| HS Code | 318931 |
| Product Name | L-Serine Ethyl Ester Hydrochloride |
| Cas Number | 26348-61-8 |
| Molecular Formula | C5H12ClNO3 |
| Molecular Weight | 169.61 g/mol |
| Appearance | White to off-white crystalline powder |
| Melting Point | 130-133 °C |
| Solubility | Soluble in water and ethanol; slightly soluble in ether |
| Purity | ≥98% (TLC) |
| Storage Conditions | Store in a cool, dry place, sealed tightly, protected from moisture |
| Synonyms | H-Ser-OEt·HCl; (S)-2-Amino-3-hydroxypropionic acid ethyl ester hydrochloride |
As an accredited L-serine Ethyl Ester Hydrochloride factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | Supplied as 25 g in a sealed glass bottle under nitrogen, with desiccant, ensuring stability and purity of L-serine ethyl ester hydrochloride. |
| Container Loading (20′ FCL) | 20′ FCL container loading of L-serine ethyl ester hydrochloride, packed in drums, palletized, secured, and properly labeled for safe transport. |
| Shipping | Ship L-serine Ethyl Ester Hydrochloride in tightly sealed, moisture-resistant containers, protected from light and heat. Avoid contact with incompatible materials. Ensure proper labeling and compliance with hazardous goods regulations. Keep container upright and ventilated during transport to maintain stability and purity. |
| Storage | Store L-serine ethyl ester hydrochloride in a tightly sealed container under inert gas (nitrogen/argon) at 2–8°C. Keep it dry in a desiccator, away from moisture, light, and heat. It is hygroscopic and may degrade upon exposure to humidity. Handle under dry conditions for optimal stability. |
| Shelf Life | Stable for at least two years when stored dry, tightly sealed, and protected from moisture at room temperature. |
In solution-phase peptide manufacturing where a C-terminal L-serine ethyl ester must remain intact through N-terminal deprotection and side-chain manipulation, the ethyl ester hydrochloride (CAS 26348-61-8) is neutralized to the free amino ester immediately before carbodiimide or phosphonium-mediated coupling. The hydrochloride form is selected because the corresponding free base undergoes self-aminolysis and discoloration during ambient storage; stability of the dry hydrochloride is controlled under ICH Q1A conditions with batch-specific acceptance limits for free L-serine and ethanol. A typical charge ratio is 1.0 mol equivalent of N-protected peptide acid to 1.0–1.2 mol equivalents of L-serine ethyl ester free base, released from the hydrochloride using 1.0–1.05 mol equivalents of N-methylmorpholine or DIPEA at −5°C to 5°C in DMF or dichloromethane. Coupling reagent is charged at 1.0–1.5 mol equivalents relative to the acid; jacket temperature during activation is maintained at 0±2°C. Process control falls under ICH Q7, ICH Q11, ICH Q3D, and USP 467. After coupling, the mass is diluted with ethyl acetate, washed with 0.5 M citric acid and 1.0 M sodium bicarbonate, dried, and crystallized as the hydrochloride by HCl gas or HCl-isopropanol at 0–10°C. Vacuum drying at 40±2°C yields the protected peptide ethyl ester. Terminal finished product types are protected peptide ethyl esters and peptide APIs after downstream saponification to the free C-terminal serine.
Fmoc and Boc protection of L-serine ethyl ester hydrochloride is a multi-kilogram route to the corresponding N-protected amino acid derivatives because the ethyl ester provides temporary carboxyl protection and the hydrochloride delivers a stable, precisely neutralizable amine. In Fmoc protection, the hydrochloride is dissolved in deionized water at 0–5°C, adjusted to pH 8.0–8.5 with 1.0 M sodium carbonate, and treated with 1.0–1.1 mol equivalents of Fmoc-OSu in dichloromethane or tetrahydrofuran. Simultaneous addition maintains pH within a ±0.3 pH unit band; pH drift above 9.5 accelerates hydrolysis of the ethyl ester and generates Fmoc-Ser-OH as a contaminant in the protected ester stream. For Boc protection, 1.0–1.2 mol equivalents of di-tert-butyl dicarbonate are fed in tert-butanol-water or dioxane-water at pH 8.5–9.0 and 0–20°C. Post-reaction saponification uses 1.0–1.2 mol equivalents of lithium hydroxide or sodium hydroxide at 0–10°C for 1–3 h. On production lines, the documented bottleneck is pH probe fouling in carbonate slurry; retractable pH probes or per-batch cleaning are needed to prevent overshoot and localized ethyl ester hydrolysis.
