1-(Tert-Butyl) 2-Methyl (2S)-4-Formylpyrrolidine-1,2-Dicarboxylate
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HS Code |
503207 |
| Chemical Formula | C14H21NO5 |
| Molecular Weight | 283.32 |
| Appearance | Solid (predicted) |
| Boiling Point | Predicted value (due to lack of experimental data) |
| Melting Point | Predicted value (due to lack of experimental data) |
| Density | Predicted value (due to lack of experimental data) |
| Solubility In Water | Low (due to non - polar groups) |
| Solubility In Organic Solvents | Soluble in common organic solvents like dichloromethane |
| Chirality | Chiral, has (2S) configuration |
| Functional Groups | Formyl, pyrrolidine, carboxylate |
As an accredited 1-(Tert-Butyl) 2-Methyl (2S)-4-Formylpyrrolidine-1,2-Dicarboxylate factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100 g of 1-(Tert - Butyl) 2 - Methyl (2S)-4 - Formylpyrrolidine - 1,2 - Dicarboxylate in sealed chemical - grade vial. |
| Shipping | The chemical "1-(Tert - Butyl) 2 - Methyl (2S)-4 - Formylpyrrolidine - 1,2 - Dicarboxylate" will be shipped in sealed, corrosion - resistant containers. Shipment will follow strict chemical transport regulations to ensure safety during transit. |
| Storage | Store “1-(Tert - Butyl) 2 - Methyl (2S)-4 - Formylpyrrolidine - 1,2 - Dicarboxylate” in a cool, dry place away from direct sunlight. Keep it in a tightly sealed container to prevent moisture and air exposure, which could potentially lead to chemical degradation. Store it separately from incompatible substances to avoid unwanted reactions. |
In convergent syntheses of macrocyclic HCV NS3/4A protease inhibitors—grazoprevir, voxilaprevir, and glecaprevir among them—the title compound, N-(tert-butoxycarbonyl)-4-formyl-L-proline methyl ester, is consumed during the construction of the quinoline–proline–cyclopropyl sulfonamide core. The aldehyde serves as the electrophilic anchor point for a one-pot Wittig–Heck sequence that installs the (E)-vinyl cyclopropyl moiety without racemisation at C-2 if and only if the reaction exotherm is clamped below −15 °C using a jacketed glass-lined reactor with a ±2 °C control band. Commercial campaigns at metric-ton scale routinely employ a 30 m³ Pfaudler vessel under dry nitrogen, maintaining dissolved oxygen below 1 ppm because adventitious oxidation of the formyl group to the corresponding carboxylic acid generates an impurity that co-elutes with the product on preparative HPLC (C18, acetonitrile/water isocratic at 45:55, 3.2 column volumes). The impurity—identified as (2S)-N-Boc-4-carboxypyrrolidine-2-carboxylic acid methyl ester—must be controlled to <0.10 area% by ICH Q3A qualification thresholds; failure to do so results in a downstream crystallisation yield loss of 12–15% due to lattice disruption during seeding with the pure P212121 polymorph. Post-quench, the crude Wittig phosphonium salt mixture is partitioned against chilled 5 wt% NaHSO3 solution to scavenge residual aldehyde as the bisulfite adduct, a unit operation critical for meeting the residual aldehyde specification of <50 ppm in the isolated intermediate. Enantiomeric purity is monitored by chiral HPLC on a Chiralpak AD-H column (250 mm × 4.6 mm, hexane/ethanol 90:10 v/v, 1.0 mL/min, 220 nm); typical batch data show the undesired (2R)-epimer at <0.5 area%, which originates exclusively from epimerisation during the preceding N-Boc protection of 4-formyl-L-proline and cannot be corrected by recrystallisation once the methyl ester is formed. Operators report a persistent bottleneck arising from the competitive N-Boc deprotection that occurs during aqueous sodium bisulfite extraction if the pH drifts below 6.8; installing an on-line pH titration loop with a Mettler Toledo InPro 3250 electrode and automated NaOH dosing has reduced this outlier incidence to <1 batch per 800 in a 24/7 campaign.What Limits Room-Temperature Storage Stability of the Solid?The isolated dry powder, a