3-(1-Piperazinyl)-1,2-Benzisothiazole Monohydrochloride

What Are the Critical In-Process Controls for Mesylate Salt Formation Using This Intermediate?

When downstream processing targets the ziprasidone mesylate salt—often preferred for its higher aqueous solubility in parenteral formulations—the monohydrochloride must first undergo complete deprotonation at 20–25°C in deionized water using 1.05 molar equivalents of sodium hydroxide relative to the hydrochloride content. The resulting free base is extracted into dichloromethane, and residual piperazine and bis-alkylated by-products are scrubbed with 5% w/w brine before solvent swap to acetone. Alkylation with 1.00 mol equivalent of 5-(2-chloroethyl)-6-chloroindolin-2-one is conducted under a nitrogen cap at 55–60°C for 4 hours, with the endpoint confirmed by HPLC (budgeted limit: unreacted chloroindolinone < 0.5% area). Mesylate counterion introduction via methanesulfonic acid (1.02 eq) in isopropanol at 35°C is the defining step; deviation of more than ±0.5°C from the prescribed seeding temperature results in a polymorphic mixture that fails USP <941> characterisation. The product isolated on a 0.6 m² agitated nutsche filter-dryer is recrystallized from 90:10 v/v isopropanol/water to reduce sulfated ash below 0.1%, a requirement specified in the EP impurity monograph for ziprasidone mesylate trihydrate. Compliance with ICH M7 option 4 control strategy is applied to the 3,3′-piperazine-bridged dimer, which is held at a TTC-based limit of 0.15%. Terminal API identity is verified by EP CRS standards, and residual methanol from the final solvate exchange is limited to 40 ppm as per ICH Q3C Option 1.

Anhydrous Perospirone Alkylation — Eliminating Oxazolidinedione Ring-Opening Side Reactions

The synthesis of perospirone free base demands strict exclusion of moisture: the 3-(1-piperazinyl)-1,2-benzisothiazole monohydrochloride is initially suspended in anhydrous N,N-dimethylformamide (water specification < 0.05% by Karl Fischer titration, verified per ISO 760:1978), then treated with 2.2 molar equivalents of milled potassium carbonate to simultaneously neutralize the hydrochloride and generate the nucleophilic amine. After stirring at 40–45°C for 60 minutes under a dry argon sweep, 1.00 molar equivalent of 3-(4-chlorobutyl)-1,3-oxazolidine-2,4-dione is added in a single portion. The temperature is raised to 75±2°C and held for 8 hours; exceeding 80°C initiates ring-opening of the oxazolidinedione moiety, generating an N-carboxymethyl impurity that co-elutes with the API on HPLC. On a 2000 L glass-lined reactor equipped with a retreat-curve impeller, triphasic inline FTIR monitoring (ReactIR 15, Mettler Toledo) tracks the disappearance of the C–Cl stretch at 650 cm⁻¹. The reaction is quenched by transferring the mixture into 4 volumes of purified water at 10°C, and the crude free base is isolated via centrifuge (Rousselet Robatel EHBL 1000) and washed isopropanol. Recrystallization from 95% ethanol yields perospirone conforming to the JP XVIII impurity profile, where the des-chloro by-product is limited to < 0.10% and the ring-opened amide-acid degradant to < 0.15%. The drying protocol (double-cone vacuum dryer, 12 h at 45°C/-0.09 MPa) is essential to drive residual DMF below the ICH Q3C Concentration Limit of 880 ppm. Terminal dosage forms are 4 mg and 8 mg perospirone hydrochloride hydrate tablets; the upstream monohydrochloride batch records are retained under JP GLP-1 archiving requirements.

