| HS Code | 633359 |
| Chemical Name | DL-Alanine Methyl Ester Hydrochloride |
| Iupac Name | Methyl 2-aminopropanoate hydrochloride |
| Cas Number | 13515-97-4 |
| Ec Number | 236-858-4 |
| Mdl Number | MFCD00037362 |
| Molecular Formula | C4H9NO2·HCl |
| Molecular Weight | 139.58 g/mol |
| Appearance | White crystalline powder |
| Melting Point | 176-180 °C (decomposes) |
| Solubility | Soluble in water, methanol, and ethanol; sparingly soluble in ethyl acetate |
| Storage Conditions | Store at 2-8 °C in a sealed, cool, dry place; protect from moisture |
| Purity | ≥98% |
| Hygroscopicity | Hygroscopic |
| Optical Rotation | 0° (racemic DL mixture) |
| Salt Ratio | 1:1 (base:hydrochloride) |
| Smiles | Cl.CC(N)C(=O)OC |
As an accredited DL-alanine Methyl Ester Hydrochloride factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 25 g in a sealed glass bottle, white crystalline powder, labeled with purity and safety information. |
| Container Loading (20′ FCL) | Load 20′ FCL with palletized, sealed drums. Ensure container is dry, clean, and moisture-protected; secure cargo tightly. |
| Shipping | DL-alanine Methyl Ester Hydrochloride should be shipped in sealed, corrosion-resistant containers, protected from moisture and light. Use sturdy packaging with absorbent material. Transport via ground or air, avoiding extreme temperatures. Ensure compliance with local regulations, proper labeling, and handling as a mild irritant. |
| Storage | Store DL-alanine Methyl Ester Hydrochloride in a tightly sealed container under an inert atmosphere, protected from moisture and light. Keep in a cool, dry place, ideally refrigerated (2–8 °C) or frozen for long-term stability. Avoid exposure to humidity, acids, bases, and oxidizing agents. Ensure proper labeling and handling in a fume hood. |
| Shelf Life | Store sealed under inert atmosphere at 2–8°C, protected from moisture; shelf life typically two years. |
DL-alanine methyl ester hydrochloride (C4H10ClNO2, molecular weight 139.58 g/mol) is handled in cGMP synthesis as a bench-stable solid whose free base is liberated in situ before peptide bond formation. The hydrochloride counterion introduces an additional proton stoichiometry that is frequently underestimated in campaign design: the coupling base must neutralize 1.00 mol of HCl per mol of substrate before deprotonating the α-ammonium group, which is why total tertiary base demand rises to 2.00–2.20 mol/mol in carbodiimide-mediated systems. In a common cGMP sequence, the salt is charged into a glass-lined reactor at 20±5 °C, dissolved in anhydrous dimethylformamide at 0.3–0.8 M, and treated with N-methylmorpholine at 1.00–1.05 mol/mol relative to the hydrochloride. The coupling partner, typically an N-protected amino acid with benzyloxycarbonyl or tert-butoxycarbonyl protection, is introduced at 1.00–1.10 mol/mol relative to the alanine ester. Activation is performed with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 1-hydroxybenzotriazole hydrate at 1.00–1.20 mol/mol each. The reaction mass is held at 0–5 °C during the first 30–60 min of activation, after which the temperature is allowed to rise to 20±2 °C for 2–4 h. Aqueous workup is conducted with 0.5 M sodium bicarbonate and ethyl acetate, maintaining the aqueous phase at pH 6.5–7.5 to minimize methyl ester hydrolysis; the organic phase is washed with 0.1 M hydrochloric acid, dried over magnesium sulfate, and concentrated by vacuum distillation below 35 °C. Industrial lots have shown that if the pH exceeds 9.0 for more than 20 min, the methyl ester cleavage product can exceed 2.0 area% by HPLC, requiring rework. The relevant compliance framework for this operation is ICH Q7 §7.10 for material handling, ICH Q7 §8.10 for production operations, ICH Q11 Section 3.2 for process development and impurity control, and FDA 21 CFR 211.84 for component testing. The resulting output consists of carbamate-protected dipeptide and tripeptide fragments, racemic peptidomimetic intermediates, and high-purity processing impurities used in generic API process qualification. The hydrochloride form is preferred over the free base because the free base is hygroscopic and forms partial carbonate salts in ambient air, causing lot-to-lot variation in coupling conversion.
