Indinavir , synthesis

We can delve deeper into one of the steps in the indinavir synthesis. In 1980 Giovanni Casiraghi, a rather less famous chemist from the University of Parma, published a paper in the Journal of the Chemical Society about selective reactions between phenols and formaldehyde. He and his colleagues made the modest discovery that controlled reactions to give salicylalde-hydes could be achieved in toluene with SnCl as catalyst. The reaction is regioselective for the ortho isomer and the paper described the rather precise conditions needed to get a good yield. 

During an investigatior of the utihty of epoxide 240 as an intermediate in the synthesis of the HIV protease inhibitor Indinavir 241, it was found that the amino alcohol 237 must first be protected prior to iodination. Without protection, the iodination of the unsaturated amide 237 gave the unstable oxazoline 239 in 83% yield (Scheme 8.65). 

Several important examples of metabolic engineering, ranging from applications in basic chemicals, such as the manufacture of propanediol from glucose, to the synthesis of chiral pharmaceutical intermediates, such as (2i )-indanediol, a building block of the HIV protease inhibitor Crixivan (Indinavir , Merck see Chapter 13, Section 13.3.3.30.), are presented in Chapter 20. 

In Chapter 13, Section 13.3.3, we discussed indinavir (Crixivan ), Merck s HIV protease inhibitor, which is currently manufactured via a chemical synthesis route. An alternative biocatalytic route, at least to intermediates, briefly discussed in Sec-... 

One of the few industrial examples of the asymmetric synthesis of halohydrins is in a process to the human immunodeficiency virus (HIV) protease inhibitor, Indinavir.190 The y,8-unsaturated carboxamide 23 is smoothly converted into iodohydrin 24 (92%, 94% de) (Scheme 9.34). (For more on the chemistry of the indanol, see Chapter 24.)191... 

The single enantiomer of indinavir has five stereogenic centers, four of which are derived either directly or indirectly from epoxide (27). Synthesis of indinavir sulfate developed by Merck is shown in Scheme-3. 

Due to the demand for inexpensive anti-HIV agents, several reactions for the synthesis of Indinavir (70, an HIV protease inhibitor of Merck Co.) have been reported. Enantioselective epoxidation of simple alkenes with bleach is achievable in the presence of the Mn " complex 69 possessing a well-designed chiral salen ancillary [69]. Scheme 20 exemplifies its application to the synthesis of Indinavir (70), by way of indene oxide (68) in 88 % ee [69]. This method is also useful for the asymmetric synthesis of a chromene epoxide in 97 % ee serving as an intermediate for Lemakalim, a K" -channel opening agent [70]. 

Asymmetric synthesis by asymmetric induction is shown in the route to manufacture indinavir sulfate (Figure 16.9). Four of the five chiral centers were established by asymmetric induction, beginning with asymmetric epoxidation to form... 

Fig. 2.7 Ligands with broad scope and versatility, (a) A concise synthesis of a non-proteinogenic amino acid developed and scaled by Dowpharma using a DuPHOS catalyst [38], (b) Merck route to c/s-aminoindanol, a key building block made via salen-catalyzed epoxidation for onwards usage, for example in the synthesis of the anti-H IV compound indinavir [39].

These may seem strange molecules to have a place in the new chiral pool but they were made on a vast scale by Merck in the synthesis of their HIV protease inhibitor crixivan (Indinavir). They both come from Jacobsen epoxidation of indene 283 (chapter 25) the anti-compound 285 by opening the epoxide 284 at the benzylic centre with azide ion.51... 

There is no cure for AIDS. Treatment seeks to suppress symptoms (e.g., antibiotics for the infections) and slow viral reproduction. Mortality rates have decreased since 1995 because of the introduction of a treatment protocol called highly active antiretroviral therapy (HAART) that consists of combinations of drugs from the following categories (1) nucleoside reverse transcriptase inhibitors (NRTIs) (e.g., azidothymidine, also called zidovudine or AZT), (2) non-nucleoside reverse transcriptase inhibitors (NNRTIs) (e.g., efavirenz) and protease inhibitors (e.g., indinavir). Both NRTIs and NNRTIs inhibit vDNA synthesis catalyzed by reverse transcriptase. Protease inhibitors are a class of drugs that prevent the processing of viral protein that is required for the assembly of new virions. 

