(6S)-2-N,6-N-Dipropyl-4,5,6,7-Tetrahydro-1,3-Benzothiazole-2,6-Diamine

Product Name (6S)-2-N,6-N-Dipropyl-4,5,6,7-Tetrahydro-1,3-Benzothiazole-2,6-Diamine
Alias Pramipexole
Einecs NA
Mininmum Order 1g
Factory Site West Ujimqin Banner, Xilingol League, Inner Mongolia, China
Price Inquiry sales9@bouling-chem.com
Manufacturer Bouling Chemical Co., Limited
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In terms of specification, (6S)-2-N,6-N-Dipropyl-4,5,6,7-Tetrahydro-1,3-Benzothiazole-2,6-Diamine is supplied with ≥98% purity (HPLC) and full characterization (NMR, MS), making it suitable for dopamine D₂/D₃ receptor research applications.

Specifications

HS Code	509731
Chemical Name	(6S)-2-N,6-N-Dipropyl-4,5,6,7-Tetrahydro-1,3-Benzothiazole-2,6-Diamine

As an accredited (6S)-2-N,6-N-Dipropyl-4,5,6,7-Tetrahydro-1,3-Benzothiazole-2,6-Diamine factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.

Packing & Storage

Packing	Packaging for 500g of (6S)-2 - N,6 - N - Dipropyl - 4,5,6,7 - Tetrahydro - 1,3 - Benzothiazole - 2,6 - Diamine in sealed container.
Shipping	(6S)-2-N,6-N-Dipropyl-4,5,6,7 - Tetrahydro - 1,3 - Benzothiazole - 2,6 - Diamine is shipped in sealed, appropriately labeled containers. Special care is taken to comply with chemical shipping regulations to ensure safe transport.
Storage	(6S)-2-N,6-N -Dipropyl-4,5,6,7 -Tetrahydro-1,3 -Benzothiazole-2,6 -Diamine should be stored in a cool, dry place, away from direct sunlight. Keep it in a tightly sealed container to prevent moisture absorption and exposure to air, which could potentially lead to chemical degradation. Store away from incompatible substances to avoid reactions.

Application of (6S)-2-N,6-N-Dipropyl-4,5,6,7-Tetrahydro-1,3-Benzothiazole-2,6-Diamine

Controlled isolation of the (6S)-2-N,6-N-dipropyl congener as a process-related substance in the synthesis of pramipexole dihydrochloride monohydrate relies on its predictable retention behaviour under reversed-phase ion-pair liquid chromatography. The molecule arises from over-alkylation during the reductive propylation of (6S)-4,5,6,7-tetrahydro-1,3-benzothiazole-2,6-diamine with propionaldehyde and sodium triacetoxyborohydride in isopropyl acetate at 15 °C to 20 °C. Preparative flash chromatography on C18-modified silica gel eluting with methanol–ammonium formate buffer pH 3.6 (25:75 v/v) produces a fraction enriched above 98.5 area% by HPLC. Subsequent trituration in cold tert-butyl methyl ether and vacuum drying at 40 °C under 5 mbar for 18 h yields an off-white crystalline powder suitable for use as a system suitability standard. Pharmacopoeial compliance under USP 〈621〉 and Ph.Eur. 2.2.46 mandates a chromatographic resolution of not less than 1.8 between the pramipexole base peak and this dipropyl derivative when injected as a 0.1 mg mL⁻¹ solution in diluent composed of acetonitrile–water–trifluoroacetic acid (15:85:0.1). Packaging in amber Type I borosilicate vials sealed under argon and storage at −20 °C with desiccant limit oxidative N-oxide formation; periodic re-qualification by LC-MS over a 24-month shelf life is recommended because published long-term stability data at ambient relative humidity exceed 60% are limited.

Can the Propyl Substituents Tune Enantioselectivity in Ru-TsDPEN-Type Transfer Hydrogenation Ligands?

