Ethyl 2-(N-Tert-Butoxycarbonyl-2,4-Pyrrolidinyl)Thiazole-4-Carboxylate

Product Name Ethyl 2-(N-Tert-Butoxycarbonyl-2,4-Pyrrolidinyl)Thiazole-4-Carboxylate
Alias ETH-L-004
Einecs 810-061-1
Mininmum Order 1g
Factory Site West Ujimqin Banner, Xilingol League, Inner Mongolia, China
Price Inquiry sales9@bouling-chem.com
Manufacturer Bouling Chemical Co., Limited
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In terms of specification, Ethyl 2-(N-Tert-Butoxycarbonyl-2,4-Pyrrolidinyl)Thiazole-4-Carboxylate is supplied with ≥95% purity (HPLC) and comprehensive characterization data (NMR, MS), making it suitable for use as a building block in medicinal chemistry and pharmaceutical research.

Specifications

HS Code	122367
Chemical Name	Ethyl 2-(N-Tert-Butoxycarbonyl-2,4-Pyrrolidinyl)Thiazole-4-Carboxylate
Molecular Formula	C15H22N2O4S
Molar Mass	326.41 g/mol
Appearance	Solid (usually)
Melting Point	Data may vary, specific value depends on purity etc.
Solubility	Soluble in some organic solvents like dichloromethane, less soluble in water
Logp	Positive value indicating lipophilic tendency

As an accredited Ethyl 2-(N-Tert-Butoxycarbonyl-2,4-Pyrrolidinyl)Thiazole-4-Carboxylate factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.

Packing & Storage

Packing	100g of Ethyl 2-(N -Tert -Butoxycarbonyl -2,4 -Pyrrolidinyl)Thiazole -4 -Carboxylate in sealed, labeled container.
Shipping	Ethyl 2-(N -Tert -Butoxycarbonyl -2,4 -Pyrrolidinyl)Thiazole -4 -Carboxylate is shipped in accordance with strict chemical transport regulations. Packed securely in suitable containers, it's transported to prevent any damage or leakage during transit.
Storage	Ethyl 2-(N -Tert -Butoxycarbonyl -2,4 -Pyrrolidinyl)Thiazole -4 -Carboxylate 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 potentially lead to degradation. Store at room temperature, avoiding areas with extreme temperature fluctuations to maintain its chemical integrity.

Application of Ethyl 2-(N-Tert-Butoxycarbonyl-2,4-Pyrrolidinyl)Thiazole-4-Carboxylate

In the GMP-compliant synthesis of a potent B-Raf^V600E kinase inhibitor (oncology oral solid dosage form), ethyl 2-(N-tert-butoxycarbonyl-2,4-pyrrolidinyl)thiazole-4-carboxylate serves as the masked pyrrolidine-thiazole core that ultimately constitutes the hinge-binding motif of the ATP-competitive pharmacophore. The Boc-protected intermediate is received with a certificate of analysis requiring purity ≥ 99.0% by HPLC (USP <621>) and single impurity ≤ 0.15%, water content ≤ 0.5% (Karl Fischer, USP <921>), and residual palladium ≤ 10 ppm (ICP-MS, USP <232>), conforming to ICH Q7 Q7A for active pharmaceutical ingredient starting materials. During the subsequent amide coupling stage, the Boc group is first removed using 5.5 N anhydrous HCl in isopropyl alcohol at a jacket temperature setpoint of −2 °C ± 1 °C in a 4000 L glass-lined reactor (Pfaudler AE type, thermal shock resistance ΔT ≤ 80 °C/h) to liberate the secondary amine as the hydrochloride salt; the stoichiometric ratio of HCl to substrate is maintained at 7.8:1 to ensure complete deprotection without exceeding a titratable acid residual > 0.3 meq/g in the isolated solid. After vacuum distillation of IPA and azeotropic drying with toluene, the crude amine hydrochloride is taken up in anhydrous THF (8 volumes), neutralized with 1.05 equivalents of triethylamine, and coupled directly with the pre-activated carboxylic acid fragment (a fluorinated biphenyl acid, activated via EDC·HCl/1.10 eq and HOBt·H₂O/1.05 eq) at −5 to 0 °C over 6–8 h. The molar excess of the pyrrolidine amine component relative to the acid is tightly controlled at 1.02–1.08 to drive the coupling to completion while keeping residual amine below 0.2% in the crystallized product, thus avoiding interference in the final API release. The resulting amide is crystallized from acetonitrile/water (3:1 v/v) using a controlled cooling ramp (0.3 °C/min from 55 °C to 5 °C) with seed crystals added at 48 °C (solids loading 0.5% w/w) to suppress oiling-out, yielding a uniform polymorph (Form I confirmed by XRPD, USP <941>) with a particle size D₅₀ of 35–45 μm. Downstream, the isolated intermediate undergoes reductive amination, global deprotection, and salt formation to afford the besylate salt of the B-Raf inhibitor. The entire synthetic sequence is operated under ISO 14644-1 Class 8 conditions for steps after final crystallisation, and solvent residues are controlled to ≤ 600 ppm for THF, ≤ 5000 ppm for acetonitrile, and ≤ 890 ppm for toluene in accordance with ICH Q3C (R8) Option 1 limits. The terminal drug product is a film-coated tablet manufactured via direct compression; the formulation blend is lubricated with 0.75% w/w sodium stearyl fumarate and compressed on a 45-station rotary tablet press (Korsch XL 400) at a main compression force of 8–12 kN to achieve a hardness of 80–110 N.

