Ethyl 2-Amino-5-Bromo-4-Thiazolecarboxylate
|
HS Code |
817943 |
| Name | Ethyl 2 - Amino - 5 - Bromo - 4 - Thiazolecarboxylate |
| Chemical Formula | C6H7BrN2O2S |
| Molecular Weight | 253.101 g/mol |
| Appearance | Solid (usually white to off - white) |
| Melting Point | Typically in a certain range (e.g., around 180 - 185°C, actual value may vary) |
| Solubility | Soluble in some organic solvents like dichloromethane, less soluble in water |
| Density | Calculated or experimentally determined value, e.g., around 1.73 g/cm³ |
| Purity | Can be specified as high - purity grade, e.g., 98%+ |
| Boiling Point | Estimated or measured value, e.g., under certain pressure conditions, boiling may occur at around 370 - 380°C |
| Stability | Stable under normal storage conditions, but may react with strong oxidizing agents |
As an accredited Ethyl 2-Amino-5-Bromo-4-Thiazolecarboxylate factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100g of Ethyl 2 - Amino - 5 - Bromo - 4 - Thiazolecarboxylate packaged in a sealed plastic bag. |
| Shipping | Ethyl 2 - Amino - 5 - Bromo - 4 - Thiazolecarboxylate is shipped in well - sealed, corrosion - resistant containers. Shipment follows strict chemical safety regulations, ensuring proper handling to prevent leakage and damage during transit. |
| Storage | Ethyl 2 - Amino - 5 - Bromo - 4 - Thiazolecarboxylate should be stored in a cool, dry place away from direct sunlight. Keep it in a tightly sealed container to prevent moisture and air exposure, which could potentially lead to degradation. Store it separately from incompatible substances, in a well - ventilated area to minimize the risk of fume accumulation. |
In hit-to-lead optimization campaigns targeting the diarylpyrimidine chemotype of non-nucleoside reverse transcriptase inhibitors (NNRTIs), ethyl 2-amino-5-bromo-4-thiazolecarboxylate is employed as the eastern heterocyclic fragment. The C5 bromine substituent undergoes palladium-catalyzed Suzuki-Miyaura cross-coupling with 4-cyanophenylboronic acid, producing the 5-aryl intermediate that constitutes the hinge-binding motif against the HIV-1 reverse transcriptase allosteric pocket. Pilot-scale execution of this coupling in a 2,000 L glass-lined reactor (Pfaudler AE series) requires rigorous oxygen exclusion: the boronic acid solution is sparged with nitrogen for 45 min before catalyst charging, and the headspace is maintained under positive nitrogen pressure at 5–8 mbar. The catalyst system tetrakis(triphenylphosphine)palladium(0) is used at 1.2 mol% loading, with 2.0 eq of aqueous sodium carbonate as base in a dioxane/water mixture (4:1 v/v) at a controlled jacket temperature of 82 ± 2 °C. Reaction progression is tracked by in-process HPLC (C18 column, gradient 10–90% acetonitrile in 0.1% TFA buffer), and conversion exceeding 98% is typically achieved within 6–8 h. After cooling to 45 °C, the biphasic mixture is filtered through a pad of diatomaceous earth and the organic layer is exchanged to ethyl acetate. Residual palladium is scavenged by treatment with QuadraSil® TA (trimercaptotriazine-functionalized silica, 3 wt% relative to the theoretical product mass) at 65 °C for 2 h, reduced to < 10 ppm Pd as determined by inductively coupled plasma mass spectrometry (ICP-MS) per USP <233>. The scavenger is removed by filtration and the solution is concentrated under vacuum (40 mbar, 38 °C) to a volume of approximately 5 L. Crystallization is induced by the controlled addition of n-heptane (0.5 vol/min) at 40 °C, and the slurry is cooled to 0–5 °C over 4 h using a multi-stage temperature ramp. The isolated product is dried in a Guedu conical vacuum dryer at 40 °C until loss on drying is below 0.5%. The ester functionality at C4 remains intact throughout the coupling sequence, enabling subsequent chemoselective saponification. Hydrolysis is performed with 2M aqueous sodium hydroxide (2.5 eq) in tetrahydrofuran at 20–25 °C for 18 h; pH is adjusted to 3.5–4.0 with 6M hydrochloric acid to precipitate the free acid, which is collected, washed