The evaluation of efficient synthetic methods for the preparation of (R)-2,4-diamino-5-(2,3-dichlorophenyl)-6-fluoromethylpyrimidine, GW273225X (1), is described. The initial synthesis using ethylfluoroacetate was evaluated against three alternative routes using either nucleophilic fluorination, electrophilic fluorination, or sodium fluoroacetate.

Through their function as epigenetic readers of the histone code, the BET family of bromodomain-containing proteins regulate expression of multiple genes of therapeutic relevance, including those involved in tumor cell growth and inflammation. BET bromodomain inhibitors have profound antiproliferative and anti-inflammatory effects which translate into efficacy in oncology and inflammation models, and the first compounds have now progressed into clinical trials. The exciting biology of the BETs has led to great interest in the discovery of novel inhibitor classes. Here we describe the identification of a novel tetrahydroquinoline series through up-regulation of apolipoprotein A1 and the optimization into potent compounds active in murine models of septic shock and neuroblastoma. At the molecular level, these effects are produced by inhibition of BET bromodomains. X-ray crystallography reveals the interactions explaining the structure-activity relationships of binding. The resulting lead molecule, I-BET726, represents a new, potent, and selective class of tetrahydroquinoline-based BET inhibitors.

AbstractA variety of benzyl fluorides is applied in the reactions using carbon, nitrogen, oxygen or sulfur nucleophiles.

AbstractTwo different halogenation procedures including both (DHQ)2‐PHAL as the enantioselective agent are developed for the preparation of fluorinated heterocyclic scaffolds which are obtained as exclusive cis isomers.

Two complementary and scalable approaches have been used to manufacture multikilogram quantities of N,O-protected-(S)-2-methylserine. The first approach uses a diastereomeric salt resolution of 2-methylserine methyl ester as the (1S)-(+)-camphorsulfonate salt, and was used to rapidly access 15 kg of (S)-3-tert-butoxycarbonyl-2,2,4-trimethyl-1,3-oxazolidine-4-carboxylic acid with > 99% ee. The second approach involves a stereoselective enolate methylation of a chiral cyclic L-serine derivative under cryogenic conditions. The four-step telescoped process, starting from L-serine methyl ester, was used to manufacture 20 kg of (2R,4S)-2-tert-butyl-3-tert-butoxycarbonyl-4-methyl-1,3-oxazolidine-4-carboxylic acid in 52% overall yield and 98% ee. The advantages and disadvantages for scale-up of both approaches are discussed.

The development of an efficient manufacturing route to 3-acetyl-N-(5,8-dichloro-1,2,3,4-tetrahydro-7-isoquinolinyl)-4-(1-methylethyoxy)-benzamide hydrochloride SB-406725A (1) is described. Title synthesis begins with dichlorination of isoquinoline, followed by nitration using nitronium tetrafluoroborate in sulpholane. Nitroisoquinoline (12) was hydrogenated under pressure using Pt/C. The resultant tetrahydroisoquinoline (13) was selectively coupled with benzoate side chain (15) under base-promoted conditions using sodium hexamethyldisilazane to yield the parent molecule SB406725 (16). SB-406725 was then converted to the HCl salt SB-406725A (1). This process has been successfully demonstrated on a pilot-plant scale to prepare similar to 30 kg of SB-406725A (1).

Synthesis of amides from coupling esters with a range of primary amines can be conveniently achieved in moderate to excellent yields (69-99%) using an air-stable adduct of trimethylaluminium (AlMe3)(2)-DABCO (DABCO is 1,4-diazobicyclo[2.2.2]octane), referred to as DABAL-Me-3. Reactions can be run without requiring the exclusion of atmospheric oxygen or the drying of solvents. (c) 2006 Elsevier Ltd. All rights reserved.

A range of reactions of cyclic lactam systems is described in which an atropisomeric C–N axis controls the stereochemical outcome of ring substitution or addition. In the case of enantiopure menthol adducts, substitution via N-acyliminium intermediates occurred with essentially complete control. However, the range of nucleophiles that participate in the reaction is very limited and at present the removal of the N-aryl substituent is problematic. A six-membered enamide is of moderate configurational stability and the axis exerts synthetically useful levels of control over enolate alkylations of the system. A novel Lewis acid mediated enamide arylation process was identified.

Unusual regiochemistry is observed in the products arising from the reaction of lithiated 1,2,4-trichlorobenzene with N,N-dimethylformamide and tetraalkyloxamides.