CA1198420A - 9-deoxy-9a-methylene isosteres of pgi.sub.2 and process for their preparation - Google Patents

Abstract

ABSTRACT
The invention relates to new compounds of formula I
I

wherein R is (a) a free or esterified carboxy group; (b) -C(OR')3, where each R' group is independently Cl-C6-alkyl or phenyl; (c) -CH2-R", where R"
is hydroxy or C2-C7-alkoxy; (d) , where Ra and Rb are chosen inde-pendently from the group hydrogen, Cl-C6-alkyl, C2-C6-alkanoyl and phenyl;
(e) -C?N; (f) radical; (g) -CHO; or (h) radical where each X' is independently -O- or -S- and the R'a and R'b groups, whether the same or different, are Cl-C6-alkyl or together form a straight or branched C2-C6-alkenylene chain; D is: (trans), -C?C-, ?C=O, -O-, -S-, or ?N-Rc, where Rc may be hydro-gen, Cl-C6-alkyl or C2-C6-alkanoyl; one of R1 and R2 and, independently, one of R3 and R4 is hydrogen, Cl-C6-alkyl, C2-C10-alkenyl, C2-C10-alkynyl, phenyl, or aryl-Cl-C6-alkyl and the other is hydrogen, hydroxy, Cl-C6-alkoxy or aryl-Cl-C6-alkoxy, or, R1 and R2 and, independently, R3 and R4 together form an oxo group; each R5 and R6, whether the same or different, may be hydrogen, Cl-C6-alkyl or halogen, or R5, R6 and the carbon atom to which they are bound form a ?C=CH2 or radical; Y is: -C?C-, (trans), (cis) where Z is halogen, -NH-CO- or -NH-CH2-; X is: -(CH2)m3-in which m3 is zero or 1, (cis), (trans), -O-, -S-, or ?N-Rc where Rc is as defined above; m1, m2, n1 and n2, whether the same or different, may be zero or an integer between 0 and 12 such that each m1 + m2 and n1 + n2 is less than or equal to 15; p and q are independently zero or an integer between 1 and 3 such that the sum p + q is an integer of 1 to 6; R7 is a cycloaliphatic radical, either unsubstituted or substituted with one or more Cl-C6-alkyl or Cl-C6-alkoxy; or a saturated or unsaturated heterocyclic ring, either unsubstituted or substituted with one or more of the following: halogen, halo-Cl-C6-alkyl, Cl-C6-alkoxy, phenyl, Cl-C6-alkyl;
and the lactones derived from compounds of formula I and the pharmaceutically or veterinarily acceptable salts thereof. The compounds display broncho-dilator, luteolytic, anti-ulcerogenic and platelet anti-aggregant activity.

Description

416,726 The object of this invention is 9-deoxy-9a-methylene-isosteres o-f PGI2, also known as 6,9u-oxide-lla, 15(S)-dihydroxy-prosta-5(Z),13(E)-dienoic acid, including a procedure for their preparation as well as pharmaceutical and veterinary compositions containing them.
Compounds covered by this invention have the fol-lowing general formula (I) Cll~(CH ) -D-(CH ) -R

(CH2~ (CH2)q H H (I) l R5 Rl R2 ( 2)nl B ( 2 n2 7 wherein R is chosen from the group a) a free or esterified carboxy group; b) -C(OR')3, where each R' group is independently Cl-C5alkyl or phenyl; c) -CH2-R", where R" is hydroxy or C2-C7alkoxy; d) -CON~R , where Ra and Rb are chos~n inde-pendently from thegroup hydrogen, Cl-C6alkyl, C2-C6alkanoyl and phenyl; e) -C-N; f) a -CNH radical; g) -CHO; h) a CH~ a radical where each Xl is independently-O- or -S- and the Rla and R'b groups, whether the same or different, are Cl-C6 alkyl or together form a straight or branched C2-C6 alkylene chain;
D is chosen from the group: -CH2-, -CH-OH, ,C=C'H (cis), C=C~H (trans), -C--C-, ~C=O, -O-, -S-, and `N-RC, where Rc may be hydrogen, Cl-C6alkyl or C2-C6alkanoyl;

one of R1 and R2 and, independently, one of R3 and R4 is hydrogen~ Cl-C6alkyl, C2-ClOalkenyl, C2-ClOalkynyl, phenyl, or aryl-Cl-C6alkyl and the other is hydrogen, hydroxy, C1-C6alkoxy or aryl-C1-C6alkoxy, or, Rl and R2 and, inde-pendently, R3 and R~ together form an oxo group; each R5 and R6, whether the same or differentj may be hydrogen, Cl-C6-alkyl or halogen, preferably fluor-ine, or R5, R6 and the carbon atom to which they are bound form a C=CH2 or ~CcH2 radical; Y is chosen from the group: -C_C-, ~I,C=C'~ (trans), =C Z
(Ci5) where Z is halogen, -NH-CO- and -NH-CH2-; X is chosen from the group:
-(CH2)m in which m3 is zero or 1, ,,C=C'H (cis), H,C=C~H ~trans), -O-, -S-and ~N-RC ~with Rc as defined above; ml, m2, nl and n2, whether the same or different, may be zero or an integer between O and 12 such that each sum ml+m2 and nl+n2 is less ~han or equal to 15; p and q are independently zero or an integer between 1 and 3 such that the sum p + q is an integer of 1 to 6; R7 is a cycloaliphatic radical, either unsubstituted or substituted with one or more Cl-C6-alkyl or Cl-C6-alkoxy; or a saturated or unsaturated heterocyclic ring, ei-ther unsubstituted or substituted with one or more of the ~ollowing: halogen, halo-Cl-C6-alkyl, Cl-C6-alkoxy, phenyl, Cl-C6 alkyl-This invention also covers lactones derived fromcompounds wi.th formula (I), as well as pharmaceutically or veterinarily acceptable salts, optical antipodes, and geometric isomers and diastereoisomers of compounds with formula (I~, plus their mixtures.
In this discussion, a dashed line (''') refers -to substituents on a ring in the configuration, that is, below the plane of the ring, to substituents on a bicyclo ~(p+q+l) .3.0l alkane system (composed of condensed rings A and B) in the endo con~iguration, and to substituents on a chain in the S configuration. A wedged line (~ ), on the other hand, refers to a ring substituent in the con~iguration, that is above the plane of -the ring, to a bicyclo L(p+q+1).3.~
alkane substituent in the exo configuration, and to a side chain substituent in the R configuration. A wavy line (~) indicates a substituent of undefined stereochemistry: ring substituents may be or ~, bicycloalkane substituents may be endo or exo, and side chain substituents may be R or S.
The compounds with formula (I) and their derivatives described here have a cis junction between condensed rings A and B; the hydrogen atoms bound to the bicyclic system at the junction are both outside the dihedral angle formed by the rings in the natural configuration.
The side chain on cyclopentane riny A (the chain) is trans with respect to riny B and exo with respect to the bicyclic system.
In the compounds covered by this invention, there are 2 possible geometric isomers arising from -the configuration of the double bond exocyclic to ring B, depending on whether the chain bound to this double bond (chain ~) is on the same side as or the opposite side from the chain on cyclopentane ring A (chain ~): in the first case, the exocyclic double bond is defined as cis;
in the second, it is trans. In both formula (I) and the formulas which follow, the symbol means that both geometric isomers are covered by this invention, both separa-tely and in mixtures.
The above notation refers to natural compounds.
However, the enantiomers covered by this invention show stereochemistry at all asymmetric sites which is the opposite of that found in the natural compounds. They are thus mirror images of the latter, and their names include the prefix "ont" to indicate precisely that. d,l mixtures contaln equimolar quantities of the natural compounds and the corresponding enantiomPrs.
The alkyl, alkenyl, alkynyl, alkoxy and alkanoyloxy groups may be straight or branched, unsubstituted or sub stituted with one or more of the following: halogen, Cl-C6-alkoxy and aryl, phenyl in particular.

B~Z~

R is preferably a Eree or esterified carboxylic groupJ or its derivative salt.
A Cl-C6alkyl group is preferably methyl, ethyl or propyl.
A C2-C7acyloxy group is preferably C2-C6alkanoyloxy, for example, acetoxy, propionyloxy, or benzoyloxy.
A C2-C6alkanoyl group is preferably acetyl or propionyl.
A C2-C6alkylene radical is preferably ethylene or propylene.
A Cl-C6-alkoxy group is preferably methoxy, ethoxy or propoxy.
An aryl-Cl-C6-alkyl group is preferably benzyl.
An aryl-Cl-C6-alkoxy group is preferably ben~yloxy.
A C2-C10-alkenyl group is preferably -C~=CH-R8, where R8 is hydrogen or straight or branched Cl-C8-alkyl, but preerably a vinyl group.
A C2-C10-alkynyl group is preferably -C_C-R8, ~here R~ is as defined above, but preferably an ethynyl group.
A halo-Cl-C6-alkyl group is preferably trihalo-Cl-C6-alkyl, particularly trifluoromethyl.
When Z is halogen, chlorine or bromine is preferred.
Preferably, R5 and R6 are independently chosen from hydrogen, Cl-C6-alkyl and fluorine.
When R7 is a cycloaliphatic radical, it may be mono-, bi- or tricyclic. If monocyclic, C3-Cg-cycloalkyl or cycloalkenyl is preferred, like cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cycloheptenyl. If bicyclic, norbornyl is preferred. IE tricyclic, adamantyl is preferred.
When R7 is a cycloaliphatic radical, a monocycloaliphatic group as defined above is preferr~d.
When R7 is a heterocyclic ring, this may be mono- or bicyclic, containing a heteroatom at least one of N, S and 0. However, the he~ero-cycle is preferably monocyclic as de:Eined above, particularly ~etrahydrofuryl, tetrahydrothienyl, tetrahydropyranyl, pyrrolyl, pyrazolyl, oxazolyl, iso-?~

~8~

xazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl.
When R is an esterified carboxy group, -COOR9 is preferred, where R9 is a Cl-C12-alkyl radical~ particularly methyl, ethyl, propyl, heptyl or C2-C12-alkenyl, allyl in particular.
Preferably, ml, m2, nl and n2 are independently zero, 1, 2 or 3.
Pharmaceutically or veterinarily acceptable salts of compounds with ~rmula (I) may be formed with both inorganic ~`! 6 -and organic acids and bases.
Pharmaceutically or veterinarily acceptable inorsanlc acids include hydrochloric, hydrobromic and sulfuric; while organic acids include citric, ~umaric, tartaric malic, maleic, methanesulfonic and ethanesulfonic.
Acceptable inorganic bases may be the hydroxides of alkali or alkaline earth metals, zinc and aluminum. ~cceptable organic bases may be amines like methylamine, die~hylamine, trimethylamine, ethylamine, dibutylamine, triisopropylamine, N-methylhexylamine, decylamine, dodecylamine, allylamine, crotylamine, cyclopentyiamine, dicyclohexylamine, benzylamine, dibenzylamine, ~-phenylethylamine, ~-phenylethylamine, ethylenediamine, diethylenetriamine, and other similar aliphatic, aromatic and heterocyclic amines like piperidine, morpholine, pyrrolidine, piperazine, as well as substituted derivatives like l-methylpiperidine, 4-ethylmorpholine, 1-isopropylpyrrolidine, 2-methylpyrrolidine, 1,4-dimethyl-piperazine, 2-methylpiperidine, hydrophilic derivatives like mono-, di- and triethanolamine, 2-amino-2-butanol,

2-amino-1-butanol, 2-amino-2-ethyl-1,3-propanediol, 2-amino-2-methyl-1-propanol, tris-(hydroxymethyl~-aminomethane, N-phenylethanolamine, N-(p-tert-amylphenyl)-diethanolamine, ephedrine, procain, and & amino acids like lysine and arginine.
Under this invention, the preferred salts are compounds with formula (I~ in which R is -COORd, where ~d is ~', .

a pharmaceutically or veterinarily accep-table cation derived from one of the bases listed above.
In this di.scussion, the compounds covered by -the invention will be referred to as bicyclo [(p+q+1).3.0~
alkane derivatives, or, preferably, as derivatives of a 20 carbon atom compound, the prostacyclanoic acid, with the following formula:

COOH

0 9a \~7 1 0~

in which the position of the oxygen atom is called the 9a position.
Therefore, a compound with formula (I) in which p=q-l is a bicyclo~3.3.d]octyl derivative or, preferably, a derivative of a 9a-deoxy-9a-methylene prostacyclanoic acid, since a methylene group has taken the place of the hetero-atom in position 9a of the prostacyclanoic acid. A compound with formula (I) in which p=2 and q=l is a bicyclo ~4.3. oJ

nonyl derivative, or, preferably, a derivative of 9a-deoxy-9a,9b-dimethylene prostacyclanoic acid, since 2 methylene groups have substituted the heteroatom in position 9a of the prostacyclanoic acid. Analogously, a compound with formula (I) in which p=3 and q=l is a byc~yclo ~5~3O0 dodecyl derivative ~1 ~9~

or, preferably, a derivative of 9a-deoxy-9a,9b,9c-trimethylene prostacyclanoic acid.
nalogous prostacyclanoic acid derivatives in which q=2 or q=3 are called "7a-homo"-or "7a,7b-dihomo" respectively, while c~mpounds with formula (I) with p or q equal to ~ero are called "9a-nor-methylene" or "7-nor-methylene" respectively.
The same notation (homo, dihomo, nor, dinor, etc.) is used to indicate lengthening (the former) or shortening (the latter) o~ the and chains by one, two or more carbon atoms, relative to the number of carbon atoms in prostacyclanoic acid.
Under this invention, preferred compounds ~ith formula (I) are those in which R is a free or salified carboxy group; R7 is a saturated mono-heterocycle (preferably tetrahydrofuryl or tetrahydrothienyl) or a C5-C7-monocycloalkyl radical and the other substituents have the meanings reported above.
The compounds covered by this invention are prepared by a p~ocess which comprises alkylation of compound II

/~
~CH2)p (CH2)q H H II

C-~C~12-)n ~~~X~-(C~12ln2 7 R~4 R6 wherein p, q, Y, nl, n2, X, R5, R6 and R7 are as defined above; one of R' and R'2 and, independently, one o~ R'3 and R'4 is hydrogen, Cl-C6-alkyl, C2-C10-alkenyl, C2-C10-alkynyl, phenyl or aryl-Cl-C6-alkyl and tile other is hydrogen, hydr~xy, Cl-C6-alkoxy, aryl-Cl-C~-alkoxy or a protecting group bound to the bicyclic system or -the side chain through an ether linkage, or .. : _ g _ q~

R'l and R'2 and, independently, R'3 cmd R'~ together orm a protecting group for the ketone function, with a compound with formula (III) E-cH-(cll2)m ~D~(C112)m2 III

wherein D, ml and m2 are as defined above; E is a (C6H5)3P- or a (Re0)2P-~(0)-group where aach R may independently be Cl-C6-alkyl or phenyl; R"' is (a") a carboxylic group, free, esterified or as i~s salt; (b") -C(OR')3, where R' is as defined above; (c") -CH2RIV, where RIV is C2-C7-acyloxy or a protecting group bound to -CH2- through an ether linkage, (d") -CON ~, where Ra and Rb are as defined above; (e") -C-N; (f") a -C~ ¦¦ radical; (g") a -CH~x,R,a radical where X', Rla and R'b are as defined above, followed if required by the removal of any protecting group present, or, if required, subjected to nucleophilic addition the free carbonyl on the c.hain of a compound of fo~mula I in which R3 and R4 together form an oxo group to afford, upon re-moval of any protecting groups, a compound of formula I in which one of R3 and R4 is hydroxy while the other is hydrogen Cl-C6-alkyl, C2-C10-alkenyl, C2-C10-alkynyl, phenyl or aryl-Cl-C6-alkyl and, if required, preparing -the ether derivative from a compound of formula I in ~Ihich one of R3 and R4 is hydroxy while the other is hydrogen, Cl-C6-alkyl, C2-C10-alkenyl, C2-C10-alkynyl, phenyl or aryl-Cl-C6-alkyl, and any other hydroxyl groups present are protected to give af~er removal of any protecting groups a compound of formula I in ~Ihich R4 is Cl-C6-alkoxy or aryl-Cl-C6-alkoxy while the other is hydrogen, Cl-C6-alkyl, C2-C10-alkenyl, C2-C10-alkynyl, phenyl or aryl-Cl-C6--alkyl; or, if required, a compound with formula I in which Y is -CH=CZ-(trans), Z is halogen, one of R3 and R~ is hydrogen, Cl-C6-alkyl, C2-C10-alkenyl, C2-C10-alkynyl, phenyl or aryl-Cl-C6-alkyl while the other is hydroxy, Cl-C~-alkoxy or aryl-Cl-C6-alkoxy, or R3 and R4 together form an oxo group, and any hydroxy, oxo or carboxy groups present are free or in protected form, is dehydrohalogenated to give, after removal of any protecting group, a com-pound of formula I in which Y is -C-C- and one of R3 and R4 is hydrogen, Cl-C6-alkyl, C2-C10-alkenyl, C2-C10-alkynyl, phenyl or aryl -Cl-C6-alkyl ```l while the other is hydroxy, Cl-C6~alkoxy or aryl-Cl-C6-alkoxy or R3 and R~
together form an oxo group, or, i~ required, converting a compound o~ formula I into another or to the lactone or pharmaceu~ically or veterinarily accept-able salt or, if required, converting a salt of a compolmd of ~o-rmula I to the free compound or, if required, separating a mixture of isomeric com~ounds of formula I into individual isomers.
Protecti.ng groups for the hydroxyl functions are ether or ester residues readily converted to hydroxyl groups under mild conditions, for instance acid hydrolysis. Preferred groups include silyl ethers; for instance trialkylsilyl ethers like trimethyl, dimethyl-tert-butyl, dimethyl-isopropyl, or dimethylethylsilyl ether; and also acetal and enol ether residues: for instance, tetrahydropyranyl ether7 tetrahydrofuranyl ether, dioxanyl ether, oxathianyl ether,~ 0-Alk where Alk is Cl-c6_alkyl.

Ketone pro~ecting groups are preferably ketal and thioketal residues: ~C-x,R~ groups in which X', Ra and Rb are as defined above.
Alkylation of a compound (II) with a compound is carried out by using at least a 1.1 molar equivalent excess of ~III) per mole of ~II).
The reaction may be run in any inert solvent e.g. in a linear or cyclic ether like diethyl ether, tetrahydrofuran, dioxane or dimethoxyethane; in an ali-phatic or aromatic hydrocarbon like n-hexane~ n-heptane, benzene or toluene;
in a halogenated hydrocarbon like dichloromethane or carbon tetrachloride, as well as i-n mixtures of these solvents.
Especially when E in compounds (III) is ~C6H5)3P-, dimethyl-sulfoxide, hexamethylphosphoramide, and other aprotic solvents are particular-ly useful. Dimethylsulfoxide gives the dimethylsulfinyl carbanion upon rsaction ~ith an alkali hydride which in turn can generate carbanions with formula (III) from the corresponding phosphoranes and phosphonates; this solvent is t}lUs particularly preferred, since carbonions (III~ can then be generated in situ.
Por the alkylations described above, the reaction temperature .~

may range from the freezing point to the boiling point of water, although room temperature is particularly preferred.
Reaction ofla compound (II) with a compound (III) gives a mixture of geometric isomers, in that the new exocyclic double bond formed in the reaction may be cis or trans. If desired, the individual geometric isomers may be separated by fractional crystalli~ation from a suitable solvent or by chromatography, either thin layer, column or liquid-liquid at low, mcdium or high pressure. Silica gel or magnesium silicate may be used as supported with a solvent like cyclohexane, n-hexane, benzene, methylene chloride, ethyl ether, isopropyl ether, ethyl acetate or methyl acetate as the mobile phase.
When necessary, the ether protecting groups may be removed from the hydroxyl functions with mild acid hydrolysis, for instance with mono-or poly-carboxylic acids like acetic, formic, citric, oxalic, or tartaric in a solvent like water, acetone, tetrahydrofuran, dimethoxyethane or a low molecular weight alcohol, or with a sulfonic acid like p-toluene-sul~onic in a lpw molecular weight alcohol like anhydrous ethanol or methanol, or with a polystyrene-sulfonic resin. Por example, a 0.1-0.25N polycarboxylic acid ~like oxalic or citric) is used with a suitable lo~-boiling solvent miscible with water and readily removable under vacuum at the end of the reaction.
Silyl ether residues may be selectively removed in the presence of ~ther protecting groups with F ions in solvents like tetrahydrofuran and dimethylformamide.
Ester protecting groups may be removed by following typical saponification procedures.
Ketal and thioketal protecting groups for ketones are generally ~emoved as are acetal or thioacetal groups, with mild acid hydrolysis as described above.
Thioketals and thioacetals may be selectively removed in the presence of other protecting groups with, for instance, mercuric chloride in 34Z~

aqueous acetone or acetonitrile, or a mixture of them, in the presence of an alkaline earth carbonate like that of calcium or magnesium.
Nucleophilic addition to the free carbonyl grou~ on the chain in a compound (I) in which R3 and R~ together form an oxo group gives a sec-ondary or tertiary alcohol, depending on the nucLeophile.
A secondary alcohol is preferably prepared with an alkali or alkaline earth (like sodium, lithium, calcium or magnesium) borohydride or with zinc borohydride to give, after any protecting groups are removed, a compound (I) in which one of R3 and R~ is hydrogen and the other is hydroxy, 0.5-6 moles of reducing agent are used per mole of the carbonyl derivative (I), in an aqueous or anhydrous solvent; for instance, a linear or cyclic ether like ethyl ether, tetrahydrofuran, dimethoxyethane or dioxane, an ali-phatic or aromatic hydrocarbon like n-heptane or benzene, a halogenated hydrocarbon like methylene chloride, or a hydroxyl-containing solvent like methyl, ethyl or isopropyl alcohol, as well as mixtures of these. The reaction temperature may range from -4VC ~o the boiling point of the solvent, but is preferably between -25C and -~25C.
A tertiary alcohol is prepared by reaction with an organometallic derivative to give, after any protecting groups are removed, a compound (I) in which one of R3 and R~ is Cl-C6-alkyl, C2-C10-alkenyl, C2-C10-alkynyl, phenyl or aryl Cl-C6-alkyl while the other is hydroxy. The organometallic may be a magnesium derivative like RlOMgHal (in which Rlo is Cl-C6-alkyl, C2-C10-alkenyl, phenyl or aryl-Cl-C6-alkyl and Hal is 2~

