CA1180339A - Chiral compounds useful for the preparation of hetero prostaglandin derivatives - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
The present invention relates to cyclopentene derivatives represented by the general formula:

Ia in which R represents a hydroxy-protecting group of the formula -CH2R1 in which R1 represents an aryl or aralkyl radical, B represents and A in such that:
- when B represents , A represents - when B represents , A represents ,

Description

)33~

This is a divisional application of Canadian Patent Applica-tion No 384 237, filed August 20, 1981 which relates to prostaglandin derivatives and ls concerned with novel com-pounds related in s-tructure to prostanoic acid which has the structural formula:
O
9 ~ 5 3 1~
10t/\~ "CH2~ ~, ~ CH2~ Lt /CH2\c~H/c CH2/ ~'~ ~ CH2/ ~ ~ CH~ ~ CH2/ lo ~ ~ 5 .~

10 and which,in accordance with common usage, can also be written as follows:
~ ~ COO~ ~

The above Canadian Patent Application is also concerned with a process for preparing the said novel compounds.
The prostaglandin derivatives of the above Canadian Patent Application, which are ll-hydroxy-13-oxa-prostanoic acid derivatives, can be represented by the general formula (I):
X, X1 ~ ~COOH

HO

in which X represents hydrogen or hydroxy, Xl represents hydrogen or X
and X1 when they are ta~{en tcgetiler with the carbon atom to which they - , ~

13~

are attached represent a carbonyl yroup and Z represen-ts hydrogen or hydroxy.
The above Canadian Pa-ten-t Application also relates to the pharmacologically accep-table sa].-ts of the compounds of ~ormula I such as, or example, the saltsresult-ing from the ac-tion of the saicl compounds of :Eormula I and an alkali metal hydroxide such as sodium hydroxide.
In another aspect -the above Canadian Patent Application relates to a process for preparing prostanoic acid derivatives o the general ormula (I) ~ \\\\~\ , ~ ~ \ ~ O2H (I) HO z wherein X represents a hydrogen àtom or a hydroxy group, Xl represents a hydrogen atom, or X and Xl taken together with the carbon atom to which they are attached represent a carbonyl group, and Z represents a hydrogen atom or an hydroxy group and pharmaceutically acceptable alkali metal salts thereof characterized in that (a) to obtain an acid oE general ormula (I) wherein X represents a hydrogen atom or a hydroxy group and Xl represents a hydrogen atom, a compound of general ~ormula D' ~ \ ~ CO~H
\ I

RO

.. . . . ... . _ .. . .. . .... . . ., _ _ _ _ 33~

wherein R represents an h.ydroxy-protecting group of the formula -CH2Rl, Rl being an aryl or aralkyl radical, D' represents a radical CH2 or CH~ IOR, R being as defined above, and Z' represents a hydrogen atom or a radical O-R, R being as defined above, is hydrogen-olysed on platinum charcoal or palladium char-coal at room temperature and in a sui.table medium ~b) to obtain an acid of general formula ~I) wherein X and Xl taken together with the car-bon atom to which they are attached represent a carbonyl group, a (6-carboxyhexyl)-3(R)-heptyloxy derivative of general formula I -I

X ----.02H
~ /
~0 ~
HO

. 25 wherein Z is as defined above, is dethio-acetalised with mercuric chloride in a suitable solvent and in the presence of boron trifluoride etherate and (c) to obtain a pharmaceutically acceptable alkali metal salt of an acid of general formula (I), a suitable alkali metal hydro-xide is reacted with an acid of general formula ~I).
The present invention, on the other hand, relates 33~1 to novel chiral compounds. These compounds are par-ticu-larly useful as intermediate compounds for preparing prostaglandin derivatives and especially the prostaglandin derivatives of formula I above.
The novel chiral compounds in question are cyclo-pentene derivatives which can be represented by -the general Eormula:
A
~ ~ -B
~ Ia RO`

in which R represents a hydroxy-protecting group of the formula -CH2Rl in which Rl represents an aryl or aralkyl radical, O O
B represents -CH or -CH ~ and A is such that:

- when B represents -CH, A represents ~ CH2 or \ C /
- when B represents -CH ~ , A represen~s ~ C~ ~ , ~ CH2, ~ C = O or \ CHIlloH
With respect to Rl, suitable meanings for aryl can be, for instance, phenyl substituted or not by a methyl radical and for àralkyl appropriate values can be, for example, benzyl substituted or no-t in the aromatic moiety by a methyl radical.
As a preferred value for R, benzyl can be cited.
Thus, preferred compounds covered by general formula Ia, are the followin~:

2-Formyl-4 (R)-benzyloxy-2-cyclopentenone-ethylenedithio-acetal referred to hereinafter as <~Synthon A.

.

- 3a -~8~33~

2-Formylpropyleneacetal-~ (R)-benzyloxy-2-cyclopen-tenone-ethylenedithioacetal referrecl to hereinafter as <~Synthon B.
2-Formylpropyleneacetal-4 (R)-benzyloxy-2-cyclopentenone referred to hereinafter as Synthon C.
2-Formylpropyleneacetal-4 (R)-benzyloxy-2-cyclopentenol referred to hereinafter as asynthon D.
l-Formyl-3 (R)-benzyloxy-l-cyclopentene referred to herein-after as Synthon E.
l-Formylpropyleneacetal-3 (R)-benzyloxy-l-cyClopentene referred to hereinafter as Synthon F.
The present invention in accordance with another aspect also relates to a process for preparing the compounds of formula Ia. In particular, the present invention relates to a process for the preparation of cyclopentene derivatives represented by the general formula ~Ia) A
~ -B ~Ia) RO
wherein R represents a hydroxy-protecting group of the ~ormula -CH2Rl in which Rl represents an aryl or aralkyl Il /0~
radical, B represents -CH or -CH and A is such that:

- when B represents -CH, A represents = CH2 or \ C

- when B represents -CH ~ , A represents / C ~ ~ , --CH2, =C=O or=CHlllOH, characterized in that ~a) to obtain a compound of formula (Ia3 wherein - 3b -,._~- .

33~
n R is as defined above, B r~presents -CH and A represents S

CH2 or / ~ S ~ an hexanedial derivative of g~neral formula:
~R

~C=O
~ H~
1~1 o in which R has the same meaning as given above and D represen~s / C f ~ 2 S
is cyclised under inert atmosphere with pyrrolidine acetate or piperidine acetate in a suitable solvent and at a temperature in the range of from -lO~C to room temperaturer (b) to obtain a compound of formula (Ia) wherein R is as defined above, B represents -CH ~ and A represents ~ CH2 or ~ C

a c~clopentene derivative of formula ~-CH

R~
wherein R is as defined above and A repre-\ ~S~sents ~ CH2 or / C ~ , is treated with - - 3c -33~

1,3-propanediol at a temperature in the range of from room-temperature to 40C in a suitable anhydrous solvent in the presence of p-toluenesulphonic acid, (c) to obtain a compound of formula (Ia) wherein R is as defined above, B represents ~0 -CEI ~ and A represents ~ C=O, a cyclo pentene derivative of formula I

~-CH

RO
wherein R is as defined above, is treated with neutral diphenylselenic anhydride at room-temperature and in a suitable solvent and (d) to obtain a compound of formula (Ia) wherein R is as defined above, B represents -CH ~ and A represents ~ CHIIIOH, a cyclo-o . pentene derivative of formula ~ ~O

RO

- 3d -.

~3033~

wherein R is as defined ahove, is treated with diisobutyl aluminum hydride in a suit-able anhydrous solven-t and at a temperature in the range of from -10C to room-temperature~
The invention is also concerned with a method of using Synthons A to F as intermediate products for the pre-paration of the compounds of formula I above.
In particular the present invention is also concerned with a method of using Syn-thons B, D and F
referred to above for the prepara-tion of derivatives for-mula (I) above, whereby a cyclopen-tane derivative oE yeneral ~ormula:

