CA1042002A - Cyclopentane derivatives - Google Patents

Abstract

ABSTRACT OF DISCLOSURE

The disclosure relates to novel 15-aryl-ll.alpha.,15-dihydroxy-16,17,18,19,20-pentanor-5-cis-prostenoic acid derivatives, for example 9.alpha.,11.alpha.,15-trihydroxy-15-(4-trifluoromethylphenyl)-16,17,18,19,20-pentanor-5-cis, 13-trans-prostadienoic acid, processes for their manufacture, pharmaceutical and veterinary compositions containing such a compound as the active ingredient, and a method of producing luteolysis in an animal host with such a compound or composition.

Description

104'~00Z

~ his invention relates to new prostanoic acid derivatives, and in particular it relates to new prostanoic acid derivatives which are analogues of the naturally occurring compounds known as prostaglandin F2a and prostaglandin E2, showing a similar spectrum of pharmacological properties and being useful for simi]ar purposes. The relative potency of the new compounds, however, in respect of the particular pharmacological effects shown is different from that of the above naturally occurring prostaglandins, and in particular they are more potent as luteolytic agents than the corresponding natural prostaglandins. That is to say, the prostaglandin F2a analogues of the present invention are more potent than natural prostaglandin F2a, and the prostaglandin E2 analogues of the present invention are more potent than natural prostaglandin E2. The new compounds are, in a similar way, more potent as stimulants of uterine smooth muscle than the corresponding natural prostaglandins F2a and E2, and the prostaglandin E2 analogues of the invention are particularly valuable in this respect. The new compounds are therefore advantageous when used as contraceptives, for the termination of pregnancy or for control of the oestrus cycle, and are also useful for addition to semen intended for artificial - 25 insemination of domestic animals~ the success rate of insemination being thereby increased, especiall~ in pigs.

- 2 -.

,. , . . ~ . : :

'' " ' : . ~ . ' ~' ' :.
- , :, ~: .

~: , Certain of the compounds are useful as vasodilators and bronchodilators, and as inhibitors of platelet aggregation and of gastric secretion.
The cyclopentane derivatives described in this specification will be named as derivatives of prostanoic acid of the formula shown below and numbered as shown:^
: H
9 1 7 5 3 lCOOH
~~ .
10 ~ 20 11 ~ 13 15 17 19 H .

~ .
According to the invention there is provided a prostanoic acid derivative of the formula:-R~ ~ Rl I ~

; ' ' ' ' ;
. ,~ ~ A.CH(OH).R4 HO
; 10 wherein Rl i5 a carboxy radical or an alkoxycarbonyl radical of up to 11 .~;
` carbon atoms, A is an ethylene or trans-vinylene radical, and R4 is a phenyl, ~ -'! naphthyl, furyl or 2-thienyl radical which is unsubstituted, or which is substituted by one or two substituents selected from chlorine, fluorine, . bromine and iodine atoms, and nitro, phenyl, chlorophenyl, methyl, ethyl, . propyl, methoxy, ethoxy, methoxymethyl and trifluoromethyl radicals, R2 is a hydroxy radical and R3 is a hydrogen atom or R2 and R3 together form an oxo ~- radical, which derivative optionally bears a 2-methyl substituent, and for those compounds wherein Rl is a carboxy radical the pharmaceutically-and veter-inarily-acceptable salts thereof.

.,. 20 A suitable value for Rl when it is an alkoxycarbonyl radical is, for example, such a radical containing up to 11 carbon atoms, for example the ~ethoxycarbonyl, n-butoxycarbonyl or n-decyloxycarbonyl radical. A

.
:-, ~1 : .

-` 104ZOO;~
suitable value for A is, for example, the trans-vinylene or ethylene radical, and a suitable value for R4 is a phenyl, naphthyl, 2- or 3-furyl or 2-thienyl radical which, if substituted, preferably contains not more than 2 substituents as defined above.
Suitable halogen substituents in the radical R4 are, for example, fluorine, chlorine, bromine or iodine atoms; a suitable alkyl ;
substituent is, for example, a methyl, ethyl or propyl radical; a suitable alkoxyalkyl substituent is, for example, the methoxymethyl, ethoxymethyl or 2-ethoxyethyl radical; a suitable halogenoalkyl radical is, for example, a ` 10 halogenomethyl radical; and suitable alkoxy, acylamino and dialkylamino radicals, are, for example, the methoxy, ethoxy, acetamido and dimethylamino radicals~ Thus, suitable values for R4 are phenyl, l-naphthyl, 2-naphthyl, 2-furyl, 3-furyl, 2-thienyl, fluorophenyl, chlorophenyl, bromophenyl, iodophenyl, nitrophenyl, biphenylyl, chlorophenyl-2-furyl, tolyl, ethylphenyl, propylphenyl, methoxymethylphenyl, ethoxymethylphenyl, (2-e~hoxyethyl) phenyl, methoxyphenyl, ethoxyphenyl, halogenomethylphenyl, acetamidophenyl and ~'~ dimethylaminophenyl radicals.
~: 4 Particular values for R are the phenyl, 2-naphthyl, 2-furyl,

3-furyl, 2-thienyl, 4-fluorophenyl, 3- and 4-chlorophenyl, 3, 4-dichlorophenyl, ~ 20 4-nitrophenyl, 4-biphenylyl, 5-~4-chlorophenyl)-2-furyl, 4-tolyl, 4-methoxy-- methylphenyl and 3- and 4-triflurormethylphenyl.
Examples of pharmaceutically- and veterinarily- acceptable salts are the ammonium, alkylammonium containing ' ' , . .

- . ;.. -...... ~- ~

~04~00;~

1 to 4 alkyl~radicals each of 1 to 6 carbon atoms, alkanolammonium containing 1 to 3 (2-hydroxyethyl) radicals 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 10 specified in formula I, and that carbon atoms 2, 3, 4 and 9 may also be asymmetrically substituted, so that it is clear that such compounds can exist in racemic form and in at least two optically active forms. It is to be understood that the useful properties of the racemate may 15 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 - which shows the above useful properties, it being a matter of common general knowledge how the optically active forms 20 may be obtained, and to determine their 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 specification, the 25 same fixed stereochemistry at C-8, 11 and 12 as that shown r~

. . . .. .. . .... . ~ . ~ . ....... .... ~ -.. - . . . . -~4ZOO;~

in formula I is implied.
A preferred group of prostanoic acid derivatives of the invention comprises those compounds wherein R4 is the 3- or 4-chlorophenyl, 3,4-dichlorophenyl, 4-nitrophenyl, 4-trifluoromethylphenyl or 4-methoxymethyl-phenyl radical, and particularly preferred are those compounds wherein R4 is the 4-chlorophenyl, 4-nitrophenyl - or 4-trifluoromethylphenyl radical.
Of the C-15 epimers, those epimers which are the more polar on silica gel thin la~er chromatography are preferred to the less polar epimers in any pair.
Particular prostanoic acid derivatives of the invention are described in the Examples, and particularly preferred are 9a,11a,15-trihydroxy-15-(4-trifluoromethylphenyl)-16,17,18,19,20-pentanor-5-cis,13-trans-prostadienoic acid, 15-(4-chlorophenyl)-9a,lla,15-trihydroxy-16,17,18,19,20-pentanor-5-cis,13-trans-prostadienoic acid, methyl 15-(4-chorophenyl)-9a,11a,15-trihydroxy-16,17,18,19,20-pentanor-5-cis,13-trans-prostadienoate, 9a,11a,15-trihydroxy-15-(4-nitrophenyl)-16,17,18,19,20-pentanor-5-cis,13-trans-prostadienoic acid, 15-(3-chlorophenyl)-9a,11a,15-trihydroxy-16,17,18,19,20-pentanor-5-cis,13-trans-prostadienoic acid, 15-(3,4-dichlorophenyl)-9a,11a,15-trihydroxy-16,17,18,19,20-pentanor-5-cis,13-trans-prostadienoic acid and 9a,11a,15-trihydroxy-15-(4-methoxymethylphenyl)-16,17,18,19~20-pentanor-5-cis,13-trans-prosta~ienoic acid.

