2-(4-Hydroxy-3-Nitrophenyl)-4-Methyl-5-Thiazolecarboxylic Acid Ethyl Ester
|
HS Code |
969461 |
| Chemical Formula | C13H12N2O5S |
| Molecular Weight | 308.31 g/mol |
| Appearance | Solid (presumed, typical for such compounds) |
| Solubility In Water | Low (due to non - polar groups) |
| Solubility In Organic Solvents | Moderate in polar organic solvents like DMSO |
| Melting Point | Data - specific experimental value needed |
| Boiling Point | Data - specific experimental value needed |
| Pka | Related to carboxylic acid group, likely around 4 - 5 |
| Density | Data - specific experimental value needed |
| Flash Point | Data - specific experimental value needed |
As an accredited 2-(4-Hydroxy-3-Nitrophenyl)-4-Methyl-5-Thiazolecarboxylic Acid Ethyl Ester factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 10 - gram vial of 2-(4 - Hydroxy - 3 - Nitrophenyl)-4 - Methyl - 5 - Thiazolecarboxylic Acid Ethyl Ester, securely packaged. |
| Shipping | 2 - (4 - Hydroxy - 3 - nitrophenyl)-4 - methyl - 5 - thiazolecarboxylic acid ethyl ester is shipped in well - sealed containers, safeguarded against physical damage. Special handling for chemicals ensures compliance with safety regulations during transportation. |
| Storage | Store 2-(4 - Hydroxy - 3 - Nitrophenyl)-4 - Methyl - 5 - Thiazolecarboxylic Acid Ethyl Ester in a cool, dry place away from direct sunlight. Keep it in a tightly sealed container to prevent moisture absorption and contact with air, which could potentially lead to degradation. Store it separately from incompatible substances to avoid chemical reactions. |
In the synthesis of the single-enantiomer xanthine oxidase inhibitor febuxostat, the ethyl ester of 2-(4-hydroxy-3-nitrophenyl)-4-methyl-5-thiazolecarboxylic acid functions as the penultimate intermediate prior to etherification and cyanation. A validated commercial route begins with 4‑hydroxybenzaldehyde and thioacetamide undergoing a Hantzsch thiazole cyclisation with ethyl 2‑chloroacetoacetate in refluxing ethanol; the resulting 2‑(4‑hydroxyphenyl)‑4‑methyl‑5‑thiazolecarboxylic acid ethyl ester is isolated by drowning into ice‑water and recrystallised from isopropanol. Regioselective nitration is carried out in a jacketed glass‑lined reactor using a pre‑cooled mixed acid composed of 65 % HNO₃ (1.05 eq) and 98 % H₂SO₄ (4.0 vol) at −5 °C to 0 °C over 90 min, maintaining the nitrating medium’s redox potential below 180 mV to suppress oxidative side‑products. After drowning onto crushed ice, the crude product is collected by centrifugation, reslurried in deionised water until the washings reach pH 5.0–6.0, and dried under vacuum at 45 °C to 50 °C until loss on drying is ≤0.5 %. The material routinely exhibits an HPLC purity (area %) exceeding 99.0 % on a C18 column (mobile phase: acetonitrile: 0.1 % phosphoric acid 60:40, detection at 254 nm), with residual 2‑(4‑hydroxyphenyl)‑4‑methyl‑5‑thiazolecarboxylic acid ethyl ester limited to ≤0.3 % and the 3,5‑dinitro impurity to ≤0.15 %. For conversion to febuxostat, the nitro group is reduced catalytically under 3 bar hydrogen using 5 % Pd/C (50 % wet) in tetrahydrofuran at 50 °C, then Sandmeyer cyanation of the resulting aniline intermediate with NaCN/CuCN in the presence of isobutyl bromide furnishes the final API after IPA recrystallisation, conforming to USP43–NF38 and Ph.Eur.10.0 monographs. On production scale, the nitro‑ester intermediate is typically purchased as a fine, yellow crystalline powder with particle size D₉₀ ≤100 µm to ensure a dissolution rate that permits a 4‑hour reduction cycle in the immediately subsequent step; a validated ICH Q7 supply chain requires residual heavy metals by ICP‑MS (Method II) below 10 ppm, and mutagenic impurity risk assessment per ICH M7(R2) with a purge factor calculation for the nitrosamine potential of the secondary amine intermediates is now mandatory for all API batches shipped into EU and US markets.What Drives the Selection of This Intermediate for High-Wash-Fastness Disperse Dyes?The electron‑withdrawing nitro group and the conjugated thiazole ring render 2‑(4‑hydroxy‑3‑nitrophenyl)‑4‑methyl‑5‑thiazolecarboxylic acid ethyl ester an efficient heterocyclic coupling component for azo disperse dyes that must withstand repeated industrial laundering. When diazotised 2‑amino‑6‑nitrobenzothiazole is coupled onto the phenolic moiety at pH 3.5–4.5 and 0–5 °C in an aqueous‑acetic acid medium containing 