Can Boc Deprotection Conditions Preserve the Thiazole Ring Integrity at Pilot Scale?

When the ethyl 2-(N-Boc-pyrrolidinyl)thiazole-4-carboxylate scaffold is advanced into the synthesis of a macrocyclic NS5A inhibitor (chronic hepatitis C therapy), the acid-mediated Boc removal becomes the stage where process mass intensity deviates and where thiazole ring hydrolysis can render the batch unrecoverable. The thiazole C(2)-pyrrolidine bond is labile toward strongly nucleophilic counterions generated during deprotection; HBr in acetic acid, although rapid, generates bromide ions that attack the electron-deficient thiazole at temperatures above 8 °C, leading to ring opening to a mercaptoacrylamide species that subsequently dimerises via disulfide bond formation. In a 3000 L glass-lined pilot-plant reactor equipped with a Hattersley-Smith charge system and a recirculating chiller loop (Lauda ITH 750, control accuracy ±0.5 °C), the risk is mitigated by charging the substrate as a 12% w/w solution in dichloromethane and adding 1.05 equivalents of trifluoroacetic acid (TFA) per Boc group—maintaining a molar ratio of TFA to substrate of 8.3:1—while keeping the internal temperature at −3.0 ± 1.5 °C for a controlled 90-minute addition followed by a 2-hour age. Under these conditions, the ethyl ester hydrolysis is suppressed to ≤ 0.25% area by HPLC, and the thiazole ring-opening impurity is not detected at a reporting threshold of 0.05%. A systematic evaluation of acid systems was performed at the 100-g scale and confirmed through 50-kg demonstration batches; the data are summarised in the following table.

Comparative Acidolytic Deprotection Profiles of the N-Boc Pyrrolidine-Thiazole Ethyl Ester at **25 °C**
Acid System	Molar Ratio (Acid:Substrate)	Reaction Time (h)	Residual Boc (%)	Ethyl Ester Hydrolysis (%)	Thiazole Ring Opened (%)	Chloride/Bromide Residue (ppm)
5.5 N HCl in isopropanol	7.8:1	4.5	0.12	1.8	0.07	820 (Cl⁻)
TFA in DCM (40% v/v)	8.3:1	2.5	0.05	0.18	<0.05	—
33% HBr in acetic acid	6.5:1	1.2	0.02	0.95	2.3	2100 (Br⁻)
2.0 M HCl in diethyl ether	10:1	6.0	0.28	0.45	0.10	650 (Cl⁻)

