| HS Code | 958866 |
| Chemical Name | D-Phenylglycine Ethyl Ester Hydrochloride |
| Synonym | (R)-Ethyl 2-amino-2-phenylacetate hydrochloride |
| Cas Number | 17609-56-2 |
| Molecular Formula | C10H13NO2·HCl |
| Molecular Weight | 215.68 g/mol |
| Appearance | White to off-white crystalline powder |
| Melting Point | 200-202 °C (dec.) |
| Optical Rotation | [α]20/D = -112° (c = 1, H2O) |
| Purity | ≥ 98% (HPLC) |
| Solubility | Soluble in water, methanol, and ethanol; slightly soluble in dichloromethane |
| Storage Conditions | Store at 2-8 °C under inert atmosphere, protected from moisture |
| Smiles | CCOC(=O)[C@H](N)c1ccccc1.Cl |
As an accredited D-phenylglycine Ethyl Ester Hydrochloride factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 25 g packaged in a sealed amber glass bottle with tamper-evident cap, labeled with purity, lot number, and handling precautions. |
| Container Loading (20′ FCL) | 20′ FCL: D-phenylglycine ethyl ester hydrochloride packed in sealed drums, palletized, secured, protected from moisture, and stowed for safe transport. |
| Shipping | Ship as a non-hazardous fine chemical in sealed, moisture-proof containers, protected from light and humidity. Store at 2–8°C during transit. Use sturdy outer packaging with adequate cushioning. Avoid extreme temperatures and prolonged shipping durations. Include proper documentation and SDS. Ensure compliance with local transportation regulations. |
| Storage | Store in a tightly sealed container in a cool, dry, well-ventilated area away from direct sunlight and moisture. Keep the hydrochloride salt protected from humidity and strong oxidizing agents. Use proper labeling and ensure the storage temperature is controlled, typically between 2–8 °C, to maintain stability and prevent decomposition. |
| Shelf Life | Stable for 24 months when stored tightly sealed in a cool, dry place, protected from moisture, heat, and light. |
D-Phenylglycine ethyl ester hydrochloride (CAS 22264-42-2) is handled in bulk as an off-white crystalline solid with a typical assay of 98.0–101.0% on the anhydrous basis. The material is hygroscopic; warehouse controls maintain 25°C and 65% RH or lower. Before use in anhydrous coupling, vacuum drying at 40°C for 8 h reduces water content below 0.1% by Karl Fischer titration. The D-configuration of the phenylglycine unit is retained only when freebase release is conducted below 10°C and at pH 8.5 or lower; prolonged caustic exposure leads to α-carbon racemization. These handling constraints define the downstream processing windows for the application tracks described below.
In β-lactam antibiotic manufacturing, the salt is first converted to an N-protected D-phenylglycine acid because the free α-amino group must be masked before acylating the 6-aminopenicillanic acid nucleus. A typical batch dissolves the hydrochloride in methanol at 0–5°C, adds triethylamine to liberate the free amine, and reacts the solution with di-tert-butyl dicarbonate in the presence of tetrahydrofuran. The resulting N-tert-butoxycarbonyl ethyl ester is extracted into ethyl acetate, washed with 1 M hydrochloric acid and saturated sodium bicarbonate, and concentrated under vacuum. Saponification uses lithium hydroxide in tetrahydrofuran/water at 0–5°C to cleave the ethyl ester without opening the carbamate. The N-Boc-D-phenylglycine is then activated as a mixed anhydride with pivaloyl chloride and N-methylmorpholine in methylene chloride at −10°C and coupled to 6-aminopenicillanic acid. Heat transfer is critical: the acylation exotherm can raise the batch temperature above 0°C within 3 min in a 2,000 L glass-lined reactor if the jacket setpoint is not maintained at −15°C. A pH-stat controls the addition of triethylamine to keep freebase pH between 7.8 and 8.2; higher pH accelerates epimerization at the α-carbon. After coupling, the Boc group is removed with trifluoroacetic acid and the ampicillin trihydrate is crystallized from water/acetone. Chiral purity is monitored by HPLC according to the USP monograph for ampicillin and by a general system suitability test under USP <621>. In-plant failure modes include incomplete freebase release when the methanol feed contains more than 0.5% water, leading to residual triethylamine hydrochloride crystals that blind the filter cloth and reduce the subsequent acylation yield by 3–5%. Residual water in the activation solvent above 500 ppm also consumes pivaloyl chloride and produces pivalic acid, which changes the mixed anhydride composition and slows the coupling rate. For batch records, three in-process control points are commonly tracked.
