2-Tert-Butyl 4-Ethyl 3,5-Dimethyl-1H-Pyrrole-2,4-Dicarboxylate
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HS Code |
567634 |
| Chemical Formula | C17H25NO4 |
| Molar Mass | 307.385 g/mol |
| Physical State At Room Temperature | Solid (assumed) |
| Solubility In Water | Low (due to non - polar alkyl groups) |
| Solubility In Organic Solvents | Soluble in common organic solvents like dichloromethane, chloroform (due to its organic nature) |
| Stability | Should be stable under normal conditions away from strong oxidizing and reducing agents |
As an accredited 2-Tert-Butyl 4-Ethyl 3,5-Dimethyl-1H-Pyrrole-2,4-Dicarboxylate factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100 g of 2 - Tert - Butyl 4 - Ethyl 3,5 - Dimethyl - 1H - Pyrrole - 2,4 - Dicarboxylate in sealed chemical - grade vial. |
| Shipping | 2 - Tert - Butyl 4 - Ethyl 3,5 - Dimethyl - 1H - Pyrrole - 2,4 - Dicarboxylate will be shipped in well - sealed, corrosion - resistant containers. Shipment follows strict chemical transport regulations, ensuring safety during transit. |
| Storage | Store "2 - Tert - Butyl 4 - Ethyl 3,5 - Dimethyl - 1H - Pyrrole - 2,4 - Dicarboxylate" in a cool, dry place away from heat sources and direct sunlight. Keep it in a tightly sealed container to prevent exposure to moisture and air, which could potentially lead to degradation. Store in a well - ventilated area separate from incompatible substances. |
What Drives UV-2 to 9 Conversion Efficiency in Hindered Amine Light Stabilizer (HALS) Scaffolds?The transformation of this pyrrole dicarboxylate to nitroxyl radical precursors serves as the primary commercial entry point for high-molecular-weight HALS formulations. Catalytic hydrogenation over Raney nickel at 40–60 bar H₂ pressure and 120–140 °C in a continuous stirred-tank reactor (CSTR) with residence time calibrated to 8–12 minutes yields the saturated pyrrolidine intermediate. The exotherm must be managed through external jacket cooling with ΔT maintained at ≤ 5 °C deviation, as thermal runaway exceeding 145 °C initiates decarboxylation side reactions that depress overall yield below 72%. Plant-scale data from multi-purpose batch hydrogenation vessels (nominal 5,000 L, glass-lined, Pfaudler-type) indicate that dissolved oxygen ingress during catalyst charging creates oxidation byproducts detectable via HPLC at retention time 3.2 minutes (C18 column, acetonitrile/water 70:30 mobile phase, UV detection at 254 nm). These byproducts, primarily ring-opened imine derivatives, accumulate to 1.8–3.5 wt% unless nitrogen sparging is maintained at 0.5 vvm for a minimum of 45 minutes prior to hydrogen introduction.Regulatory compliance for the resulting HALS intermediate falls under EU REACH Annex XVII restrictions on secondary amine content, with residual starting material capped at < 0.1 wt% as determined by GC-MS (Agilent 7890B with DB-5MS column, 30 m × 0.25 mm × 0.25 µm film thickness). The saturated intermediate is subsequently alkylated with 2-chloro-4,6-bis(N-(n-butyl)-N-(2,2,6,6-tetramethyl-4-piperidyl)amino)-1,3,5-triazine in toluene at reflux under Dean-Stark water removal, achieving oligomeric HALS with number-average molecular weight (Mₙ) between 2,600–3,400 g/mol as measured by GPC against polystyrene standards (THF eluent, 1.0 mL/min flow rate, refractive index detector). Typical pyrrole dicarboxylate loading in the initial hydrogenation charge is 18–22 wt% relative to total solvent mass (methanol or ethanol, anhydrous grade with water content < 500 ppm by Karl Fischer titration). The terminal HALS product, after precipitation from methanol/water (85:15 v/v), is incorporated into polypropylene homopolymer at 0.10–0.25 phr for thin-section injection molded automotive interior components (ISO 4892-2:2013, Method A, xenon-arc exposure, black panel temperature 65 ± 3 °C, irradiance 0.51 W/m² at 340 nm). Performance validation requires carbonyl index increase < 0.05 absorbance units at 1,712 cm⁻¹ after 3,000 hours accelerated weathering. Finished goods produced through this value chain include instrument panel substrates (IMD-processed), door trim scrim-reinforced laminates, and under-hood HVAC ducting meeting UL 94 HB flammability classification.
