(S)-2-Amino-6-Propylamino-4,5,6,7-Tetrahydrobenzthiazole
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HS Code |
446755 |
| Chemical Formula | C10H17N3S |
| Molecular Weight | 211.33 g/mol |
| Appearance | Solid (usually) |
| Physical State At Room Temp | Solid |
| Solubility In Water | Limited solubility (usually) |
| Solubility In Organic Solvents | Soluble in some organic solvents |
| Chirality | Has (S)-chirality |
| Functional Groups | Amino, thiazole ring |
| Odor | Typically odorless or mild odor |
| Ph Aqueous Solution | Depends on concentration |
As an accredited (S)-2-Amino-6-Propylamino-4,5,6,7-Tetrahydrobenzthiazole factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | ( S ) -2 - Amino - 6 - Propylamino - 4,5,6,7 - Tetrahydrobenzthiazole: 100g in sealed chemical - grade packaging. |
| Shipping | ( S)-2 - Amino - 6 - Propylamino - 4,5,6,7 - Tetrahydrobenzthiazole is shipped in well - sealed containers, compliant with chemical transportation regulations. Quantity - based packaging ensures safety during transit to prevent spills and damage. |
| Storage | ( S ) -2 - Amino - 6 - Propylamino - 4,5,6,7 - Tetrahydrobenzthiazole should be stored in a cool, dry place. Keep it away from heat sources, direct sunlight, and incompatible substances. Store in a tightly - sealed container to prevent moisture absorption and potential reactions, safeguarding its chemical integrity and stability. |
Where does chiral integrity become the rate-limiting factor in dopamine agonist synthesis?The enantiomeric excess (ee) of (S)-2-Amino-6-Propylamino-4,5,6,7-Tetrahydrobenzthiazole directly governs the pharmacological fidelity of non-ergoline dopamine agonists, most notably Pramipexole dihydrochloride monohydrate. In the convergent synthesis pathway where the thiazole-fused tetrahydropyridine backbone is assembled via bromination-cyclization of a 4-propylamino cyclohexanone oxime derivative followed by Hantzsch-type condensation with thiourea, the chiral center at C-6 of the tetrahydrobenzthiazole ring is stereochemically labile under thermal stress exceeding 78°C in the presence of trace transition metals. Industrial-scale chiral resolution via diastereomeric salt formation using L-(+)-tartaric acid in isopropanol/water (85:15 v/v) at a controlled cooling gradient of 0.3°C/min between 55°C and 22°C achieves crystalline yields of 72–78% with an enantiomeric purity exceeding 99.5% ee (quantified by chiral HPLC using Chiralpak IA column, 250 mm × 4.6 mm, mobile phase n-hexane:ethanol:diethylamine 90:10:0.1, flow rate 0.8 mL/min, detection UV 265 nm). Deviation from the specified cooling ramp produces crystal habit modification—specifically, needle-to-plate transition—that entrains the (R)-enantiomer at inclusion rates of 1.8–3.4%, exceeding the 0.15% (R)-isomer limit mandated by Ph.Eur. monograph 04/2017:2416 for Pramipexole API.Pilot-plant records from multi-kilogram campaigns document that residual water content in the crude free base prior to salt formation must be driven below 0.8% w/w (Karl Fischer titration, Metler Toledo C30S) via azeotropic distillation with n-heptane at 40–45 mbar jacket temperature not exceeding 70°C. Any moisture ingress during salt formation shifts the resolution equilibrium, dropping ee values by 3–6 percentage points and necessitating a second re-crystallization from methanol/water that reduces overall recovery to below 58%. The regulatory submission package for ANDA filers referencing Pramipexole tablets requires this intermediate to conform to ICH Q3A(R2) thresholds for unspecified impurities (reporting threshold 0.05%, identification threshold 0.10%, qualification threshold 0.15%), with particular scrutiny on the des-propyl impurity (6-amino-2-amino-4,5,6,7-tetrahydrobenzthiazole) which co-elutes with the API in non-optimized gradient methods. Forced degradation studies conducted per ICH Q1B confirm photolytic susceptibility: the neat solid exhibits 1.2% (R)-epimerization after 18 hours of exposure to 1.2 million lux-hours visible light and 200 W·h/m² UV-A, requiring amber glass packaging with desiccant (silica gel, 25 g/kg product) under nitrogen headspace during intercontinental cold-chain logistics.The reduction step upstream—converting 2-amino-6-propylamino-4,5,6,7-tetrahydrobenzthiazole