| HS Code | 686684 |
| Product Name | BOC-D-serine |
| Iupac Name | (2R)-2-[(tert-butoxycarbonyl)amino]-3-hydroxypropanoic acid |
| Cas Number | 6368-20-3 |
| Molecular Formula | C8H15NO5 |
| Molecular Weight | 205.21 g/mol |
| Appearance | White to off-white crystalline powder |
| Assay Purity | ≥98% (HPLC) |
| Melting Point | 104-106 °C |
| Optical Rotation | [α]D20 = -8.0 to -10.0° (c=1 in ethanol) |
| Storage Conditions | Store at 2-8 °C, protected from moisture |
| Solubility | Soluble in ethanol, methanol, DMF, DMSO, and aqueous base |
| Form | Solid |
As an accredited BOC-D-serine factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | BOC-D-serine is packaged as a white crystalline powder in a 25 g sealed amber glass bottle with a desiccant pouch. |
| Container Loading (20′ FCL) | 20′ FCL container loading of BOC-D-serine: drum-packed, palletized, secured, with proper labeling and segregation to ensure safe transport. |
| Shipping | BOC-D-serine ships at ambient temperature in a sealed, moisture-resistant container. Avoid prolonged heat or sunlight. Handle with standard laboratory care; if powder becomes dusty, avoid inhalation. No special transport classification is required when packaged correctly, but keep away from incompatible materials and store in a cool, dry place. |
| Storage | Store BOC-D-serine in a tightly sealed container in a cool, dry, well-ventilated area, ideally refrigerated at 2–8°C. Protect from moisture, heat, and direct light. Keep away from strong oxidizing agents and acids. Ensure the container is properly labeled and opened under inert conditions when possible to maintain stability. |
| Shelf Life | BOC-D-serine has a shelf life of typically 2–3 years when stored cool, dry, and protected from light. |
At the 100 mmol synthesis scale on aminomethyl polystyrene-divinylbenzene resin (DVB crosslink 1%, amine loading 0.9–1.1 mmol/g), the coupling of BOC-D-serine introduces an unprotected primary hydroxyl that participates in O-acylation when the activator-base pair is not controlled. This selection is deliberate for short peptide sequences where a free D-serine side chain is required in the final peptide API; for longer sequences, the protected derivative BOC-D-serine(Bzl) would typically be substituted. In a 2 L jacketed glass solid-phase synthesis reactor fitted with a PTFE-coated anchor stirrer at 45–60 rpm, the DIC-mediated activation exotherm normally raises the slurry temperature from 20°C to 24°C within 4 minutes; this thermal rise remains below the racemization threshold for the D-configuration but is sufficient to increase the O-acylation impurity when the DMF-water content exceeds 0.05%. Compliance for this pharmaceutical peptide route is governed by ICH Q7 Section 8.1 for production operations, ICH Q7 Section 12.1 for process validation, ICH Q3C for residual DMF and DCM in the lyophilized peptide, and USP <232>/<233> for elemental impurity release. The coupling charge is 3.0 eq BOC-D-serine relative to the free resin amine, 3.0 eq HOBt monohydrate, and 3.3 eq DIC in a DMF/DCM 1:1 (v/v) mixture at a final BOC-D-serine concentration of 0.18–0.22 M; when a hindered amine at the preceding residue or a high O-acylation risk is identified by resin sampling, the charge is reduced to 2.0 eq BOC-D-serine and 2.2 eq HATU with 2,4,6-collidine at 0–5°C. The downstream production process alternates 30% TFA in DCM with 2% anisole for N-terminal deprotection, neutralization with 5% DIEA in DMF, coupling for 45–60 minutes at 20–24°C, and capping of unreacted amine sites with acetic anhydride/pyridine. Final cleavage from the resin uses HF/anisole 9:1 at 0°C for 60 minutes, followed by extraction into dilute acetic acid and lyophilization. The terminal product type is a lyophilized peptide acetate API or peptide intermediate containing a D-serine residue at a defined position; peptide-related variance is controlled by preparative reversed-phase HPLC on a C18 column with mass-triggered fraction collection. BOC-D-serine storage at 2–8°C under desiccant is required before charging, and exposure to strong aqueous base during workup is avoided because the β-hydroxy acid intermediate can undergo elimination and erode enantiomeric purity.
