DE2731459A1 - PROSTAGLANDIN-TYPE CYCLOHEXANE ANALOGS, METHOD OF MANUFACTURING THEREOF AND COMPOSITIONS OF THESE - Google Patents

Description

Dr. F. Zumstein Sr. - Dr. E. Assrr.ann - Dr. R. Koenlgsberger Dipl.-Phys. R. Holzbauer - Dipl.-Ing. F. Klingseisen - Dr. F. Zumstein jun.

PA Or. Zumstein et al, BraunausstraBe 4. 8OOO Munich 2

8 MUNICH 2,

BRAUHAUSSTRASSE 4

TELEPHONE: collective number 225341 TELEGRAMS: ZUMPAT TELEX 529979

"Prostaglandins 5" H / Pi

GLAXO LABORATORIES LIMITED, Greenford, Middlesex, UK

Prostaglandin-type cyclohexane analogs, method to their preparation and compositions containing them

The invention relates to cyclohexane analogs of the prostaglandin type and a process for their preparation.

The prostaglandins are a class of naturally occurring cyclopentane derivatives whose importance in medicine is rapidly increasing. They are biological in many physiological systems active and they or substances that oppose their effects have a potential applicability, for example in the control of fertility, gastric secretion, blood pressure, blood coagulation and inflammation, the predominant type of activity depends on the exact chemical structure. A more detailed summary of their various activities is in British Patent 1,396,206 given.

More detailed studies have not only been carried out with regard to the synthesis of natural prostaglandins, but also with regard to the production of analogues of

709883/0966

ΑΛ 273U59

same that have a desired agonistic or antagonistic activity. In particular, attempts were made to make connections find that are more selective in their effects, as previously known prostaglandins due to their numerous activities lead to a number of undesirable lifting effects when used in therapy.

It has now been found that a new class of prostaglandin derivatives, in which the cyclopentane ring of the natural prostaglandins is replaced by a cyclohexane ring (which will be described in more detail below is defined) is replaced, has a desired selectivity such that these compounds in doses at which they have little effect on the respiratory system and blood pressure, have good anti-gastrointestinal secretion activity. In addition, they tend to be unlike a large number of known prostaglandins and prostaglandin-type compounds little to induce diarrhea.

The invention therefore relates to compounds of the general Formula I.

(D

X is a carbonyl or protected carbonyl group or a hydroxymethylene or protected hydroxymethylene group,

A represents a saturated or unsaturated, straight or branched aliphatic chain with 5 to 16 carbon atoms, which can contain one or more hydroxyl, protected hydroxyl, oxo or protected oxo groups and

B represents a saturated or unsaturated, straight or branched aliphatic chain with 5 to 16 carbon atoms, the one terminal carboxyl or protected carboxyl group

709883/0966

"" 273U59

contains, and may contain one or more hydroxyl, protected hydroxyl, oxo or protected oxo groups; and if

B represents a carboxyl group, its salts.

The designation ⁿ a configuration ^{n used here} means that the respective group lies below the plane of the ring, ie the plane of the paper, and is shown as a broken line like i |||| shown. The designation "β-configuration" means that the group lies above the plane of the ring, ie the plane of the paper, and is shown as <2s> f.

If there is a special configuration or assigned to one or more groups in the compounds according to the invention

can be, so are d

according to the invention

of these compounds / includes.

the mirror image optical isomers

lungs / includes. For the sake of simplicity, no distinction is made here between such isomers and the invention extends to the separate ones Isomers, as well as mixtures of these isomers including the racemates.

Evidently, in formula I, when Z is a hydroxymethylene or protected hydroxymethylene group, the Hydroxyl or protected hydroxyl group either in the a- or ß-configuration.

If X is a protected carboxyl group, the protective group can, for example, be a cyclic or acyclic Xetal- or Thioket al group, e. B. be an ethylenedioxy group.

If X means a protected hydroxymethylene type, this can for example a group of Fortsei ^ CHOZ, wherein Z is a Acyl, tri-Cnydrocarby ^ -eilyl, alkyl, aralkyl or cycloalkyl group or a tetrahydropyranyl group. Means Z is an acyl group, this is desirably an alkanoyl, aralkanoyl or aroyl group, the alkanoyl group preferably containing no more than 7 carbon atoms, e.g. B. acetyl and wherein the aralkanoyl or aroyl groups are preferably not

709883/0 * 66

'A3 273U59

contain more than 20 carbon atoms, e.g. B. benzoyl and optionally substituted by one or more C. | _G -alkoxy groups, halogen atoms, nitro groups, C _1-1 Q-ACyIoXy or Cg ^ -alkoxycarbonyl groups.

Z is a tri (hydrocarbyl) silyl group, the silyl group contains three hydrocarbon substituents, which may be identical or different, chosen from Cj_g alkyl, C ₂ _ ₆ alkenyl, C _5-7 cycloalkyl, C ₅ _ _2O - aralkyl, C ^ cycloalkenyl and C _ ₂₀ aryl groups, ^such · ^{B #} ■ kert.-butyldimethylsilyl and trimethylsilyl groups. If Z is alkyl, it is preferably C 1 - alkyl and can contain substituents, such as, for example, C 1-6 alkoxy groups, which in turn are e.g. B. can be substituted by C, g-alkoxy groups.

If Z is a cycloalkyl group, it is preferably C 1-6 -cycloalkyl. If Z is an aralkyl group, it desirably contains up to 20 carbon atoms and is preferably an arylmethyl group, e.g. B. benzyl.

X is preferably a carbonyl or hydroxymethylene group.Dle

Chains

For example, aliphatic / A and B can contain up to 13 carbon atoms. If B contains a protected carboxyl group, this can e.g. B. be an esterified carboxyl group, preferably containing an aliphatic, araliphatic ^ or aryl group as an esterifying group having 1 to 10 carbon atoms, e.g. B. Cj ^ alkyl, such as methyl, ethyl or tert-butyl or benzyl or phenyl groups. Preferred verestemde groups are C ₁ _ ₄ -Alky groups!. Physiologically labile ester groups are also of interest, such as acyloxymethyl groups such as pivaloyloxymethyl. However, it is preferred that B contain a free terminal carboxyl group.

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

If they are present in a side chain A and / or B., a hydroxyl or protected hydroxyl group is desirably in an allyl position with respect to a carbon

709883/0966

273U59

Carbon double bond and preferably further away from the 6-membered ring than the carbon-carbon double bond. Side chains containing free hydroxyl groups are preferred. A protected hydroxyl group in A and / or B can e.g. B. an acyloxy group, such as an alkanoyl, aralkanoyl, carbamoyl or carbonate ester, in which the acyl part up to has up to 24 and preferably up to 10 carbon atoms or a labile ether group, such as a tetrahydropyranyl ether or tri- (hydrocarbyl) silyl ether with a total of 3 to 24 carbon atoms in the ether group. In general, can such a protected hydroxyl group can be an OZ group as defined above.

If present in side chain A and / or B, a protected oxo group is desirably a ketal, preferably a cyclic ketal, ζ. B. an ethylene ketal formed from ethylene glycol.

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

one or it is further preferred that when / both of chains A and B are branched, a gem-dimethyl group is included. In chain A there is such a group, preferably on the carbon atom which is adjacent to and further away from the 6-membered ring, as a carbon atom that contains a hydroxyl or protected hydroxyl group. The presence of a methyl group on a carbon atom, the one Containing hydroxyl or protected hydroxyl group is also a preferred form of branched chain. In the Chain B is preferably a gem-dimethyl group on the fi-carbon atom with regard to the terminal carboxyl or protected carboxyl group.

For example, the chain B thus preferably takes the form -Alk .R, in which Alk is an alkylene or alkenylene group

709883/0986

te

273H59

and R represents a carboxyl or protected carboxyl group

ρ and the chain A is preferably in the form -QWAlk , in which Q represents a carbon-carbon bond or is an ethylene group which may contain a hydroxyl or protected hydroxyl group in the position to the group W, or is a trans-vinylene group ; W is a carbonyl group or a hydroxymethylene or protected hydroxymethylene group which may optionally be an alkyl group (which may be cyclic or may contain a phenyl substituent) on the

ρ
Contains methylene group, and Alk is a straight or branched chain alkyl or alkenyl group having 1 to 10 carbon atoms. B-side chains of particular interest include chains of the formulas

i) -CH ₂ CH ₂ CH ₂ CH ₂ Ch ₂ CH ₂ R, where R is a carboxyl or protected carboxyl group,

ii) -CH = CH-CH = CH-Ch = CH-R, where R is as defined above is,

iii) -CH ₂ CH ₂ CH = CHCH ₂ CH ₂ Ch ₂ R, where R is as defined above,

iv) -CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ Ch ₂ CH ₂ R, where R is as defined above,

v) -CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ Ch ₂ CH ₂ CH ₂ R, where R is as defined above,

vi) -CH ₂ CH ₂ CH = CH-CH = CH-Ch = CH-R, where R is as defined above and

vii) -CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ R, in which R is as defined above and in particular those in which R is a carboxyl or a lower alkoxycarbonyl group.

A side chains of particular interest include Chains of formula

i) -CH ₂ CH ₂ .CO.CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ,

ii) -CH = CH.CO.CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ,

iii) -CH-CH.CH (OH) .CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ,

iv) -CH ₂ CH ₂ CH (OH) .CH ₂ CH ₂ CH ₂ CH ₂ CH ₃

709883/0966

273H59

τ) -CH (OH) ^ H = CH-Ch ₂ CH ₂ CH ₂ CH ₂ CH ₅ ,

vi) -CH = CH-CO.C (CH ₃ ) ₂ CH ₂ CH ₂ CH ₂ CH ₅ ,

vii) -CH = CH-CH (OH) .C (CH ₃ J ₂ CH ₂ CH ₂ CH ₂ CH ₃ ,

viii) -CH = CH-C (OH) (CH ₃₎ .CH

ix) -CH ₂ CH ₂ C (OH) (CH ₃₎ .CH

χ) -CH = CH-C (OH) (CH ₃ ) CH ₂ CH ₂ CH ₂ CH (CH ₃ ) ₂ ,

xi) -CH = CH-C (OH) (C ₂ H ₅ ) CH ₂ CH ₂ Ch ₂ CH ₂ CH ₂ CH ₃ ,

xii) -CH = CH-C (OH) (cyclo C ₅ H ₉ ) CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ,

xiii) -CH-CH-C (OH) (CH ₃ ) CH ₂ CH ₂ CH ₂ CH ₂ Ch ₂ CH ₃ ,

xiv) -CH = CH-C (OH) (CH ₃ ) CH ₂ CH ₂ CH ₂ Ch ₂ CH ₂ CH ₂ CH ₃ and

xv) -CH = CH-C (OH) (CH ₃₎ CH ₂ CH ₂ CH ₂ CH _3.

In connection with the double bonds in those given above Chains mean t means a trans double bond and c means a cis double bond.

Particularly preferred B groups are (i) and (ii), in which R is a carboxyl group, and particularly preferred Α groups are (iii), (iv), (vii), (viii), (ix) and (xiii).

The invention also includes salts of the compounds of the general formula I in which the B side chain is a free one terminal carboxyl group. Such salts can, for example, be combined with physiologically compatible, non-toxic Cations such as alkali metal and alkaline earth metal cations, e.g. B. the sodium ion, potassium ion, calcium! On and magnesium ion as well with organic amine cations, e.g. B. the triethanolammonium cation are formed. It goes without saying that the salts are physiologically acceptable for pharmaceutical use, however, other salts are also found, for example, in the preparation of compounds of the formula I and of their physiological properties compatible salts use.

Particularly preferred compounds according to the invention are the following:

709883/0966

273U59

7- [2a- (3R, S-hydroxy-3-methyl-1-octenyl) -3-oxocyclohex-β-yl] -

heptanoic acid;

7- [3f-Hydroxy-2a- (3R, S-hydroxy-3-methyl-1-octenyl) -cyclohex-

β-yl] heptanoic acid;

7- [3a-Hydroxy-2a- (3R, S-hydroxy-3-methyl-1-octenyl) -cyclohex-

β-yl] heptanoic acid;

7- [3ß-Hydroxy-2a- (3R-hydroxy-4,4-dimethyl-1-octenyl) -cyclohex-

β-y1] -heptanoic acid; 7- [3 <x-hydroxy-2a- (3S-hydroxy-1-octenyl) -cyclohex-β-yl] - heptanoic acid; 7- [3a-hydroxy-2a- (3R-hydroxy-1-octenyl) -cyclohex-β-yl] - heptanoic acid;

7- [3 I -hydroxy-2o- (3R, S-hydroxy-3-methyl-octyl) -cyclohex-β-yl] -

heptanoic acid and their salts.

The compounds of the general formula (i) and their physiologically acceptable salts, if the B chain contains a carboxyl group, can be administered, for example, to can be formulated to humans in a variety of ways either alone or in conjunction with a pharmaceutical carrier or diluent. Thus are another subject of the invention pharmaceutical compositions which contain as active ingredient at least one compound of the formula I as defined above or when B is a terminal carboxyl group contains a physiologically acceptable salt thereof together with a pharmaceutical carrier or diluent contain.

The compounds and / or physiologically acceptable salts of the invention can preferably be formulated for oral or parenteral administration. Such compositions can e.g. B. in the form of tablets, coated tablets, capsules, lozenges, ampoules for injection and solutions are available.

The carriers or diluents used in such compositions

709883/0966

-A-
A% 273H59

Settlements can be used for such shapes conventional and can e.g. B. starch, lactose, magnesium stearate, talc, gelatin, sterile distilled water for injections or suspending, emulsifying, dispersing, thickening or contain flavoring agents. Unit dosage forms, such as ampoules for parenteral administration are preferred.

The compounds according to the invention can typically be used in doses of 0.01 to 100 mg / kg, preferably 0.1 to 10 mg / kg body weight, although the exact effective dosage will depend on the particular special compound, the type of administration), the treated condition and the patient depends.

