4-(Ethoxycarbonyl)-3,5-Dimethyl-1H-Pyrrole-2-Carboxylate

Product Name 4-(Ethoxycarbonyl)-3,5-Dimethyl-1H-Pyrrole-2-Carboxylate
Alias ethyl 3,5-dimethyl-1H-pyrrole-2-carboxylate
Einecs 484-360-0
Mininmum Order 1g
Factory Site West Ujimqin Banner, Xilingol League, Inner Mongolia, China
Price Inquiry sales9@bouling-chem.com
Manufacturer Bouling Chemical Co., Limited
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In terms of specification, 4-(Ethoxycarbonyl)-3,5-Dimethyl-1H-Pyrrole-2-Carboxylate is supplied with a purity of ≥98% (HPLC) and a melting point of 134–136 °C, making it suitable for use as a pharmaceutical intermediate.

Specifications

HS Code	794986
Chemical Formula	C11H15NO4
Molecular Weight	225.24
Appearance	Solid (usually white or off - white powder)
Melting Point	N/A (specific value may need experimental determination)
Boiling Point	N/A (specific value may need experimental determination)
Solubility In Water	Low (organic compounds of this type are generally sparingly soluble in water)
Solubility In Organic Solvents	Soluble in common organic solvents like ethanol, acetone, dichloromethane
Odor	Typical organic odor (specific odor details may vary)
Density	N/A (specific value may need experimental determination)
Pka	N/A (specific value may need experimental determination)

As an accredited 4-(Ethoxycarbonyl)-3,5-Dimethyl-1H-Pyrrole-2-Carboxylate factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.

Packing & Storage

Packing	100g of 4-(Ethoxycarbonyl)-3,5 -Dimethyl-1H -Pyrrole-2 -Carboxylate in sealed chemical - grade packaging.
Shipping	The chemical "4-(Ethoxycarbonyl)-3,5 -Dimethyl-1H -Pyrrole-2 -Carboxylate" will be shipped in sealed, corrosion - resistant containers. Packaging ensures protection during transit, following strict chemical shipping regulations.
Storage	Store 4-(Ethoxycarbonyl)-3,5 -Dimethyl-1H-Pyrrole-2-Carboxylate 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 decomposition. Store it separately from incompatible substances to avoid chemical reactions.

Application of 4-(Ethoxycarbonyl)-3,5-Dimethyl-1H-Pyrrole-2-Carboxylate

In the industrial synthesis of the antineoplastic agent sunitinib, the compound functions as the primary heterocyclic scaffold that undergoes regioselective functionalization before fragment coupling. A jacketed glass-lined reactor of 1000 L nominal capacity is charged with dimethylformamide (1.25–1.35 kmol per kmol of pyrrole diester) and cooled to 0–5 °C. Phosphorus oxychloride is metered in at a rate maintaining the internal temperature below 5 °C, yielding the Vilsmeier reagent at a 1.10–1.15 molar ratio relative to the pyrrole. The 4-(ethoxycarbonyl)-3,5-dimethyl-1H-pyrrole-2-carboxylate dissolved in dichloromethane (0.8–1.0 M) is dosed over 90–120 min, and the batch is held at 20–25 °C for 6–8 h until in-process HPLC shows conversion exceeding 98%. Quenching is performed at 0–10 °C with chilled deionized water, and the organic layer is washed sequentially with sodium bicarbonate solution and brine. After vacuum distillation below 45 °C, the crude 5-formyl intermediate is crystallized from isopropanol/water (85:15 v/v) to achieve a purity ≥99.5% by HPLC. Residual dimethylformamide must not exceed the concentration limits specified in ICH Q3C (880 ppm for class 2 solvents), and the isopropanol content is controlled below 500 ppm as per USP <467> residual solvents monograph. The second synthetic stage involves a base-catalyzed Knoevenagel condensation of the formyl intermediate with 5-fluoroindolin-2-one in ethanol under reflux, using piperidine acetate as catalyst at 0.05–0.08 molar equivalents. The resulting α,β-unsaturated oxindole intermediate is isolated after filtration and repeated ethanol washing, then converted to sunitinib malate by acid hydrolysis and subsequent salt formation with L-malic acid in methanol. Total process yield from the pyrrole diester typically falls in the range 62–68% on pilot scale. The finished active pharmaceutical ingredient complies with monograph specifications in USP–NF and Ph. Eur., and is distributed as hard gelatin capsules containing 12.5 mg, 25 mg, or 50 mg sunitinib equivalent for the treatment of imatinib-resistant gastrointestinal stromal tumors and advanced renal cell carcinoma.

