| HS Code | 278956 |
| Product Name | Glycine Ethyl Ester Hydrochloride |
| Chemical Name | Ethyl 2-aminoacetate hydrochloride |
| Cas Number | 623-33-6 |
| Molecular Formula | C4H10ClNO2 |
| Molecular Weight | 139.58 g/mol |
| Appearance | White crystalline powder |
| Melting Point | 144-146 °C |
| Solubility | Soluble in water, ethanol, and DMSO |
| Purity | ≥98% |
| Storage Conditions | Store in a cool, dry, airtight container, protected from light |
| Synonyms | Ethyl glycinate hydrochloride; Glycine ethyl ester HCl; Ethyl 2-aminoacetate hydrochloride |
| Hazard Classification | Irritant to eyes, respiratory system, and skin |
As an accredited Glycine Ethyl Ester Hydrochloride factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | Glycine Ethyl Ester Hydrochloride is packaged in 25 kg sealed fiber drums with polyethylene liners to ensure purity and safe handling. |
| Container Loading (20′ FCL) | 20′ FCL: Glycine Ethyl Ester Hydrochloride packed in sealed drums on pallets, containerized securely, moisture-protected, stable loading. |
| Shipping | Ship in sealed, moisture-proof containers (e.g., laminated bags or drums) with desiccant. Protect from humidity and direct sunlight. Store at ambient temperature in a cool, dry area. Classified as non-hazardous for transport; ensure packaging is labeled and accompanied by relevant documentation. Handle with standard hygiene precautions. |
| Storage | Store Glycine Ethyl Ester Hydrochloride in a tightly sealed container under dry conditions, ideally at 2–8 °C. Protect from moisture, humidity, and light. Use desiccant or store under inert gas if available. Keep away from incompatible materials and ensure the container is reopened minimally to prevent hydrolysis or decomposition. |
| Shelf Life | Store tightly sealed in a cool, dry place; typical shelf life is two to three years when handled properly. |
In fine chemical manufacturing campaigns where an alpha-diazo ester is consumed in cyclopropanation or C–H insertion, glycine ethyl ester hydrochloride functions as a solid, non-volatile precursor from which ethyl glycinate is liberated immediately before diazotization. The salt is dissolved in demineralized water at a concentration of 20–30 wt%, chilled to 0–5 °C in a jacketed glass-lined reactor, and treated with a sodium nitrite solution that has been pre-cooled to the same temperature. The addition is exothermic and generates nitrous acid in situ; the pH is maintained between 2.0 and 3.0 using dilute hydrochloric acid or buffered sodium acetate, because higher pH values slow diazonium formation and favor hydrolysis of the ethyl ester to glycine hydrochloride. In-line FTIR configured with a diamond ATR probe tracks the rising diazo stretch at approximately 2100 cm⁻¹; the reactor control system interlocks nitrite feed with the FTIR signal so that unreacted amine does not accumulate. After complete addition, the mixture is stirred for 30–60 min at 0–5 °C before extraction with methyl tert-butyl ether. The organic layer is washed twice with cold saturated brine to remove sodium chloride and residual nitrite, then dried over anhydrous sodium sulfate. The filtered organic phase is concentrated under reduced pressure with the jacket set no higher than 25 °C; ethyl diazoacetate is retained as a yellow oil that must be used immediately or stored under inert gas at -20 °C. Published calorimetric data for crude isolates from this specific hydrochloride salt are limited, so adiabatic calorimetry and blowdown disc sizing are required before any batch exceeding laboratory scale is processed.
The downstream catalytic step imposes its own purity constraints on the diazo ester. Rhodium(II) carboxylate catalysts used in intermolecular cyclopropanation are sensitive to halide and water carryover; residual chloride above 50 µg/g in the distilled ester can attenuate turnover frequency, although the exact tolerance differs by catalyst lot and should be verified through inductively coupled plasma mass spectrometry on the isolated oil. Residual water is reduced to below 0.05 wt% using 3 Å molecular sieves before the diazo ester is transferred into a catalyst charging vessel. The ester is never isolated as a dry solid; it remains in solution or under inert atmosphere because neat ethyl diazoacetate can undergo rapid thermal decomposition if heated above ambient temperature. When continuous processing is adopted, a Corning-type glass fluidic module with integrated quench zones is used to limit the in-process inventory of diazo ester to a few grams per plate; this configuration is selected because the diazo intermediate is both thermally unstable and acutely toxic by inhalation. Gas evolution during diazotization is monitored with a mass flow meter on the reactor vent, and the scrubber is charged with cold sodium hydroxide solution to absorb nitrogen oxide vapours. The main operational boundary is that the free amine must not be allowed to stand in neutral or basic aqueous solution for more than a few minutes, because it undergoes rapid self-condensation to a diketopiperazine that is unreactive toward diazo transfer and difficult to remove from the final ester without distillation.
