CA1040195A - Cyclopentane derivatives - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

The disclosure relates to prostaglandin analogues of the 2-series in which the 5,6 double bond is in the trans configuration, for example 16-(3-chlorophenoxy)-9.alpha.,11.alpha., 15-trihydroxy-17,18,19,20-tetranor-5-trans,13-trans-prostadienoic acid, to processes for their manufacture, to pharmaceutical and veterinary compositions containing them, and to methods of treatment.

Description

3~

This invention relates to cyclopentane derivatives, and in particular it relates to 5-trans-prostenoic acld derivatives which possess luteolytic activity. The new compounds are therefore advantageous when used as contraceptives, for the induction of labour or termination of preænancy, or f`or control of the oestrous cycle~ and are also useful as hypotensives or ~or the relief of bronochospasm, and as inhibitors of blood platelet aggre~ation or of gastric secretion. The new compounds are also useful for addition to semen intended for artificial insemination of domestic animals, the success rate of insemination being thereby increased, especially in pigs and cattle.
According to the invention there is provided a cyclopentane derivative of the formula:-R2~ R3 ~ (CH2)3.R
A.CH(OH).YR4 OH

wherein R is a hydroxymethyl or carboxy radical, or analkoxy~carbonyl radical of up to 11 carbon atoms either R is a hydroxy radical or an alkanoyloxy radical of 1 to 4 carbon atoms and R3 is a hydrogen atom, or R2 and R3 together form an oxo radical; A is an ethylene or trans-vinylene radical;
Y is a direct bond, or an alkylidene or alkylideneoxy radical " .
~`

.
.
.
,, .~ . : . , of l to 5 carbon atoms in ~he latter o~ which the alkylidene part is bonded to the carbon atom o~ the -CH(OH)- group and the oxygen atom is bonded to R ; and R is a phenyl or naph~hyl ;radical which is unsubstituted or is substituted by halogen atoms, nitro, hydroxy or phenyl radicals, alkyl, alkenyl, halogenoalkyl, alkoxy, alkenyloxy or acylamino radicals each of up to 4 carbon atoms, or dialkylamino radicals wherein -éach aikyl is of l to 3 carbon atoms; which compound contains O or 1 alkyl radical of l to 4 carbon atoms on carbon atom 2,3 or 4; and for those compounds wherein R is a carboxy radical, the pharmaceutically or veterinarily acceptable salts thereof.
A suitable value for R when it is an alkoxycarbonyl ~;radical is, for example, a methoxycarbonyl, ethoxycarbonyl, n-butoxycarbonyl or n-decyloxycarbonyl radical, particularly such an alkoxycarbonyl radical of up to 5 carbon atoms.
~;A suitable value for R2 when it is an alkanoyloxy radical of l to 4 carbon atoms is, for example, an acetoxy or propionyloxy radical.
A suitable value for Y when it i~ an alkylidene radical, or for the alkylidene part of Y when it is an alkylideneoxy radical-is, for example, a methylene, ethylidene, isopropylidene, propylidene, l-methylpropylidene or l-ethylpropylidene radical, more particularly such a radical of l to 3 carbon atoms ~nd es-pecially a methylene or isopropylidene radical.

25Suitable halogen atom substituents in R are, ~ 3 -'` ' .,., ~ .

for example, chlorine, bromine or fluorine atoms. Suitable alkyl~ alkoxy, alkenyl, alkenyloxy or acylamino substituents ofUP to 4 carbon atoms in R are~ for example methyl, t-butyl, allyl, methoxy, allyloxy or acetamido radicals. Suitable halo~enoalkyl substituents of 1 to 4 carbon atoms in R4 are ~or example chloroalkyl or ~luoroalkyl radicals, ~o~ example trifluoromethyl radicals. Suitable dialkylamino radicals ~herein each alkyl is of 1 to 3 carbon atoms, which may be substituents in R are, for example, dialkylamino radicals ; 10 wherein the two alkyl radicals are the same, for example the dimethylamino radical.
Thusg suitable substituted aryl radicals are for example, chlorophenyl, chloronaphthyl, bromophenyl, fluorophenyl, tolyl, xylyl, methylnaphthyl, t-butylphenyl, methylchlorophenyl, trifluoromethylphenyl, hydroxyphenyl, methoxyphenyl, methoxynaphthyl, biphenylyl, dimethylaminophenyl and tetrahy~ronaphthyl radicals.
Preferred aryl radicals contain not more than two substituents as defined above. Particular values for R4 are, therefore, the phenyl, l-naphthyl, 2-naphthyl, 2-, 3-and 4-ohlorophenyl, 4-b~omophenyl, 2-, 3- and 4-fluorophenyl, ; 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and 3,5-dichlorophenyl, 2-, 3- and 4-tolyl, 2,3-, 3,4- and 3,5-xylyl, 4-t-butylphenyl, 3-allylphenyl, 3-trifluoromethylphenyl, 4-hydroxyphenyl, ~-, 3- and 4-methoxyphenyl, 4-biphenylyl, 3-dimethylaminophenyl, ; .
- 1~ _ .

.. .
.

. - . ., ... . , :
: .: :: - . .

, ~
.
.

~41~ 95

2-chloro-4-methylphenyl, 1-chloro-2-naphthyl, 4-chloro-2-naphthyl~ 6-methyl-2-naphthyl, 6-methoxy-2-naphthyl and 5,6,7,8-tetrahydro-2-naphthyl radicals.
E~:pecially preferred aryl radicals are phenyl,

3- and 4-chlorophenyl and 3- and 4-trifluoromethylphenyl radicals. A suitable value for the alkyl radical of up to

4 carbon atoms which may be present as a substituent on carbon atom 2, 3 or 4 is, for example the methyl radical, and it is preferably on carbon atom 2.
-~ 10 ~xampl~ of pharmaceutically and veterinarily acceptable salts are the ammonium, alkyl-ammonium containing 1 to 4 alkyl radicals each of 1 to 6 carbon atoms, alkanol-~, ammonium containing 1 to 3 2-hydroxyethyl radicalsD and alkali metal salts for example the triethylammonium, ethanolammonium, diethanolammonium, sodium and potassium salts.
It will be observed that the compounds of the formula I contain at least four asymmetric carbon atoms namely carbon atoms 8, 11, 12 and 15, the relative configurations at three of which, 8, 11 and 12 are specified ~0 in formula I, and that carbon atoms 2, ~, 4, 9 and 16 may also - be asymmetrically substituted, so that it is clear that such compounds can exist in at least two optically active forms.
; It is to be understood that the useful properties of the racemate may be present to differing extents in the optical , ~ .
isomers, and that this invention relates to the racemic form of the compounds of formula I and any optically active form , ,.:

5 -,. ' , .

.

which shows the above use~ul properties, it being a ma~er of common general knowledge how the optically active forms may be obtained, and to determine ~heir respective biological properties.
It is also to be understood that the above definition encompasses both C-15 epimers and that in all chemical formulae shown hereafter in this specifica-tion, the same fixed sterochemistry at C-8, 9, 11 and 12 as that shown in formula I is i~plied.
A particular group of cyclopentane derivatives of the invention comprises compounds of the formula I wherein Rl is a carboxy or methoxycarbonyl radical, especially a carboxy radical, R is a hydroxy radical and R3 is a hydrogen atom or R2 and R3 together form an oxo radical, A
is a trans-vinylene radical, Y is a direct bond or a methylene, isopropylidene, methyleneoxy or isopropylideneoxy radical and R4 is a phenyl, 3- or 4- chlorophenyl or 3- or 4-trifluoromethylphenyl radical, and for those compounds wherein Rl is a carboxy radical, the pharmaceutically or veterinarily acceptable salts thereof as de~ined above.
A preferred group of compounds of the invention, because of their high luteolytic ac~ivity, comprises cyclopentane derivatives of the formula I wherein Y is a methylene-oxy radical and R4 is a phenyl or naphthyl radical optionally substituted with one chloro, fluoro or trifluorGmethyl radical, : - :
~ "' ~ ' '. .'. ,.
' ' . : .

