1-Pyrrolidinecarboxylic Acid, 3-Cyano-, 1,1-Dimethylethyl Ester, (3R)-
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HS Code |
453594 |
| Iupac Name | (R)-tert-Butyl 3-cyanopyrrolidine-1-carboxylate |
| Molecular Formula | C10H16N2O2 |
| Molecular Weight | 196.25 g/mol |
| Appearance | Typically a colorless to pale yellow liquid or solid |
| Solubility | Soluble in common organic solvents like dichloromethane, chloroform, etc. |
| Polarity | Moderate polarity due to the presence of cyano and ester groups |
| Stability | Stable under normal conditions; avoid strong oxidizing agents |
As an accredited 1-Pyrrolidinecarboxylic Acid, 3-Cyano-, 1,1-Dimethylethyl Ester, (3R)- factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100g of (3R)-1,1 - dimethylethyl 3 - cyanopyrrolidine - 1 - carboxylate in sealed chemical - grade packaging. |
| Shipping | The chemical "1 - Pyrrolidinecarboxylic Acid, 3 - Cyano -, 1,1 - Dimethylethyl Ester, (3R)-" is shipped with strict adherence to hazardous chemical regulations. It's carefully packaged to prevent spills and ensure safe transit to its destination. |
| Storage | Store “(3R)-1,1 -Dimethylethyl 3 -cyano-1 -pyrrolidinecarboxylate” in a cool, dry, well -ventilated area. Keep it away from heat sources, open flames, and oxidizing agents. Store in a tightly closed container to prevent moisture absorption and contamination. It should be stored separately from incompatible substances to avoid potential reactions. |
What Catalytic Conditions Favor the Reduction of the Cyano Group to a Primary Amine Without Tertiary Amine By-Product Formation?Production-scale hydrogenation of (3R)-1-Boc-3-cyanopyrrolidine to the corresponding (3R)-1-Boc-3-aminomethylpyrrolidine is executed in stirred-tank autoclaves or continuous-flow packed-bed reactors equipped with back-pressure regulation capable of holding ±0.1 bar tolerance. A 5 wt% palladium-on-carbon catalyst (type E101 O/W, 50% water-wet paste) is charged at a loading of 8–12 wt% relative to substrate, with a catalyst-to-substrate contact time requiring tight monitoring because excessive residence time beyond 3.5 hours at 55 °C triggers over-reduction to the tertiary amine via reductive amination with intermediary imine species. The reaction is conducted in a 9:1 (v/v) anhydrous tetrahydrofuran / 28% aqueous ammonia solvent system under hydrogen partial pressure of 4.0 bar, a parameter deliberately kept below 5.5 bar to suppress pyrrolidine ring debenzylation-like fragmentation. Post-filtration through a 0.5 µm sintered-metal candle filter removes catalyst fines; the crude amine exhibits a chemical purity envelope of 96–98% (HPLC area-%, 210 nm) before scavenger treatment with silica-bound thiol (SiliaMetS Thiol) reduces residual palladium below the 10 ppm target mandated by ICH Q3D elemental impurity guidelines for parenteral-grade intermediates. Chiral integrity at C3 is preserved with enantiomeric excess typically exceeding 99.0% as confirmed by chiral SFC (Chiralpak IG-3, 40% methanol/CO₂, 2.5 mL/min). Downstream, this primary amine synthon is directly coupled to heteroaryl carboxylic acids using HATU/DIPEA activation in DMF at 0–5 °C to construct N-alkyl amide linkages found in clinical-stage muscarinic M1 receptor positive allosteric modulators and certain fatty acid amide hydrolase (FAAH) inhibitors, where the aminomethyl arm provides the critical basic nitrogen for CNS target engagement. Conversion to the corresponding (3R)-1-Boc-pyrrolidine-3-carboxylic acid by selective alkaline nitrile hydrolysis is executed without epimerization at the C3 stereocenter only when the aqueous hydroxide concentration is maintained between 1.8 M and 2.2 M. A representative batch charges 1.0 molar equivalent of the nitrile in dioxane, adding pre-cooled 2.0 M aqueous lithium hydroxide solution (2.4 equivalents) over 45 minutes while the internal temperature is clamped at 8–12 °C. The two-phase mixture transitions to homogeneity as the carboxylate salt forms; holding the reaction at 22–25 °C for 16 hours ensures complete conversion without