N-Boc-2-Methylpyrrole
|
HS Code |
733155 |
| Chemical Formula | C10H15NO2 |
| Molecular Weight | 181.23 g/mol |
| Appearance | Colorless to light yellow liquid or solid |
| Boiling Point | ~250 - 260 °C (decomposes) |
| Melting Point | 42 - 46 °C |
| Solubility In Water | Insoluble |
| Solubility In Organic Solvents | Soluble in common organic solvents like dichloromethane, chloroform |
| Flash Point | 109.4 °C |
| Density | 1.024 g/cm³ |
| Purity | Typically available in high purity, e.g., 95%+ |
| Stability | Stable under normal conditions, but sensitive to strong acids and bases |
As an accredited N-Boc-2-Methylpyrrole factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100 g of N - Boc - 2 - Methylpyrrole packaged in a sealed, chemical - resistant bottle. |
| Shipping | N - Boc - 2 - Methylpyrrole is shipped with care. It's packaged in air - tight, chemical - resistant containers. Shipment occurs via approved carriers following strict safety regulations for chemical transportation to ensure safe delivery. |
| Storage | N - Boc - 2 - Methylpyrrole should be stored in a cool, dry place away from heat sources and direct sunlight. It is best kept in a tightly - sealed container to prevent exposure to air and moisture, which could potentially lead to degradation. Store it in a well - ventilated area, separate from oxidizing agents and reactive chemicals to avoid unwanted reactions. |
Controlling Boc-deprotection exotherms during large-scale neutralisation of TFA-treated N-Boc-2-methylpyrrole remains a non-trivial engineering challenge in multi-kilogram API intermediate campaigns. The substrate, typically isolated as a mobile liquid with purity exceeding 99.0% by GC-FID, serves as a protected 2-methylpyrrole building block for pyrrole-containing pharmacophores. Compliance for this intermediate is governed by ICH Q7 Section 7.3 (raw material controls) and, where destined for a registered drug substance, 21 CFR 211.84 and EudraLex Vol. 4 Part I Chapter 5. Specifications for a GMP-grade lot demand residual TFA below 10 ppm (assayed by headspace GC-MS per USP <467>), water content below 0.5% (Karl Fischer, USP <921> Method Ic), and single unspecified impurities capped at 0.10%. Heavy metals are controlled to <5 ppm Pb, <2 ppm Cd, and <2 ppm As via ICP-MS after closed-vessel microwave digestion, aligning with ICH Q3D elemental impurity risk assessment for a synthesis route that uses palladium catalysts later in the sequence. The compound is stored under dry nitrogen at –20 °C because moisture- and acid-catalysed premature Boc-cleavage can generate 2-methylpyrrole, which oligomerises to tar-coloured residues that foul downstream filtration equipment. In a representative process, 1.0 eq of N-Boc-2-methylpyrrole is dissolved in anhydrous dichloromethane (10 L/kg substrate) and treated with 1.5 eq of TFA at 0–5 °C over 45 min under a nitrogen pad. Quenching with cold 10% aqueous potassium carbonate to pH 8–9 and extraction into methyl tert-butyl ether affords the free 2-methylpyrrole, which must be telescoped immediately into the next step because gas-chromatographic monitoring shows 12% decomposition within 3 h at 20 °C. The operational window is narrow: extended agitation during neutralisation raises the liquid temperature above 8 °C, triggering detectable pyrrole-pyrrole coupling that reduces isolated yield by 5–7% and generates a yellow chromophore difficult to remove by silica plug filtration. The terminal products frequently include selective JAK inhibitor fragments and MALT1 protease inhibitor intermediates where the 2-methylpyrrole ring contributes metabolic stability and modulates logD. Equipment routinely employed for the deprotection are glass-lined reactors of 2–5 m³ capacity fitted with jacket temperature control capable of ±1 °C precision, as recorded in multiple technology transfer dossiers between Asian CDMOs and European originators.