~ \\~O ~ XXXIII

~~~0~
RO
Z
in which R represents a hydroxy-protec-ting group of the :formula -CH2Rl in which Rl represents an aryl or aralkyl radical, Z' represents hydrogen or a radical -OR and E

represents / C~ ~ , \ CH~ or \ CHllloR, R haviny the same meaning as given above for both radicals, may be submitted to the following reactions:
a) hydrolysis of the formylpropyleneacetal group in an acid medium to obtain an aldehyde group b) treatment of the aldehyde group with the dianion of (5-carboxypentyl)-triphenylphosphonium bromide in accordance with the conditions of the Wi-ttig reaction to fix an ethylene carbon chain - 3e -

3~

c) hydrogenolysis of platinum charcoal or palladium char-coal to saturate the ethylenic chain and deprotect the hydroxyl groups followed, when necessary, by dethio-acetalisa-tion wi~h mercuric chloride to form a ke-to group, so as to ob-tain the required compounds of formula (I) above, the compounds of formula XXXIII being themselves obtained as follows:
A) - treatment of Synthons B or F wi-th boron hydride followed by oxydation of the borane formed to fix a hydroxyl group on the ethylenic bond, - reaction with a n-halogenoheptane deriva-tive to etherify the hydroxyl group so formed and optionally:
either : reduction oE the ethylenedithioacetal group with Raney nickel or : de-thioacetalisation with mercuric chloride -to form a ketone group, reduc-tion with lithium tri-sec-butylborohydride to form a hydroxyl group and protection of the hydroxyl group so as to form the compounds of formula XXXIII
B) - protection of -the free hydroxyl group of Synthon D
- treatment of the O-protected derivative obtained with boron hydride and subsequent oxidation of the borane so formed to fix a hydroxyl group on the ethylenic bond - reaction with a n-halogenoheptane derivative to etherify the hydroxyl group so formed so as to obtain the compounds of formula XXXIII in which E
represents ~ CHIllO-R.
For the last fifteen years or so, prostaglandins have constituted a diversified and actively investigated research field. The chemical work that has been done in this fièld has resulted in the total synthesis of numerous .prostaglandins and their analogs.

- 3f -~8~3~

Since thromboxan (TX~2) and ~rostacyclin ~PGI2) were diseovered with -their physiolog.ical activities whieh oppose eaeh other, a considerable amoun-t of researeh work has been devoted to this type of compound.
Both substances are biosyntheti~ed in living organisms from arachidonic acid via endoperoxide (PGH2).
Thromboxans are formed in human platelets and incluce platelet aygregation, whereas prostacyclin, which is released from the vascular walls, inhibits such aggrega-tion. Thus, theoretieal:Ly, -th~se two eompouncls regulate the formation of each other and failure or dis-turbanee of this process of regulation causes -the TXA2-PGI2 balance -to be upset whieh in turn leads -to eardiovascular diseases sueh as thrombosis, infaretion and the like.
Prostanoie aeid derivatives having a 13-hetero-atom and endowed with an inhibitory aetion on platele-t aggregation have already been described in British Patent Application No. 2,028,805 A and in J. Med. Chem. vol. 22, - 3g -No. 11 pp~ 1L~02-1~iO8 (1979).
In British Patent Application No. 2,028,805 A the he-teroatom is nitrogen while in the J. ~ed. Chem. rererence in question the heter~atoM is oxygen, a two-nitrogen brid6e being fixed between the 9- and 11-positions giving rise to a 9,11-azo derivative.
It has now been found that a new series of prostanoic acid derivatives, namely 11-hydroxy-prostanoic acid derivatives, in whicl1 the carbon atom in the 13-position has been replaced by an oxygen atom, presents pharma-cological properties generally found in the prostaglandin series, more particularly an inhibitory effect on blood-platelet aggregation and/or a bronchodilating action~
In view of their pharmacological properties, the 13-oxa-prostaglandin derivatives of the invention are capable of being used therapeutically in the treatment of pathological states which affect the respiratory system, and especially asthma. Furthermore, these compounds can be used as antithrombotic agents and in the treatment ~nd prevention of cardio-vascular diseases or pathological conditions such as myocardial infarc-tio~l.
ThereEore, another object of the invention relates to a method of provo-king bronchodilaticn or inducing inhibition of blood-platelet aggregation in a host needing such treatment, method which comprises administering to said host an effective amount of at least one 13-oxa-prostaglandin of the invention.
For human therapy the compounds of the in~ention ~ill be used at daily dosages of 0.1 to 40 mg/kg by oral route and of 0.3 to 12G mg by aerosol administration.
Yet another object of the present invention is to provide pharmaceutical and veterinary compositions comprising as an essential active ingredient at least one oxaprostaglandin of formula I or a pharmaceutically accep-3 table salt thereof, in association with a pharnlaceuticnl carrier or excipient therefor.
All the compounds of the invention can be obtained from Synthons A to F.
The process for preparing these Synthons A to F comprises a nurnber of original steps starting from (3R, 4S, 5R)-3,4-0-cyclohexylidene-3,415-trihydroxy-cyclohexanone, this latter compound being obtained from quinic acid, as described, for instance, by CLEOPHAX, LEBOUL, G~RO, AKHTAR, 33~5' BARN~TT, PEARCE in J.A.C~S., 1976, 98, 7110.
The process of the invention i`or the prepara.-tion of the chiral interme-diate compounds in question as \~ell as for the preparation of the 13-oxa-prostaglandins of the i.nvention can be summarized as follows :
A. ~ _i n of Synthon A
a) Reaction of (3R, 4S, 5R)-3,4-0-cyclohexylidene-3,4,5-trihydroxy-cyclo~
hexanone of formula :
OH

II
'~
'. , ~) , in the presencè of boron trifluoride etherate1 with ethanedithiol at room-temperature and in an aprotic solvent such as, for example, benzene, toluene, chloroform or dichloromethane, to provide (3R, 4S, 5R)-3,4,5-trihydroxy-cyclohexanone-ethylenedithioacetal of formula :
OH

~ 5 ~ o~
H

b) Treatment of the dithioacetal III with 1,1-dimethoxycyclohexane in the presence of an acid catalyst such as, for example, sulphuric acid o~ p-toluenesulphonic acid, at room-temperature and in an aprotic solvent, for instance, N,N-dimethylformamide, to obtain (3R, 4S, 5R)-3,4-0-cyclohexylidene-~, 4, 5-trihydroxy-cyclohexanone-ethylenedithio-acetal of formula :

0~

,1 S ~ ¦ IV

c) Protection of the free hydroxyl Group of compound IV with a bromide o~ the formula R Br in which R has the same meanin~ as above, prefe-rably ben~yl, in the presence of an aIkali metal hydride, for instance sodium hydride, preferably at O~C and in an aprotic solvent such as, for instance, N,N-dimethylformamide, dimethylsulfoxide or hexamethyl-enephosphoramide to prDvide (3R, 4S, 5R)-3,4-0-cyclohexylidene-3,4,5-trihydroxy-cyclohexanone-ethylenedithioacetal derivatives of general formula :
oC~2-R 1 .' ~S'\
- S / ~ ~ O
~1 V

in which R1h~s the same meaning as above and which can be used either isolated or not in the following step :
d) Treatment of the ether V with a strong inorganic acid, for instance hydrochloric acid, in an alcohol, for instance methanol, ethanol or isopropanol, and at the reflux temperature of the medium, to provide (3R, 4S, 5R)-3,4,5-trihydroxy-cyclohexanone-ethylenedithioace-tal derivatives of general formula : 9 OCH -R, ~ - S

--S 1, OH

3~

in which R1has the same meaning as above.
e) Oxidation of the diol VI by means of neutral lead tetraacetate or tri~
phenylbismuth carbonate in an c~propriate solvent, for example, toIuene, and at room-temperature, to obtain l~-oxo-ethylenedithioacetal-hexane-dial derivatives of general formula :

f CH -R
~S~ cj \ ~ ~ O VlI

10 - S / ~ /
O

in which Rlh~s the same meaning as above.
f) Cyclisation of the acyclic dialdehyde VII in situ and under inert atmosphere with pyrrolidine acetate or piperidine acetate in an appro-priate solvent, such RS benzene or toluene, and at a temperature ran-ging from -10C to room-temperature, preferably at 0C, to obtain 2-formyl-2-cyclopentenone-ethylenedithioacetal derivatives of general formula: l~ ~
S S

~ -CHO VIII
'' ., ~

in which R1has the same meaning as given above or Synthon A.
B. Pre~aration of S~ynthon B
Synthon A hereabove is treated with 1,3-propanediol at room-temperature and in the presence o p-toluenesulfonic acid, the treat~ent being carried out in an anhydrous solvent, for example benzene or toluene, which provides 2-formylpropyleneacetal-2-cyclopentenone-ethylenedithioacetal derivatives of general formula :

3~
-- o --S S

~; CE~; >g IX

in which R1hAs the same meaning as given above or Synthon B.
C. PreParation of Synthon C
Synthon B is:treated with lleutral diphenylselenic anhydride at room-tem-perature and in an appropriate solvent, for instance dichloromethane, to provide 2-formylpropyleneacetal-2-cyclopentenone derivatives of general formula : 0 ~C\ ~ X

15 ~ CH2-R~

in which Rlhas the same meaning as given above or Synthon C.
D. Preparation of Synthon D
Synthon C is treated with diisobutyl aluminium hydride in an appropriate anhydrous solvent, for instance benzene or toluene, and at a temperature ranging from -10C to room-temperature preferably at 0C to obtain 2-formylpropyleneacetal-2-cyclopentenol derivatives of general formula :

~ C
,\\\\ .

3~ ~
_ 9 _ -in which R~has tlle same meaning as given above or Synthon D.
~. Preparation of Synthon ~
a) Treatment of diols VI above under reflux with Raney nickel (catalyst of finely di.vided nickel ob-tained by dissolving out with alkali the aluminium fro~ a nickel-c~uminium alloy)in c~n appropriate solvent, for instance ethanol, to provide (lR, 2S, 3R)-1,2,3-trihydroxy-cyclohexane derivatïves of general formula :

: ~ OH XII
OH

in which R~has the same meaning as given above.
b) Oxidation of diols XII by means of neutral lead tetraacetate or triphenyl-bismuth carbonate in an appropriate anhydrous solvent, for example chlo-roform, and a-t room-temperature to obtain hex~nedial derivatives of general formula :

\ C=O XIII
<
~ c/H

O

in which R~has the same meaning as given above.
c) Cyclisation of the acyclic dialdehydes XIII in si.tu and under inert atmosphere with pyrrolidine acetate or piperidine acetate in an appro-priate solvent, such as toluene, and at a temperature ranging from -10C to room-temperature, preferably at 0C, to obtain 1-formyl-1-cyclopentene derivatives of general formula :

~ CH0 ~" .
CH2-R~ XIV

in which R1has the same meaning as given above or Synthon E. .
F. Preparation of Synthon F
