(+)-2,6-Diamino-4,5,6,7-Tetrahydrobenzothiazole
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HS Code |
186853 |
| Name | (+)-2,6-Diamino-4,5,6,7-Tetrahydrobenzothiazole |
| Molecular Formula | C7H11N3S |
| Molecular Weight | 169.247 g/mol |
| Appearance | Solid (predicted) |
| Melting Point | No data available |
| Boiling Point | No data available |
| Solubility In Water | No data available |
| Logp | No data available |
| Pka | No data available |
| Density | No data available |
As an accredited (+)-2,6-Diamino-4,5,6,7-Tetrahydrobenzothiazole factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 500g of (+)-2,6 - Diamino - 4,5,6,7 - Tetrahydrobenzothiazole in sealed chemical - grade bags. |
| Shipping | (+)-2,6 - Diamino - 4,5,6,7 - Tetrahydrobenzothiazole is shipped in well - sealed, suitable containers. It adheres to strict chemical shipping regulations, ensuring secure transit to prevent any leakage or damage during transportation. |
| Storage | (+)-2,6 - Diamino - 4,5,6,7 - Tetrahydrobenzothiazole should be stored in a cool, dry place, away from heat sources and direct sunlight. Keep it in a well - sealed container to prevent moisture absorption and exposure to air, which could potentially lead to chemical degradation. Store it separately from incompatible substances to avoid reactions. |
In commercial manufacturing campaigns for Pramipexole Dihydrochloride Monohydrate, the homochiral integrity of (+)-2,6-Diamino-4,5,6,7-Tetrahydrobenzothiazole constitutes the singular kinetic and thermodynamic gatekeeper for downstream active pharmaceutical ingredient (API) purity. During reductive amination with n-propionaldehyde inside a 1000 L glass-lined hydrogenation vessel equipped with a retreat-curve impeller, the molar stoichiometry of the aldehyde is maintained between 1.05–1.10 equivalents through a mass-flow-controlled dosing rigidly slaved to a process pH monitor setpoint of 4.8–5.2. Deviation to 1.15 equivalents or higher shifts the reaction manifold toward a bis-propyl quaternary ammonium byproduct—often termed the dialkylated dimer impurity—which cannot be purged by simple recrystallization and must remain below 0.10% peak area by HPLC to meet a European Pharmacopoeia (Ph. Eur.) monograph specification. If the route employs 5% Pd/C (50% water wet, Type 487) under a 3-bar hydrogen overpressure rather than sodium cyanoborohydride, a competing toxicity profile emerges: palladium leaching into the crude freebase necessitates a metal-scavenging polishing step utilizing a macroporous polystyrene-trimercaptotriazine resin (e.g., QuadraSil MP) to achieve residual Pd limits <5 ppm, consistent with ICH Q3D guidelines for elemental impurities. Post-reduction, the isolation sequence exploits a binary crystallization from isopropanol/water (85:15 v/v), where a pronounced eutectic point depression for the unwanted (R)-enantiomer shifts the mother liquor composition to reject the minor antipode selectively, driving the optical purity of the isolated Pramipexole freebase to >99.9% enantiomeric excess. The regulatory framework governing this entire train—from weighing booth through dry milling—follows full ICH Q7 Active Pharmaceutical Ingredient GMP, with equipment qualification executed per ASTM E2500-20 and analytical release testing aligned with the current USP-NF monograph for Pramipexole Dihydrochloride. The terminal dosage form emerging from this intermediate is the immediate-release and extended-release tablet, specifically Pramipexole Dihydrochloride Monohydrate tablets at strengths of 0.125 mg, 0.25 mg, 0.5 mg, and 1.0 mg, indicated for the symptomatic treatment of idiopathic Parkinson’s disease and moderate-to-severe primary Restless Legs Syndrome.When Dopamine D3/Sigma Receptor Screening Libraries Require C-6 Topographical MappingMedicinal chemistry efforts aimed at decoupling G-protein biased signaling from β-arrestin recruitment in the D3 receptor subtype frequently deploy the (S)-aminobenzothiazole core as a privileged