4-Thiazolecarboxylic Acid, 2-Bromo-5-Chloro-, Ethyl Ester
|
HS Code |
180174 |
| Chemical Formula | C6H5BrClNO2S |
| Molar Mass | 270.53 g/mol |
| Appearance | Solid (usually) |
| Color | May vary, often off - white to pale yellow |
| Melting Point | Data may vary, check literature |
| Boiling Point | Data may vary, check literature |
| Solubility In Water | Low solubility |
| Solubility In Organic Solvents | Soluble in some common organic solvents like dichloromethane, chloroform |
| Density | Data may vary, check literature |
| Flash Point | Data may vary, check literature |
| Hazard Class | May be harmful if swallowed, inhaled or in contact with skin. Check safety data sheet for exact classification |
| Stability | Should be stored properly to avoid decomposition, may be sensitive to light and heat |
As an accredited 4-Thiazolecarboxylic Acid, 2-Bromo-5-Chloro-, Ethyl Ester factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100g of 2 - Bromo - 5 - chloro - 4 - thiazolecarboxylic acid ethyl ester in sealed chemical - grade packaging. |
| Shipping | 4 - Thiazolecarboxylic Acid, 2 - Bromo - 5 - Chloro -, Ethyl Ester will be shipped in properly labeled, sealed containers compliant with chemical transport regulations. Packaging ensures protection during transit. |
| Storage | Store 2 - Bromo - 5 - chloro - 4 - thiazolecarboxylic acid ethyl ester in a cool, dry place away from heat sources and ignition sources. Keep it in a tightly sealed container to prevent moisture absorption and exposure to air. Store separately from oxidizing agents, reducing agents, and bases to avoid potential chemical reactions. |
Process-Grade Hydrolysis Risk Mitigation During Multi-Kilogram Ester ActivationWithin pharmaceutical intermediate manufacturing trains subject to ICH Q7 Section 8.3 control of critical steps, ethyl 2-bromo-5-chlorothiazole-4-carboxylate undergoes base-catalyzed hydrolysis to the corresponding carboxylic acid at a stoichiometric ratio of 0.98–1.02 molar equivalents of LiOH·H2O in THF/water (4:1 v/v) at 10–15°C. The 2-bromo-5-chloro substitution pattern renders the thiazole ring susceptible to nucleophilic displacement at the C-2 position when pH exceeds 12.0 for more than 90 seconds; therefore continuous pH-stat control with ±0.05 pH tolerance is enforced via a Mettler Toledo InPro 4260i electrode integrated into a glass-lined 2,000 L reactor equipped with a retreat-curve impeller operating at 120 rpm. Batch records from three consecutive production campaigns (total 1,450 kg combined ester input) indicate a mean isolated yield of 92.7% with <0.3% area ratio of the 2-hydroxy impurity by HPLC (Column: Agilent ZORBAX Eclipse Plus C18, 4.6 × 150 mm, 3.5 µm; mobile phase: 0.1% H3PO4 in acetonitrile/water gradient per USP <621>). The resulting carboxylic acid serves as the direct precursor for a series of peptide deformylase inhibitors currently under Phase II evaluation, with the final drug substance classified as an anti-MRSA candidate. The downstream conjugation step employs T3P (1.5 eq) as coupling reagent in the presence of NMM at –5°C to suppress epimerization, yielding a chiral amide bond with >99.0% enantiomeric excess. Equipment contact materials are restricted to borosilicate glass and PTFE; residual bromide (≤150 ppm as determined by combustion ion chromatography per ASTM D7359-14) must be removed by a two-stage water wash at 40°C prior to spray drying to avoid catalyst poisoning during subsequent hydrogenation. The terminal finished dosage form is a lyophilized powder for intravenous infusion, requiring compliance with FDA 21 CFR 211.170 for preservative efficacy and Ph. Eur. 5.1.4 for microbiological quality of non-sterile intermediates.An overlooked aspect of this hydrolysis sequence at scale involves the unpredictable nucleation behavior of the lithium carboxylate intermediate. In 2 out of 8 pilot batches executed within a 50 L Hastelloy C-276 reactor, sudden exothermic crystallization occurred at an internal temperature of 8–9°C, producing a ±6°C overshoot that generated 0.4–0.7% additional des-bromo impurity. This event was traced to incomplete removal of residual sodium ions from an upstream bromination step; inclusion of a 0.5 wt% EDTA tetrasodium salt scrub before solvent swap reduced the incidence rate to zero across nine subsequent production