| HS Code | 609482 |
| Product Name | DL-Tryptophan Methyl Ester Hydrochloride |
| Cas Number | 14907-27-8 |
| Molecular Formula | C12H15ClN2O2 |
| Appearance | White to off-white crystalline powder |
| Melting Point | 218-220 °C (dec.) |
| Solubility | Soluble in water, methanol, ethanol, DMF |
| Purity | ≥98% |
| Optical Rotation | 0° (racemic mixture) |
| Storage Conditions | Store in a cool, dry place, under inert gas, protected from light |
| Synonyms | H-DL-Trp-OMe·HCl; DL-Tryptophan methyl ester hydrochloride |
| Smiles | COC(=O)C(N)Cc1c[nH]c2ccccc12.Cl |
As an accredited DL-Tryptophan Methyl Ester Hydrochloride factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | Sealed amber glass bottle containing 25 g of DL-Tryptophan Methyl Ester Hydrochloride, with desiccant, tamper-evident cap, and labeled purity information. |
| Container Loading (20′ FCL) | 20′ FCL container loading: 20-foot full container load, palletized, secured, dry powder chemical, non-hazardous, sealed for ocean transport. |
| Shipping | Ship DL-Tryptophan Methyl Ester Hydrochloride in sealed, moisture-resistant containers at ambient temperature, away from light and strong oxidizers. Use standard non-hazardous ground or air freight with proper labeling. Ensure packaging prevents dust exposure and protects against humidity. No special temperature control required. |
| Storage | Store DL-Tryptophan Methyl Ester Hydrochloride in a tightly sealed container in a cool, dry, well-ventilated area, protected from light and moisture. Keep away from strong oxidizing agents, acids, and incompatible materials. Ensure the workspace is clean and accessible only to trained personnel, following all safety and handling regulations. |
| Shelf Life | Shelf life is typically 2–3 years when stored cold, dry, and protected from light and moisture. |
Neutralization of DL-tryptophan methyl ester hydrochloride with tertiary amine under anhydrous conditions precedes its use as a C-terminal building block in solution-phase peptide coupling. In 10–15 volumes of dichloromethane or tetrahydrofuran, the hydrochloride is treated with N,N-diisopropylethylamine at 0–5 °C until free-base pH measured on wet pH paper remains below 8.5; this threshold is critical because higher alkalinity accelerates oxazolone formation at the tryptophan α-carbon and increases epimerization above 2.0 %. The neutralized ester is then added to a coupling system comprised of Fmoc- or Cbz-protected amino acid, N,N′-diisopropylcarbodiimide, and 1-hydroxybenzotriazole hydrate in a 1.0:1.0:1.0 molar ratio, with the tryptophan ester charged at 1.05–1.15 mol per 1 mol activated carboxyl component to compensate for residual moisture and salt effects. Compliance for peptide active pharmaceutical ingredient manufacture invokes ICH Q7 Section 5.4 for starting material qualification, ICH Q7 Section 7.3 for production operation control, ICH Q3C for residual solvent limits, and USP <467> for solvent residues in the isolated product. Once coupling reaches >98.5 % conversion by high-performance liquid chromatography, the organic layer is washed with 5 % sodium hydrogen carbonate solution and 0.1 M potassium hydrogen sulfate solution, dried over sodium sulfate, and concentrated. If terminal free acid is required, the methyl ester is hydrolyzed with 1.0–1.2 mol/L lithium hydroxide in tetrahydrofuran–water at 0–5 °C over 2–4 h; the racemic nature of the feedstock requires preparative chiral chromatography or diastereomeric crystallization if an enantiopure peptide API is the target. Equipment on production lines includes glass-lined reactors with bottom drain, jacketed temperature control from −10 °C to +25 °C, and inline pH meters; batch-to-batch variance in epimerization is minimized by maintaining moisture below 0.05 % and controlling addition time of the coupling agent over 45–90 min. Terminal finished products generated through this route include linear tryptophan-containing peptide active pharmaceutical ingredients, cyclic peptide precursors, and backbone-modified peptide fragments for further conjugation.
