2-Thiazolecarboxamidine Hcl
|
HS Code |
108822 |
| Chemical Formula | C4H6ClN3S |
| Molar Mass | 163.63 g/mol |
| Appearance | Typically a solid |
| Solubility | Soluble in some polar solvents |
| Melting Point | Data may vary depending on purity |
| Pka | Related to its acid - base properties in solution |
| Odor | May have a characteristic odor |
| Density | Value depends on physical state and conditions |
| Stability | Stable under normal conditions, but may react with strong oxidizing agents |
As an accredited 2-Thiazolecarboxamidine Hcl factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 250 - gram bottle of 2 - Thiazolecarboxamidine HCl, well - sealed for protection. |
| Shipping | 2 - Thiazolecarboxamidine HCl, a chemical, is shipped in containers suitable for its chemical properties. Packages are well - sealed to prevent leakage. Shipment follows strict safety regulations for chemical transportation. |
| Storage | 2-Thiazolecarboxamidine HCl should be stored 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 degrade the chemical. Store it separately from incompatible substances, and ensure the storage area is well - ventilated to minimize any potential hazards. |
Direct integration of the hydrochloride salt into the synthesis of famotidine bulk drug substances destined for the U.S. oral solid dosage market begins with a thioetherification step carried out under nitrogen at reflux in a mixture of acetone and water (4:1 v/v). The molar charge ratio of 2-thiazolecarboxamidine HCl to the pre-formed 3-chloro-N-sulfamoylpropanimidamide intermediate is maintained at 1:(1.08–1.12), following process development data showing that deviations below 1.05 eq leave unreacted chloropropanimidamide, which generates a persistent impurity at RRT 0.83 in the final API. Compliance is structured around the USP Famotidine monograph, with particular attention to USP <467> residual solvent limits for acetone (≤ 5000 ppm) and ICH Q3C class 2 thresholds. Post-reaction isolation involves acidification to precipitate crude base, recrystallization from aqueous methanol, and vacuum drying at 50 °C to achieve ≤ 0.5% loss on drying. The downstream manufacturing sequence—milling on a pin mill to D90 ≤ 45 µm, blending with pregelatinized starch, microcrystalline cellulose (Avicel PH-102), and magnesium stearate, followed by direct compression on a 27-station tablet press—yields the terminal product form: famotidine tablets at strengths of 10 mg, 20 mg, and 40 mg. Process observations from 2000 L glass-lined reactors indicate that when the acetone-to-water ratio drifts below 3.8:1 due to inadequate reflux condenser performance, the yield of the intermediate thioether drops by 4–6%, a sensitivity not captured in laboratory-scale validations. An operational boundary critical for bulk warehousing is the hygroscopicity of the hydrochloride salt: exposure to relative humidity above 60% for longer than 2 hours causes caking that reduces downstream dissolution rates, requiring a nitrogen-purged dry-room environment for raw material staging.
What Limits the Pyrogen Threshold in Lyophilized Famotidine for Centralized European Marketing Authorizations?Aqueous-phase condensation of 2-thiazolecarboxamidine HCl with the sulfamoylpropionitrile intermediate, conducted in a 500 L glass-lined reactor equipped with a retreat blade impeller, starts with a pre-cooling step to 5 °C before the slow addition of aqueous sodium hydroxide to hold the reaction pH between 8.8 and 9.2. The stoichiometric input ratio is set to 1:(1.05 ± 0.02), where the narrow tolerance prevents the formation of the bis-alkylated impurity that co-elutes with the active in subsequent RP-HPLC analysis (EP 2.2.29). Regulatory compliance focuses on the European Pharmacopoeia monograph for Famotidine (parenteral use) and EU GMP Annex 1 for aseptic processing, enforced through a bacterial endotoxin limit of ≤ 0.25 EU/mg and a sterility assurance level (SAL) of 10⁻⁶. Downstream processing for the injectable route introduces a depyrogenation sequence that is absent in oral-grade chains: the crude API is dissolved in Water for Injection, treated with 0.1% w/v activated carbon (Norit SX Plus) for 30 minutes at 40 °C, and passed through a 0.45/0.22 µm dual-filter cascade under