| HS Code | 714303 |
| Name | BOC-L-serine Methyl Ester |
| Cas Number | 2766-43-0 |
| Molecular Formula | C9H17NO5 |
| Molecular Weight | 219.24 g/mol |
| Iupac Name | methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-hydroxypropanoate |
| Appearance | Colorless to pale yellow viscous liquid |
| Boiling Point | 355.1°C at 760 mmHg (predicted) |
| Flash Point | 168.5°C (predicted) |
| Density | 1.1 g/cm³ (predicted) |
| Optical Rotation | -10.0° (c = 2, methanol) |
| Solubility | Soluble in methanol, dichloromethane, ethyl acetate; slightly soluble in water |
| Storage Temperature | 2-8°C, protected from moisture |
| Purity | ≥98% (HPLC) |
| Smiles | CC(C)(C)OC(=O)N[C@@H](CO)C(=O)OC |
As an accredited BOC-L-serine Methyl Ester factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | BOC-L-serine methyl ester is packaged as a white crystalline solid in a 5 g glass bottle with an airtight seal. |
| Container Loading (20′ FCL) | BOC-L-serine Methyl Ester shipped as 20′ FCL, carefully packed in sealed drums, palletized, and containerized for safe transport. |
| Shipping | BOC-L-serine methyl ester ships at ambient temperature in a tightly sealed, light-protected container with desiccant to prevent moisture uptake. It is not classified as hazardous for transport, but should be kept cool and dry during transit. Ensure packaging is intact and comply with local shipping regulations. |
| Storage | Store BOC-L-serine methyl ester in a tightly sealed container under inert gas, protected from light and moisture. Keep refrigerated at 2–8°C in a cool, dry, well-ventilated area. Avoid prolonged exposure to air, heat, or humidity to prevent degradation. Ensure the container is securely closed after each use. |
| Shelf Life | Shelf life is typically 2 years when stored at -20°C, desiccated, and protected from light. |
In liquid-phase assembly of L-serine-containing dipeptide and tripeptide active pharmaceutical intermediates, BOC-L-Ser-OMe is charged as the masked C-terminal fragment. The methyl ester remains intact through acidic N-BOC removal with trifluoroacetic acid/dichloromethane 1:1 at 0–20 °C for 30–60 min and is saponified only after peptide bond formation with lithium hydroxide in tetrahydrofuran/water 3:1 at 0–10 °C. This sequence prevents carboxylate interference during carbodiimide activation. A standard DMF charge uses 0.3–0.5 M substrate concentration, 1.05 eq EDC·HCl, 1.10 eq HOBt monohydrate, and 2.20 eq NMM at 0–5 °C. The free primary alcohol of the serine side chain is not protected in this configuration; low-temperature operation suppresses O-acylation by the activated ester. Reaction completion is monitored by HPLC area normalization at 210 nm; the BOC-L-seryl dipeptide ester is extracted into ethyl acetate and washed with 5% citric acid, saturated sodium bicarbonate, and brine. Terminal products include BOC-L-seryl-L-phenylalanine methyl ester, BOC-L-seryl-L-valine methyl ester, and related short-chain intermediates for subsequent chain extension. Residual methanol, dichloromethane, and N,N-dimethylformamide must be qualified against ICH Q3C(R8) Class 2 and Class 3 limits; methanol is applied as a conservative release criterion at not more than 3000 ppm, although published data for this specific molecular configuration remains limited. In-process controls follow ICH Q7 Section 12.3 for blending and Section 11.2 for primary reference material use.
