2,6-Benzothiazolediamine, 4,5,6,7-Tetrahydro-N(Sup 6)-Propyl-, (S)-
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HS Code |
984045 |
| Chemical Formula | C10H17N3S |
| Molecular Weight | 211.33 g/mol |
| Physical State | Solid (usually) |
| Melting Point | Data may vary, check specific sources |
| Boiling Point | Data may vary, check specific sources |
| Solubility In Water | Low solubility (estimated) |
| Solubility In Organic Solvents | Soluble in some organic solvents like ethanol (estimated) |
| Density | Data may vary, check specific sources |
| Appearance | White to off - white solid (estimated) |
| Chirality | Has an (S)-configuration |
| Odor | Odorless or mild odor (estimated) |
As an accredited 2,6-Benzothiazolediamine, 4,5,6,7-Tetrahydro-N(Sup 6)-Propyl-, (S)- factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 500g of (S)-4,5,6,7 - tetrahydro - N⁶ - propyl - 2,6 - benzothiazolediamine in sealed chemical - grade packaging. |
| Shipping | Ship 2,6 - Benzothiazolediamine derivative carefully. Use appropriate chemical - grade packaging to prevent leakage. Ensure compliance with regulations for transporting this (S)-4,5,6,7 - tetrahydro - N⁶ - propyl compound during shipping. |
| Storage | 2,6 - Benzothiazolediamine, 4,5,6,7 - Tetrahydro - N⁶ - Propyl -, (S) - should be stored in a cool, dry place away from direct sunlight and heat sources. Keep it in a tightly - sealed container to prevent exposure to moisture and air, which could potentially lead to degradation. Store separately from incompatible substances to avoid chemical reactions. |
In the production of pramipexole dihydrochloride monohydrate compliant with USP, EP 10.5, and JP XVIII, (S)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazolediamine functions as the immediate free-base precursor. A typical industrial batch charges 85.0 kg of the (S)-diamine intermediate into a 1,500 L glass-lined reactor pre-purged with nitrogen to ≤ 5% oxygen content. Purified water (340 L, conductivity ≤ 1.3 μS/cm) is introduced under vacuum, and the slurry is agitated at 120 rpm with a retreat-curve impeller. Hydrochloric acid (37% w/w, 2.08 molar equivalents relative to the free base) is metered through a PTFE-lined dosing line at a rate maintaining internal temperature 22 ± 1 °C. The exotherm is controlled by jacket circulation at 8 °C. Post-addition, the clear solution is stirred for 45 minutes before polish filtration through a 0.45 μm polypropylene cartridge into a crystallization vessel. Acetone (680 L, HPLC grade, pre-cooled to 4 °C) is added linearly over 90 minutes via a mass flow controller, yielding a controlled nucleation event at a supersaturation ratio of S = 2.8. The crystal slurry is aged for 6 hours at 5 °C, then centrifuged in a bottom-discharge Hastelloy C-22 basket centrifuge at 1,200 G. The wet cake is washed with a pre-chilled acetone-water mixture (80:20 v/v) and dried in a double-cone vacuum dryer at 42 °C and ≤ 0.5 kPa absolute pressure for 16 hours. Final moisture determined by Karl Fischer titration must be 3.8–4.5% w/w, corresponding to the monohydrate stoichiometric value. Chiral purity is verified on a Chiralpak AGP column (150 × 4.0 mm, phosphate buffer pH 6.0-isopropanol 95:5) with a specification of ≥ 99.85% enantiomeric excess; the (R)-isomer is limited to ≤ 0.05% peak area. Residual solvents are monitored per USP <467>: acetone ≤ 500 ppm, and any process-derived tetrahydrofuran below 720 ppm.What role does this intermediate play in compendial impurity qualification?Pharmacopoeial monographs for pramipexole dihydrochloride mandate identification and quantification of specified impurities, several of which are derived from—or structurally correlate with—the (S)-propyl-tetrahydrobenzothiazolediamine scaffold. Impurity A (EP nomenclature: (S)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole, the N-despropyl analogue) is synthesized by subjecting the title intermediate to oxidative N-dealkylation using 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO, 5 mol%) with sodium hypochlorite (1.05 eq.) in a biphasic dichloromethane-water system at 0–5 °C. After phase separation and silica gel flash chromatography, the isolated impurity A hydrochloride is crystallized from methanol-diethyl