The compounds of the invention can be prepared by any conventional method. According to another goal The invention therefore provides a process for the preparation of compounds of the general formula I, as above defined, in which a compound of the formula II

CH

(where R is a protected hydroxyl group) with a Compound of formula III

HR ²

S ^(III)

CHO

(where R is a protected or masked aldehyde group) to give a compound of formula IV

709883/0966

273U59

in JT and R 'as defined above) j

pich a ode? several of the following reactions

iP j) in any suitable order to meet the requirements

§ know how to be carried out beforehand, whereby the desired ver <-

feiiläUSg #er Fprmel I received wiPäf

β) WC! *? * a free and a protected or masked aldehyde group are present together, the protection or masking of the free aldehyde group ierart _f daj pine selective conversion of the protected or masked aldehyde " group in eiße happy aldehyde ^ gi'uppe becomes possible,

# The cleavage of the hat group of a protected aldehyde «*

© the renewed © conversion of a masked aldehyde group into a free aldehyde group,

§) 4J.e transfer of a free aldehyde group in 2-position | = g | lower ring with a white reagent of the formula

n / A

either ns 1, lr ^e denotes hydrogen and R * ^e pi ^ lkylphpsphpnylgruppe p is hydrogen or na 0 © denotes 1 and R ^ ^a and R * ^a together represent a trialkylphpephpr ~ anylidene or triarylphosphoranylidene group, the reaction in the presence of a Base is carried out when R is hydrogen and R ^ ^{a is} a saturated or unsaturated straight-chain or branched aliphatic chain,

709883/0966

QO 273-59

c to the exclusion of the substituents where the group (CO) _ -Ir is up to H carbon atoms and this aliphatic ^ chain is optionally substituted by one or more hydroxyl, protected hydroxyl, oxo or protected oxo groups), the group -CH-CH- (CO) _na -R ^5a or -CH-CH ₂ COR ^ in the 2-position of the 6-segment

C-H third ring is introduced,

d) the implementation of a free aldehyde group in the 1-position 6-membered ring with a reagent of formula Tb

CH - (C0) _nB - R ^5b

(wherein nb, R ^3b and R ^{4b are} as defined above for na, R ^3a and R ⁴ *, respectively, the reaction being carried out in the presence of a base when R ^{3 is} hydrogen and R ^{5 is} a saturated or unsaturated straight-chain or branched ali - phatic.chain, means "wQin the group (CO)" _V -R up to

excluding ae_r ~ jgubstituenten It has 14 carbon atoms and this aliphatic chain has one terminal carboxyl or protected carboxyl group and is optionally substituted by one or more hydroxyl, protected hydroxyl, oxo or protected oxo groups), the group -CH-CH- (CO) _nb -R ^5b or -CH-CH ₂ COR ⁵¹ 'is introduced in the 1-position of the 6-membered ring OH,

e) cleavage of the protective group from R, a free hydroxyl group being obtained in the 3-position of the 6-membered ring,

f) treatment of any free hydroxyl groups with a suitable esterification or etherification reagent to form protected hydroxyl groups,

g) splitting off of the protective group from any protected carboxyl groups,

h) reduction of the double bond in the 6-membered ring and if desired, reduction of one or more further unsaturated carbon-carbon double bonds,

709883/0966

273U59

i) reduction of any Eeto groups,

i) splitting off of the protective group from other protected hydroxyl groups than R,

k) oxidation of any -CHOH groups in carbonyl groups,

l) Reaction of a carbonyl group in a side chain in position 1 or 2 in the 6-membered ring with an organometallic layer Reagent.

If a masked aldehyde group is in the 1- or 2-position of the 6-membered ring before, so this can, for example, a hydroxymethyl or protected hydroxymethyl group or a be esterified carboxyl group.

of the six-membered ring If there is a protected aldehyde group in the 1- or 2-position / for example, this could be a cyclic or acyclic acetal or thioacetal or an oxime. In general R is preferably a di (lower alkoxy) methyl or alkylenedioxymethyl group.

In the compound of formula III, R can, for example, be a

- (C ₁ * -alkoxy) -methyl group. The reaction of the compound of formula II with the compound of formula III is preferably carried out at elevated temperatures, e.g. B. from 90 to 130 ⁰ C and preferably in the presence of an inert diluent, for. B. an aromatic hydrocarbon such as benzene performed.

The compound of formula IV obtained by reacting the compound

ρ of the formula II with the compound of the formula III, in which R represents a di- (lower-alkoxy) -methyl or alkylenedioxymethyl group, is obtained, is a new compound and, together with the process for their preparation, represents a further feature of the invention .

In reaction (a) the initially protected aldehyde group can e.g. B. be an acetal group, in which case the

709883/0966

273H59

free aldehyde group preferably converted into a group which is more stable to the action of dilute acid than the aoetal group, e.g. into an oxime or thioacetal group, or it can be reduced by reduction to form hydroxyethyl, e.g. with sodium borohydride and subsequent protection the hydroxyl group, for example, by acylation or etherification. From the initially protected aldehyde group Then tonn the protecting group by treatment with dilute Acid are split off. This way the side chain can B can be introduced before the side chain A.

You implementation (b) comprises the cleavage of the protective group from a protected aldehyde group or the renewed conversion of a masked aldehyde group into a free aldehyde group. Such reactions can be carried out by methods well known in the art. For example, an acetal group can be cleaved by hydrolysis, for example under mild acidic conditions. A thioacetal group can through Reaction with a Queeksilber-II-Salt, e.g. the -cblorid be split, Sin Ojcim can for example with titanium chloride be split.

The protecting group of a hydroxymethyl group, e.g. B. an acyloxymethyl group can be cleaved to form a free hydroxymethyl group. A hydroxymethyl group can be found in an aldehyde group can be converted by oxidation, for example with pyridinium chlorochromate.

An esterified carboxyl group can form an aldehyde group, for example using sodium bie- (2-methoxyethoxy) aluminum hydride in the presence of an amine, e.g. B. Pyrrolidine.

In reactions (c) and (d), a free aldehyde group is reacted with a ketone or with a Wittig reagent, with the desired side chain is introduced. If the reagent is a ketone, the reaction is carried out in the presence of a base,

709883/0966

"" 273U59

"for example an organic base such as pyridine or pyrrolidine (preferably used 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, carried out in such a way that an enolate salt is formed in solution . you reaction, for example benzene, Diäthylather or dioxane or mixtures thereof, is conveniently carried out in a hydrocarbon or ether solvent is performed. a preferred temperature for the reaction is from -70 to -20 ⁰ C. the reaction with a ketone reagent leads zur'Bildung a side chain having a Hydroxyl group in the 1-position of the chain, which can be dehydrated spontaneously under the reaction conditions used to form a double bond in the 2-position of the chain.If the dehydration does not take place spontaneously, it can be deliberately carried out as a separate reaction stage, e.g. by heating be carried out in an alkaline alcoholic solution.

If a Wittig reagent is used, the reaction results directly in a chain with a double bond in the 2-position of the chain. The Wittig reagent can e.g. B. a phosphorane of the formula (R ⁶ ) ₅ PeCH-CO-R ^5,. wherein R ^{5 is} as defined for R ^5a or for R ^5b , and R is an alkyl group, preferably having 1 to 4 carbon atoms or an aryl group, preferably a monocyclic, e.g. B. a phenyl group means to be. The reaction can conveniently be carried out in a non-polar solvent, for example a hydrocarbon, halogenated hydrocarbon or alcohol, e.g. B. toluene, benzene or ethanol can be carried out. The reaction temperature is preferably 20 to 120 ° C.

According to a third embodiment, a phosphonate of the formula (RO) ₂ .PO.CH ₂ -CO.R, wherein R ^{5 is} as defined above and R is an alkyl group, can be used as Wittig reagent, in which case the reaction in Presence of a base such as an alkali metal hydride, e.g. B. sodium hydride, is expediently carried out in an ether solvent, see B. tetrahydrofuran.

709883/0966

2.73U59

In a further embodiment, the Wittig reagent can be a

Phosphorane of the formula R, P * CH-R, in which R is as defined above

is fined and R is an aryl, ζ. B. a phenyl group, preferably in the presence of an alcoholic solvent, e.g. B. isopropanol.

You can use reactions (c) and (d) depending on whether the Aldehyde group is present in the starting material for the reaction in the 1- or 2-position, performed in any order will. Regardless of which of these reactions is performed first, a configuration loss occurs from the point in time the attachment of the side chain to the ring in such a way that a mixture of the α- and fi-isomers is obtained. These can be separated or the mixture can be introduced as such of the second side chain A or B can be used. However, the second of reactions (c) and (d) always leads to the second Side chain in trans configuration with respect to the first one. Thus, starting from the compound of formula IV, in which has the group in the 3-position in the α-configuration, two isomeric products are obtained in which the groups A and B in the 1 and 2 positions are present in the two possible transconfigurations to each other. However, refer to as above indicated, the formulas used here both optical isomers of a specific compound and it can 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., fi-) configuration. Accordingly, if the two reactions (c) and (d) carried out without separation of the isomers, the product as a mixture of compounds with the same configuration In the 1- and 2-positions, but which are isomeric in the 3-position, are shown.

Reaction (e), when used, involves removal of the protecting group from R to form a free hydroxyl group, which reaction can be carried out by conventional methods. Thus, for. B. if R is an acyloxy group

709883/0966

273H59

pe, for example an acetoxy group, means the free hydroxyl group can be released by alkaline hydrolysis. If R is an allylic acyloxy group, it becomes the alkaline Hydrolysis preferably under mild anhydrous conditions, for example using an alkali metal hydroxide in an anhydrous alkanol such as methanol. If R is a tri- (hydrocarbyl) -silyl group, the free Hydroxyl group can be released by acid hydrolysis or by treatment with fluoride ions. A tetrahydropyranyl group can be split by acid hydrolysis. The free hydroxyl group released in this way can, if necessary, be converted in order to introduce a further protective group according to reaction (f). Such an exchange of the protective groups can, if desired, ζ. Β. to prevent a Hydrogenation can be carried out during reaction (h) as described below.

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

According to reaction (g), the protecting group of a protected carboxyl group can conveniently with mild basic hydrolysis, e.g. B. using dilute aqueous or alcoholic caustic soda, or caustic potash removed at a slightly elevated temperature. This procedure can lead to the deprotection of protected hydroxyl groups, such that further protection with respect to these groups may be required.

The reduction of the double bond in the 6-membered ring and

709883/0986

273H59

if desired of one or more unsaturated solutions in the side chains can be carried out according to reaction (h).

The reduction can be carried out by a variety of methods, depending on whether a hydrogenation is involved ▼ on all or some of the unsaturated groups present is desired or not and / or the retention or hydrogenation of any protecting groups in the molecule is desired or not.

If it is desired to avoid hydrogenation of certain groups or the allylic double bond in the To maintain side chain, the reduction can be carried out using hydrogen and a nickel catalyst, such as from C. A. Brown, J. Org. Chem., (1,970) 3 £ 1,900, carried out will. The reduction is preferably carried out in an alkanol solvent, e.g. B. ethanol or methanol carried out. An allylic hydroxyl group must during the reduction with a Protecting group, for example an ester group, e.g. B. an acyloxy group or an ether group, e.g. B. tert-Butyldimethylsilyl or Tetrahydropyranyl or by the presence of a Alkyl group on the same carbon atom. This procedure also reduces the allylic double bond in the ring.

If it is desired to carry out a non-selective reduction of the double bonds, this can be done using Hydrogen and a noble metal catalyst, e.g. B. a palladium catalyst, conveniently in an alkanol or ester solvents, e.g. B. ethanol or ethyl acetate.

Hydrogenation of the allylic hydroxyl groups in the ring and the side chain can occur under these conditions. One allylic hydroxyl group in the ring should thus during the hydrogenation with noble metals to avoid removal

709883/0966

273U59

tion of the oxygen function by hydrogenation, for example be protected by a tri- (hydrocarbyl) -silyl group. Allylic hydroxyl groups in the side chains, provided they are can be protected in a similar manner to avoid hydrogenation.

Any keto groups that may have been introduced can be reduced to a -CHOH group according to reaction (i). This is done preferably using a metal hydride reducing agent, such as borohydride, for example zinc, Potassium, sodium or calcium or a metal hydride complex such as lithium aluminum hydride or a lithium trialkoxy aluminum hydride. The reducing strength of the reducing agent used depends on whether there are other groups in the compound are amenable to reduction by this method or not, such as a carboxyl or protected carboxyl group. The reaction is preferably carried out at low temperature and at a controlled slightly alkaline pH, e.g. B. in Range from 8 to 9, in the case of potassium or sodium borohydride.

According to reaction (j), other protected hydroxyl groups as R are subjected to splitting off of protective groups. If hydroxyl groups present elsewhere in the molecule, e.g. B. protected by a trialkylsilyl group, the protective group thereof can be obtained by hydrolysis with a dilute carboxylic acid, z. B. acetic acid or a quaternary ammonium fluoride salt or lithium fluoride in dimethylformamide can be removed as a solvent.

Any -CHOH groups in side chains A and B or in X can be oxidized to form carbonyl groups using reaction (k). This is preferably carried out using an acidified dichromate solution when free carboxyl groups are present in the molecule. The reaction can, if desired, be carried out in acetone or ether. If free carboxyl groups are not present, that is

709883/0966

38 273H59

preferred oxidizing agents pyridinium chlorochromate or chromium trioxide in pyridine in a halogenated hydrocarbon, ζ. B. methylene chloride. If it is desired to oxidize an allylic hydroxyl group to form a ketone, then the preferred reagent is dichlorodicyanobenzoquinone or manganese dioxide in a halogenated hydrocarbon.

A carbonyl group in a side chain A or B can, if desired, be reacted with an organometallic reagent such as a Grignard reagent Alk MgY, where Alk is an alkyl group (the may be cyclic or contain a phenyl substituent), e.g. B. a C ^. -Alkyl group, and Y is a halogen atom, preferably a bromine or iodine atom, according to the Reaction (l) are implemented. Such organometallic Reagents tend to attack ketone groups in preference to ester groups. The use of other organometallic see connections, e.g. B. lithium or cadmium alkylene may also be suitable. The use of low temperatures and inert solvents, e.g. B. ether solvents, such as diethyl ether, tetrahydrofuran or dioxane is preferred.

According to a modification of the invention, the side chain A and / or B can be introduced by a reaction in which a free aldehyde group in the 1- or 2-position of the 6-membered ring is first treated with a reagent of the above-defined formula (R ^3m ) (R ^4m ) .CH.R ^m , where R ^3m and R ^4m together form a trialkylphoephoranylidino or triarylphosphoranylidino group and R ^{m is} an esterified carboxyl group or saturated or unsaturated straight-chain or branched aliphatic group with up to 12 carbon atoms excluding the substituent which represents a terminal esterified one Contains carboxyl group, is reacted, the product formed in this way is reduced, the terminal esterified carboxyl group in the group R ^{m being converted} into an aldehyde group and this aldehyde-containing group introduced in this way into the desired side chain B or A by reaction with a further reagent of the formula Va or Vb as defined above inated (in which (CC) R ^ ^a or ( ^C0 ) _n | 3 ^{R tis have} 12 carbon atoms excluding the substituents and R can additionally be a carboxyl or protected carboxyl group if nb 0

709883/0966

** 273U59

is) is transferred. They are reacted with the reagent Formula Ya and / or Vb is preferably chosen from among the above carried out in connection with the reactions (c) and (d) described conditions. You reduction of the esterified carboxyl group to form the group R ^m can, for example, using sodium bis (2-methoxyethoxy) aluminum hydride in the presence of an amine, e.g. B. pyrrolidine can be carried out.

