Ethyl 2-Amino-4-Methylthiazole-5-Carboxylate
|
HS Code |
793753 |
| Chemical Formula | C7H10N2O2S |
| Molecular Weight | 186.23 g/mol |
| Appearance | Typically a solid (appearance can vary based on purity and preparation) |
| Melting Point | Specific melting point data would need further research |
| Boiling Point | Boiling point information requires more in - depth study |
| Solubility | Solubility characteristics would depend on the solvent; likely sparingly soluble in water, more soluble in some organic solvents |
| Odor | May have a characteristic odor, but specific odor details need research |
| Density | Density data would need to be determined experimentally |
| Stability | Stability can be affected by factors like heat, light, and moisture |
| Reactivity | Can react with various reagents due to the presence of the amino, carboxylate, and thiazole groups |
As an accredited Ethyl 2-Amino-4-Methylthiazole-5-Carboxylate factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 500g of Ethyl 2 - Amino - 4 - Methylthiazole - 5 - Carboxylate packaged in a sealed plastic bag. |
| Shipping | Ethyl 2 - Amino - 4 - Methylthiazole - 5 - Carboxylate is shipped in sealed, corrosion - resistant containers. It's transported under regulated conditions to prevent exposure, ensuring compliance with chemical shipping safety regulations. |
| Storage | Ethyl 2 - Amino - 4 - Methylthiazole - 5 - 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 contact with air, which could potentially lead to chemical degradation. Store it separately from incompatible substances, such as strong oxidizing agents or acids. |
In the industrial-scale manufacturing of third-generation injectable cephalosporins, the activated thiazole moiety derived from ethyl 2-amino-4-methylthiazole-5-carboxylate serves as the critical acyl donor during acylation of 7-aminocephalosporanic acid (7‑ACA). Production campaigns executed in 2000 L glass-lined reactors require the ester to be converted to its free acid via controlled alkaline hydrolysis—typically using 1.02–1.05 molar equivalents of sodium hydroxide at 10 °C–15 °C—followed by acid precipitation, isolation in a filter press, and vacuum drying at 45 °C and ≤25 mbar to reduce water content below 0.15 wt%. The dry 2-amino-4-methylthiazole-5-carboxylic acid is then treated with thionyl chloride (1.5–1.8 eq) in anhydrous methylene chloride containing a catalytic quantity of dimethylformamide (0.03 eq) at −5 °C to 0 °C to generate the corresponding acyl chloride; this intermediate exhibits a usable pot-life of less than 60 min before dimerisation becomes detectable by in-line Raman spectroscopy. Coupling with 7‑ACA is carried out in a chilled 5000 L stainless‑steel reactor by slow addition of the acyl chloride solution at a molar ratio of 1.05–1.12 relative to the β‑lactam nucleus, with triethylamine (1.15 eq) as acid scavenger and a jacket temperature maintained at −12 °C. After aqueous work‑up and pH‑controlled crystallisation, the crude cefodizime acid is washed with acetone and recrystallised from aqueous ethanol to meet the tightest impurity profile described in the European Pharmacopoeia monograph 01/2024:0663 for cefodizime sodium, with single unknown impurities held below 0.10% by HPLC (column: C18, 5 µm, 250 × 4.6 mm; mobile phase: phosphate buffer pH 3.2/acetonitrile 85:15). The terminal dosage form is a sterile lyophilised powder for injection, filled under aseptic conditions complying with 21 CFR 211.113 and EU GMP Annex 1. Active pharmaceutical ingredient intermediate manufacturers are obliged to operate under a quality management system aligned with ICH Q7 (Section 12.1) and to supply complete residual solvent data according to ICH Q3C, where the limit for methylene chloride is 600 ppm and that for dimethylformamide is 880 ppm in the final substance.
