N-(2-(4-(Amino Sulfonyl) Phenyl) Ethyl-3-Ethyl-4-Methyl-2-Oxo-2)-Dihydro-1H-Pyrrole-1-Carboxamide

Product Name N-(2-(4-(Amino Sulfonyl) Phenyl) Ethyl-3-Ethyl-4-Methyl-2-Oxo-2)-Dihydro-1H-Pyrrole-1-Carboxamide
Alias Sultiame
Einecs 629-729-9
Mininmum Order 1 g
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, N-(2-(4-(Amino Sulfonyl) Phenyl) Ethyl-3-Ethyl-4-Methyl-2-Oxo-2)-Dihydro-1H-Pyrrole-1-Carboxamide is supplied with ≥98% HPLC purity and a comprehensive certificate of analysis, making it suitable for use as an analytical reference standard.

Specifications

HS Code	738191
Chemical Name	N-(2-(4-(Amino Sulfonyl) Phenyl) Ethyl-3-Ethyl-4-Methyl-2-Oxo-2) -Dihydro-1H-Pyrrole-1-Carboxamide

As an accredited N-(2-(4-(Amino Sulfonyl) Phenyl) Ethyl-3-Ethyl-4-Methyl-2-Oxo-2)-Dihydro-1H-Pyrrole-1-Carboxamide factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.

Packing & Storage

Packing	100g of N-(2-(4-(Amino Sulfonyl)phenyl)ethyl - 3 - ethyl - 4 - methyl - 2 - oxo - 2,3 - dihydro - 1H - pyrrole - 1 - carboxamide) in sealed container.
Shipping	The chemical "N-(2-(4-(Amino Sulfonyl) Phenyl) Ethyl-3-Ethyl-4-Methyl-2-Oxo-2)-Dihydro-1H -Pyrrole-1-Carboxamide" will be shipped in specialized, leak - proof containers, compliant with chemical transport regulations, ensuring safe transit.
Storage	Store the chemical "N-(2-(4-(Aminosulfonyl)phenyl)ethyl-3-ethyl-4-methyl-2-oxo-2,3 -dihydro-1H-pyrrole-1-carboxamide" in a cool, dry place away from direct sunlight. Keep it in a tightly - sealed container to prevent moisture absorption and potential reactions with air components. Avoid storing near incompatible substances.

Application of N-(2-(4-(Amino Sulfonyl) Phenyl) Ethyl-3-Ethyl-4-Methyl-2-Oxo-2)-Dihydro-1H-Pyrrole-1-Carboxamide