| Parameter | Set point | Method / equipment |
|---|---|---|
| Substrate concentration in DMF | 0.3–0.8 M | Glass-lined reactor, inline FTIR |
| Total tertiary base ratio | 2.00–2.20 mol/mol | Automatic pH/titration feedback |
| Activation temperature | 0–5 °C | Jacket thermocouple, PID control |
| Coupling completion window | 2–4 h | HPLC area%, C18 column |
| Aqueous workup pH | 6.5–7.5 | Calibrated pH electrode |
In the manufacture of amino acid-based anionic surfactants, DL-alanine methyl ester hydrochloride is converted to N-acylalaninates by a two-stage acylation–saponification sequence, with the hydrochloride salt fed directly into the aqueous phase to avoid handling the unstable free amine. A typical batch uses a jacketed stainless-steel or glass-lined reactor equipped with a bottom drain and an anchor agitator running at 30–60 rpm. The salt is charged with water to a final concentration of 15–25 wt%, and a C8–C16 fatty acid chloride is metered concurrently with 30 wt% aqueous sodium hydroxide. The molar addition ratio is controlled at 1.00–1.05 mol fatty acid chloride per mol of DL-alanine methyl ester hydrochloride; the sodium hydroxide is added to hold the reaction pH at 9.5–10.5. Higher pH drives the acyl chloride hydrolysis, while lower pH strips the free amine nucleophilicity, so the control band is deliberately narrow. The acylation temperature is maintained at 15–25 °C, and the fatty acid chloride addition is completed over 45–75 min. After acylation, the methyl ester is saponified by adding additional 1.05–1.15 mol of sodium hydroxide per mol of ester, heating the batch to 40–50 °C, and holding until the residual ester value falls below 5 mg KOH/g. The resulting N-acylalanine sodium salt is concentrated to 25–40% active matter and may be hydrogen peroxide bleached at 60–70 °C to reduce color. For personal care intermediates, the operation falls under ISO 22716 for cosmetic GMP and requires REACH registration under EC 1907/2006 Annex VII to X depending on annual tonnage; ready biodegradability is typically assessed by OECD 301F with a pass threshold of 60% BOD/COD. Terminal finished product types from this pathway include sodium cocoyl DL-alaninate, sodium lauroyl DL-alaninate, and potassium undecylenoyl alaninate, which are used in sulfate-free rinse-off cleansers, syndet bars, baby wash formulations, and low-foam industrial emulsifiers. A production-scale failure mode is the accumulation of fatty acid sodium soap, which raises the Gardner color and can be detected by GC-FID residual fatty acid chloride above 0.1%; this is managed by keeping the acyl chloride feed rate below 0.8 kg/min per 1000-L batch.
