Shigeto Negi

Large scale synthesis of N-benzyl-4-formylpiperidine through partial reduction of esters using aluminum hydride reagents modified with pyrrolidine

Abstract The modification of sodium bis(2-methoxyethoxy)aluminum hydride (SMEAH) with pyrrolidine provided a highly selective reducing agent to transform N -benzyl-4-ethoxycarbonylpiperidine into N -benzyl-4-formylpiperidine 1 under mild conditions. However, this simple modification led to a significant amount of N -benzyl-4-(pyrrolidin-1-ylmethyl)piperidine 4 due to overreduction of an intermediate. Our extensive research revealed that an alkaline base such as potassium tert -butoxide could suppress the formation of the by-product to give the desired aldehyde, enabling us to establish a viable synthetic process for a key intermediate of donepezil hydrochloride. The potential applications of this reagent are also described.

Oxidation of 4-Oxo-4H-1-Benzopyran-3-Carboxaldehydes with N-Bromosuccinimide

Abstract 4-Oxo-4-H-1-benzopyran-3-carboxylic acids and their derivatives (esters and amides), 2, are known to possess interesting pharmacological activities.1 As part of our synthetic studies of biologically active compounds, we needed to prepare a variety of 2 (carboxylic acids, esters, amides, etc.). An elegant method for the preparation of 4-oxo-4H-1-benzopyran-3-carboxaldehydes, 1, was reported independently by Nohara et al. 2 and Harnish.3 However, despite a rather extensive effort by Nohara et al., the oxidation of 1 to 2 (Y=OH) has not been realized in good yield; thus the yields by Jones oxidation, the best reported method, ranged only from 9.5 to 39%.4

Practical Oxirane Ring Opening with In Situ Prepared LiCN; Synthesis of (2S,3R)-3-(2,4-Difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)-1-butanenitrile

Abstract Trisubstituted oxirane 1 was regiospecifically opened with LiCN in situ prepared from acetone cyanohydrin and LiH to provide the corresponding β-hydroxy nitrile 2 in satisfactory yield, enabling us to manufacture a key intermediate for a new antifungal agent on a multi-kg scale. Some applications of this method to the ring opening of other oxiranes and nucleophilic substitution are also described.

Synthesis of a radiolabelled new oral cephalosporin, E1101

The new broad-spectrum oral antibacterial agent E1101, has been labelled in the C-2 position of the aminothiazole ring using [ 14 C]thiourea. The cephalosporin analog was synthesized in 5 steps and is suitable for metabolism and disposition studies.