CA1198419A - 9-deoxy-9a-methylene isosteres of pgi.sub.2 and process for their preparation - Google Patents

Abstract

ABSTRACT
The invention relates to new compounds of formula I
I

wherein R is (a) a free or esterified carboxy group; (b) -C(OR')3, where each R' group is independently 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) radical; (g) -CHO; or (h) radical where each X' is independently -O- or -S- and the R'a and R'b groups, whether the same or different, are C1-C6-alkyl or together form a straight or branched C2-C6-alkenylene chain; D is: (trans), -C?C-, , -O-, -S-, or , 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 or radical; Y is: -C?C-, (trans), (cis) where z is halogen, -NH-CO- or -NH-CH2-; X is: -(CH2)m3-in which m3 is zero or 1, (cis), (trans), -O-, -S-, or where Rc is as defined above; m1, m2, n1 and n2, whether the same or different, may be zero or an integer between 0 and 12 such that each sum m1 + m2 and n1 + n2 is less than or equal to 15; p and q are independent-ly zero or an integer between 1 and 3 such that the sum p + q is an integer of 1 to 6; R7 is (a') hydrogen; (b') Cl-C4-alkyl; or (c') an aryl group, either unsubstituted or substituted with one or more of the following:
halogen, halo-Cl-C6-alkyl, Cl-C6-alkyl, Cl-C6-alkoxy, phenyl; and the lac-tones derived from compounds of formula I and the pharmaceutically or veter-inarily acceptable salts thereof. The compounds display bronchodilator, luteolytic, anti-ulcerogenic and platelet anti-aggregant activity.

Description

The object of this invention is 9-deoxy-9a-methyleneisosteres of PGI2, also known as 6,9~-oxide-11~,15~S)-dihydroxy-prosta-5(Z), EYE
dunk acid, including a procedure for their preparation as well as harm-aseptically and veterinary compositions containing them.
Compounds covered by this invention have the -following general formula (I) OH shim ~D~~CH2)m2 I B Schick H I/ H I) < A R3 R5 R~1 I Ye-- C-~CH2)n _~-X-(CH2)n2 7 wherein 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) Clara where R" is hydroxy or C2-C7alkoxy; at) -CON Ray where Ray and Rub are chosen independently Eros the group hydrogen Cl-C6alkyl, C2-C6 alkanoyl and phenol; e) -CON; f) a -C\ ¦¦ radical; g) -COO; h) a NH-N
-OH \ a radical where each X' is independently-O-or-S-and the Ala and Orb Rub groups, whether the same or different, are Cl-C6alkyl or together form a straight or branched C2-C6alkylene chain; H H
D is chosen from the group: -SHEA-, SHEA, I Swiss), ~C=C~ (trays), -C_C-, KIWI, -O-, -S-, and ARC where Arc may be hydrogen, Cl-C6alkyl or C2-C6alkanoYl;

79/P-2- SUE VF/ac 395C Dived -1-..
. Jo 34~9 one of Al and R2 and, independently one of R3 and I is hydrogen, Cl-C6alkyl, C2-ClOalkenyl, C2-ClOalkynyl, phenol, or aureole Cl-C6alkyl and the other is hydrogen, hydroxy, Cl-C6-alkoxy or aureole Cl-C6alkoxy, or, Al and R2 and, independently, R3 and R4 together form an ox group; each R5 and R6, whether the same or different, may be hydrogen, Cl-C6-alkyl or halogen, preferably fluorine, or R5, R6 and the carbon atom to which they are bound form C=CH2 or `C~cHl2 radical; Y is chosen from the group: -C_C-, H,C=C~ (trays), ICY Z

(is) where Z is halogen, -NH-C0- and -NH-Cl~2-; X is chosen from the group:

-(Shim in which my is zero or 1, } OH (is), HO OH (trays), -0-, -S-and NO with Arc as defined above; ml, my, no and no, whether the same or different, may be zero or an integer between 0 and 12 such that each sum ml+m2 and nl+n2 is less than or equal to 15; p and q are independently zero I an integer between 1 and 3 such that the sum p + q is an integer of 1 to 6;
R7 is chosen from the group: a) hydrogen; b') Cl-C4-alkyl; or c') an aureole group, either unsubstituted or substituted with one or more of the following:
halogen, halo-Cl-C6-alkyl, Cl-C6-alkyl, Cl-C6-alkoxy~ phenol.
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 I" 1) refers to substituents on a ring in the configuration, that is, below the plane of the ring, to substituents on a bicyclo[(p+q+l).3.0] Al Kane system (composed of condensed rings A and B) in the end configuration, and to substations on a chain in the S configuration. A wedged line (I ), on 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]alkane substituent in the ego configuration, and to a side chain substituent in the R configuration A wavy line (mu) indicates a ~ubstituent of undefined stereochemistry: ring substituents may be or I, bicycloalkane substituents may be end or ego, and side chain substituents Jay be R or S.

; - 2 -I

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 the bicyclic system at the junction are both outside the dihedral angle formed by the rings in the natural configuration.
The side chain on cyclopentane ring A (the chain) is trays 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 a) 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. However, the enantio~ers covered by this invention show stereochemistry at all asymmetric sites which is the opposite of that found in the natural compounds. They are thus mirror images of the latter, and their names include the prefix "en"
to indicate precisely that. do mixtures contain equimolar quantities of the natural compounds and the corresponding enantiomers.
The alkyd, alkenyl, alkynyl, alkoxy and alcoholics groups may be straight or branched unsubs~ituted or substituted with one or more of the following: halogen, Cl-C6-alkoxy and aureole, phenol in particular.
R is preferably a free or esterified carboxylic group, or its derivative salt.
A Cl-C6alkyl group is preferably methyl, ethyl or propel.
A C2-C7acyloxy group is preferably C~-C6alkanoyloxy) for example, Aztecs, propionyloxy, or benzoyloxy.
A C2-C6alkanoyl group is preferably acutely or propionyl.
A C2-C6alkylene radical is preferably ethylene or propylene.

I'' `'``'`'' 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 Clocker 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 trifluoromethyl.
When Z is halogen, chlorine or bromide is preferred.
Preferably, R5 and R6 are independently chosen from hydrogen, Cl-C6-alkyl and fluorine.
when R7 is Cl-C4-alkyl, methyl is preferred.
when R7 is aureole, then Honeywell a-naphthyl or ~-naphthyl is preferred.
When R is an esterified carboxyl group, -Coors is preferred, where Rug 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, or 3.
Pharmaceutically or veterinarily acceptable salts of compounds with formula I) may be formed with both inorganic I

. . .

and organic acids and bases.
Pharmaceutically or veterinarily acceptable inorganic acids include hydrochloric, hydrobromic and sulfuric; while organic acids include citric, fumaric, tartaric mafia, malefic, methanesulfonic and ethanesulonic.
Acceptable inorganic bases may be the hydroxides of alkali or alkaline earth metals, zinc and aluminum. Acceptable organic bases may be amine like methyl amine, diethylamine, trimethylamine, ethyl amine, dibutylamine, triisopropylamine, N-methylhexylamine, decylamine, dodecylamine, allele-mine, crotylamine, cyclopentylamine, dicyclohexylamine, benzylamine, dip benzylamine, ~-phenylethylamine, ~-phenylethylamine, ethylenediamine, diethylenetriamine, and other similar aliphatic, aromatic and heterocyclic amine like piperidine, morpholine, pyrrolidine, piperazine, as well as substituted derivatives like l-methylpiperidine, 4-ethylmorpholine, 1-isopropylpyrrolidine, 2-me~hylpyrrolidine, 1,4-dimethylpiperazine, 2-methylpiperidine, hydrophilic derivatives like moo-, dip and triethanol-amine, 2-amino-2-butanol, 2-amino-1-butanol,2-amino-2-ethyl-1,3-propalle-dill, 2-amino-2-methyl-1-propanol, tris-~hydroxy~ethyl)-aminomethane, N-phenylethanolamine, N-~p-tert-amylphenyl)-diethanolamine, ephedrine, pro-gain, and I amino acids like Lawson and arginine.
Under this invention, the preferred salts are compounds with formula I) in which R is -Cord, 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 be referred to as bicycle ~p*q~1).3.03alkane derivatives, or, preferably, as derivatives of a 20 carbon atom compound, the prostacyclalloic acid, with the following formula:

Jo I

COO

0 pa 7 10~ 1 in which the position of the oxygen atom is called the pa position.
Therefore, a compound with formula I) in which pal is a bicyclo[3.3.0]octyl derivative or, preferably a derivative of a adieux-9a-methylelle prostacyclanoic acid, since a ethylene group has waken the place of the heteroatom in position pa of tile prostacyclanoic acid. A
compound with formula (I) in which pi and Al is a bicyclo[4.3.0]nonyl derivative, or, preferably, a derivative of 9a-deoxy-9a,9b-dime~hylene prostacyclanoic acid, since 2 ethylene groups have substituted the hotter-atom in position pa of the prostaGyclanoic acid. Analogously, a compolmdwith formula (I) in weakly pi and Al is a bycyclo[5.3Øldodecyl derivative or, preferably, a derivative Do 9a-deoxy-9a,9b,9c-trimethylenc 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 Nero are called "9a-nor-methylene" or "7-nor-methylene" respectively.
The same notation (home, dummy, nor, donor, etc.) is used to indicate lengthening the former) or shortening (the latter) of the a 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 free or sulfide car boxy group; R7 is a straight or branched Cl-C4-alkyl or phenol optionally substituted as described above;
and the other substituents have the meanings reported above.
The following compounds are particularly preferred under this invention:
5c-lla,15S-dihydroxy-9a-deoxy-9a-methylene-prostaccycl-5-en-13-ynoic acid and its 15R epimer;
a smoothly derivative of the above mentioned acids;
5c-lla,15S-dihydroxy-9a-deoxy-9a-methylene-16R-fluuoro-prostacycl-5-en-13-yank acid;
5t-lla,15S-dihydroxy-9a-deoxy-9a-methylene-prostaccycl-5-en-13-ynoic acid, and its 15R epimer;
a smoothly derivative of the above mentioned acids;
a 20-methyl derivative of the above mentioned acids;
5t-lla,15S-dihydroxy-9a-deoxy-9a-methylene-16R-fluuoro-prostacycl-5-en-13-yank acid;
5c-lla,15S-dihydroxy-9a-deoxy-9a-nor-methylene-20--methyl-13,14-didehydro-prostacycla-5-en-13-ynoic acid;
5c-lla,15S-dihydroxy-9a-deoxy-7-nor-methylene-16S--fluoro-13,14-didehydro-prostacycla-5-en-13-ynoic acid and the 16R-fluoro isomer thereof, 5c~ ,15S-dihydroxy-9a-deoxy-9aj9b-dimethylene-prostacyycla-5-en-13-ynoic acid;
5c-11~,15S-dihydroxy-9a-deoxy-9a,7a-homo-dimethyleene-prostacycla-5-en-13-yank acid;
5t-lla,15S-dihydroxy-9a-deoxy-9a-nor-methylene-20--methyl-13,14-didehydro-prostacycla~5-en-13-ynoic acid;
5t-11~,15S-dihydroxy-9a-deoxy-7-nor-methylene-16S--fluoro-13,14,didehydro-prostacycla-5-en-13-ynoic acid and the 16R-fluoro isomer thereof;
St-11~,15S-dihydroxy-9a-deoxy-9a,9b-dimethylene-prrostacycla-5-en-13-ynoic acid;
5t-lla~15S-dihydroxy-9a-deoxy-9a,7a-homo-dimethyleene-prostacycla-5-en-13-yank acid;
as well as the ll-deoxy-derivatives, the ll-epimers, the 15R-hydroxy isomers and all the enantiomers 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 compound II

c!

I ~12 H = H

A ¦ II
I

2 3 R5 I, 2 no 2 no 7 wherein p, I Y, no, no, X, R5, R6 and R7 are as defined above one of R' and R'2 and, independently, one of R'3 and I is hydrogen, Cl-C6-alkyl, C2-C10-alkenyl, C2-C10-alkynyl, phenol or aryl-Cl-C6-alkyl and the other is hydrogen, hydroxy, Cl-C6-alkoxy, aryl-Cl-C~-alkoxy or a protecting group bound to the bicyclic system or the side chain through an ether linkage, or .

Al and R'2 and, independently, R'3 and Al together form a protecting group for the kitten function, with a compound with formula (III) E-C)-(cll2)m -D-(C112)m2 ([II) 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") -Cl-12-RIV, where RIP is C2-C7-acyloxy or a protect-in group bound. to -SHEA- through an ether linkage; (d") Conner where Ray and Rub are as defined above; (e") -C-N; (f") a -CN~I No, radical; (g") a -CH~Xx,RR,a radical where X', Ala and Rub are as defined above, followed if no-squired by the removal of any protecting group present, or, if required, subjecting to nucleophilic addition the free carbonyl on the chain of a compound of formula I in which R3 and R4 together form an ox group to afford, upon removal of any protecting groups, a compound of formula I in which one of R3 and R4 is hydroxy while the other is hydrogen Cl-C6-alkyl, C2-C10-alkenyl, C2-C10-alkynyl, phenol or aryl-Cl-C6-alkyl and, if required, pro-paring the ether derivative from a compound of formula I in which 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 I is C1-C6-alkoxy or aryl-Cl-C6-alkoxy while the other is hydrogen, Cl-C6-alkyl, C2-C10-alkenyl, C2-C10--alkynyl, phenol or aryl-Cl-C6-alkyl; or, if required, a compound with formula I in which Y is -CHIHUAHUAS- (trays), Z is halogen, one of R3 and R4 is hydrogen, Cluck-alkyd, C2-C10-alkenyl, C2-C10-alkynyl, phenol or aryl-Cl-C6-alkyl while the other is hydroxy, Cluck alkoxy or aryl-Cl-C6-alkoxy, or R3 and R4 together form an ox group, and any hydroxy, ox or car boxy groups present are free or in protected form, is dehydrohalogena~ed to give, after removal of any protecting group, a compound of formula I in which Y is -C_C- and one of R3 and R4 is hydrogen, Cl-C6-alkyl, C2-C10-alkenyl, C2-C10-alkynyl, phenol I

or aureole -Cl-C6-al~yl while the other is hydroxy, Cl-C6-alkoxy or aryl-Cl-C6-alkoxy or R3 and I together form an ox group 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 o-f a compound of formula I Jo 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- , Oily' Oak where Ask is Cl-c6_alkyl.
Kitten protecting groups are preferably petal and thioketal residues:_ C _ Era groups in which X'. Roy and Rub are as defined above.
Alkylation of a compound IT with a compound ~III) is carried out by using at least a 1.1 molar equivalent excess of ~III) per mole of IT
The reaction may be rum 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, Bunsen 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-, dim ethyl-sulfoxide, he~amethylphosphoramide, and other aprotic solvents are particular-lye 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 (III) can then be generated in situ.
For the alkylations described above, the reaction temperature 91~

may range from the freezing point to the boiling pullout ox water, although room temperature is particularly preferred.
Reaction of a compound (II) with a compound ~III) gives a mixture of geometric isomers, in thaw the new exocyclic double bond formed in the reaction may be is or trans. If desired, the individual geometric isomers may be separated by fractional crystallization from a suitable sol-vent 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 molecular 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 dimethylformamide.
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.
Thioketals and thioacetals may be selectively removed in the presence of other protecting groups with, for instance, mercuric chloride in aqueous acetone or acetonitrile, or a mixture ox them, if. the presence of an alkaline earth carbonate like what of calcium or magnesium.
Nucleophilic addition to the free carbonyl group on the chain in a compound (I) in which R3 and I 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 (like sodium, lithium, calcium or magnesium) bordered or with zinc bordered to give after any protecting groups are removed, a compo~md (I) in which one of R3 and R4 is hydrogen and the other is hydroxy.
0.5-6 moles of reducing agent are used per mole of the carbonyl derivative, (I), in an aqueous or an hydrous solvent, for instance, a linear or cyclic ether like ethyl ether, tetrahydrofuran, dimethoxyethane or Dixon, an aliphatic or aromatic hydrocarbon 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 -40C to the boiling point of the solvent, but is preferably between -25C and ~25C.
A tertiary alcohol is prepared by reaction with an organometallic derivative to give, after any protecting groups are removed, a compound (I) in which one of R3 and I is Cl-C6-alkyl, C2-C10-alkenyl, C2-C10-alkynyl, phenol or aryl-Cl-C6-alkyl while the other is hydra. The organometallic may be a magnesium derivative like RlOMgHal (in which Rio is Cl-C6-alkyl~
C2-C10-alkenyl, phenol or aryl-Cl-C6-alkyl and flat is I , I, I_ ? I.

halogen, pref~rab~.y chlorine or bromide), a lithium curate like Rockwell (R10 as above), an organolithiwn derivative I- like R1~Li (~10 as above), or an alkali or alkaline earth acetylide (R11-C_C-)n M (in which n is 1 or 2, R11 is hydrogen, straight or branched C1-C8-alkyl, aryl-C1-C6-alkyl, or aureole, particularly phenol, and M is an alkali or alkaline earth metal). The reaction between the carbonyl compound and one of these organometàllic derivatives is preferably Hun with Melissa (or slightly more) ox 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, tetrahvdrofuran, anisole, Dunn or dime~hoxyethane, or an aliphatic or aroma attic hydrocarbon like Newton, Nixon, Bunsen or Tulane.
The reaction temperature may range from approxima~e~.y -70C
to the boiling point of the solvent, but is preferably be-tweet -60C an 20C.
Whether it is a secondary or tertiary alcohol, the pro-duct of Lucy nucleophilic addition is a mixture of the opt-metric S and R alcohols. The individual S (CRY) and R
(cry ) alcohols yin which R12 is hydrogen, C1-C6-alkyl, C2 C1~-alkenyl, C2~C10-alkynyl, phenol or aryl-C1-C6-alkyl) may be separated as desired using the fractional crystals-lion and chromatography techniques described above.
- 25 The optional preparation of ethers from these secondary .... _ . . .. .. . . . . . ..

and tertiary alcohols to give, after any protecting groups are removed, compounds with formula (It in which one of R3 and R4 is Cl-C6-al~oxy or aryl-Cl-C6-alkoxy while the other is hydrogen, Cl-C6-alkyl, C2-C10-alkenyl, C2-C10-alkynyl, phenol or aryl-Cl-C6-alkyl, may be effected by reaction with an optionally aryl-substituted diazoalkane in the presence of a catalyst like fluoroboric acid or boron trifluoride in an organic solvent like 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 dimethylformc~nide.
The optional dehydrohalogenation of a compound with formula I) in which Y is -CHIHUAHUAS- (trays, Z its halogen one of R3 and R4 is hydroxy~
Cl-C6-alkoxy or aryl-Cl-C6-alkoxy while the other is hydrogen, Cl-C6-alkyl, 2 10 y , C2 C10-alkynyl, phenol, aryl-Cl-C -alkyd or R d R
getter form an ox group to give the corresponding compound (I) in which Y
is -C_C- is effected with a dehydrohalogenating agent preferably chosen from: CH3-S0-CH2e, diazabicycloundecene, dia~abicyclonollelle, and an alkali metal aside or alcohol ate. 1-5 moles (preferably 1.5-1.8) of dihedral-jointing agent is used per mole of compound (I), and the reaction is pro-fireball run in an oxygen-free atoms-AYE ' I

~L~9~341~

phone in an inert solvent live dimeth~71sulfoxide, dim ethyl-formamide, hexamethylphosphoramide, a linear or cyclic ether - or an aliphatic or aromatic hydrocarbon like those listed above, liquid ammonia, or a mixture of these solvents at a - 5 temperature ranging from -60C to the boiling joint of water.
In the absence of ammonia, room temperature is preferred.
This optional dehydrohalogenation of a compound (I) in which Y is -CHIHUAHUAS- trueness) and Z is halogen to jive the corresponding derivative in which Y is -C-C- may precede the carbonyl nucleophilic addition and the successive prepare-lion of ethers from the product alcohol The following reactions are all run using standard procedures: optional transformation ox a compound with for-mute I) into another, optional lactose or salt prepare-lion, preparation of the free compound (I) from its salt and separation of individual isomers phlegm a mixture.
For example, a compound with formula (I) in which R3 and R4 are both hydrogen may be prepared from one in which one of R3 and R4 is hydrogen while the other is hydroxy by preparing the ocelot from the alcohol, for instance by reagent with tussle chloride in the presence of base, and redwing the tessellate with Nub or NaB(CN)H3 in water, aqueous alcohol or dimethylformamide or with Lyle in an anhyarous solvent live ethyl ether or tetrahydrofuran, at a I temperature ranging from room temperature to the boiling -

3 .

