1,2-Benzisothiazole-3-(1-Piperazinyl) Hydrochloride
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HS Code |
889345 |
| Chemical Name | 1,2-Benzisothiazole-3-(1-Piperazinyl) Hydrochloride |
| Molecular Formula | C11H14ClN3S |
| Molecular Weight | 255.77 g/mol |
| Appearance | Solid (usually white to off - white powder) |
| Solubility | Soluble in polar solvents like water to some extent |
| Melting Point | Typically has a defined melting point range (exact value depends on purity) |
| Pka | The piperazine moiety has a characteristic pKa value relevant for its basicity |
| Stability | Stable under normal storage conditions if protected from moisture and light |
| Odor | Odorless or with a very faint, characteristic odor |
As an accredited 1,2-Benzisothiazole-3-(1-Piperazinyl) Hydrochloride factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100g of 1,2 - Benzisothiazole - 3 - (1 - Piperazinyl) Hydrochloride in sealed plastic bags. |
| Shipping | 1,2 - Benzisothiazole - 3 - (1 - Piperazinyl) Hydrochloride is shipped in properly sealed containers, following strict chemical shipping regulations. Ensured to prevent any leakage during transit to safeguard handlers and the environment. |
| Storage | 1,2 - Benzisothiazole - 3 - (1 - Piperazinyl) 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. Store it in a well - ventilated area, separate from incompatible substances such as strong oxidizers and bases to avoid chemical reactions. |
In large-scale ziprasidone hydrochloride monohydrate production campaigns, the hydrochloride salt of 1-(1,2-benzisothiazol-3-yl)piperazine is the pro-nucleophile that undergoes alkylation with 5-(2-chloroethyl)-6-chloro-1,3-dihydro-2H-indol-2-one. The charge ratio is deliberately pinned at 1.08–1.12 molar equivalents relative to the chloroethyl oxindole to suppress the formation of a dialkylated quaternary ammonium impurity that co-elutes with the desired product on reversed-phase C18 columns under the conditions of USP ZIPrasidone Hydrochloride monograph method Related Compounds Test 1. Process mass intensity data from 1000 L glass-lined reactors document that a deviation to 1.20 equivalents elevates the bis-alkylated impurity above the 0.10% ICH Q3A qualification threshold, requiring a secondary toluene extraction that prolongs cycle time by 8–12 hours. The coupling is run in anhydrous N,N-dimethylformamide with milled potassium carbonate (≥325 mesh) at a jacket temperature of 82–85 °C; residual water above 0.05% by Karl Fischer titration promotes hydrolysis of the oxindole ring, generating a chloro-acid degradant that partitions into the aqueous phase only after the pH is raised above 9.5. Quenching into chilled purified water precipitates the ziprasidone free base, which is subsequently converted to the hydrochloride monohydrate by treatment with concentrated hydrochloric acid in 2B ethanol at 0–5 °C and dried in a conical vacuum dryer at 40 °C/<−0.08 MPa until loss on drying is ≤3.5%. The entire sequence is executed under ICH Q7 §11.1 general controls, with in-process HPLC sampling at a reporting threshold of 0.05 area% and a final polymorph identity check by X-ray powder diffraction against the reference pattern of Form A monohydrate.What Drives the Diastereomeric Excess of the Lurasidone Reductive Coupling at Multi-Kilogram Scale?The stereochemical integrity of lurasidone hydrochloride is gated by a reductive amination between (1R,2R)-2-[(1,3-dioxoisoindolin-2-yl)methyl]cyclohexanecarbaldehyde (99.5% ee minimum) and the benzisothiazole piperazine nucleophile, which is liberated in situ from the hydrochloride salt using sodium triacetoxyborohydride. The stoichiometry window is extremely narrow: the aldehyde intermediate is charged at 1.00 equivalent, the benzisothiazole piperazine hydrochloride at 1.03–1.05 equivalents, and sodium triacetoxyborohydride at 1.40–1.45 equivalents in dichloromethane containing 2.0% v/v acetic acid. When the internal temperature drifts above +2 °C during the 45–60 minute addition of the reducing agent, the resulting exotherm accelerates iminium ion isomerization, and the undesired (S,S)-diastereomer can exceed 0.15% at the end of reaction, which cannot be reliably purged during the ethanol/water (3:1 v/v) seeded crystallization that follows. Operators on 2000 L glass-lined, brine-chilled (−10 °C jacket) vessels routinely observe a 3–5 °C overshoot at the 50 kg input scale when the stirring tip speed drops below 1.8 m/s due to fluid viscosity increase, mandating a gear-pump recirculation loop through a shell-and-tube chiller after 60% of the borohydride has been delivered. The finished lurasidone hydrochloride is tested per USP <621> (chiral purity by normal-phase HPLC on Chiralpak AD-H, 5 μm, 250 × 4.6 mm, n-hexane/ethanol/diethylamine 85:15:0.1) and residual solvents per ICH Q3C(R6) with a dichloromethane limit of 600 ppm. A secondary quality hold point is the palladium-catalyzed hydrogenolysis used to remove the isoindoledione protecting group upstream; residual palladium above 10 ppm in the penultimate intermediate poisons the subsequent reductive amination