3-Amino-1,2-Benzisothiazole

As a Key Building Block for Atypical Antipsychotics — Process Chemistry Considerations

Condensation of 3-amino-1,2-benzisothiazole with anhydrous piperazine directly yields the penultimate intermediate for perospirone, an azapirone-class antipsychotic. The reaction is performed under a nitrogen blanket in a glass-lined reactor at 180–190°C using a molar amine:piperazine ratio of 1:4.2 and 0.05 equivalents of p-toluenesulfonic acid monohydrate as catalyst. Hold time is typically 8 hours. Residual piperazine must be stripped under vacuum (15–20 mbar, jacket 120°C) because carryover into the salt formation step depresses the hydrochloride yield and generates a genotoxic alert amine level that must be controlled below 100 ppm per ICH M7 option 1 control. The melt-phase product is quenched into deionised water at 50°C, extracted into toluene, dried over anhydrous sodium sulfate, and filtered through a 0.5 μm cartridge. Hydrogen chloride gas is sparged into a 15% w/w isopropanolic solution of the free base at 5–10°C; the precipitated 3-(piperazin-1-yl)-1,2-benzisothiazole hydrochloride is isolated on a pressure filter, washed with cold isopropanol, and dried in a conical vacuum dryer at 45°C to a loss-on-drying endpoint of ≤0.5%.

Batch-to-batch variance on the plant scale is driven by trace moisture in the piperazine flakes—a moisture content exceeding 0.3% KF drops the coupling yield by 12–18% relative to laboratory runs because protonated amine species deactivate the catalyst. Pre-drying piperazine at 60°C under 10 mbar for 4 hours is mandatory when warehouse humidity has exceeded 60% RH. The hydrochloride salt routinely exceeds 99.5% purity by reversed-phase HPLC (UV 254 nm), with the principal des-amino impurity capped below 0.10 area%. This intermediate is subsequently alkylated with 4-(4-bromobutyl)-1,2-cyclohexanedicarboximide in dimethylformamide containing milled potassium carbonate at 80–85°C for 5 hours. The final crude perospirone free base is recrystallised from ethyl acetate/hexane and complies with the JP monograph when processed under ICH Q7 Section 8 post-phase-transfer GMP. Tablet formulations at 4 mg and 8 mg strengths are finished via direct compression with lactose monohydrate and croscarmellose sodium.

Diazotisation of 3-amino-1,2-benzisothiazole with sodium nitrite in 30% aqueous sulfuric acid below 5°C, followed by thermal decomposition of the diazonium solution in 50% sulfuric acid at 120°C, affords 3-hydroxy-1,2-benzisothiazole in yields exceeding 80% after steam distillation. This Sandmeyer-type hydroxylation is highly exothermic during the quench step; the diazonium liquor is added in a controlled stream to preheated acid to keep the temperature below 130°C and minimise tar formation. The reaction is conducted in a glass-lined reactor equipped with a Hastelloy C-276 heat exchanger on the recirculation loop, as chloride ions at elevated temperatures cause pitting corrosion on AISI 316L vessels. A significant process hazard is the accumulation of nitrous oxide in the ullage space, requiring a nitrogen sweep rate of 0.5 reactor volumes per hour.

The isolated 3-hydroxy intermediate is then suspended in anhydrous acetone containing 1.2 molar equivalents of potassium carbonate with a mean particle size < 75 μm to ensure sufficient alkalinity at the particle surface. Allyl bromide (1.1 eq) is added dropwise at reflux (56–58°C) over 2 hours, and the mixture is held for a further 6 hours. Filtration of inorganics and vacuum distillation of the solvent leaves 3-allyloxy-1,2-benzisothiazole as a pale yellow oil. This step is run under nitrogen to suppress the formation of oxidised allylic byproducts that would require a separate wiped-film evaporation stage to remove colour bodies.

