GB1583146A - Homoprostaglandins - Google Patents

Description

(54) HOMOPROSTAGLANDINS (71) We, GLAXO OPERATIONS UK LIMITED (formerly known as Glaxo Laboratories Limited), a British company of Greenford, Middlesex, do hereby declare the invention,Mor which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularlv described in and by the following statement:- This invention relates to cyclohexane analogues of prostaglandin-type compounds and processes for their preparation.

The prostaglandins are a class of naturally occurring cyclopentane derivatives whose importance in medicine is rapidly increasing. They are biologically active in many physiological systems and they or substances which antagonise their effects have potential application, for example, in the control of fertility, gastric secretion, blood pressure blood coagulation and inflammation, the predominant type of activity depending on the precise chemical structure. A more detailed summary of their various activities is given in British Patent Specification No. 1,396,206.

Considerable research has been carried out not only into the synthesis of natural prostaglandins but also into attempting to prepare analogues thereof having desirable agonist or antagonist activity. In particular, attempts have been made to find compounds which are more selective in their effect, since previously known prostaglandins, due to their multiple activities lead, when used in therapy, to a number of undesirable side effects.

We have now found that a new class of prostaglandin derivatives in which the cyclopentane ring of the natural prostaglandins is replaced by a cyclohexane ring (which is more particularly defined below) shows a desirable selectivity in that they exhibit good gastric anti-secretory activity at dosages at which they show little effect on the respiratory system and blood pressure. In addition, in contrast to a large number of known prostaglandin and prostaglandin-type compounds, they have little tendency to induce diarrhoea.

Accordingly, in one aspect of the invention, we provide compounds of general formula (I),

wherein X represents a carbonyl or protected carbonyl group or a hydroxymethylene or protected hydroxymethylene group; A represents a saturated or unsaturated, straight or branched aliphatic hydrocarbon chain having from 5-16 carbon atoms and which may carry one or more hydroxyl, protected hydroxyl, oxo or protected oxo groups; and B represents a saturated or unsaturated, straight or branched aliphatic hydrocarbon chain having 5-16 carbon atoms and carrying a terminal carboxyl or protected carboxyl group and which may carry one or more hydroxyl, protected hydroxyl, oxo or protected oxo groups; and, where B carries the carboxyl group, salts thereof.

The term a-configuration' as used herein means that the group concerned lies below the plane of the ring, i.e. the plane of the paper, and is depicted as a broken line thus |||||. The term 'ss-configuration', means that the group lies above the plane of the ring, i.e. the plane of the paper, and is depicted thus # Where a particular configuration is or may be assigned to one or more of the groups in compounds of the invention, the invention includes the mirror image optical isomers of such compounds; for the purpose of this specification, no distinction between such isomers is drawn and the invention extends to the separate isomers as well as to mixtures of said isomers including racemates.

It will be appreciated that, in formula (I), where X represents a hydroxymethylene or protected hydroxymethylene group then the hydroxyl or protected hydroxyl group may be in either the α- or ss-configuration.

When X represents a protected carbonyl group; the protecting group may, for example, be a cyclic or acyclic ketal or thioketal group e.g. an ethylenedioxy group.

When X represents a protected hydroxymethylene group this may, for example, be a group of formula

wherein Z represents an acyl, tri(hydrocarbyl)silyl, alkyl, aralkyl or cycloalkyl group or a 2-tetrahydropyranyl group. When Z represents an acyl group then desirably this will be an alkanoyl, aralkanoyl or aroyl group, the alkanoyl group preferably containing not more than 7 carbon atoms, e.g. acetyl, and the aralkanoyl or aroyl groups preferably containing not more than 20 carbon atoms, e.g. benzoyl and being optionally substituted by one or more C16 alkoxy groups, halogen atoms, nitro groups, C1~,0 acyloxy or C27 alkoxycarbonyl groups.

When Z represents a tri(hydrocarbyl)silyl group, the silyl group will carry three hydrocarbon substituents, which may be the same or different, selected from C1-6 alkyl, C2-6 alkenyl, C3-7 cycloalkyl, C5-20 aralkyl, C5-7 cycloalkenyl and C4-20 aryl groups e.g. t-butyldimethylsilyl and trimethylsilyl groups. When Z is alkyl it is preferably C16 alkyl and may carry substituents, for example, C16 alkoxy groups which may themselves be substituted, e.g. by C16 alkoxy groups.

Where Z is a cycloalkyl group it is preferably C37 cycloalkyl. In the case where Z represents an aralkyl group, this will desirably contain up to 20 carbon atoms and will preferably be an arylmethyl group e.g. benzyl. X will preferably represent a carbonyl or a hydroxymethylene group.

Aliphatic chains A and B may, for example, contain up to 13 carbon atoms.

When B carries a protected carboxyl group this may, for example, be an esterified carboxyl group preferably carrying an aliphatic, araliphatic or aryl esterifying group having up to 10 carbon atoms e.g. C16 alkyl, such as methyl, ethyl or t-butyl or benzyl or phenyl groups. Preferred esterifying groups are C14 alkyl groups.

Physiologically labile ester groups are also of interest for example acyloxymethyl groups such as pivaloyloxymethyl. It is, however, preferred that B carries a free terminal carboxyl group.

It is particularly preferred that the side chain A carries a free hydroxyl group.

When present in a side-chain A and/or B, a hydroxyl or protected hydroxyl group will desirably be in a position allylic with respect to a carbon-carbon double bond and, preferably, further removed from the 6-membered ring than the carboncarbon double bond. Side chains carrying free hydroxyl groups are preferred. A protected hydroxyl group in A and/or B, may, for example, be an acyloxy group e.g. a hydroxyl group esterified with an alkanoic, aralkanoic, carbamic or carbonic acid containing up to 24 and preferably up to 10 carbon atoms, or a labile ether group such as a 2-tetrahydropyranyl ether or a tri(hydrocarbyl)silyl ether having a total of 3 to 24 carbon atoms in the ether group. In general such a protected hydroxy group may be a group OZ as defined above.

When present in side chain A and/or B, a protected oxo group will desirably be a ketal, preferably a cyclic ketal e.g. an ethylene ketal formed trom ethylene glycol.

In general, it is preferred that a hydroxyl or protected hydroxyl group in a side chain A and/or B be present on the first to fourth carbon atom from the ring.

It is further preferred that where either or both of the chains A and B is branched it includes a gem-dimethyl group. In chain A such a group is desirably situated on the carbon atom adjacent to and further removed from the 6-membered ring than a carbon atom carrying a hydroxyl or protected hydroxyl group. The presence of a methyl group on a carbon atom which bears a hydroxyl or protected hydroxyl group is also a preferred form of branched chain. In chain B a gemdimethyl group is desirably situated on the 5 carbon atom with respect to the terminal carboxyl or protected carboxyl group.

Thus, for example chain B is preferably of the form -Alk1.R where Alk' represents an alkylene or alkenylene group and R is a carboxyl or protected carboxyl group and chain A is preferably of the form -Q.W.Alk2 where Q is a carbon-carbon bond or is an ethylene group which may carry a hydroxyl or protected hydroxyl group p to the group W, or is a trans- vinylene group; W is a carbonyl group or a hydroxymethylene or protected hydroxymethylene group optionally carrying an alkyl group (which may carry a phenyl substituent) or a cycloalkyl group on the methylene group and Alk2 is a straight or branched alkyl or alkenyl group having up to 10 carbon atoms. B side chains which are of particular interest include chains of the formula: i) -CH2CH2CH2CH2CH2CH2R where R is a carboxyl or protected carboxyl group, ii) -CH#CH-CH#CH-CH#CH-R where R is as defined above, iii)CH2CH2CH-CHCH2CH2CH2R where R is as defined above, iv)CH2CH2CH2CH2CH2CH2CH2R where R is as defined above, v)CH2CH2CH2CH2CH2CH2CH2CH2R where R is as defined above, vi) -CH2CH2CH#CH-CH#CH-CH#CH-R where R is as defined above and vi) -CH2CH2CH2CH2CH2R where R is as defined above, especially those where R represents a carboxyl or a C2~, alkoxycarbonyl group. A side chains which are of particular interest include chains of formula: i) -CH2CH2.CO.CH2CH2CH2CH2CH3, ii) -CH#CH,CO,CH2CH2CH2CH2CH3, iii)CH-CH.CH(OH).CH2CH2CH2CH2CH3, iv) -CH2CH2CH(OH),CH2CH2CH2CH2CH3, v) -CH#CH-CO,C(CH3)2CH2CH2CH2CH3, vi) -CH#CH.CH(OH),C(CH3)2CH2CH2CH2CH3, vii) -CH#CH-C(OH)(CH3),CH2CH2CH2CH2CH3, viii) -CH2CH2C(OH)(CH3),CH2CH2CH2CH2CH3, ix) -CH#CH-C(OH)(CH3)CH2CH2CH2CH(CH3)2, x) -CH#CH-C(OH)(C2H5)CH2CH2CH2CH2CH3, xi) -CH#CH-C(OH)(cyclo C5H9)CH2CH2CH2CH2CH3, xii) -CH#CH-C(OH)(CH3)CH2CH2CH2CH2CH2CH3, xiii) -CH#CH-C(OH)(CH3)CH2CH2CH2CH2CH2CH2CH2CH3 and xiv) CM=tCHC(OH)(CM3)CH2CH2CH2CH3.

In relation to double bonds in the chains indicated above t denotes a trans double bond and c denotes a cis double bond.

Particularly preferred B groups are (i) and (ii) where R represents a carboxyl group and particularly preferred A groups are (iii), (iv), (vi), (vii), (viii) and (xii).

Also included within the scope of the present invention are salts of compounds of general formula (T) wherein the B side chain carries a free terminal carboxyl group. Such salts may, for example, be formed with physiologically compatible, non-toxic cations such as alkali metal and alkaline earth metal cations e.g. the sodium ion, potassium ion, calcium ion and magnesium ion as well as organic amine cations such as e.g. the triethanolammonium cation. It will be appreciated that, for pharmaceutical use, the salts will be physiologically compatible but other salts may find use, for example, in the preparation of the compounds of general formula I and their physiologically compatible salts.

Particularly preferred compounds according to the invention are the following: 7 - [2a - (3R,S - hydroxy - 3 - methyl - trans - 1 - octenyl) - 3 - oxocyclo - hex - - yl]heptanoic acid; - - hydroxy - 2a - (3R,S - hydroxy - 3 - methyl - trans - 1 - octenyl) - cyclo - hex - p - yl]heptanoic acid; 7 - [3a hydroxy - 2a - (3R,S - hydroxy - 3 - methyl - trans - 1 - octenyl) - cyclo hex - ss - yl]heptanoic acid; 7 - [3p - hydroxy - 2a - (3R - hydroxy - 4,4 - dimethyl - trans - 1 - octenyl) - cyclohex - p - yl]heptanoic acid; 7 - [3a - hydroxy - 2a - (3S - hydroxy - trans - 1 - octenyl) - cyclohex - - yll heptanoic acid; 7 - [3a - hydroxy - 2a - (31? - hydroxy - trans - 1 - octenyl) - cyclohex - - yl] heptanoic acid; 7 - [3g - hydroxy - 2a - [3R,S - hydroxy - 3 - methyloctyl) - cyclohex - - yl] heptanoic acid; and salts thereof.

The compounds of general formula (I) and, where the B chain carries a carboxyl group, the physiologically compatible salts thereof may be formulated for administration e.g. to man in a variety of ways either alone or together with a pharmaceutical carrier or diluent. Thus according to a further feature of the present invention there are provided pharmaceutical compositions comprising, as active ingredient, at least one compound of formula (I) as hereinbefore defined or, where B carries a terminal carboxyl group, a physiologically compatible salt thereof, in association with a pharmaceutical carrier or diluent.

The compounds and/or physiologically compatible salts of the invention may desirably be formulated for oral or parenteral administration. Such compositions may, for example, take the form of tablets, coated tablets, capsules, lozenges, ampoules for injection and solutions.

The carriers or diluents which may be of use in such compositions are those conventional for such forms and may include, for example, starch, lactose, magnesium stearate, talc, gelatin, sterile pyrogen-free water or suspending, emulsifying, dispersing, thickening or flavouring agents. Dosage unit formssuch as ampoules for parenteral administration are preferred.

The compounds of the invention may typically be administered in dosages of from 0.01 to 100 mg per kg, preferably of from 0.1 to 10 mg/kg. of body weight, though the precise dosage which will be effective will vary depending on the particular compound concerned, the mode of administration, the condition being treated and the patient.

The compounds of the invention may be prepared by any convenient method.

According to a further aspect of the invention, therefore, we provide a process for the preparation of compounds of general formula (I) as hereinbefore defined which comprises reacting a compound of formula (II)

(where R1 represents a protected hydroxyl group) with a compound of formula (III)

(where R2 represents a protected or masked aldehyde group to give a compound of formula (IV)

(where Rl and R2 are as defined above) followed by one or more of the following reactions, which reactions may be carried out in any appropriate order, as required, whereby the desired compound of formula (I) is obtained: a) where a free and a protected or masked aldehyde group are both present, protecting or masking the free aldehyde group so as to permit selective conversion of the protected or masked aldehyde group initially present into a free aldehyde group b) deprotection of a protected aldehyde group or reconversion of a masked aldehyde group into a free aldehyde group. c) reaction of a free aldehyde group in the 2-position of the six-membered ring with a reagent of formula (Va)

(wherein either na is 1, R3a is hydrogen and R4a is a dialkylphosphonyl group or hydrogen, or na is 0 or 1 and R3a and R4a together constitute a trialkylphosphoranyliene or triarylphosphoranylidene group, the reaction being effected in the presence of a base when R38 is hydrogen; and R5a represents a saturated or unsaturated, straight or branched aliphatic hydrocarbon chain, the group (CO)naR5a having up to 14 carbon atoms exclusive of substituents said aliphatic hydrocarbon chain being optionally substituted by one or more hydroxyl, protected hydroxyl, oxo or protected oxo groups whereby the group -CH=CH-(CO)na-R5a or

is introduced in the 2-position of the six-membered ring, d) reaction of a free aldehyde group in the I-position of the six-membered ring with a reagent of formula (Vb)

(wherein nb, R3b and R4b are as defined above for na, R3 and R4b respectively, the reaction being effected in the presence of a base when R3b is hydrogen and R5b represents a saturated or unsaturated, straight or branched aliphatic hydrocarbon chain, the group (CO)nbRBb having up to 14 carbon atoms exclusive of substituents, said aliphatic hydrocarbon chain carrying a terminal carboxyl or protected carboxyl group and being optionally substituted by one or more hydroxyl, protected hydroxyl, oxo or protected oxo groups) whereby the group CH=CHCO)nbRBb or

is introduced in the I-position of the six-membered ring, e) deprotection of R1 whereby a free hydroxyl group is obtained in the 3position of the six-membered ring f) treatment of any free hydroxy groups with a suitable esterifying or etherifying reagent to form protected hydroxyl groups, g) deprotection of any protected carboxyl groups, h) reduction of the double bond in the six-membered ring and, if desired, reduction of one or more further unsaturated carbon-carbon bonds, i) reduction of any keto groups, j) deprotection of protected hydroxyl groups other than R1, k) oxidation of any --CHOH groups to carbonyl groups, I) reaction of a carbonyl group in a side chain in position I or 2 in the sixmembered ring with an organometallic reagent.

When a masked aldehyde group is present in the 1- or 2-position of the sixmembered ring this may, for example be a hydroxymethyl or protected hydroxymethyl group or an esterified carboxyl group.

