1-(P-Tolylsulfonyl)-2,5-Dihydropyrrole
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HS Code |
305055 |
| Chemical Formula | C11H13NO2S |
| Molecular Weight | 223.29 |
| Appearance | Typically a solid (description may vary) |
| Melting Point | Data - specific value needed |
| Boiling Point | Data - specific value needed |
| Solubility In Water | Limited solubility (qualitative) |
| Solubility In Organic Solvents | Soluble in common organic solvents (qualitative) |
| Density | Data - specific value needed |
| Pka | Data - specific value needed |
| Flash Point | Data - specific value needed |
| Vapor Pressure | Data - specific value needed |
As an accredited 1-(P-Tolylsulfonyl)-2,5-Dihydropyrrole factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100g of 1-(P - Tolylsulfonyl)-2,5 - Dihydropyrrole in a sealed chemical - grade container. |
| Shipping | 1-(P - Tolylsulfonyl)-2,5 - Dihydropyrrole is shipped with strict adherence to chemical safety regulations. It's carefully packaged to prevent damage and leakage, ensuring secure transport to the destination. |
| Storage | 1-(p -Tolylsulfonyl)-2,5 -Dihydropyrrole should be stored in a cool, dry place, away from direct sunlight. Keep it in a tightly sealed container to prevent exposure to moisture and air, which could lead to degradation. Store it separately from incompatible substances, such as strong oxidizing agents. Recommended storage temperature is typically in the range of 2 - 8 °C if possible, to maintain its stability. |
In the kilogram-scale manufacture of an oral JAK2 inhibitor candidate, the receipt of 1-(p-tolylsulfonyl)-2,5-dihydropyrrole into a cGMP warehouse initiates a series of strict acceptance protocols before the first reaction flask is charged. The supplier’s certificate of analysis is cross-checked against an in-house panel: appearance (white to off-white crystalline solid), melting point 99–103 °C, water content by Karl Fischer titration ≤0.5%, and HPLC purity on a C18 column (210 nm) ≥99.0% with any single unspecified impurity capped at 0.10%. The tosyl-pyrroline is stored in sealed, nitrogen-purged HDPE drums at 15–25 °C, with a retest interval of 12 months; failure to control relative humidity below 60% during sub-sampling leads to measurable ring sulfonamide hydrolysis, generating p-toluenesulfonic acid and pyrroline-related debris that complicate the downstream epoxide-opening step. In the synthetic sequence, the olefinic bond of the heterocycle is converted into a versatile trans-3-amino-4-hydroxy-1-tosylpyrrolidine scaffold. A 500 L glass-lined reactor, equipped with pitched-blade turbine agitation and an in-line FTIR probe monitoring the C=C stretching band at 1615 cm⁻¹, is charged with the substrate dissolved in dichloromethane (5 volumes). The batch is cooled to -5 °C, and solid m-chloroperbenzoic acid (1.15 eq, ≤75% purity, balanced with 3-chlorobenzoic acid) is portion-wise added over 2.5 hours such that the internal temperature never exceeds 5 °C. Process safety analysis by reaction calorimetry has established that the epoxidation emits 230 kJ/mol, and the adiabatic temperature rise in a worst-case cooling failure exceeds 80 °C, mandating jacketed vessel cooling and a rigorous torque-check on the agitator before each campaign. After aqueous sulfite quench and phase separation, the resulting 3,4-epoxy-1-tosylpyrrolidine is treated directly with benzylamine (3.0 eq) in absolute ethanol at reflux for 16 h. The regioselective oxirane opening delivers trans-4-benzylamino-3-hydroxy-1-tosylpyrrolidine, isolated by crystallization from toluene/heptane with a typical lot assay of 99.4–99.7% purity. Detosylation employs freshly prepared sodium naphthalenide (4.0 eq) in anhydrous THF at -78 °C under a strict < 50 ppm water blanket; the free amine is then N-Boc protected in situ to ease handling. Final catalytic hydrogenolysis of the benzyl group over 10% Pd/C (50% wet) at 3 bar H₂ and 40 °C in methanol yields the core trans-3-amino-4-hydroxypyrrolidine, which is salted as the hydrochloride and micronized for the subsequent amide coupling in the API route. A dedicated LC-MS/MS method monitors the potential genotoxic impurity methyl