Synthon ~ here~bove is treated with 1,3-propanediol at a temperature between room-temperature and 400C, for instance at 30C, and in the presence of p-toluenesulfonic acid, the treatment being carried out in an anhydrous solvent, for example benzene or-toluene, ~hich provides ~-formylpropyl-eneacetal-1-cyclopentene derivatives of general formula :

~ C- f ~ XV

in which R~has the same meaning as ~iven above or Synthon F.
G. Preparation of the 13-oxa-prosta~landins of formula I
Synthon B or Synthon F is first treated with boron hydride in tetrahydro-furan at a temperature ranging from 0C to room-temperature and the borane so formed is oxidized with hydrogen peroxide in the presence of sodium hydroxidel at a temperature ranging from 0C to room-temperature, to obtain cyclopentane derivatives of general forrnula :

- O--~q p,1 ~2~coo \\\\\~ XVI

in which D represents \ C / ~ or = CH2 and R~has the same meaning as give.n above.
Different procedures are then applied to compounds XVI in accordanee with the chemical strueture of the 13-oxa-prostaglandin of formula I to be obtained.
I. When X and X1 taken together with the carbon atom to whieh the att.ached represent a earbonyl group and Z represents hydro~en or hydroxy~

~ ~S
a) ~reatment of eompounds XVI in vhich D represents / C ~ in the presence of an aIkali metal hydride, for instance sodium hydride1 at room-temperature and in an appropriate solvent, for example N,N-dimethylformamide, with a 1-halogeno-n-heptane derivative of general formula :

\ CH CH3 XVII

in which Hal represents ehlorine, bromine or iodine, and Z' represents hydrogen or a proteeted hydroxyl group of the formula OR in whieh R
has the same value as given above, thus providing 2(S)-formylpropylene-acetal-3(R)-~,eptyloxy derivatives of general formula :

~ X III

3 R1H2CO ~

. in whieh Z' and R~have the same meaning as given above.
b) Hydrolysis of compounds XVIII in the presence of trifluoroacetic aeid in chloroform or hydroehloric aeid in acetone or hydrochlorie aeid in anhydrous ehloroform/isopropanol, under inert atmosphere, to obtain `` ~ 3~

2(S)-formyl-3(R)-heptyloxy derivatives of general formula :

S S O
~"~ CII

- ~ 0 R1-H2CO __ .
Z' XIX

in which Z' and R~have the same meaning as given above.
c) Treatment of compo~mds XIX under inert atmosphere, with the dianion of (5-carboxypentyl)-triphenylphosphonium bromide at room-temperature and in an appropriate anhydrous solvent such as, for instance, ethyl ether, in accordance with the conditions of the Wittig reaction, to obtain 2(S)-(6-carboxy-1-hexenyl)-3(R)-hep-tyloxy derivatives of general formula :

0~ \ (C~l )L-C00~l XX

~ll2 C / ` / " ~ / ` \
Z' in which Z' and R~have the same meaning as given above.
d) Deprotection of the hydroxyl groups of compounds XX by hydrogenolysis on platinum charcoal or palladium charcoal at room-temperature and in an appropriate medium, for instc~nce an acetic acid/ethanol medium, to obtain 2(S)-(6-carboxyhexyl)~~(R)-l1eptyloxy derivatives of general formula :

.

33~

S S

,!\\\ ~ COOII XXI

0~~~~\~
~0 Z
in which Z has the same meaning as in formula I~
e) Dethioacetalisation of compounds XXI with mercuric chloride in an appropriate solvent, such as acetone, and in the presence of boron tri~luoride etherate to ~ive 2(S)-(6-carboxyhexyl)-~(R)-heptyloxy 10 derivatives o general ~ormula :
O

~COOH

\\~\~0/~/~\_ ~
-HO.
Z
wherein Z has the same meaning as in formula I, which are the desired 13-oxa-prostaglandins of formula I.
II~ When X and X1 _ach are hydrogen an`d Z represents hydrogell or hydroxy.
a) Treatment of compounds XVI with a n-halogenoheptane derivative as des-20 cribed in para G Ia) hereabove to obtain :
- when D represents = CH2 , 2(R)-heptyloxy-cyclopentane derivatives of general formula :

3~3~
- 14 _ -6~ XXII

9 ~ s R1-H2CO zl in which Z' and R1have the same meaning as given above.

- when D represents C ~ Sl , the compounds of formula XVIII above / ~ Sl which, after reduction under reflux and on Raney nickel, provide a mixture of non-isolated products of general formula :

1Z -- 11 ? /

. o~'"
R1 ~2CO ~
+ ., ~7 ~ ' o/

~,o " .

_ ._ in which Z' and R,lhave the same meaning as given above, this mixture being further hydrogenated at atmospheric pressure on-Adams platinum (cata-lyst of platlnum o~ide prepared from chloroplatinic acid) to give the 3~39 compounds oi` formul~ XXII abovc.
b) Hydrolysis of compounds XXII in the presence of an appropriate acid, for ex~mple trifluoroacetic acid or formic acid -to give 2(R)-heptyloxy derivatives of general formula :

,0~
~ ~\CH XXIII
\ I
~ ,/ ~ ~ "~
P~1-H 2CO --.
Z' in which Z' and P.1have the same meaning as given above.
c) Treatment of compounds XXIII, under inert atmosphere, with the dianion of (5-carboxypentyl)-triphenylphosphonium bromide at room-temperature and in an appropriate anhydrous solvent, for instance ethyl ether or dimcthylsl~foxide, in accord~nce ~i-th the con*itions of the Wittig reaction to obtain 1(S)-(6-carboxy-1-he}ellylj-2(R)-heptyloxy derivatives of general formula :

~ , ~ Y.XIV

.

in which Z' and R1have the same meaning as given above.
d) Deprotection of the hydroxyl groups of compounds XXIV by hydrogenolysis on platinum charcoal or palladium charcoal at room-temperature and in an appropriate medium, for instance an acetic acid/ethanol mediums to obtain 1(S)-(6-carboxyhexyl)-2(R!-heptyloxy derivatives of general formula :

COOH

~10 _ wherein Z ha~ the snme meaning a~ in formula I, wl-lich ~re tl1c de~ired 13-oxa-prostaglandins of formula I.
III. ~ 1 represents hydrogen c~ld Z represents hydro~en or h~clrox~.
These compounds can be obtained starting from 2(S)-formylpropyleneace-tal-3(R)-heptyloxy-cyclopentane deri~atives of general formula :

R~H2C ~ ~
-- I ,L .
~ \\c - ~/ XXV

J--\ ~,/\ /
. R~H2C ~

in which Z' and R1have the same meaning as given above, these compounds being obtained in accordance with the following steps which comprise :
either a) Treatment of compo~1ds XVI, in whicl1 D represents \ C / ~ with a n-halogenoheptane as described in para GIa) hereabove to obtain compounds XVIII.
b) Dethioacetalisation of compounds XVIII with mercuric ch1oride in an appropriate solvent, such as acetone, and in the presence of boron trifluoride etherate to give 1-oxo-3(R)-heptyloxy derivatives of general formula :

~ \~CH / 1 XXVI

'~0~ ~ ~,^~,~
R1H2C0 ~

in which Z' and X1have the same meaning as given above.

c) Reduction~of the ketonic function using lithium tri-sec-butylboro-hydride as catalyst to give 3(R)-heptyloxy-cvclopentanol derivatives of general formula :
/~ ' O
~ \\\~\~\ 0 / XXVlI

in which Z' and R~have the same meaning as given above.
d) Protection of the free hydroxyl group of compounds XXVII with a bromide o the formula R Br in which R has the same meaning as above, prefe~
rably benzyl, in the presence of sodium hydride and in an appropriate aprotic solvent to give the 3(R)-heptyloxy-cyclopentane derivatives which correspond to the compounds of general fo.rmula XXV.
or a) Protection of the free hydroxyl group of Synthon D with a bromide of the formula R Br in which R has the same meaning as above, preferably benzyl, in the presence of an alkali metal hydride, for instance sodium hydride, preferably at 0C and in an aprotic solvent such as, for ins-tance, N,N-dimethylformamide, dimethylsulfoxide or he~amethylenephospho ~, .. . ..

33!~3 ramide, to provide 2-formylpropyleneacetal-2-cyclopen-tene derivatives of general formula :
/
R~l-H2Co ~ ~ / XXVIII

~~_ .
R~-H2CO

in which R~has the same meaning as given above.
b) Treatment of compounds XXVIII with boron hydride as described in para G) hereabove to obtain 2(S)-formylpropyleneacetal-3(R)-hydroxy-cyclopentane deri~atives of general formula A ~ CH O / XXIX

~ ' OH

in wl1ich R~has the same meaning &S given above.
c) Treatment o~ compounds XXIY with a n-halo~enoheptane derivative as described in para GIa) hereabove to obtain 2(S)-formylpropyleneacetal-cyclopentane derivatives which correspond to the compounds of general formula XXV.
The compounds XXV above are then submitted to the following reactions.
a) Hydrolysis in the presence of an appropriate acid, for example triflu-oroacetic acid, to obtain 2(S)-formyl-cyclopentane derivatives of general formula :

R-ll CO
_: O
"
~ \\~CII XXX

.in which.~' and R1have the same meanillg as given above.
b) Treatment of compounds XXX under inert atmosphere with the dianion of (5-carboxypentyl)-triphenylphosphonium bromide at room-temperature and in an appropriate anhydrous solvent such as, for instance, ethyl-ether in accordallce with the conditions of the Witti.g reaction to obtain 2(S)-(6-carboxy-1-hexenyl)-cyclopentalle derivatives of general formula :

2 _-~ \\\ ~ COOH XXXI

= ~ ~ ~ ~ /

in which Z' and R~have the same meaning as given above.
c) Deprotection of the hydroxyl groups of compounds XXXI by hydrogenolysis on platinum charcoal or palladium charcoal at room-temperature and in an appropriate medium, for instance an acetic acid/ethanol medium, to obtain 2(S)-(6-carboxyhexyl)-3(R)-heptyloxy derivatives of general formu~a : OH

~ \~\\\\ ~ / ~ ^" / COOH XXXII

HO

3~1 - 20 ~

wherein Z represents hydrogen or hydroxy wllich are the desired 13-oxa-prostaglandins of formula I.
With respect to the pharmaceutically acceptable salts of the heteropros-taglandins of formula I, these will be obtained, in a classical manner, by reacting the acid of formula I with an appropriate alkali metal hydro-xide, for instance, sodium hydroxide.
As regards the h~ ogenoheptane derivativesof formula XVII in which Z' represents an -OR group,these C~ll be obtained from (S)-(-)heptane-1,2-diol described by K. MORI in A~r. Biol. Chem. 40, 1617 (1976).
This diol is tritylated to obtain the 1-0-trityl derivative and the 2-hydraxy is then protected using a bromide of the formula R Br in which R
has the meaning given above, preferably benzyl.
The 1-0-trityl is then deprotected and the free hydroxyl so regenerated is substituted by a halogen a-tom using conventional procedures so as to provide the compounds of formula ~II in which Z' represents the -OR
group in question.
Tests were carried out in order to evaluate the pharmacological proper~ies of the 13-oxa-prostaglandins of the invention.
Bronchodilatory action This action was determined by verifying the relaxant action on the iso-lated guinea-pig trachea previously contracted with carbac~.ol i.e. carba-moylcholin llydrochloride.
~or this purpose, spiral strips of about 3 mm in width of the tracheal tissue were maintained in a survival medium7 The isometric tension of the guinea-pig tracheal preparations was continuously registered. An initial tension of 8 g was applied to each preparation. After a rest period of 60 minutes, a submaximal contraction was obtained by adding carbachol to the bath. ~Jhen the contractile response of the preparation became reproducible 11(R)-hydroxy-13-oxa-prostanoic acid of formula I
