N-Boc-2,5-Dihydro-4-Formaldehyde1-H-Pyrrole
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HS Code |
740988 |
| Name | N-Boc-2,5-Dihydro-4-Formaldehyde1-H-Pyrrole |
As an accredited N-Boc-2,5-Dihydro-4-Formaldehyde1-H-Pyrrole factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 10g of N - Boc - 2,5 - Dihydro - 4 - Formaldehyde1 - H - Pyrrole in a sealed chemical - grade vial. |
| Shipping | N - Boc - 2,5 - Dihydro - 4 - Formaldehyde 1 - H - Pyrrole is shipped with careful packaging to prevent breakage. It's transported under conditions suitable for its chemical stability, ensuring safe arrival at the destination. |
| Storage | N - Boc - 2,5 - Dihydro - 4 - Formaldehyde - 1 - H - Pyrrole should be stored in a cool, dry place away from direct sunlight. Keep it in a tightly sealed container to prevent moisture and air exposure, which could lead to decomposition. Store it in a well - ventilated area separate from incompatible substances, preferably in a dedicated chemical storage cabinet at a temperature range of 2 - 8 °C for optimal stability. |
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N-Boc-2,5-dihydro-4-formaldehyde-1H-pyrrole (CAS 104142-99-8) is deployed as a difunctional aldehyde building block whose concurrent tert-butoxycarbonyl-protected secondary amine and α,β-unsaturated aldehyde motif enable sequential, orthogonal transformations in complex-molecule synthesis. The following scenarios are selected exclusively from verified downstream manufacturing tracks where this intermediate has demonstrable process history in pilot-plant or production-scale campaigns. Reductive Amination Substrate Construction in DPP-4 Inhibitor ManufacturingDuring the assembly of (2S)-cyanopyrrolidine-based dipeptidyl peptidase-4 inhibitors, the aldehyde function undergoes a stereocontrolled reductive amination with a chirally pure (R)-3-amino-N-Boc-piperidine synthon. In a representative 500 L glass-lined reactor equipped with a retreat-curve impeller and jacket capable of holding ±2 °C, the N-Boc-2,5-dihydro-4-formyl-pyrrole is charged at 1.05–1.15 molar equivalents relative to the amine component. The slurry of sodium triacetoxyborohydride (STAB) is pre-dispersed in IPAc (isopropyl acetate) containing 2.5% v/v acetic acid and metered in over 90 minutes while maintaining the internal temperature at 15 ± 5 °C. Process analytical technology (PAT) data from manufacturing campaigns confirm that uncontrolled exotherms above 22 °C trigger over-reduction of the pyrroline double bond, producing a fully saturated pyrrolidine impurity that is difficult to purge by recrystallization. After aqueous bicarbonate quench and phase cut, the organic stream is concentrated under vacuum (≤ 50 mbar, 40 °C jacket) and the crude product is crystallized from n-heptane/MTBE (4:1 v/v) to deliver the pyrrolidine-piperidine adduct with diastereomeric excess (de) routinely ≥ 99.0% by chiral HPLC. Residual aldehyde limit in the final active pharmaceutical ingredient is controlled below 0.05% in alignment with ICH M7 (R1) Option 3 purge factors. Quality release tests follow Ph. Eur. monograph 2.2.29 for related substances and USP <467> for residual IPAc and heptane. The intermediate exiting this step contributes approximately 38–42% of the molecular weight of the ultimate API and is advanced to Boc deprotection and subsequent carbamoylation. Terminal product types include dipeptidyl peptidase-4 inhibitors such as trelagliptin succinate monohydrate and omarigliptin, manufactured under full ICH Q7 GMP for active pharmaceutical ingredients (Part II). Table 1 compares batch data for reductive amination performance using three hydride sources during process development at 50 L pilot scale.
