5-Bromo-2-Chlorothiazole
|
HS Code |
985116 |
| Name | 5-Bromo-2-Chlorothiazole |
| Molecular Formula | C3HBrClNS |
| Molecular Weight | 198.46 |
| Appearance | Typically a solid (appearance can vary based on purity and handling) |
| Melting Point | Data may vary, generally in a specific range depending on purity |
| Boiling Point | Data may vary, typically at a certain temperature under standard conditions |
| Solubility | Solubility characteristics can vary in different solvents like organic solvents (e.g., dichloromethane, chloroform) |
| Density | Specific density value related to its mass - volume ratio |
| Purity | Purity levels can range depending on production methods and intended use |
| Stability | Stability in different environmental conditions (light, heat, moisture) |
As an accredited 5-Bromo-2-Chlorothiazole factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 5 - Bromo - 2 - Chlorothiazole packaged in 100 - gram bottles. |
| Shipping | 5 - Bromo - 2 - Chlorothiazole is shipped in properly sealed containers. Adequate cushioning ensures protection during transit. Strict compliance with chemical shipping regulations is maintained to prevent any risks. |
| Storage | 5 - Bromo - 2 - Chlorothiazole should be stored in a cool, dry, and well - ventilated area. Keep it away from heat sources, open flames, and oxidizing agents. Store it in a tightly sealed container to prevent exposure to moisture and air, which could potentially cause degradation. This chemical should be isolated from incompatible substances to avoid dangerous reactions. |
In the manufacture of thiazolidinedione-class insulin sensitizers structurally related to netoglitazone and rivoglitazone, 5-bromo-2-chlorothiazole functions as the C5-electrophilic anchor for convergent Suzuki–Miyaura assembly. A representative kilogram-scale procedure involves charging the thiazole (1.0 eq), 4-[2-(pyridin-4-yl)ethoxy]phenylboronic acid pinacol ester (1.15 eq), and finely milled K₃PO₄ (2.5 eq) into a 200 L glass-lined reactor equipped with a retreat-blade impeller and jacket temperature control. The vessel is inerted with three vacuum-nitrogen cycles. A premixed catalyst solution of Pd(OAc)₂ (0.5 mol%) and SPhos (1.0 mol%) in degassed toluene is injected subsurface below the liquid level. The biphasic mixture is agitated at 180–200 rpm while the internal temperature is ramped to 68 ± 2 °C over 45 min. Maintaining this narrow thermal band is critical: excursion above 72 °C activates the C2–Cl bond toward oxidative addition, generating a regioisomeric bis-aryl impurity that co-elutes with the product during flash chromatography and raises the total impurity burden above the 0.50% acceptance threshold. Real-time ReactIR monitoring of the C–Br stretch decay at 512 cm⁻¹ determines endpoint, typically 6–8 h. After phase separation and brine wash, the organic phase is treated with SiliaMetS Thiol metal scavenger at 55 °C for 4 h to reduce residual palladium. Following charcoal filtration and solvent swap to isopropanol, the crystalline intermediate is isolated by centrifugation and vacuum-dried at 45 °C (−0.09 MPa) to ≤0.3% loss on drying. The material serves as a GMP starting material under ICH Q7 Q&A guidance, and full characterization against a qualified reference standard is performed per analytical protocol AM‐0457. Heavy metals by ICP-MS (USP <232>) are controlled to Pd ≤5 ppm, Ni ≤3 ppm, and As ≤1 ppm, consistent with ICH Q3D Option 1 oral permitted daily exposures. A typical certificate-of-analysis profile drawn from twelve consecutive commercial campaigns is compiled in the table below.
