2-Isopropyl-4-(Methylaminomethyl)Thiazole Dihydrochloride
|
HS Code |
741946 |
| Chemical Formula | C9H19Cl2N3S |
| Molar Mass | 274.24 g/mol |
| Appearance | Typically a solid |
| Solubility In Water | Soluble to some extent |
| Physical State At Room Temperature | Solid |
| Odor | May have a characteristic odor |
| Melting Point | Specific value depending on purity |
| Boiling Point | Data varies with conditions |
| Density | Depends on form and purity |
| Ph In Solution | Can affect solution pH |
As an accredited 2-Isopropyl-4-(Methylaminomethyl)Thiazole Dihydrochloride factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100 - gram pack of 2 - Isopropyl - 4 - (Methylaminomethyl)Thiazole Dihydrochloride in sealed container. |
| Shipping | 2 - Isopropyl - 4 - (methylaminomethyl)thiazole dihydrochloride is shipped in containers suitable for chemicals. Packaging ensures protection from moisture and damage during transit, following strict safety regulations for chemical shipments. |
| Storage | Store 2 - Isopropyl - 4 - (Methylaminomethyl)Thiazole Dihydrochloride 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 degradation. Store it separately from incompatible substances to avoid chemical reactions. Follow proper safety regulations for handling and storing this chemical. |
How Does This Thiazole Dihydrochloride Function as a Building Block in Gastrointestinal Therapeutics?In the synthesis of histamine H2 receptor antagonists and structurally related H3 receptor modulators, 2-isopropyl-4-(methylaminomethyl)thiazole dihydrochloride serves as a protected secondary amine equivalent. The free base, generated in situ by treatment with a stoichiometric amount of aqueous sodium hydroxide (1.05 molar equivalents, 10% w/w solution) at 0–5 °C, is immediately reacted with a carboxyl-activated fragment to construct the pharmacophore. Typical coupling partners include 4-sulfamoylbenzoyl chloride or furfurylthioacetic acid derivatives; the former is condensed in anhydrous dichloromethane under nitrogen, employing a triethylamine scavenger (1.1 eq.) and maintaining an internal temperature below 5 °C to suppress bis-alkylation. The process yields a thiazole-sulfonamide intermediate that, after catalytic hydrogenation or further functionalization, delivers the active pharmaceutical ingredient. Downstream steps are governed by ICH Q7 GMP guidelines for active pharmaceutical ingredients; residual thiazole starting material is controlled to ≤0.10% by HPLC (area%, 210 nm) using a C18 column and a phosphate buffer–acetonitrile gradient per the general monograph of USP <621>. The dihydrochloride’s hygroscopicity demands handling in a relative-humidity-controlled environment (≤30% RH) and Karl Fischer titration (USP <921>) is run on every incoming lot, with a water specification of ≤0.5% w/w. A forced degradation study performed at 40 °C/75% RH over 14 days reveals trace N-demethylation (0.08% area) and the formation of a dimeric impurity that is routinely monitored by LC-MS with a reporting threshold of 0.05%. Purge factors according to ICH M7 (Option 4) are calculated based on the reactivity of the methylaminomethyl side chain, and no dedicated genotoxic impurity control strategy is required when the process includes an aqueous bisulfite wash that scavenges any liberated formaldehyde. The final crystallized intermediate—typically a hydrochloride salt polymorph with a melting endotherm at 178–182 °C (DSC, 10 °C/min, ASTM E537)—meets bulk purity specifications of ≥99.5% and is drummed under argon for shipment to ethical pharmaceutical manufacturers.Thiazole-Carboxamide Fungicide Precursors and Their Process IntensificationThe amine handle of the title compound enters acylation with 2-chloronicotinoyl chloride or difluoromethylthioacetyl chloride to form intermediates en route to succinate dehydrogenase inhibitor (SDHI) fungicides. In a 500-L glass-lined vessel, the neutralized free base (1.0 eq.) is dissolved in ethyl acetate together with 1.05 eq. of triethylamine; the acyl chloride is metered at 10–15 °C over 90 minutes. A continuous-flow variant using a Corning® Advanced-Flow™ reactor (G1 module, 0.5 mm channel) achieves residence-time distribution of <15 s at 25 °C and reduces the N,O-bis-acetylated by‑product from 3.2% to 0.4% (HPLC area%, 254 nm) relative to the batch process. The amide intermediate is subsequently cyclized with Lawesson’s reagent or P2S5 in toluene at reflux to yield the 1,3,4-thiadiazole or thiazole carboxamide scaffold. Table 1 compares yield and purity profiles across three different bases tested in the acylation step.
