Note: Descriptions are shown in the official language in which they were submitted.
2'720 - ~1
~9 ~
BACI<GROUND OF THE I NVENT i ON
This invention relates to products having pros~acyclin-
like structure and to processes For preparing ~hem. In
particular lhis invention relates to 5,6-dihydro-prosta-
cyclin analogs an~ -to processes for preparing them.
Prostacyclin is an organic compound related to pros~a-
glandins and identified as 9-deoxy-6,9~-epoxy-~5-PGF1a.
It is particularly characterized as an enol ether from its
chemical properties. See R.A. Johnson e-t al., Prostaglandins
12, 915 (1976).
The prostaglandins and analogs are well-known organic
compounds derived from prostanoic acid which has thè fol-
lowing structure and atom numbering:
~ "7~C 00 H
~ S~8`~0
As drawn hereinafter the formulas represent a partic-
ular optically active isomer having ~he same absolute con-
figuratiorl as PGFIa obta1ned from mamm~lian ~issues~
In the formulas, broken line attachments to the cyclo-
pentane ring or side chain indicate substi~uents in alpha
configurationJ i,e, below the plane o-f the ring or side chain,
Heavy solid line at~achmen~s indicate substi~uen~s in be~a
~5 configurationJ i,e. above the plane,
Somewhat related compounds have been reported by C,
Pace Asciak et al,, in Biochemistry, Vol, 109 pages 3~57-
~664 (1~71), includi ngJ for example:
,~0
--2 --
2720-~.
o~<~^ " ~^\~ C~2H
~ 11
OH H
Prostacyclin and prostacyclin-type compounds, including
derivatives and analogs3 are extremely po~ent in causing
various biological responses. For that reason, these com-
~ po~nds are useful for pharmacological purposes A few of
those bioloyical responses are: inhibition of blood
platele~ aggregation, stimulation of smooth muscle,
inhibition of gastric secretion and reduction of
undesirable gastrointestinal effects from systemic
administra~ion of prostaglandin synthetase inhibitors.
Because of these biological responses, prostacyclin
and prostacyclin-type compounds are useful.to study~ pre-
vent, control, or alleviate a wide variety of diseases and
undesirable physiological conclitions in mammals, including
hllmans, useful domestic animals~ pets, and zoological
specimens, and in laboratory animals, -for example, mice~
rats, rabbits~ and monkeys.
Prostacyclin and prostacyclin-~ype compounds are
useful whenever it is desired to inhibit platelet aggre-
2~ gation, to reduce the adhesive character of platelets,and to remove or prevent the formation of -thrombi in
mammals, including man, rabbits, and rats. For exampleg
these compounds are useful in the treatment and prevention
of myocardial infarcts, to treat and prevent post-
operative surgery, and to treat conditions such as
~ ~ 2720-1
atherosclero~is, arteriosclerosis, blood clotting defects
due to lipemia, and o~her clinîcal conditions in which ~he
underlying eti~logy is associate~ with lipid imbalance or
hyp~rlipidemia. Other in v~vo applications include
geriatric patients ~o prevent cerebral ischemic attacks
and long term prophylaxis following myocardia7 infarcts
and strokes. ~or these purposes, these compounds are ad-
ministered systcmic~lly, e.g., intravenously, subcutane-
OUS1YJ intramuscularly, and in the form of s~erile implants
for prolonged action. tor rapid response, especially in
emergency situations, the intravcnous route of administra-
tion is preferred. Doses in the range about 0.01 to about
10 mg. per kg. of body weight per day are used, the exact
dose depending on the age, weight, and corldition of the
patien~ or animal, and on the frequency and route of admin-
istrat;on.