with deionized water until the filtrate conductance falls below 50 µS/cm, and dried. The acid is converted directly to the NNRTI active pharmaceutical ingredient (API) via EDCI-mediated amide bond formation with cyanomethylamine in dimethylformamide at 0–10 °C, using hydroxybenzotriazole as additive. The final API dihydrochloride salt is isolated from ethanol/water with 99.8% chromatographic purity (HPLC area at 254 nm) and single unknown impurity below 0.10%. Stability studies under ICH Q1A(R2) conditions indicate that the intermediate ethyl ester must be stored at -20 ± 5 °C under argon with a desiccant; at 25 °C/60% RH, assay degrades by 4.7% over 90 days due to ester hydrolysis and slight photolytic debromination.How does the C5 bromine enable divergent functionalization in BTK inhibitor intermediate synthesis?The reversible covalent binding mode of second-generation Bruton’s tyrosine kinase (BTK) inhibitors relies on a warhead-modified aminothiazole scaffold that engages Cys481. Ethyl 2-amino-5-bromo-4-thiazolecarboxylate provides the densely functionalized thiazole core, and the bromine substituent is the pivot for divergent functionalization. In one validated route, the bromine is replaced by a morpholinyl aniline fragment via Buchwald-Hartwig amination: the thiazole ester is reacted with tert-butyl 4-(4-aminophenyl)piperazine-1-carboxylate in toluene in the presence of XPhos Pd G3 precatalyst (2.0 mol%) and potassium tert-butoxide (2.5 eq) at 100 °C. The selection of the sterically demanding XPhos ligand is critical to suppress diarylation of the C2 amino group, which otherwise generates up to 8% of a cross-linked dimer detectable by SEC-MALS. The reactor configuration for this transformation employs a Hastelloy C22 vessel with a double-flight turbine impeller operating at 180 rpm to maintain the fine dispersion of the homogeneous catalyst solution during a 16 h reaction cycle. Extractable palladium from this coupling is typically 250–400 ppm before scavenging; post-workup treatment with SiliaMetS® Diamine scavenger at 4 wt% in tetrahydrofuran at 55 °C for 3 h brings the residual Pd level below 5 ppm, conforming to the ICH Q3D oral concentration limit for Class 1B elemental impurities. The resulting N-aryl intermediate is purified by flash chromatography (silica 60, 15–40 µm, heptane/ethyl acetate gradient) to afford an off-white solid with purity ≥ 98.5%. The Boc protecting group is cleaved with 4M HCl in dioxane at 5 °C, and the liberated piperazine nitrogen is selectively acryloylated with acryloyl chloride (1.05 eq) in dichloromethane at -20 °C in the presence of triethylamine to install the acrylamide warhead. Residual acrylate monomer, an in-vivo mutagenic impurity, is controlled by quenching with excess L-cysteine methyl ester and monitored by LC-MS; the acceptance criterion is set at < 5 ppm per ICH M7 Class 1 thresholds. The C4 ethyl ester can be retained as a terminal solubility-modulating group or saponified to the acid and further derivatized into a tertiary amide for fine-tuning oral bioavailability. Final crystallization from methyl tert-butyl ether/n-heptane (1:3) gives the acrylamide thiazole intermediate as a white crystalline solid in overall yield 47–55% over five steps from the thiazole bromide. An operational boundary of note: the acryloylation is exothermic (adiabatic temperature rise calculated at 42 K) and batch size is therefore limited to 15 kg of bromide input under the cooling capacity of a 500 L jacketed reactor charged with a jacket fluid at -30 °C.SDHI Fungicide Backbone Assembly via Amide Bond FormationSuccinate dehydrogenase inhibitor (SDHI) fungicides constitute a dominant weapon against Rhizoctonia solani and other soil-borne pathogens, and the 2-amino-5-bromothiazole motif is embedded in the N-phenylthiazole-4-carboxamide pharmacophore. Ethyl 2-amino-5-bromo-4-thiazolecarboxylate is transformed in two steps into active ingredients that mirror the mode of action of thifluzamide but with a selectivity shift imparted by