Final building blocks are isolated by crystallization or extraction and vacuum-dried at 40–50°C. Specifications for Fmoc-Ser-OH and Boc-Ser-OH typically include HPLC purity ≥99.0 area%, chiral purity ≥99.5% enantiomeric excess, residual solvent by USP 467, and elemental impurity control by ICH Q3D. The intermediates are qualified under ICH Q7 and ICH Q11 as cGMP starting materials for solid-phase peptide synthesis of peptide APIs. Terminal products include Fmoc-Ser-OH, Boc-Ser-OH, and Fmoc-Ser-OEt; these are subsequently used in peptide API campaigns for metabolic, oncologic, and infectious disease targets. Residual solvent limits for this process are shown in the following table.
| Solvent | Process step | USP 467 / ICH Q3C limit | Typical final acceptance |
|---|---|---|---|
| Dichloromethane | Fmoc-OSu coupling | 600 ppm | ≤100 ppm after vacuum drying |
| Tetrahydrofuran | Fmoc / reduction process solvent | 720 ppm | ≤100 ppm after solvent displacement |
| Ethyl acetate | Extraction and crystallization | 5000 ppm | ≤500 ppm |
| Methanol | Crystallization wash | 3000 ppm | ≤500 ppm |
Multi-kilogram reduction campaigns for chiral oxazolidinone auxiliary production use L-serine ethyl ester hydrochloride as the source of the (S)-serinol backbone after selective reduction of the ester function. The hydrochloride is first neutralized with 1.0 mol equivalent of sodium methoxide or triethylamine in anhydrous tetrahydrofuran-ethanol; the resulting free amino ester is then reduced with 2.0–3.0 mol equivalents of sodium borohydride and 2.0–3.0 mol equivalents of lithium chloride at 0–20°C. Addition of borohydride to the hydrochloride directly is avoided because acid-proton liberation causes local exotherm and premature hydrogen evolution. After reduction, the mass is quenched with aqueous ammonium chloride, extracted, and the solvent is distilled to yield (S)-serinol. Cyclization to the oxazolidinone uses 0.34–0.40 mol equivalents of triphosgene per mol of serinol in dichloromethane at 0–10°C, with aqueous bicarbonate scrub for acid removal. The product is crystallized from methyl tert-butyl ether or ethyl acetate; chiral HPLC on a Chiralpak IA-type amylose tris(3,5-dimethylphenylcarbamate) column is used for enantiomeric excess verification. Compliance is anchored to ICH Q3C for residual solvents, ICH Q3D for elemental impurities, and USP 467 for solvent testing. Terminal finished product types are (4S)-hydroxymethyl-2-oxazolidinone auxiliaries and downstream single-enantiomer APIs prepared through asymmetric imide alkylation and acylation.
Schotten-Baumann acylation of L-serine ethyl ester hydrochloride with C8–C14 fatty acyl chlorides produces N-acyl-L-serine ethyl ester intermediates, which are saponified into mild anionic or amphoteric amino acid surfactants for rinse-off personal care products. In a typical batch, 1.0 mol equivalent of the hydrochloride is dissolved in aqueous acetone or aqueous tetrahydrofuran at 10–15°C; the pH is held at 9.0–10.0 by controlled addition of 2.0–3.0 M sodium hydroxide while 1.0–1.1 mol equivalents of acyl chloride are fed over 120–180 min. The ethyl ester is then saponified with 1.0–1.5 mol equivalents of sodium hydroxide at 20–40°C for 2–5 h. The resulting N-acyl-L-serine salt is acidulated to pH 2.0–2.5, extracted into ethyl acetate, and neutralized with sodium hydroxide or triethanolamine to yield a concentrate with 25–35 wt% active matter. Compliance for the surfactant intermediate within cosmetic applications includes EC 1223/2009, ISO 22716 as the manufacturing GMP standard, and REACH registration for placed-on-market volumes. Terminal finished product types are sulfate-free rinse-off cleansers, facial washes, and baby wash bases. Published data for this specific application configuration is limited; process validation is therefore conducted on a lot-specific basis with residual acyl chloride and free fatty acid data included in the certificate of analysis.
L-serine ethyl ester hydrochloride is also used as the chiral amino alcohol precursor in heterocycle formation where the ester group is reduced to the alcohol, then condensed with carbonyl or nitrile substrates to form oxazolidine or oxazoline pharmacophoric intermediates. In a typical cyclization, 1.0 mol equivalent of free amino ester or serinol is condensed with 1.0–1.2 mol equivalents of aldehyde, ketone, or nitrile in toluene under Dean–Stark reflux; the catalyst is p-toluenesulfonic acid or a Lewis acid at 0.1–0.3 mol equivalent. Residual water above 0.1% in the reaction mass shifts the equilibrium toward ring-opened material, so azeotropic water removal is maintained until the calculated water volume is collected. After cyclization, the mixture is cooled, washed with sodium bicarbonate, concentrated, and vacuum-distilled; product fractions are analyzed by chiral GC or HPLC. Compliance requirements are ICH Q7, ICH Q3C, ICH Q3D, and USP 467. Terminal finished product types are chiral oxazolidine and oxazoline intermediates used in small-molecule API routes for anti-infective and cardiovascular compounds. Published data for this specific configuration is limited; stoichiometry and process windows are adjusted from laboratory batch data under controlled scale-up studies.