- :

Jo ~198 point of the solvent. Analogously, a compound with formula (I) in josh R1 and R2 are hot hydrogen may be prepared from one in which one of R1 and R2 is hydrogen while tune other is hydroxy, and a compound (I) in which D is -SHEA- may be pro-pared from one ill which D is SHEA.
A compound with formula (I) in which R3 and R1 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 chiorinatect solvent like ethylene chloride or sheller-form at room temperature or, alternatively, with 1.1-1.2 molar equivalents of dichlorodicyanobenzoquinone in an inert sol-vent live Dixon, Bunsen or a mixture at a temperature ran-` yin from 40C to the boiling point of the solvent.
In an analogous fashion a compound with formula (It in weakly R1 and R2 together Norm an ox group may be prey pared from one in Welch one of R1 and R2 is hydrogen while the other is hydroxy, and a compound (I) in which D is KIWI
may be prepared -from one in which D 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
is C1-C~-alkoxy or aryl-C1C6-alkoxy may be prepared from one in which one of R1 and R2 is hydroxy through etherificction analogous to that: described for a compound with formula (I) -- in which one or R3 and R4 is hydroxy. Again, when only one of several secondary alcohol functions is to react, the others must be protected; the protecting groups are then no-moved at the end of the reaction.
A compound with formula (I) in which R is a carboxylic ester group (for instance, a C1-C12-a1koxycarbonyl) may be prepared from one in which R is a free carboxylic group by on following standard procedures, for example reaction with an appropriate alcohol, like a C1-C12-aliphatic alcohol, in the presence of an acid catalyst, like p-toluenesulEonic acid, or alternatively, treatment with a diazoalkane.
The optional conversion of a compound with formula (I) in which is an est~rified carboxyl group (i.e., a Cl-C12-alkoxycarbonyl? to one in which R is a free carboxyl group may be effected using standard saponification prove-dunes: treatment with an alkali ox alkaline earth hydroxide in water or aqueous alcohol, followed by acidification.
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 esterified carboxyl group may be effected by reduction of the ester with Lyle in ethyl ether or twitter-hydrofuran at reflex.
- 25 The optional conversion of a compound with formula (I) in which R is a free carboxyl group to one in which R is -Conner era and Rub as defined above) may be effected by treatment with an amine HNRaRb in the presence of a condemn-spiny agent, for instance a carbodiirl1ide like dicyclohexyl-carbodiimide. A compound with formula (I) in which R is a carboxylic ester may be converted into one in which R is -CON by treatment with an amine HNRaRb 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 radical from one in which R is a free carboxyl group may be effected by forming first the corresponding acid halide (preferably chloride, perhaps with thinly or oxalyl chloride in refluxing ~ichloroethane or Dixie), then the aside 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 on carboxyl group to give I or -GNU 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 winch R is ECHO may be effected using standard procedures, for instance 1-he preparation of the corresponding chloride .. ..

1~9~

from the acid or ester and subsequent Rosenmund reaction as described in 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 reacting the hydra-- chloride or the carboximide ester (prepared with standard methods) tlith a suitable alcohol, according to the procedure described in J. Americium Seiko), for example.
Acetalization, for example the optional preparation of a compound with formula (X) in which R is CHAR (where Al is oxygen and Ray arid Rub are as defined above) is effected by reaction of the alluded with an alcohol or glycol in the ; presence of a catalyst like p-toluenesulfonic acid or a sup;-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 is distilled away as it forms. the acutely ma also be prepared from the corresponding thioacetal by reaction with a suitable alcohol or glycol in the presence of a mercuric salt (preferably HgCl23 as an exchange catalyst and an alga-earth carbonate, in an inert solvent.
Thioacetali~ation, for example the optional preparation of a compound with formula (It in which R is Char where 25 X' is sulfur and Ray and Rub are as defined above) from one in , I. ` .

~L~9~4~

which R is -SHEA, is preferably effused by reaction with a moo- or dimercaptan like methylmercaptan, ethylmercaptan, dithioethylene~lycol or dithiopropylene~31ycol in the pro-since ox a catalyst like boron trifIuoride ether ate in an - - 5 inert solvent, preferably a halogenated or aromatic hydra-carbon (ethylene chloride, chloroform, Bunsen, Tulane).
The corresponding petals and thioketals may be pro-pared prom kittens by following the procedure described above for acetals and thioacetals.
Lactose and 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 ox isometric compounds (I) using Sandra techniques like free-US tonal crystallization and chromatography.
Compounds with formula (IIIj il.~which E is (Wrapper as defined above) are prepared by reacting a compound (VII) R or e ~P-~2-(cH2)m ~D~lCH~)m2 IT

in which Rev my D, I and R"' are as defined above with at least one molar equivalent of one of the following bases- an alkali or alkaline earth hydrides 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 carboxyamide, live N-sodio-, , I, . .. . .. .

`
' acetamide and N-sodiosuccinimide.
Compounds with formula (III) in which E is (C6H5)3P- are pro-pared by reacting a compound with formula (VIII) Hal-CH2-(Cll2)ml~D (Shim (Vile) in which my D, my and R"' are as defined above and flat is halogen, with 1.1-1.3 molar equivalents of triphenylphosphine in an organic solvent like Bunsen, ~cetonitrile or deathly ether and then treating the product pros-phoneme salt with an equivalent quantity of an inorganic base like Noah, KIWI
Nikko or Nikko.
Compounds with formula (VII) are prepared using standard methods, r 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 (II) are new compounds covered by this invention, as are procedures for their preparation.
Compounds with formula (II) in which Y is -C-C- or -CHIHUAHUAS- (trays), Z as defined above, are prepared in a procedure involving:
avow reaction of a compound with formula (XI) / G\
(Shop Schick HUH , CXI ) I"

wherein p, q, Al and R'2 are as defined above and C is a protected carbonyl group or a group SHAG' wherein G' is a sill ether or acutely ether residue with a compound of formula (V) z R5 E-c~-c~-(cH2)n ~~X~(CH2)n2 7 (V) I

wherein E, Z, no, R5, R6, X, no and R7 are as defined above, to afford a compound of phenol (XII) Go Chop (GH2) ,!
H (XII) Al lc=c-lcl-(cll2)n ~~~X~(CH2)n -R7 : wherein G, p, q, Al Z, R'2, no, R5, R6, X, no and R7 are as defined above;
by optional conversion of a compound with formula (XII) into a compound of formula (XIII) / G
(G,H2~p (SHEA) q H H (ZOO

R i Jo y~-C-(CH2~n ~~~X~(CH2~n2 7 Jo P, q, R I R I R 3, R 4, no, R5~ R6, X, no and R7 are as defined above, and Y' is -C_C-, or -SHUCKS- trueness), Z as defined above;
suave) removal of the protecting group in G to afford a compo~md of formula ~XIV) / G \
Chop (Schick (XIV) If H

Al ~9Y'-C-(CH2)n ~~~X~(CH2)n2 7 q' P' 1' R 2' Y R I R I no Us I I no and R7 are as defined above and G" is SHEA or KIWI;
do optional oxidation of a compo~md of formula (XIV) wherein G" is GUY and the other hydroxy groups, if present, are protected as .. I, reported above.
Compounds with formula IT in which Y is -Nll-C112- are prepared by reacting a compound with formula TV

/ \, ( up ~c~2)q H H TV

I

wherein G, p and q are as defined above and Al and R'2 are as defined above with the exception of hydroxy, with an alluded ~XVI) 3 ~R5 o~lC-C-~CH2) ~~-X-~C~2)n -R7 ~XVI) in which R'3, R'4, no, R5, R6, X, no and R7 are as defined above, in the pro-since of a reducing agent, followed by removal of the protecting group in G
and optionally, of the other protecting groups, if present;
Compound with formula IT in which Y is -NH-C-0 are prepared by reacting a compound TV with a compound ~XVII) 0 R' R

~lal-C-C-~}12)n ~~~X~(CH2)nl 7 (XVII3 in which Hal is halogen, preferably chlorine, and R'3, R'4, no, R5, R6, X, no and R7 are as defined above, in the presence of a base, followed by removal of the protecting group in G and, optionally, of the other protecting groups, if present.
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 One with formula (XIII) is effected with reactions analogous to those describe Ed above for the preparation of one compound with formula (It from another-r - 23 -for example nucleophilic addition to the carbonyl on the chain, etherifi-cation of the product alcohols and dehydrohalogenation.
As stated above, when G is a group _ KEG', the protecting group G' may be a sill ether residue (for instance, a trialkylsilyl ether like trim ethyl, dimethyl-tert-butyl, dimethylisopropyl, or ~imethylethyl-sill 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 removed as described previously: that is selectively, Nit F for a sill ether and with acid hydrolysis for an acutely ether. Yen a protecting group C,' must be removed in the presence of other labile ether groups, these latter should be acutely ethers Wang' is a sill ether or sill ethers Wang' is an acutely ether.
when G is a protecting carbonyl group it is preferably protected as acutely or thioacetal, for example a dimethoxyacetal, a diethoxyacetal, a dimethylthioacetal, a diethylthioacetal, preferably a dimethoxyacetal, or as petal or thioketal for example a e~hylendioxyketal owe_, a propylendithio-ketal~c~l2)s S a propylendioxyketal Swahili , a ethylendithioketal CHIHUAHUAS_, preferably a ethylendioxyketal.
The removal of said protecting groups in a compound of formula (XIII) as well as the optional protection of the free hydroxy groups in a compound of formula (XIV), e.g. as acutely ethers or Swahili 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 sea-ondary alcohols: for example treatment of the alcohol in an organic solvent like acetone with a solution of chronic android in sulfuric acid, follow-in normal procedures.
The reductive lamination reaction between a compound with formula - I -bluff) TV and an alluded ~XVI) is run under reaction conditions typical for this procedure, preferably using a mixed hydrides like Nub or Lyle as reducing agent.
The reaction between compounds with formulas (XV) and (XVII) is run under the normal conditions for assaulting amine.
Compounds with formula (XI) are prepared with a procedure invol-vying:
VI
a ) conversion of a compound ~XXIA) or (XXIB) (Shop (Schick ~XXIA) " q ~XXIB) H H H H

in which p and q are as defined above and G"' is a protected carbonyl group as reported above into a compound ~XXII) G

XXII) o in which pi q, and G are as defined above;

. 25 _ bVI) reaction of compound ~XXII) with a compound Okra in which R13 is Cl-C6-alkyl or aryl-Cl-C6-alkyl to give a compound with formula ~XXII:l) ~12) ~H2)q H H ~XXIII) Jo COREY

in which p, q, G and R13 are as defined above;
cVI) reduction of the product compound ~XXIII} to a compound with formula ~XXIV) I- P -H H ~XXIV) COREY

in which G, p, q and R13 are as defined above;
dVI) optional separation of compound ~XXIV) into the individual optical antipodes;
evil optional conversion of compound ~XXIV) into a compound with formula ~XXV) up Ç 2)q H H ~XXV) OH H COREY

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) Go OH 2) p SHEA) q H 11 (XXVI) 1 Clue R'2 wherein G, p, q, Al and R'2 are as defined above.
A compo~md of formula (XXII) wherein G is a group CHM~WoG~ in which G' is as defined above may be prepared from one of formula ~XXIA) by know methods, e.g. 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" where X" is I -S- or -(Sheerer), according to known procedures.

lo 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 accord-in Jo Moffatt in a mixture of Bunsen end dimethylsolphoxide with duskily-hexylcarbodiimide in the presence of pyriclinium trifluoroacetate.
The reaction between a compound with formula (XXII) and 0=C
(O'ER ~R13 as defined above, but preferably methyl) is owl in the pros-once of 2-4 moles of a base like sodium methoxide, sodium ethoxide, sodium or potassium hydrides or potassium tert-butoxide, with an excess of 6-12 moles of carbonic divester per mole of kitten, neat or in an inert solvent in an oxygen- and water-free atmosphere. The temperature may range from approximately 0-80C preferably 60-80C) for a period between 10 minutes and 1 hour. The yield varies from 5% to 90%, depending on the temperature, the reaction time and the concentration.
A compound with formula ~XXIII) may be reduced with an alkali or alkaline earth bordered in aqueous solution, preferably at a pi between 5.3 and 7.2, or at -20C with ethanols Nub in ethylene chloride/ethanol.
Generally, -the reduction 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 compolmd with formula ~XXIV), in which G is as defined above may by separated by saponifying the ester using standard procedures, forming a salt of the product acid with an optically active base like quinine, chinconine, ephedrine, l-phenyl-l-amino-ethanes dihydroabietylamine, amphetamine or arginine, and separating the resulting diastereomeric salts by fractional crystallization, for example.
The optically active acid is then recovered by conversion to the sodium salt and subsequent acidification of its aqueous solution to a pi which does not interfere with the protecting group in G.
Optionally the hydrolysis of the protecting groups may precede the optical resolution: -the protecting groups are then restored at the end of the separation process.
The optically active free acid prepared in this way is then converted to an optically active ester ~XXIV) using standard procedures, for instance treatment with a suitable diaæoalkane.
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= COO in a known manner then the separated optically active keto-esters may be transformed into the optical antipodes (XXIV) and (XXV) by ketalization or acetali7ation in a conventional way.
The optional conversion of a compo~md with formula (XXIV) to one with formula (XXV) may be done on either a rhizomic mixture or the individ-vat isomers separated as described above. In this transformation, the configuration of the free hydroxyl on the cyclopelltane ring is inverted.
The procedure involves esterification of the hydroxyl, for example by treatment with 2-4 molar equivalents of triphenylphosphine and I molar equivalents of a carboxylic acid like acetic, benzoic or p-phenylbenzoic, or with I molar equivalents of ethyl ago bis-carboxylate in an inert solvent like an aromatic hydrocarbon, perhaps halogenated, 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 inert alcohol R130H in the presence of an alkali carbonate, preferably K2C03.

. J -29-isle`

compound with formula ~XXVI~ is prepared from a compound (XXIV) or (XXV) using known methods. For example, the free hydroxyl group in compo~md (XXIV) or ~XXV) may be converted to a Cl-C6-alkoxy, and aryl-Cl-C6-alkoxy or a labile ether like a sill or acutely ether using the ether prep-aeration techniques already described for the analogous reactions of come pounds 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 con-vented to a petal or thioketal according to the procedure described above for compounds with formula (I) to afford a tertiary alcohol.
A hydrogen atom may replace the free hydroxyl group in a compound with formula (XXIV) or (XXV), -for example, by treatment with a sulfonic acid chloride like p-toluenesulfonyl, methanesulfonyl or benzenesulfonyl chloride and subsequent reduction of the product sulfonate, for instance with Lyle in standard methods. In this case the carboxylic ester group (-COREY) is reduced at the same time to the primary alcohol (-SHEA which may then be oxidized to the alluded with Moffatt's reagent.
A product compound with formula (XXVII) (C3~H2)p (Schick H Icky (XXVII) I

in which one of Al" and R2" is hydrogen, Cl-C6-alkyl, C2-C10-alkenyl, aureole or aryl-Cl-C6-alkyd while the other is hydroxy, Cl-C6-alkoxy) aryl-Cl-C6-alkoxy or a labile ether group, or Al" and R2" together form a kitten protecting group may be converted to the corresponding compound with formula ~XXVI) by reduction Followir1g standard procedures, for example, with diisobutylalum-inum 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 B~13 in te*rahydrofuran. The free acid is prepared by saponification of the ester.
This primary alcohol may then be oxidized to the alluded, with Moffatt's reagent, for example, as mentioned previously.

Compounds with formula (XV) are prepared using known methods, starting for example from a compound with formula (XXVII) in which any sea-ondary alcohol functions are protected as acutely ethers if -OX' is a sill ether, or as a sill ether if -OX' is an acutely ether. or example, a compound with formula TV may be prepared from one with formula ~XXVII) in a procedure involving:
a ) optional selective removal of protecting group in G;
bVII) optional oxidation of the free hydroxyl group in case liberated from'`CH~OG' to a kitten, for example with Jones' reagent;
cVII) saponification of the ester to the acid;
dVII) conversion of the acid to a mixed android, for example by reaction with an acid chloride like an alkyd, bouncily, or pivaloylchloro-carbonate in an inert an hydrous solvent like acetone, tetrahydrofuran or ethylene chloride;
evil) conversion of the mixed android to an aside by treatment, for example, with an acetone solution of an alkali metal aside;
f ) preparation of an amine from the aside through a Curtis rearrangement;
g II) and finally optional conversion of the product amine with formula TV into another.
Compo~mds with formulas (XVI) and ~XVII~ are known compounds, available through known methods.
Compounds with formula ~XXIA) and (XXIB) are prepared with known methods. For example, a compound (XXIA~ in which pal is prepared by selective reduction of bicycle [3.3.0]octane-3,7-dione (J. Norway. Chum. So., 82,~347(1960)) or by reduction of bicyclo[3.3.0]octane-3,7-dione-monoketal Jo Org. Comma)), followed 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 i - 32 -the corresponding rhizomic silyloxy derivative, by fractional crystallization or chromatography, as described several times above.
A compound with formula (XXI~ in which pal and q=2 is prepared from bicyclo[4.3.0]non-7-en-3-one (XXVIII), which has a is junction between the two rings, in a procedure in-(XXVIII) \/~

valving the protection of the kitten as a petal or thioketal was described above), standard hydroboration of the double bond, and subsequent removal of the Cowan 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, no diehard C.N.R.S.A.O. 11257~1975).
A compound with formula ~XXI A) in which pal and q-2 (prepared, lo for example, as described above) may be converted to other ~XXI) derivatives by successive detalization or thioketalization, oxidation, Bayer-Willinger and formulation of the product using methods analogous to those reported above.
compound of formula ~XXI B) wherein p is zero and q is 1 or p is l and q is zero may be prepared from the bromidrine 5-exo-hromo-6-endo-hydroxy-bicyclo[3.2.0]nept~m-2-one [J. Chum. So., Perking 1, 1767 ~1965)]
by knoll methods: for example said bromidrine may be converted into its acutely, thioacetal, petal or thioketal, then dehalogenated to the compound ~XXI B) using the known methods of organic chemistry such as, for example, I 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 accept ion, or the reduction with tributyl tin hydrides A compo~md of formula ~XXI B) wherein p is 2 and q is 1 or q is 2 and p is 1, may be prepared, e.g., from a compound of formukl (XXVIII) by a process comprising: reducing the carbonyl group to alcohol, e.g. with .~, I

Lyle in ethyl ether, projecting the alcoholic group, e.g. as tetrahydro-pyranylether or sill ether, hydroborating, by conventional methods, the olefinic double bond, oxidizing, Deb locking the protected hydroxy group, following the acetalization or ketalization.
A compound of formula (XXI I) wherein p = q = 2 may be prepared by known methods e.g. from 2-hydroxy-perhydroazulen-6-one which in turn may be obtained as described by DO Banerjee and K. Ankara Ram. in In. J. of Chem.vol.X, page l (1972).
The connpound of formula (XXVIII) may be used as starting material also for the preparation of the compounds of formula (XI) wherein G is a group Craig' 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 preferably protected as acutely ether or as ester, following the reaction scheme reported below:

(XXVIII) (XXIX) Ox t OX

SHEA CQ2CH3 ~C2CH3 Octal acutely Octal (XXXI) (XXXIIa : G'=H)~XXXIIIa : GO
~XXXIIb : G'=silyl-~XXXIIIb : G'=silyl-ether residue) ether residue) The compound ~XXVIII), by known methods, e.g. those previously reported, 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 *hen submitted, in a conventional manner to the hydroboration at the olefinic double bond to give the alcohols (XXX-Ida) and (XXXIIIa) which are then resolved by chromatography or by fraction-ate crystallization, converted into the corresponding sill ethers ,,~
I

I

~XXXIIb) and ~XXXIIIb) and finally transformed into the compounds of formula (XI) by reduction with diisobutylaluminium hydrides in Tulane according to known methods.
The compounds of formula I) show the same pharmacological activities as the natural prostacyclin, or PGI2 but, as compared with PGI2, the compounds covered by this invention have a particular advantage in tiler greater stability in the range of pit between zero and 11, in particular, at physiologic phi this leads to longer lasting and more 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 loath acid, 6-keto-PGFl~, shows almost none of 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.
III addition, compo~mds of formula I in which there is a triple bond in the 13-14 position of the Sheehan or in which there is a hindering group, such as a Cl-C6-alkyl group or an electron receptor group, e.g.
fluorine, near the hydroxyl in position 15 ~R3 or R4 = hydroxy) are more resistant to enzyme-induced for instance, 15-PG-dehydrogenase) metabolic degradation than natural prostacyclin.