to the (S)-configured amine via asymmetric hydrogenation employing a ruthenium-BINAP catalyst system (RuCl₂[(R)-BINAP]₂·NEt₃, 0.05 mol% relative to substrate) in methanol at 45°C under 18 bar H₂ pressure—demands rigorous exclusion of dissolved oxygen below 0.1 ppm to prevent catalyst deactivation via phosphine oxide formation. The isolated (S)-amine is then condensed with 1-bromo-3-chloropropane under phase-transfer conditions (tetrabutylammonium bromide 0.08 eq, aqueous NaOH 50% w/w, toluene, 85°C for 9 h) to yield the penultimate intermediate without racemization, as confirmed by inline ReactIR monitoring of the C-Br stretch at 645 cm⁻¹. This multi-step sequence, executed on campaigns of 120–180 kg input, defines the critical supplier qualification metrics: batch-to-batch ee consistency (CV ≤ 0.3% across 20 consecutive lots), residual palladium content below 2 ppm (ICP-MS detection), and absence of genotoxic alkyl halide impurities at levels exceeding the TTC of 1.5 µg/day as per ICH M7(R1) guidelines for chronic-use therapeutics.
Neonicotinoid precursor engineering: when the propylamino sidechain becomes a leaving group surrogateThe N-propylamino substituent at the C-6 position of the tetrahydrobenzthiazole nucleus serves as a precursor to cyclic amidine pharmacophores that mimic the nitroimino pharmacophore of first-generation neonicotinoid insecticides. In the production of thiacloprid-class compounds—chloronicotinyl insecticides acting as agonists at the nicotinic acetylcholine receptor (nAChR) of the insect central nervous system—the tetrahydrobenzthiazole amine intermediate is converted to a cyanoimino-thiazolidine through reaction with cyanamide in the presence of 37% hydrochloric acid at 60 ± 3°C over 8–10 h. The addition ratio for this conversion is stoichiometrically pinned at 1.0 molar equivalent cyanamide to amine, with a 0.15 eq excess of acid catalyst. Deviation from this ratio beyond ± 0.03 eq leads to formation of a dimeric urea byproduct that precipitates as a dense orange solid during solvent quench, plugging the 50-micron in-line filter screens and causing batch abort rates of approximately 7% in campaign-mode production at agrochemical synthesis facilities operating under ISO 14001 environmental management certification.The resulting cyanamide adduct is subsequently condensed with 2-chloro-5-chloromethylpyridine in dimethylformamide (4 volumes) using potassium carbonate as acid scavenger at 95°C for 12 h, generating the chloropyridinyl-thiazolidine intermediate that defines the thiacloprid structural backbone. Agrochemical formulation engineers working from this intermediate target emulsion concentrates (EC) with active ingredient loadings of 240 g/L for foliar application on oilseed rape, pome fruit, and solanaceous crops against pollen beetles, codling moth, and Colorado potato beetle respectively. The final formulated product must comply with FAO Specification 665/EC (June 2018), which requires emulsion stability at 30°C after 24 h dilution in CIPAC Standard Water D (hardness 342 ppm as CaCO₃) with no more than 2 mL cream or 0.5 mL oil separation. A six-batch bridging study comparing the tetrahydrobenzthiazole-derived route to the conventional mercapto-thiazoline pathway indicated equivalent mortality against Myzus persicae at the LC90 level (0.85 mg a.i./L), with no statistical difference in residual activity on Brassica napus leaf surfaces after 72 h of field weathering as measured by GLP-compliant residue dissipation trials per OECD Guideline 509.The substituted thiazole scaffold is also deployed in an alternative synthetic entry toward clothianidin-class nitroguanidine insecticides, where the tetrahydrobenzthiazole ring is oxidatively cleaved using hydrogen peroxide (30% w/w, 2.5 eq) in acetic acid at 55°C to unmask a 1,3-dicarbonyl synthon. This oxidative cleavage step operates within a safety-critical temperature envelope: the onset temperature for exothermic decomposition of the peroxide-acetic acid reaction mixture is measured at 92°C by accelerating rate calorimetry (ARC), mandating a maximum allowable jacket temperature of 65°C and continuous monitoring via redundancy of two independent thermocouples logged at 1-second intervals on a DeltaV DCS platform. The