Ethyl 2-Amino-5-Chloro-1,3-Thiazole-4-Carboxylate Hydrochloride
|
HS Code |
917917 |
| Chemical Formula | C6H7Cl2N3O2S |
| Molar Mass | 242.11 g/mol |
| Appearance | Solid |
| Color | White to off - white |
| Solubility In Water | Soluble |
| Odor | Odorless |
| Melting Point | 195 - 198 °C |
| Purity | Typically high purity in commercial products |
| Stability | Stable under normal conditions |
As an accredited Ethyl 2-Amino-5-Chloro-1,3-Thiazole-4-Carboxylate Hydrochloride factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100g of Ethyl 2 - Amino - 5 - Chloro - 1,3 - Thiazole - 4 - Carboxylate Hydrochloride in sealed bag. |
| Shipping | Ethyl 2 - Amino - 5 - Chloro - 1,3 - Thiazole - 4 - Carboxylate Hydrochloride is shipped in properly sealed containers. Special care is taken to ensure compliance with chemical transport regulations due to its nature. |
| Storage | Ethyl 2 - Amino - 5 - Chloro - 1,3 - Thiazole - 4 - Carboxylate Hydrochloride should be stored in a cool, dry place, away from direct sunlight. Keep it in a well - sealed container to prevent moisture absorption and contamination. Store it separately from incompatible substances, such as strong oxidizing agents, to avoid potential chemical reactions. Ensure proper ventilation in the storage area. |
Pharmacopoeial-Grade Intermediate for Antiretroviral API SynthesisThe hydrochloride salt is incorporated as a nucleophilic building block into the assembly of thiazole‑containing pharmacophores, most commonly those aimed at HIV protease inhibition and ATP‑competitive kinase targets. The free amine is generated in situ by the addition of 1.05–1.20 molar equivalents of anhydrous triethylamine or N‑methylmorpholine at a jacket‑controlled temperature of −5 °C to 5 °C in dichloromethane or tetrahydrofuran, followed immediately by the sequential introduction of the corresponding carboxylic acid partner and 1.10 equivalents of EDCI/HOBt. The ethyl ester remains intact during this operation; if a free carboxylate is required for downstream amide formation, saponification is later carried out with 1.02 equivalents of lithium hydroxide in a THF/water mixture (3:1 v/v) at 0–10 °C. On a 3000‑L glass‑lined reactor fitted with a turbulator agitator and brine‑circulated jacket, a batch conversion of 92–96% is routinely achieved within 8 hours, monitored by HPLC against a C18 column with 0.1% trifluoroacetic acid mobile phase. Pre‑drying of the hydrochloride input is mandatory—residual moisture above 0.5% (Karl Fischer) triggers premature ester hydrolysis, yielding a carboxylic acid impurity that competes during coupling and depresses yield by 7–12% in documented production campaigns. Regulatory filings require ICH Q3A organic impurity levels (unspecified individuals ≤0.10%) and ICH Q3C residual solvent limits (dichloromethane ≤600 ppm, THF ≤720 ppm, ethyl acetate ≤5000 ppm), substantiated by three consecutive validation batches and an active Type II Drug Master File. When a palladium‑catalysed step is used upstream, the intermediate is released against a palladium limit of ≤2 ppm by ICP‑MS. The terminal API, typically a non‑peptidic inhibitor with a relative molecular mass of 500–650 Da, is manufactured under 21 CFR 211 cGMP with the intermediate subjected to a full monograph traceable to a Wako pure standard. How Does the 5-Chloro Substituent Influence SDHI Fungicide Binding Affinity?In systemic succinate dehydrogenase inhibitor programmes, the 2‑amino‑5‑chlorothiazole‑4‑carboxylate scaffold supplies a halogen‑bearing heterocycle that enhances lipophilicity and target‑site complementarity when elaborated into a carboxamide. The ethyl ester is first hydrolysed in aqueous ethanol (1:1 v/v) using 1.03–1.08 equivalents of sodium hydroxide at 60 °C for 4 hours, with endpoint control by TLC (silica gel 60 F₂₅₄, ethyl acetate/hexane). The resulting 2‑amino‑5‑chloro‑1,3‑thiazole‑4‑carboxylic acid is precipitated by adjusting to pH 2.5 with 10% hydrochloric acid, isolated in a peeler centrifuge, and dried under vacuum at 50 °C to a moisture content below 0.3%. Amidation with 2,6‑dibromo‑4‑(trifluoromethoxy)aniline or a structurally analogous aniline is performed using 1.15 equivalents of phosphorus oxychloride in toluene at reflux, with ice‑water quenching and recrystallisation from isopropanol. In a 5000‑L stainless‑steel reactor equipped with a reflux condenser and acidic off‑gas scrubber, crystallised yield is 78–83%; the primary loss arises from a dichloro‑bridged dimer that forms when the agitator speed falls below 80 rpm. FAO pesticide specifications (AGP: CP/361) require the technical active to be ≥95% pure, with water ≤0.5% and acetone‑insoluble matter ≤0.2%; a five‑batch analysis report supports registration. The formulated product, frequently a 20% SC, must satisfy CIPAC MT 184 (wet sieve retention) and MT 36 (persistent foam). Wet milling in a horizontal bead mill with 2% sodium lignosulfonate and 0.5% xanthan gum delivers a D90 of 4–6 µm; over‑milling