| HS Code | 298809 |
| Product Name | Sarcosinate Ethyl Ester Hydrochloride |
| Chemical Name | Ethyl N-methylglycinate hydrochloride |
| Cas Number | 52605-49-9 |
| Molecular Formula | C5H11NO2·HCl |
| Molecular Weight | 153.61 g/mol |
| Appearance | White crystalline powder |
| Melting Point | 116-118 °C |
| Purity | ≥98% |
| Solubility | Soluble in water and ethanol; insoluble in ether |
| Storage Condition | Store in a cool, dry, well-ventilated place; keep tightly sealed |
| Moisture Content | ≤0.5% |
As an accredited Sarcosinate Ethyl Ester Hydrochloride factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 25 kg net in a sealed polyethylene liner inside a sturdy fiber drum, labeled with product identity and safety information. |
| Container Loading (20′ FCL) | Sarcosinate Ethyl Ester Hydrochloride loaded in 20′ FCL, packed in sealed drums on pallets, securely stowed and ventilated. |
| Shipping | Ship Sarcosinate Ethyl Ester Hydrochloride as a non-hazardous or mildly irritating solid, depending on SDS. Use sealed, leak-proof containers with desiccant. Avoid moisture, heat, and incompatible materials. Label clearly, include hazard warnings and handling precautions. Transport via ground or air freight with proper documentation and compliance with local and international shipping regulations. |
| Storage | Store Sarcosinate Ethyl Ester Hydrochloride in a tightly sealed container in a cool, dry, well-ventilated area. Protect from moisture, humidity, and direct light. Keep away from incompatible substances and heat sources. Ensure container is clearly labeled and securely closed when not in use. |
| Shelf Life | Shelf life: typically 2 years when stored tightly sealed in a cool, dry, dark place. |
In solution-phase manufacture of N-methylated peptide active pharmaceutical ingredients, sarcosinate ethyl ester hydrochloride is introduced as the N-methylglycine carboxyl-protected building block after neutralization of the hydrochloride salt with DIPEA. The ethyl ester masks the carboxylic acid during coupling, prevents carboxylate salt formation, and simplifies aqueous workup after amide bond formation. Intermediate release under ICH Q7 uses a validated in-house HPLC method aligned with Ph. Eur. 2.2.29, water content by Karl Fischer titration per Ph. Eur. 2.5.32, and residual solvent control per USP <467>. In a typical coupling, 1.05–1.20 mol of the neutralized ester per 1.00 mol of N-protected amino acid is combined with 1.10 mol HATU and 2.2–2.5 mol DIPEA in DMF at 0.2 mol/L. The coupling is initiated at 0–5°C in a glass-lined reactor, held for 2–6 h at 15–25°C, and quenched with 1.0 M citric acid. Because N-methyl substitution retards aminolysis relative to primary glycine esters, the process uses HATU rather than HOBt active esters, and incomplete coupling is monitored by HPLC conversion rather than time alone. When chain extension is required, ethyl ester hydrolysis is performed with 1.0 M LiOH in tetrahydrofuran/water 3:1 at 0–5°C. The terminal products are N-methylated peptide APIs and peptide intermediates, including enzyme-resistant peptide analogs and constrained peptidomimetics for CNS and oncology programs.
Batch records for creatine ethyl ester hydrochloride production using sarcosinate ethyl ester hydrochloride as the guanylation substrate identify the narrow pH band of 9.5–10.5 as the controlling parameter. At pH 9.0 or below, the secondary amine remains partially protonated, slowing attack on cyanamide and leaving unreacted ester above 5.0 wt%. At pH above 10.5, cyanamide hydrolysis and urea/creatinine side-product formation become measurable within 8 h at 55°C. The hydrochloride salt is dissolved in purified water at 0.8–1.2 M, neutralized with 50% w/w sodium hydroxide at 35–40°C, and combined with 1.05–1.10 molar equivalents of 30% w/w aqueous cyanamide at 50–60°C. The guanylation is held at pH 9.8–10.2 with automatic 50% NaOH addition until conversion exceeds 98% by HPLC per Ph. Eur. 2.2.29. The reaction mass is then acidified with ethanolic HCl to pH 1.5–2.0, seeded, cooled linearly over 6 h to 5°C, and filtered through a centrifuge. The crystalline creatine ethyl ester hydrochloride is washed with cold ethanol and vacuum-dried at 45°C for 12 h. When the final product is placed into dietary supplements, U.S. FDA 21 CFR Part 111 governs manufacturing, and residual solvents are measured per USP <467>. Terminal product types are creatine ethyl ester HCl monohydrate and anhydrous powders for sports nutrition formulations.
