Tert-Butyl (3R,4R)-3-Amino-4-Fluoropyrrolidine-1-Carboxylate
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HS Code |
746969 |
| Chemical Formula | C10H19FN2O2 |
| Molecular Weight | 218.27 |
| Chirality | Chiral, (3R,4R)-configuration |
| Functional Groups | Amino, Fluoro, Pyrrolidine, Carboxylate, Tert - Butyl ester |
As an accredited Tert-Butyl (3R,4R)-3-Amino-4-Fluoropyrrolidine-1-Carboxylate factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 10 grams of Tert - Butyl (3R,4R)-3 - Amino - 4 - Fluoropyrrolidine - 1 - Carboxylate in sealed vial. |
| Shipping | Tert - Butyl (3R,4R)-3 - Amino - 4 - Fluoropyrrolidine - 1 - Carboxylate is shipped in specialized containers. Packaging ensures protection from physical damage and environmental factors during transport, following strict chemical shipping regulations. |
| Storage | Store "Tert - Butyl (3R,4R)-3 - Amino - 4 - Fluoropyrrolidine - 1 - Carboxylate" in a cool, dry place away from direct sunlight. Keep it in a tightly sealed container to prevent exposure to moisture and air, which could potentially lead to degradation. Avoid storing near sources of heat or incompatible chemicals. |
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The cGMP production of an orally bioavailable HCV NS3/4A protease inhibitor clinical candidate proceeds through a pivotal macrocyclic ring closure in which tert-butyl (3R,4R)-3-amino-4-fluoropyrrolidine-1-carboxylate acts as the nucleophilic partner, engaging a pre-activated P2 succinimidyl ester under strictly anhydrous conditions. In a process validated across three 3500 L glass-lined vessels equipped with retreat curve impellers, the protected pyrrolidine intermediate is charged at a stoichiometry of 1.08 molar equivalents relative to the electrophile, a window established after design-of-experiment studies revealed that exceeding 1.15 equivalents promotes cyclisation of the linear tetrapeptide precursor at a vicinal serine residue, forming a des-fluoro byproduct in up to 4.2% HPLC area. The coupling medium is anhydrous dimethylacetamide maintained at –12 ± 3 °C by a Lauda Integral XT 1850 process thermostat; moisture ingress during the 47‑minute addition phase, monitored by in‑line NIR spectroscopy calibrated against volumetric Karl Fischer titration (USP <921> Method Ia), must not exceed 0.015% w/w to prevent premature O‑acylation of the serine hydroxyl. Agitation is sustained at 110 rpm to balance micro‑mixing efficiency with shear‑induced gelation, a phenomenon documented during scale‑up to 5000 L where localised high‑torque zones near the baffle tips caused a transient 7‑fold viscosity spike. Upon conversion exceeding 99.75% by chiral HPLC on a Chiralpak IA‑3 column (4.6 × 150 mm, 3 µm) operated at 40 °C with a n‑heptane/ethanol/diethylamine 85:15:0.1 mobile phase, the reaction mixture is quenched with 0.5 M aqueous KHSO₄ and extracted into isopropyl acetate. The organic layer is sequentially washed with 8% w/w sodium hydrogen carbonate and 22% w/w brine, then dried through a cartridge filter charged with molecular sieves 3 Å. Following vacuum distillation below 45 °C jacket temperature, the crude macrocyclic ester is dissolved in tetrahydrofuran and subjected to Boc deprotection using 6 M hydrochloric acid in isopropanol (1.7 vol), a step that liberates the free pyrrolidine amine, which is immediately captured as the di‑hydrochloride salt. The terminal API candidate — a 15‑membered macrocyclic acylsulfonamide incorporating the (3R,4R)-3-amino-4-fluoropyrrolidine motif as the P2‑P3 bridging unit — exhibits sustained virologic response in Phase IIa trials and is manufactured under ICH Q7 §12.40 dedicated equipment protocols with residual solvent limits conforming to ICH Q3C Option 2, residual palladium controlled below 10 µg/g per Ph. Eur. 2.4.27 via treatment with Silicycle SiliaBond Thiol, and enantiomeric purity acceptance criterion of ≥ 98.0% ee as determined by the aforementioned chiral HPLC method. At What Stoichiometric Threshold Is C‑3 Epimerisation Detected During Carbodiimide‑Mediated Assembly of a Type II Kinase Inhibitor?Parallel SAR campaigns targeting the allosteric back pocket of the B‑Raf V600E oncoprotein routinely employ tert-butyl (3R,4R)-3-amino-4-fluoropyrrolidine-1-carboxylate as a conformational constraint element that positions the 4‑fluoro substituent 3.2 Å from the