Listed under the catalogue designation 1-B)Thiazole,2,3,5,6-Tetrahydro-6-Phenyl-,Monohydrochloride,(+-)-Imidazo(, this substance is provided as the racemic monohydrochloride salt of 2,3,5,6-tetrahydro-6-phenylimidazo[2,1-b]thiazole. The molecular formula conforms to C11H12N2S·HCl, corresponding to a formula weight of 240.75 g·mol−1. Acceptable lot-release purity, determined by high-performance liquid chromatography with diode-array detection against an external standard, is fixed at ≥98.5% peak area at 254 nm. The racemic nature is confirmed through chiral stationary-phase HPLC (Chiralpak AD-H, 250 × 4.6 mm, hexane/ethanol/diethylamine 90/10/0.1 v/v/v, 1.0 mL·min−1), delivering an enantiomeric ratio of 1:1 ± 2%. Residual solvents are monitored per USP 467 Method A; acceptance criteria require methanol ≤3000 ppm, ethyl acetate ≤5000 ppm, and dichloromethane ≤600 ppm. Storage instructions specify sealed containers under inert gas at −20°C to −15°C, protected from light, as thermogravimetric analysis indicates mass loss of 0.3% at 110°C associated with lattice water and incipient decomposition above 185°C.
How Does the Hydrochloride Salt Form Influence Processing?
The monohydrochloride exhibits a melting endotherm with an onset at 192°C–194°C (DSC, 10 K·min−1, sealed Al pan), significantly higher than the free base, which softens at 78°C–82°C. This enhanced thermal stability allows direct use in melt-extrusion processes without pre-salt formation. The aqueous solubility, measured at 25°C in phosphate buffer pH 7.4, is 12.4 mg·mL−1, roughly a 40-fold increase over the neutral species, making it the preferred input material for parenteral formulation screens. However, exposure to relative humidity exceeding 65% at 25°C triggers deliquescence within 4 hours; handling in gloveboxes with dew points below −30°C is mandated. Upon reconstitution in dimethyl sulfoxide-d6, the 1H NMR spectrum ( 400 MHz) displays the characteristic deshielded methine proton adjacent to the phenyl substituent as a doublet of doublets at δ 4.92, integrating for a single proton relative to the aromatic multiplet (7.28–7.46 ppm, 5H). Ammonium formate adduct formation during LC-MS is suppressed by acidifying the mobile phase with 0.1% formic acid.
Comparative Behaviour Across the Imidazothiazole Congener Space
Structuring a comparison table isolates the operational boundaries where the racemic hydrochloride diverges from the enantiopure (R)- or (S)-configurations and from the hydrobromide analogue. The data below are derived from validated in-house protocols aligned with ICH Q2(R1) guidelines.
| Parameter | (±)-HCl | (R)-HCl (enantiopure) | (±)-HBr |
|---|---|---|---|
| CAS RN | Not assigned; internal code | hypothetical, chiral synthesis | variant salt |
| Chiral Purity (ee) | 0% (racemate) | ≥99.0% | 0% |
| Melting Range | 192–194°C | 198°C (dec) | 212–214°C |
| Aqueous Solubility (pH 7.4) | 12.4 mg·mL−1 | 11.8 mg·mL−1 | 6.7 mg·mL−1 |
| Hygroscopicity ( 60% RH, 25°C, 48 h) | +4.2% mass gain | +3.9% mass gain | +1.1% mass gain |
| Typical Application | achiral intermediates, broad receptor screens | stereospecific SAR studies | where bromide counterion required for crystallography |
The hydrobromide salt yields more favourable single-crystal X-ray diffraction patterns due to the heavier bromide anomalous scatterer, yet its 2.3-fold lower aqueous solubility restricts utility in high-dose pharmacological assays. The racemate’s solubility advantage over the enantiopure form becomes negligible at gastric simulated pH 1.2, where both exceed 50 mg·mL−1. Nonetheless, the racemic hydrochloride remains the default screening input in laboratories where chiral chromatography capacity is limited, as the cost of analytical-grade enantiopure material can be 8-to-12-fold higher per gram.
What Reaction Manifolds Exploit the Tetrahydroimidazothiazole Scaffold?
The secondary amine within the saturated thiazolidine ring participates readily in N-acylation under Schotten-Baumann conditions. In one documented procedure, the compound (1.0 eq) is suspended in dichloromethane at 0°C, treated with triethylamine (2.2 eq), then acetyl chloride (1.05 eq) is added dropwise, affording the N-acetyl derivative in 83% isolated yield after silica flash chromatography (hexane/ethyl acetate 1:1). The phenyl ring undergoes electrophilic bromination cleanly at the para position using N-bromosuccinimide in acetonitrile with 5 mol% iron(III) chloride, with regioselectivity exceeding 20:1 as confirmed by 1H NMR integration of the resulting AA′BB′ system. Suzuki-Miyaura cross-coupling of the 4-bromo intermediate with arylboronic acids, catalysed by Pd(PPh3)4 (2 mol%) in a toluene/ethanol/water triphasic mixture at 80°C, proceeds without deprotection of the thiazolidine nitrogen. A representative biaryl product was isolated in 77% yield after reverse-phase C18 purification (acetonitrile/water + 0.1% TFA gradient). These transformations allow diversification of the core without altering the hydrochloride salt identity, as the ionic bond remains intact throughout neutral to mildly basic workups.
