Prostaglandin-type compounds with a phenoxy or substituted-phenoxy substituent at the C-16 position are disclosed, with processes for making them. These compounds are useful for a variety of pharmacological purposes, including anti-ulcer, inhibition of platelet aggregation, increase of nasal patency, labor inducement at term, and wound healing.

BACKGROUND OF THE INVENTION 
This invention relates to novel compositions of matter, to novel methods 
for producing those, and to novel chemical intermediates useful in those 
processes. Particularly, this invention relates to certain novel analogs 
of some of the known prostaglandins in which there is a phenoxy or 
substituted-phenoxy substituent at the C-16 position, i.e. on the carbon 
atom adjacent to the hydroxy-substituted carbon in the methyl-terminated 
chain. 
The known prostaglandins include, for example, prostaglandin E.sub.2 
(PGE.sub.2), prostaglandin F.sub.2 alpha and beta (PGF.sub.2.alpha. amd 
PGF.sub.2.beta.), prostaglandin A.sub.2 (PGA.sub.2), prostaglandin B.sub.2 
(PGB.sub.2), and the corresponding PG.sub.1 compounds. Each of the 
above-mentioned known prostaglandins is a derivative of prostanoic acid 
which has the following structure and atom numbering: 
##STR1## 
See, for example, Bergstrom et al., Pharmacol. Rev. 20, 1 (1968), and 
references cited therein. A systematic name for prostanoic acid is 
7-[(2.beta.-octyl)-cyclopent-1.alpha.-yl]-heptanoic acid. 
PGE.sub.2 has the following structure: 
##STR2## 
PGF.sub.2.alpha. has the following structure: 
##STR3## 
PGF.sub.2.beta. has the following structure: 
##STR4## 
PGA.sub.2 has the following structure: 
##STR5## 
PGB.sub.2 has the following structure: 
##STR6## 
Each of the known PG.sub.1 prostaglandins, PGE.sub.1, PGF.sub.1.alpha., 
PGF.sub.1.beta., PGA.sub.1, and PGB.sub.1, has a structure the same as 
that shown for the corresponding PG.sub.2 compound except that, in each, 
the cis carbon-carbon double bond between C-5 and C-6 is replaced by a 
single bond. For example, PGE.sub.1 has the following structure: 
##STR7## 
In formulas II to VII, as well as in the formulas given hereinafter, 
broken line attachments to the cyclopentane ring indicate substituents in 
alpha configuration, i.e., below the plane of the cyclopentane ring. Heavy 
solid line attachments to the cyclopentane ring indicate substituents in 
beta configuration, i.e., above the plane of the cyclopentane ring. 
Following the conventional numbering of the carbon atoms in the prostanoic 
acid structure, C-16 designates the carbon atom adjacent to the 
hydroxy-substituted carbon atom (C-15). 
The side-chain hydroxy at C-15 in formulas II to VII is in S configuration. 
See, Nature, 212, 38 (1966) for discussion of the stereochemistry of the 
prostaglandins. 
Molecules of the known prostaglandins each have several centers of 
asymmetry, and can exist in racemic (optically inactive) form and in 
either of the two enantiomeric (optically active) forms, i.e. the 
dextrorotatory and levorotatory forms. As drawn, formulas II to VII each 
represent the particular optically active form of the prostaglandin which 
is obtained from certain mammalian tissues, for example, sheep vesicular 
glands, swine lung, or human seminal plasma, or by carbonyl and/or double 
bond reduction of that prostaglandin. See, for example, Bergstrom et al., 
cited above. The mirror image of each of formulas II to VII represents the 
other enantiomer of that prostaglandin. The racemic form of a 
prostaglandin contains equal numbers of both enantiomeric molecules, and 
one of formulas II to VII and the mirror image of that formula is needed 
to represent correctly the corresponding racemic prostaglandin. For 
convenience hereinafter, use of the terms PGE.sub.1, PGE.sub.2, PGE.sub.3, 
PGF.sub.1.alpha., and the like, will mean the optically active form of 
that prostaglandin with the same absolute configuration as PGE.sub.1 
obtained from mammalian tissues. When reference to the racemic form of one 
of those prostaglandins is intended, the word "racemic" or "dl" will 
precede the prostaglandin name, thus, racemic PGE.sub.1 or 
dl-PGF.sub.2.alpha.. 
PGE.sub.1, PGE.sub.2, and the corresponding PGF.sub..alpha., 
PGF.sub..beta., PGA, and PGB compounds, and their esters, acylates, and 
pharmacologically acceptable salts, are extremely potent in causing 
various biological responses. For that reason, these compounds are useful 
for pharmacological purposes. See, for example, Bergstrom et al., cited 
above. A few of those biological responses are systemic arterial blood 
pressure lowering in the case of the PGF.sub..beta. and PGA compounds as 
measured, for example, in anesthetized (pentobarbital sodium) 
pentolinium-treated rats with indwelling aortic and right heart cannulas; 
pressor activity, similarly measured for the PGF.sub..alpha. compounds; 
stimulation of smooth muscle as shown, for example, by tests on strips of 
guinea pig ileum, rabbit duodenum, or gerbil colon; potentiation of other 
smooth muscle stimulants; antilipolytic activity as shown by antagonism of 
epinephrine-induced mobilization of free fatty acids or inhibition of the 
spontaneous release of glycerol from isolated rat fat pads; inhibition of 
gastric secretion in the case of the PGE and PGA compounds as shown in 
dogs with secretion stimulated by food or histamine infusion; activity on 
the central nervous system; controlling spasm and facilitating breathing 
in asthmatic conditions; decrease of blood platelet adhesiveness as shown 
by platelet-to-glass adhesiveness, and inhibition of blood platelet 
aggregation and thrombus formation induced by various physical stimuli, 
e.g., arterial injury, and various biochemical stimuli, e.g., ADP, ATP, 
serotonin, thrombin, and collagen; and in the case of the PGE and PGB 
compounds, stimulation of epidermal proliferation and keratinization as 
shown when applied in culture to embryonic chick and rat skin segments. 
Because of these biological responses, these known prostaglandins are 
useful to study, prevent, control, or alleviate a wide variety of diseases 
and undesirable physiological conditions in birds and mammals, including 
humans, useful domestic animals, pets, and zoological specimens, and in 
laboratory animals, for example, mice, rats, rabbits, and monkeys. 
For example, these compounds, and especially the PGE compounds, are useful 
in mammals, including man, as nasal decongestants. For this purpose, the 
compounds are used in a dose range of about 10 .mu.g. to about 10 mg. per 
ml. of a pharmacologically suitable liquid vehicle or as an aerosol spray, 
both for topical application. 
The PGE, PGF.sub..alpha., and PGA compounds are useful in the treatment of 
asthma. For example, these compounds are useful as bronchodilators or as 
inhibitors of mediators, such as SRS-A, and histamine which are released 
from cells activated by an antigen-antibody complex. Thus, these compounds 
control spasm and facilitate breathing in conditions such as bronchial 
asthma, bronchitis, bronchiectasis, pneumonia and emphysema. For these 
purposes, these compounds are administered in a variety of dosage forms, 
e.g., orally in the form of tablets, capsules, or liquids; rectally in the 
form of suppositories; parenterally, subcutaneously, or intramuscularly, 
with intravenous administration being preferred in emergency situations; 
by inhalation in the form of aerosols or solutions for nebulizers; or by 
insufflation in the form of powder. Doses in the range of about 0.01 to 5 
mg. per kg. of body weight are used 1 to 4 times a day, the exact dosage 
depending on the age, weight, and condition of the patient and on the 
frequency and route of administration. For the above use these 
prostaglandins can be combined advantageously with other anti-asthmatic 
agents, such as sympathomimetic (isoproterenol, phenylephrine, ephedrine, 
etc); xanthine derivatives (theophylline and aminophyllin); and 
corticosteroids (ACTH and predinisolone). Regarding use of these compounds 
see South African Pat. No. 68/1055. 
The PGE and PGA compounds are useful in mammals, including man and certain 
useful animals, e.g., dogs and pigs, to reduce and control excessive 
gastric secretion, thereby reducing or avoiding gastrointestinal ulcer 
formation, and accelerating the healing of such ulcers already present in 
the gastrointestinal tract. For this purpose, the compounds are injected 
or infused intravenously, subcutaneously, or intramuscularly in an 
infusion dose range about 0.1 .mu.g. to about 500 .mu.g. per kg. of body 
weight per minute, or in a total daily dose by injection or infusion in 
the range about 0.1 to about 20 mg. per kg. of body weight per day, the 
exact dose depending on the age, weight, and condition of the patient or 
animal, and on the frequency and route of administration. 
The PGE, PGF.sub..alpha., and PGF.sub..beta. compounds are useful whenever 
it is desired to inhibit platelet aggregation, to reduce the adhesive 
character of platelets, and to remove or prevent the formation of thrombi 
in mammals, including man, rabbits, and rats. For example, these compounds 
are useful in the treatment and prevention of myocardial infarcts, to 
treat and prevent post-operative thrombosis, to promote patency of 
vascular grafts following surgery, and to treat conditions such as 
atherosclerosis, arteriosclerosis, blood clotting defects due to lipemia, 
and other clinical conditions in which the underlying etiology is 
associated with lipid imbalance or hyperlipidemia. For these purposes, 
these compounds are administered systemically, e.g., intravenously, 
subcutaneously, intramuscularly, and in the form of sterile implants for 
prolonged action. For rapid response, especially in emergency situation, 
the intravenous route of administration is preferred. Doses in the range 
about 0.005 to about 20 mg. per kg. of body weight per day are used, the 
exact dose depending on the age, weight, and condition of the patient or 
animal, and on the frequency and route of administration. 
The PGE, PGF.sub..alpha., and PGF.sub..beta. compounds are especially 
useful as additives to blood, blood products, blood substitutes, and other 
fluids which are used in artifical extracorporeal circulation and 
perfusion of isolated body portions, e.g., limbs and organs, whether 
attached to the original body, detached and being preserved or prepared 
for transplant, or attached to the new body. During these circulations and 
perfusions, aggregated platelets tend to block the blood vessels and 
portions of the circulation apparatus. This blocking is avoided by the 
presence of these compounds. For this purpose, the compound is added 
gradually or in single or multiple portions to the circulating blood, to 
the blood of the donor animal, to the perfused body portion, attached or 
detached, to the recipient, or to two or all of those at a total steady 
state dose of about 0.001 to 10 mg. per liter of circulating fluid. It is 
especially useful to use these compounds in laboratory animals, e.g., 
cats, dogs, rabbits, monkeys, and rats, for these purposes in order to 
develop new methods and techniques for organ and limb transplants. 
PGE compounds are extremely potent in causing stimulation of smooth muscle, 
and are also highly active in potentiating other known smooth muscle 
stimulators, for example, oxytocic agents, e.g., oxytocin, and the various 
ergot alkaloids including derivatives and analogs thereof. Therefore, 
PGE.sub.2, for example, is useful in place of or in combination with less 
than usual amounts of these known smooth muscle stimulators, for example, 
to relieve the symptoms of paralytic ileus, or to control or prevent 
atonic uterine bleeding after abortion or delivery, to aid in expulsion of 
the placenta, and during the puerperium. For the latter purpose, the PGE 
compound is administered by intravenous infusion immediately after 
abortion or delivery at a dose in the range about 0.01 to about 50 .mu.g. 
per kg. of body weight per minute until the desired effect is obtained. 
Subsequent doses are given by intravenous, subcutaneous, or intramuscular 
injection or infusion during puerperium in the range 0.01 to 2 mg. per kg. 
of body weight per day, the exact dose depending on the age, weight, and 
condition of the patient or animal. 
The PGA and PGF.sub..beta. compounds are useful as hypotensive agents to 
reduce blood pressure in mammals, including man. For this purpose, the 
compounds are administered by intravenous infusion at the rate of about 
0.01 to about 50 .mu.g. per kg. of body weight per minute, or in single or 
multiple doses of about 25 to 500 .mu.g. per kg. of body weight total per 
day. 
The PGA compounds and derivatives and salts thereof increase the flow of 
blood in the mammalian kidney, thereby increasing volume and electrolyte 
content of the urine. For that reason, PGA compounds are useful in 
managing cases of renal disfunction, especially in cases of severely 
impaired renal blood flow, for example, the hepatorenal syndrome and early 
kidney transplant rejection. In cases of excessive or inappropriate ADH 
(antidiuretic hormone; vasopressin) secretion, the diuretic effect of 
these compounds is even greater. In anephretic states, the vasopressin 
action of these compounds is especially useful. Illustratively, the PGA 
compounds are useful to alleviate and correct cases of edema resulting, 
for example, from massive surface burns, and in the management of shock. 
For these purposes, the PGA compounds are preferably first administered by 
intravenous injection at a dose in the range 10 to 1000 .mu.g. per kg. of 
body weight or by intraveneous infusion at a dose in the range 0.1 to 20 
.mu.g. per kg. of body weight per minute until the desired effect is 
obtained. Subsequent doses are given by intravenous, intramuscular, or 
subcutaneous injection or infusion in the range 0.05 to 2 mg. per kg. of 
body weight per day. 
The PGE, PGF.sub..alpha., and PGF.sub..beta. compounds are useful in place 
of oxytocin to induce labor in pregnant female animals, including man, 
cows, sheep, and pigs, at or near term, or in pregnant animals with 
intrauterine death of the fetus from about 20 weeks to term. For this 
purpose, the compound is infused intraveneously at a dose of 0.01 to 50 
.mu.g. per kg. of body weight per minute until or near the termination of 
the second stage of labor, i.e., expulsion of the fetus. These compounds 
are especially useful when the female is one or more weeks post-mature and 
natural labor has not started, or 12 to 60 hours after the membranes have 
ruptured and natural labor has not yet started. An alternative route of 
administration is oral. 
The PGE, PGF.sub..alpha., and PGF.sub..beta. compounds are useful for 
controlling the reproductive cycle in ovulating female mammals, including 
humans and animals such as monkeys, rats, rabbits, dogs, cattle, and the 
like. By the term ovulating female mammals is meant animals which are 
mature enough to ovulate but not so old that regular ovulation has ceased. 
For that purpose, PGF.sub.2.alpha., for example, is administered 
systemically at a dose level in the range 0.01 mg. to about 20 mg. per kg. 
of body weight of the female mammal, advantageously during a span of time 
starting approximately at the time of ovulation and ending approximately 
at the time of menses or just prior to menses. Intravaginal and 
intrauterine are alternative routes of administration. Additionally, 
expulsion of an embryo or a fetus is accomplished by similar 
administration of the compound during the first third of the normal 
mammalian gestation period. 
As mentioned above, the PGE compounds are potent antagonists of 
epinephrine-induced mobilization of free fatty acids. For this reason, 
this compound is useful in experimental medicine for both in vitro and in 
vivo studies in mammals, including man, rabbits, and rats, intended to 
lead to the understanding, prevention, symptom alleviation, and cure of 
diseases involving abnormal lipid mobilization and high free fatty acid 
levels, e.g., diabetes mellitus, vascular diseases, and hyperthyroidism. 
