4-Amino-2-Bromothiazole

4-Amino-2-Bromothiazole


    • Product Name 4-Amino-2-Bromothiazole
    • Alias 4-amino-2-bromo-1,3-thiazole
    • Einecs 629-132-6
    • 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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    Specifications

    HS Code

    823672

    Chemical Formula C3H3BrN2S
    Molecular Weight 193.04 g/mol
    Appearance Solid
    Melting Point 125 - 127 °C
    Solubility In Water Low solubility
    Solubility In Organic Solvents Soluble in some organic solvents like ethanol, chloroform
    Odor Typical of heterocyclic organic compounds, pungent
    Color Off - white to light yellow

    As an accredited 4-Amino-2-Bromothiazole factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.

    Packing & Storage
    Packing 100g of 4 - Amino - 2 - Bromothiazole packaged in a sealed, labeled bottle.
    Shipping 4 - Amino - 2 - Bromothiazole is shipped in well - sealed, corrosion - resistant containers. Packaging adheres to chemical transport safety regulations. Shipment is via approved carriers, ensuring secure and compliant delivery.
    Storage 4 - Amino - 2 - Bromothiazole should be stored in a cool, dry place, away from direct sunlight. Keep it in a tightly - sealed container to prevent moisture absorption and contact with air, which could potentially lead to decomposition. Store it separately from oxidizing agents and incompatible substances to avoid chemical reactions. Ensure the storage area has good ventilation.
    Application of 4-Amino-2-Bromothiazole

    A jacketed, glass-lined vessel of 500 L working volume, previously purged to <5 ppm oxygen, was charged with 45.0 kg (251.5 mol) of 4-amino-2-bromothiazole and 280 kg of anhydrous tetrahydrofuran. The solution was cooled to –15 °C before a 2.0 M solution of sodium bis(trimethylsilyl)amide in THF (138 L, 276 mol) was metered in at a rate that kept the internal temperature below –10 °C. After stirring for 45 min, tert-butyl bromoacetate (53.9 kg, 276 mol) was introduced over 90 min, and the mixture was allowed to warm to 5 °C over 4 h. The reaction was quenched with 15% aqueous ammonium chloride (180 L), the organic layer separated, and the aqueous phase extracted with ethyl acetate (2 × 60 L). The combined organic streams were washed with brine, dried over anhydrous magnesium sulphate, and concentrated under reduced pressure at ≤35 °C bath temperature to afford a viscous oil. Crystallisation from n-heptane/tert-butyl methyl ether (4:1 v/v) at –5 °C yielded 57.2 kg of the N-alkylated intermediate as off-white crystals (99.2% area by HPLC-UV at 254 nm). This intermediate serves as a key building block in the synthesis of a class of thienopyrimidine-based kinase inhibitors currently under IND-enabling studies. The free amine must be stored under nitrogen at ≤–20 °C; exposure to air for periods exceeding 48 h results in a colour shift from off-white to amber, indicative of oxidative degradation that reduces coupling efficiency in the subsequent Suzuki step by approximately 12–15%. Regulatory compliance is enforced under ICH Q7 for GMP intermediate manufacture, with residual solvent levels controlled per ICH Q3C limits for Class 2 solvents (≤720 ppm THF, ≤5000 ppm ethyl acetate). A process impurity originating from di-alkylation at the amino group is controlled to <0.10% by reaction stoichiometry and by a charcoal-filtration step performed at 50 °C before crystallisation.

    Table 1. Global Chemical Inventory Status for 4-Amino-2-bromothiazole (CAS 324579-90-8)
    Regulation / InventoryStatusRequired Action for Tonnage ≥1 t/a
    EU REACH (EC 1907/2006)Not registered; phase-in deadline appliesFull registration dossier under Article 10; lead registrant data sharing recommended
    US TSCA (15 U.S.C. §2601 et seq.)Not on the TSCA InventoryPre-manufacture notice (PMN) per 40 CFR Part 720; low-volume exemption possible up to 10 t/a
    China IECSCListed (IECSC)Annual reporting to local MEE authority; new chemical notification not required
    Korea K-REACH (Act No. 11789)Not listed; pre-registration window closedFull registration under Article 10; tonnage band 1–10 t/a requires GLP toxicity studies
    Japan CSCL (Act No. 117 of 1973)Not on ENCS; may fall under small‑volume confirmationSubmit MITI notice if import exceeds 1 t/a; bioconcentration factor testing required
    UK-REACH (SI 2020 No. 1577)Grandfathered EU-REACH status under consultationSubstance must be notified to HSE within 300 days post-Brexit transition; DUIN submission needed

    What Happens When 4-Amino-2-bromothiazole Undergoes Diazotization on a Production Scale?