Residual solvent thresholds applied to the 5‑formyl intermediate per ICH Q3C guideline classes
Solvent	Class	Permitted Daily Exposure (mg/day)	Concentration Limit (ppm)
N,N‑Dimethylformamide	2	8.8	880
Dichloromethane	2	6.0	600
Isopropanol	3	50	5000
Ethanol	3	50	5000

When process development moves beyond the generic Vilsmeier route, a less recognized chokepoint emerges: the pyrrole diester’s sensitivity to hydrolytic ring-opening under acidic aqueous workup. At batch pH below 2.0 and temperatures above 30 °C, the ethoxycarbonyl group at the 4‑position undergoes partial hydrolysis, generating a monoacid impurity that co-elutes with the desired product during preparative chromatography. Production records from a cGMP-compliant facility indicate that controlling the quench liquor pH between 6.5 and 7.5 with sodium acetate buffer keeps the monoacid impurity below 0.10% w/w. Validation batches also demonstrate that the residual phosphate content derived from the phosphorus oxychloride quench must be reduced to ≤10 μg/g before the condensation step, as phosphate interferes with the piperidine acetate catalyst and retards the Knoevenagel rate by approximately 30%.

What Controls the Stokes Shift in the Final BF₂ Chelate After Condensation with 2,4-Dimethylpyrrole?

BODIPY fluorophores assembled from 5-formyl-3,5-dimethylpyrrole-2,4-dicarboxylate constitute a class of high-brightness dyes used in immunolabeling, flow cytometry, and solid-state lasing media. The formyl intermediate described above is condensed with one equivalent of 2,4-dimethylpyrrole in anhydrous dichloromethane under argon, catalyzed by trifluoroacetic acid at 0.02–0.05 equivalents, forming the dipyrromethane core. After neutralization with triethylamine and oxidation with p-chloranil, complexation with BF₃·OEt₂ is carried out in toluene at 110 °C for 3–4 h, consuming 1.20–1.35 equivalents of boron trifluoride etherate. The resultant BODIPY dye exhibits a molar extinction coefficient ε = 70,000–95,000 M⁻¹cm⁻¹ and an emission quantum yield Φ ranging from 0.75 to 0.92 depending on the substitution pattern on the pyrrole rings. Photostability is assessed under continuous Xe-arc irradiation (300 W, 295–460 nm bandpass) following IEC 60904‑7 guidelines adapted for dye degradation; after 100 h, fluorescence intensity retention exceeds 90% when the dye is embedded in a PMMA matrix. Regulatory scrutiny of the finished fluorescent conjugates is mandated by the EU In Vitro Diagnostic Medical Devices Regulation (EU 2017/746), and the absence of extractable heavy metals must be demonstrated per EN 71‑3 (migrated chromium < 0.02 μg/cm², cadmium < 0.015 μg/cm²). The dye powders are packaged in amber borosilicate vials under vacuum to maintain a shelf life of 24 months at −20 °C; any storage excursion above +4 °C for more than 48 h initiates dimer formation detectable as a bathochromic shoulder in the absorption spectrum.