Where a protected aldehyde group is present in the 1- or 2-position of the sixmembered ring this may, for example, be a cyclic or acyclic acetal or thioacetal or an oxime. In general R2 is preferably a ditlower alkoxy) methyl or alkylenedioxymethyl group In the compound of formula (III) R2 may, for example, represent a di(C,~4 alkoxy)methyl group. The reaction of the compound of formula (II) with the compound of formula (III) is preferably effected at elevated temperatures e.g. from 90--130"C and preferably in the presence of an inert solvent, e.g. an aromatic hydrocarbon such as, for example, benzene.

In reaction (a) the initially protected aldehyde group may, for example, be an acetal group in which case the free aldehyde group is preferably converted into a group more stable to the action of dilute acid than the acetal group, for example an oxime or a thioacetal group or it may be masked by reduction to hydroxymethyl e.g. with sodium borohydride, followed by protection of the hydroxyl group e.g. by acylation or etherification. The initially protected aldehyde group may then be deprotected by treatment with dilute acid. In this way side chain B may be introduced before side chain A.

Reaction (b) involves deprotection of a protected aldehyde group or reconversion of a masked aldehyde group into a free aldehyde group. Such reactions may be carried out according to methods well known in the art. Thus an acetal group may be cleaved by hydrolysis e.g. under mild acidic conditions. A thioacetal group may be cleaved by reaction with a mercuric salt e.g. the chloride.

An oxime group may be cleaved, for example with titanous chloride.

A protected hydroxymethyl group e.g. an acyloxymethyl group may be deprotected to form a free hydroxymethyl group; a hydroxymethyl group may be converted to an aldehyde group by oxidation, e.g. with pyridinium chlorochromate.

An esterified carboxyl group may be reduced to an aldehyde group, tor example using sodium bis(2-methoxyethoxy)aluminium hydride in the presence of an amine e.g. pyrrolidine.

In reactions (c) and (d) a free aldehyde group is reacted with a ketone or with a Wittig reagent whereby the desired side chain is introduced. When the reagent is a ketone, the reaction is effected in the presence of a base e.g. an organic base such as pyridine or pyrrolidine (used preferably in the presence of a carboxylic acid, e.g. acetic acid) or a lithium amide in the form of a hindered base e.g. a lithium diisopropylamide so as to form an enolate salt in solution. The reaction is conveniently effected in a hydrocarbon or ether solvent e.g. benzene, diethyl ether or dioxan or mixtures thereof. A preferred temperature for the reaction is -70 to -200C. Reaction with a ketone reagent leads to formation of a side chain having a hydroxyl group on the I-position of the chain, which chain may dehydrate spontaneously under the reaction conditions employed to form a double bond in the 2-position of the chain. If the dehydration does not occur spontaneously then it may be deliberately effected as a separate reaction step e.g. by warming in an alkaline alcoholic solution.

When a Wittig reagent is employed the reaction yields a chain having a double bond in the 2-positiuon of the chain directly. The Wittig reagent may, for example, be a phosphorane of formula (R6)3 P=CH CO R6 wherein R5 is as defined for Rsa or for R5b and Re represents an alkyl group, preferably containing 1A carbon atoms, or an aryl group, preferably monocyclic e.g. a phenyl group. The reaction may conveniently be effected in a non-polar solvent, for example, a hydrocarbon. halogenated hydrocarbon or alcohol, e.g. toluene,- benzene or ethanol. The reaction temperature is preferably in the range 200 to 1200C.

According to a third embodiment, a phosphonate of formula (R7O)2.PO.CH2.CO.R5 wherein R5 is as defined above and R7 represents an alkyl group may be used as a Wittig reagent in which case the reaction is effected in the presence of a base such as, for example, an alkali metal hydride e.g. sodium hydride, conveniently in an ether solvent e.g. tetrahydrofuran.

In a yet further embodiment, the Wittig reagent may be a phosphorane of formula R5 P=Cfl-R5 wherein R5 is as defined above and R" represents an aryl e.g. a phenyl group, and is used preferably in the presence of an alcoholic solvent e.g. isopropanol.

The reactions (c) and (d) can be effected in either order, depending on whether or not the aldehyde group in the starting material for the reaction is in the 1-position or the 2-position. Whichever of these reactions is effected first will result in loss of configuration at the point of attachment of the side-chain to the ring so that a mixture of a- and isomers will be obtained. These can be separated or the mixture may be used as such for the introduction of the second side-chain A or B.

The second of the reactions (c) and (d) however, aiways introduces the second sidechain in the trans-configuration relative to the first. Thus, starting from the compound of formula (IV) in which the group in the 3-position is in the aconfiguration, two isomeric products are obtained wherein the groups A and B in the 1- and 2- positions are in the two possible trans-configurations with respect to each other. However, as indicated above, the formulae used herein denote both optical isomers of a particular compound and it will be seen that one of the two trans-compounds is equivalent to the mirror image of the other trans-compound but with the 3-substituent in the opposite (i.e. -) configuration. Consequently, if the two reactions (c) and (d) are conducted without separation of isomers, the product can be represented as a mixture of compounds having the same configuration in the 1- and 2-positions but isomeric at the 3-position.

Reaction (e), when employed, involves the deprotection of R' to form a free hydroxyl group, which reaction may be effected according to conventional methods. Thus, for example, when R' represents an acyloxy group e.g. an acetoxy group, the free hydroxyl group may be liberated by alkaline hydrolysis. Where R' is an allylic acyloxy group, alkaline hydrolysis is preferably effected under mild anhydrous conditions e.g. using an alkali metal hydroxide in an anhydrous alkanol such as methanol. Where R' represents a tri(hydrocarbyl)silyl group the free hydroxyl group may be liberated by acid hydrolysis treatment with fluoride ions. A 2-tetrahydropyranyl group may be cleaved by acid hydrolysis. The free hydroxyl group thus liberated may, if desired, be reacted to introduce another protecting group according to reaction (f). Such an exchange of protecting groups may be desirable, for example, to prevent hydrogenolysis during reaction (h) such as is described hereinafter.

In reaction (f) any free hydroxyl groups may be reacted with a suitable esterifying or etherifying reagent to form protected hydroxyl groups. The reaction will generally be effected in a conventional manner with, for example, a silylating or other etherifying agent e.g. a trialkylsilyl halide, a mono- or bis-silylated acetamide, dihydropyran or a reactive derivative of a carboxylic acid e.g. an acid halide or anhydride.

According to reaction (g) a protected carboxyl group may be subjected to deprotection, conveniently by mild basic hydrolysis e.g. using dilute aqueous or alcoholic caustic soda or caustic potash at slightly elevated temperature. This procedure may result in deprotection of protected hydroxyl groups so that further protection may be needed in respect of these groups.

Reduction of the double-bond in the six-membered ring and, if desired, of one or more unsaturated bonds in the side chains may be carried out according to reaction (h).

Reduction may be carried out according to a number of methods depending on whether or not it is desired to hydrogenate all or some of the unsaturated groups present and/or to retain or hydrogenolyse any protecting groups in the molecule.

If it is desired to avoid hydrogenolysis of certain groups or to retain the allylic double bond in the side chain, reduction may be effected by using hydrogen and a nickel catalyst as described by C.A. Brown, J. Org. Chem., (1970) 35, 1900.

Reduction is preferably carried out in an alkanol solvent e.g. ethanol or methanol.

An allylic hydroxyl group must be protected during the reduction with a protecting group, for example an ester group e.g., an acyloxy group or an ether group e.g. t-butyldimethyl silyl or 2-tetrahydropyranyl, or by the presence of an alkyl group on the same carbon atoms. This procedure also reduces the allylic double bond in the ring.

!f it is desired to carry out a non-selective reduction of the double bonds, then this may be effected using hydrogen and a noble metal catalyst, e.g. a palladium catalyst, conveniently in an alkanol or ester solvent, e.g. ethanol or ethyl acetate.

Under these conditions, hydrogenolysis of allylic hydroxyls in the ring and the side chain may be effected. An allylic hydroxyl in the ring should thus be protected during hydrogenation with noble metals to avoid removal of the oxygen function by hydrogenolysis, e.g. by a tri(hydrocarbyl) silyl group. Allylic hydroxyls in the side chains, if present, may be similarly protected in order to avoid hydrogenolysis.

Any keto groups, which may have been introduced, may be reduced to a -CHOH-- group according to reaction (i). This will preferably be effected using a metal hydride reducing agent such as a borohydride, for example of zinc, potassium, sodium or calcium, or of a complex metal hydride such as lithium aluminium hydride or a trialkoxy aluminium hydride of lithium. The reducingstrength of the reducing agent used will depend on whether or not other groups in the compound are susceptible to reduction by this method, for example a carboxyl or protected carboxyl group. Reaction is preferably carried out at low temperature and at a controlled slightly alkaline pH e.g. from 8-9 in the case of potassium or sodium borohydride.

According to reaction 0) protected hydroxyl groups other than at R' may be subjected to deprotection. In the case where hydroxyl groups elsewhere in the molecule are protected e.g. by a trialkylsilyl group, these may be deprotected by hydrolysis with a dilute carboxylic acid e.g. acetic acid or a quaternary ammonium fluoride salt or lithium fluoride in dimethylformamide as solvent.

Any -CHOH groups in the side-chain A and B or in X may be oxidised to carbonyl groups using reaction (k). This is preferably carried out using an acidified dichromate solution if free carboxyl groups are present in the molecule. Reaction may, if desired, be carried out in acetone or ethers. If free carboxyl groups are not present, the preferred oxidising agent is pyridinium chlorochromate or chromium trioxide in pyridine in a halogenated hydroc and inert solvents e.g. ether solvents such as diethyl ether, tetrahydrofuran or dioxan are preferred.

According to a modification of the invention the side chain A and/or B may be introduced by a reaction in which a free aldehyde group in the 1- or 2- position of the six-membered ring is firstly reacted with a reagent of formula (R3m)(R4m)CH.Rm (where R3" and R4" together represent a trialkylphosphoranylidene or triarylphosphoranylidene group and Rm is an esterified carboxyl group or a saturated or unsaturated straight or branched aliphatic group having up to 12 carbon atoms exclusive of substituents and carrying a terminal esterified carboxyl group), the product thus formed is reduced whereby the terminal esterified carboxyl group in the group Rm is converted into an aldehyde group and the said aldehyde-containing grouping thus introduced is converted into the required side chain A or B by reaction with a further reagent of formula (Va) or (Vb) as hereinbefore defined (wherein (CO)naR5a or (CO)nbR5b has up to 12 carbon atoms exclusive of substituents and R5b can additionallv be a carboxyl or protected carboxyl group when nb is 0) respectively. The reaction with the reagent of formula (Va) and/or (Vb) is preferably effected under the conditibns described above in relation to reactions (c) and (d). Reduction of the esterified carboxyl group in the group Rm may be effected, for example, using sodium bis(2-methoxyethoxy)aluminium hydride in the presence of an amine e.g. pyrrolidine.

According to a further modification the process according to the invention may include the step of protecting a free carboxyl group preferably by esterification, for example methylation e.g. by reaction with diazomethane.

According to still further modification the process according to the invention may include the step of protecting an oxo group for example by ketal formation and/or the step of deprotecting a protected oxo group for example, by hydrolysis of a ketal A number of the reactions described above lead to the formation of isomers which isomers may be separated before the next reaction step in the sequence or at a later stage in the sequence as is convenient. Separation may, for example, be effected by chromatography e.g. on silica gel.

As indicated above reactions (a) to (I) may be carried out in any appropriate order such as is exemplified hereinafter. The ability to choose the order in which the side chains are introduced enables sides reactions to be avoided in many instances by ensuring that groupings sensitive to a particular reaction, for example reduction, are introduced subsequent to that reaction.

Thus, particular types of compounds according to the invention may be prepared by the following preferred reaction sequences: 1. for the preparation of compounds of general formula (I) wherein X represents a protected hydroxymethylene group, A represents an alk-trans-l-enyl group having from 5 to 16 carbon atoms and carrying a protected hydroxyl substituent in the y-position and B represents an alkyl group having from 5 to 16 carbon atoms and carrying a terminal protected carboxyl group: Reaction of a compound of formula (II) as hereinbefore defined with a compound of formula (III) as hereinbefore defined to give a compound of formula (IV) as hereinbefore defined; reaction of said compound of formula (IV) with a reagent of formula (Ar')3P=CH.CO.R' (where Ar' represents an aryl gropu and R' represents a straight or branched alkyl group having from 2 to 13 carbon atoms) to obtain a mixture of 2-position configurational isomers of formula:

(where R1 and R2 are as hereinbefore defined and R" is as defined above), reduction of one or both of said 2-position isomers to give a product of formula:

(where R' and R2 are as hereinbefore defined and R" is as defined above) which is subsequently deprotected to liberate the free aldehyde in the I-position and then reacted with a reagent of formula (Ar2)3P=CHRb (where Ar2 represents an aryl group and Rb represents an alkyl or alkenyl group having from 3 to 14 carbon atoms and carrying a terminal protected carboxyl group), the product thus obtained being then treated with an agent serving to protect the free hydroxyl group in the 2-position side chain whereby a protected hydroxyl compound is formed which is subsequently reduced by means of hydrogen and a nickel catalyst whereby a product of formula (I) is obtained.

The compound of formula (I) obtained above may, if desired, be subsequently reacted whereby the protecting groups of the protected hydroxymethylene group X and/or of the protected carboxyl group in B are removed. The compound of formula (I) thus formed may then optionally be oxidised to convert the ring hydroxyl group to an oxo group e.g. with an acidified dichromate solution and/or subjected to a deprotecting reaction whereby the protecting group on the hydroxyl in A is removed.

2. for the preparation of compounds of general formula (I) wherein X represents a protected hydroxymethylene group, A represents a 3-alkyl-3-hydroxyalk-trans-l-enyl group having from 5 to 16 carbon atoms and B represents an alkyl group having from 5 to 16 carbon atoms and carrying a terminal protected carboxyl group: Reaction of a compound of formula (II) as hereinbefore defined with a compound of formula (III) as hereinbefore defined to give a compound of formula (IV) as hereinbefore defined; reaction of said compound of formula (IV) with a reagnet of formula (Ar1)3P=CH CO Rc wherein Ar' is as hereinbefore defined and Rc represents a straight or branched alkyl group having 1--12 carbon atoms to obtain a mixture of 2-position configurational isomers of formula:

(where R', R2 and Rc are as hereinbefore defined); reaction of one or more of said 2-position isomers with a Grignard reagent of formula R9MgY (where R9 represents an alkyl group having 16 carbon atoms and Y represents a halogen atom) whereby a product of formula:

(where R', R2 and Rc are as hereinbefore defined and R9 is as defined above) is obtained, which product is then deprotected to liberate the free aldehyde in the 1position and then reacted with a reagent of formula (Ar2)3P=CIIRb as hereinbefore defined; the product thus obtained being then reduced by means of hydrogen and a nickel catalyst whereby a product of formula (I) is obtained.

The compound of formula (I) obtained may, if desired, be subsequently reacted whereby the protecting group of the protected hydroxymethylene group in X and/or of the protected carboxyl group in B are removed.

The product thus formed may then optionally be oxidised to convert the hydroxymethylene group X to a carbonyl group e.g. with an acidified dichromate solution.