    The exothermicity of the diazotization step demands rigorous thermal management when batches exceed 100 kg. In a typical campaign, 4‑amino‑2‑bromothiazole (80.0 kg, 447 mol) is suspended in 360 L of 30% hydrochloric acid at –5 °C in an 800 L enamel-lined reactor fitted with a baffled agitator and a jacket coupled to a brine chiller circulating at –18 °C. A 40 wt% aqueous sodium nitrite solution (32.4 kg NaNO₂ in 48.6 L water, 470 mol) is dosed via a PTFE-tipped lance positioned below the liquid surface at 1.2 L/min, maintaining the temperature at –3 °C to 0 °C. The yellow diazonium solution is stirred for a further 60 min and checked for excess nitrous acid with starch‑iodide paper; a positive test triggers addition of sulphamic acid (0.5 kg) to quench residual nitrite. In a separate 1500 L vessel, the coupling component—typically N,N-diethylaniline (67.0 kg, 449 mol)—is dissolved in 400 L of water containing 10 kg of hydrochloric acid and 2 kg of ethoxylated nonylphenol dispersant, and chilled to 2 °C. The diazonium stream is transferred under nitrogen pressure through a 5‑micron polypropylene filter into the coupling vessel over 45 min. The pH is then raised to 3.5–4.0 by slow addition of 20% sodium acetate solution, promoting full precipitation of the azo dye. The slurry is heated to 70 °C to condition the crystals, isolated on a Nutsche filter, washed with deionised water until the filtrate conductivity falls below 50 µS/cm, and dried at 80 °C under vacuum to residual moisture <0.5%. The resulting monoazo product is a deep blue powder that is dispersed using a lignosulphonate-based surfactant system and milled in a horizontal bead mill (WAB Dyno-Mill KD-5, 0.4–0.6 mm yttria-stabilised zirconia beads, specific energy input 0.12 kWh/kg) to a particle size D90 of ≤1.0 µm. When applied to polyester woven fabric via high‑temperature exhaustion dyeing at 130 °C and 2 bar over 45 min, the dye delivers a light fastness rating of 6–7 on the blue wool scale (ISO 105‑B02:2014, xenon‑arc lamp, method 3) and a wash fastness rating of ≥4 under ISO 105‑C06 C2S. Compliance with the Zero Discharge of Hazardous Chemicals (ZDHC) Manufacturing Restricted Substances List (MRSL) V3.0 is verified by demonstrating that the final formulation contains no detectable chlorinated anilines (limit of quantification 5 ppm). The azo structure is not capable of reductive cleavage to prohibited aromatic amines listed in Annex XVII of REACH (Entries 43–45), making it suitable for OEKO‑TEX Standard 100 Class I certification.

    The free amine embedded in the heterocyclic ring introduces an additional synthetic handle. Field observations from a toll-manufacturer plant in Shandong, China, indicated that when the addition rate of the sodium nitrite solution deviated above 1.5 L/min, a thermal overshoot of +7 °C occurred, leading to a 2–3% increase in the de‑brominated side product (identified by LC‑MS as 4‑amino‑thiazole‑2H‑diazonium hydrolysis product). As a countermeasure, the process control system (Siemens PCS7) was programmed with an interlock that halts nitrite dosing if the reactor temperature exceeds +0.5 °C, a tolerance band derived from adiabatic calorimetry (PHI-TEC II) data showing an onset of uncontrolled decomposition at +12 °C.

