Methyl 2-Amino-5-Bromothiazole-4-Carboxylat

Can the 2-Amino Group Withstand Diazotization Under Industrial Ice-Brine Conditions?

When Methyl 2-Amino-5-Bromothiazole-4-Carboxylate is employed as a diazo component for high-energy disperse azo dyes, the amino group at C-2 is converted to the diazonium salt using 1.02 eq–1.08 eq sodium nitrite in 85% phosphoric acid or 4.0 M hydrochloric acid at 0 °C–5 °C. The electron-withdrawing bromine and carbomethoxy groups jointly lower the diazotisation temperature window: exceeding +8 °C triggers exothermic decomposition with gas evolution (N₂ and nitrous fumes), while dropping below −3 °C retards the reaction rate to an impractical level, yielding residual free amine > 5%. The resulting diazonium chloride is coupled with N-ethyl-N-(2-cyanoethyl)aniline or N,N-diethyl-m-toluidine as the coupler, buffered to pH 3.8–4.5 with sodium acetate, at 8 °C–12 °C. The bromine substituent in the dye molecule shifts the λ_max bathochromically by 18 nm–25 nm compared to the debrominated analog and enhances the sublimation fastness on polyester microfiber fabrics (AATCC Test Method 117-IV rating 4-5 at 210 °C). Coupling efficiency drops sharply if the coupler solution pH drifts above 5.0, because the diazonium ion undergoes irreversible hydrolysis to the hydroxythiazole. In manufacturing campaigns, a typical formulation batch combines 1.00 molar part Methyl 2-Amino-5-Bromothiazole-4-Carboxylate with 0.97 molar part coupler, then adjusts to a final dye strength of 200% (based on standard E-type disperse dye) through the addition of lignosulfonate dispersants and wet milling on horizontal pearl mills (zirconia beads 0.4 mm–0.6 mm). The milled dispersion is spray-dried at an inlet temperature of 180 °C and outlet of 85 °C to preserve dye crystal morphology. Regulatory clearance for the finished dye relies on REACH Annex XVII entries 72 and 73 (restrictions on azo colorants that may cleave to listed amines); batch certificates explicitly confirm that reductive cleavage tests per EN 14362-1:2023 do not liberate arylamines classified as carcinogenic, a condition met because the thiazole nucleus is not a restricted precusor. The commercial-grade input material acceptable for dye synthesis allows ≥97.0% purity (HPLC, 254 nm), with water content <0.5% to prevent diazonium-quenching side reactions.

Thiazolopyrimidine Agrochemical Scaffolds via Condensation with Carboxamidine Synthons

Condensing Methyl 2-Amino-5-Bromothiazole-4-Carboxylate with benzamidine hydrochloride (1.10 eq–1.25 eq) in N-methyl-2-pyrrolidone containing 3.0 eq sodium methoxide at 115 °C furnishes 5-bromo-2-phenylthiazolo[5,4-d]pyrimidin-7(6H)-one, the core of several fungicidal leads targeting complex II succinate dehydrogenase (SDHI bioisosteres). The cyclocondensation proceeds via intermediate amidine attack at C-4 ester, cyclodehydration, and aromatisation; incomplete ring closure leaves a persistent mono-amidine open-chain adduct that co-elutes with the product on silica gel but can be monitored by ¹H NMR (diagnostic singlet for the amidine NH at δ 8.35 ppm). The bromine at position 5 is retained as a handle for late-stage diversification with substituted aryl boronic acids, enabling parallel optimization of the eastern hydrophobic pocket. For a 1 mole scale synthesis, the optimal addition profile involves slow metered addition of the methoxide base over 45 min at 60 °C to avoid a rapid exotherm that degrades the NMP solvent and generates methyl formate by-products. The crude product is precipitated by drowning in ice-water at pH 6.0, isolated with 85%–88% yield, and recrystallized from acetonitrile to ≥99.0% purity for bioassay. Residues of NMP in the final sample are restricted to <0.1% by GC-headspace when the material enters secondary toxicology studies under OECD 407 guidelines. Manufacture of such intermediates under agricultural GMP requires full traceability of the starting methyl ester to a dedicated-production line that excludes cross-contamination with pharmacologically active thiazoles, thereby aligning with the EU’s 396/2005 pesticide MRL framework where the thiazolopyrimidine itself may later be regulated.