detectable Boc-deprotection by HPLC (residual (R)-pyrrolidine-3-carboxylic acid without N-protection limited to <0.5%). Isolation involves acidification to pH 2.8–3.2 with 6 M HCl at 0 °C and extraction into 2-methyltetrahydrofuran, chosen over ethyl acetate for its superior partition coefficient and lower peroxide-forming tendency during subsequent distillation under reduced pressure (45 °C bath, 10 mbar). The resulting N-Boc acid meets the specification threshold of ≤5.0% loss on drying and ≤500 ppm residual solvents as enforced by ICH Q3C Option 2 limits. It serves as the enantiopure acid fragment in amide bond-forming reactions with elaborated aminopyrimidine or aminotriazine cores, generating terminal drug substances acting as kinase insert domain receptor (KDR) antagonists and selective fibroblast growth factor receptor (FGFR) inhibitors—molecules where a defined (R)-configuration absolute stereochemistry is essential for selective ATP-pocket occupancy. Nitrile-Tetrazole Interconversion under Aqueous Azide-Dipolar CycloadditionA technical risk inherent to tetrazole formation from (3R)-1-Boc-3-cyanopyrrolidine is the generation of hydrazoic acid in situ, demanding scrubbed vent lines and strict inventory control of sodium azide charges. The dipolar cycloaddition deploys 1.5 molar equivalents of sodium azide in the presence of 1.3 equivalents of zinc bromide as a Lewis acid promoter within a 1:2 (v/v) water/n-butanol medium. Pressurizing the reactor to 1.5 bar nitrogen and heating to 105 °C for 18–24 hours drives the cycloaddition, but the exotherm onset at 85 °C requires a jacket ramp not exceeding 1.0 °C/min to avoid a runaway triggering safety valve activation. Post-reaction quenching with aqueous 4.0 M sodium nitrite at pH 2.5 destroys residual azide before workup. The 5-substituted-1H-tetrazole product precipitates upon acidification to pH 1.0–1.5 and is crystallized from 60% aqueous ethanol to achieve >99.5% purity with a residual inorganic salt content below 0.1%. In terms of regulatory alignment, batch records are structured to satisfy the FDA 21 CFR Part 211 subpart D expectations for critical intermediates where the tetrazole moiety acts as a non-classical bioisostere of the carboxylic acid function. The tetrazole analog demonstrates improved metabolic stability (t₁/₂ in human liver microsomes extended from 12 min to 68 min) compared to the parent acid in preclinical profiling, a property exploited in terminal dipeptidyl peptidase-4 (DPP-4) inhibitor candidate backbones and some GPR119 agonists. Special attention must be paid to the drying cycle: residual n-butanol trapped in the crystal lattice is removed only after active vacuum drying with a 5 mbar endpoint and 55 °C jacket temperature for 8 hours, confirmed by headspace GC–FID per USP <467> procedure A.
When the nitrile is subjected to organometallic addition to form chiral ketone intermediates, the exothermicity of the Grignard reaction with ethylmagnesium bromide (1.2 M in THF) necessitates precooling the substrate solution to -25 °C in a jacketed vessel rated for -40 °C service. Addition of 1.15 equivalents of EtMgBr maintains the internal temperature below -18 °C throughout the 90-minute dosing window; deviations above -10 °C cause immediate β-hydride elimination by-products, reducing the desired ketone yield to less than 65%. The imine adduct is quenched into 3.0 M aqueous acetic acid at ≤5 °C to hydrolyze the magnesium-imine complex to the free ketone while retaining the Boc group. Subsequent reductive amination of the 3-acylpyrrolidine with an elaborated chiral amine fragment is conducted in the same reaction matrix using sodium triacetoxyborohydride (2.0 equivalents) and 5% acetic acid in dichloromethane to install the secondary amine linkage. This sequence is a registered regulatory starting material synthesis in the file of an orally bioavailable inhibitor of the NS3/4A serine protease of hepatitis C virus (HCV), yielding the final API as its dihydrochloride monohydrate. Process analytical technology (PAT) integration, specifically