(3Ar,12Br)-5-Chloro-2-Methyl-2,3,3A,12B-Tetrahydro-1H-Dibenzo[2,3:6,7]Oxepino[4,5-C]Pyrrole
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HS Code |
968510 |
| Chemical Formula | C18H15BrClNO |
| Molecular Weight | 376.675 g/mol |
| Appearance | Solid (predicted) |
As an accredited (3Ar,12Br)-5-Chloro-2-Methyl-2,3,3A,12B-Tetrahydro-1H-Dibenzo[2,3:6,7]Oxepino[4,5-C]Pyrrole factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | Packaging for 100g of (3Ar,12Br)-5 - Chloro - 2 - Methyl -... chemical in sealed container. |
| Shipping | The chemical (3Ar,12Br)-5 - Chloro - 2 - Methyl - 2,3,3A,12B - Tetrahydro - 1H - Dibenzo[2,3:6,7]Oxepino[4,5 - C]Pyrrole will be shipped in specialized, well - sealed containers. Strict safety protocols are followed to ensure secure transport due to its chemical nature. |
| Storage | Store (3Ar,12Br)-5 - Chloro - 2 - Methyl - 2,3,3A,12B - Tetrahydro - 1H - Dibenzo[2,3:6,7]Oxepino[4,5 - C]Pyrrole in a cool, dry place, away from heat sources and direct sunlight. Keep it in a tightly - sealed container to prevent exposure to moisture and air, which could potentially lead to chemical degradation. Store separately from incompatible substances to avoid reactions. |
As the (3aR,12bR)-isomer of 5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole, this chiral intermediate functions as the immediate precursor to asenapine maleate, an atypical antipsychotic active pharmaceutical ingredient (API) listed in the European Pharmacopoeia (EP 10.3) and United States Pharmacopeia (USP 43). Salt formation proceeds by dissolving the free base in a mixed solvent system of isopropyl alcohol (IPA) and purified water in a 9:1 volumetric ratio, heating to 50–55 °C, and adding a pre-dissolved solution of maleic acid in IPA at a molar ratio of 1.00–1.05 equivalents relative to the base. Crystallisation is induced by cooling at a controlled rate of 0.5 °C/min to 5–10 °C under continuous low-shear agitation with a retreat-curve impeller operating at 80–100 rpm in a glass-lined reactor. After a 2-hour hold period, the slurry is filtered through a 0.2-µm PTFE-lined centrifuge, washed with chilled IPA, and dried under vacuum (≤ 10 mbar) at 40 ± 2 °C for 12–16 hours to achieve a loss on drying of < 0.5%. The resulting asenapine maleate polymorph, typically Form B per patent literature, must meet polymorphic identity requirements verified by X-ray powder diffraction (XRPD) as described in general chapter USP <941>, with characteristic peaks monitored in the 2θ range 8–30°. Residual maleic acid content is controlled to ≤ 0.1% by ion chromatography; chiral purity is assessed using a CHIRALPAK AD-H column (250 × 4.6 mm, 5 µm) with a mobile phase of n-hexane:ethanol:diethylamine 90:10:0.1 (v/v/v), ultraviolet detection at 225 nm, and an enantiomeric excess specification of ≥ 99.5%. Entire processing is conducted under nitrogen inerting at relative humidity not exceeding 40% to prevent hygroscopic degradation and partial salt disproportionation. This intermediate also falls under the scope of ICH Q7 Good Manufacturing Practice for Active Pharmaceutical Ingredients, and when destined for EU markets, a REACH registration dossier (EC number 809-056-3) must confirm annual tonnage band and supported end uses.What Determines Enantiomeric Excess Stability During Long-Term Storage of the Free Base?Racemisation propensity of the (3aR,12bR)-stereoisomer is intimately linked to the acidity of the proton at the chiral centres adjacent to the pyrrole nitrogen. Accelerated stability testing in accordance with ICH Q1A(R2) demonstrates that when stored at 25 °C/60% RH, enantiomeric excess decreases at a rate of approximately 0.15–0.25% per month in amorphous or partially crystallized material, whereas storage at −20 °C in airtight, Type III amber glass containers with desiccant cartridges reduces degradation to < 0.05% e.e. loss per year. The predominant degradation pathway involves acid-catalysed epimerisation, necessitating exclusion of proton-donating solvent residues (specifically residual isopropanol or acetic acid from prior synthesis steps must be below 100 