halogen/ preferably chlorine or bromine), a lithium cuprate like RloCuLi (Rlo as above), an organolithium derivat:ive like RloLi (Rlo as above), or an alkali or alkaline ear-th acetylide (Rll C-C-)n Mn (in which n is 1 or 2, Rl1 is hydrogen, straight or branched Cl-C8-alkyl, aryl-Cl-C6-alkyl, or aryl, particularly phenyl, and M is an alkali or alkaline earth metal). The reaction between the carbonyl compound and one of these organometallic derivatives is pre~erably run with 1.05 moles (or slightly more) of reagent per mole of compound, in an anhydrous solvent- for instance, an aprotic solvent like dimethylsulfoxide or hexamethylphosphoramide, a linear or cyclic ether like ethyl ether, tetrahydrofuran, anisole, dioxane or dimethoxyethane, or an aliphatic or aromatic hydrocarbon like n-heptane, n-hexane, benzene or toluene. The reaction temperature may range from approximately -70 C to the boiling point of the solvent, but is preferably between -60C and 20C.
Whether it is a secondary or tertiary alcohol, the product of this nucleophilic addition is a mixture of the 0 epimeric S and R alcohcls. The individual S (`C,~R12) and R
'OH
(`C"~ORH ) alcohols (in which R12 is hydrogen, Cl-C6-alkyl, C2-C10-alkenyl, C2-C10-alkynyl, phenyl or aryl-Cl-C6-alkyl) may be separated as desired using the fractional crystalliz-ation and chromatography techniques described above.
The optional preparation of ethers from these secondary L2~
and tertiary alcohols to give, after any protecting groups are removed, compounds with formula (I) in which one of R3 and R4 is Cl-C6-alkoxy or aryl-Cl-C6-alkoxy ~hile the other is hydrogen, Cl-C6-alkyl, C2-C10-alkenyl, C2-C10-alkynyl, phenyl or aryl-Cl-C6-alkyl, may be effected by reaction with an optionally aryl-substituted diazoalkane in the presence of a,catalyst like fluoroboric acid or boron trifluoride in an organic solvent like dichloro-methane. Alternatively, it may be done by reaction of the hydroxyl group (either free or as its salt) with an alkyl or arylalkyl halide in the pre-sence of a base like silver oxide, in a solvent like dimethylsulfoxide or dimethylformamide.
The optional dehydrohalogenation of a compound with formula (I) in which Y is -CH=CZ- (trans, Z is halogen) one of R3 and R4 is hydroxy, Cl-C6-alkoxy or aryl-Cl-C6-alkoxy while the other is hydrogen, Cl-C6-alkyl, C2-C10-alkenyl, C2-C10-alkynyl, phenyl, aryl-Cl-C6-alkyl or R3 and R4 to-gether form an oxo group to give the corresponding compound (I) in which Y is -C-C- is effected with a dehydrohalogenating agent preferably chosen from:
CH3-SO-CH2e, diazabicycloundecene, diazabicyclononene, and an alkali metal amide or alcoholate. 1-5 moles (preferably 1.5-1.~) of dehydrohalogenating agent is used per mole of compound (I), and the reaction is preferably run in an oxy~gen-free atmos-~31 - 15 -phere in an inert solvent like dimethylsulfoxide, dimethyl-formamide, hexamethylphosphoramide, a linear or cyclic ether or an aliphatic or aromatic hydrocarbon like -those lis-ted above, liquld ammonia, or a mixture of these solvents at a temperature ranging from ~60 C to the boiling point of water ~n the absence of ammoni.at room temperature is preferred.
This optional dehydrohalogenation of a compound (I) in which Y is -CH=Cz- (trans) and Z is halogen to give the corresponding derivative in which Y is -C~C- may precede the carbonyl nucleophilic addition and the successive preparation of ethers from thP product alcohol.
The following reactions are all run using standard procedures: optional transformation of a compound with formula (I) into another, optional lactone or salt preparation, preparation of the free compound (I) from its salt, and separation of individual isomers from a mixture.
For example{ a compound with formula (I) in which R3 and R4 are both hydrogen may be prepared from one in which one of R3 and R~ is hydrogen while the other is hydroxy by preparing the tosylate ~rom th~ alcohol, for instance by treatment with tosyl chloride in the presence of base, and reducing the tosylate with NaBH4 or NaB(CN)H3 in water, aqueous alcohol or dimethylformamide or with LiAlH~ in an anhydrous solvent like ethyl ether or tetrahydrofuran, at a temperature ranging from room temperature to the boiling point of the solvent. Analogously, a compound with formula (I) in which P~l and R2 are both hydrogen may be prepared from one in which one of R1 and R2 is hydrogen while the other i5 hydroxy, and a compound (I) in which D is -CH2~ may be prepared from one in which D is /CH-OH.
A compound with formula (I) in which R3 and R4 together form an oxo group may be prepared from one in which one of R3 and R is hydrogen while the other is hydroxy by se~lective oxidation with excess activated MnO2 in an inert, preferably chlorinated solvent like methylene chloride or chloroform at room temperature or, alternatively, with 1.1-1.2 molar equivalents of dichlorodicyanobenzoquinone in an inert solvent like dioxane, benzene or a mixture at a temperature ranging from 40C to the boiling point of the solvent.
In an analogous fashion a compound with formula (I) in which Rl and R2 together form an oxo group may be prepared from one in which one of Rl and R2 is hydrogen while the other is hydroxy, and a compound (I) in which D is ~C=O may be prepared from one in ~hich D is ~CH-OH.
hen only one of several secondary alcohol functions is to be oxidized, the others must be protected as described above; the protecting groups are then removed at the end of the reaction.
A compound with formula (I) in which one of Rl and R2 is Cl-C6-alkoxy or aryl-ClC6-alkoxy may be prepared from one ~' in which one of Rl and R2 is hydroxy through etherification analogous to that described for a compound with formula (I) in which one or R3 and R4 is hydroxy. Again, when only one of several secondary alcohol functions is to react, the others must be protected; the protecting yroups are then removed at the end of -the reaction.
A compound with formula (I) in which R is a carboxylic ester group (for instance, a Cl-C12-alkoxycarbonyl) may be prepared from one in which R is a free carboxylic group by following standard procedures, for example reaction with an appropriate alcohol, like a cl-C12-aliphatic alcohol, in the presence of an acid catalyst, like p-toluenesulfonic acid, or alternatively, treatment with a diazoalkane.
The optional conversion of a compound with formula (I) in which R is an esterified carboxy group ~i.e., a Cl-C12-alkoxycarbonyl) to one in which R is a free carboxyl group may be effected usin~ standard saponification ~rocedures:
treatment with an alkali or alkaline earth hydroxide in water or aqueous alcohol, followed by acidification.
The optional preparation of a compound with formula (I) in which R is -CH2-R" (R"=hyaroxy) from one in which R
is a free or esterified carboxyl group may be effected by reduction of the ester with LiAlH4 in ethyl ether or tetrahydrofuran at reflux.
The optional conversion of a compound with formula (I~

in which R is a free carboxyl group to one in which R is -CO-N~Rb (Ra and Rb as defined above) may be ef~ected by treatment with an amine HNRaRb in the presence of a condensing agent, for ins-tance a carbodiimide like dicyclo-hexylcarbodiimide. A compound with formula (I) in which R is a carboxylic ester may be converted into one in which R is -CON~Ra by treatment with an amine HNRaRb in a suitable organic solvent at reflux for 2 3 hours.
The optional preparation of a compound wlth formula (I) in which R is a -C,~7H_~ radical from one in which R is a free carboxyl group may be effected by formin~ first the corresponding acid halide (preferably chloride, perhaps with thionyl or oxalyl chloride in refluxing dichloroethane or dioxane), then the amide derivative (for example, with ammonia), followed by dehydration to the nitrile (for ins~ance with p-toluenesulfonyl chloride in pyridine at 90-100C) and finally reaction of the nitrile with sodium azide and ammonium chloride in dimethylformamide at a temperature ranging from room temperature to 100 C. This reaction of the carboxyl group to give -CN or -C~NH N is pref~rably run on the starting material.
The optional conversion of a compound with formula (I) in which R is a free or esterified carboxyl group into one in which R is -CHO may be effected using standard proced~
ures, for instance the preparation of the corresponding chloride ,~ .

~2~

from the acid or ester and subse~uent Rosenmund reaction as described in Org. Reactions, 4,362,(1948).
A compound wi-th formula (~) in which R is -C(OR')3 (R' as defined above) may be prepared from one in which R
i5 a free or esterified carboxyl group by reacting the hydrochloride of the carboximide ester (prepared with standard methods) with a suitable alcohol, according to the procedure described in _ Amer. Chem. Soc.,64,1827(1942~, for example.
Acetalization, for example the optional preparation of a compound with formula (I) in which R is -CH~X,R~ (where X' is oxygen and Ra and Rb are as defined above) is effected by reaction of the aldehyde with an alcohol or glycol in the presence of a catalyst like p-toluenesulfonic acid or a sulfonic resin in a solvent which allows the removal of the water formed by azeotropic distillation, by an exchange reaction with acetone-dioxolane in which acetone is removed as it forms, or by reaction with an ortho-ester in which the alcohol is distilled away as it -forms. The acetal may also be prepared from the corresponding thioacetal by reac-tion with a suitable alcohol or glycol in the presence of a mercuric salt (preferably HgC12~ as an exchange catalyst and an alkaline earth carbonate, in an inert solvent.
Thioacetalization, for example the optional preparation of a compound with formula (I) in which R is -CH'X,Ra ~where X' is sulfur and Ra and Rb are as defined above) from one in which R is -CHO, is preferably effected by reaction with a mono- or dimercaptan like methylmercaptan, ethylmercaptan, dithioethyleneglycol or dithiopropyleneglycol in the presence of a catalyst like boron trifluoride ethera-te in an inert solvent, preferably a halogenated or aromatic hydrocarbon ~methylene chloride, chloroform, henzene, toluene).
The corresponding ketals and thioketals may be prepared from ketones by following the procedure described above for acetals and thioacetals.
Lactone and salt preparation from a compound with formula tI), as well as preparation of compound (I) from its salt, are per~ormed using standard procedures.
Individual isomers are separated from mixtures of isomeric compounds (I) using standard techniques like fractional crystallization and chromatography.
Compounds with formula (III) in which E is (ReO)2P~(O)- (Re as defined above) are prepared by reacting a compound ~VII) R o r e ~P-CH2-(C~I2)m D (C~12)m2 (VII) Re~

in which Re, ml, D, m2 and R"' are as defined above with a-t least one molar equivalent of one of the following bases: an alkali or alkaline earth hydride like sodium, potassium, lithium or calcium hydride, an alkali or alkaline earth alcoholate like sodium or potassium tert-butylate, an alkali or alkaline earth amide like sodium amide, or an alkali or alkaline earth salt of a carboxyamide, like N-sodio-L21~

acctamide and N-sodiosuccinimide.
Compounds with formula ~III) in which E is (C6H5)3P- are pre-pared by reacting a compound with formula ~VIII~
Hal-cH2-~cH2)m ~D-~CH2)m2 ~VIII) in which ml, D, m2 and R"' are as defined above and Hal is halogen, with 1.1-1.3 molar equivalents of triphenylphosphine in an organic solvent like benzene, acetonitrile or diethyl ether and then treating the product phospho-nium salt with an equivalent quantity of an inorganic base like NaOH, KOH, Na2CO3 or NaHCO3~
Compounds with formulas ~VII) are prepared using standard methods, for example those described by Corey et al. in J. Amer. Chem. Soc., 90,3247 ~1968) and 88, 5654(1966). Compounds ~VIII~ are also prepared following standard procedures.
Compounds with formula ~II) are ne~ compounds covered by this invention, as are procedures for their preparation.
Compounds with formula ~II) in which Y is -C_C- or -CH=CZ- (trans), Z as defined above, are prepared in a procedure involving:
aIV) reaction of a compound with formula ~XI) / G \ ~XI) H

R'i \~C~O

wherein p, q, R'l and R'2 are as defined above and G is a protected carbonyl group or a group~ CH~OG' ~herein G' is a silyl ether or acetal ether residue, with a compound of formula ~V) lZ R5 E-cH-lcl-~cH2~n ~~~X~(C~12)n2 7 ~V) 1`~ `~ I

~8~

wherein E, Z, nl, R5, R6, X, n2 and R7 are as deEined above, ~o afford a compound of formula (XII) / G \
(C,H2 ) p (~C~2 ) q H XII) R 1 R~z C-C-ICl (C~)n (CH2)n2 7 , P, q, l,Z,R 2,nl, R5, R6, X, n2 and R7 are as defined above;
bIV) optional conversion of a compound with formula ~XII) into a compound oE formula (XIII) / ,G \
(C,H~)p (CH2)q H H (XIII) R'l yl-C-(CH2)n -~-X (CH2)n2 7 R~4 R6 in which G, p, q, Rl, R2, R3, R4, nl, R5, R6, X, n2 and R7 are as defined above, and Y' is -~C_C-, or -CH=CZ- (trans), Z 2S de:Eined above;
cIV) removal of the protecting group in G to afford a compo~ld of formula ~XIV) / G \
(CH2)p ~CH2)q H H (XIV) R~ y~-c-(CH2)n ~~~X~(CH2)n2 7 q~ P' 1~ R 29 Y , R 3, R ~, nl, R5~ R69 X, n2 and R7 are as defined above and G" is `'CH~C~I or , C=O;

2~

dIV) optional oxidation of a compound of formula (XIV) wherein G" is CH~OH and the other hydroxy groups, if presen*, are protected as reported above~
Compounds with formula ~II) in which Y is -Nl-l-CH2- are prepared by reacting a compound with formula (XV) G \
2)p (C~2)q H H (XV) wherein G, p and q are as defined above and R'l and R'2 are as defined above with the exception of hydroxy, with an aldehyde (XVI) R'3 ~R5 OHC-C-~CH ) -C-X-~CH2) -R7 (XVI) in which R'3, R'4, nl, R5, R6, X, n2 and R7 are as defined above, in the presence of a reducing agent, followed by removal of the protecting group in G and, optionally, of the other protecting groups, if present.
Compounds with formula ~II) in which Y is -NH-C=O are prepared by reacting a compound (XV) with a compound (XVII) O R' R

3 ~5 Hal-C-~-~CH2~n ~C~X~(CH2)n2 7 ~XVII) R~4 R6 in which Hal is halogen, preferably chlorine, and R13, R'4, nl, R5, R6, X, n2 and R7 are as defined above, in the presence of a base, followed by removal of the protec*ing group in G and, optionally, of the other protecting groups, if pres nt.
The reaction be*ween a compound with formula ~XI) and one with formula ~V) is run in the same way as that reported above for the reaction between compounds ~II) and compounds ~III).
The optional conversion of a compound with formula ~XII) in*o one with formula (XIII) is effected with reactions analogous to those descri-bed above ~or the preparation of one compound ~ith formula ~1) from another:
for example, nucleophilic addition to the carbonyl ~n the ch~in, ether-ification of ~he product alcohols and dehydrohalogenation.
As stated above, when G is a group, CH~OG', the protecting group G' may be a silyl ether residue ~for instance, a trialkylsilyl ether like trimethyl, dimethyl-tert-butyl, dimethylisopropyl, or ~imethylethylsilyl ether, but preferably dimethyl-tert-butyl) or an acetal ether residue (for instance, tetrahydropyranyl ether, tetrahydrofuranyl ether, dioxanyl ether, oxathianyl ether, but preferably tetrahydropyranyl).
The protecting group G' in a compound with formula ~XIII) is re~oved as described previously: that is, selectively, with F for a silyl ether and with acid hydrolysis for an acetal ether. When a protecting group G' must be removed in the presence of other labile ether groups, these latter should be acetal e~hers when OG' is a silyl ether or silyl ~thers when OG' is an acetal ether.
~hen G is a protected carbonyl group it is preferably protected as acetal or thioacetal, for example a dimethoxyacetal, a diethoxyacetal~ a dimethylthioacetal, a diethylthioacetal, preferably a dimethoxyacetal, or as ketal, or thioketal for example a ethylendioxyketal C~12 0 , a propylendithio-ketal(Ç~123 -S-~ a propylendioxyketal ~ÇH230 o , a ethylendithioketal ~H2_S_, prefe~ably a ethylendioxyketal.
The removal of said protecting groups in a compound of formula (XIII) as well as the optional protection of the free hydroxy groups in a compound o formula (XIV), e.g. as acetal ethers or silyl ethers, may be effected as previously reported.
The optional oxidation of a compound of formula (XIV3 wherein G" is hydroxy, may be effected using standard oxidation procedures for sec-ondary alcohols: for example treatment of the alcohol in an organic solvent like acetone with a solution of chromic anhydride in sulfuric acid, follow-z~

ing normal procedures.
The reductive amination reaction between a compound with formula (XV) and an aldehyde (XVI) is run under reaction conditions typical for this procedure, preferably using a mixed hydride like NaBH4 or LiAltl~
as reducing agent.
The reaction between compounds with formulas (XV) and (XVII) is run under the normal conditions for acylating amines.
Compounds with formula ~XI) are prepared with a procedure involving:
aVI) conversion of a compound (XXIA) or (XXIB) OH "' (~H2)q (C}l~)p ~CH2)q H H (XXIA) H (XXIB) OH
in which p ~nd q are as defined above and G"'is a protected carbonyl group as reported above, into a compound (XXII) / G \
(C,tl2 ) p (~CH2 ) q H H (XXII~

in which p, q, and G are as defined above.

bVI) reaction of compound (XXII) with a eompound O=C(OR13)~
in which R13 is a Cl-C6-alkyl or aryl-Cl-C6-alkyl to give a compound with formula (XXIII) (C~12) p ~(C~12) q H H (XXIII) in whieh p, q, G and R13 are as defined above eVI) reduction of the product eompound (XXIII) to a compound with formula (XXIV) / G
(CH2)p ,~.~CH2)q H H (XXIV) in which G, p, q and R13 are as defined above;

dVI) optional separation of compound (XXIV) into the individual optieal antipodes;

e ) optional eonversion of compound (XXIV) in-to a compound with formula (XXV) ~f /G~
( CH2 ) p ~( CH2 ) q H (XX`V) OH H
in which G, p, q and R13 are as defined above;

f ) transformation of a compowld (XXIV) or (XXV) into a compound with formula (XXVI) / G \
( CH 2 ) p ~( CH 2 ) q H -I~H (XXVI) R' CHO
1 R'2 wherein G, p, q, R'l and R'2 are as defined above.
A compound of formula (XXII) wherein G is a group CH~OG', in which G' is as defined above may be prepared from one of formula (XXIA) by known methods, e.g. by reaction in the presence oE base, with a silyl halide, a silazane or a silyl trifluoroacetamide or, for example, by reaction with a vinyl : ether X~ O where X'l is -O , -S- or -(CH2)r(r=0,1), according to known procedures~
A compound of formula (XXII), in which G is a protected carbonyl, may be prepared from one of formula (XXIB) by oxidation in pyridine with an excess of the pyridine-chromic anhydride complex or by oxidation to Moffatt in a mixture of benzene and dimethylsolphoxide with dicyclohexylcarbodiimide in the presence of pyridinium trifluoroacetate~

f' - 2~ -The reaction between a compound with formula (XXII) and O=C(OR13)2 (~13 as defined above, but preEe~ably methyl) is run in the presence of 2-4 moles of a base like sodium methoxide, sodium ethoxide, sodium or potassium hydride or potassium tert-butoxide, with an excess of 6-12 moles of carbonic diester per mole of ~etone, neat or in an inert solvent in an oxygen- and water-free atmosphere. The temperature may range from approximately 0-80C (preferably 60-80C) for a period between 10 minutes and 1 hour. The yield varies from 5% to 90~, depending on the temperature, the reaction time and the concentration.
A compound with formula (XXIII) may be reduced with an alkali or alkaline earth borohydride in aqueous solution, preferably at a pH between 5.3 and 7.2, or at -20C with ethanolic ~aBH4 in methylene chloride/ ethanol.
Generally, the reduction is complete in 30 minutes and the excess reagent is quenched by adding a readily reducable species, like acetone, and a proton donor, like acetic acid.
The individual optical antipodes of a compound with formula (X~I~), in which G is as defined abcve, may be separated by saponifying the ester using standard procedures, forming a salt of the product acid with an optically active base like quinine, chinconine, ephedrine, l-phenyl-l-amino-ethane, dihydroabietylamine, amphetamine or arginine, and separating the resulting diastereomeric salts by ~ractional crystallization, for example. The optically active acid is then recovered by conversion to the sodium salt and subsequent acidification of its aqueous solution -to a pH
which does not interfere with the protecting group in G.

.i:.

Optionally the hydrolysis of -the pro-tecting groups may precede -the optical resolution: -the protec-ting groups are then restored at the end of the separation process.
The optically active free acid prepared in -this way is then converted to an optically active ester (XXIV) using standard procedures, for instance treatment with a suitable diazoalkane.
If desired, using an identical procedure, a racemic mixture of compounds (XXV) may be separated into individual optical antipodes.
Alternatively, compounds (XXIV~ and (XXV) wherein G is a protected carbonyl group may be resolved into their optical antipodes de-protecting the carbonyl group in G, reacting this with an optically active primary amine, for example arginine, lysine, alanine, l-phenyl-l-ethyl-amine, l-phenyl-l-propyl-amine and similar, to give the corresponding optically active diastereoisomeric Schiff bases: these may be separated by known methods, e.g. by fractionate crystallization or by HPLC, the imino group may be hydrolized to `C=O in a known manner then the separated optically active keto-esters may be transformed into the optical antipodes (XXIV) and (XXV3 by ketalization or acetalization in a conventional way.
The optional conversion of a compound with formula (XXIV) to one with formula (XXV) may be done on either a racemic mi~ture or the individual isomers separated as described above. In this transformation, the configuration of the free hydroxyl on the cyclopentane ring is inverted.
The procedure involves esterification of the hydroxyl, for example by treatment with 2-4 molar e~uivalen-ts of triphenylphosphine and 2-4 molar e~uivalents of a carboxylic acld like acetic, ben~oic or p-phenylbenzoi.c, or wlth 2-4 molar equivalents oE ethyl azo-bis-carboxylate in an inert solvent like an aromatic hydrocarbon, perhaps halogenated, like benzene or chlorobenzene, or a cyclic ether like tetrahydrofuran, and subsequent selective saponificaticn of the ester function formed in this way, for example by transesterification in an inert alcohol R130H
in the presence of an alkali carbona-te, preferably K2C~3.
A compound with formula (XXVI) is prepared from a compound (XXIV) or (XXV) using known methods. For example, the free hydroxyl group in compound (XXIV) or (XXV) may be converted to a Cl-C6~alkoxy, an aryl-Cl-C6~alkoxy or a labile ether like a silyl or acetal ether using the ether preparation techniques already descri~ed for the analogous reactions of compounds with formula (I).
The free hydroxyl group in a compound with formula (XXIV) or (XXV) may be oxidized to an oxo ~roup, and the product ketone may be converted to a ketal or thioketal according to the procedure described above for compounds with formula (I) to afford a tertiary alcohol.
A hydrogen atom may replace the free hydroxyl group in a compound with formula (XXIV) or (XXV), for example, by treatment with a sulfonic acid chloride like p-toluenesulfonyl, methanesulfonyl or benzenesulfonyl chloride and subsequent reduction of the product sulfonate, for instance with LiAlH4 in standard methods. In this case the carboxylic ester group (-COOR13) is reduced at the same time to the primary alcohol (~CH2OH), which may then be oxidized to the aldehyde with Moffatt's reagen-t.
A product compound with formula (XXVII) / G \
(CH2) p ~(CH2) q H H (XXVII) ~..l R"l R" 13 in which one of R"l and R"2 is hydrogen, Cl-C6-alkyl, C2-C10-alkenyl, aryl or aryl-Cl-C6-alkyl while the other is hydroxy, Cl-C6-alkoxy, aryl-Cl-C6-alkoxy or a labile ether group, ; or R"l and R"2 together form a ketone protecting group may be converted to the corresponding compound with formula (XXVI) by reduction following standard procedures, for example, with diisobutylaluminum hydride or lithium diisobutylaluminum hydride.
When a compound (XXVII) is reduced with LiAlH4 following standard procedures, the produc-t is the corresponding primary alcohol which may also be prepared from the free acid by standard reduction with BH3 in tetrahydrofuran. The free acid is prepared by saponification of the ester. This primary alcohol may then be oxidized to the aldehyde, with Moffatt's reagent, for example, as mentioned previously.

z~

Compounds with ~ormula (XV) are prepared usin~ known methods, starting for example from a compo~md with formula (XX~II) in which any secondary alcohol functions are protected as acetal ethers if ^OG' is a silyl ether, or as a silyl ether if -OG' is an acetal ether. ~or example, a com-pound with formula (XV) may be prepared from one with formula (XXVII) in a procedure involving:
aVII) optional selective removal o~ protecting group in G;
bYII) optional oxidation of the free hydroxyl group in case liberated from~ CH~0G to a ketone, for example with Jones' reagent;
cVII) saponification of the ester to the acid;
dVII) conversion of the acid to a mixed anhydride, for example by reaction with an acid chloride like an alkyl, benzyl, or pivaloylchloro-carbonate in an inert anhydrous solvent like acetone, tetrahydrofuran or methylene chloride;
eVII) conversion of the mixed anhydride to an azide by treatment~
fox example, with an acetone solution of an alkali metal a~ide;
f~II) preparation of an amine from the a~ide through a Curtius ~earrangement;
gVII) and finally optional conversion of the product amine with fo~mula (XV) into another.
Compounds with formulas ~XVI) and ~XVII) are known compounds, available through known methods.
Compounds with formula ~XXIA) and (XXIB~ are prepared with known methods. For example, a compound (XXIA) in which p=q=l is prepared by selective reduction of bicyclo [3.3.0]octane-3,7-dione (J. Amer._Chem. Soc.
82,63~7~1960)) or by reduction of bicyclo[3.3.0]octane-3,7-dione-monoketal (J. Org. Chem., _, 2377(1974)), followed by removal of the ketal from the carbonyl function. In both cases, the product hydroxy ketone ~XXI) with p=q=l is a mixture of the endo-hydroxy and exo-hydroxy derivatives, with approximately 80% endo. The two isomers may readily be separated~ using the corresponding rhizomic silyloxy derivative, by fractional crystallization or chromatography, as described several times above.
A compound with formula (XXI~ in which pal and q=2 is prepare from bicyclo[4.3.0]non-7-en-3-one (XXVIII), which has a is junction between the two rings, in a procedure in-- I _ _ 35 _ O (XXVIII) H

volving the protection of the ketone as a ketal or thioketal (as described above), standard hydroboration of the double bond, and subsequent removal of the ketone protecting group as described above.
Compound (XXVIII) may be synthesized, for example, as described by J.P. Vidal in "Stereochimie et Selectivite Reactionelle en Serie Bicyclo Ln.3.0] alcanique", presented at the Universitè de Sciences et Tecniques du Languedoc, Academie de Montpelier, n d'orde C.N.R.S.A.O. 11257(1975).
A compound with formula (XXIA) in which p=l and q=2 (prepared, for example, as described above) may be converted to other (XXI) derivatives by successive detalization or thioketalization, oxidation, Bayer-Willinger and formulation of the product using methods analogous to those reported above.
A compound of formula (XXIB) wherein p is zero and q is 1 or p is 1 and q is zero may be prepared from the bromidrine 5-exo-bromo-6-endo-hydroxy-bicyclo[3.2.0~heptan-2-one ~J. Chem. Soc., Perkin, 1. 1767 ~1965)~ by known methods: for example said bromidrine may be converted into its acetal, thioacetal, ketal or thioketal, then dehalogenated to the compound (XXIB) using the known methods of organic chemistry such as, for example, the reduction with chromium (II) salts, the cataly-tic hydrogenation in the presence of Pd/CaC03 or Pd/C and in the presence of anhalohydric acid acceptor, or the reduction with tributyl tin hydride.
A compound of formula (XXI~) wherein p is 2 and q is or q is 2 and p is 1, may be prepared, e.g., from a compound o~ formula (XXVIII) by a process comprisiny:
reducing the carbonyl group to alcohol, e.y. with ~iAlH4 in ethyl e-ther, protecting the alcoholic group, e.g. as tetra-hydropyranylether or silyl ether, hydroborating, by conventional methods, the olefinic double bond, oxidizing, deblocking the protected hydroxy group, following the acetalization or ketalization.
A compound of formula (XXIB) wherein p = q = 2 may be prepared by known methods e.g. from 2-hydroxy-per-hydroazulen-6-one which in turn may be obtained as described by D.~. ~anerjee and K. Sankara Ram. in Ind. J. of Chem.vol.X, page 1 (1972). The compound of formula (XXVIII) may be used as starting material also for the preparation of the compounds of ~ormula (XI) wherein G is a group~CH~OG' wherein G' is the residue of a silyl ether and wherein, when one of R'l or R'2 is hydrogen and the oth~r is hydroxy, the latter is preferably protected as acetal ether or as ester, following the reaction scheme reported below:

~02C113 <~--C02CH3 O O OH
(XXVIII) (XXIX) OG' (XXX) O~Acetal O-Acetal O-Acetal (XXXI) (XXXIIa : G'=H) (XXXIIIa : G'=H) (XXXIIb : G'=silyl- (XXXIIIb : G'=silyl-ether residue) ether residue) The Gompound (XXVIII), by known methods, e.g. those previously reported, is converted into the ~-keto ester (XXIX) which is , ..~ ~.

reduced -to the ~-hydroxy ester (XXX) wherein the hydroxy group is protected as acetal ether; -the obtained compound (XXXI) i5 then submitted, in a conventional manner, to the hydroboration at the olefinic double bond to yive the alcohols (XXXIIa) and (~XXIIIa) which are then resolved by chromatoyraphy or by fractionate crystallization, converted into the corresponding silyl ether (~XXIIb) and (XXXIIIb) and finally transformed into the compounds of formula (XI) by reduction with diiso-butylaluminum hydride in toluene according to known methods.
The compounds of formula (I) show the same pharma-cological activities as -the natural prostacyclin, or PGI2 but, as compared with PGI~, the compounds covered by this invention have a particular advantage in their greater stability in the range of pH bet~een zero and 11, in particular, at physiologic p~: this leads to longer lasting and more cons-tant biological activity. The source of this greater stability is the different chemical structure of these compounds as com-pared to natural prostacyclin. Since there is an oxygen heteroatom in the 2-oxa-bicyclo L3 . 3.0~octane system, natural ~0 prostacyclin is an exocyclic enol ether and so is extremely acid sensitive. The product of reaction with acid, 6-keto-PGFla, shows almost none of the biological activity charac-teristic of natural prostacyclin. On the other hand J the compounds covered by this invention have no oxygen in the bi-cyclic system and so are not enol ethers. Since they are not highly labile as are the natural derivatives, they may be administered by mouth.
In addition, compounds of formula (I) in which there is a triple bond in the 13-14 position of the ~-chain or in 30 which there is a hindering group, such as a cl-C6-alkyl group or an electron receptor group, e.g. fluorine, near the hydroxyl - aye -in position 15 (R3 or R4 = hydroxy) are more resistant to enzyme-induced (for instance, 15~PG-dehydrogenase) metabolic degradation -than natural prostacyclin.