When This Dihydrochloride Becomes a Diazotising ComponentDiazotisation of 2-isopropyl-4-(methylaminomethyl)thiazole dihydrochloride dissolved in 85% phosphoric acid with 40% w/w nitrosylsulfuric acid at −5 to 0 °C yields a stable diazonium salt that couples readily with N,N-diethyl-m-toluidine or 3-(N-ethylanilino)propionitrile. The coupling is conducted in ice-water slurry at pH 2.5–3.0, adjusted with sodium acetate, and held for 4 hours to complete precipitation of the azo dye. The resultant heterocyclic disperse dye, isolated as a dark blue powder, builds up on polyester fabric at 1.0% owf in a high-temperature exhaust dyeing cycle (130 °C, 45 min, liquor ratio 1:15) to a K/S (Kubelka-Munk) value of 22 measured at λmax 608 nm (D65 illuminant, 10° observer). Sublimation fastness tested according to ISO 105-P01 at 210 °C/30 s rates 4, whereas wash fastness (ISO 105-C06 C2S) reaches 4–5 and light fastness (ISO 105-B02, xenon arc) stands at 6 at standard depth. Table 2 collects performance data for three coupling variations explored during formulation screening.
Processing Window Extension in NR/BR Compounds via Novel Sulfenamide AcceleratorsNeutralisation of the dihydrochloride liberates the secondary amine, which is amenable to oxidative condensation with monocyclohexylamine and sulfur monochloride to produce a sulfenamide accelerator structurally analogous to N-cyclohexyl-2-benzothiazole sulfenamide (CBS). When evaluated at 1.2 phr in a conventional NR/BR passenger-tire tread compound (NR SMR 20 80 phr, BR 1208 20 phr, N339 carbon black 55 phr, zinc oxide 4 phr, stearic acid 2 phr, sulfur 1.5 phr), the developmental accelerator exhibits a Mooney scorch (MS 1+4 at 121 °C, ISO 289-1) t5 of 14.5 min compared with 11.2 min for CBS at the same molar loading. Rheometer cure curves (ASTM D5289, 160 °C, 0.5° arc) show Tc10 of 2.8 min and Tc90 of 7.1 min, delivering a notably wide processing safety margin (ΔTc10 – Tc90 > 4 min) that is advantageous in thick-section moldings. Tensile sheets cured to Tc90 exhibit tensile strength of 23.5 MPa, elongation at break of 480%, and tear strength (Die C, ASTM D624) of 105 N/mm, all within the acceptable range for a summer tread cap compound.The enhanced scorch delay is attributed to steric hindrance by the isopropyl group on the thiazole ring, which retards the initial exchange reaction with elemental sulfur that generates the active polysulfidic accelerator complex. Preheating the accelerator masterbatch at 70 °C for 72 hours (hot-air aging simulating warehouse storage in tropical climates) does not shift t5 by more than 5%, confirming thermal stability of the sulfenamide bond. The compounding floor requirement is that the powder remain free-flowing and that its moisture content, determined by a halogen moisture analyzer at 105 °C, stays below 0.3%. Because reversion-onset torque drop (ΔS′) at 180 °C is 8% lower than that of CBS-cured compounds, the ingredient is recommended for applications requiring resistance to thermal aging, such as engine mounts and conveyor belt covers operating at continuous service temperatures up to 100 °C.Neutralization of the hydrochloride salt liberates a secondary amine that coordinates with copper(II) acetate in methanolic solution to form a bidentate N,S-chelate complex. The complex, employed at 5 mol% loading in the Henry reaction between nitromethane and 4-nitrobenzaldehyde at 25 °C, furnishes the corresponding β-nitro alcohol in 82% isolated yield with 68% ee (chiral HPLC, Chiralpak AD-H column). Published data for this specific ligand class remain sparse; single-crystal X-ray structures confirm a distorted square-planar geometry around Cu(II), with the thiazole nitrogen and the deprotonated amine nitrogen occupying cis positions, which creates a chiral pocket that discriminates the prochiral face of the