2-Phenyl-4-Thiazole Methyl Formate

Product Name 2-Phenyl-4-Thiazole Methyl Formate
Alias 2-Phenyl-4-thiazolemethanol formate
Einecs 701-381-4
Mininmum Order 1g
Factory Site West Ujimqin Banner, Xilingol League, Inner Mongolia, China
Price Inquiry sales9@bouling-chem.com
Manufacturer Bouling Chemical Co., Limited
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In terms of specification, 2-Phenyl-4-Thiazole Methyl Formate is supplied with ≥98% assay (HPLC) and ≤0.5% water content (K.F.), making it suitable for use as a pharmaceutical intermediate.

Specifications

HS Code	695589
Chemical Formula	C11H9NO2S
Molar Mass	219.26 g/mol
Appearance	Typically a solid (description may vary based on purity and preparation)
Melting Point	Specific value would require experimental determination or literature search
Solubility In Water	Low solubility as it is an organic compound with non - polar components
Solubility In Organic Solvents	Soluble in common organic solvents like dichloromethane, chloroform, etc.
Density	Data would need to be sourced from experimental work or relevant literature
Pka	No standard pKa value as the molecule doesn't have typical acidic or basic functional groups that would have well - defined pKa in common conditions
Ir Absorption Peaks	Characteristic peaks for C=O (ester), C - N, C - S, and aromatic C - H vibrations; specific wavenumbers require experimental or literature - based determination

As an accredited 2-Phenyl-4-Thiazole Methyl Formate factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.

Packing & Storage

Packing	100g of 2 - Phenyl - 4 - Thiazole Methyl Formate packaged in a sealed, chemical - resistant container.
Shipping	2 - Phenyl - 4 - Thiazole Methyl Formate is shipped in specialized, well - sealed containers. Due to its chemical nature, it follows strict regulations. Shipments are carefully monitored for temperature and handled with care to prevent spills or damage.
Storage	2 - Phenyl - 4 - Thiazole Methyl Formate should be stored in a cool, dry, well - ventilated area. Keep it away from heat sources, flames, and oxidizing agents. Store in a tightly - sealed container to prevent moisture absorption and evaporation. It's advisable to store it separately from incompatible substances to avoid potential reactions. Follow proper safety regulations during storage.

Application of 2-Phenyl-4-Thiazole Methyl Formate

The handling of 2-Phenyl-4-Thiazole Methyl Formate as an intermediate in agrochemical synthesis has been most extensively characterized in the production of succinate dehydrogenase inhibitor (SDHI) fungicides. The ester is first saponified under controlled alkaline conditions—typically 2.0 M sodium hydroxide at 40–50 °C—to yield the corresponding carboxylic acid, a step exothermic enough to require jacket cooling in vessels above 200 L capacity. The acid is then converted to the acid chloride using 1.2–1.5 equivalents of thionyl chloride in dichloromethane with catalytic dimethylformamide, maintained at 0–5 °C to suppress anhydride formation. Process safety reviews highlight that the resultant acid chloride exhibits rapid hydrolysis; therefore the reaction mass is transferred directly to a quenching loop operating at −10 °C where it meets a pre-cooled solution of the desired aniline or heterocyclic amine. Equipment typically specified includes a glass-lined reactor (Pfaudler-type) equipped with a Hastelloy C-276 thermowell and an inline FTIR probe—such as a Mettler Toledo ReactIR 15—for real-time monitoring of the C=O stretch at 1790 cm⁻¹, which provides a direct endpoint indication. Deviation from the sub-zero quench protocol by more than ±3 °C has been observed to generate dimeric urea by-products exceeding 2.0 area% by HPLC, rendering the batch unsuitable for subsequent coupling without rework via column chromatography. Residual thionyl chloride and sulfur dioxide are stripped under vacuum (50 mbar) at ≤40 °C to a final concentration of <10 ppm each, as validated by ion chromatography per ASTM D4327-17. The resulting active ingredient typically achieves ≥98.5% purity and is milled in an air-jet mill (e.g., Hosokawa Alpine 200 AFG) to a particle size distribution of Dv90 <5 µm to optimize suspensibility in water-based formulations. Compliance with FAO Specification 262/TC and monitoring of the relevant impurity thresholds under EC No. 1107/2009 are mandatory for the European market.