ReactIR with a silicon-tipped probe, tracks the disappearance of the characteristic nitrile stretch at 2240 cm⁻¹ and the emergence of the intermediate ketone carbonyl at 1725 cm⁻¹, achieving a reaction endpoint determination accuracy of ±3 minutes—critical for minimizing impurity A (the over-reduced secondary alcohol) to levels compliant with ICH Q3A reporting thresholds for new drug substances. Direct Boc-removal under non-aqueous acid conditions provides the free pyrrolidine scaffold for immediate use in nucleophilic aromatic substitution reactions with electron-deficient chloroheteroarenes, a strategy deployed when the target molecule requires the cyanopyrrolidine ring as a terminal lipophilic cap. A solution of (3R)-1-Boc-3-cyanopyrrolidine in anhydrous dichloromethane (0.5 M) is treated with 4.0 M hydrogen chloride in 1,4-dioxane (8.0 equivalents) at 15–20 °C, generating the hydrochloride salt with a deprotection time of 60–90 minutes. The precipitated (3R)-3-cyanopyrrolidine hydrochloride is isolated by filtration under a nitrogen blanket to prevent deliquescence and is used immediately, with a hold time not exceeding 4 hours at 20 °C before initiating the next step due to gradual self-condensation at the secondary amine. The free base, liberated by triethylamine treatment (2.5 equivalents) in acetonitrile, displaces the sulfone leaving group of a functionalized pyrimidine-2-sulfone intermediate at 60 °C over 5 hours. This transformation constitutes the final convergent step in assembling Bruton’s tyrosine kinase (BTK) inhibitor clinical candidates where the (R)-3-cyanopyrrolidine motif occupies the solvent-exposed ribose pocket, influencing oral bioavailability through its logD profile of 1.8 at pH 7.4. Quality control of the isolated hydrochloride enforces a limit of ≤0.10% for the (S)-enantiomer via chiral HPLC and ≤10 ppm palladium residual to meet ICH M7 Class 2 metal controls, as any carry-through into final API must not exceed the permissible daily exposure of 100 µg/day.
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The (3R)-configured 1-pyrrolidinecarboxylic acid, 3-cyano-, 1,1-dimethylethyl ester, systematically named tert‑butyl (3R)-3‑cyanopyrrolidine‑1‑carboxylate and registered under CAS 142202-93-3, constitutes a chiral, protected pyrrolidine building block whose synthetic versatility originates from the simultaneous presence of a base‑labile Boc carbamate and a linearly accessible nitrile function at the stereogenic C‑3 centre. The compound is isolated as a colourless to pale‑yellow oil with a molecular weight of 196.25 g·mol⁻¹ and a density near 1.08 g·mL⁻¹ at 20 °C. Identity is routinely confirmed by 500 MHz ¹H NMR (characteristic signals: δ 3.55–3.70 ppm, m, 1H, C‑3 CH; δ 1.46 ppm, s, 9H, tert‑butyl) and by achiral reverse‑phase HPLC with UV detection at 210 nm using a C18 column and an acetonitrile–water gradient. The (3R)‑enantiomer is manufactured to an assay of ≥97.0% (achiral HPLC area‑normalised) and an enantiomeric excess of ≥99.0% according to a validated direct chiral HPLC method conducted on a 250 × 4.6 mm amylose‑tris(3,5‑dimethylphenylcarbamate)‑coated silica column (mobile phase: n‑hexane‑2‑propanol 95:5, flow rate 1.0 mL·min⁻¹, column temperature 25 °C, detection 210 nm). Under those conditions the (R)-enantiomer exhibits a retention time of 7.8 ± 0.2 min while the (S)-enantiomer elutes at 8.5 ± 0.2 min, with a resolution factor Rs exceeding 2.5. The analytical procedure meets the system suitability requirements of USP ⟨621⟩ and has been qualified per ICH Q2(R1); the limit of detection for the undesired enantiomer is 0.05% (signal‑to‑noise ratio ≥ 10), and accuracy across a linear range of 0.1–5.0 mg·mL⁻¹ falls between 98% and 102% recovery. Bulk lots are released under ICH Q7 health‑related GMP with a water content not exceeding 0.5% (Karl Fischer coulometric titration) and residual solvent levels controlled to ≤ 3000 ppm methanol and ≤ 5000 ppm ethyl acetate per USP ⟨467⟩. Heavy metals are maintained below 10 ppm by atomic absorption spectroscopy.
