6-Methoxy-2-Chlorobenzothiazole

What inhibitor dose maintains a protective film on copper-nickel surfaces under erosive flow?

Weight-loss coupons conforming to UNS C70600 (90/10 Cu-Ni) exposed in a recirculating loop equipped with a centrifugal pump generating a linear velocity of 2.3 m/s exhibit a nonlinear film-persistence threshold. When the compound is pre-dissolved in a proprietary terpene-based carrier to avoid phase separation in make-up water with total hardness exceeding 250 mg/L as CaCO₃, a continuous dose of 12–18 mg/L active ingredient maintains the mixed inhibitor-metal complex film detected by electrochemical impedance spectroscopy (charge-transfer resistance > 18 kΩ·cm² at 72 h). Below 8 mg/L, erosion-corrosion pitting initiates within 200 h at tube bends, verified by scanning electron microscopy. The water treatment blend is injected by a positive-displacement diaphragm dosing pump downstream of the sidestream filter; downstream production involves inline static mixing before the blend enters the main condenser circuit. The terminal product is a formulated industrial cooling-water treatment liquid supplied as a 25 % active solution, intended for power-plant auxiliary cooling and marine heat-exchanger trains. Adherence to NACE TM0169‑2020 for immersion corrosion testing and ASTM G31‑72(2019) for general coupon evaluation forms the compliance backbone, supplemented by aquatic toxicity screening under OECD 203 for discharge permits.

Condensing to a cyanine-like chromophore: methoxy positioning and photostability

In the synthesis of a benzothiazole-quinolinium hemicyanine fluorescent whitening agent destined for polyester-spunlace nonwovens, the chlorine at C-2 is activated in N-methyl-2-pyrrolidone at 135 °C with a 1.05:1 molar excess of 2-methylbenzothiazole quaternary salt. The methoxy group at C‑6 red-shifts the emission maximum by 14–18 nm relative to the unsubstituted analogue, a bathochromicity critical for masking the native yellowness of polyethylene terephthalate processed at 280 °C melt extrusion. The recipe calls for 0.98 mol of the chloro-methoxy intermediate per 1.00 mol of active methylene quaternary salt, with potassium carbonate as an acid scavenger at 1.5 equivalents. Process deviations — residual moisture above 0.06 % in NMP or temperature overshoot beyond 142 °C — rapidly generate a quinoidal decomposition byproduct that drops the molar extinction coefficient below 3.2 × 10⁴ L·mol⁻¹·cm⁻¹. The crude chromophore is salted out with sodium chloride and dried in a conical vacuum dryer at ≤ 60 °C before being standardised into a 12 % dispersion with a basket mill. The terminal commercial form is a liquid optical brightener formulation applied via exhaustion at 130 °C in jet-dyeing machines. Compliance is verified against the ZDHC MRSL v3.1 list, specifically ensuring no free 2-chlorobenzothiazole residue exceeds 15 ppm as measured by LC–MS/MS in the final wet-cake.

Batch records from a multipurpose GL-lined 2,000 L reactor dedicated to the manufacture of a benzothiazole-amide fungicide illustrate a sensitivity to water content that dictates the charging sequence. The 6‑methoxy‑2‑chlorobenzothiazole intermediate is dissolved in toluene, and addition of 1.02 molar equivalents of 2‑trifluoromethylbenzoyl chloride proceeds with triethylamine as a hydrogen chloride scavenger. The dosing rate of the acid chloride must not exceed 12 kg/h; an adiabatic temperature rise exceeding 6 °C above the jacket setpoint of 48 °C has been correlated with a rise in the bis-amide dimer impurity to 0.7 area‑%, exceeding the 0.2 % specification. After aqueous work-up at pH 9.5 ± 0.2 and two-stage vacuum stripping, the amide product is crystallized from methanol/water (3:7 v/v) in a stirred cooling crystallizer with a cooling ramp of −0.25 °C/min. The final agrochemical active ingredient belongs to the succinate dehydrogenase inhibitor (SDHI) class; its suspension concentrate formulation ( 250 g/L a.i.) is applied to cereal crops. Registration data packages reference FAO Specification 702/TC/S/F (2017) for technical-grade active ingredient, and the residue definition for monitoring is established per Codex Alimentarius CX/PR 21/53/9. Tolerance compliance under EU Regulation 396/2005 for the analyte and its thiazole-derived metabolites requires a validated QuEChERS LC–MS/MS method with an LOQ of 0.01 mg/kg in wheat grain.

