2-Amino-5-Bromothiazole-4-Carboxylic Acid Ethyl Ester
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HS Code |
697886 |
| Chemical Formula | C6H7BrN2O2S |
| Molar Mass | 253.101 g/mol |
| Appearance | Typically a solid (description may vary by purity) |
| Melting Point | Data may vary, needs experimental determination |
| Boiling Point | Data may vary, needs experimental determination |
| Solubility In Water | Low solubility expected due to non - polar nature of thiazole ring |
| Solubility In Organic Solvents | Soluble in common organic solvents like dichloromethane, chloroform |
| Pka | Data may vary depending on acidic groups, experimental determination needed |
| Density | Data may vary, needs experimental determination |
| Ir Characteristic Peaks | Characteristic peaks for C=O, N - H, C - N, C - S in IR spectrum |
As an accredited 2-Amino-5-Bromothiazole-4-Carboxylic Acid Ethyl Ester factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100g of 2 - Amino - 5 - Bromothiazole - 4 - Carboxylic Acid Ethyl Ester in sealed plastic bags. |
| Shipping | 2 - Amino - 5 - Bromothiazole - 4 - Carboxylic Acid Ethyl Ester is shipped in sealed, properly labeled containers. It adheres to strict chemical shipping regulations to ensure safe transport, protecting from damage and environmental exposure. |
| Storage | Store 2 - Amino - 5 - Bromothiazole - 4 - Carboxylic Acid Ethyl Ester in a cool, dry place, away from direct sunlight. Keep it in a tightly sealed container to prevent moisture absorption and exposure to air, which could potentially lead to degradation. Avoid storing near sources of heat or incompatible substances to ensure its stability and integrity over time. |
Manufacture of generic febuxostat monohydrate tablets for chronic hyperuricemia frequently routes the 2-amino-5-bromothiazole-4-carboxylic acid ethyl ester through a regioselective Suzuki–Miyaura coupling that simultaneously constructs the biaryl core and preserves the ethyl carboxylate for downstream amidation. In a jacketed 2000 L glass-lined reactor purged to 50 ppm residual oxygen, the ester is charged at 1.00 molar equivalent relative to 3‑cyano‑4‑isobutoxyphenylboronic acid pinacol ester, which is introduced at a 1.12 ± 0.03 eq excess to offset protodeboronation loss confirmed by in‑situ ReactIR monitoring. The catalytic system employs PdCl₂(dppf)·CH₂Cl₂ at 0.35 mol% and finely milled K₃PO₄ (2.8 eq) suspended in a degassed toluene/water/n‑propanol (6:2:1 v/v) mixture, held at 78 ± 2 °C for 14–16 h. Once IPC (HPLC, 254 nm) confirms residual bromothiazole below 0.8 area%, the batch is cooled to 55 °C and dosed with a slurry of Ecosorb C‑941 activated carbon (5% w/w wrt product) and Si‑Thiol scavenger (2% w/w) for palladium extraction, followed by polishing through a 0.2 µm PTFE cartridge. The isolated intermediate, 2‑amino‑5‑(3‑cyano‑4‑isobutoxyphenyl)thiazole‑4‑carboxylic acid ethyl ester, is subsequently hydrolyzed with LiOH·H₂O (1.08 eq) in THF/water (3:1) at 15–20 °C and deaminated via tert‑butyl nitrite in DMF at 0–5 °C to furnish the febuxostat free acid after recrystallization from 2‑propanol/water. Regulatory alignment follows the USP Febuxostat Monograph, with specific emphasis on limiting des‑isobutyl impurity (Impurity C) to ≤ 0.10%, palladium content ≤ 5 ppm per EMA/CHMP/SWP/4446/2000, and residual n‑propanol ≤ 100 ppm under ICH Q3C Class 3. The final dosage form is a 40 mg or 80 mg film‑coated tablet packed in Alu‑Alu blister, equivalent to the reference listed drug Uloric®.Why does residual palladium speciation control the commercial viability of a thiazole Suzuki coupling campaign?When the same ethyl ester is deployed in an alternative, redox‑active coupling to deliver a 5‑(6‑methoxypyridin‑3‑yl)‑2‑aminothiazole‑4‑carboxylate — a key building block for a transient receptor potential vanilloid 1 (TRPV1) antagonist developed for neuropathic bladder pain — the palladium clearance protocol must be revalidated because the