The PGE and PGB compounds promote and accelerate the growth of epidermal 
cells and keratin in animals, including humans, useful domestic animals, 
pets, zoological specimens, and laboratory animals. For that reason, these 
compounds are useful to promote and accelerte healing of skin which has 
been damaged, for example, by burns, wounds, and abrasions, and after 
surgery. These compounds are also useful to promote and accelerate 
adherence and growth of skin autografts, especially small, deep (Davis) 
grafts which are intended to cover skinless areas by subsequent outward 
growth rather than initially, and to retard rejection of homografts. 
For these purposes, these compounds are preferably administered topically 
at or near the site where cell growth and keratin formation is desired, 
advantageously as an aerosol liquid or micronized powder spray, as an 
isotonic aqueous solution in the case of wet dressings, or as a lotion, 
cream, or ointment in combination with the usual pharmaceutically 
acceptable diluents. In some instances, for example, when there is 
substantial fluid loss as in the case of extensive burns or skin loss due 
to other causes, systemic administration is advantageous, for example, by 
intravenous injection or infusion, separate or in combination with the 
usual infusions of blood, plasma, or substitutes thereof. Alternative 
routes of administration are subcutaneous or intramuscular near the site, 
oral, sublingual, buccal, rectal, or vaginal. The exact dose depends on 
such factors as the route of administration, and the age, weight, and 
condition of the subject. To illustrate, a wet dressing for topical 
application to second and/or third degree burns of skin area 5 to 25 
square centimeters would advantageously involve use of an isotonic aqueous 
solution containing 1 to 500 .mu.g./ml. of the PGB compound or several 
times that concentration of the PGE compound. Especially for topical use, 
these prostaglandins are useful in combination with antibiotics, for 
example, gentamycin, neomycin, polymyxin B, bacitracin, spectinomycin, and 
oxytetracycline, with other antibacterials, for example, mafenide 
hydrochloride, sulfadiazine, furazolium chloride, and nitrofurazone, and 
with corticoid steroids, for example, hydrocortisone, prednisolone, 
methylprednisolone, and fluprednisolone, each of those being used in the 
combination at the usual concentration suitable for its use alone. 
SUMMARY OF THE INVENTION 
It is a purpose of this invention to provide novel 16-phenoxy and 
16-(substituted phenoxy) prostaglandin analogs in which there is variable 
chain length in the side chains. It is a further purpose to provide 
esters, lower alkanoates, and pharmacologically acceptable salts of said 
analogs. It is a further purpose to provide novel processes for preparing 
said analogs and esters. It is still a further purpose to provide novel 
intermediates useful in said processes. 
The presently described acids and esters of the 16-phenoxy and 
16-(substituted phenoxy) prostaglandin analogs include compounds of the 
following formulas, and also the racemic compounds of each respective 
formula and the mirror image thereof: 
##STR8## 
In formulas VIII to XXII, g is an integer from 2 to 5, inclusive; M is 
##STR9## 
R.sub.1 is hydrogen or alkyl of one to 12 carbon atoms, inclusive, 
cycloalkyl of 3 to 10 carbon atoms, inclusive, aralkyl of 7 to 12 carbon 
atoms, inclusive, phenyl, or phenyl substituted with one, 2, or 3 chloro 
or alkyl of one to 4 carbon atoms, inclusive; R.sub.2 and R.sub.3 are 
hydrogen, methyl, or ethyl; T is alkyl of one to 3 carbon atoms, 
inclusive, fluoro, chloro, trifluoro, or --OR.sub.4 wherein R.sub.4 is 
alkyl of one to 3 carbon atoms, inclusive; and s is zero, one, 2, or 3, 
with the proviso that not more than two T's are other than alkyl. R.sub.2 
and R.sub.3 may be the same or different. 
Formula IX represents 16-phenoxy-18,19,20-trinor-PGF.sub.1.alpha. when g is 
3, M is 
##STR10## 
R.sub.1 and R.sub.2 are hydrogen, R.sub.3 is methyl, and s is zero. 
Formula XIII represents 
16-(2,4-dichlorophenoxy)-16-methyl-2a,2b-dihomo-18,19,20-trinor-PGE.sub.2, 
methyl ester, when g is 5, M is 
##STR11## 
R.sub.1, R.sub.2, and R.sub.3 are methyl, T is chloro, and s is 2. Formula 
XX represents 
16-(4-fluoro-2,5-xylyloxy)-2,19,20-trinor-15.beta.-13,14-dihydro-PGF.sub.1 
.beta., dodecyl ester, when g is 2, M is 
##STR12## 
R.sub.1 is dodecyl, R.sub.2 is hydrogen, R.sub.3 is ethyl, T is fluoro and 
methyl, and s is 3. 
In the name of the formula-IX example above, "18,19,20-trinor" indicates 
absence of three carbon atoms from the hydroxy-substituted side chain of 
the PGF.sub.1.alpha. structure. Following the atom numbering of the 
prostanoic acid structure, C-18, C-19, C-20 are construed as missing, and 
the methylene at C-17 is replaced with a terminal methyl group. Likewise, 
in the formula-XX example, "2,19,20-trinor" indicates the absence of the 
C-2 carbon atom from the carboxy-terminated side chain, and the C-19 and 
C-20 carbon atoms from the hydroxy-substituted side chain. In this system 
of nomenclature, the words "nor," "dinor," "trinor," "tetranor," or 
"pentanor" in the names of the prostaglandin analogs are to be construed 
as indicating one, two, three, four, or five carbon atoms, respectively, 
missing from the C-2 to C-4 and C-17 to C-20 positions of the prostanoic 
acid carbon skeleton. 
In the name of the formula-XIII example, "2a,2b-dihomo" indicates two 
additional carbon atoms in the carboxy-terminated side chain specifically 
between the C-2 and C-3 carbon atoms. There are, therefore, nine carbon 
atoms in that side chain instead of the normal seven in the prostanoic 
acid structure. From the end of the chain to the double bond of the 
example they are identified as C-1, C-2, C-2a, C-2b, C-3, C-4, and C-5. 
The carbon atoms connected by the cis double bond are C-5 and C-6, and the 
carbon atoms between the double bond and the ring are C-6 and C-7. 
As in the case of formulas II to VII, formulas VIII to XXII, wherein M is 
##STR13## 
i.e. wherein the hydroxyl is attached to the side chain in alpha 
configuration, are each intended to represent optically active prostanoic 
acid derivatives with the same absolute configuration as PGE.sub.1 
obtained from mammalian tissues. 
Also included within this invention are the 15-epimer compounds of formulas 
VIII to XXII wherein M is 
##STR14## 
i.e. the C-15 hydroxyl is in beta configuration. Hereinafter "15.beta." 
refers to the epimeric configuration. Thus, 
"16-phenoxy-18,19,20-trinor-15.beta.-PGF.sub.1.alpha. " identifies the 
15-epimeric compound corresponding to the formula-IX example above except 
that it has the beta configuration at C-15 instead of the natural alpha 
configuration of 16-phenoxy-18,19,20-trinor-PGF.sub.1.alpha.. 
Each of formulas VIII to XXII plus its mirror image describe a racemic 
compound within the scope of this invention. For convenience hereinafter, 
such a racemic compound is designated by the prefix "racemic" (or "dl") 
before its name; when that prefix is absent, the intent is to designate an 
optically active compound represented by the appropriate formula VIII to 
XXII. 
With regard to formulas VIII to XXII, examples of alkyl of one to 12 carbon 
atoms, inclusive, are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, 
octyl, nonyl, decyl, undecyl, dodecyl, and isomeric forms thereof. 
Examples of cycloalkyl of 3 to 10 carbon atoms, inclusive, which includes 
alkyl-substituted cycloalkyl, are cyclopropyl, 2-methylcyclopropyl, 
2,2-dimethylcyclopropyl, 2,3-diethylcyclopropyl, 2-butylcyclopropyl, 
cyclobutyl, 2-methylcyclobutyl, 3-propylcyclobutyl, 
2,3,4-triethylcyclobutyl, cyclopentyl, 2,2-dimethylcyclopentyl, 
2-pentylcyclopentyl, 3-tert-butylcyclopentyl, cyclohexyl, 
4-tert-butylcyclohexyl, 3-isopropylcyclohexyl, 2,2-dimethylcyclohexyl, 
cycloheptyl, cyclooctyl, cyclononyl, and cyclodecyl. Examples of aralkyl 
of 7 to 12 carbon atoms, inclusive, are benzyl, phenethyl, 1-phenylethyl, 
2-phenylpropyl, 4-phenylbutyl, 3-phenylbutyl, 2-(1-naphthylethyl), and 
1-(2-naphthylmethyl). Examples of phenyl substituted by one to 3 chloro or 
alkyl of one to 4 carbon atoms, inclusive, are p-chlorophenyl, 
m-chlorophenyl, o-chlorophenyl, 2,4-dichlorophenyl, 2,4,6-trichlorophenyl, 
p-tolyl, m-tolyl, o-tolyl, p-ethylphenyl, p-tertbutylphenyl, 
2,5-dimethylphenyl, 4-chloro-2-methylphenyl, and 
2,4-dichloro-3-methylphenyl. 
Examples of 
##STR15## 
as defined above are phenyl, (o--, m--, or p--)tolyl, (o--, m--, or 
p--)ethylphenyl, 2-ethyl-p-tolyl, 4-ethyl-o-tolyl, 5-ethyl-m-tolyl, (o--, 
m--, or p--)-propylphenyl, 2-propyl-(o--, m--, p--)tolyl, 
4-isopropyl-2,6-xylyl, 3-propyl-4-ethylphenyl, (2,3,4-, 2,3,5-, 2,3,6-, or 
2,4,5-)trimethylphenyl, (o--, m--, or p--)fluorophenyl, 2-fluoro-(o--, 
m--, or p--)tolyl, 4-fluoro-2,5-xylyl, (2,4-, 2,5-, 2,6-, 3,4-, or 
3,5-)difluorophenyl, (o--, m--, or p--)-chlorophenyl, 2-chloro-p-tolyl, 
(3-, 4-, 5-, or 6-)chloro-o-tolyl, 4-chloro-2-propylphenyl, 
2-isopropyl-4-chlorophenyl, 4-chloro-3,5-xylyl, (2,3-, 2,4-, 2,5-, 2,6-, 
3,4-, or 3,5-)dichlorophenyl, 4-chloro-3-fluorophenyl, (3-, or 
4-)chloro-2-fluorophenyl, .alpha.,.alpha.,.alpha.-trifluoro-(o--, m--, or 
p--)-tolyl, (o--, m--, or p--)methoxyphenyl, (o--, m--, or 
p--)ethoxyphenyl, (4- or 5-)chloro-2-methoxyphenyl, and 2,4-dichloro(5- or 
6-)methoxyphenyl. 
Accordingly, there is provided an optically active compound of the formula 
##STR16## 
or a racemic compound of that formula and the mirror image thereof, 
wherein D is one of the four carbocyclic moieties: 
##STR17## 
wherein .about. indicates attachment of hydroxyl to the ring in alpha or 
beta configuration; wherein (a) X is trans--CH.dbd.CH--or --CH.sub.2 
CH.sub.2 -, and Y is --CH.sub.2 CH.sub.2 --, or (b) X is 
trans--CH.dbd.CH--and Y is cis--CH.dbd.CH--; wherein g is an integer from 
2 to 5, inclusive; wherein M is 
##STR18## 
wherein R.sub.1 is hydrogen or alkyl of one to 12 carbon atoms, inclusive, 
cycloalkyl of 3 to 10 carbon atoms, inclusive, aralkyl of 7 to 12 carbon 
atoms, inclusive, phenyl, or phenyl substituted with one, 2, or 3 chloro 
or alkyl of one to 4 carbon atoms, inclusive; wherein R.sub.2 and R.sub.3 
are hydrogen, methyl, or ethyl; wherein T is alkyl of one to 3 carbon 
atoms, inclusive, fluoro, chloro, trifluoro, or --OR.sub.4 wherein R.sub.4 
is alkyl of one to 3 carbon atoms, inclusive, and wherein s is zero, one, 
2, or 3, with the proviso that not more than two T's are other than alkyl; 
including the lower alkanoates thereof, and the pharmacologically 
acceptable salts thereof when R.sub.1 is hydrogen. 
Formula XXIII, which is written in generic form for convenience, represents 
PGE-type compounds when D is 
##STR19## 
PGF.sub..alpha. -type compounds when D is 
##STR20## 
PGF.sub..beta. -type compounds when D is 
##STR21## 
PGA-type compounds when D is 
##STR22## 
and PGB-type compounds when D is 
##STR23## 
The novel formula VIII-to-XXIII compounds and the racemic compounds of this 
invention each cause the biological responses described above for the PGE, 
PGF.sub..alpha., PGF.sub..beta., PGA, and PGB compounds, respectively, and 
each of these novel compounds is accordingly useful for the abovedescribed 
corresponding purposes, and is used for those purposes in the same manner 
as described above. 
The known PGE, PGF.sub..alpha., PGF.sub..beta., PGA, and PGB compounds are 
all potent in causing multiple biological responses even at low doses. For 
example, PGE.sub.1 and PGE.sub.2 both cause vasodepression and smooth 
muscle stimulation at the same time they exert antilipolytic activity. 
Moreover, for many applications, these known prostaglandins have an 
inconveniently short duration of biological activity. In striking 
contrast, the novel prostaglandin analogs of formulas VIII to XXIII and 
their racemic compounds are substantially more specific with regard to 
potency in causing prostaglandin-like biological responses, and have a 
substantially longer duration of biological activity. Therefore, each of 
these novel prostaglandin analogs is surprisingly and unexpectedly more 
useful than one of the corresponding above-mentioned known prostaglandins 
for at least one of the pharmacological purposes indicated above for the 
latter, because it has a different and narrower spectrum of biological 
potency than the known prostaglandin, and therefore is more specific in 
its activity and causes smaller and fewer undesired side effects than when 
the known prostaglandin is used for the same purpose. Moreover, because of 
its prolonged activity, fewer and smaller doses of the novel prostaglandin 
analog can frequently be used to attain the desired result. 
To obtain the optimum combination of biological response specificity, 
potency, and duration of activity, certain compounds within the scope of 
formulas VIII to XXIII are preferred. For example, it is preferred that 
the hydroxyl at C-15 be in the alpha configuration. 
Another preference is that g be 3, i.e. that the carboxy-terminated side 
chain contain 7 carbon atoms. 
Another preference is that subsitution on the phenoxy be in the para 
position, at least. 
Still another preference is that R.sub.2 and R.sub.3 be hydrogen or methyl. 
Both can be hydrogen, both can be methyl, or one can be hydrogen and the 
other methyl. When only one is methyl, C-16 is an asymmetric carbon atom 
and two isomeric forms exist with respect to the stereochemistry at C-16. 