0.5 % sulphamic acid as a nitrite scavenger, the resulting disazo chromophore exhibits a bathochromic shift of 40–55 nm relative to the corresponding aniline‑based blue dyes, producing a deep navy hue on polyester fibre with maximum absorbance at 605–615 nm in dimethylformamide. The ethyl ester function remains intact during coupling and provides a slight temporary hydrophobicity that improves the dye’s solubility in the supercritical CO₂ dyeing process, though it does not contribute to the final wash fastness. Commercial dye‑house trials conducted on a Thies Luft‑Roto plus jet‑dyeing machine with 100 % polyethylene terephthalate knit fabric and a dye‑bath ratio of 1:10 at 130 °C for 60 min demonstrated a build‑up of 2.0 % o.w.f., achieving a colour strength (K/S) exceeding 18 when dispersed with 1.0 g/L naphthalene sulphonate‑formaldehyde condensate. After a post‑clearing treatment with 2.0 g/L sodium dithionite and 1.0 g/L NaOH at 80 °C for 20 min, the dyed fabric returns a multistaining rating of 4–5 on nylon and 5 on polyester according to ISO 105‑C06/C2S. Light fastness tested under ISO 105‑B02 (Xenon arc, 42 W/m², 35 °C black panel) reaches 6–7 on the blue wool scale, directly attributable to the stabilising intramolecular hydrogen bond between the azo linkage and the ortho‑nitro group. Dye powders standardised with 40 % dispersing agent (Marasperse N‑22) pass the 0.5 g/L aqueous dispersion filter test according to AATCC TM146, and finished shipments are accompanied by a certificate of analysis listing cadmium, mercury and lead below 5 ppm as required by OEKO‑TEX Standard 100 Annex 4.UV Absorber Performance in Bisphenol A Polycarbonate GlazingThe excited‑state intramolecular proton‑transfer (ESIPT) capability of the 2‑(4‑hydroxy‑3‑nitrophenyl)thiazole chromophore has been exploited as an ultraviolet stabiliser for bisphenol‑A polycarbonate (PC) glazing sheets exposed to tropical solar radiation. Compounding is performed on a co‑rotating twin‑screw extruder (L/D 36:1, screw diameter 25 mm) with a barrel temperature profile of 270 °C to 295 °C and a screw speed of 250 rpm. The additive is fed via a side‑feeder as a masterbatch in PC powder (10 % concentration) to a final loading of 0.3 wt% to 1.5 wt%. When incorporated at 1.0 wt%, the stabiliser shifts the onset of transmission from 385 nm to 395 nm and reduces the integrated UV‑A transmission (315–400 nm) by 60 % compared to an unstabilised control, measured by a spectrophotometer equipped with an integrating sphere in accordance with ISO 13468‑1. Accelerated weathering under ASTM G154‑16 Cycle 1 (UVA‑340 lamps, 60 °C BPT, 8 h irradiation / 4 h condensation) for 2000 h shows that the yellowness index increase (ΔYI, ASTM E313) is 3.8 for the 1.0 wt%‑loaded sheet, versus 11.2 for the unstabilised polycarbonate, while the notched Izod impact retention (ISO 180/A) remains at 88 %. Because the ethyl ester linkage is susceptible to hydrolysis under prolonged exposure to alkaline condensation water, co‑addition of a hindered amine light stabiliser is avoided, and external glazing applications require a co‑extruded 30 µm PMMA cap layer containing a hydrophobic UV absorber that blocks wavelengths 290–350 nm to prevent ester cleavage. Migration behaviour has been evaluated by immersion in distilled water at 80 °C for 14 days; the specific migration limit for the intact ester determined by HPLC‑MS/MS is 0.05 mg/dm², compliant with the EU Plastics Regulation (EU) 10/2011 overall migration limit when the stabilised sheet is used as the inner layer of a multi‑laminate food‑contact article.When Colorimetric Iron Quantitation Demands a Thiazole‑Azophenol AnalogueThe combination of a chelating thiazole nitrogen and the adjacent hydroxyl group enables 2‑(4‑hydroxy‑3‑nitrophenyl)‑4‑methyl‑5‑thiazolecarboxylic acid ethyl ester to act as a selective chromogenic ligand for ferric ions in aqueous process streams. In practice, a 0.1 % (w/v) solution of the compound in ethanol is freshly prepared and 2.0 mL is added to a 25 mL volumetric flask containing the sample acidified with 1.0 mL of pH 3.6 chloroacetate buffer. The absorbance of the violet 1:2 (Fe:ligand) complex, measured against a reagent blank in a 10 mm cell at the λmax of 528 nm, obeys the Beer‑Lambert law over the range 0.02 mg/L to 2.5 mg/L with a molar absorptivity of 1.18 × 10⁴ L mol⁻¹ cm⁻¹ and a correlation coefficient r² > 0.9995. The detection