26049-94-5

Basic information

• Product Name: ZPCK
• Synonyms: carbamicacid,[3-chloro-2-oxo-1-(phenylmethyl)propyl]-,phenylmethylester,(s;(S)-benzyl [1-benzyl-3-chloro-2-oxopropyl]carbamate;N-CBZ-L-PHENYLALANINE CHLOROMETHYL*KETON E;z-l-phe chloromethyl ketone;(S)-Penzyl [1-benzyl-3-chloro-2-oxopropyl]carbamate.;ZPCK, N-Carbobenzyloxy-L-phenylalanyl chloromethyl ketone;(3S)-1-Chloro-3-(benzyloxycarbonylamino)-4-phenyl-2-butanone;[(S)-1-Benzyl-3-chloro-2-oxopropyl]carbamic acid benzyl ester
• CAS NO: 26049-94-5
• Molecular Formula: C18H18ClNO3
• Molecular Weight: 331.79
• EINECS: 247-432-8
• Mol File: 26049-94-5.mol

Chemical Properties

• Melting Point: 107-108 °C(lit.)
• Boiling Point: 503.1 °C at 760 mmHg
• Flash Point: 258.1 °C
• Appearance: white powder
• Density: 1.1630 (rough estimate)
• Vapor Pressure: 2.99E-10mmHg at 25°C
• Refractive Index: 1.6470 (estimate)
• Storage Temp.: -15°C
• Solubility: Soluble in DMSO (up to 50 mg/ml) or in Ethanol (up to 15 mg/ml with warming).
• PKA: 10.74±0.46(Predicted)
• Stability: Stable for 2 years from date of purchase as supplied. Solutions in DMSO or ethanol may be stored at -20° for up to 1 month.
• CAS DataBase Reference: ZPCK(CAS DataBase Reference)
• NIST Chemistry Reference: ZPCK(26049-94-5)
• EPA Substance Registry System: ZPCK(26049-94-5)

Safety Data

• Hazard Codes: C
• Statements: 34
• Safety Statements: 26-27-36/37/39-45
• RIDADR: UN 3261 8/PG 2
• WGK Germany: 3
• Hazardous Substances Data: 26049-94-5(Hazardous Substances Data)

Usage

Uses

Used in Cancer Treatment:
ZPCK is used as a prodrug of gemcitabine, a nucleoside analog used intravenously to treat various cancers. It is designed for improved oral bioavailability and can inhibit the growth of human non-small cell lung cancer NCI-H460 cells, colon cancer HCT-116 cells, and breast cancer MCF-7 cells (IC50s = 0.78, 0.92, and 0.64 μM, respectively), inducing apoptosis. In nude mice bearing NCI-H460, HCT-116, or MCF-7 cancer cell xenografts, ZPCK at 10-50 μM/kg has been shown to delay tumor growth.
Used in Enzyme Inhibition:
ZPCK is used as an enzyme inhibitor, specifically inhibiting the p53-MDM2 interaction and bovine chymotrypsin A-γ. This application can be useful in various research and therapeutic contexts where the inhibition of these interactions is desired.
Used in Pharmaceutical Industry:
ZPCK is used as a peptidase with esterase activities in the pharmaceutical industry for the development of new drugs and therapies. Its ability to inhibit specific interactions and its esterase activities make it a valuable tool in the design and synthesis of novel pharmaceutical compounds.
Used in Research and Development:
ZPCK is used as a research tool in the field of molecular biology and biochemistry. Its properties as an enzyme inhibitor and its interactions with specific proteins make it a valuable asset in understanding the mechanisms of various biological processes and the development of targeted therapies.

References

1) Li et al. (2011), A cell-based high-throughput assay for the screening of small-molecule inhibitors of p53-MDM2 interaction; J. Biomol. Screening, 16 450

InChI:InChI=1/C18H18ClNO3/c19-12-17(21)16(11-14-7-3-1-4-8-14)20-18(22)23-13-15-9-5-2-6-10-15/h1-10,16H,11-13H2,(H,20,22)