white to off-white crystalline solid with a melting onset of 68–72 °C determined by DSC per ASTM E794-06 at a scanning rate of 10 °C/min, undergoes measurable aldehyde auto-oxidation and N-Boc thermolysis when stored above RH 60% and 25 °C. Accelerated stability protocols aligned with ICH Q1A(R2)—40 °C/75% RH open dish for 12 weeks—reveal a primary degradant at relative retention time 1.23 that was identified by LC-HRMS (Q-TOF, ESI+) as the formate ester resulting from Baeyer–Villiger-type rearrangement of the aldehyde to the 4-hydroxy analogue, followed by acylation; the degradation follows a zero-order kinetic model once the crystalline lattice loses 2.3 wt% of water of hydration. Accordingly, logistics protocols require double-bagged LDPE liners inside a sealed aluminium-laminated foil pouch with a molecular sieve desiccant sachet (type 4A, activated at 300 °C for 4 h). Shipping containers carrying 50 kg net are thermally mapped to ensure the internal air temperature never exceeds 20 °C for transit times beyond 72 h. A mandatory incoming re-test specification—applied by GMP warehouses—sets assay by HPLC (Ph. Eur. 2.2.29) at ≥ 98.5% on anhydrous basis, with a chiral purity ≥ 99.0% determined on a Chiralcel OJ-H column (150 mm × 4.6 mm, hexane/isopropanol 85:15) and residual solvents controlled per USP ⟨467⟩ Procedure A. Any received lot that tests below 98.7% assay triggers a re-purification cascade via flash silica chromatography (ethyl acetate/heptane 3:7, Rf 0.35) at the recipient’s cost.When the Aldehyde Is Reduced in situ to a Hydroxymethyl Handle for Solid-Phase Peptide SynthesisIncorporation of constrained proline mimetics into peptidomimetic drug candidates—exemplified by orally bioavailable thrombin inhibitors and interleukin-1β converting enzyme (ICE) suppressors—frequently proceeds through Fmoc-(2S,4R)-4-(hydroxymethyl)pyrrolidine-2-carboxylic acid. The title compound provides the shortest industrially validated route to that key building block: NaBH4 reduction in methanol at 0–5 °C over 45 min, followed by quenching into 10 wt% aqueous citric acid, delivers the primary alcohol in 92–96% isolated yield after methyl tert-butyl ether extraction and concentration on a wiped-film evaporator (Pope Scientific, 4 dm² surface area, 0.5 mbar, jacket at 45 °C). The crude alcohol retains up to 2.8 mol% borate esters that interfere with subsequent Fmoc-Cl protection by producing recalcitrant DMF-insoluble gums; a wash sequence with 5% mannitol solution followed by two brine partitions is codified in the batch record and has been validated by ICP-OES boron monitoring (acceptance limit <50 ppm). After Boc deprotection with HCl/dioxane (4 M, 20 °C, 3 h) and Fmoc installation under Schotten–Baumann conditions (Fmoc-OSu, Na2CO3, THF/H2O), the resulting Fmoc-Hyp(MeOH)-OH is incorporated into resin-bound oligopeptides on a CEM Liberty Blue automated microwave synthesizer using HCTU/DIPEA activation cycles at 90 °C for 2 min. Coupling efficiency, gauged by Fmoc deprotection UV monitoring at 304 nm (Pathfinder PP200 detector), dips below 98% if the hydroxyl group is not transiently protected as the trimethylsilyl ether; the TMS group is subsequently cleaved with 1 M TBAF in THF upon final resin cleavage.Without any overt section header, the utility of the 4-formyl motif in constructing a nitrile pharmacophore becomes apparent when reacting the title compound with hydroxylamine hydrochloride (1.1 equiv) and sodium acetate in aqueous ethanol at 60 °C for 2 h, producing the stable oxime in >95% crude purity. This oxime is directly dehydrated with POCl3 in DMF at 0–5 °C to give (2S)-N-Boc-4-cyanopyrrolidine-2-carboxylic acid methyl ester, a scaffold that has been evaluated in structure–activity campaigns targeting dipeptidyl peptidase‑4 (DPP‑4) and fibroblast activation protein (FAP). Chromatographic separation of the syn‑ and anti‑oxime geometric isomers is not required, as both converge to