.
.

The cyclopentane derivatives of the invention may be manufactured :
by methods known in themselves for the manufacture of chemically analogous -compounds. Thus, the following processes for the manufacture of the cyclopen-tane derivatives of the formula I are provided as further features of the invention~
~a) for those compounds wherein Rl is the carboxy radical, R2 is the hydroxy radical, R3 is the hydrogen atom, the reaction of a lactol of the formula:-f OH
O~\ .

\~\A-CH~oH).R4 HO
wherein A and R4 have the meanings stated above, with a C4-carboxybutyl) triphenylphosphonium salt, optionally bearing a 2-methyl substituent , in the presence of a strong base, whereafter when a salt is required the product is reacted with a base; or (b) for those compounds wherein Rl is an alkoxycarbonyl radical of 1 to 11 carbon atoms, the reaction of an acid of the formula:-R2 R3 ~ :
CH2)3-COOH

III
~v~ A-CH(OH~.R4 HO
: : .
wherein A, R2, R3 and R4 have the meanings stated above, with a diazoalkane : of 1 + 10 carbon atoms; or (c) for those compounds wherein Rl is an alkoxycarbonyl radical of up to 11 carbon atoms, the reaction of a salt, for example the silver salt, of an : acid of the formula III with an alkyl halide of 1 to 10 carbon atoms, for example an alkyl iodide; or t :` `
104;~00Z

(d) the reduction of a compound of the formula:-. R3 ~ -R ~ ~ Rl :

~ `Co.R4 IV

wherein Rl, R and R4 have the meanings stated above, and R6 and R7 are each a hydroxy radical or a protected hydroxy radical, and which optionally bears a 2-methyl substituent, for example with zinc borohydride9 aluminium tri-isopropoxide, or di-isobornyloxy aluminium isopropoxide, whereafter when R6 and R7 are each a protected hydroxy radical, the protecting groups are removed, and if a salt is required, a carboxylic acid so obtained is reacted with a :~
base; or ~e) for those compounds wherein A is the trans-vinylene radical, the hydroly-sis of a compound of the formula:- i-~. 3 R2 ~ ~ COOH V ;
~,J~ ., .
~ I ~ -fH.R4 ~ ~
R80 R8 ~ ~ ~

wherein R2, R3 and R4 have the meanings stated above, and R8 is an alkoxy-dialkylmethyl radical of 4 to 8 carbon atoms for example the l-methoxy-l-methylethyl radical; or ~; ~f) for those compounds wherein A is the ethylene radical, the hydrolysis of a compound of the formula V wherein A, R2, R3 and R4 have the meanings stated above and R8 is the tetrahydropyranyl radical, for example with aqueous acetic acid or in an aqueous or alcoholic solution of an alkali metal carbonate, for : 20 example potassium carbonate in methanol, at a temperature between ambient temperature and about 60C.

,.~ ......
: - 8 -1C~4Z002 A suitable protected hydroxy radical in process (d) is, for example, an alkanoyloxy radical of up to 6 carbon atoms, for example an acetoxy radical, or an aroyloxy radical of up to 12 carbon atoms, for example a ~ 9 _ p-phenylbenzoyloxy radical.
The starting material of the ~ormula II wherein A is the trans-vinylene radical which ma~ be used in the process of the invention, may be obtained by reacting an aldehyde VI (Ac = p-phenylbenzoyl) with a compound (CH30)2P~o.~GH.CoR4 or a phosphorane Ph3P:CH.COR4 to give an unsaturated ketone VII~ which is reduced to the enol - VIII and hydrolysed to the diol IX. The lactone ring is then reduced with di-isobutyl aluminium hydride to give the required lactol starting material II. -The starting material of the formula II wherein A is an ethylene radical, used in the process of the invention, may be obtained by hydrogenating an unsaturated ketone VII in the presence of 5% palladium-on-carbon catalyst, to give a saturated ketone, and repeating the procedure outlined above using the saturated ketone in place of an unsaturated ketone VII.
The starting material of the formula III wherein R is an alkanoyloxy radical may be obtained from the corresponding compound wherein R2 is a hydroxy radical by acylation with an acid anhydride in pyridine to give a 9-ester-1-mixed ~anhydride, which may be hydrolysed to the required starting material.
The starting material of the formula I~ may be obtained from the known compound 4~-dimethoxymethyl-2,3,3a~, ~r . . . - ~

.... - ~: , . . : -lO~ZOOZ

o ~o/
o,-~ o~

CHO ~ CO . R
AcO AcO
VI VI I

O O
o~

- ~ \~\~CH(oH).R4 ~H(oH).R4 AcO
HO
VIII IX

> I I

Ac represents an acyl radical.
' .

rA~

' , . . . . . . ~ ~

10~;200;~ .
6a~-tetrahydro-5~-hydroxy-6~-iodo-2-oxocyclopenteno [b~furan (X) by ~reatment with tribut~l tin hydride to give the de-iodinated lactone XI. The 5a-hydroxy group is protected as the tetrahydropyran-2-yl ether XII, the lactone is reduced to the lactol XIII, using di-isobutyl alumium hydride, and the lactol is reacted with (4-carboxy-butyl) triphenylphosphonium bromide to give the cylopentanol derivative XIV, which after esterification, protection of the two hydroxyl group as p-phenylbenzoate esters,hydrolysis of the acetal~reaction with a phosphonate of the formula (CH30)2Po.CH2CoR4 in the presence of a strong base,and methanolysis of the tetrahydropyranyl group gives a starting material of the formula IV (Rl = methoxycarbonyl, R6 = R7 = hydroxy).
The star$ing material of the formula ~ may be obtained from the corresponding intermediate of the formula IX by reaction thereof with 2-methoxypropene to give a bis-ketal, which is converted by di-isobutyl aluminium hydride reduction and reaction with (4-carboxybutyl)-triphenylphosphonium bromide as described above, to a starting material V (R2 = hydroxy, R3 = hydrogen), which in turn may be oxidised with chromium trioxide to the corresponding starting material V (R2 and ~3 together are oxo).
The starting material of the formula V, wherein ., .

-. . .: : , .

~, ' .

lO~ZQO'~

,o ~ ?

- I ~ ~ ClI(OCI13)2 ~ CH(OCH3)2 HO . Hd . XT DH
X

~ CH(OCH~ CH(ocH~)2 THP.O THP.O
XII XIII
.

~ ~ ~ ~ COOH
~ ~ I .
~ CH(OCH3)2 ~~ ~ IV

THP.O
XIV

THP ~ tetrahydropyran-2-yl.

.

,, ' ~, ', : ' ' .