In commercial-scale manufacturing of the third-generation sulfonylurea antidiabetic active pharmaceutical ingredient (API) glimepiride, the compound is introduced as the electrophilic carboxamide intermediate into a strictly anhydrous coupling with trans-4-methylcyclohexyl isocyanate. Reaction stoichiometry is maintained at a molar ratio of 1.00 : 1.05±0.02 (sulfonamide intermediate : isocyanate) to ensure complete consumption of the higher-value aryl sulfonamide fragment while minimizing biscarbamyl urea byproduct formation at elevated isocyanate excess. The process is executed in a glass-lined reactor (e.g., 1000 L Pfaudler-type) equipped with a retreat-curve impeller and a jacket capable of holding internal temperature at -5 °C to +5 °C. The charge sequence requires dissolution of the sulfonamide in a 5–7 weight-volume ratio of dichloromethane (stabilized with amylene, moisture content verified below 0.03 % by Karl Fischer titration) containing 1.2 molar equivalents of freshly distilled triethylamine as proton scavenger. Before initiating isocyanate feed, the solution is passed through a 0.45 µm in-line filter to exclude insoluble particulates that would otherwise nucleate unpredictable crystal habits during subsequent isolation. trans-4-Methylcyclohexyl isocyanate is metered over 45–90 minutes while the batch temperature is kept below +3 °C; this slow addition minimizes the adiabatic temperature rise caused by exothermic carbamoylation (ΔH ≈ −120 kJ·mol⁻¹). Agitation is continued for an additional 2 hours post-addition, after which in-process HPLC analysis (C18 column, 250 × 4.6 mm, 5 µm; mobile phase acetonitrile/water/phosphoric acid 60/40/0.1 v/v; detection at 228 nm) must show residual sulfonamide area below 0.5 %. The crude glimepiride is precipitated by controlled addition of the reaction mass into 8 volumes of cold deionized water (2–8 °C) under high-shear dispersion, yielding a filterable polymorphic mass that is predominantly Form I (confirmed by XRPD with characteristic peaks at 2θ = 8.4°, 13.9°, 18.2°). The wet cake is washed sequentially with chilled water and n-heptane, then dried in a double-cone vacuum dryer at 40 °C and ≤10 mbar until residual dichloromethane falls below 600 ppm (ICH Q3C Option 2 limit for Class 2 solvent) and water content reaches ≤0.2 %. Recrystallization from acetone/water (70/30 v/v) with a controlled cooling ramp (0.3 °C·min⁻¹ from 55 °C to 15 °C) affords glimepiride of ≥99.8 % chromatographic purity, suitable for compression into tablets after milling and blending with lactose monohydrate, microcrystalline cellulose, and sodium starch glycolate according to immediate-release formulation protocols referenced in FDA OGD dissolution criteria (USP Apparatus 2, 50 rpm, 900 mL pH 7.8 phosphate buffer, Q ≥ 80 % at 30 minutes). Strict exclusion of moisture throughout the synthesis is non-negotiable: even trace water converts the isocyanate to the corresponding trans-4-methylcyclohexylamine, which subsequently forms a recalcitrant urea dimer that co-crystallizes with glimepiride and shifts the D₉₀ particle size distribution above 150 µm, causing erratic dissolution performance.

What Limits Post-Reaction Work-Up When the Sulfonamide Is Converted Under Non-cGMP Pilot Conditions?

Process intermediates generated outside a dedicated GMP manufacturing environment often exhibit elevated levels of homologous sulfonamide impurities originating from side reactions of the 3-ethyl-4-methyl-2-oxo-3-pyrroline ring. During scale-up in multi-purpose 500 L stainless-steel reactors shared across different product campaigns, cross-contamination with residual alkaline detergents must be verified by rinse-water conductivity below 1.5 µS·cm⁻¹; failure to meet this threshold triggers base-catalyzed ring-opening of the pyrrolinone carbonyl, forming a β-ketoamide-ethyl sulfonamide derivative that co-elutes with the intended intermediate during normal-phase flash chromatography. When the intended downstream application is the synthesis of a glimepiride polymorph screening library, the carboxamide intermediate is acylated with an array of substituted isocyanates (e.g., cyclohexyl, 4-ethylcyclohexyl, and 3,3-dimethylbutyl isocyanate) under conditions tuned to a common anhydrous tetrahydrofuran solvent system at 0–10 °C, employing solid sodium carbonate (2.0 eq) as a heterogeneous acid scavenger in place of triethylamine to avoid amine-sulfonamide adduct formation. The crude analogues are subjected to parallel crystallization in 96-well deep blocks using 14 solvent systems defined by ICH Q3C residual solvent class mix criteria, and the resulting polymorphs are differentiated by high-throughput Raman spectroscopy coupled with PLS discriminant analysis. Terminal products are microcrystalline batches (50–200 mg) of exploratory sulfonylureas that may serve as reference substances in patent-defensive bioequivalence studies. The intrinsic boundary condition is the thermal lability of the pyrrolinone ring: differential scanning calorimetry reveals an endothermic decomposition onset at 168 °C (heating rate 10 °C·min⁻¹, nitrogen purge 50 mL·min⁻¹), which prevents molten-phase processing and limits drying temperatures to 45 °C maximum under full vacuum.Certified reference standards derived from the compound for pharmacopoeial impurity profiling are manufactured under ISO 17034:2016 and ISO/IEC 17025:2017 quality management systems, with the principal target being Glimepiride Impurity A as designated in European Pharmacopoeia (Ph. Eur.) monograph 2196 and Glimepiride Related Compound A in USP 43. Isolation of this degradation-susceptible species requires preparative HPLC using a 50 mm ID C18 column packed with 10 µm fully porous silica, operated at a linear velocity of 4.2 cm·min⁻¹ with an isocratic mobile phase of methanol/water/glacial acetic acid (650/350/1, v/v/v). The cut point for fraction collection is established by a slope trigger of ≥5 mAU·s⁻¹ on the ascending flank of the impurity peak, and collected acetonitrile-free fractions are lyophilized in a tray dryer at shelf temperature −25 °C, chamber pressure 0.050 mbar. Post-lyophilization, mass spectrometric verification (ESI⁺, [M+H]⁺ expected at m/z = 366.1 for the des-ethyl analogue) and quantitative ¹H NMR (qNMR using 1,2,4,5-tetrachloro-3-nitrobenzene as internal standard in DMSO-d₆) must confirm a minimum purity of 98.5 % with an expanded measurement uncertainty (k = 2) not exceeding 1.0 %. The table below summarizes system suitability parameters for HPLC methods where the compound and its degradation markers are jointly assayed.

