CA1093082A - 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

i()9~0~Z

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 the 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' CHO (VIIA) R.
its optical antipode or the racemic mixture thereof, wherein 1~930l~;~
o "
R' is hydrogen or CR" î
R" is alkyl of from one to four carbon atoms, ~-naphthyl, phenyl, p-biphenyl or phenylalkyl of from seven to nine carbon atoms;
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, ~-naphthyl or _-biphenyl; and ~ " is alkyl of from one to four carbon atoms or phenyl,with the proviso that when R is hydrogen or alkyl R is dimethyl-t-butylsilyloxy with ~he ylide of a compound of the formula:

3 \ ., n P ~ CH2 ~ C - A

in a reaction inert solvent at a temper-ture of from 0 to 80C.
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 - (C~2)n or Ar'-O-CH2-wherein n is 1 or 2, Ar is a-naphthyl, ~-naphthyl, ~-furyl, -thienyl, phenyl or monosubstituted phenyl wherein the sub~titu-ent is fluorine, chlorine, trifluoromethyl, phenyl or alkyl or alkoxy of from one to six aarbon atoms, and Ar' is phenyl or monosubstituted phenyl wherein the substituent is fluorine, chlorine, trifluoromethyl, phenyl, or alkyl or alkoxy of from one to six carbon atoms.
A preferred embodiment of the process of the inven-10930~Z

.ic>n i~ that.~lhelei.n the star~:ing compo~nd ha~ tlle ~or~tu1a:

' ~1 ' QCHO ~h~
R (VIIB) An especi.a11y preferred embodlment o the process is that wherein the starting compound has the formula:
o o-~-CH3 O

~ ----~ ``C~S2cH3 .- ~ CHO tVIIC) R~ - - -where;n ~ is as defined above~
- The process for prepaxing a compolmd of Formula I is also preferred when A is ~r(C~I2)- or Ar'~O-CH2- and said process is especia.lly preferred when A is ~6H5-OCH2~
The-present invention ~urther provides a process for preparlng the optica1~y active intermediate compound of the . general formuia ORi ' \~c ' '' . ~- CHO ~VII~) ., ,, ~. . . .
i*~ optica1 antipode or the racemic mi~ture t~.tereof whereir~t R' ~ and Q ~re as de~ined above, which comprises reac~ing an -- .
- op~ically active compound o~ the formu1a: .

. ", ~ ' ' , 1093~3Z
OR' ~O-~S) R (CH23m (VIA) its optic~l ant,i.pode or the racemic mixture thereof, wherein R', R 2nd Q are as defi.ned above a~d m is 2 or 3, wlth mercuric chl.orir~e in a reacti.on-inerl soivent at a temperatuxe o~ from ~5 to 80C. until the reaction is substantially ccmplete..
A pxeferrèd embodiment of.the process is when R' is h~drogen. The process wherei.n R' is hydrogen is further pre-ferred wher Q is COOR, ~7herein R is as defined abot~e. Like~ise the process is preferred when R' is hydrogen and ~ i.s tetraæol-~0 5--yl. The said process wherein R' is hydrogen is especially pre-ferred when Q is CONHSO2R"', and most especiall.y preferred when Q is CONH502CH3 ~ he said process -for preparing the compound of Folmula (VIII~) is also prefer.red when R' is COR" an~ especially when R' is COCH3. The ,said process wherein R' is COCI13 is further pre---' fexxed when Q i 5 COOR or tetrazol-5-yl, and is especially pre-~erred when Q is COMHSO2R"', and most especially preferred t~hen Q is CO~HSO2CH3.
- The present inven1,ion further provides a process for 0 preparin~ all opticall~ act.ive compound of the c~neral formula:
~H

,.S
~-- ~) --~..
~ )m (t~TI 3 it~ opt.ical ~nt.ipode or the racem.i.c mixLure tl~leof wherein R

~0~3C~8Z

is hydrogen, tetrahydropyran-2-yloxy, or dimethyl-t-butylsilyl-oxy; o O O
.. .. .. ..
Q' is tetrazol-5-yl, -CNHCR"', -CNHSO2R"' or -COH;
R"' is alkyl of from one to four carbon atoms or phenyl; and m is 2 or 3, which comprises reacting an optically active compound of the formula:

OH

O ~CH2)m its optical antipode or the racemate thereo~, wherein R and m are as defined above, with an ylide of a compound of the formula-Br ~3 03 - P - (CH2~4 - Q' in a reaction inert solvent at a temperature of from -30 to 80C. until the reaction is substantially complete. Thè proca~s for preparing the compound of Formula III' is preferred when Q
is COOH, or tetrazol-5-yl, and is e~pecially preferrad when O' iB CONHSO2R"' and mo~t especially preferred when Q' is CONHSO~CH3.
Some of the intermediate compounds of Formula (VIIA) are novel and accordingly the pre~ent invention also provides an optically active compound of the formula:
OR' ~ ~ ~ Q

R.- ~ HO
- (VIIA) . .

~093~82 i~5 op~i~al an~iLJo(le and ~he raccmic mixture the.reo~ wherein O
~' is hydrogen or CR";
R" is alk~l of ~rom one to four carbon atoms, B-naph~hyl, phenyl, ~-biphenyl or phenylalkyl of fxom seven to S nine carbon ato~s;
R is hydrogen, tetrahydro?yran-2-yloxy or dimethyl-t-hutylsilyloxy; and Q is tetrazol-5-yl, -~-iCR"', -~NHSO~R"' or -~OR, ~,therein ~. it; h~drogen, alk~l o from one to si~: carhon atoms, phenyl, phenylalkyl of from seven to nine carbon atoms, ~-napht-hyl or ~biphenyl; and R"' is alkyl of from one to four carbon atoms or phenyl, witn th~ proviso that when R is hydrog:e or al~yl R is dimethyl-t-~utylsilyloxy.
Pre~erred compounds of Formula (VIIA) provided by the invention are the following:

(i) an optically active compound of the formula:
O . .

OC-C~3 , ~ ~ Q

: .- CllO
R- .
-- its optical antipod or a xa~emic mixtul-~ thereof, wherei.n R is .
as deined above and wherein Q is COOR and R i~5 as defined aho~e;

. and wher~in Q is CON~S02R"'; especially CONIIS02C~3, or tetr~zul-5 y~ and (ii) a compound of the formula:

OH

~, \l . .
R ~ c{ln _7~. .

