| HS Code | 898887 |
| Cas Number | 6372-14-1 |
| Molecular Formula | C17H19NO3 |
| Molecular Weight | 285.34 g/mol |
| Smiles | O=C(OCc1ccccc1)N[C@@H](Cc2ccccc2)CO |
| Inchi | InChI=1S/C17H19NO3/c19-12-15(11-14-7-3-1-4-8-14)18-17(20)21-13-16-9-5-2-6-10-16/h1-10,15,19H,11-13H2,(H,18,20)/t15-/m0/s1 |
| Appearance | White to off-white crystalline solid |
| Melting Point | 91-93 °C |
| Specific Rotation | [α]D^20 = -23.5° (c=1, methanol) |
| Solubility | Soluble in methanol, ethanol, ethyl acetate, dichloromethane; practically insoluble in water |
| Storage Conditions | Store at 2-8 °C, under inert gas, protected from light |
As an accredited CBZ-L-Phenylalaninol factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | Packaged in a 5 g amber glass bottle with a tamper-evident cap, stored at room temperature, protected from light and moisture. |
| Container Loading (20′ FCL) | 20′ FCL container loading of CBZ-L-Phenylalaninol: drums on pallets, secured, labeled, sealed per hazardous chemical transport regulations. |
| Shipping | CBZ-L-Phenylalaninol is shipped as a solid in sealed containers, protected from moisture and light. Transport under ambient temperature, avoiding excessive heat. Ensure compliance with local chemical regulations; not classified as hazardous, but handle with standard laboratory precautions. Package securely to prevent spills or contamination during transit. |
| Storage | Store CBZ-L-Phenylalaninol in a tightly sealed container in a cool, dry, well-ventilated area, ideally at 2–8°C or below. Protect from light, moisture, and strong oxidizing agents. Keep away from incompatible materials. Ensure the container is clearly labeled and kept upright to prevent leakage or contamination. |
| Shelf Life | Store sealed, dry, and protected from light at -20°C; shelf life is typically at least 2 years. |
In the synthesis of hydroxyethylamine transition-state peptidomimetics, Cbz-L-phenylalaninol (CAS 6372-14-1) functions as the chiral pool entry point to a protected α-amino aldehyde intermediate. The alcohol is oxidized in a biphasic methylene chloride/water system using TEMPO (0.01–0.05 eq), sodium bromide (0.01–0.05 eq), sodium bicarbonate (1.5 eq), and 10–12% sodium hypochlorite (1.05–1.2 eq) at −5 °C to 0 °C. The resulting Cbz-L-phenylalaninal is not isolated because α-epimerization occurs; it is quenched in situ with 1.1–1.3 equivalents of a vinylmetal or alkylmetal reagent at −20 °C to −10 °C, generating the 1,2-amino alcohol scaffold under chelation-controlled addition conditions. The Cbz carbamate protects the nitrogen during organometallic addition and is removed later by hydrogenolysis or transfer hydrogenation. Production equipment is a jacketed glass-lined reactor with a retreat-curve impeller at 120–180 rpm; the oxidation endpoint is monitored by starch-iodide paper to avoid excess NaOCl, which drives carboxylic acid formation and lowers enantiomeric excess. Chiral HPLC release uses an amylose tris(3,5-dimethylphenylcarbamate) column with hexane/ethanol mobile phase; a typical specification is ≥99.0% ee. Under ICH Q3A, any impurity arising from over-oxidation or incomplete coupling is controlled relative to the clinical dose; for a 2 g/day API, identification is required at 0.10% and qualification at 0.15%. Within the EU, isolated intermediates handled under strictly controlled conditions invoke REACH Article 17/18 provisions. The terminal product is a hydroxyethylamine isostere intermediate for peptidomimetic drug candidates.
Conversion of Cbz-L-phenylalaninol to an oxazaborolidine-based chiral catalyst proceeds through hydrogenolytic removal of the benzyloxycarbonyl group, followed by condensation with a boron source. In a production-scale hydrogenator, 10% Pd/C (50% water wet) is charged at 5–10 wt% relative to substrate in methanol at 25–40 °C under 0.3–0.5 MPa H₂. The free amino alcohol is filtered through a 0.2 μm membrane and treated with borane–tetrahydrofuran complex at 0–5 °C; after N-B coordination, the mixture is heated to reflux in toluene to drive cyclization and azeotropically remove water. The resulting oxazaborolidine is used without crystallization in some asymmetric ketone reductions; turnover is sensitive to residual palladium and water. ICH Q3D Table A.2.1 sets an oral permitted daily exposure for palladium at 100 μg/day, which mandates activated-carbon polishing and ICP-MS verification below 10 ppm before the catalyst enters a pharmaceutical manufacturing train. Water content above 200 ppm in the toluene azeotrope reduces active catalyst concentration because BH₃ hydrolyzes to boric acid and hydrogen. The final product is a chiral oxazaborolidine catalyst used in sub-10 mol% loadings for asymmetric borane reduction; published data for this specific configuration is limited, but the process parameters align with general oxazaborolidine preparation from β-amino alcohols.