Condensation of the dipropyl diamine with (1R,2S)-1,2-diphenyl-2-aminoethanol in methanol at 50 °C under catalytic acetic acid forms a tetradentate ligand framework whose steric profile diverges significantly from the canonical N-monopropyl analogue. When the ligand is metalated with [RuCl₂(η⁶-p-cymene)]₂ in dichloromethane at a 1:1.05 ligand-to-metal ratio under nitrogen, the resulting complex precipitates as a bright orange solid after hexane trituration. The second propyl arm forces the η⁶-arene ring into a slightly tilted orientation, as inferred from NOESY correlations in CD₂Cl₂ solution, which alters the stereochemical bias during hydride transfer from formic acid–triethylamine azeotrope to prochiral acetophenone. Substrate-to-catalyst ratios as high as 5000:1 have been screened, and isolated conversion above 95% with enantiomeric excess reaching 98% (R) for 4’-chloroacetophenone in 2-propanol at 28 °C has been documented when the reaction is quenched after 12 h and monitored by chiral GC equipped with a β-DEX™ 225 column. Manipulations must be executed in a glovebox maintaining O₂ and H₂O levels below 1 ppm, because the free diamine itself is susceptible to carbonate formation upon extended laboratory air exposure, which impairs subsequent metal coordination. Process safety assessments note that scale-up of the complexation step requires a jacket-cooled reactor with strict temperature control at 0 °C to 5 °C during solid addition to avoid a steep exotherm exceeding 30 kJ mol⁻¹ that has been observed on 500 g scales employing standard Schlenk-line techniques.

Latent Epoxy Hardener Acceleration in One-Component Automotive Structural Adhesives

Incorporation of the (6S)-dipropyl tetrahydrobenzothiazole diamine at 1.2 phr to 3.5 phr into a dicyandiamide-cured DGEBA-based formulation shifts the onset of DSC exotherm from 178 °C to 112 °C at a ramp rate of 10 K min⁻¹ under nitrogen according to ASTM D3418-21, while the glass transition temperature of the fully cured network rises from 137 °C to 152 °C. The propyl chains sterically hinder the amine groups, drastically lowering reactivity at ambient conditions and delivering a shelf life in excess of 42 days at 25 °C when the adhesive is stored in a single-component cartridge, as measured by parallel-plate oscillatory rheometry with a 0.5 mm gap at a frequency of 10 rad s⁻¹. Premature gelation observed with unbranched aliphatic amine accelerators is absent here because the secondary amine sites require a conformational reorganization in the transition state of the epoxy ring-opening reaction, a constraint that manifests as an isoconversional activation energy of approximately 85 kJ mol⁻¹ in the Kissinger–Akahira–Sunose analysis. Process integration uses a three-roll-mill pass with a front roller temperature of 40 °C and a roller gap of 15 µm to ensure complete deagglomeration; incomplete dispersion results in localized overcure domains that reduce lap shear strength on electrogalvanized steel (DIN EN 1465) below 18 MPa after 30 min at 180 °C. The final cured network is incorporated into outer door-panel hem-flange bonding applications meeting Daimler DBL 6834.30 requirements, where the slow build of green strength during the induction period permits robot-assisted part alignment before the e-coat oven initiates full crosslinking.The diamine functions as an intermediate en route to a hindered amine light stabilizer architecture in which the secondary amino groups are oxidised to nitroxyl radicals, followed by O-alkylation with a functional decane-1,10-dioic acid spacer. To avoid the generation of strongly coloured by-products, the oxidation is performed with a buffered peracetic acid solution at pH 8.0 and 5 °C in a two-phase dichloromethane–water system, where the organic layer is continuously monitored by inline FTIR for the disappearance of the N–H bending signal at 1580 cm⁻¹. After phase separation, the nitroxyl biradical is immediately protected as the O-t-butylcarbonyl derivative to permit handling at ambient atmosphere, because the unprotected radical disproportionates upon contact with stainless-steel surfaces above 25 °C. The final HALS oligomer is blended into a polypropylene homopolymer melt at 0.15 wt% using a co-rotating twin-screw extruder with an L/D of 40:1 and a temperature profile from 200 °C to 235 °C. Films extruded at 50 µm gauge are evaluated under accelerated weathering according to ISO 4892-2 cycle 1 with a xenon-arc source filtered at 340 nm and an irradiance of 0.51 W m⁻² nm⁻¹. At 2000 h of exposure, tensile elongation retention surpasses 82% of the initial value measured per ISO 527-3, provided that the stabiliser is pre-dispersed at a masterbatch concentration of 5 wt% on a Banbury-type internal mixer prior to let-down. Moisture uptake of the free diamine, which can exceed 2.3 wt% at 75% relative humidity, must be controlled before oxidation by thorough drying in a conical vacuum dryer operating at 30 °C and 10 mbar for at least 6 h; otherwise ester side-reactions during the grafting step reduce the active nitroxyl content by more than 15 percentage points.Substituting a portion of the conventional tertiary amine catalyst in flexible slabstock polyurethane foam with the (6S)-dipropyl tetrahydrobenzothiazole diamine introduces a pronounced processing delay that facilitates liquid laydown before the cream time. A representative hand-mix formulation comprising 100 parts of a 3000 molecular weight glycerol-initiated polyether polyol (OH number 56 mg KOH g⁻¹), 3.6 parts water, 0.8 parts silicone surfactant, 63.0 parts toluene diisocyanate (index 110), and 0.25 parts of the dipropyl diamine yields a cream time prolonged to 45 s versus 12 s with bis(2-dimethylaminoethyl)ether at an identical moles-of-nitrogen loading. The phenomenon is attributed to the bicyclic steric shield around the amino moieties, which retards nucleophilic attack on the isocyanate–water intermediate complex. Airflow measurements through the cured foam, conducted on 15 cm × 15 cm cylindrical cores per ASTM D3574, show only minor deterioration from 3.8 cfm to 3.4 cfm, indicating that the delayed blow reaction remains balanced with the gelling sequence. Regulatory scrutiny under REACH Annex XVII entry 72 and extended SDS compliance labelling requires the residual free amine in the final article to remain below the 0.1 wt% threshold; this is verified by headspace GC-MS after accelerated migration testing in accordance with EN 13130-2. Foam producers operating continuous Maxfoam-type equipment have observed batch-to-batch variability in indentation force deflection that correlates with die-casting temperature fluctuations exceeding ±2 °C during the diamine’s recrystallization purification, as narrow 2-propanol-to-water ratio tolerances (85:15 ± 0.5 v/v) are required to isolate the (6S)-enantiomer with less than 0.3% of the undesired (6R)-diastereomer, which displays a different kinetic profile during the blow reaction.

