Methyl 2-Amino-5-Iodo-1,3-Thiazole-4-Carboxylate

Catalyst / Ligand System

Palladium Loading (mol%)

Conversion at 8 h (%)

Crude Pd Content (ppm)

Post‑Scavenging Pd (ppm)

Ester Hydrolysis Side Product (%)

Pd(PPh₃)₄

2.0

4.2

PdCl₂(dppf)·CH₂Cl₂

1.5

6.8

Pd(OAc)₂ / SPhos

0.5

1.1

Pd-132 (SiliaCat DPP-Pd)

0.3

0.9

What Solvent System Minimises Hydrolytic Ester Cleavage During Pd‑Mediated Biaryl Formation?

In the preparation of 4‑carboxamide‑5‑biaryl‑2‑aminothiazole intermediates used for succinate dehydrogenase inhibitor (SDHI) fungicide candidates—structural analogues of bixafen and inpyrfluxam—the iodine atom on methyl 2-amino-5-iodo-1,3-thiazole-4-carboxylate is exploited to install a substituted biaryl unit. Because the target active substance relies on the free carboxamide for target‑site hydrogen bonding in complex II of the mitochondrial respiratory chain, premature hydrolysis of the methyl ester before amidation is detrimental to overall yield. Screening data from process development indicates that employing 2-methyltetrahydrofuran (2‑MeTHF) as the primary solvent with ≤ 3 % v/v water content suppresses the ester hydrolysis side reaction to less than 2 area‑% during the coupling step. The reaction is executed with 1.25 equivalents of 3′,4′-dichloro-5‑fluoro-[1,1′-biphenyl]-2‑ylboronic acid, 1.0 mol% Pd(OAc)₂, and 2.0 mol% XPhos in the presence of K₃PO₄ (2.5 eq) at 70 °C. The biphasic aqueous‑organic system frequently recommended for Suzuki couplings is deliberately avoided because the alkaline aqueous phase accelerates methyl ester saponification, particularly when potassium phosphate is used. Instead, solid K₃PO₄ powder is suspended in dry 2‑MeTHF, maintaining the medium essentially anhydrous.

Continuous processing in a Corning Advanced‑Flow glass reactor (volume 10 mL, plate‑to‑plate spacing 0.3 mm) further diminishes the residence‑time‑dependent decomposition: with a total flow rate of 4.5 mL/min and a residence time of 2.2 min at 85 °C, conversion exceeds 95 % and the methyl ester hydrolysis product remains below 0.8 area‑%. The post‑reaction solution is quenched with aqueous HCl to protonate residual phenoxide, and the biaryl ester is precipitated by addition of n‑heptane. The isolated intermediate, after drying in a conical single‑cone dryer at 45 °C and 50 mbar, is subsequently amidated with 2‑amino‑1,3,4‑thiadiazole in methanol using sodium methoxide, giving the target SDHI fungicide. The technical‑grade active ingredient must comply with FAO specification AGP:CP/362 (or equivalent) and maintain a palladium residue below 50 ppm, verified by microwave‑assisted acid digestion followed by ICP‑OES in accordance with CIPAC method MT 184. Field‑trial formulations are prepared as 200 g/L suspension concentrates (SC) with proprietary EO‑PO block copolymer dispersants to achieve a particle size D₉₀ of 2–4 µm.

Managing Palladium Carryover in DprE1 Inhibitor Synthesis from 5‑Iodo‑2‑aminothiazole‑4‑carboxylate

Methyl 2‑amino‑5‑iodo‑1,3‑thiazole‑4‑carboxylate is employed as a building block for antitubercular agents targeting the decaprenylphosphoryl‑β‑D‑ribofuranose 2′‑epimerase (DprE1) enzyme in Mycobacterium tuberculosis. The iodo ester undergoes a sequential one‑pot procedure: a copper‑free Sonogashira coupling with 2‑ethynyl‑6‑(trifluoromethyl)benzothiazole using PdCl₂(PPh₃)₂ (1.5 mol%) and tri‑n‑butylamine in N,N‑dimethylformamide at 65 °C, followed directly by ester saponification with 1 M aqueous NaOH. The free carboxylic acid is then condensed with 2,6‑dichloro‑N‑(piperidin‑4‑yl)benzamide under peptide coupling conditions.