Conversion of BOC-D-serine to (R)-Garner’s aldehyde proceeds through a three-step sequence: methyl ester formation with thionyl chloride in methanol at 0–10°C, acetonide cyclization with 2,2-dimethoxypropane in acetone under 0.05 eq p-toluenesulfonic acid at 20–25°C, and low-temperature reduction of the oxazolidine methyl ester with DIBAL-H in anhydrous toluene at -70°C to -60°C. The applicable compliance standard for this chiral intermediate is ICH Q7 Section 5.2 for equipment cleaning and maintenance, with residual solvent release under ICH Q3C for toluene, acetone, and methanol; REACH EC 1907/2006 applies to tonne-scale import into the EU. The addition ratio is 1.00 eq N-BOC-D-serine methyl ester, 1.25 eq DIBAL-H (1.0 M in toluene) added over 45–60 minutes, 2.0 eq 2,2-dimethoxypropane, and 0.05 eq p-toluenesulfonic acid; exceeding 1.50 eq DIBAL-H or allowing the internal temperature to rise above -55°C increases the overreduction impurity to the corresponding alcohol, which is difficult to remove by distillation because its boiling point is within 12°C of the aldehyde under the operating vacuum of 10–20 mbar. In a 500 L glass-lined cryogenic reactor with a turbine impeller at 85 rpm, the DIBAL-H feed is introduced through a dip pipe below the liquid surface, and the reaction is quenched with 20% sodium potassium tartrate solution at -10°C to 0°C; the quench pH must remain below 8.0, because the aldehyde undergoes base-catalyzed racemization and the chiral purity of the product can drop below the 98.0% enantiomeric excess limit. The downstream process includes vacuum distillation of the aldehyde at 10–20 mbar and storage under nitrogen at -20°C. The terminal product type is (R)-Garner’s aldehyde, used as a chiral pool intermediate for sphingolipid and β-aminohydroxamate-derived investigational intermediates. Batch-to-batch aldehyde color is controlled by limiting the iron content of the toluene feed, and equipment vendor technical bulletins recommend in-line FTIR tracking of the carbonyl shift from 1735 cm⁻¹ to 1675 cm⁻¹ to define the reduction endpoint.
Where the target peptide chain contains D-serine at a non-terminal position and the overall sequence length remains below 8–12 residues, solution-phase convergent synthesis is selected over solid-phase operations when the C-terminal fragment carries protecting groups that would not withstand repeated TFA exposure. The applicable standard for this route is ICH Q7 Section 6.5 for batch production record review, with ICH Q11 applied to starting material characterization and impurity carryover limits. The coupling addition ratio is 1.0 eq C-terminal peptide fragment with a free amino group, 1.1 eq BOC-D-serine activated as a mixed anhydride with isobutyl chloroformate and N-methylmorpholine at -15°C; the pre-activation time is held to 90–120 seconds before fragment addition, because longer activation of the unprotected β-hydroxy amino acid leads to oxazolidinone ring closure and reduces the coupled yield by 15–25% in development batches. The downstream production process is conducted in a 50 L jacketed reactor with a paddle agitator at 120 rpm, using ethyl acetate as the reaction solvent and a 5% sodium bicarbonate quench; the organic phase is washed until the aqueous pH stabilizes at 7.0–7.5, then concentrated under vacuum below 35°C to prevent partial BOC deprotection. The terminal product type is a fully protected peptide segment that is carried into global deprotection and salt exchange to yield a peptide drug substance; the D-serine residue is retained without racemization because the activation temperature is kept below -10°C. Batch-to-batch variance is controlled by Karl Fischer titration of the ethyl acetate feed at a 0.03% water maximum.