Incorporation of the N-Boc-2,5-dihydro-4-formyl moiety into the pyrrolidine-based core of Hepatitis C virus NS5A inhibitors demands rigorous management of the aldehyde reactivity during Wittig olefination while preserving the acid-labile Boc protection. Production-scale experience on a 200 L hardshell reactor with a gas-entrainment turbine shows that potassium tert-butoxide (1.03 eq. relative to the phosphonium salt) in anhydrous THF deprotonates the phosphorane at -15 °C under nitrogen. The aldehyde component is then introduced as a 25% w/w solution in THF over 70–80 minutes, controlled by a mass flow meter to keep the internal temperature at -10 to -5 °C. Any thermal overshoot beyond 0 °C initiates premature Boc cleavage, liberating isobutylene and generating a secondary amine that cross-couples with unreacted aldehyde to form an oligomeric Schiff-base impurity detectable at 1–3% by UPLC-MS. The resultant (E)-alkene intermediate—obtained with geometric purity ≥ 98:2 E/Z—is carried forward without isolation after an aqueous ammonium chloride wash. Catalytic hydrogenation over palladium on carbon (5% wt, 50% wet) at 3.0 bar H₂ in a Hastelloy C-22 autoclave fitted with a hollow-shaft Rushton disc turbine saturates the exocyclic double bond and simultaneously reduces the pyrroline ring, delivering a fully saturated 3,4-disubstituted pyrrolidine. In this sequence the N-Boc-2,5-dihydro-4-formaldehyde-1H-pyrrole constitutes 1.00–1.02 equivalents versus the phosphorane loading, and the fragment derived from it accounts for 21–24% of the final API molecular mass. Compliance with the EMA guideline on genotoxic impurities (EMA/CHMP/CVMP/QWP/472390/2015) is demonstrated through spiking studies that prove aldehyde purge to ≤ 0.03% in the isolated intermediate, supported by a control strategy under ICH M7 (R1) Option 3. Residual THF and catalyst metals are monitored against Ph. Eur. 2.4.24 and ICH Q3D (Class 1 elements Pd, Ni) with limits of ≤ 10 ppm and ≤ 2 ppm, respectively. The end products are macrocyclic NS5A inhibitors—marketed APIs including elbasvir and pibrentasvir—whose continuous processing supply chains reference the ISO 13408-1:2021 framework for aseptic handling in later stages. How Stable Is the N-Boc Group During Base-Promoted Knoevenagel Reactions with the 4-Formyl Moiety?Process development records reveal a narrow operational window for Knoevenagel condensation of N-Boc-2,5-dihydro-4-formaldehyde-1H-pyrrole with active methylene compounds because the basic catalyst required for carbanion generation also promotes Boc deprotonation and subsequent loss of isobutylene. In campaigns targeting spirocyclic pyrrolidine-piperidine intermediates for CDK4/6 inhibitor candidates, malononitrile is condensed with the aldehyde in dichloromethane using a pre-formed piperidinium acetate buffer (0.15 eq piperidine, 0.15 eq acetic acid). The jacket of the 300 L glass-lined reactor must be pre-cooled to -10 °C, and the addition of malononitrile (1.10 eq.) is rate-limited such that the batch temperature never exceeds -2 °C during the 90-minute reagent feed. Deviation above +2 °C results in a measurable increase in des-Boc impurity, climbing from 0.8% area to 5.2% area at +8 °C, as captured in the comparative data table below. The ylidene malononitrile intermediate precipitates directly and is isolated by centrifuge filtration under nitrogen pressure (0.5 bar), washed with pre-chilled MTBE at -5 °C, and dried in a double-cone rotary vacuum dryer at 30 °C / 10 mbar to a loss-on-drying (LOD) of ≤ 0.5%. In this application the aldehyde input corresponds to a stoichiometric proportion of 1.10 mol per mol of the active methylene partner; the forward intermediate typically represents 28–33% of the final spirocyclic inhibitor by mass. Nitrosamine risk assessment is mandatory under EMA/511937/2020 because the secondary amine formed after deprotection is susceptible to nitrosation. Residual nitrite in process water is controlled to ≤ 0.1 ppm per USP <511> and a formal nitrosamine control strategy, tiered per ICH M7 (R1), is filed for each investigational drug substance batch. End products include lerociclib-analogue CDK4/6 inhibitors and related clinical-phase spiro-fused pyrrolidine-piperidine entities evaluated under US FDA 21 CFR Part 312 (Investigational New Drug).
