Amino Acid Methyl Ester Hydrochlorides Research Articles

Method for the Preparation of N‐protected β‐Cyano L‐alanine Tertiary Butyl Esters

AbstractHere we report a simple, efficient and scalable one‐pot procedure for the synthesis of N‐protected β‐cyano L‐alanine tertiary butyl esters from N‐protected L‐asparagines. Reaction of N‐protected L‐asparagines with 2.2 equivalents of (Boc)2O and catalytic amount of N,N‐dimethylamino pyridine (DMAP) in tertiary butanol at room temperature resulted N‐protected β‐cyano L‐alanine tertiary butyl esters. We also synthesized N‐protected β‐cyano L‐alanines from the obtained crude N‐protected β‐cyano L‐alanine tertiary butyl esters without column chromatography on gram scale in good yields. Control experiments gave the corresponding nitrile acids over the tertiary butyl esters. Later, we synthesized nitrile containing dipeptides by coupling N‐Boc‐β‐cyano L‐alanine 4 a with amino acid methyl ester hydrochlorides.

Synthesis of Bis-Glyoxylamide Peptidomimetics Derived from Bis-N-acetylisatins Linked at C5 by a Methylene or Oxygen Bridge.

The bis-glyoxylamide peptidomimetics have been synthesized from bis-N-acetylisatins linked at C5 by ring-opening with alcohols, amines, and amino acid methyl ester hydrochlorides. X-ray images of single crystals of bis-glyoxylamide peptidomimetics have been obtained.

Mechanochemical Synthesis of Dipeptides Using Mg‐Al Hydrotalcite as Activating Agent under Solvent‐Free Reaction Conditions

Given the high demand for green and sustainable synthetic methods for the formation of amides and peptidic bonds, herein we report the efficient, solvent‐free mechanochemical synthesis of dipeptides from N‐protected amino acids and amino acid methyl ester hydrochlorides in the presence of 1‐hydroxybenzotriazole (HOBt) and N‐ethyl‐N′‐[3‐(dimethylamino)propyl]carbodiimide hydrochloride (EDC) as coupling reagents, and using Mg‐Al hydrotalcite‐like minerals as green activating agent. From commercial Mg‐Al hydrotalcite (HT‐S), we obtained its calcined (HT‐C) and reconstructed (HT‐R) modifications, which were evaluated as activating heterogeneous bases in amidation reactions, replacing commonly used toxic and/or corrosive bases (e.g., NEt3, iPr2NEt and NaOH). As a practical application of this strategy, various α,α‐, α,β‐ and β,β‐dipeptides were prepared in good to excellent yields. Under optimized reaction conditions (vibrating mill at 25 Hz for 75 min) HT‐S and HT‐R showed higher activity (89 % yield of the desired peptide) compared with HT‐C (57 % yield). The present protocol offers several advantages, including the use of readily available reagents and inexpensive materials, easy workup, simple recovery and recyclability of the hydrotalcite activator, and short reaction times.

Theophylline-7-acetic acid derivatives with amino acids as anti-tuberculosis agents

A series of amides were synthesized by condensation of theophylline-7-acetic acid and eight commercially available amino acid methyl ester hydrochlorides. Consecutive hydrolysis of six of the amido-esters resulted in the formation of corresponding amido-acids. The newly synthesized compounds were evaluated for their in vitro activity against Mycobacterium tuberculosis H37Rv. The activity varied depending on the amino acid fragments and in seven cases exerted excellent values with MICs 0.46–0.26μM. Assessment of the cytotoxicity revealed that the compounds were not cytotoxic against the human embryonal kidney cell line HEK-293T. The theophylline-7-acetamides containing amino acid moieties appear to be promising lead compounds for the development of antimycobacterial agents.