DL-Tryptophan methyl ester hydrochloride is used as the indole-bearing 1,2-dinucleophile in acid-catalysed Pictet-Spengler condensation with aromatic aldehydes to form tetrahydro-β-carboline intermediates. In a representative pilot-scale sequence for PDE5 inhibitor-related intermediates, the hydrochloride salt is suspended in 10–15 volumes of methanol, and piperonal is added at 1.05–1.20 mol per 1 mol tryptophan methyl ester hydrochloride; methanesulfonic acid or hydrochloric acid is then charged at 2–5 mol equivalents to generate the iminium intermediate and catalyse 6-exo-trig cyclisation. Heating is controlled at 60–70 °C for 6–12 h under nitrogen, with conversion monitored by HPLC/UV at 220 nm and process control requiring ≤2.0 % residual aldehyde before cooling. Racemic feedstock yields a mixture of cis and trans product diastereomers; when a single enantiomer is required downstream, the reaction is run with enantiopure D-tryptophan methyl ester hydrochloride or chiral resolution is introduced after cyclisation. The major process conflict arises from acid strength: insufficient acid below 2 equivalents leaves uncyclised Schiff base, while excess acid above 5 equivalents promotes indole sulfonation and N-methyl ester hydrolysis. Compliance includes ICH M7 for mutagenic impurity risk assessment, ICH Q3D for elemental impurities, ISO 9001:2015 clause 8.5.1 for production control, and REACH Article 14 for chemical safety assessment in European supply chains. Terminal finished products include tetrahydro-β-carboline hydrochloride intermediates, chiral diastereomeric salts, and downstream phosphodiesterase-5 inhibitor APIs after saturation and amide formation. The table below summarizes representative parameter windows from pilot-scale campaigns; published data for the DL form under all solvent combinations is limited, and each lot requires design-of-experiment verification.
| Process parameter | Boundary window | Critical impurity trend |
|---|---|---|
| Piperonal input | 1.05–1.20 mol/mol | Excess aldehyde increases oxidation by-products above 2.0 % |
| Acid catalyst | 2–5 mol/mol | Below 2 mol/mol uncyclised imine; above 5 mol/mol ester hydrolysis |
| Reaction temperature | 60–70 °C | Above 70 °C indole ring degradation increases |
| Residual aldehyde at quench | ≤2.0 % | Higher residual aldehyde carries into final crystallisation |
Diastereomeric salt resolution of DL-tryptophan methyl ester hydrochloride is carried out in pharmaceutical intermediate plants when enantiopure D-tryptophan methyl ester hydrochloride is required for stereospecific downstream condensation. The racemate is dissolved in 8–12 volumes of ethanol–water at 85:15 v/v and 55–65 °C, and a chiral acid such as dibenzoyl-D-tartaric acid is added at 0.5–1.2 mol per 1 mol racemate; the exact ratio depends on whether a mono- or bis-salt is targeted and on competing crystallisation of the opposite diastereomer. The batch is cooled at a controlled rate of 0.1–0.5 °C/min to 0–5 °C in a baffled glass-lined crystalliser equipped with retreat-curve impeller and bottom discharge to minimize shear-induced secondary nucleation. After 8–16 h maturation, the crystalline diastereomeric salt is filtered, washed with cold ethanol–water, and recrystallized to reach enantiomeric excess above 99.0 % by chiral high-performance liquid chromatography. The salt is decomposed with 1.0 mol/L sodium hydroxide at 0–5 °C, and the free base is re-acidified with hydrogen chloride in isopropanol to yield D-tryptophan methyl ester hydrochloride; the mother liquor retains the L-enantiomer for subsequent recovery. Compliance drivers include ICH Q7 Section 9.1 for processing, ICH Q6A decision tree #5 for chiral impurity specification, and European Pharmacopoeia general method 2.2.31 for chromatographic separation. Terminal finished products include enantiopure D-tryptophan methyl ester hydrochloride for PDE5 inhibitor synthesis and L-tryptophan methyl ester hydrochloride for peptide API and research reagent pipelines. Operational boundaries require water content above 10 % to be avoided during salt formation because it reduces diastereomeric solubility difference and broadens particle size distribution; particle size distribution is typically monitored by laser diffraction, with the fraction below 10 µm controlled to <10 % to prevent downstream filtration blinding.
