| HS Code | 799998 |
| Product Name | L-Aspartic Acid Methyl Ester Salt |
| Chemical Name | L-Aspartic acid α-methyl ester hydrochloride |
| Cas Number | 32213-95-9 |
| Molecular Formula | C5H9NO4·HCl |
| Molecular Weight | 183.59 g/mol |
| Appearance | White crystalline powder |
| Melting Point | 185 °C (decomposes) |
| Optical Rotation | [α]20/D = +12.5° (c=1 in water) |
| Solubility | Soluble in water, methanol, and DMF |
| Storage Conditions | Store under inert atmosphere at 2-8 °C, protected from moisture |
| Purity | ≥98% (HPLC) |
| Isomeric Smiles | COC(=O)[C@@H](N)CC(=O)O.Cl |
| H Bond Donor Count | 3 |
| H Bond Acceptor Count | 5 |
As an accredited L-Aspartic Acid Methyl Ester Salt factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | L-Aspartic Acid Methyl Ester Salt, 25 g, packaged in a sealed glass bottle with tamper-evident cap and labeled safety information. |
| Container Loading (20′ FCL) | 20′ FCL container loading for L-Aspartic Acid Methyl Ester Salt: secure, ventilated, and dry; use palletized drums/bags, avoid moisture. |
| Shipping | L-Aspartic Acid Methyl Ester Salt is shipped at ambient temperature in sealed, moisture-resistant containers. It is not classified as dangerous goods under IATA/IMDG/ADR regulations. Ensure secure packaging, avoid exposure to humid conditions, and label as a non-hazardous chemical for routine ground or air transport. |
| Storage | Store L-Aspartic Acid Methyl Ester Salt in a tightly sealed container, protected from moisture, light, and heat. Keep in a cool, dry, well-ventilated area at room temperature, ideally 2–8°C for long-term stability. Avoid contact with strong oxidizers and acids. Ensure container is clearly labeled and kept away from incompatible materials. |
| Shelf Life | Shelf life is typically 2 years when stored sealed, dry, and at room temperature, away from light and moisture. |
In automated solid-phase peptide synthesis, the β-methyl ester hydrochloride form of L-aspartic acid methyl ester salt is processed into Fmoc-L-Asp(OMe)-OH before resin loading. The hydrochloride salt is neutralized with triethylamine at 1.05 molar equivalents in anhydrous tetrahydrofuran at 0–5°C; triethylamine hydrochloride is removed by filtration, and the free amino ester is immediately protected with Fmoc-OSu in the presence of sodium bicarbonate at 20–25°C for 8–12 h. The resulting protected aspartate derivative is coupled to Wang resin pre-swollen in dichloromethane using diisopropylcarbodiimide and 1-hydroxybenzotriazole in dimethylformamide at 25°C ± 2°C for 60–90 min. Resin substitution is controlled between 0.30 mmol/g and 0.80 mmol/g by adjusting the protected amino acid molar excess from 2.0 to 4.0 equivalents. Coupling endpoint is confirmed by Kaiser test; residual free amino groups after capping with acetic anhydride and pyridine are held below 0.1% by resin-bound ninhydrin assay. Fmoc deprotection is quantified by UV absorption of the dibenzofulvene-piperidine adduct at 301 nm using 20% piperidine in dimethylformamide. The side-chain methyl ester survives repeated 20% piperidine/dimethylformamide deprotection cycles with hydrolysis below 0.05% per cycle as measured by HPLC of the peptide-resin. Final cleavage from the resin uses trifluoroacetic acid, water, and triisopropylsilane at 95/2.5/2.5 v/v/v. Before cleavage, the methyl ester side-chain protection can be removed by saponification with lithium hydroxide in tetrahydrofuran-water at 0–5°C to release the unprotected aspartic acid residue; this two-step strategy reduces acid-catalysed aspartimide rearrangement during repeated Fmoc cycles on automated synthesizers with 0.1 mmol scale reactors.