... .

.. ' 1093~82 its optical antipode or a racemic mixture 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 CONHSO2R"', especially The invention still further provides an optically active compound of the fo.rmula:
OR' ~" ~ -\Q

O (CH2)m (VIA) its optical antipode or the racemic mixture thereof wherein R' is hydrogen or ~R" and R" is alkyl of from one to four carbon atoms, ~-naphthyl, phenyl, ~-biphenyl or phenylalkyl of from seven to nine carbon atoms; R is hydrogen, dimethyl-t-butylsilyl-oxy, or tetrahydropyran-2-yloxy; Q is tetrazol-5-yl; CNH~CR"', -~NHSO2RI'' or -~OR; 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 tVIA) above are those wherein R' is hydrogen and wherein Q is tetrazol-5-yl; COOR, especially COOH or COOCH3; or CON~SO2R~' especially CONHSO2CH3;
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"I; especially CONHSO2CH3; tetrazol-5-yl; or COOR, especially COOH or COOCH3;
and the optical antipodes or racemic mixtures thereof.
The invention yet further provides an optically active ~0930~2 c~m,?~un~ o~` t:~ f~3~

5~0}1 0~~

~> ,.

~ . 2)m (V) its optical antipode and the ra-emic mixture ~hereof wherein is hydrogen, tetxahydropyran-2-yloxy o~ dimethyl--t-butylsilyl-5. oxy; and m is 2 or 3.
The present invention will now be described in more detail with rererence to Reaction Schemes which ilLustrate the processes fo~ preparing the novel intermediate compo~lnds of Formulae (VIIA), (VA) and (V), as well as the prostaglandin l~ analogs of l'ormula (VIIIA) herein. Illustrative of the present invention is the process for preparing the compounds designated by the Formulae VIII and XIV in Scheme B hereina~ter. These com-pounds are useful intermediates for the produ~tion of prosta-~landin analogs as will be described hereinaf'er.
lS The followins Reaction Scheme A illustrates the steps leading to the prepa~ation of the key intermediate hemithio acetal of Formula VI. In this Scheme and the su~sequent Schemes the-symbols R, Q and R" have the same meanings as.defined abo~

~9;~
~` --~ .

?\a~o o ,~
0>ll_0~

II
0~ 0 ~0 110- ~ R 3~

/ ~
III / IV

0--~ H C)H
~ Q ~-- o-R- ~ R~ ~J

VI

Sch~me A

.
~10--1093VI~Z
With rel:ererlce t.o ~eact:ion Scl~emc .~ the intcrmediate lactol o~ Formula V is prepared by l-ed~lc~ioil of lactone IV with diisob~t~3. ai~mlinu~l hyt1r.ide. This reducti~n is most easily accomplish~d by cc,ntac~ing lactone IV at a low temperature, typically -75C., in dry toluene ~.~ith a 20% solution o diiso~
butyl aluminum h~dride in he~ane. }ri~her reaction temperatures may be employe~ if over reduction does not occur. The diiso--butyl alulrlinum hydrlde is added to the precooled mixture oE
lactone IV in toluene over a period of about ~0-30 minutes. The reaction mixture is then stixred for an additlonal 30 ~inutes and then quenched by the dropwise addition of methanol. The solvents are evaporated under reduced pressure and the product is isolated.
The product may be purified by column chromatography on silica gel.
Lactone IV is prepared ~rom lactone III by protection of its hy~roxyl g~^oup with a suita~le acid labile protecting group.
Such protectin~ groups are typically tetrahydropyran-2-ylo;:y or dimethyl-t-butylsiloxy. Any sufficiently acid-labile group is satisfactory; how~ver, the most usual one is tetrahydropyranyl~
which can be incorporated in the molecule by treatment with di-- - hydropyran and an acid catalyst in an anhydrous medium. Laetone 1 is typically contacted with freshly distilled dih~dropyran in dry methylene chloride at a temper~ture of 0~ to 5C. in the pxesence of an acid cat~lyst such a~ para-tol~lenesulphonic acid.
other non-aqueous acid cat:alysts may likewise be employcd. This reaction mixture .is stirred until reaction is substantially com-plete, typically after one to t~o hours at a reaction temperature of O~C., and the product is then isolated. Lactone III is pre-p~xcd ~o~ paxabiph~nyl ester II by contac~in~.~ the said paxabi-phenyl ~ster Witil a heterogen~us mixt~lre of anhydrous pot~sslum ~09308Z

carbcnate and absolute methanol. Thi~ reaction is convenientlyperformed at room temperature fcr a period of approximately 24 hours. Parabiphenyl ester II is prepared from the known alde-hycle I by treatment of said aldehyde with 2-mercaptoethanol in methylene chloride at low temperature, typically 0C., under nitrogen in the presence of a Lewis acid catalyst such as boron trifluoride etherate. The reacti,on 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 function 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 illustrated in Formula II.
Reaction Scheme A further illustrates the preparation o~ 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 dimethylsulfoxide in a molar ratio of about 2:1 (anion:salt).
The lactol of Formula V is then added (dissolved in methylsulph-oxide) to the ylide solution prepared above, and the reaction mixture stirred until reaction is substantially complete. Re-action times will vary according to the choice of phosphonium salt and typical reaction times are 1 to 16 hours, The reaction mixture is then poured into wa~er and the product isolated by methods familiar to those skilled in the axt. This xeaction may be conducted at a temperatur~ of from -30 to 80C. and the lV930~Z
reclction temperature most frequent~y 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-S-yl the appropriate phosphonium salt is (4-(tetrazol-5-yl)-n-butyl) tri-phenylphosphonium bromide. When Q is N-methane sulfonylamino-carbonyl, (4-methanesulfonylaminocarbonyl-_-butyl)-triphenyl-phosphonium bromide is used. The pxoper choice of salt will be obvious to those skilled in the art, as will the manner of preparation of the said salt.
The sequence of steps starting from the intermediate of Formula VI and leading through the novel aldehyde inter-mediates of Formulae VII and XIII are illustrated in Reaction Scheme B which follows:

~V93~82 .. ` ' 01 O~R" ~ ~

~I ` ~
~ OiI

XIl~

R.` HO VII
~_ ~ ~ . ~
" '' ' ~ ' .

