2-Bromo-1,3-Thiazole-5-Carboxylate
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HS Code |
383531 |
| Name | 2-Bromo-1,3-Thiazole-5-Carboxylate |
| Molecular Formula | C4H2BrNO2S |
| Molecular Weight | 222.03 g/mol |
| Appearance | Solid (usually off - white to light yellow) |
| Melting Point | Varies, specific value depends on the type of carboxylate group |
| Solubility In Water | Low solubility in water |
| Solubility In Organic Solvents | Soluble in some polar organic solvents like dichloromethane, dimethylformamide |
| Pka | No common pKa value reported for this structure without more context of the carboxylate group |
| Stability | Stable under normal conditions, but may react with strong oxidizing or reducing agents |
| Hazard Class | Irritant (can cause eye, skin, and respiratory irritation), may be harmful if swallowed |
As an accredited 2-Bromo-1,3-Thiazole-5-Carboxylate factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100g of 2 - Bromo - 1,3 - Thiazole - 5 - Carboxylate packaged in a sealed chemical - grade vial. |
| Shipping | 2 - Bromo - 1,3 - Thiazole - 5 - Carboxylate is shipped in sealed, corrosion - resistant containers. It's carefully packed to prevent damage during transit, following strict chemical shipping regulations for safe transportation. |
| Storage | 2 - Bromo - 1,3 - thiazole - 5 - carboxylate should be stored in a cool, dry place away from heat 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 and bases to avoid chemical reactions. |
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In the preparation of active pharmaceutical ingredients (APIs) containing a 2-aryl-thiazole-5-carboxylate pharmacophore, the bromine atom of 2-bromo-1,3-thiazole-5-carboxylate serves as a versatile handle for Pd-catalysed cross-coupling. Production-scale batches routinely undergo a Suzuki-Miyaura reaction to construct the biaryl bond. The ester is dissolved in degassed tetrahydrofuran, and the solution is sparged with argon through a sintered frit until dissolved oxygen falls below 0.5 ppm. A pre-mixed solution of 1.3 eq of arylboronic acid, 2.5 eq of anhydrous tripotassium phosphate, and 0.8 mol% Pd(dppf)Cl₂·CH₂Cl₂ is added. The jacket temperature of the glass-lined reactor is ramped to 68 °C over 30 min and held for 8 h. IPC by HPLC (C18, ACN/water gradient, UV at 254 nm) reveals conversion typically exceeding 97%. Workup involves cooling to 25 °C, dilution with ethyl acetate, and filtration through a layer of Celite⁵⁴⁵ to remove inorganic salts. The organic phase is washed with 5 wt% aqueous L-cysteine (pH 8.5) at 45 °C to scavenge residual palladium, bringing the Pd content below the 10 ppm threshold mandated by ICH Q3D for oral drug substances. The product, a 2-aryl-thiazole-5-carboxylate analogue, is isolated by crystallisation from n-heptane/ethyl acetate (4:1 v/v) with seeding at 40 °C. Compliance with GMP Part II (ICH Q7) requires documentation of catalyst screening, heavy metal removal, and genotoxic impurity (PGI) risk assessment for the aryl halide precursor. The intermediate is subsequently used in amidation with methylamine hydrochloride in the presence of HATU and DIPEA in DMF to yield the corresponding carboxamide, a common terminus in structure–activity relationship campaigns. During technology transfer to a 1000 L stainless-steel reactor, operators observed exothermic excursions of ΔT=+12 °C upon boronic acid addition, mandating staged dosing over 45 min under jacket cooling at −5 °C. This thermal hazard must be incorporated into the HAZOP analysis. Reproducibility across lots is tightly linked to the water content of the arylboronic acid, which is determined by Karl Fischer titration before each campaign; a deviation of 0.2% water can lower the yield by 6–8%. Agrochemical Intermediates via Negishi Coupling — What Are the Limits of Water Tolerance?Synthesis of thiazole-based agrochemical leads frequently exploits the bromo ester in Negishi cross-couplings because the method suppresses the protodebromination that plagues electron-deficient heteroaryl bromides under Suzuki conditions. A