| HS Code | 797915 |
| Product Name | L-Valine Ethyl Ester Hydrochloride |
| Cas Number | 17609-47-1 |
| Molecular Formula | C7H15NO2·HCl |
| Molecular Weight | 181.66 g/mol |
| Mdl Number | MFCD00038867 |
| Ec Number | 241-583-1 |
| Appearance | White crystalline powder |
| Melting Point | 240-242 °C (dec.) |
| Solubility | Soluble in water, methanol, and ethanol |
| Purity | ≥98% (HPLC) |
| Storage Conditions | Store at 2-8 °C in a sealed, dry container |
| Smiles | CCOC(=O)[C@@H](N)C(C)C.Cl |
As an accredited L-Valine Ethyl Ester Hydrochloride factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 25 g of L-Valine Ethyl Ester Hydrochloride in a sealed glass bottle, labeled with purity, storage conditions, and safety hazards. |
| Container Loading (20′ FCL) | One 20-foot FCL container loaded with L-Valine Ethyl Ester Hydrochloride in sealed drums, safely secured and documented for transport. |
| Shipping | L-Valine Ethyl Ester Hydrochloride should be shipped in sealed, corrosion-resistant containers, protected from moisture and light. Avoid exposure to heat, acids, and oxidizing agents. Use proper labeling, secure packaging, and standard transport procedures to prevent leakage. Ensure compliance with hazardous goods regulations if applicable. |
| Storage | Store L-Valine Ethyl Ester Hydrochloride in a tightly sealed container under inert gas, protected from moisture and light. Keep refrigerated (2–8°C) in a cool, dry, well-ventilated area. Avoid contact with strong oxidizing agents and acids. Ensure the container is properly labeled and opened only under dry conditions to maintain stability and purity. |
| Shelf Life | Shelf life is typically 12–24 months when stored tightly sealed, refrigerated, and protected from moisture. |
L-Valine ethyl ester hydrochloride is used as a C-terminal-protected L-valine building block in solution-phase peptide manufacturing, not as the free amino acid. The hydrochloride salt is moisture-sensitive: at relative humidity above 60%, the solid absorbs water and the ethyl ester undergoes hydrolysis. Before charging, the material is vacuum-dried at 40°C for 4 h or until Karl Fischer moisture is below 0.3% w/w. In the coupling vessel, the hydrochloride is not pre-released to the free amine, because the free amino ester is unstable and prone to diketopiperazine formation; it is neutralized in situ with N,N-diisopropylethylamine at 2.0–2.4 eq relative to the hydrochloride salt. The N-protected peptide acid is pre-activated separately with N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride at 1.1–1.3 eq and 1-hydroxybenzotriazole monohydrate at 1.0–1.2 eq in anhydrous N,N-dimethylformamide or dichloromethane. The peptide acid is activated at 0–5°C for 15–30 min; the hydrochloride salt is then added. The typical charge ratio is 1.0–1.2 eq of L-valine ethyl ester hydrochloride to 1.0 eq of N-protected peptide acid. After coupling, the organic phase is washed with 5% w/v citric acid and 8% w/v sodium bicarbonate, dried, and concentrated at a jacket temperature below 40°C to avoid ethyl ester cleavage. Alkaline saponification of the ethyl ester is performed only after peptide bond formation, using aqueous sodium hydroxide at 1.1–1.3 eq in methanol/water at 10–20°C. Compliance is governed by ICH Q7 chapters 7, 12, and 18; 21 CFR 210/211; ICH Q3C(R8); ICH Q3D; and Ph. Eur. method 2.2.29 for enantiomeric purity. Terminal product types are C-terminal valine peptide fragments and peptide APIs produced by hybrid fragment condensation; after ester cleavage, the peptide acid is lyophilized or converted to acetate or hydrochloride salts according to the downstream formulation.