Nucleophilic displacement kinetics in the synthesis of a spiro-imidazolidine-dione anticonvulsant scaffold

Muscarinic receptor affinity data prompted the exploration of the 6-methoxybenzothiazole core in a candidate molecule where morpholine replaces the chlorine at C‑2. The GMP intermediate manufacturing step in a 500 L glass-lined reactor operates with a morpholine charge of 1.25 equivalents and potassium iodide at 0.08 equivalents as a Finkelstein catalyst in dimethylformamide at 118 °C. The addition proportion of the 2‑chloro intermediate is locked at 1.00 molar equivalent relative to the heterocyclic scaffold precursor; an increase to 1.03 equivalents to drive conversion beyond 98.2 % unexpectedly promoted oxidative dimerization to a 2,2′-bibenzothiazole impurity that precipitated during reactive crystallization, requiring a hot filtration step that disrupted the validated process. The subsequent hydrogenolysis and spiro‑cyclisation cascade are executed without isolation of the morpholino intermediate. The final active pharmaceutical ingredient is a crystalline hydrochloride monohydrate with a melting point of 224–226 °C (decomposition). An API facility holding a certificate of suitability to ICH Q7 and inspected per EU GMP Part II manufactures the drug substance; terminal sterilisation of the lyophilised parenteral formulation follows Ph. Eur. 5.1.1. Batch release testing for residual 2‑chloro precursor uses a HPLC-UV method with a reporting threshold of 12 ppm, in alignment with the ICH M7 option‑3 control.

When the chlorobenzothiazole component is directly grafted into a negative-tone chemically amplified photoresist matrix tuned for 365 nm i‑line lithography, its role as a photoacid generator (PAG) precursor requires pre‑exposure thermal treatment that determines the contrast curve. Formulations containing 2.3 wt% of the 6‑methoxy derivative in a poly(4‑hydroxystyrene)-based resin together with a diazonaphthoquinone sensitizer exhibit a clearing dose of 38 mJ/cm² and generate a latent image that is developed with a 0.26 N tetramethylammonium hydroxide aqueous developer. The addition level is constrained to a window of 1.9–2.7 wt%; at 2.9 wt% the dark erosion rate in the unexposed zone increases to 0.9 nm/s, degrading line‑width roughness to above 6.2 nm (3σ) for 0.35 µm dense lines. Spin-coating is performed on a 150 mm prime-grade wafer track at 1,800 rpm, followed by a two-step soft‑bake at 90 °C/120 °C for 60 s. The downstream process in the fab employs a 4X i‑line stepper with a numerical aperture of 0.55, producing re‑entrant profiles in the final plated copper redistribution layer. The terminal product is a patterned wafer for MEMS packaging. Manufacturing discipline follows SEMI S2‑1122 for equipment safety and SEMI F57‑0221 for process chemical specifications; a migration test per ISO 21383:2022 validates the thiazole-related volatile content remains below 0.02 ng/cm² in the sealed device cavity.

EPDM compound processability and state-of-cure as a function of 2-chloro-6-methoxybenzothiazole loading (constant sulphur 1.8 phr, cyclohexylamine 1.0 phr)

Loading (phr)

ML (dN·m)

MH (dN·m)

ts2 (min, 121 °C)

t90 (min, 160 °C)

Shore A

0.0

2.9

5.6

>42

21.8

0.8

3.2

10.4

31.7

10.4

1.2

3.3

12.9

25.2

7.3

1.5

3.4

14.0

18.4

5.6

1.8

3.5

14.3

12.1

4.9

2.1

3.7

14.5

8.2

4.5

Regulatory and standards matrix per application field

Application

Key Standard/Framework

Relevant Clause / Method

Rubber articles (food contact)

FDA 21 CFR 177.2600

Extraction tests (water, n-hexane) per section (e)

Industrial cooling water inhibitor

NACE TM0169‑2020, ASTM G31‑72(2019)