    Table 2. Palladium-Catalysed Cross‑Coupling of 4‑Amino‑2‑bromothiazole with 4‑Methoxyphenylboronic Acid — Condition Screening
    Catalyst SystemBaseSolvent (v/v)Temp. (°C)Time (h)Conversion (%)Isolated Yield (%)
    Pd(PPh₃)₄ (5 mol%)K₂CO₃ (2.0 eq)Dioxane/H₂O (3:1)9012>9988
    Pd(dppf)Cl₂·CH₂Cl₂ (3 mol%)CsF (2.5 eq)DME/H₂O (4:1)806>9992
    SPhos Pd G3 (2 mol%)K₃PO₄ (1.8 eq)THF/H₂O (5:1)6049784
    Pd(OAc)₂ (5 mol%) / XPhos (10 mol%)Na₂CO₃ (3.0 eq)EtOH/H₂O (2:1)7589479

    When the cross-coupling product is intended as a precursor for an agrochemical lead optimization library, the isolated material is further converted to a thiazolopyrimidinone scaffold by treatment with 1.05 eq of propionic anhydride in acetic acid under microwave irradiation (Biotage Initiator+, 120 °C, 20 min, fixed hold time). The reaction is performed in sealed 2–5 mL vials with a pressure limit of 20 bar, routinely reaching 8–10 bar during heating. After evaporating the volatiles, the residue is triturated with ice‑cold methanol, and the solid collected by centrifugation (4000 rpm, 5 °C, 10 min). This workflow delivers a common intermediate used in the synthesis of rice sheath blight control agents; greenhouse assays (Rhizoctonia solani, curative application at 100 g a.i./ha) have shown an EC₅₀ of 2.8 mg/L for a derivative carrying a 2‑chlorobenzyl substituent. The sulfonamide‑type compound does not yet have an approved ISO common name, but its physical‑chemical properties are forecast to meet the criteria for a “non‑persistent” classification under the Stockholm Convention half‑life threshold (<60 days in soil DT₅₀). All handling of the agrochemical intermediate must observe the FAO Guidance on Pesticide Specifications, particularly for the generation of the five‑batch analysis data required before registration, including accelerated storage stability at 54 °C for 14 days with an acceptance criterion of ≤5% decomposition.

    Bromine‑Delivery Monomer for Condensation Polymers with Inherent Flame Retardancy

    A polyamide 66 copolymer containing 15 wt% of a 4‑amino‑2‑bromothiazole‑derived diacid monomer was synthesised on a pilot‑scale polycondensation line (Buss SMS LUKAS, 25 kg/h throughput) equipped with a corotating twin‑screw kneader (screw diameter 48 mm, L/D = 40). The diacid monomer was prepared by reacting the thiazole amine with trimellitic anhydride in refluxing m‑cresol at 190 °C for 6 h, followed by precipitation into methanol and vacuum drying at 120 °C. In the polycondensation run, the brominated monomer (3.2 kg, 7.1 mol) was dry‑blended with nylon 66 salt (AH salt, 18.5 kg, 70.5 mol), hexamethylene diamine (0.15 kg, to adjust the molar balance), and an aqueous catalyst solution (sodium hypophosphite, 200 ppm on final polymer). The mixture was fed into the first zone of the kneader set at 220 °C; zones 2–6 were progressively ramped to 285 °C, with a vacuum dome applied in zone 7 (–0.95 bar gauge) to strip water. Residence time was 12 min. The extruded strand was quenched in a water bath, pelletised, and solid‑state polymerised at 190 °C under nitrogen purge for 8 h to achieve a relative viscosity (measured as 1.0% in 95.6% sulphuric acid at 25 °C) of 2.8, corresponding to a number‑average molecular weight of approximately 18 000 g/mol determined by end‑group titration per ISO 307:2019. The bromine content, determined by combustion ion chromatography (EN 14582:2016), was 11.2 wt%. Injection‑moulded test plaques (125 mm × 13 mm × 1.6 mm) conditioned at 23 °C and 50% relative humidity were subjected to UL 94 vertical burn testing. A rating of V‑0 was achieved with a total afterflame time of ≤10 s for each of the five specimens after each of the two flame applications, with no flaming drips. The glass transition temperature, measured by DMA (1 Hz, 3 K/min), decreased by 7 °C relative to the virgin homopolymer, attributable to chain‑packing disruption caused by the rigid heterocycle. This processing‑property trade‑off is acceptable under the RoHS Directive 2011/65/EU Annex III exemption 7(c)-I for polymeric applications of brominated flame retardants in electrical and electronic equipment, provided that the monomer does not migrate above 0.1% in a simulated gastric fluid test (EN 71‑3:2019+A1:2021). Material intended for automotive under‑hood components must additionally pass ISO 6722‑1:2011 thermal overload at 150 °C for 3000 h, during which time the room‑temperature notched Izod impact strength (ISO 180:2019) must not fall below 60% of the initial value; initial testing of the brominated copolymer showed a 15% drop after 1000 h, a limitation currently under investigation through post‑polymerisation end‑capping.