What Limits Film Uniformity in Potentiostatic Deposition of Poly(2-methylpyrrole) on Flexible ITO Substrates?Poly(2-methylpyrrole) films are electrodeposited as hole-transport layers in organic thin-film transistors (OTFTs), and the precursor N-Boc-2-methylpyrrole improves ambient storage stability of the monomer because free 2-methylpyrrole darkens within 72 h at 25 °C upon exposure to laboratory air. Before deposition, the Boc group is removed quantitatively by passing the protected precursor through a short plug of basic alumina wetted with anhydrous acetonitrile, a technique that limits acid-catalysed pyrrole oligomerisation. Freshly liberated 2-methylpyrrole is collected directly into an electrolyte solution consisting of 0.10 M monomer, 0.10 M tetrabutylammonium hexafluorophosphate (TBAPF₆) as supporting electrolyte, and 1.0 % v/v propylene carbonate as a nucleation regulator in a solvent blend of acetonitrile and dichloromethane (4:1 v/v). The solution is sparged with argon for 30 min and maintained under argon blanket throughout the deposition. Working electrodes are 125 µm PET/ITO sheets with sheet resistance ≤ 15 Ω/sq; a platinum mesh counter electrode and a Ag/Ag⁺ (10 mM AgNO₃ in 0.1 M TBAPF₆/CH₃CN) non-aqueous reference complete the three-electrode cell. Potentiostatic polymerisation is carried out at +1.15 V vs. Ag/Ag⁺, and film thickness is monitored coulometrically, with 200–250 mC/cm² corresponding to approximately 200–250 nm dry film thickness. Film uniformity degrades when the water content of the electrolyte exceeds 20 ppm, because trace moisture hydrolyses the freshly generated 2-methylpyrrole radical cation, causing oligomeric by‑products that precipitate as dark spots observable under optical microscopy at 50× magnification. Compliance with RoHS Directive 2011/65/EU Annex II is mandatory when these films are incorporated into electronic displays sold in EU markets; consequently, the electrodeposition bath and rinsing protocol must demonstrably exclude cadmium, hexavalent chromium, and mercury with concentrations in the finished film below 100 ppm by XRF screening per IEC 62321-3-1. After deposition, films are rinsed in dried acetonitrile and vacuum-dried at 60 °C for 2 h without exposure to ambient light. The terminal product is a flexible hole-injection layer integrated into solution-processed OTFTs operating at threshold voltages below 3 V, and device yield correlates strongly with the absence of sub-µm pinholes revealed by cyclic voltammetry in a 0.1 M KCl aqueous solution with a redox probe.Thermal decarboxylation of N-Boc-2-methylpyrrole at 150–180 °C generates free 2-methylpyrrole in situ, a process adopted by flavour houses to deliver fresh roasted-nut and slightly burnt-sugar odour notes in microwaveable baked goods and extruded breakfast cereals. The protected precursor is preferred over raw 2-methylpyrrole because the latter exhibits vapour pressure of approximately 8.5 mm Hg at 25 °C and diffuses through conventional barrier packaging within 4 weeks, causing off-odour loss and oxidation to non-volatile brown oligomers. Regulatory compliance for the flavour precursor strategy falls under EU Regulation (EC) No 1334/2008 on food flavourings, where thermally generated 2-methylpyrrole must be assessed as a processing aid if not added directly, and any intentional residual of the precursor requires a FEMA GRAS number; published data for N-Boc-2-methylpyrrole in food contact materials is limited, and therefore individual national legislation under Regulation (EC) No 1935/2004 must be consulted. In a typical application, the Boc-protected compound is dry-blended into a starch carrier matrix at a loading of 0.02–0.05% w/w (relative to total dry mix) and co-milled with maltodextrin (DE 10–12) to ensure particle size distribution with D₉₀ below 75 µm. During baking at 160–180 °C for 18–22 min, decarboxylation releases 2-methylpyrrole into the headspace, and the extent of release can be modulated by dough pH: at pH 5.2–5.8 (typical of fermented doughs), liberation reaches 85–92% of theoretical yield based on headspace SPME-GC–MS quantitation after 15 min; at pH 6.8–7.2, the release drops to 60–70% because the deprotection mechanism involves acid‑catalysed tert‑butyl cation expulsion that is suppressed near neutrality. The process must avoid direct contact with free fatty acids above 2% in the dough, as these extract the precursor into the lipid phase and limit available surface area for thermal cleavage. Terminal consumer products are pre-baked frozen bread rolls and cereal bars with a “nutty” character