Methyl 2-Amino-1,3-Thiazole-4-Carboxylate
|
HS Code |
426407 |
| Name | Methyl 2 - Amino - 1,3 - Thiazole - 4 - Carboxylate |
| Molecular Formula | C5H6N2O2S |
| Molar Mass | 158.18 g/mol |
| Appearance | Solid (usually) |
| Melting Point | N/A (specify if known) |
| Boiling Point | N/A (specify if known) |
| Solubility In Water | Limited (describe solubility details if known) |
| Solubility In Organic Solvents | Soluble in some polar organic solvents (describe solvents if known) |
| Pka | N/A (specify if known) |
| Density | N/A (specify if known) |
| Flash Point | N/A (specify if known) |
| Stability | Stable under normal conditions (describe any instability factors if known) |
As an accredited Methyl 2-Amino-1,3-Thiazole-4-Carboxylate factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100 - gram vial packaging for Methyl 2 - Amino - 1,3 - Thiazole - 4 - Carboxylate. |
| Shipping | Methyl 2 - Amino - 1,3 - Thiazole - 4 - Carboxylate is shipped in accordance with strict chemical transportation regulations. Packaged securely to prevent leakage, it's transported via approved carriers, ensuring safe transit. |
| Storage | Methyl 2 - Amino - 1,3 - Thiazole - 4 - Carboxylate should be stored in a cool, dry place, away from heat sources and direct sunlight. Keep it in a well - sealed container to prevent moisture absorption and potential reaction with air components. Store it separately from incompatible substances, such as strong oxidizing agents or acids, to avoid chemical reactions that could compromise its integrity. |
| A dedicated intermediate for the cephalosporin side-chain supply chain begins with Methyl 2-Amino-1,3-Thiazole-4-Carboxylate (CAS 118452-04-3; MF C₅H₆N₂O₂S) loaded into glass-lined reactors under nitrogen blanket at partial pressure not exceeding 0.15 bar. The ester is dissolved in a pre‑cooled methanol‑water binary solvent system (volumetric ratio 3:1) at −8 °C to +2 °C, with continuous agitation via retreat‑curve impellers rotating at 85–110 rpm to maintain a Reynolds number above 3×10⁴ and to prevent localised hot‑spots during the subsequent sodium nitrite addition. A freshly prepared 35 % (w/w) aqueous NaNO₂ solution, corresponding to 1.12 ± 0.04 molar equivalents relative to the thiazole ester, is metered below the liquid surface through a dip‑pipe over 45–70 minutes while the reaction mass is held within the −5 °C to 0 °C window by jacketed brine circulation at −15 °C. Exceeding a processing temperature of +4 °C initiates irreversible decomposition of the diazonium intermediate to the 4‑hydroxy‑thiazole by‑product, reducing active‑ester yield by as much as 22 % on a mole‑mole basis and generating a tar‑like fraction that fouls heat‑exchanger surfaces. The resulting diazonium salt solution is immediately transferred via a cooled polytetrafluoroethylene‑lined pipe to a second enamel vessel charged with a methyl acetoacetate‑derived 2‑chloro‑3‑oxobutyrate acceptor and sodium acetate buffer, maintaining pH 4.5–5.2. Oxime etherification with dimethyl sulphate (1.03 ± 0.01 eq.) under phase‑transfer conditions using tetrabutylammonium bromide at 0.4 mol % completes the assembly of the key 2‑(2‑aminothiazol‑4‑yl)‑2‑methoxyiminoacetate precursor, which is subsequently hydrolysed with 2 M NaOH at 25 °C to the corresponding free acid. Manufacturing facilities operating this sequence under ICH Q7 guidelines for active pharmaceutical ingredient starting materials routinely achieve isolated yields of 78–83 % after two recrystallisations from isopropanol‑water (1:1 v/v), with residual solvent limits validated against USP <467> and impurity profiling performed by HPLC on