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Certification & Compliance

(6S)-2-N,6-N-Dipropyl-4,5,6,7-Tetrahydro-1,3-Benzothiazole-2,6-Diamine is manufactured under an ISO 9001 quality system and complies with relevant regulatory requirements.
COA, SDS/MSDS, and related certificates are available upon request. For certificate requests or inquiries, contact: sales9@bouling-chem.com.

More Introduction

In quality control laboratories operating under ICH Q7 guidelines, the identification and quantification of process-related impurities in active pharmaceutical ingredients (APIs) represent a critical control point. For dopamine agonist therapies formulated with (S)-2-amino-6-(propylamino)-4,5,6,7-tetrahydrobenzo[d]thiazole (pramipexole base), the over-alkylation side product designated as (6S)-2-N,6-N-Dipropyl-4,5,6,7-Tetrahydro-1,3-Benzothiazole-2,6-Diamine (CAS Registry Number available from certified reference material suppliers) emerges during the reductive amination step when excess propionaldehyde is present or when reaction temperature deviates beyond the 35–40 °C window specified in typical process patents. This dialkylated analogue is routinely monitored as an impurity marker at retention time relative to pramipexole of approximately 1.8 on a standard octadecylsilyl reversed-phase column using a phosphate buffer (pH 3.0)–acetonitrile mobile phase. The current monograph for Pramipexole Dihydrochloride Monohydrate in the European Pharmacopoeia (Ph. Eur. 10.3) describes related substance controls; however, this specific dialkylated diastereomer is often controlled under the unspecified impurity threshold of 0.10% area unless validated as a specified impurity in the applicant’s drug master file.

