| HS Code | 675068 |
| Product Name | L-Cysteine Ethyl Ester Hydrochloride |
| Synonyms | Ethyl L-cysteinate hydrochloride; H-Cys-OEt·HCl |
| Cas Number | 868-59-7 |
| Einecs Number | 212-779-0 |
| Molecular Formula | C5H12ClNO2S |
| Molecular Weight | 185.67 g/mol |
| Appearance | White crystalline powder |
| Assay | ≥98% |
| Melting Point | 122-125 °C (decomposes) |
| Specific Optical Rotation | [α]20D = +5.5° to +8.0° (c=2, H2O) |
| Solubility | Soluble in water, ethanol, and methanol; slightly soluble in chloroform |
| Storage Conditions | Store in a cool, dry, airtight container, protected from light |
As an accredited L-cysteine Ethyl Ester Hydrochloride factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | White crystalline powder; 25 g in a sealed amber glass bottle under nitrogen, with tamper-evident cap and labeled safety information. |
| Container Loading (20′ FCL) | L-cysteine Ethyl Ester Hydrochloride packed in sealed fiber drums with liners, loaded into a 20′ FCL, secured and labeled. |
| Shipping | L-Cysteine Ethyl Ester Hydrochloride should be shipped in sealed, moisture-proof containers, protected from light and excess heat. Avoid exposure to air and humidity to maintain stability. Use standard non-hazardous ground or air freight with adequate cushioning. Ensure labeling includes product name, purity, and storage conditions. |
| Storage | Store L-cysteine ethyl ester hydrochloride in a tightly sealed, moisture-proof container under an inert atmosphere (e.g., nitrogen or argon), protected from light and air. Refrigerate or freeze at 2–8°C or lower, ensuring desiccation. This prevents hydrolysis, oxidation of the thiol group, and degradation. |
| Shelf Life | Shelf life is approximately 2 years when stored sealed, cool, dry, and protected from moisture and light. |
Production-scale handling of L-cysteine ethyl ester hydrochloride begins with moisture and temperature control because the free thiol group influences storage stability and downstream impurity formation. The material is a crystalline solid carrying a hydrochloride counterion on the α-amino group and an ethyl ester on the carboxyl function; the molecular formula is C₅H₁₂ClNO₂S and the molecular mass is 185.67 g/mol. The CAS registry number 868-59-7 appears in export documentation and batch traceability records. Storage in lined fibre drums or double polyamide sacks at temperatures below 25°C and relative humidity below 40% is used to limit caking, disulfide formation, and loss of thiol titre. Safety data sheets prepared under CLP Regulation EC 1272/2008 identify the hydrochloride salt as a source of acidic hydrolysis products if it is exposed to strong aqueous bases or stored in unlined steel containers.
In peptide fragment assembly, L-cysteine ethyl ester hydrochloride is applied as a carboxyl-protected C-terminal building block for cysteine-containing sequences. The hydrochloride form is not directly reactive in carbodiimide-mediated coupling; the free amine is liberated with a tertiary base such as N-methylmorpholine or diisopropylethylamine in anhydrous N,N-dimethylformamide or dichloromethane. The base charge is held at 1.0–1.05 equivalents relative to the hydrochloride to prevent ethyl ester saponification, which becomes measurable at higher base loadings and more rapid in residual water. In a jacketed glass-lined reactor under nitrogen blanketing, the salt is dissolved at 0.5–1.0 mol/L and maintained at 0–5°C during coupling with N-protected amino acid active esters or carbodiimide/1-hydroxybenzotriazole systems. Pilot-plant campaigns with the unprotected thiol form frequently observe a thioester by-product when activation is too aggressive; industrial routes therefore introduce trityl, acetamidomethyl, or tert-butylthio protection on sulfur before the coupling step, or purchase the S-protected derivative directly. Residual moisture is controlled below 0.1% by Karl Fischer titration because carbodiimide reagents are moisture-sensitive and generate urea derivatives that complicate purification. Batch records from 50–100 L reactor runs indicate that the main scale-up bottleneck is not initial conversion but removal of disulfide dimer formed during extended feed times. For customers working under pharmaceutical supply chains, ICH Q7 governs starting-material control from the point of manufacturing commencement; elemental impurities are assessed under ICH Q3D, residual solvents under ICH Q3C, and LC-MS monitoring of thioester, disulfide, and ester hydrolysis products is maintained from process development through release.