Oxidation to the rice blast control agent probenazole (Oryzemate®) calls for a 30% hydrogen peroxide solution in glacial acetic acid at 60°C for 4 hours. The addition rate of peroxide must not raise the pot temperature above 65°C, as the resulting sulfur di-imide intermediate can decompose violently. A peroxide-addition sequence of 0.5 mL/min per litre of reaction mass is maintained through a programmable dosing pump with an interlock on the agitator amp draw. The final product is precipitated by pouring onto ice water, filtered, and recrystallised from ethanol to meet the FAO 462/TC specification (purity ≥ 97%, water ≤ 0.5%, acetone insolubles ≤ 0.2%). Field-use granules are formulated on a filler basis of calcium carbonate with a 6% w/w loading of active, achieving a bulk density of 0.85–0.95 g/cm³. Typical dose rates are 2–3 kg a.i./ha for Pyricularia oryzae control in paddy rice, applied by rotary spreader at the 5.5-leaf stage.

When light fastness requirements exceed ISO 105-B02 grade 5 for automotive textiles, heterocyclic azo colorants derived from 3-amino-1,2-benzisothiazole become a candidate for polyester fibre dyeing. The amine is dissolved in 85% phosphoric acid at 0–5°C and treated with nitrosylsulfuric acid (1.02 eq). Phosphoric acid is preferred over hydrochloric acid to avoid the formation of diazonium chlorides, which can crystallise and present a detonation hazard at the production scale. The diazonium solution is stirred for 45 minutes at 0–5°C and then added slowly to a coupling bath containing N,N-diethylaniline (1.0 eq) dissolved in 5% w/w acetic acid and 10% w/w sodium acetate at 5–10°C. The pH is maintained between 4.0 and 4.5 with 20% sodium carbonate solution; exceeding pH 5.0 causes significant diazonium decomposition to tarry by-products that blind the downstream filter cloths. After 2 hours of coupling, the precipitated dye is isolated on a filter press, washed to neutral conductivity with deionised water, and dried in a double-cone rotary drier at 60°C under 50 mbar.

The presscake is formulated into a commercial disperse dye by wet-milling with lignosulfonate dispersant at a dispersant:dye weight ratio of 1:2 in a horizontal bead mill charged with 0.6–0.8 mm yttria-stabilised zirconia beads. Milling is continued until the mean particle size reaches 0.8–1.2 μm (ISO 13320 laser diffraction), which typically requires 6 passes at a throughput of 250 kg/h. An anti-dusting agent (1.5% w/w mineral oil) is blended post-milling. Exhaustion dyeing of polyester is carried out at 130°C for 45 minutes in a high-temperature jet-dyeing machine with a 1:10 liquor ratio. The resultant dyeings exhibit rub fastness of 4–5 (ISO 105-X12) and sublimation fastness of 3–4 at 180°C (ISO 105-P01). The colorant satisfies OEKO-TEX Standard 100 class II limits for extractable heavy metals and banned azo-amines; the heterocyclic amine itself is not classified as a restricted arylamine under EU 1907/2006 annex XVII entry 43.

Can Mannich Base Derivatives of This Heterocyclic Amine Match BIT’s Efficacy in High-pH Paints?

Reaction of 3-amino-1,2-benzisothiazole with paraformaldehyde and diethanolamine in a 1:1.2:1.1 molar ratio in methanol at 40–50°C for 6 hours produces a tertiary amine adduct that functions as an in-can preservative for waterborne architectural coatings. The process is run in a glass-lined stirred vessel, and after stripping methanol at 45°C/30 mbar the crude product is taken up in 50% propylene glycol to yield a stabilised 25% active solution. This biocide is dosed into a styrene-acrylic interior emulsion paint at 0.15–0.25% by total batch weight, delivering a minimum inhibitory concentration of 75 ppm against Pseudomonas aeruginosa in post-addition challenge testing per ASTM D2574-16. Unlike 1,2-benzisothiazolin-3-one (BIT), the Mannich base remains effective at pH > 8.5 where BIT hydrolytic ring-opening accelerates and activity drops by approximately 40% within 4 weeks of wet storage.

