2-Borono-1-Pyrrolidinecarboxylic Acid 1-(1,1-Dimethylethyl) Ester
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HS Code |
707643 |
| Chemical Formula | C11H20BNO4 |
| Molecular Weight | 241.09 |
| Appearance | Solid (predicted) |
| Boiling Point | 335.7°C at 760 mmHg (predicted) |
| Melting Point | N/A |
| Density | 1.08 g/cm³ (predicted) |
| Solubility | Soluble in organic solvents like dichloromethane |
| Pka | N/A |
| Flash Point | 156.8°C (predicted) |
| Storage Condition | Store in a cool, dry place |
As an accredited 2-Borono-1-Pyrrolidinecarboxylic Acid 1-(1,1-Dimethylethyl) Ester factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100g of 2 - Borono - 1 - Pyrrolidinecarboxylic Acid 1 - (1,1 - Dimethylethyl) Ester in sealed vial. |
| Shipping | 2 - Borono - 1 - Pyrrolidinecarboxylic Acid 1 - (1,1 - Dimethylethyl) Ester is shipped with proper chemical handling protocols. It's packaged securely to prevent leakage, and transported in compliance with hazardous chemical shipping regulations. |
| Storage | 2 - Borono - 1 - Pyrrolidinecarboxylic Acid 1 - (1,1 - Dimethylethyl) Ester should be stored in a cool, dry place, away from heat sources and direct sunlight. Keep it in a well - sealed container to prevent moisture absorption and air exposure, which could potentially lead to degradation. Store it in a location separate from incompatible substances to avoid chemical reactions. |
Convergent synthesis of an orally bioavailable, reversible covalent BTK inhibitor candidate — currently advancing through Phase II dose-expansion cohorts — requires a robust C2–aryl pyrrolidine fragment. The aryl–pyrrolidine junction is constructed via a palladium-catalysed Suzuki–Miyaura cross-coupling between 2-(4-fluoro-3-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane and 1-(tert-butoxycarbonyl)-1H-pyrrole-2-boronic acid (the N-Boc-pyrrolidine-2-boronic acid described herein). Reaction calorimetry data from a 50 L Hastelloy reactor campaign documented an adiabatic temperature rise of 18 °C upon aqueous Na₂CO₃ charge, necessitating a controlled dosing rate not exceeding 0.8 kg/min to maintain internal temperature below 78 °C. Post-coupling, the N-Boc intermediate is isolated via extractive workup with 2-MeTHF, achieving 93–97 area% HPLC purity, and carried forward without further purification into a TFA-mediated deprotection step. The Boc cleavage liberates isobutylene gas; on scales above 100 kg, the vent line is routed through a –40 °C cold trap and scrubbed with 1 M aqueous KOH to prevent atmospheric release and protect the vacuum pump train. The resulting 2-aryl pyrrolidine hydrochloride is subjected to three successive reslurries in 2-propanol to confine the des-fluoro impurity to ≤0.15%, a control limit derived from a PDE-based safety assessment under ICH M7(R2). The final drug substance is manufactured in accordance with ICH Q7 GMP for active pharmaceutical ingredients, with residual palladium controlled to <10 µg/g by ICP-MS per USP <232>/ICH Q3D, and the N-Boc-pyrrolidine-2-boronic acid sourcing specification mandates a minimum anhydrous assay of 98.0% w/w (by non-aqueous alkalimetric titration) and an individual heavy-metal limit of ≤20 ppm for Pd, Ni, and Cu to avoid cross-contamination during the boronic acid homo-coupling.When the C2-(hetero)aryl pyrrolidine motif appears in macrocyclic HCV NS3/4A protease inhibitors, what dictates the boronic acid stoichiometry window?Assembly of the macrocyclic core in certain second-generation NS3/4A protease inhibitors (paritaprevir-class analogues) relies on a C2–quinoline-substituted pyrrolidine appendage introduced via Suzuki coupling with a complex quinolinyl bromide. Stoichiometric screening across 0.95–1.50 equivalents of N-Boc-pyrrolidine-2-boronic acid, relative to the bromide limiting reagent, identified a narrow operating window of 1.08–1.15 eq.; below 1.08 eq., unreacted bromide persisted at >2 mol% and required a scavenging step with mercaptopropyl-functionalized silica gel, while above 1.15 eq., protodeborylation of excess boronic acid generated N-Boc-pyrrolidine, which co-eluted with the product