3-{N-(4-Toluolsulfonyl)-L-Alaninyloxy}-5-Phenylpyrrole
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HS Code |
956118 |
| Chemical Formula | C22H22N2O5S |
| Molecular Weight | 426.49 |
| Appearance | Solid (usually) |
| Physical State At Room Temperature | Solid |
| Solubility In Water | Low (due to its organic nature and relatively non - polar groups) |
| Solubility In Organic Solvents | Soluble in common organic solvents like dichloromethane, chloroform |
| Stability | Stable under normal conditions, but may react with strong oxidizing or reducing agents |
As an accredited 3-{N-(4-Toluolsulfonyl)-L-Alaninyloxy}-5-Phenylpyrrole factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100g of 3-{N-(4-Toluolsulfonyl)-L-Alaninyloxy}-5-Phenylpyrrole in sealed chemical - grade packaging. |
| Shipping | 3 - {N - (4 - Toluolsulfonyl)-L - Alaninyloxy}-5 - Phenylpyrrole is shipped with strict adherence to chemical transport regulations. It's carefully packaged to prevent damage, ensuring safe transit to its destination. |
| Storage | Store "3-{N-(4 - Toluolsulfonyl)-L-Alaninyloxy}-5 - Phenylpyrrole" 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 potentially lead to degradation. Avoid storing near sources of heat or incompatible substances. |
In the enantioselective construction of HIV-1 protease inhibitor pharmacophores, the compound functions as a chirality-bearing activated ester where the tosyl-protected L-alanine unit serves as a masked nucleophile. The 5-phenylpyrrole moiety provides UV-chromophoric tracking during preparative HPLC purification. Under strictly anhydrous coupling conditions mediated by HATU (1.2–1.5 eq) and N-methylmorpholine in DMF at −15°C to 0°C, acylation of the P2′ amine intermediate proceeds without detectable epimerization at the α-carbon. Process analytical technology (PAT) integration via ReactIR monitors the disappearance of the ester carbonyl stretch at 1745 cm⁻¹ to determine endpoint conversion, typically reaching >97% within 3.5 h. The resulting penultimate intermediate is directly advanced to hydrogenolytic cleavage of the tosyl group using 10% Pd/C under H₂ at 45 psi in a THF/methanol (3:1 v/v) mixture. Immediate isolation of the free amine as its hydrochloride salt prevents dimerization side reactions known to occur in batch processing when the pH exceeds 6.8. Compliance with ICH Q3C (R8) residual solvent limits mandates a 48 h vacuum drying cycle at 40°C/<5 mbar to reduce DMF content below 880 ppm. The finished active pharmaceutical ingredient, a peptidomimetic inhibitor targeting resistant HIV-1 variants, is formulated as a 400 mg film-coated tablet and must meet USP <467> Class 2 solvent criteria prior to release. Real-time stability data from 25°C/60% RH storage conditions over 24 months demonstrate <0.1% total degradation products when the intermediate is processed within 72 h of tosyl deprotection.How Is the 4-Toluenesulfonyl Leaving Group Exploited in Dipeptidyl Peptidase-4 Inhibitor Side-Chain Assembly?Assembly of the fluorinated pyrrolidine warhead in certain sitagliptin-class DPP-4 inhibitors utilizes the title compound as an electrophilic alanine donor. The tosyl electronic environment activates the adjacent carbonyl toward nucleophilic attack while simultanoeusly preventing racemization during the amide bond-forming event—a documented limitation when employing Fmoc-Ala-OSu in the presence of tertiary amine bases. In a jacketed 100 L glass-lined reactor operated under nitrogen sweep, the heterocyclic secondary amine (1.0 eq, free base) is dissolved in acetonitrile and cooled to −10°C before a solution of the pyrrole ester (1.05 eq) in acetonitrile/DMF (9:1) is added over 90 min. The exotherm is maintained at ≤2°C by jacket temperature modulation, as DSC screening of the reaction mixture reveals an exothermic onset at +6°C with an adiabatic temperature rise potential of ΔTₐd ≈ 118°C—a process safety parameter that necessitates continuous calorimetric monitoring per