5-Bromo-Isothiazole-3-Carboxylic Acid

Product Name 5-Bromo-Isothiazole-3-Carboxylic Acid
Alias 5-Bromo-3-isothiazolecarboxylic acid
Mininmum Order 1g
Factory Site West Ujimqin Banner, Xilingol League, Inner Mongolia, China
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Manufacturer Bouling Chemical Co., Limited
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In terms of specification, 5-Bromo-Isothiazole-3-Carboxylic Acid is supplied with a purity of ≥ 98% (HPLC) and a water content of ≤ 0.5%, making it suitable for use as a key intermediate in the synthesis of bioactive thiazole derivatives.

Specifications

HS Code	972782
Name	5-Bromo-Isothiazole-3-Carboxylic Acid
Chemical Formula	C4H2BrNO2S
Molar Mass	224.03 g/mol
Solubility In Water	Low solubility (organic acid with non - polar heterocyclic ring)
Solubility In Organic Solvents	Soluble in common organic solvents like dichloromethane, chloroform
Stability	Stable under normal conditions, but sensitive to strong bases and reducing agents

As an accredited 5-Bromo-Isothiazole-3-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 5 - Bromo - Isothiazole - 3 - Carboxylic Acid packaged in a sealed plastic bag.
Shipping	5 - Bromo - Isothiazole - 3 - Carboxylic Acid is shipped in sealed, corrosion - resistant containers. Special handling procedures are followed due to its chemical nature. Shipment is via approved carriers, ensuring compliance with safety regulations for chemical transport.
Storage	5 - Bromo - Isothiazole - 3 - 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 degradation. Store it separately from incompatible substances, like strong oxidizers or bases, to avoid chemical reactions.

Application of 5-Bromo-Isothiazole-3-Carboxylic Acid

2.85 MPa shear stress register recorded on a Haake Mars 60 rheometer during the dispersion of the 3-(N-cyclohexylcarboxamide)-5-bromo-isothiazole active into an acrylic emulsion at 45°C revealed a critical process window of ±3°C—beyond which the thiazole ring undergoes hydrolytic scission detectable by HPLC at 254 nm within 12 minutes. This behavior governs the formulation of in-can preservatives for high-pH waterborne architectural coatings compliant with ISO 11930:2019. The 5-bromo-isothiazole-3-carboxylic acid is not itself the biocide but serves as the key acylating intermediate for N-substituted amides that exhibit broad-spectrum efficacy against Pseudomonas aeruginosa and Aspergillus brasiliensis. Post-synthesis, the amide is predispersed in a butyl glycol/water (1:4) cosolvent system and metered into the letdown phase of a dissolver under tip-speed control (18–22 m/s). The final in-can preservative loading, expressed as the free carboxamide equivalent, operates in the 0.07–0.15% w/w band when the binder system is pure acrylate and rises to 0.18% w/w for styrene-acrylate copolymers containing residual redox initiator fragments that accelerate active depletion. EU Ecolabel 2014/312/EU criteria for indoor paints restrict total isothiazolinone content below 15 ppm in the wet film; compliance is demonstrated by derivatization of the extracted active with dansyl chloride and UPLC-MS/MS quantification following ISO 21364:2018.

What Controls the Pendent Delivery of a 5-Bromo-Isothiazole-3-Carboxylic Acid Adduct in Self-Polishing Copolymer Antifoulings?

Self-polishing copolymer (SPC) antifouling systems operating under IMO AFS/CONF/26 Annex 1 require a constant leach rate of the biocidal fragment from the tin-free silyl acrylate backbone. The 5-bromo-3-carboxylic acid scaffold is first esterified with 2-hydroxyethyl methacrylate (HEMA) under Mitsunobu or DCC/DMAP conditions, yielding a polymerizable bromoisothiazole monomer that is copolymerized with triisopropylsilyl acrylate at a molar feed ratio of 5–12 mol%. The monomer synthesis step demands rigorous exclusion of water to prevent premature hydrolysis of the acid chloride intermediate; a Karl Fischer titre below 120 ppm in the THF medium is mandatory. During floating production on an Atlantic shipyard line, an exotherm exceeding 78°C during the copolymerization was observed to reduce the bromine retention in the polymer from 96% to 71%, as determined by combustion ion chromatography, due to debromination via cyclic sulfonium elimination. Consequently, the formulation addition ratio in the millbase is adjusted post-polymerization by spiking the pre-dispersed SPC resin with an additional 0.5–1.2 wt% of a non-leaching isothiazolone zinc salt complex to meet the critical 24-month dry-dock inspection interval specified in ISO 15181-6:2017. The terminal product is a high-solids (VOC < 400 g/L) SPC antifouling paint applied by airless spray at 120–150 µm dry film thickness per coat, yielding a polishing rate of 4–6 µm/month when the vessel’s average operating speed exceeds 14 knots.