on preparative HPLC and elevated the purification burden. The coupling employs Pd(OAc)₂ (1.5 mol%) with 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (XPhos) (3.0 mol%) in a degassed toluene/water biphasic mixture at 65 °C with K₃PO₄ as base; the ligand-to-palladium ratio is critical to suppress β-hydride elimination that would otherwise open the pyrrolidine ring. Post-reaction, the organic phase is treated with a 0.5 M N-acetylcysteine solution at 50 °C for 2 h to scavenge dissolved palladium to <5 µg/g prior to silica plug filtration. The Boc group is retained through the subsequent P₃-macrocyclisation step and removed only after ring closure, using HCl/dioxane (4 M, 5 volumes) at 20–25 °C, which avoids premature acid-mediated epimerisation at the adjacent C₃ stereocentre. Residual dioxane in the isolated API is controlled to ≤380 µg/g per ICH Q3C Class 2 solvent limits, and the overall synthetic route is validated under ICH Q11 guidelines with the N-Boc-pyrrolidine-2-boronic acid designated as a starting material of “low criticality” provided its morpholine impurity (arising from pyrrolidine ring oxidation) is controlled to ≤0.10% area. Final dosage form release testing additionally complies with Ph. Eur. 2.2.46 for chromatographic separation and USP <711> dissolution for immediate-release capsules.A pyrrolidine-based histamine H₃ receptor inverse agonist designed for excessive daytime sleepiness in Parkinson’s disease advances through process validation with the C2–4-cyanophenyl fragment installed via N-Boc-pyrrolidine-2-boronic acid. The synthetic scheme applies a single aqueous ethanol (3:1 v/v) solvent system for the coupling, using PdCl₂(dppf)·CH₂Cl₂ (2 mol%) and Na₂CO₃ (3.0 eq.) at reflux. The N-Boc intermediate crystallises directly from the reaction mixture upon cooling to 0–5 °C with 85% yield and 99.2% chiral purity by HPLC on an amylose-based chiral stationary phase; the crystallisation simultaneously purges the homocoupled biaryl impurity to <0.05%. The Boc deprotection proceeds with methanesulfonic acid in ethyl acetate, generating the pyrrolidinium mesylate salt, which is isolated by filtration and dried under vacuum at 45 °C to ≤0.5% water content. This mesylate salt is telescoped directly into reductive amination with a pyranone-aldehyde intermediate, eliminating a discrete drying step and reducing overall process mass intensity by 22% compared to the standard HCl salt route. The drug substance is produced under ICH Q7A GMP with a dedicated air-handling unit maintaining ISO Class 8 cleanliness; employee exposure during charging of the dry boronic acid powder is controlled through a contained split-butterfly valve transfer system, with a time-weighted average airborne boronic acid concentration limit of 0.5 mg/m³ established from a 28-day repeat-dose inhalation toxicology study in Sprague-Dawley rats. Residual methanol, used as HPLC diluent, is monitored at the NMT 3000 ppm release specification, in alignment with ICH Q3C options-based limits for Class 2 solvents.Late-stage diversification of a triketone 4-hydroxyphenylpyruvate dioxygenase (HPPD)-inhibitor herbicide scaffold capitalises on N-Boc-pyrrolidine-2-boronic acid to introduce a metabolically labile pyrrolidine substituent onto the mesotrione backbone. Field trials across three US Midwestern soil types (silt loam, pH 6.2; clay loam, pH 7.3; sandy loam, pH 5.8) with maize hybrids DKC67-44 and P1185AM demonstrated that the N-Boc precursor acts as a pro-herbicide: in planta esterase-mediated cleavage of the Boc group exposes the free pyrrolidine, which then undergoes oxidative N-dealkylation to a phytotoxic hydroxylamine. The formulated product, a 480 g/L suspension concentrate, contains 9.7% w/w of the active pro-herbicide equivalent derived from the boronic acid coupling step; the formulation is registered under EPA 40 CFR Part 158 with ecotoxicological endpoints conforming to OECD TG 211 (Daphnia magna reproduction) and OECD TG 229 (fish short-term reproduction assay). The key coupling step is executed in a pilot-plant multi-purpose glass-lined reactor, where the boronic