Ethyl isocyanoacetate is obtained from glycine ethyl ester hydrochloride through a two-stage sequence that begins with liberation of the free amino ester and ends with dehydration of an N-formyl intermediate. The hydrochloride is first neutralized with triethylamine in dichloromethane, and the free amine is converted to N-formylglycine ethyl ester using mixed anhydride formylation or an alkyl formate under base catalysis. The N-formyl intermediate is dehydrated with phosphoryl chloride in the presence of triethylamine at -10–0 °C; the phosphoryl chloride feed is controlled so that the internal temperature does not exceed 0 °C, because higher temperatures promote formation of tarry by-products and reduce isocyanide purity. In-line ReactIR monitoring tracks the appearance of the isocyanide band near 2150 cm⁻¹ and the disappearance of the formamide carbonyl near 1670 cm⁻¹; the reaction is quenched with cold aqueous bicarbonate when the formamide band falls below the detection limit. The organic phase is washed with brine, dried over magnesium sulfate, and concentrated under low vacuum. The crude oil is purified by short-path vacuum distillation with the heating bath maintained below 70 °C; the purified ethyl isocyanoacetate is collected as a water-white liquid and stabilized by storage under argon at -20 °C. Residual chloride is controlled by argentometric titration according to ISO 6227:1982, and residual water is determined by coulometric Karl Fischer titration according to ISO 760:1978. The isocyanide is a strong ligating reagent and must not be handled in copper or brass fittings, because copper accelerates decomposition and re-formation of the formamide.
The purified ester is used in van Leusen oxazole synthesis and related imidazole-forming reactions, where the isocyanide acts as an active methylene component. For this downstream use, the ethyl ester must be free of triethylamine hydrochloride carryover, because residual base can deprotonate the tosylmethyl isocyanide reagent and alter the reaction pH during the heterocyclization step. The process window is narrow because the free amino ester intermediate can cyclize to a diketopiperazine if the neutralization and formylation are conducted too slowly; a programmable syringe pump is typically used to add triethylamine over 10–15 min at -10 °C, after which the formylation reagent is introduced without allowing the batch to warm above 0 °C. Residual isocyanide in mother liquors and distillation residues is quenched with dilute hydrochloric acid before waste disposal, because the unreacted ester is malodorous and moderately volatile at ambient temperature. Published preparative procedures from academic laboratories give the best results with dichloromethane as the extraction solvent, but on pilot scale methyl tert-butyl ether is sometimes preferred to reduce solvent density and improve phase split times in a stainless steel reactor. The exact solvent replacement must be validated against the extraction efficiency for a specific batch, because glycine ethyl ester hydrochloride can retain water in the crystal lattice, and the liberated amine can salt out if the organic solvent is too non-polar.
Glycine ethyl ester hydrochloride serves as a C-protected glycine source in solution-phase peptide coupling when a linear dipeptide or tripeptide fragment is being assembled on multikilogram scale. The salt is suspended in anhydrous tetrahydrofuran or dimethylformamide, and the free base is liberated with N-methylmorpholine at 1.0–1.1 equiv relative to the hydrochloride; the resulting solution is added to a pre-activated N-protected amino acid coupling mixture at 0–5 °C. Carbodiimide coupling with EDC hydrochloride is performed with 1-hydroxybenzotriazole hydrate as the racemization-suppressing additive, because even though glycine itself is achiral, the adjacent activated amino acid can epimerize in the presence of an unmitigated O-acylisourea intermediate. The coupling completeness is followed by HPLC according to USP 621; the residual starting amine is kept below 1.0 area% before the reaction is worked up with aqueous citric acid. The ethyl ester protecting group remains intact during this step, preventing uncontrolled chain extension at the C-terminus. After the coupling is complete, the organic phase is washed with saturated sodium bicarbonate and brine, dried, and concentrated to an oil that is carried directly into deprotection or saponification without prolonged heating.