<--~ OH
R` ~CHO
XIII

OI~R'' ~ -- VIII

Q

R ~ Q ~ ~=,--`~ `~Q

X:~V R~ ~f'~

OH

, Q` ~--~--o HO`' ~
Il ~ ' ` O~I
Schem~ B . X
.__ __ .; ~,i .

93~Z
Thc~ pl'OCeS~ l lus~.ra~e(l in I~e;lc~ior~ Schclne B comE~riscs inter ~ a ~eactin.y a compoulld o .~;~ormula V1I or XIII wi~h the ylide of t`ie approplia~e phosp}lonate.of the fornlula:

~ P - CH~ - C - A

wherein ~ .is as defined above, in a react.ion inerl: sol~ent at a temperature of from 0~ to 80C. unt.il reactio~. is substantially complete. ., - l~he reaction is mcst conveniently conducted by firs~
p-~eparin~ the ylide under ni,trogen in a suitc.b:l.e solvent such as dimethoxyethalle, ethel^ or ~etrahydrofuran by addlng a suitable base, such as sodium hydride or n-butyllithiu.n, s~ow1y to a solu-tion of t~e appropriate phosphonate in the same solvent at a reacct.ion temperatuL-e of from 0 to ~5C., usually 0C. The form-a~ion of the ylide is usua].].y complete,~ithin an hour. At this ].5 time the ~ldehyde of Formula VII c.,r XIII is added, dissol.ved .in tha same solvellt, and the reaction mixture i~ stixred at a - temperature of from.0 to 80C., typically at room tempera~.ure, until reaction is s~lbstanti.ally complete, typ.ically for an hour.
Aldehyde VII is used to prepare intermediates for the syr.'chesis o~ prosta~landi.lls and tllei.r analogs o~ the E` si~r.ies and aldehyde XI~I is used to prcpale intermediates for prostaglandins and ' thc.'.r analo~s of the'h seriQs. The ~eaction mixture is,th~n brought to p~5 6-7 and the product isolated tiierefrom. Purifica--tion of ~he product is achieved typically by chrornatography o silica gel.
Th~. choice of the phosphonate frorn which the yl.ide is pr~parecl is c'tict,ated by thQ structure ol l:h~ d~sired ~:inal producl;. For exarnple, when th~ il~al. pLc,duc~ i.s clcsired to have ~5 ~3~82 a 5-carbon lower side chain at C15, (i.e., A is C5Hll) the phos-phonate used is dimethyl~2-oxo-heptyl~phosphonate, and if the methylenephenoxy lower side chain is desired at C15, (i.e., A is 0-OCH2) the phosphonate used is dimethyl 2-oxo-3-phenoxypropyl phosphonate.
According to the present invention the starting mate-rials for the above reaction, i.e., thP compounds of structure VII and XIII are prepared from compounds of the structure VI or XII, respectively, as shown in Scheme B by removal of the hemi-thioacetal protecting group. This is accomplished by reactinga solution of the hemithioacetal in a reaction-inert solvent, for example, acetonitrile:water (4:1), with mercuric chloride at a reaction temperature of from about 25 to 80C. until reaction is substantially complete. Reaction times will vary somewhat with the substrate but a typical reaction time is from 0.5 to 2.0 hours. Preferably the reaction is conducted when an alkaline earth metal carbonate is present in the reaction mixture since the most favorable yields are obtained when this material is present. The preferred alkaline earth metal carbonate is calcium carbonate, preferably in a molar ratio of 6:1 ~CaCO3:VI or CaCO3:XII)-The hemithioacetal XII is obtained from Compound VI byacylation. This i6 most commonly achieved u~in~ the appropriate acid anhydride in the presence of pyridine although other acyla-tion systems ~uch as acid chlorides or ketenes may be used.
As indicated in $cheme B, Intermediate VIII may be con-verted directly to Intermediate XIV by acylation. As indicated above such an acylation reaction is commonly conducted using the acid anhydride of the desired acyl group in the presence of pyridine.

~Og308Z
Intermediates XIV and VIII may be converted into prostaglandin E and F respectively in the following way:
To produce prostaglandins of the F series Compound VI]:I is converted into Compound IX by reduction with zinc boro-hyclride. 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 time necessary for complete re-duction. Other reducing agents such as lithium trialkyl ~oro-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 ~y the addition of sodium bi-tartrate and the product isolated. The two epimers produced by this reaction are separated by column chromatography on silica gel.
Compound IX then may ~e converted to the desired PGF
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 protecting group may be used. How-ever, this is accomplished most often by use of 65% aqueousacetic acid, at room temperature for about 18 hours. The product is purified as above.
~ 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 reductionVIII to IX as above. The isomers obtalned from this reduction are separated by column chromatography. Alcohol XV is then pro-tected as shown in Scheme A Reaction III to IV under the same conditions as described for that tran~formation and the result-ing protected compound XVI is then hydrolyzed by contacting it ~ o93ll8~
in ~ suitabl~ ;olv~-~nt o-- mi;:~urc o~ solvents, such as methano3..-tetr.lllydrorul:a~ ]) ~i.t}- lN :Ic~ueous sodi~m 'lydroxid~ s~lution.
This le~lC'~:i.On i.S rUI; a t LOOm temperatur~ under nit.ro~en for pe~:iods usually ranging .rorn ~ to ~ hours, although longer re--S action times are occasio~ lly n~cess~ry ~o effect cornplete hydrolysis. The re.-lction mixture is then acidi.ied by the addi-tion of l.N hydrochlo,ic acid and the acidlfled solution is ex--tracted wlth ethyl acetate to afford the desi.red product. This produc~ may be pu~ified, if desired, by column chromatography.
3.0 The resu]ting product XVII is then oxidized to pro~ide Compound XVIII. This r~act on i5 usually achieved usinq ~ones~
xeagent in acetone at reaction temperatures of from --3.' to -20C:.
- ~fter the appropriate amount of Jones' reagent has been added, the reaction usually stirred 'or an additiona]. 15 or 20 m.inutes 15 and then ~uenched by the addition of isopropyl a].co'lol. The product is then isolated in the usual way.
Ketone XVIII .is then converted to the desired p~osta-gland.in or its analog by the hydrolysis of the protecting groups in the same manner and under the same conditions as desc.rlbed ~0 'or the transLormation of Compound IX to Compound X. The result-i.ng Compound XIX may be then purified, if desired, by column chromatograp}ly on silica gel.