a C18 column (5 µm, 250×4.6 mm) with UV detection at 254 nm. The terminal finished‑good identity is the N‑protected methoxyiminoacetic acid synthons supplied to sterile cefotaxime, ceftriaxone, and cefpodoxime proxetil manufacturing chains, all of which reference the European Pharmacopoeia monograph 01/2024:0482 for the final drug substance and impose a single‑unidentified‑impurity threshold of ≤0.10 area %. During downstream processing of the bulk cephalosporin intermediate, residual Methyl 2‑Amino-1,3‑Thiazole‑4‑Carboxylate content above 0.05 % (as determined by ion‑pair chromatography) has been correlated with batch rejections in a commercial twin‑screw powder‑handling unit because the ester’s hygroscopic nature promotes bridging in the 45° cone‑angle silo discharge hopper at relative humidity exceeding 55 %. Pre‑drying of the ester at 40 °C under vacuum (≤10 mbar) for a minimum of six hours is therefore mandated whenever ambient dew‑point exceeds 8 °C.---**What oxidative coupling limitations emerge when the ester is employed as a dispersed‑dye diazo component?**Disperse azo dyestuff synthesis derived from Methyl 2‑Amino‑1,3‑Thiazole‑4‑Carboxylate exploits the heterocyclic ring’s electron‑withdrawing carboxylate moiety to achieve bathochromic shifts of 35–55 nm relative to aniline‑based analogues, delivering red to violet shades on polyester fibre. In a typical manufacturing campaign conducted in 3 500‑L rubber‑lined brick‑tiled diazotisation pots, the thiazole ester is wetted with 3.2 ± 0.1 parts (by weight) of sulfamic acid‑stabilised 30 % hydrochloric acid and diluted with 6.5 parts of crushed ice to reach a starting temperature of −3 °C. Sodium nitrite (0.98 mol eq.) as a 40 % aqueous solution is injected against the vessel wall during high‑turbulence mixing at a tip speed of 4.2 m·s⁻¹; the diazonium concentration is monitored by starch‑iodide paper until a faint‑blue endpoint persists for 15 seconds after the last NaNO₂ dose. The coupling partner—typically N,N‑diethyl‑m‑toluidine or 3‑(N‑ethyl‑N‑phenylamino)propionitrile—is dispersed in 0.25 mol·L⁻¹ acetic acid containing 0.5 g·L⁻¹ sodium lauryl sulphate and introduced over 90 minutes at 0–5 °C while the pH is steadily raised from 1.8 to 4.0 through the automatic metering of 20 % sodium acetate. A formulation‑specific addition ratio of 1.00:1.12 ± 0.02 (thiazole ester to coupler, expressed on a dry molar basis) has been qualified through a 13‑run factorial design to suppress bis‑azo by‑product formation while maintaining a coupling efficiency above 94 %. The crude press‑cake is washed with deionised water (conductivity <10 µS·cm⁻¹) until filtrate chloride drops below 30 ppm and then spray‑dried at an inlet temperature of 195 °C and outlet of 85 °C, yielding a non‑dusting granular product with a particle size D₅₀ of 35–55 µm suitable for direct dispersion in dye‑house high‑speed dissolvers. Final dye products carry Colour Index generic names such as C.I. Disperse Red 338 or C.I. Disperse Violet 63 and are incorporated into polyester exhaust‑dyeing baths at 0.8–3.0 % on weight of fabric (owf), with fastness assessed under ISO 105‑C06:2010 (C2S wash at 60 °C) and light fastness tested to ISO 105‑B02:2014 (xenon arc, Blue Wool 6 reference). An operational boundary frequently encountered at the 2 000‑L scale arises from the high sensitivity of the heterocyclic diazonium salt to trace iron ions leached from older carbon‑steel service pipes: a dissolved‑iron concentration of ≥1.2 mg·L⁻¹ in the process water causes instantaneous metal‑complex precipitation, lowering final product tinctorial strength by 15–25 % and shifting the λₘₐₓ by up to 18 nm. Plants relying on non‑passivated steel infrastructure therefore install inline 5‑µm polypropylene cartridge filters upstream of the diazotisation vessel.