| HS Code | 799048 |
| Product Name | BOC-D-phenylglycine Methyl Ester |
| Cas Number | 102069-11-2 |
| Molecular Formula | C14H19NO4 |
| Molecular Weight | 265.31 g/mol |
| Iupac Name | methyl (2R)-2-[(tert-butoxycarbonyl)amino]-2-phenylacetate |
| Synonyms | Boc-D-Phg-OMe; (R)-Methyl 2-((tert-butoxycarbonyl)amino)-2-phenylacetate |
| Appearance | White to off-white solid |
| Purity | ≥98% (HPLC) |
| Smiles | CC(C)(C)OC(=O)N[C@H](C(=O)OC)c1ccccc1 |
| Solubility | Soluble in methanol, ethanol, chloroform, ethyl acetate; insoluble in water |
| Storage Condition | Store at 2-8°C, under inert atmosphere, protected from moisture |
| Density Predicted | 1.119 g/cm3 |
| Boiling Point Predicted | 355.6 °C |
| Flash Point Predicted | 168.8 °C |
As an accredited BOC-D-phenylglycine Methyl Ester factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | BOC-D-phenylglycine methyl ester is supplied as a white solid in a sealed glass vial, packaged under inert gas, quantity 5 grams. |
| Container Loading (20′ FCL) | 20′ FCL: drummed, palletized BOC-D-phenylglycine Methyl Ester, securely braced, ventilated, labeled, and protected from moisture and heat. |
| Shipping | Ship BOC-D-phenylglycine Methyl Ester in a sealed, moisture-proof container away from heat and direct sunlight. Keep at 2–8 °C during transit to maintain stability. Ensure proper labeling, absorbent packaging, and compliance with local transport regulations. Generally non-hazardous, but avoid dust exposure, strong oxidizers, and extreme temperatures. |
| Storage | Store BOC-D-phenylglycine methyl ester in a tightly sealed container in a cool, dry, well-ventilated area, away from direct sunlight, heat, and moisture. Keep at room temperature (20–25°C) unless otherwise specified. Avoid contact with strong oxidizers, acids, and bases. Ensure container is clearly labeled and kept out of reach of incompatible materials. |
| Shelf Life | Store in a cool, dry place away from light. Under proper conditions, shelf life is typically 2–3 years. |
In solution-phase construction of peptide fragments that require a C-terminal methyl ester to remain intact until a final fragment condensation, N-Boc-D-phenylglycine methyl ester is first deprotected at the Nα-position with 4 M HCl in 1,4-dioxane at 20 °C for 1 h. The hydrochloride salt is precipitated by addition of cold methyl tert-butyl ether at 0 °C, filtered, and dried under reduced pressure at 25 °C for 12 h. The salt is then dissolved in anhydrous DMF and coupled to Boc-D-alanine using 1.15 equiv of HBTU and 2.5 equiv of 2,4,6-collidine at -5 °C under argon. The low temperature and the hindered pyridine base reduce the formation of the oxazolone intermediate that is responsible for racemization at the D-phenylglycine α-carbon. After 6 h, the reaction is quenched with ice-cold water and extracted into ethyl acetate; the organic layer is washed with 0.5 M citric acid, saturated sodium bicarbonate, and brine, then dried over anhydrous sodium sulfate. The resulting dipeptide methyl ester is analyzed by LC-MS on a reversed-phase C18 column (50 × 2.1 mm, 1.7 μm) with electrospray ionization in positive mode. The chiral purity of the crude product is measured by normal-phase HPLC on a Chiralpak AD-H column (250 × 4.6 mm, 5 μm) using n-hexane/2-propanol/TFA 90:10:0.1 (v/v/v) at 1.0 mL/min and UV detection at 254 nm; the D-enantiomer elutes before the L-isomer under these conditions. Residual DMF is controlled by two successive azeotropic distillations with toluene at 40 mbar and 35 °C, with quantification by headspace gas chromatography according to Ph. Eur. 2.4.24.