9~ .

and particularlY those cyclopentane derivatives wherein R is a carboxy, methoxycarbonyl or ethoxycarbonyl radical, R2 is a hydroxy radical, R3 is a hydrogen atom3 A is a trans~vinylene radical, Y is a methyleneoxy radical and R4 is a 3- or 4-chlorophenyl or 3- or 4-trifluoromethylPhenyl radical.
A pre~erred group of cyclopentane derivatives of ': 'the invention because of their ability to inhibit gastric secretion comprises compounds of the formula I wherein Y is - 10 an isopropylideneoxy radical and R4 is a chlorophenyl or trifluoromethylphenyl radical, and especially those compounds wherein R i~ a carboxy, methoxycarbonyl or . ethoxycarbonyl radical, particularly carboxy, R2 is a hydroxy radical and R3 is a hydrogen atom or, preferably, R2 and R3 together ~orm an oxo radical, A is a trans-vinylene radical~
Y is an isopropylideneoxy radical and R4 is a chlorophenyl radical, especially a ll-chlorophenyl radical.
Particular pre~erred cyclopentane derivatives o~
the formula I are 16-(3-chlorophenoxy)-9a,11a,15-trihydroxy-17,18,19,20-tetranor-5-trans,13-'t'rans-prostadienoic acid, 9a,11a,15-trihydroxy-16-(3-tri~luoromethylphenoxy)-17~18~19,20-:~ tetranor-5-trans,13-trans-prostadienoic acid, 16-(4-chloro-phenoxy)-lla,15-dihydroxy-16-methyl-9-oxo-18,19,20-trinor-5-~: trans,l3'-trans-prostadienoic acid, 9a,11a,15-trihydroxy-16-:
~ 25 phenyl-17,18,19,20-tetranor-5-t'rans,13-trans-prostadienoic ,.:.
acid, lla,15-dihydroxy-9-oxo-16-phenyl-17,18,19,20-tetranor-5-~ 7 ~

trans,l3-trans-proslQ~lenoic acid and lla,15-trihydroxy-9~oxo-15-(4-trifluoromethylphenyl)~16~17~18~19~20-pentanor-5-tranS~
13-trans-prostadienoic acid.
The:.new cyclopentane derivatives of the invention may be manufactured by methods known in themselves for the manufacture of chemically analogous compounds. Thus, the following processes are provided as further features o~
the invention:-(a) the separation o~ a mixture of the 5-trans-cyclo-pentane derivative of the formula I and the corresponding 5-c -isomer;
(b) for those compounds wherein R2 is a hydroxy radical and R3 is a hydrogen atom, the reduction of an enone of the formula:- R6~

~ (CH2)3-R5 II
Co YR4 wherein R4 has the meaning de~ined above, R5 is an alkoxycarbonyl :` radical-of uP to 11 carbon atoms, and R6 and R7 are each a hydroxy radical or a protected hydroxy radical, whereafter when R6 and R7 are protected hydroxy radicals, the protecting groups are removed, and whereafter when a compound of the formula wherein R is a carboxy radical is required, the product thus obtained is hydrolysed with a base,or whereafter .

-~, .: ' , when a compound of the formula I wherein Rl is a hydroxymethyl radical is required, the product so obtained is reduced, for example with a complex metal hydride such as lithium aluminium hydride;
: . 5 (c) for those compounds wherein R is a hydroxy radical and R3 is a hydrogen atom, the thermolysis of a phosphonium betaine of the formula:- P(R8)2R9 ~' R10o ~ ~(CH2)3Rl ~ 1 0 III
; ~ \ A.CH(OR10)-YR

wherein Rl, R4, A and Y have the meanings stated above R3 is a hydrogen atom, R8 is an aryl radical, for example a phenyl radical, R9 is an alkyl radical of 1 to 6 carbon atoms, for example a methyl or ethyl radical, and R is a tetrahydro-pyran-2-yl radical whereafter the protecting tetrahydropyranyl radicals R10 are hydrolysed.
In process (a) , a suitable method for the separation of the 5-trans compound of the invention from a mixture of the 5-cis and 5-trans compounds is by chromatography, for example on silica gel impregnated with silver nitrate, but other conventional methods of separating cis-trans mixture may also be used, for example fractional crystallisation.
The mixture o~ cls and trans isomers frm which _ 9 _ .

--~..

the trans isomer may be separated in ~he above process (a) may be obtained for example by reacting a lactol of the formula:- OH
` o~
IV

A.CH(OR )YR
~ Rl lo wherein A, Y and R4 have the meanings stated above and R
and R12 are each, for example, a tetrahydropyran-2-yl or alkanoyl radical, with the ylide generated from a (4-carboxybutyl)triphenylphosphonium salt, for example the bromide, by butyl-lithium in a solvent, for example sulpholane, followed by hydrolysis of the protecting groups R 1 and R12. While this reaction gives predominantly the c'is-compound when the ylide is generated using a sodium : base, the use of butyl-iithium in sulpholane gives a mixture of cls and tr'ans isomers containing up to about 40% f the''t'rans isomer. The protecting groups Rll and R12 are then removed, by treatment with an acid, for example acetic acid, orwith a base, for example potassium carbonate in methanol.
Alternatively, the mixture o.f cis and trans isomers used as starting material in the process (a) may be obtained by photolysis of the more readily available cis isomer, for example by the irradiation of an oxygen-free benzene/methanol ` .

.

.. . .
, ~ `

solution of the cis isomer, containing 2 equivalents of diphenyl sulphide, with light of waveleng~h 350 nm. ~or 24 hours.
In process (b) o~ the invention, the reduction may be carried out using, for example, zinc borohydride, aluminium tri-isoprop~xide or di-isobornyloxy aluminium isopropoxide. ~ suitable value ~or R6 or R7 ~hen it is a protected hydroxy radical is, ~or example, an acyloxy radical, for example the acetoxy or 4-phenylbenzoyloxy radical. Preferred enone starting materials o~ the ~ormula II are those wherein R6 and R7 are both hydroxy radicals or both 4-phenylbenzoyloxy radicals, or wherein R is a 4-phenylbenzoyloxy radical and R7 is a hydroxy radical. The prot~cti~g group may be removed from such a protected hydroxy radical, for example, by hydrolysis with a base.
It will be understood, o~ course, that the hydrolysis conditions may be selected so as to hydrolyse also the ester grouP R5, or so as to leave this group unchanged.
rrhe starting material of the formula II used in thç process o~ the invention may be obtained, ~or example, - by treating the known iodo-lactone V with tributyl tin hydride to give the deiodinated lactone VI. The hydroxy group is protected as the tetrahydropyran-2-yl ether VII, the lactone is reduced to the lactol VIII, using di-isobutyl aluminium hydride, and the lactol is reacted with (4-carboxybutyl)-.

.

:.; . - . : , , ~
.. ..
,:

~L~4~95 triphenylphosphonium bromide to give the acid IX. The acid IX
is esteri~ied, ~or example with diazomethane, to give the ester X which is epoxidised with m-chloroperbenzoic acid, with . concomitant removal of the tetrahydropyranyl group to ~ive the epoxide diol XI. The two hydroxy radicals are reprotected as tetrahydropyranyl ethers XII, and reaction with lithium diphenylphosphidegives a dlphenylphosphine derivative XIII of uncertain structure. Reaction of XIII
with methyl iodide gives a phosphonium betaine XlV, which readhy undergoes thermal elimination to give the trans olefin XV. The two tetrahydropyranyl groups are removed with acid to give the diol XVI (R6 = R7 = hydroxy), treatment with stronger acid hydrolyses the acetal group to give the aldehyde XVII (R = R7 = hydroxy), and reaction of 1~ the aldehyde XVII with a phosphonate derivative of the formula (CH30)2Po.CH2Co.YR4 in the presence of a strong base gives the starting material II, (R5 = methoxycarbonyl, R6 =
R = hydroxy).
Alternatively, the diol XVI (R6 - R7 - hydroxy) may be converted to a bis-ester, for example XVI (R6 = R7 =
4-phenylbenzoyloxy) which is hydrolysed to the aldehyde XVII
(R6 = R7 = 4-phenylbenzoyloxy), which.in turn is reacted with 'vhe phosphonate derivative to give a starting material of the formula II (R = R7 - 4-phenylbenzoyloxy).
Alternatively, the tetrahydropyranyl ether XII

: " : , , , :~

f~

CH ( O CH~; ) 2 CH (OCH3 )2 H O
HO
~TI
V:. ~OH
O
~ .