Given the stringent daily exposure limits for genotoxic impurities in a chronic‑dosing tuberculosis regimen, the manufacturing route incorporates both an activated‑carbon‑filtration step (Darco KB‑B, 10 % w/w relative to product) and a mercaptopropy‑functionalized silica gel chromatography as successive palladium mitigation measures. After these operations, the measured palladium content by ICP‑MS falls to 2–7 ppm—well below the oral permitted daily exposure of 100 µg/day outlined in ICH Q3D. The secondary amine functionality inherent to the 2‑aminothiazole core presents a latent risk of N‑nitrosamine formation if the intermediate comes into contact with nitrite sources during work‑up or storage. Consequently, the process design prohibits the use of sodium nitrite or acetic acid/NaNO₂ mixtures at any stage, and all aqueous phases are prepared with nitrite‑free USP‑grade water. The final active pharmaceutical ingredient (API) is tested for N‑nitrosodimethylamine (NDMA) and N‑nitrosodiethylamine (NDEA) using an LC‑MS/MS method sensitive to 0.03 ppm, fully aligning with the control recommendations of the EMA/CHMP/425842/2021 guideline. The crystalline monohydrochloride salt monohydrate is micronised to a median particle diameter of 1.5 µm for dry‑powder inhaler formulation and demonstrates >99.5 % enantiomeric purity by chiral SFC.

When the Methyl Ester Is Retained as a Prodrug Handle in Anti‑HCV NS5A Inhibitor Assembly

For a series of hepatitis C virus NS5A inhibitors containing a 2‑aminothiazole‑4‑carboxylic acid segment that ultimately requires ester prodrug derivatisation, the methyl ester of methyl 2‑amino‑5‑iodo‑1,3‑thiazole‑4‑carboxylate is deliberately preserved until the final synthetic step. Silver‑mediated or Buchwald‑Hartwig‑type couplings would compromise the ester group; therefore, a mild Suzuki–Miyaura coupling with tert‑butoxy‑protected biphenyl‑boronic acid pinacol ester is executed employing the highly active precatalyst tBuXPhos Pd G3 (0.2 mol%) in THF/water (9:1 v/v) containing 1.5 equivalents of potassium hydrogen carbonate at 30 °C. The reaction proceeds to 98 % conversion within 4 h with <0.5 % methyl ester cleavage. Without isolation of the intermediate, the biphenyl tert‑butyl ether is cleaved with trifluoroacetic acid, and the resulting phenol is alkylated with ethyl 2‑bromo‑2‑methylpropanoate in DMF with cesium carbonate.

The synthetic sequence is telescoped through five unit operations before the final amidation step with L‑valine methyl ester hydrochloride using HATU and N,N‑diisopropylethylamine in acetonitrile. At this stage the intact methyl ester of the thiazole core serves as the required carboxylic acid protecting group, allowing the selective formation of the C‑terminal valine methyl ester. The fully assembled prodrug is purified by preparative supercritical fluid chromatography (SFC) on a 2‑ethylpyridine stationary phase with a methanol/CO₂ mobile phase, isolating the single atropisomer with  > 98 % diastereomeric excess. The final spray‑dried material meets the ICH Q3D limits for palladium (≤ 10 µg/g) and is certified for residual valine ester starting material below 0.10 % by qNMR.

