Patent ID: 6278001
Filing Date: 2001-08-21
Classification: C07D

Abstract:
A process for preparing a compound of formula (Ia) or (Ib) ##STR27##wherein .psi. is a radical selected from:saturated or unsaturated, linear, branched or cyclic C.sub.1 -C.sub.40 alkyls, optionally containing ether bridges and/or substituted with at least one substituent selected from halogen, hydroxyl, C.sub.1 -C.sub.20 alkoxy, C.sub.1 -C.sub.20 acyloxy, primary, secondary or tertiary amino, nitro, thiol, carboxyl, amido, C.sub.1 -C.sub.20 alkyl carboxylate, aryl carboxylate, C.sub.1 -C.sub.20 aralkyl carboxylate, C.sub.1 -C.sub.20 alkylamido, arylamido and C.sub.1 -C.sub.20 aralkylamido groups, and from aryl radicals and saturated or unsaturated C.sub.1 -C.sub.20 nitrogen, oxygen, phosphorus and sulphur heterocycles;aryls, optionally substituted with at least one substituent selected from halogen, hydroxyl, C.sub.1 -C.sub.20 alkoxy, C.sub.1 -C.sub.20, acyloxy, amino, C.sub.1 -C.sub.20 alkylamino and dialkylamino, nitro, thiol, carboxyl, amido, C.sub.1 -C.sub.20 alkyl carboxylate, aryl carboxylate, C.sub.1 -C.sub.20 aralkyl carboxylate, C.sub.1 -C.sub.20, alkylamido, arylamido, C.sub.1 -C.sub.20 aralkylamido and C.sub.1 -C.sub.20 aryl groups, and from saturated or unsaturated, linear, branched or cyclic C.sub.1 -C.sub.20 alkyl and aralkyl radicals and saturated or unsaturated C.sub.1 -C.sub.20 nitrogen, oxygen, phosphorus and sulphur heterocycles;aralkyls, optionally substituted with at least one substituent selected from halogen, hydroxyl, C.sub.1 -C.sub.20 alkoxy, C.sub.1 -C.sub.20 acyloxy, amino, C.sub.1 -C.sub.20 alkylamino and dialkylamino, nitro, thiol, carboxylic acid, amido, C.sub.1 -C.sub.20 alkyl carboxylate, aryl carboxylate, C.sub.1 -C.sub.20 aralkyl carboxylate, C.sub.1 -C.sub.20 alkylamido, arylamido, C.sub.1 -C.sub.20 aralkylamido and C.sub.1 -C.sub.20 aryl groups, and from saturated or unsaturated, linear, branched or cyclic C.sub.1 -C.sub.20 alkyl and aralkyl radicals; andnitrogen, oxygen or sulphur heterocycles, optionally substituted with at least one substituent selected from halogen, hydroxyl, C.sub.1 -C.sub.20 alkoxy, C.sub.1 -C.sub.20 acyloxy, primary, secondary or tertiary amino, nitro, thiol, carboxylic acid, amido, C.sub.1 -C.sub.20 alkyl carboxylate, aryl carboxylate, C.sub.1 -C.sub.20 aralkyl carboxylate, C.sub.1 -C.sub.20 alkylamido, arylamido and C.sub.1 -C.sub.20 aralkylamido groups, and from aryl and aralkyl radicals and saturated or unsaturated C.sub.1 -C.sub.20 nitrogen, oxygen, phosphorus and sulphur heterocycles;said process comprising at least one of the following steps 1 to 8:step 1) reacting a tri-anion of an alkyl 3,5-dioxohexanoate compound of formula (X) with (-)- or (+)-menthyl (X's)-p-toluenesulphinate to obtain an alkyl (Xs)-:3,5-dioxo-6-(p-tolylsulphinyl)hexanoate compound of formula (II), wherein formula (X) and formula (II) have the formula:Y--CO--CH.sub.2 --CO--CH.sub.2 --CO--CH.sub.3 (X)##STR28##wherein Xs and X's each individually represent the R or S configuration of the sulphur in each of the two molecules (Ia) and (Ib); but wherein Xs does not have the same configuration as X's; and wherein Y is a saturated or unsaturated, linear or branched C.sub.1 -C.sub.18 alkyloxy radical; an aryloxy radical or an aralkyloxy radical comprising not more than 18 carbon atoms; an imidazolide radical; a saturated or unsaturated, linear or branched C.sub.1 -C.sub.18 alkyl sulphide radical; an aryl sulphide or C.sub.1 -C.sub.20 aralkyl sulphide radical, or a radical ##STR29##wherein Q is a saturated or unsaturated, linear or branched C.sub.1 -C.sub.18 alkyl radical;step 2) reducing the 5-carbonyl function of an alkyl (Xs)-3,5-dioxo-6-(para-tolylsulphinyl)hexanoate compound of formula (II) enantioselectively to alcohol to obtain an alkyl [5(X.sub.5),S(Xs)]-5-hydroxy-3-oxo-6-(para-tolylsulphinyl)hexanoate compound of formula (III): ##STR30##wherein X.sub.5 has the configuration of the C5 carbon; wherein X.sub.5 does not have the same configuration as Xs; and wherein Y is a