| HS Code | 379721 |
| Product Name | BOC-D-Aspartic Acid |
| Synonyms | N-(tert-Butoxycarbonyl)-D-aspartic acid; Boc-D-Asp-OH |
| Cas Number | 5891-45-4 |
| Mdl Number | MFCD00038219 |
| Molecular Formula | C9H15NO6 |
| Molecular Weight | 233.22 g/mol |
| Appearance | White to off-white powder |
| Melting Point | 114-118 °C |
| Optical Rotation | [α]D20 = +8.0° (c = 1 in acetic acid) |
| Solubility | Soluble in methanol, ethanol, DMF, DMSO; slightly soluble in water |
| Purity | ≥98% (HPLC) |
| Storage Condition | Store at 2-8 °C, tightly sealed, protected from moisture |
| Smiles | CC(C)(C)OC(=O)N[C@H](CC(=O)O)C(=O)O |
As an accredited BOC-D-Aspartic Acid factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | Available as 5 g of white powder in a sealed glass vial, labeled BOC-D-Aspartic Acid, with purity and lot number. |
| Container Loading (20′ FCL) | Loading BOC-D-Aspartic Acid in a 20′ FCL: secure drums/pails, avoid moisture, label properly, ensure ventilation and stable stowage. |
| Shipping | BOC-D-Aspartic acid is shipped at ambient temperature in tightly sealed, moisture-resistant containers, away from light and heat. It is not classified as dangerous goods for standard transport. Use standard laboratory handling precautions. For prolonged stability, store under refrigeration (2–8°C) upon receipt, away from incompatible materials. |
| Storage | Store BOC-D-Aspartic Acid in a tightly sealed container in a cool, dry place, ideally refrigerated at 2–8°C. Protect from light and moisture. Keep the container properly closed when not in use and avoid exposure to strong oxidizing agents. For long-term stability, storage under inert gas is recommended. |
| Shelf Life | Store under cool, dry conditions, protected from light. Typical shelf life is 2–3 years when unopened. |
At pilot scale, solution-phase ring opening of N-Boc-D-aspartic anhydride is the preferred route for preparing β-alkyl D-aspartate building blocks when the α-carboxyl remains as the N-Boc-protected free acid. The anhydride is generated from BOC-D-aspartic acid with N,N'-diisopropylcarbodiimide in anhydrous dichloromethane at 0 °C under a nitrogen blanket. BOC-D-aspartic acid (1.00 equiv) is dissolved in dichloromethane at 5 mL/g, and N,N'-diisopropylcarbodiimide (1.03 equiv) is added dropwise over 15 min. N,N'-diisopropylurea precipitates as a white solid. After 4 h at 0 °C, the slurry is filtered through a sintered glass funnel under positive nitrogen pressure. The filtrate is concentrated at 20 °C under reduced pressure to give the anhydride as a viscous oil or low-melting solid. The anhydride is dissolved in anhydrous tetrahydrofuran and treated with an alcohol nucleophile at -20 °C to -10 °C. Methanol, benzyl alcohol, and tert-butyl alcohol are typical nucleophiles. Methanol at 1.05 equivalents produces the β-methyl ester as the major regioisomer when the reaction is run in tetrahydrofuran at -20 °C for 2 h. The α-methyl ester is the principal process impurity and is controlled by chiral HPLC. The reaction is quenched with 0.5 M hydrochloric acid to pH 3.0 and extracted twice with ethyl acetate. The combined organic layer is washed with 5% sodium chloride, dried over anhydrous sodium sulfate, and concentrated at 30 °C. Purification by silica gel flash chromatography uses ethyl acetate/hexane 30:70 to 50:50. Analytical control uses a C18 column, 150 mm × 4.6 mm, 5 μm, with acetonitrile/0.1% phosphoric acid gradient from 5% to 95% over 20 min at 1.5 mL/min. Residual dichloromethane is controlled under ICH Q3C(R8) at 600 ppm. The anhydride route avoids the use of carbodiimide in the final coupling and reduces residual acylation by-products in the isolated intermediate.
