| HS Code | 814742 |
| Product Name | L-Tryptophan Methyl Ester Hydrochloride |
| Cas Number | 7524-52-9 |
| Molecular Formula | C12H15ClN2O2 |
| Appearance | White to off-white crystalline powder |
| Melting Point | 218-220°C (decomposition) |
| Solubility | Soluble in water, methanol, ethanol, and DMSO |
| Optical Rotation | [α]20/D = +18.0 to +22.0° (c=1 in methanol) |
| Purity | ≥98% (by HPLC) |
| Storage Conditions | Store at 2-8°C, tightly sealed, protected from light |
| Physical Form | Solid |
| Hygroscopicity | Hygroscopic |
As an accredited L-Tryptophan Methyl Ester Hydrochloride factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 25 g packaged in a sealed glass bottle with desiccant, labeled with purity, CAS number, and handling precautions. |
| Container Loading (20′ FCL) | 20′ FCL: L-Tryptophan Methyl Ester Hydrochloride loaded in sealed, clean container, drums/boxes secured, protected from moisture and contamination. |
| Shipping | L-Tryptophan Methyl Ester Hydrochloride should be shipped in sealed, moisture-proof containers to prevent degradation. Avoid exposure to excessive heat, humidity, and light. While typically non-hazardous for transport, standard temperature-controlled packaging is recommended for purity preservation. Proper labeling and documentation ensure safe, regulatory-compliant delivery. |
| Storage | Store L-Tryptophan Methyl Ester Hydrochloride in a tightly sealed container under an inert atmosphere, protected from light and moisture. Keep refrigerated at 2–8 °C in a cool, dry, well-ventilated area, away from heat, flames, and incompatible materials such as strong oxidizing agents. Ensure the container is properly labeled and regularly checked to maintain stability. |
| Shelf Life | Store below +30°C. Shelf life is 24 months when unopened, protected from moisture and light. |
L-Tryptophan methyl ester hydrochloride is handled as a carboxyl-protected indole-bearing amino acid synthon where the methyl ester blocks the C-terminal carboxyl function and the hydrochloride stabilizes the primary amine against uncontrolled acylation or oxidation. The salt is preferred for storage because the free amine is unstable under humid ambient conditions; the hydrochloride is nevertheless hygroscopic and requires vacuum drying at 40°C for 12 h when ambient RH exceeds 60%. Reactors used for neutralization and coupling are nitrogen-purged and shielded from light to limit indole ring oxidation. The applications below cover liquid-phase peptide coupling, tetrahydro-β-carboline synthesis through Pictet-Spengler condensation, reduction to L-tryptophanol, enzymatic ester cleavage, and N-acetylation. Downstream compliance for intermediates used in pharmaceutical campaigns follows ICH Q7 for documentation, USP <467> for residual solvent testing, and ICH Q3C for solvent limits.
In liquid-phase peptide synthesis, L-Trp-OMe·HCl is charged as the C-terminal synthon. In a 100 L glass-lined reactor, 1.0 equiv is dissolved in 8–10 volumes DMF, cooled to 0–5°C, and neutralized with 2.2 equiv N-methylmorpholine over 15 min. The exotherm from neutralization and subsequent EDC activation must keep the batch below 5°C; excursions above 10°C can induce diketopiperazine formation when the methyl ester is in the presence of a free primary amine. Fmoc-Xaa-OH 1.05 equiv, HOBt monohydrate 1.1 equiv, and EDC hydrochloride 1.1 equiv are then added. The coupling mass is held at 20–25°C for 6–12 h. In-process control uses HPLC at 220 nm on a C18 column; area normalization for Fmoc-Xaa-Trp-OMe is set at ≥ 95.0%, while residual L-Trp-OMe is kept ≤ 0.5% in validated campaigns. On completion, the batch is quenched into 1 M hydrochloric acid, washed with 5% sodium bicarbonate and brine, dried over anhydrous sodium sulfate, and solvent-exchanged into MTBE. Crystallization at 0–5°C for 8 h gives the protected dipeptide methyl ester. Residual solvent compliance follows USP <467> and ICH Q3C; DMF and DCM limits are 880 ppm and 600 ppm, respectively. Because the indole ring can undergo acid-catalyzed oxidation, prolonged exposure to pH below 1.0 during work-up is avoided.