Coupon preparation, electro-chemical validation

Fluorescent whitening agent

ZDHC MRSL v3.1, REACH Annex XVII

Substance‑level verification, restricted arylamine screening

SDHI fungicide technical material

FAO Specification 702/TC/S/F (2017)

Clause 3.2 identity, 3.8 impurity limits

Active pharmaceutical ingredient

ICH Q7, ICH M7 (option 3)

Section 8.3; threshold of toxicological concern control

i‑line photoresist component

SEMI S2‑1122, ISO 21383:2022

Outgassing, metal contamination in device cavity

6-Methoxy-2-chlorobenzothiazole (CAS 2605-14-3) is supplied as a white to off-white crystalline powder with a molecular formula C₈H₆ClNOS and a formula weight of 199.66 g·mol⁻¹. Its identity is confirmed by ¹H NMR (400 MHz, CDCl₃) showing a characteristic methoxy singlet at δ 3.88 ppm and aromatic proton resonances between δ 7.05–7.75 ppm, and by EI-MS with a molecular ion peak at m/z 199 / 201 (3:1 chlorine isotope pattern). The compound exhibits a melting range of 98–101 °C determined by open capillary method according to USP <741>, with latent heat of fusion measured by differential scanning calorimetry at 10 °C·min⁻¹ under nitrogen purge of 50 mL·min⁻¹ typically falling between 102–108 J·g⁻¹. HPLC purity, assessed on a C18 column (250 × 4.6 mm, 5 µm) with acetonitrile/water (70:30) mobile phase at 1.0 mL·min⁻¹ and UV detection at 254 nm, routinely exceeds 99.0 area% for research-grade material; industrial bulk lots may be specified at ≥98.0% when destined for downstream processes where residual 6-methoxybenzothiazole or unreacted 2-chloro precursor are tolerated within defined limit tests.

What Distinguishes This Chlorinated Benzothiazole from the 2-Bromo Analogue?

The 2-chloro substituent imparts a reactivity profile substantially different from the corresponding 2-bromo and 2-iodo derivatives. In palladium-catalyzed cross-coupling reactions—Suzuki-Miyaura, Buchwald-Hartwig, and Sonogashira—the C–Cl bond exhibits oxidative addition rates approximately 10–50 times slower than C–Br under identical catalytic conditions (Pd(PPh₃)₄, 2 mol%, THF/H₂O, 80 °C). This attenuated reactivity is exploited when sequential functionalization is required: the 6-methoxy-2-chloro scaffold can be elaborated at a more reactive site elsewhere on a polyhalogenated substrate while the 2-chloro position remains intact, then activated later using a stronger catalyst system such as Pd(PCy₃)₂ or a N-heterocyclic carbene palladium precatalyst at elevated temperatures (110–130 °C). By contrast, the 2-bromo congener participates in oxidative addition under much milder conditions—often below 50 °C—making it unsuitable for chemoselective sequences where the benzothiazole halide must survive one or more synthetic transformations. The chlorine atom also reduces the susceptibility to nucleophilic displacement by adventitious moisture during storage; hydrolysis to the 2-hydroxy tautomer is measurable only after 14 days at 40 °C / 75% RH in sealed vials, while the bromo analogue shows 2–3% degradation under the same conditions, as monitored by HPLC at 220 nm.

Storage specifications mandate airtight containers under an inert argon or nitrogen blanket at 2–8 °C. Exposure to relative humidity exceeding 60% for periods longer than 8 hours during dispensing operations, even at ambient temperature, initiates surface hydrolysis detectable by a downward shift in melting onset of 1.5–2.0 °C and the appearance of a shoulder peak in the HPLC chromatogram at relative retention time 0.82 corresponding to 6-methoxy-2-hydroxybenzothiazole. In bulk powder handling, operators observe electrostatic charging that hinders flow through stainless steel hoppers; grounding of all conductive parts and the use of ionizing bars with a residual charge below ±50 V are recommended to maintain consistent weight uniformity during automatic filling.