| pH window | Temperature | Observed process outcome |
|---|---|---|
| 9.0–9.5 | 55°C | Residual unreacted ester above 5.0 wt% |
| 9.8–10.2 | 55°C | Conversion above 98% within 8 h |
| >10.5 | 55°C | Cyanamide decomposition and urea/creatinine side products |
Representative batch data in the table indicate the sensitivity of conversion to pH; values are typical process ranges and should be confirmed by site-specific validation.
Acylation of sarcosinate ethyl ester hydrochloride in a Schotten-Baumann system proceeds only after the hydrochloride is neutralized because the free secondary amine is the nucleophilic species. In high-purity personal-care surfactant fabrication, the ethyl ester protects the carboxyl group during fatty acid chloride acylation, reducing side reactions at the carboxyl position and improving control of N-acyl selectivity. The molar ratio of lauroyl chloride to free amine is controlled at 1.00:1.03, with 2.2–2.5 mol of NaOH per mol of fatty acid chloride, at 0–10°C in water/tetrahydrofuran 70:30 v/v. After acylation, the ethyl ester is hydrolyzed with 4.0 M NaOH at 50–60°C for 6 h, the mixture is acidified to pH 2.0 with 6 M HCl to precipitate N-lauroyl sarcosine, and the filter cake is washed with deionized water and neutralized with 50% NaOH to pH 7.0–8.0. The final active content is adjusted to 25–30 wt%. Under EC 1223/2009 Article 14, the finished sodium lauroyl sarcosinate must be assessed for impurities and product safety before placement; REACH Annex VII applies to the fatty acid chloride and solvent handling. HPLC purity is determined by a validated method aligned with Ph. Eur. 2.2.29. Terminal products include sodium lauroyl sarcosinate and sodium cocoyl sarcosinate for toothpaste, sulfate-free shampoos, and micellar skin cleansers. This protected-ester route is selected where low residual free fatty acid below 0.5 wt% and light color are required, although published production-scale data for this specific configuration is limited.
For CNS research intermediates derived from GlyT1 inhibitor pharmacophores, sarcosinate ethyl ester hydrochloride supplies an N-methylglycine fragment that can be amidated or N-alkylated without exposing the carboxylic acid group. Amide coupling to substituted benzoic acids uses 1.0–1.5 mol of the neutralized ester per 1.0 mol of acid, 1.05 mol HATU, and 2.5 mol DIPEA in dichloromethane/DMF 4:1 at 0–25°C. The ethyl ester is then saponified with 1.0 M lithium hydroxide in tetrahydrofuran/water 3:1 at 0–5°C, and the N-methylglycine derivatives are isolated by acidification to pH 2.0–3.0 followed by preparative reversed-phase HPLC with methanol/water gradients. Release testing for advanced leads follows OECD GLP principles and uses HPLC per Ph. Eur. 2.2.29 with residual solvents per USP <467>. Terminal product types are N-methyl amide and acid analogs for GlyT1 inhibition screening, tool compounds, and reference standards. Published production-scale data for this specific configuration is limited; the ratios above represent typical laboratory batch parameters requiring pilot-scale verification.