where free 2-methylpyrrole concentration in the finished food matrix is typically below 0.5 ppm.Agrochemical Synthesis: Exploiting the Boc Directing Group in 2-Methylpyrrole FunctionalisationHalogenated and arylated 2-methylpyrrole derivatives form the core of several vintage and modern insecticide classes, including analogues of chlorfenapyr, and the N-Boc protecting group simultaneously acts as an ortho-directing moiety to permit regiospecific functionalisation at the pyrrole C3 and C5 positions. The technical-grade active ingredient manufacturing route often commences with N-Boc-2-methylpyrrole as a key synthetic intermediate received at > 98.5% purity and treated with 1.05 eq of N-bromosuccinimide in anhydrous DMF at 0–5 °C to deliver 4-bromo-N-Boc-2-methylpyrrole in 85–90% isolated yield after recrystallisation from cyclohexane. Bromination regiochemistry is critical: if the temperature drifts above 10 °C, dibromo impurities exceed 2.5% and require column chromatography, which is uneconomical at scale. The bromo intermediate undergoes a subsequent Suzuki–Miyaura coupling with 4-chlorophenylboronic acid (1.15 eq) catalysed by 0.5 mol% Pd(PPh₃)₄ and 2.0 eq of 2 M aqueous sodium carbonate in a degassed toluene/ethanol mixture at 80 °C for 6 h. Aqueous work-up and treatment with activated carbon (Darco KB-G, 5 wt% relative to crude) reduces residual palladium to < 20 ppm before Boc-deprotection with TFA in dichloromethane at 25 °C. Regulation of this synthesis stream is detailed in FAO Specification 454/TC (Chlorfenapyr Technical) and EPA 40 CFR § 180.518 for residues; impurities such as the des-chloro by-product must be individually quantitated and limited to ≤ 0.5% in the technical grade. Process equipment involves glass-lined reactors equipped with baffles and retreat-blade impellers; hydrogen evolution during the boronic acid activation step mandates nitrogen inertisation with oxygen levels monitored to < 5% LEL. Final active ingredient formulation as a suspension concentrate demands an average particle size D₅₀ of 2–3 µm achieved by wet bead‑milling. Physical stability of the suspension is assessed under CIPAC MT 46.3 and MT 39.3; Ostwald ripening inhibitors including block copolymer dispersants are pre-screened for compatibility with the pyrrole ring, which can undergo photo‑induced electron transfer with certain polyarylates and cause viscosity drift.Directed ortho‑metalation using n‑butyllithium constitutes the most well‑documented approach to synthesise C2‑functionalised pyrrole libraries from N‑Boc‑2‑methylpyrrole. The Boc carbonyl oxygen coordinates to the incoming lithium base and directs deprotonation exclusively to the C5 position when the C2 methyl substituent blocks the alternative C3 site under kinetic control. In a typical laboratory protocol paralleling the scale‑up guidance provided in Org. Process Res. Dev. reports, a solution of N‑Boc‑2‑methylpyrrole (1.0 eq) in anhydrous THF (10 mL per gram of substrate) is cooled to –78 °C in a Schlenk flask purged with argon, and 1.05 eq of n‑BuLi (2.5 M in hexanes) is added dropwise over 20 min. After 1 h at –78 °C, quenching with 1.5 eq of DMF and gradual warming to 0 °C over 2 h affords 5‑formyl‑N‑Boc‑2‑methylpyrrole in 72–78% isolated yield after flash chromatography. Lithium‑halogen exchange competition, which produces 5‑bromo‑N‑Boc‑2‑methylpyrrole if a bromine source is present, is suppressed by rigorously drying glassware (150 °C oven, then Ar‑flushed) and using molecular‑sieve‑dried THF with water content verified by Karl Fischer titration to be < 30 ppm. When the reaction is scaled beyond 500 g substrate, the exotherm during BuLi addition must be limited to a jacket temperature not exceeding –65 °C, otherwise the metallated pyrrole species rearranges to a 2‑methylene‑1‑pyrroline tautomer that hydrolyses to a ring‑opened amino ketone impurity—a by‑product quantified by < 0.8% in well‑controlled batches. Quality control for the resulting aldehyde relies on ASTM E203-type volumetric titrations for residual water and ISO 17025‑accredited laboratories for product certification. The formyl intermediate is subsequently reduced, oxidised, or coupled to deliver kinase inhibitor fragments and agrochemical screening compounds that bind to the ryanodine receptor or mitochondrial Complex II.Palladium Scavenging Protocols for Post‑Suzuki Coupling Streams Containing N‑Boc‑2‑methylpyrroleTransition‑metal‑catalysed cross‑coupling of halogenated N‑Boc‑2‑methylpyrrole with arylboronic acids introduces a contamination risk that conflicts with the elemental impurity