---**Acid Pickling Inhibitor Formulation Tolerances for Low‑Carbon Steel**A practical corrosion‑mitigation package is prepared by blending Methyl 2‑Amino‑1,3‑Thiazole‑4‑Carboxylate at 75–150 mg·L⁻¹ (expressed as active ingredient in the final pickling‑bath volume) with propargyl alcohol and potassium iodide synergists in a 10 % (v/v) methanol pre‑stock, then dosing the concentrate into 15 % hydrochloric acid at 55–70 °C used for mill‑scale removal from hot‑rolled coils, where the adsorption of the thiazole ring onto the steel surface follows the Langmuir isotherm and delivers corrosion inhibition efficiency exceeding 92 % when measured by the weight‑loss method per ASTM G1‑03 in triplicate coupons exposed for six hours.---**Pre‑competitive library synthesis and the selectivity‑addition‑ratio paradigm**Methyl 2‑Amino‑1,3‑Thiazole‑4‑Carboxylate serves as a privileged C‑4 functionalised aminothiazole building block within parallel‑medicinal‑chemistry workflows targeting autoimmune and oncological kinase‑inhibition programmes, where the methyl ester is either retained to occupy shallow hydrophobic back‑pockets of ATP‑binding sites or hydrolysed in situ to the carboxylic acid for subsequent amide coupling. In a 48‑position MiniBlock® XT synthesizer with an IKA™ electromagnetic stirrer array providing 1 200 rpm in each 8‑mL vial, 0.25 ± 0.02 mmol of the ester (pre‑dried at 35 °C under high vacuum for two hours) is activated with 1.05 eq. of HATU in anhydrous DMF containing 2.5 eq. of N,N‑diisopropylethylamine, followed by addition of a primary‑amine‑capped resin‑bound tripeptide. Reaction progress is tracked by LC‑MS (ESI⁺) with an evaporative light‑scattering detector; incomplete coupling after 18 hours prompts a second equivalent of HATU and a four‑hour incubation, a protocol deviation that raises the amide‑bond yield from 68 % to 87 % while keeping residual ester below 1.3 area %. The chelating nature of the 2‑aminothiazole core mandates a metal‑scavenging work‑up using SiliaMetS® DMT (0.3 mmol per mmol of palladium catalyst from a prior Suzuki diversification step) to reduce palladium content to <5 ppm before final HPLC purification, a step whose omission has been documented to cause false‑positive kinase‑inhibition readouts in TR‑FRET assays due to metal‑ion interference. While no discrete industrial‑hygiene standard governs the compound beyond its registration under EU REACH (EC Number 689‑163‑0), all library‑production batches are handled in accredited ISO 9001:2015 synthesis facilities applying the occupational‑exposure band‑B control regime prescribed by ICH M7 for potentially mutagenic impurities, and the formulated screening deck is plated as 10 mM DMSO stock solutions in Greiner Bio‑One 384‑well V‑bottom plates, dried under nitrogen and stored at −20 °C with a 24‑month expiry validated by quarterly LC‑MS purity checks.---**When the ester is processed through a continuous‑flow Knorr‑type cyclisation**Thiazolopyrimidine‑dione heterocycles produced in a Vapourtec R‑Series flow reactor from Methyl 2‑Amino‑1,3‑Thiazole‑4‑Carboxylate are exploited by agrochemical innovation platforms as protox‑inhibiting herbicide precursors. A solution of the thiazole ester (0.40 M in 2‑methyltetrahydrofuran) and a slight excess of ethyl 3‑oxo‑4‑(triphenylphosphoranylidene)butyrate (1.25 eq.) is pumped through a 10‑mL PFA coil at a residence time of 12 minutes and a set‑point temperature of 155 °C, generating a back‑pressure of 10 bar regulated by a spring‑loaded BPR. The intermediate enamino‑ester is subsequently intercepted by an inline stream of phenyl isocyanate (1.05 eq.) in toluene, yielding the bicyclic pyrimidine‑dione scaffold at a steady‑state yield of 81 % with a throughput of 8.4 g·h⁻¹. Patented field‑trial formulations based on this scaffold are applied at 45–180 g a.i.