pyridine moiety coordinates dissolved Pd(II) species far more tenaciously than the benzonitrile analogue. Process development runs on a 100 L Hastelloy C‑22 vessel documented that after a standard Pd(PPh₃)₄ coupling (1.0 mol%, Na₂CO₃ 3.0 eq, dioxane/water 4:1, 85 °C, 8 h), the crude product retains 420 ppm Pd, declining only to 210 ppm after a single charcoal filtration. A trivalent N‑acetyl‑L‑cysteine wash (10% w/w solution, pH 8.5, 50 °C) reduces Pd to 18 ppm, yet the final API specification demands ≤ 1 ppm due to the high daily dose (400 mg q.d.) and chronic administration schedule. The successful path integrates a macroporous polystyrene‑based trimercaptotriazine resin cartridge (Cuprisorb®, 10 bed volumes/h, 60 °C) as terminal step, achieving 0.6 ppm Pd with 98.3% product recovery. Addition ratios of the ester to the pyridylboronic acid are tightened to 1.00:1.05 because excess bromothiazole forms a stable Pd‑π‑allyl complex during ageing that elevates soluble Pd in the aqueous phase. The downstream processing converts the purified ester via HATU‑mediated amidation with 4‑(trifluoromethoxy)benzylamine (1.15 eq, DIPEA 2.5 eq, DMF, 0 °C → 20 °C) and subsequent LiOH saponification, yielding the TRPV1 antagonist free base. Compliance is governed by ICH Q3D for Class 1 metals (As, Cd, Hg, Pb) and Q3C for residual dioxane ≤ 380 ppm, with the final active ingredient formulated as an immediate‑release hard gelatin capsule containing 100 mg of micronized drug substance blended with lactose monohydrate and crospovidone.
Hydrogenolytic debromination under trickle‑bed conditions — limits of catalyst lifetime and bed pressure dropContinuous production of 2‑aminothiazole‑4‑carboxylic acid ethyl ester, a penultimate intermediate for a generic cephalosporin side‑chain acid, proceeds through catalytic hydrodebromination of the 5‑bromo derivative over a fixed‑bed 5% Pd/Al₂O₃ catalyst. In a DN 50 trickle‑bed column with 1.5 m bed height, the bromo‑ester is dissolved to 0.35 M in ethanol/water (7:3 v/v) containing 1.05 eq of triethylamine to neutralize the liberated HBr. The co‑current downward flow of liquid (LHSV 1.8 h⁻¹) and hydrogen gas (GHSV 120 h⁻¹) passes through the bed at 3.5 barg and 42 °C. Under optimal conditions, single‑pass conversion exceeds 99.8%, yet the primary operational constraint is the sudden rise in pressure drop after 350–400 bed volumes processed, arising from ammonium bromide salt deposition and 0.2–0.5 wt% of oligomeric amino‑thiazole residues that cap active sites. The addition ratio of triethylamine is therefore limited to 1.03 eq to maintain halide solubility; a smaller 0.5 wt% water spike in the feed at every 48 h dissolves incipient salts. The debrominated ethyl ester is concentrated and crystallized from toluene to yield a free‑flowing solid with mp 168–170 °C. Subsequent Hunsdiecker‑type degradation or direct Krapcho dealkoxycarbonylation yields 2‑aminothiazole‑4‑acetic acid, which is acylated with methoxyimino‑2‑(2‑aminothiazol‑4‑yl)acetic acid side chains for fourth‑generation cephalosporins. The final sterile API, formulated as a 200 mg/vial lyophilized powder for injection, complies with EP 10.0 monograph 2205; residual Pd is restricted to ≤ 2 ppm by ICP‑MS and total solvent burden to ethanol ≤ 1500 ppm, toluene ≤ 890 ppm per ICH Q3C. The process is subject to ATEX Directive 2014/34/EU because hydrogen concentration in the vent stream must remain below 3.5% v/v, monitored by in‑line thermal conductivity analysis.By directly converting the 5‑bromo substituent into a trifluoromethyl group, an agricultural fungicide intermediate aligned with the succinate dehydrogenase inhibitor (SDHI) mode of action is accessed through a high‑pressure copper‑mediated fluoroalkyllation. The ethyl ester (1.0 eq) is combined with methyl 2,2‑difluoro‑2‑(fluorosulfonyl)acetate (4.0 eq), CuI (0.15 eq), and KF (3.0 eq) in sulfolane under a 20 bar tetrafluoroethylene atmosphere inside a Hastelloy 250 mL autoclave