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

In the synthesis of ziprasidone hydrochloride monohydrate, a benzisothiazole-piperazine fragment serves as the nitrogenous heterocyclic anchor required for high-affinity binding at the 5-HT_2A and D₂ receptor sites. The monohydrochloride salt of 3-(1-piperazinyl)-1,2-benzisothiazole (C₁₁H₁₃N₃S·HCl, MW 255.76 g mol⁻¹) is released to its free base immediately prior to the N‑alkylation step with 6-chloro-5-(2-chloroethyl)-1,3-dihydro-2H-indol-2-one in a polar aprotic medium. Compliance in commercial campaigns is governed by ICH Q7 and the guidance for residual solvents according to USP 〈467〉; when the intermediate is filed as a Type II Drug Master File with the US FDA, the holder must provide a full disclosure of the synthetic pathway, covering genotoxic impurity risk assessment under ICH M7 thresholds. The charged molar ratio typically places the free base of the benzisothiazole-piperazine at 1.05–1.10 equivalents relative to the indolinone electrophile, translating to a practical addition level of approximately 0.62–0.65 kg of the hydrochloride salt per kilogram of ziprasidone free base at a reaction yield exceeding 87% of theory. The downstream process couples high-temperature (90–105 °C) carbonate-assisted coupling in dimethylformamide with a chain of aqueous washes, activated-carbon treatment, and final recrystallization from ethanol‑water; jacketed glass-lined reactors equipped with packed reflux columns are standard, and the crystallizer must hold a loss-on-drying specification ≤ 0.5% to prevent hydrate form interconversion in the final polymorph. Terminal dosage forms include oral gelatin capsules of 20 mg, 40 mg, 60 mg, and 80 mg ziprasidone base equivalent, as well as a lyophilised powder for intramuscular injection reconstituted in 20 mg mL⁻¹ presentations.

What Precautions Govern the Use of This Intermediate in Lurasidone Alkylation at Tonne Scale?

During the manufacture of lurasidone hydrochloride — a benzisothiazole-piperazine‑bearing atypical antipsychotic acting on D₂, 5-HT_2A, 5-HT₇, and 5-HT_1A — the mono-N-alkylation of 1,2-benzisothiazol-3-(1-piperazinyl) free base with (1R,2R)-cyclohexane-1,2-diylbis(methylene) dimethanesulfonate or the corresponding di‑p‑toluenesulfonate ester demands rigorous thermal management. The reaction is classified as a critical process step under ICH Q7 Section 12.1 because the half-life of the bis‑electrophile in the presence of the piperazine nucleophile can drop to minutes when the internal temperature exceeds 12 °C; adiabatic calorimetry (ARC) data from production‐scale campaigns indicate an onset of runaway decomposition at ΔT_ad > 72 K if the dosing rate of the sulfonate ester is not slaved to the jacket‑cooling duty. The validated master batch record therefore specifies a semi-batch protocol in which a 0.95–1.00 M solution of the free base in N-methyl-2-pyrrolidone‑acetonitrile (3:1 v/v) is maintained at −5 to 0 °C and the electrophile solution is metered over 6–8 hours while the heat-flow signal from a Mettler Toledo RC1e reaction calorimeter is logged; any transient exceeding 35 W kg⁻¹ triggers automatic interlock of the dosing pump. The additive ratio, calculated on the limiting intermediate, amounts to 1.30–1.35 molar equivalents of the bis-mesylate toward the piperazine nitrogen, which corresponds to 0.56–0.58 kg of the monohydrochloride salt per kilogram of lurasidone free base (MW 456.58) in an industrial sequence that runs at 70–78% isolated yield after chromatography on silica‑60 and ethanolic HCl salt formation. Post‑reaction quenching with 5% aqueous ammonium chloride, phase separation in a centrifugal extractor, and multi-stage wiped‑film distillation to meet a NMT 0.10% residual sulfonate ester limit — verified by LC‑MS/MS with a limit of quantification at 1 ppm — constitute the downstream purification train; filtration through a 0.2 µm sterilising cartridge prior to spray drying yields a crystalline monohydrochloride that conforms to Ph.Eur. 10.7 and USP 43 monograph specifications. The terminal finished goods are immediate‑release film‑coated tablets delivering 20 mg, 40 mg, 60 mg, 80 mg, or 120 mg of lurasidone hydrochloride, manufactured under 21 CFR 211 in dedicated suites with validated air‑handling units to prevent cross‑contamination with other benzisothiazole‑based actives.

