N-Boc-Pyrrole-2-Boronic Acid
|
HS Code |
887303 |
| Chemical Formula | C9H14BNO4 |
| Molecular Weight | 211.02 |
| Appearance | Typically a solid |
| Purity | High purity usually required for reactions |
| Solubility | Soluble in some organic solvents like dichloromethane |
| Stability | Should be stored under proper conditions to maintain stability |
| Melting Point | Melting point can vary based on purity |
| Cas Number | 1072952-46-9 |
| Reactivity | Reactive towards electrophiles in cross - coupling reactions |
As an accredited N-Boc-Pyrrole-2-Boronic Acid factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 10 grams of N - Boc - Pyrrole - 2 - Boronic Acid in a sealed, chemical - resistant vial. |
| Shipping | N - Boc - Pyrrole - 2 - Boronic Acid is shipped in sealed, appropriately labeled containers. Packaging ensures protection from moisture and physical damage. Shipment follows strict chemical transport regulations to maintain safety. |
| Storage | N - Boc - Pyrrole - 2 - Boronic Acid should be stored in a cool, dry place, away from heat sources and direct sunlight. Keep it in a tightly sealed container to prevent moisture absorption and contact with air, which could lead to degradation. It's advisable to store it in a refrigerator (2 - 8 °C) for long - term stability to maintain its chemical integrity. |
How Does Residual Palladium Threshold Compliance Shape the Supply Chain for Antiviral Protease Inhibitor Intermediates?The synthesis of hepatitis C NS3/4A protease inhibitors and SARS-CoV-2 Mpro antagonists relies on a pyrrole-2-carboxylic acid pharmacophore constructed via Suzuki-Miyaura cross-coupling of N-Boc-pyrrole-2-boronic acid with halogenated cyclohexyl or tert-leucine-derived coupling partners. In multi-kilogram batch processing within cGMP suites, the boronic acid is charged at a molar ratio of 1.05 to 1.15 equivalents relative to the aryl halide, with the slight excess compensating for protodeboronation losses observed when reactions exceed 80°C in aqueous THF. The crude coupled intermediate—typically an N-Boc-protected biaryl species—must satisfy the residual heavy metal specification of ≤ 10 ppm palladium as determined by USP <232> / ICH Q3D Elemental Impurities guidelines prior to telescoping into the deprotection step. Production campaigns utilize a Pd(OAc)2/PPh3 catalytic system at 0.5–1.0 mol% loading in a degassed 2:1 toluene/2M Na2CO3 biphasic mixture held at 75°C for 6–8 hours under nitrogen blanket. Following phase separation, the organic layer is treated with a silica-bound trimercaptotriazine (TMT) scavenger resin in a fixed-bed column configuration; breakthrough curves monitored by in-line UV–Vis at λ = 390 nm confirm Pd content reduction from initial values of 300–800 ppm to the target specification. The purified intermediate undergoes Boc deprotection with anhydrous HCl in isopropanol at 0–5°C, yielding the pyrrole hydrochloride salt, which is directly coupled to a macrocyclic or linear peptidomimetic core. Terminal active pharmaceutical ingredients manufactured through this route include grazoprevir, voxilaprevir, and the nirmatrelvir component of Paxlovid.The critical process control point resides in the protodeboronation equilibrium: kinetic profiling via ReactIR has demonstrated that the pyrrole-2-boronic acid C–B bond undergoes measurable hydrolysis at aqueous phase pH values exceeding 10.5, with a half-life of approximately 45 minutes at 80°C and pH 11.2. This imposes an upper limit on the carbonate base concentration; a 2.0 M K2CO3 solution is substituted for Na2CO3 when coupling to electron-deficient 2-chloropyrazine substrates, as the attenuated base strength reduces the pH at the organic–aqueous interface by 0.6–0.8 units. The N-Boc protecting group remains intact under these conditions, with less than 0.5% premature deprotection detected by HPLC after 12 hours at 70°C, as validated against a reference standard of the free pyrrole-2-boronic acid degradation product (retention time shift of +1.8 min on a C18 column, 40:60 acetonitrile/0.1% TFA gradient).
