In silico evaluation of various regioisomeric 5- and 3-hydroxy-substituted alkyl 1-aryl-1H-pyrazole-4-carboxylates and their acyclic precursors yielded promising results with respect to their binding in the active site of dihydroorotate dehydrogenase of Plasmodium falciparum (PfDHODH). Consequently, four ethyl 1-aryl-5-hydroxy-1H-pyrazole-4-carboxylates and their 3-hydroxy regioisomers were prepared by two-step syntheses via enaminone-type reagents or key intermediates. The synthesis of 5-hydroxy-1H-pyrazoles was carried out using the literature protocol comprising acid-catalyzed transamination of diethyl [(dimethylamino)methylene]malonate with arylhydrazines followed by base-catalyzed cyclization of the intermediate hydrazones. For the synthesis of isomeric methyl 1-aryl-3-hydroxy-1H-pyrazole-4-carboxylates, a novel two-step synthesis was developed. It comprises acylation of hydrazines with methyl malonyl chloride followed by cyclization of the hydrazines with tert-butoxy-bis(dimethylamino)methane. Testing the pyrazole derivatives for the inhibition of PfDHODH showed that 1-(naphthalene-2-yl)-5-hydroxy-1H-pyrazole-4-carboxylate and 1-(naphthalene-2-yl)-, 1-(2,4,6-trichlorophenyl)-, and 1-[4-(trifluoromethyl)phenyl]-3-hydroxy-1H-pyrazole-4-carboxylates (~30% inhibition) were slightly more potent than a known inhibitor, diethyl α-{[(1H-indazol-5-yl)amino]methylidene}malonate (19% inhibition).

The reactions between 5-substituted pyrazolidine-3-ones, aldehydes, and methyl methacrylate provided tetrahydropyrazolo[1,2-a]pyrazole-1-carboxylates as mixtures of syn- and anti-diastereomers. Testing for inhibition of dihydroorotate dehydrogenase of Plasmodium falciparum (PfDHODH) revealed high activity of some antiisomers of the methyl esters, while the corresponding carboxylic acids and carboxamides were not active. The most active representative, methyl (1S*,3S*,5R*)-1,5-dimethyl-7-oxo-3-phenyltetrahydro-1H,5H-pyrazolo [1,2-a]pyrazole-1-carboxylate (IC50, = 2.9 +/- 0.3 mu M), also exhibited very high selectivity of the parasite enzyme vs. the human enzyme, PfDHODH/HsDHODH > 350. According to the molecular docking score, this high activity is explainable by synergic interactions of the methyl, phenyl and the CO2 Me substituent with the hydrophobic pockets in the active site of the enzyme. The carboxylic acid and carboxamides derived from this compound did not inhibit PfDHODH.

For the use of analytics, European pharmacopoeial impurities A, B, C, and D of cabergoline were synthesized. Ergocryptine was chosen as a starting material and synthesis was accomplished via two approaches, different in length and stereochemical outcome. A longer, indirect approach was realized through otherwise problematic oxidations of the 9,10-dihidrolysergol derivative, to the corresponding aldehyde and carboxylic acid. This was achieved by the use of activated DMSO and a Pinnick oxidation sequence. All four synthesized impurities are used as analytical standards in cabergoline manufacturing processes.

Treatment of beta-keto ester 8 with hydrazines 9a-g gave 1'-substituted tert-butyl 2-(5-hydroxy-1H-pyrazol-3-yl) ethylcarbamates 10a-e and 2-(5-oxo-2,5-dihydro-1H-pyrazol-3-yl) ethylcarbamates 11f,g. Acidolytic deprotection of 10b,c afforded the corresponding 3-(2-aminoethyl)-5-hydroxy-1H-pyrazoles 6b,c in good yields. Acylation of 6 gave either the N-acyl compounds 12b,c and 13c, or the N,O-diacyl derivative 14. Next, three N,N-dialkyl analogues 15a, b and 26c were prepared from dimethyl acetone-1,3-dicarboxylate 21 via condensation with hydrazines 9a and 9h followed by hydrolysis of the esters 22a, b, amidation of the carboxylic acids 23a, b, and reduction of the tertiary carboxamides 24a and 25b,c.