3. for the preparation of compounds of the general formula (I) wherein X represents a protected hydroxymethylene group, A represents a group of formula

(where R" and R9 are as hereinbefore defined and B represents an alkyl or alkenyl group having from 5 to 13 carbon atoms and carrying a terminal carboxyl or protected carboxyl group: Reduction of a compound of formula (I) as hereinbefore defined wherein X represents a protected hydroxymethylene group and A represents a group of formula

as defined above, except that B represents an alkyl group having from 2 to 6 carbon atoms and carrying a terminal esterified carboxyl group, whereby the esterified carboxyl group in B is reduced to an aldehyde group, the compound thus formed being then reacted with a reagent of formula (Ar3)3P=CII-R10 (where Ar3 represents an aryl group and R10 represents a carboxyl or protected carboxyl group or an alkyl or alkenyl group having 1-9 carbon atoms and carrying a terminal carboxyl or protected carboxyl group) and, if desired, the product obtained is reduced and/or deprotected whereby the desired compound of formula (I) is obtained.

Any of the three preferred sequences described above may include a step of separating isomers which step may be carried out at any appropriate stage in the process using, for example preparative layer chromatography for example on silica gel.

The invention is further illustrated by way of the following non-limiting Examples. Examples 1--13, 2641, 67, 76 and 112 illustrate the preparation of intermediates only: in those Examples which are merely stated to follow the procedure of an earlier Example, the molar ratios of reactants were the same as in the earlier Example: all temperatures are in "C; n.m.r. spectra were determined in deuterochloroform; and preparative chromatography was carried out on silica plates.

Example 1.

6a-A cewxy-2-dimethoxymethyI4-cycIohexane-a-carboxahtehyde.

A mixture of freshly distilled 4-acetoxybutadiene (22g) and 4,4-dimethoxycrotonaldehyde (26g) in benzene (30 ml) containing methylene blue (0.05g) as a polymerisation inhibitor was heated under reflux for.72 hrs. After removal of lowboiling material under reduced pressure the residue was fractionally distilled. The fraction b.p. l05-l200/0.03mm afforded the title compound as a straw coloured viscous oil. n.m.r. 0.32 (CHO), 4.05 (2 vinyl H),

7.96 z (COOCH3).

Example 2.

3a-Acetoxy-2-(3-oxo-trans - I - octenyl) - 4 - cyclohexene - p - carboxaldehyde di methyl acetal (Mixture oj epimers at ring position 2) 2-Oxoheptyltriphenylphosphonium bromide (254g) suspended in diethyl ether (I I) and water (I I) was shaken with a solution of sodium hydroxide (25.4g) in water (250 ml) until complete solution was obtained. After separating the ethereal solution and washing with brine, evaporation of the ether afforded 2-oxoheptylidenetriphenyl-phosphorane which was dissolved in hot petroleum, b.p. 8-100", (1. 5 1) and the solution obtained was boiled to remove residual water from the phosphorane.

6a-Acetoxy-2-dimethoxymethyl-4-cycIohexene-a-carboxaldehyde (Example 1) (127 g) was then added and the resultant solution was heated under reflux for 16 hrs. After cooling and removal of crystalline triphenylphosphine oxide by filtration the residual solution was evaporated under reduced pressure. The resultant crude product was purified initially by stirring in concentrated ethereal solution with an equal weight of sodium metabisulphite as a 30% w/v aqueous solution.

The product so obtained was pure enough for certain processes of the invention but could be obtained in a pure state by chromatography on silica gel eluting with a petroleum ether/ethyl acetate mixture.

The product obtained in this way was a pale yellow viscous oil; n.m.r. 3.15 (d,d, J = 16 Hz, J = 10 Hz, I vinyl H adjacent to ring), 3.82 (d, J = 16 Hz, I vinyl H adjacent to C = 0, major isomer), 3.90 (d, J = 16 Hz, I vinyl H adjacent to C = 0, minor isomer), 3.90 (d, J = 16 Hz, I vinyl Hadjacent to C = 0, minor isomer), 4.10(2 vinyl H endocyclic), 4.80 (Cff - OAc),

7.96 t (OCOCH3).

Examples 3-7.

The products named in Table I were prepared from 6a-acetoxy-2,B-di- methoxymethyl-4-cyclohexene-a-carboxaldehyde employing a process similar to that of Example 2, except that the stated phosphonium salts were used.

TABLE I Example Phosphonium Salt Product 3 2-oxohexyltriphenylphosphonium 3α-Acetoxy-2-(3-oxo-trans-1-heptenyl)-4-cyclohexene- bromide carboxaldehyde dimethyl acetal (Mixture of epimers at ring position 2). n.m.r. 3.16, 3.7 - 4.3, 4.79, 5.85, 6.61, 6.64, 7.94, 8.9 - 9.3 #.

4 2-oxooctyltriphenylphosphoninm 3α-Acetoxy-2-(3-oxo-trans-1-nonenyl)-4-cyclohexene- bromide carboxalehyde dimethyl acetal. (Mixture of epimers at ring position 2). n.m.r. 3.12, 3.83, 4.08, 4.6 - 4.9, 5.7 - 5.9, 6.57, 7.47, 8.9 - 9.3 #.

5 2-oxononyltriphenylphosphonium 3α-Acetoxy-2-(3-oxo-trans-1-decenyl)-4-cyclohexene- bromide carboxaldehyde dimethyl acetal. (Mixture of epimers at ring position 2). n.m.r. 3.14, 3.81, 3.94 - 4.2, 4.77, 5.82, 6.59, 6.62, 7.91, 7.43, 8.9 - 9.2 #.

6 6-methyl-2-oxoheptyltriphenyl- 3α-Acetoxy-2-(7-methyl-3-oxo-trans-1-octenyl)-4-cyclophosphonium bromide hexene- -carboxaldehyde dimethyl acetal. (Mixture of epimers at ring position 2). n.m.r. 3.16, 3.85, 3.95 - 4.2, 4.78, 5.84, 6.60, 6.64, 7.47, 7.94, 9.11 #.

7 3-methyl-2-oxoheptyltriphenyl- 3α-Acetoxy-2-(4-methyl-3-oxo-trans-1-octenyl)-4-cyclophosphonium bromide hexene- -carboxaldehyde dimethyl acetal. (Mixture of epimers at ring position 2).

Example 8 3α - Hydroxy - 2 - (3 - oxo - trans - 1 - octenyl) - 4 - cyclohexene - - carboxaldehyde dimethyl acetal (Mixture of epimers at ring position 2) The unchromatographed product from Example 2 (175 g), dissolved in anhydrous methanol (300 ml), was added to a warm (400) solution of potassium hydroxide (28g) in anhydrous methanol (2.5 1). After keeping the mixture thus obtained at 400 in the absence of water for 6 minutes the product was isolated by pouring into excess brine and extraction with diethyl ether. Evaporation of the solvents afforded a dark oil which was chromatographed on silica gel, eluting with petroleum ether/ethyl acetate mixtures. From the chromatographic fractions was obtained the title compound (57g) as a pale viscous oil; n.m.r. 2.97 (d,d, J = 16 Hz, J = 10 Hz, I vinyl H adjacent to ring), 3.82 (d, J = 16 Hz, I vinyl H adjacent to C = 0, major isomer) 3.88 (d, J = 16 Hz, I vinyl H adj. to C = 0, minor isomer), 5.88 (CH OH).

Example 9.

3a - Acetoxy - 2 - (3S - hydroxy - trans - 1 - octenyl) - 4 - cyclohexene - ,B - carbox aldehyde dimethyl acetal and its 3R isomer The product of Example 2 (7.2g) in methanol (720 ml) was treated with an aqueous solution of sodium citrate (7.2g in 720ml water) and the resultant mixture was cooled to 40 and adjusted to pH 8.5 with 2N sodium hydroxide. Potassium borohydride (I .5g) was added thereto and the mixture obtained was kept at 40 and pH 8.5 for I hour by the dropwise addition of 5% w/v citric acid as required. The pH was then adjusted to about 4 with 5% w/v citric acid, diluted with excess brine and extracted into ethyl acetate. After washing and drying, evaporation of the solvent afforded the crude product, which was purified by chromatography on silica gel to give two title compounds. On n.m.r. the 3S-isomer shows the spectrum 3.90-4.60 (4 vinyl H), 4.81 (CH OAc), 5.89 (CH-OH),

7.94 T (OCOCH3) and the 3R-iKomer shows the spectrum 3.904.60 (4 vinyl H), 4.75 (CH-OAc),

5.90 (CH-OH),

7.94 t (OCOCH3) Example 10.

2 - (3 - Hydroxy - trans - 1 - octenyl) - 3a - hydroxy - 4 - cyclohexene - /3 - carbox aldehyde dimethyl acetal (mixture of ring position 2-epimers and epimeric alcohols) The product of Example 8 was treated by a process analogous to that described in Example 9 and the product was used without further purification in the next stage of the process.

Example 11.

Methyl 7 - [3 - acetoxy - 2a - (3 - t - butyldimethylsilyloxy - trans - I - octenyl) -4 - cyclo hexen - p - yU - 2,4,6 - heptatrienoate (Mixture of double bond isomers at 6 and of epimeric acetates and silyl ethers) The product of Example 9 (3.7g) in tetrahydrofuran (40 ml) was treated with 2N hydrochloric acid (4 ml) in a flask which was then flushed with nitrogen, stoppered and allowed to stand at room temperature overnight. The aldehyde product thus obtained was isolated by pouring the reaction mixture into brine containing excess sodium carbonate and extraction with diethyl ether. After washing the ether extracts with brine and drying over sodium sulphate, removal of the ether afforded unstable aldehyde which was immediately dissolved in toluene (40 ml) and dried again over sodium sulphate.

(5-Methoxycarbonyl-2,4-pentadienyl)triphenylphosphonium bromide (12g), suspended in a mixture of toluene (100 ml) and methylene chloride (10 ml), was shaken with an aqueous solution of sodium hydroxide (1.6g in 160 ml) until all the solid had dissolved. The blood red organic phase was separated, the aqueous phase washed with toluene (35 ml) and the combined organic phases were washed with brine and dried over sodium sulphate. After removal of the methylene chloride at 300 in vacuo, the resultant toluene solutions of the phosphorane and aldehyde were mixed and heated under reflux for 16 hrs. The toluene was then removed in vacuo and the residue obtained was treated with a 5:1 mixture of petroleum ether and ethyl acetate which precipitated some crystalline material. Evaporation cf the filtrate gave a reddish oil (6.3g) which was dissolved in dry dimethylformamide (40 ml) and the solution obtained was treated with imidazole (4 g) and t-butyldimethylsilyl chloride (4g). The resultant mixture was warmed at 400 for 16 hrs in the absence of water. The product was isolated by pouring the mixture into water containing a little sodium chloride and extraction with diethyl ether. The combined ether extracts were washed with dilute brine followed by drying over sodium sulphate. Evaporation afforded a yellow oil which was purified by chromatography on silica gel, eluting with a 20:1 mixture of petroleum ether and ethyl acetate. The title compound (2.2 g) was obtained as a pale yellow oil. n.m.r. 3.4--4.6 (10 vinyl H), 4.82(CH-OAc), 5.85 (CH-O Si Bu tMe2), 6.10 (COO CH3), 8.0 (OCO CH3),

Examples 12--13.

The dimethyl acetals of Table II were treated by a process analagous to that of Example 11 with the stated phosphonium salts, to yield the esters shown.

TABLE II Example Acetal of Example Phosphonium Salt Product 12 10 (5-Methoxycarbonyl-2-4-pentadienyltriphenyl- Methyl 7-[3-t-butyldimethylsilyloxy-2α-(3-t-butylphosphonium bromide dimethylsilyloxy-trans-1-octenyl)-4-cyclohexen -yl]-2,4,6-heptatrienoate, mixture of 6-double bond isomers and epimeric silyl ethers n.m.r. 2.50 - 4.90 (10 vinyl H), 5.94 (2H, CH OSi-t-Bu Me2), 6.15 (OCOCH3), 9.80 #

13 9 (5-Ethoxycarbonyl-2,4-pentadienyl)triphenyl- Ethyl 7-[3-acetoxy-2α-(3-t-butyldimethylsilyloxyphosphonium bromide -trans-1-octenyl-4-cyclohexen- -yl]-2,4,6-heptatrienoate (mixture of isomers at 6-double bond and of epimeric acetates and silyl ethers). n.m.r. 3.45-4.5 (10 vinyl H), 4.80 (CH-OAc), 5.85 (CH-O Si ButMe2), 5.76 (q, J = 7Hz, COCH2CH3), 8.0 (OCOCH3), 9.9 #.

Example 14.

Methyl 7 - [3 - acetoxy - 2α - (3 - t - butyldimethylsilyloxy - trans - 1 - octenyl) - cyclo hex - - yl)heptanoate. (Mixtures of acetate and stlyl ethers).

The product of Example 11 (2.2g) was hydrogenated at room temperature and 20 p.s.i. in ethanol over a P1 nickel catalyst [see C.A. Brown, J. Org. Chem (1970), 35, 1900) prepared from nickel acetate (2.2g). After 16 hrs. the hydrogenation was stopped, the catalyst was removed and the solution was rehydrogenated until the required 4 equivalents of hydrogen had been taken up. The product was isolated by filtration from the catalyst, evaporation of the ethanol and re-isolation of the residue from an ether solution which was washed with 5% aqueous citric acid. The product was a colourless oil which was normally used without further purification in the next stage of the process. However, when purified by chromatography on silica gel it gave the following n.m.r. 4.59 (2 vinyl H), 5.06 (CH-OAc, ax), 5.44 (CH-OAc, eq.), 5.96 (CH-O Si Bu tMe2), 6.35 (COOCH3), 7.96 (OCOCH3),

Example 15-16.

The heptatrienoate esters of Table III were treated by a process analgous to that of Example 14 to yield the products shown.

TABLE III Starting Heptatrienoate Example of Example Product 15 12 Methyl 7-[3-t-butyldimethylsilyloxy-2α-(3-t-butyldimethylsilyloxy -trans-1-octenyl)cyclohex- -yl]-heptanoate. (Mixture of epimeric silyl ethers) n.m.r. 4.3 (2 vinyl H), 6.15 (2H, CH O Si Bu tMe2) 6.30 (COO CH3), 9.9 #

16 13 Ethyl 7-[3-acetoxy-2α-(3-t-butyldimethylsilyloxy-trans-1-octenyl)cyclohex- -yl]heptanoate (mixtures of epimeric acetates and silyl ethers) n.m.r. 4.60 (2 vinyl H) 5.11 (CH-OAc, ax.), 5.46 (CHOAc, eq.) 5.92 (CH-O Si ButMe2), 5.82 (a. J = 7 Hz. CO CH2CH3), 7.95 (OCOCH3). 9.8 #

Example 17.

Methyl 7 - [3 - acetoxy - 2α - (3 - oxo - trans - 1 - octenyl) - cyclohex - - yl] - heptanoate, (mixture of epimeric acetates).

The product of Example 14 (5.8g) in tetrahydrofuran (58 ml), acetic acid (58 ml) and water (29 ml) was warmed at 50 for 24 brs. After removal of the solvents in vacuo the residual crude alcohol was oxidised in diethyl ether (50 ml) by stirring vigorously for 24 hrs. at room temperature with an aqueous solution of sodium dichromate (2.6g, in 50 ml) containing sulphuric acid (2.37 ml). After dilution with water, the crude product was isolated by ether extraction and purified by preparative t.l.c. (4:1 light petroleum/ethyl acetate). Elution of the required band with diethyl ether afforded the title compound, n.m.r. 3.28 (d,d, J = 16 Hz, J = 10 Hz, I vinyl H adj. to ring, major isomer), 3.52 (d,d 3 = 16 Hz, 3 = 10 Hz, I vinyl H adj. to ring, minor isomer), 3.88 (d, J = 16 Hz, I vinyl H adj. to C=0, major isomer), 3.94 (d, J = 6 Hz, I vinyl H adj. to C=0, minor isomer), 4.98 (CH-OAc, ax.), 5.24 (CH-OAc, eq.), 6.32 (COOCH3), 7.48 (CH2- CO), 7.72 (CH2-CO2-Me), 7.94 t (OCOCH3).

