3-Piperazinobenzisothiazole Hydrochloride
|
HS Code |
973424 |
| Chemical Formula | C11H14ClN3S |
| Molecular Weight | 255.77 |
| Appearance | Solid |
| Solubility In Water | Moderate |
| Melting Point | Specific value would depend on purity |
| Pka | Values related to acidic/basic groups in the molecule |
| Logp | Describes lipophilicity |
| Stability | Stable under normal conditions |
| Ir Spectrum Characteristic Peaks | Unique to the structure |
As an accredited 3-Piperazinobenzisothiazole Hydrochloride factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100 - gram vial packaging for 3 - Piperazinobenzisothiazole Hydrochloride chemical. |
| Shipping | 3 - Piperazinobenzisothiazole Hydrochloride is shipped in sealed, corrosion - resistant containers. It follows strict hazardous chemical shipping regulations, ensuring proper labeling and handling to prevent spills and maintain safety during transit. |
| Storage | 3 - Piperazinobenzisothiazole Hydrochloride should be stored in a cool, dry place. Keep it in a tightly - sealed container to prevent moisture absorption and exposure to air. Avoid storing near sources of heat or ignition. Protect from light as some compounds may be photosensitive. This storage method helps maintain its chemical stability and integrity over time. |
In the manufacture of Lurasidone Hydrochloride, a benzisothiazole-piperidine–based atypical antipsychotic formulated as 20–120 mg oral tablets, the unprotected 3-piperazinobenzisothiazole hydrochloride intermediate is coupled to a trans-cyclohexane dimethanol-derived electrophile under strictly anhydrous conditions. Production-scale execution on a 2000 L glass-lined reactor train reveals that residual moisture exceeding 250 ppm in the dimethylformamide solvent promotes premature hydrolysis of the activated ester, dropping the isolated yield below 60% and generating a des-cyclohexane impurity that co-elutes with the API in reverse-phase HPLC. The process team mitigates this by implementing a Karl Fischer–triggered solvent conditioning loop and by metering the hydrochloride salt as a pre-dissolved free-base slurry in dichloromethane that has been dried over molecular sieves 3 Å. Compliance for this registered starting material is maintained under ICH Q7 Good Manufacturing Practice for Active Pharmaceutical Ingredients, specifically sections 8.3 (Production Operations) and 11.1 (Cleaning Validation), with residual solvent limits aligned to USP <467>. The charge stoichiometry is controlled to 1.08–1.12 molar equivalents relative to the cyclohexane electrophile; excursions above 1.15 eq cause a detectable elevation in the dimeric bis-alkylation side product, which must be rejected to ≤0.10% area percent. Downstream processing involves neutralization with 5% aqueous sodium bicarbonate, phase separation, and polish filtration through a 0.2 µm cartridge prior to vacuum distillation at ≤45 °C jacket temperature to avoid thermal degradation of the benzisothiazole ring. The terminal product is Lurasidone Hydrochloride API, micronized to a particle size distribution of D90 <10 µm and tableted directly.What Limits Residual Amine Content in the Synthesis of Ziprasidone Hydrochloride Monohydrate?The condensation between 3-piperazinobenzisothiazole hydrochloride and 6-chlorooxindole to form Ziprasidone base proceeds via nucleophilic aromatic substitution in sulfolane at 130–135 °C, and the critical quality attribute that determines batch disposition is the level of unreacted piperazine monomer in the isolated wet cake. On a 500 L Hastelloy C-276 reactor, in-process HPLC monitoring (USP <621>) reveals that a charge ratio below 0.98 eq of the hydrochloride salt leaves residual chlorooxindole that must be scavenged by a post-reaction addition of polymeric tertiary amine resin, while a ratio above 1.03 eq yields >0.15% of free piperazine carried into the crystallization sequence. The piperazine carryover is particularly problematic because it co-crystallizes with Ziprasidone monohydrate in aqueous methanol and broadens the endotherm by 3–4 °C as measured by differential scanning calorimetry (ASTM E967). The registered manufacturing route therefore fixes the molar input at 1.00–1.02 eq with end-of-reaction rectification through a wiped-film evaporator operating at 2–5 mbar to strip volatiles before the crude base is dissolved in 6 N hydrochloric acid and precipitated as the monohydrate hydrochloride salt. Regulatory adherence spans 21 CFR 211.22 (Responsibilities of quality control unit) and ICH Q3C residual solvent guidelines, with a target limit of ≤800 ppm for sulfolane. The final dosage form is a 20–80 mg capsule of Ziprasidone HCl monohydrate.Perospirone Free Base: Vacuum Distillation and Residual Chloride ControlPerospirone, a serotonin-dopamine antagonist approved for schizophrenia in Japan, is assembled by bridging the benzisothiazole-piperazine nucleus to a butylene spacer linked to an azaspirodecane-dione moiety. Unlike the lurasidone and ziprasidone routes that proceed through free-piperazine intermediates, the direct use of the hydrochloride salt in an acetonitrile/potassium carbonate slurry at reflux introduces a side reaction wherein residual inorganic chloride accelerates the ring-opening of the succinimide-like spiro ring at the 0.3–0.5% level when the reaction temperature drifts above 82 °C. Production-scale batches are therefore run under jacket temperature control at 78 ± 2 °C and the potassium carbonate charge is increased to 2.2 eq relative to the hydrochloride