| HS Code | 726579 |
| Chemical Name | N-Trityl Glycine Methyl Ester |
| Synonyms | Methyl N-tritylglycinate; Methyl 2-(tritylamino)acetate; N-(Triphenylmethyl)glycine methyl ester |
| Cas Number | 19883-41-1 |
| Molecular Formula | C22H21NO2 |
| Molecular Weight | 331.41 g/mol |
| Exact Mass | 331.1572 g/mol |
| Appearance | White to off-white crystalline solid |
| Melting Point | 102-104 °C |
| Boiling Point | 456.2 °C (predicted) |
| Density | 1.097 g/cm³ (predicted) |
| Solubility | Soluble in methanol, dichloromethane, chloroform, and ethyl acetate; practically insoluble in water |
| Logp | 4.2 (predicted) |
| Purity | ≥98% (typical) |
| Storage Conditions | Store in a cool, dry place, protected from moisture; recommended 2-8 °C |
| Smiles | COC(=O)CNC(c1ccccc1)(c2ccccc2)c3ccccc3 |
| Inchikey | UHZQULZVLXSDIZ-UHFFFAOYSA-N |
As an accredited N-trityl Glycine Methyl Ester factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | White crystalline solid packaged in a sealed amber glass bottle with tamper-evident cap, quantity 25 grams. |
| Container Loading (20′ FCL) | 20′ FCL container loaded with N-trityl Glycine Methyl Ester, packed in sealed drums, secured for safe transport. |
| Shipping | Ship N-trityl Glycine Methyl Ester as a non-hazardous research chemical at ambient temperature in a sealed, light-protected container. Cushion adequately against breakage. Keep away from moisture during transit. Upon receipt, store desiccated, preferably at 2–8°C, and use promptly for best stability. |
| Storage | Store N-trityl Glycine Methyl Ester in a tightly sealed container in a cool, dry place away from light and moisture. Keep at room temperature, ideally between 2–8°C for prolonged stability. Avoid exposure to acids, strong bases, and oxidizing agents. Ensure the container is adequately labeled and kept out of reach of incompatible materials. |
| Shelf Life | Store under inert gas at -20°C, protected from moisture and light. Shelf life: 1–2 years if unopened. |
N-Trityl glycine methyl ester, CAS 16867-61-1, molecular mass 331.41 g/mol, is a protected glycine building block used in multi-step synthetic sequences where the amino and carboxyl functions must be unmasked at separate stages. The trityl group is cleaved under mild acid conditions, while the methyl ester remains available for hydrolysis, reduction, or enolate alkylation. Industrial material is produced in fine chemical plants under ISO 9001:2015 quality management. Typical release criteria include HPLC purity not less than 98.0 area% at 210 nm and a single largest unknown impurity not more than 0.5 area%. The product is stored at 2–8 °C in moisture-tight drums under nitrogen; moisture uptake is limited to 0.5 wt% during normal handling.
In solution-phase peptide campaigns, the methyl ester is removed first to yield N-trityl glycine free acid, a building block that avoids premature amidation of the carboxyl terminus during subsequent coupling. Hydrolysis is performed with lithium hydroxide monohydrate at 1.1–1.3 molar equivalents relative to the ester in a tetrahydrofuran/deionized water mixture of 3:1 v/v at 0–5 °C for 2–4 h. A jacketed 50 L glass-lined reactor with PTFE-coated baffles and a side-arm pH probe is used. Reaction progress is monitored by thin-layer chromatography on silica gel 60 F254 using n-heptane/ethyl acetate 1:1 v/v. The mixture is adjusted to pH 2.5–3.5 by controlled addition of 10% w/v citric acid monohydrate at or below 10 °C, extracted with methyl tert-butyl ether, and washed with deionized water. The organic phase is dried over anhydrous magnesium sulfate, filtered through a 0.45 μm PTFE membrane, and concentrated under reduced pressure at or below 35 °C. The residue is crystallized from n-heptane/ethyl acetate 6:1 v/v. A recurring plant-scale failure mode is emulsion formation when the aqueous pH exceeds 4.0 before phase separation; coalescer cartridges on the extractor outlet are required for reproducible layer cuts. For API intermediates, residual lithium is controlled to ≤50 ppm by ICP-OES, and solvent residues conform to ICH Q3C Option 1. Terminal downstream products include glycyl dipeptide and tripeptide fragments used in solution-phase assembly of registered peptide APIs, with the trityl group retained until final acidolytic cleavage.
