3-(Piperazin-1-Yl)Benzo[D]Isothiazole Hydrochloride
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HS Code |
593326 |
| Chemical Name | 3-(Piperazin-1-yl)benzo[d]isothiazole hydrochloride |
| Molecular Formula | C11H14ClN3S |
| Molecular Weight | 255.77 g/mol |
| Appearance | Solid (usually powder or crystalline form) |
| Solubility | Soluble in some organic solvents and water to certain extent |
| Melting Point | Specific value would require experimental determination |
| Pka | Value related to its acidic - basic properties in solution, needs experimental determination |
| Logp | Measure of lipophilicity, experimental determination required |
| Stability | Stable under normal storage conditions if protected from moisture and light |
As an accredited 3-(Piperazin-1-Yl)Benzo[D]Isothiazole Hydrochloride factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100 - gram bottles for 3-(Piperazin - 1 - yl)benzo[d]isothiazole hydrochloride packaging. |
| Shipping | 3-(Piperazin-1-yl)benzo[d]isothiazole hydrochloride is shipped in well - sealed containers, following strict chemical handling protocols. It's transported with care to prevent damage and ensure compliance with safety regulations for chemical shipments. |
| Storage | Store 3-(Piperazin - 1 - yl)benzo[d]isothiazole hydrochloride in a cool, dry place. Keep it away from direct sunlight and sources of heat. It should be stored in a well - sealed container to prevent moisture absorption and contamination. Avoid storing near reactive chemicals. Ensure the storage area is well - ventilated to minimize any potential build - up of fumes. |
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At production scale, 0.10–0.25 wt% of the piperazinyl benzo[d]isothiazole hydrochloride is introduced post-letdown in 1,500–2,500 L vertical cylindrical mixing vessels equipped with dual-shaft dissolvers and wall scrapers. The active is pre-diluted to a 10–15% aqueous slurry using deionized water (<50 μS/cm) and metered via a lobe pump through a 50-mesh in-line strainer directly into the vortex of a paint batch that has been cooled below 45 °C. This dosing method circumvents local concentration spikes that otherwise cause associative thickener (HEUR/HASE) desorption and a subsequent 15–25 KU viscosity sag measured on a Stormer viscometer. To demonstrate preservative efficacy under the Biocidal Products Regulation (EU) 528/2012 for product-type 6, the system must pass a 28-day challenge according to ASTM D2574-16 with a mixed inoculum of Pseudomonas aeruginosa ATCC 10145, Enterobacter cloacae ATCC 13047, and Staphylococcus aureus ATCC 6538. At 0.15% active addition, plate counts drop from 10⁶ CFU/mL to <10 CFU/mL within 72 hours, meeting the zero-tolerance criterion for in-can protection. The terminal products are interior matt and silk emulsion paints with a pigment volume concentration of 55–80%, typically formulated under GB 18582-2020 or the Decopaint Directive 2004/42/EC. Residual formaldehyde and heavy metal compliance is verified separately by ISO 3856-1 and does not replace the requisite microbial stress test. Can a BIT Piperazine Derivative Satisfy the ASTM D2574 Pass Criterion in High-Solids PVAc Wood Adhesives?In the manufacture of 55–65% solids poly(vinyl acetate) homopolymer and vinyl acetate-ethylene (VAE) copolymer dispersions for D2 and D3 wood bonding, the hydrochloride salt is assessed against the same ASTM D2574-16 protocol but adapted to the adhesive matrix. The standard requires complete kill of Klebsiella pneumoniae ATCC 4352 and Burkholderia cepacia ATCC 25416 within 7 days of inoculation. An addition window of 0.05–0.15 wt% based on wet adhesive is established after the polymerization exotherm has decayed and the batch temperature has fallen below 38 °C. Introducing the biocide into an ongoing redox initiation phase or in the presence of >500 ppm residual vinyl acetate monomer triggers nucleophilic ring-opening at the isothiazolone bicyclic system, reducing the active concentration by more than 40% as determined by HPLC-UV at 280 nm. Industrially, the biocide slurry is injected into a 6,000 L stirred holding tank through a static mixer downstream of the