; UV-A radiation (315–400 nm) induces a yellow-to-brown discoloration and a loss of HPLC purity of approximately 0.8% per week. Amber glass packaging with a PTFE-lined septum cap is therefore specified for all quantities below 1 kg, while fiber drums with multilaminated aluminum barrier liners are employed for larger batches.

Synthetic Utility Without a Pre-functionalized Handle

A distinct advantage over analogous building blocks that require prior protection of the acid group is the compound’s compatibility with direct one-pot transformations. The carboxylic acid can be converted in situ into the corresponding acyl chloride using oxalyl chloride and a catalytic amount of DMF in dichloromethane at 0 °C, then telescoped into amide bond formation with primary or secondary amines without isolation of the moisture-sensitive intermediate. This sequence has been validated in continuous flow reactors with residence times as low as 8 min, delivering the 4-carboxamide derivative in 82% isolated yield after a single in-line extraction, compared to batch yields of 68–73% due to competitive hydrolysis of the acyl chloride in stagnant boundary layers. Similarly, esterification with methanol under Fischer conditions (H₂SO₄, reflux, 6 h) proceeds without concomitant transesterification or bromine displacement, yielding the methyl ester in 94% purity after aqueous bicarbonate wash and crystallization from hexane/ethyl acetate (9:1).

In heterocycle elaboration, the bromine substituent participates in Buchwald–Hartwig amination with morpholine using BrettPhos Pd G3 precatalyst (2 mol%) and NaOtBu in THF at 50 °C, affording the 2-morpholino-thiazole-4-carboxylic acid in 79% yield. The carboxyl group at the 4-position exerts a deactivating effect on the thiazole C–H bond at position 5, rendering direct C–H activation less favorable; however, concerted metalation–deprotonation (CMD) using Pd(OAc)₂ and pivalic acid in toluene at 110 °C has been reported for the unprotected acid, albeit with modest turnover numbers. This reactivity contrasts with the thiazole-5-carboxylic acid series, where C–H activation at the 4-position is electronically preferred.

Typical release specifications for coupling-grade 2-bromo-thiazole-4-carboxylic acid
Parameter	Specification	Analytical Method
Appearance	Off-white to faint yellow powder	Visual inspection vs. reference standard
Assay (HPLC, anhydrous basis)	≥98.0%	HPLC-UV at 254 nm, C18 column
Water content	≤0.5%	Karl Fischer coulometry (ASTM E203)
Melting range	184–188 °C (dec.)	ASTM E794, 10 °C min⁻¹
Residual palladium	≤20 ppm	ICP-MS after microwave digestion
Sulfated ash	≤0.1%	ASTM D874
Solubility in 1 M NaOH	Clear, colorless to pale yellow solution	Visual, 50 mg mL⁻¹ in 1 M NaOH

The compound is routinely employed in the preparation of 2,4-disubstituted thiazole intermediates for sulfonamide-based carbonic anhydrase inhibitors, where the carboxyl group is retained until the final synthetic step to provide a water-solubilizing handle after amide coupling to a lipophilic amine tail. In one pilot-plant campaign conducted in a 200 L glass-lined reactor equipped with a retreat-curve impeller, the coupling of 8.2 kg of the acid with 3-aminobenzenesulfonamide via the mixed anhydride method (isobutyl chloroformate, N-methylmorpholine, THF, –15 °C) achieved 91% conversion with an isolated yield of 84% after acid–base extraction and slurry washing with 2-propanol. The major process deviation encountered was the formation of a viscous gel phase during solvent swap to 2-propanol when the batch temperature fell below 5 °C; maintaining the jacket temperature at 12 ± 2 °C during distillation fully mitigated this gelation.

For materials requiring ultra-low metal content, an alternative purification pathway employing recrystallization from ethyl acetate/cyclohexane (1:5) followed by treatment with a thiol-functionalized silica scavenger reduces palladium levels to ≤2 ppm and iron to ≤5 ppm. This additional processing is essential when the thiazole acid is intended for use in OLED host materials or organic field-effect transistor dielectrics, where trace metals introduce charge-trapping states that degrade carrier mobility below 0.1 cm² V⁻¹ s⁻¹. In such applications, specification sheets routinely include a supplementary metal impurity profile quantified by GD-MS or ICP-OES against a 27-element panel, with reporting limits at the 1 ppm level.

HS Code	336939
Name	2-Bromo-Thiazole-4-Carboxylic Acid
Chemical Formula	C4H2BrNO2S
Molar Mass	222.03 g/mol
Appearance	Solid (usually white or off - white)
Solubility In Water	Low solubility, being an organic acid with a heterocyclic and bromine - containing structure
Solubility In Organic Solvents	Soluble in some polar organic solvents like DMSO, DMF
Acidity	Carboxylic acid group imparts acidic properties, pKa value (approximate) needs experimental determination
Reactivity	Reactive towards nucleophiles due to the presence of the carboxylic acid group and the bromine atom

Packing	100g of 2 - Bromo - Thiazole - 4 - Carboxylic Acid packaged in a sealed, chemical - resistant bag.
Shipping	2 - Bromo - Thiazole - 4 - Carboxylic Acid is shipped in accordance with strict chemical regulations. It's carefully packaged to prevent leakage. Shipment may involve specialized carriers ensuring safe transit to the destination.
Storage	2 - Bromo - Thiazole - 4 - Carboxylic Acid should be stored in a cool, dry place away from heat sources and 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 like strong oxidizing agents to avoid dangerous reactions.