When Custom Libraries Require >95% Conversion in Single-Digit Milligram Scale Reactions

In early-stage central nervous system discovery programs, the monohydrochloride serves as a privileging scaffold for 5-HT₂A and D₂ receptor pharmacophore exploration under automated parallel synthesis workflows. The material is dispensed as a 0.25 M stock solution in anhydrous DMAc into 96-well microtiter plates using a Beckman Coulter Biomek i7 liquid handler housed in a nitrogen-purged glovebox (O₂ < 50 ppm, H₂O < 10 ppm). Each well receives 1.0 equivalent of the monohydrochloride pre-neutralized in situ with PS-DIPEA resin (2.5 eq, loading 3.2 mmol/g), followed by 1.15 equivalents of an electrophile (benzyl halides, sulfonyl chlorides, or α-bromo ketones) and catalytic tetrabutylammonium iodide (0.05 eq). Plates are sealed and heated in a Biotage Initiator+ microwave reactor at 120°C for 45 min with a vial-mode absorption level of “Very High.” Post-reaction purification uses an SCX-2 catch-and-release protocol: the reaction mixture is acidified with 1 M HCl, loaded onto 300 mg SCX-2 cartridges, washed with methanol, and the final amine products are eluted with 2 M NH₃/MeOH. LC/MS (Waters Acquity QDa, CORTECS C18 column, 2 min gradient) confirms >95% UV purity for >80% of library members, with residual palladium from catalyst carryover controlled below 10 µg/g per EMA/CHMP/SWP/4446/2000. The process follows ISO 9001:2015 Section 8.3 design and development standards, and all isolated yields are calculated on a dry-weight basis corrected for residual solvent content determined by headspace GC-FID. Scaled-up hit resynthesis moves to 1–5 g batch mode in Radleys 25 mL tube reactors using identical stoichiometric ratios, where the only adjustment is a switch to magnetic overhead stirring to prevent vortex-induced inhomogeneity observed with orbital shakers on partially soluble intermediates.

Table 1: Comparative Alkylation Parameters for Commercial Benzisothiazole Antipsychotic APIs

Parameter

Ziprasidone HCl Monohydrate

Perospirone HCl Hydrate

Lurasidone HCl

Base system

K₂CO₃ (1.2 eq) in H₂O/MeCN

K₂CO₃ (2.2 eq) in DMF

NaOH (2.0 eq) in toluene/H₂O

Molar ratio (intermediate:electrophile)

1.00:1.03

1.00:1.00

1.10:1.00

Reaction temperature

50–55°C

75±2°C

40–50°C

Key in-process limit

Chloroindolinone <0.5%

Ring-opened acid <0.8%

Ditoylated dimer <1.0%

Phase transfer catalyst

Not required

TBAB (0.05 eq)

In the convergent route to lurasidone hydrochloride, the monohydrochloride is first partitioned between toluene and 10% w/w aqueous sodium hydroxide at 25°C; the liberated free base is separated and the aqueous layer discarded within 45 minutes to avoid oxidative discoloration that shifts the product colour beyond the BY7 reference standard. The toluene solution, containing 1.10 molar equivalents of the piperazine free base relative to the subsequent electrophile, is charged into a 5000 L enamel-lined reactor containing cyclohexane-1,2-diylbis(methylene) bis(4-methylbenzenesulfonate) (1.00 eq) and tetrabutylammonium bromide at 0.05 eq. The biphasic mixture is sheared with a bottom-entering A310 hydrofoil impeller at 180 rpm; drop below 150 rpm results in macro-phase separation that halves the alkylation rate, while exceeding 210 rpm renders the interface too stable for subsequent gravity settling. Processing experience on this line indicates that a 60-minute recirculation through a static in-line mixer (Sulzer SMV) before entering the continuous decanter reduces rag-layer thickness to <2 cm, which is essential for achieving phase purity within the 4-hour target batch cycle. The organic phase is washed twice with 5% NaCl, dried over anhydrous magnesium sulfate, and concentrated under vacuum (50°C, -0.08 MPa). The crude lurasidone base is dissolved in warm acetone and converted to the hydrochloride by slow addition of 1.05 eq of 37% hydrochloric acid in isopropanol, crystalized, and micronized (jet-mill, d₉₀ < 10 µm) to meet the dissolution specification of USP <711> Apparatus II at 50 rpm in 0.1 N HCl. Residual toluene is controlled to 890 ppm per ICH Q3C, and total sulfonate esters are quantified by LC-MS/MS with a reporting threshold of 1 ppm. The finished dosage form is an immediate-release tablet of 20 mg, 40 mg, 80 mg or 120 mg lurasidone HCl, listed in the USP.

