2-Chloro-5-Nitro-1,3-Thiazole
|
HS Code |
290630 |
| Chemical Formula | C3HClN2O2S |
| Molar Mass | 180.57 g/mol |
| Appearance | Yellow solid |
| Melting Point | 167 - 170 °C |
| Boiling Point | Decomposes |
| Solubility In Water | Insoluble |
| Solubility In Organic Solvents | Soluble in common organic solvents like dichloromethane, chloroform |
| Odor | Odorless or very faint odor |
| Stability | Stable under normal conditions, but may react with strong oxidizing or reducing agents |
As an accredited 2-Chloro-5-Nitro-1,3-Thiazole factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100g of 2 - Chloro - 5 - Nitro - 1,3 - Thiazole packaged in a sealed, labeled bottle. |
| Shipping | 2 - Chloro - 5 - nitro - 1,3 - thiazole, being a chemical, requires careful shipping. It should be packaged in sealed, corrosion - resistant containers, following hazardous material regulations, and shipped via approved carriers to ensure safety during transit. |
| Storage | 2 - Chloro - 5 - nitro - 1,3 - thiazole should be stored in a cool, dry, well - ventilated area. Keep it away from heat sources, flames, and oxidizing agents. Store in a tightly closed container to prevent moisture and air exposure. Label the storage container clearly to avoid misidentification. It's best stored separately from incompatible substances to ensure safety. |
Amination of 2-chloro-5-nitrothiazole with 25–28% aqueous ammonia in a glass-lined or 316L stainless-steel jacketed reactor held at 110–120°C under autogenous pressure of 3–4 bar for 6–8 hours yields 2-amino-5-nitrothiazole (ANT), a veterinary histomonastat and coccidiostat originally cleared under FDA NADA 140-808 for prophylactic use in turkey feed. Contemporary residue control compliance relies on withdrawal-period verification aligned with VICH GL 49 and local livestock-compound authorizations; the molecule remains in certain national veterinary pharmacopoeias for non-food-producing birds. Proprietary premix formulations incorporate ANT technical powder onto a calcium carbonate or wheat middlings carrier in a twin-ribbon blender operated to a coefficient of variation below 5% (sampled per ISO 20638:2018). The resulting 15% ANT premix is dosed into final feed at 1–2 kg per tonne via a loss-in-weight micro-dosing system, delivering a therapeutic concentration of 0.025–0.05% (w/w) in the finished diet. Wet ANT cake, containing residual ammonium chloride and unreacted starting material, must be handled in vessels fabricated from 316L or higher alloys because chloride-driven pitting initiates above 80°C on standard 304 surfaces, a failure mode documented on production-scale centrifuges after 300+ batches.At What Acylation Stoichiometry Does Schotten-Baumann Addition to 2-Amino-5-Nitrothiazole Generate Minimum Diacylated Impurity?Synthesis of the antiprotozoal nitazoxanide, a thiazolide active pharmaceutical ingredient monographed in USP 43–NF38 and EP 10.8, proceeds through acylation of 2-amino-5-nitrothiazole with 2-acetoxybenzoyl chloride in anhydrous dichloromethane. Process calorimetry conducted on a 1-litre Mettler-Toledo RC1 shows that the exothermic acylation (ΔTad ≈ −380 J/g) requires dosing the acid chloride over 1.5 hours at 0–2°C while maintaining 1.15 equivalents of triethylamine relative to the amine. Multi-factor design-of-experiments data from kilo-lab campaigns demonstrate that a molar ratio of amine : acyl chloride of 1 : 1.03 depresses residual ANT below 0.10% (HPLC area, 350 nm) and limits the diacylated by-product to <0.25%, whereas ratios exceeding 1 : 1.10 push impurity levels above reporting thresholds defined in ICH Q3A(R2). GMP compliance under ICH Q7 is enforced by in-process HPLC monitoring on a C18 column (5 μm, 250 × 4.6 mm) with UV detection. After aqueous quench and crystallization from ethanol/water at a cooling rate of −0.3°C/min controlled by a Huber Unistat, the isolated nitazoxanide is formulated into immediate-release tablets (500 mg) and oral suspensions (100 mg/5 mL) indicated for cryptosporidiosis and giardiasis, with bioequivalence assessed under 21 CFR 320.24(b).Heterogeneous Catalytic Nitro Reduction and its Impact on Aminothiazole Purity in the Clothianidin Precursor ChainThe industrial preparation of 2-chloro-5-aminothiazole, the immediate precursor to the neonicotinoid insecticide clothianidin conforming to FAO specification 761/LN/2005, is