The critical processing conflict in this application is the intramolecular aminolysis of the ethyl ester to a diketopiperazine after the N-terminal protecting group is removed. When a dipeptide ethyl ester bearing a free N-terminal amine is warmed in neutral or weakly basic solution, the terminal amine attacks the adjacent ester carbonyl, displacing ethanol and forming a six-membered diketopiperazine ring. The rate of this cyclization increases with solvent polarity and with the cosolvent water content; therefore, saponification of the ethyl ester is usually conducted at controlled pH with a calcium chloride–moderated sodium hydroxide solution, or the ester is cleaved with controlled acidic hydrolysis to avoid a pH window above 7.5. Reaction monitoring uses FTIR to track the disappearance of the ester carbonyl near 1740 cm⁻¹ and the growth of the diketopiperazine carbonyl near 1660–1680 cm⁻¹. On production scale, this monitoring is carried out with a ReactIR probe inserted through a thermowell adapter, and the data are cross-checked with offline HPLC. The operational boundary is strict: a drum of ethyl glycinate hydrochloride that has absorbed moisture above 0.5 wt% must be re-dried before use, because free water accelerates both ester hydrolysis and premature diketopiperazine formation at the start of coupling.
| Processing stage | Reagent used to liberate free amine | Temperature window | Primary side reaction | Analytical tracking |
|---|---|---|---|---|
| Diazo transfer | sodium nitrite / hydrochloric acid | 0–5 °C | ethyl ester hydrolysis | in-line FTIR at 2100 cm⁻¹ |
| Isocyanide synthesis | triethylamine | -10–0 °C | diketopiperazine condensation | in-line IR at 2150 cm⁻¹ |
| Solution-phase peptide coupling | N-methylmorpholine | 0–5 °C | ethyl ester aminolysis to diketopiperazine | HPLC according to USP 621 |
| Deliberate diketopiperazine formation | sodium bicarbonate | 40–60 °C | glycine acid precipitation | FTIR carbonyl shift |
When the synthetic target is a 2,5-diketopiperazine derivative rather than a linear peptide, glycine ethyl ester hydrochloride is deliberately cyclized under aqueous or alcoholic base. The salt is dissolved in ethanol or a water-ethanol mixture at a concentration between 0.1 M and 0.5 M, and sodium bicarbonate is added to adjust the pH to 7.5–8.5. The batch is warmed to 40–60 °C and stirred until the ester carbonyl disappears; the product precipitates as a white crystalline solid and is isolated by filtration. The mother liquor is retained for analyzing the competing hydrolysis pathway, because water in the cosolvent can produce glycine acid instead of the desired cyclodipeptide. The water content of the starting ethanol is controlled to below 2.0 wt% by Karl Fischer titration before the reaction is started, and the reactor is fitted with a reflux condenser to prevent ethanol loss at the upper end of the temperature window. This controlled cyclization is used when the diketopiperazine ring is the core structure of a pharmaceutical intermediate, not merely an impurity to be avoided.
Glycine ethyl ester hydrochloride is acylated under Schotten–Baumann conditions to yield N-acyl glycine ethyl esters that serve as stable, isolable intermediates for downstream heterocyclization or amine deprotection chemistry. The hydrochloride is combined with water and a water-immiscible solvent such as methyl tert-butyl ether or toluene, and the acid chloride is added along with an aqueous base that maintains the pH between 8.0 and 9.0. The exotherm is controlled by jacket temperature at 0–10 °C, and the acid chloride feed rate is set so that the pH does not fall below 7.5, because accumulation of unreacted hydrochloride salt retards acylation and increases the probability of ethyl ester hydrolysis. After the addition, the organic layer is washed with dilute hydrochloric acid to remove triethylamine or sodium carbonate base, then washed with saturated sodium chloride solution and concentrated under vacuum. The resulting N-acyl ethyl ester is analyzed by HPLC with a low-wavelength UV detector; if the acyl group lacks a chromophore, an ELSD or charged aerosol detector is used instead. Residual glycine ethyl ester hydrochloride is monitored by ion chromatography, and the acceptance criterion is typically set at 0.10 area% or below for pharmaceutical-grade intermediates.