In a separate downstream sequence, cryogenic enolate alkylation converts the methyl ester into α-substituted N-trityl glycine methyl ester intermediates. The substrate is dissolved in anhydrous tetrahydrofuran to a concentration of 0.30–0.45 mol/L, dried over 3 Å molecular sieves to water content below 20 ppm, and charged to a 250 L glass-lined cryogenic reactor equipped with an external liquid nitrogen jacket, retreat-blade impeller, and two independent Pt100 temperature probes. Lithium diisopropylamide is generated in situ from n-butyllithium and diisopropylamine at -78 °C and added at a molar ratio of 1.05:1 relative to the substrate. The addition rate is controlled to maintain internal temperature below -65 °C. After 45 min of aging, the electrophile—a primary alkyl halide or allylic halide—is added at 1.2–1.3 molar equivalents over 30 min. The batch is warmed to -20 °C over 2 h and quenched with saturated aqueous ammonium chloride. The quenched mass is warmed to 20 °C, separated, and the aqueous layer extracted with methyl tert-butyl ether. The organic layer is washed with 15% w/v sodium chloride, dried, and concentrated. Crude material is purified by silica gel chromatography with ethyl acetate/n-heptane 1:9 to 1:4 v/v; product fractions are concentrated and crystallized from methyl tert-butyl ether/n-heptane. Moisture ingress above 20 ppm in the reaction solvent is a known batch-to-batch cause of conversion loss and dialkylation impurity formation. Oxygen is excluded below 1% v/v in the reactor headspace; the system is grounded and operated under ATEX 2014/34/EU Zone 1 classification for flammable tetrahydrofuran mixtures. This downstream segment supplies α-benzyl-, α-allyl-, and α-alkyl glycine building blocks for peptidomimetic synthesis and protease inhibitor fragments. Final products from this sequence are not isolated as APIs; they are converted in subsequent hydrolysis and coupling steps.
Direct hydride reduction of the methyl ester generates 2-(tritylamino)ethanol, a protected amino alcohol used for phospholipid and cationic lipid head group intermediates. Sodium borohydride is preferred over lithium aluminum hydride at manufacturing scale because the exotherm is controllable and hydrogen evolution can be staged. The ester is dissolved in tetrahydrofuran/ethanol 1:1 v/v at 0.8–1.2 mol/L; lithium chloride is added at 2.0 molar equivalents to activate the borohydride, followed by sodium borohydride 2.0 molar equivalents in four equal portions below 15 °C. The batch is warmed to 25–30 °C and held for 6–8 h. Conversion is monitored by gas chromatography with flame ionization detection using a 30 m × 0.25 mm DB-5 column and a temperature ramp from 100 °C to 280 °C. Workup includes slow addition of 10% w/v ammonium chloride at or below 10 °C, extraction with ethyl acetate, washing with saturated sodium bicarbonate, and drying over sodium sulfate. The crude oil is purified by silica gel chromatography with dichloromethane/methanol 20:1 v/v and crystallized from ethyl acetate/n-heptane. Excess lithium chloride above 2.5 equivalents is avoided because it forms a dense salt cake in the filter dryer and extends discharge time. The trityl-protected amino alcohol is then used in phosphoramidite condensation or acylation steps; final derivatives enter research and industrial lipid nanoparticle programs. For material intended for in vivo use, residual sodium and lithium are controlled to ≤25 ppm and ≤50 ppm respectively by ICP-MS, and residual ethanol is controlled to ≤5000 ppm following ICH Q3C Option 1. Exposure to strong protic acid during downstream workup is avoided because the trityl group cleaves below pH 2, generating triphenylmethanol and free amino alcohol.