What Limits Acyl Chloride Conversion in Anhydrous Coupling Systems When the Methyl Ester Hydrolysate is the Preferred Form?When a pharmaceutical synthesis programme evaluates ethyl 2-amino-4-methylthiazole-5-carboxylate against the corresponding benzyl or tert‑butyl ester for generating late‑stage β‑lactam side chains, the driving selection parameters rapidly converge on hydrolytic lability and crystallisation behaviour of the free acid intermediate. The ethyl ester is cleaved under significantly milder conditions—0.5 N NaOH at 10 °C reaches >99% conversion within 25 min—while the benzyl analogue requires hydrogenolysis over 5% Pd/C at 3 bar H₂, introducing a flammable atmosphere and metal‑contamination risk into the suite. This difference cascades into the downstream acyl chloride-generation step: the 2‑amino‑4‑methylthiazole‑5‑carboxylic acid derived from the ethyl ester, when dried to ≤0.1% moisture and suspended in 10 volumes of anhydrous toluene, reacts with oxalyl chloride (1.2 eq, added at 0 °C over 45 min) to deliver a conversion consistently above 97% as determined by FT‑IR decay of the carbonyl band at 1775 cm⁻¹. Nevertheless, production records from a multi‑purpose 1000 L glass-lined unit reveal a recurrent bottleneck: when ambient relative humidity exceeds 60%, atmospheric moisture ingress through the vent line forms N‑acetyl‑2‑amino‑4‑methylthiazole‑5‑carboxylic acid as a recalcitrant by‑product at levels up to 1.8%, reducing batch-to‑batch consistency. To mitigate this, the facility retrofitted a closed‑loop nitrogen blanket system with a −40 °C methanol‑dry ice condenser and an in‑line Karl Fischer analyser that cuts off reagent feed if water content in the toluene stream rises above 50 ppm. The addition ratio for the activated side chain in the subsequent acylation of the amino‑cephalosporin core is maintained at 1.08–1.13 molar equivalents; excursions above 1.15 lead to diacylated impurities that require a supplementary column chromatography step on macroporous poly‑styrene‑DVB resin, increasing the cost per kilogram by an estimated 18–22%. The target terminal products are diverse injectable cephalosporins falling under the J01DD ATC classification, with free‑acid intermediates destined for lyophilised sodium salts that must satisfy the clarity-of-solution test as per EP 2.2.1 and pass the bacterial endotoxin limit of ≤0.10 EU/mg when the material is intended for a 1 g per vial presentation. Regulatory alignment depends on the full suite of ICH Q6A decision trees for specification setting, alongside 21 CFR 211.84 for incoming raw material testing, which requires identity confirmation by FT‑IR matching a qualified reference spectrum and assay by non‑aqueous titration with perchloric acid.Methylthiazole Carboxamide Fungicides and the Hydrolytic Stability Threshold During Scale‑UpThe conversion of ethyl 2-amino-4-methylthiazole-5-carboxylate into fungicidally active carboxamides for crop protection requires that the ester withstand the mildly acidic or basic conditions of a cascade that often includes a concurrent amidation step without premature hydrolysis of the thiazole carboxylate. In the preparation of a suspect‑resistant succinate dehydrogenase inhibitor (SDHI) backbone, the ethyl ester is first hydrolysed with 1.05 eq of lithium hydroxide in tetrahydrofuran‑water (3:1) at 25 °C for 12 h to quantitatively liberate the parent acid, which precipitates upon acidification to pH 3.0 and is isolated with 98.5% purity. The subsequent amide bond formation with a substituted aniline is accomplished by activating the acid with N,N’‑dicyclohexylcarbodiimide (1.10 eq) and 1‑hydroxybenzotriazole (0.10 eq) in dimethylformamide at 0–5 °C, maintaining a strict 1.0:1.0 stoichiometry between acid and anime to avoid the formation of an anilide impurity that co‑elutes with the target carboxamide on a normal‑phase silica column. Pilot‑plant batches executed in a 500 L Hastelloy C‑276 vessel at −5 °C jacket temperature showed a sudden exothermic excursion to 18 °C during DCC addition, which reduced yield by 7% and triggered a haze failure in the subsequent 250 g/L suspension concentrate (SC) formulation test; root‑cause analysis traced the event to insufficient heat‑transfer area—the