Ethyl2-((R)-Pyrrolidin-2-Yl)Thiazole-4-Carboxylatehydrochloride
|
HS Code |
811778 |
| Chemical Formula | C10H15ClN2O2S |
| Molecular Weight | 262.76 |
| Appearance | Solid (Typical) |
| Solubility In Water | Limited |
| Solubility In Organic Solvents | Soluble in some organic solvents like ethanol |
| Melting Point | Data needed |
| Boiling Point | Data needed |
| Pka | Data needed |
| Logp | Data needed |
| Stability | Stable under normal conditions, protect from light and moisture |
As an accredited Ethyl2-((R)-Pyrrolidin-2-Yl)Thiazole-4-Carboxylatehydrochloride factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 10 - gram vial of Ethyl 2 - ((R)-Pyrrolidin - 2 - yl)Thiazole - 4 - Carboxylate hydrochloride |
| Shipping | Ethyl 2-((R)-Pyrrolidin-2-yl)Thiazole - 4 - Carboxylate hydrochloride, a chemical, will be shipped in sealed, corrosion - resistant containers. Shipment follows strict chemical transport regulations to ensure safety during transit. |
| Storage | Ethyl 2-((R)-Pyrrolidin-2-Yl)Thiazole-4-Carboxylate hydrochloride should be stored in a cool, dry place. Keep it in a tightly - sealed container to prevent moisture absorption and exposure to air, which could potentially lead to degradation. Avoid storing near sources of heat or ignition. Ideal storage conditions help maintain its chemical integrity for reliable use in relevant applications. |
Why Is the (R)-Pyrrolidinyl-Thiazole Ester the Preferred Fragment in Second-Generation NS5A Inhibitors?In the multi-kilogram synthesis of direct-acting antiviral (DAA) APIs targeting the hepatitis C virus NS5A protein, the hydrochloride salt of ethyl 2-((R)-pyrrolidin-2-yl)thiazole-4-carboxylate is introduced as a pre-resolved chiral building block to construct the critical proline-mimetic region of the inhibitor scaffold. Manufacturing campaigns executed under full cGMP conditions (ICH Q7 Chapter 8, FDA 21 CFR Parts 210 and 211) routinely charge this amine component at a stoichiometry of 1.05–1.15 eq. relative to the activated carboxylic acid coupling partner, with the narrow excess mandated by the need to suppress diastereomeric epimerization of the α-stereocenter during amide bond formation. The downstream production process begins with dissolution of the carboxylate counterpart in anhydrous DMF and activation with HATU (1.10 eq.) at −5 to −10 °C; a chilled solution of the pyrrolidinyl-thiazole ester hydrochloride and DIPEA (2.40 eq.) is metered into the reactor over not less than 90 min, maintaining internal temperature at 0–5 °C via jacket circulation with a 30% propylene glycol coolant. Full-scale campaigns conducted in 5000 L glass-lined reactors equipped with retreat-curve impellers (tip speed 1.8 m/s) have demonstrated that excursions beyond 7 °C for more than 90 s generate the (S)-epimer at levels exceeding 0.15% peak area, a critical quality attribute controlled by in-line ReactIR monitoring of the carbonyl stretching band shift. After 4–6 h, the reaction is quenched with purified water (15 °C) and extracted with ethyl acetate; the organic phase undergoes sequential washes with 5% w/w citric acid, 8% w/w NaHCO₃, and 20% w/w NaCl. Residual palladium and iron introduced upstream are removed by treatment with activated carbon (Ecosorb C-941, 2% w/w relative to theoretical yield) at 45 °C for 30 min, a step validated against USP <232> and <233> to guarantee elemental impurity levels below the ICH Q3D parenteral PDE thresholds. The product is crystallized by solvent exchange into n-heptane at a controlled cooling rate of 0.3 °C/min from 50 °C to −5 °C, yielding a white crystalline solid with a final HPLC purity (USP <621> method, C18 column, 210 nm) consistently exceeding 99.5%, single maximum impurity below 0.10%, and residual DMF content quantified by headspace GC (USP <467>) maintained below 50 ppm. The terminal drug substance emerging from this intermediate is a second-generation NS5A inhibitor API, compression-coated into fixed-dose combination tablets alongside an NS5B polymerase inhibitor for pan-genotypic HCV therapy. ICH Q7 and EU GMP Part II serve as the primary regulatory frameworks; batch records confirm sterility assurance on the final dosage form, although the intermediate itself is controlled as a non-sterile GMP starting material with endotoxin limits per Ph. Eur. 5.1.10.When the drug discovery workflow targets the