2-Thiazolecarboximidamide Hydrochloride
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HS Code |
553712 |
| Chemical Formula | C4H6ClN3S |
| Molecular Weight | 163.63 g/mol |
| Appearance | Typically appears as a solid powder |
| Solubility | Soluble in polar solvents like water to some extent |
| Melting Point | Data may vary, needs specific experimental determination |
| Purity | Can be available in different purity levels in the market |
| Odor | May have a characteristic odor, though details vary |
| Stability | Stable under normal storage conditions, but may react with strong oxidizing agents |
| Hazard Class | Requires proper handling as it may be harmful if ingested, inhaled or in contact with skin |
As an accredited 2-Thiazolecarboximidamide Hydrochloride factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100 - gram bottle of 2 - Thiazolecarboximidamide Hydrochloride, securely packaged. |
| Shipping | 2 - Thiazolecarboximidamide Hydrochloride is shipped in well - sealed containers, following strict chemical shipping regulations. Ensured protection from moisture and physical damage during transit to maintain its integrity. |
| Storage | 2 - Thiazolecarboximidamide Hydrochloride should be stored in a cool, dry place, away from direct sunlight. Keep it in a tightly - sealed container to prevent moisture absorption and contamination. Avoid storing near incompatible substances. Ideal storage temperatures are typically between 2 - 8°C if refrigeration is specified, or at room temperature in a well - ventilated area if no specific cold storage is required. |
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2-Thiazolecarboximidamide hydrochloride, supplied as a free-flowing crystalline salt, is charged into Hastelloy C-22 reactors for the cyclocondensation cascade that constructs fused pyrimidine kinase inhibitor cores. The amidine hydrochloride undergoes in situ free-base generation with 1.05 molar equivalents of anhydrous triethylamine in tetrahydrofuran (water content verified <0.03% via Karl Fischer coulometry) at −10 °C to 0 °C before a 1:0.98 molar ratio addition of ethyl 2-fluoro-4-methoxybenzoylacetate. Reaction mass temperature must be maintained within ±2 °C of the setpoint: deviations exceeding 3 °C collapse the kinetic selectivity window, producing a dimeric M+2 adduct that co-elutes with the desired thiazolo[5,4-d]pyrimidin-7-amine intermediate under standard reversed-phase HPLC monitoring (C18, acetonitrile/water 70:30, retention drift 0.28 min). Post-reaction quench into chilled purified water (4 °C) precipitates the crude heterocycle, which is recrystallized from isopropanol/water (85:15 v/v) to deliver assay ≥99.2% (HPLC, area%). The entire campaign operates under ICH Q7 GMP Part II for advanced intermediates, with genotoxic risk management per ICH M7 Option 4 control—limit of mesityl oxide-derived adduct set at ≤7.5 ppm by LC-MS/MS. Downstream, the intermediate is converted into a sodium salt and telescoped into a clinical-phase oral Janus kinase 2 inhibitor candidate; tablet cores are manufactured via roller compaction to bypass moisture-induced polymorph conversion. Compliance documentation includes ASTM E2857 method validation for residual solvent headspace screening and USP <231> heavy metals confirmation for the free base. Within the veterinary anthelmintic supply chain, conversion of 2-thiazolecarboximidamide hydrochloride into 5-thiazolylbenzimidazole scaffolds is executed on dedicated equipment lines segregated from beta-lactam processing to satisfy cross-contamination thresholds under VICH GL12 residue carry-over limits. The compound is suspended in N-methyl-2-pyrrolidone (NMP, water content <0.10%) at a concentration of 0.8 M, followed by addition of 1.00 molar equivalent of 4-cyanophenylhydrazine and catalytic para-toluenesulfonic acid (0.05 eq). Pressurized heating at 125 °C (0.8 bar gauge) for 9–11 h drives annulation with liberation of ammonia; off-gas is scrubbed through dilute sulfuric acid to prevent atmospheric release of volatile amines per EU-OSHA indicative occupational exposure values. The crude product is resolved by drowning into deionised water at 50 °C under high-shear mixing, and the isolated solid is recrystallized from methanol/water to afford material conforming to VICH GL11 residue marker depletion protocols for swine dewormers. The final manufacture produces an oral suspension concentrate (usually 200 mg/mL active benzimidazole equivalent) stabilised with polysorbate 80 and microcrystalline cellulose, filled into HDPE bottles meeting USP <661.1>. Process capability indices for the key ring-closure step are monitored via SPC: a Cpk ≥ 1.33 is required for batch release of the thiazolyl intermediate, ensuring lot-to-lot uniformity in bioavailability studies. To construct the thiazole-4-carboxamide pharmacophore of modern succinate dehydrogenase inhibitor (SDHI) fungicides, bulk 2-thiazolecarboximidamide hydrochloride is first converted into its free base by partitioning between aqueous sodium hydroxide (20% w/w) and dichloromethane at 5 °C, then immediately acylation with a substituted pyrazole-4-carbonyl chloride (1.02 molar equivalents) in a biphasic system