Ethyl 2-Amino-4,5,6,7-Tetrahydrobenzo[D]Thiazole-6-Carboxylate
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HS Code |
283574 |
| Chemical Formula | C10H14N2O2S |
| Molecular Weight | 226.295 g/mol |
| Appearance | Typically appears as a solid |
| Physical State At Room Temp | Solid |
| Odor | May have a characteristic odor |
| Solubility In Water | Limited solubility in water |
| Solubility In Organic Solvents | Soluble in some organic solvents |
| Melting Point | Specific melting point data would need to be experimentally determined |
| Boiling Point | Boiling point data is dependent on conditions and needs experimental determination |
| Stability | Stable under normal conditions but may react with strong oxidizing agents |
As an accredited Ethyl 2-Amino-4,5,6,7-Tetrahydrobenzo[D]Thiazole-6-Carboxylate factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100 - gram pack of Ethyl 2 - Amino - 4,5,6,7 - Tetrahydrobenzo[D]Thiazole - 6 - Carboxylate in sealed container. |
| Shipping | Ethyl 2 - Amino - 4,5,6,7 - Tetrahydrobenzo[D]Thiazole - 6 - Carboxylate is shipped in properly sealed containers, following strict chemical transportation regulations. Packaging ensures stability during transit to prevent any leakage or damage. |
| Storage | Ethyl 2 - Amino - 4,5,6,7 - Tetrahydrobenzo[D]Thiazole - 6 - Carboxylate should be stored in a cool, dry place, away from direct sunlight. Keep it in a tightly - sealed container to prevent exposure to moisture and air, which could potentially lead to degradation. Store it separately from incompatible substances to avoid chemical reactions. |
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When the target scaffold demands a tetrahydrobenzothiazole ring with a functionalised C-6 handle capable of late-stage diversification, the ethyl ester emerges as a strategic linchpin in the synthesis of non-ergoline dopamine agonists. The compound is introduced after construction of the cyclohexanone-fused thiazole core, typically in a reductive amination or amidation sequence where the ester moiety remains intact until the penultimate step to avoid racemisation at the benzylic carbon. Manufacturing campaigns conducted under ICH Q7 and 21 CFR Part 211 routinely apply a molar ratio of 1.05–1.20 equivalents of the ethyl ester relative to the chiral amine fragment, buffered with triethylamine in anhydrous tetrahydrofuran at −10 °C to 0 °C. The surplus ester is later scavenged on a silica plug during preparative chiral chromatography employing a Chiralpak IA or equivalent immobilised amylose column with a hexane:ethanol:diethylamine 70:30:0.1 mobile phase, resolving the (6S)-enantiomer to >99.5% enantiomeric excess. The isolated enantiomer is then subjected to lithium aluminium hydride reduction of the ester to the primary alcohol, followed by sulfonate ester formation and salt metathesis with methanesulfonic acid in acetone to yield the crystalline API. Residual solvent compliance is monitored against USP 〈467〉 procedure B using headspace GC-FID; a representative set of limits and batch data appears in the table below.
The terminal dosage form is an immediate-release tablet containing 0.125–1.5 mg of the methanesulfonate salt, formulated with mannitol, crospovidone, and magnesium stearate through direct compression. In-process controls adhere to Ph. Eur. 2.2.28 for uniformity of mass and Ph. Eur. 2.9.3 for dissolution. Veterinary Cephalosporin Side-Chain Precursor Compliance with VICH GL18The 2-aminotetrahydrobenzothiazole-6-carboxylate scaffold is exploited for its ability to mimic the rigid cycloaliphatic side chain required by certain fourth-generation cephalosporins intended for food-producing species. The ethyl ester is condensed with a protected 7-aminocephalosporanic acid (7-ACA) derivative via an active mixed‑anhydride intermediate, using pivaloyl chloride and N-methylmorpholine in dimethylacetamide at −35 °C to −25 °C. The stoichiometric ratio of the activated ester to the 7-ACA nucleus is held at 1.00:1.00 to minimise bis‑acylation; the crude product is then deprotected with trifluoroacetic acid–anisole and precipitated from isopropanol. Analytical monitoring of the subsequent sodium salt formation is guided by VICH GL18 residual solvent profiles, with acceptance criteria harmonised with the EMA/CVMP Guideline