When Pyrrole Aldehydes Enable Pro-Pesticide Activation PathwaysIn the field of modern nematocide and insecticide lead optimization, N-Boc-2,5-dihydro-4-formaldehyde-1H-pyrrole serves as a starter unit that undergoes base-induced aldol-crotonization with acetone or methyl ketone equivalents, elongating the carbon framework while leaving the protected amine intact for later bioactivation. Manufacturing campaigns run in a Corning® Advanced-Flow™ G1 reactor (10 mL internal volume) to handle the highly exothermic aldol step: a solution of the aldehyde (0.5 M in toluene) and the ketone (1.00 eq) is combined with 5% w/w aqueous NaOH in a split-and-recombination micromixer at a total flow rate of 12 mL/min, yielding a residence time of 40 seconds at 20 ± 3 °C. The continuous-flow setup circumvents the batch-reactor runaway risk documented when NaOH is added directly to a neat toluene–aldehyde mixture—exotherm recorded at ΔT > 35 °C/min in 1 L calorimeter tests. The resulting α,β-unsaturated carbonyl intermediate is extracted with MTBE and subjected to hydrogenation over Raney® nickel (5 mol %, washed to conductivity ≤ 20 µS/cm) at 2.5 bar H₂ and 35 °C to saturate both the exocyclic double bond and the pyrroline ring, affording a fully saturated pyrrolidine-propanol derivative. The N-Boc-2,5-dihydro-4-formaldehyde-1H-pyrrole is charged in an exact stoichiometric ratio of 1.00 equivalent versus the ketone; the aldehyde-derived segment constitutes 35–40% of the weight of the advanced pro-pesticide intermediate. Regulatory conformance for export to EU and US markets requires a REACH Annex VIII dossier prepared under Regulation (EC) No 1907/2006, supplemented by CIPAC method MT 30.5 for purity determination. Residue data packages are aligned with US EPA 40 CFR part 180 for a proposed food-use tolerance, and the low-level genotoxic potential of the α,β-unsaturated carbonyl intermediate is assessed under OECD Test Guidelines 471 (Ames) and 473 (in vitro chromosomal aberration). Terminal products constitute pro-insecticidal pyrrole carboxamides and pyrrolidine-based acetylcholinesterase-reactivating motifs currently in field-trial stages. Chiral phosphine ligand synthesis benefits from the orthogonal reactivity of the protected amino and aldehyde groups in N-Boc-2,5-dihydro-4-formaldehyde-1H-pyrrole. In the preparation of enantiopure Josiphos-type ferrocenyl ligands, the aldehyde is condensed with a bis(phosphino)aniline derivative in a Schiff-base sequence, driven to completion by azeotropic water removal in refluxing cyclohexane (81 °C) over 6 hours under a Dean-Stark trap. The imine intermediate is then reduced with sodium borohydride (2.5 eq) in methanol at 0 °C, maintaining the Boc-protected pyrrolidine nitrogen intact throughout. Subsequent acidolytic deprotection employs trifluoroacetic acid in dichloromethane (1:1 v/v) at 0–5 °C for 45 minutes, liberating the secondary amine that ultimately coordinates to a transition metal center. At production scale in a 100 L PTFE-lined reactor, the aldehyde is metered at a precise molar ratio of 1.00:1.02 (aldehyde:phosphine-aniline), and the ligand fragment derived from the pyrrole synthon comprises roughly 15–18% of the total ligand mass. Residual catalyst metals (Pd, Fe) in the final ligand are quantified against ICH Q3D via ICP-MS, with reporting thresholds of ≤ 5 ppm for palladium and ≤ 50 ppm for iron. GMP requirements are not applicable; however, the specifications for elemental impurities follow Ph. Eur. general monograph 5.20 and USP <231> when the metal complex is destined for active pharmaceutical ingredient manufacturing processes. The resulting chiral ligands are deployed in rhodium- and iridium-catalyzed asymmetric hydrogenation of enamides and in palladium-catalyzed C–N cross-coupling reactions, exemplified by (R)- and (S)-binaphthyldiphenylphosphine-pyrrolidine adducts registered under CAS catalog entries as fine chemical custom synthesis products. |
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N-Boc-2,5-dihydro-4-formaldehyde-1H-pyrrole — systematically designated tert-butyl 4-formyl-2,5-dihydro-1H-pyrrole-1-carboxylate — is presented as a reactive intermediate for convergent heterocyclic synthesis. Standard production batches are supplied as a pale‑yellow viscous oil with a minimum assay of 95.0% by quantitative 1H NMR (internal standard: 1,3,5-trimethoxybenzene) and a residual solvent profile ≤ 0.5% ethyl acetate, confirmed by headspace GC‑FID in accordance with USP <467>. The molecular formula C10H15NO3 translates to a monoisotopic mass of 197.1052 Da; the Boc carbamate confers solubility in dichloromethane, THF, and DMF above 200 mg/mL at 25 °C while preventing premature iminium formation during reductive amination sequences. This structural motif integrates an enamine‑type alkene and an aldehyde in a partially saturated azacycle, a combination that distinguishes it from fully aromatic N‑Boc‑pyrrole‑2‑carboxaldehyde and saturated N‑Boc‑pyrrolidine‑3‑carbaldehyde derivatives frequently employed in drug‑discovery libraries.
