4-Isopropyl-1,3-Thiazole-2-Carboxylic Acid
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HS Code |
300827 |
| Chemical Formula | C7H9NO2S |
| Molecular Weight | 171.22 g/mol |
| Appearance | Solid (usually) |
| Odor | Typical of thiazole - carboxylic acid compounds (specific odor may vary) |
| Solubility In Water | Low solubility (organic acids with such structures generally have limited water solubility) |
| Solubility In Organic Solvents | Soluble in common organic solvents like ethanol, acetone |
| Melting Point | Data may vary depending on purity, but within a certain range characteristic of this compound |
| Boiling Point | Higher boiling point due to presence of polar groups |
| Acidity | Weakly acidic due to the carboxylic acid group |
| Stability | Stable under normal conditions, but may react with strong oxidizing or reducing agents |
As an accredited 4-Isopropyl-1,3-Thiazole-2-Carboxylic Acid factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 1 kg of 4 - Isopropyl - 1,3 - Thiazole - 2 - Carboxylic Acid packaged in a sealed plastic bag. |
| Shipping | 4 - Isopropyl - 1,3 - Thiazole - 2 - Carboxylic Acid is shipped in sealed, corrosion - resistant containers. It follows strict chemical transport regulations to ensure safe handling during transit, protecting from environmental exposure and potential spills. |
| Storage | 4 - Isopropyl - 1,3 - Thiazole - 2 - Carboxylic Acid should be stored in a cool, dry place away from heat sources and direct sunlight. Keep it in a tightly - sealed container to prevent moisture absorption and contamination. Store it separately from incompatible substances like strong oxidizers and bases to avoid potential chemical reactions. |
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Within continuous-flow peptide coupling reactors operating under ICH Q7 Good Manufacturing Practice for active pharmaceutical ingredients, 4-isopropyl-1,3-thiazole-2-carboxylic acid functions as a conformationally constrained carboxylate building block in the synthesis of hepatitis C NS3/4A serine protease inhibitor peptidomimetics. The acid is pre-activated as a mixed anhydride using isobutyl chloroformate and N-methylmorpholine in anhydrous tetrahydrofuran at a precisely controlled jacket temperature of −15 °C to −10 °C; the activated intermediate is then metered into a chilled stream of (1R,2S)-2-amino-1-cyclopentanol derivative dissolved in dimethylacetamide, maintaining a stoichiometric excess of 1.05–1.20 molar equivalents of the thiazole acid relative to the amine to compensate for competitive hydrolytic degradation of the anhydride. Residual water content in the solvent train is held below 0.05 % by Karl Fischer titration; excursions above 0.15 % trigger automatic diversion of the product stream to waste because symmetrical anhydride dimer formation eclipses 8 % area-under-curve and precipitates as a crystalline foulant on the static mixer elements. The crude amide stream is quenched with 8% w/w aqueous sodium bicarbonate, phase-separated in a membrane-coalescing settler, and the organic layer is concentrated under 60 mbar vacuum on a wiped-film evaporator before anti-solvent crystallization from n-heptane/tetrahydrofuran (5:1 v/v). Terminal column purification via simulated moving bed chromatography delivers the penultimate intermediate with enantiomeric purity exceeding 99.5 % as determined by chiral HPLC on an amylose tris(3,5-dimethylphenylcarbamate) column. The final dosage form manufactured from this intermediate is an oral pan-genotypic antiviral tablet co-formulated with a cytochrome P450 inhibitor booster, subject to FDA 21 CFR Part 211 finished pharmaceutical current good manufacturing practice and requiring Process Analytical Technology monitoring of the coupling step as a Critical Quality Attribute node.