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L-Serine ethyl ester hydrochloride (CAS 26348-61-8; IUPAC ethyl (2S)-2-amino-3-hydroxypropanoate hydrochloride; H-Ser-OEt·HCl) is the hydrochloride salt of the ethyl ester of L-serine. The empirical formula is C5H12ClNO3, with a formula weight of 169.61 g/mol, an exact monoisotopic mass of 169.0506 g/mol, and a theoretical chloride content of 20.9% w/w. The compound is supplied as a white to off-white crystalline powder, with free-flowing or slightly aggregated habit depending on residual moisture and storage history. It is prepared by Fischer esterification of L-serine with ethanol in the presence of hydrogen chloride, followed by crystallization from ethanol/diethyl ether or ethyl acetate. The hydrochloride form suppresses the zwitterionic character of L-serine and presents the amino group as a protonated ammonium chloride, which must be neutralized before acylation or other N-functionalization. In peptide synthesis and chiral intermediate routes, the ethyl ester serves as a carboxyl-protected L-serine building block with improved solubility in polar aprotic solvents after in situ neutralization compared with the free amino acid. It is used where the carboxyl group must remain masked during N-acylation, O-protection, or chain-extension steps. Published data for this specific ester salt as a formulation additive is limited; the technical profile below therefore focuses on chemical identity, release specifications, and established synthetic use.
Commercial material for synthesis applications is typically released against an in-house specification aligned with reagent-grade amino acid derivatives. The principal identity and purity tests include non-aqueous titration for assay, polarimetry for optical rotation, loss on drying, residue on ignition, and chloride determination. Release acceptance ranges vary by manufacturer; representative values for laboratory and pilot-scale material are given in Table 1. The analytical methods are not a pharmacopoeial monograph; they follow general techniques described in Ph. Eur. 2.5.23 for potentiometric titration and USP <731> for loss on drying.
| Parameter | Typical acceptance range or result | Analytical basis |
|---|---|---|
| Appearance | White to off-white crystalline powder | Visual inspection |
| Assay | ≥98.0% | Non-aqueous titration with perchloric acid |
| Specific rotation | +4.0° to +5.0° (c=1, methanol, 20°C) | Polarimetry |
| Loss on drying | ≤0.5% | Vacuum drying at 60°C |
| Residue on ignition | ≤0.1% | Gravimetric |
| Theoretical chloride | 20.9% w/w | Calculated from molecular formula |
Because L-serine ethyl ester hydrochloride is hygroscopic, loss-on-drying results from unopened containers may be lower than those observed after repeated operator sampling. For continuous processes, a moisture specification of ≤0.3% is often applied before charging to moisture-sensitive coupling reactions. Exposure to relative humidity above 60% promotes moisture uptake; re-drying under vacuum at 40°C is used where residual moisture exceeds the process limit. The compound is soluble in water and methanol. After neutralization, it dissolves in dichloromethane, tetrahydrofuran, and N,N-dimethylformamide, whereas the free amino acid is sparingly soluble in these solvents.
The ethyl ester occupies a middle position between the methyl and higher alkyl or aralkyl esters in deprotection chemistry. Selection among serine ester hydrochlorides is not governed by purity alone; it is driven by the downstream carboxyl-release step and the compatibility with other protecting groups present in the molecule. Table 2 summarizes the structural and deprotection contrasts used in synthesis design.
| Derivative | Formula weight | General deprotection method | Typical selectivity boundary |
|---|---|---|---|
| Methyl ester HCl | 155.58 g/mol | Alkaline hydrolysis | Fastest saponification; methanol by-product |
| Ethyl ester HCl | 169.61 g/mol | Alkaline hydrolysis | Moderate; stable to hydrogenolysis and common Fmoc chemistry |
| Benzyl ester HCl | 231.68 g/mol | Hydrogenolysis using H2/Pd-C | UV-detectable; incompatible with reducible groups |
| tert-Butyl ester HCl | 197.66 g/mol | Acidolysis using trifluoroacetic acid/dichloromethane | Base-stable; removed under acidic conditions |
Compared with the free amino acid L-serine, the ethyl ester hydrochloride presents a single reactive amine species after neutralization. L-serine itself is zwitterionic and often requires coupling reagents to activate the carboxylate; the ester protects this carboxylate and permits N-acylation with acid chlorides, chloroformates, and activated esters under basic conditions. Compared with the methyl ester hydrochloride, the ethyl derivative has a slightly higher formula weight and yields ethanol rather than methanol during ester hydrolysis. Ethanol has a higher normal boiling point of 78.3°C than methanol at 64.7°C, which can alter solvent replacement and evaporative isolation steps. The methyl ester is more compact and may be preferred when a low-molecular-weight by-product is desired. The benzyl ester provides a chromophore that simplifies reverse-phase HPLC detection at 254 nm; however, the ethyl ester is preferred when Cbz or benzyl ether protection is present because hydrogenolysis for benzyl ester removal would cleave those groups. The tert-butyl ester is the choice for base-stable routes; the ethyl ester can be saponified but is not cleaved by the trifluoroacetic acid conditions used to remove tert-butyl esters, so the two are complementary in orthogonal protection strategies.
