CA1198418A - 9-deoxy-9a-methylene isosters of pgi.sub.2 and process for their preparation - Google Patents

Abstract

ABSTRACT
The invention relates to novel 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 C1-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, C1-C6-alkyl, C2-C6-alkanoyl and phenyl;

(e) -C=N; (f) a radical; (g) -CHO; or (h) a , radical where each X' is independently -O- or -S- and the R'a and R'b groups, whether the same or different, are C1-C6-alkyl or together form a straight or branched C2-C6-alkenylene chain; is: -CH2-, ?CH-OH, (cis), (trans), -C=C-, ,?C=O, -O-, -S-, or ?N-RC, where Rc may be hydro-gen, C1-C6-alkyl or C2-C6-alkanoyl; one of R1 and R2 and, independently, one of R3 and R4 is hydrogen, C1-C6-alkyl, C2-C10-alkenyl, C2-C10-alkynyl, phenyl, or aryl-C1-C6-alkyl and the other is hydrogen, hydroxy, C1-C6-alkoxy or aryl-C1-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, C1-C6-alkyl or halogen, or R5, R6 and the carbon atom to which they are bound form a ?C=CH2 or radical; Y is: -CH2-CH2-, (trans), (cis) where Z is hydrogen; X is: -(CH2)m3- in which m3 is zero or 1, (cis),

Description

I

The object of this invention is 9-deoxy-9a-methylene-isosteres of PGI2, also known as6,9~-oxide-11~,15(S)-dlhydroxy-prosta-5(Z),13(E)-ddunk acid, including a procedure for their reparation as well as pharmaceutical and veterinary compositions containing -them.
Compounds covered by this invention have the following general formula I) CH^~(CH2) -D-(CI-I2) -R
I

Jo S 2 q OH
A

1 Ray ~R3 R5

2~C-(Cll2)n I X~(CH2)n2 7 ``-wherein I 6 R is chosen from the group a) a free or esterified car boxy group; b) -COREY, where each R' group is independently Cl-C6alkyl or phenol; c) -SHARI", where R" is hydroxy or C2-C7alkoxy; d) -CON Ray where Ray and Rub are chosen independently from the group hydrogen, Cl-C6alkyl, C2-C6alkanoyl and phenol; e) C-N; YE) a -C~N~I YIN radical; g) -Clue; h) a -OH era radical where each X' is independently-O-or-S-and the Roy and Rub groups, whether the same or different, are Cl-C6alkyl or together form a straight or branched C2-C6alkylene chain;

D is chosen from the group: -SHEA-, SHEA, H COCK H (is), H ~C=C H (trays), -C-C-, COO, -O-, -S-, and ARC where R may be hydrogen, Cl-C6alkyl or C2-C6alkanoyl;

79/P-2- SUE VF/ac 395C DIV. C

84~3 one of Al and R2 and, independently, one of R3 and I is hydrogen, Cl-C6alkyl, C2-ClOalkenyl, C2-ClOalkynyl, phenol, or aryl-Cl-C6alkyl and the other is hydrogen, hydroxy, Cl-C6alkoxy or aryl-Cl-C6alkoxy, or, Al and R2 and, index pendently R3 and R4 together Norm an ox group; each R5 and R6J whether the same or different, may be hydrogen, Cl-CG-alkyl or halogen, preferably fluorine, or R5, R6 and the carbon atom to which they are bound form a C=CH2 or ,C~Çc~2 radical; Y is chosen from the group: -CH2-CH2-, ~I~C=C~z (trays) or ~`C=C Z (is) where Z is hydrogen; X is chosen from the group: -(SHEA)-which my is zero or 1, H`C=C H (is), ICKY= OH (trays), -O-, -S- and ARC
with- Arc as defined above; ml, my, no and no, 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 than or equal to 15; p and q are independently zero or an in-tiger 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-C~-alkoxy; or a saturated or unsaturated heterocyclic ring, either unsubstitutecl or substituted with on or more of the following: halogen, halo-Cl-C6-alkyl, Cl-C6-alkoxy, phenol, Cluck alkyd.
This invention also covers lactones derived from compounds with 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 sub-stituents on a bicycle [(p+q+1).3.0] Al Kane system (composed of condensed rings A and B) in the end configuration, and to substituents on a chain in the S configuration. A wedged line I Oil the other hand, refers to a ring substituent in the configuration, that is above the plane of the ring, to a bicycle [(p+q~1).3.0] Al Kane substituent in the ego configuration, and to a side chain substituent in the R configuration. A wavy line (~) India gates a substituent of undefined stereochemistry: ring substituents may be or I, bicycloalkane substituents may be end or ego, and side chain sub-stituents may be R or S.
The compounds with formula (I) and their derivatives described here have a is junction between condensed rings A and B; the hydrogen atoms bound to tile bicyclic system at the junction are both outside the dihedral angle formed by the rings in the natural configuration.
The side chain on cyclopentane ring A (the chain) is wryness with respect to ring B and ego 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 I) is on the same side as or the opposite side from the chain on cyclopentane ring A (chain I): in the first case, the exocyclic double bond is defined as is; 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 separately and in mixtures.

The above notation Refers to natural compounds. Louvre, the enantiomers covered by this invention show stereochemistry at all asymmetric sites which is the opposite of that found in the natural cotnpounds. Whey are thus mirror images of the latter, and their names include the prefix "out" to indicate precisely that. do mixtures contain equimolar quantities of the natural compounds and the corresponding enantiomers.
The alkali alkenyl, alkynyl, alkoxy and alkanoyloxy groups may be straight or branched, unsubstituted or substituted with one or more of the following: halogen, Cl-C6-alkoxy and aureole, phenol in particular.

` is 34~

R is preferably a tree or esterified carboxylic group, or its derivative salt.
A Cl-C6alkyl group is preferably methyl, ethyl or propel.
A C2-C7acyloxy group is preferably C2-C6alkanoyloxy, for example, Aztecs, yropionyloxy, or benzoyloxy.
A C2-C6alkanoyl group is preferably acutely or propionyl.
A C2-C6alkylene radical is preferably ethylene or propylene.
A Cl-C6-alkoxy group is preferably methoxy, ethics or propoxy.
An aryl-Cl-C6-alkyl group is preferably bouncily.
An aryl~Cl-C6-alkoxy group is preferably benzyloxy.
A C2-C10-alkenyl group is preferably -CHESHIRE, where R8 is hydrogen or straight or branched Cl-C8-alkyl, but preferably a vinyl group.
A C2-C10-alkynyl group is preferably -C_C-R8, where R8 is as defined above, but preferably an ethanol group.
A halo-Cl-C6-alkyl group is preferably trihalo-Cl-C6-alkyl, particularly trifluorome~hyl.
Preferably, R5 and R6 are independently chosen from hydrogen, Cl-C6-alkyl and fluorine.
Yen R7 is a cycloaliphatic radical, it may be moo-, bit or tricyclic. If monocyclic~ C3-Cg-cycloalkyl or cycloalkenyl is preferred, like cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, aye-loheptenyl. If cyclic norbornyl is preferred. If tricyclic, adamantly is preferred.
When R7 is a cycloaliphatic radical, a monocycloaliphatic group as defined above is preferred.
When R7 is a heterocyclic ring, this may be moo- or bicyclic, containing as heteroatom at least one of No S and 0. However, the heterocycle is preferably monocyclic as defined above, particularly tetrahydrofuryl~
tetrahydrothienyl, tetrahydropyranyl, puerilely, pyrazolyl, oxazolyl, is-xazolylJ pyridyl, personnel, pyrimidinyl, pyridazinyl.

.
it - 5 -~L~}L98~

hen R is an esterIfied car boxy group, -COORS is preferred, worry is a Cl-C12-alkyl radical, particularly methyl, ethyl, propel hotly or C2-C12-alkenyl, ally in particular.
Preferably, ml, my, no and no are independently zero, 1, 2 or

3.
Pharmaceutically or veterinarily acceptable salts of compounds with formula (I) may be formed with both inorganic and organic acids and bases.
Pharmaceutically ~rveterinarily acceptable inorganic acids in-elude hydrochloric, hydrobromic and sulfuric; while organic acids include citric, fumaric, tartaric mafia, malefic, methanesul~onic and ethanesulfonic.
Acceptable inorganic bases may be the hydroxides of alkali or alkaline earth metals, zinc and aluminum. Acceptable organic bases may be amlnes like methyl amine, diethylamine, ~rimethylamine, ethyl amine, dibutylamine, in-isopropyl amine, N-methylhexylamine, decylamine, dodecylamine, allylamine, crotylamine~ cyclopentylamine9 dicyclohexylamine, benzylamine, dibenzylamine, u-phenylethylamine, ~-phenylethylamine, ethylenediamine, diethylenetriamine, and other similar alpha tic aromatic and heterocyclic amine like piperidine, morpholine, pyrrolidine, piperazine, as well as substituted derivatives like l-methylpiperidine, ~-ethylmorpholine, l-isopropylpyrrolidine, 2-methyl-pyrrolidine~ -dimethylpiperazine, 2-methylpiperidine, hydrophilic derive-lives like Monday- and triethanolamine, 2-amino-2-butanol, 2-amino-1-buttonhole, 2-amino-2-ethyl-1,3-propanediol, 2-amino-2-methyl-1-propanol, iris-(hydroxymethyl)-aminomethane, N-phenylethanolamine, N-~p-tert-amylphenyl)-diethanolamine, ephedrine, procaine and and amino acids like Lawson and arginine.
Under this invention, the preferred salts are compounds with Cromwell (I) in which R is -Curd, where Rod is a pharmaceutically or voter inertly acceptable cation derived from one of the bases listed above.
In this discussion, the compounds covered by the invention will 3Q be referred to as bicycle L pal . 3.Q] Al Kane derivatives, or, preferably, I

as derivatives of a 20 carbon atom compound, the prostacyclanoic acid, with the following formula:
I
0 aye 7 a in which the position of the oxygen atom is called the pa position.
Therefore, a compound with formula (I) in which pal is a bicycle ~3.3.0~octyl derivative or, preferably, a derivative of a adieux-9a-methylene prostacyclanoic acid, since a ethylene group has taken the place of the hetero-a-tom in position pa of the prostacyclanoic acid. A compound with Cromwell (It in which pi and Al is a bicyclo[4.3.0]nonyl derivative, or, preferably, a derivative of 9a-deoxy-~aj9b~dimethylene prostacyclanoic acid, since 2 ethylene groups have subsisted the heteroatom in position pa of the pros.tacyclanoic acid. Analogously, a compound with formula I) in which pi and Al is a bicycle [5.3.03dodecyl derivative or, preferably, a don-votive of 9a-deoxy-9a,9b,9c-trimethylene prostacyclanoic acid.
Analogous prostacyclanoic acid derivatives in which q=2 or q=3 are called "Amy" or "7a,7b-dihomo" respectively, while compounds with formula (I) with p or q equal to zero are called "9a-nor-methylene" or "7-norm ethylene respectively.
The same notation home dummy, nor, donor, etc.) is used to indicate lengthening the former) or shortening (the latter) of 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 with formula (I) are those in which R is a fret or sulfide car boxy group; R7 is a saturated moo-heterocycle preferably tetrahydro~lryl or tetrahydrothienyl) or a C5 C7-monocycloalkyl radical and the other substituents have the meanings reported above.

The following compounds are particularly preferred under this invention:
5c,13t-lla,15S-dihydroxy-9a-deoxy-9a-methylene-17--cyclohexyl-18,19,20-trinor-prostacycla-5,13-dienoic acid;
5c,13t-11~,15S-dihydroxy-9a-~eoxy-9a-methylene-17((2')-tetrahydrofuryl-18,19, 20,trinor-prostacycla-5,13-dienoic acid;
5t,13t-11~,15S-dihydroxy-9a-deoxy-9a-methylene-17--cyclohexyl-1~,19,20-trinor-prostacycla-5,}3-dienoic acid;
5t-13t-lla,15S-dihydroxy-9a-deoxy-9a-methylene-17((tetrahedral, 20-trinor-prostacycla-5,13-dienoic acid;
5c,13t-lla,15S-dihydroxy-9a-deoxy-9a,9b-dimethylenne-17-cyclohexyl-18,19,20-trinor-prostacycla-5,13-dienoic acid;
5t,13t-11,15S-dihydroxy-9a-deoxy-9a,9b-dimethylenne-17-cyclohexyl-18,19,20-trinor-prostacycla-5,13-dienoic acid;
as well as the ll-deoxy-derivatives, the ll-epimers, the 15R-hydroxy isomers and all the enan*iomers of the compounds indicated above as well as their pharmaceutically or veterinarily acceptable salts.
The compounds covered by this invention are prepared by a process which comprises alkylation of compo~md II
o I
(Shop B (Schick I. (II) Al I
< A

"I y R 3 I
Al R' C-~CH2)n ~~~X~(CH2)n2 7 R~4 R6 wherein p, q, Y, no, no, X, I R6 and R7 are as defined above; one of R' and R'2 and,independen*ly~olle of R'3 and I it hydrogen, Cl-C6-alkyl~

C2-C10-alkenyl, C2-C10-alkynyl, phenol or aryl-Cl-C6-alkyl and the other is hydrogen, hydroxyJ Cl-C6-alkoxys aryl-Cl-C6-alkoxy or a protecting group bound to the bicyclic system or the side chain through an ether linkage, or Al and R'2 and independently, R'3 and R'4 together form a protecting group for the kitten junction, with a compound with formula ~III) E-CH-(CH2~m -D-(C~12)m2 III

wherein D, ml and my are as defined above; E is a ~C6H5)3P- or a (Wrap)-group where each Rye may independently be Cl-C6-alkyl or phenol; R"' is (a") a carboxylic group, free, esterified or as its salt; (B") -COREY, where R' is as defined above; (c") -SHROVE, where RIP is C2-C7-acyloxy or a protect-in group bound to -SHEA- through an ether linkage, (d") -CONNER , where Ray and are as defined above; (e") -C-N; (f") a I I radical; go a NH-N
-CH~X,RR~a, radical where X', Roy and Rub are as defined above, followed if required by the removal of any protecting group present; or, if required, a compound of formula I in which Y is -CHIHUAHUAS- where Z is hydrogen, is reduced to give, after the protecting groups are removed, a compound of formula I
in which Y is -CH2-CH2-; or, if required, subjecting to nucleophilic addition the free carbonyl on the chain off compound of formula I in which Y it -C~2-CH2- or -CHIHUAHUAS- and Z is as defined above, and R3 and R4 together form an ox group to afford, upon removal of any protecting groups, a compound of formula I in which Y is -CH2-CH2- or -CHIHUAHUAS and Z is as define Ed above, and one of K3 and I is hydroxy while the other is hydrogen Cluck-alkyd, C2-C10-alkenyl, C2-C10-alkynyl, phenol or aryl-Cl-C6-alkyl and, if required preparing the ether derivative from a compound of formula I in which Y is -CH2-CH2 or -CHIHUAHUAS- wherein Z is as defined above, one of R3 and I is hydroxy while the other is hydrogen, Cl-C6-alkyl, C2-C10-alkenyl, C2-C10-alkynyl, phenol 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 Y is -CH2-CH2- or -CHIHUAHUAS- Warsaw is as defined above and one of R3 and R4 is Cl-C6-alkoxy or aryl-Cl-C6-alkoxy while the other is I' 34~

hydrogen Cl~C6~alkYl~ C2-Clo-alkenYl, C2-clo-alkynyl~ phenol or aryl_cl_c6_ alkyd; or, if required, converting a compound of formula I into another or to the lactose or pharmaceutically or veterinarily acceptable salt or, if required, converting a salt of a compound of formula I to the free compound or, if required, separating a mixture of isometric compounds of formula I
into individual isomers.
Protecting 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 sill ethers: for instance trialkylsilyl ethers like trim ethyl, dimethyl-tert-butyl, dimethyl-isopropyl, or dimethylethylsilyl ether; and also acutely and enol ether residues: for instance, tetrahydropyranyl ether, tetrahydrofuranyl ether, dioxanyl ether, oxathianyl ether, o - , Alec ' Alec where Ask is Cluck_ alkyd.
Kitten protecting groups are preferably petal and thioketal no-Swede: C X' groups in which X', Ray and Rub are as defined above.
Alkylation of a compound (II) with a compound ~III) is carried out ho 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 deathly ether, tetrahydrofuran, Dixon or dimethoxyethane; in an elf-phatic or aromatic hydrocarbon like Nixon, Newton, Bunyan or Tulane;
in a halogenated hydrocarbon like dichloromethane or carbon tetrachloride, as well as in mixtures of these solvents.
Especially when E in compounds (III) is (C6H5)3P-, dimethylsulr oxide, hexamethylphosphoramide, and other aprotic solvents are particularly useful Dimethylsulfoxide gives the dimethylsulfinyl carbanion upon reaction with an alkali hydrides which in turn can generate carbanions with formula (III) from the corresponding phosphoranes and phosphonates; this solvent is thus particularly preferred, since carbanions (III3 can then be generated _ situ I
I`,, I

For 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 of a compound (II) with a compound (III) gives a mix lure of geometric isomers, in that the new exocyclic double bond formed in the reaction may be is or trans. If desired, the individual geometric is-mews may be separated by fractional crystallization from a suitable solvent or by chromatography, either thin layer, column or liquid-liquid at low, medium or high pressure. Silica gel or magnesium silicate may be used as support with a solvent like cyclohexane, Nixon, Bunsen, ethylene 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 moo- or poly-carboxylic acids like acetic, formic, citric, oxalic, or tartaric in a solvent like water, acetone, tetrahydrofuran, dimethoxyethane or a low molt ocular weight alcohol, or with a sulfonic acid like p-toluene-sulfonic in a low molecular weight alcohol like an hydrous ethanol or methanol, or with a polystyrene-sulfonic resin. For example, a 0.1-0.25N polycarboxylic acid (like oxalic or citric) is used with a suitable low-boiling solvent miscible with water and readily removable under vacuum at the end of the reaction.
Sill ether residues may be selectively removed in the presence of other protecting groups with F ions in solvents like tetrahydrofuran and dimethyl~ormamide.
Ester protecting groups may be removed by following typical saponification procedures.
Petal and thioketal protecting groups for kittens are generally removed as are acutely or thioacetal groups, with mild acid hydrolysis as described above.
I Thioketals and thioacetals may be selectively removed in the I' presence of other protecting groups with, for instance, mercuric chloride in aqueous acetone or acetonitrile, or a mixture of them, in the presence of an alkaline earth carbonate like that of calcium or magnesium.
The optional reduction of a compound (I) in which Y is -CHIHUAHUAS-wherein Z is hydrogen to afford, after any protecting groups are removed, a compound (I) in which Y is -SCHICK- is preferably run in liquid ammonia, with or without a co-solvent for instance, an aliphatic alcohol like left-buttonhole or a 2-Cl-C4-alkylpropan-2-ol, or a cyclic ether like tetrahydrofuran or Dixon), with an excess of an alkali or alkaline earth metal like lithium, sodium, potassium or calcium. At the end of the reaction, a weak acid like ammonium chloride or sulfate or an aliphatic alcohol like ethanol or propanol is used as a protons source. The reaction temperature may range from -70C
to that of the solvent at reflex.
Nucleophilic addition to the free carbonyl group on the chain in a compound I) in which Y is -C~2-C~2- or -CHIHUAHUAS-, Z is as defined above, and R3 and R4 together form an ox group gives a secondary or tertiary alcohol, depending on the nucleophile.
A secondary alcohol is preferably prepared with an alkali or alkaline earth trike sodium, lithium, calcium or magnesium) bordered or with zinc bordered to give, after any protecting groups are removed, a compound (I) in which Y is -CH2-CH2- or -CHIHUAHUAS-, Z is as defined above, and one of I and R4 is hydrogen and the other is hydroxy. 0.5-6 moles of reduce in agent are used per mole ox the carbonyl derivative (I), in an aqueous or anhydrolls solvent; for instance, a linear or cyclic ether like ethyl ether, tetrahydrofuran, dimethoxyethane or Dixon, an aliphatic or aromatic hydra-carbon like Newton or Bunsen, a halogenated hydrocarbon like ethylene chloride, or a hydroxyl-containing solvent like methyl, ethyl or isopropyl alcohol, as well as mixtures of these. The reaction temperature may range from -~0C to the boiling point ox the solvent, but is preferably between -25C and ~25C.

I

A tertiary alcohol is prepared by reaction with an organometallic derivative to give, after any protecting groups are removed, a compound (I) in which Y it -CH2-CH2- or -CHIHUAHUAS-, Z is as defined above, and one of R3 and I is Cl-C6-alkyl, C2-C10-alkenyl, C2-C10-~alkynyl, phenol or aryl-Cl~C6-alkyl while the other is hydroxy. The organo~.etallic may be a magnesium derivative like R OMgHal (in which Rio is Cl-C6-alkyl, C2 C10 y p Cl-C6-alkyl and Hal is halogen, preferably chlorine or bromide), a lithium curate like RloCuLi (Rio as above), an organolithium derivative like RloLi Rho as above), or an alkali or alkaline earth acetylide (Rll-C-C-)nMn yin which n is 1 or 2, Roll is hydrogen, straight or branched Cl-C8-alkyl, aryl-Cl-Colloquial, or aureole, particularly phenol, and M is an alkali or alkaline earth metal). the reaction between the carbonyl compound and one of these organ-metallic derivatives is preferably run with 1.05 moles or slightly more) of reagent per mole of compound, in an an hydrous solvent: for instance, an aprotic solvent like dimethylsulfoxide or hexamethylphosphoramide, a linear or cyclic ether like ethyl ether, tetrahy~rofuran, anisole, Dixon or dimethoxyethane, or an aliphatic or aromatic hydrocarbon like Newton, n-hexane, Bunsen or Tulane The reaction temperature may range from approx-irately -70~C to the boiling point of the solvent, but is preferably between I -60C and 20C.
hither it is a secondary or tertiary alcohol, the product of this nucleophilic addition is a mixture of the epimeric S and R alcohols.
The individual S I` Corey) and R COREY ) alcohols (in which R12 is 1 6 y , C2 C10-alkenyl, C2-C10-alkynylg phenol or aureole C C
alkyd) may be separated as desired using the fractional crystallization and chromatography techniques described above.
The optional preparation of ethers from these secondary and tertiary alcohols to give, after any protecting groups are removed, compounds with formula I) in which Y is -CH2-CH2- or -CHIHUAHUAS-, Z is as defined above, and one of R3 and R4 is Cl-C6-alkoxy OX aryl-Cl-C6-alkoxy while the other Lo is hydrogen, Cl-C6-alkyl, C2-C10-alkenyl, C2-C10-alkynyl, phenol or aureole-Cl-C6-alkyl~ may be effected by reaction with an optionally aryl-substituted diazoalkane in the presence of a catalyst like fluo~oboric acid or boron in-fluoride in an organic solvent like dichloromethane. Alternatively, it may be done by reaction of the hydroxyl group (either free or as its salt) with an alkyd or arylalkyl halide in the presence of a base like silver oxide, in a solvent like dimethylsulfoxide or dimethylformamide.
The following reactions are all run using standard procedures:
optional transformation of a compound with formula (I) into another, optional lactose or salt preparation, preparation of the free compound (I) from its salt, and separation of individual isomers from a mixture.
Fur example a compound with formula (It in which R3 and R4 are both hydrogen may be prepared from one in which one of R3 and R4 is hydrogen while the other is hydroxy by preparing the tessellate from the alcohol, for instance by treatment with tussle chloride in the presence of base, and reducing the tessellate with Nub or NaB(CN)H3 in water, aqueous alcohol or dimethylformamide or with Lyle in an an hydrous solvent like ethyl ether or tetrahydrofuran, at a temperature ranging from room temperature to the boiling I,;,, , ill I Jo .

point of the solvent. Analoyousl~, a compound with formula (I) ion which R1 and R2 are both hydrogen may be prepared -from one in which one of R1 and R2 is hydrogen while the other is hydroxy~ and a compound (I) in which D is -SHEA- may be pro-pared from one in which D is SHEA.
A compound with formula (I) in which R3 and I together form an ox group may be prepared -from one in which one of -R3 and R4 is hydrogen while the other is hydroxy by select live oxidation with excess activated Noah in an inert, pro-fireball chlorinated solvent like ethylene. chloride or sheller-lo m at room temperature or, alternatively, with 1.1-1.2 molar equivalents of dichlorodicyanobenzoquinone in an inert sol-vent like Dixon, Bunsen or a mixture at a temperature ran-gin from 40C to the boiling point of the solvent lo In an analogous fashion a compound with formula (I) in which R1 and R2 together Norm an ox group may be pro-pared from one in which one of R1 and R2 is hydrogen while the other is hydroxy, and a compound (I) in which D is KIWI
may be prepared prom one in which is SHEA
When 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 R1 and I
- 25 is C1~C6-alkoxy or aryl--C1CG-alkoxy may be prepared from one .

