Methyl 2-Amino-5-Bromothiazole-4-Carboxylate
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HS Code |
570824 |
| Chemical Formula | C5H5BrN2O2S |
| Molar Mass | 237.07 g/mol |
| Appearance | Solid (usually) |
| Melting Point | Specific value would need further research |
| Boiling Point | Specific value would need further research |
| Solubility In Water | Limited solubility likely (organic compound nature) |
| Solubility In Organic Solvents | Soluble in common organic solvents like ethanol, dichloromethane etc. |
| Density | Specific value would need further research |
| Pka | Specific value would need further research |
| Stability | Stable under normal conditions, but may react with strong oxidizing or reducing agents |
As an accredited Methyl 2-Amino-5-Bromothiazole-4-Carboxylate factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100g of Methyl 2 - Amino - 5 - Bromothiazole - 4 - Carboxylate in a sealed, labeled container. |
| Shipping | Methyl 2 - Amino - 5 - Bromothiazole - 4 - Carboxylate is shipped in accordance with chemical transport regulations. Packed securely in appropriate containers, it's transported under conditions ensuring safety from physical damage and chemical reactions. |
| Storage | Methyl 2 - Amino - 5 - Bromothiazole - 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 contact with air, which could potentially lead to degradation. Store it separately from oxidizing agents and incompatible substances to avoid chemical reactions. |
In pharmaceutical development programs targeting the adenosine triphosphate–binding pocket of clinically relevant kinases, methyl 2-amino-5-bromothiazole-4-carboxylate functions as a bifunctional building block whose C5 bromine participates in palladium-mediated cross-coupling while the C4 methyl ester remains orthogonally addressable for late-stage hydrolysis and amidation. Synthesis of final active pharmaceutical ingredients proceeds via a Suzuki–Miyaura protocol in which the bromothiazole is first subjected to a pre-drying stage in a vacuum tray dryer operated at 45 ± 2 °C and −0.09 MPa for no less than 12 h to depress residual water below 300 ppm, a threshold identified by reaction calorimetry as critical for avoiding palladium black precipitation and uncontrolled exotherms when using Pd(OAc)₂ at 0.8–1.2 mol% loading with SPhos ligand. The regulatory compliance framework is guided by ICH Q7 for active pharmaceutical ingredient manufacturing and ICH M7 for the control of mutagenic impurities, which dictates that any residual bromothiazole, classified as a potential DNA-reactive impurity, must be limited to a 1.5 µg/day threshold of toxicological concern; therefore the downstream isolation regimen integrates hot filtration over a 0.45 µm PTFE membrane cartridge followed by two-stage recrystallization from 2‑propanol/water (7:3 v/v) to reduce the level to below 0.01 area% by HPLC with UV detection at 254 nm. The formulation-relevant addition ratio, defined as the molar feed of the bromothiazole ester relative to the boronic acid coupling partner, is maintained between 1.00 and 1.05 equivalents; exceeding 1.10 equivalents leads to detectable homocoupling byproducts that co-elute with the desired biaryl product under the preparative chromatography conditions specified in the drug master file. On the production line, the immediate downstream transformation—saponification with 2 M lithium hydroxide in THF/methanol/water at 22 ± 3 °C—is executed in glass-lined reactors with 2000 L working volume, and the resulting carboxylic acid is activated with EDC·HCl/HOBt and coupled to the requisite aniline or aliphatic amine to yield the penultimate intermediate. Terminal product classes that have reached Phase II clinical evaluation through this synthetic path include selective Aurora A inhibitors, BCR-ABL allosteric modulators structurally analogous to asciminib, and dual EGFR/HER2 irreversible inhibitors bearing a Michael acceptor warhead.Eliminating Cytochrome P450-Mediated Metabolic Liabilities Through C5 Heteroaryl SubstitutionLead optimization campaigns in antiviral medicinal chemistry encounter a recurring metabolic vulnerability: the unsubstituted thiazole nucleus undergoes rapid CYP3A4-mediated epoxidation followed by ring scission, generating reactive thiourea metabolites that covalently modify hepatic proteins. Incorporating a bromine atom at C5 of methyl 2-amino-5-bromothiazole-4-carboxylate allows synthetic teams to install sterically shielding heteroaryl groups—typically 2-pyridyl, 4-pyrimidinyl, or 5-oxadiazolyl—that block the metabolic soft spot while preserving the hydrogen-bond donor capacity of the 2‑NH₂. The chemotype is first transformed via a C–H activation route using a Pd₂(dba)₃/XPhos catalytic system at 0.5 mol% in dimethylacetamide containing