Galina L. Levit

KINETIC RESOLUTION OF ()-2,3-DIHYDRO-3-METHYL-4H-1,4-BENZOXAZINES WITH (S)-NAPROXEN

Abstract A very effective method for the preparation of the ( S )-enantiomers of 2,3-dihydro-3-methyl- and 7,8-difluoro-2,3-dihydro-3-methyl-4 H -1,4-benzoxazines ( 1a and 2a ) was developed using ( S )-(+)-naproxen acyl chloride as the chiral agent for kinetic resolution of racemates. This method enables one to obtain the ( S )-enantiomers of benzoxazines 1a and 2a of high enantiomeric purity (99% ee ) in nearly 50% yield, taking into account that the ( R )-enantiomers are recycled after their racemisation.

Kinetic resolution of (′)-2,3-dihydro-3-methyl-4H-1,4-benzoxazine, (′) -2-methyl-1,2,3,4-tetrahydroquinoline and (′)-2-methylindoline using N-tosyl-(S)-prolyl chloride

Acylation of racemic 2,3-dihydro-3-methyl-4H-1,4-benzoxazine, 2-methyl-1,2,3,4-tetrahydroquinoline and 2-methylindoline with N-tosyl-(S)-prolyl chloride resulted in their kinetic resolution with the predominant formation of (R,S)-diastereoisomeric amides, des being 80, 66 and 38%, respectively. Recrystallisation of the amides followed by acid hydrolysis gave individual (R)-enantiomers of heterocyclic amines.

Enantiomers of 3-amino-1-methyl-1,2-dicarba-closo-dodecaborane

The enantiomers of 3-amino-1-methyl-1,2-dicarba-closo-dodecaborane were prepared by means of resolution of the racemic mixture via acylation by (S)-naproxen chloride followed by separation and subsequent acid hydrolysis of each of the diastereoisomeric amides. Partial racemization of enantiomeric 3-aminocarboranes was observed during acid hydrolysis.

Synthesis of enantiomers of 6-nitro- and 6-amino-2-methyl-1,2,3,4-tetrahydroquinolines

Enantiomers of 2-methyl-6-nitro-1,2,3,4-tetrahydroquinoline have been obtained by kinetic resolution of racemic 2-methyl-1,2,3,4-tetrahydroquinoline in acylation with acyl chlorides of N-protected amino acids followed by regioselective nitration of the diastereoisomeric amides and acidic hydrolysis. The introduction of a trifluoroacetyl protecting group into the position 1 of the enantio pure nitro compound followed by the reduction led to (S)-6-amino-2-methyl-1-trifluoroacetyl-1,2,3,4-tetra-hydroquinoline in a high yield.

Kinetic resolution of racemic 2-methyl-1,2,3,4-tetrahydroquinoline and its structural analogs by using 2-arylpropionyl chlorides

Acylation of 2-methyl-1,2,3,4-tetrahydroquinoline and 2-methylindoline with the acyl chlorides of naproxen, ibuprofen, and 2-phenylpropionic acid has been found to lead to efficient kinetic resolution with predominant formation of the (S,S)-(R,R)-diastereoisomers. The highest acylation stereoselectivity was found in toluene at -20°C. No significant kinetic resolution of N-(sec-butyl)aniline and 2-methylpiperidine was achieved by using 2-arylpropionyl chlorides.

Synthesis and Antiinflammatory and Analgesic Activity of Naproxen Amides with Amino Acid Derivatives

In recent years, there have been attempts to modify the well-known nonsteroidal antiinflammatory drugs by reactions with natural amino acids, aimed at eliminating undesired side effects of the drug action [1]. In particular, the synthesis of naproxen amide with glycine was reported in [2, 3]. The aim of this study was to obtain naproxen amides with some amino acid derivatives and characterize the products with respect to the antiinflammatory and analgesic activity and acute toxicity. The synthesis of naproxen amides (II – V) with methyl esters of (S )-methionine, (S )-phenylalanine, (S )-histidine, and (S )-leucine was based on the condensation of (S )-naproxen chloroanhydride (I) with the corresponding amino acid esters in DMF in the presence of triethanolamine (TEA) [4]:

N-Tosyl-(S)-Prolyl Chloride in Kinetic Resolution of Racemic Heterocyclic Amines

The kinetic resolution of racemic heterocyclic amines via acylation with N-tosyl-(S)-prolyl chloride was systematically investigated. It was established that racemic mixtures of aromatic amines could be resolved with high efficiency, while the acylation of 2- and 3-methylpiperidines occurred with low diastereoselectivity. A method for the preparation of enantiomerically pure (3R)-7,8-difluoro-3-methyl-3,4-dihydro-2H-[1,4]benzoxazine was developed.

Kinetic resolution of heterocyclic amines by reaction with optically active acid chlorides. The effect of reaction conditions on the diastereoselectivity of acylation of (′)-3-methyl-2,3-dihydro-4H-1,4-benzoxazine

The influence of the reaction conditions (solvent, base) on the diastereoselectivity of acylation of (±)-3-methyl-2,3-dihydro-4H-1,4-benzoxazine with (S)-naproxen and N-tosyl-(S)-proline chlorides was studied. The highest diastereoselectivity was observed for the reaction carried out in benzene in the presence of aliphatic tertiary amines.

Efficient large (ca. 40 g) laboratory scale preparation of (S)- and (R)-valine tert-butyl esters

A large laboratory scale (ca. 40 g) method for the preparation of enantiomerically pure (S)- and (R)-valine tert-butyl esters has been developed. The method involves three steps: preparation of N-TFA-valines, preparation of valine tert-butyl esters using 2-methylpropene in dioxane in the presence of sulfuric acid, and isolation of the target compounds as the acetate derivative. The overall yield is up to 70% relative to the starting valine, ee being more than 98% (by HPLC).

Direct diastereoselective addition of l-menthol to activated 1,2,4-triazin-5(4H)-one

Abstract For the first time in a triazine series it has been found that addition of a chiral O -nucleophile, l -menthol, to the C 6 -unsubstituted atom of 3-phenyl-1,2,4-triazin-5(4 H )-one 1 activated by aliphatic acid anhydrides proceeds diastereoselectively to form a mixture of 1-acyl-6-[(1′ R ,3′ R ,4′ S )-menthyl-3′)]-3-phenyl-(6 S )-1,6-dihydro-1,2,4-triazin-5(4 H )-ones 2 and 1-acyl-6-[(1′ R ,3′ R ,4′ S )-menthyl-3′)]-3-phenyl-(6 R )-1,6-dihydro-1,2,4-triazin-5(4 H )-ones 3 in which the diastereomers 2 predominate. The diastereoselectivity of the process improves as the size of the N 1 -acyl substituent increases.