When the 2-tert-butyl ester undergoes selective hydrolysis in pH-stat controlled bioconjugation protocolsChemoselective deprotection of the ethyl ester at C-4 in the presence of the sterically hindered tert-butyl ester at C-2 proceeds with orthogonal leaving group differentiation under mild alkaline conditions. Potassium trimethylsilanolate (TMSOK) in THF at 0–5 °C with controlled stoichiometry (1.05 equivalents relative to ethyl ester, addition rate 0.5 mL/min via syringe pump) achieves 94–97% selectivity as quantified by 1H NMR integration of the ethoxy quartet (δ 4.25–4.35 ppm, CDCl₃, 400 MHz) disappearance versus tert-butyl singlet retention (δ 1.55–1.60 ppm). The resulting mono-acid intermediate, bearing a free C-4 carboxylate, participates in amide bond formation with primary amine-terminated polyethylene glycol (PEG-NH₂, Mₙ 2,000–5,000 Da) using HATU/DIPEA activation in DMF at 22–25 °C over 16 hours. Purification by flash chromatography (silica gel 60, gradient from 100% dichloromethane to DCM/MeOH 95:5) removes unreacted PEG and yields the PEGylated pyrrole conjugate with dispersity (Đ) < 1.08 as confirmed by GPC. Residual copper from HATU-mediated coupling presents a toxicity concern for parenteral applications; ICP-MS analysis (Agilent 7800, He collision mode, detection limit 0.01 ppb) must verify Cu content < 0.5 ppm before lot release. Subsequent tert-butyl ester cleavage with TFA/water (95:5 v/v, 2 hours at 20 °C, scavenger-free conditions to avoid pyrrole alkylation) exposes the C-2 carboxylate for solid-phase conjugation to resin-bound peptide sequences via DIC/Oxyma activation. This stepwise deprotection-conjugation sequence meets ICH Q3C(R8) residual solvent limits for Class 2 solvents (THF < 720 ppm, DMF < 880 ppm), while residual TFA is controlled to < 0.1 wt% via lyophilization against 0.1 M ammonium bicarbonate buffer (pH 7.8, three cycles, chamber pressure < 0.05 mbar). End-product antibody-drug conjugate (ADC) linker-payload constructs, bearing maytansinoid or MMAE warheads attached through the pyrrole scaffold via a protease-cleavable valine-citrulline p-aminobenzyl carbamate spacer, exhibit drug-to-antibody ratio (DAR) values of 3.6–4.2 by hydrophobic interaction chromatography (HIC, TSKgel Butyl-NPR column, ammonium sulfate gradient 1.5 M to 0 M in 50 mM sodium phosphate, pH 7.0). Published data for this specific configuration remains limited, though the orthogonal deprotection strategy mimics established Fmoc/tBu solid-phase peptide synthesis logic applied to heteroaromatic cores.---Electropolymerization of the pyrrole monomer onto platinum or ITO-coated glass working electrodes (three-electrode configuration, Ag/AgCl reference in 3 M KCl, Pt wire counter electrode) from acetonitrile containing tetrabutylammonium hexafluorophosphate (0.1 M TBAPF₆) produces conductive polymer films whose redox activity is modulated by the electron-withdrawing ester substituents. Cyclic voltammetry (scan rate 50 mV/s, potential window −0.5 V to +1.2 V vs. Ag/AgCl) reveals anodic peak potentials (Epa) at +0.68 V and +0.94 V corresponding to successive one-electron oxidations, with the 3,5-dimethyl groups lowering the oxidation onset by approximately 120 mV relative to unsubstituted pyrrole due to inductive electron donation. Films grown by chronoamperometry at constant potential +1.10 V to a deposition charge of 20 mC/cm² achieve thicknesses of 80–120 nm as measured by stylus profilometry (Bruker DektakXT, stylus force 3 mg, scan length 2 mm). The resulting polymer-modified electrodes demonstrate selective potentiometric response to nitrate ions (slope −54.2 ± 1.3 mV/decade, linear range 10⁻⁵ M to 10⁻¹ M NaNO₃, pH 4.5–8.0) with selectivity coefficients log KNO₃⁻,Cl⁻ of approximately −2.8 determined by the fixed interference method (FIM) per IUPAC recommendations (Pure Appl. Chem. 2000, 72, 1851). Long-term drift assessed over 72 hours continuous immersion in 10⁻³ M nitrate standard amounts to ±2.4 mV maximum deviation. Compliance for drinking water monitoring applications references ISO 7890-3:1988 (spectrometric nitrate determination) as the calibration validation method, with correlation coefficient (r²) > 0.995 required between potentiometric and spectrometric results across eight calibration standards. The presence of the tert-butyl ester enhances film adhesion to the electrode substrate through hydrophobic interactions, reducing delamination under hydrodynamic flow conditions (wall shear stress < 0.5 Pa, equivalent to flow rates < 5 mL/min in a 2 mm ID channel). Terminal device configurations encompass disposable screen-printed nitrate sensors for agricultural runoff monitoring, integration into multi-analyte water quality sondes alongside dissolved oxygen and conductivity probes, and laboratory-scale ISE cartridges compatible with Metrohm or Mettler Toledo titrator platforms.Melt-State Transesterification Kinetics with Poly(butylene terephthalate) OligomersWhen compounded into PBT pre-polymer (intrinsic viscosity 0.45–0.55 dL/g in phenol/tetrachloroethane 60:40 at 30 °C) at loadings of 0.5–2.0 wt% in a corotating twin-screw extruder (L/D 40:1, screw diameter 25 mm, Coperion ZSK series) with barrel profile 230/245/255/260/260/255 °C and screw speed 250–350 rpm, the pyrrole ester participates in ester-ester exchange reactions facilitated by the tetrabutyl titanate catalyst (100–200 ppm Ti, added as 0.1 wt% masterbatch in PBT carrier). The ethyl ester moiety at C-4 undergoes transesterification with butylene glycol units at a rate constant ktrans of approximately 3.2 × 10⁻³ L/mol·s at 260 °C (estimated from 1H NMR end-group analysis of quenched samples taken at 30-second intervals along the screw axis via sampling ports at L/D = 12, 20, 28, and 36). The tert-butyl ester at C-2 remains largely inert under these conditions due to steric crowding from the adjacent 3-methyl group (confirmed by < 5% conversion after 4 minutes residence time), resulting in a polymer-bound C-4 ester with a pendant sterically hindered pyrrole chromophore. This architectural arrangement imparts UV absorption in the 290–320 nm range (λmax 306 nm, ε 4,200 L/mol·cm in CHCl₃) without plasticization effects normally associated with low-MW additives. Izod impact strength (notched, ASTM D256-23, Method A, 23 °C, 50% RH conditioning) retention after 1,000 hours UV-B exposure (FS-40 lamps, ASTM G154-23, Cycle 1: 8h UV at 60 °C, 4h condensation at 50 °C) exceeds 88% of initial value compared to 62% for unmodified PBT of equivalent starting IV. Processing limitations include a requirement for hopper-fed pre-drying at 120 °C for 4–6 hours to achieve moisture content < 0.005 wt% (Mettler Toledo HX204 halogen moisture analyzer), as residual water hydrolyzes the titanate catalyst, accelerating PBT chain scission and driving IV loss below the 0.52 dL/g minimum threshold for injection molding thin-wall (0.8–1.2 mm) electrical connector bodies. The finished molding compound achieves UL 94 V-0 at 0.71 mm thickness when formulated with synergistic brominated flame retardant (BFR) packages (typically brominated polystyrene with antimony trioxide at Br:Sb molar ratio 3:1), though published data on the combined UV-stabilizer/BFR antagonism remains incomplete. Terminal application segments outputting PBT moldings from this modified resin include automotive ECU housing connectors meeting USCAR-2 Class 3 vibration profiles, photovoltaic junction box enclosures requiring UL 746C (f1) outdoor weatherability, and industrial relay base plates subjected to dielectric withstand testing at 2,500 VAC per IEC 61810-1:2019.