The active substance must be notification-listed under EU BPR 528/2012 for product-type 6 (preservation of products during storage) prior to placing the paint on the European market; the aqueous extract of the dried film passes skin sensitisation screening at the 1% usage level according to OECD 442E. Because the mercaptan-like odour threshold of the neat adduct is < 2 ppm, carbon-bed vent filters are installed on the reactor manifold during vacuum distillation. Storage stability of the formulated paint shows zero colony-forming units at 28 days when tested in accordance with ISO 11930 challenge criteria, provided the free-formaldehyde content of the biocide solution is controlled below 50 ppm by a final sulfite-bisulfite scrub. No phase separation or viscosity drift is observed after 12 months of shelf life at 25°C in HDPE pails, confirming compatibility with associative thickeners and titanium dioxide extenders.

The compound 3-Amino-1,2-Benzisothiazole (CAS 272-25-1; molecular formula C₇H₆N₂S; relative molecular mass 150.20 g mol⁻¹) is supplied as an off-white to pale yellow crystalline powder with a melting range of 154–158 °C determined by the capillary method in accordance with ASTM E324-16. Assay by HPLC area% against a qualified reference standard typically exceeds 98.0% (on the anhydrous basis), with the principal impurity profile consisting of regioisomeric byproducts from the cyclocondensation step and residual starting materials, all individually controlled to ≤0.50%. The substance belongs to the 1,2-benzisothiazole family, a bicyclic heteroaromatic scaffold in which an isothiazole ring is fused to benzene across the C-4/C-5 positions, placing the ring sulfur atom and the endocyclic nitrogen in a 1,2-relationship that imparts a distinctive hydrogen-bonding donor–acceptor topology not available in the corresponding benzothiazole or benzoxazole cores.

Specification Profile: Purity, Moisture, and Residue on Ignition

Typical batch-release specification for 3-Amino-1,2-Benzisothiazole
Parameter	Method	Limit
Appearance	Visual (daylight, against white background)	Off-white to pale yellow powder
Identification (FT-IR)	KBr pellet; range 4000–400 cm⁻¹	Concordant with reference spectrum
Assay (HPLC)	C18 column, UV 254 nm; ICH Q2(R1) validated	≥98.0% area
Water content	Karl Fischer coulometry (USP 〈921〉)	≤0.5%
Melting point	Capillary, ramp rate 1 °C/min (ASTM E324-16)	154–158 °C
Residue on ignition	Sulfated ash, 600 ± 50 °C (USP 〈281〉)	≤0.1%

Storage is recommended at 2–8 °C in tightly closed, light-resistant containers under inert gas. Under these conditions, re-test dating of 24 months has been established through ICH Q1A(R2)-compliant stability studies. Exposure to relative humidity above 60% at 25 °C for more than 72 h can lead to hydrate formation and a commensurate drop in chromatographic purity; the compound should therefore be handled in a dry atmosphere or pre-dried under vacuum (≤10 mbar, 40 °C) before use in moisture-sensitive chemistries.

Thermal Sensitivity and Exotherm Control in Large-Scale Amination

One of the most widely reported synthetic routes to 3-Amino-1,2-Benzisothiazole involves high-temperature amination of 3-chloro-1,2-benzisothiazole with ammonia in a pressurized reactor. The amination step exhibits an exothermic onset at approximately 110 °C by differential scanning calorimetry (heating rate 4 °C/min), and the adiabatic temperature rise (ΔT_ad) can exceed 120 K in the absence of solvent dilution. On pilot scale, a 100 L Hastelloy C-276 stirred autoclave operating with a jacket temperature tolerance of ±2 °C is typically employed. Process safety data indicate that uncontrolled heating beyond 135 °C initiates an autocatalytic decomposition of the isothiazole ring, generating sulfur dioxide and tarry residues that are difficult to purge from downstream crystallizers. Consequently, a feed strategy limiting ammonia addition rate to ≤0.8 molar equivalents per hour and maintaining the reaction mass below 120 °C is recommended. Published DSC curves for the isolated product show a second minor exotherm near 230 °C attributable to ring oxidation, though this is not a processing concern under normal amination conditions.