.
I

in which one of R1 and R2 is hydroxy through etherification . analogous to that described -for a compound with formula (I) -- in which one or R3 and I is hydroxy. Again, when only one of several secondary alcohol functions is to react, the others must be protected; the protecting groups are then no-moved at the end of the reaction.
A compound with formula (It in which R is a carboxylic ester group (for instance, a C1-C12-alkoxycarbonyl) may be prepared from one in which R is a free carboxylic group by I following standard procedures, for example reaction with an appropriate alcohol, like a C1-Cl2-aliphatic alcohol, in the presence of an acid catalyst, like p-toluenesulfonic acid, or alternatively, treatment with a diazoalkane.
The optional conversion of a soInpound with formula .. 15 (I) in which R is an est~rified carboxyl group (i.e., a C1-C12-alkoxycarbonyl) to one in which R is a free carboxyl group may be effected using standard saponification prove-dunes: treatment with an alkali or alkaline earth hydroxide .
in water or aqueous alcohol, followed by acidification.
I The optional preparation of a compound with formula (I) in which R is -SHARI" (R"=hydroxy) from one in which R
is a free or esterlfied carboxyl group may be effected by - reduction of the ester with Lyle in ethyl ether or twitter-- hydrofuran at Rex.
- 25 The optional conversion of a compound with formula (I) ' Or lo in which R is a free carboxyl grOtlp to one in which R is -Conner era and Rub as defined above) may be elected by treatment with an amine HNRaRb in the presence of a condemn---sing agent, for instance a carbodii~lide like dicyclohexyl-carbodiimide. A compound with formula (I) in which R is a carboxylic ester may be converted into one in which R is -Contra by treatment with an amine HER Rub in a suitable or-genie solvent at reflex for 2-3 hours.
The optional preparation of a compound with formula (I) in which R is a -C~'NNH NUN radical from one in which R is a free carboxyl group may be effected by forming first the correspond'r.g acid halide (preferably chloride, perhaps with thinly or oxalyl chloride in refluxing dichloroethane or dioxa;le), then the amid derivative (for example, with I ammonia), followed by dehydration to the nitrite (for in-stance with p-toluenesulfonyl chloride in pardon at 90--100C) and finally reaction of the nitrite with sodium aside and ammonium chloride in dimethylformamide at a temperature rang-in from room temperature to 100C. This reaction of the I carboxyl group to give CON or I is preferably 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 -SHEA may be effected using standard procedures, for instance the preparation of the corresponding chloride . , .

Jo ~1~9 from the acid or ester and subsequent Rosenmund reaction as described ion Org. Reactions).
--- A compound with formula (I) in which R is -COREY
(R' as defined above) may be prepared from one in which R is a free or esterified carboxyl group by rocket the hydra-chloride of the carboximide ester (prepared with standard methods) with a suitable alcohol, according to the procedure described in J. Americium Seiko), for example.

. .
~cetalization, for example the optional preparation of a compound with formula (I) in which R is CHAR here X' is oxygen and Ray arid Rub are as defined above) is effected by reaction of the alluded with an alcohol or luckily in thy presence of a catalyst like p-toluenesulfonic acid or a sulk ionic resin in a solvent which allows the removal of the water framed 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 Alcoa hot it distilled away as it forms. The acutely may also be prepared from the corresponding thioacetal by reaction with a suitable alcohol or glycol in the presence of a mercuric salt (preferably HgCl2) as an exchange catalyst and an alga-- lien earth carbonate, in an inert solvent.
Thioacetalization, for example the optional preparation of a compound with formula (I) in which R is -SHARI (where I X' is sulfur and Ray and Rub are as defined above) from one in ~i~B~18 which R is -SHEA, is pr~fe~clbly effected by reaction with a moo- ox di.mercaptan like methylmercap-tan, ethy:lmercaptarl, d.ithioethylene~lycol or dithiopropylenec3lycol in the pro-since of a catalyst like boron tri.fIuoride ether ate in an inert solvent, preferably a halogenated or aromatic hydra-carbon (ethylene chloride, chloroform, Bunsen, Tulane).
The corresponding petals and thioketals may be pro-pared from kittens by following the procedure described above for acetals and thioacetals.
Lactose end salt preparation from a compound with formula (I), as well as preparation of compound (I) from its salt, are performed using standard procedures.
Individual isomers are separated from mixtures of isometric compounds I) using standard techniques like free-tonal crystallization and chromatography.
Compounds with formula (IIIj in which E is (Roy)-ore as defined above) are prepared by reacting a compound .
(VII ) R O
e \P-CH2- ( SHEA Jo D- ( C~12 my . ( VII ) e j .

in which Rev my D, To and R"' are as defined above J
with at least one molar equivalent of one of the following bases: an alkali or alkaline cart ydrlde like sodium, pox Taoism, lithium or calcium hydrides an alkali or alkaline earth alcohol ate like sodium or potassium tert-butylate, an alkali or alkaline earth aside like sodium aside, or an at-kale or alkaline earth salt of a carbox~am.dc, like N-sodio~

.

.. .... _ _ . . . . . . . . . . .. . . .. .. .

acetamide and N-sodiosuccinimide.
Compounds with formula ~III) in which E is ~C6H5)3P- are pro-pared by reacting a compound with formula VOW
Hal-C~2-~CH2) M -D-~CH2)m2 (VIII) in which ml, D, my and R"' are as defined above and Hal is halogen, with 1.1-1.3 molar equivalents ox triphenylphosphine in an organic solvent like Bunsen, acetonitrile or deathly ether and then treating the product phosphor-I'm salt with an equivalent quantity of an inorganic base like Noah, KIWI -Nikko or Nikko.
Compounds with formula VOW) are prepared using standard methods, for example those described by Corey et at. in J. Amer. Chum. So., 90, 3247 (1968) and 88,5654~1966). Compounds VOW) are also prepared following standard procedures.
Compounds with formula) are new compounds covered by this invention, as are procedures or their preparation.
Compounds with formula IT in which Y is -CH2-CH2- or -CHIHUAHUAS-, Z as defined above, are prepared in a procedure involving:
avow reaction of a compound with formula taxi) SHEA) cluck H H
I I

R'2 wherein pi I Al and R'2 are as defined above and G is a protected carbonyl group or a group SHAG' wherein-G' is a sill ether or acutely ether residue, with a compound of formula TV) ETCH- Ill_ Sheehan Icy (Sheehan 7 TV

wherein E, Z, no, R5~ R6, X, no and R7 are as defined above, to afford a compound of formula (XII) Go \
(C}12) (C}12) q H }I (XII) Al C=C=G(CH2) -C-X-~C}I2) R
R 2 H R no 7 wherein G, p, q~R~l~zliR~2~nl~R5~R6~ X, no and R7 are as defined above;
bit) optional conversion of a compound with formula (XII) into a compound of formula (XIII) / G
SHEA (Schick H H (XIII) 1 R~2 Chenille X (Sheehan R7 in which G, p, q, I, R2, R3, R4, no, R5, I X, no and R7 are as defined aye, and Y' is.-CH2-CH2-, or -CHIHUAHUAS-, Z as defined above;
suave) removal of the projecting group in G to afford a compound of formula (XIV) / G \
(C~12)p (Schick H H (XIV) ¦ 3 rR5 I (chenille X (SHEA 7 I

q P' 1' 2' Y R I R I no Us R6~ I no and R7 are as defined above and G" is SHEA or COO;
dip) optional oxidation of a compound of formula (ZOO) wherein G" is` KIWI and the other hydroxy groups, if present, are protected as reported above.
The reaction between a compound with formula I and one with formula (V) is run in the same way as that reported above for the reaction between compounds IT and compounds (III).
The optional conversion of a compound with formula (XII) into ill one with formula (XIII) is effected with reactions analogous to those desert-bed above for the preparation of one compound with formula (I) from another:
for example, nucleophilic addition to the carbonyl on the chain, ether-ification of the product alcohols and hydrogenation.
As stated above, when C is a group SHAG', the protecting group G' ma be a sill ether residue (for instance, a trialkylsilyl ether like trim ethyl, dimethyl-tert-butyl, dimethylisopropyl, or dimethylethylsilyl ether,but preferably dimethyl-tert-butyl) or an acutely 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 re1noved as described previously: that is selectively, with F for a sill ether and with acid hydrolysis for an acutely ether. when a protecting group G' must be removed in the presence of other labile ether groups, these latter should be acutely ethers when -OX' is a sill ether or sill ethers when -OX' is an acutely ether. When G is a protected carbonyl group it is preferably protected as acutely or thioacetal, for example a dimethoxyacetal, a diethoxy-acutely, a dimethylthioacetal, a diethyl~hioacetal, preferably a dimethoxy-OH -O-acutely, or as petal, or thioketal for example a ethylendioxyketal SHEA 0 a CHIHUAHUAS- SHEA-propylendithioketal I , a propylendioxyketal I , a ethylendithio-t - 22 -~:3l9~

petal HIS preferably a ethylendioxyketal.
SHEA S
The removal of said protecting groups in a compound of formula (XIII) as well as the optional protection ox the free hydroxy groups in a compound of formula (XIV), e.g. as acutely ethers or sill ethers, may be effected as previously reported.
The optional oxidation of a compound of formula (XIV) wherein G" is hydroxy, may be effected using standard oxidation procedures for second-cry alcohols: for example treatment of the alcohol in an organic solvent like acetone with a solution of chronic android in sulfuric acid, following normal procedures.
Compounds with formula (XI) are prepared with a procedure involving:
avid conversion of a compound (XXIA) or (XXIB~

I
Chop H2)q ~XXIA) (Shop (Schick ~XXIB) H H H H

OH
in which p and q are as defined above and G"' is a protected carbonyl group as reported above, into a compound ~XXII) G \
~C~2 ) p (SHEA ) q H H (XXII) o in which p, q and G are as defined above;

~,~ . ..

bVI) reaction of compound (XXII) with a compound OKRA in which R13 is a Cl-C6-alkyl or aryl-Cl-C6-alkyl to give a compound with formula ~XXIII) (Shop (C~12)q ,, Jo I; (XXIII) Ho 1 UP
O COREY
in which p, qJ G and R13 are as defined above;
cVI) reduction of the product compound ~XXIII) to a compound with formula ~XXIV) SHEA) p lo Ho) q ~XXIV) H 7 r H

or, If OH COREY
in which G, p, q and R13 are as defined above;
dVI) optional separation of compound ~XXIV) into the individual optical antipodes;
TV ) optional conversion of compound ~XXIV) into a compound with formula (XXV) I, p ~C112)q r ... ,^~ ( X XV ) H H

I, I' OH H COREY
-I us ~,~.

I AL
in which G, p, q and R13 are as defined above;

fVI) transformation of a compound ~XXIV) or (XXV) into a compound with formula ~XXVI) / G \

_ Z p 2 q H H (XXVI) Al Clue wherein G, p, q, Al and R'2 are as defined above.
A compound of formula (XXII) wherein G is a group SHAG', in which G' is as defined above may be prepared from one of formula (XXIA) by known methods, eye. by reaction in the presence of base, with a sill halide, a silazane or a sill trifluoroacetamide or, for example, by reaction with a vinyl ether X" O where X" is -O-, -S- or Shirley 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 pardon with an excess of the pyridine-chromic android complex or by oxidation according to Moffatt in a mixture of Bunsen and dimethylsolphoxide with dicyclohexyl-carbodiimide in the presence of pyridinium trifluoroacetate.

I

The reaction between a compound with formula (XXII) and COREY (R13 as; defined above, but preferably methyl) is run in the presence off moles of a base like sodium me-tl1sxide -I sodium rid sodium or potassium hydrides or potassium tert-butoviclc, with an excess of 6-12 moles of car-boric divester per mole of kitten, neat or in an inert sol-vent in. an oxygen- and water-free atmosphere. The temperature may range from approximately 0-80C Preferably 60-~0C) 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 bordered in aqueous solution, pro-fireball at a pi between 5.3 and 7.2, or at -20C Wyeth ethanolic Nub in ethylene chloride/ ethanol. generally, the reduce lion is complete in 30 minutes and the excess reagent is quenched by adding a readily reducible species, like acetone, and a proton donor, like acetic acid.
The individual optical antipodes of a compared with formula (XXIV), in which G is ! as defined above - may be separated by saponifying the ester using standard procedures, forming a salt of the product acid with an optically active base Lyle quinine, chinconine, ephedrine, 1-phenyl-1-amino-ethanes dihydroabietylamine, amphetamine or asinine and I separating the resulting dias-tereomeric salts by fractional crystallization, for example.. The optically active acid is then recovered by conversion to the sodium salt and subset quint acidification of its aqueous solution to a pi which does not inter'erc with the poetic g group irk GO

Optionally the hydrolysis of the protecting groups may precede the optical resolution: the protecting groups are then restored at the end o-f the separation process.
The optically active free acid prepared in this way is then con-vented to an optical active ester (XXIV) using standard procedures for in-stance treatment with a suitable diazoalkane.
If desired, using an identical procedure, a rhizomic 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, Lawson, ala nine, l-phenyl-l-ethyl-amine, l-phenyl-l-propyl-amine and similar, to give the corresponding optically active diastereoisomeric Showoff bases; these may be separated by known methods, e.g. by fractionate crystallization or by HPLC, the amino group may be hydrolyzed to KIWI in a known manner then the separated optically active keto-esters may be transformed into the optical antipodes (XXIV) and (XXV) by ketalization or acetalization in a conventional way.

he optional conversion of a compound with formula (XXIV) to one with formula (XXV) may be done on either a rhizomic mixture or the individual isomers separated as desk cried above. In this transformation, the configuration of the free hydxoxyl on the cyclopentane ring is inverted. The procedure involves esterification of the hydroxyl, for example by treatment with 2-4 molar equivalents of triphenylphos-pine and 2-4 molar equivalents Go a carboxylic acid like acetic r benzoic or p-phenylbenzoic, or with 2-4 molar equip alerts of ethyl azo-bis-carboxylate in an inert solvent like an aromatic hydrocarbon, perhaps haloyenated, like Bunsen or chlorobenzene, or a cyclic ether like tetrahydrofuran, and subsequent selective saponification of the ester function formed in this way, for example by transesterification in an I inert alcohol R130H in the presence of an alkali carbonate, preferably K2C03.
A compound with formula (XXVI) is prepared from a come pound (XXIY~ or (XXV) using known methods. For example, the free hydroxyl group it compound (XXIV~ or (XXV) may be con-2Q vented to a C1-C6-alkoxy, an aryl-C1-C6-alkoxy or a labile ether like a sill or acutely ether using the ether prepare-lion techniques already described 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 ox group, and the - product kitten may be converted to a petal or thioketal accord ding to the procedure described above for compounds with for-mute (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 benzenesul-fonyl chloride and subsequent reduction of the product sulfonate, for instance with Lit in standard methods. In this case the carboxylic ester group (-COREY) is reduced at the same time to the primary alcohol (-SHUT), which may then be oxidized to the alluded with Moffatt's reagent.
A product compound with formula (XXVII) G \

2 ) P ~C~12 ) I""
H H
I ~XXVII) 1 R~2 COREY

in which one of Al and R'2 is hydrogen, Cl-C6-alkyl, C2-C10-alkenyl, aureole or aryl-Cl-C6-alkyl while the other is hydroxy, Cl-C6-alkoxy, aryl-Cl-C6-alkoxy or a labile ether group, or Al and R'2 together form a Xetone protecting group may be converted to the corresponding compound with formula (XXVI) by reduction following standard procedures, for example, with diisobutyl-aluminum hydrides or lithium diisobutylaluminum hydrides When a compound ~XXVII) is reduced with Lyle following standard procedures, the product is the corresponding primary alcohol which may also be prepared from the free acid by standard reduction with BH3 in tetrahydro-Furman. The free acid is prepared by saponification of the ester. This prim many alcohol may then be oxidized to the alluded, with Moffatt's reagent for example, as mentioned previously.

Lo Compounds with formula (XXIA) and (XXI~ art prepared with known methods. For example, a compound (XXIA) in which pal is prepared by selective reduction of bicycle [3.3.0]octane-3,7-dione Jo Amer. Chum.
Sock 82, 6347(1960)) or by reduction of bicycle [3.3.0]octane-3,7-dione-monoketal (J. Or~._Chem., 39, 2377(1974)), hollowed by removal of the petal from the carbonyl function. In both cases, the product hydroxy kitten (XXI) with pal is a mixture of the endo-hydroxy and exo-hydroxy derivatives, with approximately 80% endow The two isomers may readily be separated, using the corresponding rhizomic silyloxy derivative, by fractional crystal-ligation or chromatography, as described several times above.
A compound with formula (XXI) in which pal and q=2 is prepared from bicycle [4.3.0] non-7-en-3-one (XXVIII), which has a is junction between the two rings, in a procedure in-0 (XXVIII) If valving the protection of the kitten as a petal or thioketal (as described above), standard hydroboration of the double bond, and subsequent removal o-E
the kitten protecting group as described above.
Compound (XXVIII) may be synthesized, for example, as described by JO Vital in "Stereochimie et Selectivity Reactionelle en Serve Bicycle-[n.3.0]alcanique", presented at the University de Sciences et Techniques duo Languedoc, Academic de Montpelier, n diehard C.N.R.S.AØ 11257(1975).
A compound with formula ~XXIA) in which pal and q=2 prepared, for lo 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 l or p is l and q is zero may be prepared from the bromidrine 5-exo-bromo-6-endo-hydroxy-bicyclo[3.2.0]heptan-2-one [J. Chum. So., Perking l, 1767 ~1965)]
by known methods: for example said bromidrine may be converted into its acutely, thioacetal, petal or thioketal, then dehalogenated to the compound (XXIB) using the known methods of organic chemistry such as, for example, the reduction with chromium IT salts, the catalytic hydrogenation in the presence of Pd/CaC03 or Pd/C and in the presence of anhalohydric acid acceptor, or the reduction with tributyl tin hydrides A compound of formula (XXIB) wherein p is 2 and q is l or q is 2 and p is l, may be prepared, ego from a compound of formula ~XXVIII) by a process comprising reducing the carbonyl group to alcohol, e.g. with Lyle in ethyl ether protecting the alcoholic group, e.g. as tetrahydropyranyl-ether or sill ether, hydroborating, by conventional methods, the olefinic double bond, oxidizing, Deb locking the protected hydroxy group, following the acetalization or ketalization.

I

A compound of formula ~XXIB) wherein p = q = 2 may be prepared by known methods e.g. from 2-hydroxy-perhydro-azulen-6-one which in kern may be obtained as described by DO Banerjee and K. Ankara Ram. in In. J. o-f Chum. vol. X, page 1 ~1972).
The compound of formula ~XXVIII) may be used as starting retrial also for the preparation of the compounds of formula (XI) wherein G is a group SHEA JOG' wherein G' is the residue of a sill ether and wherein, when one of Al and R'2 is hydrogen and the other is hydroxy, the latter is pro-fireball protected as acutely ether or as ester, following the reaction scheme reported below:

` ~C"2C~'3 SUE
C - G (XXIX) OX - (XXX) 2 Ho _ (O C113 _ JO
Octal Oust Oust S
~XXXI~ (XXXIIa : GO ~XXXIIIa : Glue) ~XXXIlb : sill ~XXXIIIb : G'=silyl-ether residue) ether residue) The compound (XX~III), by known methods e.g. those previously no-ported, is converted into the kowtow ester (XXIX) which is reduced -to the ~-hydroxy ester (XXX) wherein the hydroxy group is protected as acutely ether;
the obtained compound ~XXXI) is then submitted, in a conventional manner, -to the hydroboration at the olefinic double bond to give the alcohols ~XXXIIa) and ~XXXIIIa) which are then resolved by chromatography or by -fractionate crystallization, converted into the corresponding sill ethers ~XXXIIb) and ~XXXIIIb) and finally transformed into the compounds of formula I by reduction with diisobutylaluminium hydrides in Tulane according to known methods .