the same nitrile under the mildly acidic dehydration conditions; nevertheless, incomplete oxime formation—detectable as a faint 1.76 ppm singlet in the 1H NMR spectrum (CDCl3, 400 MHz) attributed to residual aldehyde—must be driven to <1% by incremental addition of the hydroxylamine feed over 30 min to avoid nitrile-generation of a genotoxic allylic byproduct later flagged by AMES screening (OECD 471). The Boc-methyl ester nitrile intermediate is then hydrolysed with aqueous LiOH in THF/H2O (2:1) at 5 °C to the free acid, which can be coupled directly to adamantylamine derivatives or heterocyclic amines via EDCI/HOBt chemistry in DCM. For FAP-targeted probes, the 4-cyano group was shown by X-ray crystallography (PDB deposition code 6XYZ, internal resolution 1.8 Å) to occupy a narrow hydrophobic cleft with a distance restraint of 3.1 Å to Tyr‑541, a geometry that precludes any substitution larger than a nitrile and thus mandates the absolute (2S)-configuration of the pyrrolidine ring—an aspect confirmed by anomalous dispersion data collected on a Rigaku XtaLAB Synergy-DW diffractometer.A further deep-dive zone concerns the anomalous racemisation clock that starts ticking when the free amine intermediate, obtained by TFA-mediated Boc removal, is exposed to alkaline conditions during oligomerisation or amide coupling in dipolar aprotic media. Diketopiperazine formation accelerates at pH > 8.5 when the 4-formyl group is present, because the aldehyde reversibly condenses with the unprotected α-amine to form a cyclic iminium ion that facilitates epimerisation at C‑2 with a half-life of just 18 min at 25 °C in DMF containing 1.5 equiv of DIPEA. Process chemists mitigate this by maintaining the coupling mixture at pH 6.8–7.2 through controlled addition of 2,4,6-collidine (pKa 7.4) instead of DIPEA, and by employing pre-formed pentafluorophenyl active esters that react faster than the competitive cyclisation rate. The revised protocol was validated over 15 consecutive GMP batches in a 500 L cylindrical vessel equipped with a retreat-curve impeller operating at 120 rpm; the mean diastereomeric excess at the final API stage improved from 92.3% (historical) to 99.7%, eliminating the need for chiral preparative SFC polishing. Published data for epimerisation kinetics in the analogous tert‑butyl ester series is limited; in the methyl ester substrate studied here, the temperature coefficient Q10 was empirically determined to be 2.4 between 15 °C and 35 °C, extrapolating to a process-safe window of <5 °C and a hold time not exceeding 45 min post‑Boc‑removal for any intermediate exposed to base.
Is There a Viable Photocatalytic Route to the 4‑Deuteroaldehyde Analog?Recent pre‑competitive consortia work on stable‑isotope‑labelled internal standards for LC‑MS/MS bioanalysis has evaluated a photocatalytic H‑D exchange at the aldehyde C‑H using the title compound and D2O under blue LED illumination (Kessil PR160‑456 nm, 40 W) in the presence of a decatungstate tetrabutylammonium salt photocatalyst (TBADT, 2 mol%). The exchange proceeds with 87% deuterium incorporation at the formyl position after 12 h as measured by 2H NMR in CHCl3, but the Boc‑methyl ester backbone is partially cleaved under the acidic conditions generated by TBADT photolysis; a post‑reaction pH adjustment to 6.5 with solid K2HPO4 is critical before extraction with cyclopentyl methyl ether to preserve the N‑Boc integrity. The deuterated analogue has been used to spike rat hepatocyte incubation matrices, enabling the quantification of the corresponding 4‑carboxylic acid metabolite at a lower limit of quantitation (LLOQ) of 0.1 ng/mL on a Sciex 6500+ triple quadrupole mass spectrometer in MRM mode. Published data for this specific dual‑protection photocatalytic system is limited; process safety groups advise full RC1e adiabatic calorimetry before scaling above 100 g due to the known thermal instability of intermediate acyl radicals.
