| HS Code | 425027 |
| Product Name | L-Tyrosine Ethyl Ester Hydrochloride |
| Cas Number | 340-06-7 |
| Molecular Formula | C11H16ClNO3 |
| Molecular Weight | 245.70 g/mol |
| Appearance | White to off-white crystalline powder |
| Melting Point | 166-168 °C (dec.) |
| Optical Rotation | [α]20/D = +20.5° (c=2, water) |
| Solubility | Soluble in water, methanol, ethanol; sparingly soluble in ethyl acetate |
| Purity | ≥98% (HPLC) |
| Storage Conditions | Store at 2-8°C, desiccated, under inert gas, protected from light |
| Synonyms | H-Tyr-OEt·HCl; Ethyl L-tyrosinate hydrochloride |
| Smiles | CCOC(=O)[C@@H](Cc1ccc(O)cc1)N.Cl |
As an accredited L-tyrosine 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-tyrosine Ethyl Ester Hydrochloride in a sealed glass bottle, with desiccant, under nitrogen, labeled with handling precautions. |
| Container Loading (20′ FCL) | 20′ FCL of L-tyrosine Ethyl Ester Hydrochloride, packed in sealed drums, properly secured and ventilated for safe transit. |
| Shipping | Ship L-tyrosine Ethyl Ester Hydrochloride as a non-hazardous or irritant chemical, depending on regulations. Package in sealed, moisture-resistant containers (glass/PE) with desiccant. Avoid exposure to heat, sunlight, and humidity. Label clearly, include SDS, and use trusted courier compliant with local transport rules for laboratory chemicals. |
| Storage | Store L-tyrosine Ethyl Ester Hydrochloride in a tightly sealed container in a cool, dry place, ideally between 2–8 °C. Protect from moisture and direct light; keep away from strong oxidizers. Ensure the container remains desiccated and tightly capped after each use, allowing storage under inert gas if available. |
| Shelf Life | Store tightly sealed at 2–8°C, protected from moisture and light; stable for up to 2 years. |
In solution-phase synthesis of tyrosine-containing peptide active pharmaceutical ingredients, L-tyrosine ethyl ester hydrochloride is handled as a protected amino component rather than as a direct dosage form excipient. The α-carboxyl is already blocked as the ethyl ester, so the building block is not activated at its own carboxyl during peptide bond formation; this limits oxazolone-mediated racemization at the C-terminal residue when the compound is used as the amino component under standard carbodiimide or uronium coupling conditions. At production scale, the hydrochloride is charged at 1.00–1.08 molar equivalents relative to the N-protected carboxyl component. The reactor, a jacketed glass-lined vessel with working volume of 100–2000 L, is inerted with nitrogen at 0.2–0.5 bar(g) and agitated with a retreat-curve impeller at 80–120 rpm. Before coupling, the salt is neutralized with N-methylmorpholine at 1.05 ± 0.03 molar equivalents, added at 0.2–0.5 kg/min per 100 kg batch to maintain the jacket inlet at −5 °C and the internal exotherm within ΔT ≤ 3 °C. The activated N-protected amino acid is then introduced over 30–45 min; when base addition exceeds 0.5 kg/min, localized pH excursions above 8.0 in the feed zone have been associated with racemization of the activated amino acid and elevated torsional load on the agitator, occasionally reaching 1.4–1.6 times nominal torque. After the coupling reaction, the organic phase is washed with 5 wt% citric acid and 10 wt% sodium chloride, followed by vacuum distillation at 50–60 mbar to remove residual water. If the free carboxyl is required for a subsequent coupling, the ethyl ester is cleaved with 1 M sodium hydroxide in dioxane/water at 0–5 °C. The intermediate is released under ICH Q7 Section 7.1 and EU GMP Part II; where the peptide is destined for a finished dosage form, later stages fall under 21 CFR 210/211. Analytical release includes chiral HPLC enantiomeric excess not less than 99.0% and residual ethanol not more than 0.5 wt%. Finished product types include protected peptide fragments with C-terminal tyrosine ethyl ester, which are subsequently saponified to the free acid or coupled directly in convergent peptide API manufacturing.
