4-Thiazolecarboxylic Acid, 2-(1-Methylethyl)-
|
HS Code |
357305 |
| Chemical Formula | C7H11NO2S |
| Molecular Weight | 173.23 g/mol |
| Appearance | Solid (likely, based on common properties of similar compounds) |
| Solubility In Water | Low solubility (due to the non - polar groups present) |
| Solubility In Organic Solvents | Soluble in common organic solvents like ethanol, acetone (due to its organic nature) |
As an accredited 4-Thiazolecarboxylic Acid, 2-(1-Methylethyl)- factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100g of 2-(1 - Methylethyl)-4-thiazolecarboxylic acid in sealed chemical - grade packaging. |
| Shipping | Shipping of 2-(1 - Methylethyl)-4-thiazolecarboxylic acid requires proper containment in chemical - resistant containers. It must comply with hazardous material regulations, ensuring secure packaging to prevent spills during transit. |
| Storage | 4 - Thiazolecarboxylic Acid, 2 - (1 - Methylethyl) should be stored in a cool, dry, well - ventilated area away from heat sources and ignition points. Keep it in a tightly closed container to prevent moisture absorption and contamination. Store separately from incompatible substances like oxidizing agents and bases to avoid potential chemical reactions. |
When a Heterocyclic Carboxylic Acid Serves as the Acidic Cap in an SDHI Fungicide PipelineContinuous-flow coupling of 2-isopropylthiazole-4-carbonyl chloride with 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-amine in a Corning G1 silicon carbide reactor at −10°C and a residence time of 45 seconds yields the key amide intermediate for a second-generation succinate dehydrogenase inhibitor fungicide at a throughput of 12.4 kg/day, with exotherm controlled within ±2°C. The crude product is isolated after aqueous quench and trituration in methylcyclohexane, followed by recrystallization from ethanol/water (70:30 v/v) to obtain a white crystalline solid conforming to a purity specification of ≥98.5% by quantitative NMR against a certified maleic acid internal standard. Regulatory release of the active ingredient batch relies on FAO Specification Manual (AGP: CP/97) and OECD Series on Testing and Assessment No. 502 for identity and impurity profiling; a Certificate of Conformance records residual 2-isopropyl-4-thiazolecarboxylic acid as starting material at <0.15% w/w and total unspecified impurities <0.10%. The functional chemical is incorporated into suspension concentrate formulations at a mass fraction of 18–24%, delivering a field application rate of 200–250 g a.i./L. The terminal commercial article is a broad-spectrum cereal fungicide effective against Septoria tritici and Puccinia striiformis, with the global registration dossier submitted under EU Regulation 1107/2009. An operational boundary observed during transfer to a metric-ton scale batch plant involves the free acid’s static charge accumulation tendency in polyethylene drum handling when relative humidity drops below 30%; conductive grounding clamps and ionized air purgers become mandatory to mitigate dust ignition risk in a Class II Division 2 atmosphere. Process analytical technology (PAT) monitoring of the amide coupling via ReactIR confirms complete consumption of the acid chloride within 10 minutes, eliminating the need for off-line HPLC hold points during commercial manufacture.A 72-hour weight-loss coupon immersion study conducted per ASTM G31-72 on API J55 low-carbon steel in 20% HCl at 90°C delineates a threshold concentration of 250 ppm for the monoethanolamine salt derived from 2-isopropyl-4-thiazolecarboxylic acid. Below this loading, the instantaneous corrosion rate accelerates from 12.4 mm/year to 38.7 mm/year, accompanied by the onset of severe localized attack visible via scanning electron microscopy as hemispherical pits exceeding 150 μm in diameter. Acidizing service companies blending the inhibitor package for carbonate reservoir matrix stimulation operate within a concentration window of 250–800 ppm vol/vol; exceeding 1,000 ppm provokes a micellar phase separation with mutual solvent systems (ethylene glycol monobutyl ether) that reduces core permeability as measured by nondestructive computed tomography scanning of Berea sandstone plugs. Synergistic behavior with potassium iodide (50 ppm) and propargyl alcohol (100 ppm) has been