limit calculated as three times the standard deviation of the blank is 0.012 mg/L. Interference from Cu(II) and Al(III) is masked by the addition of 0.5 mL of 2 % thioglycolic acid, while phosphate and silicate at concentrations up to 50 mg/L do not interfere. The method has been cross‑validated against the ISO 6332:1988 1,10‑phenanthroline procedure on boiler blowdown water and electroplating rinse baths; recovery on spiked samples ranged from 97.5 % to 102.8 % with a relative standard deviation of ≤1.9 % (n=6). Because the ligand solution is photosensitive and develops a yellow‑brown tint within 8 h under fluorescent lighting, all standards and blanks are stored in amber‑glass volumetric ware at 4 °C when not in use, and a calibration curve is constructed daily. The complex is instantly formed at room temperature and remains stable for at least 4 h, making it suitable for discrete analyser platforms that complete a measurement cycle within 3 min. Users are warned that the ethanolic reagent is incompatible with silicone‑based antifoams; the use of PTFE‑coated stir bars and polyethylene‑lined sample vials is recommended throughout.Conversion to Thiazole-4-carboxamide Agrochemical Lead StructuresThe ester moiety of 2‑(4‑hydroxy‑3‑nitrophenyl)‑4‑methyl‑5‑thiazolecarboxylic acid ethyl ester serves as a convenient anchor for generating an amide library in discovery‑phase fungicide and herbicide programmes. Alkaline hydrolysis with 2 N NaOH in methanol at 60 °C for 2 h gives the free carboxylic acid in quantitative yield; the acid is then activated with thionyl chloride in dichloromethane containing a catalytic amount of dimethylformamide to produce the acid chloride, which is telescoped into acylation of substituted anilines or heterocyclic amines in the presence of triethylamine at 10 °C. One disclosed series of N‑[2‑(4‑chlorophenyl)‑2‑oxoethyl]‑2‑(4‑hydroxy‑3‑nitrophenyl)‑4‑methyl‑5‑thiazolecarboxamide exhibited post‑emergence herbicidal activity against Amaranthus retroflexus and Setaria viridis at application rates of 250 g a.i./ha in a standardised greenhouse assay conducted according to EPPO PP 1/135(4), with a shoot fresh‑weight reduction of ≥85 % relative to an untreated control 21 days after treatment. The 3‑nitro‑4‑hydroxyphenyl motif contributes to the overall lipophilicity and is retained throughout the synthesis because subsequent structure‑activity relationship studies have shown that replacement with an unsubstituted phenyl group leads to a 10‑fold loss of potency. Minor modifications of the phenolic hydroxyl—methylation or acetylation before amide coupling—proved detrimental to herbicidal activity, underscoring the requirement for the free phenol in the pharmacophore. Pilot‑scale production of the amide under GMP‑like conditions for toxicology batches employs a carbodiimide coupling procedure (EDC·HCl, HOBt, DMF, 25 °C) that avoids acid chloride sensitivity to moisture and achieves a purity of ≥97 % after silica gel chromatography. Residual solvent analysis of the final amide by headspace GC‑FID (USP <467> method) must confirm dichloromethane below 600 ppm and DMF below 880 ppm; ecotoxicological profiling with Daphnia magna following OECD 202 and algal growth inhibition per OECD 201 has shown an acute EC₅₀ of >100 mg/L for the parent ester, classifying it as practically non‑toxic to aquatic organisms and permitting its use in tier‑1 synthesis campaigns without a full negative‑pressure enclosure. |
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Designated by its IUPAC nomenclature as ethyl 2-(4-hydroxy-3-nitrophenyl)-4-methyl-1,3-thiazole-5-carboxylate, this fine chemical intermediate is supplied as a yellow to orange crystalline powder with a standard batch purity exceeding 98.5% by HPLC peak area at 254 nm. The molecule integrates three orthogonal reactive centres—a nitro group at the meta position relative to a phenolic hydroxyl, a thiazole ring bearing a methyl substituent at C-4, and a carboxyethyl ester at C-5—making it a convergent building block for heterocycle-focused medicinal chemistry libraries and disperse dye chromophores. Typical lots exhibit a loss on drying of less than 0.5% w/w (60°C vacuum, 4 h) and a sulfated ash content below 0.1%. Storage at 2–8°C in amber borosilicate containers under argon blanket is advised to suppress photolytic decomposition of the o-nitrophenol chromophore and atmospheric moisture uptake.