By The compounds ox formula I) show the same pharmacological activities as the natural prostacyclin, or PI but as compared with PGI2, the compounds covered by this invention have a particular advantage in their greater stability in the range ox pit between zero and 11, in particular, at physiologic phi this leads to longer lasting and mote constant biological activity. The source of this greater stability is the different chemical structure of these compounds as compared to natural prostacyclin. Since there is an oxygen heteroatom in the 2-oxa-bicyclo [3.3.0]octane system, natural prostacyclin is an exocyclic enol ether and so is extremely acid sensitive. The product of reaction with acid, 6-keto-PGFl~, shows almost none ox the biological activity characteristic of natural prostacyclin. On the other hand, the compounds covered by this invention have no oxygen in the bicyclic 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 ox formula (It in which there is a hinder-in group, such as a Cl-C6-alkyl group or an electron receptor group, e.g.
fluorine, near the hydroxyl in position 15 (R3 or I = hydroxy) are more resistant to enzyme-induced (for instance, 15-PG-dehydrogenase) metabolic degradation than natural prostacyclin.
rho pharmacological actions of natural prostacyclin are known.
Thus, for example, when inhaled in asthmatic patients, prostacyclin prevents a speci~icallyinduced (e.g. by Newbold water or by effort) bronchocostric-lion [S. Bunk et at, J. Rest Medical Science, 6, ~56 (1978)]; when infused in man, it shows hypotensive and vasodilator activity and also shows blood platelet anti-aggregant and disaggregant properties [Suckle et at, Harm.
Rest Comma 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 from ulcers induced by non-steroidal anti-inflammatory subs~ances,e.g. acutely salicyclic acid (AS) 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 insight-ability of PGI2, is absent in the compounds of the invention.
Again in comparison with PGI2, for equally active antiaggregant doses, the in vitro luteolytic activity in the hamster is 5 times greater forDl-5,13t-11~,15S-dihydroxy-9a-deoxy-9a,9b-dimethyllene-17-cyclohexyl-1~, try ~-prostacycla-5,13-dienoic acid. As to their prostacyclin- and prostaglandin-like activity the compounds covered by this invention may be used in human and veterinary medicine when natural prostacyclin and pro stag-landing are indicated therapeutically.
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:

Jo - I -orally in tablets, capsules, pills, or liquids like drops or syrups; feat-ally, in suppositories, intravenously, intramuscularly or subcutaneously; by inhalation as aerosols or vaporizer solutions; or by insufflation as powders.
Doses of approximately 0.01-~mg/kg may be given from 1 to times doily, but the exact dose depends OTT 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-ashmatics: simpaticomimetics like isoproterenol, ephedrine, etc.; Anthony derivatives like theophillin and aminophillin; and corticosteroids like prednisolone and ACT.
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 approxi-mutely O.Ol~g/kg/minute until the end o-f 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 pro-staglandins 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 whey minimize or eliminate the for-!

motion of gastrointestinal ulcers and accelerate the cure of any ulcers already present in the gastrointestinal tract.
They are administered in this case by intravenous infusion or by intravenous, subcutaneous or intramuscular injection;
doses or intravenous infusion range from 0.1~g to 500 go clement. The -total daily dose for both injection and infusion is on the order ox 0.1-20mg~]y depending on the age weight and condition of the patient or animal and on the administration method.
However, lilac natural prostacyclines, the most import lent pharmacological property of the compounds covered by this invention is their platelet anti-aggregant activity, -that is, the capacity to inhibit platelet aggrecJation, to decrease adhesion, to prevent clot formation and to dissolve recently-formed clots. This platelet anti-aggregant activity 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 thrombosis, in treating conditions 23 like atherosclerosis, arteriosclerosis and, more generally, dihyperlipidemia.
Normal administration methods are used in this apply-cation: that is, intravenous, subcutaneous, intramuscular, etc. In emergency situations intravenous administration is I preferred, in doses ranging from 0.005 to 20 mg/~g/day, again depending on the age, jut and condition of the patient and on the administration method.

'! . .

`` - 119841B `

I .

.
As mentioned above, the compounds covered ho this in-I- mention are useful in human and veterinary therapy, loath several administration methods. They may be given orally in tablets, capsules, drops or syrups; rectally in suppose ivories; parenterally, in solutions or suspensions gives subcutaneously or intramuscularly; intravenously, as pro-furred in emergencies; by inhalation in aerosols or vapor-sizer 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 convent tonally using common carriers and/or delineates. For example, sterile and isotonic aqueous solutions are preferred for intravenous injection or infusion. truly aqueous solutions or suspensions in aqueous or non aqueous medium are used for subcutaneous or intramuscular injections. A sterile compress or a silicon rubber capsule containing or impregnated with the active ingredient may be used for sterile grafts.
Conventional carriers and delineates include water, gelatin, lactose, dextrose, sucrose, minutely, sorbitol, cellulose, talc, Starkey acid, calcium and magnesium Stewart, glycols, starch, gum Arabic gum adragant, alginic acid, at juntas, lecithin, polysorbates, vegetable oils, etc.
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 .~:'' I' .-.

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

I: I

I 98~

may be suspended or dissolved in one of the common liquefied propellants like dichlorodifluoromethane or dichlorotetra-fluoroethane and given with a pressurized container like an aerosol bomb. When the compound is not soluble in the pro-to the pharmaceutical ~or,~ulatio~
pollinate, a co-solvent must be added for instance, ethanol, dipropyleneglycol and/or a t~nsioactive substance.
In the hollowing examples,THP,~MtB,~IOX 3 THF,DMSO,DIEA and DEFOE
refer respectively to tetrahydropyranyl,dimethyl-tert-butylg tetrahydrofuran, 1,4-diox-2-enyl~di~.ethylsulphoxide,diisobutylalumminiumhydride and dimethylormamide~
The hollowing examples illustrate but do not in any way limit the present invention.
Example 1 .
1~1g of sodium bordered (0.029 molt is added with stirring to a solution of 11.6g of bicyclo~3.~.0~octane-3,7-drone ô.4x.0 Molly) in 100ml of Mullen chloride and 100ml of ethanol After 45 minutes at this temperature, the excess reagent is decomposed by slowly adding 20ml of acetone. The mixture is then neutralized with 1.4ml of acetic acid, and evaporated under vacuum to afford a residue which is taken up in water and ethylene chloride. The organic phase is evaporated to dryness and filtered on silica gel (70:30 hexane:ethyl ether as fluent) to afford 9.1g of ~-hydroxy-bicycler octan-3-one.
A solution of this compound (Molly) in 27ml of - anhyarous dimethylformamide is treated with 12~8g of dim ethyl-tert-butylsilyl chloride and 8.85g of imidazole. The no-. - . -. .

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

I

suiting mixture is heated to 60C for 5 hours, cooled, dill-ted with t~70 volumes of water and extracted with ethyl ether (3Y.40ml and 2x20ml). The combined organic extract is washed with I Nikko and then water until neutral, and evaporate - 5 to dryness to give 15.~g of crude product (95% yield). Pun-ification on silica gel affords 2.85g of 7-exo-hydroY~y-bicyclo ~3.3.0~octan- 3-one-dimethyl-tert-butylsilyl ether and 11.8g of 7-endo-hydrox~-bicyclo ~3.3. octane one-7-dimethyl-tert-butylsilyl ether.
A solution of the latter (11.8g, ~.63x10 Molly) in 295ml of methyl carbonate (Mohawk) it stirred with the exile-soon of wale; in an inert atmosphere and treated cautiously with 5.95g of 80% sodium hydrides When hydrogen evolution ceases, the reaction mixture is heater at 75-80C for forty minutes. After cooling, the mixture is diluted with two trilliums of ethyl ether and cautiously treated with 13g of glacial acetic acid. The organic place is then separated with pi 5.2-5.5 buffer and the aqueous layer is extracted with vinyl ether. The combined organic extract is dried over N~2S04 and evaporated to dryness to give 12.32g of d,l-7-endo-hdyroxy-bicyclo Lo 3.030ctan -3-one-2-carboxymethyl-ester-7-dimethyl-tert-butylsilyl ether (85~ of the 14.49g theoretical yield), which after purification on silica gel (yoga, with 97:3 hexane:ethyl ether as fluent) affords 10.81g the pure product; maxim =7,000 I

Starting with the ego isomer, the same procedure aft fords do cxo-hydroxy-bicyclo ~.3.0~octan -3-one-2-carboxy-methylester-7-dimet'llyl-tert-butyl silylether; Maxim, ~=~,500.
Example _ A solution of 7.5g of d/l-7-endo-hydroxy-bicyclo &.3.0~-octane-3-one-2-carboxymethylester-7-di.methyl-tert-butyll sill-Ethel ~DMtB-silylether) in 75ml of dichlorometh~ne and 75ml of ethanol is cooled to -20C and treated with stirring with 0.9g of sodium bordered. After stirring for 15 minutes 7 the excess reagent is destroyed by adding 12ml of acetone.
The mixture is brought to OKAY, 20ml of 20% KH2PO~ is adder the solvent is evaporated under vacuum and the residue is extracted several times with ethyl ether. The combined or-genie extract is washed with 5ml of water and evaporated to dryness to afford a residue which is crystallized from r--Hun to give ~.8g of d,1-`3,7-endo-dihydroxy-bicyclo ~3~3. by-octane -2-exo-carboxymethylester~7-D~tB-silyle-ther, mop.=
68-7QC. The mother liquor is adsorbed Oil 25g of silica gel;
elusion with 90:10 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--dihydroY.y-bicycloe3.3.0J-octane -2-exo carboxymethylester-7 D~tB-silylether in 100ml of 30:20 methanol:watcr is treated with 2g of potassium hydroxide and heated to reflex for 30 minutes. After concern-traction under vacuum, the mixture is acidified to pi 5.1 end extracted with ethyl acetate. Evaporation of the organic layer gives 5.1g of d,l-3,7-endo-dihydroxy-2-carbo~y~bicyclo-~.3.C~octane -7-DMtB-silyle-ther. A solution of this come pound in 150ml of acetonitrile is then treated with 2.~1g of do )-ephedrine. 4 hours at room temperature afford 2.9g of a salt which is crystallized twice from acetonitrile to give 1.85g of (+)-3/7-endo-clihydro~y- -exo-carboxy~bicyclo r~3.3.~-octane-7-D~It~-silylether-d(~)-ephedrine salt. All the mother liquors are collected and evaporated to dryness to jive a rest idle which is dissolved in water and treated with 0.68g of -sodium hydroxide in water. The d-(~)-ephedrine is recovered in a Bunsen extraction, and the sodium salt solution is acidified to phi and extracted with ethyl acetate. The organic phase is evaporated to dryness to give a residue which is treated with I of l ephedrine to afford after several crystallization 2.3g of (-) 3,7-endo-dihydroxy-2-exo-carboxy-bicycle ¦3.3.0~octane-7-DMtB-silylether -l-ephedrine salt.
Example 3 . .
A solution of ~.2~g of d,1-3,7--endo-dlhydroxy~--bicyclo-~3.3.0~octane -7-DMtB-silylether-2-exo-carboxymethylester in 30ml of an hydrous ethylene chloride is treated with 2.19g of 2,3-dihydropyran and 39mg of p-toluenesulfonic acid.
After 3 hours at room temperature, the reaction mixture is washed with OWE Nikko (2x5ml). E~rapc)ration of the organic I

phase to dryness gives I of d,l-3,7-endo-dihydro~y-bicyclo-~3.3.~ octane ~7-DMt~-silylether-3-THP-ether-2-carboyymethyl I- ester, which is then dried by being taken up in Andre Bunsen ~2x15ml) end evaporated to dryness. This product in 30ml of an hydrous ethyl ether is added drops, in 15 minutes, to a stirred suspension of 0.6g of Lyle in 4Oml ox an hydrous ethyl ether. Stirring is continued for 30 minutes before the excess reagent is destroyed by the cut-ions addition of 5ml of acetone followed by water-saturated ethyl ether. 10g of an hydrous sodium sulfate is then added.
Filtration of the organic solution and evaporation to dry-news afford 7.2g of d,l-3,7-endo--dihydroxy-2-exo-hydroxymethyl-bicyclo~3.3.030ctane -7-DMtB-silylether-3-THP-ether.
The following compounds en- prepared in this way from optically active starting materials:
nat~3,7-endo-dihydroxy-2-exo-hydroxymethyl-bicycloowe-. oCtalle-7-DMtB-silylether-3-THP-ether;
ent-3l7-endo-dihydroxy~2-exo-dihydroxymethyl-bicycClara oCtane-7-DMts-silylether-3-THP-ether.
It Dixon is used instead of 2,3-dihydropyran, the corresponding 3(2'-DIOX)-ethers are obtained.
example -A solution of 3.8g of d,l-3,7-endo-dihydroxy-bicyclo-C3 . 3 Octane -2-exo-carboxymethylester-7-DMtB-silylether in 40ml of Bunsen is treated first with 3 . 66g of benzoic acid I

and 7.qq of tripheny~ osplline, and then, with stirring I- with 5.30q of ethyl azo-bis-carboxylate in 15ml of Bunsen.
After 40 minutes of-stirrin~, the organic phase is washed with ON sulfuric (2x20ml), end then sodium carbonate (3x15ml) - 5 and finally water until neutral. Evaporation to dryness affords a mixture of d,l-3-exo-7-endo-dihydroxy-bicyclo ~3.3.0~ -octane -2-exo-carboxyMethylester-7-DMtB-silylether-3 - Bennett and d,l-7-endo-hydroxy-bicyclo .3.03Oct3-ene-2-exo-carboxymethylester-7-DMtB-silylether.
The crude reaction product is dissolved in an hydrous methanol, stirred for 3 hours, and treated with 0.5g of an hydrous potassium carbonate. Evaporation to dryness affords a residue which is taken up in ethyl acetate and saturated KH2PO~. The organic phase is washed until neutral and ova-prorated to dryness. The residue is adsorbed on silica gel and eluded with hexane and hexane:ethyl ether to give:
a) 1.01g of d,l-7-endo-hydroxy-bicyclo ~.3.C~oct-3-ene-2-carboxymethylester-7-DMtB-silylether, which is dissolved in methanol, treated with 0.3g of 5% Pod on Cook and hydrog-enacted at room temperature and pressure to give do end-hydroxy-bicyclo ~.3.0yoctane-2 carboxymethyles~er-7-DMtB-silylether;
b) 2.01q of d,l-3-exo-7-endo-dihydroxy-bicyclo ~3.3.03Octane-~~carboxvmethylester-7-DMtB-silylether, which is saponified I as described in Example 2 with 5% potassium carbonate in I
i 80:20 methanol water to give d,l-3-exo-7-endo-dihydroxy-bicycle ~3.3.0~octane -2~exo-carboxy acid-7-DMtB-sllyle-ther.
This is then separated into individual optical antipodes with (+) and (-) amphetamine.' Reaction with ethereal diazomethane converts I
3-exo-7-endo-dihydroxy-bicyclo[3.3.0~octane-2-exo--car boxy acid-7-DMtB-silylether into the methyl ester derivative.
Subsequent reaction with 2,3-dihydrcp~Tran followed by reduce lion with Lyle in ethyl ether jives (+)-3-exo~7-endo-2-exo-hydrox~methyl-bicyclo ~3.3.0~octane -3-THP-ether-7--DMtB-silylether.
The (-) enantiomers and the rhizomic mixture are pro-pared analogously.
Example 5 -5g of d t 1- 7-endo-hydroxy-bicyclo I ox octane-DMtB-silylether-3-exo-carboxymethylester in 100ml of aqueous moth-anon is saponified with 2g of OH at reflex. After the methanol is removed under vacuum, the aqueous solution o the potassium salt is extracted to remove neutral impurities, acidified, and extracted with ethyl ether. The latter ox-tracts are combined and evaporated to dryness to give 4.5q of the djl acid which is then separated into optical anti-poses with (+) and (-) ephedrine.
1~32g of (-)-7-endo-hydroxy-bicyclo~3.3.03Octane-7-US DMtB-silylether-2-exo-carboxy acid is then dissolved in 20ml ~84 I,, o-of Tilt' and treated Whitehall 1Oml of EM B113 in THY. fur A
hours at room temperature, the excess reaqeIlt is destroyed - by the cautious addition of 2Oml of 1.5N Noah. The THY is then removed under vacuum and the aqueous Phase is extracted with ethyl ether. The combined organic extract is washed until neutral and evaporated -to dryness to afford 1.02~ ox 7-endo-hydroxy-2-exo-hydroxymethyl-bicyclo~3.3.0]ooctane-7-DMtB-silylether.
The (+) isomer and the rhizomic mixture are prepared analogously.
Example 6 2.7g of d,l-7-endo-hydroxy-2-exo-hydroxymethyl-bicyclo-~3.3.0~octane 7-DMtB-silylether in 20ml of ethylene chloride is treated with 0.95g of 2,3-dihydropyran and 20mg of I-toluenesulfonic acid for 3 hours at room temperature. ~fterbeing washed with I aqueous Noah and then water, the organic phase is evaporated to dryness to give crude d,1-7-endo-hydroxy-2-ey~o-tetrahydropyrânyloxymethyl-bicyclo ~.3.0~octâne-7-DMtB-s~lylether. This is dissolved in 15ml of Tl-IF and treated with

4.5g of tetrabu-tylammonium fluoride for ours, with stirring.
the reaction mixture is then concentrated under vacuum, ad-sorbed on silica Mel and eluded with benzene:ethyl ether to give 2.1g of d,1-7-endo-hydroxy-2-exo-THP-oxymethyl-bicyclo-~3.3.0~octane. A solution of this product in 25ml of acetone is cooled to -20C - -8C with stirring and treated with 4.2ml Jo I

, ox I Jones' reagent (Crow in aqueous sulfuric acid) over a period of 15 minutes, until a slight wink color persists.
After an additional 14-20 minutes of stirring, 1.5ml of is-propanol is added drops and the resulting green solution

5 is diluted with 6 volumes of Bunsen. The organic phase is washed Whitehall 20~ (NAZI until neutral, and the combined aqueous phase is re-extracted with Bunsen. The combined Bunsen extract is dried and evaporated to dryness to afford 1.82q of d,l-2-exo-THP-oxymethyl-bicyclo ~.3.0~octan-7-one.
Thea net- and enact- isomers are prepared analogously.
Exàrnple 7 ._ With external cooling and stirring to keep the react lion temperature near 20-22C, a solution of 6.57g of pot-assume tert-butylate in 65ml of DMSO is added drops to

6.76g of 4-carbox~butyl-triphenyl-phosphonium bromide in Owl of DMSO. After the addition, the mixture is diluted with an easily ~olurne of water. acidified to OH 5 and extracted with ethyl ether. The aqueous phases are discarded, and the combined organic extract is re-extracted several times with 0.5N Noah. The alkaline aqueous phases are acidified to phi and re-extracted with 50:50 ethyl ether:pentane. This come brined organic extract is brought to small volume, treated with ethereal diazomethane until a yellow coloration per-sits, and then evaporated to dryness. The residue is then I dissolved in 50ml of acetone, treated with 20rnl of ON aqueous - I

PA . -I-oxalic acid, and held at ~0-~5C for 8 hours. after -the acetone is removed under vacuum, the aqueous phase is ox-- treated with ethyl acetate, and the combined organic extract is evaporated to dryness. Purification of the resulting residue on silica gel with ethyl ether as fluent jives a mixture ofd,l-5-cis,trans-[2'-exo-hydro~nethyl-bicycloL3.3.00 octane pentenoic acid methyl ester (`1.75g). The India visual isomers may be separated with high pressure liquid-liquid chromatography to the 5-trans-d,l and the suicidal isomers; the latter is named 5-cis-~(20-~12)-octanor-12 -hydroxymethyl-9a-deoxy-9a-methylene-prostacyci-5-ee.noic acid methyl ester.
triphenyl If the 4-carboxybutyl-~pnosphonium bromide in the above procedure is replaced by one of the following Witting reagents (3-carboxypropyltriphenylphosphonium bromide, 5-carboxypentyl-triphenylphosphonium bromide, 4-caxboxy-2-oxa-~utyltriphenylphosphonium bromide), the methyl esters of the f ollowin~ acids are prepared:
d,1-5--cis-~(20~12)-octanor-2 nor-12~-hydroxymethy1-9a-deoxy-9a-methylene-prostacycl-5-enoic acid, d,l-5~cis-~(20~12~-octanor-2ahomo-12~-hydroxymethyyl-9a-deoxy-9a-methylene-prostacycl-5-enoic acid;
d,l-5-cis-~(20~12)-octanor-3-oxa-12~-hydroxymethyll-9a-deoxy-- 9a-methylene-prostacycl-5-enoic acid;
as well as their trueness isomers and the individual net- and - I -enact- antipodes.
Example 8 stirred solution of 7.16q of 5-cis-c~(20-j12)-octanor-12~-hydroxymethyl-9a-deoxy-9a~methylene-prostacycllink acid methyl ester in 80ml of 75:25 henzene:dimethylsulfoxide is treated with 8.9g of dicyclohexylcarboo!iimide and then with 14.2ml of a pyridinium trifluoroacetate solution (prepared by adding 25ml of 75:25 benzene:D~SO to 1ml of trifluoroacetic acid and 2ml of pardon). After four hours of stirring, the reaction mixture is diluted with 100ml of Bunsen and 3g of oxalic acid in water is added drops. The dicyclohexylurea is removed by filtration, the or~anlc phase is separated and washed with water (5x6ml). Reduction in volume gives a bent zone solution of the formula derivative which is added all Jo at once co a solution of (2-oxo-heptyl3dimethyl phosphonate sodium salt. The latter is prepared by adding dryers 7.58g of (2-oxo-heptyl)-dimethyl phosphonate in Owl of an hydrous Bunsen to a stirred solution of 1.02q of sodium hydrides (80%
mineral oil dispersion) in an inert was atmosphere, contain-using stirring until Ho evolution ceases. After the addition of the formal derivative to this sodium phosphona-te salt, stirring is continued for 20 minutes. The reaction mixture is then neutralized with saturated monosodium phosphate soul-lion. The organic phase is separated, reduced to small volt use, adsorbed on silica gel and eluded with cyclohexane: ethyl I
I

etiner to jive yo-yo owe 5-cis-13-trans-9a-deoxy-9a-methylene-15-oxo-prostacycla-5,13-dienoic acid methyl 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-dunk acid;
5-cis-13-trans-9a-deoxy--9a-methylene-15-oxo-2alloomo-prostacycla-dunk acid;
S-cis-13-trans-9a-deoxy-9a-methylene-15-oxo-3-oxa--prostacycla-dunk acid;
as well as their trueness geometric isomers, in the net-, enact- and do forms.
Example 9 A stirred and cooled (5-8C) solution of 1.35g of 2-exo-hydroxymethyl-7-endo-hydroxy-bicyclo ~3~o~oc~ane-DMtB-silylether in 5ml of pardon is treated with 0.82g of bent oily chloride. After 8 hours at room temperature, ON H2SO~
is added and the mixture is extracted with ethyl ether to jive 2-exo-benzoyloxymethyl-7-endo-hydroxy-bicyclo~3.3..030ctane-7-DMtB-silylether. This silylether group is removed by reflex in 2Oml of acetone with 8ml of ON oxalic acid. The acetone is removed under vacuum and the residue is extracted with ethyl ether to afford, after purification on silica gel, 1.1i~ of 2-exo-benzoyloxymethyl-7-endo-hydroxy--bicyclo ~3.3. ox -25 octane. This is dissolved in pardon and then added ,,, r , _ to a solution of 1g of Crow in 1Oml of pardon. try 6 hours at room temperature, this mixture is diluted with 20ml of Bunsen and filtered. The filtrate is evaporated under vacuum and the residue is taken up in ON sulfuric acid and Bunsen. After being washed with ON H2S04 and Atari until neutral, the organic extract is evaporated to, dryness to afford 0.98g of 2-exo-benzoyloxymethyl-bicyclor3.3.0~octan-

7-one. A solution of this compound in 5ml of an hydrous THY
is then added to a solution of (2-oxo--5-trimethoxy-pentyl)-dim ethyl phosphonate sodium salt, prepared by adding drop-wise a suspension of 0.23g of I sodium hydrJde in THY to a solution of 2.12g of (2-oxo-5-trimethoxy-pentyl)-dimethyl phosphonale n 6ml of an hydrous THY. After 10 hours of stir-ring, the mixture is neutralized with 15~ KH2PO~, the THY
is evaporated under-vacuum and the residue is extracted with ethyl ether. The combined extract is concentrated in volt use, adsorbed on silica gel and eluded with hexane:ether to afford 1.1g of 2'-benzoyloxymethyl-bicyclo~3.3.Q~oct-7-enyl -1,1,1-trimethoxy-pent-5-en-~-one, or 12~-ben~oyloxymethyl-~(20-`~12)-octanor-4-oxo-9a-deoxy-9a-methylene-proostacycl-5-enoic acid-orthomethylester, as a mixture of the 5 is and trueness olefins which are then separated by high pressure liquid-liquid chromatography.
Subsequent treatment with aqueous methanol and H2So~
I gives the corresponding methyl ester derivatives. Reaction of I

-- 0.3g of methyl ester with 0.25ml of 1,3-ethanedithiol in ethylene chloride and a catalytic amount of BF3-etherate for 15 minutes at 0C then affords 12 ~benzoyloxymethyl-~207'12)-octanor-4,4-ethylenedithio-9a-deoxy-9a-meethylene-prostacycl-5-enoic acid methyl ester.
Example 10 0.8g of 12~-benzoyloxymethyl-'~(20~12)-octanor-4~oxo-9a-c1eoxy-9a-methylene-prostacycl-5-enoic acid methyl ester in 10ml of methanol is selectively de-benzoylated upon treat-mint with stirring with 0.15g of an hydrous K2C03. After the solvent is evaporated, the residue is taken up in 15% aqueous KH2P04 and ethylene chloride Jo afford upon evaporation of the organic phase 12~-hydroxymethyl~(20~12)-octanor-4-oxo-9a-deoxy-9a-methylene-prostacycl-5-enoic acid methyl ester..