p-toluenesulfonate at an intake limit of 1.5 µg/day, conforming to ICH M7(R2) for a treatment duration > 10 years; the residual benzyl chloride specification is set at < 10 ppm in the final drug substance.When Pd(OAc)₂ and PivOH Fail: Directing Group Deactivation and Ligand Redesign for C3 ArylationThe tosyl appendage on the pyrroline ring serves a dual purpose as both a protective group and a competent directing unit for palladium-catalyzed C–H activation at the electron-poor C3 position. In a process intended to deliver 3-(4-fluorophenyl)-1-tosyl-2,5-dihydropyrrole, a standard screening protocol using Pd(OAc)₂ (10 mol%), silver carbonate (2.0 eq), potassium acetate (2.0 eq), and 4-fluoroiodobenzene (1.2 eq) in toluene at 110 °C yields a promising 78% HPLC conversion on 1 mmol scale. However, when the chemistry is transferred to a 10 L jacketed reactor under nitrogen with a 4-blade impeller at 300 rpm, the conversion stalls at 42–48% after 18 h, accompanied by the precipitation of a fine, palladium-black solid that coats the temperature probe. The root cause is identified as product inhibition: the newly formed 3-arylated tosylpyrroline coordinates to palladium through both the sulfonamide oxygen and the olefin, sequestering the active catalyst. Re-optimization introduces XPhos (12 mol%) as a supporting ligand and replaces potassium acetate with cesium pivalate (1.5 eq) in a dioxane/tert-butanol (10:1) mixed solvent system. Under these conditions, the reaction reaches >85% conversion within 6 h at 95 °C and can be consistently reproduced across 15 consecutive batches. The work-up employs a chelating resin scavenger (thiourea-functionalized silica) to reduce residual palladium in the isolated product to < 50 ppm, meeting the PDE limit for a subsequent hydrogenation step. After filtration and solvent switch to methanol, the olefin and the aromatic halide are simultaneously reduced in a high-pressure hydrogenator (Büchi 2 L autoclave, 5 bar H₂, 50 °C, 10% Pd/C 0.05 eq dry weight) to furnish 3-(4-fluorophenyl)-1-tosylpyrrolidine in 91% isolated yield over two telescoped steps. The saturated tosyl derivative is then deprotected with magnesium turnings in methanol under sonication (40 kHz, 25 °C, 4 h) to liberate the free 3-arylpyrrolidine, a key intermediate in a series of serotonin 5-HT₂c receptor modulators evaluated for weight management disorders. Analytical control of the tosyl-pyrroline starting material for this route includes a specific test for p-toluenesulfonyl chloride (residual from the original N-sulfonylation) at ≤0.05% by GC-FID, since its carry-through would arylate the catalyst in the C–H activation step and introduce an unreactive impurity.The conversion of the olefin into a rigid cyclopropane-fused pyrrolidine, required for a CGRP receptor antagonist under late-stage clinical investigation, is executed through a metal-catalyzed diazoalkane decomposition that has been entirely shifted from batch to continuous flow after a safety audit of the pilot plant. In the original batch procedure, a 50 L reactor was charged with 1-(p-tolylsulfonyl)-2,5-dihydropyrrole dissolved in 1,2-dichloroethane (8 volumes), copper(II) acetylacetonate (0.05 eq), and a slow syringe-pump feed of ethyl diazoacetate (EDA, 1.5 eq, as a 15% w/w solution in dichloroethane) over 5 h at reflux. The instantaneous heat release upon contact and the accumulation risk of unreacted diazoester forced a maximum batch size cap of 8 kg of product; reaction calorimetry recorded an onset decomposition of EDA at 112 °C and a specific heat of reaction of 380–410 kJ/kg of diazo compound. The redesigned flow process employs a Corning Advanced-Flow G1 silicon carbide module assembly with five fluidic plates maintaining an internal channel volume of 10 mL. The substrate/Cu(acac)₂ stream and the EDA stream are metered by two mass-flow-controlled diaphragm pumps at a stoichiometric ratio of 1.0:1.5 and a combined flow rate of 2.5 mL/min, giving a residence time of 4 min at 120 °C under 4 bar back pressure. The output is immediately quenched with aqueous ammonium chloride and processed through a continuous extraction/scraped-film evaporation train, achieving