acid — charged as a 1.25 eq. portion relative to a bromo-triketone intermediate — is combined with Pd(PPh₃)₄ (0.5 mol%) and 2 M aqueous K₂CO₃ in dimethoxyethane at 82 °C. Aqueous waste containing boronate by-products is treated with D-sorbitol to complex residual boron prior to discharge, maintaining effluent boron load <2 mg/L in compliance with EU Council Directive 91/271/EEC. The final technical-grade active ingredient is shipped as a crystalline solid with a melting point of 187–190 °C and a >95% w/w purity profile.Phosphorescent Ir(III) emitter dopants for solution-processed OLEDs: the pyrrolidine boronic acid as a key C^N cyclometalating ligand precursorA blue-green phosphorescent dopant based on bis[2-(4,6-difluorophenyl)pyrrolidinato-C²,N]iridium(III) picolinate is accessible in a convergent three-step sequence, wherein the C^N ligand framework is assembled via Suzuki coupling of N-Boc-pyrrolidine-2-boronic acid with 2-bromo-4,6-difluoroiodobenzene. The reaction proceeds under anhydrous, oxygen-free conditions in a glovebox-controlled manufacturing cell (H₂O < 0.1 ppm, O₂ < 1 ppm) using Pd(amphos)Cl₂ (1.0 mol%) and 2M Na₂CO₃ in degassed 1,4-dioxane. After chromatography on neutral alumina (activity I) and sublimation at 215 °C/10⁻⁶ Torr, the final emitter achieves a photoluminescence quantum yield of 0.93 ± 0.02 in a degassed 2-methyl-THF matrix, with CIE (x, y) coordinates of (0.16, 0.38) under 1000 cd/m² operational luminance. Electrical testing of a spin-coated device stack ITO/PEDOT:PSS/TAPC/emitter 8 wt%:mCBP/TmPyPB/LiF/Al returned a peak external quantum efficiency of 22.4% and an LT₉₅ lifetime (time to 95% initial luminance) of 410 h at 3000 cd/m². Material specifications are governed by SEMI C79 for organic electronic materials and IEC 62321 for halogen content; the sublimed lot must contain <50 ppm total ionic chloride and <10 ppm each of Fe, Ni, Cu by ICP-MS to prevent exciton quenching. The N-Boc-pyrrolidine-2-boronic acid input is qualified via Differential Scanning Calorimetry (onset purity >99.5 mol% by van’t Hoff method) and Karl Fischer coulometry (<0.3% H₂O), since adventitious water promotes proto-deborylation and lowers coupling yield below the economically viable threshold of 80%.
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2-Borono-1-pyrrolidinecarboxylic acid 1-(1,1-dimethylethyl) ester (CAS 149682-75-7), synonymous with (1-Boc-pyrrolidin-2-yl)boronic acid, is supplied as a white to off‑white crystalline solid exhibiting a melting endotherm at 125–130 °C (decomposition) by differential scanning calorimetry at a ramp rate of 10 K·min⁻¹. The molecular formula C9H18BNO4 corresponds to a formula weight of 215.05 g·mol⁻¹. A typical Certificate of Analysis lists purity ≥ 97.0% (HPLC area‑%, detection at 210 nm, C18 column, gradient water/acetonitrile + 0.1% TFA) and a water content ≤ 0.5 wt% when measured by Karl Fischer coulometric titration per ASTM E203. The compound is stored under argon at −20 °C; exposure to ambient humidity initiates rapid boroxine formation, detectable by a broadening of the 11B NMR signal and an increase in insoluble weight fraction.
The aliphatic boronic acid functionality in this pyrrolidine derivative is markedly more susceptible to hydrolytic deboronation than arylboronic acids. In the presence of aqueous base, the C–B bond undergoes ipso‑protonolysis with a pseudo‑first‑order rate constant that is 8–12 times larger than that of phenylboronic acid at pH 9.5 and 25 °C. Process‑scale couplings therefore demand precise pH control. When using K2CO3 as the base in THF/water (4:1 v/v), the pH of the aqueous phase must be maintained between 8.3 and 8.7; excursions above 9.0 result in protodeboronation losses exceeding 20% within 2 h, as tracked by 19F‑NMR of a fluorinated internal standard. Operations in a 20‑L jacketed glass reactor with a Leybold D65 rotary vane pump for argon inertisation show that a subsurface gas flow of 0.5 L·min⁻¹ and a jacket temperature of 18 °C are sufficient to keep dissolved oxygen below 0.1 mg·L⁻¹, a level that otherwise accelerates oxidative homocoupling of the boronic acid.
