GB2045745A - Intermediates for prostaglandin analogues - Google Patents

Abstract

Compounds of the general formula:- <IMAGE> wherein Y represents <IMAGE> (in which R<4> represents H or a hydroxy- protecting group which is eliminated under basic conditions), Z represents <IMAGE> (in which R<5> represents H or a tetrahydropyran- 2-yl group), R<1> represents a formyl group, or a group of the formula -CH2OR<4>, R<2> represents a single bond, or a C1-5 alkylene group R<3> represents H, a C1-8 alkyl or C1-8 alkoxy group, or a C4-7 cycloakyl or C4-7 cycloalkyloxy group unsubstituted or substituted by at least one C1-8 alkyl group, or represents a phenyl or phenoxy group unsubstituted or substituted by at least one halogen atom, trifluoromethyl group or C1-4 alkyl group, with the proviso that, when R<2> represents a single bond, R<3> does not represent an alkoxy, cycloalkyloxy or phenoxy group, THP represents a tetrahydropyran-2-yl group, and the double bond between the carbon atoms in positions 13 and 14 is trans, with the provisos that, (i) when Z represents <IMAGE> (in which R<5> represents H), Y represents <IMAGE> (in which R<4> represents a hydroxy- protecting group) and R<1> represents a group of the formula -CH2OR<4> (in which R<4> represents a hydroxy-protecting group), and (ii) when Y represents <IMAGE> R<1> represents a formyl group, are useful as intermediates in the synthesis of therapeutically useful prostaglandin analogues.

Description

SPECIFICATION Intermediates for prostaglandin analogues This invention relates to new chemical compounds useful as intermediates for the preparation of trans-A2-prostaglandin E, analogues, to processes for their preparation and to their use in the preparation of trnnsA2-prnstaglandin E, analogues.

Prostaglandins are derivatives of prostanoic acid which has the following formula:

Various types of prostaglandins are known, the types depending inter alia on the structure and substituents on the alicyclic ring. For example, the alicyclic ring of prostaglandin E(PGE) has the structure:

The dotted lines in the foregoing formulae and in other formulae throughout this specification denote, in accordance with generally accepted rules of nomenclature, that the attached grouping lies behind the general plane of the ring system, i.e. that the grouping is in a-configuration, the thickened lines

denote that the grouping lies in front of the general plane of the system, i.e. that the grouping is in ss-configuration, and the wavy line

indicates that the grouping is in a- or P-configuration.

Such compounds are sub-classified according to the position of double bond(s) in the side chain(s) attached to the 8- and 1 2-positions of the alicyclic ring. Thus PG, compounds have a trans- double bond between C,3-C,4 (trans'3) and PG2 compounds have a cisclouble bond between C5-C6 and a transdouble bond between C,3-C,4 (risk5, transA13). For example, prostaglandin El (PGE1) is characterised by the following structure Ill.

The structure of PGE2, as a member of the PG2 group, corresponds to that of formula Ill with a cisdouble bond between the carbon atoms in positions 5 and 6. Compounds in which the double bond between the carbon atoms in positions 1 3 and 14 of members of the PG1 group is replaced by ethylene are known as dihydroprostaglandins, e.g. dihydro-prostaglandin E (dihydro-PGE1).

PGE compounds with a trnnsdouble bond between the carbon atoms in positions 2 and 3 are known as trans-A2-PGE compounds and the structure of transt2-PGE1 corresponds to that of formula Ill with a transdouble bond between the carbon atoms in positions 2 and 3.

Moreover, when one or more methylene groups are added to, or eliminated from, the co-chain, i.e. the aliphatic group attached to the 1 2-position of the alicyclic ring of the prostaglandins, and/or the a-chain, i.e. the aliphatic group attached to the 8-position of the alicyclic ring of the prostaglandins, the compounds are known, in accordance with the usual rules of organic nomenclature, as homo-prostaglandins (methylene group added) or nor-prostaglandins (methylene group eliminated), and, when more than one methylene group is added or eliminated, the number is indicated by di-, tri- etc. before the prefix "homo" or "nor Prostaglandins are generally known to possess pharmacological properties, for example they stimulate smooth muscle, have hypotensive, diuretic, bronchodilating and antilipolytic activities, and also inhibit blood platelet aggregation and gastric acid secretion, and are, accordingly, useful in the treatment of hypertension, thrombosis, asthma and gastro-intestinal ulcers, in the induction of labour and abortion in pregnant female mammals, in the prevention of arteriosclerosis, and as diuretic agents. They are fat-soluble substances obtainable in very small quantities from various tissues of animals which secrete the prostaglandins in the living body.

For example, PGE's have an inhibiting effect on gastric acid secretion and may, accordingly, be used in the treatment of gastric ulcers. They also inhibit the release of free fatty acid induced by epinephrine and as a result they reduce the concentration of free fatty acid in blood, and are, accordingly, useful in the prevention of arteriosclerosis and hyperlipemia. PGE, inhibits blood platelet aggregation and also removes the thrombus and prevents thrombosis. PGE's have a stimulating effect on smooth muscle and increase the intestinal peristalsis; these actions indicate therapeutic utility on post-operative ileus and as purgatives. PGE's may also be used as oxytocics, as abortifacients in the first and second trimesters; in the post-labour abortion of the placenta, and as oral contraceptives because they regulate the sexual cycle of female mammals.

PGE's have vasodilator and diuretic activities. They are useful for improvement in patients suffering from cerebral vascular disease because they increase the cerebral blood flow, and are also useful in the treatment of asthmatic conditions in patients because of their bronchodilating activity.

Two methods for introducing a trans- (or E)-double bond between the carbon atoms in positions 2 and 3 of prostaglandin compounds are known.

A first method is described in our British Patent Specification No. 1,416,410, published 3rd December 1 975. However, in order to form the double bond between the carbon atoms in positions 5 and 6 the method requires the use of a phosphorane compound (C6H5)3P = CH CH2COOH, the carboxy group (-COOH) of which is unconjugated. The resulting instability of the phosphorane compound makes it difficult to obtain high yields. In addition, in the series of reactions described to prepare the transt2-prostaglandins a selective hydrogenation is necessary if a trans-2-PGE, analogue is to be obtained. It is necessary to hydrogenate a double bond between carbon atoms in positions 5 and 6 whilst leaving a double bond between carbon atoms in positions 1 3 and 14 unaffected.There is a risk of hydrogenation of both double bonds leading to a lowering of the yield of the desired product. Finally, the co-chain is introduced at an early stage in the series of reactions leading to the desired trans-2-prnstaglandin, so that a large amount of expensive substrate required to introduce any desired co-chain is required.

The second method is described in our British Patent Specifications Nos. 1,483,240 and 1,540,427, published 17th August 1977 and 14th February 1979, respectively. The introduction of the double bond between the carbon atoms in positions 2 and 3 requires the use of selenium or sulphur compounds. Trace amounts of such compounds are harmful to human beings and if the final trans-A2-prostaglandin products are to be used as medicines the sulphur or selenium compounds must be removed. Such removal is difficult and requires considerable care. In addition, the selenium or sulphur compounds possess a very unpleasant smell which presents difficulties in their preparation and use.

As a result of research and experimentation there have been discovered new chemical compounds which are useful as intermediates in improved processes for the preparation of trans A2-PGE1 analogues.

The new chemical compounds of the present invention, useful for the preparation of trans prostaglandin E, analogues, are those compounds of the general formula:

wherein Y represents

(in which R4 represents a hydrogen atom, or a hydroxy-protecting group which is eliminated under basic conditions), Z represents

(in which R5 represents a hydrogen atom, or a tetrahydropyran-2-yl group), R' represents a formyl group, or a grouping of the formula -CH20R4 (in which R4 is as hereinbefore defined), R2 represents a single bond, or an alkylene group containing from 1 to 5 carbon atoms, R3 represents a hydrogen atom, an alkyl or alkoxy group containing from 1 to 8 carbon atoms, or a cycloalkyl or cycloalkyloxy group containing from 4 to 7 carbon atoms unsubstituted-6r substituted by at least one alkyl group containing from 1 to 8 carbon atoms, or represents a phenyl or phenoxy group unsubstituted or substituted by at least one halogen atom, trifluoromethyl group or alkyl group containing from 1 to 4 carbon atoms, with the proviso that when R2 represents a single bond, R3 does not represent an alkoxy, cycloalkyloxy or phenoxy group, THP represents a tetrahydropyran-2-yl group, and the double bond between the carbon atoms in positions 1 3 and 14 is trans, i.e.E, with the provisos that (i) when Z represents

(in which R5 represents a hydrogen atom), Y represents

(in which R4 represents a hydroxy-protecting group which is eliminated under basic conditions) and R' represents a grouping of the formula -CH20R4 (in which R4 represents a hydroxyprotecting group which is eliminated under basic conditions), and (ii) when Y represents

R' represents a formyl group.