| Activation system | Charge ratio (Boc-Ser-OMe / activator / additive / base) | Temperature range | Main process constraint |
|---|---|---|---|
| EDC·HCl / HOBt | 1.00 / 1.05 / 1.10 / 2.20 NMM | 0–5 °C | EDC urea by-product removal |
| DIC / HOBt | 1.00 / 1.05 / 1.10 / 2.00 DIPEA | 0–15 °C | diisopropylurea filtration |
| HATU / HOAt | 1.00 / 1.00 / 1.00 / 2.50 DIPEA | −5 to +5 °C | pre-activation ≤ 3 min |
For customers requiring the free carboxylic acid downstream, BOC-L-Ser-OMe is saponified before resin loading or mixed-anhydride coupling. A typical saponification uses 1.02–1.05 eq lithium hydroxide monohydrate in tetrahydrofuran/water 3:1 (v/v) at 0–10 °C for 30–90 min. The methyl ester is consumed selectively; no other labile ester is present, but prolonged exposure to strong base slowly promotes base-catalyzed cleavage of the BOC carbamate. Base-mediated hydrolysis above 15 °C increases α-carbon racemization risk; the preferred temperature window is therefore 0–10 °C. Conversion is monitored by TLC with UV 254 nm and potassium permanganate dip, and by reverse-phase HPLC at 214 nm. After neutralization with citric acid to pH 3.5–4.0, the free acid is extracted into ethyl acetate. Optical rotation is measured in methanol at 20 °C and concentration c=1 according to USP <781>; the release specification is set against a qualified reference standard because batch-to-batch rotation can shift with residual methanol. Residual lithium content is controlled by water washes until conductivity falls below 50 µS/cm. The final product BOC-L-Ser-OH is used directly in resin loading or mixed-anhydride couplings. Compliance follows ICH Q7 Section 12.4 for reprocessing limits; methanol formed in the hydrolysis is removed under reduced pressure and must meet ICH Q3C(R8) Class 3 residual solvent criteria.
Driven by azeotropic removal of methanol and acetone, the N-Boc-1,2-amino alcohol system of BOC-L-Ser-OMe undergoes acetonide formation in refluxing toluene with 2,2-dimethoxypropane and catalytic p-toluenesulfonic acid. Typical charge ratios are 2.0–2.5 eq 2,2-dimethoxypropane and 0.05 eq p-toluenesulfonic acid monohydrate under a Dean-Stark trap in a jacketed glass-lined reactor at 85–90 °C for 4–8 h. The free hydroxyl and the carbamate nitrogen are locked into a 2,2-dimethyloxazolidine ring, giving methyl (S)-3-Boc-2,2-dimethyloxazolidine-4-carboxylate. The product is washed with saturated sodium bicarbonate and brine, dried over sodium sulfate, and concentrated. This oxazolidine ester is reduced with 1.2–1.5 eq diisobutylaluminium hydride in toluene at −30 to −20 °C to the corresponding alcohol; oxidation with sodium periodate or Dess-Martin periodinane yields Garner’s aldehyde. The aldehyde is used as a chiral C3 building block in asymmetric synthesis of β-amino alcohols, sphingoid bases, and chiral ligands. The critical process control is aldehyde racemization; the DIBAL-H reduction must be quenched with methanol and sodium potassium tartrate rather than protic acid. If water is not controlled, acetonide ring closure stalls at the mixed acetal intermediate. Residual toluene must comply with ICH Q3C(R8) Class 2 limit of 890 ppm, and the final aldehyde is assayed by 1H NMR and HPLC. Published data for exact throughput on production-scale equipment is limited; batch sizes above 50 kg input may require extended Dean-Stark removal and nitrogen stripping.
Before the protected aldehyde is used in sphingoid backbone assembly, BOC-L-Ser-OMe is converted into Garner’s aldehyde via the oxazolidine intermediate. The protected aldehyde is subjected to Grignard or organolithium addition at −78 to −60 °C with 1.5–2.0 eq of a long-chain alkenyl nucleophile in tetrahydrofuran under inert atmosphere. The organometallic feed is controlled by syringe pump over 30–60 min. The resulting secondary alcohol is formed with diastereoselectivity that depends on the chiral acetonide environment; chelation-controlled addition is dominant when no strong Lewis acid is added. After addition and methanesulfonyl chloride activation, the C2 nitrogen is liberated by cleavage of the BOC group with trifluoroacetic acid/dichloromethane 1:1 at 0–20 °C for 30–60 min. Acylation with palmitoyl chloride or stearic acid provides the N-acyl sphingoid backbone. Final products include D-erythro-sphingosine, N-palmitoyl-D-erythro-sphingosine, and phytosphingosine intermediates used in cosmetic and dermatological lipid research. The main operational boundary is the organometallic quench step: aqueous quench must be conducted below −40 °C to prevent retro-aldolization of the oxazolidine. Residual aluminum from DIBAL-H or Grignard workup is controlled by citric acid washes and monitored by ICP-MS; acceptance limits are derived from ICH Q3D permitted daily exposure rather than set as a single universal value. Compliance follows ICH Q7 Section 12.5 for validation of critical process parameters. ISO 14644-1 Class 8 cleanroom classification is applied for final sphingoid intermediate isolation if destined for aseptic formulation.