For antimicrobial peptide screening libraries that require D-amino acid incorporation on Merrifield resin, BOC-D-serine is used without side-chain protection because the primary hydroxyl remains inert under the acidic deprotection and neutralization steps. The applicable standard is ISO 9001:2015 for non-GMP custom peptide synthesis and ICH Q3C for residual dichloromethane after lyophilization. The addition ratio is 1.5–2.0 eq BOC-D-serine per amine site in an automated peptide synthesizer with a 45 mL reaction vessel and vortex agitation; coupling is performed with DIC/HOBt in DMF for 30 minutes at 20–25°C. The terminal product type is a crude peptide library set for antimicrobial screening; each peptide is cleaved with HF/anisole and lyophilized without subsequent preparative chromatography. Incomplete coupling at D-serine can occur if the resin lot moisture exceeds 0.10%, and a ninhydrin-positive result triggers a double-coupling cycle.
The reduction of BOC-D-serine to N-BOC-D-serinol is used when the downstream target is a chiral oxazolidine ligand precursor or a peptide C-terminal alcohol isostere. The applicable compliance framework for this conversion is ICH Q7 Section 5.1 when the N-BOC-D-serinol is released as an API intermediate, with residual solvents controlled under ICH Q3C for THF and methanol; for non-pharmaceutical catalyst ligand production, ISO 9001:2015 is applied. The addition ratio is 1.0 eq BOC-D-serine, 1.05 eq isobutyl chloroformate, 1.1 eq N-methylmorpholine, and 2.0 eq sodium borohydride in THF at -10°C to 0°C; the borohydride charge is limited to 2.0 eq because larger excesses generate hydrogen off-gas during the quench and reduce the isolated N-BOC-D-serinol by over-reduction. The downstream production process uses a 100 L glass-lined reactor with a thermal oil system, mixed anhydride activation for 90–120 seconds, sodium borohydride addition as a 2 M solution in THF over 30 minutes, and a quench with 10% ammonium chloride; the crude product is extracted into ethyl acetate and purified by distillation or crystallization. The terminal product type is N-BOC-D-serinol, which is converted to chiral oxazolidine catalysts or used as a protected amino alcohol building block in peptide mimetic research. Published data for this specific mixed-anhydride reduction at production scale is limited; the stated ranges are carried from pilot development and require verification under the specific thermal fluid response. Batch-to-batch variation in the residual acid profile is controlled by in-process pH measurement at the quench stage.
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BOC-D-serine is the common name for N-(tert-butoxycarbonyl)-D-serine, (2R)-2-[(tert-butoxycarbonyl)amino]-3-hydroxypropanoic acid, assigned CAS 6368-20-3, molecular formula C8H15NO5, molar mass 205.21 g/mol, and monoisotopic mass 205.0950 g/mol. The product is supplied as a white to off-white crystalline powder in research-grade, custom GMP-grade, and multi-kilogram intermediate lots. It functions as an acid-labile N-protected chiral building block for solid-phase peptide synthesis, solution-phase fragment coupling, and the preparation of D-serine-containing peptidomimetics. The Boc group blocks the α-amino nitrogen during carboxyl activation, while the D-configuration prevents stereochemical mismatch when D-serine is required in a sequence. The standard grade carries an unprotected hydroxymethyl side chain, which controls its reactivity, storage, and comparison with side-chain-protected analogues. Specific rotation and melting-point data are solvent-dependent and lot-specific; the certificate of analysis is the primary release authority.
The material is available in small-scale research quantities and larger production lots. Research-grade material is typically supplied in 5 g to 100 g containers, while multi-kilogram intermediate lots include additional residual solvent and enantiomeric purity data generated by the manufacturer. Custom GMP-grade batches are produced under ICH Q7 principles when the material is intended as a registered peptide intermediate.