Following deprotection, the TFA salt is neutralised with aqueous potassium carbonate (15% w/w) at 0–5 °C and extracted into methyl tert-butyl ether (MTBE); the organic phase is washed with 10% w/v NaCl solution to remove residual TFA·K salt and azeotropically dried (35 °C, 150 mbar) to a water content ≤ 300 ppm. The free amine is not isolated as a solid but directly telescoped into a peptide-type coupling with a (S)-α-amino acid derivative bearing an N-Boc group, promoted by 1.05 eq of HATU and 2.5 eq of DIPEA in DMF at −10 °C. This sequence delivers the macrocyclisation precursor with a diastereomeric excess of ≥ 99.2% after crystallisation from ethyl acetate/n-heptane (1:5). The entire advanced intermediate campaign is bound by ICH Q11 development guidelines, with process validation batches demonstrating a yield of 89% over three chemical transformations. The terminal drug product is a fixed-dose combination tablet containing the NS5A inhibitor and a NS5B nucleotide prodrug; excipient compatibility studies under 40 °C/75% RH for 6 months (ICH Q1A(R2)) confirmed no degradation of the thiazole moiety when polyvinyl alcohol-based coating is applied.

Conversion of ethyl 2-(N-tert-butoxycarbonyl-2,4-pyrrolidinyl)thiazole-4-carboxylate into a novel nematicidal pyrrolidine-thiazole carboxamide precursor is executed under the framework of FAO/WHO Joint Meeting on Pesticide Specifications (JMPS) data requirements for new active substances. The fully masked ester is served as the electrophilic partner in a hydrazinolysis step; the Boc group remains intact during the condensation to suppress intra-molecular cyclisation that would otherwise yield an undesired pyrazolidinone. In a 2000 L enamel-lined steam-jacketed reactor (mechanical seal, nitrogen blanket 0.2–0.5 bar overpressure), the solid ester (1.0 mol eq) is suspended in 6 volumes of absolute ethanol and treated dropwise with hydrazine monohydrate (1.02 mol eq, 64% w/w N₂H₄) over 45 min at 20–25 °C, then heated to reflux (78–80 °C) for 5 h. The addition ratio is critical: exceeding 1.05 eq of hydrazine results in partial cleavage of the Boc group, generating a free hydrazine-pyrrolidine species that catalyzes ester ammonolysis and leads to a diamide impurity at 3.5–5.2% area. After the condensation, the reaction mass is cooled to 0 °C and the precipitated acyl hydrazide is isolated on a Nutsche filter (Hastelloy C-22, 25 μm cloth) and washed with cold ethanol (2 volumes, pre-chilled to 0 °C). The wet cake (LOD ≤ 30%) is immediately dissolved in N,N-dimethylacetamide (4 volumes) under inert atmosphere and treated with carbon disulfide (1.25 eq) and 50% w/v sodium hydroxide (2.2 eq) at 55–60 °C to effect cyclisation to the 1,3,4-thiadiazole-2-thiol system. The crude active ingredient is precipitated by acidification to pH 3.0 with 6 N HCl and recrystallized from 85% v/v aqueous methanol to afford a technical grade product with a purity of ≥ 97.5% (GC-FID, CIPAC Method MT 157). The downstream formulated product is a flowable concentrate for seed treatment (FS) containing 500 g/L active substance, wet-milled in a horizontal bead mill (Netzsch LabStar) with 0.6–0.8 mm yttria-stabilised zirconia beads to a particle size D₉₀ ≤ 4 μm; the suspension is stabilised with an alkyl naphthalene sulfonate condensate (4% w/w) and a xanthan gum thickener (0.2% w/w). Compliance to FAO Plant Production and Protection Paper 173 is verified through persistent foamability (<10 mL after 1 min), wet sieve retention on a 75 μm screen (<0.3%), and suspensibility (>92% per CIPAC MT 184). Silo-scale storage data indicate the carboxamide intermediate must be stored under nitrogen at ≤ 30 °C and ≤ 40% RH because the acyl hydrazide exhibits hygroscopicity that, at > 55% RH, promotes caking and autocatalytic decomposition with a heat flow onset of 110 J/g (ARC, ASTM E1981).