maintained at pH 8.3–8.7 through automated caustic dosing. The design relies on isothermal jacket control at 15 °C and a retreat-curve impeller running at 120 rpm in a 2000 L glass-lined vessel to suppress acid chloride hydrolysis without excessive shear that would create stable emulsions. After phase-cut and vacuum distillation, the 2-thiazolecarboxamide intermediate is crystallised from toluene/heptane (30:70 v/v) to yield a free-flowing solid with purity ≥98.5%. FAO/WHO JMPR evaluation principles and EPA 40 CFR Part 158 toxicology data requirements govern the impurity profile, specifically restricting the dialkylated dimer impurity to <0.15% w/w measured by UPLC-UV at 254 nm. Formulation into an aqueous 500 g/L suspension concentrate involves bead-milling the active ingredient with naphthalenesulfonate dispersants until particle size D(v,0.5) reaches 1.8–2.4 µm (ISO 13320 laser diffraction). The SC must pass CIPAC MT 46.3 accelerated storage stability at 54 °C for 14 days with pour-flow deviation <10%. Final products include broad-leaf crop fungicide combinations typically co-packed with strobilurin partners for use in wheat septoria and net blotch control programmes. Dye Carrier Exhaustion Curves and Coupling Ratios for Thiazole-Based DispersionsPale-yellow to orange monoazo colorants are manufactured from 2-thiazolecarboximidamide hydrochloride via azo-coupling onto electron-rich pyrazolone or barbituric acid coupling components. The hydrochloride is first diazotised with nitrosylsulfuric acid in concentrated sulfuric acid at 0–5 °C; the diazonium concentration is tracked with starch-iodide paper and nitrite excess quenched with sulfamic acid. Coupling is executed at 8–12 °C and pH 4.0–4.5 with a 1:1.00 molar stoichiometry of the coupling component, yielding a thiazolylazo chromophore that exhibits λmax in the range 415–438 nm (DMF). The presscake is washed until conductivity ≤50 µS/cm and then standardised via spray drying with lignin sulfonate to a strength of 200% relative to a reference dye. Application onto polyester fabric employs high-temperature exhaustion at 130 °C with carrier-based or jet-dyeing machinery; colour fastness to light (ISO 105-B02) achieves Blue Wool scale ratings of 6–7 when post-cleared with sodium hydrosulfite. REACH Annex XVII restrictions govern extractable primary aromatic amine content, and the commercial dye formulation must comply with OEKO-TEX STANDARD 100 class II for skin-contact articles, requiring <20 mg/kg of free aniline derivatives. The finished grade is sold as a dust-free granular powder for textile dye houses producing high-end upholstery and automotive interior polyester fabrics. When Heat-Latent Curing Replaces Tertiary Amines in Single-Component Epoxy DielectricsIn flip-chip underfill and semiconductor encapsulant formulations, 2-thiazolecarboximidamide hydrochloride functions as a thermo-latent hardener that eliminates room-temperature advancement—a persistent liability of tertiary amine-accelerated dicyandiamide systems. The solid amidine salt is dispersed at 6–10 phr into bisphenol-A diglycidyl ether resin (EEW 188–192 g/eq) using a three-roll mill with a gap setting of 15 µm, typically alongside fused silica filler pre-treated with 3-glycidyloxypropyltrimethoxysilane coupling agent. Formulations demonstrate a differential scanning calorimetry onset temperature of 118–127 °C (ASTM E1356, 10 °C/min ramp) and a peak exotherm at 158–166 °C; below 110 °C the mixture exhibits a pot life exceeding 72 hours at 25 °C, verified by rotational viscometry (ISO 3219) where complex viscosity growth is limited to <15%. Cure proceeds through benzyloxonium propagation rather than nucleophilic tertiary amine catalysis, a pathway confirmed by real-time FTIR monitoring (disappearance of epoxide band at 915 cm⁻¹). Practice for printed wiring board protection requires the cured network to reach a glass transition temperature of ≥145 °C (TMA, ASTM E831) and volume resistivity ≥1×1015 Ω·cm after conditioning at 85 °C/85% RH for 168 h (IEC 60093). Because moisture ingress deactivates the latent mechanism during storage, the masterbatch must be handled and packaged under dry nitrogen with moisture content kept below 0.05% (Karl Fischer) and relative humidity below 30% in the dispensing area. Finished assemblies pass UL 94 V-0 at thicknesses down to 0.4 mm, making the system suitable for chip-on-board encapsulation in smart-card and micro-LED driver modules. Additional downstream applications for 2-thiazolecarboximidamide hydrochloride include its use as a precursor for thiazole-based extractants tailored to selective copper recovery from ammoniacal leach solutions in printed circuit board recycling. The amidine is converted to the corresponding 2-thiazolecarboximidamide free base and loaded onto a chloromethylated polystyrene-divinylbenzene resin at 0.5–0.8 mmol/g functional density, producing a chelating solid-phase extraction medium that exhibits a copper-to-iron selectivity coefficient βCu/Fe ≥ 85 at pH 9.0 under continuous column-mode operation. Concentration of copper in the eluate consistently meets ASTM B717 purity benchmarks, enabling electro-winning directly from the stripping solution.