With dibenzyl N,N-diisopropylphosphoramidite as the phosphitylating agent, the unprotected primary hydroxyl in BOC-L-Ser-OMe is converted into a protected phosphoserine ester. A typical charge uses 1.1–1.3 eq phosphitylating agent and 1.5–2.0 eq tetrazole activator in dichloromethane at 0–5 °C for 15–30 min. The intermediate phosphite is oxidized in situ with 1.2 eq tert-butyl hydroperoxide or iodine/water at 0 °C for 30 min. Workup includes sodium thiosulfate reduction of excess iodine and phosphate buffer extraction at pH 6.8. The product, N-BOC-O-dibenzylphospho-L-serine methyl ester, is purified by normal-phase chromatography or ethyl acetate/hexane crystallization. Hydrogenolysis over 5% palladium on carbon at 1–3 bar hydrogen removes the dibenzyl esters, giving N-BOC-O-phospho-L-serine methyl ester as an ammonium salt. This monomer is then selectively deprotected to produce free O-phospho-L-serine or incorporated into phosphopeptide intermediates for signal transduction research. The main process constraint is the prevention of β-elimination of the phosphate under basic conditions; all post-oxidation pH values are maintained below 7.5. 31P NMR at 162 MHz is used to confirm the single phosphorous signal and absence of pyrophosphate. Compliance follows ICH Q7 Section 12.2 for raw material identification and ICH Q3D for palladium; the palladium catalyst is filtered through a 0.45 µm membrane before lyophilization.
When N-methylation of the carbamate nitrogen is required for N-methyl-peptide scaffolds, BOC-L-Ser-OMe is treated with methyl iodide and sodium hydride. The reaction uses 1.2–1.5 eq methyl iodide and 1.2–1.5 eq sodium hydride as a 60% mineral oil dispersion in N,N-dimethylformamide at 0–5 °C, with tetrahydrofuran added at 20–30% of the total volume to reduce slurry viscosity. Reaction time is 1–3 h; excess hydride is quenched with saturated ammonium chloride at 0 °C. The product BOC-N-methyl-L-serine methyl ester is extracted with ethyl acetate and washed with water to pH 6.5–7.0. This protected N-methyl amino acid is used in solution-phase or fragment coupling of N-methylated peptide bond motifs, where the N-methyl group restricts backbone rotation and improves proteolytic stability of the final peptide. The resulting N-methyl amide bond is more resistant to saponification and displays slower cis-trans isomerization, which can be characterized by 1H NMR chemical shift splitting at 400 MHz. The main operational boundary is moisture sensitivity of sodium hydride; equipment must be nitrogen-inerted, and residual mineral oil is removed by hexane trituration. The final product is assayed by HPLC at 210 nm and by 1H NMR for the N-CH3 singlet in the region δ 2.8–3.0 ppm. Compliance uses ICH Q7 Section 12.3 for in-process controls and ICH Q3C(R8) for residual tetrahydrofuran and N,N-dimethylformamide; published data for production-scale tightness of this specific hydride slurry is limited.
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BOC-L-serine methyl ester is the N-α-tert-butoxycarbonyl-protected methyl ester of L-serine, identified by the chemical name (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-hydroxypropanoate and CAS registry number 2766-43-6. The compound has the linear formula C9H17NO5 and a molecular weight of 219.24 g/mol. It is supplied as a white to off-white crystalline powder and is used as a chiral building block in solution-phase peptide synthesis, in the preparation of modified amino acid esters for medicinal chemistry, and in the synthesis of oxazolidine, aziridine, and dehydroalanine intermediates. In contrast to L-serine methyl ester hydrochloride, the Boc-protected derivative carries a neutral carbamate shield at the α-amine, which suppresses premature N-functionalization and permits selective manipulation of the side-chain hydroxyl group. Commercial ordering is defined by the CAS registry number, linear formula, stereochemical prefix, and release specifications rather than by a single moulded-product model designation. The principal quality variables are chromatographic purity, enantiomeric purity, residual water, residual solvents, and storage stability.