1093~82 ocr~ ~
~Q

.'' ~~'~
X IV

R~ ~(~\~/
¦ X~ OH
V

OCR "

R~ ~y-.R XIX

OH O
--~~/~Q J~ ~Q

. -- H~R -- \~ ' R
XVII XVIII

Scheme C

' J ~ .

~L093V8Z
. .

Thc v~.i.ous s~eps illustratod in Sc:h~-~mes B arld C start~~
i.n~J fron~ colnpound~s Vl:I an~ ~III and l.cadin~ to prostac71andin analogs of Forrnula XIX arc analogous ko methods kno~n in the art bul: thc production of the int~rm~diate co~poun~s VII and ~III
S from the key hemithj.oacetal intermediat:e o~ I;orm~la VI is notel and ~rovides a surprisir-g and ad~antageous rou~e for the prepara-tion of the final prostaglandin pxoducts.
~ ccordingly the invention still further provides in a process or preparing a prost.aglandin f.rom an optically active aldehyde intermediate of the formula:
OR' ' ~ CHO (VII.~.) R' its opt;.cal antipode and the racemic mixture thereof, wherein R
~ .
is hydrog~n or - ~R" and R" is alkyl of from one to four carbon atoms, ~-naphthyl, phenyl r p-biphenyl or ph~nylalkyl or from seven to nine carbon atoms; R is hydrogen~ tetrahydropyran-2-yl-oxy or dimethyl-t-butylsilylo:iy; and Q is tetrazol-5-yl, ~NH~R"', ~NE~SO2R"' or -~OR, wherei.n R is hydrogen, alkyl of one to six carbon atoms, phenyl, phenylall~yl o~ rom 7 to 9 carbon atoms, B-naphthylr or ~-biphenyl and R"' i5 alkyl of one to four carhon atoms or phenyl, by methods known .in the art, 1he improveme~t which comprises prepari.ng the aldehyde of Formula~
(VI~) by rcact.ing an opticall.y active compound o~ the formula:
' ' . ~2.0~

.

1093()82 0~?.' ~ . ~ _ ~ ~ Q

O `~~-~S~
o (Cl~2)m (VIA) its opt-ical antipode or the racemic ,nixture thereof, wherein R', R and Q are as defined ahove and m is two or three, with mercu~-ic chloricle i.n a reaction--inext solvent at a tempera~ure from 25 to 80~C. untll the reaction is subst~ ticl71y com1~lete.
A preferred embodiment of the above process is that wherein the in-c.ermediate of Fo~mula (VIIA) is an aldehyde ~om pound ~7herein Q is -~NHSO2CII3, R' is -~CH3 and R is tetrahydro-pyran~2-ylo~:y and the inal prostaglandin product is N-methane-sulfonyl 9--oxo-11~,15~-dihydroxy-16--phenoxy-5-cis--13-trans-.7,18,19,20-tetranorprostadienamide.
FGX the pr~paration of ll-desoxy ana-Logs o prosta~
glandins the hemithioacetal intermediate of Formula VI wherein R is hydrogen is prepared from the known lac~one III' b~ the same method as that illustrated in Scheme A above by the reac-` tiOIl sequence i:Llustrated in Scheme D ~hich follows:

10931)82 .
~ ~ o ~o A~ . f >

~0 ~ ~

I ~ .~/

VH
O--,~H OH

VI ~ R = H) .5cheme D

, "

~! 2 . ' " :
:

rl ~
1~:)9308~
~ s u~cd herei.n all thc strucl;uxal for~nu].as are mcant to rc~ c.~ t ~it-hcr ar. opticall~ ac~ive corrlpovnd, its ~ntipo(le or a racell-ic mj.~ture oi the tWG.
:r~ ~ill be appr-ccia~ed by those skilled in the art that the foregc)i.n~ s~ntllet:ic sequences of the present invention posscss the bxoad fle~ibility very much to be desi.red i.n the preparation of ~rost.aglandiJI ana.l.ogs.
In the .sequenc~s describe~ above, a considerable latitude exlsts in t.he selection o~ the prot~ctillg group used at a particular sta~e. Thus, in protectiny alc~hols, dihydropyran~
yloxy groups or dimethyl-t butyl silyl groups may be emplcyed in those situati.ons ~hexe the protecting group is represented in the Formulae as R. Similarly the acyl group of Compounds XII
through XVI may be select~d rom a broad range o acyl groups such as formyl or alkanoyl of from 2 to 4 carbon atoms, ~-naphth-yl,carbonyl, benzoyl, parabiphenylcarbonyl or phenylalkylcarbonyI
wherein an alkyl group may be of from 7 to 9 carbon atoms.
In n~merous _ vivo and i.n vitro t~sts ~7e havc demon-strated that the prostaglandin analogs prepared by the process 20 o~ the present invention possess physiological acti~ities com-- parable to those exhibited by the natural prostaglandins. These t~sts i.nclude, among others, a test for e~fect on isolated smooth muscle from gui.n~a pig uterus and xat uter~s, inhibition of histamille-induced broncllospasm in the ~uinea pigl and e~fect on dog blood pressure, inhi~ition o stress-induced ulceratioll in ~he rat, inhibition o~ gastr:ic acid and ~epsin secretion in rat and dog, inhibitiol~ o~ collagen or ~D~-i.nduced blood p:Lat.~-let a~c~regatiol- and abortifacient ac~ivit~ in rats and guinea pi.gs by luteo.~ytic alld non-lut~olytic mechanisms~
The physiologi.-al. respons~s obscrved in thesc t~sts . ~3-~0~308Z
are useful in determinlng the utility of -the test substance for the treat~ent of various natural and pathological conditions.
Such determined utilities include: antihypertensive activity, bronchodilator actlvity, antithrombogenic activity, antiulcer activity, smooth muscle activity ~useful as an anti-fertility agent, for the induction of labor, and as an abortifacient); and anti-fertility activity through a mechanism not affecting 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 example, N-methanesulfonyl 16-phenoxy-~-tetranorprostaglandin E2 carbox-amide which exhibits smooth muscle stimulating activity comparabl~
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 acti~ity of great-ly enhanced potency and duration as compared with PGE2 itself.At the same time, 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 15-indanyl-~-pentanorprostaglandins and 17-aryl-~-trisnorprosta-~301~3Z

glandins of the E2 and F2~ 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-~-tetranorprostaglandins of the E2 series based on out-standing antiulcer and antisecretory activity and at 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 ca~es, however, the selectivity that these compounds display exceeds that of the epimeric compounds.
For induction of abortion, tablets or an aqueous sus-pension or alcoholic solution of the 15-substituted ~-pentanor-prostaglandins of the E and F series would appropriately be administered at oral doses of about 0.1-20 mg., with 1-7 doses per day being employed. For intravaginal administration a suit-able formulation would be lactose tablets or an impregnated tampon of the same agent. For such treatm~nts suitable doses would be from about 0.1-20 mg./dose with 1-7 dose~ being employ-ed. For intra-amniotic admini~tration 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 suitakle formulation 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

