Patent GB-1431561-A (GB)
Title: Cyclopentane derivatives
IPC: C07F9/6553
Filed: 1973-01-31
Abstract: 1431561 Prostaglandins; phosphonate intermediates IMPERIAL CHEMICAL INDUSTRIES Ltd 10 Jan 1974 [31 Jan 1973] 4769/73 Headings C2C and C2P [Also in Division C3] The invention comprises prostaglandins of the Formula I wherein R<SP>1</SP> is a carboxy or hydroxymethyl radical, or an alkoxycarbonyl radical of up to 11 carbon atoms; either R<SP>2</SP> is a hydroxy radical or an alkanoyloxy radical of 1 to 4 carbon atoms and R<SP>3</SP> is a hydrogen atom, or R<SP>2</SP> and R<SP>3</SP> together form an oxo radical; X is an ethylene or cis-vinylene radical; Y is an ethylene or transvinylene; Z is a direct bond or an alkylidene radical of 1 to 5 carbon atoms; either A is an alkylidene radical of 1 to 5 carbon atoms or an ethylene radical and B is a direct bond, an oxygen or sulphur atom, or an alkylidene radical of 1 to 5 carbon atoms, or A is an oxygen atom and B is an oxygen atom, an alkylideneoxy radical of 1 to 5 carbon atoms wherein the oxygen atom is linked directly to the benzene ring, or an alkylidene(alkylimino) radical wherein the alkylidene radical is of 1 to 5 carbon atoms and the alkyl radical is of 1 to 4 carbon atoms, and wherein the nitrogen atom is linked directly to the benzene ring ; R<SP>4</SP> is a hydrogen atom or an alkyl radical of 1 to 4 carbon atoms, or CR<SP>4</SP> together with an adjacent carbon atom of A or B forms a double bond; R<SP>5</SP> is a halogen atom or an alkyl, alkoxy or halogenalkyl radical of 1 to 3 carbon atoms, and n is 0, 1 or 2; which compound bears 0 or 1 alkyl substituent of 1 to 4 carbon atoms on the trimethylene group; and for those compounds wherein R<SP>1</SP> is a carboxy radical, the pharmaceutically- or veterinarilyacceptable base addition salts thereof, and processes for their preparation. The compounds of Formula I are prepared by one of the following methods: (a) for those compounds in which R<SP>1</SP> is COOH, the hydrolysis of compounds of the Formula IV or mixed anhydrides thereof, wherein R<SP>6</SP> is 2- tetrahydropyranyloxy or C 1-6  acyloxy; or (b) for those compounds in which R<SP>1</SP> is alkoxycarbonyl, the esterification of the corresponding compounds in which R<SP>1</SP> is COOH; or (c) for those compounds in which R<SP>1</SP> is CH 2 OH, the reduction of the corresponding compounds in which R<SP>1</SP> is alkoxycarbonyl; or (e) for those compounds in which R<SP>1</SP> is COOH, R<SP>2</SP> is OH and R<SP>3</SP> is H, the reaction of lactals of the Formula V with (4-carboxybutyl)phosphonium salts, bearing 0 to 1 alkyl on the trimethylene group, in the presence of strong bases; or (f) the reduction of ketones of the Formula VI wherein R<SP>7</SP> and R<SP>8</SP> are OH or protected OH, whereafter when R<SP>7</SP> and R<SP>8</SP> are each a protected OH the protecting groups are removed; or (g) for those compounds in which R<SP>2</SP> is OH and R<SP>3</SP> is H, the reduction of the corresponding compounds wherein R<SP>2</SP> and R<SP>3</SP> together form an oxo group. The following intermediates