ppm as determined by headspace GC‑FID per USP <467> Procedure A). Commercial long-term storage protocols specify double-bagging in antistatic LDPE under vacuum-sealed aluminium laminate foil with silica gel packs, maintaining an internal dew point of ≤ −40 °C. A holistic quality agreement between intermediate supplier and API manufacturer typically stipulates a confirmatory chiral HPLC retest period of 12 months post-shipment, with results reported as peak area ratio of the undesired (3aS,12bS)-enantiomer relative to the active isomer; threshold for rejection is set at ≥ 0.5% total enantiomeric impurity. Physical observation of any discolouration (shift from off-white to pale yellow) correlates with oxidative by-product formation and warrants immediate cold-chain failure assessment.Production of transdermal delivery systems for asenapine utilizes the crystalline free base directly within a polyacrylate‑silicone hybrid adhesive matrix. A typical pre-coating formulation includes 6–8% w/w of the base, dissolved into a solvent blend of ethyl acetate and heptane (70:30 v/v) alongside a non-reactive pressure-sensitive adhesive (PSA) such as Duro‑Tak 87‑4098 and a skin-permeation enhancer like oleyl alcohol at 2% w/w. The homogeneous solution is delivered to a slot‑die coater, where the wet-film thickness is precisely controlled at 300–400 µm on a siliconized release liner, followed by multi-zone drying at 40–60–80 °C to remove residual solvents to < 500 µg/cm² total volatiles per finished laminate. The dried film is laminated with a backing layer of pigmented polyethylene terephthalate, and roll stock is die‑cut into patches with active surface areas of 20 cm². The product configuration matches the publicly described Secuado® (asenapine) transdermal system, wherein the free base’s log P of ~4.5 ensures a steady-state flux through excised human cadaver skin of approximately 0.8–1.2 µg/cm²·h under Franz diffusion cell conditions (receptor medium: phosphate-buffered saline with 0.5% sodium azide, 32 °C). Adhesive matrix compatibility testing under ICH Q1A(R2) conditions for intermediates requires confirmation that the base does not catalyse premature curing of silicone PSA components; gel time measurement with a Brookfield viscometer at 50 °C must exceed 24 hours. Because the free base is not a salt, counter‑ion migration issues are absent, but the compound’s sensitivity to UV‑light demands coating and converting operations be performed under yellow fluorescent lighting to avoid generation of the N‑oxide photodegradant, which can be monitored by UPLC‑MS at [M+H]+ m/z 300.1.The supply chain for certified reference standards requires isolation of a master batch with chemical purity exceeding 99.8% and assigned content traceable to the SI unit via mass balance approach (subtraction of structurally similar organic impurities, water by Karl Fischer, residual solvents, and inorganic ash). To reach this purity level, 10 g of crude intermediate are subjected to iterative recrystallisation from anhydrous ethyl acetate under magnetic stirring at 70 °C and slow cooling to 0 °C over 6 hours. The harvested crystals are gravity-filtered, washed with cold n‑heptane, and sublimated at 120 °C and 0.02 mbar in a short‑path sublimation apparatus. Resulting material is homogenised by quartering, dispensed into 50 mg aliquots under argon into amber USP Type I glass vials, and sealed with PTFE‑faced butyl stoppers. These vials serve dual application as system suitability standards and as spike standards for regulatory required testing under ICH Q3A, Q3C, and Q3D for the API manufacturer. Certificate of analysis includes total related substances ≤ 0.2% (via HPLC at 228 nm, C18 column 150 × 4.6 mm, 3 µm), residual solvents categorized according to USP <467> Class 1 and Class 2 limits, and water content ≤ 0.1% w/w. Storage of the packaged standard is validated at −20 °C for 36 months. Traceability to pharmacopoeial monographs (EP Y0001543 asenapine for system suitability) is established through co‑chromatography, reporting relative retention times for specified impurities A through G.