2~
The pharmacological actions of natural prostacyclin are known.
Thus, for example, when inhaled in asthmatic patients) prostacyclin prevents aspecifically induced (e.g. by nebuli~ed water or by ef~ort) bronchocostric~
tion [S. Bianco et al, J. Res. Medical Science, 6, 256 ~1978~; when infused in ~an, it shows hypotensive and vasodilator activity and also shows blood platelet anti-aggregant and disaggregant properties ~S7ekely et al, Pharm.
Res. Comm. 10, 545 (1978)]; prostacyclin also possess uterus stimulant action in the monkey and in woman; furthermore, prostacyclin exhibits luteolytic activity in test animals and is able to protect the gastric mucous membrane lU from ulcers induced by non-steroidal anti-inflammatory substances, e.g. acetyl salicyclic acid (ASA) and indomethacin, in test animals, e~g. the rat.
In natural prostacyclin these activities are combined with a marked chemical instability which is unsuitable for pharmaceutical use. As already reported, the compounds of formula (I) have pharmacological actions similar to those of natural prostacyclin but the undesired chemical instabili ty of PGI2, is absent in the compounds of the invention.
As to their prostacyclin- and prostaglandin-like activity the compo~ds covered by this invention may be used in human and veterinary medicine when natural prostacyclin and prostaglandins are indicated thera-peutically.
For instance, these compounds are useful in treating asthma because of their pronounced bronchodilatory effect. In this application, they may be administered by various routes:

- 3q orally in tablets, capsules, pills, or liquids like drops or syrups; rectally, in suppositories, intravenously, in-tra-muscularly or subcutaneously; by inhalation as aerosols or vaporizer solutions; or by insufElation as powders. Doses of approximately 0.01-4mg/kg may be given from 1 -to 4 times daily, but the exact dose depends on the age, weight and condition of the patient as well as the administration method.
For anti-asthmatic applications the compounds covered by this invention may be combined with other anti-asthmatics: simpaticomimetics like isoproterenol, ephedrine,etc.; xanthine derivatives like theophillin and aminophillin;
and corticosteroids like prednisolone and ACTH.
In addition the compounds covered by this invention exhibit oxytocic activity and so may be used in place of oxytocin to induce labor or expel a dead fetus, both in human and veterinary obstetrics. For this application, the compounds are given intravenously at a dose of approximately O.Ol~g/kg/minute until the end of labor, or by mouth.
The compounds covered by this invention are also luteolytic and so are useful in fertility control, with the advantage that they stimulate the smooth muscles much less and so are free of the side effects of natural prostaglandins like vomiting and diarrhea.
Further, these compounds are anti-ulcerogenic and thus may be used to reduce and control excessive gastric secretion in mammals. In this way they minimize or elimina-te ' "`; ,f' the formation of gastrointestinal ulcers and accelerate the cure of any ulcers already present in the gastroin-testinal tract. They are adminis-tered in this case by intravenous infusion or by intravenous, subcutaneous or intramuscular injection; doses for intravenous infusion range from O.l~g to 500 ~g/kilo/minute. The total daily dose for both injection and infusion is on the order of 0.1-20 mg/kg depending on the age, weight and condition of the patient or animal and on the administration method.
- 10 However, like natural prostacyclines, the most important pharmacological property of the compounds covered by this invention is their platelet anti-aggregant activity, that is, the capacity to inhibit platelet aggregation, to decrease adhesion, to prevent clot formation and to dissolve recently-formed clots. This platelet an-ti-aggregant actlvity is also associated with a relaxing of the coronary arteries.
For these reasons, these compounds are useful in preventing and treating myocardial infarctions and, in general, in treating and preventing thromboses, in treating conditions like atherosclerosis, artereosclerosis and, more generally, dihyperlipidemia.
Normaladmirlistration methods are used in this application: that is, intravenous, subcutaneous, intramuscular, etc. In emergency situa~ions intravenous administration is preferred, in doses ranging from O.OOS to 20 mg/kg/day, again depending on the age, weight and condition of the patient and on the administration method.

~L~9~
As mentioned above, the compounds covered by this inven-tion are useful in human and veterinary -therapy, with several administration methods. They may be given orally in tablets, capsules, drops or syrups; rectally in suppositories; parenterally, in solutions or suspensions given subcutaneously or intramuscularly; intravenously, as preferred in emergencies; by inhalation in aerosols or vaporizer solutions; in sterile grafts for prolonged action;
or endovaginally, for instance in vaginal suppositories.
Pharmaceutical and veterinary compositions of the compounds covered by this invention may be prepared conventionally using common carriers and/or diluents.
For example, sterile and isotonic aqueous solutions are preferred for intravenous injection or infusion. Sterile aqueous solutions or suspensions in aqueous or nona~ueous medium are used or subcutaneous or intramuscular injections.
sterile compress or a silicon rubber capsule containing or impregnated with -the active ingredient may be used for sterile grafts.
Conventional carriers and diluents include water, gelatine, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, talc, stearic acid, calcium and magnesium stearate, glycols, s-tarch, gum arabic, gum adragant, alginic acid, alginates, lecithin, polysorbates, vegetable oils, e-tc.
The compounds may be given with a vaporizer using an aqueous suspension or solution of them, preferably in their salt forms, for instance the sodium salt. Or the compounds f-~

may be suspended or dissolved in one of the common liquified propellants like dichlorodifluoromethane or dichloro-tetra-fluoroethane and given with a pressurized container like an aerosol bomb. When the compound is not soluble in the ~ro-to the pharmaceutical ~ormulatior pellant, a co solvent must be added/:for instance, ethanol, dipropyleneglycol and/or a t~nsioactive substance. :`
~n the followi-ng examples,THP~DMtB,~IOX,THF,D~ISO,~I~A and D~IF
re~r respectively to tetrahydropyranyl,dimethyl-tert-butyl, tetrah~drofuran, 1,4-diox-2-enyl~di~r~ethylsulphoxide"diisobutylaluminiurnhydride and dimethyl~ormamide.
The follo~ving examples illustrate but do not in any way limit ~he present in~entlon.
. .
Example 1 1.1g of sodium borohydride (0.029 mol) is added with stirring to a solution of 11;6g of bicyclo r3 . 3 o~ octane 3,7-dione (~.4x~ 2mol) in 100ml of me~hylene chloride ana 100ml of ethanol. After 45 minutes at this temparature, the excess reagent is decomposed by slowly adding ~Oml of acetone. The mixtur~ is then neutralized with 1.4ml of acetic acid, and 2Q evaporated under vacuum to afford a residue which is taken up in water and methylene chloride. The organic phase is evaporated to dryness and filtered on silica gel (70:30 hexane:ethyl ether as e1uent) to afford 9.1g of 7~-hydroxy-bicyclQ~3.3.0~ octan-3-one.
A solution of this compound (0.065mol) in 27ml of - anhydrous dimethylformamide is treated with 1?.8g of dimethyl-tert-butylsilyl chloride and 8.85g of imidazole. The re-.

... . . . . . . . . .. .. .. .

4~
~L3 ~A

sulting mi~ture is heated to G0C for 5 hours, cooled, dilu-ted with t~o volumes of water and extracted with ethyl ether (3x40ml and 2x20ml). The combined organic extract is washed with 5~ NaHCO3 and then water until neutral, and evapora-te to dryness to give 15.8g of crude product (95% yield). Pur-ification on silica gel affords ~.35g of 7-exo-hydroY~y-blcyclo ~3.3.0~octan- 3-one-dimethyl-tert-butylsilyl ether and 11.8g of 7-endo-hydrox~--bicyclo ~3.3.o~octan-3--one-7-dimethyl-tert butylsilyl ether.
A solution of the latter (11.8g, 4.~3x10 2mol) in 295ml of methyl carbonate (Me2CO3~ is stirred ~ith the exclu-sion of wate; in an inert atmosphere and treated cautiously with 6.95~ of 80% sodium hydride. When hydrogen evolution ceases, the reaction mixture is heated at 75-80C for forty ` 15 minutes. After cooIing, the mixture is diluted with two volumes of ethyl ether and cautiously treated with 13g of glacial acetic acid. The organic phace is then separated with pH 5.2-S.5 buffer and the aqueous layer is extracted ~ith ethyl ether. The combined organic extract is dried over Na2SO4 and evaporated to dryness to give 12.S2g of dll-7-endo-hd~7roxy-bicyc]o L3. 3.03Oc~an -3-one-2-carboxymethyl-ester-7 dime-thyl-tert~butylsilyl ether (85% of the 14.49g theoretical yield) J which after purification on silica gel ~45g/y, with 9,:3 hexane:ethyl ether as eluent) affords 10.81g f the pure product; ~maX=254mJ~ 7~

Starting ~,~ith the exo isomer, the same procedure a-~ords d,l-Z-e~o-hydroxy-bicyclo [.3.0~octan -3-one-2-carboxy-methylester-7-dimethyl-ter~-butyl sily~.ether; maX=254m~, ~=6,5000 A solution of 7.5g of d,l-7-endo-nydroxy-bicyclo ~3.3.0~-octan -3-one-2-carboxymethylester-7-di.methyl-tert-butyl silyl-ether (DMtB-silylether) in 75ml of dichloromethane and 75ml of ethanol is cooled to -20C and treated with stirring with 0.9g of sodium borohydride. After stirring for 15 minutes, the excess rea~ent is destroyed by addi.ng 12ml of acetor.e.
The mixture is brought to OC, 20ml Or 206 KH2PO4 is added, the solvent is evaporated under vacuum and the resi~ue is ~xtracted several times with ethyl etner. The combined or-- ganic e~tract is washed with 5ml of water and evaporated to dryness to afford a residue which is crystallized rom n-hexane to give ~.8g of d,1~`3,7-endo-dihydroxy-bicyclo ~3.3.0~-octane -2.-exo-carhoxymethylester-7-DMtB--silylether, m.p =
~8~70C. The mother li~uor is adsorhed on 25g of silica gel;
elution with 90:1Q n-heptane:ethyl ether gives another 2g of product pure enough to be used as is.
A solution of 6g of d,l-3,7-endo~dihydroYy-bicyclo ~.3.0J--octane -2-exo-carboxymethylester-7-DI~ltB-silylether in 100ml of 80:20 methanol:watcr is treated with 2y of potassium hydroxide and heated to reflux for 30 minutes. ~fter concen-~i~

tration under vacuum, the rnix-ture is acidified to pM 5.1 and ex~racted with ethyl acetate. Evaporation o the oryanic layer gives 5.1g o~ d,l-3,7-endo-dihydroxy-2-carboxy-bicyclo-~3.3.C~octane -7-D~tB-silyle-ther. A solution of this com-pound in 150ml of acetonitrile is then treated with 2.81g of d-(~)-ephedrine. 4 hours at room temperature afford 2.9g of a salt which is crystal:lized twice from acetonitrile to give 1.85g oE (~)~3,7-endo~dihydro~y-~-exo-carboxy-bicyclo ~.3.Q~-octane-7-D~'t~-silylether-d(~)-ephedrine salt. All the mother liquors are collected and evaporated to dryness to ~ive a res-idue which is dissolved in water and treated with 0.68y of sodium hycroxide in water. The d-(+)-ephedrine is recovered in a benzene extraction, and the sodium salt solution is acidified to p~lS and extracted with ethyl acetate. The organic phase is evaporated to dryness to give a residue which - is treated with 2.2g o~ l~ephedrine to afford after several crystaJlizations 2.3g of (-)~3,7-endo-dihy3roxy-2-exo-carboxy-bicyclo ~3.3.0~octane-7-DMtB-silylether -l-ephedrine salt.
Example_3 .
A solution of ~.2~y of d,l-~,7--endo dihydroxy~-bicyclo-t3 . 3.03Octane --7-DMtB-silylether-2-exo-carboxymethylester in 30ml of anhydrous methylene chloride is treated with 2.19 of 2,3-dihydropyran and 39mg of p-toluenesulfonic a^id.
After 3 hours at room temperature, the reaction mixture is washed with 5~ ~1aIICO3 (2x5ml). Evaporation of the or~anic phase to dryness gives 8~ of d,l-3,7-eJldo-dihydroxy~bicyclo-~3.3.~ oc-tane -7-DMtB-silyle-ther-3-THP-ether-2-carboxymethyl ~- ester, which is then dried by being taken up in anhydrous benzene l2x15ml) and evaporated to dryness. This product in 30ml of anhydrous e-thyl ether is added dropwise, in 15 minutes J to a stirred suspension of 0.6~ of LiAlH4 in 40ml of anhydrous ethyl ether. Stirring is continued for 30 minutes before the excess rea~ent is destroyed by the caut-ious addition of 5ml of acetone followed by water-saturated ethyl ether. 10g of anhydrous sodium sulfate is then added.
Filtration of the organic solution and evaporation to dry-ness afford 7.~g of d,l-3,7-endo-dihydroxy-2-exo-hydroxymethyl-bicyclo~3.3.0]octane -7-DMtB-silylether-3-THP-ether.
The following compounds are prepared in this way from optically active startincr materials:
nat 3,7-endo-dihydroxy-2-exo-hydroxy!nethyl-bicycloL3.3.0~-octane-7-DMtB-silylether-3-TH~-ether;
ent-3,7-endo-dihydroxy-2--exo-dihydroxymethyl-bicyclo~3.3.0~-oCtane~7-DMtB-silylether-3-THP-ether.
If 1,4 diox-2-ene is used instead of 2,3-dihydropyran, the corresponding 3(2'-DIOX)-ethers are obt~ined.
x.ample 4 -A solution of 3.8~ of d,l-3,7-endo-dihydroxy-bicyclo-~3.3.0~octane -2-exo-carboxymethylester-7-DMtB-silyle-ther in 40ml of benzene is treated first with 3.66~ of benzoic acid y~1 and 7.~q of triphenylphosplline, and then, with stirringi with 5.30q of ethyl azo~bis-carboxylate in 15ml of benzene.
- After 40 minutes of-stirri.ng, the orqanic phase is washed with 2N sulfuric (2x20ml), and then sodium carbonate (3x15rnl) and finally water until neutral. Evaporation to dryness affords Q mixture of d,l-3-exo-7-endo-dihydroxy-bicyclo ~3.3.0~ -octane -2-exo-carboxymethylester-7-DMtB-silylether-3 benzoate and d,l-7-endo-hydroxy-bic~clo ~.3.03Oct3-ene-2-exo-carboxymethylester-7-DMtB-silylether.
The crude reaction produc-t is dissolved in anhydrous methanol, stirred for 3 hours, and treated with 0.5g of anhydrous potassium carbonate. Evaporation to dryness affords a residue which is taken up in ethyl acetate and saturated KII2P0~. The organic phase is washed until neutral and eva-porated to dryness. The residue is adsorbed on silica qel and elu~ed with hexane and hexane:ethyl ether to give:
a) 1.01g of d,l-7-endo-hydroxy-bicyclo ~.3.0~oct-3-ene-2-carboxymethylester-7-DMtB-silylether~ which is dissolved in methanol, treated with 0.3y of S% Pd on CaC03 and hydrog-enated at room temperature and pressure to qive d,l-7-endo~
hydroxy-bicyclo ~.3.0~octane-2-carboxymethylester-7-DMtB-silylether;
b) 2.01q of d,1-3-exo-7-endo-dihydroxy-bicyclo L3 . 3.03Octane-- 2-carboxymethylester-7-DMtB-silylether, which is saponified as described in Example 2 with 5% potassium carbonate in -80:20 methanol:~ater. to give d,1-3-exo-7-endo-di]lydroxy-bicyclo ~3.3.0~octane -2-exo-car~oxy acid-7-DMtB-silyletller.
This is then separated into individual optical antipodes with (+) and (-) amphetamine!
Reaction with ethereal diazomethane converts (+)-3-exo-7-endo-dihydroxy-bicyclo[3.3.0~octane-2-exo-carboxy acid-7-DMtB-silylether into the methyl ester derivative.
Subsequent reaction with 2,3-dihydrcp-,~ran follow~d by reduc-tion with LiAlH4 in ethyl ether gives (+)-3-exo-7-endo-2-exo-hydr~oxymethyl-~icyclo ~3.3.0~octane -3-THP-ether-7-DMtB-silylether.
- The (-) enantiomers and the l-acemic mixture are pre-pared analogously.
Example 5

5~J of d,l-7-endo-hydroxy-bicyclo ~.3.03Oc-tane-DMtB-silylether-3-exo-carboxymethylester in 100ml o aqueous meth-anol is saponified with 2~ of K~l, at reflux. After the methanol is removed under vacuum, the aqueous solu~ion of the potas~ium salt is extracted to remove neutral impurities, acidified, alld extracted with ethyl ether. The latter ex-tracts are combined and evaporated to dryness to yive 4~5q of the d,l acid which is tnen separa-ted into optical anti-podes with (+) and (-) ephedrine.
1.32g of (-)-7-endo-hydroxy--bicyclo~3.3.0~octane-7-nMtB-silylether-2-exo-carboxy acid is then dissolved in 20ml 9~

of.TIIF and treated witl1 1Oml of 1M ~3 in THF. Ater 4 hours at room temperature, the excess reaqent is destroyed -- by the cautious addition of 20ml of 1.5N NaOII. The THF is then removed under vacuum and the aqueous ~hase is extracted with-ethyl ether. The combined organic extract is washed until neutral and evaPorated to dryness to afford 1.02~ of endo-hydroxy-~-exo-hydroxymethyl-bicyclo~3.3.0]octane-7-DMtB-silylether.
The (+) isomer and the racemic mixture are prepared analogously.
Fxample 6 2.7g of d,l-7-endo-hydroxy-2-exo-hydroxymethyl-bicyclo-.3.0~octane-7-DMtB-silylether in 20ml of methylene chloride is treated with 0.95g of 2,3-dihydropyran and 20mg of toluenesulfonic acid for 3 hours at room temperature. After being washed with 7~ aqueous NaH~03 and then water, the organic phase is evaporated to dryness to give crude d,1-7-endo-hydroxy-2-e~o-tetrahydropyranyloxymethyl-bicyclG ~.3.0~octane-7 DMtB-si.lylether. This is dissolved in 15ml of THF and treated with 4.5~ of tetrabutylammonium fluoride for 1Ohours, with sti.rring.
The reaction mixture is then concentrated under vacuum, ad-sorbed on silica gel and eluted with benzene:ethyl ether to give 2~1g of d,1-.7-endo-hydroxy-2-exo-TIlP-oxymethyl-bicyclo- .
.3.0~octane. A solution of this produc-t in 25ml of acetone is cooled to -20C - -8C with stirring and treated with 4.2ml ? - ~19~3~Z~ .

o~ 8% Jones' reagent (CrO3 in aqucous sulfuric acid) over a period of 15 minutes, until a sliqht ~ink color persists.
After an additional 14-20 minutes of stirring, 1.5ml of iso~
propanol is added dropwlse and the resulting green solution is diluted wi~h 6 vo].umes of benzene. The orqanic phase is washed Witil 20~ (NH,1)2SO~ until neutral, and the combined aqueous phase is re-extracted with benzene. The combined . .benzene extract is dried and evaporated to dryness to afford 1.82q of d,l-2-exo-THP-oxymethyl-bicyclo ~3.3.0~octan-7-one.
The nat- and enant- isomers are prepared analogously.
. _xample 7 With external cooling and stirrinq to keep the reac-tion temperature near 20-22C, a solution of G.57g of pot-assiu~ tert-butylate in 65ml of DMSO is added dropwise to ..15 6.76g of 4-carbox~Jbutyl-triphenyl-phosphonium brorl.idc in 40ml of DMSO. After the addition, the mixture is diluted with an e~ual vol~u~e oE water. acidified to ~H 5 and extracted with ethyl ether. The aqueous phases are discarded, and the combined or~anic extract is re-extracted several times with ~0 0.5N NaOII. The alkaline aqueous phases are acidified to pH5 and re-extracted with 50:50 ethyl ether:pentane. This com-bined organic extra.ct is brought to small volume, treated with ethereal diazomethane until a yellow coloration per-sists, and then evaporated to dryness. The residue is then - 25 dissolved in 50ml of acetone, treated wi.th 20ml of 2N aqueous Z~ ' oxalic acid, and held at 40-45C for g hours. After the acetone is removed under vacuum, the aqueous phase is ex-- tracted with ethyl acetate, and the combined organic extract is evaporated to dryness. Purification of the resulting residue on silica gel with ethyl ether as eluent qives a mixture of d,1-5-cis,trans-[2'~exo-hydro~ hyl-bicyclo ~.3.
oci-i'-eny pentenoic acid methyl ester (`1.75g). The indi-vidual isomers may be separated with high pressure li~uid-liquid chromatography to the 5-trans-d,l and the 5-cis-d,l isomers; the latter is named 5-cis-~(20-~12)-octanor-12 -hydroxymethyl-9a-deoxy-9a-methylene-prostacyci-5-enoic acid methyl ester.
' ~riphe~yl If the 4~carboxybutyl~phosphonium bromide in the above procedure is replaced by one o the following Wittig i rea~ents (3-carboxypropyltxiphenylph~sphonium bromide, 5-carboxypentyltriphenylphosphonium bromide, 4-carboxy-2-oxa~
~utyltriphenylphosphonium bromide), the methyl esters of the ~ollowing acids are prepared:
d,l-5--cis-~(2,0~12)-octanor-2 no,r-12~-hydroxymethyl-9a deoxy-?O 9a-methylene-prostacycl-S-enoic acid, d,l-5-cis-~(20~12)-octanor-2ahomo-12~-hydroxymethyl-9a-deoxy-9a-methylene-prostacycl-5-enoic acid;
d,1~5-cis-~(20712)-octanor-3-oxa-12~-hydroxymethyl-9a~deoxy~
9a-methylene-pros-tacycl-5-enoic acid;
as well as their 5-trans isomers and the indivldual nat- and 2~
.