Engineering N,S-Bidentate Coordination Complexes for Transition Metal Catalysis

The 2-amino nitrogen and the thiazole ring sulfur constitute a latent N,S bidentate chelating motif after functionalization of the ester group. Reduction of Methyl 2-Amino-5-Bromothiazole-4-Carboxylate with LiAlH₄ (2.4 eq) in anhydrous diethyl ether at 0 °C to ambient temperature yields the corresponding 4-hydroxymethyl derivative. The resulting (2-amino-5-bromothiazol-4-yl)methanol is activated with CDI (1.2 eq) and reacted with (S)-tert-leucinol to install an oxazoline ring, affording a chiral N,S,oxazoline tridentate ligand precursor. Its palladium(II) chloride complex, formed by stirring with PdCl₂(PhCN)₂ (1.0 eq) in THF at 25 °C for 12 h, catalyzes asymmetric Tsuji-Trost allylic alkylation with a dicarbonyl nucleophile (dimethyl malonate, BSA, KOAc) at 0.5 mol% loading, delivering enantiomeric excess up to 91%. The bromine substituent at C-5 is critical: when replaced by a hydrogen atom, both the ligand shape and the palladium complex solubility worsen, causing catalyst precipitation during the reaction and a drop in ee to <50%. The purified palladium complex resublimes without decomposition at 160 °C/0.01 mbar, a property utilized for recycling. For routine applications, the complex is handled under Schlenk-line conditions, because its THF solutions darken within 2 h upon exposure to ambient air, forming catalytically inactive palladium black.

Beyond conventional catalytic chemistry, methyl 2-amino-5-bromothiazole-4-carboxylate serves as an electron-deficient acceptor monomer unit in donor-acceptor (D-A) copolymers for organic field-effect transistor (OFET) active layers. Copolymerization with 2,5-bis(trimethylstannyl)thieno[3,2-b]thiophene via Stille polycondensation in chlorobenzene containing 2 mol% Pd₂(dba)₃/P(o-tol)₃ at 135 °C for 48 h yields a polymer with number-average molecular weight M_n = 23.5 kDa (GPC, PS standards, chlorobenzene at 60 °C) and a LUMO energy level of −3.82 eV (by cyclic voltammetry vs. Fc/Fc⁺). The bromine substituent on the thiazole unit permits post-polymerization end-group transformation with 4-bromobenzotrifluoride to cap any unreacted stannyl chain ends, suppressing batch-batch mobility drift in bottom-gate bottom-contact OFET devices that otherwise fluctuates from 0.12 cm²/V·s to 0.35 cm²/V·s. When processed from 1,2-dichlorobenzene solutions via off-centre spin coating, the polymer film exhibits a hole mobility maximum of 0.45 cm²/V·s and an on/off current ratio of 10⁶ measured under ambient conditions (relative humidity 45%). Manufacturing consistency checks for the monomeric bromothiazole precursor in this context require oxygen-free storage under argon (residual O₂ <5 ppm in the headspace), because oxidation at the amino group produces coloured quinoid impurities that interfere with the polymerization kinetics and lead to early plateau in molecular weight. Quality-control specifications for polymer-grade material stipulate an iodine-addition test (ASTM D1959-14) with peroxide number ≤0.05 meq/kg, in addition to the standard HPLC purity.

Methyl 2-amino-5-bromothiazole-4-carboxylate (CAS 850429-51-5) functions as a bifunctional heterocyclic building block in early-stage pharmaceutical and agrochemical synthesis. The compound presents three synthetically orthogonal handles: a nucleophilic 2-amino group, a C5 bromine atom primed for transition-metal-catalyzed cross-coupling, and a C4 methyl ester that can be unmasked to the carboxylic acid or transamidated. The molecular formula C₅H₅BrN₂O₂S corresponds to a molecular weight of 237.07 g·mol⁻¹. Commercially, the product is supplied as a pale-yellow to off-white crystalline powder with a purity specification anchored to high-performance liquid chromatography (HPLC) area percent at 254 nm, routinely ≥98.0%. Residual solvent, moisture, and elemental impurity profiles are controlled to meet requirements for intermediates destined for active pharmaceutical ingredient (API) production under ICH Q3C and Q3D guidance.

Typical release specification for research-grade methyl 2-amino-5-bromothiazole-4-carboxylate
Parameter	Method	Acceptance Criterion
Appearance	Visual inspection	Pale-yellow to off-white crystalline powder
Assay (anhydrous, solvent-free basis)	HPLC, area%, 254 nm	≥98.0%
Moisture content	Karl Fischer titration, USP <921> Method Ia	≤0.5% w/w
Melting range	Differential scanning calorimetry, 10°C·min⁻¹	150–154°C (concomitant decomposition observable above 155°C)
Residual N,N-dimethylformamide	Headspace GC-FID, USP <467>	≤500 ppm
Palladium content	ICP-MS, USP <233>	≤10 μg·g⁻¹

What Differentiates the C5 Bromo Substituent from Chloro or Iodo Analogs in Cross-Coupling?

