4-Thiazolecarboxylic Acid, 2-(Chloromethyl)-, Ethyl Ester
|
HS Code |
119445 |
| Name | 4-Thiazolecarboxylic Acid, 2-(Chloromethyl)-, Ethyl Ester |
| Chemical Formula | C7H8ClNO2S |
| Molar Mass | 207.66 g/mol |
| Appearance | Typically a solid (but can vary depending on purity and conditions) |
| Solubility In Water | Low solubility, as it is an organic ester with a polar - non - polar balance favoring non - aqueous solvents |
| Solubility In Organic Solvents | Soluble in common organic solvents like dichloromethane, chloroform, ethyl acetate |
| Boiling Point | Estimated to be in the range where organic esters with similar structures boil, likely above 200°C (but exact value depends on purity and pressure) |
| Melting Point | Specific melting point data would require experimental determination, but expected to be in the range typical for such organic solids, perhaps around 50 - 100°C |
| Density | Estimated density based on similar esters, around 1.2 - 1.3 g/cm³ |
| Reactivity | The chloromethyl group is reactive, can participate in nucleophilic substitution reactions; the ester group can undergo hydrolysis, transesterification reactions |
As an accredited 4-Thiazolecarboxylic Acid, 2-(Chloromethyl)-, Ethyl Ester factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100g of 2-(Chloromethyl)-4-thiazolecarboxylic acid ethyl ester in sealed chemical - grade packaging. |
| Shipping | Ship 2-(Chloromethyl)-4-thiazolecarboxylic acid ethyl ester with extreme caution. Package it in suitable chemical - resistant containers. Follow all regulations for shipping hazardous chemicals, ensuring proper labeling and documentation. |
| Storage | Store 2-(Chloromethyl)-4-thiazolecarboxylic acid ethyl ester in a cool, dry, well - ventilated area, away from heat sources and open flames. Keep it in a tightly sealed container to prevent moisture and air exposure, which could potentially lead to degradation. This chemical should be stored separately from incompatible substances like oxidizing agents and bases to avoid dangerous reactions. |
In cephalosporin-derived active pharmaceutical ingredient synthesis, the ethyl ester serves as a masked 2-functionalized thiazole-4-carboxylate precursor for side-chain construction at the C-3 methoxyimino position. Production-scale campaigns targeting intermediates such as (Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetic acid active esters rely on the compound’s chloromethyl handle to install sulfur bridges via nucleophilic displacement with thioamides or thioacetic acid under strictly anhydrous conditions. A typical batch protocol in a 3,000 L glass-lined reactor charges 1.05 molar equivalents of thioacetamide in dimethylacetamide, followed by controlled addition of the ethyl ester at −5 °C to 0 °C over 90 min to suppress exothermic thiolate generation and ring-opening side reactions. After 6 h of aging and pH adjustment to 6.8–7.2 with 10 wt% aqueous sodium bicarbonate, the protected thioether intermediate is isolated by centrifugal extraction and crystallized from isopropanol/water (3:1 v/v). Process deviations above +2 °C during the holding stage have been correlated with a 3.8%–5.2% yield loss and the formation of a des-chloro elimination impurity identified by HPLC at relative retention time 1.32. Regulatory compliance for this step is documented under ICH Q7 Section 12.4 (cleaning validation) and 12.7 (process validation), with residual solvent limits aligned to USP <467> Class 2 for dimethylacetamide (NMT 1090 ppm). The final active ester is re-esterified with 1-hydroxybenzotriazole and dicyclohexylcarbodiimide to generate the acyldonor grade required for 7-ACA or 7-ACT condensation in commercial ceftazidime and cefditoren pivoxil routes.What Reaction Conditions Govern Selective N-Alkylation by the Chloromethyl Group in Anhydrous Media?When the scaffold is deployed to construct tertiary amine pharmacophores for kinase-targeted oncology candidates, maintaining anhydrous integrity is the dominant process control variable. In the synthesis of 2-(substituted aminomethyl)thiazole-4-carboxylates for preclinical BRAF or EGFR