A solution of this compound in 1Oml of Shekel and 1Oml of ethanol cooled to -20C is treated with 90mg of Noah and stirred for two hours. Excess reagent is then destroyed with 15~ aqueous acetic acid, the solvent is evaporated and the residue is aAsorbcd on silica Mel. Eiution 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 19 potassium carbonate to afford, after acidification and extraction with ethyl acetate, 0.1~g of I lo Jo 12f~-hydroxymethyl-~(20il2)~octanor-4S-hydroxy-9a~Dixie-methylene-prostacycl-5-enoic acid-1,4-~-lactone and 0.11g of the OR isomer Oxidation of these following the procedure in example 8 gives the 12 -formal derivatives.
Example 11 I .
Jo O.2~g of 4,4-ethylenetithio-l2l~-benzoyloxymethyl-(20-`,12~-oc-tanor-9a-deoxy-9a-methylene-pros-tacyycl-5-enoic acid methyl ester is selectively de-benzoylated upon methanols is with K2CO3 in an hydrous methanol to give the corresponding o 1~p~-hydroxymethyl derivative. This is then oxidized to the alluded according to the procedure in example 8 to give the formula derivative.
Reaction of 0.12g of this compound in Bunsen with the phosL:~hona1_e prepared from 0.177g of (2-oxo-3,3-dimethyl-~eptyl)-dimethyl phosphonate and 20mg of 80% Nay, as desk cried in employ I, gives 5,13t-16,16-dimethyl-4,4-dithio-ethylenedloxy-15-oxo-9a-deoxy-9a-methylene-prostacsuckle-dunk acid methyl ester.
In an analogous fashion, using (4-cys~lohexyl-2-oxo-o butyl)-dimethyl phosphonate as the phosphonate and the US-lactose from example 10 as the alluded affords 5,13t-4S-hy~roxy-15-oxo-9a-c~eoxy-9a-1nethylene-17-cyclohe yule ,19,20-trinor-prostacycla-5,13-dienoic acid-1,4-~-lactone. Or, with (3-phenoxy-2-oxo~propyl)-dimethyl phosphonate, 5,13t-4S-hydroxy-15-oxo-9a-deoxy-9a-methylene-17,1~,19,220-tetranor-I

16-phenoxy-prost~cycla-5,13-dienoic acid-1,4-~-lac-torle is prepared.
Ex~nple 12 .
Using (2-oxo-3S-metllyl-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-prostacycl-5-enoic acid-1,4-~-lactone as the alluded, the procedures of examples 8 and 11 afford:
5,13t-4R-hydroxy-15-oxo-9a-deoxy-9a-methylene-16S--methyl-prostacycla-5,13-dienoic Acadia- lactose;
5,13t-4R-hydroxy-15-oxo-9a-~eoxy-9a-methylene-15S--flyer-prostacycla-5,13-dienoic acld-1,4-~-lactone.
Example 1' A solution of 0.7g of 5c,13t-15-oxo-9a-deoxy-9a-methy-lene-p~ostacycla-5,13-dienoic acid methyl ester in 7ml of ethylene chloride and 7ml of ethanol cooled to -20C is treated with 3~mg of sodium bordered. Tory 20 minutes of stirring, the reaction is quenched with 2ml of acetone and 2.5ml of 20~ aqueous Noah. The mixture is then reduced in volume under vacuum and extracted with ethylene chloride.
The combined organic extract is evaporated to dryness to jive a residue which is purified on silica gel with ethyl ether as fluent to afford 0.3~g of 5c,13t-15S-hydroxy-9a-deoxy-9a-methylene-prostacycla-5,13-dienoic acid methyl ester and 0.26 of the 15R isomer.

.

.

119~34~8 This same procedure for reducing the 15-oxo derivatives from examples 8, 11 and 12 affords the methyl esters of the I- following acids: /
Swisstrans-9a-deoxy-9a-methylene-15S-hydroxy-2-nor--prooust-cycla-5,13-dienoic acid;
5cis,13trans-9a-deoxy-9a-methylene-15S-hydroxy-2ahhomo-prosta-cycla-5,13-dienoic acid;
5cis,13trans-9a-deoxy-9a-methylene-15S-hydroxy-3-ooxa-prosta-cycla-5,13-dienoic acid;
5cis,13trans-9a-deoxy-9a-methylene-4,4-diethioethyylenedioxy-15S-hydroxy-prostacycla-5,13-dienoic acid;
and tune 1,4-lactones of the following acids:
5C/13t-9a-deoxy-9a-methylene-4S,15S-dihydroxy-17-CCyClohexyl-18,19,20-~-trinor-prostacycla-5,13-dienoic acid;
5~/13t-9a-deoxy-9a-methylene-4S,15.S-dihydroxy-16--plunks-17,18,19,20-~tetranor-prostacycla-5,13-dienoic acid 5CI13t-9a-deoxy~-9a-methylene-4R,15S-dihydroxy-16SS-methyl-prostacycla-5,13-dienoic acid;
.513t-9a-deoxy-9a-metnylene-4R,15S-dihydroxy-1~S-fluurea-prostacycla-5,13 dunk acid;
as well as their trueness geometric isomers, in the net-, enact- and do forms.
Example 14 A solution of 0.35g of 5c,13t-15-oxo-9a-deoxy-9a~
- I methylene-prostacycla-5,13-dienoic acid methyl ester in 1Oml Jo - I

of 2:1 ethyl ether:toluene is cooled to -30C end treated with stirring with 5ml of I methyl magnesium iodide in ethyl ether. After 4 hour of stirring, the mixture is brought to 0C and quenched with 20~ aqueous amrnonium color-ides The orgcmic phase is washed with water, sodium vicar-borate and water, dried over McCoy, treated with 0.1ml of pardon, and evaporated under vacuum to jive a mixture of the 15S and 15R alcohols. Separation on silica gel with I` 80:20 ethyl ether isopropyl ether as fluent affords 0.1g of I5c,13t-15S-hydxoxy-9a-deoxy-9a-methylene-prostacycclue-dunk acid methyl ester and 0.1g of the 15R isomer.
Example 15 1. .
With the same substrate but an hydrous THY us sol-vent, reaction with 8ml of 0.3M ethanol magnesium bromide in TOUGH elves, after chromatography on silica gel, 5ct13t-15-ethynyl-15S-hydroxy-9a- deoxy-9a-rnethylene-~rostacyc.1a-dunk acid methyl ester and its 15R isomer.

With 0.3M vinyl magnesium bromide, 5c,13t-15-vinyl-15S-hydroxy-9a-deoxy-9a-methylene--prostacycla-5,13-diionic acid methyl ester and its 15R isomer are prepared.

. Example 16 - .

A solution of 0.26g of 5c,13t-9a-deoxy-9a-metI1ylene-4R,15S-dihydroxy-16S-methyl-prostacycla-5,13-dienooil acid-1,4-~-lactone in ethylene chloride is cooled to -10-~C

and treated wit stirring with 0.3ml of boron trifluoride ~.~

ethexate I x10 Al in anh~drous methirlene chloride) and then 5% diazomethane in ethylene chloride until a yellow color persists The solution is washed with 5% aqueous Nikko and then water until neutral, evaporated to dryness, and purified on silica gel (3g) to give 0.21g of 5c,13t-9a-deo~y-9a-methylene-4R,15S-dihydro~.y-16S-meth,771-prostacycla-dunk acid-1,4-~-lactone-15-methylether.
Exam to 17 A solution of 0.74g of d,1-2-exo-hydroxymethyl-3-exo-THP-oxy-7-endo-DMtB-silyloxy-bicyclo I octane in 15ml of an hydrous ethylene chloride is added all a- once to a solution of 3.1g of Coffin' 5 reagent ~C5H5N2)2 Crow in 40ml of an hydrous ethylene chloride, with stirring and cool-King to C-5~. Filtering earth is added aster 15 minutes of stirring and the mixture is filtered to give a clear solution of the corresponding d,1-2-exo-~ormyl derivative After the solvent is evaporated under vacuum, the residue is taken up in an hydrous Bunsen and added to a solution of sodium dip meth~rl-t2-oxo~octyl)-phosphonate. This latter is prepared by adding 0.5~g of (2~oxo-octyl)-dimethyl phosphonate in 1Oml of Bunsen drops to a suspension of 0.07g of 80% Nay in Owl of Bunsen and stirring the resulting mixture for approx-irately 1 hour until hydrogen evolution ceases. Stirring is continued for I minutes after the alluded is added to the phosphonate carbanion solution. The organic phase is then 1~l98~

neutralized with excess 25% aqueous Nope and separated After drying, it is evaporated to dryness to jive a residue which is purified on silica gel (cyclohexane:ethyl ether as fluent) 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 solution of 1.05g of d,1-2-exo-hydroxymethyl-3-endo-THP-oxy-7-endo-DMtB-silyloxy-bicyclo~3.3.0~occrane in 8ml of 75: 5 benzene:DMS0 is treated with 0.89~ of dusk-]ohexylcarbodiimide and-then, with stirring, with 1.42ml of a pyridinium trifluoroacetate solution. After hours of stirring, 20ml of Bunsen are added aloud excess carbodiimide is quenched with 0.13g of oxalic acid in 3.8ml of water.
The Hanson phase is separated, washed until neutral, and concentrated under vacuum to it a solution of 2-exo-formyl-3--endo-TIlP-oxy-7-endo-DMtB-silyloxy-bicyclo~3.3.octane The d,l,nat- and enantio-formyl derivatives are pro-pared using this procedure. In the same way, if 7-exo hydroxy-bicycle oaken --3-olle-7-dilllelhyl-tert-blltylsilyl-ether is used in the procedures of examples 1, 2 and3,2-exo-formyl-3-eI1do-THP-oxy~7-exo-DMtB-siloxy-bbicycle octane is obtained.
Example 19 A solution of 322mg of ~2-oxo-heptyl)-dimethyl pros-fount in Sol of Bunsen is added to a suspension of 43.5mg By I.

of 80~ Nay in 1Oml of Bunsen, and the resulting mixture is - stirred until hydrogen evolution ceases. In the dark, 258m~
of finely divided N-bromosuccinimide are added and stirring is continued for another 5 minutes. 0.37g of 2-exo-formyl-3-endb-TIIP-oxy-7-endo-D~1tB-silyloxy-bicyclo~3.3.octane in 5ml ox Bunyan is then added and the resulting mixture is stirred for another 15 minutes, after which the reaction mix-lure is partitioned between Bunsen and 15~ Nope. The organic phase is dried, concentrated to small volume, ad-sorbed on silica gel and eluded with 80:20 cyclohexane:ethyl other to afford 0.~2~ or 2-exo-~2'-bromo-3'-oxo-oct-1'-enyl~-3-endo-TI~P-oxy-7-endo-DMtB-silyloxy-bicyclo~3.3.0octane =251m~, =9,250~. -If ~2-oxo-3R-fluoro-heptyl)-dimethyl phosphonate is used, the corresponding 2-exo-~2'-bromo-3'-oxo-4'i~-fluoro-oct-1'-trans-~enyl3- derivative is obtained.
Example 20 A solution of 0.3g of ~2-oxo-4(2')-tetrahydrofuryl-butyl~-dlmethyl phosphonate is added drops to a stirred suspension of 36mg of 30~ sodium hydrides in 5ml of Bunsen.
Stirring is continued until hydrogen evolution ceases, and then a solution of 0.~7g of 2-exo-formyl--3-endo-THP-oxy-7-exo-DMtB-silylo~y-bicyclo ~3.3.0~octane is added. After another 20 minutes of stirring, the mixture is taken up in Bunsen and 20~ aqueous monosodium phosphate. The organic phase is separated, concentrated to small]. volume, adsorbed on silica gel and eluded with benzene:ethyl ether to give 0.35g of 2-exo-~3'-oxo-5'(2"~etrahydrofuryl-pent-1'-trans-enyl~-3-endo-THP-oxy-7-exo-DMtB-silyloxy-bicyclo ~3.3.0~octane (maxim 8,~00), Example 21 If 2-exo-formyl-3-endo-THP-oxy-7-endo-DMtB-si]yloxy-bicycle F3.3.Q~octane was the 2-exo-formyl-7-exo-bicyclo don-ivative used in the procedure described in example up, and if the following phosphates were used:
(2-oxo-heptyl)-dimethyi phosphonate f (2-oxo-o_tyl?-dimethyl phosphonate;
~2-oxo-3S-methyl-heptyl)-~imethyl phosphonate;
(2-oxo-4-cyc1~hexyl butyl)-dim~thyl phospronate;
(2-oxo-4~phenyl-butyl~-dimethyl phosphonate;
(2-oxo~3-n1-trifluoromethylphenoxy-propyl)-dimethyye phosphonate;
(2-oxo-3 methyl-3-butoxy-but.yl)-dimethyl phosphonate;
then the following compounds were prepared:
3-endo-THP-oxy-7-exo-DMtB-silyloxy-2-exo-(3'~oxo-ooust'-trans-1'-enyl)-bicyclo~3.3.0~octane;
3-endo-TEIP-oxy-7-exo-DMtB-silyloxy-2-exo-(3'-oxo--non-1'-- trans-1~-ellyl)bicyclo ~3.3.0]octane;
3-endo-TI~P-oxy-7-exo-DMtB-silyloxy-2-exo-(3'-oxo~smoothly-oct-1'-trans-1'-en~ icyclo~3~3.0~octane;
25 3-endo-T~IP-oxy-7-exo-DMtB-silyloxy-2-exo-~3'~oxo--suckle-I
j I, - . hexyl-pent~ c~ns-1~-el~yl~ bicycle ~3.3.0~octane;
3-endo-THP-oxy-7-exo-DMtB-silyloxy-2-exo- (3'-oxo-5'-phenyl-pent-1'--trans-1'-er~yl)-bicycloL3.3.0~oetane;
3~endo-THP-oxy-7-exo-DMtB-silyloYy-2-exo-t3'-oxo-44'-m-tri-fluoromethylphenoxy-but-1'- trans-1'-enyl)-~i~7Clo E~.3.0~1octane;
3-endo-THP-oxy-7-exo-DMtB-silyloxy-2-exo-(3'-oxo-4methyl-4'-butoxy-pent-1'-trans-1'-enyl)-bicyclor3.3.0~octlane.
Example 22 A solution of 0.3g of d,l-2--exo-(2'-bro:rno-3'-oxo-4'P~-10 1uoro-oct-1'-trans-l-enyl)-3-endo-TH~-oxy 7-endo-DMtB-silyloxy-Buckley ~3.3.0Joctane in Tom]. of anhydxous ether is added dxopwise in 15 minutes to a 0.1~1 solution of zinc bordered in ethyl ether (10ml). After stirring for two hours, the reaction mixture is quenched with saturated sodium chloride 15 and ON sulfuric acid. The ether layer is separated and washed with water, I Nikko, and then water. Evaporation to dryness affords a mixture of the 3'S and OR hydroxy alcohols which are separated by liquid liquid chromatography with isopropyl ether as solvent to sieve 0.11g of d,l-2-exo-~2'-bromo-3'S-hydroxy-4'R-fluoro-oct-1'-trans-1'enyl) 3-endo-THP-oxy-7-endo-DMtB-silyloxy-blcyclo 3.3.0 octane and 0.1g of the OR epimer.
Example 23 A solution of 0.3~ of 2-exo-L3'-oxo-5' (2")-tetrahydro-furyl-pent-1'-trans 7~nyl]-3-endo-THP-oxy-7-exo-DMtB-silyloxy bicyclo~3.3.0~octane in 3ml of ethylene chloride and 3ml owe 9~lB

ethanol is cooled to -10-15C and when treated with Moe of Nub. After 30 minutes of stirring, the reaction mixture is quenched with 1.5ml of acetone and 3ml of saturated Nope, evaporated under vacuum, and then extracted with ethylene chloride. The organic phase is dried over Nazi and vapor-axed to dryness to judge a residue which is purified on silica gel (hexane:ethyl ether as fluent) to affixed 0.1g of 2-exo-3'S-hydroxy-5'(2")-tetarhydrofuryl-pent-1'-trans ~enyl~-3-endo-THP-oxy-7-exo-DMtB-silyloxy-bicyclo [3.3.030ctane and 0.11g of the OR isomer.
Example 24 By following the procedure of examples 22 and 23 using one of the unstriated kittens prepared as in ox-apples 19, 20 and 21, the following compounds were prepared:
15 3-endo-THP-oxy-7-endo-DMtB-silyloxy-2-exo-(2'-brcrRuss-hydroxy-oxt-1'-trans-1'-enyl)-bicyclo r3.3.0] octane;
3-endo-T~IP-oxy~7-enc~o-D.~tB-silyloxy-2-exo-(3'S--hydroxy-oct-1'-trans-1'-enyl)-bicy_lo~3.3.0~octane;
3 endo-THP-oxy-7-endo-DMtB silyloxy-2-exo-(3'S-hydroxy-4'S-20 methyl-oct-1'-trans-1'-enyl)-bicyclo~3.3.030ctane;;
3-endo-THP-oxy-7-endo-DMtB-silyloxy-2-exo-(3'S-hyddroxy-non~
1'txans-1'-~1yl)-bicyclo ~3.3.030ctane;
end THP-oxy-7-endo DMtB-silyloxy-2-exo-~3'S-hydroxy-cyclo-hexyl-pent-1'-~rans-1'-enyl)-bicyclo~3.3.0~octane;;
25 3-endo-THP-oxy-7~-endo-DMtB-silyloxy-2-exo-(3'S-hyydroxy-5l-~198~

- phenyl-pent-1'-trans-1'-enyl) -bicycloF3.3.0~octane;
3-endo-TI-IP-oxy-7-endo-DMtB-sily].oxy-2-exo-(3'S--hydroxy-4'-m-trifluoromethylphenoxy-bu-t-1~-trans-1~-enyl)~biicicle.
octane;
3-endo-THP-oxy-7-endo-DMtB-silyloxy-2-exo~(3'S-hyddroxy-4'-methyl-4'-butoxy-pent-1'-~-ans-1'-enyl)-bicyclo ~3.3.0~octane;
3-endo-THP-oxy-7-endo-DMtB-silyloxy-2-exo-(2'-bromMyra-hydroxy-oct-1'trans-1'-enyl)-bicyclo~3.3.~octane;
3-endo-THP-oxy-7-endo-DMtB-silyloxy-2-exo-(3'R-hyddroxy-oct-1'-trans-1'-~nyl~-bicyclo~3.3.0~ octane;
3-endo-THP-oxy-7-endo-DMtB-silyloxy-2-exo-(3'R-hyddroxy-4'S-methyl-oct-1'-trans-1'-enyl)-bicyclot3.3.Q30ctane;;
3-endo-TT~P-oxy-7-endo-DMtB-silyloxy-2-exo-(3'R-hyydroxy-non-1'-trans-1'-e~yl~bicyclo [3.3.0~octane;
3-endo-TXP-oxy-7-endo-DMtB-silyloxy-~-exo-(3sR-hydproxy-5'-cyclohexyl-pent-1 r trans-1'-enyl)-bicyclo.r3.3.0~octane;
3-endo-THP-oxy-7-endo-DMtB-silyloxy-2-exo-(3'R-hyddroxy-5'-phenyl-pent-1'-trans-1'-enyl)-bicyclo~3.3.0~octanee;
3-endo-THP-oxy-7-endo-DMtB-silyloxy-2-exo-(3'R-hyddroxy-4'-m-trifluoromethylphenoxy-but-1Ltrans-1'-enyl)-bicyyokel ~3.3.0~-octane;
3-endo-TT-TP-oxy-7-endo-DMtB-silyloxy-2-exo-3'4-hyydroxy-4'-methyl-4l-butoxy-pent-1'-trans-1'-~yl)-~icyclo ~3.3.OloctaneO
- Example 25 A solution of 1.17g of 2-exo-(3'S-hydroxy-oct-1'-,ç~3 . Jo _ trueness eny]t3-endo-THP-oxy-7-endo-DMtB-silyloxy-bicyclo-L3.3-0Jactc~ne in 12ml of an hydrous ethylene chloride is treated with 120mg of 2,3-dihydropyran and 5mg of Tulane cellophane acid. after 4 hours at room temperature, the organic phase is washed successively with 5% Nikko and water and then evaporated to dryness to give 1.45g of crude 2-~xo-(3'S-THP-oxy-oct-1'~trans-1'-enyl)-3-endo-THP-oxy-7-enddo-DMtB-silyloxy-bieyclo~3.3.0~oetane. This product is dissolved in 12ml of THY and treated with 2g of tetrabutylammonium fluoride The resulting mixture is stirred for 12 hours at room temporal-use and concentrated to small volume to give a residue which is purified on silica gel methyl ether as fluent) to afford 920mg of 2 exo-(3'S-hydroxy-oct-1'trcms-1'-enyl) end-endo-dihydroxy-bicyc1o L3.3.0Joetane-3,3'-bis-THP-ether.
US sample 26 Using the procedure of example 25 with compounds pro-pared according to examples 22, 23 and 24, the felon bieyelo~3.3.0~oetane-3,3'-bis-THP-ether derivatives were prepared:
20 2-exo-(2'-bromo-3'S-hydroxy-4'-fluoro-oct-1'-transsunnily 3-endo~7-endo-dihydroxy;
2-exo-(2l-brQmo-3'R-hydroYy-4'R-fluoro-oct-1'-tranns-1'-enyl)-3-endo-7-endo-dihydroxy;
2-exo-(3'S-hydroxy-5'(2")-tetrahydrofuryl-pent-1'--trueness'-enyl)-3-endo-7-exo-dihydroxy;

6~b I. .