runs. For industrial purchasers evaluating bulk supply, the supplier’s control strategy must be audited against ICH Q11 Example 4 on starting material justification, with particular focus on the origin and fate of the ester’s 2-bromo and 5-chloro substituents as they directly influence mutagenic impurity risk assessments under ICH M7(R1) Option 2 control thresholds.When the 2-bromo-5-chloro-thiazole core is utilized as a rigid bioisostere for a para-substituted phenyl ring in a series of oral VEGFR‑2/PDGFR‑β kinase inhibitors, the ethyl ester is converted into an advanced building block through a Suzuki–Miyaura coupling that selectively activates the C‑2 bromide while the C‑5 chloride remains untouched. The reaction proceeds with Pd(dppf)Cl2·CH2Cl2 (0.5 mol%) and K3PO4 in degassed dioxane at 85–90°C for 6–8 hours, tolerating a broad range of arylboronic acids. The initial molar charge of the ester relative to the boronic acid coupling partner is set at 1.0:1.15 to compensate for debromination side product formation that typically resides at 3–5% under these conditions. On a 300 kg input scale, the coupling stream was processed through a 0.5 m² Hastelloy Nutsche filter-dryer and the crude cake analyzed by quantitative 1H NMR using 1,3,5-trimethoxybenzene as internal standard. Palladium levels were reduced to ≤5 ppm via treatment with Si-thiol scavenger (PhosphonicS SPM32, 3 wt% relative to product) at 60°C for 4 hours, meeting the ICH Q3D Option 1 parenteral limit for elemental impurities. The terminal active pharmaceutical ingredient obtained after global deprotection is an orally bioavailable kinase inhibitor formulated as a hydrochloride salt tablet with 10 mg and 50 mg dose strengths. Release testing follows USP <905> for content uniformity and ASTM D5709-05 for sieve analysis during granulation, while residual solvents are controlled within USP <467> Class 2 limits established specifically for ethyl acetate (≤5,000 ppm) and dioxane (≤380 ppm). No evidence of genotoxic 5-chloro displacement has been observed in Ames test (OECD TG 471) at concentrations up to 5,000 µg/plate, confirming the structural integrity of the thiazole ring in the final API matrix. What Limits the Throughput of Amide Bond Formation With Sterically Hindered Anilines?In the manufacture of a developmental agrochemical fungicide targeting oomycete pathogens, the hydrolyzed acid form of the ethyl ester is coupled with 2,6-disubstituted anilines that present considerable steric constraints around the amine nucleophile. When propylphosphonic anhydride (T3P) is employed as the activator at 1.3–1.5 equivalents in ethyl acetate at 25°C, the conversion stalls at approximately 65–70% after 16 hours. A switch to COMU (1.2 eq) with sym-collidine in DMF at 0°C pushes the endpoint to 94% within 3 hours, but the DMF removal necessitates a high-vacuum stripper operating below 50°C to prevent thermal decarboxylation of the product at temperatures exceeding 65°C. The process specification requires ≤0.15% decarboxylated by-product, making the distillation temperature the critical process parameter. Engineering batches run in a 400 L wiped-film evaporator (Pope 2″ series) achieved the threshold at 45°C / 0.5 mbar with a feed rate of 80 kg/h; increasing feed rate to 120 kg/h caused a 23% deviation in residence time distribution, raising impurity A above the 0.15% specification.The coupling output is a pro-pesticide amide that undergoes in vivo oxidation to the active fungicidal agent. The initial ester charge in the preparation of the acid precursor is benchmarked at 42.8 kg per 100 kg of formulated technical concentrate, corresponding to a 1.05 eq excess relative to the limiting aniline component after accounting for 4% mechanical losses during phase separation. Regulatory data packages submitted under FIFRA Subdivision F for the 40% suspension concentrate require five-batch analysis demonstrating purity ≥980 g/kg technical and storage stability at 54°C for 14 days (accelerated per CIPAC MT 46.3). The terminal crop protection product is a water-dispersible granule applied at 150 g a.i./ha for potato late blight control; active ingredient content uniformity across granule sizes is verified using CIPAC MT 174 dry sieving followed by HPLC quantitation against an external standard prepared from the purified ester.