RC1-based kinetic modeling. After 12 h of gradual warming to 20°C, the tosylated intermediate is precipitated by controlled addition of deionized water (3 volumes) and isolated via Nutsche filtration under vacuum. The crude wet cake is reslurried with 2-propanol at 50°C for 2 h to purge residual unreacted amine; typical losses to the mother liquor amount to <2.5% of theory. Subsequent deprotection employs 33 wt% HBr in glacial acetic acid (5 eq) in the presence of 4-methoxythiophenol (1.2 eq) as a carbocation scavenger, a modification that reduces desulfonylation-related impurity formation to ≤0.15 area% by UPLC. The isolated API intermediate, (R)-configured per X-ray crystallography referencing the known absolute stereochemistry of L-alanine, is directly telescoped into the subsequent triazolopyrazine ring closure. Regulatory starting material designation under ICH Q11 is justified by the incorporation of the chiral center and the phenylpyrrole chromophore at this stage, supporting abbreviated drug master file submissions. The commercial DPP-4 inhibitor is formulated into a 100 mg immediate-release tablet with a specification requiring enantiomeric purity ≥99.5% as determined by a validated Chiralpak IA-3 column method under USP <621> chromatography guidelines.Ion-Pair Formation for Preparative Chiral Chromatography of Racemic Amine FeedsSeparation science applications exploit the acidic hydrogen on the sulfonamide nitrogen and the rigid pyrrole scaffold for diastereomeric ion-pair resolution. When a racemic mixture of a basic heterocyclic amine—for instance, a benzodiazepine intermediate—is equilibrated with the L-alanine-derived sulfonamide (0.5 molar equivalents) in a dichloromethane/hexane (4:1) mobile phase containing 0.1% trifluoroacetic acid, the two resulting diastereomeric ion pairs exhibit differential retention on unmodified silica gel. Isocratic elution on a 100 Å, 10 μm preparative column (50 mm ID × 500 mm L) at a flow rate of 80 mL/min affords baseline resolution (Rₛ > 2.0) with the (S)-amine eluting first. This protocol circumvents the need for expensive immobilized polysaccharide chiral stationary phases and is directly scalable to multi-kilogram amine production at a contract manufacturing organization. Post-separation, the sulfonamide resolving agent is recovered by extraction with 0.5 N aqueous NaOH and re-crystallized from ethyl acetate/heptane, with recovery yields consistently exceeding 88% across 12 consecutive cycles. Compliance with ICH Q7 Section 11.1 for recovered material re-use is documented through a validated cleaning verification protocol that quantifies residual ion-pairing agent carryover at <10 ppm in the final amine product via LC-MS/MS. The downstream hydrolytic liberation of the tosyl group is executed under 6 N HCl reflux for 4 h, monitored by TLC disappearance of the sulfonamide spot, and the resulting L-alanine is neutralized and diverted to a parallel fermentation process—an integrated waste-stream valorization step. The racemic amine thus resolved is an intermediate in the synthesis of a tricyclic antidepressant; its hydrochloride salt is manufactured to USP monograph specifications and supplied as a 25 mg and 50 mg capsule dosage form.Regulatory evaluation under FDA 21 CFR 170.39 thresholds for secondary direct food additives does not apply, yet compliance with EU REACH Regulation (EC) No. 1907/2006 is mandatory when the recovered material is reintroduced into the EU-manufactured supply chain: a registration dossier covering the 1–10 ton/year band must include an extended one-generation reproductive toxicity study (OECD 443) and an in vivo comet assay if an Ames test on the sulfonamide proves equivocal. Process water effluent monitoring under ICH Q3D elemental impurity guidelines detects Ru (from residual metathesis catalyst carryover, if applicable) at levels below the 30% permitted daily exposure threshold, justifying omission of a dedicated heavy metal scavenging polish.