| Activation system | Charge ratio relative to L-Trp-OMe·HCl | Temperature window | Critical process control |
|---|---|---|---|
| EDC·HCl / HOBt monohydrate / NMM | 1.1 / 1.1 / 2.2 | 20–25°C | Maintain pH 8.0–8.5 during coupling; avoid primary amine contact before neutralization |
| HBTU / DIEA | 1.05 / 2.5 | 0–5°C to 20°C | Dissolve in DMF; add base last to limit over-activation and oxazolone formation |
Where chiral pool access to tetrahydro-β-carboline scaffolds is required, the methyl ester hydrochloride is condensed with an aldehyde under acid catalysis. In a jacketed 50 L reactor under nitrogen, L-Trp-OMe·HCl 1.0 equiv is suspended in dichloromethane–trifluoroacetic acid 9:1 v/v at 0°C. An aldehyde such as benzaldehyde is added at 1.2 equiv over 30 min, and the mass is warmed to 20–25°C for 18–24 h. The reaction is monitored by chiral HPLC on a polysaccharide-based column; the mobile phase is n-hexane–ethanol–trifluoroacetic acid with UV detection at 254 nm. The methyl ester remains on the tetrahydro-β-carboline scaffold, allowing subsequent amidation or ester hydrolysis. Diastereomeric ratios are system-dependent; published data for this exact substrate–aldehyde configuration is limited, so each aldehyde must be validated against isolated markers. The resulting tetrahydro-β-carboline ester is used in alkaloid intermediate synthesis and in the preparation of chiral 1,2,3,4-tetrahydro-β-carboline acid building blocks. Work-up quenches TFA with 20% aqueous sodium carbonate to pH 8.0, then extracts into dichloromethane and distills under vacuum below 40°C to preserve the indole ring. Residual TFA is controlled by 19F NMR or ion chromatography; acceptance is typically ≤ 0.1% w/w in the isolated oil.
For synthesis of L-tryptophanol, L-Trp-OMe·HCl 1.0 equiv is dissolved in THF–ethanol 1:1 v/v at 0–5°C. Sodium borohydride 2.2 equiv and lithium chloride 2.0 equiv are charged in portions; the reactor is allowed to reach 20–25°C and stirred for 12–18 h under nitrogen. Quenching with 1 M hydrochloric acid at 0–5°C stops hydride carryover and cleaves borate esters. The product is extracted into ethyl acetate after adjusting the aqueous phase to pH 9.0 with sodium hydroxide. Vacuum distillation below 45°C yields L-tryptophanol as an oil, which may be isolated as the oxalate salt. Chiral purity of L-tryptophanol is confirmed by HPLC with a chiral column; the acceptance threshold is typically ≥ 98.0% enantiomeric excess. The amino alcohol is then used as a chiral ligand or as a building block for indole-derived oxazolines and imidazolines. Published production-scale data for this exact reduction is limited; laboratory batch data indicate that moisture above 0.5% w/w in the starting ester reduces hydride efficiency and must be controlled by prior vacuum drying.
Enzymatic methyl ester cleavage is used where L-tryptophan free base is required without acid-promoted indole degradation. The hydrochloride is neutralized to pH 6.5–7.0 with dilute sodium hydroxide and incubated with an immobilized esterase in a packed-bed reactor at 30–35°C. Methanol generated during hydrolysis is removed under vacuum below 40°C to shift equilibrium. The resulting L-tryptophan is crystallized from water at pH 5.5–6.0 and dried. This route offers a selective deprotection path for peptide synthesis campaigns where the methyl ester hydrochloride was used as a protected intermediate and the final target is the free amino acid. Enzyme loading and residence time must be validated for the specific immobilized carrier; published data for this specific substrate is limited.