How Does Amide Formation with Sterically Hindered 4-Fluoro-3-trifluoromethyl Aniline Drive Selective Triazolinone Herbicide Bioactivity?Under phase-transfer catalysis (PTC) conditions compliant with CIPAC MT 75 and referenced in FAO pesticide specifications for technical-grade active ingredients, 4-isopropyl-1,3-thiazole-2-carboxylic acid is converted to its acid chloride via treatment with thionyl chloride in toluene at 75–80 °C using catalytic N,N-dimethylformamide (0.05 eq) to generate the Vilsmeier adduct in situ. The resulting acyl chloride is coupled with 4-fluoro-3-(trifluoromethyl)aniline in a biphasic mixture of toluene and 25 % w/w potassium carbonate at 35–40 °C, employing tetrabutylammonium bromide at 3 mol% to facilitate interfacial transfer. The molar charge of the thiazole acid relative to the substituted aniline is maintained at 0.80 to 0.95 eq, deliberately sub-stoichiometric to suppress bis-acylation and to ensure residual free amine is subsequently scavenged in the downstream cyclisation with triphosgene to the triazolinone core, which forms the actual herbicide pharmacophore. Reaction progress is monitored by thin-layer chromatography on silica gel 60 F₂₅₄ plates with ethyl acetate/n-hexane (1:3 v/v) until the aniline spot disappears; typical batch cycle time at 2,000 L scale is 5–6 hours to the crude amide stage. After phase cut, the organic layer is washed with demineralised water at 45 °C to remove TBAB residues, then azeotropically dried under partial vacuum (300 mbar) with a Dean-Stark trap before being telescoped directly into the triazolinone ring closure without isolation of the intermediate. The final formulated product is a suspension concentrate herbicide containing 480 g/L active ingredient, registered under EC 1107/2009 for pre-emergent control of broadleaf weeds in maize. Operational boundary note: the acid chloride must be generated and consumed within 8 hours; prolonged storage above 10 °C leads to decarboxylative degradation generating 4-isopropylthiazole as a volatile by-product detectable by headspace GC, and any batch exhibiting a thiazole peak area exceeding 2 % is rejected for failing the purity specification in the subsequent ring-closure step. In reactive flavour generation for high-protein snack manufacturing, 4-isopropyl-1,3-thiazole-2-carboxylic acid serves as a latent aroma precursor that undergoes thermal decarboxylation during the extrusion or frying process to liberate 4-isopropylthiazole, a heterocyclic volatile with a tropical green mango and overripe tomato sensory profile recognised under FEMA and compliant with EU Regulation 1334/2008 on food flavourings. The precursor is dispersed in a vegetable oil slurry containing 0.02–0.20 % w/w of the thiazole acid on a dry seasoning blend basis, then co-extruded with a maize-soy base at barrel zone temperatures programmed from 80 °C in the feed section to 155 °C at the die plate of a co-rotating twin-screw extruder with a 27:1 L/D ratio and 400–450 rpm screw speed; decarboxylation kinetics at the die exit reach 85–92 % conversion within a residence time of 28–35 seconds as confirmed by stable isotope dilution analysis using d₅-4-isopropylthiazole as internal standard. The generated aroma compound partitions preferentially into the lipid phase of the expanded collet, giving a burst of tropical fruit top-note that persists through shelf-life when the product is packed in aluminium-laminated film with oxygen transmission rate below 0.5 cm³/(m²·d·bar). The downstream production process is validated under FSSC 22000 with a critical control point at the post-extrusion moisture quenching zone, where residual free acid is neutralised with food-grade sodium bicarbonate to prevent decarboxylation continuing at ambient storage temperatures above 35 °C. The finished consumer product is a barbecue-flavoured indirect-expanded snack pellet with the volatile fingerprint characterised by 4-isopropylthiazole at 0.8–1.2 mg/kg, accompanied by pyrazine and thiazoline congeners that are documented in the flavour house’s Substance Identification Declaration. Formulators note that addition of the precursor at levels exceeding 0.25 % in dry mix results in a metallic aftertaste and a loss of green character, thus the operable window is narrow and confirmed through paired-comparison sensory panels with n = 24 trained assessors under ISO 8586.Copper Corrosion Inhibitor Package in Synthetic Metalworking FluidsCorrosion rates for cartridge brass UNS C26000 immersed in a 5 % dilution of semi‑synthetic metalworking fluid prepared from a concentrate containing 0.5–2.0 wt% 4-isopropyl-1,3-thiazole-2-carboxylic acid are evaluated per ASTM D130-19 at 50 °C for 24 hours under aerated conditions; the inhibitor reduces the tarnish rating from 4B (severe blackening) to 1A (slight orange tint) on the classification chart, corresponding to a decrease in mass loss from 0.82 mg/cm² to 0.09 mg/cm². Potentiodynamic