~, ., I
.~ . . `, . .

enant- antipodes.
Example 8 A stirred solution of 7.16g of 5-cis-~(20~12) octanor-12~-hydroxymethyl-9a-deo~y-9a-methylene-prostacycl-5-enoic acid methyl ester in 80ml of 75:25 benzene:dimethylsulfoxide is treated with 8.9g of dicyclohexylcarbo~iimide and then wi h 14.2ml of a pyridinium trifluoroacetate solution (prepared by adding 25ml of 75:25 benzene:DMSO to lml of trifluoroacetic acid and 2ml of pyridine). After four hours of stirring the reaction mixture is diluted with 100ml of benzene and 3g of oxalic acid in water is added dropwise. The dicyciohexylurea is removed by filtration, the organ;c ~hase is separated and washed ~lith water (5x6ml). Re~uction in volume gives a ben-zene solution of the 12~-formyl derivative which is added all at once to a solution of (2-oxo-heptll)dimethyl phosphonaLe sodium salt. The latter is prepared by adding dropwise 7.58g of (2-oxo-heptyl)-dimethyl phosphonate in 40ml of anhydrous benzene to a stirred solution of 1.02~ of sodium hydride (80%
mineral oil dispersion) in an inert qas a~mosphere, contin-~0 uing stirring until H2 evolution ceases. After the addition of the formyl deriva-tive to this sodium phosphonate salt stirring is continued for 20 minutes. The reaction mixture is then neutralized with saturated mQnosodium ~hosphate solu-tion. The orqanic phase is separated reduced to small vol-ume, adsorbed on silica qel and eiuted with cyclohexane: ethyl et;ner to give 6.4g of 5-cis-13-trans-9a-deoxy-9~ met}lylene~
15-oxo-prostacycla-5,13-dienoic acid methy]. ester.
Using an analogous 12~ -hydroxymethyl derivative from example 7 gives the methyl esters of the following acids:
5-cis-13-trans-9a-deoxy-9a-methylene-15-oxo-2-nor-prostacycla-5,13-dienoic acid;
5-cis-13-~rans-9a-deoxy 9a me~hylene-15-oxo-2a~lomo-prostacycla-- 5,13-dienoic-a~id;
5-cis-13 trans-9a-deoxy-9a--methylene-15-oxo-3-oxa-prostacycla-5,13-dienoic acid;
as well as their 5-trans geometric isomers, in the nat-, enant- and d,l forms.
_xample 9 A stirred and cooled (5-8C) solution of 1.35g of 2-- 15 exo-hydroxymethyl~7-endo-hydroxy-bicyclo ~.3.030c-ane-DMtB-silylether in 5ml of pyrid ne is treated with 0.82g of ben-20yl chloride. Afte.r 8 hours at room temperature, 2N H2S04 is added and the mixture is extracted with ethyl ether to give 2-exo-benzoyloxymethyl-7-endo-hydroxy-bicyclo~3.3.03Octane-7-VMtB-silylether. This silylether ~roup is removed by r~flux in 20ml of acetone w.ith 8ml of 2N oxalic acid. The acetone is removed under vacuum and the residue is extracted ~.7ith ethyl ether to afford, after purification on silica gel, 1.1ig of 2-exo-benzoyloxymethyl-7-endo-hydroxy--bicyclo ~3.3.0~-25 octane. This is dissolved in pyridine and then added --~~

!.`s ~l to a solution o~ 1g o~ CrO3 in 10ml of pyridine. A~ter 6 hovrs at room temperature, this mix-ture is diluted ~ith 20ml of benzene and filtered. The filtrate is evaporated under vacuum and the residue is taken up in 2N sulfuric acid and benzene. After being washed with 2N H2S04 and ~ater un~il neutral, the organic extract is evaporated to dryness to afford 0.98g of 2-exo-benzoyloxymethyl-bicyclor3~3. octan-- 7-one. A solution of this compound in 5ml of anhydrous THF
is then added to a solution of (2-oxo-5-trimethoxy-pentyl)-dimethyl phosphonate sodium salt, prepared by adding drop-wise a suspension of 0~23g of 80% sodium hydr~de in THF to a solution of 2.12g of ~2-oxo-5-trimethoxy-pentyl)-dimethyl phosphonate in 6ml of anhydrous TFfF. After 10 hcurs of stir-ring, tho mi~ture is neutralized with 15% KEI2PO~, the THF
. 15 is evaporated under vacuum and the residue is extravted with ethyl ether. The combined extract is concentrated in vol-ume, adsorbed on silica cJel and eluted with hexane:ether to affoxd 1.1g of 2'-benzoyloxymethyl-bicyclo~3.3.Q~oct-7-enyl --1,1,1-trimethoxy-pent-5-en-~-one, or 12~-benzoyloxymethyl-~(20~12)-octanor-4-oxo-9a-deoxy-9a-methylene-prostacycl-5-enoic acid-orthomethylester, as a mixture of ~he 5-cis and 5-trans olefins which are then separated by high pressllce liquid-liquid chromatography~
Subsequent treatment with aqueous methanol and H2SO~
gives the corresponding methyl ester derivatives. Reaction of 134;2~

_~g -- 0.3g of methyl ester with OA 25ml o~ 1,3-ethanedithiol in methylene chloride and a catalytic amoun-t of BF3-etherate for 15 minutes at 0C then affords 12 ~benzoyloxymethyl ~20~12)-octanor-4,4-ethylenedithio-9a-deoxy-9a-methylene-prostacycl-5-enoic acid methyl ester.
Example 10 0.8g of 12~-benzoyloxymethyl-e~(20~12)-octanor-4-oxo-9a-deoxy-9a-methylene-prostacycl-5-enoic acid methyl ester in 1Oml of methanol is selectively de-benzoylated upon treat-ment with stirriny with n .15g of anhydrous K2C03. After the solvent is evaporated, the residue is taken up in 15% a~ueous KH2P04 and methylene chloride ~o affo_d upon evaporation of the organic phase 12~-hydroxyrlethyl~(20~ 2)-octanor-4-oxo-9a-deoxy-9a-methylene--prostacycl-5-enoic acid methylester..

A solutJon o~ this compound in 10ml of CH2Cl2 and 10ml of ethanol cooled to -20C is ~reated with 90mg of Na~H~ and stirred for twc hours. Excess reagent is then destroyed with 15% aqueous acetic acid, the solvent is evaporated and the residue is adsorbcd on silica gel. ~lution with ethyl ether affords 0.21g of 12~-hydroxymethyl-~(20-~12)-octanor-4S-hydroxy-9a-deoxy-9a-methylene-prostacycl-5-enoic acid methyl ester and 0.13g of the 4R-hydroxy isomer.
- The individual products are then saponified with 20%
aqueous methanol and 19o potas~i~m carbonate to a~ord, after acidi~ication and extraction ~ith ethyl acetate, 0.1~g of - -~tl 12~-hydroxyme thyl-~(20-;l2)-octanor-4S-hydroxy-9a-deoxy-9a-methylene-prostacycl-5-enoic acid-1,4-~-lactone and Q.11g of the 4R isomer. Oxidation of these following the procedure in example 8 gives the 12 -formyl deriv~.tives.
Examl?le 1l , ' `~ O.28g of 4,4-ethylenetithio-l2l~-benzovloxymethyl-(20~12)-octa;lor-9a-deoxy-9a-methylene-prostacycl-5-enoic acid methyl ester is selectively de-benzoylated upon methanolysis with K2CO3 in anhydrous methanol to give the corresponding O - 12~-hydroxymethyl derivative. This is then ox~.dized to the aIdehyde according to the procedure in example g to ~ive the 12~-formyl derivative.
Re~c~ion of 0.12g of this compound in benzene with the phosphonate prepared from 0.177g of 52-oxo-3,3-dimethyl-heptyl)-dimethyl phosphonate anc~ 20m~ of 80% NaH, as des-cribed in example 3, gives 5,13t-16 r 16-dimethyl-4,4-dithio-ethylenedloxy-15-oxo-9a-deoxy-9a-methylene-prostacycla-$,13-dielloic acid methylester.
In an analogous fashion, using (4-cyclohexyl-2-oxo-o butyl~-dimethyl phosphonate as tne phosphonate and the 4S-lactone from example 10 as the aldehyde affords 5,13t-4S-hy~roxy-15-oxo-9a-deoxy-9a-methylene~17~cyclohexyl-18,19,20-trinor-prostacyc]a-5,13-dienoic acid-1,4-~f-lactone. Or, with (3-phenoxy-2-oxo-propyl)-dimethyl phosphollate, 5,13t-4S-hydroxy-15-oxo-9a-deoxy-9a-methylene-17,1~3,19,20-tetranor-1~ 2~ ^

Sl-16-phenoxy-prostacycla-5,13-dicnoic acid-1,4-~-lactone is prepared.
E~ample 12 Usiny (2-oxo-3S-methyl-heptyl)-dimethyl phosphonate and (2-oxo-3S-fluoro-heptyl)-dimethyl phosphonate as the phosphonates and 12~-formyl-~(20-~12;-octanor-4R-hydroxy-9a-deoxy-9a-methylene-prGstacycl-5-enoic acid-1,4-~'-lactone as the aldehyde, the procedures of examples 8 and 11 afford:
5,13t-4R-hydroxy-15-o~o-9a-deoxy-9a-methylene-16S-methyl-~O prostacycla-5,13-dienoic acid~ lactone;
5,13t-4R-hydroxy-15-oxo-9a-deoxy-9a-methylene-16~-fluoro-prostacycla-5,13-dienoic acid-1,4-d-lactone.

Example 1 A soiution of 0.7g of 5c,13t-15-oxo-9a-deoxy-9a-methy-lene-prostacycla-5,13-dienoic acid methyl ester in 7ml of methylene chloride and 7ml of ethanol cooled to -20C is treated with 38mg of sodium borohydride. Aft2r 20 minutes of stirring, the reaction is quenched with 2ml of acet-one and 2.5ml Gf 20Q aqueous Na~2~O4. The mixture is then reduced in volume under vacuum and extracted with methylene chloride.
The combined organic extract is evaporated to dryness to give a residue which is purified on silica gel with ethyl ether as eluent to afford 0.32g of 5c,13t-15S-hydroxy-9a-deoxy-9a-methylene-prostacycla-5,13-dienoic acid methylester and 0O26g of the 15R isomer.

9~

~g )' _ C,, This same procedure for reducing the 15-oxo derivat~ves from examples 8, 11 and 12 affords the methyl esters of the ~- following acids:
5cis,13-trans-ga-deoxy 9a-methylene~15S-hydroxy--2-nor--prosta-cycla-5,13-dienoic acid;
5cis,13trans 9a-deoxy-9a-methylene-15S-hydroxy-2a~omo-prosta-cycla-5,13-dienoic acid;
5cis,13trans-9a-~eoxy-9a-methylene-15S-hydroxy-3-oxa-prosta-cycla-5,13-dienoic acid;
5cis,13trans-9a-deoxy-9a methylene-4,4-diethioethylenedioxy-1.5S-hydroxy-prostacycla-5,13-dienoic acid;
and the 1,4-lzctones of the followillg acids:
5C~13t-9a-deoxy-9a-methylene- 4S,15S-dihydroxy-17-cyClohexyl-18,19,20-uJ-trinor-prostacycla-5,13-dienoic acid;
5~t13t-9a-deoxy-9a-methylene-4S,15S-dihydroxy-16-pilenoxy-1/,18,19,20-~tetranor-pros-tacycla-5,13-dienoic acid 5G/13t-9a-deoxy~-9a-methylene-4R,15S-dihydroxy-16S-methyl-prostacycla-5,13-dienoic acid;
5 13t-9a-deoxy-9a~methylene-4R,15S-dihydroxy-16S-fluoro-prostacycla-5,13-dienoic acid;
as well as their 5-trans geometric isomers, in the nat-, enant- and d,l forms.
Example 14 A solution of 0.35g of 5c,13t-15-oxo-9a-deoxy-9a - ~5 methylene-prostacycla-5,13-dienoic acid methylester in 1Oml ,~

of 2:1 ethyl ether:toluene is cooled to ~30C and treated with stirriny with 5ml of 5~ methyl magnesium iodide in ethyl ether. A~ter 4 hour$ of stirring, the mixture is brought to 0C and quenched with 20% a~ueous ammonium chlor-ide. The organic phase is washed with water, sodium bicar-bonate and water, dried over MgSO4, treated with 0.1ml of pyridine, and evaporated under vacuum to give a mixture of the 15S and 15R alcohols. Separation on silica gel with . 80:20 ethyl ether:isopropyl ether as eluent affords 0.1g of 1~ 5c,13t-15S-hydroxy-9a-deoxy-9a-methylene-prostacycla-5,13-dienoic acid methylester and 0.1g of the 15R isomer.
Ex~nple 15 With the same substrate but anhydrous THF as sol-vent, reaction with 8ml of 0.3M ethynil magnesium bromide .in T~IF oives, aEter chromatogra.phy on silica gel, 5c,13t-15-ethynyl-15S-hydroxy-9a- deoxy-9a-methylene-~rostacyc1a-5,13-dienoic ac~d methylester an~ its 15R isomer.
l~ith 0.3M vinyl ma~nesium bromide, 5c,13t-15-vinyl-15S-hydroxy-9a-deoxy~9a-methylene prostacycla-5,13-dienoic aGld methylester and its 15R isomer are preparedO
. Example 16 A solution of 0.26g of 5cr13t-9a-deoxy-9a-methylene-4R,15S-dihydroxy~16S-methyl-prostacycla-5,13-dienoic acid--lactone in methylene chloride is cooled to ~10-~C
and treated with stirring with 0.3ml of boron trifluoride 2~ -_ ~r etherate (1.~ x10 4~1 in allhydrous methylcne chloride) and then 5% diazome-thane in methylene chloride until a yellow color persists. The solution is washed with 5% aqueous NaHC03 and then water until neutral, evaporated to drynes-s, and purified on silica gel (3g) to give 0.21g of 5c,13t-9a-deo~y-9a-methylene-~R,15S-dihydro~i-16S-meth,rl-prostacycla-5,13-dienoic acid-1,4-~-lactone-15-methylether.
Exa~ le 17 A solution of 0.74g of d,1-2-exo-hydroxymethyl-3-exo-THP-Gxy-7-endo-DMtB-silyloxy-bicyclo~3... 0~octane in 15ml of anhydrous methylene chloride is added all at once to a solution of 3.1g of Collin's reagent (C5H5N2)2 CrO3 in 40ml of anhydrous methylene chloride, with stirring and cool-ing to 0-5 Filtering earth is added after 15 minutes of stirring and ~he mixture is filtered to give a clear solu'-ion of the corresponding d,l-2-exo-formyl derivative. After the solvent is evaporated under vacuum, the residue is taken up in anhydrous benzene and added to a solution of sodium di-met.hy].-(2-oxo-octyl)-phosphonate. This latter is pre~ared by adding 0.59g of (2-oxo-octyl)-dimethyl phosphonate in 1Oml of benzene dropwise to a suspension of 0.07g of 80% NaH in 2Oml of benzene and 5 tirring the resulting mixture for approx~
imately 1 hour, until hydrogen evolution ceases. Stirring is continued for 20 minutes after the aldehyde is added to the ~5 phosphonate carbanion solution~ The organic phase is then neutralized with excess 25% aqueous NaH2P04 and separated.
After drying, it is evaporated to dryness to ~ive a residue ~hich is purified on silic~ gel (cyclohexane:ethyl ether as - eluent) to afford 0.81g of d,l-2-exo-[3'--oxo-non-1'-trans-1-enyl~-3-exo-THP-oxy-7-endo-DMtB-silyloxy-bicyclo 3.3.0 octane.
Example 18 A solutisn of 1.05g of d,l-2-exo-hydroxymethyl-3-endo-THP-oxy-7-endo-DMtB-silyloxy-bicyclo~3.3.0~octane in 8ml of 75:25 benzene:DMS0 is treated with 0.89~ of dicyc-]ohexylcarbodiimide and then, with stirrin~, with 1.42ml ofa pyridinium trifluoroacetate solution. After 3 hours of stirring, 20ml of benzene are added and excess carbodiimide is quenched with 0.13g of oxa;~c acid in 3.8ml of ~7ater.
The henzene ph~se is separated, washed until neutral, and concentrated under vacuum to give a solution of 2-exo-formyl 3--endo-TMP-oxy-7--endo-DMtB-silyloxy~bicyclo~3.3.0~octane.
- The d,l,nat- and enantio-formyl derivatives are pre-pared using this procedure. In the same way, if 7-exo-hydroxy-bicyclo ~.3.0~octan -3-orle-7-dilllethyl-tert-blltylsilyl-ether is used in the procedures of examples 1, 2 and 3,2-exo-formyl-3-endo-THP-oxy-7-exo-DMtB-siloxy-bicyclo~3.3.0~~
octane is obtained.
Example 19 -A solution o 322m~ of (2-oxo-heptyl) dimethyl phos-phonate in 5ml of benzene is added to a suspension of 43.5mg ' `'1' of 80% NaH in 10ml of benzene, and the resulting m:ixture is stirred until hydrogen evolution ceases. In the dark, 258mg of inely divided N-bromosuccinimide are added and stirrir;g is continued or another 5 minutes. 0.37g of 2-exo-formyl-3-endb-TIIP-oxy-7-endo-D~ItB-silyloxy-bicyclo~3.3.03Octane in 5ml of ben~ene is tllen added and the resulting mixture is stirred for another 15 minutes, after which the reaction mix-ture is partitioIled between benzene and 15% NaH2PO4. The organic phase is dried, concencrated to small volume, ad-O sorbed on silic~. gel and eluted with 80:20 cyclohexane:e~hyl ~ther to afford 0.~2g or 2-exo-~2'-brcmo-3'-oxo-oct-1'-eny]~-3-endo-TI~P-oxy-7-endo-DMtB-silyloxy-bicyclo L3.3.07Octane ~max 251mr, =9,250). -If (2-oxo-3R-fluoro-heptyl)-diInethyl phosphonate is used, the corresponding 2-exo-~2'-bromo-3'-oxo-4'i;-luoro~oct-1'-trans-~enyl3- derivative is obtained.
Example 20 -A solution o~ 0.3g of ~2-oxo-4~2')~tetrahydrofuryl-butyl~-dimethyl phosphonate is added dropwise to a stirred suspension of 36mg of 80% sodium hydride in 5ml of benzene Stirring is continued until hydrogen evolution ceases, and - then a solution of 0.37g of 2-exo-formyl--3-endo~THP-oxy-7-exo-DMtB-silylo~y bicyclo t3.3.0~octane is added. After another 20 minutes of stirring, the mixture is taken up in ben~ene and 20% aqueous monosodium phosphate. The organic 2~

phase i5 separated, concentrated to small volume, adsorbed on silica gel and elu-ted with-benzene:ethyl etller to cJive 0.35g oE 2-exo-3'-oxo-5'(2"~-tetrahydrofuryl-pent~ trans enyl~-3--endo-THP oxy-7-exo-DMtB-silyloxy-bicyclo ~3.3.0~octane (~maX=229m~ =8,800).
Example 2.1 If 2-exo-formyl-3-endo-THP-oxy-7-endo-DMtB-silyloxy-bicyclo ~3.3.0~octane was ~the 2-exo-formyl-7-exo-bicyclo der-ivati.ve used in the procedure described in example 2p, and if the following phosphates were used:
(2-oxo-heptyl)-dimethyi phosphollate;
~2-oxo-octyl?-dimethyl phosphonate;
(2--oxo-3S-methyl-heptyl)-dimethyl phosphonate;
(2-oxo-4-cyc'ohexyl-butyl)-dimethy] phosphonate;
(2-oxo-4~phenyl-butyl)-dimethyl phosphonate;
(2-oxo-3 m-trifluoromethylphenoxy-propyl)~dimethyl phospnonate;
(2-oxo-3-methyl-3-butoxy but.yl)-dimethyl p~osphonate;
then the following compounds were prepared:
3-endo-THP-oxy-7-exo-DMtB-silyloxy-2-exo-(3'--oxo-oct-1'-trans-1'-enyl)-bicyclo~3.3.0~octane;
3-endo-T~IP-oxy-7-exo-DMtB-silyloxy-2-exo-(3'-oxo-non-1'-- trans-1~-ellyl)bicyclo r3.3.0~octane;
3-endo-T~IP-oxy-7-exo-DMtB-silyloxy-2 exo-(3'-oxo-4'S~methyl-oct-1'-trans-1'-e~ icyclo~3.3.0~octane;
3-endo-T~IP-oxy-7-exo-DMtB-silyloxy--2-exo-(3'-oxo-5'-cyclo-Gq~
., , --~5 --. .,~, ~9~

- hexyl-pent~ tra~1s~ enyl~bicyclo [3.3.0~octane;
3-endo-THP-oxy-7-exo-DI~ItB-silyloxy-2-exo-(3'-oxo-5'-phenyl-pent-1'-trans-1'-enyl)-bicycloL3~3~o~octane;
3-endo-THP-oxy-7-exo-DMtB-sily loxy- 2-exo-(3'-oxo-41-m-tri-fluoromethylphenoxy-but-1'-trans-1'-enyl)-~i~clo ~.3.0]octane;
3-endo-THP-vxy-7-exo-DMtB-silyloxy-2-exo-(3'-oxo-4'-methyl-4'-butoxy-pe~t-1'-trans~ enyl)-bicyclo r3.3.0~octane.
Example 22 .~ ; A solution of 0.3g of d,l-2--exo-(2'-bromo-3'-oxo-4'R-luoro-oct-1'-trans-1-enyl)-3-endo-TH~-oxv-7-endo-DMtB-silyloxy-bicyclo [3.3. octane in 10ml of anhydrous ether is added dropwise in 1 r~ minutes to a 0.1~1 solution of zinc borohydride in etnyl ~ther (1Oml). After stirring for two hours, the reaction mixture is quenched with saturated sodi-~ chloride and 2N sulfuric acid. The ether layer is separated and washed with water, 5~ NaI-IC03, and then water. Evaporation to dryness a~fords a mixture of the 3IS and 3'R hydroxy alcohols which are separated by liquid-liquid chromatography with iso~ropyl ether as sol~.7ent to give 0.11g of d,l-2-exo-(2'-bromo-3'S-hydroxy-4'R-fluoro-oct-1'-trans-1'eI1yl)3-endo-THP-oxy-7 endo-DMtB-silyloxy~bicyclo 3.3.0 octane and 0~.1g of the 3'R epimer.
Example 23 A sol~;tion of 0.3g of 2-exo- ~3'-oxo-5'(2'7) tetrahydro-furyl-pent-1i-trans,~nyl]-3-endo-THP-oxy-7-exo-DMtR-silyloxy-~5 bic~clo~3.3. octane in 3ml of methylene chloride and 3ml of ethanol is cooled to ~10-15C and then treated with 25mg of NaBH4. After 30 minutes of stirring, the reacti.on mixture is quenched with 1.5ml of acetone and 3ml of saturated NaH2P04, evaporated under vacuum, and then extracted with methylene chloride. The or~anic phase is dried over Na2S0~ and evapor-ated to dxyness to gi~e a residue which is purified on sili.ca gel ~hexane:ethyl ether as eluent) to afford 0.1g of 2-exo-~3'S-hydroxy-5'(2")-tetarhydrofuryl-pent-1'-trans ~nyl~-3-endo-THP-oxy-7-exo-DMtB-silyloxy-bicyclo~3.3.0~octane and 0.11g of the 3'R isomer.
Example 24 By follcwing the procedure of examples 22 and 23 using one of the unsaturated ketones prepared as in ex-amples 19, 20 and 21, the ollowing compounds were prepar~d:
3-endo-THP-oxy-7-endo-DMtB-silyloxy-2-exo-(2'-bromo-3'S-hydroxy-oxt-1'-trans-1~-enyl)-bicyclo~3.3. o3 octane;
3-endo-THP-oxy-7 enc~o-DMtB-silyloxy-2-exo-(3'S-hydroxy-oct-1'-trans-1'-enyl)-bicyclo~3.3.0~octane;
3-endo-THP-oxy-7-endo-DMtB-silyloxy-2-exo-(3'S-hydroxy-4'S-methyl-oct-1'-trans-1'-enyl)-bicyclo~3.3.030ctane; .
3-endo~THP-oxy-7-endo-DMtB-silyloxy-2-exo-(3'S-hydroxy-non- :^
1'trans-1'-~lyl)-bicyclo F3.3.0~octane;
3-endo-THP-oxy-7-endo-DMtB-silyloxy-2-exo-(3'S-hydroxy-cyclo-hexyl-pent-1'-trans-1'-enyl~-bicyclo~3.3.0~oc-tane;
~5 3-endo-THP-oxy-7-endo-DMtB-silyloxy-2-exo-(3'S-hydroxy-5'-GG

~198~Z~

- phenyl-pent~ t^ans-1'-enyl) -bicyclo~3.3.0~octane;
3 endo-THP-oxy-7-endo--DMtB-silyloxy-2-exo-(3'S-hydroxy-4'-m-trifluoromethylphenoxy-but-1~-~-ans-1~-enyl)~bicycloL3 3.0~-octane;
3-endo-THP-oxy-7-endo-DMtB-silyloxy-2-exo-(3'S-hydroxy-4'-methyl-4'-butoxy-pent-1'-~^ans-1'-enyl)-bicyclo ~3.3.0Joctanei 3-endo-THP-oxy-7-endo-DMtB-silyloxy-2-exo-(2'-bromo-3'R-hydroxy-oct-1'trans-1'-enyl)-bicyclo~3.3.0~octane;
3-endo-THP-oxy-7-endo-DMtB-silyloxy-2-exo-(3'R-hydroxy-oct-1'-trans-1'-enyl)-hicyclo L3 3~0~ octane;
3-endo-THP-oxy-7-endo-DMtB-silyloxy-2-exo-(3'R-hydroxy-4'S-methyl-oct-1'-trans~ enyl) -bicyclo~3. 3 ~30ctane;
3-endo-TE~P-oxy-7-endo-DMtB-si~.yloxy-2-exo-(3'R-hydroxy-non-1'--trans-1'-enyltbicyclo ~.3.0~octane;
3-endo-THP-oY.y-7-endo-DMtB-silyloxy-2-exo-(3'R-hydroxy-5'-cyclohexyl-pent-1~trans-1' enyl)-bicyclo E3 . 3.0~octane;
3-endo-THP-oxy-7-endo-DMtB-silyloxy-2-exo-(3'R-hydroxy-5'-phenyl-pent-1'-trans-1'-enyl)-bicyclo ~.3.0~octane;
3-endo-THP-oxy-7-endo-DMtB-silyloxy-2-exo-(3'R-hydroxy-4'-m--trifluoromethylphenoxy-but-1Ltrans-1'-enyl)-bicyclo C3.3.0~-octane;
3-endo-THP-oxy-7-endo-DMtB-silyloxy-2-exo-3'4-hydroxy-4'-- methyl-4' butoxy-pent-1'-trans-1t-enyl)-bicyclo ~3.3.030ctane.
Example 25 A solution of 1.17g of 2-exo-(3'S-IIydroxy-oct-1'-~1 84~0 trcms-1'-enylt3-endo-THP-oxy-7-endo-DMt:13-silyloxy-bicyclo-~3.3.0~ctar~e in 12ml of anhydrous methylene chloride is treated with 120mg of 2,3-dihydropyran and 5mg of p-toluene-sulfonic acid. After 4 hours at room temperature, the organic phase is washed successively with 5% NaHCO3 and water and then - evaporated to dryness to give 1.45g of crude 2-exo- (3'S-THP-oxy-oct-1'-trans~ enyl)-3-endo-THP-oxy-7-endo-DMtB-silyloxy-bicyclo~3.3.0~octane. This product is dissolved in 12ml of THF and treated with 2g of tetrabutylammonium fluoride. The resulti.ng mixture is stirred for 12 hours at room temperat-ure and concentrated to small vc,lume to give a residue which is purifieci on silica gel (ethyl ether as eluent) to afford 920mg of 2 -exo-(3'S-hydroxy-oct-1'trans-1'-enyl)--3-endo-7-endo-dihydroxl7-bicyc1O ~3.3.0~octane-3,3'-bis~THP-ether.
l~xaml?le 26 Using the procedure of example 25 with compounds pre-pared according to examples 22, 23 and 24, the ~ollowing bicyclo~3.3.0~octane-3,3'-bis-TIIP-ether derivatives were prepared:
Z-exo- (2'-bromo-3'S-hydroxy-4'-fluoro-oct-1'-trans- 1'-enyl)-3-endo-7-endo-dihydroxy;
2-exo- (2'-bromo-3'R-hydroxy-4'R-fluoro-oct-1'-trans- 1'-enyl)-3-endo-7-endo-dihydroxy;
2-exo- (3'S-hydroxy-5' (2")-tetrahydrofury:l-pent-1'-trans- 1'-enyl)-3-endo-7-exo-dihydroxy;

- .~ . .