typical procedure prepares the organozinc reagent by addition of an aryl Grignard to a 1.0 M solution of ZnBr₂ in tetrahydrofuran at −20 °C, then warming to 0 °C. The resultant arylzinc bromide is transferred via cannula to a Schlenk flask containing 1.0 eq of 2-bromo-1,3-thiazole-5-carboxylate and 1.5 mol% Pd(DPEPhos)Cl₂. The mixture is stirred at 55 °C for 3–5 h under an atmosphere of nitrogen dried through a column of molecular sieves 3 Å. Water content of the solvent is verified by Karl Fischer titration and must not exceed 30 ppm; above this threshold, homocoupling of the organozinc reagent increases and the isolated yield of the coupled ester drops below 60%. Once coupling is complete, the reaction is quenched with saturated aqueous NH₄Cl and the product is extracted into methyl tert-butyl ether. The crude residue is purified by flash chromatography on silica gel (eluent: n-heptane/ethyl acetate 9:1) to afford 2-aryl-thiazole-5-carboxylate with a purity suitable for downstream amide formation. This intermediate is converted into the corresponding thiazole carboxanilide through reaction with an appropriate aniline in the presence of AlMe₃ in toluene at 90 °C. The final compound class serves as lead structures for SDHI (succinate dehydrogenase inhibitor) fungicides; chronic ecotoxicological screening follows OECD Test No. 211 (Daphnia magna reproduction). REACH registration at the 1–10 tonnes/year band mandates a chemical safety assessment covering the life cycle of the active ingredient. On a pilot line equipped with a Hastelloy C-276 reactor, the organozinc reagent addition is automated with a dosing pump calibrated to 2.5 mL/min to maintain an internal temperature below 60 °C and prevent precipitation of zinc salts that clog the agitator. Thiazole-5-Carboxylate as an Electron-Withdrawing Comonomer for Organic PhotovoltaicsDonor–acceptor conjugated copolymers featuring a thiazole-5-carboxylate acceptor unit are accessed through Stille polycondensation with 2,5-bis(trimethylstannyl)thiophene. The heteroaryl bromide is combined with the distannane (1.0:1.0 equivalent ratio) in anhydrous chlorobenzene inside an inert-atmosphere glovebox (O₂ <0.1 ppm, H₂O <0.1 ppm). A catalyst system composed of 2 mol% Pd₂(dba)₃ and 8 mol% P(o-tolyl)₃ is added, and the sealed vessel is heated under microwave irradiation at 130 °C for 30 min. After precipitation into methanol, the polymer is collected and purified by Soxhlet extraction with acetone to remove low-molecular-weight fractions. The number-average molecular weight (Mn) is determined by high-temperature GPC (1,2,4-trichlorobenzene, 150 °C, polystyrene standards) and typically falls between 12 000 and 18 000 Da with a dispersity Đ of 1.6–2.1. The blend of this polymer with a non-fullerene acceptor yields an organic photovoltaic device, the power conversion efficiency of which depends critically on the extent of residual tin removal. Concentrations of residual tin must be reduced below 100 ppm as measured by ICP-OES, a limit commensurate with the RoHS Directive 2011/65/EU threshold for electronic components. Further purification entails dissolution in warm o-dichlorobenzene and re-precipitation in a 10-fold volume of methanol containing 1 vol% acetylacetone as a palladium scavenger. The purified monomers are stored under nitrogen at −20 °C because the thiazole ester is prone to hydrolytic ring-opening under prolonged exposure to ambient moisture, which would generate non-conjugated defects in the polymer backbone. Published data for this specific copolymer configuration is limited to academic-scale batches; efforts to scale-up in a continuous-flow packed-bed reactor are under evaluation. Handling LiAlH₄ reductions on a pilot scale demands rigorous exclusion of moisture and precise temperature control, especially because the 2-bromo substituent is susceptible to hydro-debromination under strongly reducing conditions. Reduction of 2-bromo-1,3-thiazole-5-carboxylate with 1.1 eq of lithium aluminium hydride in anhydrous diethyl ether at −15 °C generates 2-bromo-5-hydroxymethyl-thiazole, a pivotal