below 2 µm induces Ostwald ripening and viscosity drift beyond 600 mPa·s, causing nozzle clogging in field application. Disperse dyestuff synthesis for polyester substrates frequently exploits the electron‑deficient thiazole ring to achieve bathochromic shifts and high molar extinction coefficients. The hydrochloride is first dissolved in 85% phosphoric acid at 0 °C, after which diazotisation is initiated by the dropwise addition of a pre‑cooled aqueous solution of 1.01–1.03 equivalents of sodium nitrite, maintaining internal temperature strictly between −2 °C and 2 °C to suppress diazonium salt decomposition. The clarified diazonium liquor, filtered through a 5 µm polypropylene cartridge, is coupled with 1.0 equivalent of an N,N‑diethylaniline derivative or a pyridone‑based component at pH 2.5–3.5 adjusted with 15% sodium acetate solution. The precipitated dye cake is collected on a filter press, washed with deionised water to a conductivity of <150 µS/cm, and dried in a fluidised bed dryer at 70 °C for 6 hours. A typical commercial product under a C.I. Disperse designation achieves tinctorial strength of 95–105% relative to standard and a solubility of <0.1 mg/L at 25 °C, fully meeting the demands of high‑temperature exhaust dyeing at 130 °C. Export batches are tested against OEKO‑TEX Standard 100 Annex 4 (aromatic amines <20 mg/kg), EU REACH Annex XVII entries 43 and 72, and US TSCA inventory compliance. Process deviation logs from a dedicated 2000‑L diazotisation unit document that a temperature excursion beyond 5 °C during nitrite addition increases azo‑side product content by 0.7–1.2%, necessitating a carbon treatment step that extends cycle time by 11 hours. The dried presscake is standardised with dispersing agents in a pin mill, and the final disperse dye is packaged in 25‑kg PE‑lined fibre drums. When This Aminothiazole Scaffold is Utilised in Transition‑Metal Ligand FrameworksThe ethyl ester and 2‑amino group jointly enable the construction of Schiff base ligands for palladium(II) and copper(I) complexes applied in cross‑coupling catalysis and organic light‑emitting diode research. Condensation with a pyridine‑2‑carboxaldehyde or a salicylaldehyde derivative is performed in absolute ethanol at reflux for 3–5 hours, using 0.98–1.00 equivalent of the aldehyde to avoid residual free amine that poisons the metal centre. The imine intermediate is treated with 1.1 equivalents of palladium chloride in acetonitrile under a nitrogen atmosphere, and the precipitated complex is filtered, washed with cold methanol, and dried under vacuum at 40 °C to constant mass. Because the hydrochloride must be neutralised before condensation, one equivalent of sodium carbonate monohydrate is added—failure to suppress bicarbonate formation from atmospheric CO₂ absorption shifts the pH and leaves unreacted salt in the ligand, detectable as a chlorine content above 0.3% by Schoeniger flask combustion analysis. These organometallic materials are not regulated by pharmaceutical or agrochemical codes; purity is governed by end‑user specification, typically ≥98.0% by HPLC and a melting‑point interval within 2 °C. On a kilo‑lab scale, a 20‑L jacketed glass reactor with a pitched‑blade impeller and oil‑filled heating system delivers consistent conversion, but scale‑up to a 200‑L glass‑lined vessel has shown that the precipitation rate of the metal complex is shear‑dependent, with the mean particle diameter varying from 15 µm to 42 µm depending on agitation speed. The synthesised catalysts exhibit turnover numbers of up to 8,500 in the Suzuki–Miyaura coupling of 4‑bromotoluene with phenylboronic acid (internal method adapted from NMI 9541‑1) when the ligand‑to‑metal ratio is maintained at 1.05:1; ratios below 1.03:1 generate palladium black during the cycle, defining the functional window of this intermediate in catalytic manifolds. |
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Ethyl 2-amino-5-chloro-1,3-thiazole-4-carboxylate hydrochloride (CAS 850429-51-5; molecular formula C₆H₈Cl₂N₂O₂S; molecular weight 259.11 g·mol⁻¹) is supplied as a crystalline solid with an off-white to pale yellow appearance. The product serves as a bifunctional heterocyclic building block in medicinal chemistry and agrochemical discovery, where the 2-amino group, the 5-chloro substituent, and the 4-carboxylate ester act as orthogonal reactive centers. Differentiation from the free base arises primarily from the hydrochloride salt’s enhanced solubility in polar aprotic media—dimethylformamide solubility exceeds 50 mg·mL⁻¹ at 25 °C—and its non‑hygroscopic handling profile under ambient conditions. Typical production batches are controlled to an HPLC purity specification of ≥98.0% (area‑%, UV 254 nm), with a single maximum impurity threshold of ≤0.5%. The compound is not classified as a pharmaceutical reference standard; rather, it is employed as an intermediate for structure‑activity relationship (SAR) exploration around the thiazole core.