Another embodiment of the process according to the invention can include the step of protecting a free carboxyl group, preferably by esterification, e.g. B. ethylation, e.g. B. by Reaction with diazomethane include.

Another embodiment of the process of the invention may include the step of protecting an oxo group, e.g. B. by

Eetal formation and / or the step of removing the protecting group of a protected oxo group, e.g. B. by hydrolysis of a ketal.

A number of the reactions described above lead to the formation of isomers, which before the next reaction stage in the reaction sequence or can be separated at a suitable later stage of the reaction sequence. They can be separated, for example, by chromatography, e.g. B. be done on silica gel.

As indicated above, reactions (a) through (1) can be carried out in any suitable order as illustrated below be performed. The ability to choose the order in which the side chains are introduced enables in many cases avoid side reactions by ensuring that groups which are sensitive to a particular reaction, e.g. reduction, after it Reaction are introduced.

Thus, special types of the compounds according to the invention can be prepared according to the following preferred reaction sequences will:

1. For the preparation of compounds of the general formula!, In which X is a protected hydroxymethylene group,

709883/0966

30 ^273U59

A represents an alk-1-enyl group having 15 to 16 carbon atoms and has a protected hydroxyl group in the OC position and B an alkyl group having 5 to 16 carbon atoms means and contains a terminal protected carboxyl group:

Reaction of a compound of the formula II, as defined above, with a compound of the formula III, as defined above, to obtain a compound of the formula IV, as defined above; Reaction of this compound of the formula IV with a reagent of the formula (Ar), P «CH.CO.R ^a (where Ar is an aryl group and R ^{a is} a straight-chain or branched alkyl group having 2 to 3 carbon atoms) to obtain a mixture of configurational isomers With regard to the 2-position of the formula

.2

# 1 2 ■ a.

(wherein R and R are as defined above and R is as defined above), reduction of either or both of these Isomers with regard to the 2-position to achieve a Product of the formula

19 O

(wherein R and R are as defined above and R is as defined above), which is subsequently deprotected to liberate the free aldehyde in the 1-position and then with a reagent of the formula (Ar) -P "CH-R (where Ar is an aryl group and R is

7,9883 / 9,96

273H59

Means alkyl or alkenyl group with 3 to 14 carbon atoms and contains a terminal protected carboxyl group) is reacted, the product thus obtained then with a to protect the free hydroxyl group in the side chain in the 2-position serving agent is treated, with a protected Hydroxyl group is formed, which is then reduced with the aid of hydrogen and a nickel catalyst, wherein a product of formula I is obtained.

The compound of the formula I obtained above can, if desired, then be reacted, with the protective groups the protected hydroxymethylene group X and / or the protected carboxyl group in B can be removed. The compound of the formula I thus formed can optionally then be oxidized to converting the hydroxyl group in the ring into an oxo group, z. B. an acidified dichromate solution is used, and / or are subjected to removal of the protecting group, the protecting group on the hydroxyl group in A being removed.

2. For the preparation of compounds of the general formula I in which X is a protected hydroxymethylene group, A is a Represents 3-alkyl-3-hydroxy-alk-1-enyl group with 5 to 16 carbon atoms and B represents an alkyl group with 5 to 16 carbon atoms and contains a terminal protected carboxyl group:

The reaction of a compound of the formula II, as defined above, with a compound of the formula III, as defined above, to obtain a compound of the formula IV, as defined above, the reaction of this compound of the formula IV with a reagent of the formula (Ar) , P = CH.CO.R ^c , in which Ar is as defined above and R is a straight-chain or branched alkyl group having 1 to 12 carbon atoms, to form a mixture of isomers of configuration with regard to the 2-position of the formula

709883/0966

273H59

(in which R, R and R are as defined above) to obtain the reaction of one or more of these isomers with regard to the 2-position with a Grignard reagent of the formula R ^ igY (in which R ^ is an alkyl group with 1 to 6 carbon atoms and Y represents a halogen atom), where a product of the formula

(wherein R, R and R ^c are as defined above and r "is defined as above), which product is then deprotected to liberate the free aldehyde at 1-position and then treated with a reagent of formula (Ar ), P »CH - R, as defined above, is reacted, the product thus obtained then being reduced with the aid of hydrogen and a nickel catalyst in order to obtain a product of the formula I.

The compound of the formula I obtained can optionally then be reacted, the protecting group of the protected hydroxymethylene group in X and / or the protected Carboxyl group in B can be removed.

The product thus formed can then optionally be oxidized to convert the hydroxymethylene group X into a carbonyl group transfer, where z. B. an acidified dichromate solution

709883/0966

s-

273U59

used.

3. For the preparation of compounds of the general formula I in which X is a protected hydroxymethylene group, A is a group of the formula -Ch £ ch-C (OH) -R ⁰ (in which R ^c and R ⁹ , as

R ⁹ are defined above) and B is an alkyl or Al kenyl group with 5 to 13 carbon atoms, which contains a terminal carboxyl or protected carboxyl group, means:

You reduction of a compound of the formula I, as defined above, in which X is a protected hydroxymethylene group and A is a group of the formula -CH ^ CH-C (OH) -R ⁰ , as before-

defined standing means, with the exception that B is a Represents an alkyl group of 2 to 6 carbon atoms containing a terminal esterified carboxyl group, the esterified carboxyl group in B to form an aldehyde group is reduced and the compound thus formed then with a reagent of the formula (Ar) »P» CH-R (where Ar is an aryl

10 ^

group and R is a carboxyl or protected carboxyl group or an alkyl or alkenyl group with 1 to 8

Represents carbon atoms that have a terminal carboxy1-

implemented or contains protected carboxyl group, means 7 / and desired if necessary, the product obtained is reduced and / or subjected to a protective group removal, the desired compound of the formula I being obtained.

Each of the three preferred reaction sequences described above may include an isomer separation step, wherein this step at any suitable state of the process, for example using thin-layer chromatography, see e.g. on silica gel.

The invention is illustrated by means of the following examples. Examples 2 to 13, 26 to 61, 67, 76 and 112 merely illustrate the preparation of intermediates: In

709883/0366

273U59

In these examples, given merely to follow the procedure of an earlier example, the molar ratios and reactants are the same as in the earlier example: the NMR spectra were determined in deuterochloroform and the preparatory chromatography was performed on silica plates.

709883/0966

example 1

6a-Acetoxy-2ß-dimethoxymethyl-4-cyclohexene-g-carboxaldehyde A mixture of 22 g of freshly distilled 4,4-acetoxybutadiene and 26 g of 4,4-di-methoxycrotonaldehyde in 50 ml of benzene, containing 0.05 g of methylene blue as a polymerization inhibitor, was heated contained under reflux for 72 hours. After removing low-boiling material under reduced pressure, the residue was fractionally distilled. The fraction with a boiling point of 105 to 120 ° C./0.03 mm Hg gave the title compound in the form of a straw-colored viscous oil. , »-,"

NMR 0.32 (CHO), 4.05 (2-vinyl-H), 6.62 (CH ' ^p ),

~ " ^N OCH,

OMe ■ *

5.69 (CH ') 7.96 r (COOCH,). ^v OMe "^

Example 2

3a-Acetoxy-2- (3-oxo-i-octenyl) -4-cyclohexene-ß-carboxaldehyddlmethyl acetal (mixture of the Eplmeres with regard to the ring position 2)

254 g of 2-oxoheptyltriphenylphosphonium bromide, suspended in 1 liter of ether and 1 liter of water, were shaken with a solution of 25.4 g of sodium hydroxide in 250 ml of water until complete dissolution was achieved. After separating the ethereal solution and washing with brine, the evaporation gave the ether 2-Oxoheptylidentriphenyl-phosphorane, which hot in 1.5 1 of petroleum ether was dissolved with bp. Of 80 to 100 ⁰ C, and the resulting solution was the removal the remaining water from the phosphorane is heated to the boil.

127 g of 6a-acetoxy-2ß-dimethoxymethyl-4-cyclohexene-carboxaldehyde were then added (Example 1) and the resulting solution was refluxed for 16 hours. After cooling and Removal of crystalline triphenylphosphine oxide by filtration, the remaining solution was evaporated under reduced pressure. The crude product obtained was first stirred in conc. essential solution with an equal weight Sodium metabisulphite purified in the form of a JO ^ igen aqueous solution .

709883/0966

2731A59 36

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

The product thus obtained was a pale yellow viscous oil. NMR 3.15 (d, d, J = 16 Hz, J = 10 Hz, 1-vinyl-H adjacent to the ring), 3.82 (d, J = 16 Hz, 1-vinyl-II adjacent to C = O , predominant isomer), 3.90 (d, J = 16 Hz, 1-vinyl-H adjacent to C = 0, isomer present in a minor amount), 3.90 (d, J = 16 Hz, 1-vinyl-H adjacent to C = 0, isomer present in smaller amounts), 4.10 (2-vinyl-IJ, endocyclic), 4.80 (CH - OAc), 5.75 (caC ^0Me ), 6.65 (C ^0C - 3 ), 7.96y (0C0CH,).

^ 0Me OCH, '

Examples 3 to 7

The products given in Table I were prepared from 6a-acetoxy-2ß-dimethoxymethyl-4-cyclohexene-a-carboxaldehyde, using a procedure analogous to Example 2, but using the specified phosphonium salts.

709883/0966

TABLE I.

Example Phosphonium Salt 3 2-Oxohexyltriphenylphosphonium bromide product

3a-acetoxy-2- (3-oxo-i-heptenyl) -4-cyclohexene-ß-carboxaldehyde dimethylacetal (mixture of epimers with regard to the 2-3 division of the ring)

NMR 3.16, 3.7-4.3, 4.79, 5.85, 6.61, 6.64, 7.94, 8.9-9.3 τ.

2-oxooctyltriphenylphosphonium bromide 3α-acetoxy-2- (3-0X0-1-nonenyl) -4-cyclohexene-ß carboxaldehyde dimethylacetal (mixture of

Epimers with regard to the 2-position of the

Rings)

NMR 3.12, 3.83, 4.08, 4.6-4.9, 5.7-5.9, 6.57, 7.47, 8.9-9.3V.

TABLE I Port Setting

Example phosphonium salt . product

2-oxononyltriphenylphosphonium bromide 3a-acetoxy-2- (3-oxo-i-decenyl) -4-cyclohexene

ß-carboxaldehyde dimethyl acetal (mixture of the epimers with regard to the 2-position of the ring)

-a NMR 3.1 ^, 3.81, 3.94-4.2, 4.77, 5.82, 6.59,

S ⁶ * ⁶² * 7.91, 7.43, 8.9-9.2 *.

o-methyl - ^ - oxoheptyltriphenylphosphonium-

e »bromide 3g-Acetoxy-2- (7 - ^ 'nethyl -3-oxo-1-octenyl) -4-

cyclohexene-ß-carboxaldehyde dimethyl acetal (Mixture of the epimers with regard to the 2-position of the ring)

NMR 3.16, 3.85, 3.95-4.2, 4.78, 5.84, 6.6o, 6.64, 7.47, 7.94, 9, ht.

3-methyl-2-oxoheptyltriphenylphosphonium- _w

bromide 3a-acetoxy-2- (4-methyl-3-oxo-1-octenyl) -4- - *

cyclohexene-ß-carboxaldehyde-dimethylacetal cn ' (mixture of the epimers with regard to the *** vjp 2-position of the ring) '

Example 8

methyl acetal (mixture of the components with regard to the setting of the ring)

Were added 175 ε not ehromatographlertes product of Example 2 dissolved in 300 ml of anhydrous methanol and warm to 40 ⁰ C solution of 28 g of potassium hydroxide in 2.5 1 of anhydrous methanol. After the mixture thus obtained was kept at 40 ° C. for 6 minutes in the absence of water, the product was isolated by pouring it into an excess of saline solution and extracting it with ether. Evaporation of the solvents gave a dark oil, which was chromatographed on silica gel, whereupon chromatography was carried out with petroleum ether / ethyl acetate mixtures. 57 g of the title compound were obtained from the chromatographic fractions in the form of a colorless oil, NMR 2.97 (d, d, J «16 Hz, J <* 10 Hz, 1-vinyl-H adjacent to gum ring), 3.82 (d, J« 16 Hz, 1-vinyl-H adjacent to C * Ö, predominant isomer) 3.88 (i.e. , J · »16 Hz, 1-vinyl-H adjacent to C ** 0, present in a smaller amount

laomtresT, 5 # 88 (GH - OH), 6.6 τ (^ ⁰⁰ Sj).

OCH

OCH ₃

dimethylacetal and its 3R-Ieomers8

Was treated 7.2 g of product from Example Z in720 ml of methanol with an aqueous solution of 7.2 g Natriumeltrat in 720 ml of water, the resulting mixture kUhlte at 4 ⁰ C and the pH was adjusted with sodium hydroxide to 8.5 g N a. Were added 1.5 g of potassium borohydride 8U and kept the mixture at I ⁰ C and the pH by dropwise addition of 0 ^ citric acid for 1 hour. 8.5, The pH was then adjusted with citric acid S £ to about 4 and it was diluted with excess brine and extracted into ethyl acetate. After washing and drying, evaporation of the solvent gave a crude product which was purified by chromatography on silica gel to give the two title compounds. In the case of NMR, the 3S-isomer appears there? ScpeJctrumj

709883/0966

40 273H59

3.90-4.60 (4-Vinyl-H), 4.81 (CH-OAc), 5.89 (CH-OH), 5 * 75 (£ ^S 3), 7.94 ^ (OCOCH ₅ ) , and the JR isomer showed the spectrum 5.98% -4.60 (4-vinyl-H), 4.75 (CH-OAc), 5.74

(CH ' ^0CH 3), 5.90 (CH-OH), 6.59 (CH ^ ⁰⁰ S ₅ ), 7.9 * f (OCOCH,). ^V OCH, - OCH, ^

Example 10

2- (3-Hydroxy-i-octenyl) -3g-hydroxy-4-cyclohexene-ß-carboxaldehyde dimethylacetal (Mixture of the epimers with regard to the ring position 2 and the higher alcohols) The product of Example 8 was prepared by a method which is analogous to that described in Example 9, and the product was used in the next process stage without further purification.