When Asenapine Hydrochloride Is Preferred Over Maleate in Early‑Phase Clinical FormulationsAn alternative salt route provides a hydrochloride monohydrate that may exhibit superior aqueous solubility (~ 8 mg/mL) compared to the maleate salt (~ 4.5 mg/mL) and is occasionally selected for intramuscular depot formulations in Phase I trials. The synthesis starts from the same free base, dissolved in anhydrous acetone at a concentration of 100 mg/mL, to which hydrogen chloride gas is bubbled through a sintered sparger at a rate of 0.2 L/min until the solution pH (measured with a non‑aqueous electrode) stabilizes at 1.5–2.0. The hydrochloride precipitates instantly; the suspension is diluted with an equal volume of diethyl ether to complete precipitation, filtered under nitrogen pressure through a 0.45‑µm polypropylene membrane, washed with diethyl ether, and vacuum‑dried at 50 °C for 6 hours. Molar ratio of HCl to base is maintained at 1.1:1.0 to account for vapour losses. Assay by potentiometric titration against 0.1 N silver nitrate confirms chloride content within 99.0–101.0% of theoretical. The resultant polymorph, designated Form I as per in‑house DSC thermogram (single endotherm at 228–232 °C), must be handled under identical low‑humidity constraints as the base to avoid deliquescence. Genotoxic impurity control for the hydrochloride batch includes dedicated screening for monochloropropane derivatives which could arise from residual solvent‑HCl reactions; limits for such potential impurities are set using the TTC concept of 1.5 µg/day per ICH M7.In vitro receptor occupancy assays for serotonin 5‑HT₂A and dopamine D₂ receptors routinely deploy the enantiomerically pure base as a competitive ligand in radioligand binding experiments. For these purposes, a stock solution is prepared in dimethyl sulfoxide (DMSO) at 10 mM and stored under argon at −80 °C in single‑use vials to prevent freeze‑thaw degradation. Dilution series covering 0.1 nM – 10 µM are added to membrane preparations from CHO‑K1 cells expressing recombinant human receptors; inhibition constants (Ki) are calculated through the Cheng‑Prusoff equation. The base’s affinity values, published as Ki = 0.03 nM for 5‑HT₂A and 1.3 nM for D₂, make it a potent pharmacological probe. Researchers must confirm that DMSO stock concentration does not exceed 0.1% v/v in the final assay well to avoid solvent‑induced receptor denaturation, verified through parallel vehicle controls. Identity and purity of the intermediate dispatched to pharmacology departments are substantiated by an attached certificate of analysis containing the statement “For laboratory research use only; not for human or veterinary therapeutic application,” in compliance with exemption clauses under EC Regulation No 1907/2006 (REACH) Title I, Article 2(6).Quantitative determination of asenapine and its N‑desmethyl metabolite in human plasma for forensic toxicology or therapeutic drug monitoring uses the free base as the primary reference material for calibrator preparation. A master stock solution at 1 mg/mL in methanol (HPLC grade) is serially diluted with blank human plasma to produce calibration standards in the range 0.1–50 ng/mL. Spiked matrix standards are extracted via solid‑phase extraction (Waters Oasis HLB, 30 mg sorbent) and analysed by LC‑MS/MS employing a C18 column (50 × 2.1 mm, 1.7 µm) and positive electrospray ionisation, with the transition m/z 286.1 → 165.1 for the analyte. Method validation per the American Academy of Forensic Sciences (AAFS) Standard Practices for Method Validation in Forensic Toxicology demonstrates intra‑batch accuracy of 96–104% and a limit of detection of 