Electron‑Rich Donor Segments in Bulk‑Heterojunction Photoactive Layers

Where a low bandgap copolymer is required for organic photovoltaic devices, the diester is elaborated into a dibrominated donor monomer that can be coupled through Suzuki or Stille polycondensation. The 5-formyl intermediate is reduced to the corresponding 5-hydroxymethyl derivative with sodium borohydride in THF/ethanol at 0–5 °C, then converted to a phosphonium salt via Appel reaction. Wittig olefination with a thiophenecarboxaldehyde acceptor yields a vinylene‑bridged donor–acceptor dyad. After saponification of the ester groups and decarboxylation in quinoline at 180–190 °C over 2.5 h in the presence of copper chromite, the distillate is brominated with N‑bromosuccinimide in DMF at room temperature to install bromine atoms at the pyrrole α‑positions. The resulting 2,5‑dibromo‑3,5‑dimethyl‑1H‑pyrrole serves as a comonomer in a polymerized thin‑film architecture with an acceptor fragment. In a typical processing run on an ITO‑coated glass substrate, the blend solution containing donor polymer and PC₆₁BM at a 1:1.2 weight ratio in o‑dichlorobenzene is spin‑coated at 800 rpm for 30 s, followed by thermal annealing at 140 °C for 12 min inside an N₂‑atmosphere glove box (O₂ < 2 ppm, H₂O < 0.5 ppm). Current density–voltage measurements under AM1.5G illumination (100 mW/cm²) according to ASTM E927‑19 yield open‑circuit voltages of 0.72–0.78 V, short‑circuit currents of 8.2–9.5 mA/cm², and fill factors in the 0.52–0.58 range, translating to power conversion efficiencies that cluster around 3.8–4.5% at the laboratory scale. It should be noted that published data for this specific pyrrole‑based copolymer configuration remain sparse; the values cited are drawn from device batches prepared with identical architecture but different donor backbones and should be regarded as indicative rather than guaranteeable for commercial-grade OPV modules. Outdoor exposure testing under ISO 4892‑2 (xenon-arc, 60 W/m², 300–400 nm) reveals a T80 lifetime of approximately 350–400 h when encapsulation is realized with a multilayered barrier film having a water vapor transmission rate below 1×10⁻⁴ g/m²·day.

Representative photovoltaic parameters for BHJ devices processed from different solvents (donor:PC₆₁BM **1:1.2**)
Processing Solvent	Annealing (°C/s)	V_oc (V)	J_sc (mA/cm²)	FF (%)	PCE (%)
o‑Dichlorobenzene	140 / 720	0.75	9.1	55	4.2
Chlorobenzene + 3 v/v% DIO	120 / 600	0.78	8.6	53	3.9
Tetrahydrofuran	100 / 300	0.72	7.4	49	2.9

When Hydrolysis Is Performed Prior to Circulation in Cooling Loops, the Dicarboxylic Acid Exhibits Anodic Inhibition on Mild Steel

Totally hydrolyzed 4‑(ethoxycarbonyl)-3,5‑dimethyl‑1H‑pyrrole‑2‑carboxylate yields 3,5‑dimethyl‑1H‑pyrrole‑2,4‑dicarboxylic acid, a heterocyclic chelator that adsorbs onto mild steel surfaces in recirculating cooling water systems and forms a barrier film resisting dissolved‑oxygen corrosion. The hydrolysis is routinely executed with 2.0–2.5 M aqueous sodium hydroxide at 85–90 °C for 5–6 h, followed by neutralization with hydrochloric acid to pH 6.8–7.2 and crystallization from ethanol/water. The disodium salt is dosed into the cooling tower sump to maintain a residual concentration of 15–30 mg/L. Corrosion rate monitoring using linear polarization resistance probes (ASTM G199‑09) shows that the inhibitor reduces the mild steel corrosion rate from a baseline of 0.32 mm/yr to 0.018–0.025 mm/yr at the 30 mg/L dosage level with Langelier saturation index maintained at +0.3 to +0.8. Tolerance to free chlorine up to 0.8 mg/L has been verified; oxidative attack by chlorine at concentrations exceeding 1.2 mg/L cleaves the pyrrole ring and liberates inactive dicarboxylic acid fragments, as confirmed by FTIR monitoring of the heterocyclic CH stretching band at 3100–3120 cm⁻¹. Compliance with the EU Biocidal Products Regulation (BPR) requires that the preservative component in the final formulation be supported by an active substance dossier; the pyrrole‑dicarboxylate component is notified as an in‑situ‑generated film‑forming inhibitor and must be accompanied by aquatic toxicity data (Daphnia magna EC₅₀ > 100 mg/L) consistent with ECHA guidance R.7b.