Condensation with substituted benzaldehydes provides thiazolidine-4-carboxylate intermediates that retain the original L-cysteine stereochemical configuration. The reaction is carried out in anhydrous ethanol or methanol with sodium acetate added at 1.0–1.2 equivalents to neutralise the hydrochloride and generate a mildly acidic buffer. The aldehyde is charged slowly at 20–30°C to limit exotherm and avoid precipitation of the free amine as a sticky film on reactor walls. Unlike peptide coupling, this condensation is not terminated by moisture but the equilibrium shifts toward the starting aldehyde when water accumulates. Molecular sieves or anhydrous sodium sulfate are charged when the aldehyde is electron-poor and the water of reaction is generated in a low-volume solvent system. The ethyl ester group remains intact if the water content is kept below 5% and the reaction is quenched before the mixture warms above 40°C. Pilot-scale isolation typically involves vacuum concentration below 40°C followed by recrystallisation from ethyl acetate/n-heptane. The main purity problem observed in kilogram campaigns is residual unreacted aldehyde, which co-distils with the solvent and raises the residual solvent burden; a thin-film evaporator or repeated vacuum stripping is required to bring Class 2 solvents into ICH Q3C limits. The resulting thiazolidine derivatives enter downstream medicinal and agrochemical routes as masked cysteine units that can be oxidised, alkylated, or ring-opened under controlled conditions.
For preparation of N-acetyl-L-cysteine ethyl ester, the hydrochloride salt is dissolved in water and the pH is held between 4.5 and 5.5 during simultaneous addition of acetic anhydride and aqueous sodium hydroxide. At this pH window the α-amino group is sufficiently deprotonated for acetylation while the thiol group remains largely protonated, so S-acetyl impurity formation is limited. The pH-stat controls the feed ratio; acetic anhydride is used in slight molar excess, and the total reaction volume is maintained so that heat generation does not push the batch above 10°C. The ester function is the process-limiting group because pH excursions above 7.0 cause measurable hydrolysis to N-acetyl-L-cysteine and ethanol, especially in the aqueous reaction medium. After acetylation, the product is extracted into ethyl acetate or isobutyl acetate, washed with 5% sodium chloride solution, and dried over magnesium sulfate. Residual S-acetyl impurity is monitored by reverse-phase HPLC with UV detection at 210 nm. If the S-acetyl content exceeds the downstream purchaser’s specification, selective thiol deprotection is not normally attempted on the ester because alkaline hydroxide reagents cleave the ester at a comparable rate; the batch is either chromatographed or reworked through the N-acetylation step. Published data for industrial-scale production of the ethyl ester under cGMP is limited, so contract manufacturing organisations typically validate the pH-stat control loop, ester hydrolysis kinetics, and solvent residue profile before scaling to 100 kg. Analytical documentation for research intermediates includes residual acetic acid, residual solvents, free amine content, and disulfide titre.
Reducing lotions based on cysteine chemistry use the thiol group to cleave keratin disulfide bonds during the restructuring phase of permanent waving or straightening. L-cysteine ethyl ester hydrochloride is dissolved in demineralised water together with a chelator such as EDTA and a fibre-swelling agent; formulation pH is buffered between 8.0 and 9.2 because below pH 7.0 disulfide exchange is too slow for acceptable processing time and above pH 9.8 the ethyl ester may undergo hydrolysis. The hydrochloride salt contributes no ammonium ion and therefore reduces the characteristic ammonia vapour associated with ammonium thioglycolate systems, but the ethyl ester is more hydrophobic than free L-cysteine. Evaluation batches include a nonionic or amphoteric surfactant system to maintain a clear lotion at 20°C. After the reduction phase, the treating solution is removed and the fibre is neutralised with hydrogen peroxide or sodium bromate, which re-forms disulfide bonds and oxidises excess thiol to the corresponding disulfide. The safety dossier for a marketed formulation is controlled by EC 1223/2009 Annex I and manufacturing is conducted under ISO 22716:2007. Cosmetic toxicology assessments must specifically address the ester hydrochloride because published hair-perm data are primarily available for L-cysteine and ammonium thioglycolate rather than for this ester salt. Stability tests should cover pH drift, thiol titre, and colour development in clear packaging under accelerated storage at 45°C; opened-bottle oxygen ingress is a known cause of lotion yellowing and reduction power loss in multi-use salon formats.