Representative fine-chemical release specifications state an HPLC assay of not less than 98.0% area and an enantiomeric purity of not less than 99.0% for the L-isomer. A suitable procedure for assay and related-substance profiling uses a reversed-phase C18 column of 150 × 4.6 mm and 5 µm particle size, with a water/acetonitrile mobile phase containing 0.1% trifluoroacetic acid at 1.0 mL/min and UV detection at 210 nm. System suitability is assessed according to the chromatographic requirements of USP <621>. Enantiomeric purity is typically measured by chiral HPLC on an immobilized polysaccharide column, for example a 250 × 4.6 mm CHIRALPAK IA column, using an n-hexane/2-propanol mobile phase. Specific rotation data are reported at the sodium D line in methanol at 25 °C and should be interpreted according to USP <781>; the value is not sufficient as the sole identity test because traces of water, residual solvent, and partial ester hydrolysis alter the measured rotation.
| Parameter | Typical release criterion | Method |
|---|---|---|
| Appearance | White to off-white crystalline powder | Visual |
| Assay | ≥ 98.0% | RP-HPLC, USP <621> |
| Enantiomeric purity | ≥ 99.0% | Chiral HPLC |
| Loss on drying | ≤ 0.50% | Karl Fischer titration |
| Residual solvents | ICH Q3C Class 3 limits | Headspace GC |
| Storage | −20 °C under inert gas | Stability data |
Long-term storage should be at −20 °C under dry argon or nitrogen. If the relative humidity exceeds 60%, the powder should be equilibrated to ambient temperature inside a desiccator and used promptly after opening. Pre-drying under vacuum at room temperature is advisable only if the material is confirmed to be free of solvent and if the ester is not exposed to drying temperatures above 35 °C. The compound should not be stored in contact with basic desiccants, because the methyl ester is hydrolytically unstable in the presence of adsorbed water and alkali.
The methyl ester form is selected when a C-terminal carboxylate must remain masked during α-amine deprotection and subsequent chain elongation. Removal of the Boc group with 4 M hydrogen chloride in 1,4-dioxane or with trifluoroacetic acid in dichloromethane at 1:1 v/v containing triisopropylsilane produces the corresponding amine hydrochloride or trifluoroacetate while retaining the methyl ester. The acidic cleavage is exothermic; in a jacketed reactor the internal temperature should be held below 15 °C during addition, and the off-gas scrubber should be sized for carbon dioxide and isobutylene evolution. The resulting amine salt is then coupled to a protected amino acid using EDC·HCl and HOBt in DMF or dichloromethane at 0–4 °C. This route reduces the number of ionizable carboxyl groups in the coupling system compared with the use of Boc-L-serine itself, and it gives cleaner ethyl acetate or dichloromethane extracts after dilute bicarbonate washing; the extract can be assayed by HPLC to confirm that the methyl ester remains intact at >98% area after aqueous workup.
A process conflict exists during one-pot telescoped sequences because residual TFA from Boc cleavage lowers the pH of aqueous wash streams and accelerates methyl ester hydrolysis at the liquid–liquid interface. Complete acid removal by three successive cold aqueous sodium carbonate washes is therefore required before any prolonged aqueous standing. Racemization of the α-carbon is minimized by keeping the coupling temperature below 5 °C when the free amine is activated as an active ester in the presence of tertiary amines. The use of N-methylmorpholine rather than triethylamine is preferable in DMF-based systems because it reduces β-elimination of the serine side chain under basic conditions. Published data for the specific rate of racemization under all solvent combinations is limited, so chiral HPLC monitoring is recommended for batches above laboratory scale before process qualification.