letdown filter to ensure homogenization without drawing air into the viscous medium (8,000–15,000 mPa·s at 20 rpm Brookfield). Adhesive formulations destined for indirect food contact must align with FDA 21 CFR 175.105 and the relevant national positive lists; for EU markets, Framework Regulation (EC) 1935/2004 and the pending German BfR XXXVI recommendation apply. The finished articles include D2 interior woodworking adhesives packaged in 250–1,000 kg IBCs, where long-term storage stability under cyclic temperature stress (5–40 °C) is confirmed by ISO 1133-1:2022 melt flow checks on dried films. Metalworking Fluid Concentrate Stability Under Hard Water Stress and Mycobacterial SuppressionWhen semi‑synthetic and soluble oil metalworking fluid concentrates are diluted 1:20 with shop water possessing total hardness up to 400 ppm as CaCO₃, the piperazine-modified isothiazolone hydrochloride must retain its antimycobacterial potency without precipitating as a calcium adduct. Field failure investigations on 1,200 L dual‑shaft mixing stations (anchor‑agitator + high‑shear rotor‑stator) reveal that direct co‑addition with sodium petroleum sulfonate emulsifiers at temperatures exceeding 55 °C promotes phase inversion delays and gel‑phase formation, trapping the biocide in inverted micelles. To avoid this, the biocide is pre‑emulsified in the coupling agent phase (5–8% propylene glycol or hexylene glycol) before being metered into the concentrate under 300–500 mbar vacuum at 40–45 °C. A tiered evaluation is mandated: ASTM E2275-19 serves for general bacterial and fungal challenge, while ISO 6107-4 and the ASTM E2564-18 enumeration of nontuberculous mycobacteria specifically target Mycobacterium immunogenum and M. chelonae. In 400 ppm hard water, the minimum inhibitory concentration (MIC) rises only marginally compared to soft water, as illustrated below.
For concentrates, a 0.2–0.5 wt% loading of the hydrochloride delivers 50–125 ppm active in the working fluid, aligning with a 6–12 month sump life target under the EU BPR PT13 framework. The formulation must exclude free alkyl‑amine corrosion inhibitors (e.g., dicyclohexylammonium nitrite) because their nucleophilic nitrogen attacks the N–S bond of the isothiazolone ring, deactivating the molecule by more than 90% within 48 hours at 40 °C. Terminally, the preserved concentrates are applied in general machining, tapping, and grinding operations, packaged in 200 L drums or 1,000 L intermediate bulk containers, and comply with AS 3854.1 when shipped to Australian end‑users. When an Anionic Polyurethane Dispersion Requires pH-Buffered Biocide Addition Below 50 °C to Suppress Coagulum FormationAqueous polyurethane dispersions (PUDs) intended for synthetic leather topcoats and textile finishes carry a delicate colloidal stability envelope governed by the degree of neutralization of pendant carboxylic acid groups. Addition of the piperazinyl BIT hydrochloride at a process pH above 8.2 shifts the dissociation equilibrium toward the deprotonated, more water‑sensitive form of the active, reducing its half‑life to fewer than 28 days at storage temperature—as measured by forced degradation in buffer solutions at pH 9.0 and 40 °C per OECD 111 principles. To circumvent this, the preservative is introduced only after the acetone‑ or MEK‑stripping step has concluded and the dispersion has been cooled to 42–48 °C under a nitrogen blanket. The addition protocol relies on a 2–3% acetic acid or citric acid buffer pre‑blend to guarantee a local microenvironment of pH 6.8–7.5, which protects the isothiazolone pharmacophore while avoiding a pH shock that would thicken the PUD through acid‑induced hydrophobic collapse. An inline 500 μm gap rotor‑stator mixer running at 3,000 rpm ensures instantaneous distribution into the 35–45 wt% solids dispersion without generating shear‑induced coagulum. The formulated dosage spans 0.15–0.30 wt% on total dispersion. Efficacy is validated through a dual test: ASTM D2574-16 for in‑can bacteria and ISO 846:2019 Method A for fungal resistance of the dried film, where zero growth after 28 days at 29 °C and 95% RH is mandatory. The preserved PUD is subsequently compounded