S-(2-Dimethyl Amino Methyl)-4-Thiazole Methyl Isothiourea Dihcl
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HS Code |
732305 |
| Chemical Name | S-(2-Dimethyl Amino Methyl)-4-Thiazole Methyl Isothiourea Dihcl |
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| Packing | 100g of S-(2 - Dimethyl Amino Methyl)-4 - Thiazole Methyl Isothiourea Dihcl in sealed chemical - grade bag. |
| Shipping | The chemical "S-(2 - Dimethyl Amino Methyl)-4-Thiazole Methyl Isothiourea Dihcl" should be shipped in well - sealed containers, following all hazardous chemical regulations. Ensure proper labeling and handling to prevent spills during transit. |
| Storage | Store “S-(2 - Dimethyl Amino Methyl)-4-Thiazole Methyl Isothiourea Dihcl” 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. Avoid storing near incompatible substances. |
In the commercial synthesis of the H₂-receptor antagonist nizatidine—an active pharmaceutical ingredient listed in the USP monograph under the chemical name N-[2-[[[2-[(dimethylamino)methyl]-4-thiazolyl]methyl]thio]ethyl]-N′-methyl-2-nitro-1,1-ethenediamine—S-(2-Dimethylamino methyl)-4-thiazole methyl isothiourea dihydrochloride functions as a direct latent thiol equivalent, eliminating the need for handling free thiol in bulk. A 2,000 L DIN 28136-compliant glass-lined reactor, equipped with a retreat-curve impeller and a jacket rated for −15 °C to 200 °C, receives the crystalline dihydrochloride salt (HPLC purity ≥99.5%, water ≤0.2% by USP <921> Method Ic) in a charge that corresponds to 102–105 kg of free thiol equivalent. The solid is suspended in 8.0 L of deionized water per kilogram of salt and purged with pharmaceutical-grade nitrogen (99.999%, O₂ <1 ppm) through a sintered sparger for 45 minutes to maintain a residual oxygen headspace concentration below 0.5% v/v, verified by an in-line ASTM E3244-21 paramagnetic analyzer. The jacket is then fed with chilled brine to hold the internal temperature at 5 °C ± 1 °C, and 30% w/w sodium hydroxide solution is metered at a rate not exceeding 0.5 L/min to raise the pH to 12.8–13.1, which represents 2.40–2.55 molar equivalents based on the salt. After 60–75 minutes of hydrolysis confirmed by the disappearance of the isothiourea peak at relative retention 0.63 on a C18 column (250 × 4.6 mm, 5 μm) with a mobile phase of acetonitrile/0.05 M phosphate buffer pH 3.0 (25:75 v/v) run at 1.0 mL/min, the liberate thiol solution is transferred over 90 minutes into a second identical reactor containing a pre-dissolved hydrochloride salt of the N-[2-(methylamino)ethyl]-N′-methyl-2-nitro-1,1-ethenediamine side chain (1.00 molar equivalent) in water–isopropanol (70:30 v/v) at 2 °C. The molar ratio of thiol to electrophile is strictly maintained at 1.02:1.00 to restrict the formation of the sulfide-bridged dimer impurity, which must be held at ≤0.10% area by the in-house release method harmonized with USP Organic Impurities Procedure 1. Crude nizatidine base is extracted with dichloromethane, the organic layer washed with 15% brine, concentrated under vacuum at a bath temperature no higher than 40 °C, and recrystallized twice from 95% ethanol with 0.5% w/w activated charcoal treatment to yield Form I crystalline nizatidine (≥99.8% purity). The API synthesized via this route is compressed into 150 mg and 300 mg film-coated tablets and filled into hard gelatin capsules, all required to meet USP <711> dissolution criteria (Q ≥80% in 30 min at pH 1.2). Residual solvent levels comply with ICH Q3C Option 2, with isopropanol ≤5000 ppm, dichloromethane ≤600 ppm, and ethanol ≤4000 ppm; elemental contaminants conform to ICH Q3D Draft Guideline, with palladium ≤5 ppm and nickel ≤1 ppm based on USP <232> permitted daily exposures.What governs the alkylation selectivity when the thiol couples with (Z)-4-halo-2-butenoate esters in lafutidine manufacture?In lafutidine hydrochloride production—an H₂-receptor antagonist under the JAN designation and compliant with the Japanese Pharmacopoeia (JP) monograph—the