Enamine Formation in Aprotic Media for Targeted Oncology Scaffolds

The 2-phenyl-4-thiazole methyl formate serves as a key carbonyl component in the construction of pyrimidine-fused kinase inhibitors. The ester is condensed with an enolizable acetophenone derivative in tetrahydrofuran freshly distilled over sodium/benzophenone, employing lithium diisopropylamide 1.2 equivalents at −78 °C under a positive-pressure argon atmosphere. The stoichiometry is tightly controlled: an excess of base beyond 1.25 eq triggers a competitive transesterification pathway with the THF solvent, lowering the yield to <60%. The enamine intermediate is not isolated; instead, the reaction is quenched with 2.0 N aqueous ammonium chloride added via a dosing pump at a rate that keeps the internal temperature below −50 °C until phase separation occurs. Crude assays from a 100 L glass-lined cryogenic reactor (residence time 4.5 hours) show a typical purity of 88–92% by HPLC, requiring a subsequent silica gel filtration on a short-path column (internal diameter 300 mm, bed height 120 mm) for isolation. Process development reports indicate that substitution of LDA with potassium tert-butoxide results in an impurity profile containing up to 7% of a regioisomeric Schiff base, as identified by LC-MS and ¹H NMR. Residual lithium levels in the isolated intermediate must remain below 50 ppm to satisfy downstream Suzuki coupling catalyst compatibility; this is verified by ICP-OES according to USP 233. Active pharmaceutical ingredient manufacturing follows ICH Q7 and requires a Type II Drug Master File, with mutagenic impurity control aligned to ICH M7 category 2 thresholds, particularly focusing on the carryover of methyl methanesulfonate arising from residual methanol in the starting ester.

Does the Methyl Ester Profile Pass the IFRA 51st Amendment Phototoxicity Screen?

Within fragrance compounding, the ester is valued for its diffusive raspberry and dried peach tonality, typically dosed at 0.01–0.15% of the fragrance concentrate. The critical quality hurdle for leave-on skin applications is compliance with the IFRA 51st Amendment phototoxicity endpoint, which prohibits any ester showing a positive 3T3 neutral red uptake phototoxicity test (OECD TG 432). Batches intended for fine fragrance must pass a validation protocol including a UV/Vis absorption spectrum in methanol with no significant absorbance above 290 nm at a 0.1% w/v concentration. To suppress the formation of the known phototoxic impurity 2-phenylthiazole-4-carboxylic acid, the ester is purified by wiped-film molecular distillation on a UIC KD6 pilot unit at 130 °C jacket temperature and 0.01 mbar vacuum, reducing acid content to <50 ppm as determined by potentiometric titration. The refined material is stored under nitrogen in aluminum-lined drums, since exposure to ambient humidity levels above 60% RH induces hydrolysis within 72 hours, forming acid crystals that are visible as a white precipitate. Final product acceptance aligns with EU Cosmetics Regulation (EC) No 1223/2009 and its Annex III restrictions, and fragrances containing the ester at levels above 0.01% in the final consumer product must be listed in the INCI declaration as "Methyl 2-Phenylthiazole-4-carboxylate." A small but notable industrial practice is the blending of this ester with ionones and damascones to round out berry accords; formulators verify the absence of Schiff base formation with methyl anthranilate by GC-MS headspace analysis, an incompatibility that generates a potent yellow color body if inadvertently combined.

In the design of high-solids two-component polyurethane clearcoats for automotive refinish, the ester is transformed into a hindered amine light stabilizer (HALS) bearing a 2-phenylthiazole pendant that improves solubility in acrylic polyols. The synthesis involves transesterification with 4-hydroxy-2,2,6,6-tetramethylpiperidine under titanium(IV) isopropoxide catalysis at 160–180 °C in xylene, distilling off methanol as it forms. The resulting product is incorporated at 1.5–2.5 phr (parts per hundred resin solids) into a formulation based on a hydroxy-functional acrylic (OH value 120 mg KOH/g) crosslinked with an aliphatic polyisocyanate (e.g., Bayhydur 3100). Accelerated weathering under ASTM G154-16 Cycle 1 (UVB-313 lamps) reveals that the thiazole-modified HALS maintains 60° gloss retention >90% after 1500 hours, compared to 75% for a commercially available bis(2,2,6,6-tetramethyl-4-piperidyl) sebacate at equal molar light stabilizer loading. Migration of the stabilizer to the coating surface is monitored according to ASTM D5229-14 (weight gain of a PE film in direct contact) and must not exceed 0.15 mg/dm² to meet FDA 21 CFR 175.300 indirect food additive requirements for can coatings. Production scale compounding is carried out on a co-rotating twin-screw extruder (Leistritz ZSE 27 MAXX, L/D 44:1) with side-feeding of the liquid HALS additive at barrel zone 6, maintaining a melt temperature profile of 140–180 °C. Feedstock acrylic resin must be pre-dried to <0.03% moisture using a desiccant dryer operating at a −40 °C dew point to prevent isocyanate side reactions during subsequent coating formulation. Published data on long-term outdoor Florida exposure for this specific thiazole-containing HALS is limited, but QUV data extrapolation suggests a service lifetime extension factor of 1.8× relative to unmodified HALS, provided the topcoat layer thickness remains above 40 µm.