jacket‑to‑volume ratio was 0.85 m²/m³, whereas ≥1.40 m²/m³ is recommended for carbodiimide‑mediated couplings. After retrofitting with a 2.4 m² plate‑and‑frame heat exchanger in a recirculation loop, the reaction temperature was maintained within ±1 °C of the setpoint, and the isolated yield of the key carboxamide intermediate levelled at 92–94% with a melting point of 187–189 °C. The carboxamide is then readily formulated into an aqueous SC using a 5 L basket mill filled with 0.6–0.8 mm yttria‑stabilised zirconia beads, employing 2.0 wt% of a sulfosuccinate‑based dispersant and 0.15 wt% of a polysiloxane defoamer; particle size measured by laser diffraction (Malvern Mastersizer 3000) shows D₅₀ below 2.5 µm and D₉₀ below 8.0 µm. The proprietary fungicide (a thiazole‑pyridinyl‑propanamide derivative disclosed in several patent families) is targeted for foliar application on cereals at a field rate of 100–150 g active ingredient per hectare. Pre‑registration dossiers require compliance with FAO Specification 2017 for SC formulations, stability data under CIPAC MT 46.3 (accelerated storage at 54 °C for 14 days), and acute toxicity profiling adhering to EPA 40 CFR Part 158.500. Producers of the intermediate are expected to hold a valid ISO 14001 certificate and to report emissions of volatile organic compounds—especially from the dimethylformamide recycling loop—under EU Directive 2010/75, while the active ingredient technical material must pass the 5‑batch analysis requirement of OECD 509 for impurity fingerprinting.
When Disperse Dyes Require a Methylthiazole Auxochrome to Shift Absorption into the Deep Red RegionThe electron‑rich 2‑aminothiazole chromophore has long served as a diazo component in mono‑azo disperse dyes for polyester, and the presence of a 4‑methyl‑5‑carboxylic ester substituent on the thiazole ring provides a bathochromic shift of approximately 35–50 nm relative to the unsubstituted 2‑aminothiazole precursor, moving the absorption maximum in dyed polyethylene terephthalate (PET) into the rubine‑to‑scarlet window near 515–530 nm. The ester is first hydrolysed to the free amine‑acid—achieved by heating at 80 °C with 2.0 N hydrochloric acid for 4 h—and the resulting 2‑amino‑4‑methylthiazole‑5‑carboxylic acid is diazotised at 0–2 °C by dropwise addition of a 30% sodium nitrite solution to a suspension in 2.5 eq of hydrochloric acid, ensuring a slight excess of nitrous acid detectable on starch‑iodide paper. The cold diazonium salt solution, maintained at ≤3 °C and clarified by filtration through a pre‑cooled sparkler filter, is then coupled with a stoichiometric amount (1.00 eq) of N‑ethyl‑N‑(2‑cyanoethyl)aniline dissolved in methanol at pH 4.0–4.5; the coupling bath is buffered with sodium acetate‑acetic acid and the reaction is allowed to proceed over 3–5 h with gradual warming to 15 °C. The resulting mono‑azo dye is precipitated by addition of 5% sodium chloride, collected in a plate‑and‑frame filter press, and washed with ice‑cold deionised water until the filtrate conductivity drops below 200 µS/cm. After drying in a 60 °C fluid‑bed dryer to a moisture content of ≤0.5%, the crude dye is standardised with lignin sulfonate dispersant in a pin mill to yield the commercial formulation, which typically contains 35–45% colourant, 50–60% dispersant, and 1–3% dedusting oil. The dyed polyester fabric achieves a build‑up to 2.0% owf (on weight of fabric) under high‑temperature exhaust conditions at 130 °C for 45 min, exhibiting wash fastness values of grade 4–5 according to ISO 105‑C06 A2S and light fastness of grade 6–7 under ISO 105‑B02 (Xenon arc). Because the dye contains a primary aromatic amine derived from the di‑azo linkage, the manufacturer is obligated to demonstrate that no carcinogenic arylamine is liberated under reductive cleavage conditions specified in DIN EN ISO 14362‑1:2023; the test requires that the free amine concentration remain below 30 mg/kg for each of the amines listed in EU Regulation 1907/2006, Annex XVII, entry 43, and that the overall ZDHC MRSL v3.0 conformance be verified by the supplier’s stage‑1 wastewater analysis in accordance with ISO 17294‑2. The terminal commercial product is an aqueous press‑cake or granular form of a deep‑red heterogeneous disperse dye marketed for polyester sportswear and automotive interior textiles, which must additionally meet the OEKO‑TEX STANDARD 100 class I threshold for formaldehyde (≤ 16 mg/kg) and extractable heavy metals. |
