3-(Piperazin-1-Yl)Benzo[D]Isothiazole
|
HS Code |
129095 |
| Chemical Formula | C11H12N4S |
| Molar Mass | 232.31 g/mol |
| Appearance | Solid (predicted) |
As an accredited 3-(Piperazin-1-Yl)Benzo[D]Isothiazole factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100 - gram bottles containing 3-(Piperazin - 1 - yl)benzo[d]isothiazole, well - sealed. |
| Shipping | 3-(Piperazin - 1 - yl)benzo[d]isothiazole is shipped in accordance with strict chemical regulations. It's packaged securely in appropriate containers to prevent leakage during transit, ensuring safe transportation. |
| Storage | Store 3-(Piperazin-1-yl)benzo[d]isothiazole in a cool, dry place away from direct sunlight. Keep it in a tightly sealed container to prevent exposure to air and moisture, which could potentially lead to degradation. Store it separately from incompatible substances to avoid chemical reactions. Ensure the storage area is well - ventilated. |
In the manufacture of lurasidone hydrochloride, an atypical antipsychotic approved under NDA 200603 and detailed in US prescribing information, the compound 3-(piperazin-1-yl)benzo[d]isothiazole serves as the nucleophilic coupling partner for the mesylate derivative of trans-2-(((3aR,4S,7R,7aS)-octahydro-1,3-dioxo-4,7-methano-2H-isoindol-2-yl)methyl)cyclohexanemethanol. Batch production records from commercial-scale campaigns document a molar input ratio of 1.00 to 1.15 equivalents of the mesylate relative to the piperazinyl intermediate when the reaction is executed in anhydrous N,N-dimethylformamide containing 2.5 molar equivalents of milled potassium carbonate at a jacket temperature setpoint of 68–72°C. In process analytical testing per a validated HPLC method calibrated against a reference standard of the intermediate (purity acceptance limit ≥99.0 area percent, retention time relative standard deviation ≤0.5% across six replicate injections) determines endpoint status by monitoring residual piperazine derivative below 0.8%. Once the alkylation is complete, the mixture is cooled to 40–45°C, quenched with process water, and extracted into ethyl acetate; the organic phase is sequentially washed with 5% w/w aqueous NaCl solution and treated with activated carbon (Norit SX Plus, 0.5% w/w relative to theoretical yield) at 50°C for 60 minutes to adsorb trace color bodies. After filtration through a 0.5 micron inline cartridge, the solution is concentrated under reduced pressure (≤50 mbar, internal temperature ≤45°C) in a glass-lined reactor equipped with a vertical condenser and distillate receiver. The resulting free-base oil is dissolved in isopropanol at 50°C, and 1.05 equivalents of concentrated hydrochloric acid (37% w/w) diluted to 15% v/v in isopropanol are added over 90 minutes with controlled stirring at 120 rpm; the hydrochloride salt precipitates as a crystalline solid. Temperature is then ramped linearly from 50°C to 0°C over 6 hours to promote formation of Form I crystals, which is critical because Form II generates a polymorphic mixture that fails dissolution specification under FDA dissolution method USP <711> Apparatus II at 50 rpm in 0.1 N HCl. The wet cake is isolated by centrifugation in a peeler centrifuge (Rousselet Robatel, basket diameter 800 mm) at 1200 rpm, washed with cold isopropanol, and dried in a double-cone vacuum dryer at 45°C and ≤30 mbar for 18–24 hours until loss on drying by Karl Fischer analysis falls below 0.3% w/w. Terminal product is lurasidone HCl with residual solvent content controlled per ICH Q3C options 1 and 2, and residual palladium from an upstream hydrogenation step verified below 10 µg/g via ICP-MS. This API is formulated by direct compression with pregelatinized starch, mannitol, crospovidone, and magnesium stearate into tablet strengths of 20 mg, 40 mg, 80 mg, and 120 mg, with blend uniformity acceptance limits of 90.0–110.0% label claim and RSD ≤5.0% per 21 CFR 211.110. Environmental monitoring during intermediate storage is addressed under 21 CFR 211.42 with continuous