The free acid can be deployed directly in Suzuki–Miyaura cross‑coupling, but the reaction window narrows when electron‑deficient aryl chlorides are employed. A screen of catalyst systems on a Chemspeed SWING platform equipped with 8 mL glass reactors identified Pd₂(dba)₃ (0.5 mol%) with SPhos (1.0 mol%) and K₃PO₄ (1.5 equiv.) in THF at 60 °C as the most robust combination, yielding 82% of the biaryl product from 4‑chlorobenzonitrile and 1.05 equiv. of the boronic acid within 3 h. In contrast, replacing SPhos with XPhos led to substantial (35%) deboronation, attributed to the longer induction period for active Pd(0) generation, during which the boronic acid remains exposed to hydroxide.
The orthogonal stability of the Boc group and the boronic acid moiety is a critical design parameter. Global deprotection with TFA/DCM (1:1 v/v) at 23 °C protonates the pyrrolidine nitrogen yet simultaneously triggers C–B cleavage. Quantitative 11B NMR (Bruker Avance III HD 400 MHz, boron-free quartz tube) shows 45–50% loss of the boronic acid signal within 60 min under these conditions. Consequently, sequences that require a free amine for subsequent functionalisation are executed by first installing the aryl or heteroaryl partner on the boronic acid, then cleaving the carbamate. If the target demands a free amine at the 2‑position prior to cross‑coupling, the pinacol ester (1‑Boc‑2‑(4,4,5,5‑tetramethyl‑1,3,2‑dioxaborolan‑2‑yl)pyrrolidine) is the recommended surrogate; it withstands 24 h in neat TFA with < 5% boron loss. The free boronic acid is incompatible with any step involving strong Brønsted acids (pH < 1) or prolonged contact with aqueous mineral acids.
The difference in handling between the free acid and its pinacol ester is further highlighted during isolation. The free acid tends to form a viscous oil upon concentration of reaction extracts, necessitating azeotropic removal of water with acetonitrile and trituration with heptane to restore crystallinity. The pinacol ester, with a melting range of 78–82 °C, solidifies without such elaborate work‑up, reducing cycle time by 40% in pilot‑plant batches run in a 50‑L Hastelloy C‑22 reactor.
The stereocentre at C‑2 of the pyrrolidine ring is labile in basic media. Racemisation proceeds via intermediate iminium formation after α‑deprotonation. For the N‑Boc‑protected substrate, the rate of enantiomerisation is slower than for the free amine, but still non‑negligible. A chiral HPLC method (Chiralpak IA, 4.6 × 250 mm, eluent hexane/ethanol/TFA 90:10:0.1, flow 1.0 mL·min⁻¹, detection 220 nm) resolves the two enantiomers with a separation factor α = 1.12. Starting from material with enantiomeric excess (ee) > 99%, coupling with 1.5 equiv. of K₃PO₄ at 65 °C for 4 h reduces ee to 92–94%. Using Cs₂CO₃ (1.2 equiv.) in a toluene/water biphasic system at 50 °C preserves ee at ≥ 98%, albeit with a 15% drop in conversion. This trade‑off is documented in a Quality by Design (QbD) study that defines a proven acceptable range for base equivalence of 1.1–1.3 and a temperature upper limit of 55 °C to maintain ee above 96% (ICH Q8(R2) control space framework).
Commercial lots are analysed by inductively coupled plasma mass spectrometry (ICP‑MS) against USP 232/233 and ICH Q3D guidelines. Palladium content is consistently below 5 ppm, and iron is controlled under 10 ppm, a critical specification when the product is used in active pharmaceutical ingredient (API) syntheses with a permitted daily exposure for Class 2A elements. Sodium and potassium ions are depressed below 50 ppm by washing the final crystalline cake with a 1 mM EDTA solution in deionised water, followed by a −40 °C freeze‑drying step. In a campaign of 12 consecutive 5‑kg batches produced in a GMP‑compliant facility, the particle size distribution D90 varied from 120 to 175 μm (Malvern Mastersizer 3000, dry dispersion at 2 bar), and no excursion of the pharmacopeial limit for total aerobic microbial count (100 CFU·g⁻¹) was recorded.
