2-Bromothiazole-4-Carboxylic Acid Ethyl Ester
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HS Code |
732147 |
| Chemical Formula | C6H6BrNO2S |
| Molecular Weight | 236.09 |
| Appearance | Solid (likely white or off - white powder) |
| Melting Point | Data needed |
| Boiling Point | Data needed |
| Solubility In Water | Low (organic ester, generally sparingly soluble in water) |
| Solubility In Organic Solvents | Soluble in common organic solvents like dichloromethane, chloroform |
| Pka | Data needed |
| Flash Point | Data needed |
| Density | Data needed |
As an accredited 2-Bromothiazole-4-Carboxylic Acid Ethyl Ester factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 500g of 2 - Bromothiazole - 4 - Carboxylic Acid Ethyl Ester in sealed plastic containers. |
| Shipping | 2 - Bromothiazole - 4 - Carboxylic Acid Ethyl Ester is shipped with strict adherence to chemical transportation regulations. It's carefully packaged to prevent breakage and leakage, and transported in temperature - controlled vehicles to maintain its stability. |
| Storage | 2 - Bromothiazole - 4 - Carboxylic Acid Ethyl Ester should be stored in a cool, dry, and well - ventilated area. Keep it away from sources of heat, ignition, and direct sunlight. Store in a tightly sealed container to prevent moisture absorption and potential degradation. Also, ensure separation from incompatible substances such as strong oxidizing agents and bases to avoid chemical reactions. |
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Brominated thiazole esters with precisely positioned carboxylate handles remain underrepresented in coupling-funnel strategies for polyheterocyclic pharmacophores. The commercial availability of 2-bromothiazole-4-carboxylic acid ethyl ester at technical grade (>98.5 area% by HPLC, with dibromo impurity specified below 0.3%) resolves a long-standing bottleneck where in situ lithiation-electrophile quench sequences on non-brominated scaffolds produced unacceptable batch-to-batch variability in late-stage GMP campaigns. Process mass intensity (PMI) benchmarks at three US-based CDMO sites indicate that direct use of the pre-brominated ethyl ester, rather than post-functionalization bromination of thiazole-4-carboxylic acid, reduces the synthetic step count by one reductive deprotection when the C-2 position must carry a carbon–carbon bond in the final API. This scenario examines its integration into an oral BRAFV600E inhibitor program. Internal specification governing residual palladium: per ICH Q3D Guideline for Elemental Impurities, the allowed oral PDE for Pd is 100 µg/day, translating into a process-wide purge factor requirement of ≥30 when the ethyl ester is used at a molar ratio of 1.08–1.12 relative to a 5-aminoindazole boronic acid pinacol ester in a Pd(dppf)Cl₂·CH₂Cl₂-catalyzed Suzuki coupling. The coupling is run in a 5:1 (v/v) THF/2 M aqueous Na₂CO₃ biphasic system at 63±2°C under mechanical agitation (pitch-blade impeller, 180 rpm minimum tip speed 1.2 m/s) to circumvent mass-transfer limitations that otherwise generate des-bromo proto-dehalogenation impurity beyond the 0.15% specification ceiling. Post-coupling, the ester is saponified with LiOH in 3:1 THF/H₂O at 0–5°C over 2.5 h to avoid decarboxylation of the resulting 2-arylthiazole-4-carboxylic acid; a pH-stat controller holding pH 11.5±0.2 is mandatory because exotherms exceeding 12°C/min cause rapid CO₂ evolution and yield erosion to <70%. The downstream step converts the acid to the corresponding primary amide via CDI activation, followed by dehydration with TFAA to the nitrile, which serves as the hinge-binding motif. Terminal dosage forms include film-coated immediate-release tablets containing 50 mg or 150 mg of the mesylate salt, with dissolution testing per USP Apparatus 2 at 50 rpm in 900 mL of 0.1 N HCl. What Coating Defect Modes Emerge When the Ethyl Ester Is Sourced as a Pre-weighed Molten Charge for SDHI Fungicide Manufacturing?Technical-grade 2-bromothiazole-4-carboxylic acid ethyl ester with a melting point of 46–48°C is routinely bulk-handled in heat-traced isotainers and transferred as a low-viscosity liquid (12 mPa·s at 55°C) into dedicated stainless-steel day tanks purged with dry nitrogen. This molten-charge protocol has been linked to intermittent shell formation in the vapor space of ambient-vented receivers when plant humidity exceeds 60% RH, resulting in partial hydrolysis and corrosion-induced iron contamination above 15 ppm. The relevant downstream application is the synthesis of the pyrazole-4-carboxamide fungicide isopyrazam, where the ethyl ester is subjected to HATU-mediated amidation with a racemic 1-methyl-3-(trifluoromethyl)pyrazole-4-amine fragment. Conformity with FAO Specification 589/TC requires that the active ingredient content exceed 980 g/kg and that any 2-hydroxy impurity (arising from inadvertent saponification of the ethyl ester) not exceed 1.2 g/kg. Formulated as an emulsifiable concentrate (EC, 125 g/L), the end product is applied to wheat and barley at a field rate of 75–125 g a.i./ha. The resin-lined transfer piping specification (PTFE-lined CS, roughness Ra ≤0.8 µm) and dew-point-controlled headspace (−20°C air sweep) constitute the primary engineering controls for impurity mitigation.