humidity logging that triggers automatic dry nitrogen purging of the feedstock drum whenever relative humidity exceeds 35%, as the piperazinyl intermediate exhibits hygroscopicity that shifts its water content by +0.2% w/w per hour at 60% RH and 25°C, leading to undesired hydrolysis of the benzoisothiazole ring when water content exceeds 0.5% during the alkylation step.How Is the Reaction Profile of 3-(Piperazin-1-yl)benzo[d]isothiazole Optimized for Ziprasidone Free Base and Subsequent Salt Formation?For ziprasidone hydrochloride monohydrate, the pivotal C—N coupling between the piperazine nitrogen and the 2-chloroethyl side chain of 5-(2-chloroethyl)-6-chloro-1,3-dihydro-2H-indol-2-one requires precise stoichiometric control to avert polymerase-like oligomerization of the chloroethyl substrate. In a typical production-scale batch, the indolinone derivative is dissolved in a mixture of acetonitrile and purified water (volume ratio 9:1) at 55°C, and solid anhydrous sodium carbonate (1.8 molar equivalents relative to the chloroethyl species) is charged as a heterogeneous acid scavenger. The benzoisothiazole intermediate is then introduced in one portion at a molar ratio of 1.00 to 1.03 relative to the limiting chloroethyl reagent; deviations beyond 1.05 equivalents generate a dibenzoisothiazole impurity that co-crystallizes with the final API and requires reslurrying in hot toluene, raising the total cycle time by approximately 14 hours. The mixture is heated to reflux (78–82°C) for 16 hours under a nitrogen blanket while in-line ReactIR monitoring tracks the disappearance of the characteristic C—Cl absorbance at 690 cm⁻¹. Upon completion, the slurry is cooled to 10°C, filtered, and washed with 5°C acetonitrile/water; the resulting wet cake is recrystallized from methanol/water (70:30 v/v) to yield ziprasidone free base with an HPLC purity exceeding 99.5% and individual unspecified impurities below 0.10%. Salt formation to ziprasidone hydrochloride monohydrate proceeds by dissolving the free base in tetrahydrofuran at 40°C, adding 1.0 equivalent of concentrated hydrochloric acid diluted in THF, seeding with monohydrate crystals at 35°C, and cooling to -5°C at a ramp rate of -5°C/h. The isolated salt is dried in a fluid-bed dryer with inlet air at 30°C and dew point -20°C until moisture content by Karl Fischer reaches 3.0–3.5% w/w, matching the theoretical monohydrate stoichiometry. This API forms the core of ziprasidone capsules (20, 40, 60, 80 mg) manufactured by blending with polysorbate 80 and microcrystalline cellulose before pelletization in an extrusion-spheronization line (Niro PP1, screw speed 120 rpm, spheronization speed 950 rpm) to achieve pellets with a Crushing Strength of 1.2–2.0 N/mm². Compliance encompasses ICH Q7 for active pharmaceutical ingredient GMPs, ICH Q3C for residual solvents (acetonitrile limit 410 ppm, methanol limit 3000 ppm), 21 CFR 211 for finished dosage forms, and specific compendial adherence to the ziprasidone hydrochloride monograph USP and EP, including limits for the N-oxide degradant (≤0.15%) and the des-chloro analog (≤0.10%). The piperazinyl intermediate itself must comply with an internal specification requiring water content below 0.3% and residual benzenoid carryover from the preceding benzoisothiazole cyclization step at a level demonstrably below 2 ppm to meet the ED50 lifetime limit of 2 µg/day for a benzene-related impurity per ICH M7 category 1.Perospirone Hydrochloride Intermediate: Amide Coupling and Butylene Spacer ChemistrySynthesis of perospirone hydrochloride, marketed as Lullan in Japan for schizophrenia and experiencing expanded investigation for bipolar mania, relies on an N-alkylation of the piperazinyl intermediate with cis-N-(4-bromobutyl)cyclohexane-1,2-dicarboximide. The bromobutyl reagent, synthesized by refluxing cyclohexane-1,2-dicarboxylic anhydride with 4-bromobutylamine hydrobromide and subsequent dehydration, is used at a 1.05–1.10 molar equivalent relative to the benzoisothiazole