The α-proton of D-phenylglycine methyl ester is activated by both the adjacent ester and the phenyl ring, so tertiary amine bases can abstract it during slow coupling reactions. This generates a planar enolate that partitions between protonation and ring closure to an oxazolone, leading to loss of D-configuration. When DIPEA (pKa 11.4 in DMSO) is used at 25 °C, the free base concentration remains high throughout the coupling; for carbodiimide and HBTU-mediated condensations, this can produce measurable racemization within 1 h as shown by the chiral HPLC method described below. In contrast, 2,6-lutidine (pKa 6.6 in DMSO) and 2,4,6-collidine (pKa 6.7 in DMSO) are weaker bases, and their conjugate acids compete less effectively with the α-carbon for the base, reducing the steady-state enolate concentration. At -20 °C, using 2,6-lutidine with HATU as coupling reagent can maintain the D/L ratio above 99.0:1.0 for couplings to L-amino acid esters, but reaction time extends to 8–12 h. The reactor must be jacketed, glass or PTFE-lined, and fitted with a thermocouple; batch temperatures rising above -5 °C during the exothermic activation step accelerate oxazolone formation even with a hindered base. For batches above 1 mol, the base is added via a pressure-equalizing addition funnel over 5 min to avoid local pH excursions. Chiral purity is measured only after aqueous workup because excess coupling reagent and base can shift retention on the CSP. These low-temperature conditions are not directly transferable to aqueous mixed-anhydride acylations because water accelerates oxazolone hydrolysis and changes the base equilibrium.
Hydrolysis of the methyl ester followed by low-temperature mixed anhydride activation provides a route to the D-phenylglycyl side chain of β-lactam antibiotics. The ester is dissolved in THF/water (4:1 v/v) and treated with 1.02 equiv of lithium hydroxide monohydrate at 0 °C for 45 min, with the pH maintained at 10.5 by a Metrohm 848 Titrino plus autotitrator. The reaction is quenched with solid citric acid to pH 3.0, and the free acid is extracted into ethyl acetate, washed with brine, and concentrated at 30 °C under reduced pressure. The residue is dissolved in anhydrous THF and cooled to -25 °C. Isobutyl chloroformate (1.05 equiv) and N-methylmorpholine (1.10 equiv) are added sequentially at a rate that maintains the internal temperature below -15 °C. After 20 min, a pre-cooled solution of 6-aminopenicillanic acid in water/acetone (1:1 v/v) is added in a single portion, and the pH is adjusted to 7.8–8.2 with 10% w/v aqueous NaOH. The acylation is stirred at -10 °C for 3 h, then warmed to 10 °C over 1 h to drive the reaction to completion. The resulting N-Boc-ampicillin intermediate is isolated by acidification to pH 2.5 with 1 M HCl and extraction into ethyl acetate. Subsequent N-Boc removal with trifluoroacetic acid in dichloromethane (1:1 v/v) containing 5% anisole at 20 °C for 2 h yields ampicillin, which is crystallized from water at pH 4.8 as the trihydrate. Process impurities, including D-phenylglycine and 6-aminopenicillanic acid, are quantified by reversed-phase HPLC according to the Ph. Eur. monograph for ampicillin trihydrate using a Zorbax SB-C18 column (250 × 4.6 mm, 5 μm) and detection at 210 nm. Chiral purity of the side chain is verified after acid hydrolysis of the β-lactam by the normal-phase method described in the next section.
Analytical release of N-Boc-D-phenylglycine methyl ester and its downstream intermediates requires a chiral LC method that separates the D and L antipodes without derivatization. A representative normal-phase procedure uses a high-pressure system with a quaternary pump, autosampler, and diode-array detector, fitted with an immobilized Chiralpak IA-3 column (150 × 4.6 mm, 3 μm) or equivalent. The mobile phase consists of n-hexane/2-propanol/trifluoroacetic acid 90:10:0.1 (v/v/v), delivered at 1.0 mL/min at 30 °C. Detection is carried out at 254 nm with a reference wavelength of 360 nm. The sample is prepared at 1.0 mg/mL in isopropanol, and 5 μL is injected. Under these conditions, the D-isomer elutes first, with the L-antipode resolved at a relative retention of 1.10–1.20. System suitability criteria follow USP <621>: the resolution between D and L peaks must be not less than 2.0, and the tailing factor must not exceed 1.5. The limit of quantification for the L-antipode is 0.05% w/w. For method validation, specificity is demonstrated by forced degradation with 0.1 M NaOH at 40 °C for 24 h, which generates the corresponding acid without racemization, and by thermal stress at 60 °C for 48 h, which produces trace amounts of the tert-butyloxazolidinone decomposition product. Peak purity is confirmed using the diode-array detector by collecting spectra from 200 nm to 400 nm; no co-eluting impurity is observed. The method is used for in-process control after coupling and for final release of the building block, with acceptance criteria of 98.5% area purity and 99.0% enantiomeric excess.