-, ~' ,: ', .. ' . -104200'~
R8 is the tetrahydropyranyl radical~ used in process (g), may be obtained by reacting the diol fX with 2,3-dihydropyran to give the bis-ether, followed by reduction to the lactol and reaction thereof with (4-carboxybutyl)triphenyl-phosphonium bromide in the presence of a strong base, asdescribed above~

As stated above, the compounds of the invention possess a profile of pharmacological properties which differs from that of the naturally occurring prostaglandins F2a and E2. Thus, for example the more polar C-15 epimer of l-(4-chlorophenyl)-9a,11a,15-trihydroxy-16,17,18,19,20-pentanor-5-cis,13-trans-prostadienoic acid is at least 50 times as active as prostaglandin F2~ as a luteolytic agent, yet has only approximately the same smooth muscle stimulant activity as prostaglandin F2a.
When a compound of the invention is to be used, for example for the induction of labour, it is used in --the same way as it is known to use the naturally-occurring prostaglandins E2 and F2a, that is to say, by administering a sterile, substantially aqueous solution containing up to lmg./ml. of active compound, by intravenous i.nfusion~by transcervical extra-ammotic injection,or by intra-ammotic injection,until labour commences.
Thus, according to a further feature of the invention there is provided aPharmaceutical or veterinary composition comprising a prostanoic acid derivative of the )~
_ ~ _ - . . . ~
- - - , .. . :

- .

10420Q~

invention, together With a pharmaceutically- or veterinarily- acceptable diluent or carrier The compositionsmay be in a form 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 intra-uterine infusion or parenteral administration for example a sterile, substantially aqueous solution, or in the form of a suppository, suitable for anal or vaginal use. As stated above, when the compound of the invention is to be used for the induction of labour in childbirth, a preferred composition of the invention is a sterile, substantially aqueous, solution.
The compositions of the invention may be prepared by conventional means, and may incorporate conventional excipients.
The invention is illustrated, but not limited by the following Examples. RF values refer to thin layer chromatography on Merck silica gel, unless otherwise ` 20 stated.
Example 1 Finely powdered (4-carboxybutyl)triphenylphosphonium bromide (0 532 g.) was heated to 100C. under vacuum for 1 h~ur. The evacuated reaction vessel was filled with an ~ 25 atmosphere of dry nitrogen~ the solid was dissolved in : :
. 1 .: ~, _ ~ _ ,~
:

.. . :

.. , . ~ , . - . .. .
. : - . . . . : : . .
: :. . -: - .~: -104Z00~
dimethylsulphoxide (2 ml.~ and the solution was cooled ~n room temperature ~o this solution was added dropwise 1.1 ml. of a 2M solution of methanesulphinylmethyl sodium in dimethyl sulphoxide followed by a solution of the mixture of epimers of 4~-(3-p-chlorophenyl-3-hydroxy-1-trans-propenyl)-2,3,3a~,6a~-tetrahydro-2,5a-dihydroxycyclopenteno[b]furan (72 mg.) in a mixture of dimethylsulphoxide (2 ml.) and benzene (0.3ml.). The solution was stirred for 3 hours, and the solvent was removed by evaporation under reduced pressure at a temperature below 40C. ~he residue was shaken with water (10 ml.) and ethyl acetate (10 ml.) and the aqueous phase was separated, extracted with ethyl acetate (2 x 10 ml.) and the extracts discarded. The aqueous solution was acidified to pH 3-4 with 2N aqueous oxalic acid, and extracted with a mixture of equal parts of ether and petroleum ether (b.p. 40-60C.) (5 x 10 ml.). The organic phase was separated, washed with saturated brine ; and was dried. Evaporation of the solvents gave a mixture of the C-15 epimers of 9a,11~,15-trihydroxy-15-'~ (4-chlorophenyl)-16,17,18,19"20-pentanor-5-cis,13-trans-pro~adienoic acid. Thin layer chromatography, ùsing 3%
acetic acid in ethyl acetate, separated the C-15 epimers, having RF values of 0.3 and 0~4 respectively. The n,m.r. spectrum of each isomer (in deuterated acetone) ~, .

.- ~

, . .

showed the follo~Ting characteristic bands (~ values):-7,35, doublet, 4 aromatic protons 5 1 - 5.6, 4 olefinic protons.
The mass spectrum of the tetra(trimethylsilyl)derivative showed M = 682.3410 (calculated 682.3129).
The cyclopenteno[b]furan used as starting material may be obtained as follows:-n-Butyl-lithium (39 ml. of a 2.2M solution in hexane) was added to a solution of dimethyl methylphosphonate (11.3 g.) in dry tetrahydrofuran at -78C. in an atmosphere of nitrogen. After 10 minutes, a solution of ethyl 4-chlorobenzoate (8.o g.) in dry tetrahydrofuran (20 ml.) was added dropwise, and the mixture was stirred for

4 hours at -78C. The reaction mixture was neutralised with acetic acid and the solvents were removed under reduced pressure. The Pesidue was shaken with a mixture ~-of ethyl acetate (100 ml.) and water (20 ml,), and the organic phase was separated and washed with brine. The solution was dried, the solvents were evaporated and the residue was distilled in a bulb distillation apparatus at -an oven temperature of 210C. and 0.1 mm. pressure, to give dimethyl 2-(~chlorophenyl)æ-oxoethylphosphonate.
A solution of dimethyl 2-(4-chlorophenyl)-2-oxoethylphosphonate (2.36g.) in dry 1,2-dimethoxyethane (40 ml.) at -78C. was treated with n-butyl-lithium ,~ _ ~_ , .

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

104~:00;~

(5.6 ml. of a 1.4~ solution in hexane), and the mixture was stirred for 15 minutes. To this mixture was added a solution of 4~-formyl-2,3,3aB,6a~-tetrahydro-2-oxo-5a-(4-phenylbenzoyloxy)cyclopenteno[b]furan (2.1 g.) in 1,2-dimethoxyethane (10 ml.), and after 1 hour the reaction mixture was neutralised with glacial acetic acid and all ~ -solvents were removed by evaporation under reduced pressure below 35C. The residue was triturated with ether to yield the unsaturated ketone product, as a white solid, RF = 0.6, (50~ ethyl acetate in toluene), The unsaturated ketone (1.5 g.) was dissolved in dry benzene (50 ml.) and to the solution was added 11 ml.
of a 0.515M solution of aluminium isopropoxide in benzene.
The mixture was stirred under reflux for 2 hours, then saturated sodium hydrogen tartrate solution was added.
Ethyl acetate (200 ml.) was added, the organic layer was separated, washed with a 1:1 mixture of saturated brine and water, thendried. The solvents were evaporated to give a mixture of epimeric unsaturated alcohols, RF = 0 2 (50%
ethyl acetate in toluene).
The mixture of epimeric unsaturated alcohols (1.5 g.) was stirred vigorously for 2 hours with finely powdered anhydrous potassium carbonate (427 mg.) in methanol (20 ml.). lN Hydrochloric acid (6 .o8 ml.) was added, followed by ethyl acetate (100 ml.). The organic - ' ' - ' .
:
'' ' ~

~-layer was separated, washed successively with saturated sodium bicarbonate solution and saturated brine, and dried, and the solvents were evaporated. The residue was chromatographed on Florisil (20 g.). Elution with ether removed by-products, and subsequent elution with ethyl acetate gave a mixture of the C-15 epimeric diols, RF = -3 (ethyl acetate).
; To a solution of the epimeric diols (369 mg.) in dry toluene (5 ml.) under an atmosphere of nitrogen at -78C. was added 0.5 ml. of a 2.2 m mole/ml. solution of di-isobutyl aluminium hydride in toluene. After 30 minutes the reaction was quenched by the dropwise addition of methanol(3 ml.) and after a further 15 minutes at room temperature a mixture of 1:1 saturated brine/water ~
(25 ml.) was added, and the mixture was extracted with --ethyl acetate (3 x 50 ml.~. The extract was washed with saturated brine, and dried, and the solvents were evaporated to give a mixture of epimers of 4~-(3-p-chlorophenyl-3-hydroxy-l-trans-propenyl)-2,3~3a~,6a~-tetrahydro-2,5a-dihydroxycyclopenteno[b]furan, RF = -3 (2~ methanol in ethylacetate).
Example 2 The process described in Example 1 was repeated using the appropriate cyclopenteno[b~furan to give the ~;~
compounds shown in the Table below. MaEs spectrum ~ ~rade Mc~rk .
,. . . ~ .