Aminothiazole Acceptor Units in Donor–Acceptor Copolymer Backbones for Organic Photovoltaics

In non‑fullerene acceptor (NFA) and wide‑bandgap donor polymer research, the electron‑deficient 2‑aminothiazole‑4‑carboxylate heterocycle functions as an acceptor unit when the iodine atom is replaced with a trialkylstannyl or boronic ester handle for Stille or Suzuki polycondensation. Methyl 2‑amino‑5‑iodo‑1,3‑thiazole‑4‑carboxylate is first subjected to a palladium‑catalysed distannylation with hexamethylditin in degassed toluene, yielding the 5‑trimethylstannyl derivative. This monomer is copolymerised with a 3,6‑bis(5‑bromothiophen‑2‑yl)‑2,5‑dioctylpyrrolo[3,4‑c]pyrrole‑1,4‑dione (DPP) comonomer using 1.5 mol% Pd₂(dba)₃ and 6 mol% P(o‑tolyl)₃ in chlorobenzene at 120 °C for 48 h. The resulting alternating copolymer exhibits a number‑average molecular weight of 18 kDa and a dispersity of 1.8 by high‑temperature GPC in 1,2,4‑trichlorobenzene at 150 °C. When blended with the acceptor ITIC‑4F and processed from o‑xylene in blade‑coated devices, the photoactive layer delivers a power conversion efficiency of 9.2 % under AM 1.5G illumination, as referenced in a published academic study. Residual tin residues from the Stille polymerization are scavenged by precipitation into methanol containing 0.1 % tetrabutylammonium fluoride.

Methyl 2-amino-5-iodo-1,3-thiazole-4-carboxylate (CAS 850429-50-4) is a heterobifunctional thiazole building block incorporating a primary amine at the 2-position, a methyl ester at the 4-position, and an iodine atom at the 5-position of the 1,3-thiazole ring. The compound is supplied as a white-to-off-white crystalline solid with an HPLC area% purity specification of ≥98.0% (detection at 254 nm, area normalization). Water content, determined by coulometric Karl Fischer titration per USP ⟨921⟩, is routinely controlled to ≤0.5% w/w. Residual solvent levels conform to ICH Q3C (R8) limits for Class 2 solvents, specifically for ethyl acetate and tetrahydrofuran, which are encountered in the terminal recrystallization pathway.

What Sets the 5-Iodo Substituent Apart in Cross-Coupling Reactions?

The iodine atom at the 5-position confers a distinct reactivity profile relative to the 5-bromo and 5-chloro congeners. Under standard Suzuki–Miyaura conditions using Pd(PPh₃)₄ (2 mol%) and aqueous Na₂CO₃ in 1,4-dioxane at 80 °C, oxidative addition rates follow the expected periodic trend I > Br >> Cl. This makes the iodo-thiazole ester the electrophile of choice when coupling sterically demanding or electron-rich aryl boronic acids that require lower activation energy. In head-to-head comparisons, quantitative conversion of the iodo derivative is typically achieved within 2 h, while the bromo analogue requires 8–12 h under identical catalyst loading; the chloro derivative shows <10% conversion. This rate acceleration is critical when sequential functionalization of the thiazole scaffold is planned, as the amine at C2 and the ester at C4 can be elaborately modified before or after the palladium-mediated step.

Comparative Reactivity of C5-Halogenated Methyl 2-Amino-1,3-Thiazole-4-Carboxylate Esters
Property	5-Iodo	5-Bromo	5-Chloro
Oxidative addition relative rate^†	~5	1.0 (reference)	<0.1
Typical Suzuki coupling time to >95% conv.	1.5–3 h	8–12 h	incomplete
Thermal stability threshold (DSC onset, N₂)	160 °C (exotherm)	210 °C	235 °C
Sensitivity to ambient light (solid state)	high (discoloration 24 h)	moderate	low
Preferred storage condition	−20 °C, argon, dark	2–8 °C, desiccated	ambient, sealed

^† Estimated from competitive experiments with 4-methoxyphenylboronic acid, Pd(PPh₃)₄ catalyst, dioxane/water, Na₂CO₃ base. Published kinetic data for this specific thiazole series is limited; values represent trends observed in medicinal chemistry process development laboratories.