What Process Window Maintains High Selectivity During Lithium–Bromine Exchange for Agrochemical Precursors?Conversion of 5-bromo-2-chlorothiazole into 2-chloro-5-(chloromethyl)thiazole (CCMT) — the immediate progenitor of neonicotinoid insecticides clothianidin and thiamethoxam — hinges on a cryogenic metal–halogen exchange that discriminates between C5–Br and C2–Cl. In a 500 L stainless steel cryogenic reactor fitted with a magnetically driven agitator and a secondary liquid-nitrogen expansion loop, the thiazole (1.0 eq, dissolved in anhydrous THF to 0.8 M) is cooled to −78 ± 3 °C. An n-butyllithium solution (2.5 M in hexanes, 0.98–1.02 eq) is transferred via a mass-flow-controlled dosing lance at a rate keeping the internal temperature below −72 °C. Deviation of even 5 °C above the set-point triggers Wurtz-type homocoupling detected as a 1.8% rise in the dimer peak (GC retention time 14.2 min). After a 30 min post-addition hold, paraformaldehyde (2.5 eq, pre-dried over P₂O₅) is added in four equal portions, and the mixture is allowed to warm to −20 °C over 2 h. The resulting hydroxymethyl intermediate is then quenched with thionyl chloride (2.2 eq) at 0–5 °C, generating CCMT in 82–87% isolated yield after fractional distillation at 4 mbar (head temperature 94–96 °C). For operators seeking to avoid organolithium inventory, an alternative iPrMgCl·LiCl (Turbo Grignard) protocol at −20 °C is operational in continuous-flow microreactors (Corning Advanced-Flow G1, 0.45 mL internal volume, residence time 45 s), delivering comparable yields with <0.2% chloride displacement — a value verified by ion chromatography of the aqueous quench stream. CCMT obtained through this route meets FAO specification AGP: CP/299 for agrochemical intermediate purity, specifically dibutylamine content ≤0.1% and water ≤0.2%. Downstream, CCMT is condensed with N-methyl-N′-nitro-2-guanidine or 2-methyl-3-nitroisothiourea to yield the respective insecticide with full compliance to OECD Test Guideline 503 fate studies.Exploiting Differential Halogen Reactivity: Orthogonal Palladium-Catalysed Cross-CouplingsThe intrinsic oxidative addition bias of Pd⁰ toward C5–Br over C2–Cl makes 5-bromo-2-chlorothiazole a benchmark substrate for sequential carbon–carbon bond construction in polypharmacophore libraries. A chemo-selective Suzuki coupling conducted in a 30 L jacketed baffled reactor with a pitched-blade turbine demonstrates the kinetic window available. With aryl boronic acid (1.08 eq), Na₂CO₃ (3.0 eq), and a degassed THF–water mixture (3:1 v/v), Pd(PPh₃)₄ (0.3 mol%) gives complete C5–Br consumption within 4 h at 55 ± 2 °C. Under these conditions, C2–Cl retention exceeds 98.5% as quantified by GC-MS extracted-ion chromatograms at m/z 179/181 (chlorine isotope pattern). Elevating the jacket temperature to 85 °C erodes this fidelity: C2–Cl participation rises to 7–12%, forming a borylated by-product that complicates crystallisation. The table below collates performance data for alternative ligand–metal combinations adapted from multi-kilo campaigns and patent exemplifications.
Buchwald–Hartwig Amination Selectivity When Both Bromine and Chlorine Are PresentUtilising 5-bromo-2-chlorothiazole as an electrophile for C–N bond formation pits the high innate reactivity of C5–Br against the attenuated lability of C2–Cl under strongly basic conditions. In a representative protocol targeting a CNS-penetrant histamine H₃ receptor candidate, a 2 L three-neck flask is charged with Pd₂(dba)₃ (0.03 eq), BrettPhos (0.09 eq), and sodium tert-butoxide (1.4 eq) inside a glovebox maintaining <1 ppm O₂ and <1 ppm H₂O. The thiazole (1.0 eq) and N-Boc-piperazine (1.2 eq) are added as a pre-mixed toluene solution. Heating to 100 °C for 16 h delivers the C5-aminated product with 91:6 selectivity over the C2-isomer, as determined by UPLC-ELSD. Selectivity is highly sensitive to the steric bulk of the phosphine ligand: switching to P(t-Bu)₃ drops the product ratio to 65:28, because the less congested palladium centre undergoes oxidative addition with C2–Cl at a competitive rate. On a pilot scale, 10–15% w/w of dehalogenated side products are tracked by LC–MS and must be purged by normal-phase chromatography with a silica bed residence time of >8 min. In-process pH