CA1095916A - Preparation of optically active cyclopentyl derivatives - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
Novel optically active cyclopentyl derivatives of heptenoic acids useful as intermediates in the preparation of prostaglandin analogs and processes for the preparation thereof.

Description

This is a divisional of Application No. 275,929, filed on April 12, 1977.
This invention relates to a novel process for the preparation of certain prostaglandin analogs and novel inter-mediate compounds employed in t'he process.
The prostaglandins are C-20 unsaturated fatty acids which exhibit diverse physiological effects. The chemistry~
stereochemistry, nomenclature and uses thereof are extensively discussed in the literature and reviewed in Belgian Patent 10 800,580 granted on December 7, 1973 and also in our copending (5674) Application Canadian 254,785 filed June 14,1976.
In accordance with the present invention there is provided a process for preparing an optically active compound of the general formula:
OR' ~ " \ ~ Q
.~
R- ~ (VIIIA) and its optical antipode and the racemic mixture thereof which comprises reacting a compound of the formula:
OR' Q
.- CHO (VIIA) its optical antipode or the racemic mixture thereof, wherein ~b~

~; J

' , ' ..;.~

~ ' ~

R' is hydrogen or CR~';
R" is alkyl of from one to four carbon atoms, ~-naphthyl, phenyl, ~-biphenyl or phenylalkyl of rom seven to nine carbon atoms;
s R is hydrogen; tetrahydropyranyl-2-yloxy or dimethyl-t-butylsilyloxy;
O O o O
,. .. .. ..
Q is tetrazol-5-yl, -CNHCR"', ~CNHS02R"'or -COR wherein R is hydrogen, alkyl of from one to six carbon atoms, phenyl, phenalkyl of from seven to nine carbon atoms, ~-na~hthyl or p-biphenyl; and ~ " is alkyl o from one to four carbon atoms or phenyl, with the proviso that when R is hydrogen or alkyl ~ iB dimethyl-t-butylsilyloxy with the ylide of a compound of the formula:

~ ,. ..
/ P ~ CH2 ~ C - A

in a reaction inert solvent at a temperature of from 0 to 80~C.
until the reaction is substantially complete, wherein A is alkyl of from four to eight carbon atoms, 2-indanyl, or a group of the formula:
Ar ~ (CH2)n~ or Ar'-O-CH2-wherein n is 1 or 2, Ar is a-naphthyl, ~-naphthyl, a-furyl, a-thienyl, phenyl or monosubstituted phenyl wherein the substitu-ent is 1uorine, chlorine, trifluoromethyl, phenyl or alkyl or alkoxy of from one to six carbon atoms, and Ar' is phenyl or monosubstitut:ed phenyl wh~rein the substituent is fluorine, chlorine, tri.fluoromethyl, phenyl, or alkyl or alkoxy of fxom one to six carbon atoms.
A preferred embodiment of the process of the inven-:.
` .

. ~ . . ~ :

tion is that wherein the starting compolmd has the ormula:
E~
H-O ~N ~

~CHO ~N~N
R- (VIIB) An especially preferred embodiment of the process is that wherein the starting compound has the ormula:
0-~-CH3 ~' -- ~NHS02CH3 .- CH0 (VIIC) wherein R i~ as defined above.
The process for preparing a compound of Formula I i8 also preferred when A is Ar(CH2)- or Ar'-0-CH2- and ~aid proce~s is especially preferred when A i3 C6H5-~CH2-.
The present invention further pxovidss a proce~ for preparing the optically active intermediate compound of the general formula:

~ ' ~ Q
.- ~ CH0 ~VIIA) its optical antipode or the racemic mixture thersof wherein R' R and Q are as defined above, which comprises reacting an optically active compound of the formula:

i`~` .....

~' :

. ~sss~

or~ .
Q
,~s ~- (C~l~)m (VI~) its optical an~ipode or the racemic mixture thereof, whereill ~', R and Q are as deined above and n, is 2 or 3, ~lith mercuric chloride in a reactioll-inert solvent at a temperature of from 25~ to 80C. until the rea~tioll is substantiall~ complete.
A preferred embodiment of the proess is when R' is hydrogen. The process wherein R' is hydrogen is further pre-ferred ~her Q is COO~, wherein R is as defined above. Likewise the process is preferred t~hen R' is hydrogen and Q is tetrazol--10 5-yl. The said process ~herein R' is hy~ro~en is especially pr2-- feli-ed when Q is CQNHSO2R"', and most especially pre'ferred ~Yhen Q is CONHSO2CH3. , , The said process for prep~rin~ the compound of Folmula (VIIIA) is also preferred when R' is COR" and~especially when R' is COCH3. The said process wherein R' is COCH3 is further pre-~erred when Q is COO~ or tetr~2Ol-5-yl, and is especially pre-ferred when Q is CONIESO2R''', and most especially preferred ~hen Q is CONEIS02C~3~ . . . .
Th~ present invention- further provides a process for preparin~ an optical'~ active ccmpoulld o~ the-general formul~:
OH

Q~
.~ ~~~ .....
_ o ~CEI~)m (VI'~-. .
i~ op~ica~ antipode or th~ racemlc mixt~lre ti~e~eo~ wherein R

: - ` ..

-- . . ..:...
:
. . , . ~

i.s hydro~3er., tetr~l}-~d~o~7yran-2-yloxy, or dimethyl-~-b~ltyl~ilyl-oxy; O O ~
Q' i.s ~etraæol.--S~ CN~ICR"', --C:NIISO~R'~' or -C0~5;
~ ~11t iS alkyl o from one to four c~.r~o~ a~om.~ or S phenvl; and ` m is 2 or 3;
- which comprises reacti.ng an optically actj.ve compoun~l of the formul~:

O~I

R
o ~,C~ 2 ~ m s optical anti.poae or t.ha racemate thereo~ hereill R and m ~re as de . i~e~ abo~Je, t~ith an y-l iae o~ ~ c~mpo~lld of the formul~
Br ~3 ~ 3. ..
~3 P - (C1~2)4 - Q~
in a reaction inert solvent at a temperature of from -30~ to 8~C. until the reac-Lion is subsbantially comple~e. The process ol ~rep~ring the compound of Fo.rmula III' is preferred when Q' is COOH, or tetra~ol-5-yl, and is especially pxe~erred when ~' is CO~iSO2~"' and most especially preferred when Q' is CON~-I502C~13.
Some o the intermediate compounds of Formula (~
are novel anct accordingly t:he present inven~ion a:Lso provides an ~0 opticall~ ac~ive compound of the formula:
OR

~C~O
R~ C,~

35~
i~:s opti.ca;l ~;ntipodc~ ~I;t~ l:h~ accm:~.c m.~x~:ure ~;hex~of wh~rein ~) ~' is h~clxo;~ or CR" r Rll .i5 al~yl o fro.n o~ our car~on atom.s, ~
naphthyl, phen~ biphenyl or phenylalk~l o from ~even to nine carbon ~t~m~; -R is hydrogen, tetrahydropyran~2~y70~y o~ dimethyl-t butylsilyloxy; and Q is tetrazol~S-yl~ -~NEICR"', -~N~SO2.R"' or -~OR, ~Iherein R i~ hydrc~en, al~yl of from one-to si~ carbon -atoms, phenyl, phenyl.alkyl of from ~even tQ nine carbon atoms, .0 ~-naphthyl or p--biphenyl; and R~" is al~yl o~ from on.e to four carbon atom~ or phenyl, with the roviso that w hen R is hydrogen or alkyl R is dimethyl-t-butylsilyloxy.
Preferred compounds of Formula (VIIA) provided by the invention ar~Q the following:

s~ (i) an optically acti~e com~ound o~ the formula:
O . .