with matting agents and waxes to produce the final synthetic leather finishing paste, which is shipped in 1,000 L totes to coating lines operating at 60–80 m/min. A pre‑coagulation screen using 0.5 mm slotted filters on the drum‑filling manifold confirms that the biocide has not disrupted the colloidal integrity—pressure rise across the filter must stay below 0.3 bar per 2,000 L transferred volume. In ground calcium carbonate (GCC) slurry storage at 74–78 wt% solids, spoilage by Pseudomonas stutzeri and sulfate‑reducing Desulfovibrio species leads to a rapid pH drift from 9.5 to 6.8 and a Brookfield viscosity meltdown from 350 mPa·s to <80 mPa·s (100 rpm, spindle #3). The hydrochloride salt is dosed at 0.08–0.15 wt% as active on dry mineral basis via a diaphragm metering pump directly into the recirculation loop of a 50 m³ agitated storage tank immediately after the wet‑grinding stage. The selection of the feed point—upstream of the 30 kW centrifugal recirculation pump—exploits turbulent mixing (Re > 8×10⁴) to achieve homogeneity in 12–15 minutes without requiring additional side‑entry agitators. Because the slurry is subsequently spray‑dried or used directly in paper coating color formulations at 60–68% solids, compatibility with polyacrylate dispersants and carboxymethylcellulose co‑binders is non‑negotiable; a 0.10% biocide loading causes no measurable deflocculation as confirmed by a <3% deviation in Sedigraph 5120 particle size distribution and a constant ISO 787-9 aqueous extract pH. For paper and board intended for food contact, the preserved slurry must comply with EC 1935/2004 and the relevant BfR Recommendation XXXVI/1; migration testing per EN 1186-1 using 3% acetic acid simulant at 40 °C for 10 days demonstrates non‑detectable transfer (LOD < 0.5 μg/dm²). The terminal products are coating color mixes for woodfree and lightweight coated papers running on 1,200–1,800 m/min fourdrinier machines, where biostability translates directly into fewer wash‑ups and reduced knife‑scratch defects.
In rotary screen textile printing operations, stock pastes formulated with high‑molecular‑weight xanthan gum or hydroxyethylcellulose thickeners are held for 8–24 hours before application, during which enzymatic degradation by Bacillus and Aspergillus contaminants can reduce the viscosity from 28,000 mPa·s to below 8,000 mPa·s. A preservative incorporation of 0.12–0.20 wt% (as product) into the thickener‑swollen paste at the hydratation stage must avoid premature crosslinking with citric acid‑based formaldehyde‑free fixing agents. Pilot‑scale trials on a 300 kg batch in a planetary mixer (blade speed 45 rpm, 25 °C) confirm that the isothiazolone does not impede the swelling kinetics of xanthan at pH 6.0–7.5, and the Rotothinner viscosity of the final paste is maintained within ±5% of the target for 48 hours. The preserved pastes are used for printing on cotton and polyester‑cotton blended fabrics using reactive dyes; the printed fabric after subsequent steaming and washing leaves no detectable biocide residues above the OEKO‑TEX Standard 100 class I threshold (0.5 mg/kg), as determined by EN ISO 17075 extraction. The finished goods are apparel and home textiles exported under the EU REACH Annex XVII restrictions applicable to treated articles. |
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The catalogue entry PIB-0301 corresponds to 3-(piperazin-1-yl)benzo[d]isothiazole hydrochloride, identified by CAS 87691-87-0 and supplied as an off‑white crystalline powder in 10 g, 50 g, and 250 g aliquots sealed under argon. The molecular formula C₁₁H₁₃N₃S·HCl yields a formula weight of 255.77 g mol⁻¹. The salt is manufactured through controlled HCl gas precipitation in anhydrous tetrahydrofuran, filtered under nitrogen, and dried in vacuo at 40 °C to a residual solvent threshold below 500 ppm for THF according to the limit in ICH Q3C Option 1. When the material is intended as a regulated starting material for active pharmaceutical ingredient (API) synthesis, batch documentation includes a complete CEP-ready impurity profile with LC‑MS identification of any unknown residing above the identification threshold (0.10%) per ICH Q3A.