Exhaustive acylation of the amino function is run in dichloromethane with acetic anhydride and pyridine. L-Trp-OMe·HCl 1.0 equiv is suspended in DCM at 0–5°C; pyridine 2.5 equiv is added, followed by acetic anhydride 1.1 equiv dropwise. The batch is warmed to 20–25°C and held for 4–6 h. Quenching with water, washing with 1 M hydrochloric acid and 5% sodium bicarbonate, and drying yields N-acetyl-L-tryptophan methyl ester. The product is used as a protected amino acid intermediate and as an esterase substrate where selective hydrolysis releases the free acid for assay readout. Residual acetic acid is controlled below 0.5% w/w by vacuum stripping at 40°C; residual pyridine is controlled according to ICH Q3C limits for pharmaceutical intermediates. This acylation route preserves the methyl ester for downstream coupling or hydrolysis and avoids unprotected primary amine storage degradation.
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L-Tryptophan methyl ester hydrochloride, CAS 7524-52-9, molecular formula C12H14N2O2·HCl, and formula weight 254.71 g mol−1, is supplied as a white to off-white crystalline solid. The material is also designated L-Trp-OMe·HCl in peptide-synthesis catalogues. Commercial model descriptors are not harmonized; typical entries distinguish the hydrochloride salt from the free-base methyl ester and from N-protected derivatives by catalogue suffix and by the analytical release method rather than by a pharmacopeial monograph. A supplier description may read “≥98.0% by HPLC” or “peptide synthesis grade,” but such descriptors are not a substitute for batch-specific certificate-of-analysis data because the substance has no USP, Ph. Eur., or JP monograph. Supplier product codes generally append an acid-salt suffix to the base ester catalogue number; the free-base methyl ester and the hydrochloride salt are not interchangeable in inventory systems because the salt has a different CAS registry number and formula weight.
The hydrochloride is the preferred physical form when the free-base methyl ester is not easily isolated or stored as a dry solid. Protonation of the α-amine suppresses atmospheric autoxidation and yields a crystalline salt that is easier to charge, weigh, and blend in subsequent reactions. The salt is hygroscopic above roughly 60% relative humidity; containers should be resealed under dry nitrogen and stored at 2–8 °C or lower over desiccant. The ester group is stable in the approximate pH window of 3 to 7. Strongly alkaline aqueous solutions promote saponification to L-tryptophan, while strongly acidic exposure can cleave the ester and can oxidize the indole ring during prolonged contact. Avoid storage or processing with strong oxidizers, concentrated strong acids, and aqueous bases above 0.1 mol L−1 unless the specific hydrolytic half-life has been established for the intended process.
The release profile centers on moisture, chemical purity, and enantiomeric identity because residual water and non-tryptophan impurities alter coupling stoichiometry. A representative acceptance set includes the following.
On a production line, moisture excursion is a more common batch-rejection cause than low chromatographic purity. Drums should not be opened under uncontrolled humidity, and single-use aliquots under argon reduce repeated Karl Fischer sampling. A batch that exceeds the water limit during storage should be quarantined rather than automatically re-dried; vacuum drying at moderate temperature can remove surface water, but thermal treatment above 60 °C is generally avoided because indole degradation discolors the batch and creates impurities that confuse later HPLC release. If a vendor CoA does not report enantiomeric purity, a chiral HPLC method using an amylose or cellulose tris(3,5-dimethylphenylcarbamate) column should be added because the achiral assay does not separate D-tryptophan methyl ester from the L-isomer.