~H ( O CH3 ) 2 CH (OCH
3 2 THP. O
THP, O
.. .
: ~ VII . VIII

HO OH
f CH2)3COOCH3 H( H3)2 CH(OCH3)2 THP, O OTHP
IX X;

THP = 'Cetrahydropyran-2-yl `, :

..

~ ~ .

. : , , ~4C~95 ~OH OTHP
~(cH2)3cOOCH3 ~ ~(CH2)3COOcH3 CH (OCH3 ) ? , H ( OCH3 ) 2 OH OTHP

XI XII:

OTHE' - _ /~r ~'(CH?)~COo~H3 XIV ~ ' ~ ~ J

CH ( O CH3 ) 2 OTHP
XV
R6 . R6 p~ (CH2 l~coo~ COOCIH

~ CH (OcH3 ) 2 HO
R~ R7 XVI XVII.

., . ~ : . . , : ..
:: . : : , :.. :: :

: : :: .: `: :

~ , is converted to a trithiocarbonate of the formula:-OTHP S ~
~ , ~ (CH2)3~coocH3 < I XX

CH ( O CH 3 ) 2 OTHP

for example with potassium methyl xanthate, and the trithiocarbonate XX is desulphurised, for example with trimethyl phosphite, to give the trans olefin XV
Alternatively, a compound XVI (R6 = R7 = 4-phenylbenzoyloxy)may be obtained from the cis-compound XIX, by oxidative cleavage thereof with~ for example os~ium tetroxide andsodium periodate to give an aldehyde XX which is reacted with a phosphonate of the formula (CH30)2PO.CH2CO(CH2)2COOH in the presence of a strong base to produce an enone XXI. The enone is reduced to the olefin XXII by forming a thioketal thereof which is desulphurised~ for example with Raney nickel. The olefin XXII is then esterified ~o give the required compound XVII
(R6. = R7 - 4-phenylbenzoyloxy).
In process (c) of the invention, the phosphonium betaine III used as starting material may be obtained from the known bis-(tetrahydropyranyl ether) of the formula:-HO

,~, ~/( CH2 ) 3. COOH
< XXIII
~ \ A.CH(oTHP).YR4 THPO

.. . . .

- .

h~4CD195 P~O PBO

~ ~HO

PBO / CH(OCH3)2 CH(OCH3)2 PBO~

XIX XX

PBO~
~ C 2 H
~
/ \ CHtoCH
PBO
XXI

P~
' ~ / 2 CH(OCH3)?
PBO/
XXII

XVI (R5 = methoxycarbonyl, R6 = R7 = 4-phenylbenzoyloxy) PB _ 4-phenylbenzoyl.

.: : ~ .

: :: : :: , lg,5 by selectively epoxidising the cis double bond with m-chloroperbenzoic acid, esterifying the carboxy radical and protecting the 9-hydroxyl radical also as a tetrahydropyranyl ether, ~ollowed by reaction o~ the protected epoxide with a lithium diarylphosphide, LiP(R8)2 and quarternisation with an alkyl halide, R9.halogen. The protecting tetrahydropyranyl radicals R are conveniently removed by acid hydrolysis, ~or example l~rith acetic acid.
It is, of course, to be understood that an optically active compound of the invention may be obtained either by resolving the corresponding racemate, or by carrying out the above-described process starting from an optically active starting material.
As stated above, the cyclopentane derivatives of the invention possess luteolytic activity. For example, 16-(3-chlorophenoxy)-9~,lla,15a-trihydroxy-5-trans, 13-trans-prostadienoic acid is about 50 times more active than prostaglandin F2a in a luteolytic test in the hamster, on sub-cutaneous dosing.
The compounds of the invention are therefore usefulj for example, for the induction of labour in childbirth, and for this purpose are used in the same say as it is known to use the naturally-occurring prostaglandin El and E2, that is to say, by administering a sterile, substantially a~ueous soluticn containing from 0 01 to lO~g.~ml., preferably 0.01 to l~g./ml. of active compound, by intravenous, extraovular or intra-amniotic administration until labour commences. Also, for this ~ 17 -' ~ :
;, ~L~41~3~9~
purpose, the compounds of the invention may be used in combination~ or concurrently, with a uterine stimulant, ~or example oxytocin, in the same way that it is known to use prosta~landin F2~ in combination, or concurrently, with o~tocin for the induction of labour.
When a compound of the invention is to be used for the control of the oestrus cycle in animals, it may be used in combination, or concurrently, with a gonadotrophin, for example PMSG (pregnant mare serum gonadotrophin) or HCG (human chorionic gonadotrophin) to hasten the onset of the next cycle.
Thus, according to a further feature of the invention there is provided a pharmaceutical or veterinary composition comprising a cyclopentane derivative of the invention, together with a pharmaceutically or veterinarily acceptable diluent or carrier.
The compositions may be in a ~orm suitable for oral administration, for example tablets or capsules, in a form suitable for inhalation, for example an aerosol or a solution suitable for spraying, in a form suitable for parenteral administration, for example sterile injectable aqueous or oily solutions or suspensions, or in a form of a suppository, suitable for anal or vaginal use.
The compo$itions of the invention may be prepared by conventional means, and may incorporate conventional excipients.

..... ~ - ~ .

: . .
.
, . . . . .

~6~4~5 The invention is illustrated but not limited by the following Examples:-Example 1 A mixture of 16-(3-chlorophenoxy)-9a,11a,154,-trihydroxy-17,18,19,20-tetranor-5-cis, 13-trans-prostadienoic acid and the corresponding 5-trans, 13-trans compound was thin-layer chromatographed on silica gel C~ 254 plates, supplied by Merck of Darmstadt, which had been impregnated with silver nitrate before use. The plates were developed with 10% acetic acid in ethyl acetate, and the separated compounds were located by removin~ a strip frorn the edge of one plate, spraying the strip with ceric sulphate solution, and developing the strip by heating. The trans isomer had RF = -4, and the cis isomer RF = -3- The 1~ required strips corresponding to the trans isomer were removed from the plates, and the required 16-(3-chlorophenoxy)-9a,11a,15a-trihydroxy-17,18,19,20-tetranor-5-trans, 13-trans-prostadienoic acid was eluted therefrom. The n.m.r. spectrum in deuteriochloroform showed the :~ollowing characteristic peaks (~g values):-2.28, 2H, triplet, -C_2-COOH
3.98, 3H, multiplet ~ ! _ 4.16, lH, multiplet ~ ~CH.0-4.46, lH, multiplet J
5.50, 2H, multiplet, 5,6-trans olefinic protons 5.70, 2H, multiplet, 13,14-trans olefinic protons

6.8-7.4, 4H, multiplet, aromatic protons.

- 19 - ~' ,.
, ~ . , .

