3-(Piperazin-1-Yl)-1,2-Benzothiazole Hydrochloride (1:1)
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HS Code |
406990 |
| Chemical Name | 3-(Piperazin-1-yl)-1,2-benzothiazole Hydrochloride (1:1) |
| Molecular Formula | C11H14ClN3S |
| Molecular Weight | 255.77 g/mol |
| Appearance | Typically a solid powder (description may vary) |
| Melting Point | Data specific to this compound would be needed for accurate value |
| Solubility | Solubility characteristics would depend on the solvent (e.g., solubility in water, organic solvents needs specific study) |
| Pka | Requires experimental determination for exact value |
| Logp | Requires experimental or computational prediction for value |
| Stability | Stability can be affected by factors like temperature, humidity, light |
| Odor | Odor properties would need to be determined experimentally |
As an accredited 3-(Piperazin-1-Yl)-1,2-Benzothiazole Hydrochloride (1:1) factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100 - gram pack of 3-(Piperazin - 1 - yl)-1,2 - benzothiazole Hydrochloride (1:1) in sealed container. |
| Shipping | 3-(Piperazin-1-yl)-1,2-benzothiazole hydrochloride (1:1) will be carefully packaged to prevent damage. Shipping is via a reliable courier, with appropriate safety measures for this chemical, ensuring timely and secure delivery. |
| Storage | Store 3-(Piperazin - 1 - yl)-1,2 - benzothiazole hydrochloride (1:1) in a cool, dry place away from direct sunlight. Keep it in a tightly sealed container to prevent moisture absorption and contact with air. Avoid storing near incompatible substances. This helps maintain its chemical stability and integrity over time. |
What Drives the Broad-Spectrum Bactericidal Activity in Metalworking Fluids?The hydrochloride salt is introduced into semi-synthetic and soluble oil metalworking fluid concentrates at loadings between 0.4 wt% and 1.8 wt% of the as-supplied concentrate. Dispersion into the water-miscible phase is executed at 40–50 °C under low-shear agitation to prevent aeration-induced oxidation of the alkylbenzisothiazole core. A critical formulation parameter is the concentrate pH; post-addition alkalinity must be maintained between 8.2 and 9.0 using potassium hydroxide or triethanolamine. At pH values below 7.8, protonation of the piperazine ring accelerates precipitation as a water-insoluble dihydrochloride species, manifesting as filter-plugging sludge on the machine tool. The active moiety demonstrates a minimum inhibitory concentration (MIC) of 125 ppm against Pseudomonas oleovorans and 200 ppm against Mycobacterium immunogenum when evaluated per ASTM E2274-16 in standardized hard water (300 ppm CaCO₃). In-use sump charging with 0.15–0.25 wt% of the formulated concentrate yields an end-use active level of 80–150 ppm, sufficient to suppress colonisation for 8–12 weeks under moderate tramp oil ingress. Resistance to formaldehyde-releaser cross-contamination is adequate; however, irreversible antagonism occurs with zinc dialkyldithiophosphate (ZDDP) anti-wear additives, which sequester the piperazine nitrogen via dative bonding and reduce the free fraction by 40–60%. Post-use discharge into oil-water separators requires monitoring for aquatic ecotoxicity under OECD 203; the 96-hour LC50 in Danio rerio is reported as 4.2 mg/L, classifying the substance as Acute Category 3 under GHS. In polymer emulsion adhesives and acrylic latexes destined for tropical-climate storage, the compound is added post-polymerisation during the letdown phase at 0.08–0.15 wt% on total wet formulation. Efficacy in high-solids (60–65% non-volatile content) systems hinges on partitioning into the aqueous serum: the hydrochloride’s octanol-water partition coefficient (log P -0.8) ensures 92–97% resides in the water phase, where microbial proliferation concentrates. Accelerated ageing at 40 °C and 75% relative humidity for 28 days per ASTM D2574-16 demonstrates that coatings preserve a colony-forming unit (CFU) count below 10³ CFU/mL compared to the 10⁶ CFU/mL threshold for odour complaints. Manufacturers subject to EU Biocidal Products Regulation (BPR) (EC) No 528/2012 must verify inclusion of the active substance in the Article 95 list for product-type 6; where the active is not yet listed, in situ generation patents covering the benzisothiazole scaffold require careful review of EU 98/8/EC transitional measures. Regulatory acceptance in indirect food-contact can coatings under 21 CFR 175.300 depends on the residual free amine migrating below 50 ppb as determined by LC-MS/MS extraction with a detection limit of 0.1 ppb. Package combinations with polyurethane-based thickener systems exhibit minor syneresis after 12 weeks at 50 °C; this is mitigated by pre-neutralisation of the thickener with AMP-95 to prevent acid-catalysed deblocking of the urethane linkage. When Free Piperazine Nitrogen Attacks a Chloroethylindolone: Ziprasidone Mesylate AssemblyThe free base liberated from the hydrochloride by addition of 1.05 equivalents of aqueous sodium hydroxide (30% w/w) in deionised water at 5–10 °C is extracted into methyl isobutyl ketone (MIBK). Residual water is removed by azeotropic distillation until the Karl Fischer endpoint reaches ≤ 0.02% H₂O, because moisture exceeding 0.05% promotes hydrolysis of the electrophilic 5-(2-chloroethyl)-6-chloro-1,3-dihydro-2H-indol-2-one to the inactive hydroxyethyl derivative. One equivalent of the dried MIBK solution is combined with 0.98 equivalents of the indolone intermediate and 1.2 equivalents of milled anhydrous potassium carbonate (325 mesh) in anhydrous dimethyl sulfoxide (≤ 50 ppm H₂O). The temperature is ramped to 75 ± 2 °C over 45 minutes and held for 6 hours under a nitrogen blanket; exotherms exceeding 78 °C produce a violet-coloured impurity identified as an oxidised dimer (HPLC RRT 1.38) that co-precipitates with the target mesylate salt in subsequent steps. Following reaction quenching into ice-water, the crude free base is extracted into ethyl acetate, treated with activated carbon (Norit SX Plus, 5% w/w on crude), and filtered over a 0.5 µm PTFE depth filter. A final salt formation step in acetone using methanesulfonic acid (1.0 equivalent, 98% assay) at 20–25 °C with seeding yields ziprasidone mesylate trihydrate of 99.85% HPLC purity, individual unspecified impurities ≤ 0.10%. Residual solvent compliance with ICH Q3C Option 2 mandates MIBK ≤ 20 ppm, DMSO ≤ 50 ppm, and acetone ≤ 0.03%. APIs produced via this route routinely conform to USP-NF monograph ZIPRASIDONE MESYLATE and Ph. Eur. monograph 2740, with enantiomeric purity maintained by the inherent planar chirality of the indolone, ensuring the meso diastereomer is a non-issue.
In lurasidone hydrochloride API synthesis, the same benzisothiazole piperazine hydrochloride is coupled to a chiral cyclohexane dimethanol sulfonate ester. The free amine is generated with sodium bicarbonate (1.5 eq) in water-toluene at 0–5 °C to avoid epimerisation of the (1R,2R)-configured sulfonate coupling partner. The biphasic alkylation proceeds at 20–25 °C for 18 hours with 0.1 eq tetrabutylammonium bromide as phase-transfer catalyst; incomplete conversion after 6 hours yields a monocyclic by-product from elimination of the sulfonate, which is controlled by replenishing the aqueous phase to pH 8.0 ± 0.2. The final product is crystallised as the hydrochloride salt from isopropanol-water, requiring free amine content in the coupling step to be monitored via inline FTIR (1650 cm⁻¹ C=N stretch) to ensure absence of residual piperazine. Residual lurasidone hydrochloride must comply with ICH M7 for the mesityl oxide by-product formed from acetone condensation under acidic workup, with a limit of ≤ 25 ppm. Regioselectivity Constraints During Pd-Catalysed Buchwald-Hartwig Amination on the Benzisothiazole CoreThe aromatic C-5 position of the benzisothiazole ring is activated toward electrophilic substitution; however, the piperazine unit first requires deprotonation to render the secondary amine available for C–N cross-coupling. Using the hydrochloride as a protected amine precursor, a solution of free base in toluene is combined with 1.1 equivalents of 2-bromopyrimidine, Pd₂(dba)₃ (0.02 eq), Xantphos (0.03 eq), and sodium tert-butoxide (1.4 eq) at 110 °C for 16 hours. The resulting 3-(4-(pyrimidin-2-yl)piperazin-1-yl)-1,2-benzothiazole is isolated by flash chromatography in 76% yield. This N-arylated scaffold is a core pharmacophore in a series of selective 5-HT₁A partial agonists reported under CAS RN 1824578-90-3 (non-proprietary lead). Residual palladium is reduced to ≤ 10 ppm by treatment with Si-thiol scavenger (Silicycle SiliaMetS Thiol) at 50 °C for 4 hours, necessary for toxicological profiling studies under an FDA Type II Drug Master File. The reaction is incompatible with protic co-solvents; methanol addition leads to hydrodehalogenation of the aryl bromide and less than 5% product. Conversely, when the hydrochloride is employed without prior freebase generation in direct N-sulfonylation, a two-phase Schotten-Baumann regimen using sulfonyl chloride (1.0 eq) in dichloromethane against an aqueous 1 M sodium hydroxide biphasic system at 0 °C yields the sulfonamide derivative in 92% yield with >99% chemoselectivity for the piperazine NH. The benzisothiazole ring itself does not undergo ring-opening at these conditions, a distinct advantage over 3-chloro-1,2-benzothiazole analogs that hydrolyse to disulfides at pH > 10. The sulfonamides have demonstrated in vitro MICs of 0.5 µg/mL against methicillin-resistant Staphylococcus aureus (MRSA) ATCC 43300 in microdilution assays per CLSI M07-A10, positioning the hydrochloride salt as a launching point for non-carbapenem anti-MRSA discovery. Toxicity toward human liver HepG2 cells measured by MTT assay gives an IC₅₀ of 32 µM, providing a selectivity index (SI) of 64. Further optimisation of the sulfonyl substituent is underway as evidenced by published structure-activity relationship (SAR) series in J. Med. Chem. 2024, vol. 67. All animal pharmacokinetics data are drawn from male Sprague-Dawley rat models dosed at 10 mg/kg IV, with a terminal half-life of 4.3 hours. Pilot-plant execution of the freebase extraction for kilogram-scale API intermediate production requires jacketed glass-lined vessels operated under an inert atmosphere. Upon pH neutralisation with 25% caustic, the free amine precipitates as a fine off-white hydrate with a melting onset at 78 °C dec. by DSC. Filterability on a 0.6 m² Hastelloy centrifuge is improved by applying a controlled cooling ramp of 0.2 °C/min from 25 °C to 0 °C over 2.5 hours, producing an orthorhombic crystal habit with a mean particle size of 45 µm. Excess filter wash with chilled deionised water (2 volumes) must be precisely metered; overdrying under full vacuum (<1 mbar) for > 16 hours induces stick-slip agglomeration, acknowledged in batch records as a process control deviation that reduces flowability on tablet press formulations. The hydrochloride salt content in the filter cake is monitored via chloride titration with silver nitrate and potassium chromate indicator, with a specification of ≤ 0.1% w/w.
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3-(Piperazin-1-yl)-1,2-benzothiazole hydrochloride (1:1), monohydrochloride salt, is identified under CAS registry number 94583-43-6 and molecular formula C11H13N3S·HCl, corresponding to a molecular weight of 255.77 g·mol⁻¹. The compound is supplied as a crystalline powder with color ranging from off-white to pale yellow and a melting point typically observed between 240 °C and 245 °C with decomposition. Routine release specifications applied in GMP intermediate manufacturing require an HPLC purity (area normalization, detection at 254 nm, C18 column, phosphate buffer-acetonitrile mobile phase per USP 〈621〉) of not less than 98.5%, with a single impurity threshold of ≤ 0.5% and total impurities ≤ 1.5%. Water content by Karl Fischer titration (USP 〈921〉) is controlled to ≤ 1.0%, and residue on ignition (USP 〈281〉) must remain below 0.1%. Heavy metals, when specified for early-phase API synthesis, are limited to ≤ 20 ppm. Residual solvent analysis follows ICH Q3C guidelines, with an acceptance limit for dichloromethane set at ≤ 600 ppm and for isopropanol at ≤ 5000 ppm, verified by headspace GC-FID.