| Fatty acid chloride | Acylation temperature | Saponification time at 45±5 °C | Final active matter | pH at 25 °C |
|---|---|---|---|---|
| C8–C10 | 15–20 °C | 2–3 h | 25–30% | 9.0–9.8 |
| C12–C14 | 20–25 °C | 3–4 h | 30–35% | 9.2–10.0 |
| C16 | 22–25 °C | 4–5 h | 35–40% | 9.3–10.0 |
When chromatographic release methods must separate D- and L-alanine methyl ester derivatives, the DL hydrochloride is used as a racemic system-suitability marker because it supplies both enantiomers in a single crystalline charge. The standard solution is prepared at 0.1–2.0 mg/mL in methanol–water 50:50 v/v and is derivatized with N-(5-fluoro-2,4-dinitrophenyl)-L-alaninamide at 1.5–2.0 mol/mol relative to the amino ester, with 1.0–1.2 mol sodium bicarbonate per mol hydrochloride included to neutralize the counterion. Derivatization is carried out in a thermostatted autosampler vial at 40±2 °C for 60±5 min, followed by dilution with 0.1% trifluoroacetic acid in water. The sample is then injected onto a reversed-phase C18 column of dimensions 150 mm × 4.6 mm, 3 µm particle size, with mobile phase composed of 0.1% trifluoroacetic acid in water and acetonitrile, and detected at 340 nm by diode-array detector. For a method to be considered suitable, the racemic derivatization marker must show a resolution of at least 2.0 between the D and L derivative peaks, with tailing factor below 1.5 and relative standard deviation of peak area below 1.0% across 5 replicate injections. The QC laboratory operates under ISO/IEC 17025:2017 clause 7.2 for method validation and USP 621 for chromatographic system suitability; data are managed under ICH Q2(R1) guidelines for analytical procedure validation when the method supports API release. The addition ratio in this context is not a production formulation but a spiking and derivatization stoichiometry: standard solutions prepared outside the 1.5–2.0 mol/mol derivatization reagent window show incomplete labeling and split peaks. Terminal outputs include racemic reference standards, chiral method suitability kits, and re-certified working solutions used for retention time identity checks in peptide intermediate QC. The operational boundary is that aqueous stock solutions are stable for 7 days at 2–8 °C in amber vials; longer storage leads to free-base hydrolysis and a shift in the D/L area ratio.
Under reflux in anhydrous methanol, DL-alanine methyl ester hydrochloride can be cyclodimerized to 3,6-dimethylpiperazine-2,5-dione when the liberated primary amine is held at a sufficiently low protonation level. The substrate is suspended in methanol at a mass ratio of 8:1–12:1 solvent to salt, and triethylamine is added at 2.0–2.2 mol/mol; the first equivalent neutralizes the hydrochloride, while the remaining base promotes intramolecular aminolysis of the methyl ester. The mixture is heated to 60–65 °C for 4–6 h, with HPLC monitoring at 210 nm to confirm consumption of the starting methyl ester. If the methanol content drops below 5% during reflux through evaporative loss, the reaction shifts toward an acyclic oligomer byproduct, and the target diketopiperazine yield can fall below 75%. The crude product is cooled to 0–5 °C, filtered, and triturated with cold isopropanol to remove triethylamine hydrochloride; typical isolated purity after vacuum drying at 50 °C for 6 h is 98.0–99.0 area%. Compliance for sale of the diketopiperazine intermediate follows REACH EC 1907/2006 Annex VII for registration and may require ISO 9001:2015 batch release documentation when supplied to agrochemical and pharmaceutical synthesis campaigns. Terminal product types from this route include substituted 2,5-diketopiperazine building blocks, N-alkylated piperazine-2,5-dione derivatives, and chiral resolution substrates used in early-stage crop protection and pharmaceutical lead synthesis. This is a narrower production route than the peptide coupling path, but it is used where the methyl ester group is retained as an activating leaving group and the hydrochloride salt avoids the need for separate methyl ester isolation.