I;

The pharmacological actions of natural prostacyclin are known.
Thus, for example when inhaled in asthmatic patients, prostacyclin prevents specifically induced ego. by nebulized water or by effort) bronchocostri-cation US. Bunk et at, J. Rest Medical Science, 6, 256 (197~]; when infused in man, it shows hypotensive and vasodilator activity and also shows blood platelet anti-aggre~ant 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 substances, e.g. acutely salicylic 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..
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 prostaglandins are indicated there-I poetical.
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:

- 37 _ orally in tablets, capsules, pills, or liquids like drops or syrups; rectal--lye in suppositories, intravenollsly, 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 4 times daily, but the exact dose depends on the age, weight and condition of the patient as well as the administration method.
For anti-asthmatic applications the compounds covered by this in-mention may be combined with other anti-asthmatics: simpaticomimetics like isoproterenol, ephedrine, etc.; xanthine 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 approximate-lye 0.01 g/kg~minute until the end of labor, or by mouth.
The compounds covered by this invention are also luteolytic and so are useful in fertility control, with the advantage that they stimulate the smooth muscles much less and so are free of the side effects of natural prostaglandins like vomiting and diarrhea.
Further, these compounds are anti-ulcerogenic and thus may be used to reduce and control excessive gastric secretion in mammals. In this way they minimize or eliminate the formation 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 for intravenous infusion range from 0.1 go to 500 ~g/kilo/minute. The total daily dose for both injection and infusion is on the order of 0.1-20mg/kg depending on the age, weight and condition of the patient or animal and on the administration method.
however, Mike natural prostacyclines, the most important forum-,..~, I,, ecological property of the compounds covered by this invention is their platelet anti-aggregant activity, that is, the capacity to inhibit platelet aggregation, to decrease adhesion, to prevent clot -formation and to dissolve recently-formed clots. This platelet anti-aggregank 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 condo-lions like atherosclerosis, arteriosclerosis and, more generally, dopier-lipidemia.
Normal administration methods are used in this application:
that is, intravenous subcutaneous, intramuscular, etc. In emergency situations intravenous administration is preferred, in doses ranging from 0.005 to 20 mg/kg/day, again depending on the age, weight and condition ox the patient and on the administration method.

ISLE
, . Jo , As mentioned above, the compounds sobered by this in-I- mention are useful in human and veterinary therapy, with 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-erred 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 sterile aqueous solutions or suspensions in aqueous or nonaque~us 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, glycvls, starch, gum Arabic gum adragant, alyinic 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 .

, . .
, .. . . . ..

" _~' '_ may be suspended or dissolved in one of the common liquefied propellants like dichlorodifluoromethane or ~ichlorotetra-fluoroethane and given with a pressurized container like an aerosol bomb When the compound is not soluble in the pro-to the pharmaceutical formulation pollinate, a co-solvent must be added for instance, ethanol, - dipropy1eneglycol and/or a tensioacti~e substance.
- ; In the following examples,THP,DMtB,3IOX,THF,DklSOtDI~A and DEFOE
refer respectively to te~r~hyoropyranyl,dimethyl-tert-butyl~
tetrah~drofuran;
1~4-diox-2-enyl~di~ethylsulphoxide,diisobutylalumiiniu~hydride JO arid dimethyl~ormamide.
The following 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 bicycle Noah-drone (0.4X10 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 7~-hydroxy-bicycle octan-3-one.
A solution of this compound (Molly) in 27ml of - an hydrous dimethylformamide is treated with 12.8g of dim ethyl-text-butylsilyl chloride and 3.85g of imidazole. The no-.. . . .

, _ .. . . ... ... _ . .. .. .

suiting mixture is heated to 60C for 5 hours, cooled, dill-ted with t~70 volumes of water- and extracted with ethyl ether (3x~40ml and 2x20ml). The combined organic extract is washed with I N~HCO3 and then water until neutral, and evaporate to dryness to give 15.8g of crude product (95% yield). Pun-ification on silica gel affords ?. 85g of 7-exo-hydroY~y-bicyclo -~.3.0~octan- 3-one-dimethyl-tert-butylsilyl ether and 11.8g Ox 7-endo-hydrox~-bicyclo ~3.3.0~octan-3 one-7-dimethyl-tert-butylsilyl ether.
A solution of the latter (11.8g, 4.63x10 Molly) in 295ml of methyl carbonate (Mohawk) is stirred with the exile-soon of wale; in an inert atmosphere and treated cautiously with ~,95g of 80% sodium h~-dride. When hydrogen evolution ceases, the reaction mixture is heated at 75-80C for forty minutes. After cooling, the mixture is diluted with two volumes of ethyl ether an cautiously treated with 13g of glacial acetic acid. The orc3anic place is then separated with pi 5.2-5.5 buffer and the aqueous layer is extracted with ethyl ether. The combined organic extract it dried over Nazi and evaporated to dryness to give 12.82g of d,l-7-endo-hdyroxy-bicyclo oaken -3-one-2-carboxymethyl-ester~7-dimethyl-tert-butylsilyl ether (85% of the 14.49g theoretical yield), which after purification on silica gel (45g/s, with 97:3 hexane:etllyl ether as fluent) affords 10.81g of the pure product; Mecca =7,000.

to Startle Ruth the ego isomer, -the same procedure aft - fords do 7-exo-hydroxy-bicyclo ~.3.0~octan -3-one-2-carboxy methylester-7-dimethyl-tert-butyl sily]etller; ~n~aX=254m~1, ~=6,500.
Example 2 A solution of 7.5g of d,l-7-endo-hydroxy-bicyclo ~3.3.0~-octane -3-one-2-carboxymethylester-7-dimethyl-tert-butyl sill-ether (DMtB-silylether) in 75ml of dichloromethane and 75ml of ethanol is cooled to -20C and treated with stirring with 0.9g of sodium bordered. After stirring for 15 minutes, C the excess reaccent is destroyed by adding 12ml of Austria.
The mixture is brought to OKAY, 20ml Or 20% KH2P04 is added, 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 Atari and evaporated to dryness to afford a residue which is crystallized from n-hexane to give go of a,l-`3,7-endo-dihydroxy-bicyclo ~3.3.b~-octane -2-exo-carboxymethylester-7-DMtB--silylether, mop.=
68-7QC. The mother liquor is adsorbed on 25g of silica sol;
elusion with 90:10 n-heptane:ethyl other gives another 2g of product pure enough to be used as is.
A solution of 6g of d,l-3,7-endo~dihydroY~y-bicyclo ~.3.QJ-octane ~2-exo-carboxymethylester-7-D~ltB-silylether in 100ml of $0:20 meth2nol:watcr is treated with 2g of potassium hydroxide and heated to reflex for 30 minutes. After concern-Jo ?

~98~3 traction under vacuum, the mixture is acidified -to pi 5.1 and extracted with ethyl acetate. Evaporation owe the organic layer gives 5.1g of d,l--3,7-endo-dihydroxy-2-carboxy-bicyclo-~.3.C~octane -7-DMtB-silylether. A solution ox this come pound in 150ml of ace-toni-trile is then treated with 2.~1g of d-(-l)-ephedrineO 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 I ox-octane-7-DMtB-silylether-d(+)-ephedrine salt. All the mother liquors are collected and evaporated to dryness to give a rest idle which is dissolved in water and treated with Q.6~g 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 Sue of l--ephedrinQ to afford after several crysta]llzations 2.3g ox 3,7-endo-c1ihyc~roxy-~-exo-carboxy--bicycle ~3.3.0~octane-7-DMtB-silylether -l-ephedrine salt.
Example 3 Jo solution of G.28g of d,l-~,7~-endo dihydroxy~-bicyclo-~3.3.03Octane -7-DMtB-silylether-2-exo-carboxymethylester in 30ml of an hydrous ethylene chloride is treated with 2.19g of 2J3-dihydropyran and 39mg of p-toluenesulfonic avid.
After 3 hours at room temperature, the reaction mixture is washed with OWE joke (2x5ml). Evaporation of the orc3anic 'to .
phase to dryness jives I of d,l-3,7-endo-dihydro~y-bicyclo-~3~3.0~ octane ~7-DMtB-silylether-3-THP-ether 2-carboxymethyl I- ester, which is then dried by being taken up in Andre Bunsen ~2x15ml) and 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 of 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-dil~ydroxy-2-exo-hydroxymethyl-bicyclo~3.3.0~octane -7-DMt~-silylether-3-THR-ether.
The following compounds axe prepared in this way from optically active starting materials:
Natendo-d.thydroxy-2-exo-hydroxymethyl-bicyclo~3.3.0~I-octane-7-DMtB-silylether-3-THP-ether;
ent~3,7-endo-dihydroxy-2-exo-dihydroxymethyl~bicycclue-octane~7-DMtB-si].ylether-3-THP-ether.
If Dixon is used instead of 2,3-dihydropyran, the corresponding 3(2'-DIOX)-ethers are obtained.

eye A solution of 3.8~ of d,l-3,7-cndo-dihydroxy-bicyclo-~3.3.0~octane -2-exo-carboxymethylester-7-DMtB-silyle~her in - 25 40ml of Bunsen is treated first with 3.66g of benzoic acid by g -.

- ~9~9 and 7.~q of triphenylphosphine, and then, with stirring, I- with 5.30q of ethyl azo-bis~carboxylate in 15ml of Hanson.
After 40 minutes of stirring, the organic phase is washed with ON sulfuric (2x20ml), and then sodium carbonate (3x15ml) and finally water until neutral. Evaporation to dryness affords a mixture of d,l-3-exo-7-endo-dihydroxy-bicyclo Eye -octane -2-exo-carboxyme-thylester 7-DMtB-silylether-3-bonniest and d,l-7~endo-hydroxy-bicyclo~3.3. octane-2-exo-carboxymethylester-7-D~ltB-silylether.
Thea crude reaction product is dissolved in an hydrous methanol, stirred for 3 hours, and treated with 0.5q of an hydrous potassium carbonate. Evaporation to dryness affords a residue which is taken up in ethyl acetate and saturated KH2PO1. 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,1-7-endo-hydroxy-bicyclo ~.3.C~oct-3-ene-2-carboxymethylester-7-DMtB-silylether, which is dissolved in methanol, treated with 0.3~ of 5% Pod on Cook and hydrog-enacted at room temperature and pressure to give d,1-7 endow hydroxy~bicyclo ~3.3 0 octane-2-carboxymethylester-7-DMtB-silylether;
by 2.01q of d,l-3-exo-7-endo-dihydroxy-bicyclo r3.3.03Octane--2-carbox~methylester-7-DMtB-silylether, which is saponified as described in Example 2 with 5% potassium carbonate in I , 80~20 methanol water Jo give d,l-3-exo-7-endo-dillydroxy-bicycle ~3.3.0~octane -2--exo-carboxy acid-7-DM-tB-silylether This is then separated into individual optical antipodes with (+) and (-) amphetamine.' Reaction with ethereal diazome-thane converts I
3-exo-7-endo-dihydroxy-bicyclo~3.3.030ctane-2-exo--car boxy acid-7-DMtB-silylether into the methyl ester derivative.
Subsequent reaction with 2,3-dihydrcp-~ran followed by reduce lion with Lyle in ethyl ether gives (-exiled-exo-hydroxymethyl-bicyclo ~3.3~C~octane -3-THP-ether-7-DMt~-silylether.
The (-) enantiomers and the rhizomic mixture are pro-pared analogously.
Example 5 .
5g of d,l-7-endo-hydroxy-bicyclo ~.3.0Joctane-DMtB-silylether-3-exo-carboxymethylester in 100ml of aqueous moth-anon is saponified with 2g of KOCH, at reflex. After the methanol is removed under vacuum, the aqueous solution of the potassium salt is extracted to remove neutral impurities, acidified, aloud extracted with ethyl ether. The latter ox-tracts are combined and evaporated to dryness to give 4.5q OX the do acid which is then separated into optical anti-poses with (-I) and (-) ephedrineO
1.32~ of (-)-7-endo-hydroxy bicyclor3.3.030ctane-7-- 25 DMtB-silylether-2~exo-carboxy acid is then dissolved in 20ml ?
to Jo of TIFF and treated with 1Oml of EM B1~3 in THY. After 4 hours at room temperature, the excess reagent is destroyed - by the cautious addition of 20ml of 1.5N Lowe 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 1.02q of t-)~7-endo-hydroxy-2-exo-hydroxymethyl-bicyclo~3.33.0]octane-7-D~ltB-silylether.
The (~) isomer and the rhizomic mixture are prepared JO analogously.
Example 6 2.7g of d,l-7-endo-hydroxy-2-exo-hydroxymethyl-bicyclo-~.3.0~octane-7-DM-tB-silylether in 20ml of ethylene chloride is treated with 0.95g of 2,3-dihydxopyran and omega of I-toluenesu].fonic acid for 3 hours a-t room temperature. After being washed with 7% aqueous Noah and then water, the organic phase is evaporated to dryness to give crude d,1-7-endo-hydroxy-2-exo-tetrahydropyranyloxymethyl-bicyclc [3.3.0~octane-7-DMtB-silylether. This is dissolved in 15ml of THY and treated with

4.~g of tetrabutylammonium fluoride for ours, with stirring.
The reaction mixture is then concentrated under vacuum, ad-sorbed on silica gel and eluded with benzene:ethyl ether to give 2.1g of d,l-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 - 3C with stirring and treated with 4.2ml ' I

I

of 8% 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 is diluted with 6 volumes of Bunsen. The organic phase is washed with I (NH4)2SO~ until neutral, and the combined aqueous phase is re-extrac-ted with Bunsen. The combined ensign extract is dried and evaporated to dryness to afford 1.82q of d,l-2-exo-THP-oxymethyl-bicyclo ~3.3.0~octan-7~one.
Thea net- and enact- isomers are prepared analogously.
_aJnple 7 With external cooling and stirring to keep the react lion temperature near 20-22C, a solution of 6.57g of jot-assay tert-butylate in 65ml of DMSQ is added drops to 6.76g of 4-carboxybutyl-triphenyl-phosphonium bromide in 40ml ox DMSO. After the addition, the mixture is diluted with an equal volume 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 ethcr: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 dissolved in 50ml of acetone treated with 20ml of ON aqueous I

o~alic acid, and held at 40-45C for S hours. Tory 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 of d,1-5-cis,trans-[2'-exo-hydroxymethyl-bicyclo ~.3.0 octane pentenoic acid methyl ester (1.75g). The India idyll isomers may be separated with high pressure liquid-liquid chromatography to the 5-trans-d,l and the suicidal lo isomers-; the latter is named 5-cis-~(20-~12)-octanor-12 -hydroxymethvl-9a-deoxy-ga-methylene-prostacyci-5-eelk acid methyl ester.
trlphenyl If the 4-carboxybutyl-~phosphonium bromide in the above procedure is replaced by one of the following Witting i reagents (3-carboxypropyltriphenylphosphonium bromide, 5-carboxypentyltriphenylphosphonium bromide, 4-carboxy-2-ox~.-~utyltriphenylphosphonium bromide), the methyl esters of the hollowing acids are prepared:
d,l-5--cis-l~(20~12)-octanor-2 nor-12~-hydroxymethyl-9a-deoxy-9a-methylene-prostacycl-5-enoic acid;
d,1-5-cis-~(20~12) octanor-2a~omo-12~-hydroxymethyl-9a-deoxy-9a-methylene-prostacycl-5-enoic acid;
d,1~5-cis-~(20~12)-octanor-3-oxa-12~ hydroxymethyl-9a-deoxy-- 9a-methylene-prostacycl-5-enoic acid;
as well as their trueness isomers and the individual net- and I/
Jo 1~9B419 enact- antipodes.
Example 8 stirred solution of 7.16g of 5-cis-~(20-j12)-octanor-12~hydroxymethyl-~a-deoxy-9a-methylene-prostacycl-5-eenoic acid methyl ester in 80ml of 75:25 benzene:dimethylsulfoxide is treated with 8.9g of dicyclohexylcarboo!iimide and then with 14.2ml of a pyridinium trifluoroacetate solution (prepared by adding 25ml of 75:2~ benzene:D~lSO 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 organic phase is separated and washed with water (5x6ml). Reduction in volume gives a bent zone solution of the formula derivative which is added all at once to a solution of (2-oxo-heptyl)dimethyl phosphonate sodium salt. The latter is prepared by adding drops 7.58g of ~2-oxo-heptyl)-dimethyl phosphonate in Owl of an hydrous Bunsen to a stirred solution of 1.02~ 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 phosphonate 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 ether to give Gig of cisterns 9a-cleoxy-9a-methylene-15-oxo-prostacycla-5,13-dieno-ic 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--met-hylene-15-oxo-2alllomo-prostacycla-dunk acid;
5-cis-13-trans-9a-deoxy-9a-methylene-15-oxo-3-oxa--prostacycla-5 r dunk acid;
as well as their trueness geometric isomers, in the Nat enact- and do forms.
example 9 A stirred and cooled t5-8C) solution of 1.35g of 2-exo-hydroxymethyl~7-endo-hydroxy-hicyclo okay ane-D~t~-silylether in 5ml of pardon is treated with O. yo-yo of bent oily chloride. After 3 hours at room temperature, ON H2SO~
is added and the mixture is extracted with ethyl ether to give 2-exo-ben~oyloxymethyl-7-endo-hydroxy-bicyclo~3.3..030ctane-7-DMtB-silylether. This silylether group is removed by Rex 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, 1.11g of 2-exo-benzoyloxymethyl~7-endo-hydroxy-^bicyclo ~3.3.0~ -octane. This is dissolved in pardon and then added ~11 9~34~

_ S _ to a solution of 1g of Crow in 1Oml of pardon. After 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 wasted with ON H2S04 and water 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 7 23g of 80% sodium hydrae in THY to a solution of 2.12g of (2-oxo-5-trimethoxy-pentyl)-dimethyl phosphonate in 6ml of anhydxous THIEF After 10 hours ox stir-ring, two mixture is neutralized with 15% KH2P04, 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~3.3.0~oct-7-enyl -1,1,1-trimethoxy-pent-5-en-~-one, or 12~-benzoyloxymethyl-~(20-`~12)-octanor-4~oxo-9a-deoxy-9a-~ethylene-proostacycl-5-eno-c acid-orthomethylester, as a mixture of the Swiss and trueness olef~ns which are then separated by high pressure liquid-liquid chromatography.
Subsequent treatment with aqueous methanol and H2S0~
25 gives the corresponding methyl ester derivatives. Reaction of 3 - Lowe . So -- or ---- 0.3g or methyl ester with 0.25ml of 1,3-ethanedithiol in ethylene chloride and a catalytic amount of BF3-etherate or 15 minutes at 0C then affords 12 ~benzoyloxymethyl-~20-~12)-octanor-4,4-ethylenedithio-9a-deoxy-9a~meethylene-prostacycl-5-enoic acid methyl ester.
Example 10 0.8g of 12~-benzoyloxymethyl-'.~(20-S~12) octanor-4-oxo-9a-deoxy-9a-methylene-prostacycl-5-enoic acid methyl ester in 1Oml of methanol is selectively de-benzoylated upon treat-mint with stirring it 0.15g of an hydrous K2C03. After the solvent is evaporated, the residue is taken up in 15% assuages KH2PO~ and ethylene chloride to 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 US% aqueous acetic acid, the solvent is evaporated and the residue is adsorbed on silica sol. Louisiana 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 1 9Q~ potassium carbonate to afford, after acidification and extraction with ethyl acetate, 0.1~g of so 12~-hydroxymethyl-~(20il2)-octallor-4S-hydrory-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 0.28g of 4,~-ethylenetithio-l2~-benzoyloxymethyl-~(20~r~12~-octanor 9a-deox~9a-methylene-prostacycl-5-enoic acid methyl ester is selectively de-benzoylated upon methanolysis with K2CO3 in an hydrous methanol to give the corresponding `-o 12~,-hydroxymethyl derivative. This is then oxidized to the alluded according to the procedure in example 8 to jive the formula derivative.
Reaction of 0.12g of this compound in Bunsen with the fuzzily prepared from 0.177g of (2-oxo-3,3-dimethyl-neptyl)-dimethyl phosphonate and 20mg of 80% Nay, as desk cried in example 8, gives 5,13t-16,16-dimethyl-4,4-dithio-ethylenedioxy-15-oxo-9a-deoxy-9a-methylene-prostacsuckle-dunk acid methyl ester.
In an analogous fashion, using (~-cyclohexyl-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-deoxy-9a-methylene-17-cyclohexyyule-trinor-prostacyc]a-5,13-dienoic acid -lactose. Or, with (3-phenoxy~2-oxo-propyl)-dimethyl phosphonate, 5,13t-~S-hydroxy~15-oxo-9a-deoxy-9a-me-thylene-17,18,19,,20-tetranor so _ .