`
~g 2~

2-exo-(3'R-hydroxy-5'(2")~-tetrahydrofuryl-pent~ tranS-1'-enyl)-3-endo-7-exo-dihydroxy;-2-exo-~2'-bromo-3'S-hydroxy-oCt-1'-trans-1t-en~ 3-endo-7-endo-dihydroxy;
2-exo-(2'-bromo-3'R-hydroxy-oct-1'trans-1'-enyl)-3-endo-7-endo-dihyd~oxy;
2~exo-(3'S-hydroxy-oct-1'-trans-1'-enyl)-3-endo-7-endo-dihydroxy;
`2-exo-(3'R-hydroxy-o~t-1'-trans-1'-enyl)-3-endo-7-endo-dihydroxy 2-exo-(3'S-hydroxy-4'S-methyl-oct-1'-trans-1'-enyl)~3-endo-7 endo-dihydroxy;
2-exo-(3lR-hydroxy-~ls-methyl-oct-1~-trans-1l-enyl)-3-endo-7 endo-dihydroxy;
2-exo-(3'S-hydroxy-non-1'-trans-1'-enyl) 3-endo-7-endo-dihydroxy;
2-exo-(3'R-hdyroxy-non-1'-trans-1'-er.yl~3-~endo-7-endo-dihydroxy;
2-exo-(3'S-hydroxy-5'-cyclohexyl-pent-1'-trans-1'-enyl)-3-end 7-endo-dihydroxy;
2-exo-(3ls-hydroxy-5l-phenyl-pent-1'-trar.s-1'-enyl)-3-endo-7 ~ndo-dihydroxy;
2-exo-(3'R-hydroxy-5'-phenyl-pent-1i-trans-1l-enyl)-3-endo-7 endo-dihydroxy;`
2-exo-(3'S-hydroxy-4'-m-trifluoromethylphenoxy-but-1'-trans-1 enyl)-3-endo-7-endo-dihydroxy;
2-exo-(3'R~hydroxy-4'-m-trifluoromethylphenoxy-bU-t-1'-trans-1'-enyl)-3-endo-7-endo-dihydroxy;
2-exo-(3'S-hydroxy-4l-methyl-4'-butoxy-pent-1'-trans-1~-enyl)-3-endo-7-endo-dihydroxy;

2-exo--(3'R-hyclroxy-4'~methyl-~'-bUtoXy-pent~ trans-1'-en~
3-endo~7-endo-dlhydroxy.
~xample __ Successive portions of a so]ution of 0.4g of chromic anhydride are added with stirring to 4ml of pyridine. Once the complex is formed, this mixture is treated wi-th 0.36g of 2-exo-(3'S-hydroxy-5'(2")-tetrahydrofur-~l-pent-1'-trallS-1'-enyl)-3-endo-7-exo-dihydroxy-bicyclot3.3.0~octane-3,3'-bis-THP-ether in 4ml of pyridine. The reaction mixture i5 held over-night at room temperature, dilutcd ~Jith 3 volumes of benzene, and filtered. The filtrate is then evaporated lo give a resi-due which s partitioned betwee.n benz ne and 2N sulfuric acid.
The a~ueous portion is re-extracted with benzene, washed suc-cessiveliT wjth water, NaHCO3 and water, and evaporated to ~rvness to give 0.3lg of 2-exQ-(3'S-hydroxy-5'(2"- tetra-hdyrofuryl-pent-1~-trans-1~-enyl~3-endo-hydroxy-bicyclo L3 . 3 0~-octan-7-one-3,3'-bis-THP-ether.
Example 28 A stirred and cooled (-10-5C) solu~ion of 0.8g of 2-exo-(3lS-hydroxy-oct-1'-trans-1'-enyl)-3-endo-7-endo-dihydroxy bicyclo .3.03Octane-3,3'-bis-THP-ether in 20ml of acetone is treated with 1.6ml of ~ones' reagent in 15 minutes. After another 15 minutes of stirring, 80ml of ben~ene is added.
The organic phase is separated, washed with 15~ aqueous (NH4)2SO4 until neutral, dried and evaporat d to dryness to ~o ~L9~34 -~ a~Eord 0.71y of 2-eY~o-(3'S-hydroxy-oct-1'-trans-1'-cnyl) endo-hydroxy-bicyclo ~3.3.~ octan-7-one-3,3'~bis-tetrahydro-pyranylether.
Example 29 Usi.ng either of the oxidation procedures described in examples 27 and 28 on the triols of example 26, the following 3-endo-hydroxy-bicyclo ~3.3.0]octan-7 one-3,3'-bis-THP-ethers are prepared:
2-exo-(2'-bromo-3'S~hydroxy-a'R-luoro-oct 1' trans-~'-enyl);
2-exo-(2'-bromo-3'R-hydroxy-4'R-fluoro-oct-1'-trans-1'-enyl);
2-exo-(3'S-hydroxy-5'(2")-tetrahydrofuryl-pent-1'-trans-1l-enyl);
2-exo-(3'R-hydroxy-5'(2")-tetrahydrof~lryl-pent-1'-trans-1'-enyl);
2-exo-(2'-bromo-3'S-hydroxy-oct-1'-tranS 1'-enyl);
2-exo-(2'-bromo-3'R-hydroxy-oct-1'-t~ans~ nyl);
2--exo-(3'S-hydroxy-oct-1:-tl-ans~1'-enyl);
2-exo-(3'R-hydroxy-oc~.-1'-tranS-1l--enyl);
2-exo-(3'S-hydroxy-4'S-methyl-oct-1'-trans-1'-enyl);
2-exo-(3~R-hydroxy-4~s-methyl-oGt-1~-trans-1~-enyl);
2-exo-(3'S-hydroxy-non-1' trans~1'-enyl!;
2-exo-(3'R-hydroxy-non-1'-trans--1'-enyl);
2-exo-(3'S-hydroxy-S'-cyclohexyl-pent-1'-trans-1'-enyl);
2-exo-(3'R-hydroxy-5'-cyclohexyl-pent-1'-tran5~1'-enyl);
2-exo-(3'S-hydroxy-5'-phenyl-pent-1'-trans~1'-enyl);
2-exo-(3'R-hydroxy-5'-phenyl-pent-1`-tranS~1'-enylj;
2-exo-(3'S-hydroxy-4'-m-trifluoromethylphenoxy-but-1'-trans-?

. .

~9~z~

enyl~;
2-exo-(3'R-hydroxy-4'-m-trifluoromethylpllenoxy-but-1'-trans-1'-enyl);
2-exo-(3ls-hydroxy-4~-methyl-4~-butoxy-pent~ trans-1~-envl);
2-exo-(3'R-hydroxy-4'-methyl-4'-butoxy-pent-1'-trans-1'-enyl);
Example 30 A solution of 2.1g of d!l-2-exo-(3'-oxo-non-1'-trans-1'-enyl~-3-exo-THP-oxy-7-endo-DMtB-silyloxy-bicycloL3.3.03Octane (prepared accoridng to example 17) is reduced at -15C in methylene chloride:ethanol with 0.17~ of NaBH4, following the procedure of example 23, to afford 2.01g of d,l-2-exo-(3'(SIR)-hydroxy-non-1'trans-1'-enyl)-3-exo-THP-oxy-7-endo-DMtB-silyl-oxy-bicyclo C3.3.0~octane. Without separating the 3'S ~nd 3'R alcohols, this product is reacted in 30ml of methylene chloride with 0.4g of 2,3-dihydropyran in the presence of 25mg of p-toluenesulfonic acid to give -the corresponding d,l e~o-(3'(S,R)-hydroxy-non-1'-trans-1'-el1yl)-3-exo-hydroxy-7-endo-DMtB-silyloxy-bicyclo~3.3~0~octane-3,3'-bis-THP-ether.
With no further purification, this product is ireated with e~ 1l; V~ ~ntS
L ~20 2.5 molar of tetrabutyl al~nonium fluoride in THF
to remove the silyl ether.
The product d,l~2-exo-(3'(5,R)-hydroxy-nor~ trans-1'-enyl)-3-exo-7-endo-dihydroxy bicyclo~3.3.0~octane-3,3'-bis-THP-ether (1.660g) is then oxidized w:ith pyridine - chromic anhydride to give 1.25g of d,l-~-exo-(3'(S~R)-hydroxy-non-.

r/~

c, 1'-trans~ enyl)-3-exo-hydroxy-bicyclo[3.3.0~oc-tan-7-one-3,3'-bis-THP-ether.
Example 31 A solution o (2-oxo-5,5,5-trimethoxy-pentyl)-dimethyl phosphonate in 1Oml of TH~ is added dropwise to a skirred suspension of 68my of NaH (80%) in 1Oml of anhydrous THF.
Stirring is continued until hydrogen evolution ceases, and then a solution of 0.67g of d,l-2-exo-~3'(S,R)-hydroxy-non-1'trans-1'-enyl)-3-exo-hydroxy-bicycloL3.3.0~ octan-7-one-3,3'-bis~THP-ether in Sml of THF is added. ~fter 6 hours of stir-ring at 40-~5C, 20ml cf 20% NaH2P04 is added and the THF is removed under vacuum. The residue is extra~ted with ethyl ether ! and the organic extract is dried over ~a2S04 and eva-porated. Adsorption of the residue on silica gel and elution ~ith cyclohexane:ethyl ether afford 0.76g of d,l-5t,13t-4-oxo-11~,15(S,R)-dihydroxy-20-metllyl-9a-deoxy-9a-methylene-prosta-cycla-5,13-dienoic acid-trimethylorthoester~11,15-bis-THP-ether.
A solution of this product in 15ml of anhydrous meth-anol is treated with 6mg of p-toluenesulfonic acid for 5 hours ~0 at room temperature. 0.1ml-of pyridine is added, the solu tion is evaporated to dryness, and the residue is purified on silica gel (.sopropyl ether:ethyl ether as eluent) to afford 0.20g of d,l-5t,13t-4-oxo~ ,15S~dihydroxy-20-methyl-9a-deoxy-9a-methylene-prostacycla-5,13-dienoic acid-trimethyl orthoester and 0.21g of the 15R epimer.

~9~

Example 32 Following the procedure of example 31 with a bicyclo-~3.3.03Octan-7-one prepared as in examples 27, 2~ and 29, the following trimethylorthoesters were prepared:
5,13t-4-oxo-11~,15S~dihydroxy-9a-deoxy-9a-methylene-prosta-cycla-5,13-dienoic acid;
5,13t-5-oxo-11~,15S-dihydroxy-9a-deoxy-9a-methylene-20-methyl-prostacycla-5,13-dienoic acid;
5/13t-4-oxo-11~,15S-dihydroxy-9a deoxy-9a-methylene-17(2')-tetrahydrofuryl-18,19,20-trinor-prostacycla-5,13-dienoic acid;
5,13t-4-oxo-11~,15S-dihydroxy-9a-deoxy-9a-methylene-16-m-trifluoromethylphenoxy-17,18,19,20-_etranor-prostacycla-5,13-dienoic acid;
as well as their 15R epimers.
Each of the ortho--esters of examples 31 and 32 is then converted to its methyl ester by refluxing it in methanol (15ml/g) with 2ml of 0.2N oxalic acid and recovering the pro-duct by evaporating the methanol and extracting with ethyl ether. Subsequent saponification with 2% KHCO3 in 80o aqueous methanol gives the free acid.
Example 33 solution of 0.45g of 5,13t-4-oxo-11~,15S-dihydroxy-9a-deoxy-9a-methylene-prostacycla-5,13-dienoic acid-trimethyl-orthoester (~maX=244m~,~ =91850) in 6ml of methanol and 1.2ml of 0.2N oxalic acid is refluxed for t~o hours. Evaporation of `
t , r 3~Z~ :

the methanol uncler vacuum and extraction with ethyl e-ther give 0.~2~ of the correspondin~ methyl ester.
A solution of this product in 6ml of anhydrous ethyl s ether is added dropwise to a stirred 0.1M solution of zinc ; borohydride (1Oml) in 10 minutes. After 1 hour of s-tirring at room temperature, the reaction is quenched with 2N sul-furlc acid. The organic ph`ase is separated, washed until -neutral, and evaporated to dryness to give 0.4g of s,13t-4(S,R),11~,15S-trihydroxy-9a-deoxy-9a-methylene-prostacycla-I 5,13-dlenoic acid methyl ester. Chromatographic separation on silica gel (ethyl ether:ethyl acetate as eluent~ affords 0.11g of 5,13t-4S,11~,15S-trihydroxy-9a-deoxy-9a-methylene-prostacycla-5,13-dienoic acid methyl ester and 0.14~ of the 4R-epimer methyl ester.
A solution of the latter compound in 5ml of mQthanol is treated with 0.05g of lithium hydrate and 0.3ml of H20 and then stirred at room temperature for 6 hours. Removal of the methanol under vacuum, acidification of pH 5.6 and rapid extraction with ethyl acetate afford s,13t-4R,11~,15S-~O trihydroxy-9a-deoxy-9a-methylene-prostacycla-5,13-dienoic ~^
acid. Treatment of a stirred ethyl acetate solution of this compound with C.5 parts of a polystyrenesul onic resin (hy-dro~en ion form) ~ives 5,13t-4R,11'~15S-trihydroxy-9a-deoxy-9a-methylene-prostacycla-5,13-dienoic acid-1,4-~-lactone quantit~tively.

.
j.

The 4S epimer-~-lactone was prepared analo~ously.
Example 34 t, A solution of 0.8g of 5,13t-4-oxo~ ,15S-dihydroxy-20-methyl-9a-deoxy-9a-methylene-prostacycla-5,13-dienoic acid-trimethylorthoester-11,15-bis-THP-ether in 20ml of methylene chloride:ethanol is cooled to -20C a.,d treated with 50mg of NaBH4. .~fter 30 minutes of stirring~ the reaction is quenched with 2ml of acètone and 5ml of saturated monosodium phosphate. Evaporation of the methylene chloride and ethanol under vacuum and repeated extraction with ethyl ether afford, after the combined oryanic extract is dried and evaporated, 0.75g of 5,13t-4(S,R),11~,15S trihydroxy-20-methyl-ga-deoxy-9a-methylen~ rostacycla-5,13-dienoic acid-trimethylorthoester-11,15-bi---THP~-ether.
1~ This crude product is dissolved in 2.2 ml of methane-sulfonyl ch~oride. The reaction mixture is held overnight at room temperature and then partitioned between iced 2 sul,uric acid and ethyl ether. The combined organic ex-tract is washed with brine, dried and e~raporated at low tem-perature to yive 5,13t-4(S,R),11~15S-trihydroxy-20-methyl-9a-deoxy-9a-methylene-prostacycla-5,13-dienoic acid-trimethyl-orthoester-4-mesylate-11,15-bis-~-ether.
With noiEurther purification, this product is dissolved in anhydrous ethyl ether and treated with 50mg of lithium aluminum hydride in ethyl ether. After stirriny for 2 hours :~ f at room temperature and 1 hour at reflux, -the re~ction miY.-~ure is quenched with 2ml of ethyl acetate and then ~e-t ethyl ether. Dryin~ over Na2SO4 and evaporating the ethyl ether give 0.5g of crude 5,13t~ ,15S-dihydroxy-2~-methyl-9a-deoxy-9a-methylene-prostacycla-5,13-dienoic acid-trimethyl-orthoester-11,15-bis-THP-ether.
After treatment at reflux with 12ml of methanol and -4ml of 0.3N aq~1eous oxalic acid, standard work-up gives 0 2g of 5,13t-11~"15(S)-dihydroxy-20-methyl-9a-deoxy-9a-methylene-prostacycla-5,13-dienoic acid methyl ester. Liquid-liquid - chromatography shows that the product is mainly trans (~5~), with 15 % of the cis isomer.
Example 35 In an inert gas atmosphere, a stirred suspension of -15 0.4g of NaH (75% mineral oil dispersion) in 13.5ml of DMSO
is heated to 60-65C for 4 nours. The mixture is then cooled to room temperature and held at 20-22C while 2.6g of 4-carboxy-butyl-triphenyl phosphonium bromide in 6ml of DMSO
and 0.85g of 2-exo-(3'S--hydroxy-non-1'-trans~ enyl)-3-endo-2~ hydroxy-bicyclo ~3.3. octan-7-one-3,3'-bis-TlIP-ether are added successively. After stirring for 3 hours, the mixture is diluted with 35ml of water and the aqueous phase is ex-tracted with ethyl ether (5x12ml) and e~hyl ether:benzene ~7x12ml). The combined organic extract is re-extracted with 25 0.5N NaOH (3x15ml) and then water until neutral, and then 1'~

.1 .

discardedO The combined aqueous alkaline extract is acidiied to pM 5.3 and extracted with 1:1 ethyl e-ther:pen-tane. ~iash-, ing until neutral, drying over Na2S04 and removing the sol-vent afford 0.~6g of ~5,13t-11~,15S-dihydroxy-9a-deoxy-9a-methylene-20-methyl-prostacycla-5,13-dienoic acid-11,15-- bis-THP-ether~ This product is then esteriied by treatment with diazomethane, and the pyranyl protecting groups are removed, as follows:
The methyl ester is dissolved in anhydrous methanol and treated with a solution of 10 2 molar eauivalents of p-toluenesulfonic acid. After hours, the p-toluenesulfonic acid is neutralized with pyridine and the mixture is evapora-ted to drvnes.s. Purification on silica gel affords 5,13t-11~,1jS-dihydroxy-9a-deoxy-9a-methylene-20-methyl prostacycla-5,13-dienoic acid methyl ester, which is then separated into the individual 5c,13t and 5t,13t isomers by liquid-liquid chromatography.
Example 36 With stirring and external cooling to keep the reac-tion temperature at 20-22C, a solution of freshly sublimed potassi~lm tert-butylate in 12ml of anhydrous DMSO is treated success;,vely with 1.8g of 4-carboxybutyl-triphenyl phosphonium bromide in 1Oml o DMSO and 0.65g of 2-exo-(2l-bromo~3'S-- hydroxy-oct-1'-trans-13-enyl)-3-endo-hydroxy-bicyclo ~3.3.~ - octan-7-one-3,3'-bis-THP-ether in 5ml of DMSO. After stirring 9~42 i1g for 8 hours at room temperature, the mixture is diluted with an equal volume of water, acidified to pH 5 and extracted with 1:1 ethyl ether:pentane. The acidic aqueous phase is discarded, and the combined organic extract is extracted with 0.8N NaOH (5x20ml) and then water water until neutral.
While this ^rganic phase is discarded, the aqueous alkaline extract is acidified to pH 5 and extracted with 1:1 ethyl ether:pentane. The combined extract is dried over Na2S04, filtered and treated with ethereal diazomethane until a yellow colorat1on persists. Evaporation to dryness gives crude 11~,15S-dihydrcxy-9a-deoxy-9a-methylene-prostacycl-5-en-13-ynoic acid methylester-11,15-bis-TH~-ether. Removal of the pyranyl protecting group followed by liquid-liquid chromatography gives 5c-11~,15S-dihydroxy-9a-deoxy-9a-meth- -vnotc ylene-prostacycl-5-en~13- acid methyl ester, plus the 5t geometric isomer.
Example 37 When the bicyclo L3 . 3 . 0~octan-7-one 3 3~-bis-THP-ethers prepared according to examples 27,28,29 and 30 were used in the procedure of examples 35 and 36, the methyl esters of the following acids were obtained-5c,1 3t-~ i 5S-dihydroxy-9a-deoxy-3a~me~hylene-prostacycla-5,13-dienoic acid;
5c -11~,15$-dihydroxy-9a-deoxy-9a-nethylene-16R-fluoro-prostacycl-5-en-13-y-noic acid;

L~

5c~ ,i5S-dihydroxy-9a~deoxy 9a-methylene-16S-fluoro-prostacycl-5-en-13-ynoic acid, 5c-11~,15S-dihydroxy-9a-deoxy~9a-mcthylene 17(2')-tetra-hydrofuryl-18,19,20-trinor-prostacycl-5-en 13-~noic acid;
5c-11~,15S-dihydroxy-9a-deoxy-9a-methyl~ne-prostacycl-5-en-13-~/~oic acid;
5c,13t-11~,15S-dihydroxy-9a-deoxy-9a-methylene-prostacycla-5,13-dienoic acid;
5c,13t~ ,15S-dihydroxy-9a-deoxy-9a-methylene-16S-methyl-prostacycla-5,13--dienoic acid;
- 5c,13t-11~,15S-dihydroxy-9a-deoxy-9a-methylene-''0-methyl-prostacycla-5,13-dienoic acid;
5c,13t-11~,15S-dihydroxy-9a-deoxy-9a-methylene-17-phenyl-18,19,20-trinor-prostacycla-5,13-~ierlois acid;
5c,13t-11~,15S-dihydrox~--9a--deoxy-9a-methylene-16-m-CF3 phenoxy-17,18,19,20-tetranor-prostacycla-5~13-dienoic acid;
5c,13t-11~15S-dihdyroxy-9a-deoxy-9a-Methylene-16-methyl-16-butoxy-18,19~20-trinor-prostacycla-5,13-dienoic acid;
as well as their 5-trans geometric isomers, plus the 15R
epimers of both.
These were then saponified to give ~he free acids.
Example 38 A solution of 0.45g of 2-exo-(3'S-hydroxy-oct-1'-trans-1~-enyl~3-endo-hydroxy-bicyclo ~3.3.~ octan-7-one-3,3'-~5 bis-TMP-ether in ethyl acetate is hydrogenated at ambient ~o temperature and pressure in the presenc2 of 0.1y of 5~ Pd/
CaC03, until 1.01 equivalents of hydrogen are absorbed.
Filtration and evaporation to dryness give 0.42g of 2-exo-~3'S-hydroxy-octan-1'-yl)-3-endo-hydroxy-bicyclo~3.3.0~-octan-7-one-3,3'-bis-THP-ether. Treatment of this with the Wittig reagent prepared from 4-carb- y-butyl phosphonium bromide according to examples 35, 36 and 37 a fords a pro-duct which is esterified with diazomethane and depyranylized to give 0.12g of 11~,15S-dihydroxy 9a-deoxy-9a-methylene-prostacycl-5-enoic acid methylester. The 5-cis and 5-trans geometric isomers are separated by liquid-liquid chromatography.
Exxmple 39 Using (3-carboxy-propyl)-phosphonium bromide in the procedure of examples 37 and 38 instead of (4-carboxy-butyl)-phosphonium ~romide ~a~e the following acids:
5c,13t-11~,15S--dihydroxy-9a-deoxy-9a-methylene-2-nor-prosta-cycla-5,13-dienoic;
5c-11~,15S-dihydroxy-9a-deoxy-9a-methylene-2-nor-prostacycl-5-enoic;
5c-11~,15S-dihydroxy-9a-deoxy-9a-methylene-2-nor-prostacycl-5-en-13-ynoic acid.
Example 40 , By using (5-carboxy-pentyl)-phosphonium bromide in the procedure of examples 37 and 38, 5c,13t-11~,15S-dihydroxy - 25 9a-deoxy-9a-methylene-2ahomo-prostacycla-5,13~dienoic acid ~:~L9~
gl_ ., ~, , , - and 5,13t-11~,15S-dihydroxy-9a-deoYy-9a-methylene-20-methyl-2a~lomo-prostacycla-5,13-dienoi-c acid were prepared.
Example 41 A solution of 0.37g of 5c,13t-11~,15S-dihydroxy-9a~
deoxy-9a-methylene-prostacycla-5,13-dienoic acid methyl ester in 10ml of berzene is heated to 50C with 250mg of 2,3~dichloro--5,6-dicyano-benzoquinone for 8 hours. The pre-cipitate is removed hy filtration, and the benzene solution is pu~ified on a short alumina column to give 0.29g of 10 5c,13t-11~-hydroxy-15-oxo-9a-deoxy-9a-rnethylene-prostacycla-5,13-dienoic acid me~hyl ester.
A solution of this product in ethyl ether:toluene is eooled to -20C and treated with 1.2ml of 1M methyl magnesium bromide in ethyl ether. After 2.5 hours at ~20~, the rea_-tion is quenched with NH4Cl solut on~ The organic ~hase isseparated, reduced in volume and purified on silica gel (ethyl ether:ethyl acetate as eluent) to give 0.1g of 5c,13t-11~,15S-dihydroxy-15-methyl-9a-deoxy-9a-methylene-prostacycla-5,13-dienoic acid methyl ester and 0.072g of the 15~ hydroxy epimer.
2~ Example 42 A solution of 2.2g of 3-endo-hydroxy-bicyclo ~3.3.0~ -octan-7-one in 100ml of anhydrous benzene is trcated with 4ml of ethylene glycol and 0.2g of p-toluenesulfonic acid mono-hydrate and refluxed for 12 hours while the water which forms ?5 druing the reaction is collectedO 0.25ml of pyridine is then g~