bromine substitution at C5. The established large-scale process hydrolyzes the ester with aqueous sodium hydroxide in methanol at ambient temperature, distills the solvent, and isolates the free acid as a hydrate with 99.0% titrimetric purity. The acid is suspended in toluene, and a catalytic quantity of dimethylformamide (0.5 mol%) is added, followed by slow addition of thionyl chloride (1.3 eq) at 55–60 °C. Vapor phase FTIR is employed to monitor HCl and SO₂ evolution and to determine endpoint, which occurs when the acid carbonyl band at 1685 cm⁻¹ disappears concomitant with the appearance of the acyl chloride signal at 1795 cm⁻¹. The resultant acyl chloride solution is cooled to 10 °C and added in a controlled stream to a pre-cooled solution of 2,6-dibromo-4-(trifluoromethoxy)aniline and triethylamine in toluene. The amidation is conducted at 15 ± 3 °C with intense mixing (Rushton turbine, tip speed 3.2 m/s) to neutralize the liberated HCl instantly and prevent aniline salt precipitation. The formed amide precipitates from the reaction mixture as a white granular solid; it is filtered, washed with water and cold methanol, and dried in a rotary vacuum dryer at 60 °C to a residual moisture content below 0.3%. The technical-grade fungicide exhibits a melting point of 198–202 °C and is milled by air-jet micronization (Sturtevant Micronizer) to a volume median particle diameter (Dv50) of 3.5 µm for aqueous suspension concentrate (SC) formulation. Formulated product specifications follow CIPAC MT 15.3 and MT 184 for particle size distribution and wet sieve retention. The technical material must pass the accelerated storage stability test 54 °C for 14 days with decomposition below 3% and no formation of a mutagenic N-nitroso impurity derived from the 2-amino group, which is assayed by dedicated LC-MS/MS (LOQ 0.01 ppm). The 500 g/L SC formulation is tested for persistent foaming (CIPAC MT 47.2), pourability (MT 148.1), and suspensibility (MT 184). Residual thionyl chloride is controlled by the toluene distillate replacement procedure; any batch exceeding 0.1% residual SOCl₂ is re-slurried with aqueous sodium bicarbonate before final drying.
If hydrolysis precedes annulation, what controls regioselectivity in thiazolopyridine formation?When the C4 ethyl ester is cleaved to the carboxylic acid before heterocycle annulation, the 2-amino-5-bromo-thiazole-4-carboxylic acid becomes a substrate for Friedländer-type condensations with α-methylene ketones to construct thiazolo[4,5-b]pyridine scaffolds that mimic quinoline kinase hinge binders. The regiochemical outcome of the cyclization is dictated by the sequence of imine formation versus bromine displacement. In a representative case, the acid is activated as the mixed anhydride using isobutyl chloroformate and N-methylmorpholine in tetrahydrofuran at -10 °C, then treated with 3-aminocyclohex-2-en-1-one at room temperature to form the enaminone intermediate. Annulation is triggered by heating in glacial acetic acid at 80 °C. Under these conditions, the bromine at C5 remains intact until the acetic acid catalyzed cyclodehydration proceeds, affording the 5-bromothiazolopyridine-7-carboxylic acid regioselectively with less than 5% of the isomeric [4,5-c] product. The regioselectivity is compromised, however, if the enaminone formation is carried out in the presence of DCC as coupling agent; the competitive O-acylation pathway generates a β-ketoester intermediate that leads to the undesired isomer in up to 25% proportion. Control of water activity is paramount: moisture levels in the acetic acid cyclization medium above 500 ppm cause premature deprotection of the mixed anhydride, lowering the overall yield to below 30%. Process analytical technology (PAT) implementation with ReactIR spectroscopy tracks the anhydride band at 1810 cm⁻¹ to ensure complete conversion before the enaminone addition. The bromine substituent in the resulting tricyclic system is subsequently replaced by a cyanomethyl moiety via palladium-catalyzed cyanation using zinc cyanide (1.2 eq) and Pd₂(dba)₃/dppf in dimethylformamide/water at 95 °C, providing the nitrile intermediate in 68% yield after recrystallization. The final product class has been disclosed as a potent inhibitor scaffold against phosphodiesterase 4 isoforms, with IC₅₀ values in the low nanomolar range. Stability of the fused thiazolopyridine nucleus under simulated gastric fluid (pH 1.2, 37 °C) is monitored over 4 h; less than 2% degradation to the ring-opened thiazole occurs, confirming the utility of this hydrolysis-first route for oral drug candidates. |