In acid cleaning formulations, sulfur-bearing organic molecules are screened because the thiol and amino groups adsorb onto carbon steel surfaces and retard both hydrogen evolution and iron dissolution. L-cysteine ethyl ester hydrochloride has been evaluated as a candidate for hydrochloric acid pickling baths at acid concentrations of 0.5–1.0 mol/L. Electrochemical test protocols follow ASTM G59 for polarisation resistance measurement and ASTM G102 for corrosion rate calculation; weight-loss coupons are prepared according to ASTM G1 and exposed for 6–24 h at 25–40°C. The hydrochloride salt is pre-dissolved in a small volume of acid before addition to the main bath to avoid localised ester hydrolysis at elevated temperature. In screening trials, the open-circuit potential is recorded for 30–60 min before potentiodynamic polarisation to allow adsorption equilibrium to develop. Inhibition efficiency is calculated from the polarisation resistance ratio with and without inhibitor; because published data for this specific ester hydrochloride in pickling baths is limited, pilot-scale validation should include surface analysis by scanning electron microscopy and X-ray photoelectron spectroscopy to confirm sulfur adsorption. Spent pickling liquor containing the chlorinated thiol derivative requires wastewater treatment evaluation under local discharge limits because the organic sulfur load increases chemical oxygen demand and may interfere with conventional neutralisation-precipitation. Segregated collection is therefore common in industrial trials. The material does not fall under a REACH restriction when used as an industrial additive in closed systems, but the safety data sheet must identify corrosivity of the acid matrix and liberation of hydrogen chloride from the hydrochloride counterion.
The thiol group of L-cysteine ethyl ester hydrochloride reacts with nitrosating agents to form S-nitroso derivatives that release nitric oxide under controlled decomposition conditions. Acidified sodium nitrite is added below 5°C to a methanolic solution of the ester hydrochloride; the reaction is complete within minutes, and the resulting S-nitroso compound is stable only in the dark at subambient temperature. The main process hazard is release of nitrogen oxides if the pH falls below 2.0 or if the batch is warmed above 10°C during concentration. The ethoxycarbonyl group increases lipophilicity compared with S-nitrosocysteine and changes the partition coefficient; researchers evaluating membrane penetration select this ester for laboratory-scale nitric oxide donor studies, but published pharmaceutical development data for this specific compound is limited. Isolation is usually by low-temperature precipitation from cold diethyl ether or by lyophilisation, and the solid is stored in amber glass vials under argon at -20°C. The absorbance of the S-nitroso group at 330–350 nm is used for quantification, while reverse-phase HPLC resolves the parent thiol and disulfide oxidation product. This application remains laboratory constrained because the S-nitroso intermediate is photolabile and heat-sensitive; vessels for larger batches would require amber sight glasses, a jacketed cooling system, and pressure relief sized for nitrogen dioxide evolution.
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L-Cysteine ethyl ester hydrochloride is identified by CAS 868-59-7 and the molecular formula C5H12ClNO2S, corresponding to a relative molecular weight of 185.67 g/mol and a theoretical chloride content of 19.1% (w/w). The product is supplied as a white to almost white crystalline solid under supplier-specific catalogue numbers; no universal model designation exists, and procurement should reference the CAS registry number and the salt form to avoid confusion with L-cysteine methyl ester hydrochloride or L-cystine diethyl ester hydrochloride. The IUPAC designation is ethyl (2R)-2-amino-3-sulfanylpropanoate hydrochloride; the material is also listed as H-Cys-OEt·HCl or L-cysteine ethyl ester monohydrochloride.
Structurally, the α-amino group is protonated and paired with a chloride anion, while the thiol side chain remains unsubstituted. This protonated ammonium–thiol arrangement differentiates the material from the zwitterionic free amino acid and from N-acetylated derivatives. In the dry state, the hydrochloride exhibits crystalline character and can be weighed in normal laboratory or production environments without the pronounced odour and air-sensitivity found with some free-base thiols. The thiol remains the dominant reactive site under controlled pH; it is susceptible to oxidative dimerization to the corresponding L-cystine diethyl ester hydrochloride when solutions are exposed to atmospheric oxygen or redox-active metal ions.
Industrial applications are concentrated in solution-phase peptide synthesis, preparation of S-alkyl cysteine building blocks, and derivatization for analytical detection of cysteine residues. Because the ethyl ester protects the carboxylic acid function, coupling can proceed selectively at the amino group after neutralization with a hindered tertiary amine. The ester is removed later by saponification under conditions that must be balanced against thiol oxidation and potential β-elimination at elevated temperature.