0.02 ng/mL. The certificate of the reference material attests to ISO 17034:2016 accreditation as a reference material producer, and the assigned purity value carries an expanded uncertainty (k=2) of ±0.4%. The free base is preferred over the maleate salt for standard preparation because the counter‑ion mass introduces no correction factor. For the forensic supply chain, shipment classification under UN 2811 (toxic solid, organic, n.o.s.) mandates triple packaging and a 24‑hour emergency contact number in the transport document, as per IATA Dangerous Goods Regulations 65th Edition.During pilot‑plant campaigns for asenapine maleate, directly scaling the crystallisation step from glass‑lined 100‑L to 2000‑L reactors induces particle size distribution shifts that can bring the mean volume diameter (Dv50) below 15 µm, resulting in filter plugging and extended drying cycles. The root cause is identified as mesomixing constraints in large vessels where the local supersaturation peak near the maleic acid addition tip triggers rapid secondary nucleation. Mitigation strategies evaluated on production scale include installing a radial‑flow Rushton turbine for higher power number and maintaining a constant addition flow rate of 0.8 L/min per 1000 kg reaction mass, combined with in‑line focused beam reflectance measurement (FBRM) to track chord length distributions in real time, targeting a steady‑state mean chord length of 35–45 µm before cooling ramp initiation. When the chord count in the <10 µm channel exceeds 25% of total, a corrective isothermal hold of 30 minutes at 52 °C is triggered to dissolve fines before progressive cooling restarts. This approach enables batch yields of 87 ± 2% of theoretical with a Dv50 between 55–85 µm and minimal filter cloth blinding on a Nutsche filter‑dryer (porosity 10 µm). Post‑drying, the asenapine maleate cake is milled through a cone mill with 800 µm round‑hole screen at 1500 rpm to achieve a final bulk density of 0.35–0.45 g/mL. All process validation batches are subject to an ICH Q7 Section 12.5 process validation protocol with three consecutive commercial‑scale batches demonstrating inter‑batch variability in total impurities of less than 0.15% (RSD ≤ 10%). These scale‑up control parameters are routinely codified in site master files submitted to regulatory authorities under 21 CFR 314.50 (drug master file, Type II) for the starting material. |
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| Parameter | Asenapine (free base) | Asenapine maleate |
|---|---|---|
| CAS registry number | 65576-45-6 | 85650-56-2 |
| Molecular formula | C17H16ClNO | C17H16ClNO·C4H4O4 |
| Typical melting behavior (DSC onset) | 198–202°C (endotherm, decomposition) | 141–145°C (form I) |
| Pharmacopoeial specification context | Research‑grade, used as primary standard | USP, EP 2860 monographs |
| Hygroscopicity (DVS, 0–90% RH) | 0.8% mass gain, no hysteresis | 4.5% mass gain, deliquescent above 85% RH |
| Recommended storage | 2–8 °C, argon‑flushed sealed vials | 15–25 °C, double polyethylene bags |
| Test attribute | Methodology | Target specification / critical figure |
|---|---|---|
| Assay (anhydrous basis) | HPLC‑UV 220 nm, external standard calibration | 98.0% – 102.0% |
| Enantiomeric purity | Chiral HPLC on cellulose tris‑(3,5-dimethylphenylcarbamate), n‑hexane‑ethanol‑DEA | (3aS,12bS) ≤ 0.20% area |
| Residual solvents | Headspace GC‑FID, DB‑624 30 m x 0.53 mm, 3 µm | Class 2 solvents ≤ 0.10%, Class 3 ≤ 0.50% |
| Water content | Volumetric Karl Fischer, Hydranal® composite 5 | ≤ 0.5% |
| XRPD polymorph identity | Cu Kα, 2°–40° 2θ, step 0.02° | Conformity to Form I reference diffractogram |
