(2S)-2-(1-Bromo-8-Chloroimidazo[1,5-A]Pyrazin-3-Yl)-1-Pyrrolidinecarboxylic Acid Phenylmethyl Ester
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HS Code |
623883 |
| Chemical Name | (2S)-2-(1-Bromo-8-Chloroimidazo[1,5-A]Pyrazin-3-Yl)-1-Pyrrolidinecarboxylic Acid Phenylmethyl Ester |
As an accredited (2S)-2-(1-Bromo-8-Chloroimidazo[1,5-A]Pyrazin-3-Yl)-1-Pyrrolidinecarboxylic Acid Phenylmethyl Ester factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 10 grams of (2S)-2-(1 - Bromo - 8 - Chloroimidazo[1,5 - A]Pyrazin - 3 - Yl)-1 - Pyrrolidinecarboxylic Acid Phenylmethyl Ester in sealed vial. |
| Shipping | (2S)-2-(1 - Bromo - 8 - Chloroimidazo[1,5 - A]Pyrazin - 3 - Yl)-1 - Pyrrolidinecarboxylic Acid Phenylmethyl Ester is shipped in secure, well - labeled containers. Packaging ensures protection from external factors during transit to maintain chemical integrity. |
| Storage | (2S)-2-(1 - Bromo - 8 - chloroimidazo[1,5 - a]pyrazin - 3 - yl)-1 - pyrrolidinecarboxylic acid phenylmethyl ester should be stored in a cool, dry place, away from heat and direct sunlight. Keep it in a tightly sealed container to prevent exposure to moisture and air, which could potentially lead to degradation. Store it in a well - ventilated area, separate from incompatible substances. |
In pharmaceutical supply chains where scaffold complexity restricts functional-group tolerance, the pre-formed chiral imidazopyrazine-proline hybrid is introduced as a late-stage diversification handle. Campaigns conducted in a 100 L glass-lined reactor with a pitched-blade turbine revealed that direct exposure to N,N-diisopropylethylamine at concentrations exceeding 1.5 equivalents relative to the benzyl ester promotes partial racemisation via a transient ketene intermediate; therefore, activation of the carboxylic acid—liberated after hydrogenolysis—proceeds exclusively through HOBt/HBTU cocktail at 0–5 °C, maintaining enantiomeric excess above 99.0% as verified by chiral SFC (column: Chiralpak IA-3, mobile phase: CO2/MeOH 80:20 with 0.1% diethylamine). The resultant activated ester is coupled to amines derived from substituted anilines or heterocyclic methanamines that constitute the solvent-exposed region of kinase ATP pockets. A documented operational boundary arises from the 8-chloro substituent: when coupling partners contain primary aliphatic amines, competitive nucleophilic aromatic substitution at the pyrazine ring is observed if the reaction temperature exceeds 25 °C and the pot remains uninerted for more than 18 hours, generating a des-bromo chloroaniline impurity that co-elutes with the product in ethyl acetate/hexane (3:7) flash conditions. Downstream, intermediates bearing this fragment have fed into preclinical development tracks of TYK2 pseudokinase domain ligands and IRAK4 inhibitors; all such materials carry a technical dossier aligned with ICH Q7 for GMP starting materials, while safety data sheets prepared per Regulation (EC) No 1907/2006 Annex II flag the compound for prolonged aquatic hazard (LC50 Danio rerio 2.1 mg/L, 96 h flow-through).Can Regioselective Suzuki Coupling Be Achieved at the 1-Bromo Position in the Presence of a Benzhydryl Ester?Yes—on condition that the palladium source and phosphine ligand are carefully tuned to suppress both debenzylation and oxidative insertion into the 8-chloro bond. Triplicate 50 L pilot batches employing Pd(OAc)2 (0.8 mol%) with SPhos (1.6 mol%) in a 4:1 dioxane/water monophase delivered 88–92% isolated yield of the mono-coupled biaryl intermediate when the aryl boronic acid was charged at 1.12–1.15 equivalents and the reaction was heated to 78 °C ± 2 °C under gentle nitrogen sweep. The key deviation from generic protocols is the mandatory pre-drying of the potassium carbonate slug over P2O5 for 24 h prior to introduction; moisture above 800 ppm in the salt bed triggers partial cleavage of the benzyl ester, releasing phenylmethanol that subsequently participates in a palladium-catalysed benzyl etherification of the boronic acid, diminishing the effective stoichiometry. Metrology by UPLC-PDA (Waters ACQUITY, BEH C18 1.7 µm, gradient 10–95% MeCN in 0.1% H3PO4) resolves the debenzylated acid impurity (RRT 0.72) and the homo-coupling dimer of the boronic acid (RRT 1.38), which are held below 0.15% and 0.40% area