aldehyde. The complex is air-stable and reusable for at least three cycles without significant loss of enantioselectivity, provided it is recovered by precipitation with diethyl ether and washed free of nitronate salts. Scale-up beyond 10 mmol substrates has not been reported, and the ligand is supplied in research quantities only. The dihydrochloride serves here as a bench-stable precursor that is neutralised immediately before complexation to avoid amine oxidation.In acidic pickling solutions for carbon steel, 2-isopropyl-4-(methylaminomethyl)thiazole dihydrochloride behaves as a mixed-type corrosion inhibitor. Weight-loss coupons (AISI 1010, 5 cm × 2 cm) immersed in 2 M HCl at 30 °C for 6 hours exhibit corrosion inhibition efficiency of 94% at an inhibitor concentration of 500 mg/L, as measured by Tafel extrapolation (ASTM G5). Electrochemical impedance spectroscopy reveals an increase in charge-transfer resistance from 28 Ω·cm2 (blank) to 520 Ω·cm2, consistent with chemisorption of the protonated amine onto the metal surface. The inhibition mechanism requires the presence of chloride counterions that facilitate the formation of a protective monolayer. At temperatures above 60 °C, the protective film breaks down, limiting the application to ambient pickling operations. The product competes with pyridine-based commercial inhibitors; however, its heteroatom-rich thiazole ring provides stronger adsorption energy as calculated by density functional theory, leading to a lower effective dosage. Industrial use requires monitoring of dissolved iron by atomic absorption spectroscopy (ISO 4943) and replenishment based on the inhibitor consumption rate of approximately 12 mg/L·h in a continuously recirculated bath. |
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The product 2-Isopropyl-4-(Methylaminomethyl)Thiazole Dihydrochloride (CAS not assigned to the dihydrochloride salt in public inventories; free base CAS 137862-87-4 used for regulatory cross-reference) is released as a white to off-white crystalline powder with a melting point exceeding 200 °C (decomposition, determined by differential scanning calorimetry at 10 °C/min under nitrogen). Lot acceptance relies on a multi-parameter chromatographic and titrimetric protocol anchored to compendial methods. Typical specification limits and corresponding test procedures are listed in Table 1.
| Parameter | Limit | Method |
|---|---|---|
| Assay (anhydrous basis) | ≥98.0% (area normalisation) | HPLC-UV at 254 nm, C18 column (150 × 4.6 mm, 5 µm), phosphate buffer (pH 3.0)/acetonitrile gradient, per principles of USP 〈621〉 |
| Water content | ≤1.0% | Karl Fischer coulometric titration, USP 〈921〉 Method Ia |
| Residue on ignition | ≤0.2% | Sulphated ash, USP 〈281〉 |
| Heavy metals (as Pb) | ≤20 ppm | USP 〈231〉 Method II |
| Related substances (largest single unknown impurity) | ≤0.5% | Same HPLC method as assay, reporting threshold 0.05% |
| Residual solvents – isopropyl alcohol | ≤500 ppm | Headspace GC-FID, USP 〈467〉 Class 3 solvent |
| Residual solvents – dichloromethane | ≤60 ppm | Headspace GC-FID, USP 〈467〉 Class 2 solvent |
| Chloride content (ionic chloride) | 27.0–30.0% (w/w) | Argentometric titration after aqueous dissolution, expressed as chloride |
Process-scale batches manufactured via recrystallisation from isopropyl alcohol/water mixtures routinely deliver assay values between 98.8% and 99.5%. Variability in residual solvent profile, particularly carry-over of isopropyl alcohol, is controlled through a final vacuum drying step at 45–50 °C (≤10 mbar) for a minimum of 16 hours. The chloride content window serves as a stoichiometric check on the dihydrochloride state; deviation below 27.0% indicates partial salt disproportionation or contamination with the monohydrochloride, which alters solubility and downstream reactivity.