16-phenoxy-prostacycla-5,13-dienoic acid-1,4-~-lac-tol-.e is prepared.
Example 12 Using (2-oxo-3S-met}lyl-}leptyl)-dimethyl phosphonate - and (2-oxo-3S-fluoro-heptyl)-dime-thyl phosphonate as the phosphonates and 12~-formyl-~(20~12j-octanor-4R-hydroxy-9a-deoxy-9a~meth~lene-prostacycl-5-enoic acid-1,4-~f-lactone as the alluded, the procedures of examples 3 and 11 afford`: ;
try hydroxy-15-oxo-9a-deoxy-9a-methylene-16S-methyl-prostacycla-5,13-dienoic Acadia- lactose;
5,13t4R-hydroxy-15-oxo-9a-deoxy-9a-1nethylene-15~-fluorno-prostacycla-5,13-dienoic acid-1,~-d-lactone.
Example I
A solution of 0.7g of 5c,13t-15-oxo-9a-deoxy-9a-methy-15` lene-prostacycla-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. After 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 give a residue which is purified on silica gel with ethyl ether as fluent to afford 0.32g of 5c,13t-15S-hydroxy-9a-deo~y-9a-methylene-prostacybla-5,13-dienoic acid met}lylester and 0.26g of the 15R isomer.

.

:' This same procedure for reducing the 15-oxo derivatives from examples 8, 11 and 12 affords the methyl esters of the I- following acids: /
5cis,13-trans-9a-deoxy-9a-methylene-15S-hydroxy-2--nor--prosta-cycla-5,13-dienoic acid;
5cis,13trans-9a-deoxy-9a-methylene-15S-hydroxy-2a~~omo-prosta-cycla-5,13-dienoic acid;
-5cis,13trans-9a-deoxy-9a-methylene-15S-hydroxy-3--oxa-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-4sr15s-dihydroxy-17-ccyclone 18,19,20-u~-trinor-prostacycla-5,13-dienoic acid;
5c~13t-9a-deoxy-9a-methylene-4s~15s-dihydroxy-16-pplan 17,18,19,20-~tetranor-prostacycla-5,13-dienoic acid 5G/13t-9a-deoxy~9a-methylene-4R,15S-dihydroxy-16S--methyl-prostacycla-5,13-dienoic acid;
513t-9a-deoxy-9a-methylene-4R,15S-dihydroxy-1~S-fluurea- .
prostacycla-5,13-dienoic acid;
as well as their trueness geometric isomers, in the net-, enact- and do forms.
E mule 14 A solution of 0.35g of 5c,13t-15-oxo-9a-deoxy-9a-- I methylene-prostacycla-5,13-dienoic acid methyl ester in 10ml 3L~9~

of 2:1 ethyl ether:toluene is cooled to -30C and 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 ammonium color-- 5 ides The organic phase is washed with water, sodium vicar-borate and water, dried over McCoy, treated with 0.1ml of pardon, and evaporated under vacuum to give a mixture of the 15S and 1SR alcohols. Separation on silica gel with - 80:20 ethyl ether isopropyl ether as fluent affords 0.1g of I 5c,13t-15S-hydroxy-9a-deoxy-9a-methylene-prostacycclue-dunk acid methyl ester and 0.1g of the 15R isomer.
- Exam With the same substrate but ~lnhydrous THY as sol-vent, reaction with 8ml of 0.3M ethanol magnesium bromide in TO glvèsr after chromatography on silica gel, 5c,13t-15-ethynyl-1SS-hydroxy-9a- deoxy-9a-methylene-~rostacycla-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-dieenoic acid mel-hylester and its 15R isomer are prepared.
Example 16 A solution of 0.26g of 5c,13t-9a-deoxy-9a-metllylene-4R,15S-dihydroxy-1~S-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 I

ether ate I ~10 EM yin an hydrous ethylene chloride) and then 5% diazomethane in ethylene chloride until a yellow color persists. The solution is washed with I aqueous Nikko and then water until neutral, evaporated to dryness, and purified on silica gel ~3g) to give yo-yo of 5c,13t-9a-deoxy~9a~methylene-4R,15S-dihydro~y-16S-meth~ prostacycla-dunk acid-1,4-~-lactone-15-methyletller.
Example 17 A solution of 0.74g of d,1-2-exo~hydroxymethyl-3-exo-THP-oxy-7-endo-DMtB-silyloXy-bicyclo ~3.~.0~octane in 15ml of an hydrous ethylene chloride is added all at once to a solution of 3.1g of Collins reagent (C5H5N2)2 Crow in 40ml of an hydrous ethylene chloride, with stirring and cool-King to 0~5 Filtering earth is added after 15 minutes of stirring and the mixture is filtered to give a clear Solon 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 methyl-(2-oxo-octyl)-phosphonate. This latter is prepared by adding 0.59g of (2-oxo-octyl)-dimethyl phosphonate in 1Oml of Bunsen drops to a suspension of 0.07g of 80% Nay in 20ml of Bunsen and stirring the resulting mixture for approx-irately 1 hour, until hydrogen evolution ceases. Stirring is continued for 20 minutes after the alluded is added to the phosphonate carbanion solution. The organic phase is then neutralized with excess 25~ aqueous Nope and separated.
After drying, it is evaporated to dryness to give a residue which is purified on silica gel (cyclohexane:ethyl ether as Ellen.) to afford 0.81g of d,l-2-exo-~3'-oxo-non-1'-trans-~-enyl~-3-exo-THP~oxy-7-endo-DMtB-silyloxy-bicyclo 3.3.0 octane.
Example 18 A solution of 1.05g of d,l-2-exo-hydroxymethyl-3-endo-THP-oxy-7-endo-DMtB-silyloxy-bicyclo~3.3.0~occrane in 8ml of 75:~5 benzene:DMSO is treated with 0.89g of dusk-I ~ohexylcarbodiimide and then, with stirring, with 1.42ml ova pyridinium trifluoroacetate solution After 3 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 give a solution of 2-exo-formyl-3-endo-TI1P-oxy-7-endo-DMtB-silyloxy-bicyclo~3.3.0octane The d,l,nat- and enantio-formyl derivatives are pro-pared using this procedure In the same way, if 7-exo-hydroxy-bicycle .O~octan -3-one-7-diIllethyl-tert-butylsilyl-ether is used in the procedures of examples 1, 2 and3,2-exo-formyl-3-endo-THP-oxy-7-exo-DMtB-siloxy-biicicle octane is obtained.
example 19 A solution of 322mg of (2-oxo-heptyl)-dimethyl pros-fount in 5ml of beIlzene is added to a suspension of 43.5mg I

of 80~ Nay in 1Oml of Bunsen, and the resulting mixture is stirred until hydrogen evolution ceases. In the dark, 258mg of finely divided N-bromosuccinimide are added and stirring is continued for another 5 minutes, 0.37g of 2-exo-~ormyl-3-endo-THP-oxy-7-endo-D~1tB-silyloxy-bicyclo~3.3.0030ctane in 5ml of bcnzene is then added and the resulting mixture is stirred owe another 15 minutes, after which the reaction mix-lure is partitioned between Bunsen and 15% ape. The or~nic phase is dried, concentrated to small volume, ad-sorbed on silica Mel and eluded with 80:20 cyclohexane:ethyl ether to afford 0.~2g or 2-exo-~2'-brcmo-3'-oxo-oct-1'-enyl~-3-endo-T~P-oxy-7-endo-DMtB-silyloxy-bicycloL3.3.0~octane (maxim S,250).
If (2-oxo-3~-fluoro-heptyl)-dilnethyl phosphonate is I used, the corresponding 2-exo-~2'-bromo-3'-oxo-4'i~-~luoro~oct-1'-trans-enyl~ derivative is obtained.
Example 20 A solution of 0,3g of ~2-oxo-4(2')-tetrahydrofuryl-butyl~-d.imethyl phosphonate is added drops to a stirred suspicion of 36mg of 80% sodium hydrides in 5ml of Bunsen, Stirring is continued until hydrogen evolution ceases, and - then a solution of 0.37g of 2-exo-for~yl--3-endo--THP-oxy-7-exo-DMtB-silyloxy-bicyclo~3,3. 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, ad~orbcd on silica gel and eluded loath ben~ene:ethyl other to chive 0.35g of2-exo-~3'-oxo-5'(2")-~etrahyclrofuryl-pent-1'-tranno-enyl~-3--endo-THP-oYy-7-exo-DMtB-silyloxy-bicyclo ~3.3.0~octane (maxim 3,800).
Example 21 If2-exo-formyl-3-endo-THP-oxy-7-endo-DM-tB-silyloxy--bicycle ~.3.0~octane was the 2-exo-formyl-7-exo-bicyclo don-ivative used in the procedure described in example 20, and if the following phosphates were used:
(2-oxo-heptyl)-dimethyl phosphonate;
(2-oxo-octyl?-dimethyl phosphonate;
(2-oxo-3S-methyl-heptyl)-dimethyl phosphonate;
(2-oxo-4-cyclohexyl-butyl.)-dimethyl phcsphonate;
-15 (2-oxo-4-phenyl-butyl)-dimethyl phosphonate;
(2-oxo-3-m-trifluoromethylphenoxy-propyl)-dimethyll phosphonate;
(2-oxo-3-methyl-3-butoxy-butyl)-dimethyl phosphona-te, 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-THP-oxy-7-exo-DMtB-silyloxy-2-exo-(3'-oxo-nnon - trans-1'-ellyl)b-icyclo ~3.3.0]octane;
3~endo-T~IP-o~y-7-exo-DMtB-silyloxy-2-exo-(3'-oxo--~lS-methyl-oct-1'-txans-1'-e.ny.)bicyclo.~3.3. octane;
3~endo-T~IP-oxy-7-exo-DMtB-silyloxy-2-exo-(3'-oxo--suckle-I

-- hexyl-pent-1'-tran5~ r~yl~bicyclo ~3.3.0~octanei 3-endo-THP-oxy-7-exo-DMtB-silyloxy-2-~xo-(3'-oxo-5phenol-pent-1'~trans-1~-enyl) -bicycloL3 . 3.0~octane;
3-endo-THP-oxy-7-exo-DM-tB-silyloxy-2-exo-(3'-oxo--4'-m-tri-5 fluoromethylphenoxy-but-1'-tîans-1'-enyl)-~i~clo ~.3.0~octane;
3-endo-THP-oxy-7-exo-DMtB-silyloxy-2-exo-(3'-oxo-4methyl-4'-butoxy-pent-1'-trans-1l-enyl)-bicyclo r3.3.0~octane.
Example 22 ; A solution of 0.3g of d,l-2--exo-(2'-bromo-3'-oxo-4'R-fluoro-oct-1'-trans-l-enyl)-3-endo-TH~-oxy-7-endo--DMtB-silyloxy-bicycle [3.3.0~octane in 10ml of an hydrous ether is added drops in 15 minutes to a 0.1M solution of zinc bordered in ethyl ether (10ml). After stirring for two hours, the reaction mixture is quenched with saturated sodium chloride and ON sulfuric acid. The ether layer is separated and washed with water, 5% Nikko, and then water. Evaporation to dryness affords mixture of the 3'S and OR hydroxy alcohols which are separated by liquid-liquid chromatography with isopropyl ether as solvent to give 0.11g of d,l-2-exo-(2'-bror.lo-3'S-20 hydroxy-4'R-fluoro-oct-1'-trans-1'enyl)3-endo-THP--oxy-7-endo-DMtB-silyloxy-bicyclo 3.3.0 octane and 0.1g of the OR epimer.
Example 23 A solution of 0.3~ of 2-exo- Lo' oxo-5'(2"~-tetrahydro-furyl-pent-1'-trans7~nyl]-3-endo-THP-oxy-7-exo-DMttB-silyloxy-bicyclot3.3.0~octane in 3ml of ethylene chloride and 3ml of 8~9 ,. . . . .

_ Jo _ ethanol is cooled to -10-15C and then -treated loath 25mg of Nub. After 30 minutes of stirring the reaction mixture is quenched with Smalley of acetone and 3ml of saturated Nope, evaporated under vacuum, and then extracted with ethylene . 5 chloride. The organic phase is dried over Nazi and vapor-axed to dryness to give a residue which is purified on silica gel (hexane:ethyl ether as fluent) to afford 0.1g of 2-exo-~3'S-hydroxy-5'(2")-tetarhydrofuryl-pent-1'-trans Noel-endo-THP-oxy-7-exo-DMtB-silyloxy-bicyclo~3.3.0~octlane and 0.11g of the OR isomer.
Example 24 By following the procedure ox examples 22 and 23 using one of the unstriated kittens prepared as in ox-apples 19, 20 and 21, the following compounds jury prepared:
3-endo-THP-oxy-7-endo-DMtB-silyloxy-2-exo-(2'-brcrRuss-hydrc)xy-oxt-1'-trans-1'-enyl)-bicyclo~3.3.0~ octane;
3-endo-THP-oxy-7-enc.o-DMtB-silyloxy-2-exo-(3'S-hyydroxy-oct-1'-trans-1'-enyl)-bicyclc)& .3.0~octane;
3-endo-T~-IP oxy-7-endo-DMtB-silyloxy-2-exo-(3'S-hydroxy-4'S-methyl-oct-1'-trans-1'-enyl)-kicyclo~3.3.0~octane;;
3-endo-THP-oxy-7-endo-DMtB~sllyloxy-2-exo-(3'S-hyddroxy-non~
1Ltxans~ Noel) -bicyclo~3.3.03Octane;
3-endo-THP-oxy-7-endo-DMtB-silyloxy-2-exo-(3'S-hyddroxy-cyclo-hexyl-pent-1'-trans-1'-enyl)-bicyclo~3.3.0~octane;;
I 3-endo-THP~oxy-7-endo--DMtB-silyloxy-2-exo-(3'S-hyydroxy-5'-- phenyl-pent-1'-trans-1'-enyl) -bicycle ~3.3.0~octane;
3-endo-TIIP-oxy-7-endo-D~ItB-s.ilyloxy-2-exo- (3'S-hydroxy-4 7 -m-trifluoromethylphenoxy-bu-t-1'--trans-1'-e}lyl)~bicycle C3.3.0~-octane;
3-enclo-THP-o~y-7-endo-DMtB-silyloxy-2-exo-(3'S-hyydroxy-4'-methyl-4l-bu-toxy-pent-1'-.îans-1'-enyl)-bicyclo ~3.3.OJoctane;
3-endo-THP-oxy-7-endo-DMtB-silyloxy-2-exo- (2'-bromo-3'R-hydroxy-oct-1 Ltrans-1'-enyl)--bicyclo~3.3.0~ octane;
3-endo-THP-oxy-7~endo-DMtB-silyloxy-2-exo- (3'R-hydroxy-oct-1'-trans-1'-enyl)-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)-bicyclor3.3.Q~octane;;
3-endo-TIIP-oxy-7-endo-DMtB-silyloxy-2-exo- (3'R-hydroxy-non-1'-trans-1'-enyl~bicyclo [~.3.0~octane;
3-endo-~lP-o~y 7-endo-DMtB-silyloxy-2-exo- (3'R--hydroxy-5'-cyclohexyl-pent-1'trans-1'-enyl)-- bicycle .3.0~octane;
3-endo-THP-oxy-7-endo-~MtB-silyloxy-2-exo- (3'R-hydroxy-5'-phenyl-pent~ trans-1'-~yl)-bicyclo ~3.3.0~octane;
3-endo-THP oxy-7-endo-DMt~3-sily10xy-2-exo- (3'R-hydroxy-4'-m-trifluoromethylphenoxy-but-1 Ltrans-1'-enyl)- bicycle ~3.3.0~ -octane;
3-endo-T~IP-oxy-7-endo-DMtB-silyl.oxy-2-exo 3'4-hydroxy-4'-methyl 4'--butoxy~pent-1'-trans-1'-enyl)-hicyclo ~3.3.030ctane.
Example 25 .

A solution of 1.17g of 2 ego- (3'S~hydroxy-oct-1'-I

trueness enylJ3-endo-THP-oxy-7-endo-DMtB-silyloxy-bicyclo-C3.3-0Joctane in 12ml of an hydrous ethylene chloride is treated with 12Om~ of 2,3~dihydropyran and em of Tulane sulfonic acid. after 4 hours at room temperature, the organic - 5 phase is washed successively with 5% Nikko and water and then evaporated to dryness to give 1.45g of crude excuse-THP-oxy-oct-1'--trans-1'-enyl)-3~endo-THP-oxy-7-enndo-D~tB-silyloxy-bicyclo~3.3.030ctane. 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 (ethyl ether as fluent) to afford 920mg of2-exo-(3'S-hydroxy-oct-1'trans-1'-enyl)--3-endo-7--endo-dihydrox~-bicyclo Lo 3~0]octane-3,3'-bis-THP-ether.
` 15 sample 26 Using the procedure of example 25 with compounds pro-pared according to examples 22, 23 and 24, the following bicyclo~3.3.0~octane-3,3'-~is-T~IP-ether derivatives were prepared:
JO 2-exo-(2~-bromo-3's-hydroxy-4~-fluoro-oct-1'-transsunnily) 3-endo-7-endo-dihydroxy;
2-exo-(2'-bromo-3'R-hydroxy-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;

98~

2-exo- (3IR-hydroxy-5' (2")-tetrahydrofuryl-pent~ trueness'-enyl)-3-endo-7-exo-dihydroxy;
2-exo~ (2'-bromo-3'S-hydroxy-oct-1'-trans-1l-en~ end-endo-dihydroxy;
2-exo- (2'-bromo-3'R-hydroxy-oct-1'trans-1'-enyl) -end-endo-dihydroxy;
2-exo-(3~S-hydroxy-oct-1'-trans-1'-enyl)-3-endo-7-endo-ddihydroxy;
`2-exo- (3'R-hydroxy-oct-1~-tralls-1~-enyl)-3-endo-7-e~ o-dihydroxy;
2-exo(3'S-hydroxy-4'S-methyl-oct-1'-trans-1'-enyl)-3-enndo-7-endo-dihydroxy;
2-exo-(3'R-hydroxy-4'S-methyl-oct-1'-trans-1'-enyl)-3-enndo-7 endo-dihydroxy;
ego I 7S-hydroxy-non-1l-trans-1'-enyl)~3-endo-7-endo-dihyydroxy;
2-exo-(3'R-hdyroxy-non-1~-trans-1'-enyl~3-~endo-7-endo-ddodder ` 15 2-exo-(3'S-hydroxy-5'-cyclohexy]-pent-1~-trans-1'-enyl)--3-end 7-endo-dihydroxy;
2-exo-(3'S-hydroxy-5'-phenyl-pent-1'-trar,-1'-enyl)-3-enndo-7-~ndo-dihydroxy;
2-exo-t3'R-hydroxy-5'-phenyl-pent-1'-trans-1'-enyl)-3-enndo-7-endo-dihydroxy;`
2-exo-(3'S-hydroxy-4'-m-trifluoromethylphenoxy-but-1'-trfans- 1'-enyl)-3-endo-7-endo-dihydroxy;
2-exo-(3~R-hydroxy-4~-m-trifluoromethylphenoxy-but-1'-trrolls- 1'-enyl)-3-endo-7-endo-dihydroxy;
2-exo-(3'S-hydroxy-4'-methyl-4'-butoxy-pent-1'-trans-1'--enyl)-3-endo-7-endo dihydroxy5 lo 2-exo~(3'R-hydroxy-4'-methyl-~'-butoXy-pent-1'-traans-1'-enyl)-3-endo-7-endo-dihydroxy.
Employ _ -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-hydroxy-5'(2'')-tetrahydrofurll-pent-1''-trans-1'-enyl) end exo-dihydroxy-bicyclo t3.3.0~octane-3 7 3'-bis-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 us partitioned between Bunsen and ON sulfuric acid.
The aqueous portion is re-extracted with Bunsen, washed sue-cessivel~ wit to water, Nikko and water, and evaporated to -15 ~rvness to give 0.31g of 2-exo-(3'S-hydroxy-5'(2"~ twitter-hdyrofuryl-pent-1'-trans~1'-enyl~3-endo-hydroxy-biicicle ~3.3.01-octan-7-one-3,3'-bis-THP-ether.
Example 28 A stirred and cooled (-1Q-5C) solution of 0.8g of 2-exo-(3'S-hydroxy-oct-1'-trans~ enyl)~3-endo-7-endo-dihydroxy-bicyclo~3.3.030ctane-3,3'-bis-THP-ether in 20ml 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 15% aqueous (NH4)2S04 until neutral, dried and evaporated to dryness to 34~
4:

-I afford 0~71g of 2-exo-(3'S-hydroxy-oct-1'-trans-1'-enyl)-endo-hydroxy-bicyclo ~3.3.0~octan-7-one-3,3'-bis-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-31S-hydroxy-4'R-fluoro-oct-1'-tranns-~'-enyl);
I 2-exo-(2'-bromo-3'R-hydroxy-4'R-fluoro-oct-1'-tranns-1'-enyl);
2-exo-(3'S-hydroxy-5'(2") tetrahydrofuryl-pent-l'-trans-1'-enyl);
2-exo-(3~R-hydroxy-5l(2ll)-tetrahydro~llryl-pent-11l-trans~1l-enyl);
2-exo-(2'-bromo-3'S-hydroxy-oct-1'-trans 1'-enyl);
2-exo-(2'-bromo-3'R-hydroxy-oct~ tIans-1'-enyl);
2-exo-(~'S-hydroxy-oct-1 ! -trans~1'-enyl);
2-exo-(3'R-hydroxy-oct-1'-trans-1'-enyl);
2-exo-(3'S-hydroxy-4ls-methyl-oct-1l-trans-il-enyll);
2-exo-(3'R-hydroxy-4lS-methyl-oct~1'-trans-1' enyl);
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-1l-trans~1'--enyl);
2-exo-(3lS-hydroxy-5'-phenyl-pent-1'-trans~1'-enyll);
2~exo-(3'R-hydroxy-5'-phenyl-pent-1'-tranS~1'-enyll);
2-exo-(3'S-hydroxy-4'-m-trifl~oromethylphenoxy-butt-1'-trans-Jo . 1'-enyl);
2-exo-(3'R-hydroxy-4'-m-trifluoromethylphenoxy-but-1'-trfans-1'-enyl);
2-exo- (3~S-hydroxy-4'-methyl-4~-butoxy-pent-1'-trans~ enYl);
2-exo (3'R-hydroxy-4'-methyl-4'-butoxy-pent-1'-trans~ 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 L3.3.0~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' (SIR)-hydroxy-non-1 ~trans-1'-enyl)-- 3-exo-THP-oxy-7-endo-DMtB-silyl-oxy-bicyclo [3.3.0~octane. Without separating the 3'S end OR alcohols, this product is reacted in 30ml of ethylene chloride with 0~4g of 2,3-dihydropyran in the prison of 25mg of p-toluenesulonic acid to give the corresponding do ego- (3'(S,R)-hydroxy-non-1'-trans-1'-enyl)-3-exo-hydroxy--7-endo-DMtB-silyloxy-bicyclo [3.3.03Octane-3,3' bis-THP-ether.
With no further purification, this product is Ideated with 'Ye l eats t -I 0 2.5 molar Casey of tetrabutyl ammonium fluoride in THY
to remove the sill ether.
The product Dixie- (3' (S,R)-hydrs~xy-non-1'-trans~
enyl)--3-exo-7-endo-dihydroxy-bicyclo~3.3.0~octaneebbs-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.