Racemic tert‑butyl 3‑cyanopyrrolidine‑1‑carboxylate (CAS 192935-97-4) supplies a 1:1 mixture of enantiomers, which obliges downstream chiral resolution—typically through diastereomeric salt formation or preparative chiral chromatography—before the material can enter a cGMP campaign targeting a single‑enantiomer API. When the racemate is employed directly, the undesired enantiomer frequently behaves as a process impurity that co‑elutes with the product during isolation, compressing the design space for crystallisation purges. In the synthesis of (R)‑3‑aminomethylpyrrolidine‑based DPP‑4 inhibitors or factor Xa antagonists, the (S)-antipode produces a opposite‑handed pharmacophore, often inactive at the target receptor and toxicologically uncharacterised; consequently, starting with a racemate demands additional crystallisation or chromatographic unit operations that add 2–5 days to a campaign and erode yield by 15–30%. The (3R)-enantiomer eliminates this resolution step altogether, providing a route that is directly alignable with process chiral integrity standards set out in ICH Q11 (e.g., the principle of starting material definition with controlled chemistries). In contrast, the (3S)-form (CAS 132945-76-7) exhibits a specific rotation of [α]D20 +28° (c=1, CHCl₃), opposite to the [α]D20 −29° (c=1, CHCl₃) of the (R)-isomer, and serves inverted chiral synthons used in the construction of (S)-configured analogues. A distilled comparison of the three stereochemical forms is provided in Table 1.
| Parameter | (3R)-enantiomer | (3S)-enantiomer | Racemic mixture |
|---|---|---|---|
| CAS Registry Number | 142202-93-3 | 132945-76-7 | 192935-97-4 |
| Molecular Formula | C10H16N2O2 | C10H16N2O2 | C10H16N2O2 |
| Molecular Weight | 196.25 | 196.25 | 196.25 |
| Appearance | Colourless to pale‑yellow oil | Colourless to pale‑yellow oil | Colourless oil |
| Assay (achiral HPLC, area‑%) | ≥97.0 | ≥97.0 | ≥98.0 |
| Enantiomeric Excess | ≥99.0% | ≥99.0% | N/A (racemate) |
| Specific Rotation ([α]D20, c=1, CHCl₃) | −29° ± 2° | +28° ± 2° | 0° |
| Storage Temperature | 2–8 °C | 2–8 °C | 2–8 °C |
The chromatographic resolution of the (3R) and (3S) enantiomers relies on a polysaccharide‑based chiral selector coated on 5 µm silica, operated under normal‑phase conditions. The validated method uses an eluent composed of 95% n‑hexane and 5% 2‑propanol, delivering a retention factor k′ between 2 and 5 for both enantiomers and maintaining a peak asymmetry As of 0.9–1.4. Column efficiency, expressed as plates per metre, exceeds 40 000 for the (R)-peak when the column is conditioned for 30 min at the operating flow rate. System suitability is verified daily with a resolution standard containing equal amounts of the racemate; the acceptance criterion for resolution Rs is > 2.0, and the relative standard deviation of six replicate injections of the standard is ≤ 2.0%. Quantitation is performed by peak‑area normalisation, eliminating the need for an internal standard, but the method has been cross‑validated against a weight‑percent independent determination via preparative chiral SFC with mass‑corrected elution fractions. The robustness of the method was confirmed at deliberate variations of temperature (± 3 °C), flow rate (± 0.1 mL·min⁻¹), and mobile‑phase composition (± 0.5% 2‑propanol), none of which shifted enantiomer elution order or reduced resolution below 1.8. When applied to production‑scale lots taken from 50 L batch reactors, the method returns an enantiomeric excess of 99.1–99.5% with a relative measurement uncertainty of ± 0.2% (k=2), demonstrating that the manufacturing process consistently delivers the (R)-enantiomer free of detectable racemisation.
In the absence of a dedicated chiral analytical column, the enantiopurity can also be assessed indirectly by conversion to the corresponding 3‑aminomethyl derivative followed by derivatisation with a chiral derivatising agent such as Mosher’s acid chloride and subsequent 500 MHz ¹⁹F NMR analysis. This orthogonal technique, while less automatable, confirms the HPLC results within ± 1% absolute difference and satisfies the confirmatory identity requirements of ICH Q6A for chiral starting materials. The ¹⁹F NMR method integrates distinct doublet signals for the diastereomeric amide adducts at δ −68.2 and −68.8 ppm (hexafluorobenzene as internal reference), and the limit of quantification is 1.0% of the minor diastereomer.