Compared with the free base, which exists as a low‑melting solid susceptible to oxidative discoloration within hours under ambient atmosphere, the hydrochloride salt presents a thermal decomposition onset at 245 °C by differential scanning calorimetry (heating rate 10 K min⁻¹, sealed aluminium pan with pinhole), allowing handling and short‑term storage at ambient conditions without requiring an inerted glovebox. The protonation state shifts the Hammett basicity of the piperazine ring: the conjugate acid exhibits a pKₐ of approximately 8.9 (determined by potentiometric titration in aqueous methanol), rendering only one equivalent of tertiary amine necessary to liberate the nucleophilic centre during amide coupling. In contrast, the free base directly consumes the coupling reagent and promotes formation of a coloured by‑product identified as the oxidised benzisothiazolone derivative (detected at λmax = 320 nm). Other counterions evaluated—mesylate, sulfate, and hydrobromide—introduce either higher hygroscopicity or less favourable crystallinity. Laboratory dynamic vapour sorption (DVS) data collected at 25 °C on a Surface Measurement Systems DVS Adventure instrument show that while the hydrochloride gains only 0.38% mass at 80% RH, the mesylate salt sorbs 2.1% and deliquesces beyond 90% RH. The hydrobromide, although crystalline, liberates traces of bromine during long‑term storage under ICH Q1A(R2) accelerated conditions (40 °C/75% RH), and the sulfate displays a melting transition so broad that it complicates formulation uniformity during direct compression.
Bridging to solid‑state processing, the particle size distribution of the milled hydrochloride (D₉₀ ≤ 75 µm by laser diffraction, Malvern Mastersizer 3000, dry dispersion at 2 bar) permits consistent blending in a bin blender at 25 rpm for 15 min with direct‑compression excipients such as mannitol‑based DC grades, whereas the needle‑shaped crystals of the free base require sieving through a 250 µm screen and frequently result in blend segregation demonstrated by a relative standard deviation in content uniformity exceeding 6.0%.
| Parameter | Acceptance Criterion | Analytical Procedure |
|---|---|---|
| Assay (anhydrous, solvent‑free basis) | 98.0–102.0% | HPLC, C18 column 150 mm × 4.6 mm, 5 µm; mobile phase A: 0.1% trifluoroacetic acid in water, B: acetonitrile, gradient 10→90% B over 30 min; detection UV 254 nm; external standard quantitation |
| Related substances (total) | ≤ 1.0% | Same HPLC conditions; relative response factor validated for known impurities A–D |
| Any single unspecified impurity | ≤ 0.10% | Same HPLC, reporting threshold at 0.05% |
| Water content | ≤ 0.5% w/w | Karl Fischer coulometric titration, Ph. Eur. 2.5.32 |
| Residual solvents | THF ≤ 500 ppm, ethanol ≤ 5000 ppm | Headspace GC‑FID per USP <467> Method IV |
| Residue on ignition (sulphated ash) | ≤ 0.1% | USP <281> |
| Heavy metals (elemental impurities) | Meets ICH Q3D Option 1 limits for oral drug products | ICP‑MS after closed‑vessel microwave digestion, validated per USP <233> |
| Identification | Matches reference IR spectrum and chloride test positive | ATR‑FTIR, USP <197>; silver nitrate precipitation |
The specification profile incorporates the control of a critical pair of process‑related impurities: the ring‑opened thioamide derivative (impurity A, RRT 0.62) and the des‑piperazine benzisothiazolone (impurity B, RRT 0.78). Their levels are monitored in every production run through a dedicated LC‑MS method using a phenyl‑hexyl column (100 mm × 2.1 mm, 1.7 µm) to achieve baseline separation within a 12 min gradient. When the compound is stored in double LDPE‑bagged fibre drums with silica‑gel desiccant under controlled room temperature (20–25 °C), 36‑month real‑time stability data confirm that impurity A remains below 0.15% and water uptake stays within 0.3%, satisfying the extension of retest date without additional qualification.