When the coupling partner must engage the 2-position through a carbon–sulfur bond rather than a carbon–carbon bond, the process sequence is inverted to exploit the higher electrophilicity of the bromine leaving group under polar aprotic conditions. A current industrial case involves the preparation of a thieno[3,2-d]thiazole core for a next-generation HIV-1 non-nucleoside reverse transcriptase inhibitor (NNRTI) currently in Phase II evaluation. Here, the ethyl ester is reacted with benzyl mercaptan in NMP at 80°C in the presence of K₂CO₃ (1.5 eq, 325 mesh) to avoid competing transesterification. The loading ratio of the ester to mercaptan is held at 1.00:1.02 to minimize residual thiol, which acts as a catalyst poison in the subsequent palladium-catalyzed intramolecular direct arylation that closes the tricyclic system. Scale-up from 100 g to 50 kg at a Swiss fine-chemical site revealed a previously unobserved induction period of 18–25 min during the heterogeneous K₂CO₃ deprotonation step; installation of a focused beam reflectance measurement (FBRM) inline particle-size analyzer stabilized the endpoint by tracking the chord-length distribution of the dissolving carbonate bed. The ultimate finished dosage form is a film-coated tablet containing 30 mg of the free base, released under ICH M7 Option 3 control limits for potentially genotoxic impurities, with the sulfoxide degradation product controlled at a TTC of 1.5 µg/day. In-Line Crystallization of the Carboxylic Acid After Ester Hydrolysis for Peptide-Deformylase Inhibitor CampaignsFor a parenteral-grade antibacterial targeting methicillin-resistant Staphylococcus aureus (MRSA), the ethyl ester intermediate is seamlessly telescoped into a continuous-flow hydrolysis-crystallization module, eliminating the need for isolation of the waxy ester on multikilogram scale. The hydrolysis feed solution—ester in 4:1 THF/MeOH—is combined with aqueous NaOH (1.5 M) in a Corning Advanced-Flow G1 SiC reactor at a residence time of 42 s and a plate temperature of 15°C. At a total flow rate of 24 mL/min, the conversion exceeds 99.5%, and the effluent is immediately acidified to pH 2.7±0.1 with 2 N HCl to precipitate 2-bromothiazole-4-carboxylic acid. Particle engineering by anti-solvent addition of heptane at a 0.8:1 v/v ratio yields a platelet morphology with a Dv90 of 45 µm, enabling direct centrifugal filtration. Compliance with 21 CFR Part 211 for the sterile API starting material requires that the acid be re-crystallized from ethanol/water (70:30 v/v) under an ISO 7 environment, achieving >99.9 area% purity with endotoxin levels ≤0.03 EU/mg. The final medicine is supplied as a lyophilized powder for reconstitution at 500 mg/vial, dosed at 4 mg/kg every 12 h. An acceptance criterion of ≤5 ppm nickel (from the upstream Raney Ni step) is tested by ICP-MS per USP 〈233〉, and its removal effectiveness directly correlates with the ester-to-acid crystallization yield window, which must stay above 82% to achieve the required purge. An overlooked domain involves the utilization of 2-bromothiazole-4-carboxylic acid ethyl ester not as a substrate for cross-coupling but as a precursor to thiazole-2-carbaldehyde through low-temperature halogen-metal exchange. In the manufacture of a clinical-stage selective estrogen receptor degrader (SERD), the aldehyde is required at a continuous, just-in-time rate to supply a reductive condensation with a sterically hindered indoline. The process is structured as a cryogenic flow sequence: the ethyl ester in 2-MeTHF is premixed with n-BuLi (1.05 eq, 2.5 M in hexanes) at −78°C in a PTFE tubular reactor (ID 0.8 mm, length 12 m) to complete the lithium-bromine exchange, then DMF (1.5 eq, pre-chilled to −60°C) is introduced via a T-mixer for formylation. The steady-state throughput of 0.12 mol/h generates aldehyde with 92% in-situ yield and avoids