are also prepared: compounds of the Formula IV above; compounds of the Formula VI above and the corresponding hydroxy compounds obtained by their reduction; ethyl 4-methyl-1,4-benzoxazine-2- carboxylate, 4# - [3 - (2,3 - dihydrobenzo[b]- fur - 2 - yl) - 3 - oxo (and 3 - hydroxy) - trans- 1 - propenyl] - 5α - (4 - phenylbenzoyloxy)- 3,3a#,4,5,6,6a# - hexahydro - 2H - cyclo - penta- [b]furan - 2 - one; 4# - [3 - (2,3 - dihydrobenzo- [b] - fur - 2 - yl) - 3 - hydroxy - trans - 1 - propenyl) - 5α - hydroxy - 3,3a#,4,5,6,6a# - hexahydro - 2H - cyclopenta[b]furan - 2 - one and its bis-(2 - tetrahydropyranyl) ether; 4#- dimethoxymethyl - 3,3a#,4,5,6,6a# - hexahydro - 5α - hydroxy - 2H - cyclopenta[b]- furan - 2 - one and its tetrahydropyranyl ether; 4# - dimethoxymethyl - 3,3a#,4,5,6,6a#- hexahydro - 5α - (2 - tetrahydropyranyloxy)- 2H - cyclopenta[b]furan - 2 - ol; 7 - [2# - dimethoxymethyl - 5α - hydroxy - 3α - (2 - tetrahydropyranyloxy) - cyclopent - 1α - yl]heptcis - 5 enoic acid and the corresponding 2- methyl - cis - 5 - heptenoic acid, and its methyl ester; methyl 7 - (2# - dimethoxymethyl - 3α,5α - dihydroxy - 1α - cyclopentyl)- hept - cis - 5 - enoate and the 3α,5α - di - pphenylbenzoate thereof; methyl 7-[2#-formyl- 3α,5α - di(4 - phenyl - benzoyloxy) - 1α - cyclopentyl]hept - cis - 5 - enoate; compounds of Formula IV above and their bis-(2-tetrahydropyranyl) ethers; 4#-[3-(2-indanyl)-3-oxo (and hydroxy) - trans - 1 - propenyl] - 5α - (4 - phenylbenzoyloxy) - 3,3a#,4,5,6,6a# - hexahydro- 2N - cyclopenta[b]furan - 2 - one; 4# - [3 - hydroxy - 3 - (2 - indanyl) - trans - 1 - propenyl)- 5α - hydroxy - 3,3a#,4,5,6,6a# - hexahydro - 2H- cyclopenta[b]furan - 2 - one and its bis-(2- tetrahydropyranyl) ether; 4#-[3-R-3-oxo-trans- 1 - propenyl] - 5α - (4 - phenylbenzoyloxy)- 3,3a#,4,6,6,6a# - hexahydro - 2H - cyclopenta- [b]furan-2-one, wherein R is 5-chloro-2,3-dihydrobenzo[b]fur - 2 - yl, 2 - benzo[1,3]dioxolyl and 1,2 - dihydro - 1 - benzocyclobutenyl; methyl 7 - [2# - dimethoxymethyl - 3α - hydroxy- 5α - (4 - phenylbenzoyloxy)cyclopent - 1α - yl]- 2 - methyl - 5 - cis - heptenoate and its tetrahydropyranyl ether; methyl 7 - [2# formyl, 3α hydroxy , 5α (4 - phenyl - benzoyloxy)- cyclopent - 1α - yl] - 2 - methyl - 5 - cis - heptenoate; methyl 15-(5-chloroindan-2-yl)-11α,15- dihydroxy - 2 - methyl - 9α - (4 - phenylbenzoyloxy) - 16,17,18,19,20 - pentanor - 5 - cis, 13- trans - prostadienoate; and methyl 15-(5- chloro - 2,3 - dihydro - benzo[b]fur - 2 - yl)- 11α,15 - dihydroxy - 2 - methyl - 9α - (4 - phenylbenzoyloxy) - 16,17,18,19,20 - pentanor - 5- cis, 13 - trans - prostadienoate. Phosphonates of the formula are prepared by reacting dimethyl methylphosphonate with esters of the formula R<SP>9</SP>ZCOOR<SP>10</SP>, where R<SP>10</SP> is methyl or ethyl and Z has the above significance, in the presence of butyl lithium. Pharmaceutical compositions, in a form suitable for oral, rectal, vaginal or parenteral administration or for inhalation, contain the above prostaglandins or salts thereof together with pharmaceutically acceptable carriers or diluents.