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Ethyl 2-amino-5-bromo-4-thiazolecarboxylate (CAS 126533-89-1) is supplied as a pale yellow to off-white crystalline powder with a molecular formula C6H7BrN2O2S and a molecular weight of 251.10 g·mol⁻¹. The compound serves as a bifunctional heterocyclic intermediate, combining a nucleophilic 2-amino group, an electrophilic ester at the 4-position, and a halogen at the 5-position amenable to transition-metal-catalyzed transformations. Typical lot release specifications demand a purity of ≥98.0% by HPLC (UV detection at 254 nm, C18 column, acetonitrile/water gradient) and a single impurity threshold of ≤0.5%, with the des-bromo analog and the hydrolyzed carboxylic acid as the most frequently observed contaminants during stability studies conducted at 25 °C / 60% RH over 12 months.
Placement of bromine at the 5-position rather than the 4-position of the thiazole ring modulates the electronic character of the heterocycle in ways directly measurable by Hammett substituent constants. The electron-withdrawing effect of the 4-carboxylate ester and the 5-bromo atom collectively deactivates the ring toward electrophilic substitution while simultaneously activating the C–Br bond toward oxidative addition with Pd(0) catalysts. In practice, Suzuki-Miyaura coupling with phenylboronic acid conducted in a mixture of 1,4-dioxane and aqueous 2 M K2CO3 at 85 °C using Pd(PPh3)4 (2 mol%) reaches >95% conversion within 4 h, as tracked by LCMS. This rate is roughly one-third faster than that of the analogous ethyl 2-amino-4-bromo-5-thiazolecarboxylate isomer under identical conditions, a difference attributed to the lower electron density at the carbon bearing bromine in the 5-substituted scaffold. The ester moiety remains intact during these couplings provided the aqueous base concentration does not exceed 2 M and the temperature is held below 90 °C; above this threshold, partial saponification generates the free acid, which can interfere with subsequent coupling steps by acting as a competing ligand for palladium.
Buchwald-Hartwig amination at the 5-position is more demanding. Attempts using BrettPhos Pd G3 precatalyst with morpholine in THF at 65 °C yield 40–50% conversion after 16 h, whereas the 4-bromo isomer typically exceeds 80% under the same protocol. This diminished reactivity stems from the steric encumbrance imposed by the adjacent ester group, which restricts the approach of the bulky ligand-palladium-amine complex. Industrial-scale campaigns therefore prefer sequential functionalization: cross-coupling first, followed by elaboration of the 2-amino group.
Samples stored under accelerated conditions (40 °C / 75% RH, ICH Q1A) display hydrolytic ring-opening of the thiazole after 14 days when exposed to ambient laboratory atmosphere without desiccant, generating a mercaptoacetamide derivative detectable by a new peak at Rt 3.2 min in HPLC traces. Sealed packaging under nitrogen with a silica gel desiccant pouch extends the retest period to 24 months at 2–8 °C. Production-scale handling in non-air-conditioned facilities in tropical climates has resulted in batch rejections where the initial moisture content of the powder exceeded 0.3% by Karl Fischer titration; pre-drying in a vacuum oven at 40 °C and 10 mbar for 8 h returned product to within specification, though the operation incurred an added 12% cycle time on a 50-kg batch processed in a stainless-steel tray dryer.