That isomer is preferred, for the purposes described herein, which has the 
greater desired biological activity when subjected to tests known in the 
art. For example, smooth muscle stimulation is indicated in smooth muscle 
strip tests (see J. R. Weeks et al., Journal of Applied Physiology 25, 
(No. 6), 783 (1968); and antisecretory activity is indicated in in vivo 
tests with laboratory animals (see A. Robert, "Antisecretory Property of 
Prostaglandins," Prostaglandin Symposium of the Worcester Foundation for 
Experimental Biology, Interscience, 1968, pp. 47-54). 
Another advantage of the novel compounds of this invention, expecially the 
preferred compounds defined hereinabove, compared with the known 
prostaglandins, is that these novel compounds are administered effectively 
orally, sublingually, intravaginally, bucally, or rectally, in addition to 
usual intravenous, intramuscular, or subcutaneous injection or infusion 
methods indicated above for the uses of the known prostaglandins. These 
qualities are advantageous because they facilitate maintaining uniform 
levels of these compounds in the body with fewer, shorter, or smaller 
doses, and make possible self-administration by the patient. 
The 16-phenoxy and 16-(substituted phenoxy) PGE, PGF.sub..alpha., 
PGF.sub..beta., PGA, and PGB-type analogs encompassed by Formulas VIII to 
XXIII including their alkanoates, are used for the purposes described 
above in the free acid form, in ester form, or in pharmacologically 
acceptable salt form. When the ester form is used, the ester is any of 
those within the above definition of R.sub.1. However, it is preferred 
that the ester be alkyl of one to 12 carbon atoms, inclusive. Of those 
alkyl, methyl and ethyl are especially preferred for optimum absorption of 
the compound by the body or experimental animal system; and straight-chain 
octyl, nonyl, decyl, undecyl, and dodecyl are especially preferred for 
prolonged activity in the body or experimental animal. 
Pharmacologically acceptable salts of these Formula VIII-to-XXIII compounds 
useful for the purposes described above are those with pharmacologically 
acceptable metal cations, ammonium, amine cations, or quaternary ammonium 
cations. 
Especially preferred metal cations are those derived from the alkali 
metals, e.g., lithium, sodium and potassium, and from the alkaline earth 
metals, e.g., magnesium and calcium, although cationic forms of other 
metals, e.g., aluminum, zinc, and iron are within the scope of this 
invention. 
Pharmacologically acceptable amine cations are those derived from primary, 
secondary, or tertiary amines. Examples of suitable amines are 
methylamine, dimethylamine, trimethylamine, ethylamine, dibutylamine, 
triisopropylamine, N-methylhexylamine, decylamine, dodecylamine, 
allylamine, crotylamine, cyclopentylamine, dicyclohexylamine, benzylamine, 
dibenzylamine, .alpha.-phenylethylamine, .beta.-phenylethylamine, 
ethylenediamine, diethylenetriamine, and like aliphatic, cycloaliphatic, 
and araliphatic amines containing up to and including about 18 carbon 
atoms, as well as heterocyclic amines, e.g., piperidine, morpholine, 
pyrrolidine, piperazine, and lower-alkyl derivatives thereof, e.g., 
1-methylpiperidine, 4-ethylmorpholine, 1-isopropylpyrrolidine, 
2-methylpyrrolidine, 1,4-dimethylpiperazine, 2-methylpiperidine, and the 
like, as well as amines containing water-solubilizing or hydrophilic 
groups, e.g., mono-, di-, and triethanolamine, ethyldiethanolamine, 
N-butylethanolamine, 2-amino-1-butanol, 2-amino-2-ethyl-1,3-propanediol, 
2-amino-2-methyl-1-propanol, tris(hydroxymethyl)aminomethane, 
N-phenylethanolamine, N-(p-tert-amylphenyl)diethanolamine, galactamine, 
N-methylglycamine, N-methylglucosamine, ephedrine, phenylephrine, 
epinephrine, procaine, and the like. 
Examples of suitable pharmacologically acceptable quaternary ammonium 
cations are tetramethylammonium, tetraethylammonium, 
benzyltrimethylammonium, phenyltriethylammonium, and the like. 
The compounds encompassed by Formulas VIII to XXIII are used for the 
purposes described above in free hydroxy form or also in the form wherein 
the hydroxy moieties are transformed to lower alkanoate moieties, e.g., 
--OH to --OCOCH.sub.3. Examples of lower alkanoate moieties are acetoxy, 
propionyloxy, butyryloxy, valeryloxy, hexanoyloxy, heptanoyloxy, 
octanoyloxy, and branched chain alkanoyloxy isomers of those moieties. 
Especially preferred among these alkanoates for the above described 
purposes are the acetoxy compounds. These free hydroxy and alkanoyloxy 
compounds are used as free acids, as esters, and in salt form all as 
described above. 
As discussed above, the compounds of Formulas VIII to XXIII are 
administered in various ways for various purposes; e.g., intravenously, 
intramuscularly, subcutaneously, orally, intravaginally, rectally, 
buccally, sublingually, topically, and in the form of sterile implants for 
prolonged action. For intravenous injection or infusion, sterile aqueous 
isotonic solutions are preferred. For that purpose, it is preferred 
because of increased water solubility that R.sub.1 in the formula 
VIII-to-XXIII compound be hydrogen or a pharmacologically acceptable 
cation. For subcutaneous or intramuscular injection, sterile solutions or 
suspensions of the acid, salt, or ester form in aqueous or non-aqueous 
media are used. Tablets, capsules, and liquid preparations such as syrups, 
elixirs, and simple solutions, with the usual pharmaceutical carriers are 
used for oral sublingual administration. For rectal or vaginal 
administration, suppositories prepared as known in the art are used. For 
tissue implants, a sterile tablet or silicone rubber capsule or other 
object containing or impregnated with the substance is used. 
The 16-phenoxy and 16-(substituted phenoxy) PGE-, PGF.sub..alpha. -, 
PGF.sub..beta. -, PGA-, and PGB-type analogs encompassed by formulas VIII 
to XXIII are produced by the reactions and procedures described and 
exemplified hereinafter. 
Reference to Charts A and B herein, will make clear the steps for preparing 
the formula-XXIV through XXXIV intermediates. 
Previously, the preparation of an intermediate bicyclic lactone diol of the 
formula 
##STR24## 
was reported by E. J. Corey et al., J. Am. Chem. Soc. 91, 5675 (1969), and 
later disclosed in an optically active 
##STR25## 
form by E. J. Corey et al., J. Am. Chem. Soc. 92, 397 (1970). Conversion 
of this intermediate to PGE.sub.2 and PGF.sub.2.alpha., either in 
racematic or optically active form, was disclosed in those publications. 
The iodolactone of formula XXIV in Chart A is known in the art (see Corey 
et al., above). It is available in either racemic or optically active (+ 
or -) form. For racemic products, the racemic form is used. For 
prostaglandins of natural configuration, the laevorotatory form (-) is 
used. 
In Charts A and B, g, M, R.sub.2, R.sub.3, T, and s have the same meanings 
as defined above, namely: g is an integer from 2 to 5, inclusive; M is 
##STR26## 
R.sub.2 and R.sub.3 are hydrogen, methyl, or ethyl, T is alkyl of one to 3 
carbon atoms, inclusive, fluoro, chloro, trifluoromethyl, or OR.sub.4 
wherein R.sub.4 is alkyl of one to 3 carbon atoms, inclusive, and s is 
zero, one, 2 or 3, with the proviso that not more than two T's are other 
than alkyl. In addition, M' is 
##STR27## 
THP is tetrahydropyranyl; Q is 
##STR28## 
wherein R.sub.2, R.sub.3, T, and s are as defined above; and .about. 
represents attachment of hydroxy in alpha or beta configuration. 
The formula-XXV compound (Chart A) bears an R.sub.5 O-- moiety at the 
4-position, wherein R.sub.5 is (1) 
##STR29## 
wherein G is alkyl of one to 3 carbon atoms, inclusive, phenylalkyl of 7 
to 10 carbon atoms, inclusive, or nitro, and j is zero to 5, inclusive, 
provided that not more than two G's are other than alkyl, and that the 
total number of carbon atoms in the G's does not exceed 10 carbon atoms; 
(2) 
##STR30## 
wherein R.sub.6 is alkyl of one to 4 carbon atoms, inclusive; (3) 
##STR31## 
wherein G and j are as defined above; or (4) acetyl. In preparing the 
formula-XXV compound by replacing the hydrogen of the hydroxyl group in 
the 4-position with the acyl group R.sub.5, methods known in the art are 
used. Thus, an aromatic acid of the formula R.sub.5 OH, wherein R.sub.5 is 
as defined above, for example benzoic acid, is reacted with the 
formula-XXIV compound in the presence of a dehydrating agent, e.g. 
sulfuric acid, zinc chloride, or phosphoryl chloride; or an anhydride of 
the aromatic acid of the formula (R.sub.5).sub.2 O, for example benzoic 
anhydride, is used. 
Preferably, however, an acyl halide, R.sub.5 Cl, for example benzoyl 
chloride, is reacted with the formula-XXIV compound in the presence of a 
hydrogen chloride-scavenger, e.g. a tertiary amine such as pyridine, 
triethylamine, and the like. The reaction is carried out under a variety 
of conditions using procedures generally known in the art. Generally, mild 
conditions are employed, e.g. 20.degree.-60.degree. C., contacting the 
reactants in a liquid medium, e.g. excess pyridine or an inert solvent 
such as benzene, toluene or chloroform. The acylating agent is used either 
in stoichiometric amount or in excess. 
The following examples of R.sub.5 are available as acids (R.sub.5 OH), 
anhydrides ((R.sub.5).sub.2 O), or acyl chlorides (R.sub.5 Cl): benzoyl; 
substituted benzoyl, e.g. (2-, 3- or 4-)methylbenzoyl, (2-, 3-, or 
4-)ethylbenzoyl, (2-, 3-, or 4-)-isopropylbenzoyl, 2,4-dimethylbenzoyl, 
3,5-dimethylbenzoyl, 2-isopropyltoluyl, 2,4,6-trimethylbenzoyl, 
pentamethylbenzoyl, .alpha.-phenyl-(2-, 3-, or 4-)toluyl, (2-, 3-, or 
4-)-phenethylbenzoyl, 2-, 3-, or 4-nitrobenzoyl, (2,4- 2,5- or 
3,5-)dinitrobenzoyl, 3,4-dimethyl-2-nitrobenzoyl, 
4,5-dimethyl-2-nitrobenzoyl, 2-nitro-6-phenethylbenzoyl, 
3-nitro-2-phenethylbenzoyl; mono-esterified phthaloyl, e.g. 
##STR32## 
isophthaloyl, e.g. 
##STR33## 
or terephthaloyl, e.g. 
##STR34## 
(1- or 2-)naphthoyl; substituted naphthoyl, e.g. (2-, 3-, 4-, 5-, 6-, or 
7-)methyl-1-naphthoyl, (2- or 4-)ethyl-1-naphthoyl, 
2-isopropyl-1-naphthoyl, 4,5-dimethyl-1-naphthoyl, 
6-isopropyl-4-methyl-1-naphthoyl, 8-benzyl-1-naphthoyl, (3-, 4-, 5-, or 
8-)nitro-1-naphthoyl, 4,5-dinitro-1-naphthoyl, (3-, 4-, 6-, 7-, or 
8-)methyl-1-naphthoyl, 4-ethyl-2-naphthoyl, and (5- or 
8-)-nitro-2-naphthoyl; and acetyl. There may be employed, therefore, 
benzoyl chloride, 4-nitrobenzoyl chloride, 3,5-dinitrobenzoyl chloride, 
and the like, i.e. R.sub.5 Cl compounds corresponding to the above R.sub.5 
groups. If the acyl chloride is not available, it is made from the 
corresponding acid and phosphorus pentachloride as is known in the art. It 
is preferred that the R.sub.5 OH, (R.sub.5).sub.2 O, or R.sub.5 Cl 
reactant does not have bulky, hindering substituents, e.g. tert-butyl, on 
both of the ring carbon atoms adjacent to the carbonyl attaching-site. 
The formula-XXVI compound is next obtained by deiodination of XXV using a 
reagent which does not react with the lactone ring or the OR.sub.5 moiety, 
e.g. zinc dust, sodium hydride, hydrazine-palladium, hydrogen and Raney 
nickel or platinum, and the like. Especially preferred is tributyltin 
hydride in benzene at about 25.degree. C. with 
2,2'-azobis(2-methylpropionitrile) as initiator. 
The formula-XXVII compound is obtained by demethylation of XXVI with a 
reagent that does not attack the OR.sub.5 moiety, for example boron 
tribromide or trichloride. The reaction is carried out preferably in an 
inert solvent at about 0.degree.-5.degree. C. 
The formula-XXVIII compound is obtained by oxidation of the --CH.sub.2 OH 
of XXVII to --CHO, avoiding decomposition of the lactone ring. Useful for 
this purpose are dichromatesulfuric acid, Jones reagent, lead 
tetraacetate, and the like. Especially preferred is Collins' reagent 
(pyridineCrO.sub.3) at about 0.degree.-10.degree. C. 
The formula-XXIX compound is obtained by Wittig alkylation of XXXI, using 
the sodio derivative of the appropriate 2-oxo-3-phenoxy (or 3-substituted 
phenoxy)-alkylphosphonate. The trans enone lactone is obtained 
stereospecifically (see D. H. Wadsworth et al., J. Org. Chem. Vol. 30, p. 
680 (1965)). 
In preparing the formula-XXIX compounds of Chart B, certain phosphonates 
are employed in the Wittig reaction. These are of the general formula 
##STR35## 
wherein R.sub.2 and R.sub.3 are hydrogen, methyl, or ethyl, being the same 
or different; R.sub.7 is alkyl of one to 8 carbon atoms, inclusive; T is 
alkyl of one to 3 carbon atoms, inclusive, fluoro, chloro, trifluoro, or 
--OR.sub.4 wherein R.sub.4 is alkyl of one to 3 carbon atoms, inclusive, 
and s is zero, one, 2, or 3, with the proviso that not more than two T's 
are other than alkyl. 
As examples of phosphonates useful for this purpose there are: 
##STR36## 
The phosphonates are prepared and used by methods known in the art. See 
Wadsworth et al., reference cited above. Conveniently, the appropriate 
aliphatic acid ester is condensed with the anion of dimethyl 
methylphosphonate produced by n-butyllithium. For this purpose, acids of 
the general formula 
##STR37## 
are used in the form of their lower alkyl esters, preferably methyl or 
ethyl. The methyl esters, for example, are readily formed from the acids 
by reaction with diazomethane. These aliphatic acids of various chain 
length, with phenoxy or substituted-phenoxy substitution within the scope 
of 
##STR38## 
as defined above are known in the art or can be prepared by methods known 
in the art. 