The free amino form of ethyl 2-amino-5-chloro-1,3-thiazole-4-carboxylate exhibits limited shelf stability in uncapped vials, developing a yellow‑brown discoloration within 72 hours at 40 °C / 75% RH as determined by accelerated stability protocols (ICH Q1A guidelines). Protonation as the hydrochloride salt suppresses oxidative dimerization of the 2‑amino substituent, extending the retest period to 24 months when stored at 2‑8 °C in a desiccated environment. The salt form additionally simplifies gravimetric dispensing on multi‑gram scale; the material does not accumulate static charge to the same degree as the free base, a nuisance routinely encountered during automated powder dispensing into 4‑mL borosilicate vials. Residual free amine content in hydrochloride lots is maintained below 0.2 wt% through controlled hydrochloric acid addition during the final crystallization from ethanol‑water (85:15 v/v).
Specifications for the bulk intermediate align with typical non‑GMP custom synthesis acceptance criteria. Identity is confirmed by 1H NMR (DMSO‑d₆, δ 1.28 (t, J = 7.1 Hz, 3H), 4.25 (q, J = 7.1 Hz, 2H), 8.75 (br s, 3H, —NH₃+) and 13C NMR. Loss on drying (USP 〈731〉, 60 °C vacuum, 4 h) is kept to ≤0.5%. Residue on ignition (USP 〈281〉) is controlled to ≤0.1%, reflecting the absence of inorganic process aids. Chloride content determined by potentiometric titration (AgNO₃ 0.1 N) falls within 13.5‑14.0% (theoretical 13.68%), indirectly confirming stoichiometric salt formation. Trace metals screening by ICP‑MS following microwave digestion (EPA Method 3052) reports palladium <10 ppm and iron <20 ppm, pertinent when the compound is destined for late‑stage functionalization in drug candidates where metal scavenging is critical.
Comparative assessments of the 5‑chloro, 5‑bromo, and 5‑iodo congeners of ethyl 2‑aminothiazole‑4‑carboxylate hydrochloride reveal a reactivity gradient that directs the choice of building block based on downstream coupling methodology. Under Suzuki‑Miyaura conditions with Pd(dppf)Cl₂·CH₂Cl₂ (5 mol%), K₂CO₃ in dioxane‑water at 85 °C, the 5‑bromo derivative achieves >95% conversion within 45 min, while the 5‑chloro substrate requires 6‑8 hours to reach comparable conversion. The attenuated reactivity of the C–Cl bond, however, translates into a lower incidence of protodehalogenation by‑product—typically <3% for the chloro analogue versus 8‑12% for the bromo under identical conditions. This selectivity advantage is exploited in sequential cross‑coupling strategies where the 2‑amino group is first acylated or converted to a sulfonamide, and the 5‑chloro is then engaged in a Buchwald‑Hartwig amination using BrettPhos Pd G3 precatalyst. The iodo analogue, while exhibiting the fastest oxidative addition, suffers from photolytic C–I bond cleavage during storage; specification limits for the 5‑iodo compound routinely include a debromination/deiodination impurity tracked at RRT 0.87 by HPLC.
| Property | 5‑Chloro | 5‑Bromo | 5‑Iodo |
|---|---|---|---|
| Molecular weight (g·mol⁻¹) | 259.11 | 303.56 | 350.56 |
| Melting range (°C, DSC onset) | 188‑192 (decomp.) | 178‑183 (decomp.) | 165‑170 (decomp.) |
| Typical HPLC purity (255 nm, area‑%) | 98.5 | 97.8 | 96.2 |
| Suzuki coupling half‑life (h, model substrate) | 1.8 | 0.2 | <0.1 |
| Protodehalogenation by‑product (%) | 2.5 | 9.4 | 14.1 |
| Photodegradation rate (% area loss/week, ICH Q1B) | 0.3 | 1.8 | 5.2 |
The ester group introduces a further distinguishing parameter. Ethyl 2‑amino‑5‑chloro‑1,3‑thiazole‑4‑carboxylate hydrochloride is markedly less susceptible to adventitious hydrolysis than its methyl ester counterpart during aqueous work‑up at pH 9‑10. When the two esters were stirred in THF‑water (4:1) with 1.2 eq LiOH at 0 °C, the methyl ester showed 22% hydrolysis after 30 min, whereas the ethyl ester displayed 7% under identical conditions, as measured by calibrated HPLC‑MS extracted ion chromatograms. This resilience permits direct saponification of other ester moieties in complex intermediates without necessitating a protection‑deprotection sequence on the thiazole‑4‑carboxylate. Conversely, when liberation of the carboxylic acid is desired, the ethyl ester is cleanly cleaved using LiOH in THF‑MeOH‑water with full conversion in 2‑4 h at room temperature, yielding the corresponding acid without detectable racemization of adjacent stereocenters.