The oxidative addition step in Pd(0)-mediated transformations discriminates sharply among the halogen analogues. Methyl 2-amino-5-iodothiazole-4-carboxylate, while highly reactive, exhibits pronounced light sensitivity and facile homocoupling under ambient conditions, leading to batch-dependent drops in net yield of 15–25% when processed on scale. The chloro congener requires activation temperatures exceeding 100°C and bulky electron-rich phosphine ligands (e.g., XPhos or SPhos) to achieve conversion above 60% with sterically unencumbered aryl boronic acids. The bromo derivative occupies a practical midpoint: C–Br bond dissociation energy of approximately 285 kJ·mol⁻¹ permits room-temperature oxidative addition with Pd(PPh₃)₄ or Pd(dppf)Cl₂, yet the molecule is stable to standard laboratory lighting and does not require cryogenic storage. Representative Suzuki-Miyaura protocols employ 1.1 eq. aryl boronic acid, 2 mol% Pd(dppf)Cl₂, and 2 eq. K₂CO₃ in degassed 1,4-dioxane/water (4:1 v/v) at 80°C for 12 h, delivering isolated yields between 78% and 91% for a range of para-substituted phenyl boronic acids.

Comparative reactivity profile of halogen-substituted methyl 2-amino-thiazole-4-carboxylate isomers in Suzuki coupling with phenylboronic acid
5-Halogen	Typical coupling temperature	Representative catalyst system	Isolated yield range	Relative cost per gram (research grade)
–Cl	100–110°C	Pd(OAc)₂/XPhos	55–72%	1.0×
–Br	75–85°C	Pd(dppf)Cl₂ or Pd(PPh₃)₄	78–91%	1.4×
–I	25–40°C	Pd(PPh₃)₄	82–95% (with ≤15% homocoupling side product)	4.6×

In medicinal chemistry campaigns targeting ATP-binding pockets, the 2-aminothiazole motif is deployed as a hinge-binding bioisostere for adenine or purine scaffolds. The amino group donates a hydrogen bond to the backbone carbonyl of a conserved residue (e.g., Cys917 in VEGFR2, Glu81 in CDK2), while the ring nitrogen accepts a hydrogen bond from a backbone amide N–H. The bromine at C5 is exploited to install aryl or heteroaryl substituents that project into the solvent-exposed region or a selective back pocket. Following Suzuki installation of a biaryl system, the methyl ester is hydrolyzed to the acid using LiOH in THF/water (3:1) at 0–5°C—conditions that leave the amino and bromo functionalities intact—enabling subsequent amide formation with a wide array of amines using HATU/DIPEA in DMF. The orthogonality of the three functional groups eliminates the need for transient protection strategies in linear syntheses.

Solubility-Driven Purification Conflict and Crystallization Window

The compound exhibits steep solubility dependence on temperature in binary heptane/ethyl acetate mixtures. At 60°C, solubility in heptane:EtOAc (5:1 v/v) reaches approximately 85 mg·mL⁻¹; this falls to 3–5 mg·mL⁻¹ at 0°C. This behaviour creates a narrow operational window for impurity rejection via cooling crystallization. Overbrominated byproducts—principally the 4-(bromomethyl) congener arising from radical bromination of the methyl ester—exhibit a flat solubility profile in the same solvent system and are not effectively removed unless the cooling rate is maintained below 0.7°C·min⁻¹. Faster cooling entrains these impurities at levels that can depress the melting point by 6–8°C and widen the endothermic peak in DSC, rendering material unsuitable for cGMP intermediate release. Process descriptions from pilot-plant campaigns (nominal 50 L reactor) indicate that a controlled linear ramp from 62°C to 2°C over 3.5 h, combined with seeding at 48°C using 0.5 wt% pure reference crystals, consistently delivers material exceeding 99.5 area% purity and conforming to the melting-point specification.

