Crixivan, intermediate

This procedure can be used to synthesize the key intermediate 34 of Merck s HIV protease inhibitor Crixivan 35 (Fig. 5) [25]. This reaction is done using dichloroacetaldehyde 26 instead of chloroacetaldehyde, forming the classical Ugi product 30. This intermediate is then treated with triethylamine to obtain the corresponding vinylchloride 31. Cyclization with KO Bu followed by stereoselective hydrogenation using the chiral catalyst Rh-BINAP afforded the Crixivan intermediate 34. (Scheme 5) The classical way to make this intermediate requires five steps, and thus makes the MCR route more attractive [25]. 

LiN(SiMe3)2 to form crixivan intermediate 4 [13]. The reactivity of bases may be dependent on the nature of the alkali metal portion of the base, as seen in the hetero-Michael additions shown in Figure 3.7 [14]. Phase-transfer catalyzed reactions (PTC) are often overlooked [15], and can provide safe, economic, and very productive alternatives to reactions using strong bases (see Figure 2.18). 

Isopropyl acetate (IPAc) is much more resistant to hydrolysis than EtOAc in the preparation of the methanesulfonate salts 3 (Figure 4.3) significant amounts of the acetic acid solvates were formed when the solvent was EtOAc, and IPAc was preferred [12], Crixivan intermediate 4 was prepared under Schotten-Baumann conditions by using IPAc at elevated temperatures (Figure 4.4) [13], which suggests the resistance of IPAc to hydrolysis. 

Many metal-based catalysts are in fact precatalysts. The Mn (III) salen catalyst used for the production of a Crixivan intermediate proceeds through generation of... 

Scheme 11 Pilot process for crixivan intermediate (Lonza)...

A critical requirement for this interaction is the hydroxyl (OH) group near the center of Crixivan. This hydroxyl group of Crixivan mimics the true chemical intermediate that forms when HIV protease performs its task in the AIDS virus. 

DIPAMP-Rh complex to give the corresponding chiral a-amino acid derivative in over 98% ee. The chiral product has been used for the synthesis of (S)-(-)-ac-romelobic acid [88]. Hydrogenation of a tetrahydropyrazine derivative catalyzed by a PHANEPHOS-Rh complex at -40"C gives an intermediate for the synthesis of Crixivan in 86% ee [82a]. Hydrogenation of another tetrahydropyrazine carboxamide derivative catalyzed by an (R)-BINAP-Rh catalyst leads to the chiral product in 99% ee [89]. 

Scheme 5 Asymmetric MCR synthesis to piperazine intermediate (34) of the Merck HIV protease inhibitor Crixivan (BINAP 2,2 -bis(diphenylphosphino)-1,10-binaphthyl COD cyclo-octadiene)...

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. 

The key goals of the reaction network from indene to as- (IS, 2 J )-indanediol, an intermediate via as-aminoindanol to indinavir (Crixivan ), Merck s HIV protease inhibitor, are to enhance toluene dioxygenase over monooxygenase activity, and to avoid degradation of cis-(lS,2J )-indanediol. Still to achieve are a low enough by-product spectrum and commercially attractive yields. 

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-... 

Rossen et al. [71a] has reported a synthesis of piperazine 113, a key intermediate in the synthesis of the HIV protease inhibitor Crixivan . The reaction between a preformed imine 110, f-butyl isocyanide, and formic acid afforded the Ugi product 111, which was dehydrohalogenated with triethylamine and cyclized with KO Bu to the tetrahydropyrazine 112. Catalytic hydrogenation in the presence of Rh-BINAP (97% ee) and deformylation with aqueous hydrazine gave the target piperazine 113 (Scheme 2.40). 

The asymmetric oxidation of indene to the corresponding epoxide (Equation 24) is carried out commercially by Sepracor on a small scale. Chiral indene oxide is an intermediate in the synthesis of crixivan (an HIV protease inhibitor). Reaction is carried out at 5°C with moderately high turnover numbers in the presence of an exotic donor ligand ( P3NO , 3-phenylpropylpyridine N oxide) and sodium hypochlorite as the terminal oxidant. A similar epoxidation of a simple cis olefin (Equation 25) leads to an enantiomerically pure amino-alcohol used in the synthesis of taxol, a potent anticancer drug. 