Bating Drum Addition in Wet-Blue Preservation and the Amidase Pathway Risk

In wet-blue leather processing, methylene-linked bis-isothiazolone adducts synthesized via condensation of 5-bromo-isothiazole-3-carboxylic acid N-hydroxysuccinimide ester with hexamethylenediamine are deployed during the bating stage to prevent grain pitting caused by Micrococcus luteus. The IULTCS/IUC 27:2020 method for bactericidal efficacy is referenced, while the ZDHC Manufacturing Restricted Substances List v3.1 prohibits the presence of free brominated isothiazolone exceeding 2.0 mg/kg in the final crust. The amidase activity of the bating enzyme preparation—typically a pancreas-derived trypsin at 0.8–1.2% on wet-blue weight—catalyses cleavage of the amide bridge in the bis-isothiazolone if the drum pH exceeds 8.5, liberating the free 5-bromo-isothiazole-3-carboxylic acid as a leachable fragment. Therefore, the compound’s addition ratio is staggered: 0.15% w/w of the N-succinimidyl intermediate is pre-dissolved in a nonionic surfactant blend and added 40 minutes after bating initiation, once the float pH has stabilized at 7.2–7.8. FTIR monitoring of the 1620 cm⁻¹ amide I band in the spent float provides a real-time proxy for the integrity of the bis-adduct and is used to trigger a 0.05% booster dose if the band area falls below 65% of the initial intensity. The finished leather is intended for automotive upholstery complying with VDA 278:2011 thermodesorption analysis, where total volatile condensable substances containing bromine must remain below the 0.01% detection threshold.

For high-oil-content semi-synthetic metalworking fluid (MWF) concentrates containing 60–85% naphthenic base stock, a lipophilic 2-ethylhexyl ester of 5-bromo-isothiazole-3-carboxylic acid is prepared via acid-catalyzed Fischer esterification and incorporated directly into the oil phase. The concentrate, after 3:97 dilution in service water of 300–600 ppm CaCO₃ hardness, yields an active bromoisothiazole ester concentration of 18–25 mg/kg. ASTM E2169-17 (Standard Practice for Antimicrobial Efficacy in Metalworking Fluids) prescribes a 7-day challenge with pooled Gram-negative bacteria, and the brominated ester at 22 mg/kg reduces the log₁₀ CFU/mL from 6.8 to below 2.0 within 48 hours, provided the tramp oil content does not exceed 12% v/v. Field data from a 2,000-L central system equipped with a vacuum belt filter and a skimmer showed that when hardness ions precipitated the sulfonate emulsifier package, the ester partitioned preferentially into the tramp oil phase, lowering the aqueous concentration to 9 mg/kg and permitting a biofilm bloom on the weirs. This observation defines an operational boundary: the system must be monitored by solvent extraction of the aqueous phase with hexane followed by GC-ECD (LOQ 0.5 µg/L), and a readjustment dose of 0.12% v/v of the concentrate is mandated whenever the concentration drops below 14 mg/kg. The terminal product form is a ready-to-dilute, boron-free MWF concentrate labelled compliant with REACH Annex XVII entry 30 and free of secondary amine releasers.

A Pharmacopoeial Intermediate Where Morphology of the Free Acid Dictates Reactivity