Production-scale synthesis of ziprasidone hydrochloride monohydrate relies on the monohydrochloride as a cost-determining building block. In a standard campaign executed in a 6300 L glass-lined reactor train, 1.0 molar equivalent of the monohydrochloride is suspended in 4 volumes of acetonitrile at 22°C, and 1.2 equivalents of anhydrous potassium carbonate are added. While the slurry is agitated at 120 rpm with a pitched-blade turbine, 1.03 equivalents of 5-(2-chloroethyl)-6-chloroindolin-2-one (purity >99.8% by external standard method) are introduced in three equal portions over 45 min to moderate the exotherm. The mixture is heated to 52–54°C and maintained for 3 hours; reaction completion is defined as residual indolinone derivative <0.3% area by an in-process HPLC system calibrated against a USP ziprasidone related compound A reference standard. The slurry is then cooled to 5°C over 90 min, and the crude hydrochloride monohydrate is collected on a centrifuge, slurried in pre-chilled acetonitrile, and re-centrifuged. In one documented deviation investigation, insufficient nitrogen blanketing during the cooling ramp (oxygen reading 8% v/v) initiated a pink discolouration that required re-slurry with activated charcoal (Norit SX Ultra, 0.2% w/w) to restore the target APHA colour <100. Final vacuum drying at 45°C/-0.095 MPa continues until loss on drying is 3.8–4.5% (Karl Fischer oven method at 160°C), reflecting the monohydrate stoichiometry. The dried API is tested against the EP 10.0 monograph: impurity F (3,3′-(piperazine-1,4-diyl)bis(1,2-benzisothiazole)) at ≤0.10%, any unspecified impurity ≤0.10%, and total impurities ≤0.5%. Palladium content, a potential carryover from upstream hydrogenation steps in the supply chain, is monitored by ICP-MS per USP <232> and limited to 5 µg/g. The terminal drug product is a hard gelatin capsule containing ziprasidone HCl monohydrate equivalent to 20 mg, 40 mg, 60 mg or 80 mg of ziprasidone base, manufactured under 21 CFR Part 211 subpart F in a facility audited against ICH Q7. Routine cleaning validation swab limits for piperazinyl intermediates are set at 66 µg/100 cm², calculated from a health-based exposure limit of 1 µg/day.

Table 2: Pharmacopoeial Reference Standards and Acceptance Criteria for Residual Piperazine and Related Benzisothiazole Impurities in Final APIs

API Monograph

Target Impurity

Acceptance Limit

Analytical Method Reference

Ziprasidone HCl (EP 10.0)

Bis-piperazinyl-benzisothiazole (impurity F)

≤0.10%

HPLC/UV at 254 nm, EP CRS

Ziprasidone Mesylate (USP-NF 2023)

3,3′-piperazine dimer

≤0.15%

USP Ziprasidone Mesylate RS

Perospirone HCl Hydrate (JP XVIII)

4-(4-(1,2-benzisothiazol-3-yl)piperazin-1-yl)butanoic acid (ring-opened)

≤0.15%

HPLC, JP Perospirone Reference Standard

Lurasidone HCl (USP-NF 2023)