1Ltrans-1'-enyl)~3-exo-hydroxy-bicyclo~3.3.030ctann-7-one-3,3'-bis-THP-ether.
Example 31 A solution of (2-oxo-5,5,5-trimethoxy-pentyl)-dime-thyl - 5 phosphonate in 1Oml of THY is added drops to a stirred suspension of 68mg of Nay (80%) in 10ml 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-1'trans-1'-enyl)-3-exo-hydroxy-bicyclo~3.3.o~ octan-7-one-3,3'-bis-THP-ether in 5ml of THY is added. After hours of stir-ring at 40-45C, 20ml of 20% N~H~P04 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 - 15 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 I 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,l-5t,13t-4-oxo-11~,15S-dihydroxy-20-methyl-9a-deoxy-9a-methylene-prostacycla-5,13-dienoic acid-trimethyl-orthoester and 0.21g of the 15R epimer.

I

Example 32 Following the procedure of example 31 with a bicycle-~3.3.0~octan-7-one prepared as in examples 27, I and 29, the following trimethylorthoesters were prepared:
tweaks MY ,1 5S-dihydroxy-9a-deoxy-9a-methylene-prosta-suckle dunk acid;
5 913t-5-oxo-11~,15S-dihydroxy-9a-deoxy-9a-methylene-220-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;
tweaks ,1SS-dihydroxy-9a-deoxy-9a-methvlene-16-m-trifluoromethylphenoxy-17,18,19,20--etranor-prostaacycla-dunk acid;
as well as their 15R epimers.
- 15 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 tweaks ,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 0.42g of the corresponding methyl ester.
A solution of this product in 6ml of anhydro~ls ethyl ether is added drops to a stirred 0.1M solution of zinc borohydrlde (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-deoxy-9a-methylene-prrostacycla-dunk acid methyl ester. Chxomatographic separation on silica gel (ethyl ether ethyl acetate as fluent) affords 0.11g of5,13t-4S,11~,15S~trihydroxy-9a-deoxy-9a-methylene--prostacycla-5,13-dienoic acid methyl ester and 0.14~ of the 4R-epimer methyl ester.
A solution of the latter compound in 5ml o' methanol it treated with 0.05g of lithium hydrate and 0.3ml of H20 `.
and then stirred at room temperature for 6 hours. Removal of the methanol under vacuum, acidification of pi 5.6 and rapid extraction with ethyl acetate afford Strauss-trihydro~;y-9a-deoxy-9a-methylene-prostacycla-5,13dunk acid. Treatment of a stirred ethyl acetate solution of this compound with C.5 parts of a polystyrenesul~onic resin (ho-drogen ion form) jives 5,13t-4R,11~,15S-trihydroxy-9a-deoxy-9a-methylene-prostacycla-5,13-dienoic acld-1,4-~-lactone quantitatively.

The US epimer-~-lactone was prepared analogously.
Example 34 A solution of 0.8g of tweaks dodder-20-methyl-ga-deoxy-9a-methylene-prostacycla-5~13-dDick acid-trimethylorthoester-11,15-bis-THP-ether in 20ml of ethylene chloride ethanol is cooled to -20C aloud treated with 50mg of Nub. After 30 minutes of stirring, the reaction is quenched with 2ml ox 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 of5,13t-4(S,R),11~,15S-trihydroxy-20-methyl-9a-deoxyy-9a-me~hylen~-~rostacycla-5,13-dienoic acid-trimethylorthoester-11,15-bi---THP-~ther.
I This crude product is dissolved in 2.2 ml of methane-sulfonyl chloride. The reaction mixture is held overnight at room temperature and 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-dienoic acid-trimethyl-orthoester-4-mesylate-11,15-bis~-ether.
With noiEurther purification, this product is dissolved in anh~drous ethyl ether and treated with 50mg of lithium aluminum hydrides in ethyl ether. after strung for 2 hours ~19~

at room temperature and 1 hour at reflex, the reaction mix-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 iota ,15S-dihydroxy-20--methyl-9a-deoxy-9a-methylene-prostacycla-5,13-dienoic acid-trimethyl-orthoester-11,15-bi~-THP-ether.
Aster treatment at reflex with 12ml of methanol and 4ml of 0.3N aqueous oxalic acid, standard work-up gives 0.2g of5/13t-11~.~,15(S)-dihydroxy-20-methyl-9a-deoxy-9a--methylen2-prostacycla-5,13-dienoic 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 ox 0.4g of Nay (75% mineral oil dispersion) in 13.5ml of Also is heated to 60-65C for 4 hours. The mixture is then cooled to room temperature and held at 20-22C while 2.6g of 4-carboxy-butyl-triphenyl phosphonium bromide in 6ml of DMSO
and 0.85g of 2-exo-(3;S--hydroxy-non-1'trans-1'-enyl)-3-endo-hydroxy-bicyclo ~3.3.0~octan-7-one-3,3'-bis-THP-ether are added successively. After stirring for 3 hours, the mixture it diluted with 35ml of water and the aqueous phase is ox-treated with ethyl ether (5x12ml) and ethyl ether:ben~ene (7x12ml). The combined organic extract is re-extracted with 25 0.5N Noah (3x15ml~ and then water until neutral, and then l~9B419 discarded. The combined azaleas 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~ ,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 4 hours, the p-toluenesulfonic acid is neutralized with pardon and the mixture is evapora-ted to dryness. Purification on silica gel affords 5,13t-11~,15S-dihydroxy~9a-deoxy-9a-methylene-20-methyl--prostacycla-dunk acid methyl ester, which is then separated into the individual Crete and 5t,13t isomers by liquid-liquid chromatography.
example 36 i With stirring and external cooling to keep the react 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 DMSO and 0.65g of 2-exo-(2'-bromo-3'S-- hydroxy-oct-1'-trans-1'-enyl)-3-endo-hydroxy-bicyccoo ~3.3.0~ -octan-7-one-3,3'-bis-THP-ether in 5ml of DMSO. After stirring I

-, 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 ether:pentane. The acidic aqueous phase is discarded, and the combined organic extract is extracted with 0.8N Noah (5x20ml~ and then water water until neutral.
Chile this rink phase is discarded, the aqueous alkaline extract is acidified -to pi 5 and extracted with 1:1 ethyl ether:pentane. The combined extract is dried over Nazi, filtered and treated with ethereal diazomethane until a JO yellow coloration persists. Evaporation to dryness gives crude11~,15S-dihydrcxy-9a-deoxy-9a-methylene-prostacycll-5-en-~3-ynoic acid methylester-11,15-bis-THP-ether. Removal of the perineal protecting group followed by liquid-liquid chromatography gives 5c~ ,15S-dihydroxy-9a-deoxy-9a-meth-ylene-prostacycl-5-èn-13- acid methyl ester, plus the it geometric isomer.
Example 37 -When the bicycle Lo. 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~,l5S-dihydroxy-9a-deoxy-3a-meLhylene-proostacycla~
dunk acid;
5c-11~,15S-dihydroxy-9a-deoxy-9a-methylene-16R-fluorno-pros-tacycl-5-en-13-ynoic acid;

Jo 5c~ ,15S-dihydroxy-9a-deoxy-9a-me-thylcne-16S-fluoro-prostacycl-5-en-13-ynoic acid;
5c~ ,15S-dihydroxy 9a-deoxy-9a-methylene-17(2')-tetra-hydrofuryl-18,19,20-trinor-prostacycl-5-en-13-~noito acid;
5c~,15S-dihydroxy-9a-deoxy-9a-methylene-prostacycl-5--en-13-ynoic 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- Q-methyl-prostacycla-5,13-dienoic acid, 5c,13t~ ,15S-dihydroxy-9a-deoxy-9a-methylene-17-phenyl-18,19,20-trinor-prostacycla-5,13-~ienoio acid;
-15 5c,13t-11~,15S-dihy~rox~--9a--deoxy-9a-methylene-116-m-~F3-phenoxy-17,18,19,20-tetranor-prostacycla-5,13-diennote acid;
5c,13t-11~,15S-dihdyroxy-9a-deoxy-9a-methylene-16--methyl-16-butoxy-18,19,20-trinor-prostacycla-5,13-dienoic acid;
as well as their trueness geometric isomers, plus the 15R
epimers of both.
These were then saponified to give the frog 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 temperature and pressure in -the presence of 0.1~ 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~33.3.0]-octan-7-one-3,3'-bis-THP-etherO Treatment of this with the Witting reagent prepared from 4-carbc y-butyl phosphonium bromide according to examples 35, 36 and 37 affords a pro-. duct which is esterified with diazomethane and depyranyllzed to give 0.12g of 11~,15S-dihydroxy-9a-deoxy-9a-methylene-pros~acycl-5-enoic acid methyl ester. the Swiss and trueness geometric isomers are separated by liquid-liquid chromatography.
Example 39 Using (3-carboxy-propyl)-phosphonium bromide in the procedure of examples 37 and 38 instead of (~-carboxy-butyl)-.15 phosphonium bromide gave the following acids:
5cl13t-11~,15S--dihydroxy-9a-deoxy-9a~methylene-2--nor priest-cycla-5,13-dienoic;
5c-11~,15S-dihydroxy-9a-deoxy-9a-methylene-2-nor-pprostacycl-5-enoic;
5c-11~,15S-dihydroxy-9a-deoxy-9a-methylene-2-nor-pprostacycl-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-9a-methylene-2ahomo-prostacycla-5,13-diennote acid . S, _ I -- and5,13t~11~,15S-dlhydroxy-9a-deoYy-9a-methylene-20-mmethyl-2a~1omo-prostacycla-5,13-dienoic acid were prepared.
Example 41 A solution of 0.37g of 5c,13t-11~,15S-dihydroxy-9a-deoxy-9a-methylene-prostacycla-5,13-dienoic acid methyl ester in 10ml of Bunyan is heated to 50C with 250mg of 2,3-dichloro-5,6-dicyano-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 5c,13t-11~-hydr^xy-15-oxo-9a-deoxy-ga-methylene-prrostacycla-dunk 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 -20C, the fee_-lion is quenched with NH4Cl 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 5ct13t-11~,15S-dihydroxy-15-methyl-9a-deoxy-9a-methylene-prostacyyokel-dunk acid methyl ester and O.Q72g of the 15R hydroxy epimer.
Exam A solution of 2.2g of 3-endo-hydroxy-bicyclo~3.3.0~
octan-7-one in 100ml of anhydrolls Bunsen is treated with 4ml of ethylene glycol and 0.2g of p-toluenesulfonic acid moo-hydrate and reflexed for 12 hours while the water which forms during the reaction is collected. 0.25ml of pardon is then Jo 984L~9 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-hyc1roxy-bicyclo ~3.3.0~octan-7-one-7,7-ethylenedioxide.
A solution of this product in 40rnl of acetone is cooled to -5C and treated at this temperature with 4.1ml of Jones' reagent. After 20 minutes a-t -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 ofdrl-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 SCHICK an 20ml of ethanol is ` 15 reduced with Nub at -2C~ C to give 1.72g of d,l-3~endo-hydroxy-bicycle Lo. 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-I butyl-silyl chloride and n . 885g of imida~ol, and then held at OKAY for 5 hours. After cooling, water is added and the usual warp affords 2.3g of d,l-3-endo-hydroxy-bicyclo I -octan-7-one-2-exo-carboxymethylester -7,7-ethylenediXide-3-di~ethyl-tert-butylsilylether. Subsequent reduction with - 25 Lyle in an hydrous ethyl ether as described in example 3, 4~L''3 gives d,l-3-endo-hydroxy-2-exo~-liydrox~7me~ -ethylene-dioxy-b~cyclo [3.3. octan-7-one-3-dimethyl-tert-hutyl sill ether quantitatively.
Example 43 By using dithioethylene glycol in the procedure of example 42 instead of ethylene gawk, the corresponding 7,7-ethylenedithio analogies were prepared.
Example 44 108g of d,l-3-endo~hydroxy-~-exo-hydroxymethyl-7,7-ethylenedioxy-bicyclo I ~ctan-7-one-3-dimethyl-tert-butyl sill ether it oxidized according to the procedure of example 18 to give 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~
oct-1'-trans-1'-enyl)-7,7-ethylenedioxy-bicyclo ~3.3.0~octan-7-one -3-dimethyl-tert-butyl silylether (~naX-22~m~ =8980).
According to the procedure in example 22, this is reduced with zinc bordered in ether to give 1.22g of dunned-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 cellular.
A solution of this compound in 25ml of methanol is treated with 10ml of ON H2S04 at reflex for 50 minutes. the methanol is evaporated under vacuum, the residue is ox-treated with ethyl ether, and the organic phase is evaporated to dryness to afford yo-yo of crude d,l-3-endo-hyclroxy-2-exo-(3'(S,R)-hydroxy-oct-1'~trans-1'-enyl)-bicyclooC3~3.~octar~-- 7-one. The individual isomers are separated by chromatog-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 indent eel in all respects to 2~exo-(3'S-hydroxy-oct-1'-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 3'S-hydroxy isomer.
Similarly, with the procedure-- of examples 42 and 44, all the compounds prepared as in ex~nples 27, 28 and 2 were obtained.
Example 45 Saponification of 4.8g of d,l-3-endo-hydroxy-2-exo-carboxymethylester-7,7-Qthylenedioxy-bicyclo ~3.3.Q~octan-7-one with 100ml of 2.5-3 potassium carbonate in 80:20 methanol water at reflex for 40 minutes and subsequent work-up as described in example 2 gave 4.02g of d,l-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 triethylamine in 12ml of an hydrous tetrahydrofuran and then 2.2g of ethyl chlorocarbonate in 12ml of an hydrous tetrahydrofuran, while weeping the temperature at -10C. After 1 hour of stirring at 10C, 1.4g of sodium aside in 12ml of water is added slowly and stirring is continued for another 25 minutes.
The reaction mixture is then concentrated under vacuum and diluted with water. The 2-exo-carboxy aside 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. The 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-~3.3~.~ oct~n--7-one -3-acetate-7,7-ethylene-dioxide.

This product is suspended on 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 ~3.3.030ctan-7-one --3-acetate. Reaction of this with the mixed ashy-drive from ethoxycarboyl chloride and 2S-hydroxy-heptanoic Jo : ?

acid-2-acetate affords 3-enclo-}~ydroxy-2-exo-(2'S-acetoxy~
heptanoyl-amide)~bicyc1o ~,.3.0~octan-7-one--3-acetate.
.. A solution ox this compound in an hydrous dimethylsulfoxide is then reacted with the slide obtained from car boxy butyl-triphenyl phosphonium bromide to give, after supine-ification, St-11~,15S-dihydroxy-9a-deoxy-9a-methylene-12-aza-13-oxo-prostacycl-5-enoic acid In an analogous fashion the wrap analoc;ue was prepared from the 2'R-hydroxy-heptanoic acid.

- go - .

Example 46 _ . ... . . . .. . .. ... . . . . . .
_. . _ _ Jo __,_ _, _ _ __ . _ ,_ _ . . . _ . :
Ethylene glycol ~15 ml) and p-toluensulf'onic acid (0.9 g) are added to a solution ox 2-exo-bromo~3-endo-hydroxy-bicyclo ~3.2.0 hep~ane-6-one in Bunsen and the mixture is reflexed or 12 hours, withdrawing water which forms during the reaction, then the mixture is added by pardon (006 ml) and cooled at room - temperature.
The organic phase it washed with water, 2. 5% aqueous Nikko and water, dried. Bunsen (100 ml) is partially removed in vacuum, then the mixture is treated with tributyltinthe~hdridet(41 g) in No atmosphere at 55 for 8 hours.
- Aster cooling at omit organic phase is washed with saturated aqueous NaHzPO4, dried and evaporated to dryness. Purification of the resulting residue on Sue (240 g) with benzene-ethylether as fluent affords lo. 9 g of 1 3-endo-hydroxy-bicyclo[3.~ heptane-6-one-6,6-etllylene dioxide.
15 Example 47 A stirred solution of 3-endo-hvdroxy-bicycloL3. 2. hootenanny 6-ethylendioxide (12. 75 g) in Bunsen ~340 ml) and DMSO (l 12 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 (do ml) and water (50 ml), filtered from duskily hexylurea 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 dimethylcarbonate (70 ml) is added to 2 suspension of sodium hydrides (80% in mineral oil, 4 g). The mixture is 25 stirred until Ho development ceases at room temperature then is is warmed or 40 minutes at 75-S0.
After cooling, the reaction mixture is diluted with Bunyan (350 ml) arid acetic acid (8. 4 g), washed with water, dried and evaporated to dryness affording a mixture lo of d,l-bicyclo¦3.Z.~heptane-3,6-dione-2-carbo~;y 30 l methylester-6, 6-ethylendioxide (p= O, q= l) and d~l~bicyclot3. Z. eighteen i. . .