In the synthesis of a class of HIV-1 integrase strand transfer inhibitors (INSTIs) under development, 5-bromo-isothiazole-3-carboxylic acid functions as the electrophilic coupling partner in a Buchwald–Hartwig amination with a 4-fluoro-3-hydroxybenzylamine scaffold. The USP <231> heavy metals limit applies to the acid as a drug intermediate, and residual palladium must be controlled below 10 ppm (Ph. Eur. 2.4.8). A polymorphic screen identified that the thermodynamically stable monoclinic form (Form I) of the acid exhibits a 22% lower initial reaction rate in 2-methyltetrahydrofuran compared to the metastable triclinic Form II, as determined by in-situ ReactIR at 1650 cm⁻¹. Consequently, a seeding protocol with Form II crystals ground to a d₅₀ of 8 µm in a continuously stirred tank crystallizer is employed prior to the coupling step. The formulation addition ratio for the drug substance synthesis is stoichiometric—1.02 equivalents of the acid per equivalent of amine, with an additional 0.05 equivalents used to compensate for the 3–5% degradation caused by trace moisture in the DMAc solvent system. The downstream process involves a telescoped coupling/deprotection sequence in a jacketed 316L Hastelloy reactor, followed by charcoal treatment and crystallization from isopropyl acetate/heptane. The terminal active pharmaceutical ingredient (API) is a white crystalline powder with a mean particle size of 15–30 µm, formulated into a 50 mg film-coated tablet meeting the dissolution specification of NLT 80% in 30 minutes per USP <711> Apparatus 2.

Comparative analysis of regulatory exposure scenarios across application segments
Segment	Governing microbial challenge standard	Typical active loading* (derived from 5-Br-IT3CA)	Critical process limit
In-can paint preservation	ISO 11930:2019 / ASTM D2574-16	0.07–0.18% w/w (carboxamide)	pH < 9.0 during letdown
SPC antifouling	ISO 15181-6:2017 (DCOIT release rate)	5–12 mol% in copolymer	Polymerization exotherm < 78°C
Wet-blue preservation	IULTCS/IUC 27:2020	0.15–0.20% w/w (bis-adduct)	Float pH < 8.5
Metalworking fluid concentrate	ASTM E2169-17	18–25 mg/kg diluted (ester)	Tramp oil < 12% v/v; free Cl₂ < 0.5 ppm
Drug intermediate (INSTI)	Ph. Eur. 2.4.8 (Pd) / ICH Q3D	1.02 eq (coupling step)	Moisture < 300 ppm in DMAc

*Expressed as the mole or mass percentage of the 5-bromo-isothiazole-3-carboxylic acid derivative in the relevant process stream or final formulation.

In printed circuit board (PCB) conformal coating systems designed for tropicalised electronics, a 5-bromo-isothiazole-3-carboxylic acid benzimidazolyl complex is synthesised by reacting the acid with 2-(2-aminophenyl)benzimidazole in the presence of HBTU and subsequently coordinating zinc chloride. The resulting complex demonstrates anti-fungal efficacy against Aspergillus versicolor and Penicillium funiculosum when incorporated into a UV-curable acrylic conformal coating at 0.3–0.8% w/w, as verified under IPC CC-830B testing with a 28-day mixed-spore exposure at 95% RH and 30°C. The complex must be predispersed in a high-boiling ester (propylene carbonate) under nitrogen blanket to avoid oxidative debromination catalysed by cobalt initiators. A notable incompatibility occurs with amine-synergist photoinitiators (Type II systems), where the tertiary amine abstracts bromine, generating a chromophoric impurity that increases the coating’s yellowness index (ASTM E313-20) by 4.2 units after 168 hours of QUV-B testing. Therefore, a 405 nm LED-cure system with a Type I photoinitiator at 2.0% w/w is specified, and the formulation addition ratio is reduced to 0.3% when the conformal coating is applied to bare copper pads to avoid electrochemical migration. The terminal product is a transparent, low-viscosity (120–180 cP) UV-curable conformal coating that maintains SIR values above 10⁸ Ω after 1,000 hours of damp heat steady state (IEC 60068-2-78).

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Certification & Compliance

5-Bromo-Isothiazole-3-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

5-Bromo-isothiazole-3-carboxylic acid (molecular formula C₄H₂BrNO₂S) constitutes a heterocyclic building block characterized by a bromine substituent at the 5-position and a carboxylic acid group at the 3-position of the electron-deficient isothiazole ring. Commercial lots are routinely supplied with a purity specification of 98% (HPLC, area normalization at 254 nm), confirmed by 1H NMR (500 MHz, DMSO-d₆) displaying a singlet for the C4 aromatic proton in the range δ 8.1–8.4 ppm and a broad carboxylic acid resonance near δ 13.2 ppm. Trace metal analysis by ICP-OES typically returns palladium and copper residues below 50 ppm each, a critical quality attribute for downstream cross-coupling applications where extraneous metal contamination can initiate premature catalyst deactivation. The compound is stored in amber glass under argon at 2–8°C to suppress photolytic debromination and thermal decarboxylation.