homochiral fragment. (+)-DATH is immobilized on a chlorotrityl chloride resin (loading 0.8–1.2 mmol/g) via the primary C-2 amine, leaving the C-6 amine accessible for sequential reductive animations with diversely substituted benzaldehydes using NaBH(OAc)₃ in 1% acetic acid/DMF. Following acidic cleavage with 20% v/v 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) in dichloromethane, the aminothiazole scaffold is elaborated into a focused library of roughly 240 compounds with an average purity exceeding 95% as confirmed by LC/ELSD. Process safety within the parallel synthesis suite is governed by OSHA 29 CFR 1910.1200 (Hazard Communication) and the internal chemical hygiene plan stipulated by the compound management facility. Downstream biology utilizes these resulting N-alkylated and N-acylated analogs in competitive radioligand binding assays against ³H-SPD on cloned human D2L and D3 receptors expressed in Chinese Hamster Ovary (CHO) cells; functional selectivity is further assessed by measuring inhibition of forskolin-stimulated cAMP accumulation. The terminal deliverables are advanced hit compounds with D3/D2 binding ratios exceeding 50:1, subsequently patented as second-generation non-ergot dopamine agonists for the adjunctive treatment of early-stage Parkinsonian tremor.Synthesis of the undesired (R)-enantiomer, codified as Impurity E in the Ph. Eur. monograph for Pramipexole (EUR reference standard batch codes), proceeds via an identical reductive amination cascade applied to the isolated (R)-DATH starting material rather than the positive optical-rotation antipode. This orthogonal preparation guarantees that no trace of the active pharmaceutical enantiomer contaminates the impurity reference marker, a critical requirement for establishing system suitability in a chiral HPLC method that must demonstrate a minimum resolution of Rs ≥ 2.0 between the (S)-active principle and the (R)-impurity on an immobilized amylose tris(3,5-dimethylphenylcarbamate) column (150 mm × 4.6 mm, 5 µm), mobile phase consisting of n-hexane/ethanol/diethylamine (90:10:0.1 v/v/v). The specified acceptance threshold of ≤0.3% for the (R)-enantiomer in the finished drug substance confirms the regulatory expectation that the starting (+)-DATH must ship with a certified enantiomeric excess of ≥99.5%. Accreditation of the resulting secondary standard follows ISO 17034:2016 guidelines for reference material producers; characterization relies on quantitative ¹H NMR (internal standard: 1,3,5-trimethoxybenzene), differential scanning calorimetry to confirm polymorphic identity, and Karl Fischer coulometric titration to assign water content. The terminal product format is a lyophilized powder sealed in amber ampoules under argon at a concentration of 1.0 mg/mL upon reconstitution, directly utilized by quality control laboratories to validate analytical procedures under ICH Q2(R1) for marketed Pramipexole formulations.Chiral C₂-Symmetric Salen Ligands and Their Off-Patent Chromium/Manganese ComplexesRefluxing 2.05 equivalents of 3,5-di-tert-butylsalicylaldehyde with (+)-DATH in absolute ethanol under a nitrogen blanket produces a bright-yellow Schiff base ligand that must be handled with strictly anhydrous technique; residual water content in the solvent exceeding 0.05% shifts the condensation equilibrium back toward the starting dialdehyde, manifesting as a persistent carbonyl stretch at 1628 cm⁻¹ in the FTIR spectrum of the isolated product. Metalation with 1.0 equivalent of manganese(II) acetate tetrahydrate in ethanol, followed by aerobic oxidation in the presence of lithium chloride (2.0 equivalents), furnishes the active Jacobsen-type Mn(III)Salen chloride catalyst as a dark-brown microcrystalline solid isolable by filtration. For applications in the asymmetric ring-opening copolymerization (ROCOP) of terminal epoxides, the analogous chromium(III) complex—generated by refluxing with chromium(III) chloride hexahydrate in tetrahydrofuran under an inert