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Ethyl 2-amino-4-methylthiazole-5-carboxylate (CAS 7210-76-6, empirical formula C₇H₁₀N₂O₂S, molecular weight 186.23 g·mol⁻¹, SMILES: CCOC(=O)c1sc(N)nc1C) is a heterocyclic ester supplied as a crystalline powder with an off-white to pale yellow hue and a melting point range of 95–98°C (capillary method, DIN 53736). Commercial lots are routinely certified at purities exceeding 98.0% by HPLC peak area (λ = 254 nm, C18 column, isocratic acetonitrile/water) and are packaged in 25 kg fibre drums with double polyethylene liners under nitrogen headspace. The molecule functions primarily as a protected form of 2-amino-4-methylthiazole-5-carboxylic acid, enabling its incorporation into amide bonds without the solubility and activation penalties of the free acid. In pharmaceutical intermediate supply chains, the ethyl ester is valued for its balance of crystallinity, organic-phase solubility, and hydrolytic stability, which distinguishes it from the parent acid and the corresponding methyl ester. The acid (CAS 49708-82-9, MW 172.20 g·mol⁻¹) melts with decomposition above 240°C and exhibits negligible solubility in dichloromethane, rendering direct coupling protocols impractical without aggressive activation. Substitution of the carboxylic acid moiety with an ethoxycarbonyl group shifts the compound’s solubility profile dramatically: solubility in dichloromethane at 25°C exceeds 100 g·L⁻¹, and the solid remains free-flowing under ambient conditions when protected from moisture. These properties facilitate large-scale peptide-type coupling reactions in glass-lined reactors where efficient dissolution and consistent stoichiometry are critical. Lot-to-lot variability in particle size distribution is controlled through milling and sieving to a specification of D₉₀ ≤ 250 µm (laser diffraction, ISO 13320:2020), a parameter that has been shown to affect dissolution time in anhydrous tetrahydrofuran by up to 30% across different batches observed on a 500 L production line. The compound is not intended for direct human use and is manufactured under a quality system aligned with ICH Q7 for active pharmaceutical ingredient starting materials.
| Parameter | Specification | Test procedure |
|---|---|---|
| Appearance | Off-white to pale yellow crystalline powder | Visual observation under D65 illumination |
| Assay (HPLC) | ≥98.0% area | USP <621>; C18, 5 µm, 250×4.6 mm; mobile phase acetonitrile/water (40:60 v/v); 1.0 mL·min⁻¹; detection 254 nm |
| Loss on drying | ≤0.5% | USP <731>; vacuum, 70°C, 4 h |
| Residue on ignition | ≤0.1% | USP <281>; 600 ± 50°C |
| Heavy metals (as Pb) | ≤10 ppm | USP <231> Method II |
| Melting point | 95–98°C | USP <741> Class I |
| Residual ethanol | ≤5000 ppm | Headspace GC-FID, USP <467> |
| Water (Karl Fischer) | ≤0.3% | USP <921> Method Ia |
Each parameter is validated across multiple production campaigns on a 100 kg scale. The HPLC assay method employs a gradient-free separation to minimize baseline drift during sequence runs exceeding 48 hours and uses an external standard of 99.5% purity (traceable to NIST SRM 916c for purity assessment principles). The loss-on-drying specification is critical: residual moisture in excess of 0.5% has been observed to accelerate ester hydrolysis during prolonged storage in polyethylene containers exposed to relative humidity above 60% at 30°C, as evidenced by a 1.2% drop in assay over 12 months in accelerated stability trials (40°C/75% RH, ICH Q1A). The residue-on-ignition limit ensures compatibility with subsequent catalytic hydrogenation steps—palladium-on-carbon deactivation has been noted when sulfated ash exceeds 0.3% in downstream reductive amination processes. Routine heavy-metals monitoring by colorimetric Method II remains sufficient for non-parenteral applications; however, customers requiring compliance with ICH Q3D elemental impurity guidelines (particularly Class 1 elements such as As, Cd, Hg, Pb) can request quantitative ICP-MS data generated in accordance with USP <233>.