The addition of prostacyclin and prostacyclin-type
compounds to whole blood provides In vi~ro applications
such as storage of whole blood to be used in heart-lung
machines. Additionally whole blood containincJ these com-
pounds can be circulated through limbs and organs, e.g.
heart and kldneys, whether attached to the original body,
detached and being preserved or prepared for -transplant,
or attached to a new body Blocking of aggregated plate-
lets is avoided by the presence of these compounds. Forthis purposeJ the compound is added gradually or in single
or multiple portions to the circulating blood, to the
blood of the donor person or animal~ to the perfused body
portion, attached or de-tached, to the recipient, or to
3~ two or all of those at a total steady s-tate dose of about
-4-
2720-1
0.001-1.0 ~y./ml. of whole blood. These compollnds are also
useful in preparing platelet-rich concentrates from blood
for use in treating thrombocytopenia or in chemotherapy.
Prostacyclin and prostacyclin-type compounds are
-
5 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 eryot alkaloicls including
derivatives and analogs thereof. There-fore, they are
useFul in place Or or in combination with less than usual
amounts oF these known smooth muscle stimulators, for
example, to relieve the symp~oms of paralytic i12us, or to
control or prevent at~nic uteri ne bleeding after aborti~n or
delivery, ~o aid in expulsion of ~he placen~a3 and during
the pllerperium. For the latter purpose, the compound is
adminis~red by intraveno~s in~usion immediately af~er
aboreion or delivery a~ a dose in the rang~ about 0.01 to
about 50 ~9~ per ky. of body weight per minute until the
desired efrect is obtained. Subsequen~doses are glven by
~ intravenous, subcutaneous, or intramuscular injection or
inflJsion during puerperium in the range 0.01 to 2 mg. per
kg. of body weight per day, ~he exact dose depending ~n the
age, weight~ ~nd condi~ion of the patien~ or arlimal.
Prostacyclin and prostacyclin-type compounds are also
useful in mammals, including man and certain useful animalsJ
e.g. dogs and pigs, to reduce and con-trol excessive gastric
secretion, thereby reduce or avoid gastrointestinal ulcer
formation, and accelera~e the healing of such ulcers al-
ready present in the gastrointes-tinal -tract. For this
3 purpose, these compounds are injected or infused in-tra-
-5
2720-1
3~
venously, subcutaneously, or intramuscularly in an infusion
dose range about 0.1 ~9, per kg. of body weight per minute~
or in a total daily dose by injection or infusion in the
range about C.01 to about 10 mg. per kg.. of body weigh~
per day, the exact dose depending on the age, weight, and
condition of the patien~ or animal, and on the frequency
and route of adminis~ration.
Prostacyclin and prostacyclin-type compounds are also
useful in reducing the undesirable gastrointes~inal effects
resulting from systemic administra~ion of anti-inflammatory
prostaglandin synthetase inhibi~ors3 and are used for that
purpose by concomitant adminis~ration of ~he prostacyclin
or prostacyclin-type compound and the anti-inflammatory
prostaglandin synthetase inhibitor. See Partridge et al.,
U.S. Pat. No, 3,781,429g for a disclosure that the ulcero-
genic effec~ induced by cer~ain non-steroidal anti-inflam-
matory agents in rats is inhibited by concomitant oral
administra~ion of certain prostaglandins oF the E and A
series, including PGE~/ PGE29 PGE3, 13,14-dihydro-PGEl, and
the corresponding 11-deoxy-PGE and PGA compounds. Prosta-
cyclin and prostacyclin-type compounds are useful~ for
example~ in reducing the undesirable gas~roin~estinal e-F-
fects resulting from systemic adminis-tration of indome~hacin,
phenylb~tazone, and Aspirin. These are substances speciFical~
ly mentioned in Partridge et al.9 as non-steroidal~ anti-
inflamma~ory agents. These are also known to be prosta-
glandin synthe~ase inhibitorsO
The anti-inflammatory synthetase inhibitor, for ex-
ample indomethacin, aspirin, or phenylbutazone is adminis-
~0 tered in any of ~he ways known in the ar~ ~o alleviate an
Trademaxk
~,.~ 'I
2720-1
inflammatory condition, for example, in any dos~ge regimen
and by any of the known routes of systemic administration
The prostacyclin or pros~acyclin-type compound is ad-
ministered along with the anti-inflammatory prostaglandin
synthetase inhibitor either by the same route of adminis-
tration or by a different route. For example, if the anti-
inflammatory substance is being administered orally, the
prostacyclin or prostacyclin-type compound is also adminis-
tered orally, or~ alternatively, is administered rectally
in the form of a suppository or, in the case of women,
va~inally in the form of a suppository or a vaginal device
for slow release, for example as described in U.S. Patent
No. ~,545,439, Alternatively, if the anti-inflammatory
substance is being administered rectal 1YJ the prostacyciin
or prostacyclin-type compound is also administered rectally.