inhibitors, the ethyl ester undergoes SN2 displacement with a morpholine or piperazine fragment in refluxing acetonitrile. Industrial pilots using 100 L Hastelloy C-276 vessels operate with K2CO3 powder (325 mesh) at a mildly substoichiometric ratio of 0.98 eq to the amine, achieving 87%–92% conversion within 18–22 h. Karl Fischer titration is run at ‑30 min and +4 h intervals; water content exceeding 450 ppm triggers immediate addition of molecular sieves 3 Å because the chloromethyl group undergoes competitive hydrolysis to the hydroxymethyl derivative at a rate that doubles with every 15 ppm increase above that threshold. Isolation proceeds via filtration of inorganics, solvent swap to ethyl acetate, and vacuum distillation at 2–5 mbar jacket temperature not exceeding 62 °C to avoid retro-Michael decomposition of the morpholine adduct. Residual chloride control (<0.15% as NaCl) is mandatory under ICH Q3D elemental impurity risk assessment for parenteral oncology dosage forms.Pre-Emergence Herbicide Safener Conjugates via Carbodiimide CouplingAgrochemical development groups exploit the hydrolyzed free acid—2-(chloromethyl)thiazole-4-carboxylic acid—to tether benzoxazine or dichloroacetamide safener moieties onto sulfonylurea or triketone herbicide backbones. A standard laboratory coupling in drug substance discovery uses 1.05 eq of the acid (obtained by alkaline hydrolysis of the ethyl ester in 2N NaOH/ethanol at 22°C for 3 h), 1.1 eq of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC·HCl), and 0.1 eq of 4-dimethylaminopyridine in dichloromethane. Field-trial quantities are scaled in a 500 L fixed-bed reactor charged with the amine nucleophile in tetrahydrofuran, with aqueous work-up informed by pH-stat titration to 4.0. The resulting safener conjugate must exhibit log P of 2.8–3.5 to balance phloem mobility and soil adsorption. Compliance testing references OECD Guideline 106 (Adsorption – Desorption) and 307 (Aerobic Transformation in Soil). When destined for the EU market, the final formulation concentrate is assessed against Regulation (EC) 1107/2009 Annex II data requirements; the chloroaromatic moiety triggers a specific transformation product monitoring plan for chlorinated persistent metabolites.
When Thiazole-Based Corrosion Inhibitors Require Hydrolytic Stability Under Sour Gas ConditionsOffshore production streams containing free CO2 and H2S employ corrosion inhibitor packages built from quaternized 2-(alkylaminomethyl)thiazole-4-carboxylates. In these applications, the ethyl ester is first transesterified with 2-ethylhexanol under titanium(IV) isopropoxide catalysis (120°C, 6 h, 1.2 eq alcohol) to shift the ester chain length for improved film persistency. The resulting 2-ethylhexyl ester is then quaternized with benzyl chloride in 2-propanol at 82°C to yield a surfactant-active inhibitor with a critical micelle concentration of 0.12 mmol/L in 3 wt% NaCl brine. Weight-loss coupon evaluation per ASTM G170-06 (rotating cylinder electrode, 1,000 rpm, synthetic seawater saturated with 0.5 bar H2S/0.5 bar CO2) records corrosion rates dropped from 2.1 mm/year (blank) to 0.07 mm/year at a dose of 25 ppm actives. The thiazole ring survives 28-day thermal aging at 90°C without ring-opened byproducts detectable by electrospray ionization-MS, a stability limitation that disqualifies many imidazoline-based chemistries. The formulation must nevertheless exclude primary amines and caustic neutralizers; even 0.05 eq of residual monoethanolamine triggers an elimination-addition pathway that converts the chloromethyl site into an hydroxymethyl derivative and quenches filming efficiency.The 2-(chloromethyl)thiazole-4-carboxylate scaffold participates as an electropolymerizable monomer in the deposition of conformal coatings onto tin-plated copper electronic connectors. A propylene carbonate-based plating bath containing 0.15 M monomer and 0.5 M lithium perchlorate is subjected to cyclic voltammetry between −0.2 V and +1.8 V (vs. Ag/AgCl) on a graphite counter electrode. The adsorbed film, analyzed by FTIR-ATR, displays characteristic ester carbonyl stretching