Example 11

Methyl ^ -t ^ -acetoxy ^ q-fa-t-butyldimethylsllyloxy-i-octenyl) -4-cyclohexen-ß-yl] -2,4,6-heptatrlenoate (mixture of the double bond isomers in the 6-position and the specific acetates and Sllyl ether)

3.7 g of the product from Example 9 in 40 ml of tetrahydrofuran were treated with 4 ml of 2N hydrochloric acid in a flask which was then filled with Nitrogen was purged, sealed and allowed to stand overnight at room temperature. The one obtained in this way The aldehyde product was made by pouring the reaction mixture into a saline solution containing excess sodium carbonate and Extraction with ether isolated. After washing the ether extracts with brine and drying over sodium sulfate, removal resulted of the ether unstable aldehyde, which was immediately dissolved in 40 ml of toluene and dried again over sodium sulfate.

12 g of methoxycarbonyl - ^^ - pentadienyltriphenylphosphonium bromide, suspended in a mixture of 100 ml of toluene and 10 ml of methylene chloride with 160 ml of an aqueous solution of 1.6 g of sodium hydroxide, until all the pesticides had dissolved. The blood-red organic phase was separated off, the aqueous phase was washed with 35 ml of toluene and the combined organic phases were washed with brine and dried over sodium sulfate. After removal of the methylene chloride at 30 ^° C. in vacuo

709883/0966

173U59

the resulting toluene solutions of phosphorane and aldehyde were mixed and refluxed for 16 hours. The toluene was then removed in vacuo and the residue obtained was treated with a mixture of petroleum ether and ethyl acetate which caused some crystalline material to precipitate _f Evaporation of the Piltrafcs yielded 6,? g fines reddish oil which was dissolved in 40 ml of dry dimethylformamide and the solution was treated with 4 g Imtdazol and 4 g of tert ^ Butyldimethylsilylchlprid The Misehung was for 16 hr, heated in the absence of water at 4Q ⁰ C. The product was by pouring the mixture in water, gas something sodium chloride and extraction with ether isgUert, 5i ^e combined Htherextrakte were washed with dilute fJalglösung what check drying over sodium sulfate gnisehlpß, evaporation ej? gave a yellow oil which by Chromatrographie to §ilipagel was purified, wpbei eluiepte with a mixture γρη Petrpjäther and ethyl acetate. Man?,? g title compound in Ferm of a fela | yellow © n oil, NMR |, A = 4.0 (ip _Ä vinyl = H), 4.8 g (OH, OAe), §, 85 (CiJ-0 Si, 8, Q ( OQQ.QH), 9, f ^Ο %

Examples Jg ^ j »is r $

The pimetny acetals of Table II were prepared by one of the methods 11 analogous procedure with the specified Phpsphonium- §8i? En treated with the achievement of the specified E§ter.

709883/0966

TABLE II

example Acetal of example phosphonium salt product

10 methoxycarbonyl-2,4-penta- methyl-7- [3-tert-butyldlmethyl-

dienyltriphenylphosphonium silyloxy-2a- (5-tert-butyldimethyl bromide sllyloxy-1-octenyl) -4-cyclohexene

β-yl] -2,4,6-heptatrienoate, mixture of the 6-double bond isomers and epimeric silyl ethers NMR 2.50-4.90 (10-vinyl-H), 5.94 (2H, CH-OSi-tert .-Bu Me ₂ ), _CH

6.15 (ococH,), 9.80 r (si '"" ⁵ ).

CH ₃

S ^{13 9} Äthoxycarbonyl ^^ - pentadienyl- _Ätftyl . _{7th [> ace} toxy-2a- (3-tert-buty] -

σ> triphenylphosphonium bromide dimethylsilyloxy-1-octeny ^ -4-cyclo-

hexen-β-yl] -2,4,6-heptatrienoate (mixture of the 6-double bond isomers and epimeric acetates and silyl ethers; NMR 3.45-4.5 (10-vinyl-H), 4.80 (CH -OAc), 5.85 (CH-O Si Bu ¹¹ Me ₂ ), 5.76 (q, J-7 Hz, COCH ₀ CH,), 8.0

j

i.

Methyl 7-r3-acetoxy-2a (3-tert-butyldlmethylsllyloxy-1-octenyl) -cyclohex-β-yl) -heptanoate. (Mixtures of acetate and sllyl ethers).

2.2 g of the product from Example 11 were hydrogenated at room temperature and 1.41 at (20 psi) in ethanol over a PI nickel catalyst [see CA. Brown, J. Org. Chem. (1970), 35, 1900], made from 2.2 g of nickel acetate. After 16 hours, the hydrogenation was stopped, the catalyst was removed and the solution was hydrogenated again until the required four equivalents of hydrogen had been taken up. The product was isolated by filtering off the catalyst, evaporating the ethanol and re-isolating the residue from an ether solution which was washed with 5% aqueous citric acid. The product was a colorless oil that was normally used in the next stage of the process without further purification. However, when purified by chromatography on silica gel, it gave the following NMR data 4.59 (2-vinyl-H), 5.06 (CH-OAc, ax.), 5.44 (CH-OAc, eq.), 5 * 96 (CH-O Si Bu ^fc Me ₂ ), 6.35 (COOCH,), 7.96 (OCOCH ₃ ), 9.9v (sicgJ3)

Examples 15 to 16

The heptatrienoate esters of Table III were by a dem Procedure of Example 14 treated analogous to the procedure to obtain specified products.

709883/0966

Starting heptatrienoate example by example

TABLE III Product

Methyl 7- [j5-tert-butyldimethylsilyloxy-2a- (3-tert, butyldimethylsilyloxy-i-octenylj-cyclohex-β-yl] -heptanoate (mixture of the epimeric silyl ethers) NMR 4.3 (2-vinyl-H) , 6.15 (2H, CH 0 Si Bu ^ e ₃ ) 6.30 (COO CH ₅ ) 9.9 «(Si <gj3).

CD OO OO

16 Rthyl 7- [3-acetoxy-2a- (3-tert-butyldimethylsilyloxy-i-octenylj-cyclohex-β-ylj-heptanoate (Mixtures of epimeric acetates and silyl ethers)

NMR 4.60 (2-vinyl-H), 5 * 11 (CH-OAc, ax.) »5.46 (CHOAc, eq.) 5.92 (CH-O Si Bu ¹⁵ Me ₂ ), 5.82 (q , J - 7 Hz, CO CH ₃ CH,), 7.95 (OCOCH ₃ ), 9.8v (S1Cch5) ·

Üc 273U59

Example 17 *

Methyl 7-f 3-acetoxy-2a- (3-oxo-i-octenyl) cyclohex-ß-ylΊ-heptanoate (mixture of epimeric acetates) » 5 * 8 g of product from Example 14 were heated in 58 ml of tetrahydrofuran, 58 ml of acetic acid and 29 ml of water for 24 hours at 50 ° C. After removing the solvent in vacuo, the remaining crude alcohol in 50 ml of ether was stirred vigorously for 24 hours at room temperature with 50 ml of an aqueous solution of 2.6 g of sodium dichromate containing 2.37 ml of sulfuric acid, oxidized. After dilution with water, the crude product was isolated by ether extraction and purified by preparative thin layer chromatography (4: 1 light petroleum / ethyl acetate). Elution of the required band with ether gave the title compound, NMR 3 »28 (d, d, J = 16 Hz, J = 10 Hz, 1-vinyl-H adjacent to the ring, predominant isomer), 3 * 52 (d, d , J = 16 Hz, J β 10 Hz, 1-vinyl-H adjacent to the ring, isomer present in a smaller amount), 3.88 (d, J = 16 Hz, 1-vinyl-H adjacent to C = O, predominant Isomer), 3.94 (d, J = 16 Hz, 1-vinyl-H adjacent to C = O, isomer present in a smaller amount), 4.98 (CH-OAc, ax.), 5.24 (CH- OAc, eq.), 6.32 (COOCH ₃ ), 7.48 (CH ₂ -CO), 7.72 (CH ₂ -CO ₂ -Me), 7.94 ^ (OCOCH ₅ ).

Example 18

Methyl 7- [3-acetoxy-2q- (3-oxo-octyl) -cyclohex-β-yl) -heptanoate (Mixture of the epimeric acetates).

0.8 g of product from Example 17, dissolved in 90 ml of ethanol, was hydrogenated at room temperature and atmospheric pressure over 5 % palladium on activated carbon (0.1 g). After the theoretical uptake of hydrogen had taken place, the catalyst was filtered off and the title compound was isolated by solvent evaporation; NMR 4.92 (CH-OAc, ax.), 5 * 34 (CH-OAc, eq.), 6.29 (COOCH ₃ ), 7.66 * (CH ₂ -CO-CH ₂ and CH ₂ CO ₃ Me).

709883/0966

- yr -

Example 19

7- [2g- (3-Hydroxyoctyl) -3-oxocyclohex-β-yl] -heptanoic acid (Mixture of eplmer alcohols)

0.6 g of the product from Example 18 in 6 ml of methanol containing two drops of 2N sodium hydroxide solution was treated with 0.22 g of sodium borohydride. After standing for 4 hours at room temperature, the resulting mixture was acidified and extracted with ether. The oil obtained was dissolved in 2.5 ml of dry dimethylformamide and treated with 0.23 g of imidazole and 0.23 g of tert-butyldimethylsilyl chloride. After standing at room temperature in a closed vessel for 68 hours, the mixture was diluted with water and extracted with ether. The extracts were carefully washed with water, then with brine, dried and evaporated to give 0.7 g of crude silyl ether. This was dissolved in > 6 ml of methanol and treated with aqueous sodium hydroxide (0.53 g in 9 ml of water). After stirring for 3 days at room temperature, the crude silylated hydroxy acid was isolated by acidification and ether extraction. 0.6 g of crude acid was then oxidized in 6 ml of an ethereal solution by stirring with an aqueous solution of sodium dichromate (0.32 g in 6 ml of water) containing 0.29 ml of sulfuric acid. After 24 hours at room temperature, the product was isolated by dilution with water and ether extraction. The water washed extracts were dried and evaporated to give 0.5 g of crude silyl keto acid. This was then dissolved in a 3ϊ2: 1 mixture of tetrahydrofuran, acetic acid and water (5 ml) and heated ^{to 50 ° C. overnight.} Evaporation of the solvents under reduced pressure gave a crude product which was purified by preparative thin layer chromatography (20: 1 chloroform / methanol). Elution of the desired band with methanol and subsequent renewed isolation with ether, washed with 5% citric acid, gave the title compound, NMR 6.3 (CH — OH), 7.641 * (CH ₂ CO ₂ H and CHgCO).

709883/0966

273U59.

Example 20

7- [3-Hydroxy-2a- (3-tert-butyldlmethylsilyloxy-1 ~ octenyl) -cyclohex-β-yl] -heptanoic acid (mixture of the epimeric alcohols and Sllyl ether)

11.3 g of the product from Example 14 were stirred in 240 ml of methanol with 120 ml of an aqueous solution of 12.2 g of sodium hydroxide for 16 hours (homogeneity was achieved after approx. 8 hours achieved). The resulting mixture was poured into an excess of 5 # citric acid solution and extracted with Xther. The extracts were washed with brine, dried and evaporated to give 8 g of crude product, which is normally was used without further purification in the following process steps.

Example 21

7-r3g-Hydroxy-2q- (3S-hydroxy-i-octenyl) -cyclohex-ß-yl1-heptanoic acid and the corresponding 3R isomer.

The mixture was heated 4 g of product from Example 20 in 75 ml of tetrahydrofuran for 16 hr. With 50 ml of glacial acetic acid and 25 ml of water at 50 ⁰ C. The solvents were then removed in vacuo and the residue from remaining acetic acid and Silylnebenprodukten by repeated dissolution in toluene and evaporation freed. Purification of the residue by preparative thin layer chromatography on silica gel gave the title compounds. The more polar S-isomer (0.8 g) crystallized from ethyl acetate / petroleum ether with a mp = 94-96 ° C. NMR (CD, OD) 4.42 (2-vinyl-H),

OH 5.96 (CH-C-C), 6.12 (CH-OH), 7 * 72 ^ (CHgCOOH). That less

polar R-isomers (1.1 g) crystallized on standing and became from ethyl acetate / cyclohexane with a mp = 76-77 ° C. tuncrystallized. NMR (CD ₃ OD), 4.50 (2-vinyl-H), 5.96

OH
(CH-C = C), 6.18 (CH-OH), 7.74 X (CH ₂ COOH).

$ 709883/096

Example 22 ^ *

7- [2a- (3-tert-butyldimethylsllyloxy-1-octenyl) -3-oxocyclohexfl-yl] -heptanoic acid (mixture of the epimeric silyl ethers).

10 g of the product from Example 20 in 100 ml of ether were treated with a solution of 30 g of sodium dichromate in 100 ml of water and 5> 5 g of sulfuric acid. The two-phase mixture was stirred at room temperature overnight; the product was then isolated with water and extracted with ether. The combined extracts were washed with water, dried and evaporated to give a colorless oil which was purified by preparative thin layer chromatography on silica gel with evolution with a 2: 1 mixture of petroleum ether and ethyl acetate. The title compound was eluted as 3.7 g of a colorless oil. NMR 4.50 (2-vinyl-H), 5.9 ^ (CH-O Si Bu ¹ ^ Me ₂ ), 7.32 (CO-CH-CH = CH), 7.70 (CH ₂ -CO and CHgCOgH), 9.9 t

CH,

Example 23

7-r2q- (3-Hydroxy-1-octenyl) -3-oxocyclohex-β-yl] -heptanoic acid (mixed eplmers).

3.2 g of product from Example 22 in 48 ml of tetrahydrofuran, 32 ml of acetic acid and 16 ml of water were heated for 18 h. At 50 ⁰ C. After the solvents had been removed in vacuo, the residue was freed from remaining traces of acetic acid by repeated evaporation of toluene solutions. The crude product was then purified by preparative thin layer chromatography on silica gel, using multiple developments with a hexane / methylene chloride / tetrahydrofuran / acetic acid (3O: 1O: 3: 3) mixture.

610 mg of the oil obtained, which consisted of a mixture of the Tltel 3S and 3R isomers, crystallized on standing. Recrystallization from ethyl acetate / cyclohexane gave 380 mg of the title compound. M.p.-62-63 ^° C; NMR 4.48 (2-vinyl-H), 5.82 (CH-OH), 7.27 (CO-CH-C = C), 7.68 t (CH ₂ -CO and CH ₂ COOH).

709883/0966

3 273H59

Example 24

Methyl 7-r3-tert-butyldlmethylsllyloxy-2g- (3-hydroxy- »i-octenyl) -cyclohex-β-yll-heptanoate (mixture of epimeric alcohols and Silyl ether).