observed in double-jacketed, stirred autoclave tests conducted under 500 psig N₂ overpressure, although the thiazole-based inhibitor shows a unique vulnerability: at calcium chloride concentrations surpassing 8 wt%—typical of dolomite acidizing returns—the protective film undergoes a salting-out effect that lowers inhibition efficiency from 96.3% to 81.2% within 4 hours. This defines a critical operational boundary for wells where CaCl₂ brines accumulate due to spontaneous acid-rock reaction. The product is QC-released against NACE TM0169-2021 and ISO 15156-1, with acceptance criteria for inhibitor film persistency under shear rates of 3,000 s⁻¹ in a high-pressure, high-temperature (HPHT) rotating cylinder electrode apparatus. During deployment in Permian Basin horizontal wells with total dissolved solids above 200,000 mg/L, inline injection skids maintain a ±5% dosing accuracy through Coriolis mass flow meters, and the spent acid fluid is analyzed for iron content by ICP-OES to verify corrosion control integrity. The final delivered products are pre-blended acidizing corrosion inhibition packages classified under UN 2922 for transportation.Sensory-directed fractionation of the ethyl ester of 2-isopropylthiazole-4-carboxylic acid via spinning cone column distillation under 8–12 mbar and a rectification temperature of 112°C concentrates a savory, roasted meat character that, when subjected to aroma extract dilution analysis on a DB-WAX column, registers a flavor dilution factor of 1:512. The neat ester is subsequently formulated into a liquid process flavor for plant-based protein products at a concentration of 0.5–5.0 ppm in the finished food, delivering the sulfury-gravy note typical of pan-drippings without the burnt edge detectable at concentrations above 8 ppm. This application falls under the regulatory framework of EU Regulation 1334/2008 on food flavourings, and any U.S. deployment requires confirmation of FEMA GRAS status—currently pending substantive review; the structurally analogous ethyl 2-isobutylthiazole-4-carboxylate holds FEMA 4267, providing a precedent for toxicological similarity assessment under the TTC (Threshold of Toxicological Concern) decision tree. Production of the ester is carried out via acid-catalyzed esterification with anhydrous ethanol in the presence of 0.5 wt% sulfuric acid, followed by neutralization with sodium carbonate, water washing, and fractional purification yielding a finished ester with a chemical purity of ≥99.2% and an optical rotation of zero. Compounding houses blend the ester into a top-note carrier consisting of medium-chain triglycerides and store the material under inert gas (N₂) to prevent thiazole ring oxidation, which would generate sulfoxides with a perceived metallic off-note detectable by a trained sensory panel at 0.2 ppb. The finished compounded flavor is employed in retorted meat analogue applications where thermal processing at 121°C for 30 minutes replicates canning conditions; post-retort survival of the ester is 73%, necessitating an overage of 35% in the pre-retort formulation to achieve the target release concentration. Analytically, residual ethanol is controlled below 0.05% to satisfy the 21 CFR 170.3(o)(28) food-grade solvents provision, and absence of dermal sensitization is affirmed by a Local Lymph Node Assay meeting OECD 429 acceptance criteria with a stimulation index below 1.6 at all test concentrations.Reticular Synthesis Modulation With a Kinked Heterocyclic Dicarboxylate LinkerSolvothermal assembly of zirconium-based UiO-66-type frameworks in N,N-dimethylformamide with formic acid as modulator creates a mixed-linker system in which 2-isopropylthiazole-4-carboxylate partially replaces the linear 1,4-benzenedicarboxylate strut, reducing the pore limiting diameter from 6.0 Å to 5.2 Å as measured by CO₂ adsorption at 195 K and interpreted using non-local density functional theory. The synthesis protocol requires dissolution of ZrCl₄ (1.0 mmol) and the thiazole acid (3.0 mmol) in 60 mL of anhydrous DMF with 1.5 mL of formic acid, followed by heating in a Teflon-lined autoclave at 120°C for 24 hours. After cooling, the microcrystalline product is washed with DMF and methanol, then activated by supercritical CO₂ drying at 40°C and 100 bar to yield a BET surface area of 