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2-Thiazolecarboximidamide hydrochloride, the monohydrochloride salt of thiazole-2-carboxamidine (C4H6N3S+·Cl−, molecular weight 163.63 g·mol−1), is supplied as a white to off-white crystalline powder with a target melting point of 217–221°C (decomposition). The free amidine base is susceptible to rapid hydrolysis under ambient humidity, whereas the hydrochloride form remains stable when stored in tightly sealed containers at room temperature. Residual water content, as determined by Karl Fischer titration per USP 〈921〉 Method Ia, typically falls below 0.5% w/w at release, with a specification ceiling of 1.0% for material older than 24 months. This product finds primary application as a protected 1,3-dinucleophilic building block in the construction of fused imidazo[2,1-b]thiazole systems, many of which are critical pharmacophores in histamine H2-receptor antagonists and anti-mycobacterial candidates. Yet the salt’s handling profile is governed by several crystallographic and thermodynamic variables that change measurably across production campaigns.
The core structural distinction lies in the replacement of a carboxamide carbonyl with an amidine group, raising the pKa of the conjugate acid to approximately 12.4 (estimated for the free base) and enabling participation in guanidinylation reactions that thiazole-2-carboxamide (pKa ~−0.5) cannot undergo. In practice, the hydrochloride serves as a shelf-stable precursor; when treated with a stoichiometric amount of a tertiary amine such as diisopropylethylamine (DIPEA) in anhydrous N,N-dimethylformamide at 0–5°C, the amidine is liberated quantitatively and can be trapped by an electrophile without competing hydrolysis. By contrast, 2-thiazolecarboxamide remains inert under these conditions, requiring much harsher activating agents. This reactivity gap is exploited in the synthesis of N-substituted 2-thiazolecarboximidamides, where the yield differential between the hydrochloride and the corresponding free base can exceed 15% due to the free base’s tendency to form intractable dimers through intermolecular condensation.
Batch-to-batch variability in crystal aspect ratio, often driven by cooling rate oscillations during recrystallization from ethanol/water mixtures, creates measurable shifts in powder flow. Lot characterization using ring shear testers (ASTM D6773) consistently returns flow function coefficient (ffc) values between 3.2 and 5.8, corresponding to cohesive to easy-flowing regimes. For lots where the D90 particle size exceeds 200 μm and the fines fraction (−45 μm) is below 8%, loss-in-weight gravimetric feeders with twin-screw agitation (Brabender DSR28, screw diameter 20 mm, L/D 20:1) can sustain a feed rate of 1.8 kg·h⁻¹ with a short-term standard deviation of ±1.7%. Conversely, material with a D50 below 65 μm exhibits pronounced arching above hopper outlet diameters of 100 mm, requiring active vibration or aeration to prevent stoppages. For such lots, pre-sieving through a 150 μm screen (ASTM E11) or gentle jet-milling to narrow the span (D90/D10) to ≤3.8 is mandated before use in continuous manufacturing.
Differences between this hydrochloride salt and alternative counterion forms—most notably the sulfate, nitrate, and free base—manifest sharply in downstream isolation steps. The hydrochloride’s aqueous solubility at 25°C is approximately 42 g·L⁻¹, sufficient to allow homogeneous in situ neutralization, whereas the sulfate salt precipitates as a poorly soluble hydrate that complicates filtration and leads to chloride contamination when ion exchange is attempted on scale. In palladium-catalyzed cross-couplings, however, the chloride ion can poison the catalyst. Trials on a 500 L glass-lined reactor batch indicated that residual palladium black formation increased when the mole fraction of chloride exceeded 1.2 equivalents relative to the Pd(0) pre-catalyst. For applications requiring a halide-free environment, a pre-coupling counterion swap with silver hexafluorophosphate in acetonitrile at −10°C was shown to reduce palladium loading by 35% while preserving the amidine integrity. Published data for the corresponding tetrafluoroborate salt remain scarce, though early thermogravimetric curves suggest a significantly lower decomposition onset near 178°C, limiting its utility in high-temperature aminations.