catalyst system and depresses the diastereomeric ratio outside the 99.5:0.5 specification.Activated Carbon Re-Processing Thresholds for Residual Piperazine Monomer in the Benzisothiazole-Piperazine FreebaseThe freebase form generated by basification of the hydrochloride—typically with 30% w/w aqueous sodium hydroxide in toluene at 20–25 °C—carries residual unreacted piperazine monomer that is not detectable by GC-FID at the manufacturing stage but accumulates through the downstream cyano-indole alkylation used in perospirone intermediate synthesis. If free piperazine exceeds 0.15% w/w in the freebase oil, it functions as a competing nucleophile, forming a piperazinyl-cyanoindole side product that co-crystallizes with perospirone base in isopropanol/n-heptane (1:4) and raises the total impurities above the 0.30% ICH Q3A qualification ceiling. A validated re-processing protocol involves dissolving the freebase in toluene at 50 °C, adding 2.0% w/w of activated carbon (Norit SX Plus) relative to the freebase mass, agitating for 1 hour, and filtering through a 0.5 μm cartridge under nitrogen pressure. The carbon treatment reduces piperazine monomer to <0.03% w/w without measurable loss of the benzisothiazole-piperazine, confirmed by LC-MS in selected ion monitoring mode (m/z 219.1 for the active, m/z 86.1 for piperazine). This unit operation is executed only when a composite sample from the first three commercial synthesis batches shows monomer above the action limit; otherwise, direct distillation is sufficient. The European Pharmacopoeia 10.0 monograph for perospirone hydrochloride dihydrate lists Impurity D—the bis-piperazinyl indole analogue—at a specification limit of ≤0.10%, creating a direct analytical bridge back to the upstream piperazine scavenging step.In the perospirone synthesis route that proceeds via a nitrile intermediate, the benzisothiazole piperazine hydrochloride is condensed with 3-(bromomethyl)-1,2-dimethyl-1H-indole-4-carbonitrile in acetonitrile at reflux using triethylamine (1.2 equivalents) as the proton scavenger. The charged hydrochloride is 1.02–1.05 molar equivalents relative to the bromomethyl indole, a slight excess chosen to consume the alkylating agent completely because residual benzyl bromide functionality reacts with triethylamine to form a quaternary ammonium salt that complicates aqueous washing. The mixture is held at 80–82 °C for 6–8 hours under a slow nitrogen sweep to remove liberated HBr, which otherwise darkens the reaction mass by catalyzing indole polymerisation. Post-reaction, the slurry is cooled to 10 °C, filtered to remove triethylamine hydrobromide, and the filtrate is concentrated to an oil. Crystallization from isopropanol/water (85:15 v/v) in a 500 L stainless steel crystallizer equipped with an anchor agitator yields crude perospirone base. The critical parameter for polymorph consistency is the cooling rate: uncontrolled natural cooling (0.5 °C/min) produces a mixture of Form I and Form II, whereas a controlled linear profile of 0.15 °C/min from 50 °C to 5 °C consistently delivers Form II dihydrate. Residual solvents are monitored against ICH Q3C(R6): acetonitrile NMT 410 ppm, triethylamine NMT 320 ppm, and isopropanol NMT 5000 ppm. The terminal perospirone hydrochloride dihydrate complies with JP 18 General Test chapter 2.48 for heavy metals and achieves an assay of 98.5–101.0% on dried basis by non-aqueous titration with perchloric acid.When the Metal-Free Sonogashira-Type Coupling Departs from Forecasted Diarylacetylene YieldA divergent application outside antipsychotic APIs uses the benzisothiazole-piperazine scaffold to construct diarylacetylene-based 5-HT7 receptor ligand libraries through a copper-free Sonogashira coupling. Here the piperazine nitrogen is first acylated with 4-iodobenzoic acid (1.0 equivalent, HATU 1.1 equivalent, DIPEA 2.0 equivalent in DMF) to form the aryl iodide intermediate, which is then reacted with terminal alkyne blocks in the presence of Pd(PPh3)2Cl2 (0.03 eq.) and Cs2CO3 (2.0 eq.) in 1,4-dioxane/water (4:1) at 95 °C. The benzisothiazole ring itself is susceptible to ring-opening by adventitious thiol nucleophiles under these conditions, making strict control of dissolved oxygen and the use of degassed solvents mandatory; a nitrogen sparge for 25 minutes prior to catalyst addition reduces the benzoisothiazole decomposition product from 3.8 area% (non-degassed) to <0.3 area%. The library synthesis is GLP-compliant and abides by FDA 21 CFR Part 58 for non-clinical laboratory studies. Target compounds, once isolated as hydrochloride salts by treatment with 2 M HCl in diethyl ether, are characterized for purity against an internal specification of ≥95.0% by UPLC-UV at 254 nm using an Acquity BEH C18 1.7 μm column and a gradient of 0.1% formic acid in water/acetonitrile. Batches that fail the purity threshold due to residual alkyne starting material are submitted to semi-preparative HPLC on a C18 5 μm 19×250 mm column with isocratic 65:35 methanol/ammonium acetate buffer yielding >99.0% purity isolates suitable for in vivo pharmacodynamic profiling.