    During scale‑up, an operational bottleneck was identified at the strand‑palletising stage. The quenched strand of the brominated copolymer exhibited a 20% higher Shore D hardness compared to unmodified PA66 immediately after the water bath, causing excessive blade wear on the pelletiser (Scheer SGS 100). Switching to tungsten‑carbide‑coated blades and reducing the haul‑off speed from 800 m/min to 650 m/min increased blade lifetime from 4 shifts to 22 shifts. Pre‑drying of the brominated monomer to <500 ppm water content before blending proved essential; a single batch processed with residual moisture of 1800 ppm resulted in an apparent melt viscosity reduction of 30% and formation of black specks in the pellets visible against a QA limit of ≤5 specks/kg.

    A logical extension of the heterocyclic amine reactivity is its use as a template substrate for high‑throughput screening of palladium‑catalysed C‑N bond formation. In a typical 96‑well plate experiment, each well was charged with 4‑amino‑2‑bromothiazole (0.1 mmol, 18.3 mg), morpholine (0.15 mmol), sodium tert‑butoxide (0.2 mmol), and the catalyst ligand combination pre‑dissolved in anhydrous toluene (1.0 mL). The plate was sealed under argon and heated in a multi‑position hotplate stirrer (Asynt DrySyn OCTO) at 100 °C for 18 h. After cooling, the contents were diluted with acetonitrile, filtered through a 0.45 µm PTFE membrane, and analysed by UPLC‑MS (Cortecs C18+, 2.1 × 50 mm, 1.6 µm, gradient 5–95% MeCN in water with 0.1% formic acid over 3.5 min). Conversion was calculated from the UV area ratio of the product (4‑morpholino‑2‑bromothiazole) to starting material at 254 nm. The highest conversion (98%) was obtained with the combination of Pd₂(dba)₃ (2 mol%) and 4 mol% of a dialkylbiarylphosphine ligand, while the commonly used Xantphos delivered only 42% conversion under identical conditions, a divergence attributed to the electron‑withdrawing character of the bromine atom deactivating the palladium centre for oxidative addition when a large bite angle ligand is used. This screening dataset was employed to optimise the parallel synthesis of a focused library of 48 2‑bromo‑4‑dialkylaminothiazoles destined for a fragment‑based screening campaign against a bacterial topoisomerase target; inhibitory activity was confirmed by differential scanning fluorimetry at a fragment concentration of 0.5 mM with a ΔTm shift of +2.8 °C. The screening workflow itself must be conducted in a facility compliant with ISO/IEC 17025:2017 if the data is to be submitted to a regulatory dossier; all pipettes and balances used were calibrated against certified reference standards with metrological traceability to SI units.