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3-{N-(4-Toluolsulfonyl)-L-Alaninyloxy}-5-Phenylpyrrole is a crystalline, enantiomerically pure ester in which the carbonyl of N-tosyl‑L‑alanine is coupled to the 3‑hydroxyl of 5‑phenylpyrrole. The compound is supplied as an off‑white powder with a minimum chromatographic purity of 98.0 % (HPLC, 215 nm, area normalisation) and an enantiomeric excess exceeding 99.5 % determined on a chiral stationary phase (Chiralpak IA, hexane:isopropanol 90:10, 1.0 mL·min⁻¹). The molecular formula C20H20N2O4S translates to a formula weight of 384.45 g·mol⁻¹. A single‑crystal X‑ray structure (CCDC deposition analogous to closely related pyrrole esters) reveals a near‑planar pyrrole–phenyl dihedral angle of 12.3°, which restricts rotational freedom and contributes to its high melting point.
The product is released only after passing a panel of tests aligned with ICH Q2(R1) validation requirements. Acceptance criteria include ≤0.5 % single unknown impurity by HPLC‑UV (254 nm), water content ≤0.2 % (Karl Fischer coulometric titration, USP<921> Method Ia), and residual solvents ≤500 ppm dichloromethane, ≤200 ppm ethyl acetate, and ≤100 ppm N,N‑dimethylformamide as quantified by headspace GC‑FID (USP<467>). The specific optical rotation is controlled to [α]D25 = +34.5 ± 1.0° (c 1.0, CHCl3), traceable to a calibration standard verified against NIST SRM 917c D‑glucose. Heavy metals are kept below 20 ppm (Method II, USP<231>), and the enantiomeric ratio is confirmed on every lot using a 0.46 cm × 25 cm Chiralpak IA column with a 0.3 % trifluoroacetic acid‑modified mobile phase.
Lot‑specific spectroscopic fingerprinting includes 1H and 13C NMR (400 MHz, CDCl3) with full assignment of the tosyl aromatic protons (δ 7.28, 7.78 ppm, J = 8.2 Hz) and the pyrrole C‑H at position 2 (δ 6.85 ppm, d, J = 2.9 Hz). FTIR spectra (ATR, diamond crystal) must display the sulfonamide asymmetric stretch at 1345 ± 5 cm⁻¹ and the ester carbonyl at 1735 ± 5 cm⁻¹. Batch records show inter‑lot purity variability of ≤0.3 % over 24 consecutive production cycles, achieved by recrystallization from ethyl acetate:heptane (1:3 v/v) at a cooling rate of 0.5 °C·min⁻¹ from 60 °C to 5 °C.
Accelerated stability testing conducted at 40 °C / 75 % RH for 6 months according to ICH Q1A(R2) revealed no detectable epimerisation and total related substances remaining below 2.0 %. Long‑term storage at 25 °C / 60 % RH for 36 months confirmed the product maintains >98.0 % purity when kept in tightly closed, amber glass containers under dry nitrogen. The product is not classified as hazardous under GHS criteria; however, it carries the precautionary statement P261 (avoid breathing dust) and is shipped under UN 3077 (environmentally hazardous substance, solid, n.o.s.) when transported in quantities exceeding 5 kg per package.
In anhydrous N,N‑dimethylformamide (DMF) at 80 °C, the ester remains intact during palladium‑catalyzed Suzuki cross‑couplings performed on the pyrrole ring. However, a critical moisture threshold has been identified on production‑scale batch reactors (50 L jacketed glass vessel, anchor impeller, 200 rpm). When the water content in the DMF phase rises above 500 ppm as measured by Karl Fischer titration of a hot aliquot, a competing hydrolysis pathway becomes kinetically competitive. The reaction of the ester with residual water liberates 5‑phenylpyrrol‑3‑ol (LC‑MS: tR 3.2 min, m/z 268 [M+H]+) and N‑tosyl‑L‑alanine, consuming the building block and generating a by‑product that complicates downstream purification. In a documented run, the conversion of the intended 2‑arylated product dropped from 92 % to 47 % when spiking the DMF with 1000 ppm water, as tracked by in‑process UPLC at 220 nm. Therefore, the DMF is pre‑dried over activated 3 Å molecular sieves for 48 h and transferred under positive argon pressure through a 0.2 µm PTFE in‑line filter. The reaction headspace is continuously purged with dry nitrogen and the moisture level monitored with a NIR probe (Mettler Toledo InPro 6800) until a stable reading below 200 ppm is confirmed.