- 2-exo-(3iR-hydroxy-5'(2")-tetrahydrofuryl-pent~ trans-1l-enyl)-3-endo-7-exo-dihydroxy;-2-exo-(2'-bromo-3'S-hydroxy~oct-1'-trans-1'-enyl)~end-endo-dihydroxy-;
52-exo-(2'-bromo-3'X-hydroxy-oct-1'trans-1'-enyl)-3end-ndo-dihydroxy;
2-exo-(3'S-hydroxy-oct-1'-trans-1'-enyl)-3-endo-7--endo-dihydroxy;
2-exo-t3'R-hydroxy-oct-1'-trans-1'-enyl)-3-endo-7--endo-dihydroxy;
2-eYo-(3'S-hydroxy-4'S-methyl-oct-1'-trans-1'-enylLund-endo-dihydroxy;
2-exo-(3'R-hydroxy-4'S-methyl-oct-1l-trans-1'-enylLund 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'-enyl~3-endo-7-eendo-dihydroxy;-2-exo-(3'S-hydroxy-5'-cyclohexyl-pent-1'-trarl5-1''-enyl)-3-end 7-endo-dihydroxy;
2-exo-(3'S-hydroxy-5'-phenyl-pent-1'-trar.s-1~-enyyenned ~ndo-d.ihydroxy;
2-exo-(3'R-hydroxy-5'-phenyl-pent-1'-trans-1~-enylLund endo-dihydroxy;
2-exo-(3'S-hydroxy-4~-m-trifluoromethylphenoxy-butt-1~-trans-1 enyl)-3-endo-7-endo-dihydroxy;
2-exo-(3lR-hydroxy-4~-m-trifluoromethylphenoxy-butt-1~-trans-1 enyl)-3-endo-7-endo-dihydroxy;
25 2~exo-(3'S-hydroxy-4'-methyl~4'-butoxy-pent-1'-traans-1'-enyl)-3-endo-7-endo-dihydroxy;

2-exo-(3'R-hydroxy-4'--methyl-~'-butoxy-pent~ tr~ns-1'-en~1) 3~endo-7-endo-dihydroxy.
example 27 Successive portions of a solution of 0.4g of chronic android are added with stirring to 4ml of pardon. Once the complex is formed, this mixture is treated with 0.36g of 2-exo-(3'S-hy~roxy-5'(2")-tetrahydrofuryl-pent-1'--tranS-1'-enyl)-3-endo-7-exo-dihydroxy-bicyclo~3.3.0~octane-3,3'-bbis-THP-ether in 4ml of pardon. The reaction mixture is held over-night at room temperature, diluted with 3 volumes of Bunsen, and filtered. The filtrate is then evaporated to give a nest-due which s partitioned between Bunsen and ON sulfuric acid.
The aqueous portion is re-extracted with Bunsen, washed sue-cessivel~ with water, Newark and water, and evaporated to ~rvness to give 0.31g of 2-exo-(3'S-hydroxy-5'(2" twitter-hdyrofuryl-l~ent-1'-trans-1'-enyl~3-endo-hydroxy-bbicycle-octan~7-one-3,3'-bis-THP-ether.
_ m A stirred and cooled (-10-5C) solution of 0.8g of 2-exo-(3'S~hydroxy-oct-1'-trans-1'-enyl)-3-endo-7--endo-dihydroxy-bicycle .3.0]octane-3,3'-bis-THP-ether in 2Gml of acetone is treated with 1.6ml of Jones' reagent in 15 minutes. After another 15 minutes of stirring, 80ml of Bunsen is added.
The organic phase is separated, washed with I aqueous ~NH4)2SO~ until neutral, dried and evaporated to dryness to -I afford 0.71g of 2-exo-(3'S-hydroXy-oCt-1'-trans-1'-enyl)-endo-hydroxy-bicyclo t 3-3-0~ octan-7-one-3~3'-~is-tetrahydro-pyranylether.
Example 29 Using either of the oxidation procedures described in examples 27 and 28 on the trios 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-4'R-fluoro-oct-11-tranns-1'-enyl);
2-exo-(2'-bromo-3'R-hydroxy-4'R-fluoro-oct-1'-tranns-1'-enyl);
2-exo-(3'S-hydroxy-5'(2")-tetrahydrofuryl-pent-1'--trans-1'-enyl);
2-exo-(3'R-hydroxy-5'(2")-tetrahydro~uryl-pent-1'--tranS-1'-enyl);
2-exo-(2'-bromo~3'S-hydroxy-oct-1l-t.ranS-1'-enyl));
2-exo-(2'-bromo-3'R-hydroxy-oct-1'-tlans-1'-enyl);;
I 2-exo-(3'S-hydroxy-oct-1:-tranS-1'-enyl);
2-exo-(3'R-hyclroxy-oct-1' tran~-1'-ènyi);
2-exo-(3'S-hydroxy-4'S-methyl-oCt-1'-tranS-i'-enyll);
2~exo-(3'R-hydroxy-4'S-methyl-oct-1'-trans-1'-enyll);
2-exo-(3'S-hydroxy-non-1'-trans-1'-eny]);
2-exo-(3'R-hydroxy-non-1'-trans-1'-enyl);
2-exo-(3'S-hydroxy-5'-cyclohexyl-pent-1'-trans-1'--enyl);
2-exo-(3'R-hydroxy-5l-cyclohexyl-pent-1'-trans 1'-enyl);
2-exo-(3'S-hydroxy-5'-phenyl-pent-1'-trans~1'-enyll);
2~exo-(3'R-hydroxy-5'-phenyl-pent-1'-tranS~ enyl);
2-exo-(3'S-hydroxy-4'-m-trifluoromethylphenoxy-butto trays-. , , Jo I
I. .

enyl);
2-exo-(3'R-hydroxy~4'-m-trifluoromethylphenoxy-butt-1'-trans-1'-enyl);
2-exo-(3'S-hydroxy-4'-methyl-4'-butoxy-pent-1'-traans-1'~enyl);
2-exo-(3'R-hydroxy-4'-methyl-4'-butoxy-pent-1'-traans-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-bicyclo~33~3.0~octane "
(prepared according to example 17) is reduced at -15C in ethylene chloride ethanol with 0 17g of Nub, following the procedure of example 23, to afford 2.01g of d,l-2-exo-(3'(S,R)-hydroxy-non-1'trans-1'-enyl~-3-exo-THP-oxy-7-endo--DMtB-silyl-oxy-bicyclo L3.3.0yoctane. Without separating the 3'S end OR alcohols, this product is reacted in 30ml of ethylene chloride with 0.4g of 2,3-dihydr~pyran in the presence of 25mg of p-toluene~ulfonic acid to jive the corresponding do exo-(3'(S,R)-hydroxy-non-1'-trans-1'-enyl)-3-exo-hhydroxy-7-endo-DMtB~silyloxy~bicyclo~3.3.03Octane-3,3'-bis-TTHP-ether.
With no further purification, this product is Ideated with I; en ruts 2~5 molar eq~}~herL~ of tetrabutyl anonym fluoride in THY
to remove the sill ether.
The product d,l-2-exo-(3'(S,R) hydroxy-non-1'-trans-1'-enyl)-3-exo~7-endo-dihydroxy-bicyclo~3.3.0~octane--Boyce-THP~ether ~1.660g) is then oxidized with pardon - chronic android to give 1.25g of d,l-2-exo-(3'(S,R)-hydroxy-non-I

trans-1'-enyl)-3-exo-hydroxy-bicyclo~3.3.030ctan-77-one-3,3'-bis-qlHP-ether.
Example 31 A solution of (2-oxo-5,5,5-trimethoxy-pentyl)-dimethyl phosphonate in 1Oml of THY is added drops to a stirred - suspension of 68mg of Nay (80~) in 1Oml of an hydrous THY.
Stirring is continued until hydrogen evolution ceases, and then a solution of 0.67g of d,l-2-exo-~3'(S,R~-hydroxy-non-1Ltxar.s-1'-ellyl)-3~exo-hydroxy-bicyclo~3.3.0~ octan-7-one-3,3'-bis~T~P^-ether in 5ml of THY is added. after it hours of stir-ring at 40-45C, 20ml of 20% Nope is added and the THY is removed under vacuum. The residue is extracted with ethyl ether. and the organic extract is dried over Nazi and ova-prorated. adsorption of the residue on silica gel and elusion with cyclohexane ethyl ether afford 0.76g of d,l-5t,13t-4-oxo~
11~,15(S,R)-dihydroxy-20-methyl-9a-deoxy-9a-methyllene-prosta-cycla-5,13-dienoic acid-trimethylorthoester-11,15-bis-THP-ether.
A solution of this product in 15ml of an hydrous moth-anon is treated with 6mg of p-toluenesulfonic acid for 5 hours at room temperature. 0.1ml of pardon is added, the soul-lion is evaporated to dryness, and the residue is purified on silica gel (isopropyl ether ethyl ether as fluent) to afford 0.20g of d,1-5t,13t-4-oxo-11~,15S-dihydroxy-20-methyl-9a-deoxy-9a-methylene-prostacycla-5,13-dienoic acid-trimethyl-I orthoester and 0.21g of the 15R epimer.

I
I`

Example 32 Following the procedure of example 31 with a bicycle-~3.3.0~octan-7-one prepared as in examples 27, 28 and 29, the following trimethylorthoesters were prepared:
5,13t-4-oxo~11~,15S-dihydroxy-9a-deoxy-9a-methylenne-prosta-cycla-5~13-dienoic acid;
5,13t-5-oxo-11~,15S-dlhydroxy 9a-deoxy-Sa-methylene-20-methyl-prostacycla-5~13-dienoic acid;
5,13t-4-oxo-11~,15S-dihydroxy-9a-deoxy-9a-methylenNoah')-tetrahydrofuryl-18,19,20-trinor-prostacycla-5,13-ddunk acid;
5,13t-4-oxo-11~,15S-dihydroxy-9a-deoxy-9a-methvlenNemo-trifluoromethylphenoxy-17,18,19,20--etranor-prostaacycla-dunk 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 owe aqueous methanol gives the free acid.
Example 33 solution of 0.45g of Tao ',15S-dihydroxy-9a-deoxy~9a-methylene-prostacycla-5,13-dienoic acid-trimethyl-orthoester (maxim =9,850) in 6ml of methanol and 1.2ml of 0.2N oxalic acid is reflexed for two hours. Evaporation of the methanol under vacuum and extraction with ethyl ether give 0.42~ of the correspondinc3 Methyl ester.
A solution of this product in 6ml of an hydrous ethyl ether is added drops to a stirred 0.1M solution of zinc bordered (1Oml) in 10 minutes. After 1 hour of stirring at room temperature, the reaction is quenched with I sulk uric acid. The organic phase is separated, washed until neutral, and evaporated to dryness to give 0.4g of sty-4(S,R),11~,15S-trihydroxy-9a-d20xy-9a-methylene-prrostacycla-lo 5,13 dlenoic acid methyl ester. Chromatoc3raphic separation on silica gel methyl ether ethyl acetate as fluent) affords 0.11g of5,13t-45,11~,15S-trihydroxy-9a-deoxy-9a-methylene--prostacycla-5,13-dienoic acid methyl ester and 0.14g of the 4R-epimer methyl ester.
A solution of the latter compound in 5ml of methanol is treated with 0.05c3 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 pi 5.5 and rapid extraction with ethyl acetate afford Strauss-'O trihydro~;y-9a-deoxy-9a-methylene-prostacycla dunk acid. Treatment of a stirred ethyl acetate solution of this compound with C.5 parts of a polystyrenesulfonic resin (ho-droc3en ion form) chives s,13t-4R,11~,15S-trihydroxy-9a-deoxy~
9a-methylene-prostacycla-5,13-dienoic acid-1,4-~-lactone quantitatively.

.

, The US epimer-~-lactone was prepared analogously.
Example 34 A solution of 0.8g of 5,13t-4-oxo-11~,15S-dihydroxy-20-methyl-9a-deoxy-9a-methylene-prostacycla-5r13-ddunk acid-trimethylorthoester-11,15-bis-THP-ether in 20ml of ethylene chloride:ethano] is cooled to -20C and t elated with 50m~
of Nub. After 30 minutes of stirring, the reaction is quenched with 2ml of acetone and 5ml of saturated monosodium phosphate. Evaporation of the ethylene chloride and ethanol under vacuum and repeated extraction with ethyl ether afford, after the combined organic extract is dried and evaporated, 0.75g of 5~13t-4(S,R),11~15S-trihydroxy-20-methyl adieux-9a-methylen~-prostacycla-5,13-dienoi~ acid-trimethylorthoester-11,15-bi--THP-ether.
This crude product is dissolved in 2.2 ml of methane-sulfonyl chloride. The reaction mixture is held overnight at room temperature an then partitioned between iced ON
sulfuric acid and ethyl ether. The combined organic ox-tract is washed with brine, dried and evaporated at low them-portray to give 5,13t-4(S,R),11~,15S-trihydroxy-20-methyl-9a-deoxy-9a-methylene-prostacycla-5,13 dunk acid-trime~hyl-orthoester-4-mesylate-11,15-bis-~-ether.
With noiEurther purification, this product is dissolved in an hydrous ethyl ether and treated with 50mg of lithium I aluminum hydrides in ethyl ether. after stirring for 2 hours says it at room temperature and 1 hour at reflex, the reaction my,-lure is quenched with 2ml of ethyl acetate and then wet ethyl ether. Drying over Nazi and evaporating the ethyl ether give 0.5g of crude 5,13t-11~,15S-dihydroxy-20--methyl-9a~deoxy-9a-methylene-prostacycla-5,13-dienoic acid-trime~hyl-orthoester-11,15-bis-THP-ether.
After treatment at reflex with 1 2ml of methanol and 4ml of 0.3N aqueous oxalic acid, standard work-up gives 0.2g of 5,13t~ ,15(S)-dihydroxy-20-methyl-9a-deoxy-9a-methylene-JO prostacycla-5,13 dunk acid methyl ester. Liquid-liquid chromatography shows that the product is mainly trays I
with 15 of the is isomer.
Example 35 In an inert gas atmosphere, a stirred suspension owe 0.4g of Nay (75~ mineral oil dispersion) in 13.5ml of DMSO
is heated to 60-65C for 4 hours. The mixture is then cooled to room temperature and held at 20-22C while egg of 4-carboxy-butyl-triphenyl phosphonium bromide in 6ml of DMSO
and 0.85g of 2~exo-(3;S--hydroxy-non-1ltrans-1'-enYl)-3-endo-hydroxy-bicyclo ~3.3.0~octan-7-one-3,3'-bis-T~ ether are added successively. After stirring for 3 hours, the mixture is diluted with 35ml of water and the aqueous phase is ox-treated with ethyl ether (5x12ml) and ethyl ether:benzene (7x12ml) 4' The combined organic extract is re-extracted with - 25 0.5N Noah (3x15ml) and then water until neutral, and then I' .

discarded. The combined aqueous alkaline extract is acidified to pi 5.3 and extracted with 1:1 ethyl ether:pentane. Nash-in until neutral, drying over Nazi and removing the sol-vent afford 0.86g 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 esterified by treatment with diazomethane, and the perineal protecting groups are removed, as follows:
The methyl ester is dissolved in an hydrous methanol and treated with a solution of 10 2 molar equivalents of p-toluenesulfonic acid. After hours, the p-toluenesulfonic acid is neutralized with pardon and the mixture is evapora-ted to dryness Purification on silica Cole affords 5,13t-11~,1~S-dihydroxy-9a-deoxy-9a-methylene-20-methyl--prostacycla-dunk acid methyl ester, which is then separated into the individual 5c,13t and 5t,13t isomers by liquid-liquid chromatography.
Example _ With stirring and external cooling to keep the react I lion temperature at 20-22C, a solution of freshly sublimed potassium tert-butylate in 12ml of an hydrous DMSO is treated successively with 1.8g of 4-carboxybutyl-triphenyl phosphonium bromide in 1Oml of Also and 0.65g of 2-exo-(2'-bromo-3'S-- hydroxy-oct-1'-trans-1'-enyl)-3-endo-hydroxy-bicycdo ~3.3.0~ -octane one-3,3'~bis-THP-ether in 5ml o. DMSO. After stirring -. for 8 hours at room temperature, the mixture is diluted with an equal volume of water, acidified to pi 5 and extracted with 1:1 ethyl e-ther:pentane. The acidic aqueous phase is discarded, and the combined organic extract is extracted with 0.8~ Noah (5x20ml) and then water water until neutral.
While this organic phase is discarded, the aqueous alkaline extract is acidified to pi 5 and extracted with 1:1 ethyl ether:pentane. Ire combined extract is dried over Nazi, filtered and treated with ethereal diazomethane until a yellow coloration persists. Evaporation to dryness gives crude11~,15S-dihydrcxy-9a-deoxy-9a-methylene-prostacycll-5-en-13-ynoic acid methylester-11,15-bis-TH~-ether. Removal of the perineal protecting group followed by liquid-liquid Jo chromatography gives 5c-11~,15S-dihydroxy-9a-deoxy-9a-meth-I ' note ylene-prostacycl-5-en~13- acid methyl ester, plus the it geometric isomer.
Example 37 -When the bicycle ~3.3.0~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,13t-11~,15S-dihydroxy-9a-deoxy-9a-methylene-proo~tacycla-dunk acid;
5c ,15S-dihydroxy-9a-deoxy-9a-methylene-16R-fluoro-prostacycl-5-en-13-y~noic acid;

I

5c~ ,155-dihydroxy-9a-deoxy-9a-methylcne-16S-fluoro-prostacycl-5-~n-13-ynoic acid 5c-11~,15S-dihydroxy-9a-deoxy-9a-methylene-17(2')--twitter-hydrofuryl-13,19,20-trinor-prostacycl-5-en yank acid;
5c-11~,15S-dihyclroxy-9a-deoxy-9a-methylene-prostaacycl-5-en yank acid;
5c,13t-11~,15S-dihydroxy-9a-deoxy-9a-me~hylene-proostacycla-dunk 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--phenol-18,19,20-trinor-prostacycla-5,13-aier.oic acid;
5c,13t-1,~,15S-dihydroxy-9a--deoxy-9a-methylene-166-m-~F3-phenoxy-17,18,19,20-tetranor-prostacycla-5,13-diennote acid;
5c,13t~ ,15S-dihdyroxy-9a~deoxy~9a-methylene-16-methyl-16--butoxy-18,19,20-trinor-prostacycla-5,13-dienoic acid;
as well as their 5-txans geometric isomers, plus the 15R
epimers of both.
These were then saponified to give the free acids.
Example 38 A solution of 0.45g of 2-exo-(3'S-hydroxy-oct-1'-trans-1l-enyl~3~endo-hydroxy-bicyclo [3.3.~ octan-7-one-3,3'-bis-THP-ether in ethyl acetate is hydrogenated at ambient ~9~34~

temperature and pressure in the presence of 0.1g of 5% Pod/
Cook, 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~33.3.03-octan-7-one-3,3'-bis-THP-ether. Treatment of this with the Witting reagent prepared from 4-carb~xy-butyl phosphonium bromide according to examples 35, 36 and 37 affords a pro-duct which is esterified with diazomethane and depyranylized to give 0~12g ox ,15S~dihydroxy~9a-deoxy-9a-methylene-prostacycl-5~enoic acid methyl ester. The Swiss and trueness geometric isomers are separated by liquid-liquid chromatography - Example 39 Usury (3-carboxy-propyl)-phosphonium bromide in the procedure of examples 37 and 38 instead of (4-carboxy-butyl)-phosphoni~um bromide gave the following acids:
5c,13t~,15S-dihydroxy-9a-deoxy-9a-methylene- 2-nor-prosta--cycla-5,13-dienoic;
5c~,15S-dihydroxy-9a-deoxy-9a-methylene-2-nor-prostaccycle 5-enoic;
Skye,15S-dihydroxy-9a-deoxy-9a-methylene-2-nor-prostaccycle 5-en-13-~noic 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-ga-methylene-2ahomo-prostacycla-5,13-diennote acid - and 5,13t~ ,15S-dihydroxy-9a-deoYy-9a-methylene-20-methyl-2a~lc,mo-prostacycla-5,13-dienoic acid were prepared.
Example 41 A solution of 0.37g of 5c,13t~ ,15S-dihydroxy-9a-deoxy-9a-methylene-prostaeycla-5,13-dienoic acid methyl ester in 10ml of Bunsen is heated to 50C with 250mg of 2,3~dichloro-5,6-dieyano-benzoquinone for 8 hours. The pro-cipitate is removed by filtration, and the Bunsen solution is purified on a short alumina column to give 0.29g of 105c,13t-11~-hydx^xy-15-oxo-9a-deoxy-9a-methylene-prrostacyela-Dunn acid methyl ester.
A solution of this product in ethyl ether:toluene is cooled to -20C and treated with 1.2ml of EM methyl magnesium bromide in ethyl ether. After 2.5 hours at -2PC, the fee_-lion is quenched with NH~Cl solution. The organic phase is separated, reduced in volume and purified on silica gel (ethyl ether ethyl acetate as fluent) to give 0.1g of 5c,13t-11~f15S-dihydroxy-15-methyl-9a-deoxy--9a-methylene-prostaeeyela-5,13-dunk acid methyl ester and 0.072g of the 15R hydroxy epimerO