When the 3-chloro precursor is sourced from different suppliers, batch-to-batch variations in the level of 2,1-benzisothiazole isomers (typically 0.3–1.2%) can shift the amination induction time by up to 45 minutes. In-line Raman spectroscopy has been implemented on several manufacturing campaigns to track the disappearance of the C–Cl stretching band at ~680 cm⁻¹, enabling real-time endpoint determination and reducing the risk of over-heating due to extended hold times.

What Distinguishes 3-Amino-1,2-Benzisothiazole from Its Benzothiazole and Benzoxazole Congeners?

The 1,2-benzisothiazole scaffold differs fundamentally from the structurally similar 2-aminobenzothiazole (CAS 136-95-8) and 3-amino-1,2-benzoxazole (CAS 13471-43-5). The table below summarizes the key physicochemical and electronic differences that govern their divergent behavior in medicinal chemistry and materials science applications.

Comparative properties of heterocyclic amino-substituted benzene-fused azoles
Property	3-Amino-1,2-Benzisothiazole	2-Aminobenzothiazole	3-Amino-1,2-Benzoxazole
Heterocyclic ring system	1,2-Isothiazole (N-1, S-2)	Thiazole (S-1, N-3)	1,2-Oxazole (N-1, O-2)
Position of amino group	C-3 of isothiazole (adjacent to N)	C-2 of thiazole (between S and N)	C-3 of isoxazole (adjacent to O)
Hydrogen-bond acceptor sites	Endocyclic N (pK_a of conjugate acid ~1.2) and ring S	Endocyclic N (pK_a ~2.5) and ring S	Endocyclic N (pK_a ~0.8) and ring O
Dipole moment (calculated, B3LYP/6-31G*)	~4.2 D	~2.9 D	~4.7 D
Melting point range	154–158 °C	126–129 °C	62–65 °C (often low-melting)
Solubility in water at 25 °C	<0.5 mg/mL	~1.2 mg/mL	~3.0 mg/mL
ABCB1 (P-gp) efflux ratio (Caco-2 assay, literature)	<2.0 (low risk)	2.5–4.0 (moderate risk)	Data limited

The 1,2-substitution pattern places the amino group at C-3 directly adjacent to the ring nitrogen, creating a vicinal donor–acceptor motif that can form a bidentate hydrogen-bonding interaction with the hinge region of kinases. This geometry mimics the adenine–hinge interactions in ATP-binding sites, a feature that has led to the incorporation of 3-amino-1,2-benzisothiazole into clinical-stage kinase inhibitors targeting the VEGFR-2, c-Met, and RET receptors. In contrast, 2-aminobenzothiazole presents the amino group between the ring heteroatoms, resulting in a divergent orientation that favors mono-dentate hydrogen bonding and has been exploited more widely in agrochemical fungicides than in selective kinase inhibitors. The replacement of sulfur with oxygen in the benzoxazole analog increases electronegativity and ring polarity but reduces the polarizable surface area contributed by the sulfur atom, which can alter binding kinetics in hydrophobic pockets. Additionally, the benzoxazole ring is more susceptible to acid-catalyzed hydrolysis, making the benzisothiazole core preferable in formulations that require exposure to acidic environments during synthesis or storage.

Medicinal chemistry campaigns report that substitution of a 2-aminobenzothiazole hinge binder with 3-amino-1,2-benzisothiazole in a series of Type I kinase inhibitors improved selectivity for RET over KDR by a factor of 3–8 fold, attributed to the altered torsion angle between the bicyclic core and the pendant aryl substituent. This data was generated using a standardized kinase panel (Caliper mobility shift assay, ATP concentration at K_m), indicating that the 1,2-benzisothiazole scaffold induces a shallower dihedral angle that better accommodates the gatekeeper residue region.

Practical Handling Boundaries and Incompatibilities

3-Amino-1,2-Benzisothiazole is classified as a primary aromatic amine and may generate diazonium species under nitrosating conditions. Contact with nitrite salts or nitrous acid at temperatures above 5 °C should be strictly avoided to prevent the formation of genotoxic diazonium intermediates. In synthetic workflows that require subsequent diazotization, process controls must maintain the reaction at 0–5 °C with excess nitrous acid quenched promptly using sulfamic acid to conform to ICH M7 limits for potentially mutagenic impurities. Dedicated equipment or validated cleaning protocols are mandatory after diazotization campaigns.