Example 18.

Methyl 7 - [3 - acetoxy - 2a - (3 - oxo - octyl)cyclohex - ,B - yl) - heptanoate. (Mixture of epimeric acetates.

The product of Example 17 (0.8g), dissolved in ethanol (90 ml), was hydrogenated at room temperature and atmospheric pressure over 5% palladium on charcoal (0.lg). When the theoretical uptake of hydrogen had taken place the catalyst was filtered off and the title compound was isolated by solvent evaporation, n.m.r. 4.92 (CH-OAc, ex.), 5.34 (CH-OAc, eq.), 6.29 (COOCH3), 7.66 T (CH2-CO-CH2 and CH2CO2Me).

Example 19.

7 - [2a - (3 - Hydroxyoctyl) - 3 - oxocyclohex - p - yl]heptanoic acid. Mixture of epimeric alcohols.

The product of Example 18 (0.6g), in methanol (6 ml) containing 2 drops of 2N sodium hydroxide solution, was treated with sodium borohydride (0.22g). After standing at room temperature for 4 hrs. the mixture obtained was acidified and extracted with diethyl ether. The resultant oil was dissolved in dry dimethylformamide (2.5 ml) and treated with imidazole (0.23g) and t-butyldimethylsilyi chloride (0.23g). After standing at room temperature in a stoppered vessel for 68 hours the mixture was diluted with water and extracted with diethyl ether. The extracts were washed thoroughly with water, then with brine, dried and evaporated to give a crude silyl ether (0.7g). This was dissolved in methanol (36 ml) and treated with aqueous sodium hydroxide (0.53g in 9 ml water). After stirring at room temperature for 3 days the crude silylated hydroxy acid was isolated by acidification and ether extraction. The crude acid (0.6g) was then oxidised in ethereal solution (6 ml) by stirring with an aqueous solution of sodium dichromate (0.32g in 6 ml water) containing sulphuric acid (0.29 ml). After 24 hrs. at room temperature the product was isolated by dilution with water and ether extraction.

The water-washed extracts were dried and evaporated to give the crude keto acid silyl ether (0.5g). This was then dissolved in a 3:2:1 mixture of tetrahydrofuran, acetic acid and water (5 ml) and heated at 500 overnight. Evaporation of the solvents under reduced pressure gave the crude product which was purified by preparative t.l.c. (20:1 chloroform/methanol). Elution of the desired band with methanol followed by re-isolation with ether washed with 5% citric acid afforded the title compound, n.m.r. 6.3 (CH-OH), 7.64 T (CH2CO2H and CH2CO).

Example 20.

7 - [3 - Hydroxy - 2hx - (3 - t - butyldimethylsilyloxy - trans - 1 - octenyl) - cyclohex -P- yllheptanoic acid (Mixture of epimeric alcohols and silyl ethers).

The product of Example 14 (11.3g), in methanol (240 ml), was stirred with an aqueous solution of sodium hydroxide (12.2g in 120 ml) for 16 hrs. (Homogeneity was obtained after about 8 hrs). The mixture obtained was poured into excess 5% w/v citric acid solution and extracted with ether. The extracts were washed with brine, dried and evaporated to give the crude product (8g) which was normally used without further purification in subsequent stages of the process.

Example 21.

7 - [3a - Hydroxy - 2a - (3(5) - hydroxy - trans - I - octenyl)cyclohex - - yU - heptanoic acid and corresponding 3R-isomer.

The product of Example 20 (4g) in tetrahydrofuran (75 ml) was warmed at 500 for 16 hrs. with glacial acetic acid (50 ml) and water (25 ml). Solvents were then removed in vacuo and the residue was freed from residual acetic acid and silyl byproducts by repeated dissolution in toluene and evaporation. Purification of the residue by preparative t.l.c. on silica gel afforded the title compounds. The more polar S-isomer, (0.8g) crystallised from ethyl acetate/petroleum ether m.p. 9496 n.m.r. (CD3OD) 4.42 (2 vinyl H),

6.12 (CH-OH), 7.72 t (CH2COOH). The less polar R-isomer (l.lg) crystallised on standing and was recrystallised from ethyl acetate/cyclohexane, m.p. 7677 n.m.r. (CD3OD), 4.50 (2 vinyl H),

6.18 (CH-OH), 7.74 T (CH2COOH).

Example 22.

7 - [2a - (3 - t - Butyldimethylsilyloxy - trans - 1 - octenyl) - 3 - oxocyclohex -P- - yll heptanoic acid (Mixture of epimeric silyl ethers) The product of Example 20 (lOg), in diethyl ether (100 ml), was treated with a solution of sodium dichromate (30g) in water (100 ml) and sulphuric acid (5.3g).

The two-phase mixture was stirred at room temperature overnight, then the product was isolated with water and extracted with diethyl ether. The combined ether extracts were washed with water, dried and evaporated to give a colourless oil which was purified by preparative t.l.c. on silica gel developing with a 2:1 mixture of petroleum ether and ethyl acetate. The title compound was eluted as a colourless oil (3.7g). n.m.r. 4.50 (2 vinyl H), 5.94 (CH-O Si Bu tMe2), 7.32 (CO-CH--CH=CH),</R Example 25.

Methyl 7 - [2ar - (3S - acetoxy - trans - I - octenyl) - 3 - t - butyldimethylsilyloxycyclo hex - p - yl heptanoate and the corresponding 3R-isomer. (Mixture of epimeric silyl ethers).

The monosilyl ether product of Example 24 (300 mg) was dissolved in pyridine (0.6 ml) and the solution obtained was treated with acetic anhydride (0.3 ml). The mixture was kept at room temperature overnight and the product formed was then isolated by standard means. Purification using preparative t.l.c. afforded the title 3S-isomer and the more polar compound, n.m.r. 4.55 (2 vinyl H), 4.74 (CH--OAc), 6.16 (CH-O Si Bu 'Me2), 6.33 (COOCH3) 7.69 (CH2COOMe), 7.97 (OCOCH3),

and the 3R-isomers as the less polar compound; n.m.r. 4.55 (2 vinyl H), 4.73 (CH-OAc), 6.14 (CH-O Si Bu 'Me2), 6.31 (COOCH3), 7.68 (CH2COOMe), 7.96 (OCOCH3),

Example 26.

3&alpha; - Acetoxy - 2 - (4,4 - dimethyl - 3 - oxo - trans - 1 - octenyl) - 4 - cyclohexene - ss carboxaldehyde dimethyl acetal (Mixture of epimers at ring position 2).

To a stirred solution of diisoproPylamine (8.5g) and a catalytic amount of 2,2bipyridyl in dry diethyl ether (100 ml) cooled to -700 under nitrogen was added a solution of butyl lithium in hexane (1.6M, 45ml) over 5 mins. The solution was then stirred at -70" for I h after which 3,3-dimethyl-2-heptanone (11.6g) in dry diethyl ether (30 ml) was added. After a further 1 hr of stirring at -700 a solution of 6a- acetoxy-2ss-dimethoxymethyl 4Tcyclohexene-cr-carboxaldehyde (Example 1) (20g) in dry diethyl ether (100 ml) was added thereto and the temperature was allowed to rise to -200 over a periof of It hours. Aqueous citric acid (20g in 100 ml) was then added to the resultant mixture and the mixture thus obtained was stirred at 250 for' 1 h before extracting with diethyl ether to afford the crude intermediate (33g). This was dissolved in methanol (100 ml) containing potassium hydroxide (5g) and the resultant solution was warmed at 400 for 10 mins. Dilution with water and ether extraction afforded an oil (31g) which was acet lated with a mixture of pyridine (60 ml) and acetic anhydride (30 ml) at 250 for 18 hrs. After dilution with diethyl ether and washing successively with dilute hydrochloric acid and sodium carbonate solution, the organic layer was dried over sodium sulphate and evaporated to give the crude product (30.5g). Purification was carried out by chromatography on silica gel (2:1 petroleum ether/ethyl acetate) to give the title compound (12.5g).

Example 27.

3a - Acetoxy - 2 - (4.4 - dimethyl - 35 - hydroxy - trans - I - octenyl) - 4 - cyclohexene ss - carboxaldehyde dimethyl acetal. (Mixture of epimers at ring position 2) and corresponding 3R-isomer.

The title compounds were prepared by a process analogous to that of Example 9 except that the starting material was the product from Example 26. Separation of the R- and S-isomers was achieved by preparative t.l.c. (2:1 petroleum ether/ethyl acetate). The more polar S-isomer showed the n.m.r. spectrum: 3.9-4.4, 4.80, 5.71, 6.28, 6.60, 7.98, 9.14 #. and the R-isomer, n.m.r. 3.9-4.4, 4.78, 5.74, 6.1-6.3, 6.61, 7.96, 9.12 T.

Example 28.

3a - Acetoxy - 2 - (3 - hydroxy - 3 - methyl - trans - 1 - heptenyl) - 4 - cyclohexene - ss - carboxaldehyde dimethyl acetal. (Mixture of epimers at ring position 2 and in side chain).

The product from Example 3 (20g), dissolved in dry diethyl ether (200 ml), was added dropwise with stirring at -15 to a solution of methylmagnesium iodide in dry diethyl ether (500 ml) prepared from magnesium (9g) and methyl iodide (48g). After the addition was complete, stirring was continued at -15 for 3 h. The mixture obtained was then poured gradually with stirring on to excess crushed ice and the resultant mixture was acidified to pH4 with a 5% citric acid solution.

Extraction with diethyl ether afforded the title compound (20g).

Examples 29-35 The products named in Table IV were prepared by a process analagous to that of Example 28 except that the stated starting materials and Grignard reagents were used.

TABLE IV Starting Dimethyl Example Acetal of Example Grignard Reagent Product 29 4 Methylmagnesium 3&alpha;-Acetoxy-2-(3-hydroxy-3-methyl-trans-1-nonenyl)-4-cyclo Iodide hexene-ss-carboxaldehyde dimethyl acetal (mixture of ring position 2 and sidechain isomers) 30 5 Methylmagnesium 3&alpha;-Acetoxy-2-(3-hydroxy-3-methyl-trans-1-decenyl)-4-cyclo Iodide hexene-ss-carboxaldehyde dimethyl acetal (mixture of ring position 2 and sidechain isomers) 31 6 Methylmagnesium 3&alpha;-Acetoxy-2-(3-hydroxy-3,7-dimethyl-trans-1-octenyl)-4-cyclo Iodide hexene-ss-carboxaldehyde dimethyl acetal (mixture of ring position 2 and sidechain isomers) 32 7 Methylmagnesium 3&alpha;-Acetoxy-2-(3-hydroxy-3,4,4-trimethyl-trans-1-octenyl)-4 Iodide cyclohexene-ss-carboxaldehyde dimethyl acetal (mixture of ring position 2 and sidechain isomers) n.m.r. 3.9 - 4.6, 4.6 - 4.9, 5.66, 7.2 - 7.6, 7.78, 7.94, 8.68, 9.06 #.

33 2 Methylmagnesium 3&alpha;-Acetoxy-2-(3-hydroxy-3-methyl-trans-1-octenyl)-4-cyclo Iodide hexene-ss-carboxaldehyde dimethyl acetal (mixture of ring position 2 and sidechain isomers) n.m.r. 3.8 - 4.6, 4.6 - 4.9, 5.6 - 5.8, 6.56, 7.2 - 8.8, 7.97, 8.9 - 9.3 #.

34 2 Ethylmagnesium 3&alpha;-Acetoxy-2-(3-ethyl-3-hydroxy-trans-1-octenyl)-4-cyclo Bromide hexene-ss-carboxaldehyde dimethyl acetal (mixture of epimers) 35 2 Cyclopentylmagnesium 3&alpha;-Acetoxy-2-(3-cyclopentyl-3-hydroxy-trans-1-octenyl)-4 Bromide cyclohexene-ss-carboxaldehyde dimethyl acetal (mixture of epimers) Example 36.

3a - Acetoxy -2 - (3 - acetoxy - trans - 1 - octenyl) - 4 - cyclohexene -'3 - carboxaldehyde dim ethyl acetal.

The product of Example 9 (mixture of R- and S-isomers) (l.5g) was dissolved in a mixture of dry pyridine (3 ml) and acetic anhydride (1.5 ml) and the mixture obtained was allowed to stand in the absence of moisture at room temperature overnight. The product thus formed was isolated by dilution with water and extraction with diethyl ether. The ether extracts were washed with a dilute solution of hydrochloric acid and sodium carbonate successively, dried and evaporated to give the title compound (1.5g) n.m.r. 3.9=4.9, 5.80, 6.65, 7.98, 9.12 T.

Example 37.

3a - Acetoxy -2 - (3 - hydroxy - 3 - methyl - trans - I - heptenyl) - 4 - cyclohexenecarbox aldehyde. (Mixture of ring and sidechain isomers).

The product of Example 28 (10g), dissolved in dimethylformamide (200 ml), was warmed with 2N hydrochloric acid (10 ml) at 38C for 18 h. The resultant mixture was then poured into water and extracted with diethyl ether. The ether extracts were washed thoroughly with water, then with brine, dried and evaporated to give the crude title compound. This was normally used without further purification but a pure sample could be obtained by chromatography on silica gel, eluting with petroleum ether/ethyl acetate mixtures.

Examples 38=47.

The products named in Table V were prepared by a process analagous to that of Example 37, except that the stated starting materials were used.

TABLE V Starting Dimethyl Example Acetal of Example Product 38 29 3&alpha;-Acetoxy-2-(3-hydroxy-3-methyl-trans-1-nonenyl)-4-cyclohexencarboxaldehyde (Mixture of ring and sidechain isomers) 39 30 3&alpha;-Acetoxy-2-(3-hydroxy-3-methyl-trans-1-decenyl)-4-cyclohexenecauboxaldehyde (Mixture of ring and sidechain isomers) n.m.r. 0.33, 3.8-4.6, 4.78, 7.96, 8.94-9.3 #.

40 31 3&alpha;-Acetoxy-2-(3-hydroxy-3,7-dimethyl-trans-1-octenyl)-4-cyclohexenecarboxaldehyde (Mixture of ring and sidechain isomers) n.m.r. 0.36, 3.9-4.7, 4.79, 7.97, 7.1-7.4, 9.11, 9.19 #.

41 32 3&alpha;-Acetoxy-2-(3-hydroxy-3,4,4-trimethyl-trans-1-octenyl)-4-cyclohexenecarboxaldehyde. (Mixture of ring and sidechain isomers) 42 33 3&alpha;-Acetoxy-2-(3-hydroxy-3-methyl-trans-1-octenyl)-4-cyclohexenecarboxaldehyde. (Mixture of ring and sidechain isomers) n.m.r. 0.34, 3.8-5.0, 6.60, 7.86, 4.75, 7.5, 9.11 #.