~4~5 The mass spectrum of the tetra(trimethylsilyl) derivative showed (M-CH3) = 697.3000 (calculated for The mixture of 5 -c-is, l~-trans and 5-trans, 13-trans 5 compounds used as starting material may be obtained as follows:-(4-Carboxybutyl)-triphenylphosphonium bromide (156mg., 0.35mmole) was dried at 60C. in vacuo for 1 hour, and was then dissolved in sulpholane (2.7ml.) in an inert atmosphere. n-Butyl--lithium (290~1. of a 2.29M solution in hexane) was added dropwise, and the mixture was stirred at 35 C. for 45 minutes. 4~- r4-(3-Ohlorophenoxy)-3~-ttetrahydropyran-2-yloxy)-but-1-trans-enyl]-2,3,3a~,6a~-tetrah~rdro-2-hydroxy-5~-(tetrahydropyran-2-yloxy)cyclopenteno-[b]furan (67mg., 0.13 mmole) was a~eotroped with toluene and dried _ vacuo. I~; was then dissolved in a mi xture of sulpholane (0.8ml.) and toluene (0.27ml.) and added to the phosphorane solution. After 2 hours, the mixture was diluted with water (lOml.) and extracted with ether (4 x lOml.) 20 and the ether~;~l extracts were dissolved. The aqueous solution was adJusted to pH 3.0 with 2N oxalic acid, and extracted with 1:1 ether/pent~ne (5 x lOml.). The combined extracts were dried and the solvent evaporated under reduced pressure.
The residue was purif`ied by preparative thin layer 25 chromatography on silica gel GF 254 plates with 5,~ methanol , 1~4~95 in methylene chloride, to give a mixture of 16-(3-chlorophenoxy)-9a-hydroxy-lla,15~-bis-(tetrah~ropyran-2-yloxy)-17,18,19,20-tetranor-5- iS, 13-trans-prostadienoic a¢id and the corresponding 5-trans, 13-trans compound, RF = '3' The mixture of bis-(tetrahydropyranyl ethers) (63mg.) was dissolved in tetrahydrofuran (0.46ml.), a 2:1 mixture of acetic acid and water (3.7ml.) was added, and the mixture was heated at 50 C. for 2 hours. The residue was dried by azetroping with toluene, to give the required mixture of 5-cis, 13-trans and 5-trans, 13-trans compounds.
Example 2 The process described in the first part~' of Example 1 was repeated, using the corresponding 16-(3-trifluoromethyl-phenoxy) starting material in place of the 16-(3-chlorophenoxy), to give 9a~11a,15-trihydroxy-16-(3-trifluoromethylphenoxy)- ' 17,18,19,20-tetranor-5-trans,13-trans-prostadienoic acid, RF, - 0.4 (10% acetic acid in ethyl acetate on silver nitrate impregnated silica gel). The n.m.r. spectrum in hexadeuterio-acetone showed the following characteristic features ( ~ values):-2.28, triplet, 2H, -C_2.C02H
3.9-4.6, multiplet, 5H, \CH-0-5.45, multiplet, 2H, 5,6-trans olefinic protons 5.65, multiplet, 2H, 13,1'4'-'trans olefinic protons

7.1-7.8, multiplet, 3H, aromatic protons.

'.

.

The 16-(3-trifluoromethylphenoxy) starting material used in the above process was prepared by the process described in the second part of~ Example 1, using the corresponding 3-(trifluoromethylphenoxy)butenyl cyclopenteno-[b]furan derivative in place of the 3-chlorophenoxy compound.
Example 3 The process described in the first part of Example 1 was repeated, using the corresponding 16-phenyl starting materlal in place of the 16-(3-chlorophenoxy), to give 9a~11a~15a-trihydroxy-16-phenyl-17~18~19,20-tetranor-5-tranS~
13-trans-prostadienoic acid, RF = - 35 (10% acetic acid in ethyl acetate on silver nitrate impre~nated silica gel). The n.m.r. spectrum in hexadeuterioacetone showed the ~ollowing characteristic features ( ~ values):-2.28, triplet, 2H, -CH2COOH
2.8, multiplet, 2H, -CH2Ph 3.5-4.5, multiplet, 7H, ~C_-O and -OH
5.5, multiplet, 4H, olef`inic protons 7.2, singlet, 5H, aromatic protons.
The mass spectrum o~ the tetra(trimethylsilyl)derivative showed M - 647.3360 (calculated for C33H5905Si4 = 647.3443).
The mixture of 5-cis, 13-trans and 5-trans, 13-trans compounds used as starting material may be obtained as described in the latter Part of Example 1 using the mixed side-chain C-3 epimers of 2,3,3a~,6a~-tetrahydro-2-hydroxy-4~-[4-phenyl-3-(tetrahydropyran`-~yloxy)-aut-1 t~ans enyl]-5a-~tetrahydropyran-2-yloxy)cyclopenteno[b]furan,to give a mixture of` the mixed C-15 epimers of` 9a-hydroxy-16-phenyl-lla,15-bis-: ' ~ , .
, ~ ~4~9S
(tetrahydropyran-2-yloxy)-17,18,19,20-tetranor 5-cis,13-trans-prostadienoic acid and the mixed C-15 epimers of the corresponding 5-trans, 13-trans compound.
The mixture of bis-(tetrahydropyran-2-yl ethers) (200mg.) was dissolved in tetrahdyrofuran (4.2ml.), a 2:1 mixture of acetic acid and water (11.5ml.) was added, and the mixture was heated at 50C. for 1 hour. The residue was dried by azeotropic distillation with toluene, to give a ~ixture of the mixed C-15 epimers of 9~,11a,15-trihydroxy-16-phenyl-17,18,19,20-tetranor-5-cis,~13-k'rans-prostadienoic acid and the mixed C-15 epimers of the corresponding 5-trans, 13-trans compound.
This mixture of two pairs of epirrers was separated by thin layer chromatography on silic gel GF 254 plates, supplied by Merck of Darmstadt, developed with 3% acetic acid in ethyl acetate, to give a mixture of the more polar C-15 epimers of the 5-cis,13-trans and 5-trans,13-trans compounds, RF = 0.25~,the required starting material, and a mixture of the less polar C-15 epimers of the 5-cis,13-trans and 5-t'rans,13-trans e~mpounds, RF = 0 35 Example 4 The process described in t'he first part of Example 1 was repeated, using the corresponding 9-oxo-16-phenyl starting material in place of the 16-(3-chlorophenoxy), to give lla,15a~ihydroxy-9-oxo-16-phenyl-17,18,19,20-tetranor-5-trans, 13-tr'ans-prostadienoic acid, RF = 0 35 (10% acetic acid in ethyl .
"

, acetate on silver nitrate impregnated silica gel) The n.m.r. spectrum in hexadeuterioacetone shc~ed ~he ~ollowing characteristic features ( ~ values):-2.85, multiplet, 2H 7 -CH2Ph 3.5-4.5, multiplet, 5H, ~CH-O- and -OH
5.4, multiplet, 2H, 5,6-trans olefinic protons 5.6, multiplet, 2H, 13,14-trans olefinic protons 7.2, singlet, 5H, aromatic protons.
The mass spectrum of the tris(trimethylsilyl)-9-methoxime derivative showed M = 617.3358 (calculated for 32 55 5 3 7-33 ).
The mixture of 5-cis, 13-trans and 5-trans, 13-trans compounds used as starting material may be obtained as follows:-The mixture of the mixed C-15 epimers of 9a-hydroxy-16-phenyl-lla,15-bis(tetrahydropyran-2-yloxy)-17,18,19,20-tetranor-5-cis,13-trans prostadienoic acid and the mixed C-15 epimers of the corresponding 5'-'trans, 13-'t'rans compound (737mg.), prepared as described in the second part of Example 3, was dissolved in pure acetone (16ml.), and cooled to 0C., Jones' reagent (chromic acid in acetone, 0.45ml.) was added and the solution was stirred for 15minutes at 0C.
Isopropanol (3 drops)was added, ~llowed by ethyl acetate.
The solution was washed with saturated brine and dried, and the solvent was evaporated to give a mixture of the mixed C-15 epimers of 9-oxo-16-phenyl-lla,15-bis-(tetrahydropyran-2-yloxy~
17,18,19,20-tetranor-5-c`is,13-trans prostadienoic acid and the mixed C-15 epimers of the corresponding 5-trans, 13-trans ~, , .