2.8 g of product from Example 15 in 50 ml of tetrahydrofuran were treated with a mixture of 33 ml of acetic acid and 17 ml of water at 50 ^{° C. for 6 days.} After removing the solvents under reduced pressure and evaporating a toluene solution of the residue to remove traces of acid and silyl by-products, the crude product was chromatographed on silica gel. The title monosilyl ethers were obtained from the fractions which were eluted with a 5: 1 mixture of petroleum ether and ethyl acetate. NMR 4.50 (2-vinyl-H), 5.6 (CHOH), 6.15 (CHOSi Bu * Μβ ₂ ), 6.32 (COOCH,), 7.72 (CHgCO 9.98 * (Si ( JI).

Example 25

Methyl 7- * r2g- (3S-acetoxy-i-octenyl) -3-tert-butyldimethylsllyloxy-cyclohex-β-yl] -heptanoate and the corresponding 3R-isomer. (Mixture of the epimeric silyl ethers)

300 mg of the monosilyl ether product from Example 24 were dissolved in 0.6 ml of pyridine and the resulting solution was treated with 0.3 ml of acetic anhydride. The mixture was kept at room temperature overnight and the product formed was then isolated using standard methods. Purification using preparative thin layer chromatography gave the title 3S isomer as the more polar compound. NMR 4.55 (2-Vinyl-H), 4.74 (CH-OAc), 6.16 (CH-O Si Bu ^fc Me ₂ ), 6.33 (COOCH ₅ ), 7.69 (CHgCOOMe), 7.97

• ^CH .- = S
(OCOCH,), 9.98 r (Si ** ) and the 3R isonate as less polar

^N CH

Link; NMR 4.55 (2-vinyl-H), 4.73 (CH-OAc), 6.14 (CH-O Si Bu ^ e ₂ ), 6.31 (COOCH ₅ ), 7.68 (CH ₂ COOMe ), 7.96 (OCOCH ₅ ), 9.98 f

CH

709883/0966

ä 273H59

Example 26

3a-Acetoxy-2- (4,4-dimethyl-3-oxo-1-octenyl) -4-cyclohexene-ßcarboxaldehyde-dlmethylacetal (mixture of epimers with regard to on the ring position 2)

Were added to a stirred solution of 8.5 g Diisopropylarain and a catalytic amount of 2,2-bipyridyl in 100 ml of dry ether which had been cooled to -70 ⁰ C, under nitrogen 45 ml of a 1.6M solution of butyllithium in hexane over 5 min .. The solution was then stirred at -70 ⁰ C for 1 hr., after which 11.6 g 3J3-dimethyl-2-heptanone was added in 30 ml of dry ether. After a further hour stirring at -70 ⁰ C a solution of 20 g of 6-acetoxy-2ß-dimethoxymethyl-4-cyclohexene-a-carboxaldehyde (Example 1) was added in 100 ml of dry ether and the temperature was allowed during 1 1 / Rise to -20 ° C for 2 hours. Aqueous citric acid (20 g in 100 ml) was then added to the resulting mixture, and the mixture thus obtained was stirred for 1 hour at 25 ° C. before being extracted with ether to obtain 33 g of crude intermediate. This was dissolved in 100 ml of methanol containing 5 g of potassium hydroxide and the resulting solution was heated to 40 ° C. over 10 minutes. Dilution with water and ether extraction yielded 31 g of oil, which was acetylated with a mixture of 60 ml of pyridine and 30 ml acetic anhydride for 18 hrs. At 25 ⁰ C. After diluting with ether and washing with dilute hydrochloric acid and then with a sodium carbonate solution, the organic layer was dried over sodium sulfate and evaporated to give 30.5 g of crude product. Purification was carried out by chromatography on silica gel (2: 1 petroleum ether / ethyl acetate) to give 12.5 g of the title compound.

709883/0966

Z73U59

Example 27

3a-Acetoxy-2- (4,4-dlmethyl-3S-hydroxy-i-octenyl) -4-cyclohexenß-carboxaldehyde-dimethylacetal (mixture of epimers with regard to on the ring position 2) and the corresponding 3R isomer.

The title compounds were followed by one of the procedure of the example 9 analogous process, but using the starting material was the product of Example 26. The separation of the R and S isomers was determined by preparative thin-layer chromatography (2: 1 Petroleum ether / ethyl acetate). The more polar S-isomer showed the following NMR spectrum: 3.9-4.4, 4.80, 5.7 "», 6.28, 6.60, 7.98, 9.14 "Z" and the R isomer had the following NMR spectrum: 3.9-4.4, 4.78, 5.74, 6.1-6.3, 6.61, 7.96.9.122.

Example 28

3a-Acetoxy-2- (3-hydroxy-3-methyl-1-heptenyl) -4-cyclohexene-β-carboxaldehyde-dl-methyl acetal (mixture of the Eplmeres with regard to on the ring position 2 and the rare chain).

20 g of product from Example 3 dissolved in 200 ml of dry ether was dropwise added with stirring at -15 ⁰ C to a solution of methylmagnesium iodide in 500 ml of dry ether, made of 9 g of magnesium and 48 g methyl iodide. After completion of the addition, the stirring for 3 hrs. At -15 ⁰ C was continued. The mixture obtained was then gradually poured onto excess crushed ice with stirring, and the mixture obtained was acidified to pH 4 with a 5% citric acid solution. Extraction with ether gave 20 g of the title compound.

Example 29 to 35

The products shown in Table IV were prepared by a procedure analogous to the procedure of Example 28, wherein however the indicated starting materials and Grignard reagents were used.

709883/0966

TABLE IV example

29

Starting dimethyl acetal of example

Grignard reagent

Methyl magnesium iodide

product

3a-Acetoxy-2- (5-hydroxy-3-methyl-1-nonenyl) -4-cyclohexene-β-earboxaldehyde dimethyl acetal (Mixture of isomers with regard to ring position 2 and the side chain)

Methy! Magnesium iodide

3a-acetoxy-2- (3-hydroxy-3-methyl-1-decenyl) - ^ cyclohexene-ß-carboxaldehyde dimethyl acetal (Mixture of isomers with regard to ring position 2 and the side chain)

Methy! Magnesium iodide

5a-acetoxy-2- (3-hydroxy-3 * 7-dimethyl-1 octenyl) -4-cyclohexene-ß-carboxaldehyde dimethyl acetal (Mixture of isomers with regard to ring position 2 and the side chain)

Example Starting dimethyl acetal from Example

33

35

TABLE IV continued Grlgnard reagent product

ω cn

Methyl magnesium iodine

3a-Acetoxy-2- (3-hydroxy-3,4,4-trimethyl-1-octenyl) -4-cyclohexene-ß-carboxaldehyde / methyl acetal (mixture of the isomers Im With regard to the ring position 2 and the

» 4 * 6 - 4.9, 5.66,

Side chain) NMR 3,
7.2 - 7.6, T, 78, 7,

- 4th
4 8.5

Methylmagne s iumiodide

3a-acetoxy-2- (3-hydroxy-3-methyl-1-octenyl) - 4-cyclohexene-ß-carboxaldehyde ^ dimethylacetal (Mixture of isomers with regard to the

Ring position 2 and the rare chain)

NMR 3.8-4.6, 4.6-4.9, 5.6-5.8, 6.56, 7.2 - 8.8, 7.97, 8.9 -

Ethyl magnesium bromide

3a-Acetoxy-2- (3-ethyl-3-hydroxy-1-octenyl) -4-cyclohexene-β-carboxaldehyde dimethylacetal (Eplmerenmlerung) '

Cyclopentylmagneslum bromide

3a-Aoetoxy-2- (3-cyclopentyl-3-hydroxy-1-octenyl) -4-cyclohexene-ß-carboxaldehyde-dlmethyl acetal (EPLM deletion)

-Ai- 273U59

Example 36

^ -Acetoxy ^ - ^ - acetoxy-i-octenyl ^^ - cyclohexene-fi-carboxaldehyddlmethyl acetal.

1.5 g of the product from Example 9 (mixture of R and S isomers) were dissolved in a mixture of 3 ml of pyridine and 1.5 ml of acetic anhydride and the resulting mixture was allowed to stand in the absence of moisture at room temperature overnight. The product so formed was isolated by dilution with water and extraction with ether. The ether extracts were washed with a dilute solution of hydrochloric acid and then sodium carbonate, dried and evaporated to give 1.5 g of the title compound.
NMR 3.9-4.9, 5.80, 6.65, 7.98, 9.12t.

Example 37

3tt-Acetoxy-2- (3-hydroxy-3-methyl-1-heptenyl) -4-cyclohexenecarboxaldehyde (mixture of the ring and side chain isomers).

10 g of product from Example 28 dissolved in 200 ml of dimethylformamide, were during 18 h. Heated with 10 ml of 2N hydrochloric acid at 38 ⁰ C. The resulting mixture was then poured into water and extracted with ether. The ether extracts were carefully washed with water and then 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 to 47

The products shown in Table V were prepared by a procedure analogous to the procedure of Example 37, wherein however the indicated starting materials were used.

709883/0968

TABLE V

Example Starting dimethyl acetal Product of Example

3ot-acetoxy-2- (3-hydroxy-5-methyl-1-nonenyl) -4-cyclohexene

carboxaldehyde (mixture of ring and side chain isomers)

30 3a-Acetoxy-2- (5-hydroxy-3-methyl-1-decenyl) -4-cyclohexene-^ j

carboxaldehyde (mixture of ring and side chain isomers) - ^k Jj NMR 0.33, 3.8-4.6, 4.78, 7.96, 8.94-9.3 t. J

u »CD c

<»40 31 3a-acetoxy-2- (3-hydroxy-3,7-dimethyl-1-octenyl) -4-cyclohexene <

oj, carboxaldehyde (mixture of ring and side chain isomers)

NMR 0 * 36, 3.9-4.7, 4.79, 7.97, 7.99, 7.1-7.4, 9.11, 9.19 *.

β »41 32 3a-acetoxy-2- (3-hydroxy-3,4,4-trimethyl-1-octenyl) -4-cyclo-

hexencarboxaldehyde (mixture of ring and side chain isomers)

-33 3a-acetoxy-2- (3-hydroxy-j3-methyl) -i-octenyl) -4-cyclohexen-

carboxaldehyde (mixture of ring and side chain isomers) NMR 0.34, 3.8-5.0, 6.60, 7.86, 4.75, 7.5, 9.11 ν.

34 3a-acetoxy-2- (3-hydroxy-j5-ethyl-1-octenyl) -4-cyclohexene

carboxaldehyde (mixture of ring and side chain isomers)

Starting dimethyl acetal

Example by example

44

TABLE V continued

product

3oc-acetoxy-2- (3-hydroxy-3-cyelopentyl-1-octenyl) -4-cyclohexenecarboxaldehyde (Mixture of ring and side chain isomers)

45 27 (3S epimers) 3a-acetoxy-2- (3S-hydroxy-4,4-dimethyl-1-octenyl) -4-cyclohexene
carboxaldehyde (mixture of ring epimers) 46 27 (3R epimers) 3a-acetoxy-2- (3R-hydroxy-4 _J 4-dimethyl - '! - octenyl) -4-cyclohexene
carboxaldehyde (mixture of ring epimers) 47 36 3a-Acetoxy-2- (3-acetoxy-i-octenyl) -4-cyclohexenecarboxaldehyde
(Epimer mixture)

273H59

Example 48

4-cyclohexen-ß-yl] -2,4,6-heptatrlenoate (mixture of acetates)

A suspension of 5.8 g of 5-methoxycarbonyl-2,4-pentadienyltriphenylphosphonium bromide was shaken in 19O ml of toluene and 190 ml of water with a sodium hydroxide solution (0.76 g in 5 ml), until complete resolution has been achieved. The resulting blood-red solution of phosphorane in toluene was separated off, washed with brine, dried and concentrated to half its volume.

1.2 g of the product from Example 57 in 10 ml of toluene were added to this solution and the mixture obtained was refluxed for 18 hours. After evaporating the toluene and treating 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 1.2 g of the title compound in the form of a yellow viscous oil. NMR 5.1-4.6, 2.5-2.9, 4.76, 6.23, 7.9 *, 7.97, 8.9-9.3 *.

Examples 49 to 58

The products shown in Table VI were prepared by a procedure analogous to the procedure of Example 48, wherein Anyway the specified starting materials and phosphonium salts were used.

709883/0366

TABLE VI

Example cyclohexene Salt product

carboxaldehyde
of example

³⁸

phosphonium bromide nonenyl) -4-cyclohexen-β-yl] -2,4,6-heptatri

enoat (mixture of acetates)

^ phosphonium bromide decenyl) -4-cyclohexen-ß-yl] -2,4,6-heptatri-

enoat (mixture of acetates)

u> NMR 2.5-2.9, 3.3-4.6, 4.78, 6.28, 7.99, 9.12

phosphonium bromide i-octenyl) -4-cyclohexen-i3-yl] -2,4,6-hepta-

trienoate (mixture of acetates) NMR 3.3-4.6, 4.5-5.0, 4.78, 6.28, 7.99, 8.81, 9.17 ?.

⁴¹ ? ÄtidlS? U53i ^ "methyl-7- [3-acetoxy-2a- (3-hydroxy-3,4,4-tri-

phosphonium bromide methyl-1-octenyl) -4-cyclohexen-ß-yl] -2,4,6-

heptatrienoate (mixture of acetates) NMR 3.0-4.8, 4.7-4.9, 6.29, 8.04, 9.0-9.3if.

47 ^ methoxycarbonyl-2,4. _Methyl _ ₇ _ _{[> ace} toxy-2a- (3-acetoxy-

^ yy, _methyl _ ₇ _ _{[> ace} toxy-2a- (3-acetoxyphosphonium bromide 1-octenyl) -4-cyclohexen-ß-yl] -2,4,6-hepta-

trienoate

Example cyclohexene

carboxaldehyde
of example

43

salt

TABLE VI continued product

5-methoxycarbonyl-2,4-

pentadienyl triphenyl

phosphonium bromide Methyl 7- [3-acetoxy-2a- (3-ethyl-3-hydroxy-1-octenyl) -4-cyclohexen-β-yl] -2,4,6-heptatrienoate (Mixture of acetates) NMR 2.5-3.0, 3.3-4.9, 5.09, 6.27, 7.99, 8.9-9.3 *.

ro

-ο

U)

cn CO

CO
OO
OO

55

56

42

5-methoxycarbonyl-2,4 pentadienyl triphenylphosphonium bromide Methyl 7- [3-acetoxy-2a- (3-cyclopenty1-3-hydroxy-1-octenyl) -4-cyclohexen-β-yl] -2,4,6-heptatrienoate (Mixture of acetates)

Ethoxycarbonylmethyl triphenylphosphonium bromide

Ethyl 3- [3-acetoxy-2a- (3-hydroxy-3-methyl-1-octenyl) -4-cyclohexen-β-yl] -2-propenoate (mixture of acetates) NMR 4.78, 5.82 , 7.96, 7.98, 8.72, 9.12 χ.