Further, the prostacyclin derivative can be conveniently
administered orally or, in the case of women, vaginally.
It is especially convenient when the administration route
is to be the same for both anti-inflammatory substance and
prostacyclin or prostacyclin-type compound to combine both
into a single dosage form.
The dosa~e regimen for the prostacyclin or prostacyclin-
type compound in accord with this treatment will depend upon
a variety of factorsJ including the type, age, weight, sex
and medical condition of the mammalg the na~ure and dosage
regimen of the anti-inflammatory syn-thetase inhibitor being
administered to the mammal~ the sensitivity of the partic-
ular prostacyclln or prostacyclin-type compound to be
administered. For e~ample, not every human in need of an
~0 anti-in-flammatory substance experiences the same adverse
7-
~ 720-1
gastrointes~inal effects when ~aking the substance. The
gastrointestinal effec~s will frequently vary substantially
in kind and degree But it is within the skill of the at-
-tending physician or veterinarian to determine tha-t admin-
istration of the anti-inflammatory substance is causing
undesirable gastrointestinal effects in the human Ol- animal
subjec-t and to prescribe an effective amount of the prosta-
cyclin or prostacyclin-~ype compound to reduce and then
~ubstantially to eliminate those undesirable effects.
Prostacyclin or pros~acyclin-type compounds are also
useful in the treatment of asthma. For example, these com-
pounds 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 compour~ds con~rol spasm and facilitate breathing in
conditions such as bronchial asthma, bronchitis, bronchi-
ectasls, 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 , sub-
cutaneously) or intramuscLilarly, with intravenous adminis-
tration being preferred in emergency situations; by inha1a-
tion 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 dcse depending on the
age, weight, and condition of ~he patient and on the fre-
quency and route of administration. For the above use the
.prostacyclin or prostacyclin-type compound can be combined
~0 advantageously with other anti-asthmatic agents, such as
-8-
2720-1
~663;Z
sympa-thomimetics ~isoproterenol~ phenylephrine, ephedrine,
etc.); xanthine derivatives (theophylline and aminophy11ine);
and corticosteroids (ACTH and prednisolone).
Prostacyclin or prostacyclin-type compounds are efFec-
-tively administered to human asthma patients by oral
inhalation or by aerosol inhalation.
~ or administration by the oral inhalation route with
conventional nebulizers or by oxygen aerosolization it is
convenient to provide the prostacyclin ingredient in
dilute solution, preferably at concentrations of about 1
part of medicament to form about 100 to 200 parts by
weight of total solution. Entirely conventional additives
may be employed to stabilize these solutions or to pro
vide isotonic media3 for example, sodium chloride, sodium
citrate, citric acid, and the like
can be employed.
For administration as a self-propelled dosage unit for
administering the active ingredient in aerosol form suita-
ble for inhalation therapy the composition can comprise
20 the active ingredient suspended in an inert propellant
(such as a mixture of dichlorodifluoromethane and di-
chlorotetrafluoroethane) together with a co-solvent5 such
as ethanol, flavoring materials and stabilizers. Instead
` of a co-solvent there can a~lso be used a dispensing agen~
such as oleyl alcohol. Suitable means to employ the
aerosol inhaiation therapy technique are described fully
in U.S. 2,868,691 for example.