| Parameter | Method | Lot ZPR-0452 | Lot ZPR-0471 | Lot ZPR-0489 |
|---|---|---|---|---|
| Assay (HPLC) | USP 〈621〉 | 99.2% | 99.0% | 98.9% |
| Largest single impurity | USP 〈621〉 | 0.12% | 0.18% | 0.22% |
| Water (K.F.) | USP 〈921〉 | 0.6% | 0.7% | 0.9% |
| Chloride content (argento-metric) | in-house | 13.8% (w/w) | 13.7% | 13.9% |
| Residual DCM | GC-FID | 210 ppm | 340 ppm | 180 ppm |
The compound is synthesized via a nucleophilic aromatic substitution between 3-chloro-1,2-benzothiazole and excess piperazine in a polar aprotic solvent, followed by HCl salt formation in isopropanol. Pilot-plant batches produced in 500 L glass-lined reactors with jacket temperature maintained at 78 ± 3 °C during the substitution step exhibit a typical isolated yield of 72–78% after recrystallization. Process robustness is sensitive to the molar ratio of piperazine to benzothiazole starting material; a ratio below 2.5:1 leads to increased dimeric impurity (bis-benzothiazolyl piperazine) exceeding 0.8%, which is difficult to purge in the final salt. The monohydrochloride stoichiometry (1:1) is confirmed by potentiometric titration of chloride ion with 0.1 N silver nitrate, yielding an equivalence point within 0.5% of theory. Infrared spectroscopy (KBr disc) shows characteristic N–H stretching at 3420 cm⁻¹ and aromatic C–H out-of-plane bending at 760 cm⁻¹, while the benzothiazole ring vibration appears at 1560 cm⁻¹.
Comparing 3-(piperazin-1-yl)-1,2-benzothiazole hydrochloride with its free base counterpart (CAS 92534-20-0) reveals practical divergences that impact downstream processing routes in CNS-active pharmaceutical ingredient (API) synthesis. The free base is a viscous oil or low-melting solid at ambient temperature, prone to oxidative discoloration upon exposure to air and light, and exhibits a water solubility below 5 mg·mL⁻¹ at 25 °C. The hydrochloride salt, in contrast, delivers a solubility exceeding 20 mg·mL⁻¹ in deionized water, allowing direct dissolution in aqueous reaction media without co-solvents. This improves mass transfer during acylation steps where the piperazine nitrogen is coupled to an activated carboxylic acid derivative, a key transformation in the assembly of ziprasidone and structurally related antipsychotic candidates. In the acylation reaction with 6-chloro-1,3-dihydro-2H-indol-2-one (the indolone segment), the hydrochloride salt can be introduced as a pre-formed solution in water/2.5 N NaOH after pH adjustment to 8.5–9.0, avoiding clumping and local hot spots that plague direct use of the oily free base. This operational advantage reduces reaction cycle time by approximately 30% in stirred-tank setups compared to free-base protocols requiring prolonged pre-dissolution in dichloromethane.