It is to be understood that alkyl and alkylene groups and alkyl and alkylene moieties of groups referred to in this specification and the accompanying claims may be straight- or branchedchain.

The present invention is concerned with all compounds of general formula IV in the optically active "natural" form or its enantiomeric form, or mixtures thereof, more particularly the racemic form, consisting of equimolecular mixtures of the optically active "natural" form and its enantiomeric form.

As will be apparent to those skilled in the art, the compounds depicted in general formula IV have at least three centres of chirality at the C-8, C-il and C-12 carbon atoms. Still further centres of chirality may occur in branched-chain alkyl or alkylene groups, or when the symbol Y represents a group

R4 being as hereinbefore defined, or when the symbol Z represents a group

R5 being as hereinbefore defined. The presence of chirality leads, as is well known, to the existance of isomerism. However, the compounds of general formula IV all have such a configuration that the substituent groups attached to the cyclopentane ring carbon atoms in positions identified as 8 and 1 2 are trans with respect to each other.Accordingly, all isomers of general formula IV, and mixtures thereof, which have those substituent groups attached to the cyclopentane ring carbon atoms in positions 8 and 1 2 in the transconfiguration are to be considered within the scope of general formula IV.

Preferably the grouping -R2-R3 represents, for example methyl, ethyl, 1-methylethyl, propyl, 1-methylpropyl, 2-methylpropyl, 1-ethylpropyl, butyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1-ethylbutyl, 2-ethylbutyl, pentyl, 1 -methylpentyl, '2-methyl pentyl, 3-methylpentyl, 4-methylpentyl, 1 ,1 -dimethylpentyl, 1 ,2-dimethylpentyl, 1,4-dimethylpentyl, 1 -ethylpentyl, 2-ethylpentyl, 1-propylpentyl, 2-propylpentyl, hexyl, 1 -methylhexyl, 2-methylhexyl, 1 ,1 -dimethylhexyl, 1-ethylhexyl, 2-ethylhexyl, heptyl, 2-ethylheptyl, nonyl, undecyl, cyclobutyl, 1 -propylcyclobutyl, 1 butylcyclobutyl, 1-pentylcyclobutyl, 1-hexylcyclobutyl, 2-methylcyclobutyl, 2-propylcyclobutyl, 3- ethylcyclobutyl, 3-propylcyclobutyl, 2,3,4-triethylcyclobutyl, cyclopentyl, cyclopentylmethyl, 1cyclopentylethyl, 2-cyclopentylethyl, 2-cyclopentylpropyl, 3-cyclopentylpropyl, 2-pentylcyclopentyl, 2,2-dimethylcyclopentyl, 3-ethylcyclopentyl, 3-propylcyclopentyl, 3-butylcyclopentyl, 3-tertbutylcyclopentyl, (1 -methyl-3-propyl)cyclopentyl, (2-methyl-3-propyl)cyclopentyl, (2-methyl-4-p. j- pyl)cyclopentyl, cyclohexyl, cyclohexylmethyl, 1-cyclohexylethyl, 2-cyclohexylethyl, 3-cyclohexylpropyl, (1 -methyl-2-cyclohexyl)ethyl, 2-cyclohexylpropyl, (1-methyl- 1 -cyclohexyl)ethyl, 4-cyclohexylbutyl, 3-ethylcyclohexyl, 3-isopropylcyclohexyl, 4-methylcyclohexyl, 4-ethylcyclohexyl, 4propylcyclohexyl, 4-tertbutylcyclohexyl, 2,6-dimethylcyclohexyl, 2,2-dimethylcyclohexyl, (2,6dimethyl-4-propyl)cyclohexyl, 1 -methylcyclohexylmethyl, cycloheptyl, cycloheptylmethyl, 1-cyclo- heptylethyl, 2-cycloheptylethyl, phenyl, benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 4phenylbutyl, 5-phenylpentyl, (1 -methyl-2-phenyl)ethyl, (1 , 1 -di methyl-2-phenyl)ethyl, (1-methyl 1-phenyl)ethyl, 1-phenylpentyl, phenoxymethyl, 2-phenoxyethyl, 3-phenoxypropyl 4-phenoxybutyl, 5-phenoxypentyl, 3-chlorophenoxymethyl, 4-chlorophenoxymethyl, 4-fluorophenoxymethyl, 3-trifluoromethylphenoxymethyl, 2-methyiphenoxymethyl, 3-methylphenoxymethyl, 4-methylphenoxymethyl, 4-ethylphenoxymethyl, 4-tert-butylphenoxymethyl, 4-sec-butylphenoxymethyi, propoxymethyl, isopropoxymethyl, butoxymethyl, pentyloxymethyl, hexyloxymethyl, 1-ethoxye- thyl, 1-propoxyethyl, 1-isopropoxyethyl, 1 -neopentyloxyethyl, 1-pentyloxyethyl, (1 -methyl-1 - ethoxy)-ethyl, (1 -methyl-1 -propoxy)ethyl, (1 -methyl-1 -isobutoxy)-ethyl, (1 -methyl-1 -neopentyloxy) ethyl, (1 -methyl-1 -butoxy)ethyl, (1 -methyl-1 -isopentyloxy)ethyl, (1 -methyl-1 -pentyloxy)ethyl, 2ethoxyethyl, 2-propoxyethyl, 2-butoxyethyl, 2-(1 -ethylbutoxy)ethyl, 2-pentyloxyethyl, 1-ethoxy- propyl, 1 -propoxypropyl, 1-(2-methylbutoxy)propyl, 1-pentyloxypropyl, 2-methoxypropyl, 3-methoxypropyl, 3-ethoxypropyl, 3-propoxypropyl, 3-sec-butoxypropyl, 3-isobutoxypropyl, 3-butoxypropyl, (1 -methyl-2-methoxy)ethyl, (1-methyl-2-ethoxy)ethyl, (1 -methyl-2-isobutoxy)ethyI, 1-pen- tyloxybutyl, (1 -pentyloxy-2-methyl)propyl, 4-methoxybutyl, 4-ethoxybutyl, 4-propoxybutyl, (1methyl-3-methoxy)propyl, (1 -methyl-3-propoxy)propyl, (2-methyl-3-methoxy)propyl, (1 ,1-dime- thyl-2-ethoxy)ethyl, (1,1 -dimethyl-2-propoxy)ethyl, (1,1 -dimethyl-2-isobutoxy)ethyl, 5-methoxypentyl, 5-ethoxypentyl, 1-pentyloxypentyl, (1 -ethyl-3-propoxy)propyl, cyclobutyloxymethyl, cyclopentyloxymethyl, cyclohexyloxymethyl, cycloheptyloxymethyl, 2-cyclopentyloxyethyl or 2-cyclohexyloxyethyl. 1 , 1 -Dimethylpentyl is particularly preferred.

The hydroxy-protecting groups which are eliminated under basic conditions represented by R4 as used in this specification and the accompanying claims are groups which have no influence on other parts of the compounds during elimination of the protecting group, and which are easily eliminated under mild basic conditions. Preferably, the hydroxy-protecting group is, for example, an acyl group such as acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, propionyl, benzoyl, pphenylbenzoyl, or naphthyloyl; acetyl is particularly preferred.

According to a feature of the present invention, the compounds of general formula IV, wherein R1 represents a grouping -CH20R4, Y represents

Z represents

R4 represents a hydroxy-protecting group which is eliminated under basic conditions, and the

~ ed, i.e. compounds of the general formula: IVA otecting group which is eliminated under basic conditions, and the other symbols are as nereinbefore defined), are prepared by the Wittig reaction of a compound of the general formula:

(wherein the various symbols are as hereinbefore defined) with a sodium derivative of a dialkyl phosphonate of the general formula:

(wherein R6 represents an alkyl group containing from 1 to 4 carbon atoms, preferably methyl or ethyl, and the other symbols are as hereinbefore defined), or with a phosphorane compound of the general formula::

(wherein R7 represents a phenyl group unsubstituted or substituted by at least one alkyl group containing from 1 to 4 carbon atoms, preferably phenyl, or represents an alkyl group containing from 1 to 6 carbon atoms, preferably butyl or hexyl or represents a cyclohexyl group, and the other symbols are as hereinbefore defined). The sodium derivative of the dialkyl phosphonate of general formula VI may be prepared by the reaction of the dialkyl phosphonate and sodium hydride.