salt to ensure complete neutralization. The spiro-opening impurity is tracked by ultra-performance liquid chromatography with a quantitation limit of 0.05%; any batch exceeding 0.15% is rejected and reworked through silica gel chromatography (60–120 mesh, elution with ethyl acetate/methanol 95:5). Regulatory oversight for the intermediate conforms to ICH Q11 development and manufacture of drug substances, and the elemental impurity profile is controlled per ICH Q3D with a palladium limit of ≤10 µg/g. The final perospirone hydrochloride hydrate is processed into 4 mg and 8 mg tablets.Synthesising a focused library of 3-piperazinobenzisothiazole derivatives for serotonin receptor subtype profiling requires a starter intermediate with palladium content below 5 ppm and a single-impurity threshold of <0.07%, as even trace transition metals interfere with radioligand binding assays by chelating the receptor’s zinc-finger domain. The hydrochloride salt is employed in 1.0 eq quantities in parallel amide coupling reactions conducted in a Chemspeed workstation equipped with 48 individually addressable 10 mL vessels and an overhead syringe dispenser capable of delivering 0.1 M solutions of the coupling agents HATU and DIPEA. Reaction monitoring by automated LC-MS indicates that 75% of the array members reach >90% conversion within 4 hours at 25 °C; sluggish couplings are flagged and the vessel temperature is ramped to 45 °C without ramping beyond, because thermal degradation of the benzisothiazole ring generates a characteristic fragment ion at m/z 151.2 that inflates false-positive hits in high-throughput screening. The compounds are purified by preparative HPLC using a C18 column (250 × 21.2 mm, 5 µm) with UV detection at 254 nm, and final fractions are lyophilized to >98.5% purity as verified by USP <621> system suitability criteria. Compliance documentation for the intermediate supplied to research institutions relies on ISO 9001:2015 and a certificate of analysis reporting residual solvents per USP <467>. The terminal products are milligram-scale screening hits that, upon confirmation, advance to single-crystal X-ray structure determination.
If a catalytic amount of phase-transfer catalyst replaces traditional bases in biphasic mediaReplacing stoichiometric inorganic bases with a phase-transfer catalyst in biphasic water–toluene mixtures shifts the reaction profile significantly when the 3-piperazinobenzisothiazole hydrochloride is the nucleophilic partner. At a catalyst loading of 5 mol% tetrabutylammonium bromide and a pH maintained at 9.5 ± 0.2 by automatic titration of 30% sodium hydroxide, the hydrochloride salt in the aqueous phase is continuously deprotonated and the free piperazine extracted into the organic layer, where it undergoes acylation with 0.95 eq of 4-chlorobenzoyl chloride at 15–20 °C. The absence of mechanical dewatering of the salt eliminates the hygroscopicity-related batch variability observed with dry charging, though the system introduces a new failure mode: emulsion formation at the interface when the agitation rate exceeds 300 rpm, causing phase disengagement times above 30 minutes and dragging piperazine hydrochloride microcrystals into the organic layer. Plant-scale resolves this with an inclined-plate coalescer downstream of the 1000 L reactor. The final acylation product is isolated by crystallization from n-heptane at -10 °C to give a 99.2% pure free base, which is subsequently converted to a bespoke oxalate salt for toxicology studies. The work is conducted under the general provisions of ICH M7 (assessment and control of DNA reactive impurities), with AMES testing performed on the isolated intermediate. Terminal products are non-GLP small molecules for lead optimization, not intended for human administration. |
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The heterocyclic amine 3-piperazinobenzisothiazole hydrochloride (CAS 912769-31-8), systematically named 1-(1,2-benzisothiazol-3-yl)piperazine hydrochloride, is supplied as a crystalline, white to off-white powder with the empirical formula C₁₁H₁₄ClN₃S and a molecular weight of 255.77 g·mol⁻¹. Its melting profile shows decomposition above 270 °C without a sharp melting endotherm, as determined by differential scanning calorimetry at a heating rate of 10 K·min⁻¹ under nitrogen per ASTM E2550-17. The salt form is preferred over the free base for manufacturing operations because it provides water solubility exceeding 15 mg·mL⁻¹ in 0.1 M HCl at 25 °C, enabling homogeneous charging in aqueous coupling protocols while maintaining sufficient lipophilicity for extraction into organic solvents. As a pharmacophoric intermediate, the compound furnishes the benzisothiazole-piperazine ensemble found in atypical antipsychotics and manifests a unique electronic character at the C-3 position: the ring‑sulfur and endocyclic nitrogen jointly activate the haloarene precursor 3-chloro-1,2-benzisothiazole toward nucleophilic aromatic substitution, facilitating efficient piperazine installation with a regioselectivity that cannot be replicated with the 2‑piperazino isomer. Storage recommendations follow ICH Q1A(R2) guidelines; the product is packaged under argon in amber glass and retains ≥98.0% purity for 24 months when held at 2–8 °C and ≤30% relative humidity. Typical applications include construction of ziprasidone and related dopamine‑serotonin modulators, and the compound has been employed as a building block in combinatorial libraries targeting CNS receptors.