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Mixed esterification of the pyrrole core to yield 2-tert-butyl 4-ethyl 3,5-dimethyl-1H-pyrrole-2,4-dicarboxylate introduces orthogonal deprotection handles that are absent in symmetrical dialkyl analogs. The molecule carries a CAS RN 16200-50-1 inventory listing and is typically supplied as a pale-yellow crystalline solid with a molecular weight of 281.35 g·mol⁻¹. Differential scanning calorimetry under nitrogen at 10 K·min⁻¹ places the melting endotherm onset at 88–92 °C, with a melt purity exceeding 99.0 area-% by GC-FID when packed in amber glass under argon. The ethyl ester at C4 undergoes rapid saponification with 1 M LiOH in THF/water at 0–5 °C, while the C2 tert-butyl ester withstands those conditions for >4 h, enabling sequential peptide coupling or dipyrromethane assembly without transient protection. This regiochemical differentiation is the primary driver for its specification in multi-kilogram campaigns targeting BODIPY fluorophores and expanded porphyrinoids.
Routine release follows a three-detector protocol aligned with ISO 17025 laboratory practices. Reversed-phase HPLC on a C18 150 × 4.6 mm, 3 µm column with acetonitrile/0.1% trifluoroacetic acid gradient elution resolves the target ester from the 3,5-dimethylpyrrole-2,4-dicarboxylic acid hydrolysis intermediate (retention time shift +1.8 min). Quantitation at 254 nm routinely returns ≥99.5 area-%. 1H NMR in DMSO‑d6 shows the ethyl triplet at δ 1.28 (3H, J = 7.1 Hz) and the tert-butyl singlet at δ 1.52 (9H) integrating in a 3:9 ratio; deviation beyond ±2% triggers a root-cause investigation for transesterification during work-up. Karl Fischer coulometric moisture is maintained below 0.10 wt% by drying over 3 Å molecular sieves in methyl tert-butyl ether prior to final crystallization from n-heptane/toluene (4:1 v/v).
Residual solvent headspace GC-MS, performed per USP ⟨467⟩ Procedure A, must confirm n-heptane < 500 ppm and toluene < 200 ppm. The single largest unknown impurity, often the N-methyl derivative formed when dimethyl sulfate is used as a methylating agent upstream, is capped at < 0.15 area-%. When the ester is destined for GMP intermediate use, the manufacturer adds a dedicated LC-MS screen for genotoxic pyrrole N-oxide byproducts with a reporting threshold of 1 ppm.
In the acid-catalyzed condensation with aromatic aldehydes, the tert-butyl ester confers solubility in dichloromethane while resisting premature decarboxylation. Typical loading: 1.0 equiv of the pyrrole dicarboxylate, 0.5 equiv of benzaldehyde, and 0.1 equiv of trifluoroacetic acid in 0.5 M dichloromethane at 25 °C under nitrogen. After 30 min, the ethyl ester remains intact, whereas the dimethyl analog undergoes 3–5% transesterification with liberated methanol, generating a mixed methyl-ethyl population that complicates downstream crystallizations. The target dipyrromethane precipitates upon addition of n-hexane and is isolated with a 92–96% corrected yield after vacuum drying at 40 °C/10 mbar. Multi-batch campaigns on a 100-L glass-lined reactor have confirmed that the adiabatic temperature rise from the condensation exotherm does not exceed 4 °C when addition is controlled to 0.8 kg·h⁻¹, keeping the bulk below the ethyl ester solvolysis threshold observed in DMF at >45 °C.