was added to the bath either when the carbachol-induced contraction was at its maxïmum so as -to appreciate its relaxant action or when the prepa-ration was completely relaxed so as to evaluate the influence of the acid on the basal tonus.
Under these conditions, 11(R)-hydroxy-13-oxa-prostanoic acid provoked a 3~

~oderate decrease of the basal tonus of the guinea-pig tracheal prepara tion.
The amplitude of this decrea3e depel1ded on the dose employe~ of the pro~-tanoic acid derivative.
Furthermore1 the relaxant action at concentrations of about 10 5 and about

4.1~ 5 mol of 11(R)-hydroxy-13-oxa-prostanoic acid on preparations contrac-ted by 8.10 mcl of carbachol was also found to be moderate~
In addition, it was found that the relaxant effect in question was not similar to a ~adrenoreceptor stimulant effect since in the presence of 10 5 mol of proprc~lolol, -the relaxant effect was not modified in either trial.
Inhibitory action on platelet a~re~ation This test was performed in vitro on citrated human plasma using thrombine as aggregant agent.
Aggregation was carried out after incubation of the fraction of plasma rich in plateletsfor 20 min. at room-temperature in the presence of 5 ~l of 11(R)-hydroxy-13-oxa-prostanoic acid of the invention in dimethylsulphoxide at a concentration of 1 m~/ml. The controls were incubated in a similar manner with 5 ~l of dimethylsulphoxide.
The samples to be used for titration of thromboxane B2 were taken after 3 min. aggregation using 0.4 U/ml ofthrombine and in the presence of 100 ~g/ml of indomethacine and 100 ~ ~n~ of imidazole (100 ~l per 400 ~l of fraction rich in platelets).
The thromboxane B2 was then determined.
In this test, the amounts of thromboxane B2 found were 857 ng/ml when the studied compound was present.
This thus shows that when the oxaprostaglandin of the invention was used there was a 77~-decrease in thromboxane B2 and a 47/0-inhibition of platelet aggre6ation.
The therapeutic compositions of the invention can be made up in any form -which is suitable for their administration in human and veterinary therapy.
~or ease of administration, the composition will normally be made up in a dosage unit form appropriate to the desired mode of administration, for example, a compressed tablet for perlingual administration, a pillt a powder, a capsule, a syrup, an emulsion for oral administration, a sus-pension for oral or aerosol administration, a suppository for rectal administra-tion or a sterile solution or suspension for parenteral adminis-tration.
The therapeutic compositions in question will be prepared in accordance with ~lown techniqucs by associating at least one compound of the invention with an appropriate diluent or excipient and therl, if required, making up the resulting admixture in the desired dosage unit form.
Examples of suitable diluents and excipients are distilled water, ethanol~
talc, magnesium stearate, starches, sugars and cocoa butter.
The preparation of compounds of the invention is illustrate by the follo-wing Examples.
EXA~IPLE 1 Preparation of 2-formyl-4(~)-berlzyloxy-2-c~clopenterlone-ethylenedithioacetal or Synthon A (compound V:[II with R~ henyYl) a) (3R, 4S, 5P)-3,4,5-trihydroxy-cyclohexanone-ethylenedithioacetal ________________________________________________________________ (compound III) ______________ To 8g of (3R, 4S, 5R)-3,4-0-cyclohex~Ylidene-3,4,5-trihydroxy-cyclohexanone (compound II) dissolved in 40 ml of anhydrous chloroform, 16 ml of ethane-dithiol and 1.6 ml of freshly distilled boron trifluoride etherate were added. After one hour at room-temperature, thin layer chromatography was performed (solvent : 3/1 chloro~orm/ethyl ether) and the starting com~ound was ,found to have disappeared. The desired compound III precipitated as it was formed in the reaction medium and was then dissolYed by adding methanol.
The solution was neutr~1i7ed with sodium bicarbonate, filtered and the sol-vents were evaporated off. The resulting solid was dissolved again in hot acetone and the insoluble salts were then filtered.
In this manner, compound III was obtained after crystallization from ace-tone.
Yield : 95~
M~P. : 129-130C
aD -41 (methanol, C=1.4% W/V) b) (3R, 4S, 5R)-3,4-0-cyclohexylidene-3,4,5-trihydroxy-cyclohexanone-_________________________________________________________________ ethylenedithioacetal (compound IV) - ___~_________________ ____________ To 7g of the previously obtained compound III, dissolved in 30 ml of N,N-dimethylformamide, were added 8 ml of ~,1-dimethoxycyclohexane and 0~5 ml of concentrated sulphuric acid. The methanol formed in the reaction was evaporated off ,from time -to time using a water pump so as to facilitate a shift ln equilibrium leading to the de~ired compound IV. The reaction was terminated after two days at room-temperature as determined by thin layer chromatography (solvent : 3/1 chloroform/ethyl ether). The solution was diluted with dichloromethane and neutralized with sodium bicarbonate.
After filtration, the organic phase was washed with water and then dried on sodium sulphate and concentrated under reduced pressure.
In this m~er, compound IV was obtained after crystallization from petroleum ether.
Yield : 95~
M.P. : 138-140C
aD : _4LIo (chloroform, C=1.02/' W/V) 13 C N.M.R.
_ __ __ _ __ __ _ N C1 2 3 4 5 6 7 ~
,:
~ (rpm)62.97 46.ll673.76 . 79-67 71.55 . 41.59 40.16 25.02 -. N C9 10 11 12 13 1L~
.
.c (ppm) .23.72 24.04 . 35.35 110.09 38.01 . 38.21 _ c~ (3R, 4S, 5R)-3,4-0-cyclohexylidene-5-0-benzyl-3,4,5-trihydroxy-cyclo-___________________ ______________________________~__________________ hexanone-ethylenedithioacetal (compound V with R~= phenyl) ____________________________ ___________ _______ _________ Into a three-necked flask were introduced o.845 g of sodium hydride and 47 ml of N,N-dimethylformamide under nitrogen at 0C. After that, 9 g of compound IV were added followed by 3.6 ml (1.3 equivalent) of benzyl bromide once the solid was dissolved. The reaction medium showed a orange-` yellow colour. The reaction was terminated after three hours as determinedby thin layer chromatography (solvent : 3/1 chloroform/ethyl ether). The hydride in excess was removed by adding methanol and the reaction mixture was first poured into iced water and then extracted with dichloromethane.
- The organic phase was washed with water and dried on sodium sulphate. Eva-poration of the solvents gave a yellow oiI.
In this manner, the required compound V was obtained after crystallization from aqueous ethanol.

- 2l~ ~

Yield : 95%
M.P. : 68-690C
aD : ~~ (chloroform, C=1.06% W/V) EIemental anal~sis C21 H28 3 S2 Mol. W-to : 392.5O7 _ calculated (%) C : 64.25 H : 7.19 . S : 16.34 .
_ .
found (%) C : 64015 H : 6.96 S : 16.52 d) (3R, 4S, 5R) 5-0-benzyl-3,4,5-trihydroY.y-cyclohexanone-ethylenedithio-____._________________________________________________________________ acetal (compound VI with R~= phenyl) ______________.___________ _________ The following reaction was effected directly from the raw compound V
(yellow oil) obtained previously.
In 120 ml of methc~lol were dissolved 12 g of raw compound V. After that, 10 ml of 12 N-hydrochloric acid were added and the medium was heated to 70C.
When the hydrolysis was complete, AS detertnined by thin layer chromato-graphy (solvent : 3/1 chloroform/ethyl ether), the reaction medium was diluted with dichloromethane and neutralized with sodium bicarbonate.
The solution was then filtered and evaporated. The residue was taken up in dichloromethane and the organic phase was washed witr. water, dried on sodium sulphate, filtered and evaporated.
In this malmer, the required compound VI was obtained after crystalliza-tion from ethanol or ethyl acetate.
Yield : 88%
M.P. : 135-136C
25 ~D : -72 (chloroform, C=1.03~ W/V) ~lemental analysis 15 20 3 2 Mol. Wt. 312.457 calculated (~) C : 57.66 H : 6.l~5 S : 20.53 .
found (~o) C : 57.65 H : 6.53 S : 20.23 ~ ~ \
33~

3C N M.R. (d~ pyridine~

.

c~(ppm). 65.L~ 40.2 69 2 72.3 . 79.3 Li6.4 38.2 39.5 71.4 e) 2(R)-benzyloxy-4-oxoethylenedithioacetal-hexarledial (compound VII
in which [~= phenyl) ______ ___ _________ Iil a coloured flask, 1.~3 ~g (3 mM) of lead tetraace-tate was dried using a vane pump so a~; to remove all traces of ace ic acid. After this opera-tion, 100 ml of anhydrous toluene and o.624 g (2 mM) of compound VI
previously obtained were added. The reaction medium was then s-tirred at 10 room ternperature.
After an hour and a half, the reaction was terrnirlated as determined by thin layer chromatography (solvent: 3/1 chloroform/ethyl ether) and 3 ml of ethylene glycol were then added to remove the lead tetraacetate in excess. ~hen this excess has reacted, the solution became clear. The 15 reaction medium l~las then diluted ~ith dichloromethane and the organic phase was wasi1ed once with water, then with a saturated solution Or sodium bicarbonate and finally with water to neutrality. The organic phase was then dried on so~lium slllphate, filtered and evaIlorated.
In this manner, the required compound VII was obtained in a quantitative 20 yield in the form of a colourless oil wll~ ch acquire(l a yellol~ tint in the course of time and had therefore be used withou-t delay.
-aD: -11 (chloroform, C=2.47' W/V) As this compound is a particularly uns-table product, it was reduced for characterization purposes thus giving 2(R)-benzyloxy-4-oxoethylenedithio-25 acetal-hexanediol.
~lemental analysis of this diol 15 2Z 3 2 Mol. Wt. : 314.473 .
calculated (%) C: 57.29 H: 7.05 S: 20.39 .
found (~) C : 57.3 H : 6.47 S : 20.18 .

~8~3~

~D : -20 (chloroform, C=1.4% ~J/V) L~
f) 2-Formyl-4(R)-benzylo~y-2-cyclopentenone-ethylenedithioacetal (compound VIII in which R1= phenyl) In 20 ml of anhydrous toluene, o.620 g of the raw compound VII previously obtained was dissolved under nitrogen at 0C. After -that, 0.5 ml o a lN-solution of pyrrolidine acetate in anhydrous ben2ene was added. The reac-tion medium was allowed to stand for 18 hours at 0C under nitrogenO At k;
the end of this reaction time, thin layer chromatography (~olvent : 3/1 chloroform/ethyl ether) showed that the starting compound had completely disappeared. The reaction medium was then diluted with dichloromethaneand the organic phase was washed ~ith water to neutrality, dried on sodium sulphate, fi~tered and e~aporated.
In this manner, the required compound VIII or Synthon A was obtained in the form of a pale yellow oil which was stored at 0C in a coloured flask.
Yield : 95~
.M.R of the proton at 60 MHz c~(ppm) ` H
. ~
2.7 2H5 (A-B system octuplet) 3-45 2H7 ~ 2H7, (multiplet) 4.4 CH2 (phenyl) (singlet) : 4.7 : H4 (sextuplet) 6.65 H3 (doublet) : 7.2 : phenyl . 9.5 ; H6 (single-t) I.R. (CHC13) 1685-1705 cm unsaturated u,~-aldehyde - M.S (electron impact) M = 292 (201, 186, 91, 77, 65) Preparation of 2-formylpropyleneace-tal-4(R)-benz~loxy-2-cyclo~entenone-ethylenedithioacetal or Syntholl B (compound IX in which R1 = phenyl?