The electron-withdrawing nitro group deactivates the pendant phenyl ring, shifting the 1H NMR resonance of the adjacent thiazole C-H proton downfield to approximately 8.2–8.4 ppm (DMSO-d6, 400 MHz). Simultaneously, intramolecular hydrogen bonding between the phenolic proton and one nitro oxygen atom rigidifies the biaryl conformation, imposing a dihedral angle near 15° as estimated by DFT calculations at the B3LYP/6-31G(d) level. This near-planar geometry enhances π-conjugation between the donor phenol and the acceptor thiazole-ester system, which manifests as a bathochromic shift of 40–50 nm in the UV–vis absorption maximum relative to the 4-hydroxy-3-nitrophenyl-free analogue. In practice, these electronic features translate into a Hammett σp constant of approximately +0.78 for the nitrophenol moiety, directly affecting the rate of electrophilic substitution at the thiazole C-2 position and necessitating adjusted catalyst loadings during Suzuki–Miyaura couplings. Published kinetic data for this specific scaffold remain limited; however, comparative studies on 4-methylthiazole derivatives indicate a relative rate retardation factor of 2–3× when the nitrophenol ring is introduced, as monitored by in-situ ReactIR tracking of ester carbonyl consumption.
| Parameter | Specification | Method |
|---|---|---|
| Assay (HPLC) | ≥ 98.0% area | In-house SOP based on Ph. Eur. 2.2.29; column: C18, 150 × 4.6 mm, 5 μm; mobile phase: acetonitrile / water 60:40 with 0.1% TFA; flow 1.0 mL/min; detection 254 nm |
| Identity (IR) | Conforms to reference spectrum | ATR-FTIR, 4000–650 cm⁻¹; characteristic bands: 1698 cm⁻¹ (ester C=O), 1528 cm⁻¹ (NO₂ asym), 1336 cm⁻¹ (NO₂ sym), 3440 cm⁻¹ (phenolic O–H) |
| Melting range | 162–166°C | Differential scanning calorimetry (DSC), 10 K/min, N₂ purge, sealed Al pan; onset temperature reported |
| Water content | ≤ 0.3% w/w | Karl Fischer coulometric titration (Metrohm 831 KF Coulometer) per USP <921> Method Ic |
| Purity by TLC | Single spot, Rf 0.45 ± 0.03 | Silica gel 60 F₂₅₄, ethyl acetate / hexane 1:2 (v/v); visualization UV 254 nm and iodine |
| Residual solvents | Ethanol ≤ 0.5%; DMF ≤ 0.1% | GC-FID headspace per USP <467> Procedure A |
| Heavy metals | Pb ≤ 10 ppm, Cd ≤ 5 ppm, As ≤ 3 ppm | ICP-MS (Agilent 7800) after microwave-assisted acid digestion; method validated against ICH Q3D |
The most frequently executed downstream transformation on multi-kilogram scale is catalytic reduction of the nitro group to yield the corresponding aniline derivative, 2-(3-amino-4-hydroxyphenyl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester. This step is carried out in a 50 L Hastelloy C-22 autoclave equipped with a gas-entrainment impeller (typical power number Np ≈ 4.5), using 5% Pd/C (Johnson Matthey type 394, 50% water wet) at a substrate-to-catalyst ratio of 10:1 w/w. The solvent system of choice is tetrahydrofuran at 3.0 L/kg substrate, with hydrogen pressure maintained at 3.0 ± 0.2 bar and internal temperature held at 25–30°C. Under these conditions, hydrogen uptake typically ceases after 90–120 min, and in-process control by HPLC indicates < 0.5% residual starting material. Exotherms exceeding 35°C are to be avoided, as they promote secondary reduction of the thiazole ring, producing a desulfurized by-product that co-elutes with the desired aniline under standard reversed-phase conditions. Published data for this specific configuration is limited, but batch records from toll manufacturers indicate a typical isolated yield of 82–88% after recrystallization from isopropanol/water (7:3 v/v), with a final purity of 99.2–99.7%. The aniline intermediate itself is oxygen-sensitive in solution; strictly inert blanketing with nitrogen during work-up and vacuum tray drying at 45°C / 10 mbar for 16 h is enforced to prevent oxidative oligomerization.