The Wittig reaction is described in "Organic Reactions", Volume 14, Chapter 3(1965), John Wiley 8 Sons, Inc. (USA). The reaction may be effected in an inert organic solvent, e.g. an ether such as diethyl ether, tetrahydrofuran, dioxan or 1 ,2-dimethoxyethane, a hydrocarbon such as benzene, toluene, xylene or hexane, a dialkyl sulphoxide such as dimethyl sulphoxide, a dialkylformamide such as N,N < Iimethylformamide, a halogenated hydrocarbon such as methylene chloride or chloroform, or an alkanol containing from 1 to 4 carbon atoms such as methanol or ethanol, or a mixture of two or more of them, at a temperatuer from - 78"C to the reflux temperature of the reaction mixture.

Dialkyl phosphonates of general formula VI and phosphorane compounds of general formula VII are well known, or may easily be prepared by methods known per se. By the term "methods known per se" as used in this specification is meant methods heretofore used or described in the chemical literature.

The compounds of general formula IV, wherein R1 represents a grouping -CH2OR4, Y represents

Z represents

R4 represents a hydroxy-protecting group which is eliminated under basic conditions. R5 represents a hydrogen atom, and the other symbols are as hereinbefore defined, i.e. compounds of the general formula:

(wherein the various symbols are as herein before defined) are prepared by reduction of compounds of general formula IVA to convert the 15-oxo group to a 15-hydroxy group.

The reduction to convert the oxo group to a hydroxy group may be carried out by using any suitable reducing reagent such as sodium borohydride, potassium borohydride, lithium borohydride, zinc borohydride, lithium tri-tertbutoxyaluminium hydride, lithium trimethoxyaluminium hydride, sodium cyanoborohydride, potassium tri-sec-butylborohydride, lithium aluminium hydride-quinine complex, (-- )-isobornyloxymagnesium iodide in an inert organic solvent, e.g. an alkanol containing from 1 to 4 carbon atoms such as methanol, ethanol or isopropanol, or an ether such as tetrahydrofuran, dioxan or 1 ,2-dimethoxyethane, or a mixture of two or more of them, at a temperature from - 78"C to ambient.Preferably, the reduction is effected using diisobornyloxyaluminiumisopropoxide (described in our Japanese Patent Kokai No. 54-76552), or a diisobutyl(alkyl-substituted or unsubstituted) phenoxyaluminium [described in our Japanese Patent Kokai No. 54-154739 and J. Org. Chem., 44, 1363(1979)], or a lithium 1,1'binaphthyl-2,2'-dioxyaluminium hydride [described in J. Amer. Chem. Soc., 101, 5843(1979 The product thus obtained is a mixture of isomers in which the 15-hydroxy group is in a- or ss- configuration and the mixture is separated by conventional means, for example, by thin layer, column or high-speed liquid chromatography on silica gel to give the desired isomer of general formula IVB.

The compounds of general formula IV, wherein R' represents a grouping -CH20R4, Y represents

Z represents

R4 represents a hydroxyprotecting group eliminated under basic conditions, R5 represents a tetrahydropyran-2-yl group, and the other symbols are as hereinbefore defined, i.e. compounds of the general formula:

(wherein the various symbols are as hereinbefore defined), are prepared by etherification of the 1 5-hydroxy group of a compound of general formula IVB with 2,3-dihydropyran in an inert organic solvent, e.g. methylene chloride or tetrahydrofuran, in the presence of an acidic catalyst, e.g. p-toluenesulphonic acid, sulphuric acid, trifluoroborane-etherate or phosphorus oxychloride, at or below ambient temperature.

The compounds of general formula IV, wherein R represents a grouping -CH2OR4, Y represents

Z represents

R4 represents a hydrogen atom, R5 represents a tetrahydropyran-2-yl group, and the other symbols are as hereinbefore defined, i.e. compounds of the general formula:

(wherein the various symbols are as herein before defined), are prepared by saponification of compounds of general formula IVC to convert the groups OR4a to hydroxy groups. The saponification may be effected by using an aqueous solution of an alkali metal, e.g. sodium, potassium or lithium, hydroxide, carbonate or bicarbonate, or of an alkaline earth metal, e.g.

calcium or barium, hydroxide or carbonate in the absence or presence of a water-miscible solvent, e.g. an ether such as tetrahydrofuran, dioxan or 1 ,2-dimethoxyethane, or an alkanol containing from 1 to 4 carbon atoms such as methanol or ethanol, at a temperature from - 0 C to the reflux temperature of the reaction mixture, preferably at a temperature from ambient to 50"C or by using an anhydrous solution of an alkali metal, e.g. sodium, potassium or lithium, hydroxide or carbonate in an anhydrous alkanol containing from 1 to 4 carbon atoms, e.g. absolute methanol or ethanol, at a temperature from - 1 0 C to the reflux temperature of the reaction mixture, preferably at a temperature from ambient to 50"C.

The compounds of general formula IV, wherein R1 represents a formyl group, Y represents

Z represents

in which R5 represents a tetrahydropyran-2-yl group, and the other symbols are as hereinbefore defined, i.e. compounds of the general formula:

IVE (wherein the various symbols are as herein before defined), are prepared from compounds of general formula IVD by oxidation to convert the 9-hydroxy group to a 9-oxo group and simultaneously to convert the hydroxymethyl group to a formyl group.

The oxidation is carried out by methods known per se for the conversion of a hydroxy group to an oxo group, for example by methods described in (1) Tetsuji Kameya, "Synthetic Organic Chemistry Ill, Organic Synthesis 1", pp 176-206 (1976), Nankodo (Japan), or in (2) "Compendium of Organic Synthetic Methods", Volume 1 (1971), 2 (1974) and 3 (1977), Section 48, John Wiley 8 Sons, Inc. (USA). Preferably the oxidation is carried out under mild and neutral conditions, for example, with dimethyl sulphide-N-chlorosuccinimide complex, thioanisole-Nchlornsuccinimide complex, dimethyl sulphide-chlorine complex or thioanisolechlorine complex [cf. J. Amer. Chem. Soc., 94, 7586 (1 972)], dicyclohexylcarbodiimidedimethyl sulphoxide complex [cf. J. Amer. Chem.Soc., 87,5661(1965)], pyridinium chlorochromate (C5H5NHCrO3CI) [cf. Tetrahedron Letters, 2647 (1 975)], sulphur trioxidepyridine complex [cf. J. Amer. Chem. Soc., 89, 5505 (1 967)], chromyl chloride [cf. J. Amer.

Chem. Soc., 97, 5929 (1975)], chromium trioxide-pyridine complex (e.g. Collins' reagent) or Jones' reagent.

The oxidation using dimethyl sulphide-N-chlorosuccinimide complex, thioanisole-N-chlorosuc- cinimide complex, dimethyl sulphide-chlorine complex or thioanisole-chlorine complex may be effected by reaction in a halogenated hydrocarbon such as chloroform, methylene chloride or carbon tetrachloride, or toluene at - 30" to O"C, and then treatment with triethylamine. The oxidation using the dicyclohexylcarbodiimide-dimethyl sulphoxide complex is normally effected by reaction in excess dimethyl sulphoxide in the presence of an acid, e.g. phosphoric acid, phosphorous acid, cyanoacetic acid, pyridine-phosphoric acid salt or trifluoroacetic acid, as catalyst.The oxidation using pyridinium chlorochromate may be effected by reaction in a halogenated hydrocarbon such as chloroform, methylene chloride or carbon tetrachloride in the presence of sodium acetate, normally at ambient temperature. The oxidation using the sulphur trioxide-pyridine complex is normally effected by reaction in dimethyl sulphoxide in the presence of triethylamine at ambient temperature. The oxidation using chromyl chloride is normally effected by reaction in a halogenated hydrocarbon such as chloroform, methylene chloride or carbon tetrachloride in the presence of tertbutanol and pyridine at a temperature from - 30"C to the reflux temperature of the reaction mixture.The oxidation using the chromium trioxidepyridine complex may be effected by reaction in a halogenated hydrocarbon such as chloroform, methylene chloride or carbon tetrachloride at a temperature from O"C to ambient, preferably at 0 C. The oxidation using Jones' reagent is normally effected with acetone and dilute sulphuric acid at a temperature from 0 C to ambient.