polarisation scans conducted in a three-electrode cell with a saturated calomel reference and platinum counter electrode at a scan rate of 0.16 mV/s in 3.5 % w/w NaCl background show a pronounced anodic shift in the Tafel region, with the corrosion current density (icorr) suppressed from 4.2 µA/cm² to below 0.3 µA/cm², consistent with the formation of a chemisorbed cuprous-thiazole complex identified by ex-situ X-ray photoelectron spectroscopy on the Cu 2p₃/₂ peak at 932.6 eV. In concentrate formulation, the thiazole acid is neutralised to its potassium salt with 45 % KOH to ensure full solubility in the hydrocarbon phase without precipitation of the free acid, and is co-formulated with a medium‑chain chlorinated paraffin extreme‑pressure additive and a boric acid‑based amide friction modifier. The finished fluid concentrate is subject to ISO 4618 terminology and classification. Operational limits require monitoring of fluid pH in the sump between 8.8 and 9.3; a drop below 8.4 triggers re‑protonation of the inhibitor and a measurable rise in dissolved copper by inductively coupled plasma optical emission spectrometry, eventually leading to blue stain formation on aluminium‑6000 series workpieces. Industrial fluid life in a centralised 80,000 L system machining brass synchroniser rings has been documented to extend from 8 weeks to 22 weeks without biocide top‑up when the thiazole inhibitor is maintained above a threshold of 35 ppm free acid equivalent. When Used as a Carrier Suppressor in Acid Copper Via-Fill FormulationsAt a typical via‑fill operating current density of 2.0 A/dm² (20 ASD) and bath temperature of 25 °C, 4-isopropyl-1,3-thiazole-2-carboxylic acid is blended into the makeup solution at 1.0–5.0 mg/L together with a poloxamine block copolymer carrier and sodium polydisulfide propane sulfonate as the accelerator, conforming to IPC-4552A requirements for electroless nickel/immersion gold surface finishes on printed circuit boards. The thiazole compound functions as a leveler that selectively adsorbs on high‑current‑density areas at the board surface while remaining depleted inside the microvias, thereby promoting bottom‑up fill in blind structures with an aspect ratio up to 1.2:1 and via diameter 100 µm. Cyclic voltammetric stripping (CVS) analysis using a rotating platinum disk electrode at 2,500 rpm and a scan rate of 100 mV/s in a standardised 70 mL cell quantifies the suppressor concentration through the ratio of the stripping peak area of the working bath to that of a fresh VMS; the addition target is adjusted by a dosing pump controlled by a real‑time CVS feedback loop that maintains the peak ratio within 0.85–0.92. When the 4-isopropyl-1,3-thiazole-2-carboxylic acid concentration falls below 0.8 mg/L, surface dimple depth measured by white‑light interferometry on a coupon cross‑section increases from <5 µm to >12 µm, compromising coplanarity. In a production environment, the anolyte is separated by a cation‑exchange membrane to prevent oxidation of the thiazole ring at the insoluble anode, and the breakdown product 4-isopropylthiazole is volatilised and captured by an integrated activated carbon exhaust filter monitored monthly under ISO 14001 for VOC emission compliance. The downstream plated panel proceeds through a horizontal wet-chemistry line to deposit 3–5 µm of immersion tin before routing, yielding a fully filled blind via with an acceptance criterion of ≤10 % void area detected by X‑ray inspection at 45 kV. In open recirculating cooling water systems operating under high-cycle concentration where the calcium hardness as CaCO₃ can exceed 800 mg/L and the Langelier Saturation Index approaches +2.5, 4-isopropyl-1,3-thiazole-2-carboxylic acid is dosed as a non-phosphorus scale inhibitor at 10–30 mg/L active concentration, in accordance with the dynamic scale loop method described in ISO 16712 and the hardness stability evaluation of ASTM D3240. The heterocyclic carboxylate exerts threshold inhibition by complexing calcium ions through the carboxylic acid moiety while the thiazole ring provides dispersancy for calcium carbonate nanocrystallites, delaying the induction time for calcite nucleation from 45 minutes to over 240 minutes in a turbidimetric assay at 60 °C and a stirring rate of 300 rpm. The treatment is fed to the cooling tower basin via a positive displacement metering pump slaved to make‑up water flow, with residual inhibitor concentration verified by UV absorbance at 268 nm after passing the sample through a 0.45 µm syringe filter to remove insoluble carbonate solids. The terminal output of the process is the protection of shell‑and‑tube heat exchanger bundles in a petrochemical cracker complex, where the absence of phosphate‑based inhibitors avoids eutrophication risk in the blowdown discharge, a requirement codified in the facility’s EU BAT Reference Document (BREF) for cooling systems. Field data from a 30‑day trial on a forced‑draft cell with a heat load of 25 MW showed a Ryznar Stability Index maintained between 5.5 and 6.5, and an overall heat transfer coefficient decay of less than 3 %—measured by data‑logged approach temperature trending—validating the inhibitor under alkaline pH conditions (pH 8.5–9.0). An incompatibility exists with cationic polyelectrolyte flocculants used in sidestream filtration; simultaneous injection at the pump suction leads to precipitation of a thiazole‑polymer coacervate that fouls the bag filter socks, thus a minimum 15‑minute residence time between injection points is enforced in the chemical dosing manifold. |