, :. , , : ' .

compound, R~ = 0.3 (5% methanol in methylene di-chloride).
A solution of these mixed epimers (761mg.) in a mixture of acetic acid (29ml.), water (15ml.) and tetrahydrofuran (16ml ) was stirred at 50C. for 1 hour, and the solvents were evaporated to leave a residue consisting of a mixture of the mixed C-15 epimers of 11~,15~-dihydroxy-9-oxo-16-phenyl-17,18, 19,20-tetranor-5-cis, 13-trans-prostadienoic acid and the mixed C-15 epimers of the corresponding 5-trans, 13-trans compound.
The C-15 epimers we~ separated by the process described in the last paragraph of Example 3 to give the mixture of more polar ~-15iepi~s~fthe 5-cis, 13-trans and 5-trans, 13-trans compounds, the required starting material.
ExampIe 5 1~ A mixture of methyl 15-(4-trifluoromethylphenyl) 9-oxo-11~,15a-dihydroxy-16,17,18,19,20-pentanor-5-cis, 13-trans-prostadienoate and the corresponding 5-trans, 13-trans compound was thin-layer chromatographed on silica gel GF 254 plates, supplied by Merck of Darmstadt, which had been impregnated with silver nitrate before use. The plates were developed by eluting twice with 33% acetone in methylene chloride, and the separated compounds were located by removing a strip from the edge of one plate, spraying the strip with ceric sulphate solution, and developing the strip by heating. The trans isomer had RF = 0.58, and the cis isomer, RF = 54 The strips corresponding to the trans isomer were removed from the plates, and methyl 11~,15~-dihydroxy-9-oxo-15-(4-trlfluoromethylphenyl)-16,17,18,19,20-pentanor-5-trans, 13-,:
.
. . .

trans-prostadienoate was eluted thereform. The n.m.r.
, _.
spectrum in hexadeuterioacetone showed the following characteristic peaks ( ~ values).-3.6, singlet, 3H, -COOCH3 4.o-4.8, multipletg 3H, C~ proton and -OH
5.3-5.5, multiplet, 3H, 5,6-trans olefinic protons plus C-15~ prot on 5.8-6.o, multiplet, 2H, 13,14-trans-olefinic protons 7.65, singlet, 4H, aromaticprotons.
The mass spectrum of the bis(trimethylsilyl)-9-methoxime derivative showed M = 613.2889, (calculated for C30H46F3N05Si2 ~13.2867).
The mixture of methyl 15-(4-trifluoromethylphenyl)-S-oxo-lla,15~-dihydroxy-16,17,18,19,20-pentanor-5-cis,13-trans-prostadienoate and the corresponding 5-trans, 13-trans compound used as starting material was prepared as follows:-To a solution of 5a-hydroxy-2-oxo-4~- [3-(ll-trifl~oro~ethylphenyl)-2,3,3a~,6a~-tetrahydro-3-hydroxy-1-trans-propenyl]-cyclopenteno[b]furan (300mg.) in toluene (lOml.) under an atmosphere of nitrogen at O C., were added successively redistilled 2-methoxypropene (0.9ml.) and a solution of anhydrous toluene-p-sulphonic acid in tetrahydrofuran (0.04ml. of a 1% solution). The solution was warmed to room temperature and after 25 minutes pyridine (0.002ml.) was added. The solution was cooled to -78C. and di-isobutyl aluminium hydride (0.9ml. of 1.95M solution in toluene) was added. After 10 minutes, the reaction was quenched by the ~4~:~95 dropwise addition of methanol (0.2ml.) and warmed to room temperature. The reaction mixture was added to ethyl acetate (25ml.)~ which was rapidly washed with a mixture of 1:1 saturated brine/water (2 x 5~1.) and was dried. The solvent was evaporated to give a mixture of epimeric lactols~
2,3,3a~,6a~-tetrahydro-2-hydroxy-5a-(1-methoxy-1-methylethoxy)-4~-[3-(1-methoxy-1-methylethoxy)-3-(4-trifluoromethylphenyl)-i-trans-propenyl]cyclopenteno[b]furan, RF = 4 (1:1 ethyl acetate/toluene).
(4-Carboxybutyl)-triphenylphosphoniu~ bromide (1.03g~,2.33mmole) was dried at 70C. 'in vac'uo for 1 hour, and was then dissolved in sulpholane (20ml.) in an inert atmosphere. n-~utyl-lithium (3.lml. of a 1.42M solution in hexane) was added dropwise, and the mixture was stirred -' at 35C. for 30 minutes. The above described epimeric lactols (503mg. 0.88rnmole) were azeotroped with toluene, dried in vacuo, dissolved in sulpholane (2ml.) and added to the phosphorane solution. After 1 hour the mixture was diluted with water (lOml.) and extracted with ether (3 x 20ml.), and the ether~ extracts were discarded. The aqueous solution was adjusted to pH 5.0 with a saturated aqueous ~ution of oxalic acid, and extracted with 1:1 ether/pentane (5 x 20~1.).
The combined extracts were dried and the solvent evaporated under reduced pressure, to give a mixture of the mixed C-15 epimers of 9~-hydroxy-11~,15-bis(l-methoxy-1-methylethoxy)-15-(4-trifluoromethylphenyl)-16,17,18,19,20-pentanor-5-cis,13-trans prostadienoic acid and the mixed C-15 epimers of the corresponding' 5-tran 13'-'trans compound RF = 0.29 (5% methanol in methylene . , .
:~ ' , ~:

chloride) together with some residual sulpholane.
A solution of the above mixture of prostadienoic acid derivatives (30~ ,) in methylene chloride (2ml.) was added to Collins reagent [chromium trioxide (480mg.) added to 5 pure dry methylene chloride (lOml.) and pyridine (0.774ml.) and stirred before use at room temperature for 15 minutes]
and stirred at room temperature for 10 minutes. Isopropanol (3 drops) was added,and the reaction mixture was filtered through "Celite" (I;rade mark~, evaporated to dryness and 10 further dried by azeotropic distillation with cyclohexane.
The residue was dissolved in ether and filtered throu~h "Celite", and the solvent was evaporated to give a mixture of the mixed C-15 epimers of 11~,15-bis(l-methoxy-1-methyl-ethoxy)-9~oxo-15-(4-trifluoromethylphenyl)-16,17,18,19,20-15 pentanor-5-cis,13-trans-prostadienoic acid and the mixed C-15 epimers of the corresponding 5-trans, 13-trans compound, RF = 44 tlO% methanol in methylene dichloride) to~ether with some residual sulpholane.
The above mixture was dis~olved ln 3. 3ml. of pH 3 20 citric acid buffer and 6.6ml. of acetone, and stirred at room temperature for 18 hours. The solvents were evaporated, and the residue was dried by azeotropic distillation with toluene and submitted to column chromatography on CC4 silica gel (Mallinckrodt Chemical Works) (35g.), eluting with a 25 gradient of increasing proportions of ethyl acetate in - 28 ~