Synthesis and evaluation of some amino acid conjugates of suprofen

Amino acid conjugates of suprofen were synthesized by coupling the carboxylic group (as acid chloride) of suprofen and various amino acid methyl ester hydrochlorides. The structures of the synthesized conjugates were characterized by analytical and spectral data. Release of the drug from the conjugates was investigated by performing hydrolytic studies in simulated gastric fluid (SGF) at pH 1.2, simulated intestinal fluid (SIF) at pH 7.4 and SIF + 80% human plasma at pH 7.4. The results revealed that the drug was readily released from the conjugates in SIF at pH 7.4 and SIF + 80% human plasma at pH 7.4 following first order kinetics except for SGF at pH 1.2 where it exhibited negligible hydrolysis. The amino acid conjugates were evaluated for analgesic, acute and chronic anti-inflammatory and ulcerogenic activities. The results suggest that the amino acid conjugates showed comparable analgesic and anti-inflammatory activities to free drug with marked reduction in ulcerogenicity.

Synthesis and evaluation of some amino acid conjugates of pirprofen

Amino acid conjugates of pirprofen were synthesized by coupling reaction of acid chloride of drug and various amino acid methyl ester hydrochlorides. The synthesized conjugates were characterized by IR, NMR and mass spectral analysis. The hydrolysis study of the conjugates was performed to investigate the kinetic (release rate) behavior of the conjugates and the results showed that the release rate followed first order kinetics. A faster release of the parent drug from the conjugates was observed in 0.05M phosphate buffer with 80% human plasma owing to presence of amidases. The conjugates were evaluated for analgesic, anti-inflammatory and ulcerogenic activity. Higher anti-inflammatory activity shown by PTME (62.06%) may be due to synergistic effect of amino acid and pirprofen. The conjugates showed comparable analgesic and anti-inflammatory activities to free drug with much reduced ulcerogenicity.

Synthesis, characterization and in vitro hydrolysis studies of ester and amide prodrugs of dexibuprofen

Ten prodrugs of dexibuprofen having ester and amide moieties instead of free carboxylic acid which involves in gastrointestinal side effects have been synthesized. Dexibuprofen acid chloride was condensed with different amino acid methyl ester hydrochlorides and five alcohols to afford the amide and ester prodrugs. All of the synthesized prodrugs were characterized by their mp, R f, elemental analysis, FTIR, 1H NMR, and 13C NMR spectroscopy. The in vitro hydrolysis studies in plasma reflect prodrugs have been varied in terms of reactivity toward hydrolysis, owing to the different chemical structures. In alkyl substitution the branched chain alkyl substituents or aromatic substituents resulted in enhanced lipophilicity but diminished dissolution and hydrolysis rate. The amide prodrugs with branched and aromatic substitution can also be considered for sustained release. Prodrugs are less irritating to gastric mucosa than dexibuprofen.

ChemInform Abstract: A Comparative Study of the Reactions of Thiophene-2-carboxanilides and Related Compounds.

Thiophene-2-carboxanilide and itsp-chloro andp-bromo derivatives react with chlorosulfonic acid to give the corresponding sulfonyl chlorides, which react with amino acids to give the respective derivatives. Several methyl esters of the latter were prepared. Hydrazinolysis of these methyl esters yielded the hydrazides. Coupling reactions of some sulfonylamino acids with amino acid methyl ester hydrochlorides in THF-Et3N medium using the dicyclohexylcarbodiimide method give the corresponding dipeptide methyl esters. The spectral data of the compounds are briefly discussed.

Synthesis and antimicrobial screening of peptidyl derivatives of bromocoumarins/methylimidazoles.