ether to ≥ 98.5% chromatographic purity. Impurity C, the N-oxide arising from oxidation at the propylamino nitrogen, is obtained by controlled oxidation with hydrogen peroxide (30% w/w, 1.02 eq.) in methanol at 10 °C with residence time limited to 40 minutes to prevent over-oxidation to the sulfoxide on the benzothiazole ring. The crude N-oxide is purified by preparative HPLC on a C18 column using 0.1% trifluoroacetic acid-acetonitrile mobile phase, followed by ion-exchange conversion to the hydrochloride salt. Impurity F, the dimeric species formed via oxidative coupling of two (S)-diamine molecules through the 6-amino position, is generated by prolonged heating of the free base in air at 80 °C in dimethyl sulfoxide, and its structure is confirmed by HRMS (Q-TOF, resolution > 30,000) and 1H-13C HMBC NMR. These impurities serve as reference standards for the HPLC system suitability test described in EP 2.2.46, using a 150 mm × 4.6 mm, 3 μm base-deactivated octadecylsilyl column with a gradient of phosphate buffer pH 3.0 and acetonitrile. The resolution between impurity A and pramipexole must be ≥ 4.0, and the signal-to-noise ratio for the 0.05% impurity standard injection is specified at ≥ 10.Deuterium-labeled internal standards for quantitative LC-MS/MS bioanalysis of pramipexole in human plasma are manufactured from the (S)-free base precursor by reductive amination with propionaldehyde-d6 (98 atom% D). The intermediate is dissolved in anhydrous methanol (water < 100 ppm) at a concentration of 0.8 M, and 1.10 equivalents of propionaldehyde-d6 are added along with sodium cyanoborohydride (1.20 eq.) and acetic acid (0.15 eq.) to maintain pH 5.5–6.0. The mixture is stirred for 18 hours at 22 °C under argon, then quenched with 1 M sodium hydroxide and extracted with methyl tert-butyl ether. The crude pramipexole-d6 free base is purified by flash chromatography and converted to the hydrochloride salt monohydrate using the same stoichiometric protocol applied to the non-labeled API. Isotopic enrichment is verified by UPLC-HRMS: the [M+H]+ ion cluster at m/z 218.2 must show < 0.2% residual unlabeled species. A stock solution in methanol (1.0 mg/mL) is prepared and calibrated against a certified pramipexole reference standard using a triple quadrupole MS in multiple reaction monitoring mode, transition m/z 218.2 → 111.1, with a linearity range of 0.050–100 ng/mL (r² ≥ 0.995). This internal standard is used for clinical pharmacokinetic studies per FDA Guidance for Industry, M10 Bioanalytical Method Validation, enabling correction for matrix effects and extraction recovery variability in human EDTA plasma samples.Chiral Selector Immobilization on Silica for Enantioselective HPLC PhaseThe (S)-diamine scaffold is employed as a π-basic chiral selector in brush-type stationary phases for the direct resolution of underivatized profen non-steroidal anti-inflammatory drugs and N-protected amino acids. Activation of spherical amino-silica gel (5 μm, pore size 120 Å, specific surface area 300 m²/g) is performed by refluxing with 3-aminopropyltrimethoxysilane in dry toluene for 24 hours. The resulting aminopropyl-silica is then reacted with 1,6-hexamethylene diisocyanate (3.0 eq. relative to surface amine) in anhydrous dichloromethane at 40 °C for 6 hours under nitrogen, forming an isocyanate-terminated spacer. After rigorous washing to remove excess diisocyanate, the activated silica is slurried with a solution of the (S)-propyl intermediate (0.5 M in DMF) containing 0.1% w/w dibutyltin dilaurate as catalyst. The coupling reaction proceeds at 70 °C for 12 hours with continuous gentle mechanical agitation to avoid particle attrition. Residual isocyanate groups are end-capped with n-butylamine. Elemental analysis indicates a carbon loading of 8.3–9.1% w/w, corresponding to a surface coverage of approximately 0.38 μmol/m² chiral selector. The bonded phase is slurry-packed into 250 × 4.6 mm stainless steel columns at 800 bar using a high-pressure pneumatic pump. Enantioselectivity for ibuprofen enantiomers is evaluated with a mobile phase of hexane-isopropanol-acetic acid 90:10:0.5 (v/v/v). The (S)-enantiomer elutes first with a separation factor α of 1.18 ± 0.02 and resolution Rs of 2.1 at 1.0 mL/min flow rate.