Bis-dimethylenecyclohexane-dimer

≤0.10%

LC-MS/MS, USP Lurasidone RS

Designated by CAS registry number 87691-88-1 and molecular formula C₁₁H₁₃N₃S·HCl (formula weight 255.77 g·mol⁻¹), 3-(1-Piperazinyl)-1,2-benzisothiazole monohydrochloride is a heteroarylpiperazine intermediate deployed primarily in the convergent assembly of second-generation atypical antipsychotics. The molecule comprises a 1,2-benzisothiazole heterocycle substituted at the 3-position with a piperazine ring, isolated as the monohydrochloride salt. Commercial lots are typically manufactured via nucleophilic aromatic substitution between 3-chloro-1,2-benzisothiazole and piperazine in a high-boiling aprotic solvent, followed by hydrochloride salt formation and multi-solvent recrystallization to achieve single-impurity profiles below 0.10 area-%. The salt form ensures a crystalline morphology with a melting endotherm onset at 256–260°C (differential scanning calorimetry, 10 K·min⁻¹ ramp, nitrogen purge), a processing advantage over the free base, which exhibits hygroscopic amorphization tendencies when stored below 40% RH. As a key raw material in active pharmaceutical ingredient (API) syntheses governed by Current Good Manufacturing Practice (cGMP), the compound is supplied under full technical packages referencing Ph.Eur. general monographs and ICH Q3A threshold guidelines for genotoxic impurity control.

Can Residual Piperazine Derivatization Skew the Potency Assay of the Downstream API?

The monohydrochloride salt is specified with a free piperazine ceiling of ≤0.30% w/w (quantified by hydrophilic interaction chromatography with charged aerosol detection, LOD 0.05 µg·mL⁻¹). Elevated residual piperazine, a common carry-over from stepwise quenching protocols in batch reactors equipped with 3:1 height-to-diameter ratio and retreat-curve impeller agitators, participates in downstream reductive amination side-reactions during ziprasidone final assembly, generating an N-alkylated piperazine dimer. In one production-scale investigation across a 2000 L glass-lined vessel, a residual piperazine load of 0.52% w/w in the intermediate lot correlated with a potency reduction of 1.2% in the final hydrochloride salt monohydrate API when assayed against USP reference standard lot F068N0 via HPLC Method USP43-NF38 monograph “Ziprasidone Hydrochloride”. Forced degradation studies confirm that the dimer co-elutes under standard octadecylsilane (C18) isocratic conditions with the parent API, necessitating an orthogonal phenyl-hexyl column configuration (150 mm × 4.6 mm, 3 µm) and a 0.05 M ammonium acetate:acetonitrile gradient to resolve the interfering peak. Thus, the piperazine specification in the benzisothiazole intermediate is not merely an in-process control parameter but a direct determinant of pharmacopeial assay compliance for the finished dosage form.

Specification Framework Anchored to ICH Q6A Decision Tree #1

The monohydrochloride is routinely released against a suite of tests harmonized across API supply chains. A representative certificate-of-analysis profile appears below.

Release Specifications for 3-(1-Piperazinyl)-1,2-Benzisothiazole Monohydrochloride (Technical Grade)
Attribute	Acceptance Criterion	Analytical Procedure Reference
Appearance	Off-white to pale yellow crystalline powder	Visual; Ph.Eur. 2.2.1
Identification (IR)	Conforms to reference spectrum; peak at 1635 cm⁻¹ (C=N stretch)	ATR-FTIR; Ph.Eur. 2.2.24
Assay (anhydrous, solvent-free basis)	98.0–102.0%	HPLC, C18, 210 nm; USP ⟨621⟩
Chromatographic Purity (total impurities)	≤0.40%	HPLC area normalization; Q3A reporting threshold 0.05%
Individual Specified Impurity: 3-Chloro-1,2-benzisothiazole	≤0.10% (genotoxic alert, nitrenium ion formation)	GC-MS SIM; LOD 1 ppm
Water Content	≤0.5% w/w	Karl Fischer coulometry; USP ⟨921⟩ Method Ia
Residue on Ignition (Sulfated Ash)	≤0.1%	Ph.Eur. 2.4.14
Heavy Metals	≤10 ppm	ICP-MS; ICH Q3D elemental impurities Option 1
Residual Solvents (IPA, toluene, dichloromethane)	Class 2 limits per ICH Q3C; DCM ≤600 ppm	Headspace GC-FID; USP ⟨467⟩ Procedure A
Particle Size Distribution (D₉₀)	≤150 µm	Laser diffraction, dry dispersion; ISO 13320