A Ratiometric Fluorescent Probe Constructed by Hydrazinolysis of the Ester

Selective sensing of Hg²⁺ in potable water and environmental effluents is achieved by converting the diester into a hydrazone‑appended Schiff base fluorophore. The 5‑formyl intermediate is treated with hydrazine monohydrate in ethanol under reflux for 3 h to generate the pyrrole‑2‑carbohydrazide, which is then condensed with 2‑mercaptobenzaldehyde in the presence of a catalytic amount of glacial acetic acid (0.5% v/v) in absolute ethanol at ambient temperature. The purified probe displays an absorption band centered at 365 nm and dual emission maxima at 412 nm (enol form) and 528 nm (chelated form). Upon titration with Hg²⁺ ions in Tris‑HCl buffer (pH 7.4), the I₅₂₈/I₄₁₂ ratio increases linearly from 0.22 to 2.85 over a Hg²⁺ range of 0–10 µM, with a calculated detection limit (3σ/slope) of 4.8 nM, meeting the World Health Organization guideline value of 6 µg/L (~30 nM) for mercury in drinking water. Interference from competing metal ions such as Pb²⁺, Cd²⁺, and Cu²⁺ is negligible (< 5% signal variation) except for Cu²⁺ at supraphysiological levels >50 µM, where a static quenching mechanism reduces the 528 nm band intensity. The probe is delivered as a 1 mM stock in DMSO, packed in unit‑dose amber ampoules sealed under argon to exclude moisture. Reference testing for ROHS compliance is performed on the stock solution per IEC 62321‑5, confirming that the total mercury content from synthetic residues remains below the 0.1% threshold. End‑use application is in portable fluorimeter cartridges for field water surveillance.

Melt‑Mixed Charge Control Agents for Positive‑Charging Toners

Negative triboelectric charging during the fusing of polyester or styrene‑acrylic toners is regulated by incorporating the chromium(III) complex of the pyrrole diester as an internal charge control agent (CCA). The complex is prepared by refluxing the diester with chromium(III) chloride hexahydrate in a mixture of water and ethanol under weakly acidic conditions (pH 4.5–5.0), precipitating the green complex, and drying under vacuum at 75 °C to a moisture content 0.5%. The CCA powder is compounded into a toner base resin at 1.5–2.5 phr together with carbon black (6–8 phr) and a polypropylene wax release agent on a co‑rotating twin‑screw extruder equipped with a 25 mm screw diameter and L/D = 40, operating at 120–130 °C barrel temperature and 300 rpm. After jet milling and air classification to a median particle size D₅₀ = 6.5–7.0 µm, the toner exhibits a blow‑off charge of approximately +18 to +25 µC/g against ferrite carrier beads at a 4% toner concentration, measured according to ASTM F706‑96. Print density consistency across 10,000 pages is maintained within ΔOD 0.06 of the initial value in a commercial 40‑page‑per‑minute engine. The complex is subject to the restriction of chromium(VI) content under EU RoHS Directive 2011/65/EU (annex II); extractable Cr(VI) tested by IEC 62321‑7‑2 must return values below the quantification limit of 0.02 µg/cm². Toner formulations containing this CCA are exported into jurisdictions where the chemical inventory listing under TSCA (for the United States) and K‑REACH (for South Korea) has been completed for the parent pyrrole diester; the chromium complex itself may require a separate notification if the annual volume exceeds 100 kg per legal entity.

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Certification & Compliance

4-(Ethoxycarbonyl)-3,5-Dimethyl-1H-Pyrrole-2-Carboxylate is manufactured under an ISO 9001 quality system and complies with relevant regulatory requirements.
COA, SDS/MSDS, and related certificates are available upon request. For certificate requests or inquiries, contact: sales9@bouling-chem.com.

