3-Methoxy-Benz[D]Isothiazole
|
HS Code |
776048 |
| Chemical Formula | C8H7NO2S |
| Molar Mass | 181.21 g/mol |
| Appearance | Solid (usually) |
| Physical State At Rt | Solid |
| Melting Point | Data needed |
| Boiling Point | Data needed |
| Solubility In Water | Low solubility in water |
| Solubility In Organic Solvents | Soluble in some organic solvents |
| Density | Data needed |
| Vapor Pressure | Low vapor pressure |
| Pka | Data needed |
| Flash Point | Data needed |
| Stability | Stable under normal conditions |
As an accredited 3-Methoxy-Benz[D]Isothiazole factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100g of 3 - Methoxy - Benz[D]Isothiazole packaged in a sealed, labeled chemical - grade bottle. |
| Shipping | 3 - Methoxy - Benz[D]Isothiazole is shipped in accordance with strict chemical regulations. Packed in appropriate, leak - proof containers, it is transported via approved carriers ensuring safe handling and compliance with safety and environmental standards. |
| Storage | Store 3 - Methoxy - Benz[D]Isothiazole in a cool, dry, well - ventilated area, away from heat sources and open flames. Keep it in a tightly closed container to prevent exposure to air and moisture, which could potentially cause degradation. Store separately from incompatible substances such as strong oxidizing agents or bases to avoid chemical reactions. |
In a cGMP-compliant synthesis train rated for 2000-L glass-lined reactors, 3-methoxybenzo[d]isothiazole serves as the heterocyclic nucleophile in the construction of a benzoisothiazol-3-yl acetate pharmacophore destined for a selective PI3Kδ inhibitor currently undergoing Phase II clinical evaluation. The alkylation step with ethyl 2-bromoacetate proceeds at 1.0:1.05 molar equivalents (isothiazole:bromoester) in dimethylformamide under an inert nitrogen cap, held at 67 ± 2 °C through jacket-controlled cooling capable of dissipating ≥150 W L⁻¹ to manage a reaction exotherm measured at ΔH ≈ −123 kJ·mol⁻¹. Process analytical technology, specifically inline attenuated total reflectance FTIR tracking the carbonyl stretch at 1745 cm⁻¹, governs endpoint determination. Isolation involves wiped-film evaporation at 2 Torr and 110 °C, followed by dissolution in methyl tert-butyl ether and washing with 0.1 M NaOH to extract unreacted starting material; final recrystallization from n-heptane yields material with chromatographic purity exceeding 99.5 area% (HPLC, 210 nm). The pre-existing batch record review identifies a persistent bottleneck: the formation of a quaternary dimeric impurity (3–7 % under standard feed rates) that crystallizes as a polymorphic inclusion compound during work-up, demanding semi-batch addition of the alkylating agent stretched over 4 h to suppress the dimer below 1.5 %. Regulatory compliance adheres to ICH Q7 for active pharmaceutical ingredient manufacture, with residual solvent limits drawn from ICH Q3C(R8) (DMF 880 ppm, methyl tert-butyl ether 5000 ppm), and elemental impurity monitoring per USP ⟨232⟩/⟨233⟩ ensuring palladium carryover remains beneath 10 µg g⁻¹ from an upstream Suzuki coupling. The isolated intermediate is subsequently elaborated to the active molecule and compressed into oral tablet form.What Limits in-Sump Biocide Stability in Water-Miscible Metalworking Fluids?Stored aqueous concentrates of 3-MBIT exhibit a shelf life exceeding 24 months at pH 8.0–9.2, yet alkaline hydrolysis of the methoxy group accelerates sharply above pH 9.5, converting the active species into 3‑hydroxybenzo[d]isothiazole whose minimum inhibitory concentration against Pseudomonas aeruginosa migrates from 50 µg mL⁻¹ to above 2000 µg mL⁻¹—a potency loss of roughly 1.6 log orders. This pH cusp dictates the formulation strategy for semi‑synthetic boron‑ester coolants used in aerospace aluminium milling, where aminic alkalinity reserves must be capped below the critical threshold. The biocide is typically introduced as a 10 % (w/w) predispersion in anhydrous propylene glycol at a use rate of 0.05–0.15 wt% relative to the ready-to-use emulsion; the predispersion is metered into the concentrate phase after the addition of the emulsifier package but before the final water letdown, utilizing an Ika Ultra‑Turrax UTL 1000 high‑shear inline mixer operating at 2000 rpm to achieve a mean droplet size D[4,3] < 2 µm and prevent the formation of biocide‑depleted zones that would permit slime‑forming bacteria to proliferate. A mandatory validation run per ASTM E2169‑17 must demonstrate a ≥99.9 % reduction in a mixed inoculum (including Fusarium solani and Mycobacterium immunogenum) after 48 h of challenge. Compliance further requires alignment with the German TRGS 611 limit values for water‑miscible coolants and the EU Biocidal Products Regulation (EU 528/2012), with active substance notification as a film preservation product‑type 13. Production‑scale processing on a 10,000‑L compounding vessel frequently encounters a localised viscosity increase when the glycolic biocide stream contacts the anionic emulsifier, generating a temporary gel phase that stalls the bottom‑mounted Cowles blade; this is mitigated by diluting the biocide predispersion with an equal volume of the base oil (hydrotreated paraffinic 40 cSt) prior to injection, restoring a plateau shear stress below 150 Pa at 100 s⁻¹. The finished coolant is employed in high-pressure through‑spindle delivery systems machining 2024‑T3 airframe components.