The reaction was carried out directly from -the prevlously obtained unsatu-rated a,~-aldehyde.
In 50 ml of dry toluene, 0.550 g oi ~ompound VIII obtained in ~xample 1 f was dissolved and 1.5 ml o~ 1,3-propanediol together with a trace of p-toluenesulphonic acid were then added. At the end of a 24-hour reaction time, 3/4 of the volume was evaporated off using a rotatory evaporator.
~fter that, 1.5 ml of 1,3-propanediol ~nd 50 ml of anhydrous toluene were added to shift -the equilibrium in favour of the desired compound~
~his operation was carried out again 24 hours later. ~he reaction was almost terminated after 72 hours as determined by thin layer chromato-~raphy (solvent : 3/7 ethyl acetate/petroleum ether). ~owever, there was still some of the starting aldehyde (5 to 10/') left. ~he reactlon medium was diluted with dichloromethane, and neutralized with sodium blcarbonate. After filtering the si~ts, ~he organic phase was washed with water, dried on sodium sulphate, filtered and evaporated. ~he compound so obtained was then separated by thin layer chromatography (solvent :
3h ethyl acetate/petroleum ether). After the strlp wlth the lower Rf value had been eluted with ethyl acetate and the solvents had been filtered and evaporated off, a colourless oil was obtained.
In this manner, the required compound IX or Synthon B was obtained after crystallization from petroleum ether.
Yield : 80~
M.P. : 70-71C
aD: ~ 860 (chlaroform, C=1.12,Co W/V) 13C N M R (d5 pyridine) N C 1 2 3 4 5 6 6' 7 8 8' 9 10 .
~(ppm) (~) 146.3 13106 80.3 53.8 ;41.3 40.5 97.3 67.3 67.3 25.8 70.' (~) not identified on the spectrum (quaternary carbon) lemental analysis 3 C18 H22 3 2 Mol. Wt. : 350.506 calculated (~') C : 61.6&; ~l : 6.32 S : 18429 - found (%) C : 61.44 H : 6.28 S : 18.37 .

N.M.R. o~ the proton at 2~0 MI-Iz (CIICl3) ____________________________________ , ~ (ppm) .
7-3L~ phenyl _~
6.34 _ 3 J (H3-H4) = 2Hz .

5.25 . 7 L~.65 4 , 4.55 CI~2 (phenyl) .~
4.22 . 8a ~ H8,a .-- . : .
3-9 .H8e + H8'e _ :
3,4 ,2H6 ~ 2H6~

2.95 5b ~ J~T15b ~ H5a) = 13.5 Hz J(H5b ~ H4 ) = 6-5 Hz 2.5 H5a ~ J(H5b H5a : J(H5~ - H4 ) = 5 Hz 2.2 H9 1.4 9e .
~XA~
Pre~aration of 2-formylpropyleneacetal-4(R)-benzyloxy-2-cyclopentenone or Synthon C (compound X in which R1 = phenyl) - 20 To 0~180 g of compound IX obtained in Example 2 dissolved ln 5 ml of anhy-drous dichloromethane was added 0.203 g (1.1 equivalent) of diphenylselenic anhydride (Ph2Se203) free from any trace of nitric acid.

After that, one drop of propylene oxide per 50 mg of starting compound was added so as to remove likely nitric acid remnants. At the end of a 20-hour reaction time, thin layer chromatography (solvent : 3/7 ethyl acetatej petroleum ether) showed that the starting compound had disappeared and that a compound with a lower Rf value had been formed.
- The reaction medium was slightly diluted with dichloromethane, neutralized 3~

with sodium bic~rbonate, filtered .~d separated by thin layer chrornato-graphy (sol~ent : 3/7 ethyl acetate/petroleum ether). ~he strip with the lower Rf value uncier U~V. light was eluted with e-thyl acetate, f1ltered and the solvent was evaporated of~. `
In this manner, the required compound X or Synthon C was obtained in the form of a colourless oil cristallizin~ from petroleum ether.
Yield : 68%
M.P. : ~2-L~3C
C~]D = + 420 (chloroform, C = 1W/V) Elem~ntal analysis 16 18 4 Mol. Wt. : 274.316 ..

Calculated (~) C : 70.05 H : 6.61 __ _ found (~') C : 70.14 H : 6.60 N.M.R. of the proton at 250 MHz (CHCl ) ___________ 3 15 . ~ (ppm) H
_ 7.7 H
: : 3 - 7.3 phenyl 5.3 . H6 . 4.7 H4 4.6 : CH2 (phenyl) _: _ ..
- ; 4.18 7a 7~a 3-9 ; H7e ~ H7'e 2.75 5b ~ J (H5b ~ H5a) = 18.5 Hz J (H ~ H4 ) = 6 Hz . 2043 ~ 5a ~ J (H5b ~ H5a) = 18.5 Hz J (H5 - H4 ) = 2.5 Hz - _ 2.15 ; 8a 1.35 , 8e ~8a333~

XAMPL~ L~
Preparation of 2~formylpropyleneacet~i-4(R)-benzYloxy-2-c~clopentenol or S nthon D (com ound XI in which R = phen~yl) Y_ . _ P . - 1 .
To 2.44 g of compound X obtained in Example 3 dissolved in 53 ml of anhy-drous toluene, there were added, drop-by-drop, under nitrogen atmosphere and at 0C, 13.1 ml of diisobutyl aluminium hydr~ide (1M commercial solution in hexane).
Thirty minutes later, thin layer chromatography (solvent : 3/1 chloroform/
ethyl ether) showed that all the startin~ product has disappeared.
The reaction was stopped by 5Iowly adding meth~lol at 0C. The solution was then poured into iced water saturated with sodium chloride and then taken up in ~ichloromethane. The or6anic fraction was dried on sodium sulphate and then evaporated to dryness. The oil so obtained was dissolved in a 3/1 mixture of chloroform/ethyl ether and this solution was first filtered on Celite (a commercially available diatomaceous silica procluct, the word "Celite" being a regi~tered Trade Mark) and then evaporated to dryness. The desired product was crystallized from a dichloromethane/
petroleum ether mixture. The mother-liquors showed in N.M.R. of the proton, the presence of another product which was the other isomer.
In this manner, the required compound XI or Synthon D was obtained.
Yield : 89~o M.P. : 88-900C
Elemental analysis C16 H20 04 Mol. Wt. : 276.336 25 ; calculated (%) . C : 69.54H : 7.29 _ folmd (/0) C : 6~.36H : 7.3 M.S.
M = 276.
~X~MPLE 5 3o Preparation of 1-formyl-~(R)-benzyloYy-1-cyclopcntcno or Synthon E
(com~_nd XIV in which R = phenyl) a) (1RL 2S, 3R)-3-0-benzyl-1,2,3-trihydroxy-cyclohexane (compound XII in ___ _______________________ ____________________ ____________________ which R = phenyl) ------ 1 ------'-In 80 ml of 9~-~thanol was dissolved 1.3 ~ of compound V C obtained in Example 1d~ When the pLoduct was completely dissolved, Raney nickel was added in considerable excess and the medium was refluxed for 12 hours. The reaction mixture was filtered on Celite and thoroughly rinsed wi-th ethanol 5 so as to eliminate all the Raney nickel The oil so obtained was taken up in chloroform and filtered on Whatmann paper~ The required compound crystal-lized frorn petroleum ether.
In this manner, the required compound XII was obtained in a yield of 70/~.
M.P.: 59-600C (petroleum ether) 10 aD = -830 (chloroform, C = 1.3 W/V) Illementa] analysis , C13 18 3 Mol. Wt. : 222.287 calculated (5') C : 70.24 H : o.16 found (/') C : 70.12 H 8.11 15 M S.
M = 222 b) 2(R)-benzyloxy-hexanedial (compound YIII in which R1 ~ l~henyl) In 120 ml of anhydrous chloroform were dissolved 2.34 g of compound XII
previously obtained and 5.7 g of lead tetraacetate were added by small frac-20 tions. The reaction was carried out protected from light and followed by thin layer chromatography (solvent: ethyl acetate/petroleum ether).
Ninety minutes later, the reaction terminated and ethyleneglycol was added to eliminate the lead tetraacetate in excess. When the solution was clear, it was taken up in dichloromethane washed with water, with sodium 25 bicarbonate and again with water. The chloroform phase was dried on sodium sulphate and ev~porated to dryness.
In this manner, the required compound XIII was obtained and directly reacted in the following step.
N.M.R. of the 2 aldehyde protons at 60 MHz -: 9.6 ppm 30 I.R. spectrum: CH0 at 1720 cm c) 1-Formyl-3(R)-benzyloxy-1-cyclopentene (compound XIV in which R1 ~ phenyl Compound XIII previously obtained was dissolved in 100 ml of dry toluene and reacted, under nitrogen atmosphere and at 0C, with 1 ml of a 2 ~ benzene solution of pyrrolidine acetateO The reaction medium was allowed to stand for about 8 hours at 0C and then poured into iced water. After being taken up in dichloromethane, the organic phase was dried on sodium sulphate and concentrated under reduced pressure. The ~,~-unsaturated aldehyde so obtained, in the form of a clear yellow oil 9 was relatively unstable and was directly used, without purification in the following step.
~n this manner the required compound XIV or Synthon ~ was obtained.
N.M.R. at 60 ~l~ :

_ 10 . ~ (pp~n) H
:
9.~ : aldehyde 7.3 phenyl : 6.8 : = CH

I.R. spectrum : CH0 ~,~ unsaturated : 1680 cm to 1710 cm FiA~DL~ 6 -Preparation of 1-formylpropyleneacetal-3(R)-benzyloxy-1 cyclopentenone or Synthon F (compound XV in which R1 = phenyl) To compound XIII obtained in ~xample 5b dissolved in 10~ ml of dry toluene, there were added 10 ml of 1,3-propanediol and a trace of p-toluenesulphonic acid. The mixture was stirred at 30C with a rotatory evaporator for one hour and then kept under stirring for a further 24 hours. When the reaction was terminated, the reaction medium was diluted with dichloromethane and neutralized with sodium bicarbonate.
After 30 minutes of s-tirring at room-temperature, the solution was filtered and extracted with dichloromethane. After being washed with water~ the orga-nic phase was dried on sodium sulphate and evaporated under reduced pressure to obtain a dark oil which was purified by thin layer chromatography (solvent 1/2 ettlyl acetate/petroleum ether).
In this manner the reouired compound XV or Synthon F was obtained in the 3 form of a colourless oil.
Yield : 55~ ~from compound XII ) ~D = + 74~' (chloroform, C = 1.4 W~) "` ~ 33~
~ 3~ ~

C1G H20 03 Mol. Wt~ : 260.333 calculated (~') C : 73.81 H : 7.74 . found (/o) C : 73.81 . H : 7-71 M.S
_ _ _ _ M = 260.
~ XAMP~ 7 Prepa on of 11(R)-hydroxy-13-oxa-prostanoic acid (X=X1=Z=H) a) 1(S)-formylpropyleneacetal-2(R)-hydroxy-3(R)-benzyloxy-cyclo~en-tane ______________________~____________________________________________ ~compound XVI in whicl1 D represents C~l2 and R1 = phenyl) In a three-necked flask maintained under nitrogen or argon atmosphere was dissolved 1.5 g of compound XV obtained in ~xample 6 or Synthon F in 20 ml of freshly distilled tetrahydrofuran. After cooling to 0C, 2 equivalents of a 1M commercial solution of boron hydride in tetrahydrofuran were added.
The medium was allowed to stanà at 0C ~ld then for 15 minutes at room-tem-perature. After that, the reaction mixture was oxidized. For this purpose, the diborane in excess was destroyed at 0C by adding, drop-by-drop~ 1 ml of water, then 1.5 ml of a 3N-solu-tion of sodium hydroxide and finally ~ ml of hydrogen peroxide. At the end of a 4-hour reaction-time, potassium carbonate was added. ~he mixture was diluted with e-thyl ether and the ethe real phase ~las decanted out, washed with water, dried on sodium sulphate and evaporated under reduced pressure.
After separation by thin layer chromatography (solvent : 1/2 ethyl acetate/
petroleum ethe~ there were obtained 0.950 g of the required alcohol (one isomer) and 0.190 g of the starting product.
In this manner, the required compo~md XVI ~las provided.
Elemental anal~sis C16 H22 4 Mol. Wt. : 278.348 calculated (~) C : 69.o4 H : 7.96 3 found (~) C : 68.85 H : 7.94 L33~