57

42

3-ethoxycarbonyl-2-

propenyl triphenyl

phosphonium bromide Sthyl 5- [3-acetoxy-2a- (3-hydroxy-3-methyl-1-octenyl) -4-cyclohexen-β-yl] -2.4 _r pentadienoate (mixture of acetates) NMR 3.5 - 4.6, 4.80, 5.79, 7.97, 9.12 γ.

58

42

5-methoxycarbonyl-4,4-dimethyl-2-oxopentyl triphenylphosphonium bromide

Methyl 7- [3-acetoxy-2a- (3-hydroxy-3-methyl-1-octenyl) -4-cyclohexen-β-yl] -?, 3-dimethyl-5-oxo-6-heptenoate (mixture of Acfetate) NMR 3.32, 3.6-4.6, 4.85, 6.32, 7.93-7.95, 8.9-9.3, 8.72

-jf- 273H59

Example 59

Methyl 7-r3-acetoxy-2a- (3S-tert-butyldlmethylsllyloxy-4,4-dimethyl-1-octenyl) ^ -cyclohexen-β-yll ^, 4,6-heptatrienoate (Mixture of acetates)

A suspension of 7.6 g of 5-methoxycarbonyl-2,4-pentadienyltriphenylphosphonium bromide in 380 ml of toluene and 580 ml of water was shaken with sodium hydroxide (1.52 g in 5 ml) until complete dissolution was obtained. The resulting blood-red solution of phosphorane in toluene was separated off, washed with brine, dried and concentrated to half its volume. 2.4 g of the product from Example 45 in 20 ml of toluene were added to this solution and the mixture obtained was heated under reflux for 18 hours. 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 was, after evaporation, dissolved in 30 ml of dry dimethylformamide and treated with 3 g of imidazole and 3 g of tert.-butyldimethylsilyl chloride. The mixture was heated in the absence of water for 16 hrs. At 40 ⁰ C. The product obtained was isolated by dilution with water and extraction with ether. The water washed extracts were dried over sodium sulfate 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. 2.1 g of the title compound was eluted as a yellow oil.

Example 60

Methyl 7- r3-acetoxy-2q- (3R-tert-butyldimethylsilyloxy-4,4-dlmethyl-1-octenyl) -4-cyclohexen-β-yl1-2,4,6-heptatrlenoate (Mixture of acetates)

The oil compound was prepared according to one of that used in Example 59 Procedure analogous procedure hel-provided, however the starting material was the product: of Example 46.

09 8 83/096 6

273U59

Example 61

6-Γ 3-acetoxy-2a- (3-hydroxy-3-diethyl-1-octenyl) -4-cyclohexenß-yli-5-cis-hexenoic acid (mixture of acetates) and the corresponding methyl esters

Sodium hydride was freed in the form of a 50% dispersion in oil (3 * 12 g) by washing three times with petroleum ether

from the oil. The obtained petroleum ether-wet slurry was dried in a nitrogen stream. 60 ml of dry dimethyl sulfoxide were then added and the mixture obtained was heated to 70 to 80 ° C. until the evolution of gas had completely ceased. The resulting solution was allowed to cool and any precipitate to settle out. 30 ml of the clear supernatant solution was carefully withdrawn and transferred to a flask containing 1.2% 4-carboxybutyltriphenylphosphonium bromide which had been flushed with nitrogen. The obtained mixture was stirred under nitrogen before 2.5 g of product from Example 42 in 10 ml of dry dimethyl sulfoxide admitted, after which the mixture is kept for 1 hr. At 25 ° C and heated for 3 hrs. At 50 ⁰ C for 15 min. Was . The crude acid was isolated by dilution with water, extraction with ether to remove undesired neutral material and subsequent acidification of the aqueous phase with 5% citric acid, followed by extraction with ether.

Evaporation of the extracts gave 3.5 g of crude acid which was purified by preparative thin layer chromatography. (9: 1 CHCl, / MeOH). NMR 3.6-5.2, 7.96 ". The acid was then esterified by treatment with an excess of essential diazomethane. Excess diazomethane was then destroyed with acetic acid and the resulting ethereal solution of the product was washed with dilute sodium carbonate solution and with brine and evaporated. The title ester was a colorless oil, NMR 4.0-5.0, 6.28, 7.62, 7.9-8.0, 9.08 r.

709883/0966

273U59

Example 62

Methyl 7- [3-acetoxy-2g- (3-hydroxy-3-niethyl-1-heptenyl) -cyclohex-ß-yll-heptanoate (mixture of acetates)

It was carefully added to a solution of 1.2 g of nickel acetate in 10 ml of water in a 250 ml flask filled with nitrogen Was rinsed contained powdered sodium borohydride. After the vigorous evolution of gas had subsided, was the precipitated black granular catalyst separated by decantation under nitrogen and twice with 30 ml Methanol washed by a decantation method.

A solution of 1.2 g of the product from Example 48 in 50 ml of methanol was then added to the catalyst and the mixture was hydrogenated at room temperature and atmospheric pressure until the required amount of hydrogen has been absorbed (usually approx. 24 hours). Removal of the catalyst by filtration and solvent evaporation then gave 1.2 g of the title compound.

Examples 63 to 73

The products shown in Table VII were prepared by a procedure analogous to the procedure of Example 62, wherein however the indicated starting materials were used.

709883/0966

TABLE VII

Example of starting ester product CJ

from example - *

63 49 Methyl-7- [3-acetoxy-2a- (3-hydroxy-3-methyl-1-nonenyl) -cyclohex-β-yl] - (J ₁

heptanoate (mixture of acetates) <&

64 50 methyl-7- [3-acetoxy-2a- (3-hydroxy-3-methyl-1-decenyl) -cyclohex-β-yl] -

heptanoate (mixture of acetates) NMR 4.2 - 4.6, 6.34, 7.70 (t, J - 7), 7.96, 8.03, 8.9-9, 3 V.

ο 65 51 methyl-7- [3-acetoxy-2a- (3-hydroxy-3,7-dimethyl-1-octenyl) -cyclohex-ß-yll-

00 heptanoate (mixture of acetates) NMR 4.2-4.6, 5.02, 6.32, 7.8θ, 7.96,

2 8.02, 8.73, 8.76, 9.12 (d, J = 6) τ ·. Ο

° 66 52 methyl 7- [3-acetoxy-2a- (3-hydroxy-3,4,4-trlmethyl-1-octenyl) -cyclohex-β-yl] -σ> heptanoate (mixture of acetates) NMR 4, 0 - 4.6, 4.98, 6.28, 7.1 - 7.5,

^OT 7.70, 7.96, 8.02, 8.9 - 9.4 tr.

67 56 Xthyl-3- [3-acetoxy-2a- (3-hydroxy-3-methyl-1-octenyl) -cyclohex-β-yl] -

propionate (mixture of acetates) NMR 4.2-4.6, 4.99, 5.86, 7.72, 7.94, 8.01, 8.70, 9.11

68 57 Ethyl 5- [3-acetoxy-2a- (3-hydroxy-3-methyl-i-octenyl) -cyclohex-β-yl] -

Pentanoate (mixture of acetates) NMR 4.3-4.6, 5.00, 5.86, 7.71.7.94.9.11 V.

TABLE VII continued

Example starting ester product

of example

69

73

61

55

Methyl 6- [5-acetoxy-2a- (3-hydroxy-3-methyl-1-octenyl) -cyclohex-β-yl] - <* J hexanoate (mixture of acetates) ^ * »

58 methyl-7- [3-acetoxy-2a- (3-hydroxy-3-methyl-1-octenyl) -cyclohex-β-yl] -

5,5-dimethyl-5-oxoheptanoate (mixture of acetates) NMR 4.5-4.6, 5.00, 6.34, 7.94, 8.01, 9.0-9.5 γ.

53 Methyl 7- [5-acetoxy-2a- (5-acetoxy-1-octenyl) -cyclohex-β-yl] -heptanoate

(Mixture of acetates)

NMR 4.2-4.9, 5.03, 5.84, 6.53, 7.70 (t, J = 7), 7.95, 7.97,

8.02, 8.9 - 9.3, 7.8 - 9.0 f.

5 ^ methyl-7- [3-acetoxy-2a- (3-ethyl-3-hydroxy-i-octenyl) -cyclohex-β-yl] -

heptanoate (mixture of acetates)

NMR 4.3-4.8, 4.9-5.5, 6.55, 7.73, 8.03, 9.0-9.3 *.

Methyl-7- [3-ace toxy-2.cz- (5-cyclopentyl-5-hydroxy-1-oc tenyl) -cyclohex-ß-yl] heptanoate (mixture of acetates)

mm 4.2-4.7, 5.04, 5.96, 6.56, 7.72, 7.98, 8.9-9.3 *.

ST 273U59

Example 74

Methyl 7-r3tt-acetoxy-2a- (3S-tert-butyldimethylsllyloxy-4,4-dimethyl-i-octenyl) -cyclohex-β-yl] -heptanoate and the corresponding 3ß-acetate

The title compounds were prepared by a procedure analogous to the procedure of Example 62, except that the Starting material was the product of Example 59. The separation of the 3a- and 3β-acetates was carried out by preparative thin-layer chromatography on silica gel (10: 1 petroleum ether / ethyl acetate). The more polar β- (equatorial) acetate showed the following Nuclear Magnetic Resonance Spectrum: 4.4-4.6, 5.1-5.3, 6.1-6.3, 6.32, 7.70, 8.00, 9.16 t.

The less polar α- (axial) acetate showed the following NMR spectrum: 4.4-4.8, 6.2-6.4, 6.33, 7.70, 7.99, 8.01 *.

Example 75

Methyl 7- [3g-acetoxy-2q- (3R-tert-butyldlmethylsilyloxy-4,4-dimethyl-1-octenyl) -cyclohex-β-yl] -heptanoate and the corresponding 3β-acetate

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

The separation of the 3a- and 3β-acetates was effected by preparative thin-layer chromatography on silica gel (10: 1 petroleum ether / ethyl acetate). The more polar β- (equatorial) acetate showed the following NMR spectrum: 4.3-4.6, 6.31, 6.58, 7.99, 9.04 t and the less polar α- (axial) acetate the following NMR spectrum: 4.4-4.7, 4.9-5.1, 6.2-6.3, 6.26, 7.61, 7.87,

9.09 r.

709883/0966

"5" 273U59

Example 76

3-r3-acetoxy-2tt- (3-hydroxy-3-methyl-1- (octenyl) cyclohex-β-yl] propionaldehyde

It was brought into a nitrogen-flushed, 34 ml of toluene containing 250 ml flask 34 ml of a 70 percent solution of Sodium bis (2-methoxyethoxy) aluminum hydride in benzene. The flask was then fitted with a septum cap. The resulting solution was cooled in ice and slowly treated with the aid of a syringe with 11 g of morpholine and 60 ml of toluene. (The evolution of hydrogen made the presence of a small sampling needle required in the 7-part closure to avoid pressure build-up).

After completion of the addition of the reagent was added dropwise via syringe to a stirred, cooled to -40 ⁰ C solution of 4.8 g of product from Example 67 in 100 ml of toluene under nitrogen. The temperature was kept during the addition below -40 ⁰ C. The reaction mixture thus obtained was stirred at -40 to -60 ⁰ C for 5 hours under nitrogen and the mixture was then poured onto excess crushed ice. The resulting mixture was acidified with 5 percent citric acid and extracted with ether. The extracts were washed, dried and evaporated to give 4.5 g of crude product which was purified by chromatography on silica gel (petroleum ether / ethyl acetate 1: 1). The 1.1 g title compound had the following NMR spectrum: 0.28, 4.2-4.6, 5.01, 7.59, 7.96, 8.02, 8.9-9.3T.

Example 77

Methyl 8-r3-acetoxy-2g- (3-hydroxy-3-methyl-1-octenyl) -cyclohexß-yli-5-cis-octenoate (mixture of acetates)

The title compound was prepared by a procedure analogous to that of Example 61, except that the Starting material was the product of Example 32. Nuclear Magnetic Resonance Spectrum: 4.4-4.8, 5.08, 6.38, 7.72, 8.00, 8.07, 8.81, 8.78, 8.9-9.3T-

709883/0966

273U59

Example 78

Ethyl-9 ~ r5-acetoxy-2a- (3-hydroxy-3-methyl-1-octenyI) -cyclohex-ß-yl1-2 _t 4t6-nonatrlenoate (mixture of acetates)

Nuclear Magnetic Resonance Spectrum: 2.5-3.0, 3.4-4.6, 5.00, 6.23, 7.93, 8.0OT. The title compound was prepared by a procedure analogous to that of Example 48, but using the starting material was the product of Example 76.

Example 79

Methyl 8-r3-acetoxy-2g- (3-hydroxy-3-methyl-1-octenyl) -cyclohex-ß-yll-octanoate (mixture of acetates)

The title compound was prepared by a procedure analogous to that of Example 62 except that the Starting material was the product of Example 77.

Example 80

Methyl-9-r3-acetoxy-2a- (3-hydroxy-3-methyl-1-octenyl) -cyclohex-ß-yli-nonanoate (mixture of acetates)

JJMR spectrum; 4.3 - 4.6, 5.00, 6.31, 7.68, 7.93, 8.00, 8.9 - 9.2 r. -

The title compound was prepared by a procedure analogous to that of Example 62, except that the Starting material was the product of Example 78,

Example 81

Methyl-7-r3-acetoxy-2g- (3-hydroxy-3-methyl-1-octenyl) -cyolohex-ß-yl1-heptanoate (mixture of the Epmers)

Were added 2.45 g of product from Example 17 in 400 ml of dry Xther slowly with stirring to a solution of methyl Magne-Biumjodid (from 1.83 g of magnesium and 9.6 g of methyl iodide in 100 ml of dry ether) previously to -15 ⁰ C had been cooled . After 2 hours at -15 ⁰ C, the obtained mixture into an excess of ice and 5 percent citric acid solution was poured. Compartment separating the organic layer and back-extracting the aqueous layer with Xther were combined

709883/0966

273U59

organic extracts washed with brine, dried and evaporated. The crude product was chromatographed on silica gel (2: 1 light petroleum / ethyl acetate) to give the title compound; NMR Spectrum: 4.5 (2 vinyl H), 5.00 (CH-OAc, ax.), 5.38 (CH-OAc, eq.) 6.32 (COOCH ₃ ), 7.70 (CH ₂ COOMe), 7.96T (OCOCH ₅ ).