OC-C1~3 "
Q

~ CHo .
its o~tical antipode or a racemic ~i~ture thereof, wherein R is as deined above and wherein Q is COGR and R is as defined abo~e;
and whe.^ein Q is CO~IHSG2R"'; espeel.ally CONHSO~ 3, or t~trazol-~ 5-y~ and a conlpound of the for~.nula:
0}1 - \ I ~ .

.' ~C.t~O

.

.
:.

its optical ~ntipode or a racemic mi~ture thereof, wherein R is defined above and wherein Q is COOR and R is as defined above, and wherein Q is tetrazol-5-yl or CONHSO~R"', especially CONHSO2CH3 .
The invention still further provides an optically active compound of the formula:
OR' ~ ~ ~ Q

R- ~ ) o (CH2)m (VIA) its optical antipode or the racemic mixture thereof whersin R' is hydrogen or ~R" and R" is alkyl of rom onP to four carbon atoms, ~-naphthyl, phenyl, p-biphenyl or phenylalkyl of fxom seven to nine carbon atoms; R is hydrogen, dimethyl-t-butylsilyl-oxy, or tetrahydropyran-2-yloxy; Q is tetrazol-5-yl; CNH~R"', -~NHSO2R"' or -~COR; wherein R is hydrogen, alkyl of from one to six carbon atoms, phenyl, phenylalkyl of from seven to nine carbon atoms, ~-naphthyl or ~-biphenyl; R"' is alkyl of from one to four carbon atoms or phenyl and m is 2 or 3.
Preferred compounds of Formula (VIA) above are those wherein R' is hydrogen and wherein Q is tetrazol-5-yl; COOR, especially COOH or COOCH3; or CONHSO2R~' especially CONHSO~CH3;
and the optical antipodes and racemic mixtures thereof.
Other preferred compounds of Formula (C) are those wherein R' is -COCH3 and wherein Q is CONHSO2R"'; especially CONHSO2CH3; tetrazol-5-yl; or COOR, especially COOH or COOCH3;
and the optical antipodas or racemic mixtures thereof.
The invention yet further provides an optically active '~ ~

- .

compound o ti~e loxm~
- 0~1 0~
~,.
. p~. ~) (C112)m (V) its optical antipode and the ra~emic mixture thereof wherein R
is hydrogen, tetrahydropyran-2-yloxy or dimet}~ t~but~lsilyl-oxy; and m is ~ or 3.
~ he presen, in~.rention will now be descrlbed in more detail with reference to Reaction Schemes which illustrate the processes Lor preparinc~ the novel intermediate compounds of Formulae (VIIA), (VA) and (V)~ as ~ell as the prosta~landin analogs of Formula (VIIL~) herein. Illustrative o~ the present invention is the proc~ss for preparing the compounds designated by ~he For~ulae VIII and XIV in Scheme B hereinafter. These com-pounds are useful ir.termediates for the produstion of prosta-g~andin analogs as will ~e described hereinafter.
1~ The following ~eac~ion Scheme A illustrates the steps leading to tne preparation o~ the ke~- intermediate hemithio-acetal o Formula VI. In this Sche~le and the subsequent Schemes the symbols R, Q and ~" have the same meanings as-defined abo~e.

.: ' :.~ ' ~:

5S~
o~

~'\r ' ~ r ~
O` C~

G-~

'~ J

~ I I
0~' o~ O

HO' ~ R~

III / ~ ~7 ' 0~1 ~/ - . ' 0-- ~H OH ~.~

~ l R - ~ 0/ ~
V V:~

Sch~m~ A

--lt)-- , .
.

~ ith ~-eerence tc> ~eac~.ion Schcme ~ the intcLme~liate lac~ol o,. -F-~mul;.~ V~ is pre~-~a~:ed b~ r c~luction oi~ lact:or,c IV with clliso~utyl a]lmlinum ny;lri.de. This reduc~ion is mos~ e~sil~
~ecomplishecl L)~ CO~ tactinc, ].a~tone ~V at a low temperature, typieally -75C., in dry 1:oluene with a ~0~ sol.ution o~ diiso-butyl aluminum hyd~ide in hex~.ne. ~ her reaction tempe.-acures may be employed if c~ver reduction does not oceur~ Thc diiso-butyl alur~.inum hydride is added to the preeooled mi.xture of laetone IV in toluene o~er a yeriod of about 20 30 minut2s. The reaetion mix~ure is then stirrèd for an additi.onal 30 minu~es and then quenched by the dropwise addition o~ methanol. ~he solvents are evapo~ated under reduced pressure and the produet is isolated~
~he product may be puriIied by eolumn chromatography on siliea 5e' -Laetone I~J is prepared ~rom :lactone III by pro~ee~.ion of its hydroxyl group wi.'.-.h a suitabl,e aeid labile protecting grou~.
Sueh protecting ~roups are typieally tetrahydropyran-2-~lo;:y or dimethyl-t-butylsilo~y. ~,ny sufficiently ae~id~labile group is ~ati~faetory; ho~tever, the most usual one is tetrahydropyranyl, whieh ean be incorporated in the moleeule by treatment with di-hyclrop~ran and an aeid ea~alyst in an anhydrous medium. Laetone IIT is typically contacted with freshly distilied dihydropyran ir dry meihyler:e ehloride at a ternperature ~f 0 to 5C. in the presence of an aeid eatalvst such as para-toluenesulphon~c acid.
~ other n~n-aqueous aei.d-catalysts may li.~e~iise be employed~ This reaetion inixture ,s stirrecl until reaetion is substantially com-plete, t~pieal].y after one to two hours at a reaction temperature o~ ~C., and the l~roduct is then i.solated. Lactone I~ is pre--~arec't from ~)arabi~hen~l est:er :CI ~r)~ con~,ac.~ e s~id parabi.-~ nyl cster wi~h a nc~e~l-o~enous mi~:ln~re of anhydrou.s potassi.um carbcnate and absolute methanol. This reaction is conveniently performed at room temperatur~ for a period of approximately 24 hours. Parabiphenyl ester II is prepared from the known alde-hyde I by treatment of said aldehyde with 2-mercaptoethanol in methylene chloride at low temperature, typically 0C., under nitrogen in the presence of a L~wis acid catalyst such as boron trifluoride etherate. The reaction time is approximately lO to 30 minutes. The resulting solution is then warmed to room temperature and stirred for an additional two hours. The product is then isolated. Another suitable hemithioacetal protecting group for the aldehyde ~unction may be generated by substituting 3-mercaptopropanol for 2-mercaptoethanol in the above reaction.
In this case the protecting group is a six membered hemithio-acetal rather than the 5-membered one i'llustrated in Formula II.
Reaction Scheme A further illustrates the preparation of the hemithioacetal of Formula VI which is a key intermediate compound in the synthetic sequence of the present invention.
In the preparation of the hemithioacetal of Formula VI the desired ylide reagent is prepared from the appropriate phosphonium salt dissolved in dimethylsulphoxide by adding to the solution a solution of sodium methylsulphonylmethylide in dimathylsulfoxide in a mo~ar ratio of about 2:1 (anion:salt).
The lactol of Formula ~,is then added (dissolved in methylsulph-oxide) to the ylide solùtion prepared above, and the reaction mixture stirred unti,~ re`action is substantially complete. Re-action times will vary according to the choice of phosphonium salt and typical reaction times are l tc 16 hours. The reaction ~. , ~ mdxture~i~ the~n poured into water and the product isolated by ~ , _ thods familiar to those skilled in the art. This reaction ' 30 may be conducted at a temperature of from -30 to 80C. and the reaction temperature most frequently employed is room tempera-ture. The choice of phosphonium salt is dictated by the struc-ture of the desired final product. When Q is COOH the salt used is 5-triphenylphosphoniopentanoic acid; when Q is to be COOR the product obtained from the above reaction wherein Q is COOH is esterified by for example a diazoalkane or by treatment of the acid with a mixture of dicyclohexyl carbodiimide and the appropriate hydroxyl compound. When Q is tetrazol-5-yl the appropriate phosphonium salt is (4-ttetrazol-5-Yl)-n-butYl) tri-phenylphosphonium bromide. When Q is N-methane sulfonylamino-carbonyl, (4-methanesulfonylaminocarbonyl-n-butyl)-triphenyl-phosphonium bromide is used. The proper choice of salt will be obvious to those skilled in the art, as will the manner of preparation of the said salt.
The sequencP of steps starting from the intermediate of Formula VI and leading through the no~el aldehyde inter-mediates of Formulae VII and XIII are illustrated in Reaction Scheme B which follows:

'~; -13-.. , ' .
Q c C~R" ~ O__~ V~ \

Q ~~ Q ~, ~7 XI ~ ~ ' Q

R.' ~HO VII
~ ~ , .