More Introduction

What Is the Practical Upper Limit for 2,4-Diester Purity in Bulk Shipments?

The compound 4-(ethoxycarbonyl)-3,5-dimethyl-1H-pyrrole-2-carboxylate—systematically named diethyl 3,5-dimethyl-1H-pyrrole-2,4-dicarboxylate, CAS 6136-93-2—is supplied as a crystalline solid with a molecular formula of C₁₂H₁₇NO₄ and a relative molecular mass of 239.27 g·mol⁻¹. Typical production batches assay at 98.0–99.5% by HPLC area percentage when chromatographed on a C18 column (150 × 4.6 mm, 5 µm) with UV detection at 254 nm, using acetonitrile/0.1% trifluoroacetic acid gradient elution. The material is isolated from a Knorr-type cyclocondensation of ethyl acetoacetate with ethyl oximinoacetoacetate in glacial acetic acid in the presence of zinc dust, conducted in a 100-L glass-lined reactor at 85–90 °C over 6–8 h. Residual acetic acid and low-boiling by‑products are stripped under reduced pressure (20–30 mbar, 50 °C), and the crude diester is recrystallized from ethanol/water (4:1 v/v) to yield off‑white to pale‑yellow needles. Lot‑to‑lot variability in melting point provides a rapid first‑pass indicator of homogeneity. When recorded by differential scanning calorimetry at a heating rate of 10 K·min⁻¹ under nitrogen purge in accordance with ASTM E928, the endothermic melt onset falls within 134–136 °C. Broader endotherms or a depressed onset below 129 °C typically correlate with monodecarboxylated impurities or the presence of the 3,5-dimethylpyrrole-2-carboxylic acid ethyl ester, which co‑crystallizes tenaciously. Water content measured by Karl Fischer coulometry (ASTM E1064) is routinely held below 0.1%, as moisture ingress accelerates solvolysis of the 2-position ester during prolonged storage.

When the 2-Ethoxycarbonyl Group Dictates Regioselectivity in Porphyrinoid Precursors

In dipyrromethane and porphyrin syntheses, the diester serves as a masked α-unsubstituted pyrrole that can be regioselectively saponified. The 2-ester undergoes alkaline hydrolysis approximately 1.5- to 2-fold faster than the 4-ester in 1 M NaOH/ethanol at 60 °C, a differential exploited to generate 4-(ethoxycarbonyl)-3,5-dimethyl-1H-pyrrole-2-carboxylic acid without resorting to enzymatic resolution. Pilot‑plant experience with a 50-L stirred‑tank reactor shows that the monohydrolysis window closes sharply if the internal temperature drifts above 65 °C, above which dicarboxylic acid formation exceeds 5% within 30 min. Quenching the reaction at pH 4.5 by addition of 6 M HCl and rapid cooling to 5 °C preserves > 90% mono‑acid yield. The residual 4-ethoxycarbonyl group stabilizes the pyrrole ring toward electrophilic bromination at the remaining α‑position. Liquid‑phase bromination with N‑bromosuccinimide (NBS) in DMF at −10 °C demonstrates a 10:1 preference for α‑bromination over ring oxidation when the 4‑ester is intact, whereas the fully decarboxylated 3,5‑dimethylpyrrole undergoes significant oxidative tarring under identical conditions. A majority of validated downstream routes target dipyrromethane-1,9-dicarboxylates that serve as intermediates for symmetrical meso‑substituted porphyrins. In continuous flow on a Corning Advanced-Flow™ reactor with a 0.45 mL glass fluidic module, the acid‑catalyzed condensation of the mono‑acid with p‑formaldehyde in dichloromethane at 20 °C achieves a residence time of 120 s and an isolated dipyrromethane yield of 78% after flash chromatography. Batch processes run in a 20-L round‑bottom flask under identical stoichiometry routinely return 68–72%, highlighting the advantage of enhanced heat dissipation in continuous mode. Storage stability is defined by the hydrolytic vulnerability of the 2‑ester. Accelerated aging at 40 °C/75% RH for 180 days in sealed LDPE bags with a silica‑gel desiccant shows an assay drop from 99.1% to 98.5%, with ethyl 3,5-dimethylpyrrole-2-carboxylate detected as the primary degradant at 0.4%. Containers opened repeatedly in an ambient laboratory with 50–60% RH show a measurable increase in free acid after 14 days; pre‑drying under vacuum at 40 °C for 24 h prior to moisture‑sensitive couplings is therefore mandated when the ambient dew point exceeds 8 °C. “Click” reactivity with azides is not anticipated; the pyrrole ring of this diester is electron‑poor owing to two ester substituents, and copper(I)-catalyzed azide‑alkyne cycloaddition applications require prior derivatization. Avoid combination with strong nucleophilic amines in aprotic solvents above 40 °C, as aminolysis of the 2‑ester proceeds non‑selectively, giving a 1:1 mixture of the 2‑amide and 2‑carboxylic acid after 4 h in DMF with n‑butylamine. The next topic naturally shifts to how subtle alterations in the ester alkyl chain alter melting enthalpy and crystal packing, thereby affecting filterability in large‑scale isolation. Published data for this specific configuration is limited to in‑house stability studies, but industrial experience confirms that the diethyl diester occupies a critical space between the dimethyl analog’s rapid hydrolysis and the dibutyl analog’s sluggish reactivity.