Oxidation of Cbz-L-phenylalaninol to Cbz-L-phenylalaninal exhibits a narrow pH and temperature window, and its process limits govern batch size. The aldehyde’s α-carbon epimerizes via an enolate or enol pathway when the reactor wall temperature exceeds 5 °C; at −5 °C the aldehyde persists long enough for an in situ quench if the organometallic addition is completed within 30–45 minutes. The pH is held at 8.5–9.0 with sodium bicarbonate; below pH 8 the TEMPO nitroxyl radical cycle stalls, while above pH 9.5 aldehyde hydration and over-oxidation to the carboxylic acid are promoted. The oxidation is run in a 500 L glass-lined reactor with a retreat-curve impeller at 120–180 rpm and a jacket inlet temperature of −10 °C to maintain bulk temperature at −5 °C to 0 °C. Sodium hypochlorite is added over 90–150 minutes; faster addition creates a local exotherm that degrades enantiomeric excess. The methylene chloride phase is separated and the aldehyde solution is dosed directly into a quench vessel at −20 °C to −10 °C. The terminal output is a non-isolated N-Cbz α-amino aldehyde stream used immediately for diastereoselective carbon-carbon bond formation; any attempt to store the stream by evaporating solvent triggers oligomerization and epimerization.
For impurity profiling and enantiomeric purity release, Cbz-L-phenylalaninol is employed as a chromatographic reference material. Because the Cbz chromophore absorbs at 258 nm with a secondary maximum near 254 nm, reversed-phase HPLC methods typically use a 150 mm × 4.6 mm, 5 µm C18 column with acetonitrile and 0.1% phosphoric acid (pH 2.0–2.5) gradient at 1.0 mL/min and 30 °C. A working standard is prepared at 10.0 mg/100.0 mL in acetonitrile/water 50:50 (v/v) and injected at 10 µL; relative response factor is calculated against a primary standard. Chiral purity is determined with a 250 mm × 4.6 mm, 5 µm amylose tris(3,5-dimethylphenylcarbamate) column using n-hexane/ethanol 90:10 (v/v) at 1.0 mL/min; the opposite enantiomer elutes as a separate peak under these conditions, and retention time order must be confirmed with a certified single-enantiomer standard. Method validation follows ICH Q2(R1) for specificity, linearity, accuracy, and precision; forced degradation under 0.1 N HCl, 0.1 N NaOH, and 3% H₂O₂ confirms that the Cbz group is labile under basic and oxidative conditions. The reference material supports release of intermediates intended for GMP pharmaceutical manufacturing under 21 CFR 210 and 211; the certificate of analysis includes loss on drying by USP 731, specific rotation by Ph. Eur. 2.2.28, residual solvents by USP 467, and chromatographic purity. This application is analytical control rather than reactive synthesis; the reference standard is not consumed in manufacturing but is delivered at defined purity and water content.
Cbz-L-phenylalaninol also enters peptide alcohol synthesis where the C-terminus of a peptide or peptidomimetic must terminate as a primary alcohol rather than an acid or amide. In such routes, the protected amino alcohol is coupled through its free hydroxyl to a protected amino acid or peptide acid using a carbodiimide and catalytic DMAP; the low nucleophilicity of the primary alcohol and steric shielding from the adjacent Cbz-protected nitrogen require controlled stoichiometry. A typical charging ratio is 1.05 equivalents of Cbz-L-phenylalaninol to 1.0 equivalent of the activated peptide acid, with 1.1 equivalents of DCC and 0.05 equivalents of DMAP in dichloromethane at 0–20 °C. The Cbz group is retained through the coupling and is removed at the final step by catalytic hydrogenation or transfer hydrogenation with ammonium formate and 10% Pd/C, avoiding acidic conditions that would cleave the Cbz group prematurely. The terminal product is a peptide alcohol or reduced peptide isostere used in protease inhibitor programs; the hydroxyl terminus can be oxidized later to an aldehyde for reversible covalent inhibitor design. This route is chosen when a free C-terminal carboxylic acid would generate an unwanted charged terminus or when the alcohol is required for subsequent oxidation to the aldehyde pharmacophore. The process is monitored by TLC and confirmed by LC-MS; unreacted Cbz-L-phenylalaninol is removed by aqueous workup rather than distillation.