~0~3()82 series of this invention can be infus~d 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-o-pentanorprosta-glandins of the E and F series is as an inducer of labor. Forthis purpose an ethanol-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-~-pentanorprosta-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 sèries is administered subcutaneously from 1-4 days.
15-Substituted-~-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, 1~3~32 exci~ients or carriers may be employed. Such substances in-clude, for example, water, ethanol, gelatins, lactose, starches, magnesium stearate, talc, ~eg~table oils, ben2yl aleohols, 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, wetting agents, stabilizing agents, or other therapeutic agents such as antibiotics.
The following Examples illustrate the preparation of intermediates and prostaglandin final products 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 parts per million and using a TMS standard.
EXAMPLE I
2~[3~~(p-biphenylcarboxy)-5~-hydroxy-2~-~2 thioxalanyl)cyclopent-l~-yl]acetic acid, y-lactone (II) To a solution of 2-[3a-(_-biphenylcarboxy)-5~-hydroxy-2~-formyl cyclopent-la-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 t4 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 undar reduced pressure yielded 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.

10930~

Substitution of 3-mercapto-1-propanol for 2-mercapto-ethanol in the above procedure will provide the corresponding homologous protected aldehyde which may be converted into the E2- and F,~-prostaglandins by the procedures of Examples II-XVIII.
EXAMPLE Ia 2-[5~-hydroxy-2~-(2-thioxalanyl~cyclopent-1~-yl]acetic acid, y-lactone (III') To a solution of 2-[5~-hydroxy-2~-formylcyclopent-1~-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 hours.
~he reaction is diluted to 900 ml. with more methylene 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 o~ Examples IV-XVIII.
EXAMPLE II
2-~3~,5a-dihydroxy-2~-(2-thioxalanyl)cyclopent-1-yl]acetic acid, y-lactone (III) A heterogeneous mixture of crude 2-[3~ -biphenylcarb-oxy)-5-hydroxy-2~-(2-thioxalanyl)cyclopent-1~-yl acetic acid, y-lactone (23.5 g., 0.057 mole) absolute methanol ~230 ml.) and -~8-~09308Z
finely powdered anhydrous potassium carbonate (3.95 g., 0.028 mole) was stirred at room temperature overnight. The precipit-ated solid was filtered and washed with methanol. The filtrate was evaporated to approximately 100 ml. and cooled in ice. To the cooled solution was added O.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).
EXAMPLE III
2-[3a-(tetrahydropyran-2-yloxy)-Sa-hydroxy-2~-(2-thioxalanyl)-cyclo~ent-la-yl]aceti¢ acid, y-l~ctone (IV) To a cooled ~olution (0-5) of crude 2-[3a,5~-~ihydroxy-2~-(2-thioxalanyl)cyalopent-la~yl]acetic acid, y-}actone (2.5 g., 10.9 mmoles) and freshly distilled dihydropyran (1.47 ml., 16.3 mmoles) in dry methylene chloride (25 ml.) was added p-toluene-sulfonic acid monohydrate (250 mg., 1.31 mmoles). The reaction mixture was stirred for 1.5 hour~ at 0C., then diluted with ether (60 ml.). The organic solution was wa~hed with saturated sodium bicar~onate ~10 ml.), ~aturated brine (10 ml.) and dried ov~r anhydrou~ ~odium sulfate. Concentration under vacuum ` afforded the title compound (3.4 g., 100~ yiald) a8 an oil.
! EXAMPLE IIIa 2-[3~-(dimethyl-t-butyl~ilyloxy)-5a-hydroxy-2~-(2-thioxalanyl)-cyclo~ent-la-yl] acetia acid, y-lactone (IV) A mixture of 2-[3a,5a-dihydroxy-2~-(2-thioxalanyl)cyclo-pent-la-yl]acetic acid, ~-lactone ~2.25 g., 10 mmole~), dimethyl-t-butyl~ilyl chloride (1088 g., 12.5 mmole~) and imidazole (1.87 g., 27.5 mmole~) in 5 ml. of dimethylformamide i~ 3tirred under ` -29-~ 093(~3Z
nitrogen at 37 for 18 hours. The reaction is concentrated under reduced pressure and diluted with methylene chloride. The organic solution is washed with water, dried (anhydrous magnes-ium sulfate) and concentrated under reduced pressure. Purifi-cation of the crude product by silica gel chromatography pro-vides the title compound.
The product of this Example may be converted into the ll-hydroxyprostaglandins by the procedures of Examples IV-XVII.
EXAMP~E_IV
2-~3~-(tetrahydropyran-2-yloxy)-5a-hydroxy-2~-~2-thioxalanyl)-cyclopent-la-yl]acetaldehyde, y-hemiacetal (V) To a solution, cooled to -75 under nitrogen, of crude 2-[3a-(tetrahydropyran-2-yloxy)-5a-hydroxy-2~-(2-thioxalanyl)-cyclopent~ yl]acetic acid, y-lactone (3.24 g., 10.3 mmoles) in dry toluene ~50 ml.) was added over a period of 25 minutes a 20% solution of diisobutylaluminum hydride in hexane (14.9 ml., 12.0 mmoles). After an additional 30 minutes the reaction was quenched by dropwise addition of-methanol and allowed to warm to room temperature. The toluene was evaporated under reduced pressure and the residue diluted with ether (200 ml.). The organic solution was washed with a 50% sodium potassiùm tartrate solution (3X), saturated brine, then dried with anhydrous Na2SO4 and was concentrated to afford the title compound (3.1 g., 95~
yield) as an oil. The product was purified by column chromato-graphy on 90 g. of Baker silica gel (60-200 mesh) using benzene~
ethyl acetate as eluents to give the pure title compound (2.9 g.).
The pxoduct of this Example may be treated with a phos-phorane of the structure ~Br~3 wherein Q' is tetrazol-5-yl, 03P(CH2)4Q