| Nucleophile | Solvent | Temperature | Reaction time | Workup pH |
|---|---|---|---|---|
| Methanol | Tetrahydrofuran | -20 °C | 2 h | 3.0 |
| Benzyl alcohol | Dichloromethane | -10 °C | 3 h | 4.0 |
| Tert-butyl alcohol | Tetrahydrofuran | 0 °C | 8 h | 3.0 |
Side-chain branching occurs when an activated amino acid acylates the unprotected β-carboxyl of a resin-bound D-aspartate residue. In Boc-SPPS, BOC-D-aspartic acid is therefore not used directly as an internal residue when the sequence requires elongation beyond the D-Asp position. Instead, the compound is converted to BOC-D-aspartic acid β-benzyl ester or BOC-D-aspartic acid β-cyclohexyl ester before loading onto hydroxyl-terminated or aminomethyl resins. Esterification of the β-carboxyl is carried out with benzyl bromide and cesium carbonate in anhydrous N,N-dimethylformamide at 0 °C to 20 °C for 16 h, using 1.05 equivalents of benzyl bromide and 1.1 equivalents of cesium carbonate relative to BOC-D-aspartic acid. The product is isolated by ethyl acetate extraction after pH adjustment to 4.0 with 5% citric acid. The protected derivative is then used in solid-phase assembly at 0.4 M concentration in N,N-dimethylformamide. Coupling reagent is HBTU or BOP with N,N-diisopropylethylamine at a 1.0:1.0:2.0 molar ratio relative to the protected amino acid. Deprotection of the N-terminal Boc group uses trifluoroacetic acid/dichloromethane 40:60 v/v with 2% triisopropylsilane at 25 °C for 30 min. Resin washing uses N,N-dimethylformamide and dichloromethane in alternating cycles of 5 resin volumes. Quantitative racemization data for unprotected β-carboxyl in this configuration are limited; process transfer to a different synthesizer requires verification with a model peptide according to USP <621> system suitability and a chiral purity method. Terminal products include D-aspartate-containing peptide APIs for investigational enzyme inhibitor programs. Residual N,N-dimethylformamide is controlled at 880 ppm in bulk peptide batches under ICH Q3C(R8). Water content is measured by Karl Fischer titration according to USP <921>. Chiral identity is confirmed by specific rotation using USP <781>. Elemental impurities are controlled according to ICH Q3D.
Solution-phase synthesis of β-amide derivatives from N-Boc-D-aspartic anhydride and primary amines is used to generate D-aspartic acid β-amide scaffolds for metalloprotease inhibitor screening. The anhydride is prepared as described above and then treated with 1.0 equivalent of a primary amine in dichloromethane at -10 °C to 0 °C. The ring opens at the β-carbonyl to yield the β-amide free acid, while the α-carboxyl remains as the N-Boc-protected free acid and can be coupled later. Reaction progress is monitored by LC-MS with an electrospray ionization source. The crude library compounds are purified by mass-directed reversed-phase HPLC. Typical amine inputs are benzylamine, cyclopropylmethylamine, and 3-methoxybenzylamine. The α-amide regioisomer is the major process impurity and is separated by preparative HPLC using a C18 column, 250 mm × 21.2 mm, 5 μm, with a water/acetonitrile/0.1% trifluoroacetic acid gradient. Purified fractions are lyophilized at -40 °C and 0.2 mbar for 24 h. Analytical data include 1H NMR, 13C NMR, and high-resolution mass spectrometry. The terminal products are D-aspartic acid β-amide peptidomimetics with a free α-carboxyl, used as substrates in enzyme inhibition assays. Compliance for laboratory-scale synthesis is governed by ISO 9001:2015 and ICH Q7. Residual dichloromethane is controlled at 600 ppm under ICH Q3C(R8). Residual acetonitrile is controlled at 410 ppm. The process is maintained under nitrogen with moisture ingress below 200 ppm in the reactor headspace. Published kinetic data for this specific anhydride-amine ring opening are limited; reaction completion is therefore determined by LC-MS area percent rather than by fixed kinetic assumptions.
Direct attachment of BOC-D-aspartic acid to 4-(hydroxymethyl)phenoxymethyl polystyrene resin enables the synthesis of C-terminal D-aspartate peptides without a subsequent deprotection of the side-chain carboxyl. The resin is preswollen in N,N-dimethylformamide for 30 min. BOC-D-aspartic acid (2.0 equivalents relative to resin loading) is dissolved in anhydrous N,N-dimethylformamide at 0.2 M. N,N'-diisopropylcarbodiimide (2.0 equivalents) and 4-dimethylaminopyridine (0.1 equivalent) are added to the resin at 25 °C. The suspension is stirred for 16 h. The resin is washed with N,N-dimethylformamide, dichloromethane, and methanol, then dried under vacuum at 25 °C to a residual N,N-dimethylformamide content below 1000 ppm by USP <467>. Resin loading is determined by cleavage of an aliquot with trifluoroacetic acid and HPLC quantification of the free D-aspartic acid. Capping is performed with acetic anhydride/pyridine/N,N-dimethylformamide 1:1:8 v/v/v for 30 min at 25 °C. Final cleavage uses trifluoroacetic acid/triisopropylsilane/water 95:2.5:2.5 v/v/v for 2 h at 25 °C. The crude peptide is precipitated in cold diethyl ether and dried under vacuum at 25 °C for 12 h. Equipment includes a 500 mL glass peptide synthesis vessel with a PTFE frit and overhead agitation at 60 rpm. The free β-carboxyl remains intact during trifluoroacetic acid cleavage but may undergo partial dehydration to aspartimide if cleavage is extended beyond 4 h at 40 °C. The process is therefore limited to cleavage at 25 °C for 2 h. Reversed-phase HPLC with a C18 column and 0.1% trifluoroacetic acid/acetonitrile gradient is used to control C-terminal D-aspartate peptide purity at ≥95.0%. This direct loading route is used for short D-peptides of 5 to 15 residues where terminal side-chain charge is required.