' cyclohexane, to give the more polar C-15 epimers of the mixture of lla,15a-dihydroxy-9-oxo-15-(4-trifluoromethylphenyl)-16,17,18,19,20-pentanor-5-c'is,13-trans-prostadienoic acid and the corresponding 5-trans, 13-trans co~poun~ R = 0.27 (3% acetic acid in ethyl acetate).
To a solution of this mixture of the more polar C-15 epimers of 5-cis,13-trans and 5-'trans,13-trans compounds (26mg.) in ether (3ml.~ at 0C. was added an excess of diazomethane in ether. After 15 minutes~ the solvents were evaporated to give a mixture of methyl lla,15a-dihydroxy-9-oxo-15-(4-trifluoromethylphenyl)-16,17,18,19,20-pentanor-5-cis,13-trans-prostadienoate and the corresponding 5-trans, 13-trans compound, the required starting material.
Exa'mple'6 ' A solution of the mixed C-15 epimers of 16-(4-chlorophenyl)-16-methyl-9-oxo-lla,15-bis(tetrahydropyran-2-yloxy)-18,19,20-trinor-5-trans,13-trans-prostadienoic acid (78.4mg.) in a mixture of acetic acid (3.7ml.), water ~0.92ml.) and tetrahydrofuran (1.8ml.) was stirred at 50C. for 5~hours.
Tjhe solvents were evaporated under reduced pressure and the residue was dried by azeotropic distillation with toluene to give the mixed C-15 epimers of 16-(4-chlorophenyl)-lla,15-dihydroxy-16-methyl-9-oxb-18,19,20-trinor-5-trans,13-trans-prostadienoic acid. The C-15 epi~.ers were separated by thin-layer chromatography on silica gel GF 254 plates, supplied by Merck of Darmstadt, eluting twice with 1% acetic acid in ethyl acetate. The required strips corresponding to the more polar epimer were removed from the plates, and the single :, ~

' s epimer of 16-(4-chlorophenyl)~ ,15-dlhydroxy-16-methyl-9-oxo-18~19,20-trinor-5-trans,13-trans-prostadlenoic acid, RF =
0.4, was eluted there~rom. The n.m.r. spectrum in hexadeuterioacetor~ showed the following characteristic peaks 5 ( ~ values):-1.25, doublet, 6H, -CH(OH)-C(CH3)2-0-2.25, triplet, 3H, -CH2.COOH
4.15, multiplet~ 2H, C-ll~ proton 5.4, multiplet, 2H, 5,6-trans olefinic protons 5.85, multiplet, 2H, 13,14-trans olefinic protons 7.15, quartet, 4H, aromatic protons.
The mass spectrum for the 9-methoxirre-tris(trim.ethylsilyl)~vat~Te ~howed (M-CH3) - 680.3046 (calculated for C25H48M~:)5Si3- 680.3025 The mixed C-15 epimers used as the starting material in the above process may be prepared as follows:-(4-Carboxybutyl)triphenylphosphonium bromide (7.92g.) was dissolved in sulpholane (136ml.) under nitrogen, and n-butyl-lithium (23.4ml. o~ a 1.42M solution in hexane) was added with stirring. After 30 minutes at 30 C., a solution of 4~-dimethoxymethyl-2,3,3a~,6a~-tetrahydro-2-hydroxy-5a-(tetrahydropyran-2-yloxy)-cyclopenteno[b]furan (2.0g.) in a mixture of sulpholane (24m~) and toluene (8ml.) was added. After stirring for 1 hour, water (400ml.) was added, and the mixture was extracted with ether (5 x 400ml.).
The aqueous solution was acidified with oxalic acid to pH 5 and extracted with 50% ether in pentane (4 x 400ml.).
The organic phases were combined and dried, and the solvent was .

9s evaporated under reduced pressure. The residue was submitted to dry column chromatography on silica gel (300g.) eluting with ethyl acetate, to give a mixture of the 5-cis and 5-t`rans isomers of 7-[2~-dimethoxymethyl-3a-hydroxy-5~-(4-phenylbenzoyloxy)cyclopent-1~-yllhept-5-enoic acid, RF =
0 ~3 (5% methanol in methylene dichloride). The n.m.r.
spectrum in deuteriochl~for~ showed the following characteristic features ( ~ values):-3.4, singlet, 6H, -OCH3 5.5, multiplet, 2H, olefinic protons To a solution of the mixture o~ cis and trans isomers (2.47g.) in ether (25ml.) was added an excess of a solution o~ diazomethane in ether. After 20 minutes at room temperature, the excess of diazomethane was evaporated in a stream of argon, and the ether solution evaporated in vacuo, The residue was submitted to dry ~olumn chromatography on silica gel (240g.) eluting with 50% ethyl acetate in toluene, and the product so obtained was rechromatographed on a dry column of silica gel S'~50g.) impregnated with silver nitrate (54g.), eluting with 50% ethyl acetate in tolu~ne, to give methyl 7-[2~-dimethoxymethyl-5a-hydroxy-3~-(tetrahydro-pyran-2-yloxy)-cyclopent-1~-yl]hept-5-trans-enoate as a clear oil, RF = -7 (5% ethyl acetate in toluene on silver nitrate impregnated silica gel). The n.m.r. spectrum in deuteriochlor~orm showed the following characteristic features ( ~ values):-.

.,.

`

3.37, singlet, 6H, ~ C-(OCH3)2 3.63, singlet, 3H, -COOCH3 4.65, multiplet, lH, tetrahydropyranyl C-2 proton 5.49, multiplet, 2H, trans olefinic protons.
Methyl 7-[2~-dimethoxymethyl-5a-hydroxy-3~-(tetrahydropyran-2-yloxy)cyclopent-la-yl]hept-5-trans-enoate (379mg.) was dissolved in dry pyridine (4.4ml.) under argon, and treated with p-phenylbenzoyl chloride (411mg.) and the mixture was stirred for 17 hours. Water (150ml.) was then introduced and stirring was continued for 2 hours. The mixture was evaporated under reduced pressure and toluene was added to assist azeotropic removal of the pyridine. The residue was partitioned between toluene (30ml.) and saturated sodium bicarbonate solution (15ml.). The whole mixture was filtered through "Hyflo"
~5 (trade mark) and the organic phase was separated. The aqueous layer was extracted with toluene (15ml.), and the organic extracts were combined, washed with brine (lOml.), d~ied over sodium sulphate, and ~iltered and the solvent was evaporated to give methyl 7-[2~-dimethoxymethyl-5a-(4-phenylbenæoyloxy)-3a-(tetrahydropyran-2-yloxy)cyclopent-la-yl~-hept-5-trans-enoate as a clear oil, RF = 0 57 (25% pentane in ether). The n.m.r. spectrum in deuteriochloroform showed the following characteristic features ( ~ values):-3.41, multiplet, 6H, ~ C(OCH3)2 3.6, singlet, 3H, -COOCH3 .

.~

5~3-5.5, multiplet, 3H, trans olefinic and C-5 protons 7.1-7.7, multiplet, 7H, aromatic protons

8.08-8.21, multiplet, 2H, A solution of methyl 7-[2~-dimethoxymethyl-5a-(4-phenylbenzoyloxy)-3a-(tetrahydropyran-2-yloxy)cyclopent-1~-yl]hept-5-trans-enoate (550mg.) in dry methanol (12ml.) was stirred under argon at room temperature with toluene-p-sulphonic acid (1.6ml. of a 1% solution of anhydrous toluene-p-sulphonic acid in dry tetrahydrofuran) for 17 hours.
Pyridine (2 drops) and toluene (40ml.) were added, and the solvents were evaporated under reduced pressure. ~he residue was partitioned between ethyl acetate (50ml.) and water ~25ml.), the organic phase was separated, washed successively with saturated sodium bicarbonate (2 x 15ml.) and saturated brine (15ml.) and dried, and the solvent was evaporated to give methyl 7-[2~-dimethoxymethyl-3a-hydroxy-5a-(4-phenyl-benzoyloxy)cyclopent-la-yl]hept-5-trans-enoate as a clear oil, R~ = 0.47 (10% ethyl acetate in methylene dichloride).
me n.m.r. spectrum in deuteriochlo~?oform showed the following characteristic features ( ~ values):-3.43 ~
~ singlets, 6H, ~C(OC_3)2 3.61, singlet, 3H, -COOCH3 4.17-4.48, multiplet, 2H, -CH(OCH3)2 and C-3~ protons - 33 ~

. . .
.