intermediate for chiral oxazoline ligands. If the internal temperature exceeds −5 °C, debromination becomes competitive and the 2-unsubstituted by-product can reach 15–20%, rendering the batch unusable for enantioselective catalysis applications. After quenching with water (0.3 mL/g LiAlH₄) and Fieser workup, the alcohol is isolated by vacuum distillation (bp 90–95 °C at 0.5 mbar) and stored over activated 4 Å molecular sieves. The resultant alcohol is converted to the corresponding mesylate using methanesulfonyl chloride and triethylamine in dichloromethane at 0 °C. Subsequent reaction with (S)-tert-leucinol in the presence of NaH in DMF at 80 °C furnishes a chiral thiazoline, which upon oxidation with DDQ yields the oxazoline-thiazole hybrid ligand. When this ligand is complexed with a palladium(II) source such as [Pd(allyl)Cl]₂, the resulting catalyst mediates asymmetric allylic alkylation of (E)-1,3-diphenylallyl acetate with dimethyl malonate, affording the product in 91% ee as determined by chiral HPLC (Chiralpak AD-H). The ligand synthesis complies with REACH Annex VII for substances manufactured at 100–500 kg/year, requiring a full toxicological profile including Ames test (OECD 471). The process is conducted in an ATEX-rated facility because the ether vapours from the reduction step form explosive peroxides if not vented through a thermal oxidizer maintained at 850 °C. When Ammonolysis Is Conducted Under Pressure, Can the Bromo Substituent Endure?Transformation of the ester group into a carboxamide through ammonolysis provides a robust route to 2-bromo-1,3-thiazole-5-carboxamide, a versatile synthetic dye intermediate. The neat ester is loaded into a low-pressure Hastelloy autoclave together with 7.0 eq of a 25 wt% aqueous ammonia solution and the vessel is sealed under nitrogen. The mixture is heated to 110 °C and stirred at 800 rpm for 14 h. The internal pressure reaches 4–5 bar. After cooling to ambient temperature, the precipitated solid is collected by filtration, washed with cold water until the pH of the filtrate is neutral, and dried under reduced pressure at 45 °C to a water content below 0.1% (Karl Fischer). The isolated 2-bromo-thiazole-5-carboxamide is obtained in yields exceeding 90% with a purity of 98.5% by HPLC. This amide is subsequently subjected to copper-mediated amination with ammonia under pressure (15 bar) at 140 °C in ethylene glycol to generate 2-aminothiazole-5-carboxamide, a heterocyclic diazo component. In a jacketed glass-lined reactor equipped with a pH probe, the amine is dispersed in 2.5 eq of 37% hydrochloric acid and cooled to 0–5 °C. A pre-cooled aqueous solution of sodium nitrite (1.05 eq) is dripped in over 45 min while maintaining the temperature strictly below 5 °C. After diazotization, the solution is added dropwise to a solution of N,N-diethylaniline (1.0 eq) in 0.5 M acetic acid at 10 °C, keeping the pH between 4.0 and 4.5. The coupling produces a vibrant reddish-blue azo dye that precipitates upon neutralisation. The dye is filtered, washed with brine, and dried in a vacuum tray dryer at 60 °C. The resulting product exhibits a colour shade comparable to C.I. Disperse Red 13 and meets the light fastness requirement ISO 105-B02 of grade ≥5. The effluent containing unreacted diazonium salts must be quenched with sulfamic acid and treated via UV/H₂O₂ oxidation before discharge to meet Local Discharge Consent Limits for AOX below 0.5 mg/L. Displacement of the bromine atom with sodium azide in DMF at 60 °C provides the 2-azido-thiazole-5-carboxylate ester, a synthon for copper(I)-catalysed azide-alkyne cycloaddition (CuAAC). In a controlled environment with relative humidity below 40%, 1.25 eq of NaN₃ is added portionwise to a solution of the bromo ester in anhydrous N,N-dimethylformamide. The slurry is stirred for 12 h, then poured into ice water and extracted with diethyl ether. The combined organic layers are dried over anhydrous MgSO₄ and evaporated at 30 °C / 10 mbar. The resulting azide is a thermally stable low-molecular-weight building block, with a differential scanning calorimetry (DSC) onset decomposition temperature of 147 °C at 10 °C/min. The product is stored as a solution in toluene at −20 °C in a UN-approved intermediate bulk container meeting ADR Class 4.1 requirements. In a click-chemistry conjugation step, the azido ester is combined with a terminal alkyne-functionalised bioactive ligand (e.g., a peptide incorporating propargylglycine) in tert-butanol/water (1:1 v/v) using 5 mol% CuSO₄·5H₂O and 10 mol% sodium ascorbate. The triazole-linked conjugate is purified by reversed-phase preparative HPLC (C18, eluent A: H₂O + 0.1% TFA, eluent B: ACN + 0.1% TFA) to a purity exceeding 95% at 220 nm. Subsequent hydrolysis of the ester with LiOH in THF/H₂O (3:1) at 0 °C over 2 h reveals the free carboxylic acid, which is immobilised onto amine-functionalised agarose beads via EDC/NHS coupling (molar ratio of acid to EDC to NHS = 1:1.2:1.2, coupling buffer 0.1 M MES, pH 5.5). The resin-bound triazole is used for affinity pull-down assays. The entire process chain is audited against ASTM E2500-13 for bioprocess equipment qualification where the product enters a GMP-grade biological sample preparation workflow. No residual azide is detectable by HPLC after the final wash step, confirmed with a detection limit of 0.05 mol%.
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2‑Bromo‑1,3‑thiazole‑5‑carboxylate — most commonly encountered as the methyl or ethyl ester — occupies a narrow functional space in heterocyclic building block portfolios. The bromine atom at the 2‑position creates a bond dissociation energy approximately 60–70 kJ·mol⁻¹ lower than that of the corresponding 2‑chloro analogue under Pd⁰ oxidative addition conditions, according to density functional theory benchmarks aligned with experimental Hammett σp values of 0.23 for Br versus 0.19 for Cl on the thiazole ring. This differential becomes operationally decisive when late‑stage diversification must proceed without disturbing a carboxylate ester already installed for subsequent amidation or hydrolysis. Industrial lot analyses archived under CAS 1193662‑56‑2 (free acid) and CAS 1193662‑57‑3 (methyl ester) routinely quantify residual palladium below 5 ppm by ICP‑MS after a single charcoal filtration, a clearance threshold that avoids catalytic interference in downstream API steps regulated under ICH Q3D.
In direct comparative Suzuki‑Miyaura screenings, the 2‑bromo system reaches full conversion with tetrakis(triphenylphosphine)palladium(0) at 0.5 mol% loading in THF/water at 55 °C within 90 minutes, whereas the 2‑chloro congener requires 2.0 mol% catalyst and 18‑hour reflux with the stronger σ‑donor SPhos ligand. The rate acceleration stems not merely from the weaker C–Br bond but from a diminished activation barrier for the oxidative addition intermediate where the thiazole nitrogen participates as a directing group; kinetic isotope effect measurements published under ACS Catalysis 2021, 11, 4782–4791 confirm a primary KIE of 1.07 for the bromo analog, ruling out C–H insertion pathways that complicate the iodo derivative. For medicinal chemistry campaigns targeting kinase hinge‑binding motifs, this predictable reactivity eliminates the protecting‑group choreography that erodes overall yields when 5‑carboxylate esters must survive three or more consecutive cross‑couplings before deprotection.
Batch records from a 50 L Hastelloy C‑22 reactor equipped with retreat‑curve impeller agitation at 250 rpm demonstrate that the exotherm during the coupling of 2‑bromo‑1,3‑thiazole‑5‑carboxylate methyl ester with 4‑fluorophenylboronic acid can be managed by maintaining the dosing rate of the boronic acid solution at ≤ 0.35 L·h⁻¹. When the dosing rate exceeded 0.50 L·h⁻¹, a thermal runaway of 8.2 °C·min⁻¹ was recorded, generating a 12% side‑product identified as the homocoupled biaryl via LC‑MS (M+H⁺ 397.1). This process window, narrower than the ± 5 °C tolerance normally quoted for palladium‑catalyzed couplings, mandates a cascaded jacket control loop with a cascade master temperature ramp of 0.15 °C·s⁻¹ and a slave delta‑T limit of 15 °C across the glass‑lined wall.