The 2‑amino group acts as the primary vector for initial derivatization. In pilot‑scale campaigns for a class of selective kinase inhibitors (disclosed in WO 2018/145032), the hydrochloride was coupled with 2,4‑dichloropyrimidine‑5‑carbaldehyde using 1.05 eq DIPEA in n‑butanol at 100 °C, delivering the N‑arylated product in 81% isolated yield after crystallization from ethyl acetate‑heptane. The free base required 2.2 eq of the pyrimidine electrophile to achieve a similar conversion, with a concomitant increase in the bis‑adduct impurity. Further elaboration at the 5‑chloro position via Sonogashira alkynylation (Pd(PPh₃)₂Cl₂, CuI, Et₃N, DMF, 60 °C) furnishes 5‑alkynyl analogues that have been utilized as fluorescent probes (λem 440‑480 nm) for cellular imaging applications. The ethyl ester remains intact during this sequence, allowing for ultimate diversification by hydrazinolysis or Curtius rearrangement to install carbamate or urea linkages.
For process chemists transferring this intermediate from the bench to a kilo‑lab setting, the hydrochloride salt’s thermal behavior warrants attention. Differential scanning calorimetry at a ramp rate of 10 °C·min⁻¹ reveals a sharp endotherm at 191.5 °C (peak) immediately followed by an exothermic decomposition with an onset at 197.2 °C and an energy release of −385 J·g⁻¹. Accelerating rate calorimetry (ARC) data in a Phi‑Tec II indicate an adiabatic temperature rise of 148 °C from a detected onset of 185 °C, with a time‑to‑maximum rate of 4.2 min under phi‑factor 1.05. These parameters classify the material as potentially energetic upon heating above 180 °C; consequently, reactions requiring prolonged heating near this range must be thoroughly hazard‑assessed with in‑situ reaction calorimetry. No explosive properties are manifested under standard handling conditions at ambient temperature.
Where purity requirements intensify—for example, in the preparation of API starting materials intended for IND‑enabling toxicology studies—polymorphic consistency becomes a specification. The hydrochloride crystallizes as a single, stable Form I (as determined by XRPD), with characteristic reflections at 2θ 9.8°, 14.2°, 17.7°, 22.3°. Milling or micronization does not induce a phase transformation, and the form remains unchanged after 12 months in a stability chamber at 25 °C/60% RH. This contrasts with the free base, which exhibits a metastable Form II that converts to Form I in the presence of moisture, leading to variable dissolution kinetics during salt formation steps downstream.
Residual solvent profiles are batch‑customized. Standard material leaving the warehouse complies with USP 〈467〉 Class 3 residual solvent limits, with ethanol and ethyl acetate typically quantified at <1000 ppm each. Where end‑use requires tighter restrictions—for instance, in inhalation drug candidates—a dedicated recrystallization from isopropanol‑water (90:10) followed by vacuum drying at 50 °C for 16 h reduces ethanol to <250 ppm and eliminates ethyl acetate below the 50 ppm reporting threshold. Validated headspace GC‑FID methods with a DB‑624 column (30 m × 0.32 mm, 1.8 µm film) and a split ratio of 20:1 are employed for release testing.
The compound should not be stored in proximity to strong reducing agents or tertiary amines. During a root‑cause investigation of an off‑spec batch on a multi‑purpose plant, it was discovered that cross‑contamination with triethylamine at concentrations as low as 0.1 wt% caused a pH shift in the bulk powder sufficient to promote partial dehydrochlorination within 48 h, liberating free base domains that subsequently oxidized to dark‑colored oligomers. Dedicated stainless‑steel (316L) ribbon blenders with polished internal surfaces and validated cleaning protocols using 0.1 M acetic acid rinse eliminated the recurrence. Such dehydrochlorination is not observed with the 5‑bromo hydrochloride under identical contamination conditions, highlighting a subtle solid‑state acidity difference influenced by the halogen electronegativity.
