Patent GB-1345934-A (GB)
Title: Cyclopentane derivatives
IPC: C07C51/60
Filed: 1971-07-14
Abstract: 1345934 Prosteglandin derivatives; phosphoric acid esters IMPERIAL CHEMICAL INDUSTRIES Ltd 13 June 1972 [14 July 1971] 33048/71 Headings C2C and C2P [Also in Divisions A5 and C3] The invention comprise prosteglandin derivatives of the formula wherein R<SP>1</SP> is hydroxymethyl, carboxyl or alkoxycarbonyl of up to 11 carbon atoms; either R<SP>2</SP> is OH or C 1-4  alkanoyloxy and R<SP>3</SP> is H, or R<SP>2</SP> and R<SP>3</SP> together form an oxo radical; A is -CH 2 CH 2 - or trans-CH=CH-; X is C 1-9  alkylene, and R<SP>4</SP> is C 1-9  alkyl or C 5-7  cycloalkyl provided that X and R<SP>4</SP> together contain not more than 10 carbon atoms, and for those compounds wherein R<SP>1</SP> is carboxy, pharmaceutically acceptable salts. Compounds of the above formula in which R<SP>1</SP> is carboxy are obtained by hydrolysing compounds of the formula or mixed anhydrides thereof, wherein R<SP>5</SP> and R<SP>6</SP> each are a tetrahydropyren-2-yloxy radical. The acids thus obtained may be converted to the corresponding esters by reacting them with diazoalkanes of the formula R<SP>7</SP>.N. 2 , wherein R<SP>7</SP> is C 1-10  alkyl, or reacting salts thereof with C 1-10  alkyl halides, and the esters reduced to compounds of the Formula I above in which R<SP>1</SP> is hydroxymethyl. 9α - Hydroxy - 16 - pentyloxy - 11α,15 - bis- (tetrahydropyran - 2 - yloxy) - 17,18,19,20- tetranor - 5 - cis,13 - trans - prostadienoic acid is prepared by reacting (4-carboxybutyl)triphenylphosphonium bromide with 3,3a#,4,5, 6,6a# - hexahydro - 2 - hydroxy - 4# - [4- pentyloxy - 3 - (tetrahydropyran - 2 - yloxy) - 1 - transbutenyl] - 5α - (tetrahydropyran - 2 - yloxy) 2H - cyclopenta[b]furan, obtained by reducing 3,3a#,4,5,6,6a# - hexahydro - 2 - oxo - 4# - [4- pentyloxy - 3 - (tetrahydropyran - 2 - yloxy) - 1- trans - butenyl] - 5α - (tetrahydropyran - 2 - yloxy)- 2H - cyclopenta[b]furan, resulting from the reaction between dihydropyran and 3,3a#,4,5,6, 6a# - hexahydro - 5α - hydroxy - 2 - oxo - 4#- (4 - pentyloxy - 3 - hydroxy - 1 - trans - butenyl)- 2H-cyclopenta[b]furan, which is made by hydrolysing 3,3a#,4,5,6,6a# - hexahydro - 2 - oxo - 4#- (4 - pentyloxy - 3 - hydroxy - 1 - trans - butenyl)- 5α - (4 - phenylbenzoyloxy) - 2H - cyclopenta[b]- furan obtained by reducing 3,3a,4,5,6,6a#- hexahydro - 2 - oxo - 4# - (3 - oxo - 4 - pentyloxy- 1 - trans - butenyl) - 5α - (4 - phenylbenzoyloxy)- 2H - cyclopenta[b]furan, resulting from the reaction between dimethyl 2-oxo-3-pentyloxypropylphosphonate and 5α - (4 - phenylbenzoyloxy) - 4# - formyl - 3,3a#,4,5,6,6a#- hexahydro - 2H - cyclopenta[b]furan - 2 one. The following compounds are prepared by reacting the appropriate phosphonate with 5α - (4 - phenylbenzoyloxy) - 4# - formyl- 3,3a#,4,5,6,6a# - hexahydrocyclo - 2H - penteno- [b]furan: 3,3a#,4,5,6,6a# - hexahydro - 5α - (4- phenylbenzoyloxy) - 4# - [3 - oxo - 4 - propoxy (or butoxy or isobutoxy, or hexyloxy) - 1 - transbutenyl], 2H-cyclopenteno[b]furan-2-one. 3,3a#,4,5,6,6a# - Hexahydro - 4# - (3 - oxo - 4- pentyloxybutyl) - 5α - (4 - phenylbenzoyloxy) - 2H- cyclopenteno[b]furan-2-one is obtained by hydrogenerating the corresponding unsaturated ketone. Butyl 3-butoxypropionate is prepared by reacting ethyl acrylate with a solution of sodium dissolved in n-butanol. Methyl 4-propoxybutyrate is obtained by esterifying 4-propoxybutyric acid, made by reacting 4- bromobutyric acid with a solution of sodium in n-propanol. Ethyl 5-ethoxypentanoate is made by hydrogenating ethyl 5-ethoxy-2-pentenoate obtained by reacting triethyl phosphonoacetate with 3- ethoxypropionaldehyde resulting from the hydrolysis of the corresponding diethyl acetal 6- methoxyhexanoyl chloride is prepared by reacting thionyl chloride with 6-methoxyhexanoic acid, resulting from the hydrolysis of ethyl 6-methoxyhexanoate, obtained by reacting ethyl 6-bromohexanoate and a solution of sodium in methanol. Phosphonates of the formula are prepared by reacting dimethyl methylphosphonate with compounds of the formula R<SP>4</SP>.O.XCOR<SP>5</SP>, where R<SP>5</SP> is alkoxy or halogen, in the presence of butyl-lithium.