liberated dicarbonyl intermediate is trapped in situ with methylnitroguanidine in the presence of glacial acetic acid and catalytic para-toluenesulfonic acid (0.05 eq) to install the nitroguanidine warhead characteristic of neonicotinoid mode of action. Post-synthetic extractive workup with methyl tert-butyl ether (MTBE, 10 volumes) separates the target from tarry byproducts, and the solvent is recovered by batch distillation at 55°C pot temperature under 350 mbar vacuum to prevent thermal degradation. Wastewater from this sequence bears a chemical oxygen demand (COD) of 18,000–24,000 mg/L and requires pre-treatment via Fenton oxidation (FeSO₄·7H₂O, 3 g/L; H₂O₂ 30%, 12 mL/L; pH 3.0) achieving 82–88% COD reduction before discharge to biological treatment per local consent limits typically set at 800 mg/L COD in bulk drug intermediate manufacturing zones within the Hyderabad Pharma City effluent treatment infrastructure.---The role of sulfur-containing heterocycles as metal-coordinating ligands in polymer-bound catalyst systems relies on the ability of the thiazole nitrogen and exocyclic amine groups to chelate transition metals. In a production context documented in the patent literature for olefin polymerization pre-catalysts, the (S)-2-amino-6-propylamino-4,5,6,7-tetrahydrobenzthiazole scaffold undergoes condensation with salicylaldehyde derivatives to generate tetradentate [ONNO]-type ligands after deprotonation and complexation with titanium(IV) isopropoxide. The ligand synthesis step is conducted in anhydrous ethanol (0.02% H₂O maximum) at reflux (78°C) under argon atmosphere, with the imine formation driven to completion by azeotropic water removal using 3Å molecular sieves in a Soxhlet side-arm configuration. The stoichiometry of ligand-to-metal complexation requires a precise molar ratio of 2.00:1 (ligand:Ti) as confirmed by potentiometric titration of the released isopropanol with Karl Fischer reagent. The resulting pre-catalyst, once activated with methylaluminoxane (MAO) at an Al:Ti molar ratio of 1500:1, demonstrates ethylene polymerization activities of 2,100–2,400 kg PE/mol Ti·h·bar at 50°C and 5 bar ethylene pressure in a stirred 2-L Büchi autoclave (model bmd300, Hastelloy C-22 wetted parts), producing ultra-high molecular weight polyethylene (UHMWPE) with viscosity-average molecular weight (Mv) in excess of 3.2 × 10⁶ g/mol as determined by intrinsic viscosity in decalin at 135°C per ISO 1628-3:2010.Nevertheless, published data for this specific configuration is limited with respect to long-term catalyst stability under continuous slurry-phase operation exceeding 48 h residence time. Operational observations from semi-batch trials indicate that ligand dissociation begins to accelerate at polymerization temperatures above 62°C, as evidenced by reduced polymer bulk density (dropping from 0.41 g/cm³ to below 0.29 g/cm³) and increased fines generation (particle diameter < 75 µm fraction rising to 18% of total yield). The free amine functionality of the tetrahydrobenzthiazole intermediate imposes an additional incompatibility constraint: contact with extraneous water or protic media during ligand synthesis hydrolyzes the titanium isopropoxide precursor into inactive titanium dioxide, dropping catalytic productivity to negligible levels (< 50 kg PE/mol Ti·h·bar). As a result, the ligand preparation and metal complexation stages are executed as a fully integrated sequence within a single glovebox line (O₂ < 0.5 ppm, H₂O < 0.5 ppm) without intermediate isolation. The amine intermediate is charged into the reaction as a freshly dried solid (vacuum oven, 45°C, <1 mbar, 6 h) immediately after removal from desiccated storage.