O~R" . .

~?~ OH ``
,~ C:~O
XIII Q

,o,~O!R" ~ V

~ ~ OH ~ .

R~ ~/1 ~/~ \ = ~"\Q
XIV ,~

IX I-l .' ~ .~ .

H~'' OH
~che~ne ~B . X
_ _ ~ l ;i - .

~l~g~ 6 The process illustrated in Reaction Scheme B comprises inter alia reacting a compound of Formula VII or XIII with the ylide of the appropriate phosphonate of the formula:

~ ~ P 2 wherein A is as defined above, in a reaction inert solvent at a temperature of from 0 to 80C. until reaction is substantially complete.
The reaction is most conveniently conducted by first preparing the ylide under nitrogen in a suitable solv nt such as dimethoxyethane, ether or tetrahydrofuran by adding a suitable base, such as sodium hydride or _-butyllithium, slowly to a solu-tion of the appropriate phosphonate in the same solvent at a reaction temperature of from 0 to 25C., usually 0C. The form-ation of the ylide is usually complete within an hour. At this time the aldehyde of Formula VII or XIII is added, dissolved in the same solvent, and the reaction mixture is stirred at a temperature of from 0 to 80C., typically at room temperature, until reaction is substantially complete, typically for an hour.
Aldehyde VII is used to prepare intermediates for the synthesis of prostaglandins and their analogs of the F series and aldehyde XIII iq used to prepare intermediates for prostaglandins and the_r analogs of the E series. The reaction mixture is then brought to pFl 6-7 and the product isolated therefrom. Purifica-tion of the product is achieved typically by chromatography on silica gel.
The choice of the phosphonate from which the ylide is prepared is dictated by the structure of the desired final product. For example, when the final product is desired to have !`-;~
, :~ : .....
.
..

~ 7~S~
a S car~o1l lower side ch.11 a~ C~5, (i.e., A is CS11ll) the phos-~pnonate ~;ed i5 dimethyl(~--o~:o-heptyl)pnos-pho~atc~, and if the methylclleE)i~cno~y lower side chain is desir~d at Cl5, (i.e., ~ is 0-~C~12) the p~sp1lon~te us~d i~ dimet}lyl 2 oxo-3-l)]lenOxypropyl phosphon~e.
- J~ccording to the pres~.lt invention th~ startlnq mat~-rials for the above reaction, i.e., the compounds ~f structure VII and XIII are prepared from compo~nds of th~ ~tr~2cture VI Ol X~I, r2sp~ctively, as shown in Scheme B by removal of the hemi-thio~.cetal protPcting group. This is accomplished by reacting a solution of the hemithioacetal in a reactiol~-inert solvent, for exa~lple, acetonitrile:water (~:l), wit~l mercuric chloricle at a reacLion temperatuxe of from about 25 to 80C. until reaction is substantially complete. Reaction times wilI vary somew~at with the s-~bstr~te but a typical reactio.~ tim~ is from 0.5 to 2.0 hours. Preferably ~he reaction is conducted wnen an alkaline earth met~l carbonaLe is present in tlle reactioI1 mixture since the most favorable yie]ds a~e obtained when~this material is present. The pre~erred al~aline earth ~neial carbonate is calcium ~0 car~onate, preferably in a molar ratio of 6:1 (Caco3:vI or CaCO3~
The ~emithioacetal XII is obtained from Compound VI by acyla~ion. This is most cor.unonly achieved using the appropriate acid anhydrlde in the presence of pyridine althou~h other acyla-tion sys.ems such as acid chloridQs ox ~:~tenes may be used.
~ s indicated in Scheme B/ Intermedi~te VIII may be con--verted directly to Intermediate ';IV b~ acylation As indicated above such an acylation re~ction is co~mo1lLy conducted using the nc.icl a!lllydL-ide o.f the desired acyl ~!~oUp i1~ the presence of 3n pyridine.

Intermediates XIV and VIII may be converted into prostaglandin E and F respectively in the following way:
To produce prostaglandins of the F ~eries Compound VIII is converted into Compound Ix by reduction with zinc boro-hydride. This reduction is usually carried out in dimethoxy-ethane with a molar ratio of zinc borohydride to Compound VIII
of 1:2. The reaction is usually conducted at room temperature under nitrogen and a reaction tirne necessar~ for complete re-duction. other reducing agents such as lithium trialkyl boro-hydrides may be employed and solvents such as tetrahydrofuranmay be used. The reaction mixture is then cooled in an ice bath, the cold reaction mixture quenched by the addition of sodium bi-tartrate and the product isoiated. The two epimers produced by this reaction are separated by column chromatography on silica gel.
Compound IX then may be converted to the desired PG~
analog by an acidic hydrolysis of the tetrahydropyranyl group.
Any acid which does not cause destruction of the molecule in the course of the removal of the protectlng group may be used. How-ever, this is accomplished most often by use of 65% aqueousacetic acid, at room temperature for about 18 hour~. The product is purified as above.
E series prostaglandins and their analogs may be ob-tained from Intermediate XIV as shown in Scheme C. The reduc~
tion to XV is accomplished in the same manner as the reduction VIII to IX as above. The isomers obtained from this reduction are separated by column chromatography. Alcohol XV is then pro-tected as sho~l in Scheme A Reaction III to IV under the same conditions as described for that transformation and the result-ing protected compound XVI is then hydrolyzed by contacting it ~-ir. a suitable solvent or mixture of solvents, such as methanol-tetrahydrofuran (l:1) with lN a~ueous sodium hydroxide solution.
This reaction is run at room temperature under nitrogen for periods usually ranging from 8 to 2g hours, a]though longer re-action times are occasionally necessary to effect completehydrolysis. The reaction mixture is then acidified by the addi-tion of lN hydrochloric acid and the acidlfiQd solution is ex-tracted with ethyl acetate to afford the desired product. This product may be purified, if desired, by column chromatography.
The resulting product XVII is then oxidized to provide Compound XVIII. This reaction is usually achieved using Jones' reagent in acetone at reaction temperatures of from -15 to -20C.
After the appropriate amount of Jones' reagent has been added, the reaction usually stirred for an addi~ional 15 or 20 minutes and then quenched by the addition of isopropyl alcohol. The product is then isolated in the usual way.
Ketone XVIII is then converted to the desired prosta-glandin or its analog by the hydrolysis of the protecting groups in the same manner and under the same conditions as described for the transformation of Compound IX to Compound X. The result-ing Compound XIX may be then purified, if desired, by column chromatography on silica gel.

o CICI~"

~ Q
~A

~ IV
OCR"

R ~ ~A
x~r OH

O- . . .
O~_R" O

~_~//yA HO ' ~
XVI H .R XIX H ~OH
.
.