High-Shear Dispersion of a Hydrophobic Biocide into Aqueous Acrylic EmulsionsIncorporation of this heterocycle into a styrene‑acrylic binder for low‑VOC semi‑gloss architectural latex necessitates overcoming a substantial aqueous solubility deficit ( < 0.1 g L⁻¹ at 20 °C), which otherwise yields a heterogeneous distribution and erratic in‑can preservation. A mill‑base‑style premix is prepared by dispersing 0.15–0.30 wt% (on total paint weight) of the crystalline solid directly into the hydroxyethylcellulose thickener solution (2 % solids) using a Cozzini‑type high‑shear disperser at a tip speed of 12 m s⁻¹ for 15 min until a Hegman gauge reading of 6+ confirms the absence of agglomerates above 25 µm. The resultant biocide‑thickener slurry is introduced during the letdown phase after the pH has been adjusted to 8.0–8.5 with concentrated ammonia. Full‑scale batches of 3000 L have demonstrated that incomplete pre‑dispersion leads to transient colloidal flocculation when the biocide particles act as nuclei for extender pigment agglomeration, visible as a 15–20 KU viscosity spike on a Stormer viscometer within the first 6 h of storage. Validation of preservative efficacy follows ASTM D2574‑16 (Standard Test Method for Resistance of Emulsion Paints in the Container to Attack by Microorganisms), requiring zero visible colonies on streak‑plate isolation after triple bacterial challenge with Enterobacter cloacae, Pseudomonas putida, and Bacillus subtilis. Supplementary long‑term dry‑film fungal resistance is assessed according to ASTM G21‑15, with a target Zone Rating of 1 or better. From a regulatory standpoint, the active substance must satisfy the EU Biocidal Products Regulation’s dossier requirements for product‑type 6 (in‑can preservation), including a specific environmental emission scenario calculated for wastewater treatment plant release using the CHESAR tool. The final dried coating forms a 40 µm film on gypsum wallboard with Category 3 scrub resistance (ISO 11998:2006).When processing challenges involving incompatible additives are encountered, the use of a non‑ionic polyurethane associative thickener instead of the cellulosic has reduced the wet‑state biocide adsorption onto internal void surfaces and maintained the free biocide concentration above the critical anti‑microbial threshold for 18 months in sealed containers stored at 40 °C.When 3-MBIT Replaces MBT in Sulfur-Cured Diene RubberAt loadings above 1.2 phr in a silica‑reinforced NR/BR passenger‑tread compound, 3‑methoxybenzo[d]isothiazole imposes a distinctive cure retardation envelope that extends the Mooney scorch time (MS t5, 127 °C) by 28–35 % relative to mercaptobenzothiazole (MBT) at equivalent molar concentration, a property leveraged to widen the processing safety margin in thick‑section tire sidewalls where premature crosslinking during extrusion at 105 °C can generate scorch nuclei. The compound is added at 0.8–1.5 phr alongside 2.0 phr sulfur and 0.3 phr tetrabenzylthiuram disulfide as the primary accelerator system; mixing is executed on a 1.5‑L intermeshing tangential internal mixer (Banbury BR1600) with a fill factor of 0.72, where the biocide is charged into the second non‑productive stage with the vulcanization agents at 50 °C to prevent thermal decomposition that has been observed above 100 °C via differential scanning calorimetry. Cure kinetics obtained from a moving‑die rheometer (ASTM D5289‑17) at 160 °C reveal a reduction in maximum torque (MH) of approximately 8–10 % compared with the MBT reference, compensated by an increase in the filler‑bonding modifier (resorcinol‑hexamethylenetetramine) from 1.0 to 1.3 phr to recover the 300 % modulus target of 9.5 MPa. The vulcanisation press (Dieffenbacher, 400‑ton clamping force) operates at 15 MPa and 155 °C for a optimized cure time Tc90 + 5 min, after which physical testing per ISO 37:2024 reports tensile strength ≥ 22 MPa and elongation at break 525 ± 25 %. The critical process constraint emerges from the methoxy group’s potential to liberate methanol during scorch‑delayed vulcanization, creating micro‑porosity in sections thicker than 6 mm unless a post‑cure vacuum step (−0.95 bar for 10 min) is applied to the hot mould. Compliance with EU Directive 93/11/EEC regarding N‑nitrosamines demands a post‑vulcanisation washing step that eliminates traces of volatile N‑nitrosatable amines; 3‑MBIT itself generates < 0.1 µg m⁻² of N‑nitrosodimethylamine in the standard migration test EN 12868:2017, placing the compound within the 0.5 µg m⁻² threshold for rubber articles intended for repeated skin contact. The finished sidewall stock is co‑extruded with a bromobutyl inner liner and cured in a segmented press to produce radial passenger tires.