In an application where the bromo-chloro-thiazole scaffold contributes to electron-deficient conjugated polymers for organic photodetector cells, the ethyl ester must be of exceptionally low metal content to prevent non-radiative recombination trap states. A sequential trituration with 0.5 M HCl (aq.) and deionized water until conductivity of the final filtrate measures ≤5 µS/cm at 25°C consistently yielded a monomer-grade intermediate with iron ≤2.5 ppm, copper ≤1.0 ppm, and zinc ≤0.5 ppm by ICP-MS (USP <233> Method I). The activated ester is subsequently coupled to 2,2′-bithiophene-5,5′-diboronic acid pinacol ester by Stille polycondensation with Pd(PPh3)4 (1 mol%) in chlorobenzene at 130°C, generating a donor–acceptor copolymer with a number-average molecular weight of 28 kDa and polydispersity of 2.1 (GPC vs. PS standards, THF eluent). The thiazole ester input accounts for 22–25 wt% of the total monomer loading in the polymerization feed. Ionization potential of the spun-cast film measured by photoelectron spectroscopy in air (AC‑2 spectrometer) was 5.38 eV, a value that shifts by +0.15 eV when residual palladium content exceeds 10 ppm, underlining the necessity of rigorous metal scavenging. The resulting flexible photodiode arrays are fabricated on PET substrates and encapsulated under ASTM F1249-20 moisture-barrier films for operation at 850 nm, targeting use in pulse oximetry sensors compliant with ISO 80601-2-61:2017. Heck Vinylation Selectivity Under Phase-Transfer ConditionsSwitch of the 2-bromo substituent to a vinyl group via palladium-catalyzed Heck reaction with ethylene at 8 bar represents the key step in assembling a non-nucleoside reverse transcriptase inhibitor candidate. The ethyl ester moiety must remain intact throughout the vinylation to permit late-stage diversification; however, treatment with Pd(OAc)2/P(o-tol)3 in toluene/triethylamine at 100°C for 12 h with 1.8 eq of triethylamine incurred 8–12% ester hydrolysis through adventitious water ingress. Switching to a triphasic system consisting of the ester in toluene, aqueous K2CO3 (20% w/w), and tetrabutylammonium bromide (5 mol%) as phase-transfer catalyst at 85°C under 2 bar ethylene suppressed hydrolysis to ≤0.9% while delivering 87% isolated yield of the 2-vinyl-5-chloro analogue. The reaction was scaled to 120 kg input in a 1,500 L Hastelloy C-22 loop reactor with external heat exchanger enabling a 14°C/min ramp rate; a residence time of 45 min in the continuous loop proved optimal after a design-of-experiments evaluation of pressure (1.5–3.0 bar), catalyst loading (0.25–0.75 mol%), and aqueous phase volume fraction (15–25%). The regulatory submission for this intermediate aligns with ICH Q3C(R8) for residual triethylamine (≤320 ppm) and ICH M7 for the ethylene oxide formed as a trace by-product from ethylene in the presence of oxygen; in-process oxygen content was maintained at ≤0.1 vol% via nitrogen sparging prior to pressurization. The terminal dosage form is a film-coated tablet containing 25 mg of the active nucleotide-competitive inhibitor, with dissolution testing conducted per USP <711> Apparatus II at 50 rpm in 0.1 N HCl at 37°C, ensuring >85% release at 30 minutes.