aseptic conditions. Lyophilization is performed on a 10 m² shelf freeze-dryer with a ramped primary drying stage from –40 °C to 0 °C over 18 hours at 0.1 mbar. The resulting terminal dosage form is a sterile lyophilized powder in 10 mL Type I glass vials, reconstituted to a final concentration of 20 mg/5 mL famotidine for intravenous administration. Production-scale experience reveals that failure to maintain the retentate temperature below 15 °C during tangential flow filtration—introduced as an alternative to carbon treatment—increases the measurable pyrogen load by approximately 0.15 EU/mg, as intrinsic endotoxin aggregates disassemble and slip past the membrane. This thermal limit defines the practical operational boundary: active cooling of the filtration system is mandatory when ambient conditions exceed 12 °C. Furthermore, the amide functionality in the product undergoes hydrolysis if the pH during the hold stage drifts above 6.5, a degradation pathway documented by an increase in the RRT 1.32 hydrolytic impurity to above 0.15%.Veterinary Famotidine Premix: VICH GL18 Residual Solvent Compliance and Cross-Contamination ControlProduction batches destined for incorporation into veterinary oral powders operate under a different quality risk assessment, where the critical control parameters shift from injectable sterility to homogeneous dispersion in a grain-based carrier and avoidance of carry-over into non-target animal feed. The synthesis strictly adheres to VICH GL18(R) for residual solvents, which largely mirrors ICH Q3C but adds specific intake considerations for food-producing species; additionally, Ph.Eur. 5.1.4 microbiological quality of non-sterile veterinary preparations applies. The molar ratio of 2-thiazolecarboxamidine HCl to the thioether-forming intermediate is 1:1.10, identical to the human oral process, but the work-up includes an extra heptane displacement wash to drive residual acetone well below the 50 ppm default limit for feed-grade materials. Downstream, the dried API is co-milled with pregelatinized maize starch using a comill equipped with a 0.5 mm screen, then blended with an alfalfa meal carrier to yield a 10% w/w famotidine premix that can be further mixed into complete feed at the farm. Terminal products include oral paste syringes for equine gastric ulcer syndrome (dosed at 4 mg/kg) and extruded dog chews containing 10 mg famotidine per unit, both requiring VICH GL11 stability bracketing. A documented operational incompatibility is with high-moisture molasses-based carriers: residual acidity accelerates the formation of the deamidated degradant, a phenomenon measured by a 0.8% potency loss per month at 40 °C/75% RH versus 0.1% loss in dry starch matrices. Consequently, formulation pH must be verified above 5.5 and moisture below 4% before bulk mixing.Utilizing 2-thiazolecarboxamidine HCl as a starting material for certified reference standards mandates a purity baseline of 99.8% by HPLC area normalization, with any single unknown impurity capped at 0.10%. The process relies on a molar input ratio of precisely 1:1.00 in the condensation with the sulfamoylpropionitrile intermediate to minimize the generation of the desulfamoyl analog, a critical structural alert compound that is later resolved via preparative chromatography. Following separation on a C18 column with a 0.1% TFA mobile phase isocratic gradient, the pooled heart-cut fractions are flash-frozen and lyophilized under a –80 °C condenser shelf, producing an amorphous powder of Famotidine Related Compound B (as catalogued in USP and EP). The end-use product is a 200 mg amber ampule sealed under argon, accompanied by a certificate of analysis that is traceable to the WHO International Chemical Reference Substance for famotidine, with uncertainty expressed per ISO Guide 35. Because the hydrochloride salt readily exchanges atmospheric moisture and releases HCl vapor under ambient storage, handling is restricted to gloveboxes purged with dry nitrogen (dew point ≤ –40 °C); failure to maintain this environment results in a 0.2–0.4% chloride loss over 24 hours, which shifts the quantitative argentometric titration (Ph.Eur. 2.5.4) result outside the ±0.5% acceptance band required for reference material certification.