measurement is non-negotiable: residual NaOtBu above 0.02 M after reaction quench deprotonates the product thiazole C2–H, promoting onward base-mediated chloride hydrolysis to the hydroxythiazole, which crystallises as a persistent impurity in the final API.A convergent route to next-generation bromodomain BET inhibitors utilises 5-bromo-2-chlorothiazole as the electrophilic warhead for installing a 3,5-dimethylisoxazole fragment via Suzuki coupling, leaving the chlorine intact for a subsequent SₙAr with a piperazine-linked triazolopyridazine. In a process executed in a 10 L Hastelloy reactor, the first coupling employs the Pd(OAc)₂/SPhos system described earlier, with potassium carbonate substituted to reduce base-catalysed ester hydrolysis in the boronate partner. The isolated intermediate is not dried entirely but retained as a toluene wet cake (LOD 18–22%) to prevent agglomeration that retards the rate of the second displacement step. That SₙAr is run in DMSO at 120 °C with 2.5 eq of DIPEA, and complete consumption of the chloride requires 36 h. Real-time ¹⁹F NMR (using a 0.5% 4-fluoroanisole internal standard) replaces intermittent sampling and reduces operator exposure to the genotoxic intermediate. The finished drug substance intermediate is crystallised from ethyl acetate/heptane with a final purity of 99.7% area by HPLC (UV 254 nm) and a residual DMSO content below 0.15%, meeting the ICH M7 limit for the alkyl chloride alert structure by purge factor calculation.A monomeric electron-accepting unit for deep-blue thermally activated delayed fluorescence emitters is accessed by magnesium-mediated Kumada coupling of 5-bromo-2-chlorothiazole with 2,7-dibromo-9,9-dimethylfluorene. The coupling is conducted in a 500 mL jacketed vessel under a positive argon atmosphere using turbo-Grignard reagent iPrMgCl·LiCl (1.05 eq) at −10 °C to generate the heteroaryl magnesium species in situ. Transmetallation with ZnCl₂ (1.2 eq) before introducing Pd(PPh₃)₄ (1.5 mol%) and the dibromofluorene (1.0 eq) ensures monofunctionalisation at the sterically less hindered C7-position of fluorene with 73% isolated yield after gradient sublimation (240 °C, 10⁻⁶ mbar). The chlorine substituent on the thiazole ring is preserved through the sublimation step and later participates in a hindered Suzuki coupling with a meta-terphenyl boronic acid to tune the electroluminescence maximum to 457 nm. The resulting emitter, when doped at 12 wt% into a 9,9′-spirobifluorene host, exhibits a photoluminescence quantum yield of 0.84 measured via integrating sphere per DIN EN 61331-3, and the sublimed intermediate itself conforms to purity requirements for organic electronic materials: total metal content ≤20 ppm, chloride specification ≤100 ppm by combustion ion chromatography per ASTM D7359, and an optical density at 400 nm below 0.08 Au/g in tetrahydrofuran. Such data support the role of the non-cleaved chlorine as a latent reactive handle that survives high-vacuum processing, a practical advantage over bromine-only analogues that suffer protodehalogenation during device fabrication. |
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5-Bromo-2-chlorothiazole (CAS 3034-56-8) enters synthetic pathways as a bifunctionalized, electron-deficient heterocyclic building block supplied as a clear, pale yellow liquid with a minimum purity of 97.0% determined by gas chromatography with flame ionization detection (GC-FID) using a DB-5 capillary column (15 m × 0.25 mm × 0.25 µm film). The molecular formula C₃HBrClNS corresponds to a molecular weight of 198.47 g/mol. At 25 °C, the bulk liquid exhibits a density of 1.933 g/mL and a refractive index of n20/D 1.617. The distillation range under reduced pressure (0.5 mmHg) is sharply defined at 75–78 °C, permitting purification by short-path vacuum evaporation with a 100 mm Vigreux column. Storage under a static argon blanket at 2–8 °C, shielded from light, suppresses photolytic dehalogenation and maintains spec integrity for 12 months from the date of manufacture. This heterocycle’s synthetic value arises from a programmed reactivity gradient between the bromine at the 5-position and the chlorine at the 2-position, enabling sequential orthogonal functionalization without intermediate protecting-group chemistry.