Synthesis of Phase II Metabolites for Drug-Drug Interaction StudiesThe (S)-intermediate provides the enantiomerically pure core required for preparation of pramipexole glucuronide and sulfate conjugates—compounds essential in evaluating UGT enzyme-mediated metabolic pathways. Direct N-glucuronidation at the propylamino nitrogen is achieved by incubating the (S)-free base with uridine 5′-diphosphoglucuronic acid trisodium salt (2.5 eq.) in the presence of recombinant human UGT1A9 Supersomes (protein concentration 1.0 mg/mL) in 50 mM Tris-HCl buffer pH 7.5 containing 5 mM MgCl₂ and 25 μg/mL alamethicin at 37 °C for 4 hours. The reaction is terminated with ice-cold acetonitrile, and the quaternary ammonium-linked glucuronide is isolated using a semi-preparative HILIC column with ammonium formate buffer pH 4.5-acetonitrile gradient. For the sulfate conjugate, the (S)-intermediate is dissolved in anhydrous pyridine and heated with sulfur trioxide-pyridine complex (3.0 eq.) at 60 °C under argon for 3 hours. After evaporation of pyridine, the residue is reconstituted in water and subjected to ion-pair chromatography on a C8 column using 10 mM tetrabutylammonium hydrogen sulfate as the ion-pairing reagent. The purified metabolites are quantified by 1H-NMR using 1,4-dioxane as an internal standard (δ 3.55 ppm, 8H), and their identity is established via collision-induced dissociation fragmentation patterns on a Q-Exactive Orbitrap mass spectrometer with mass accuracy < 3 ppm. These reference metabolites are integrated into an LC-MS/MS method validated per EMA Guideline on Bioanalytical Method Validation for simultaneous determination of pramipexole and its glucuronide in human hepatocyte incubation supernatant, enabling in vitro inhibition assays to assess perpetrator potential against UGT1A9.A related industrial use emerges in the preparation of N-propylbenzothiazole-derived haptens for immunochemical assay development. The primary amino group at the 2-position of the benzothiazole ring is diazotized with sodium nitrite (1.02 eq.) in 2 M hydrochloric acid at 0 °C, and the resulting diazonium salt is immediately coupled to bovine serum albumin in 0.1 M borate buffer pH 9.2, maintaining the (S)-configuration at the 6-position throughout. The hapten-protein conjugate, with a hapten density of 12–18 moles per mole BSA as determined by MALDI-TOF MS, is used as an immunogen in polyclonal antibody production in rabbits following standard immunization protocols. The resulting polyclonal antisera exhibit cross-reactivity with despropyl-pramipexole of less than 5% in competitive ELISA format, demonstrating the significance of the intact (S)-propylamino pharmacophore for antibody recognition.
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Designated chemically as (S)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazolediamine, the compound is registered under CAS 104632-26-0 for the anhydrous free base and is internationally recognized as pramipexole. The dihydrochloride monohydrate salt (CAS 191217-81-9) constitutes the active pharmaceutical ingredient in all approved oral solid dosage forms. The molecular framework comprises a tetrahydrobenzothiazole bicyclic core functionalized at the 2-position with a primary amino group and at the 6-position with an (S)-configured N-propyl side chain; this specific stereochemistry is a prerequisite for high-affinity interaction with the D2 subfamily of dopamine receptors, particularly the D3 subtype.
The free base is a white to off-white crystalline solid with a melting range of 148–151 °C and an aqueous solubility below 0.5 mg/mL at 25 °C. Conversion to the dihydrochloride salt raises solubility to greater than 20 mg/mL, enabling formulation of immediate- and extended-release tablets. Pharmacopoeial models differentiate between the anhydrous free base (CAS 104632-26-0) and the dihydrochloride monohydrate (CAS 191217-81-9); the former is employed principally as a reference standard for chromatographic identification and chiral purity testing, while the latter is the only form recognized in USP and EP monographs for therapeutic use. The monohydrate stoichiometry is confirmed by Karl Fischer titration, with water content specified at 3.5–4.5% w/w. Residual solvent limits follow ICH Q3C guidelines, with ethanol capped at 5000 ppm and isopropyl alcohol at 5000 ppm when the final crystallization employs these vehicles.
Stability studies conducted at 40 °C/75% RH over 6 months demonstrate that the monohydrate does not undergo deliquescence, but the free base exhibits hygroscopic uptake mass change exceeding 0.3% when exposed to relative humidity above 60% for more than 48 hours. Consequently, bulk packaging for the free base reference standard requires double polyethylene liners with a desiccant pouch and storage at controlled room temperature not exceeding 25 °C. Light exposure accelerates oxidative formation of the N-oxide impurity, necessitating amber glass containers and compliance with ICH Q1B photostability testing.