Once automated solid dispensing has delivered DL-alanine methyl ester hydrochloride to the parallel reactor block, the salt is suspended in dichloromethane at 0.5–1.0 M, and a substituted carboxylic acid is coupled using a carbodiimide at 1.0–1.2 mol/mol relative to substrate. Diisopropylethylamine is added at 2.0–2.3 mol/mol to neutralize both the hydrochloride and the carboxylic acid proton; water is added as a co-solvent at 5–10 vol% to dissolve the tertiary ammonium salts without hydrolyzing the methyl ester. The reaction is held at 0–10 °C for the first 30 min, then warmed to 23±2 °C for 12–18 h, with agitation provided by a 96-position parallel reactor block. Workup is conducted by automated liquid–liquid extraction using 0.5 M sodium bicarbonate and dichloromethane, followed by solvent removal in a centrifugal evaporator at 35 °C. The resulting methyl esters are either screened directly as hydrolytically stable pro-herbicide candidates or converted to amides and hydrazides for greenhouse screening. Compliance for these non-registered intermediates follows REACH EC 1907/2006 for substance manufacture and ISO 9001:2015 for batch traceability; the final test articles are handled under OECD 423 acute toxicology when advanced beyond in vitro screens. Terminal products are substituted N-acyl alanine methyl esters, alanine-derived amides, and hydrazide intermediates for early-stage fungicide and herbicide lead synthesis. The limiting process parameter is the water content of the reaction block: at relative humidity above 60% during storage, the salt gains surface moisture that biases dispense mass by up to 2% and produces variable coupling conversion across first and last rows of the array.
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DL-alanine methyl ester hydrochloride, systematic name methyl 2-aminopropanoate hydrochloride, corresponds to the empirical formula C4H10ClNO2, a formula weight of 139.58 g/mol, and CAS registry designation 13515-97-4. The substance is supplied as a white to off-white crystalline solid and is released in technical, synthesis, and high-purity grades that differ principally in assay, water content, residual methanol, and heavy-metal limits. A typical synthesis-grade certificate specifies assay ≥98.0% on the anhydrous basis, chloride content 24.8–25.5%, loss on drying ≤0.50%, residue on ignition ≤0.10%, and optical rotation between −0.5° and +0.5° measured at 589 nm in methanol. As the protonated methyl ester of racemic alanine, the product is a non-volatile ionic solid used for achiral amidation, hydrazinolysis, heterocycle assembly, and analytical derivatization. It is not interchangeable with enantiopure L-alanine methyl ester hydrochloride in peptide synthesis, because the racemic amine introduces both configurations and generates racemic or diastereomeric products. Compared with the free base, which is a liquid that self-condenses on standing, the hydrochloride provides defined stoichiometry, solid-phase handling, and a longer unopened shelf life under desiccant.
The racemic character imposes a process boundary wherever chiral enrichment, asymmetric induction, or enantiomeric identity is required. In peptide coupling, the DL salt introduces L and D configurations at the same amine position; downstream chiral HPLC or capillary electrophoresis then must resolve the resulting diastereomers or enantiomers. Release systems therefore specify the material as a racemate rather than an enantiopure intermediate, with optical rotation limited to a narrow band around zero. For achiral building blocks—racemic alanine-derived amides, hydrazides, pyrazinones, and quaternary ammonium derivatives—the racemic composition is not a defect. The same racemate may serve as a substrate in enzyme-catalyzed kinetic resolution. In a pH-stat reactor, the hydrochloride is neutralized to free base before lipase- or protease-catalyzed hydrolysis, and continuous addition of dilute sodium hydroxide maintains the reaction medium between pH 7.0 and 7.8; if the pH falls below this band, chloride accumulation stabilizes the protonated amine and reduces conversion. Published data for this specific configuration is limited, but the observed rate loss in conventional amino acid ester hydrolysis systems is consistent with pH depletion rather than enzyme inactivation at these chloride concentrations. The DL salt also cannot be used in asymmetric hydrogenation or organocatalytic processes that rely on a single enantiomer; for such routes, the L or D salt is mandatory.
Procurement specifications are commonly built around the CAS registry and release criteria rather than a universal product model number. Commercial grades include a technical grade at ≥95.0% for non-pharmaceutical intermediates, a synthesis grade at ≥98.0% for custom manufacturing, and a high-purity grade at ≥99.0% with reduced residual metal and solvent content for controlled laboratories. Supplier-specific model names may distinguish granular, milled, and low-dust forms; a milled grade with D90 ≤ 250 µm is used in automated solid charging systems, whereas the standard crystalline grade is appropriate for manual weighing. Residual DL-alanine, DL-alanine hydrochloride, and chloride salts are the principal solid impurities controlled by ion chromatography and silver-ion titration.