In this investigation, it was of interest to synthesize novel series of peptide analogs of 3bromocoumarins and 2-methylimidazoles. Substituted coumarinyl-oxyacetic acids 1, 2 were synthesized by alkylation of corresponding hydroxycoumarins with chloroacetic acid. The imidazolyl derivatives 13, 14 were prepared by interaction of 2-methylimidazole with substituted/unsubstituted anthranilic acids. Coupling of compounds 1, 2, 13 and 14 with different amino acid methyl ester hydrochlorides, dipeptide, tripeptide and tetrapeptide methyl esters afforded novel coumarino/imidazolopeptide derivatives 3-10 and 15-22. Selected peptide ester derivatives were further hydrolyzed by using lithium hydroxide to afford corresponding acid derivatives 11, 12 and 23, 24. The antibacterial and antifungal effects of synthesized peptide derivatives were studied against eight pathogenic microbes. Among the tested compounds, 19, 22 and its hydrolyzed analog 24 exhibited good antimicrobial activity against Pseudomonas aeruginosa, Klebsiella pneumoniae, Trichophyton mentagrophytes and Microsporum audouinii, and compounds 8, 10 and 12 displayed good antifungal activity against Candida albicans with minimum inhibitory concentration of 6.25 g/ml.

Synthesis and Biological Activities of New Chiral Imidazolinone Derivatives

New optically active 2-thio-4-imidazolinones 3 with a chiral carbon at position-3 were synthesized from isothiocyanates 2, which were obtained from aza-Wittig reactions of vinyliminophosphoranes 1 with CS2, with easily accessible chiral (S)- or (R)-amino acid methyl ester hydrochlorides. 2-Methylthio-4H-imidazolin-4-ones 4 were obtained by the S-alkylation of compounds 3 in the presence of K2CO3 causing partial racemization of the enantiomeric pure products. These compounds were identified by MS, IR, 1H NMR, 13C NMR spectroscopy, and elemental analysis. The structures of enantiomers 3c and 3d were also confirmed by X-ray diffraction analysis. The results of preliminary bioassay indicated that compounds 4 exhibited growth inhibition of barnyard grass and cole root and stalk, and fungicidal activities against Fusarium oxysporium, Rhizoctonia solani, Gibberella zeae, Dothiorella gregaria, and Colletotrichum gossypii. Supplemental materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.

Syntheses and reactions of methyl [3-(4-phenyl-thiazol-2-yl)-thioureido] alkanoates and related compounds

Thiazole thioureas 4a-d and 6 bearing an amino acid ester residue were prepared by a one-pot sequential reaction of methyl thiocarbamate 2 with amino acid methyl ester hydrochlorides. Some chemoselective reactions of 4a,b with alkyl halides were studied.

Enantiomeric Recognition in Host-Guest Complexation Using Chiral Bis-pyridino-18-crown-6 Ethers, by Electrospray Ionization Mass Spectrometry (ESI-MS) Enantiomer-Labelled (EL) Guest Method

Enantiomeric recognition of chiral amino acids by synthetic and natural host compounds is one of the most challenging subjects in modern host-guest chemistry. Hostguest chiral recognition plays an important role in biological process, resolution of enantiomers, and asymmetric catalysis reactions. A number of synthetic model compounds have been designed and synthesized as chiral host molecules that help chemists understand the basis of the mechanism of host-guest complexations and their chiral recognitions. Hence, the successful design, synthesis, and application of chiral macrocyclic ligands with the selective recognition of the guests have attracted much attention for the investigations of catalysis, separations, and enzyme mimics. To determine the chiral recognition of these hosts, various methods of extraction/NMR, extraction/polarimetry, NMR titration, variable temperature NMR, nuclear overhauser effects (NOE), UV-vis titration, HPLC, capillary electrophoresis, transport, and membrane electrode have been used. A high degree of chiral recognition was observed in these studies. In the host-guest complex systems, chiral recognition has been detected by Sawada and his co-workers using fast atom bombardment mass spectrometry (FAB-MS) and electrospray ionization mass spectrometry (ESI-MS). In this reports, ESI-MS enantiomer-labeled (EL) guest method is utilized. This method requires the isotopic labeling of guest (G) enantiomers, and detects the complexation of a target host (H) compound with a 1:1 mixture of the unlabeled (GR) and labeled enantiomer guests (GS-dn). The peak intensity ratio, I[(H + GR) ]/I[(H + GS-dn), of two diasteromeric host-guest complex, which appeared simultaneously with n mass-unit difference in one ESI mass spectrum, was abbreviated as ‘IRIS’ for shot and adopted here as a critical measure for detecting chiral recognition ability. This method is a direct and operationally simple method, and it is a major feature of the stream needed for rapid screening of enantiomeric recognition. We studied the synthesis of chiral bis-pyridino-18-crown6 ethers, and the chiral recognition of α-amino acids and chiral amines by FAB-MS EL guest method, UV-vis titration, and H-NMR titration. Our interest has been focused on the enantiomeric recognition of amino acids by utilizing synthetic chiral bis-pyridino-18-crown-6 ether. We report herein the synthesis of chiral bis-pyridino-18-crown-6, (R,R,R,R)-5 and 6 with tetraethyl tetracarboxylate and tetramethyl tetracarboxamide groups as chiral barriers, and their enantiomeric recognition of several amino acid methyl ester hydrochlorides (7-16) by ESI-MS EL guest method. The IRIS values for the enantiomeric recognition of amino acid methyl ester hydrochlorides (7-16) using chiral bispyridino-18-crown-6 ether, (R,R,R,R)-5 and 6, were detected by ESI-MS EL guest method.