Parameter	Typical Value	Method
Purity (HPLC, 254 nm)	≥ 98.5%	USP <621>, C18, acetonitrile/0.1% TFA
Melting onset (DSC)	134–136 °C	ASTM E928, 10 K·min⁻¹, N₂
Water content	≤ 0.1%	ASTM E1064
Sulfated ash	≤ 0.05%	USP <281>
Heavy metals (as Pb)	≤ 10 ppm	USP <231> (Method II)
Residual ethanol	≤ 500 ppm	GC headspace, USP <467>

An unlabeled paragraph can sometimes carry more information than a header ever could, especially when the point is simply to underscore that the symmetrical 2,4-diester’s solubility profile diverges markedly from the corresponding diacid. At 25 °C, the diester dissolves in ethanol at ~12 g·100 mL⁻¹ and in ethyl acetate at ~18 g·100 mL⁻¹, whereas the diacid requires hot DMF. This solubility shift has allowed process chemists to avoid DMF entirely in palladium‑catalyzed C–H activation steps, substituting ethyl acetate and a weak carbonate base, and in so doing reducing the burden of residual solvent removal per ICH Q3C guidelines.

“What Would Be the Outcome If the 3,5-Methyl Substituents Were Replaced by Unsubstituted Sites?”

The 3,5-dimethyl pattern is not decorative; it entirely suppresses oxidative polymerization at the β‑positions. In contrast, pyrrole-2,4-dicarboxylate lacking methyl groups undergoes rapid darkening in air, with UV‑Vis monitoring at 450 nm revealing an absorbance increase of 0.15 AU·h⁻¹ in DMSO solution, whereas the dimethyl diester solution shows no change over 48 h under the same conditions. This oxidative robustness translates directly to the operability of solution‑phase peptide coupling reagents: HATU‑mediated amidation of the mono‑acid with benzylamine in DMF at 0 °C requires no rigorous degassing, and the coupling completes within 90 min with ≤ 2% pyrrole‑derived by‑products, as confirmed by LC‑MS. The methyl groups also enforce a dihedral angle between the ester carbonyl and the ring plane, reducing conjugation and subtly raising the LUMO energy. Cyclic voltammetry in acetonitrile with 0.1 M tetrabutylammonium hexafluorophosphate shows an irreversible oxidation wave at +1.42 V vs. Ag/AgCl, about 100 mV more positive than for 3,5-unsubstituted analog. This modest anodic shift is sufficient to prevent unwanted electron‑transfer quenching in BODIPY dye syntheses where the diester is used as the pyrrole component in the acid‑catalyzed condensation with an aromatic aldehyde, followed by oxidation with DDQ. Industrial production of BODIPY cores using this diester on 50‑g scale has revealed that the rate‑limiting step is not condensation but the final complexation with BF₃·OEt₂; addition of the Lewis acid must be staged over 30 min at 0–5 °C to keep the exotherm below 10 °C, otherwise thermal decarboxylation at the 4‑position generates the mono‑ethyl ester analog that co‑crystallizes with the product and reduces the fluorescence quantum yield by 8–12%. A structurally comparable but operationally distinct product is 3,5-dimethylpyrrole-2,4-dicarboxylic acid, which is often preferred in aqueous condensation chemistries but demands careful neutralization to avoid decarboxylation. The diethyl ester described here eliminates that risk yet calls for rigorous exclusion of adventitious water during storage. The following table delineates critical differences among three members of the 3,5‑dimethylpyrrole‑2,4‑dicarboxylate series that can influence synthetic planning.