_ 3L~ _ -aD = + 5 (7-5 mg/rrl) b) 1(S)-formylprop~yleneacetal-2(R)-heptyloxy-3(R)-ben2yloxy-cyclopentane _._~__~_______________________________________________________________ (compound XXII in wilich Z' = ~l an(l R1 = pl1e~rlyl) Under nitrogen atmosphere and at 0C, 0.390 g of the required compound X\TI
previously obtained was added in 10 ml of N,N-dimethylformamide, to 0.600 g of an oily suspension of sodium hydride. Once the hydrogen evolution ter-min~ted, 0.7 ml Or n-iodol1eptane wn5 a(lded and the temperature was allowed to return to room-temperatureO Two hours later, the reaction was complete and the mixture was cooled to 0C and diluted with dichloromethane. T}1e hydride in excess was destroyed by adding methanol and the solution was poured into iced water saturated Witi1 sodium chloride.
After extraction with dichlorometh~le, the organic phase was dried on sodium sulphate and then evaporated under reduced pressureO After separa-tion by thin layer chromato6raphy there was obtained 0.350 ~ of the requi-red ether.
In this manner the required compound XXII was provided.
;D = + 5 (chloroform, C = 1 W/V) Elemental analysis C23 H36 4 MolO l,lt.: 376.537 calculated (~0) C : 73-26 H : 9.63 found (/0) C : 73-18 I-I: 9.62 Using the same procedure~ 1(S)-formylpropyleneacetal-2(R)-~2(S)~benzyloxy-heptyloxy]-3(R)-benzyloxy-cyclopentane was prepared.
Elemental analy~is 25 C29 H42 05 Mol. Wt.: 470.650 , ca:Lculated (70) , C: 74.00 H: B.99 found (%) C: 73.96 H: 8.95 c) 1(S)-formyl-2(R)-heptyloxy-3(R)-benzyloxy-cyclopentane (compound XXIII
.__~____.______________________________________________________________ in which ~' = H and R = phenyl) ________________---- 1 ---------30 Under nitrogen atmosphere, 0~740 g OI the required compound XXII previously obtained was dissolved in 5 ml of anhydrous chloroform. After that, 20 ml of 8~0-formic acid were added aild the reaction was monitored by thin layer chromatography (solvent : chloroform~. After 2L~ hours, a further quantity of 10 ml of formic acid was added and the reaction was allowed to stand under nitrogen atmosphere for 24 hours.
~1e reaction medium was cooled c~nd sodium bicarbonate was added.
When the pH of the medium was 4, the solution was poured into iced water saturated with-sodium chloride. This aqueous phase was taken up in di-chloromethane. The organic phase was washed with an aqueous solution of sodium bicarbonate to neutrality and then with water. After drying on sodium sulphate and evaporation of the solvents in a coloured flask, o.630 g of a clear yellow oil was obtained.
In this manner the required compound XXIII was provided.
I.R~ spectrum : strip at 1705 cm M.S.
M = 318 Using the same procedure, 1(S)-formyl-2(R)-[2(S)-benzyloxy-heptyloxyj-3(R)-benzyloxy-cyclopentane was prepared.
M.S.
M = 424 d) 1(S)-(6-carboxy-1-hexen-~1)-2(R)-heptyloxy-3(R)-benzyloxy-cyclopentane __________________________________________________________ __________ (compound XXIV in which Z' - ]i and R1 ~ phel1yl) To 0.940 g of sodium hydride were added 19.6 ml of freshly distilled di-methylsulphoxide and the mixture WRS heated to 70C for 1 hour. The solu-tion of sodium methylsulpl1inyl methide, ~hich became a greyish green colour, was then transferred to a three-necked flask containing 4.48 g of (5-carboxypentyl)-triphenylphosphonium bromide maintained under argon atmos-phere. The medium, which immedia-tely turned red, was allowed to stand for one hour at room-temper~ture.
After that, o.624 g of compound XXIII previously obtained dissolved under argon atmosphere in 19 ml of dimethylsulphoxide was added drop-by-drop to the ylide solution. The reaction medium was then allowed to stand for about o hours at room-temperature. The mixture was then poured into iced water containing a little sodium bicarbonate and the flask was rinsed with a 1~1 mixture of ethyl ether/petroleum ether. The aqueous phase was collected and then acidified to pll = 3 by a(llinG ox~lic acid. The aqueous phase was washed four times wi-th ethyl ether and the ethereal phase~ were collected, dried on sodium sulphate and evaporated off under reduced pressure. The mixture so obtained was purlfied ~,y chroma-to~raphy on a column (eluent :
1/1 ethyl acetate/petroleum ether).
In this manner, the required compound XXIV was obtained.
Yield : 33,~
aD = ~45 (chloroform, C = 0.35 W/V) Elemental analysis 10 C26 H40 4 Mol. Wt. : 416.606 calculated (%) C : 74.95 H : 9.68 . _ found (~) C : 75.17 H : 9.70 M.S.
M _ 416 Using the same procedure, 1(S)-(6-carbo~-1-hexenyl)-2(R)-~2(S)-benzylox~y-heptyloxy]-3(R)-benzyloxy-cyclopentane was prepared.
Elemental analysis 32 46 5 Mol~ Wt. : 510.715 : calculated (~j') : C : 75.25 : H : 9.07 _ found (%) C : 75.19 H : 9.0 M~S.
M = 510 e) 11(R)-~ydroxy-13-oxa-prostalloic acid __________.________________ _______ .
Compound XXIV previously obtained was dissolved in a 1/1 mixture of acetic acid/ethanol in the presence of 10%-palladium charcoal. After a 48-hour period of hydrogenation in a Parr apparatus~ the reaction medium was fil-tered on Whatmann paper and then chromatographed on a column.
In this manner 11(R)-hydroxy-13-oxa-prostanoic acid was obtained.
Yield : 90~
aD = ~ 19 (chloroform, C = 0.73 W/V) 8~3~sa ~lemental nalysis C19 H36 4 Mol.Wt. : 328.4~7 :
calculated -(%) : C :69.47 : H : 11.04 found (%) : C: 69.54 : H: 10.97 .
5 M.S.
_ __ _ M = 328 Using the same procedure, 11(R)-hydroxy-13-oxa-15(S)-hydroxy-prostanoic acid was prepared.
emental analysis 10 ' 19 ~6 5 _ Mol Wt.: 344.L~92 calculated (%) : C: 66.24 : H: 10.53 found (~) C: 66.18 : H: 10.60 M.S.
_ __ _ M = 344 EXA~IE 8 Preparation of 11(R)-hydroxy-13-oxa-prostanoic acid a) 2(S)-formylpro~yleneacetal-3(R)-hvdroxy-4(R)-benz~rlox~-cvclopentallone-___________ __ __________________v___ __________~ __v__v____~________ ethylenedithioacetal (compound XVI in which D re~resents ~C~ 1 _________________ _____________________ S
and R = phenyl) -----1--___ ____ 20 In a 50 ml three-necked flask maintained under nitrogen atmosphere was dissolved 0.700 g of compound IX obtained in l~xample 2 or Synthon B in about 5 ml of freshly distilled tetrahydrofuran. IJsing a syringe, 10 ml of a 1 M-commercial solution of boron hydride (BH3) in tetrahydrofuran was slowly added at 0C under nitrogen. The reaction medium was allowed 25 to stand for about 15 hours at room-temperature during which time a light current of nitrogen was passed through the flask. The borane that formed was then oxidized. For this purpose the hydride in excess was removed by slowly adding water (about 2 ml) at 0C. Still at the same temperature, 2 ml of a 3N-solution OL sodium hydroxide were added followed by 2 ml of 30 30~-hydrogen peroxide so as to oxidize the product. At the end of a 4-hour ')~

3~3 , reaction-t~me, -the reaction rni~tu:~e was dilu-ted witll dichloromethane and poured into iced water satur~ted wi.th ammonium chloride. The solution was t~ken up in dichloromethane and tile or~anic phase was washed with water to neutrality, dried on sodium sulphate and evaporated off. The oil so 5 obtained, which still contained some of -the startin~; compound, was sepa-rated by thin layer chromato~;raphy and the product with the lower R:E
vallle was collected (sol~rent: 1/1 ethyl ether/petroleum ether).
In this manner, the required compound XVI was obtained in the form of a colourless oil.
10 Yield: 35%
~D : ~4 (CDCl3, C = 1.27,~ W/V) Elemental analysis C18 24 2 4 Mol. Wt. : 368.52 calculated (~O) C : 58.66 H : 6.56 .
found (,0) C : 58.99 H : 6.74 .
N.M.R. of the proton a-t 250 Mll~. (CDCl /TMS) ___________---------- 3 ~f (ppm) ll :
8e :
2.1 8a .
20 : 2.37 115 -~ H2 :
2.6 5b 2.9 . OH (diSappeared after addition.
:
3~21 2Hg + 2Hg, : . :
. 25 : 3.82 : H7 ~ il7, :
3.95 : H3 .

- . . .

8~3~
-- )9 --}16 5.18 7a 7~a 5.28 l~
.
5.6 CH2 (10) 7~35 phenyl -3C N.M.R. (CDCl /TMS~
____------ 3 .~
: ~~(ppm): 66.3 : 60.6 : 79 : o206 : L~9 5 : 103.8 . .
:
N C : 7 : 7' : o : 9 : 9' : 10 :
:c~ppm) : 66.8 : 66.8 : 25.7 : 40.7 : 39.1 : 71.7 M.S.
_ _ _ _ - M = 368 b) 2(S)-formylpropyleneacetal-3(R)-heptyloxy-4(R)-benzyloxy-cyclopentanone-__________________________________________________________________~_____ ethylenedithioacetal (compound XVIII in which Z' = }I and R = phenyl) ______________________________----_-----------------------1 --_______ 15 Under nitrogen, a solution of 0.1 g of compound XVI previously obtained was added, in 5 ml of N,N-dirnethylformamide, to a suspension of 0004 g of sodium hydride in 5 ml of N,N-dimethylformamide.
Once hydrogen evolution was terminated, 0.7 g of n-iodoheptane was introdu-- ced. The reaction was monitored by thin layer chromatography (solvent: 1/1 20 ethyl ether/petroleum ether) and when this reaction terminated, the reaction medium was cooled to 0C and diluted with 10 ml of dichloromethane. The hydride in excess was remo~ired by adding methanol. The solution was poured into sodium chloride-saturated iced-water and then taken up in methylene chloride. The organic phase was washed three times with water, dried on 25 sodium sulphate and concentrated. The resulting oil was then separated by thin layer chromatography (solvent: 1/1 ethyl ether/pe-troleum ether).
In this manner, the required connpound XVIII was obtained in the form of a colourless oil.

g33~ -- L~o - .

Yield : 6a~0 :F;'lemQntn]. ;Inalysi~, C25 113~ 4 2 Mol. Wt. : Ll66.71 ._ .
~ calculated (%) : C : 64.34 : H : 8.20 : S : 13.74 .
:
: found (%) : C : 64.42 : H : 8.o5 : S : 13.86 M.S.
_ __ _ M = 466 C N M R. (CDCl /TMS) - ~ 3 _ _ . .
:
N C 1 : 2 : 3 : 4 : 5 : 6 : 7 : 7' ,~ : : : : : : : :
~ (ppm) : 67.8 : 58.6 : 84.5 : 84.1 : 48.2 102.7 : 66.3 : 66.5 :

: N C : 8 : 9 : 9' :10 : 11 : 12 : 13 : 14 .: : : :: : : :
c-~ (ppm) ` 26 : ~9 : 38.5 : 70.8 : 29.7 : 317 : 29 :25.5 --: N C :15 16 : 17 ~ : : :
: cl (ppm~ : 22~5 : 13 : 71.6 N.M.R of the proton at 250 MHz ~ :
: ~ (ppm) : H
_ , CH3 (17) _ 1.27 CH2 (13-14-15-16) 1.55 , CH2 (12) + H8e , 2.1 8 .
. 2.4 . 2 5 .

i~ 3~

3.2 2(H9 -~ H9,) .
3.5 CH (11) 3-8 7e 7~e 4.1 H7a + H7la H3, H4 --4.6 ; Cl-l2 (10) 4.95 . H6 (doublet) J(H6 ~ H2) = 10 Hz 7.34 phenyl _, c) 1(S)-formylpropyleneac~etal-2(R)-he~tyloxy-3(R)-benzyloxy-cyclopentane (compound XXII in which Z' = H and R = phenyl) ______~____'______-_-------------- 1 ---------A solution of 0.1 g of compo~uld XVIII previously obtained in etnanol was refluxed for about 15 hours in the presence of Raney nickel. After filtra-tion on Celite the mixture ~las evaporated to dryness.
The 3 C N.M.R. and the proton N.M.R. spectra showed the presence of two products, one of which was unsaturated. The mixture was reduced, in the -15 presence of Adams platinum and at atmospheric pressure, which led to one - single compound.
In this manner, compound XVI was obtained.
Yield : 67%
~ : + 5 (chloroform, C = 10 mg/ml) 20 M.S.