N-protected aspartate derivatives are manufactured from the methyl ester salt by two principal routes. The first route introduces the 9-fluorenylmethoxycarbonyl group via Fmoc-OSu under Schotten-Baumann conditions at pH 8.0–8.5. The second route introduces the tert-butyloxycarbonyl group with Boc₂O in tert-butanol-water at 35–40°C. In both routes the β-methyl ester is retained, and the derivatives are isolated as white to off-white powders by precipitation from ethyl acetate-hexane at 0–5°C. Reverse-phase HPLC purity is specified at ≥99.0% area, with the des-methyl hydrolysed impurity controlled at ≤0.50%. Enantiomeric excess by chiral HPLC is ≥99.5%, with L-aspartic acid as the chiral reference. Residual chloride from the starting hydrochloride is controlled by ion chromatography to ≤500 ppm. Because the free amino acid methyl ester is hygroscopic and prone to ester hydrolysis, the salt-to-free-base conversion must be followed by immediate N-protection or controlled dehydration. Packaging under nitrogen in sealed polyethylene-aluminium bags with desiccant is standard when moisture content exceeds 0.20% w/w by Karl Fischer titration. The controlled residual solvent profile is summarized below.
| Solvent | ICH Q3C class | Acceptance criterion |
|---|---|---|
| Methanol | Class 2 | ≤3000 ppm |
| Dichloromethane | Class 2 | ≤600 ppm |
| N,N-Dimethylformamide | Class 2 | ≤880 ppm |
| Ethyl acetate | Class 3 | ≤5000 ppm |
Solution-phase preparation of α-aspartyl dipeptide derivatives uses the methyl ester salt as a regioselectively protected aspartic acid equivalent. The hydrochloride is neutralized with 4-methylmorpholine in dichloromethane at −10°C, and then L-phenylalanine methyl ester is added with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 1-hydroxybenzotriazole. The coupling mass is held at 0–5°C for 16–20 h. The β-methyl ester remains intact during activation at the α-carboxyl group, preventing formation of the β-isomer by-product. After aqueous workup, the β-methyl ester is removed by sodium hydroxide hydrolysis at 15–20°C in methanol-water 4/1 v/v. This route is used for laboratory-scale synthesis of aspartame-like compounds and custom dipeptide APIs where the anhydride route is not suitable. Published data for industrial-scale yield optimization of this exact configuration is limited. The main operational boundary is the hydrolysis step: the α-peptide bond is stable at pH 10.5–11.0 for less than 30 min, but prolonged exposure above pH 12 leads to measurable α-peptide cleavage. Epimerization of the aspartic acid α-carbon is kept below 0.3% by maintaining coupling temperature below 5°C and excluding triethylamine from the activation mixture.
The β-methyl ester salt is the preferred commercial form because the side-chain carboxyl is blocked while the α-carboxyl remains available for selective activation. In chiral pool preparations of β-amino acid derivatives, the α-amino group is first protected, and then the side-chain ester is reduced with lithium borohydride in anhydrous tetrahydrofuran at 0–5°C; the reduction is complete within 4 h and the α-carboxyl, if converted to the tert-butyl ester, remains untouched. The crystalline hydrochloride salt is stored at 25°C ± 2°C and 60% RH ± 5% for stability evaluation according to ICH Q1A; this salt form suppresses premature nucleophilic reactions of the free amino group during transit. Once neutralized, the free amino methyl ester undergoes measurable hydrolysis at pH above 9; N-protection must therefore be initiated within 60 min after neutralization at 20–25°C. Process deviations above pH 9.5 generate the corresponding aspartic acid salt as an impurity that is detected by ion chromatography with a quantification limit of 0.05% w/w. This operational boundary is the main reason that reagent manufacturer protocols recommend fresh neutralization immediately before coupling.
