Xianhua Pan

The asymmetric synthesis of Sitagliptin, a selective dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes

An efficient asymmetric synthesis of Sitagliptin, a new DPP-IV inhibitor for the treatment of type 2 diabetes mellitus has been developed. The beta-amino acid fragment of Sitagliptin was prepared by asymmetric Michael addition of the corresponding α, β-unsaturated ester to (R)-(α-methylbenzyl)benzylamine followed by a two-step elaboration to obtain N-boc beta-amino ester. Hydrolysis of the ester and coupling with the triazolopiperazine afforded Sitagliptin after cleavage of the N-boc group and salt formation. The overall yield was 31% over nine steps.

The synthesis of a chiral β-amino acid derivative by the Grignard reaction of an aspartic acid equivalent

A novel synthetic route to chiral β-amino acid derivative has been developed by a Grignard reaction of 2,4,5-trifluo-rophenyl magnesium bromide with the Weinreb amide derivative of L-aspartic acid. The aspartic equivalent was synthesised from L-aspartic acid in four steps, and the Grignard reagent was prepared by Br–Mg-exchange reaction. The target compound was achieved after the Grignard reaction and a subsequent reduction. Tthe stereo structure of the chiral amine was well preserved from the L-aspartic acid.

Synthesis of a chiral β-amino acid derivative by a cobalt-catalysed coupling reaction

A chiral β-amino acid derivative was synthesised by a cobalt-catalysed alkylation of 2,4,5-trifluorophenyl magnesium bromide with the alkyl halide derivative of L-aspartic acid, using an efficient catalytic reagent: CoCl2/TMEDA. The halide derivative was synthesised from protected L-aspartic acid β-methyl ester and the Grignard reagent was made by bromine- magnesium exchange. The stereo-structure was well preserved from L-aspartic acid.

An efficient synthesis of (R)-3-aminothiolane

An efficient synthesis of (R)-3-aminothiolane is described based on a one-pot tandem hydroxyl activation-intramolecular cyclisation of Ts-protected-D-methioninol in the presence of methanesulfonyl chloride/pyridine. Removal of the tosyl group then gave (R)-3-aminothiolane in good yield. (R)-3-Aminothiolane derivatives are important building blocks for the synthesis of biologically active compounds.

An improvement to the preparation of prasugrel hydrochloride

An efficient synthesis of prasugrel, a thienopyridine ADP-receptor antagonists, is described. A thienopyridine inter-mediate was prepared by N-protection, boric acid substitution and N-substitution. After acid hydrolysis of the methyl ether and subsequent acetylation, prasugrel was obtained with a total yield of 50% after seven linear steps from 4,5,6,7-tetrahydrothieno [3,2-c]pyridine and 2-bromo-1-cyclopropyl-2-(2- fluorophenyl)ethan-1-one as raw materials.

Efficient Synthesis of 3-R-Boc-amino-4-(2,4,5-trifluorophenyl)butyric Acid

Abstract 3-R-Boc-amino-4-(2,4,5-trifluorophenyl)butyric acid (9) was obtained from L-methionine in six steps with a total yield of 32%. The α-amino acid segment of L-methionine was transferred to chiral aziridine by amino protection, reduction, hydroxyl derivation, and cyclization. After ring opening of 2,4,5-trifluoro-phenyl magnesium bromide, the methylthiomethyl group was then hydrolyzed to β-amino alcohol and oxidized to the target β-amino acid. GRAPHICAL ABSTRACT

Synthesis of S -3-hydroxyadamantylglycine ester by a Pd/C promoted mild Leuckart–Wallach reaction and an L-dibenzoyltartaric acid resolution

A mild Leuckart-Wallach reaction in the presence of catalytic amount Pd/C was developed. Under the optimised reaction conditions, 30% Pd/C loading, 40 °C, 6 atm N2 atmosphere, racemic 3-hydroxyadamantylglycine ester was obtained in 85% yield. The racemic amino esters were resolved chemically. The ethyl ester was resolved with L-dibenzoyltartaric acid in i-PrOH, give (S)-3-hydroxyadamantylglycine ester in 99% ee and 34% yield. The enantiomerically enriched unwanted isomer was converted to the racemic amino ester and resolved again.

Synthesis of Three Fluoroquinolone Compounds

Pazufloxacin, one of the representative compounds of many fluoroquinolones (Scheme-I), was jointly developed by Toyama Chemical Co., Ltd. and Mitsubishi Pharma Corporation in 2002. Because of an intriguing action on Topoisomerase and DNA gyrase collectively, pazufloxacin has an advantage in inhibiting bacterial DNA replication and exerting antibacterial effect. Many synthetic procedures about fluoroquinolones were described in the last thirty years. The biological activity of fluoroquinolones is highly dependent on their constitutions: R1 group can help to enhance the antibacterial effect and prolong the time of half-life; R2 and R4 groups are related to phototoxicity; and R3 group is associated with many adverse drug reactions in vivo. When if the R3 group of fluoroquinolones is amino cyclopropyl (pazufloxacin), will help enhance the water-solubility and the antibacterial activity of Gram-positive bacteria. Some reported efficient antibacterial drugs, such as gemifloxacin and moxifloxacin, both have appropriate modification in R3 group. After more than a decades clinical application, there have been many adverse drug reactions of pazufloxacin. It is now well documented that the slight adverse drug reactions in gastrointestinal tract are related to the basic structure of fluoroquinolone, especially the R3 analoges (Scheme-II) .

A novel method for the synthesis of 2-(3-hydroxy-1-adamantyl)-2-oxoacetic acid

A simple and efficient synthetic route to 2-(3-hydroxy-1-adamantyl)-2-oxoacetic acid is described by a direct oxidation reaction of adamantan-1-yl-ethan-1-one which could be prepared by a Grignard reaction. In this approach, the oxidation reaction introduced the hydroxyl and carboxyl group by a one-pot reaction.