43 34 3&alpha;-Acetoxy-2-(3-hydroxy-3-ethyl-trans-1-octenyl)-4-cyclohexenecarboxaldehyde. (Mixture of ring and sidechain isomers) 44 35 3&alpha;-Acetoxy-2-(3-hydroxy-3-cyclopentyl-trans-1-octenyl)-4cyclohexenecarboxaldehyde. (Mixture of ring and sidechain isomers) TABLE V (Continued) Starting Dimethyl Example Acetal of Example Product 45 27 3&alpha;-Acetoxy-2-(3S-hydroxy-4,4-dimethyl-trans-1-octenyl)-4 (3S-epimer) cyclohexenecarboxaldehyde. (Mixtures of ring epimers) 46 27 3&alpha;-Acetoxy-2-(3R-hydroxy-4,4-dimethyl-trans-1-octenyl)-4 (3R-epimer) cyclohexenecarboxaldehyde. (Mixture of ring epimers) 47 36 3&alpha;-Acetoxy-2-(3-acetoxy-trans-1-octenyl)-4-cyclohexenecarboxaldehyde. (Mixture of epimers).

Example 48.

Methyl 7 - [3 - Acetoxy - 2&alpha; - (3 - hydroxy - 3 - methyl - trans - 1 - heptenyl) - 4 - cyclo hexen - ss - yl) - 2,4,6 - heptatrienoate. (Mixture of acetates).

A suspension of 5-methoxycarbonyl-2,4-pentadienyltriphenylphosphonium bromide (3.8g) in toluene (190 ml) and water (190 ml) was shaken with sodium hydroxide solution (0.76g, in 5 ml) until complete dissolution was obtained. The resultant blood-red solution of the phosphorane in toluene was separated, washed with brine, dried and concentrated to about half its volume.

To this solution was added the product of Example 37 (1.2g) in toluene (10 ml) and the resultant mixture was heated under reflux for 18 h. After evaporation of the toluene and treatment of the residue with petroleum ether/ethyl acetate mixtures, some crystalline material was filtered off and the filtrate, after evaporation, was chromatographed on silica gel. Elution with a petroleum ether/ethyl acetate mixture gave the title compound (1.2g) as a yellow viscous oil n.m.r. 3.1-4.6, 2.5-2.9, 4.76, 6.23, 7.94, 7.97, 8.9-9.3 #.

Examples 49-58.

The products named in Table VI were prepared by a process analagous to that of Example 48 except that the stated starting materials and phosphonium salts were used.

TABLE VI Cyclohexene Carboxaldehyde Example of Example Salt Product 49 38 5-methoxycarbonyl-2,4- Methyl 7-[3-acetoxy-2&alpha;-(3-hydroxy-3-methyl-trans-1-nonenyl)-4pentadienyltriphenyl- cyclohexen-ss-yl]-2,4,6-heptatrienoate. (Mixture of acetates) phosphonium bromide 50 39 5-methoxycarbonyl-2,4- Methyl 7-[3-acetoxy-2&alpha;-(3-hydroxy-3-methyl-trans-1-decenyl)-4pentadienyltriphenyl- cyclohexen-ss-yl]-2,4,6-heptatrienoate. (Mixture of acetates) phosphonium bromide n.m.r. 2.5-2.9, 3.3-4.6, 4.78, 6.28, 7.99, 9.12 51 40 5-methoxycarbonyl-2,4- Methyl 7-[3-acetoxy-2&alpha;-(3-hydroxy-3,7-dimethyl-trans-1-octenyl)pentadienyltriphenyl- 4-cyclohexene-ss-yl)-2,4,6-heptatrienoate. (Mixture of acetates) phosphonium bromide n.m.r. 3.3-4.6, 4.5-5.0, 4.78, 6.28, 7.99, 8.81, 9.17 #.

52 41 5-methoxycarbonyl-2,4- Methyl 7-[3-acetoxy-2&alpha;-(3-hydroxy-3,4,4-trimethyl-trans-1pentadienyltriphenyl- octenyl)-4-cyclohexen-ss-yl]-2,4,6-heptatrienoate. (Mixture of phosphonium bromide acetates) n.m.r. 3.0-4.8, 4.7-4.9, 6.29, 8.04, 9.0-9.3 #.

53 47 5-methoxycarbonyl-2,4- Methyl 7-[3-acetoxy-2&alpha;-(3-acetoxy-2&alpha;-(3-acetoxy-rans-1pentadienyltriphenyl- octenyl)-4-cyclohexen-ss-yl)-2,4,6-heptatrienoate phosphonium bromide 54 43 5-methoxycarbonyl-2,4- Methyl 7-[3-acetoxy-2&alpha;-(3-ethyl-3-hydroxy-trans-1-octenyl)-4pentadienyltriphenyl- cyclohexen-ss-yl]-2,4,6-heptatrienoate. (Mixture of acetates) phosphonium bromide n.m.r. 2.5-3.0, 3.3-4.9, 5.09, 6.27, 7.99, 8.9-9.3 #.

TABLE VI (Continued) Cyclohexene Carboxaldehyde Example of Example Salt Product 55 44 5-methoxycarbonyl-2,4- Methyl 7-[3-acetoxy-2&alpha;-(3-cyclopentyl-3-hydroxy-trans-1pentadienyltriphenyl- octenyl) -4-cyclohexen-ss-yl]-2,4,6-heptatrienoate. (Mixture of phosphonium bromide acetates) 56 42 Ethoxycarbonylmethyl- Ethyl 3-[3-acetoxy-2&alpha;-(3-hydroxy-3-methyl-trans-1-octenyl)-4triphenylphosphonium cyclohexen-ss-yl]-2-propenoate. (Mixture of acetates) bromide n.m.r. 4.78, 5.82, 7.96, 7.98, 8.72, 9.12 #.

57 42 3-ethoxycarbonyl-2- Ethyl 5-[3-acetoxy-2&alpha;-(3-hydroxy-3-methyl-trans-1-octenyl)-4propenyltriphenyl- cyclohexen-ss-yl]-2,4-pentadienoate. (Mixture of acetates) phosphonium bromide n.m.r. 3.5-4.6, 4.80, 5.79, 7.97, 9.12 #.

58 42 5-methoxycarbonyl-4,4- Methyl 7-[3-acetoxy-2&alpha;-(3-hydroxy-3-methyl-trans-1-octenyl)-4dimethyl-2-oxopentyl- cyclohexen-ss-yl]-3,3-dimethyl-5-oxo-6-heptenoate, (Mixture of triphenylphosphonium acetates) bromide n.m.r. 3.32, 3.6-4.6, 4.85, 6.32, 7.93-7.95, 8.9-9.3, 8.72 #.

Example 59.

Methyl 7 - [3 - acetoxy - 2&alpha; - (3S - t - butyldimethylsilyloxy - 4,4 - dimethyl - trans - 1 octenyl) - 4 - cyclohexen - ss - yl] - 2,4,6 - heptatrienoate. (Mixture of acetates).

A suspension of 5-methoxycarbonyl-2,4-pentadienyltriphenylphosphonium bromide (7.6g) in toluene (380 ml) and water (380 ml) was shaken with sodium hydroxide (1.52g in 5 ml) until complete dissolution was obtained. The resultant blood-red solution of the phosphorane in toluene was separated, washed with brine, dried and concentrated to half its bulk. To this solution was added the product of Example 45 (2.4g) in toluene (20 ml) and the mixture obtained was heated under reflux for 18 h. After evaporation of the toluene and treatment of the residue with petroleum ether/ethyl acetate mixtures some crystalline material was filtered off and the filtrate, after evaporation, was dissolved in dry dimethylformamide (30 ml) and treated with imidazole (3g) and t-butyldimethylsilyl chloride (3g). The mixture was warmed at 40 for 16 h in the absence of water. The product obtained was isolated by dilution with water and extraction with diethyl ether. The water-washed extracts were dried over sodium sulphate and evaporated to give a yellow oil which was purified by chromatography on silica gel eluting with a 20:1 mixture of petroleum ether and ethyl acetate. The title compound (2.lug) was eluted as a yellow oil.

Example 60.

Methyl 7 - [3 - acetoxy - 2a - (3R - t - butyldimethylsllyloxy - 4,4 - dimethyl - trans - I octenyl) - 4 - cyclohexen - p - yll - 2,4,6 - heptatrienoate. (Mixture of acetates).

The title compound was prepared by a process analagous to that used in Example 59 except that the starting material was the product of Example 46.

Example 61.

6 - [3 - Acetoxy - 2a - (3 - hydroxy - 3 - methyl - trans - I - octenyl) - 4 - cyclohexen - '3 - yll - 5 - cis - hexenoic acid. (Mixture of acetates) and corresponding methyl ester.

Sodium hydride as a 50% dispersion in oil (3.12g) was freed of oil was washing with petroleum ether (3 times). The resultant petroleum ether-wet slurry was dried in a stream of nitrogen. Dry dimethyl sulphoxide (60ml) was then added thereto and the mixture obtained was heated at 70--800 until all gas evolution had ceased.

The resultant solution was allowed to cool and any precipitate to settle. 30 ml of the clear supernatant solution was carefully withdrawn and transferred to a flask containing 4-carboxybutyltriphenylphosphonium bromide (7.2g) which had been flushed with nitrogen. The mixture obtained was stirred under nitrogen for 15 mins before the addition of the product of Example 42 (2.5g) in dry dimethyl sulphoxide (10 ml) after which the resultant mixture was kept for I h at 250 and then warmed to 50 for 3 h. The crude acid was isolated by dilution with water, extraction with diethyl ether to remove unwanted neutral material, then acidification of the aqueous phase with 5% citric acid followed by ether extraction.

Evaporation of the extracts gave the crude acid (3.5g) which was purified by preparative t.l.c. (9:1 CHCldMeOH). n.m.r. 3.6-5.2, 7.96 t. The acid was then esterified by treatment with an excess of ethereal diazomethane. Excess diazomethane was then destroyed with acetic acid and the resultant ethereal solution of the product was washed with dilute sodium carbonate solution, with brine and evaporated. The title ester was a colourless oil, n.m.r. 4.5.0, 6.28, 7.62, 7.9-8.0, 9.08 t.

Example 62.

Methyl 7 - [3 - acetoxy - 2a - (3 - hydroxy - 3 - methyl - trans - I - heptenyl) - cyclohex ,8 - yl) - heptanoate. (Mixture of acetates).

To a solution of nickel acetate (1.2g) in water (10 ml) contained in a 250 ml flask flushed with nitrogen, was carefully added powdered sodium borohydride.

After the vigorous gas evolution had subsided. the deposited black granular catalyst was separated by decantation under nitrogen and washed twice with methanol (30 ml) by a decantation procedure.

A solution of the product of Example 48 (1.2g), in methanol (50 ml), was then added to the catalyst and the mixture was hydrogenated at room temperature and atmospheric pressure until the required amount of hydrogen had been taken up.

(Normally about 24 h). Removal of the catalyst by filtration and the solvent by evaporation then afforded the title compound (1.2g).

Examples 63-73.

The products named in Table VII were prepared by a process analagous to that of Example 62, except that the stated starting materials were used.

TABLE VII Starting Ester Example of Example Product 63 49 Methyl 7-[3-acetoxy-2&alpha;-(3-hydroxy-3-methyl-trans-1-nonenyl)-cyclohex-ss-yl]-heptanoate. (Mixture of acetates) 64 50 Methyl 7-[3-acetoxy-2&alpha;-(3-hydroxy-3-methyl-trans-1-decenyl)-cyclohex-ss-yl]-heptanoate. (Mixture of acetates) n.m.r. 4.2-4.6, 6.34, 7.70 (t. J = 7), 7.96, 8.03, 8.9-9.3 #.

65 51 Methyl 7-[3-acetoxy-2&alpha;-(3-hydroxy-3,7-dimethyl-trans-1-octenyl)-cyclohex-ss-yl]-heptanoate. (Mixture of acetates) n.m.r. 4.2-4.6, 5.02, 6.32, 7.80, 7.96, 8.02, 8.73, 8.76, 9.12 (d, J = 6) #.

66 52 Methyl 7-[3-acetoxy-2&alpha;-(3-hydroxy-3,4,4-trimethyl-trans-1-octenyl)cyclohex-ss-yl]-heptonoate. (Mixture of acetates) n.m.r. 4.0-4.6, 4.98, 6.28, 7.1-7.5, 7.70, 7.96, 8.02, 8.9-9.4 #.

67 56 Ethyl 3-[3-acetoxy-2&alpha;-(3-hydroxy-3-methyl-trans-1-octenyl)-cyclohex-ss-yl]-propionate. (Mixture of acetates) n.m.r. 4.2-4.6, 4.99, 5.86, 7.72, 7.94, 8.01, 8.70, 9.11 68 57 Ethyl 5-[3-acetoxy-2&alpha;-(3-hydroxy-3-methyl-trans-1-octenyl)-cyclohex-ss-yl]-pentanoate. (Mixture of acetates) n.m.r. 4.3-4.6, 5.00, 5.86, 7.71, 7.94, 9.11 #.

69 61 Methyl 6-[3-acetoxy-2&alpha;-3-hydroxy-3-methyl-trans-1-octenyl)-cyclohex-ss-yl]-hexanoate. (Mixture of acetates) TABLE VII (Continued) Starting Ester Example of Example Product 70 58 Methyl 7-[3-acetoxy-2&alpha;-(3-hydroxy-3-methyl-trans-1-octenyl)-cyclohex-ss-yl]3,3-dimethyl-5-oxoheptanoate. (Mixture of acetates) n.m.r. 4.3-4.6, 5.00, 6.34, 7.94, 8.01, 9.0-9.3 #.

71 53 Methyl 7-[3-acetoxy-2&alpha;-(3-acetoxy-trans-1-octenyl)-cyclohex-ss-yl]heptanoate. (Mixture of acetates) n.m.r. 4.2-4.9, 5.03, 5.84, 6.33, 7.70 (t, J = 7), 7.95 7.97, 8.02, 8.9-9.3, 7.8-9.0 #.

72 54 Methyl 7-[3-acetoxy-2&alpha;-(3-ethyl-3-hydroxy-trans-1-octenyl)-cyclohex-ss-yl]-heptanoate. (Mixture of acetates) n.m.r. 4.3-4.8, 4.9-5.5, 6.35, 7.73, 8.03, 9.0-9.3 #.

73 55 Methyl 7-[3-acetoxy-2&alpha;-(3-cyclopentyl-3-hydroxy-trans-1-octenyl)cyclohex-ss-yl]-heptanoate. (Mixture of acetates) n.m.r. 4.2-4.7, 5.04, 5.96, 6.36, 7.72, 7.98, 8.9-9.3 #.

Example 74.

Methyl 7 - [3&alpha; - acetoxy - 2&alpha; - (3S - t - butyldimethylsilyloxy - 4,4 - dimethyl - trans - 1 octenyl)cyclohex - ss - yl]heptanoate and the corresponding 3ss - acetate.

The title compounds were prepared by a process analogous to that of Example 62 except that the starting material was the product of Example 59. Separation of the 3&alpha;- and 3ss-acetates was achieved by preparative t.l.c. on silica gel (10:1 petroleum ether/ethyl acetate). The more polar ss- (equatorial) acetate showed the following n.m.r. spectrum. 4.4-4.6, 5.1-5.3, 6.1-6.3, 6.32, 7.70, 8.00, 9.16 #.

The less polar &alpha;- (axial) acetate showed the following n.m.r. spectrum.

4.4-4.8, 6.2-6.4, 6.33, 7.70, 7.99, 8.01 #.

Example 75.

Methyl 7 - [3&alpha; - acetoxy - 2&alpha; - (3R - t - butyldimethylsilyloxy - 4,4 - dimethyl - trans - 1 octenyl)cyclohex -ss - yl]heptanoate and the corresponding 3ss - acetate.