The effect of substituents on the chiral solvating properties of 13 different (S)-1,6-dialkylpiperazine-2,5-diones (S)-1a–m and five (3S,6S)-1,3,6-trialkyl analogues (S,S)-1n–r was studied by NMR in CDCl3 with methyl (RS)-N-benzoylleucinate (RS)-2a as the model analyte. Most diketopiperazines exhibited typical resolution, ΔΔδRS-20∼0.1ppm. Increased performance was observed with 6-CH2R substituted compounds (S)-1h–j. The best resolution of the NH protons of (R)-2a and (S)-2a, ΔΔδRS-20=0.227ppm, was obtained with (S)-1-isopropyl-6-(4-nitrobenzyl)piperazine-2,5-dione (S)-1j. An additional syn-oriented substituent at the C(3) position decreased the enantioselectivity. Association constants for the binding of (S)-1j to each enantiomer of (RS)-2a in CDCl3 at −20°C were determined by NMR titration.

Treatment of β-keto ester 8 with hydrazines 9a-g gave 1'-substituted tert-butyl 2-(5-hydroxy-1Hpyrazol-3-yl)ethylcarbamates 10a-e and 2-(5-oxo-2,5-dihydro-1H-pyrazol-3-yl)ethylcarbamates 11f,g.Acidolytic deprotection of 10b,c afforded the corresponding 3-(2-aminoethyl)-5-hydroxy-1H-pyrazoles 6b,c in good yields.Acylation of 6 gave either the N-acyl compounds 12b,c and 13c, or the N,O-diacyl derivative 14.Next, three N,N-dialkyl analogues 15a,b and 26c were prepared from dimethyl acetone-1,3-dicarboxylate 21 via condensation with hydrazines 9a and 9h followed by hydrolysis of the esters 22a,b, amidation of the carboxylic acids 23a,b, and reduction of the tertiary carboxamides 24a and 25b,c.

Eleven (S)-1,6-dialkylpiperazine-2,5-diones and five (3S,6S)-1,3,6-trialkylpiperazine-2,5-diones were prepared in three steps from the corresponding (S)-α-amino acid esters comprising of reductive N-alkylation, N-acylation and cyclisation. The synthesis of (S)-1,6-dialkylpiperazine-2,5-diones has a broad scope allowing preparation of diketopiperazines with primary and secondary alkyl groups at N(1), while the synthesis of (3S,6S)-1,3,6-trialkylpiperazine-2,5-diones is limited to compounds with primary alkyl groups at N(1). Reductive alkylation of amino acid ester hydrochlorides by catalytic hydrogenation in the presence of a carbonyl compound proved to be a simple, efficient and general method for the preparation of stable (storable) α-alkylamino acid ester hydrochlorides. The structures of the novel compounds were determined by NMR and X-ray diffraction.

AbstractThe dialkylpiperazines are prepared from α‐amino acid ester hydrochlorides in three steps.

Microwave-assisted [2+2] cycloaddition of (E)-3-dimethylamino-1-heteroaryl-prop-2-en-1-ones to dimethyl acetylenedicarboxylates gives (2E,3E)-dimethyl-2-[(dimethylamino)methylene]-3-(substituted)succinates in 8–91% yield. In the case of a 4,5-dihydrothiazoline derivative, cycloaddition also took place at the endocyclic CN double bond.

Two N-benzylated analogues of the antioxidant, radical scavenging, and neuroprotective alkaloid neoechinulin A were prepared. Since, according to SAR studies, stereochemistry does not play an important role, both analogues were prepared in racemic form, using enaminone chemistry.

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

A seven-step synthesis of 1-substituted 5-(2-acylaminoethyl)-1H-pyrazole-4-carboxamides 20 as the pyrazole analogues of histamine was developed. The synthesis starts with a three-step preparation of N(1)-substituted methyl 5-(2-tert-butoxycarbonylaminoethyl)-1H-pyrazole-4-carboxylates 7 from commercially available Boc-β-alanine (1). Subsequent four-step transformation of the key-intermediates 7 into the final products 20 was performed following two complementary reaction sequences comprising acidolytic removal of the Boc group, hydrolysis of the COOMe group, amidations of the COOH group, and acylations of the NH2 group. The structures of pyrazole derivatives were determined by spectroscopic methods and by X-ray diffraction.