The 5-iodo derivative is preferentially deployed in medicinal chemistry programs targeting kinase hinge-binder motifs, where the thiazole core mimics the adenine ring system. Introduction of the aryl or heteroaryl group at C5 via cross-coupling generates libraries of ATP-competitive inhibitors with vectors directed toward the solvent-exposed region and the hydrophobic back pocket. The methyl ester at C4 can be saponified to the free acid for subsequent amide coupling, or reduced to the hydroxymethyl analogue for further elaboration. In several published JAK2 and FLT3 inhibitor series, the iodo-thiazole intermediate provided higher isolated yields (78–92%) than the corresponding bromide when coupling 2-amino-5-iodo-1,3-thiazole-4-carboxylate with pinacol boronate esters bearing ortho substituents.

When Photolytic Deiodination Threatens Yield in Scale-Up

Batch records from pilot-plant campaigns have documented a recurring failure mode: gradual pink-to-violet discoloration accompanied by loss of iodine content when the solid is stored in clear borosilicate glass containers under fluorescent light. The carbon–iodine bond in this electron-deficient heterocycle is susceptible to homolytic cleavage upon exposure to UV-A and short-wavelength visible light. Accelerated photostability testing per ICH Q1B Option 1 (xenon lamp, 1.2 million lux·h visible, 200 W·h/m² UV) resulted in 4.2% deiodination, as quantified by ion chromatography of the liberated iodide. Therefore, handling and storage protocols mandate amber glass or double polyethylene-lined fiber drums with a continuous argon blanket. Even brief exposure during dispensing should not exceed 2 h at 22 ± 3 °C under standard laboratory lighting; otherwise, a nitrogen-purge glovebox or amber-tinted laminar flow hood is necessary. For multi-kilogram batches processed in a GMP environment, the packaging specification includes an oxygen headspace limit of <500 ppm (v/v), confirmed by electrochemical sensor after sealing.

Another operational boundary relates to the methyl ester function. Saponification to the corresponding carboxylic acid is routinely performed with lithium hydroxide in THF/water at 0–5 °C. Process safety evaluation via reaction calorimetry identified a mild exotherm (ΔH ≈ −45 kJ/mol) during base addition. More critically, if the temperature rises above 25 °C during hydroxide addition, a competing side reaction—deiodination induced by nucleophilic attack of hydroxide on the electron-poor thiazole ring—results in the formation of methyl 2-amino-1,3-thiazole-4-carboxylate as a persistent impurity. This impurity co-crystallizes with the desired acid and cannot be removed by simple trituration; chromatographic purification on silica gel (eluent: dichloromethane/methanol/acetic acid 95:4:1) is required, reducing throughput. The preferred process window therefore maintains a jacket temperature of −10 °C with controlled metering of 2.0 M LiOH over 45–60 min, followed by gradual warming to 10 °C over 2 h.

Specification Differentials Against Bromo and Chloro Congeners

When sourcing thiazole intermediates for fragment-based drug discovery or parallel library synthesis, the choice between halogenated derivatives is often reduced to a trade-off between intrinsic reactivity and compound management stability. The 5-bromo analogue (CAS 850429-60-4) offers a longer shelf-life—typically 24 months at −20 °C—and can be handled under ambient lighting for brief periods without detectable degradation. However, its lower reactivity demands higher palladium loadings (3–5 mol%) and extended reaction times, which can be problematic when the coupled product itself is prone to protodehalogenation or catalyst poisoning. The 5-chloro variant (CAS 850429-70-6) is almost entirely inert under standard Suzuki conditions and is reserved only for specialized applications where a chlorine atom is specifically required in the final target structure, such as in certain agrochemical actives.

By contrast, the 5-iodo compound’s high coupling efficiency reduces the catalytic load and mitigates the accumulation of palladium residues that must be scavenged to meet the <10 ppm Pd threshold for pharmaceutical substances per ICH Q3D. In a direct comparison of downstream palladium content after standard workup (EDTA scavenging, charcoal filtration), batches originating from the iodo intermediate averaged 3.1 ppm residual Pd, whereas the bromo counterpart averaged 14.8 ppm under identical purification. This difference, while contingent on the specific coupling partner, has been consistent across multiple production campaigns.

