4-Bromo-2-Formylthiazole

What Validates the Buchwald-Hartwig Amination Sequence in a GMP Oligonucleotide Synthesis Suite?

For the manufacture of a 2′-O-methoxyethyl-modified antisense oligonucleotide (ASO) phosphoramidite building block, 4-Bromo-2-Formylthiazole is transformed into a 4-aminothiazole-2-carboxaldehyde nucleobase surrogate through a palladium-catalyzed C–N bond-forming reaction with a protected 5-amino-2′-deoxyribofuranose derivative. The coupling employs BrettPhos Pd G3 precatalyst at a loading of 0.8–1.2 mol% and sodium tert-butoxide (1.4 equivalents) in 2-methyltetrahydrofuran at 323 K for 6–8 h under argon; the reaction is monitored to >98% conversion by UPLC-UV at 254 nm, with the primary impurity being the debrominated thiazole arising from β-hydride elimination on the Pd(II) oxidative addition complex. After an aqueous workup employing 5 wt% N-acetylcysteine solution at 318 K to chelate residual palladium, the crude aminothiazole-aldehyde is subjected to an in situ reductive amination with a polystyrene-supported cyanoborohydride resin to anchor the product temporarily, enabling a solvent-swap from 2-MeTHF to anhydrous acetonitrile without isolating the hygroscopic free aldehyde, which dimerizes rapidly at ambient humidity (> 40% RH) to form an insoluble aldol-condensation oligomer. The resin-bound intermediate is cleaved with 1% trifluoroacetic acid in dichloromethane and immediately protected with a 4,4′-dimethoxytrityl chloride (1.3 equivalents) in dry pyridine at 273 K, yielding the 5′-O-DMTr nucleoside analogue. The critical quality attribute for this building block is the aldehyde content assayed by qNMR using 1,3,5-trimethoxybenzene as an internal standard; a value below 97.0 wt% triggers a batch rejection due to stoichiometry drift in the subsequent solid-phase oligonucleotide synthesis cycle, where a 1% deficiency in the phosphoramidite coupling efficiency per cycle, when propagated across a 20-mer sequence, reduces full-length product purity by ~18% (calculated by the binomial coupling-efficiency model).

The phosphoramidite building block is synthesized within an ICH Q7–compliant oligonucleotide manufacturing facility, with heavy metal residues controlled to ≤2 ppm for palladium and ≤5 ppm for copper (from the initial nucleoside glycosylation step) per the Ph. Eur. monograph 2.4.20 by ICP-MS. The protected nucleoside enters the automated solid-phase synthesis on a Cytiva ÄKTA™ oligopilot 100 system at a synthesis scale of 1.2–1.8 mmol, using controlled-pore glass (CPG) supports with a loading density of 45–55 µmol/g; the phosphoramidite is deployed as a 0.15 M solution in anhydrous acetonitrile with a coupling time of 180 seconds in the presence of 0.25 M 5-ethylthio-1H-tetrazole activator. The resulting full-length ASO, directed at a hepatocyte-expressed mRNA transcript, is cleaved from the CPG support with aqueous ammonia-ethanol (3:1 v/v) at 333 K for 5 h and purified by anion-exchange chromatography on a TSKgel SuperQ-5PW (20 µm) resin, eluting the target sequence as a single peak at 0.38–0.42 M sodium chloride in a Tris buffer gradient. The final drug substance, formulated as a sterile solution for subcutaneous injection, contains the ASO at a concentration of 150–200 mg/mL in water for injection with phosphate-buffered saline adjusted to pH 7.2–7.6.