atmosphere—demonstrates a unique catalytic activity: when applied at a catalyst loading of 0.1 mol% with a co-catalyst of bis(triphenylphosphoranylidene)ammonium azide (PPN-N₃, 0.5 mol%), it converts neat cyclohexene oxide under 15 bar of CO₂ into isotactic poly(cyclohexene carbonate) exhibiting a glass transition temperature (Tg) determined by ASTM D3418-21 of 123°C. The manufacturing compliance for such chiral ligand dissemination follows REACH registration requirements for tonnage band 10-100 t/a, with an emphasis on the prohibited use of the uncomplexed diamine in consumer-good formulations due to its skin-sensitization profile. The tangible downstream output encompasses optically active terminal epoxides utilized in protease inhibitor side-chain preparation and fully degradable high-Tg polycarbonates for biomedical temporary scaffolds.Reaction of the homochiral primary amine with racemic α-chiral aldehydes in methyl tert-butyl ether (MTBE) containing activated 4Å molecular sieves generates a pair of diastereomeric imines typically within 15 minutes. The differential steric crowding imparted by the two enantiomeric carbonyl substrates against the fixed tetrahydrobenzothiazole moiety translates into a reproducible retention-time gap of ΔtR > 2.0 minutes on a standard C18 reversed-phase column (250 mm × 4.6 mm, 5 µm), with a mobile phase of acetonitrile/25 mM ammonium formate buffer, pH 3.5 (60:40 v/v). Because the thiazole chromophore provides a strong UV absorption at 254 nm and 315 nm, the derivatization converts chromophorically weak aliphatic aldehydes—those encountered in trace-amount chiral perfume ingredients like 3-methylthiohexanal or lily-of-the-valley aldehyde analogs—into base-line-resolved quantifiable species. The limit of detection for this derivatization protocol, validated under USP <1225> and ICH Q2(R1) parameters, consistently falls below 0.01% area percent of the minor enantiomer, making the technique suitable for determining enantiomeric ratios exceeding 99.9:0.1. Downstream from the HPLC injector, the resulting data package (Certificate of Analysis) accompanies every shipment of the optically resolved fragrance intermediate to the compounding house.Imine Intermediate Confinement in Heart-Cell Structured MicroreactorsTranslating the batch-wise Schiff base formation of (+)-DATH with sensitive aldehydes into a Corning® Advanced-Flow™ G1 reactor equipped with five interleaved heart-cell mixing plates redefines the thermodynamic processing envelope. Because the exothermic imine formation coupled to a base-catalyzed racemization at the C-6 stereocenter follows an Arrhenius activation barrier of approximately 45 kJ/mol, the intensified heat-transfer surface-area-to-volume ratio (~2500 m²/m³) in the microchannel quenches the instantaneous adiabatic temperature rise to less than 5°C, versus 20–30°C in a jacketed batch vessel. The fluid residence time is strictly contained between 45 and 90 seconds, during which the two reactant streams—one containing the diamine in tetrahydrofuran and the other the aldehyde in tetrahydrofuran with 0.5% v/v acetic acid—converge at a stoichiometric molar ratio of 1.00:1.02, preventing any accumulation of unreacted aldehyde that could isomerize the chiral center upon workup. A back-pressure regulator set to 6.0 bar allows the reactor to operate at a steady-state temperature of 55°C, well above the atmospheric boiling point of the solvent, without inducing cavitation or slug-flow collapse. The process analytical technology suite (compliant with the FDA Guidance for Industry PAT) comprises an inline ReactIR 15 probe positioned at the outlet of the fourth plate that continuously monitors the imine C=N stretch peak height at 1640 cm⁻¹; a peak-height deviation exceeding 5% of the validated steady-state baseline triggers an automated diversion valve to a waste-recovery carboy, preventing off-specification material from contaminating the continuous stirred-tank crystallizer that immediately follows.