Continuous-Flow N-Alkylation Eliminates Hot-Spot-Mediated Quaternary Ammonium Dimer FormationTransferring the batch process for ziprasidone intermediate condensation to a continuous-flow microreactor has been demonstrated to solve the 3–4% dimer formation that plagues jacketed vessel operation where localized overheating at the steam-heated wall intermittently rises to 105 °C (measured by inserted fiber-optic probe) despite the bulk fluid average of 82 °C. A pilot-scale setup using a Corning Advanced-Flow G1 SiC reactor (16 mL internal volume) with a feed of benzisothiazole piperazine hydrochloride as a 1.5 M solution in DMF and the chloroethyl oxindole as a 1.4 M solution in the same solvent, both pre-heated to 75 °C and mixed in a 1:1 volumetric ratio at a combined flow rate of 24 mL/min, achieves a residence time of 40 seconds at 85 °C under a back-pressure regulator set to 4 bar. The quaternary ammonium dimer impurity is suppressed to <0.5 area% without the need for excess benzisothiazole piperazine beyond 1.03 equivalents, translating to a 9% improvement in atom economy relative to the batch protocol and eliminating the toluene back-extraction step. The reactor effluent is directly quenched into a stirred aqueous receiver and processed through an inline centrifuge to isolate the ziprasidone freebase cake, which is washed with deionized water until the conductivity of the filtrate drops below 100 μS/cm. cGMP compliance for this setup falls under ICH Q7 §11.1 and §13.2 (cleaning validation for multipurpose equipment), with PAT integration via a flow cell Fourier-transform infrared spectrometer tracking the carbonyl stretch at 1705 cm−1 to monitor reaction progression. The final ziprasidone hydrochloride monohydrate produced by this route meets all compendial tests of USP 43–NF 38 and EP 10.3, and the dedicated campaign mode reduces carryover risk for non-dedicated facilities manufacturing other piperazine-bearing APIs.
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The synthesis of the atypical antipsychotic agents lurasidone and ziprasidone relies upon a benzisothiazolyl-piperazine building block whose hydrochloride salt, 3-(piperazin-1-yl)-1,2-benzisothiazole hydrochloride (CAS 131486-34-5), is the form of choice for industrial-scale production. The compound is supplied as a white to off-white crystalline powder with a purity specification of ≥99.0% (HPLC, area normalization at 254 nm), individual unspecified impurities limited to ≤0.10%, and total impurities ≤0.50%. In contrast to the free base, which exists as a viscous, hygroscopic oil and requires solvent-assisted transfer, the hydrochloride offers a sharp melting point (245–248 °C with decomposition) and a critical moisture equilibrium that simplifies weighing and vacuum-drying operations in multi-kilogram batch campaigns. The product is catalogued under product code BIP-101-HCl by specialty fine chemical suppliers and is routinely stocked in GMP-certified inventories for pivotal clinical supply chains.
Long-term stability of the hydrochloride salt is governed by polymorphic phase transitions and the propensity of the benzisothiazole ring to undergo acid-catalyzed hydrolysis under elevated humidity. Dynamic vapor sorption (DVS) experiments conducted on a Surface Measurement Systems DVS Advantage instrument reveal that at 25 °C the monohydrochloride monohydrate form is dimensionally stable below 40% RH. When relative humidity exceeds 60% RH, a reversible conversion to a dihydrate is observed over a 12-hour equilibration period; exposure to >85% RH triggers deliquescence and the formation of a liquid phase that accelerates hydrolytic ring-opening, generating 2-(piperazin-1-yl)benzenesulfonamide derivatives detectable by LC-MS at masses m/z 258.1 and 274.1. Kinetic modeling of the decomposition at 40 °C/75% RH (ICH Zone IVb accelerated conditions) yields a degradation rate constant of 6.8 × 10⁻⁴ day⁻¹, corresponding to a shelf-life of approximately 36 months when packaged in double high-density polyethylene bags containing molecular-sieve desiccant and heat-sealed within a laminated aluminum foil overwrap.