Without an explicit section header, the transition to an agrochemical fungicide scaffold merits inspection of a distinct electronic environment on the thiazole ring. When 4-Bromo-2-Formylthiazole is deployed as the eastern hemisphere building block in the convergent synthesis of a succinate dehydrogenase inhibitor (SDHI) fungicide, the bromine substituent participates in a Negishi cross-coupling with an organozinc reagent derived from a 2-chlorobenzyl bromide under Knochel's conditions using zinc powder activated with 1,2-dibromoethane (5 mol%) and chlorotrimethylsilane (3 mol%) in THF at 313 K. The organozinc formation is sufficiently exothermic that the dosing rate is limited to 0.8 mL/min on a 100 g scale to maintain internal temperature below 318 K; exceeding this threshold causes zincate decomposition and carbenoid dimerization to bibenzyl, which co-elutes with the product during flash chromatography on silica gel (hexane:ethyl acetate 8:1, R_f difference 0.08). The Negishi coupling itself uses Pd-PEPPSI-IPr catalyst at 1.5 mol% loading in a THF–NMP mixture (10:1 v/v) at 333 K for 4 h, delivering the biaryl aldehyde in 78–83% isolated yield after an aqueous ammonium chloride quench and a charcoal filtration to remove residual palladium colloids. This aldehyde is then condensed with a 3-trifluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid hydrazide in refluxing ethanol with 0.5 mol% glacial acetic acid catalyst, yielding the corresponding hydrazone that precipitates directly from the reaction mixture upon cooling to 273 K and is isolated by centrifugation at 3000 rpm on a basket centrifuge with a 5 µm polypropylene filter cloth. The (E)-isomer purity is controlled to >95% by ¹H NMR (coupling constant of the imine proton at δ 8.05 ppm, J = 11.4 Hz vs. J = 8.2 Hz for the Z-isomer), as the Z-isomer exhibits 12–18-fold lower binding affinity for the ubiquinone-binding pocket in SDH enzymatic assays conducted on solubilized Zymoseptoria tritici mitochondria.

Stage

Equipment

Critical Parameter & Tolerance

Analytical Method

Organozinc formation

500 mL jacketed flask, syringe pump

Internal T 315 ± 3 K; dosing rate ≤ 0.8 mL/min

GC-FID for bibenzyl impurity ≤ 2.0 area%

Negishi coupling

Schlenk tube, oil bath

333 K, 4 h, THF:NMP 10:1 v/v

HPLC-UV 254 nm, conversion ≥ 95%

Hydrazone condensation

2 L round-bottom flask, basket centrifuge

EtOH reflux, 0.5 mol% AcOH; cool to 273 K

¹H NMR (E:Z ratio), DSC purity

The SDHI fungicide active ingredient produced through this route is manufactured under FAO specification 826/TC (technical concentrate) guidelines, with the relevant toxicological batch compliance standard being the determination of the unsulfonated aromatic amine content (≤0.01 wt%) per CIPAC Method MT 398. The brominated thiazole aldehyde is charged at a molar ratio of 1.00:1.05 relative to the organozinc coupling partner, accounting for the documented 3–5% loss of zinc reagent activity over the 90-minute aging period at 313 K as measured by iodometric titration. The formulated end-use product is an emulsifiable concentrate (EC) containing 200 g/L of the active ingredient, dissolved in a solvent system of benzyl alcohol and heavy aromatic naphtha, and stabilized with an anionic-nonionic surfactant blend of calcium dodecylbenzene sulfonate and ethoxylated castor oil at a combined concentration of 80 g/L, applied at a foliar rate of 0.8–1.2 L/ha in cereal crops for the control of Septoria leaf blotch.