In analytical method transfer for D-aspartic acid quantification, BOC-D-aspartic acid is deprotected with 6 M hydrochloric acid at 110 °C for 22 h in a sealed hydrolysis tube. The acid is removed under vacuum at 45 °C. The free D-aspartic acid is reconstituted in 0.01 M hydrochloric acid and used as a chiral reference standard for amino acid analysis. Chromatographic separation is performed on a hydrophilic interaction liquid chromatography column, 100 mm × 2.1 mm, 3 μm, with mobile phase acetonitrile/50 mM ammonium formate 75:25 at 0.4 mL/min. Detection is by tandem mass spectrometry in multiple reaction monitoring mode. The deprotected standard is qualified for system suitability under USP <621>. This route is confined to analytical use and is not applied to preparative peptide manufacture. Published data for this specific deprotection configuration are limited; each batch of BOC-D-aspartic acid is therefore qualified for hydrolysis recovery before use in method validation.
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BOC-D-aspartic acid (N-tert-butoxycarbonyl-D-aspartic acid, CAS 62396-48-9) is an Nα-protected D-aspartic acid derivative with molecular formula C9H15NO6 and molar mass 233.22 g mol−1. Commercial lots are generally released as a white to off-white crystalline powder. The substance is catalogued under synonyms including Boc-D-Asp-OH and (2R)-2-((tert-butoxycarbonyl)amino)butanedioic acid; because a single-molecule reagent is not a formulated product with a model number, the formal model identifier in procurement specifications is the CAS registry plus the stereochemical descriptor D. The most common purity grade is an HPLC assay of 98.0% or greater, although peptide-grade material with residual enantiomer profiling is specified where chiral purity is critical.
Coupling efficiency is governed primarily by the unprotected β-carboxylic acid. In a solid-phase reactor with a polyethylene frit, the free β-carboxyl competes with the α-carboxyl for activated ester formation; the resulting intramolecular cyclization can generate succinimide-linked side products and lower stepwise yield. A 250 mL jacketed reaction vessel charged with a resin loading of 1.0 mmol and 2.5 equiv of Boc-D-aspartic acid in DMF requires pre-activation at 0–5 °C with HBTU and N,N-diisopropylethylamine for 12–15 min before transfer. Batch-to-batch variance in residual water or chloride from the protected amino acid can alter activation half-life; raw-material acceptance therefore includes loss-on-drying and ion chromatography limits. Published data for this specific configuration is limited at production scale, and pilot runs are monitored by LC-MS for aspartimide content.
A representative release specification for the reagent is tabulated below. The specification is used for incoming raw-material acceptance and does not include a polymer or formulation model number. Analytical values are reported on the certificate of analysis as lot-specific data.
| Parameter | Acceptance criterion | Method or equipment |
|---|---|---|
| Appearance | White to off-white crystalline powder | Visual inspection |
| Assay | ≥ 98.0% area by HPLC | USP 621 |
| Loss on drying | ≤ 0.5% | USP 731 |
| Residue on ignition | ≤ 0.1% | USP 281 |
| Chiral purity | D-enantiomer ≥ 99.0% | Chiral HPLC, Chiralpak QD-AX 150 mm × 4.6 mm, 5 μm |
| Solubility | Clear at 0.1 g/mL in DMF or DMSO | Visual inspection |
| Residual chloride | ≤ 0.05% | Ion chromatography |
The tabulated solvent threshold at 0.1 g/mL in DMF and DMSO is a formulation-screening parameter; dissolution is generally exothermic and should be conducted at 15–25 °C to avoid localized acid generation. Water solubility is pH dependent and increases above pH 6.5 as the carboxylic acid groups ionize. This ionization behavior is used in extractive workup: below pH 2.0 the protonated form partitions into ethyl acetate, while above pH 8.0 the dianion remains in the aqueous phase.