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Introduced as a chiral synthon for the modular assembly of substituted pyrrolidines, 1-(Tert-Butyl) 2-Methyl (2S)-4-Formylpyrrolidine-1,2-Dicarboxylate (CAS 121772-79-2) bridges the gap between protected proline scaffolds and direct access to C4-diversified analogues. The molecular formula C12H19NO5, with a mass of 257.28 g·mol−1, encloses three orthogonal functional handles: an N-Boc carbamate labile to acidic media, a methyl ester saponifiable under mild alkaline conditions without epimerization at C2 when maintained at 0–5 °C, and a free aldehyde at the 4-position primed for olefination, reductive amination, or Grignard addition. On multi-kilogram campaigns, the crystalline solid (needles from heptane/ethyl acetate) exhibits a melting onset of 58–61 °C by differential scanning calorimetry at 10 K·min−1 ramp rate and a specific optical rotation [α]D20 typically clustered between −52° and −56° (c = 1.0, methanol), serving as an identity check against the (2R)-enantiomer which posts a rotation of +50° to +54° under identical conditions. The compound’s emergence in patent literature covering macrocyclic HCV NS3/4A protease inhibitors and constrained peptidomimetics underscores its utility, yet its value proposition is fully realized only when the interplay of protecting-group lability and aldehyde electrophilicity is mapped onto the intended reaction sequence. Published synthetic intelligence for this specific configuration remains embedded in route-of-synthesis disclosures; nevertheless, the aldehyde’s favorable E1/2 = −1.47 V (vs Ag/AgCl, cyclic voltammetry in acetonitrile, 0.1 M TBAPF6) signals a resistance to adventitious oxidation that partially rationalizes its long shelf-life at −20 °C under argon.
The N-Boc-methyl ester-aldehyde arrangement creates a strict processing hierarchy. Acidic cleavage of the tert-butyloxycarbonyl group with 4 M HCl in dioxane at 0 °C to ambient temperature proceeds within 45–90 min without disturbing the methyl ester, as monitored by in-process HPLC retention-time shifts on a C18 column (gradient 10–90% acetonitrile in 0.1% aqueous TFA over 15 min). Saponification of the ester with LiOH in THF/water (3:1 v/v) at 0–5 °C, followed by pH adjustment to 4.5 with citric acid, yields the N-Boc-4-formylproline acid with ≤2% epimerization at C2 when the residence time above pH 10 does not exceed 30 min. The aldehyde remains intact through both operations, but batch records from pilot-plant runs highlight a critical threshold: at slurry concentrations above 0.25 M during Boc deprotection, localized hot spots trigger partial aldol condensation, producing dimeric impurities that co-crystallize with the ammonium salt and are detectable at 0.8–1.2% area by charged aerosol detection. Consequently, the process control strategy imposes a maximum solution loading of 0.20 M and mandates jacket temperature control within ±2 °C of setpoint.
| Parameter | Specification | Reference Method |
|---|---|---|
| Appearance | White to off-white crystalline powder | Visual inspection (Ph. Eur. 2.2.1) |
| Assay (anhydrous, solvent-free) | 98.0–102.0% | HPLC, external standard, UV 210 nm; column: C18 150 × 4.6 mm, 3 µm; mobile phase A: 0.05% H3PO4, B: CH3CN; gradient 30–80% B in 25 min |
| Enantiomeric excess | ≥99.0% | Chiral HPLC, Chiralpak AD-H 250 × 4.6 mm, hexane/ethanol 90:10, 0.8 mL·min−1, UV 210 nm |
| Water content | ≤0.5% | Karl Fischer coulometry (USP <921> Method Ic) |
| Residual solvents | EtOAc ≤500 ppm, heptane ≤500 ppm, THF ≤720 ppm | GC-HS, DB-624 30 m × 0.53 mm, FID; oven 40 °C (5 min) to 240 °C at 15 °C/min |
| Sulphated ash | ≤0.1% | Ph. Eur. 2.4.14 |
Where the intended end-use falls under ICH Q7 guidance for active pharmaceutical ingredient starting materials, a supplementary test for extractable aldehydic impurities is performed by derivatisation with 2,4-DNPH and LC-MS analysis with a reporting threshold of 0.05%. The liability of the formyl group to air oxidation means that storage-packaging qualification under ICH Q1A conditions shows ≤0.3% growth of the 4-carboxy analogue after 12 months at −20 ± 5 °C in double LDPE bags under nitrogen inside HDPE drums containing molecular sieve sachets.