Lithium aluminium hydride reduction of sarcosinate ethyl ester hydrochloride in tetrahydrofuran yields 2-(methylamino)ethanol after the ester group is converted to the primary alcohol. The hydrochloride must be pre-neutralized and rigorously dried before reduction to avoid consumption of the hydride by water or hydrogen chloride. The charge is 2.0–2.5 mol LiAlH4 per 1.0 mol ester as a 1 M tetrahydrofuran solution, with the substrate concentration maintained at 0.8–1.2 mol/L and the addition temperature held at -10 to 5°C. After 3–5 h of aging, excess hydride is quenched by sequential addition of water, 15% w/w sodium hydroxide, and water, and the aluminium hydroxide sludge is removed through a pressure filter. The crude 2-(methylamino)ethanol is then distilled under 50–100 mbar at 50–70°C in a packed column. The downstream product is handled under ISO 9001:2015 contract manufacturing controls; assay is performed by gas chromatography with area normalization against a reference standard, water content by Karl Fischer titration, and residual solvents per USP <467>. Terminal product types are 2-(methylamino)ethanol for cationic polyurethane chain extenders, textile auxiliaries, and pharmaceutical alkylation intermediates.
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Ethyl sarcosinate hydrochloride, chemical name ethyl N-methylglycinate hydrochloride, is listed under CAS 5324-27-0 with empirical formula C5H12ClNO2 and relative molecular mass 153.61. The compound is supplied as a white to off-white crystalline solid; particle size and bulk density are batch-dependent, and no harmonized model nomenclature exists across manufacturers. Procurement documentation therefore specifies the CAS registry number, assay tier, residual solvent profile, and sieve fraction where relevant. Commercial material is generally separated into a technical grade with assay not less than 97.0% by non-aqueous titration and a high-purity grade with assay not less than 99.0%. The hydrochloride counterion confers water solubility and suppresses oxidation of the N-methylamino group during ambient storage, while the ethyl ester blocks the carboxyl terminus until alkaline hydrolysis. Compared with sarcosine free base, the salt has a defined chloride content and improved handling in closed transfer lines, but it is hygroscopic above 60% relative humidity and must be stored in sealed polyethylene-lined fibre drums.
Functionally, the three derivatives are not interchangeable. Sarcosine free base (CAS 107-97-1) is a zwitterionic amino acid with high melting point and limited solubility in nonpolar organic solvents; it is used predominantly in aqueous or solid-state transformations where the carboxylate is retained. Sodium sarcosinate is a water-soluble anionic intermediate formed by neutralization of sarcosine with sodium hydroxide; it serves as the feedstock for N-acyl sarcosinate surfactants through Schotten-Baumann acylation. By contrast, ethyl sarcosinate hydrochloride is a protected amino acid ester in which both the amine and carboxylic acid sites are masked. The hydrochloride form blocks the secondary amine as the ammonium chloride, preventing premature acylation or oxidation, and the ethyl ester protects the acid against ionization. This arrangement allows selective release of the free amine by in situ neutralization with a hindered tertiary base. The difference is critical in process settings: sodium sarcosinate is not suitable for anhydrous peptide coupling, whereas the hydrochloride is compatible with standard coupling reagents after neutralization with 1.5 to 2.0 molar equivalents of N-methylmorpholine or diisopropylethylamine. In addition, the chloride counterion of the hydrochloride is not a passive impurity; it changes the solubility profile and must be accounted for in stoichiometric calculations for downstream reactions.
Commercially released lots are tested against methods that are not fully harmonized across producers. The certificate of analysis typically includes appearance, identification by Fourier-transform infrared spectroscopy against a reference spectrum, assay by non-aqueous titration with perchloric acid in glacial acetic acid, loss on drying by vacuum desiccation, and residue on ignition by combustion at 600 °C. Chloride content forms a useful quality check because the theoretical chloride content is 23.08% on an anhydrous basis; low chloride values indicate residual free base or incomplete hydrochloride formation. HPLC area-percent is sometimes reported, but it is less reliable for absolute purity because the analyte has a low chromophore and chloride adducts can distort quantification. Suppliers following pharmacopoeial frameworks may use a limit test for heavy metals aligned with ICH Q3D principles rather than a wet chemical sulfide test. Residue on ignition is normally specified at not more than 0.1% for high-purity material. This is not a universal specification, but it appears in technical data sheets and should be confirmed against the lot-specific certificate.