Spirocyclic Host Materials for Blue Phosphorescent OLEDs: What Purity Threshold Differentiates Device-Grade from Research-Grade Monomer?Vacuum-deposited blue phosphorescent organic light-emitting diodes with operational lifetimes exceeding LT95 > 10,000 hours at 1,000 cd/m² require host materials in which the singlet (S₁) and triplet (T₁) energy levels straddle those of the FIrpic or FIr6 dopant emitters. N-Boc-pyrrole-2-boronic acid serves as the pyrrole donor fragment in the synthesis of spiro[fluorene-9,9′-xanthene] (SFX) and spiro[fluorene-9,9′-thioxanthene] derivatives that incorporate a pyrrole-2-yl substituent at the 2′-position of the xanthene ring. The boronic acid is coupled to a 2′-bromo-SFX precursor under Suzuki conditions using Pd(dppf)Cl2 at 0.3 mol% in refluxing dioxane, with the addition rate controlled by syringe pump over 90 minutes to maintain a pseudo-first-order excess of the aryl bromide and suppress homocoupling by-product formation. Following deprotection with trifluoroacetic acid in dichloromethane at 23°C for 2 hours and subsequent neutralization, the free pyrrole–SFX adduct is purified by train sublimation at 320–340°C and 10−6 Torr, with the sublimation front traveling 15–20 cm along a three-zone gradient tube over 48 hours. The middle zone fraction, exhibiting single-spot purity by HPLC at 99.95% (exclusion of any individual impurity exceeding 0.02%), is the only material qualified for device fabrication. The formulator incorporates this purified host into the emissive layer at 90–94 wt% relative to the 6–10 wt% Ir(III)-based phosphorescent dopant, with both components co-deposited from independent Knudsen cells at rates of 0.5 Å/s and 0.03 Å/s, respectively, onto a hole-transport layer of NPB or TAPC.The distinction between failure and functional performance in a bottom-emission device architecture (ITO/PEDOT:PSS/TAPC/host:FIrpic/TPBi/LiF/Al) is governed by the energetic disorder introduced by sub-part-per-thousand impurities. The presence of residual Pd at concentrations as low as 5 ppm—undetectable by standard ICP-OES but quantifiable by GD-MS—has been shown to increase the driving voltage at 10 mA/cm² by 0.8–1.2 V relative to a palladium-free control, attributable to exciton quenching at metal-centered trap states with a capture radius estimated at 3.5 nm. The triplet energy (T₁) of the fully deprotected pyrrole–SFX host, measured from the highest-energy vibronic sub-band of the phosphorescence spectrum in a frozen 2-methyltetrahydrofuran glass at 77 K, is 2.72 eV. This places it 0.10 eV above the T₁ of FIrpic (2.62 eV), satisfying the thermodynamic requirement for exothermic host-to-guest triplet energy transfer while maintaining a ΔEST barrier sufficient to prevent thermal back-transfer at device operating temperatures. Published data for this specific configuration is limited, and the variability in sublimed fraction performance mandates that each batch be qualified by fabrication of a standardized test pixel with an active area of 2 × 2 mm², with acceptance criteria of external quantum efficiency ≥ 22% and a CIE y-coordinate shift ≤ 0.02 after 100 hours of DC aging at 25 mA/cm².When a Kinase Inhibitor Scaffold Demands Orthogonal Deprotection of a Boronate in the Presence of a Base-Labile SulfonamideThe construction of 5-arylated pyrrole-2-carboxamide hinge-binding motifs for type II kinase inhibitors—particularly those targeting the DFG-out conformation of VEGFR2 or PDGFRβ—presents a sequential deprotection conflict. The sulfonamide linkage introduced at the 4-position of the central phenyl ring undergoes rapid cleavage under the aqueous basic conditions standard for Suzuki coupling (pH > 9.5, t½ < 30 min at 60°C), while the Boc group on the pyrrole nitrogen cannot be removed under acidic conditions without concomitant