OH . o - \ ~ Q <~ ~ \ c/ /\Q
!I~A ~ " ~,~ /

XVII XVIII

- ' '`c~ m~ i~

'I'he ~trious steps lllustrate~ Scnem~s B and C start-in~ 0m .ompo~ ls V3I and X~ and leadln(~ to prosta~landin analot~ of ~orm-~la i~IX a:r~ an~loqous ~ methods ~.no~n in th~ a~t but the production of the iTlt ermediate compountls VII and XIII
fxom the key nemit:hioacetal inte~mediate of For.m~lla VI is novel and provides, a surprisil-~ and advanta~eous route for ~he prep~ra-tion of the final prostaglandi.n products.
Accoraingly the inventi~n still further provides in a p~ocess for preparing ~. prostaglc~nain ~rom c.~n optically active aldehyae intel-mediate of the formula:

OR' .' C~IO (VIIA) its opcical antipode and the racemic ~ ture thereof, wherein ~' is hydrog~n or -~R" and R" ls alk~l of from one to four carbon atoms, ~-naphthyl, phenyl, p-biphenyl or ph~nylalkyl of from seven to nine carbon atoms; R i~ hydrogen, tetrahydropyran-2~yl oxy or dimethyl-t-butylsilyloxy, and Q is te~razol-5-yl, -CNH~R"', -CNHS~2R"' or -~OR, wherein R is hydrogen, alkyl of one to ~i~ carbon atoms, phenyl, phenylalkvl of frorll 7 to 9 carbon atom~ -naphthyl, or ~=biphen~rl and R"' is alkyl of one ~`co four carbon atoms or phenvl, by methods known in th~ art, the ir.~provement which compIises preparin~ the aldehyde of Formu:l.ct (VII~) by reacting an op~ically act.i~ compound of the ~ormula:

.

5~
~R' . .

,~ .
R- ~ ~
~ ~___~(Cll2)m (VIA) its opti.cal .anti.pode or the raremic miV~ture thereof, wherein R', R and Q are as defir.ed above and m is two ox three, with mercuric chloride in a reaction-i:n_rt solvent at a temper.lture from 25 to 80C. UI~til the reaction is su~stantially complete.
~ preferred embodimen~ of the above process is that wherein the intermediate of Formula (VII~) is all a].dehvde com-pound ~?herein Q is -~NHSO2Ci~3, ~' is -~CH3 and R is tetrahydro-pyran-2-yloxy and the final prostaglandin product is N-methane-sulfonyl 9-o~o-11~ ,15~-dihydroxy-16-phenGxy 5-cis-13-trans-17,13,1a,20-tetranorprostadienamide.
For the preparation of ll-desoxy analogs of prost.a-glandins the hemithioacetal intermediate of Formula ~7I ~her2in R is hydrogen is p.repared from ~he known lac~.one III' by the same method as tnat illustrated ir. Scheme A above by the reac-tion sequence illustratecl ln Scheme D which follo~ls .

: ~ . . . ~

o-~<o - ~o ~ Q`
~o ~, I' O~
/, III ' .;

O--~H OH .

~\ R ~

YI (R = H) V' ' , . ' .

Scheme D

-22-- .

. .~ . .

''" ;' ~ "' ' , ' ~s~

As used herein all the structural formulas are meant to represent either an optically active compound, its antipode or a racemic mixture of the two.
It will be appreciated by those skilled in the ar~
that the foregoing synthetic sequences of the present invention possess the broad flexibility very much to be deslred in the preparation of prostaglandin ana:Logs.
In the sequences aescr:Lbed above, a considerable latitude exists in the selection of the protecting group used at a particular stage. Thus, in protecting alcohols, dihydropyran-yloxy groups or dimethyl-t-butyl silyl groups may be employed in those situations where the protecting group is represented in the Formulae as R. Similarly the acyl group o Compounds XII
~hrough XVI may be selected f~om a broad range of acyl groups such as formyl or alkanoyl of from 2 ~o 4 carbon atoms, ~-naphth-yl,carbonyl, benzoyl, parabiphenylcarbonyi or phenylalkylcarbonyl wherein an alkyl group may be of from 7 to 9 carbon atoms.
In numerous ln vivo and in vitro tests we have demon-strated that the prostaglandin analogs prepared by the process of the present invention possess physiological activities com-parable to those exhibited by the natural prostaglandins. ~hese tests include, among others, a test for e~fect on isolated smooth muscle from guinea pig uterus and rat uterus, inhibition of histamine-induced bronchospasm in the guinea pig, and effect on dog blood pressure, inhibition of stress-induced ulceration in the rat, inhibition of gastric acid and pepsin secretion in rat and dog, inhibition of collagen or ADP-induced blood plate-let aggregation and abortifacient activity in rats and guinea pigs by luteolytic and non-luteolytic mechanisms.
The physiological response~ observed in these tests ~;

~35~

are use~ul in det~rmining the utility of the test substance for the treatment of various natural and pathological conditions.
Such determined utilities include: antihypertensive activity, bronchodilator activity, antithrombo~enic activity, antlulcer activity, smooth muscle activity tuseful as an anti-fertility agent, for the induction of labor, and as an abortifacient); and anti-fertility activity through a mechanism not affec-ting smooth muscle, for example, luteolytic mechanisms, and the synchroniza-tion of the estrous cycle in farm animals.
The prostaglandin analogs prepared by the process of this invention possess more selective activity profiles than the corresponding naturally occurring prostaglandins, and in many cases, exhibit a longer duration of action. For axample, N-methanesulfonyl 16-phenoxy-~-tetranorprostaglandin E2 carbox-amide which exhibits smooth muscle stimulating activity comparablt to PGE2, is inactive in inhibition of histamine-induced broncho-spasms in guinea pigs. Furthermore, although the threshold dose of hypotensive response of N-methanesulfonyl 16-phenoxy-~-tetranor PGE2 carboxamide in dogs is higher than that of PGE2.
Another prime example of the therapeutic importance of these prostaglandin analogs is the efficacy of 2-descarboxy-2-(tetrazol-5-yl)-11-desoxy-16-phenyl-~-tetranorprostaglandin E2 and 2-des-carboxy-2-(tetrazol-5-yl)-11-desoxy-16-(p-fluorophenyl)-~-tetra-norprostaglandin E2 which exhibits hypotensive activity of gr~at-ly enhanced potency and duration as compared with PGE2 itself.At the same t:ime, the smooth muscle stimulating activity is markedly depressed in comparison with PGE2.
Particularly useful for fertility control, abortion and induction of labor are the 16-phenoxy-~-tetranorprostaglandins . 30 15-indanyl~ pentanorprostaglandins and 17-aryl-~-trisnorprosta-~ ~24-glandins of the E2 and F2U series based on especially outstand-ing smooth muscle stimulating activity, and at the same time reduced diarrheal, bronchodilator or blood pressure effects.
Particularly useful for antiulcer activity are the 16-aryl-t~-tetranorprostaglandins of the E2 series based on out-standing antiulcer and antisecret:ory activi~y and ak the same time reduced diarrheal and smooth muscle effects.
Also useful for antihypertensive activity are the

2-descarboxy-2-(tetrazol-5-yl)-11-desoxy-16-aryl-~-tetranor-prostaglandins of the E2-series based on outstanding oral hypo-tensive activity and at the same time reduced diarrheal and smooth muscle effects.
The prostaglandin analogs which have a beta hydroxyl at C15 have action which is similar to their epimers. In some cases, however, the selectivity that these compounds di~play exceed~ that of the epimeric compounds.
For induction of abortion, tablets or an aqueous SU8-pension or alcoholic solution of the 15-substituted ~-pentanor-prostaglandins of the E and F serie~ would appropriately be administered at oral doses of about 0.1-20 mg., with 1-7 dose~
per day being employed. For intravaginal administration a ~uit-able formulation would be lactose tablet~ or an impregnated tampon of the same agent. For such treabments suitable dose~
would be from about 0.1-20 mg./dose with 1-7 doses being employ-ed! For intra-amniotic administration a suitable formulation would be an aqueous solution containing 0.05-10 mg./dose with 1-7 doses being employed. For extra-amniotic administration a suitable ~ormulation would be an aqueous solution containing 0.005-1 mg./dose with 1-5 doses being employed. Alternatively, the 15-substituted-~-pentanorprostaglandins of the E and F