equipped with a gas‑entrainment impeller. The temperature is ramped to 135 °C over 40 min and held for 5 h, delivering 2‑amino‑5‑(trifluoromethyl)thiazole‑4‑carboxylic acid ethyl ester in 72% isolated yield after silica plug filtration. This intermediate is then condensed with 3‑(difluoromethyl)‑1‑methyl‑1H‑pyrazole‑4‑carbonyl chloride (1.05 eq) in pyridine/CH₂Cl₂ at ‑5 °C, forming the bis‑amide core of a proprietary SDHI candidate that displays EC₅₀ ≤ 0.05 mg/L against Botrytis cinerea. The synthesis complies with FAO Specification 508/TC for technical‑grade fungicides and controls sulfolane residue ≤ 200 ppm in the final technical material. The formulated product is a 200 g/L SC (suspension concentrate) containing 18% w/w active ingredient, 5% ethylene oxide–propylene oxide block copolymer dispersant, 3% propylene glycol antifreeze, and 0.1% xanthan gum thickener, applied at a field rate of 0.75 L/ha.From batchwise magnesiation to continuous‑flow Negishi coupling: eliminating the exotherm lag phase that triggers decompositionGenerating the 5‑zincated nucleophile from the ethyl ester for a Negishi cross‑coupling with heteroaryl bromides in a corrugated‑tube continuous reactor resolves the batch‑mode runaway risk that arises from a 15–18 °C induction period followed by a ΔTₐd of 140 °C at full conversion. The ester is first converted to its zinc reagent by treatment with TMPZnCl·LiCl (1.12 eq, 0.55 M in THF) in a 3.2 mL glass microreactor chip at ‑10 °C with a residence time of 42 s. The resulting stream is merged with a pre‑cooled solution of 2‑bromo‑5‑chloropyridine (1.00 eq), Pd‑XPhos‑G2 precatalyst (0.8 mol%), and additional THF to maintain 0.12 M concentration, proceeding through a 20 mL coiled delay loop at 65 °C for 4.8 min. Steady‑state operation for 8 h yielded 93% HPLC assay of the coupled biheteroaryl ester, which upon acidic hydrolysis and hydrogenation furnishes a 5‑(6‑chloropyridin‑3‑yl)‑2‑aminothiazole‑4‑carboxylic acid advanced intermediate destined for a novel gamma‑aminobutyric acid (GABA)‑gated chloride channel activator for crop protection. The process is tuned to consume >99.5% of the bromopyridine within the loop; exceeding a 5.2 min residence time triggers protodezincation of the unstable thiazole‑zinc species, dropping yield by 12% absolute per additional minute. Equipment compliance with ISO 4126‑1 overpressure protection is mandatory due to the zinc reagent’s reactivity, and the final formulated technical active is registered under EPA 40 CFR Part 158 data requirements for biochemical pesticides. The finished product is a 150 g/L EW (emulsion, oil in water) containing 15% active ingredient pre‑dissolved in Solvesso 200 ND and emulsified with calcium dodecylbenzenesulfonate (4.5% w/w).
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2-Amino-5-bromothiazole-4-carboxylic acid ethyl ester (C6H7BrN2O2S, CAS 98138-34-2, molecular weight 251.11 g·mol⁻¹) is a heterobifunctional heterocyclic intermediate that combines a primary aromatic amine, an aryl bromide, and an ethyl ester on the thiazole scaffold. The molecule is manufactured via Fischer esterification of 2-amino-5-bromothiazole-4-carboxylic acid with absolute ethanol and sulfuric acid (2 wt% with respect to acid), followed by neutralisation with aqueous sodium bicarbonate to pH 7.0–7.5, phase separation, and crystallisation from ethanol/water (4:1 v/v). Typical batch yields at the 50 kg input scale are 82–89%, with a product appearance of a white to off-white crystalline powder. The compound serves as a versatile building block in medicinal chemistry for the assembly of kinase inhibitors, allosteric modulators, and agricultural fungicides that necessitate sequential Pd-catalysed cross-coupling at the 5‑position and subsequent functionalisation of the 2‑amino group. The specifications, derived from in-house production data across 23 batch runs and aligned with the requirements of early-phase GMP synthesis, are listed below.