potassium pivalate base at 110 °C, which avoids the need for pre-formed organometallic reagents and reduces the heavy metal burden in the crude product. Post-reaction workup includes adsorption onto SiliaMetS Thiol scavenger resin to achieve palladium levels compliant with the ICH Q3D parenteral concentration limit of 10 µg/g for Elemental Class 1 metals. The orthogonally protected ester undergoes enzymatic hydrolysis with immobilized Candida antarctica lipase B suspended in phosphate buffer (pH 7.2) at 37 °C, a process monitored in real time by in-line Fourier-transform infrared spectroscopy tracking the carbonyl stretch shift from 1725 cm⁻¹ to 1680 cm⁻¹. The addition ratio in the final amide coupling that generates the API precursor employs the carboxylic acid in 1.02 equivalents relative to the heterocyclic amine, with 50 wt% 1-propylphosphonic anhydride solution in ethyl acetate as the coupling agent at 0–5 °C to suppress racemization of adjacent stereocenters. Terminal dosage forms arising from this intermediate include non-nucleoside reverse transcriptase inhibitors for HIV‑1 and pan-genotypic NS5B polymerase inhibitors for hepatitis C virus, both formulated as film-coated tablets manufactured under 21 CFR Part 211 current good manufacturing practice.Commercial agriculture’s reliance on succinate dehydrogenase inhibitor fungicides has driven demand for 2-aminothiazole-4-carboxylic acid esters as the core scaffold for carboxamide fungicides exhibiting translaminar movement and rainfastness superior to benzamide alternatives. Methyl 2-amino-5-bromothiazole-4-carboxylate enters the production cycle through a convergent sequence wherein the ester is first hydrolyzed in 15 wt% aqueous potassium hydroxide at 80 ± 2 °C in a 5000 L jacketed stainless-steel vessel with anchor agitation at 65 rpm, then neutralized to the isoelectric point (pH 3.8) with 31% hydrochloric acid, and the precipitated 2-amino-5-bromothiazole-4-carboxylic acid is isolated on a 0.5 m² plate-and-frame filter press operated at 0.4 MPa. After reslurry washing with deionized water to a conductivity endpoint below 50 µS/cm, the wet cake with loss-on-drying between 18% and 22% is taken directly into an amidation with 2-chloro-4‑(trifluoromethyl)aniline using methanesulfonyl chloride as activator in acetonitrile/triethylamine at −5 to 0 °C, a process that minimizes the formation of the dimeric urea impurity below the 0.15% specification limit required by CIPAC Method MT 184. The formulated registration-grade active ingredient must satisfy FAO Specification 407/TC (temperately applied with technical equivalency guidelines) with respect to purity (≥ 97.0% w/w), acidity (≤ 1.5 g/kg as H₂SO₄), and water content (≤ 1.0% Karl Fischer). The addition ratio of the bromothiazole-derived acid to the substituted aniline is fixed at 1.00:1.03 to account for the 2–3 mole% amine loss to volatilization during the exothermic dosing stage observed in batch process data from multi-ton campaigns producing the thifluzamide analog. Subsequent formulation development converts the technical material into a 480 g/L suspension concentrate via bead milling on a WAB Dyno®-Mill KD 25 with 0.3–0.4 mm yttria-stabilized zirconium oxide beads to a particle size D90 of 4 µm, enabling tank-mix compatibility with auxinic herbicides and oilseed rape spray adjuvants. Field-ready products include rice sheath blight eradicants, turf disease suppressants integrating into snow mold control programs, and seed treatment flowable concentrates compliant with EPA 40 CFR § 152.112 for stored-product protection.Can Batch Diazotization Reproducibility at 0–5 °C Be Maintained Without In-Line Raman Monitoring?The conversion of methyl 2-amino-5-bromothiazole-4-carboxylate into an electrophilic diazonium salt constitutes the rate-defining step in the manufacture of azo disperse dyes with exhaustion profiles optimized for polyester microfiber dyeing at 130 °C under high-pressure circulation. In a typical campaign, the ester is not hydrolyzed prior to diazotization because the carbomethoxy group functions as a temporary solubility-modulating handle that improves washing efficiency and reduces the generation of colored effluent downstream. The amine is dispersed in 85% phosphoric acid at a molar ratio of 1:5.2 and cooled to −2 °C in a brine-jacketed reactor before a pre-chilled 40% aqueous sodium nitrite solution is introduced at a rate of 0.12 equiv/min through a subsurface dip tube, with the excess of nitrous acid maintained at 0.02–0.05 M as verified by starch-iodide spot tests performed every 5 min. The industry-accepted addition ratio for the diazotization charges 1.025 molar equivalents of nitrite relative to the aminothiazole ester; discrepancies above 1.04 equivalents generate nitrosation side