| Parameter | Specification |
|---|---|
| Column | Chiralpak IA-3, 150 × 4.6 mm, 3 μm |
| Mobile phase | n-hexane/2-propanol/TFA 90:10:0.1 (v/v/v) |
| Flow rate | 1.0 mL/min |
| Column temperature | 30 °C |
| Detection | 254 nm (reference 360 nm) |
| Injection volume | 5 μL |
| Retention order | D before L |
| System suitability resolution | ≥2.0 (USP <621>) |
When the downstream route requires a free C-terminal carboxylate for amide bond formation with a hindered amine or for attachment to a resin, selective saponification of the methyl ester is performed without disturbing the N-Boc group. The methyl ester is dissolved in THF/methanol/water (5:3:2 v/v/v) and cooled to 0 °C. Lithium hydroxide monohydrate (1.05 equiv) is added in three portions over 15 min, and the solution is stirred until chiral HPLC shows no measurable starting material remains. The pH is kept below 12.0 throughout the reaction; higher pH accelerates cleavage of the Boc group and promotes α-carbon racemization. Upon completion, the mixture is concentrated at 25 °C to remove organic solvents, diluted with water, and washed with tert-butyl methyl ether. The aqueous layer is acidified with 1 M citric acid to pH 3.0 and extracted with ethyl acetate. The organic phase is dried over anhydrous sodium sulfate and concentrated at 30 °C. The resulting N-Boc-D-phenylglycine is characterized by NMR and LC-MS, then activated with HATU and used directly in subsequent fragment coupling. In a 5 L jacketed reactor, hydrolysis of a 1 mol batch is terminated when the residual ester content falls below 2.0% by HPLC peak area. The product is isolated by crystallization from ethyl acetate/n-heptane (1:4 v/v) at -20 °C. Residual lithium content is measured by ion chromatography and controlled to below 50 ppm before the intermediate is advanced to peptide coupling, because lithium can interfere with downstream phase-transfer catalytic steps. This saponification is not recommended with NaOH in methanol alone, because sodium methoxide generated in situ can hydrolyze the Boc group at a measurable rate above 20 °C.
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N-Boc-D-phenylglycine methyl ester, systematically methyl (2R)-2-[(tert-butoxycarbonyl)amino]-2-phenylacetate, is a protected chiral α-aryl glycine derivative with the molecular formula C14H19NO4 and a molecular weight of 265.31 g/mol. The product is supplied as a white to off-white crystalline powder and is conventionally designated under supplier-specific catalogue codes rather than a single international model number. The molecule carries two orthogonal protecting groups: the tert-butoxycarbonyl group on the α-amino position and the methyl ester on the carboxylic acid terminus. This combination blocks the zwitterionic character of the free amino acid and provides solubility in chlorinated and polar aprotic solvents, which is required for homogeneous peptide coupling and for selective carboxyl derivatization. The D-configuration at the α-carbon is the critical structural feature for applications in β-lactam side-chain intermediates and in other stereochemically defined peptide sequences. In comparison with the corresponding L-isomer, the D-enantiomer shows opposite sign of optical rotation and different behaviour in chiral chromatographic systems; only the D-form is compatible with the stereochemistry of the ampicillin/amoxicillin class of semisynthetic penicillins.