Bulk enzyme manufacturers require a reproducible, UV-detectable substrate for chymotrypsin activity testing. The free α-amino group of L-tyrosine ethyl ester hydrochloride shifts protonation with pH and reduces esterase specificity; therefore the hydrochloride is first acylated to N-acetyl-L-tyrosine ethyl ester. In a 500 L enamel-lined reactor, the hydrochloride is suspended in anhydrous ethyl acetate at 0–10 °C. Acetic anhydride is charged at 1.02–1.10 molar equivalents and pyridine at 1.0–1.1 molar equivalents as hydrochloric acid scavenger. The acylation is held for 6–10 h, then quenched with water; the ethyl acetate layer is washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated at 35–40 °C under vacuum not less than 20 kPa. Residual pyridine is controlled to below 0.1 wt% by headspace GC. For the final diagnostic working solution, N-acetyl-L-tyrosine ethyl ester is dissolved at 0.8–1.2 mM in 50 mM Tris-HCl buffer pH 7.8 containing 10 mM calcium chloride. Hydrolysis by chymotrypsin is followed at 237 nm in a 1 cm quartz cuvette at 25 ± 0.1 °C. Finished reagent products include lyophilized chymotrypsin substrate vials, ready-to-use protease activity kits, and bulk QC substrate solutions. Compliance for finished diagnostic reagents is anchored to ISO 13485:2016, EU 2017/746 IVDR, and 21 CFR 820. Compendial potency methods may add pharmacopeial enzyme activity acceptance criteria specific to the target monograph, and method transfer should verify linearity across 0.2–2.0 mM substrate with initial velocities between 0.010 ΔA/min and 0.050 ΔA/min. At relative humidity above 65%, the hydrochloride takes up moisture and alters charge accuracy; pre-drying at 40 ± 2 °C under vacuum ≤ 10 kPa for 4–6 h is required before acylation.
| Reagent | Working concentration | Function | Specification boundary |
|---|---|---|---|
| N-acetyl-L-tyrosine ethyl ester | 0.8–1.2 mM | substrate | UV purity ≥ 98.0% at 237 nm |
| Tris-HCl buffer | 50 mM | pH control | pH 7.8 ± 0.05 |
| Calcium chloride | 10 mM | enzyme stabilizer | heavy metals ≤ 0.1% |
| Chymotrypsin | 0.02–0.05 U/mL | catalyst | linear ΔA/min 0.010–0.050 |
Where the target peptide is intended for topical cosmetic use rather than pharmaceutical or diagnostic application, the ethyl ester group adjusts the partitioning of the protected intermediate during organic-phase workup and can be retained or selectively cleaved depending on the desired polarity of the finished peptide. In this production route, the hydrochloride is neutralized with N-methylmorpholine at 1.0–1.05 molar equivalents and coupled to an N-acylated amino acid in 2-methyltetrahydrofuran or ethyl acetate at −5 to 5 °C using EDC/HOBt activation. After coupling, the reaction mass is washed sequentially with 5 wt% sodium bicarbonate and 1 M hydrochloric acid to remove unreacted ester hydrochloride and water-soluble urea byproducts. If the finished peptide requires a free carboxyl, the ethyl ester is cleaved with lithium hydroxide at 1.1 molar equivalents in THF/water at 0–10 °C; when ester retention is intended to increase lipid compatibility, the final peptide may remain as the ethyl ester. In the finished cosmetic formulation, the peptide active is dosed at 0.0005–0.05 wt% dry peptide, while the starting hydrochloride is not present in the final product. The process is controlled under ISO 22716:2007, and the substance itself is supplied under REACH Annex VII-X registration obligations; the final cosmetic product must satisfy EC 1223/2009 Annex II screening and Article 18 labelling requirements. Finished product types include peptide concentrates, serum ampoules, and topical peptide delivery systems. Published diffusion cell data for tyrosine-containing peptide ethyl esters in leave-on emulsions are limited; no transport claim should be made before obtaining OECD 428 data in the intended vehicle.