Post-Emergence Triazolopyrimidine Herbicide Key Intermediate SynthesisSynthesis proceeds via a one‑pot, two‑step sequence starting from 3‑MBIT and hydrazine monohydrate at 1.0:1.05 molar ratio in ethanol under reflux (78 °C) to open the isothiazole ring, generating a thiohydrazide that cyclizes upon addition of trimethyl orthoformate at 0.5 MPa in a Hastelloy C‑276 autoclave, yielding the Triazolopyrimidine scaffold. The process is registered under ISO 9001:2015 quality management and the final product meets FAO specification 612/TC (April 2023) for technical‑grade herbicide purity ≥ 97 %. Residual solvent control must comply with the maximum residue limits in EP Directive 2009/128/EC, with ethanol limited to 0.5 % and methyl formate below 100 ppm in the technical concentrate. The intermediate is subsequently converted by sulfonamide coupling into a selective post‑emergence herbicide controlling broadleaf weeds in cereal crops, applied as a wettable granule formulation containing 75 % active ingredient. |
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As a heteroaromatic building block for kinase inhibitor scaffolds and central nervous system (CNS) drug candidates, 3-Methoxy-Benz[D]isothiazole is supplied under the product reference BTZ-3MeO-001 for discovery-phase synthesis and non-GMP pilot campaigns. The compound is isolated as an off-white crystalline powder with a melting point of 78–82 °C by differential scanning calorimetry (ASTM E794) and an HPLC purity specification of ≥98.0% (area percentage, UV 210 nm, C18 column). The 3-methoxy substitution distinguishes this benzisothiazole from halogenated or hydrogen-bearing analogs by providing a moderate electron-donating effect that tunes oxidative addition kinetics without the lability associated with amino or hydroxy substituents.
| Parameter | Specification | Analytical Reference |
|---|---|---|
| Appearance | Off-white to pale yellow crystalline powder | Visual inspection under D65 illumination |
| Assay (HPLC, anhydrous basis) | ≥98.0% | UV 210 nm, C18, acetonitrile/water (70:30) isocratic |
| Melting range | 78–82 °C | DSC, ASTM E794, heating rate 10 °C/min |
| Water content | ≤0.5% w/w | Karl Fischer coulometric titration, USP ⟨921⟩ Method Ia |
| Residual solvents | Ethyl acetate ≤5000 ppm, DMF ≤880 ppm | GC-headspace, USP ⟨467⟩ |
| Sulfated ash | ≤0.1% | USP ⟨281⟩ |
| Heavy metals | ≤20 ppm (as Pb) | ICP-MS, USP ⟨233⟩ |
| Particle size (D90) | ≤150 µm | Laser diffraction, ISO 13320:2020 |
| Storage condition | −20 °C ±5 °C, under argon, protect from light | Stability protocol ICH Q1A(R2) |
The methoxy group at the 3-position raises the HOMO energy by approximately 0.28 eV relative to the 3-chloro congener (DFT B3LYP/6-31G*), which manifests in heterogeneous palladium-catalyzed couplings as a reduction in required catalyst loading. In a model Suzuki-Miyaura reaction with 4-cyanophenylboronic acid, Pd(PPh3)4 loading drops from 2.0 mol% to 0.5 mol% when 3-chloro is replaced by 3-methoxy, with identical toluene/ethanol/2 M K2CO3 biphasic conditions at 80 °C. The sulfur atom in the isothiazole ring contributes a logP increase of ~0.5 units versus the corresponding benzoxazole, yielding a measured aqueous solubility of 0.12 mg/mL in phosphate buffer (pH 7.4, shake-flask method) while preserving a brain-to-plasma ratio of 0.8 in Sprague-Dawley rat pharmacokinetic studies.