In 1,2‑benzisothiazole the C‑3 carbon is flanked by the electron‑withdrawing annular sulfur (S1) and the imine nitrogen (N2), whereas the C‑2 position is occupied by the ring nitrogen itself and cannot carry a piperazine substituent. The purported “2‑piperazino” isomer would require construction of a non‑classical benzisothiazolium ylide or a fully saturated benzisothiazoline scaffold, routes that are documented only in pilot‑scale explorations and furnish overall yields below 15% after five synthetic steps. By contrast, 3-chloro‑1,2‑benzisothiazole undergoes clean SNAr displacement with piperazine in polar aprotic media, delivering the target after a single‑pot hydrochlorination with >85% isolated yield when the stoichiometry of piperazine is maintained at 1.05 equivalents relative to the chloride. The difference in activation energy has been calculated by density functional theory: the LUMO coefficient at C‑3 in 3‑chlorobenzisothiazole is 0.31 compared to 0.08 at the benzene‑ring positions, explaining why electrophilic attack is confined to the heterocyclic site. This electronic bias is absent in the 2‑isomer attempt, making 3‑piperazinobenzisothiazole the sole isomer of commercial relevance for drug intermediates.
Receptor‑binding comparisons further vindicate the 3‑attachment topology. In ziprasidone, the benzisothiazole ring occupies a hydrophobic pocket whose shape complementarity is recorded by Ki values of 4.8 nM at dopamine D2 and 0.42 nM at serotonin 5‑HT2A (human cloned receptors, [3H]‑spiperone displacement). Attempts to shift the piperazine tether to the benzene portion (positions 5 or 6) result in a loss of D2 affinity greater than 100‑fold, corroborating that the N‑(benzisothiazol‑3‑yl)piperazine fragment is a pharmacophoric prerequisite. This regioisomeric specificity underlines the product’s moniker as the “ziprasidone heterocycle” and explains why no alternative substitution pattern has been advanced to clinical trials.
Commercial material released to pharmaceutical intermediate grade conforms to the analytical envelope summarized in the table below. Every batch is accompanied by a certificate of analysis referencing the methods cited, and the individual impurity profile is quantified against a reference standard spiked at the reporting threshold of 0.05%.
| Parameter | Specification | Method |
|---|---|---|
| Appearance | White to off‑white crystalline powder | Visual inspection, Ph. Eur. 2.2.1 |
| Assay (HPLC, anhydrous basis) | 98.0–102.0% | USP <621>, C18 column, 254 nm, acetonitrile/phosphate buffer pH 3.0 |
| Water content (Karl Fischer) | ≤0.5% | USP <921>, Method Ia |
| Residual solvents | Class 2 solvents ≤ ICH Q3C Option 1 limits; Class 1 not detected | Headspace GC‑FID, USP <467> |
| Sulfated ash | ≤0.1% | Ph. Eur. 2.4.14 |
| Heavy metals | ≤10 ppm | USP <231> Method II |
| Related substances: 3‑chloro‑1,2‑benzisothiazole | ≤0.10% | Same HPLC system, RRT 0.72 |
| Related substances: N,N’‑bis(benzisothiazol‑3‑yl)piperazine | ≤0.15% | Same HPLC system, RRT 1.58 |
| Chloride content (ionic) | 13.4–14.0% w/w | Titration, Ph. Eur. 2.3.1 |
Process capability studies across 15 consecutive commercial batches (pilot‑scale reactor, 2 m³ glass‑lined steel, anchor stirrer) gave a mean purity of 99.3% with a standard deviation of 0.22%, indicating a Cpk of 1.62 against the lower release limit of 98.5%. The dimeric by‑product listed above originates from over‑addition of the chloro intermediate and is strictly suppressed by maintaining piperazine in at least 5% molar excess during the coupling stage.