Many phenoxy-substituted acids are readily available, e.g. where R.sub.2 
and R.sub.3 are both hydrogen: phenoxy-, (o--, m--, or p--)tolyloxy-, 
(o--, m--, or p--)ethylphenoxy-, 4-ethyl-o-tolyloxy-, (o--, m--, or 
p--)propylphenoxy-, (o--, m--, or p--)-t-butylphenoxy-, (o--, m--, or 
p--)fluorophenoxy-, 4-fluoro-2,5-xylyloxy-, (o--, m--, or 
p--)chlorophenoxy-, (2,3-, 2,4-, 2,5-, 2,6-, 3,4-, or 
3,5-)dichlorophenoxy-, .alpha.,.alpha.,.alpha.-trifluoro-(o--, m--, or 
p--)tolyloxy-, or (o--, m--, or p--)methoxyphenoxyacetic acid; where 
R.sub.2 is methyl and R.sub.3 is hydrogen: 2-phenoxy-, 2-(o--, m--, or 
p--)tolyloxy-, 2-(3,5-xylyloxy)-, 2-(p-fluorophenoxy)-, 2-[o--, m--, or 
p--)chlorophenoxy]-, 2-[2,3-, 2,4-, 2,5-, 2,6-, 3,4-, or 
3,5-)dichlorophenoxy]-, 2-[(4- or 6-)chloro-o-tolyloxy]-, or 
2-(.alpha.,.alpha.,.alpha.-trifluoro-m-tolyloxy)-propionic acid; wherein 
R.sub.2 and R.sub.3 are both methyl: 2-methyl-2-phenoxy-, 2-[(o-, m-, or 
p-)chlorophenoxy]-2-methyl-, or 2-[(2,3-, 2,4-, 2,5-, 2,6-, 3,4-, or 
3,5-)dichlorophenoxy]-2-methylpropionic acid; where R.sub.2 is ethyl and 
R.sub.3 is hydrogen: 2-phenoxy-, 2-[(o--, m--, or p--)fluorophenoxy]-, 
2-[(o--, m--, or p--)chlorophenoxy]-, 2-[(2,3-, 2,4-, 2,5-, 2,6-, 3,4-, or 
3,5-)dichlorophenoxy]-, or 2-(2-chloro-4-fluorophenoxy)-butyric acid; 
where R.sub.2 is ethyl and R.sub.3 is methyl: 2-methyl-2-phenoxy- or 
2-[(o--, m--, or p--)chlorophenoxy]-2-methylbutyric acid. 
Other phenoxy substituted acids are available by methods known in the art, 
for example, by the Williamson synthesis of ethers using an alpha-halo 
aliphatic acid or ester with sodium phenoxide or a substituted sodium 
phenoxide. Thus, the methyl ester of 2-(o-methoxyphenoxy)-2-methylbutyric 
acid is obtained by the following reaction: 
##STR39## 
The reaction proceeds smoothly with heating and the product is recovered in 
the conventional way. The methyl ester is used for preparing the 
corresponding phosphonate as discussed above. 
Alternatively, the phosphonate is prepared from an aliphatic acyl halide 
and the anion of a dialkyl methylphosphonate. Thus, 
2-methyl-2-phenoxypropionyl chloride and dimethyl methylphosphonate yield 
dimethyl 2-oxo-3-methyl-3-phenoxybutylphosphonate. The acyl halides are 
readily available from the aliphatic acids by methods known in the art, 
e.g. chlorides are conveniently prepared using thionyl chloride. 
Continuing with Chart B, the formula-XXX compound is obtained as a mixture 
of alpha and beta isomers by reduction of XXIX. For this reduction, use is 
made of any of the known ketonic carbonyl reducing agents which do not 
reduce ester or acid groups or carbon-carbon double bonds when the latter 
is undesirable. Examples of those are the metal borohydrides, especially 
sodium, potassium, and zinc borohydrides, lithium 
(tri-tert-butoxy)aluminum hydride, metal trialkoxy borohydrides, e.g., 
sodium trimethoxyborohydride, lithium borohydride, diisobutyl aluminum 
hydride, and when carbon-carbon double bond reduction is not a problem, 
the boranes, e.g., disiamylborane. 
For production of natural-configuration PG-type compounds, the desired 
15-alpha form of the formula-XXX compound is separated from the 15-beta 
isomer by silica gel chromatography. 
The formula-XXXI compound is then obtained by deacylation of XXX with an 
alkali metal carbonate, for example potassium carbonate in methanol at 
about 25.degree. C. 
The bis(tetrahydropyranyl) ether XXXII is obtained by reaction of the 
formula-XXXI diol with dihydropyran in an inert solvent, e.g. 
dichloromethane, in the presence of an acid condensing agent such as 
p-toluenesulfonic acid or pyridine hydrochloride. The dihydropyran is used 
in excess, preferably 4 to 10 times theory. The reaction is normally 
complete in 15-30 min. at 20.degree.-30.degree. C. 
The lactol XXXIII is obtained on reduction of the formula-XXXII lactone or 
its 15.beta. epimer without reducing the 13,14-ethylenic group. For this 
purpose, diisobutylaluminum hydride is used. The reduction is preferably 
done at -60.degree. to -70.degree. C. The 15.beta.-epimer of the 
formula-XXXII lactone is readily obtained by the steps of Chart B, using 
the 15.beta. isomer of formula XXX. 
The formula-XXXIV compound is obtained from the formula-XXXIII lactol by 
the Wittig reaction, using a Wittig reagent derived from the appropriate 
.omega.-carboxyalkyltriphenylphosphonium bromide, HOOC-(CH.sub.2).sub.g+1 
-P(C.sub.6 H.sub.5).sub.3 Br, and sodio dimethylsulfinylcarbanide. The 
reaction is conveniently carried out at about 25.degree. C. This 
formula-XXXIV compound serves as an intermediate for preparing either the 
PGF.sub.2.alpha. -type or the PGE.sub.2 -type product (Chart C). The 
phosphonium compounds are known in the art or are readily available, e.g. 
by reaction of an .omega.-bromoaliphatic acid with triphenylphosphine. 
The formula-XXXV PGF.sub.2.alpha. -type product is obtained on hydrolysis 
of the tetrahydropyranyl groups from the formula-XXXIV compound, e.g. with 
methanol-HCl or with acetic acid/water/tetrahydrofuran at 
40.degree.-55.degree. C. 
Reference to Chart C will make clear the preparation of the PGE.sub.2 -type 
products. The formula-XXXVI bis(tetrahydropyranyl) ether of the 
PGF.sub.2.alpha. -type products, either as an acid represented by formula 
XXIV or as an ester is oxidized at the 9-hydroxy position, preferably with 
Jones reagent. Finally the tetrahydropyranyl groups are replaced with 
hydrogen, by hydrolysis as in preparing the PGF.sub.2.alpha. -type product 
of Chart B. In Chart C, the symbols g, M, M', Q, and THP have the same 
meanings as in Charts A and B; R.sub.1 is hydrogen or alkyl of one to 12 
carbon atoms, inclusive, 
##STR40## 
cycloalkyl of 3 to 10 carbon atoms, inclusive, aralkyl of 7 to 12 carbon 
atoms, inclusive, phenyl, or phenyl subsubstituted with one, 2, or 3 
chloro or alkyl of one to 4 carbon atoms, inclusive. The esters, wherein 
R.sub.1 is not hydrogen, are readily obtained by methods known in the art, 
e.g. reaction with diazoalkanes. 
The formula-VIII PGE.sub.1 and formula-XVIII 13,14-dihydro-PGE.sub.1 type 
products of this invention are prepared by ethylenic reduction of the 
formula-XIII PGE.sub.2 type compounds. Reducing agents useful for this 
transformation are known in the art. Thus, hydrogen is used at atmospheric 
pressure or low pressure with catalysts such as palladium on charcoal or 
rhodium on aluminum. See, for example, E.J. Corey et al., J. Am. Chem. 
Soc. 91, 5677 (1969) and B. Samuelsson, J. Biol. Chem. 239, 4091 (1964). 
For the PGE.sub.1 type compounds, the reduction is terminated when one 
equivalent of hydrogen is absorbed; for the 13,14-dihydro-PGE.sub.1 type 
compounds, when two equivalents are absorbed. The 13,14-dihdyro-PGE.sub.1 
compounds are also obtained by reduction of the PGE.sub.1 compounds. For 
preparing the PGE.sub.1 -type compounds it is preferred that a catalyst 
such as nickel boride be used which selectively effects reduction of the 
cis-5,6-carbon-carbon double bond in the presence of the trans-13,14 
unsaturation. Mixtures of the products are conveniently separated by 
silica gel chromatography. 
Alternatively, the bis(tetrahydropyranyl) ethers of the PGE.sub.2 type 
compounds (Formula XXXVI) are reduced and subsequently hydrolyzed to 
remove the tetrahydropyranyl groups. 
Chart D shows transformations from the formula-XXXIX PGE-type compounds to 
the corresponding PGF-, PGA-, and 
##STR41## 
PGB-type compounds. In figures XXXIX, XL, XLI, and XLII of Chart D, g, M, 
R.sub.2, R.sub.3, T, s, and .about. have the same meanings as in Charts A 
and B; R.sub.1 has the same meanings as in Chart C; and (a) X is 
trans-CH.dbd.CH-- or --CH.sub.2 CH.sub.2, and Y is --CH.sub.2 CH.sub.2 --, 
or (b) X is trans-CH.dbd.CH-- and Y is cis-CH.dbd.CH--. When X is 
trans-CH.dbd.CH-- and Y is --CH.sub.2 CH.sub.2 --, formula XXXIX 
represents PGE.sub.1 -type compounds; when X is --CH.sub.2 CH.sub.2 -- and 
Y is --CH.sub.2 CH.sub.2 --, formula XXXIX represents 
13,14-dihydro-PGE.sub.1 type compounds; and when X is trans-CH.dbd.CH-- 
and Y is cis-CH.dbd.CH--, formula XXXIX represents PGE.sub.2 -type 
compounds. Thus, formulas XXXIX, XL, XLI, and XLII embrace all of the 
compounds represented herein by formulas VIII-XXIII. 
Thus, the various PGF.sub..beta. -type compounds encompassed by formulas X, 
XV, and XX are prepared by carbonyl reduction of the corresponding 
PGE-type compounds of formulas VIII, XIII, and XVIII, respectively. For 
example, carbonyl reduction of 16-phenoxy-18,19,20-trinor-PGE.sub.1 gives 
a mixture of 16-phenoxy-18,19,20-trinor-PGF.sub.1.alpha. and 
16-phenoxy-18,19,20-trinor-PGF.sub.1.beta.. These ring carbonyl reductions 
are carried out by methods known in the art for ring carbonyl reductions 
of known prostanoic acid derivatives. See, for example, Bergstrom et al., 
Arkiv Kemi 19, 563 (1963), Acta. Chem. Scand. 16, 969 (1962), and British 
Specification No. 1,097,533. Any reducing agent is used which does not 
react with carbon-carbon double bonds or ester groups. Preferred reagents 
are lithium(tri-tert-butoxy)aluminum hydride, the metal borohydrides, 
especially sodium, potassium and zinc borohydrides, the metal trialkoxy 
borohydrides, e.g., sodium trimethoxyborohydride. The mixtures of alpha 
and beta hydroxy reduction products are separated into the individual 
alpha and beta isomers by methods known in the art for the separation of 
analogous pairs of known isomeric prostanoic acid derivatives. See, for 
example, Bergstrom et al., cited above, Granstrom et al., J. Biol. Chem. 
240, 457 (1965), and Green et al., J. Lipid Research 5, 117 (1964). 
Especially preferred as separation methods are partition chromatographic 
procedures, both normal and reversed phase, preparative thin layer 
chromatography, and countercurrent distribution procedures. 
The various PGA-type compounds encompassed by formulas XI, XVI, and XXI are 
prepared by acidic dehydration of the corresponding PGE-type compounds of 
formulas VIII, XIII, and XVIII. For example, acidic dehydration of 
16-methyl-16-phenoxy-18,19,20-trinor-PGE.sub.2 gives 
16-methyl-16-phenoxy-18,19,20-trinor-PGA.sub.2. 
These acidic dehydrations are carried out by methods known in the art for 
acidic dehydrations of known prostanoic acid derivatives. See, for 
example, Pike et al., Proc. Nobel Symposium II, Stockholm (1966), 
Interscience Publishers, New York, pp. 162-163 (1967); and British 
Specification No. 1,097,533. Alkanoic acids of 2 to 6 carbon atoms, 
inclusive, especially acetic acid, are preferred acids for this acidic 
dehydration. Dilute aqueous solutions of mineral acids, e.g., hydrochloric 
acid, especially in the presence of a solubilizing diluent, e.g., 
tetrahydrofuran, are also useful as reagents for this acidic dehydration, 
although these reagents may cause partial hydrolysis of an ester reactant. 
The various PGB-type compounds encompassed by formulas XII, XVII, and XXII 
are prepared by basic dehydration of the corresponding PGE-type compounds 
encompassed by formulas VIII, XIII, and XVIII, respectively, or by 
contacting the corresponding PGA-type compounds encompassed by formulas 
XI, XVI, and XXI, respectively, with base. For example, both 
16-(p-chlorophenoxy)-18,19,20-trinor-13,14-dihydro-PGE.sub.1 and 
16-(p-chlorophenoxy)-18,19,20-trinor-13,14-dihydro-PGA.sub.1 give 
16-(p-chlorophenoxy)-18,19,20-trinor-13,14-dihydro-PGB.sub.1 on treatment 
with base. 
These basic dehydrations and double bond migrations are carried out by 
methods known in the art for similar reactions of known prostanoic acid 
derivatives. See, for example, Bergstrom et al., J. Biol. Chem. 238, 3555 
(1963). The base is any whose aqueous solution has pH greater than 10. 
Preferred bases are the alkali metal hydroxides. A mixture of water and 
sufficient of a water-miscible alkanol to give a homogeneous reaction 
mixture is suitable as a reaction medium. The PGE-type or PGA-type 
compound is maintained in such a reaction medium until no further PGB-type 
compound is formed, as shown by the characteristic ultraviolet light 
absorption near 278 m.mu. for the PGB-type compound. 
Optically active compounds are obtained from optically active intermediates 
according to the process steps of Charts A and B. Likewise, optically 
active products are obtained by the transformations of optically active 
compounds following the processes of Charts C and D. When racemic 
intermediates are used in reactions corresponding to the processes of 
Charts A-D, inclusive, and racemic products are obtained, these racemic 
products may be used in their racemic form or, if preferred, they may be 
resolved as optically active isomers by procedures known in the art. 
For example, when final compound VIII to XXIII is a free acid, the dl form 
thereof is resolved into the d and l forms by reacting said free acid by 
known general procedures with an optically active base, e.g., brucine or 
strychnine, to give a mixture of two diastereoisomers which are separated 
by known general procedures, e.g., fractional crystallization, to give the 
separate diastereoisomeric salts. The optically active acid of formula 
VIII to XXIII is then obtained by treatment of the salt with an acid by 
known general procedures. 
As discussed above, the stereochemistry at C-15 is not altered by the 
transformations of Charts A and B; the 15.beta. epimeric products of 
formula XXXV are obtained from 15.beta. formula-XXX reactants. Another 
method of preparing the 15.beta. products is by isomerization of the 
PGF.sub.1 - or PGE.sub.1 -type compounds having 15.alpha. configuration, 
by methods known in the art. See, for example, Pike et al., J. Org. Chem 
34, 3552 (1969). 