Compounds of general formula V may be prepared by the series of reactions depicted schematically below in Scheme A, wherein R8 represents a benzyl group, or a hydroxy-protecting group which is eliminated more easily than a tetrahydropyran-2-yl group under acidic conditions, the double bond is Eor Z or a mixture thereof, i.e. EZ, and the other symbols are as herein before defined. The (1 -methoxy- 1 -methyl)ethyl, 1 -methoxycyclohexyl, 1-methoxy-1-phenyl- ethyl, 1-ethoxyethyl, tetrahydrofuran-2-yl and trimethylsilyl groups are suitable hydroxy-protecting groups removed more easily than the tetrahydropyran-2-yl group.

SCHEME A

Referring to Scheme A, the conversion [a] may be carried out by using an ylide of a phosphonium compound of the general formula: 0 (R7)3 PCH2CH2CH20HX XII (wherein X represents a halogen atom, and R7 is as hereinbefore defined) by means heretofore mentioned for the conversion of compounds of general formula V to those of general formula IVA.

The ylide of a phosphonium compound of general formula XII may be prepared by reaction of a phosphonium compound of general formula XII with an appropriate base, e.g. butyllithium, or a lithium compound of the general formula:

(wherein R9 and R'O, which may be the same or different, each represent an alkyl group containing from 1 to 6 carbon atoms, or a cycloalkyl group containing from 3 to 6 carbon atoms), e.g. lithium diisopropylamide, in an inert organic solvent, at a temperature from - 78"C to ambient, for example a solvent hereinbefore described as suitable for the Wittig reaction of a compound of general formula V.

Phosphonium compounds of general formula XII are well known, or may easily be prepared by methods known per se.

The conversion [b] may be carried out, for example when R4a represents an acyl group, by using an acyl chloride R4aCI, R4" being as hereinbefore defined, or an acid anhydride (R4a)20, R4a being as hereinbefore defined, in an inert organic solvent, e.g. methylene chloride or pyridine, in the presence of a tertiary amine, e.g. pyridine or triethylamine, at a temperature below ambient, preferably at a temperature below 0 C.

In the conversion [c], when R8 represents a benzyl group, compounds of general formula XI may be prepared by reduction of compounds of general formula X to convert simultaneously the vinylene and benzyloxy groups to ethylene and hydroxy groups, respectively.

The reduction may be suitably carried out under an atmosphere of hydrogen in the presence of a hydrogenation catalyst, e.g. palladium on carbon, palladium black, platinum dioxide, or Raney Nickel, in an inert organic solvent, e.g. an alkanol containing from 1 to 4 carbon atoms such as methanol or ethanol, or ethyl acetate, or a mixture of two or more of them, at a temperature from ambient to the reflux temperature of the reaction mixture at normal or elevated pressure, e.g. at a hydrogen pressure from atmospheric to 1 5 kg/cm2.

When RB is other than a benzyl group, compounds of general formula X may be converted to compounds of the general formula:

(wherein the various symbols are as hereinbefore defined) by mild hydrolysis under acidic conditions avoiding the risk of elimination of the tetrahydropyran-2-yl group, followed by hydrogenation of the compound of general formula XIV obtained by means heretofore mentioned for the conversion of compounds of general formula X wherein R8 represents a benzyl group to those of general formula Xl, to convert the vinylene group in formula XIV to an ethylene group.

The mild hydrolysis under acidic conditions may be effected (1) with an aqueous solution of an organic acid, e.g. acetic acid, propionic acid, oxalic acid or p-toluenesulphonic acid, or an inorganic acid, e.g. hydrochloric acid, sulphuric acid or phosphoric acid, advantageously in the presence of a water-miscible organic solvent, e.g. an alkanol containing from 1 to 4 carbon atoms such as methanol or ethanol, preferably methanol, or an ether such as 1,2-dimethoxyethane, dioxan or tetrahydrofuran, preferably tetrahydrofuran, at or below ambient temperature, preferably at 0 C, or (2) with an an hydros solution of an organic acid such as ptoluenesul- phonic acid or trifluoroacetic acid in an anhydrous alkanol containing from 1 to 4 carbon atoms such as absolute methanol or ethanol, at or below 0 C.

The conversion [d] may be carried out by means heretofore mentioned for the conversion of compounds of general formula IVD to those of general formula IVE.

The starting material of general formula VEIL, wherein R8 represents a benzyl group, is a known compound described in J. Org. Chem., 37, 2921 (1972). The starting materials of general formula VIII, wherein R8 is other than a benzyl group, are prepared as described in our Japanese Patent Kokai No. 53-149954.

According to a further feature of the present invention, the compounds of general formula IV, wherein R' represents a formyl group, Y represents

Z represents

R5 represents a tetrahydropyran-2-yl group, and the other symbols are as hereinbefore defined, i.e. compounds of general formula IVE are converted to compounds of the general formula:

(wherein R11 represents an alkyl group containing from 1 to 4 carbon atoms, the double bonds between the carbon atoms in positions 2 and 3, and positions 1 3 and 14, are trans (i.e.E), and the other symbols are as hereinbefore defined) by the Wittig reaction with a phosphorane compound of the general formula: (R7)3P = CHCOOR" XVI (wherein R7 and R" are as hereinbefore defined) by means heretofore mentioned for the conversion of compounds of general formula V to those of general formula IVA.

Phosphorane compounds of general formula XVI are well known, or may easily be prepared by methods known per se.

Compounds of general formula XV are converted to transt2-prostaglandin E1 analogues of the general formula:

(wherein the various symbols are as hereinbefore defined) by hydrolysis under acidic conditions to convert the tetrahydropyran-2-yloxy groups to hydroxy groups.

The hydrolysis to convert the tetrahydropyran-2-yloxy groups into hydroxy groups under acidic conditions is well known. The hydrolysis may be carried out for example with (1) an aqueous solution of an organic acid such as acetic acid, propionic acid, oxalic acid, ptoluenesulphonic acid, or of an inorganic acid such as hydrochloric acid, sulphuric acid, phosphoric acid, advantageously in the presence of an inert organic solvent miscible with water, e.g. a lower alkanol such as methanol or ethanol, preferably methanol, or an ether such as 1,2dimethoxyethane, dioxan, tetrahydrofuran, preferably tetrahydrofuran, at a temperature from ambient to 75"C, or (2) an anhydrous solution of an organic acid such as p-toluenesulphonic acid or trifluoroacetic acid in a lower alkanol such as methanol or ethanol at a temperature from 0" to 45"C, or (3) an anhydrous solution of p4oluenesulphonic acid-pyridine complex or trifluoroacetic acidpyridine complex in a lower alkanol such as methanol or ethanol at a temperature from 10 to 60"C. Advantageously the mild hydrolysis under acidic conditions may be carried out with a mixture of dilute hydrochloric acid and tetrahydrofuran, a mixture of dilute hydrochloric acid and methanol, a mixture of acetic acid, water and tetrahydrofuran, a mixture of phosphoric acid, water and tetrahydrofuran, a mixture of p-toluenesulphonic acid and methanol, a mixture of ptoluenesulphonic acid-pyridine complex and methanol or a mixture of trifluoroacetic acid-pyridine complex and methanol.

The transt2-prostaglandin E1 analogues of general formula XVII, thus obtained, are useful in human or veterinary medicines as described in our British Patent Specification Nos. 1,416,410, 1,483,240 and 1,540,427. They possess the valuable pharmacological properties typical of prostaglandins in a selective fashion including, in particular, hypotensive activity, inhibitory activity on blood platelet aggregation, inhibitory activity on gastric acid secretion and gastric ulceration and bronchodilator activity and are useful in the treatment of hypertension, in the treatment of disorders of the peripheral circulation, in the prevention and treatment of cerebral thrombosis and myocardial infarction, in the treatment of gastric ulceration and in the treatment of asthma.The trans-A2-prostaglandin E1 analogue of general formula XVII, wherein the group -R2-R3 represents a 1,1-dimethylpentyl group and R11 represents a methyl group, i.e. (2E,13E) (11 a, 1 5R)-9-oxo-1 1,1 5-dihydroxy-l 6, 1 6-dimethylprosta-2, 1 3-dienoic acid methyl ester which is described and claimed in British Patent Specification No. 1,540,427 is useful in the termination of pregnancy and induction of labour in pregnant female mammals and in the control of oestrus, contraception and menstrual regulation in female mammals.