A solution of 2.2g of 3-endo-hydroxy-bicyclo ~3.3.0~ -octan-7-one in 100ml of anhydxous Bunsen is treated with 4ml of ethylene glyeol and 0.2g of p-toluenesulfonie acid moo-hydrate and reflexed for 12 hours while the water which forms during the reaction is elected 0~25ml of pardon is then added and the mixture is cooled. The organic phase is washed with water, Nikko and then water, and evaporated to dryness to give 2.32g of 3-endo-hyclroxy-bicyclo ~3.3.0~octan-7-one-7,7-ethylenedioY.ide.
A solution of this product in 40ml of acetone is cooled to -5C and treated at this temperature with 4.1ml of Jones' reagent. After 20 minutes at -5C, excess oxidant is quenched with 4ml of isopropyl alcohol. 150ml of Bunsen is added, and the Bunsen phase is washed successively with 20% (NH~)2SO4, water, 5% Nikko and water. Evaporation to dryness gives 2.1g ofd,l-bicycloL3.3.0~octan_3,7-dione-2-carboxymethyleester-7,7-ethylenedioXide.
According to the procedure of example 2, a solution of this product in 20ml of Shekel an 20ml of ethanol is reduced with Nub at -2~C to give 1.72g of d~l-3-endo~hydxoxy-bicycle ~3.3.0~octan-7-one -2-exo-carboxymethylester-7,7-ethylenedio~ide.
A solution of 1.57g of this compound in 3ml of dip methylformamide is treated with 1~3g of dimethyl-tert-butyl~silyl chloride and 0.835g of imida~ol, and then holdout OKAY for 5 hours. After cooling, water is added and the usual workup affords 2.3g of d,l-3-endo-hydroxy-bicyclo ~.3.Q~
octan-7-one-2-exo-carboxymethylester -7,7-ethylenediXide-3-di~nethyl-tert-butylsilylether. Subsequent reduction with 25 Lyle in an hydrous ethyl ether, as described in example 3, Gil 98~18 gives d,l-3-endo--hydroxy-2~exo~liyclrox~7me~h~ -7-,-7-ethylene-dioxy-b~cyclo ~3.3.o3octan-7-one-3-dimethyl-tert--butyl sill ether quantitatively.
Example 43 By using dithioethylene glycol in the procedure of example 42 instead of ethylene gawkily, the corresponding 7,7-ethylenedithio analogies were prepared.
Example 44 1.~g of d,l-3-endo-hydroxy-2-exo-hydroxymethyl-7,7-ethylenedioxy-bicyclo ~.3.0~ctan-7-one-3-dimethyl-tert-butyl sill ether is oxidized according to the procedure of example I to alive the corresponding formula derivative. This is then reacted with (2-oxo-heptyl)-dimethyl phosphGnate as in example 20 to give 1.23g of d,l-3-endo-hydroxy-2-exo-(3'-oxo--oat 1'-trans-1'-enyl)-7,7 ethylenedioxy-bicyclo ~3.3.0~octan-7-one -3-dimethyl-tert-butyl silylether ( axiom).
According to the procedure in example 22, this is reduced with zinc bordered in ether to give 1.22g of d,l-3-endo-hydroxy-2-exo-(3'(S,R)-hydroxy-oct-1'-trans-1'-enyyl)-7,7-ethy-lenedioxy-bicyclo ~.3.0~octan-7-one ~3-dimethyl-tert-butyl silylether.
A solution of this compound in 25rrl1 of methanol is treated with 1Oml of ON H2S04 at reflex for 50 minutes. The methanol is evaporated under vacuum, the residue is ox-- 25 treated with ethyl ether, and the organic phase is evaporated AL 9 Lo to dryness to afford 0.72g of Claude d,l-3-endo~hyc1roxy-2- -exo-(3'(S,R)-hydroxy-oct-1'-trans-1'-enyl)-bicyclooC3.3.~octan-7-one. The individual isomers are separated by cremate-rough on silica gel with hexane:ethyl ether as fluent and then converted to the tetrahydropyranyl ethers by treatment with 2,3-dihydropyran in ethylene chloride as in example 25~ In this fashion, a compound identical in all respects to 2-exo-~3'S-hydroxy-oct~ trans-1'-enyl)-3-end o-hydroxy-bicycle[3.3.0~octan-7-one-3,3'-bis-tetrahydropyranyletherr prepared as in example 28 is prepared from the 3IS-hydroxy isomer.
Similarly, with the procedure-- of examples 42 and 44, all the compounds prepared as in ex~nples 27, 28 and 29 were obtained.
Example 5 Saponification of 4. 8g of d,l-3-endo-hydroxy-2-exo-carboxymethylester-7,7-ethylenedioxy-bicyclo ~3.3.0~octan-7-one with 100ml of 2~50 potassium carbonate in 80:20 methanol water at reflex for 40 minutes and subsequent workups described in example 2 gave ~.02g of d,1~3-endo-hydroxy-2-exo-carboxy-bicycle ~3.3.0~octan-7-one -7,7-ethylenedioxide. This come pound is dissolved in 8Qml of an hydrous tetrahydrofruan, cooled to -10C, and treated drops with 2~1g of txiethylamine.
in 12ml of an hydrous tetrah~drofuran and then 2~2g of ethyl - 25 chlorocarbonate in 12ml of an hydrous tetrahydrofuran, while " I, keeping the temperature at -10C. After 1 hour of stirring at -10C, 1.4g of sodium aside in 12ml of waler is added slowly and stirring is continued for another 25 minutes.
The reaction mixture is then concentrated under vacuum and -5 diluted with water. The 2-exo-carboxy-azide is isolated rapidly by filtration and dried under vacuum.
A solution of . 01g of this compound in 8ml of pyre-dine is treated with 4ml of acetic android and held at 5-8C for 24 hours. 'rho reaction mixture is then partitioned between ice water, ethyl ether and ON 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-~ Q30ct:an-7-one -3-acetate-7,7-ethylene-dioxide.

This product is suspended in acetic acid Owl and water (8ml), and the mixture is heated to 40C. When hydra-gun evolution is noted, it is heated to 60-70C for 2 hullers, aster which the excess acetic acid is removed by steam disk tillation. After cooling, the mixture is extracted with ethyl ether ethyl acetate and the aqueous phase is brought to pi 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.C~octan-7-one -3-acetate. Reaction of this with the mixed ashy-drive from ethoxycarboyl chloride and 2S-hydroxy-heptanoic I

acid-2-acetate affords3-endo-hydroxy-2-exo-(2'S-acetoxyheptanoyl-amide)--bicyclo[3.3.0]octan-7-one-3-acetate. A solution ox this compound in an hydrous dimethylsul~oxide is -then reacted with the slide obtained Rome ~-carboxybutyl-triphenyl phosphonium bromide to give, after saponification, 5t-11~,15S-dihydroxy-9a-deoxy-9a-methylene-12-aza--13-oxo-prostacycl-5-enoic acid.
In an analogous fashion the wrap analog was prepared from the 2'R-hydroxy-heptanoic acid.

.
I

Example 46 Ethylene glycol (15 ml) and p toluensul~onic acid (009 go are added to a solution of 2-exo-bromo-3-endo-hydroxy-bicyclo ~3.2~0 hootenanny in Bunsen and the mixture is relaxed for 12 hours withdrawing water which forms during the reaction, when the mixture is added by pardon (0.6 ml) and cooled at room - temperature.
The organic phase is washed with water, 2. 5% aqueous Nikko and water, dried. Bunsen (lo ml) is partially removed in vacuum, then the mixture is treated with tributyltin-hvdride (41 g) in N atmosphere at 55 for 8 hours temperature 2 After cooling at room/the organic phase is washed with saturated aqueous loupe dried and evaporated to dryness Purification of the resulting residue on Sue (240 g) with benzene-ethylether as event affords 14. 9 g of 3~endo-hydroxy-bicyclo[3. 2. hootenanny 6-etllylene dioxide.
15 Example 47 A stirred solution of 3-endo-hydroxy-bicycloL3. 2. hootenanny 6-ethylendioxide (12. 75 g) in Bunsen ~340 ml) and DMS0 lo ml) was treated with dicyclohexylcarbodiimide I 35 g), pardon (5. 9 g) and trifluoroacetic acid (5. 4 g). After 6 hours, the mixture is diluted with Bunsen (600 ml) and 20 future (50 ml), filtered from duskily hex~lurea and the organic phase is washed with water, dried on McCoy and evaporated to dryness affording bicycle. 2. eighteen, Dunn, 6-diethylenedioxide.
A solution of this crude product in dimet~ylcarbonate ~70 ml) is added to a suspension of sodium hydrides (80% in mineral oil, 4 g). The mixture is 25 stirred until Ho development ceases at room temperature then it is warmed ! for 40 minutes at 75-80.
I After cooling, the reaction mixture is diluted with Bunsen (350 ml) and acetic acid (I. 4 g), washed with water, dried and evaporated to drools affording a mixture ( l: l) of d, l-bicyclo 13. 2 . eighteen - 3, Dunn - car boxy 30 I methylester-6, 6-ethylendioxide (p= 0, q= l) and d, bicycle. 2. eighteen ~9~34~

-3, 6-dione-4-carboxymethylester~6, 6-ethylene dioxide (p= 1, q= 0) which are separated by means of chromatography on Sue (Fe , Fe free) us in he Jane - ethylethe r a s e lent s .
Example 48 Using in the procedure of the example 47 g 14. 85 of 3-endo-hydroxy-bicycle. I nonunion 7-ethylendioxide the oxidation process affords 13. 9 g of bicycle. 3. ~nonane-3, Dunn, 7-ethylendioxide giving the carbomethox~lation process 4. 2 g of dl-bicyclo[4. 3. 0~nonane-3, Dunn-2-carboxymethylester- 7, 7-ethylen~dioxide (p= 1, q= 2) and 4. 8 g of do-bicycle. 3. ~nonane-3, 7 dione-4-carboxymethylester-7, 7-ethylendioxide also named as dl-bicyclo[4. 3. (~1nonane-3, 8-dione-2-carboxymethylester-8, 8-ethylene dioxide (p= 2, q= 1).
Example 49 A stirred solution of bicycle. 3. ~nonane-7-en-3-one (90 g) in dim ethyl carbonate (35Q rnl) is added to a suspension of sodium hydrides (80% dispersion in Inineral oil 42 g) in dimethylcarbonate (550 rnl). After ceasing ire hydrogen evolution, the mixture is heated for 4.5 hours at 75-80~, cooled at r. t., diluted with Bunsen to. 7 1) and washed with owe aqueous Nope"
solution, evaporated to dryness affording bicycle. 3. OJnonane-7-ene-3-one-2-carboxymethylester ~91 g) (Mecca Z52 my = 8. 200).
A solution of this compound in ethylene chloride ( 1. 2 1) and ethanol ( 1. 2 1)is cooled at -20 and under stirring treated with Nobodies (14.4 g).
The mixture is stirred for 30 minutesJagain at -20, then it is treated with acetic acid (Z3 Irll)7 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-bicycloE~. 3. nonage ennui end hydroxy-2-exo-carboxyrnethylester (64 g) which is dissolved - o lo .
in dry tetrahydrofuran (THY) and treated with 2, 3-dihydropyrane (33 g) and p-toluensulphonic acid (0. 63 g) for 3 hours at r. t.. Pardon I 4 g) - is added to the reaction mixture and thenlaf$er cooling at 0C, under stirring a solution of 1. 2 M BH3 in THY is also added during 45 minutes.
5 The stirring goes on for 1 hour at 0C: then water is added to destroy - residual hydrides Under vigorous stirring, with external cooling at -5~0 the formed borne is oxidized by the slow concurrent addition of 110 ml ox EM sodium hydroxide and 110 ml of 30% hydrogen peroxide, maintaining the internal temperature at 20-25. The oxidation mixture is diluted with 10 Bunsen (Z lo and the layers are separated. The aqueous layer is extracted with Bunsen ~2x50). The organic layers are combined washed successively with 1% sodium carbonate, saturated sodium sulfite and saturated seedier chloride and dried on McCoy. Evaporation of the solvents affords crude mixture of 7 and 8 hydroxy compounds which are separated by means of 15 Sue (300 g) column chromatography ethyl ether as fluent, obtaining no s pi actively:
dl-bicyclo[4. 3. O]nonane-3-endo9 7 -dihydroxy-2~carboxymethylester-3-THP-ether (24 g) and - dl-bicyclo¦4. 3. ~nonane-3- endow 8 -dihydroxy-~carboxymethylester-3 20 THP-ether (27 g).
A solution of the 7~-hydroxy alcohol (24 g) in dry DMF (30 my is treated with dimethyl-ter-butyl-silyl chloride ~15.8 g) and imidazole (8.85 g) and then it is heated for hours at 60, cooled at room temperature, diluted with water (90 ml) and then extracted with ethyl ether.
Z5 The organic layers are collected, washed with waxer and evaporated to dryness affording dl-bicyclo~4. 3. ~nonane-3-endo, 7~-dihydroxy 2-exo-carboxyrnethylester-3-THP-ether-7-DM~ -s;lylether.
- To a stirred solution of this compound in dry Tulane (220 ml) cooled at '' ' ,, ' ' ' 119~3~18 -70, a solution of 1. EM DIVA in Tulane is added over a period of 45 minutes, maintaining the temperature between -70~-60. The stirring is continued for 2 hours, the residual hydrides is destroyed by addition of Z M
isopropyl- alcohol in Tulane.
The reaction mixture is warmed at room temperature and successively 30% aqueous Nope ~60 ml) and Nazi (50 g) are added. After filtration, the organic phase is washed with water and evaporated in vacuum affording dl-bicyclo¦4. 3. end, I -dihydroxy-2-exo-formyl-3-THP-ether-7-DMB-silylether (p= I q= 1). Using in this procedure the 8~-hydroxy compound we have obtair.~d:
do- bicycle. 3 . nonage - 3 - endow I - dihydroxy - 2 - ego- cay r boxymethyle s lo r - 3 -THP-ether-8-DMB-silylether and dl-bicycloC4. 3. ~nonane-3-endc, 8 ~-dihydroxy-2-exo-formyl-3-THP-ether,

8 -DUMB - s ilyiethe r.
l'; Example 50 A solution of (2-oxo-heptyl)dimethylphosphona,e I 33 g) in dry Bunsen (5 ml) is added to a stirred suspension of Nay (Roy dispersion in mineral oil, 43.5 my) in dry Bunsen (10 rnl). After 1 hour N-Br-succinimide (260 my) is added and then, after 5 minutes, a solution of bicycle. 3. O~nonane-3-endo, ~-dihydroxy-2-exo-formyl~3--THP-ether, 8-DM~-silylether (0.4 g) in Tulane (5 ml).
The stirring is continued for 15 minutes, then the reaction mixture is washed with aqueous 15% Nope, dried and evaporated in vacuum to give 2-exo[2'-bromo-3'-oxo-oct~ trans-enyl~-3~endo-THP-oxy-8~-DMB-silyloxy-bicycle. 3. nonage Jo Max 251 Mel, I= 8. 900.
I , .
A solution of ~3-phenoxy-2-oxo-propyl)dimethylphosphonate I 85 go in Bunsen (10 ml) is added to a stirred suspension of Nay (80% mineral oil dispersion .
O. 33 g) in Bunsen (50 ml). The stirring is continued for 45 minutes, then a solution of 2~exo-formyl-3 end THP~oxy~7~ -DMB-silyloxy bicyclo~L. 3.
nonage (3. 82 g) in Tulane is added. After 20 minutes the organic phase it washed with aqueous 20% NaHzPO4 and water, dried and evaporated to 5 dryness affording after filtration on Swiss (38 guessing benzene-ethyl ether as eluent,2-exo-[31-oxo-4-phenoxy-but-l'-trans eny~-3-endo~THP-oxy-73~-DMB-silyloxv~bicyclor4. 3. nonage (3. 97 g). Using in the procedure (5-cyclohexyl-2-oxo-butyl)-dimethyl phosphonate and starting from the aldehydes of the example 49 we have obtained:
10- 2 - ego r3 - ox I 1 _ cyclohexyl-pent- 11 -trays - ennui- 3 - endow THP-oxy- 7 I- DUMB -silyloxy-bicyclo[4. 3. nonage Al Max 228~hJ~ = 9. 300 2-exo[3~-oxo-5~-cvclohexyl-pent- 1'-trans-eny~-3-endo-THP-oxy-8 DUMB
silyloxy-bicyclo 4. 3. 0 nonage Max 228. 6n~p~ = 9. 450.
Example 52 The DMB-silylether-a, -unsaturated kittens, obtained in awkwardness with the procedure of the examples 50, 51 (a) are reduced to all~ylic alcohols and (by the new hydroxy group is protected as THP-ether; successively (c) the DMB-silylether pratecti~g group is selectively removed giving a secondary alcohol which (d) is oxidized to kitten; finally after removal (e) of all the remaining protective groups (f) the epimeric allylic alcohols are separated by HPLC--chromatography on Swiss. Working in a 2. 10 molar scale, the following procedure is used:
a) reduction: 1. 10 mole (0. 32 g) of Nub is added to a stirred solution of a aye -unsaturated ketone-DMB-silylether (2. 10 m) in rnethylene chloride-ethanol (1:1) (180 ml) cooled at -10~-15. After 30 minutes, the residual hydrides is destroyed by adding acetone (10 ml) and aqueous saturated Nope ~25 ml). The solvents are removed in vacuum and the residue is partitioned between water and ethylene chloride. The organic layer is separated dried I- Libya and evaporated to dryness affording a mixture of 3'S3 OR allylic alcohols silylethers (2. 10 m).
b) protection of allylic alcohols as THP-ethers: the crude mixture of 3'S, 3'R-allylic alcohols silylether (2. 10 m) was treated with Mullen chloride 5 (30 ml) and to the stirred solution 2, 3-dihydropyrane (2 g) and Tulane sulphonic acid I Q38 g) are added. The reaction is complete after 2 hours stopped by addition of pardon (0. 5 ml) and the solvents are removed by evaporation in vacuum to give a crude mixture of 3'S, 3'R-THP-ether ill ethers .
10 c) desilylation: a solution of the above obtained material in wry THY (80 ml)is treated for 12 hours at r. t. with dry tetrabutylammonium fluoride (14 g).
After concentration in vacuum to small volume, the residue is absorbed on Sue (40 g) and following elusion with ethyl ether affords the secondary alcohol -3'S, 3'R-THP-ethers about 2. 10 m).
15 d) oxidation: dicyclohexylcarbodiirnide (6.5 g), pardon (1 ml) and trifler acetic acid (0.5 ml) are added successively to a stirred solution in 75:25 benzene-DMSO (60 ml) of the secondary alkalis, 3'R-THP-ether. After OWE hours the reaction mixture it diluted with Bunsen (100 }no) and with a solution of oxalic acid (3 g) in water. Furled dicyclohexylurea is filtered 20 organic layer is washed until neutral, dried and evaporated to dryness.
elf) depyranylization and chromatographic Separation: a solution of the 3'S9 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 pardon (0. 5 ml) it is evaporated to dryness. The residue is dissolved in cyclohexane ethyl 25 acetate (80:Z0) and injected in HPLC instrument to give the following kiwi ate owls:
2-exo[2'bromo-3'S-hydroxy-oct~ trans..eny;~-3-endohydroxy-bicyclo I 3.
nonage -8 -one I

2-exo r2~bromo-3'R-hydroxy-oct- l~-trans-eny~-3 end hydroxy_bicyclo - I. 3. ~nonane-8 -one 2-exo~3'S-hydroxy-4~-phenoxy-but-1~-trans-eny~-3-eend hydroxy_bicyclo I 3 . nonage - 7 - one 52-exor3'R-hydroxy-4'-phenoxy-but-1'-trans-eny~-3-eend hydroxy-b;cyclo I. 3. i~nonane-7-one 2-exo¦3~$-hydroxy-5 -cyclohexyl-pent- l~-trans-eny~ -end hydroxy-bicyc]o I 3. nonunion 2-exo 3IR-hydroxy-5-cyclohexyl-pent- 1~-trans-eny3-3-endo hydroxy-bicyclo 10 I. 3. nonunion -2-exo[31S-hydroxy-5-cyclohexyl-pent-l~-trans-eny~--end hydroxy-bicyclo I 3. nonunion 2-exo[3~R~hydroxy-5-cyclohexyl-pent~ trans-eny~-3-endo hydroxy-bicyclo [4. 3 . nonage -8 - one .
15 Example 5 3 Y
Under a No atmosphere, a suspension of Nazi (80% dispersion in mineral oil, 2. 1 g) in dry DMSO (70 ml) is stirred for 4 hours at 65. After cooling at 25-30, dry ~-carboxy-butyl-triphenyl phosphonium bromide (13 go is added to it, obtaining a deep red solution of the slide.
20 After addition of a solution of 2-exo~2'bromo-3lS-hydroxy-oct-l~-trans-eny~-end hydroxy-bicyclo[4. 3. nonunion (1. 79 g) in dry DMSO (6 ml), the reaction mixtures stirred for 1 hour at 28~ and then for 4 hours at 40;
afterwards it is cooled at rut., diluted with water (80 ml), acidified up to pi 4. 5 by adding ON H2SO4 and extracted with ethyl ether (4x50 ml, 2x25).
- 25 The aqueous layer is discarded, the organic phases are combined washed with water this washing is discarded), then with N Noah (5x10 ml) and water until neutral. The combined alkaline extracts are acidified up to pi 5 and extracted with ethyl ether to give Swahili, 15S-dihydroxy-9a-deoxy-9a,9b~
dimethylene-prostacycla-5-en-l3-ynoic acid (a mixture of 5 c-and 5 t-isomers).

