Efficient synthesis of NK(1) receptor antagonist aprepitant using a crystallization-induced diastereoselective transformation

An efficient stereoselective synthesis of the orally active NK(1) receptor antagonist Aprepitant is described. A direct condensation of N-benzyl ethanolamine with glyoxylic acid yielded a 2-hydroxy-1,4-oxazin-3-one which was activated as the corresponding trifluoroacetate. A Lewis acid mediated coupling with enantiopure (R)-1-(3,5-bis(trifluoromethyl)phenyl)ethan-1-ol afforded a 1:1 mixture of acetal diastereomers which was converted into a single isomer via a novel crystallization-induced asymmetric transformation. The resulting 1,4-oxazin-3-one was converted via a unique and highly stereoselective one-pot process to the desired alpha-(fluorophenyl)morpholine derivative. Interesting and unexpected [1,2]-Wittig and [1,3]-sigmatropic rearrangements were identified during the optimization of these key steps. In the final step, a triazolinone side chain was appended to the morpholine core. The targeted clinical candidate was thus obtained in 55% overall yield over the longest linear sequence.     

Asymmetric addition reactions of Grignard reagents to chiral 2-trifluoromethyl tert-butyl (Ellman) sulfinimine-ethanol adducts

The addition of Grignard reagents to chiral trifluoromethyl tert-butyl sulfinimine-ethanol adducts affords protected trifluoromethylamines in high yields with good to excellent diastereoselectivities. The stereochemical outcome of the addition is opposite to that expected via a chelation controlled transition state.     

Preparation of 2,5,7-trithiabicyclo[2.2.1]heptane from 1,2-bis-triisopropylsilanylsulfanyl alkenes

[reaction: see text] The chemical behavior of 1,2-bis-triisopropylsilanylsulfanyl alkenes 1 is relatively unexplored, and the weak sulfur-silicon bonds give rise to various transformations. Under acidic conditions (HCl) and in the presence of a Lewis acid at room temperature the bicyclic adduct 2 is obtained in good yield. The structure was confirmed by X-ray crystal analysis with R = benzyl.     

On some methods for performance ranking and correspondence analysis in the DEA context

Two novel methods named performance baseline and performance correspondence matrices are proposed to evaluate the performance of decision making units (DMUs) based on the techniques of singular value decomposition (SVD). The performance baseline matrix can be used to rank all the DMUs because it provides a common basis for performance comparison. The performance correspondence matrix can be used to conduct performance cluster analysis, with which to explore the structure of input/output variables that are associated with DMUs. The analysis can reveal the performance difference of the DMUs and the key input/output variables determining the efficiency of a certain DMU, and provides valuable quantitative information for adjusting variables to improve efficiency of the DMU. Three case studies are presented to demonstrate that the proposed methods in this work are effective and easy to use and can provide insights into proper selection of input/output variables for performance comparison to avoid over manipulating DEA models in practice.     

Cyclization of 2- and 3-indolylthiobenzoic,phenylacetic and nicotinic acids and esters to novel indole-containing tetracyclic ring systems

A series of 2- and 3-indolylthio benzoic, phenylacetic and nicotinic acids or esters were cyclized under dehydrative conditions affording several tetracyclic indole-containing ketones, several of which constitute the first reported examples of novel ring systems, such as the [1]benzothiepino[2,3-b] and [3,2-b]indole and the pyrido[3′2′:5,6] and [3′4′:5,6]thiopyrano[2,3-b] and [3,2-b]indole as well as the [3′2′:5,6] and [3′4′:5,6][1,3]thiazino[3,2-a]indole ring systems.     

一个亲脂的环腺苷酸类似物的合成及其活性

基于高度亲脂的分子可能增强对神经细胞膜的渗透力的设想,合成了一种新的环腺苷酸的类似物2'-O-oleoy1-2-(?)aza-adenosine 3',5'-cyclic phosphate(3),发现在10~(-3),10~(-4)和10~(-5)M时,该化合物对小鼠神经胶质癌组织培养细胞的杀灭率分别是97%,86%和60%。     

Updates to the dualized standard model on fermion masses and mixings

The dualized standard model has scored a number of successes in explaining the fermion mass hierarchy and mixing pattern. This note contains updates to those results including (a) an improved treatment of neutrino oscillations free from previous assumptions on the neutrino masses, and hence admitting now the preferred LMA solution to solar neutrinos; (b) an understanding of the limitation of the one-loop calculation so far performed, thus explaining the two previous discrepancies with the data; and (c) an analytic derivation with some new insights and confirmation of the numerical results previously obtained.Received: 5 March 2003, Revised: 24 April 2003, Published online: 11 July 2003     

Circumstantial evidence for rotating mass matrix from fermion mass and mixing data

It is shown that existing data on the mixing between up and down fermion states and on the hierarchical mass ratios between fermion generations, as far as can be so analyzed at present, are all consistent with the two phenomena being both consequences of a mass matrix rotating in generation space with changing energy scale. As a result, the rotating mass matrix can be traced over some 14 orders of magnitude in energy from the mass scale of the t quark at 175 GeV to below that of the atmospheric neutrino at 0.05 eV. Received: 27 August 2002 / Published online: 24 January 2003 RID="a" ID="a" e-mail: jose.m.bordes@uv.es RID="b" ID="b" e-mail: h.m.chan@rl.ac.uk RID="c" ID="c" e-mail: tsou@maths.ox.ac.uk