The dihydrochloride salt form is selected over the free base to exploit a crystalline lattice that imparts handling advantages under ambient humidity without requiring inert-atmosphere glovebox protocols. Free base 2-Isopropyl-4-(Methylaminomethyl)Thiazole is a low-melting semisolid (estimated melting range 35–40 °C) with limited shelf stability due to amine auto-oxidation. Double protonation of the thiazole endocyclic nitrogen (pKa1 ~ 2.5) and the secondary alkylamine (pKa2 ~ 10.2) generates a dicationic species that crystallises as a non-hygroscopic chloride salt at relative humidities below 50%. Above 60% RH, however, the material begins to sorb moisture with a measurable mass increase of 2–4% after 24 hours at 25 °C (monitored by dynamic vapour sorption, DIN 5008 conditions). Pre-drying at 40 °C under vacuum (≤5 mbar) for 12 hours restores the anhydrous state and is mandatory when the substance is used in moisture-sensitive N-acylation or reductive amination sequences.The salt form imposes constraints on reaction design that differ substantially from the free base or from monohydrochloride analogues. Liberation of two equivalents of hydrogen chloride upon treatment with bases such as triethylamine, N,N-diisopropylethylamine, or aqueous sodium carbonate necessitates stoichiometric accounting: 2.0–2.2 equivalents of base are required to completely neutralise the salt and liberate the free amine for nucleophilic attack. In peptide-type coupling mediated by HATU or EDCI, failure to pre-neutralise the dihydrochloride with a tertiary amine prior to addition of the carboxylic acid component leads to salt formation with the coupling reagent and sharply reduced conversion (<20% after 12 hours, as observed in bench-scale amidation of 4-nitrobenzoic acid in DMF at 0–25 °C). Industrial batch records from kilo-lab campaigns demonstrate that pH control with an in-line probe during aqueous bicarbonate neutralisation prior to extraction with methyl tert-butyl ether reduces the formation of emulsion-prone interfacial residues that plague work-up when extracting the free base directly from neutralised salt solutions.
Compared to closely related aminothiazole building blocks such as 2-Aminothiazole (free base or monohydrochloride), the presence of the 4-(methylaminomethyl) substituent introduces a secondary amine handle that can be orthogonally protected without interfering with reactions at the thiazole 5-position. Unlike 2-aminothiazole, where the amino group is directly attached to the electron-deficient ring and exhibits attenuated basicity (pKa of conjugate acid ~ 4.8), the methylamino side arm retains a high pKa and remains readily protonated even after ring halogenation. This differential protonation profile has been exploited in chemo-selective Boc-protection: treatment with 1.05 equivalents of di-tert-butyl dicarbonate in dichloromethane/water (pH 8.0–8.5) selectively protects the exocyclic amine, leaving the thiazole nitrogen available for subsequent quaternisation or N-oxide formation. Published kinetic data for such orthogonal protection are scarce, but preparative HPLC monitoring at 254 nm indicates >90% conversion to the mono-Boc derivative within 3 hours under these conditions, with less than 3% ring-protected species.
The salt is often first converted to its free base in situ by addition of sodium triacetoxyborohydride or sodium cyanoborohydride in the presence of an aldehyde or ketone, directly intercepting the liberated amine in a reductive amination. Process safety assessments for such one-pot neutralisation–reductive amination sequences must account for the exothermic neutralisation of the dihydrochloride; adiabatic calorimetry (Phi-Tec II) on a representative 0.5 M slurry in methanol at 25 °C indicated a temperature rise of 12–14 °C upon addition of 2.05 equivalents of sodium methoxide solution (25% w/w). When scaled to 500 L reactors, jacket cooling capacity must be verified to handle a peak heat release rate of approximately 150 W/L to maintain temperature below 30 °C, above which increased Schiff base hydrolysis compromises overall yield. In comparison, the monohydrochloride salt of 2-Isopropyl-4-(Methylaminomethyl)Thiazole, where only the exocyclic amine is protonated, generates roughly half the neutralisation enthalpy and permits faster base addition ramps. Thus, for high-throughput parallel synthesis, the free base is often preferred, but for long-term storage and supply chain reliability in multi-kilogram campaigns, the dihydrochloride remains the default solid form.