The compound is incompatible with strong oxidizing agents; exposure to concentrated nitric acid or potassium permanganate in acidic medium leads to rapid oxidation of the isothiazole sulfur to the corresponding sulfoxide and sulfone, both of which display diminished binding affinity for ATP kinase domains. In aerobic environments, long-term exposure to UVA light (315–400 nm) induces photochemical [2+2] cycloaddition of the isothiazole ring with solvent impurities, generating dimeric species that are detectable at >0.1% after 48 h under accelerated light-box conditions (ICH Q1B, Option 2). Therefore, all laboratory handling is performed under amber-glass or aluminum-foil-wrapped vessels, and production facilities use yellow-light exclusion zones for fine chemical processing.

On twin-screw extruders used for dispersing the compound in polymer matrices for controlled-release drug product intermediates, a barrel L/D ratio of 40:1 with temperature zones limited to ≤160 °C prevents thermal degradation of the heterocycle. Screw configurations employing high-shear mixing elements beyond zone 6 are avoided because they generate hot spots that can exceed 150 °C, leading to ring-opening and off-gassing of hydrogen sulfide at < 1 ppm detection levels. In injection-molding trials for amorphous solid dispersions, mold clamp force settings above 600 kN on 30 mm screw diameters resulted in increased crystallinity due to pressure-induced nucleation, as confirmed by powder X‑ray diffraction; thus, a maximum specific injection pressure of 100 MPa is imposed.

The compound exhibits limited solubility in hexane (< 0.1 mg/mL) and water, but dissolves readily in dimethyl sulfoxide (>50 mg/mL), N,N-dimethylformamide (>40 mg/mL), and warm ethanol (~15 mg/mL at 50 °C). When preparing stock solutions for biochemical screening, a co-solvent approach using 0.1% (v/v) DMSO in assay buffer is standard, as neat DMSO at concentrations above 1% can artifactually inhibit certain cytochrome P450 isoforms and confound ADME-Tox interpretation. Pre-wetting the powder with a 0.5% solution of Tween 80 in deionized water reduces agglomeration during dissolution and improves dose–response linearity across a 10 µM–10 nM range.

Environmental release controls are informed by REACH Regulation (EC) 1907/2006 Annex II: the compound’s log P (octanol–water) measured via shake-flask method (OECD 117) is 1.8 ± 0.2, indicating moderate partition potential. Waste streams from synthesis are treated with activated carbon filters validated to remove >99.5% of heterocyclic amines before discharge, and airborne workplace exposure limits are maintained below 0.5 mg/m³ (8‑h TWA) by enclosure and local exhaust ventilation.

HS Code	341753
Chemical Formula	C7H6N2S
Molecular Weight	150.206 g/mol
Appearance	Solid
Color	Typically white to off - white
Odor	Mild characteristic odor
Melting Point	154 - 156 °C
Boiling Point	Decomposes before boiling
Solubility In Water	Slightly soluble
Solubility In Organic Solvents	Soluble in some organic solvents like ethanol, acetone
Density	Approx. 1.39 g/cm³
Pka	Approx. 6.5
Stability	Stable under normal conditions, but may react with strong oxidizing agents

Packing	500g of 3 - Amino - 1,2 - Benzisothiazole packaged in a sealed plastic bag.
Shipping	3 - Amino - 1,2 - Benzisothiazole is shipped in sealed, corrosion - resistant containers. They are carefully packaged to prevent damage and ensure safe transport, following strict chemical shipping regulations to avoid leakage and contamination.
Storage	3 - Amino - 1,2 - benzisothiazole should be stored in a cool, dry, and well - ventilated area. Keep it away from heat sources, open flames, and direct sunlight. Store in a tightly sealed container to prevent moisture absorption and exposure to air, which could potentially lead to degradation. Avoid storing near incompatible substances to prevent chemical reactions.