Acidic removal of the trityl group from the methyl ester yields glycine methyl ester as its acid salt, which is directly N-acylated in a two-phase Schotten-Baumann system. The substrate is suspended in dichloromethane and treated with trifluoroacetic acid/dichloromethane 1:1 v/v at 0 °C for 30–60 min; triphenylmethanol is removed by repeated extraction with cold n-heptane. The aqueous phase containing glycine methyl ester hydrochloride is adjusted to pH 8.0–8.5 with sodium bicarbonate, and an acylating agent—commonly benzoyl chloride or acetyl chloride—is added at 1.05 molar equivalents at 0–5 °C over 20 min. The reactor is a 100 L jacketed vessel with a mixed impeller and gas-sealed charging port; pH is maintained by automatic titration with 10% w/v sodium carbonate. Residual trifluoroacetic acid in the crude salt produces N-trifluoroacetyl glycine methyl ester if neutralization is delayed; a 10 min hold at pH 8.0–8.5 before acylation suppresses this side product. The product, N-acyl glycine methyl ester, is extracted with ethyl acetate, washed with 5% w/v citric acid, dried over sodium sulfate, and concentrated under reduced pressure at or below 40 °C. Crystallization from ethyl acetate/n-heptane 1:4 v/v gives the amide intermediate. Terminal products from this sequence include N-benzoyl glycine methyl ester, used as a starting material for oxazole, imidazole, and isoindole heterocycle synthesis in medicinal chemistry and agrochemical discovery. The acid-cleavage step is not compatible with substrates carrying acid-sensitive oxygen protecting groups; such cases require catalytic hydrogenolysis over 5% Pd/C in methanol/ethyl acetate at 1–2 bar and 25 °C. Residual palladium in API-tracked intermediates is controlled to ≤10 ppm by ICP-MS under ICH Q3D guidance. Published data for this specific catalytic hydrogenolysis configuration is limited; process parameters are established per campaign.
Bulk manufacturers and API process development groups use N-trityl glycine methyl ester as a reference standard for tracking carryover of an upstream protected intermediate into subsequent peptide or amino acid API stages. A standard UPLC-UV/ESI-MS method uses a 2.1 × 50 mm, 1.7 μm C18 column with a 10–95% acetonitrile gradient in 0.1% formic acid over 5.0 min at 0.45 mL/min and 40 °C; UV detection is set at 210 nm with reference at 360 nm. The parent compound is baseline-resolved from triphenylmethanol and N-trityl glycine free acid under these conditions. Retention time shifts of 0.10–0.15 min are observed across column lots, so system suitability requires resolution of not less than 2.0 from triphenylmethanol. Quantitation is performed by external calibration from 0.05% to 1.00% w/w relative to the API. In late-phase impurity control, reporting thresholds follow ICH Q3A: 0.05% for daily doses ≤2 g/day, 0.03% for doses above 2 g/day. The qualified reference standard is also used for spiked recovery studies during process validation; recovery at the reporting threshold is expected to fall within 70–130% for LC-UV methods as per ICH Q2(R2) accuracy criteria. The material is not a pharmacopeial reference standard; it is qualified internally by qNMR, HPLC-UV, Karl Fischer titration, headspace gas chromatography, and sulfated ash. This analytical application is downstream of synthesis but central to foreign trade transactions where the product is supplied as a starting material for registered APIs and the buyer requires verified processing origin.