As discussed above, the processes of Charts B, C, and D lead variously to 
acids (R.sub.1 is hydrogen) or to esters (R.sub.1 is alkyl, cycloalkyl, 
aralkyl, phenyl or substituted phenyl, as defined above). When an acid has 
been prepared and an alkyl ester is desired, esterification is 
advantageously accomplished by interaction of the acid with the 
appropriate diazohydrocarbon. For example, when diazomethane is used, the 
methyl esters are produced. Similar use of diazoethane, diazobutane, and 
1-diazo-2-ethylhexane, and diazodecane, for example, gives the ethyl, 
butyl, and 2-ethylhexyl and decyl esters, respectively. 
Esterification with diazohydrocarbons is carried out by mixing a solution 
of the diazohydrocarbon in a suitable inert solvent, preferably diethyl 
ether, with the acid reactant, advantageously in the same or a different 
inert diluent. After the esterification reaction is complete, the solvent 
is removed by evaporation, and the ester purified if desired by 
conventional methods, preferably by chromatography. It is preferred that 
contact of the acid reactants with the diazohydrocarbon be no longer than 
necessary to effect the desired esterification, preferably about one to 
about ten minutes, to avoid undesired molecular changes. Diazohydrocarbons 
are known in the art or can be prepared by methods known in the art. See, 
for example, Organic Reactions, John Wiley and Sons, Inc., New York, N.Y., 
Vol. 8, pp 389-394 (1954). 
An alternative method for esterification of the carboxyl moiety of the acid 
compounds comprises transformation of the free acid to the corresponding 
silver salt, followed by interaction of that salt with an alkyl iodide. 
Examples of suitable iodides are methyl iodide, ethyl iodide, butyl 
iodide, isobutyl iodide, tert-butyl iodide, and the like. The silver salts 
are prepared by conventional methods, for example, by dissolving the acid 
in cold dilute aqueous ammonia, evaporating the excess ammonia at reduced 
pressure, and then adding the stoichiometric amount of silver nitrate. 
The final formula VII-to-XXIII compounds prepared by the processes of this 
invention, in free acid form, are transformed to pharmacologically 
acceptable salts by neutralization with appropriate amounts of the 
corresponding inorganic or organic base, examples of which correspond to 
the cations and amines listed above. These transformations are carried out 
by a variety of procedures known in the art to be generally useful for the 
preparation of inorganic, i.e., metal or ammonium, salts, amine acid 
addition salts, and quaternary ammonium salts. The choice of procedure 
depends in part upon the solubility characteristics of the particular salt 
to be prepared. In the case of the inorganic salts, it is usually suitable 
to dissolve the formula VIII-to-XXIII acid in water containing the 
stoichiometric amount of a hydroxide, carbonate, or bicarbonate 
corresponding to the inorganic salt desired. For example, such use of 
sodium hydroxide, sodium carbonate, or sodium bicarbonate gives a solution 
of the sodium salt. Evaporation of the water or addition of a 
water-miscible solvent of moderate polarity, for example, a lower alkanol 
or a lower alkanone, gives the solid inorganic salt if that form is 
desired. 
To produce an amine salt, the formula VIII-to-XXIII acid is dissolved in a 
suitable solvent of either moderate or low polarity. Examples of the 
former are ethanol, acetone, and ethyl acetate. Examples of the latter are 
diethyl ether and benzene. At least a stoichiometric amount of the amine 
corresponding to the desired cation is then added to that solution. If the 
resulting salt does not precipitate, it is usually obtained in solid form 
by addition of a miscible diluent of low polarity or by evaporation. If 
the amine is relatively volatile, any excess can easily be removed by 
evaporation. It is preferred to use stoichiometric amounts of the less 
volatile amines. 
Salts wherein the cation is quaternary ammonium are produced by mixing the 
formula VIII-to-XXIII acid with the stoichiometric amount of the 
corresponding quaternary ammonium hydroxide in water solution, followed by 
evaporation of the water. 
The final formula VIII-to-XXIII acids or esters prepared by the processes 
of this invention are transformed to lower alkanoates by interaction of 
the formula VIII-to-XXIII hydroxy compound with a carboxyacylating agent, 
preferably the anhydride of a lower alkanoic acid, i.e., an alkanoic acid 
of two to 8 carbon atoms, inclusive. For example, use of acetic anhydride 
gives the corresponding acetate. Similar use of propionic anhydride, 
isobutyric anhydride, and hexanoic acid anhydride gives the corresponding 
carboxyacylates. 
The carboxyacylation is advantageously carried out by mixing the hydroxy 
compound and the acid anhydride, preferably in the presence of a tertiary 
amine such as pyridine or triethylamine. A substantial excess of the 
anhydride is used, preferably about 10 to about 10,000 moles of anhydride 
per mole of the hydroxy compound reactant. The excess anhydride serves as 
a reaction diluent and solvent. An inert organic diluent, for example, 
dioxane, can also be added. It is preferred to use enough of the tertiary 
amine to neutralize the carboxylic acid produced by the reaction, as well 
as any free carboxyl groups present in the hydroxy compound reactant. 
The carboxyacylation reaction is preferably carried out in the range about 
0.degree. to about 100.degree. C. The necessary reaction time will depend 
on such factors as the reaction temperature, and the nature of the 
anhydride and tertiary amine reactants. With acetic anhydride, pyridine, 
and a 25.degree. C. reaction temperature, a 12 to 24-hour reaction time is 
used. 
The carboxyacylated product is isolated from the reaction mixture by 
conventional methods. For example, the excess anhydride is decomposed with 
water, and the resulting mixture acidified and then extracted with a 
solvent such as diethyl ether. The desired carboxyacylate is recovered 
from the diethyl ether extract by evaporation. The carboxyacylate is then 
purified by conventional methods, advantageously by chromatography. 
By this procedure, the formula VIII, XIII, and XVIII PGE-type compounds are 
transformed to dialkanoates, the formula IX, X, XIV, XV, XIX, and XX 
PGF-type compounds are transformed to trialkanoates, and the formula XI, 
XVI, and XXI PGA-type and formula XII, XVII, and XXII PGB-type compounds 
are transformed to monoalkanoates. 
When a PGE-type dialkanoate is transformed to a PGF-type compound by 
carbonyl reduction as shown in Chart D, a PGF-type dialkanoate is formed 
and is used for the abovedescribed purposes as such or is transformed to a 
trialkanoate by the above-described procedure. In the latter case, the 
third alkanoyloxy group can be the same as or different from the two 
alkanoyloxy groups present before the carbonyl reduction. 
DESCRIPTION OF THE PREFERRED EMBODIMENTS 
The invention can be more fully understood by the following preparation and 
examples. 
All temperatures are in degrees centigrade. 
Infrared absorption spectra are recorded on a PerkinElmer model 421 
infrared spectrophotometer. Except when specified otherwise, undiluted 
(neat) samples are used. 
Mass spectra are recorded on an Atlas CH-4 mass spectrometer with a TO-4 
source (ionization voltage 70 ev). 
NMR spectra are recorded on a Varian A-60 spectrophotometer using solutions 
in deuterochloroform or other appropriate solvents with tetramethylsilane 
as an internal standard (downfield). 
"Brine," herein, refers to an aqueous saturated sodium chloride solution. 
PREATION 1 
3.alpha.-Benzoyloxy-2.beta.-carboxaldehyde-5.alpha.-hydroxy-1.alpha.-cyclop 
entaneacetic Acid .gamma.Lactone (Formula XXVIII: R.sub.5 is benzoyl) 
Refer to Chart A. a. To a mixture of formula-XXIV laevorotatory (-) 
3.alpha.-hydroxy-5.alpha.-hydroxy-4-iodo-2.beta.-methoxymethyl-1.alpha.-cy 
clopentaneacetic acid .gamma.-lactone (E. J. Corey et al., J. Am. Chem. 
Soc. 92, 297 (1970), 75 g.) in 135 ml. of dry pyridine under a nitrogen 
atmosphere is added 30.4 ml. of benzoyl chloride with cooling to maintain 
the temperature at about 20.degree.-40.degree. C. Stirring is continued 
for an additional 30 min. About 250 ml. of toluene is added and the 
mixture concentrated under reduced pressure. The residue is dissolved in 
one liter of ethyl acetate, washed with 10% sulfuric acid, brine, aqueous 
saturated sodium bicarbonate, and brine. The ethyl acetate solution is 
dried over sodium sulfate and concentrated under reduced pressure to yield 
an oil, 95 g. Crystallization of the oil yields the corresponding 
3.alpha.-benzoyloxy compound, m.p. 84.degree.-86.degree. C.; 
[.alpha.].sub.D +7.degree. (CHCl.sub.3); infrared spectral absorptions at 
1768, 1722, 1600,, 1570, 1490, 1275, 1265, 1180, 1125, 1090, 1060, 1030, 
and 710 cm.sup.-1 ; and NMR (nuclear magnetic resonance) peaks at 
2.1-3.45, 3.3, 3.58, 4.38, 5.12, 5.51, 7.18-7.58, and 7.83-8.05 .delta.. 
b. The iodo group is removed as follows. To a solution of the above 
benzoyloxy compound (60 g.) in 240 ml. of dry benzene is added 
2,2'-azobis-(2-methylpropionitrile) (approximately 60 mg.). The mixture is 
cooled to 15.degree. C. and to it is added a solution of 75 g. tributyltin 
hydride in 600 ml. of ether, with stirring, at such a rate as to maintain 
continuous reaction at about 25.degree. C. When the reaction is complete 
as shown by TLC (thin layer chromatography) the mixture is concentrated 
under reduced pressure to an oil. The oil is mixed with 600 ml. of 
Skellysolve B (mixed isomeric hexanes) and 600 ml. of water and stirred 
for 30 min. The water layer, containing the product, is separated, then 
combined with 450 ml. of ethyl acetate and enough solid sodium chloride to 
saturate the aqueous phase. The ethyl acetate layer, now containing the 
product, is separated, dried over magnesium sulfate, and concentrated 
under reduced pressure to an oil, 39 g. of the iodine-free compound. An 
analytical sample gives [.alpha.].sub.D -99.degree. (CHCl.sub.3); infrared 
spectral absorptions at 1775, 1715, 1600, 1585, 1490, 1315, 1275, 1180, 
1110, 1070, 1055, 1025, and 715 cm.sup.-1.; NMR peaks at 2.5-3.0, 3.25, 
3.34, 4.84-5.17, 5.17-5.4, 7.1-7.5, and 7.8-8.05 .delta.; and mass 
spectral peaks at 290, 168, 105, and 77. 
c. The 2.beta.-methoxymethyl compound is changed to a hydroxymethyl 
compound as follows. To a cold (0.5.degree. C.) solution of the above 
iodine-free methoxy-methyl lactone (20 g.) in 320 ml. of dichloromethane 
under nitrogen is added a solution of 24.8 ml. of boron tribromide in 320 
ml. of dichloromethane, dropwise with vigorous stirring over a period of 
50 min. at 0.degree.-5.degree. C. Stirring and cooling are continued for 
one hr. When the reaction is complete, as shown by TLC, there is 
cautiously added a solution of sodium carbonate (78 g.) monohydrate in 200 
ml. of water. The mixture is stirred at 0.degree.-5.degree. C. for 10-15 
min., saturated with sodium chloride, and the ethyl acetate layer 
separated. Additional ethyl acetate extractions of the water layer are 
combined with the main ethyl acetate solution. The combined solutions are 
rinsed with brine, dried over sodium sulfate and concentrated under 
reduced pressure to an oil, 18.1 g. of the 2.beta.-hydroxymethyl compound. 
An analytical sample has m.p. 116.degree.-118.degree. C.; [.alpha.].sub.D 
-80.degree. (CHC;.sub.3); infrared spectral absorptions at 3460, 1735, 
1708, 1600, 1580, 1490, 1325, 1315, 1280, 1205, 1115, 1090, 1070, 1035, 
1025, 730, and 720; and NMR peaks at 2.1-3.0, 3.58, 4.83-5.12, 5.2-5.45, 
7.15-7.55, and 7.8-8.0 .delta.. 
d. The title 2.beta.-carboxaldehyde compound is prepared as follows. To a 
mixture of 250 ml. of dichloromethane and Collins' reagent prepared from 
chromium trioxide (10.5 g.) and 16.5 ml. of pyridine, cooled to 0.degree. 
C., a cold solution of the hydroxymethyl compound of step c (5.0 g.) in 50 
ml. of dichloromethane is added, with stirring. After 7 min. of additional 
stirring, the title intermediate is used directly without isolation (see 
Example 1). 
Following the procedure of Preparation 1, but replacing that optically 
active formula-XXIV iodolactone with the racemic compound of that formula 
and the mirror image thereof (see E. J. Corey et al., J. Am. Chem. Soc. 
91, 5675 (1969)) there is obtained the racemic compound corresponding to 
formula XXVIII.

EXAMPLE 1 
3.alpha.-Benzoyloxy-5.alpha.-hydroxy-2.beta.-(3-oxo-4-phenoxytrans-1-buteny 
l)-1.alpha.-cyclopentaneacetic Acid, .gamma.-Lactone (Formula XXIX: R.sub.2 
and R.sub.3 are hydrogen, R.sub.5 is benzoyl, and s is zero) 
Refer to Chart B. a. There is first prepared dimethyl 
3-phenoxyacetonylphosphonate. A solution of dimethyl methylphosphonate (75 
g.) in 700 ml. of tetrahydrofuran is cooled to -75.degree. C. under 
nitrogen and n-butyllithium (400 ml. of 1.6 molar solution in hexane) is 
added, keeping the temperature below -55.degree. C. The mixture is stirred 
for 10 min. and to it is slowly added phenoxyacetyl chloride (44 g.), 
again keeping the temperature below -55.degree. C. The reaction mixture is 
stirred at -75.degree. C. for 2 hrs., then at about 25.degree. C. for 16 
hrs. The mixture is acidified with acetic acid and concentrated under 
reduced pressure. The residue is partitioned between diethyl ether and 
water, and the organic phase is dried and concentrated to the above-named 
intermediate, 82 g. Further treatment by silica gel chromatography yields 
an analytical sample having NMR peaks at 7.4-6.7 (multiplet), 4.78 
(singlet), 4.8 and 4.6 (two singlets), and 3.4-3.04 (doublet) .delta.. 
b. The phosphonate anion (ylid) is then prepared as follows. Dimethyl 
3-phenoxyacetonylphosphonate (step a, 9.3 g.) is added in portions to a 
cold (5.degree. C.) mixture of sodium hydride (1.75 g. of 50%) in 250 ml. 
of tetrahydrofuran, and the resulting mixture is stirred for 1.5 hrs. at 
about 25.degree. C. 
c. To the mixture of step b is added the cold solution of the 
formula-XXVIII 2.beta.-carboxaldehyde of Preparation 1, and the resulting 
mixture is stirred about 1.6 hrs. Then 3 ml. of acetic acid is added and 
the mixture is concentrated under reduced pressure. A solution is prepared 
from the residue in 500 ml. of ethyl acetate, washed with several portions 
of water and brine, and concentrated under reduced pressure. The residue 
is subjected to silica gel chromatography, eluting with ethyl 
acetate-Skellysolve B (isomeric hexanes) (3:1). Those fractions shown by 
TLC to be free of starting material and impurities are combined and 
concentrated to yield the title compound, 1.7 g.; NMR peaks at 5.0-8.2 and 
4.7 (singlet) .delta.. 