Example 82

7-r3-hydroxy-2a- (3-hydroxy-3-methyl-1-octenyl) -cyclohex-ßyl "l-heptanoic acid (mixture of epimers)

0.56 g of the product from Example 81 was dissolved in 12 ml of methanol and the resulting solution was treated with an aqueous solution of sodium hydroxide (0.56 g in 6 ml) for 16 hours at room temperature. After acidification and ether extraction, the crude product obtained was purified by preparative thin layer chromatography (9: 1 chloroform / methanol). Elution of the required band with methanol and subsequent re- isolation of the residue from an ethereal solution which was washed with 5 percent citric acid gave the title compound; Nuclear Magnetic Resonance Spectrum: 4.38 (2 vinyl H), 4.76 (3H, OH and COOH), 6.14 (CH-OH), 7.68 (fTcHg-COOH).

Examples 83 to 95

The products listed in Table 8 were prepared by a procedure analogous to the procedure of Example 82, but using the starting materials indicated .

709883/0966

CO CD OO

84 85 86

Tatelle VIII

First example of example

product

62

63

65

7-r3-Hydro3cy-2tt-C3-hydroxy-3-methyl-1-'heptenyl) -cyclohex-ß-yli-heptanoic acid (mixture of Eplmeres) CMR: 4.1 - 4.6, 4.9 - 5, 3, 6.13, 7.67, 9.08 r-

7-r3-Hydro3cy "2a- (3-hydroxy-3-methyl-1-nonenyl)" -cyclohex -β-yli-heptanoic acid (mixture of the epimers) NMR: 4.2-4.5, 5.0-5 , 6, 6.12, 7.64, 8.9 - 9.3 T.

7-r3-Hydroxy-2tt- (3-hydroxy-3-methyl-1-decenyl) -cyclohex-ß-yli-heptanoic acid (mixture of epimers) NMR: 4.2 - 4.5, 4.9 - 5.5, 8.95-9.3

7-r3 ~ hydroxy-2tt ~ (3-hydroxy-3,7-dimethyl ~ 1-octenyl) ' cyclohex-ß-yli-heptanoic acid (mixture of epimers) NMR: 4.2 - 4.5, 4.9 - 5.5, 6.1, 7.67, 9.1

Table VIII (continued)

Starting ester
Example of example product

66 7- r3-Hydro3r7-2a- (3-hydroxy-3 «4« 4-trime thy 1- »1 -octeny1) -

cyclohex-ß-yli-heptanoic acid (mixture of the epimers) NMR: 3.8-4.5, 4.97, 5.86, 7.94, 7.64, 6, Ot.

ο 88 68 5-r3-acetoxy-2tt- (3-hydroxy ~ 3 ~ methyl-1-octenyl) -cyclohex-

££ ß-yl1-pentanoic acid (mixture of Eplmeres)

NMR: 4.2-4.5, 4.6-5.0, 6.12, 7.66, 9.1 Or- '

*? 89 69 6-r3-Hydroxy-2a- (3-hydroxy-3-methyl-1-octenyl) -cyclohex- '

ß-yll-hexanoic acid (mixture of epimers)
NMR: 4.1-4.4, 4.3-4.8, 7.68, 9.11 *.

70 7-r3-hydroxy ~ 2tt- (3-hydroxy-3-methyl-1-octenyl) -cyclohex-

ß-yl] -3,3-dlmethyl-5-oxoheptanoic acid (mixture of epimers)

J. J. C ^ ₀

NMR: 4.1-4.7, 6.12, 7.3-7.8, 8.9-9.3 t. ^

Table VIII (continued)

First example of sample product

91 80 9 ~ r3-Hydroxy-2a- (3 ~ hydroxy-3-methyl-1-octenyl) '- cyclohex-

β-yli-nonanoic acid (mixture of epimers) NMR: 4.2-4.5, 5.0-5.6, 6.12, 7.64, 8.9-9.3U.

° 92 79 8-r3-hydroxy-2g- (3-hydroxy-3-methyl-1 ~ octenyl) ~ cyclohex- '

OD

° * ß-yl1-octanoic acid (mixture of epimers)

ti NMR: 4.2-4.6, 4.7-5.2, 6.13, 7.67, 8.9-9.3Έ ·

ο> 93 77 8- [3-Hydroxy ~ 2g- (3 ~ hydroxy-3-methyl-1-octenyl) -cyclohex ~

_σ> - - -

ß-yl1-5-cis-oc1: enoic acid (mixture of epimers)

NMR: 4.1-4.5, 4.5-4.9, 4.9-5.3, 6.14, 7.63, 8.9-9.3t ;.

Table VIII (continued)

First example of Example product

94-78 9- [3-Hydroxy-2g- (5-hydroxy-3-niethy1-1-octeny I) -Cy

β-yl 1-2,4,6-nonatrienoic acid
NMR: 2.3-2.8, 3.4-4.5, 5.0-5.4, 6.10, 8.9-9.3f

71 7-r3-Hydroxy-2a- (3-hydroxy-1-octenyl) -cyclohex-ß-yl1-

——

heptanoic acid (mixture of epimers)

Example 96

7-r2g- (3-Hydroxy-3-methyl-1-heptenyl) -3-oxocyclohexß-yl1-heptanoic acid

The mixture was cooled 0.7 g of product from Example 83 in 20 ml ether at -12 ⁰ C and stirred during the dropwise addition of a solution of 0.4 g Natriumdiehromat in 12 ml of water containing 0.26 ml of concentrated sulfuric acid. The temperature was kept during the addition below -1O ⁰ C. The mixture obtained was stirred at -15 ° C. for 4 hours. The crude product thus formed was isolated by dilution with water and ether extraction. Purification by preparative thin layer chromatography (9: 1 chloroform / methanol) gave 0.22 g of the title compound. NMR: 4.2-4.6, 3.0, 3.7, 7.1-7.45, 7.66, 8.95-9.3Of.

Examples 97 to 100

The products shown in Table 9 were prepared by a procedure analogous to the procedure of Example 96, wherein however the indicated starting materials were used.

709883/0966

Table IX

Starting acid
Example of example product

97 82 7 ~ r2a- (3-Hydroxy-3-methvl-1-octenyl) "5-oxocyclohex-ß-yll-

heptanoic acid

NMR: 2.92 (2H, OH and COOH), 4.42 (2 vinyl H), 7.24

(CH-CO), 7.66 1 ^ (CH ₂ COOH and CH ₂ CO)

S ^ ^{8 8} ^ 7-r2g- (3 »hydroxy-3-methyl-1-decenyl)» 3-oxocyclohex ~ β-ylV oo heptanoic acid
o »- ^c

5J NMR: 3.8-4.4, 4.4-4.6, 7.66, 9.0-9.3 τΊ

ο »99 86 7-r2g- (3-hydroxy-3,7-dlmethyl-1-octenyl) ^ -oxocyclohex- ° * ß-yl1-heptanoic acid

NMR: 3.9-4.8, 4.4-4.6, 7.66, 9.11 T.

100 91 9-r2g- (3-Hydroxy ~ 3-methyl-1-octenyl) -3 ~ oxocyclohex-ß-yl1-

nonanoic acid

NMR: 3.7-4.6, 7.1-7.4, 7.61, 8.9-9.3r «

273U59

Example 101

Methyl 7-r3-acetoxy-2a- (3-hydroxy-3-methyl-1-octenyl) -cyclohex-β-yl 1-3-3-dimethyl 1-5-hydroxyheptanoate (Mixture of isomers)

The title compound was prepared by a procedure analogous to that of Example 27 except that the product of Example 70 was used as starting material. NMR: 4.2-4.7, 5.04, 6.36, 7.59, 7.99, 8.97, 8.9-9.3 χ ..

Example 102

7-f3tt-Hydroxy-2a- (3S-hydroxy-4,4-dimethyl-1-octenyl) -cyclohex-β-yl1-heptanoic acid

0.7 ml of 5N hydrochloric acid were added to a solution of 0.7 g of 3a product from Example in 7 ml of dimethylformamide. The mixture obtained was heated ^{to 50 ° C. for 72 hours.} The dilution with water and the ether extraction gave 0.65 g of crude intermediate product, which was dissolved in 13 ml of methanol without further purification and treated ^{with 6.5 ml of a 10 percent sodium hydroxide solution at 25 ° C. for 18 hours.} The resulting mixture was then diluted with saturated saline, acidified with 5 percent citric acid solution, and extracted with ether. The extracts were washed with brine, dried and evaporated to give a crude product which was purified by preparative thin layer chromatography (10: 1 chloroform / methanol). The title compound was obtained as 0.3 g of a colorless viscous oil. NMR: 4.3-4.4, 4.8-5.3, 6.0-6.2, 7.68, 9.0-9.2T <

Examples 103-105

The products listed in Table X were produced by a method that was analogous to that of Example 102, but using the starting materials indicated became.

709883/0966

Table I.

Auegangseeter example of example

product

74 7-r3ß-hydroxy-2g- (3S-hydroxy-4 «4-dlmethyl-1-octenyl) -

(3ß-acetate) cyclohex-β-yl1-heptanoic acid

KMR: 4.28, 5.0-5.4, 6.08, 6.2-6.5, 7.66, 9.1Of.

7-r3g ~ hydroxy ~ 2g- (3R "hydroxy-4,4-dlmethyl-1-octenyl) ~ cyclohex-ß-yll-heptanaäiire

HMR: 4.2 - 4.5, 4.9 - 5.30, 6.0 - 6.3, 7.67, 9.0 - 9.2 Tl

7-f3β-Hydroxy-2tt- (3R-hydroxy-4i4-dimethyl-1-octenyl) -cyclohex-β-yl 1 "-heptanoic acid

KMR: 4.2-4.5, 4.7-5.1, 6.1-6.6, 7.68, 9.1OT *

104 75

(3ß-acetate)

105 75

(3ß-acetate)

273U59

Example 106

Methyl 7-r3-hydroxy-2tt- (3-oxo-1-octenyl) -cyclohex-β-yl1-heptanoate (Mixture of the Eplmers)

An excess of ethereal diazomethane was added to an ethereal solution of 0.4 g of the product of Example 95. The excess diazomethane was destroyed with acetic acid and the resulting solution was then washed with dilute sodium carbonate solution, dried over sodium sulfate and evaporated. The 0.4 g of methyl esters obtained in 20 ml of dioxane were stirred while 0.62 g of dichlorodicyanobenzoquinone was added, and the orange-red solution thus formed was kept at room temperature for 72 hours. After filtering to remove precipitated pests, 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. NMR: 3.10, 3.91, 6.0-6.2, 6.33, 7.44, 7.72, 8.9-9.3 T. Example 107

Methyl 7-r3g-hydroxy-2a- (3-hydroxy-3-methyl-1-octenyl) -cyclohex-ß-yli-heptanoate and the corresponding 3ß-epimer

A solution of 0.2 g of the product of Example 82 in 2 ml of ether was treated with excess ethereal diazomethane and then sufficient glacial acetic acid to destroy excess diazomethane. The essential solution was then diluted with Washed sodium carbonate solution, dried and evaporated. The resulting mixture of the title esters was then added to the 3A and 3β epimers separated by preparative thin layer chromatography (2: 1 petroleum ether / ethyl acetate). The less polar one 3a- (axial) alcohol (0.1 g) showed the following NMR spectrum: 4.0-4.8, 6.32, 7.69, 9, O9f

The more polar 3β- (equatorial) alcohol (0.05 g) had the following NMR spectrum: 4.2-4.6, 6.33
7.71 (t, J - 7), 8.0 - 8.9, 8.9 - 9.3τ

709883/0966

273H59

^ Example 108

fteptanoic acid

The hydrolysis of the 3a epimer of Example 107 under the conditions used in Example 82 gave the title Jot epimer. JfMRf 4.3-4.5, 4.8 * - 5.3, 6.17, 7.69, 9.13f, example 109

7 * -f3ß-Hydroxy-2g- (3-hydroxy-3-methyl-1-octenyl) -cyclohex-ß-yl'l -Aßalog pu Example 108 the 3ß-epimer was obtained. , heptanoic acid NMR; 4.3-4.5, 4.8-5.3, 6.17, 7.70, 9.12 V *

Example 110

Methyl 7-r3-acetoxy-2g- (3-hydroxy-3-methyl-octyl) -cyclohexß-yl 1-heptanoate (mixture of epimers)

The product of Example 81 was treated by a procedure analogous to that of Betspiel 18 to give the title compound PU received,

geisplel 111

7 "[3-hydroxy-2g- (3-hydroxy-3-methyl-octyl) -cyclohex-β-yl1- ^ eptanoic acid (mixture of epimers)

The product of Example 110 was prepared according to one of the procedures of Example 82 treated analogous to the title compound PU received,

yellow game 112

Preparation of 2-oxononyl triphenylphosphonium bromide

A solution of 142.2 g of 2-nonanone in 750 ml of dry Methanol containing 4.5 g of cupribromide, a solution of §0 g of bromine in 250 ml of methanol. The resulting mixture was at Stirred at room temperature until a color change from deep red to green-black was observed (approx. 12 minutes). The mix was then immediately thereafter poured into a quenched saturated aqueous Iip'sung of sodium carbonate and the obtained

701883/0966

273H59

Mixture was diluted to about 4500 ml with water and with Ether extracted. The combined extracts were washed with brine, dried and diluted with 500 ml of benzene. To distilling at atmospheric pressure to remove ether gave a solution of 52 g triphenylphosphine in 250 ml benzene added and the slow distillation continued for a further hour.

The hot solution was then diluted with excess ethyl acetate which precipitated the crude product in the form of an oil which was obtained by decanting the supernatant liquid. Redissolving the oil in benzene followed by further treatment with excess ethyl acetate precipitated a product which crystallized on standing. Recrystallization from methylene chloride / ethyl acetate at room temperature gave 50 g of pure title compound in the form of white needles.
NMR: 1.8-2.6, 4.2 (d, J-> 11.5) 8.1-9.1, 9.0-9.4 T.

The following phosphonium salts were prepared using an analogous procedure made 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) 2-0xo-6-methylheptylphosphonium bromide from 6-methyl-2-heptanone.

709883/0966

273U59

The product yields of the preceding examples and the weight of the starting cyclohexyl compound used are in given in the following table.