accomplished through selective nitro reduction of 2-chloro-5-nitrothiazole using either activated iron powder (Fe/HCl) in a water/methanol biphasic system or catalytic hydrogenation over 5% Pd/C at 0.5–1.0% catalyst loading (w/w substrate) at 50–60°C under 0.5–1.0 MPa hydrogen. In a batch hydrogenator fitted with a hollow-shaft self-inducing turbine, the dissolved hydrogen is maintained above 30% saturation by ramping substrate addition rate; failure to do so permits hydroxylamine intermediate accumulation that self-condenses to azoxy species, reducing isolated yield below 88%. Catalyst removal by cross-flow filtration through a 0.2 µm ceramic membrane is followed by pH adjustment to liberate the free aminothiazole, which is immediately condensed with methylnitroguanidine in the presence of triphosgene inside a Hastelloy C-276 reactor to resist chloride-induced stress corrosion. The technical clothianidin is packed under UN 3077 (Class 9) and subjected to impurity profiling per OECD TG 471 (Ames test) to verify mutagenic nitro-thiazole carryover remains below 1 ppm. Downstream formulation delivers water-dispersible granules (50% WG) and seed-treatment flowable concentrates (480 g/L FS) applied at field rates of 25–50 g a.i./ha, with suspensibility requirements tested under CIPAC MT 184.Coupling of diazotized 2-amino-5-nitrothiazole with N-ethyl-N-(2-cyanoethyl)-m-toluidine at pH 3.5–4.0 in the presence of sulfamic acid generates a bluish-red heterocyclic disperse dye that exhausts onto polyester at 130°C with fixation above 92% under 24 bar dynamic pressure in a Then-AFD jet-dyeing machine. Compliance with OEKO-TEX Standard 100 requires that primary aromatic amines arising from the azo reductive-cleavability test (per DIN EN ISO 14362-1:2017) remain below 20 mg/kg per listed amine; the critical manufacturing intervention is washing the ANT press cake with water/acetone to a residual 2-amino-5-nitrothiazole level of <0.3% before diazotization. Diazo charge stoichiometry employs 1.02 equivalents of nitrosylsulfuric acid per mole of amine to ensure complete conversion without free nitrite that causes coupler nitrosation. Transfer from a laboratory Drais bead mill to a production Netzsch LMZ-25 horizontal agitator mill requires real-time particle-size reduction to a D90 < 1.0 µm monitored by laser diffraction (ISO 13320:2020); this prevents filter-press blinding during isolation. The commercial dye is supplied as a 30% press cake or a spray-dried powder with 150% tinctorial strength relative to the standard, targeting automotive upholstery and continuous-filament polyester yarns where light fastness of >7 on the Blue Wool Scale (ISO 105-B02:2014) is specified.For use as a pharmacopoeial system-suitability standard, the compound is purified by two successive recrystallizations from toluene/hexane (3:1 v/v) to a purity of ≥99.8% (HPLC area, 230 nm), dispensed in 100 mg amber ampoules under ISO 17034:2016, and assessed for crystalline homogeneity via differential scanning calorimetry (ASTM E928-19); this segment represents the lowest-volume demand, with batch sizes held below 0.3 kg. |
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2-Chloro-5-nitro-1,3-thiazole (CAS 6285-05-8; systematic name: 2-chloro-5-nitro-1,3-thiazole; molecular formula C3HClN2O2S, molar mass 164.57 g·mol−1) operates as a finely tuned electrophilic building block in heterocyclic synthesis, finding its principal deployment in ant parasitic pharmacophores derived from the nitazoxanide scaffold and in agrochemical intermediates requiring a low-energy nucleophilic displacement pathway. The solid appears as pale yellow crystals with a melting endotherm onset recorded by differential scanning calorimetry at 29.5–31.2 °C (heating rate 10 K·min−1, sealed aluminium pan, Mettler Toledo DSC 3+). The 5-nitro substituent imparts a Hammett σp value of +0.78, rendering the thiazole π-system significantly electron-deficient and activating C-2 toward SNAr attack even by moderately nucleophilic aliphatic amines without transition-metal mediation. This intrinsic activation profile differentiates the compound from 2-chlorothiazole, which requires elevated temperatures and stoichiometric fluoride or copper promoters for displacement, and from 2-amino-5-nitrothiazole, where the amine must be converted to a diazonium salt for further functionalization.
