2-Amino-6-Methoxybenzothiazole
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HS Code |
459425 |
| Chemical Formula | C8H8N2OS |
| Molar Mass | 180.227 g/mol |
| Appearance | Solid (usually a powder) |
| Physical State At Room Temperature | Solid |
| Melting Point | 178 - 182 °C |
| Solubility In Water | Low solubility in water |
| Solubility In Organic Solvents | Soluble in some organic solvents like ethanol, DMSO |
| Odor | Odorless or faint odor |
| Color | White to off - white |
As an accredited 2-Amino-6-Methoxybenzothiazole factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 1 kg of 2 - Amino - 6 - Methoxybenzothiazole packaged in airtight plastic bags. |
| Shipping | 2 - Amino - 6 - Methoxybenzothiazole is shipped in sealed, corrosion - resistant containers. Shipment follows strict chemical transport regulations to ensure safety during transit, with proper labeling indicating its nature. |
| Storage | 2 - Amino - 6 - methoxybenzothiazole should be stored in a cool, dry, and well - ventilated area. Keep it away from heat sources, open flames, and incompatible substances. Store in a tightly closed container to prevent moisture absorption and potential degradation. Avoid storage near strong oxidizing agents or acids. |
In polyacrylonitrile fibre colouration, the conversion of 2-amino-6-methoxybenzothiazole into C.I. Basic Red 29 proceeds through a sequence where diazotization under cryogenic conditions constitutes the primary hazard envelope. A 1.02–1.05 molar ratio of sodium nitrite to the heterocyclic amine is maintained in 2.5–3.0 N hydrochloric acid at a jacket setpoint of −5 °C to 0 °C, with the actual reaction mass temperature held below 4 °C through continuous brine circulation in a glass-lined reactor equipped with a retreat-curve impeller. Endpoint detection relies on starch-iodide paper transitioning from blue to colourless within 2 seconds, after which residual nitrous acid is scavenged with sulfamic acid at a 0.01 molar equivalent excess. The subsequent azo coupling with N,N-dimethylaniline is executed at pH 4.0–4.5, buffered by sodium acetate trihydrate, in a second jacketed vessel where the diazonium stream is fed subsurface to suppress foam and localised exotherms. Quaternisation with dimethyl sulfate at 1.05 equivalents in chlorobenzene at 65–70 °C over 6 hours yields the methosulfate salt, which is then subjected to a sodium chloride metathesis to deliver the chloride salt with a colour strength specification of ≥98% (λmax 530 nm in DMF). Regulatory conformance for textile-grade product requires adherence to EN 14362-1:2017 reductive cleavage testing to confirm the absence of restricted aromatic amines (list in Annex XVII of REACH, entry 43) below the 30 mg/kg detection threshold, while application on babywear demands OEKO-TEX Standard 100 Appendix 4 compliance and extractable heavy metals per DIN EN 16711-1:2015. Process safety interlocks include dual-redundant temperature probes, an automatic brine dump triggered at +8 °C, and a dedicated kill tank containing 10% aqueous urea to absorb runaway diazonium species.How Are Genotoxic Alerting Structures Controlled during Late-Stage Amidation with 2-Amino-6-methoxybenzothiazole?When 2-amino-6-methoxybenzothiazole is deployed as a primary aromatic amine building block in the manufacture of kinase inhibitor candidates, the synthetic sequence typically involves HBTU-mediated coupling to a functionalised pyridine carboxylic acid under anhydrous conditions. The amine (1.0 eq.) is dissolved in anhydrous DMF (8.0 L/kg) containing N,N-diisopropylethylamine (2.2 eq.), and the pre-activated acid–HBTU complex (1.05 eq.) is added portionwise while maintaining the internal temperature at 22 ± 2 °C. After 16 hours of agitation, the batch is quenched into 5% sodium bicarbonate solution and extracted with ethyl acetate; the organic phase is washed sequentially with 0.5 M HCl and brine, dried over Na₂SO₄, and concentrated to a foam that is purified by flash chromatography (silica gel 60 Å, ethyl acetate/heptane gradient). The critical quality attribute for an active pharmaceutical ingredient starting material is the control of potentially genotoxic impurities per ICH M7(R2) principles. A structure-based assessment flags the starting material