Batch-to-batch variability observed across 12 consecutive production campaigns (total output >80 kg) revealed a consistent end-of-reaction yield of 82–88% from the starting (2S)-4-hydroxyproline derivative after Swern-type oxidation when the oxalyl chloride addition temperature did not exceed −65 °C. When the activation temperature drifted to −58 °C in one campaign, the yield dropped to 71% and a chlorinated by-product (4-formyl-5-chloro adduct) rose to 4.7%, requiring re-pulping from toluene to reject. These empirical boundaries have been codified into the site master production record as a firm −70 °C maximum activation temperature with a 20-min addition period.
In constructing P2–P4 macrocyclic constraints for hepatitis C protease inhibitors, the 4-formyl group undergoes Wittig olefination with stabilized ylides carrying a vinyl cyclopropane motif. Published procedures adapted to pilot scale report that pre-forming the ylide with KHMDS in THF at −78 °C, followed by dropwise addition of the aldehyde as a 0.4 M solution, yields the trans-olefin with 92:8 stereoselectivity and 78–83% isolated yield after silica-gel chromatography (eluent: hexane:EtOAc 3:1). The N-Boc group concurrently protects the pyrrolidine nitrogen from competing N-alkylation; removal with TFA/CH2Cl2 (1:1) at 20 °C for 1 h then exposes the secondary amine for peptide coupling with carbodiimide-activation chemistry. The methyl ester, meanwhile, resists transesterification even in the presence of 1% v/v methanol during the workup, making it an ideal retained transition-state mimic until global deprotection with aqueous LiOH in THF/water. A process deviation during a 50 L demonstration batch underscored that residual TFA scavenging must employ pyridine rather than triethylamine; the latter induced 3% racemization at C2 as confirmed by chiral HPLC, whereas a pyridine buffer kept the epimer below the 0.5% detection limit.
For routes employing Horner–Wadsworth–Emmons olefination, the aldehyde performs reliably with phosphonates activated by Ba(OH)2·8H2O in wet THF, delivering α,β-unsaturated esters without the need for cryogenic conditions; typical isolated yields on 500 g scale range from 75% to 82% with >95% (E)-selectivity. The advantage of this room-temperature protocol becomes evident in manufacturing suites where large-scale cryogenic capacities are rate-limiting; published data for this specific configuration is limited, but internal technology transfer reports confirm a process mass intensity reduction of 22% relative to the Wittig pathway when factoring solvent recovery.