Avecia identified approximately 60 microorganisms with amidase activity capable of resolving racemic amines [17, 18]. Arthrobacter species predominated in the list of microorganisms identified. The kinetic resolution of N acetyl 1 aminoindanol 35 by a freeze dried microbial sample (BH2 NI amidase) allowed access to (1S,2R) N acetyl 1 aminoindanol 35 in high enantiomeric excess (96%). This compound is a key intermediate in the synthesis of Merck s HIV protease inhibitor Crixivan 37 (indin avir) (Figure 14.12). 

Let us examine the interaction of Crixivan with HIV protease in more detail. Crixivan is constructed around an alcohol that mimics the tetrahedral intermediate other groups are present to bind into the S2, Sj, S/, and S2 recognition sites on the enzyme (Figure 9.20). The results of x-ray crystallographic studies revealed the structure of the enzyme-Crixivan complex, showing that Crixivan adopts a conformation that approximates the twofold symmetry of the enzyme (Figure 9.21). The active site of HIV protease is covered by two apparently flexible flaps that fold down on top of the bound in-... 

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. 

Piperazinecarboxylic acid derivatives are interesting intermediates, e.g., for Crixivan, the well-known HIV protease inhibitor of Merck. The Rh/josiphos-catalyzed hydrogenation of a substituted cyclic enamide was used by Lonza [38] to produce >200 kg of the piperazine intermediate depicted in Scheme 11. A related catalyst was successfully employed by Merck [39] to pilot the hydrogenation of... 

Fill in missing compounds and reagents in the following outline of a hypothetical synthesis of the acyclic central portion of Crixivan. Note that more than one intermediate compound may be involved between some of the structures shown below. 

The hydrogenations in Equations 15.31 and 15.32 illustrate the reduction of more complex substrates leading to a-amino acid amides. The first example demonstrates a diaste-reoselective hydrogenation conducted by the fine chemicals company Lonza as part of the synthesis of the vitamin biotin. " The second example shows an a-amino acid product produced in quantities greater than 200 tons by Lonza using a rhodium catalyst containing the Josiphos ligand shown. This product is an intermediate in the synthesis of Indinavir (Crixivan), which was used in combination with a reverse transcriptase inhibitor to create the first effective treatment for... 

Indene Oxide (ChiRex). The epoxidation of indene is an attractive route to cis l-amino-2-indanol, an intermediate in the Crixivan synthesis (HIV protease inhibitor of Merck) and ligand for BH3 reductions of ketones (60a,61). 

HIV protease inhibitors are often quite large and therefore, the synthesis needs up to 20 steps. The development of much shorter reactions will thus be of great interest. The piperazine key intermediate 435 in the synthesis of HIV protease inhibitor Crixivan (Indinavir ) 436 can be synthesized with an Ugi fonr-multicomponent reaction (Scheme 6.66) [134]. 

SCHEME 6.66 Four-component Ugi reaction in the synthesis of key intermediate 435 in the synthesis of Crixivan 436. 

A number of drug companies have tried to develop AIDS drugs based on this principle. These drugs are hence called HIV protease inhibitors. Four HIV protease inhibitors have been approved for use in treating AIDS. They are saquinavir (trade name=Inverase developed by Hoffman-La Roche), ritonavir (Norvir by Abbots Lab), indinavir sulfate (Crixivan by Merck), and nellinavir mesylate (Viracept by Agouron Pharmaceuticals). All of these compounds try to mimic the structure of intermediate (B), but they are not decomposable. 

Of the currently available HIV medications, seven are HTV protease inhibitors. Similar to the above-mentioned HCV NS3 protease inhibitors, the described inhibitors are quite large and have a peptide-like appearance. Often, they have to be synthesized in sequence with up to 20 synthesis steps. Therefore, it is worthwhile considering alternative synthetic approaches involving MCRs. For example, the key intermediate piperazine 49 of Crixivan (Indinavir) produced by Merck was advantageously and stereoselectively synthesized using a key and quantitative U-4CR followed by an enantioselective hydrogenation [28]. 

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