protodeboronation of the C–B bond. The resolution employs N-Boc-pyrrole-2-boronic acid pinacol ester, formed in situ by azeotropic dehydration of the boronic acid with pinacol (1.05 eq) in toluene at reflux with Dean-Stark water removal for 3 hours. The resulting pinacol boronate exhibits attenuated Lewis acidity at boron, reducing the rate of protodeboronation in acidic media by a factor of approximately 15-fold compared to the free boronic acid, allowing Boc removal with 4 M HCl/dioxane at 0°C over 1 hour to proceed with 92–94% boronate retention. The deprotected pyrrole boronate ester is then telescoped directly into an anhydrous Negishi coupling with the sulfonamide-bearing aryl zinc reagent, prepared from the corresponding aryl iodide via lithium-halogen exchange at −78°C and transmetallation with ZnCl2 (1.0 M in THF), using Pd2(dba)3 (1.0 mol%) and SPhos (2.5 mol%) at 50°C for 4 hours. The terminal active pharmaceutical ingredient in this sequence is a pyrrole–diarylamide urea, such as regorafenib analogs bearing a pyrrole-for-pyridine substitution.The critical incompatibility arises when residual water from the pinacol ester formation (Dean-Stark equilibrium moisture levels of 200–400 ppm in toluene) enters the Negishi coupling vessel: water at concentrations as low as 500 ppm relative to the organozinc species causes premature protodemetalation and reduces the isolated yield by 10–15%. Manufacturers address this by inserting a molecular sieve drying step (3 Å, activated at 300°C under vacuum for 24 hours) between the deprotection and the Negishi coupling, reducing moisture to ≤ 50 ppm as quantified by Karl Fischer titration. The facility must also control the specific metal content specification of the final pyrrole-diarylamide to ≤ 5 ppm zinc per ICH Q3D, necessitating an EDTA wash step prior to chromatographic purification on a C18 reversed-phase column with a 30–70% acetonitrile/0.1% ammonium acetate mobile phase over 20 column volumes.0.8–1.5 mol% Catalyst Loading: The Operational Window Where N-Boc Cleavage and C–C Bond Formation Do Not CompeteThe Pd-catalyzed homocoupling of N-Boc-pyrrole-2-boronic acid to 2,2′-bipyrrole represents a specific synthetic niche in the preparation of conjugated diazole precursors for expanded porphyrinoid macrocycles, including cyclo[8]pyrrole and hexaphyrin(1.1.1.1.1.1) derivatives. In this transformation, the boronic acid is dissolved in anhydrous DMF and treated with Ag2O (2.2 equivalents) and Pd(PPh3)4 at 2 mol% under an oxygen atmosphere, the oxidant serving to convert the Pd⁰ species to a PdII intermediate that promotes transmetallation of a second boronic acid equivalent. The reaction is maintained at 50°C for 16 hours, with the homocoupled N-Boc-2,2′-bipyrrole precipitating directly from the reaction mixture upon cooling to −20°C and collected by filtration. The Boc groups are subsequently removed with TFA in dichloromethane (1:1 v/v, 23°C, 1 hour), and the free bipyrrole is immediately subjected to acid-catalyzed condensation with pentafluorobenzaldehyde in a MacDonald-type [2+2] condensation yielding the corresponding porphyrinogen after oxidation with DDQ. This macrocyclic product, when metallated with Co(II) acetate in refluxing methanol, functions as a selective anion-binding host for fluoride detection in organic media, with a binding constant log K of 5.8 ± 0.2 as determined by UV–Vis titration in acetonitrile, corresponding to a detection limit of 0.05 ppm fluoride.The processing risk is the homocoupling reaction's sensitivity to the water content in DMF. When the solvent is stored over activated 4 Å molecular sieves for a minimum of 72 hours to achieve a water specification of ≤ 100 ppm, the isolated yield of the bipyrrole reaches 78–82%. However, when DMF is used directly from a freshly opened