It will be appreciated, therefore, that the new compounds of the present invention of general formula IV, i.e. compounds of general formula IVA, IVB, IVC, IVD and IVE, are useful and important intermediates for the preparation of therapeutically useful transt2-prostaglandin E analogues.

In addition, the new compounds of general formula V, IX, X, XI and XIV, i.e. compounds of the general formula:

[wherein X represents an ethylene or vinylene group, R12 represents a hydrogen atom, or a hydroxy-protecting group which is eliminated under basic conditions, R13 represents a formyl group, a hydroxymethyl group (-CH2OH), or a group -CH20R8, in which R8 is as hereinbefore defined, and the other symbols are as hereinbefore defined, with the provisos that (i) when R13 represents a formyl group, X represents an ethylene group and R12 represents a hydroxyprotecting group which is eliminated under basic conditions, (ii) when R'3 represents a hydroxymethyl group, R12 represents a hydroxy-protecting group which is eliminated under basic conditions and (iii) when R'3 represents a group -CH20R8, X represents a vinylene group] are also useful and important intermediates for the preparation of trans2-prnstaglandin E1 analogues. When X represents a vinylene group the double bond may be E, Zor a mixture thereof.

The use of the compounds of general formulae IV and XVIII allows the synthesis of transd2- prostaglandin E1 analogues by the methods hereinbefore described which avoid certain disadvantages of the two known methods heretofore mentioned. Use of the phosphonium compounds of general formula XII avoids the need to use the unstable phosphorane compound required in the method described in British Specification No. 1,416,410 (the compounds of formula XII have the group -CH2OH in place of the unconjugated carboxy group and are therefore more stable, leading to higher yields); a selective hydrogenation, which carries a risk of a reduced yield of the desired product is not required; and the co-chain is introduced at a relatively late stage in the method.Furthermore the use of selenium or sulphur compounds, and the necessary careful purification steps to remove traces of such compounds in the final prostaglandin products, are not required.

The following Examples illustrate the present invention. In the Examples "TLC", "IR" and "NMR" represent respectively "Thin layer chromatography", "Infrared absorption spectrum", and "Nuclear magnetic resonance spectrum". Where solvent ratios are specified in chromatographic separations, the ratios are by volume: the solvents in parentheses show the developing solvents used. Except when specified otherwise, infrared spectra are recorded by the liquid film method, and nuclear magnetic resonance spectra are recorded in deuterochloroform (CDCl3) solution.

EXAMPLE 1 (EZ)-2a-(5-Hydroxypent-2-enyl)-3fi-( 1 -methoxy- 1-methyl)-ethoxymethyl-4a-(tetrahydropyran-2-yl- oxylcyclopentan-l 1a-ol Under an atmosphere of nitrogen, 29.1 ml of a 1 .5M solution of butyllithium in hexane were added to a suspension of 8.748 g of 3-hydroxypropyltriphenylphosphonium bromide in 70 ml of tetrahydrofuran, and the mixture was stirred at room temperature for 10 minutes to give an ylide solution.To the ylide solution, thus obtained, was added a solution of 3 g of 2-oxa-6-syn (1 -methoxy- 1 -methyl)ethoxymethyl-7-anti-(tetrahyd ropyran-2-yloxy)- cis-bicycloC3 .3 .O]octan-3-ol (prepared as described in Reference Example 2 of our Japanese Patent Kokai No. 53-149954) in 10 ml of tetrahydrofuran, and the mixture was stirred at room temperature for one hour, and then at 40"C for 30 minutes. The reaction mixture was poured into a saturated aqueous solution of ammonium chloride, and the mixture extracted with ethyl acetate. The extract was washed with water and a saturated aqueous solution of sodium chloride, dried over magnesium sulphate, and concentrated under reduced pressure to give the crude title compound having the following physical characteristic. The crude product was used in the next step without purification.

TLC (ethyl acetate:cyclohexane = 2:1): Rf = 0.23.

(a) Using the procedure described above, but replacing the 2-oxa-6-syn41-methoxy-1- methyl)ethoxymethyl-7-anti(tetrnhydropyran-2-yloxy)- cisicyclo[3 .3. û]octan-3-ol by 2-oxa-6-syn benzyloxymethyl-7-anfiXtetrahydropyran-2-yloxy)-ciSbicyclo[3.3.0]octan-3-ol [prepared as described in J. Org. Chem., 37,2921(1972)], there was obtained (EZ)-2a-(5-hydroxypent-2-enyl)- 3ss-benzyloxymethyl-4a-(tetrahyd ropyran-2-yloxy)cyclopentan- 1 a-ol having the following physical characteristic: TLC (ethyl acetate:cyclohexane = 2:1 ):Rf = 0.25.

EXAMPLE2 ( EZ)- 1 a-Acetoxy-2a-(5-acetoxypent-2-enyl)-3ss-(1 -methoxy- 1 -methyl)ethoxymethyl-4a-(tetrahydropyran-2-yloxy)cyclopentane The crude product, prepared as described in Example 1, was stirred overnight with 14 ml of acetic anhydride and 33 ml of pyridine at room temperature. The reaction mixture was diluted with ethyl acetate, washed with 0.5N hydrochloric acid, water and a saturated aqueous solution of sodium chloride, dried over magnesium sulphate, and concentrated under reduced pressure to give the crude title compound having the following physical characteristic. The crude product was used in the next step without purification.

TLC (ethyl acetate:cyclohexane = 2:1): Rf = 0.79.

(a) Following the procedure described above, but replacing the crude product of Example 1 used as starting material by the crude product of Example 1(a), the following compound was prepared. The product was purified by column chromatography on silica gel using a mixture of ethyl acetate and cyclohexane (1:2) as eluent to give in 73% yield based on the starting material of Example 1(a): (E2)-1 a-acetoxy-2a-(5-acetoxypent-2-enyl)-3, & benzyloxymethyl-4a-(tet- rahydropyran-2-yloxy)cyclopentane: TLC (cyclohexane:ethyl acetate = 2:1): Rf= 0.82; IR:v= 1740, 1243, 1021 cm-'; NMR (CCI4 solution): S = 7.12 (5H, m), 5.40 (2H, m), 5.00 (1H, m), 4.61 (1H, m), 4.36 (2H, s), 3.97 (2H, t), 3.40 (2H, d), 4.20-3.20 (3H, m), 2.00 (6H, s).

EXAMPLE 3 (EZ)- 1 el -Acetoxy-2a-(5-acetoxypent-2-enylJ-3ss-hydroxymethyl-4a-(tetrahydropyran-2-yloxy-cyclo- pentane The crude product, prepared as described in Example 2, was stirred with 40 ml of tetrahydrofuran and 1 5 ml of 1 N hydrochloric acid at 0 C for 30 minutes. The reaction mixture was neutralised with a saturated aqueous solution of sodium bicarbonate, washed with water and a saturated aqueous solution of sodium chloride, dried over magnesium sulphate, and concentrated under reduced pressure.The residue was purified by column chromatography on silica gel using diethyl ether as eluent to give 2.30 g of the title compund having the following physical charateristics: TLC (ethyl acetate:cyclohexane = 2:1): Rf = 0.42; IR: y= 3460, 1737, 1243, 1023 cm-'; NMR (CCI4 solution): 8 = 5.35 (2H, m), 4.97 (1 H, m), 4.56 (1 H, m), 3.95 (2H, t), 4.20-3.16 (5H, m), 1.97 (6H, s).

EXAMPLE 4 1 aS-Acetoxy-2a-(5-acetoxypentyl)-3yB-hydroxymethyl-4aS-(tetrahydropyran-2-yloxy)cyclopentane Under an atmosphere of hydrogen, a mixture of 10.402 g of the pentenyl compound prepared as described in Example 3, 120 ml of methanol and 100 mg of platinum dioxide was stirred at room temperature for 3 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give 10.264 g of the title compound having the following physical characteristics: TLC (ethyl acetate:benzene = 2:1, utilising a silica gel plate pre-treated with silver nitrate): Rf= 0.47; IR:v=3460, 1740,1247,1020cm-1; NMR (CCI4 solution): S = 4.96 (1 H, m), 4.52 (1 H, m), 3.93 (2H, t), 4.20-3.15 (5H, m), 1.97 (6H, s).