.

f ~1984~

-3, 6-dione-4-carboxymethylester-6, ethylene dioxide (p= 1, q= 0) which are separated by means of chromatography on Sue (Fe , Fe free) using hexane-ethylether as eluents.
Example 48 Using in the procedure of the example 47 g 14. 85 of 3-endo-hydroxy-bicycle. 3. (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. O]nonane-3, Dunn-2-carboxvmethylester-7, 7-ethylenedioxide to= 1, q= 2) and 4. 8 g of do-bicycle. 3. ;~nonane-3, 7-dione-4-earboxymethylester-7, 7-ethylendioxide also named as dl~bicycloEL. 3 ~nonane-3, 8-dione-2-carboxymethyles~er-89 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 (350 ml) is added to a suspension of sodium hydrides (80% dispersion in Inineral oil, 42 g) in dimethylcarbonate (550 ml). After ceasing the hydrogen elrolution, the mixture is heated for 4.5 hours at 75-80~, cooled at r. t., diluted with Bunsen (2. 7 1) and washed with Z5% aqueous ape solution, evaporated to dryness affording bicycle. 3. OJnonane-7-ene one 2-carboxymethylester (91 g) (Mecca 252 Mel = 8. 200).
A solution of this compound in ethylene chloride (1.2 1) and ethanol (1.2 1) is cooled at -20 alld,under stirring treated with Nub (14. 4 g).
The mixture is stirred for 30 minutes again at -20, then it is treated wit acetic acid (Z3 ml)9 warmed at room temperature, and the solvents are evaporated in vacuum.
The residue is partitioned between ethyl acetate and water, the organic phase is dried and evaporated in vacuum affording dl-bicyclo~4. I nonage 7 ene-3-endo-hydroxy-2-exo_carboxymethylester (64 g) which is dissolved ~843L~

, in dry tetrahydrofuran (THY) and treated with Z, 3-dihydropyrane t33 go - and p-toluensulphonic acid (0. 63 g) for 3 hours at r. t.. Pardon (0. g) - is added to the reaction mixture and thenlafter cooling at 0C, under stirring a solution of 1. 2 M BH3 in THY is also added during I 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 rnl of EM sodium hydroxide and 110 ml of 30% hydrogen peroxide, maintaining the internal terr~perature at 20-25. The oxidation mixture is diluted with 10 Bunyan (2 it and the layers are separated. The aqueous layer is extracted with Bunsen (2x50). The organic layers are combined, washed successively with 1% Sydney carbonate, saturated sodium sulfite and saturated sodium chloride and dried on McCoy. Evaporation of the solvents affords a crude mixture of 7 and 8 hydroxy compounds vouch are separated by means of 15 Swiss (300 g) column chromatography ethyl ether as fluent, obtaining respectively: ;
dl-bicyclo~4. 3. (~nonane-3-endo, 7 -dihydroxy-2~carboxymethylester-3-- THP-ether (24 g) and do bicycle. 3. ~nonane-3-endo, 8 -dihydroxy-~carboxymethylester-3-20 THP-ether (27 g).
A solution of the 7~-hydroxy alcohol Ed g) in dry DMF (30 ml) is treated with dimethyl-ter-butyl sill 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.
25 The organic layers are collected, washed with water and evaporated to dryness affording dl-bicyclo[4. 3. (~nonane-3-endo, 7~-dihydroxy-2-exo-carboxy~nethylester-3-THP-ether-7-DM~-silylether.
To a stirred solution of this confound in dry Tulane (Z20 my cooled at .
..

-. . .

1~9B4~
.
.

-70, a solution of 1.4M DIB~ in toluene is added over a period of 45 minutesJ ~aintaining the temperature between -70~-60. The stirring is continued for 2 hours, the residual hydride is destroyed by addition of 2 M
isopropyl alcohol in toluene.
The reaction mixture is warmed at room temperature and successively 30% aqueous NaH2PO4 (60 ml) and Na2SO4 (50 g) are added. After filtration, the organic phase is washed with water and evapora-ted in vacuum affording dl-bicyclo~4. 3. ~3-endo, 7~ -dihydroxy-2-exo-formyl-3-THP-ether-7-DMB-silylether (p= 2, q= 1). Using in this procedure the 8~-hydroxy co~npound, - lO we have obtained:
dl- bicyclor4 . 3 . ~nonane - 3 - endo, 8~ -dihydroxy- 2 - exo- carboxymethyle s te r - 3 -THP-ether-8-DMB-silylether and dl-bicyclo~4. 3. ~3nonane-3-endo, 8 ~-dihydroxy-Z-exo-formyl-3-THP-ether, 8 -DMB - s ilyiethe r.
Exar~ple 50 A sol-._tioIl of (2-oxo-heptyl)dimethylphosphonate (0. 33 g) in dry benzene (5 ml) is added to a stirred suspe21sion of NaH (80% dispersion in mineral oil, 43.5 mg) in dry benzene (lQ ml). After l hour N-Br-succinimide (260 mg) is added and then, after 5~ m;nutes, a solution of bicyclo[4. 3. O~nonane-3-endo, 8~-dihydroxy-2-exo-formyl-3-THP-ether, 8-DM~3-silylether (0.4 g) in toluene (5 ml).
The stirring is continued for 15 minutes, then the reaction mixture is washed with aqueous 15~o NaH2PO4, dried and evaporated in ~acuum to give 2-exo[2'-bromo-3~-oxo-oct l9-trans-eny~-3-endo-THP-oxy-8~-DMB-silyloxy-bicyclo~. 3.~nonaneJ )~ max 251 m~u, = 8. 900.
Example 5 1 A solution of (3-phenoxy-2-oxo-propyl)dimethylphosphonate 12. 85 g) in benzene (10 ml) is added to a stirred suspension of NaH (80% mineral oil dispersion, ~o O. 33 g) in benzene (50 ml). The stirring is continued for 45 minutes~ then a solution of 2-exo-formyl-3-endo~THP-oxy-7~ )MB-silyloxy-bicyclo~. 3.
nonane (3.82 g) in toluene is added. After 20 minutes the organic phase is washed wi~h aqueous 20% NaHzPO4 and water, dried and evaporated to 5 dryness affording a~ter filtration on SiO2 (38 g),using benzene-ethyl ether as eluent,2-exo-~31-oxo-4'-phenoxy-but- 1'-trans-eny~-3-endo-THP-oxy-7~-DMB-silyloxv~bicyclo¦4. 3. I~nonane (3. 97 g). Using in the procedure (5-cyclohexyl-2-oxo-butyl)-dirnethyl phosphonate and starting from the aldehydes of the example 49 we have obtained:
' 10 2-exor3'-oxo-5'-cyclohexyl-pent-1'-trans-eny~-3-endo-THP-oxy-7~-DMB-silyloxy-bicyclo[4. 3. ~3nonane max 228q~;~ = 9. 300 2 -exo[3~-oxo 5 -cvclohexyl-pent- 1~ -trans -eny~ -3-endo- THP-oxy-8 ~-DMB -silsrloxy-bicyclo 4. 3. 0 nonane 3l max 228. 6~p,~:: = 9. 450.
Example 52 I5 The DMB-silylether-a, -unsaturated ketones, obtained in accordance with the procedure of the examples 50, 51 (a) are reduced to allylic alcohols and (b) the new hydroxy group is protected as THP-ether; successively (c) the DMB-silylether protectin~ group is s-lectively removed giving a secondary alcohol which (d) is oxidized to ketone; finally after removal (e) of all the 20 remaining protective groups (f) the epimeric allylic alcohols are separated by HPLC;-chromatography on SiO2. Working in a 2. 10 molar scale, the following procedure is used:
a) reduction: 1. 10 mole (0. 32 g) of NaBH4 is added ts~ a stirred solution of a a, -unsaturat4d ketone-DMB-silylether (2. 10 m) in methylene chloride-25 ethanol (1:1) (180 ml) cooled at -10~-15. After 30 minutes, the residual hydride is destroyed by adding acetone (10 ml) and aqueous saturated NaH2P04 (25 ml). The solvents are removed in vacuum and the residue is partiticned between water and methylene chloride. The organic layer is separated dried r~,,, ~, and evaporated to dryness affording a n~ixture of 3'S, 3'R allylic alcohols-silylethers (2. 10 m).
b3 protection of allylic alcohols as THP-ethers: the crude mixture of 3'S, 3'R allylic alcohols silylether (2. 10 m) was treated with methylene chloride 5 (30 ml) and to the stirred solution 2, 3-dihydropyrane (2 g) and p-toluen-sulphonic acid (0. 038 g) are added. The reaction is complete after 2 hours stopped by addition of pyridine (0. 5 ml) and the solvents are removed by evaporation in vacuum to give a crude mixture of 3~S, 3~R--THP-ether ~ilyl-ethe r s .
10 c) desilylation: a solution of the above obtained material in dry THF (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 SiO2 (40 g) and following elution with ethylether affords the secondary alcchol~ -3'S, 3~R-THP-ethers (about 2. 10 m).
15 d) oxidation: dicyclohexylcarbodiimide (6 5 g), pyridine (1 ml) and trifluoroacetic acid (0. 5 ml) are added successively ~o a stirred solution in 75:25 benzene-DMSO (60 rnl) of the secol~ary alcohol-3'S, 37R-THP-ether. After 4. 5 hours the reaction mixture i5 diluted with benzene (100 ml) and with a solution of oxalic acid (3 g) in water. Forlned dicyclohexylurea is filtered, ZO organic layer is washed until neutral, dried alld evaporated to dryness.
e,f) depyranylization and chromatographic ~paration: a solution of the 3'S, 3'R-THP-ether-ketones in methanol (30 ml) is stirred at r. t. for 3 hours with p-toluensulphonic acid (0. 18 g); after addition of pyridine (0. 5 ml~ it is evaporated to dryness. The residue is dissolved in cyclohexane- ethyl 25 acetate (80:20) and injected in HPLC instrument to give the following keto alc ohols:
2-exo~2~bromo-3'S hydroxy-oct- lt-trans-enyi3-3-endohydroxy-bicyclo ~. 3.
nonane -8 - one :13L9~

2 -exo [2 ' bromo - 3 ' R-hydroxy- oct- l ' -trans - eny~- 3 - endo hydroxy_bicyclo ~. 3. 0 nonane-8-one 2~exo[3'S-hydroxy-4'-phenoxy-but-1'-trans-eny~-3-endo hydroxy-bicyclo [4 . 3 . nonane - 7 - one 5 Z-exo~,3'R hydroxy-4'-phenoxy-but-1'-trans-eny~-3-endo hydroxy-bicyclo ~. 3. ~nonane-7-one ;! exo¦3'S-hydroxy-5-cyclohexyl-pent-1'-trans-eny~-3-endo hydroxy-bicyclo ~4. 3. ~nonane-7-one - 2-exo ~3'R-hydroxy-5-cyclohexyl-pent-1'-trans-eny~-3-endo hydroxy-bicyclo10 E~. 3. ~nonane-7-one 2-exo[3'S-hydroxy-5-cyclohexyl-pent~ trans-eny!~-3-endo hydroxy-bicyclo [~4. 3. ~nonane-8-one 2-exo[3'R-hydroxy-5-cyclohexyl-pent-1l-trans-eny~-~-endo hydroxy-bicyclo [4. 3. ~Lnonane-8-one.
15 Example 53 i Under a N2 atmosphere, a suspension of NaH (80% dispersion in mineral oil, 2. 1 g) in dry DMSO (70 ml) is stirred for 4 hours at 65. After cooling at ~5-30, dry ~-carboxy-butyl~triphenyl phosphonium bromide (13 gi is added to it, obtaining a deep red solution of the ylide.
20 After addition of a solution of 2-exo~2'bromo-3'S-hydroxy-oct-l'-trarls-eny~-3-endo hydroxy-bicyclo~4. 3. ~nonane-8-one (1. 79 g) in dry DMSO ~6 ml), the reaction mixtureis stirred for 1 hour at 28 and then for 4 hours at 40;
afterwards it is cooled at r.t., diluted with water (80 ml~, acidified up to pH 4. 5 by adding 4N H2SO4 and extracted with ethyl ether (4x50 ml, 2x~5).
- 25 The aqueous layer is discarded, the organic phases are combined washed with water (this washing is discarded), then with N NaOH (5x10 ml) and water tmtil neutral. The combined alkaline extracts are acidified up to pH 5 and extracted with ethyl ether to give 5(Z,E)~lla, 15S-dihydroxy-9a~deoxy-9a,9b-dimethylene-prostacycla.-5_en-13-ynoic acid (a mixture of 5 c-and 5 t-isomers).

.

41~1t The individual geometric isomers are obtained after chromatographic separation on acidic SiO2 (40 g/each g of acid) using cyclohexane-ethyl acetate as eluents.
E mple 54 5 Under a N2 atmosphere, to a stirred solution of potassium-ter-butoxide (3. 36 g), freshly sublimated, in dry DMSO 136 ml) it is added 6. 5 g of 4-carboxy-butyl-triphenyl-phosphonium bromide to give a deep red solution of the ylide. After addition of a solution of Z-exor3~R-hydroxy-4'-phenoxy~
but-l~-trans-eny~3-endo hydroxy-bicyclo[40 3. ~1nonane-7-one (O. 8 g) in 10 dry DMSO (3 ml), the reaction mixture is stirred for 5 'nours at 42, cooled diluted with water (50 ml) acidified up to pH 5 and extracted ~vith ethyl ether (4xlO ml). The aaueous phase is discarded the combined ethereal extracts are ~.vashed with ~vater (10 ml, ~his washing is discar~d), and with 0. 5 N
NaOH (4x~ ml) and water until neutral. The combined alkaline extracts are 15 acidified up to pH 5 and extracted ~vith ethyl ether. The organic phases are combined dried and evaporated to dryness to give:
51~E)J 13t-1ia, 15R-dihydroxy-~a-deoxy- 7a homo-9a-methylene-16-phenoxy-17, 18, 19, 20-tetranor-prostacycla-5, 13-dienoic acid (a mix.ure of 5 c and 5 t-geometrical` isorr~ers) .
ZO The individual geometric isomers are obtained after chromatog~aphic separation on acidic SiOz (40 g/each g of acid) using cyclohexane-ethyl acetate as eluents.
E~ample 55 ._ .
Using the keto alcohols of the example 52 in the procedure of the examples 25 53, 54 we have prepared the following prostacyclanoic acids:
5 c - 11 a, 1 5S - dihydroxy- 9a- deoxy 9 a, 9b~ dimethylene - pro s tacycla- 5 - cn 1~ -ynoic acid .
5c, 13t-lla, 15S-dihydroxy-9a deoxy-7a homo-9a-methylene-16_pheno~cy-17, 18, 19, 20 tetranor-prostacycla-5, 13-dienoic acid !
. :

913~

5c, 13t- 1 la, 15S-dihydroxy-9a-deoxy-9a, 9b-dimethylene- 17-cyclohe ~yl 18, 19, 20-trinor-prostacycla_5, 13-dienoic acid 5c, 13t-lla, 15S-dihydroxy-9a-deoxy-7a homo-9a-methylene-17-cyclohexyl-18-19,20-trinor-prostacycla-5~ 13~dienoic acid - 5 5t-lla, 15S-dihydroxy-9a-deoxy-9a, 9b-dimethylene--prostacycla-5-en-13-ynoic acid 5t, 13t-lla, 15S dihydroxy-9a-deoxy-7a homo-9a-methylene-l6-phenoxy-... .
17, 18, 19~ 20-tetranor-prostacycla-5, 13-dienoic acid - 5t, 13t-lla, 15S-dihydroxy-9a-dèoxy-9a,9b-dimethylene-17-cyclohexyl-18, 19,%0-trinor-prostacycla-5, 13-dienoic acid 5t, 13t-lla, 15S-dihydroxy-9a-deoxy-7a homo-9a-methylene-l7-cyclohe 18, 1~ Z0-trinor-prostacycla-5, 13-dienoic acid.
E:x~ple 56 - tlt6 >C Using the procedure of the example~l, 30 g of 2-acetoxyperhydro azulen 6-one, also named as 3-endo-hydroxy-bicyclo~i. 3.~decane-8-one acetate (obtained in accordance with D. K. Banerjee et al. Indian J. Chem. 10, 1, 1972) is transformed into its eth~,rlendioxide (29. 1 g). Then the compound is saponified by treatment with 2% K2CO3 in aqueous methanol to give 3-endo-hydroxy-bicyclo¦5. 3. ~3decane-8;one-8, 8-ethylenedioxide and oxidized using 20X the procedure of the exarnple and treated with dimethylcarbonate (see the procedure of example~to obtain dl-bicycloL5.3.~decane~3,8-dione-2-carboxymethylester-8, 8-ethylene dioxide~ Z1.2 g, max 254 nm; = 7. 000.
Example 57 The bicyclo-~ -keto ester-ethylene dioxides obtained in the examples 47, 48 25 and 56 are reduced with the following procedure:
NaBH,~ (0. 9 g) is added ps:~rtionwise to a stirred solution of the bicyclo~
keto ester-ethylene dioxides (2.5. 10 m) iQ 1:1 methylene chloride-ethanol (150 ml), cooled at -Z0. After additional stirring for 30 minutes at ~20, the ~9~9 residual hydride is destroyed by adding acetone (12 ml). The reaction mixture is warmed at room temperature treal:ed with aqueolls 20% KH~P04 and after removal of solvents, and dilution with water (20 ml) it is extracted with -. methylene chloride. The organic phases are combined, washed until neutral 5 with water, dried and evaporated to dryness. The residue is equilibrated by treatment with absolute methanol (20 ml) and sodium methoxide (O. 54 g), for 12 hours at r. t.; acetic acid (O. 59 g) ..ddition followed by evaporation of solvents and extraction with methylene chloride gives about 0. 22. lO m of the followina bicyclo~ hydroxy ester-ethylenedioxides:
10 dl-3 endo hydroxy-bicyclo¦3. 2. ~heptane 6-one-2~arboxymethylester-6, 6-ethylene dioxide dl-3-endo hydroxy-bicyclo~3. 2.~heptane-6~one~4~arboxylnethylester-6, 6-ethylene dioxide, also named as: dl-3 endo hydro.cy-bicyclo[3. 2. ~heptane - exo 7-one -2 ~carboxymethyle ster- 7, 7 -ethylene dioxide exo 15 dl-3-endo hydloxy-bicyclo~. 3. OJnonane-7-one-2~carboxymethylester-7, 7-ethylt:ne dioxide dl 3 endo nydroxy~bicyclo~. 3. ~nonane-8-one-2~carboxymethylester~8,8-ethylene dioxicle ,_ _ exo dl-3-endo hydroxy-bicycloL5. 3. 0 decane-8-one-~carboxymethylester-8, 8-20 ethylene dioxide.In ~he following, a solution of 2. 10 rn of each of these compounds in dry methylene chl~ride9 25 ml, is reacted with 2, 3-dihydro pyran [2 g) and p toluensulphonic acid ~38 mg, 2. 10 m~ for 2 hours at r.t. The reaction is stopped by adding pyridine (O. l ml) and the mixture is evaporated to dryness 25 in vacuum affording the corresponding 3~THP-ethers whîch are used without any further purification.
Example 58 The 3-endo-hydroxy-2-exo-carboxymethyles~ers and their 3 THP-ethers, obtained with the procedure of the example 57 are reduced to giYe the corresponding 2-exo-hydroxymethyl derivatives with followin,a, procedure:

~g ~9~9 .
a solution of 2. 10 m of the - lcetoester (both alcohol and 3-THP ether) in dry ethylether (25 ml) is added dropwise to a stirred suspension of LiAlH,L
0. 4) in dry ethylethe r (5 0 ml) . Afte r additional stir ring fo r 3 0 minute s the residual hydride is destroyed by adding acetone (5 ml) and ethylether 5 saturated with water. Dry MgSO4~12 g~is added to, then the orgJanic phase is filtered and evaporated to dryness.
We obtain th~ following 3-endohydroxy-2-exo-hydroxymethyl:
bicyclo~3. 2. O¦heptane-6-one-6, 6-ethylenedioxide bicyclo[~3. 2. ~heptane-7-one-7, 7-ethylenedioxide 10 bicyclo~. 3. O~nonane-7-one-7, 7-ethylenedioxide bicyclo L4. 3O ~nonane-8-one-8, 8-ethylenedioxide bicyclor5. 3. O~decane-8-one-8, 8-ethylenedioxide and their 3-endo-hyd-oxy-THP-ethers both racemic and optical active form (nat, ent) when optical active material, comin~ from optical resolutio-.
15 successively described~ is used in the reductive process.
Exaln~le 5 9 Frce ketone is obtained by treatment of a solution of 3-endo hydroxy-2-exo-hydroxymethyl-bicyclo[S. 3. O~decane-8-one-~, 8-ethylenedioxide (5g~ 2. 10 m) in me$hanol (20 ml) and water (2 r~l) with p-toluensulphonic acid (0. 3 g) for 20 2 hours at reflux terrlperature. The solvents are evaporated in vacuum and the re~idue is filtered through a short column of SiO2.
Working in accordance with the procedure of the example 54, a solution of the so obtained 3-endo-hydroxy-2-exo-hydroxymethyl~bicyclo[5. 3. 0~8-one ~4. 7 g) in dry DMSO (17 ml) is reacted with the ylide formed ~rom potassiu~n 25 ter-butoxide (27 g), DMSO (280 ml)and 3-carboxy-propyl~phosphoniumbromide for 5 hours at 40. The reaction mixture is diluted with water (300 ml) and extracted with 80:20 ethylether-ben2;ene to ~èmove triphenylphosphoxide. lhese extracts are discarded and alkaline phases are acidified up to pH 5 and repeatedly extracted with ethylether (8x200) and with 3 1 ethylether-ethylacetate (5xlO0). The combined organic extracts are dried, concentrated to a small volume (100 ml) treated with ethereal diazomethane to achieve the methyl ester and then evaporated to dryness.
The crude material is chromatographed on SiO2 ~100 g) ethylace-tate as eluent) to give 5 (Z,E)-~(20-~12) octanor-12~-hydroxymethyl~ -hydr-oxy-9a-deoxy-7a-homo-9a,9b-dimethyLene-2-nor-porstacycla-5-enoic acid methylester (4.1 g).
By treating this compound in dry DMF ~12 ml) with dimethyl-ter-butyl-silylchloride (2.2 g) and imidazole (1.55 g) at 15 for 24 hours, followed from dilution with water (2~l ml) and extraction with ethylether and chromatographic purification on SiO2 ~25 g, cyclohexane-ethylether as eluen-t) we obtain its mono 12~-DMB-silyloxy methyl-ether (~.31 g 80%).
Treatment with pyridine (10 ml), acetic anhydride (5 ml) atr.t.
for 12 hours and hydrolysis with aqueous methanol and p-toluensulphonic acid afford 5(Z,E)-~-(20-~12) octanor-12~-hydroxymethyl-11~-hydroxy-9~-deoxy-7a-homo-9a,9b-dimethylene-2-nor-prostacycla-5~en-oic acid methylester-ll-acetate. Preparative chromatography ~using a HPLC-instrument and monitor-ing with refractive index) on SiO2 treated with 3% AgNO3 (with methylene-chlorideethylacetate as eluent~ affords the individual geometric 5c and 5t isomers.
In similar way, 5~Z,E)-~-~20-~12)octanor-12~-hydroxymethyl-11~-hydroxy-9a-deoxy-7a-homo-9a-methylene-prostacycla-5-enoic acid me~hyl ester-ll-acetate and their 5c and 5t individual geometric isomers are prepared when 3-endo-hydroxy-bicyclo~4.3.0]nonane-7-one-2-exocarboxymethylester-7, 7-ethylenedioxide is used in side o the corresponding per-hydroa~ulene compound and the ~-carboxybutylphosphonium bromide is utili3ed in side of the 3-carboxypropyl-one.
Examp~ 60 Starting ~rom the 2-exo-hydroxymethyl-THP-ether compounds of ; the example 58 and ~rom 12~-hydroxymethyl-11-acetate of the example 59, we h~ve obtained the corresponding aldehydes by the ~ollowing oxidative pro-cedure:

34~

Successively~ dicyclollex~ylcarbodiimide (0. 6~ g), pyridinc (0. 1 ml) trifluoroacetic acid (0. 05 ml) are addcd to a stirred solution oE the hydl-o~-me~hyl con~pound (2. 10 m) in 75:25 benzene-DMSO (6 ml). Aftcr 4.5 hours, the reaction mixture is diluted with benzene (20 ml) and water (10 ml) and 5 stirred for 30 minutes again. Dicyclohexylurea is filtered oIf and the organiclayer is washed with water until neutral and the concentrated up to 10 n~l affording a solution in dry benzene of the following aldehydes:
3-endo-THP-oxy-2-exo-formyl-bicyclo~3. 2. (~heptane-6-one-6, 6-ethylene dioxide 10 3-endo-THP-oxy-2~e~;o-formyl-bicyclo¦3. 2. ~heptane-7-one-7, 7-ethylene dioxide 3-endo~THP-oxy-2-exo-formyl-bicyclo~4. 3. (~nonane-7-one-7, 7-ethylene dioxide 3-endo-THP-oxy-2-exo-forrnyl-bicycloLd. 3. ~nonane-8-one-8,S-ethylene 15 dio~ide 3-endo-THP-oxy 2 -exo-formyl-bicycloCs . 3. ~decane -8 -one-8, 8 -ethylene dioxide W (20 12)octanor-12~ -formyl-lla-hydro~y-7 homo_9a,9b-dimethylene-2-nor-prostacycla-5-enoic acid methylester-ll-acetate 20 ~5 (%, E); 5c; 5t).
Il) (20~ 12)octanor- 12~ -formyl- l lct -hydroxy~9a-deoxy- 7a-homo-9a-methylene-prostacycla-5-enoic acid methyles~er-ll-acetate ~5(Z,E) ;5c,5t) .
These compounds are used in the ollowing Wittig-~Iorner reactions witll any further purifica~ion.
2 5 Example 61 A solution o (2-oxo-heptyl)climethylphosphonate (0. ~19 g~ in benzene (6 ml) is added dropwise to a stirred suspension cf NaH (80% dispersion in mineral oil, 66 mg, 2.2. 10 m) in benzene (15 ml). After an addition~l stirring for 4~' we add a soluti~n ol 2. 10 m of 5 t-~)(Z0--D 12)octanor-12~-forn-yl-s~
~q , -- 'L, P"~ --1~9~

a-hydroxr~ deo~;y-7~-homo-9~9b-dimethylene-2-nor-pr~s~ac~cla 5-enoic acid methylester-ll-acctate in ben~cne (10 ml) to it. After an additional hour the reaction is stopped by adcling a solut;on of acetic acid (132 mcr) in benzene (5 ml); the organic phase is washecl ~vith ~vater until 5 neutral, dried and evaporated to dryness.
The residue, 1.2 gl is absorbed on SiO2 (10 g), following elution ~vith cyclohexane-ethylacetate gives 5t, 13t~ t-hydroxy-15-oxo-9a-deox~-7a-hQmo-9a,9b dimethylene-2-nor-p~o5tacycla-5, 13-dienoic acict metllyl ester-ll-acetate (0.76 g), max 228m)l = ~.800.
10 The follo~ing a, ~3 -unsaturated ketones are obtained wllen the other aldeh~,rdes of the example 60 are used in the above procedure:
5c, 13t- 1 la -hydro.{y- l5-oxo-9a-deoxy-7a-}lomo-9a~9b-dimethylsne- -nor prostacycla-5, 13-dienoic acid-methylester-ll-acetate~max Z28 m}l, = 9.900 and the mixture of their 5(Z, E) isomers 15 5t, 1 3t- 1 1 a -h-ydroxy- 15 -oxo-9 a- deoxy- 7a-homo-9a-methyl ene-prostac~;c 1~ -5, 17-dienoic acid methylester-ll-acetate ( max 229 m~, ~= 10. 000) and its 5t and 5(:~;, E)-isomers and the following 2-exol3'-oxo-oct-ll-trans-eny~3-endo-hydroxy- i~P-ethers:
bicyclo~3. 2.~heptane-6-one 6, 6-ethylenedioxide 20 bicyclo~. 2. ~heptane-7-one-7, 7-ethylenedicxide bicyclo[4. 3. ~nonane-7-one-7, 7-ethylenedioxide bicycloC4. 3. O~nonane-8-one-~,8-ethylcnedioxide bicyclo[. 3. ~decane-8-one-8, 8-ethylenedioxide.
~ple 62 25 Using in the procedure of the cxample 61, dilferent dimethylphosphonales we have prepared the following ~, ~3 -unsaturated ketones:
a~ by reaction oI 3-endo-T~IP-oxy-2-cxo-forn~yl-bicycloL3. 2. O~heptanc-7-one-7) 7-ethylenedioxide (2. 10 m) ~vith (2~oxo-3(S, R)-fluoro-heptyl)dimetyl pho s phonate ( 0. 5 4 g) we obtain 3 - endo - FHI'-oxy - 2 -e~:o L3 - oxo -4 ' R, S) f luo o -84~

o c t~ t rans - eny~bicyclo~3 . Z . ~he ptane - 7 - one - 7, 7 - ethylene c~ioxide ( 0 . 72 g) max 229 nm, = 9. 900, ~lD= ~98 (CHC13) b) by reaction of the heptane-6-one-6, 6-ethylenedioxide aldehyde (2. 10 m) with ~2-oxo-octyl)dimethylphosphonate we obtain 3-endo-THP-oxy-2-exo~37-oxo-non- 1'-trans-eny~bicyclo[3. 2. ~heptane-6-one-6, 6-ethylenedio~ide )~ max 228 nm = 9- 300 c) by reacti~n with the heptane-7 -one-7, 7-ethylenedioxidealdehyde ~vith ~2-oxo-4-phenyl-butyl)dimethylphosphonate (0.565 g) we obtain 3-endo-THP-oxy-2-exo-[3t oxo 5'-phenyl-pent-1'-trans-eny~bicyclor3.2. I~heptane-7-one-7, 7-ethylenedio~ide d) by reaction with the nonane-7-one-7, 7-ethylenedioxide with 0. 52 g of (2-oxo-35-methylheptyl)and with (2-oxo-3R-methyl-heptyl)dimethyl phosphonate we obtain respectively:
3-endo-THP-oxy-2-exo[3'-oxo-4'S-methyl-oct-l'-trans-eny~bicyclo~4. 3. (~
nonane -7~ one- 7, 7-ethylenedioxide and 3-endo-THP-oxy-2-exo[3'-oxo-4'R-methyl-oct-l'-trans-eny~bi.:yclo~. 3.
nonane-7--one-7~ 7-ethylenedioxide.
_ample 63 Pyridine hydrobromideperbromide (C5H5N. HBr. Brz), 0. 8 g, is added to a stirred solution of 3-endo-THP-oxy-2-exo~3'-oxo 4'(R, S)-fluoro-cct~ trans-enyi¦bicyclo~3. 2. ~heptane-7-one-7~ 7-ethylenedioxide in dry pyridine (15 ml).
After additional stirring for 4 hours at r. t., the precipitate is filtered off ancl the organic eluate is partitioned among ice, 2N H2S04 and ethyiacetate.
The organic layer is washed with cooled 0~5NH2SO~g~ brine, 1% sodium 2S carbonate, water until neutral affording 0O 71 g o 2'bromo-4'(R, S)~fluorocompound, which is a mixture of 2 diasteroisomeric 4'S and 47R derivatives.
HPLC--chrolnatography on SiO2 with CH2C12-ethylether (85:15) affords the individual isomers:

: s 1:~L9~9 0.22 g of 3-endo TIIP-o~y-2-exol2tbromo-3'-oxo-4'R-Iluc-ro-oct l'-trans~
eny~bicyclo[3. 2r ~heptane-7-one-7, 7-ethylcnedio ide ~l max 250 nm - 9.830 and 0. 19 of the-4~S-fluro isomer )\ max Z51 nm - 9. 750 Using in the above procedure dirferent a, ~3 -unsaturated ketones~ve obtain the follo~vings: -3-endo-THP-oxy-2-exo~2~bromo-3~-oxo-non-1~-trans-eny~bicyclol3~ 2.
heptane-6-one~6, G-ethylenedioxide and 3-endo-THP-oxy-2-exo[2'bromo-3'-oxo-oct-1'-trans-eny~bicyclo~L. 3.
nonane-7-one-7, 7-ethylenedioxide.
E~ample 64 An ethereal solution of 5% methylmagnesium iodide (5 Inl) is added to a stirred solution of 5t, 13t-lla-hydroxy-l5-oxe-9a-deoxy-7a-llom 9~-methylene-prostacycla-5, 13-dienoic acid methylesier (0. 4 g) in 2 1 ethyl ether-toluene (12 ml)9 cooled at -30. After stirring for aclditional 4 hours, the reaction mixture is warmed to 0~ and the residual reagent is destroyed by add ng of 207~ aqueous NH~Cl. The organic layer is separated, washed with water, dried and after addition o~ pyridine (0. 1 ml) is evaporated to dryness. The residue dissolved in dry metllanol (10 ml) is stirred -~vith anhydrous ~2CO3 (0. 1 ~) for 2 hours. The solution is filtered, evaporated in vacuum and the resulting crude material is partitioned betv~een ethyl acetatc 20~o NaI~2P04. The organic layer after the usual ~vorlc-up is concentratcd to small volunle; the resi(luc is absorl~ed on SiO2 (20 g). Elution ~vith S0:20 ethylether:
isopropylether gives 5tl 13t~ 15S-dihydroxy-15-mcthyl-9a-deo-7a-homo-sa_n!ethylene-prostacycla~5, 13-dienoic acid methylester (0. 1 g) and its 15R-isomer (0. 085 g).
With this procedure it is also obtained:
5t, 13t lla, 15S-dihydroxy-15-methyl-9a-dcoxy-7a-homo-9a,9b-dimeth~lene-2-nor-prostacycla-5, 13-dienoic acid-methylester and its 15R-epimer.

1~9~

The Eree acids are obtalned heating at the reElux temperature a solution of methyLesters in 80:20 ,nethanol-water in the presellce of 2% K2CO3.
The solvent is evaporated in vacuum and the residue is parti-tioned between ethylether and water. The organic layers are reextracted with 0.5% K2CO3 and discarded. The combined alkaline phases are acidified up to pH 6 and extracted with ethylether. Combined organic phases are washed, dried on MgSO4 and evaporated to dryness to give free acids.
Example 65 Using ln the procedure of the example 6~ ethynyl magnesium brom-ide, vinyl magnesium bromide and ethyl magnesium bromide in side of themethyl magnesium iodide, the corresponding 15-ethynyl, 15-vinyl and 15-ethyl prostacycladienoic acids are obtained.
Example 66 Starting from the unsaturated ketones of the examples 61,62, 63, secondary allylic alcohols are obtained using the following procedure:
a solution of ~,~-unsaturated ketone (2.10 3m) in dry ethylether ~20 ml) is added to a stirred solution of 0.25 ~l ~inc borohydride ~S ml) in dry ethyl-ether, dropwise in a period of 30 minutes. After an additional stirring for 2 hours, the residual hydride is destroyed by adding staturated NaCl.

The organic layer is separated, washed until neutral, dried on Na2SO~ and evaporated to dryness. Preparative HPLC-chromatography on SiO2, using as eluent methylene chloride/ethylacetate, affords:
5c, 13t-11~, 15S-dihydroxy-9a-deoxy-7a-homo-9a,9b-dimethylene-2-nor-prostacy-cla-5,13-dienoic acid methylester-ll-acetate and i~s 5(Z,E~ and 5t geometric isomers.
5t,13t-11N~ 15S-dihydroxy-9a-deoxy-7a-homo-9a-methylene-prostacycla-5,13-dienoic acid methylester-ll-acetate and its 5(Z,E) and Sc-geometric isomers.
The following 2-exo [3'S-hydroxy-oct-l'-trans-enyl] 3-endo-THP-oxy:

`I -102-1~ .

bicyclo~3. 2. 01heptane-6-one-6~ 6-ethylcnc:dioxide bicyclo~3 2 . (~heptane-7-one-7, 7-ethylc1ledio~ idc bicyclo[4. 3. O~nonane-7-one-7, 7-ethylenedioxide bicyclo ~4 3 O~nonane-8-one-8, 8-ethylenedioxide 5 and the Iollowing 3-endo-THP-oxy 2-exo~2 ~bromo-3~S -llydroxy-4~R-fluoro-oct- 1 ~-trans -eny~bicyclo~3. 2 . (~
heptane - 7-one- 7, 7 - cthylenedioxide 2-exo¦2~bromo-3~S-hydroxy-4~S-fluoro-oct- l'-trans-eny~bicyclo¦3. 2.
heptane-7-one-7, 7-ethylenedioxide 2-exo~2~bromo-3~S-llydroxy-non- l~-trans-eny;~bicyclo~,3. 2 . ~heptane-~-one-G, 6-ethylenedioxide 2-exo¦3~S-hydroxy-non- l~-trans-eny~ bicyclo~3. 2. l~heptane-6-one-6, 6-ethylenedioxide 2-exol3'S-hydroxy-5 '-phenyl-pent- 1 ' -trans -eny~ bicyclo~3 . 2 . ~heptane-7-one -7, 7-el:hylenedloxide Z exor2'brorrlo 3tS-hydroxy--oct-l~-trans-eny~bicyclo~. 3. ~nonane-7-one-7, 7-ethylenedioxide 2-exo[3~S-hy~roxy-4~S-methyl-oct-l~-trans-eny~bicyclor4. 3. ~noll~ne-7--~ne-7, 7-ethylenedioxide 2 0 2 - e~coC3 'S -hydroxy - 4' R- methyl-o ct - 1~ -trans - eny~ bi cy C 1G [4. 3 . nonane - 7 - one - i '7, 7-ethylenedioxide 5c, 13t- l lCL 15~-dihydroxy 9a-deoxy- 7a-homo-ga,9b-dimethylene- !-nor-prostacyc:la-5, 13-dienoic acid methylester-ll-acetate and its 5(ZJEi and St geometric isoIners.
5t, 13t-llCi, 15R~dihydroxy-9a-deox~-7a-homo-9a-me~hylene-prostacycla-5, 13-dienoic acid methylester-ll-acetate and its 5tZ,E) and 5c-geomclric isomers .
Th~ fol1~wing ~-exo~-'R-bydr~xy-oct- l '-.ra~ s-c~ y~l3-cndo-TI-IP-oxy:

.