The side-chain hydroxymethyl group of BOC-L-serine methyl ester can be acylated, sulfonylated, phosphorylated, or halogenated without disturbance of the α-amine and α-carboxyl protecting groups. Acylation with acetyl chloride in dichloromethane in the presence of triethylamine at 0 °C yields the O-acetyl derivative; the product remains extractable and can be purified by silica gel chromatography using ethyl acetate/hexane. The methyl ester is not compatible with strong aqueous hydroxide at ambient temperature, because saponification begins at pH above 10 and is accompanied by increasing α-carbon racemization and formation of dehydroalanine derivatives through β-elimination. For selective ester hydrolysis, lithium hydroxide in THF/water at 3:1 v/v and 0–5 °C is preferred, with the reaction quenched by cold phosphate buffer at pH 6.5 immediately after HPLC shows disappearance of the starting ester. The Boc group remains intact under these short hydrolysis windows but is cleaved by the same acid conditions used for final peptide deprotection. This orthogonality distinguishes the tert-butyloxycarbonyl system from Fmoc protection, which requires secondary-amine bases and is removed by piperidine rather than strong acid.
When side-chain activation is required for ring closure or displacement, the methyl ester form offers an advantage over the free acid because it avoids carboxylate coordination of metal reagents. Mesylation of the hydroxyl group with methanesulfonyl chloride in dichloromethane at −10 °C to 0 °C gives a chiral N-protected methyl ester sulfonate that can undergo nucleophilic displacement with azide or thiols. The reaction should be free of water and alcohol impurities, because the sulfonate is also susceptible to methanolysis and hydrolysis. The absence of residual methanol is determined by headspace GC before scale-up, and the sulfonate intermediate is typically carried directly into the next step without isolation to avoid thermal decomposition.
Relative to Boc-L-serine, the methyl ester is less hydrophilic and partitions more efficiently into ethyl acetate or dichloromethane during extractive workup, which reduces emulsion formation and shortens phase-separation times in stirred tanks. HPLC analysis after extraction typically shows no more than 5% loss of the ester to the aqueous phase when the final aqueous pH is kept between 6.5 and 7.5. Relative to L-serine methyl ester hydrochloride, the Boc-protected product has no free protonated amine and therefore cannot undergo premature acyl migration or salt metathesis under basic coupling conditions. This is particularly relevant when the material is used with organometallic reagents or with strong non-nucleophilic bases. Relative to the benzyl ester analogue, the methyl ester has a lower molecular weight and avoids palladium-catalysed hydrogenolysis for its removal, but it is more sensitive to alkaline hydrolysis. The benzyl ester remains the preferred derivative when the C-terminal mask must survive repeated aqueous bicarbonate washes or when final deprotection is conveniently performed by hydrogenation over palladium on carbon.
Chiral HPLC with an immobilized polysaccharide column resolves the L- and D-forms; elution order should be verified with an authentic reference standard because stationary-phase age and mobile-phase modifier content can affect retention. For applications where the side-chain configuration is critical, the certificate of analysis should report enantiomeric purity rather than only specific rotation, because specific rotation is not a linear indicator of low enantiomeric excess for this compound class. The D-enantiomer is handled separately, and even small enantiomeric crossover can alter downstream chiral purity in peptide intermediates.
At kilogram scale, the main processing bottleneck is not the peptide coupling itself but the removal of reaction by-products and the control of residual amide solvent. When EDC·HCl is used instead of DCC, the urea by-product is water-soluble and can be removed by acidic aqueous washing, whereas DCC produces dicyclohexylurea that requires cooling and filtration. In a 50 L glass-lined reactor, the EDC/HOBt coupling of the deprotected methyl ester is typically completed within 8–12 h at 0–5 °C, with the endpoint determined by HPLC disappearance of the amine starting material. The reactor jacket should maintain ±2 °C control during the exothermic activation step. Batch-to-batch variance in the starting material is most often observed as a change in water content, which alters the stoichiometry of carbodiimide coupling. Karl Fischer titration before charging is therefore mandatory at risk of incomplete conversion and difficult-to-remove active ester intermediates.
Residual solvents in commercial lots are evaluated against the limits in ICH Q3C. Methanol, dichloromethane, and ethyl acetate are the common process solvents for this product; acceptance concentrations follow the ICH Q3C Class 2 and Class 3 tables. For use in active pharmaceutical ingredient synthesis, the supplier should provide a TSE/BSE statement, and the product should be handled under local occupational exposure limits for fine powders. The compound is not a formulated pharmaceutical preparation and is not assigned a therapeutic indication; its regulatory status is that of a synthetic intermediate, and the user is responsible for qualification in the intended synthetic route under applicable good manufacturing practice requirements.