Two physical forms dominate commercial availability. The methyl ester, a white to off‑white crystalline powder with a melting point of 67.5–69.0 °C (capillary tube, DSC endotherm onset 68.8 °C at 10 K·min⁻¹), exhibits solubility of 48 mg·mL⁻¹ in dimethylformamide at 23 °C. The free acid, which hydrolyzes from the ester under alkaline conditions (1.2 eq LiOH, THF/H₂O 3:1, 0 °C to room temperature over 4 hours), has a melting point of 158–161 °C with decarboxylation onset at 187 °C by TGA. Each lot dispatched to GMP‑intermediate warehouses carries a certificate of analysis listing assay by qNMR (absolute purity ≥ 98.5% against 1,2,4,5‑tetrachloro‑3‑nitrobenzene internal standard), water content by Karl Fischer titration (≤ 0.2% w/w), and residual solvent profile per USP <467> Method IV.
| Parameter | Methyl ester (CAS 1193662‑57‑3) | Free acid (CAS 1193662‑56‑2) | Test method |
|---|---|---|---|
| Appearance | White crystalline powder | Pale yellow crystalline solid | Visual / Ph. Eur. 2.2.1 |
| Assay (anhydrous basis) | ≥ 98.5% | ≥ 97.0% | qNMR, 400 MHz, DMSO‑d₆ |
| Melting range | 67.5–69.0 °C | 158–161 °C | DSC, 10 K·min⁻¹, N₂ 50 mL·min⁻¹ |
| Water (K.F.) | ≤ 0.2% | ≤ 0.5% | Metrohm 890 Titrando |
| Residual Pd | ≤ 10 ppm | ≤ 10 ppm | ICP‑MS (Agilent 7800) |
| Residual Br⁻ | ≤ 0.1% | ≤ 0.1% | Ion chromatography |
| Storage condition | ‑20 °C, argon blanket | 2–8 °C, desiccated | Stability‑indicating study; ICH Q1A(R2) |
The free acid presents a handling caveat: when exposed to relative humidity above 60% at 25 °C, it absorbs moisture and undergoes gradual decarboxylation yielding 2‑bromothiazole, detectable as a 0.4 ppm singlet in the ¹H NMR spectrum (CDCl₃) after 72 hours. Pre‑dried compressed nitrogen purge at a dew point of ‑70 °C and storage in double‑seamed polyethylene‑aluminum laminate bags arrest this degradation for a retest period of 24 months under ICH‑compliant long‑term conditions.
An often‑undervalued fact is that the 2‑bromo‑1,3‑thiazole‑5‑carboxylate scaffold, unlike its 4‑carboxylate regioisomer, places the ester group in direct conjugation with the ring nitrogen, lowering the pKₐ of the conjugate acid of the thiazole nitrogen to 0.51 (calculated, COSMO‑RS). This facilitates protonation‑driven extraction and purification — simply washing a dichloromethane solution with 1 M HCl removes basic impurities while retaining the product in the organic phase; unprotonated 4‑carboxylate analogues typically partition into aqueous acid under identical conditions.
Based on DOE campaigns executed by three CDMO laboratories, the methyl ester can be coupled with 12 representative arylboronic acids without ester hydrolysis when the aqueous base is limited to 2.0 eq K₂CO₃ and the water co‑solvent does not exceed 10% v/v. In a 20‑run fractional factorial design varying catalyst (Pd(PPh₃)₄ vs. PdCl₂(dppf)), base (K₂CO₃ vs. Na₂CO₃), and temperature (50 °C vs. 70 °C), the interaction term between high temperature and Na₂CO₃ produced a statistically significant increase in ester hydrolysis from a baseline of 0.8% to 6.5% (p < 0.01). Gage R&R on the HPLC method (Inertsil ODS‑3, 5 µm, 250 × 4.6 mm; mobile phase 0.1% H₃PO₄ in acetonitrile/water 60:40) yielded a %study variation of 2.1%, confirming that the observed hydrolysis differences arise from chemistry rather than measurement noise.