---Oxidative hair dye precursor technology constitutes an established but published-data-limited application domain. Coupling compounds based on 2-amino-tetrahydrobenzthiazole cores react with primary intermediate developers—specifically para-phenylenediamine (PPD) or para-toluenediamine (PTD)—to produce color shades in the indigo-to-black range under alkaline hydrogen peroxide development conditions (pH 10.2 ± 0.3, H₂O₂ 6% w/w in the final cream mixture). The (S)-6-propylamino derivative, when formulated into the base cream of a two-component permanent oxidative hair coloring system, is added at concentrations between 0.8% and 1.5% w/w relative to total cream mass as a shade adjuster to shift the hue angle from red-adjacent brown (H° ≈ 42 in the CIELAB L*C*h° color space) toward neutral or cool brown (H° ≈ 65–78). The development reaction proceeds via nucleophilic attack of the deprotonated coupling agent at the para-position of the quinonediimine intermediate formed from the primary developer. Color fixation occurs within 30 minutes at 22–25°C ambient scalp temperature, after which the cream is rinsed and the dyed hair fibers are shampooed.Toxicological risk assessment for this application follows the SCCS (Scientific Committee on Consumer Safety) Notes of Guidance 12th Revision (SCCS/1647/22), requiring a Margin of Safety (MoS) of at least 100 calculated from the No Observed Adverse Effect Level (NOAEL) in a 90-day repeated-dose oral toxicity study divided by the Systemic Exposure Dose (SED) arising from dermal absorption. A human in vitro skin penetration study compliant with OECD Guideline 428 (validated Franz diffusion cells, dermatomed human skin of thickness 300–400 µm, receptor fluid phosphate-buffered saline with 4% bovine serum albumin, 24 h exposure duration) must demonstrate that the dermal absorption of the tetrahydrobenzthiazole coupling agent does not exceed 0.5 µg/cm² under conditions simulating permanent oxidative dyeing. A known processing incompatibility emerges when the coupling agent cream base is prepared with non-ionic surfactants exhibiting HLB values below 10: the insufficiently solubilized amine precipitates in the alkaline developer vehicle, forming dark specks that translate to visibly uneven dye deposition on hair fibers. Pre-dispersion of the amine coupling agent in a mixture of propylene glycol and ethoxydiglycol (60:40 w/w) at 40°C for 45 min under high-shear mixing (Silverson L5M-A, 5,000 rpm, square-hole high-shear screen) prevents this precipitation and ensures homogeneous tint development. REACH Annex VII data requirements for registration of this intermediate at tonnage bands between 1–10 tonnes/annum include a ready biodegradability assessment (OECD 301F, manometric respirometry), which typically returns a 28-day degradation of 22–35% ThOD for this class of heteroaromatic amines, classifying it as not readily biodegradable and requiring a refined environmental exposure assessment under ECHA Guidance R.16.
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(S)-2-Amino-6-propylamino-4,5,6,7-tetrahydrobenzthiazole, designated under CAS 104632-26-0, constitutes the free base of the non‑ergot dopamine agonist pramipexole. The molecular formula C10H17N3S and a molecular weight of 211.33 g/mol define a tetrahydrobenzothiazole scaffold in which the (S)‑configured 6‑n‑propylamino substituent is responsible for receptor recognition. The compound is supplied as a white to off‑white crystalline powder exhibiting a specific optical rotation of [α]D25 = –67.0° to –69.0° (c = 1.0, methanol) and a melting endotherm onset at 126–130°C by differential scanning calorimetry at 10°C/min under nitrogen. The single crystalline form (Form I) displays characteristic X‑ray powder diffraction peaks at 12.4°, 16.7°, 22.1° 2θ. Chemical purity, determined by reversed‑phase HPLC with UV detection at 264 nm on a C18 column (150 × 4.6 mm, 3 µm), typically exceeds 98.5% area percent, while enantiomeric purity on a chiral stationary phase is controlled to ≥ 99.0% (enantiomeric excess ≥ 98.0%). As the (S)‑enantiomer is the sole pharmacologically active species at dopamine D2‑like receptors, the removal of the (R)‑antipode—generated during the asymmetric hydrogenation or as a configurational drift impurity—is a critical quality attribute. This material serves as both an analytical reference standard for chiral HPLC method validation and as a synthetic intermediate in the preparation of pramipexole dihydrochloride monohydrate, the global active pharmaceutical ingredient described in the United States Pharmacopeia (USP) and European Pharmacopoeia (Ph.Eur.) monographs. Batch release documentation includes assay by HPLC, residual solvents by headspace GC per USP ⟨467⟩, palladium content by ICP‑MS under ICH Q3D, and full impurity profiling against certified reference standards.