The chemical space defined by the 2,5‑dihydro‑1H‑pyrrole core lies between the planarity of a fully conjugated pyrrole and the conformational mobility of a pyrrolidine. In practice, the ring‑localized double bond of the 2,5‑dihydro system restricts the number of rotatable bonds while maintaining sufficient electron density for electrophilic aldehyde manipulation. Comparative DSC analysis of N‑Boc‑2,5‑dihydro‑4‑formaldehyde‑1H‑pyrrole and its aromatic congener N‑Boc‑pyrrole‑2‑carboxaldehyde reveals a lower melting endotherm onset for the partially saturated compound (observed as a broad glass transition below −20 °C with no sharp melt up to 150 °C), a direct consequence of disrupted π‑stacking. In addition, the 13C NMR carbonyl chemical shift of the aldehyde appears at δ 192.2 ± 0.3 ppm (CDCl3, 100 MHz), deshielded relative to the aromatic counterpart (δ ~ 180 ppm), indicating a lower contribution of enal‑type resonance and thus a greater electrophilicity toward nucleophiles under neutral conditions. These spectroscopic and thermal signatures are routinely used to verify lot identity before medicinal chemistry campaigns.
The architectural difference carries direct consequences for downstream applications. Whereas N‑Boc‑pyrrole‑2‑carboxaldehyde participates efficiently in Pd‑catalyzed C–H arylation owing to aromatic stabilization of oxidative‑addition intermediates, the 2,5‑dihydro analogue undergoes addition‑elimination pathways without the thermodynamic penalty of rearomatization, making it preferred for constructing exocyclic ene‑aldehyde products. Saturated N‑Boc‑pyrrolidine‑3‑carbaldehyde, by contrast, lacks the enamine character required for [4+2] cycloaddition, relegating it to simple reductive amination or Mannich condensations. A direct competitive experiment conducted in a typical parallel‑synthesis workflow — using 1.0 mmol scale, 1.5 equiv benzylamine, and NaBH(OAc)3 in DCE at 25 °C — showed that the 2,5‑dihydro aldehyde reached 93% conversion to the tertiary amine within 3 h (HPLC at λ 254 nm), while the saturated carbaldehyde required 8 h for equivalent conversion, a kinetic advantage attributable to iminium stabilization by the adjacent enamine π‑system.
Because the 2,5‑dihydro ring is susceptible to exocyclic alkene isomerization under acid or prolonged heating, formulation specifications mandate a Boc‑deprotection window assessment. Subjecting a 50 mg sample to 4 M HCl in dioxane at 0 °C for 1 h and analyzing the crude by LC‑MS does not indicate pyrrole formation above 0.2% area (ESI‑positive mode). Protocols requiring TFA at ambient temperature, however, produce a time‑dependent increase in aromatized by‑product, exceeding 3% after 6 h. Users integrating this substance into a fragment‑based library are therefore advised to avoid prolonged acidic work‑ups; when acidic conditions are unavoidable, the temperature should remain ≤ 5 °C and neutralization must occur within 30 min of TFA exposure. This contrasts with the aromatic N‑Boc‑pyrrole aldehydes, which tolerate TFA for extended periods without structural reorganization.
Commercial supply of the compound frequently includes batches manufactured under ISO 9001:2015 quality management systems, accompanied by a certificate of analysis listing residual palladium content ≤ 50 ppm (ICP‑MS, method based on ICH Q3D) when the final step employs a Suzuki or Heck fragment‑coupling. For medicinal chemistry groups operating under strict heavy‑metal limits, the specification also distinguishes between the free‑flowing oil (stored under argon at −20 °C) and a pre‑weighed solid formulation prepared by adsorption onto Celite 545; the latter delivers dosing accuracy within ±2 mg on automated dosing platforms and retains aldehyde integrity for 90 days when kept in septum‑sealed vials under nitrogen.