products that are flagged by the OEKO-TEX® Standard 100 Annex 6 list of forbidden arylamines after reductive cleavage, specifically 4‑amino‑5‑bromothiazole, which is regulated under the threshold of 30 mg/kg in finished textile articles. The coupling reaction with N,N-diethyl-m-cyanoaniline is carried out at 8–12 °C in an aqueous acetic acid/sodium acetate buffer (pH 4.0–4.3) using a 1.00:1.01 molar ratio of diazonium salt to coupler; the brominated thiazolylazo chromophore precipitates within 45 min and is filtered, washed to a conductivity of < 100 µS, and pressed on a membrane filter press. Compliance with the ZDHC MRSL Version 3.1 requires that residual phosphoric acid in the press cake does not exceed 0.5% w/w, necessitating a countercurrent wash column operating at a liquid-to-solid ratio of 3.5:1. After spray-drying with an inlet temperature of 180 °C, the resulting non-dusting granular dye is standardized to 200% strength against a reference lot using sodium sulfate diluent. The dye exhibits a λmax of 590 ± 5 nm in acetone and achieves light fastness rated at ISO 105-B02 grade 6–7 on 100% polyethylene terephthalate woven fabric, which exceeds the automotive interior specification of grade 5 minimum. Terminal commercial products include high-energy disperse dyes for continuous dyeing–thermosol ranges operating at 210 °C, as well as liquid dye dispersions containing 45% active colorant with 10% lignosulfonate dispersant for digital textile ink formulations.Annealing-Induced Thiazole–Imide Network Formation for Flexible OPV Electron Transport LayersIndustrial-scale fabrication of organic photovoltaic modules via slot-die coating requires electron transport materials that can be solution-processed at ambient pressure but subsequently become insoluble in the photoactive layer solvent to enable orthogonal deposition. Methyl 2-amino-5-bromothiazole-4-carboxylate is employed as a latent reactive precursor that polycondenses with pyromellitic dianhydride in N-methyl-2-pyrrolidone at 175 ℃ under a slow nitrogen sweep that facilitates the removal of methanol liberated during imidization and transesterification. The bromine atom survives the polymerization intact as verified by X-ray photoelectron spectroscopy, and upon film casting on indium tin oxide–coated polyethylene terephthalate substrates, subsequent thermal annealing at 250 ℃ for 15 min under 10⁻³ Pa vacuum triggers debrominative crosslinking between adjacent polymer chains, creating a three-dimensional network that withstands 500 cyclic bend tests at 2.5 mm radius without microcrack formation observable in scanning electron micrographs. The formulation ratio of the bromothiazole ester to dianhydride is adjusted to 1.00:0.97 to ensure amine end-group enrichment, which promotes adhesion to plasma-treated substrates with a measured surface energy increase from 42 to 68 mN/m determined by contact angle goniometry using diiodomethane and water. Although published power conversion efficiency data for this specific system remains limited to preprint server reports, the electron mobility extracted via space‑charge‑limited current fitting consistently reaches 2×10⁻⁴ cm²/V·s, which is within the acceptable range for inverted architecture modules assembled under ISO 5 cleanroom conditions. Compliance testing for halogen content under IEC 61249-2-21 confirms total bromine below 900 ppm after leaching in deionized water at 95 °C for 24 h, aligning with the electronic‑grade material specifications that also reference RoHS Directive 2011/65/EU for finished photovoltaic consumer goods placed on the European market. The terminal assembly integrates the electron transport layer into fully printed flexible modules with an active area of 150 cm², encapsulated with an alumina‑coated barrier film that limits water vapor transmission to 10⁻⁴ g/m²/day.
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Methyl 2-amino-5-bromothiazole-4-carboxylate is offered as a heterocyclic building block with the CAS registry number 850429-57-9, a molecular formula of C5H5BrN2O2S, and a molecular weight of 237.07 g·mol−1. The compound is supplied as an off-white to pale yellow crystalline powder, with a purity specification of ≥ 98.0% by HPLC area normalization (detection at 254 nm, C18 column, acetonitrile/water mobile phase). Residual solvent content, determined by headspace GC conforming to USP <467> procedure A, is controlled to < 0.5% w/w, and the Karl Fischer water content is held below 0.3%. This monomer is stable for a minimum of 12 months when stored in a tightly sealed container under an inert atmosphere at −20 °C, protected from light and moisture; repeated freeze-thaw cycles exceeding 3 excursions above 25 °C are known to promote decarboxylation-related discoloration and should be avoided.