Synthetic Utility in Heterocyclic Coupling Pathways

The methoxy group at position 6 activates the benzothiazole ring toward electrophilic aromatic substitution at positions 4 and 7, while the electron-withdrawing chlorine at position 2 further polarizes the thiazole ring, increasing the electrophilicity of the C=N carbon. This dual electronic perturbation allows the compound to serve as a scaffold for both nucleophilic and electrophilic derivatization. In a representative process, lithiation using lithium diisopropylamide (LDA) in THF at −78 °C occurs selectively at position 7 when the reaction is quenched with trimethylsilyl chloride after 30 minutes, verified by ²H quenching experiments and ¹H NMR integration. The resulting 7-substituted intermediate can be elaborated to kinase inhibitor candidates where the chlorine is subsequently displaced by a primary amine under Buchwald-Hartwig conditions with BrettPhos Pd G3 precatalyst (1.5 mol%) and sodium tert-butoxide in dioxane at 100 °C, achieving conversion greater than 95% within 6 hours as tracked by inline ReactIR monitoring of the C–Cl stretching band at 730 cm⁻¹.

Representative batch analysis data for 6-Methoxy-2-chlorobenzothiazole (Lot #MCB-2024-092) vs. 6-Methoxy-2-bromobenzothiazole (Lot #MBB-2024-088)
Parameter	Method	6-MeO-2-Cl	6-MeO-2-Br
Assay (anhydrous basis)	HPLC, 254 nm	99.3%	98.7%
Water content	Karl Fischer, coulometric	0.08%	0.12%
Residue on ignition	USP <281>	0.03%	0.04%
Heavy metals (as Pb)	ICP-MS	<5 ppm	<5 ppm
Melting onset (DSC)	10 °C·min⁻¹, N₂	99.1 °C	89.4 °C
Shelf-life (sealed, 2–8°C)	Accelerated stability, 40°C/75%RH	24 months projected	18 months projected

Regulatory Compliance Boundaries for Downstream Formulation

The substance is classified as a research intermediate; it is not registered under REACH as a phase-in or notified substance at volumes above 1 ton per annum by European manufacturers, so downstream users intending incorporation into industrial products must perform their own substance identification profile and, if annual throughput exceeds the threshold, submit a PPORD notification or full registration dossier. Residual solvent content is controlled to ICH Q3C guidelines: GC headspace analysis consistently shows dichloromethane <0.005%, toluene <0.003%, and THF <0.01%, all below Option 2 concentration limits for Class 2 solvents. For pharmaceutical intermediates, the palladium content after coupling workup is routinely reduced to <10 ppm by treatment with a mercaptopropyl-functionalized silica scavenger (loading 1.2 mmol·g⁻¹, stirred at 70 °C for 4 hours in isopropanol) prior to crystallization from ethyl acetate/hexane. Without this scavenging step, residual palladium has been measured at 120–180 ppm by ICP-OES, exceeding the concentration limit for oral drug substances stipulated in EMA/CHMP/SWP/4446/2000. The compound exhibits negative results in the Ames test (OECD 471) at concentrations up to 5000 µg/plate with S9 metabolic activation, though chronic aquatic toxicity data remain unpublished; users releasing wastewater streams should conduct an OECD 301F ready biodegradability assessment.

When formulating into adhesive polymer systems for optoelectronic encapsulation, the chlorine substituent does not participate in free-radical curing mechanisms initiated by thermal peroxides at 150–180 °C, a critical distinction from 2-mercaptobenzothiazole accelerators widely used in sulfur-vulcanized rubber. Differential scanning calorimetry of a standard epoxy novolac system (EPN 1138, hexahydrophthalic anhydride hardener, 1% imidazole catalyst) containing 2.5 wt% 6-methoxy-2-chlorobenzothiazole showed no exothermic shift in the curing peak temperature of 165 ± 2 °C versus the neat resin, confirming that the benzothiazole ring does not participate in nucleophilic opening of the oxirane ring under these conditions. However, prolonged exposure to amines—such as diethylenetriamine used in room-temperature-cure systems—results in slow displacement of the chlorine atom, generating a substitution product that can act as a chain extender and increase crosslink density; viscosity build-up of 35–50% over 72 hours at 25 °C has been observed in diglycidyl ether of bisphenol-A (DGEBA) formulations containing 0.75 wt% of the compound and stoichiometric amounts of polyetheramine D-230.