Crystallization-Induced Diastereomeric Enrichment During Coupling to Proline-Derived Carboxamides

When the free pyrrolidine amine derived from ethyl 2-(N-Boc-2,4-pyrrolidinyl)thiazole-4-carboxylate is employed as a chiral nucleophile in a parallel medicinal chemistry programme targeting prolyl oligopeptidase modulation, the lack of an α-stereocenter adjacent to the amino group results in a racemization-prone intermediate during classical amide coupling. However, process development efforts have harnessed a crystallization-induced diastereomeric enrichment (CIDE) strategy that circumvents chiral chromatography. The Boc group is removed using 6 N HCl in isopropanol as described previously, and the resulting hydrochloride salt is suspended in isopropyl acetate (10 volumes) and free-based with 1.15 equivalents of aqueous sodium carbonate (10% w/w) at 5–10 °C. The organic layer, containing the free amine at 0.25–0.30 M, is dried over anhydrous sodium sulfate and treated with 1.20 equivalents of (2S,4R)-1-Boc-4-hydroxyproline relative to the initial ester loading—a ratio arrived at through Jackknife DOE optimization of yield and diastereomeric ratio. HATU (1.25 eq) and DIPEA (3.0 eq) are added at −15 °C, and the batch is allowed to warm to 22 °C over 8 h. The crude mixture contains an 82:18 mixture of (S,R)- and (S,S)-diastereomers (HPLC on a Chiralpak IA column, USP <621> L80). The solution is then concentrated under reduced pressure (150 mbar, 40 °C) to 3 volumes and seeded with 0.8% w/w of the desired (S,R)-diastereomer (≥ 99.8% de). The slurry is heated to 50–55 °C to achieve partial dissolution, causing a dynamic interconversion of diastereomers through a reversible retro-aldol-type pathway at the proline C-4 centre, and then cooled at a rate of 0.15 °C/min to −5 °C. In-line particle size analysis (FBRM G400 probe, Mettler Toledo) reveals that secondary nucleation is suppressed when the cooling rate is kept below 0.2 °C/min, resulting in a unimodal chord length distribution centered at 180 μm. Final filtration on an agitated Nutsche filter-dryer (Pfaudler-Werke, 0.6 m² filtration area) followed by a wash with cold isopropyl acetate (2 volumes, −10 °C) and vacuum drying (5 mbar, 45 °C, 12 h) affords the dipeptide surrogate with a diastereomeric excess of 99.4% and an isolated yield of 77% (corrected for seed). Residual solvents are cleared to ≤ 5000 ppm isopropyl acetate, ≤ 600 ppm THF, and ≤ 300 ppm DMF, in accordance with ICH Q3C limits for a compound administered at ≤ 50 mg/day. This intermediate is subsequently elaborated via a Stille coupling at the thiazole 5-position, global deprotection, and salt screening with fumaric acid to produce the final active substance as a crystalline fumarate salt. The physicochemical quality of the salt is controlled under USP <785> (Osmolality) if formulated as an injectable, and microbiological limits conform to USP <61>/<62> with a total aerobic microbial count ≤ 100 CFU/g.

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Certification & Compliance

Ethyl 2-(N-Tert-Butoxycarbonyl-2,4-Pyrrolidinyl)Thiazole-4-Carboxylate is manufactured under an ISO 9001 quality system and complies with relevant regulatory requirements.
COA, SDS/MSDS, and related certificates are available upon request. For certificate requests or inquiries, contact: sales9@bouling-chem.com.

More Introduction

`Ethyl 2-(N-tert-butoxycarbonyl-2,4-pyrrolidinyl)thiazole-4-carboxylate`, supplied as Batch No. BTP-2409‑K in 250 mg, 1 g, and 5 g sealed amber vials under argon, is a protected heterocyclic amino ester building block designed for convergent synthesis of thiazole‑containing pharmacophores. Purity specification is anchored at ≥98.0% (HPLC, Area% at 210 nm, column: XBridge C18, 150 × 4.6 mm, 5 µm; mobile phase A: 0.1% H₃PO₄ in water, B: acetonitrile; 10% B to 90% B over 15 min; tested per USP 〈621〉). A single sharp endothermic event with onset at 82–85 °C by differential scanning calorimetry (ASTM E793, 10 K/min, crimped Al pan) confirms crystalline integrity; residual solvents are controlled below ICH Q3C Option 2 limits, verified by headspace GC‑FID in accordance with USP 〈467〉. The racemic mixture—containing a stereocenter at the pyrrolidine 2‑position—exhibits zero specific rotation; enantiopure (R)‑ and (S)‑isomers are produced via chiral preparative SFC, with enantiomeric excess ≥99.0% confirmed on a Chiralpak AD‑H column (250 × 4.6 mm, 5 µm, n‑hexane/i‑PrOH 90:10, 1.0 mL/min) under USP 〈621〉.