: ' ' '' ~ : ' ; ~ , ' , ., :,, . .:. :, - , ~t~L95 5.3-5.5, multiplet, 3H~ olefinic and C-5~ protons 7.4-7.75, multiplet, 7H, aromatic protons 8.07-8.2, multiplet, 2H, ~
~COO--Methyl 7-[2~-dimethoxymethyl-3a-hydroxy-5a-(4-phenylbenzoyloxy)cyclopent-la-yl~hept-5-trans-enoate ~306mg.) was ~igorously stirred under argon for 10 minutes in a two-phase system consisting o~ 2% isopropanol in chloro~orm (12ml.) and concentrated hydrochloric acid (6ml.). The total reaction mixture was poured into an excess of saturated bicarbonate and the organic layer was separated. The~aqueous solution was extracted with ethyl acetate (3 x 50ml.) and the combined organic extracts were washed with brine (50ml.) and dried, and evaporated to give methyl`7Y~2~-~ermyl-3a-hydroxy-5~-(4 phenylbenzoyloxy)cyclopent-la-yl~hept-5-trans-enoate as a clear oil, RF ' 0.4 (50% ethyl acetate in 'oluene).
Dimethyl 2-oxo-3-methyl-3-(4-chlorophenoxy)-butylphosphonate (48~mg.) and methyl 7-[2~-formyl-3a~hydroxy-5a-(4-phenylbenzoyloxy)-cyclopent-1~-yl~hept-5-trans-enoate (269mg.) were suspended under argon in a mixture of toluene (9ml.). Aqueous lM sodium hydroxide solution (1.2ml.) was added and the two phase mixture was stirred vigorously for 16 hours. The reaction mixbure was shaken with ethyl acetate (20ml.) and saturated brine (20ml.), and the organic layer was separated. The aqueous layer was extracted with ethyl 2~ acetate (2 x 40ml.), the combined organic extracts were dried, and the solvent was evaporated. Dry column chromatography using silica gel (150g.) and 50% ethyl acetate ~ 34 -::.
.. . . .

, , 33L~

in t~lu~r~e ~s elu~nt ~aYe the enone, methyl 76- !4 -chloro-phenoxy)-lla-hydroxy-16-methyl-15-oxo-9a-(4 -phenylbenzoyloxy)-18,19,20-trinor-5-trans,13_trans-prostadienoate, RF = 0.66 (ether) as an oil.
The n.m.r. spectrum in deuteriochloroform showed the following characteristic features (~ values):-1.52, singlet, 6H, two methyls 3.61, singlet, 3H, -OCH3 5.2-5.5, multiplet, 3H, 5,6-trans olefinic and C-9~ protons 6.7-7.7, multiplet, 13H, aromatic and 13,14-trans olefinic protons 8.0-8.2, multiplet, 2H, _~

The enone (225 mg.) was stirred under argon at room temperature with a 0.36M solution of di-isobornyloxyaluminium isopropoxide in toluene (5.84 ml., 6 equivalents). After 16 hours, the mixture was partitioned between water and ethyl acetate and filtered through "Hyflo"*, washing the filter pad 20 with ethyl acetate. The organic layer was separated, washed with brine, dried over magnesium sulphate and filtered, and the solvent was evaporated to leave a crude product, which was purified by dry column chromatography over silica gel (120 g.) eluting with 50% ethyl acetate in toluene, to give a mixture of epimeric diols, methyl 16-(4-chlorophenyl)-lla, 15-dihydroxy-16-methyl-9a-(4 -phenylbenzoyloxy)-18,19,20-trinor-5-trans, 13-trans-prostadienoate, together with the corresponding lso-propyl esters.

*Trade Mark :

.-- ~

To a solution of the epimeric diols (1~2mg.) ln methylene dichloride (2ml.) under an atmosphere of nitrogen at 0C., were added successively redistilled 2,3-dihydropyran (175mg.) followed by a solution of toluene-_-sulphonic acid 5 (50ml.) of a 1% solution in tetrah~ rofuran). After 10 minutes, one drop of pyridine was added, and the solution was washed successively with saturated sodium bicarbonate solution and saturated brine, and was dried. Evaporation of ~he solvents gave a mixture of C-15 epimeric bis(tetrahydro-10 pyranyl ether), RF = 0.8 (25~ ethyl acetate in toluene).

The crude epimeric bis(tetrahydropyran-2-yl ethers) (170mg.) were stirred at room temperature under argon in a mixture of methanol (2ml.), water (2ml.), and 1,2-dimethoxyethane (1.5ml.) with potassium hydroxide (2.05ml. of a lM solution in 15 methanol, 10 equivalents) for 16 hours. Glacial acetic acid was added to adjust the pH. of the solution to 7 and the solvents were evaporated under reduced pressure. I'he residue was partitioned between water and ethyl acetate and extracted with ethyl acetate, (2x 30ml.). The combined organic phases 20 were washed with brine and dried, and the solvent was evaporated to give~ the mixed C-15 epimers o~ 16-(4-chlorophenyl)-16-methyl-lla,15-bis(tetrahydropyran-2-yloxy)-18,19,20-trinor-5-trans, 13-trans-prostadienoic acid, RF = -5 (ethyl acetate), together with a small amount of 4-phenylbenzoic acid.
The above mixture (127mg.) was dissolved in pure acetone (2.8ml.) and cooled to -0C., Jones~ reagent (chromic acid in acetone, 0.67ml.) was added and the solution was stirred for 15 minutes at 0 C. Isopropanol (3 drops) was ::

:.
~ ~.
., .

~ ?~
3dded follow~d by Pt~yI ~cet~te The scl~}~r. was ~a~
with saturated brine and dried, and the solvent was evapo-rated to give the mixed C-15 epimers o~ 16-(4-chlorophenyl)~
16-methyl-9-oxo~ 5-bis(tetrahydropyran-2-yloxy)-l8~l9~2 trinor-5~trans, 13-trans-prostadienoic acid, RF = 0 7 (ethyl acetate), th2 required starting material.

, /0 w/v - 16-~4-Chlorophenoxy)-9a,11~,15-trihydroxy-17,18,19,20-tetranor-5-trans-13-trans-prostadienoic acid 0.003 - Sodium phosphonate ~.90 - Sodium hydrogen phosphate 0.30 - Water for injection to 100 The sodium phosphate was dissolved in about 80%
of the water, followed by the prostadienoic acid derivative, ana, when dissolved, the sodium hydrogen phosphate. The ~L~tion was made up to volume with water for injection, and the pH was checked to be between 6.7 and 7.7. The sol-ution was filtered to remove particulate matter, sterilisedby filtration, and filled into presterilised neutral glass ampoules under aseptic conditions. Immediately before use, the contents of an ampoule are diluted in sodium chloride B.P. for administration by intravenous infusion.
The prostadienoic acid derivative may, of course, be . , - - . -replaced by an equivalent amount of another prostanoic acid derivative of the invention.

The process described in Example 7 was repeated, omitting the sodium phosphate B.P. and sodium acid phosphate B.P., to give ampoules containing a sterile aqueous solution of 16-(4-chlorophenoxy)-9a,11a,15-trihydroxy-17,18,19,20-tetranor-5-trans,13-trans-prostadienoic acid, which are used in the manner described in Example 7O
The prostadienoic acid derivative may be replaced by an equivalent amount of another prostadienoic acid of the invention, to give other sterile aqueous solutions.