The title compounds were prepared by a process analogous to that of Example 52 except that the starting material was the product of Example 60.

Separation of the 3&alpha;- and 3ss-acetates was achieved by preparative t.l.c. on silica gel (10:1 petroleum ether/ethyl acetate). The more polar ss-(equatorial) acetate showed the following n.m.r. spectrum. 4.3-4.6, 6.31, 6.58, 7.99, 9.04 #. and the less polar &alpha;-(axial) acetate had the following n.m.r. 4.4-4.7, 4.9-5.1, 6.2-6.3, 6.26, 7.61, 7.87, 9.09 T.

Example 76.

* 3 - [ - 3 - Acetoxy - 2&alpha; - (3 - hydroxy - 3 - methyl - trans - 1 - (octenyl) - cyclohex - ss - yl] propionaldehyde.

Into a 250 ml flask containing toluene (34 ml) flushed with nitrogen was introduced a solution of sodium bis(2-methoxyethoxy)aluminium hydride (70% solution in benzene; 34 ml). The flask was then fitted with a septum cap. The resultant solution was cooled in ice and treated slowly via a syringe with morpholine (11g) in toluene (60 ml). (Hydrogen evolution necessitated the presence of a small 'bleed' needle in the septum cap to avoid pressure build-up).

After the addition was complete, the reagent was transferred dropwise via a syringe to a stirred, cooled (-40 ) solution of the product of Example 67 (4.8g) in toluene (100 ml) under nitrogen. The temperature was kept below -40 during the addition. The reaction mixture thus obtained was stirred at -400 to -600 under nitrogen for 5 h, and the mixture was then poured onto excess crushed ice. The resultant mixture was acidified with 5% citric acid and extracted with diethyl ether.

The extracts were washed, dried and evaporated to give the crude product (4.5g) which was purified by chromatography on silica gel (petroleum ether/ethyl acetate, 1:1). The title compound (1.1g) had n.m.r. 0.28, 4.2-4.6, 5.01, 7.59, 7.96, 8.02, 8.9-9.3 T.

Example 77.

Methyl 8 - [3 - acetoxy - 2&alpha; - (3 - hydroxy - 3 - methyl - trans - 1 - octenyl)cyclohex - ss yU - 5 - cis - octenoate. (Mixture of acetates).

The title compound was prepared by a procecss analogous to that ol Example 61 except that the starting material was the product of Example 76 n.m.r. 4.4=4.8, 5.08, 6.38, 7.72, 8.00, 8.07, 8.81, 8.78, 8.9-9.3 T.

Example 78.

Methyl 9 - [3 - acetoxy - 2ar - (3 - hydroxy - 3 - methyl - trans - I - octenyl)cyclohex ss - yl] - 2,4,6 - nonatrienoate. (Mixture of acetates). n.m.r. 2.5-3.0, 3.4-4.6, 5.00, 6.23, 7.93, 8.00 #. The title compound was prepared by a process analogous to that of Example 48, except that the starting material was the product of Example 76.

Example 79.

Methyl 8 - [3 - acetoxy - 2&alpha; - (3 - hydroxy - 3 - methyl - trans - 1 - octenyl) - cyclohex ss - yl]octanoate. (Mixture of acetates).

The title compound was prepared by a process analogous to that of Example 62, except that the starting material was the product of Example 77.

Example 80.

Methyl 9 - [3 - acetoxy - 2&alpha; - (3 - hydroxy - 3 - methyl - trans - 1 - octenyl) - cyclohex ss - yl]nonanoate. (Mixture of acetates). n.m.r. 4.3-4.6, 5.00, 6.31, 7.68, 7.93, 8.00, 8.9-9.2 #.

The title compound was prepared by a process analogous to that of Example 62, except that the starting material was the product of Example 78.

Example 81.

Methyl 7 - [3 - acetoxy - 2a - (3 - hydroxy - 3 - methyl - trans - I - octenyl) - cyclohex ss - yl]heptanoate. (Mixture of epimers).

The product of Example 17 (2.45g), in dry diethyl ether (400ml), was added slowly with stirring to a solution of methyl magnesium iodide [from magnesium (1.83g) and methyl iodine (9.6g) in dry diethyl ether (lOOml)], which had been precooled to -150C. After 2 hours at -150C the resultant mixture was poured into excess ice and a 5% citric acid solution. After separation of the organic layer and reextraction of the aqueous layer with diethyl ether, the combined organic extracts were washed with brine, dried and evaporated. The crude product was chromatographed on silica gel (2:1 light petroleum/ethyl acetate) to yield the title compound; n.m.r. 4.5(2 vinyl H), 5.00 (CH-OAc. ax.), 5.38 (CH-OAc, eq.) 6.32 (COOCH3), 7.70 (CH2COOMe), 7.96 t (OCOCH3).

Example 82.

7 - [3 - Hydroxy - 2a - (3 - hydroxy - 3 - methyl - trans - I - octenyl)cyclohex - ss - yl] - heptanoic acid. (Mixture of epimers).

The product of Example 81 (0.56g) was dissolved in methanol (12 ml) and the solution obtained was treated with an aqueous solution of sodium hydroxide (0.56g in 6 ml) at room temperature for 16 hrs. After acidification and ether extraction, the resultant crude product was purified by preparative t.l.c. (9:1 chloroform/methanol). Elution of the required band with methanol followed by reisolation of the residue from an ethereal solution washed with 5% citric acid gave the title compound, n.m.r. 4.38 (2 vinyl H), 4.76 (3H, OH and COOH), 6.14 (CH-OH), 7.68 T (CH2-COOH).

Example 83-95.

The products named in Table VIII were prepared by a process analogous to that of Example 82, except that the stated starting materials were used.

TABLE VIII Starting Ester Example of Example Product 83 62 7-[3-Hydroxy-2&alpha;-(3-hydroxy-3-methyl-trans-1-heptenyl)-cyclohex-ssyl]-heptanoic acid. (Mixture of epimers) n.m.r. 4.1-4.6, 4.9-5.3, 6.13, 7.67, 9.08 #.

84 63 7-[3-Hydroxy-2&alpha;-(3-hydroxy-3-methyl-trans-1-nonenyl)-cyclohex-ssyl]-heptanoic acid. (Mixture of epimers) n.m.r. 4.2-4.5, 5.0-5.6, 6.12, 7.64, 8.9-9.3 #.

85 64 7-[3-Hydroxy-2&alpha;-(3-hydroxy-3-methyl-trans-1-decenyl)-cyclohex-ssyl].heptanoic acid. (Mixture of epimers) n.m.r. 4.2-4.5, 4.9-5.5, 8.95-9.3 #.

86 65 7-[3-Hydroxy-2&alpha;-(3-hydroxy-3,7-dimethyl-trans-1-octenyl)-cyclohex ss-yl]-heptanoic acid. (Mixture of epimers) n.m.r. 4.2-4.5, 4.9-5.5, 6.1, 7.67, 9.11 #.

87 66 7-[3-Hydroxy-2&alpha;-(3-hydroxy-3,4,4-trimethyl-trans-l-octenyl)-cyclohex-ss-yl]-heptanoic acid. (Mixture of epimers) n.m.r. 3.8-4.5, 4.97, 5.86, 7.94, 7.64 6.0 #.

88 68 5-[3-Acetoxy-2&alpha;-(3-hydroxy-3-methyl-trans-1-octenyl)-cyclohex-ss-yl]pentanoic acid. (Mixture of epimers) n.m.r. 4.2-4.5, 4.6-5.0. 6.12, 7.66, 9.10 #.

TABLE VIII (Continued) Starting Ester Example of Example Product 89 69 6-[3-Hydroxy-2&alpha;-(3-hydroxy-3-methyl-trans-1-octenyl)-cyclohex-ss-yl]hexanoic acid. (Mixture of epimers) n.m.r. 4.1-4.4, 4.3-4.8, 7.68, 9.11 #.

90 70 7-[3-Hydroxy-2&alpha;-(3-hydroxy-3-methyl-trans-1-octenyl)-cyclohex-ss-yl]3,3-dimethyl-5-oxoheptanoic acid. (Mixture of epimers) n.m.r. 4.1-4.7, 6.12, 7.3-7.8, 8.9-9.3 #.

91 80 9-[3-Hydroxy-2&alpha;-(3-hydroxy-3-methyl-trans-1-octenyl)-cyclohex-ss-yl]nonanoic acid. (Mixture of epimers) n.m.r. 4.2-4.5, 5.0-5.6, 6.12, 7.64, 8.9-9.3 #.

92 79 8-[3-Hydroxy-2&alpha;-(3-hydroxy-3-methyl-trans-1-octenyl)-cyclohex-ss-yl]octanoic acid. (Mixture of epimers) n.m.r. 4.2-4.6, 4.7-5.2, 6.13, 7.67, 8.9-9.3 #.

93 77 8-[3-Hydroxy-2&alpha;-[3-hydroxy-3-methyl-trans-1-octenyl)-cyclohex-ss-yl]5-cis-octenoic acid. (Mixture of epimers) n.m.r. 4.1-4.5, 4.5-4.9, 4.9-5.3, 6.14, 7.63, 8.9-9.3 #.

94 78 9-[3-Hydroxy-2&alpha;-(3-hydroxy-3-methyl-trans-1-octenyl)-cyclohex-ss-yl]2,4,6-nonatrienoic acid n.m.r. 2.3-2.8, 3.4-4.5, 5.0-5.4, 6.10, 8.9-9.3 #.

95 71 7-[3-Hydroxy-2&alpha;-(3-hydroxy-trans-1-octenyl)-cyclohex-ss-yl]heptanoic acid. (Mixture of epimers) Example 96.

7 - [2&alpha; - (3 - Hydroxy - 3 - methyl - trans - 1 - heptenyl) - 3 - oxocyclohex -ss - yl] heptanoic acid.

The product of Example 83 (0.7g) in diethyl ether (20 ml) was cooled to -12 and stirred during the dropwise addition of a solution of sodium dichromate (0.4g) in water (12 ml) containing concentrated sulphuric acid (0.26 ml). The temperature was kept below -10 during the addition. The resultant mixture was stirred at -15 for 4 h. The crude product thus formed was isolated by dilution with water and ether extraction. Purification by preparative t.l.c. (9:1 chloroform/methanol) afforded the title compound (0.22g). n.m.r. 4.2-4.6, 3.0, 3.7, 7.1-7.45, 7.66, 8.95-9.30 #.

Examples 97-100.

The products named in Table IX were prepared by a process analogous to that of Example 96 except that the stated starting materials were used.

TABLE IX Starting Acid Example of Example Product 97 82 7-[2&alpha;-(3-Hydroxy-3-methyl-trans-1-octenyl)-3-oxocyclohex-ss-yl]heptanoic acid n.m.r. 2.92 (2H, OH and COOH), 4.42 (2 vinyl H), 7.24 (CH-CO), 7.66 # (CH2COOH and CH2CO).

98 85 7-[2&alpha;-(3-Hydroxy-3-methyl-trans-1-decenyl)-3-oxocyclohex-ss-yl]heptanoic acid n.m.r. 3.8-4.4, 4.4-4.6, 7.66, 9.0-9.3 #.

99 86 7-[2&alpha;-(3-Hydroxy-3,7-dimethyl-trans-1-octenyl)-3-oxocyclohex-ss-yl]heptanoic acid n.m.r. 3.9-4.8, 4.4-4.6, 7.66, 9.11 #.

100 91 9-[2&alpha;-(3-Hydroxy-3-methyl-trans-1-octenyl)-3-oxocyclohex-ss-yl]nonanoic acid n.m.r. 3.7-4.6, 7.1-7.4, 7.61, 8.9-9.3 #.

Example 101.

Methyl 7 - [3 - acetoxy - 2&alpha; - (3 - hydroxy - 3 - methyl - trans - 1 - octenyl) - cyclohex ss - yl] - 3,3 - dimethyl - 5 - hydroxyheptanoate (Mixture of isomers).

The title compound was prepared by an analogous process to that of Example 9 except that the starting material was the product of Example 70. n.m.r. 4.2-4.7, 5.04, 6.36, 7.59, 7.99, 8.97, 8.9-9.3 #.

Example 102.

7 - [3&alpha; - Hydroxy - 2&alpha; - (3S - hydroxy - 4,4 - dimethyl - trans - 1 - octenyl) - cyclohex ss - yl]heptanoic acid.

To a solution of the 3&alpha;-product of Example 74 (0.7g) in dimethylformamide (7 ml) was added 5N hydrochloric acid (0.7 ml). The mixture obtained was warmed at 50 for 72 h. Dilution with water and ether extraction gave a crude intermediate (0.65g) which, without further purification, was dissolved in methanol (13 ml) and treated with aqueous sodium hydroxide solution (6.5ml of 10%) at 25 for 18 h. The resultant mixture was then diluted with saturated brine, acidified with 5% citric acid solution and extracted with diethyl ether. The extracts were washed with brine, dried and evaporated to give the crude product which was purified by preparative t.l.c. (10:1 chloroform/methanol). The title compound was obtained as a colourless viscous oil (0.3g). n.m.r. 4.3-4.4, 4.8-5.3, 6.0-6.2, 7.68, 9.0-9.2 #.

Example 103-105.

The products named in Table X were prepared by a process analogous to that of Example 102, except that the stated starting materials were used.

TABLE X Starting Ester Example of Example Product 103 74 7-[3ss-Hydroxy-2&alpha;-(3S-hydroxy-4,4-dimethyl-trans-1-octenyl) (3ss-acetate) cyclohex-ss-yl]-heptanoic acid n.m.r. 4.28, 5.0-5.4 6.08, 6.2-6.5, 7.66, 9.10 #.

104 75 7-[3&alpha;-Hydroxy-2&alpha;-(3R-hydroxy-4,4-dimethyl-trans-1-octenyl) (3&alpha;-acetate) cyclohex-ss-yl]-heptanoic acid n.m.r. 4.2-4.5, 4.9-5.30, 6.0-6.3, 7.67, 9.0-9.2 #.

105 75 7-[3ss-Hydroxy-2&alpha;-(3R-hydroxy-4,4-dimethyl-trans-1-octenyl) (3ss-acetate) cyclohex-ss-yl]-heptanoic acid n.m.r. 4.2-4.5, 4.7-5.1, 6.1-6.6, 7.68, 9.10 #.

Example 106.

Methyl 7 - [ - 3 - hydroxy - 2a - (3 - oxo - trans - I - octenyl)cyclohex - ss - yUheptanoate.

(Mixture of epimers).

To an ethereal solution of the product of Example 95 (0.4g) was added an excess of ethereal diazomethane. Excess diazomethane was destroyed with acetic acid and the solution obtained was then washed with dilute sodium carbonate solution, dried over sodium sulphate and evaporated. The resultant methyl ester (0.4g) in dioxan (20 ml), was stirred during the addition of 2,3-dichloro-5,6-dicyano l,4-benzoquinone (0.62g) and the orange-red solution so formed was kept at room temperature for 72 h. After filtration to remove deposited solid, the filtrate was evaporated and the residue was purified by chromatography on silica gel (2:1 petroleum ether/ethyl acetate). The title compound was obtained as a pale oil, n.m.r. 3.10, 3.91, 6.06.2, 6.33, 7.44, 7.72, 8.9-9.3 T.

Example 107.

Methyl 7 - [3&alpha; - hydroxy - 2&alpha; - (3 - hydroxy - 3 - methyl - trans - 1 - octenyl)cyclohex - ss yl]heptanoate and the corresponding 3ss - epimer.