In valsartan-type API synthesis, L-valine ethyl ester hydrochloride supplies the chiral L-valine backbone before the tetrazole-biphenyl side chain is attached. The first step is N-alkylation of the neutralized amine with 4-(bromomethyl)-2′-cyanobiphenyl. The hydrochloride salt is suspended in dimethylformamide at 8–12 mL/g; anhydrous potassium carbonate is charged at 2.0–3.0 eq, and the alkylating agent is charged at 1.05–1.2 eq. The batch is heated to 65–75°C and monitored by HPLC until the residual L-valine ethyl ester hydrochloride peak is below 2.0% area. The critical process limit is 75°C: above this point, N,N-dialkylation and ester hydrolysis both accelerate. The N-alkylated intermediate is then acylated with valeryl chloride at 1.1–1.3 eq in dichloromethane at 0–5°C, using 1.1–1.4 eq of DIPEA as hydrogen chloride scavenger. Residual valeric acid is removed by aqueous bicarbonate wash before tetrazole ring closure. Tetrazole formation is conducted with sodium azide at 1.3–1.5 eq and zinc chloride at 1.0–1.2 eq in toluene at 110–115°C; when tin-based azide reagents are substituted, the charge is 1.1–1.3 eq and the thermal profile is identical. Final ester hydrolysis uses sodium hydroxide at 1.2–1.5 eq in methanol/water at 20–35°C. Compliance is anchored to ICH Q3A/B, ICH Q3C(R8), ICH Q3D, and ICH M7 for azide-related mutagenic risk; the final API must meet the USP Valsartan monograph and the Ph. Eur. Valsartan monograph. Terminal finished product types are valsartan API, valsartan/hydrochlorothiazide fixed-dose combination tablets, and other sartan-series intermediates where the same N-acyl-L-valine ester route is applied.
| Control point | Impurity class | Standard or guideline | Typical release limit |
| Dimethylformamide after alkylation | Residual solvent | ICH Q3C(R8) Class 2 | 880 ppm |
| Dichloromethane after acylation | Residual solvent | ICH Q3C(R8) Class 2 | 600 ppm |
| Sodium azide-derived reactive impurity | Mutagenic/reactive impurity | ICH M7 threshold of toxicological concern | 1.5 µg/day |
| Palladium and zinc after tetrazole/ring closure | Elemental impurities | ICH Q3D | per ICH Q3D Option 1 |
Sodium borohydride and lithium chloride are charged into a jacketed glass-lined reduction vessel at 2.0–4.0 mol per mol of L-valine ethyl ester hydrochloride and 2.0–4.0 mol per mol, respectively, in tetrahydrofuran/ethanol (4:1 v/v). The hydrochloride salt is fed gradually below 25°C because the initial reduction exotherm is rapid; the batch is then warmed to 50–60°C and held for 3–6 h. The reduction target is L-valinol, the β-amino alcohol. Overcharging sodium borohydride above 4.0 mol produces deaminated hydrocarbon byproducts, while lithium chloride below 2.0 mol leaves unreacted ester. After quenching with 10% v/v acetic acid and extracting into dichloromethane, the valinol is converted to chiral oxazolines by condensation with nitrile or imidate partners under acid catalysis. The product class is C2-symmetric bisoxazoline ligands and monoxazoline-phosphine ligands used in asymmetric catalysis. The compliance framework is non-pharmacopoeial: REACH EU 1907/2006, CLP EU 1272/2008, OSHA 29 CFR 1910.1200, and ISO 9001:2015. Terminal finished product types are chiral ligands supplied to pharmaceutical intermediate manufacturers; these ligands are used in asymmetric hydrogenation and cyclopropanation reactions that produce single-enantiomer intermediates for APIs. Published batch data for specific ligand yields in this configuration is limited, but the reduction-to-valinol step is common industrial practice.
Production of N-benzyloxycarbonyl-L-valine for antiviral L-valyl ester prodrugs starts from L-valine ethyl ester hydrochloride rather than free L-valine because the protected ester intermediate can be isolated without ion-exchange workup. In the Schotten-Baumann protection step, the hydrochloride is suspended in aqueous tetrahydrofuran and treated with benzyl chloroformate at 1.05–1.3 eq while pH is maintained at 8.0–9.0 with 20% w/v sodium carbonate at 0–5°C. The resulting N-benzyloxycarbonyl-L-valine ethyl ester is extracted and then saponified with sodium hydroxide 1.05–1.2 eq in methanol/water at 10–20°C. The isolated N-benzyloxycarbonyl-L-valine is activated with carbonyldiimidazole at 1.2–1.4 eq in dichloromethane and coupled with the antiviral nucleoside alcohol; hydrogenolysis with 5% w/w palladium on carbon at 0.5–0.8 bar hydrogen pressure then removes the protecting group. Incompatibility: the carbonyldiimidazole activation stream must be kept below 0.1% w/w water, or the activated intermediate hydrolyzes. Compliance standards include ICH Q7, 21 CFR 210/211, ICH Q3C(R8), ICH M7, and the USP Valacyclovir Hydrochloride or Valganciclovir Hydrochloride monographs. Terminal finished product types are oral antiviral tablets and capsules containing valacyclovir hydrochloride or valganciclovir hydrochloride, including 250 mg, 500 mg, and 1000 mg label-strength solid dosage forms.