| Control point | Acceptance range | Analytical method or standard | Typical sampling point |
|---|---|---|---|
| Freebase organic-phase water content | ≤0.05% | Karl Fischer titration; USP <921> | After sodium sulfate drying |
| N-Boc-D-phenylglycine ethyl ester purity | ≥98.5% | HPLC; USP <621> | Purified extract before saponification |
| Saponification endpoint residual ester | ≤0.5% | GC-FID | After aqueous quench of reaction aliquot |
| Final API enantiomeric purity | ≥99.0% | HPLC chiral; USP monograph | Crystallized solid after drying |
An alternative to chiral chromatographic separation in the manufacture of certain 2-arylpropanoic acid derivatives uses the free base form of D-phenylglycine ethyl ester as a diastereomeric resolving agent. The hydrochloride is neutralized with saturated sodium bicarbonate until the aqueous phase remains at pH 8.2–8.5; the free amine is extracted into ethyl acetate and dried over sodium sulfate. In a 4,000 L glass-lined crystallizer, the ethyl acetate stream is combined with a racemic acid dissolved in an 85:15 v/v isopropanol/water mixture at 60–65°C. The batch is seeded with the less soluble diastereomeric salt after the solution has clarified. Cooling is controlled at 0.3 K/min to 5°C using a retreat-curve impeller; faster cooling results in oiling-out and loss of resolution efficiency. The crystallized salt is isolated on a plate filter, washed with cold isopropanol/water, and recrystallized from the same solvent system to raise diastereomeric excess above 99.0%. The free acid is regenerated by acidification with 2 M hydrochloric acid and extracted into toluene; the resolving agent remains in the aqueous phase as the hydrochloride and is recovered by basification and extraction. Mother liquors are combined and the enantiomeric composition is tracked by chiral HPLC using a polysaccharide-based column under USP <621> and validated according to ICH Q2(R1). Process bottlenecks observed on production lines include excessive crystal fines when the agitator tip speed exceeds 1.2 m/s, causing filter cloth blinding and requiring a subsequent reslurry step. This resolution method is preferred when the downstream API must avoid heavy-metal catalysts; however, published data for the exact solubility ratios of the D-phenylglycine ethyl ester salts in non-isopropanol solvent systems is limited, and laboratory solubility screening is required before changing the crystallization medium. The free base should not be stored in chlorinated solvents for more than 24 h because slow alkylation reduces resolving capacity and introduces tertiary amine impurities.
Reduction of D-phenylglycine ethyl ester hydrochloride to D-phenylglycinol is the first unit operation in a sequence that supplies enantiopure amino alcohol for chiral oxazolidinone and bisoxazoline synthesis. The hydrochloride is suspended in tetrahydrofuran and added to a slurry of lithium aluminium hydride at 0–5°C under a nitrogen atmosphere. The reduction is strongly exothermic; in a 500 L stainless steel reactor, the addition rate is set so that the internal temperature does not exceed 10°C and the hydrogen-off gas flow remains below 5 m³/h. The standard workup uses sequential addition of water, 15 wt% sodium hydroxide, and water in the ratio of 1:1:3 relative to aluminium hydride, followed by extraction with ethyl acetate. D-Phenylglycinol is isolated by vacuum distillation at 120–130°C and 1–2 mbar. For oxazolidinone auxiliary manufacture, the amino alcohol is condensed with diethyl carbonate in refluxing toluene under a Dean-Stark trap until ethanol evolution ceases. The resulting (4R)-phenyloxazolidin-2-one is crystallized from isopropanol and dried at 50°C. Chiral HPLC confirms enantiomeric excess above 99.0%. Deprotonation with n-butyllithium in tetrahydrofuran at −78°C followed by acylation with propanoyl chloride yields the lithium imide used in asymmetric aldol condensations; field experience shows that residual water above 50 ppm in the solvent reduces the lithium imide yield by decomposing the organolithium reagent before acylation. The same D-phenylglycinol stream can be converted to C2-symmetric bisoxazolines by condensation with dimethylmalonyl dichloride, cyclization with methanesulfonyl chloride and triethylamine, and crystallization from ethyl acetate/heptane. These ligands are then complexed with copper(I) triflate for asymmetric cyclopropanation reactions. Published data for the exact induction levels in pharmaceutical intermediates is limited because ligand performance is highly substrate-dependent. The reduction quench and subsequent solvent recovery require pressure relief sizing for hydrogen evolution; batch sheets typically specify a nitrogen sweep and spark-proof agitation until the aluminium salts are fully decomposed.