L-Tryptophan methyl ester hydrochloride is not directly reactive as an amine nucleophile; the α-ammonium must be deprotonated in situ. In anhydrous N,N-dimethylformamide at 0–5 °C, a slight excess of N-methylmorpholine (1.05–1.10 equivalents) or N,N-diisopropylethylamine is added before the coupling reagent. Direct addition of the salt to a carbodiimide-mediated activation without pre-neutralization consumes base, lowers pH, and slows acylation. Pilot-scale campaigns often show that the neutralization operation, rather than the coupling itself, controls isolated yield because poor mixing can leave an oily free-base layer on reactor internals. After neutralization, the methyl ester can be coupled to N-protected amino acids with carbodiimide/HOBt, uronium, or phosphonium reagents under the usual anhydrous conditions. The indole N-H is generally tolerated in carbodiimide/HOBt systems at low temperature, but strongly acylating reagents, long activation times, or temperatures above 20 °C can produce indole N-acylation by-products. Racemization at the Cα position is managed by limiting activation time and avoiding excess base; the achiral HPLC method will not detect D-enantiomer, so chiral HPLC or derivatization is required for enantiopurity verification.
Process solutions should be blanketed with nitrogen and protected from light when held for more than a few hours. Oxidative discoloration from white to yellow or brown is a sign of indole degradation; such material should not be carried forward unless preparative HPLC demonstrates that the required purity and intact ester functionality are maintained. The methyl ester can be deprotected by saponification with lithium hydroxide in tetrahydrofuran/water at low temperature; this step must be quenched promptly to avoid overhydrolysis to L-tryptophan and to minimize racemization at the newly exposed acid.
Relative to L-tryptophan free acid, the methyl ester hydrochloride removes the carboxylate anion and thereby changes solvent compatibility. The free acid is a zwitterion with low solubility in neutral organic solvents; the ester salt is readily soluble in methanol, N,N-dimethylformamide, and dimethyl sulfoxide, and moderately soluble in water after dissolution. This difference determines its use in solution-phase peptide sequences in which the carboxyl terminus must be masked to prevent salt formation or uncontrolled oligomerization. Compared with L-tryptophan ethyl ester hydrochloride, the methyl ester has a lower molecular weight and reduced lipophilicity, and it elutes earlier on reversed-phase columns under equivalent gradient conditions. Direct comparative long-term stability data for the methyl and ethyl ester salts are limited; solvent compatibility, chromatographic retention, and final deprotection behavior therefore drive selection rather than a published stability hierarchy.
The unsubstituted methyl ester hydrochloride is chosen when the target molecule does not require the C5 phenolic oxygen present in 5-hydroxy-L-tryptophan methyl ester hydrochloride. The 5-hydroxy analogue introduces an additional oxidative coupling pathway and requires stricter oxygen exclusion; the unsubstituted indole avoids that redox complexity. The unprotected hydrochloride is not a substitute for N-Boc-L-tryptophan methyl ester or N-Fmoc-L-tryptophan methyl ester in Fmoc solid-phase peptide synthesis because the amino group is not orthogonally protected. If inserted into an Fmoc-SPPS protocol without prior N-protection, the protonated amine remains unreactive under acidic activation conditions. Conversely, solution-phase routes that generate the free amine in situ and consume it immediately benefit from the salt’s direct availability and the absence of a carbamate deprotection step. The hydrochloride is also not suitable when the N-terminus must remain masked during strongly acidic transformations; Boc, Fmoc, or Cbz protection should be installed first.
The hydrochloride salt is incompatible with strong oxidizing agents, sulfur-containing strong electrophiles, and halogenating acids, which can attack the indole C2/C3 positions. When neutralized, the free amine should not be stored as a process hold because it can revert to the hydrochloride by carbon dioxide uptake, discolor, or participate in self-condensation. In multi-step syntheses, the methyl ester should be introduced after any step that requires aqueous caustic or long residence time at high pH, because ester hydrolysis will compete with the desired transformation. Forced-air drying above 60 °C is not recommended; if drying is required, use vacuum desiccation over phosphorus pentoxide or a drying oven with a nitrogen purge and a gentle temperature ramp not exceeding 40 °C.
Because the material has no pharmacopeial monograph, users in regulated synthesis must qualify the supplier method and establish that residual solvent, elemental impurity, and mutagenic impurity profiles are suitable for the intended stage. The product is typically released as a fine chemical or peptide-synthesis intermediate; its use as an active pharmaceutical ingredient or in sterile manufacturing requires additional qualification.