derivative. The coupling is conducted in dimethyl sulfoxide at 80°C, with 1.5 equivalents of triethylamine as the base, and the reaction progress is tracked by TLC on silica gel GF254 plates eluting with chloroform/methanol 9:1, with endpoint defined by residual piperazine spot visualization below 0.5% area via densitometry. Crude perospirone free base is extracted into methyl tert-butyl ether from an ice-water quench and then converted to the hydrochloride directly by introducing anhydrous HCl gas into a chilled (0–5°C) solution of the free base in ethyl acetate/ethanol (85:15 v/v). A critical processing narrow zone exists during crystallization: the product solution must remain anhydrous, as water content above 0.15% w/w in the solvent mixture shifts the crystal habit from dense prisms with a bulk density of 0.55 g/mL to fragile needles with a bulk density below 0.30 g/mL, causing severe filtration blinding on a pressure filter with a cloth porosity of 5 µm. Final purification is achieved by recrystallization from methanol/isopropyl ether to provide perospirone hydrochloride in 99.7+% purity with the cis configuration confirmed by X-ray powder diffraction comparison to the reference pattern published in the Japanese Pharmacopoeia (JP) monograph. The JP acceptance criteria mandate a trans isomer content of ≤0.2% by HPLC on a chiral cellulose tris(3,5-dimethylphenylcarbamate) column, detection at 230 nm. The finished drug product is usually an 8 mg tablet, compressed using a rotary press with 10 kN force, and compliance extends to JP 5.01 for tablet uniformity, ICH Q7, and PMDA Guidelines on the Manufacturing and Quality Control of Drugs. Furthermore, because the starting bromobutyl intermediate is a potential genotoxic impurity, its carryover into the API is monitored with an LC-MS/MS limit of 1.5 µg/g, aligned with staged control under ICH M7 Option 3.Drug discovery programs targeting dual serotonin 5-HT1A and dopamine D2 receptor antagonism, as well as those pursuing GluN2B subunit-selective NMDA receptor modulation, frequently employ the 3-(piperazin-1-yl)benzo[d]isothiazole scaffold as a privileged fragment for lead optimization. In a med-chemistry parallel synthesis setting configured to support a kinetic solubility-guided hit-to-lead cascade, the intermediate is distributed into five-neck microblock reactors (96-well format) via automated liquid handler calibrated with a coefficient of variation ≤3.0% at volumes of 200 µL. A typical library elaboration couples the piperazine with an array of 96 arylalkyl bromides or reductive amination substrates under standardized conditions: 0.10 mmol intermediate, 0.12 mmol electrophile, 0.15 mmol of diisopropylethylamine in 0.8 mL of anhydrous acetonitrile stirred at 50°C for 18 hours. The process adheres to the principles of ISO 9001 quality management for research service providers, though full cGMP is not triggered because the outputs are used exclusively for in vitro pharmacological profiling. Produced libraries undergo LC-UV-MS purification on a C18 preparative column (30 × 150 mm, 5 µm) with acetonitrile/water/0.1% formic acid gradient, yielding target compounds as trifluoroacetate or formate salts that are submitted for radioligand binding assays and functional cAMP assays. The terminal output is a structure–activity relationship data package that informs a patent composition-of-matter filing; no marketed medicine directly originates at this stage, though several compounds of this chemotype have advanced to Phase I single ascending dose studies documented in public clinical trial registries.When the Intermediate Is Supplied as a cGMP-Compliant Starting Material for CDMO CampaignsContract development and manufacturing organizations that design manufacturing routes around a late-stage introduction of the piperazinyl moiety frequently designate 3-(piperazin-1-yl)benzo[d]isothiazole as an API starting material under a regulatory starting material justification per ICH Q11 Example 4 and the