Patent EP-0216127-A2 (EP)
Inventor: WESS GUNTHER DR
IPC: A61K31/365
Filed: 1986-08-18
Abstract: 1. Claims for the Contracting States : BE, CH, DE, FR, GB, IT, LI, LU, NL, SE A 6-phenoxymethyl-4-hydroxytetrahydropyran-2-one of the general formula I  see diagramm : EP0216127,P57,F1  in which R**1 and R**5 are identical or different and denote a) halogen, b) cycloalkyl having 4-8 carbon atoms, or a phenyl radical which can be substituted in the nucleus once to 3 times by halogen, trifluoromethyl, and/or alkyl or alkoxy each having 1-4 carbon atoms, or c) a straight-chain or branched alkyl radical having 1 to 18 carbon atoms, or a straight-chain or branched alkenyl radical having 2 to 18 carbon atoms, it being possible for the alkyl and alkenyl radicals in turn to be substituted 1-3 times by alpha) straight-chain or branched alkoxy radicals having up to 10 carbon atoms, or cycloalkyl radicals having 3 to 7 carbon atoms, or straight-chain or branched alkenyloxy or alkynyloxy radicals having 3 to 6 carbon atoms, beta) halogen, hydroxyl, cycloalkyl having 3-7 carbon atoms, unsubstituted phenyl or alpha- or beta-thienyl radicals, or phenyl or alpha- or beta-thienyl radicals which in turn are substituted in the nucleus once to 3 times by halogen, trifluoromethyl and/or alkyl or alkoxy having 1-4 carbon atoms, gamma) unsubstituted phenoxy, benzyloxy, alpha- or beta-thienyloxy radicals, or phenoxy, benzyloxy, alpha- or beta-thienyloxy radicals which in turn are substituted in the nucleus once to 3 times by halogen, trifluoromethyl and/or alkyl or alkoxy having 1 to 4 carbon atoms, delta) the group  see diagramm : EP0216127,P57,F2  R**6 denoting : a straight-chain or branched alkyl or alkenyl radical having up to 8 carbon atoms, or a cycloalkyl or cycloalkenyl radical each having 3-8 carbon atoms, or an unsubstituted phenyl radical, or a phenyl radical which in turn is substituted in the nucleus once to 3 times by halogen, trifluoromethyl and/or alkyl or alkoxy having 1-4 carbon atoms, or a 3-pyridyl radical, R**2 and R**4 denote hydrogen, and R**3 is alkyl or alkenyl having up to 4 carbon atoms, halogen or alkoxy having 1-4 carbon atoms, and the corresponding open-chain dihydroxy carboxylic acid, their pharmacologically tolerated salts with bases, and their pharmacologically tolerated esters. 1. Claims for the Contracting State : AT A process for the preparation of a 6-phenoxymethyl-4-hydroxytetrahydropyran-2-one of the general formula I  see diagramm : EP0216127,P62,F1  in which R**1 and R**5 are identical or different and denote a) halogen, b) cycloalkyl having 4-8 carbon atoms, or a phenyl radical which can be substituted in the nucleus once to 3 times by halogen, trifluoromethyl and/or alkyl or alkoxy each having 1-4 carbon atoms, or c) a straight-chain or branched alkyl radical having 1 to 18 carbon atoms, or a straight-chain or branched alkenyl radical having 2 to 18 carbon atoms, it being possible for the alkyl and alkenyl radicals in turn to be substituted 2-3 times by alpha) straight-chain or branched alkoxy radicals having up to 10 carbon atoms, or cycloalkoxy radicals having 3 to 7 carbon atoms, or straight-chain or branched alkenyloxy or alkynyloxy radicals having 3 to 6 carbon atoms, beta) halogen, hydroxyl, cycloalkyl having 3-7 carbon atoms, unsubstituted phenyl or alpha- or beta-thienyl radicals, or phenyl or alpha- or beta-thienyl radicals which in turn are substituted in the nucleus once to 3 times by halogen, trifluoromethyl and/or alkyl or alkoxy having 1-4 carbon atoms, gamma) unsubstituted phenoxy, benzyloxy, alpha- or beta-thienyloxy radicals, or phenoxy, benzyloxy, alpha- or beta-thienyloxy radicals which in turn are substituted in the nucleus once to 3 times by halogen, trifluoromethyl and/or alkyl or alkoxy having 1 to 4 carbon atoms, delta) the group  see diagramm : EP0216127,P62,F2  R**6 denoting : a straight-chain or branched alkyl or alkenyl having up to 8 carbon atoms, or a cycloalkyl or cycloalkenyl radical each having 3-8 carbon atoms, or an unsubstituted phenyl radical, or a phenyl radical which in turn is substituted in the nucleus once to 3 times by halogen, trifluoromethyl and/or alkyl or alkoxy having 1-4 carbon atoms, or a 3-pyridyl radical, R**2 and R**4 denote hydrogen, and R**3 is alkyl or alkenyl having up to 4 carbon atoms, halogen or alkoxy having 1-4 carbon atoms, and the corresponding open-chain dihydroxy carboxylic acid, their pharmacologically tolerated salts with bases, and their pharmacologically tolerated esters, which comprises a) conversion of an appropriately substituted phenol of the formula II  see diagramm : EP0216127,P62,F3  in which R**1 , R**2 , R**3 , R**4 and R**5 have the indicated meanings, with the chiral iodide of the formula III see diagramm : EP0216127,P63,F1  in which R**10 denotes a protective group which is stable to bases and weak acids, into an ether of the formula IV  see diagramm : EP0216127,P63,F2  in which R**1 to R**5 have the meanings indicated for formula I and R**10 has the meanings indicated for formula III, b) hydrolysis of the ether of the formula IV to give the corresponding hemiacetal of the formula V  see diagramm : EP0216127,P63,F3  in which R**1 to R**5 and R**10 have the meanings indicated for formula I or III, c) oxidation of the hemiacetal of the formula V to give the corresponding lactone of the formula VI  see diagramm : EP0216127,P64,F1  in which R**1 to R**5 have the meanings indicated for formula I and R**10 has the meanings indicated for formula III, and d) conversion of the protected hydroxylactone of the formula VI into the 6-phenoxymethyl-4-hydroxytetrahydropyran-2-one of the formula I  see diagramm : EP0216127,P64,F2  where appropriate the compound of the formula I which has been obtained being converted into the corresponding open-chain dihydroxy carboxylic acid of the formula VII see diagramm : EP0216127,P64,F3  its salt or its ester, where appropriate a salt or ester which has been obtained being converted into the free dihydroxy carboxylic acid or, where appropriate, the free carboxylic acid being converted into the salt or ester.