-CNHCR"', -CNHSO2R"' or ~OH, wherein R"' is alkyl of from one to ~093(:~8;:
four carbon atoms, according to the procedures of Example V. The product of this reaction may be converted into the E2- and F2 ~
prostaglandins by the procedures of Examples VII IX and XI-XVIII.
EXAMPLE V
7-[2~-(2-thioxalanyl)-3~-(tetrahydropyran-2-yloxy)-5~-hydroxy-cyclopent-la-yl]-cls-5-heptenoic acid ~VI) To a solution of 5-triphenylphosphoniopentanoic acid (23.045 g., 52.0 mmoles) in dry dimethyl sulfoxide (46 ml.) was added dropwise an approximately 2.ON solution of sodium methyl-sulfinylmethylide (49.3 ml., 98.6 mmoles) in dimethyl sulfoxide.
To the resultant red solution was added over the course of 1.0 hour a solution of 2-[2~-(2-thioxalanyl)-3~-(tetrahydropyran-2-yloxy)-5a-hydroxycyclopent~ yl]acetaldehyde, y-hemiacetal (6.6 g., 20.8 mmoles) in dry dimethyl sulfoxide (63 ml.~. After being stirred for an additional half hour r the reaction was pour-ed into ice-water (600 ml.). The basic aqueous solution was ex-tracted with 2:1 mixture of ethyl acetate:ether (2 x 300 ml.).
The cold aqueous layer was covered with ethyl acetate and acidifi-ed to pH ~3 with 10% hydrochloric acid. The aqueous layer was further extracted with ethyl acetate (2 x 200 ml.) and the com-bined organic extracts were washed with water followed by brine.
Drying the organic layer over anhydrous sodium sulfate and ~on-centrating afforded a yellow oil weighing 20 g. Addition of 150 ml. o a mixture of ethyl acetate:ether (2:1) precipitated a solid which was filtered, washed with ether and the filtrate evaporated. The yield of crude title compound was 10.2 g. ~120%) which wa~ used directly in the next step.
The product of this Example may be esterified according to the procedure of Example Va with an alkyl diazo compound of from one to six carbon atoms or phenylalkyl diazo compound of ~31-~ 93~;)82 from seven to nine carbon atoms. Alternatively, one equivalent of the product of this Example may be contacted with ten equiv-alents of phenol, ~-naphthol or _-phenylphenol and 1.2 equival-ents of dicyclohexylcarbodiimide. The resultant esters may be converted into the E2- and F2~-prostaglandins by the procedures of Examples VI-IX and XI-XVII.
EXAMPLE Va Methyl 7-[2~-(2-thioxalanyl)-3~-(tetrahydropyran-2-yloxy)~5~-hydroxycyclopent-la-yl]-cis-5-heptenoate (VI) A solution of 7-~2~-(2-thioxalanyl)-3a-(tetrahydropyran-2-yloxy)-5a-hydroxycyclopent-la-yl~-cls-5-heptenoic acid (520 mg., 1.3 mmoles) in 5 ml. o~ anhydrous ether is titrated at room temperature with an ethereal diazomethane 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 undex reduced pressure to provide the title compound.
The product of this Example may be con~erted into E2-and F2~-prostaglandins by the procedures of Examples VI-IX and XI-XVII.
EXAMPLE VI
7-[2~-~ormyl-3a-(tetrahydropyran-2-yloxy)-5a-hydroxycyclopent-la-yl]-cis-5-heptenoic acid (VII) - _ _ _ _ To a solution of 7-[2~-(2-thioxalanyl)-3~-(tetrahydro-pyran-2-yloxy)-Sa-hydroxycyclopent-l~-yl]-c -5-heptenoic acid '(2.0 g., 0O005 mole) 4:1 acetonitrile:water (85 ml.) was added sequentially anhydrous calcium carbonate (2087 g., 0.029 mole) and mercuric chloride (5.4 g., 0.020 mole). The mixture was stirred and heated at 50C. under nitrogen for a half hour. The mixture was filtered through Celite and washed wlth ether (250 ml.~. The combined filtrate 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 reduced 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 substituent of the formula Ar(CH2)n- or Ar'OCH2- wherein n is one or two and Ar is a-naphthyl, ~-naphthyl, a-furyl, ~-thienyl, phenyl or mono-substituted phenyl in which the substituent is fluorine, chlorine, trifluoromethyl, phenyl or alkyl or alkoxy 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 of 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
9a-hydroxy-lla-(tetrahydropyran-2-yloxy)-15-oxo-cis-5-trans-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-3~ (tetrahydro-pyran-2-yloxy)-5a-hydroxycyclopent-la-yl]-cis-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 . .

~Og3~8Z
h~lf hOU1-, .it waC; brouc;ht to pi~ -7 t~ith glacial acetic acid.
~`he neut~alized so~ution w~s concentra~ed by rotary evaporation and the rcs~1tant xolid ~as slurried in benzene and filtered.
Concentratlon of the iltrate afforded tlle crude title compound ~"hich was purified by chromatography on silica ~el using ben~ene-~eth~lacetate as eluant to give the pure title compound ~710 mg.).
The product of this l~xample may be acylated according to the procedure of Example X~ to ~orm the product of Example XIII.
X~MPLE VIII
9~~15}dih~ro~y~ (tetrahydropyran--2-yloxy)-cis-5--trans--13-prostadi~noic acid (IX) To a solution of 9~-hydroxy~ -(tetrahydropyran-2-yl-oxy3-15-oxo-c~s-S-trans-13~prostadienoic acid tO.15 g., 0.3~3 ~nole) in dimethoxyetllane (3 ml.) was added a 0.5M solution of ~,inc borohydride (1.75 ml., 0.17 ~Nmole) iII dimethoxyethane. The reaction was stirred at room temperature unde~^ nitrogen for 2.5 hours then was cooled in ice. The cold reaction mixture was ~n quenc~ed by the addition of a saturated sodium bitartrate 501u-tion dropwise until hydrogen evolution ceased. T~le mixture was diluted with ethyl acetate (25 ml.), acidified to about p~ 4 with cold lN HCl with rapid stirring. ~rhe ethyl acetate la~er was dried with sodium sul~ate and con~entrated to afford the ~5 oil~ epimerlc mixture of the title compounds weighing 0.13 ~., ~R~ 0.25 on t.l.c. u~ing 15:5:~ mixture of benzene:dioxan:formic ~cid as eluant), suitab1e for directly usin~ in the next step.
~X~ I.tJ IX
, ~ pGY2~y (X) A l~oniogerieous SOllitiOII 0~ crude ~,lS~-dihydroxy~ll~-: ~ -3~-~093(~8Z
(tct:tal~ydrc)L~yrar.-~-yloxy)-c~.c~-5-~ralls~13~plosta;1icnc)ic aclcl ~0.117 g., 0.261 ~nolc) in a 6~:35 m.ixt~lr~ c,f glacial acetic acld:~Ta~er (5 ml.) was stirLcd under nitrogen at room tempcra-ture for 16 hours ~hcn ~Jcl~ con~ntrafed by rotary e~raporation ol.lowed by oil pump at 25C. The xesultant oil was chrornato-^
graphed on 5 c3. silica ~el (CC-7) using chloroform+~thyl acetate to give 15 mg. 15-epi-rGF~ followed by 30 mg. of PGF2a, ident-ical wi.th an authentic sample by IR and NMR.