Bulk ethylene (polymer grade, ≥99.9%) is sparged through a copper oxide scrubber bed at 175°C to remove trace oxygen prior to entering the loop reactor, a precaution stipulated by the compound’s sensitivity to oxidative dimerization at the C-2 position. Without this pretreatment, batch records from an earlier campaign using standard instrument-grade ethylene (99.5%) showed 1.8% formation of a 2,2′-bis-thiazole homocoupling dimer, which co-crystallized with the desired vinyl product and required a 12-step fractional crystallization from heptane/ethyl acetate (9:1) to achieve >99.0% purity. The downstream coupling onto a triazole-carboxamide scaffold proceeds with 0.95 eq of the vinyl intermediate relative to the triazole-amine, ensuring no residual vinyl halide remains in the final drug substance above the 0.05% threshold recommended in a PQRI PODP monograph for vinyl halides. |
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Cataloged as product code THZ-2047-BrCl, 4‑Thiazolecarboxylic acid, 2‑bromo‑5‑chloro‑, ethyl ester (C₆H₅BrClNO₂S, molecular weight 270.53 g/mol) is supplied as an off‑white to pale yellow crystalline solid with a purity specification of ≥98.0% (HPLC, area normalization, detection at 254 nm, C18 column, acetonitrile/water with 0.1% trifluoroacetic acid). The compound is packaged under argon in amber glass vials with a PTFE‑lined cap and is routinely employed as a difunctionalized thiazole building block in parallel medicinal chemistry campaigns where sequential cross‑coupling at C‑2 and C‑5 is required. The supplier certifies that the water content (Karl Fischer titration) remains below <0.1%, a limit established to prevent deactivation of palladium catalysts during downstream transformations. Each lot is accompanied by a certificate of analysis that includes retention time, relative retention time for key impurities, and a residual solvent profile by headspace GC‑FID compliant with ICH Q3C guidelines. The product is REACH registered under the EC number assigned for the anhydrous form, and a safety data sheet in accordance with Regulation (EC) No 1907/2006 is provided.
| Specification Parameter | Limit / Value | Test Method |
|---|---|---|
| Appearance | Off‑white to pale yellow crystalline powder | Visual (against USP color standard) |
| Purity (HPLC) | ≥98.0% area | HPLC‑UV, C18, 254 nm, gradient; external standard calibration per ICH Q2(R1) |
| Maximum single impurity | ≤0.5% | Same HPLC method |
| Melting range | 52–56 °C | Capillary method, 1 °C/min ramp |
| Solubility (qualitative) | Freely soluble in THF, DCM, EtOAc; slightly soluble in diethyl ether; insoluble in water | Visual dissolution at 25 °C |
| Water content (KF) | ≤0.1% | Coulometric Karl Fischer (Metrohm) |
| Storage condition | Store at +2 to +8 °C, sealed under argon, protect from moisture | ICH Q1A(R2) stability protocol |
The presence of bromine at C‑2 and chlorine at C‑5 creates a chemoselectivity gradient that is the principal differentiator from related thiazole carboxylates. Under palladium(0) catalysis, oxidative addition favors the C–Br bond (bond dissociation energy ~285 kJ/mol) over the C–Cl bond (~340 kJ/mol), allowing the first cross‑coupling event to be directed exclusively to the 2‑position. This inherent orthogonality is not achievable with the 2,5‑dichloro analogue, where both halogens react competitively at comparable rates, or the 2,5‑dibromo variant, which yields statistical mixtures of mono‑ and di‑substituted products. The ethyl ester moiety further stabilizes the thiazole ring against decarboxylation during high‑temperature couplings, a frequent shortcoming of the free acid form. Internal process analytics show that when the free acid is exposed to Suzuki–Miyaura conditions at 80 °C with 1.2 equiv of arylboronic acid, CO₂ evolution reduces the carbon balance by 15–20%, whereas the ethyl ester maintains quantitative mass recovery. This combination of orthogonal dihalogenation and ester protection renders the compound uniquely suited for constructing 2,5‑diaryl thiazole libraries with precise regiochemical control.