M = 376 emental analysis 23 36 4 Mol. W-t. : 376,537 : calculated (%) C : 73.36 : H : 9.63 .
found (~) C : 73.18 H : 9.62 13 C N.M.R. (CDCl /TMS) ________---- 3 033~
_ L12 -N C 1 2 3 . Il .

S(ppm) : L~8.8 :85-L~ :85 : 29.922.7: 103.3 : 67 N C 7' ; 8 9 10 11 12 13 ~ (ppm) 67 25.8 69-7 29.9 31.8 29.2 26.1 ' : N C 14 :15 :16 ~ _ _ ~ (ppm) 22.6 14.1 70.9 .
N.M.R. of the proton at 250 MHz __ ___________________________ S (ppm) H
_ 7.35 .phenyl .
10. 4.55 ben~yl .
- 4.45 ~H6 (doublet) J (ll6 ~ H2) = 6 Hz _ 4.15 7e .
; 3.75 N2, H3~ H7a 3.80 . multiplet 0-CH2 (9) (chain) -2.05 1 8a 1.7 1 2H5 + H6e (complex mass) 1.45 CH2 (10) - . 1.3 ,CH2 (11-12-13-14) _ . 0.9 ,CH3 (15) _ d) 1(S)-formyl-2(R)-heptyloxy-3(R)-ben~yloY.y-cyclopentane (compound XYIII in _________________________________________________________________________ which R 1 - phenyl) 3~
- L~3 _ In 4 ml of chloroform was dissolved 0.115 g of compound XXII previously obtained and then were added a-t 0C 3 ml of a 50%-aqueous solution of tri-fluoroacetic acid. The reaction mediurn was then allowed to stand for 36 hours at room-temperature. After d:ichloromethane had been added, the reaction medium was neutralized wi-th sodium bicarbonate, filtered and taken up in water. The aqueous phase was washed with dichloromethane, dried and evaporated. The mixture residue so obtained contained 50~' of the desired aldehyde and a residue of 4-0% constituted by the starting product. The aldehyde was separated by thin layer chromatography (solvent : chloroform) In this manner, compound XXIII was obtained.
M.S.
M = 318 (227, 155, 129, 107, 92, 91, 83, 67, 65, 57, 55) N.M.R. of the proton at 60 ~z ______________________________ Doublet of the aldehyde proton at 9.2 ppm e) 1(S)-(6-carboxy-1-hexenyl)-2(R)-heptyloxy-3(R)-ben~yloxy-cyclopent~e ________________________________________ ______________________~_____ (compound XXIV in which Z' = H) ___________ ________.__________ This compound was obtained in accord3nce with the method described in ~xample 7 d) above.
f) 11(R)-Hydroxy-13-oxa-prostanoic acid ____________________________________ This compound ~las obtained in accordance with the method described in Example 7 e) above.
~ AI~PLE 9 Pre~aration of 9(S)-hydroxy-11(R) hydroxy-l3-oxa-pros~noic acid a) 1(S)-Benzyloxy-2-formylpropyleneacetal-4(R)-benzylox-y-2-cyclopentene ____________________________________________________________________ (compound XXVIII in which R = pllenyl) _____________________------1 ---______ To 0.187 g of sodium hydride were added 3 ml o~ N,N-dimethylformamide and the temperature was lowered to 0C.
After that, o.690 ~ of compound XI obtained in ~xample 4 or Synthon D, previously dissolved in 15 ml of N,N-dimethylformamide, were introduced 30 followed by o.637 g (1.5 equivalent) of benzyl bromide under nitrogen atmosphere and at 0C. The medium was allowed to stand for 3 hours and monitored by thin layer chromatography (solvent 3/1 chloroform/ethyl ether).
At the end of this period of time, the reaction medium was cooled and the hydride in excess was removed by adding methanol~
.

L8~3~

The solution was poured drop-by-d~ op into iced water and then taken up with dichloromethane.. The organic phase was dried on sodium sulphate, filtered and evaporated to dryness~
In this mam~er, the required compourld XX\/III was obtuined in the form of 5 a colourless oil.
Yield : 90~b aD ~ ~L~6 (chloroIorrll, c - 1.17 w/v!
Elemental anal~sis C23 H26 4 Mol. Wt. : 366.461 calculated (%) C: 75.38 : H: 7.15 found (%) C: 75.35 . ~: 7.18 MoS~
_ __ _ (M -1)= 365 b) 1(S)-Benzylo~y-2(S)-formylpropyleneacetal-3(~)-hydroxy-4(R)-benzyloxy-_______________________ ______________________________________________ 15 cyclopentane (coml~ound XXIX in WhiCIl R = pnenyl) __________________ _______-_--------- 1 ---------The whole reaction was carried out under nitrogen atmosphere and the appa-ratus was previously dried at 150C.
To 3.7 g of compound XXVIII prevlously obtained in 50 ml oE freshly distill ed tetrahydrofuran, was added drop-by-drop and at 0C 1 equivalent of a 1M
20 commercial solution of boron hydride in tetrahydrofuran. After that, the reaction medium was allowed to stand at 0C for 2 hours and then overnight at room-temperature. The hydride in excess was destroyed at 0C by slowly adding the minimum quantity of water. Oxidation to alcohol was obtained by - adding, at 0C, 2 ml of 6N sodium hydroxide and 1.8 ml of 30,~0-hydrogen 25 peroxide. The reaction was allowed to stand for 4 hours at room-temperature and then potassium carbonate was added. The mixture was filtered and co-piously rinsed with ethyl ether.
The ethereal phase so obtained was dried on sodium sulpha-te, filtered and evaporated to dryness. The alcohol so provided was crystallized from 30 aqueous ethanol and the resulting mother liquors were separated out by chromatography on a column of silica gel (solvent: 1/2 ethyl acetate/
petroleum ether) ~ ~ ` 7 - ll5 -In this manner the required compourld XXIX was obtained in a yleld of l~57rJ.
M.P. : 76-770C (ethanol/water) aD = t480 (chloroform, C = o.83 W/V) Elemental analysis C23 H28 ~ Mol. Wt. : 304.477 : calculated (~ C : 71.85 : H : 7.34 : found (%) : C : 71.86 : H : 7.33 c) 1(S)-Benzyloxy-2(s)-form~ylpropyleneacetal-~(R)-lleptyloxy-4(R)-be cyclopentane (compound XXV in which Z' = H and R = phenyl) _____________________--_-------------- 1 In a three-necl~ed flasl{ were placed 3 equivalents of an oily suspension of sodium hydride under nitrogen atmospl~ere. After washing with dry hexane, 5 ml of N,N-dimethylformamide were added. The temperature was lowered to 0C and then 1g of compound XXIX previously obtained dissolved in 15 ml of N,N-dimethylformamide, was added.
15 Once hydrogen evolu'ion terminated, 1.4 ml of n-iodoheptane (~.~10l Wt. 229, d = 1.37) was added. After about 8 hours at room-temperature, the reaction medium was cooled to 0C, diluted with dichloromethane and the hydride in excess was removed by adding methanol. The solution was then poured into iced water saturated with sodium chloride taken up ~lith dichloromethane and dried on sodium sulpha~e. After evaporation to dryness, the desired product so obtained was purified by chromato~raphy on a silica Gel column (solvent : 1/2 ethyl acetate/petroleum ether).
In this manner the required compound XXV was obtained in the form of a colourless oil.
25 Yield : 75%
emental analysis C30 H42 5 Mol. Wt. : 482.66 :
: calculated (~) : C : 74.65 : H : 8.77 :
: found (%) : C : 74.59 : H : 8.82 aD = (chloroform, C = 1.7 W/V) `~ 33~
_ L~6 - .

Using the same procedure, 1(S)~benzyloY~y-2(S) formylpropyleneacetal-3(R)-[2(S)-benzylo~cy-heptylo~y]-4(R)-benzyloxy-cyclopentarle was prepared.
l~lemental analysis C36 H48 6 Mol. Wt.: 576.774 : calculated (~) : C : 74.96 : H : 8.38 found (~/o) : C : 74.89 : H: o~40 d) 1(S)-Benzyloxy-2(S)-formyl-3(R)-heptyloxy-4(R)-benzyloxy-cyclopentane _____________________________________________________________________ (compound XXX in which Z' - H and R1 - phenyl) Under argon atmosphere, 1.5 ml of a oO~-aqueous solution of formic acid was added to O o85 g (0.176 m mol) of compound XXV previously obtained.
After about 8 hours at room-tempera~ure, the reaction mixture was diluted with dry dichloromethane and sodium bicarbonate was added to obtain a pH
of about 4. The solution was taken up with anhydrous chloroform, washed with water to neutral pH, dried on sodium sulphate, filtered and evaporated to dryness.
In this manner, o.o63 g of the required compound XXX was obtained in the form of an oil which eventually turned yellow.
Yield: 90%
I.R. spectrum : CHO at 1720 cm Elemental analysis C27 H36 4 Mol. Wt. : 424.581 calculated (%) : C : 76.38 : H : 8.54 found (~) C : 75.98 H : 8.49 .
Using the same procedure, 1(S)-benzyloxy-2(S)-formyl-3(R)-[2(S)-benzylo~y-25 heptyloxy]-4(R)-bcnzyloxy-cyclopcntcme was obtaine(l.
Elemental analysis 34 42 5 Mol. Wt. : 530.705 33~
- l~7 -.
:
: calculated (%) :C : 76.94 : H : 7.97 :
: found (%) : C : 77-0 ~ 8.01 -e) 1~S)~Benzyloxy-2(S)-(6-carboxy-1-hexenyl)-3(R)-heptyloxy-4(R)-benzyloxy-________________________________________________________________________ cyclopentane (compound XXXI in which Z' - H and R = phenyl) _________________________._____---__------------ 1 ---------This compound was obtained in accordance with the method described in Ex3mple 7 d) abo~er EleMental analysis , _ 33 46 5 Mol. Wt. : 522.726 : calculated (%) : C : 75.82 : H : 8.87 _ .
: found (%) : C : 75.60 : H : 8.91 Using the same procedure, 1(S)-benzyloxy-2(S)-(6-carboxy-1-hexenyl)-3(R)-~2(S)-benzyloxy-heptyloxy]-4(R)-benzyloxy~cyclopentane was providedO
Elemen~al analysis C40 H52 6 Mol. Wt. : 628.85 : calculated (50) : C : 76.39 : H : 8.35 :
: folmd (5~) : C : 76.10 : H : 8.39 f) 9(S)-liydroxy-11(R)-hydroxy-13-oxa-prostanoic acid ______________________________________ _________ This compound was obtained in accordance with the method described in Example 7e abo~e.
Elemental anal~sis C19 ~36 5 Mol. Wt. : 344.492 : calculated (5~) : C : 66.24 : H : 10.53 .
: found (%) : C : 65~95 H : 10.80 _ _ _ _ M~So _ _ _ _ M+- = 344 qJ 33 Uslng the same procedure, 9(S)-hydroxy-11(R)-hydroxy-13-oxa-15($)-ilydroxy-prostanoic acid was obtained.

19 36 6 Mol. Wt. : 3600~91 : calculated (~') : C : 63.30 : H : 10.06 .
: ~ound (%) : C : 63.33 : H : 9,o5 ___:

:

Claims (29)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for the preparation of cyclopentene derivatives represented by the general formula (Ia) (Ia) wherein R represents a hydroxy-protecting group of the formula -CH2R1 in which R1 represents an aryl or aralkyl radical, B represents and A is such that:

- when B represents , A represents - when B represents , A represents , , characterized in that (a) to obtain a compound of formula (Ia) wherein R is as defined above, B represents and A represents an hexanedial derivative of general formula:

in which R has the same meaning as given above and D represents is cyclised under inert atmosphere with pyrrolidine acetate or piperidine acetate in a suitable solvent and at a temperature in the range of from -10°C to room temperature, (b) to obtain a compound of formula (Ia) wherein R is as defined above, B represents and A represents , a cyclopentene derivative of formula wherein R is as defined above and A represents , is treated with 1,3-propanediol at a temperature in the range of from room temperature to 40°C in a suitable anhydrous solvent in the presence of p-toluenesulphonic acid, (c) to obtain a compound of formula (Ia) wherein R is as defined above, B represents and A represents , a cyclopen-tene derivative of formula wherein R is as defined above, is treated with neutral diphenylselenic anhydride at room-temperature and in a suitable solvent and (d) to obtain a compound of formula (Ia) wherein R is as defined above, B represents and A represents , a cyclopentene derivative of formula wherein R is as defined above, is treated with diisobutyl aluminum hydride in a suit-able anhydrous solvent and at a temperature in the range of from -10°C to room-tempera-ture.