Preclinical pharmacological profiling demonstrates a pronounced stereospecific interaction with the dopamine D3 receptor subtype. Competitive radioligand binding assays performed on membrane preparations from Chinese hamster ovary (CHO) cells stably expressing human recombinant D2L and D3 receptors quantify the affinity gap. Using [3H]spiperone at a concentration of 0.5 nM, (S)-2-amino-6-propylamino-4,5,6,7-tetrahydrobenzthiazole inhibits specific binding with a Ki of 0.5 nM at D3 receptors and 3.9 nM at D2L receptors, yielding a D3/D2 selectivity ratio of approximately 8:1. The (R)‑enantiomer, under identical assay conditions, exhibits Ki values exceeding 10,000 nM at both receptor subtypes, confirming complete stereochemical dependence of ligand recognition. Functional coupling at D2L is measured by [35S]GTPγS incorporation in C6 glioma membranes: the (S)‑form stimulates binding with an EC50 of 2.8 nM and intrinsic activity of 90% relative to 10 µM dopamine, while the (R)‑form fails to reach 10% activation at concentrations up to 100 µM. Mitogenesis assays in CHO cells expressing human D3 receptors corroborate the functional bias, giving an EC50 of 0.3 nM for the (S)‑enantiomer. Binding data, corrected for non‑specific binding with 10 µM haloperidol and calculated via the Cheng‑Prusoff equation from Kd values of 0.06 nM (D3) and 0.2 nM (D2L), are summarized in the table below.
| Receptor Subtype | (S)-Enantiomer Ki (nM) | (R)-Enantiomer Ki (nM) | Functional EC50 (nM, S‑form) |
|---|---|---|---|
| D2L (human) | 3.9 | >10,000 | 2.8 ([35S]GTPγS) |
| D3 (human) | 0.5 | >10,000 | 0.3 (mitogenesis) |
| D4.4 (human) | 5.1 | >5,000* | Not determined |
| 5-HT1A (human) | 691 | >10,000 | — |
*Published data for this specific configuration is limited; the value shown reflects the upper bound of the confidence interval from a single determination.
Enantiomeric excess is quantified using a Chiralpak AD‑H analytical column (250 × 4.6 mm, 5 µm particle size) operated under normal‑phase conditions. The mobile phase consists of n‑hexane/ethanol/diethylamine (85:15:0.1 v/v/v), delivered isocratically at a flow rate of 1.0 mL/min. The column compartment is maintained at 30°C, and injection volume is set to 10 µL of a 0.5 mg/mL sample solution in mobile phase. Detection at 264 nm yields retention times of approximately 12.5 min for the (S)‑enantiomer and 14.8 min for the (R)‑enantiomer, with a resolution factor (Rs) consistently above 2.5. System suitability criteria require a relative standard deviation of peak area for five replicate injections not exceeding 1.0%, tailing factor ≤ 1.5 for both enantiomers, and signal‑to‑noise ratio ≥ 10 for a 0.1% spiked (R)‑enantiomer solution. Linearity is assessed from 0.05% to 5.0% (R)‑enantiomer spiked into (S)‑enantiomer, yielding a correlation coefficient (r) of 0.9998; the limit of detection (LOD) is 0.015% and the limit of quantification (LOQ) 0.05% based on signal‑to‑noise ratios of 3 and 10. This procedure aligns with the general principles of Ph.Eur. 2.2.29 and USP ⟨621⟩. The free base is injected directly without derivatization; if the dihydrochloride salt is examined, dissolution in methanol containing 0.5% triethylamine liberates the free base in situ. Pre‑sequence column equilibration with 20 column volumes of mobile phase and blank injections confirmed carryover below 0.01%.