Release testing for the synthesis grade uses the following acceptance criteria and instrumentation.
| Parameter | Specification | Method / Equipment |
|---|---|---|
| Appearance | White to off-white crystalline powder | Visual inspection, D65 daylight booth |
| Assay (anhydrous) | ≥98.0% | Potentiometric titration with 0.1 mol/L perchloric acid in glacial acetic acid |
| Chloride content | 24.8–25.5% | Argentometric titration with 0.1 mol/L silver nitrate, potassium chromate indicator |
| Loss on drying | ≤0.50% | Vacuum oven 60°C, 4 h, ≤10 mmHg |
| Water | ≤0.20% | Coulometric Karl Fischer, USP <921> Method Ia |
| Residue on ignition | ≤0.10% | Muffle furnace 600 ± 50°C, USP <281> |
| Methanol | ≤3000 ppm | Headspace GC-FID, ICH Q3C Class 2 |
| Elemental impurities | Pb ≤10 mg/kg; As ≤3 mg/kg | ICP-MS after microwave digestion, USP <232>/<233> |
| Optical rotation | −0.5° to +0.5° (c=1, methanol, 589 nm, 20°C) | Automatic polarimeter |
On production-scale filling lines, residual water is the main batch-to-batch variable. Material exposed to ambient humidity for more than 30 min during drum filling can exceed the ≤0.20% water criterion and require vacuum drying before release. For moisture-sensitive downstream operations, pre-drying at 50°C under ≤10 mmHg for 4 h is considered mandatory before N-acylation with acid chlorides or coupling with moisture-sensitive organometallic reagents. Particle size distribution is not normally a release parameter unless automatic dispensing is specified; however, caking under compression can increase the D90 and requires mechanical delumping before use.
The hydrochloride is hygroscopic. Open-dish exposure at 25°C and 60% relative humidity produces visible surface wetting and caking within 24–72 h; above 80% relative humidity, deliquescence can form a localized aqueous layer that accelerates acid-catalyzed methyl ester hydrolysis to alanine hydrochloride. Recommended bulk storage is 2–8°C in high-density polyethylene drums with double polyethylene liners and a desiccant pouch. Extended storage above 30°C is not advised. If water content rises above 0.50%, vacuum drying at 50°C can often recover the material without assay loss, provided hydrolysis has not progressed; once free water is present, the methyl ester hydrolyzes under proton catalysis, shifting mass balance toward amino acid hydrochloride and methanol. Thermal stability is limited by salt decomposition rather than ester volatility. Prolonged heating above 80°C can produce discoloration in some batches, and melting point values reported on supplier certificates vary with scanning rate and particle size; a single universal melting range is therefore not used for release. Published data for this specific configuration is limited.
Industrial preparation typically begins with racemic alanine, methanol, and hydrogen chloride. In a conventional esterification, the amino acid is charged to a glass-lined reactor with 3–5 mol equivalents of methanol and 1.0–1.2 mol equivalents of hydrogen chloride gas, then held at 20–40°C until the liquid chromatographic area for alanine falls below the acceptance threshold. Water is removed by azeotropic distillation or by adding thionyl chloride as a dehydrating agent. When thionyl chloride is used, sulfur dioxide and residual hydrogen chloride are routed through a caustic scrubber before discharge. The product crystallizes from the cooled reaction mixture; centrifugation followed by vacuum drying under inert gas gives the hydrochloride. Drying is the critical kinetic bottleneck: product containing more than 1.0% water forms hard lumps in the dryer, while over-drying can generate static charge and dusting. The racemic route does not require chiral raw material or simulated moving-bed chromatography, which is a key cost difference from the L and D salts.