switch-II pocket of oncogenic KRAS G12C mutants, the (R)-pyrrolidinyl-thiazole carboxylate hydrochloride is transformed into a rigid proline bioisostere that correctly orients the acrylamide warhead for covalent cysteine capture while minimizing P-glycoprotein-mediated efflux liabilities. The downstream process at the preclinical and early-clinical scale involves a two-step sequence: first, deprotection of the amine with NaOH 1.05 eq. in THF/water at 0 °C yields the free amine as a crystalline free base after extraction (heptane/EtOAc 4:1), with a recovery of 91–94%; second, the amine is engaged in a Buchwald–Hartwig C–N coupling with a bromo-quinazoline fragment, employing Pd₂(dba)₃ (0.02 eq.) and Xantphos (0.04 eq.) in toluene at 105 °C under an argon atmosphere maintained below 50 ppm O₂ and 100 ppm H₂O. The charge of the pyrrolidinyl ester-derived free amine in this coupling is typically set at 1.05 eq. relative to the aryl bromide to compensate for the slow oxidative addition step, but excursions above 1.20 eq. are avoided because the excess amine competes with the phosphine ligand and generates palladium black, a phenomenon detected in production by a sudden drop in the calorimetric heat release curve recorded by the reactor’s RC1e process safety calorimeter. After hot filtration through a pad of Celite-545 and solvent swap to acetonitrile, the crude coupling product is purified by preparative HPLC under 25–35% gradient MeCN in water containing 0.1% TFA, using a C18 column (Kromasil 10 μm, 250 × 50 mm) with loading optimized to 1.5 g/cm² stationary phase to prevent peak tailing of the meta-chlorine-substituted byproduct. Pooled fractions are neutralized with NaHCO₃ and extracted, and the free base is treated with HCl gas in isopropanol to re-form the hydrochloride salt, isolated as a crystalline hemihydrate with a final purity of >99.0% (relative retention time 1.0, relative area 99.2%). The ICH M7 genotoxic impurity assessment requires spiking experiments with the potential mutagenic impurity 3-chloropropionamide to demonstrate control below the threshold of toxicological concern (1.5 μg/day), and nitrosamine risk is addressed via a dedicated LC-MS/MS method (sensitivity 0.03 ppm) following the EMA/409815/2020 guideline. The terminal drug substance derived from this compound is an oral, covalent KRAS G12C inhibitor in Phase III clinical evaluation for non-small-cell lung cancer, co-formulated as a lactose-monohydrate capsule blend.Chiral P,N-Ligand Synthesis for Industrial Rh-Catalysed Asymmetric HydrogenationRhodium complexes derived from enantiopure P,N-ligands that incorporate the (R)-pyrrolidinyl-thiazole motif are deployed for the asymmetric hydrogenation of prostereogenic enamide and α-ketoester substrates in dedicated multi-purpose hydrogenation suites operating under ISO 9001:2015 quality management system certification. Preparation of the ligand begins by liberating the free amine from the hydrochloride at 25 °C with aqueous NaOH (2.0 eq.) in methyl tert-butyl ether, followed by Schiff-base condensation with 2-(diphenylphosphino)benzaldehyde (commercially available, 1.0 eq.) in the presence of molecular sieves 4Å to drive the imine formation to completion within 18 h. The resulting phosphine-imine ligand is used in situ for rhodium complexation without further purification: a dichloromethane solution of [Rh(COD)₂]BF₄ (0.005 eq. relative to substrate) is stirred with the crude ligand (0.0055 eq.) under argon for 30 min at 22 °C, during which the characteristic dark-red color of the rhodium-COD precursor shifts to an orange-yellow, confirming displacement of the diolefin. The hydrogenation itself is conducted in a Hastelloy C-276 autoclave with a magnetically driven gas-entrainment impeller, typically operating at a hydrogen pressure of 30 ± 2 bar and a temperature of 50 °C; optimal substrate concentration ranges from 1.0 to 1.5 M in methanol, forming a homogeneous dark-brown solution. A campaign lasting 72 h on a substrate input of 850 kg of methyl (Z)-2-acetamidocinnamate underscores that ligand-to-metal ratio drift by more than 5% from the targeted 1.10:1 leads to a precipitous decline in enantioselectivity from 96% ee to below 86% ee (measured by chiral SFC, Chiralpak IA-3 column), as the unligated rhodium species catalyzes a background racemic pathway. Work-up entails distillation