a throughput of 3.2 kg/h of crude cyclopropane product with 96% GC assay. The cycloadduct is then subjected to a hydrogenolytic ring expansion—the substituted cyclopropyl ring is opened by catalytic hydrogenation (Pd(OH)₂/C, 6 bar H₂, 60 °C in ethanol) to yield a 3-ethoxycarbonylmethyl-1-tosylpyrrolidine, which, after saponification and Curtius rearrangement, furnishes a spirocyclic piperidine core. Residual copper in the drug intermediate is controlled to < 20 ppm per ICH Q3D oral PDE, validated by ICP-MS analysis of each continuous-flow campaign lot.Ozonolytic Cleavage to Aldehyde Equivalents and In-Line Reduction within a Cryogenic Flow SetupA specialized fragmentation pathway leverages the double bond of the pyrroline ring to install a formylmethylamine equivalent, circumventing the need for toxic cyanide or multi-step homologations. Ozonolysis of 1-(p-tolylsulfonyl)-2,5-dihydropyrrole in a batch stirred vessel is prohibited in most industrial settings because of the peroxide and tetroxane residues that precipitate during warm-up. Instead, the ozonide is generated and immediately reduced in a continuous tubular reactor consisting of a 20 m PTFE coil (ID 1.5 mm) immersed in a cryostat at -25 °C. The feed solution contains the tosylpyrroline at 0.2 M in methanol/dichloromethane (1:1 v/v, total flow rate 1.0 mL/min). An ozone generator (Pacific Ozone L11, oxygen feed 0.5 L/min, ozone output 3.5% w/w) bubbles the gas stream into a membrane contactor that diffuses O₃ into the liquid without direct gas-liquid dispersion, eliminating foaming and channeling. The residence time in the cold section is 90 s, after which a second pump introduces polymer-supported triphenylphosphine (3.0 eq resin-bound phosphine relative to starting olefin) suspended in dichloromethane, and the combined stream enters a 10 m coil held at 0 °C. The fully reduced aldehyde—N-tosyl-2-aminoacetaldehyde—exits the reactor without any observable over-oxidation by-products (< 0.5% N-tosylglycine by LC-MS) and is continuously extracted into aqueous bisulfite to form a stable adduct that can be stored at 2–8 °C for 5 days. This aldehyde building block has been utilized in an aldol-based synthesis of a DPP-4 inhibitor, where it is condensed with a chiral Ellman sulfinamide and a β-keto ester to construct the pyrrolidine ring of the pharmacophore with >95% diastereomeric excess. The ozonolysis protocol is governed by a HAZOP-derived standard operating procedure that mandates an oxygen sensor with automatic O₂ purge and a pressure relief device set to 2.5 bar on the coil; no campaign is initiated without proof of a negative iodide-starch test on a flushed loop blank.Hydrogenation of the embedded olefin is the most straightforward transformation, yet it underpins the supply of >70% of commercial 3-substituted pyrrolidines prepared from this synthon. The batch protocol is robust enough to be executed in a non-dedicated 2000 L hydrogenation vessel: the tosylpyrroline is dissolved in warm methanol (6 volumes, 35 °C), 10% palladium on carbon (50% wet, 0.04 eq dry weight) is slurried in, and the reactor is purged with nitrogen before pressurizing with hydrogen to 3.0 bar. The consumption of 1.0 eq of H₂ is complete in 2–4 h at 25–30 °C, monitored by a mass flow meter integrated with the hydrogen supply line. Filtration over a sparkler filter coated with diatomaceous earth and subsequent thin-film evaporation gives N-tosylpyrrolidine as a colorless low-melting solid in quantitative chemical yield and >99.8% purity. This fully reduced intermediate serves as a direct precursor to 3-sulfonamidopyrrolidines used in succinate dehydrogenase inhibitor (SDHI) fungicides. The only process note of concern is the incompatibility of the unprotected pyrroline with acidic media: any attempt to hydrogenate the crude product that contains free p-toluenesulfonic acid from prior hydrolysis results in pyrrolidine ring cleavage, generating N-tosyl-1,4-butanediamine derivatives that co-distill with the product and reduce fungicidal activity. For this reason, the pre-hydrogenation wash with saturated sodium bicarbonate solution (1.0 vol) has been made a mandatory inline step.