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

104'~002 measurements refer to the tetra-(trimethylsilyl) derivatives.
Characterising data for the phosphonate reagents (CH30)2 Po.CH2CoR4 and for the enones ~II (Ac = p-phenylbenzoyl) are also shown:-HO~ H 2 ~ ,- \ ~ ~ COOH

,~ ~ CH(OH) ~

R

. . . - - ,. ,.
No. R9Other substituent in prostanoic acid . . , 1 3-chloro 2 4-chloro _ 3 4-fluoro _ 4 ; 4-methyl _ 3-trifluoromethyl _ 6 4-trifluoromethyl _ 7 4-trifluoromethyl2-methyl _ . ~ .... . .
r--~ . .. __ .
No. Mass Spectrum Phosphonate Enone . b.p. C./mm Hg.

Found Calculate d _ ~ ~
1M+=682.3095682.3129 RF = 0.2 a)m.p.l63-164G.
2M+=682.3140682.3129 210/0.1RF = 0.65 b) 3M+=666.3387666.3425 RF = 0.3 c)m.p.l29-130C.
4M+=662.3669662.3670 210/0.1m.p.170-176C.
570~.3126 701.3159 RF = 0.3 a )RF = 6 b 6"=701.3133701.3159 140/0.4m.p.178 C.
7M+=730.351173.3549 _ r-... . - . .

. . . ~ . . 1 ~
-;. .
:; .~
.

a) in 50% ethyl acetate/chloroform.
b) in 50% ethyl acetate,!toluene.
c) in 75% ethyl acetate/methylene dichloride.
For No.2, the mass spectrum data refer to each C-15 epimer, for Nos. 1 and 3 to 8, the data refer to the mixed C-15 epimers. -Example 3 , Methyl 15-(4-methoxymethylphenyl)-15-oxo-9, lla-di-(4-phenylbenzoyloxy)-5-cis,13-trans-prostadienoate (110 mg.) was stirred in dry toluene (5.0 ml.) under argon at room temperature, and treated with a 0.323M solution of di-isobornyloxyaluminium isopropoxide in toluene (2.Oml.).
After 1~ hours, the mixture was partitioned between water (0.5 ml.) and ethyl acetate (1 0 ml.), and filtered through 'Hyflo,' washing the filter pad with ethyl acetate (2 x 4ml.).
The organic layer was separated, washed with brine (4ml.), dried over magnesium sulphate and filtered, and the solvent was evaporated to leave a crude oily product, which was chromatographed on 'Florisil~ (2g.). Elution with 5-10%
ethyl acetate in toluene gave the enol, methyl 15-hydroxy-15-(4-methoxymethylphenyl)-9a,11a-di-(4-phenylbenzoyloxy)-

5-cis,13-trans-prostadienoate as a viscous oil, RF = 4 (20% ethyl acetate in methylene dichloride) The crude enol (69 mg.) was stirred under argon in a mixture of methanol (4 ml.), water (0.7 ml.) and N potassium hydroxide (0.9 ml.) for 18 hrs. The mixture Trqde l~ rk :. .- . . ~ ~ . -: . ~

104200~
was acidified to pH 5 with oxalic acid, and extracted with ethvl acetate, the extracts were washed with 1:1 saturated brine/water, and dried. Evaporation of the solvents gave a residue, from which the two C-15 epimers were separated by thin layer chromatography, using 3%
acetic acid in ethyl acetate, RF = 3 and 0.4. The n.m.r. spectrum of each epimer in deuterated acetone - showed the following characteristic peaks (~ values):-7.2-7,4, 4H, aromatic.
105.1-5.6, 5H, 4 olefinic protons and -CH(OH).CH=CH-4.4, 2H, -CH2.OMe 3.32, 3H, -CH2.OMe The mass spectrum showed (M-CH3) = 677.3493, calculated for C35H6406Si4 = 677.3547 (for the tetra-trimethvlsilyl deriv~tive).
15The methyl 15-(4-methoxymethylphenyl)-15-oxo-9~,11a-di-(4-phenylbenzoyloxy)-5-cis,13-tra:ns-prostadienoate ; used as starting material in the above process may be obtained as follows:-4~-Dimethoxymethyl-2,3,3a~,6a~-tetrahydro-5~-hydroxy-6~-iodo-2-oxocyclopenteno[b~furan (4.0g.) in dry toluene (40ml.) was stirred under argon at 80C. with tri-n-butyl tin hydride (6.6g.) for 18 hours. The solvent was evaporated under reduced pressure and the residue was stirred with pe~roleum ether (b.p. 40-60C., lOOml.) for 3 minutes The solvent was decanted and the residual ':
r~ ~
.

.

104Z00;~ ;

~A~ oil was chromatographed on ~Florisil~ (50g~). Elution with mixtures containing 25% ethyl acetate in toluene and finally with ethyl acetate gave 4~dimethoxymethyl-2,3,3a~,6a~~tetrahydro-5a-hydroxy-2-oxocyclopenteno [blfuran 5 as an oil, RF = 3 (20% acetone in chloroform). The n.m.r. spectrum in deuteriochloroform showed the following characteristic peaks (S values):-3.40 and 3.42, 6H, 2 singlets, methoxy 4.04-4.36 f lH, multiplet 5~ proton 10li lH, doublet, -CH(OMe)2 lH, multiplet, 6a~ proton 4~-Dimethoxymethyl-2,3,3a~,6a~-tetrahvdro-5~-- hydroxy-2-oxoc~Tclopenteno[b~furan (4.01g ) was stirred under argon in dry toluene (30ml.), and the resulting 15 solution was treated with an excess of freshly distilled dihydropyran (17 ml.), followed bv 2.0 ml, of a 0.1%w/v solution of toluene-p-sulphonic acid in drv tetrahydrofuran.
After 3/4 hour, the mixture was treated with pyridine (0.50ml.) and then partitioned between ethyl acetate tl50ml.) 20 and saturated sodium bicarbonate (75ml.). The organic layer was separated, washed with saturated brine (50ml.), dried over magnesium sulphate and filtered, and the solvent was evaporated to give a crude lactone, 4~-dimethoxyvmeth~l-2,3,3a~,6a~-tetrahydro-2-oxo-5~-(tetrahydropyran-2-yloxy)-25 cyclopenteno[b]furan, RF = -7 (20% acetone in chloroform).
The crude lactone (6.2g ) was dissolved by ~_ ~23 TrRde, n;~O~f~

. . . -', .' ' ., . , - , . . . .

. .
- . . ,, ~ .