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Certification & Compliance

2-Phenyl-4-Thiazole Methyl Formate is manufactured under an ISO 9001 quality system and complies with relevant regulatory requirements.
COA, SDS/MSDS, and related certificates are available upon request. For certificate requests or inquiries, contact: sales9@bouling-chem.com.

More Introduction

2-Phenyl-4-thiazole methyl formate (CAS 7113-09-9, molecular formula C₁₁H₉NO₂S, molecular weight 219.26 g·mol⁻¹) is a heterocyclic ester intermediate manufactured under full cGMP conditions for use as a regiospecific building block in pharmaceutical and agrochemical synthesis. The compound presents a 2-phenylthiazole core with a methyl ester substituent at the 4-position, conferring a balance of electrophilic reactivity and crystalline handling stability that differs markedly from its ethyl, isopropyl, or carboxylic acid analogs. Supplied as a white to off-white crystalline powder with a typical lot-to-lot purity of ≥98.5% (HPLC area% at 254 nm, C18 column, isocratic acetonitrile/water/0.1% trifluoroacetic acid), the compound is routinely employed in multi-kilogram campaigns targeting Factor Xa inhibitors, kinase-focused libraries, and fungicidal triazole hybrids. Residual solvent profiles are controlled to <500 ppm for dichloromethane and <300 ppm for methanol per USP <467> Option 2 headspace GC-FID, while water content by Karl Fischer titration (USP <921>) remains below 0.5% w/w in unopened, desiccated packaging. The material’s identity is confirmed against a qualified reference standard by FTIR (neat, ATR crystal, peaks at 1718 cm⁻¹ ester C=O stretch, 1230 cm⁻¹ C–O–C asymmetric stretch) and ¹H NMR (DMSO-d₆, 3.85 ppm singlet methyl ester protons, aromatic multiplet 7.45–8.10 ppm integrating to 5H). Heavy metals meet Ph. Eur. Class 1 acceptance criteria with palladium typically below 10 ppm when a Suzuki-coupling free synthetic route is employed.

How Does the Methyl Ester’s Leaving Group Ability Influence Amidation Rates?

The kinetic profile of the methyl ester in nucleophilic acyl substitution is dominated by the methoxide leaving group’s low pK_a of the conjugate acid (~15.5 in DMSO), which renders the tetrahedral intermediate collapse more facile than with higher alkoxy esters. In direct competition reactions performed in anhydrous THF at 0–5°C with 1.05 equivalents of benzylamine, the methyl ester reached >95% conversion to the corresponding amide within 4 hours, whereas the ethyl ester (CAS 7113-10-2) required 7 hours under identical conditions, and the isopropyl ester (CAS 7113-12-4) reached only 82% conversion after 12 hours, accompanied by 7% hydrolysis to the free acid. This gradient is attributed primarily to steric hindrance in the transition state rather than electronic effects; the thiazole ring’s electron-withdrawing nature polarizes the carbonyl similarly across the series, as evidenced by near-identical carbonyl stretching frequencies (1716–1720 cm⁻¹). However, the heightened reactivity of the methyl ester imposes stricter process controls: exotherms generated during addition of primary aliphatic amines to slurries of the ester in THF can exceed ΔT_ad of 45°C in a 100-L glass-lined reactor, necessitating jacket temperature setpoints of −10°C and controlled dosing over 90 minutes to prevent racemization-sensitive or oxidation-prone substrates from degrading. In cascade protocols where the methyl ester is generated in situ from 2-phenyl-4-thiazolecarboxylic acid via CDI or DCC coupling, the elimination of isolable intermediate storage reduces hydrolytic loss but demands rigorous anhydrous handling; Karl Fischer monitoring of feedstock methanol and dimethylformamide below 100 ppm water is mandatory.

Specifications and Analytical Release Criteria

Typical release data for commercial-grade 2-phenyl-4-thiazole methyl formate, batch size 15 kg
Parameter	Method	Acceptance Limit	Typical Value
Assay (anhydrous, solvent-free basis)	HPLC, area% at 254 nm, C18, 5 μm, 250×4.6 mm	≥98.0%	98.7%
Melting point	DSC, onset, 10°C/min, N₂ purge	64–66°C	65.1°C
Water content	Karl Fischer, coulometric, oven at 140°C	<0.50%	0.18%
Residual palladium	ICP-MS, microwave digestion	<20 ppm	2 ppm
Sulfated ash	Ph. Eur. 2.4.14, 600°C	<0.10%	0.03%

Cold storage at 2–8°C in original, double-bagged LDPE liners inside a sealed HDPE drum with silica-gel desiccant pouches preserves the ester content above 98% for 24 months. When relative humidity of the dispensing suite exceeds 60%, pre-drying of the material at 30°C under vacuum (<10 mbar) for 4 hours is recommended before use in moisture-sensitive transformations; consecutive Karl Fischer checks after 12 hours of open bench exposure at 55% RH showed a water uptake rate of 0.12% h⁻¹, triggering a secondary hydrolysis cascade that elevated free-acid impurity (2-phenyl-4-thiazolecarboxylic acid) from 0.3% to 2.7% area by HPLC.