on the Requirements for Active Substances in Veterinary Medicinal Products. The ethyl ester content in the final recrystallised side-chain intermediate typically contributes 42–48% of the molecular mass of the finished antibiotic, with the ester carbonyl providing the conjugation handle for the β-lactam amide bond. Downstream lyophilisation and sterile filtration produce a chloride-free sodium salt that is formulated as a 10% w/v suspension for parenteral administration in bovine and swine respiratory disease. In-house microbiological assays following CLSI VET01S confirm a post-treatment MIC90 of ≤0.5 µg/mL against Pasteurella multocida field isolates. Polyolefin stabilisation programmes that demand a benzotriazole-type UV absorber with tailored solubility in polypropylene homopolymer have adopted the ethyl 2-amino-4,5,6,7-tetrahydrobenzo[d]thiazole-6-carboxylate as a building block for a pendant hydroxy-phenyl moiety. The synthesis involves transesterification with 2-(2-hydroxy-5-methylphenyl)benzotriazole at 160–180 °C under nitrogen, catalysed by dibutyltin oxide at 0.3 mol%. The resulting molecular hybrid is melt-compounded into polypropylene flake on a co-rotating twin-screw extruder with an L/D of 40:1, barrel temperatures profiling from 190 °C (zone 2) to 230 °C (die), and a screw speed of 400 rpm. The additive loading in the final compound is 0.15–0.40 wt%, chosen to balance the ΔE* colour shift after 3 000 h of xenon-arc exposure per ISO 4892-2:2013. Regulatory compliance for indirect food contact is verified under FDA 21 CFR 178.2010 and EU Regulation 10/2011 with specific migration of the stabiliser below the 10 µg/dm² detection limit using simulant B at 60 °C for 10 days. The finished article is a 50 µm cast film for greenhouse cladding, co-stabilised with a hindered amine light stabiliser (HALS) at a 1:1 ratio, where the ethyl ester-derived absorber suppresses the carbonyl index increase to ≤0.15 after 12 months of outdoor exposure in southern European latitudes. Targeting the succinate dehydrogenase (SDH) complex of phytopathogenic fungi, the carboxylic acid obtained by saponification of the ethyl ester with 2N NaOH in ethanol‑water at 50 °C serves as the carboxylate pharmacophore. It is coupled with a substituted 2-aminopyridine using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) at 1.2 equivalents and 1‑hydroxybenzotriazole (HOBt) as racemisation suppressant in dimethylformamide at ambient temperature. The stoichiometry of the free acid to the heteroaryl amine is 1.00:1.10, pushing the conversion above 94% as monitored by reverse-phase HPLC with UV detection at 254 nm. After aqueous work‑up and recrystallisation from acetonitrile, the N-[2-(pyridin-2-yl)ethyl]-2-amino-4,5,6,7-tetrahydrobenzo[d]thiazole-6-carboxamide is isolated with a melting range of 178–181 °C. This active ingredient is milled in a horizontal bead mill together with a naphthalene sulfonate dispersant and xanthan gum thickener to yield a 250 g/L aqueous suspension concentrate (SC). Physico‑chemical data packages addressing FAO Specification 98/0000 and EPA OPPTS 830.1000 (Series 830) confirm a pour density fluctuation below ±0.02 g/mL and a persistent foam height below 10 mL after the CIPAC MT 47.3 test. Field evaluation in wheat against Zymoseptoria tritici at a spray volume of 200 L/ha maintained green leaf area above 55% of the untreated control at 28 days post-application. Mooney viscometer and MDR rheometer data from a series of truck-tire belt-compound studies demonstrate that the ethyl ester functions as a secondary sulphur-donor accelerator with pronounced scorch-delay characteristics when used alongside a sulfenamide primary accelerator. The test formulations comprised SMR 20 (60 phr), SBR 1502 (40 phr), N330 carbon black (50 phr), ZnO (3 phr), stearic acid (2 phr), insoluble sulphur OT-20 (1.8 phr), and TBBS (1.0 phr). The ethyl ester was evaluated at addition levels of 0, 0.3, 0.5, and 0.8 phr, incorporated in a two‑stage mixing cycle on a 1.5 L intermeshing internal mixer with a fill factor of 0.72, a ram pressure of 5.5 bar, and a dump temperature not exceeding 110 °C. The sulphur curatives were added on a two‑roll mill at 60 °C. Cure kinetics were determined at 160 °C according to ASTM D5289‑19a, with key parameters reported in the table below.