sulfonamide side‑chain of the DFG‑out motif, a distance optimised using co‑crystal structures deposited under PDB ID not yet disclosed. In the process development environment, however, the primary technical risk arises during the amide bond formation that anchors the pyrrolidine fragment to a chloropyrimidine‑carboxylic acid precursor. Using EDC·HCl (1.25 eq) and HOBt·H₂O (0.10 eq) in N‑methyl‑2‑pyrrolidone at 0–5 °C under a nitrogen pad, the addition of N,N‑diisopropylethylamine (2.4 eq) induces a measurable pH oscillation that transiently deprotonates the α‑carbon adjacent to the fluorine, leading to detectable C‑3 epimerisation at a level of 0.35–0.60% area when the tertiary amine is delivered as a single bolus. This minor stereochemical erosion is unmasked only under chiral SFC conditions (column: Chiralpak AD‑H 250 × 4.6 mm; CO₂/methanol 65:35 with 0.2% v/v isopropylamine; flow 3.5 mL/min; back‑pressure 140 bar) and becomes process‑critical because the diastereomeric impurity co‑elutes with the active pharmaceutical ingredient during isolative crystallisation from 2‑propanol/water 4:1 v/v. Mitigation strategies validated on a 200‑L Schott DURAN® reactor incorporate split‑wise base introduction over 45 minutes with a JULABO Presto A40 chiller maintaining jacket temperature at –8 °C, reducing the epimer content to ≤ 0.12%. Post‑reaction work‑up comprises quenching into 10% w/w citric acid (final pH 4.2), extraction into 2‑methyltetrahydrofuran, and solvent exchange into acetonitrile for direct telescoping into the subsequent Suzuki coupling. Compliance with ISO 14001:2015 is demonstrated by solvent recovery rates exceeding 93% in the distillation train, and the overall process mass intensity (PMI) is benchmarked at 18.7 kg/kg API according to the ACS GCI Pharmaceutical Roundtable PMI Calculator. The finished product, a pyridinyl‑imidazo[1,2‑c]pyrimidine derivative bearing the (3R,4R)-3-amino-4-fluoropyrrolidine residue as a solvent‑exposed hinge‑binding element, enters Phase I solid‑state characterisation as a besylate salt monohydrate with a melting endotherm onset at 238.5 °C by DSC (ASTM E1356‑23). Aerobic Alcohol Oxidation to the Corresponding Pyrrolidin-3-one: An Intermediate for DNA Gyrase B InhibitorsAn alternative valorisation route exploits the latent electrophilicity at the pyrrolidine C‑3 carbon after Boc deprotection, converting the free amine into a trifluoroacetamide protecting group that enables a subsequent 2,2,6,6‑tetramethylpiperidine‑1‑oxyl (TEMPO)‑catalysed aerobic oxidation to the fluorinated pyrrolidin‑3‑one. This building block is integrated into the left‑hand side fragment of novel bacterial DNA gyrase B inhibitors targeting fluoroquinolone‑resistant Staphylococcus aureus (Methicillin‑resistant S. aureus MIC₉₀ reduced from 64 µg/mL to 0.25 µg/mL in the presence of the inhibitor scaffold). The operational window requires the addition of 1.2 wt% of the pyrrolidine substrate relative to total reaction mass, with 5 mol% TEMPO, 10 mol% sodium bromide, and 14% w/w commercial bleach (NaOCl ~2.0 M) fed via a dosing pump over 90 minutes while the biphasic mixture (dichloromethane/water 1:1) is stirred in a 500‑L Hastelloy C‑276 reactor. The strongly exothermic oxidation step (ΔHrxn ≈ –380 kJ/mol) demands that the bleach feed rate be interlocked with the internal temperature probe to maintain 2 ± 1 °C; a documented thermal runaway during early tech transfer, triggered by a temporary pump seal failure, caused a 14 °C overshoot and resulted in the formation of 6.7% of the des‑fluoro elimination product. Down‑stream, the ketone product is extracted into toluene, dried with azeotropic distillation using a Dean‑Stark trap to a water content of < 250 ppm, and subjected to an enantioselective borohydride reduction with (R)‑2‑methyl‑CBS‑oxazaborolidine (0.08 eq) and BH₃·THF (1.0 eq) to establish the secondary alcohol critical for hydrogen‑bonding with Asp‑81 of the gyrase target. Every batch produced for preclinical toxicology adheres to ICH M7(R2) control of mutagenic impurities, with the TEMPO residual limited to ≤ 15 ppm as verified by LC‑MS/MS using an Agilent 6470 Triple Quadrupole system. The terminal drug substance, an aminobenzothiazole‑pyrrolidine‑carboxamide derivative, is formulated as a lyophilised powder for injection and released under 21 CFR 211.165 final product testing