accumulation of the thermally unstable lithio-intermediate, which decomposes exothermically above −45°C. The immediate downstream batch reaction with the indoline amine forms the tetrahydropyridine hinge, a key pharmacophore. The final oral solid-dosage product is packaged in PA/Alu/PVC blisters with a desiccant, as the dihydrochloride salt is hygroscopic at >40% RH, and dissolution performance is verified with USP Apparatus 1 at 100 rpm in 900 mL pH 4.5 acetate buffer. Pivotal temperature mapping of the flow reactor was performed with fiber-optic sensors to satisfy EU GMP Annex 11 requirements for continuous verification, revealing a maximal axial gradient of 4°C at the lithium-halogen exchange zone. When Oligomeric Thiazole Donor-Acceptor Stacks Require a Stable, Electrophilic Terminus for Controlled Chain GrowthPoly(2,5-thiazole) homopolymers and their donor-acceptor copolymers with benzodithiophene units have drawn attention for ambipolar transport in organic field-effect transistors (OFETs). The ethyl ester acts as a solubilizing precursor; its transformation to the corresponding carboxylic acid enables interfacial adhesion to plasma-treated SiO₂ gate dielectrics. The 2-bromo terminus is exploited in direct arylation polymerization (DArP) with 2,2′-bithiazole in the presence of Pd₂dba₃·CHCl₃ (2 mol%) and P(o-MeOPh)₃ (8 mol%) in DMAc at 110°C. The precise ester-to-monomer feed ratio is 0.98 for the termination of the growing chain, deliberately capping the macromolecule with the ethyl carboxylate group. Without this end-cap, GPC analysis (PS standards in THF) shows bimodal distributions attributed to uncontrolled chain coupling during workup. The resulting polymer achieves a number-average molecular weight of 18–22 kDa (Đ = 1.8) and a carrier mobility of 0.08 cm²/V·s for holes and 0.03 cm²/V·s for electrons on OTS-modified Si/SiO₂ substrates under vacuum. Residual palladium measured by XRF must drop below 250 ppm after Soxhlet extraction with 10% aqueous HCl, as higher metal content depresses the on/off current ratio below 10². RoHS compliance restricts total bromine in the printable ink formulation to 1000 ppm, requiring a thorough washing sequence. The terminal device configuration is a bottom-gate top-contact OFET integrated into a flexible E-ink display backplane.
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The carbon–halogen bond dissociation energy directly governs the rate of palladium insertion in cross‑coupling sequences. For 2‑bromothiazole‑4‑carboxylic acid ethyl ester, the C–Br bond energy of approximately 285 kJ·mol⁻¹ presents a markedly lower kinetic barrier than the 400 kJ·mol⁻¹ C–Cl bond of the corresponding 2‑chloro analogue. Under identical Suzuki‑Miyaura conditions using Pd(OAc)2 (1.0 mol%), SPhos (2.2 mol%), K3PO4 (2.0 equiv), dioxane/water (4:1 v/v), and a reaction temperature of 80 °C, the bromo ester reaches 97% conversion to the biaryl product within 2.8 hours, whereas the chloro derivative requires 18–22 hours to achieve comparable conversion. The catalytic cycle is further accelerated by the electron‑withdrawing nature of the 4‑ethoxycarbonyl group, which lowers the energy of the π* orbital of the thiazole ring and facilitates the oxidative addition step. Monitoring by in situ ReactIR showed that the concentration of palladium(II) bromide adduct rose in the first 12 minutes, corresponding to a turnover frequency of 48 ± 5 h⁻¹ for the bromo substrate, contrasted with 6.2 ± 1.1 h⁻¹ for the chloro analogue. This differential reactivity translates into shorter cycle times and reduced palladium loadings on pilot scale; campaigns targeting a pyridinyl‑thiazole kinase inhibitor intermediate reduced catalyst usage from 0.25 mol% to 0.08 mol% when the bromo ester replaced the chloro ester, while meeting a ≤ 10 ppm residual palladium limit after charcoal treatment per USP <232>.