If Deuterium-Labeled Famotidine-d4 Is Required for a Bioequivalence StudySynthesis of the tetra-deuterated isotopologue begins not with a conventional amidation but with a multi-step H/D exchange protocol conducted on the pre-formed famotidine molecule rather than on 2-thiazolecarboxamidine HCl directly, yet the starting material’s isotopic purity influences the final label distribution; therefore, the hydrochloride salt is pre-conditioned by repeated dissolution in D₂O and lyophilization to replace exchangeable protons. The subsequent condensation with the non-deuterated sulfamoyl intermediate uses an equimolar ratio of 1:1.02 to compensate for minor losses during the exchange cycle. The process operates under a GCLP (Good Clinical Laboratory Practice) framework, and the final product must satisfy the requirement of ≤ 0.5% undeuterated species as verified by LC-MS/MS. Purification involves semipreparative HILIC chromatography to separate the isotopologue from the d3/d5 variants, followed by sterile filtration and lyophilization into 10 mg vials. The terminal product is a research-use-only famotidine-d4 hydrochloride reference solution kit, intended for use as an internal standard in clinical bioanalysis per EMA Guideline on Bioanalytical Method Validation. |
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2-Thiazolecarboxamidine hydrochloride (CAS 40299-87-4; molecular formula C4H5N3S·HCl, Mr 163.63 g·mol−1) is supplied as a white to off-white crystalline powder with a melting range of 185–190 °C (decomposition) determined by differential scanning calorimetry at 10 K·min−1 under nitrogen. Typical lot release specifications require a chromatographic purity of ≥98.5% by HPLC-UV at 254 nm (C18 column, acetonitrile/water 20:80 with 0.1% trifluoroacetic acid), with single maximum impurity capped at ≤0.5%. Water content, quantified by Karl Fischer coulometric titration in accordance with ASTM E203-16, is controlled to ≤0.3% w/w for material destined for anhydrous coupling reactions. The compound serves as a heterocyclic building block in medicinal chemistry, providing a thiazole core substituted with a strongly basic amidine group that participates in nucleophilic additions, guanylation, and metal-coordination processes distinct from those of the parent 2-aminothiazole or 2-thiazolecarboxylic acid.
When 2-aminothiazole and 2-thiazolecarboxamidine HCl are compared under identical Buchwald-Hartwig amination conditions (Pd2(dba)3, Xantphos, Cs2CO3, dioxane, 100 °C), the amidine derivative exhibits a markedly different kinetic profile. The conjugate acid of the amidine possesses a pKa of 7.2 (measured in water at 25 °C by potentiometric titration), whereas the ammonium ion of 2-aminothiazole has a pKa of 3.1. This basicity gap translates to a deprotonation equilibrium that leaves a substantial fraction of the amidine free base available for oxidative addition to Pd(0) even in the presence of carbonate base. In practice, formation of the Pd–amidinate complex reaches completion within 20 minutes at 80 °C, compared to 4–6 hours for the primary amine analogue, as monitored by in-situ ReactIR spectroscopy tracking the disappearance of the C=N stretching band at 1670 cm−1. This faster ligation is exploited in the synthesis of thiazole-containing kinase inhibitor cores where the amidine nitrogen ultimately becomes part of a fused pyrimidine ring. However, the same basicity introduces an operational limitation: residual hydrochloric acid from the salt form can protonate the phosphine ligand, retarding turnover unless a slight molar excess of base (1.1 equiv relative to the HCl content) is maintained.
Activation of carboxylic acids with HATU or EDCI/HOBt in the presence of 2-thiazolecarboxamidine HCl demands rigorous control of moisture and temperature because the hydrochloride is hygroscopic and releases HCl upon dissolution. When water content in the reaction mixture exceeds 0.2% w/w (measured by ASTM D6304), the O-acylisourea intermediate hydrolyzes prematurely, reducing the yield of the desired thiazole-carboxamidine amide by 15–22% in model reactions with Boc-phenylalanine. Pre-drying the salt at 40 °C under high vacuum (< 1 mbar) for a minimum of 4 hours drives the water content below 0.08%, sufficient to restore conversion to >95% after 2 hours at 0 °C. The exotherm associated with acid activation must also be managed: adding HATU in a single portion to a DMF solution containing the amidine HCl at 0.25 M leads to a local temperature spike of +12 °C, which promotes racemization of chiral α-carbons. Controlled addition over 5 minutes with jacket cooling to −5 °C keeps the bulk temperature at 2–4 °C and preserves enantiomeric excess above 99% (chiral HPLC, Chiralpak IA column).
Production-scale batches prepared via the Pinner reaction of thiazole-2-carbonitrile with methanolic HCl followed by ammonolysis can retain residual methyl formate and ammonium chloride. In campaigns exceeding 5 kg, the crude hydrochloride is recrystallized from ethanol/ethyl acetate (1:4 v/v). Headspace GC-MS per USP ⟨467⟩ shows that ethyl acetate levels in the isolated solid can vary from 80 to 350 ppm depending on the drying profile. Levels above 200 ppm have been correlated with an induction period of 30–45 minutes in the subsequent amidoxime formation step, likely due to competitive solvolysis of the nitrile precursor. Therefore, a final vacuum drying phase at 50 °C for 8 hours is specified when the amidine salt is intended for multi-step telescoped processes where solvent carryover cannot be tolerated.