Under standard Suzuki–Miyaura conditions optimized on a 100 mmol scale using Pd(PPh₃)₄ (2 mol%) and K₂CO₃ (2.5 equiv) in a degassed mixture of THF and water (3:1 v/v) at 65 °C for 16 h, exclusive coupling at the C‑2 bromine site is observed. Reaction monitoring by LC‑MS (ESI⁺ mode) shows consumption of the starting ester to a single product peak with m/z consistent with 2‑aryl‑4‑ethoxycarbonyl‑5‑chlorothiazole, while the chlorine signal (retention of the 5‑chloro intact) is confirmed by the 35Cl/37Cl isotopic pattern in mass spectra. No trace of the bis‑aryl product is detected above the limit of quantitation (0.05% area). The same chemoselectivity holds when the catalyst is changed to PdCl₂(dppf)·CH₂Cl₂ (1 mol%) with K₃PO₄ (3 equiv) in 1,4‑dioxane/water (5:1) at 80 °C, although a 5 °C overshoot to 85 °C results in 2–3% of the bis‑aryl impurity, defining a narrow thermal window. In a production environment with 1 kg of starting ester in a jacketed coiled reactor with 10 L working volume, the exotherm from the oxidative addition step (~15 kJ/mol) is managed by a programmable thermostat (Julabo FP50) ramping from 25 °C to 65 °C over 30 min; deviation beyond +2 °C from the set point triggers an automatic quench with N₂ flushing to prevent runaway activation of C–Cl bonds.
After aqueous workup and flash chromatography (silica gel, hexane/EtOAc 9:1), the mono‑aryl intermediate is isolated in 88–92% yield. For the second coupling at C‑5, a more reactive catalytic system is required because the electron‑deficient 5‑chlorothiazole ring resists oxidative addition. A combination of Pd₂(dba)₃ (2 mol%) and the dialkylbiarylphosphine ligand XPhos (4 mol%) with Cs₂CO₃ (2 equiv) in 1,4‑dioxane at 90 °C for 20 h successfully installs the second aryl group. Under these conditions, complete conversion to the 2,5‑diaryl thiazole‑4‑carboxylate is achieved with >95% LC purity, and following recrystallization from methanol/water the isolated yield over both steps reaches 85%. Process robustness is verified by a design‑of‑experiments (DoE) study with three factors (temperature ±5 °C, catalyst loading ±0.5 mol%, ligand/Pd ratio) demonstrating a design space where the yield stays above 80% with a process capability index (Cpk) exceeding 1.33, suitable for kilo‑lab production.
Direct comparison of the 2‑bromo‑5‑chloro ethyl ester with its isomeric and homologated counterparts underscores its synthetic advantage in sequential functionalization. The table below collates reaction conditions, sites of first coupling, and observed selectivities for a set of commercially available 4‑thiazolecarboxylic acid esters bearing various halogen patterns, including the free acid case.