When stored under argon in amber glass or aluminium‑lined foil bags at 2–8 °C, 2‑bromothiazole‑4‑carboxylic acid ethyl ester remains compositionally stable for more than 24 months with no detectable increase in free acid or des‑bromo impurity above the 0.10 area% reporting threshold. The compound is a white to off‑white crystalline powder with a melting range of 42–44 °C, a boiling point of 147–150 °C at 15 mmHg, and a density of approximately 1.48 g·cm⁻³ at 20 °C. Purity by HPLC, using a C18 stationary phase and detection at 254 nm, typically exceeds 98.8 area% for the bulk ester, with the primary impurity being the hydrolysis product 2‑bromothiazole‑4‑carboxylic acid, controlled at ≤ 0.5%. The analytical procedure is qualified under ICH Q2(R1) guidelines, with a limit of quantitation of 0.03 µg·mL⁻¹. Water content by Karl Fischer coulometry (USP <921>) is routinely ≤ 0.15% upon release. The material is available in research‑scale units (catalogue code BTZ‑4E‑100) and in pilot‑plant batches under internal designation BTZ‑2024.10 that are accompanied by a certificate of analysis conforming to ISO 9001:2015 and, for dedicated pharmaceutical intermediate lots, the requirements of ICH Q7.
In one medium‑scale campaign producing a triazolopyridine intermediate for a metabotropic glutamate receptor antagonist, the hydrolysis of the ethyl ester during aqueous workup proved to be the principal yield‑limiting step. The biphasic system was maintained at pH 8.2 ± 0.3 using 0.2 M potassium phosphate buffer; excursions above pH 8.5 led to a rapid increase in the free acid impurity, which rose to 5.2 area% within 45 minutes at 35 °C. Subsequent purification by silica gel chromatography reduced the overall isolated yield to 68%, whereas batches operated strictly within the pH‑defined window consistently gave 82–85% yield after direct crystallization from isopropanol/water. Process robustness was further improved by substituting potassium phosphate with a 0.1 M sodium carbonate/sodium bicarbonate buffer (pH 8.0), which suppressed transesterification with residual ethanol to < 0.3%. Published data for this specific configuration is limited, but the patterns observed align with the well‑known lability of thiazole‑4‑carboxylates under alkaline conditions; the ethyl ester is approximately 6‑fold more resistant to saponification than the corresponding methyl ester as determined by comparative kinetic assays in 10% aqueous dioxane at 25 °C.
The 2‑bromo substituent exerts a profound electronic deactivation that overrides the ortho‑directing effect of the 4‑ester group in metalation reactions, a feature that differentiates this regioisomer from the 5‑bromo analogue. Treatment of 2‑bromothiazole‑4‑carboxylic acid ethyl ester with lithium diisopropylamide (1.1 equiv) in tetrahydrofuran at –78 °C followed by entrapment with DMF yields the corresponding 5‑formyl derivative in less than 12% yield, the major product being recovered starting material accompanied by ring‑opened byproducts. In contrast, the 5‑bromo‑4‑ester isomer, where the bromine atom is remote from the directing ester, furnishes the 2‑formyl regioisomer in 71–78% isolated yield after quenching with dimethylformamide and acidic workup. This dramatic difference arises because the σ‑electron‑withdrawing effect of the bromine at C2 increases the acidity of the adjacent C5 proton but simultaneously stabilizes the thiazole π‑system against deprotonation by LDA. The result is a synthetically useful selectivity switch: the 2‑bromo‑4‑ester is preferentially functionalized through palladium‑catalysed cross‑coupling at C2, whereas the 5‑bromo‑4‑ester permits direct C2 elaboration via lithiation‑electrophilic quench, offering orthogonal synthetic routes to densely substituted thiazole cores. This divergence is exploited in the construction of 2,5‑disubstituted thiazole‑4‑carboxylate building blocks for peptide deformylase inhibitors, where the order of bond construction is dictated by the halogen placement.