DL-Tryptophan methyl ester hydrochloride is converted to N-acetyl-DL-tryptophan methyl ester for use as a substrate in esterolytic protease activity measurements. Acetylation is performed in aqueous tetrahydrofuran at 0–5 °C with acetic anhydride added at 1.05–1.3 mol per 1 mol amine under Schotten-Baumann conditions; pH is held at 8.0–8.5 by automatic titration with 2 mol/L sodium hydroxide, and the exotherm is controlled by jacket cooling because the acetylation enthalpy can raise the batch temperature by 8–12 °C if addition is faster than 30 min. The resulting N-acetyl derivative is extracted into ethyl acetate, dried over sodium sulfate, concentrated, and crystallized from n-heptane–ethyl acetate; residual free amine is controlled to <0.5 % by acid-base titration. Diagnostic reagent manufacturers formulate the substrate at 0.5–2.0 mmol/L in 50 mmol/L Tris-HCl buffer, pH 8.0, containing 10 mmol/L calcium chloride; esterase activity is monitored by pH-stat titration or by the decrease in absorbance at 280 nm after a 30 min equilibration at 25 °C. Compliance for these reagent intermediates falls under ISO 13485:2016 clause 7.5.2 for production controls and CLSI EP05-A3 for precision testing when the formulation is used in quantitative clinical laboratory applications; if sold as research-use-only, the product label must clearly exclude FDA 21 CFR 809.10(b) diagnostic claims. Terminal finished products include esterase activity assay kits, pancreatic enzyme function diagnostic intermediates, and protease screening reagents used in pharmaceutical development laboratories.
Loading of DL-tryptophan methyl ester hydrochloride onto 2-chlorotrityl chloride resin is used to prepare peptide methyl ester fragments that retain a C-terminal ester through acidolytic cleavage. The hydrochloride is suspended in anhydrous dichloromethane at 10–15 mL/g resin, and N,N-diisopropylethylamine is added at 1.2–1.5 mol per 1 mol resin active chloride; the mixture is agitated for 12–18 h at 20–25 °C in a glass solid-phase synthesis vessel with overhead stirring, then residual active chloride is capped with methanol. When the loading is complete, the resin displays a substitution range of 0.4–0.9 mmol/g determined by UV absorbance of the fulvene-piperidine adduct; batch-to-batch substitution variance is controlled by moisture exclusion below 0.05 % and by preconditioning the resin with 1,2-dichloroethane. The process differs from standard Fmoc-SPPS because the C-terminal methyl ester remains on the substrate after acidic cleavage with 20 % trifluoroacetic acid in dichloromethane for 30 min at room temperature; this creates C-terminal peptide methyl ester fragments that are then coupled to other protected fragments or hydrolysed to free acids under immobilized lipase catalysis. Compliance for pharmaceutical peptide fragment production includes ICH Q7 Section 7.3 for process control and ICH Q3C for residual solvents; if the fragment enters a finished peptide API under US FDA jurisdiction, 21 CFR 210.3(b)(4) definitions apply to the starting material chain. Terminal finished products include peptide methyl ester fragments for fragment condensation, C-terminal modified peptides, and resin-bound tryptophan intermediates used in peptide library synthesis. Published data for the DL methyl ester on 2-chlorotrityl resin are limited relative to the L-form, so pilot-scale loading studies are required before committing to commercial batches.
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DL-Tryptophan methyl ester hydrochloride is the racemic hydrochloride salt of methyl 2-amino-3-(1H-indol-3-yl)propanoate, with molecular formula C12H14N2O2·HCl and molecular weight 254.71 g·mol−1. The descriptor “DL” specifies an approximately 50:50 mixture of D- and L-tryptophan-derived ester enantiomers, not a single stereoisomer. Because the carboxyl group is blocked as a methyl ester and the α-amine is protonated as the hydrochloride, the material is supplied as a white to off-white crystalline powder that can be introduced into non-aqueous coupling systems after in situ neutralization. No ISO or pharmacopoeial model designation exists; the product is identified by structural descriptor and supplier catalogue code, typically “DL-Trp-OMe·HCl” or “H-DL-Trp-OMe·HCl.” Procurement documents should therefore specify the racemic descriptor, molecular formula, and assay method rather than relying on a model number alone. The methyl ester hydrochloride is distinct from DL-tryptophan free base and from enantiopure L- or D-tryptophan methyl ester hydrochlorides in three operational respects: carboxyl protection, salt stoichiometry, and chiral composition.