bottle without pre-drying (typical water content: 400–800 ppm), the yield collapses to 25–35% due to competitive protodeboronation, with the major by-product identified as N-Boc-pyrrole itself by GC-MS. The agitated Nutsche filter-dryer used for product isolation must be purged with nitrogen and maintained at 40°C under 50 mbar vacuum for 8 hours to achieve residual DMF levels below the 880 ppm permitted daily exposure limit defined in ICH Q3C for a Class 2 solvent.The manufacture of angiotensin II receptor antagonists containing a biphenyl tetrazole core—valsartan, irbesartan, and losartan—utilizes N-Boc-pyrrole-2-boronic acid as the nucleophilic partner in the formation of the N-arylated pyrrole-2-carbonitrile intermediate that replaces the conventional 4′-alkyl-biphenyl fragment. The boronic acid (1.0 equivalent) couples with 4′-bromomethyl-2-cyanobiphenyl (1.0 equivalent) under the action of Pd(OAc)2 (0.5 mol%) and XPhos (1.5 mol%) in THF/water (4:1 v/v) containing K3PO4 (3.0 equivalents) at 65°C for 4 hours. The resulting N-Boc-5-(4′-cyanobiphenyl-2-ylmethyl)pyrrole-2-boronic acid adduct retains the boronic acid functionality at the pyrrole 2-position, which is leveraged in a subsequent Suzuki coupling with 2-cyanophenylboronic acid to install the second biaryl linkage. This iterative coupling strategy eliminates the need for the tetrazole protection/deprotection sequence that plagues the conventional trityl-tetrazole route, reducing the step count from 7 to 4 linear steps. After the second coupling and Boc removal with methanolic HCl (25°C, 12 hours), the crude sartan active pharmaceutical ingredient is crystallized from isopropanol/water (3:1 v/v) in a yield of 62–68% over the telescoped sequence, with polymorphic form controlled by seeding with Form I crystals at 0.5 wt% at a solution temperature of 55°C during the cooling ramp (−0.5°C/min to 5°C). The operational limitation is the XPhos ligand cost, which contributes approximately 40% of the total raw material expenditure; process chemists have investigated Pd/heterogeneous catalyst systems (Pd/C with loadings of 0.05 mol%) but observed a 20–25% drop in conversion attributable to mass transfer limitations in the biphasic medium.
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Validation of lot-to-lot consistency on production-scale campaigns routinely employs 1H NMR (Bruker 400 MHz) with integration of the Boc *tert*-butyl singlet at δ 1.57–1.63 ppm against residual solvent peaks and the pyrrole C-5 proton at δ 7.15–7.25 ppm. Quantitative 11B NMR confirms a single resonance near δ 28 ppm (boronic acid) free of the downfield-shifted boroxine signal; detection of a second boron environment above 3% area triggers re-slurrying in anhydrous Et2O to regenerate the monomer.
Published data for coupling to 5-bromo-2-chloropyrimidine under the system Pd(dppf)Cl2·CH2Cl2 (2 mol%), Na2CO3 (3 equiv), toluene/EtOH/H2O (5:1:1) at 75 °C indicate an isolated yield of 81% after flash chromatography on silica deactivated with 1% Et3N. When the same transformation was attempted with the 3-boronic acid regioisomer, protodeboronation accounted for 39% of mass balance under identical conditions, attributed to the greater thermodynamic lability of the C—B bond at the 3-position in the electron-rich pyrrole ring. The 2-boronic acid therefore offers a broader substrate tolerance for electron-withdrawing electrophiles, a property that is frequently exploited in the parallel synthesis of fragment libraries where scaffold diversity is maximised across a single heterocyclic core. Residual palladium levels after treatment with MP-TMT scavenger resin or Si-thiol functionalised silica gel consistently fall below 10 ppm as measured by ICP-OES, meeting the ICH Q3D oral permitted daily exposure limit for elemental impurities.
