2-Amino-5-Methylbenzothiazole

2-Amino-5-methylbenzothiazole (CAS 14779-17-0, molecular formula C₈H₈N₂S, formula weight 164.23 g·mol⁻¹) is supplied as a pale-yellow to off-white crystalline powder with a melting range of 97–100 °C (literature value 98–99 °C) and an assay specification of ≥98.0% by HPLC (area normalization, detection at 254 nm). The amine value, determined by non-aqueous titration, typically falls within 340–342 mg KOH·g⁻¹. Loss on drying after 2 h at 60 °C under vacuum does not exceed 0.5 wt%. This aminobenzothiazole is manufactured via high-pressure amination of 2-chloro-5-methylbenzothiazole in the presence of an ammonia-methanol mixture at 140–160 °C and 1.2–1.8 MPa in a 2,000 L stainless-steel autoclave, followed by recrystallization from toluene to achieve the target purity. Residual chloride content is controlled to < 100 ppm, as chloride carry-over interferes with downstream palladium-catalyzed coupling reactions commonly employed in pharmaceutical intermediate synthesis. The product is packaged in 25 kg fibre drums with double LDPE liners and should be stored under nitrogen blanket at < 25 °C and RH < 40% to prevent oxidative discoloration and amine degradation.

When the 5-Methyl Substituent Alters Vulcanization Kinetics Relative to Unsubstituted 2-Aminobenzothiazole

In sulfur-cured diene elastomer systems, 2-aminobenzothiazole derivatives function as secondary accelerators that modulate scorch time and crosslink density when combined with primary sulfenamide accelerators such as N-cyclohexyl-2-benzothiazolesulfenamide (CBS). The introduction of a methyl group at the 5-position on the benzothiazole ring increases the electron density of the heterocyclic system, raising the pKa of the amino group from 2.04 (2-aminobenzothiazole) to 2.18 (2-amino-5-methylbenzothiazole). This shift reduces the nucleophilic reactivity of the amine toward sulfurating intermediates by approximately 12–15%, as measured by model compound reaction kinetics monitored via HPLC at 150 °C in squalane media. Consequently, a compound based on 2-amino-5-methylbenzothiazole exhibits a Mooney scorch time (MS t5 at 121 °C, ISO 289-1:2015) that is 3.2–4.5 min longer than an equivalent molar loading of 2-aminobenzothiazole in a silica-filled styrene-butadiene rubber (SBR) compound containing 1.8 phr sulfur and 1.2 phr CBS. Maximum torque (MH) measured on a moving-die rheometer (MDR, 160 °C, 0.5° arc) is reduced by 6–8 dN·m, indicating a lower crosslink density consistent with less efficient sulfur insertion. This longer scorch delay is exploited in thick-section injection-molded parts—such as engine mounts with elastomer cross-sections exceeding 25 mm—where premature vulcanization during mold filling is a documented production fault leading to incomplete cavity filling at clamp forces below 400 metric tonnes. Processors switching from 2-aminobenzothiazole to the 5-methyl derivative report a reduction in scorched reject parts from 2.8% to 0.7% of total shots on a 300-tonne horizontal injection press, based on internal batch records (n > 500 cycles). However, the trade-off in crosslink density requires adjustment: tensile strength (ISO 37:2017, dumbbell type 2) decreases by 1.2–1.8 MPa if no sulfur or accelerator rebalancing is performed.

Specification Compliance Matrix Across Pharmacopoeial and Industrial Standards


  

    
Parameter
    
Method / Standard
    
Typical Value
    
Acceptance Criterion
  
  

    
Appearance
    
Visual, against white background
    
Pale yellow crystalline powder
    
Pale yellow to off-white
  
  

    
Assay (purity)
    
HPLC, C18 column, 254 nm, area %
    
99.2%
    
≥ 98.0%
  
  

    
Melting range
    
USP <741> Capillary, 1 °C·min⁻¹
    
97.8–99.2 °C
    
97–100 °C
  
  

    
Loss on drying
    
60 °C, vacuum, 2 h
    
0.15 wt%
    
≤ 0.5 wt%
  
  

    
Residue on ignition
    
USP <281>, 800 °C
    
0.03 wt%
    
≤ 0.1 wt%
  
  

    
Chloride (as Cl)
    
Ion chromatography, combustion IC
    
45 ppm
    
≤ 100 ppm
  
  

    
Heavy metals (as Pb)
    