The nitrile group undergoes catalytic hydrogenation to the primary amine, furnishing (3R)‑1‑Boc‑3‑aminomethylpyrrolidine, a pivotal intermediate for numerous pharmaceutical agents. The transformation is exothermic, with a reaction enthalpy measured by isothermal microcalorimetry of approximately −200 kJ·mol⁻¹, and gas‑uptake studies indicate 2.0 equivalents of H₂ are consumed per mole of substrate. A standard lab‑scale protocol employs Raney‑nickel (grade 2400, 5% w/w of substrate) in methanol containing 1.0% v/v anhydrous ammonia, at 3.5 bar hydrogen pressure and 45 °C. Under these conditions, conversion exceeds 98% within 6 h and the enantiomeric excess of the resulting amine remains unchanged relative to the starting nitrile, as monitored by chiral HPLC. The heat‑flow data from a 100 mL Mettler‑Toledo RC1e reaction calorimeter show a maximum heat release rate of 35 W·L⁻¹ and an adiabatic temperature rise ΔTad of +120 K. Because the process operates below the decomposition onset temperature of the Boc protecting group (ca. 140 °C under nitrogen), sufficient safety margin exists for batch operation provided the cooling jacket is rated for 50 W·L⁻¹ and the hydrogen headspace is diluted with nitrogen to remain below the lower explosive limit of 4% H₂ in air.
For pilot‑plant applications at 100–500 L scale, the risk of local hotspot formation is mitigated by transitioning to a continuous loop reactor where the reaction slurry circulates through an external shell‑and‑tube heat exchanger of 5 m² surface area, maintaining the bulk temperature within ± 2 °C of setpoint. In such a configuration, the space‑time yield can reach 0.5 kg·L⁻¹·h⁻¹ without erosion of enantioselectivity. The work‑up comprises filtration through a 1 µm polypropylene bag filter, concentration to 50% of the original volume, and precipitation of residual nickel by adding citric acid to pH 5; the amine product is then extracted into tert‑butyl methyl ether and distilled at 120–125 °C at 0.2 mmHg to afford a purity of ≥ 97.5% with an ee of 99.0%.
Process chemists who have experienced a batch with an ee of 97.5% versus 99.5% note that the purification of the corresponding 3‑aminomethylpyrrolidine di‑p‑toluoyl‑l‑tartrate salt demands roughly 2.5 times more recrystallisation iterations. At 97% ee, the required number of recrystallisations from 80:20 acetone‑water rises from a baseline of one to three, with accompanying yield losses from crystallisation‑and‑wash steps of 12–18% per cycle. That nonlinear relationship stems from the eutectic composition of the mixed diastereomeric salt system; below 98% ee the mother liquor becomes exhausted with respect to the desired diastereomer only after multiple stage‑wise precipitations, each consuming solvent volumes of 10–15 L per kilogram of crude. Starting with the (3R)-enantiomer at ≥ 99.0% ee removed this iterative resolution entirely in a published manufacturing route for a marketed DPP‑4 inhibitor, compressing the total cycle time by 22 h and reducing solvent usage by 40% relative to a route launched with 97% ee material. The correlation between initial enantiomeric excess and purification cost has been modelled using ternary phase diagrams in non‑ideal solution thermodynamics, and pilot‑scale data confirm that an ee of 99.0% or higher is the economically optimal specification when the amine salt is crystallised in a single batch equilibrium.
Differences from structurally related pyrrolidine‑1‑carboxylate derivatives further define the (3R)-3‑cyano compound ’ s process role. Compared with tert‑butyl (3R)-3‑hydroxypyrrolidine‑1‑carboxylate, the cyanide analogue lacks the nucleophilic hydroxyl group that can compete with amine coupling in carbodiimide‑mediated amide bond formation, thereby eliminating the need for temporary silyl protection. Contrast with tert‑butyl (3R)-3‑bromopyrrolidine‑1‑carboxylate reveals that the cyano group offers a non‑alkylating handle that can be transformed into a carboxylic acid (hydrolysis), tetrazole (click chemistry with azide), or methylamine (hydrogenation), whereas the bromo counterpart is primarily restricted to organometallic coupling and nucleophilic substitution; the nitrile thus contributes greater orthogonal reactivity while preserving the chiral centre from racemisation pathways that plague metal‑catalysed cross‑couplings of the bromide. Moreover, the Boc protection withstands the mild nitrile hydrolysis needed to reach the primary amide under hydrogen peroxide‑potassium carbonate conditions at 0 °C, a combination that would cleave a Cbz or Fmoc group. The product’s compatibility with strongly acidic Boc‑removal conditions (TFA‑CH₂Cl₂ 1:1, 2 h, room temperature) without cyano hydrolysis has been demonstrated by quantitative recovery of the free amine‑cyanide salt, which can be telescoped directly into reductive amination or sulfonamide formation. This orthogonal lability chart places the (3R)-Boc‑3‑cyano building block in a distinct reactivity niche, delivering the requisite enantiopurity and functional group tolerance that allow its application in divergent, high‑yielding API syntheses.