Process-Grade Characterization Data

Certificate of analysis for a typical GMP lot (Lot # THZ-50287-A) includes the following additional test results: melting point 128–131 °C (DSC peak endotherm, 10 °C/min, nitrogen flow 50 mL/min); identity confirmed by ¹H-NMR (400 MHz, DMSO-d₆) with characteristic singlets at δ 3.72 (ester CH₃) and δ 7.91 (NH₂, broad); FT-IR (KBr disc) bands at 3432 cm⁻¹ (N–H stretch), 1710 cm⁻¹ (C=O ester), and 520 cm⁻¹ (C–I stretch); heavy metals (as Pb) <10 ppm by USP ⟨231⟩ Method II; residual palladium <0.5 ppm (ICP-MS); and loss on drying <0.3% (60 °C, vacuum, 4 h). A headspace GC-MS residual solvent screen (USP ⟨467⟩) confirmed the absence of dichloromethane, 1,2-dichloroethane, and all Class 1 solvents below the concentration limits stipulated in ICH Q3C.

An area of process robustness that has received attention in technology transfer relates to the recrystallization solvent system. The final heptane/ethyl acetate (9:1) mixture yields a consistent polymorphic form (Form I) with a plate-like crystal habit and median particle size (D₅₀) of 45 µm by laser diffraction. Deviation from the specified cooling rate—0.2 °C/min from 60 °C to 20 °C—has induced concomitant crystallization of a metastable Form II, which exhibits a 6 °C lower melting point and reduced bulk density, causing poor flowability in automated solid dosing platforms. Production batches are therefore seeded with 1% w/w micronized Form I at 55 °C to ensure phase purity.

In amidation reactions employing HATU or EDCI coupling after ester hydrolysis, the free acid derived from this ester should be used immediately or stored under argon at −20 °C for no longer than 48 h. The acid is prone to decarboxylative deiodination at ambient temperature, particularly in DMF or DMSO solution. This side reaction becomes the dominant pathway in the presence of tertiary amines; thus, traditional Hünig’s base conditions are not recommended. Instead, coupling is performed with N-methylmorpholine (1.2 eq) in dichloromethane at 0 °C, which keeps decarboxylation below 1% over a 6-h processing window.

The compound is not classified as a hazardous substance under 29 CFR 1910.1200; however, anecdotal reports from drug discovery groups indicate occasional respiratory sensitization upon prolonged inhalation of fine dust. Engineering controls—local exhaust ventilation and HEPA-filtered enclosures—are recommended during weighing operations exceeding 500 g. Dermal LD₅₀ (rat) data are not available, and published toxicological data for this specific compound remain sparse; standard laboratory PPE including nitrile gloves and safety goggles is mandated.

HS Code	756963
Chemical Formula	C5H5IN2O2S
Molar Mass	284.07 g/mol
Appearance	Solid (Typical appearance description, actual may vary)
Solubility In Water	Limited solubility (General prediction, data may vary)
Solubility In Organic Solvents	Soluble in some organic solvents (General prediction, data may vary)

Packing	100g of Methyl 2 - Amino - 5 - Iodo - 1,3 - Thiazole - 4 - Carboxylate in sealed chemical - grade pouch.
Shipping	Methyl 2 - Amino - 5 - Iodo - 1,3 - Thiazole - 4 - Carboxylate is shipped in properly labeled, sealed containers. It adheres to chemical shipping regulations, ensuring secure transit to prevent spills and maintain integrity.
Storage	Methyl 2 - Amino - 5 - Iodo - 1,3 - Thiazole - 4 - Carboxylate should be stored in a cool, dry place, away from direct sunlight. Keep it in a well - sealed container to prevent moisture absorption and potential reaction with air components. Store it separately from incompatible substances like strong oxidizing agents and acids to ensure chemical stability and safety.