EXAI`~IPLE X
N-Metllanesulfonyl 7-12~~(1,3-oxathialan-2-yl)-3~ ,etrahydro-pyran-2 yloxy)-5~-hydroxycyclopent-la-y]]-cis-5-heptenamide (VI) To a solution o~ 27.0 ~. (52.0 mmoles) of (4-methane-sulfonylaminocarbonyl-n-butyl)triphenylphosphonium bromide in 46 ml. o dimethyl sulfoxide is addcd dropwise 49.3 ml. (98.6 mmoles) o~ a 2.OM solulion of sodi.um methylsulfonylmethy].ide in dimethyl sul.foxid~. To the resultant red solut;ion is added over the course of 15 minutes a solution o 6.6 g. (20.8 mmoles) o~
the hemiacetal prepared in Example IV in 63 ml. of dimethyl sulf-oxide. AftPr being stirred for an additional 2.0 hours, t}~e re-action is poured onto 600 ml. of ice-water. The cold aqueo~s layer is covercd with ethyl acetate and acldified to p~I ~3 with 10~ hydrochloric acid. The acic'i.fied aqucous layer is furtner extracted wi.th ethyl acetate (2 ~ 200 ml.) and ~he combined orc3anic extracts are washed Wit}l ~ater followed by brine. Dryin~
2.5 the organic lay~r over anhydrous sodium sul~ate and concentration a~oxds the crude product which i5 triturated with ether. Concen-tration o the ether provides N-n~ethanes-llfonyl 7-[2~
~xathialan-2-yl)-3~-~tetrahyclropyran-2-yl.o~y)-5~ hydroxycvclo~
pent~ yl)J cl~-5-heptcnamidc (VI). '~
The ~roduct of this E~ample may be acylated accor.din(3 to ~t5 ~ .

~93l~3Z
the procedure of Example XI employing either ~R"~) ~0 or R"~Cl wherein R" is alkyl of from one to four carbon atoms, 3-naphthyl, phenyl, p-biphenyl or phenylalkyl of from seven to nine carbons.
ThLs product may be converted into the E2-prostaglandins accord-ing to the procedures of Examples XII-XVIII.
EXAMPLE XI
N-Methanesulfonyl 7-[2~-(1,3-oxathialan-2-yl)-3~-(tetrahydropyran-2-yloxy)-5a-acetoxycyclopent-1~-yl]-cis-5-heptenamide ~XII) _ A mixture of 1.69 g. (3.54 mmoles) of the crude hydroxy compound VI prepared in Example X, 5.0 ml. of pyridine and 0.368 ml. (3.89 mmoles) of acetic anhydride is stirred under nitrogen 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 (anhydrous magnesium sulfate), and is concentrated to afford the desired N-methanesulfonyl 7-[2~-~1,3-oxathialan-2-yl)-3a-(tetrahydropyran-2-yloxy~-5a-acetoxycyclopent-la-yl]-c -5-heptenamide (XII).
EXAMPLE XII
N-Methanesulfonyl 7-[2e-formyl-3~-(tetrahydropyran-2-yloxy)-5~-acetoxycyclopent-la-yl]-cis-5-heptenamide (XIII) To a solution of 2.9 g. (S.0 mmoles) of the hemit~io-acetal XII prepared in Example XI in 85 ml. of acetonitrile:water (4:1) is added sequentially 2.87 g. (0.029 mmole) anhydrous calcium carbonate and 5.4 g. (0.020 mmole) mercuric chloride.
The mixture i5 stirred and heated at 50 under nitrogen for 0.5 hr. The mixture is filtered through Celite and washed with 250 ml. ether. The combined filtrate is stirred and treated with 3 ~ ml. of lN hydrochloric acid. The ether layer is separated and washed with brine (3 x 15 ml.). Drying over anhydrous sodium 10930~3Z
sulfate and concentratlon at reduced pressure afforded the de-sired N-methancsulfonyl 7-[2R-formyl-3~-~tetrahydropyran-2-yl-oxy)--5~-acetoxycyclopent~ yl~-cis-5-heptenamlde (XIII~.
The product of this Example may be treated with a phos-phonate of the formula (MeO)2~CH2~A wherein A ls 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 AL is ~-naphthyl, 3-naphthyl, ~-furyl, ~-thlenyl, phenyl or monosub-stituted phenyl in which the substituent is fluorine, chlorine, trifluoromethyl, phenyl or alkyl or alkoxy 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 of from one to six carbon atoms accord-ing to the procedures of Examples VII or XIII. The product of 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-~-tetranorprostadienamide (XIV) To a suspension of 220 mg. (5.22 mmoles) of a 57.0%
di~persion of sodium hydride in mineral oil in 20 ml. of tetra-hydrofuran is added 1.34 g. (5.22 mmoles~ of dimethyl 2-oxo-3-phenoxypropyl phosphonate. The mixture is stirred at room temperature for 1 hour under nitrogen, then a solution of 1.23 g. t2.37 mmoles) of the crude aldehyde XIII prepared in Example XII in 4 ml. of tetrahydro~uran 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 is concentrated by rotary evaporation.
The resultant mixture is dissolved in ethyl acetate, ~093~8Z
the or~anlc laycr is ~ashcd ~1ith 0.1l~ hydroc~loric acid, water and satuJ,ated h~ine, is clricd (anhy~rous macJI~esium sulia~e) and conccntrated. I~urifica~ion or t:he crude product b~ coll~mn c~.romato~raphy affords the desired M-m~thanesulon~1 9~-acetoxy-11~-(tet,ahydrop~ran-2-yloxy~-15-o~o-5-cis-13-trans-16-phenoxy-~-tetranorprostadienamide (~IV).
EXAMPL~ XIV
N-Methanesulfony1 9~-acetoxy-11~-(tetrahydropyran-2-ylo~y)-15~-hydroxy~l6-phen~xy-S-cis-13-trans-~-tetranor~rc)stadienamide (~Va j and N-Methanesulfonyl 9~-acetoxy~ll~-(tetrahydropyran-2--yloxy)~15~3~
hydroxy-16-phe~o,:y--5-cis-13-trans ~-tetranorprostadienamide (XVb) To a solution, cooled to -'18 under nitrogen, of 1.2~ g.
(2.1 mmoles) of the lactone XIV prepared in Example XIII in 12 ml. of tet~-~hydrofuran is added ~.3 rnl. of a 1.0~l solution c~
lithium triethylborohydride in tetrahydrofuran. The mixture is stirred in the cold ~or 45 minutes then quenched by the addition of a 9:1 mixture of water:acetic acid. rrhe mixture is let warm then diluted with ethyl acetate. The organic solution is washecl with water (2x) and saturated brine, is dxied (anhydrous ma~nes-ium sulfate) and concentrated. Purification o~ the c ude product b~ colu~nn chromatography provides irst N~metllanesul~onyl 9~-acetoxy~ (tetrahydropyran-2--yloxy)-~15~ ydroxy-16~p}lenoxy-5--cis-13-trans-w-tetranorprosladienamide (XVb) and fu~ther elution provides N-methanesull~onyl 9~-acetoxy~ -(tetrahydropyran-2-yl^
oxy)-15~-hydroxy-16-phenoxy-5-cis-13-trans-~ tet~anorprostadien-ami~e (~Va).
The 15~3~compounds o this F;xamplc may be converted intv , the l5~epi-~-prostaglandins by the procedures o~ Exarlples XV-XVlIX.
.