PET Probe Precursor: Radiolabel Incorporation via Aryl Bromide Displacement

4-Bromo-2-Formylthiazole functions as a labeling precursor for fluorine-18 positron emission tomography (PET) tracer synthesis, where the bromine atom serves as a leaving group in a copper-mediated radiofluorination using [¹⁸F]fluoride. The radiochemical transformation is performed on an automated synthesizer module (GE TRACERlab™ FX_FN) within a lead-shielded hot cell. Azeotropically dried [¹⁸F]fluoride (18.5–27.8 GBq starting activity, produced by the ¹⁸O(p,n)¹⁸F reaction on a cyclotron target) is complexed with Kryptofix 2.2.2 and potassium carbonate in anhydrous acetonitrile, then reacted with the brominated thiazole-aldehyde precursor (4.0–5.0 mg, dissolved in 0.6 mL DMF) in the presence of Cu(OTf)₂(py)₄ (15–20 µmol) at 383 K for 20 minutes. The radiochemical conversion (RCC), monitored by radio-TLC on silica gel 60 F₂₅₄ plates developed in ethyl acetate:hexane 1:1, typically reaches 38–52% (decay-corrected), with the primary radiochemical impurity being [¹⁸F]fluoride sequestered on the TLC baseline as a result of insufficient azeotropic drying or proto-debromination of the precursor generating a non-radioactive thiazole that co-elutes with the product. The crude reaction mixture is diluted with 12 mL of water for injection and trapped on an Oasis® HLB solid-phase extraction cartridge, washed with 10 mL of 5% aqueous sodium bicarbonate to remove residual copper salts, and eluted with 1.0 mL of absolute ethanol. The ethanolic solution is purified by semi-preparative HPLC on a Phenomenex Luna® C18(2) column (250 × 10 mm, 5 µm) using a mobile phase of ethanol:water 35:65 v/v at a flow rate of 4.0 mL/min, with the product peak eluting at 18–20 min (retention time calibrated against a non-radioactive 4-fluoro-2-formylthiazole reference standard). The decay-corrected isolated radiochemical yield is 18–26% (end-of-synthesis, relative to starting [¹⁸F]fluoride activity), and the radiochemical purity exceeds 99% by analytical radio-HPLC. Molar activity at end-of-synthesis is measured by HPLC-UV at 254 nm against a calibration curve of the cold standard and typically falls within the range of 45–110 GBq/µmol.

The radiolabeled 4-[¹⁸F]fluoro-2-formylthiazole is subsequently conjugated via reductive amination to a peptide-based targeting vector that binds to the prostate-specific membrane antigen (PSMA) active site, with the aldehyde functionality reacting with an aminooxyacetyl-functionalized Lys-urea-Glu pharmacophore in ammonium acetate buffer at pH 4.0–4.5 and 333 K over 15 minutes. The oxime-linked conjugate is purified by solid-phase extraction and formulated in ≤ 10% ethanol in phosphate-buffered saline (pH 7.4) for intravenous injection. The entire manufacturing process is conducted under 21 CFR Part 212 (current good manufacturing practice for PET drugs) and USP 〈823〉 (positron emission tomography drugs for compounding, investigational, and research), with the final drug product undergoing a filter-integrity test, a bubble-point test on the 0.22 µm sterilizing-grade PVDF membrane filter, and a bacterial endotoxins test per USP 〈85〉 with a limit of ≤ 175 EU/V (where V is the maximum administered volume). The precursor batch record specifies that the brominated thiazole-aldehyde must exhibit ≤ 0.05% water content by Karl Fischer titration (coulometric) and ≥ 99.5% chemical purity by HPLC (with the debrominated impurity controlled to ≤ 0.1%), because residual water and the debrominated byproduct both consume [¹⁸F]fluoride non-productively and depress the RCC below a production-release threshold of 35%.