series of this invention can be infused intravenously for induc-tion of abortion at doses of 0.05-50 ~g./minute for a period of from about 1-24 hours.
Another use for the 15-substituted-~-pentanorprosta-glandins of the E and F series is as an inducer of labor. Forthis purpose an Pthanol-saline solution is employed as an intra-venous infusion in the amount of from about 0.1-10 ~g./kg./min.
for from about 1-24 hours.
Another use for the 15-substituted-~-pentanorprost~-glandins of the E and F series is for fertility control. Forthis purpose a tablet is employed for intravaginal or oral admin-istration containing 0.1~20 mg. of prostaglandin per dose with 1-7 doses being employed at or following the expected day of menstruation. For synchronization of the estrous cycle in pigs, sheep, cows or horses, a solution or suspension containing 0.03-30 mg./dose of 15-substituted-~-pentanorprostaglandin of the E
- and F series is administered subcutaneously from 1-4 days.
15-Substitutèd-~-pentanorprostaglandins of the E series are useful gastric antisecretory and antiulcer agents. For treatment of peptic ulcers these compounds are administered preferably orally in the form of capsules or tablets at doses of 0.001 to 0.1 mg./kg./day.
The 15-substituted-~-pentanorprostaglandin analogs of the E series of the present invention are useful hypotensive agents. For treatment of hypertension these drugs could appro-priately be administered as an intravenous injection at doses of about 0.5-10 ~g./kg. or preferably in the form of capsules or tablets at doses of 0.005 to 0.5 mg./kg./day.
To prepare any of the above dosage forms or any of the numerous other forms possible, various reaction-inert diluents, .. ' .

, , - ;

59~L~

exci~ients or carriers may be employed. Such substances in-clude, for example, water, ethan~l, gelatins, lactose, starches, magnesium stearate, talc, vegetable oils, benzyl alcohols, gums, polyalkylene glycols, petroleum jelly, cholesterol and other known carriers for medicaments. If desired, these pharmaceu-tical compositions may contain auxiliary substances such as preserving agents, wettin~ agents, stabilizing agents, or other therapeutic agents such as antibiotics.
The following Examples illustrate the preparation of intermediates and prostaglandin final product5 according to the process of the invention. Melting points and boiling points are given in degrees Centigrade and are uncorrected. Infrared data are given in microns and NMR data are given in part~ per million and using a TMS standard.
EXAMPLE I
2-~3-(~-biphenylcarboxy)-5~-hydroxy-2~-(2-thioxalanyl)cyclopent-1~- l]acetic acid, -lactone (II) Y . Y _ .
To a solution of 2-[3a-(p-biphenylcarboxy)-5a-hydroxy-2~-formyl cyclopent-l~-yl]acetic acid, y-lactone (21 g., 0.06 mole) in dry methylene chloride (500 ml.) and 2-mercaptoethanol (4.68 g., 0.06 mole) cooled to 0C. under nitrogen was added boron trifluoride etherate (4 ml., 0.03 mole) over a 15 minute period. The resultant solution was warmed to room temperature and stirred for two hours. The reaction was diluted to 900 ml.
with more methylene chloride and washed with water (2 x 100 ml.).
Drying the methylene chloride layer with anhydrous Na2SO4 follow-ed by filtering and evaporating under reduced pressure yialded an oil which ~solidified upon trituration with hexane. Filtra-tion, washing with hexane and drying under vacuum yielded the . title compound (23.9 g., 97% yield) m.p. 146 .
I

Substitution of 3-mercapto-1-propanol for 2-mercapto-ethanol in the above procedure will provide the corresponding homologous protected aldehyde which may be conver~ed into the E2- and F~-prostaglandins by the procedures of Examples II-XVIII.
EXAMPLE Ia 2-[5a-hydroxy-2~-(2-thioxalanyl)cyclopent-1~-yl]acetic acid, r-lactone (III') To a solution of 2- [5a-hydroxy-2~-formylcyclopent-lu-yl]acetic acid, y-lactone (18.5 g., 0.12 mole) in dry methylene chloride (500 ml.) and 2-mercaptoethanol (9.36 g., 0.12 mole) cooled to 0C. under nitrogen is added boron trifluoride ether-ate (8 ml., 0.06 mole) over a 15 minute period. The resultant solution is warmed to room temperature and stirred for two hour~.
The reaction is diluted to 900 ml. with more m~thylene chloride and washed with water (2 x 100 ml.). Drying the methylene chlor~
ide layer with anhydrous Na2SO4 followed by filtering and evapor-ating under reduced pressure yields the title compound.
The product of this Example may be converted into 11-desoxyprostaglandins by the procedures of Examples IV-XVIII.
Treatment of the formyllactone starting material with 3-mercapto-l-propanol under the above described conditions provides the corresponding protected aldehyde which may be converted into the ll-desoxyprostaglandins by the procedures of Examples IV-XVIII.
EXAMPLE II
2- r 3~,5a-dihydroxy-2~-(2-thioxalanyl)cyclopent-1-yl]acetic acid, y-lactone (III) A heterogeneous mixture of crude 2-[3a-(p-biphenylcarb-oxyj-5a-hydroxy-2~-(2-thioxalanyl)cyclopent-1]-yl acetic acid, y-lactone (23.5 g., 0.057 mole) absolute methanol (230 ml.) and ' ~ ':

finely powdered anhydrous potassium carbonate (3.95 g., 0.028 mole) was stirred at room temperature overni~ht. The pre~ipit-ated solid was filtered and washed with methanol. The filtrate was evaporated to approximately lO0 ml. and cooled in ice. To the cooled solution was added 0 lN HCl dropwise to bring the solution to a pH of 3, and the precipitated solids were filter-ed off. The aqueous layer was saturated with solid sodium chloride and extracted with ethyl acetate (3 x 50 ml.). Drying the combined organic layer with anhydrous Na2S04 followed by evaporation gave the title compound (12.6 g., 96% yield).
ExAMæLE III
2-[3a-(tetrahydropyran-2-yloxy)-5a-hydroxy-2~-~2-thioxalanyl) cyclopènt-la-yl]acetic acid, y-lactone (IV) _ _ To a cooled solution (0-5) of crude 2-[3~,5a-dihydroxy-2~-(2-thioxalanyl)cyclopent-la-yl]acetic acid, y-lactone (2.5 g., lO.9 mmoles) and freshly distilled dihydropyran (1.47 ml., 16.3 mmoles) in dry methylene chloride (25 ml.) was added ~-toluene-sulfonic acid monohydrate (250 mg., 1.31 mmoles). The reaction mixture was stirred for 1.5 hours at 0C., then diluted with ether (60 ml.). The organic solution was wa~hed with ~aturated sodium bicarbonate (10 ml.), saturated brine (10 ml.) and dried over anhydrous sodium sulfate. Concentration under vacuum afforded the title compound (3.4 g., 100~ yield) as an oil.
EXAMPLE IIIa 2-[3a-(dimethyl-t-butylsilyloxy)-5a-hydroxy-2~-~2-thioxalanyl)-cyclopent-la-yl]acetic acid, ~-lactone (IV) A mixture of 2-l3,5a-dihydroxy-2~-(2-thioxalanyl)cyclo-pent-la-yl~acetic acid, y-lactone (2.25 g., 10 mmoles), dimethyl-t-butylsilyl chloride (1.88 g., 12.5 mmoles) and imidazole (1.87 g., 27.5 mmoles) in 5 ml. of dimethylformamide is stirred under . .