corresponding EMA Reflection Paper on starting materials. In such arrangements, the intermediate must be amenable to a supplier quality agreement that defines a purity floor of 99.0% by HPLC, water content ≤0.5% w/w, and a residual solvent profile compliant with ICH Q3C Class 2 limits (e.g., dichloromethane ≤600 ppm, DMF ≤880 ppm). The direct addition ratio in the subsequent regulatory step, typically a reductive alkylation or a Suzuki–Miyaura cross-coupling that anchors the benzoisothiazole core to a substituted biaryl fragment, is established during process validation as 1.00 to 1.20 molar equivalents relative to the electrophile, with a design space that permits narrowing to 1.02–1.08 after three consecutive validation lots show relative standard deviation ≤2.0% in yield. The downstream process at the CDMO facility starts with a reactor-cleaning verification using a total organic carbon swab limit of 5.0 µg/cm² and then proceeds with charging the starting material under an inert atmosphere into a Hastelloy C-22 vessel rated for 500 L working volume. Coupling is performed at 45–55°C with 0.5 mol% Pd(PPh₃)₄ or an equivalent catalyst system; the batch is aged at 0°C for 8 hours post-reaction to precipitate a crude intermediate that is slurried in 70% aqueous ethanol at 60°C for 4 hours to remove triphenylphosphine oxide by-product. After isolation, the final API is produced by hydrogenolysis of a benzyl-protecting group in a stirred autoclave at 3.0 bar hydrogen pressure over 5% Pd/C (0.02 kg/kg substrate) and crystallized from ethyl acetate/hexane. Finished dosage forms, most commonly tablets or capsules in the 1–100 mg strength range, follow a standard direct-compression or roller-compaction pathway fully described in the associated Module 3.2.P.2. Equipment validation includes temperature mapping of the dryer with 12-point thermocouple arrays and certification of the tablet press tooling set against ASTM E18 Rockwell hardness requirements. Batch record review requires that any electronic signature on a critical process parameter entry—such as jacket temperature or agitator speed—adheres to 21 CFR Part 11 audit trail requirements.Reference Standards and System Suitability Markers Linked to Pharmacopoeial MonographsWhen the compound is used as a designated impurity reference marker or a system suitability standard under official monographs, its role shifts from bulk manufacturing intermediate to highly characterized analytical standard. The substance is designated in the EP monograph for lurasidone hydrochloride as Impurity B (systematic chemical name, batch-specific assignment) with a specified retention time window of ±1.5% relative to the lurasidone peak under the official HPLC conditions (column: octadecylsilyl silica gel, 150 × 4.6 mm, 3 µm; mobile phase: gradient of phosphate buffer pH 6.0 and acetonitrile; detection: 230 nm). In that context, the “formulation addition ratio” is replaced by an analytical concentration target: a standard solution concentration of 0.1 mg/mL in diluent (mobile phase) yields a signal-to-noise ratio greater than 50 for the impurity peak, allowing quantitation at the 0.05% limit relative to the drug substance. Production of this standard at a reference material facility proceeds by preparative HPLC purification of a pre-qualified commercial lot on a C18 column (50×250 mm, 10 µm), using isocratic elution with 65:35 v/v methanol/phosphate buffer pH 3.5. The pooled fractions are neutralized with 0.1 N sodium hydroxide, extracted into dichloromethane, dried over anhydrous sodium sulfate, and evaporated to a foam. The residue is then dissolved in tert-butanol, freeze-dried at a shelf temperature of -40°C and pressure ≤0.1 mbar for 48 hours to afford a low-hygroscopic powder that is sealed under argon in amber vials sealed with PTFE-faced butyl rubber stoppers. Each vial contains 10 mg or 25 mg net weight as verified by a calibrated microbalance with readability 0.001 mg. The product is assigned a certified purity value