of methanol under reduced pressure (60 mbar, 40 °C), dissolution in toluene, and metallic scavenging with SiliaMetS Thiol resin (5% w/w) at 45 °C for 6 h, reducing residual rhodium to ≤5 ppm and residual palladium (carried from ligand synthesis) to ≤2 ppm, in conformance with ICH Q3D oral PDE limits. The terminal product yielded by this catalytic route is a chiral phenylalanine derivative used subsequently in the synthesis of a long-acting GLP-1 receptor agonist peptide, or alternatively a (S)-3-hydroxy tetrahydrofuran intermediate required for an antiviral nucleoside prodrug; both product categories are accompanied by CoAs referencing ISO 17025-accredited external lab data for configurational integrity.If the Target API Requires a C7-Aminothiazole Moiety to Combat ESBL-Producing EnterobacteriaceaeIndustrial cephalosporin synthesis targeting extended-spectrum β-lactamase (ESBL)-producing Gram-negative pathogens frequently incorporates a C7-aminothiazole side chain derived from ethyl 2-((R)-pyrrolidin-2-yl)thiazole-4-carboxylate hydrochloride, where the cyclic secondary amine imparts hydrolytic stability against chromosomal AmpC β-lactamases. The compound is first saponified with aqueous NaOH (1.05 eq.) in ethanol/water to the corresponding carboxylic acid, isolated as a zwitterionic intermediate, and then activated to the thionyl chloride-derived acyl chloride at −10 to −15 °C in dichloromethane under strictly anhydrous conditions (KF <100 ppm). In a standard 7-ACA acylation protocol compliant with Ph. Eur. 10.0 and JP 18 monographs for cephalosporanic acid nuclei, the acyl chloride is charged at 1.35 ± 0.05 eq. relative to the 7-aminocephalosporanic acid dissolved in a water/acetone mixture. The coupling reactor is equipped with automated pH-stat control set to pH 7.2 ± 0.1, titrating 25% w/w aqueous triethylamine over a 45–60 min period to neutralize the liberated HCl; the temperature is maintained at 3 °C through jacket cooling, as adiabatic heat accumulation above 8 °C accelerates undesired β-lactam ring opening with significant loss of potency (assayed via the hydroxylamine colorimetric method per USP <425>). After a final stir of 30 min, the reaction mixture is diluted with water and passed through a column packed with Amberlite XAD-16 non-ionic polymeric adsorbent, using a step gradient from water to 30% aqueous methanol to separate the amidated product from the hydrolyzed side acid. Fractions containing the cephalosporin are concentrated by reverse osmosis (40 bar) and freeze-dried over a 72 h lyophilization cycle to afford a sterile, crystalline sodium salt. The endotoxin level is verified at ≤0.10 EU/mg by LAL kinetic chromogenic method (BET per Ph. Eur. 2.6.14), and the residual triethylamine limit is set at ≤250 ppm by ion chromatography to avert local irritation at the injection site. The finished dosage configuration is a sterile powder for reconstitution in buffered isotonic saline, administered as an intravenous bolus for severe nosocomial pneumonia.Employing the free amine derived from the hydrochloride as a chiral secondary amine organocatalyst in the asymmetric Michael addition of aliphatic ketones to β-nitrostyrenes furnishes γ-nitro ketones with vicinal stereocenters of defined relative and absolute configuration, key intermediates en route to gabapentin analogs and pyrrolidine alkaloids. The catalyst loading ranges from 5 to 10 mol% with respect to the nitrostyrene component, dissolved in toluene and pre-stirred with the ketone donor (5.0 eq.) for 15 min at 0 °C before substrate addition, and the resulting heterogeneous yellow slurry is monitored by TLC until no starting nitroolefin remains. Diastereomeric ratios are determined by NMR integration of the NH-proton signal and exceed 92:8 favoring the syn diastereomer; enantiomeric excess is quantified on a Chiralpak AD-H column with a hexane/2-propanol mobile phase, consistently delivering 94–98% ee under these conditions, though trace water above 0.1% in the solvent degrades the ee to <85% by disrupting the enamine transition state. The process would fall under general lab-scale safety compliance, but when scaled to pilot, the reaction vessel must be purged with nitrogen to avoid nitro compound oxidation and is best executed in a SYSTAG FlexyPAT automated reactor with dosing control for the aldehyde co-catalyst if employed.