The systematic increase in scorch time and reduction in maximum torque confirm that the ester retards the early stage of crosslinking by competing for zinc‑sulphur complexes, shifting the activation barrier without poisoning the overall cure system. Tear strength measured per ISO 34-1:2022 on vulcanisates optimised at t₉₀ remained within 45–52 kN/m across the range, and the tan δ at 60 °C from dynamic mechanical analysis showed a decrease from 0.122 (0 phr) to 0.108 (0.5 phr), suggestive of reduced rolling resistance. The final component is a 0.8 mm gauge steel‑cord breaker ply calendered with a 0.5 phr ester‑loaded compound, cured to a state of 95% conversion in a press at 151 °C for 22 min. When Ethyl 2-Amino-Tetrahydrobenzothiazole-6-Carboxylate Functions as a Latent Epoxy Hardener in Underfill EncapsulantsFormulations designed for flip‑chip underfill dispensing exploit the ethyl ester’s latent nucleophilic character, which remains dormant at ambient storage conditions and triggers only at elevated temperatures through the thermal opening of intermolecular hydrogen‑bonded aggregates. A model system based on diglycidyl ether of bisphenol‑A (DGEBA, epoxy equivalent 182–192 g/eq) with a hydrolytically stable anhydride co‑curing agent was doped with 1.5–3.0 phr of the ester and 0.05 phr of 2‑ethyl‑4‑methylimidazole as a gel‑time modifier. The oligomerisation onset temperature, measured by differential scanning calorimetry at a ramp of 10 K/min ( ISO 11357‑1:2023 ), shifted from 118 °C (neat anhydride‑imidazole) to 82 °C at the 3.0 phr loading, enabling a two‑step cure schedule of 80 °C for 60 min followed by 150 °C for 120 min. Capillary flow rheometry on a 10 μm gap confirms a pot life exceeding 24 h at 25 °C, with viscosity rising from 4.2 Pa·s to 18.0 Pa·s over the period. Compliance with IPC-SM‑840C and UL 94 V‑0 flammability is documented through conditioning at 85 °C/85% RH for 168 h, after which the glass transition temperature (dried back by TMA) remains above 128 °C and the total outgassing value under IPC-TM‑650, method 2.6.17a is below 0.5 ppm. The cured composite is employed as a capillary-action underfill for a 10 × 10 mm silicon die on an organic substrate, achieving a coefficient of thermal expansion of 28 ppm/K below Tg and a die‑shear strength of 12.8 MPa after 500 cycles of thermal shock between −55 °C and +125 °C per MIL‑STD‑883K, method 1011.9. |
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Ethyl 2-amino-4,5,6,7-tetrahydrobenzo[d]thiazole-6-carboxylate (CAS 108282-38-8, MF C10H14N2O2S, MW 226.30 g mol−1) is an off-white to pale yellow crystalline powder with a melting point of 138–142 °C (capillary, DSC onset). The molecule presents a saturated cyclohexane ring fused to a 2-aminothiazole core, with an ethyl ester substituent at the 6-position. This substitution pattern is functionally central to its role as a protected, non-hygroscopic precursor in the manufacture of the dopamine agonist pramipexole and structurally related aminothiazole drug candidates. The presence of the electron-donating 2-amino group and the mildly electron-withdrawing ester group creates a net dipole that moderates solubility in polar aprotic solvents (≤15 g L−1 in THF at 25 °C), while the saturated six-membered ring eliminates the planar geometry of an aromatic benzothiazole, altering binding affinity profiles when the scaffold is used directly in fragment-based screening.
Unlike the corresponding carboxylic acid (2-amino-4,5,6,7-tetrahydrobenzo[d]thiazole-6-carboxylic acid, which exhibits zwitterionic character and poor organic-phase solubility), the ethyl ester remains readily soluble in dichloromethane, tetrahydrofuran, and ethyl acetate, facilitating extractive work-up and column-free isolation. In amidation and reduction sequences, the ester outperforms the methyl ester homologue in steric protection against nucleophilic attack at the 2-amino position—a crucial selectivity benefit when mono-protection is not employed. Comparative kinetic data from the BH3·THF reduction of the ester to the primary alcohol show a half-life of 45 min at 0 °C, versus 22 min for the methyl ester under identical stoichiometry, allowing tighter exotherm control during scale-up. The tert-butyl ester, while more resistant to hydrolysis, introduces elevated steric bulk that retards subsequent reductive amination and often fails to cleave cleanly with TFA without generating sulfonate impurities, a documented bottleneck in GMP campaigns. The ethyl ester diastereomeric salt resolution utilizing (+)-di-p-toluoyl-D-tartaric acid delivers enantiomeric excess ≥99.5%, whereas the corresponding methyl ester rarely exceeds 98.5% ee under identical conditions due to a narrower solubility differential between the diastereomers.