Differences from 2,4-diethyl 3,5-dimethyl-1H-pyrrole-2,4-dicarboxylate are most evident during selective deprotection. The diethyl ester requires high-temperature basic hydrolysis (1 M NaOH, reflux, 18 h) that partially decarboxylates the α-free pyrrole position, generating up to 12% monodecarboxylated byproduct. The tert-butyl ethyl mixed ester avoids this because the tert-butyl group is cleaved with trifluoroacetic acid/CH₂Cl₂ (1:1 v/v) at 0 °C in 20 min, leaving the ethyl ester untouched as confirmed by TLC (Rf shift from 0.65 to 0.45 in 30% ethyl acetate/hexane). This allows the synthesis of unsymmetrical porphyrinoids bearing two distinct handles for sequential functionalization.
For BODIPY dye synthesis, the pyrrole is first converted to the corresponding dipyrromethene via acid-mediated condensation, then complexed with BF₃·OEt₂. The ethyl ester remains stable to the Lewis acid, while the tert-butyl group retards aggregation during dye formation because of steric bulk in the meso position. Published photophysical characterization of dyes derived from this mixed ester in toluene yields quantum yields of 0.72–0.85 relative to Rhodamine 6G, with Stokes shifts of 18–22 nm. The processing window narrows at the conversion of the dipyrromethene hydrochloride: addition of N,N-diisopropylethylamine must be performed below 10 °C and the subsequent BF₃ complexation kept at −5 to 0 °C for 2 h. Any excursion above +5 °C triggers tert-butyl ester cleavage by the Lewis acidic boron intermediate, liberating isobutylene and forming a carboxylic acid that quenches the fluorescence quantum yield by 30–40%. Pilot-plant runs on a 20-L jacketed vessel with a Dowtherm J secondary loop reported a 7% batch failure rate when cooling ramp rates exceeded 2 °C·min⁻¹, attributed to localized hot spots near the BF₃·OEt₂ feed dip tube.
| Substrate | Condition A (1 M LiOH, THF/H₂O, 0 °C, 4 h) | Condition B (TFA/CH₂Cl₂ 1:1, 0 °C, 20 min) | Condition C (1 M NaOH, reflux, 18 h) |
|---|---|---|---|
| 2-tert-Butyl 4-ethyl 3,5-dimethyl | Ethyl ester cleaved selectively; tert-butyl remains (>95%) | tert-Butyl group removed quantitatively; ethyl ester intact (>98%) | Both esters cleaved; 15% decarboxylation observed |
| 2,4-Diethyl 3,5-dimethyl | No reaction | No reaction | Full deprotection; 12% monodecarboxylation |
| 2,4-Dimethyl 3,5-dimethyl | No reaction | No reaction | Full deprotection; 8% decarboxylation |
The handling envelope in a production environment demands rigorous moisture exclusion. Exposure of the solid to relative humidity above 60% at 22 °C for 4 h increases the hydrolysis impurity to 0.8%, surpassing the 0.3% specification used for optical applications. Warehousing therefore relies on double vapor-barrier packaging with desiccant sachets containing molecular sieve 13X, and drum liners are specified to have a water vapor transmission rate <0.01 g·m⁻²·day⁻¹ per ASTM F1249-20.