For asymmetric phase-transfer applications, quaternary ammonium salts with a chiral L-valine scaffold are prepared from L-valine ethyl ester hydrochloride through exhaustive alkylation and quaternization. The hydrochloride salt is dissolved in acetonitrile; potassium carbonate is charged at 3.0–4.0 eq, and methyl iodide is added at 2.0–2.2 eq. The alkylation is held at 35–40°C for 16–24 h to form the N,N-dimethyl tertiary amino ester. After solvent exchange into toluene, arylmethyl bromide is added at 1.05–1.2 eq and the batch is heated at 80–90°C for 8–12 h to complete quaternization. The resulting chiral quaternary ammonium bromide is purified by recrystallization from ethyl acetate/2-propanol and dried at 50°C under vacuum. This product class is used as a chiral phase-transfer catalyst for asymmetric α-alkylation of glycine Schiff bases. Compliance is non-pharmacopoeial: REACH EU 1907/2006, CLP EU 1272/2008, and ISO 9001:2015. Terminal finished product types are enantioselective phase-transfer catalysts supplied to fine-chemical and pharmaceutical intermediate manufacturers producing nonproteinogenic α-amino acid intermediates for small-molecule APIs.
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L-Valine ethyl ester hydrochloride is a carboxyl-protected amino acid salt supplied as a white to off-white crystalline powder. The product has the molecular formula C7H15NO2·HCl and a formula weight of 181.66 g/mol. It is commonly indexed as CAS 17609-47-1 and carries the IUPAC name ethyl (2S)-2-amino-3-methylbutanoate hydrochloride. Commercial model designations are based on assay and moisture content: a standard reagent grade is typically released at ≥98.0% by HPLC, while a low-water peptide synthesis grade is released at ≥99.0% with water ≤0.3%. The hydrochloride form is used in solution-phase peptide construction because it suppresses the free-amine volatility and handling losses associated with the neutral ethyl ester. The salt is neutralized in situ with a tertiary amine, permitting selective N-acylation while the carboxyl terminus remains protected as the ethyl ester.
No dedicated monograph for L-valine ethyl ester hydrochloride appears in USP or Ph. Eur.; supplier specifications are therefore adapted from compendial general chapters. The following profile is representative of commercial peptide synthesis grades. Residual solvent reporting follows ICH Q3C and USP 467.
| Parameter | Typical range or limit | Method reference |
|---|---|---|
| Appearance | White to off-white crystalline powder | Visual |
| Assay (anhydrous basis) | 98.0%–101.0% | Non-aqueous titration or HPLC per USP 621 |
| Specific optical rotation | +14.5° to +16.5° (c=2, ethanol, 20 °C) | USP 781 / Ph. Eur. 2.2.7 |
| Loss on drying | ≤0.5% | USP 731 |
| Water (Karl Fischer) | ≤0.3% | USP 921 Method 1a |
| Residue on ignition | ≤0.1% | USP 281 |
| Enantiomeric impurity | D-valine ethyl ester hydrochloride ≤0.5% | Chiral HPLC with UV 210 nm |
| Residual solvents | Ethanol ≤5000 ppm; other Class 3 solvents per ICH Q3C | USP 467 / Ph. Eur. 2.4.24 |
Commercial lots may contain valine ethyl ester free base as a minor impurity due to incomplete salt formation; this species is quantified by the reversed-phase purity method as a separate peak. Chloride content is monitored by argentometric titration with silver nitrate 0.1 N and a limit of 95.0%–105.0% of theoretical. Residual water in the peptide synthesis grade is set at ≤0.3% because Karl Fischer titration is performed on a 0.1 g sample with a blank-corrected drift endpoint. The optical rotation specification is applied to the dried substance and controls both enantiomeric excess and salt stoichiometry; incorrect drying can shift the measured rotation because ethanol of crystallization may be present in certain lots.