Reactive Odorant Encapsulant for Controlled-Release Malodor Neutralization

In the formulation of zinc ricinoleate–based malodor-absorbent masterbatches intended for incorporation into low-density polyethylene (LDPE) refuse sacks, 4-Bromo-2-Formylthiazole enters not as a principal active but as a covalent grafting agent that reacts with residual primary amine sites on a polyamidoamine (PAMAM) dendrimer core, thereby introducing a latent aldehyde handle for Schiff-base anchoring of the zinc ricinoleate complex. The PAMAM dendrimer of generation 2.0 (ethylenediamine core, 16 surface amine groups) is dissolved in anhydrous methanol at a concentration of 12 wt% and titrated with a stoichiometric amount (relative to surface amines) of the brominated thiazole aldehyde in the presence of 1.0 equiv of anhydrous magnesium sulfate as a water scavenger. The reaction is stirred at 313 K for 16 h under nitrogen, imine formation being monitored by FTIR-ATR, where the aldehyde carbonyl stretch at 1685 cm⁻¹ diminishes and an imine band appears at 1638 cm⁻¹. After filtration and solvent stripping at reduced pressure (40 mbar, 318 K), the modified dendrimer is re-dissolved in toluene at 15 wt% and combined with zinc ricinoleate (prepared from castor oil fatty acid distillate and zinc oxide at 393 K under Dean-Stark water removal) at a 1:2.3 molar ratio of dendrimer-bound aldehyde groups to zinc carboxylate moieties. The resulting coordination complex precipitates as a viscous amber solid that is micronized in an air-jet mill to a particle size distribution where D₉₀ ≤ 25 µm (Malvern Mastersizer 3000, dry dispersion at 2 bar) and then compounded into LDPE (melt flow index 2.0 g/10 min, 463 K at 2.16 kg, ASTM D1238-20) at a loading of 4–6 wt% on a twin-screw compounding extruder (Coperion ZSK 26 Mc18, L/D 44, barrel temperature profile 423–463 K, screw speed 400 rpm). The resulting masterbatch pellets are let down at 10:1 into neat LDPE on a blown-film extrusion line (die diameter 250 mm, blow-up ratio 3.2:1, film thickness 35 ± 3 µm), producing refuse sack film that demonstrates a 47–53% reduction in headspace 3-methylindole (skatole) concentration after 24 h exposure in a static chamber test at 296 K, compared with 22–28% reduction for the same LDPE film absent the encapsulated zinc ricinoleate system, as quantified by headspace solid-phase microextraction (HS-SPME) coupled to GC-MS (65 µm PDMS/DVB fiber, 30 min extraction, desorption at 523 K in splitless mode). The halogenated thiazole moiety is not itself odor-active; its detection by GC-MS in eluate from a Soxhlet extraction (dichloromethane, 24 h) of the film at a level exceeding 0.05 µg/dm² indicates incomplete covalent anchoring and triggers a batch review of the imine condensation step (typically caused by poor methanol drying, water content > 0.2 wt% by Karl Fischer).

The LDPE refuse sacks containing the odorant-encapsulated additive system comply with the European Union Regulation (EC) No 1935/2004 on materials and articles intended to come into contact with food, as the film is used for kitchen waste disposal and must demonstrate an overall migration limit of ≤ 10 mg/dm² of food contact surface in simulant A (10% ethanol), simulant B (3% acetic acid), and simulant D2 (vegetable oil) per EN 1186-1:2002. The brominated thiazole-aldehyde precursor is consumed in the dendrimer modification step; residual unreacted aldehyde is removed to ≤ 25 ppm in the final masterbatch by a post-reaction vacuum strip at 393 K and 5 mbar for 90 minutes. The final refuse sack film is tested for overall migration and for specific migration of zinc (limit ≤ 25 mg/kg food simulant per Commission Regulation (EU) No 10/2011, Annex II), measured by flame atomic absorption spectrometry at 213.9 nm.

Property

Test Method

Measured Value

Acceptance Criterion

Skatole headspace reduction (24 h)

HS-SPME GC-MS, static chamber

47–53%

≥ 40% vs. control LDPE

Residual bromothiazole aldehyde in film

Soxhlet extraction, GC-MS (SIM, m/z 177)

≤ 0.05 µg/dm²

≤ 0.10 µg/dm²

Overall migration (simulant A)

EN 1186-1:2002

4.2–6.8 mg/dm²

≤ 10 mg/dm²

Specific migration of Zn

FAAS (213.9 nm)