| Property | Specification | Test Method |
|---|---|---|
| CAS Number | 98138-34-2 | — |
| Molecular Formula | C6H7BrN2O2S | — |
| Molecular Weight | 251.11 g·mol⁻¹ | — |
| Appearance | White to off-white crystalline powder | Visual inspection |
| Assay (HPLC) | ≥ 98.0% (area %, 254 nm) | In‑house RP‑HPLC, C18 column, acetonitrile/water 0.1% TFA |
| Water Content | ≤ 0.5% | Karl Fischer titration (USP <921>) |
| Melting Range | 120–124 °C (onset, DSC, 10 °C·min⁻¹, N2) | ASTM D3418 |
| Residual Ethanol | ≤ 5000 ppm | GC‑FID, ICH Q3C class 3 |
| Chloro Analogue Impurity | ≤ 0.15% | HPLC |
| Dehalogenated Impurity | ≤ 0.10% | HPLC |
The electronic and steric profile of the bromine atom and the ethyl ester group together dictate a reactivity window that is narrower and more controllable than the chloro congener, yet more robust toward hydrolysis than the methyl ester. The C–Br bond dissociation energy (BDE) of ~ 326 kJ·mol⁻¹ is substantially lower than the C–Cl BDE (~ 397 kJ·mol⁻¹), translating into a lower activation barrier for oxidative addition to Pd(0). Density functional theory (B3LYP/6‑31G*) estimates place the free‑energy barrier for Pd(PPh3)2 oxidative addition at ~ 15 kcal·mol⁻¹ lower for the bromo ester than for its chloro counterpart. In practice, Suzuki–Miyaura couplings with phenylboronic acid proceed to > 95% conversion in 4 h at 80 °C using Pd(PPh3)4 (1 mol%), whereas the chloro ester requires temperatures above 100 °C and often demands XPhos Pd G3 precatalyst to reach the same conversion. The bromine atom also facilitates the use of electron‑deficient boronic acids without excessive catalyst loading. Regarding ester stability, under basic biphasic coupling conditions (pH ~ 10–11, K2CO3, 80 °C), the ethyl ester hydrolyses at a rate approximately 5- to 8‑fold slower than the methyl ester, a distinction that becomes critical in prolonged reactions where premature carboxylate formation can sequester palladium and stall catalytic turnover. The solubility advantage is marked: at 25 °C, the ethyl ester dissolves to > 200 g·L⁻¹ in THF, whereas the free acid achieves less than 50 g·L⁻¹. Predicted logP values (ChemAxon) are 1.8, 1.3, and 0.7 for the ethyl ester, methyl ester, and carboxylic acid, respectively, highlighting the ethyl ester’s superior partition into organic phases during workup.
Process-scale Suzuki coupling on 73.7 mol of 2-amino-5-bromothiazole-4-carboxylic acid ethyl ester was executed in a 200 L glass‑lined reactor equipped with a retreat‑curve impeller. The ester (18.5 kg) was dissolved in toluene (100 L) and ethanol (33 L), and a solution of K2CO3 (20.3 kg, 147 mol) in water (60 L) was added. The biphasic mixture was sparged with nitrogen (0.5 vvm) for 45 min to reduce dissolved oxygen below 1 ppm, a precaution essential to suppress debromination, which otherwise arises from β‑hydride elimination‑like side reactions when oxygen is present. Pd(PPh3)4 (852 g, 0.74 mol, 1 mol%) was charged, followed by phenylboronic acid (10.8 kg, 88.4 mol, 1.2 equiv). The reactor was heated to 78–82 °C and stirred at an impeller tip speed of 4.2 m·s⁻¹ while maintaining a 0.1 bar N2 blanket. In‑process HPLC monitoring revealed complete consumption of the bromide within 5 h; the area of the debrominated by‑product (ethyl 2-aminothiazole-4-carboxylate) was 1.8% at this endpoint. After cooling to 45 °C, the aqueous layer was separated. The organic phase was treated with activated carbon (1.5 kg) and silica‑thiol scavenger (200 g) for 30 min, then filtered through a sparkler filter. The filtrate was washed with 10% aqueous sodium metabisulfite (20 L) and water. Concentration under vacuum (50 mbar, jacket temperature 45 °C) gave a crude residue that was crystallised from 95% ethanol (3 volumes) with seeding. The isolated mass of 2-amino-5-phenylthiazole-4-carboxylic acid ethyl ester was 16.1 kg (87% yield), with HPLC purity 99.2%. ICP‑OES analysis recorded palladium at 4 ppm. Importantly, when nitrogen sparging was inadvertently shortened to 20 min in a parallel campaign, debromination jumped to 4.5%, and the purification forced an additional recrystallisation that eroded yield to 78%.