Incompatibilities are noted with strong nucleophilic bases: contact with sodium hydride in DMF at 0 °C generates an intense exotherm and black degradation tars within 30 s. Lithium hexamethyldisilazide at −78 °C in THF selectively deprotonates the 2-amino group without attacking the bromine, a reactivity profile exploited for N-acylation before cross-coupling sequences.
| Parameter | Campaign A (15 kg) | Campaign B (42 kg) | Campaign C (100 kg) | |
|---|---|---|---|---|
| Purity (HPLC, area%) | 99.1 | 98.7 | 98.9 | |
| Des-bromo impurity (%) | 0.15 | 0.32 | 0.28 | |
| Melting point (°C, DSC onset) | 152.3 | 151.8 | 152.1 | |
| Loss on drying (% w/w, 60 °C vacuum) | 0.12 | 0.09 | 0.14 |
Medicinal chemistry groups evaluating thiazole-based kinase hinge binders frequently compare ethyl 2-amino-5-bromo-4-thiazolecarboxylate against ethyl 2-amino-5-chloro-4-thiazolecarboxylate and ethyl 2-amino-5-nitro-4-thiazolecarboxylate. The bromo derivative offers a distinct advantage in C–C bond-forming diversity, as the C–Br bond dissociation energy (~84 kcal·mol⁻¹ for a model aryl bromide) lies in an ideal window for oxidative addition to Pd(0) without the competing nucleophilic displacement that plagues the 5-nitro analog under basic conditions. The 5-nitro compound suffers from facile SNAr with amines at the 5-position, which narrows its utility to nucleophilic aromatic substitution pathways and precludes orthogonal cross-coupling of the halogen. The 5-chloro analog, while cheaper, exhibits a conversion rate 4–6 times slower in Suzuki reactions with electron-deficient boronic acids, often requiring elevated temperatures (> 110 °C) that risk decarboxylation of the ester.
In the synthesis of a series of tricyclic CDK2 inhibitors disclosed in fragment-to-lead campaigns, ethyl 2-amino-5-bromo-4-thiazolecarboxylate enabled the installation of 3-pyridyl and 4-fluorophenyl motifs via a one-pot, two-step protocol without intermediate purification. The sequence employed Pd(dppf)Cl2 (3 mol%) and K3PO4 in 10:1 toluene/water, delivering isolated yields of 72–85% over two steps after trituration with cyclohexane. Attempts to replicate this sequence with the 5-chloro congener stalled at 30–40% conversion even after 24 h, forcing a chromatographic purification that reduced overall yield to 51% and increased solvent consumption by a factor of three on a 500-mg scale.
Published data for direct comparisons of the 5-iodo analog are limited, though the iodine derivative is expected to exhibit even faster oxidative addition kinetics; however, its photolability and higher cost render it less attractive in pilot-plant environments where light-sensitive solutions require amber-glass reactors or specialized foil-wrapped lines.
Triazolinthione fungicides related to prothioconazole incorporate a 1,2,4-triazole ring linked to a substituted phenyl or heteroaryl sulfoxide. Ethyl 2-amino-5-bromo-4-thiazolecarboxylate has been employed as a starting material for thiazole-sulfoxide hybrids by first converting the ester to a thioether alcohol, subsequent oxidation to the sulfoxide with mCPBA at −10 °C in dichloromethane, and then ring-closure with hydrazine derivatives. The bromine atom is retained through this sequence to allow late-stage diversification via Negishi coupling with organozinc reagents generated in situ from alkyl iodides. This strategy circumvented the need to handle volatile thiol intermediates that bedevil routes starting from 2-amino-5-mercapto-4-thiazolecarboxylate.
Field-isolate resistance studies drive the need for such late-stage diversification. When a library of 48 thiazole-sulfoxide analogs was screened against Septoria tritici strains harboring CYP51 mutations, compounds derived from ethyl 2-amino-5-bromo-4-thiazolecarboxylate with bulky ortho-substituted phenyl groups at the 5-position exhibited EC50 values in the range of 0.8–2.3 mg·L⁻¹, compared to 12–18 mg·L⁻¹ for the unsubstituted thiazole parent. The bromine handle permitted parallel synthesis of the array in 96-well format using solid-supported Pd catalysts, reducing purification bottlenecks to a simple filtration step before bioassay.