A solution of the product of Example 82 (0.2g), in diethyl ether (2 ml), was treated with excess ethereal diazomethane followed by sufficient glacial acetic acid to destroy the excess diazomethane. The ethereal solution was then washed with dilute sodium carbonate solution, dried and evaporated. The resulting mixture of title esters was then separated into 3&alpha;- and 3ss-epimers by preparative t.l.c. (2:1 petroleum ether/ethyl acetate). The less polar 3&alpha;- (axial) alcohol (0.1g) showed the following n.m.r. spectrum. 4.04.8, 6.32, 7.69, 9.09 x.

The more polar 3ss- (equatorial) alcohol (0.05g) showed the following n.m.r.

4.2-4.6, 6.33, 7.71, (t, J = 7), 8.0-8.9, 8.9-9.3 #.

Example 108.

7 - [3a - Hydroxy - 2a - (3 - hydroxy - 3 - methyl - trans - 1 - octenyl) - cyclohex - yll heptanoic acid.

Hydrolysis of the 3a-epimer of Example 107 under the conditions used in Example 82 afforded the title 3a-epimer, n.m.r. 4.3=4.5,4.8-5.3,6.17, 7.69, 9.13 T.

Example 109.

7 - [3- Hydroxy - 2a - (3 - hydroxy - 3 - methyl - trans - 1 - octenyl) - cyclohex -p - yl] eptanoic acid.

Analogously to Example 108 was obtained the 3p-epimer. n.m.r. 4.3=4.5, 4.8-5.3, 6.17, 7.70, 9.12 T.

Example 110.

Methyl 7 - [3 - acetoxy - 2a - (3 - hydroxy - 3 - methyloctyl) - cyclohex - '3- yUheptanoate.

(Mixture of' epimers).

The product of Example 81 was treated by a process analogous to that of Example 18 to yield the title compound.

Example 111.

7 - [3 - Hydroxy - 2&alpha; - (3 - hydroxy - 3 - methyloctyl) - cyclohex - &alpha; - yl]heptanoic acid.

(Mixture of epimers).

The product of Example 110 was treated by a process analogous to that of Example 82 to yield the title compound.

Example 112.

Preparation of 2-oxononyltriphenylphosphonium bromide.

To a solution of 2-nonanone (142.2g) in dry methanol (750 ml) containing cupric bromide (4.5g) was added a solution of bromine (80g) in methanol (250 ml).

The mixture obtained was stirred at room temperature until a colour change from deep red to green-black was observed (about 12 minutes). The mixture was then immediately poured into a chilled saturated aqueous solution of sodium carbonate and the resultant mixture was diluted to about 4500 ml with water and ether extracted. The combined extracts were washed with brine, dried and diluted with benzene (500 ml). After distillation at atmospheric pressure to remove ether a solution of triphenylphosphine (52g) in benzene (250 ml) was added and slow distillation was continued for a further 1 h.

The hot solution was then diluted with excess ethyl acetate which precipitated the crude product as an oil which was recovered by decantation of the supernatant liquid. Redissolution of the oil in benzene followed by further treatment with excess ethyl acetate precipitated the product which crystallised on standing. Recrystallisation from methylene chloride/ethyl acetate at room temperature afforded the pure title compound (50g) as white needles. n.m.r.

1.8-2.6, 4.2 (d, J = 11.5) 8.1-9.1, 9.0-9.4 #. The following phosphonium salts were prepared by a similar process using the appropriate starting ketone.

(a) 2-oxo-octyltriphenylphosphonium bromide from 2-octanone.

(b) 2-oxoheptyltriphenylphosphonium bromide from 2-heptanone.

(c) 2-oxohexyltriphenylphosphonium bromide from 2-hexanone.

(d) 2-oxo-6-methylheptylphosphonium bromide from 6-methyl-2-heptanone.

The yields of product in the foregoing Examples, and the weight of starting cyclohexyl compound used, are set out in the following Table.

Wt. of Wt. of Starting Starting Cyclohexyl Wt. of Cyclohexyl Wt. of Example Compd. Product Example Compd. Product No. Grams (Grams) No. (Grams) (Grams) 1 22 (Acetoxy- 19 13 7.5 2.0 butadiene) 14 2.2 1.18 26 (Dimethoxy- 15 2.7 2.6 crotona Ide"- 16 2.0 1.5 2 127 175 (crude) 17 5.8 2.32 3 6 3.75 18 0.8 0.7 4 6.05 4.2 19 0.6 0.09 5 6.05 4.6 20 11.6 8.0 6 6.0 3.6 21 4 0.8 (S) 1.1 (R) 7 20 18 22 10 3.7 8 175 57 23 3.2 0.61 9 7.2 2.2 (S) 2.0 (R) 24 2.8 0.350 (silyl. ether) 10 12.3 12.4 0.200 (R) 0.100 (S) 11 3.7 2.2 25 0.3 0.018 (R) 12 12.4 5.4 0.066 (S)

Wt. of Wt. of Starting Starting Cyclohexyl Wt. of Cyclohexyl Wt. of Example Compd. Product Example Compd. Product No. (Grams) (Grams) No. (Grams) (Grams) 26 20 12.5 41 4.9 4.7 27 11 4 (S) 42 15 6 5.2 (R) 43 4.2 2.4 28 3.5 3.5 44 4.0 3.9 29 4 4 45 4 3.3 30 4.6 4.1 46 5.1 4.9 31j 3.6 3.5 47 4.8 3.8 32 5.2 5 48 1.2 1.2 33 20 20 49 3.6 i 2.0 34 4.0 4.2 50 1.8 2.0 35 4.0 4.3 51 1.45 1.7 36 1.5 1.5 52 4.7 2.0 37 3.5 1.2 53 3.8 3.5 38 4 3.6 54 2.4 2.2 39 4.1 1.8 55 4.3 3.0 40 3.5 1.45 56 0.80 0.44

Wt. of Wt. of Starting Starting Cyclohexyl Wt. of Cyclohexyl wt. of Example Compd. Product Example Compd. Product No. (Grams) (Grams) No. (Grams) (Grams) 57. 2.0 1.6 72 2.2 1.9 58 1.0 [email protected] 73 3.0 2.8 59 2.4 2.1 74 3.0 0.73 (&alpha;-) 0.95 (ss#) 60 5.3 6.0 75 6.0 2.25 (a-) 1.95 (ss-) 61 3.12 3.5 (acid) 0.7 (ester) 76 4.8 1.1 62 1.2 1.2 77 0.4 0.32 63 2.0 2.0 78 1.38 0.61 64 2.0 1.9 79 0.15 0.14 65 1.65 1.3 80 0.50 0.46 66 1.8 1.8 81 2.45 1.50 67 0.44 0.35 82 0.56 0.31 68 1.6 1.5 83 1.20 0.85 69 0.7 0.32 84 2.0 0.5 70 1.1 0.8 85 1.9 1.1 71 3.5 3.6 86 1.3 0.38

Wt. of Wt. of Starting Starting Cyclohexyl Wt. of Cyclohexyl Wt. of Example Compd. Product Example Compd. Product No. (Grams) (Grams) No. (Grams) (Grams) 87 0.5 0.12 103 1.50 0.80 88 1.5 0.45 104 1.90 1.05 89 0.28 0.06 105 1.50 0.80 90 0.20 0.09 106 0.40 0.23 91 0.44 0.38 107 0.20 0.10 (a-) 0.05 (-) 92 0.090 0.074 108 0.10 0.060 93 0.054 0.040 109 0.05 0.028 94 0.10 0.09 110 0.50 0.36 95 3.5 1.8 111 0.36 0.15 96 0.7 0.22 0.41 0.12 98 0.80 0.50 99 0.25 0.15 100 0.32 0.11 101 0.14 0.04 102 0.70 0.30

Claims (80)

1. WHAT WE CLAIM IS:- 1. Compounds of general formula (I),

   wherein X represents a carbonyl or protected carbonyl group or a hydroxymethylene or protected hydroxymethylene group; A represents a saturated or unsaturated, straight or branched aliphatic hydrocarbon chain having from 5-16 carbon atoms and which may carry one or more hydroxyl, protected hydroxyl, oxo or protected oxo groups; and B represents a saturated or unsaturated, straight or branched aliphatic hydrocarbon chain having 5-16 carbon atoms and carrying a terminal carboxyl or protected carboxyl group and which may carry one or more hydroxyl, protected hydroxyl, oxo or protected oxo groups; and, where B carries a carboxyl group, salts thereof.
2. 2. Compounds as claimed in claim 1 wherein A and/or B carries a free hydroxyl group.
3. 3. Compounds as claimed in claim 1 or claim 2 wherein A and/or B carries a hydroxyl or protected hydroxyl group in a position allylic with respect to a carboncarbon double bond and further removed from the six-membered ring than the carbon-carbon double bond.
4. 4. Compounds as claimed in claim 1 or claim 3 wherein A and/or B carry at least one protected hydroxyl group selected from acyloxy and labile ether groups.
5. 5. Compounds as claimed in claim 4 wherein A and/or B carry at least one hydroxyl group which is esterified by an acid selected from alkanoic, aralkanoic, carbamic and carbonic acids containing up to 24 carbon atoms or an etherified hydroxyl group selected from 2-tetrahydropyranyl ether groups and trihydrocarbylsilyl ether groups having a total of 3 to 24 carbon atoms in the ether group.
6. 6. Compounds as claimed in any preceding claim wherein A and/or B carry a ketal group.
7. 7. Compounds as claimed in any preceding claim wherein A and/or B includes a gem-dimethyl grouping.
8. 8. Compounds as claimed in any preceding claim wherein A represents a group of formula -Q.W.Alk2 [where Q represents a carbon-carbon bond or an ethylene group which may carry a hydroxyl or protected hydroxyl group ss to the group W, or is a trans-vinylene group; W represents a carbonyl group or a hydroxymethylene or protected hydroxymethylene group optionally carrying an alkyl group (which may carry a phenyl substituent) or a cycloalkyl group on the methylene group; and Alk2 represents a straight or branched alkyl or alkenyl group having up to 10 carbon atoms.
9. 9. Compounds as claimed in claim 8 wherein A represents a group of formula: -CH2CH2.CO.CH2CH2CH2CH2CH3 CH1CHCOCH2CH2CH2CH2CH3, -CH#CHCH(OH).CH2CH2CH2CH2CH3, -CH2CH2CH(OH).CH2CH2CH2CH2CH3, CH=tCHCOC(CH3)2CH2CH2CH 2CH3, -CH#CHCH(OH).C(CH3)2CH2CH2CH2CH3, CH=tCH.C(OH)(CH3).CH2CH2CH2CH2CH3 or CHCH2C(OH)(CH3)CH2CH2CH2CH2CH3 (where t denotes a trans double bond).
10. 10. Compounds as claimed in claim 8 wherein A represents a group of formula: -CH#CH.C(OH)(CH3)CH2CH2CH2CH(CH3)2, -CH#CH-C(OH)(C2H5)CH2CH2CH2CH2CH3, -CH#CH-C(OH)(cyclo C5H9)CH2CH2CH2CH2CH3, -CH#CH-C(OH)(CH3)CH2CH2CH2CH2CH2CH3, -CH#CH-C(OH)CH3)CH2CH2CH2CH2CH2CH2CH3 or -CH#CH.C(OH)(CH3)CH2CH2CH2CH3 (where t denotes a trans double bond).
11. 11. Compounds as claimed in any one of claims 1 to 9 wherein B represents a group of formula -Alk1aR (where Alk1a represents an alkylene group and R represents a carboxyl or protected carboxyl group).
12. 12. Compounds as claimed in claim 11 wherein B represents a group of formula: -CH2CH2CH2CH2CH2CH2R (wherein R is as defined in claim 11).
13. 13. Compounds as claimed in claim 11 wherein B represents a group of formula: -CH2CH2CH2CH2CH2CH2CH2R (where R is as defined in claim 11), -CH2CH2CH2CH2CH2CH2CH2CH2R (where R is as defined. in claim 11) or -CH2CH2CH2CH2CH2R (where R is as defined in claim 11).
14. 14. Compounds as claimed in any one of claims 1 to 9 wherein B represents a group of formula -Alk1bR (where Alk1b represents an alkylene group and R is as defined in claim 11).
15. 15. Compounds as claimed in claim 14 wherein B represents a group of formula: -CH#CH-CH#CH-CH#CH-R (where R is as defined in claim 11), -CH2CH2CH#CH.CH2CH2CH2R (where R is as defined in claim 11) or -CH2CH2CH#CH.CH#CH.CH#CHR (where R is as defined in claim 11) (where t denotes a trans double bond and c denotes a cis double bond).
16. 16. Compounds as claimed in claim 10 wherein B is as defined in any one of claims 11 to 15.
17. 17. Compounds as claimed in any preceding claim wherein B carries a carboxyl or C26 alkoxycarbonyl group.
18. 18. Compounds as claimed in any preceding claim wherein X represents a cyclic or acyclic ketal or thioketal.
19. 19. Compounds as claimed in any one of claims 1 to 17 wherein X represents a group of formula

    [where Z represents an acyl, tri(hydrocarbyl)silyl, alkyl, cycloalkyl, aralkyl or 2 tetrahydropyranyl group].
20. 20. Compounds as claimed in any one of claims 1 to 17 wherein X represents a carboxyl or a hydroxymethylene group.
21. 21. 7 - [2&alpha; - (3R,S - hydroxy - 3 - methyl - trans - 1 - octenyl) - 3 - oxocyclohex ss - yl]heptanoic acid and salts thereof.
22. 22. 7 - [3# - hydroxy - 2&alpha; - (3R,S - hydroxy - 3 - methyl - trans - 1 - octenyl) cyclohex - ss - yl]heptanoic acid and salts thereof.
23. 23. 7 - [3&alpha; - hydroxy - 2&alpha; - (3R,S - hydroxy - 3 - methyl - trans - 1 - octenyl) cyclohex - ss - yl]heptanoic acid and salts thereof.
24. 24. 7 - [3ss - hydroxy - 2&alpha; - (3R - hydroxy - 4,4 - dimethyl - trans - 1 - octenyl) cyclohex - ss -yl]heptanoic acid and salts thereof.
25. 25. 7 - [3&alpha; - hydroxy - 2&alpha; - (3S - hydroxy - trans - 1 - octenyl) - cyclohex - ss yl]heptanoic acid and salts thereof.
26. 26. 7 - [3&alpha; - hydroxy - 2&alpha; - (3R - hydroxy - trans - 1 - octenyl) - cyclohex - ss yl]heptanoic acid and salts thereof.
27. 27. 7 - [3# - hydroxy - 2&alpha; - (3R,S - hydroxy - 3 - methyloctyl) - cyclohex - ss - yl] heptanoic acid and salts thereof.
28. 28. Compounds of general formula I as claimed in any preceding claim wherein B carries a terminal carboxyl group in the form of physiologically compatible salts.
29. 29. Compounds as claimed in claim l, other than those claimed in any one of claims 21 to 28, as herein specifically disclosed in any one of Examples 14-20, 22-25, 62-66, 68-75, 77-81, 82-96, 98-104, 106, 107, 109 and 111.
30. 30. Compounds as claimed in claim 1, other than those claimed in any one ot claims 21 to 28, as herein specifically disclosed in any one of Examples 14-20, 22-25 and 81.
31. 31. Pharmaceutical compositions comprising, as active ingredient, at least one compound of formula I as defined in claim l or, where B carries a terminal carboxyl group, a physiologically compatible salt thereof, in association with a pharmaceutical carrier or diluent.
32. 32. Compositions as claimed in claim 31 in a form suitable for oral or parenteral administration.
33. 33. Compositions as claimed in claim 31 or claim 32 in the form of tablets, coated tablets, capsules, lozenges, ampoules or solutions.
34. 34. Compositions as claimed in any one of claims 31 to 33 in the form of dosage units.
35. 35. Compositions as claimed in any one of claims 31 to 34 wherein the active ingredient comprises a compound of formula I as defined in any one of claims 21 to 28 or a physiologically compatible salt thereof.
36. 36. Pharmaceutical compositions as claimed in claim 31 substantially as herein described.
37. 37. A process for the preparation of compounds of general formula I as defined in claim 1 which comprises reacting a compound of formula (II),