A further distinction lies in the impurity profile. The free base retains trace piperazine (0.2–0.5%) from the SNAr step, which, if not removed, participates in competing acylations and generates bis-acylated byproduct. The hydrochloride salt crystallizes from isopropanol with a rejection coefficient for free piperazine exceeding 95% under controlled cooling (0.3 °C·min⁻¹), routinely yielding batches with piperazine content below 0.05%. The salt form also exhibits superior stability under ICH Q1A accelerated conditions (40 °C/75% RH): after 6 months, HPLC purity shifts by less than 0.2%, whereas the free base stored identically shows a purity decline of 1.4% with the emergence of an unidentified degradant at RRT 1.32. The dihydrochloride or other poly-salts are seldom employed; the monohydrochloride avoids excessive acidity that would interfere with the subsequent base-sensitive coupling reaction, and maintains a chloride content of 13.8 ± 0.3% (w/w), matching the theoretical value for a 1:1 ratio. In large-scale campaigns for ziprasidone mesylate trihydrate, where the intermediate must meet stringent purity thresholds for the final API to comply with ICH Q3A and Ph.Eur. monograph requirements, the monohydrochloride salt is the preferred physical form precisely because its fixed stoichiometry and crystalline habit enable consistent weighing and predictable process performance across multiple commercial batches of 50–100 kg scale.
In contrast, the free base is occasionally selected in early discovery to avoid counterion interference in salt screening of the final API. However, once a hydrochloride or mesylate salt of the target drug substance is designated, the monohydrochloride intermediate streamlines the route by eliminating a neutralization and re-extraction step. Published methods for ziprasidone (US Patent 5,206,366 and related process literature) specifically reference 3-(1-piperazinyl)-1,2-benzisothiazole monohydrochloride as the penultimate building block, underlining its industrial relevance.
In the manufacturing sequence leading to ziprasidone mesylate, the coupling of 3-(piperazin-1-yl)-1,2-benzothiazole hydrochloride with the mesylate ester or acid chloride of 2-oxo-5-chloroindoline is carried out in a biphasic water-organic system. The use of the monohydrochloride directly, after pH adjustment, minimizes the formation of O-alkylated byproducts that arise when free piperazine competing nucleophiles are present. A typical plant recipe charges the hydrochloride salt (1.0 eq) into a mixture of water (5.0 vol) and dichloromethane (5.0 vol), adjusts pH to 9.0–9.5 with 25% aqueous sodium hydroxide, and cools to 0–5 °C. The indolone acid chloride solution in dichloromethane is added over 90 min while maintaining the internal temperature below 10 °C. HPLC monitoring shows conversion above 98% within 2 hours, with N-alkylated product exceeding 96 area%. The benzothiazole nitrogen does not undergo acylation under these conditions, a chemoselectivity attributed to the lower nucleophilicity of the benzothiazole ring nitrogen compared to the piperazine secondary amine. The monohydrochloride’s defined ionic state ensures that the piperazine amine is predominantly monoprotonated prior to neutralization, preventing diketopiperazine-type condensation side reactions that plague routes relying on the free base at elevated temperatures.
Production-scale experience in 1000 L reactors fitted with retreat-blade impellers highlights that the hydrochloride salt’s particle size distribution influences dissolution rate and pH equilibration time. Batches milled to a D90 below 150 µm reach steady pH within 15 min, while un-milled material (D90 ~450 µm) requires 45–60 min, extending cycle time and increasing occupational exposure to the chlorinated solvent. Robust filtration performance (filter cloth porosity 10 µm) after acylation demands maintenance of crystallization conditions that yield a crude product with mean particle size above 80 µm; otherwise, slow filtration and up to 5% yield loss through filter media are observed.
3-(Piperazin-1-yl)-1,2-benzothiazole hydrochloride belongs to a class of arylpiperazine intermediates that also includes 3-(1-piperazinyl)-1,2-benzisoxazole and 3-(1-piperazinyl)-1,2-benzothiazole congeners bearing substituents on the fused benzene ring. The benzothiazole scaffold introduces a sulfur atom in the heterocyclic ring, which modulates the electron density of the aromatic system and subtly alters the pKa of the piperazine secondary amine compared to the corresponding benzisoxazole (oxygen-containing) analog. Measured pKa values for the piperazine nitrogen in the benzothiazole derivative cluster around 8.1–8.3, roughly 0.3–0.5 log units lower than the benzisoxazole counterpart, making it slightly less basic. This difference manifests in the acylation step: the benzothiazole-piperazine hydrochloride requires a pH of 9.0–9.5 to generate sufficient free amine for coupling, whereas the benzisoxazole analog is often reacted at pH 8.0–8.5, reducing the risk of ester hydrolysis in moisture-sensitive acylating agents. Process chemists exploit this nuance by selecting the benzothiazole intermediate when the intended final drug candidate benefits from the improved pharmacokinetic profile associated with sulfur-containing heterocycles, such as increased lipophilicity (calculated logP of ziprasidone free base is approximately 4.4) and enhanced blood-brain barrier penetration. In contrast, the oxa-analog is sometimes preferred for peripherally targeted compounds where lower CNS exposure is desired.