saturated or unsaturated, linear or branched C.sub.1 -C.sub.18 alkyloxy radical; an aryloxy radical or an aralkyloxy radical comprising not more than 18 carbon atoms; an imidazolide radical; a saturated or unsaturated, linear or branched C.sub.1 -C.sub.18 alkyl sulphide radical; an aryl sulphide or C.sub.1 -C.sub.20 aralkyl sulphide radical; or a radical ##STR31##wherein Q is a saturated or unsaturated, linear or branched C.sub.1 -C.sub.18 alkyl radical;step 3) reducing the 3-carbonyl function of an alkyl [5(X.sub.5),S(Xs)]-5-hydroxy-3-oxo-6-(para-tolylsulphinyl)hexanoate compound of formula (III) diastereoselectively to obtain an alkyl [3(X.sub.3),5(X.sub. 5),S(Xs)]-3,5-dihydroxy-6-(para-tolylsulphinyl)hexanoate compound of formula (IV): ##STR32##wherein X.sub.3 has the configuration of the C3 carbon; wherein a method of reduction is used that gives X.sub.5 in the same configuration as X.sub.3 to obtain an anti configuration or a method of reduction is used that gives X.sub.5 not having the same configuration as X.sub.3 to obtain a syn configuration for the two alcohol functions; andwherein Y is a saturated or unsaturated, linear or branched C.sub.1 -C.sub.18 alkyloxy radical; an aryloxy radical or an aralkyloxy radical comprising not more than 18 carbon atoms; an imidazolide radical; a saturated or unsaturated, linear or branched C.sub.1 -C.sub.18 alkyl sulphide radical; an aryl sulphide or C.sub.1 -C.sub.20 aralkyl sulphide radical; or a radical ##STR33##wherein Q is a saturated or unsaturated, linear or branched C.sub.1 -C.sub.18, alkyl radical;step 4) protecting two hydroxyl functions of an alkyl [3(X.sub.3),5(X.sub. 5),S(Xs)]-3,5dihydroxy-6-(para-tolylsulphinyl)hexanoate compound of formula (IV) with a radical R selected from a C.sub.1 -C.sub.8 alkyl radical, aryl or aralkyl radical, trialkylsilyl radical, a C.sub.1 -C.sub.8 alkanediyl radical and a benzylidene radical, to obtain an alkyl [3(X.sub.3),5(X.sub. 5),S(Xs)]-3,5-dialkyloxy-6-(para-tolylsulphinyl)hexanoate compound of formula (V): ##STR34##wherein Y is a saturated or unsaturated, linear or branched C.sub.1 -C.sub.18 alkyloxy radical; an aryloxy radical or an aralkyloxy radical comprising not more than 18 carbon atoms; an imidazolide radical; a saturated or unsaturated, linear or branched C.sub.1 -C.sub.18 alkyl sulphide radical; an aryl sulphide or C.sub.1 -C.sub.20 aralkyl sulphide radical; or a radical ##STR35##wherein Q is a saturated or unsaturated, linear or branched C.sub.1 -C.sub.18 alkyl radical; and the R radical is not displaced under the conditions of steps 5 and 6 below;step 5) reducing the sulphoxide function of an alkyl [3(X.sub.3),5(X.sub. 5),S(Xs)]-3,5-dialkyloxy-6-(para-tolylsulphinyl)hexanoate compound of formula (V) to thioether by a Pummerer reaction to obtain an alkyl [3(X.sub.3),5(X.sub. 5)]-6-acetoxy-3,5-dialkyloxy-6-(para-tolylthio)hexanoate compound of formula (VI): ##STR36##wherein R is selected from a C.sub.1 -C.sub.8 alkyl radical, aryl or aralkyl radical, trialkylsilyl radical, a C.sub.1 -C.sub.8 alkanediyl radical and a benzylidene radical; and wherein Y is a saturated or unsaturated, linear or branched C.sub.1 -C.sub.18 alkyloxy radical; an aryloxy radical or an aralkyloxy radical comprising not more than 18 carbon atoms; an imidazolide radical; a saturated or unsaturated, linear or branched C.sub.1 -C.sub.18 alkyl sulphide radical; an aryl sulphide or C.sub.1 -C.sub.20 aralkyl sulphide radical; or a radical ##STR37##wherein Q is a saturated or unsaturated, linear or branched C.sub.1 -C.sub.18 alkyl radical;step 6) converting the functions at C6 of an alkyl [3(X.sub.3),5(X.sub. 5)]-6-acetoxy-3,5-dialkyloxy-6-(para-tolylthio)hexanoate compound of formula (VI) to aldehyde to obtain an alkyl [3(X.sub.3),5(X.sub.5)]-6-oxo-3,5-dialkyloxyhexanoate compound of formula (VII): ##STR38##wherein Y is a saturated or unsaturated, linear or branched C.sub.1 -C.sub.18 alkyloxy radical; an aryloxy radical or an aralkyloxy radical comprising not more than 18 carbon atoms; an imidazolide radical; a saturated or