Chiral stationary phase manufacturing can begin with D-phenylglycine ethyl ester hydrochloride through hydrolysis to D-phenylglycine and subsequent amide coupling to aminopropyl-functionalized silica. In a typical bonding batch, 10 kg of spherical silica with 5 µm particle diameter, 120 Å mean pore size, and 300 m²/g BET surface area is silanized with 3-aminopropyltriethoxysilane in refluxing toluene at 110°C for 18 h. The amino-functionalized silica is then coupled to D-phenylglycine under carbodiimide activation in tetrahydrofuran at 25°C. Elemental analysis is used to calculate surface coverage; typical loadings fall between 0.6 µmol/m² and 0.9 µmol/m². Residual silanol groups are endcapped with trimethylchlorosilane to reduce polar tailing. The bonded phase is packed into 250 mm × 4.6 mm HPLC columns from a high-pressure slurry in acetone at 350 bar using a pneumatic pump. Column efficiency is checked with a test solute under USP <621>; reduced plate heights below 2.5 and asymmetry factors between 0.8 and 1.8 are typical acceptance windows. Mobile-phase stability is highest within pH 2.0–7.5; above pH 7.5, dissolution of the silica backbone shortens column lifetime to fewer than 500 injections. Chiral separations are most reliable when the mobile phase is a 90:10:0.1 v/v/v hexane/isopropanol/trifluoroacetic acid mixture at a flow rate of 1.0 mL/min with UV detection at 254 nm. Field failure data indicate that incomplete endcapping leaves residual silanol groups that broaden late-eluting enantiomers and increase tailing factor above 2.0, forcing column repacking. Published data for this specific D-phenylglycine selector on aminopropyl silica is limited; therefore, method validation should follow ICH Q2(R1) and column qualification should include three consecutive injections with relative standard deviation below 1.0% for retention time. The bonded silica should not be exposed to aqueous mobile phases above pH 7.5 for extended campaigns because siloxane bond hydrolysis progressively reduces column plate count.
In solution-phase peptide fragment assembly, the principal constraint is the generation of the free amine in aprotic media without exposing the phenylglycine α-carbon to racemizing bases. D-Phenylglycine ethyl ester hydrochloride is neutralized with N-methylmorpholine in N,N-dimethylformamide at 0°C. If a stronger base such as sodium hydroxide is used to pre-neutralize the salt, residual water in the reaction mixture promotes phase separation and lowers coupling efficiency. The free amine is acylated with an Fmoc-protected amino acid pentafluorophenyl ester or with HATU and 6-chloro-1-hydroxybenzotriazole. Coupling is performed at 0–5°C; the addition of the activated ester is extended over 30–60 min to control the exotherm. The batch is quenched with 0.5 M hydrochloric acid and extracted with ethyl acetate. The N-acylated ethyl ester is purified by crystallization from ethyl acetate/n-heptane. Selective saponification of the ethyl ester uses lithium hydroxide in tetrahydrofuran/water at 0°C; the endpoint is confirmed by TLC or GC when residual ester is below 0.5%. The resulting N-acyl-D-phenylglycine acid is then used as a carboxyl component in fragment coupling. Operational limits are defined by the stability of the Fmoc group, which is rapidly lost at pH above 9; the neutralization step therefore must not exceed pH 8.0. In production, a 200 L glass-lined reactor with a bottom drain is preferred over stainless steel when hydrogen chloride is generated during neutralization. Process-scale HPLC monitoring under USP <621> is required because trace amounts of the L-isomer cannot be removed by crystallization once the fragment is incorporated into a larger peptide. Batch records from multi-kilogram campaigns show that moisture in N,N-dimethylformamide above 500 ppm increases the residual free amine after coupling by 2–4%, requiring a silica gel plug filtration that adds 6 h to cycle time. The ethyl ester group is retained as a C-terminal protective function throughout the early fragment sequence; it is cleaved only after the desired amide bond is formed, which avoids premature chain extension at the carboxyl terminus.
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D-Phenylglycine ethyl ester hydrochloride is supplied as a white to off-white crystalline solid with the molecular formula C10H14ClNO2 and a formula weight of 215.68 g mol−1. The substance is the hydrochloride salt of the ethyl ester of D-α-aminophenylacetic acid, also named D-phenylglycine ethyl ester. The D-configuration corresponds to the (R)-absolute configuration at the α-carbon. Salt formation with hydrogen chloride stabilizes the primary amine and provides a crystalline, free-flowing intermediate for chiral building-block and peptide synthesis. Commercial models are typically grouped by stereochemical quality—research grade with enantiomeric excess not less than 98.0 percent and pharmaceutical intermediate grade with enantiomeric excess not less than 99.0 percent—but the grade names are not harmonized and must be read against the certificate of analysis.