added and the mixture is cooled. The organic phase is waslled with water, NaHC03 and then water, and evaporated to dryness to give 2032g of 3-endo-hydroxy-bicyclo ~.3.0~octan-7-one-7,7-ethylenedioY.ide.
A solution of this product i~ 40ml of acetone is cooled to -5C and treated at this temperature with 4.1ml of Jones' reagent. After 20 minutes at -5C, ex~ess oxidant is quenched with 4ml of isopropyl alcohol. 150ml o-f benzene is added, and the benzene phase is washed successively with 2090 (NH~)2S0~, water, 5% NaHC03 and water. Evaporation to dryness gives 2.1g of djl-bicyclo~3.3.0~octan-3,7-dione-2-carboxymethylester-7,7-ethylenedioXide.
ccording to the procedure o example 2, a solution of this product in 20ml o CH2C12 an~ 20ml of ethanol is reduced with NaBH4 at -2C~ C to give 1.7~g of dll-3-endo-hydr bicyclo L3.3.0~octan-7-one ~2-exo-carboxymethylester-7,7-ethylenedio~ide.
A solution of 1.57g of this compound in 3ml of di-methylformamide is treated with 1.3g of dimethyl-tert-2~ butyl-silyl chloride and 0.885g of imida~ol, and then held at 0C for 5 hours. After cooling, water is added and the usual worl~-up affords 2.3g of d,1-3-endo-hydroxy-bicyclo ~.3.Q~ -octan-7-one-2-exo-carboxymethylester -7,7-ethylenediXide-3-di~n~thyl-tert-butylsilylether. Subsequent reduction with LiAlH4 in anhydrous ethyl ether, as described in example 3, ~3 gives d~l~3-endo-~hydroxy 2 exo-hydro~me~hy~-7,7-ethylene-dioxy-b~cyclo r3.3. octan-7-one-3-dimethyl-tert-butyl 5ilyl ether quantitatively.
Example 43 By using dithioethylene glycol in the procedure of example 42 instead of ethylene g]yc~l, the corresponding 7,7-ethylenedithio analogues were prepared.
Example ~4 1.8g oE d,l-3-endo hydroxy-2-exo-hydroxymethyl-7,7-ethylenedioxy-bicycl`o ~.3.0~ctan-7-one-3-dimethyl-tert-butyl silyl ether is oxidized according to the procedure of example 18 to give the corresponding 2-formyl derivative. This is then reacted with (2-oxo-heptyl)-dimethyl phosphGnate as in example 20 t~ give 1.23g of d,l-3-endo-hydroxy-2-exo-(3'-oxo-1~ oct 1'-trans-1'-enyl)-7,7-ethylenedioxy-bicyclo C3.3.0~octan-7-one -3-dimethyl-tert-butyl silylether ( ~ax--228m~ =8980).
According to the procedure in example 22, this is reduced with zinc borohydride in ether to give 1.22g of d,l-3-endo-hydroxy-2~exo-(3'(S,R)-hydroxy-oct-1'-trans-1'-enyl)-7,7-ethy-lenedioxy-bicyclo ~.3.0~octan-7-one -3-dimethyl-tert-butyl silyle~her.
solution of this compound in 25ml of methanol is treated with 10ml of 1N H2S04 at reflux for 50 minutes. The methanol is evapora~ed under vacuum, the residue is ex~
tracted with ethyl ether~ and the organic phase is evaporated to dryness to af-Eord 0.72g of crude d,l~3-endo-hyc~roxy-2- -exo-(3'(S,R)-hydroxy-oct-1l-trans-1'-enyl)-bicyclo~3.3.Q~oc-tan-- 7-one. The individual i.somers are separated by chromatog-raphy on silica gel with hexane:ethyl ether as eluent and then converted to the tetrahydropyranyl ethers by treatment with 2,3-dihydropyran in methylene chloride as in example 25. In this fashion, a compound identical in all respects to 2-exo-(3'S-hydroxy-oct-1'-trans-1'-enyl)-3-end o-hydroxy-bicyclo[3.3.0~octan-7-one-3,3'-bis-tetrahydropyranylether prepared as in example 28 is prepared from the 3'S-hydroxy isomer.
Similarly, with the procedure of examples 42 and ~4, all the compounds prepared as in ex~nples 27, 28 and 2 were obtained.
Example 45 Saponification of 4.8g of d,1-3-endo-hydroxy-2-exo-carboxymethylester-7,7-ethylenedioxy-bicyclo ~.3.Q~octan-7-one with 100ml of 2.5-~ potassium ~arbonate in 80:20 methanol:water at reflux for 40 minutes and subsequent work-up as described in example 2 gave 4.02g of d,1-3-endo-hydroxy-2-exo-carboxy-bicyclo ~3.3. octan-7-one -7,7-ethylenedioxide. This com-pound is dissolved in 80ml of anhydrous tetrahydrofruan, cooled to -10C, and treated dropwise with 2.1g of triethylamine in 12ml of anhydrous tetrahyd~ofuran and then 2.2g of ethyl ~5 chlorocarbonate in 12ml of anhydrous tetrahydrofuran, while ~9~o keeping the temperature at -10 C. After 1 hour o stirring at -10C, 1.4g of sodium azide in 12ml of water is added slowly and stirring is continued for another 25 minutes.
The reaction mixture is then concentrated under vacuum and diluted with water. The 2-exo-carboxy-azide is isolated rapidly by f;ltration and dried under vacuum.
A solution of 4.01g of this compound in 8ml of pyri-dine is treated with 4ml of acetic anhydride and held at 5-8C for 24 hours. The reaction mixture is then partitioned between ice water, ethyl ether and 2N sulfuric acid. The - organic layer is separated, washed until neutral, dried and evaporated to dryness to give 4.1g of 3-endo-hydroxy-2-exo-carboxyazide-bicyclo~ Q30c~n-7-one -3-acetate-7,7-ethylene-dioxide.

1~ This produ_t is suspended in acetic acid (~Oml) and water ~8ml), and the mixture is heated to 40C. ~1hen hydro-gen evolution is noted, it ls heated to 60-70C for 2 hours, ~ter which the excess acetic acid is removed by steam dis-tillation. After cooling, the mixture is extracted with ethyl ether:ethyl acetate and the aqueous phase is brought to pH 9 with sodium hydrate. The alkaline phase is washed with saturated salt solution and evaporated to dryness to give 1.92g of 3-endo-hydroxy-2-exo~amino-bicyclo ~3.3.030ctan-7-one -3-acetate. Reaction of this with the mixed anhy-dride from ethoxycarboyl chloride and 2S-hydroxy-heptanoic G

~j3 ` 42 acid-2-~cetate affords 3-endo~h~droxy-2-exo-(2'S~acetOxy-heptanoyl-amide)-bicyclo ~3.3.030ctan-7-one 3-acetate.
- A solution of this compound in anhydrous dimethylsulfoxide is then reacted with the ylide obtained from 4-carboxy-butyl-triphenyl phosphonium bromide to give, after saponi-ification, 5t-11~,15S-dihydroxy-9a-deoxy-9a-methylene-12 a~a-13-oxo-prostacycl-5-enoic acidO
In an analogous fash.ion the 15R-epi analo~ue was prepared from the 2IR-hydroxy-heptanoic acid.

~JJ 1~ 9~'12~

Example 4h Ethylene glycol (~5 ml) and p-toluensulfonic acid (0.9 g) are added to a solution of 2-exo-bromo-3-endo-hyc~oxy-bicyclo ~302.0 heptane-6 one in benzene and the mixture is refluxed ~or 12 hours9 withdrawing water which ~orms during the reaction, then the mixture is added by piridine (0.6 ml) and cooled at room - temperature~ . -The organic phase is washed with water, 2. S% aqueous NaHCO3 and water, dried. Benzene (100 ml) is partially removed in vacuurn~ thenthe mixture is 1(~ treated with tributyltinthemdridet(41 g) in N2 atmospnere at 55 for 8 hoursO
- After cooling at room/the organic phase is washed with saturated aqueous NaH2P04, dried and evaporated to dryness. Purification of the resulting residue on SiO2 (240 g) with benzene-ethylether as eluent ffords 14. 9 g of 3-endo-hydroxy-bicyclo[3. 2. i~heptane-6-one-6p 6-etllylene dioxide.
15 E.xample 47 A stirred so;ution of 3-endo-hydroxy-bicycloL3. 2. ~hep~ane-6-one-6, 6-ethylendicxide ~1~.75 g~ in benzene (340 ml) and DMSO (112 ml) was treated with dicyclohexylcarbodiimide (~6. 35 g)~ pyridine (5. 9 g) and trifluoroacetic acid (5. 4 g). ~fter 6 hours, the mixture is diluted with benzene (6~0 ml) and 20 , water (50 rrll), filtered from dicyclo hexylurea and the organic phase is washed with water, dried on MgSO4 and evaporated to dryness affording bicyclo~3. 2. ~1heptane-3, 6-dione-6, 6-diethylenedioxide.
A solution of this crude product in dimethylcarbonate (70 ml) is added to 2 suspension of sodium hydride (80% in mineral oil, 4 g). The mixture i5 25 stirred until H2 development ceases at room temperature then it is warn~ed ! for 40 minutes at 75-80.
i After cooling, the reaction mixture is diluted with benzene (350 ml~ and acetic acid (8. 4 g)p washed with water, dried and evaporated to drynLess affording a mi~cture (1:1) of d,l-bicyclo¦3.2.~heptane-3,6-dione-2-carboxy methylester-6, 6-ethylendioxide (p= 0, ~3= 1) and d, 1-bicyclo[3. 2. ~heptane gg g~34 _3, 6~diGne-4-carboxymethylester-6, 6-ethylene dioxide (p~ 1, q= 0) which are separated by means of chromatography on SiO2 (Fe , Fe free) us ing hexane - e thyle-the r as eluents .
Exam~ 48 Using in the procedure of the example 47 g 14.85 of 3-endo-hydroxy_ bicyclol4. 3. I~nonane-7-one 7, 7-ethylendioxide the oxidation process affords 13. 9 g of bicyclo~4. 3. ~nonane-3, 7-dione-7, 7-ethylendioxide giving the carbomethox~lation process 4. 2 g of dl-bicyclo[4. 3. O~nonane-3, 7-dione-2-carboxymethylester-7, 7-ethylenedioxide (p= 1, q= 2~ and 4.8 g of dl-bicyclo[4. 3. ~nonane-3, 7-dione-4-carboxymethylester-7, 7-ethylendioxide also named as dl-bicyclo~4. 3. ~nonane-3, 8-dione--2-carboxymethylester~8, 8-ethylenedioxide ~p= 2, q= 1).
Example 49 A stirred solution of bicyclo~4. 3. ~nonane-7-en-3-one ~90 g) in dimethyl carbonate (350 ml) is added to a suspension of sodium hydride (80% dispersion in ~nireral oil, 42 g) in dimethylcarbonate (550 ml). After ceas;ng the hydrogen evolution, the mixture is heated for 4.5 hours at 75-80, cooled at r. t., diluted with benzene ~2. 7 1) and washed with 25% aqueous NaH2PO
solution, evaporated to dryness affording bicyclo~4. 3. O~nonane-7-ene-3-one-2 0 2 - carboxyme thyle ste r ( 91 g) ( )~ max 2 5 2 m~ = 8 . 2 0 0) .
A solution of this compound in methylene chloride (1. 2 1) and ethanol ~1. 2 1) is cooled at -20~ and,under stirring,treated with NaBH4 (14.4 g).
The mixture is stirred for 30 minutes~again at ~20, then it is treated with acetic acid (23 ml)9 warmed at room temperature, and the solvents are evaporated in vacuum.
The residue is partitioned between ethyl acetate and water, the organic phase is dried and evaporated in vacuum affording dl-bicyclol14. 3. ~lnonane-7-ene-3-endo-hydroxy-2_exo_carboxymethylester ~64 g) which is dissolved ~fj .
8~o in dry tetrahydrofuran (THF) and treated with 2~ 3-dihydropyrane ~33 g) and p-toluensulphonic acid (0. 63 g) for 3 hours at r. t.. Pyridine (0. g) is added to the reaction mixture and then~after cooling at 0C, under . stirring a solution of 1. 2 M BH3 in THF is also added during 45 minutes.
5 The stirri$~g goes on for 1 hour at 0C then water i5 added to destroy .- residual hydride. Under vigorous stirring, with external cooling at -5~0, the formed borane is oxidized by the slow concurrent addition of 110 rnl of 3M sodium hydroxide and 110 ml of 30% hydrogen peroxide, maintaining the internal temperature at 20-25. The oxidation mixture is diluted with - lO benzene (2 1) and the layers are separated. The aqueous layer is extracted with benzene (2x50~. The organic layers are combined, washed successively with 1% sodium carbonate, saturated sodium sulphite and saturated sodiu~
chloride and dried on MgSO4. Evaporation of the solvents affords a crude mixture of 7 and 8 hydro~Yy compounds which are separated by means of 15 SiO2 (300 g) column chromatography7 ethyl ether as eluent, obtaining respectively: `
- . r exo--dl-bicyclo 4. 3. O~nonane-3-endo~ 7 ~;lihydroxy-2~c:~rboxymethylester-3-THP-ether (Z4 g) and dl-bicyclo¦4. 3. ~nonane-3-endo~ 8 -dihydroxy-~carboxymethylester-3-2 0 THP- ethe r (~ 7 g) .
A solution of the 7~-hydroxy alcohol (2~ g) in dry DMF (30 ml~ is treated with dimethyl-ter-butyl-silyl chloride (15.8 g) and iInidazole (8.85 g) and then it is heated for 5 hours at 60, cooled at room ternperature, diluted with water (90 ml) and then extracted with ethyl ether.
Z5 The organi~ layers are collected, washed with water and e~aporated to dryness affording dl-bicyclo[4. 3. I~nonane-3-endo, 7~dihydroxy-2-exo-carboxymethylester-3-THP-èther-7-DM~-silylether.
To a stirred solution of this compound in dry toluene (~Z0 ml) cooled at .. . . .... _ .. .. .... _ ..

9~b .
.
.
-70, a solution of 1.4M DIBA in toluene is added over a period of 4,5 minutes, maintaining the temperature between -70t-60. The stirring is continued for 2 hours, the residual hydride is destroyed by addition of 2 M
- isopropyl alcohol in toluene.
5 The reaction mixture is warmed at room temperature and successively 30% aqueous NaH2PO4 (60 ml) and Na2SO4 (50 g) are added. After filtration, the organic phase is washed with water and evaporated in vacuum affording dl-bicyclo~4. 3. ~3-endo, 7~ -dihydroxy-2-exo-formyl-3-THP-ether-7-DMB-- silylether (p= 2, q= 1). Using in this procedure the 8f~-hydroxy compound, - 10 we have obtained:
dl- bicyclo~4 . 3 . ~nonane - 3 - endo, 8~ - dihydr oxy- 2 - exo- c arboxyme thyle s te r - 3 -THP-ether-8-DMB-silylether and dl-bicycloC4~ 3. ~nonane-3-endo, 8~-dihydroxy-Z-exo-formyl 3-THP-ether, 8 -DMB - s ilyiethe r.
15 Example 50 A solution of (2-oxo-heptyl)dimethylphosphonate (0. 33 g) in dry benzene (:) ml) is added to a stirred suspe~sion of NaH (80% dispersion in mineral oil, 43.5 mg) in dry benzene (10 ml). After 1 hour N-Br-succinimide (~60 mg) is added and then, after 5~ minutes~ a solution of bicyclor4. 3. ~nonane-3-endo, 8~-dihydroxy-2-exo-formyl-3-THP-ether, 8-DM~-silylether (0.4 g) in toluene (5 ml).
The stirring is continued for 15 minutes, then the reaction mixture is washed with aqueous 15% NaH2PO4, dried and evaporated in vacuum to give 2-exo[2~-bromo-3~-oxo~oct~ 1~-tra~is-eny~-3-endo-THP-o~sy-8~ -DMB-silylo~cy-bicyclo~. 3.~nonane, )~ max 251 m~, - 8. 900.
Example 5 1 A solution of (3-phenoxy-Z -oxo-propyl)dimethylphosphonate (2. 85 g) in benzene (10 rnl) is added to a stirred suspenslon of NaH (80% mineral oil dispersion, 9j 0. 33 g) in benzene (50 ml). The stirring is continued for 45 minutes, then solution of 2-exo-formyl-3~ endo-THP-oxy-7~ -DMB-silyloxy-bicyclo~. 3.
.
nonane t3.82 g) in toluene is added. After 20 minutes the organic phase is washed with aqueous 20% NaH2PO4 and water, dried and evaporated to 5 dryness affording after filtration on SiO2 (3B g),using benzene-ethyl ether aseluent, 2-exo-~3'-oxo-41-phenoxy-but- I'-trans -eny~-3-endo-THP-oxy-7 - -DMB-silyloxv-bicyclo~4. 3. I~nonane (3. ~7 g~. Using in the procedure (5-cyclohexyl-2-oxo-butyl)-dimethyl phosphonate and starting from the aldehydes of the example 49 we ha~te obtained:
10 2 exo r3 - oxo - 5 - cyclohexyl-pent~ trans - eny~- 3 - endo - THP- oxy - 7 ~- DMB -silyloxy-bicycloE. 3. ~nonane max 228~; = 9. 300 2-exo[3'-oxo-5'-cvclohexyl-pent-1'-trans-eny~-3-endo-THP-oxy-8~-DMB-silyloxy-bicyclo 4. 3. 0 nonane max Z28. 6~ = 9. 450.
Example 52 15 The DMB-silylether-a, -unsaturated ketones, obtained in accordance with tke procedure of the example~ 50, 51 (a) are reduced to allylic ~lcohols and ~b) the ~ew hydroxy group is protected as THP-ether; successively (c) the DMB-silylether protecting group is selectively removed giving a secondary alcohol which (d) is oxidized to ketone; finally after removal (e) of all .he 20 remaining protective groups (f) the epimeric allylic alcohols are æeparated by HPLC-chromatography OIl SiO2. Working in a 2. 10 molar scale, the following procedure is used:
a) reduction: 1. 10 mole (0. 32 g) of NaBH4 is added to a stirred solution of a a, -unsaturated ketone--DMB-silylether (2. 10 m~ in methylene chloride-25 ethanol (1:1) ~180 ml) cooled at 10~-15. After 30 minutes, the residual hydride is destroyed by adding acetone ~10 ml) and aqueous saturated NaH2PO4 (25 ml~. The solvents are removed in ~acuum and the residue is partiticned between water and methylene chloride. The organic layer is separated dried 9~-and evaporated to dryness affording a mixture of 3'S, 3'R allylic alcohols-silylethers (2. 10 m).
b) protection of allylic alcohols as THP-ethers: the crude mixture of 3'S, 3'R~allyllc alcohols silylether ~2. 10 rn) was treated with methylene chloride (30 ml) and to the stirred solution 29 3-dihydropyrane (2 g) and p-toluen-sulphonic acid (0. 038 g) are added. The reaction is complete after 2 hours stopped by addition of pyridine (0. 5 ml) and the solvents are removed by evaporation in vacuum to give a crude mixture of 3'S, 3'R-THP-ether .,ilyl-~thers .
c) desilylation: a solution of the above obtained material in dry THF (80 rnl) is treated for 12 hours at r. t. with dry tetrabutylammonium fluoride ~14 g).
After concentratioll in vacuum to small volume, the residue is absorbed on SiO2 (40 g) and following elution with ethylether affords the secondary alco~ol~ -3'S, 3'R-THP-ethers (about 2. 10 m).
d) oxidation: dicyclohexylcarbodiimide (6.5 g), pyridine (1 ml) and trifluoro acetic acid (0. 5 ml) are added successively 40 a stirred solùtion in 75:25 benzene-DMSO (60 ml) of the seco~idary alcohol-3'S, 3'R-THP-ether. A~ter 4.5 hours the reaction mixture is diluted with benæene (100 rnl) and with a solution vf oxalic acid (3 g) in water. Forlned dicyclohexylurea is filtered, organic layer is washed until neùtral, dried and evaporated to dryness.
e,f~ depyranylization and chromatographic ~eparation: a solution of the 3'S, 3'R-THP-ether~ketones in methanol (30 ml) is stirred at r. t. for 3 hours with p-toluensulphonic acid (0. 18 g~; after addition of pyridine (0. 5 ml) it is evaporated to dryness. The residue is dissolved in cyclohexane-ethyl acetate (80:20) and injected in HPLC instrument to give the following keto alcohols:
2-exo~2'bromo-3'S-hydroxy-oct~ trans-eny~-3-endohydroxy-bicyclo ~. 3.
nonane -8 - one .

q3 t~

r - .
,~ , ' '.
.
ZO
.
f 2-exo L2'bromo-3~R-hydroxy-oct--l'-trans-er~ 3-endo hydroxSr-bicyclo ~. 3. (~nonane 8-one 2-exol3'S-hydroxy-4'-phenoxy-but 1'-trans-eny~-3-endo hydroxy-bicyclo [4. 3 . nonane - 7 - one 5 2--exor3tR-hydroxy-4'-phenoxy-but- 1'-trans-eny~-3-endo hydroxy-bicyclo E~. 3. ~nonane-7-one 2-exo~3'S-hydroxy-5-cyclohexyl-pent-1'-trans-eny~-3-endo hydroxy-bicyclo ~4. 3. ~nonane-7-one 2-exo ¦ 31R-hydroxy-5-cyclohexyl-pent-lt-trans-eny;1-3-endo hydroxy-bicyclo 10 E~. 3. ~nonane-?-one 2-exo~3tS-hydroxy~5-cyclohexyl-pent-1'-trans-eny~-3-endo hydroxy-bicycl~
_ ~. 3. 0 jnonane-8-one 2-exo[3'R-hydroxy-5-cyclohexyl-pent-1' trans-eny~-3-endo hydroxy-bicyclo E~. 3. ~nonane-8-one.
15 Example 53 Under a N2 atmosphere, a suspension of NaH (80% dispersion in mineral oil, 2. 1 g) in dly DMSO (70 ml) is stirred for 4 hours at 65. After cooling at 25-30~, dry ~-carboxy-butyl-triphenyl phosphonium bromide (13 gj is added to itg obtaining a deep red solution of the ylide.
20 After addition of a solution of Z-exo[21bromo-3'S-hydroxy-oct-l'-trans-erly~-3-endo hydroxy-bicyclo~4. 3. ~nonane-8-one (1. 79 g) in dry DMSO (6 ml), the reaction mixtureis stirred for 1 hour at 28 and then for 4 hours at 40;
afterwards it is cooled at r.t., diluted with water (80 ml), acidified up to pH 4. 5 by adding 4N H2SO4 and extracted with ethyl ether (4x50 ml, 2x~5).
25 The aqueous layer is discarded, the organic phases are combined washed with water (this washing is discarded), then with N NaOH (5x10 ml) and water until neutral. The combined alkaline extracts are acidified up to pH 5 and extracted with ethyl ether to give 5(z,E~-lla~ 15S-dihydroxy-9a-deoxy-9a,9b-dimethylene-prostacycla-5-en- 13-ynoic acid (a mixture of 5 c-and 5 t-isomers).

--a l q~ .
~, 98~2~

Tlle individual geometric isomcrs are obtained after chrornatographic separation on acidic SiO2 (40 g/each g of acid) using cyclohexane-ethyl acetate as eluents.
Example 54 5 Under a N2 atmosphere, to a stirred solution of potassium-ter-butoxide ~3. 36 g)9 freshly sublimated, in dry DMSO ~36 ml) it is added 6. 5 g of ~-carboxy-butyl-triphenyl-phosphonium bromide to give a deep red solution of the ylide. After addition of a solution of 2-exor3'R-hydroxy-4'-phenoxy-but~ trans-eny~13-endo hydroxy-bicyclo[4. 3. ~3nonane-7-one (0. 8 g) .n dry DMSO (3 ml3, the reaction mixture is stirred for 5 hours at 42, cooled diluted with water ~50 ml) acidified up to pH 5 and extracted ~.vith ethyl ether(4x10 rnl). The aaueous ?hase is discarded the combined ethereal e~ctracts are washed with water (10 ml, ~his washing is discar~ed), and with 0. 5 N
NaOH ~4x6 ml) and water until neutral. The combined alkaline extracts are 15 acidified up to pH 5 and extracted with ethyl ether. The organic phases are combined dried and evaporated to dryness to give:
5(~;,E), 13t-lla, loR-dihydroxy-9a-deoxy-7a homo-9a-rnethylene-16-phenoxy-li, 18, 19,20-tetranor-prost-1cycla-5, 13-dienoic acid (a mlxture of 5 c and 5 t-geometrical isomers)~
20 The individual geomctric isomers are obtained after chromatographic separation on acidic SiO2 (40 g/each g of acid) using cyclohexane-etkyl acetate as eluents.
~ple 55 , Using the keto alcohols of the example 52 in the procedure of the examples 25 53, 54 we have prepared the following prostacyclanoic acids:
- 5c- 11 a, 1 5S-dihydroxy- 9a-deoxy-9a, ~b-dimethylene-pros tacycla-5 -en- 1~ -ynoic acid 5c, 13t-lla~ 15S-dihydroxy-9a-deoxy-7a homo-9a-methylene-16-pheno~y-17, 18, 19, 20-tetrarlor-prostacJrcl~-5, 13_dienoic acid , .
:, 9~ ~9~42~ !

t~ .