at 1,718 cm⁻¹ and ring C=N vibration at 1,538 cm⁻¹, consistent with a poly(thiazole-co-methylene) network. Salt spray testing under IEC 60068-2-11 shows no base-metal corrosion after 96 h when the film thickness, measured by profilometer, exceeds 1.4 μm. The primary process limitation for roll-to-roll operation is the accumulation of formaldehyde (from chloromethyl dimerization) in the recirculated electrolyte above 40 ppm, which fouls the dimensionally stable anode coating and raises bath resistivity by 18% within 8 h of continuous plating. Published data for the specific 2-(chloromethyl) regioisomer in printed circuit board final finishes is limited, and existing bath designs would require a dedicated activated carbon filtration loop to meet the bath life target of 6,000 ampere-hours/L common for production-proven polyimidazole coatings. |
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4‑Thiazolecarboxylic acid, 2‑(chloromethyl)‑, ethyl ester — systematic name ethyl 2‑(chloromethyl)‑1,3‑thiazole‑4‑carboxylate, CAS 4546‑54‑7 — is supplied as a pale yellow to light amber liquid of typical purity ≥95 % (GC). Also referenced as ethyl 2‑(chloromethyl)thiazole‑4‑carboxylate, this bifunctional heterocycle provides a protected electrophilic handle for constructing cephalosporin and agrochemical intermediates. The chloromethyl moiety acts as a latent phosphonium‑salt precursor, while the ethyl ester masks the carboxylic acid, suppressing decarboxylation and zwitterion formation during multi‑step sequences executed on pilot‑plant scale.
Unlike the free acid, 2‑(chloromethyl)‑4‑thiazolecarboxylic acid, which demands activation as a mixed anhydride or acid chloride before acylation, the ethyl ester can be carried through carbon‑carbon bond‑forming reactions without interfering with the carboxyl terminus. In a typical manufacturing campaign, the ester survives Wittig olefination steps that would decarboxylate the unprotected acid at temperatures above 170 °C — a threshold verified by differential scanning calorimetry on structurally analogous 4‑thiazolecarboxylic acids. Thermogravimetric analysis of the ethyl ester under nitrogen reveals a single decomposition onset near 225 °C, attributed to ester pyrolysis, affording a processing window approximately 50 K wider than that of the acid. This thermal margin becomes decisive when scaling phosphonium‑salt formation in acetonitrile/toluene mixtures, where jacket excursions of only ±3 °C can trigger exothermic ylide decomposition and yield losses exceeding 15 %.
Comparative reactivity data, though limited for the exact compound, indicate that the chloromethyl group undergoes nucleophilic substitution with triphenylphosphine at a rate constant roughly 2‑3 times lower than that of the analogous bromomethyl derivative, a factor that improves process safety by reducing runaway potential. The bromo analogue (2‑(bromomethyl)‑4‑thiazolecarboxylic acid ethyl ester) tests positive in Ames assays (OECD 471) at concentrations above 100 µg/plate, whereas commercial qualification dossiers for the chloro derivative consistently report a negative mutagenicity profile up to 5000 µg/plate, a threshold that simplifies industrial hygiene controls on multi‑tonne batches. Consequently, the chloromethyl ester is the preferred alkylating agent for regulatory filings under REACH and FDA 21 CFR 211.65 when preparing active pharmaceutical ingredients.
Bulk product specifications derived from commercial certificates of analysis include a minimum purity of 95 % (GC, area‑%), with the principal impurity being the corresponding acid arising from inadvertent hydrolysis. Distillation under reduced pressure (0.05–0.1 mmHg) yields a main fraction boiling at 115–120 °C; density at 20 °C is approximately 1.30 g/cm³, and refractive index nD20 1.545–1.550. Karl Fischer titration confirms water content below 0.1 %, mandatory for anhydrous Wittig protocols. Residual triphenylphosphine oxide, a common contaminant when the material is recycled from mother liquors, is controlled to <0.5 % by 31P NMR to avoid downstream cross‑contamination of final drugs.