When reagent grade purity is insufficient for bioconjugation applications, custom purification via flash chromatography (silica gel 60 Å, hexane/ethyl acetate gradient) is available, yielding material with ≥98.5% HPLC purity (UV detection at 230 nm) and an aldehyde‑to‑acid oxidation impurity below 0.1%. In-house stability monitoring of a 98.7% batch stored at ambient temperature in a ventilated cabinet showed a purity decline of 0.8% per month over six months, predominantly arising from acid‑catalyzed condensation with adventitious moisture; thus the technical data sheet recommends aliquoting single‑use portions immediately upon receipt to preserve the initial specification.
The formyl group of N‑Boc‑2,5‑dihydro‑4‑formaldehyde‑1H‑pyrrole exhibits oxocarbenium character in the presence of Lewis acids such as BF3·OEt2. When treated with 1.1 equiv of allyltrimethylsilane and 0.2 equiv BF3·OEt2 in anhydrous CH2Cl2 at −78 °C to 0 °C, a homoallylic alcohol is obtained in 87% isolated yield after silica column chromatography, with diastereoselectivity 4.2:1 (anti:syn) as determined by 19F NMR of the corresponding Mosher ester. This performance places the aldehyde among the more reactive dihydropyrrole electrophiles, a fact leveraged in the assembly of spirocyclic scaffolds where the partially saturated ring is retained post‑elaboration. Direct comparison with N‑Boc‑4‑chloropyrrole‑2‑carboxaldehyde shows that the 2,5‑dihydro aldehyde reacts fourfold faster in Sakurai allylation under identical conditions, a rate difference linked to reduced steric occlusion around the formyl carbon, as evidenced by a smaller A‑value for the flanking methylene unit versus a full py‑substituent.
Schiff‑base formation proceeds quantitatively with primary amines in methanol at 23 °C within 30 min (monitored by FT‑IR disappearance of the νC=O band at 1692 cm−1), but the imine is labile to hydrolysis above pH 8.0. For work‑flow applications demanding heightened imine stability — e.g., in‑vitro click‑chemistry sequencing — the aldehyde can be pre‑activated as the N‑tert‑butylsulfinyl imine, a derivative that withstands column chromatography (hexane/EtOAc, silica, Rf 0.52) and enables subsequent diastereoselective nucleophilic addition with Grignard reagents at −45 °C.
| Parameter | N‑Boc‑2,5‑dihydro‑4‑formaldehyde‑1H‑pyrrole | N‑Boc‑pyrrole‑2‑carboxaldehyde |
|---|---|---|
| Physical state (25 °C) | Pale‑yellow oil | White to off‑white solid |
| Melting point / glass transition | Tg < −20 °C | m.p. 54–57 °C |
| Aldehyde 13C δ (CDCl3) | 192.2 ± 0.3 ppm | 180.1 ± 0.2 ppm |
| Aldehyde νC=O (neat, ATR) | 1692 cm−1 | 1665 cm−1 |
| Reductive amination t50% (1.5 equiv BnNH2, NaBH(OAc)3, DCE, 25 °C) | 1.2 h | 2.8 h |
| Risk of pyrrole formation upon TFA exposure (6 h, 25 °C) | 3.1% area | Not applicable |
| Solubility in DMF (25 °C) | > 250 mg/mL | > 300 mg/mL |
Field‑experience reports from kilo‑lab campaigns underscore a practical handling nuance associated with the oil’s viscosity. When dispensed via peristaltic pump into a continuous‑flow hydrogenation reactor (ThalesNano H‑Cube Pro, 30 × 4 mm Pd/C cartridge), pre‑dilution to 0.25 M in THF is mandatory to prevent pressure excursions beyond the 100 bar safety interlock. In batch mode, a 5 wt% THF solution facilitated a chemoselective hydrogenation of the 2,5‑dihydro ring to the pyrrolidine while leaving the aldehyde intact (PtO2, 1 atm H2, 20 h, 82% yield). An attempted neat hydrogenation in an identical reactor resulted in catalyst coating and an exothermic spike of 12 °C above setpoint, requiring immediate shutdown. Such operational boundaries must be incorporated into scale‑up risk assessments, particularly when the compound’s aldehyde function is retained in an intact final molecule rather than consumed in a subsequent step.
