Patent GB-1414881-A (GB)
Title: Difluoromethylene substituted prostaglandin derivatives
IPC: A61P15/04
Filed: 1973-08-29
Abstract: 1414881 Prostaglandins SYNTEX (USA) Inc 29 Aug 1973 [8 Sept 1972 13 July 1973] 40736/73 Headings C2C and C2P The invention comprises antimers and racemic mixtures of prostaglandins of the Formula I wherein R is C 3-9  alkyl (straight chain); R 2  is =O R<SP>3</SP> is H, CH 3  or CH 3 CH 2 ; and Z is a single bond or a cis double bond, provided that (a) when the side chain attached at the 12-position in beta, the difluoromethylene group at the 11,12- positions is 11α, 12α only; and when the side chain attached at the 12 position is alpha, the difluoromethylene at the 11,12-positions is 11#, 12# only; and (b) when R<SP>3</SP> is alpha, the OH group, attached to the same carbon as R<SP>3</SP>, is beta, and when R<SP>3</SP> is beta, the OH group attached to the same carbon as R<SP>3</SP>, is alpha; and the pharmaceutically acceptable or methyl esters thereof. The compounds are prepared by (a) treating a 1<SP>1</SP>R-antimoric or racemic compounds of the Formula III with difluorocarbene generating sources in organic solvents to yield mixtures of compounds of the formulae (b) separating the mixtures of step (a) and selectively reducing the ozo groups in the side chains thereby yielding the corresponding alpha and beta hydroxy compounds; (c) separating the alpha and beta hydroxy compounds obtained in step (b) and reacting the separated compounds with dihydropyran in the presence of a catalytic amount of an acid, thereby yielding the corresponding tetrahydropyranyl ethers; (d) reducing the lactone ozo group of the etherified compounds with diisobutylaluminium hydride in inert organic solvents, thereby yielding the corresponding lactols; (e) condensing the lactols of step (d) with the Witlig reagent derived from (4-carboxybutyl)triphenylphosphonium bromide and sodium methylsulphinylmethylide, thereby yielding the corresponding compounds of the formulae wherein THP is 2-tetrahydropyranyl; (f) selectively reducing the cis double bond in the compounds of step (e), thereby yielding the corresponding mono unsaturated compounds; (g) oxidizing the hydroxyl group in the compounds of steps (e) and (f), thereby yielding the corresponding 9-oxo-derivatives; (h) hydrolysing the tetrahydropyranyloxy group in compounds of step (g) under mild acidic conditions to yield compounds of the above Formula I in which R<SP>2</SP> is = O and R<SP>3</SP> is H; (i) converting the compounds of step (h) into the corresponding methyl esters; (j) reducing the ozo group in the methyl esters of step (i) with sodium borohydride in lower aliphatic alcohols, and, if desired hydrolysing the resulting esters, thereby yielding compound of the Formula I in which R<SP>2</SP> is and R<SP>3</SP> is H; (k) treating the compounds of step (h) with alcoholic solutions of alkali metal alkoxides to invert the configuration of the carboxylic acid chain, followed by strong mineral acids, thereby yielding compounds as in step (h) with the carboxy side chains in the opposite configurations; (l) converting the compounds of step (k) into the corresponding methyl esters; (m) reducing the ozo group and, if desired, hydrolysing the resulting esters, thereby yielding compounds or in step (j) with the carboxy side chains in the opposite configuration; (n) separating the individual 9α and 9# isomers in steps (j) and (m); (o) selectively oxidizing the 15- hydroxy group in the compounds of step (n) with an excess of manganese dioxide or 2,3- dichloro-5,6-dicyano-1,4-benzoquinone in inert organic solvents, thereby yielding the corresponding 15-oxo compounds; (p) treating the 15- oxo compounds of step (n) with methyl or ethyl magnesium halides or methy or ethyl-lithium, thereby yielding compounds of Formula I above in which R<SP>2</SP> is and R<SP>3</SP> is CH 3  or CH 3 CH 2  (as the methyl esters); (q) oxidizing the 9-hydroxy group in the compounds of step (p), thereby yielding compounds of Formula I above in which R<SP>2</SP> is = O and R<SP>3</SP> is CH 3  or CH 3 CH 2  (as the methyl esters); (r) hydrolysing the esters of steps (p) and (q) and (s) converting the resulting free acids of steps (h), (j), (k), (m) and (r) into salts. Compounds of Formula III and 5α-acetoxy- 4# - (3 - oxo - trans - 1 - alkenyl) - 3,3α#,4,5,6,6α#- hexahydro - 2H - cyclopenta[b]fura - 2 - ones are obtained by treating 5α-acetoxy-4#-formyl- 3,3α#,4,5,6,6α# - hexahydro - 2H - cyclopenta- [b]furan-2-ones with the sodium anions of the appropriate phosphonates of the formula CH 3 (CH 2 ) m .CO.CH 2 .P(O)(OCH 3 ) 2  wherein m is 2 to 8, in 1,2-dimethoxyethane. Dimethyl 2-oxooctylphosphonate, dimethyl 2- oxoheptylphosphonate, dimethyl 2-oxohexyphosphonate, dimethyl 2-oxopentylphosphonate, dimethyl 2-oxononylphosphonate and dimethyl oxoundecylphosphonate are obtained by reacting dimethyl methylphosphonate with butyllithium and the appropriate methyl alkanoates. Pharmaceutical compositions, suitable for oral, parenteral administration or inhalation, contain the above prostaglandins I or salts and suitable carriers. The compounds possess similar activities to those of the naturally occurring prostaglandins.