Tabel

example Weight of the • Product example Weight of product No. Starting weight No. Starting weight cyclohexyl ■ (g) cyclohexyl (G) link link (G) (G) 1 22 (acetoxy 19th 13th 7.5 2.0 butadiene) 14th 2.2 1.18 26th (Dimethoxy 15th 2.7 2.6 crojtonalde- hyd) 16 2.0 1.5 2 127 175 (raw) 17th 5.8 2.32 3 6th 3.75 18th 0.8 0.7 4th 6.05- 4.2 19th 0.6 0.09 5 6.05 4.6 20th 11.6 8.0 6th 6.0 3.6 21 4th 0.8 (S) 1-1 (R) 7th 20th 18th 22nd 10 3.7 I. 8th 175 57 23 3.2 0.61 9 7.2 2.2 (S) 2.0 (R) 24 2.8 0.350 (SiIy] ether] 10 12.3 12.4 D. 200 (R) 0.100 (S) 11 3.7 2.2 25th 0.3 D. 018 (R) 12th 12.4 5.4 3.066 (S)

709883/0966

273H59

Table (continued)

Example no.

Weight de: starting cyclohexyl · -; connection (g)

jProduct weight

(G)

example

Weight of
Starting cyclohexyl
link

(G)

Product weight

(G)

26 27

28 29 30 31 32 33 34 35 36

20 11

3.5

4.6

3.6

5.2

20th

4.0

4.0

1.5

3.5

4.1

3.5

12.5

4 (S) 5.2 (R)

3.5 4

4.1 3.5

20th

4.2

4.3

1.5

1.2

3.6

1.8

1.45

41 42

4.9
15th

43 4.2 44 4.0 45 4th 46 5.1 47 .4.8 48 1.2 49 3.6 50 1.8 51 1.45 52 4.7 53 3.8 54 2.4 55 4.3 56 0.80

4.7 6

2.4

3.9

3.3

4.9

3.8

1.2

2.0

2.0

1.7

2.0

3.5.

2.2

3.0

0.44

709883/0966

273U59

Table (continued)

example
No. Weight de
Starting
cyclohexyl
link
(G) ι product
weight
(G) example
No. Weight of
Starting
cyclohexyl
link
(G) product
weight
(G) 57 2.0 1.6 72 2.2 1.9 58 UO 1.2 73 3.0 2.8 59
60
61 2.4
5.3
3.12 2.1
6.0
3. 5 (acid)
0.7 (ester) 74
75
76 3.0
6.0
4.8 0.73 (α-)
0.95 (β-).
2.25 (α-)
1.95 (β-)
1.1 62 U2 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
I. 1.1 0.8 85 1.9 1.1 71 3.5 3.6 86 1.3 • 0.38
——.

709883/0966

η - SZ

273U59

Table (continued)

example Weight de] Product- example j weight of product No. Starting weight Kr. I output weight cyclohexyl (G) cyclohexyl (G) link
(G) link
(G) 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 (α-) P.P5 (β-) 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 97 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

709883/0966

Claims (1)

Claims X is a carbonyl or protected carbonyl group or a hydro means xymethylene or protected hydroxymethylene group, A is a saturated or unsaturated straight or branched chain denotes an aliphatic chain with 5 to 16 carbon atoms which can contain one or more hydroxyl, protected hydroxyl, oxo or protected oxo groups and B a saturated or unsaturated straight or branched chain aliphatic chain with 5 to 16 carbon atoms, which contains a terminal carboxyl or protected carboxyl group and which has one or more hydroxyl, protected hydroxyl, May contain oxo or protected oxo groups, and when B contains a carboxyl group, their salts. 2. Compounds according to claim 1, wherein A and / or B contains a free hydroxyl group. 3. Compounds according to claim 1 or 2, wherein A and / or B is a hydroxyl or protected hydroxyl group in the allyl position in terms of a carbon-carbon double bond farther from the 6-membered ring than the carbon-carbon double bond. 4. Compounds according to claim 1 or 3, wherein A and / or B at least one protected hydroxyl group selected from Contains acyloxy and labile ether groups. 709883/0966 INSPECTED 5. Compounds according to claim 4, wherein A and / or B at least one protected hydroxyl group selected from alkanoyl, Aralkanoyl, carbamoyl and carbonate ester groups with up to 24 carbon atoms, tetrahydropyranyl ether groups and trihydrocarbylsilyl ether groups with a total of 3 to 24 carbon atoms in the ether group. 6. Compounds according to any one of the preceding claims, wherein A and / or B contain a ketal group. 7. Compounds according to any one of the preceding claims, wherein A and / or B comprise a gem-dimethyl grouping. 8. Compounds according to any one of the preceding claims, 2 wherein A is a group of the formula -Q.V / .Alk, wherein Q a carbon-carbon double bond or an ethylene group means which can contain a hydroxyl or protected hydroxyl group in ß-position to the group W or a is trans-vinylene group, W is a carbonyl group or a hydroxymethylene or means protected hydroxymethylene group, optionally containing an alkyl group (which can be cyclic may or may contain a phenyl substituent) on the Methylene group and Alk denotes a straight-chain or branched alkyl or alkenyl group having 1 to 10 carbon atoms. 9 · Compounds according to claim 8, wherein A is a group of Formulas -CH ₂ CH ₂ .CO.CH ₂ CH ₂ CH ₂ CH ₂ CH ₅ , -CH = CH CO CH ₂ CH ₂ CH ₂ CH ₂ CH ₅ , -CH = CH CH (OH) -CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ , -CH ₂ CH ₂ CH (OH) -CH ₂ CH ₂ CH ₂ CH ₂ CH ₅ , -CH = CH CO C (CH ₃ ) ₂ CH ₂ CH ₂ CH ₂ CH ₃ , -CH = CH CH (OH) .C (CH ₃ ) ₂ CH ₂ CH ₂ CH ₂ CH ₃ , -CH = CH.C (OH) (CH ₃ ) .CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ 709883/0066 -CH ₂ CH ₂ C (OH) (CH ₃ ) CH ₂ CH ₂ CH ₂ Ch ₂ CH ₃ means in which t means a trans double bond. 10. Compounds according to claim 8, wherein A is a group of Formulas -CH (OH) .CH = CH-CH ₂ CH ₂ CH ₂ Ch ₂ CH ₃ , -ch-ch.c (oh) (ch ₃ ) ch ₂ ch ₂ ch ₂ ch (ch ₃ ) ₂ , -ch = ch-c (oh) (c ₂ h ₅ ) ch ₂ ch ₂ ch ₂ ch ₂ ch ₃ , -CH = CH-C (OH) (cyclo C ₅ H ₉₂₂₂₂₃ -CHiCH-C (OH) (CH ₃ ) CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ , -CH = CH-C (OH) (CH ₃ ) CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ Ch ₃ or -CH = CH-C (OH) (CH ₃₎ CH ₂ CH ₂ CH ₂ CH ₃ means in which t means a trans double bond. 11. Compounds according to any one of claims 1 to 9, wherein B 1a 1a is a group of the formula -Alk R, in which Alk is Al represents kylengruppe and R is a carboxyl or protected one Means carboyl group. 12. Compounds according to claim 11, wherein B is a group of the formula -CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ Ch ₂ R, wherein R is as defined in claim 11. 13 · Compounds according to claim 11, wherein B is a group of Formulas ₂₂₂₂ CH ₂ CH ₂ CH ₂ R, wherein R is as defined in claim 11, -CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ Ch ₂ R, wherein R is as defined in claim 11 or 709883/0966 wherein R is as defined in claim 11. 14. Compounds according to any one of claims 1 to 9, wherein B is a group of the formula -Alk R, wherein Alk is an alkenylene group and R is as defined in claim 11. 15. Compounds according to claim 14 »wherein B is a group of Formulas -CH = CH-CH = CH-CH = CH-R, wherein R is as defined in claim 11, -CH ₂ CH ₂ CH = CH.CH ₂ CH ₂ CH ₂ R,
wherein R is as defined in claim 11 or -CH ₂ CH ₂ CH = CH.CH = CH.CH = CHR, wherein R is as defined in claim 11, wherein t denotes a trans double bond and c denotes a cis double bond means. 16. Compounds according to claim 10, wherein B is as in one of the Claims 11 to 15 is defined. 1-7. Compounds according to any one of the preceding claims, wherein B contains a carboxyl or lower alkoxycarbonyl group. 18. Compounds according to any one of the preceding claims, wherein X is a cyclic or acyclic ketal or thioketal means. 19 · Compounds according to any one of claims 1 to 17, wherein X represents a group of the formula ^ CHOZ, wherein Z is an acyl, Means tri (hydrocarbyl) silyl, alkyl (including cycloalkyl), aralkyl or tetrahydropyranyl group. 20. Compounds according to any one of claims 1 to 17, wherein X is a carbonyl or hydroxymethylene group. '21. Compound selected from the following: 709863/0966 a) 7- [2a- (3R, S-hydroxy-3-methyl-1-octenyl) -3 ^; i £ Ocyclohexß-yι] -heptanoic acid, b) 7- [3 | -Hydroxy-2a- (3R, S-hydroxy-3-methy1-1-octeny1) -cyclohex-β-yl] -heptanoic acid, c) 7- [3a-Hydroxy-2a- (3R, S-hydroxy-3-methy1-1-octenyl) -cyclohex-β-y1] -heptanoic acid, d) 7- [3β-Hydroxy-2a- (3R-hydroxy-4,4-dimethyl-1-octenyl) -cyclohex-β-y1] -heptanoic acid, e) 7- [3a-hydroxy-2a- (3S-hydroxy-1-octenyl) -cyclohex-ß-yl] -heptanoic acid, f) 7- [3a-hydroxy-2a- (3R-hydroxy-1-octenyl) -cyclohex-ß-yl] -heptanoic acid, g) 7- [3 £ -hydroxy-2a- (3R, S-hydroxy-3-methyl-octyl) -cyclohex-β-y 1] -heptanoic acid and their salts. 22. Compounds of general formula I according to one of the preceding claims, wherein B contains a terminal carboxyl group, in the form of physiologically acceptable salts. 23. Pharmaceutical compositions containing at least one compound of the formula I according to claim 1 as active ingredient or when B contains a terminal carboxyl group, a physiologically acceptable salt thereof, along with one pharmaceutical carriers or diluents. 24. Compositions according to claim 23 in the form of tablets, coated tablets, capsules, fastilles, ampoules or solutions. 25th Compositions according to claim 23 or 24 in the form of dosage units. 26. Process for the preparation of compounds of the general formula I according to claim 1, characterized in that a compound of formula II 709883/0966 -aö - * 273U59 HC HC ⁵ ^ CH (II) R ¹ wherein R is a protected hydroxyl group with a compound of formula III / V H CHO ρ
wherein R is a masked or protected aldehyde group, to give a compound of formula IV .2 (IV) "" 'CHO R ¹ 1 2
wherein R and R are as defined above, followed by one or more of the following reactions which can be carried out in any suitable order as required to give the desired compound of formula I: a) When a free and a protected masked aldehyde group coexist, protecting or masking the free Aldehyde group such that a selective conversion of the protected or masked aldehyde group that was initially present, becomes possible into a free aldehyde group, b) Cleavage of protective groups from a protected aldehyde group and renewed conversion of a masked aldehyde group into one free aldehyde group, c) Implementation of a free aldehyde group in the 2-position of the 6-membered one Rings with a reagent of formula Va 709883/0966 2.73U59 R ³ \ CH - (CO) -R ^{ba na} (Va) wherein either na is 1, R ^{5a is} hydrogen and R ^ ^{a is} a dialkylphosphonyl group or hydrogen or na is 0 or 1 and R ^ia and R together form a trialkylphosphoranylidene or triarylphosphoranylidene group, the reaction being carried out in the presence of a base when R 5a
Is hydrogen and R is a saturated or unsaturated straight or branched aliphatic "chain". where the . . ς «excluding the substituents Group - (CO) -R has up to 14 carbon atoms / and the Il et aliphatic chain optionally by one or more hydroxyl or protected hydroxyl, oxo or protected oxo groups is substituted, whereby the group -CH ^ CH- (CO) "-R or -CH-CH ₀ COR ^ in the na ι c. OH 2-position of the 6-membered ring is introduced, d) conversion of a free aldehyde group in the 1-position of the 6-membered one Ring with a reagent of formula Vb wherein nb, R * and R ^ are defined as above for na, R ^ ^a or R ^ ^a and the reaction is carried out in the presence of a base, if r 'is hydrogen and R ^ is a saturated or unsaturated straight or branched aliphatic Group means, where the group - (CO) ^ R up to 14 Kohlenhlisslih JSbtitt ^nD exclusively <Jer ^ substituents,,. ._. . . , ... .. material atoms / and the aliphatic chain contains a terminal carboxyl or protected carboxyl group and is optionally substituted by one or more hydroxyl, protected hydroxyl, oxo or protected oxo groups, whereby the group -CH = CH- (CO) _nb -R ^5b or -CH-CH ₂ COR ^ in OH 709883/0966 273U59 1-position of the 6-membered ring is introduced, e) Cleavage of protective groups from R, with a free hydroxyl group is obtained in the 3-position of the 6-membered ring, f) Treatment of any hydroxyl groups with a suitable one Esterification or etherification reagent for the formation of protected Hydroxyl groups, g) splitting off of any protected carboxyl groups, h) reduction of the double bond in the 6-membered ring and if desired Reduction of one or more further unsaturated carbon-carbon double bonds, i) reduction of any keto groups, j) splitting off of protecting groups from other protected hydroxyl groups as R, k) Oxidation of any -CHOH groups with the formation of carbonyl groups, l) reaction of a carbonyl group in a side chain in position 1 or 2 in the 6-membered ring with an organometallic see Reagent. 27 · Modification of a method according to claim 26, characterized in that that a free aldehyde group in the 1- or 2-position of the 6-membered ring first with a reagent of the formula (R ^5m ) (R ^4m ) .CH.R ^m , where R ^3m and R ^4m together form a trialkylphosphoranylidino or triarylphosphoranylidino group and R ^{m is} an esterified carboxyl group or saturated or unsaturated straight-chain or branched aliphatic group with up to 12 carbon atoms excluding the substituents represents, which contains a terminal esterified carboxyl group, is reacted, the product formed in this way is reduced, the terminal esterified carboxyl group in the group R ^{m being converted} into an aldehyde group and this aldehyde-containing group introduced in this way into the 709883/0966 "j}" 273U59 desired side chain B or A by reaction with a further reagent of the formula Va or Vb as defined in claim 26, (in which (COV _e R or (CO), R have up to 12 carbon atoms excluding the substituents and R can additionally be a carboxyl group if nb is 0) is transferred. 28. Modification of the method according to claim 26 or 27, characterized in that it includes the step of a protection Oxo or carboxyl group and / or the step of splitting off a protected oxo group. 29. A compound of the formula IV according to claim 26, wherein R is a Denotes di (lower alkoxy) methyl or alkylenedioxymethyl group. 709883/0966