The main limitation in this application is the competing formation of acylated glycine acid when the ester is exposed to aqueous base for extended periods. Ethyl esters of glycine are more labile than the corresponding methyl or tert-butyl esters under basic conditions, and in biphasic acylations the hydrolysis rate increases with the solubility of water in the organic phase. Methyl tert-butyl ether gives lower water solubility than dichloromethane and is preferred when the acid chloride is sufficiently stable; dichloromethane may be used for less reactive acid chlorides, but the water content of the organic layer must be checked by Karl Fischer titration before the acylation begins. The isolated N-acyl glycine ethyl ester can be used in subsequent heterocyclic condensations, such as the formation of oxazoles, imidazoles, or thiazoles, where the ethyl ester serves as a masked carboxylate that is cleaved by mild saponification after ring construction. No single universally applicable work-up is suitable for every N-acyl derivative, and the phase separation time, residual acid value, and HPLC profile must be established for each individual acylating agent at the pilot scale.
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Glycine ethyl ester hydrochloride, also referred to as ethyl glycinate hydrochloride or H-Gly-OEt·HCl, is a crystalline C-terminal protected amino acid building block with the molecular formula C4H10ClNO2, a CAS registry number of 623-33-6, and a formula weight of 139.58 g/mol. Commercial designations include Gly-OEt·HCl, ethyl aminoacetate hydrochloride, and ethyl glycinate monohydrochloride; no unified product model exists because the material is distributed by multiple manufacturers under the same CAS registry number. The compound is supplied as technical grade for early-route screening and as pharmaceutical intermediate grade with a certificate of analysis covering assay, melting range, loss on drying, water content, chloride content, residue on ignition, heavy metals, and residual solvents. The hydrochloride salt is selected when the primary amino group must be masked as a non-nucleophilic solid until a coupling, formylation, or neutralization step. It differs from glycine ethyl ester free base in that the free base is a liquid at ambient temperature, whereas the hydrochloride is a white to off-white crystalline powder that can be filtered, dried, and charged as a solid.
Typical release limits for pharmaceutical intermediate grade material are shown in Table 1. These values represent supplier-certified limits rather than a compendial monograph, and batch certificates may use equivalent methods validated according to ICH Q2(R1). The assay is determined by non-aqueous titration with perchloric acid in anhydrous acetic acid. Because the compound contains a primary amine salt, mercury-free potentiometric detection is used. Aqueous dissolution followed by argentometric titration with 0.1 M silver nitrate verifies chloride content; the theoretical chloride content is 25.39% on an anhydrous basis. The release range of 25.0–25.8% accounts for normal moisture and assay variation.
| Parameter | Limit | Analytical method |
|---|---|---|
| Appearance | White to off-white crystalline powder | Visual inspection |
| Assay on dried basis | ≥98.0% | Non-aqueous titration |
| Melting range | 140–145 °C | Capillary method or differential scanning calorimetry |
| Loss on drying | ≤0.50% | USP <731> |
| Water content | ≤0.50% | Karl Fischer titration, Ph. Eur. 2.5.12 |
| Chloride content | 25.0–25.8% | Argentometric titration |
| Residue on ignition | ≤0.10% | USP <281> |
| Heavy metals | ≤10 mg/kg | Ph. Eur. 2.4.8 or equivalent |
| Residual ethanol | ≤5000 mg/kg | Static headspace GC-FID |
Residual ethanol is controlled under ICH Q3C guidance for Class 3 solvents. The lower limit does not imply that ethanol has a toxicological alert at 5000 mg/kg; it reflects the normal limit applied to a solvent used in the final crystallization. Water content is measured separately from loss on drying because the salt is hygroscopic and can reabsorb atmospheric moisture during sample handling. If water content exceeds 0.50%, the product may still be used after vacuum drying, but the melting range broadens and the assay must be re-established on the dried material. The non-aqueous titration must be performed in dry glassware because the primary amine salt titrates as a monobasic species in acetic acid.