Commercial release specifications are generally harmonized around HPLC assay, chloride content, loss on drying, and residual solvent limits. The theoretical chloride content is 13.92% w/w, calculated from the molecular weight and chloride anion; a specification band of 13.5–14.4% w/w by argentometric titration is common. HPLC assay at 220 nm or 280 nm on a C18 column is used because the indole chromophore provides strong absorbance; an area-percent limit of ≥98.0% is typical for synthetic-grade material, while peptide-synthesis batches may require ≥99.0%. Loss on drying is controlled at ≤0.50% when dried at 105 °C to constant weight, although vacuum drying at 60 °C is preferred to reduce indole oxidation. Specific rotation should be 0°±0.5° in methanol at 20±0.5 °C using the sodium D-line; a non-zero value outside this band indicates enantiomeric contamination or resolution failure. Published data for specific pharmacopoeial monograph coverage of the DL form is limited; users should treat supplier COA methods as the controlling document.
| Parameter | Typical specification | Reference method |
|---|---|---|
| Appearance | White to off-white crystalline powder | Visual inspection under ICH Q6A decision tree |
| HPLC assay | ≥98.0% area at 220 nm | RP-HPLC, C18 150×4.6 mm, 5 µm; water–acetonitrile with 0.1% TFA |
| Chloride content | 13.5–14.4% w/w | Argentometric titration after dilution in 50% methanol/water |
| Loss on drying | ≤0.50% | 105 °C to constant weight or vacuum at 60 °C |
| Enantiomeric ratio | D:L 48:52–52:48 | Chiral HPLC with cellulose tris(3,5-dimethylphenylcarbamate) column |
| Residual solvents | Methanol ≤3000 ppm; diethyl ether ≤5000 ppm | HS-GC per Ph. Eur. 5.4 and ICH Q3C |
| Elemental impurities | Per ICH Q3D Option 1 limits | ICP-MS after microwave digestion |
No uniform pharmacopoeial monograph governs the DL racemate, so the above values represent a typical commercial compliance matrix rather than a harmonized regulatory specification. Batch release should require a certificate of analysis that reports the actual HPLC method, chiral method, and residual solvent conditions because column selectivity and sample preparation can change the apparent purity by 0.2–0.5% area.
On pilot scale, DL-tryptophan is suspended in anhydrous methanol at a solids loading of 0.8–1.2 mol·L−1 in a glass-lined reactor. Thionyl chloride is added at 1.1–1.3 molar equivalents relative to tryptophan, with the addition rate controlled to keep the internal temperature below 10 °C during the initial exothermic phase. The mixture is then heated to reflux, typically 60–65 °C at ambient pressure, and held for 18–24 h under nitrogen. Evolution of sulfur dioxide and hydrogen chloride requires caustic scrubbing or a packed vent absorber; direct atmospheric discharge is incompatible with workplace exposure limits for HCl and SO2. After reaction, the solution is filtered hot if a small amount of unreacted DL-tryptophan remains suspended. The filtrate is concentrated under reduced pressure at a jacket temperature no higher than 45 °C, because prolonged heating of the hydrochloride salt in methanol can generate colored indole oxidation by-products. The residue is reslurried in cold diethyl ether or methyl tert-butyl ether, isolated on a Nutsche filter, and dried under vacuum at 40–50 °C to a moisture endpoint below 0.5% w/w. Batch-to-batch color variation is most commonly traced to oxygen ingress during vacuum concentration, residual thionyl chloride, or use of recycled methanol containing dissolved iron; a nitrogen purge through the reactor dip tube during reflux reduces this variability on a 500–2000 L line. Published process data for the DL racemate at commercial scale are limited; the described ranges are consistent with standard protected amino acid esterification practice and require site-specific qualification.
In solution-phase peptide coupling, the protonated α-amine is neutralized before activation. A tertiary amine such as N-methylmorpholine or diisopropylethylamine is added at 2.0–2.2 equivalents relative to the hydrochloride, giving a free amine that can react with an activated acyl donor. The methyl ester masks the C-terminus, preventing oligomerization at that position and allowing selective C-terminal deprotection later by alkaline hydrolysis with lithium hydroxide in tetrahydrofuran/water. Because the indole nitrogen is not protected, coupling conditions are normally kept below 0.5% w/w water and below 25 °C when using carbodiimide/oxyma systems to reduce racemization and indole alkylation. The choice of DL rather than L changes the stereochemical outcome: any downstream peptide or alkaloid built from this building block is racemic unless resolution is performed.