Selective deprotection is governed by the orthogonal acid-lability of the Boc group and the alkaline-lability of the methyl ester. In the common N-first sequence, the product is dissolved in dichloromethane and treated with 20–50% v/v trifluoroacetic acid at 0–20°C for 1–2 h. Under these conditions the methyl ester remains intact because carboxylic acid methyl esters are not hydrolysed by trifluoroacetic acid at ambient temperature over short contact times. The liberated tert-butyl cation is trapped with 5% v/v triisopropylsilane or anisole to prevent alkylation of the phenyl ring. The resulting D-phenylglycine methyl ester TFA salt is isolated by precipitation with diethyl ether. In the carboxyl-first sequence, saponification is carried out with 1.0–1.1 equivalents of lithium hydroxide in tetrahydrofuran/water at 0–5°C for 30–60 min. The Boc group remains intact under these mild alkaline conditions, although the α-carbon of D-phenylglycine is configurationally labile and extended exposure to base at higher temperature causes enantiomeric drift. The hydrolysis endpoint is therefore monitored by in-process thin-layer chromatography or reversed-phase HPLC rather than by fixed reaction time alone.
Commercial batches are typically released against the following specification matrix. Values are representative of research-grade and peptide-synthesis-grade material, and actual certificates of analysis vary by supplier.
| Parameter | Representative limit | Method or reference |
|---|---|---|
| Appearance | White to off-white crystalline powder | Visual inspection against certified reference |
| Molecular weight | 265.31 g/mol | Calculated from C14H19NO4 |
| Chiral purity | ≥99.0% enantiomeric excess | Chiral HPLC on amylose tris(3,5-dimethylphenylcarbamate) column, 250 × 4.6 mm, UV 210 nm, n-hexane/isopropanol/TFA 95:5:0.1 v/v/v, 1.0 mL/min, 25°C |
| Assay | ≥98.0% peak area | Achiral HPLC, C18 column, UV 210 nm |
| Water content | ≤0.5% w/w | Karl Fischer coulometric titration, EP 2.5.12 |
| Residue on ignition | ≤0.1% w/w | USP 281 |
| Storage | 2–8°C under inert gas | Supplier stability data |
Chiral purity is controlled because the L-enantiomer produces the opposite diastereomeric series in downstream peptide couplings. With D-phenylglycine, the α-aryl substituent increases the steric and electronic propensity for oxazolone formation, so chiral HPLC area normalization at 210 nm is a routine release criterion. The use of an amylose-based chiral stationary phase with an acidic additive suppresses peak tailing from the free amino group after TFA deprotection. Packaging for pilot-scale use is typically in amber glass or fluoropolymer-lined drums under nitrogen. The material is not considered stable when exposed to repeated moisture ingress; containers should be equilibrated to room temperature before opening to avoid condensation on chilled solids.
The compound is stable in tightly closed containers at 2–8°C under argon or nitrogen for at least 12 months according to typical supplier retest data. It is soluble in dichloromethane, tetrahydrofuran, ethyl acetate, dimethylformamide, and dimethyl sulfoxide; solubility in methanol and ethanol is moderate, and solubility in water is low. Aqueous solubility is pH-dependent and increases as the methyl ester is hydrolysed under alkaline conditions. The Boc group undergoes thermal cleavage at elevated temperature, particularly in the presence of acid; drying above 40°C is not recommended without vacuum and short residence time. Methyl ester hydrolysis is accelerated at pH above 8.0; therefore, the compound should not be stored in contact with residual lithium hydroxide or tertiary amines. At pilot scale, solution transfers should be conducted with nitrogen pressure and low-moisture piping to avoid precipitation in unheated lines.
The product is used primarily as a protected building block in solution-phase peptide synthesis and in the preparation of D-phenylglycine-containing β-lactam side chains. In a representative coupling, the methyl ester is first saponified to Boc-D-phenylglycine, then activated with ethyl chloroformate and N-methylmorpholine in tetrahydrofuran at −15°C to −10°C to generate a mixed anhydride. The activated intermediate is condensed with 6-aminopenicillanic acid or a 7-aminocephalosporin derivative to introduce the D-phenylglycine side chain. The low-temperature window is not arbitrary: the α-aryl substituent accelerates oxazolone-mediated racemization in the presence of tertiary base, and the mixed anhydride route is selected because it reduces the racemization rate relative to carbodiimide-mediated activation. At production scale, the reaction is run in glass-lined reactors with jacket control capable of maintaining −15°C ± 2°C and with controlled dosing of ethyl chloroformate below −10°C. The Boc group is subsequently removed with trifluoroacetic acid to expose the acylated β-lactam intermediate.