~04ZOO;~
stirring in dry dimethoxyethane (120ml.) under argon at ~! about -60C~ (chloroform ~ 'Dr~kold' cooling bath), and 1.7~ di-isobutylaluminium hydride (11.2M) was added. After 30 minutes, methanol (3ml~) was added, the mixture was allowed to warm up to room temperature, and was partitioned between ethyl acetate (600ml.) and 1:1 saturated brine~water (300ml.). The whole mixture was filtered through 'Hyrlo' and the two phases were separated. The aqueous phase was re-extracted with ethyl acetate (300ml.) and the combined organic layers were washed with water (lOOml.), dried over magnesium sulphate and filtered, and the solvents were evaporated to give the crude lactol (VI) 4~-dimethoxymethyl-2,3,3a~,6a~-tetrahydro-2-hydroxy-5~-(tetrahydropyran-2-yloxy)-cyclopenteno[b]furan, as an oil, RF = -4 (20% acetone in chloroform).
A stirred solution of (4-carboxybutyl)triphenyl-phosphonium bromide (24 8g.) in dry dimethylsulphoxide (DMSO, 50ml.) was treated slowly under argon and with cooling in an ice-water bath, with 2M methanesulphinylmethyl sodium in DMSO (54.5ml~, 2.5 equivalents) to form a solution of the corresponding ylide. The crude lactol (6.3g.) in dry DMSO (150ml.) was then added to the ylide solution at room temperature, The mixture was stirred for 11 hours, then water (lml.) was added. The DMSO was then 2~
~ -Tr~de ~ rk . - . . . . ~ ~... . . :

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

lO~ZOOZ
evaporated at high Vacuum at a temperature not exceeding 50C The resldual gum was partitioned between ether (4 x 225ml.) and water (150ml.). The aqueous layer was separated, acidified with 2N oxalic acid to approximately pH 4, and then extracted with 1;1 mixture of ether and pentane (3 x 300ml )~ The extracts were washed with saturated brine (150ml.) dried over magnesium sulphate - and filtered, and the solvent was evaporated to give the crude acid, 2~-dimethoxy_methyl-5a-hydroxy-3a-10 (tetrahydropyran-2-yloxv)cYclopent-la-ylhept-5-cis-enoic acid as an oil, suitable for use in the next stage of the synthesis. A sample was ~urified by chromatography on silica (70:1) eluting the product with 2% methanol in toluene as an oil, RF = -4 (5% methanol in meth~lene chloride). The n.m~r spectrum in deuteriochloroform showed the following characteristic peaks (~ values):-3.35, 6H, singlet, methoxy 3.3-3.65, lH, 3.68-4.o, lH, ~

4.00-4.19, 2H,~ multiplets, ~CH-0-4.19-4,38, lH, - 4.6-4.8, lH, 5.09-5 78, 2H, multiplet, olefinic protons The crude acid (4,48~ ) in methanol (45ml.~ was stirred under argon at room temperature with toluene-p-sulphonic acid (240mg,) for 23/4 hours The solution was ~5 -104~002 then partitioned between ethyl acetate (300ml.~ and saturated sodium bicarbonate (60ml.) followed by saturated brine (60ml.), The organic phase was dried over magnesium sulphate and filtered, and the solvent was evaporated to leave a crude ester-diol, methyl 2~-dimethoxymethyl-3~,5~-dihydroxycyclopent-1~-ylhept-5-cis-enoate as an oil, RF = o.65 (10% methanol in methylene chloride). The n.m.r. spectrum in deuteriochloroform showed the ~ollowing principal peaks (~ values):-3.39, 6H, singlet~~
3.64, 3H, singlet 3 3 methyl groups 4,03-4.3, 3H, ( multiplet, ~CH-0-¦ doublet, ~CH(OMe)2 5.1-5.7, 2H, multiplet, olefinic protons The crude ester-diol (3.3g~) was dissolved in dry pyridine (50ml.) under argon, and treated with p-phenylbenzoyl chloride (9.2g.) and the mixture was stirred for 17 hours. Water (0,8ml ) was then introduced and stirring was continued for 3-4 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 (300ml.) and saturated sodium bicarbonate solution (150ml.), The whole mixture was filtered through 'Hyflo~ and the organic phase was separated. The aqueous layer was extracted with toluene ~G
T~ dQ ll/lo~rk - ~

: . , . . - .

.

~04200~
(150ml.), and the organic extracts were combined, washed with brine (lOOml.), dried over magnesium sulphate, and filtered, and the solvent was evaporated to leave a solid crystalline residue This was thoroughly triturated with methanol (70ml.), the mixture was filtered, and the product was washed with more methanol (3 x lOml ) to give the dimethylacetal, methyl 2~-dimethoxymethyl-3a,5a-di-(4-phenylbenzoyloxy)cyclopent-la-ylhept-5-cis-enoate as a white solid, m.p 104.5-106.5C., RF = 5 (5% acetone in toluene). The n.m.r. spectrum in deuteriochloroform showed the following characteristic signals (~ values):-3.41, 3H, singlet 1 3.47, 3H, singlet ~ methyls 3.52, 3H, singlet 4.59-4.61, lH doublet, ,CH(OMe)2 5.17-5.70, 4H, multiplet, 2 x ~CH-O- and 2 olefinic protons 7.80-8.00, 2H,~ H
ldoublet ~ G~ CO 0-8.oo-8.20, 2H,~
An analytical sample recrystallised three times from ethanol had m.p. 105-107C.
Methyl 2~-dimethoxymethyl-3~,5a-di-(4-phenyl-benzoyloxy)-cyclopent-la-ylhept-5- CiS -enoate (500mg.) was vigorously stirred under argon for 10 minutes in a two-phase system consisting of 2% isopropanol in chloroform (20ml.) and concentrated hydrochloric acid (lOml~) The chloroform ~ ~: , - - ., : -. ;

,. - ... , . ~ . . . . . .. ... .. . .

.

~04ZOUZ

layer was separated and the aqueous layer was extracted - with chloroform (20ml.). The organic layers were combined, washed successively with aqueous saturated sodium bicarbonate (20ml.) and saturated brine (lOml.), dried over magnesium sulphate and filtered, and the solvent was evaporated. The oily residue crystallised on drying under high vacuum to give methyl 2~-formyl-3a,5a-di-(4-phenylbenzoyloxy)cyclopent-la-ylhept-5-cis-enoate, RF on Merck silica gel GF 254 plates was 0.4 (5% ethyl acetate in toluene). The n m.r. spectrum in deuteriochloroform was consistent with the required structure, and showed the -following principal signals (~ values):-3.51, 3H, singlet, methyl ester.
5,3-5.6, 4H, multiplet, ,CH-O- and olefinic protons.
7.8-8.o, 2H,~ H
8.0_8 2 2H 3 dOubletS ~co. o -7 22-7 73, 14H, multiplet, rest of aromatic protons 10.01-10 14, lH, doublet, -CHO
An analytical sample, m.p. 93-97C., was obtained by triturating the above-described product with ether.
A solution of dimethyl 2-(4-methoxymethylphenyl)-2-oxo-phosphonate (104 mg 1.5 equivalent) in tetrahydrofuran (3.0ml.) was stirred under argon and cooled in a A chloroform/'Drikold' bath, and treated with 2.2M butyl-lithium in hexane (148 ~1.) followed after a few minutes "~ _ ~g _ Irqde ~ Q ~k , . . . ~ . . i . . , . - . - . . . . , i . ~.~ ... .:: . . . ...
- . ~ . . . , ;.; ... . . ;: ., . ... , -~ . - . . -.. . . ..... : .. ~ .. ~ . ~ .... . .