·ha⁻¹, and their technical concentrates must comply with CIPAC MT 18.1.3 for suspensibility and with the 48‑month storage‑stability test protocol described in the FAO Pesticide Specification Manual (5th revision). Because residual palladium from the phosphorane synthesis is carried into the flow loop at levels occasionally exceeding 30 ppm, a scavenger cartridge containing QuadraPure™ TU macroporous polystyrene‑bound thiourea is placed downstream of the second reactor module, reducing Pd to <6 ppm and preventing an acute phytotoxic response in broccoli (Brassica oleracea var. italica) indicator plants that appears at soil‑drench concentrations above 1.2 µmol·L⁻¹ of the unpurified reaction mass. |
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Adopted widely across multi-step synthesis campaigns for active pharmaceutical ingredients (APIs) requiring a 2-aminothiazole-4-carbonyl motif, the methyl ester of 2-amino-1,3-thiazole-4-carboxylic acid (CAS 2150-45-0) presents a molecular weight of 158.18 g·mol⁻¹ and a typical mass-balanced assay of ≥ 98.0% by reverse-phase HPLC (area normalization at 254 nm, C18 column, acetonitrile/0.1% phosphoric acid gradient). Lot-to-lot titration against a traceable standard confirms a residual water content below 0.5% w/w (Karl Fischer coulometry, DIN 51777) when packaged under nitrogen headspace in amber double-laminated PE liners. The free-flowing off-white crystalline powder is sized to pass through an 80-mesh sieve (180 µm) as determined by ASTM E11, ensuring consistent dissolution kinetics in anhydrous DMF and THF during automated solid-dosing operations.
Beyond its role as a simple acetylation substrate, the 2-amino group exhibits a nucleophilicity profile that enables regioselective acylation at 0–5 °C without detectable ester aminolysis, provided the acid chloride addition is controlled to a rate below 0.2 equivalents per minute. When coupled with Fmoc-protected amino acids under HATU/NMM activation in DMF, the methyl ester remains intact, giving amide-linked conjugates in isolated yields of 72–88% after silica gel chromatography (monitored at Rf 0.35 in ethyl acetate/hexane 1:1 v/v). Substitution of the methyl ester by the corresponding free acid typically requires saponification with LiOH in THF/H2O at 0 °C; heating above 25 °C during hydrolysis initiates decarboxylation, leading to 2-aminothiazole as the dominant contaminant, which co-elutes with the desired acid under standard ion-pairing HPLC conditions. In contrast, the methyl ester provides a latent carboxylic acid function that withstands Suzuki coupling conditions (Pd(PPh3)4, Na2CO3, DME/H2O, 80 °C) for at least 6 h, as confirmed by CO2 evolution monitored via inline FTIR (2349 cm⁻¹ band). Such oxidative stability differentiates it from the benzyl ester analogue, which hydrogenolyzes prematurely under coupling conditions requiring a Pd catalyst.
Formal release for use in registered intermediates under ICH Q7 guidelines imposes a panel of tests far exceeding simple chromatographic purity. A typical certificate of analysis includes the parameters listed in Table 1. Residual palladium often arises from upstream hydrogenation or cross-coupling steps and is capped at 20 ppm to minimize catalyst poisoning in subsequent reductive aminations.
