A highly enantioselective and practical synthesis of the HIV-1 reverse transcriptase inhibitor efavirenz (1) is described. The synthesis proceeds in 62% overall yield in seven steps from 4-chloroaniline (6) to give efavirenz (1) in excellent chemical and optical purity. A novel, enantioselective addition of Li-cyclopropyl acetylide (4a) to p-methoxybenzyl-protected ketoaniline 3a mediated by (1R,2S)-N-pyrrolidinylnorephedrine lithium alkoxide (5a) establishes the stereogenic center in the target with a remarkable level of stereocontrol.

This report describes a new convergent, selective, and economical synthesis of DMP 777, 1 ending with the coupling of the chiral -lactam half of the molecule (1) to the chiral amine as the isocyanate (2). Other steps involve the coupling of the -lactam 3 to the phenolic moiety under phase-transfer conditions, followed by resolution of the resulting piperazine derivative using a chiral acid, and recycling of the undesired enantiomer also under phase-transfer conditions. The chiral amine 4 was produced efficiently starting from (R)-r-methylbenzylamine and the corresponding butyrophenone.Contemporary pharmaceuticals often contain multiple chiral centers which provide a significant challenge to the process chemist. Fortunately, an array of tools is now available to address absolute stereochemistry, including classical resolution, chiral auxiliaries, asymmetric catalysis, and enzyme resolution. It is increasingly evident that no single method is consistently superior. A thorough approach to process development requires the consideration of all available chiral technologies to provide the most efficient route to a given drug candidate.DMP 777, an inhibitor of leukocyte elastase, could prevent degradation of the structural proteins elastin and collagen, a process implicated in cystic fibrosis and rheumatoid arthritis. 2 Retrosynthetic analysis indicates that DMP 777 should be accessible by coupling two enantiopure fragments, -lactam 1 and isocyanate 2 (Figure 1). Potentially, -lactam 1 may derive from the commercially available racemic lactam 3. 3 Consequently route-development efforts focused on identifying efficient conditions for elaboration of 3 into racemic 1, and its subsequent resolution. The precursor to isocyanate 2, amine 4, is not an article of commerce; therefore, a process from simple materials had to be devised. We will discuss in turn the synthesis of fragments 1 and 2 and conclude by describing a procedure for their efficient coupling.A short convergent process required a practical synthesis and resolution of the -lactam portion (Scheme 1). The reaction conditions had to be balanced to provide the requisite basic elimination of propionic acid from 3 to give the reactive 3,3-diethylazetin-2-one, 5, without hydrolysis of lactam. Phase-transfer catalytic conditions using a tetrabutylammonium salt gave the most efficient reaction, with an isolated yield of 88%. 4 About 25 chiral acids were screened for utility in the resolution. Diacetoneketogulonic acid (DAG) gave by far the best resolution, with the R-enantiomer DAG salt crystallizing out in high ee and thus overcoming a 10-bond separation between amine group and the chiral center. The S-isomer was then easily precipitated, DAG was recovered, and the R-isomer was racemized under phase-transfer conditions similar to those for its original synthesis (conversion of 3 to 1-racemate). Clarke, G. D. E.; Dowle, M. D.; Harrison, L. A.; Hodgson, S. T.; Inglis, G. G. A.; Johnson, M. R.; Shah, P.; Upton, R. J.; Walls, S. B. J. Org. Chem. 1999, 64, 5166-5175 and ref...

The case of disappearing/late-appearing stable polymorphs and their impact is well-understood by scientists in the pharmaceutical industry. This paper discusses an instance where a more stable crystal form was discovered during the development of a fast-track drug candidate. Challenges in adapting to the discovery of the new crystal form during this accelerated drug development program and approaches to develop a robust crystallization process are discussed.

The practical and highly diastereoselective syntheses of CF(3)-substituted dihydroquinazolinones via 1,4-additions of nucleophiles to chiral auxiliary substituted 2(3H)-quinazolinones is described. This methodology is applied to the syntheses of the NNRTIs (nonnucleoside reverse transcriptase inhibitors) DPC 961 (1) and DPC 083 (2), which are useful for the treatment of HIV (human immunodeficiency virus). The synthesis of DPC 961 (1) requires three steps, proceeds in >55% overall yield from the keto-aniline 9, and gives synthetic access to DPC 083 (2). In addition, the scope of the new diastereoselective 1,4-addition chemistry is investigated. The first preparation of DPC 961 (1) described in this paper is a derivatization fractional crystallization protocol.

Fused pyrimidine derivativesFused pyrimidine derivatives R 0515 General Scope of 1,4-Diastereoselective Additions to a 2(3H)-Quinazolinone: Practical Preparation of HIV Therapeutics. -The imine generated from the hemiaminal (III) is found to undergoes diastereoselective 1,4-addition with a variety of nucleophiles. The product (Va) can smoothly be transformed into the HIV therapeutic (VI), which is a useful precursor of other HIV therapeutics. -(MAGNUS*, N. A.; CONFALONE, P. N.; STORACE, L.; PATEL, M.; WOOD, C. C.; DAVIS, W. P.; PARSONS*, R. L. J.; J. Org. Chem. 68 (2003) 3, 754-761; Chem. Process Res. Dev.