limits mandated for pharmaceutical substances under ICH Q3D. Palladium, typically present at 2000–5000 ppm in the crude organic phase after a Suzuki reaction, must be reduced to ≤ 5 ppm before the deprotected pyrrole can proceed to late‑stage API amination. Scavenging experiments on gravimetrically‑spiked solutions have benchmarked macroporous polystyrene‑bound trimercaptotriazine (TMT) resin at 5 wt% loading, agitated at 60 °C for 4 h, as capable of lowering Pd from 1240 ppm to 3.2 ppm in THF/water mixtures (4:1 v/v) when the initial pH is adjusted to 3.5 with phosphoric acid. The same resin performs poorly in DMF‑rich streams typical of the bromination step, where residual Pd remains at 18–25 ppm unless the solvent is first exchanged to ethyl acetate and aqueous washes are implemented. Regulatory documentation for the final drug substance requires method validation data per USP <233> showing spike recovery between 90–110% for the Pd analyte at the 1 ppm level. An alternative scavenging approach suitable for kilogram‑scale batches involves treatment with 0.2 eq of N‑acetyl‑l‑cysteine and 0.5 eq of activated carbon (Norit SX+) in ethanol at 50 °C for 8 h, which simultaneously decolourises the solution and reduces Pd to 5–8 ppm without introducing the odour of mercaptan‑functionalised resins that may cause olfactory contamination in open‑plant dissolution. The cleaned N‑Boc‑protected intermediate is precipitated from n‑heptane, filtered, and dried under vacuum (10 mbar, 40 °C). Each lot of the scavenged product is tested for palladium by ICP‑OES with a method detection limit of 0.5 ppm. Terminal output is an advanced intermediate for Phase II clinical supplies where the drug substance monograph explicitly requires Pd content not to exceed 2 ppm. |
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A colorless to pale yellow liquid under ambient lighting and possessing a faint tertiary amine odor, N-Boc-2-methylpyrrole (tert-butyl 2-methyl-1H-pyrrole-1-carboxylate) serves as a protected 1,2-disubstituted pyrrole engineered for iterative C–H functionalization sequences. The compound is supplied at a minimum HPLC purity of 98.0% (area% at 254 nm), with identity confirmed by 1H NMR (characteristic N–CH3 signal absent, Boc singlet at 1.60 ppm in CDCl3) and 13C NMR (carbonyl at 149.8 ppm). Molecular formula C10H15NO2 and a molecular weight of 181.23 g·mol−1 define its stoichiometric ratios in palladium-catalyzed couplings. The CAS registry number 144688-70-0 and MDL MFCD01321237 are cross-referenced in electronic laboratory notebooks to ensure supply chain traceability. When stored at 2–8 °C in septa-sealed amber vials under argon, the material exhibits less than 0.5% deprotection over 12 months, as monitored by quarterly GC-FID analysis. The tert-butoxycarbonyl (Boc) group is thermal-labile, and solution-phase heating above 60 °C triggers β-elimination to isobutylene and CO2, regenerating free 2-methylpyrrole—a design feature exploited for in situ release during continuous-flow lithiation-borylation campaigns.
| Property | Specification | Test Method |
|---|---|---|
| Appearance | Colorless to pale yellow liquid | Visual inspection against Ph. Eur. reference solution Y5 |
| Purity (GC/HPLC) | ≥ 98.0% | GC-FID (DB-5, 30 m × 0.25 mm, 0.25 µm) or HPLC (C18, 60:40 ACN/H2O, 254 nm) per USP <617> / <621> |
| Density (20 °C) | 1.03 ± 0.02 g/cm³ | Oscillating U-tube, ASTM D4052 |
| Refractive index n20/D | 1.5030 ± 0.005 | ISO 5661, Abbé-type refractometer |
| Water content | ≤ 0.5% w/w | Karl Fischer coulometric titration |
| Boc deprotection byproduct | ≤ 1.0% 2-methylpyrrole | GC-MS, selected ion monitoring m/z 81 |
| Storage temperature | 2–8 °C | Validated cold-chain packaging per WHO/PQS/E06 |
| Compound | Key Structural Feature | Primary Lithiation Site | Deprotection Conditions | Compatibility with Acid‑Labile Substrates |
|---|---|---|---|---|
| N-Boc-2-methylpyrrole | 2‑CH3 blocks C-2; Boc is acid‑labile | C-5 (LiTMP, THF, −78 °C) | TFA/CH2Cl2 (1:1), 30 min, r.t. | Low; typical TFA treatment cleaves acetals |
| N-Boc-pyrrole | Unsubstituted at C-2; C-2 and C-5 both accessible | C-2 ≫ C-5, often mixed | Identical acidolytic conditions | Low; same acid sensitivity |
| N-Tosyl-2-methylpyrrole | 2‑CH3; tosyl group electron‑withdrawing | C-5 requires harsher bases (LTMP, −20 °C) | Mg/MeOH or HBr/AcOH reflux | Higher; ring remains protected under mild acid |
| N-Cbz-2-methylpyrrole | 2‑CH3; Cbz removed by hydrogenolysis | C-5 (LDA, −78 °C), slower kinetics | H2, 5% Pd/C, EtOAc, 1 atm | Low; Pd/C reduces pyrrole ring partially |
