D-Phenylglycine methyl ester hydrochloride, identified by CAS 19883-41-1 and molecular formula C9H11NO2·HCl, is the hydrochloric acid salt of the methyl ester of (R)-2-amino-2-phenylacetic acid. The material is supplied as a white to off-white crystalline powder with a formula weight of 201.65 g mol⁻¹. Commercial designations include D-PG-OMe·HCl and (R)-phenylglycine methyl ester hydrochloride; the salt is preferred over the free amino ester in multistep synthesis because it remains free-flowing and less colour-sensitive at 25 °C and 50% RH. The theoretical chloride content of the salt is 17.6% w/w, and the amino centre is present as the protonated hydrochloride, which means the free amine must be released in situ before acylation.

At ambient storage, the salt is stable in tightly closed containers. Long-term retention at 2–8 °C can be used to preserve chiral integrity, but published data for holding beyond 36 months are limited; open containers above 60% RH pick up water and may require vacuum drying at 40–50 °C. The compound is freely soluble in water and methanol, partially soluble in ethanol, and only sparingly soluble in ethyl acetate after basification. In process design, this solubility profile permits aqueous extraction of the hydrochloride at pH 2–4, while the free base partitions into ethyl acetate at pH 8–9 with a target contact time not exceeding 30 min to limit base-catalysed racemization.

How Does the Salt Differ from L-Phenylglycine Methyl Ester Hydrochloride and N-Protected Analogs?

Configuration is the primary difference from the L-isomer. L-phenylglycine methyl ester hydrochloride has the opposite sign of optical rotation and is used when the target requires an (S)-α-amino acid motif; the D-isomer is specified for (R)-configured intermediates. Chiral HPLC on a polysaccharide chiral stationary phase with hexane/2-propanol containing 0.1% triethylamine separates the D- and L-forms, and a typical release lot shows ≥ 99.0% enantiomeric excess. The two enantiomers have essentially identical molecular weight and solubility, so process equipment is interchangeable, but a chiral method must be used to verify identity after precipitation or recrystallization.

Compared with D-4-hydroxyphenylglycine methyl ester hydrochloride, the present compound lacks the para-hydroxy substituent. This difference reduces aqueous solubility at basic pH and removes the need to protect a phenolic oxygen during oxidations or esterifications. Consequently, the non-hydroxylated methyl ester is less polar and tends to crystallise more readily from ethyl acetate/hexane; the 4-hydroxy analog more often requires saline aqueous workup or methanolic recrystallization. In coupling reactions, the phenolic group of the 4-hydroxy analog can compete as an oxygen nucleophile if not protected, whereas the phenylglycine methyl ester hydrochloride carries only the amino centre as a reactive site.

N-Boc-D-phenylglycine methyl ester is not a process-equivalent product. The Boc group blocks the amine, so the material is used after acidic deprotection, most commonly with trifluoroacetic acid in dichloromethane. By contrast, the hydrochloride does not require an acidic deprotection step; it is neutralised with a tertiary amine immediately before coupling. Using the hydrochloride in a protocol designed for the N-Boc material would leave a protonated amine and lead to incomplete acylation, while using the N-Boc material in a direct coupling protocol without deprotection yields no new amide bond.

Specification and Analytical Control Points

The lot release specification for peptide-grade material combines chemical, optical, and residual-solvent controls. Total assay alone is insufficient because non-chiral impurities can co-elute on standard reversed-phase HPLC; enantiomeric excess and residual water are required to prevent false confidence in downstream optical purity.

The chiral release method uses a 150 mm × 4.6 mm amylose-based analytical column with a mobile phase of hexane/2-propanol/triethylamine 80:20:0.1 at 0.8 mL min⁻¹. Under these conditions, the L-isomer is baseline-resolved from the D-isomer; exact relative retention times are column-specific. A mass spectrometric identity check is not sufficient to distinguish the enantiomers because they produce identical fragmentation patterns.

Residual methanol is controlled to ≤ 3000 ppm, consistent with ICH Q3C Option 2; the limit is derived from a permitted daily exposure of 30 mg day⁻¹. Residual water is measured by ASTM E203-21 Karl Fischer titration. For moisture-sensitive activation, if water content exceeds 0.3%, the lot is dried under vacuum at 40–50 °C for 4 h and re-tested before charging to an acid chloride or mixed anhydride reactor.