Cosmetic peptide actives containing aspartic acid residues are prepared on solid-phase synthesizers using N-protected aspartate derivatives derived from the methyl ester salt. Peptide-resin cleavage with trifluoroacetic acid produces trifluoroacetate salts in the crude peptide; residual trifluoroacetic acid is removed by ion-exchange chromatography on a strong anion resin or by repeated lyophilization from dilute hydrochloric acid, then measured by ion chromatography. Cosmetic manufacturers commonly set a residual trifluoroacetic acid limit of 0.1% w/w in the final lyophilised peptide based on finished formulation safety requirements. The methyl ester salt provides a route to the Fmoc-protected aspartate residue without the need for side-chain tert-butyl protection, which reduces the generation of isobutylene during acidic cleavage. In this application, the limiting factor is residual methanol and ethyl acetate from the protected amino acid synthesis; these are controlled to 3000 ppm and 5000 ppm respectively according to ICH Q3C. For low-residual-solvent formulations, the peptide is additionally lyophilized from water at −40°C shelf temperature for 24 h to reduce residual solvent below the detection limit of 50 ppm by headspace GC-MS.
As an analytical reference standard, L-aspartic acid methyl ester salt is dissolved in mobile phase and injected to identify residual underivatised methyl ester intermediates in protected amino acid batches by reverse-phase HPLC with UV detection at 210 nm. Retention time is confirmed against a co-injected standard, and peak area response linearity is evaluated over 0.05–2.0 mg/mL. No additional downstream use is claimed for this material in this context.
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L-Aspartic acid methyl ester salt is supplied most commonly as the β-methyl ester hydrochloride, represented in peptide chemistry notation as H-Asp(OMe)-OH·HCl and assigned CAS 16856-13-6. The corresponding α-methyl ester hydrochloride is a separate regioisomer assigned CAS 17812-32-7 and carries the notation H-Asp-OMe·HCl. The β-hydrochloride has the molecular formula C5H10ClNO4 and a molecular mass of 183.59 g/mol. Theoretical chloride content is 19.31%, nitrogen content is 7.63%, and the residual carboxyl is at the α-position. Commercial models are typically classified as peptide synthesis grade, chiral intermediate grade, or API starting-material grade under ICH Q7. Supplier stock-keeping units differ, but the H-Asp(OMe)-OH·HCl notation is the most reliable cross-specification identifier. The compound is isolated as a white to off-white crystalline solid and is freely soluble in water and methanol, moderately soluble in dimethylformamide and dimethyl sulfoxide, sparingly soluble in ethyl acetate, and practically insoluble in hexane and toluene. This solubility profile differs from the free acid L-aspartic acid, which remains poorly soluble in common organic solvents and requires salt formation or esterification for homogeneous reaction systems.
The regioisomeric placement of the methyl ester determines which carboxyl is available for subsequent activation. In the β-methyl ester hydrochloride, the α-carboxyl is free and the side-chain carboxyl is masked. This arrangement is used when the main-chain carboxyl must be activated for amide bond formation while the β-position is temporarily protected. In the α-methyl ester hydrochloride, the β-carboxyl is free, which is preferred when side-chain modification is required before main-chain coupling. The dimethyl ester hydrochloride has both carboxyls protected as methyl esters and no free carboxylic acid unless selective hydrolysis is performed.
| Derivative | Model notation | CAS | Molecular mass | Free carboxyl position | Principal synthetic role |
|---|---|---|---|---|---|
| L-Aspartic acid β-methyl ester hydrochloride | H-Asp(OMe)-OH·HCl | 16856-13-6 | 183.59 g/mol | α | Main-chain coupling with side-chain methyl ester protection |
| L-Aspartic acid α-methyl ester hydrochloride | H-Asp-OMe·HCl | 17812-32-7 | 183.59 g/mol | β | Side-chain modification and selective amidation |
| L-Aspartic acid dimethyl ester hydrochloride | H-Asp(OMe)-OMe·HCl | 32213-95-9 | 197.62 g/mol | none | Chiral synthon requiring selective hydrolysis before chain elongation |
These structural differences also affect HPLC retention under acidic mobile phases. The α-methyl and β-methyl esters are baseline-resolved on C18 columns using 0.1% trifluoroacetic acid and acetonitrile gradients; exact resolution factors are method- and column-batch-specific. Published thermodynamic data for the pure hydrochloride salts in mixed aqueous-organic solvent systems is limited, and process development should confirm retention and solubility in the intended solvent matrix.