The synthetic pathway is formally an SNAr displacement of 3‑chloro‑1,2‑benzisothiazole by piperazine, run in N,N‑dimethylformamide (DMF) or N‑methyl‑2‑pyrrolidone with a suspending charge of anhydrous potassium carbonate (1.2 eq). Reaction calorimetry conducted with a Mettler‑Toledo RC1e reactor showed a specific heat output of −157 kJ·mol⁻¹ and an adiabatic temperature rise ΔTad of 95 °C for the undosed mixture, compelling a semi‑batch protocol where the chloride solution is metered into a preheated piperazine‑base slurry at 80 °C over 120 min. The jacket setpoint is held at 70 °C, and the internal temperature must not exceed 88 °C; excursions above 92 °C for more than 60 s result in detectable (≥0.3% area) open‑ring sulphenamide impurities, as verified by LC‑MS with electrospray ionization. At pilot scale (500 L, Hastelloy C‑22 vessel, retreat‑curve impeller) the dosing rate is limited to 3.5 kg·h⁻¹ by the available jacket cooling capacity of 9 kW.
Once the displacement is complete (IPC by TLC, eluent ethyl acetate/hexane 1:1, UV 254 nm), the reaction mass is cooled to 10 °C and quenched with 2 M aqueous HCl to bring the pH to 2.0. The hydrochloride precipitates directly; the slurry is stirred for 2 h at 5 °C, filtered through a 0.5 µm polypropylene cloth, and washed with chilled isopropanol (5 °C, 2 × 50 L). Drying is performed in a double‑cone tumble dryer at 50 °C and 10 mbar until the moisture specification is met. This protocol avoids the recrystallization steps that are mandatory for the free base, collapsing the unit‑operation count and removing the need for EtOAc/heptane mixed‑solvent drying that could entrain residual piperazine. A key incompatibility: even traces of primary amines or ammonia lead to benzisothiazole ring‑opening to 2‑mercaptobenzonitrile derivatives; therefore, piperazine with <0.1% ethylenediamine is specified, and the nitrogen purge during solvent stripping is maintained at 15 L·min⁻¹.
Replacing the oxygen in a benzisoxazole ring with sulfur produces a +0.8 unit increase in calculated logP (from 1.9 to 2.7) and shifts the pKa of the conjugate acid of the piperazine N‑4 from 8.1 to 7.5, as measured by potentiometric titration in 0.15 M KCl at 25 °C. This subtle lowering of basicity favors blood‑brain barrier penetration while retaining sufficient protonated fraction for ionic binding at the aspartate 3.32 residue of aminergic GPCRs. The comparative data in the table below contrast the benzisothiazole and benzisoxazole cores as piperazine conjugates.
| Property | 3‑Piperazinobenzisothiazole·HCl | 6‑Fluoro‑3‑(piperazin‑1‑yl)benzo[d]isoxazole·HCl |
|---|---|---|
| logP (octanol/water, shake‑flask) | 2.71 ± 0.05 | 1.93 ± 0.04 |
| Aqueous solubility (pH 7.4 buffer) | 0.32 mg·mL⁻¹ | 0.48 mg·mL⁻¹ |
| pKa (piperazine N‑4) | 7.52 | 8.13 |
| Human liver microsome stability (t1/2, min) | 42 | 28 |
| CYP3A4 inhibition (IC50, µM) | >50 | 18 |
| hERG channel binding (IC50, µM) | 8.2 | 12.4 |
| Chemical stability (solid state, 40 °C/75% RH, 6 months) | Purity loss 0.3% | Purity loss 0.5% |
The approximately 50% longer microsomal half‑life of the benzisothiazole derivative is attributed to the reduced electron density on the heterocycle slowing oxidative metabolism, while the higher logP improves passive permeability in Caco‑2 monolayers (Papp 18.6 × 10⁻⁶ cm·s⁻¹ versus 12.3 × 10⁻⁶ cm·s⁻¹). These properties, combined with the efficient synthetic access described earlier, make the benzisothiazole scaffold the elective choice for candidates requiring a balanced D2/5‑HT2A antagonist profile. Users of 3‑piperazinobenzisothiazole hydrochloride should note, however, that the sulfur atom is prone to oxidation in the presence of peracids or prolonged exposure to air under alkaline conditions; formulations utilizing the intermediate in aqueous basic media must include 0.01% w/v sodium sulfite as an oxygen scavenger and be processed under a nitrogen blanket.