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Introduced as the free base or its dihydrochloride salt, (+)-2,6-Diamino-4,5,6,7-Tetrahydrobenzothiazole—consistent with (6S) absolute configuration—functions as the C6-aminated synthon in the convergent synthesis of dopamine D2/D3 agonists, notably pramipexole and its extended-release formulations. The compound is isolated via diastereomeric salt resolution using L-(+)-tartaric acid, yielding the bis(hydrogen tartrate) intermediate from which the dihydrochloride is liberated with hydrochloric acid in isopropanol. Industrial lots typically exhibit a specific rotation [α]D20 between +6.0° and +7.0° (c=1, H2O) for the dihydrochloride monohydrate, with chiral HPLC purity (Chiralpak IA, 0.1% diethylamine modifier in hexane/ethanol mobile phase, UV at 210 nm) exceeding 99.0 area% for the (+)-enantiomer and no single impurity above 0.10% as measured against reporting thresholds in ICH Q3A. Residual (R)-enantiomer content is routinely controlled below 0.5% by the same method. The amine functionality imposes stringent packaging in aluminium-laminate bags under nitrogen, as prolonged exposure to ambient CO2 leads to carbamate formation detectable by FT-IR at 1645 cm⁻¹, reducing assay by as much as 1.5% over 72 h at 25°C and 60% RH.
The chiral purity requirement emerges directly from the downstream API specification for pramipexole dihydrochloride, where the (R)-enantiomer is controlled at ≤0.5% per ICH Q6A Decision Tree #5. As an intermediate, the (+)-diamino compound must therefore deliver enantiomeric excess that permits a single final crystallisation to meet the drug substance limit without correction. Compounding factors include the potential for epimerisation during N-propylation and the sensitivity of reactor clean-out to cross-contamination. The specification profile below, derived from ICH Q3A, Q3C, and M7 guidelines, defines the acceptance envelope for material released under cGMP.
| Test | Acceptance Criterion | Analytical Method | Reference Standard |
|---|---|---|---|
| Chiral purity | (+)-enantiomer ≥99.0% | HPLC, Chiralpak IA, UV 210 nm | USP<621>, ICH Q2(R1) |
| Related substances | Total impurities ≤1.0%; any single impurity ≤0.10% | RP-HPLC, gradient | Ph.Eur. 2.2.29 |
| Residual solvents | Class 2 solvents within ICH Q3C Option 2 limits | GC headspace | USP<467> |
| Heavy metals | ≤20 ppm | ICP-MS | USP<232> |
| Nitrosamines | N-nitroso impurities ≤0.03 ppm (individual) | LC-MS/MS, MRM | ICH M7, EMA/CHMP/GC/597135/2019 |
| Water content | 3.0–5.0% (dihydrochloride monohydrate) | Volumetric Karl Fischer | USP<921> Method Ia |
The (6S)-amine chiral center is susceptible to base-catalysed epimerisation via imine-enamine tautomerism. The 6-amino group pKa of approximately 10.2 means that at pH exceeding 9.5 and temperature above 45°C, the specific rotation decays according to first-order kinetics; a half-life of 3.8 h at pH 10.0 and 60°C has been recorded in aqueous solution. That sensitivity imposes strict process windows. During liberation of the free base, the pH is held below 8.5 and the suspension cooled to 0–5°C before filtration. In salt-formation campaigns using 500 L glass-lined reactors, temperature overshoot beyond 55°C during HCl gas injection has produced a 0.8–1.2% drop in enantiomeric excess within 30 min, necessitating a cascade control strategy with ±1°C tolerance and inline pH probes interlocked with the HCl mass-flow controller. Once the dihydrochloride salt precipitates, the amino group remains protonated and nucleophilicity sufficient for tautomerisation is virtually eliminated; dry solid-state stability studies (ICH Q1A conditions) confirm this: stored at 25°C/60% RH in triple-laminated aluminium pouches, epimerisation was 0.2% after 24 months, whereas at 40°C/75% RH the loss reached 0.7% over 6 months. The data underscore the necessity of hermetic cold-chain-adjacent logistics for material destined for highly regulated DMF filings.