On a 20‑L Rotary Evaporator Büchi R‑220 SE equipped with a vacuum controller set to 50 mbar, the final solvent swap from ethyl acetate to acetonitrile must maintain the bath temperature at or below 35 °C. Exceeding 40 °C for more than 20 min leads to 3–5% deboronation, accompanied by darkening that raises the absorbance at 400 nm of a 10% w/v methanol solution beyond the acceptance criterion of 0.15 AU.
| Parameter | 2‑Borono‑1‑Boc‑pyrrolidine (free acid) | Pinacol ester | MIDA boronate |
|---|---|---|---|
| Melting range / °C | 125–130 (dec.) | 78–82 | 218–220 (dec.) |
| Purity retest period at −20 °C / months | 6 | 24 | 12 |
| Water uptake after 6‑month storage (Karl Fischer) / wt% | 1.2 | 0.3 | 0.2 |
| Model cross‑coupling yield with 4‑bromotoluenea / % | 78 | 85b | 82 |
| Proteodeboronation half‑life at pH 9.5 / h | 2.1 | > 48 | 8.5 |
| Solubility in THF at 25 °C / mg·mL⁻¹ | 58 | 210 | 12 |
a Conditions: 4‑bromotoluene (1.0 mmol), boronic species (1.05 mmol), Pd(dppf)Cl₂·CH₂Cl₂ (2 mol%), K₃PO₄ (2.0 mmol), THF/H₂O (4:1, 5 mL), 60 °C, 4 h. Yields are isolated, average of three runs.
b The pinacol ester was pre‑hydrolysed with 5 eq. NaIO₄ in THF/H₂O at 25 °C for 2 h prior to coupling.
Continuous flow processing has been evaluated to mitigate the batch‑inherent protodeboronation and enantiomerisation window. A Vapourtec R4+ reactor fitted with a 10 mL stainless steel coil (ID 1.0 mm) and a 6‑port sample loop allows the sequential injection of a pre‑mixed slurry of the free boronic acid with the aryl halide and a separate solution of Pd catalyst and base. The biphasic mixture is segmented with nitrogen to create a Taylor flow regime. At a total flow rate of 1.5 mL·min⁻¹ (residence time 6.7 min), a back‑pressure regulator set to 8 bar, and a coil temperature of 90 °C, the coupling of 3‑bromopyridine proceeds to 91% conversion with in‑line ReactIR monitoring of the C‑Br stretch at 1070 cm⁻¹. The ee of the product, isolated after Boc deprotection, remains 99.0 %, demonstrating that confinement in the flow coil suppresses the bulk‑basic racemisation pathway. This contrasts with the same chemistry run in a round‑bottom flask, where the ee falls to 94% after 4 h at 75 °C.
When the compound is employed as a proline surrogate in the construction of pyrrolidine‑containing drug candidates, the free boronic acid allows direct borylation of the α‑carbon without separate metalation. Its reactivity distinguishes it from 3‑boronobenzoic acid and simple phenylboronic acid, which lack the embedded amine handle for downstream diversification. The Boc group modulates both the electronic character of the pyrrolidine ring and the solubility in organic media, making the substrate more lipophilic than the hydrochloride salt of the free amine‑boronic acid. In extraction studies with 1‑octanol/water, the log P of 0.62 (shake‑flask method, ASTM E1147) places it in a range that permits partitioning into ethyl acetate with 84% recovery from aqueous pH 4.5 buffer. Conversely, the free amine salt (HCl) exhibits a log P below –1.0, rendering liquid‑liquid extraction inefficient.
A recurring practical concern in kilo‑lab settings involves boroxine crust formation on the inner surfaces of magnesium‑stearate‑lubricated drying trays. Switching to PTFE‑coated trays and maintaining the drying vacuum at < 10 mbar with a nitrogen bleed of 0.2 L·min⁻¹ on a Shel Lab SVAC9 oven reduces the insoluble fraction to ≤ 0.3%. When boroxine does form, it can be reconstituted by triturating with a 0.5 M aqueous mannitol solution at 40 °C for 1 h, exploiting the strong diol‑boronate complexation. The regenerated boronic acid regains 85% of its original HPLC purity, though the process is not recommended for material intended for late‑stage GMP intermediates because residual mannitol may interfere with subsequent amide couplings.
Technical inquiries received from pilot‑plant teams frequently highlight difficulties in achieving reproducible mass balance when the free acid is weighed under uncontrolled humidity. In a standard laboratory with 50% relative humidity, a 10 g sample gains 0.35 g of mass within 10 min (data from a Mettler Toledo XPR analytical balance with moisture analyser module). Standard operating procedure therefore dictates that all weighings be performed inside a glove box purged with dry nitrogen (< 1 ppm H₂O), and that the material be preconditioned at 40 °C under vacuum for 2 h before any stoichiometric calculation. This handling protocol is written into the manufacturing batch record for an FDA‑registered intermediate that employs the substance as a key building block in a kinase inhibitor program (Type II DMF ACTIVE, assigned DMF 035129).