Selecting Boc-D-aspartic acid rather than Fmoc-D-aspartic acid is justified when a synthetic sequence requires base-labile side-chain protection or acid-labile final deprotection. Boc removal proceeds with 20–50% trifluoroacetic acid in dichloromethane at 20–25 °C over 10–30 min, whereas Fmoc removal requires 20% piperidine in DMF. In a convergent route, Boc-D-aspartic acid can be coupled to an N-terminal segment without disturbing an Fmoc-protected lysine side chain; the reverse is not possible where piperidine exposure would deblock Fmoc. The D configuration is retained during TFA deprotection if the temperature remains below 25 °C and a scavenger such as triisopropylsilane is added at 2.5–5% by volume. The free β-carboxyl is then available for further derivatization, although carbodiimide coupling at this position can produce racemization at the α-carbon if activation is prolonged.
In a 5 L automated synthesizer with a recirculation loop, coupling of Boc-D-aspartic acid to aminomethyl resin is run at 15–18 °C using DIC/HOBt in DMF. The heat of neutralization from N,N-diisopropylethylamine addition is controlled by a jacket setpoint of 10 °C; a temperature override above 28 °C pauses reagent delivery and increases post-activation hold time only if the active ester half-life remains within the validated window. Diastereomeric purity after coupling is checked by LC-MS with an L,D epimer content below 0.5% indicating acceptable activation. Where the β-carboxyl is intended as a conjugation site, activation with DIC/HOBt at −10 °C is used to reduce succinimide formation. Published data for this specific configuration is limited beyond vendor application notes, so pilot batches are monitored for aspartimide and racemization markers before scale-up.
The D and L Boc-aspartic acid derivatives have identical molecular mass and similar infrared spectra; polarimetry alone cannot provide sufficient specificity for release. Chiral HPLC on a quinine-derived anion-exchange phase separates the enantiomers under a methanol/acetic acid/triethylamine mobile phase. The method is suitable for lot release when a racemic Boc-DL-aspartic acid reference injection resolves to a resolution factor Rs of ≥ 1.5. A representative lot of Boc-D-aspartic acid shows a D-enantiomer area of ≥ 99.0% and residual L-isomer area of ≤ 0.5%; the limit is tightened to ≤ 0.2% when the product is used as a chiral derivatizing agent. Column temperature is held at 20 °C because the unprotected β-carboxyl group can exhibit ionization shifts at higher temperatures.
The following table provides a direct comparison with the L-enantiomer and the Fmoc-protected D derivative. The comparison is based on protecting-group lability, because the D aspartic acid core is identical in each entry except for the N-protecting group.
| Reagent | CAS | Molar mass | N-protecting group | Removal condition | Primary synthetic role |
|---|---|---|---|---|---|
| BOC-D-aspartic acid | 62396-48-9 | 233.22 g mol−1 | Boc | 20–50% TFA in DCM at 20–25 °C | Boc/Bzl SPPS and solution-phase D-peptide blocks |
| BOC-L-aspartic acid | 13726-67-5 | 233.22 g mol−1 | Boc | 20–50% TFA in DCM at 20–25 °C | Native L-configuration sequences |
| Fmoc-D-aspartic acid | 136083-57-3 | 355.34 g mol−1 | Fmoc | 20% piperidine in DMF at 20–25 °C | Fmoc/tBu SPPS with base-labile deprotection |
For sequences that require hydrogenolytic deprotection, Cbz-D-aspartic acid occupies an intermediate position and is selected when neither acid nor base exposure is tolerable at the N-terminus. In practice, the Fmoc derivative is preferred for acid-sensitive side-chain protecting groups, while the Boc derivative is preferred for sequences that tolerate repeated TFA treatment.
Moisture uptake in unopened fibre drums is concentrated at the lid gasket and can exceed 0.3% after repeated opening under 60% relative humidity. The compound is stored at 2–8 °C in a desiccator or sealed foil laminate; if a container is opened outside a nitrogen-purged glovebox, the next use should be preceded by vacuum drying at 30 °C and 0.1 mbar for 4 h. Thermal gravimetric analysis of a representative lot shows a 0.2% mass loss between 25 °C and 100 °C, consistent with surface water and residual solvent; decomposition onset is reported above 150 °C. The material is not compatible with primary or secondary amines under storage conditions because free amine accelerates carbamate cleavage; storage adjacent to morpholine or piperidine containers is therefore excluded.
Bulk handling requires segregation from strong mineral acids, anhydrides, and carbodiimide stock solutions. When the Boc group must remain intact, the compound is not mixed with amine bases beyond the short activation time required for coupling; extended exposure to more than 2 equiv of N,N-diisopropylethylamine at 25 °C causes premature carbamate cleavage. Waste streams containing TFA deprotection mixtures should be quenched and neutralized, and the material should not be autoclaved. Incoming raw-material acceptance includes ion chromatography for chloride and trifluoroacetate; commercial lots may vary in residual solvent profile depending on the crystallization solvent, and peptide-grade vendors provide lot-specific LC-MS data for aspartimide and succinimide impurities. Transport classification is non-hazardous under IATA and IMDG criteria, but REACH registration status is document-controlled per region.