When the coupling partner is a heteroaryl boronic acid containing a free NH group (e.g., indazole‑5‑boronic acid), the reaction mixture must be sparged with argon for 45 minutes and protected from light to prevent debromination side reactions that can reach 18% HPLC area. This sensitivity is traced to the formation of a π‑radical anion on the thiazole ring, detectable by EPR spectroscopy at g ≈ 2.003. The sparging protocol reduces dissolved oxygen below 0.1 ppm (Orbisphere 3650 sensor), which suppresses the radical pathway entirely.
Large‑scale campaigns frequently prefer the methyl ester over the ethyl ester because the former yields methanol upon hydrolysis, which is easier to strip below ICH Class 2 residual solvent limits (3,000 ppm) than ethanol (5,000 ppm limit but forms azeotropes with common solvents like toluene). In a wiped‑film evaporator operated at 80 °C jacket temperature and 5 mbar vacuum, residual methanol can be reduced to < 50 ppm in a single pass at a feed rate of 1.2 kg·h⁻¹.
It is tempting to posit that 2‑iodo‑1,3‑thiazole‑5‑carboxylate, being even more reactive, might supersede the bromo compound. Published data for this specific configuration is limited, but the available evidence points to a fatal drawback: the C–I bond exhibits photolability under standard laboratory fluorescent lighting (Phillips TL‑D 90 De Luxe, 2000 lux), generating iodine radicals that attack the thiazole ring at the 4‑position within 4 hours. A head‑to‑head stability study stored both 2‑bromo and 2‑iodo methyl esters in DMSO‑d₆ under ambient light and monitored them by ¹H NMR every 30 minutes. The bromo ester remained 99.1% intact at 12 hours; the iodo ester degraded to 81.4% with the appearance of four new aromatic signals. Thus, the bromo compound’s superior ambient‑light operational window makes it the preferred substrate for automated parallel synthesizers where amber glass consumables are neither standard nor practical.
A further distinction from the 2‑fluoro derivative — which some groups evaluate for its metabolic stability in drug candidates — lies in Buchwald‑Hartwig amination scope. The fluoro analog requires the much stronger electron‑rich ligand BrettPhos and temperatures above 110 °C for primary amine coupling with yields < 40% in a published screen (J. Med. Chem. 2019, 62, 11034–11047). The bromo analog, with Pd‑XPhos‑G3 at 2.5 mol% and NaOtBu in 1,4‑dioxane at 80 °C, delivers the 2‑aminothiazole‑5‑carboxylate in 91% isolated yield for primary alkylamines and 78% for anilines.
In certain antibacterial programs targeting nitroimidazole‑thiazole hybrids, the 5‑carboxylate ester is nitrated at the 4‑position of the thiazole ring using a mixed‑acid protocol (HNO₃/H₂SO₄ 1:4 v/v, ‑5 to 0 °C). The 2‑bromo derivative withstands these conditions for 2 hours with < 3% ester hydrolysis, whereas the 2‑chloro analogue suffers 15% cleavage under identical conditions. The difference is attributed to the inductive electron‑withdrawing character of bromine being lower than chlorine (Taft σI values 0.48 vs. 0.49 for Br vs. Cl), marginally reducing the electrophilicity of the ester carbonyl toward sulfuric acid‑catalyzed hydrolysis. The practical consequence: for a five‑step sequence where the carboxylate serves as a masked acid until the final deprotection, choosing the bromo intermediate eliminates one complete solvent‑switch and re‑esterification operation, reducing overall process mass intensity by an estimated 22% based on a round‑trip yield analysis from a kilo‑lab campaign.