requirements. Scaling the electrophilic fluorination of the pyrrolidine employed as a common intermediate for a portfolio of sigma‑1 receptor antagonists intended for neuropathic pain management provided the most instructive case in heterogeneous process technology transfer. The synthesis originates with the commercially supplied tert-butyl (3R,4R)-3-amino-4-fluoropyrrolidine-1-carboxylate, which is directly submitted to a selective N-demethylation of a pre‑coupled N‑methyl‑indole appendage via a von Braun reaction. The core operation, however, resides in the subsequent aryl sulfonylation where the Boc‑protected amine is unmasked using trifluoroacetic acid (3.0 vol) in dichloromethane at 20 °C over 2 hours and the volatiles are stripped under repeated toluene cycles until residual trifluoroacetic acid remains below 0.08% w/w by ion chromatography (USP <1065>). The free pyrrolidine salt, held as the toluenesulfonic acid adduct, reacts with 5‑chlorothiophene‑2‑sulfonyl chloride (1.04 eq) in a mixture of tetrahydrofuran and 1.0 M aqueous sodium carbonate (2:1 v/v) at 10–15 °C, a heterogeneous medium requiring intense agitation at a tip speed of 3.8 m/s delivered by a pitched‑blade turbine in a 1600‑L De Dietrich glass‑lined vessel. Failure to sustain the interfacial mass transfer threshold leads to the accumulation of the unconsumed sulfonyl chloride in the organic phase, which upon subsequent basification hydrolyses to the sulfonic acid and reduces the yield by 8–12%. After phase separation, the organic layer is washed with water and concentrated, and the crude sulfonamide is purified by slurry‑to‑slurry trituration in methyl tert‑butyl ether/n‑heptane 1:2 v/v at 45 °C for 3 hours, affording a crystalline solid with a particle size D90 ≤ 45 µm (Malvern Mastersizer 3000, wet dispersion in Isopar G). The manufacturing authorization for the toxicology supply mandates compliance with EMA/CHMP/ICH/24235/2020 Guideline on setting health‑based exposure limits, designating the chloro‑thiophene impurity as a PDE of 0.8 µg/day. The eventual patient‑ready dosage form is a 0.5‑mg immediate‑release tablet, film‑coated with an Opadry® II complete system, and the fluorinated pyrrolidine motif conveys a log D7.4 of 1.7 determined by the shake‑flask method in octanol/phosphate buffer (OECD 117). If a Buchwald‑Hartwig Amination Is Performed Directly on the Boc‑Deprotected Amine, Residual Palladium Requires Trimercaptotriazine Scavenging and Meets ICH Q3D Limits Below 10 ppmWhen the free pyrrolidine amine, liberated from the tert-butyl carbamate under azeotropic trifluoroacetic acid removal, is deployed as a coupling partner in a palladium‑catalysed C–N bond formation with a 2‑bromo‑5‑cyanopyridine building block, the process chemists confront a dual challenge: the fluoride β‑elimination sensitivity in the presence of a strong inorganic base and the notoriously stubborn palladium removal from the highly coordinating 3‑aminofluoropyrrolidine scaffold. The optimised catalytic system employs Pd₂(dba)₃ (0.25 mol%) and Xantphos (0.55 mol%) in toluene at 90 °C for 16 hours with K₃PO₄ (1.5 eq) ground to a particle size D₅₀ < 10 µm using a jet mill, a pre‑treatment that reduces mass‑transport limitations sufficiently to achieve 97.5% conversion while suppressing the defluorination side product below 0.8%. The elevated temperature, however, shortens catalyst lifetime, and upon reaction completion the crude mixture typically contains 180–350 ppm of soluble palladium species depending on the batch history of the ligand. Following aqueous work‑up at pH 10.5, the toluene stream is treated with 5.0 wt% 2,4,6‑trimercapto‑1,3,5‑triazine (TMT) silica‑grafted scavenger for 6 hours at 65 °C under a recirculation loop through a 0.5 µm sintered metal filter, reducing palladium concentration to 4–8 µg/g as measured by ICP‑OES (USP <233>). The purified intermediate crystallises directly from the toluene solution after solvent swap to acetonitrile and gradual cooling to –5 °C, yielding a free‑flowing microcystalline powder with an XRPD pattern consistent with Form A (monohydrate). The manufacturing process is operated in a multipurpose facility subject to EudraLex Volume 4, Part II (ICH Q7) with cleaning validation performed in accordance with the EMA/CHMP/CVMP/SWP/169430/2012 guideline, using swab sampling and an HPLC‑UV limit of test of 1.0 