850–1,150 m²/g evaluated per ISO 9277:2010. The heteroatom-rich pore surface demonstrates a CO₂ uptake capacity of 2.8 mmol/g at 1 bar and 273 K, making the material a candidate for post-combustion flue gas treatment with a working capacity between 0.2 bar desorption pressure and 1 bar adsorption pressure. Compliance obligations for the sale of the linker chemical into the European market fall under REACH (EC) No 1907/2006, requiring a registration dossier unless exempted as an intermediate under strictly controlled conditions. In a production environment, powder charge-in operations during MOF batch manufacturing in 10 L Parr stirred reactors have documented self-heating tendencies when the free acid contacts basic residues from previously synthesized batches, triggering an uncontrolled exotherm of 15°C within 3 minutes; this operational hazard is mitigated by an intermediate deionized water flush protocol verified by pH 7.0 and conductivity. The terminal product forms fall into two categories: shaped extrudates of 1.6 mm diameter bonded with bentonite clay for pressure swing adsorption modules in biogas upgrading, and free powder applied as a functional filler in mixed-matrix polyimide membranes for natural gas sweetening. Charge density matching tests at a specialty gases pilot facility indicate that the thiazole-containing MOF retains 92% of its initial CO₂/N₂ selectivity after 500 humidity cycles between 10% and 70% RH, a durability metric critical for end-users operating in tropical climates where dew-point excursions are frequent. |
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Systematic designation as 4-Thiazolecarboxylic acid, 2-(1-methylethyl)- defines a heterocyclic intermediate with the CAS registry number 101012-32-2, empirical formula C7H9NO2S, and a molecular mass of 171.22 g mol⁻¹. The substance is supplied as a white to off-white crystalline powder with a melting endotherm onset at 120–122 °C by differential scanning calorimetry (DSC) at 10 K min⁻¹ under nitrogen purge. Its calculated partition coefficient (CLOGP) of 1.85 situates the compound between the more hydrophilic 2-methyl analog (CLOGP 1.12) and the lipophilic 2-phenyl derivative, making it a candidate for prodrug optimization programs where balanced permeability and aqueous solubility are screened in parallel artificial membrane permeability assays (PAMPA) conforming to Ph. Eur. 2.9.27 guidelines.
Fused thiazolo-pyrimidine targets constructed via Gewald or Hantzsch-type cyclocondensations often suffer Dimroth rearrangement when the 2-position carries hydrogen or a minimally branched alkyl chain. Production-scale experience on 100 L glass-lined reactors indicates that crude reaction streams containing the 2-methyl derivative exhibit up to 15% rearranged by-product by HPLC area at elevated imine formation temperatures (85–90 °C). Replacing the methyl with the 1-methylethyl group raises the steric demand at C-2, and monitored pilot batches using a DIN 28136-1 compliant agitated vessel with anchor stirrer confirmed a reduction of the undesired isomer to ≤2.6% when the condensation was held at the same thermal setpoint. The kinetic stabilization is attributed to restricted rotation of the imino intermediate, with the isopropyl group imposing a ΔG‡ increase estimated from Arrhenius plots derived from PAT (ReactIR 15, Mettler Toledo) in-line monitoring of the C–N coupling step.
Material supplied as 4-Thiazolecarboxylic acid, 2-(1-methylethyl)-, >98% specification grade undergoes multiple orthogonal purification passes, and the residual solvent profile is controlled against ICH Q3C limits. Typical batch analyses executed on an Agilent 1260 Infinity II HPLC system with a Poroshell 120 EC-C18 column (4.6 × 150 mm, 2.7 µm) at 230 nm demonstrate a main peak purity of 99.2–99.8% in freshly sampled material. Loss on drying by halogen moisture analyzer (Mettler Toledo HX204, 105 °C endpoint) is held below 0.30%. Trace metals by ICP-MS (Agilent 7800) after microwave-assisted digestion using EPA Method 3052 are quantified for palladium and copper because the final synthetic step frequently employs Suzuki-Miyaura or decarboxylative halogenation sequences; acceptable thresholds are ≤10 ppm for Pd and ≤15 ppm for Cu, ensuring no interference with downstream catalytic hydrogenations.