| Transformation | Reagent system | Molar ratio | Temperature | Downstream product type |
|---|---|---|---|---|
| Ester hydrolysis | LiOH·H₂O in THF/H₂O 3:1 v/v | 1.1–1.3 eq | 0–5 °C | N-trityl glycine free acid; glycyl peptide fragments |
| Cryogenic enolate alkylation | LDA in anhydrous THF | 1.05 eq base; 1.2–1.3 eq electrophile | -78 °C to -20 °C | α-substituted glycine methyl ester intermediates |
| Ester reduction | NaBH₄/LiCl in THF/ethanol 1:1 v/v | 2.0 eq NaBH₄; 2.0 eq LiCl | 25–30 °C | 2-(tritylamino)ethanol |
| Acidic trityl removal and N-acylation | TFA/DCM 1:1 v/v; acyl chloride | 1.05 eq acyl chloride | 0–5 °C | N-acyl glycine methyl ester heterocycle precursors |
Competitive N-trityl Glycine Methyl Ester prices that fit your budget—flexible terms and customized quotes for every order.
For samples, pricing, or more information, please contact us at +8615365186327 or mail to admin@ascent-chem.com.
We will respond to you as soon as possible.
Tel: +8615365186327
Email: admin@ascent-chem.com
Flexible payment, competitive price, premium service - Inquire now!
N-Trityl glycine methyl ester, systematically N-(triphenylmethyl)glycine methyl ester and assigned CAS RN 52672-47-4, is a protected glycine derivative with the linear formula (C6H5)3C–NH–CH2–COOCH3 and molecular weight 331.41 g/mol. The compound is supplied as a white to off-white crystalline solid; melting range determined by the capillary method is 121–124 °C. Solubility behavior separates it from the free acid: the methyl ester is freely soluble in dichloromethane, tetrahydrofuran, and ethyl acetate, sparingly soluble in methanol, and practically insoluble in water. The lipophilic trityl substituent retains the masked glycine fragment in the organic layer during neutral or mildly basic workup, which simplifies purification of intermediates that carry no acid-labile groups.
The product is not the subject of a harmonized pharmacopoeial monograph; release specifications are defined by the supplier. Two common grades include a research grade with HPLC area purity ≥98.0% and a high-purity grade with HPLC area purity ≥99.0%, both measured at 220 nm on a C18 column. Moisture by Karl Fischer titration is controlled to ≤0.5%. Residual triphenylmethanol and glycine methyl ester hydrochloride are typical impurity markers and are limited individually to ≤0.5% for the research grade and ≤0.2% for the high-purity grade where the supplier’s certificate of analysis specifies them.
| Parameter | Limit | Method |
|---|---|---|
| Appearance | White to off-white crystalline powder | Visual |
| Assay | ≥98.0% / ≥99.0% by HPLC area | USP <621> |
| Melting range | 121–124 °C | USP <741> |
| Moisture | ≤0.5% | USP <921> Method Ia |
| Solubility | Freely soluble in CH2Cl2, THF, EtOAc; practically insoluble in water | Ph. Eur. solubility criteria |
Neutral or mildly buffered mobile phases are required for HPLC purity determination because the trityl substituent undergoes rapid acidolytic cleavage. A typical analytical system uses acetonitrile and 5 mM ammonium acetate adjusted to pH 6.8–7.2; retention times are column-specific and must be established against a qualified reference lot. Acidic modifiers such as 0.1% trifluoroacetic acid are unsuitable for this molecule because partial on-column deprotection yields glycine methyl ester and triphenylmethanol. Infrared analysis of the solid typically shows an ester carbonyl stretch near 1740 cm−1 and N–H stretching near 3320 cm−1. 1H NMR spectra in CDCl3 contain the methyl ester singlet near 3.42 ppm and the glycine methylene singlet near 3.10–3.20 ppm, with aromatic multiplets from the trityl group between 7.15–7.45 ppm. Electrospray ionization mass spectrometry typically gives the molecular adduct [M+Na]+ at 354.1 m/z. Where residual solvents are tested, headspace gas chromatography according to USP <467> may be applied to confirm methanol and dichloromethane below ICH Q3C limits.
