No abstract

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.

37) One of the reviewers has suggested that this could be a trans isomer on the basis of IR spectral evidence presented in a manuscript that is under editorial consideration. However, we feel IR spectral evidence alone would prove insufficient for the correct assignment of the isomer. 'H NMR spectral study for this compound, which is presently being undertaken in our laboratory, might solve this problem, and this will form the basis for a future paper. for some of the electrochemical measurements. V.P. acknowledges the financial assistance (Senior Research Fellowship) by the CSIR, New Delhi, India. Registry No. [ ( b~y )~R u ( N C S e )~l , 115794-05-3; [ ( b~y )~R u ( N c S e ) -CI], 115704-98-8; [(bpy)2Ru(SeCN)CI], 115704-99-9; [Cl-(bpy)2RuNCSeRu(bpy)2C1]BPh4, 1 15705-03-8; [(bpy)2Ru(NCSe)C1]-BPh4, 115705-01-6; [(bpy)2Ru(NCSe)(SeCN)]BPh4, 115731-26-5; [Cl(bpy)2RuNCSeRu(bpy)2Cl](BPh4)3, 115705-05-0; [CI-(bpy)2RuNCSeRu(bpy)2CI](BPh4)2, 1 15705-07-2; [(bpy),Ru(NO)-Cl] (PF,),, 58575-12-5; cis-[(bpy)2RuC12], 19542-80-4; potassium azide, 20762-60-1.The reaction between [WCp*Me4]+ and 4 equiv of hydrazine (2-equiv excess) yields thermally unstable WCp*Me4(NHNH2). Crystals of WCp*Me4(NHNH2) obtained from a mixture of pentane and T H F retain 1 equiv of T H F per metal at low temperature, the T H F being bonded to two N H 2 protons in a symmetrically bound q2-NHNH2 ligand in one of the two WCp*Me4(NHNH2) molecules in each asymmetric unit. Evaluation of the potential hydrogen bonds between the two molecules in the asymmetric unit allows us to conclude that the lone pair on the pyramidal N H nitrogen atom is pointing toward the Cp* ligand. (Crystal data: a = 15.100 (7) A, b = 16.551 (6) A, c = 8.860 (8) A, (Y = 97.26 (6)O, 0 = 100.92 (5)O, y = 66.08 (4)O, V = 1984.4 A', space group P i , 2 = 4, M, = 410.31, p(ca1cd) = 1.564 g p = 55.4 cm-'. Final R, = 0.0973 and R2 = 0.1153.) IH and lSN N M R studies show that two of the three hydrazido(1-) protons equilibrate first, probably by a shift to the lone pair on the N H nitrogen atom of the N H 2 proton that points toward the Cp* ligand. WCp*Me4(NHNH2) loses methane in an apparent first-order decomposition reaction to give WCp*Me3(NNH2) in high yield. Protonation of WCp*Me3(NNH2) yields [WCp*Me3(NHNH2)]+, a structure study of which showed it also to contain an q2-NHNH2 ligand, but one that is unsymmetrically bound with the N H nitrogen atom being sp2 hybridized. (Crystal data for the triflate derivative: a = 23.619 (4) A, b = 8.486 (2) A, c = 21.921 (6) A, 0 = 100.40 (2)O, V = 4321 (3) A3, space group C2/c, 2 = 8, M , = 544.28, p(ca1cd) = 1.78 g cm-3, p = 57.9 cm-I. Final Rl =. 0.049 and Rz = 0.059.) WCp*Me,(NHNH2) is protonated to give what is postulated to be an q2-hydrazine complex, [ WCp*Me4(NH2NH2)]+, with a structure closely related to that of WCp*Me4(NHNH2).(1) (a) Coughlin, M., Ed. Molybdenum and Molybdenum-Containing Enzymes; . Current Perspectives in Nitrogen Fixation; Elsevier: Amsterdam, 1981. (d) Henderson, R. A.; Leigh, J.; Pickett, C. J. Adv. Znorg. Chem. Radioch...

Dimethyltitanocene R Titanocene dichloride P Dimethyltitanocene

2-Indolyl borates are prepared via addition of LDA to a mixture of N-Boc-indole and triisopropyl borate at 0-5 degrees C. Following acidic hydrolysis, the boronic acids are isolated by crystallization in good to excellent yield (73-99%). The method is quite general, tolerating a wide range of functional groups, and also provides access to 2-silyl derivatives (80-91%).