EXAMPLE 5 1 aA cetoxy-2a-(5-acetoxypen tyi)-3fi-form y!-4a-(tetrahydropyra n-2-y!oxy)cyclopen tane To a suspension of 5.79 9 of N-chlorosuccinimide in 300 ml of toluene were added 3.94 ml of dimethyl sulphide at 0 C, and the mixture was stirred at that temperature for 40 minutes. To the solution obtained was added a solution of 11.1 9 of the hydroxymethyl compound, prepared as described in Example 4, in 20 ml of toluene at - 20"C. The mixture was stirred at the same temperature for one hour, and then stirred with 1 2. 1 ml of triethylamine at - 20"C for 30 minutes.The reaction mixture was neutralised with 0.1 N hydrochloric acid, diluted with diethyl ether, washed with 0.1 N hydrochloric acid, a saturated aqueous solution of sodium bicarbonate, water and a saturated aqueous solution of sodium chloride, dried over magnesium sulphate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of ethyl acetate and cyclohexane (1:1) as eluent to give 10.327 g of the title compound having the following physical characteristics: TLC (ethyl acetate:benzene = 2:1): Rf = 0.74; IR: z'= 1740, 1377, 1247, 1025 cm-'; NMR: 8= 9.65 (1H, t), 5.30-4.85 (1H, m), 4.8-3.1 (6H, m).

EXAMPLE 6 1&alpha;-Acetoxy-2&alpha;-(5-acetoxypentyl)-3ss-hydroxymethyl-4&alpha;-(tetrahydropyran-2-yloxy)cyclopentane Under an atmosphere of hydrogen, a mixture of 4.74 g of the benzyloxymethyl compound, prepared as described in Example 2(a). 100 ml of ethanol and 20 g of Raney nickel (W-7) was heated under reflux for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give 3.48 g of the title compound having the same physical characteristics as the product of Example 4.

EXAMPLE 7 (E)- 1 a-Acetoxy-2a-(5-acetoxypentyl)-3ss-(3-oxo-4, 4-dimethyloct- 1-enylJ-40r-(tetrahydropyran-2-yl- oxy)cyclopentane Under an atmosphere of nitrogen, a solution of 11.154-9 of dimethyl 2-oxo-3,3-dimethylheptylphosphonate in 50 ml of tetrahydrofuran was added dropwise to a suspension of 1.317 g of sodium hydride (content 63.5%) in 250 ml of tetrahydrofuran at room temperature, and the mixture was stirred at ambient temperature for 30 minutes. To the solution, thus obtained, was added a solution of 10.987 g of the formyl compound, prepared as described in Example 5 in 100 ml of tetrahydrofuran, and the mixture was stirred at room temperature for 2.5 hours. The reaction mixture was acidified with acetic acid, filtered, and the filtrate was concentrated under reduced pressure.The residue was purified by column chromatography on silica gel using a mixture of cyclohexane and ethyl acetate (3:1) as eluent to give 12.3 9 of the title compound having the following physical characteristics: TLC (cyclohexane:ethyl acetate = 1:1): Rf = 0.70; IR: p = 1740, 1695, 1625, 1246, 1025cm-1; NMR: 8 = 7.10.6.30 (2H, m), 5.40-5.00 (1H, m), 4.80-4.35 (1H, m), 4.35-3.10 (5H, m).

EXAMPLE 8 (E)- 1 1&alpha;-Acetoxy-2&alpha;-(5-acetoxypentyl)-3ss-(3R-hydroxy-4,4-dimethyloct- 1-enyl)-4a-(tetrahydropyran- 2-yloxy)cyclopentane Under an atmosphere of nitrogen, 100 ml of a 25% (w/v) solution of diisobutylaluminium hydride in toluene were added dropwise to a solution of 1.8 g of 2,6-di-tertbutyl-4- methylphenol in 660 ml of toluene at 0 to 5"C, and the mixture was stirred at the same temperature for one hour. To the solution was added a solution of 8.64 9 of the 3-oxo compound, prepared as described in Example7, in 60 ml of toluene at - 78"C, and the mixture was stirred at - 30" to - 20"C for 3 hours.The reaction mixture was stirred with 80 ml of water at 40"C for 30 minutes, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of methylene chloride and ethyl acetate (4:1) as eluent to give 7.5 9 of the title compound having the following physical characteristics: TLC (benzene:acetate = 3:1): Rf = 0.30, (3Sisomer, Rf = 0.39); IR:v=3740, 1738, 1372, 1243, 1017cm-; NMR (CCl4solution): 6= 5.42 (2H, m), 4.96 (1H, m), 4.46 (1H, m), 3.90 (2H, t), 4.10-3.15 (4H, m), 1.97 (3H, s), 1.93 (3H, s).

EXAMPLE 9 (E)- I 1&alpha;-Acetoxy-2&alpha;-(5-acetoxypentyl)-3ss-[3R-(tetrahydropyran-2-yloxy)-4,4-dimethyloct- 1-en yU-4a- (tetrahydropyran-2-yloxy)cyclopen tane A mixture of 7.5 9 of the 3R-hydroxy compound, prepared as described in Example 8, 3 ml of 2,3-dihydropyran, 25 mg of p-toluenesulphonic acid and 80 ml of methylene chloride was stirred at room temperature for 1 5 minutes. The reaction mixture was neutralised with a saturated aqueous solution of sodium bicarbonate, and extracted with ethyl acetate. The extract was washed with water and a saturated aqueous solution of sodium chloride, dried over magnesium sulphate, and concentrated under reduced pressure to give 8.88 9 of the title compound having the following physical characteristic: TLC (cyclohexane:ethyl acetate = 2:1): Rf = 0.57.

EXAMPLE 10 (E)-2a-(5-Hydroxypentyl)-3ss-[3R-(tetrahydro pyran-2-yloxy)-4, 4-dim eth yloct- 1-en y-4a-(tetrnh ydro- pyran-2-yloxy)-cyclopentan- 1 or ol A mixture of 8.88 9 of the acetoxy compound, prepared as described in Example 9, 4.05 9 of potassium carbonate and 80 ml of methanol was stirred at 50"C for 1.5 hours. The reaction mixture was diluted with ethyl acetate, washed with a saturated aqueous solution of ammonium chloride, dried over magnesium sulphate, and concentrated under reduced pressure.The residue was purified by column chromatography on silica gel using a mixture of ethyl acetate and cyclohexane (2:1) as eluent to give 7.2 9 of the title compound having the following physical characteristics: TLC (ethyl acetate:cyclohexane = 2:1): Rf = 0.27; lR:v=3400, 1137, 1026, 978 cm-'; NMR: 8 = 5.60-5.23 (2H, m), 4.60 (2H, m), 4.30-3.20 (9H, m).

EXAMPLE 11 (E)-206(4-Formylbutyl)-3ss-[3R-(tetrahydropyran-2-yloxy)-4, 4-dimethyloct- 1 -enyl]-4a-(tetrahydropy- ran-2-yloxyl-cyclopentan- 1-one A solution of 0.335 ml of chromyl chloride in 2 ml of carbon tetrachloride was added dropwise to a solution of 0.786 ml of tertbutanol and 1.01 ml of pyridine in 1 3 ml of methylene chloride at - 78"C. To the solution was added a solution of 902 mg of the cyclopentan-la-ol compound, prepared as described in Example 10, in 5 ml of methylene chloride at room temperature, and the mixture was stirred at ambient temperature for 2 hours, then at 34"C for 40 minutes.The reaction mixture was stirred with 0.5 ml of dimethyl sulphide at room temperature for 10 minutes; 60 ml of diethyl ether and 20 ml of water were added, and the mixture filtered through a pad of infusorial earth. The ethereal layer of the filtrate was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulphate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of cyclohexane and ethyl acetate (3:1) as eluent to give 675 mg of the title compound having the following physical characteristics: TLC (cyclohexane:ethyl acetate = 2:1): Rf = 0.44; IR: y= 1745, 1730, 1130, 1078, 1037, 1023 cm-'; NMR (CCI4 solution): S = 9.50 (1 H, t). 5.70-5.30 (2H, m), 4.71-4.42 (2H, m), 4.31-3.07 (6H, m).