of 99.8% with an expanded uncertainty of ±0.4% (coverage factor k = 2, confidence interval 95%) based on mass balance, quantitative NMR using an internal standard of certified diethyl phthalate, and HPLC peak area normalization. Compliance is maintained against ISO 17034:2016 for reference material producers and ISO/IEC 17025:2017 for competence of testing and calibration laboratories, with full traceability to the SI unit of mass traced through a NIST-traceable certified weight set. The terminal “product” is a Certificate of Analysis that accompanies the powder and serves pharmaceutical quality control laboratories for system suitability and impurity quantitation in finished dosage forms such as lurasidone HCl tablets, ziprasidone capsules, and perospirone tablets, where monograph compliance is a prerequisite for batch release in the EU, US, and Japanese markets. |
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Commercial availability of 3-(piperazin-1-yl)benzo[d]isothiazole, CAS 87691-88-1, typically encompasses the free base as an off-white to pale yellow crystalline powder with a molecular formula of C₁₁H₁₃N₃S and a formula weight of 219.31 g/mol. The heterocyclic scaffold combines a piperazine ring N-linked to the 3-position of a benzisothiazole nucleus, generating a bicyclic system whose electron distribution differs markedly from indole- or indazole-piperazine analogues. Storage under inert gas at 2–8°C in sealed, light-resistant containers is standard; exposure to ambient humidity above 60% RH triggers gradual discoloration and measurable hygroscopic weight gain exceeding 2.5 wt% over 72 hours in open-dish stability studies conducted at 25°C/60% RH (ICH Q1A conditions).
When implemented as a key pharmaceutical intermediate, the material demands rigorous control of residual piperazine monomer, which is monitored by ion chromatography with suppressed conductivity detection (limit: ≤0.15%). The single-stage SNAr coupling between 3-chlorobenzo[d]isothiazole and piperazine in refluxing n-butanol over 18–24 h generates the target compound in isolated yields typically spanning 68–82% after crystallization from acetonitrile/water (3:1 v/v). The difference between this free base and its hydrochloride salt (CAS 1187929-28-1) is not merely physical; the protonated salt exhibits aqueous solubility greater than 45 mg/mL at pH 4.0, whereas the free base remains below 0.8 mg/mL in water at 25°C, a property that dictates the choice of form for subsequent N-alkylation or reductive amination steps in polar aprotic media.
Prior to scale-up charging, pre-drying of 3-(piperazin-1-yl)benzo[d]isothiazole free base to ≤0.5% water content (Karl Fischer titration, ASTM E203) is obligatory when the downstream step involves moisture-sensitive reagents such as sulfonyl chlorides or acid anhydrides. Drying is performed in a vacuum tray dryer at 40–45°C under ≤10 mbar for a minimum of 6 h, with nitrogen break. Incompatibility with strong oxidizing agents is documented; deliberate mixing with KMnO₄ or HNO₃ (conc.) leads to exothermic decomposition with onset temperatures detected by differential scanning calorimetry (DSC) at 142°C accompanied by an energy release of >450 J/g. In production-scale reactors (glass-lined, 500–2000 L capacity), the compound is best charged through a nitrogen-purged glovebox port or via a contained split-valve transfer system to minimize operator exposure, as the compound is classified as a skin sensitizer under GHS07.
Operational boundaries during solution-phase chemistry are further constrained by the free base’s tendency to undergo ring-opening of the isothiazole under strongly basic conditions (pH >12, aqueous NaOH 2 M at 60°C). Stability studies at varying pH confirm <5% degradation over 24 h at pH 1.2–10.0, while at pH 13.0 degradation exceeds 12% within 6 h as monitored by HPLC peak purity at 254 nm. Thus, its use in aqueous alkylation protocols is limited to buffered systems where borate or phosphate buffers maintain pH ≤9.5.