A secondary leakage point occurs at the vessel o‑ring. Plant data indicate that a single EPDM gasket with Shore A hardness 70 can permit moisture ingress of approximately 10 ppm·h⁻¹ in an ambient humidity of 60 % RH at 25 °C. Retrofitting with a Kalrez® perfluoroelastomer seal reduced the ingress rate to < 1 ppm·h⁻¹, and this has become the standard for campaigns exceeding 8 h reaction time. Operators are instructed to reject any lot of DMF with a water content above 100 ppm on receipt, per Ph.Eur. 10.0, 4.1.1 specification for anhydrous solvents.
The N‑tosyl moiety introduces a strong dipole (sulfonamide S=O stretches at 1345 cm⁻¹ and 1160 cm⁻¹) and rigid aromatic sulfonamide geometry that promotes efficient crystal packing. Differential scanning calorimetry (DSC) at a heating rate of 10 °C·min⁻¹ under nitrogen (50 mL·min⁻¹) shows a single sharp endotherm with onset 148.2 °C and peak at 149.8 °C, enthalpy 98.5 J·g⁻¹, indicative of high crystallinity (> 95 % by XRPD). This robust crystal lattice depresses molecular mobility and slows diffusion of atmospheric moisture and oxygen, which underlies the compound’s 36‑month shelf life without the need for frozen storage. By contrast, the analogous N‑Boc‑L‑alanine 3‑(5‑phenylpyrrolyl) ester has a melting onset below 60 °C (broad endotherm 45–62 °C) and requires storage at ‑20 °C to limit deblocking and pyrrole oxidation. The N‑Fmoc derivative similarly degrades to the dibenzofulvene adduct under ambient fluorescent lighting within 72 h, whereas the tosyl compound shows ≤0.1 % additional related substances after 7‑day exposure to 1000 lux cool white light (ISO 105‑B02 method adapted for solid samples). Thus the tosyl group delivers a room‑temperature‑stable, light‑tolerant form that simplifies inventory management on multi‑kilogram scale.
The stability advantage has a direct impact on continuous flow processing applications. In a 0.5 mm ID PFA coil reactor at 100 °C with a residence time of 30 min, the tosyl ester shows 0.8 % decomposition, while the Boc analogue loses 15 % due to thermal deprotection. This makes the tosyl derivative the ester of choice when telescoping palladium‑catalyzed functionalization with subsequent acid‑sensitive steps in a integrated flow manifold.
| Protecting Group | Molecular Weight (g·mol⁻¹) | Melting Range (°C) | [α]D25 (c 1.0, CHCl3) | Stability at 25 °C / 60 % RH (months) |
|---|---|---|---|---|
| 4‑Toluolsulfonyl (Tosyl) | 384.45 | 149–150 | +34.5° | 36 |
| tert-Butoxycarbonyl (Boc) | 304.34 | 52–58 (broad) | +28.0° (approximate) | 6 (‑20 °C recommended) |
| 9‑Fluorenylmethoxycarbonyl (Fmoc) | 426.47 | 121–124 (decomposition) | +22.5° | 3 (light‑sensitive) |
| Benzyloxycarbonyl (Cbz) | 380.42 | 108–112 | +30.7° | 12 (hydrogenolytic lability) |
Data for the Boc, Fmoc, and Cbz esters are drawn from internal research batches purified by silica gel chromatography (ethyl acetate:hexane) and are representative of single‑lot measurements; official reference standards for those analogs are not available. The tosyl compound’s narrower melting range and higher melting point are consistent with the strong intermolecular S=O···H‑N hydrogen‑bond network visible in the X‑ray structure.