The methyl ester derivative is distinguished from the free acid, the ethyl ester, the tert-butyl ester, and the benzyl ester. The free acid requires activation before coupling and has poor solubility in ethyl acetate. The ethyl ester is slower to saponify and may leave more residual ester in process streams. The tert-butyl ester is incompatible with TFA deprotection because it is removed under the same conditions; the methyl ester survives. The benzyl ester is removed by hydrogenolysis and is useful when the methyl ester is too stable for a subsequent carboxyl deprotection, but it introduces a hydrogenation step that may be incompatible with sulfur-containing substrates. Fmoc protection is removed by 20% piperidine in dimethylformamide, which is a base exposure that can racemize D-phenylglycine; therefore, Boc protection is preferred despite its requirement for acid deprotection.
| Derivative | N-protecting group | Carboxyl protecting group | Selective removal condition | Racemization-sensitive process step |
|---|---|---|---|---|
| Boc-D-phenylglycine methyl ester | Boc | Methyl ester | TFA/DCM for N; LiOH/THF for ester | LiOH saponification or coupling base |
| Boc-D-phenylglycine tert-butyl ester | Boc | tert-Butyl ester | TFA/DCM removes both N and ester | Acidic N removal is non-selective for carboxyl |
| Cbz-D-phenylglycine methyl ester | Cbz | Methyl ester | H2/Pd for N; LiOH/THF for ester | Hydrogenolysis avoids base exposure |
| Fmoc-D-phenylglycine methyl ester | Fmoc | Methyl ester | Piperidine/DMF for N; LiOH/THF for ester | Piperidine base may promote α-carbon racemization |
D-Phenylglycine derivatives are unusually prone to racemization because the α-aryl group stabilizes the deprotonated oxazolone intermediate. In process development, the disappearance of the starting material is not sufficient to confirm retention of configuration; chiral HPLC of the crude coupling product or of the D-phenylglycine derivative after hydrolysis is required. The rate of racemization is base- and temperature-dependent. For carbodiimide couplings, the addition of 1-hydroxy-7-azabenzotriazole and the use of 2,4,6-collidine as a hindered base reduce the concentration of free carboxylate and slow oxazolone formation. The reaction temperature is maintained at 0–5°C, with the activation step performed at −10°C to 0°C. When the substrate itself contains a base-sensitive functional group, the methyl ester is retained and the coupling is carried out in dichloromethane instead of dimethylformamide to reduce dielectric assistance of ionisation. The process window is usually narrower than ±5°C at activation; deviation above 5°C for more than 10–15 min may produce a measurable increase in L-enantiomer by chiral HPLC at 210 nm.
For routine release, the intact protected methyl ester is analysed by reversed-phase HPLC for chemical purity and by chiral HPLC for enantiomeric excess. The chiral method typically resolves the D- and L-forms with a resolution factor greater than 1.5 on an amylose tris(3,5-dimethylphenylcarbamate) column. If the sample is first deprotected to the free amino acid, an acidic mobile phase is used to suppress ionisation and peak tailing. Proton NMR is used to confirm the Boc tert-butyl singlet at δ 1.42–1.44 in CDCl3, the methoxy singlet at δ 3.70–3.72, and the methine doublet at δ 5.24–5.28 with J ≈ 7.0 Hz. The carbonyl region shows two resonances: one for the methyl ester near δ 171.0–171.5 and one for the Boc carbamate near δ 154.5–155.0. The absence of a broad carboxylic acid proton near δ 10–12 is used to verify ester integrity. Residual solvent content is controlled according to ICH Q3C, with methanol and ethyl acetate being the most common residual solvents in bulk material.