On pilot-scale manufacture, final purity is influenced primarily by the recrystallization solvent composition and the efficiency of residual solvent removal. The material is commonly crystallized from ethanol or ethanol/water mixtures. Needle-like crystals form under slow cooling, and those crystals can entrap ethanol in the crystal lattice. Vacuum tray drying at 40–50 °C under 5–10 kPa absolute pressure is preferred over fluidized-bed drying because the crystalline needles can undergo attrition and generate fine particles with poor flowability. Published data for continuous vacuum-drying configurations for this specific product is limited; therefore, batch drying in a double-cone dryer is retained in multipurpose plants that produce other amino ester hydrochlorides. If the dryer temperature exceeds 60 °C in the presence of residual moisture, the ester can undergo partial hydrolysis to glycine hydrochloride and ethanol. That degradation produces a broad melting range and a low assay after drying.
Selection among glycine building blocks is governed by three parameters: mass per amine equivalent, susceptibility of the ester to hydrolysis, and physical state during feed. The ethyl ester hydrochloride has a mass per amine equivalent of 139.58 g/eq, whereas the methyl ester hydrochloride has 125.55 g/eq and the free base has 103.12 g/eq. The free base is a clear liquid at room temperature and must be stored under inert gas to suppress carbamic acid formation from atmospheric carbon dioxide. The hydrochloride salts eliminate that storage hazard but require stoichiometric tertiary base for amide coupling. In a direct comparison of the methyl and ethyl hydrochlorides, the methyl compound releases a smaller mass of neutral amine per unit throughput, which reduces raw-material cost in high-volume synthon manufacture. However, the ethyl ester is less susceptible than the methyl ester to saponification during mildly basic aqueous workup, a difference that becomes relevant when the N-acylated product is washed with 5% sodium bicarbonate at 0–5 °C.
The hydrochloride salts are freely soluble in water and methanol, soluble in ethanol, and practically insoluble in diethyl ether and hexanes. The ethyl ester hydrochloride dissolves in ethanol more readily than the methyl analogue, which simplifies recrystallization. In contrast, the free base is miscible with many organic solvents but cannot be stored in open vessels because it absorbs carbon dioxide and forms a carbamate mass. Aqueous solutions of the hydrochloride are acidic; the pH of a 10% solution is typically between 3.0 and 4.0 at 25 °C. The free amine generated upon neutralization has an amine pKa near 7.7; therefore, the auxiliary base used for coupling must be at least two pKa units higher to ensure essentially complete deprotonation.
| Property | Gly-OEt·HCl | Gly-OMe·HCl | Gly-OEt free base |
|---|---|---|---|
| Molecular formula | C4H10ClNO2 | C3H8ClNO2 | C4H9NO2 |
| Molecular weight | 139.58 g/mol | 125.55 g/mol | 103.12 g/mol |
| Physical state at 25 °C | White crystalline powder | White crystalline powder | Clear liquid |
| Melting range | 140–145 °C | 170–175 °C supplier-reported | Not applicable |
| Acid lability | Stable to TFA | Stable to TFA | Not applicable |
| Base hydrolysis resistance | Moderate | Slightly lower | High |
| Main handling issue | Hygroscopic caking | Higher melting point requires grinding before dissolution in cold solvent | Aminolysis and carbamate formation on exposure to CO2 |
From a process engineering standpoint, the higher melting point of the methyl ester hydrochloride requires pre-milling before dissolution in cold dimethylformamide, whereas the ethyl ester dissolves more readily at 0–5 °C. This influences coupling reactions that must be run at low temperature to suppress epimerization of activated amino acids. Although glycine is achiral, the activated ester of the coupling partner may be temperature-sensitive; therefore, maintaining the reaction mixture below 10 °C can be necessary. The additional methylene unit in the ethyl ester also increases lipophilicity sufficiently to improve extraction into ethyl acetate after aqueous workup.
