Indinavir epoxidation

Davies and Reider (1996) have given some details of the HIV protease inhibitor CRDCIVAN (INDINAVIR) for which (lS,2R)-c -amino indanol is required. Indene is epoxidized enantioselectively, using the lacobsen strategy (SS-salen Mn catalyst, aqueous NaOH and PiNO), to (lS,2/ )-indene oxide in a two-phase system, in which the OH concentration is controlled. Indene oxide was subjected to the Ritter reaction with MeCN, in the presence of oleum, and subsequent hydrolysis and crystallization in the presence of tartaric acid gives the desired amino indanol. 

Enantiomerically pure epoxides and diols, readily available through the asymmetric epoxidation and asymmetric dihydroxylation reactions, are ideal precursors to prepare cis-amino alcohols via the Ritter reaction. " " A Merck group has shown that indene oxide 175a can be converted effectively to c/i-l-amino-2-indanol, a key fragment of the HlV-protease inhibitor Indinavir via the cis-... 

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). 

The industrial production of Crixivan (9 H2S04) took advantage of the chirality of (IS,2R)-aminoindanol to set the two central chiral centers of 9 by an efficient diastereoselective alkylation-epoxidation sequence.17 The lithium enolate of 12 reacted with allyl bromide to give 13 in 94% yield and 96 4 diastereoselective ratio. Treatment of a mixture of olefin 13 and V-chlorosuccinimide in isopropyl acetate-aqueous sodium carbonate with an aqueous solution of sodium iodide led to the desired iodohydrin in 92% yield and 97 3 diastereoselectivity. The resulting compound was converted to the epoxide 14 in quantitative yield. Epoxide opening with piperazine 15 in refluxing methanol followed by Boc-removal gave 16 in 94% yield. Finally, treatment of piperazine derivative 16 with 3-picolyl chloride in sulfuric acid afforded Indinavir sulfate in 75% yield from epoxide 14 and 56% yield for the overall process (Scheme 24.1).17-22... 

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... 

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. 

Suggest reagents and conditions for the asymmetric synthesis of the epoxide 9, used in a synthesis of the HIV protease inhibitor indinavir. 

This epoxide plays a starring role in the synthesis of the anti-HIV compound indinavir see Chapter 43. 

Take the millions of lives saved by the synthesis of indinavir, for example. This drug would not have been possible had not the Sharpless and Jacobsen asymmetric epoxidations, the catalytic asymmetric reduction, and the stereoselective enolate alkylation, along with many of the methods tried but not used in the final synthesis, been invented and developed by organic chemists in academic and industrial research laboratories. Some of the more famous names involved, like Sharpless, Jacobsen, and Noyori, invented new methods, while others modified and optimized those methods, and still others applied the methods to new types of molecules. Yet all built on the work of other chemists. 

A key step in the assembly of the HIV protease inhibitor Crixivan (Indinavir) is the coupling of the enantiomerically pure epoxide 48 with the enantiomerically pure piperazine 49 to afford the backbone of the drug (Scheme 15.14). 

Synthesis of Indinavir An example of the application of the Jacobsen asymmetric epoxidation method is the large... 

SCHEME 34.20. Mn(salen)-catalyzed asymmetric epoxidation in the synthesis of indinavir. 

The chiral Mn-salen catalysts have successfully been used in pharmaceutical industry processes. For example, enantioselective epoxidation of indene 43 under Jacobsen et al. s conditions provided epoxide 44 in 71% yield and 84—86% ee. It was reported that both yield and enantiose-lectivity were increased by adding 4-phenylpyridine N-oxide (PPNO) as co-oxidant in the system. A modified Ritter reaction converted indene oxide 44 into the c -amino alcohol 46. The enantiomeric purity of 46 was enhanced to >99% ee by formation of the corresponding L-tartrate salt followed by recrystallization. Amino alcohol 46 was identified as a critical component of the highly effective HIV protease inhibitor Indinavir 47 developed by Merck (White-house Station, NJ) (Scheme 35.12). ... 

After the discovery that chromenes can be epoxidized with 80 in excellent enantioselectivity [92], a process was developed with isoquinoline N-oxide as an additive (10mol%) to give access to the potassium channel inhibitor BRL 55834 (89, Scheme 9.9) [93]. The efficiency of the transformation is impressive as it requires the use of only 0.2 mol % of catalyst 80. Additionally, enantioselective epoxidation of indene 90 leads to 91 [94], which was incorporated in a synthesis of Merck s HIV-protease inhibitor indinavir (94, Scheme 9.10) [95]. The ease with which both enantiomers of amino alcohol 93 can be... 

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