A series of racemic and enantiopure (S,Z)-3-[(1H-indol-3-yl)methylidene]hexahydropyrrolo[1,2-a]pyrazin-4(1H)-one (cyclic Pro–ΔTrp) dipeptide analogues were prepared. Racemic analogues 6a–c were prepared by direct coupling of racemic cyclodipeptide enaminone (R,S)-5 with various indole derivatives. On the other hand, enantiopure analogues were prepared through a copper(I) catalyzed vinyl amidation reaction in which acyclic (S)-Pro–ΔTrp dipeptide analogues 20 and 21 were formed. Acyclic dipeptides were cyclized to enantiopure (S)-Pro–ΔTrp dipeptide analogues 24 and 25. For coupling reactions, vinyl bromides were prepared in several steps. From ethyl acetate (7), enaminone 8 was prepared and coupled with 2-methylindole and 2-phenylindole to give 9 and 10. Direct bromination of 3-(indole-3-yl)propenoates 9 and 10 at position 2 results in vinyl bromides 11 and 12. The Boc protecting group on the indole nitrogen 1′ in vinyl bromides 11 and 12 was introduced, before the copper(I) catalyzed coupling with N-Boc prolinamide 18 was performed. Enantiomeric purity of chiral intermediates and final products was determined mostly by HPLC or 1H NMR spectroscopy and X-ray diffraction.

Three closely related diketopiperazines, (S)-1-benzyl-6-methylpiperazine-2,5-dione (S)-1a, (S)-1-benzyl-3-methylpiperazine-2,5-dione (S)-1b, and (S)-6-methyl-1-(pentafluorobenzyl)piperazine-2,5-dione (S)-1c, were prepared and screened as potential chiral solvating agents in NMR spectroscopy. The 1H NMR spectra of 13 racemic α-amino acid derivatives (RS)-5a–5m were taken in CDCl3 in the presence of equimolar amounts of enantiopure diketopiperazines (S)-1a–1c at 29°C, 0°C, and −20°C. Compound (S)-1a exhibited the strongest chiral solvating properties for racemic α-amino acid derivatives (RS)-5a–5m and was recognized as a suitable CSA for the determination of their enantiomer composition. Weaker interactions of diketopiperazines (S)-1b and (S)-1c with compounds (RS)-5a–5m indicate that the position and properties of substituents play an important role in the binding affinity of diketopiperazines 1 towards amino acid derivatives 5. Association constants for binding of (S)-1a to each enantiomer of the leucine derivative (RS)-5d in CDCl3 at −20°C were also determined by NMR titration.

Novel racemic and enantiomerically enriched unsaturated tryprostatin B analogues were synthesised by an enaminone-based strategy. The synthesis also features a novel copper(I)-catalysed dipeptide formation. In addition, the enantiomeric purity of an enantiomerically enriched analogue was determined by H-1 NMR spectroscopy by use of our own chiral solvating agent.

In CDCl3 solution, enantiopure (S)-1-benzyl-6-methylpiperazine-2,5-dione (S)-1a formed diastereomeric CO⋯H–N hydrogen-bonded associates with racemic (RS,Z)-1-benzyl-3-[(dimethylamino)methylidene]piperazine-2,5-diones 2a and 2b, (RS)-tert-butyl pyroglutamate (RS)-2c and (RS)-N-benzoylalanine methyl ester (RS)-2d. This resulted in splitting (doubling) of the characteristic signals in the 1H NMR and 13C spectra of racemic compounds 2a–d in the presence of 1equiv of (S)-1a. The formation of hydrogen-bonded dimers in CDCl3 solution was studied by 1H NMR, 13C NMR and 2D NMR and confirmed by the intermolecular NOE observed between the hydrogen-bonded amide protons from each of the monomeric units, (S)-1a and 2a–c. On the other hand, a slightly different binding mode was proposed for association of (S)-1a with alaninamide (RS)-2d. Enantiomer compositions of known (weighed) mixtures of both enantiomers of tert-butyl pyroglutamate 2c were re-determined by 1H NMR in the presence of (S)-1a in CDCl3. The experimental values were in good agreement with the theoretical values, thus indicating the potential applicability of (S)-1a and related diketopiperazines as chiral solvating agents in NMR spectroscopy.