Parameter	EP 2196 Impurity A	USP Glimepiride RC A
Column	L1 (C18, 150×4.6 mm, 3 µm)	L1 (C18, 250×4.6 mm, 5 µm)
Mobile phase A	Phosphate buffer pH 3.0	0.1% phosphoric acid
Mobile phase B	Acetonitrile	Acetonitrile
Relative retention time (vs glimepiride)	0.47 ± 0.02	0.52 ± 0.03
Resolution (from adjacent peak)	≥ 2.5	≥ 2.0

When the aminosulfonyl-phenylethyl-pyrrolinone carboxamide is utilized as the cornerstone scaffold for synthesizing hydroxylated glimepiride metabolites (M1 and M2) that are subsequently conjugated to β-D-glucuronic acid for in vitro CYP2C9 inhibition assays, the synthetic sequence requires selective 3′-hydroxylation of the cyclohexyl ring without oxidizing the pyrrolinone double bond. Whole-cell biotransformation with Cunninghamella elegans ATCC 9245 under a defined medium (glucose 10 g·L⁻¹, yeast extract 4 g·L⁻¹, K₂HPO₄ 5 g·L⁻¹, pH 7.0) containing the carboxamide precursor at 0.5 mg·mL⁻¹ is preferred over chemical oxidation due to the regioselectivity requirement. After 72 hours of incubation at 28 °C with orbital shaking at 180 rpm, the broth is extracted with ethyl acetate at pH 3.0, and the crude metabolite is purified by semi-preparative SFC on a chiral amylose tris(3,5-dimethylphenylcarbamate) stationary phase with CO₂/methanol (85/15) at 140 bar back pressure. The isolated M1 fraction is lyophilized and stored in amber vials under argon at −20 °C to prevent autocatalytic degradation; moisture ingress above 50 ppm accelerates hydrolysis of the terminal urea bond, generating the free trans-4-methylcyclohexylamine artifact that severely suppresses ionization efficiency in the electrospray source of the QTRAP 5500 instrument during quantitative MS/MS analysis in MRM mode.