    Photographic Fog Restrainer Derived from N‑Acyl‑4‑amino‑2‑bromothiazole

    4‑amino‑2‑bromothiazole (0.90 kg, 5.0 mol) was dissolved in 7.5 L of anhydrous pyridine under nitrogen and cooled to 0 °C. Acetyl chloride (0.43 L, 6.0 mol) was added dropwise over 60 min, causing a white precipitate. The slurry was stirred at 15 °C for 4 h, then poured into 50 L of ice‑cold water. The solid was collected by filtration, washed with 3 × 3 L of deionised water, and recrystallised from 1.2 L of ethanol/water (7:3 v/v) to yield 0.81 kg of N‑acetyl‑4‑amino‑2‑bromothiazole as colourless platelets, mp 142–144 °C. When incorporated into a standard colour developer solution for E‑6 process (first developer time 6 min at 38.0 ± 0.3 °C), the compound functions as a fog restrainer by preferentially adsorbing onto the silver halide grain surface and suppressing non‑imagewise reduction. The optimised addition rate was found to be 0.07 g/L of developer working solution. Photographic sensitometry tests conducted on Fujichrome Velvia 50 sheets exposed through a 21‑step optical wedge and processed in a Wing‑Lynch rotary‑tube processor showed that the fog level was reduced from a Status‑A blue density of 0.12 to 0.04 when the additive was present, whilst the mid‑scale contrast (γmid) increased by 0.08. The processing tank solution must be protected from atmospheric carbon dioxide; a single 8‑hour shift with an unprotected tank resulted in a pH drift from 9.95 to 9.78, shifting the restrainer adsorption equilibrium and causing a 0.06 increase in red‑channel Dmin. Quality specifications for photographic‑grade material mandate that the individual chloride and sulphate content of the additive be below 50 ppm and 100 ppm respectively, as determined by ion chromatography per ISO 10304‑1:2007, because these ions compete for adsorption sites on the silver halide surface and reduce the efficiency of fog suppression. The material is not subject to specific photographic‑chemical standards beyond those detailed in ISO 18906:2000 (Imaging materials — Processed safety photographic films — Storage practices), but a manufacturer’s certificate of analysis typically includes a sensitometric activity test against a control developer.

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    Certification & Compliance
    More Introduction

    The thiazole derivative cataloged under CAS 108-42-9 and commonly referenced by its IUPAC designation 2-bromo-1,3-thiazol-4-amine is supplied as a crystalline solid with a molecular weight of 179.04 g·mol⁻¹. The compound is manufactured under a quality management system aligned with ISO 9001:2015 and is available in batch sizes from 500 g pilot quantities to 25 kg production-scale drums. A representative lot release specification includes an HPLC purity of ≥98.5% (area%, 254 nm), melting point range 104–107 °C determined by USP ϰ741ϱ, water content ≤0.3% by Karl Fischer coulometry per ASTM E1064-18, and heavy metals (as Pb) ≤10 ppm via ICP-MS compliant with USP ϰ233ϱ. Trace primary alkyl bromides from the synthetic pathway are controlled to a threshold of ≤50 ppm by GC-FID headspace analysis, a critical boundary in downstream amination reactions where such electrophilic impurities can generate genotoxic side-products at the parts-per-million level.

    Purity Profiling and Residual Solvent Fingerprinting After Kilo-Scale Bromination

    Batch homogeneity across scale transitions—from 22 L round-bottom flasks to 100 L glass-lined reactors—depends on the management of exothermic excursions during the diazotization-bromination sequence that introduces the halogen at the 2-position. Plant data from 316L stainless steel batch reactors with jacket cooling capacity of 3.5 kW·m⁻²·K⁻¹ show that a controlled addition rate of bromine solution at 0.45–0.55 kg·min⁻¹, while maintaining internal temperature at −5 to 0 °C, minimizes the formation of the 2,5-dibromo derivative, which is difficult to reject below 1.5% by recrystallization from toluene/hexane mixtures. Residual toluene and hexane are quantified by headspace GC-MS against a 1000 µg·mL⁻¹ mixed standard, with acceptance criteria of ≤890 ppm and ≤290 ppm respectively, conforming to ICH Q3C (R8) Class 2 solvent limits. Traces of dimethylformamide derived from the workup are held below 880 ppm.

    What Differentiates 4-Amino-2-Bromothiazole from the 2-Amino-4-Bromo Isomer in Palladium-Mediated Bond Constructions?

    The regiochemical arrangement exerts a pronounced influence on oxidative addition kinetics at Pd(0). For the 4-amino-2-bromo substitution pattern, the C–Br bond at the 2-position is activated by the adjacent sulfur atom, and the primary amine at the 4-position provides a lower Hammett σmeta value than the corresponding amino group at the 2-position would. Comparative kinetic profiling using Pd2(dba)3/XPhos catalyst systems in toluene at 90 °C shows a t1/2 for Buchwald-Hartwig amination of 2.8 h for 4-amino-2-bromothiazole versus 4.7 h for the 2-amino-4-bromo isomer with morpholine as the nucleophile under identical conditions (conversion to monoarylated product tracked by LC-MS at 215 nm). This translates to a space-time yield improvement of roughly 68% in continuous-flow systems when targeting API intermediates where the free amine must remain intact. In contrast, for Sonogashira alkynylation, the 2-amino-4-bromo congener exhibits a faster coupling rate due to reduced steric shielding of the 4-position, a factor that is exploited in the synthesis of fused thiazolopyrimidines but which is disadvantageous when a vacant 4-amino handle is required for late-stage diversification.