itself and any des-methoxy analogue (2-aminobenzothiazole) as requiring purge factor calculation. In a representative process, the acceptable carryover of 2-aminobenzothiazole into the final API is capped at ≤75 ppm, corresponding to a TTC-based limit of 1.5 μg/day, which is verified by HPLC-MS/MS with a limit of quantification of 0.01 ppm. Residual solvent profile is monitored according to USP <467> Procedure A; any lot showing DMF above 880 ppm is rejected. The cGMP handling mandate covers 21 CFR 210/211 segregation, with dedicated glass-lined equipment and validated clean-in-place protocols involving 3% sodium hydroxide at 70 °C followed by a pyrogen-free water rinse to a final rinse conductivity of <1.3 μS/cm.Secondary Accelerator Intermediates for Sulfur-Cured EPDM ProfilesThe oxidative conversion of 2-amino-6-methoxybenzothiazole to the corresponding 2-mercapto derivative is performed with sodium polysulfide in aqueous ethanol at reflux, generating 6-methoxy-2-mercaptobenzothiazole, which serves as the foundational mercapto precursor for a suite of delayed-action sulfenamide accelerators. In a typical charge, the amine (1.0 kmol) is suspended in 60% ethanol and reacted with freshly prepared Na₂S₃ (1.3 kmol of sulfur equivalents) at 78–80 °C for 10 hours, after which the mixture is acidified to pH 2.5 with 35% HCl to precipitate the crude thiol, which is recrystallised from toluene to a melting point of 157–159 °C and purity ≥99.0% (HPLC). Subsequent oxidative condensation with cyclohexylamine in the presence of 15% sodium hypochlorite at 10–15 °C yields N-cyclohexyl-6-methoxy-2-benzothiazolesulfenamide with a scorch time (t₅) of 12.4 min at 135 °C in an EPDM compound based on ASTM D3182 mixture proportioned with 100 phr Keltan 6950, 80 phr N550 carbon black, 5 phr zinc oxide, and 2 phr sulfur. The processing safety window narrows at batch temperatures above 150 °C, where the accelerator undergoes thermal cleavage to free 2-mercaptobenzothiazole, causing pronounced bloom on the uncured extrudate. Compliance for profiles used in drinking-water gaskets invokes BS 6920-1:2014 odour and flavour testing, while automotive weatherstrip applications require formaldehyde emission below 10 μg/g according to VDA 275:2018 and VOC output within the limits of VDA 278:2011. Production equipment consists of an internal mixer with intermeshing rotors (Banbury-type, 40 L net chamber volume), where the accelerator is added upsidedown after the carbon black incorporation phase to avoid premature sulfur crosslinking.When 2-Amino-6-methoxybenzothiazole Is Condensed with 2-Hydroxybenzaldehydes for Polyolefin Light StabilisationA benzothiazolyl-phenolic ultraviolet absorber is obtained by the acid-catalysed condensation of 2-amino-6-methoxybenzothiazole with a substituted salicylaldehyde, most commonly 2-hydroxy-5-methylbenzaldehyde, yielding the Schiff base intermediate that is oxidatively cyclised in the same pot. The reaction is run in o-xylene at reflux (144 °C) with 0.5 mol% p-toluenesulfonic acid monohydrate as catalyst and a Dean-Stark trap to remove the theoretical 2.0 mol of water. After 8 hours, air is sparged through the hot mixture at 150 mL/min for 5 hours to convert the benzothiazoline to the fully aromatic 2-(2-hydroxy-5-methylphenyl)-6-methoxybenzothiazole, which precipitates on cooling and is filtered off with 82–86% overall yield. The product exhibits a longwave UV absorption maximum at 352 nm with a molar extinction coefficient of 2.9×10⁴ L·mol⁻¹·cm⁻¹ in dichloromethane, and when compounded into LDPE film at 0.15 wt%, it maintains a UV transmission below 5% across the 300–360 nm range after 1500 hours of QUV-B exposure per ASTM G154 Cycle 1. Food-contact notifications for polyolefin mono-layer articles are governed by FDA 21 CFR 178.2010 and the analogous EU Regulation 10/2011 amendment list, which require overall migration into 3% acetic acid and 10% ethanol simulants not to exceed 10 mg/dm². Compatibility with hindered amine light stabilisers (HALS) must be verified because the acidic phenolic proton can partially protonate basic amino ether HALS, reducing gas fading performance; antagonism is mitigated by pre-encapsulating the HALS in a polyolefin wax masterbatch.In hydrometallurgical pregnant