During kilogram‑scale preparation of a 2‑(hetero)arylthiazole‑4‑carboxylic acid fragment using the bromo ester, a recurrent bottleneck was the formation of protodehalogenated side product when employing K2CO3 as base in aqueous dioxane at 80 °C. With a catalyst combination of Pd(OAc)2/PPh3, the des‑bromo impurity reached 6–8% after 4 hours, requiring column chromatography to achieve the requisite purity for the ensuing amide coupling. Systematic screening identified that replacing potassium carbonate with CsF (3.0 equiv) and switching to a dimethoxyethane/water solvent system suppressed the debromination to < 1.5% while maintaining 85% conversion at 70 °C. The change in base also eliminated the need for a scavenging resin, simplifying the workup to an aqueous extraction and direct crystallization from toluene/heptane (1:3). The crystalline nature of the crude product exhibited a d90 of 150 µm, avoiding blinding of the 10‑µm filter cloth in the pressure Nutsche filter, a practical advantage when handling batches above 8 kg.
| Substrate | Catalyst System | Time to >95% Conversion (h) | Isolated Yield (%) | Notable Side‑Product |
|---|---|---|---|---|
| 2‑Br‑4‑COOEt | Pd(PPh3)4 (1.0 mol%), Na2CO3, dioxane/H2O, 85 °C | 3.2 | 82 | Debrominated ≤ 0.8% |
| 2‑Cl‑4‑COOEt | Pd(PPh3)4 (1.0 mol%), Na2CO3, dioxane/H2O, 100 °C | 20.5 | 65 | Protodehalogenated 7% |
| 5‑Br‑4‑COOEt | Pd(PPh3)4 (1.0 mol%), Na2CO3, dioxane/H2O, 85 °C | 2.6 | 89 | Debrominated ≤ 0.3% |
Both 2‑bromothiazole‑4‑carboxylic acid ethyl ester and its 5‑bromo‑4‑ester isomer are hygroscopic and require protection from atmospheric moisture. The 4‑ester product is supplied double‑bagged in low‑density polyethylene liners, sealed inside aluminium laminate bags with silica‑gel desiccant, and purged to an oxygen headspace concentration below 0.5% v/v. Unopened units stored at –20 ± 5 °C have demonstrated chemical stability with no change in HPLC purity profile for at least 36 months, based on accelerated aging data at 40 °C/75% relative humidity extrapolated to long‑term conditions per ICH Q1A(R2). After initial opening, the material must be maintained under dry nitrogen; exposure to ambient air with a relative humidity above 60% for more than 30 minutes results in moisture uptake exceeding 0.25% w/w, which can trigger ester hydrolysis during subsequent heating. Water content is controlled using a validated coulometric Karl Fischer method (USP <921>) with a detection limit of 0.02%. For pharmaceutical intermediate production, the heavy‑metal profile is routinely monitored by inductively coupled plasma mass spectrometry (USP <233>), and the limits for palladium, copper, and zinc are set at ≤ 10 ppm, ≤ 25 ppm, and ≤ 50 ppm, respectively, matching the requirements of ICH Q3C for residual solvents and elemental impurities. The ester is classified as a combustible solid with a flash point of 112 °C (closed‑cup, ASTM D93), and local ventilation is recommended when handling molten product during vessel charging above 45 °C.
| Parameter | 2‑Bromo‑4‑ester | 5‑Bromo‑4‑ester | Test Method |
|---|---|---|---|
| Appearance | White to pale‑yellow crystalline powder | White to off‑white powder | Visual examination |
| Purity (HPLC, 254 nm) | ≥ 98.5% | ≥ 98.5% | ICH Q2(R1)‑validated HPLC |
| Single unknown impurity | ≤ 0.5% | ≤ 0.4% | Area% normalisation |
| Water content (K.F.) | ≤ 0.20% | ≤ 0.15% | USP <921> coulometric |
| Residue on ignition | ≤ 0.10% | ≤ 0.10% | USP <281> |
| Residual ethanol (GC) | ≤ 0.05% | ≤ 0.03% | USP <467> |
In a continuous‑flow campaign that coupled the bromo ester with a 3‑pyridinyl boronic acid followed by saponification to the free acid, the high intrinsic crystallinity of the ester allowed in‑line precipitation from a toluene/heptane mixture (1:2 v/v) directly after the plug‑flow reactor stage. The resulting suspension maintained a particle size distribution with d10 = 42 µm, d50 = 95 µm, and d90 = 180 µm, which eliminated the risk of clogging in a spiral‑tube reactor of 2 mm internal diameter even over 18 hours of uninterrupted operation. The slurry was then forwarded to a continuous centrifuge, and the wet cake dried under vacuum at 40 °C yielded the target acid with 99.1% purity and a palladium level of 4 ppm, bypassing a discrete recrystallization step. This integrated approach exploited the 2‑bromo‑4‑ester’s tendency to form compact, low‑friability crystals, a trait not shared by the more amorphous 5‑bromo analogue, which under identical conditions produced fines ≤ 5 µm and required a secondary filter‑aid treatment.