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CBZ-L-Phenylalaninol, registered under CAS 6372-14-1 and systematically named benzyl N-[(1S)-1-benzyl-2-hydroxyethyl]carbamate, is commercially supplied as a white to off-white crystalline powder with a molecular formula C17H19NO3 and a formula weight of 285.34 g/mol. The standard release specification for bulk lots includes chromatographic purity of 98.0% area by HPLC at 215 nm according to USP <621> and an enantiomeric excess of 98.0% by chiral HPLC. The optical rotation [α]20D is typically controlled within −42° to −46° at c = 1.0 in methanol, while the melting range is 91.0°C–95.0°C and water content is ≤ 0.5% by Karl Fischer titration aligned with USP <921>. The material is soluble in dichloromethane, ethyl acetate, tetrahydrofuran, and methanol, but poorly soluble in water and n-hexane. Storage at 2–8°C under nitrogen in a tightly sealed container is specified to reduce moisture uptake and oxidative discoloration during warehouse holding.
The primary structural distinction lies in the coexistence of a Cbz-protected amine and an unprotected primary hydroxyl group. CBZ-L-Phenylalaninol therefore presents a nucleophilic oxygen while retaining a protected nitrogen that can be selectively unmasked by hydrogenolysis. In contrast, CBZ-L-phenylalanine contains a free carboxylic acid and is used directly in peptide coupling; its acid function can interfere with hydride-mediated reductions or organometallic displacement steps. Boc-L-phenylalaninol is cleaved under acidic conditions, whereas the Cbz group remains intact in many trifluoroacetic acid–dichloromethane deprotection mixtures, enabling orthogonal protection strategies. L-Phenylalaninol free base has no nitrogen protection, leading to uncontrolled acylation at both nitrogen and oxygen and higher inherent basicity.
| Parameter | CBZ-L-Phenylalaninol | CBZ-L-Phenylalanine | Boc-L-Phenylalaninol | L-Phenylalaninol |
|---|---|---|---|---|
| Protected amine | Cbz, removable by hydrogenolysis | Cbz, removable by hydrogenolysis | Boc, removable by acid | None |
| Free functional group | Primary alcohol | Carboxylic acid | Primary alcohol | Primary alcohol and primary amine |
| Typical orthogonal deprotection condition | H2/Pd-C at 0.2–0.5 MPa, 20–30°C | H2/Pd-C at 0.2–0.5 MPa, then coupling at C-terminus | Trifluoroacetic acid in CH2Cl2 or HCl in dioxane | Not applicable |
| Controlled release metric | Chiral HPLC ee ≥ 98.0% | Chiral HPLC ee ≥ 98.0% | Chiral HPLC ee ≥ 98.0% | Chiral HPLC or titration |
The difference in orthogonal reactivity allows CBZ-L-Phenylalaninol to be elaborated into ethers, sulfonate esters, and oxazolidinones without exposing the nitrogen. By comparison, unprotected amino alcohol requires selective N-acylation under Schotten-Baumann conditions; competitive O-acylation must be controlled by maintaining pH at 9.0–10.5 and temperature below 5°C to keep the O-acylated fraction below the process specification.
Under process-development conditions, CBZ-L-Phenylalaninol is most frequently converted to its methanesulfonate or p-toluenesulfonate ester for nucleophilic displacement. The sulfonate derivative is prepared in dichloromethane at 0–5°C using methanesulfonyl chloride and triethylamine; the free hydroxyl is consumed while the Cbz-protected amine remains intact. The resulting sulfonate serves as an alkylating agent in the construction of hydroxyethylamine isosteres, a substitution pattern encountered in aspartic protease inhibitor scaffolds. The stereochemical integrity of the Cbz-protected amino alcohol is retained when sulfonate formation is maintained below 5°C; prolonged exposure to excess triethylamine at ambient temperature can promote oxazolidinone formation via intramolecular carbamate attack, consuming the product and lowering isolated yield. The intramolecular cyclization rate is particularly sensitive to base strength and solvent polarity. In tetrahydrofuran, the reaction proceeds more slowly than in dichloromethane, but the competing formation of a five-membered oxazolidinone is observed by 1H NMR as a diagnostic downfield shift of the oxazolidinone C5 methylene protons. The mesylate is typically quenched with aqueous sodium bicarbonate, dried over sodium sulfate, and concentrated below 30°C to minimize thermal degradation.
The removal of the benzyloxycarbonyl group from CBZ-L-Phenylalaninol is carried out by catalytic hydrogenolysis rather than acidolysis. A standard laboratory procedure uses 5% or 10% palladium on activated carbon at a loading of 10–20% by weight relative to substrate, methanol or ethanol as solvent, and hydrogen pressure of 0.2–0.5 MPa at 20–30°C. The reaction produces L-phenylalaninol and toluene; residual toluene is removed by vacuum stripping below 40°C because the free amino alcohol has limited volatility but can undergo oxidation if overheated. The principal process risk is catalyst deactivation when the substrate lot contains residual sulfur-containing impurities or when unprotected thiols are present in downstream reaction mixtures. Pre-filtration through activated carbon and nitrogen sparging are used to protect the palladium surface. If the subsequent step is acid-sensitive, the deprotected amino alcohol is not isolated as a free base; the hydrogenation is instead performed directly in a solvent compatible with the next operation, such as 2-methyltetrahydrofuran or ethyl acetate.