In the approved Japanese manufacturing route for perospirone hydrochloride (Lullan^®), the benzisothiazole‑piperazine hydrochloride intermediate is condensed with N-(4-bromobutyl)-1,2,3,4-tetrahydro-2,3-dioxoisoquinoline-5-sulfonamide via a Williamson‑type etherification preceded by free‑basing in situ with sodium carbonate. The heterogeneous reaction in dimethyl sulfoxide (DMSO) proceeds at 55–60 °C under a nitrogen pad, and the particle‑size distribution of the intermediate salt proves critical: sieve analysis must confirm d₅₀ ≤ 75 µm because coarser crystals lead to incomplete conversion and residual reactants above the action limit of 0.15 area-% on HPLC. The addition table for a 500 L glass‑lined vessel lists 42.0 kg of the monohydrochloride (0.164 kmol) alongside 48.5 kg of the bromo‑butyl isoquinoline sulfonamide (0.156 kmol) — an 1.05‑fold molar excess of the benzisothiazole side — to compensate for partition losses to the aqueous sodium bromide phase that accumulates during the work‑up. On a mass basis, this equates to roughly 0.50–0.51 kg of the hydrochloride salt per kilogram of perospirone free base (MW 510.63). Supervisory control of the batch relies on inline FTIR to track the disappearance of the C‑Br stretch at 643 cm⁻¹; endpoint is declared when the signal drops below 0.2% of the initial absorbance. Following vacuum steam stripping to remove DMSO below 0.1% residual, the crude perospirone base is taken up in methyl isobutyl ketone and washed with 1.0 N sodium hydroxide, then treated with ethanolic hydrogen chloride to precipitate perospirone hydrochloride. Recrystallization from 2‑propanol:water (9:1) yields compact prisms with a melting point of 232–234 °C (dec.) that meet the Japanese Pharmacopoeia monograph identity tests. The final dosage forms registered in Japan are oral tablets containing 4 mg and 8 mg perospirone hydrochloride; Hong Kong and South Korean supplementary approvals additionally cover an extemporaneous oral suspension (4 mg mL⁻¹) prepared with Ora‑Sweet^® vehicle.

When the Benzisothiazole-Piperazine Scaffold Enters Fragment-Based Library Production

Beyond fully commercialised active pharmaceutical ingredients, the monohydrochloride salt of 3-(1-piperazinyl)-1,2-benzisothiazole functions as a privileged fragment within the piperazine‑extended heterocycle chemical space that contemporary CNS drug-discovery programmes exploit for D₂/5-HT_1A/5-HT_2A poly‑pharmacology. Contract research organisations and early-phase medicinal chemistry groups procure the compound under an analytical certificate confirming purity ≥98.0 area-% (HPLC at 254 nm), water content ≤0.3% (Karl Fischer, titration to dead‑stop), and elemental chlorine content within ±0.5% of the theoretical 13.86% for C₁₁H₁₃N₃S·HCl. The additive ratio in parallel solution‑phase arrays is dictated by the library design: for a 96‑well plate each well receives 0.20 mmol of the benzisothiazole‑piperazine free base (generated by washing a dichloromethane solution of the salt with 2.0 M aqueous NaOH) and 0.24 mmol of a chloro‑ or bromo‑heteroaryl capping reagent dissolved in 0.6 mL of anhydrous dimethylacetamide, together with 0.44 mmol of N,N‑diisopropylethylamine. Reaction blocks are agitated at 800 rpm orbitally at 80 °C for 16 h in a glove box under dry argon, after which automated solid‑phase extraction on 50 mg silica cartridges with an ethyl acetate‑hexane gradient removes the tertiary amine hydrochloride by‑product; the eluted fractions are evaporated in a Genevac HT‑12 centrifugal evaporator and checked for uniformity by LC‑MS using a single‑quadrupole instrument operating in APCI+ mode. Process‑scale‑up to 50 g batch size for lead‑optimisation campaigns utilises a 2 L jacketed reactor with a Hastelloy‑C impeller, and the settled slurry of the hydrochloride salt in dry tetrahydrofuran is activated by slow addition of 1.05 eq. sodium hexamethyldisilazide (2.0 M in THF) at 0–5 °C before the electrophile is introduced. The resulting focused libraries feed structure‑activity‑relationship matrices and deliver tool compounds — later evaluated in rodent behavioural models — with typical purity after preparative HPLC exceeding 95%. Compliance in this discovery environment is aligned with ISO 9001:2015 laboratory quality management systems rather than GMP, because the terminal products are not intended for human administration but serve as pharmacological probes.

Material Input Profiles Across Commercial Benzisothiazole‑Piperazine‑Containing Active Substances

Irrespective of the final application, the hydrochloride salt’s hygroscopicity forces a common storage boundary: bulk drums must be kept under a dry‑nitrogen blanket at ≤ 25 °C and re‑conditioned for 8 h at 40 °C under 50 mbar vacuum if the container has been opened at relative humidity exceeding 60%. Failure to perform this step in the lurasidone route depresses the equilibrium conversion by 8–12% because water competes for the sulfonate ester electrophile and generates free alcohol intermediates that act as terminating impurities. Combination of the free base with acetic anhydride or succinic anhydride during storage tank cleaning constitutes an additional incompatibility — spontaneous acylation at the piperazine‑NH yields an amide that is inert in downstream N‑alkylation and must be removed by flash chromatography before the main charge can be committed. These operational constraints are documented in the internal process‑hazard analysis records and periodically audited under ISO 14001:2015 and OHSAS 18001 site certifications, ensuring that safety datasheets provided to tolling partners reflect current findings from production‑scale campaigns.