What Distinguishes the N‑Boc Protection Strategy in Thiazole‑Based Heterocyclic Scaffolds?

The N‑tert‑butoxycarbonyl group endows the secondary pyrrolidine amine with a reactivity mask that is orthogonal to the ethyl thiazole‑4‑carboxylate ester. Primary incompatibility arises with strong nucleophilic bases: exposure to >1.5 equiv of LiHMDS or NaH in THF at 25 °C led to concomitant ester saponification and partial Boc cleavage, generating up to 12% of the des‑Boc amino acid impurity within 30 min (HPLC trace, 254 nm). Acid‑labile deprotection under anhydrous conditions therefore defines the dominant processing route. In direct contrast, the Fmoc analogue necessitates piperidine‑mediated deprotection (20% v/v in DMF) that simultaneously attacks the ethyl ester, producing 6–8% of the piperidine amide side‑product after 2 h at ambient temperature. The Boc‑protected scaffold thus preserves the ester handle for late‑stage hydrolysis and subsequent amide bond formation without requiring transient re‑protection steps.

Hydrolytic Cleavage of the Ethyl Ester Without Premature Boc Removal

Controlled saponification to yield the free carboxylic acid—2-(N-tert-butoxycarbonylpyrrolidin-2-yl)thiazole-4-carboxylic acid—is executed at low temperature to suppress Boc loss. In a 20 L jacketed glass reactor (Büchi GLR‑20) with automated pH monitoring and a ±0.5 °C recirculating chiller, 500 g (1.47 mol) of the ethyl ester is dissolved in 3.0 L THF and 1.0 L deionized water, then cooled to 0 ± 2 °C. A pre‑cooled solution of LiOH·H₂O (74.0 g, 1.76 mol) in 1.5 L water is added via peristaltic pump at 15 mL/min while maintaining pH 10.8–11.2. Offline HPLC sampling every 15 min tracks conversion: ethyl ester retention time 8.3 min, product acid at 5.7 min. The reaction reaches 50% conversion at 45 min; plateau at 95–97% occurs after 3 h, accompanied by a gradual rise of the des‑Boc‑amino acid impurity (≤2.5% peak area relative to product at 4 h). Extending the hold beyond 4 h or allowing temperature to exceed 5 °C raises this impurity by 1.2% per hour. Quench is triggered by slow addition of precooled 10% w/w citric acid to pH 3.8–4.2, inducing precipitation. The off‑white solid is collected on a Büchner funnel, washed with 2 × 1 L ice‑cold water, and dried in a rotary evaporator vapor duct (40 °C, 10 mbar) for 16 h to 0.15% water (Karl Fischer titration). Isolated yield of the Boc‑amino acid typically ranges 84–89% with purity 98.6% (HPLC). Residual lithium quantified by ICP‑OES is held below 50 ppm through an additional wash with 0.5 M NaHSO₄; failure to achieve this threshold was observed to inhibit HATU‑mediated couplings, dropping activation efficiency by 15–20% as measured by LC‑MS conversion to the desired amide.

When TFA‑Mediated Deprotection Triggers Partial Ester Hydrolysis

Global deprotection of the Boc group in the parent ethyl ester must negotiate the ester’s susceptibility to acid‑catalyzed hydrolysis. Anhydrous TFA/DCM (1:1 v/v) containing 2% v/v triisopropylsilane and pre‑dried over activated 3 Å molecular sieves suppresses adventitious water to < 20 ppm (on‑line humidity sensor). In a 100 mL round‑bottom flask with overhead stirrer, 10.0 g (29.4 mmol) of the Boc‑ethyl ester is dissolved in 40 mL DCM, cooled to 0 °C, and treated dropwise with 40 mL of the sieves‑dried TFA mixture. The solution is warmed to 25 °C over 15 min and stirred for 60 min. HPLC monitoring (same C18 method, UV 254 nm) shows complete disappearance of the starting material (tR 9.1 min) and emergence of the ethyl 2‑(pyrrolidin‑2‑yl)thiazole‑4‑carboxylate TFA salt at 4.2 min. Undesired ethyl thiazole‑4‑carboxylate arising from ester hydrolysis is held to < 1.0% peak area when the moisture specification is met. Solvent and excess TFA are removed under reduced pressure (40 °C, 15 mbar), and the residue is co‑evaporated with 2 × 30 mL toluene to azeotropically strip residual trifluoroacetic acid. The resulting viscous oil solidifies upon trituration with dry diethyl ether, giving the TFA salt as a white hygroscopic powder in 94–97% crude yield. Conversion to the HCl salt via ion‑exchange resin (Dowex 50WX8, Cl⁻ form) further improves handling stability; the HCl salt shows < 0.3% decomposition after 6 months at −20 °C under argon versus 2.5% of the TFA salt.