In Cbz-protected amino alcohol systems, the free hydroxyl group is sterically hindered by the adjacent benzyl side chain but remains sufficiently nucleophilic to participate in intramolecular cyclization when the oxygen is activated as a sulfonate. The most common side product in synthetic sequences is (4S)-4-benzyloxazolidin-2-one, which is formed by intramolecular displacement of the sulfonate leaving group by the Cbz carbonyl. This side reaction is accelerated by the presence of potassium carbonate or cesium carbonate in dipolar aprotic solvents at temperatures above 40°C; therefore, O-alkylation of CBZ-L-Phenylalaninol is generally conducted in tetrahydrofuran with sodium hydride at 0–10°C, followed by slow addition of the alkyl halide. The formation of the oxazolidinone can be tracked by HPLC at 210 nm, where the cyclic carbamate elutes earlier than the O-alkylated product under reversed-phase conditions. For pilot-scale reactions, the reactor jacket setpoint is commonly maintained at 0°C during the addition phase to offset the exotherm.
Storage stability of CBZ-L-Phenylalaninol at 25°C and 60% relative humidity is limited by moisture uptake and surface agglomeration. For processing sites where humidity exceeds 60%, pre-drying under vacuum at 30–35°C for 4–6 h is specified before weighing for moisture-sensitive steps. The carbamate nitrogen is stable toward mildly basic aqueous workup at pH 7.0–9.0 for short contact times, but prolonged exposure to aqueous sodium hydroxide above pH 12 and above 40°C leads to partial carbamate hydrolysis and release of benzyl alcohol.
| Attribute | Specification/Method | Typical Value |
|---|---|---|
| Appearance | Visual inspection | White to off-white crystalline powder |
| Chromatographic purity | USP <621>, HPLC at 215 nm | ≥ 98.0% area |
| Enantiomeric excess | Chiral HPLC, Chiralpak AD-H, hexane/2-propanol | ≥ 98.0% |
| Water content | USP <921> Karl Fischer | ≤ 0.5% |
| Melting range | Ph. Eur. 2.2.14 | 91.0°C–95.0°C |
| Specific rotation | Ph. Eur. 2.2.7, c = 1.0 in methanol | [α]20D −42° to −46° |
| Residual solvents | USP <467> headspace GC | ≤ 0.5% total |
Specifications for custom bulk lots can include additional limits for residual palladium after hydrogenolytic deprotection, for benzyl alcohol content, or for oxazolidinone-related impurities. Because the product is not a single pharmaceutical substance, compendial monographs do not apply; the release matrix is therefore supplier-specific and should be fixed in the purchaser’s quality agreement before process validation.
Boc-protected amino alcohols are removed under acidic conditions that may cleave tert-butyl esters and tert-butyl ethers, or may promote epimerization in peptide sequences. CBZ-L-Phenylalaninol is selected when the synthetic route contains acid-sensitive functionality, because the Cbz group can be removed under neutral hydrogenolysis conditions that leave tert-butyl-protected residues intact. This lability profile is reversed relative to Fmoc chemistry, which is removed by secondary amines such as piperidine; Cbz protection therefore occupies the same niche as benzyl-type protection in peptide and carbohydrate synthesis. The operational boundary is that Cbz removal requires a hydrogenation reactor and careful exclusion of oxygen; the hydrogenolytic step is not compatible with nitro groups, aryl halides, or other reducible functionalities unless selectivity is engineered with poisoned catalysts.
During pilot-scale isolation of CBZ-L-Phenylalaninol after carbamate formation from L-phenylalaninol and benzyl chloroformate, the crude product is usually extracted into ethyl acetate and washed with dilute hydrochloric acid and sodium bicarbonate. The organic layer is dried over sodium sulfate, filtered, and concentrated at 35–40°C under reduced pressure. Crystallization from ethyl acetate/n-heptane mixtures yields a white crystalline solid with a melting range consistent with the release specification. The isolation yield is influenced by the free base quality: L-phenylalaninol batches containing residual ethanol from amino alcohol manufacture lead to lower crystallization yields because the alcohol competes for hydrogen-bonding sites in the crystal lattice. This observation has been reported in production-scale campaigns but is not fully captured in standard certificates of analysis. The final product is incompatible with strong oxidizing agents, acid chlorides when no base is present, and palladium on carbon under hydrogen when retention of the Cbz group is required.