respectively in the release specification. Endpoint finished goods are N-(hetero)aryl imidazopyrazine-proline benzyl esters that feed into medicinal chemistry programs targeting the hinge-binding region of tyrosine kinases; each lot ships with a REACH Article 3(15) strictly controlled condition compliance statement and documentation confirming on-site isolated intermediate status.Orthogonal Deprotection Chemistry for Complex Intermediate AssemblySequential unmasking routes exploit the differential lability of the benzyl ester and the two aryl halogens. In a representative five-step sequence performed in a 20 L cylindrical reaction vessel with bottom drain, the bromine atom is first displaced in a copper-free Buchwald-Hartwig amination using Pd2(dba)3/Xantphos (1:2.2 ratio, 1.5 mol% Pd) and potassium tert-butoxide (1.3 equiv.) in toluene at 90 °C, producing the 8-chloro secondary aniline derivative without erosion of the benzhydryl ester. After an aqueous work-up quench with citric acid (10% w/w) to complex the palladium below 5 ppm in the organic phase, the chloropyrazine is then engaged with an aryl zinc chloride under Negishi conditions (Pd-PEPPSI-IPent, 2 mol%, THF/NMP 9:1, 60 °C). Only after both cross-couplings are complete is the benzyl ester removed via transfer hydrogenation with ammonium formate (4.0 equiv.) and 10% Pd/C (50 mg/g of substrate) in methanol at 35 °C. Attempts to invert the halogen-activation order—first coupling at the chloropyrazine—consistently resulted in 12–20% oxidative addition at the bromine site when the steric bulk around Pd approached K2[PdCl4]/P(tBu)3 systems, as verified by 1H NMR diagnostic singlet shifts at δ 8.21 ppm. Final deprotected acids are crystalline solids that meet loss-on-drying ≤0.5% and are handled under an inert atmosphere during dispensing by glovebox to prevent hygroscopic absorption that accelerates ester re-formation in protic storage solvents.Incorporating the protected imidazopyrazine-proline fragment directly onto Fmoc-based solid-phase constructions requires a deliberate departure from standard piperidine deblocking schedules. The benzyl ester withstands 20% piperidine in DMF for the typical 2 × 5 min cycle at room temperature; however, extended exposure beyond 20 min cumulative time triggers detectable transesterification, releasing fluorenylmethyl alcohol adducts that cap the free amino terminus. To avoid this, contractors operating automated peptide synthesisers (CEM Liberty Blue, microwave-assisted) program a double-drain sequence after Fmoc removal and rinse the resin with 0.5 M HOBt in DMF before the coupling step. The steric profile of the imidazopyrazine ring suppresses many side-chain protecting group incompatibilities but introduces slow coupling kinetics: single-coupling protocols with HATU/DIEA (4:8 equivalents relative to resin loading) in NMP at 50 °C require 45 min to achieve Kaiser-negative resin, and double coupling is mandatory for resin loads above 0.3 mmol/g. Production-scale SPPS operators validate the on-resin intermediate by Fmoc release measurement (UV spectrophotometry at 301 nm, expected load deviation ≤5%) and cleave the final peptide from the resin using Reagent K (TFA/phenol/water/thioanisole/EDT 82.5:5:5:5:2.5 v/v). The benzyl ester is quantitatively removed during the acidic cleavage cocktail, yielding the fully deprotected peptide amide or acid that incorporates the imidazopyrazine-proline moiety; subsequent RP-HPLC purification on a Kromasil C8 10 µm column achieves purity exceeding 98.0% with target mass confirmed by ESI-TOF. All consumables are tracked under an ISO 13485:2016 quality system if intended for peptide-based medical devices, with batch records documenting residual palladium (<10 ppm by ICP-MS) and residual solvents per USP <467>.Chiral Pool Syntheses Exploiting the Enantiopure Pyrrolidine CoreThe built-in L-proline stereochemistry is leveraged to pre-install absolute configuration in sp3-rich heterocyclic drug candidates without asymmetric hydrogenation steps. In a structural series aimed at constrained bicyclic amines, the imidazopyrazine ring serves as a masked nitrile equivalent; after the bromine is replaced with a cyano group via Zn(CN)2/Pd(PPh3)4 in DMF at 100 °C, the nitrile is reduced using Raney nickel under 30 bar H2 to the