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4-Isopropyl-1,3-thiazole-2-carboxylic acid (CAS 234446-90-5) is supplied as a crystalline solid with a typical purity of ≥97% by reversed-phase HPLC (monitored at 254 nm), and is available in batch sizes ranging from 1 g to 25 kg for research and pilot-scale synthesis. The molecular formula is C₇H₉NO₂S, with a molecular weight of 171.22 g·mol⁻¹. Residual solvent levels conform to USP <467> Option 1 limits, and the compound is stored at 2–8 °C under inert gas to prevent hygroscopic degradation and oxidative discoloration observed in unprotected samples stored above 60% relative humidity.
When integrated into a process stream at manufacturing scale, the steric demand of the isopropyl substituent at the 4-position distinguishes this scaffold from the more compact 4-methyl-1,3-thiazole-2-carboxylic acid. In amide-coupling reactions conducted in jacketed glass-lined reactors, the bulkier alkyl group retards the rate of N-acylation by approximately 15–20% relative to the 4-methyl analogue when using HATU/DIEA activation in DMF at 0 °C. This kinetic offset requires extension of the hold time at the controlled temperature ramp stage, but it also suppresses the formation of the bis-acylated byproduct that plagues the methyl-substituted variant when stoichiometric control drifts above 1.05 equivalents of the acyl chloride. For process chemists accustomed to the 4-methyl benchmark, the difference is immediately apparent in the HPLC chromatogram at 210 nm: the isopropyl derivative’s activated ester intermediate elutes with a retention time shift of +1.3 min under standard 0.1% TFA/MeCN–H₂O gradients, providing a window for in-process control sampling that is absent in the methyl analogue’s crowded product profile.
The 2-carboxylic acid function, situated on the electron-deficient thiazole ring, exhibits lower intrinsic reactivity toward nucleophiles than the corresponding 2-bromo or 2-chloro derivatives. In a head-to-head comparison using a Buchwald-type amination screening plate under Pd₂(dba)₃/Xantphos catalysis at 100 °C, the carboxy group remains inert, whereas 4-isopropyl-2-bromothiazole undergoes rapid C–N bond formation within 2 h. This orthogonal stability is deliberately exploited in fragment-based drug discovery where a late-stage carboxylate moiety must survive a sequence of metal-catalyzed cross-couplings on remote positions of a scaffold. The pKₐ of the carboxylic acid proton is estimated at 2.8–3.2 (calculated using the Advanced Chemistry Development model at ionic strength 0.1 M), placing it slightly weaker than the 4-unsubstituted thiazole-2-carboxylic acid by roughly 0.3 log units, an effect attributed to electron-donating induction from the isopropyl group transmitted through the ring. This subtle shift influences the extraction behavior: in a water/methyl tert-butyl ether biphasic system, the compound partitions preferentially into the organic layer above pH 4.5 with a distribution ratio D of 3.8, compared to 2.1 for the unsubstituted acid under identical conditions.
| Parameter | 4-Isopropyl derivative | 4-Methyl derivative | Unsubstituted |
|---|---|---|---|
| Molecular weight (g·mol⁻¹) | 171.22 | 143.17 | 129.14 |
| LogP (octanol-water, pH 2.0) | 1.9 | 1.1 | 0.5 |
| Relative N-acylation rate vs. benzylamine in DMF at 0 °C | 0.8 | 1.0 (reference) | 1.3 |
| Melting onset by DSC (°C, 10 K/min) | 96–98 | 138–140 | 100–102 |
| Thermal decomposition onset (°C, TGA, N₂) | 210 | 225 | 215 |
The lower melting point of the isopropyl compound relative to the 4-methyl homolog is a critical factor during continuous drying in a conical screw vacuum dryer operating at jacket temperatures of 45–50 °C. Whereas the methyl derivative can withstand a 12 h cycle without particle agglomeration, the isopropyl-containing material requires intermittent tumbling at 20 rpm and a maximum jacket setting of 40 °C to avoid partial sintering that has been observed in production campaigns exceeding 500 g scale. This behavior was documented during a tech transfer run at a kilo lab facility equipped with a 20 L Hastelloy filter-dryer; after an unplanned temperature excursion to 52 °C, the batch exhibited lump formation requiring a manual reslurry step that added 3 h to the overall turnaround time.