EXAMPLE 12 (2E, 1 3E)-(1 la, 1 5R)-9-Oxo- 11, 1 5-bis(tetrahydropyran-2-yloxy)- 16, 1 6-dimethylprosta-2, 13-dienoic acid methyl ester Under an atmosphere of nitrogen, a mixture of 184 mg of the cyclopentan-1-one, prepared as described in Example 11, 231 mg of methoxycarbonylmethylidenetriphenylphosphorane and 2 ml of chloroform was stirred at room temperature for 2 hours, and then concentrated under reduced pressure.The residue was purified by column chromatography on silica gel using a mixture of cyclohexane and ethyl acetate (3:1) as eluent to give 1 92 mg of the title compound having the following physical characteristics: TLC (benzene:ethyl acetate = 2:1): Rf = 0.74; lR:p=1745, 1726, 1654, 1196, 1128, 1030 cm-'; NMR: S = 6.90 (1 H, dt), 5.70 (1 H, d), 5.80-5.40 (2H, m), 4.60 (2H, m).

The title compound was also prepared by the procedure described above, replacing the methoxycarbonyl methylidenetriphenylphosphorane by a phosphorane compound (R7)3P = CHCOOCH3, in which R7 is as indicated in the Table below, and modifying the reaction temperature, reaction time and solvent.

R7 reaction reaction solvent yield temperature time -C4H9 -20' to OC 2 hours toluene 100% cyclohexyl r.t. * 1 5 hours chloroform 94. 1% C6H,3 r.t * 1.5 hours tetrahydrofuran 98% "r.t. is room temperature.

EXAMPLE 13 (2E, 1 3E)-(1 1a, 1 5R)-9-Oxo- 11, 1 5-dihydroxy- 16, 1 6-dimethylprosta-2, 1 3-dienoic acid methyl ester To a solution of 732 mg of (2E,1 3E)-(1 1 a, 1 5 R)-9-oxo-l 1,1 5-bis(tetrahydropyran-2-yloxy)- 16,1 6-dimethylprosta-2, 13-dienoic acid methyl ester (which may be prepared as described in Example 12) in 1.9 ml of tetrahydrofuran was added 1 9 ml of a 65% (v/v) aqueous solution of acetic acid and the solution was stirred at 55 to 60"C. for one hour. The reaction mixture was then extracted with ethyl acetate and the extract was washed with water and an aqueous solution of sodium chloride, dried over magnesium sulphate and concentrated under reduced pressure to give 11 9 mg of the title compound having the following physical characteristics: TLC (developing solvent, chloroform:tetrahydrofuran: acetic acid = 10:2:1): Rf = 0.51; IR: v=3400, 2940, 2850, 1750, 1730, 1660, 1440, 1280cm-1 NMR: 5=7.10-6.75 (1H, m), 5.95-5.40 (3H, m), 3.71 (3H, s), 4.20-3.60 (2H, m), 2.75 (1 H, dd), 1.00-0.75 (9H, m).

Claims (41)

1. Compounds of the general formula:

wherein Y represents

(in which R4 represents a hydrogen atom, or a hydroxy-protecting group which is eliminated under basic conditions), Z represents

(in which R5 represents a hydrogen atom, or a tetrahydropyran-2-yl group), R' represents a formyl group, or a grouping of the formula -CH2OR4 (in which R4 is as hereinbefore defined), R2 represents a single bond, or an alkylene group containing from 1 to 5 carbon atoms, R3 represents a hydrogen atom, an alkyl or alkoxy group containing from 1 to 8 carbon atoms, or a cycloalkyl or cycloalkyloxy group containing from 4 to 7 carbon atoms unsubstituted or substituted by at least one alkyl group containing from 1 to 8 carbon atoms, or represents a phenyl or phenoxy group unsubstituted or substituted by at least one halogen atom, trifluoromethyl group or alkyl group containing from 1 to 4 carbon atoms, with the proviso that, when R2 represents a single bond, R3 does not represent an alkoxy, cycloalkyloxy or phenoxy group, THP represents a tetrahydropyran-2-yl group, and the double bond between the carbon atoms in positions 1 3 and 14 is trans, with the provisos that, (i) when Z represents

(in which R5 represents a hydrogen atom), Y represents

(in which R4 represents a hydroxy-protecting group which is eliminated under basic conditions) and R' represents a grouping of the formula -CH2OR4 (in which R4 represents a hydroxyprotecting group which is eliminated under basic conditions), and (ii) when Y represents

R' represents a formyl group.

2. Compounds according to claim 1 wherein the grouping -R2-R2 represents the 1,1dimethylpentyl group.

3. Compounds according to claim 1 or 2 wherein the hydroxy-protecting group represented by the symbol R4 is acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, propionyl, benzoyl, pphenylbenzoyl or naphthyloyl.

4. Compounds according to claim 1, 2 or 3 wherein the hydroxy-protecting group represented by R4 is acetyl.

5. Compounds according to any one of claims 1 to 4 wherein R' represents a grouping -CH2OR4, Y represents

Z represents

R4 represents a hydroxy-protecting group which is eliminated under basic conditions and the other symbols are as defined in claim 1.

6. Compounds according to any one of claims 1 to 4 wherein R' represents a grouping -CH2OR4, Y represents

Z represents

R4 represents a hydroxy-protecting group which is eliminated under basic conditions, R5 represents a hydrogen atom and the other symbols are as defined in claim 1.

7. Compounds according to any one of claims 1 to 4 wherein R' represents a grouping -CH2OR4, Y represents

Z represents

R4 represents a hydroxy-protecting group which is eliminated under basic conditions, R5 represents a tetrahydropyran-2-yl group and the other symbols are as defined in claim 1.

8. Compounds according to any one of claims 1 to 4 wherein R' represents a grouping -CH2OR4, Y represents

Z represents

R4 represents a hydrogen atom, R5 represents a tetrahydropyran-2-yl group and the other symbols are as defined in claim 1.

9. Compounds according to claim 1 or 2 wherein R' represents a formyl group, Y represents

Z represents

R5 represents a tetrahydropyran-2-yl group and the other symbols are as defined in claim 1.

10. (1 E)-1 &alpha;-Acetoxy-2&alpha;-(5-acetoxypentyl)-3ss-(3-oxo-4, 4-dimethyloct- 1 -enyl)-4a-(tetrahydropy- ran-2-yloxy) cyclopentane.

11. (E-1 a-Acetoxy-2a-(5-acetoxypentyl)-3P-(3 R-hydroxy-4,4-dimethyloct-1 -enyl)-4a-(tetrahydropyran-2-yloxy)cyclopentane.

12. ( 9- 1 a-Acetoxy-2a-(5-acetoxypentyl)3ss-[3 R-(tetrahydropyran-2-yloxy)-4,4-dimethyloct- 1 enyl]-4a-(tetrahydropyran-2-yloxy)cyclopentane.

1 3. ( E)-2a-(5-Hydroxypentyl)-3ss-[3 R-(tetrahydropyran-2-yloxy)-4, 4-dimethyloct- I -enyl]-4a-(t etrahydropyran-2-yloxy)cyclopentan- 1 a-ol.

14. ( E)-2a-(4-Formylbutyl)-3ss-[3 R-(tetrahydropyran-2-yloxy)-4,4-dimethyloct- 1 -enyl]-4a-(tet rahyd ropyran-2-yloxy)cyclopentan- 1-one.

15. Process for the preparation of a compound of general formula IV depicted in claim 1 wherein the various symbols are as defined in claim 1 which comprises the reaction of a compound of the general formula:

(wherein R4" represents a hydroxy-protecting group which is eliminated under basic conditions and THP represents a tetrahydropyran-2-yl group) with a sodium derivative of a dialkyl phosphonate of the general formula:

(wherein R5 represents an alkyl group containing from 1 to 4 carbon atoms and R2 and R3 are as defined in claim 1) or with a phosphorane compound of the general formula::

(wherein R7 represents a phenyl group unsubstituted or substituted by at least one alkyl group containing from 1 to 4 carbon atoms, or represents an alkyl group containing from 1 to 6 carbon atoms, or represents a cyclohexyl group and R2 and R3 are as defined in claim 1) to obtain a compound of the general formula:

(wherein R4" and THP are as hereinbefore defined and the other symbols are as defined in claim 1) followed successively, if desired, by one or more of the following steps:: (a) reduction of the compound of general formula IVA to convert the 1 5-oxo group to a 15hydroxy group, (b) etherification of the product of step (a) with 2,3-dihydropyran in an inert organic solvent in the presence of an acidic catalyst at or below room temperature, to convert the 1 5-hydroxy group to a 1 5-tetrahydropyran-2-yloxy group, (c) saponification of the product of step (b) to convert groups OR4a to hydroxy groups, and (d) oxidation of the product of step (c) to convert a hydroxymethyl group, and a hydroxy group in the 9-position, to formyl and oxo groups, respectively.