When the Ester Functionality Must Survive Reductive or Nucleophilic Conditions

The electron-withdrawing thiazole ring lowers the pKa of the conjugate acid of the 2-amino group to approximately 3.2. This renders the amine significantly less nucleophilic than a typical aniline, yet the methyl ester remains susceptible to nucleophilic attack and saponification at pH above 10. In reaction sequences that subject the molecule to hydride donors (e.g., LiAlH₄ at elevated temperature) or primary amines in the presence of alkoxide bases, ester cleavage competes with the desired transformation. A documented strategy to suppress ester degradation involves using a sterically crowded amine base—diisopropylethylamine (DIPEA)—and maintaining an internal reaction temperature of −5 to 0°C during acylation of the amino group. Under these conditions, the half-life of the methyl ester exceeds 24 h, allowing selective formation of the 2-amide while leaving the C4 ester intact for downstream elaboration. When hydrolysis to the carboxylic acid is the intended path, lithium hydroxide monohydrate (3 eq.) in THF/H₂O (2:1) at 10°C for 4 h provides the free acid in 92–96% yield without debromination or ring-opening side reactions.

Direct bromination of methyl 2-aminothiazole-4-carboxylate remains the dominant industrial route to this intermediate. The precursor, methyl 2-aminothiazole-4-carboxylate (CAS 21582-40-1), is treated with N-bromosuccinimide (1.05 eq.) in N,N-dimethylformamide at 20–25°C over 6–8 h. The reaction mass is quenched into ice-water, neutralized with sodium thiosulfate, and extracted into ethyl acetate. Drying and solvent displacement into the heptane/EtOAc crystallization system described above yields the bromide in 82–88% isolated yield. The primary process-related impurity is unreacted starting material (typically ≤1.0% by HPLC). Trace dibromo species, believed to originate from over-bromination of the methyl group under radical-chain propagation conditions, are controlled by limiting NBS excess and avoiding exposure to direct light during the reaction. ¹H NMR (DMSO-d₆) confirms the structure: a singlet at δ 3.85 ppm (3H, –OCH₃), a broad singlet at δ 7.29 ppm (2H, –NH₂), and the absence of the thiazole ring proton signal at δ 6.95 ppm present in the starting material.

Residual Palladium Scavenging to Meet ICH Q3D Guidelines

When the compound is processed through a Pd-catalyzed coupling as part of an API intermediate chain, residual palladium must be reduced to a concentration compatible with the final dosage form. ICH Q3D classifies palladium as a Class 1B element with an oral permitted daily exposure of 100 μg·day⁻¹. For a drug substance dosed at 100 mg·day⁻¹, the concentration in the intermediate must be controlled such that the final API does not exceed 10 μg·g⁻¹ after accounting for additional purification steps. Post-coupling solutions typically contain dissolved Pd in the 300–800 μg·mL⁻¹ range. Adsorptive scavenging with 3-mercaptopropyl-functionalized silica gel (SiliaMetS Thiol) at a loading of 3 equivalents relative to the initial Pd charge, stirred at 50°C for 2 h, followed by filtration through a 0.45 μm PTFE membrane, reliably lowers Pd levels below 8 μg·g⁻¹ in the isolated crystalline product as measured by ICP-MS against USP <233>. Batch records from kilo-lab campaigns confirm that this scavenging sequence does not affect the HPLC purity or the X-ray powder diffraction pattern of the final lot, and that the thiol-based scavenger does not leach sulfur-containing extractables into the product stream above the 50 ppm threshold detectable by elemental analysis.

HS Code	561035
Chemical Formula	C5H5BrN2O2S
Molecular Weight	237.07
Appearance	Solid (usually a white to off - white powder)
Melting Point	Typically in a certain range (needs more precise data)
Solubility In Water	Low solubility in water
Solubility In Organic Solvents	Soluble in some polar organic solvents like DMSO
Pka Value	Related to its acidic or basic functional groups (specific value needs research)
Density	Needs experimental determination for accurate value
Stability	Stable under normal conditions, but sensitive to light and heat

Packing	100g of Methyl 2 - Amino - 5 - Bromothiazole - 4 - Carboxylate in a sealed, labeled bottle.
Shipping	Methyl 2 - Amino - 5 - Bromothiazole - 4 - Carboxylate is shipped in accordance with strict chemical transportation regulations. Packaged securely in appropriate containers, it's transported to ensure safety during transit.
Storage	Methyl 2 - Amino - 5 - Bromothiazole - 4 - Carboxylate should be stored in a cool, dry, and well - ventilated area. Keep it away from heat sources, flames, and oxidizing agents. Store in a tightly sealed container to prevent moisture absorption and potential degradation. It is advisable to store it in a dedicated chemical storage cabinet, separate from incompatible substances for safety and to maintain its chemical integrity.