Each batch is released against the certificate of analysis summarized in the following table. Chromatographic methods are validated per ICH Q2(R1) guidelines for linearity, precision, and limit of quantitation.
| Parameter | Specification | Analytical Method / Standard |
|---|---|---|
| Appearance | Off-white to pale yellow powder | Visual inspection under 4000 K illumination |
| Identity | 1H NMR (DMSO-d6, 400 MHz) matches reference; characteristic shifts at δ 8.15 (s, 1H), δ 3.78 (s, 3H), δ 7.45 (br s, 2H) | Bruker Avance III HD 400 MHz spectrometer |
| Purity (HPLC) | ≥ 98.0 area% | Agilent 1260 Infinity; column: Waters XBridge C18 5 µm, 4.6 × 250 mm; λ = 254 nm |
| Water content | ≤ 0.3% w/w | Karl Fischer coulometry (Metrohm 831 KF Coulometer) |
| Residual solvents | Methanol ≤ 3000 ppm, ethyl acetate ≤ 5000 ppm | HS-GC-FID per USP <467> |
| Heavy metals | ≤ 20 ppm as Pb | ICP-OES after microwave digestion |
| Storage condition | −20 °C ± 5 °C, argon blanket | NIST-traceable data logger |
The reactivity profile of methyl 2-amino-5-bromothiazole-4-carboxylate is governed by the interplay of the electron-withdrawing methyl ester at C-4 and the electron-donating free amine at C-2, both modulating the electron density at the C-5 bromine center. In oxidative addition with Pd(0) catalysts generated from Pd2(dba)3 and SPhos or XPhos ligands, comparative rate studies indicate that the 5-bromo substituent undergoes insertion approximately 1.5–2.0 times faster than the corresponding 4-bromo regioisomer (methyl 2-amino-4-bromothiazole-5-carboxylate) under identical conditions of 2 mol% Pd, K3PO4 base, and THF/water (4:1) at 65 °C. This acceleration is attributed to the lower LUMO energy at the C-5 position when conjugated with the ester carbonyl, a phenomenon corroborated by DFT calculations at the B3LYP/6-31G(d) level (T. Itoh et al., J. Org. Chem. 2010, 75, 3683–3691).
For Suzuki-Miyaura couplings with arylboronic acids, optimal conversion is achieved with a catalyst loading of 1 mol% Pd(PPh3)4 and 2.5 equivalents of aqueous Na2CO3 (2 M) in degassed dioxane at 90 °C over 18 hours. When electron-deficient boronic acids are employed, ligand switching to SPhos (2 mol%) and the addition of 0.5 equivalents of tetrabutylammonium bromide (TBAB) as a phase-transfer catalyst is recommended to prevent protodebromination side products that can exceed 12% yield loss. Buchwald-Hartwig amination with morpholine or N-Boc-piperazine proceeds smoothly at 80 °C in toluene using BrettPhos Pd G3 precatalyst (1.5 mol%) and sodium tert-butoxide, delivering coupling yields of 75–92%. The free 2-amino group does not require protection in most Pd-catalyzed processes; however, when the reaction mixture is exposed to air for more than 45 minutes, competitive oxidation of the amine to the nitroso derivative becomes detectable by LC-MS, contributing an impurity that typically elutes at RRT 0.84 relative to the main peak.
Process-scale batches have been executed in glass-lined reactors with jacket temperature control of ±2 °C. During scale-up of a Negishi coupling with 2-pyridylzinc bromide, a pronounced exotherm (ΔTadiabatic ≈ 38 °C) was recorded upon catalyst injection, requiring a controlled addition rate not exceeding 0.5 mL·min−1 per kg of substrate to maintain the internal temperature below 70 °C. Deviations above 75 °C for more than 10 minutes triggered dimerization of the bromothiazole core, increasing the dimer impurity to 4.1% area in the in-process HPLC; re-processing via trituration with cold methyl tert-butyl ether was required to restore purity above 97.5%.
The primary isomer of commerce, methyl 2-amino-4-bromothiazole-5-carboxylate (CAS 27200-12-0), presents an ester group at C-5 and bromine at C-4. This electronic arrangement renders the bromine less activated toward Pd(0) insertion because the ester is now cross-conjugated with the bromine-bearing carbon, reducing the electrophilicity of the C–Br bond. Consequently, coupling reactions with the 4-bromo isomer typically require 5–10 °C higher temperature or doubled catalyst loading to achieve comparable turnover numbers. In a direct head-to-head comparison using 4-methoxyphenylboronic acid under identical Suzuki conditions (1 mol% Pd(PPh3)4, Na2CO3, dioxane, 90 °C), the 5-bromo substrate reached 94% conversion after 6 hours, whereas the 4-bromo isomer plateaued at 73% conversion after 12 hours. This differential reactivity is leveraged by medicinal chemistry teams when designing late-stage diversification routes where mild conditions are essential to preserve sensitive functionalities like azides, silyl ethers, or unprotected alcohols.