A convenient synthesis of amino acid methyl esters.

A series of amino acid methyl ester hydrochlorides were prepared in good to excellent yields by the room temperature reaction of amino acids with methanol in the presence of trimethylchlorosilane. This method is not only compatible with natural amino acids, but also with other aromatic and aliphatic amino acids.

Synthesis and reactions of methyl 2-[3-(2-phenylquinazolin-4-yl)thioureido]alkanoates

Methyl 2-[3-(2-phenylquinazolin-4-yl)thioureido]alkanoates bearing an amino acid ester residue were prepared by a novel three step sequential reaction of N-(2-cyanophenyl)benzimidoyl isothioyanate with amino acid methyl ester hydrochlorides. Some chemoselective reactions of methyl 2-[3-(2-phenylquinazolin-4-yl)thioureido]alkanoates with alkyl halides were studied.

Novel Communication: Some Novel Organosulfur Amino Acid Derivatives as Potential Antiparasitic Agents

The chalones 1, 14, and 26 reacted with chlorosulfonic acid to give corresponding sulfonyl chlorides 2, 15, and 27, which condensed with nucleophiles to give amino acid derivatives 3–6, 16–18, and 28–31. Some of the corresponding methyl esters 7, 8, 19–20, and 32–34 were prepared. Hydrazinolysis of these methyl esters yielded hydrazides 9, 10, 21, 22, and 35–36. Coupling reaction of some amino acid derivatives with amino acid methyl ester hydrochloride in THF-Et 3 N using dicyclohexylcarbodiimide method furnished the desired dipeptide methyl ester's 11–13, 23–25, and 37–38. Some spectroscopic evidence including NMR spectra analysis are briefly discussed.

Some Novel Sulfanilyl Amino Acids and Dipeptides Derivatives

3-(N-phenylcarboxamido)-coumarin 1 reacted with chlorosulfonic acid to give the corresponding sulfaniyl chloride 2 . However, isonicotinic acid anilide 14 , and nicotinic acid anilide 33 , reacted with chlorosulfonic acid in a 1:6 molar ratio, only for conversion into sulfanilyl chlorides 15 and 34 . Treatment with nucleophilic reagents afforded amino acid derivatives 3–6 , 16–20 , and 35–37 . Some of the corresponding methyl esters 7–9 , 21 , 24 , and 38–39 were prepared. Hydrazinolysis of some methyl esters yielded hydrazides 25–28 and 40–41 . Coupling reactions of some amino acid derivatives with amino acid methyl ester hydrochloride in THF-Et 3 N medium using the dicyclohexyl carbodiimide DCC furnished the desired dipeptide methyl esters 10–13 , 29–32 , and 42–43 . The spectral properties of the compounds are briefly discussed.