Bulk storage should be maintained at 2–8 °C in an airtight container under dry nitrogen or argon. The unprotected hydroxyl makes the material hygroscopic; open weighing at relative humidity above 60% RH can elevate water content and distort loss-on-drying values. Multi-kilogram dispensing operations for analogous N-Boc amino acids apply nitrogen-blanketed laminar-flow enclosures and immediate resealing after each withdrawal. The compound is incompatible with strong acids, which remove the Boc group, and with strong acylating agents under basic conditions, which can acylate the side-chain oxygen. Storage near peptide-coupling reagents such as carbodiimides, uronium salts, or acid chlorides should be avoided unless the container is sealed and segregated.
In process development and manufacturing, the material is dissolved in dry dimethylformamide or N-methyl-2-pyrrolidone at 0.2–0.5 M immediately before activation. On automated peptide synthesizers, delayed transfer of the activated amino acid can produce a slower-eluting peak in reversed-phase HPLC at 210 nm consistent with O-acylation. Consequently, inline activation immediately before coupling is preferred over batch preactivation for the unprotected compound. If the material has been exposed to humidity above 60% RH, vacuum drying at 25–30 °C is applied before gravimetric dispensing.
| Parameter | Typical specification | Method |
|---|---|---|
| Appearance | White to off-white crystalline powder | Visual inspection |
| Identification | IR spectrum conforms to reference | USP <197> |
| Purity | ≥ 98.5% | HPLC, USP <621> |
| Enantiomeric purity | ≥ 99.0% | Chiral HPLC |
| Loss on drying | ≤ 0.5% | USP <731> |
| Residual solvents | Conforms | USP <467> |
In analytical quality control, the compound is assayed by reversed-phase HPLC using a C18 column and UV detection. The typical mobile phase consists of phosphate buffer and acetonitrile at acidic pH, but the exact method is supplier-specific. Chiral purity is determined separately because reversed-phase HPLC cannot distinguish D- and L-enantiomers. The enantiomeric excess is the parameter most sensitive to manufacturing pH excursions and upstream D-serine feedstock quality.
Process-scale batch-to-batch variance is controlled mainly through enantiomeric purity and residual solvent profiles. A batch with a small excess of the L-enantiomer can alter biological recognition in D-amino acid-containing antimicrobial peptides and receptor probes; chiral HPLC is therefore used for lot acceptance rather than relying on optical rotation alone. Residual solvent data are generated according to USP <467>, and loss on drying is controlled by USP <731>. Suppliers of custom GMP-grade lots typically add heavy metals and bacterial endotoxin testing when the material is destined for an injectable peptide manufacturing route.
The manufacture of BOC-D-serine from D-serine and di-tert-butyl dicarbonate is carried out in aqueous-organic medium at mildly basic pH, typically 8.0–10.0 and 0–10 °C. pH-stat control is used to keep the free amino group deprotonated enough for acylation without driving prolonged exposure to strongly alkaline conditions that can compromise enantiomeric excess. In-process HPLC and polarimetric measurement at 589 nm are used to track the reaction. The isolated material is then washed and dried to remove unreacted di-tert-butyl dicarbonate byproducts and residual base. Published data for this specific configuration is limited, but for N-Boc amino acids the racemization risk is generally lower than for free amino acid activation because the carbamate-protected nitrogen reduces oxazolone formation.
In Boc/benzyl solid-phase peptide synthesis, BOC-D-serine is used when the target sequence requires D-serine and a free hydroxyl at the end of assembly. Coupling with DIC/HOBt in DMF or NMP at 0–5 °C is preferred over prolonged HATU/DIEA activation because the side-chain oxygen remains nucleophilic. On a 0.1 mmol resin bed, 4.0 equiv of the amino acid relative to resin loading is typical; ninhydrin monitoring or quantitative UV detection after cleavage confirms whether a second coupling is needed. Sequences longer than approximately 8–10 residues usually replace BOC-D-serine with BOC-D-Ser(Bzl)-OH or BOC-D-Ser(tBu)-OH to avoid repeated exposure of the free hydroxyl to coupling reagents. The unprotected derivative is specifically selected when the D-serine hydroxyl is intended for later phosphorylation, sulfation, or esterification.