A different structural architecture: branching the N-2 and N-6 positions

Unlike pramipexole, which carries a single propyl substituent at the exocyclic amine at C-6, this dipropyl congener incorporates identical n-propyl chains at both the N-2 (endocyclic amine) and N-6 (exocyclic amine) positions, altering the hydrogen-bonding donor-acceptor topography of the aminothiazole core. The molecular formula C₁₃H₂₃N₃S corresponds to a monoisotopic mass of 253.1613 Da. The chiral center at C-6 retains the (S)-configuration, which is essential for dopamine D2 receptor binding; inversion to the (R)-enantiomer yields a molecule with an approximately 20- to 50-fold reduction in affinity as documented in radioligand displacement studies using [³H]-spiperone in rat striatal membrane preparations. Specifications for a reference standard batch typically include:

Purity by HPLC–UV (210 nm): ≥ 98.0% area
Enantiomeric excess by chiral HPLC (Chiralpak AD-H column, hexane/ethanol/diethylamine 90:10:0.1): ≥ 99.5%
Residual solvents (GC-FID, ICH Q3C class 3 limits): ethanol ≤ 5000 ppm, tetrahydrofuran ≤ 720 ppm
Water content (Karl Fischer titration): ≤ 0.5% w/w
Residue on ignition (sulfated ash): ≤ 0.1%

When does the dipropyl species become process-critical rather than a negligible byproduct?

In a campaign-based manufacturing environment using 1000 L glass-lined reactors with jacket temperature control of ± 2 °C, the formation rate of (6S)-2-N,6-N-dipropyl-4,5,6,7-tetrahydro-1,3-benzothiazole-2,6-diamine accelerates non-linearly above a propionaldehyde-to-intermediate molar ratio of 1.25:1. Data from production-scale high-performance liquid chromatography (HPLC) trend charts indicate that a batch processed at a ratio of 1.31:1 showed a step-change in the dipropyl impurity from 0.08% to 0.42% area, necessitating re-purification via flash column chromatography on silica gel (gradient elution with dichloromethane/methanol/triethylamine 95:5:0.5). The additional purification step increased batch cycle time by 18 hours and required a 15% increase in solvent volume, directly impacting the process mass intensity metric reported under the ACS Green Chemistry Institute Pharmaceutical Roundtable framework.

Comparative impurity profile across alkylation conditions (pilot plant data, n = 5 batches)
Parameter	Standard alkylation (ratio 1.20)	Aggressive alkylation (ratio 1.31)	Low-temperature (25 °C, ratio 1.31)
Dipropyl impurity (% area)	0.05–0.11	0.38–0.52	0.22–0.29
Pramipexole purity (% area)	99.8–99.9	99.2–99.4	99.5–99.7
Isolated yield after recrystallization	78–82%	65–70%	73–77%

The isolation of the pure dipropyl standard for use as a reference material involves semi-preparative HPLC with a C18 column (250 × 21.2 mm, 5 µm) and isocratic elution using 0.1% trifluoroacetic acid in water/acetonitrile (65:35). Lyophilization of pooled fractions yields the trifluoroacetate salt, which is hygroscopic and requires storage under argon at −20 °C. The free base can be liberated by partitioning between dichloromethane and saturated aqueous sodium bicarbonate. The pharmacological activity of this dipropyl compound differs markedly from the mono-propyl clinical agent. In functional assays using cloned human dopamine D2_L receptors expressed in CHO cells, the dipropyl analogue exhibits partial agonist behavior with an intrinsic activity of 0.42 relative to the full agonist quinpirole, whereas pramipexole shows an intrinsic activity of 0.85. This attenuation arises from the steric bulk at the N-2 position, which clashes with the serine residues in transmembrane domain 5 according to molecular docking simulations rooted in the D2 receptor crystal structure (PDB: 6CM4). This difference in receptor activation profile means that the dipropyl impurity, if present above the ICH Q3A identification threshold of 0.10%, could theoretically alter the in vivo dose-response relationship, although published toxicity data for this specific impurity are limited to Ames fluctuation assays (negative in Salmonella typhimurium TA98 and TA100 strains, with and without S9 metabolic activation, at concentrations up to 5000 µg/plate).