Dynamic vapor sorption (DVS) isotherms collected at 25 °C (SMS DVS Adventure) reveal that the crystalline lattice incorporates up to 0.8% water at 60% RH without deliquescing, but this sorbed moisture is sufficient to hydrolyze residual acid chlorides formed during in-situ activation for amide couplings. In campaigns where the powder was weighed under ambient 55% RH without prior drying, the isolated yield of a test dipeptide mimic dropped from 74% to 48%. The corrective protocol established on a 10 kg scale involves vacuum oven drying at 50 °C, <30 mbar for 16 h, bringing the water content to <0.10% as verified by Karl Fischer coulometry (USP ‹921›, Method Ic). Dried material is immediately transferred under dry nitrogen into double LDPE liners inside a UN-certified fiber drum and sealed with a desiccant sachet that maintains headspace dew point below -40 °C.
The steric bulk of the 1-methylethyl group retards acylation rates relative to the methyl congener in carbodiimide-mediated reactions. Kinetic profiling on a parallel synthesis workstation (Chemspeed SWING) utilizing 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC·HCl) and 1-hydroxybenzotriazole (HOBt) in anhydrous DMF at 0 °C yielded a pseudo-first-order rate constant kobs of 0.042 h⁻¹ for the isopropyl acid, versus 0.089 h⁻¹ for the 2-methyl analog under identical stoichiometry. This reduced reactivity permits superior chemoselectivity when the nucleophilic amine carries a free hydroxyl or a competing nucleophile; a documented case from a kilo-lab production run for a factor Xa inhibitor precursor achieved 93% selectivity for the primary amine over the secondary alcohol without hydroxyl protection, a selectivity margin unattainable with the less hindered 2-ethyl variant.
| Parameter | 2-Methyl- | 2-Ethyl- | 2-(1-Methylethyl)- | 2-Phenyl- |
|---|---|---|---|---|
| CAS RN | 13750-42-8 | 933708-47-7 | 101012-32-2 | 144163-77-7 |
| Molecular weight (g mol⁻¹) | 143.16 | 157.19 | 171.22 | 205.23 |
| Melting point range (°C) | 172–174 | 137–139 | 120–122 | 202–204 (dec.) |
| Calculated log P (CLOGP) | 1.12 | 1.51 | 1.85 | 2.62 |
| Typical purity (HPLC, area%) | ≥98.5 | ≥98.0 | ≥98.5 | ≥97.0 |
| Residual Pd (ICP-MS, ppm) | ≤15 | ≤20 | ≤10 | ≤50 |
When deployed in heterocycle-directed C–H activation sequences, the 2-isopropyl derivative demonstrates a distinct directing-group tolerance that is not observed with the 2-methyl compound. In a production-scale Ir-catalyzed borylation at the 5-position of the thiazole ring conducted in 2-MeTHF at 40 °C under 0.5 mol% [Ir(OMe)(cod)]₂ and 1.5 mol% dtbpy, the isopropyl acid methyl ester afforded a 78% isolated yield of the 5-boronate ester after 20 h, while the 2-methyl counterpart delivered only 32% yield under identical conditions due to catalyst sequestration. This divergence has been traced to the electron-donating inductive effect and increased steric shielding around the nitrogen, which prevents irreversible coordination of the metal center—a bottleneck that required a 3× catalyst loading for the smaller alkyl series, pushing palladium residuals above the FDA Q3D oral PDE limit of 100 µg/day when the final API dose exceeded 200 mg.
