Reaction development and mechanistic study of a ruthenium catalyzed intramolecular asymmetric reductive amination en route to the dual Orexin inhibitor Suvorexant (MK-4305)

The first example of an intramolecular asymmetric reductive amination of a dialkyl ketone with an aliphatic amine has been developed for the synthesis of Suvorexant (MK-4305), a potent dual Orexin antagonist under development for the treatment of sleep disorders. This challenging transformation is mediated by a novel Ru-based transfer hydrogenation catalyst that provides the desired diazepane ring in 97% yield and 94.5% ee. Mechanistic studies have revealed that CO(2), produced as a necessary byproduct of this transfer hydrogenation reaction, has pronounced effects on the efficiency of the Ru catalyst, the form of the amine product, and the kinetics of the transformation. A simple kinetic model explains how product inhibition by CO(2) leads to overall first-order kinetics, but yields an apparent zero-order dependence on initial substrate concentration. The deleterious effects of CO(2) on reaction rates and product isolation can be overcome by purging CO(2) from the system. Moreover, the rate of ketone hydrogenation can be greatly accelerated by purging of CO(2) or trapping with nucleophilic secondary amines.     

Practical asymmetric synthesis of a gamma-secretase inhibitor exploiting substrate-controlled intramolecular nitrile oxide-olefin cycloaddition

A practical asymmetric synthesis of the gamma-secretase inhibitor (-)-1 is described. As the key transformation, a highly diastereoselective intramolecular nitrile oxide cycloaddition forms the hexahydrobenzisoxazole core of 3 in four operations. Other aspects of the route include a highly stereoselective reduction of an isoxazole to form a cis-gamma-amino alcohol, an efficient chemical resolution, a dianion cyclization to construct a sultam ring, and the alpha-alkylation of a sultam with excellent diastereoselectivity. In each instance, the relative stereochemistry was evolved by way of substrate-based induction with > or = 96% ds. Kilogram quantities of the targeted drug candidate (-)-1 were obtained, without recourse to chromatography, by way of 10 isolated intermediates and in 13% overall yield.     

1,2,5-thiadiazole-1-oxides,IV, ring transformation to 1,2,3,5-thiatriazole- and 1,2,4,6-thiatriazene-1-oxide

2-Alkyl-1,2,5-thiadiazole-3-one-1-oxides were converted to 1,2,3,5-thiatriazole-1-oxides and 1,2,4,6-thiatriazene-1-oxides. The postulated intermediate of these rearrangements, a sulfinylamine, was isolated.     

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.     

Isolation and identification of impurities in L-696, 229 drug substance

Two low level impurities in 3-[2-(2-benzoxazolyl)ethyl]-5-ethyl-6-methyl-2(1H)-pyridinone drug substance (L-696,229) have been isolated by a combination of preparative HPLC, solid-phase extraction and liquid-liquid extraction. They were identified as 3-[2-(2-benzoxazolyl)ethyl]-5-ethyl-6-(2-phenylethyl)-2(1H)-pyridinone (I) and 6,6'-(2-phenyl-1,3-propanediyl)bis[3-[2-(2-benzoxazolyl)ethyl]-5-ethyl-2(1H)-pyridinone] (II) by mass spectrometry and by their (13)C and (1)H-NMR spectra.     

Efficient enantioselective synthesis of sertraline, a potent antidepressant, via a novel intramolecular nucleophilic addition to imine

[formula: see text] An efficient enantioselective synthesis of sertraline, an antidepressant, utilizing anionic imine ring closure is described.     

A regioselective approach to 5-substituted-3-amino-1,2,4-triazines

Nucleophilic displacement of readily available alpha,alpha-dibromoketones with excess morpholine gave the corresponding ketoaminals, which upon condensation with aminoguanidine in MeOH in the presence of AcOH afforded 5-substituted-3-amino-1,2,4-triazines in >95% regioselectivity and 45-76% isolated yield. [reaction: see text]     

Preparation of a clinically investigated ras farnesyl transferase inhibitor

The synthesis of ras farnesyl‐protein transferase inhibitor 1 is described on a multi‐kilogram scale. Retrosynthetic analysis reveals chloromethylimidazole 2 and a piperazinone 3 as viable precursors. The 1,5‐disubstituted imidazole system was regioselectively assembled via an improved Marckwald imidazole synthesis. A new imidazole dethionation procedure has been developed to convert the Marckwald mercaptoim‐idazole product to the desired imidazole. This methodology was found to be tolerant of a variety of functional groups providing good to excellent yields of 1,5‐disubstituted imidazoles. A new Mitsunobu cycliza‐tion strategy was developed to prepare the arylpiperazinone fragment 3 .     

Imino-bridged heterocycles. VI . An unusual bridge structure resulting from an attempted ritter reaction in the benzo[5,6]cyclohepta[1,2-c]pyridine system

An attempt to generate a tertiary carbinamine from 1 , through use of the Ritter reaction, resulted in the formation of the new bridged system 2 . This product apparently resulted from an intramolecular cyclization of the 5,6 olefin to the C-11 nitrilium ion of 4 , followed by a second Ritter reaction at C-6.     

Practical synthesis of a potent hepatitis C virus RNA replication inhibitor

A practical, efficient synthesis of 1, a hepatitis C virus RNA replication inhibitor, is described. Starting with the inexpensive diacetone glucose, the 12-step synthesis features a novel stereoselective rearrangement to prepare the key crystalline furanose diol intermediate. This is followed by a highly selective glycosidation to couple the C-2 branched furanose epoxide with deazapurine.