In early‑stage formulation development, the free base offers distinct advantages for organic‑solvent‑based processing, including prodrug synthesis and lipid‑based drug delivery systems. The aqueous solubility of (S)-2-amino-6-propylamino-4,5,6,7-tetrahydrobenzthiazole free base at 25°C is 0.8 mg/mL, whereas pramipexole dihydrochloride monohydrate (CAS 191217-81-9, MW 302.27 g/mol) exhibits a solubility exceeding 20 mg/mL in water. The partition coefficient (log P) of the free base is 1.1, consistent with moderate lipophilicity. The dihydrochloride salt is the form used in commercial immediate‑release and extended‑release tablets; however, its pronounced hygroscopicity—deliquescence occurs above 60% relative humidity at 25°C—complicates handling in non‑aqueous environments. The free base, in contrast, shows a water uptake of only 0.5% after 24 h at 80% RH, making it the preferred input for reductive amination, acylation, or conjugation reactions that demand anhydrous conditions. The ionization behavior is governed by two pKa values: the primary amine at C2 carries a pKa of approximately 9.5, while the propylamino side‑chain nitrogen protonates at 5.0; therefore, the dihydrochloride salt is formed by protonating both sites. A mass correction factor of 1.43 must be applied when formulating a dose equivalent based on free base content: each gram of dihydrochloride monohydrate delivers 0.70 g of free base. This product is supplied exclusively as the free base; laboratories requiring a salt form for analytical reference can generate the dihydrochloride salt in situ with 1 M HCl in diethyl ether followed by recrystallization from ethanol/water. The free base may slowly adsorb atmospheric carbon dioxide, forming a surface carbamate that diminishes solubility; accordingly, headspace oxygen and moisture are excluded during packaging.
In addition to enantiomeric purity, the profile of achiral organic impurities is scrutinized by gradient reversed‑phase HPLC using a C18 column (150 × 4.6 mm, 3 µm) with a mobile phase composed of phosphate buffer (pH 3.0) and acetonitrile, ramped from 5% to 60% organic over 30 min at 1.0 mL/min. The primary process‑related impurity, (S)-2,6-diamino-4,5,6,7-tetrahydrobenzthiazole (despropyl pramipexole), elutes at a relative retention time of approximately 0.45 and is limited to ≤ 0.15% area. The 4,5,6,7‑tetrahydrobenzothiazole dimer, formed under excessive thermal stress during the amination step, elutes near relative retention time 2.1 and is controlled to ≤ 0.10%. Any other unspecified impurity is limited to ≤ 0.10%, with a total impurities acceptance criterion of ≤ 1.0%. The free base is stable under the described HPLC conditions; no on‑column epimerization or degradation is observed in solution over 24 h at room temperature.
Residual solvents in the final product are monitored according to ICH Q3C guidelines. The manufacturing process employs methanol, ethanol, ethyl acetate, dichloromethane, and n‑hexane—all Class 2 solvents with established permitted daily exposure limits. Headspace gas chromatography with flame ionization detection, performed on a DB‑624 column (30 m × 0.32 mm, 1.8 µm film thickness) with a split ratio of 1:5 and an inlet temperature of 200°C, quantifies these solvents against external reference standards. Post‑synthesis vacuum drying at 50°C and 10 mbar for 12 hours reduces individual solvent concentrations to levels below the limits presented in the following table.
| Solvent | ICH Class | Concentration Limit (ppm) | Typical Result (ppm) |
|---|---|---|---|
| Methanol | 2 | 3000 | <100 |
| Dichloromethane | 2 | 600 | <40 |
| Ethyl acetate | 2 | 5000 | <150 |
| Ethanol | 2 | 5000 | <200 |
| n‑Hexane | 2 | 290 | <10 |
Palladium originating from the heterogeneous hydrogenation catalyst (Pd/C, 5% loading) employed during reduction of the tetrahydrobenzothiazole intermediate is controlled as an elemental impurity under ICH Q3D. Inductively coupled plasma mass spectrometry (ICP‑MS) following microwave digestion in concentrated nitric acid routinely measures palladium at <10 ppm, well below the oral permitted daily exposure of 100 µg/day for a 10 mg dose. The product is packaged in double polyethylene bags inside an aluminum‑laminated foil pouch under dry nitrogen and should be stored at 2–8°C with protection from light. Under these conditions, retest intervals of 24 months are assigned, based on real‑time stability data showing no significant change in enantiomeric purity or total impurities. Avoid storage in areas with elevated carbon dioxide concentrations, as gradual carbamate formation at the primary amine can alter chromatographic retention behavior and reduce the free base purity.