The table below consolidates physical constants and purity metrics recorded on production batches released under an ISO 9001:2015 quality management system, with lot-specific certificates of analysis available for each shipment.
| Property | Specification / Typical Value | Test Method |
|---|---|---|
| Assay (GC, area %) | ≥ 97.0% | In-house GC-FID; DB-5 15 m × 0.25 mm × 0.25 μm film, He carrier 1.2 mL/min |
| Water content (Karl Fischer) | ≤ 0.5% | ASTM D6304-16e1 (coulometric, oven method) |
| Refractive index (n20/D) | 1.616–1.619 | ISO 6331:2017 (Abbe refractometer, sodium D line) |
| Density (25 °C) | 1.930–1.935 g/mL | Oscillating U-tube, calibrated with degassed water |
| Boiling range (0.5 mmHg) | 75–78 °C | Microdistillation apparatus, dynamic vacuum |
| Appearance | Clear, pale yellow liquid; no visible particulates | Visual inspection against backlight, Room 20–25 °C |
The chemoselectivity observed with 5-bromo-2-chlorothiazole originates in the disparate carbon–halogen bond dissociation energies and the electronic landscape of the thiazole ring. The C–Br bond at the 5-position requires approximately 66 kcal/mol for homolytic cleavage, whereas the C–Cl bond at the 2-position is substantially stronger at 78 kcal/mol. In palladium-catalyzed cross-couplings, oxidative addition of Pd(0) into the weaker C–Br bond proceeds with a rate constant typically 10²–10³ times greater under identical ligand and solvent conditions. The electron-withdrawing nitrogen and sulfur atoms embedded in the ring further polarize the C‑2 position, increasing the ionic character of the C–Cl linkage and rendering it less susceptible to the two-electron oxidative addition manifold. Experimental evidence from competitive coupling experiments conducted in a parallel reactor block (Chemspeed Accelerator SLT100, 8 × 15 mL glass vials, overhead stirring at 600 rpm) confirms that when equimolar quantities of phenylboronic acid are employed with Pd(PPh₃)₄ (2 mol%) and K₂CO₃ (2 equiv) in DME/H₂O (3:1 v/v) at 80 °C, GC conversion at the bromine site reaches >95% within 6 hours, while the chlorine substituent remains completely unreacted over 24 hours.
In practical batch manufacturing, the first coupling is routinely executed in a 500 mL jacketed glass reactor with mechanical stirring (250 rpm), a thermocouple probe immersed in the liquid phase, and nitrogen inerting. The typical charge consists of 5-bromo-2-chlorothiazole (50 mmol, 9.92 g), phenylboronic acid (55 mmol, 6.71 g), Pd(PPh₃)₄ (1.0 mmol, 1.16 g), and K₂CO₃ (100 mmol, 13.82 g) in degassed DME (150 mL) and water (50 mL). The jacket temperature is held at 85 °C to maintain an internal reaction temperature of 80 ± 2 °C. After 8 hours, HPLC analysis (C18 column, 254 nm) indicates disappearance of the starting material. The organic phase is separated and washed with brine (2 × 100 mL), dried over anhydrous Na₂SO₄, and concentrated on a rotary evaporator with a bath temperature of 40 °C. Short-path chromatography on silica gel (230–400 mesh) using a hexane/ethyl acetate gradient from 100:0 to 95:5 yields the 5-phenyl-2-chlorothiazole intermediate, typically with an isolated purity exceeding 98% by GC and a yield of 87–91% as recorded across 12 consecutive production batches.
The most direct structural analogue, 2,5-dibromothiazole, presents both halogen atoms as bromine, generating a near-symmetric reactivity profile. Under the identical Suzuki conditions described above, the bis-brominated substrate yields a statistical mixture of 2-phenyl, 5-phenyl, and 2,5-diphenyl derivatives in a ratio of approximately 1:1:2, as determined by GC-MS total ion current integration. Complete suppression of diarylation requires lowering the reaction temperature to 40 °C and increasing the ligand loading to 10 mol% P(t-Bu)₃, which slows the consumption of the starting material to >24 hours and drops the isolated yield of the mono-coupled species to 55–60%. By contrast, the 5-bromo-2-chlorothiazole scaffold uncouples this timing electronically, allowing sequential elaboration without temperature program interruption and without the need for precisely controlled sub-stoichiometric additions of the arylboronic acid. For synthetic programs requiring a single regiochemical outcome, the chlorobromo system eliminates the multi-step chromatographic separations that plague the dibromo route. The following table captures the operational contrasts between the two building blocks in a Suzuki-Miyaura manifold measured under a standard set of conditions (Pd(PPh₃)₄ 2 mol%, K₂CO₃ 2 equiv, DME/H₂O 3:1, 80 °C).