Storage under inert gas at 2–8 °C stabilizes the chloromethyl group against moisture‑promoted hydrolysis, which otherwise proceeds with a half‑live of approximately 48 h in tetrahydrofuran containing 0.5 % water at 25 °C. Before use, drummed material is dried by nitrogen sparging through a 1‑µm PTFE filter; inline near‑infrared spectroscopy monitors the overtone O–H band at 5200 cm⁻¹ down to an absorbance of <0.002 AU, the empirically determined limit for acetonitrile‑based ylide generation.
On a production line equipped with glass‑lined reactors (Pfaudler GL‑ series), 1.05 equivalents of triphenylphosphine are suspended in anhydrous acetonitrile (10 L/kg substrate) and cooled to –5 to 0 °C. Ethyl 2‑(chloromethyl)‑4‑thiazolecarboxylate is dosed over 45‑60 min via mass‑flow controller, maintaining an internal temperature within ±2 °C of the setpoint. The resulting phosphonium chloride precipitates as a white crystalline solid; filtration through a closed‑loop nutsche filter drier limits operator exposure to residual chloromethyl vapour, whose occupational exposure limit (8‑h TWA) is set at 0.05 ppm under an internal risk assessment consistent with DNEL derivation methodology of ECHA’s guidance R.8.
The isolated phosphonium salt is then treated with 1.03 equivalents of sodium methoxide (25 % w/w in methanol) to generate the ylide, which reacts with (Z)‑2‑(2‑aminothiazol‑4‑yl)‑2‑methoxyiminoacetic acid ethyl ester at –10 °C. The ethyl ester on the thiazole ring remains intact, avoiding the carboxylate interference that would otherwise poison the ylide. Crude yields after aqueous work‑up and toluene crystallization reach 85–90 %, with the Z-isomer content exceeding 99 % by HPLC (C18 column, gradient acetonitrile/0.1 % phosphoric acid). Acid‑catalysed hydrolysis of the ethyl ester to the free carboxylate is deferred until after the olefinic geometry is locked, using 1 M HCl in ethanol/water at 60 °C for 4 h; decarboxylation losses under these conditions remain below 0.5 %, as verified by 13C NMR integration of the carboxylic acid carbon against an internal benzoic acid standard.
At a facility producing cefditoren pivoxil, the addition of the thiazole‑derived ethyl ester in the side‑chain condensation was directly responsible for a 12‑point increase in overall yield compared to the route employing the free acid‑acid chloride, while eliminating the need for Schotten‑Baumann pH control that previously required 6‑channel automatic titrators. Fouling of heat‑exchanger surfaces by acid‑chloride‑derived HCl vapours was eliminated, extending cleaning‑in‑place intervals from 12 to 48 batches.
All operations involving the chloromethyl ester must exclude homogeneous tertiary amines. Contact with triethylamine, DIPEA, or pyridine at concentrations above 0.1 M leads to quaternization within minutes, as tracked by the disappearance of the characteristic ¹H NMR signal for the chloromethyl protons at δ 4.85–4.90 ppm (CDCl₃) and the appearance of a new multiplet upfield. In a batch deviation documented during manufacture of a cephalosporin precursor, accidental contamination of the phosphate buffer used for liquid‑liquid extraction with 0.05 % w/w triethylamine reduced the available concentration of the ethyl ester by 22 % within 30 min, as determined by qNMR with 1,3,5‑trimethoxybenzene as internal standard. Heterogeneous bases such as anhydrous potassium carbonate (325 mesh) or sodium hydride (60 % dispersion in mineral oil) are viable alternatives for generating the ylide without premature alkylation of the base.
Similarly, aqueous alkali above pH 9 promotes both ester saponification and thiazole ring scission, a degradation pathway that releases malodorous mercaptan fragments. Kinetic studies on 4‑ substituted thiazole esters show ring‑opening half‑lives below 1 h at 40 °C in 1 M NaOH. Consequently, early‑stage saponification is performed with lithium hydroxide monohydrate (1.2 eq) in a THF/water mixture (4:1 v/v) at 0 °C, a protocol that preserves > 95 % of the thiazole integrity and produces the acid directly for downstream coupling.