- `

by a solution of methyl 2~-dimethoxymethvl-3a,5a-di-(4-phenylbenzoyloxy)cyclopent-la-ylhept-5-cis-enoate (157mg.), also in tetrahydrofuran (2~0ml~) The cooling bath was then removed, and after 2 hours a few drops of acetic acid and then water (200~1~) were added to adjust the pH to about 6. The solvent was evaporated under reduced pressure and the residue was partitioned between water (15ml.) and ethyl acetate (1 x 30ml., 1 x 15ml.). The organic layer was separated, washed with water (lOml.) then dried over magnesium sulphate, and filtered, and the solvent was evaporated to give a viscous oil. This ~Al oil was purified by chromatography on 'Florisil~
(2g.) eluting with 10% ethyl acetate in toluene to afford the required enone starting material, methyl 15-(4-methoxymethylphenyl)-15-oxo-9a,11a-di-(4-phenylbenzoyloxy)-5-cis,13-trans-prostadienoate, as an oil, RF = -4 (20%
ethyl acetate in methylene dichloride). The n.m.r.
spectrum in deuteriochloroform showed the following principal peaks (~ values)--3.35, 3H, singlet, methoxy.
3 50, 3H, singlet, -COOCH3.
4 45, 2H, -CH20CH3.
5.4-5.6, 4H, multiplet, cis olefinic protons and ,CH-O-

6.12-7.1, lH, doublet, =CH.CO-

7.86-8.02, 2H, doublet ) ~ COO-

8 02-8.23, 2H, doublet ~r~ C

.

.
- ~

- ~ . . .

7.3-7.7, 15H, multiplet, rest of aromatic protons + -CH=CH.C0-Example 4 The process described in Example 3 was repeated, using the appropriate enone, to give the compounds shown in the Table below. Mass spectrum measurements refer to the tetra-(trimethylsilyl) derivatives. Characterising data are given also for the phosphonate reagents (CH30)2Po.CH2CoR4 and for the enone starting materials:-H0~ ~H

~ ' C2H
~ CH(oH).R4 ; H0 No, _ ~_ _ 3~cct . ~
Found Calculated ~ - __~ ... .. ~
1 phenyl M =648.3462 648.3462 2 2-chlorophenyl (M-CH3) =667.2829 667.2895 3 3,4-dichlorophenyl m.p.,M+=716.2722 716.2746 l.p.,M =716 4 4-nitrophenyl (M -CH3~678.3144 678.3136 4-biphenylyl M+=724.3831 724.3832 6 2-naphthyl M =698.3620 698.3676 7 2-furyl M+=638.3252 638.3312 8 5-p-chlorophenyl-2-furyl M+=748.3201 748.3235

9 3-furyl M+=638.3303 638.3312 2-thienyl m.p.,654.3045 654,3084 l.p.,654 -- ~ 7- ' ~~' ~ - --~---.- . __ r~ - ~ -- . - . . .~ . . .

104Z00~

_ ~ ~
No. Phosphonate Enone _ . , .. ~ ~_ 1 b.p.162C /O.lmm.Hg, RF=0 7,ethylacetate/
toluene 2 b p,185C /0 05mm.Hg. a) 3 RF=0.3,ethylacetate . m.p.107-109C, 4 m p.73-75C RF=0,8,50%ethylacetate/
toluene m.p,85-87C RF=0.77~ether, 6 b.p 240C./0 5mm.Hg. RF=0.93,ether.
7 b p 150C /O.lmm.Hg RF=0.76,ether.
8 RF=0,22,ethylacetate RF=0,81,ether.
9 b p.150C./O.lmm.Hg, RF=0 82,ether.
RF=0.19,50% ethylacetate/ RF=0.79,ether. -methylene dichloride ~_ _ . , _, ~ ~_ a) Mass spectrum gave (M-phenylbenzoyl) = 568.1973, calculated from C35H3305C1 568.
~ ..
., To a solution of a mixture of the C-15 epimers of 15-(4-chlorophenyl)-9a,11a,15-trihydroxy-16,17,18,19, 20-pentanor-5-cis,13-trans-prostadienoic acid (12mg ) in methanol (1 ml.) at 0C. was added an excess of a solution of diazomethane in ether. After 10 minutes, the solvents ~were evaporated to give a mixture of the C-15 epimers of methyl 15-(4-chlorophenyl)-9a,11a,15-trihydroxy-16,17,18,19 20-pentanor-5-cis,13-trans-prostadienate as a clear oil, RF = -3 and 0.4 (ethyl acetate). For the more polar _ 3~_ ',: .......... . .:.~' ' . '` -t .. ' ~ ' 104'~00;~

epimer, the tris-(trimethylsilyl)derivative showed M
624.2840, calculated for C31H53C105Si3 = 624.2889 Exam~le 6 A solution of 15-(4-chlorophenyl)-9a-hydroxy-lla,15-bis(tetrahydropyran-2-yloxy)-16,17,18,19,20-pentanor-5-cis-prostenoic acid (270mg.) in 3 ml of a 2:1 mixture of acetic acid and water, was stirred at 50C. for 4 hours. The solvents were evaporated~ the residue was dissolved in dilute aqueous sodium bicarbonate -~
solution (2 ml.) and the solution was extracted with ethyl acetate (3 x 2 ml.) and the extracts were discarded.
The aqueous solution was acidifi~dto pH 3-4 with 2N
aqueous oxalic acid and the acidified solution was -extracted with ethyl acetate (4 x 5 ml.). The ethyl acetate extracts were washed with a 1:1 mixture of saturated brine and water, and were then dried. After evaporation of the ethyl acetate, the residue consisted of a mixture of the C-15 epimers of 15-(4-chlorophenyl)-9a,11~,15-trihydroxy-16,17,18,19,20-pentanor-5-cis, 20 prostenoic acid. The mass spectrum of the tetra-(trimethylsilyl) derivative gave (M-CH3) = 669.3031, calculated for C32H58C105Si4 = 669.3051.
The bis-tetrahydropyranyl ether used as starting material in the above reaction may be obtained as follows:~
5% Palladium-on-charcoal (300mg.) was added to a solution of 4~-[3-(4-chlorophenyl)-3-oxo-1-trans-propenyl]-.. , , .: . .... . -: ' :. - ' ': ' - -. ,~. . ~ .~ , ,, 104'~Z
2,3,3a~,6a~-tetrahydro-2-oxo-5a-(4-phenylbenzoyloxy) cyclopenteno[b]furan (974mg.) (the unsaturated ketone described in the second part of Example 1) in chloroform (15ml.), and the mixture was shaken in an atmosphe~ of hydrogen for 20 minutes. The mixture was filtered, and the filtrate evaporated to dryness to give the saturated ketone 4~-[3-(4-chlorophenyl)-3-oxopropyl~-2,3,3a~,6a~-tetrahydro-2-oxo-5-(4-phenylbenzoyloxy)cyclopenteno[b~furan , RF = -3 (5% ethyl acetate in toluene).
The remainder of the process described in the second part of Example 1 was repeated, using this saturated ketone in place of the unsaturated ketone to give successively mixed epimeric alcohols, and mixed epimeric diols, which were converted in conventional manner to epimeric bis-(tetrahydropyran-2-yl) ethers with 2,3-dihydropyran in tetrahydrofuran in the presence of toluene-p-sulphonic acid. The lactone ring in the bis-ether was reduced to the corresponding lactol in conventional manner using di-isobutyl aluminium hydride in toluene, and the lactol was reacted in conventional manner with (4-carboxybutyl)-triphenylphosphonium bromide in dimethylsulphoxide in the ; presence of methanesulphinylmethyl sodium to give the required bis-(tetrahydropyranyl) ether starting material~
15-(4-chlorophenyl)-9~-hydroxy-11~15-bis-(tetrahydropyran-2-yloxy)-16,17,18,19,20-pentanor-5-cis-prostenoic acid.