On multi-kilogram production lines, the material is isolated by crystallization from methanol or methanol/diethyl ether mixtures in glass-lined reactors, filtered, and dried in vacuum tray dryers at 40–50°C under a vacuum of 10–20 kPa absolute for 6–12 h. At warehouse relative humidity above 60%, the product adsorbs moisture and can develop lumps; drying is therefore extended and the material is transferred to sealed HDPE drums with low-moisture barrier liners. In a double-cone vacuum dryer with a 500 L working volume, batch charges of 80–120 kg typically reach loss-on-drying values below 0.5% within the specified drying window, provided the circulating water jacket is maintained at 45°C. Agglomeration observed during unloaded storage is traced to incomplete solvent removal and residual methanol above 0.3%, not to polymorphic transition. The product remains a crystalline solid; no hydrate phase is specified in release documentation.
Release testing for the β-methyl ester hydrochloride is configured around identity, purity, and residue controls. The acceptance criteria below are representative of commercially released peptide synthesis grade material and are aligned to pharmacopeial general chapters when direct monographs are not available for this exact intermediate.
| Test | Acceptance limit | Analytical method or standard designation |
|---|---|---|
| HPLC purity | ≥ 98.5 area% at 210 nm | USP <621>, Ph. Eur. 2.2.46 |
| D-Enantiomer | ≤ 0.5 area% | Chiral HPLC, UV detection at 210 nm, USP <621> |
| Chloride content | 18.8–19.6% | Argentometric titration, USP <221> |
| Loss on drying | ≤ 0.5% | Vacuum at 60°C for 4 h, USP <731> |
| Residue on ignition | ≤ 0.1% | 600°C ignition, USP <281> |
| Residual methanol | ≤ 3000 ppm | Headspace gas chromatography, ICH Q3C Class 2 |
| Specific rotation | Report value at 25°C, sodium D line | USP <781> |
| Water, Karl Fischer | ≤ 1.0% | USP <921> Method Ia |
The specific rotation acceptance range is referenced to an in-house secondary standard, not to a universal external value, because the exact value depends on water content and residual solvent. If the product is used in a registered synthetic route for a sterile injectable drug substance, additional testing for bacterial endotoxins may be specified with a limit of ≤0.25 EU/mg by a compendial kinetic chromogenic method, and residual chloride after free-base conversion may be monitored by ion chromatography. Such additional tests are not part of the standard peptide synthesis grade release schedule.
In solution-phase peptide synthesis, the β-methyl ester hydrochloride is neutralised before activation. A 1.0–1.05 molar equivalent of N,N-diisopropylethylamine or N-methylmorpholine is added to a stirred suspension in dimethylformamide at 0–5°C; the free α-carboxyl is then activated with a carbodiimide such as DIC or EDC in the presence of HOBt or HOAt. Maintaining the pH between 7.0 and 8.5 is critical. Below 7.0, neutralization of the hydrochloride is incomplete and carbodiimide activation is suppressed by protonated amine species. Above 8.5, the methyl ester undergoes saponification at a rate that becomes measurable over a 4–6 h coupling; the resulting free aspartic acid contaminant then competes for activated sites and produces the double-addition impurity. The exotherm from carbodiimide addition is controlled by maintaining jacket temperature at 0–5°C for charges above 50 kg in glass-lined reactors. A process analytical technology probe is recommended because the reaction mass transitions from suspension to clear solution within 20–40 min, and delayed clearance indicates insufficient base neutralization or moisture ingress. For sterically hindered amines, HATU with N,N-diisopropylethylamine in dimethylformamide is preferred over carbodiimide activation, but the same pH window applies.