5c, 13t-lla, 15S-dihydroxy-9a-deoxy-9a,91)-d;methylene-17-cyclohexyL-18, 19, 20 ~trinor-prostacycla-5, 13-dienoic acid .

5c, 13t-lla, 15S-dihydroxy-9a-deoxy-7a homo-9a-methylene-17-cyclohe~yl-18-19,20-trinor-prostacycla-5~ 13-dienoic acid - 5 5t- 1 la, 15S-dihydroxy-9a-deoxy-9a, 9b-dirnethylene--prostacycla-5-en- 13-ynoic acid 5t, 13t-lla, 15S-dihydroxy-9a-deoxy-7a homo-9a-methylene-l6-phenoxy-17, 18, 19, 20-tetranor-prostacycla-5, 13-dienoic acid 5t, 13t- 1 la, 15S-dihydroxy-9a-deoxy-9a, 9b-dimethylene- 17-cyclohexyl- 18, 193 ? 0-trinor-prostacycla-5, 13-dienoic acid 5t, 13t-llc~, 15S-dihydroxy-9a-deo~r-7a homo-9a-methylene-l7-cyclohe~
18, 1 ~, 2 0-trinor-prostacycla-5, 13-dienoic acid.
Example 56 46 Using the procedure of the example~, 30 g of 2-acetoxyperhydro azulen-6-one, r ~, also named as 3-endo-hydroxy-bicyclo~ . C¦decane-8-one acetate (obtained in accordance with D. K. Banerjee et al. Indian J. Chem. 10, 1~ 1972) is transformed into its ethylendioxide (29. 1 g). Then the compound is saponified by treatment with 2% K2CO3 in aqueous methanol to give 3-endo-hydroxy-bicyclo[5. 3. ~decane-8-one-8, 8-ethylenedioxide and oxidized using ;~0 the procedure of the exa~mple and treated with dimethylcarbonate (see theprocedure of example ,Z~ to obtain dl-bicycloL5. 3. ~decane-3,8-dione-Z- ' carboxymethylester-8J 8~ethylene dioxide, 21.2 g, max 254 nm; = 7. 000.
Example 5 7 The bicyclo-~-keto ester-ethylene dioxides obtained in the examples 47, 48 and 56 are reduced with the following procedure:
NaBH,L (0. 9 g~ is added portionwise to a stirred solution of the bicyclo-~ - i keto ester-ethylene dioxides (2.5. 10 m) i-n 1 1 methylene chloride-ethanol ~150 ml), cooled at -20 . After additional stirring for 30 minutes at -'0~, tho - Il `- !
,. .

q~

~L~9~

residual hydride is destroyed by adding acetone (12 ml). The reaction mixture is ~varmed at room temperature treated with aqueous 20% KH2P~ and a'ter removal of solvents, and dilution with water (20 ml) it is extracted with . methylene chloride. The organic phases are combined, washed until neutral 5 with water, dried and evaporated to dryness. The residue is equilibrated by ~:reatlnent with absolute methanol (20 ml) and sodium mcthoxide (0. 54 g), for 12 ho~lrs at r. t.; acetic acid (0. 59 g) aJdition followed by evaporation of solvents and extraction with methylene chloride gives about Q. 22. 10 m of the following bicyclo-~-hydroxy ester-ethylenedioxides:
_ QXO
10 dl- 3 endo hydroxy-bicyclo~3 . 2 . O~heptane - 6- one -2 -~carboxymethyle s ter - 6, 6-ethylene dioxide r - exo dl-3-endo hydroxy-bicyclo~. 2. 0 heptane-6-cne-4~\carboxymethylester-6, 6-ethylene dioxide, also named as: dl-3-endo hydroxy-bicyclo[3. 2. ~heptane exo 7-one -2~ar~oxymethylester- 7, 7-ethylene dioxide exo 15 dl-3~endo hydloxy-bicyclo 4. 3. OJnonane-7-one-2~\~carboxymethylester-7, 7-ethyl~:ne dioxide dl-3 endo hydroxy~bicyclol~4. 3. ~3nonane-8-one-2~carboxymethylester-8, 8-ei-hylene dioxicle dl-3-endo hydroxy-bicyclo[5. 3. ~decane-8-one-~carboxymethylester-8, 8;
20 ethylene dioxide.
In the following, a solution of 2. 10 m of each of these compounds in dry methylene chloride, 25 ml, is reacted with 2; 3-dihydro pyran (2 g) and toluensulphonic acid ~38 mg, 2. 10 m~ for 2 hours at rOt. The reaction is stopped by adding pyridine (0. 1 ml) and the mixture is evaporated to dryness 25 in ~racuurn affording the corresponding 3-THP--ethers which are used without any further purification.
Exarnple 58 The 3-endo-hydroxy-2-exo-carboxymethylesters and their 3-THP-ethers, obtained with the procedure of the example 57 are reduced to give the corresponding Z e~ h~dro~methy~ deriv-tives with following procedure:

~' q~l ~,,.

`
~L~9~

a solution o~ 2. 10 m of the ~-ketoes'cer (both alcohol and 3-THP ether) in dry ethylether (25 ml) is added dropwise to a stirred suspension of Li~lH,L
(0. 4) in dry ethylether (50 ml). After additional stirring for 30 minutes the residual hydride is destroyed by adding acetone (5 ml) and ethylether 5 saturated witll water. Dry MgSO4~1Z gJiS added to, then the organic phase is filtered and evaporated to dryness.
We obtain thf~ following 3~endohydroxy-2-exo hydroxymethyl:
bicyclo[3. 2. O¦heptane-6-one-6, 6-ethylenedioxide bicyclo~3. 2. (~heptane-7-one- 7, 7-ethylenedioxide bicyclo[4. 3. O~nonane-7-one-7, 7-ethylenedioxide bicyclo ~. 3. ~1nonane-8-one-8, 8-ethylenedioxide bicyclorS. 3. O]decane-8-one-8, 8-ethylenedioxide and their 3-endo-hydroxy~THP-ethers both racemic and optical active form (nat, ent) when optical active material, coming from optical resolutio .
15 successively described, is used in the reducti~e process.
Exa~ple 5 9 Frce ketone is obtained by treatment of a solution of 3-endo hydroxy-2-exo--hydroxymethyl-bicyclo[5. 3. O~decane-~one-~, 8-ethylenedioxide ~5g, 2. 10 m) in methanol (20 ml) and water (2 ml) with p-toluensulphonic acid (0. 3 g) for 2 hours at reflux temperature. The solvents are evaporat^cl in vacuur~ and the resiclue is filtered through a short column of SiO2. - `
Working ir accordance wlth the procedure of the example 54, a solution of the so obtained 3-endo-hydroxy-2-exo-hydroxyrnethyl-bicyclo[5. 3. 0~8-one (~. 7 g) in dry DMSO ~17 ml) is reacted with the ylide formed frorn potassiwn ter-butoxide ~27 g), DMSO (280 ml)and 3 carboxy~ propyl phosphoniumbrornide for 5 hours at 40. The reac~ion mixture is diluted with water (300 ml) and extracted with 80:20 ethylether-benzene to rèmove triphenylphosphoxide. These extracts are discarded and alkaline phases are acidified up to pH 5 and repeatedly extracted with ethylether (8x200) and with 3:1 ethylether ethylacetate (5xlO0). The combined organic extracts are dried, concentrated to a small - q -volurne ~100 ml) trc~ted with ethcreal diazomelhane to achicve llle metllyl ester and then evaporated to dryness.
The crude material is chromatographed on SiO;~ (100 g) (ethylace.ate as eluent) to give 5 (Z, E)~ (20~ I2) octanor- l2~ ~hydroxylnctllyl- l la-hytlr 9a-deoxy- 7a-homo-9a,9b-dimethylene-2-nor-prostacycla-5-enoic aci~
methylester (4. 1 g).
By treating this compound in dry DMF (12 ml) ~ith dimethyl-ter-butyl-silyl-chloride (2.2 g) and imidazole (1.55 g) at 15 for 24 hours, follo~ved fro~n dilution with water (24 ml) and extraction with ethylether and chrornatographic purification on SiO2 (25 g, cyclohexane-ethylether as èluent) we obtain its mono 12~-DMB-silyloxy methyl-ether (4. 31 g 80%).
Treatment with pyridine (10 ml), acetic anhydride (5 ml) at~. t. for 12 hours and hydrolysis with aqueous methanol ancl p-toluensulphonic acid afford 5(Z, E) - ~)-(20~ 12) octanor- 12~ -hydroxymethyl- 1 la -hydroxy-9~ -deoxy-7a-homo-9a,9b-dimethyl~ne-?-nor-prostacycla-5-en-oiC acid methylester 11-acetate. Preparative chromatography (usi;lg a HPLC-irlstrument and moni~orina ~vith refractive indeY) on SiO2 tr-aied with 3% AgNO3 (with methylen~chloride~
ethylacetate as eluent) affords the individual geo~netric 5 c and 5t isomers.
In simiL~r way, 5(Z,E)-W-(20--R 12)octanor-12~-hydroxy.-nethyl~
hydroxy-9a-deoxy- 7a-homo-9a-methylene-prostacycla-5-e11oic acid methyl ester-ll-acetate and their 5c and 5t -ndividual geomel:ric ison~ers are prepared when 3-endo -hydros y-bicycloL4. 3. O~nonane-7-one-2 -exo-carboxymethylester-7, 7-ethylenedioxide is used in side of the corresponding per-hydroazulene compound and the 4-carboxybutylphosphonium brornide is utilized in side of the 3-carboxypropyl-one.
Example 60 Starting from the 2-exo-hydroxymethyl-THP-eth~r compounds of the e:;ample 58 and from 12~3-hydroxymethyl-11-acetate of the example 59, ~ve have obtained the corresponding a1d~hydes by the fo11owin, oxiil~tive procedure:

_ 99 _ 3~
Successively, dicyclohexylcarbodiimide (0.64 y), pyridine (0.1 ml) -trifluoroacetic acid (OOQ5 ml) are added to a stirred solution of the hydroxymethyl compound (2.10 3m) in 75:25 benzene-DMSO (6 ml). After 4.5 hours, the reaction mixture is diluted with benzene (20 ml) and wa-ter (10 ml) and stirred for 30 minutes again. Dicyclohexylurea is fil-tered off and the organic layer is washed with water until neutral and then concentrated up to 10 ml affording a solution in dry benzene of the following aldehydes:
3-endo-THP-oxy-2-exo-formyl-bicyclor3.2.0~heptane 6-one-6,6-ethylene dioxide 3-endo-THP-oxy-2-exo-formyl-bicyclo~3.2.0}heptane-7-one-7,7-ethylene dioxide 3-endo-THP-oxy-2-exo-formyl-bicyclo ~4 . 3.0~nonane-7-one-7,7-ethylene dioxide 3-endo-THP-oxy-2-exo-formyl-bicyclo L4 . 3.0~nonane-8-one-8,3-ethylene dioxide 3-endo-THP-oxy-2-exo-formyl-bicyclo~5.3.0~decane-8-one-8,8-ethylene dioxide ~(20-~12)octanor-12~-formyl-11~-hydroxy-7-homo-9a,9b-dimethyl-ene-2-nor-prostacycla-5-enoic acid methylester-ll-acetate (5(Z,~);5c;5t).
~20-~12)octanor 12~-formyl~ -hydroxy -9a-deoxy-7a-homo-9a-methylene-prostacycla-5-enoic acid methylester-ll-acetate (5(Z,E);5c;5t) These compounds are used in the following Wittig-Horner reactions with any further purification.
xample 61 _ A solution of (2-oxo-heptyl)dimethylphosphonate (0.49 g) in ben~ene (6 ml) is added dropwise to a stirred suspension of NaH (80% dispersion in mineral oil, 66 mg, 2.2.10 3m) in ~, `t~

benzene (15 ml). After an additional s-tirring for ~5' we add a solution of 2.10 3m of 5 t-~(20-~12)oc-tanor-12~-formyl-ll~-hydrox~-9a-deox~-7a-homo-9a,9b-dimethylene-2-nor-prost-acycla 5-enoic acid methylester~ acetate in benzene ~10 ml) to it. After an additional hour the reaction is stopped by adding a solution o-f acetic acid (132 mg) in benzene (5 ml);
the organic phase is washed with water until neutral, dried and evaporated to dryness.
The residue, 1.2 g, is absorbed on SiO2 (10 g~, following elution with cyclohexane-ethylacetate gi~es 5t,13t-ll~-hydroxy-15-oxo-9a-deoxy-7a-homo-9a,9b-dimethylene-2-nor-prostacycla-5,13-dienoic acid methyl ester-ll-acetate (0.76 g), ~max 228 m~l F=9.800.
The following ~,~-unsaturated ke~ones are obtained when ~he other aldehydes of the example 60 are used in the above procedure:
5c,~3t~1~-hydroxy-15-oxo-9a-deoxy-7a-homo-9a,9b-dimethylene-2-nor prostacycla-5,13-dienoic acid-methylester-ll-acetate ~max 228 m~, ~=9.900 and the mixture of their 5(Z,E) isomers 5t,13t-11~-hydroxy-15-oxo-9a-deoxy-7a-homo-9a-methylene-prostacycla-5,13-dienoic acid methylester-ll-acetate ~max 229 m~, ~=10.000) and its 5t and 5(Z,E)-isomers and the following 2-exo C3'-oxo-oct-1'-trans-enyl] 3-endo-hydroxy-THP-ethers:
bicyclo~3.2.~ heptane-6-one-6,6-ethylenediox:ide bicyclo~3.2.0]heptane-7-one-7,7-ethylenedioxide bicyclo ~4.3.0~ nonane-7-one-7,7-ethylenedioxide bicyclo ~4.3.~ nonane-8-one-8,8-ethylenedioxide bicylco~5.3.0~decane-8-one-8,8~ethylenedioxide Example 62 Using in the procedure of the example 61l different dimethyl-.~, .~.~.i - lOOa -phosphona-tes we have prepared the following ~,~-unsaturated ketones:
a) by reaction of 3-endo-THP-oxy-2-exo-formyl-bicyclo[3.2.
heptane-7-one-7,7-ethylenedioxide (2.10 3m) wi-th (2-oxo-3(S,R)-fluoro-heptyl)dimethyl phosphonate (0.54 g) we obtain 3-endo-THP-oxy-2-exo L3'-oxo-4'(R,S)fluoro-IDi ~L913~2 oct~ trans-eny~bicyclo~3. 2. ~heptane-7-one-7, 7-ethylenedioxide (0. 72 g) max 229 nm~ = 9. 900, ~a~D= ~98 (CHC13) b) by reaction of the heptane-6-one-6, 6~ethylenedioxide aldehyde (2. 10 m) with t2-oxo-octyl)dimethylphosphonate we obtain 3-endo-lHP-oY.y-2-exo[31-oxo-non-1~-trans-eny~bicyclo[3. 2. ~heptane-6-one-6, 6-ethylenedioxide ~max 228 nln = 9.300 - c) by reacti--n with the heptane-7-one-7, 7-ethylenedioxidealdehyde with ~2-oxo-4-phenyl-butyl)dimethylphosphonate (O. 565 g) we obtain 3-endo-THP~
oxy-2-exo-¦3~-oxo-5 7-phenyl-pent- i'-trans-eny~bicyclor3. 2. ~heptane-7-one-7, 7-ethylenedioxide d) by reaction with the nonane~7-one-7, 7-ethylenedioxide with 0. 52 g o~i (2~oxo-3S-n~.ethylheptyl)and with (2~oxo-3R-methyl-heptyl)dimethyl phosphonate we obtain respectiv~ly:
3-endo-THP-oxy-2-exo~3'-oxo-4~S~methyl~oct-l'~trans-eny~bicyclo~4. 3.
nonane -7-one - 7, 7-ethylenedioxide and 3-endo-THP-oxy~2~exo[3~-oxo-41R-methyl-oct- 17 trans-eny~bi~yclQ¦4. 3.
nonane - 7 - one - 7, 7 - ethylenedioxide .
Exarnl?le 63 .
Pyricline hydrobromideperbromide (C5H5N HBr. Br2), 0. 8 g, is added to a 20 stirred solution of 3-endo-THP-oxy-2-exol3'-oxo-4'~R,S)-fluoro-cct-l~-trans-enyi~bicyclo[3. 2~ l~hep1-ane-7-one-7, 7-ethylenedioxide in dry pyridine (15 n~
After additional stirring for 4 hours at r. t., the precipitate is filtered of ancl the organic eluate is partitioned among ice, 2N H;~SO4 and ethyiacetate.
The organic layer is washed with cooled G.5NH2SO4, brine, 1% sodium 25 carbonate, wa~er until neutral affording 0. 71 g of 2tbromo-47(R, S)-1uoro compound, which is a mixture of 2 diasteroisomeric 47S and 4'R derivatives.
HPLC-chromatography o~ SiO2 with CH2C12-ethylether (85:15~ affords the indivldual isomers:

j 9l342 0.22 g of 3-enclo-TIIP-oxy-2-e~:ol2'bromo-3'-oxo-4'R-fluclro-oct--l'-trans-eny~bicyclo[3. 2. ~heptane-7-one-7, 7-ethylcnedioxide max 250 nm = 9.&30 and 0. 19 g of the 4'S-fluro isonler )~ max 251 nm - 9. 750 Using in the above procedure di~ferent a, -unsaturated ketolles/~ve obtain 5 the follo~rings:
3-endo-THP-oxy-2-exo¦2'bromo-3' oxo-non-11-trans-eny~bicyclol3. 2.
heptane-6-one-6, 6-ethylenedioxide and 3-endo-THP oxy-2-exo[2'bromo-3'-oxo oct-1'-trans-eny~bicyclo[4. 3.
nonane-7-one-7, 7-ethylenedioxide.
10 Example 64 An ethereal solution of 5~o methylmagnesium iodide (5 ml) is added to a stirred solution of 5t, 13t- 11 a -hydro~y- 15-oxo-9a~deoxy-7a-homo-9~-methylene-prostacycla-5, 13-dienoic acid methylester (0. 4 g) in 2 1 ethyl ether-toluene (12 ml), cooled at -30. After stirring for aclditional 4 hours, 15 the reaction m;xture is warmed to 0 and the residual reagent is destroyed by ad~..ng o~ 20~o aqueous NH LCl. The organic layer is separated9 washed with water, dried arld after addition of pyridine tO. 1 ml) is evaporated to dryness. The residue dissolved in dry methanol (10 ml) is stirred with anhydrousK2CO3 (0. 1 ~) for 2 hour3. The solution is filtered, e~aporated in vacuum 20 and the resulting crude material is partitioned bet~een ethyl acetate 20q~
NaH2PV4. The organic layer after the usual ~vork~up is concentrated to small olunle; the residue i9 al~sorl~ed on SiO2 (20 g). Elution ~vith ~0:~0 ethylethcr:
isopropylether gives 5t, 13t-lla, 15S dihydroxy-15 mcthyl-9a deo_7a-homo-9a-n~ethylene-prostacycla-59 13-dienoic acid methylcster (0. 1 g) and its 25 15R-isomer ~0. 085 g).
Wilh this procedure it is also obtained:
5t7 l3t-lla~ 15S dihydroxy-15-methyl-9a-deoxy-7a-homo-9a,9b-dimethylene-2-nor-prostacycla-5, 13-dicnoic acid-methylester and its 15R-epimer.

The free acids are obtained hea-ting at -the reflux-temperature a solution of methylesters in 80:20 methanol~water in the presence of 2% K2CO3. The solvent is evapora-ted in vacuu~l and the residue is partitioned between ethyle-ther and water.
The organic layers are reextracted with 0.5% K2CO3 and discarded. The combined alkaline phases are acidi~ied up to pH 6 and e~tracted with ethylether. Combined organic phases are washed, dried on MgSO4 and evaporated to dryness to give free acids.
Example 65 Using in the procedure of the example 64 ethynyl magnesium bromide, vinyl magnesium bromide and ethyl magnesium bromide in side of the methyl magnesium iodide, the corresponding 15-ethynyl, 15-vinyl and 15-ethyl prostacycladienoic acids are obtained.
Example 66 Starting from the ~,~-unsaturated ketones of the examples 61, 62, 63, secondary allylic alcohols are obtained using -the following procedure:
a solution of -unsaturated ketone (2.10 3m) in dry ethyl-ether (20 ml) is added to a stirred solution of 0.25 M zinc borohydride(48 ml) in dry ethylether, dropwise in a period of 30 minutes. ~fter an additional stirring for 2 hours, the residual hydride is destroyed by adding saturated NaCl.
The organic layer is separated, washed until neutral, dried on Na2SO4 and evaporated to dryness. Preparative HPLC-chromatography on SiO2, using as eluent me-thylene chloride/
ethylacetate, afforcls:
5c,13t~ ,15S-dihydroxy-9a-deoxy-7a-homo-9a,9~-dimethylene-2-nor-prostacycla-5,13-dienoic acid methylester-ll-acetate and its 5(Z,E~ and 5t geometric isomers.

-- 10~ --5t,13-11~,15S-dihydroxy-9a-deoxy-7a-homo-9a-methylene-prostacysla-5,13-dienoic acid methylester-ll-acetate and its 5(Z,E) and 5c-geometric isomers.
The following 2-exo L3'S-hydroxy-oct-l'trans-enyl~3-endo-r~HP-o~y :
bicyclo ~3.2.0~heptane-6-one-6,6-ethylenedioxide bicyclo~3.2.0~heptane-7-one-7,7-ethylenedioxide bicyclo L4 . 3.0~nonane-7-one-7,7-ethylenedioxide bicyclo ~.3.0~nonane-3-one-8,8-ethylenedioxide 10 and the ~ollowing 3-endo-THP-oxy:
2-exo~2'~romo-3'S-hydroxy-4`R-fluoro-oct-l`-trans-eny~¦
bicyclo ~3 . 2.0~ heptane-7-one-7,7-ethylenedioxide 2-exo ~2'bromo-3'S-hydroxy-4'S-fluoro-oct-l'-trans-enyl~
bicyclo L3 . 2.0~heptane-7-one-7/7-ethylenedioxide 2-exo C2'bromo-3'S-hydroxy-non-l'-trans-eny~ bicyclo c3 . 2.
heptane-6-one-6,6-ethylenedioxide 2~exo ~'S-hydroxy-non-l'-trans-eny~ bicyclo ~3.2.0~ heptane-

6-one-6,6-ethylenedioxide 2-e~o ~'S-hydroxy-5'-phenyl-pent-1'-trans-eny~ bicyclo ~3.2.0¦
20 heptane-7-one-7,7-ethylenedioxide 2-exo ~2'bromo- 3 S-hydroxy-oct-l'-trans-eny bicyclo ~.3.
nonane-7-one-7,7-ethylenedioxide 2-exo ~3'S-hydroxy-4'S-methyl-oct-1'-trans-eny~ bicyclo ~4.3.
nonane-7-one-7,7-ethylenedioxide 2-exo ~3'S-hydroxy 4'R-methyl-oct-1'-trans-enyl~bicyclo~4.3.0 nonane-7-one-7,7-ethylenedioxide 5c,13t-11~,15R-dihydroxy-9a-deoxy-7a-homo-9a,9b-dimethylene-2-nor-prostacycla-5,13-dienoic acid methylester-ll-acetate and its 5(Z~) and 5t geometric isomers.
30 5t,13-11~l15R-dihydroxy-9a-deoxy-7a-homo-9a-methylene-- aye -prostacycla-5,13-dienoic acid methylester-ll-acetate and its SUE) and 5c-geome-tric isomers.
The following 2-exo ~3'R-hydroxy-oct-l'-trans-enyl¦3-endo-THP-o~y:

j ~9~34~(~

,. ... . . ........ . . . . . . . . . . . .. . .. . . . . .. .
bicyclorL3. 2. ~heptane-6-one-6, 6-ethylenedioxide bicyclo 13- 2 . ~heptane - 7-one -7, i- ethylenedioxide bicyclo 3. ~nonane~7-one--7, 7-ethylenedioxide bicyclo 3. O~nonane-8-one~8, 8-ethylenedioxide and the ~ollowing 3-endo- THP-oxy: -2-exo¦ 2~bromo-3~R-hydroxy-a~R~fluoro-oct- l~-trans-eny~lbicyclo[3 2. ~3 heptane -7 one - 7, 7 -ethylenedioxide 2-exo~21bromo-3~R-hydroxy-~S-fluoro-oct~ trans-eny~bicyclo[3. 2.
heptane-r7-one-7, 7-ethyienedioxide Z - exo¦ 2 bro~no- 3 ~R-hydroxy-non- 1~ - tr ans - eny~3bicyclo l3 . 2 . heptane - 6-one-6~ 6-ethylenedioYide 2-exo[3sR-hydroxy-non-li-trans-eny~bicyclo~.2. O~heptane-6-one-~, 6-' ethyleneclioxide 2-exo[3'R-hydroxy-57-phenyl-pent-l~-trans-eny~bicyclor3. 2. ~heptane- I-one-15 7, 7-ethylenedioxide 2-exo¦2~bromo 3~R~hydroxy-oct-l~-trans~eny~bicyclo~. 3. (;~nonane-7-one-

7, 7-e1:hylenedioxide 2..exo!, 3~R-hydro~y-~LtS-m~thyl-oct- i ~trans-ony~ bicyc7O~L4. ~. ~nonane-7-one-7, 7-ethylenedioxide Z0 2-exo[3~R-hydroxy-4sR-methyl-oct-l~-trans enyl~bicycloC4. 3. ~nonane--7-one-7, 7--ethylenedioxide ., . . . . . .
Example 67 .
The individual ll-acetate prostacycladienoic acid methylesters are converted both in their 1 l-hydroxy methylesters by trans esterification in dry methanol 25 with anhydrous K2CO3 (0. 5 mol equiv) and in their ll-hydroxy Iree acid by treatment ~ith K2CO3 in 80% aqueous methanol.
Example 6g Every one of the bicyclo~THP-oxy-ethylenedioxides obtained in the proccdure lo~