Upstream product

• 34351-19-4 (3S)-3-amino-1-chloro-4-phenyl-2-butanone hydrochloride 
• 501-53-1 benzyl chloroformate 
• 109453-49-8 (C₈H₇O₂)(NHCHCOO)(CH₂C₆H₅)(CO₂C₂H₅) 
• 1161-13-3 N-Cbz-L-Phe 
• 41518-17-6 Z-Phe-O-COO-isoBu 
• 286019-77-0 (3S)-1-chloro-3-(diphenylmethylene)amino-4-phenyl-2-butanone 
• 339190-43-1 N-benzylidene (S)-phenylalanine methyl ester 
• 120238-42-8 methyl (S)-2-(diphenylmethylideneamino)-3-phenylpropanoate 
• 143601-45-0 (S)-tert-butyl 4-<(benzyloxycarbonyl)amino>-3-oxo-5-phenylpentanoate 
• 7524-50-7 methyl (2S)-2-amino-3-phenylpropanoate hydrochloride 
• 35909-92-3 N-carbobenzoxy-L-phenylalanine methyl ester 
• 186581-53-3 diazomethane 
• 191226-90-1 tert-butyl (4S)-4-N-benzyloxycarbonylamino-2-chloro-3-oxo-5-phenylpentanoate 
• 74-97-5 chlorobromomethane 

Downstream Products

• 128018-43-9 N-benzyloxycarbonyl-3(S)-amino-1-chloro-4-phenyl-2(S)-butanol 
• 183255-96-1 (2R,3S)-1-chloro-2-hydroxy-3-N-benzyloxycarbonylamino-4-phenylbutane 
• 93204-47-8 {2-Oxo-1-[1-phenyl-meth-(E)-ylidene]-propyl}-carbamic acid benzyl ester 
• 111491-96-4 (S)-3-(N-(benzyloxycarbonyl)amino)-4-phenyl-2-butanone 
• 36979-87-0 Phenylalanylmethane hydrochloride 
• 25487-25-6 PheCH₂Cl, HBr 
• 186463-41-2 2(R,S)-3(S)-1-chloro-2-hydroxy-3-phenylmethoxycarbonylamino-4-phenylbutane 
• 1026417-42-4 (S)-2-{(2S,3S)-2-[(S)-2-((S)-3-Benzyloxycarbonylamino-2-oxo-4-phenyl-butylamino)-3-phenyl-propionylamino]-3-methyl-pentanoylamino}-3-phenyl-propionic acid methyl ester 
• 1027266-29-0 (S)-2-{(2S,3S)-2-[2-((S)-3-Benzyloxycarbonylamino-2-oxo-4-phenyl-butylamino)-acetylamino]-3-methyl-pentanoylamino}-3-phenyl-propionic acid methyl ester 
• 1427161-73-6 C₃₀H₃₀N₄O₂S 

Relevant articles and documents

Continuous flow synthesis of α-halo ketones: Essential building blocks of antiretroviral agents

The development of a continuous flow process for the multistep synthesis of α-halo ketones starting from N-protected amino acids is described. The obtained α-halo ketones are chiral building blocks for the synthesis of HIV protease inhibitors, such as atazanavir and darunavir. The synthesis starts with the formation of a mixed anhydride in a first tubular reactor. The anhydride is subsequently combined with anhydrous diazomethane in a tube-in-tube reactor. The tube-in-tube reactor consists of an inner tube, made from a gas-permeable, hydrophobic material, enclosed in a thick-walled, impermeable outer tube. Diazomethane is generated in the inner tube in an aqueous medium, and anhydrous diazomethane subsequently diffuses through the permeable membrane into the outer chamber. The α-diazo ketone is produced from the mixed anhydride and diazomethane in the outer chamber, and the resulting diazo ketone is finally converted to the halo ketone with anhydrous ethereal hydrogen halide. This method eliminates the need to store, transport, or handle diazomethane and produces α-halo ketone building blocks in a multistep system without racemization in excellent yields. A fully continuous process allowed the synthesis of 1.84 g of α-chloro ketone from the respective N-protected amino acid within ～4.5 h (87% yield).

Synthesis and anti-Candida activity of novel 2-hydrazino-1,3-thiazole derivatives

Eighteen new hydrazino-1,3-thiazole derivatives were evaluated against 8 strains of multi-resistant Candida spp. Introduction of an indolyl moiety linked to the hydrazone function enhanced the in vitro anti-Candida activity, with an activity spectrum towards Candida albicans strains. Introduction of a (S)-2-aminoethyl chain on the thiazole nucleus largely enhanced the in vitro antifungal activity, with a selectivity oriented towards non-C. albicans species.