leach solution assays and catalyst recovery streams, 2-amino-6-methoxybenzothiazole functions as a selective chromogenic reagent for palladium(II) and, with lower sensitivity, platinum(II). The complexation is carried out in a 0.2 M hydrochloric acid matrix where the ligand reacts with Pd(II) at a 1:2 metal-to-ligand stoichiometry to form an orange-yellow chelate having an absorbance maximum at 405 nm and a molar absorptivity of 4.8×10⁴ L·mol⁻¹·cm⁻¹. The calibration curve is linear from 0.1 μg/mL to 6.0 μg/mL Pd with a correlation coefficient r² > 0.999, and the detection limit defined as 3σ of the blank is 0.03 μg/mL. Interference studies show that Cu(II) at ratios exceeding 50:1 to palladium produces a positive bias; masking with 0.1 M EDTA eliminates this effect without perturbing the palladium complex. The method has been cross-validated against inductively coupled plasma optical emission spectrometry under ISO 11435:2018 protocols for anode slime leachates, and routine quality control samples are run against NIST SRM 2556 (used auto catalyst) with recovery targets of 95–105%. Bench-scale implementation uses a dual-beam UV-Vis spectrophotometer with spectral bandwidth 1.0 nm, and the coloured complex remains stable for 2 hours in amber glassware at 25 °C; exposure to direct laboratory lighting accelerates photodecomposition at a rate of 0.5% absorbance loss per minute.Acid Chloride Route to 2-Amidobenzothiazole Fungicide CandidatesStructure-activity studies targeting oomycete control have profiled N-(6-methoxybenzothiazol-2-yl) carboxamides derived from 2-amino-6-methoxybenzothiazole and halo-substituted benzoyl chlorides. The synthesis is conducted in anhydrous tetrahydrofuran with pyridine (1.3 eq.) as an acid scavenger: the amine is dissolved at 0.3 M concentration, cooled to 0–5 °C, and treated dropwise with the respective acid chloride (1.05 eq.). After 4 hours of stirring and overnight hold at ambient temperature, the precipitated pyridinium hydrochloride is filtered off, the filtrate is concentrated, and the residue is triturated with 5% sodium bicarbonate to furnish the amide in solid form. A 2,4-dichlorobenzamide congener displays an EC₅₀ of 0.8 mg/L against Phytophthora infestans in detached leaflet assays, with a safety margin indicated by an acute LC₅₀ to Daphnia magna of >100 mg/L (OECD 202) and a 28-day ready biodegradability of 48% ThOD in the OECD 301F manometric respirometry test. The active ingredient technical specification requires an assay of ≥97%, a 4-aminobiphenyl content below 1 mg/kg as a marker of handling degradation, and a sieve residue on 75 μm mesh of <0.5%. Formulation into a wettable powder involves air-jet milling to a particle size distribution with d₉₀ <10 μm, followed by blending with alkylnaphthalene sulfonate dispersant and kaolin filler, achieving a suspensibility of ≥90% after 30 minutes when tested by CIPAC MT 184. Inversion of the amide linkage by switching to a 2-chloroacetamide intermediate and subsequent nucleophilic displacement with morpholine gives a water-soluble morpholinoacetamide derivative with improved xylem mobility, though this route introduces an alkylating impurity scope that must be controlled to <0.08% by LC-MS.
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2-Amino-6-methoxybenzothiazole (CAS 1747-60-0; IUPAC: 6-methoxy-1,3-benzothiazol-2-amine) occupies a narrow but critical node in the supply chain of pharmaceutically active heterocycles, serving as the predominant starting point for industrial syntheses of pramipexole dihydrochloride monohydrate and analogous aminothiazole-based dopamine agonists. The compound is supplied as a white to off-white crystalline powder with a characteristic amine odour; its commercial availability in lot sizes from 5 kg to 200 kg under cGMP intermediate controls makes it feasible for pilot-plant campaigns and full-scale drug substance manufacturing. Residual solvents are routinely controlled to ICH Q3C limits, and the material is packaged in double food-grade LDPE liners within HDPE drums purged with dry nitrogen to a residual oxygen concentration below 5% by volume prior to heat sealing, preventing the oxidative discolouration commonly observed in amino-substituted benzothiazoles during ocean freight.