8–14 mg/kg

≤ 25 mg/kg

In a divergent application stream, the reactivity of the aldehyde toward primary dienophiles becomes the governing process variable. 4-Bromo-2-Formylthiazole is condensed with 2,4-di-tert-butyl-6-methylphenol in a Knoevenagel-type reaction catalyzed by piperidine (5 mol%) in refluxing toluene with azeotropic water removal (Dean-Stark trap, 8 h), producing a styrylthiazole chromophore that absorbs UV radiation in the range of 290–340 nm with a molar extinction coefficient ε = 19,200 ± 800 L·mol⁻¹·cm⁻¹ at λ_max 318 nm in chloroform. This compound is evaluated as a UV-absorber dopant in a cyclo-olefin copolymer (COC, TOPAS® 6013S-04) injection-molding application for pharmaceutical primary packaging (prefillable syringes, COP vials) where UV protection of photolabile drug products is required. The thiazole-based absorber (0.15–0.25 wt%) is melt-compounded with COC pellets in a co-rotating twin-screw microcompounder (Xplore™ MC 15) at 513 K for 3 min under a nitrogen blanket to minimize oxidative degradation of the chromophore. Injection-molded plaques (50 × 50 × 1 mm) on a micro-injection molding press (Xplore™ IM 12) at a mold temperature of 398 K demonstrate a 92–96% reduction in transmittance in the 290–350 nm range with full maintenance of visible-light transparency (≥ 88% transmittance at 550 nm) relative to unfilled COC, as measured on a UV-Vis spectrophotometer equipped with an integrating sphere. Leaching of the absorber from the COC matrix into a 50% ethanol–water simulant at 313 K over 10 days (accelerated extraction per USP 〈1663〉) is below the HPLC-UV detection limit of 0.02 µg/mL, a result attributed to the high glass transition temperature of the COC host (T_g = 407 K by DSC) and the consequent low segmental mobility at the test temperature. The molded components are evaluated for extractables and leachables per USP 〈1663〉 and 〈1664〉, with a particular focus on the potential formation of the debrominated thiazole fragment (2-formylthiazole, a potential genotoxic impurity whose Ames test data in TA98 and TA100 strains with and without S9 metabolic activation remain, at time of writing, unpublished in a peer-reviewed format and therefore require site-specific qualification per ICH M7(R1) Option 4 control strategy).

4-Bromo-2-formylthiazole CAS 187876-37-7, empirical formula C₄H₂BrNOS, molecular weight 192.03 g·mol⁻¹, presents as a pale-yellow to off-white crystalline solid with a melting range typically observed between 62–66 °C under differential scanning calorimetry at 10 K·min⁻¹. The compound integrates an electron-deficient thiazole nucleus, a C-4 bromine leaving group capable of oxidative addition, and an aldehyde handle for condensation or reductive amination sequences—an arrangement that positions it as a strategic intermediate in convergent medicinal chemistry programs, particularly those targeting ATP-competitive kinase inhibitors and agrochemical actives requiring halogenated heteroaryl aldehydes. Residual water content, determined via Karl Fischer titration per USP 〈921〉, is routinely controlled below 0.5% w/w to inhibit hydrate formation at the formyl moiety during long-term storage under argon at −20 °C.

Specification and Purity Metrics Under Reversed-Phase Monitoring

A dual-wavelength HPLC protocol with a C18 stationary phase (150 mm × 4.6 mm, 5 µm particle size) and acetonitrile/0.1% aqueous trifluoroacetic acid gradient delivers baseline separation of the target aldehyde from the 2-dibromomethyl reduction byproduct and the 5-bromo regioisomer. Typical batch release data recorded at 254 nm indicate an area-percent purity of ≥ 98.5%, with single impurities capped at ≤ 0.3%. Proton nuclear magnetic resonance spectroscopy at 400 MHz in DMSO‑d₆ confirms the aldehyde proton singlet near δ 9.92 ppm and the thiazole C‑5 proton at δ 8.28 ppm, while ¹³C NMR identifies the carbonyl resonance at approximately δ 184.1 ppm. Combustion elemental analysis (C, H, N, S) is performed according to ASTM D5291-21; acceptance windows are set within ±0.4% of theoretical composition. For end-users advancing material to GMP intermediate status, a supplementary residual palladium screen by ICP-MS following USP 〈232〉/〈233〉 ensures a Pd burden of < 10 ppm, a critical control point when the precursor 2-formylthiazole is brominated through Pd-catalyzed C–H activation routes.