| Parameter | Analytical Method | Acceptance Criterion |
|---|---|---|
| Appearance | Visual inspection | White to practically white crystalline powder |
| Identification | IR spectrophotometry (USP <197K>), HPLC retention time | Concordant with reference standard |
| Assay (anhydrous, solvent-free basis) | HPLC (USP <621>) | 98.0–102.0% |
| Enantiomeric purity (R-isomer) | Chiral HPLC (Chiralpak AGP column, phosphate buffer pH 6.5/isopropanol) | ≤ 0.15% |
| Despropyl pramipexole (Impurity A) | HPLC, gradient elution | ≤ 0.10% |
| Any unspecified individual impurity | HPLC | ≤ 0.10% |
| Total impurities | Summation of all HPLC peaks | ≤ 0.5% |
| Heavy metals | USP <231> Method II | ≤ 20 ppm |
| Residue on ignition | USP <281> | ≤ 0.1% |
| Residual solvents | Headspace GC (USP <467>) | Meets ICH Q3C limits |
The R-enantiomer (CAS 104632-27-1) is the primary stereochemical impurity; its pharmacological activity at human D2 receptors is reported to be over 200-fold lower than that of the (S)-isomer. Manufacturing processes relying on asymmetric reductive amination of the prochiral 6-keto intermediate or resolution of a racemic precursor with N-acetyl-L-leucine are designed to deliver a chiral purity floor of 99.5% ee. When a batch tests above 0.15% R-isomer, reprocessing through diastereomeric salt formation is triggered before release. Forced degradation studies (acid, base, peroxide, thermal, and photolytic conditions per ICH Q1A) reveal that the N-oxide and despropyl species are the predominant degradation products, both quantifiable by the validated HPLC method with a quantitation limit of 0.05%.
| Receptor Subtype | Pramipexole (S)-isomer | Ropinirole | Rotigotine |
|---|---|---|---|
| D2S | 3.31 | 4.52 | 13.53 |
| D2L | 2.21 | 4.82 | 15.23 |
| D3 | 0.51 | 2.92 | 0.713 |
| D4.4 | 5.11 | 1102 | 3.93 |
| D2L/D3 selectivity ratio | 4.4 | 1.7 | 21.4 |
1 Mierau et al., Eur. J. Pharmacol. 290 (1995) 29–36. 2 Coldwell et al., Br. J. Pharmacol. 127 (1999) 1696–1702. 3 Wood et al., J. Pharmacol. Exp. Ther. 352 (2015) 444–454. Values represent mean Ki from at least three independent experiments.
The data reveal a distinct D3-preferring profile for pramipexole relative to ropinirole; the (S)-propylamino extension into the accessory hydrophobic pocket of the D3 orthosteric site is proposed to underlie the 5.8-fold lower Ki at D3 compared to ropinirole. Rotigotine achieves the highest absolute D3 affinity among the three, yet its weaker D2 binding yields a larger D2/D3 ratio, a distinction that translates into differential functional selectivity in vivo. These receptor occupancy characteristics are crucial when considering adjunctive therapy in Parkinson’s disease, where sustained D3 stimulation has been correlated with reduced dyskinesia potential in MPTP-lesioned primate models.
In early Parkinson’s disease where levodopa-sparing strategies are prioritized, pramipexole dihydrochloride monohydrate is titrated from an initial dose of 0.125 mg three times daily, escalated over 5–7 weeks to a maintenance range of 1.5–4.5 mg/day administered in three divided doses. Extended-release tablets permit once-daily dosing and demonstrate reduced peak-to-trough fluctuation in plasma concentration, with steady-state Cmax values achieved within 5 days of consistent administration. Unlike ropinirole, which undergoes extensive CYP1A2-mediated hepatic metabolism and risk of drug-drug interaction with ciprofloxacin or fluvoxamine, pramipexole is predominantly eliminated renally as unchanged drug (approximately 90% of an oral dose), making creatinine clearance a critical parameter for dose adjustment in patients with renal impairment. In contrast to the transdermal rotigotine system, pramipexole does not rely on continuous skin absorption; local site reactions—a limitation inherent to once-daily patch technology—are absent, though orthostatic hypotension and impulse control disorders remain class-wide clinical concerns documented across all non-ergot dopamine agonists.
For moderate-to-severe idiopathic restless legs syndrome (RLS), the same dihydrochloride monohydrate entity is formulated at a lower dose band, typically starting at 0.125 mg once daily 2–3 hours before bedtime, with a maximum recommended dose of 0.5 mg/day. Augmentation—a paradoxical worsening of symptoms observed with prolonged dopaminergic therapy—has been reported less frequently with pramipexole than with levodopa in long-term open-label extensions, though comparative RLS trials with rotigotine show similar augmentation rates at 52 weeks (approximately 7–9%). The free base is not administered directly to patients; its primary role remains as the reference material for chiral identity testing and dissolution method development per USP <711>. All finished-product specifications for pramipexole tablets require confirmation that the (S)-enantiomer is not racemized during tablet compression and coating, a test performed with the validated chiral HPLC protocol employing a 150 × 4.6 mm Chiralpak AGP column thermostatted at 30 °C and UV detection at 262 nm.