N-Boc deprotection in peptide synthesis is performed with 20–50% v/v trifluoroacetic acid in dichloromethane, commonly containing 2–5% v/v water and 2–5% v/v triisopropylsilane as scavenger. These conditions release the D-serine amino group as a trifluoroacetate salt while the tert-butyl cation is trapped before it alkylates electron-rich side chains. Residual trifluoroacetate in the final peptide is removed by preparative reversed-phase chromatography or ion exchange and measured by ion chromatography with conductivity detection. The acceptance limit is derived from the drug substance specification; failure to control this residual can alter lyophilization behavior and create a stoichiometric salt at the N-terminal D-serine residue.
For solution-phase fragment coupling, BOC-D-serine is often converted to the N-hydroxysuccinimide ester or a mixed anhydride under controlled carbodiimide conditions; purification is required to remove any O-acylated species because the free hydroxymethyl competes with the intended amine. The compound has also been used to prepare D-serine methyl ester and D-serine amide intermediates after N-protection. Because the product is a chemical intermediate rather than a pharmaceutical dosage form, it is handled under local exhaust ventilation, and long-term storage follows the supplier’s retest date rather than a fixed expiry without lot-specific data.
In convergent routes an activated BOC-D-serine species may be added to a peptide fragment that contains a hindered N-terminus. The free hydroxymethyl can compete with the desired amination, especially when the activated ester is added too rapidly or the reaction temperature is above 10 °C. Process chemists therefore add the active ester slowly at 0–5 °C and use a slight excess of the free amine or a weak non-nucleophilic base. The reaction is followed by reversed-phase HPLC at 210 nm, where the desired amide and the O-acyl byproduct are separated; confirmation by LC-MS is used if the masses are close. Published data for this specific configuration is limited, so site-specific validation is required because the byproduct ratio depends on the steric and electronic environment of the fragment.
BOC-D-serine differs from Fmoc-D-serine in the removal chemistry of the Nα protecting group. The Boc group is acid-labile, while Fmoc is base-labile, making the two compounds orthogonal. BOC-D-serine is therefore selected for Boc/benzyl SPPS and for substrates that cannot tolerate repeated piperidine exposure. Fmoc-D-serine is used in Fmoc/tBu synthesis, but the standard free hydroxyl form presents the same O-acylation risk; Fmoc-D-Ser(tBu)-OH is frequently substituted. Cbz-D-serine is removed by catalytic hydrogenolysis or transfer hydrogenation and is incompatible with reducible functionalities such as aryl halides, azides, or certain alkenes. Unprotected D-serine cannot be used for selective N-coupling because the free amine competes with the intended nucleophile and leads to oligomerization. The choice between BOC-D-serine and side-chain-protected variants is therefore driven by the deprotection protocol, the sequence length, and the desired final side-chain functionality.
| Attribute | BOC-D-serine | Fmoc-D-serine | Cbz-D-serine | D-serine |
|---|---|---|---|---|
| Nα protection | tert-Butoxycarbonyl | 9-Fluorenylmethoxycarbonyl | Benzyloxycarbonyl | None |
| Removal conditions | 20–50% TFA in DCM, scavengers | 20% piperidine in DMF | Hydrogen, Pd/C or transfer hydrogenation | Not applicable |
| Orthogonality | Stable to base and hydrogenolysis; labile to acid | Stable to acid; labile to secondary amines | Stable to acid and base; labile to hydrogenolysis | Not applicable |
| Main side-reaction risk | O-acylation of free hydroxyl | O-acylation of free hydroxyl | Reduction of sensitive groups | Uncontrolled self-condensation |
For lot acceptance, enantiomeric purity by chiral HPLC is more informative than specific rotation alone, because small L-enantiomer content may not shift the rotation enough for detection in a mixed solvent. The compound should be used with dry dimethylformamide or N-methyl-2-pyrrolidone, stored over molecular sieves, and protected from atmospheric moisture. The free hydroxyl also means that the powder should not be stored in open containers in an amine-rich atmosphere where an acylating agent is present, because alkaline conditions can promote side-chain O-acylation. These operational boundaries, rather than simple purity value, govern successful use in peptide synthesis.