| Parameter | Method | Acceptance Criterion |
|---|---|---|
| Appearance | Visual inspection | Pale yellow crystalline powder |
| Assay (HPLC, area-%) | In-house SOP based on USP ⟨621⟩ | ≥ 99.5% |
| Melting range | DSC, 10 K·min⁻¹, N₂ | 88–92 °C |
| Water content | Karl Fischer coulometry | ≤ 0.10% |
| Residual solvents – n-heptane | GC-HS, USP ⟨467⟩ | ≤ 500 ppm |
| Residual solvents – toluene | GC-HS, USP ⟨467⟩ | ≤ 200 ppm |
| Single unknown impurity | HPLC, 254 nm | ≤ 0.15% |
| Sulfated ash | USP ⟨281⟩ | ≤ 0.05% |
| Heavy metals (as Pb) | USP ⟨231⟩ Method II | ≤ 10 ppm |
| Genotoxic pyrrole N-oxide | LC-MS/MS, LOQ 1 ppm | ≤ 1 ppm |
Users who have replaced the dimethyl ester with this mixed ester in solid-phase porphyrin syntheses report a reduction in coupling cycle time from 6 h to 2.5 h, ascribed to the absence of steric congestion at the reactive α-position while retaining solubility in chlorinated solvents. However, the tert-butyl group decomposes slowly in the presence of catalytic p-toluenesulfonic acid at concentrations above 0.2 M, so direct one-flask porphyrinogen formation with acid catalysis above 0.05 equiv is contraindicated unless the acid is quenched within 15 min.
Incompatibility with amine-based additives requires careful line flushing. Residual triethylamine from a previous campaign, if present at > 0.01% in a shared multi-purpose reactor, accelerates ethyl ester aminolysis at 60 °C within 30 min, producing the corresponding amide impurity that co-elutes with the target ester on silica gel. A documented manufacturing directive therefore separates production of this pyrrole from any operation involving aliphatic amines by a mandatory water/acetone boil-out and a blank run verified by ion chromatography.
The compound crystallizes from n-heptane/toluene mixtures as needles with a median aspect ratio of 8:1 as measured by dynamic image analysis on a Sympatec QICPIC system. Needles with length >150 µm slow filtration on a 0.5-m² Hastelloy Nutsche filter to 120 L·m⁻²·h⁻¹, while the process target is ≥ 200 L·m⁻²·h⁻¹. To maintain productivity, the crystallization protocol specifies a controlled cooling ramp of 0.3 °C·min⁻¹ from 65 °C to 45 °C, followed by a 2-h isothermal hold that narrows the crystal size distribution. Wet cake washing with pre-cooled n-heptane at 5 °C displaces mother liquor without appreciable dissolution (solubility at 5 °C is < 2 mg·mL⁻¹). Drying under vacuum at 40 °C to constant weight completes the isolation. A PATROL™ focused beam reflectance measurement probe installed in the crystallizer correlates chord length count to final filter cake permeability; excursions outside the 100–140 µm mean chord length window automatically divert the batch to a re-dissolution hold tank.
Differences from the di-tert-butyl analog are equally process-relevant: the di-tert-butyl 3,5-dimethylpyrrole-2,4-dicarboxylate crystallizes as dense prisms that filter rapidly but lack the solubility differential needed for selective mono-deprotection. That compound also requires a 15-h crystallization cycle to achieve a 99.5% purity because of a ternary solid-solution formation with a dimedone-derived impurity, whereas the ethyl tert-butyl mixed ester achieves the same purity in a single 6-h cycle.
Published toxicological assessments under OECD Test Guideline 423 classify the compound as Acute Toxicity Category 4 via oral route, with an LD₅₀ exceeding 500 mg·kg⁻¹ in Sprague-Dawley rats. Ames testing per OECD 471 with and without S9 metabolic activation returned negative mutagenicity across strains TA98, TA100, TA1535, and TA1537. For transport, the material is not regulated under UN Model Regulations as a hazardous substance when packaged in non-friable solid form, although a Safety Data Sheet compliant with GHS Rev. 9 must accompany every consignment to document the risk of respiratory sensitization reported in a single guinea pig maximization test.
Storage life is validated at 24 months when held at 2–8 °C in sealed, light-resistant containers, per an ICH Q1A(R2)-based stability protocol. Accelerated testing at 40 °C/75% RH for 6 months showed 0.4% increase in total related substances, primarily the mono-acid hydrolysis product. No statistically significant change in melting point or assay was observed at the 12-month real-time condition. The data package is available to qualified customers under a Confidential Disclosure Agreement.