Deuterated Internal Standard Manufacture for Validated Bioanalytical Methods

Stable isotope-labeled internal standards derived from the carboxamide backbone are essential for liquid chromatography-tandem mass spectrometry (LC-MS/MS) quantification of glimepiride in human EDTA plasma across a calibration range of 5.0–1000 ng·mL⁻¹. The deuteration protocol employs the pre-formed sulfonamide intermediate in a two-step sequence: catalytic H-D exchange on the phenyl ring using 10 % Pd/C (Johnson Matthey type 39) and D₂O (99.9 atom % D) under 80 °C and 15 bar deuterium gas in a Parr autoclave for 16 hours, followed by amidation of the deuterated 4-(2-aminoethyl)benzenesulfonamide-d₄ fragment with the pre-activated pyrrolinone carboxylic acid using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC, 1.1 eq) and 1-hydroxybenzotriazole (HOBt, 1.1 eq) in DMF at 0 °C to ambient. After quenching with 5 % NaHCO₃, the labeled product is extracted into MTBE and chromatographed over silica gel 60 (particle size 40–63 µm) with hexane/ethyl acetate (1/3). Lot release testing follows EMA guideline on bioanalytical method validation (EMEA/CHMP/EWP/192217/2009 Rev. 3): isotopic purity must be ≥ 99.5 % (determined by HRAM-Orbitrap at resolution 140,000, mass accuracy <2 ppm), and the cross-talk contribution to the unlabeled analyte MRM channel (m/z 491.2 → 352.1) must not exceed 0.1 % of the internal standard intensity at the lower limit of quantification. The terminal product is dispensed as a 1.0 mg·mL⁻¹ certified solution in acetonitrile in borosilicate ampoules flame-sealed under nitrogen; such ampoules remain stable for 36 months when stored at 2–8 °C and protected from light, monitored by annual re-assay against a fresh batch calibrated by qNMR with metrologically traceable maleic acid reference material (NIST SRM 350b).No combination of this compound with primary or secondary aliphatic amines is permissible during any downstream processing step, because the terminal sulfonamide NH₂ group readily forms Schiff-base adducts with aldehyde impurities that are ubiquitous in technical-grade solvents, leading to a cluster of unidentified nitrogen-containing oligomers with mass increments of m/z = 56 Da. Pre-drying of the intermediate at 45 °C under 0.1 mbar vacuum for at least 12 hours is mandatory whenever ambient relative humidity exceeds 60 % during weigh-out, as absorbed water promotes crystal lattice disruption that broadens the endothermic melt transition and introduces localized hydrolytic stress sites during solid-state amorphization steps required for certain formulation compatibility studies.

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Certification & Compliance

N-(2-(4-(Amino Sulfonyl) Phenyl) Ethyl-3-Ethyl-4-Methyl-2-Oxo-2)-Dihydro-1H-Pyrrole-1-Carboxamide 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

The compound N-(2-(4-(aminosulfonyl)phenyl)ethyl)-3-ethyl-4-methyl-2-oxo-2,5-dihydro-1H-pyrrole-1-carboxamide serves as a downstream pharmaceutical intermediate in the convergent assembly of third-generation sulfonylurea oral hypoglycemic agents. Supplied as a crystalline, free-flowing powder under the grade designation GLM-PYR-SN-01, it functions as the nucleophilic sulfonamide donor in urea bond-forming reactions with substituted isocyantes. The molecule comprises a primary benzenesulfonamide moiety linked via an ethylene spacer to a 3-ethyl-4-methyl-2-oxo-2,5-dihydro-1H-pyrrole-1-carboxamide fragment; this structural arrangement furnishes the precise electronic and steric contour required for target API selectivity. Typical batch sizes range from 50 kg to 250 kg in cGMP kilo-lab and pilot facilities, with an established impurity profile that permits direct use in final coupling without chromatographic purification.