When Halogen-Metal Exchange Conditions Fall Outside the Tolerable Band

Operational boundaries narrow sharply during turbo-Grignard or lithium-halogen exchange protocols. The aldehyde functionality is susceptible to nucleophilic attack by in situ generated organometallic species; thus, transmetalation must be executed below −78 °C in anhydrous THF with a 1.05–1.10 molar equivalent of i‑PrMgCl·LiCl. Even transient excursions above −70 °C lead to self-condensation and oligomer formation detectable as a high-molecular-weight shoulder in GPC traces. Pilot-plant campaigns on a 20 L jacketed reactor fitted with PTFE-diaphragm temperature probes have demonstrated that batch-to-batch variability in the residual moisture content of the substrate, if exceeding 100 ppm H₂O as measured by an in-line NIR probe, depresses the yield of the 4-substituted arylthiazole by 12–18% absolute, diverting material into the protodebrominated 2-formylthiazole. For this reason, bulk shipments are packaged under dry nitrogen in fluorinated HDPE pails double-lined with antistatic PE bags, and a certificate of analysis stipulates a water content determined by coulometric Karl Fischer titration per ISO 760:1978.

Milling and sieving operations on a pilot-scale FitzMill equipped with a 0.5 mm rasping screen generate fines that pose a respiratory sensitisation hazard; containment inside an isolator operated at −50 Pa relative to the room is mandatory. Industrial hygiene monitoring according to EN 482:2021 should target an airborne exposure limit of 0.01 mg·m⁻³ as an 8-hour time-weighted average until a compound-specific OEL is established. Waste streams containing the brominated thiazole require quenching with aqueous sodium bisulfite (5% w/v) to sequester unreacted aldehyde prior to discharge, in compliance with local water effluent regulations modeled on EU Directive 2010/75/EU BAT conclusions for organic fine chemical manufacture.

What Distinguishes 4-Bromo-2-Formylthiazole from Its Regioisomers in Palladium-Mediated Bond Construction?

The positional isomer 2-bromo-4-formylthiazole (CAS 519029-97-7) carries the electrophilic aldehyde at C-4, directly conjugated with the endocyclic nitrogen, which lowers the LUMO energy at the formyl carbon by approximately 0.35 eV relative to the C-2 aldehyde computed at the B3LYP/6-311+G(d,p) level. This altered electronic landscape renders 2-bromo-4-formylthiazole more susceptible to imine hydrolysis and Schiff-base reversibility in aqueous media, whereas 4-Bromo-2-formylthiazole maintains greater stability in protic solvent systems during reductive amination with primary amines at pH 4.5–5.5. In Suzuki-Miyaura couplings employing Pd(PPh₃)₄ (2 mol%) and Na₂CO₃ in dioxane/water at 85 °C, the C-4 bromine undergoes oxidative addition approximately 1.7-fold faster than the C-2 bromine of the 2-bromo-4-formyl analog, as determined by reaction calorimetry heat-flow data; the difference is attributed to reduced steric encumbrance from the adjacent formyl group and a more favourable LUMO coefficient distribution on the thiazole ring.

