5-[2-Methoxy-5-(4-pyridinyl)phenyl]-2,1,3-benzoxadiazole (PDE472) is a selective inhibitor of the phosphodiesterase PDE4D isoenzyme, which is a recognised drug target for the treatment of asthma. Different synthetic routes to PDE472 were investigated, and the research synthesis was optimised to prepare a phase I batch on pilot-plant scale with the focus on the elimination or minimization of inherent process risks. An important refinement of the key Negishi aryl-aryl coupling involved preforming the arylpalladium complex, which was then added to the arylzinc intermediate. Residual palladium was removed from PDE472 via crystallization of the hemi-maleate salt, which afforded drug-substance containing <2 ppm Pd.

(28.V11.86) EtAIC1,-promoted additions of organocopper reagents to camphor-derived, conjugated N-enoyl-sultams gave saturated and olefinic P-silylcarboxyl derivatives with high diastereodifferentiation. Nondestructive removal of the chiral auxiliary followed by oxidative Si-C bond cleavage furnished enantiomerically pure acetate-derived aldols and propionate-derived 'unfi'-aldols (oirr silyl-directed a methylation).P-Silylcarbonyl compounds show significant promise in organic synthesis. Two features of the P-SiPhMe, substituent are particularly interesting: 1 j its topological bias on a-enolate protonation and methylation [l] as well as 2) its convertibility into a OH group with retention of configuration [2].In continuation of previous work on asymmetric and hydride additions [4] to conjugated N-acyl-sultams, we report here the first asymmetric synthesis of p-silylcarboxylates and their transformation into enantiomerically pure acetate-derived aldols and propionate-derived 'anti'-aldols. Furthermore, we describe the analogous -face-selective preparation of y,6-alkenyl-,8-silylcarboxyl derivatives which offer additional synthetic possibilities via SET -type allylsilane substitutions2).For reasons of versatility, it was advantageous to incorporate the silyl group into the prochiral substrate. The starting N-1/3-(silyl)enoyl]sultam 1 (R'=SiPhMe,, (Scheme was readily prepared by successive treatment of ( E j-3(dimethylphenylsilyl)acrylicPresented at the IASOC-11-Meeting, Ischia, May 1986. For an alternative approach to racemic and to enantiomcrically pure ~,fi-alkenyl-B-silylcarbonyl derivatives by Cluisen rearrangements see [ S ] ; for asymmetric syntheses of non-functionalized allylsilanes, see [6]; for revicws on stercospecific SE2'-type substitutions of allylsilanes, see [7]. All new compounds were characterized by IR, 'H-NMR (360 MHL), and mass spectra. This acid (m.p. 89-91") was prepared in analogy to 3-(trimethylsilyl)acrylic acid [8] by successive treatment of ( E l -1,2-bis(tributylstannyl)ethylene [9] at -78" with BuLi, CISiPhMc,, BuLi, and CO,. ')4,

No abstract

Dienyl acetates 2 lacking a geminal disulfone or a malonate group cyclize selectively to (E)-l-methylidene-2-styrylcyclopentanes 4 in the presence of 7 mol-% of [Pd(PPh,),].cyclizations of 1-acetoxy-, l-tetrahydropyranyloxy-, I-bromo-, and l-iodo-2,7-octadienes (or -2,8-nonadienes) A exemplify part of a new stereospecific methodology leading to an array of carbo-and heterocycles F (Scheme I ) . Precursors A containing the ally1 or the enophile unit as part of a ring gave

The development of the robust synthesis of quinolin-1-yl]-phenyl]propionitrile (dactolisib) on a commercial scale is described. The key step is a Pd-catalyzed Suzuki coupling of 2-[4-(8-bromo-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-phenyl]-2-methyl-propionitrile to 3-quinoline boronic acid. A special focus is placed on reducing the amount of Pd catalyst used in the Suzuki coupling and purifying the crude drug substance, including removing traces of Pd.