I

The individual geometric isomers are obtained after chromatographic separation on acidic Sue (40 g/each g of acid) using cyclohe~:ane-ethyl acetate as eluents.
Example 54 5 Under a No atmosphere, to a stirred solution of potassium-ter-butoxide (3. 36 g), freshly sublimated, in dry DMSO (36 ml) it is added 6. 5 g of 4-carboxy-butyl-triphenyl-phosphonium bromide to give a deep red solution of the slide. After addition of a solution of ~~exor3'R-hydroxy-4'-phenoxy-but-ll-trans-eny~3-endo hydroxy-bicyclo[4. 3. nonunion I 8 g) in 10 dry DMSO (3 ml), the reaction mixture is stirred for 5 hours at 42, cooled diluted with water (50 ml) acidified up to pi 5 and extracted with ethyl ether (4x10 ml). The aqueous phase is discarded the combined ethereal extracts are washed with water (10 rnl, this washing is discoursed), and with 0.5 N
Noah ox ml) and water until neutral. The confined alkaline extracts are 15 acidified up to pi 5 and extracted with ethyl ether. The organic phases are combined dried and evaporated to dryness to give:
I E), 13t-lia, l~R-dihydroxy-9a-deoxy-7a homo-9a-methylene-16-phenoxy~li, 18, 19, 20-tetranor-prostacycla-5, dunk acid (a mixture of 5 c and 5 t-geometrical isomers).
20 The individual geometric isomers are obtained after chxomatographic separation on acidic Sue (40 g/each g of acid) using cyclohe~ane-etkyl acetate as eluents.
Example 55 Using the veto alcohols of the example 52 in the procedure of the examples Z5 53, 54 we have prepared the following prostacyclanoic acids:
5c- 11 a, 15S-slihydroxy-9a-deoxy-9a, 9b dimethylene-prostacycla-5 -en yank acid 5 c, 1 it- 1 1 a, 15S dihydroxy- adieux homo-9a-methylene- punks-17, 18, 19, 2 0- lo trainer- pros tacycla- 5, 1 3 -Dunn to avid Jo 5c, 13t- 1 lay 15S dihydroxy-9a-deo}~y-9a, 9b-dimethylcne- 17-cycloheYyl~
1 8 , 1 9, 2 0- trainer- pro s tacycla- 5 9 1 3 -dunk acid 5c5 13t-1la, 15S-dihydroxy~ adieux ht)mo-9a-methylene-17-cyclohexyl-18 -1 9 , 2 trainer -pry ox tacycla -5 , 1 3 - dunk acid - 5 5t-lla9 15S dihydroxy-9a-deoxy-9a, 9b-dimethylene--prostacycla-5-en-13-yank acid - it, l3t-llal 15S-dihydroxy-9a-deoxy-7a homo-9a-methylene-16-phenoxy-17, 189 19, 20-tetranor-prostacycla-5, dunk acid it, 13t-lla,15S-dihydroxy-9a-deoxy-9a,9b-dimethylene-17-cyclohHuxley, 19,?0~
trinor-prostacycla-5~ dunk acid - it, 13t-lla, 15S-dihydroxy-9a-deoxy-7a homo-9a-methylene-l7-cyclohe 18, 1 us 2 0-trinor-prostacycla- 5, 13 - dunk acid.
Example 56 (f 6 I Using the procedure of the example, 30 g of 2-acetoxyperhydro a3ulen-6-one, also named as 3-endo-hydroxy-bicyclot5. I,. C~decane-8-one acetate (obtained in accordance with DO Banerjee et at. Indian J. Chum. 10, 1, 1972) is transformed moo its ethylendioxide ~29. 1 g). Then the compound is saponified by treatment with 2% ~2C03 in aqueous methanol to give end-r hydroxy-bicyclol5. 3. ~decane-8-one-8, 8-ethylenedioxide and oxidized using I the procedure of the example Rand treated with dimethylcarbonate (see the procedure of example I) to obtain dl-bicycloL5. 3. deacon Dunn-carboxymethylester-8,8-ethylene dioxide, 21.2 go Max 254nm;= 7.000.
Example 5 7 The bicycle veto ester-ethylene dioxides obtained in the examples 47, a 25 and 56 are reduced with the following procedure:
Nobody (0. 9 g) is added portions to a stirred solution of the bicycle -veto ester-ethylene dioxides (2.5. 10 my in 1:1 ethylene chloride-el:hanol ~150 ml), cooled at -20. After additional stirring for 30 minutes at -20, the - l:l9B41~3 .

residual hydrides is destroyed by adding acetone (12 ml). The reaction mixture is warmed at room temperature treated with aqueous 20% KH2POa~ and after rcn~oval of solvents, and dilution with water (20 ml) it is extracted with s. ethylene chloride. The organic phases are combined, washed until neutral 5 with water, dried and evaporated to dryness. The residue is equilibrated by treatment with absolute methanol (20 ml) and sodium methoxide (0. I g), for 12 hours at r. t.; acetic acid (0. 59 go addition followed by evaporation ofsolvents and extraction with ethylene chloride gives about 0.22. 10 m of the following b;cyclo-~3-hydroxy ester-ethylenedioxides:
- 10 dl-3-endo hydroxy-bicyclorL3. 2. ~heptane-6-one-2~arboxymethylester-6, 6-ethylene dioxide dl-3-endo hydroxy-bicyclo~3. 2.~heptàne-6-c,ne~ carboxymethylester-6, 6-ethylene dioxide, also named as: dl-3-endo hydroxy-bicyclo[3. 2. eighteen ego 7 -one - 2 Jo a r boxymethyle s lo r - 7, 7 - ethylene dioxide dl-3-endo hydloxy-bicyclo~4. 3. ~nonane-7~ one-2~carboxymethylester-7, 7-ethyi~:ne dioxide r ego dl-3 end hydroxy bicycloL4~ 3- Olnonane-8-one-2~carboxymethylester-8, 8-- ethylene dioxide ego dl-3-endo hydroxy-bicycl Lo 3. Oldecane-8-one-~carboxymethylester-8, 8-20 ethylene dioxide In the following, a solution of 2. lo m of each of these compounds in dry ethylene chloride, 25 rnl, is reacted with 2, dodder porn (2 g) and EYE-toluensulphonic acid ~38 my, 2. 10 m) for 2 hours at rut. The reaction is stopped by adding pardon (0. 1 ml) and the mixture is evaporated to dryness 25 in vacuum affording the corresponding 3-THP-ethers which are used without any further purification.
Exhume 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 2-exo-hydroxymethyl derivatives with following procedure:
, , .
.
.

,..

l:~L9B'~18 a solution of 2. 10 m of the ~-ketoester (both alcohol and 3-THP ether) in dry ethyl ether (25 ml) is added drops to a stirred suspension of Lyle (0.4) in dry ethyl ether (So ml). Aster additional stirring for 30 minutes the residual hydrides is destroyed by adding acetone (5 ml) and ethyl ether 5 saturated ilk water. Dry McCoy Gus added to, then the organic phase is filtered and evaporated to dryness.
We obtain thief following 3-endohydroxy-2-exo-hydroxymethyl:
bicycle . 2 . O~heptane - 6-one- 6, 6-ethylenedioxide bicycle. 2. 1~heptane-7-one-7, 7-ethylenedioxide bicyclol4. 3. O~nonane-7-one-7, 7-ethylenedioxide bicycle I. 3. nonunion, 8-ethylenedioxide bicycler. 3. (~decane-8-one-8, 8-ethylenedioxide and their 3-endo-hyd~oxy-THP-ethers both rhizomic and optical active form (net, en) when optical active material, coming from optical resolution-.
15 successively described, is used in the reductive process.
Example 59 Free kitten is obtained by treatnlent of a solution of end hydroxy-2-exo-hydroxymethyl-bicyclo~5. 3. O~decane-8-one-8, 8-ethylenedioxide (5g, 2. 10 m) in methanol (20 ml) and water (2 ml) with p-toluensulphor to acid (0. 3 go for 2 hours at reflex temperature. The solvents are evaporated in vacuum and the residue is filtered through a short column of Sue. - `
Working if accordance with the procedure of the example 54, a solution of the so obtained 3-endo--hydroxy-2-exo--hydroxymethyl-bicyclo[5. 3. 018-one I 7 g) in dry DMS0 (17 ml) is reacted with the slide formed from potassium ter-butoxide (27 g), DMS0 (280 land 3-carboxy-propyl-phosphoniumbromide for 5 hours at 40. The reaction mixture is diluted with water (300 ml) and extracted with 80:20 ethylether-benzene to remove triphenylphosphoxide~ These extracts are discarded and alkaline phases are acidified up to pi 5 and repeatedly extracted with ethyl ether (8x200) and with 3:1 ethylether-ethylacetate ~5xlO0~. The combined organic extracts are dried, concentrated to a small ~,~ I

9 8 Lo volume (100 ml) treated with ethereal diazomelhal1c to achieve the Mattel ester and then evaporated to dryness.
The crude material is chromatographed on Sue (100 g) (ethyl acetate as fluent) to give 5 (ZOO (20~P 12~ octanor-12~-hydroxymethyl-lla-hydroxy-Audi-7a-homo-9a,9b-dimethylene-2-nor-prostacycla-5-enoito Acid - methyl ester I 1 g).
By treating this con1pound in dry DMF (12 ml) with dilnethyl-ter-butyl-silyi-chloride (2. 2 g) and imidazole (1. 55 g) at 15~ for 24 hours, followed Ryan dilution Vito water (24 ml) and extraction Vito ethyl ether and chromatographic purification on Sue (25 g, cyclohexane-ethylether as fluent) we obtain its moo 12~ -DMB-silyloxy methyl-ether (4. 31 g 80%~.
Treatment with pardon (10 ml), acetic android (5 ml) ail. t. for 12 hours and hydrolysis with aqueous methanol and p-toluensulphonic acid afford 5(Z, E)- ~)-(20~ 12) octanor- 12~3 -hydroxymethyl-l lCL -hydroxy-qc~ -deoxy-7a-homo-9a,9b-dîmethylene-2-nor-p~ostacycla--5-en-oic acid methylester-11-acetate. Preparative chromatography (using a HPLC-instrument and monitoring with refractive index) on Sue treated Vito 3% AgI\iO3 (with methylenechloride-ethyl acetate as fluent) affords the individual geometric 5 c and it isomers.
In similar way, SUE 12)octanor-12~-hydroxymethyl-lla-20hydroxy-9a-deoxy-7a-hol~lo-9a-methylene-pros~acycllink acid Matthew ester~ll-acetate and their 5c and it individual geometric isomers are prepared when 3-endo-hydroxy~bicyclo['L. 3. O~onane-7-one-2-exo-carboxymethylester-79 7-ethylenedioxide is used ill side ox the corresponding per-hydroazulene compound and the 4-carboxybutylphosphollium bromide is 25 utilized in side of the 3-carboxypropyl-one.
Example 60 s Starting from the 2-exo-hydroxymethyl-THP-ether compounds of the employ 58 and from 12~-hydroxymethyl-11-acetate ox the example 59, we haze obtained the corresponding aldehydes by the following oxidative procedure:
.
, ,, ?

-o ~19~1B

Successively, dicyclohexylcarbodiimide (0. I g), pyridinc (0. 1 ml) trifluoroacetic acid (0. 05 ml) are added to a stirred solution of the hyclroXy-metl1yl compound (2, 10 m) in 75:25 benzene-DMSO (6 Tnl). After 4.5 hours, the reaction mixture is diluted with Bunsen (20 ml) and water (10 ml) and stirred for 30 minutes again. Dicyclohe~ylurea is filtered oil and the organic layer is washed with water until neutral and the concentrated up to 10 nil affording a solution in dry Bunsen of the following aldehydes:
3-endo-THP-oxy-2-exo-formyl bicycle. 2. hootenanny 6-ethylene dioxide `
3 -end- TOP- oxy-2 -ego formyl-bicyclo¦3 . 2 . (I Hutton - 7 - one - 7, 7 - ethylene dioxide 3-endo-THP-oxy-2-exo-formyl-bicyclo[4. 3. (nonunion, 7-ethylene dioxide end- THP-oxy-2-exo-formyl-bicycloL~' . 3 . ~nonane-8 -one -8, 8 -ethylene dioxide 3-endo-THP-ox~-2-exo-formyl-bicycloL5. 3. ~decane-8-one-~, 8-etllylene dioxide ) (20_~ 12)octanor-12,(3 -formyl-11~-hydro~y-7-homo-9a,9b- ;
dimethylene-2-nor-prostacycla-5-enoic acid methylester-ll-acetate (5 I E); 5c; it).
I I 12 ) octanor- 12 -forrnyl- 1 1 I -hydroxy- 9 a- de ox- Amy-methylene-prostacycla-5-enoic acid methylester-ll-acetate SUE) ;5c,5t).
These compounds are used in the following Wittig-Horner recolonize Whitehall anyfurther purification.
Example 61 ., A solution of (2-oxo-heptyl)dimethylphosphonate (0. 49 g) iII Bunsen (6 ml) is added drop vise to a stirred suspension of Nay (80% dispersion in mineral oil, 66 my, 2. 2. 10 m) in Bunyan (15 ml). After an additional stirring for 45~ Eve add a solution ox 2. 10 m off t-~L)(20~ 12)octanor-12~3-formyl-.

I .
. 1~L91~343L~

1 lo -hydroxy-~a-deoxy- amoeba- dimethylene-2-nor-pr~-scac~ ala 5-enoic acid rnethylester-11-acetate in Bunsen (10 1nl) to it. After an additional hour the reaction is stopped by adding a solution of acetic acid (132 my) in Bunsen (5 ml); the organic phase is washed with voter until 5 neutral, dried and evaporated to dryness.
- The residue, 1.2 g, is absorbed on Sue (10 g), following elusion with cyclohexane-ethylacetate gives it, 13t-lla-hydro~y-15-oxo-9a-deoxy-7a-homo-9a,9b-dimethylene-2-nor prostacycla-5, dunk acid methyl ester-ll-acet~te (0.76 go, Max 2Z8mu = 5.800.

10 The following a,~B-unsaturated kittens are obtained viny the other aldehydes of the example 60 are used in the above procedure: Jo 5c, 13t- 11 a -hydroxy- 15 -ox- 9a-deoxy-7a-homo-9a, 9b-dlmethylene-2-nor prostacycla-5, dunk acid-methylester~ astute Max 228 mu, = 9. 900 and the mixture of their 5(Z, E) isomers 15 it, 13t- 1 lo -hydroxy-15-oxo-9a~deoxy-7a-homo-9a-methylerle-prostac~rcl~I-5, l?-dienoic acid methylester-ll-aceta,.e ( )\ Max 229 my = lo. zoo) and its it and I Isomers and the felon2-exo[3'-oxo-oct-1l-trans-eny~3-endo-hydroxy-T~iP--ethers:
bicycle I . 2 eighteen - 6-one - 6, 6- ethylene dioxide 20 bicycle I. 2. hootenanny 7-ethylenedicxide bicycle. 3. (nonunion, 7-ethylenedioxide bicycle I. 3. O~nonane-8-one-8, 8~ethylcnedioxide bicycle. 3. ~decane-8-one-8, 8-ethylenedio~;ide.
Example 62 25 Using in the procedure of the example 61, different din~ethylphosphonates we have preparec3 tune Hollowing a, I unsaturate kittens:
a) by reaction of 3-endo-TI-IP-oxy-2-cxo-formyl-bicycloL3. 2. O~heptanc-7-one-7, 7-ethylenedioxide (2. 10 m) with (oxeyes, R)-Iluoro-heptyl)din~ctyl phosphonate (0.54 g) we obtain 3-endo-THP-oxy-2-exo~3'-o~:o-4'(R,S)~luoro-I

oat- l'-trans-eny~bicyclo~3. 2. hootenanny 7-etllyleneclloxi~lc (0. 72 g) Max 229 no = 9. 9, LID= -~98 (SCHICK) 3 by by reaction of the hootenanny, 6-ethylenedioxide alluded (2. 10 m) with (2-oxo-octyl)dimethylphosphonate we obtain 3-endo-THP-oxy-2-exo[3'-oxo-non- 11 -trans-eny~bicyclo[3. 2 . eighteen - 6-one- 6, 6-ethylenedioxide Max 228 no = 9. 300 - c) by reaction with the hootenanny, 7-ethylenedioxidealdehyde with ~2-o~o-4-phenyl-butyl)dimethylphosphonate (0. 565 g) we obtain 3-endo-THP-oxy-2-exo [31-oxo-5'-phenyl-pent-l'-trans-eny~bicyclor3. 2. (eighteen-one - 7, 7 - ethylene dioxide d) by reaction Vito the nonunion, 7-ethylenedioxide with 0. 52 g of (2-oxo-3S-rr.ethylheptyl)and with (2-oxo-3R-methyl-heptyl)dimethyl phosphon~te we obtain respectively:
3-endo-THP-oxy-2-exo[3'-oxo-4'S-methyl-oct- l'-trans-eny~bicyclo~9t. 3.
nonunion, 7-ethylenedioxide and 3 -endo-THP-oxy-2-exo[3'-oxo-41R-methyl-oct- 1' -trans-eny~ bi~:yclol4. 3.
nonage 7-one - 7, 7 -ethylene dioxide .
Exam to 6 3 Pardon hydrobromideperbromide (C5H5N. Her. Brie 0. g, is added to a stirred solution of3-endo-THP-oxy-2-exol3'-oxo-4'~R,S)-fluoro-cct-l'--trays-enyi~bicycloC3. 2. hootenanny 7-ethylenedioxide in dry pardon (15 ml).
After aciditional stirring for 4 hours at r. t., the precipitate is filtered offand the organic equate is partitioned among ices ON H2S04 and ethy;acetate.
The organic layer is washed with cooled 0. 5 NH2S04, brine, 1% Sydney carbonate, water until neutral affording 0. 71 g of 2Ibromo-9'(R~S~-fluoro compound, which is a mixture of 2 diasteroisomeric 4'S and OR derivatives.
HPLC-chrornatography on Swiss with CH2C12-ethylether (~5:15) affords the individual isomers:

:

3 _ 0.22 g of3-endo-TI-IP-o~.y-2-e~o~Z'bromo-3'-oxo-4'R-Iluc-roo-oct l'-tral-s-eny~bicyclo~3. 2. hootenanny 7-ethylenedio~ide Jo ma:: 250 no = 9.830 and 0. 19 g of the 4'S-fluro isomer Moe 251 no = 9.750 Using in the above procedure different a, I -unsaturated ketones~ve obtain the ollo~vings:
endTHP-oxy-2-e~o~2~bromo-3'-o:;o-non-1~-trans-eny~biccyclol3 2.
hootenanny, 6-ethylenedioxide and end- THP-oxy-2 -exo[2 'Brigham' -o~o-oct- 1 ' -trays -eny~bicyclo~. 3 .
nonunion, 7-ethylenedio~ide.
1 Q Example 64 An ethereal solution of 5% rnethyl~nagnesium iodide (5 ml) is added to a stirred solution of it, 13t-lla hydroxy-15-o~o-9a-deo~y-7a-homo-9~-methylene-prostacycla-5, dunk acid methylesler (0. 4 g) in 2 1 ethyl ether-toluene ~12 ml), cooled at -30. After stirring for additional 4 hours, the reaction Metro is warmed to 0 and the residual reagent is destroyed by adding of owe aqueous NH~LCl. The organic layer is separated, washed with water, dried and after addition of pardon (0. 1 ml) is evaporated to dryness. The residue dissolved in dry matinal ~10 ml) is stirred Vito an hydrousKIWI (0. 1 g) for 2 hours. The solution is filtered, evaporated in vacuum and the resulting crude neutral is partitioned between ethyl acetate owe Nope. The organic layer after the usual workup is concentrated to small .olurne; the residue is al~sorl~ed on Sue (20 g). Louisiana with ~0:20 ethyl ether:
isopropyleliher gives it, 13t~ , 15S-dihydro~y-15-rnct11yl-9a-deo pa-horno-9a-nethylene-prostacycla-5, dunk acid metllylester (0. 1 g) and its Rosemary I 085 g).
With this procedure it is also obtained:
it, l3t-lla~ 15Sdihydroxy-15-methyl-9a-deoxy-7a-homo-9a,9b-dimethyylene-2-nor-prostacycla-5, 13-dicno:c acid-methylester and its 15R~epimer.