| Property | Ethyl ester | Methyl ester | Isopropyl ester | Free acid |
|---|---|---|---|---|
| CAS | 7210-76-6 | 66358-24-7 | — | 49708-82-9 |
| Molecular weight (g·mol⁻¹) | 186.23 | 172.20 | 214.28 | 158.18 |
| Melting point (°C) | 95–98 | 105–108 | limited availability, estimated 80–85 | decomp. >240 |
| Solubility in dichloromethane (g·L⁻¹, 25°C) | >100 | >100 | — | <1 |
| Solubility in toluene (g·L⁻¹, 25°C) | ~45 | ~28 | — | insoluble |
| Hydrolytic stability (pH 9, 25°C, half-life relative to methyl ester) | 1.7× longer | baseline | — | not applicable |
| Typical use | Cephalosporin side-chain protection; generic API synthesis | Small-scale research; light-sensitive couplings | Not commercialised | Salt formation; prodrug development |
The methyl ester (CAS 66358-24-7, MW 172.20 g·mol⁻¹) crystallises with a higher melting point (105–108°C) and shares excellent solubility in chlorinated solvents, yet the ethyl homologue demonstrates superior performance in industrial amidation sequences for two primary reasons. First, the additional methylene unit in the alkoxy chain imposes steric hindrance that retards nucleophilic attack by hydroxide ion, resulting in an alkaline hydrolysis rate constant that is approximately 1.7-fold lower than that of the methyl ester under identical buffer conditions (pH 9.0, carbonate buffer, 25°C). This translates into a wider operating window during aqueous work-up procedures, where residual base can prematurely cleave the ester if contact times exceed 10–15 minutes. Second, the ethyl ester’s melting point, being 10–15°C below that of the methyl homologue, eases the dissolution process in anhydrous tetrahydrofuran at the 0–5°C temperatures required for active-ester formation with isobutyl chloroformate; operators on 50 L and 200 L jacketed reactors report a reduction in the time needed to achieve a clear solution from typically 45 minutes to approximately 25 minutes when switching from methyl to ethyl ester. The isopropyl ester has never gained traction in multi-kilogram supply because of its low melting point and propensity to form oils during isolation—published data for this specific configuration is limited, and no commercial manufacturing campaign exceeds laboratory scale. The free acid, while the simplest building block, cannot be directly solubilised in the low-polarity media favoured for carbodiimide-mediated couplings; attempts to slurry the acid in dichloromethane with dicyclohexylcarbodiimide (DCC) result in incomplete conversion and the formation of N-acylurea by-products that require chromatographic removal, rendering yields below 50%. The ethyl ester bypasses this limitation and provides a crystalline, filterable intermediate that aligns with the downstream purification infrastructure of generic cephalosporin manufacturers.