After a Suzuki coupling, the crude product typically retains palladium at 5–50 ppm unless deliberate scavenging is performed. The 2-aminothiazole moiety can coordinate Pd(II) species, forming stable complexes that survive aqueous washes and even silica gel chromatography. In a model Buchwald–Hartwig amination with morpholine (1.2 equiv) and Xantphos Pd G4 (2 mol%) at 100 °C for 12 h, product isolated yield fell from 84% to 26% when the input ester contained 15 ppm versus < 5 ppm palladium. This deactivation is attributed to palladium‑mediated poisoning of the amination catalyst and formation of inactive Pd–amine clusters. To ensure robust downstream performance, a purification protocol involving a filtration through a bed of silica‑thiol metal scavenger (50 g per kg of ester) or a charcoal treatment followed by a 5% N‑acetyl‑L‑cysteine wash at 60 °C is implemented. This consistently reduces palladium to < 5 ppm as confirmed by ICP‑OES, which is mandated for every lot prior to release for amination chemistry. Activated carbon alone, without functionalised thiol groups, typically leaves 12–20 ppm palladium, insufficient for sensitive amination sequences.
The ethyl ester exhibits appreciable resistance to hydrolysis at pH 9–10, but saponifies under stronger alkaline conditions. In a kinetic study at 80 °C in 1:1 v/v dioxane/water containing KOH (0.5 M), the parent ester showed 12% hydrolysis after 1 h and 34% after 3 h. Under identical conditions, the methyl ester hydrolysed to 41% in 1 h. This difference allows the ethyl ester to survive standard Suzuki conditions (K2CO3 2 equiv, 3:1 toluene/water, 80 °C, 5 h) with acid formation remaining below 6%, meaning the ester can serve as a protected carboxylate in multi‑step sequences without premature deprotection interfering with catalysis. For reactions demanding strong bases such as sodium tert‑butoxide, the ethyl ester is cleaved completely in < 30 min; the corresponding tert‑butyl ester should be employed instead.
The most frequently encountered process‑related impurities are the hydrolytically generated 2‑amino‑5‑bromothiazole‑4‑carboxylic acid, the debrominated ethyl 2‑aminothiazole‑4‑carboxylate, the decarboxylated 2‑amino‑5‑bromothiazole, and trace levels of the chloro analogue arising from halogen exchange during bromination. Their relative retention times (RRT) on a C18 column (mobile phase 0.1% TFA in water/acetonitrile gradient) are tabulated below. The HPLC method uses detection at 254 nm with a signal‑to‑noise ratio exceeding 1000:1 for the main peak, ensuring reliable quantification at the 0.05% level.
| Impurity | RRT | Typical Specification Limit |
|---|---|---|
| 2‑Amino‑5‑bromothiazole‑4‑carboxylic acid | 0.55 | ≤ 0.15% |
| Ethyl 2‑aminothiazole‑4‑carboxylate (debrominated) | 0.78 | ≤ 0.10% |
| 2‑Amino‑5‑bromothiazole (decarboxylated) | 1.15 | ≤ 0.05% |
| 2‑Amino‑5‑chlorothiazole‑4‑carboxylic acid ethyl ester | 0.92 | ≤ 0.10% |
Electrophilic bromination of 2‑aminothiazole‑4‑carboxylic acid—the direct precursor of the ester—is carried out with N‑bromosuccinimide (NBS, 1.05 equiv) in DMF at 0–5 °C. On a 50 kg scale, the acid (31.5 kg, 143 mol) is dissolved in DMF (150 L), and NBS is added portion‑wise over 4 h while maintaining the internal temperature below 5 °C. Quenching with ice‑water (600 L), filtration, and washing with chilled water gives crude 2‑amino‑5‑bromothiazole‑4‑carboxylic acid in 91–94% crude yield with a regioisomeric purity exceeding 99.5% (the alternative 5‑bromination is overwhelmingly favoured over potential 4‑bromination). Residual succinimide by‑product is removed by a water‑ethanol slurry wash, reducing its level to < 0.2% prior to esterification. This tight control of the bromination step is essential, as any dibrominated species formed at elevated temperature (> 15 °C) persist through the esterification and complicate subsequent cross‑coupling selectivity. Published data for this specific configuration is limited, but in‑house campaigns have demonstrated that a reproducible bromination endpoint can be achieved when the NBS addition rate does not exceed 0.25 kg·min⁻¹, keeping the exotherm within 5 °C of the set point.
For long‑term stability, the product must be stored in tightly sealed containers under dry nitrogen at 2–8 °C. Under these conditions, hydrolytic degradation over 12 months has been measured as < 0.2% acid formation and no detectable increase in debrominated content. Exposure to > 60% relative humidity at 25 °C for 48 h results in a moisture uptake of 1.2% and a corresponding rise in carboxylic acid impurity to 0.4%, reinforcing the need for desiccated storage.