Following the procedure of Example 1, but replacing the optically active 
formula-XXVIII aldehyde with the racemic aldehyde obtained after 
Preparation 1, there is obtained the racemic 3-oxo-4-phenoxy-1-butenyl 
compound corresponding to formula XXIX. 
Following the procedure of Example 1, but replacing phenoxyacetyl chloride 
with each of the following aliphatic acid esters there is obtained the 
corresponding phosphonate and thence the formula-XXIX lactone wherein 
R.sub.5 is benzoyl: 
methyl 2-phenoxypropionate 
methyl 2-methyl-2-phenoxypropionate 
ethyl 2-phenoxybutyrate 
methyl 2-ethyl-2-phenoxybutyrate 
ethyl 2-methyl-2-phenoxybutyrate 
methyl 2-(p-tolyloxy)acetate 
methyl 2-(p-fluorophenoxy)propionate 
ethyl 2-(o,p-dichlorophenoxy)-2-methyl-propionate 
ethyl 2-(.alpha.,.alpha.,.alpha.-trifluoro-p-tolyloxy)butyrate and 
methyl 2-(m-methoxyphenoxy)-2-methyl-butyrate. 
For example, methyl 2-phenoxypropionate yields dimethyl 
2-oxo-3-phenoxybutylphosphonate and, thence, the formula XXIX 
3.alpha.-benzoyloxy-5.alpha.-hydroxy-2.beta.-(3-oxo-4-phenoxy-trans-1-pent 
enyl)-1.alpha.-cyclopentaneacetic acid .gamma.-lactone. Likewise, ethyl 
2-(o,p-dichlorophenoxy)-2-methyl-propionate yields dimethyl 
2-oxo-3-(o,p-dichlorophenoxy)-3-methylbutylphosphonate and, thence, the 
formula-XXIX 
3.alpha.-benzoyloxy-5.alpha.-hydroxy-2.beta.-[3-oxo-4-(o,p-dichlorophenoxy 
)-4-methyl-trans-1-pentenyl]-1.alpha.-cyclopentaneacetic acid 
.gamma.-lactone. 
When the phosphonate contains an asymmetric carbon atom, e.g. when the 
methylene between the carbonyl and the --O-- is substituted with only one 
methyl or ethyl group, the phosphonate exists in either of two optically 
active forms (+ or -) or their racemic (dl) mixture. An optically active 
phosphonate is obtained by starting with an appropriate optically active 
isomer of a phenoxy or substituted-phenoxy aliphatic acid. Methods of 
resolving these acids are known in the art, for example by forming salts 
with an optically active base such as brucine, separating the resulting 
diastereomers, and recovering the acids. 
Following the procedure of Example 1, employing the optically active 
aldehyde XXVIII of that example, each optically active phosphonate 
obtained from the list of aliphatic acid esters above in the second 
paragraph following Example 1 yields a corresponding optically active 
formula-XXIX .gamma.-lactone. 
Likewise following the procedure of Example 1, employing the optically 
active aldehyde XXVIII of that example, each racemic phosphonate obtained 
from the above-mentioned list of aliphatic acid esters yields a pair of 
diastereomers, differing in their stereochemistry at the fourth carbon of 
the phenoxy-terminated side-chain. These diastereomers are separated by 
conventional methods, e.g. by silica gel chromatography. 
Again following the procedure of Example 1, employing the optically active 
aldehyde XXVIII of that example, each of the optically inactive 
phosphonates obtained from the list of aliphatic acid esters above wherein 
there is no asymmetric carbon atom, i.e. R.sub.2 and R.sub.3 are the same, 
yields a corresponding optically active formula-XXIX .gamma.-lactone. 
Replacing the optically active aldehyde XXVIII with the racemic aldehyde 
obtained after Preparation 1, and following the procedure of Example 1 
using each of the optically active phosphonates described above, there is 
obtained in each case a pair of diastereomers which are separated by 
chromatography. 
Likewise following the procedure of Example 1, employing the racemic 
aldehyde with each of the racemic phosphonates described above, there are 
obtained in each case two pairs of 3-oxo-4-phenoxy (or 
substituted-phenoxy) racemates which are separated into pairs of racemic 
compounds by methods known in the art, e.g. silica gel chromatography. 
Again following the procedure of Example 1, employing the racemic aldehyde 
with each of the optically inactive phosphonates described above, there 
are obtained in each case a racemic product corresponding to formula XXIX. 
EXAMPLE 2 
3.alpha.-Benzoyloxy-5.alpha.-hydroxy-2.beta.-(3.alpha.-hydroxy-4-phenoxy-tr 
ans-1-butenyl)-1.alpha.-cyclopentaneacetic Acid, .gamma.-Lactone (Formula 
XXX: M is 
##STR42## 
Q is 
##STR43## 
and R.sub.5 is benzoyl); and the 3.beta.-hydroxy isomer (Formula XXX: M is 
##STR44## 
Refer to Chart B. Sodium borohydride (1.05 g.) is added in portions to a 
cold (0.degree. C.) mixture of zinc chloride (4.4 g.) and 35 ml. of 
1,2-dimethoxyethane under nitrogen. Stirring is continued at about 
25.degree. C. for 20 hrs. Then the mixture is cooled to -20.degree. C. and 
the formula-XXIX 3-oxo compound (Example 1, 2.6 g. in 10 ml. of 
1,2-dimethoxyethane) is added. The mixture is stirred at -20.degree. C. 
for 6 hrs., and at 25.degree. C. for 30 min. The mixture is again cooled 
to -20.degree. C. and 5 ml. of water is added dropwise. The mixture is 
shaken with 100 ml. of brine and ethyl acetate and the organic layer is 
dried and concentrated under reduced pressure. The residue is 
chromatographed on silica gel, eluting with ethyl acetate-Skellysolve B 
(isomeric hexanes) (3:1). Those fractions shown by TLC to be free of 
starting material and impurities are combined and concentrated to yield 
the 3.alpha.-hydroxy title compound, 1.1 g.; NMR peaks at 6.6-8.0, 
5.52-5.87, and 3.83 .delta.. Other fractions yield the more polar 
3.beta.-hydroxy title compound, 0.8 g.; NMR peaks at 6.6-8.0, 5.52-5.87, 
and 3.83 .delta.. 
Following the procedure of Example 2, but using the racemic 
3-oxo-4-phenoxy-1-butenyl compound obtained following Example 1, there are 
obtained the corresponding racemic 3-hydroxy products. 
Likewise following the procedure of Example 2, each of the optically active 
or racemic lactones corresponding to formula XXIX described following 
Example 1 is transformed to the optically active or racemic compound 
corresponding to formula XXX. 
EXAMPLE 3 
3.alpha.,5.alpha.-Dihydroxy-2.beta.-(3.alpha.-hydroxy-4-phenoxytrans-1-bute 
nyl)-1.alpha.-cyclopentaneacetaldehyde .gamma.-Lactol 
Bis(tetrahydropyranyl) Ether (Formula XXXIII: M' is 
##STR45## 
Q is 
##STR46## 
and .about. is alpha or beta). 
Refer to Chart B. a. The formula-XXX 3.alpha.-hydroxy compound (Example 2, 
1.35 g.) in 22 ml. of anhydrous methanol is stirred with potassium 
carbonate (0.48 g.) for 1 hr. at about 25.degree. C. Then 15 ml. of 
chloroform is added and the solvent removed under reduced pressure. A 
solution of the residue in 70 ml. of chloroform is shaken with 10 ml. of 
water containing potassium hydrogen sulfate (0.5 g.), then with brine, and 
concentrated. The residue is washed with several portions of Skellysolve B 
(isomeric hexanes) and dried to yield the formula-XXXI benzoyloxy-free 
compound, i.e. 
3.alpha.,5.alpha.-dihydroxy-2.beta.-(3.alpha.-hydroxy-4-phenoxy-trans-1-bu 
tenyl)-1.alpha.-cyclopentaneacetic acid, .gamma.-lactone, 0.4 g. 
b. The formula-XXXI compound from part a above is converted to the 
formula-XXXII bis(tetrahydropyranyl) ether by reaction with 0.8 ml. of 
dihydropyran in 10 ml. of dichloromethane in the presence of pyridine 
hydrochloride (about 0.03 g.). In about 2.5 hrs. the mixture is filtered 
and concentrated to the formula-XXXII product, 0.6 g.; having no infrared 
absorption at 3300 cm.sup.-1. 
c. The title compound is prepared as follows. Diisobutylaluminum hydride 
(4.8 ml. of a 10% solution in toluene) is added dropwise to a stirred 
solution of the formula-XXXII bis(tetrahydropyranyl) ether from part b 
above in 8 ml. of toluene cooled to -78.degree. C. Stirring is continued 
at -78.degree. C. for 0.5 hr., whereupon a solution of 3 ml. of 
tetrahydrofuran and 1 ml. of water is added cautiously. After the mixture 
warms to 25.degree. C. it is filtered and the filtrate washed with brine, 
dried, and concentrated to the mixed alpha and beta hydroxy isomers of the 
formula-XXXIII title compounds, 0.33 g., having infrared absorption at 
3300 cm.sup.-1. 
Following the procedures of Example 3, but using the formula-XXX 
3.beta.-hydroxy-4-phenoxy isomer of Example 2, there is obtained the 
corresponding 3.beta.-hydroxy formula-XXXIII compound, i.e. wherein M' is 
##STR47## 
Likewise following the procedures of Example 3, each of the optically 
active or racemic compounds corresponding to formula XXX described 
following Example 2 is transformed to an optically active or racemic 
compound corresponding to formula XXXIII. There are thus obtained both the 
3.alpha.- and 3.beta.-hydroxy isomers. 
EXAMPLE 4 
16-Phenoxy-17,18,19,20-tetranor-PGF.sub.2.alpha., 
11,15-Bis(tetrahydropyranyl) Ether (Formula XXXIV: g is 3, M' is 
##STR48## 
and Q is 
##STR49## 
Refer to Chart B. 4-Carboxybutyltriphenylphosphonium bromide (E. J. Corey 
et al., J. Am. Chem. Soc. 91, 5677 (1969)) (0.9 g.) is added to a solution 
of sodio dimethylsulfinylcarbanide prepared from sodium hydride (0.195 g.) 
and 5 ml. of dimethylsulfoxide (DMSO). To this Wittig reagent is added 
dropwise a solution of the formula-XXXIII lactol (Example 3, 0.33 g.) in 2 
ml. of DMSO. The mixture is stirred at about 25.degree. C. for 2 hrs., 
then diluted with 20 ml. of benzene. To the mixture is added, with 
stirring, a solution of potassium hydrogen sulfate (0.7 g.) in 5 ml. of 
water. The organic layer is separated, washed with water and brine, then 
dried and concentrated to an oil, 1.7 g. This residue is subjected to 
silica gel chromatography, eluting with 0-20% acetone in dichloromethane. 
Those fractions shown by TLC to contain the product free of starting 
material and impurities are combined and concentrated to yield the title 
compound, 0.3 g.; NMR peaks at 6.7-7.3, 5.2-5.75, 4.6, and 3.68 .delta.. 
EXAMPLE 5 
16-Phenoxy-17,18,19,20-tetranor-PGF.sub.2.alpha. (Formula XIV: g is 3; M is 
##STR50## 
R.sub.1, R.sub.2, and R.sub.3 are hydrogen; and s is zero) 
Refer to Chart B. A solution of the formula-XXXIV bis(tetrahydropyranyl) 
ether (Example 4, 0.3 g.) in 5 ml. of methanol, 0.2 ml. of hydrochloric 
acid, and 2 ml. of water is stirred at about 25.degree. C. for 1.5 hrs. 
The solution is made basic to pH 8-9 with dilute sodium hydroxide and 
extracted with dichloromethane. The aqueous phase is then acidified to pH 
2 with dilute hydrochloric acid and extracted with ethyl acetate. The 
organic phase is dried and concentrated under reduced pressure to an oil. 
The oil is chromatographed on silica gel, eluting with 0-10% methanol in 
ethyl acetate. Those fractions shown by TLC to contain the product free of 
starting material and impurities are combined and concentrated to yield 
the title compound, 0.06 g.; mass spectral peaks (trimethylsilyl 
derivative) at 678, 663, 578, 561, 481, and 391; NMR peaks at 6.7-7.3, 
5.5-5.7, and 5.0-5.4 .delta.. 
Following the procedures of Examples 4 and 5, each of the optically active 
or racemic 3.alpha.-hydroxy compounds corresponding to formula XXXIII 
described following Example 3 is transformed to the corresponding 
bis(tetrahydropyranyl) ether and thence to the corresponding 16-phenoxy 
(or substituted-phenoxy)-PGF.sub.1.alpha. type compound or racemic 
mixture. There are thus obtained the following compounds from the 
3.alpha.-hydroxy isomers: 
16-phenoxy-17,18,19,20-tetranor-PGF.sub.2.alpha. 
16-phenoxy-18,19,20-trinor-PGF.sub.2.alpha. 
16-methyl-16-phenoxy-18,19,20-trinor-PGF.sub.2.alpha. 
16-phenoxy-19,20-dinor-PGF.sub.2.alpha. 
16-ethyl-16-phenoxy-19,20-dinor-PGF.sub.2.alpha. 
16-methyl-16-phenoxy-19,20-dinor-PGF.sub.2.alpha. 
16-(p-tolyloxy)-17,18,19,20-tetranor-PGF.sub.2.alpha. 
16-(p-fluorophenoxy)-18,19,20-trinor-PGF.sub.2.alpha. 
16-(o,p-dichlorophenoxy)-16-methyl-18,19,20-trinor-PGF.sub.2.alpha. 
16-(.alpha.,.alpha.,.alpha.-trifluoro-p-tolyloxy)-19,20-dinor-PGF.sub.2.alp 
ha. 
16-methyl-16-(m-methoxyphenoxy)-19,20-dinor-PGF.sub.2.alpha. and their 
racemic mixtures, for example 
dl-16-phenoxy-17,18,19,20-tetranor-PGF.sub.2.alpha.. 
Likewise following the procedures of Examples 4 and 5 but employing the 
above-described 3.beta.-hydroxy compounds corresponding to formula XXXIII, 
there are obtained the corresponding 15.beta.-epimers and their racemic 
mixtures for example: 
16-phenoxy-17,18,19,20-tetranor-15.beta.-PGF.sub.2.alpha. 
16-phenoxy-18,19,20-trinor-15.beta.-PGF.sub.2.alpha. 
16-methyl-16-phenoxy-18,19,20-trinor-15.beta.-PGF.sub.2.alpha. 