Design, biologic evaluation, and SAR of novel pseudo-peptide incorporating benzheterocycles as HIV-1 protease inhibitors

A series of novel HIV-1 protease inhibitors based on the (hydroxyethylamino)-sulfonamide isostere incorporating substituted phenyls and benzheterocycle derivatives bearing rich hydrogen bonding acceptors as P 2 ligands were synthesized. Prolonged chain linking the benzhereocycle to the carbonyl group resulted in partial loss of binding affinities. Introduction of a small alkyl substituent with appropriate size to the -CH2- of P1-P2 linkage as a side chain resulted in improved inhibitory potency, and in this study, isopropyl was the best side chain. Replacement of the isobutyl substituent at P 1′group with phenyl substituent decreased the inhibitory potency. One of the most potent inhibitor, compound 23 showing high affinity to HIV-1 protease with an IC50 value of 5 nm, also exhibited good anti-SIV activity (EC50 = 0.8 μm) with low toxicity (TC 50 > 100 μm). The flexible docking of inhibitor 23 to HIV-1 protease active site rationalized the interactions with protease.

Expanding the scope of PNA-encoded libraries: divergent synthesis of libraries targeting cysteine, serine and metallo-proteases as well as tyrosine phosphatases

Seven PNA-encoded combinatorial libraries targeting proteases and phosphatases with covalent reversible and irreversible mechanism-based inhibitors were prepared. The libraries were synthesized using modified PNA monomers, which dramatically increase the water solubility of the libraries in biologically relevant buffers. The libraries were shown to selectively inhibit targeted enzymes.

New approaches to the industrial synthesis of HIV protease inhibitors

Efficient and industrially applicable synthetic processes for precursors of HIV protease inhibitors (Amprenavir, Fosamprenavir) are described. These involve a novel and economical method for the preparation of a key intermediate, (3S)-hydroxytetrahydrofuran, from L-malic acid. Three new approaches to the assembly of Amprenavir are also discussed. Of these, a synthetic route in which an (S)-tetrahydrofuranyloxy carbonyl is attached to L-phenylalanine appears to be the most promising manufacturing process, in that it offers satisfactory stereoselectivity in fewer steps.

Synthesis of optically active α-aminoalkyl α′-halomethyl ketone: A cross-claisen condensation approach

(Equation presented) A simple and versatile method was developed for the synthesis of α-aminoalkyl α′-halomethyl ketone derivatives, which are useful intermediates of protease inhibitors. It involves selective halogenation of the α-position on a β-ketoester, which is prepared by cross-Claisen condensation using N-protected amino acid ester. The title compound is obtained in high yield after decarboxylation of the α-halo-β-ketoester.

Process for producing alpha-aminoketones

An amino group of an α-amino acid ester is protected as an imine, and it is then reacted with a halomethyllithium to obtain an N-protected-α-aminohalomethylketone. Further, this N-protected-α-aminohalomethylketone is treated with an acid to obtain an α-aminohalomethylketone. This process is suited for industrial production, and can produce an α-aminohalomethylketone and its related compounds economically and efficiently.

Process for producing alpha-aminoketones

A process for producing α-aminohalomethyl ketones or N-protected α-aminohalomethyl ketones from specified 3-oxazolidin-5-one derivatives via 5-halomethyl-5-hydroxy-3-oxazolidine derivatives. By this process, α-aminohalomethyl ketones and compounds relating to them can be obtained efficiently and economically in industrial scale.

Practical synthesis of α-aminoalkyl-α′-chloromethylketone derivatives. Part 2: Chloromethylation of N-imine-protected amino acid esters

Chloromethylation of N-imine-protected amino acid esters followed by acid hydrolysis gave α-aminoalkyl-α′-chloromethylketone as a HCl salt form in good yield without racemization. The amino group was conveniently protected with carbamate protecting reagents to give various useful intermediates for the protease inhibitors.

Practical synthesis of α-aminoalkyl-α′-chloromethylketone derivatives. Part 1: Chloromethylation of N-protected 3-oxazolidin-5-ones

Reaction of N-protected 3-oxazolidin-5-ones with in situ-generated chloromethyllithium afforded N-protected 5-chloromethyl-5-hydroxy-3-oxazolidines without racemization. They were easily hydrolyzed to give α-aminoalkyl-α′-chloromethylketone derivatives, which are useful intermediates for several protease inhibitors.