Moisture content determined by Karl Fischer coulometry (Metrohm 851 Titrando) must not exceed 0.5% (w/w) at release. When the water content breaches this threshold—a scenario encountered during campaigns in tropical manufacturing sites without humidity-controlled weigh rooms—the powder is subjected to vacuum pre-drying at 50 °C, ≤10 mbar, for a minimum of 12 hours in a vacuum tray dryer (e.g., De Dietrich Rosenmund RW6) fitted with a nitrogen bleed to displace evolved water. The hydrochloride should not be stored in proximity to volatile amines or anhydrous ammonia, because base-induced deprotonation liberates the free base, yielding a tacky semi-solid that coats transfer lines and compromises metering accuracy in downstream coupling steps. Incompatibility with strong oxidizing agents (e.g., hydrogen peroxide, peracetic acid) must be noted, as the benzisothiazole sulfur atom can undergo oxidation to the sulfoxide and sulfone, altering the crystalline lattice and reducing purity. The hydrochloride form remains stable under amber glass protection; photostability chambers (Atlas SUNTEST CPS+) indicate that exposure to light sources meeting ICH Q1B Option 1 (visible light ≥1.2 million lux·h and UV ≥200 W·h/m²) causes negligible degradation (<0.05% increase in total impurities), supporting the absence of a mandatory light-protective label for bulk storage.
Consistency across manufacturing campaigns is maintained by a control strategy aligned with ICH Q6A and relevant pharmacopoeial monographs where available. While a dedicated monograph for 3-(piperazin-1-yl)-1,2-benzisothiazole hydrochloride has not yet been included in the USP or Ph. Eur., internal specifications are cross-referenced with USP <621> (Chromatography), USP <467> (Residual Solvents), and USP <232>/Ph. Eur. 5.20 (Elemental Impurities). The limits adopted for process-related impurities reflect a toxicological assessment compliant with ICH M7 and are supported by Ames test results (Ames II, S. typhimurium strains TA98 and TA100, both with and without S9 metabolic activation).
| Parameter | Specification | Test Method |
|---|---|---|
| Assay (anhydrous basis) | 98.5–101.0% | HPLC (C18, 5 µm, 250 × 4.6 mm; 0.1% TFA in water/acetonitrile gradient; 254 nm); Quantitative NMR (qNMR) with maleic acid internal standard when HPLC shows fronting |
| Individual unspecified impurity | ≤0.10% | Same HPLC system; RRT window from 0.3 to 2.5 |
| Piperazine (Impurity A) | ≤0.15% | IC with suppressed conductivity (Metrohm 940 Professional IC Vario; Metrosep C4 column) or HPLC after derivatization with Fmoc-Cl at 265 nm |
| Residual methanol | ≤3000 ppm | Headspace GC-FID (Agilent 7890B, DB-624 column); ICH Q3C Class 2 |
| Residual toluene | ≤890 ppm | Same GC-HS method |
| Residual dichloromethane | ≤600 ppm | Headspace GC-FID; ICH Q3C Class 2 |
| Water content | ≤0.5% | Karl Fischer coulometry (Metrohm 851) |
| Heavy metals | Cadmium ≤2 ppm, lead ≤5 ppm, arsenic ≤2 ppm, mercury ≤3 ppm | ICP-MS (Agilent 7800) after microwave-assisted digestion; validation per USP <232> |
| Residue on ignition | ≤0.1% | USP <281> |
Lot-to-lot crystallinity is confirmed via X-ray powder diffraction (XRPD) using a PANalytical X’Pert PRO diffractometer with Cu Kα radiation, scanning in the range 3–40° 2θ. The hydrochloride consistently displays characteristic reflections at 10.2°, 16.8°, and 24.5° 2θ, whereas the free base exhibits a broad halo pattern indicative of an amorphous oil, and the mesylate salt shows a distinct set of peaks at 8.5°, 14.3°, and 21.7° 2θ with pronounced preferred orientation. Crystalline form purity data are used to issue a batch certificate confirming that the material corresponds to the thermodynamically stable monohydrochloride monohydrate Form I.
