Enantioselective hydrogenation of intermediates in the synthesis of tipranavir

#The present invention relates to a process for preparing intermediates in the synthesis of tipranavir, particularly enantioselective hydrogenation. Using this method it is easily possible to obtain intermediate products which can be used as starting compounds for the production of pharmaceutically effective compounds.

#Chirality plays a crucial part in numerous biological processes and has also acquired increasing importance for the pharmaceutical industry, as evidenced for example by the fact that of the drugs developed hitherto more than 80% have chiral properties. The various enantiomers may develop completely different effects in the body, so that only one of the enantiomeric forms is effective and is administered. For example, enzymes whose chiral components are the amino acids are able to distinguish between the individual enantiomeric forms in the body.

#In particular, the enantiomers of 5,6-dihydro-4-hydroxy-2-pyrones are important structural elements in a number of pharmaceutically effective compounds, the category of the 5,6-dihydro-4-hydroxy-2-pyrone-sulphonamides being particularly important. Thus, [R-(R*,R*)]-N-[3-[1-[5,6-dihydro-4-hydroxy-2-oxo-6-(2-phenylethyl) -6-propyl-2H-pyran-3-yl]propyl]phenyl]-5-(trifluoromethyl)-2-pyridinesulphonamide, known as tipranavir (PNU-140690), is a protease inhibitor which is used to treat HIV and has the following structure:

#Surprisingly, it has been found that the above-mentioned problem of the present invention is solved by a process for preparing the compounds of general formula I: wherein R1 and R2 independently of one another denote hydrogen or a group which is selected from the group consisting of C1–C6-alkyl, C3–C8-cycloalkyl, C6–C10-aryl and C1–C4-alkylene-C6–C10-aryl, optionally with one, two or three substituents, selected from the group consisting of OH, NH2, NH—CO—CH3 or N(—CO—CH3)2, halogen, C1–C4-alkoxy and CF3, while R1 and R2 do not simultaneously have the same meaning; R3 denotes an aryl substituted in the meta position, which optionally comprises at least one other substituent, the substituents being selected from the group consisting of F, Cl, Br, I, OH, O—SO2—CF3, NO2, NH2, NH—SO2—(4-trifluoromethylpyridin-2-yl), N(—CH2-aryl)2, NY1Y2 with Y1 and Y2 selected from H, COO-alkyl, COO—CH2-aryl, CO-alkyl and CO-aryl; R4 is selected from the group consisting of H and C1–C8-alkyl; and R5 is selected from the group consisting of H, Si(CH3)3, Li, Na, K, Cs, N(R′)4, while all the R′ groups may be identical or different and are selected from C1–C8-alkyl and CH2-aryl; by hydrogenating the compounds of general formula II: wherein the groups R1 to R5 may have the meanings given above, in the presence of a catalyst which contains at least one ligand in the form of a chiral 1,2-bis(phospholano)maleic anhydride.

#The starting compounds of general formula I are intermediates in the preparation of tipranavir and related products, which are used as starting compounds for the preparation of pharmaceutically active compounds. Mixtures of E/Z isomers (based on the double bond which is to be hydrogenated) may be used, from which surprisingly only one isomer is then selectively hydrogenated. Preferably a mixture of about 50% E and about 50% Z isomer is used.

#According to a preferred variant of the invention, in general formulae I and II, R1 and R2 independently of one another may be selected from the group consisting of methyl, ethyl, propyl, butyl, phenyl, benzyl, cyclohexyl, phenylethyl and phenylpropyl, optionally with a substituent selected from the group consisting of hydroxy, fluorine, chlorine, bromine, methoxy, ethoxy and CF3. Most preferably, R1 denotes phenylethyl and R2 denotes propyl or R1 denotes propyl and R2 denotes phenylethyl.