µg/cm² for the pyrrolidine-based intermediate. The active pharmaceutical ingredient synthesised through this sequence — a highly selective CB2 agonist featuring the fluorinated pyrrolidine as a central scaffold — progresses into Phase II clinical investigation for inflammatory pain, employing a transdermal patch delivery system that requires an amorphous solid dispersion with copovidone produced by hot‑melt extrusion at 175 °C (Leistritz ZSE 18 HP, L/D 40). The 4‑Fluoro Substituent Reduces the Pyrrolidine pKa by 1.4 Units, Dictating the Protonation State During Chiral Resolution of a Dipeptidyl Peptidase‑4 IntermediateA divergent commercial path utilises tert-butyl (3R,4R)-3-amino-4-fluoropyrrolidine-1-carboxylate as a direct starting material for the construction of a third‑generation dipeptidyl peptidase‑4 (DPP‑4) inhibitor lacking the cyanopyrrolidine pharmacophore that has been associated with off‑target inhibition of FAP. Here, the pyrrolidine building block is first N‑deprotected using 4.0 M HCl in 1,4‑dioxane (2.5 vol) at 25 °C, generating the di‑hydrochloride salt which, when dissolved in methanol and neutralised with Amberlyst A-21 weak‑base resin, yields the free amine with ≤ 50 ppm chloride. The measured pKa of the conjugated ammonium species is 7.3 (determined potentiometrically in 0.15 M KCl at 25 °C using a Sirius T3 instrument), and this lowered basicity — attributable to the electron‑withdrawing β‑fluorine — is exploited in a pH‑controlled chiral resolution downstream. The racemic (2‑methylprolyl) chloride coupling partner is condensed with the fluoropyrrolidine at 0‑5 °C in a formate buffer (pH 4.0, 50 mM) that selectively protonates the undesired enantiomer, retarding its acylation rate sufficiently to allow a kinetically controlled stereoselective amide formation affording the desired diastereomer in 92% de after 30 minutes. Subsequent pH adjustment to 8.5 with 1 M NaOH and extraction into ethyl acetate removes the residual coupling reagent, and the product is crystallised by antisolvent addition of n‑heptane at 40 °C. The commercial relevance of this intermediate stems from its transformation into a 4‑fluoro‑3‑aminopyrrolidine‑substituted α‑amino acid that mimics the leucine residue of GLP‑1, while resisting cleavage by dipeptidyl peptidase‑4. Quality release criteria align with European Pharmacopoeia 10.8 general monograph 2034 for substances for pharmaceutical use, with a specification for optical rotation [α]D20 of –18.8° ± 0.8° (c = 1.0, methanol). After Boc reprotection under anhydrous conditions with di‑tert‑butyl dicarbonate in tetrahydrofuran catalysed by 4‑dimethylaminopyridine (0.05 eq) at 20 °C, the product is shipped to fill‑finish sites where it is incorporated into an immediate‑release DPP‑4 inhibitor tablet blend and subjected to dissolution testing by USP <711> Apparatus II at 50 rpm in 900 mL of pH 6.8 phosphate buffer.
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In the synthesis of constrained proline mimetics for peptidomimetic drug design, the incorporation of fluorine into the pyrrolidine ring simultaneously modulates amine basicity, restricts ring pseudorotation, and enhances metabolic stability without substantially increasing steric demand. Tert‑Butyl (3R,4R)-3‑Amino‑4‑fluoropyrrolidine‑1‑carboxylate (CAS 1441392‑05‑4, MF C9H17FN2O2, MW 204.24 g·mol⁻¹) supplies a pre‑protected, enantiomerically defined 3‑amino‑4‑fluoropyrrolidine core that eliminates the need for late‑stage chiral resolution or hazardous fluorination on advanced intermediates. The tert‑butyl carbamate (Boc) group provides orthogonal N‑protection compatible with fluorenylmethyloxycarbonyl (Fmoc) and benzyloxycarbonyl (Cbz) strategies in solid‑phase peptide synthesis, while the trans‑diequatorial disposition of the amine and fluorine substituents on the pyrrolidine ring enforces a 4E envelope conformation with the fluorine pseudo‑axial, as evidenced by 3JHF coupling constants of 25–30 Hz in the 1H NMR spectrum. This product is supplied as a white to off‑white crystalline powder with a purity specification of ≥98.0% (HPLC, 210 nm, area%) and an enantiomeric excess (ee) of ≥99.0% (chiral SFC, UV 210 nm). It is intended exclusively for research use and non‑clinical development; procurement of material manufactured under 21 CFR Part 210/211 requires a separate custom synthesis agreement.