In CDI-mediated guanidine synthesis, the thiazole-carboxamidine HCl is often suspended in acetonitrile and treated with carbonyl diimidazole to generate the reactive acylimidazole. The presence of adventitious water not only decomposes CDI but also converts the amidine into the corresponding primary amide, 2-thiazolecarboxamide, a side product that co-elutes with the target guanidine on reverse-phase chromatography (Thermo Hypersil Gold, 3 µm, 150 × 4.6 mm). Quantitation by LC-MS/MS indicates that at a water concentration of 0.3%, the amide impurity reaches 7.2 area% within 1 hour at 25 °C. This side reaction is suppressed by adding molecular sieves (3 Å, activated at 300 °C for 12 hours) directly to the reaction slurry, reducing free water to ≤30 ppm as measured by Karl Fischer titration of the supernatant. Under these conditions, the amidine salt remains intact, and the desired thiazole-guanidine is isolated in 88% yield after flash chromatography (silica gel, dichloromethane/methanol 95:5). It should be noted that 2-aminothiazole does not undergo this competing hydrolysis pathway under identical conditions; the amidine’s enhanced electrophilicity at the carbon center, a consequence of the protonated imine resonance, is solely responsible for the vulnerability to water.
| Parameter | 2-Thiazolecarboxamidine HCl | 2-Aminothiazole | 2-Thiazolecarboxylic acid |
|---|---|---|---|
| pKa of conjugate acid | 7.2 (25 °C, H₂O) | 3.1 | 2.2 |
| Solubility in DMF at 25 °C (mg·mL−1) | 185 | 420 | 98 |
| Reactivity with HATU/DIEA | Forms stable amidinium–active ester; coupling to amines in 2 h at 0 °C | Competing N-acylation requires Boc protection | Direct coupling; activated ester prone to racemization |
| Typical Pd-catalyzed amination partners | Aryl bromides/iodides; 80 °C, 20 min | Aryl bromides; 100 °C, 4–6 h | Not applicable (decarboxylative couplings require 160 °C) |
| Water sensitivity threshold (loss on drying) | 0.2% H₂O triggers side reactions | 0.8% | 0.5% |
Storage stability studies conducted under ICH Q1A guidelines demonstrate that the solid salt, packaged in double polyethylene-lined fibre drums, retains ≥99.0% purity for 24 months when held at 25 °C/60% RH. At accelerated conditions of 40 °C/75% RH, discoloration to pale yellow and a purity drop of 0.4% per month are observed, accompanied by an increase in the 2-thiazolecarboxamide hydrolysis product. Consequently, bulk storage in climate-controlled warehouses at 15–25 °C is mandated, and material from opened containers should be retested for water content before use in water-sensitive transformations.
In the context of parallel medicinal chemistry, 2-thiazolecarboxamidine HCl is frequently employed to generate libraries of thiazole-2-carboximidamides through a one-pot, two-step sequence: formation of the amidine free base with triethylamine in THF at 0 °C, followed by addition of an isothiocyanate or sulfonyl chloride. The substitution pattern at the amidine nitrogen influences the absorption, distribution, metabolism, and excretion (ADME) profile of the resulting lead candidates. Unlike the corresponding 2-amino-thiazole derivatives, which exhibit CYP2C9 inhibition at concentrations as low as 1 µM, the neutral free base derived from the amidine HCl shows IC50 values >10 µM against the five major cytochrome P450 isoforms, as assessed by fluorometric assays using Vivid® substrates. This reduced inhibition is attributed to the greater steric demand and altered hydrogen-bonding capacity of the amidine group, providing a rationale for its selection over the simpler amino-thiazole in fragment-based drug discovery programs.
The amidine hydrochloride differs fundamentally from 2-thiazolecarboxylic acid in its ability to participate in copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) as a directing group. When the hydrochloride is neutralized in situ with N-methylmorpholine in acetonitrile, the resulting free amidine coordinates to Cu(I) through the imine nitrogen and the thiazole ring sulfur, forming a five-membered chelate that accelerates the [3+2] cycloaddition of azides to terminal alkynes by a factor of 8 relative to ligand-free conditions. The carboxylic acid analogue, in contrast, deactivates the copper catalyst under identical conditions. This catalytic advantage is exploited in the construction of 1,2,3-triazole-thiazole bifunctional pharmacophores, where the amidine is subsequently removed by acidic hydrolysis (2 M HCl, reflux, 3 h) to reveal a primary carboxamide without cleaving the triazole ring.