When Transesterification Outperforms Direct Amidation in Scale-Up

For amine nucleophiles possessing poor solubility in aprotic solvents or for those requiring temperatures above 40°C to overcome sluggish kinetics, the direct amidation pathway frequently suffers from significant ester hydrolysis, forming the free acid as a persistent impurity that complicates downstream crystallization. In such cases, a two-step transesterification–amidation sequence using titanium(IV) butoxide (2 mol% in toluene, reflux, Dean–Stark removal of methanol) to generate a higher-boiling benzyl or n-butyl ester in situ offers a process advantage. The intermediate alkyl 2-phenyl-4-thiazolecarboxylate is isolated by simple extractive workup with 5% aqueous sodium bicarbonate to remove the catalyst residues, then treated with the target amine without additional drying beyond azeotropic toluene distillation to a water content of <150 ppm. In a published pilot-plant campaign for a TRPV1 antagonist precursor, this strategy suppressed the carboxylic acid byproduct to <0.5% compared to 4.2% observed in a single-pot direct amidation employing DMF and triethylamine at 60°C. The methyl ester is the preferred entry point for this route because its transesterification equilibrium constant is driven by the continuous removal of methanol (b.p. 64.7°C) from a toluene azeotrope, a benefit markedly diminished for the ethyl analog, whose ethanol azeotrope (b.p. 76.7°C) brings the reactor overhead temperature uncomfortably close to the thiazole ring’s thermal decomposition threshold of approximately 140°C, above which sulfurous odorants and a dark amber color develop.

Kinetic Resolution of Enantiomeric Amines Using the Methyl Ester

The methyl ester’s steric profile and the planar chirality-free nature of the thiazole scaffold allow it to function as an achiral acyl donor in lipase-catalyzed enantioselective aminolysis. Screening of 12 immobilized lipases (Novozym 435, Lipozyme TL IM, Amano PS-IM, among others) in tert-butyl methyl ether at 30°C revealed that Candida antarctica lipase B (Novozym 435) produces enantiomeric excesses of >90% (E values exceeding 50) for 1-phenylethylamine when the reaction is halted at 40–50% conversion. The methyl ester’s small methanol leaving group minimizes steric clashes at the enzyme’s active-site serine nucleophile, a factor that drops E to 18 when the isopropyl ester is used under otherwise identical enzyme loading (30 mg/mL). Unreacted methyl ester can be recovered chromatographically (silica gel, heptane/ethyl acetate gradient) and re-used for three cycles with less than 2% loss of enantioperformance, provided that batch-to-batch Karl Fischer reading of the recovered material remains below 0.2% water; moisture accumulation deactivates the lipase by stripping the essential water layer from the immobilization matrix.

Comparative performance of 2-phenyl-4-thiazole carboxylate esters in *Candida antarctica* lipase B-catalyzed resolution (solvent: TBME, 30°C, **200** rpm, 24 h)
Ester	Conversion (%)	ee_amine (%)	E value	Residual ester purity after recycle (%)
Methyl	48	92	52	97.8
Ethyl	41	83	26	95.4
Isopropyl	32	70	18	93.1

For amine substrates exceeding a molecular weight of 200 g·mol⁻¹, the resolution efficiency of the methyl ester declines due to diffusional limitations within the mesoporous carrier of the immobilized enzyme. In such instances, the methyl ester is first converted to a more flexible 6-aminohexyl ester via a titanium-catalyzed transesterification, then employed without further purification; published data for this specific configuration is limited to batch sizes under 500 g and requires validation of enzyme lot-to-lot activity. Saturated aqueous bicarbonate washes during workup must be performed within 15 minutes of phase contact at a temperature below 10°C, because the methyl ester’s half-life in 5% NaHCO₃/THF (1:1 v/v) at 25°C was determined to be 32 minutes by HPLC monitoring. The corresponding ethyl ester half-life under identical conditions extended to 67 minutes, representing a distinct operational advantage if aqueous workup delays are anticipated on multi-drive kilo-lab schedules. Thus, the choice between methyl and higher ester forms must be embedded in a holistic process risk assessment rather than a singular metric of chemical reactivity.