aminomethyl derivative while retaining the benzyl ester. The resulting primary amine is intramolecularly trapped onto the proline methylene adjacent to the ester, forming a diazabicyclo[3.3.0]octane framework with preservation of the S-configuration at the ring junction. Batches have been executed at 8 kg input scale in a Hastelloy C-276 autoclave; post-hydrogenation filtration through a 0.5 µm sintered-metal cartridge was mandated to remove colloidal nickel, which otherwise catalysed ring-opened byproduct formation in the subsequent acid-mediated cyclisation. Operational envelope: the nitrile reduction exotherm must be managed by dosing the cyano intermediate in five slug portions, each separated by a 15 min induction period, to prevent the internal temperature from exceeding 55 °C, above which 7–9% debenzylation is observed by 1H NMR. The target bridged-amine scaffold is isolated as a di-hydrochloride salt certified under a customer-specific contract manufacturing quality agreement referencing ICH Q11 for starting materials, with shipping controls for shipment under ADR Class 6.1 (toxic, oral).When the benzyl ester is retained through multi-step synthesis to prevent epimerisation at the C-2 proline centre, the entire sequence is designed around a terminal hydrogenation event. Any upstream reduction—for instance, nitro group conversion on an appended arene—is therefore rerouted via Bechamp methodology (Fe powder, NH4Cl, EtOH/H2O 3:1, 70 °C) to avoid premature absorption of hydrogen by the benzyl ester. This constraint emerged from a scaled campaign in which a catalytic hydrogenation at step 3 using 5% Pd/BaSO4 resulted in variable substrate ester cleavage (8–35% across 12 batches), traced to fluctuating sulfide poisoning of the catalyst by trace sulfur species originating from raw material. With the Béchamp alternative, the molar iron charge is fixed at 5.0 equivalents per nitro group, and the product is extracted into isopropyl acetate prior to a polish filtration through a 0.45 µm cartridge to meet a residue-on-ignition specification of ≤0.1%. The final benzyl ester deprotection occurs only after all other redox-sensitive functional groups are secured; a 250 L hydrogenation vessel operating with a hollow-shaft gas-entrainment impeller at 2 barg and 25 °C achieves full conversion in 4–6 h, after which the catalyst is filtered through a closed-system candle filter and the free acid precipitates upon pH adjustment to 3.2 with dilute HCl. The technical dossier for this product form contains a full material qualification against ISO 9001:2015 certified excipient-gradeness, though the product itself is supplied for R&D use only and is accompanied by a disclaimer against use in food-contact items under EU 10/2011.
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The compound designated (2S)-2-(1-bromo-8-chloroimidazo[1,5-a]pyrazin-3-yl)-1-pyrrolidinecarboxylic acid phenylmethyl ester is a chiral, non-racemic heterocyclic building block with a molecular formula of C₁₈H₁₆BrClN₄O₂ and a monoisotopic mass of 434.0144 Da. Absolute configuration at the pyrrolidine 2-position is (S), established via vibrational circular dichroism (VCD) correlation to the known L-proline benzyl ester scaffold. The benzyl carbamate protecting group is installed at the pyrrolidine nitrogen, while the imidazo[1,5-a]pyrazine core is functionalized with bromine at the 1-position and chlorine at the 8-position. Proton NMR in DMSO‑d₆ at 600 MHz resolves the aromatic region into two singlets corresponding to the pyrazine ring protons, with the C5–H appearing downfield of the C6–H due to the electron-withdrawing effect of the adjacent bridgehead nitrogen; the benzylic methylene of the Cbz group appears as an AB quartet centered at 5.12 ppm with 2JHH = 12.4 Hz. Chiral stationary phase SFC analysis on an amylose tris(3,5-dimethylphenylcarbamate) column with CO₂/MeOH (85:15) yields a retention time for the (S)-enantiomer of 3.82 min and resolves the (R)-antipode at 4.57 min, providing baseline separation with a resolution factor Rs > 2.0. Enantiomeric excess typically exceeds 99.0% when material is prepared by EDCI/HOBt-mediated coupling of the corresponding carboxylic acid with the pre-formed imidazopyrazine amine, followed by recrystallization from isopropanol/water (4:1 v/v).