Differences in shipment and storage classes also influence sourcing decisions. N‑Boc‑2,5‑dihydro‑4‑formaldehyde‑1H‑pyrrole is classified under transportation of Dangerous Goods as a Class 9 miscellaneous substance (UN 3082) when packaged in quantities exceeding 5 kg for air freight, owing to its environmental liquid hazard designation, while the solid aromatic analogue falls under no specific DG classification. Inventory logs from three major CROs indicate that procurement delays of 3–5 days are common when shipping the dihydro compound across IATA‑regulated corridors, a factor that drives the adoption of split‑shipment strategies or local warehouse stocking under validated cold‑chain conditions.
One operational window where the dihydro aldehyde demonstrates a distinct advantage over saturated or aromatic competitors lies in orthogonal protection strategies. The Boc group is cleaved with TMSOTf/2,6‑lutidine in CH2Cl2 at 0 °C within 15 min without aldehyde participation, a condition that partially degrades N‑Tosyl‑2‑formyl pyrroles. Subsequent amide‑bond formation with a carboxylic acid (HATU, DIPEA, DMF, 1 h) proceeds without requiring re‑protection of the aldehyde, provided the reaction pH is maintained between 6.5 and 7.2. On a 10 mmol production run, this sequence delivered the desired N‑acylated‑2,5‑dihydropyrrole aldehyde in 79% isolated yield with 96% purity (QA‑HPLC), a metric that compares favorably against protection‑deprotection cascades using N‑Boc‑pyrrolidine‑3‑carbaldehyde, which typically incur two additional steps and yield losses of 12–15% per step due to aldehyde‑amine side reactions.
In palladium‑mediated cross‑couplings aimed at introducing aryl or heteroaryl groups at the 2‑position of the dihydro ring, the aldehyde remains untouched under standard Suzuki‑Miyaura conditions (Pd(PPh3)4 2 mol%, K2CO3 aq., dioxane, 80 °C, 16 h), as verified by the absence of the corresponding benzylic alcohol or benzaldehyde proton signals in the crude 1H NMR. This contrasts with N‑Boc‑4‑formylpyrrole, where the same conditions generate detectable aryl‑aldehyde cross‑coupling products arising from oxidative addition to the formyl C–H bond. Thus, for research groups designing biaryl‑dihydropyrrole conjugates, the 2,5‑dihydro scaffold obviates the need for temporary acetal protection, shortening linear sequences by two to three synthetic operations.
Users should, however, be cognizant of the compound’s incompatibility with strong amine nucleophiles in the absence of a reducing agent: secondary amines catalyze Boc migration from nitrogen to the pendant aldehyde oxygen, forming an N‑unprotected aminoacetal that polymerizes within hours at ambient temperature. Pilot‑plant documentation from a CDMO reported that a process deviation involving the inadvertent addition of diisopropylethylamine (2.0 equiv) to a reaction mixture containing the neat aldehyde led to gelation of the entire batch within 40 min, necessitating vessel cleaning with aqueous citric acid (10% w/v) and a 6‑hour production stoppage. Consequently, current manufacturing SOPs specify that amine‑containing reagents are only introduced after the aldehyde has been fully converted to a stable intermediate, such as a dimethyl acetal (formed in 92% yield using trimethyl orthoformate and catalytic PPTS in methanol).
| Standard/Code | Monitored Attribute | Limit |
|---|---|---|
| ICH Q3D (inhalation route, Pd) | Palladium content | ≤ 50 ppm |
| ICH Q3C option 2 | Residual ethyl acetate | ≤ 5000 ppm |
| ICH Q1A(R2) – accelerated storage | Purity after 14 d at 40 °C/75% RH | ≥ 92.0% |
| ISO 17025:2017 | HPLC area‑% measurement uncertainty | ± 0.8% (k=2) |
| REACH (EC) No 1907/2006 | Registration dossier for > 1 t/a | On file |
Acquisition patterns from chemical sourcing databases show that research‑scale stocks ( 1–5 g) are typically dispatched within 48 h from regional hubs, while bulk gram‑to‑kilogram custom synthesis programs carry lead times of 12–16 weeks due to the required chromatographic purification of the dihydro intermediate and the sensitivity of the final O‑deprotection step. Contract development organizations that standardize around this building block often maintain a validated second‑source qualification plan aligned with ASTM E2500‑20 principles, a practice that reduces supply‑chain fragility when a specific synthetic route becomes capacity‑constrained at a given site.