Deprotection of N-trityl glycine methyl ester proceeds by heterolysis of the nitrogen–triphenylmethyl bond to give the stabilized triphenylmethyl cation and glycine methyl ester. Under conditions of 1–5% trifluoroacetic acid in dichloromethane or 0.1 M HCl in dioxane at 0–25 °C, cleavage is typically complete within 5–30 min. The reaction is markedly faster than removal of a Boc group under identical conditions, and this differential sensitivity defines the operational envelope. Selective trityl deprotection in the presence of a Boc-protected amine is not reliably achieved because both groups are acid-labile, although trityl removal can be carried out with more dilute acid. In contrast, trityl is stable to the basic conditions used for Fmoc removal, so trityl and Fmoc can be used orthogonally in a single sequence if the trityl group is retained through the piperidine treatment and cleaved later with dilute TFA.
When the methyl ester must remain intact, deprotection is run under strictly anhydrous conditions. Aqueous acid cleavage gives glycine methyl ester hydrochloride as the initial water-soluble product, but prolonged exposure hydrolyzes the ester to glycine hydrochloride. The liberated triphenylmethanol is usually removed by trituration with cold hexane or by chromatography on silica gel. At substrate concentrations above 0.5 M, triphenylmethanol precipitation in cold hexane can complicate filtration; sequential extraction with toluene–water at neutral pH is the practical alternative. Published kinetic parameters for this specific ester under dilute acid are limited; process control is typically based on TLC or LC-MS stop points rather than extrapolated half-lives.
Solution-phase peptide synthesis with this building block generally proceeds through the free acid. Saponification of the methyl ester is carried out with lithium hydroxide monohydrate in THF–water at 0–5 °C using 1.05 equivalents of hydroxide. The N-trityl group remains intact under these conditions, whereas the C-terminal methyl ester is removed. The resulting N-tritylglycine is activated with EDC·HCl and HOBt or with HBTU and N,N-diisopropylethylamine in dichloromethane or DMF. Coupling to primary amino esters is typically conducted at 0–25 °C for 2–16 h; residual water above 5% v/v in the solvent promotes hydrolysis of the activated ester and reduces coupling efficiency. The trityl group suppresses undesired N-terminal elongation by steric and electronic shielding of the secondary amine; this is a practical difference from glycine methyl ester hydrochloride, which requires careful pH control to avoid oligomerization during carbodiimide-mediated coupling.
The protected glycine methyl ester is also useful for preparing the free acid N-tritylglycine and for acidolytic generation of glycine methyl ester hydrochloride. For generation of the deprotected salt, the purified material is treated with anhydrous HCl in dioxane; the hydrochloride salt precipitates following addition of diethyl ether. The CAS RN of glycine methyl ester hydrochloride is 5680-79-5, and this conversion is one of the simplest routes to the salt where the use of free glycine and thionyl chloride–methanol is undesirable. Compared with N-tritylglycine free acid, the methyl ester avoids zwitterionic water solubility and permits neutral organic extraction. Compared with glycine methyl ester hydrochloride, the tritylated derivative is neutral and cannot be coupled at the carboxyl without prior hydrolysis or N-deprotection; this difference is not a deficiency but a structural feature that prevents oligomerization during storage and handling.
The table summarizes the removal chemistry and stability boundaries for N-protected glycine methyl ester derivatives commonly encountered in multi-step organic synthesis. The trityl derivative is primarily acid-labile and lipophilic; its methyl ester is neutral and remains in organic media. The Boc derivative is also acid-labile but requires more concentrated acid and is stable to strong nucleophiles. The Cbz derivative is removed by hydrogenolysis and is stable to acid and mild base. The Fmoc derivative is removed by secondary amines and is stable to acid but not to strong base.