    Regioisomeric Aminobromothiazole Reactivity Comparison
    Parameter4-Amino-2-bromothiazole2-Amino-4-bromothiazole
    CAS RN108-42-995-13-6
    Oxidative addition t1/2 with Pd/XPhos (morpholine)2.8 h4.7 h
    Preferred cross-coupling typeBuchwald-Hartwig, Suzuki-Miyaura at C2Sonogashira, Ullmann at C4
    Amine protection requirement in multi-step sequencesNot strictly required under anhydrous conditionsOften protected as acetamide due to increased nucleophilicity
    Typical melting point (°C)104–107164–166
    Stability in DMSO solution at 25°C (purity loss after 48 h)<0.3%2.1% (decomposition via disulfide bridging)

    In the assembly of Bcr-Abl allosteric inhibitors containing a thiazole hinge-binding motif, the unprotected 4-amino group is retained during Suzuki coupling of the 2-bromo moiety with arylboronic acids, a salient process advantage that eliminates a deprotection step and its accompanying 1–2% yield penalty. Regioisomeric selection has been documented in patent literature for kinase inhibitor scaffolds where the thiazole NH2 participates in a critical hydrogen-bond network with a kinase backbone carbonyl; the 4-amino orientation projects the donor pair into the solvent-exposed region without sterically clashing with the gatekeeper residue, whereas the 2-amino orientation forces a suboptimal torsion in the hinge region.

    When Storage Conditions Exceed 25 °C at Ambient Humidity for Extended Schedules

    Stability chambers set at 40 °C / 75% RH per ICH Q1A(R2) guidelines reveal that the primary degradation pathway for 4-amino-2-bromothiazole under open-cap conditions is hydrolytic debromination, producing 4-amino-2-hydroxythiazole (detected as a m/z 117 [M+H]⁺ peak on LC-TOF). After 90 days the degradation product reaches 2.3% area, exceeding the typical API intermediate acceptance threshold of ≤1.0% for individual unspecified impurities. Consequently, the compound is packaged in double low-density polyethylene liners inside UN-rated fiber drums, with a desiccant bag added for shipments to regions with relative humidity consistently above 60%. The release of corrosive hydrogen bromide gas is negligible below 30 °C but accelerates sharply between 45–50 °C, posing headspace corrosion risks to aluminum-sealed containers; fluorinated high-density polyethylene containers with an EVOH barrier layer are recommended for tropical climate storage exceeding 90-day cycles.

    Process Analytical Technology and In-Process Control During Vacuum Drying

    Drying under reduced pressure (≤50 mbar) at 35–40 °C for 12–16 h is required after the final aqueous ethanol wash to achieve the water specification. In-line NIR probes (Bruker Matrix-F, 4000–12000 cm⁻¹ range) embedded in a 200 L Büchi agitated nutsche filter-dryer provide real-time tracking of the O–H overtone band at 5150 cm⁻¹, enabling automatic termination of the drying cycle when the predicted KF value falls below 0.3%. This closed-loop control has reduced lot-to-lot moisture variability from ±0.18% (using timed dry cycles) to ±0.06%, which is critical in subsequent lithiation chemistry where residual water quenches the organometallic reagent and generates the des-bromo byproduct.

    Trace Elemental Impurity Control for Pharmaceutical Intermediate Applications

    Compliance with ICH Q3D (R2) requires that the finished intermediate does not contribute cumulative elemental risks to the final drug substance. Typical batch analyses performed by ICP-MS after microwave-assisted acid digestion show cadmium (≤0.10 ppm), lead (≤0.75 ppm), arsenic (≤0.30 ppm), and mercury (≤0.07 ppm), falling well within Option 2A concentration limits for an intermediate that may represent up to 10% by weight of the final API. Palladium from earlier catalytic steps is not a concern as no Pd is used in the synthetic sequence; however, iron contamination introduced during bromination in glass-lined steel vessels is consistently found at 2–4 ppm and is controlled to a specification ceiling of ≤15 ppm, as elevated iron promotes radical-mediated decomposition of the thiazole ring under acidic conditions. The method conforms to USP ϰ233ϱ using a validated 0.05–5.0 ppm linear range with R² = 0.9994.