The hydrochloride salt is more water-soluble than the neutral free base because the protonated ammonium group interacts strongly with water and because the chloride counterion disrupts crystal packing. In practice, a 0.1 M aqueous solution can be prepared with vigorous mixing under a nitrogen blanket; the resulting solution is clear and acidic, and it should not be stored in open vessels because the free thiol undergoes autoxidation. For coupling reactions in organic media, the salt is neutralized in situ with N-methylmorpholine or N,N-diisopropylethylamine in anhydrous N,N-dimethylformamide or dichloromethane. The neutral amine is more soluble in the organic phase but also more prone to re-protonation if traces of acid remain.
The protonation state raises a processing conflict: complete dissolution at acidic pH stabilizes the thiol against disulfide formation but suppresses nucleophilic coupling at the amino group, while neutral pH activates the amino group and increases thiolate concentration, accelerating oxidative dimerization. For this reason, scale-up procedures often neutralize to pH 6.5–7.5 only after the coupling reagent and the carboxyl component have been added, or they maintain a continuous nitrogen purge and add chelating agents such as EDTA at 0.1–1 mM. In bulk solid handling, the material becomes tacky and caked at relative humidity above 60% if containers are left open; aluminium-laminated polyethylene liners and desiccant assemblies are common in production warehouses.
Solubility is high in water and methanol, lower in ethanol, and negligible in nonpolar solvents such as toluene or hexane. This solvent profile permits aqueous workup: the hydrochloride form can be extracted from organic layers into dilute hydrochloric acid, while the neutral free base can be recovered by careful basification and immediate extraction into ethyl acetate or dichloromethane under nitrogen. These operations should be performed cold, in the range 2–8 °C, because the thiolate ion has a shorter oxidation half-life at higher pH and temperature.
For release of pharmaceutical intermediate grade, typical certificates of analysis include the following controls; these are not universal and should be verified against the supplier batch documentation.
| Specification parameter | Acceptance criterion | Method / standard |
| Appearance | White to almost white crystalline powder | Visual |
| Assay (HPLC, anhydrous basis) | ≥98.0% | In-house reversed-phase HPLC; method validated per ICH Q2(R1) |
| Chloride content | 18.5–19.5% | Argentometric titration; theoretical 19.1% |
| Residual ethanol | ≤5000 ppm | USP <467> headspace GC-FID; ICH Q3C(R8) Class 3 solvent |
| Loss on drying | ≤0.5% | Vacuum oven, 60 °C, 2 h |
| Elemental impurities | ≤10 ppm target elements | USP <233> ICP-MS; ICH Q3D risk assessment |
The tabulated limits represent typical release criteria for non-compendial fine chemical and pharmaceutical intermediate grades. Published data for exact acceptance intervals across all global suppliers is limited; for validated processes, the certificate of analysis should be treated as the primary source. Residual solvent declarations are especially important when the product is synthesized by Fischer esterification of L-cysteine in ethanol, because ethanol is a Class 3 solvent under ICH Q3C(R8) with a permitted daily exposure of 50 mg/day; pharmaceutical users often apply a tighter internal limit when the intermediate appears late in synthesis. The loss-on-drying limit is not a trivial assignable criterion: residual water in a sealed container can hydrolyze the ester at elevated temperature, and the resulting free acid can generate intra-batch variability in peptide coupling yield. For this reason, containers should be closed immediately after sampling and pre-dried material should be used in moisture-sensitive reactions.
In solution-phase peptide synthesis, the hydrochloride is neutralized in situ with 1.0–1.2 equivalents of a hindered tertiary amine in anhydrous solvent before coupling to an N-protected amino acid. Typical coupling reagents include carbodiimide/1-hydroxybenzotriazole systems or O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate; these reagents activate the carboxyl component rather than the ester. The ethyl ester remains intact under standard Fmoc-based coupling conditions but should not be exposed to strong aqueous alkali for prolonged periods. Saponification with lithium hydroxide in THF/water at 0–5 °C removes the ester after chain assembly; however, the same conditions can deprotonate the thiol and promote disulfide formation unless an inert atmosphere and a chelator are present.