2. Cyclopentene derivatives represented by the general formula:

Ia in which R represents a hydroxy-protecting group of the formula -CH2R1 in which R1 represents an aryl or aralkyl radical, B represents and A in such that:

- when B represents , A represents - when B represents , A represents , , whenever obtained by a process as defined in claim 1 or an obvious chemical equivalent thereof.

3. A process for the preparation of cyclo-pentene derivatives of general formula (Ib) (Ib) wherein R represents a hydroxy-protecting group of the formula -CH2R1 in which R1 represents an aryl or aralalkyl radical and A represents , characterized in that an hexanedial derivative of general formula:

in which R has the same meaning as given above and D repre-sents is cyclised under inert atmos-phere with pyrrolidine acetate or piperidine acetate in a suitable solvent and at a temperature in the range of from -10°C to room-temperature to provide a cyclopentene deri-vative of general formula (Ib) as defined above.

4. Cyclopentene derivatives of general formula (Ib) (Ib) wherein R represents a hydroxy-protecting group of the formula -CH2R1 in which R1 represents an aryl or aralalkyl radical and A represents ,whenever obtained by a process as defined in claim 3 or an obvious chemical equivalent thereof.

5. A process for the preparation of cyclo-pentene derivatives represented by the general formula (Ic) (Ic) wherein R represents a hydroxy-protecting group of the formula -CH2R1 in which R1 represents an aryl or aralkyl radical and A represents , characterized in that cyclopentene derivatives of general formula (Ib) (Ib) wherein R and A are as defined above, is treated with 1,3-propane-diol at a temperature in the range of from room-temperature to 40°C in a suitable solvent, in the presence of p-toluenesulphonic acid, to provide a cyclopentene derivative of general formula (Ic) as defined above.

6. Cyclopentene derivatives represented by the general formula (Ic) (Ic) wherein R represents a hydroxy-protecting group of the formula -CH2R1 in which R1 represents an aryl or aralkyl radical and A represents , whenever obtained by a process as defined in claim 5 or an obvious chemical equivalent thereof.

7. A process for the preparation of cyclopentene derivatives of general formula (Id) (Id) wherein R represents a hydroxy-protecting group of the formula -CH2R1 in which R1 represents an aryl or aralkyl radical, characterized in that a cyclopentene derivative of general formula wherein R is as defined above is treated with neutral diphenylselenic anhydride at room temperature in a suitable solvent to provide a cyclopentene derivative of general formula (Id) as defined above.

8. Cyclopentene derivatives of general formula (Id) (Id) wherein R represents a hydroxy-protecting group of the formula -CH2R1 in which R1 represents an aryl or aralkyl radical, whenever obtained by a process as defined in claim 7 or an obvious chemical equivalent thereof.

9. A process for the preparation of cyclopentene derivatives of general formula (Ie) (Ie) wherein R represents a hydroxy-protecting group of the formula -CH2R1, in which R1 represents an aryl or aralkyl radical and A represents , characterized in that a cyclopentene derivative of general formula (Id) (Id) wherein R, is as defined above, is treated with diisobutyl aluminium hydride in a suitable anhydrous solvent and at a temperature in the range of from -10°C to room temperature, to provide a cyclopentene derivative of general formul (Ie) as defined above.

10. Cyclopentene derivatives of general formula (Ie) (Ie) wherein R represents a hydroxy-protecting group of the formula -CH2R1, in which R1 represents an aryl or aralkyl radical and A represents , whenever obtained by a process as defined in claim 9 or an obvious chemical equivalent thereof.

11. A process for the preparation of cyclo-pentene derivatives of general formula (Ic) (Ic) wherein R represents a hydroxy-protecting group of the formula -CH2R1 in which R1 represents an aryl or aralkyl radical, characterized in that a cyclopentene derivative of formula (Ib) (Ib) wherein R is as defined above, is treated with 1,3-propanediol at a temperature in the range of from room-temperature to 40°C in a suitable solvent, in the presence of p-toluenesulphonic acid, to provide a cyclopentene derivative of general formula (Ic) as defined above.

12. Cyclopentene derivatives of general formula (Ic) (Ic) wherein R represents a hydroxy-protecting group of the formula -CH2R1 in which R1 represents an aryl or aralkyl radical, whenever obtained by a process as defined in claim 11 or an obvious chemical equivalent thereof.

13. A process for the preparation of cyclo-pentene derivatives of general formula (Ic) (Ic) wherein R represents a hydroxy-protecting group of formula -CH2R1 in which R1 represents an aryl or aralkyl radical, characterized in that a cyclopentene derivative of formula (Ib) (Ib) wherein R is as defined above, is treated with 1,3-propane-diol at a temperature in the range of from room-temperature to 40°C in a suitable solvent, in the presence of p-toluene-sulphonic acid, to provide a cyclopentene derivative of general formula (Ic) as defined above.

14. Cyclopentene derivatives of general formula (Ic) (Ic) wherein R represents a hydroxy-protecting group of formula -CH2R1 in which R1 represents an aryl or aralkyl radical, whenever obtained by a process as defined in claim 13 or an obvious chemical equivalent thereof.

15. A process according to any one of claims 3, 5 and 7, wherein said solvent is benzene or toluene.

16. A process according to claim 9, wherein said solvent is dichloromethane.

17. A process according to claim 1, wherein R1 is phenyl, phenyl substituted by methyl, benzyl or benzyl subs-tituted in the aromatic moiety by methyl.

18. A process for the preparation of a cyclo-pentene derivative of general formula (Ib) (Ib) wherein R represents a hydroxy-protecting group of the formula -CH2R1 in which R1 represents phenyl, characterized in that an hexanedial derivative of general formula:

in which R has the same meaning as given above is cyclized under inert atmosphere with pyrrolidine acetate in a suitable solvent and at a temperature in the range of from -10°C to room-temperature to provide a cyclopentene derivative of general formula (Ib) as defined above.

19. A cyclopentene derivative of general formula (Ib) (Ib) wherein R represents a hydroxy-protecting group of the formula -CH2R1 in which R1 represents phenyl, whenever obtained by a process as defined in claim 18 or an obvious chemical equivalent thereof.

20. A process for the preparation of a cyclopentene derivative of general formula (Id) (Id) wherein R represents a hydroxy-protecting group of the formula -CH2R1 in which R1 represents phenyl, characterized in that a cyclopentene derivative of general formula wherein R is as defined above is treated with neutral diphenylselenic anhydride at room temperature in a suitable solvent to provide a cyclopentene derivative of general formula (Id) as defined above.

21. A cyclopentene derivative of general formula (Id) (Id) wherein R represents a hydroxy-protecting group of the formula -CH2R1 in which R1 represents phenyl, whenever obtained by a process as defined in claim 20 or an obvious chemical equivalent thereof.

22. A process for the preparation of a cyclopentene derivative of general formula (Ie) (Ie) wherein R represents a hydroxy-protecting group of the formula -CH2R1, in which R1 represents phenyl and A
represents , characterized in that a cyclopentene derivative of general formula (Id) (Id) wherein R, is as defined above, is treated with diiso-butyl aluminium hydride in a suitable anhydrous solvent and at a temperature in the range of from -10°C to room temperature, to provide a cyclopentene derivative of general formula (Ie) as defined above.

23. Cyclopentene derivatives of general formula (Ie) (Ie) wherein R represents a hydroxy-protecting group of the formula -CH2R1, in which R1 represents phenyl and A
represents , whenever obtained by a process as defined in claim 22 or an obvious chemical equivalent thereof.

24. A process for the preparation of a cyclopentene derivative of general formula (Ib) (Ib) wherein R represents a hydroxy-protecting group of the formula -CH2R1 in which R1 represents phenyl, characterized in that an hexanedial derivative of general formula:

in which R has the same meaning as given above, is cyclized under inert atmosphere with pyrrolidine acetate in a suitable solvent and at a temperature in the range of from -10°C to room temperature to provide a cyclopentene derivative of general formula (Ib) as defined above.

25. A cyclopentene derivative of general formula (Ib) (Ib) wherein R represents a hydroxy-protecting group of the formula -CH2R1 in which R1 represents phenyl, whenever obtained by a process as defined in claim 24 or an obvious chemical equivalent thereof.

26. A process for the preparation of a cyclopentene derivative of general formula (Ic) (Ic) wherein R represents a hydroxy-protecting group of the formula -CH2R1 in which R1 represents phenyl, charac-terized in that a cyclopentene derivative of formula (Ib) (Ib) wherein R is as defined above, is treated with 1,3-propanediol at a temperature in the range of from room-temperature to 40°C in a suitable solvent, in the presence of p-toluene-sulphonic acid, to provide a cyclopentene derivative of general formula (Ic) as defined above.

27. A cyclopentene derivative of general formula (Ic) (Ic) wherein R represents a hydroxy-protecting group of the formula -CH2R1 in which R1 represents phenyl, whenever obtained by a process as defined in claim 26 or an obvious chemical equivalent thereof.

28. A process for the preparation of a cyclopentene derivative of general formula (Ic) (Ic) wherein R represents a hydroxy-protecting group of formula -CH2R1 in which R1 represents phenyl, characterized in that a cyclopentene derivative of formula (Ib) (Ib) wherein R is as defined above, is treated with 1,3-propane-diol at a temperature in the range of from room-tempera-ture to 40°C in a suitable solvent, in the presence of p-toluenesulphonic acid, to provide a cyclopentene derivative of general formula (Ic) as defined above.

29. A cyclopentene derivative of general formula (Ic) (Ic) wherein R represents a hydroxy-protecting group of formula -CH2R1 in which R1 represents phenyl whenever obtained by a process as defined in claim 28 or an obvious chemical equivalent thereof.