Where the product is intended for peptide synthesis or moisture-sensitive heterocycle construction, release criteria are tightened around water, free amine, and non-volatile residue. The following parameter set represents a composite of commercial data sheets and is not a single regulatory monograph.
| Parameter | Typical release limit | Method |
|---|---|---|
| Appearance | White to off-white crystalline powder | Visual inspection |
| Assay on anhydrous basis | ≥ 99.0% | Non-aqueous titration |
| Loss on drying | ≤ 0.50% | Vacuum 60 °C, 4 h |
| Residue on ignition | ≤ 0.10% | Ignition 600 °C |
| Chloride content | 22.9–23.3% | Argentometric titration |
| Heavy metals | ≤ 10 ppm | ICH Q3D risk-based |
| Identification | IR spectrum matches reference | FTIR KBr dispersion |
Batch-to-batch variation in residual ethanol is the most common cause of downstream yield drift in peptide coupling. Ethyl sarcosinate hydrochloride produced by Fischer esterification of sarcosine with ethanol and hydrogen chloride retains ethanol in the crystal lattice, and incomplete drying leaves residual ethanol levels between 0.5% and 2.0%. This is not detected by assay unless a specific residual solvent method is used. Gas chromatographic headspace analysis with flame ionization detection and a polar column can quantify ethanol and ethyl acetate. In peptide syntheses using 0.98 equivalents of coupling reagent relative to the amino acid, ethanol can consume the reagent and produce ethyl esters with wrong-chain impurities; therefore the high-purity grade should specify residual ethanol not more than 0.1%. Production operators have observed that residual ethyl acetate is less problematic because it does not compete strongly for active ester intermediates. Certificates of analysis for peptide-grade material should therefore include a residual solvent panel rather than only loss on drying, because loss on drying does not distinguish water from retained ethanol.
In solution-phase synthesis, the salt is dissolved in dichloromethane or dimethylformamide and cooled to 0–5 °C before addition of a hindered tertiary amine. The neutralization step releases the free ester and generates ammonium chloride by-product; if the amine is added faster than the cooling loop can remove heat, the batch can exceed 15 °C, increasing the rate of ethyl ester hydrolysis and reducing coupling yield. Production-scale reactors fitted with jacket temperature control and impeller speed 80–120 rpm are used, though published data for this specific configuration is limited. Manual addition through an open manway is not recommended because localized high pH causes free base oiling. The liberated free base is then coupled to an Fmoc- or Boc-protected amino acid using 1.0 equivalent of HATU or PyBOP in the presence of the same tertiary base. After aqueous work-up, the ethyl ester is cleaved with lithium hydroxide in tetrahydrofuran/water at 0 °C to avoid N-methylamide formation. Users should not combine the hydrochloride directly with carbodiimide reagents without pre-neutralization, because the salt does not dissolve sufficiently and the free base is not generated. In multi-kilo campaigns, the pre-neutralization point is monitored by in-reactor pH or by carbon dioxide evolution from residual carbonate, but the most reproducible control point remains the maintained jacket set point during base charge.
Several process pathways require the free sarcosine ethyl ester rather than the hydrochloride. The free base can be generated by partitioning the hydrochloride between dichloromethane and saturated sodium bicarbonate, followed by drying over anhydrous sodium sulfate and evaporation at reduced pressure below 25 °C. In this state, the secondary amine participates in reductive amination with aldehydes or ketones using sodium triacetoxyborohydride in dichloromethane. Residual water in the organic stream must be controlled to low levels, commonly below 0.05% by Karl Fischer titration, before alkylation; otherwise the reducing agent is consumed and the aldehyde is reduced to the alcohol. The free base is also sensitive to atmospheric carbon dioxide, which can form a carbamate salt and reduce nucleophilicity. Nitrogen blanketing is required during storage if the free base is isolated. Because the free base has a lower flash point than the hydrochloride, extraction and evaporation should occur in equipment rated for flammable solvents under inert gas. The free base can oil out of aqueous-organic mixtures if the pH exceeds 8.0, and re-acidification with dilute hydrochloric acid may not restore the original crystalline salt due to partial ester hydrolysis.