In a 500 L glass-lined reactor equipped with a retreat-curve agitator and PTFE baffles, the hydrochloride is suspended in dichloromethane and cooled to 0–5°C before addition of triethylamine or diisopropylethylamine. The free base partitions into the organic phase at pH 8.5–9.0; washing below pH 8.0 leaves protonated material in the aqueous layer and lowers recovery. For mixed-anhydride amidation, the neutralized methyl ester is added to an anhydride prepared from the carboxylic acid and ethyl chloroformate in the presence of N-methylmorpholine at −10°C. The addition rate is controlled to maintain internal temperature below 0°C because the acylation exotherm can overshoot and promote ester cleavage under basic conditions. For carbodiimide-mediated coupling, the hydrochloride can be used directly if the tertiary amine is added before the coupling reagent; adding the coupling reagent first converts the carboxyl component to an O-acylisourea that reacts poorly with the suspended salt. In reductive amination, the free base is generated in tetrahydrofuran with diisopropylethylamine, the aldehyde is added, and sodium triacetoxyborohydride is charged in portions at 0–5°C; direct reduction without neutralization slows imine formation and increases the alcohol byproduct from aldehyde reduction. These process limitations do not apply to the isolated free base; however, the free base is a lachrymatory liquid with limited storage stability, which is the principal reason the hydrochloride is specified for large batch operations.
The salt form is compared with the enantiopure hydrochloride salts in the following process-selection table.
| Product form | CAS registry | Physical form at 25°C | Chiral specification | Typical use boundary |
|---|---|---|---|---|
| DL-alanine methyl ester hydrochloride | 13515-97-4 | Crystalline solid | Racemic, optical rotation −0.5° to +0.5° | Achiral amides, hydrazides, heterocycles; kinetic resolution substrate |
| L-alanine methyl ester hydrochloride | 2491-20-5 | Crystalline solid | Chiral purity ≥99.0% by chiral HPLC | Peptide coupling; asymmetric synthesis |
| D-alanine methyl ester hydrochloride | 14316-06-4 | Crystalline solid | Chiral purity ≥99.0% by chiral HPLC | D-peptide and antibiotic building blocks |
For an achiral target, the L and D salts are chemically equivalent to the DL salt but carry stricter chiral release testing and are typically more expensive per kilogram. Conversely, a chiral peptide synthesis using the DL salt produces epimeric impurities that are difficult to purge by recrystallization because the methyl ester hydrochloride salts of the formed peptides often have similar solubility profiles. Where process chromatography is available, the DL salt may be used in early synthetic exploration; in registered manufacturing routes, the enantiopure salt is normally required when optical purity is a critical quality attribute.
Available safety data sheets classify the hydrochloride as a skin and eye irritant; the specific H-phrases vary by regional inventory and residual solvent profile. The product is intended for chemical manufacturing and laboratory synthesis, not for direct pharmaceutical, food, or cosmetic use. Under REACH, registration obligations apply at ≥1 t/a unless the strictly controlled intermediate exemption is met under the applicable conditions. Residual methanol is controlled under ICH Q3C as a Class 2 solvent when downstream pharmaceutical intermediates are targeted. Incompatibilities include strong aqueous bases, which release heat and free base; acid chlorides and anhydrides, which can react before the amine is neutralized; and nitrite ions in acidic solution, which decompose the amino group with gas evolution. Spills are collected with dry chemical absorbents rather than water-washing to prevent the water-soluble salt from entering drains. Bulk handling equipment should be stainless steel or glass-lined; carbon steel is avoided because wet material and chloride ion can initiate pitting corrosion.
For bulk supply, the product is typically packed in 25 kg high-density polyethylene drums with double polyethylene liners and is stored under nitrogen or with silica gel. Smaller packaging is available in 1 kg and 5 kg fluorinated polyethylene bottles for laboratory process development. Automated dispensing lines may require a controlled particle size distribution or flow additive; if a flow additive is used, it must be specified on the certificate of analysis because it dilutes assay and affects downstream stoichiometry. The material is not classified as flammable as a solid, but thermal decomposition products should be assumed to include hydrogen chloride and nitrogen oxides; local exhaust ventilation is therefore applied at charge ports and drying equipment.
