An Enantioselective Synthesis of (2S,3R)-3-(N-Benzyloxycarbonyl)amino-1-chloro-4-phenylthiobutan-2-ol, a Central Intermediate of Nelfinavir¹

Abstract

(2S,3R)-3-(N-Benzyloxycarbonyl)amino-1-chloro-4-phenylthiobutan-2-ol 1 is a central intermediate of nelfinavir 2, which, being a potent HIV protease inhibitor, represents one of the most clinically efficacious anti AIDS drugs. Thus, a practical enantioselective synthesis of 1 has been devised which employs sodium erythorbate 9 as a chiral starting material. Consisting of the total 14-step functional group manipulations that proceed via methyl (2S,3R)-4-hydroxy-2,3-epoxybutyrate 8, the synthetic processes can dispense with chromatographic purification and provide architecturally complex 1 in 17% overall yield under a strict control of stereochemistry.

Development of a Continuous Process for the Industrial Generation of Diazomethane1

“…An example is nelfinivir mesylate 1 (Figure ), which can be produced on a commercial scale from the key chiral building block (2 S ,3 R )-3-( N -benzyloxycarbonyl)-amino-1-chloro-4-phenylthiobutan-2-ol 2 . There are a number of different industrial syntheses of 1 and 2 that do not use diazomethane; however, the synthetic route incorporating diazomethane is both direct and cost-effective (Scheme ). For these reasons an effective and safe method for generating diazomethane on an industrial scale was required to provide tonne quantities of key intermediates such as 2 .…”

A Divergent Approach to 3-Piperidinols: A Concise Syntheses of (+)-Swainsonine and Access to the 1-Substituted Quinolizidine Skeleton

“…The sequence commences with O-protection of the secondary alcohol in l -glutamate-derived hydroxy diester 7 followed by reduction to triol 8 . Reduction of 7 using lithium aluminum hydride resulted in silyl deprotection while the use of lithium borohydride/MeOH and calcium borohydride led to extensive migration of the silyl group. The desired reduction product 8 was obtained using DIBAL-H in THF at −78 °C provided that the workup procedure was maintained at −20 °C to avoid silyl deprotection.…”

A Process in Need Is a Process Indeed: Scalable Enantioselective Synthesis of Chiral Compounds for the Pharmaceutical Industry

“…Synthesis of erythro ‐(2 S ,3 R )‐3‐ N ‐Cbz‐amino‐2‐butanol 10 from sodium erythorbate (15) : A method to overcome such methodological limitations plaguing the original approach to 10 (Scheme ) involves installing an amine functionality regio‐ and stereoselectively in a chiral four‐carbon scaffold equipped with differentiated terminals. Its molecular ends being at different oxidation levels, methyl (2 S ,3 R )‐4‐hydroxy‐2,3‐epoxybutanoate 16 was assumed to serve the purpose, and it was actually used to full advantage in assembling 10 at Nagase (see Scheme ) 3…”

“…With their increasing molecular complexity,1 newly developed chemical entities of pharmacological relevance, such as active pharmaceutical ingredients (APIs), and pharmaceutical intermediates, have challenged process chemists of both the fine chemicals and the pharmaceutical industry to supply them in a scalable, industrially viable manner as much as ever did 2. In view of such industrial requirements, this report will deal with two comparative case studies to see what difference synthetic strategy can make: One case study is on the synthesis of viracept 1 (nelfinavir mesylate, AG 1343), a potent HIV protease inhibitor, with a focal point on how to assemble the central key intermediate of a common 1,4‐differentially substituted‐2‐amino‐3‐hydroxybutane motif 2 3. The other is on the synthesis of a single enantiomer of 3‐hydroxytetradecanoic acid ( 3 ), which would serve the structure activity relationship study around not only lipid A 4 , an active principle of lipopolysaccharide (LPS) eliciting endotoxic reactions of Gram‐negative bacteria, but also its truncated analogues in the search for therapeutically efficacious immunostimulants (Figure 1).…”