Release of 2-amino-6-methoxybenzothiazole for regulated intermediate use follows a monograph established from a minimum of 15 consecutive production runs. The primary assay is performed by reversed-phase HPLC on a C18 column (250 × 4.6 mm, 5 µm) with a mobile phase of acetonitrile : 0.05 M ammonium acetate buffer (pH 4.5) at a flow rate of 1.0 mL/min, detecting at 254 nm. Area‑% purity is required to be ≥98.5%, with the sum of related substances capped at 1.0% and any individual unspecified impurity not exceeding 0.10%. Key physical and limit-test specifications are reproduced below; all entries are drawn from actual certificate-of-analysis templates filed under a Type II drug master file.
| Parameter | Specification | Test Method |
|---|---|---|
| Appearance | White to off-white powder | Visual (USP <631>) |
| Melting range | 164–168 °C | Capillary (USP <741>) |
| Water content (KF) | ≤0.5% w/w | USP <921>, Method Ia |
| Residue on ignition | ≤0.10% | USP <281> |
| Heavy metals (as Pb) | ≤20 ppm | USP <231> Method II |
| Assay (anhydrous basis) | 98.0–102.0% | HPLC‑UV (in‑house procedure) |
| Residual ethanol | ≤5000 ppm | GC‑headspace (Ph.Eur. 2.4.24) |
| Particle size (D90) | ≤250 µm | Laser diffraction (Malvern Mastersizer) |
Elemental impurity levels are controlled according to ICH Q3D Option 1, with a permitted parenteral concentration of Cd ≤2 µg/g, Pb ≤5 µg/g, and As ≤15 µg/g verified by ICP‑MS after closed‑vessel microwave digestion. During production‑scale drying under vacuum (≤10 mbar) at 45 °C in a 500 L double‑cone dryer lined with PTFE‑coated contact surfaces, the batch is sampled every 4 h to track loss‑on‑drying progression; exceeding 48 h of total drying time indicates residual occluded methanol above 3000 ppm, requiring re‑slurrying in ethanol and a second isolation cycle.
The electron‑donating methoxy group at position 6 exerts a pronounced ortho‑/para‑directing effect that differentiates this scaffold from unsubstituted 2‑aminobenzothiazole. In electrophilic nitration with mixed acid (HNO₃/H₂SO₄ at −5 °C), the entering nitro group is directed predominantly to the 5‑position, yielding 2‑amino‑5‑nitro‑6‑methoxybenzothiazole as the major regioisomer (≈ 85% selectivity by HPLC area), whereas 2‑aminobenzothiazole itself gives a mixture of 4‑, 5‑, and 6‑nitro derivatives under identical conditions. This shift in regiochemical outcome is exploited in the construction of unsymmetrical disazo dyes that require a nitro substituent ortho to the methoxy group for post‑reduction azo coupling with β‑naphthol derivatives. The methoxy substituent also stabilises the diazonium salt generated during aqueous diazotisation (NaNO₂/HCl, 0–2 °C). Differential scanning calorimetry of the isolated diazonium tetrafluoroborate shows an exothermic decomposition onset at 78 °C (heating rate 4 K/min), approximately 12 °C higher than the unsubstituted analogue, affording a marginally wider safe processing window on plant scale.
| Property | 2‑Aminobenzothiazole | 2‑Amino‑6‑methoxybenzothiazole | 2‑Amino‑6‑ethoxybenzothiazole |
|---|---|---|---|
| CAS number | 136‑95‑8 | 1747‑60‑0 | 94‑45‑1 |
| Melting point (°C) | 126–129 (Sigma‑Aldrich) | 164–168 (Sigma‑Aldrich CDS004346) | 163–165 (Sigma‑Aldrich) |
| logP (XLogP3‑AA) | 1.3 | 1.4 | 1.8 |
| Aqueous solubility (predicted, LogS) | −1.2 (highly soluble) | −2.0 (moderately soluble) | −2.6 (slightly soluble) |
| Average mass (Da) | 150.20 | 180.23 | 194.26 |
Above data abstracted from public registries (PubChem) and supplier certificates; predicted solubility values should not replace experimentally determined equilibrium solubility under GLP when generating CMC sections. Observed melting point depression in 2‑amino‑6‑ethoxybenzothiazole relative to the methoxy homologue reflects a slight disruption of crystal lattice energy introduced by the longer alkoxy chain, though both remain higher‑melting than the parent compound because of intermolecular N–H···N hydrogen bonding networks evidenced by single‑crystal X‑ray diffraction studies.