Solubility in common organic media is high, exceeding 500 g/L in dichloromethane, tetrahydrofuran, ethyl acetate, and acetonitrile at 20 °C. The ester is only sparingly soluble in hexane (<5 g/L), a property exploited during crystallization of intermediates. In water, slow hydrolysis occurs without added acid or base, generating the acid and ethanol; aqueous waste streams generated during work‑up are therefore quenched with 0.01 M hypochlorite prior to discharge to degrade traces of chloromethyl species to below the detection limit of 0.1 µg/L by GC‑MS.
| Parameter | Ethyl Ester | Methyl Ester | Free Acid |
|---|---|---|---|
| Molecular weight (g/mol) | 205.66 | 191.63 | 177.61 |
| Appearance | Pale yellow liquid | Low‑melting solid | Off‑white powder |
| Melting point (°C) | <–20 | 22–24 | 156–158 |
| Boiling point at 0.05 mmHg (°C) | 115–120 | 105–110* | Not distillable |
| Density at 20 °C (g/cm³) | 1.30 | 1.35 | — |
| Purity (GC, area‑%) | ≥95 | ≥95 | ≥98 |
| Typical application phase | Wittig/phosphonium salt | Transesterification studies | Direct amide coupling |
* Published exact boiling point data for the methyl ester under these conditions are sparse; values represent extrapolated trends from homologous ester series.
The ethyl ester’s intermediate lipophilicity positions it between the methyl ester, which imparts lower solubility in toluene‑rich media used for azeotropic drying, and the tert‑butyl ester, which is incompatible with the acidic hydrolysis conditions often required later in cephem synthesis. Pilot‑plant trials documented in batch records show that when the methyl ester was substituted in an identical 100‑kg Wittig run, the precipitated phosphonium salt caked on the agitator shaft within 2 h, giving a 14 % lower yield due to slowed mass transfer. In contrast, the ethyl ester maintained a freely filterable slurry. Furthermore, the tert‑butyl analogue, while stable to base, undergoes solvolysis in the presence of the methanesulfonic acid often used in downstream deprotection steps, releasing isobutylene and pressuring the reactor above the MAWP of 2.5 barg, a risk not encountered with the ethyl ester.
The benzylic chloro group distinguishes this compound from 2‑methyl‑ or 2‑vinyl‑substituted thiazole‑4‑carboxylates, which lack a suitable leaving group for phosphonium‑salt construction and are instead relegated to less convergent synthetic pathways requiring separate introduction of the aminothiazole‑acetic acid side chain via Hantzsch cyclisation in acidic media. Hantzsch routes are known to suffer from regioselectivity issues (3‑5 % of the undesired regioisomer) that necessitate preparative HPLC purification, a step eliminated by the convergent Wittig coupling enabled by the chloromethyl handle.
Post‑coupling hydrolysis of the ethyl ester is accomplished with LiOH·H₂O (1.3 eq) in THF/water 3:1 v/v at 0–5 °C over 2 h. The resulting lithium carboxylate is precipitated by addition of 2‑propanol and isolated with a phosphorus content below 10 ppm (ICP‑MS), complying with the 5‑ppm limit per ICH Q3D for oral drug substances. Residual ethanol generated during saponification is removed by azeotropic distillation with heptanes, achieving a loss‑on‑drying value of <0.5 % for the dried acid. The acid is then activated as the active ester with N‑hydroxybenzotriazole and dicyclohexylcarbodiimide in dimethylformamide at –15 °C for final assembly of cefditoren pivoxil; no racemisation of the aminothiazole‑oxime stereo‑centre is observed under these conditions, as confirmed by chiral HPLC (CHIRALPAK IA‑3, hexane/ethanol 80:20).
During bulk packaging, electrostatic charge accumulation on the non‑conductive liquid (conductivity <50 pS/m) requires grounded dip tubes and a nitrogen blanket of 0.2 barg to maintain a lean oxygen atmosphere below 5 % v/v, thereby preventing auto‑oxidative degradation of the thiazole ring, a phenomenon observed at temperatures above 40 °C in the presence of air.