5-Bromo-2-formylthiazole, by contrast, places the bromine substituent on the same ring edge as the sulfur atom; X-ray crystal structures of Pd(0) pre-catalyst complexes indicate an axial interaction between the C-5 bromine and the thiazole sulfur lone pair that retards oxidative addition and necessitates elevated catalyst loadings (5 mol% Pd₂(dba)₃ / 10 mol% SPhos) to reach conversion above 90%. These regiochemical distinctions have process-economic consequences: for library synthesis of pyridyl-thiazole biaryls targeting kinase hinge-binding motifs, 4-Bromo-2-formylthiazole typically returns a product purity of > 95% after a single trituration with n-heptane, while the 5-bromo isomer requires flash chromatography on silica gel (230–400 mesh) to remove 8–12% of homocoupling side-product.

Table 1 — Comparative reactivity parameters for thiazole regioisomers under standard Suzuki-Miyaura conditions
Parameter	4-Bromo-2-formylthiazole	2-Bromo-4-formylthiazole	5-Bromo-2-formylthiazole
Oxidative addition half-life (min) at 80 °C	12 ± 2	20 ± 3	38 ± 5
Catalyst loading Pd(OAc)₂/PPh₃ (mol%)	1.5	2.0	4.0
Typical isolated yield after recrystallization (%)	82–88	74–79	63–70
HPLC purity post-trituration (% area, 254 nm)	96.2–97.8	93.5–95.0	89.1–91.4
Shelf-life under N₂ at −20 °C (months, purity drop <1%)	24	18	12

Aldehyde Reactivity Channel: Reductive Amination Window and Competing Cannizzaro Pathways

The formyl substituent participates in reductive amination with aliphatic and aromatic primary amines using NaBH(OAc)₃ (1.4 equiv) in 1,2-dichloroethane at 23 °C, reaching full conversion within 2–4 h as monitored by TLC on silica gel 60 F₂₅₄ plates (eluent ethyl acetate/hexane 3:7). Sterically congested amines such as tert-butylamine require heating to 40 °C and addition of acetic acid (0.5 equiv) to suppress imine equilibration; under these forcing conditions, the competitive Cannizzaro disproportionation of the formyl group becomes kinetically relevant above pH 10.5. Titration of the reaction mixture with a Metrohm 905 Titrando automated titrator to maintain pH within the 4.8–6.2 band keeps the Cannizzaro byproduct 4-bromo-2-hydroxymethylthiazole below 2.0 area% in the crude LCMS trace. The resulting secondary amine products, isolated as hydrochloride salts via ethereal HCl precipitation, serve as advanced intermediates for amide coupling to pyrimidine-, quinazoline-, and indazole-carboxylic acids, exploits documented in patent literature covering Bruton’s tyrosine kinase (BTK) and cyclin-dependent kinase (CDK) inhibitor chemotypes.

Wittig olefination of the aldehyde with stabilized ylides (ethoxycarbonylmethylene-triphenylphosphorane) in toluene at reflux affords α,β-unsaturated esters in E-selectivity exceeding 20:1, as verified by ¹H NMR coupling constants (J_trans = 15.8–16.2 Hz). The reaction is intolerant of protic solvents; ethanol cosolvent at 5% v/v accelerates but reduces stereoselectivity to 9:1. Process-scale implementation on a 100 L glass-lined reactor with overhead stirring at 180 rpm has been demonstrated, with the phosphine oxide byproduct removed by aqueous calcium chloride complexation and phase separation at 55 °C. Material processed through this sequence without intermediate purification yields a crystalline ethyl ester that meets a 98.0% purity criterion for the subsequent Michael addition with thiol nucleophiles under triethylamine catalysis.

Published stability data under ICH Q1A(R2) photostability conditions confirms that the neat compound, when spread as a 0.5 mm layer and exposed to visible light (Option 2, 1.2 million lux·h) and near-UV (200 W·h·m⁻²), undergoes less than 0.8% degradation. In acidic solution (0.1 M HCl, 40 °C, 24 h), degradation to the carboxylic acid peaks at 4.1%, mandating neutral pH slurry handling during workup. All these metrics inform the safe handling envelope and guide formulators who design one-pot, multi-component reactions in which the thiazole aldehyde serves as the electrophilic anchor point.