2C) of the example 66 is converted in,~he corresponding prostacyclenoic acidS
working up with the following procedure:
a solut-ion of 1. 10 m.of the bicyclo-THP-oxy-ethylenedioxide in acetone (15 ml)i5 refluxed with N aqueous oxalic acid (10 ml) for 8 hours. The acetone is 5 evaporated in vacuum and the aqueous phase is extracted with ethylether. The combined extract~after the usual work-up,are evaporated to dryness affording about 0 6- 1. 10 m.of the hydro~y ketone. A solution of this compo~lnd in dry DMSO (2 ml) is added to a solution of the ylide obtained so on: in a N2 atmosphere potassium-tert butoxide ( 1. 35 g) is added to dry DMSO ( 15 ml), 10 then to it we added 4-carboxy-butyl-triphenyl-phosphoniumbromide (2. 6g) to obtain a deep-red solution of the ylicle. Afl:er addition of the ketone, the reaction mixture is warmed at 40-42 for 6 hours, cooled, diluted ~.vith water (20 ml), acidified up to pH 5. 1 and extracted with ethylether (5x25 ml).
The aqueous phase is discarded, and the organic extracts are collected, 15 washed wit~ vater ~5 rnl; this washing is descarded) and extracted with 0. 5 N
NaOH (6x6 ml) and ater until neulral. The sombined alkaline extracts are combined, acidified to pH 5 and extracted svith ethylether. Tl~e coInbined organic e:,~tracts a.re ~ashed ~vith water (2 inl), dried on Na~S04, arld e~aporatcd to dryness giving a mixture of the 5 Z and 5 E acids.
The individual geolnetric isomers are obtained after chromatographic separation on acidic SiO2 (Fe " Fe free) using C1~2C12-ethylacetate as eluent (SiO2 30 g for each of û. 2 g of the acid).
In this way w-e have prepared .~ 5t, 13t-lla, 15s-dihydroxy-9a-deoxy-9a-nor-methylene~prostacycla-5~ 13-25 dienoic acid 5t, 13t~11CI, 155-dihydroxy-9a-deoxy-9a-nor mcthylene-20-methyl-prostacycla-5, 13-dienoic acid 5t-11 a, 15S-dihydroxy-9a-deoxy-9a-nor-methylene-20-metllyl-prost:acycla-5-en-13-ynoic acid 2~) 5t~l3t-lla~l5s-dihydroxy-9a-deoxy-9a-lncthylcne-7-nor~ ethylen prostacycla-5,13-~ienoic acid 5t,13t-11~,15S-dih$rdroxy-9a-deox~r- 7a-homo-9a-methylene-prostacycla-5,13-dienoic acid 5t~l3t-lla~l5s-dihydloxy-9a-deoxy-9a~9h-dim ethylene-prostacycla-5,13-- dienoic acid 5t-lla~l5s-dihydroxy-9a-dcoxy-9a- methvlene-7 -nor-met~ylene-16S-flucro-prostacycla-5-en-13-ynoic acid 5t-1 la, 15S-dihydroxy-9a-deoxy-9a- methylene-7-nor-methylene-16R-fluoro-prostacycla-5-en-13-ynoic acid 5t,13t-lla,15S-dihydroxy-9a-deoxy-~à- methylene-7-nor-methvlene-17-phenyl-18,19,20-trinor-prostacycla-5,13-dienoic acid 5t,13t-lla~15S-dihydroxy-9a-deox~y-7a-homo-9a-me hylene-16S-me~hyl-prostacycla-5113-dienoic acid 5t~l3t-lla~l55-dihydro~yy-9a-deoxy-7a-homo-9a-methylene-l6~-meth prostacycla--5~13:dienoic acid 5t~ ,15S-dillydroxy-9a-deoxy~ 7a-homo-9a-methylene-~rostacycla-5-en-13-ynoic acid 5c,13t-lla,15S-dillydroxy-9a~deoxy-9a-nor-1nethylene-prostacycla-5,13-dienoic acid 5c,~3t-lla,15S-dihydroxy-9a-deoxy-9a-nor- met'nylene-20- methyl-prostacycla-5,13-dienoic acid 5c-11~,15S-dihydroxy-9a-deoxy~9a-nor- m ethylene-20- m eth~ prostacycla-5-en-13-ynoic acid 5c~l3t-lla~l5s-dihydroxy-9a-deoxy-9a- m ethylcnc-7-nor-methylene-prostacycla 5,13-dienoic acid 5c,13t-lla,15S-dihydroxy-9a~deoxy-7a-homo-9a-methylene-prostacycla-5~13-dicnoic acid .

~'1 ,~

~L~L91~4;~

- 5c, 13t-lla, 15s-dihyclro}:y-9a-deoxy-9a~9b-dimctllylenc-prostacycla-5~ 13-dienoic acid 5c 1 la, 15s-dillydroxy-9a-declxy-9a-metllylcne-7-nor-methylene-lss-fluor prostacycla-5-en- 13-ynoic acid 5c- l la, 15S-dihydroxy-9a~deoxy-9a-methylene-7-nor-methylene-16R-rluoro-prostacycla-5-en- 13-ynoic acid 5c, I3t-lla, 15S-dihydroxy-9a deoxy-9a-nletllylcne-7-nor-metllylene-17 phenyl-18, 19,20-trinor-prostacycla-5, 13-dienoic acid 5c, 13t-lla, 15S-dihydroYy-9a deoxy-7a-ilomo-9a-methylene-l6s-~et]
prostacycla-5, 13-dienoic acid 5c, 13t-1 la, 15s-dihydroxy-9a-deoxy- 7a-homo-9a-methylene-l6R-meth prostacycla-5, l~-dienoic acid 5c- 11 a, 15s-dihydroxy-9a-deoxy- 7a-ho~l~o-9a-methylene-prostacycla-5-en 13 -yno ic ac id and the ir 15 R- is on~e r s .
Exam~?le 69 Successively dicyclohexylcarbodiimide (0. 32 g) pyridine (0. 044 ml) ~nd - tri1uoroacetic acid (0. 022 3nl) are added to a stirrcd solution of 5t, 13t-llct, 15S -dihydroxy-9 a- deoxy- 9a, 7a-homo - dirne thyl~ne- 15 -nlethyl- prostacycla- 5, 13 -dienoic acid methylester (0. 39 g) in 75:25 benzene-DMSO (6 ml). l~fter 5 hours the reaction mixture is diluted ~vith benzene (20 ml) and 1. 2 g of oxalic acid i31 ~vater (10 ml). The stirring is continued for 20 minutes, the mixture is filtered and the organic pnase is washed until neutral, dried and finally evaporated to dryness.
Chromatographic purification on SiO2 (4 g), ethyl ether as eluent, gives 0. 26 g Or 5 t, 13t- 11 -oxo- 15S -hydroxy- 9a-deoxy- 7a-homo-9a-meth~l ene- ].5-3nethyl-prostacycla-5, 13 dienoic acid methylester which is hyclrolysed witl 2% aqueous K2CO3 to give the.ree acid.
E~;ample 7 0 ___ Sodium borohydride (2. 5 g) in p~rtionwise is added to a stirred solution OI

, /~q ~S

:~.3L9~

bicyclor~. 3. (~nonane-7 en~3-one (11.42 g) in ethanol (80 rnl), After an additio1lal stirring for 2 hours~ acetic acid (5 ml) is added ancl tlle mixture is evaporated to dryness. The residue is partitioned between water ancl CH2C12, and the organic layer is evaporated to dryness. A solution of the the resulting bicyclo~. 3. ~1nonane-7-en-3-hydroxy (11 g~ in dry DMF is heated successively with dimethyl-tert-butyl-silyl-chloride (15. 6 g) and imidazole (10.85 g), warmed at 60 for 6 hours~ cooled and diluted with waier (66 ml). After exhaustive extraction with ethylether ancl usual work-up we obtain bicycloL4. 3. 0¦nonane~7-ene-3~hydroxy-3-DMB-silyl-ether ( 19. 1 g).
Its solution in dry THF (100 ml), cooled at 0C is treated (under stirring~
in N2 atrnosphele) with MB~I3 so'lution in THF (75 ml). Afte~ 2 hours, maintaining the temperature at 25, we add N NaO~ ~25 ml) and 30%
hydrogen peroxide (25 lnl). The mixture is heated at 6Q~ for 2 hours, cooled and diluted wi,h benzene (400 ml). The organic layer is washed with 1% Na2C03, saturated sodiurn sulphite~ saturated NaCl, dried and evaporated to dryness gi~ing cruc~ bicyclo~4. 3. ~nonane-7(8)~ -3-dillydro~y-3-DMB~silyletller (20. 3 g). A solution of the resulting alcohol in 75/25 benzene-DMSC) (150 ml) is treated successively with dicyclohexylcarbodiimide (16 g) pyridirle (2 ~nl~
trifluoro acetic acid (1 ml), under stirring. ~fter 5 hours, the mixturc is diluted with benzene (~00 rnl), water (50 ml) ~ith a solution of oxalic ac;d (6 g) in water (75 ml), and after additional stirring for 30 minutes is filtered.
The organic phase is washed with water until neutral afording bicyclo~. 3.
nonane-7(8) one-3-hydroxy~DM~-silylether (18. 25 G') which is dissolved in methanol (Go ml) and treated with 1. 8 g of p-toluensulphonic acid. After 12 hours, the rnixture is treated with pyridine (1. 95 ml) and evaporated to dryness.
The residue is filtered on SiO2 (ethylether-ethylacetate as eluent) to give bicy clo [4 . 3 . 0~nonane - 7 (8 ) - one - 3 ~hydroxy ( 10 g) .
solution of this compound in benzene (50 ml) is refluxed in the presence OI
dry ethylene glycol (5. 2 g) and ~-toluensulphonic acid (0. 62 g) withdrawing /

~8~2 the water forlned during the reaction.A~ter 14 hours we add pyridine (2 ml) and the organic phase is cooled, washed with water, 2% Na2C03 and saturated NaCl until neutral. I~:vaporation of solvcnts gives bicycloEL. 3. ~nonane-7(8) one 3-hydroxy- ~, 7(8, 8 ) -ethylenedioxide .
, 5 Example 71 Saponification with 2~to K CO in 80% aqueous methanol of the dlA3-endo-,_ 2 3 hydroxy-bicycloL4. 3. 0 nonane-8 -~one-8, -diethylenedioxide-2-exo-carboxy-methylester (4. 5 g) gives the free acid (4. 2 g).
To a solution of the free acid t4. 2 g) in acetonitrile (120 ml) it is added d(~10 ephedrine (2.3 ~); after 4 hours at r.t. 2.8 g of salt crystalizes giving after further crystali~ation from acetonitrile 2. 15 g of (t)bicyclo~4. 3 ~Jnonane-8-one-8, 8-ethylenedioxide-3~endo-hydroxy-2~exo carboxylic acid d(+)-ephedri-rlium salt. All the liquor waters are combined, evaporated to dryness; the residue is dissolved in water and treated with N NaOH up to alkaline pH (12-13).i5 d(+) Ephedrine is recovered by extraction with ether, then alkaline aqueous solution is acidified to pH 5 extrac~ed ~ith ethylacetate and organic layer combined are evaporated to dryness. The residue is diluted in acetonitrile and the p.ocedure is repeated using (-)ephedrine to give (-)bicyclo~4. 3. ~nonane-

8 -one-8~ 8 -ethylenedioxide- 3-endo-hydroxy-2-exo-~carboxyl;c acid 1(-)ephedri-.0 nium salt. Every one of th~ salts is separately dissolved in water/NaOH;the optica]ly active base is recovered by extraction with ethylether, the alkaline aqueous phase is acidified up to pH 5~5, 1 and extracted with ethyl-acetate, affording ~)bicyclo~4. 3. ~nonane-8 -one-8, 8-ethylenedioxide-3-endo-hydroxy-2-exo 25 carboxylic acid and (-)bicyclo~4. 3. ~nonane-8-one-8, 8-ethylenedioxide-3-endo-hydroxy-2-exo-carboxylic acid, which are converted into the methylester with diaz;omethane treatment .

`1?

,~
~9~3~Z~

Example 72 A solu-tiorl of 26 g oI dl-3-eI~clo-hydroxy~bicycloEL. 3. ~-2 exo~carboxy-methylester-7-one-7, 7-ethylenedioxide in acetone ~100 n-l) is reIluxed v~ith 2N H2SO4 (20 ml) for 4 hours.
5 Acetone is evaporated in VaCl,lUm and aqueous phase is extracted ~ith ethyl~
acetate. Combined organic extracts are washed until neutralS dried and evaporated to give 21.2 g of dl-3~-endoDhydroxy-bicyclolL4. 3. ~-2-exo-carboxymethylester 7-one. To a solution of ~-he ketone in dry acetonitrile ~250 ml) it is added d-l-phenyl-l-ethyl-amine (12. 1 g) and solvent is 10 slo~vly distilled of E recovering 50 ml in 30~ -minutes. The mixture is slo~vly cooled at r.t. and then 12. 12 g of (+) 3-endo-hydroxy-7j7-(1~-phcnyl-1~-ethylid~nin~inoj 2--exo-carboxymethylester-bicyclor4~ 3. O!are collccted after filtration. The liquor ~vaters are concentrated urther to give 6 g of racernic m ~erial. Finally, a further concentration up to 30 ml affords 11. 42 of (-) 3-enclv-1lydroxy 7, 7(1'-phenyl-1'-ethylidenimino)-2-eY~o~carboxy-methyleste~r-bicycl.r4. 3. ~3 Separately, the two Schiff bases are cleaved ~ith 80:20 metllallol 2N ~I2S04 ~200 rrll) at reIlux tempera-ture for 2 hours. Solvent is evaporated in vacuu~n ancl after extraction with ethyla_etate~ the cor~bined organic phases are 20 washe~ until neutral, dried and evaporated in vacuum to give:
8. 1 g of (+; 3~endo hydroxy-~icyclo~4. 3. ~12-exo-carboxy~nethylester-7-one a 7. 2 g o (-) 3~endo--hydroxy-bicyclo~4. 3. ~2-exo-carboxymethylester-7 one re s pe ctively.
Using this procedure, all the bicyclo~~ hydroxy-carboxylic ester-cthylene 25 dioxides Or the cxalnple 57 are submitted to optical resol~ltion to givc the f~llov~ing 3-endo~hydroxy alcohols:
~+) bicyclo~3. 2. ~heptane 6-one-2-exo-carboxymethylester (~) bicyclo[~. 2 (~heptane-7 one-2-exo-carhoxymethylester (~ bicycloEi. 3. ~)nonane-7-orle-2-exo-carboxymethylester (~) bicyclo ~.3.~ nonane-8-one-2-exo-carboxyme-thylester (-~) bicycloC5.300] decane-~-one-2-exo-carboxyme-thylester (-) bicyclo~3.2.0~ heptane-6-one-2-exo-carboxymethylester (-) bicyclo¦3.2.0~ heptane-7-one-2-exo-carboxymethylester (-) bicyclo C4.3.0~ nonane-7-one-2-exo-carboxymethylester (-) bicyclo~4.3.0~ nonane-8-one-2-exo-carboxymethylester (-) bicycloC5~3.~ decane-3-one-2-exo-carboxymethylester Using the procedure of the example 56; these ketones are converted into their ethylenedioxide derivatives.

~,

Claims (14)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for preparing compounds having the following formula I

I

wherein R is (a) a free or esterified carboxy group; (b) -C(OR')3, where each R' group is independently Cl-C6-alkyl or phenyl; (c) -CH2-R", where R"
is hydroxy or C2-C7-alkoxy; (d) , where Ra and Rb are chosen inde-pendently from the group hydrogen, Cl-C6-alkyl, C2-C6-alkanoyl and phenyl;
(e) -C?N; (f) radical; (g) -CHO; or (h) radical where each X' is independently -O- or -S- and the R'a and R'b groups, whether the same or different, are Cl-C6-alkyl or together form a straight or branched C2-C6-alkenylene chain; D is: (trans), -C?C-, ?C=O, -O-, -S-, or ?N-Rc, where Rc may be hydro-gen, Cl-C6-alkyl or C2-C6-alkanoyl; one of R1 and R2 and, independently, one of R3 and R4 is hydrogen, Cl-C6-alkyl, C2-C10-alkenyl, C2-C10-alkynyl, phenyl, or aryl-Cl-C6-alkyl and the other is hydrogen, hydroxy, Cl-C6-alkoxy or aryl-Cl-C6-alkoxy, or, R1 and R2 and, independently, R3 and R4 together form an oxo group; each R5 and R6, whether the same or different, may be hydrogen, Cl-C6-alkyl or halogen, or R5, R6 and the carbon atom to which they are bound form a ?C=CH2 or radical; Y is: -C?C-, (trans), (cis) where Z is halogen, (-NH-CO- or -NH-CH2-;) X is: -(CH2)m3-in which m3 is zero or 1, (cis), (trans), -O-, -S-or ?N-Rc where Rc is as defined above; m1, m2, n1 and n2, whether the same or different, may be zero or an integer between 0 and 12 such that each sum sum m1 + m2 and n1 + n2 is less than or equal to 15; p and q are independently zero or an integer between 1 and 3 such that the sum p + q is an integer of of 1 to 6; R7 is cycloaliphatic radical, either unsubstituted or substituted with one or more Cl-C6-alkyl, Cl-C6-alkoxy; or a saturated or unsaturated heterocyclic ring, either unsubstituted or substituted with one or more of the following: halogen, halo-Cl-C6-alkyl, Cl-C6-alkoxy, phenyl, Cl-C6-alkyl;
and the lactones derived from compounds of formula I and the pharmaceutically or veterinarily acceptable salts thereof, which process comprises alkylation of compound II

II

wherein p, q, Y, n1, n2, X, R5, R6 and R7 are as defined above; one of R'1 and R'2 and, independently, one of R'3 and R'4 is hydrogen, Cl-C6-alkyl, C2-C10-alkenyl, C2-C10-alkynyl, phenyl or aryl-Cl-C6-alkyl and the other is hydrogen, hydroxy, Cl-C6-alkoxy, aryl-Cl-C6-alkoxy or a protecting group bound to the bicyclic system or the side chain through an ether linkage, or R'1 and R'2 and, independently, R'3 and R'4 together form a protecting group for the ketone function, with a compound with formula III
III

wherein D, m1 and m2 are as defined above; E is a (C6H5)3P- or a (ReO)2P?(O)- group where each Rc may independently be Cl-C6-alkyl or phenyl;
R''' is (a") a carboxylic group, free, esterified or as its salt;
(b") -C(OR')3, where R' is as defined above; (c") -CH2-RIV, where RIV is C2-C7-acyloxy or a protecting group bound to -CH2- through an ether linkage;

(d") , where Ra and Rb are as defined above; (e") -C?N; (f") a radical; (g") radical where X', R'a and R'b are as defined above, followed if required by the removal of any protecting group present, or, if required, subjecting to nucleophilic addition the free carbonyl on the .omega. chain of a compound of formula I in which R3 and R4 together form an oxo group to afford, upon removal of any protecting groups, a compound of formula I in which one of R3 and R4 is hydroxy while the other is hydrogen, Cl-C6-alkyl, C2-C10-alkenyl, C2-C10-alkynyl, phenyl or aryl-Cl-C6-alkyl and, if required, preparing the ether derivative from a compound of formula I in which one of R3 and R4 is hydroxy while the other is hydro-gen, Cl-C6-alkyl, C2-C10-alkenyl, C2-C10-alkynyl, phenyl or aryl-Cl-C6-alkyl, and any other hydroxyl groups present are protected to give after removal of any protecting groups a compound of formula I in which one of R3 and R4 is Cl-C6-alkoxy or aryl-Cl-C6-alkoxy while the other is hydrogen, Cl-C6-alkyl, C2-C10-alkenyl, C2-C10-alkynyl, phenyl or aryl-Cl-C6-alkyl; or, if required, a compound with formula I in which Y is -CH=CZ- (trans), Z is halogen, one of R3 and R4 is hydrogen, Cl-C6-alkyl, C2-C10-alkenyl, C2-C10-alkynyl, phenyl or aryl-Cl-C6-alkyl while the other is hydroxy, Cl-C6-alkoxy or aryl-Cl-C6-alkoxy, or R3 and R4 together form an oxo group, and any hydroxy, oxo or carboxy groups present are free or in protected form, is dehydrohalogenated to give, after removal of any protecting group, a compound of formula I in which Y is -C?C-and one of R3 and R4 is hydrogen, Cl-C6-alkyl, C2-C10-alkenyl, C2-C10-alkynyl, phenyl or aryl-Cl-C6-alkyl while the other is hydroxy, Cl-C6-alkoxy or aryl-Cl-C6-alkoxy or R3 and R4 together form an oxo group, or, if required, converting a compound of formula I into another or to the lactone or pharmaceutically or veterinarily acceptable salt or, if required, con-verting a salt of a compound of formula I to the free compound or, if required, separating a mixture of isomeric compounds of formula I into individual isomers.
115.

2. A process according to claim 1 wherein R''' is a carboxyl group, m1 is zero, m2 is 2, D or D' is -CH2-, ?C=O or ?CHOH in the S- or R- con-figuration, p and q are both 1, R'1 is hydroxyl or protected hydroxyl, R'2 is hydrogen, Y is -C?C, one of R'3 and R'4 is hydroxyl or protected hydroxyl, n1 is zero, n2 is zero, 3 or 4, R5 is hydrogen or methyl, R6 is hydrogen, fluorine or methyl, X is -O- or -(CH2)m3- wherein m3 is 1 and R7 is cyclo-hexyl or 2'-tetrahydrofuryl.

3. A process according to claim 2 wherein D is ?CHOH and the process includes formation of a lactone of the obtained compound of formula I.

4. A process according to claim 1 wherein R''' is a carboxyl group, m1 is zero, D is -CH2-, m2 is 1 or 2, p is zero, 1 or 2, q is zero, 1 or 2, R'1 is hydroxyl or protected hydroxyl, R'2 is hydrogen, Y is -C?C-, R'3 is hydroxyl or protected hydroxyl, R'4 is hydrogen or methyl, R5 is hydrogen, methyl or fluorine, R6 is hydrogen, methyl or fluorine, n1 is zero, n2 is zero or 3, X is -O- or is -(CH2)m3- in which m3 is 1 and R7 is cyclohexyl.

5. A process according to claim 4 wherein n2 is zero and R7 is cyclo-hexyl.

6. A process according to claim 4 or 5 wherein R5 is hydrogen or methyl and R6 is hydrogen or methyl.

7. A process according to claim 4 or 5 wherein R5 is hydrogen or methyl and R6 is hydrogen or methyl, and m2 is 2.

8. A process according to claim 1 or 2 which includes the step of separating a mixture of compounds of formula I which are cis-trans isomers at the exocyclic double bond to obtain the individual cis- or trans-isomer.

9. A process according to claim 1 or 2 wherein a compound of formula II which is of cis or trans configuration at the exocyclic double bond is used to obtain a compound of formula I which is cis or trans, respectively.
116.

10. A compound of formula I as defined in claim 1 or a pharmaceutically or veterinarily acceptable salt thereof, when prepared by a process according to claim 1 or an obvious chem-ical equivalent thereof.

11. A process for preparing a compound having the general formula I
(I) wherein R1 represents a hydrogen atom or an alkyl group having 1 to 10 carbon atoms; one of R3 and R4 is hydrogen or methyl and the other is hydroxy; each of R5 and R6 whether the same or different may be hydrogen, methyl or fluorine; X is -(CH2)m- in which m is zero or 1, or -O-; n may be zero or an integer between 1 and 9 and R7 is a cycloalkyl group which is substi-tuted by one or more alkyl groups having 1 to 4 carbon atoms or a heterocyclic group or a pharmaceutically acceptable salt thereof, which comprises reacting a compound of the general formula II

(II) wherein n, X, R5, R6 and R7 are as defined above; R2 represents a free or functionally converted hydroxy group, one of R'3 and R'4 is hydrogen or methyl and the other is a free or function-ally converted hydroxy group, with a Wittig reagent of the formula III
(III) and when required subsequently in any order the isomers are separated, or protected hydroxy groups are liberated or a free carboxy group is esterified or an esterified carboxy group is hydrolysed or a carboxy group is converted into a salt.

12. A compound of formula I as defined in claim 11 or a pharmaceutically acceptable salt thereof, when prepared by a process according to claim 11 or an obvious chemical equivalent thereof.
118.

13. A process for preparing a compound having the general formula I

I

wherein R1 represents a hydrogen atom or an alkyl group having 1 to 10 car-bon atoms; one of R3 and R4 is hydrogen or methyl and the other is hydroxy;
each of R5 and R6 whether the same or different may be hydrogen, methyl or fluorine; X is -(CH2)m2- in which m is zero or 1, or -O-; n may be zero or an integer between 1 and 9 and R7 is a cycloalkyl group which is substituted by one or more alkyl groups having 1 to 4 carbon atoms or a heterocyclic group or a pharmaceutically acceptable salt thereof, which comprises reacting a compound of the general formula wherein n, X, R5, R6 and R7 are as defined above; R2 represents a free or functionally converted hydroxy group, Z is halogen, one of R'3 and R'4 is hydrogen or methyl and the other is a free or functionally converted hydroxy group, with a Wittig reagent of the formula III

III

and when required subsequently in any order the isomers are separated, or protected hydroxy groups are liberated or a free carboxy group is esterified or an esterified carboxy group is hydrolys-ed or a carboxy group is converted into a salt.

14. A compound of formula I as defined in claim 13 or a pharmaceuti-cally acceptable salt thereof, when prepared by a process according to claim 13 or an obvious chemical equivalent thereof.

120.