same isothiourea dihydrochloride serves as the 4-mercaptomethyl precursor, but the downstream conjugation demands radically different pH-stat conditions to suppress vinylogous hydrolysis of the α,β-unsaturated ester. The thiol is generated in situ using the same hydrolysis protocol as described for nizatidine; however, the aqueous thiolate stream is adjusted to a lower operational pH of 9.5 ± 0.3 with 10% phosphoric acid before being combined with a solution of (Z)-4-bromo-2-butenoic acid methyl ester (1.00 equivalent) in tetrahydrofuran containing 2.5 mol% tetrabutylammonium bromide as phase-transfer catalyst. The mass ratio of thiol to ester is controlled at 1.08:1.00 to offset side reactions with trace hypobromite formed under ambient light; the jacketed reactor fitted with a blue-light-filtered sight glass and an ISO 4589-2 oxygen-index-monitored nitrogen blanket maintains a batch temperature of 0–5 °C during the 3-hour addition. Process analytical technology (ReactIR, DiComp probe) tracks the disappearance of the ester carbonyl stretch at 1724 cm⁻¹ in real time, triggering a sequential addition of 5 N sodium hydroxide to hydrolyze the methyl ester to the corresponding carboxylic acid at 10 °C without isolating the thioether intermediate. The resulting acid is activated with 1.2 equivalents of N,N′-carbonyldiimidazole in DMF at −5 °C and condensed with 2-[(2-furylmethyl)sulfinyl]acetamide. Lafutidine base is crystallized from ethyl acetate–hexane (4:1 v/v) to obtain crystals of ≥99.5% chromatographic purity, which are then converted to the hydrochloride salt in ethanolic HCl. Terminal pharmaceutical forms are 5 mg and 10 mg immediate-release tablets complying with JP <6.10> dissolution (paddle method, 900 mL pH 1.2 fluid, 50 rpm, ≥85% released in 15 minutes). Impurity profiling of the final substance includes a tight limit of ≤0.15% for the des-furylmethyl analog arising from over-reduction, enforced by a validated HPLC method using a porous graphitic carbon column operated at 45 °C. The overall process yield calculated from the isothiourea salt is capped at 72–78% because of the deliberate sacrificial excess of thiol; attempts to lower the ratio below 1.05 equivalents have been observed in pilot-scale campaigns to generate the bromohydrin ether impurity at levels exceeding 0.3%, necessitating a secondary reslurry in acetone.Effluent gas scrubbing of methyl mercaptan during tank-farm scale thiol liberationWhen the thiazole isothiourea salt is hydrolyzed on a multi-ton scale in a manufacturing plant that operates under US EPA 40 CFR Part 63 hazardous air pollutant standards, the off-gas stream containing 250–400 ppmv of methyl mercaptan (measured by EPA Method 18 via gas chromatography with flame photometric detection) must be treated in a dedicated packed-bed scrubber prior to release. The scrubber column, typically 3.0 m in height with 0.6 m internal diameter and packed with 25 mm polypropylene Pall rings, circulates 15–20% w/w sodium hypochlorite solution at a flow rate of 8–12 m³/h driven by a magnetically coupled centrifugal pump. The hydrolysis batch (3,000–5,000 L scale) is blanketed with nitrogen and the headspace is drawn through a condenser operating at −10 °C before entering the scrubber at a superficial velocity of 0.8–1.2 m/s. The oxidation of methyl mercaptan to methyl sulfonate requires a molar ratio of hypochlorite to odorant of at least 3.5:1, maintained by an inline oxidation-reduction potential probe set to +720 mV (Ag/AgCl reference) that cascades to a sodium hypochlorite dosing pump. Under these conditions, destruction efficiency consistently exceeds 99.8%, and the exhaust stack can meet a ground-level concentration threshold of <2 ppb as dictated by local nuisance odor regulations. The caustic hydrolysis step itself uses 2.5 equivalents of 50% w/w NaOH relative to the dihydrochloride, added via a side-arm injection nozzle at a rate limited by the jacket heat-removal capacity of approximately −30 kW/m³ for the