Prostacycl~n or prostacyclin-type compounds are use-
ful in mammals5 including man~ as nasal decongestants and
~0 are used for this purpose in a dose range of about 10 ~9O
~ 63~ 2720~
to about 10 mg. per m1. o-f a pharmacologically suitable
liquid vehicle or as an aerosol spray~ both for topical
application.
Prostacyclin or prostacyclin-type compounds are also
useFul in treating peripheral vascular disease in humans.
The term peripheral vascular disease as used herein means
disease of any of the blood vessels outside of the heart
and to disease of the lymph vessels, for example, frostbite~
ischemic cerebrovascular disease~ arteriovenous fistulas,
ischemic leg ulcers, phlebitis, venous insufficiency~ gan-
grene, hepatorenal syndrome, ductus arteriosus~ non-
obstructive mesenteric ischemia, arteritis lymphangitis and
the like. These examples are included to be iliustrative
and should not be construed as limiting the term peripheral
vascular disease. For these conditions the prostacyclin
compounds are administered orally or parenterally via
injection or infusion directly into a vein or artery.
The dosages o~ these compounds are in the range
of 0.01-1.0 ,u,g. administered by inFusions at an hourly
rate or by injection on a daily basis, i.e. 1-4 times a
dayJ the exact dose depending ~n the age, weight,and
condi~ion of the patient and on the frequency and route
of administratiorl Treatment is continued for one to
2~ five daysJ although threP days is ordinarily sufficient
to assure long-lasting therapeutic action. In the
event that systemic or side effects are observed the
dosage is lowered below the threshold at which such
systemic or side effects are observed.
Prostacyclin or prostacyclin-type compounds are ac-
-10 -
2720-1
663~
cordingly useful for treating peripheral vascular diseases
in the extremities of humans who have circulatory insuf-
ficiencies in said extremities, such treatment affording re-
lief of rest pain and induc~ion of healing of ulcers.
For a complete discussion of the nature of and
clinical manifestations of human peripheral vascular
disease and the method previously known of its treat-
ment with prostaglandins see South African Patent No.
74/0149 referenced as Derwent Farmdoc No. 5~,400V.
See Elliott, et al., Lancet, ~anuary 18, 1975, pp. 140^142.
Prostacyclin or prostacyclin-type compounds are useful
in place of oxytocin to induce labor in pregnant female
animals~ including man, COW55 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
compourld is infused intravenously at a dose of 0.01 to 50 ~g.
per kg. of body weight per minute until or near ~he termin-
ation of the second stage of labor, i.e., expulsion of the
fetus. These compounds are especially useful when the
~ ~emale is one or more weel<s post-mature and natural
labor has not started, or 12 to 60 hours after the mem-
branes have ruptured and natural labor has not yet started.
An alternative route of administration is oral.
Prostacyclin or prostacyclin-type compounds are further
use-ful for controlling the reproductive cycle in menstruating
female rnammals, including humans. By the term menstruating
female mammals is meant animals which are mature enough to
menstruate, but not so old ~hat regular menstrua-tion has
ceased. For that purpose the prostacyclin compound is admin~
istered sys~emically at a dose levei in the range 0.01 mg. to
!
2720-1
6~3~
about 20 my. per kg of body weight of the female mammal,
advantageously durin~ 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 routes are alternate methods of administra-
tion. Additionally, expulsion of an embryo or a fetus is
accomplished by similar administration of the compound
during the first or second trimester of the normal mam-
malian gestation perlod.
Prostacyclin or prostacyclin-type compounds are further
useFul in causing cervical dilation in pregnant and non-
pregnant female mammals for purposes of gynecology and obstet-
rics. In labor induction and in clinical abor~ion produced
by these compounds~ cervical dilation;is also observed. In
~5 cases of infertility, cervical dilation produced by these
compounds is useful in assisting sperm movement to the
uterus Cervical dilation by prostacyc1in compounds is also
use~ul in operative gynecology such as D and C (CervTcal
Dilation and Uterine Curettage) where mechanical dilation
may cause performation of the uterus, cervical tears, or
infections. I~ is also useful For diagnostic procedures
where dilation is necessary for tissue examination. For
these purposes~ the prostacyclin compound is administered
locally or systémically.