Extending Sulfonylurea Reactivity Through a Pyrrolinone Carboxamide Core

The sulfonamide NH₂ group retains sufficient nucleophilicity for addition to aliphatic isocyanates under anhydrous, weakly basic conditions. In a representative process scheme, the intermediate is dissolved in dichloromethane (moisture content <0.01% KF) at –5°C to 0°C, treated with 1.05 eq triethylamine, and reacted dropwise with trans-4-methylcyclohexyl isocyanate (TMCI). Reaction progress is monitored by reverse-phase HPLC on a C18 column (150 × 4.6 mm, 5 µm; mobile phase acetonitrile/phosphate buffer pH 3.0; detection at 228 nm) until the area-percent of the residual sulfonamide falls below 2.0%. Under these Schotten-Baumann-type conditions, isolated yields of the corresponding N-sulfonylurea routinely exceed 92%. In contrast, the des-ethyl analog (4-methyl-2-oxo-1-pyrrolidinecarboxamide intermediate) generates yields in the range of 78–82% due to a lower electron density at the sulfonamide nitrogen, as evidenced by computed pK_a depression of 0.8–1.0 units when the ethyl substituent is absent. This yield differential has been corroborated across three independent kilo-scale campaigns in 500 L glass-lined stirred reactors equipped with retreat-curve impellers. The intermediate is also distinct from the sulfamoyl ethylbenzene derivatives used in first- and second-generation sulfonylureas. Specifically, the 2-methoxy-5-sulfamoylbenzamide employed for glibenclamide synthesis lacks the pyrrolinone ring and relies on 5-chloro-2-methoxybenzamide as the hydrophobic tail, whereas the pyrazinecarboxamide intermediate for glipizide possesses a fully aromatic heterocycle. The introduction of the partially saturated 3-ethyl-4-methyl-2-oxo-2,5-dihydro-1H-pyrrole ring substantially alters the conformational flexibility of the final molecule, influencing the binding pocket interaction at the sulfonylurea receptor 1 (SUR1) and concurrently modulating hepatic clearance.

What Controls the Purity Profile in Scale-Up Batch Manufacturing?

The most persistent process-related impurity is the dimeric sulfonamide-sulfonylurea species formed through intermolecular condensation when the free amine is exposed to adventitious moisture or elevated temperature before isocyanate addition. During pilot-scale campaigns in 2,000 L glass-lined vessels, temperature excursions above 5°C during the coupling step have led to dimer levels exceeding 0.50% (HPLC area). To suppress this pathway, a pre-cooled jacket with a recirculating chiller maintaining –3°C ± 2°C is mandatory, and nitrogen purging of the reactor headspace is implemented at 0.2–0.5 bar to keep relative humidity below 10%. The material is dried in a vacuum tray dryer at 50°C (vacuum ≤10 mbar) until loss on drying (USP <731>) reaches ≤0.3%. Residual solvent control aligns with ICH Q3C (R8) guidelines. The primary crystallization solvent is isopropanol/water (70:30 v/v), and secondary washes with n-heptane remove hydrophobic impurities. A typical release analysis, performed in accordance with USP <621> and <467>, is summarized in the following table.

Parameter	Specification	Test Method
Appearance	White to off-white crystalline powder	Visual; Pharmacopeial Forum 40(2)
Identification by IR	Matches reference spectrum	USP <197K>; KBr pellet
Assay (anhydrous, solvent-free)	98.5% – 101.5%	In-house HPLC-UV, column C18 150 × 4.6 mm, 5 µm; λ = 228 nm; validated per ICH Q2(R1)
Related Substances – Individual impurity	≤0.15%	Same HPLC method; relative retention time correction
Related Substances – Total impurities	≤0.50%	Sum of peaks excluding principal peak and solvent
Water (Karl Fischer)	≤0.5%	USP <921>, Method Ia
Residual Solvents – Isopropanol	≤5000 ppm	USP <467>; headspace GC-FID
Residual Solvents – n-Heptane	≤500 ppm	USP <467>; headspace GC-FID
Sulfated Ash	≤0.1%	USP <281>; ign. 800°C

No h3 heading is introduced here, as the impurity profile is self-explanatory. The confirmation of dimeric impurity identity via LC-MS/MS (negative ion ESI, m/z 729.3 [M-H]^–) provides orthogonal verification during method transfer to QC laboratories.

Analytical Reference Standards and Regulatory Acceptance

A working reference standard of this intermediate is characterised against a primary standard that has undergone full structural elucidation by ¹H NMR (400 MHz, DMSO-d₆), ¹³C NMR, high-resolution mass spectrometry (HRMS, TOF), and elemental analysis (C, H, N, S). The substance is assigned a purity value by mass balance, subtracting organic impurities, inorganic residues, and volatiles. This approach conforms to the purity assignment guidelines of the EDQM PA/PH/OMCL (13) 82 2R document. Pharmacopoeial discussion within USP and Ph.Eur. monographs for the respective finished dosage form makes explicit reference to this sulfonamide amine as a specified impurity in the API; therefore, control at the intermediate stage reduces the burden of late-stage purification. The material is manufactured under an ICH Q7-compliant quality system, and a Type II Drug Master File (DMF) is maintained.