Typical release criteria include chromatographic assay on the dried basis not less than 98.5 percent, enantiomeric excess not less than 99.0 percent for the D-enantiomer, loss on drying not more than 0.5 percent, residue on ignition not more than 0.2 percent, and residual solvents within ICH Q3C limits. The chloride content can be checked against the theoretical value of 16.44 percent; a narrow acceptance window such as 16.2 to 16.8 percent is a useful process check for correct salt stoichiometry. The phenyl chromophore allows detection by high-performance liquid chromatography at wavelengths of 210 to 254 nm. Because the compound is non-monographed in the major pharmacopoeias, the specific acceptance values are supplier-specific and should be cross-referenced to USP General Chapters 621, 731, and 281 as applicable method platforms.
Enantiomeric purity is influenced more by process conditions than by storage temperature alone. The α-carbon of phenylglycine can racemize through base-catalysed enolization; therefore the final salt-formation step is normally conducted under acidic or neutral conditions to lock the stereochemical configuration. A chiral HPLC method on a polysaccharide-based stationary phase—commonly an amylose tris(3,5-dimethylphenylcarbamate) column—separates the D and L enantiomers using an alkane/alcohol mobile phase with a small amount of diethylamine or trifluoroacetic acid modifier. Detection at 254 nm is used for higher-level impurities, while 210 to 220 nm improves sensitivity for trace free base. Residual free amine arises when the hydrochloride salt partially dissociates during aqueous work-up at pH above 7.5; below pH 7.0 the ammonium form is retained. On production-scale batches, the drying step is often a source of variation: rapid heating in a vacuum tray dryer at settings above 50 °C can cause the wet cake to form a case-hardened outer layer that traps solvent and raises residual ethyl acetate above the ICH Q3C limit. Drying at 40 °C to 50 °C with staged vacuum and occasional cake rotation reduces this failure mode. Published data for this specific configuration is limited, but the behaviour is consistent with general fine-chemical drying practice.
When used as a masked D-phenylglycine fragment in amide and peptide coupling routes, the hydrochloride must first be neutralized with a tertiary amine in anhydrous solvent. Triethylamine, N,N-diisopropylethylamine, or N-methylmorpholine is added to a slurry of the salt in dichloromethane or tetrahydrofuran at 0 °C to 5 °C; the resulting free amine is then available for acylation. If the amine is not fully liberated—either because the base charge is insufficient or because water is present—the coupling reagent is protonated by residual ammonium salt and conversion stalls at an intermediate plateau. The ethyl ester remains intact during N-acylation, which allows later cleavage to the free acid by saponification with lithium hydroxide in aqueous tetrahydrofuran or with sodium hydroxide in aqueous ethanol. This protection strategy is selected when the free D-phenylglycine acid would interfere with the coupling reagent or precipitate as a poorly reactive carboxylate salt. The phenyl ring increases ultraviolet traceability and modifies solvent partitioning relative to glycine ethyl ester hydrochloride; the product partitions well into ethyl acetate after neutralization, but the exact distribution ratio must be measured for each buffer because it varies with pH and ionic strength. In glass-lined reactor charging, a nitrogen-purged solids-transfer system is preferred to reduce moisture uptake and fine particle exposure.
In peptide coupling, the hydrochloride is not added directly to a carbodiimide such as EDC in the absence of base; the acid liberated by the hydrochloride can shift the pH and reduce reaction rate. The preferred sequence is to pre-neutralize in a separate vessel or to add a stoichiometric amount of auxiliary base with the solid. For moisture-sensitive amidation, pre-dried material is charged from a vacuum oven at 40 °C and not more than 1 kPa. Batch records should capture the neutralization endpoint and the water content of the dried salt because these parameters explain many lot-to-lot changes in conversion. The product is not typically used as a final isolated active ingredient; its position in the supply chain is as an advanced intermediate, so the process analytical technology controls are usually placed on achiral purity, chiral purity, and residual solvent rather than on finished dose-form specifications.