r -- - ~ .

lO~Z002 Example 7 ....... . .. . .
The process described in Example 6 was repeated using 15-(4-chlorophenyl)-9-oxo-11~i,15-bis-(tetrahydropyran-2-yloxy)-16,17,18319,20-pentanor-5-cis-prostanoic acid in place of the corresponding 9~-hvdroxy compound, to give 15-(4-chlorophenyl)-11~i,15-dihydroxy-9-oxo-16,17,18,19,20-pentanor-5-cis-prostenoic acid, RF = -4 (3% acetic acid in ethyl acetate). The mass spectrum of the bis-trimethylsilyl-9-methoxime methyl ester showed r~+ = 581.2745, calculated for C29H48ClN05Si2 = 581-2759 The bis-(tetrahydropyranyl)ether used as starting material may be obtained by oxidation of the corresponding 9a-hydroxy-bis-ether, described in the second part of Example 6, as follows:-To a solution of 15-(4-chlorophenyl)-9a-hydroxy-~ lla,15-bis-(tetrahydropyran-2-yloxy)-16,17,18,19,20-pentanor-5--cis-prostenoic acid (lOOmg.) in acetone (2 ml.) at -10C. was added Jones' reagent (0.06ml.). After 15 minutes, isopropanol (1 drop) was added, followed by ethyl acetate (lOml.). The solution was washed with 1:1 brine/water, and was dried. Evaporation of the solvents, and chromatography of the residue on silica, using 1:1 ether/petroleum ether (b,p. 40-60C,) as eluting solvent, gave the required 9-oxo-bis-ether starting material, RF =
0.2 (50% ethyl acetate in toluene). -~
Example 8 A solution of 15-(4-chlorophenyl)-lla~15-bis-~ ., . ~ .,, . . - .

(l-methoxy-l-methylethoxy)-9-oxo-16,17,18,19,20-pentanor-5-c ,13-trans-prostadienoic acid (50mg.) in 0.25ml. of pH 3 citric acid buffer and 0 75 ml. of acetone was stirred at room temperature for 18 hours The solvents were evaporated and the residue wàs extracted with ethyl acetate (3 x 2 mls~). The extracts were washed with a 1:1 mixture of saturated brine and water, and were then dried. After evaporation of theethyl acetate, the residue consisted of a mixture of the C-15 epimers of 15-(4-chlorophenyl)-11~,15-dihydroxy-9-oxo-16,17,18,19~20-pentanor-5-cis,13-trans-prostadienoic acid. Chromatography of this residue on CC4 Malinkrodt silica gel (2g.), and elution with ethyl acetate/cyclohexane gave the separated C-15 epimers of 15-(4-chlorophenyl)-11~,15-dihydroxy-9-~, oxo-16,17,18,19,20-penatnor-5-cis,13-trans-prostadienoic acid, RF = 0.2 and 0.3 (10% methanol in methylene chloride).
The n.m.r. spectrum of each epimer ~n deuterated acetone) showed the following characteristic bands (~ values):-7.25-7.45, 4 aromatic protons.
5.0-5.9, 8H, 4 olefinic protons, 3 exchangable protons and PhC_(OH).CH=CH-4 1, lH, 11~ proton.
The mass spectrum of the bis-trimethylsil~l-g-methoxime meth~l ester showed M =579.2603, calculated for C29H46ClN05Si2 = 579.2603. The 9-oxo-bis-ester used 3~
- ~6 -, , .

.

.- -.
-as starting material may be prepared as follows:-To a solution of 4~-[3-(4-chlorophenyl)-2,3,3a~, 6a~-tetrahydro-3-hydroxy-1-trans-propenyll-5~-hydroxy-2-oxocyclopenteno[b~furan (165mg.) in methylene chloride (5 ml.) under an atmosphere of nitrogen were added successively redistilled 2-methoxypropene (0.45 ml.) and a solution of anhydrous toluene-p-sulphonic acid in tetrahydrofuran (0.2ml. of a 1% solution). After 25 mins., pyridine (2 drops) was added, followed by ethyl acetate (30 ml.). The solution was washed successively with saturated sodium bicarbonate and saturated brine, and was dried Evaporation of the solvents gave a mixture of epimeric l-methoxy-l-methylethyl ethers, as a clear oil, RF = 3 and 0.4 (25% ethyl acetate in toluene).
To a solution of the epimeric ether (228mg.) in dry tGluene (lOml.) under an atmosphere of nitrogen at -78C., was added 0.4 ml. of a 1.96 m mole/ml. solution of di-isobutyl aluminium hydride in toluene. After 30 mins., the reaction was quenched by the dropwise addition of methanol(2 ml.), and after a further 15 minutes at room temperature, a mixture of 1:1 saturated brine/water (15 ml.) was added, and the mixture was extracted with ethylacetate (3 x 25 ml.). The extract was washed with saturated brine and dried, and the solvents were evaporated to give a mixture of epimers of the lactol, 4~-[3-(4-chlorophenyl)-3-~ 3~

., .

- . .. ~ -.. . ~ ....... ~ . . . . - .

~ ~ . .. . . ~ .

lO~Z002 (l-methoxy-l-methylethoxy)-l-trans-propenylJ-2,3,3aB,6a~-tetrahydro-2~-hydroxy-5~-~-methoxy-1-methylethoxy)-cyclopenteno[b~furan, RF = -3 (1:1 ethyl acetate/toluene).
A solution of the lactol (243mg.) in dimethyl sulphoxide (5 ml.) was added to a solution of sodium 5-triphenylpilophoranylidene va1era'e prepared from 1 mole of (4-carboxybutyl)triphenyl phosphonium bromide with 2 moles of methane sulphinyl methyl sodium in dimethyl sulphoxide. The solution was stirred for 1 hour, and the solvent was removed by evaporation under reduced pressure. The residue was shaken with water (5 ml.) and ether (3 ml.), the aqueous layer was separated and extracted with ether (4 x 3 ml.) and the extracts were discarded. The aqueous solution was acidified to pH 5.5 with oxalic acid and extracted with a mixture of equal parts of ether and petroleum ether (b.p. 40-60C.) (6 x 4 ml.). The combined extracts were washed with saturated brine and dried, and evaporation of the solvents gave 15-(4-chlorophenyl)-9~-hvdroxy-11~,15-bis-(1-methoxy-1-methylethoxy)-16,17,18,19,20-pentanor-5-cis,13-trans-prostadienoic acid. RF = 5 (20% methanol in methylene chloride).
A solution of this prostadienoic acid derivative (98mg.) in methylene chloride (1 ml.) was added to a stirred solution of chromium trioxide (145 mg.) in .., : , i ' ~:

10~2Q02 methylene chloride (3 ml.). After 15 minutes at room temperature the mixture was extracted with ether (2 x 10 ml.), and the extracts were washed with saturated brine and dried. Evaporation of the solvents give the required 5 9-oxo-bis-ether, RF ~ 0.6 (10% methanol in methylene chloride).
Example 9 % w/v 15-(4-trifluromethylphenyl)-9a,11a,15-trihydroxy-16,17,18,19,20-pentanor-5-cis,13-trans-prostadienoic acid 0.1 Sodium phosphate 2.9 Sodium hydrogen phosphate 0.3 Water for injection to 100 The sodium phosphate was dissolved in about 80% of the water, followed by the prostadienoic acid derivative, and, when dissolved, the sodium hydrogen phosphate. The solution was made up to volume with water for injection, and the pH was checked to be between 6,7 and 7,7. The solution was filtered to remove particulate matter, sterilised by filtration, and filled into presterilised neutral glass ampoules under aseptic conditions.
The prostadienoic acid derivative may, of course, be replaced by an equivalent amount of another prostanoic acid derivative of the invention.