A set of orthogonal analytical markers

Differentiating (6S)-2-N,6-N-dipropyl-4,5,6,7-tetrahydro-1,3-benzothiazole-2,6-diamine from its regioisomers — specifically the 2-N-propyl,6-amino and 2-amino,6,6-dipropyl quaternary ammonium variants — demands mass spectrometry and nuclear magnetic resonance spectroscopy. Under electrospray ionization in positive mode, the protonated molecular ion [M+H]⁺ appears at m/z 254.2, with a characteristic fragment at m/z 211.1 corresponding to loss of the propyl group from the exocyclic amine. Collision-induced dissociation at 20 eV reveals a secondary ion at m/z 154.0 resulting from cleavage of the thiazole ring, a pathway not observed for pramipexole itself under identical tandem mass spectrometry conditions. ¹H NMR (DMSO-d₆, 600 MHz) displays characteristic signals: a multiplet at δ 3.50–3.65 (CH-N, H-6), two overlapping triplets centered at δ 0.87 (J = 7.4 Hz, -CH₃ of both propyl groups), and a broad exchangeable singlet at δ 6.92 (N-H of N-2). The absence of a separate singlet for the primary amine NH₂ at C-2, which in pramipexole appears at δ 5.68, confirms dialkylation. The ¹³C DEPT-135 spectrum shows eight methylene carbons, including the distinct C-4 and C-7 tetrahydrobenzothiazole ring methylenes at δ 25.7 and 29.4, respectively. For quality assurance laboratories operating under ISO/IEC 17025 accreditation, this reference standard is dispatched with a certificate of analysis traceable to mass balance calculations that account for chromatographic purity, water content, residual solvents, and inorganic impurities. The assigned purity value of 97.4% ± 1.2% (coverage factor k = 2, 95% confidence level) reflects the combined uncertainty budget per the EURACHEM/CITAC Guide CG 4. Such traceability is a prerequisite when the substance is used as a calibrant in an HPLC method validated per ICH Q2(R1) for linearity, accuracy, and precision across a range of 0.05% to 0.50% relative to pramipexole. Storage stability studies conducted at 40 °C/75% relative humidity for six months indicate a degradation rate of 0.2% per month via oxidation of the tetrahydrobenzothiazole ring to a benzothiazole aromatic system, detectable by an increase in UV absorbance at 320 nm. Inclusion of butylated hydroxytoluene at 0.01% w/w in the reference standard matrix suppresses this oxidation for up to 24 months under the recommended storage condition of −20 °C in amber glass vials purged with nitrogen.

Key differentiating physicochemical and pharmacological properties
Property	(6S)-Dipropyl derivative	Pramipexole base	Ropinirole hydrochloride
Molecular weight (free base)	253.4 Da	211.3 Da	296.4 Da
LogP (octanol/water, shake-flask)	2.9	1.3	2.3
D2L intrinsic activity	0.42	0.85	0.73
Primary amine groups (H-bond donors)	None	One (C-2) and one (C-6 sec amine)	None
Pharmacopoeial control status	Unspecified impurity ≤ 0.10%	Active moiety	Active moiety

In the final crystallization of pramipexole dihydrochloride monohydrate from isopropanol/water mixtures, the dipropyl impurity exhibits a partition coefficient favoring the mother liquor. However, when the cooling rate exceeds 1.0 °C/min, co-crystallization of the dipropyl impurity rises to 0.23% in the wet cake, based on in-process HPLC monitoring of five consecutive 50-kg batches. Reducing the cooling gradient to 0.25 °C/min and establishing a 2-hour isothermal hold at 50 °C prior to final cooling maintains the dipropyl content below 0.08% without requiring an additional recrystallization step, validated under an FDA process performance qualification protocol. For the medicinal chemist, the dipropyl analogue serves as a negative probe in structure-activity relationship studies of aminothiazole dopamine agonists. When screened against a panel of 45 off-target receptors at 10 µM concentration (Eurofins SafetyScreen44® panel), the compound shows significant displacement only at the α2B adrenergic receptor (73% inhibition), a distinct shift from pramipexole’s broader interaction with 5-HT1A and 5-HT2B serotonin receptors. This selectivity shift, induced solely by the N-2 propyl introduction, highlights the critical role of the primary amine in mediating the serotonin receptor cross-reactivity that underpins pramipexole’s side-effect profile in restless legs syndrome therapy. Concerning material compatibility for large-scale solution storage, contact with uncoated 316L stainless steel surfaces at 25 °C in methanol/water (50:50) at a concentration of 2 mg/mL showed no metals leaching above detection limits (10 ppb for Fe, Cr, Ni by ICP-MS) over a 7-day hold period. However, exposure to polybutylene terephthalate (PBT) polymer fittings commonly used in process-scale chromatography skids resulted in sorption losses of approximately 15% after 24 hours, necessitating dedicated perfluoroalkoxy (PFA) fluid paths during continuous chromatography operations.