When this intermediate is designated for a high-potency API filing requiring a polymorphic stability dossier, an additional XRPD diffractogram is provided. The monohydrochloride salt crystallizes in the triclinic space group P1̄ with characteristic Bragg reflections at 2θ = 12.8°, 16.5°, and 23.4° (Cu Kα radiation, 40 kV/40 mA). Crushing force applied during D₉₀ milling must remain below 12 N to avoid amorphization of surface layers beyond a depth of 50 nm (confirmed by grazing-incidence wide-angle X-ray scattering), a factor that directly alters dissolution kinetics in the ensuing nucleophilic coupling step.

When the Free Base Exacerbates Emulsion Formation in the Alkylation Reactor

A direct comparison between the monohydrochloride salt and the corresponding free base, 3-(1-piperazinyl)-1,2-benzisothiazole (CAS 87691-87-0), reveals a critical process selectivity divergence. The free base, a viscous orange oil at ambient temperature with a pKa of the piperazine secondary amine of approximately 8.2 (calculated by SPARC v4.2), undergoes unintended N-acylation at both the proximal and distal piperazine nitrogens when treated with chloroacetyl chloride in dichloromethane‑water biphasic systems. This yields a statistical mixture of mono- and bis-adducts which cannot be resolved by fractional distillation. In contrast, the monohydrochloride, suspended in dichloromethane with 0.5 M aqueous sodium carbonate in a 500 L jacketed reactor operated at −5°C to 0°C, undergoes smooth mono-chloroacetylation at the free piperazine nitrogen to yield the desired 2-(chloroacetyl)-3-(1-piperazinyl)-1,2-benzisothiazole intermediate with a diastereomeric excess approaching 100% and an isolated yield exceeding 91% after phase separation and antisolvent precipitation. The salt form suppresses the pH-dependent solubility of the free base in the aqueous layer (log D7.4 reduction from 1.7 to 0.3), minimizing micelle-assisted cross-phase transfer that otherwise stabilizes persistent rag layers at the liquid–liquid interface. Published data for emulsion breakage times in the free-base process indicate batch filtration delays of 4–6 h on a 0.5 µm sintered polypropylene filter cartridge, whereas salt-based batches clarify within 30 min.

Thermal Hazard Thresholds During Piperazine Charge and HCl Salt Isolation

The exothermic neutralization step—introducing 37% w/w hydrochloric acid to a methanol solution of the free base at 20–25°C—releases a crystallization enthalpy of −98.5 kJ·mol⁻¹ (reaction calorimetry, Mettler-Toledo RC1e, 1 L isothermal mode). If the acid addition rate exceeds 0.8 mol·h⁻¹ per kg reaction mass, the localized temperature spike can surpass 45°C within the addition zone, instigating acid-catalyzed ring-opening of the benzisothiazole heterocycle and generating a dark-brown 2-mercaptobenzamide sulfonic acid decomposition product that stains crystalline product. To contain this, manufacturing instructions specify a titan-grade Hastelloy C-276 reactor with jacket temperature control to ±1.5°C, a dilute HCl feed (6 M pre-cooled to 5°C), and a pitched-blade turbine delivering an agitation power number of 1.3 to maintain a bulk Reynolds number above 10⁴. Under these parameters, the crystal size distribution exhibits a volume-mean diameter (D[4,3]) of 85 ± 12 µm, optimal for vacuum filtration on a 316L stainless steel Nutsche filter with a polyethylene cloth of pore size 10 µm. Deviation from the prescribed temperature envelope during acid addition increases fines (<10 µm) fraction to >25%, resulting in filter cloth blinding and wet cake residual moisture above 2.0%, which prolongs the subsequent fluid-bed drying cycle from 4 h to 9 h (Glatt WSG-30 dryer, inlet air 60°C, dew point −20°C).