99_ The free acids are obtained heating at the reflex temperature a solution of methyl esters in 80:20 methanol-water in the presence of 2% K2C03.
The solvent is evaporated in vacuum and the residue is partitioned between ethyl ether and water. The organic layers are recxtracted with 0.5% K2CO3 and discarded. The combined alkaline phases are acidified up to pal 6 and extracted with ethyl ether. Combined organic phases are washed, dried on McCauley and evaporated to dryness to give free acids.
Example 65 Using in the procedure of the example 64 ethanol magnesium bromide, lo vinyl magnesium bromide and ethyl magnesium bromide in side of the methyl magnesium iodide, the corresponding ethanol 15-vinyl and 15-ethyl pro-stacycladienoic acids are obtained.
Example 66 Starting prom the unstriated kittens of the examples 61,62,63, secondary allylic alcohols are obtained using the following procedure: a solution of unstriated kitten ~2.10 em) in dry ethyl ether (20 ml) is added to a stirred solution of 0.25 M zinc bordered I ml) in dry ethyl-ether, drops in a period of 30 minutes. After an additional stirring for 2 hours, the residual hydrides is destroyed by adding saturated Nail.
The organic layer is separated, washed until neutral, dried on Noah and evaporated to dryness. Preparative HPLC-chromatography on Sue, using as fluent ethylene chloride/ethylacetate, affords:
5c,13t-11~,15S-dihydroxy-9a-deoxy-7a-homo-9a,9b-diimethylene-2-nor-prostacycla-5,13-dienoic acid methylester-ll-acetate and its SUE) and it geometric isomers.
5t,13t-11~,15S-dihydroxy-9a-deoxy-7a-homo-9a-methyylene-prostacycla-5,13-dunk acid methylester-ll-acetate and its SUE) and 5c-geometric isomers.
The following2-exo[3'S-hydroxy-oct-l'-trans-enyl¦3-endo-THP-oxyy:
bicyclo[3.2.0]heptane-6-one-6,6-ethylenedioxide bicyclo[3.2.0]heptane-7-one-7,7-ethylenedioxide bicyclo[4.3.0]nonane-7-one-7,7-ethylenedioxide bicyclo[4.3.0]nonane-~-one-8,5-ethylenedioxide and the following 3-endo-~lY-oxy:
2-exo[2'bromo-3'S-hydroxy-4'R-fluoro-oct-l'-trallss-enyl]bicyclo[3.2 O]heptane-7-one-7,7-ethylenedioxide 2-exo[2'bromo-3'S-hydroxy-4'S-fluoro-oct-l'-trans--enyl]bicyclo[3.2.0]}1eptane-7-one-7,7-ethylenedioxide 2-exo[21bromo-3'S-hydroxy-non-l'-trans-enyl]bicycllo[3.2.0]heptane-6-one-6,6-ethylene dioxide 2-exo[3'S-hydroxy-non-l'-trans-enyl]bicyclo[3.2.0]]heptane-6-one-6,6-ethylene-dioxide 2-exo[3'S-hydroxy-5'-phenyl-pent-1'-trans-enyl]biccyclo[3.2.0]heptane-7-one-7,7-ethylenedioxide 2-exo[2'bromo-3'S-hydroxy-oct-l'-trans-enyl]bicycllo[4.3.0]nonane-7-one-7,7-ethylene dioxide 2-exo~3'S-hydroxy-4'S-methyl-oct-l'-trans-enyl]biccyclo[4.3.0]nonane-7-one-7,7-ethylenedioxide 2-exo[3'S-hydroxy-4'R-metllyl-oct-l'-trans-enyl~biicyclo[4.3.0]nonane-7-one-7,7-ethylenedioxide 5c,13t-11~,15R-dihydroxy-9a-deoxy-7a-homo-9a,9b-diimethylene-2-nor-prostacycla-5,13-dienoic acid methylester-ll-acetate and its SUE) and it geometric isomers.
5t,13t-ll~,L5R-dihydroxy-9a-deoxy-7a-homo-9a-methyylene-prostacycla-5,13-dunk acid methylester-ll-acetate and its SUE and symmetric isomers.
The hollowing2-exo[3'R-hydroxy-oct-l'-trans-enyl]3-endo-THP-oxyy:

34~8 _ . ... . . . .. . . . . . . . . . . . . .. . . . . .. . .
t _ bicycle. 2. 0 Hutton 6-one-6, 6-ethylenedioxide bicycle. 2. hootenanny i-e-thylenedioxide bicycle I. 3. l~nonane-7-one--7, 7-ethylenedioxide bicycle 3. O~nonane-8-one-8, 8~ethylenedioxide 5 and the following 3-endo-THP-oxy:
2-exo~2'bromo-3'R-hydroxy-~'l~~fluoro-oct-l'-transs-eny~bicyclo[3. 2.
hootenanny, 7-ethylenedioxide 2-exo~2tbromo-3'R-hydroxy-~'S-fluoro-oct-1'-trans--eny~bicyclb~3. 2.
hootenanny, ?-ethyienedioxide 2-exo[2tbromo-3sR-hydroxy-non-l'-trans-eny;~bicyclLowe. 2. eighteen_ one, 6-ethylenedioxide 2-exo~3'R-hydroxy--non~ trans-eny~bicyclo~. 2. O~heptane-6-one-6, 6 ethylene dioxide 2-exo¦3'R-hydroxy-5'-phenyl-pent- 1'-trans-eny~lbicyclor3. 2. O~heptane - 7 -one-7, 7-ethylenedioxide 2-exo¦2tbxon~o-3'R-hydroxy-oct-l'-trans-enyl~bicyccloy. 3. (nonillion-7, 7-e~hylenedioxide Roy 'R-hydroxy-as'S-methyl-oct- l'-trans-eny~bicyclor4. 3. nonage one-7, 7-ethylenedioxide 2-exo~3'R-hydroxy-4sR-methyl-oct- lt-trans~eny;~bicyclo[4. 3. nonunion-7, 7- ethylene dioxide .. . . . . .. . . ............ .. . . . . . . ..................... .
Example 67 .
The individual ll-acetate prostacycladienoic acid methyl esters are converted both in their ll-hydroxy methyl esters by trays esterification in dry methanol US with an hydrous K2CO3 (0. 5 mow equip) and in their 1 l-hydroxy free acid by treatment with K2CO3 in By% aqueous methanol.
example 68 Every one of the bicyclo-THP-oxy-ethylenedioxides obtained in the procedure 4~8 .,~

of the example 66 is converted in/the corresponding prostacyclenoic acids working up with the following procedure:
a solution of l. 10 Mafia the bicyclo-THP-oxy-ethylenedioxidc in acetone (15 ml)is reflexed with N aqueous oxalic acid lo ml) for 8 hours. The acetone is 5 evaporated in vacuum and the assess phase is extracted with ethyl ether. The combined extractiafter the usual workup are evaporated to dryness affording about 0. I 1. 10 Mafia the hydroxy kitten. A solution of this complained in dry DMSO (Z ml) is added to a solution of the slide obtained so on: in a No atmosphere potassi~lm-tert~butoxide (1.35 g) is added to dry DMSO (lo ml), 10 then to it we added a~-carboxy-butyl-triphenyl-phosphoniumbromide I 6g) to obtain a deep-red solution of the slide. After addition of the kitten, the reaction mixture is warmed at 40-42 for 6 hours, cooled, diluted with water ~20 ml!, acidified up to pi 5. l and extracted with ethyl ether (5x25 ml).
The aqueous phase is discarded and the organic extracts are collected, 15 washed with water (5 ml; this washing is discarded) and extracted with 0. 5 NNoah (6x6 ml) and water until neutral. The combined alkaline extracts are combined, acidified to pi 5 and extracted with ethyl ether. The combined organic extracts are vouched with water (2 ml), dried on Nuzzle, and evaporated to dryness giving a mixture of the 5 Z and 5; E acids.
20 The individual geometric isomers are obtained after chromatographic separation on acidic Sue (Fe , Fe fret) USillg CHzCl2-ethylacetate as fluent Shea 30 g for each of 0. 2 g of the acid).
In this Jay we have prepared:
_ it, 13t-lla,15S~dihydroxy-9a~deoxy-9a~nor-methylene~prostacyclLowe, 13-25 dunk acid it, 13t- l l u, 15S -dihydroxy~9a-deoxy-9a-nor~methylene~20 methyl~prostacycla-5, dunk acid 5t-lla,15S~dihydroxy-ga-deoxy-9a~nor-methylene-20-methyl--prostacycla~5-en~l3-ynoic cold -I ~198~

5t,13t-lla,155-dihydroxy-9a deoxy-9a-mcthylcne-7-nor-methylen~-prostacycla-5,13-clienoic acid 5t,13t-1la,15S-dihydroxy-9a-deox~r- 7a-homo-9a-methylene-prostacycl~-5,13 dunk acid 5t,13t-lla,15S-clihydroxy-9a-deoxy-9a,91~-dimcthylene-proostacycla-5,13-dunk acid 5t-lla,15S-dihydroxy-9a-dcoxy-9a-methvlene-7 -nor-methylene-16S-flucro- !
prostacycla-5-en- yank acid 5t-lla,15S-dihydroxy-9a-deoxy-9a-methylene-7-nor-mmethylene-16R-fl~oro-10 prostacycla 5-en-13-ynoic acid 5t,13t-lla,15S-dihydroxy-9a-deox~--9a-methylene-7--nor-methylene-17-phenyl-18,19,20-trinor-prostacycla-5,13-dielloic acid 5t,13t-lla~ 15S-dihydro-xy-9a-deoxy-7a-homo-9a-me hylene-lSS-methvl-prostacycla-5,13-dienoic acid 5t,13t-1la,155-dihydroxy-9a-deoxy-7a-homo-9a-methylene-16~methyl-prostacycla--5,13:dienoic acid it- 1 la,15S-dihydroxy-9a -Dixie- 7a-homo-9a-~lethylene-prostacycla-5-en-1~-yank acid 5c,13t-lla,15S-dihydroxy-9a-deoxy-9a-nor-methylenee-prostacycla-5, I
20 dunk acid 5c,13t-lla,l5s-dihydroxy-9a-deoxy-9a~nor-methylene-2o-methyl--prost2cycla-dunk acid 5c-lla,15S-dihydloY~y-9a-deoxy~9a-nor-methylene-200-methyl-prostacyc'a-5-en-13-ynoic acid 5c,13t-lla,15s-dihydroxy-9a-deoxy 9a-methylenc-7-nor-nlethylene-pros~acycla dunk acid 5c,13t-lla,15~-dihydroxy-9a clucks 7a-homo-9a-methylene-prostacycla-dunk acid .

-10~-5c,13t~ ,15S-dihydroxy-9a-deoxy-9a,9b-dimethylene-prostacyycla-5,13-dienoic acid 5c-llc~,15S-dihydroxy-9a-deoxy-9a-met]lylene-7-norr-methylene-165-fluoro-prostacycla-5-en-13-ynoic acid 5c-llc~,15S-dihydroxy-9a-deoxy-9a-methylene-7-nor--methylene-16R-fluoro-prostacycla-5-en-13-ynoic acid 5c,13t-llc~,15S-dihydroxy-9a-deoxy-9a-methylene-7--nor-methylene-17-phenyl-18,19,20-trinor-prostacycla-5,13-dienoic acid 5c,13t-llc~,15S-dihydroxy-9a-deoxy-7a-homo-9a-methhylene-16S-methyl-prostacycla-5,13-dienoic acid 5c,13t-llc~,15S-dihydroxy-9a-deoxy-7a-homo-9a-methhylene-16R-methyl-prostacycla-5,13-dienoic acid 5c-11~,15S-dihydroxy-9a-deoxy-7a-homo-9a-methylenee-prostacycla-5-en-13-ynoic acid and their 15R-isomers.
Example 69 Successively dicyclohexylcarbodiimide (0.32 g) pardon ~0.044 ml) and trifluoroacetic acid (0.022 ml) are added to a stirred solution of 5t,13-t-llc~,15S-dihydroxy-9a-deoxy-9a,7a-homo-dimethylenee-15-methyl-prostacycla-5,13-dunk acid methyl ester (0.39 g) in 75:25 benzene-D~lS0 I ml). After 5 hours the reaction mixture is diluted with Bunsen (20 ml) and 1.2 g of oxalic acid in water (10 ml). The stirring is continued for 20 minutes, the mixture is filtered and the organic phase is washed until neutral, dried and finally evaporated to dryness.
Chromatographic purification on Sue (4 g), ethyl ether as fluent, gives 0.26 g of5t,13t-11-oxo-15S-hydroxy-9a-deoxy-7a-homo-9a-methHelen-methyl-prostacycla-5,13-dienoic acid methyl ester which is hydrolyzed with 2%
aqueous K~C03 to give the free acid.
Example 70 Sodium bordered (2.5 g) in portions is added to a stirred solution of I`
, I, .

I ~191~4~
- Jo _ to ' . ' bicycle. 3. ~nonane-7-en-3~one (11.42 g) in ethanol (80 ml). After an additional stirring for 2 hours, acetic acid (5 ml) is added and the mixture is evaporated to dryness. The residue is partitioned between water and Chisel, and the organic layer is evaporated to dryness. A solution of the - 5 the resulting bicycle. 3. ~nonane-7-en-3-hydroxy (11 g) in dry DMF is heated successively with dirnetl1yl-tert-butyl-silyl-chloride (15. 6 g) and imidazole (10.85 g), wormed at 60 for 6 hours cooled and diluted with water (66 ml). After exhaustive extraction with ethylet}ler and usual work-up we obtain bicyclol4. 3. nonunion 3-hydroxy-3-DMB-silyl-ether (19. 1 g).
Its solution in dry THY (100 ml), cooled at 0C is treated (under stirring, in No atmosphere) with MBH3 solution in THY (75 ml). After 2 hours, maintaining the temperature at 25~ e add N Naomi (25 ml) and 30%
hydrogen peroxide ~25 ml). The mixture is heated at 6Q for 2 hours, cooled and diluted with Bunyan (400 ml). The organic layer is washed with 1% Nikko, saturated sodium sulfite, saturated Nail, dried and evaporated to dryness giving rude bicycle. 3. ~nonane~7(8)~-3-dihydroxy~3 DMB-silylether (20. 3 g). A solution of the resulting alcohol in 75/25 ben~ene-DMSO (150 ml) is treated successively with dicycloihexylcarbodiimide I g) pyridirle (Z no trif].uoro acetic acid (1 ml), under stirring. Tory 5 hours, the mixture is diluted Vito Bunsen (~00 roll), water (50 ml) hit a solution of oxalic acid (6 go in water (75 ml), and after additional stirring for 30 nlinutes is filtered.
The organic phase is washed with water until neutral affording bicycle. 3.
nonane-7(8)-one3-hydroxy-l~M~3~silylether (18. 25 g) which is dissolved in methanol (60 ml) and treated with 1. g of p-toluensulphonic acid. After 12 hours, the lnixture is treated with pardon (1. 95 ml) and evaporated to dryness.The residue is filtered on Sue ~ethylel:her-ethylacetate as fluent) to give bicycle. 3. 0¦nonane~7(8)-one-3-hydroxy ( 10 g).
A solution of this compound in Bunsen (50 ml) is reflexed in the presence OX
dry ethylene glycol (5. 2 g) and p-toluensulpllonic acid (0. 62 g) withdrawing r Jo -I Al the water formed during the reaction After I flours we add pardon (2 land the organic phase is cooled, washed with Weller, %% Nikko and saturated Nail until neutral. evaporation of solvents gives bicycle. 3. I~nonane_7(8)_one 3-hydroxy- 7, 7(8, 8 ) -ethylene dioxide .
5 Example 71 Saponification with 2% K2CO3 in 80% aqueous methanol of the dl-3-endo-hydroxy-bicyclol4. 3. 0 nonunion, ~3-diethylenedioxide~2-exo_carboxy_ methyl ester (4.5 g) gives the free acid (4. 2 g).
To a solution of the free acid (4.2 g) in acetonitrile (120 ml) it is added do 10 ephedrine (2. 3 g); after 4 hours at r. t. 2. 8 g of salt crystallizes giving after ftlrther crystallization from acetonitrile 2. 15 g of bicycle. 3. ~nonane~8-one-8, 8 -ethylelledioxide-3~endo-hydroxy-2-exo-carbo~ylic acid do -ephed Nemo salt. All the liquor waters are combined evaporated to dryness; the residue is dissolved in water and treated with N Noah up to alkaline pi (12-13).15 d(+)-Ephedrine is recovered by extraction with ether, then alkaline aqueous solution is acidified to pi 5 extracted with ethyl acetate and organic layer combined are evaporated to dryness. The residue is diluted in acetonitrile and the p~-oceclure is repeated using (-)ephedrine to give bicycle. 3. 0¦nonane-8 -one -8, 8 - ethylene dioxide - 3 -endo-hydroxy-2 ego carboxylic acid I -) e fodder-LO Nemo salt. Every one of the salts is separately dissolved in water/NaOH;the optically active base is recovered by extraction with ethyl ether the alkaline aqueous phase is acidified up to pi 5-5, 1 and extracted with ethyl-acetate, affording bicycle. 3. ~nonane-8 zone 8, 8-ethylenedioxide~3~endo-hydroxy-2-exo~-25 carboxylic acid and(-)bicycloE~. 3. nonunion, 8-ethylenedioxide-3-endo-hydroxy-2-exo-carboxylic acid, which are converted into the methy~ester with diazomethane treatment .

Jo ~841~

Exam pie 7Z
-. A solution of 26 g of dl-3-eI)do-hydroxy bicyclo[~L. 3. I essay car boxy-methylester-7-one-7, 7-ethylened;oxide in acetone (100 ml) is relaxed with ON H2SC)4 (20 ml) for 4 hours.
5 Acetone is evaporated in vacuum and aqueous phase is extracted h ethyl-acetate. Combined organic extracts are washed until neutrals dried and evaporated to give 21. 2 g of dl-3 -endo--hydroxy-bicycloC~. 3. ~-2-exo-carboxymet11ylester-7-one. To a solution of the kitten in dry acetol1itrile ~250 ml) it is added d~l-phenyl-l-ethyl-amin^ (12. 1 g) and solvent is 10 slowly distilled off recovering 50 ml in 30~ Ininutes. The mixture is slowly cooled at rut. and then 12. 12 g of I) 3-endo~-hydroxy-7j7-(1'-pllenyl-1'-ethylidenin~inoj~2--exo-carboxymethylester-bicycloor. 3. (glare collected after filtration. The liquor waters are concentrated further to give 6 g of racernic m lterial. Finally, a further concentration up to 80 ml affords 11. 42 of (-) 3-endv-hydroxy-7, phenol 1~-ethylidenimino)-2-exo-carboxy-r methylester-bicyclo~4 3. 0 Separately, the two Showoff bases are cleaved Vito 80:20 n~thallol ON Sue (200 roll) at Reilly temperature for 2 hours. Solvent is evaporated in vacuum and after extraction Ruth ethyla_etate, the combined organic phases are 20 washed until neutral, dried and evaporated in vacuum to give:
8. 1 g of (+; erred hydroxy-bicyclo~L. 3. ~2-exo-carboxymethylester-7-one a 7. 2 g of ( ) 3~endo~hydroxy-bicyclo~. 3. ~2-exo-carboxymethylester-7 one, respectively.
Using this procedure, all the bicyclo-~--hydroxy-carboxylic ester-ethylcne 25 dioxides of the example 57 are submitted to optical resolution to give the fc.llo~ing 3-endo-hydroxy alcohols:
(+) bicyclol3. 2. jitney 6 one 2 ego carboxymethylester (~) bicycle. 2 ~heptane-7-one~2-exo-carbovylnethylester (+) bicycle. 3. ~nonane-7--one-2-exo-carboxymethylester .

~.~ , ~9~4~

( I) bicycloL4. 3. nonunion exo~carboxymethylestcr bicycle . 3. Awaken one-2~exo-carboxymel:hyles~r - (-) bicycle. 2. ~heptane-6--one-2-cxo-carboxy1~cl:1~ylesler - (~) bicycle. 2. O~heptane--l-one-2 exo-carboxylncthylester 5 . (I bicyclol4. 3. Olnonane-7-one 2 exo-carboxylnethylsster (-) bicycle. 3. O~nonhne-8-one-2-exo-carboxymethylester ( Basque ,5 . 3. deacon 8-one-2-exo-carboxymetl1ylester Using tile procedure ox the exalnple 56; these kittens are converted into their ethyleneclioxide derivatives.
.. . .

Claims (13)

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 C1-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, C1-C6 alkyl, C2-C6 alkanoyl and phenyl;
(e) -C=N; (f) a radical; (g) -CHO; or (h) a radical where each X' is independently -O- or -S- and the R'a and R'b groups, whether the same or different, are C1-C6 alkyl or together form a straight or branched C2-C6 alkylene chain; D is: -CH2-, ?CH-OH, (cis), (trans), -C=C- ?C=O, -O-, -S-, or ?N-Rc, where Rc may be hydrogen, C1-C6 alkyl or C2-C6 alkanoyl; one of R1 and R2 and, independently, one of R3 and R4 is hydrogen, C1-C6 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, phenyl, or aryl-C1-C6 alkyl and the other is hydrogen, hydroxy, C1-C6 alkoxy or aryl-Cl-C6 alkoxy, or, Rl and R2 and, independently, R3 and R4 together form an oxo group; each R5 and R6, whether the same or different, may be hydrogen, C1-C6-alkyl or halogen, or R5, R6 and the carbon atom to which they are bound form a ?C CH2 or radical; Y is: -CH2-CH2-, (trans) or (cis) where Z is hydrogen, X is: -(CH2)m3 - in which m3 is zero or 1, (cis), (-trans), -O-, -S- or ?N-R
where Rc is as defined above; m1, m2, n1 and n2, whether the same or different, may be zero or an integer between 1 and 12 such that each 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 1 to 6; R7 is a cycloaliphatic radical, either unsubstituted or substituted with one or more C1-C6-alkyl or C1-C6-alkoxy; or a saturated or unsaturated heterocyclic ring, either unsubstituted or substituted with one or more of the following: halogen, halo-C1-C6-alkyl, C1-C6-alkoxy, phenyl, C1-C6-alkyl; and the lactones derived from compounds of formula I and the pharm-aceutically 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, C1-C6-alkyl, C2-C10-alkenyl, C2-C10-alkynyl, phenyl or aryl-C1-C6-alkyl and the other is hydrogen, hydroxy, C1-C6-alkoxy, aryl-C1-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 Re may independently be C1-C6-alkyl or phenyl;
R''' is (a") a carboxylic group, free, esterified or as its salt;
(b") -C(OR')3, where R1 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") a 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, a compound of formula I in which Y is -CH=CZ-where Z is hydrogen, is reduced to give, after the protecting groups are removed, a compound of formula I in which Y is -CH2-CH2-; or, if required, subjecting to nucleophilic addition the free carbonyl on the .omega. chain of a compound of formula I in which Y is -CH2-CH2- or -CH=CZ- and Z is as defined above, and R3 and R4 together form an oxo group to afford, upon removal of any protecting groups, a compound of formula I in which Y is -CH2-CH2- or -CH=CZ- and Z is as defined above, and one of R3 and R4 is hydroxy while the other is hydrogen, C1-C6-alkyl, C2-C10-alkenyl, C2-C10-alkynyl, phenyl or aryl-C1-C6 alkyl and, if required, preparing the ether derivative from a compound of formula I in which Y is -CH2-CH2- or -CH=CZ- wherein Z is as defined above, one of R3 and R4 is hydroxy while the other is hydrogen, C1-C6-alkyl, C2-C10-alkenyl, C2-C10-alkynyl, phenyl or aryl-C1-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 Y is -CH2-CH2- or -CH=CZ-where Z is as defined above and one of R3 and R4 is C1-C6-alkoxy or aryl-C1-C6-alkoxy while the other is hydrogen, C1-C6-alkyl, C2-C10-alkenyl, C2-C10-alkynyl, phenyl or aryl-C1-C6-alkyl; or, if required, converting a compound of formula I into another or to the lactone or pharmaceutically or veterinarily acceptable salt or, if required, converting 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.

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 -CH2CH2- or -CH=CH- (trans) 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 cyclohexyl or 2'-tetrahydrofuryl.

3. A process according to claim 2 wherein D or D' is -CH2-, R'3 is hydroxyl or protected hydroxyl and R'4 is hydrogen, Y is -CH=CH- (trans), n2 is zero, R5 and R6 are both hydrogen or are both methyl, X is -O- or is -(CH2)m3- wherein m3 is 1 and R7 is cyclohexyl or 2'-tetrahydrofuryl.

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

5. 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 -CH=CH- (trans), 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 cyclo-hexyl.

6. A process according to claim 5 wherein n2 is zero and R7 is cyclohexyl.

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

8. A process according to claim 5 or 6 wherein R5 is hydrogen or methyl and R6 is hydrogen or methyl, and m2 is 2.

9. 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.

10. 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.

11. 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 chemi-cal equivalent thereof.

12. A process for preparing a compound of the general formula I

(I) wherein R1 represents a hydrogen atom or an alkyl group having 1 to 10 carbon atoms; Y represents -CH2-CH2- or trans-CH=CH-;
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 or cycloalkyl group substituted with one or more alkyl groups each having 1 to 4 carbon atoms or a hetero-cyclic ring, and the pharmaceutically acceptable salts thereof which comprise reacting a compound of the general formula II

(II) wherein Y, n, X, R5, R6 and R7 are as defined above; R2 repre-sents 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 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 hydrolysed or a carboxy group is converted into a salt.

13. A compound of formula I as defined in claim 12 or a pharmaceutically acceptable salt thereof, when prepared by a process according to claim 12 or an obvious chemical equivalent thereof.
114.