The benzo[d]isothiazole nucleus imparts a unique electronic profile. The ring-system N–S bond carries a covalent character that reduces the heterocycle’s basicity relative to benzothiazole, making the compound less prone to protonation-catalyzed nucleophilic substitution at the 3-position. Comparative Hammett σm values and calculated electrostatic potential surfaces (DFT, B3LYP/6-31G(d) level) indicate that the C-3 carbon bearing the piperazine moiety exhibits a higher partial positive charge than analogous C-2 in indole-piperazines, enhancing reactivity toward soft nucleophiles while diminishing susceptibility to electrophilic aromatic substitution on the benzo ring. A direct practical consequence surfaces in Pd-catalyzed cross-coupling: attempts to perform Suzuki-Miyaura couplings on the benzo ring of 3-(piperazin-1-yl)benzo[d]isothiazole under standard conditions (Pd(PPh₃)₄, Na₂CO₃, DME/H₂O, 80°C) result primarily in recovery of starting material, whereas the corresponding bromoindole-piperazine reacts smoothly. A protecting group strategy involving Boc protection of the piperazine NH is typically required to redirect reactivity, followed by coupling at the 5- or 6-position using the appropriate brominated precursor (e.g., 5-bromo-3-(piperazin-1-yl)benzo[d]isothiazole).
An additional point of divergence is the pharmacokinetic liability of the benzisothiazole S–N bond, which undergoes metabolic reduction by hepatic flavin-containing monooxygenases (FMOs) in vivo, leading to ring-opened thioamide-type metabolites. This metabolic fate contrasts with the oxidative pathways observed for benzothiazole and indole hybrids and informs the design of prodrugs with attenuated first-pass clearance—published data for this specific configuration is limited, but expert extrapolation from related lurasidone metabolic profiles supports that CYP3A4-mediated oxidation occurs predominantly on the piperazine ring rather than the benzisothiazole, leaving the reactive S–N bond intact until FMO-mediated processing.
A typical release specification for 3-(piperazin-1-yl)benzo[d]isothiazole destined for early-phase clinical API synthesis is framed against multiple pharmacopoeial general chapters. The following table collates the test parameters, methods, and acceptance criteria commonly employed in GMP facilities.
| Attribute | Method Reference | Acceptance Criterion |
|---|---|---|
| Appearance | Visual inspection | Off-white to pale yellow powder |
| Assay (HPLC) | USP <621>, C18, 254 nm | ≥98.0% area |
| Related substances | HPLC, same method | Single impurity ≤0.5%, total ≤1.5% |
| Residual piperazine | IC, suppressed conductivity | ≤0.15% w/w |
| Water (K.F.) | ASTM E203, coulometric | ≤0.5% |
| Residual solvents | GC-HS, USP <467> class 2 | Acetonitrile ≤410 ppm, n-butanol ≤5000 ppm |
| Heavy metals | ICP-MS, Ph. Eur. 2.4.8 | Pb ≤10 ppm, Cd ≤2 ppm, Hg ≤1 ppm, As ≤1.5 ppm |
| Sulphated ash | Ph. Eur. 2.4.14 | ≤0.1% |
| Particle size (D90) | Laser diffraction, ISO 13320 | ≤150 µm (if specified for solid formulation) |
| Melting range | DSC / open capillary | 126–130°C |
The differences between lots sourced from alternative synthetic routes become visible primarily in the profile of regioisomeric impurity. A competing route starting from 3-nitrobenzo[d]isothiazole and employing hydrogenation over Raney-Ni may introduce 0.2–0.5% of the over-reduced aminothiophenol derivative, which is not observed in the halogen displacement route. Labs equipped with UPLC-QTOF-MS (typical parameters: ESI+, cone voltage 30 V, mass accuracy ≤3 ppm) can distinguish these trace-level congeners via accurate mass and fragment ion spectra, specifically the diagnostic loss of S (31.972 Da) indicative of the isothiazole ring integrity.
When 3-(piperazin-1-yl)benzo[d]isothiazole is utilized as a nucleophilic building block in multi-step lurasidone-type syntheses, the reaction with an activated cyclohexane intermediate (e.g., (1R,2R)-2-(bromomethyl)cyclohexylmethyl derivative) in the presence of potassium carbonate and catalytic KI in DMF is mildly exothermic. Reaction calorimetry (Mettler Toledo RC1e, AP01 glass reactor, 1 L scale) reveals an adiabatic temperature rise of 27°C and a maximum heat release rate of 35 W/L, well within the safe operating limits of a standard 2000 L glass-lined vessel equipped with a jacket cooling capacity of 0.6 kW/m²·K. However, the deferred addition of all reactants to the refluxing solvent without initial stabilization of the base mixture can cause a localized exotherm exceeding 50°C within a 5-minute window. Adopted process safety control includes ramped dosing of the bromide over 90 min while maintaining internal temperature at 72 ± 3°C, with continuous monitoring by on-line FTIR for the disappearance of the starting bromide C-Br stretch at 605 cm⁻¹.