The hydrochloride is freely soluble in water, methanol, and ethanol; it is sparingly soluble in ethyl acetate and hexane. During process charging, the salt is added to a pre-cooled mixture of dichloromethane or N,N-dimethylformamide and a tertiary base such as N-methylmorpholine or N,N-diisopropylethylamine. The neutralization exotherm is controlled at 0–5 °C, and the free amine is acylated within 30–60 min to minimize standing losses. Because the free ester is often obtained as a low-melting solid or oil, the crystalline hydrochloride is the practical isolated form for weighing and reactor charging. Moisture must be kept below 0.3% before carbodiimide- or uronium-mediated couplings; residual water consumes the activating reagent and depresses isolated yield. Elevated pH above 8.5 during workup accelerates ester hydrolysis, so liquid-liquid extractions are conducted with saturated aqueous sodium bicarbonate rather than stronger alkali where possible.
In multistep peptide segment synthesis, the ethyl ester salt is used to prepare C-terminal valine building blocks that remain protected during amide bond formation and subsequent N-terminal deprotection. The ester is removed by saponification with lithium hydroxide in tetrahydrofuran/water at 0 °C to 20 °C; alternatively, hydrogen chloride in ethyl acetate cleaves the tert-butyloxycarbonyl group without disturbing the ethyl ester. The choice of this product over the free acid depends on the need for organic-solvent solubility and selective C-terminal protection in solution-phase routes.
L-Valine free base is a zwitterionic solid with low solubility in chlorinated and ethereal reaction solvents. The ethyl ester hydrochloride after in situ neutralization dissolves readily in dichloromethane, tetrahydrofuran, and N,N-dimethylformamide, allowing homogeneous peptide coupling and N-protection. The methyl ester hydrochloride has a lower formula weight of 167.63 g/mol, but the ethyl ester provides greater steric resistance to saponification; this difference is useful when a C-terminal methyl ester would be cleaved too rapidly during basic aqueous workup. The ethyl ester is removed by saponification in aqueous tetrahydrofuran containing 1.0–1.5 M lithium hydroxide at 0–20 °C, generating ethanol rather than methanol as the volatile alcohol by-product. Ethanol is assigned to ICH Q3C Class 3 with a 5000 ppm general limit, simplifying residual solvent reconciliation in regulated intermediates.
| Property | L-Valine ethyl ester hydrochloride | L-Valine methyl ester hydrochloride | L-Valine free base |
|---|---|---|---|
| Formula weight | 181.66 g/mol | 167.63 g/mol | 117.15 g/mol |
| Physical state at 20–25 °C | Crystalline solid | Crystalline solid | Crystalline solid |
| Solubility in DMF/DCM after neutralization | High | High | Low |
| C-terminal protection | Ethyl ester | Methyl ester | Not protected |
| Relative base hydrolysis rate | Lower than methyl ester | Higher than ethyl ester | Not applicable |
| Typical use | Solution-phase C-terminal protection | Solution-phase C-terminal protection | Direct coupling without carboxyl protection |
In pharmaceutical intermediate synthesis, L-valine ethyl ester hydrochloride is used to prepare chiral auxiliaries and valine-derived oxazolidinones. Treatment with phosgene or triphosgene under Schotten-Baumann conditions yields the corresponding N-carboxyanhydride after cyclization; this use requires strict pH control at 10.0–10.5 and rapid removal of hydrogen chloride. The product is also used in the synthesis of valine-derived ketones, amides, and sulfonamides for medicinal chemistry. Because the ester is a protected carboxylate, it remains compatible with reductive amination and amine alkylation conditions that would otherwise form carboxylate salts with free valine.
In pilot-scale batches run in 100 L to 500 L glass-lined reactors, the hydrochloride is charged through a solids addition port into a nitrogen-blanketed solvent/base mixture. Jacket temperature is held at 0–5 °C during free-basing, and the coupling reagent is added only after complete dissolution to avoid localized high pH and racemization. When 1.0–1.1 equivalents of N,N-diisopropylethylamine are used, the internal pH remains below 8.0 during the critical first 15 min of activation. Failure to control this window leads to detection of the D-isomer by chiral HPLC at levels above 0.5% and requires rework by recrystallization. Process descriptions for this specific intermediate are limited in public literature; the operational boundaries stated here are derived from common peptide manufacturing practices rather than a single published campaign.