unsaturated, linear or branched C.sub.1 -C.sub.18 alkyl sulphide radical; an aryl sulphide or C.sub.1 -C.sub.20 aralkyl sulphide radical; or a radical ##STR39##wherein Q is a saturated or unsaturated, linear or branched C.sub.1 -C.sub.18 alkyl radical; and wherein R is selected from a C.sub.1 -C.sub.8 alkyl radical, aryl or aralkyl radical, trialkylsilyl radical, a C.sub.1 -C.sub.8 alkanediyl radical and a benzylidene radical;step 7) condensing the alkyl [3(X.sub.3),5(X.sub.5)]-6-oxo-3,5-dialkyloxyhexanote compound of formula (VII) with a Wittig reagent (Ph,P=CH.psi.), wherein .psi. is a radical selected from:saturated or unsaturated, linear, branched or cyclic C.sub.1 -C.sub.40 alkyls, optionally containing ether bridges and/or substituted with at least one substituent selected from halogen, hydroxyl, C.sub.1 -C.sub.20 alkoxy, C.sub.1 -C.sub.20 acyloxy, primary, secondary or tertiary amino, nitro, thiol, carboxyl, amido, C.sub.1 -C.sub.20 alkyl carboxylate, aryl carboxylate, C.sub.1 -C.sub.20 aralkyl carboxylate, C.sub.1 -C.sub.20 alkylamido, arylamido and C.sub.1 -C.sub.20 aralkylamido groups, and from aryl radicals and saturated or unsaturated C.sub.1 -C.sub.20 nitrogen, oxygen, phosphorus and sulphur heterocycles;aryls, optionally substituted with at least one substituent selected from halogen, hydroxyl, C.sub.1 -C.sub.20 alkoxy, C.sub.1 -C.sub.20 acyloxy, amino, C.sub.1 -C.sub.20 alkylamino and dialkylamino, nitro, thiol, carboxyl, amido, C.sub.1 -C.sub.20 alkyl carboxylate, aryl carboxylate, C.sub.1 -C.sub.20 aralkyl carboxylate, C.sub.1 -C.sub.20 alkylamido, arylamido, C.sub.1 -C.sub.20 aralkylamido and C.sub.1 -C.sub.20 aryl groups, and from saturated or unsaturated, linear, branched or cyclic C.sub.1 -C.sub.20 alkyl and aralkyl radicals and saturated or unsaturated C.sub.1 -C.sub.20 nitrogen, oxygen, phosphorus and sulphur heterocycles;aralkyls, optionally substituted with at least one substituent selected from halogen, hydroxyl, C.sub.1 -C.sub.20 alkoxy, C.sub.1 -C.sub.20 acyloxy, amino, C.sub.1 -C.sub.20 alkylamino and dialkylamino, nitro, thiol, carboxylic acid, amido, C.sub.1 -C.sub.20 alkyl carboxylate, aryl carboxylate, C.sub.1 -C.sub.20 aralkyl carboxylate, C.sub.1 -C.sub.20 alkylamido, arylamido, C.sub.1 -C.sub.20 aralkylamido and C.sub.1 -C.sub.20 aryl groups, and from saturated or unsaturated, linear, branched or cyclic C.sub.1 -C.sub.20 alkyl and aralkyl radicals; andnitrogen, oxygen or sulphur heterocycles, optionally substituted with at least one substituent selected from halogen, hydroxyl, C.sub.1 -C.sub.20 alkoxy, C.sub.1 -C.sub.20 acyloxy, primary, secondary or tertiary amino, nitro, thiol, carboxylic acid, amido, C.sub.1 -C.sub.20 alkyl carboxylate, aryl carboxylate, C.sub.1 -C.sub.20 aralkyl carboxylate, C.sub.1 -C.sub.20 alkylamido, arylamido and C.sub.1 -C.sub.20 aralkylamido groups, and from aryl and aralkyl radicals and saturated or unsaturated C.sub.1 -C.sub.20 nitrogen, oxygen, phosphorus and sulphur heterocycles, to yield the compound of formula (VIII): ##STR40##wherein R is selected from a C.sub.1 -C.sub.8 alkyl radical, aryl or aralkyl radical, trialkylsilyl radical, a C.sub.1 -C.sub.8 alkanediyl radical, and a benzylidene radical; and wherein Y is a saturated or unsaturated, linear or branched C.sub.1 -C.sub.18 alkyloxy radical; an aryloxy radical or an aralkyloxy radical comprising not more than 18 carbon atoms; an imidazolide radical; a saturated or unsaturated, linear or branched C.sub.1 -C.sub.18 alkyl sulphide radical; an aryl sulphide or C.sub.1 -C.sub.20 aralkyl sulphide radical; or a radical ##STR41##wherein Q is a saturated or unsaturated, linear or branched C.sub.1 -C.sub.18 alkyl radical; andstep 8) reducing the double bond of a compound of formula (VIII) to obtain a compound of formula (IX): ##STR42##and, in a final step 9), removing the protective groups R from the hydroxyls, and hydrolyzing the ester --COY of a compound of formula (VIII) or of a compound of formula (IX) to obtain a compound of formula (Ib) or formula (Ia), respectively.