.
-:
.

nl~rocJen at 37 ~or 1~ hour.s~ Tile rc~lcti.on is conccnt.rated undcl l-ed~c~ yressu~e anc~ di.ll~ted wir.h mc-th~le~e chloride. q'ne orq2nic solu~ic;n is ;~s]l~cl with t~atcr~ dr.iecl (~nhyd:~ous mac~nes-ium sulfcnte) and concentra',:e,~ undcr reduced pressure. Purifi-catioll o~ the crude product ~y si'~.i.ca gel cl-rorl~atocJraphy pro-vides the title compound.
Tha product o~ ~nis '.xample may be converted into tne ll-hydroxyprostaglandins by the procedures o~ Examples IV-XVII.
X~PJE IV
2-13cl-(tetrahydropyran-2-~loxyj~5~-hydroxy-2~-(2-thio~alanyl)-cyclopent-l~-yl~ac~t ldenyde, y-hemiacetal (V) _.
To a solution, cooled to -75 undex nitrogen, of crude 2-~3a-~tetrahydropyr~n-2--yloxy)-5~-hydroxy-2~-(2-thio~alanyl)-cyclopent-lG-yl]acetic acld, y-lactone (3.24 c3., 10.3 mmoles) in dry toluelle (50 ml.) was added over a period of 25 minutes a 20C~ solution of diisobutylaluminum hyc~ride in hexane (14.9 ml., 1~.0 mmoles). Ater an .additional 30 minutes the reaction was quenchecl by dropt~ise addition of methanol an~ allowed to warm to roo.n temp~rature. Ihe toluene t~as evaporated under reduced pressure and the residue diluted-with ether (200 ml.). Th~
organic solution was washed with a 50% sodium pot~ssiùm tartrate solution (3X~, sa~urated brine, then dried with anhydrous Na2SO~
alld was concent.rated to a~ford the ti,l.e compound (3.1 g., 95%
yield) as an oil. T}~e product w~s purified by column chromato-`25 ~-aph~ Oll 90 ~. o ~aker silica ~el (60-200 mesh) us.i.n~ benzene-~
ethyl acetate as eluents to give the pure title compound (2.9 ~.).
Th~ product of this Example ma~ be treated with a phos p'.l~rane of the s~.ructure ~ r wh~reil Q' is t~tra.zo~
03~(C~ Q' -~N)!~`R'`', -~NIISO~"' or ~O~, w!lereir. R"' is al.~yl oE fro~ one t~

. 30-5~

~ur carbo.~.l a~c~ms, accor~incJ -to thc! proc~lures o~ ~xamr,l~ V. The proluc~: of ~hi`-- rc~a~-ion may b~ converted into thi~ and F~
proslagla..~lins by thc- procedures o Examp:les VII-~ and XI~XVI.I.

EX~MrL5 7~2~B-(7-t}lio~alanyl)-3~(tetl-all~ydrop~ran-2-yloxy)-S~-h,~d.roxy-cy.lopent~ yl.]-cls~5-heptenoic acid (VI) To a solution o~ 5-triphenylphosphoniopentalloic acid (23.045 g., 52,0 mmoles) in dry dimethyl, sulfoxide (46 ml~) wa.s added dropwise an approxima~ely 2.0N solution.of sodium methyl-sulfinylmethylide (49.3 .nl., 98.6 mmoles) in dimethyl sulfo.~ide.
To ihe resultant red soluti.on was added over the course of 1.0 h~ur a solution of 2-[2~B-~2-thioxalanyl)-3iî-(tetrah~Jdropyran-2--yloxy)-5~-hydroxycycloper~ -yl]acetaldellyde, y-heiniacet21 (6.6 g., 20.~ mmoles) in dry dimethyl sulfoxide (~3 ml.). A~ter being stirred for an addi~ional half hour, the react1.on was pour-ed in-lo ice-t~ater (600 ml.j. The basi-c aqueous solution was ex tracted with 2:1 mixture of ethyl acetate:ether ~2 x 300 ml.).
The cold aqueous la~er was co~tered with ethyl acetate an~d acidif.i-ed to pH -3 with 10% hydrochloric acid. The aqueous 1ayer was further extracted with ethyl acetate (2 x 200 ml.) and the com-binecl organic e~tracts were ~ashed with ~7ater followed by hr;.ne~
Dry~g the orylnic layer over anhydrous sodi~ sulfate and con-centrating afiorded a yellow oil weighing 20 g. ~ddit.ion of 15~ ml. of a mixture of ethyl acetat~:ether (~:l) precipi-`-ated a so1id which was filtered, washed with ether and the filtra1-e e~apo~ated. The yield of crude title compound was lO~.~ g. (:12Q~;) ~hich was used directlv .in the ne.~t step.
Th~ liroduct of this ~x~m~le m~y ~C? estcri~i.ed ac~ordi.n~3 to.the ~..ocedure ~r Exc~mpl.e ~7a wlt:h ~n ~l~;yl d.;.a.~o colllpollnd oS.' 0 ~ om co~ t:o six c,~ rl atc~rnY c)r pher~ lkyl di<~,ro c~olr,poulld oi:
' ~3~- ' , ~ ~

s~

from seven to nine carbon atoms. Alternatively, one equivalent of the product of this Example may be cont~cted with ten equiv-alents of phenol, ~-naphthol or p-phenylphenol and 1.2 equival-ents of dicyclohexylcarbodiimide. The resultant esters may be converted into the E2- and F2~-~?rostaglandins by the procedures of Examples VI-IX and XI-XVII~
EX~?LE Va Methyl 7-~2~-(2-thioxalanyl)-3a-(tetrahydropyran-2-yloxy)-5~-hydroxycyclopent-la-yl]-cis-5-heptenoate (VI) A solution of 7-[2~-(2-thioxalanyl)-3~-(tetrahydropyran-2-yloxy)-5~-hydroxycyclopent-1~-yl]-cls-5-heptenoic acid (520 mg., 1.3 mmole3) in 5 ml. of anhydrous ether is titrated at room temperature with an ethereal dia~omethane solution until the yellow color persists for 5 minutes. The reaction is then decolorized by the dropwise addition of glacial acetic acid. The ethereal solution is then washed with saturated sodium bicarbon-ate and saturated brine, is dried (anhydrous magnesium sulfate), and is concentrated under reduced pressure to provide the title compound.
The product of this Example may be converted into E2-and F2a-prostaglandins by the procedures of Example~ VI-IX and XI-XVII.
EXAMPLE VI
7-[2~-formyl-3a-(tetrahydropyran-2-yloxy)-5a-hydroxycyclopent-la-yl]-cis-5-heptenoic acid (VII) To a solution of 7-[2~-(2-thioxalanyl)-3a-(tetrahydro-pyran-2-yloxy)-5a-hydroxycyclopent-la-yl]-cis-5-heptenoic acid (2.0 g., o.0ocj mole) 4:1 acetonitrile:water (85 ml.) was added sequentially anhydrous calcium carbonate (2.87 g., 0.029 mole) and mercuric chloride (5.4 g., 0.020 mole). The mixture was !

' ~s~

stirred and heated at 50OC. under nitrogen -Eor a half hour. The mixture was filtered through Celite and washed with ether (250 ml.). The combined ~iltrate was stirred and treated with lN
hydrochloric acid (3 ml. ) . The ether layer was separated and washed with brine (3 x 15 ml.). Drying over anhydrous sodium sulfate and concentration at recluced pressure afforded 1.7 g.
(100~) of the title compound as an oil.
The product of this Example may be treated with a phosphonate of the formula (MeO)2~CH2~A wherein A is alkyl of from four to eight carbon atoms, 2-indanyl, or a ~ubstituent of the formula Ar(CH2)n- or Ar'OCH2- wherein n is one or two and Ar is ~-naphthyl, ~-naphthyl, ~-furyl, ~-thienyl, phenyl or mono-substituted phenyl in which the substituent is fluorine, chlorine, trifluoromethyl, phenyl or alkyl or alkaxy of from one to six carbon atoms; and Ar' is phenyl or monosubstituted phenyl in which the substituent is fluorine, chlorine, trifluoromethyl, phenyl or alkyl or alkoxy o~ from one to six carbon atoms accord-ing to the procedures of Example VII or XIII. The product of this reaction may be converted into the PGF2~,S by the procedures of Example VIII and IX.
EXAMPLE VII
9~-hydroxy-ll~-(tetrahydropyran-2-yloxy)-15-oxo-cis-5-tran3-13-prostadienoic acid ~VIII) To a solution, under nitrogen, of dimethyl(2-oxo-heptyl)-phosphonate -(2 g., 0.009 mole) in dimethoxyethane (30 ml.) cooled to 0C. was added dropwise 2.2M n-butyl lithium (3.96 ml., 0.0087 mole). After stirring for one hour 7-~2~-formyl-3a-(tetrahydro-pyran-2-yloxy)-S~-hydroxycyclopent-la-yl]-cls-5-heptenoic acid (1.02 g., 0.003 mole) dissolved in dimethoxyethane (6 ml.) was added quickly and the mixture stirred at room temperature for a ..;

