Process for making 1,3-dioxane derivatives

A process for the manufacture of a (4-phenyl-1,3-dioxan-cis-5-yl)alkenoic acid of the formula I set out herein wherein Ra and Rb are independently hydrogen, (2-6C)alkenyl, (1-8C)alkyl optionally bearing up to three halogeno substituents, pentafluorophenyl, aryl or aryl-(1-4C)alkyl, the latter two of which may optionally bear up to three substituents selected from halogeno, (1-6C)alkyl, 1-6C)alkoxy, (1-4C)alkylenedioxy, trifluoromethyl, cyano, nitro, hydroxy, (2-6C)alkanoyloxy, (1-6C)alkylthio, (1-6C)alkanesulphonyl, (1-6C)alkanoylamino, and oxapolymethylene of 2 to 4 carbon atoms, provided that when both Ra and Rb are alkyl or alkenyl, the total number of carbon atoms in Ra and Rb taken together is 8 or less;

• or Ra and Rb together form polymethylene of 2 to 7 carbon atoms, optionally bearing one or two (1-4C)alkyl substituents;
• Rc is hydroxy, (1-6C)alkoxy or (1-6C)alkanesulphonamido;
• n is 1;
• A is ethylene or vinylene;
• Y is polymethylene of 2 to 5 carbon atoms optionally bearing (1-4C)alkyl as a substituent;
• benzene ring B optionally bears one or two substituents selected from halogeno, (1-6C)alkyl, (1-6C)alkoxy, hydroxy, (1-6C)alkanoyloxy, (1-6C)alkanoylamino, trifluoromethyl and nitro;
• and the substituents at positions 4 and 5 of the dioxane ring have cis-relative stereochemistry;
• or for those compounds wherein Rc is hydroxy, a salt thereof with a base affording a physiologically acceptable cation;
• which is characterised by carrying out the steps of:
• (i) reacting an erythro-4-hydroxy-3-hydroxymethyl-4-phenylbutyraldehyde of the formula II, or an alkali metal salt thereof, or the corresponding [2,3-trans]-tetrahydro-5-hydroxy-3-hydroxymethyl-2-phenylfuran of the formula IIa, wherein benzene ring B has the meaning defined above, and the hydroxy and hydroxymethyl groups in formula II have the indicated cis-relative stereochemistry, with an ylid of the formula (Rd).sub.3 P.dbd.CH.Y CO.Q wherein Rd is (1-6C)alkyl or aryl and Q stands for --OM or --NM.SO.sub.2 Re in which M is an alkali metal, Re is (1-6C)alkyl and Y has the meaning defined above, to give after acidification an erythrodiol of the formula III wherein benzene ring B has the meaning defined above, and Rf is hydroxy or (1-6)C alkanesulphonamido;
• and
• (ii) reacting the diol of formula III, or a mono (1-6C)alkanesulphonyl or arenesulphonyl ester thereof, with a carbonyl compound of the formula RaRb.CO, or an acetal, hemiacetal or hydrate thereof;
• whereafter:
• when a compound of formula I wherein A is ethylene is required, the corresponding compound of formula I wherein A is vinylene is hydrogenated in the presence of a suitable catalyst;
• when a compound of formula I wherein Ra or Rb is hydroxyphenyl, or benzene ring B bears a hydroxy substituent is required, the corresponding compound of formula I wherein the hydroxy group is protected by a trimethylsilyl, (1-6C)alkyl, acyl or benzyl protecting group is deprotected;
• when an optically active form is required, steps (i) and (ii) above are carried out starting with an optically active aldehyde of formula II or furan of the formula IIa, or a racemic form of a compound of formula I wherein Rc is hydroxy is resolved by reaction with an optically active form of a suitable organic base, by a conventional procedure;
• when a pharmaceutically acceptable salt is required, a compound of formula I wherein Rc is hydroxy is reacted with the appropriate base affording a physiologically acceptable cation;
• or
• when a (1-6C)alkyl ester or (1-6C)alkanesulphonamide is required, the corresponding compound of formula I wherein Rc in hydroxy in racemic or optically active form, or a reactive derivative thereof, is reacted with the appropriate (1-6C)alkanol or (1-6C)alkanesulphonamide, or with an alkali metal salt thereof.