| Parameter | 5-Bromo-2-chlorothiazole | 2,5-Dibromothiazole |
|---|---|---|
| Mono-coupling conversion (GC, 6 h) | >95% | 42% (sum of both regioisomers) |
| Diarylated byproduct (LCMS) | <5% | 31% |
| Optimal temperature for regioselectivity | 80 °C | 40 °C |
| Required catalyst loading for >90% mono-selectivity | 2 mol% Pd(PPh₃)₄ | 10 mol% Pd(PPh₃)₄ / 20 mol% P(t-Bu)₃ |
| Isolated mono-coupled yield (typical) | 87–91% | 55–60% |
| Purification complexity | Simple flash column, single isocratic step | Preparative HPLC required to separate regioisomers |
The 2-chloro substituent, once the 5-position is fully elaborated, becomes the focus of a second coupling event that exploits newer catalyst systems designed for aryl chlorides. Standard Pd(PPh₃)₄ lacks the electron-rich character needed to insert into the C–Cl bond of a thiazole; however, the combination of Pd₂(dba)₃ (2 mol%) with XPhos (5 mol%) and Cs₂CO₃ (3 equiv) in toluene or o-xylene at 120–130 °C drives oxidative addition into the C2–Cl bond with complete conversion within 16–20 hours. In a 100 mL pressure tube charged with 5-aryl-2-chlorothiazole (10 mmol), the second arylboronic acid (12 mmol), Pd₂(dba)₃ (0.2 mmol), XPhos (0.5 mmol), and Cs₂CO₃ (30 mmol), the tube is evacuated and backfilled with argon three times before being sealed and immersed in an oil bath at 125 °C for 18 hours. LCMS analysis at the end point reveals full consumption of the chlorothiazole; the diaryl thiazole is obtained after aqueous workup and flash chromatography in 78–83% yield. The same catalytic manifold can be applied to an SNAr pathway using secondary amines: pyrrolidine in DMF at 120 °C displaces the chlorine with a half-life of 3.5 hours, providing an amine-substituted thiazole without palladium. The chlorine thus functions as both a blocking group in the first coupling and a latent synthetic handle for nucleophilic aromatic substitution or demanding cross-couplings.
The dichloro analogue, 2,5-dichlorothiazole, lacks the necessary reactivity differential to enable selective mono-functionalization, as both C–Cl bonds remain inert under mild NMR-tube conditions and require forcing oxidative addition protocols (Pd(PCy₃)₂, 140 °C), at which temperature selectivity erodes. 5-Bromo-2-methylthiazole, by contrast, places a non-halogen substituent at the 2-position, surrendering the second synthetic handle entirely. The dual-halogen architecture of 5-bromo-2-chlorothiazole therefore delivers a unique stagewise diversification logic that is not replicated by closely related thiazole building blocks available in bulk quantities.
Supply-chain and handling specifications: The product is packaged under a positive argon headspace in amber glass bottles sealed with PTFE-lined phenolic caps, offered in 25 g and 100 g research quantities. Bulk commercial orders are filled in 1 kg and 5 kg HDPE drums with internal nitrogen pressurization and desiccant inserts. It is manufactured under a process validated according to ICH Q7A guidance for active pharmaceutical ingredient starting materials, with a mass balance closure typically exceeding 98.5%. The compound is listed on the TSCA inventory and conforms to EU REACH requirements for substances manufactured or imported in quantities below 10 tonnes/year. Decomposition is observed when exposed to strong bases (DBU, NaH) at ambient temperature for extended periods, generating debrominated thiazole byproducts detectable by GC at m/z = 119; combination with pyrophoric reagents or LiAlH₄ should be avoided unless controlled addition with syringe pump at -78 °C is feasible. Safety data sheets (SDS) in compliance with GHS Revision 8 are provided with every shipment.