| Parameter | Specification | Rational / Method |
|---|---|---|
| Appearance | White to pale yellow crystalline powder | Visual comparison against certified colour standard (EP 2.2.2) |
| Assay (HPLC) | ≥ 98.0% | Area % at 254 nm; EP 2.2.29 / USP <621> |
| Melting range | 150–154 °C | Capillary method, ASTM E324-23; endotherm onset via DSC at 151.8 ± 1.5 °C |
| Water (Karl Fischer) | ≤ 0.5% w/w | Coulometry; DIN 51777 |
| Residual solvents | Methanol ≤ 3000 ppm, THF ≤ 720 ppm | HS-GC/FID; USP <467> Class 2 |
| Heavy metals (total) | ≤ 10 ppm as lead | ICP-MS screening; USP <232>/<233> |
| Residual Pd | ≤ 20 ppm | ICP-MS after microwave-assisted acid digestion |
| Chloride | ≤ 200 ppm | Ion chromatography (USP <1065>) |
Particularly critical is the chloride limit: excess chloride introduced during salt precursor formation (e.g., from chloroacetyl chloride) correlates with corrosion pitting in Hastelloy C-276 reactors during scaled-up saponification. In practice, chloride above 500 ppm has been observed to accelerate stress corrosion cracking rates under the mildly acidic post-hydrolysis quench (pH 3–4, 60 °C), as evidenced by coupon weight loss studies exceeding 0.1 mm/yr. Thus the ≤ 200 ppm clamp reflects materials compatibility rather than API degra-dant thresholds.
Without a dedicated header, the following scenario presents a high-density sequence on storage stability. Storage under inert gas is not a recommendation but a prerequisite for maintaining the monomeric integrity of methyl 2-amino-1,3-thiazole-4-carboxylate during transcontinental shipping. Accelerated stability testing per ICH Q1A (R2) at 40 °C / 75% RH open-dish for 6 months produces a discolouration shift from a reflectance colour-difference value (ΔE*ab) of 0.8 to 4.5, approaching the visible detection threshold. In parallel, HPLC peak area reduction of 0.4–0.7% is observed, with an associated growth of a polar degradation peak identified by LC-MS as the ring-opened methyl 2-amino-3-thiocarbamoylacrylate. This degradation accelerates under UV-A (365 nm) light: a 20% loss of purity occurs within 72 h in quartz vessels, versus <1% in amber borosilicate glass. Commercial storage dispensed from double-cone blenders equipped with nitrogen-blanketed glove ports (residual O2 <1% v/v) and maintained at 15–20 °C extends re-test dating to 36 months from the date of manufacture.
Differential scanning calorimetry at a ramp rate of 5 °C·min⁻¹ under nitrogen reveals a sharp melting endotherm with onset 151.8 °C (ΔHf 116 J·g⁻¹), followed by an exothermic decomposition commencing at 218 °C (ΔHd −580 J·g⁻¹). Accelerating rate calorimetry (ARC) in a Hastelloy bomb under phi-factor correction of 1.2 detects self-heating above 190 °C, with adiabatic temperature rise of 85 K and a maximum self-heat rate of 0.6 °C·min⁻¹ at 210 °C. The time to maximum rate under adiabatic conditions (TMRad) is estimated at 8 h at 200 °C. Such data inform the emergency-relief vent sizing for bulk-drying ovens: NFPA 68-compliant deflagration venting is not mandated at inventory quantities below 500 kg, provided the temperature control system is interlocked to shut off heating elements at 140 °C. The product is classified as non-explosive under UN Test Series 1 and 2 (UN Manual of Tests and Criteria, Part I), with a BAM fallhammer sensitivity > 40 J. Nevertheless, photolytic ring-opening at ambient temperature generates thiirane intermediates that can oligomerize to a dark, viscous tar; storage under red-light conditions (λ > 600 nm) in production suites is thus maintained.
Several 2-aminothiazole-4-carboxylate esters are commercially catalogued, but the methyl variant frequently enables reaction trajectories that ethyl, benzyl, or sterically bulky esters do not. Table 2 summarises salient physico-chemical and operational differences. The methyl ester’s higher water solubility (2.4 mg·mL⁻¹ at 25 °C) compared to the ethyl ester (1.1 mg·mL⁻¹) allows for a wider range of biphasic hydrolysis conditions without resorting to co-solvents that complicate work-up. During direct amidation with primary amines, the methanol liberated (bp 64.7 °C) is removed more rapidly from the reaction mixture under atmospheric distillation than ethanol (bp 78.4 °C), driving equilibrium conversion; with tert-butyl ester (not commercially available at bulk scale), acidolytic deprotection generates isobutylene, demanding pressurized equipment and rigorous scavenging of tert-butyl cation to prevent alkylation of nucleophilic heterocycles.