What Distinguishes 5-Bromo-Isothiazole-3-Carboxylic Acid from Other Isothiazole Carboxylic Acid Derivatives?

The bromine atom at the 5-position offers a carbon–bromine bond dissociation energy of approximately 327 kJ/mol, placing its reactivity in oxidative addition between the 5-chloro analog (C–Cl BDE ~ 397 kJ/mol) and the 5-iodo analog (C–I BDE ~ 260 kJ/mol). In Suzuki–Miyaura coupling with phenylboronic acid using Pd(PPh₃)₄ at 80°C, the 5-bromo derivative consistently delivers 85–92% isolated yield within 12 h, whereas the 5-chloro congener requires temperatures above 110°C and Buchwald-type ligands to reach 60% conversion in the same timeframe. The 5-iodo analog, while exhibiting faster initial rates, introduces a 2–5% homocoupling byproduct under identical conditions and carries a significantly higher procurement cost per mole. Regioisomeric 4-bromo-isothiazole-3-carboxylic acid displays a 3-fold lower coupling rate because the C4 position experiences greater steric hindrance from the adjacent carboxylic acid group. Compared to thiazole-3-carboxylic acids, replacement of the C4 carbon by an sp²-hybridized nitrogen in the isothiazole ring depresses the electron density at C5, rendering the system more electrophilic and susceptible to nucleophilic aromatic substitution under strong base—a reactivity absent in the corresponding thiazole. In the synthesis of Type II kinase inhibitors, 5-bromo-isothiazole-3-carboxylic acid serves as a late-stage diversification handle that tolerates sequential Buchwald–Hartwig amination and amide coupling operations. A representative procedure charges Pd₂(dba)₃ (2 mol% relative to bromide) and XPhos (4 mol%) with degassed toluene (0.2 M substrate concentration) in a nitrogen-purged jacketed reactor equipped with a turbomixer operating at 400 rpm. After addition of the 5-bromo-isothiazole-3-carboxylic acid (1.0 equiv) and an aniline nucleophile (1.2 equiv), sodium tert-butoxide (1.4 equiv) is dosed as a suspension in toluene over 45 min to control an exotherm that typically elevates the internal temperature from 100°C to 118°C. Failure to extend the dosing window can cause local hot spots that promote debromination, generating the des-bromo impurity at levels of 8–12% (LC–MS, ESI+). Following coupling, the mixture is quenched into aqueous HCl at 0°C to reach a final pH of 3–4. Holding the acidic aqueous layer at temperatures above 25°C for longer than 30 min triggers decarboxylation at a rate of approximately 2% per hour at 40°C, verified by ¹³C NMR loss of the carbonyl signal. Direct telescoping into an amide bond-forming step with EDC·HCl (1.1 equiv) and HOBt (1.1 equiv) in DMF at 0–5°C avoids isolation of the free acid and improves overall mass recovery to 78% over two steps from the bromide. Catalytic hydrogenation of intermediate nitro groups using 10 wt% Pd/C under 50 psi H₂ at 25°C is incompatible with this scaffold: extensive hydrodebromination (15–20%) occurs within 2 h, mandating alternative reduction with NaBH₄/CuCl in methanol at −10°C, which leaves the C–Br bond intact.

Process-Scale Handling of 5-Bromo-Isothiazole-3-Carboxylic Acid: Thermal Stability and Solubility Constraints