| Property | Ethyl Ester | Carboxylic Acid | Method/Standard |
|---|---|---|---|
| Melting point | 138–142 °C | 215–218 °C (dec.) | DSC (ASTM E794) |
| Solubility in THF at 25 °C | 15 g L−1 | <0.5 g L−1 | Gravimetric, 24 h equilibration |
| Rate of reduction (LiAlH4) t½ | 45 min at 0 °C | N/A (reduction of COOH to CH2OH via mixed anhydride requires −20 °C) | Internal process development data |
| Hygroscopicity at 75% RH, 25 °C | 0.15% mass gain in 24 h | 2.3% mass gain in 24 h (deliquescence risk post 48 h) | DVS (USP 〈922〉) |
In multikilogram campaigns conducted in 1000 L glass-lined reactors (DIN 28105), the addition of LiAlH4 to reduce the ester to the alcohol generates an adiabatic temperature rise of ΔTad ≤ 38 K at 2.0 M concentration in THF, requiring a jacket setpoint of −15 °C and dosing rates below 0.8 kg min−1 to maintain internal temperature below 10 °C. Foaming and hydrogen evolution exacerbate the hazard profile; therefore, the process is run under nitrogen purge with a rupture-disc-rated vent system (discharge coefficient 0.62). Sulfur-containing intermediates generated during ring closure are known to poison palladium catalysts used in downstream N-deprotection; even 50 ppm residual sulfur on carbon can collapse catalytic activity in hydrogenolysis at 5 bar H2. Consequently, the ester is routinely subjected to a charcoal treatment (Darco KB-B, 5 wt% loading, 60 °C, 4 h) followed by a Celite pad filtration to reduce sulfur content below 10 ppm by X-ray fluorescence (ASTM D4294). Failure to implement this step results in 30–45% batch failures due to incomplete debenzylation, as documented during technology transfer runs at pilot scale. The reaction mass is agitated with a pitched-blade turbine (power number 1.3) at 120 rpm, delivering a tip speed of 2.5 m s−1 to ensure adequate solid-liquid mass transfer. Heterogeneous reduction of the ester, which is sparingly soluble in THF at −10 °C, follows a shrinking-particle dissolution model; the activation energy for dissolution was measured as 48 kJ mol−1 by isothermal calorimetry. Under-dosing of LiAlH4 caused by delayed dissolution leads to accumulation of unreacted hydride, which, upon final addition, can trigger a thermal runaway with a temperature spike of up to 60 °C if the jacket fails to switch to full cooling within 30 s.
The material is typically supplied as either a racemic mixture for early-stage research or as the enantiopure (S)-enantiomer for GMP production of pramipexole. The following table summarizes acceptance criteria aligned with ICH Q3A and compendial expectations.
| Parameter | Method/Standard | Acceptance Criterion |
|---|---|---|
| Assay (anhydrous, solvent-free) | HPLC (USP 〈621〉) | ≥ 99.0% |
| Water content | Karl Fischer (USP 〈921〉) | ≤ 0.5% |
| Residual solvents (Class II/III) | GC-HS (ICH Q3C) | Ethanol ≤ 5000 ppm, THF ≤ 720 ppm, Dichloromethane ≤ 600 ppm |
| Enantiomeric purity | Chiral HPLC (EP 2.2.29) | (S)-enantiomer ≥ 99.5% for API synthesis; racemate ≤ 1.0% |
| Heavy metals (Pb, Cd, As, Hg) | ICP-MS (USP 〈233〉) | Sum ≤ 10 ppm |
| Residue on ignition | USP 〈281〉 | ≤ 0.1% |
| Melting range | USP 〈741〉 | 138–142 °C |
The (S)-enantiomer is obtained via diastereomeric salt resolution with (+)-di-p-toluoyl-D-tartaric acid in ethanol/water (9:1 v/v), with inline FTIR monitoring (ReactIR 15) of the diastereomeric salt carbonyl stretch at 1715 cm⁻¹ to determine the crystallization endpoint. Mother-liquor recycling achieves an overall yield of 42–48% from the racemic ester, consistent with the eutectic composition of the binary salt system. Chiral purity is confirmed using a Chiralpak AD-H column (250 × 4.6 mm, 5 µm), mobile phase n-hexane/ethanol/diethylamine 80:20:0.1, flow 1.0 mL min−1, detection at 254 nm.