Claims (23)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for the manufacture of a cyclopentane derivative of the formula:
I
wherein R1 is a hydroxymethyl or carboxy radical or an alkoxy-carbonyl radical of 2 to 5 carbon atoms, either R2 is a hydroxy radical and R3 is a hydrogen atom or R2 and R3 together form an oxo radical, A is an ethylene or trans-vinylene radical, Y is a direct bond or an alkylidene or alkylideneoxy radical of 1 to 5 carbon atoms, in the latter of which the alkylidene part is bonded to the carbon atom of the -CH(OH)- group and the oxygen atom is bonded to R4, and R4 is a phenyl radical which is unsubstituted or is substituted by halogen or halo-genoalkyl of 1 to 4 carbon atoms, and for those compounds wherein R1 is a carboxy radical, the pharmaceutically or veterinarily acceptable salts thereof, which comprises:
(a) the separation of a mixture of the 5-trans-cyclopentane derivative of the formula I and the corresponding 5-cis-isomer by chromatography or fractional crystallisation;
(b) for those compounds wherein R2 is a hydroxy radical and R3 is a hydrogen atom, the reaction of an enone of the formula:
II

wherein R4 has the meaning defined above, R5 is an alkoxy-carbonyl radical of up to 11 carbon atoms, and R6 and R7 are each a hydroxy radical or a protected hydroxy radical, with a reducing agent, whereafter when R6 and R7 are protected hydroxy radicals, the protecting groups are removed, and whereafter when a compound of the formula wherein R1 is a carboxy radical is required, the product thus obtained is hydrolysed with a base, or whereafter when a compound of the formula I wherein R1 is the hydroxymethyl radical is required, the product so obtained is reacted with a reducing agent; or (c) for those compounds wherein R2 is a hydroxy radical and R3 is a hydrogen atom, heating a phosphonium betaine of the formula:
III
wherein R1, R4, A and Y have the meanings stated above, R3 is a hydrogen atom, R8 is an aryl radical, R9 is an alkyl radical of 1 to 6 carbon atoms, and R10 is a tetrahydropyran-2-yl radical whereafter the protecting tetrahydropyran radicals R10 are hydrolysed.

2. A cyclopentane derivative of the formula I as defined in Claim 1 whenever prepared by the process claimed in Claim 1 or by an obvious chemical equivalent thereof.

3. A process as claimed in Claim 1 wherein the separation of a mixture of the 5-trans-cyclopentane derivative of the formula I and the corresponding 5-cis-isomer is effected by chromatography or fractional crystallisation.

4. A process as claimed in Claim 3 wherein the chromatography is on silica gel impregnated with silver nitrate.

5. A process as claimed in Claim 1 wherein the reduction of an enone of the formula II is carried out using zinc borohydride, aluminium tri-isopropoxide or di-isobornyl-oxy aluminium isopropoxide.

6. A process as claimed in Claim 1 wherein in the starting material of the formula II, R6 and R7 are both hydroxy radicals or both 4-phenylbenzoyloxy radicals, or R6 is a 4-phenylbenzoyloxy radical and R7 is a hydroxy radical.

7. A process as claimed in Claim 1 wherein, in the starting material of the formula III, R8 is a phenyl radical and R9 is a methyl or ethyl radical.

8. A process as claimed in Claim 1, 3 or 4 wherein R1 is a carboxy or methoxycarbonyl radical, R2 is a hydroxy radical and R3 is a hydrogen atom or R2 and R3 together form an oxo radical, A is a trans-vinylene radical, Y is a direct bond or a methylene, isopropylidene, methyleneoxy or iso-propylideneoxy radical and R4 is a phenyl, 3- or 4-chloro-phenyl or 3- or 4-trifluoromethylphenyl radical, and for those compounds wherein R1 is a carboxy radical the pharma-ceutically or veterinarily acceptable salts thereof.

9. A process as claimed in Claim 5, 6 or 7 wherein R1 is a carboxy or methoxycarbonyl radical, R2 is a hydroxy radical and R3 is a hydrogen atom or R2 and R3 together form an oxo radical, A is a trans-vinylene radical, Y is a direct bond or a methylene, isopropylidene methyleneoxy or iso-propylideneoxy radical and R4 is a phenyl, 3- or 4-chloro-phenyl or 3- or 4-trifluoromethylphenyl radical, and for those compounds wherein R1 is a carboxy radical the pharma-ceutically or veterinarily acceptable salts thereof.

10. A process as claimed in Claim 1, 3 or 4 wherein Y is a direct bond or a methylene, isopropylene, methyleneoxy or isopropylideneoxy radical and R4 is a phenyl, 3- or 4-chlorophenyl or 3- or 4-trifluoromethylphenyl radical and for those compounds wherein R1 is a carboxy radical the pharmaceutically or veterinarily acceptable salts thereof

11. A process as claimed in Claim 5, 6 or 7 wherein Y is a direct bond or a methylene, isopropylene, methyleneoxy or isopropylideneoxy radical and R4 is a phenyl, 3- or 4-chlorophenyl or 3- or 4-trifluoromethylphenyl radical, and for those compounds wherein R1 is a carboxy radical the pharmaceutically or veterinarily acceptable salts thereof

12. A process as claimed in Claim 1, 3 or 4 wherein R1 is a carboxy, methoxycarbonyl or ethoxycarbonyl radical, R2 is a hydroxy radical, R3 is a hydrogen atom, A is a trans-vinylene radical, Y is a methyleneoxy radical and R4 is a 3- or 4-chlorophenyl or 3- or 4-trifluoromethyl-phenyl radical.

13. A process as claimed in Claim 5, 6 or 7 wherein R1 is a carboxy, methoxycarbonyl or ethoxycarbonyl radical, R2 is a hydroxy radical, R3 is a hydrogen atom, A is a trans-vinylene radical, Y is a methyleneoxy radical and R4 is a 3- or 4-chlorophenyl or 3- or 4-trifluoromethyl-phenyl radical.

14. A process as claimed in Claim 1, 3 or 4 wherein Y is an isopropylideneoxy radical and R4 is a chlorophenyl or trifluoromethylphenyl radical.

15. A process as claimed in Claim 5, 6 or 7 wherein Y is an isopropylideneoxy radical and R4 is a chloro-phenyl or trifluoromethylphenyl radical.

16. A process as claimed in Claim 1, 3 ox 4 wherein Y is an isoprolideneoxy radical and R4 is a chloro-phenyl radical.

17. A process as claimed in Claim 5, 6 or 7 wherein Y is an isopropylideneoxy radical and R4 is a chloro-phenyl radical.

18. A process as claimed in Claim 1 wherein R2 and R3 together form an oxo radical.

19. A process as claimed in Claim 3, 4 or 7 wherein R2 and R3 together form an oxo radical.

20. A process as claimed in Claim 1, 3 or 4 wherein R4 is a 4-chlorophenyl radical.

21. A process as claimed in Claim 5, 6 or 7 wherein R4 is a 4-chlorophenyl radical.

22. A process for the manufacture of 16-(3-chloro-phenoxy)-9.alpha.,11.alpha.,15-trihydroxy-17,18,19,20-tetranor-5-trans, 13-trans-prostadienoic acid which comprises the chromatographic separation of a mixture of that compound with 16-(3-chloro-phenoxy)-9.alpha.,11.alpha.,15-txihydroxy-17,18,19,20-tetranor-5-cis, 13-trans-prostadienoic acid.

23. A process for the manufacture of 9.alpha.,11.alpha.,15-trihydroxy-16-(3-trifluoromethylphenoxy)-17,18,19,20-tetranor-5-trans,13-trans-prostadienoic acid, 16-(4-chlorophenoxy)-11.alpha.,15-dihydroxy-16-methyl-9-oxo-18,19,20-trinor-5-trans,13-trans-prostadienoic acid, 9.alpha.,11.alpha.-15-trihydroxy-16-phenyl-17, 18,19,20-tetranor-5-trans,13-trans-prostadienoic acid, 11.alpha., 15-dihydroxy-9-oxo-16-phenyl-17,18,19,20-tetranor-5-trans,13-trans-prostadienoic acid and 11.alpha.,15-dihydroxy-9-oxo-15-(4-tri-fluoromethylphenyl)-16,17,18,19,20-pentanor-5-trans,13-trans-prostadienoic acid which comprises, in each case, the chromato-graphic separation of a mixture of that compound and the corresponding 5-cis compound.