In solution-phase peptide synthesis, glycine ethyl ester hydrochloride is neutralized in the reactor with N,N-diisopropylethylamine or N-methylmorpholine. Coupling to Fmoc- or Boc-protected amino acids proceeds with carbodiimide/1-hydroxybenzotriazole systems in dichloromethane or dimethylformamide. The hydrochloride’s acidic proton contributes to pH drift in aqueous workup, and buffered washes with 0.5 M potassium hydrogensulfate are used to maintain the product in the organic layer. On pilot-scale equipment, pH-controlled dosing of the auxiliary base requires an in-line pH probe in the addition vessel; otherwise the neutralization exotherm can raise the batch temperature above 25 °C and accelerate ester hydrolysis. This effect is observed in jacketed glass-lined reactors of 500 L nominal volume when the feed line is discharged below the solvent surface to prevent localized amine concentration gradients.
Unlike the tert-butyl ester of glycine, the ethyl ester remains intact during trifluoroacetic acid-mediated deprotection of the Boc group. This property allows N-Boc-Gly-OEt to be deprotected without loss of the C-terminal protecting group, a sequence that is not possible with tert-butyl ester building blocks. The ethyl ester can therefore be used in routes where the free acid is generated later by alkaline saponification with 1 M lithium hydroxide in tetrahydrofuran/water at 0–5 °C. The carboxylate is then obtained after acidic neutralization and extraction. In process-scale work, the extraction is performed in a centrifugal extractor rather than a gravity settling decanter because the aqueous and organic phases are prone to slow separation when the product is concentrated above 200 g/L.
Another established use is the preparation of ethyl isocyanoacetate through N-formylation followed by dehydration with phosphorus oxychloride in the presence of a tertiary base. The resulting isocyanide participates in the van Leusen oxazole synthesis. Here the solid hydrochloride is advantageous because the free base is a liquid and the formylation can be run as a two-phase process; the HCl salt is neutralized in situ and the free ester is retained in the organic layer. Published kinetic data for this specific configuration is limited, and the dehydration step is highly exothermic, requiring controlled addition at −5 to 0 °C and a vessel with sufficient heat-transfer area to manage the adiabatic temperature rise. The isocyanide product is monitored by GC-FID rather than HPLC because the isocyanide lacks a strong chromophore.
Material stored in original containers under nitrogen or argon at ≤25 °C and relative humidity ≤60% retains its melting range and assay for the supplier-defined retest interval, commonly 24 months from the date of manufacture. Once a drum is opened and exposed to ambient moisture, surface caking occurs because the hydrochloride is hygroscopic. Caked material should be removed before automated solids dosing because it can bridge in loss-in-weight feeders and cause feed-rate variability. Plants that operate continuous peptide synthesizers frequently specify milled material with a controlled particle size distribution and avoid storage near open steam lines, glycol chiller condensate, and other sources of humidity. Pre-drying is required if the material has been exposed to relative humidity above 60% or if the certificate of analysis shows water content above 0.50%.
The product is incompatible with strong bases, aqueous ammonia, and primary amines at elevated temperatures because of ester aminolysis and oligomer formation. Under alkaline conditions above pH 12, both the ethyl and methyl esters hydrolyze rapidly to glycine. This boundary is operationally important during saponification, where the reaction is conducted at low temperature and monitored by thin-layer chromatography or HPLC to stop the reaction before over-hydrolysis. The hydrochloride salt also reacts with formaldehyde under basic conditions to form an imine, and storage with oxidizing agents should be avoided because the primary amine can undergo oxidative degradation. Within these operational limits, the ethyl ester hydrochloride is preferred over the liquid free base for solid feeding in automated synthesis and over the methyl ester when the extra methylene unit improves phase transfer without a significant mass penalty.
In a continuous manufacturing line, the solid is fed from a loss-in-weight feeder into a temperature-controlled dissolution vessel. The feeder hopper must be purged with low-humidity nitrogen and fitted with a rotary valve to prevent atmospheric moisture ingress. Dissolution in dimethylformamide at 100 g/L is endothermic; uncontrolled addition can cause local cooling below 0 °C and transient viscosity changes in the solvent. Published data for this specific configuration is limited, so dissolution endpoint is confirmed by in-line conductivity rather than visual inspection because undissolved fines are difficult to detect in opaque jacketed reactors. The hydrochloride is charged into peptide synthesizers as a pre-weighed solid to avoid the volume metering errors associated with the free base liquid and to retain the ester through acidolytic Boc removal steps.