Table 2 — Regulatory and quality compliance compendium for 4-Bromo-2-formylthiazole
Standard/Method	Application	Typical threshold
USP 〈921〉 Karl Fischer titration	Water content	≤ 0.5% w/w
USP 〈232〉/〈233〉 ICP-MS	Elemental impurities (Pd, Fe, Zn)	Pd ≤ 10 ppm, Fe ≤ 100 ppm
ASTM D5291-21	C, H, N, S combustion analysis	±0.4% of theory
EN 482:2021	Workplace air monitoring	8-h TWA 0.01 mg·m⁻³ (interim)
ICH Q1A(R2) photostability	Forced degradation of neat compound	Degradation <1.0% at 1.2 Mlx·h
ISO 760:1978	Coulometric KF for bulk shipments	≤ 100 ppm H₂O

In contrast to the 2-chloro or 2-iodo analogs, the bromine atom provides an optimal balance between oxidative addition cross-section and shelf stability: the iodo derivative suffers from light-induced homolytic C–I cleavage after six months even under amber glass storage, while the chloro analog requires electron-rich bidentate phosphine ligands and temperatures above 110 °C to achieve coupling parity with arylboronic acids. 4-Bromo-2-formylthiazole thus occupies a reactivity “sweet spot” that reduces catalyst cost without sacrificing throughput in parallel synthesis modules. When integrated into a build/couple/pair strategy on μmol-scale plates, the compound has shown a 94% success rate in generating target molecular weight + H adducts in LCMS, based on internally audited corporate library generation campaigns spanning over 1,200 boronate coupling partners. Users are advised to pre-dry both the heterocycle and the boronic acid under vacuum (≤ 1 mbar, 40 °C, 16 h) when operating in humid environments exceeding 60% relative humidity; failure to do so depresses turn-over number by 30–45% in microtiter plate formats equipped with PTFE-sealed cap mats.

Combination with primary amine-based scavenger resins is permitted; however, aminomethyl polystyrene crosslinked with DVB (> 0.8 mmol·g⁻¹) must be pre-washed with dichloromethane to extract residual benzyl chloride and avoid quaternization of the thiazole nitrogen, a side-reaction that manifests as irreversible colour darkening from pale yellow to deep amber and a concomitant 5–7% loss in assay. Integration into continuous flow platforms utilizing a Vapourtec R-series reactor fitted with a 10 mL PFA coil at 0.5 mL·min⁻¹ has been demonstrated for the telescoped Suzuki-condensation sequence, eliminating manual handling of the aldehyde intermediate and achieving a steady-state productivity of 1.8 g·h⁻¹ of biaryl aldehyde output. Such process intensification aligns with the General Considerations for Process Validation of Active Pharmaceutical Ingredients ICH Q11 and supports the compound’s role in scalable routes to candidate molecules in preclinical development.

HS Code	143618
Chemical Formula	C4H2BrNOS
Molecular Weight	192.03 g/mol
Appearance	Solid (usually)
Color	Typically pale - colored
Odor	May have a characteristic odor
Melting Point	Specific value depends on purity, but generally in a certain range
Boiling Point	Relevant value based on its physical properties
Solubility In Water	Low solubility in water
Solubility In Organic Solvents	Soluble in some common organic solvents like dichloromethane
Density	Appropriate density value for the compound

Packing	50 g of 4 - Bromo - 2 - Formylthiazole packaged in a sealed, chemical - resistant bottle.
Shipping	4 - Bromo - 2 - Formylthiazole is shipped in well - sealed containers. Packaging is designed to prevent spills and ensure safety. Shipment follows strict chemical transport regulations, with proper labeling for hazard identification.
Storage	4 - Bromo - 2 - Formylthiazole should be stored in a cool, dry, well - ventilated area, away from heat sources and open flames. Keep it in a tightly closed container to prevent exposure to air and moisture, which could potentially lead to decomposition. Store it separately from incompatible substances, like oxidizing agents and bases, to avoid chemical reactions.