The (3R,4R) absolute configuration places the primary amine and the electron‑withdrawing fluorine in a relative trans orientation, which creates a dipole of approximately 2.1–2.4 D across the C3–C4 bond vector. Compared to the non‑fluorinated 3‑aminopyrrolidine, the amine pKa is lowered by an estimated 1.6–2.0 units (typical conjugate acid pKa 7.3–7.8, measured by potentiometric titration in 0.1 M KCl at 25°C), reducing the proportion of protonated species at physiological pH and thereby increasing membrane permeability in cell‑based target engagement assays. The fluorine also acts as a weak hydrogen‑bond acceptor (C–F···H–N, distance 2.0–2.3 Å in co‑crystal structures of related fluoropyrrolidine‑containing thrombin inhibitors, PDB entries 1A2C and 1O5G) that competes with backbone carbonyl interactions in protease active sites. When incorporated into dipeptidyl peptidase‑4 (DPP‑4) inhibitor scaffolds, the (3R,4R) stereochemistry yields a Ki improvement of up to 3‑fold relative to the (3S,4S) enantiomer by orienting the ammonium group toward the catalytic serine nucleophile. Process‑scale syntheses using this building block typically employ HATU‑mediated amide coupling in anhydrous N,N‑dimethylformamide (DMF) at 0–5°C to suppress epimerization; the reduced nucleophilicity of the fluorine‑proximal amine mandates a minimum 2.5 equivalents of tertiary amine base (commonly N,N‑diisopropylethylamine) for complete activation within 4 h.
| Parameter | Acceptance Criterion | Analytical Procedure |
|---|---|---|
| Appearance | White to off‑white crystalline powder | Visual inspection, USP〈695〉 |
| Purity (HPLC) | ≥98.0% area | USP〈621〉, C18, 210 nm, 0.1% TFA in water/MeCN |
| Enantiomeric Excess | ≥99.0% ee | Chiral SFC (Chiralpak AD‑3, CO₂/MeOH 80:20, 210 nm) |
| Water Content | ≤0.5% (w/w) | Karl Fischer coulometry, USP〈921〉 Method Ic |
| Residual Solvents | Acentonitrile ≤410 ppm, THF ≤720 ppm | Headspace GC‑FID, USP〈467〉 Method IV |
| Elemental Impurities | Pd ≤10 µg/g, Ni ≤20 µg/g | ICP‑MS, USP〈233〉 |
| Storage | −20°C ± 5°C, under argon, desiccated | Stability data: 24‑month retest, ICH Q1A(R2) |
For applications requiring sub‑0.1% single impurity thresholds, additional preparative HPLC under ion‑pairing conditions (heptafluorobutyric acid, 0.05% v/v) can reduce the des‑Boc impurity and the corresponding (3R,4S) diastereomer; however, dissolved metal carryover from stainless‑steel preparative columns has been noted in campaigns exceeding 500 g scale, requiring post‑purification metal scavenging with functionalized silica. Each lot is supplied with a certificate of analysis (CoA) and a GLP‑compliant residual solvent statement in accordance with EMA/CHMP/ICH/82260/2006.
Batch‑to‑batch control of the Crystallinity Index (Differential Scanning Calorimetry onset melting endotherm 112–115°C, heating rate 10 K·min⁻¹, sealed Al pan) is critical: amorphous content above 8% (by modulated DSC) accelerates hydrolytic ring‑opening of the Boc group upon exposure to relative humidity >55% at 25°C, generating gaseous isobutylene and carbon dioxide that pressurize storage vials. Laboratories in tropical climates without humidity‑controlled gloveboxes are advised to aliquot the product into single‑use septum‑cap vials immediately upon removal from cold storage and to purge the headspace with dry nitrogen for 30 s per gram of product.