Drying of the hydrochloride before use is necessary when the material has been stored above 60% relative humidity. Vacuum tray drying at 40–50 °C and 1–5 kPa for 4–12 h reduces free moisture without volatilizing the intact compound; deeper drying at temperatures above 60 °C may generate residual ethanol and sarcosine through partial ester hydrolysis. Thermal gravimetric analysis of representative samples shows an onset of weight loss associated with decomposition rather than simple sublimation, but published data for this specific configuration is limited. Process operators on bulk drying lines report caking and discoloration when the dryer reaches local hot spots above 80 °C, and the resulting off-white to tan powder exhibits reduced acid-base titration strength. The hydrochloride is stable under ambient storage in unopened sealed containers, but repeated partial discharges from bulk bags in humid locations increase water uptake and reduce flow. If caking occurs, deagglomeration through a conical mill with nitrogen blanketing restores particle size distribution without returning the material to the drying oven. Production lines that dry this salt in the same tray dryer used for sarcosine free base frequently encounter cross-contamination because residual free base neutralizes the hydrochloride and alters the assay profile of the next lot.
Regulatory documentation for export shipments generally includes Safety Data Sheet, residual solvent statement, and elemental impurity declaration aligned with ICH Q3D guidance. The product is not a pharmacopoeial monograph substance; however, test procedures may be adapted from general titration chapters and ICH Q3C for residual ethanol and ethyl acetate. For import into the European Economic Area, the substance is subject to REACH registration; buyers should confirm the supplier’s registration number for the annual tonnage band. Workplace exposure controls under the SDS commonly specify local exhaust ventilation and closed conveying systems because the powder is irritating to the respiratory tract. The product should not be combined with strong bases in bulk storage, because exothermic hydrolysis releases ethanol and forms sarcosine hydrochloride, nor with oxidizing agents due to potential decomposition of the N-methylamino group. Because the hydrochloride is hygroscopic, warehouse transfer at relative humidity above 60% should be limited to closed systems or nitrogen-purged transfer hoppers. Stability data under accelerated conditions are batch-specific; the compound is not typically packaged in moisture-permeable paper bags for long-term storage.
Selection between sarcosinate derivatives should be based on the required reaction state, handling property, and impurity profile. The following comparison summarizes documented differences relevant to process chemistry.
| Derivative | Ionic form | Solubility | Primary process role | Critical limitation |
|---|---|---|---|---|
| Ethyl sarcosinate hydrochloride | Hydrochloride salt | Water, methanol; low in dichloromethane unless neutralized | Protected N-methylglycine for peptide coupling | Hygroscopic; chloride counterion requires stoichiometric base |
| Sarcosine free base | Zwitterion | Water; poor in nonpolar solvents | Aqueous N-methylamino transformations | High melting point; limited organic solubility |
| Sodium sarcosinate | Sodium salt | Water | Acyl sarcosinate surfactant precursor | Not suitable for anhydrous coupling |
| Ethyl sarcosinate free base | Free amine ester | Organic solvents; water-sensitive | Reductive amination and nucleophilic alkylation | Carbon dioxide sensitivity; lower flash point |
Material substitution is not advised without revalidating the work-up sequence. When ethyl sarcosinate hydrochloride is used in a reactor previously used for sodium sarcosinate surfactant production, residual alkaline detergent left in the bottom valve can neutralize the hydrochloride and release free base prematurely, causing the subsequent coupling to proceed without the intended tertiary base concentration and altering stoichiometry. The same incompatibility applies to formulation with amine-based additives; in bulk mixing, the hydrochloride should be charged first and dissolved before any basic reagent is introduced. Because the ester group hydrolyzes under strongly acidic conditions, long-term processing in aqueous hydrochloric acid above 1 M should be avoided. These process boundaries are more restrictive than those for sodium sarcosinate and define the operational window for this product in multi-step synthesis.