The compound is classified as a skin and eye irritant per EC 1272/2008 (CLP) criteria; airborne dust generation during weighing and charging is controlled through containment enclosures validated to an occupational exposure limit of 0.5 mg·m⁻³ (8-h TWA). Chronic stability data from 12-month retests stored at 2–8 °C under nitrogen arc-flushed fluorinated HDPE bottles show purity retention within 0.4% of the initial value when moisture ingress is excluded. Contact with strong oxidizing agents—particularly peroxides used in epoxidation processes—must be avoided, as DSC screening revealed an exothermic event with an onset of 180 °C and a specific heat of 820 J·g⁻¹ for a 1:1 mixture with m-chloroperbenzoic acid. This energy release magnitude is sufficient to rupture a 100 mL Easymax reactor if uncontrolled, mandating a dedicated cleaning protocol for shared equipment.
Polymer-bound applications of this building block have been explored in solid-phase peptide mimetic libraries. On a Rink amide resin preloaded at 0.8 mmol·g⁻¹, the free acid is coupled using HOBt/DIC activation in NMP with a double-coupling protocol at 45 °C. The steric penalty incurred by the isopropyl group increases the second coupling dwell time from 30 min (for the 4-methyl analogue) to 50 min to achieve the same Kaiser test negative readout. However, the resulting amide bond exhibits higher resistance to TFA cleavage at the global deprotection step, requiring a cleavage cocktail extended from 2 h to 2.5 h for complete release.
In cyclocondensation reactions with α‑haloketones, the 4‑isopropyl substituent imparts a diastereoselectivity advantage that is not attainable with the 4-methyl or 4‑cyclopropyl analogues. When this acid is first converted to the thioamide and then reacted with 2‑bromo‑1‑phenylethanone in refluxing ethanol, the resulting 2,4‑disubstituted thiazole is formed with a diastereomeric ratio of 8:1, as determined by 1H NMR integration of the C‑5 proton signals. By contrast, the 4‑methyl thioamide yields a 2.3:1 ratio under identical conditions. The steric influence of the isopropyl group forces the enolate intermediate to adopt a specific facial approach on the thioamide carbon, a model supported by a 3.2 kcal·mol⁻¹ difference in DFT-calculated transition state energies at the B3LYP/6‑31G* level. This finding has been leveraged in the preparation of a focused library of 120 trisubstituted thiazoles for a kinase selectivity panel where the isopropyl-substituted entries showed a substantially lower promiscuity score than the methyl analogues.
Published data for the specific configuration of this compound in vapor‑phase continuous flow hydrogenation is limited; attempts to reduce the carboxylic acid to the corresponding alcohol over a 5% Ru/C catalyst bed at 150 °C and 10 bar H₂ in a H‑Cube Pro reactor resulted in partial desulfurization (~12% area by GC‑MS) that was not observed with the unsubstituted thiazole‑2‑carboxylic acid under matching throughput conditions. The desulfurization product, identified as 3‑methylbutanamide after hydrolysis of the intermediate, arises from a competing hydrogenolysis pathway on the thiazole ring, a reactivity profile that must be accounted for when designing catalytic route scouting experiments.
For registered pharmaceutical intermediate filings, the technical grade of 4‑isopropyl‑1,3‑thiazole‑2‑carboxylic acid is supplied with a full certificate of analysis including residual palladium (<10 ppm), heavy metals per Ph. Eur. 2.4.8, and endotoxin levels (<0.25 EU·mg⁻¹) when requested for parenteral drug substance development. The compound does not appear on any Annex XVII restriction list under REACH, and a Toxic Substances Control Act (TSCA) inventory search confirms exclusion from active PMN notifications as of the most recent update cycle.