The ethyl ester variant differs from the methyl ester hydrochloride by the replacement of the methoxy group with an ethoxy group, increasing the molecular weight by 14.02 g mol−1 and reducing the molar optical rotation when the same specific rotation is expressed per mole. The higher free-base boiling point and lower vapour pressure reduce evaporative losses during solvent exchange after neutralization. The ethyl ester is also less susceptible to base-catalysed hydrolysis than the methyl ester under weakly alkaline conditions, which can allow a wider operating window during aqueous work-up at pH 8.0 to 9.0. This is not an absolute safeguard: saponification still proceeds rapidly above pH 10, and the release of ethanol can complicate solvent recovery if the hydrolysis is unintentional. The methyl ester, by contrast, is more reactive in aminolysis and is often preferred for fast, low-temperature acylations. The difference in hygroscopicity between the two salts is often smaller than the effect of particle-size distribution and crystallinity; published data for the specific crystalline hydrochloride powders is limited. Consequently, the selection between methyl and ethyl esters should be based on the desired hydrolysis lag, vapour-handling constraints, and the solvent system, not on a general rule concerning stability.
Relative to L-phenylglycine ethyl ester hydrochloride and the racemic mixture, the D-enantiomer is distinguished by the (R)-configuration at the α-carbon and by its optical rotation sign; however, optical rotation alone is not sufficient for release because the L-enantiomer can be present at levels that are difficult to detect by polarimetry. Chiral HPLC or supercritical fluid chromatography is required. In pharmaceutical use, the L-enantiomer is treated as a process impurity; a common control limit is not more than 1.0 percent relative to the D-isomer. Compared with the free base, the hydrochloride salt is the preferred commercial form because the amine is protected from atmospheric carbon dioxide and oxidative discolouration. The salt also avoids the need to handle a potentially oily, amine-susceptible free base at large scale. The free base is usually liberated only at the point of use.
The substance differs from D-4-hydroxyphenylglycine ethyl ester hydrochloride by the absence of the para-hydroxy group. That structural difference changes redox behaviour, hydrogen-bonding capacity, and chromatographic retention; the para-hydroxy derivative is more polar and can be prone to quinone-like discolouration under air, while the parent phenyl compound is comparatively simpler to dry and store. Compared with glycine ethyl ester hydrochloride, D-phenylglycine ethyl ester hydrochloride carries a phenyl substituent at the α-carbon, which increases molecular weight, UV detectability, lipophilicity, and steric demand around the reacting amine. This steric demand can reduce acylation rate and, in some peptide coupling routes, requires a longer residence time or a stronger coupling reagent. Published data for this specific configuration is limited, so pilot-scale work should not assume kinetic identity with the unsubstituted glycine analogue.
When the product is exposed to relative humidity above 60 percent, surface hydration and caking occur, and the resulting water content can alter stoichiometric charging. Pre-drying in a vacuum oven at 40 °C and not more than 1 kPa for several hours is applied before use in moisture-sensitive transformations. Milling or sieving in high-humidity air should be avoided because shear heating can soften the crystals and generate electrostatically charged fines that cling to equipment surfaces. The compound is incompatible with strong oxidizing agents, concentrated mineral acids, and acid chlorides, which can react with the primary amine or the ester group. Contact with aqueous sodium hydroxide above pH 10 causes ester saponification and free-amine liberation; this may be desirable as a process step but is not acceptable for storage. Chlorinated solvents and polar aprotic solvents are used for solution handling, whereas aliphatic hydrocarbons have poor solubilizing power for the hydrochloride salt. Residual solvent testing is typically performed by headspace gas chromatography and evaluated against ICH Q3C for ethyl acetate, methanol, ethanol, and dichloromethane, because these solvents are frequent residues from the final crystallization and washing sequence.
Regulatory control is normally established through the applicant’s drug master file, EU REACH dossier, or both, rather than through a harmonized pharmacopoeial monograph. Downstream users are responsible for confirming that the stereochemical method has a limit of quantitation low enough to support the proposed enantiomeric specification; a limit of quantitation of 0.05 percent is preferred when the acceptance limit is 1.0 percent. The certificate of analysis should report lot-specific data for assay, enantiomeric excess, loss on drying, residue on ignition, chloride stoichiometry, and residual solvents. When the material is transferred from one supplier to another, the change should trigger verification of the crystal form, particle-size distribution, and residual solvent profile, because these physical factors can affect neutralization time and downstream filtration rate in commercial reactors. Published data for this specific configuration is limited; therefore process development should treat the hydrochloride salt as a distinct entity rather than assuming that observations made on the free base or methyl ester hydrochloride are transferable.