Batch records from multi-kilogram scale production indicate that the hydrochloride salt is isolated via a two-solvent recrystallization using methanol/MTBE, achieving a consistent particle size distribution with D90 typically <250 µm (Malvern Mastersizer 3000, dry dispersion). The free base, conversely, requires vacuum distillation (0.1 mbar, 160–180 °C pot temperature) and immediate dissolution in anhydrous THF to prevent rapid color degradation; this procedure extends cycle times by 8–12 hours per campaign in a standard 500 L glass-lined reactor setup, while introducing the occupational exposure risk of airborne amine vapors. By opting for the hydrochloride, the number of unit operations is reduced from five to three, and the overall process mass intensity (PMI) for the intermediate step falls from 28 to 12 when water is excluded from the solvent inventory, as documented in environmental life-cycle assessments for the lurasidone manufacturing route.
During route scouting for ziprasidone, the methanesulfonate salt of the piperazinyl-benzisothiazole was evaluated to increase water solubility and eliminate the need for strong acidic conditions in the final coupling reaction. While the mesylate salt afforded a solubility of >200 mg/mL in water at 25 °C, the resulting high solution osmotic pressure caused uncontrolled nucleation in sodium bicarbonate quench steps, generating agglomerates that resisted re-dissolution. More critically, the mesylate powder absorbed 15.8% moisture over 24 h at 80% RH (DVS), exceeding the threshold for safe glovebox handling and leading to partial deliquescence in ambient storage at 50% RH within 72 h. By comparison, the hydrochloride maintains a weight gain of only 0.6% under identical conditions, remaining free-flowing and directly dischargeable from bulk containers into the reactor feed hopper. The physical attribute contrasts are summarized in the table below.
| Property | Free Base | Hydrochloride Salt | Methanesulfonate Salt |
|---|---|---|---|
| Physical form at 25 °C | Amber viscous oil | White crystalline powder | Off-white hygroscopic solid |
| Melting point (°C) | N/A (oil) | 245–248 (dec.) | 160–165 (dec.) |
| Solubility in water (mg/mL, 25 °C) | 0.8 | 28 | 208 |
| Weight gain at 80% RH, 24 h (%) | 4.2 | 0.6 | 15.8 |
| Particle breakage tendency (jet milling) | Not processable | Low – D50 reducible below 20 µm | Agglomerate formation at D50 <40 µm |
The product is shipped in 25 kg or 50 kg fiber drums with inner LDPE liner, double-bagged with a polyethylene desiccant pouch, and labeled with the CAS number 131486-34-5 and lot-specific retest date.
Substituting the piperazine moiety with a primary amine—as in 3-amino-1,2-benzisothiazole—eliminates the rigid ring scaffold required for optimal occupancy at the D₂ and 5‑HT₂A receptor pockets, and the resulting amide derivatives display a loss of atypical antipsychotic activity in in vitro binding assays (Ki shifts of >>100 nM vs. sub 10 nM for piperazine-linked structures). From a process chemistry standpoint, the 3-amino analog presents poor N-acylation selectivity, with competing formation of N,N′-diacylated species reducing yield to <50% when reacted with activated trans-cyclohexane-1,4-diamine intermediates. The hydrochloride salt of the piperazine-substituted benzisothiazole uniquely balances basicity (pKa of the piperazine nitrogen ≈ 8.7) with sufficient latence after protonation, allowing selective deprotection with mild bases such as N-methylmorpholine (NMM) in DMF at –10 °C, which prevents racemization of a neighbouring stereocenter in the lurasidone skeleton. Additionally, the benzisothiazole core imparts metabolic stability; cytochrome P450-driven oxidation primarily occurs on the piperazine ring rather than the fused heterocycle, limiting the formation of reactive quinone-imine intermediates that are problematic with the benzothiazole analog. The hydrochloride’s consistent batch-to-batch viscosity-normalized particle charge, measured by a Faraday pail tribocharger, ensures stable electrostatic feeding into loss-in-weight systems that dose the intermediate into EDC/HOBt-mediated couplings under cGMP conditions, a critical advantage over the high-charge free base that adheres to stainless steel contact surfaces. When the hydrochloride is used with the standard coupling protocol (EDC·HCl 1.5 eq, HOBt 1.3 eq, NMM 1.8 eq in DMF at –15 to –5 °C), process analytical technology (ReactIR 15, Mettler Toledo) confirms acylation completion within 4 hours, after which direct phase separation and anti-solvent crystallization yield lurasidone hydrochloride in 91% isolated yield and 99.7% purity, obviating the need for the additional chiral resolution step mandated when the mesylate or free base is employed.