Ethyl 2-amino-4-methylthiazole-5-carboxylate is typically activated as a mixed carbonic anhydride prior to coupling with the C-7 amino group of 7-ACA or 7-ACT. A representative procedure on a 50 L glass-lined reactor (jacket temperature set to –5°C, anchor stirrer at 120–150 rpm) involves dissolving the ester (4.0 kg, 21.5 mol) in anhydrous tetrahydrofuran (24 L, moisture content <0.01% by Karl Fischer) and adding N-methylmorpholine (2.6 kg, 26 mol) under nitrogen blanketing. After cooling to –10°C, isobutyl chloroformate (2.9 kg, 21.5 mol) is dosed over 45 min while maintaining the internal temperature below 0°C. The mixed anhydride formation is verified by TLC (silica gel, ethyl acetate/hexane 1:1, Rf shift from 0.5 to 0.8). The reaction mixture is then transferred to a suspension of silylated 7-ACA in dichloromethane at 0°C; coupling proceeds over 2–3 h and is quenched with aqueous sodium bicarbonate. Reported yields of the protected intermediate fall in the range 80–92% after solvent swap and crystallisation from ethyl acetate/hexane. The ethyl ester’s steric profile reduces the incidence of racemisation at the α-carbon of the cephalosporin side chain, a problem flagged in legacy methyl-ester processes that operated at pH values exceeding 8.5 during work-up—chiral HPLC monitoring (USP <621> with a Chiralpak IA column) consistently shows <0.5% of the D-isomer when the ethyl ester is employed. In contrast, the methyl ester under identical conditions can generate up to 2.1% of the undesired enantiomer, necessitating a recrystallisation step that reduces overall yield by 8–12%. Process analytical technology (PAT) is occasionally implemented on these lines: in-line ReactIR probes tracking the carbonyl stretch of the anhydride at ~1820 cm⁻¹ have been used to determine reaction endpoint, replacing manual sampling and shortening cycle time by 35 minutes per batch in a 200 L campaign. Once the amide bond is formed, the ethyl ester is removed by mild alkaline hydrolysis (1M NaOH, 0–5°C, monitored to pH 9.5 endpoint) without affecting the β-lactam ring, a cleavage tolerant only when the steric bulk of the ethoxy group imposes the correct deprotection rate.
Bulk ethyl 2-amino-4-methylthiazole-5-carboxylate, when packed in polyethylene liners inside sealed fibre drums containing silica gel desiccant (500 g per 25 kg unit), maintains an HPLC assay above 98.0% for 24 months at storage temperatures not exceeding 25°C. Accelerated stability data generated per ICH Q1A (40°C/75% RH, 6 months) show no single impurity exceeding 0.15% when the container closure remains intact; opening and re-sealing under ambient humidity (60% RH) introduces moisture that can drive ester hydrolysis, producing 2-amino-4-methylthiazole-5-carboxylic acid as the principal degradant. Once a container has been opened, the remaining material should be kept under dry nitrogen in a vacuum desiccator at ≤8°C and used within 30 days to stay within the 98.0% assay window. The compound should not be stored alongside strong oxidising agents (e.g., peroxides, hypochlorites), as thermogravimetric analysis coupled with FTIR has revealed exothermic decomposition onset at ~180°C with charring in the presence of oxidisers. Incompatibility with primary and secondary amines in solution is pronounced: when the ester is dissolved in tetrahydrofuran containing morpholine at 1% v/v and held at 25°C, the half-life of the ester bond drops to under 6 hours due to transesterification and aminolysis side reactions. This reactivity prohibits the use of amine-based additives—frequently employed as acid scavengers—in pre-mixed solutions; instead, sterically hindered tertiary amines such as N,N-diisopropylethylamine (DIPEA) must be used, and even then only at 1.0–1.1 equivalents relative to the substrate. Contact with heavy-metal surfaces (copper, bronze) has been observed to catalyse oxidative degradation of the thiazole ring, turning the solid faint green within 48 hours at 30°C; all process equipment is therefore specified in 316L stainless steel or glass-lined construction, with gaskets of EPDM rated for pH 2–12. In synthesis suites operating under cGMP for late-stage intermediates, dedicated charging booths with dew-point control set to –20°C are employed to prevent moisture ingress during dispensing, and transfer hoses are purged with dry nitrogen with a dew-point specification of ≤ –40°C as verified by a portable hygrometer.