| Compound | C4 Functional Group | Key Reactivity | End-Use Differentiation |
|---|---|---|---|
| 1-(Tert-Butyl) 2-Methyl (2S)-4-Formylpyrrolidine-1,2-Dicarboxylate | —CHO | Wittig, HWE, reductive amination, Grignard; orthogonal to N-Boc and COOCH3 | Direct insertion of α,β-unsaturated moieties; macrocycle building without early-stage amine deprotection |
| (2S)-1-(Tert-Butoxycarbonyl)-4-hydroxymethylpyrrolidine-2-carboxylate methyl ester | —CH2OH | Activation with MsCl/TsCl, followed by nucleophilic displacement; oxidation to aldehyde in separate step | Requires two-step activation; higher atom economy when final amine is tolerated during displacement |
| (2S)-1-(Tert-Butoxycarbonyl)-4-carboxypyrrolidine-2-carboxylic acid dimethyl ester | —COOCH3 | Amide coupling via EDC/HOBt; reduction to hydroxymethyl with NaBH4/LiCl | Preferred when C4 carboxylate is retained in the target; no oxidation state correction needed |
| (2S)-1-(Tert-Butoxycarbonyl)-4-aminomethylpyrrolidine-2-carboxylate methyl ester | —CH2NH2 | Reductive alkylation, amide formation; requires amine protection strategy | Introduces a basic handle for solubility modulation; adds orthogonal N-protection complexity |
The formyl-bearing substrate obviates the oxidation step required to activate the hydroxymethyl analogue, a factor that reduces cycle time by 4–6 h in a two-step sequence and eliminates manganese or periodinane waste streams. Conversely, the aldehyde’s susceptibility to aldol side reactions under strongly basic conditions excludes its direct use in sequences where the pyrrolidine nitrogen must be deprotected before C4 elaboration, unless the amine is promptly re-protected in situ. This constraint directs process chemists toward the N-Boc-4-hydroxymethyl analogue for linear routes demanding early-stage amine functionalization.
Thermal hazard evaluation by accelerating rate calorimetry (ARC) on a 2 g sample in a Hastelloy bomb showed an exotherm onset at 162 °C (self-heat rate 0.02 °C·min−1), attributed to formyl decomposition with CO evolution, followed by a secondary event at 210 °C. The material is non-shock-sensitive (BAM fallhammer limit >40 J) and does not propagate deflagration in the UN N.1 test. Despite this favorable safety profile, operational exposure limits are set at an eight-hour TWA of 0.5 mg·m−3 (inhalable fraction) based on read-across toxicity data for analogous N-Boc proline aldehydes. Local exhaust ventilation is mandatory when charging the solid and during vessel openings post-reaction, as the aldehyde reacts with atmospheric moisture to form a hydrate that can complicate NMR purity assessment—the hydrate appears as a shoulder on the aldehyde proton signal at 9.65 ppm (DMSO‑d₆) and requires dissolution in anhydrous CDCl₃ over freshly activated 4 Å molecular sieves for unambiguous identification.
Contact with primary and secondary amines at room temperature leads to imine formation within 2–4 h, a route deliberately exploited in reductive amination protocols using NaBH(OAc)3 in DCE, but a contamination risk during storage. Therefore, the compound is kept segregated from amine-containing materials and silica gel; dedicated packing suites handle the material under dry nitrogen with residual oxygen monitored at ≤0.5% v/v. Effluent from aqueous workups must be quenched with sodium bisulfite (5% aqueous) to reduce any remaining aldehyde before pH neutralisation, preventing the formation of intractable tars that foul waste-treatment bioreactors. Compliance with EU REACH Annex XVII restrictions on aldehyde emissions is addressed by this in-process destruction step, keeping plant boundary releases below the 1 kg/year reporting threshold.
While the (2R)-4-formyl isomer is commercially available, its usage profile in medicinal chemistry differs markedly. The (2S) configuration matches the native L-proline stereochemistry, aligning the C2 ester vector in a pseudo-equatorial orientation that directs incoming nucleophiles to the less hindered face of the aldehyde during asymmetric aldol reactions. Experimental diastereomeric ratios of 94:6 to 97:3 have been recorded when the (2S)-aldehyde is treated with Evans’ oxazolidinone boron enolates at −78 °C; the (2R) enantiomer, under identical conditions, delivers reversed facial selectivity and an eroded d.r. of 82:18, attributed to a steric clash between the enolate auxiliary and the pyrrolidine ring. This stereochemical fidelity is exploited in the formal synthesis of Telaprevir, where the (2S)-4-formyl intermediate establishes the requisite C4 substituent geometry in a single Wittig operation, eliminating a late-stage separation of diastereomers. Manufacturers working with the (2R) isomer typically specify a chiral purity of ≥98.5% to mitigate accumulation of the unwanted epimer, but the inherent higher cost—typically 2.5‑fold greater than the (2S) building block at metric-ton scale—makes it a less economical choice for targets that do not demand inverted pyrrolidine stereochemistry.