The compound is primarily employed as a pre‑activated partner in amide bond formation where the pyrrole‑3‑ol ester serves as a latent acid. Although the pyrrolyl ester is not a classical active ester, dissolution in anhydrous THF at –15 °C followed by addition of 1.2 equiv of lithium bis(trimethylsilyl)amide (LiHMDS, 1.0 M in THF) generates the corresponding lithium carboxylate of N‑tosyl‑L‑alanine and the pyrrol‑3‑ol in a single operation. The lithium salt is then trapped in situ with 1.05 equiv of a primary amine hydrochloride in the presence of 1.5 equiv of HATU and 3 equiv of N,N‑diisopropylethylamine (DIPEA) in DMF, giving the tosyl‑protected alanine amide in typical isolated yields of 82–91 % after aqueous work‑up. The chiral integrity under these conditions is preserved: post‑reaction HPLC shows ≤0.8 % of the D‑enantiomer. This strategy has been validated on a 500 g scale in a jacketed 10 L reactor with retreatment of the recovered pyrrol‑3‑ol for further esterification cycles, improving atom economy. A complementary approach exploits the stability of the tosylated ester toward common organometallic reagents. The ester remains unchanged during lithium‑halogen exchange at the pyrrole 2‑position using n‑BuLi (1.6 M in hexanes, 1.0 equiv) at –78 °C in THF, followed by quenching with 1.1 equiv of trimethylborate and oxidative work‑up to install a boronic acid handle. The resultant 2‑boronate–5‑phenylpyrrole‑3‑yl ester is then directly subjected to Suzuki coupling with aryl bromides (1.2 equiv, Pd(PPh3)4 5 mol%, K2CO3 3 equiv, DMF/H2O 4:1, 85 °C) to afford 2‑aryl‑5‑phenylpyrrole derivatives that retain the sensitive tosylalanine ester intact. No competing protodeboronation or ester hydrolysis is observed when the water volume fraction is held below 20 %. This sequence has been executed in an automated flow reactor (Vapourtec R‑Series, 2 mm i.d. reactor coil, 10 mL total volume) with 98 % conversion at a flow rate of 0.5 mL·min⁻¹, demonstrating scalability without cryogenic batch limitations. The product’s incompatibility with strongly nucleophilic amines warrants mention: direct treatment with primary or secondary amines in aprotic solvents leads to slow aminolysis at 40–60 °C (half‑life ≈ 6 h for benzylamine in THF), forming the amide and pyrrol‑3‑ol, which can be exploited deliberately but must be avoided when the ester is meant as a protecting group. A TLC control (silica gel, ethyl acetate:hexane 1:1, Rf 0.45 for the ester, 0.15 for the aminolysis product) should accompany any prolonged reaction in the presence of amines.
The compound has shown utility in the construction of pyrrole‑based peptidomimetic inhibitors of serine proteases. In a published protocol for a urokinase‑type plasminogen activator (uPA) inhibitor series, the tosylalanine ester was coupled with a 2‑aminomethyl‑5‑phenylpyrrole core using the LiHMDS/HATU method, and the tosyl group was subsequently removed with samarium diiodide (0.1 M in THF, 4 equiv, –78 °C to 25 °C) to unveil the free amine. The overall yield from the ester to the deprotected active pharmaceutical intermediate was 68 % over two steps. This demonstrates that the tosyl group’s reductive cleavage conditions are orthogonal to acid‑ and base‑labile protecting groups present in advanced intermediates, a key differentiator from Boc and Fmoc strategies that require either acid or amine deprotection conditions that may erode the pyrrole ring’s electron‑rich character.
The product is designated in the laboratory catalogue under the code PP‑TosAla‑001 and is supplied in standard pack sizes of 1 g, 5 g, and 25 g in amber borosilicate glass vials crimped with PTFE‑lined septa. Custom quantities up to 10 kg are available upon consultation, with lead times of 6–8 weeks for non‑stocked lots. Air‑ and moisture‑sensitive handling is required only after opening; unopened containers stored at 2–8 °C maintain specification for the entire labelled shelf life. Forced degradation studies confirm that exposure to 0.1 M aqueous HCl at 37 °C for 24 h results in < 2 % ester hydrolysis, while 0.1 M NaOH under identical conditions leads to complete cleavage within 2 h, consistent with the base‑lability of phenolic esters. Thus, the product is incompatible with strongly alkaline media during downstream processing.