During early-stage metabolic stability screening, L-tyrosine ethyl ester hydrochloride is used as a soluble aromatic amino acid ester probe for carboxylesterase activity in hepatic fractions. The probe is prepared as a 10 mM stock in 50 mM HEPES buffer pH 7.4, then diluted to 0.05–0.5 mM per incubation well. Incubations are conducted with human liver microsomes at 0.25 mg protein/mL or primary hepatocytes at 0.5–1.0 million cells/mL for 0–60 min at 37 °C. Reactions are terminated with acetonitrile containing an internal standard, and the remaining ester or released L-tyrosine is separated on a reversed-phase C18 column with UV detection at 275 nm. Spontaneous hydrolysis at pH 7.4 is lower than at pH 7.8; reagent solutions should be prepared fresh daily because storage at 4 °C for 24 h can produce 2% non-enzymatic hydrolysis. Batch-to-batch signal drift in hepatocyte incubations has been traced to moisture uptake in the hydrochloride exceeding 3 wt%, which alters actual substrate concentration and flattens initial velocity curves. Ancillary reagent supply follows ISO 9001:2015; if the assay is used within a regulatory nonclinical study, the laboratory phase typically falls under 21 CFR Part 58. Finished product types include carboxylesterase activity reagent vials, microsomal hydrolysis screening kits, and hepatocyte incubation substrate kits. Published data for this specific hydrochloride probe in CES2-selective versus CES1-selective systems are limited; enzyme selectivity should be confirmed with selective inhibitors before assigning isoform-specific activity.
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L-Tyrosine ethyl ester hydrochloride (CAS 4089-07-6; product model H-Tyr-OEt·HCl; molecular formula C11H16ClNO3; molecular weight 245.70 g/mol) is the ethyl ester hydrochloride salt of L-tyrosine. The product is most commonly released as a white to off-white crystalline powder under a synthesis-grade or bulk intermediate model; because no USP or Ph. Eur. monograph exists for this derivative, certificate-of-analysis limits are vendor-specific. Typical release parameters include an HPLC assay of ≥98.0% on the anhydrous basis, loss on drying ≤0.5% by USP 731, residue on ignition ≤0.1% by USP 281, and water content ≤0.5% by USP 921. The material is used primarily as a carboxyl-protected L-tyrosine building block in solution-phase peptide synthesis and as a synthetic intermediate for pharmaceutical candidates; it is also evaluated as a prodrug ester for delivery of L-tyrosine where the free amino acid solubility of 0.45 mg/mL at 25°C is insufficient.
| Parameter | Typical release limit | Method designation |
|---|---|---|
| Appearance | white to off-white crystalline powder | visual inspection |
| Identification | retention time concordant with reference standard | USP 621; Ph. Eur. 2.2.29 |
| Assay | ≥98.0% area by HPLC, anhydrous basis | USP 621 |
| Loss on drying | ≤0.5% | USP 731 |
| Water | ≤0.5% Karl Fischer | USP 921 |
| Residue on ignition | ≤0.1% | USP 281 |
| Chloride | 13.8–15.0% argentometric | Ph. Eur. 2.5.4 |
Underivatized L-tyrosine is a zwitterion at pH values above its isoelectric point of 5.66 and exhibits both free α-carboxylic acid and free α-amino functions. Direct solution-phase coupling with a single amino acid or peptide segment requires chemoselective activation; without temporary protection, the α-amino group of one tyrosine molecule can compete with the amino component and the α-carboxylic acid can form oligomers through carbodiimide or mixed anhydride activation. The free acid also has very low solubility in aprotic coupling solvents: the cited aqueous solubility of L-tyrosine is 0.45 mg/mL at 25°C, but its solubility in dichloromethane or tetrahydrofuran is generally insufficient for homogeneous carbodiimide-mediated coupling. The ethyl ester hydrochloride resolves the acid-side issue by masking the C-terminus as an ethyl ester; protonation of the α-amino group provides a stable salt form for storage. After neutralization with a tertiary amine, the free amino group can be introduced as a nucleophile in coupling with an activated carboxyl component. The α-carbon racemization risk at C-terminal activation is therefore bypassed because the C-terminus is not being activated; the material is used as the amino nucleophile, not as the carboxyl-activated electrophile.