In solution-phase peptide coupling, the carboxyl component is typically N-Boc-L-valine or N-Fmoc-L-valine, and the amino component is the free amine derived from L-valine ethyl ester hydrochloride. The hydrochloride is free-based with N,N-diisopropylethylamine (1.0–1.1 equivalents) in anhydrous N,N-dimethylformamide at 0 °C. The electrophilic coupling reagent HATU or HBTU is charged as a pre-dissolved solution in DMF to avoid solid reagent agglomeration. Carbodiimide-mediated coupling with 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole remains used where cost constraints limit uronium reagents. A key process conflict is the simultaneous presence of free amine and water: water competes with the amino group for the activated ester and consumes carbodiimide. The reaction is therefore run under a nitrogen atmosphere with solvent water content ≤0.01% by Karl Fischer. Typical coupling conversion reaches ≥97% by HPLC after 12 h at 20 °C; if conversion stalls below 95%, a second charge of 0.1 equivalents of coupling reagent is made, and the mixture is re-analyzed before workup.
After coupling, the reaction is quenched with 5% citric acid at 0–5 °C to remove unreacted base. The ethyl ester is stable under these acidic workup conditions, while tert-butyl ethers or tert-butyl esters would undergo partial cleavage. The organic phase is washed with 5% sodium bicarbonate to remove residual acid; this wash must be rapid because the ethyl ester hydrolyzes measurably above pH 8.5. The combined organic phase is dried over magnesium sulfate and concentrated at ≤35 °C under reduced pressure. Rotary evaporation above 45 °C can cause thermal elimination or decomposition of the ethyl ester hydrochloride in the presence of residual mineral acid. Crystallization from ethyl acetate/hexane yields the N-protected dipeptide ester as a solid.
The enantiomeric impurity D-valine ethyl ester hydrochloride is resolved on derivatized polysaccharide chiral stationary phases using n-hexane/ethanol/trifluoroacetic acid mobile phases; detection is at 210 nm. A specification of ≤0.5% D-isomer is typical because downstream peptide APIs can retain diastereomeric contamination through recrystallization. Reversed-phase purity is monitored on a C18 column with a phosphate buffer at pH 3.0 and acetonitrile; the method separates the free ester from valine and N-protected impurities. Residual chloride content is verified by argentometric titration or ion chromatography to confirm salt stoichiometry.
In-process control for free-base formation is performed by TLC on silica gel 60 F254 using ethyl acetate/heptane (1:1); ninhydrin staining reveals residual free amine. The limit of detection for the free amine is 0.1% relative to the N-protected product. Chiral method linearity has been qualified over the range 0.05%–1.0% for the D-isomer; the correlation coefficient is ≥0.999 and the limit of quantitation is 0.05%. When the material is shipped in fiber drums with polyethylene liners and silica gel desiccant, the moisture content remains below 0.3% for 24 months when stored at 2–8 °C; published data for longer storage under high-humidity conditions are limited.
The salt is stored at 2–8 °C under inert gas. Differential scanning calorimetry of amino acid ester hydrochlorides commonly shows an endothermic melt followed by decomposition; for this compound, supplier certificates of analysis should be consulted for the exact melting range because published thermal data vary. The hydrochloride is less volatile than the free amino ester but is hygroscopic under high relative humidity. Transfer in open vessels above 60% relative humidity can increase water content and promote ester hydrolysis. Bags should be resealed under nitrogen after each withdrawal, and bulk bins should be kept in a dry room maintained at ≤40% relative humidity. No oxidative instability of the valine side chain is expected, but the free amine generated by neutralization can discolor if left exposed to air for extended periods.
Compatibility boundaries must be observed when combining the free amine with strong acylating agents or sulfonyl chlorides. The ethyl ester salt should not be mixed with aqueous sodium hydroxide above 1 M during prolonged workup because the hydrolysis rate increases rapidly with pH. It is also incompatible with strong oxidizing acids, acid chlorides in the absence of base, and concentrated mineral acids at elevated temperature. For peptide synthesis applications, the material is reconstituted only in dried polar aprotic solvents, and any residual water is removed by azeotropic distillation or molecular sieves before coupling. Published data for this specific configuration are limited; therefore, process validation should include lot-specific stability studies under the intended solvent and temperature conditions.