glass-lined vessel, ensuring that the transient exotherm never pushes the internal temperature beyond 15 °C. This setup integrates directly with the downstream nizatidine or lafutidine coupling described previously, treating the liberated thiol as a captive intermediate without inventorying the hazardous thiol liquid.A development-scale route where the isothiourea dihydrochloride is deliberately used to generate and isolate 2-(dimethylaminomethyl)-4-mercaptomethylthiazole hydrochloride as a white to off-white crystalline solid has been transferred to multiple contract manufacturing organizations operating under ISO 9001:2015 and audited against the ICH Q7 guidance for active pharmaceutical ingredient starting materials. The hydrolysis is performed in deionized water with 2.2 equivalents of 37% hydrochloric acid added at 20–25 °C to keep the thiol product in its protonated, less odoriferous form, followed by extraction into purified ethyl acetate and precipitation by adding 2.5 volumes of n-heptane at 0 °C. The isolated yield after vacuum drying at 35 °C for 16 hours is 88–92% with a thiol content of >97% by iodometric titration. This solid intermediate serves as a convenience item for laboratories that require the thiol in pre-weighed, oxygen-protected ampoules for parallel library synthesis of H₂-antagonist analogs; the specification sheet lists a limit of ≤0.50% disulfide dimer (HPLC, 210 nm) and a palladium content <2 ppm complying with typical catalyst-metal budgets for early-phase drug candidates. End-user applications span the preparation of exploratory N-substituted thioethers destined for receptor-binding screening in histamine H₂ and H₃ modulation programs.If the downstream sequence requires transient masking before late-stage deprotectionCertain convergent schemes for polyfunctional thiazole antifungal or antineoplastic candidates exploit the isothiourea entity as an acid-stable S-protecting group that survives transformations at the dimethylaminomethyl tertiary amine. In one documented kilogram-scale campaign for a proprietary azole derivative, the dihydrochloride salt was coupled with a side chain bearing a terminal mesylate in anhydrous dimethylacetamide containing 1.5 equivalents of potassium carbonate at 40 °C for 18 hours under a nitrogen atmosphere, forming the protected thioether with >85% conversion. The S-isothiuronium linkage remained intact during a subsequent Suzuki–Miyaura cross-coupling step employing Pd(dppf)Cl₂ (2 mol%) in a THF–water mixture at 65 °C, where a free thiol would have instantly poisoned the palladium catalyst by forming non-labile Pd-S clusters evident as a black precipitate. To liberate the target thiol for final elaboration, the crude product was treated with 0.5 M sodium methoxide in methanol at ambient temperature for 4 hours, a deprotection step that releases the thiolate with concomitant formation of dimethylcyanamide as a volatile byproduct, which was removed by repeated chase distillation with toluene. The operational boundary is narrow: residual water content of the sodium methoxide solution must remain below 0.1% to avoid regenerating methyl mercaptan via premature hydrolysis of the isothiourea. The final compound was isolated as a hydrochloride salt with 96.5% purity suitable for in vivo toxicology studies under a standard GLP protocol. This masking strategy has been cited in regulatory starting material justifications submitted to the US FDA under 21 CFR 314.50 to demonstrate that the isothiourea constitutes a well-characterized intermediate with a comprehensive impurity fate map.Pharmacopoeia-aligned quality attributes and cross-site analytical benchmarkingA comparison of the critical quality attributes mandated for the dihydrochloride intermediate when intended for nizatidine versus lafutidine full-scale synthesis reveals distinct impurity concerns that directly impact downstream processing robustness. The table below captures the main acceptnace criteria applied across the two supply chains.