Applications that require anhydrous conditions—such as esterification, peptide coupling to acid chlorides, or conversion to N-carboxyanhydride intermediates—demand special handling of the hydrochloride salt because the counterion and any free chloride can interfere with silver, palladium, or tin catalysts and with moisture-sensitive reagents. In these transformations, the hydrochloride is converted to the free amino ester by treatment with a stoichiometric tertiary amine in dichloromethane or ethyl acetate, and the precipitated amine hydrochloride is removed by filtration under nitrogen before the filtrate enters the subsequent reaction. Residual chloride below 0.1% by ion chromatography is targeted for such processes, although the released material specification permits 18.8–19.6% total chloride due to the hydrochloride form. For non-aqueous coating formulations or polymer encapsulation, free-base solubility in dichloromethane is lower than in dimethylformamide; warming to 30–35°C improves dissolution, but sustained temperatures above 40°C accelerate methyl ester methanolysis and are avoided. Published quantitative solubility data for the exact non-aqueous solvent pairs is limited; laboratory-scale solubility screening with Karl Fischer moisture verification is required before batch scale-up.
The hydrochloride salt is converted to the N-(9-fluorenylmethoxycarbonyl) derivative by treatment with Fmoc-OSu in aqueous sodium carbonate/dioxane at pH 8.0–8.5 and temperature ≤ 5°C for up to 2 h. Under these conditions the methyl ester remains intact, and the resulting Fmoc-L-aspartic acid β-methyl ester is suitable for subsequent solid-phase or solution-phase peptide chain assembly. Preparation of the pentafluorophenyl ester or N-hydroxysuccinimide ester from the free α-carboxyl proceeds through standard activation chemistry after removal of amine hydrochloride and drying of the isolated free base. These activated intermediates are used immediately; storage of activated amino acid esters is limited by hydrolysis and racemization risks.
Hydrolytic stability of the methyl ester group defines the upper processing temperature. At pH 8.5 and 25°C, less than 2% hydrolysis is observed over 24 h; at pH 10.0, the same degree of hydrolysis is reached within approximately 1 h. The degradation product is L-aspartic acid hydrochloride or its sodium salt, which can be quantified by ion-exclusion HPLC with UV detection at 210 nm. The hydrochloride salt shows an endothermic event above 150°C with decomposition, rather than a sharp melting point, because the methyl ester hydrochloride eliminates methanol or hydrolyzes from adventitious water; thermal data vary with residual solvent content and heating rate. Differential scanning calorimetry at 10 K/min under nitrogen is used in compatibility studies with excipients, but decomposition onset is not a release criterion. For polymer extrusion applications, the compound is not recommended in polyamide melts above 220°C because thermal dehydrochlorination and methyl ester degradation produce discoloration products.
Long-term storage of L-aspartic acid β-methyl ester hydrochloride requires sealed primary containers with low water-vapor transmission. Multi-layer polyethylene-aluminium foil bags inside 25 kg HDPE drums are used for export shipments; the recommended storage temperature is 15–25°C, and excursions above 35°C should be limited to 72 h cumulative during land transport. At 60% RH and 25°C, open-container water uptake reaches 1.0% within 6–8 h in uncontrolled warehouse trials; closed-container lots remain below 0.5% Karl Fischer value for 24 months when the liner is intact. The product should not be stored in direct contact with ferrous metals because chloride-initiated corrosion and iron contamination can exceed 10 ppm over extended contact at welded drum seams. Incompatibility with strong bases and strong oxidizing agents is documented; contact with aqueous sodium hydroxide above 0.1 N causes rapid saponification of the methyl ester and converts the material to L-aspartic acid sodium salt.