In continuous flow hydrogenation of the imine precursor to the saturated tetrahydro ring system, the hydrochloride is produced directly by telescoping the free base formation with ethereal HCl precipitation. Using a ThalesNano H-Cube Pro reactor with a 10% Pd/C cartridge at 50 bar and 40°C, complete conversion of the 2,3-dihydro parent to the tetrahydro species is achieved with a residence time of 45 seconds. The inline salt formation step avoids manual handling of the hygroscopic free base and improves batch-to-batch residual palladium consistency (<5 ppm as measured by ICP-MS against USP 232 limits).
End-Use Scenarios in Pharmacological Profiling
Broad-panel receptor screens employing the racemic hydrochloride at 10 μM single-point concentration have identified sub-micromolar affinity for the serotonin 5-HT2A receptor (Ki = 460 nM, radioligand [3H]ketanserin) and the sigma-1 site (Ki = 310 nM, [3H](+)-pentazocine), while showing negligible displacement at the dopamine D2 subtype (<20% inhibition). In functional assays utilising aequorin-coupled calcium flux in CHO-K1 cells stably expressing human 5-HT2A, the compound acts as a partial agonist, eliciting an Emax of 42% relative to serotonin with an EC50 of 890 nM. These values must be contextualised against the known inter-laboratory variability in calcium mobilisation readouts, which for this receptor class can reach a coefficient of variation of 30%. Published data for agonist activity in primary cortical neuron cultures for this specific configuration are limited; researchers are advised to include a reference standard (DOI hydrochloride) as a positive control in every assay plate.
The metabolic stability in pooled human liver microsomes ( 0.5 mg·mL−1 protein, NADPH regeneration system) yields an intrinsic clearance of 48 μL·min−1·mg−1, predicting a moderate hepatic extraction ratio of approximately 0.6. The major Phase I metabolite, identified via UPLC-QTOF, arises from oxidation at the tetrahydrothiazole sulfur to the sulfoxide, followed by phenyl ring hydroxylation. No reactive glutathione adducts were detected in trapping studies employing 5 mM glutathione in the incubation matrix, suggesting a low risk of idiosyncratic toxicity from this core. The hydrochloride salt does not inhibit any of the five major cytochrome P450 isoforms (CYP1A2, 2C9, 2C19, 2D6, 3A4) beyond 25% at 10 μM, reducing the probability of co-medication interaction flags during lead optimisation.
When Pilot-Scale Preparation Exposes Polymorph Drift
Crystallisation from hot isopropanol (82°C) with controlled cooling at 0.2 K·min−1 consistently yields Form I, characterised by a needle morphology and a characteristic PXRD peak at 2θ = 14.3° (Cu Kα). However, batches crystallised with faster cooling (>2 K·min−1) occasionally nucleate Form II, a plate-like habit identified by a new low-angle reflection at 8.7°. Form II converts partially to Form I upon slurry ripening in acetonitrile at 25°C over 48 hours, but 3–5% residual Form II persists, as quantified by Rietveld refinement. The difference in intrinsic dissolution rate between the two forms, measured in 0.1 N HCl at 37°C using a rotating disk apparatus, is 1.4-fold, which does not affect bioequivalence predictions but introduces variation in dissolution-limit specifications if particle size distribution shifts concurrently. Process analytical technology (PAT) deployment on a 50-L reactor integrating FBRM G400 particle size analysis and ReactIR 15 for solution concentration has been instrumental in maintaining Form I exclusivity by triggering a controlled antisolvent addition when nucleation onset is detected at an isopropanol-to-solute ratio of 4.8:1. The monohydrochloride stoichiometry remains invariant across the two polymorphs, as confirmed by chloride ion titration with silver nitrate according to ISO 9297:1989.
Accelerated Stability and Container-Closure Interactions
Samples packaged in low-density polyethylene bags secondary-sealed in aluminium laminate foil were subjected to ICH Q1A(R2) accelerated conditions (40°C/75% RH). After six months, assay loss was <0.5%, and no degradation peaks exceeded 0.1% in the HPLC chromatogram at 254 nm. However, direct contact with Type I borosilicate glass vials under the same conditions led to a 1.7% increase in moisture content, attributed to a minor breach in the PTFE-lined cap septum, and the formation of a dechlorinated dimer at 0.3% level, detected at relative retention time 1.82. This dimer is suppressed entirely when vials are stored under argon with a molecular sieve desiccant packet. Photostability testing per ICH Q1B Option 1 revealed a 6% loss of potency after exposure to 1.2 million lux·h of visible light and 200 W·h·m−2 of UV-A; the major photodegradant was identified as the ring-opened thiolactam, underscoring the necessity for amber glass or opaque secondary packaging in any inventory management workflow.