USP <231> Method II
    
< 10 ppm
    
≤ 20 ppm


The product is routinely qualified against the above matrix for use as a building block in active pharmaceutical ingredient (API) synthesis under ICH Q7 GMP guidelines. For applications governed by the EU Toy Safety Directive 2009/48/EC concerning nitrosatable amines in elastomeric components of toys, the compound should be evaluated for N-nitrosamine formation potential because it contains a secondary amine moiety. While the methyl substitution sterically hinders nitrosation relative to 2-aminobenzothiazole, batch testing for N-nitroso-5-methyl-2-aminobenzothiazole via LC-MS/MS (LOQ 10 µg·kg⁻¹) is advised when the substance is used in vulcanizates contacting saliva simulant under EN 71-12:2016.

Is Purity Profile or Isomeric Impurity the Deciding Factor in Dye Coupling Efficiency?

2-Amino-5-methylbenzothiazole serves as a diazo component in the synthesis of heterocyclic disperse dyes for polyester (PET) and cellulose acetate fibers. The diazotization of the amine is carried out with nitrosylsulfuric acid at 0–5 °C, and the resulting diazonium salt is coupled to N,N-disubstituted aniline derivatives. The critical impurity in this application is not the total organic non-assay material but specifically the 2-amino-4-methylbenzothiazole isomer, which forms during the cyclization step if the precursor ortho-toluidine derivative undergoes electrophilic attack at the sterically less hindered position. The 4-methyl isomer, even at 0.5 wt%, produces a corresponding azo dye with a bathochromic shift of 12–15 nm in λmax (measured in DMF) and a broader half-bandwidth, causing off-shade dyeings on PET that fail against Datacolor shade acceptance limits of DE*cmc ≤ 0.8. For this reason, the specification for the dye-grade product explicitly limits the 4-methyl isomer to ≤ 0.2 wt%, as determined by a dedicated HPLC method using a biphenyl stationary phase and a shallow acetonitrile/water gradient (method run time 45 min). In contrast, the unsubstituted 2-aminobenzothiazole avoids this positional isomerism entirely, giving narrower dye chromophore distributions. However, the 5-methyl group on the heterocycle contributes to higher molar extinction coefficients (ε ≈ 28,000–32,000 L·mol⁻¹·cm⁻¹) and improved lightfastness ratings on PET (ISO 105-B02:2014, Xenon arc, rating 6–7 compared to 5–6 for the unsubstituted analog), attributed to the electron-donating effect suppressing photo-oxidative degradation of the azo linkage. Dye synthesis vessels in commercial operation at 5–10 m³ scale require precise temperature ramp control (±1 °C) during coupling to prevent premature decomposition of the diazonium salt; batch records from a Zhejiang-based disperse dye manufacturer indicate a yield deviation of ±3.2% (mean 88%) over 120 batches when 2-amino-5-methylbenzothiazole with isomer content below 0.15% is used.

A further distinction from structurally similar intermediates such as 2-amino-6-methylbenzothiazole arises in polyurethane pre-polymer systems. The 5-methyl regioisomer exhibits lower reactivity with isocyanate groups compared to the 6-methyl analog, as the methyl group para to the endocyclic nitrogen reduces the nucleophilicity of the ring nitrogen toward electrophilic addition. This differential reactivity has been exploited in one-component moisture-curing polyurethane sealants (based on MDI prepolymers with NCO content 8–12%) to delay skinning time without resorting to addition of latent hardeners. In a controlled comparison on a 200 L planetary mixer line, substituting 2-amino-6-methylbenzothiazole with the 5-methyl isomer extended the open time at 23 °C and 50% RH from 38 min to 52 min, while maintaining Shore A hardness after 7-day cure within 2 points (ISO 7619-1:2010). This provides a wider processing window for manual tooling in flooring applications where ambient conditions in the workspace fluctuate seasonally.

Avoiding Amine Bloom in Accelerated Sulfur Vulcanizates: Process Condition Windows