1 6. Process according to claim 1 5 in which the reaction of the compound of formula V with the dialkyl phosphonate of general formula VI or with the phosphorane of general formula VII is carried out in an inert organic solvent at a temperature from - 78"C to the reflux temperature of the reaction mixture.

1 7. Process according to claim 1 5 in which the reduction is step (a) is effected using diisobornyloxyaluminiumisopropoxide, a diisobutyl(alkylsubstituted or unsubstituted)phenoxyaluminium or a lithium 1,1 '-binaphthyl-2,2'-dioxyaluminium hydride.

1 8. Process according to claim 1 5 in which step (c) is effected using an aqueous solution of an alkali metal hydroxide, carbonate or bicarbonate or of an alkaline earth metal hydroxide or carbonate in the absence or presence of a water-miscible solvent at a temperature from - 10"C to the reflux temperature of the reaction mixture or using an anhydrous solution of an alkali metal hydroxide or carbonate in an anhydrous alkanol containing from 1 to 4 carbon atoms at a temperature from - 1 0'C to the reflux temperature of the reaction mixture.

1 9. Process according to claim 1 5 in which step (d) is effected under mild and neutral conditions.

20. Process according to claim 1 5 substantially as hereinbefore described.

21. Process according to claim 15 subatantially as hereinbefore described with especial reference to one or more of Examples 7, 8, 9, 10 and 11.

22. Compounds of general formula IV when prepared by the process claimed in any one of claims 1 5 to 21.

23. Process for the conversion of a compound of general formula IV depicted in claim 1, wherein R' represents a formyl group, Y represents

Z represents

R5 represents a tetrahydropyran-2-yl group and the other symbols are as defined in claim 1 into a compound of the general formula:

(wherein A11 represents an alkyl group containing from 1 to 4 carbon atoms, the double bonds between the carbon atoms in positions 2 and 3, and positions 1 3 and 14, are trans, and the other symbols are as defined in claim 1), which comprises reacting the compound of general formula IV with a phosphorane compound of the general formula:: (R7)3P = CHCOOR" XVI (wherein R7 is as defined in claim 1 5 and R" is as hereinbefore defined) followed if desired by hydrolysis of the compound of general formula XV to convert the 11 - and 1 5-tetrahydropyran-2yloxy groups to hydroxy groups to obtain a compound of the general formula:

wherein R" is as hereinbefore defined and the other symbols are as defined in claim 1.

24. Process according to claim 23 in which the reaction of the compound of general formula IV with the phosphorane compound of general formula XVI is carried out in an inert organic solvent at a temperature from - 78"C to the reflux temperature of the reaction mixture.

25. Process according to claim 23 in which the hydrolysis of the compound of general formula XV is carried out with a mixture of dilute hydrochloric acid and tetrahydrofuran, a mixture of dilute hydrochloric acid and methanol, a mixture of acetic acid, water and tetrahydrofuran, a mixture of phosphoric acid, water and tetrahydrofuran, a mixture of ptoluenesulphonic acid and methanol, a mixture of p-toluenesulphonic acid-pyridine complex and methanol or a mixture of trifluoroacetic acid-pyridine complex and methanol.

26. Process according to claim 23 substantially as hereinbefore described.

27. Process according to claim 23 substantially as herein before described with especial reference to Example 1 2 or Examples 1 2 and 1 3.

28. A compound of general formula XV or XVII when prepared by the process claimed in any one of claims 23 to 27.

29. (2 E, 1 3 E)-(1 1 a, 1 5 P)-9-Oxo- 11,1 5-dihydroxy-1 6,1 6-dimethylprosta-2, 1 3-dienoic acid methyl ester when prepared by the process claimed in any one of claims 23 to 27.

30. Compounds of the general formula:

wherein X represents an ethylene or vinylene group, R12 represents a hydrogen atom or a hydroxy-protecting group which is eliminated under basic conditions, R13 represents a formyl group, a hydroxymethyl group or a group -CH20R3 in which R8 represents a benzyl group or a hydroxy-protecting group which is eliminated more easily than a tetrahydropyran-2-yl group under acidic conditions, THP is as defined in claim 1 and the configuration of the vinylene group is Eor Zor a mixture thereof, with the provisos that (i) when R'3 represents a formyl group, X represents an ethylene group and R12 represents a hydroxy-protecting group which is eliminated under basic conditions, (ii) when R13 represents a hydroxymethyl group, R12 represents a hydroxy-protecting group which is eliminated under basic conditions and (iii) when R'3 represents a group -CH2 OR8, X represents a vinylene group.

31. ( EZ)-2a-(5-Hydroxypent-2-enyl)-3ss-( 1 -methoxy- 1 -methyl)ethoxymethyl-4a-(tetrahydropy- ran-2-yloxy)cyclopentan-1 a-ol.

32. ( EZ- 1 EZ)-1 a-Acetoxy-2a-(5-acetoxypent-2-enyl)-3ss-( 1 -methoxy- 1 -methyl)ethoxymethyl-4a-(tet- rahydropyran-2-yloxy)cyclopentane.

33. ( EZ)- 1 a-Acetoxy-2a-(5-acetoxypent-2-enyl)-3-hyd roxymethyl-4a-(tetrahydropyran-2-ylox- y)cyclopentane.

34. 1 a-Acetoxy-2a-(5-acetoxypentyl)-3fl-hyd roxymethyl-4a-(tetrahyd ropyran-2-yloxy)cyclopentane.

35. 1 a-Acetoxy-2a-(5-acetoxypentyl)-34ormyl-4a-(tetrahydropyran-2-yloxy)cyclopentane.

36. ( EZ)-2a-(5-Hydroxypent-2-enyl)-3ssbenzyloxymethyl-4a-(tetrahydropyran-2-yloxy)cyclo- pentan-1 a-ol.

37. ( EZ)- 1 &alpha;-Acetoxy-2&alpha;-(5-acetoxypent-2-enyl)-3ss-benzyloxymethyl-4&alpha;-(tetrahydropyran-2-yl- oxy)cyclopentane.

38. Process for the preparation of compounds of the general formula specified in claim 30, wherein the various symbols are as defined in claim 30, which comprises the reaction of a compound of the general formula:

(wherein R8 represents a benzyl group of a hydroxy-protecting group which is removed more easily than a tetrahydropyran-2-yl group under acidic conditions and THP is as defined in claim 1) with an ylide of a phosphonim compound of the general formula: G (R7)3 PCH2CH2CH2OH'X XII (wherein X represents a halogen atom and R7 is as defined in claim 1 5) to obtain a compound of the general formula:

(wherein R8 is as hereinbefore defined and THP is as defined in claim 1) followed successively, if desired, by one or more of the following steps:: (a) conversion of the hydroxy groups in the compound of formula IX to groups OR4" (in which R4" is as defined in claim 15), (b) reduction of the product of step (a) to convert the vinylene group to an ethylene group and, when R8 represents a benzyl group, the benzyloxymethyl group to hydroxymethyl or, when R8 is other than benzyl, mild hydrolysis of the product of step (a) under acidic conditions avoiding the risk of elimination of the tetrahydropyran-2-yl group to convert the group -CH2OR8 to hydroxymethyl followed by reduction of the hydrolysis product to convert the vinylene group to an ethylene group, and (c) oxidation of the product of step (b) to convert the hydroxymethyl group to a formyl group.

39. Process according to claim 38 substantially as hereinbefore described.

40. Process according to claim 38 substantially as herein before described with especial reference to one or more of Examples 1, 2, 3, 4, 5 and 6.

41. Compounds of general formula XVIII when prepared by the process claimed in any one of claims 38 to 40.