In solution-phase peptide assembly, L-serine ethyl ester hydrochloride is neutralized with 1.0–1.1 equivalents of a tertiary amine—N-methylmorpholine, N,N-diisopropylethylamine, or triethylamine—in an aprotic solvent at −5°C to 0°C before coupling. The free amine is then acylated with an activated Fmoc-amino acid, such as the pentafluorophenyl ester or the 1-hydroxybenzotriazole/1-ethyl-3-(3-dimethylaminopropyl)carbodiimide activated species. The ethyl ester remains intact during these coupling steps under neutral-to-mildly basic conditions. At the end of the sequence, saponification with 1.0–1.2 M lithium hydroxide in tetrahydrofuran/water (3:1) at 0–5°C removes the ester. Hydrolysis above 10°C or at pH above 12 for extended periods increases the risk of α-carbon racemization; the reaction is therefore monitored by chiral HPLC until the starting ester is ≤1.0% area. After hydrolysis, the pH is adjusted to 5–6 to stabilize the product and minimize base-catalyzed degradation.
At pilot scale, neutralization of the hydrochloride in a 50 L glass-lined reactor with a retreat-curve impeller requires slow addition of N,N-diisopropylethylamine because the protonated ammonium salt can form a transient thick slurry before the free base dissolves. A minimum stirrer speed of 120 rpm and nitrogen sweep prevent localized pH excursions that would otherwise hydrolyze the ethyl ester before coupling. Batch-to-batch residual ethanol content can vary with drying endpoint; headspace GC is used to confirm ethanol below 0.1% before charging to moisture-sensitive acylations.
Beyond peptide coupling, the compound is used as a chiral starting material for sphingolipid intermediates, oxazolidinones, amino alcohols, and aziridine precursors. In a typical sequence, L-serine ethyl ester hydrochloride is O-protected with trityl chloride, tert-butyldimethylsilyl chloride, or benzyl bromide, then reduced with lithium aluminum hydride or sodium borohydride/calcium chloride to give a protected serinol. The ester can also be converted to an amide by direct aminolysis with ammonia or primary amines in methanol; the hydrochloride is neutralized in situ, and the liberated ethanol is removed by distillation. In these routes the hydrochloride protonates both the amine and the ester carbonyl under acidic conditions, so non-aqueous workup requires washing with aqueous sodium bicarbonate to avoid emulsions caused by residual ammonium salts.
The dry solid is chemically stable for at least 24 months when stored in tightly sealed containers at 2–8°C with desiccant. The free base is prone to ester hydrolysis in aqueous solution; therefore neutralized solutions should be prepared immediately before use. The hydrochloride salt should not be combined with aqueous alkali above pH 10 during storage because the ethyl ester will saponify. Strong oxidizing agents may react with the β-hydroxy group, and strong reducing agents can convert the ester to the corresponding alcohol. Avoid combination with acid chlorides until the amine has been neutralized, because the protonated form will not acylate efficiently and the residual hydrochloride can generate corrosive hydrogen chloride.
Milling of agglomerated powder through a 0.5 mm screen with a conical mill improves bulk flow; however, passive loss-in-weight feeding at high humidity can be limited by moisture uptake. The material is not classified as a pharmaceutical active; as an intermediate it should be handled under ICH Q7A quality systems when used in GMP synthesis. No specialty model designation is available; the product is typically sold as synthesis-grade or high-purity grade, with the grade being defined by the assay, loss on drying, and specific rotation release limits rather than by a fixed commercial model number.
Analytically, the ethyl ester hydrochloride can be distinguished from L-serine and the methyl ester by 1H NMR. The ethyl ester shows a characteristic quartet near 4.2 ppm and a triplet near 1.3 ppm, while the methyl ester shows a singlet near 3.8 ppm; the free amino acid lacks these ester resonances. Reversed-phase HPLC methods with volatile acidic modifiers can resolve the ethyl ester from serine and serine amide. LC-MS in positive electrospray ionization gives a protonated molecular ion at m/z 134.1 for the free base [M+H]+, whereas the corresponding methyl ester free base appears at m/z 120.1. These signals provide confirmation of identity and differentiate the ethyl ester from the free amino acid and other serine ester derivatives.