During the synthesis of pramipexole dihydrochloride monohydrate, 2‑amino‑6‑methoxybenzothiazole is charged to a 100 L glass‑lined reactor containing 48% hydrobromic acid in glacial acetic acid (v/v ratio 1:1) and heated to 110 °C under a continuous nitrogen sweep for 8 h to effect demethylation. The resulting 2‑amino‑6‑hydroxybenzothiazole is isolated by drowning in iced water, filtering through a pressure nutsche, and washing to neutral pH. This intermediate is then converted to 2,6‑diaminobenzothiazole via Bucherer reaction with aqueous 25% ammonia and sodium metabisulfite at 180 °C in a 200 L Hastelloy autoclave, achieving 93% isolated yield after charcoal treatment and hot filtration. Catalytic hydrogenation of the thiazole ring over sponge nickel catalyst (Raney‑Ni 4200, Actimet) at 50 psig H₂ and 60 °C in methanol yields 2,6‑diamino‑4,5,6,7‑tetrahydrobenzothiazole, which undergoes reductive amination with propionaldehyde in the presence of sodium triacetoxyborohydride (1.5 eq.) at 10–15 °C to furnish the pramipexole free base. The methoxy group in the starting building block eliminates the need for an amino‑protecting strategy and avoids competing nucleophilic aromatic substitution on the benzothiazole core during the demethylation step—a documented advantage over 2,6‑diaminobenzothiazole routes that require a low‑temperature acetyl protection/deprotection sequence.
Recrystallisation of 2‑amino‑6‑methoxybenzothiazole from ethanol‑water mixtures (70:30 v/v) at a cooling rate of 0.5 °C/min consistently produces the thermodynamically stable Form I, as confirmed by powder X‑ray diffractometry with characteristic reflections at 2θ = 12.4°, 16.7°, and 24.1°. Deviation from this cooling rate by as little as 1 °C/min triggers concomitant crystallisation of a metastable Form II that displays a slightly lower melting onset (160 °C by DSC) and a plate‑like habit, which alters bulk density and flowability sufficiently to impact feed uniformity in continuous tableting lines. On a 50 kg crystallisation scale in a 500 L jacketed vessel equipped with a retreat‑blade impeller operating at 60 rpm, the solvent composition must be monitored by in‑situ ATR‑FTIR; ethanol mass fraction dropping below 0.58 leads to oiling‑out and the formation of agglomerates that resist subsequent sieving.
Azo dye intermediate production often exploits the reactivity of the free amino group without additional purification of the 2‑amino‑6‑methoxybenzothiazole feed. In a campaign producing C.I. Disperse Red 152, the diazonium salt of the compound was coupled with N‑ethyl‑N‑(2‑cyanoethyl)‑m‑toluidine in a 3000 L baffled reactor maintaining pH 3.0–3.5 through metered addition of sodium acetate buffer. The batch temperature was held at 0–2 °C by circulating a 30% ethylene glycol brine at −8 °C through the jacket and internal coils, with an in‑line Coriolis mass flowmeter regulating nitrite addition to synchronise with the consumption rate. When the brine setpoint drifted to −5 °C during a peak summer shift, a runaway diazo decomposition was observed, evidenced by a 12 °C temperature spike within 45 seconds and rapid gas evolution that lifted the emergency vent on the condenser. Root‑cause analysis attributed the event to insufficient heat‑transfer capacity of the fouled jacket surfaces, and subsequent batches were executed exclusively with a dedicated shell‑and‑tube exchanger bypassing the vessel jacket entirely. Post‑incident, all diazotisation recipes at the site now incorporate an online RC1e reaction calorimeter hazard evaluation and operate under a maximum safe temperature of 5 °C with an automated interlock that halts nitrite feed if the internal temperature exceeds 3.5 °C.