The LUMO lobe distribution computed at the B3LYP/6-31+G(d) level localizes predominantly on the C-2 carbon, with a coefficient 0.41 in the conjugated π* orbital that encompasses the nitro group’s oxygen atoms. In practice, this orbital topology enables facile chloride departure upon nucleophilic approach; measured rate constants for morpholine substitution in DMF at 25 °C (kobs = 2.7 × 10−3 s−1) exceed those for the analogous 2-bromo-5-nitrothiazole by a factor of 0.63—the reverse of SN2 leaving-group expectations, confirming a concerted Meisenheimer-type addition-elimination where polarizability of the halide is less critical than stabilization of the negative charge build-up at C-2. Consequently, metal-free coupling with unhindered alkylamines proceeds to completion within 2–6 h at 40–55 °C in acetonitrile or THF containing 1.5 eq of N,N-diisopropylethylamine. The absence of palladium or copper residues eliminates the need for post-reaction scavenging resins and simplifies ICH Q3D elemental impurity compliance, a particular advantage when the target API carries a permitted daily exposure for palladium below 10 µg·day−1.
However, the same electron deficiency imposes a sensitivity to strong aqueous bases. Contact with >0.5 M NaOH at temperatures exceeding 30 °C initiates ring-opening via nucleophilic attack at C-5, forming transient thiolate intermediates that oligomerize. Process Development work documented in kilo-lab campaigns ( 50–80 mol scale) recommends maintaining the reaction pH below 9.2 and dosing the amine at a controlled rate not exceeding 2.5 mol·h−1 to limit the pronounced adiabatic temperature rise. Reaction calorimetry (Mettler Toledo RC1, isothermal mode at 40 °C, jacket temperature tracking) recorded a specific heat release of −ΔH = 178 ± 8 kJ·mol−1 and a thermal accumulation factor below 0.15 when using a pulse-feed protocol, confirming that worst-case MTSR remains 28 K below the onset of the secondary exotherm assigned to nitro group decomposition (DSC onset 192 °C). Such data align with the emergency relief design guidance of DIERS methodology and allow safe scale-up in glass-lined reactors rated for 6 bar.
Industrial producers characterise the bulk substance against a multi-parameter specification anchored to the testing strategies of Ph. Eur. 2.2.46 (HPLC) and USP <621> (chromatography). A representative certificate of analysis is condensed in the table below.
| Parameter | Method / Standard | Acceptance Criterion |
|---|---|---|
| Purity (GC-FID, area%) | DB-5 column, 30 m × 0.32 mm, film 0.25 µm, He 1.2 mL·min−1 | ≥98.5% |
| Purity (HPLC-UV, 254 nm) | C18, 150×4.6 mm, 5 µm; MeCN/H2O 60:40 +0.1% TFA | ≥99.0% |
| Melting range | USP <741> Class I, capillary | 28.5–32.0 °C |
| Water content (Karl Fischer) | Ph. Eur. 2.5.12, coulometric | ≤0.5% |
| Sulphated ash | Ph. Eur. 2.4.14 | ≤0.1% |
| Heavy metals (as Pb) | USP <231> Method II | ≤10 ppm |
| Individual unknown impurity | HPLC, relative retention | ≤0.15% |
For customer-facing pharmaceutical projects where compendial monographs have not been finalised, suppliers typically provide a comprehensive elemental impurity risk assessment in accordance with ICH Q3D (Step 4). The volatile chloro-nitroheterocycle may entrain residual synthesis solvents such as dichloromethane or ethyl acetate; batch-to-batch headspace GC-MS (Agilent 7697A/7890B) targeting Class 2 solvents per ICH Q3C routinely demonstrates levels below the option 1 concentration limits (e.g., dichloromethane <20 ppm). Storage under inert gas at 2–8 °C in amber HDPE bottles fitted with PTFE-lined caps is recommended; under these conditions, any single re-test period of 24 months shows no out-of-trend loss of assay when monitored by stability-indicating UPLC (sub-2 µm column, AQbD-driven mobile phase).