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The compound S-(2-dimethylaminomethyl)-4-thiazolemethyl isothiourea dihydrochloride (C8H16Cl2N4S2, 303.3 g·mol−1) is a synthetic isothiourea derivative bearing a 2,4-disubstituted thiazole core. The molecule incorporates a tertiary dimethylamino side chain at the thiazole 2-position and an S-methyl-linked isothiourea group at the 4-position, supplied as the dihydrochloride salt to enhance aqueous solubility and long-term solid-state stability. Its primary utility resides in pharmacological receptor characterization, where it serves as a potent histamine H2 receptor agonist for in vitro functional and binding assays. The substitution pattern introduces a hydrogen-bond-accepting thiazole ring that is absent in the simpler alkylisothiourea tool compound dimaprit, altering both receptor affinity and protonation behavior of the aliphatic nitrogen. The compound is typically >98% pure by reversed-phase HPLC and requires storage at −20 °C under dry argon to prevent hydrolytic degradation of the isothiourea moiety.
| Parameter | Method | Acceptance Criteria |
|---|---|---|
| Appearance | Visual inspection | White to off-white crystalline powder |
| Identity | 1H NMR (400 MHz, D2O) | Characteristic resonances at δ 2.92 (s, 6H, N(CH3)2), 4.51 (s, 2H, CH2N), 4.69 (s, 2H, CH2S), 7.64 (s, 1H, thiazole H5) |
| Purity | HPLC (Phenomenex Luna C18(2), 250 × 4.6 mm, 5 µm; gradient acetonitrile/water 0.1% TFA, 1.0 mL·min−1, 220 nm) | ≥98.0% area |
| Water content | Karl Fischer titration, USP ⟨921⟩ Method Ia | ≤2.0% w/w |
| Heavy metals | ICP-MS | ≤10 ppm |
| Residual solvents | Headspace GC, ICH Q3C | Conforms |
Solubility in phosphate-buffered saline (pH 7.4) exceeds 50 mg·mL−1 as the dihydrochloride; however, the isothiourea group undergoes slow hydrolysis under alkaline conditions. In 50 mM Tris-HCl (pH 8.0) at 25 °C, a 10 mM stock exhibits a pseudo-first-order degradation rate constant of approximately 0.003 h−1, translating to a half-life near 230 h. Inclusion of chelating agents such as 1 mM EDTA does not alter the degradation profile, indicating that trace metals do not catalyze the decomposition. Pre-formulation screening further demonstrates that 10% (v/v) dimethyl sulfoxide (DMSO) stock solutions stored at −80 °C remain viable for 4 weeks when headspace is purged with argon. Use of carbonate-based buffers is discouraged: the nucleophilic bicarbonate ion accelerates isothiourea cleavage, reducing recovery to < 40% after 24 h.
In pharmacological profiling, the compound is frequently benchmarked against dimaprit (S-[3-(dimethylamino)propyl]isothiourea dihydrobromide) to discriminate contributions of the thiazole spacer. The 2-dimethylaminomethyl group lowers the calculated pKa of the tertiary nitrogen to approximately 7.2, meaning that at physiological pH a substantial fraction of the molecule populates the unprotonated state, whereas dimaprit’s dimethylamino group (pKa ~9.0) remains largely cationic. This shift influences membrane permeability and the desolvation penalty upon receptor binding. In cAMP accumulation assays using CHO-K1 cells stably expressing the human H2 receptor, the thiazole-containing analog generates a concentration-response curve that is left-shifted relative to dimaprit; published head-to-head EC50 values from a single assay platform are limited, although structure-activity modeling indicates that the thiazole ring contributes an additional hydrogen bond with a tyrosine residue in transmembrane helix 3, raising calculated binding energy by −1.8 kcal·mol−1. Practically, this means the compound elicits half-maximal response at lower extracellular concentrations, reducing the quantity required for screening workflows.