bicyclor3. 2. ~heptane-6-one-6, 6-ethylenedioxide bicyclo~3. 2. ~heptane-7-one-7, 7-ethylenedioxide - bicyclo 3. ~nonane-7-one~7, 7-ethylenedioxide bicyclo 3. O~nonane-8-one-~, 8-ethylenedioxicle 5 and the lollowing 3-endo-THP--oxy:
Z-exo~2~bromo-3~R-hydroxy-~R-fluoro-oct~ trans-eny~bicyclo~3. 2.
heptane - 7-one - 7, 7 -ethylenedioxide 2-exo¦2tbromo-3~R-hydroxy-4'S-fluoro-oct-ll-trans-eny~bicyclo~3. 2.
heptane-7-one-7, 7-ethyienedioxide 2-exo[Z~bromo-3'R-hydroxy-non- l~-trans-eny~bicycloL3. 2. ~heptane-6-- one-6~ 6-ethylenedioxide 2 - exb ~3 sR-hydroxy-non- 1~ - trans - eny~ bicyclo . 2 . O~heptane - 6- one - 6~ 6-ethylenedioxide 2~ exo[3'~-hydroxy-5'-phenyl-pent-1~-trans-eny~bicyclor3.2. O~hept~ne-l-one-15 7, 7-ethylenedioxide 2-exo¦~bron~o-3~R-hydro~y~oct~l~-trans-eny~bicyclo~. 3. O~nonane-7-one~
7, 7-ethylenedioxide 2r-exo~3~R-hydroxy~4tS-methyl-oct-l~-trans-eny`3bicyc1or4. 3. ~nonane-7-one-7, 7-ethylenedioxide 20- 2-exo[3~R-hydroxy-4~R-methyl-oc~ -trans-enyl¦bicyclo~L. 3. ~nonane--7-one-7, 7-ethylenedioxide Exa_ple 67 .
The individual ll-acetate prostacycladienoic acid methylesters are converted both in their 1 l-hydroxy methylesters by trans esterifica~ion in dry methanol with anhydrous K2C03 (0. 5 mol equiv) and in their 11-hydroxy free acid by treatrnent with K2CO3 in 80% aqueous methanol.
Example 6~
Every one of the bicyclo-THP-oxy-ethylenedioxides obtained in the proccdure ll9B43,''3 of the example 66 is converted in~le corresponding prostacyclenoic acidS
working up with the following procedure:
a solution of 1. 10 m.of l:he bicyclo-THP-oxy-ethylenedioxide in acetone (15 ml)is refluxed with N aqueous oxalic acid (10 ml) for 8 hours. The acetone is 5 evaporated in vacuum and the aqueous phase is extracted with ethylether. The cc,mbined extract~fter the usual work-up,are evaporated to dryness affording about 0. 6~ 1. 10 m.of the hydroxy ketone. A solution of this compol~nd in dry DMSO (Z ml) is added to a solution of the ylide obta;ned so on: in a N2 atmosphere potassium-tert~butoxide (1. 35 g) is added to dry DMSO (15 ml), 10 then to it we added 4-carboxy-butyl-triphenyl-phosphoniumbromide (2. 6g) to obtain a deep-red solution of the ylide. After addition of the ketone, the reaction mixture is warmed at 40-42 for 6 hours, cooled, diluted with water (20 m7!, acidified up to pH 5. 1 and extracted with ethylether (5x25 ml).
The aqueous phase is discarded, and the organic extracts are collected, 15 ~ashed with water (5 ml; this washing is des-:arded~ and extracted with 0. 5 N
NaOH (6x6 ml) and water until neut al. The combined alkaline extracts are combined, acidified to pH 5 and extracted with ethylether. The combined organic extracts are ~vashed with water (2 ml), dried on Na~,S04, and e~raporated to dryness giving a mixture of the 5 Z and 5 E acids.
20 The individual geolnetric isomers are obtained after chromatographic separation on acidic SiO2 (Fe t Fe free) using CH2C12-ethylacetate as eluent (SiO2 30 g for each of 0. 2 g of the acid).
In this way we have prepared:
.~ 5t, 13t-lla, 15S-dihydroxy-9a-deoxy-9a-nor-methylene-prostacycla-5, 13-25 dienoic acid 5t, 13t-11u, 155-dihydroxy-9a-deoxy-9a-nor-methylene-20-methyl prostacycla-5, 13-dienoic acid St- 1 la, 15S-dih-ydroxy-9a--deoxy-~a-nor-methylene-20-methyl-proslacycla-5-en-13-ynoic acid 5t,13t~ ,15S-dihydroxy-9a-deoxy-9a-methylene-7-nor-methylene-prostacycla-5,13-dienoic acid 5t,13t-11~,15S-dihydroxy-9a-deoxy-7a-homo-9a-methylelle-prostacycla-5,13-dienoic acid 5t,13t-11~,15S-dihydroxy-9a-deoxy-9a,9b-dimethylene-prostacycla-5,13-dienoic acid 5t-11~,15S-dihydroxy-9a-deoxy-9a-methylene-7-nor-methylene-16S-fluoro-prost-acycla-5-en-13-ynoic acid 5t-11~,15S-dihydr~xy-9a-deoxy-9a-methylene-7-nor-methylene-16R-fluoro-prost-acycla-5-en-13-ynoic acid 5t,13t-11~,15S-dihydroxy-9a-deoxy-9a-methylene-7-nor-methylene-17-phenyl-18, 19,20-trinor-prostacycla-5,13-dienoic acid 5t,13t-11~,15S-dihydroxy-9a-deoxy-7a-homo-9a-me hylene-16S-methyl-prostacyc-la-5,13-dienoic acid 5t,13t-11~,15S-dihydroxy-9a-deoxy-7a-homo-9a-methylene-16R-methyl-prostacyc-la-5,13-dienoic acid 5t-11~,15S-dihydroxy-9a-deoxy-7a-homo-9a-methylene-prostacycla-5-en-13-ynoic acid 5c,13t-1 1N~ 15S-dihydroxy-9a-deoxy-9a-nor-methylene-prostacycla-5,13-dienoic acid 5c,13t-11~,15S-dihydroxy-9a-deoxy-9a-nor-methylene-20-methyl-prostacycla-5, 13--dienoic acid 5c-11~,15S-dihyclroxy-9a-deoxy-9a-nor-methylene-20-methyl-prostacycla-5-en-13-ynoic acid 5c,13t-11~,15S-dihydroxy-9a-deoxy-9a-methylene-7-nor-methylene-prostacycla-5,13-dienoic acid 5c,13t-11~,15S-dihydroxy-9a-deoxy-7a-homo-9a-methylene-prostacycla-5,13-dienoic acid 5c,13t-11~,15S-dihydroxy-9a-deoxy-9a,9b-dimethylene-prostacycla-5,13-dienoic acid 5c~ ,15S-dihydroxy-9a-deoxy-9a-methylene-7-nor-methylene-16S-fluoro-prost-acycla-5-en-13-ynoic acid 5c-]1~,15S-dihydroxy-9a-deoxy-9a-methylene-7-nor-methylene-16R-fllloro-pros-t-acycla-5-en-13-ynoic acid 5c,13t-11~,15S-dihydroxy-9a-deoxy-9a-methylene-7-nor-methylene-17 phenyl-18, 19,20-tinor-prostacycla-5,13-dienoic acid 5c,13t-11~,15S-dihydroxy-9a-deoxy-7a-homo-9a-methylene-16S-methyl-prosta-cycla-5,13-dienoic acid 5c,13t-11~,15S-dihydroxy-9a-deoxy-7a-homo-9a-methylene-16R-methyl-prosta-cycla-5,13-dienoic acid 5c-11~,15S-dihydroxy-9a-deoxy-7a-homo-9a-methylene-prostacycla-5-en-13-ynoic acid and their 15R-isomers.
Example 69 Successively dicyclohexylcarbodiimide (0.32 g) pyridine (0.044 ml) and trifluoroace~ate acid (0.022 ml) are added to a stirred solution of 5t,13t-11~,15S-dihydroxy-9a-deoxy-9a,7a-homo-dimethylene-15-methyl-prosta-cycla-5,13-dienoic acid methylester ~0.39 g) in 75:25 benzene-DMS0 ~6 ml).
After 5 hours the reaction mixture is diluted wîth benzene ~20 ml) and 1.2 g oE 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 SiO2 (4 g), ethyl ether as eluent, gives 0.26 g of 5t,13t-11-oxo-15S-hydroxy-9a-deoxy-7a-homo-9a-methylene-15-methyl-prostacycla-5,13-dienoic acid methylester which is hydrolysed with 2% aqueous K2C03 to give the free acid.
~xample 70 -Sodium borohydride (2.5 g) in portionwise is added to a stirred solution of i'~

f`~

~8~L9 bicyclor~. 3. 0~nonane-7-en-3 one (11. 42 g) in ethanoL (~30 ml). Ater 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 CE-I2C12, and the organic layer is evaporated to dryness. A solution of the the resu1ting bicycloC4.3. ~nonane-7-en-3-hydroxy (11 g) in dry DMF is heated successively with dimethyl-tert-butyl-silyl chloride ~15. 6 g) and imidazole (10.85 g), warmed at 60~ for 6 hours, cooled and diluted with water (66 ml). After exhaustive extraction with ethylether and usual work-up we obtain bicyrloL4. 3. 0~nonane~7-ene--3~hydroxy-3-DMB-silyl-ether (19. 1 g).
Its solution in dry THF (100 ml), cooled at 0C is treated (uncler stirring, in N2 atmosphere) with M BH3 solution in THI~ (75 ml). After 2 hours, maintaining the temperature at 25C, we add N NaOI~ (25 ml) and 30%
hydrogen peroxide ~25 ml). The mixture is heated at 6Q for 2 hours, cooled and diluted with ben~ene (400 ml). The organic layer is washed with 1% Na2C03, satur~ted sodiurn sulphite, saturated NaCl, dried and evaporated to dryness gi~ing crude bicyclo¦4. 3. ~nonane-7(~ 3-dihydroxy-3-DMB~silylet11er (20. 3 g). solution of the resulting alcohol in 75¦25 benzene-DMSO (150 ml) is treated sucsessively with dicyclohexylcarbodiimide (16 g) pyridirle (2 mll) trifluoro acetic acid (1 ml), under stirring. ~fter 5 hours, the mi~cture is diluted ~vith benzene (400 rnl), water (50 n~l) ~ith 2 solution of oxalic acid (6 g) in water (75 ml), and after additional stirring for 3û minutes is filtered.
The organic phase is washed ~,vitn water until neutral affording bicycloE~. 3.
nonane-7(8)-one-3-hydroxy-D~B-silylether (18. 25 g) which is dissolved in rnethanol (60 ml) and treated with 1. 8 g of p~toluensulphonic acid. After 12 hours, the mixture is treated with pyridinc (1. 95 ml) and evaporated to dryness.
The residue i;, fil~ered on SiO2 (ethylether-ethy1ace~ate as eluent) to give bicy clo [4. 3 . 0~nonane - 7 (8 ) one - 3 -hydroxy ( 10 g) .
A solution of this compound in benzene (50 ml) is refluxed in the presence OI
dry et'hylcne glycol (5. 2 g) and ~-to1uensu1phonic acid (0. 62 g) withdrawing r~
/~q the water forlned during the reaction. After 1~ hours we add pyridine (2 ml) and the organic phase is cooled, washed with ~ater, 2% Na2CO3 and saturated NaCl until neutral. Evaporation of solvcnts gives bicyclo~'L. 3. ~nonane-7(8)-one 3-hydroxy-7, 7(8, 8)-ethylenedioxide.
5 Example 71 Saponification with 2% Kj?CO3 in 80% aqueous methanol of the dl~3-endo--r hydroxy-bicycloIL~. 3. 0Jnona?ne-8-one-8, 8-diethylenedioxide 2-exo-carboxy-nlethylester (4. 5 g) gives the free acid (4. 2 g).
To a solution of the Iree acid (4.2 g) in acetonitrile (120 ml) it is added d(l~)-10 ephedrine (2. 3 g); after 4 hours at r. t. 2. 8 g of salt crystaliz;es giving ater further crystalization from acetonitrile 2. 15 g of (+)bicyclol,4. 3. ~nonane-8-one-8, 8 -~ ethylene dioxide - 3-endo-hydroxy- 2 -exo- carboxylic acid d(~) - ephedri~
nium salt. All the liquor waters are combined, evaporated to dryness; the residue is dissolved in water and treated ~-ith N NaOH up eo alkaline pH (12-13).
15 d(~) Ephedrine is recovered by extraction with ether, then allcaline aqueous solution is acidified to pH 5 extracted with ethylacetate and organic layer combined are evaporated to dryness. The residue is diluted in acetonitrile and the procedure is repeate-l using (-)ephedrine to give (-)bicyclo~4. 3. 0~nonane-8 -one-8, 8 - ethylenedioxide - 3~endo-hydroxy-2 -exo-- carboxylic acid 1( -) ephc dri~
LO nium salt. Every one of the salts is separately dissolved in ~vater/NaOH;
the optica]ly active base is recovered by extraction with ethylether, the alkaline aqueous phase is acidified up to pH 5-5, 1 and extracted with ethyl-acetate, affording (+) bicyclolj-4 . 3 . nonane -8 - one -8, 8 - ethylenedioxide - 3 endo -hydroxy- 2 - exo~
25 carboxylic acid and (-)bicyclo~4. 3. ~nonane-8 one-8, 8-et1lylenedioxide-3-endo-hydroxy-2-exo-carboxylic acid, which are converted into the methylester ~ith diazomethane tre atment .

t~O

~19~41~

E~a~E~ 72 A solution of 26 g, ol dl-3-endo-hydroxy-bicycloEL. 3. (~-~ exo-carboxy-methylester~7-one-7, 7-ethyleIledioxide in acetone (100 ml) is reIluxed with 2N H2SO4 (20 ml) for 4 hours.
5 Acetone is evaporated in vacuum and aqueous phase is extracted V~ittl ethyl-acetate. Combined organic extracts are washed until neutralS dried and evaporated to give 21. 2 g of dl-3 -endo--hydroxy-bicycloEL. 3. ~-2~exo-carboxymethylester 7-one. To a solution of the ketone in dry acetonitrile (250 ml~ it is added d-l-plienyl-l-ethyl-amine (12. 1 g) and solvent is 10 slo~vly distilled off recovering 50 ml in 3or minutes. The mixture is slowly cooled at r.t. and then 12. 12 g of (~) 3-endo hy-lroxy-7j 7-(1'-phenyl-1'-ethylidenin~ino)~2--exo-carboxymethylester-bicyclor4. 3. Ol~re collected after filtration. The liquor ~vaters are concentrated further to give 6 g of r~cernic n~ ~erial. Finally, a further concentration up to 80 ml affords 11. 42 15 of (-) 3-eindv-hydroxy-7, 7( l~-phenyl- l'~ethylidenimino)-2-exo-carboxy-methyle~ter bicyclo~4. 3.
Separately9 the two Schiff bases are cleaved witll ~0:20 metllallo] 2I~ ~I2SO4 (200 n-ll) at reflux temperature for 2 hours. ~;olvent is evaporated in vacu~lm and after extlaction with ethyla-etate, the combincd organic phases are 20 washed until neutral, dried and evaporated in vacuum to give:
8. 1 g of (~; 3~endc hydroxy-~icyclo~4. 3. ~2-exo-carboxymethylester-7-one a 7. 2 g of (--) 3-endo hydroxy--bicyclo~4. 3. ~2-exo-carboxymethylester-7-one7 respectively.
Using this procedure, al] the bicyclo-~--hydroxy-carboxylic ester-ethylene 25 dioxides of the example 57 are submitted to optical resolution to givc lhe follov~ing 3-endo-hydroxy alcohols:
(+) bicyclo l3. . ~heptane-6-one-2-exo-carboxymethylester (~) bicyclo[~.2. ~heptane-7-one 2-exo-carhoxymethylester (~) bicycloÇi. 3. ~nonane 7~one-2-exo-carboxymethylester o~
-- 1"~--4~9 (-.') bicyc]oL4. 3. ~nonalle-8-one-2~exo-carboxymcthylestcr ( .') bicycloiL5. 3. i~ decane-8-olle-2-exo-carboxynle~cllylester ( - ) bicyc lo ~3 . 2 . he ptane - 6- one 2 - exo c arboxymc thyle ste r (-) bicyclo~3. 2. O~hcptane-7-one-2~cxo~carboxymcthylester (-) bicyclo~4. 3. O~nonane-7-one-2-exo-carboxylnethylester (-) bicyclo~4. 3 . O~nonane-8 -one-2 -exo-~ carboxylnethyle ste r (-) bicyc]oL5 . 3. decane~ 8 -one-2-exo~carboxymeth~lester Using the proccdure oI 'che example 56; these ketones are converted intO
their ethylenedioxide deLivatives.

Claims (18)

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) radical; (g) -CHO; or (h) radical where each X' is independently -O- or -S- and the R'a and R'b groups, whether the same or different, are C1-C6-alkyl or together form a straight or branched C2-C6-alkenylene chain; D is: -CH2, (trans), -C?C-, , -O-, -S-, or , 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 or radical; Y is: -C?C-, (trans), (cis) where z is halogen, (-NH-CO- or -NH-CH2-); X is: -(CH2)m3-in which m3 is zero or 1, (cis), (trans), -O-, -S-, or where Rc is as defined above; m1, m2, n1 and n2, whether the same or different, may be zero or an integer between 0 and 12 such that each sum m1 + m2 and n1 + n2 is less than or equal to 15; p and q are independent-ly zero or an integer between 1 and 3 such that the sum p + q is an integer of 1 to 6; R7 is (a') hydrogen; (b') Cl-C4-alkyl; or (c') an aryl group, either unsubstituted or substituted with one or more of the following:
halogen, halo-Cl-C6-alkyl, Cl-C6-alkyl, Cl-C6-alkoxy, phenyl; and the lactones derived from compounds of formula I and the pharmaceutically or veterinarily acceptable salts thereof, which comprises alkylation of compound II

II

wherein p, q, Y, n1, n2, X, R5, R6 and R7 are as defined above; one of R'1 and R'2 and, independently, one of R'3 and R'4 is hydrogen, Cl-C6-alkyl, C2-C10-alkenyl, C2-C10-alkynyl, phenyl or aryl-C1-C6-alkyl and the other is hydrogen, hydroxy, Cl-C6-alkoxy, aryl-Cl-C6-alkoxy or a protecting group bound to the bicyclic system or the side chain through an ether linkage, or R'1 and R'2 and, independently, R'3 and R'4 together form a protecting group for the ketone function, with a compound with formula III
III

wherein D, m1 and m2 are as defined above; E is a (C6H5)3P- or a (ReO)2P?(O)- group where each Rc may independently be Cl-C6-alkyl or phenyl;
R''' is (a") a carboxylic group, free, esterified or as its salt;
(b") -C(OR')3, where R' is as defined above; (c") -CH2-RIV, where RIV is C2-C7-acyloxy or a protecting group bound to -CH2- through an ether linkage;
(d") , where Ra and Rb are as defined above; (e") -C?N; (f") a radical; (g") radical where X', R'a and R'b are as defined above, followed if required by the removal of any protecting group present, or, if required, subjecting to nucleophilic addition the free carbonyl on the .omega. chain of a compound of formula I in which R3 and R4 together form an oxo group to afford, upon removal of any protecting groups, a compound of formula I in which one of R3 and R4 is hydroxy while the other is hydrogen, 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 one of R3 and R4 is hydroxy while the other is hydro-gen, 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 one of R3 and R4 is C1-C6-alkoxy or aryl-C1-C6-alkaxy while the other is hydrogen, C1-C6-alkyl, C2-C10-alkenyl, C2-C10-alkynyl, phenyl or aryl-C1-C6-alkyl; or, if required, a com-pound with formula I in which Y is -CH=CZ- (trans), Z is halogen, one of R3 and R4 is hydrogen, C1-C6-alkyl, C2-C10-alkenyl, C2-C10-alkynyl, phenyl or aryl-C1-C6-alkyl while the other is hydroxy, C1-C6-alkoxy or aryl-C1-C6-alkoxy, or R3 and R4 together form an oxo group, and any hydroxy, oxo or carboxy groups present are free or in protected form, is dehydrohalogenated to give, after removal of any protecting group, a compound of formula I in which Y is -C?C- and one of R3 and R4 is hydrogen, C1-C6-alkyl, C2-C10-alkenyl, C2-C10-alkynyl, phenyl or aryl-C1-C6-alkyl while the other is hydroxy, C1-C6-alkoxy or aryl-C1-C6-alkoxy or R3 and R4 together form an oxo group, or, if required, converting a compound of formula I into another or to the lactone or pharmaceutically or veterinarily acceptable salt or, if required, 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 -C?C-, one of R'3 and R'4 is hydroxyl or protected hydroxyl, n1 is zero, n2 is zero, 3 or 4, R5 is hydrogen or methyl, R6 is hydrogen, fluorine or methyl, X is -O- or -(CH2)m3- wherein m3 is 1 and R7 is hydrogen, phenyl, m-trifluoromethylphenyl or butyl.

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, n2 is 3 or 4, R5 is hydrogen or methyl, X is -(CH2)m3- wherein m3 is 1 and R7 is hydrogen.

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 2 wherein n2 is 3, R5 is hydrogen or methyl, X is -(CH2)m3- in which m3 is 1 and R7 is hydrogen.

6. A process according to claim 2 wherein n2 is 4, R5 is hydrogen or methyl, X is -(CH2)m3- in which m3 is 1 and R7 is hydrogen.

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

8. A process according to claim 7 wherein n2 is 3, X is -(CH2)m3- in which m3 is 1 and R7 is hydrogen.

9. A process according to claim 7 wherein n2 is zero and R7 is phenyl.
115.

10. A process according to claim 7, 8 or 9 wherein R5 is hydrogen or methyl and R6 is hydrogen or methyl.

11. A process according to claim 7, 8 or 9 wherein R5 is hydrogen or methyl and R6 is hydrogen or methyl, and m2 is 2.

12. A process according to claim 1, 2 or 3 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.

13. A process according to claim 1, 2 or 3 wherein a com-pound of formula II which is of cis or trans configuration at the exocyclic double bond is used to obtain a compound of formu-la I which is cis or trans, respectively.

14. 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.

15. 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; 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-; n1 and n2, whether the same or different may be zero or an integer between 1 and 9 such that the sum n1 + n2 is less than or equal to 15; and R7 is hydrogen, alkyl having 1 to 4 carbon atoms or a phenyl which may be sub-stituted by 1 to 3 halogen atoms, a phenyl group, 1 to 3 alkyl groups having 1 to 4 carbon atoms, a halomethyl group, or alkoxy having 1 to 6 carbon atoms and the pharmaceutically acceptable salts thereof, which comprises reacting a compound of the general formula II
(II) wherein n1, n2, 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.

16. A compound of formula I as defined in claim 15 or a pharmaceutically acceptable salt thereof, when prepared by a process according to claim 15 or an obvious chemical equivalent thereof.
117.

17. 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 car-bon atoms; one of R3 and R4 is hydrogen or methyl and the other is hydroxy;
each of R5 and R6 whether the same or different may be hydrogen, methyl or fluorine; X is -(CH2)m- in which m is zero or 1, or -O-; n1 and n2, whether the same or different may be zero or an integer between 1 and 9 such that the sum n1 + n2 is less than or equal to 15; and R7 is hydrogen, alkyl having 1 to 4 carbon atoms or a phenyl which may be substituted by 1 to 3 halogen atoms, a phenyl group, 1 to 3 alkyl groups having 1 to 4 carbon atoms, a halomethyl group, or alkoxy having 1 to 6 carbon atoms and the pharmaceutically acceptable salts thereof, which comprises reacting a com-pound of the general formula wherein n1, n2, X, R5, R6 and R7 are as defined above; R2 represents a free or functionally converted hydroxy group, Z is halogen, one of R'3 and R'4 is hydrogen or methyl and the other is a free or functionally converted hydroxy group, with a Wittig reagent of the formula III
III
118.

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

18. A compound of formula I as defined in claim 17 or a pharmaceuti-cally acceptable salt thereof, when prepared by a process according to claim 17 or an obvious chemical equivalent thereof.