Primary amine acylation is the most common consumption route. The hydrochloride is dissolved in dichloromethane or DMF, neutralized, and treated with an activated ester or acid chloride at 0–5 °C; triethylamine dosage is 1.0–1.2 equivalents relative to acid chloride to avoid indole N-acylation. If the pH is allowed to rise above 9.5 or if strong acylating agents are present in large excess, the indole nitrogen can compete, producing N-acylated or N-alkylated tryptophan derivatives that reduce yield. Reductive amination with aldehydes is performed after salt neutralization; sodium cyanoborohydride or sodium triacetoxyborohydride is used at 1.5–3.0 equivalents in dichloroethane or methanol, with pH adjusted to 5–6 using acetic acid. The methyl ester survives these conditions but is not stable to strong aqueous alkali above pH 12 for extended periods. The compound is not a direct coupling reagent; it is a protected amino acid intermediate. Its use in solid-phase peptide synthesis is less common than Fmoc-Trp(Boc)-OH because the C-terminus is already blocked and the α-amine is salt-bound, but it is used in solution-phase fragment condensations and in the synthesis of tryptamine natural products and indole alkaloid precursors.
Compared with L-tryptophan methyl ester hydrochloride, the DL material has the same molecular weight, the same salt stoichiometry, and similar solubility in methanol, but the chiral composition is fundamentally different. In a coupling route intended for an enantiopure active pharmaceutical ingredient, substitution of the DL methyl ester produces a racemic intermediate that cannot be corrected by routine workup; preparative chiral chromatography or diastereomeric salt resolution is then required. Supply chain documentation should therefore include chiral HPLC area ratios, not only achiral HPLC assay. The L-form is listed under CAS 7524-52-9; the DL racemate is commonly supplied under structural descriptor and supplier registry codes, and the CAS should be verified with the certificate of analysis. Compared with DL-tryptophan free base, the methyl ester hydrochloride is substantially more soluble in water and polar aprotic solvents because the zwitterionic free amino acid structure has been disrupted; the free base remains largely insoluble in non-polar media and requires prior esterification before use in non-aqueous coupling.
| Attribute | DL-Tryptophan methyl ester HCl | L-Tryptophan methyl ester HCl | DL-Tryptophan free base |
|---|---|---|---|
| Chiral composition | Approximately 50:50 D/L; specific rotation near 0° | Single L-enantiomer; positive specific rotation | Racemic; no ester protection |
| Carboxyl group | Methyl ester blocked | Methyl ester blocked | Free acid |
| Amine state | HCl salt; requires neutralization | HCl salt; requires neutralization | Zwitterionic; low reactivity in non-aqueous media |
| Water solubility | High, due to salt and ester | High, due to salt and ester | Low; limited in non-polar solvents |
| Common use | Racemic peptide intermediate or alkaloid precursor | Enantiopure peptide synthesis | Raw material for esterification or amino acid derivatives |
| Critical release test | Chiral HPLC plus assay | Enantiomeric purity plus assay | Assay and residual solvents |
The DL methyl ester hydrochloride also differs from N-protected tryptophan esters such as Boc-DL-Trp-OMe or Fmoc-DL-Trp-OMe in that the α-amine is available for direct coupling after neutralization. This reduces step count when a free amine is required, but it introduces a salt-removal step and makes the amine susceptible to competing protonation under acidic conditions. The indole nitrogen remains unprotected in all three forms, so reactions requiring selective indole modification must be designed to avoid α-amine interference.
Because the hydrochloride is hygroscopic, handling at relative humidity above 60% leads to water absorption and potential agglomeration during dispensing. The material should be stored in sealed double polyethylene bags inside a fiber drum at 2–8 °C or 15–25 °C according to supplier label; refrigerated storage reduces indole discoloration but requires equilibration to room temperature before opening to prevent condensation. Weighing operations should be performed in a fume hood with local exhaust or a balance enclosure, using nitrile gloves and dust mask. Contact with strong bases releases free amine and can generate heat; contact with strong oxidizing agents such as hydrogen peroxide or peracids can oxidize the indole ring. Aqueous solutions at 10–50 g·L−1 should be used within 24 h when stored at 2–8 °C under nitrogen, because slow hydrolysis of the methyl ester can occur at higher pH. The hydrochloride is a chemical intermediate, not a pharmaceutical dosage form, and occupational exposure limits have not been established; users should apply local risk assessment and engineering controls consistent with the quantities handled.