Hydrolytic ring-opening is negligible at pH 1–10 over 48 h at 25 °C, yet the solid-state stability is governed by photo-oxidative dimerization. Exposure to ambient fluorescent light (400–700 nm, 500 lux) for 72 h produces a dimer impurity at relative retention time 1.42 (HPLC, UV 210 nm) exceeding 0.15% area. Storage under inert headspace (O2 < 50 ppm) in amber glass vials at −20 °C limits dimer formation to ≤0.05% over 24 months. Incompatibility with strong mineral acids is observed: methanesulfonic acid (1.0 eq) at 40 °C in dichloromethane generates a des-methyl impurity (3-hydroxy-benzisothiazole) at a rate of 2.3% per hour, necessitating neutral or mildly basic workup conditions.
In CYP3A4 inhibition assays, the 3-methoxy analog exhibits an IC50 > 50 µM, whereas the 3-amino derivative shows time-dependent inhibition (IC50 shift > 5-fold after 30 min NADPH pre-incubation). The methoxy group’s metabolic soft spot is O-demethylation, which occurs with an intrinsic clearance of 12 µL/min/mg in human liver microsomes, compared to 45 µL/min/mg for the 3-methyl analog undergoing benzylic hydroxylation. hERG patch-clamp data (HEK293 cells, 37 °C) give an IC50 of 28 µM for a 3-methoxy benzisothiazole-piperazine derivative, representing a 3.5-fold improvement over the 3-chloro matched pair. In terms of process chemistry, the 3-methoxy derivative demonstrates superior crystallinity: a 20 °C cooling crystallization from isopropanol/water (60:40) delivers a median particle size D50 of 85 µm and a bulk density of 0.42 g/mL, eliminating the need for jet-milling that the 3-amino analog requires to achieve comparable filterability.
In a 10 L glass-lined reactor equipped with a retreat-curve impeller (150 rpm), a degassed mixture of 1.0 eq BTZ-3MeO-001, 1.15 eq arylboronic acid, and 0.5 mol% Pd(PPh3)4 in toluene (8.0 vol) and ethanol (2.0 vol) is heated to 78–80 °C. An aqueous 2 M K2CO3 solution (2.5 eq) is metered in over 30 min using a peristaltic pump with a flow rate not exceeding 12 mL/min to maintain a positive nitrogen sweep and limit exotherm overshoot to ≤ +3 °C. Reaction progress is monitored by in-process HPLC: the target product retention time is 4.8 min (210 nm). After 4 h, conversion reaches 96–98%; extending the hold time to 6 h increases the dehalogenated impurity (relative retention time 0.72) from 0.8% to 1.9% without further conversion gain. The organic phase is washed with 5% NaCl solution (2 × 3.0 vol) and concentrated under reduced pressure (40 °C bath, 50 mbar). The crude solid is crystallized from isopropanol/water (60:40 v/v, 6.0 vol) with a cooling ramp of 0.3 °C/min from 60 °C to 5 °C. Filtration on a Nutsche filter with polypropylene cloth (10 µm rating) followed by vacuum drying at 40 °C for 12 h yields the coupled product at 78–85% isolated yield, with typical purity 99.2–99.7% by HPLC.
| Process Hold Point | Time (h) | Product Area% | Impurity RRT 0.72 (Area%) | Remaining BTZ-3MeO-001 (Area%) |
|---|---|---|---|---|
| After boronic acid addition | 0.5 | 42 | < 0.1 | 58 |
| Midpoint conversion | 2.0 | 78 | 0.3 | 21 |
| Target endpoint | 4.0 | 97 | 0.8 | 2.1 |
| Extended hold | 6.0 | 96 | 1.9 | 1.8 |
Differences from benzisoxazole-based intermediates become operationally evident at this scale. The sulfur-containing isothiazole ring exhibits a higher thermal tolerance—no exothermic decomposition observed up to 200 °C by DSC—while the analogous benzisoxazole-3-methoxy derivative shows an exotherm onset at 162 °C with an energy release of −320 J/g. In addition, the 3-methoxy benzisothiazole displays a broader palladium catalyst window: ligandless Pd/C (5% wt, 0.8 mol% Pd) furnishes 91% conversion after 8 h, whereas the benzisoxazole requires strictly homogeneous Pd conditions to avoid ring scission. However, this compound is incompatible with amine bases stronger than triethylamine (pKa of conjugate acid >10.8) due to premature ring-opening at the S–N bond, which is detectable as a sulfide odor and an amine adduct at RRT 1.62 in the HPLC trace. Process analytical technology (ReactIR, SiComp probe) confirms a characteristic isothiazole C=N stretch at 1478 cm⁻¹ that can be used to track depletion in flow chemistry setups.