~ 5 9 ~

half hour, it was brought to pll ~7 with glacial acetic acid.
The neutralized solution was concentrated by rotary evaporation and the resultant solid was slurried in benzene and filtered.
Concentration of the filtrate afforded the crude title compound which was purified by chromatography on silica gel using benzene~ethylacetate as eluant to give the pure title compound (710 mg.).
The product of this Example may be acylated according to the procedure of Example XI to form the product of Example XIII.
EXAMPLE VIII
9~-15}dihydroxy-lla-(tetrahydropyran-2-yloxy)-c~s-5-trans~13-prostadienoic acld (IX) To a solution of 9~-hydroxy-11~-~tetrahydropyran-2-yl-oxy)-15-oxo-cis-5-trans-13-prostadienoic acid (0.15 g., 0.343 mmole) in dimethoxyethane ~3 ml.) was added a 0.5M solution of zinc borohydride (1.75 ml., 0.17 mmole) in dimethoxyethane. The reaction was stirred at room temperature under nitrogen for 2.5 hours then was cooled in ice. The cold reaction mixture was quenched by the addition of a saturated sodium bitartrate ~olu-tion dropwise until hydrogen evolution ceased. The mixture was diluted with ethyl acetate (25 ml.), acidified to about pH 4 wi~h cold lN HCl with rapid stirring. The ethyl acetate layer was dried with sodium sulfate and concentrated to afford the oily epimeric mixture of the title compounds weighing 0.13 g., (Rf 0.25 on t.l.c~ using 15:5:7 mixture of benzene:dioxan-formic acid as eluant), suitable for directly using in the next step.
EXAMPLE IX

~ PGF (X) A homogeneous solution of crude 9~,15-dihydroxy-lla-.~ -3~-:.

(tetrahydropyran-2-yloxy)-cis-5-trans-13-prostadienoic ~cid (0.117 g., 0.267 mmole) in a 65:35 mixture of ylacial acetic acid:water (5 ml.) ~as stlrred under nitrogen at room tempera-ture for 16 hours then was concentrated by rotary evaporation followed by oil pump at 25~C. I'he resultant oil was chromato-graphed on 5 g. silica gel (CC-7) using chloroform~ethyl acetate to give 15 mg. 15-epi-PGF2~ followed by 30 mg. o~ PGF2~, ident-ical with an authentic sample by IR and NMR.
EXAMPLE X
~i~ N-Methanesulfonyl 7-[2~ 3-oxathialan-2-yl)-3a-(tetrahydro-pyran-2-yloxy)-5~-hydroxycyclopent-la-yl]-cis-5-heptenamide tvI) .
To a solution of 27.0 g. (52.0 mmoles) of (4-methane-sulfonylaminocarbonyl-n-butyl)triphenylphosphonium bromide in 46 ml. of dimethyl sulfoxide is added dropwise 49.3 ml. (98.6 15 mmoles) of a 2.OM solution of sodium methylsulfonylmethylide in dimethyl sulfoxide. To the resultant red solution is added over the course of 15 minutes a solution o 6.6 g. (20.8 mmoles) of the hemiacetal prepared in Example IV in 63 ml. of dimethyl sulf-oxide. After being stirred for an additional 2.0 hours, the re-20 action is poured onto 600 ml. of ice-water. The cold aqueous layer is covered with ethyl acetate and acidified to pH ~3 with 10~ hydrochloric acid. The acidified aqueous layer is further extracted with ethyl acetate (2 x 200 ml.) and the combined organic extracts are washed with water followed by brine. Drying 25 the organic layer over anhydrous sodium sulfate and concentration affords the cxude product which is triturated with ether. Concen-tration of the ether provides N-methanesulfonyl 7-[2~-(1,3~
oxathialan-2-yl)-3~-(tetrahydropyran-2-yloxy)-5~-hydroxycyclo-pent-~ yl)]-c:is-5-heptenamide (VIj.
The product of this Example may be acylated according to . . ~ ,.~

the procedure of Example XI employing either (R"~)20 or R"~Cl wherein R" is alkyl of from one to four carbon atoms, ~-naphthyl, phenyl, ~-biphenyl or phenylalkyl of from seven to nine carbons.
This product may be converted into the E2-prostaglandins accord-ing to the procedures of Examples XII-XVIII.
EXAMP.LE XI
N-Methanesulfonyl 7-[2~-(1,3-oxathialan-2-yl)-3~-(tetrahydropyran-2-yloxy)-5~-acetoxycyc~_~_ent-1~-yl]-cis-5-heptenamide (XII) A mixture of 1.69 g. (3.54 mmoles) of the crude hydrox~
compound VI prepared in Example X, S.0 ml. of pyridine and 0.368 ml. (3.89 mmoles) of acetic anhydride is stirred under nitrog2n at 50 overnight. The mixture is then cooled to room tempera-ture and is diluted with ether (75 ml.). The ethereal solution is washed with water (lx) and with saturated copper sulfate (3x), is dried (anhydrou~ magnesium sulfate), and is concentrated to afford the desired N-methanesulfonyl 7-[2B-(l~3-oxathialan-2-yl)

3~-(tetrahydropyran-2-yloxy)-5-acetoxycyclopent-1~-yl]-cis-5-heptenamide (XII).
EXAMPLE XII
N-Methanesulfonyl 7-~2~-formyl-3~-(tetrahydropyran-2-yloxy)-5~-acetoxycyclopent-la-yl]-cis-5-he~tenamide (XIII) To a solution of 2.9 g. (5.0 mmole~1 of the hemithio-acetal XII prepared in Example XI in 85 ml. o~ acetonitrile:water (4:1) is added sequentially ~.87 g. (0.029 mmole) anhydrous calcium carbonclte and 5.4 g. (0.020 mmole) mercuric chloride.
The mixture i~ stirred and heated at 50 under nitrogen for 0.5 hr. The mixture is filtered through Celite and washed wi~h 250 ml. ether. The combLned flltrate is stirred and treated with 3 mL. of lN hydrochloric acid. The ether layer is separated and washed with brLne (3 x 15 ml.). Drying over anhydrou~ sodium ~ 9 ~ ~ ~

sulfate and concentratlon at reduced pressure afforded the de-sired N-methanesul~onyl 7-[2~-formyl-3~-(tetrahydropyra~-2-yl-oxy)-5~-acetoxycyclopent-1~-yl]-cls-5-heptenamide (XIII ~ .
The product o~ this Example may be treated with a phos-phonate of the formula (~eO~2~CH~A whereln A is alkyl of from four to eight carbon atoms, 2-indanyl, or a substituent of the formula Ar(CH2)n- or Ar'OCH2- wherein n is one or two and Ar is ~-naphthyl, ~-naphthyl, ~-furyl, ~-thienyl, phenyl or monosub-stituted phenyl in which the substituent is fluorine, chlorine, trifluoromethyl, phenyl or alkyl or alkoxy of from one to isix carbon atoms; and Ar' is phenyl or monosubstituted phenyl in which the substituent is fluorine, chlorine, trifluoromethyl, phenyl or alkyl or alkoxy of from one to six carbon atoms accord-ing to the procedures of Examples VII or XIII. The product of 15 ~ this reaction may be converted into the E2-prostaglandins by the procedures of Examples XIV-XVIII.
EXAMPLE XIII
N-Methanesulfonyl 9a-acetoxy-lla-(tetrahydropyran-2-yloxy)-15-oxo-5-cis-13-trans-16-phenoxy-~-tetranorprostadlenamide (XIVL
To a suspension of 220 mg. (5.22 mmoles) of a 57.0%
dispersion of sodium hydride in mineral oil in 20 ml. of tetra-hydrofuran is added l.34 g. (5.22 mmoles) of dimethyl 2-oxo-3-phenoxypropyl phosphonate. The mixture is stirred at room temperature for 1 hour under ni~rogen, then a solution of 1.23 g. (2.37 mmoles) of the crude aldehyde XIII prepared in Example XII in 4 ml. of tetrahydrofuran is added. The resultant mix-ture is stirred at room temperature for 2.0 hours under nitrogen.
The reaction is then quenched by the addition of glacial acid ~ to pH ~6 and i.s concentrated by rotary evaporation.