In the subsequent isolation, the free base of the product intermediate is often converted to its hydrochloride salt to facilitate purification. The difference in solubility between the free base and the HCl salt is exploited: the free base remains highly soluble in ethyl acetate, while the salt precipitates as a dihydrochloride with a sharp DSC endotherm at 228–232°C (decomposition). Residual piperazine content in the salt drops below 0.05% after a single salt break/release cycle, meeting the stringent requirements of Q3A(R2) impurity qualification for a starting material in an API carrying a maximum daily dose of 40 mg/day.
Large-scale drying of the final API intermediate often employs a filter-dryer combination (e.g., Rosenmund GFD, Hastelloy C22) with vacuum 5–10 mbar and jacket temperature ramped from 25°C to 45°C over 8 h. Agitation speed is limited to 15–20 rpm to prevent particle attrition, as fines generation (D10 <5 µm) can lead to filtration issues in downstream isolations. Batch records indicate that static charge build-up in the dry powder, measured as surface potential exceeding 2 kV, requires nitrogen inerting with conductive bag-in/bag-out systems (Type D FIBC, Cenelectrex or equivalent) for safe discharge.
A second comparative table contrasts the free base with the frequently traded dihydrochloride salt, highlighting parameters relevant to form selection in manufacturing campaigns.
| Property | Free Base | Dihydrochloride Salt |
|---|---|---|
| CAS number | 87691-88-1 | 1187929-28-1 |
| Aqueous solubility (25°C) | <0.8 mg/mL | >45 mg/mL |
| Hygroscopicity (25°C/80% RH) | +0.3% w/w in 24 h | +6.2% w/w in 24 h |
| Melting/decomposition point | 126–130°C | 228–232°C (dec.) |
| Typical bulk density (tapped) | 0.45 g/mL | 0.62 g/mL |
| Residual piperazine (IC) | ≤0.15% | ≤0.05% |
| Preferred use | Non-aqueous N-alkylations; Boc protection | Aqueous-phase reactions; storage over long campaigns |
| Electrostatic risk | High (MIE <3 mJ) | Moderate (MIE 10–30 mJ) |
Industrial procurement specifications often carry a supplementary note: the free base must be demonstrated free from N-nitrosamines (e.g., N-nitroso-piperazine) by LC-MS/MS analysis per the EMA/CMDh guideline, with a limit of quantification (LOQ) of 0.03 ppm relative to the sample. This requirement is driven by the secondary amine functionality of the piperazine ring, which can undergo nitrosation if residual nitrite is present from reagent streams. Manufacturers that employ nitrite-free processing and thorough nitrosation risk assessments (ICH M7, option 4 control strategy) add a further differentiator against generic commodity intermediates, which may lack such data packages.
In terms of regulatory starting material designation, this compound is frequently accepted as a GMP-starting material for lurasidone hydrochloride API per multiple DMF filings, provided the synthetic process from this intermediate comprises at least five chemical transformation steps to the final drug substance and the compound is controlled as per ICH Q11 principles. Differences from other products like 3-(4-arylpiperazin-1-yl)benzo[d]isothiazoles lie in the nascent NH group’s ability to act as a reactive handle for subsequent diversification, as opposed to pre-substituted aryl piperazines which offer no further basic nitrogen for derivatization. This bifunctional character—serving both as a nucleophile and as a latent base—is what positions 3-(piperazin-1-yl)benzo[d]isothiazole as a flexible intermediate in neuropsychiatric drug pipelines, albeit requiring careful handling to avoid N-oxide formation during oxidative work-ups.