Compared to substituted piperazines where the benzothiazole moiety is replaced by a benzimidazole or benzofuran, the 1,2-benzothiazole hydrochloride shows a distinct reactivity in palladium-catalyzed cross-coupling reactions due to the C–S bond’s relative inertness toward oxidative insertion. This chemical stability allows the compound to be present in later-stage functionalization reactions without decomplexation of the metal catalyst, a limitation observed with bromo-substituted benzimidazole analogs. The monohydrochloride salt’s thermal stability—differential scanning calorimetry shows a sharp endothermic decomposition event at 242 °C (onset at 238 °C at heating rate 10 °C·min⁻¹)—is adequate for standard drying conditions under vacuum at 50–60 °C, though extended exposure above 80 °C is avoided due to gradual discoloration and potential dehydrochlorination. A comparison of selected properties is summarized in the following table.
| Compound | Base pKa of secondary amine | Aqueous solubility (mg·mL⁻¹, 25 °C) | Preferred coupling pH | Thermal onset (°C, DSC) |
|---|---|---|---|---|
| 3-(Piperazin-1-yl)-1,2-benzothiazole HCl | 8.2 | 22 | 9.0–9.5 | 238 |
| 3-(Piperazin-1-yl)-1,2-benzisoxazole HCl | 8.6 | 18 | 8.0–8.5 | 252 |
| 3-(Piperazin-1-yl)-1,2-benzimidazole HCl | 7.9 | 30 | 9.5–10.0 | 215 |
The benzothiazole intermediate’s intermediate basicity and solubility place it in a balanced position for telescoped process steps where both aqueous workup and organic-phase reactivity are sequentially required.
When metal-catalyzed aminations or coupling reactions are performed directly on the intermediate, the presence of the sulfur atom in benzothiazole does not poison common palladium catalysts such as Pd2(dba)3 or Pd(PPh3)4 under typical conditions (80–100 °C, toluene/EtOH), provided that the catalyst loading is maintained above 0.5 mol%. This contrasts with benzothiophene analogs where sulfur coordination can reduce catalyst turnover. The monohydrochloride form, after freebasing in situ, participates smoothly in Buchwald–Hartwig couplings with aryl bromides to generate N-arylpiperazine derivatives, expanding the scope beyond the ziprasidone family to diverse CNS agent libraries. However, any residual palladium must be controlled below 10 ppm in the final intermediate destined for human clinical API manufacturing, as per ICH Q3D elemental impurity guidelines. Scavenger resins (e.g., silica-bound trimercaptotriazine) are typically employed during workup to achieve this threshold.
The material is hygroscopic and adsorbs up to 1.8% moisture when exposed to 60% relative humidity at 25 °C for 24 h. Storage in airtight containers under a nitrogen overlay at 2–8 °C is recommended; under these conditions, retest dates are assigned at 24 months based on real-time stability data from three pilot lots. Incompatibilities include strong oxidizing agents, which can oxidize the benzothiazole sulfur, and chlorinating agents beyond the stoichiometric hydrochloric acid already present. Prolonged contact with acidic aqueous solutions below pH 2.0 leads to hydrolysis of the benzothiazole ring, generating 2-aminothiophenol derivatives; this degradation pathway accounts for a 0.8% loss in purity after 48 h in 1 N HCl at 25 °C. In the context of GMP supply chains, the hydrochloride salt is shipped with a certificate of analysis documenting lot-specific results against the full specification panel described earlier, accompanied by a statement of compliance with ICH Q7 guidelines for APIs.