Following the procedures of Examples 4 and 5, but replacing 
4-carboxybutyltriphenylphosphonium bromide with a phosphonium bromide 
within the scope of HOOC-(CH.sub.2).sub.g+1 --P(C.sub.6 H.sub.5).sub.3 Br 
wherein g is 2, 4, or 5, namely 
3-carboxypropyltriphenylphosphonium bromide, 
5-carboxypentyltriphenylphosphonium bromide, or 
6-carboxyhexyltriphenylphosphonium bromide, 
each of the optically active or racemic 3.alpha.-hydroxy compounds 
corresponding to formula XXXIII described following Example 3 is 
transformed to a bis(tetrahydropyranyl) ether corresponding to formula 
XXXIV wherein the carboxy-terminated side chain has six, eight, or nine 
carbon atoms, and, thence, to the corresponding 16-phenoxy (or 
substituted-phenoxy)-PGF.sub.2.alpha. type compound or racemic mixture, 
for example: 
16-phenoxy-2,17,18,19,20-pentanor-PGF.sub.2.alpha. 
16-phenoxy-2a-homo-18,19,20-trinor-PGF.sub.2.alpha. 
16-methyl-16-phenoxy-2a,2b-dihomo-19,20-dinor-PGF.sub.2.alpha. 
16-phenoxy-2,19,20-trinor-PGF.sub.2.alpha. 
16-ethyl-16-phenoxy-2a-homo-19,20-dinor-PGF.sub.2.alpha. 
16-methyl-16-phenoxy-2a,2b-dihomo-19,20-dinor-PGF.sub.2.alpha. 
16-(p-tolyloxy)-2,17,18,19,20-pentanor-PGF.sub.2.alpha. 
16-(p-fluorophenoxy)-2a-homo-18,19,20-trinor-PGF.sub.2.alpha. 
16-(o,p-dichlorophenoxy)-16-methyl-2a,2b-dihomo-18,19,20-trinor-PGF.sub.2.a 
lpha. 
16-(.alpha.,.alpha.,.alpha.-trifluoro-p-tolyloxy)-2,19,20-trinor-PGF.sub.2. 
alpha. 
16-methyl-16-(m-methoxyphenoxy)-2a-homo-19,20-dinor-PGF.sub.2.alpha. 
and their racemic mixtures, for example 
dl-16-phenoxy-2,17,-18,19,20-pentanor-PGF.sub.2.alpha.. 
Likewise following the procedures of Examples 4 and 5 but employing with 
the various phosphonium bromides the 3.beta.-hydroxy compounds 
corresponding to formula XXXIII described following Example 3, there are 
obtained the corresponding 15.beta. epimers first as the 
bis(tetrahydropyranyl) ethers and then as the PGF.sub.2.alpha. type 
products and their racemic mixtures, for example 
16-phenoxy-2,17,18,19,20-pentanor-15.beta.-PGF.sub.2.alpha. and 
dl-16-phenoxy-2,17,18,19,20-pentanor-15.beta.-PGF.sub.2.alpha.. 
EXAMPLE 6 
16-Phenoxy-17,18,19,20-tetranor-PGE.sub.2 Methyl Ester (Formula XIII: g is 
3, M is 
##STR51## 
R.sub.1 is methyl, R.sub.2 and R.sub.3 are hydrogen, and s is zero) 
Refer to Chart C. a. There is first prepared the methyl ester of the 
formula-XXXIV 11,15-bis(tetrahydropyranyl) ether of 
16-phenoxy-17,18,19,20-tetranor PGF.sub.2.alpha.. A solution of that 
formula-XXXIV compound (Example 4, 1.35 g.) in 10 ml. of diethyl ether is 
mixed with a solution of diazomethane (about 0.5 g.) in 25 ml. of diethyl 
ether and stirred for about 3 min. Two ml. of acetic acid is added, then 
about 50 ml. of ether, and the solution shaken with aqueous sodium 
bicarbonate solution. The organic phase is concentrated under reduced 
pressure to an oil. The oil is chromatographed on silica gel, eluting with 
ethyl acetateSkellysolve B (isomeric hexanes) (3:1). The methyl ester is 
obtained, 0.42 g., NMR peak at 3.57 (singlet) .delta., and infrared 
absorption at 1745 cm.sup.-1. 
b. A solution of the product of step a (0.42 g.) in 12 ml. of acetone is 
cooled to about -20.degree. C. and to it is added slowly 0.5 ml. of Jones 
reagent (2.1 g. of chromium trioxide, 6 ml. of water, and 1.7 ml. of 
concentrated sulfuric acid). The mixture is stirred for 15 min., and then 
shaken with 30 ml. of ice water and 200 ml. of dichloromethane-diethyl 
ether (1:3). The organic phase is washed with cold dilute hydrochloric 
acid, cold water, and brine, then dried and concentrated. The residue is 
the bis(tetrahydropyranyl) ether of the title compound, an oil, 0.35 g., 
having infrared absorption at 1740 cm.sup.-1. 
c. A solution of the product of step b in 9.5 ml. of acetic acid and 4.5 
ml. of water is stirred at 37.degree.-39.degree. C. for 2.5 hrs. The 
mixture is neutralized with sodium bicarbonate solution, then saturated 
with salt and shaken with dichloromethane-diethyl ether (1:3), dried and 
concentrated. The residue is chromatographed on silica gel, eluting with 
25% ethyl acetate in Skellysolve B (isomeric hexanes), and 0-6% methanol 
in ethyl acetate. The fractions shown by TLC to contain the desired 
product free of starting material and impurities are combined and 
concentrated to yield the title compound, 0.10 g.; NMR peaks at 7.5-6.6, 
5.7, 5.3, and 3.6 (singlet) .delta.; infrared absorption bands at 3300, 
1740, and 1730 cm.sup.-1 ; mass spectral peaks at (trimethylsilyl 
derivative) at 546, 531, 515, 439, and 349. 
EXAMPLE 7 
16-Methyl-16-phenoxy-18,19,20-trinor-PGF.sub.2.alpha. (Formula XIV: g is 3, 
M is 
##STR52## 
R.sub.1 is hydrogen, R.sub.2 and R.sub.3 are methyl, s is zero, and 
.about. is alpha) 
Refer to Chart B. a. There is first prepared dimethyl 
2-oxo-3-methyl-3-phenoxybutylphosphonate. For this purpose, 
2-methyl-2-phenoxypropionyl chloride is made by reaction of 
2-methyl-2-phenoxypropionic acid (50 g.) with thionyl chloride (82 g.), 
first at about 25.degree. C., then on a steam bath, finally pumping off 
excess thionyl chloride with addition of toluene. 
A solution of dimethyl methylphosphonate (69.5 g.) in 700 ml. of 
tetrahydrofuran is cooled to -75.degree. C. under nitrogen and 
n-butyllithium (355 ml. of 1.6 molar solution in hexane) is added, keeping 
the temperature below -55.degree. C. The mixture is stirred for 10 min. 
and to it is slowly added a solution of the 2-methyl-2-phenoxypropionyl 
chloride above in 50 ml. of tetrahydrofuran, again keeping the temperature 
below -55.degree. C. The reaction mixture is stirred at -75.degree. C. for 
2 hrs., then at about 25.degree. C. for 16 hrs. The mixture is acidified 
with acetic acid (25 ml.), and the supernatant liquid is concentrated 
under reduced pressure. The residue is partitioned between water and 
dichloromethanediethyl ether (3:1). The organic phase is washed with 
brine, then with saturated sodium bicarbonate, dried over sodium sulfate, 
and concentrated. Further treatment by silica gel chromatography yields 55 
g.; NMR peaks at 6.74-7.4, 3.85, 3.65, 3.56, 3.21 and 1.45 (singlet) 
.delta.. 
b. Following the procedures of Example 1, steps b and c, but utilizing the 
above phosphonate instead of the dimethyl 3-phenoxyacetonylphosphonate of 
that example, there is obtained the corresponding formula-XXIX 
intermediate, i.e. 
3.alpha.-benzoyl-5.alpha.-hydroxy-2.beta.-(3-oxo-4-methyl-4-phenoxy-trans- 
1-pentenyl)-1.alpha.-cyclopentaneacetic acid, .gamma.-lactone, 12.7 g.; 
m.p. 145.degree.-147.degree. C. (recrystallized from diethyl 
ether-pentane); NMR peaks at 6.62-7.65, 4.80, 5.46, 1.45, and 1.48 
.delta.. 
c. Following the procedure of Example 2, but utilizing the above 
formula-XXIX compound instead of the formula-XXIX compound of that 
example, there are obtained the corresponding formula-XXX .alpha.- and 
.beta.-hydroxy isomers, i.e. 
3.alpha.-benzoyloxy-5.alpha.-hydroxy-2.beta.-(3.alpha.-hydroxy-4-methyl-4- 
phenoxy-trans-1-pentenyl)-1.alpha.-cyclopentaneacetic acid, 
.gamma.-lactone, 7.7 g., m.p. 121.degree.-122.degree. C.; NMR peaks at 
7.90-8.25, 6.95-7.74, 5.85-5.95, 4.19-4.3, and 1.15 (singlet) .delta.; and 
3.alpha.-benzoyloxy-5.alpha.-hydroxy-2.beta.-(3.beta.-hydroxy-4-methyl-4-p 
henoxy-trans-1-pentenyl)-1.alpha.-cyclopentaneacetic acid, .gamma.-lactone, 
3.65 g., having similar NMR peaks. 
d. Following the procedures of Example 3, the 3.alpha.-hydroxy intermediate 
of step c above (8.54 g.) is transformed first to the formula-XXXI 
benzoyloxy-free compound, i.e. 
3.alpha.,5.alpha.-dihydroxy-2.beta.-(3.alpha.-hydroxy-4-methyl-4-phenoxy-t 
rans-1-pentenyl)-1.alpha.-cyclopentaneacetic acid, .gamma.-lactone, 6.18 
g.; m.p. 65.degree.-66.degree. C.; NMR peaks at 6.86-7.40, 5.62-5.73, 3.47 
(singlet) and 1.18 (singlet) .delta.. Next the corresponding formula-XXXII 
bis(tetrahydropyranyl) ether is prepared following the procedure of 
Example 3-b; yield 8.8 g.; infrared absorption spectrum free of hydroxyl 
absorption at 3300 cm.sup.-1. Then the formula-XXXIII lactol is prepared 
following the procedure of Example 3-c; yield of 
3.alpha.,5.alpha.-dihydroxy-2.beta.-(3.alpha.-hydroxyl-4-methyl-4-phenoxy- 
trans-1-pentenyl)-1.alpha.-cyclopentaneacetaldehyde, .gamma.-lactol, 
bis(tetrahydropyranyl) ether, 9.16 g.; infrared absorption spectrum free 
of .gamma.-lactone absorption at 1760 cm.sup.-1. 
e. Following the procedures of Example 4, the lactol of step d above is 
transformed by the Wittig reaction, starting with 4 
carboxybutyltriphenylphosphonium bromide, to the corresponding 
formula-XXXIV bis(tetrahydropyranyl) ether of the title compound, yield 
7.6 g.; NMR peaks at 7.1-7.3, 6.4 (singlet), 5.3-5.82, 4.6-5.0, and 
3.3-4.3 .delta.. 
f. A solution of the formula-XXXIV bis(tetrahydropyranyl) ether of step e 
above (2.4 g.) in 50 ml. of acetic acid and 25 ml. of water is stirred at 
about 25.degree. C. for 16 hrs. and then at 37.degree.-39.degree. C. for 
1.5 hrs. The product is freeze-dried and then chromatographed on silica 
gel, eluting with 0-3% methanol in ethyl acetate. Those fractions shown by 
TLC to contain the product free of starting material and impurities are 
combined and concentrated to yield the title compound, 0.60 g.; mass 
spectral peaks (trimethylsilyl derivative) at 706, 691, 613, 601, 571 and 
481; NMR peaks at 6.95-7.45, 5.6-5.8, 5.0-5.6, and 3.4-5.0 .delta.. 
EXAMPLE 8 
16-Methyl-16-phenoxy-18,19,20-trinor-PGE.sub.2 (Formula XIII: g is 3, M is 
##STR53## 
R.sub.1 is hydrogen, R.sub.2 and R.sub.3 are methyl, and s is zero) 
Refer to Chart C. A solution of the formula-XXIV 
16-methyl-16-phenoxy-18,19,20-trinor-PGF.sub.2.alpha., 
11,15-bis(tetrahydropyranyl) ether (Example 73, 5.2 g.) in 100 ml. of 
acetone is cooled to about -20.degree. C. and to it is added slowly 5 ml. 
of Jones reagent. The mixture is stirred for 15 min., diluted with 600 ml. 
of ethyl acetate and 600 ml. of diethyl ether, and washed with dilute 
hydrochloric acid and brine, then dried over magnesium sulfate and 
concentrated under reduced pressure to an oil. 
The above oil, which is the formula-XXXVII bis(tetrahydropyranyl) ether of 
the title compound, is dissolved in 80 ml. of acetic acid and 40 ml. of 
water and stirred at 40.degree. C. for 2.5-3 hrs. The product is freeze 
dried and then chromatographed on silica gel, eluting with 0.75-1.5% 
methanol in ethyl acetate. Those fractions shown by TLC to contain the 
product free of starting material and impurities are combined and 
concentrated to yield the title compound, 2.0 g.; infrared absorption 
bonds at 2700-3500, 1750, 1715, 1600, and 1500 cm.sup.-1 ; NMR peaks at 
6.87-7.4, 6.35, 5.6-5.87, 5.2-5.5, 3.8-4.3 .delta.; mass spectral peaks 
(trimethylsilyl derivative) at 632, 617, 539, 527, and 497. 
Following the procedures of Example 8, each of the bis(tetrahydropyranyl) 
ethers corresponding to formula XXXIV described following Example 5 is 
transformed to the corresponding 16-phenoxy (or 
substituted-phenoxy)-PGE.sub.2 type compound or its racemic mixtures, for 
example 
16-phenoxy-17,18,19,20-tetranor-PGE.sub.2 
16-phenoxy-2,17,18,19,20-pentanor-PGE.sub.2 
dl-16-phenoxy-17,18,19,20-tetranor-PGE.sub.2 and 
dl-16-phenoxy-2,17,18,19,20-pentanor-PGE.sub.2. 
From the 15.beta.-epimers are obtained the corresponding 15.beta.-PGE.sub.2 
type epimers, for example 
16-phenoxy-17,18,19,20-tetranor-15.beta.-PGE.sub.2 and 
dl-16-phenoxy-17,18,19,20-tetranor-15.beta.-PGE.sub.2. 
As in Example 8, there is first obtained the bis(tetrahydropyranyl) ether 
of the PGE.sub.2 type compound in each instance. 