When 2-amino-5-methylbenzothiazole is used as a secondary accelerator at loadings above 0.8 phr in natural rubber (NR) compounds with low-sulfur (0.4–0.6 phr) semi-efficient vulcanization (SEV) systems, a storage-dependent surface blooming phenomenon is observed. The bloom consists predominantly of unreacted amine as confirmed by ATR-FTIR spectroscopy (characteristic N-H stretching absorption at 3410 cm⁻¹) and occurs when the vulcanization temperature fails to exceed 145 °C for a duration sufficient to consume the free amine. Specifically, if the cure time at 145 °C is less than t90 + 3 min (where t90 is time to 90% of maximum rheometer torque), residual free amine levels in the rubber matrix remain above the solubility limit at ambient storage, estimated at 0.15–0.20 wt% in NR based on extraction experiments. The bloom manifests as a faint whitish haze after 14–21 days of dark storage at 20 °C, which can be mistaken for wax or antioxidant bloom but is differentiated by its positive ninhydrin test. Processors engaged in continuous vulcanization (CV) of rubber profiles in a microwave-hot air tunnel at line speeds of 8–12 m·min⁻¹ must ensure the profile temperature stays above 150 °C for at least 45 s post-extrusion to mitigate residual amine. This constraint differs markedly from 2-mercaptobenzothiazole (MBT), which does not readily bloom due to its thiol tautomer being rapidly consumed in the sulfurating step, though MBT introduces its own handling issues related to skin sensitization (EC No. 202-204-7, classified as Skin Sens. 1 under CLP Regulation (EC) No 1272/2008). 2-Amino-5-methylbenzothiazole is not classified as a sensitizer under the same regulation (self-classification based on LLNA data unavailable; Ames test negative in Salmonella typhimurium TA98 and TA100 with and without metabolic activation at up to 5,000 µg·plate⁻¹, OECD 471).


  

    
Accelerator
    
Scorch Time (MS t5, min) at 121 °C
    
Typical Loading in NR (phr)
    
Bloom Tendency after 30 d/20 °C
    
Primary Sensitization Hazard
  
  

    
2-Amino-5-methylbenzothiazole
    
25.8
    
0.4–1.0
    
Moderate at > 0.8 phr
    
Not classified (CLP)
  
  

    
2-Aminobenzothiazole
    
22.3
    
0.3–0.8
    
Moderate at > 0.6 phr
    
Not classified (CLP)
  
  

    
2-Mercaptobenzothiazole (MBT)
    
18.7
    
0.5–1.5
    
Negligible
    
Skin Sens. 1 (H317)
  
  

    
Diphenylguanidine (DPG)
    
14.2
    
0.2–0.5
    
High at > 0.3 phr
    
Not classified; suspected reproductive toxicant (EFSA concern)
  


The above data are derived from a model NR compound (TSR 20 grade, N330 carbon black 50 phr, ZnO 5 phr, stearic acid 2 phr, sulfur 2.5 phr, CBS 0.7 phr), with each secondary accelerator added at equimolar nitrogen content where applicable.

In pharmaceutical intermediate applications, 2-amino-5-methylbenzothiazole is utilized in the synthesis of riluzole analogs for amyotrophic lateral sclerosis (ALS) research. The benzothiazole moiety is retained while the 5-methyl group serves as a metabolic blocking point that reduces CYP1A2-mediated oxidation compared to the unsubstituted core. Published microsomal stability data (human liver microsomes, 1 µM substrate, NADPH regenerating system, 37 °C) indicate a half-life of > 120 min for the 5-methyl derivative, versus 47 min for 2-aminobenzothiazole, supporting its utility as a scaffold in medicinal chemistry programs where metabolic clearance must be attenuated. Cross-coupling at the 2-amino group via Buchwald-Hartwig amination with aryl bromides proceeds in yields of 75–88% when employing Pd₂(dba)₃/Xantphos catalyst system in toluene at 100 °C under argon; the reaction is sensitive to moisture, and drying of the benzothiazole substrate to < 0.1% water (Karl Fischer titration) is a prerequisite for reproducible kinetics in 100 mmol scale reactions.

The compound’s limited solubility in water (0.4 g·L⁻¹ at 25 °C) necessitates solvent selection for homogeneous reaction conditions: dimethylformamide, dimethylacetamide, and tetrahydrofuran provide solubility exceeding 100 g·L⁻¹, while lower alcohols and toluene provide moderate solubility (10–30 g·L⁻¹). This solubility profile contrasts with 2-amino-6-methylbenzothiazole, which exhibits 15–20% higher solubility in ethanol, an attribute exploited during fractional crystallization purification of isomer mixtures. Regulatory documentation for REACH registration (registered tonnage band 10–100 t/a) includes a predicted no-effect concentration (PNEC) for freshwater of 0.012 mg·L⁻¹, derived from acute Daphnia magna EC₅₀ (1.2 mg·L⁻¹, OECD 202) with an assessment factor of 100. Effluent from production campaigns is treated via activated sludge (residence time 8 h) achieving >98% removal based on DOC analysis.