For selective S-alkylation, the thiol is reacted with iodoacetamide, maleimide, or vinyl sulfone electrophiles in phosphate buffer at pH 6.5–7.5. Under mildly acidic-to-neutral conditions, the thiol can be alkylated while the α-amino group remains partially protected by protonation; selectivity is electrophile-dependent and should be verified by LC-MS. Reactions are usually complete within 30–90 min at 20–25 °C, but the exact rate depends on the electrophile and on dissolved oxygen. Alkylation can be monitored by reversed-phase C18 HPLC with detection at 210 nm using a 0.1% trifluoroacetic acid/acetonitrile gradient; the ethyl ester increases retention relative to free cysteine and improves peak shape under acidic ion-pairing conditions.
When the free thiol must be protected on scale, the hydrochloride can be oxidized to L-cystine diethyl ester hydrochloride with air or hydrogen peroxide under mildly basic conditions. This conversion is essentially quantitative when carried out at pH 8–9, but care is required because over-oxidation to sulfinic or sulfonic acid impurities can occur if hydrogen peroxide is not quenched or if the temperature exceeds 25 °C. For analytical quantification of the free thiol, reaction with 5,5′-dithiobis(2-nitrobenzoic acid) releases 2-nitro-5-thiobenzoate with absorbance at 412 nm; this method is suitable for release testing of process solutions but not for solid-state assay because the salt contains no chromophore at that wavelength until derivatized.
Among related cysteine derivatives, the ethyl ester hydrochloride occupies a specific stability–reactivity window. Free L-cysteine is a zwitterionic solid with a free carboxylate and a more polar aqueous profile, but it cannot be used directly in carboxyl-protected coupling and gives off a strong thiol odour. L-Cysteine methyl ester hydrochloride has the formula C4H10ClNO2S and a relative molecular weight of 171.64 g/mol; its methyl ester is removed more rapidly under alkaline hydrolysis, but methanol is a Class 2 residual solvent under ICH Q3C(R8) with a permitted daily exposure of 30 mg/day, whereas ethanol is Class 3 with a permitted daily exposure of 50 mg/day. This difference becomes critical in pharmaceutical intermediates that are carried into late-stage steps. The ethyl ester also shows slower ester hydrolysis at neutral pH, providing a wider processing window in aqueous workup than the methyl analogue.
N-Acetyl-L-cysteine is not a direct substitute because the acetyl group blocks the α-amino functionality and prevents peptide coupling at that position. L-Cystine diethyl ester hydrochloride is the disulfide dimer and contains no free thiol; it is used when a protected cystine unit is desired, or it can be reduced with dithiothreitol, tris(2-carboxyethyl)phosphine, or sodium borohydride to regenerate the cysteine ethyl ester. The hydrochloride salt of L-cysteine ethyl ester is therefore selected when a crystalline, C-protected cysteine monomer with a free thiol is required. The salt form adds convenient handling relative to the free base but introduces a chloride counterion that may need to be controlled if total chloride limits are specified in the final isolated product.
Bulk storage conditions are determined by the free thiol and the hygroscopic hydrochloride counterion. The dry powder is stable in sealed containers at 2–8 °C under nitrogen or argon; at ambient temperature, surface discoloration and disulfide formation are observed when the material is repeatedly exposed to moist air. The product should not be stored in unlined fibre drums; aluminium-laminated polyethylene bags or high-density polyethylene drums with gasketed lids and desiccant pillows are standard for production-scale quantities. If water content exceeds the loss-on-drying limit, the material can be pre-dried in a vacuum oven at 35–40 °C for moisture-sensitive coupling; higher temperatures should be avoided because residual hydrochloric acid and water can catalyze ester hydrolysis, reducing assay and generating L-cysteine-containing impurities.
Aqueous process solutions should be prepared immediately before use and blanketed with nitrogen. Oxidative dimerization to L-cystine diethyl ester hydrochloride is accelerated by trace Fe(III) and Cu(II); adding EDTA at 0.1–1 mM is an established control. The free thiol is incompatible with strong bases, peroxides, hypochlorite cleaning residuals, and sulfhydryl-reactive electrophiles such as maleimides, iodoacetamide, and vinyl sulfones unless the specific derivatization is intended. In reactor trains, contact with carbon steel or copper-containing alloys should be avoided for aqueous alkaline feeds; glass-lined or 316L stainless steel equipment with nitrogen purging is preferred. For processes requiring the neutral free base, the neutralization should be staged at 0–5 °C and the solution used within the shortest holding time that the process validation supports; free-thiol content can be checked by the 5,5′-dithiobis(2-nitrobenzoic acid) method at 412 nm before charging to a coupling vessel.