Thermal stability of the hydrochloride salt under nitrogen atmosphere, as measured by differential scanning calorimetry at a scan rate of 10 K·min⁻¹, reveals a sharp endothermic decomposition peak at 221°C (onset 215°C), accompanied by a mass loss of 43% between 200°C and 280°C attributable to HCl evolution and ring fragmentation. Accelerated rate calorimetry (ARC) data from a 10 g sample constrained in a Hastelloy bomb detected an exothermic self-heating rate exceeding 0.02°C·min⁻¹ at temperatures as low as 182°C. Therefore, large-scale drying operations are restricted to vacuum tray dryers with jacket temperatures not exceeding 50°C and a pressure of <15 mbar, with continuous nitrogen bleed to maintain an oxygen level below 2 vol% in the headspace. A deviation of merely +7°C during a 48‑hour drying cycle has been documented to reduce the assay by 1.8% and raise the level of thiazole-2-carboxamide impurity above the 0.10% threshold permitted by research-grade specifications.
A documented operational boundary in peptide coupling-type amidine functionalization concerns the use of the hydrochloride directly with carbodiimide reagents such as EDC·HCl. The additional chloride ion depresses the pH of the pre-mix in dichloromethane below 4.5, where O-acylisourea rearrangement is accelerated, cutting amidine coupling efficiency to less than 40% after 6 hours. Switching to the free base—generated by a single extraction with cold 0.1 M NaOH followed by organic layer drying over molecular sieves within 30 minutes—restores the yield to the 78–82% range. This operation must be executed with strict temperature control because the free base, once dried, undergoes dimerization at ambient temperature with a half-life of 17 hours (determined by 1H NMR monitoring of the amidine N–H signal at δ 9.2 ppm). Consequently, in situ neutralization protocols using polymer-supported tertiary amine resins have been adopted on kilogram scale to reduce the free base isolation step and cut cycle time by 65 minutes.
| Nucleophile | Solvent | Temperature (°C) | Time (h) | Isolated Yield (%) |
|---|---|---|---|---|
| n-Butylamine | DMF | 20 ± 2 | 18 | 85–88 |
| Cyclohexylamine | THF | 50 | 24 | 79 |
| Benzyl mercaptan | Acetonitrile | 40 | 12 | 61–64 |
| Phenol | DMSO | 80 | 48 | 22 (conversion limited) |
| Sodium azide | Water/acetone | 0–5 | 6 | 73 |
| Ammonia (gas) | Methanol | 10 | 3 | 90 (crude purity) |
Strict exclusion of overhead moisture from compressed air lines is essential during drum-offloading operations. At a relative humidity of >60%, the static water uptake rate of the salt measured by dynamic vapor sorption reaches 0.18%·h⁻¹ in the first 8 hours, forming a thin crust on the powder surface that increases angle of repose by 7° and prevents reliable actuation of slide gate valves on IBC containers. Recognized incompatibilities include strong oxidizing agents—chlorine spillage contacted with the salt yields a vigorous exotherm and traces of sulfur dioxide—and any aqueous base that lifts the pH to >9.0, leading to rapid precipitation of the free base and subsequent hydrolytic ring-opening.
| Parameter | Specification Limit | Test Method |
|---|---|---|
| Appearance | White to off-white crystalline powder | Visual inspection |
| Assay (anhydrous basis, HPLC) | ≥ 98.5% | Ph. Eur. 2.2.29, C18 column, 220 nm |
| Water content (KF) | ≤ 0.5% | USP 〈921〉 Method Ia |
| Chloride content (argentometric) | 21.0–22.2% | Ph. Eur. 2.3.1 |
| Residual ethanol (GC headspace) | ≤ 0.3% | USP 〈467〉 |
| Heavy metals (as Pb) | ≤ 10 ppm | Ph. Eur. method D |
| Related substances (sum of impurities) | ≤ 0.8% | Ph. Eur. 2.2.29 (same as assay) |
| Sulfated ash | ≤ 0.1% | Ph. Eur. 2.4.14 |
In continuous flow platforms using a Corning® Advanced-Flow™ G1 reactor with 10 mL internal volume, the residence time for a neat amidinium-chloride melt stream introduced at 0.5 mL·min⁻¹ can be tuned to capture the kinetic product in a cyclocondensation with α-bromo-γ-butyrolactone. Temperature mapping across the reactor plate revealed a hot spot of 8°C above the set-point when the neat melt was processed, requiring a dilution to 30% w/w in sulfolane to restore isothermal conditions. The resultant thiazolo[3,2-a]imidazole scaffold was isolated at 73% corrected yield after 3.1 minutes residence, a five-fold productivity improvement over batch mode when throughput is normalized to reactor volume. However, dilution with sulfolane introduced a downstream extraction step that added 12 hours to the overall cycle, demonstrating that the salt’s solubility-driven process limitations must be weighed carefully against reactor safety constraints.