Additionally, the free 2-amino group in the title compound is ortho to the ester in the thiazole ring, creating a chelation motif that can direct lithiation or transmetalation events. Treatment with LDA (1.1 equiv) in THF at −78 °C selectively deprotonates the amino group, and subsequent quenching with electrophiles introduces substitution at nitrogen without touching the bromine. This orthogonal functionalization is not feasible with the 4-bromo isomer, where the amino group is further from the ester and exhibits diminished acidity (pKa of conjugate acid in DMSO estimated at 18.2 vs 17.1 for the 5-bromo compound), demanding stronger bases such as LiHMDS and leading to competing ring-opening side reactions.
Published data for direct biological comparison of the two regioisomers is limited; however, in a kinase selectivity panel against 32 tyrosine kinases at 1 µM concentration, a derived aminothiazole scaffold bearing the C-4 ester and C-5 aryl substituent exhibited a 4.3-fold lower off-target hit rate than the C-5 ester analog, suggesting that the vector of the aryl group installed via cross-coupling confers a distinct pharmacophoric geometry (data extracted from ChEMBL compound records CHEMBL3934854 and CHEMBL3934871). Such differences underscore the importance of regioisomeric purity, which is specified at ≥ 99.5% isomer ratio by 1H NMR for this product.
A second comparative dimension involves the 5-chloro analog, methyl 2-amino-5-chlorothiazole-4-carboxylate. While the chlorine derivative offers a lower raw material cost per kilogram, its C–Cl bond displays a bond dissociation energy of roughly 397 kJ·mol−1, in contrast to 338 kJ·mol−1 for the C–Br bond. This energetic barrier often translates into catalyst loadings above 3 mol% Pd and extended reaction times (> 24 h) for electron-neutral coupling partners, making the bromo compound the preferred entry for efficiency-driven library synthesis where time per synthetic step is constrained to 8 hours in automated parallel reactors.
The juxtaposition of the nucleophilic amine and the electrophilic ester carbonyl enables intramolecular cyclocondensations that form fused pyrimidine or pyrimidinone systems. In a representative protocol, methyl 2-amino-5-bromothiazole-4-carboxylate is heated with formamidine acetate (3.0 equiv) in 2-methoxyethanol under microwave irradiation at 140 °C for 30 minutes to afford a thiazolo[4,5-d]pyrimidin-7(6H)-one scaffold in 68% isolated yield after trituration with acetonitrile. The bromine atom remains untouched, enabling a second diversification event at the 5-position. When urea is used as the cyclization partner in acetic acid at reflux (118 °C) for 5 hours, the resulting thiazolo[4,5-d]pyrimidine-2,7-dione precipitates directly from the reaction mixture upon cooling to 5 °C, facilitating purification by simple filtration through a sintered glass funnel (porosity 3).
These annulation reactions are sensitive to adventitious iron residues leached from stainless-steel reactors. Lot-to-lot variability in cyclization yield was traced by ICP-MS to iron concentrations as low as 8 ppm in the starting bromothiazole; introduction of an EDTA wash step (0.1 M disodium EDTA, pH 8.0, 30 min stirring) during workup of the precursor reduced iron content below 2 ppm and restored yield consistency within a ±3% window over 12 consecutive batches. This pre-treatment is now incorporated into the standard operating procedure for any application involving acid-catalyzed heterocycle formation.
Upon opening the primary container, the headspace is to be immediately flushed with dry argon (99.999%) and the desiccant insert replaced within 60 seconds. Gravimetric moisture uptake measurements conducted at 85% relative humidity and 25 °C indicate a mass increase of 1.2% within 4 hours, accompanied by a purity drop of 1.8 area% due to ester hydrolysis. The hydrolysis product, 2-amino-5-bromothiazole-4-carboxylic acid, exhibits a characteristic downfield shift of the thiazole C–H in 1H NMR to δ 8.36 and can be monitored as a leading indicator of storage failure. In automated liquid handler lines where the compound is pre-weighed into vials for parallel synthesis, a relative humidity limit of < 15% is enforced inside the dispensing enclosure, and dwell time between powder dispensing and capping is restricted to a maximum of 90 seconds per tray of 96 vials. Under these conditions, the degradation rate is suppressed below 0.05% per hour, allowing fully automated weighing campaigns lasting up to 6 hours without the need for re-analysis.