Typical activation reagents for the opposing carboxyl component include EDC/HOBt, PyBOP, or HATU in DMF or NMP. The temperature is maintained at 0–5°C during addition because the ethyl ester is base-sensitive and the liberated free base should not be exposed to prolonged alkaline conditions. Coupling progress is monitored by reversed-phase HPLC at 214 nm; unreacted ester below 2.0% by area is a common process checkpoint, but the limit is not harmonized.
Across a 20 L jacketed glass reactor train with a retreat-blade impeller, the hydrochloride salt is first dissolved in DMF or dichloromethane and treated with N-methylmorpholine at 0–5°C. The neutralization step is exothermic, and addition of the tertiary amine is controlled at 0.5 mol/min or less to keep the internal temperature inside the 0–5°C window. The resulting free base is not isolated; it is consumed in the subsequent coupling. Residual water in the reaction matrix above 0.5% by Karl Fischer is known to reduce conversion in carbodiimide-mediated couplings because water competes for activated carboxyl species. Pre-drying of the hydrochloride salt in a vacuum oven at 40°C under 5–10 kPa for 16 h is therefore specified in several process descriptions. After coupling, the crude dipeptide ester is isolated by extraction at pH 5.0–6.5, below the alkaline saponification threshold for the ethyl ester.
The replacement of the free carboxylic acid with an ethyl ester and the protonation of the α-amino group alter the aqueous solution behavior of L-tyrosine. The parent amino acid has a measured aqueous solubility of 0.45 mg/mL at 25°C and is zwitterionic; the hydrochloride salt of the ethyl ester is soluble in water and partially soluble in methanol and ethanol, although no harmonized quantitative solubility value exists in the USP or Ph. Eur. public monographs. Supplier certificates often describe the material as freely soluble in water, but this is not a pharmacopeial definition. The ethyl ester bond is stable under acidic to neutral aqueous conditions; hydrolysis becomes significant above pH 8.0 at 25°C and accelerates at elevated temperature. Aqueous buffers used for extraction or formulation work should therefore be maintained at pH 5.0–6.5 unless the intent is deliberate saponification to L-tyrosine.
Compared with the methyl ester hydrochloride analogue, the ethyl ester is expected to hydrolyze more slowly in alkaline media due to the larger alkoxy substituent. Published kinetic rate constants for this single compound in standard ICH stability buffers are limited; the available general ester hydrolysis literature supports the retardation but not a product-specific rate coefficient.
Because the hydrochloride salt is hygroscopic, storage in tightly closed containers at 2–8°C with desiccant is specified by supplier documentation. Exposure to ambient air at relative humidity above 60% should be minimized; if water content exceeds 0.5% by Karl Fischer, vacuum drying at 40°C under 5–10 kPa is used before coupling. Combinations with strong bases, strong oxidizing agents, or primary amines under protic conditions are incompatible: the ester is cleaved by alkaline saponification or amine-mediated aminolysis, and the phenolic ring is susceptible to oxidative discoloration. The product should not be stored in unbuffered aqueous solution above pH 7.5 for more than a working day unless the storage medium has been validated.
Solution-phase fragment condensation sometimes requires a tyrosine residue that is free at the α-amino group while the carboxy terminus is masked. In this context, L-tyrosine ethyl ester hydrochloride is differentiated from N-acetyl-L-tyrosine, which carries a free carboxy group and a protected amino group, and from L-tyrosine methyl ester hydrochloride, which provides a different ester cleavage profile. The ethyl ester group is selectively removed after chain extension by saponification with 1 M sodium hydroxide in aqueous methanol or by controlled esterase treatment; however, the strong base conditions require post-saponification neutralization and can cause tyrosine side-chain phenolate formation if pH rises uncontrolled. The hydrochloride salt is preferred when an N-terminal tyrosine residue must be coupled to a pre-formed peptide segment without constructing a resin-bound intermediate.
