Patent GB-1194911-A (GB)
Title: Improvements in or relating to Lactones derived from Benzoic Acid
IPC: C07D313/00
Filed: 1967-06-06
Abstract: 1,194,911. Lactones derived from benzoic acid. SYNTEX CORP. 6 June, 1967 [27 June, 1966], No. 26073/67. Headings C2C and C2J. Lactones of the Formula E in which each of R<SP>1</SP> and R<SP>2</SP> is H, OH, alkoxy, halogen, cyclopentyloxy, tetrahydrofuran-2<SP>1</SP>- yloxy, tetrahydropyran-2<SP>1</SP>-yloxy, hydrocarbon carboxylic acyl or acyloxy of less than 12 carbon atoms or when taken together 4,5-benzo; R<SP>3</SP> is H or C 1-6  alkyl, R<SP>4</SP> is halogen or (C n H 2n )-H in which n is 0 to 6, R<SP>5</SP> is in which R<SP>6</SP> is H, cyclopentyl, tetrahydrofuran- 2<SP>1</SP>-yl, tetrahydropyran-2<SP>1</SP>-yl or hydrocarbon carboxylic acyl of less than 12 carbon atoms; R<SP>7</SP> is H, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl or halo-C 2-6  alkynyl; R<SP>8</SP> is methylene, ethylene, 1,2-propylene or trimethylene; Z is a carboncarbon single bond or a carbon-carbon double bond, and Z<SP>1</SP> indicates that one or more of the benzene unsaturated linkages may be saturated, are prepared by reacting the 2-aldehydes of benzoic acid ester with triphenylphosphorane adduct of an aliphatic hydroxy-alkanes of the general Formula B above to give the corresponding 2 - (hydroxyalkenyl) benzoates of the partial Formula C above, treating the thusobtained benzoate with a base to cleave the ester group and lactonizing the resulting benzoic acid, to give 2-(hydroxyalkenyl) benzoic acid lactone of the partial Formula D above, and carrying out, in optional order and to the extent desired and required, the following steps:- (1) acid hydrolysis of the 6<SP>1</SP>-ketals to give the 6<SP>1</SP>-keto compounds; (2) reduction of the 6<SP>1</SP>- keto compounds to give the 6<SP>1</SP>-hydroxy compounds; (3) treating the 6<SP>1</SP>-keto compounds with an organometallic reagent to give the 6- aliphatic-6 -hydroxy compounds; (4) converting 6-keto groups to 6<SP>1</SP>,6<SP>1</SP>-thioketal groups and cleaving these to give 6-unsubstituted compounds; (5) forming p-tosylates of 6<SP>1</SP>-hydroxy compounds and removing the p-tosylate groups to give 5<SP>1</SP>- and 6<SP>1</SP>-unsaturated compounds; (6) converting 6-keto compounds to 6<SP>1</SP>,6<SP>1</SP>-difluoro compounds; (7) forming acetals of the 6-keto compounds; (8) selectively hydrogenating the 2<SP>1</SP>-unsaturated bond; (9) etherifying any hydroxy groups to give the alkyl, cyclopentyl, tetrahydrofuran-2<SP>1</SP>-yl, and tetrahydropyran-2<SP>1</SP>-yl ethers; (10) esterifying any hydroxy groups to give the hydrocarbon carboxylic acyloxy esters of less than 12 carbon atoms; (11) selectively hydrogenating one or more of the unsaturated bonds of the benzene rings. An alternative process for preparing 2-(6<SP>1</SP>-keto- 10<SP>1</SP> - hydroxyundec - 11 - enyl) - 4,6 - dihydroxybenzoic acid-10<SP>1</SP>-lactone comprises refluxing the adduct of cyclopentanone and pyrrolidine with 1-chloro-4-hydroxypentane to give 2-(#-hydroxypentyl) - cyclopentan - 1 - one, which is converted to the ring lactone with peracetic acid in chloroform and this lactone reduced and the resulting 1,5,9-trihydroxydecane, converted by treatment with p-toluenesulphonyl chloride to the corresponding primary tosylate, which is refluxed in the acetone in the presence of excess sodium iodide to give the 6,9-dihydroxydecyl iodide. Treatment thereof with excess triphenyl phosphine and butyl lithium gives the triphenyl phosphine dilithium salt product, which with ethyl - 4,6 - bistetrahydropyran - 2<SP>1 </SP>- yloxybenzoate-2-al gives ethyl 2-(6<SP>1</SP>,10<SP>1</SP>-dihydroxyundec - 1<SP>1</SP> - enyl) - 4,6 - bistetrahydropyran - 2<SP>1</SP> - yloxybenzoate. This compound is converted via the acid to 2-(6<SP>1</SP>-10<SP>1</SP>-dihydroxyundec-1<SP>1</SP>-enyl)- 4,6 - bistetrahydropyran - 2<SP>1</SP> - yloxy benzoic acid-10<SP>1</SP>-lactone, which on oxidation and hydrolysis gives the desired product. Ethyl 4,6 - bistetrahydropyran - 2<SP>1 </SP>- yloxybenzoate-2-al is obtained by reacting dihydropyran with ethyl 4,6-dihydroxybenzoate-2-al, obtained by refluxing a solution of potassium hydroxide with a methanolic solution of ethyl 4,6-diacetoxybenzoate-2-al, resulting from acid hydrolysis of ethyl - 2 - diacetozymethyl - 4,6 - diacetoxybenzoate which is in turn made by oxidizing with chromium trioxide in acetic acid-acetic anhydride mixture and ethyl 2-methyl-4,6-diacetoxybenzoate resulting from the reaction of acetic anhydride on ethyl 2-methyl-4,6-dihydroxy-benzoate. A phosphorane of the Formula III above is obtained by reacting excess triphenylphosphine with 1 - chloro - 5,5 - ethylenedioxy - 9 - hydroxydecane obtained by refluxing a mixture of ethylene glycol, p-toluenesulphonic acid and 1 - chloro - 5 - keto - 9 - hydroxydecane, resulting from the reaction of 5-chlorovaleronitrile on the Grignard compound obtained by adding magnesium turnings to a solution of 1-chloro-4- tetrahydropyran-2<SP>1</SP>-yloxypentane, obtained by reacting 1-chloro-4-hydroxypentane with dihydropyran, in tetrahydrofuran. Reference has been directed by the Comptroller to Specifications 951,349, 1,101,134, 1,107,735, 1,107,738, 1,107,740, 1,107,741, 1,107,744 and 1,107,745.