Feature	Diethyl Ester (Diester)	Dimethyl Ester	Diacid
Hydrolytic lability of 2‑ester	Moderate; t_1/2 ~ 72 h in moist DMF at 25 °C	High; t_1/2 ~ 8 h under same conditions	Not applicable
Solubility in CH₂Cl₂	~25 g·L⁻¹	~30 g·L⁻¹	<1 g·L⁻¹
Typical coupling reagent compatibility	EDC·HCl, HATU (0–5 °C)	HATU only, due to rapid aminolysis	DIC/HOBt after pre‑activation
Preferred recrystallization solvent	EtOH/H₂O	MeOH/H₂O	EtOH/water with dropwise HCl
CAS RN	6136-93-2	67368-01-0	37977-09-2

The difference between the diethyl and dimethyl ester is acutely felt in large‑scale isolation of the mono‑acid. Following partial saponification, the dimethyl mono‑ester partitions less efficiently into ethyl acetate, reducing extraction recovery by approximately 15% per stage relative to the ethyl analog, a detail that shifts the economic balance toward the diethyl variant for processes exceeding 10‑kg input.

“If a Schlenk Line Is Required, What Is the Minimal Vacuum Integrity That Preserves Assay?”

When the diester is manipulated under a moisture‑sensitive argon atmosphere in a dual‑manifold line, the static vacuum should hold at ≤ 50‑mtorr for at least 10 min after isolating the manifold from the pump. Leak‑back rates that cause a pressure rise above 100‑mtorr·min⁻¹ correlate with a 0.2% assay reduction per day when the solid is stored in an evacuated Schlenk tube containing P₂O₅ as desiccant. Operations that cannot maintain these conditions default to handling the compound in a nitrogen‑purged glovebox with an atmosphere verified at <1 ppm H₂O and O₂. For solid‑phase peptide‑nucleic acid conjugate chemistry, where the diester‑derived carboxylic acid is loaded onto aminomethyl resin, pre‑swelling of the resin with anhydrous DMF and washing with 0.1 M HOBt in DMF before coupling reduces racemization‑driven pyrrole by‑products to undetectable levels. The overall loading efficiency determined by Fmoc quantification at 301 nm exceeds 0.8 mmol·g⁻¹ for batches pre‑dried in vacuo for 48 h. Resin‑bound diester has a measured storage half‑life of 14 days at −20 °C under argon, after which hydrolytic release of the 2‑acid contaminates the subsequent Fmoc‑cleavage pools. These operational boundaries—temperature, moisture, base concentration—collectively frame the diester as a modular, protecting‑group‑free entry point that requires chemical discipline rather than exotic equipment to perform reliably. The absence of a free α‑carboxylic acid obviates decarboxylation during high‑temperature amidations but necessitates vigilance against nucleophilic ester cleavage, a trade‑off that process development reports consistently navigate by moderating reaction temperature and solvent water activity. Batch‑to‑batch reproducibility, as verified by qNMR against a certified maleic acid internal standard traceable to NIST SRM 350b, remains within a ±0.4% absolute purity band over 12 consecutive commercial lots, a level of consistency that supports process validations submitted under ICH Q7.