A high-yielding five-step synthesis of the title compound, methyl 7,9-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-1-carboxylate, starting from 2,4-dimethylaniline was developed. This synthesis involved N-alkylation of 2,4-dimethylaniline with ethyl 4-bromobutyrate to obtain ethyl 4-[(2,4-dimethylphenyl)amino] butanoate. Carbamoylation of the latter followed by hydrolysis of the resulting ester provided 4-[(2,4-dimethylphenyl)(methoxycarbonyl) amino] butanoic acid. Activation of the carboxylic acid using thionyl chloride followed by intramolecular cyclization via a Friedel-Crafts reaction using aluminum trichloride provided the title compound in good yield. Analogues of the title compound were also prepared similarly.

For the synthesis of cholesteryl ester transfer protein (CETP) inhibitor evacetrapib, a hydrogenative reductive amination was chosen to join the substituted cyclohexyl subunit to the benzazepine core. The addition of water, which suppressed undesired epimerization without affecting the rate of product formation, was key to the reaction's success. The process was scaled to produce more than 1100 kg of material.

An intramolecular thermal cyclization protocol was developed in a flow reactor to take advantage of the high pressures and temperatures that are easily obtained in small scale autoclave reactors that have been modified to handle slurries. This reactor was equipped with a fill/empty pumping system to enable easy and nearly complete transfer of slurries. The reaction conditions were designed to take advantage of the insolubility of the product in order to separate it from residual starting material by filtration after short reaction times. Recycling of the filtrate maximized the yield and throughput while minimizing decomposition. Recycles were accomplished using a strip to dryness protocol that was easily performed in a rotary evaporator. This new equipment set was designed with lab-hood manufacturing in mind, a minimized footprint, and the system was completely automated for charging, emptying, rinsing, and reacting. Additional efforts for quick screening and alternate modes of addition were also investigated.

The identification and development of an aldehyde–bisulfite adduct as an isolable starting material in the synthesis of the CETP inhibitor Evacetrapib are described. The physical properties of the sodium and potassium analogs are compared, and the extension of the scope of this study to include an investigation into the solid state properties of a range of sodium and potassium bisulfite adducts of commonly encountered aldehydes is discussed.

Routes to (2-chlorophenyl)[2-(phenylsulfonyl)pyridin-3-yl]methanone, 1, an intermediate in the manufacture of NK1-II inhibitor LY686017 are described which produce 1 in >75% yield and 95% purity. A highly selective telescoped ortho lithation/condensation/oxidation process was developed and successfully scaled to the clinical pilot plant to produce 25 kg of 1. For the pilot-plant campaign, the lithiation step was developed to operate at −50 °C using commercial lithium diisopropylamide (LDA), and the oxidation step employed catalytic TEMPO as the primary and NaOCl as the terminal oxidant. After completion of the pilot-plant campaign second-generation approaches to 1 were developed to improve process greenness where the lithiation and condensation step were operated as warm as −10 °C, the highly efficient AZADO catalyst was used as a substitute for TEMPO in the Anelli−Montanari oxidation, and process mass intensity was reduced 25%.

3-Alkylindoles were prepared in one step from indoles and ketones via a convenient reductive alkylation procedure using triethylsilane and trichloroacetic acid. Under this particular condition, unsubstituted indoles could be tolerated to afford good yields of 3-sec-alkylation products. (C) 2008 Elsevier Ltd. All rights reserved.

PPAR ligands with varied subtype selectivity have been synthesized using an achiral aminomethyl dihydrocinnamate template. Several compounds in this series have demonstrated potent plasma glucose and triglyceride lowering capability in rodent models of type 2 diabetes.

Process development and a pilot-plant process for the synthesis of 4 and its resolution to obtain (1S,2S,5R,6S)-spiro[bicyclo-[3.1.0]hexane-2',5'-dioxo-2,4'-imidazolidine]-6-carboxylic acid, (R)-alpha-methylbenzenemethanamine salt (5) are described. Starting from the inexpensive raw 2-cyclopenten-1-one and sulfur ylide 1 the racemic bicyclo keto ester 2 was synthesized. Reaction of 2 with potassium cyanide and ammonium carbonate under Bucherer-Berg's reaction conditions affords racemic 3 in 80% yield. Hydrolysis of 3 followed by the resolution with (R)-(+)-alpha-methylbenzylamine gave 4 in excellent yield and purity under optimized conditions. The improvement of the original discovery process to accommodate safety and environmental requirements for scale-up in manufacturing facilities is also discussed.

[GRAPHICS]The synthesis of the peroxime proliferator activated receptor (PPAR) α,γ-agonist (1) was accomplished with high enantio- and diastereoselectivity by employing an asymmetric hydrogenation strategy, of an α-alkoxy cinnamic acid derivative, to set the C-2 chiral center. A diastereospecific S(N)2 displacement under mild basic conditions established the C-10 stereochemistry without any detectable racemization of the two epimerizable chiral centers.

An efficient and fast screening methodology for optical resolution agents through the classical crystallization of the corresponding diastereomeric salts is described. In this contribution, we demonstrate that the determination of the eutectic composition by chiral analysis of the corresponding mother liquor (ML) obtained under appropriate experimental conditions provides us with a very fast screening methodology. We also demonstrate that solvent can have a profound effect not only on the efficiency of the resolution process by modifying the eutectic composition but also on the ease of crystallization.

Herein we describe a series of potent and selective PPARγ agonists with moderate PPARα affinity and little to no affinity for other nuclear receptors. In vivo studies in a NIDDM animal model (ZDF rat) showed that these compounds are efficacious at low doses in glucose normalization and plasma triglyceride reduction. Compound 1b (LY519818) was selected from our SAR studies to be advanced to clinical evaluation for the treatment of type II diabetes.

2-(p-Methoxyphenyl)-6-methoxybenzothiophene (3) was synthesized by acid-catalyzed cyclization and rearrangement of the beta-ketosulfide precursor 1, The use of Amberlyst 15 resin as a catalyst for the cyclization increased the isomer ratio from 75: 25 to 88:12, compared to a conventional approach using polyphosphoric acid (PPA), Although solid acid catalysts were also evaluated for the rearrangement, a two-phase mixture of methanesulfonic acid in toluene was found to be the best alternative to the use of PPA for this reaction. The rearrangement, which was shown to be equilibrium controlled, was driven towards completion by crystallization of the product as it formed. An Amberlyst 15 catalyzed cyclization, combined with an MsOH-catalyzed rearrangement, raised the overall isolated yield from 70 to 80%, and difficulties associated with the use of PPA on a large scale were eliminated. This process has been successfully scaled to a pilot plant and manufacturing scale.

The reactions of 4-hydroxy-5-oximino-3-thiophenecarboxylates with hydrazine and substituted hydrazines have been investigated. The products of the reactions have been shown to be pyrazole-3- or 5-thiohydroxamic acids rather than the hydrazones previously described by Benary and Silberstrom. Two alternate mechanisms are proposed which account for the regiochemical outcome. The structures of the pyrazole3- and 5-thiohydroxamic acids and corresponding nitriles have been proven by independent synthesis, comparison to known compounds, and by proton and carbon magnetic resonance and long range HETCOR experiments.