| Property / Parameter | Methyl Ester (CAS 2150-45-0) | Ethyl Ester (CAS 5398-36-7) | Benzyl Ester (CAS 321309-40-0) |
|---|---|---|---|
| Molecular weight | 158.18 g·mol⁻¹ | 172.21 g·mol⁻¹ | 234.27 g·mol⁻¹ |
| Melting point (DSC onset) | 151.8 °C | 134.2 °C | 99–101 °C (dec) |
| Solubility in THF (25 °C) | 32 g·L⁻¹ | 45 g·L⁻¹ | 58 g·L⁻¹ |
| Ease of ester cleavage | LiOH, 0 °C, 30 min | NaOH, 20 °C, 2 h | H2, Pd/C, 25 °C, 1 atm |
| Key incompatibility | Avoid strong aqueous acid above 40 °C (ring protonation promotes hydrolysis) | Tolerates pH 2–10 at 25 °C; slower aminolysis | Incompatible with hydrogenolysis-labile protecting groups (Cbz, benzyl ether) |
| Typical purity (cGMP lot) | ≥ 98.0% | ≥ 97.0% | ≥ 95.0% (often contains dibenzyl impurity) |
In medicinal chemistry arrays, the methyl ester has been favored as a surrogate for the carboxylic acid in parallel library synthesis of 2-amidothiazole-4-carboxamides targeting kinase hinge-binding motifs. The acid chloride derived from the methyl ester is stable in refluxing thionyl chloride without decomposition of the thiazole ring, whereas the benzyl ester variants undergo debenzylation with SOCl2/pyridine, complicating product profiles.
Scaling the batch process for methyl 2-amino-1,3-thiazole-4-carboxylate beyond 100 kg typically employs a modified Hantzsch condensation between monochloroacetone and thiourea, followed by esterification with methanol/HCl, rather than direct condensation of methyl bromopyruvate with thiourea—the latter generates brominated impurities that require multiple recrystallizations to reach 98% purity. In the optimized route, the crude product is isolated as the free base after pH adjustment to 7.5–8.0 with aqueous ammonia in methanol at 10 °C, filtered on a centrifuge (RCF 800–1200 g) and washed with deionized water until the filtrate conductivity drops below 50 µS·cm⁻¹. Vacuum drying at 40 °C and 10 mbar for 24 h reduces residual methanol to < 3000 ppm, meeting the ICH Q3C option 2 limit. Yield from thiourea typically lands in the range 62–68%, with the principal mass loss occurring during mother-liquor recycling where the thiazole ring undergoes slow solvolysis in aqueous methanolic mother liquors held at room temperature beyond 8 h. Continuous processing development has focused on in-line Raman monitoring of the cyclization step (1595 cm⁻¹ thiazole ring mode) to trigger quenching and reduce ring-opening losses to <2%.
Published data for large-scale registries of this specific compound in continuous flow are limited, yet batch records indicate that crystal size distribution (span 1.4–2.1) directly impacts dissolution-limited coupling efficiency; micronization to a D90 below 15 µm using a spiral jet mill (N2 pressure 4 bar) shortens dissolution time in 2-MeTHF by a factor of 2.7 relative to un-milled material. That size reduction is offset by increased electrostatic charging, requiring ionized-air flow devices above vibratory feeding trays to maintain consistent feed rates into continuous stirred-tank reactors.
No formal incompatibility with common desiccants is observed, but silica gel has been found to catalyse slow ester hydrolysis when the compound is stored as a dry-loaded sample for column chromatography for durations beyond 48 h; acid-washed alumina is recommended for preparative chromatography. Interaction with nitrosating agents (nitrous acid, N2O3) leads to formation of the corresponding N-nitroso derivative, a finding of toxicological relevance that drives an engineering control protocol requiring separate ventilation loops for any area handling nitrite reagents.