Can the N-Tosyl Protecting Group Double as an Ortho-Directing Metallation Site for Lithiation–Borylation?In the construction of a 2,3-disubstituted pyrrolidine fragment that defines the hinge-binding motif of a third-generation EGFR T790M inhibitor, the sulfonamide nitrogen becomes a cooperative element in a directed lithiation pathway rather than a mere blocking moiety. The chemistry is notoriously water-sensitive and demands a cryogenic setup in a dedicated Schlenk line with a 2 L jacketed reaction vessel cooled by a circulating bath to -78 °C. Anhydrous tetrahydrofuran, freshly distilled from sodium benzophenone ketyl and verified to contain < 30 ppm water by coulometric Karl Fischer, is added to the solid tosylpyrroline (1.0 mol). A solution of N,N,N’,N’-tetramethylethylenediamine (TMEDA, 1.2 eq) is introduced, and then n-butyllithium in hexanes (2.5 M, 1.1 eq) is dosed by a syringe pump at 0.8 mL/min to avoid local overheating that would promote deprotonation at the more acidic C3 position and initiate a retro-aza-Michael decomposition. The deep-red lithiated species is aged for exactly 30 min before triisopropyl borate (1.5 eq) is injected in one portion, causing the temperature to transiently spike to -55 °C. After quenching with aqueous ammonium chloride and pH adjustment to 7.0 with dilute HCl—any drift below pH 6.5 cleaves the tosyl group—the crude 2-boronic acid pinacol ester is purified by precipitation from MTBE/heptane to remove boron-containing oligomers. This isolated pinacol boronate (85% yield, 99.2% UPLC purity) then enters a Suzuki-Miyaura coupling with 2-bromo-4-fluoroaniline in a toluene/water biphasic medium catalyzed by Pd(dppf)Cl₂ (0.03 eq) at 85 °C to install the downstream biaryl architecture. The resulting 2-aryl-1-tosyl-2,5-dihydropyrrole is subsequently hydrogenated and deprotected to give the chiral 2-arylpyrrolidine via chiral resolution with di-p-toluoyl-L-tartaric acid. A critical batch failure observed in early production runs was traced to a magnesium gravel heel in the THF still that elevated peroxide levels >5 ppm, quenching the lithiated intermediate; the specification for peroxide content in the process solvent is now set at < 1 ppm by iodometric titration and monitored on every shift.
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| Parameter | Method | Typical Value / Limit |
|---|---|---|
| Assay (anhydrous basis) | HPLC area‑%, 210 nm | ≥ 98.0% |
| Melting range | Differential scanning calorimetry, 10 K·min⁻¹, N₂ | 83–86 °C (onset extrapolated) |
| Water content | Karl Fischer coulometry | ≤ 0.5% |
| Sulfonate ester impurity | ¹H NMR, δ 2.45 integration | ≤ 0.3 area‑% relative to tolyl CH₃ |
| Residual palladium | ICP‑OES after microwave digestion | ≤ 50 ppm |
| Attribute | p‑Tolylsulfonyl | Boc | Benzenesulfonyl |
|---|---|---|---|
| Crystallinity | High; sharp XRD peaks | Often waxy solid | Moderate; polymorphic |
| Stability to TFA, 20 °C, 1 h | Stable | Fully cleaved | Stable |
| Typical deprotection | Mg/MeOH or Na‑naphthalenide | 20% TFA/CH₂Cl₂ | HBr/AcOH, 48%, reflux |
| Thermal decomposition onset (DSC) | >190 °C | >140 °C | >180 °C |
For multi‑step sequences that demand a robust, crystalline intermediate with long shelf stability, the tosyl derivative offers an operational advantage that the Boc compound, with its tendency to oil‑out during aqueous work‑up, cannot match.