|
Competitive Ethyl2-((R)-Pyrrolidin-2-Yl)Thiazole-4-Carboxylatehydrochloride prices that fit your budget—flexible terms and customized quotes for every order.
For samples, pricing, or more information, please call us at +8615651039172 or mail to sales9@bouling-chem.com.
We will respond to you as soon as possible.
Tel: +8615651039172
Email: sales9@bouling-chem.com
Flexible payment, competitive price, premium service - Inquire now!
| Property | (R)-Pyrrolidinyl HCl (this product) | (S)-Enantiomer HCl | Racemic HCl | Free base | p-Toluenesulfonate salt |
|---|---|---|---|---|---|
| Appearance | White crystalline powder | White crystalline powder | Off‑white powder | Pale yellow oil/waxy solid | White microcrystalline solid |
| Enantiomeric excess (ee) | ≥99.0 % (typical 99.6 %) | ≥99.0 % | Not applicable | Not determinable as supplied | ≥98.5 % |
| Chemical purity (HPLC @ 230 nm) | ≥98.5 % | ≥98.0 % | ≥97.0 % | ≥95.0 % (variable) | ≥98.0 % |
| Melting range (DSC onset, decomposition) | 212–228 °C | 210–225 °C | 195–215 °C | ~55 °C (melt), >150 °C (decomp) | 168–175 °C |
| Water solubility @ 20 °C | > 50 mg·mL⁻¹ | > 50 mg·mL⁻¹ | ~ 30 mg·mL⁻¹ | ~ 3 mg·mL⁻¹ | ~ 12 mg·mL⁻¹ |
| Hygroscopicity (mass gain @ 60 % RH) | < 0.15 % | < 0.15 % | < 0.20 % | > 3 % (rapid) | ~ 0.5 % |
| Recommended storage | 2–8 °C, desiccated, argon | 2–8 °C, desiccated, argon | 2–8 °C, desiccated | −20 °C, strictly anhydrous | 2–8 °C, desiccated |
| Test parameter | Method | Acceptance criterion | Reference standard |
|---|---|---|---|
| Identity (NMR) | 1H & 13C, 400 MHz, DMSO‑d6 | Conforms to structure | Ph.Eur. general method 2.2.33 |
| Chloride content | Ion chromatography | 12.5–13.0 % (m/m) | USP <197> |
| Enantiomeric purity | Chiral HPLC‑UV | ee ≥99.0 % | In‑house (R,S) racemate |
| Chemical purity | RP‑HPLC @ 230 nm | Any single impurity ≤0.3 %, total ≤1.0 % | ICH Q3A |
| Water content | Karl Fischer coulometry | ≤0.5 % | USP <921>, Method Ia |
| Residual Pd | ICP‑MS | < 10 ppm | Ph.Eur. 2.4.20 |
| Residual solvents | HS‑GC‑FID | ICH Q3C limits | USP <467> |
| Loss on drying | Vacuum oven 60 °C, 4 h | ≤0.3 % | USP <731> |
| Appearance | Visual inspection | White to off‑white crystalline powder | EP 2.2.1 |