| Product | CAS | Molecular weight | Protecting group orientation | Typical synthetic role |
|---|---|---|---|---|
| L-Tyrosine | 60-18-4 | 181.19 g/mol | free α-amino and free α-carboxy | feedstock; requires protection at both termini for stepwise coupling |
| L-Tyrosine ethyl ester hydrochloride | 4089-07-6 | 245.70 g/mol | α-amino protonated; carboxy masked as ethyl ester | carboxyl-protected building block for N-terminal extension |
| N-Acetyl-L-tyrosine | 537-55-3 | 223.23 g/mol | α-amino acetylated; carboxy free | N-protected building block for C-terminal activation |
This orthogonality is relevant when a tyrosine residue is introduced into a sequence after an N-acetylated segment has been assembled; the ethyl ester salt supplies the free amino nucleophile, whereas N-acetyl-L-tyrosine would require carboxyl activation. The selection between methyl and ethyl esters is usually based on the saponification rate and the boiling point of the released alcohol; ethanol is often preferred over methanol in larger-scale work because of lower acute inhalation risk. The ethyl ester hydrochloride is not a direct substitute for N-acetyl-L-tyrosine ethyl ester in chymotrypsin substrate assays, because the free α-amino group alters enzyme recognition unless N-acylation is performed separately.
For Fmoc/tBu solid-phase synthesis, the ethyl ester hydrochloride is not used directly on the resin because the resin anchor already protects the C-terminus; instead, free L-tyrosine with Fmoc protection at the α-amino group and tert-butyl protection at the phenolic hydroxyl is loaded as an Fmoc-Tyr(tBu)-OH derivative. The ethyl ester hydrochloride becomes relevant for convergent solution-phase routes, where a protected peptide segment is activated at its C-terminus and condensed with the tyrosine ester as the amino component. This distinction avoids the misconception that the ethyl ester is interchangeable with resin-bound L-tyrosine in standard Fmoc solid-phase peptide synthesis.
Analytical confirmation of the salt is performed by electrospray ionization mass spectrometry in positive mode with the protonated free ester at m/z 210.11; infrared spectra contain the ester carbonyl band near 1735 cm−1 and ammonium bands typical of hydrochloride salts. The phenolic hydroxyl in the side chain remains free unless protected. In peptide work, that phenolic group may be left unprotected only when the activation chemistry is known to be compatible with a weakly acidic aromatic hydroxyl; otherwise it is protected as the tert-butyl ether, which is stable to the acid conditions used for the hydrochloride salt and is removed later with trifluoroacetic acid.
Where the ethyl ester hydrochloride is evaluated as a prodrug for enhancing L-tyrosine delivery, the relevant testing platform is the Franz diffusion cell with dermatomed human skin or ex vivo porcine skin under OECD 428. A saturated solution prepared at pH 5.0 is applied to the donor compartment; samples are withdrawn at 1 h, 3 h, and 6 h and analyzed by LC-MS/MS. Published data for this specific compound in human epidermis are limited, so any claim concerning dermal bioavailability should be regarded as unverified until supported by a full validation report. In oral prodrug screening, the ester is incubated in simulated gastric fluid USP at pH 1.2 and simulated intestinal fluid USP at pH 6.8 to estimate acid stability and esterase-mediated conversion. The ester bond is anticipated to be acid-stable in the gastric compartment but may be cleaved by intestinal esterases; the hydrochloride salt form does not by itself guarantee that the prodrug will remain intact until absorption.
Release documentation for the synthesis-grade material is normally issued under ISO 9001:2015; when the product is qualified as an active pharmaceutical ingredient starting material, ICH Q7 good manufacturing practice expectations apply to the supplier and to the receiving quality unit. The product has no USP or Ph. Eur. monograph, so each batch should be qualified by the end-user against a release specification derived from the intended process. Residual solvents are process-dependent; if the material is manufactured via thionyl chloride esterification in ethanol, the relevant ICH Q3C residual solvent limits for ethanol and dichloromethane apply. Elemental impurities should be assessed under ICH Q3D based on the final drug product dose, rather than by default heavy metal test alone. This derivative is not included in FDA 21 CFR 172 or 21 CFR 175 food-contact listings, and no public GRAS conclusion has been located; application work is therefore limited to synthetic chemistry and pharmaceutical development unless regulatory clearance is obtained.