A single 10-L jacketed vessel trial documented a representative SNAr coupling using cyclopropylamine (1.08 eq) in 2-methyltetrahydrofuran. The amine was dosed over 45 min via a peristaltic pump calibrated to deliver 11.4 mL·min−1. The batch temperature, maintained at 48.0 ± 1.5 °C by a Julabo Presto A40 circulator, showed a maximal excursion of +3.2 °C when the dosing rate momentarily drifted during the first 15% of the addition, a deviation traced to a transient crystallisation event of the amine hydrochloride salt that temporarily raised viscosity to 820 mPa·s (Brookfield DV2T, spindle SC4-18). In-line FTIR (Mettler Toledo ReactIR 15) monitoring of the nitro asymmetric stretch at 1342 cm−1 confirmed loss of starting material with t90 = 47 min. After aqueous work-up and crystallisation from 85:15 v/v heptane/ethyl acetate, the isolated 2-(cyclopropylamino)-5-nitrothiazole exhibited an HPLC purity of 99.1% and a corrected yield of 87%, meeting a release specification of NMT 0.10% for des-chloro impurity. That single-stage process avoided palladium entirely, a contrast with the typical Suzuki route to 2-aryl-5-nitrothiazoles that demands 0.5–2 mol% Pd2(dba)3/XPhos and subsequent metal scavenging with Si-Thiol cartridges to achieve residual Pd < 5 ppm.While direct SNAr constitutes the most atom-economic entry to 2-aminated 5-nitrothiazoles, certain sterically demanding or electronically deactivated amines (e.g., diarylamines, electron-poor anilines) require the switch to palladium catalysis. Under these conditions, 2-bromo-5-nitrothiazole (CAS 3034-48-8) demonstrates markedly better performance owing to the lower bond dissociation energy of C–Br ( ≈280 kJ·mol−1 vs. ≈350 kJ·mol−1 for C–Cl) and faster oxidative addition to Pd(0). Comparative screening data on a model substrate, 4-cyanoaniline, in toluene at 80 °C using Pd(OAc)2/BINAP (1 mol%) and Cs2CO3 gave isolated yields of <15% for the chloro derivative versus 72% for the bromo analogue after 12 h. The iodo congener, 2-iodo-5-nitrothiazole, pushes yields to 91% but suffers from light-sensitivity and rapid dehalogenation during storage unless stabilised over copper wire. These trade-offs are summarised in the following table.
| 2-Halo-5-nitrothiazole | SNAr Half-life (morpholine, 25 °C) | Suzuki Coupling Yield (PhB(OH)2, 2 mol% Pd) | Recommended Storage |
|---|---|---|---|
| 2-Chloro- (CAS 6285-05-8) | 257 min | 22–34%a | 2–8 °C, N2, 24 months |
| 2-Bromo- (CAS 3034-48-8) | 98 min | 68–81%a | −20 °C, desiccated, 12 months |
| 2-Iodo- | 41 min | 87–94%a | −20 °C, dark, 6 months |
| 2-Amino- (CAS 121-66-4) | Not applicable | Nil (no halide) | Ambient, stable |
Thus, the 2-chloro variant excels where metal-sensitive impurity thresholds are paramount, as in radiopharmaceutical precursor synthesis that must adhere to EudraLex Vol. 4 Annex 1 cleanroom classifications, whereas the bromo derivative is preferred for diversified analogue libraries demanding broad amine scope. Both compounds share a common decomposition pathway above 180 °C that generates NOx and SO2, demanding that all drying steps be conducted under vacuum (<10 mbar) at temperatures not exceeding 35 °C.
The substance is classified under UN GHS Rev.8 as Acute Toxicity Category 4 (Harmful if swallowed, H302), Skin Irritation Category 2 (H315), Eye Irritation Category 2A (H319), and Specific Target Organ Toxicity – Single Exposure Category 3 (Respiratory tract irritation, H335). Although a definitive in vivo sensitisation study (OECD 406) has not been lodged publicly, structural alerts in the thiazole nucleus warrant a precautionary designation of H317 (May cause an allergic skin reaction) in extended Safety Data Sheets following Regulation (EC) No 1272/2008. Control banding assessments at lab scale recommend local exhaust ventilation maintaining a capture velocity of 0.5–0.7 m·s−1 at the powder handling station, coupled with nitrile gloves tested for permeation breakthrough > 480 min (Ansell TouchNTuff 93-500 or equivalent). In the event of a spill, sweeping should be avoided; instead, an inert absorbent such as vermiculite wetted with a 5% sodium bicarbonate solution is applied within a secondary containment tray to limit airborne dust and neutralise acidic hydrolysis products.
Industrial shipments normally utilise UN 4G fibreboard boxes containing 1 kg or 5 kg HDPE jars inside sealed aluminium barrier bags loaded under a nitrogen blanket to an oxygen headspace concentration of <0.5%. Transport classification under ADR/RID is UN 3077 (Environmentally Hazardous Substance, Solid, n.o.s., Packing Group III, Marine Pollutant) when residual solvent levels exceed the 0.1% threshold for GHS Acute Chronic 1 classification. Manufacturers holding ISO 9001:2015 and ISO 14001:2015 certifications supply the product with full REACH (Regulation (EC) No 1907/2006) compliance documentation, including a Chemical Safety Report where the Derived No-Effect Level (DNEL) for long-term inhalation exposure by workers has been provisionally set at 0.74 mg·m−3 based on read-across from structurally similar nitrothiazoles.
