Compounds of the formula (E), in which R'<SUB>3 </SUB>is isopropyl and R'<SUB>4</SUB> is C<SUB>1</SUB>-C<SUB>8</SUB>-alkyl, and in which the carbon atom to which the R'<SUB>3</SUB> radical is bonded has either (R) or (S) configuration, preference being given to (R) configuration, are obtainable in high yields A) by a stereoselective addition of isopropyl-substitutedpropionic esters to 6- methoxy-5-(3-methoxypropoxy)pyridine-3-carbaldehyde to give corresponding 2- {hydroxy-[6-methoxy-5-(3-methoxypropoxy)pyridin-3-yl]methyl}-3-methylbutanoic esters, subsequent conversion of the OH group to a leaving group, and a subsequent regioselective elimination to give 2-[1-[6-methoxy-5-(3-methoxypropoxy)pyridin-3-yl]- meth-(E)-ylidene]-3-methylbutanoic esters, followed by 1) hydrolysis to give the corresponding 2-[1-[6-methoxy-5-(3-methoxypropoxy)- pyridin-3-yl]meth-(E)-ylidene]-3-methylbutanoic acid, the enantioselective hydrogenation thereof to the corresponding chiral 2-[6-methoxy-5-(3-methoxy- propoxy)pyridin-3-ylmethyl]-3-methylbutanoic acid and the reduction thereof,or 2) hydrolysis to the corresponding 2-[1-[6-methoxy-5-(3-methoxypropoxy)pyridin-3- yl]meth-(E)-ylidene]-3-methylbutanoic acid, the reduction thereof to the corresponding 2-[1-[6-methoxy-5-(3-methoxypropoxy)pyridin-3-yl]meth-(E)-ylidene]-3- methylbutan-1-ol and the enantioselective hydrogenation thereof, or 3) reduction to the corresponding 2-[1-[6-methoxy-5-(3-methoxypropoxy)pyridin-3-yl]- meth-(E)-ylidene]-3-methylbutan-1-ol and the enantioselective hydrogenation thereof, or B) by a Sonogashira coupling of 5-bromo-2-methoxy-3-(3-methoxypropoxy)pyridine, SP-P2216_ATE -80- 5-iodo-2-methoxy-3-(3-methoxypropoxy)pyridine or of trifluoromethanesulphonic acid 6-methoxy-5-(3-methoxypropoxy)pyridin-3-yl ester with 2-propyn-1-ol to give 3-[6- methoxy-5-(3-methoxypropoxy)pyridin-3-yl]prop-2-yn-1-ol, followed by addition of an R' <SUB>3</SUB>-Grignard compound to give 2-[1-[6-methoxy-5-(3-methoxypropoxy)pyridin-3-yl]- meth-(E)-ylidene]-3-methylbutan-1-ol and the enantioselective hydrogenation thereof; substitution of the chiral 2-[6-methoxy-5-(3-methoxy-propoxy)-pyridin-3-ylmethyl]-3- methyl-butan-1-ol resulting from pathways A) or B)to give 5-(2-halomethyl-3-methyl- butyl)-2-methoxy-3-(3-methoxy-propoxy)-pyridine, coupling thereof with a (E)-(R)-5- halo-2-alkyl-pent-4-enoic acid amide, followed by halogenation,hydroxylation lactonizatization and azidation.

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Document History
  • Publication: Sep 25, 2008
  • Application: Mar 19, 2008
    WO EP 2008053323 W
  • Priority: Jul 27, 2007
    EP EP 07113309 A
  • Priority: Mar 21, 2007
    EP EP 07104611 A

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