1093V~2 EXAMPLE XV
N-Methanesulfonyl 9~-acetoxy~ ,15~-bis-(tetrahydr~pyran-2-yl-ox~)-16-phenoxy-5-cls-13-trans-~-tetranorprostadienamide (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 1 crystal of ~-toluenesulfonic acld monohydrate is stirred at room temperature under nitrogen for 20 mlnutes. The reaction mixture is then diluted with ether, lS washed with water and saturated brine, is dried (anhydrous magneslum sulfate), and concentrated to give the desired N-methanesulfonyl 9~-acetoxy-11~,15~-bis-(tetrahydropyran-2-yloxy)-16-phenoxy-5-c -13-trans-~-tetranor-prostadienamide (XVI~.
EXAMPLE XVI
N-Methanesulfonyl 9a-hydroxy-lla,15a-bis-(tetrahydropyran-2-yl-oxy)-16-phenoxy-5-cis-13-trans-~-tetranorprostadienamide (XVII) A homogenous solution of O.295 g. (0.436 mmole) of the crude bls-THP ester XVI prepared in Example XV, 1.3 ml. (1.30 mmoles) of a l.ON aqueous sodium hydroxide solution, 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 solu-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).

~0~3 L)~Z
EX~MPLE XVII
N-Methanesulfonyl 9-oxo-11~,15~-bis-(tetrahydropyran-2-yloxy)-16-phenoxy-5-cis-13-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 Jones' 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 is stirred in the cold for 5 minutes then is diluted with ethyl acetate. The organic solution is washed with water (2x) and saturated brine (lx), is dried (anhydrous magnesium sulfate), and is concentrated to afford the desired N-methanesulfonyl 9-oxo-110l,,15c~-bis-(tetrahydropyran-2-yloxy)-16-phenoxy-5-cls-13-trans-~-tetranorprostadienamide (XVIII).
EXAMPLE XVIII
N-Methanesulfonyl 9-oxo-11~,15~-dihydroxy-16-phenoxy-5-cis-13-_ trans-~-tetranorprostadienamide (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 reaction is concentrated by rotary evaporation followed by oil pump. The crude, product i~
purified by column chromatography on silica gel to provide the desired N-methanesulfonyl 9-oxo-11~,15~-dihydroxy~ phenoxy-5-cis-13-trans-~-tetranorprostadienamide (XIX).

Claims (10)

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 alde-hyde intermediate of the formula:

(VIIA) its optical antipode and the racemic mixture thereof, wherein R' is hydrogen or and R" is alkyl of from one to four carbon atoms, .beta.-naphthyl, phenyl, p-biphenyl or phenylalkyl of from seven to nine carbon atoms; R is hydrogen, tetra-hydropyran-2-yloxy or dimethyl-t-butylsilyloxy; and Q is tetrazol-5-yl, , or -COOR, wherein R is hydrogen, alkyl of one to six carbon atoms, phenyl, phenyl-alkyl of from 7 to 9 carbon atoms, B-naphthyl, or p-biphenyl and R"' is alkyl of one to four carbon atoms or phenyl, which comprises reacting an optically active compound of the formula:

(VIA) its optical antipode or the racemic mixture wherein R', R
and Q are as defined above and m is two or three, with mer-curio chloride in a reaction-inert solvent at a temperature of from 25 to 80°C. until the reaction is substantially com-plete.

2. A process according to claim 1, wherein the reaction is conducted in the presence of an alkaline earth metal carbonate.

3. A process according to claim 2, wherein the alkaline earth metal carbonate is calcium carbonate.

4. A process according to claim 1, wherein R1 in the starting compound of Formula VIA is hydrogen or

5. A process according to claim 4, wherein Q in the compound of Formula VIA is -COOR, and R is as defined in claim 1.

6. A process according to claim 4, wherein Q in the compound of Formula VIA is tetrazol-5-yl.

7. A process according to claim 4, wherein Q in the compound of Formula VIA is and R"' is alkyl of one to four carbon atoms or phenyl.

8. A process according to claim 7, wherein Q is .

9. A process according to claim 4, wherein m is 2.

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