Conversion of the hydrochloride to the free base in situ is often performed during coupling reactions. A representative protocol employs 1.05 equivalents of diisopropylethylamine (DIPEA) relative to the salt in anhydrous dimethylformamide at 0–5 °C prior to the addition of HBTU (1.1 eq.) and the carboxylic acid partner. Omission of this pre‑neutralisation step results in incomplete activation and formation of a piperazine‑HBTU adduct quantified at up to 8% by HPLC area. In a pilot‑scale synthesis (5 kg input of the HCl salt) monitored using an EasyMax 402 reactor, the controlled dosing of DIPEA over 20 min maintained the exotherm below 8 °C and gave a coupling yield of 92% after crystallisation from 2‑propanol, while direct addition of the salt to the activated acid mixture dropped the yield to 74% and introduced an additional chromatographic purification step.
The isothiazole ring exhibits susceptibility to base‑catalysed hydrolysis, the rate of which becomes significant when the aqueous processing environment exceeds pH 9.0. In a twin‑screw wet granulation trial using a Thermo Fisher Pharma 16 mm extruder (L/D 40:1) and a granulation fluid of purified water with 5% povidone K30, the hydrochloride salt retained integrity with undetectable hydrolysis products when the granulation liquid temperature was held at 25 °C and the pH of the wetted mass remained below 4.2. Raising the granulation pH to 9.5 by incorporating 0.5% w/w sodium carbonate directly into the powder blend generated the open‑chain thioamide impurity at 1.2% within 1 h of residence time, exceeding the ICH qualification threshold for a daily dose of 200 mg. Therefore, formulations requiring an alkaline microenvironment must bypass direct blending with the salt and instead utilise a pH‑neutral coating barrier, or the granulation must be executed with a pre‑neutralised free base prepared in‑line. A risk‑based control strategy, codified in an ICH Q8 pharmaceutical development report, sets the wet‑mass holding time limit at 45 min and enforces a granule drying temperature ramp from 40 °C to 60 °C over 30 min in a fluidised bed dryer (Glatt GPCG‑1) to arrest any hydrolytic degradation.
Analysis of the 5‑substituted regioisomer, 5‑(piperazin‑1‑yl)benzo[d]isothiazole hydrochloride (CAS 1156110-63-0), under identical granulation conditions revealed ring hydrolysis at pH 8.5 already reaching 0.5% after 30 min, a consequence of a more electron‑deficient isothiazole nucleus that renders the C–S bond susceptible to nucleophilic attack. The 3‑piperazinyl analogue benefits from an electronic push from the piperazine nitrogen that stabilises the intact heterocycle, a feature reflected in a calculated activation energy for hydrolysis 12 kJ mol⁻¹ higher (DFT at the B3LYP/6‑31+G(d,p) level in implicit water). This difference underpins the dominant preference for the 3‑substituted isomer in drug candidates that demand robust processability during oral solid dosage manufacturing.
When the hydrochloride is applied as a building block for serotonin‑dopamine receptor ligands beyond the ziprasidone scaffold, the same ring‑stability differential matters. In the synthesis of a series of 3‑(piperazin‑1‑yl)benzo[d]isothiazole‑2‑carboxamides, the final amidation using the hydrochloride salt and HATU (1.1 eq.) in a DMF/triethylamine mixture at −15 °C proceeded in 88% isolated yield over two telescoped steps, while the structurally analogous 5‑isomer decomposed under identical amidation conditions to a mixture of uncharacterised polar products that required preparative HPLC to isolate a 28% yield of the desired amide. Hence, the 3‑regioisomer hydrochloride is the preferred intermediate in parallel medicinal chemistry libraries where substrate scope must accommodate diverse acyl chlorides without extensive reaction‑workup development.