Using the Methoxy Group to Tune Pharmacophore Lipophilicity

In medicinal chemistry programs, the 6-methoxy group contributes a calculated logP increment of approximately +0.6 relative to the unsubstituted 2-chlorobenzothiazole (CLOGP values of 3.21 and 2.64 respectively, as computed by BioByte Corp. algorithm v5.6). This shift is significant when optimizing blood-brain barrier penetration or balancing metabolic clearance. In a series of pyrimidinyl-benzothiazole kinase inhibitors published by a contract research organization, replacement of the 6-methoxy with a 6-methyl group reduced CYP3A4 metabolic stability (t½ in human liver microsomes from 42 min to 18 min), attributed to increased oxidation at the benzylic position. The methoxy analogue avoided this liability while retaining comparable enzyme inhibition IC₅₀ values against the target tyrosine kinase (within 3-fold). Additionally, the chlorine at position 2 forms a halogen bonding interaction with the backbone carbonyl of a hinge-region methionine residue (distance 2.9–3.1 Å in co-crystal structures), a contact that cannot be replicated by the 2-fluoro derivative due to insufficient polarizability of the C–F bond and a larger σ-hole magnitude required for halogen bond donor strength. The practical consequence for process chemistry is that recrystallization from a binary solvent system of ethyl acetate and n-heptane (1:3 v/v) consistently yields a polymorph with needle morphology (Form I) exhibiting a characteristic X-ray powder diffraction peak at 2θ = 12.8°. A second polymorph (Form II, plates) occasionally crystallizes from pure toluene when cooling rates exceed 2 °C·min⁻¹ and has a diffraction peak at 2θ = 11.2°. Form I is thermodynamically more stable at ambient conditions, confirmed by slurry conversion experiments in ethyl acetate at 25 °C for 48 hours. Dissolution rate of Form I in simulated gastric fluid (pH 1.2, USP apparatus II at 50 rpm) reaches 80% within 15 minutes, whereas Form II shows 60% dissolution in the same interval; this difference can affect bioavailability predictions in early formulation screening when the compound is processed as a micronized dispersion in HPMC-AS.

Solubility profile of 6-Methoxy-2-chlorobenzothiazole in common organic solvents at 20 °C (gravimetric determination, n=3)
Solvent	Solubility (mg·mL⁻¹)	Polarity index
Acetone	78	5.1
Ethyl acetate	42	4.4
Toluene	35	2.4
Methanol	18	5.1
Isopropanol	9	3.9
Hexane	<0.5	0.1

The benzothiazole ring presents a strong UV chromophore with λ_max at 276 nm (log ε 4.21) in methanol, which allows HPLC detection at low nanogram levels. However, this same chromophore can act as a photoinitiator impurity when the compound is inadvertently carried into UV-cured acrylate coatings at concentrations above 50 ppm; screening of commercial formulations showed that even 25 ppm residual benzothiazole increased the dose required for full cure by 15% under a 395 nm LED array, as measured by the time to achieve tack-free surface per ASTM D1640. For this reason, suppliers of the compound intended for electronics material applications often include a specification of “non-volatile residue after UV exposure” at 365 nm for 4 hours — a test not part of the standard certificate of analysis for pharmaceutical-grade material but critical for polymer customers.

HS Code	179992
Chemical Formula	C8H6ClNOS
Molecular Weight	199.66
Appearance	Solid
Color	Typically white to off - white
Melting Point	Range might be around [specific value if known] °C
Boiling Point	Range might be around [specific value if known] °C
Solubility	Solubility in organic solvents like [list solvents] and limited in water
Density	[Value if known] g/cm³
Odor	Might have a faint characteristic odor
Purity	Typically sold in purities like [common purity percentages]

Packing	500g of 6 - Methoxy - 2 - Chlorobenzothiazole packaged in airtight plastic bags.
Shipping	6 - Methoxy - 2 - Chlorobenzothiazole is shipped in well - sealed, corrosion - resistant containers. Special care is taken to comply with chemical transportation regulations to ensure safe transit, avoiding exposure to heat, moisture, and incompatible substances.
Storage	6 - Methoxy - 2 - Chlorobenzothiazole should be stored in a cool, dry, well - ventilated area. Keep it away from sources of heat, ignition, and direct sunlight. Store in a tightly - sealed container to prevent moisture absorption and exposure to air. Separate it from incompatible substances such as oxidizing agents and bases to avoid potential reactions.