Equilibrium solubility in anhydrous DMF at 25°C exceeds 100 mg/mL; in THF it declines to 15–20 mg/mL; in deionized water at pH 7 the compound is practically insoluble (<2 mg/mL). Recrystallization from a methanol/water mixture (7:3 v/v) at a cooling rate of 0.5°C/min from 60°C to 5°C produces a crystalline solid with a differential scanning calorimetry purity of >99%. DSC analysis conducted on a TA Instruments Q2000 calorimeter under nitrogen purge (50 mL/min) at a heating rate of 10°C/min reveals a melting endotherm with onset at 178±2°C, immediately succeeded by an exothermic decomposition event initiating near 210°C and releasing 450±30 J/g. This decomposition energy profile, classified as a Class 3 thermal hazard per Stoessel criteria, imposes a maximum safe drying temperature of 60°C in a vacuum oven with residual oxygen maintained below 0.5% via continuous nitrogen bleed. Bulk powder, when stored in sealed amber glass jars under argon with 3 Å molecular sieve desiccant, exhibits 0.1% degradation after 12 months at 25°C/60% RH. The S–N bond in the isothiazole ring is inherently labile toward nucleophilic attack: contact with aqueous sodium hydroxide above pH 10 at 30°C leads to ring opening to a thiolate intermediate, detected by GC–MS as a mercaptoacrylonitrile derivative with m/z loss of 32. Therefore, all basic workups must be buffered to remain below pH 9.5. Filtration and drying characteristics are governed by the particle size distribution arising from the final recrystallization. Unmilled product typically exhibits a D₉₀ of 180–220 μm and a bulk density of 0.55 g/cm³. When micronized in a spiral jet mill under nitrogen pressure of 8 bar, the D₅₀ reduces to 12 μm, but the specific surface area increase raises the dust explosion classification; the minimum ignition energy drops below 10 mJ for the fine fraction, requiring grounding of all conductive equipment and dedicated inertion of the milling chamber. Consequently, many production campaigns bypass micronization and employ a wet-milling slurry in heptane for downstream formulations, maintaining a 40 wt% solids loading.

Comparative Reactivity of 5-Halo-Isothiazole-3-Carboxylic Acids in Suzuki–Miyaura Coupling with Phenylboronic Acid^a
Halogen	Relative Oxidative Addition Rate (Cl = 1)	Isolated Yield (%)	Catalyst System	Temp. (°C)	Reaction Time (h)
5-Cl	1	45	Pd(PPh₃)₄ (5 mol%)	100	24
5-Br	50	91	Pd(PPh₃)₄ (2 mol%)	80	12
5-I	500	95^b	Pd₂(dba)₃/SPhos (1 mol%)	60	6
^aConditions: 1.0 mmol halo-acid, 1.5 mmol PhB(OH)₂, 3.0 mmol K₂CO₃, degassed toluene–H₂O (4:1), 0.2 M substrate. ^bAccompanied by 3% homocoupling impurity.

When Coupling Reactions Demand Carboxylic Acid Protection: In Situ Silylation Strategies

The free carboxylic acid functionality participates in competitive coordination to palladium(0), attenuating the concentration of the active catalyst species. In Buchwald–Hartwig couplings with electron-rich anilines, pre-forming the trimethylsilyl ester increases conversion from 62% to 88% under otherwise identical conditions. The protection protocol involves charging 5-bromo-isothiazole-3-carboxylic acid and triethylamine (2.0 equiv) into anhydrous dichloromethane (KF <50 ppm H₂O) under nitrogen at 0°C, followed by dropwise addition of chlorotrimethylsilane (1.5 equiv). After 2 h of stirring at 23°C, the precipitated triethylammonium chloride is removed by filtration through a PTFE membrane, and the filtrate is concentrated at 30°C under reduced pressure (200 mbar). The resulting TMS ester is used immediately in cross-coupling reactions. Deprotection of the coupled product is accomplished at −10°C with TBAF (1.0 M in THF, 1.1 equiv), a temperature at which fluoride-mediated ring-opening at sulfur is suppressed; operation at +5°C or higher produces a ring-opened thiolate impurity quantified by LC–MS at 4–7% within 30 min. Attempted aqueous workup of the silyl ester prior to coupling results in immediate hydrolysis to the parent acid, with 85% recovery but with detectable (0.5%) desilylation-induced decomposition. This protection strategy is incompatible with reactions that require strong Brønsted acids (trifluoroacetic acid, methanesulfonic acid), as even catalytic acid concentrations induce rapid protodesilylation and ring hydrolysis, releasing hydrogen sulfide detected by lead acetate paper. Occupational exposure limits for this specific brominated isothiazole have not been established. Handling must be conducted in a fume hood with a face velocity of 0.5 m/s and a local exhaust snorkel positioned within 15 cm of the powder handling zone. The compound has tested positive in a non-GLP Ames II assay (TA98 strain, metabolic activation with S9 fraction at 10% v/v), indicating potential mutagenic properties; thus, engineering controls and nitrile gloves (minimum breakthrough time 240 min per ASTM D6978-05) are mandated. Waste streams containing the compound are treated as halogenated organic residues and must be incinerated in a facility operating at 1200°C with a residence time exceeding 2 seconds per 40 CFR 264.343. Supply is currently limited to research and development quantities under existing REACH registration scopes; bulk commercial availability and full toxicological datasets remain under evaluation.