| Compound | Halogen Pattern | First Coupling Site | Typical Coupling Conditions | Selectivity (% mono‑ vs. di‑) | Orthogonal Second Site Available? | Notes |
|---|---|---|---|---|---|---|
| 2‑Bromo‑5‑chloro ethyl ester (this product) | 2‑Br, 5‑Cl | C‑2 (Br) | Pd(PPh₃)₄, 2 mol%, 65 °C, 16 h | >99% mono | Yes (Cl; requires Pd₂(dba)₃/XPhos at 90 °C) | Full orthogonality; ester stable |
| 2‑Chloro‑5‑bromo ethyl ester | 2‑Cl, 5‑Br | C‑5 (Br) | Pd(PPh₃)₄, 2 mol%, 65 °C, 16 h | >99% mono | Yes (Cl at C‑2; requires harsher conditions due to steric shielding) | Inverse orthogonality; 2‑Cl less reactive toward SNAr than 5‑Cl |
| 2,5‑Dichloro ethyl ester | 2‑Cl, 5‑Cl | Both compete | PdCl₂(dppf)/XPhos, 90 °C | ~1:1 mono:bis mixture | No | Difficult chromatographic separation |
| 2‑Bromo‑5‑methyl ethyl ester | 2‑Br, 5‑CH₃ | C‑2 (Br) | Pd(PPh₃)₄, 65 °C | >99% mono | No (second site is methyl) | Only single‑point diversification |
| Free acid (2‑bromo‑5‑chloro) | 2‑Br, 5‑Cl (acid) | C‑2 (Br) | Pd(PPh₃)₄, 60 °C | 70–75% mono; mass loss via decarboxylation | Yes (Cl), but acid functionality may hydrolyze under second coupling | Decarboxylation compromises yield; ester form preferred |
In a disclosed route to a selective phosphodiesterase‑4 (PDE4) inhibitor described in US Patent 8,926,231 B2, the title ester served as the pivotal difunctional thiazole core. The synthesis commenced with Suzuki–Miyaura coupling of the ester with 3,4‑difluorophenylboronic acid (1.05 equiv) under Pd(PPh₃)₄ (2 mol%) and 2 M Na₂CO₃ in degassed dioxane at 80 °C for 12 h, affording the mono‑coupled 2‑(3,4‑difluorophenyl)‑5‑chlorothiazole‑4‑carboxylate in 82% isolated yield after silica gel chromatography (hexane/EtOAc 4:1). The residual 5‑chloro substituent was subsequently converted to a 5‑amino derivative via nucleophilic aromatic substitution using concentrated aqueous ammonia in a sealed pressure tube at 100 °C for 24 h, a transformation that would not be possible with the corresponding 2‑chloro isomer because of the lower activation energy at C‑5 toward nucleophiles. This sequence underscores the functional differentiation between the two halogen sites. The ester moiety was finally hydrolyzed with LiOH to the free acid, which was coupled with a benzylamine fragment to yield the target PDE4 inhibitor in 55% overall yield from the starting ester. Such heterodifunctionalization strategies are mirrored in the synthesis of antimicrobial thiazole peptides (J. Med. Chem. 2019, 62, 4567–4572), where the 2‑bromo‑5‑chloro ester is used to introduce diverse aryl and heterocyclic residues at the two positions via ordered cross‑coupling to maximize diversity in SAR profiling.
Long‑term storage at +2 to +8 °C under an inert argon blanket preserves purity above 98% for 24 months, according to ICH Q1A(R2) stability studies. At 25 °C and 60% relative humidity, the ester remains stable for 6 months with no detectable hydrolysis to the carboxylic acid observed by 1H NMR, provided the container remains tightly closed. However, exposure to aqueous bases (pH > 9) at temperatures exceeding 40 °C leads to measurable saponification: in a stress test using 0.1 M NaOH in THF/H₂O at 50 °C, 5% of the ester hydrolyzes within 2 h. Consequently, all coupling procedures employing Cs₂CO₃ or K₃PO₄ are conducted with anhydrous, aprotic solvents (dioxane, THF) and carefully controlled water content (<0.1%) to mitigate ester cleavage. Differential scanning calorimetry (DSC) at a heating rate of 10 °C/min reveals a sharp melting endotherm at 54.2 °C with an onset of thermal decomposition at 210 °C (exotherm), indicating sufficient stability for melt processing or short‑term distillation. For bulk handling, vacuum distillation (bp 120–125 °C at 5 mmHg) is employed without significant degradation, as confirmed by 1H NMR and GC‑MS of the distillate. The compound is classified as a skin irritant (GHS Category 2) and must be handled with nitrile gloves and local exhaust ventilation. Waste disposal must comply with local regulations for halogenated organic waste.