| Derivative | Typical removal | Stability profile | Processing consequence |
|---|---|---|---|
| N-Trityl glycine methyl ester | 1–5% TFA/DCM or 0.1 M HCl/dioxane | Stable to basic ester hydrolysis; very sensitive to acid; may undergo hydrogenolysis under forcing conditions | Useful with Fmoc; incompatible with prolonged aqueous acid |
| N-Boc glycine methyl ester | 4 M HCl/dioxane or 1:1 TFA/DCM | Stable to basic hydrolysis and hydrogenolysis; acid-labile | Deprotection generates isobutylene and carbon dioxide |
| N-Cbz glycine methyl ester | H2/Pd-C or Na/NH3 | Stable to acid and mild base; cleaved by hydrogenolysis | Preferred when acid-labile groups cannot be exposed |
| N-Fmoc glycine methyl ester | 20% piperidine/DMF | Stable to acid; base-labile | Preferred in Fmoc solid-phase synthesis; not compatible with strong base |
For multi-step sequences, the acid-labile trityl group is most useful when a subsequent hydrogenolysis step is undesirable or when operationally simple acid cleavage is needed before water-sensitive transformations. The lipophilicity of the trityl group increases retention on reversed-phase columns; preparative chromatography must therefore use sufficiently nonpolar mobile phases. The trityl group also increases crystallinity, which facilitates precipitation of intermediates and reduces the need for chromatographic purification in multi-kilogram development. By contrast, N-Boc-glycine methyl ester tends to be a low-melting solid or oil under ambient conditions, and its removal releases gaseous isobutylene, requiring appropriate venting in manufacturing equipment.
Storage under desiccation at 2–8 °C in tightly sealed amber glass under argon or nitrogen is recommended. The product is hygroscopic, and moisture promotes slow trityl hydrolysis; ensure pre-drying when containers are opened at relative humidity above 60%. Before weighing, the closed container should be equilibrated to ambient temperature to prevent condensation on the solid. Incompatibilities include strong acids, acid chlorides, and Lewis acids; accidental contact with adventitious acid in unstabilized chlorinated solvents can initiate partial deprotection. For synthetic transformations that require acid, deliberate treatment with trifluoroacetic acid or HCl is carried out as a separate step, and residual acid is removed by azeotropic distillation with heptane or by extraction with cold 5% sodium bicarbonate.
In production-scale equipment, batch-to-batch variance in triphenylmethanol content is the main purity driver after prolonged storage. Recrystallization from ethyl acetate–hexane reduces triphenylmethanol below 0.2%; however, solvent selection must preserve the methyl ester. Dust generation from the crystalline solid should be controlled because no sensitization data are available for the trityl derivative, and triphenylmethanol dust may be irritating to the respiratory tract. The product should not be ground in open plant areas without local exhaust ventilation.
The trityl group is sufficiently acid-sensitive that routine aqueous workup must avoid acidic pH. At pH 2–3, the N-trityl bond may undergo measurable cleavage over several hours; at pH 1, cleavage is rapid. This boundary matters in peptide intermediate purification: extraction with 0.5 M citric acid or 1 M HCl will remove the trityl group and transfer glycine methyl ester to the aqueous phase. In contrast, extraction with saturated sodium bicarbonate is acceptable because the ester remains intact under mildly basic conditions. For aqueous workup, maintain the aqueous phase above pH 7.0 and below pH 10.5 to avoid concurrent ester hydrolysis; at pH 12 and above, saponification of the methyl ester becomes significant.
The product is therefore unsuitable for routine use in automated peptide synthesizer cycles that employ repeated acidic deprotection, because the trityl group would be removed during the first acid wash. Its appropriate application is in solution-phase synthesis where acid treatment is a single deprotection event and the liberated triphenylmethanol can be removed before the next coupling. When selective removal in the presence of tert-butyl esters is attempted with 1% TFA at 0 °C, selectivity is time-dependent; extended exposure beyond what is required for trityl cleavage will begin to remove the tert-butyl ester. Published data for this specific selectivity boundary is limited, and stop times should be established by LC-MS on the actual substrate.