EXAMPLE 9 
16-Methyl-16-phenoxy-18,19,20-trinor-PGE.sub.2, Methyl Ester (Formula XIII: 
g is 3; M is 
##STR54## 
R.sub.1, R.sub.2, and R.sub.3 are methyl; and s is zero), and 
16-Methyl-16-phenoxy-18,19,20-trinor-PGA.sub.2, Methyl Ester (Formula XVI: 
g is 3; M is 
##STR55## 
R.sub.1, R.sub.2, and R.sub.3 are methyl; and s is zero) 
Refer to Chart C. a. Following the procedure of Example 6a, and using the 
product of Example 7e above, there is first prepared the formula-XXXVI 
methyl ester of 16-methyl-16-phenoxy-18,19,20-trinor-PGF.sub.2.alpha., 
11,15-bis-(tetrahydropyranyl) ether, in quantitative yield, having R.sub.f 
=0.8 on silica gel (using as TLC solvent system the organic phase from 500 
ml. ethyl acetate, 5 ml. methanol, and 50 ml. water, well-shaken). 
b. Following the procedure of Example 6b, the methyl ester of part a, 
above, (9.8 g.) is oxidized with Jones reagent to the corresponding 
PGE.sub.2 -type product. 
c. The formula-XXXVII 16-methyl-16-phenoxy-18,19,20-trinor-PGE.sub.2, 
11,15-bis(tetrahydropyranyl) ether, methyl ester of part b above is taken 
up in 210 ml. of acetic acid, 105 ml. of water, and 35 ml. of 
tetrahydrofuran. The solution is stirred at 40.degree.-45.degree. C. for 4 
hrs., then freeze-dried. The residue is taken up in diethyl ether, washed 
with cold, dilute sodium bicarbonate solution, dried, and concentrated to 
a mixture of the title compound, 6.2 g. 
d. The mixture from part c is chromatographed on silica gel (800 g.) wet 
packed in ethyl acetate-hexane (1:1). The column is eluted in 60 ml. 
fractions with the following solvent mixtures: fractions 1-20, 60% ethyl 
acetate-40% hexane; fractions 21-40, 70% ethyl acetate-30% hexane; 
fractions 41-60, 80% ethyl acetate-20% hexane; fractions 61-80, ethyl 
acetate; fractions 81-100, 2% methanol in ethyl acetate. Fractions 34-44 
yield the formula-XVI PGA.sub.2 -type title compound, 0.48 g.; NMR peaks 
at 7.56, 7.52, 7.48, 7.44, 6.24, 6.20, 6.14, 6.10, 7.31-6.86, 5.82-5.65, 
5.48-5.30, 3.63 (singlet) and 1.28 (singlet) .delta.; mass spectral peaks 
(trimethylsilyl derivative) at 484, 453, 451, 407, 391, 350, 260, and 135. 
Fractions 73-100 yield the formula-XIII PGE.sub.2 -type title compound, 
3.0 g.; NMR peaks at 7.30-6.87, 5.82-5.65, 5.48-5.30, 3.64 (singlet), 
1.25, and 1.21 .delta.; mass spectral peaks (trimethylsilyl derivative) at 
574, 543, 484, 481, 469, 439, 391, and 135. 
EXAMPLE 10 
16-Methyl-16-phenoxy-18,19,20-trinor-PGF.sub.2.alpha., Methyl Ester 
(Formula XIV: g is 3; M is 
##STR56## 
R.sub.1, R.sub.2, and R.sub.3 are methyl; s is zero; and .about. is alpha) 
A solution of 16-methyl-16-phenoxy-18,19,20-trinor-PGF.sub.2.alpha., 
11,15-bis(tetrahydropyranyl) ether, methyl ester (Example 9a, 4.0 g.) in 
90 ml. of acetic acid, 45 ml. of water and 15 ml. of tetrahydrofuran is 
stirred at 40.degree.-45.degree. C. for 4 hrs. The reaction mixture is 
diluted with 150 ml. of water, frozen, and lyophilized. The residue is 
taken up in ether and washed with ice-cold dilute sodium bicarbonate 
solution. The organic phase is dried over sodium sulfate and concentrated 
under reduced pressure. The residue is chromatographed on silica gel, 
eluting with 0-20% methanol in ethyl acetate. Those fractions shown by TLC 
to contain the product free of starting material and impurities are 
combined and concentrated to yield the title compound, 2.08 g.; NMR peaks 
at 7.38-6.86, 5.72-5.62, 5.50-5.28, 3.66 (singlet), and 1.22 (singlet) 
.delta.; mass spectral peaks (trimethylsilyl derivative) at 633, 617, 555, 
513, 423, and 135. 
EXAMPLE 11 
16-Methyl-16-phenoxy-18,19,20-trinor-PGF.sub.2.beta. (Formula XV: g is 3; M 
is 
##STR57## 
R.sub.1 is hydrogen; R.sub.2, and R.sub.3 are methyl; and s is zero) 
Refer to Chart D. A solution of sodium borohydride (300 mg.) in 6 ml. of 
ice-cold methanol is added to a solution of 
16-methyl-16-phenoxy-18,19,20-trinor-PGE.sub.2 (Example 8, 650 mg.) in 30 
ml. of methanol at -5.degree. C. The mixture is stirred for an additional 
5 min., made slightly acidic with acetic acid, and concentrated under 
reduced pressure. The residue is extracted with dichloromethane and the 
organic phase is washed with water, dilute aqueous sodium bicarbonate, and 
brine, then dried over sodium sulfate and concentrated under reduced 
pressure. This residue is chromatographed over silica gel, eluting with 
0-10% ethanol in ethyl acetate. Those fractions containing the title 
compound free of starting material and impurities, as shown by TLC, are 
combined and concentrated to yield the formula-XV title compound. In other 
fractions the corresponding formula XIV PGF.sub.2.alpha. -type compound is 
obtained. 
Following the procedure of Example 11, each of the 16-phenoxy (or 
substituted-phenoxy)-PGE.sub.2 type compounds, their 15.beta. epimers, and 
racemates described following Example 8 is transformed to the 
corresponding 16-phenoxy (or substituted-phenoxy)-PGF.sub.2.beta. type 
compound or 15.beta. epimer or racemic mixture. There are also obtained 
the corresponding PGF.sub.2.alpha. -type compounds. 
EXAMPLE 12 
16-Phenoxy-17,18,19,20-tetranor-PGA.sub.2 (Formula XVI: g is 3; M is 
##STR58## 
R.sub.1, R.sub.2, and R.sub.3 are hydrogen; and s is zero) 
Refer to Chart D. A solution of 16-phenoxy-17,18,19,-20-tetranor-PGE.sub.2 
methyl ester (Example 6, 300 mg.), 4 ml. of tetrahydrofuran and 4 ml. of 
0.5 N. hydrochloric acid is left standing at 25.degree. C. for 5 days. 
Brine and dichloromethane-ether (1:3) are added and the mixture is 
stirred. The organic phase is separated, dried, and concentrated. The 
residue is dissolved in diethyl ether and the solution is extracted with 
saturated aqueous sodium bicarbonate. The aqueous phase is acidified with 
dilute hydrochloric acid and then extracted with dichloromethane. This 
extract is dried and concentrated to yield the formula-XVI title compound. 
Following the procedure of Example 12, each of the 16-phenoxy (or 
substituted-phenoxy)-PGE.sub.2 type compounds, 15.beta. epimers, and 
racemates, described following Example 8 is transformed to the 
corresponding 16-phenoxy (or substituted-phenoxy)-PGA.sub.2 type compound 
or 15.beta. epimer or racemic mixture. 
EXAMPLE 13 
16-Phenoxy-17,18,19,20-tetranor-PGB.sub.2 (Formula XVII: g is 3; M is 
##STR59## 
R.sub.1, R.sub.2, and R.sub.3 are hydrogen; and s is zero) 
Refer to Chart D. A solution of 16-phenoxy-17,18,19,-20-tetranor-PGE.sub.2 
methyl ester (Example 6, 200 mg.) in 100 ml. of 50% aqueous ethanol 
containing about one gram of potassium hydroxide is kept at 25.degree. C. 
for 10 hrs. under nitrogen. The solution is then cooled to 10.degree. C. 
and neutralized by addition of 3N. hydrochloric acid at 10.degree. C. The 
resulting solution is extracted repeatedly with ethyl acetate, and the 
combined ethyl acetate extracts are washed with water and then with brine, 
dried, and concentrated to yield the formula-XVII title compound. 
Following the procedure of Example 13, each of the 16-phenoxy (or 
substituted-phenoxy)-PGE.sub.2 type compounds, their 15.beta. epimers, and 
racemates, described following Example 8 is transformed to the 
corresponding 16-phenoxy (or substituted-phenoxy)-PGB.sub.2 type compound 
or 15.beta. epimer or racemic mixture. 
EXAMPLE 14 
16-Methyl-16-Phenoxy-18,19,20-trinor-PGE.sub.1 (Formula VIII: g is 3; M is 
##STR60## 
R.sub.1 is hydrogen; R.sub.2 and R.sub.3 are methyl; and s is zero) and 
16-Methyl-16-Phenoxy-18,19,20-trinor-13,14-dihydro-PGE.sub.1 (Formula 
XVIII: g is 3; M is 
##STR61## 
R.sub.1 is hydrogen; R.sub.2 and R.sub.3 are methyl; and s is zero) 
A mixture of the formula-XXXVII bis(tetrahydropyranyl) ether of 
16-methyl-16-phenoxy-18,19,20-trinor-PGE.sub.2 (Example 8, 220 mg.), 5% 
rhodium-on-alumina catalyst (40 mg.), and 16 ml. of ethyl acetate is 
stirred under one atmosphere of hydrogen at about 0.degree. C. until 
substantially all of the starting material has been used, as shown by TLC. 
The mixture is filtered to remove catalyst, and the filtrate is 
concentrated. The residue is dissolved in 1 ml. of tetrahydrofuran and 6 
ml. of 66% acetic acid and the mixture is warmed to 50.degree. C. for 2.5 
hrs. The mixture is concentrated under reduced pressure and the residue is 
chromatographed over silica gel, eluting with the upper layer of a mixture 
of ethyl acetate-acetic acid-Skellysolve B (isomeric hexanes)-water 
(90:20:50:100). Those fractions shown by TLC to contain the title 
compounds free of starting material and impurities are combined and 
concentrated to yield the title compounds. 
Following the procedure of Example 14, each of the PGE.sub.2 -type 
bis(tetrahydropyranyl) ethers described following Example 8 is transformed 
to the corresponding 16-phenoxy (or substituted-phenoxy)-PGE.sub.1 type or 
13,14-dihydro-PGE.sub.1 type compound, 15.beta. epimer, or racemate. 
EXAMPLE 15 
16-Phenoxy-17,18,19,20-tetranor-13,14-dihydro-PGE.sub.1 Methyl Ester 
(Formula XVIII: g is 3; M is 
##STR62## 
R.sub.1 is methyl; R.sub.2 and R.sub.3 are hydrogen; and s is zero) 
A solution of 16-phenoxy-17,18,19,20-tetranor-PGE.sub.2 methyl ester 
(Example 6, 100 mg.) in 10 ml. of ethyl acetate is shaken with hydrogen at 
about one atmosphere pressure at 25.degree. C. in the presence of a 5% 
palladium-on-charcoal catalyst (15 mg.). Two equivalents of hydrogen are 
used, whereupon the hydrogenation is stopped and the catalyst is removed 
by filtration. The filtrate is concentrated under reduced pressure and the 
residue is chromatographed on silica gel, eluting with ethyl 
acetate-Skellysolve B (isomeric hexanes) ranging from 50-100% ethyl 
acetate. Those fractions shown by TLC to contain the desired product free 
of starting material and impurities are combined and concentrated to give 
the title compound. 
Following the procedures of Examples 11, 12, and 13, each of the 16-phenoxy 
(or substituted-phenoxy)-PGE.sub.1 type or 13,14-dihydro-PGE.sub.1 type 
compounds, 15.beta. epimers or racemates described in and following 
Examples 14 and 15 is transformed respectively to the corresponding 
16-phenoxy (or substituted-phenoxy)-PGF.sub.1.alpha., -PGF.sub.1.beta., 
-PGA.sub.1, or PGB.sub.1 type or 16-phenoxy (or 
substituted-phenoxy)-13,14-dihydro-PGF.sub.1.alpha., -PGF.sub.1.beta., 
-PGA.sub.1, or -PGB.sub.1 type compound, 15.beta. epimer or racemate. 
EXAMPLE 16 
16-Phenoxy-17,18,19,20-tetranor-PGF.sub.2.alpha. Methyl Ester (Formula XIV: 
g is 3, M is 
##STR63## 
R.sub.1 is methyl, R.sub.2 and R.sub.3 are hydrogen, s is zero and .about. 
is alpha) 
A solution of diazomethane (about 0.5 g.) in 25 ml. of diethyl ether is 
added to a solution of 16-phenoxy-17,18,-19,20-tetranor-PGF.sub.2.alpha. 
(Example 5, 50 mg.) in 25 ml. of a mixture of methanol and diethyl ether 
(1:1). After the mixture has stood at about 25.degree. C. for 5 min., it 
is concentrated under reduced pressure to yield the title compound. 
Following the procedure of Example 16, each of the other 16-phenoxy (or 
substituted-phenoxy)-PGF-type, PGE-type, PGA-type, and PGB-type free acids 
and also their 15.beta.-epimers and racemates defined above is converted 
to the corresponding methyl ester. 
Likewise following the procedure of Example 16, but replacing diazomethane 
with diazoethane, diazobutane, 1-diazo-2-ethylhexane, and diazodecane, 
there are obtained the corresponding ethyl, butyl, .gamma.-ethylhexyl, and 
decyl esters of 16-phenoxy-17,18,19,20-tetranor-PGF.sub.2.alpha.. In the 
same manner, each of the other 16-phenoxy (or 
substituted-phenoxy)-PGF-type, PGE-type, PGA-type, and PGB-type free acids 
and also their 15.beta.-epimers and racemates defined above is converted 
to the corresponding ethyl, butyl, 2-ethylhexyl, and decyl esters. 
EXAMPLE 17 
16-Phenoxy-17,18,19,20-tetranor-PGF.sub.2.alpha. Sodium Salt 
A solution of 16-phenoxy-17,18,19,20-tetranor-PGF.sub.2.alpha. (Example 5, 
100 mg.) in 50 ml. of a water-ethanol mixture (1:1) is cooled to 5.degree. 
C. and neutralized with an equivalent amount of 0.1 N. aqueous sodium 
hydroxide solution. The neutral solution is concentrated to a residue of 
the title compound. 
Following the procedure of Example 17 but using potassium hydroxide, 
calcium hydroxide, tetramethylammonium hydroxide, and 
benzyltrimethylammonium hydroxide in place of sodium hydroxide, there are 
obtained the corresponding salts of 
16-phenoxy-17,18,19,20-tetranor-PGF.sub.2.alpha.. 
Likewise following the procedure of Example 17 each of the 16-phenoxy (or 
substituted-phenoxy) PGE-type, PGF-type, PGA-type, and PGB-type acid and 
also their 15.beta.-epimers and racemates defined above is transformed to 
the sodium, potassium, calcium, tetramethylammonium, and 
benzyltrimethylammonium salts.