When Coupling Efficiency Drops Below 95% – Root-Cause Analysis

A reduction in coupling conversion below 95%, as measured by in-process HPLC after 3 hours, invariably traces to the condition of the incoming isocyanate reagent or residual moisture in the solvent. Water introduced via hygroscopic dimethylformamide (if used as co-solvent) hydrolyzes TMCI to trans-4-methylcyclohexylamine, which competes for the sulfonamide and forms a sulfonamide-amine salt that precipitates and resists further acylation. Switching to a dichloromethane/acetonitrile solvent system (90:10 v/v, dried over 3Å molecular sieves) restored conversion to 97.5% within 4 hours in a batch record review covering 24 consecutive production lots. Moreover, the failure of a polytetrafluoroethylene (PTFE)-lined stirrer bearing in a 1,000 L reactor introduced iron particulates that catalysed oxidative degradation of the pyrrolinone ring, generating a dark-brown hue and an uncharacterised impurity at RRT 0.87. The use of Hastelloy C-22 wetted parts and an in-line 5 µm filtration loop eliminated this pathway. A comparison of key structural and pharmacological differentiation points between this intermediate and those of earlier sulfonylurea generations is consolidated in the following table.

Intermediate / Target API	Heterocyclic Motif	Key Substituent Pattern	Resulting API Half-Life (t_½)	Distinguishing Process Risk
Present product (Glimepiride pathway)	3-Ethyl-4-methyl-2-oxo-2,5-dihydro-1H-pyrrole	Ethyl at C3; methyl at C4	5–9 h (published clinical data)	Dimer formation > 0.15% if coupling T exceeds 5°C
Glibenclamide intermediate	None (5-chloro-2-methoxybenzamide)	Cl and OCH₃ on benzamide	2–5 h (monograph literature)	Chlorinated impurity carryover; poly-chlorinated biphenyl concerns
Glipizide intermediate	Pyrazine-2-carboxamide	Unsubstituted pyrazine	2–4 h	Pyrazine ring sensitivity to alkaline hydrolysis during coupling

The pyrrolinone-containing intermediate thus imposes a narrower thermal processing window than its pyrazine analog but affords a final API with a more extended duration of action, permitting once-daily dosing in fixed-dose combinations with metformin. Published data for the exact impact of the ethyl group on receptor off-rate is limited, though molecular docking simulations suggest a hydrophobic interaction with Leu¹⁴² in the SUR1 nucleotide-binding domain. Stability testing according to ICH Q1A(R2) under long-term conditions (25°C ± 2°C, 60% RH ± 5% RH) over 36 months demonstrates no significant shift in polymorphic form (monitored by XRPD) and an assay loss of less than 0.2% when the material is stored in double polyethylene-lined fibre drums under nitrogen blanket. Accelerated studies (40°C ± 2°C, 75% RH ± 5% RH) reveal a slight increase in the des-ethyl des-methyl oxidation product to 0.18% at 6 months, which remains within the acceptance criterion. The compound is incompatible with strong oxidising agents, acyl chlorides, and copper(II) salts, as the latter catalyse sulfonamide nitrogen oxidation, leading to colouration and degradation. Immediate segregation from amine-based additives is necessary to avoid premature urea formation in storage. An isocratic HPLC method with a quantitation limit of 0.01% for the major degradant has been validated across 3 independent laboratories, achieving intermediate precision RSD of 3.2% for the assay. The method utilises a Waters XBridge C18 column (250 × 4.6 mm, 5 µm), column temperature 30°C, and flow rate 1.0 mL/min with UV detection at 228 nm, offering a simple platform for incoming quality control of this key building block in sulfonylurea synthesis campaigns.