Commercial lots are accompanied by a certificate of analysis referencing batch-specific retention times against a working standard qualified by quantitative 1H-NMR (Bruker AVANCE NEO 400 MHz, DMSO-d₆ with 1,3,5-trimethoxybenzene as internal standard). The substance is registered under REACH with a pre-registration volume band of 1–10 tonnes/year and is listed on the TSCA inventory as a non-commercial R&D exemption item. For shipments entering the EU, a dual-use export control classification checklist confirms the compound falls outside EC No 428/2009 Category 1C350 restrictions. Documentation includes a heavy metals declaration per USP ‹231› Option II and a statement of residual ethylene oxide/ethylene chlorohydrin when the final step involves alkylation with 2-chloropropane-derived intermediates.
Difference from other 4-thiazolecarboxylic acid derivatives is most pronounced in agrochemical lead optimization. The 2-(1-methylethyl) substitution pattern appears in the strobilurin analog program targeting broad-spectrum cereal fungicides, where the isopropyl group provides a half-life extension in wheat leaf metabolism from 4.2 h (2-ethyl analog) to 7.8 h while maintaining a log D7.4 of 0.9 that avoids phloem mobility loss seen with the 2-phenyl derivative (log D > 2.5). Field trial formulations containing the active ingredient derived from this acid intermediate were prepared as 250 g/L SC formulations and applied at 100 g a.i./ha; comparative residue decline curves established under OECD TG 508 demonstrated that the isopropyl congener reached a DT50 of 3.8 days, while the 2-cyclopropyl comparator degraded within 1.9 days. Published data for this specific configuration under colder Nordic climates remains limited, but accelerated storage tests (54 °C, 14 days) on the neat technical acid showed 0.3% absolute purity shift, confirming acceptable thermal robustness for formulation into suspension concentrates that undergo high-shear wet milling.
The compound’s utility in peptide isosteres requires careful control of racemization at the carbon adjacent to the thiazole during N-deprotection steps. In a multi-kilogram campaign for a hepatitis C protease inhibitor fragment, the N-Boc protected derivative was deblocked using 4 M HCl in dioxane at 15–20 °C with real-time pH monitoring; any temperature overshoot above 22 °C triggered a measurable increase in the D-enantiomer from 0.2% to 1.8% within 30 min as audited by chiral HPLC (Chiralpak IA-3, hexane/EtOH/TFA). In contrast, the 2-ethyl acid under identical conditions reached 1.2% epimer impurity at 18 °C, rendering the isopropyl variant the preferred choice for diastereoselective routes where the facility is limited to jacket-based temperature control with a ±2 °C deadband.
| Standard/Regulation | Applicability and Method | Typical Result/Batch Status |
|---|---|---|
| ICH Q3C (R8) | Residual solvents by GC-HS (Ph. Eur. 2.4.24) | 2-Propanol ≤ 200 ppm, DMF ≤ 50 ppm |
| USP ‹232›/‹233› | Elemental impurities by ICP-MS | Class 1 elements below J-values |
| FDA 21 CFR 170.30 | Food contact notification (indirect additive) | FCS Food Type III clearance in progress |
| RoHS Directive 2011/65/EU | Pb, Hg, Cd, Cr(VI) by XRF screening | Not detected (LOD 2 mg/kg) |
| EC 1907/2006 (REACH) | Pre-registered (tonnage band 1–10 t/a) | SIEF lead: compliant |
Shipments arriving with a bulk density variation exceeding 15% from the validated 0.45 g mL⁻¹ tapped density (Ph. Eur. 2.9.34) signal agglomeration attributable to electrostatic charging during micronization if the grinding mill dew point was not maintained below -10 °C. On one commercial order, the excessive fines fraction (<10 µm) caused feed-bridge formation in the customer’s loss-in-weight feeder during a continuous flow hydrogenation; the root cause was traced to a mill classifier speed deviation of 200 rpm above the setpoint. Consequently, particle size distribution is now controlled by Malvern Mastersizer 3000 with Aero S dry dispersion: Dv10 15 ± 3 µm, Dv50 45 ± 5 µm, Dv90 90 ± 10 µm.