In pharmaceutical intermediate manufacturing, batch-to-batch consistency of the ethyl ester protecting group is critical for subsequent amide bond formations in API syntheses. The ester is commonly activated via saponification to the free carboxylic acid using 1.2 equivalents of LiOH in THF/water (3:1) at 0–5°C, with saponification complete within 4 h as monitored by the disappearance of the 1698 cm⁻¹ IR band. Direct aminolysis without hydrolysis is feasible when employing T3P® (propanephosphonic acid anhydride) as coupling agent in the presence of 2.5 equivalents of DIPEA, a route preferred when the target amine is sensitive to the alkaline hydrolysis conditions. Differences from other 2-arylthiazole-5-carboxylates become most apparent here: the 3-nitro-4-hydroxy substitution pattern imparts sufficient acidity (pKa phenol ~ 5.8) that partial phenolate formation occurs during aqueous work-up at pH > 7, causing inadvertent partitioning into the aqueous layer. Thus, liquid-liquid extractions during purification are buffered to pH 4.5–5.0 with citrate buffer to maintain the phenol in its neutral form and secure > 95% recovery in the organic phase.
The solid-state behaviour of this ester is dominated by a single thermodynamically stable polymorph (Form I) under ambient conditions, characterized by a monoclinic space group P21/c with unit cell parameters a = 12.45 Å, b = 7.82 Å, c = 16.31 Å, and β = 98.3°, as determined by single-crystal X-ray diffraction on crystals grown from ethyl acetate/hexane. The packing motif features a head-to-tail hydrogen-bonded chain along the b-axis between the phenolic OH and the thiazole nitrogen of a neighbouring molecule (O···N distance 2.78 Å). This robust supramolecular synthon explains both the relatively high melting point and the low solubility in non-polar media: equilibrium solubility in ethyl acetate at 20°C is only 8.2 mg/mL, rising to 42 mg/mL in DMF. A metastable polymorph (Form II) can be kinetically trapped when the melt is quenched to –20°C on a stainless-steel chill roll, but it converts quantitatively to Form I within 48 h at 25°C / 60% RH, as confirmed by variable-temperature XRPD. For industrial grinding and milling steps, the particle size distribution is controlled via pin-milling under liquid nitrogen to achieve a d50 of 15–25 μm, which ensures sufficient dissolution kinetics during reactor charging without generating excessive fines that promote dust explosion hazards (minimum ignition energy measured at 8 mJ per EN 13821).
| Substituent on 2-Phenyl Ring | Melting Range (°C) | HPLC Purity (typical, %) | Solubility in Acetone (mg/mL, 25°C) | Electrophilic Substitution Reactivity (relative rate) |
|---|---|---|---|---|
| Unsubstituted (H) | 92–94 | 99.0 | > 200 | 1.00 (reference) |
| 4-Nitrophenyl | 138–141 | 98.5 | 45 | 0.60 |
| 3-Nitro-4-hydroxyphenyl (this product) | 162–166 | 98.0–99.2 | 22 | 0.35 |
| 4-Hydroxy-3-methoxyphenyl | 118–122 | 98.8 | 80 | 0.85 |
Residual moisture is the dominant degradation driver: when water content exceeds 0.5% w/w, autocatalytic ester cleavage accelerates at ambient temperature, reaching a hydrolysis rate of approximately 0.03% per day at 25°C as tracked by the free acid impurity at RRT 0.75. To maintain retest integrity beyond 24 months, the product is double-bag packed in LDPE under vacuum, sealed inside a secondary aluminium laminate pouch containing a silica-gel desiccant sachet (activated at 110°C for 3 h prior to insertion). Incompatibilities include strong bases, primary and secondary amines, and nucleophilic solvents such as methanol, which transesterify the ethyl ester at elevated temperatures via acid-catalysed or lipase-mediated pathways. For formulation into dispersion dyes, the use of anionic lignosulfonate dispersants at 10–15% w/w on pigment solids is recommended; non-ionic polyethylene glycol-based levelling agents should be restricted to < 2% due to eutectic formation that depresses the melting point of the bulk dye cake by 8–12°C, complicating the drying granulation step on a Fielder Pharma Matrix PMA-300 mixer-granulator.