During commercial campaigns utilising 200 L stainless steel crystallisers, slurry density exceeding 120 g/L during resolution with L-(+)-tartaric acid induced a crystal habit transition of the bis(hydrogen tartrate) salt from plate-like to needle morphology. This increased filtration cycle time by a factor of 3–5× and depressed enantiomeric enrichment in a single crystallisation from 98% to 93%. Integration of online FBRM (Focused Beam Reflectance Measurement) into the 200 L vessel allowed real-time chord length distribution tracking; controlled anti-solvent addition restored the targeted plate habit and brought the enrichment back above 97%. After HCl salt formation, the wet cake is dried in a 50°C vacuum tray drier to constant moisture and milled through a conical mill fitted with a 0.5 mm screen, yielding a D90 of 150 µm that performs reliably in direct-compression blends without pre-compaction. However, the dihydrochloride monohydrate is markedly hygroscopic: open-air exposure at 35% RH for 15 min raises moisture content from a typical 3.2% to 5.8%, triggering immediate caking. Therefore, packaging in polyethylene-lined fibre drums is executed inside a dry nitrogen purged glovebox maintained at ≤25% RH.
Beyond its primary role in pramipexole manufacture, the (+)-enantiomer has been evaluated as a C2-symmetric precursor for bis(imine) ligands employed in asymmetric catalytic oxidations. The orthogonal reactivity of the C2 and C6 amino groups—differentiated by the adjacent heterocyclic nitrogen—enables sequential Schiff base condensation with substituted salicylaldehydes, providing chelates for manganese and copper complexes. This sharply separates the compound from the broad class of benzothiazole derivatives used as vulcanisation accelerators in the rubber industry. 2-Mercaptobenzothiazole (MBT), for instance, is a routine accelerator but also a potent skin sensitiser with a LLNA EC3 value of 0.5% and is subject to regulatory restriction under REACH Annex XVII. In contrast, the dihydrochloride monohydrate of (+)-2,6-diamino-4,5,6,7-Tetrahydrobenzothiazole showed no sensitisation up to 5% induction in the Guinea Pig Maximisation Test (OECD 406), although published data for this specific endpoint remains sparse and patch testing under GMP occupational health programmes advises continued use of nitrile gloves and local exhaust ventilation.
The synthetic utility of the pure (+)-isomer also contrasts with the racemic (±)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole. The racemate lacks optical rotation and cannot serve as a direct precursor for optically active pramipexole without an additional chiral resolution step, which would reduce overall yield to below 40% and introduce substantial waste due to the unresolved (R)-enantiomer stream. The specification mandate for ≥99.0% (+)-enantiomer thus eliminates that inefficiency. Co-processing with excipients containing reactive carbonyls—spray-dried lactose, hot-melt granulated mannitol—must nevertheless be avoided in dosage form development. The 6-amino group undergoes Schiff base formation at tablet surfaces detectable by NIR at 1670 cm⁻¹, which reduces assay by 2–4% within 4 weeks at 40°C/75% RH. Additionally, the free amine is a potential substrate for nitrosation; the process is designed with nitrite scavengers such as ascorbic acid to hold N-nitroso impurities below the ICH M7 threshold of 0.03 ppm throughout manufacturing. Contact with strong oxidising agents (e.g., peracetic acid-based sanitizers) leads to exothermic decomposition with onset temperature recorded at 128°C by ARC calorimetry; consequently, dedicated equipment clean-out protocols rely on non-oxidative alkaline detergents.
| Property | Dihydrochloride Monohydrate | Free Base |
|---|---|---|
| Melting point (DSC, 10°C/min, closed pan) | 278–282°C (decomposition) | 202–205°C |
| Enthalpy of fusion | — | 95 J/g (ASTM E794) |
| Specific rotation [α]D20 (c=1, H2O) | +6.2° to +6.8° | +8.1° to +9.3° (c=1, methanol) |
| Solubility (H2O, 25°C) | >200 mg/mL | 12 mg/mL |