..
~ . . , . ; . . . . .

.. . . - .. i . :
- . .. . . .
.

.. . . .. . .

Claims (14)

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 prostanoic acid derivative of the formula:- I

wherein R1 is a carboxy radical or an alkoxycarbonyl radical of up to 11 carbon atoms, A is an ethylene or trans-vinylene radical, and R4 is a phenyl, naphthyl, furyl or 2-thienyl radical which is unsubstituted, or which is substituted by one or two substituents selected from chlorine, fluorine, bromine and iodine atoms, and nitro, phenyl, chlorophenyl, methyl, ethyl, propyl, methoxy, ethoxy, methoxymethyl and trifluoromethyl radicals, R2 is a hydroxy radical and R3 is a hydrogen atom or R2 and R3 together form an oxo radical, which derivative optionally bears a 2-methyl substituent, and for those compounds wherein R1 is a carboxy radical the pharmaceutically-and veterinarily-acceptable salts thereof which comprises:-a) for those compounds wherein R is a carboxy radical, R2 is a hydroxy radical, R3 is a hydrogen atom, the reaction of a lactol of the formula:- II

wherein A and R4 have the meanings stated above, with a (4-carboxybutyl)triphenylphosphonium salt, optionally bearing a 2-methyl substituent, in the presence of a strong base, whereafter when a salt is required the product is reacted with a base; or b) for those compounds wherein R1 is an alkoxycarbonyl radical of up to 11 carbon atoms, the reaction of an acid of the formula:- III

wherein A, R2, R3 and R4 have the meanings stated above, with a diazoalkane of 1 to 10 carbon atoms; or c) for those compounds wherein R1 is an alkoxycarbonyl radical of up to 11 carbon atoms, the reaction of a salt of an acid of the formula III with an alkyl halide of 1 to 10 carbon atoms; or d) the reduction of a compound of the formula:- IV

wherein R1, R3 and R4 have the meanings stated above, and R6 and R7 are each a hydroxy radical or a protected hydroxy radical, and which optionally bears a 2-methyl substituent whereafter when R6 and R7 are each a protected hydroxy radical, the protecting groups are removed, and if a salt is required, a carboxylic acid so obtained is reacted with a base; or e) for those compounds wherein A is a trans-vinylene radical, the hydrolysis of a compound of the formula:- V

wherein R2, R3 and R4 have the meanings stated above, and R8 is an alkoxy-dialkylmethyl radical of 4 to 8 carbon atoms, whereafter if a salt is required the product is react-ed with a base; or f) for those compounds wherein A is an ethylene radical; the hydrolysis of a compound of the formula V wherein A, R2, R3 and R4 have the meanings stated above and R8 is the tetra-hydropyranyl radical, whereafter if a salt is required, the product is reacted with a base.

2. A process as claimed in claim 1c) wherein the salt of the acid of the formula III is the silver salt.

3. A process as claimed in claim 1c) wherein the alkyl halide is an alkyl iodide.

4. A process as claimed in claim 1d) wherein the reduction is effected by zinc borohydride, aluminium tri-isopropoxide or di-isobornyloxy aluminium isopropoxide.

5. A process as claimed in claim 1d) wherein in the starting material the protected hydroxy radical is an alkanoyloxy radical of up to 6 carbon atoms or an aroyloxy radical of up to 12 carbon atoms.

6. A process as claimed in claim 1e) wherein in the starting material the alkoxydialkylmethyl radical is a 1-methoxy-1-methylethyl radical.

7. A process ascclaimed in claim 1f) wherein the hydrolysis is effected with aqueous acetic acid or with an aqueous or alcoholic solution of an alkali metal carbonate.

8. A process as claimed in claim 7 which is carried out at a temperature between ambient temperature and about 60°C.

9. A process as claimed in claim 1, 2 or 3 wherein in the starting materials R1 is a carboxy or methoxycarbonyl radical, A is an ethylene or trans-vinylene radical, R2 is a hydroxy radical and R3 is a hydrogen atom or R2 and R3 together form an oxo radical, and R4 is a phenyl, 2-naphthyl, 2-furyl, 3-furyl, 2-thienyl, 4-fluorophenyl, 3- or 4-chlorophenyl, 3,4-dichlorophenyl, 4-nitrophenyl, 4-biphenylyl, 5-(4-chlorophenyl)-2-furyl, 4-tolyl, 4-methoxymethylphenyl or 3- or 4-trifluoromethyl radical, and wherein the starting material optionally bears a 2-methyl substituent.

10. A process as claimed in claim 4,5 or 6, wherein, in the starting materials, R1 is a carboxy or methoxycarbonyl radical, A is an ethylene or trans-vinylene radical, R2 is a hydroxy radical and R3 is a hydrogen atom or R2 and R3 together form an oxo radical, and R4 is a phenyl, 2-naphthyl, 2-furyl, 3-furyl, 2-thienyl, 4-fluorophenyl, 3- or 4-chlorophenyl, 3,4-dichlorophenyl, 4-nitrophenyl, 4-biphenylyl, 5-(4-chlorophenyl)-2-furyl, 4-tolyl, 4-methoxy-methylphenyl or 3- or 4-trifluoromethyl radical, and wherein the starting material optionally bears a 2-methyl substituent.

11. A process as claimed in claim 7 or 8 wherein in the starting materials, R1 is a carboxy or methoxycarbonyl radical, A is an ethylene or trans-vinylene radical, R2 is a hydroxy radical and R3 is a hydrogen atom or R2 and R3 together form an oxo radical, and R4 is a phenyl, 2-naphthyl, 2-furyl, 3-furyl, 2-thienyl, 4-fluorophenyl, 3- or 4-chlorophenyl, 3,4-dichlorophenyl, 4-nitrophenyl, 4-biphenylyl, 5-(4-chlorophenyl)-2-furyl, 4-tolyl, 4-methoxymethylphenyl or 3- or 4-trifluoromethyl radical, and wherein the starting material optionally bears a 2-methyl substituent.

12. A process for the manufacture of 9.alpha.,11.alpha.,15-trihydroxy-15-(4-tri-fluoromethylphenyl)-16,17,18,19,20-pentanor-5-cis,13-trans-prostadienoic acid which comprises reacting 2,3,3a.beta.,6a.beta.-tetrahydro-2,5.alpha.-dihydroxy-4.beta.-[3-hydroxy-3-(4-trifluoromethylphenyl)propenyl]cyclopenteno[b]furan with (4-carboxybutyl) triphenylphosphonium bromide in the presence of a strong base.

13. A prostanoic acid derivative, of the formula I wherein A,Rl, R2, R3 and R4 have the meanings stated in claim 1, and optionally bearing a 2-methyl substituent, whenever prepared by the process claimed in claim 1, or by an obvious chemical equivalent thereof.

14. 9.alpha.,11.alpha.,15-Trihydroxy-15-(4-trifluoromethylphenyl)-16,17,18,19,20-pentanor-5-cis,13-trans-prostadienoic acid, whenever prepared by the process claimed in claim 12, or by an obvious chemical equivalent thereof.