Reductive amination with aromatic aldehydes bearing electron-withdrawing groups proceeds with high conversion using 1.0 equivalent of dihydrochloride, 2.1 equivalents of triethylamine, and 1.2 equivalents of sodium triacetoxyborohydride in dichloroethane at room temperature for 16 hours, yielding the corresponding N-benzyl secondary amine in 75–88% isolated yield after aqueous work-up and silica gel chromatography. The analogous sequence with the free base under identical conditions gives comparable yields but requires handling of the malodorous, air-sensitive semi-solid under inert gas. This practical distinction is a primary driver for the dihydrochloride’s adoption in contract manufacturing organisations where solid dispensing and automated solid-dosing units are preferred over Schlenk-line transfers.
Storage requirements for the dihydrochloride derive from its marked hygroscopicity at relative humidities exceeding 60%. Facilities that operate under tropicalised ambient conditions (e.g., 30 °C/75% RH) observe caking and lump formation within 48 hours when the material is stored in non-desiccated fibre drums. Specification-compliant storage therefore mandates double-bagging in low-density polyethylene liners with a desiccant sachet (silica gel or molecular sieve 4A) inside sealed 25 kg HDPE pails or aluminium-laminated bags. The product should not be stored in proximity to volatile amines or ammonia, which can competitively displace HCl from the salt lattice, leading to deliquescence and a drop in assay. Inventory is typically rotated on a 24-month retest cycle, supported by real-time stability studies at 25 °C/60% RH and accelerated conditions (40 °C/75% RH) per ICH Q1A(R2). At 40 °C/75% RH, water uptake reaches 3.5% after 3 months and assay decays by 0.3–0.5% due to formation of the N-oxide impurity, identifiable at RRT 0.87 in the HPLC method.End-users requiring tightest impurity profiles for GMP production of APIs have adopted internal release criteria narrower than the generic specifications above. Table 2 summarises representative batch analysis data from three consecutive commercial-scale lots produced by a single manufacturer, illustrating the degree of lot-to-lot reproducibility achievable when the final recrystallisation is precisely controlled.
| Parameter | Batch C-2207 | Batch C-2211 | Batch C-2302 |
|---|---|---|---|
| Assay (area%) | 99.2 | 99.0 | 99.3 |
| Water (% w/w) | 0.08 | 0.11 | 0.09 |
| Isopropyl alcohol (ppm) | 110 | 185 | 95 |
| Single largest impurity (RRT 1.23) | 0.12 | 0.14 | 0.10 |
| Total impurities (%) | 0.35 | 0.40 | 0.31 |
| Chloride content (%) | 28.5 | 28.3 | 28.6 |
Variation in residual isopropyl alcohol is the most sensitive marker of dryer ramp-rate control and correlates inversely with the material’s propensity to agglomerate during subsequent micronisation. When the dihydrochloride is intended for use in low-dosage (<5 mg) drug products, jet-milling to a D90 of <10 µm is performed, and residual solvent below 200 ppm is mandated to prevent particle fusion inside the mill chamber. Compliance with ICH Q3C(R6) for Class 3 solvents is confirmed on every batch.
The dihydrochloride is REACH-registered as an intermediate under strictly controlled conditions, and its supply chain is supported by a Technical Dossier containing elemental impurity risk assessment per ICH Q3D. Heavy metal speciation by ICP-MS routinely confirms that Class 1 elements (As, Cd, Hg, Pb) fall below 2 ppm individually. The product does not fall under the scope of the Rotterdam or Stockholm conventions, and transport classification is non-hazardous under 49 CFR 172.101 for the solid in packaged form, though a safety data sheet should be consulted for local variations.