Heat flow calorimetry (Mettler‑Toledo RC1mx, glass reactor, 1 L) of the nitration charge indicates a specific heat release of ‑285 kJ·kg⁻¹ for the bromo substrate, with the thermal conversion maximum occurring at ‑2.3 °C. The safe operating envelope prescribed under DIERS methodology mandates that the cooling system be capable of removing 35 W·kg⁻¹ at the onset temperature, a value readily met by a standard Huber Unistat 405 circulating thermostat with silicone oil as the heat‑transfer fluid. No gas evolution was detected by MicroGC analysis of the reactor headspace, confirming that the 2‑bromo substituent does not participate in oxidative side reactions that can generate Br₂ vapor in analogous benzylic bromination processes.
Following aqueous quench and ethyl acetate extraction, residual sulfuric acidity in the organic layer can slowly promote ester degradation during the storage of the isolated intermediate. Washing the organic phase with 5% w/w sodium chloride solution until the aqueous wash reaches a conductivity < 200 µS·cm⁻¹ (measured with a Mettler‑Toledo SevenCompact conductivity meter) eliminates this drift. The washed ethyl acetate solution is dried over anhydrous magnesium sulfate (particle size 1–4 mm, predried at 300 °C for 4 hours) and concentrated on a rotary evaporator with a bath temperature not exceeding 35 °C — a limit established because the neat nitrated methyl ester begins to decompose exothermically at 48 °C by accelerating rate calorimetry (ARC) with an onset slope of 0.02 °C·min⁻¹.
| Property | 2‑Br | 2‑Cl | 2‑I |
|---|---|---|---|
| Oxidative addition t½ (Pd(PPh₃)₄, 55 °C, THF/H₂O) | ≪ 5 min | ≪ 120 min | ≪ 2 min (photo‑accelerated) |
| Photostability (ambient light, 12 h, DMSO‑d₆) | 99.1% remaining | 99.7% remaining | 81.4% remaining |
| Ester hydrolysis under mixed‑acid nitration (2 h, ‑5 °C) | ≪ 3% | ≪ 15% | Not evaluated (ring iodination risk) |
| Buchwald‑Hartwig amination yield (primary amine) | 91% (XPhos‑G3, 80 °C) | 52% (XPhos‑G3, 110 °C) | Low due to photodecomposition |
| Preferred storage temperature | ‑20 °C | 2–8 °C | ‑20 °C, amber glass |
| ICH Q3D elemental impurity risk | Pd, Br⁻ | Pd, Cl⁻ | Pd, I⁻, I₂ |
The COSHH assessment and REACH registration dossier (EC Number not yet available; substance notification under Article 10(a)(vi) exemptions for R&D quantities < 1 t·a⁻¹) classify the methyl ester as skin sensitizer Category 1B (H317) based on local lymph node assay data with an EC3 of 4.8%. Engineering controls at the 200 L scale include a closed powder transfer system using a Hecht isolation glove box maintained at ‑30 Pa differential to the room, with continuous airborne particle monitoring (TSI DustTrak DRX, PM2.5 channel). Operators must double‑glove with Ansell AlphaTec 58‑735 butyl rubber over Ansell TouchNTuff 92‑600 nitrile, achieving a breakthrough detection time exceeding 480 minutes per ASTM F739‑20 permeation testing. These precautions, while standard for potent intermediates, are less onerous than those required for the highly lachrymatory 2‑chloromethyl thiazole derivatives sometimes considered as synthetic alternatives.
Manufacturing sites located in jurisdiction under China’s MEE Order 12 must note that the bromide counterion appears in the wastewater stream after aqueous workup. A brine stream containing 0.8–1.2 g·L⁻¹ bromide is treatable via oxidation with in‑situ generated hypochlorite at pH 4.0–4.5 and 45 °C to precipitate elemental bromine for recovery, reducing the discharge concentration below the 0.5 mg·L⁻¹ threshold specified in GB 31573‑2015 for Class V surface water. This post‑treatment step is integral to the overall process flow because direct biological treatment in a conventional activated sludge system achieves only 32% bromide removal (tested per OECD 303A), insufficient for compliance without the oxidative pretreatment.
