Patent GB-1414383-A (GB)
Title: Prostatrienoic acid derivatives and process
IPC: B01J31/00
Filed: 1973-07-04
Abstract: 1414383 Prostaglandins SYNTEX CORP 4 July 1973 [14 Nov 1972 5 March 1973 11 June 1973] 31900/73 Addition to 1413831 Heading C2C [Also in Division C3] The invention comprises racemic mixtures and 8R-antimers of prostaglandins represented by the following formulae wherein R and R<SP>5</SP> each are H, methyl, ethyl or propyl; R<SP>1</SP> is H, OH or esterified or etherified hydroxy; R<SP>2</SP> and R<SP>3</SP> each are OH or esterified or etherified hydroxy; provided that if R<SP>1</SP> is not hydrogen it is the same as R<SP>2</SP> and R<SP>3</SP>; R<SP>6</SP> is methyl, ethyl or propyl; R<SP>4</SP> is H or C 1-3  alkyl; and n is 2 to 9; and pharmaceutically acceptable, non-toxic salts of compound in which R<SP>4</SP> is H; provided that racemic mixtures are excluded when n is 4 in the case of formulae A and C and when n is 4 and R<SP>3</SP> is α-hydroxy in the case of formulae B and D. Compounds of the above formulae A and B are prepared by (a) treating racemic compounds and 1R-antimers thereof of the Formula E wherein R<SP>1</SP> is H or 2-tetrahydropyranyloxy, with the dilithium salt or pent-4-yn-1-ol to obtain trihydroxy compounds of the Formula (b) converting the compounds of step (a) into triesters, or (c) selectively oxidizing the OH at C-6 (d) treating the dihydroxy-oxo-acetylenic compounds then obtained with C 1-3  alkyl lithiums or C 1-3  alkylmagnesium halides to produce compounds of the formulae (e) converting the compounds of step (d) into triesters; (f) treating the triesters of steps (b) or (e) with lithium di-(C 1-3  alkyl) copper reagents under inert atmospheres in ether solvents, using about 4 molar equivalents of lithium dialkyl copper at about -70 C. or about 1-molar equivalent of lithium dialkyl copper at about 0 C. to produce compounds of the formula wherein Ac is C 1-4  acyl; (g) hydrolyzing the compounds of step (f) under basic conditions; (h) oxidizing the mono- or di-hydroxy compounds obtained in step (g); (i) hydrolyzing the protected hydroxy groups which remain in the molecule, and (j) optionally esterifying or etherifying the hydroxy groups and/or converting the carboxylic acid groups into C 1-4  alkyl esters or salts thereof. Compounds of formula C above are obtained by (a) esterifying compound of the formula wherein R<SP>11</SP> is H or 2-tetrahydropyranyloxy; (b) hydrolyzing the tetrahydropyranyloxy groups; (c) reacting the resulting compounds with hydroxylamine; (d) selectively oxidizing the OH groups as C-15 in the rsulting oximes; (e) protecting the OH groups at C11 (when present) as the trimethylsilyl ether; (f) treating the 15- oxo compounds with C 1-3  alkyl lithiums or C 1-3  alkylmagnesium halides; (g) hydrolyzing the trimethylsilyloxy groups (when present); (h) optionally separating the resulting mixtures of hydroxy compounds; (j) hydrolysing the alkyl ester groups; and optionally esterifying or etherifying the secondary hydroxy groups (when present) and/or converting the carboxylic acid groups to alkyl esters or salts. Compounds of Formula D above are prepared by starting with compounds of the formula and carrying out steps (a), (b), (d), (e), (f), (g), (i) and (j) listed above for the preparation of compounds of Formula C. The following intermediates are also prepared; (2α - hydroxy - 4α - p - phenylbenzoyloxy - 3#- iodo-5#-benzyloxymethyl (or methoxymethyl) cyclopent-1α-yl)-acetic acid γ-lactone, (2α-hydroxy - 4α - p - phenylbenzyloxy - 5# - benzyloxymethyl (or methoxymethyl)-cyclopent-1α- yl) acetic acid γ-lactone, (2α-hydroxy-4α-pphenylbenzoyloxy - 5# - hydroxymethyl - cyclopent-1α-yl) acetic acid γ-lactone, (2α-hydroxy- 4α-p-phenylbenzoyloxy-5#-formylcyclopent-1α- yl)-acetic acid γ-lactone, (2α-hydroxy-5#-benzyloxymethyl (or methoxymethyl)-cyclopent-3- en-1α-yl)-acetic acid and its γ-lactone, (2α- hydroxy-5#-benzyloxymethyl (or methoxymethyl)-cyclopent-1α-yl) acetic acid γ-lactone- (2α - hydroxy - 5# - hydroxymethylcyclopent- 1α-yl) acetic acid γ-lactone, (2α-hydroxymethyl, 5#-formylcyclopent-1α-yl) acetic acid γ-lactone- [2α - hydroxy - 4α - p - phenylbenzoyloxy - 5#- (3-ozo (or hydroxy) alk-trans-1-enyl)cyclopent- 1α-yl] acetic acid γ-lactone, [2α-hydroxy-5#-(3- oxo (or hydroxy)-alk-trans-1-enyl)cyclopent-1α- yl] acetic acid γ-lactone, [2α,4α-dihydroxy-5#- (3 hydroxyalk-trans-1-en-yl)cyclopent-1α-yl]- acetic acid γ-lactone and its bis-tetrahydropyronyl ether, [2α-hydroxy-5#-(3-tetrahydropyran - 2<SP>1</SP> - yloxyalk - trans - 1 - enyl) - cyclopent- 1α-yl] acetic acid γ-lactone, and the compounds of Formula E above. Pharmaceutical compositions, suitable for administration orally, parenterally or by inhalation, contain the above novel prostaglandins or non-toxic salt thereof and excipients therefor. The compounds possess activities similar to those of the naturally occurring prostaglandins.