Scheme 19.27 Additional HTS-derived HIV-1 Protease inhibitors and their initial hit compounds. 94 is indinavir and 95 is tipranavir. LE = Lead enhancement wherein synthesis of numerous analogs eventually led to the next depicted molecule. (With permission from Proudfoot.)...

Chemical synthesis remains as important to society as it became during World War II, when the modem pharmaceutical industry originated in its efforts to develop penicillins. Ever since, organic chemists literally have made the drugs that relieve our illnesses. Further examples include the antiinflammatory cortisone, developed in the 1940s to treat arthritis, and the protease inhibitors indinavir, ritonavir, and saquyinavir, introduced in 1995 to suppress the human immunodeficiency virus (HfV). 

The development of practical routes to the title compound has been the focus of intensive research effort since cis-aminoindanol was identified as a critical component of the highly effective HIV protease inhibitor indinavir (Crixivan ).7,8 Reported routes include racemate synthesis followed by resolution via diastereomeric salts,8 enzymatic resolution,9 and asymmetric hydroxylation.10 However, the use of a modified Ritter... 

In addition to serving as a key stereochemical controlling element for synthesis of indinavir,5 the title compound has proven to be a remarkably versatile chiral ligand and auxiliary for a range of asymmetric transformations including Diels-Alder reactions,13 carbonyl reductions,14 diethylzinc additions to aldehydes,15 and enolate additions.16... 

The synthesis of enantiomerically pure (1S,2R)- -aminoindanol became a subject of frontline industrial research activity after the Merck group discovered a series of HIV-protease inhibitors that contained this moiety. Merck s discovery eventually led to the development of indinavir sulfate as one of the leading drugs for the treatment of AIDS, and, as a consequence, to an industrially feasible, large-scale preparation of (1S,27 )-1-aminoindanol in enantiomeric pure form [71,72]. 

N-Alkylation with 3-picolyl chloride led to 79 and eventually to the target compound 80 by formation of the sulfate salt. Thus, the two stereocenters established by the epoxidation procedure served to control the formation of two other stereocenters at the benzyl and hydroxyl bearing carbon atoms. This stresses the centrality of the stereoselective preparation of 73 to the synthesis of indinavir sulfate. 

Figure 24. Stereoselective synthesis of (lS,2/ )-l-aminoindanol and indinavir sulfate. Reagents a, NaOCl, 4-(3-phenyl propyl)-pyridinc-/V-oxidc b, oleum, MeCN c, H20 d, tartaric acid e, NH3, MeOH f, PhCOCl, NaOH g, 80% H2S04 h, LHMDS, allylbromide i, NBS, Nal j, H20, NaHCO, k, MeONa I, MeOH m, HQ g n, 3-picolyl chloride o, H2S04.

Protease inhibitors are well-characterized chiral drugs in terms of their mechanism of action. An important new class of protease inhibitors comprises molecules designed to treat HIV infection. In particular, indinavir sulfate (CRIXIVAN, Merck and Co., Inc.) contains five chiral centers that must be of a specific orientation for the molecule to have the desired therapeutic effect. Manufacturing processes for these compounds involving chemical synthesis steps can be quite inefficient, due to yield reduction caused by racemization at each step where a chiral center is formed. A key intermediate in the synthesis of CRIXIVAN is cis-(lS,2R)-l-amino-2-indanol [(-)-CAI], an indene derivative that contributes two chiral centers to indinavir sulfate (Fig. 1). To circumvent the technically demanding chemical synthesis of (-)-CAI and reduce product loss, Merck scientists conceptualized a bioconversion process in which indene is oxidized to one of three derivatives that can serve as precursors to (-)-CAI cis-(lS,2R)-indandiol, trans-(lR,2R)-indandiol, or (lS,2R)-indan oxide. Oxygenases that have been identified in isolates of the genus Pseudomonas and Rhodococcus can catalyze this transformation. 

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