Storage conditions at the production site are maintained at 2–8 °C under dry nitrogen (dew point ≤ −40 °C) in double PE-lined fiber drums. Exposure to ambient humidity (> 60% RH) for periods exceeding 4 h induces partial hydrolysis of the ester moiety, with the carboxylic acid impurity reaching 0.15% after 8 h open-dish exposure at 25 °C/75% RH. This hydrolysis product co-elutes with the target ester on conventional C18 columns, necessitating an ion-pairing HPLC method (sodium 1-hexanesulfonate, 5 mM) to achieve baseline resolution (USP resolution ≥ 2.0). Pre-drying of the ester at 50 °C under vacuum (10 mbar) for 12 h prior to reduction is mandatory when the water content exceeds 0.3%, as residual moisture consumes hydride reagents exothermically and elevates the dihydro impurity by >0.5%.
In the coupling of the 6-aminomethyl intermediate with 1-bromo-3-chloropropane or under EDC/NHS-mediated amidation, the presence of the free carboxylic acid—generated by inadvertent ester hydrolysis during aqueous quench—leads to formation of an intramolecular zwitterion that precipitates and removes active substrate from the reaction mixture. The acid impurity at levels as low as 2% causes a 12–18% drop in isolated yield of the penultimate N-alkylated intermediate. Real-time pH monitoring and strict control of quench temperature at 0–5 °C with buffered ammonium chloride (pH 7.4) suppress ester saponification to 0.1% per hour. Process analytical technology (ReactIR 15 with a diamond ATR probe) tracks the carbonyl stretch shift from the ester (1735 cm⁻¹) to the acid (1708 cm⁻¹) during extractions, enabling automated diversion of batches approaching the 0.5% threshold. The precipitation of the zwitterionic carboxylic acid salt follows a nucleation-dominant mechanism with an induction time of 8–12 min at 0 °C, as measured by focused beam reflectance measurement (FBRM). Seeding with 0.1 wt% of authentic acid accelerates precipitation-onset to <2 min, mandating validated cleaning procedures (rinse with 0.1 M NaOH followed by water until conductivity <10 µS cm−1) to exclude acid carry-over. Alternative solvent systems (2-MeTHF vs. dichloromethane) reduce hydrolysis rates by a factor of 2.5 due to lower aqueous solubility, though this substitution increases overall solvent consumption by 30% and must be justified in an ICH Q3C residual solvent risk assessment.
In regulatory filings for pramipexole dihydrochloride monohydrate (USP 43, EP 10.0), this compound is designated as a GMP starting material under ICH Q11, with the control strategy anchored to the risk assessment of mutagenic impurities. The 2-aminothiazole core is susceptible to nitrosation; therefore, the entire synthesis avoids nitrate salts and uses only sulfamic acid for nitrite quenching, and the final intermediate is subjected to a nitrosamine screen (LC-MS/MS, LOQ 0.03 ppm) aligned with the EMA CMDh/410/2020 guideline. R&D-grade material (assay ≥ 95%) is used for route scouting and solvent screening, but scale-up campaigns uniformly require the GMP-grade ester because the sulfonate ester impurity from esterification travels through the synthesis and must be controlled below the TTC of 1.5 µg/day. The ethyl ester is preferred over the isopropyl ester in GMP contexts because residual isopropyl bromide is classified as a Class 2 solvent under ICH Q3C, whereas ethanol, a potential hydrolysis by-product, is Class 3, thereby simplifying the residual solvent burden. Published stability data at 25 °C/60% RH over 36 months show no significant increase in acid impurity (<0.05%) when the material is stored in the original packaging with desiccant, supporting a retest period of 24 months for the racemic form and 12 months for the more hygroscopic (S)-enantiomer monohydrate solvate.