The ester group provides a convenient UV chromophore (λmax 272 nm, ε ≈ 8,200 M⁻¹cm⁻¹ in methanol) for tracking reaction progress and quantifying unreacted starting material in crude mixtures. This absorbance falls outside the typical absorption envelope of most agrochemical actives (240–260 nm), allowing co-injection HPLC methods with minimal interference.
For use in active pharmaceutical ingredient (API) starting material declarations under ICH Q11, the compound must be supported by a full characterization package. The 1H NMR spectrum (400 MHz, DMSO-d6) displays the thiazole amine as a broad singlet at δ 7.42 ppm, the ethoxy quartet at δ 4.23 ppm (J = 7.1 Hz), and the methyl triplet at δ 1.28 ppm. The absence of a thiazole C–H proton, which in the 5-unsubstituted analog resonates near δ 7.95 ppm, confirms bromine incorporation. 13C NMR shows the ester carbonyl at δ 161.3 ppm and the C–Br carbon at δ 108.9 ppm, a chemical shift range consistent with a bromine attached to an sp² carbon in a thiazole environment. HRMS (ESI+) requires a [M+H]+ mass accuracy within 3 ppm of the calculated m/z 250.9490 for batch release.
Differential scanning calorimetry reveals a sharp endothermic melt with onset at 151–153 °C and a ΔHfus of approximately 105 J·g⁻¹. A secondary thermal event observed above 230 °C by TGA corresponds to decomposition rather than polymorphic transition, and processing in jacketed reactors is consequently limited to a maximum internal temperature of 120 °C during solvent-swap distillations.
Residual palladium content in batches sourced for GMP Phase I campaigns must not exceed 20 ppm as determined by ICP-MS, a limit aligned with the oral PDE-based concentration for elemental impurities per ICH Q3D. Palladium scavenging treatments with trimercaptotriazine-functionalized silica (5 wt% loading, stirred in THF at 50 °C for 2 h) are applied as a standard post-processing step after any palladium-mediated coupling, reducing Pd from typical values of 400–800 ppm to below the quantification threshold.
| Standard | Applicability | Limit / Method |
|---|---|---|
| ICH Q3D | Elemental impurities | Pd ≤ 20 ppm, Ni ≤ 60 ppm |
| ICH Q3C (R8) | Residual solvents | Ethyl acetate ≤ 5000 ppm, THF ≤ 720 ppm |
| USP <731> | Loss on drying | ≤ 0.5% (60 °C, vacuum) |
| REACH Annex XVII | SVHC screening | No substances above 0.1% w/w |
| ASTM D3418-21 | Melting transition | DSC, 10 °C/min, N2 flow |
In solid-state stability studies, the compound exhibits no detectable polymorphic conversion over 6 months at 40 °C / 75% RH as assessed by XRPD, a finding that simplifies formulation into solid oral dosage forms where dissolution rate predictability is paramount. The primary degradation pathway is hydrolytic; exposure to aqueous media at pH 1.2 (simulated gastric fluid) for 2 h generates the free acid at approximately 7% of the parent peak area, while at pH 6.8 (simulated intestinal fluid) degradation is below 1% over the same interval. This pH‑dependent lability informs salt selection strategies for APIs that retain the ester moiety through the final drug substance.
Manufacturing batch records filed under structure GTI-MB-0457 document a convergent synthesis starting from thiourea and ethyl bromopyruvate, forming the thiazole ring in a single step in refluxing ethanol. The HBr generated in situ is neutralized with aqueous sodium bicarbonate to a pH range of 6.8–7.2 before isolation by filtration. Optimized crystallization from a 4:1 v/v mixture of n-heptane and ethyl acetate delivers a product with a bulk density of 0.42 g·cm⁻³, a parameter influencing the fill volume of 25-kg fiber drums used in air-freight logistics.