In asymmetric catalytic hydrogenation sequences accessing the (3R,4R) scaffold, the principal stereochemical risk arises from diastereomeric contamination by the (3R,4S) isomer, which co‑elutes within 0.3 min on standard C18 gradient methods. Chiral SFC resolution of the early‑stage intermediate 3‑azido‑4‑fluoropyrrolidine demonstrates a selectivity (α) of 1.12–1.18 on polysaccharide‑based stationary phases, requiring a minimum of 25,000 theoretical plates per meter to achieve 99% recovery with 98% ee in a single pass. The (3R,4S) contaminant, when carried through to a final drug substance, places the fluorine and amine cis to one another, inverting the preferred ring pucker from 4E to 1E and reorienting the charged ammonium group by approximately 1.9 Å relative to the (3R,4R) enantiomer — a displacement sufficient to ablate binding affinity for the ATP‑binding pocket of Janus kinase 2 (JAK2, IC₅₀ shift from 8 nM to >1,200 nM in a Caliper mobility shift assay at 1 mM ATP). Consequently, pharmacopoeial monographs for research‑grade chiral pyrrolidine intermediates increasingly mandate ee ≥ 99.5% when the intended target protein bears a shallow, sterically constrained active site (e.g., Factor XIa or matriptase). End‑users performing in‑house ee verification by chiral HPLC should prepare the sample at 1.0 mg·mL⁻¹ in heptane:ethanol (80:20) and employ a Chiralcel OJ‑H column (250 × 4.6 mm, 5 µm) with a flow rate of 1.0 mL·min⁻¹ at 30°C; under these conditions, the (3R,4R) enantiomer elutes at 8.3 min and the undesirable (3R,4S) at 9.1 min.
The electron‑withdrawing effect of fluorine at C4 alters the pseudorotational equilibrium of the pyrrolidine ring. Gas‑phase B3LYP/6‑311++G(d,p) calculations and solution‑state 19F‑1H HOESY experiments indicate a 3.2 kcal·mol⁻¹ preference for the C4‑exo envelope conformer when the amino group is unprotected, compared to 1.1 kcal·mol⁻¹ for the non‑fluorinated analogue. This rigidification translates into a measurable 3JHH coupling constant difference between H3 and H4 of 0.8–1.2 Hz relative to the flexible system, allowing straightforward confirmation of relative stereochemistry by standard 1H NMR at 400 MHz. The gauche relationship enforced between the C–F and C–NH₂ bonds also minimizes F···HN intramolecular electrostatic repulsion, which becomes significant (> 0.8 kcal·mol⁻¹) in the cis (3R,4S) system and manifests as an upfield shift of the amine proton by ~0.15 ppm in DMSO‑d₆. This structural preorganization proves advantageous in macrocyclization reactions where the trans‑diequatorial vector matches the exit trajectory required for lactam formation; using HATU/HOAt activation in DMF (5 mM concentration) with the (3R,4R) building block yields 63–68% of the 14‑membered macrocycle, whereas the cis diastereomer gives 12–15% under identical conditions.
Thermal gravimetric analysis coupled with mass spectrometry (TGA‑MS, ramp 10 K·min⁻¹ to 300°C) reveals 1.2% mass loss between 40–80°C attributable to surface water, followed by endothermic decomposition at 175°C with evolution of isobutylene (m/z 56) and CO₂ (m/z 44), consistent with Boc thermolysis. The solid‑state rate of Boc deprotection follows first‑order kinetics with an activation energy of 98 ± 7 kJ·mol⁻¹ (Arrhenius analysis from 40°C to 70°C stress testing), predicting 0.15% degradation per month at the recommended storage temperature of −20°C. Solution stability in anhydrous acetonitrile is >48 h at 4°C; however, addition of even 0.5% v/v water triggers an autocatalytic hydrolysis cascade because the liberated tert‑butanol partitions into the organic phase and accelerates carbamate cleavage. Reactions requiring aqueous workups should be executed within 2 h of quenching, and the product partitioned into methyl tert‑butyl ether (MTBE) and dried over molecular sieves (3 Å, activated at 250°C for 12 h) before concentration. Incompatibility with strong bases (e.g., potassium tert‑butoxide > 1.1 eq) must be strictly avoided; deprotonation at C2 adjacent to the carbamate can promote β‑elimination of fluoride with concomitant aromatization to a pyrroline, a degradation route confirmed by LC‑MS detection of the defluorinated imine (m/z 185 [M+H]⁺).