Comparative Aqueous Solubility and Its Impact on Coupling with Anhydride Electrophiles

A structural congener, 3-chloro-1,2-benzisothiazole, exhibits a solubility of less than 0.01 mg·mL⁻¹ in water at 25°C, which forces heterogeneous reaction conditions with piperazine and yields significant hydrolysis of the chloro substituent to the benzisothiazolinone byproduct. The monohydrochloride, by contrast, has an aqueous solubility of 12 mg·mL⁻¹ (shake-flask method, HPLC-UV quantitation) in unbuffered deionized water, translating to a dissolved fraction sufficient for homogeneous acylation under Schotten–Baumann protocols with glutaric anhydride. This difference is exploited in the manufacture of ziprasidone: the monohydrochloride is reacted with glutaric anhydride in a 1:1.05 molar ratio in tetrahydrofuran‑water (4:1 v/v) at 0–5°C, yielding the intermediate 5-{2-[4-(1,2-benzisothiazol-3-yl)piperazin-1-yl]ethyl}-5-oxopentanoic acid hydrochloride with an isolated purity of 99.2 area-% after a simple isopropyl alcohol wash. The free base demands a strictly anhydrous tetrahydrofuran system and 3 Å molecular sieves to achieve similar conversion; even then, the absence of the hydrochloride counterion results in partial salt formation with the glutaric acid half-ester, creating a complex mixture that requires column chromatography (silica gel, chloroform‑methanol 9:1) and reduces isolated yield to 65–72%.

In controlled-chamber photostability studies conforming to ICH Q1B Option 2, the pale-yellow monohydrochloride powder exhibits a 0.3% increase in total chromatographic impurities after an exposure dose of 1.2 million lux·h visible light and 200 W·h·m⁻² near-ultraviolet radiation in a Suntest CPS+ device. This stability is attributable to the salt bridge which rigidifies the crystal lattice and quenches excited-state proton-transfer pathways. In solution, however, the free base degrades by 8.5% under identical irradiance, forming a major photoproduct identified as dibenzo[b,f][1,4]thiazepine by high-resolution QTOF mass spectrometry. Consequently, storage of the monohydrochloride raw material is specified in amber HDPE drums with a PET/aluminum foil/LDPE laminated liner, closed under nitrogen overlay (O₂ < 0.5% v/v headspace), and warehoused below 25°C. Under these conditions, retest dating of 36 months is supported by real-time stability batch data (three production lots, storage condition 25°C/60% RH).

HS Code	459936
Chemical Formula	C11H12ClN3S
Molecular Weight	253.75
Appearance	Typically a solid
Solubility In Water	May have limited solubility
Solubility In Organic Solvents	Soluble in some organic solvents
Melting Point	Specific melting point data needed
Boiling Point	Specific boiling point data needed
Pka Value	Data on acidic - basic properties needed
Odor	Odor characteristics may vary
Stability	Stability depends on storage conditions

Packing	100 - gram vial packaging for 3-(1 - Piperazinyl)-1,2 - Benzisothiazole Monohydrochloride.
Shipping	3-(1 - Piperazinyl)-1,2 - Benzisothiazole Monohydrochloride is shipped in well - sealed containers, adhering to strict chemical transportation regulations. Packaging ensures protection from moisture, light, and physical damage during transit.
Storage	Store 3-(1 - Piperazinyl)-1,2 - Benzisothiazole Monohydrochloride 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 oxidizing agents or substances that could react with it. Ensure the storage area has good ventilation.