Enantiomeric Recognition of d- and l-Amino Acid Methyl Ester Hydrochlorides by New Chiral Bis-pyridino-18-crown-6 Substituted with Urea, and Diphenyl Groups

The article reports the synthesis and chiral recognition properties of a new chiral bis-pyridino-18-crown-6 (7), having urea, diphenyl, and allyloxy groups. The chiral bis-pyridino-18-crown-6 was prepared by a thirteen-steps procedure from the commercially available (S)-(+)-mandelic acid and chelidamic acid. The association constants (K a) (1.33 × 103–3.20 × 103) for enantiomeric recognition of d- and l-amino acid methyl ester hydrochlorides using the chiral bis-pyridino-18-crown-6 have been examined by 1H-NMR titration method in CDCl3 at 25 °C. The chiral bis-pyridino-18-crown-6 showed higher association constants for the d-series amino acid methyl ester (d-AlaOMe, d-LeuOMe, d-MetOMe) hydrochlorides as compared to the corresponding l-series (l-AlaOMe, l-LeuOMe, l-MetOMe) hydrochlorides.

Synthesis of Heterocyclic Thiourea Compounds with Amino Acid Side Chain as Nonnucleoside Inhibitors of HIV‐1 Reverse Transcriptase

Heterocyclic thioureas having an amino acid ester side chain were prepared in two steps with overall yields of 65–85%. Condensation of a substituted heterocyclic amine with thiocarbonyldiimidazole, followed by treatment with an amino acid methyl ester hydrochloride in DMF, yielded the desired heterocyclic thioureas as crystalline solids. Amino acid esters such as glycine, leucine, valine, phenyl alanine, and tryptophan were used to prepare these thioureas.

Curtius Rearrangement Using Ultrasonication: Isolation of Isocyanates of Fmoc-Amino Acids and Their Utility for the Synthesis of Dipeptidyl Ureas

An efficient conversion of NI±-(P-fluorenylmethytyoxy carbonyl (Fmoc) amino acid azides to the corresponding isocyanates using ultrasound is described. The Curtius rearrangement was accomplished using acid azides in toluene solution as well as solid powder at room temperature. All isocyanates synthesized have been obtained as crystalline solids and were characterized. Coupling of isocyanates with amino acid methyl ester hydrochloride salts in presence of N-methylmorpholine (NMM) resulted in Fmoc-protected dipeptidyl urea esters, which have been well characterized by 1H NMR, 13C NMR and mass spectrometry. © 2005 Springer Science+Business Media, Inc.

Thermodynamics of Amino Acid Methyl Ester Hydrochlorides—Crown Ether Complexes in Methanol at 25°C

Stability constants, free energies, and enthalpies and entropies of the complexation of L-alanine methyl ester hydrochloride (L-Ala-HCl), L-phenylalanine methyl ester hydrochloride (L-Phe-HCl), and valine methyl ester hydrochloride (L-Val-HCl) with 15-crown-5 (15C5), benzo-15-crown-5 (B15C5), 18-crown-6 (18C6), benzo-18-crown-6 (B18C6), dicyclohexano-18-crown-6 (DC18C6), and dicyclohexano-24-crown-8 (DC24C8) in methanol are reported for 20°C. No significant variation in the stability constants and free energies of complexation is observed, indicating that the various crown ethers are poorly selective in binding the amino acids. However, the nature of the crown ether and the amino acid and their pattern of substitution cause a remarkable variation in the enthalpies and entropies of complexation. This indicates a strong enthalpy–entropy compensation effect. The enthalpy–entropy compensation effect for the crown ether complexes of the amino acid methyl ester hydrochlorides reported herein is compared with that of the crown ethers complexes of the amino alcohols and the free amino acid. It is found that the enthalpy–entropy compensation effect holds equally for the three classes of complexes.