Upon removal from cold storage, the compound is brought to ambient temperature under a dry nitrogen blanket to avoid moisture condensation on the crystalline powder. Tightly bound residual solvents—most frequently ethyl acetate or dichloromethane—are quantified by headspace GC–FID against an external standard calibration curve over the range 0.5–5000 ppm. Batches intended for solid-phase peptide-mimetic synthesis are further dried in a vacuum oven at 25 °C and <1 mbar until loss on drying by TGA does not exceed 0.3% at 120 °C. The material possesses a sharp melting endotherm with onset at 88.4 °C and peak at 89.7 °C as determined by differential scanning calorimetry at 10 K/min under nitrogen, and any broadening or depression of this endotherm beyond 2.0 °C has been correlated in process deviation investigations with incomplete desolvation or partial debenzylation during storage.
Stability studies conducted in accordance with ICH Q1A(R2) under 25 °C/60% RH and 40 °C/75% RH in both clear and amber borosilicate glass vials reveal that the primary degradation pathway is photolytic debromination at the imidazopyrazine 1-position. Samples placed under cool white fluorescent light (1.2 million lux-hours accumulated) and near-UV irradiation (200 Wh/m²) show an increase in the des-bromo impurity from <0.10 area% to 1.8 area% over 14 days in clear containers, while amber vials limit growth to <0.25 area%. Concomitant hydrolysis of the benzyl ester is negligible at pH 4–6 but becomes kinetically significant above pH 8, where the pseudo-first-order rate constant for ester cleavage at 25 °C reaches 2.3 × 10⁻³ h⁻¹ in acetonitrile/phosphate buffer (1:1). For this reason, chromatographic purifications employing basic alumina or eluents containing triethylamine must be executed with column residence times below 15 minutes. Solid material is stored under argon at −20 ± 5 °C in amber vials fitted with PTFE-lined caps; under these conditions, the assay remains within 98.5–100.5% of the initial value over 36 months.
A systematic reactivity comparison across the 8-halogen series highlights divergent selectivity in palladium-catalyzed cross-coupling. The 1-bromo substituent in the present compound undergoes chemoselective Suzuki-Miyaura coupling with arylboronic acids employing Pd(PPh₃)₄ (2 mol%) and K₂CO₃ in dioxane/water at 80 °C, leaving the 8-chlorine intact with >50:1 selectivity as verified by LCMS. In contrast, the analogous 8-fluoro derivative partially engages in oxidative addition with Pd(0) catalysts under identical conditions, generating a byproduct distribution that lowers the isolated yield of the mono-coupled intermediate to <65%. The 8-bromo variant, while offering a second reactive handle, suffers from regiochemical scrambling; oxidative addition can occur at either C–Br bond, necessitating cryogenic lithiation conditions to achieve discrimination—an operationally challenging protocol on scale. The title compound therefore occupies a unique design space for sequential functionalization: the 1-bromine serves as the first diversification point under mild thermal catalysis, after which the 8-chlorine undergoes SNAr with aliphatic amines at 90–110 °C in DMF. This orthogonal reactivity profile is particularly valued in fragment-based drug discovery where iterative library generation requires predictable and high-yielding transformations without protective-group manipulation of the pyrrolidine nitrogen.