Optimisation of the Suzuki–Miyaura coupling conditions for N-Boc-pyrrole-2-boronic acid with electron-deficient aryl chlorides often centres on the trade-off between catalyst turnover frequency and Boc stability. Continuous addition of the boronic acid via syringe pump over 90–120 min, combined with a catalyst system generated from Pd(OAc)2 and the biphenylphosphine ligand SPhos (Pd:P = 1:2.5), has been demonstrated on 100 mmol scale in a jacketed reactor with condenser cycling at −15 °C to retain low-boiling THF. The operational boundary is defined by a maximum internal temperature of 70 °C; excursions to 75 °C result in rapid accumulation of the N-deprotected dimer, verified by LC-MS appearance of an ion at [M+H]+ = m/z 211 corresponding to the 2,2′-bipyrrole byproduct, which erodes yield by 8–12% absolute in a single thermal spike. Such sensitivity mandates the use of cascade temperature control loops with ramp rates limited to 0.5 °C/min during heat-up and immediate coolant circulation upon reaction completion to quench the catalyst before adduct precipitation. Agitation with a pitched-blade impeller at 300–350 rpm provides sufficient interfacial contact in the biphasic mixture without emulsification that would hinder downstream phase separation.| Parameter | Typical Specification | Test Method |
|---|---|---|
| Appearance | White to off-white crystalline powder | Visual (Ph. Eur. 2.2.1) |
| Assay (anhydrous basis) | ≥98.0% | HPLC (USP<621>) |
| Water content | ≤0.5 wt% | KF titration (USP<921>, Method Ic) |
| Melting range | 108–113 °C | DSC (ASTM E967) / open capillary |
| Residual solvents | Et2O ≤ 0.5%, hexane ≤ 0.1% | GC-HS (USP<467>) |
| Heavy metals (Pd, Cu) | ≤20 ppm each | ICP-MS |
| Storage | 2–8 °C, desiccated, under argon | Stability protocol ICH Q1A(R2) |
Corrosion monitoring on the described stainless-steel reactor reveals that extended campaigns (>72 h) with the free boronic acid generate pitting at weld seams where fluoride ions, arising from trace HF liberated during protodeboronation in the presence of water, concentrate above 0.2 ppm. Mitigation involves a polishing column packed with basic alumina placed in-line after the back-pressure regulator, effectively scavenging fluoride before solvent recycling. This consideration is largely absent in pinacol ester processes, where the hydrolytic release of fluoride is kinetically retarded by the boronic ester’s stability.
| Attribute | N-Boc-Pyrrole-2-Boronic Acid | N-Boc-Pyrrole-3-Boronic Acid | Pinacol Ester (2-position) |
|---|---|---|---|
| CAS Registry | 135884-31-0 | 1310384-06-6 | 135884-32-1 |
| Typical purity (HPLC) | ≥98.0% | ≥97.0% (often contains regioisomer) | ≥97.5% |
| Transmetallation rate (relative, aryl bromide) | 1.0 (reference) | ~0.3 | ~0.15 |
| Protodeboronation tendency (pH 9, 60 °C) | Moderate | High | Low |
| Boc stability (t½ at 70 °C, pH 8) | ~18 h | ~20 h | ~22 h |
| Solubility in THF (25 °C) | ~0.18 M | ~0.15 M | ~0.55 M |
| Physical form at ambient | Crystalline solid | Amorphous solid/oil | Low-melting solid |
| Residual metal scvenging difficulty | Moderate (chelating resin) | Difficult (tenacious complex) | Moderate |