The resultant mixture is dissolved in ethyl acetate, ;9~

the organic layer is washed with 0. lN hydrochloric acid, wa-ter and saturated brine, is dried (anhydrous magnesium sulfate) and concentrated. Puriflcation o~ the crude product by column c~romatography affords the desired N-methanesulfonyl 9~-acetoxy-11~-(tetrahydropyran-2-yloxy)-15-oxo-5-cis-13-trans-16-phenoxy-~-tetranorprostadienamide (XIV).
EXAMPLE XIV
N-Methanesulfonyl 9~-acetoxy-llu-(tetrahydropyran-2-yloxy)-15~-hydroxy-l6-~enoxy-5-cis-l3-trans-~-tetranorprostadienamide (XVa) and N-Methanesulfonyl 9a-acetoxy-11-(tetrahydropyran-2-yloxy)-15~-hydroxy-l6-phenoxy-5-cis-l3-trans-~-tetranorprostadienamide (XVb) To a solution, cooled to -78 under nitrogen, of 1.24 g.
(2.1 mmoles) of the lactone XIV prepared in Example XIII in 12 ml. of tetrahydrofuran is added 4.3 ml. of a l.OM solution of lithium triethylborohydride in tetrahydrofuran. The mixture is stirred in the cold for 45 minutes then quenched by the addition of a 9:1 mixture of water:acetic acid. The mixture is let warm then diluted with ethyl acetate. The organic solution is washed with water (2x) and saturated brine, is dried (anhydrous magnes-ium sulfate) and concentrated. Purification of the crude product by column chromatography provides first N-methanesulfonyl 9a-acstoxy-ll-(tetrahydropyran-2-yloxy)-15~-hydroxy-16-phenoxy-5-c -13-trans-~-tetranorpros~adienamide (XVb) and further elution provides N-methanesulfonyl 9a-acetoxy-11-(tetrahydropyran-2-yl-oxy)-15-hydroxy-16-phenoxy-5-cis-13-trans-~-tetranorprost,adien-amide (XVa).
The 15~-compounds of this Example may be converted into the 15-epi-E-prostaglandins by the procedures of Examples XV-XVIII.

: -., ~, . - .
:' ~

EXAMPLE XV
N-Methanesulfonyl 9~-acetoxy~ ,15~-bis-(tetrahydropyran-2-yl-oxy)-16-phenoxy-5-cls-13-trans-ll)-tet:ranorprostadienamide (XVI) A mixture of 0.303 g. (0.510 mmole) of the chromato-graphed alcohol XVa of Example XIV, 0.14 ml. (1.53 mmoles) of dihydropyran, 4.2 ml. of methylene chloride, and l crystal of ~-toluenesulfonic acid monohydrate is stirred at room temperature under nitrogen for 20 mlnutes. The reaction mixture is then diluted with ether, is wa~hed with water and saturated brine, is dried (anhydrous magnesium sulfate), and concentrated to give the desired N-methanesulfonyl 9~-acetoxy-11~,15~-bis-(tetrahydropyran-2-yloxy)-16-phenoxy-5-cls-13-trans-~-tetranor-prostadienamide (XVI).
EXAMPLE XVI
N-Methanesulfonyl 9~-hydroxy-11~,15~-bis-(tetrahydropyran-2-yl-oxy)-16-phenoxy-5-cis-13-trans-~-tetranorprostadienamide (XVII) A homogenous solution of 0.295 g. (0.436 mmole) of the crude bis-THP ester XVI prepared in Example XV, 1.3 ml. (1.30 mmoles) of a l.ON aqueous sodium hydroxide ~olution, 1.3 ml. of methanol, and 1.3 ml. of tetrahydrofuran is stirred under nitro-gen overnight. The reaction is then quenched by the addition of 1.30 ml. (1.30 mmoles) of a l.ON aqueous hydrochloric acid ~olu-tion. The quenched solution is diluted with ethyl acetate. The organic layer is dried (anhydrous magnesium sulfate) and concen-trated. The crude product is purified by column chromatography to afford the desired N-methanesulfonyl 9~-hydroxy-11~,15~-bls-(tetrahydropyran-2-yloxy)-16-phenoxy-5-cis-13-trans-~-tetranor-prostadienamide (XVII).

X .

, ' , EXAMPLE XVII
~-Methanesulfo~yl 9-oxo-ll~,lS~-bis-(tetrahydropyran-2-yloxy)-16-phenoxy-5-cis-l3-trans-~-tetranorprostadienamide (XVIII) To a solution, cooled under nitrogen to -15 to -20 of 236 mg. (0.371 mmole) of the chromatographed methanesulfonimide XVII in Example XVI in 4.0 ml. of acetone is added dropwise 0.163 ml. (0.408 mmole) of Jonesl reagent. The reaction is stirred in the cold for 15 minutes then is quenched by the addi-tion of 0.194 ml. of isopropanol. The quenched reaction ls stirred in the cold for 5 minutes then is diluted with ethyl acetate. The organic solution is washed with water (2x) and saturated brin~ (lx), is dried (anhydrous magnesium sulfate), and is concentrated to afford the desired N-methanesulfonyl 9-oxo-11,15~-bis-(tetrahydropyran-2-yloxy)-16-phenoxy-5-c -13-trans-w-tetranorprostadienamide (X~III).
EXAMPLE XVIII
N-Methanesulfonyl 9-oxo-11~,15~-dihydroxy-16-phenoxy-5-cis-13 trans-~-tetranorprostadlenamide (XIX) A homogenous solution of 208 mg. (0.328 mmole) of the crude THP ether XVIII of Example XVII in 5 ml. of a 65:35 mix-ture of acetic acid:water is stirred under nitrogen at ambient temperature for 18 hours. The xeaction is concentrated by rotary evaporation followed by oil pump. The crude, product is purified by column chromatography on silica gel to provide the desired N-methanesulfonyl 9-oxo-11~,15~-dihydroxy-16-phenoxy-5-cis-13-trans-~-tetranorproRtadienamide (XIX).

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Claims (4)

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

1. A process for preparing an optically active com-pound of the formula:

(VI') its optical antipode or the racemic mixture thereof wherein Q' is a tetrazol-5-yl, , or -COOH; R is hydrogen, tetrahydropyran-2-yloxy or dimethyl-t-butylsilyloxy;
R''' is alkyl of from one to four carbon atoms or phenyl, and m is two or three; which comprises reacting an optically active compound of the formula:

its optical antipode or the racemate thereof with the ylide of a compound of the formula:

in a reaction-inert solvent at a temperature of from -30° to 80°C. until the reaction is substantially complete.

2. A process according to claim 1, wherein Q' is .

3. A process according to claim 1, wherein m is 2.

4. A compound of Formula (VI') as defined in claim 1, when prepared by a process according to claim 1.