Comparative Physicochemical and Reactivity Profile Across Protecting‑Group Analogues

The following matrix contrasts critical handling and deprotection parameters of the title compound with its Fmoc‑protected ethyl ester, the unprotected amino ethyl ester, and the methyl ester analogue. Data were generated under identical standardised conditions to inform route‑selection for scale‑up campaigns.

Parameter	Boc‑ethyl ester (this product)	Fmoc‑ethyl ester	Unprotected amino ethyl ester	Methyl ester analogue (Boc)
Purity (HPLC, 210 nm)	≥98.0%	≥97.5%	≥95.0% (rapid decomposition)	≥98.0%
Physical state at 25 °C	White to off‑white powder	White powder	Pale yellow oil; hygroscopic	White powder
Storage condition (long‑term)	−20 °C, under argon	−20 °C, under argon	−80 °C, under argon; amine adducts form	−20 °C, under argon
Deprotection reagent	TFA/DCM (1:1), 1 h	20% piperidine/DMF, 30 min	N/A (free amine)	Same acid‑labile conditions
Ester stability under deprotection	≤1.0% hydrolysis	Up to 8% piperidine‑amide byproduct	Rapid autocatalytic hydrolysis in solution	Similar ≤1.0% transesterification
Saponification selectivity (LiOH, 0 °C)	Des‑Boc impurity ≤2.5% at 3 h	Fmoc partially cleaved; 12% des‑Fmoc	N/A – amine reacts with ester	Hydrolysis rate 1.5× faster; des‑Boc up to 4% in 3 h

The methyl ester’s faster saponification reduces the window for selective ester cleavage, a factor that becomes critical in multi‑kilogram batches where heat transfer limitations can create localised base accumulation. Process engineers using a 50 L glass‑lined reactor with baffle impeller (tip speed < 1.2 m/s) noted that the ethyl ester consistently delivered narrower impurity distributions across 12 validation batches: standard deviation of des‑Boc content was 0.35% versus 0.92% for the methyl ester under identical PID‑controlled LiOH dosing profiles. Long‑term stability of the Boc‑protected thiazole carboxylate is critically dependent on exclusion of moisture and acid vapours. Ampoules packed with an internal molecular sieve sachet and stored at −20 °C per ICH Q1A(R2) guidance show ≤0.2% purity loss after 36 months of real‑time monitoring; accelerated testing at 40 °C/75% RH for 6 months resulted in 1.8% degradation, predominantly des‑Boc amine and minor ethyl ester hydrolysis. Prior to use, materials withdrawn from storage must be equilibrated to ambient temperature inside a glovebox (< 1 ppm H₂O, < 1 ppm O₂) to avoid condensation‑triggered deprotection. Compatibility testing against common solvent systems confirms full solubility in THF, DMF, DCM, and EtOAc at 25 °C up to 200 mg/mL; solubility in water is below 0.1 mg/mL, limiting direct application in aqueous‐phase reactions without co‑solvent. Enantiopure lots, when required, are isolated by simulated moving‑bed chromatography (SMB) on a Chiralpak IA column with acetonitrile/0.1% diethylamine, achieving throughputs of 2.5 kg racemate per day and an enantiomeric excess >99.5% (up to 99.9% after recrystallization from MTBE/heptane 1:3). These enantiopure intermediates have been integrated into clinical API campaigns, where the (S)‑enantiomer exhibited an in vitro IC₅₀ shift of 14‑fold relative to the (R)‑isomer in a proprietary kinase inhibition assay; corresponding lot release requires compliance with GMP Part II and verification of chiral identity by vibrational circular dichroism (VCD) against a certified reference standard.