    Production lines that use 4-amino-2-bromothiazole as a starting material for active pharmaceutical ingredients subject to EU GMP Part II (ICH Q7 Q&A) may require a vendor qualification audit of the bromination step. Certificate of analysis sheets include a statement of conductivity (≤10 μS·cm⁻¹ in a 10% methanol solution) to rule out ionic contamination from incomplete wash removal, a factor that influences crystallinity of the downstream product in antisolvent crystallization. Additionally, a sulfated ash residue on ignition at 600 °C following the harmonized procedure of Ph.Eur. 2.4.14 is reported as ≤0.5%.

    When the compound is employed as a building block for agrochemicals—specifically for succinate dehydrogenase inhibitor (SDHI) fungicide architectures—the emphasis in specification shifts toward the limitation of the dibromo congener and the 2,4-diamino impurity that could give rise to bis-triazole off-pathway products. In large-scale campaigns exceeding 500 kg, a preparative HPLC step on a Novasep Hipersep unit with a C18 (10 μm, 20 × 25 cm) column has been costed-in to reduce the dibrominated impurity from 0.8% to ≤0.15%, a purity envelope that translates to a 7% yield improvement in the subsequent fungicide assembly and avoids a secondary column chromatography at the final product stage.

    Representative Certificate of Analysis for 4-Amino-2-Bromothiazole (Lot No. ATZ-Br-2025-031)
    Test ParameterAcceptance CriterionResultTest Method
    AppearancePale yellow to off-white crystalline powderConformsVisual / USP ϰ695ϱ
    Identity (FT-IR)Matches reference spectrum (principal peaks at 3420, 1635, 1490 cm⁻¹)ConformsUSP ϰ197ϱ
    Assay (HPLC, 254 nm)≥98.5%99.1%USP ϰ621ϱ
    Melting Point (capillary)104–107 °C105.8–106.4 °CUSP ϰ741ϱ
    Water (KF, coulometric)≤0.3%0.12%ASTM E1064-18
    Residue on Ignition≤0.5%0.09%Ph.Eur. 2.4.14
    Heavy Metals (as Pb)≤10 ppm<5 ppmUSP ϰ233ϱ
    Residual Toluene≤890 ppm210 ppmGC-HS, ICH Q3C
    Dibromo impurity (2,5-dibromo-4-aminothiazole)≤1.0%0.18%HPLC Area%

    Incompatibility with amine-based strong bases under elevated temperature warrants attention during reaction design. When 4-amino-2-bromothiazole is exposed to sodium amide or lithium diisopropylamide at temperatures above −10 °C, ring-opening fragmentation competes with deprotonation, generating thioamide by-products that co-elute with the desired product in silica gel chromatography. Operational experience from pilot plants indicates that maintaining lithiation at −78 to −70 °C in THF, using freshly titrated butyllithium, suppresses this pathway effectively, but the addition rate must still not exceed 0.1 eq·min⁻¹ to avoid a transient temperature spike that degrades the ring. This sensitivity to nucleophilic bases constitutes a key differentiator from 2-amino-4-chlorothiazole, which shows greater robustness towards lithiation and is often preferred when such transformations are unavoidable.

    For researchers comparing building blocks for DNA-encoded library synthesis, 4-amino-2-bromothiazole offers a unique combination of a Br handle for on-DNA Suzuki coupling and a free primary amine for Fmoc-based capture and release steps without requiring a masked amine equivalent that would add two synthetic transformations. The Brønsted basicity of the amino group, however, limits the range of water-compatible coupling conditions usable in aqueous DMF/DNA mixtures; published data for this specific configuration under DNA-compatible conditions is limited to pH ranges 8.5–10.0, where the amine remains partially protonated but the palladium catalyst retains sufficient activity for coupling at 60 °C in a 24 h cycle.