Area-percent purity by UV-detected HPLC, while essential, does not distinguish co-eluting isobaric impurities or quantify inorganic counterions that may shift apparent potency in biological assays. For that reason, batch release includes ion chromatography (IC) with suppressed conductivity detection to verify chloride stoichiometry. A Dionex ICS-2100 system equipped with an IonPac AS19 column (4 × 250 mm) and a 20 mM KOH eluent confirms a chloride mass fraction of 23.4 ± 0.3% (theoretical 23.4% for the dihydrochloride). Further, 1H-13C HSQC NMR at 600 MHz provides a fingerprint of the carbon-proton correlations across the thiazole and isothiourea units; the diagnostic 13C shifts of the thioureido carbon (δ ~168 ppm) and the thiazole C2 (δ ~164 ppm) are monitored. For high-sensitivity applications, ultra-high-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry (UHPLC-QTOF, Agilent 6545) with electrospray ionization in positive mode yields an [M+H]+ ion at m/z 231.0738 (Δ < 2 ppm) and key fragment ion at m/z 46.065 corresponding to the dimethylimmonium cation. This accurate-mass data confirms molecular identity without ambiguity and can be used to cross-validate any lot suspected of oxidative impurities.
When employed as a displacing ligand in radioligand binding experiments with [3H]tiotidine on rat brain cortical membranes, the compound demonstrates rapid association kinetics and complete displacement at 100 µM. Membrane preparations are resuspended in 50 mM Tris-HCl (pH 7.4, 10 mM MgCl2) and incubated with increasing concentrations (0.1 nM – 100 µM) of the isothiourea dihydrochloride for 60 min at 25 °C. Non-specific binding is defined by 100 µM unlabeled tiotidine. The dihydrochloride salt’s high aqueous solubility allows construction of a full dose-response from a single aqueous stock, eliminating DMSO vehicle artifacts that often distort binding curves above 1% (v/v) organic co-solvent. Nevertheless, the free isothiourea group is reactive toward thiols; assays that routinely include 1 mM dithiothreitol (DTT) as a reducing agent show a 30–40% loss in specific binding signal after 2 h of pre-incubation at 37 °C. For this reason, assay buffers are prepared with 0.1% (w/v) bovine serum albumin as an alternative antioxidant, and the compound is added within 30 min of initiating the binding reaction.
Reconstitution at 100 mM in neat anhydrous DMSO followed by stepwise dilution into serum-free culture medium yields final DMSO concentrations down to 0.1% (v/v) for typical EC50 determinations; at this concentration, no reduction in cell viability is observed over 48 h when measured by MTT assay in HEK293 or HepG2 lines. Concentrations above 0.5% DMSO produce an approximately 12% drop in mitochondrial reductase activity, necessitating vehicle-matched controls. Furthermore, the dihydrochloride salt is hygroscopic; vials opened in ambient humidity above 60% RH gain mass up to 4% within 15 min. Pre-weighing must therefore be executed inside a dry-nitrogen glove bag, and the powder desiccated over phosphorus pentoxide overnight before use if ambient exposure exceeds 5 min. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) of cell lysates from treated cultures reveals no non-specific protein adduct formation when the compound is incubated at 10 µM for 24 h, distinguishing it from older methylisothiourea derivatives that covalently modify cysteine residues in albumin. This absence of detectable adducts, confirmed via LC-MS/MS peptide mapping, supports its suitability for long-term receptor desensitization studies without confounding off-target protein alkylation.