For continuous downstream use, particle size is a processing boundary. A lot with a d50 near 120 μm and fines below 15% through 75 μm feeds uniformly from a loss-in-weight dosing unit. If moisture-induced caking raises aggregate size above 2 mm, a rotary lump breaker with 0.5 mm mesh is installed before the feed hopper. Because the salt contains 17.6% chloride, 316L stainless-steel contact surfaces are preferred; wet cake should not be held in carbon steel pans under ambient humidity because chloride can initiate pitting.

The α-carbon of the phenylglycine is stereogenic and activated by the adjacent ester and aryl groups. Racemization is base-catalysed via a deprotonation-reprotonation sequence; therefore, aqueous workup is maintained below pH 8.5. In coupling reactions, the tertiary amine is charged at 0–5 °C and the free amine is acylated promptly to avoid α-deprotonation. Holding the free base in solution for more than 30 min at 20 °C under basic conditions can erode enantiomeric purity and hydrolyse the methyl ester.

When the Methyl Ester Hydrochloride Is Selected Over the Free Base in Peptide Coupling Campaigns

The methyl ester hydrochloride is selected when the route requires an unprotected α-amino acid methyl ester that must be stored as a stable crystalline solid. The free base is not the preferred shipment form because it is more hygroscopic and may undergo discoloration or methyl ester hydrolysis during transport. In solution-phase coupling, the salt is neutralised with 1.0–1.1 equivalents of triethylamine or N-methylmorpholine; this releases the free amine in situ. The methyl ester remains intact during carbodiimide-mediated couplings but is removed by saponification with lithium hydroxide at 0–5 °C when the free acid is required.

The hydrochloride is not suitable for direct use in non-neutralised form with electrophilic acylation reagents; if the tertiary amine charge is omitted, the protonated amino group does not function as a nucleophile and the reaction stalls at low conversion. In such a case, the residual starting material can be recovered from the aqueous layer at pH 2–4 as the hydrochloride. The chloride counterion is incompatible with silver salts because silver chloride precipitates and fouls filter cloths; it should also be excluded from cyanide, strong oxidising acid, and peroxymonosulfate process streams.

Compared with the ethyl ester hydrochloride, the methyl ester is less sterically hindered and more easily hydrolysed; this is advantageous when deprotection is desired after coupling, but it is a liability when hot alkaline workup is required. Methyl ester hydrolysis by-products are also more volatile than ethyl ester by-products, simplifying solvent recovery by distillation. The ethyl analog may be selected for more hydrophobic intermediates, but its hydrolysis in water/tetrahydrofuran at pH 10 and 25 °C proceeds on a longer timescale.

In a pilot-scale coupling campaign, a 100 L glass-lined reactor is charged with dimethylformamide and the hydrochloride. Nitrogen blanketing is used, and the jacket is held at 0–5 °C during the addition of N-methylmorpholine. The resulting suspension is aged for 30 min before the activated acid solution is fed. Agitation at 120–180 rpm is used to disperse the exotherm; the addition rate is controlled so the internal temperature does not exceed 10 °C. Following reaction, the mixture is quenched with dilute hydrochloric acid and extracted with ethyl acetate.

Drying of the wet product on a vacuum tray dryer uses a bed depth of 2–3 cm at 45 °C and 200 mbar absolute pressure for 6–8 h. The vacuum pump is protected by a cold trap because traces of methyl ester can volatilise. Drying above 60 °C is not recommended because the salt may discolour and residual moisture can accelerate ester hydrolysis. The dried material is passed through a 0.5 mm rotary sieve before packaging.

In β-lactam side-chain precursor synthesis, D-phenylglycine methyl ester hydrochloride is used as a chiral building block where the methyl ester protects the carboxyl terminus during amide formation. The hydrochloride is not a direct replacement for D-4-hydroxyphenylglycine methyl ester hydrochloride in amoxicillin-related side chains because the para-hydroxy group changes hydrogen-bonding and aqueous solubility. Published data for this specific configuration in amoxicillin side-chain assembly is limited. Process-scale work with the non-hydroxylated compound generally uses the hydrochloride for crystallinity and storage stability, and the free amine is generated in the reactor immediately before the coupling step. In a typical route, the salt is dissolved in dimethylacetamide, neutralised with N-methylmorpholine at 0–5 °C, and converted to an activated intermediate such as a mixed anhydride; after coupling, the methyl ester is saponified with lithium hydroxide at 0–5 °C and the product is isolated by acidification to pH 2–3.