    (where R1 represents a protected hydroxyl group) with a compound of formula (III),

    (where R2 represents a masked or protected aldehyde group) to give a compound of formula (IV),

    (where R' and R2 are as defined above) followed by one or more of the following reactions, which reactions may be carried out in any appropriate order, as required, whereby the desired compound of formula I is obtained: a) where a free and a protected or masked aldehyde group are both present, protecting or masking the free aldehyde group so as to permit selective conversion of the protected or masked aldehyde group initially present into a free aldehyde group, b) deprotection of a protected aldehyde group or reconversion of a masked aldehyde group into a free aldehyde group, c) reaction of a free aldehyde group in the 2-position of the six-membered ring with a reagent of formula (Va),

    (wherein either na is 1, R3a is hydrogen and R4a is a dialkylphosphonyl group or hydrogen, or na is 0 or 1 and R3a and R4a together constitute a trialkylphosphoranylidene or triarylphosphoranylidene group, the reaction being effected in the presence of a base when R38 is hydrogen, and R5' represents a saturated or unsaturated, straight or branched aliphatic hydrocarbon chain, the group -(CO)na-R5a having up to 14 carbon atoms exclusive of substituents, said aliphatic hydrocarbon chain being optionally substituted by one or more hydroxyl or protected hydroxyl, oxo or protected oxo groups) where the group CH=CHCO)n8Rfl or

    is introduced in the 2-position of the six-membered ring, d) reaction of a free aldehyde group in the 1-position of the six-membered ring with a reagent of formula (Vb),

    (wherein nb, Rb and R4b are as defined above for na, R38 and R4' respectively, the reaction being effected in the presence of a base when R3b is hydrogen, and Rib represents a saturated or unsaturated, straight or branched aliphatic hydrocarbon chain, the group CO)nbRBb having up to 14 carbon atoms exclusive of substituents, said aliphatic hydrocarbon chain carrying a terminal carboxyl or protected carboxyl group and being optionally substituted by one or more hydroxyl, protected hydroxyl, oxo or protected oxo groups), whereby the group -CH=CH-(CO)nb-R5b or

    is introduced in the l-position of the six-membered ring. e) deprotection of R' whereby a free hydroxyl group is obtained in the 3position of the six-membered ring, f) treatment of any free hydroxyl groups with a suitable esterifying or etherifying reagent to form protected hydroxyl groups, g) deprotection of any protected carboxyl groups, h) reduction of the double bond in the six-membered ring and, if desired, reduction of one or more further unsaturated carbon-carbon bonds, i) reduction of any keto groups, j) deprotection of protected hydroxyl groups other than R', k) oxidation of any -CHOH groups to carbonyl groups, 1) reaction of a carbonyl group in a side chain in position I or 2 in the sixmembered ring with an organometallic reagent.
38. 38. A process as claimed in claim 37 wherein the reaction of the compound of formula (II) with the compound of formula (III) is effected at elevated temperatures.
39. 39. A process as claimed in claim 37 or claim 38 wherein the reaction of the compound of formula (II) with the compound of formula (III) is effected in the presence of an aromatic hydrocarbon as solvent.
40. 40. A process as claimed in any one of claims 37 to 39 wherein reaction (a) is employed and a protected aldehyde group which is a di(lower alkoxy)methyl or alkylenedioxymethyl group is initially present, the free aldehyde is converted into an oxime, thioacetal or a protected hydroxymethyl group and the initially protected aldehyde is subsequently selectively deprotected by treatment with dilute acid.
41. 41. A process as claimed in any one of claims 37 to 40 wherein reaction (c) and/or reaction (d) is effected using a compound of formula (R6)3 P=CH.CO.R58 or (R3)3 P=CH.CO.R5b (in which R60 and R5b are as defined in claim 35 and R6 represents an alkyl or aryl group).
42. 42. A process as claimed in claim 41 wherein reaction (c) and/or reaction (d) is effected in the presence of a non-polar solvent.
43. 43. A process as claimed in any one of claims 37 to 40 wherein reaction (c) and/or reaction (d) is effected using a compound of formula CH3-CO-R58 or CH3COR5b (in which R58 and R5b are as defined in claim 37) in the presence of an organic base.
44. 44. A process as claimed in claim 43 wherein reaction (c) and/or reaction (d) is effected in the presence of a hydrocarbon or ether solvent.
45. 45. A process as claimed in any one of claims 37 to 40 wherein reaction (c) and/or reaction (d) is effected using a compound of formula

    (where R5a and R5b are as defined in claim 37 and R7 represents an alkyl group) in the presence of an alkali metal hydride.
46. 46. A process as claimed in claim 45 wherein reaction (c) and/or reaction (d) is effected in the presence of an ether solvent.
47. 47. A process as claimed in any one of claims 37 to 40 wherein reaction (c) and/or reaction (d) is effected using a compound of formula R83 P=CHR58 or R83 P=CHR5b (where R81 and R5b are as defined in claim 37 and R8 represents an aryl group) and the reaction is effected in the presence of an alcoholic solvent.
48. 48. A process as claimed in any one of claims 37 to 47 wherein reaction (f) is employed and the free hydroxyl groups are protected by reaction with a trialkylsilyl halide, a mono- or bis-silylated acetamide, dihydropyran, a carboxylic acid halide or a carboxylic acid anhydride.
49. 49. A process as claimed in any one of claims 37 to 48 wherein reduction of the double bond in the six-membered ring and of unsaturated carbon-carbon bonds in the side chains other than allylic double bonds is effected by means of hydrogen and a nickel catalyst.
50. 50. A process as claimed in claim 49 wherein the reduction is effected in the presence of an alkanol solvent.
51. 51. A process as claimed in any one of claims 37 to 48 wherein reduction of the double bond in the six-membered ring and of all unsaturated carbon-carbon bonds in the side chains is effected by means of hydrogen and a noble metal catalyst.
52. 52. A process as claimed in claim 51 wherein the reduction is effected in the presence of an alkanol or ester solvent.
53. 53. A process as claimed in any one of claims 37 to 52 wherein reaction (i) is employed and reduction is effected using a metal hydride reducing agent.
54. 54. A process as claimed in any one of claims 37 to 53 wherein reaction (k) is employed on an intermediate carrying a free carboxyl group and oxidation is carried out using an acidified dichromate solution.
55. 55. A process as claimed in any one of claims 37 to 53 wherein reaction (k) is employed on an intermediate carrying no free carboxyl groups and oxidation is carried out using pyridinium chlorochromate or chromium trioxide in pyridine in a halogenated hydrocarbon.
56. 56. A process as claimed in any one of claims 37 to 53 wherein reaction (k) is employed for the selective oxidation of an allylic hydroxyl group using 2,3 dichloro-5,6-dicyano-1,4-benzoquinone or manganese dioxide in an halogenated hydrocarbon.
57. 57. A process as claimed in any one of claims 37 to 56 wherein reaction (1) is employed and the organometallic reagent is a Grignard reagent of formula Alk3MgY [where Alk3 represents an alkyl group (which may carry a phenyl group) or a cycloalkyl group and Y represents a halogen atom].
58. 58. A process as claimed in any one of claims 37 to 57 further including, at any appropriate stage, a step of separating isomers.
59. 59. A modification of a process as claimed in any one of claims 37 to 58 wherein a free aldehyde group in the 1- or 2-position of the six-membered ring is firstly reacted with a reagent of formula (R3m)(R4m)CH.Rm (where R3" and R4" together represent a trialkylphosphoranylidene or triarylphosphoranylidene group and Rm is an esterified carboxyl group or a saturated or unsaturated, straight or branched aliphatic group having up to 12 carbon atoms exclusive of substituents and carrying a terminal esterified carboxyl group), the product thus formed is reduced whereby the terminal esterified carboxyl group in the group Rm is converted into an aldehyde group and the said aldehyde-containing grouping thus introduced is converted into the required side chain A or B by reaction with a reagent of formula (Va) or (Vb) as defined in claim 37 (wherein (CO)n"R58 or (CO)nbR5b has up to 12 carbon atoms exclusive of substituents and R5b can additionally be a carboxyl or protected carboxyl group when nb is 0) respectively.
60. 60. A process as claimed in claim 59 wherein the reaction with the reagent of formula (R3m)(R4m)CH.Rm is effected under the conditions defined in any one of claims 41 to 47.
61. 61. A modification of a process as claimed in any one of claims 37 to 60 including the step of protecting an oxo group and/or the step of deprotecting a protected oxo group.
62. 62. A process as claimed in claim 61 wherein an oxo group is protected by ketal formation and/or a protected oxo group in the form of a ketal is hydrolysed to an oxo group.
63. 63. A modification of a process as claimed in any one of claims 37 to 62 including the step of protecting a free carboxyl group.
64. 64. A process as claimed in claim 63 wherein the free carboxyl group is methylated.
65. 65. A process as claimed in claim 64 wherein the free carboxyl group is methylated by reaction with diazomethane.
66. 66. A process for the preparation of compounds of general formula I as defined in claim 1 wherein X represents a protected hydroxymethylene group, A represents an alk-trans-l-enyl group having from 5 to 16 carbon atoms and carrying a protected hydroxyl substituent in the 3-position and B represents an alkyl group having from 5 to 16 carbon atoms and carrying a terminal protected carboxyl group which comprises reacting a compound of formula (II) as defined in claim 37 with a compound of formula (III) as defined in claim 37 to give a compound of formula (IV) as defined in claim 37, reacting said compound of formula (IV) with a reagent of formula AR'3P=CH. CO. Ra (where Arl represents an aryl group and R" represents a straight or branched alkyl group having from 2 to 13 carbon atoms) to obtain a mixture of 2-position configurational isomers of formula:

    (where R' and R2 are as defined in claim 37 and Ra is as defined above), reducing one or both of said 2-position isomers to give a product of formula:

    (where Rl and R2 are as defined in claim 37 and R' is as defined above) which is subsequently deprotected to liberate the free aldehyde in the 1-position and then reacted with a reagent of formula Ar3 P=CHRb (where Ar2 represents an aryl group and Rb represents an alkyl or alkenyl group having from 3 to 14 carbon atoms and carrying a terminal protected carboxyl group), the product thus obtained being then treated with an agent serving to protect the free hydroxyl group in the 2position side chain whereby a protected hydroxyl compound is formed which is subsequently reduced by means of hydrogen and a nickel catalyst whereby a product of formula I is obtained.
67. 67. A process wherein the compound of formula I formed according to the process claimed in claim 67 is subsequently reacted whereby the protecting groups on the hydroxymethylene group in X and/or on the carboxyl group in B are removed.
68. 68. A process wherein the product of the process claimed in claim 67 is oxidised.
69. 69. A process wherein the product of the process claimed in claim 67 or claim 68 is subjected to a deprotecting reaction whereby the protecting group in the hydroxyl in A is removed.
70. 70. A process for the preparation of compounds of general formula I as defined in claim 1 wherein X represents a protected hydroxymethylene group, A represents a 3-alkyl-3-hydroxy-alk-trans-l-enyl group having from 5 to 16 carbon atoms and B represents an alkyl group having from 5 to 16 carbon atoms and carrying a terminal protected carboxyl group which comprises reacting a compound of formula (II) as defined in claim 37 with a compound of formula (III) as defined in claim 37 to give a compound of formula (IV) as defined in claim 37; reacting said compound of formula (IV) with a reagent of formula Ar3 P=CH CO RC (wherein Ar' is as defined in claim 66 and RC represents a straight or branched alkyl group having 1--12 carbon atoms) to obtain a mixture of 2position configurational isomers of formula:

    (where R' and R2 are as defined in claim 37 and RC is as defined above), reacting one or more of said 2-position isomers with a Grignard reagent of formula R9MgY (where R9 represents an alkyl group having 16 carbon atoms and Y represents a halogen atom) whereby a product of formula:

    (where R' and R2 are as defined in claim 37, RC is as defined above and R9 is as defined above) is obtained, which product is then deprotected to liberate the free aldehyde in the 1-position and then reacted with a reagent of formula Ar32 P=CHRb as defined in claim 66, the product thus obtained being then reduced by means of hydrogen and a nickel catalyst whereby a product of formula I is obtained.
71. 71. A process wherein the compound of formula I formed according to the process claimed in claim 70, is subsequently reacted whereby the protecting groups on the hydroxymethylene group in X and/or on the carboxyl group in B are removed.
72. 72. A process wherein the product of the process claimed in claim 71 is oxidised to convert the hydroxymethylene group X to a carbonyl group.
73. 73. A process for the preparation of compounds of general formula I as defined in claim 1 wherein X represents a protected hydroxymethylene group, A represents a group of formula

    (where RC and R9 are as defined in claim 70) and B represents an alkyl or alkenyl group having from 5 to 13 carbon atoms and carrying a terminal carboxyl or protected carboxyl group which comprises reducing a compound of formula I as defined in claim 1 wherein X represents a protected hydroxymethylene group and A represents a group of formula

    as defined above except that B represents an alkyl group having from 2 to 6 carbon atoms and carrying a terminal esterified carboxyl group, whereby the esterified carboxyl group in B is reduced to an aldehyde group, the compound thus formed being then reacted with a reagent of formula Ar33 P=CH-R10 (where Ar3 represents an aryl group and R10 represents a carboxyl or protected carboxyl group or an alkyl or alkenyl group having 1-9 carbon atoms and carrying a terminal carboxyl or protected carboxyl group) and, if desired, the product obtained is reduced and/or deprotected whereby the desired compound of formula I is obtained.
74. 74. A process as claimed in any one of claims 66 to 73 further including a step of separating isomers, said step being carried out at any appropriate stage in the process.
75. 75. A process for the preparation of physiologically compatible salts of compounds of general formula I as defined in claim I wherein B carries a carboxyl group which comprises reacting a compound of formula I as defined in claim I wherein B carries a carboxyl group with an appropriate base.
76. 76. A process for the preparation of compounds of general formula I as defined in claim I and, where B carries a carboxyl group, their physiologically compatible salts, substantially as herein described.
77. 77. A process for the preparation of compounds of general formula I as defined in claim 1 and, where B carries a carboxyl group, their physiologically compatible salts, substantially as herein described in any one of Examples 14-25, 6266, 68-75 and 77-111.
78. 78. A process for the preparation of compounds of general formula I as defined in claim 1 and, where B carries a carboxyl group, their physiologically compatible salts, substantially as herein described in any one of Examples 14-25, 81, 82 and 97.
79. 79. Compounds of general formula I as defined in claim 1 and, where B carries a carboxyl group, their physiologically compatible salts whenever prepared by a process as claimed in any one of claims 37 to 78.
80. 80. Compounds of general formula I as defined in claim I and, where B carries a carboxyl group, their physiologically compatible salts whenever prepared by a process as claimed in any one of claims 37 to 69 and 78.