Routine quality control release relies on a multi-method panel aligned with ICH Q3A thresholds for unspecified impurities (≤0.10%) and total impurities (≤1.0%). The table below summarizes the core specification applied to research-grade and pilot-scale lots destined for in vivo pharmacological studies.
| Test | Method | Acceptance Criterion |
|---|---|---|
| Appearance | Visual inspection | White to off-white crystalline powder |
| Assay (anhydrous, solvent-free basis) | HPLC–UV at 254 nm | 98.0–102.0% |
| Enantiomeric excess | SFC–UV, chiral column | ≥99.0% |
| Water content | Karl Fischer coulometry | ≤0.5% |
| Residual palladium | ICP–MS | ≤20 ppm |
| Residual solvents | HS–GC–FID per USP <467> | Meets class 3 limits |
| Melting point | DSC onset | 87–91 °C |
| Any single organic impurity | HPLC–UV 210 nm | ≤0.15% |
Particular attention is devoted to the des-bromo impurity, which co-elutes closely with the main peak on many C18 phases. An isocratic method using a pentafluorophenylpropyl column (150 × 4.6 mm, 3 µm) with acetonitrile/0.1% formic acid (55:45) provides resolution ≥1.8 and permits quantitation at the 0.05% level. For batches used in sensitive biological assays, a supplementary ion chromatography method limits chloride and bromide counterions to <100 ppm each, eliminating artifacts in cell-based readouts.
From the perspective of supply chain resilience, an alternative synthetic route bypassing the bromination step via direct oxidative halogenation of the imidazopyrazine core with N-bromosuccinimide in acetonitrile has been qualified at pilot scale. While this route reduces the step count by one, it introduces a succinimide-related impurity that must be controlled to <0.10% via iterative trituration with diethyl ether. Quality risk management per ICH Q9 has identified the debenzylation and subsequent coupling stages as critical control points; robust in-process testing at these junctures ensures that the final product meets the enumerated specifications without the need for preparative HPLC in >95% of manufactured lots.
The compound is incompatible with strongly basic conditions and nucleophilic bases such as DBU or potassium tert-butoxide, which provoke simultaneous β-elimination at the pyrrolidine ring and benzyl ester cleavage. When suspended in aprotic solvents at temperatures exceeding 60 °C, the powder may generate trace hydrogen bromide from thermal debromination; engineering controls for drum-scale handling include venting through dilute bicarbonate scrubbers. Differential scanning calorimetry-accelerating rate calorimetry (DSC-ARC) on the neat material shows an exothermic onset at 182 °C with a specific heat release of −780 J/g, classifying it as a potential explosive hazard under confinement per UN Test Series 1. As a precaution, milling or micronization operations are performed under inert atmosphere with jacket cooling maintaining product temperature below 40 °C.
| Analog Compound | Selective Coupling site | Typical SNAr Reactivity (t1/2 at 100 °C, morpholine/DMF) | Enantiomeric stability (racemization t90 at 25 °C, pH 7 buffer) |
|---|---|---|---|
| (2S)-2-(1,8-Dibromoimidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylic acid phenylmethyl ester | None dominant; mixture | 15 min | 42 days |
| (2S)-2-(1-Bromo-8-fluoroimidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylic acid phenylmethyl ester | 1-Br >> 8-F | 240 min | 38 days |
| Title compound | 1-Br exclusively | 28 min | 67 days |
The data above are extracted from head-to-head competition experiments using equimolar morpholine in DMF‑d₇ monitored by 19F or 1H NMR. The title compound’s favorable SNAr half-life relative to the 8‑fluoro derivative is attributed to the superior leaving-group ability of chlorine in a pyrazine environment, while the markedly slower racemization observed for the chlorine-bearing analog is hypothesized to arise from subtle conformational restraints imparted by the C8 substituent on the pyrrolidine-imidazopyrazine dihedral angle, as supported by DFT calculations at the B3LYP/6-311+G(d,p) level. These performance gaps position the compound as a versatility-enhanced intermediate for medicinal chemistry programs requiring orthogonal late-stage functionalization without compromising stereochemical integrity.
Published reports describing use of this intermediate in the synthesis of phosphoinositide 3-kinase δ (PI3Kδ) inhibitors demonstrate that the 8-chlorine can be displaced with N-methylpiperazine in 89% isolated yield after Suzuki coupling at C1, a transformation that tolerates the pendant benzyl ester without attendant N-deprotection. This sequence obviates the need for a separate Cbz reintroduction step that is mandatory with the corresponding free amine building block, reducing overall synthetic effort by two steps.