The prostacyclin compound, for example, is admin-
istered crally or vaginally at doses of about 5 to 50 mg.
per treatment oF an adult female humang ~ith from one to
five treatments per 24 hour period. Alternatively the
compound is administered intramuscularly or subcutaneously
at doses of about one to 25 mg. per treatment~ The exact
-12-
2720-1
i63~
dosages for these purposes depond on the age, weight, and
condition of the patient or animal.
Prostacyclin and prostacyclin-type compounds are further
useful in domestic animals as in abortifacients(especially
for feedlot heifers), as an aid to estrus detection, and
for regulation or synchronization of estrus. Domestic
animals incl~ude horses, cattle, sheep, and swine. The
regulation or synchronization of estrus allows for more
effiçi~nt management of bo-th conception and labor by enabling
the herdsman to breed all his females in short pre-defined
intervals. This synchronization results in a lligher per-
centage of live births than the percentage achieved by
natural control. The prostacyclin compound is injected
or applied in a feed at doses of 0.1-100 mg. per animal
and may be combined with other agents such as steroids.
Dosing schedules will depend on the species treated. For
example, mares are given the prostacyclin compound 5 to 8
days after ovulation and return to estrus. Cattle are
treated at regular interv~ls over a ~ week period to
advantageously bring all into es~rus at the same time.
Prostacyclin or prostacyclin-type compounds increase
the flow of blood in the mammalian kidney, thereby increas-
ing volume and electrolyte content of the urine. For that
reason, ~hese çompounds are useful in managing cases of
renal dysfunction, especially those involving blockage of
the renal vascular bed. Illustratively, these compounds
are useful to alleviate and correct cases oF edema result-
ing~ for example, -from massive surface burns, and in the
management of shock. For these purposes, these compounds are
~0 preferably first administered by intravenous injection 3~
2720-1
q ii3~2
a dose in the range 10 -to 1000 ~g. per kg. of body weight or
by intravenous infusion at a dose in the range 0.1 to 20 ug.
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 2mg. per kg. of body weight per day.
These prostacyclin or prostacyclin-type çompounds are
useful for treating proliferating skin diseases of man and
domesticated animals, including psoriasis~ atopic dermatitis,
non-specific dermatitis, primary irritant contact dermatitis,
allergic contact dermatitis, basal and squamous cell
carcinomas of the skin, lamellar ichthyosisg epidermolytic
hyperkeratosis, premalignant sun-induced keratosis, non-
malignant keratosis, acne~ and seborrheic dermatitis in
humans and atopic dermatitis and manye in domesticated
animals. These compounds alleviate the symptoms of these
proliferative skin diseases: psoriasis~ for example,
being alleviated when a scale-free psoriasis lesion
is noticeably decreased in thickness or noticeably but
incompletely cleared or completely cleared.
For those purposes, these compounds are applied
topically as compositions including a suitable pharma-
ceutical carrier, for example as an ointment, lotion,
paste, jel ly3 spray, or aerosol~ using ~opical bases
such as petrolatum, lanolin, polyethylene glycols, and
alcohols. These compounds, as the active ingredients,
constitute from about 0.1~ to about 15~ by weight of
the composition, preferably -from about 0.5% to abou~ 2~.
In addition to topical administration, injection may be
~0 employed, as intradermally, intra- or perilesionally~ or
-14~
27~0-1
663~
subcutaneously, using appropriate sterile saline composi~ions.
Prostacyclin or prostacyclin-type compounds are use~ul
as antiflammatory agents for inhibiting chronic inflammation
in mammals tncluding the swelling and other unpleasant ef-
fects thereof using methods of treatmen~ and dosages gener-
ally in accord with U.S. Patent No. 3~885304~.
SUMMARY OF THE INVENTION
It is the purpose oF this invention to provide novel
products having pharmacological activity. It is a further
purpose to provide processes ~or preparing these products
and their intermediates.
The presently provided cyclic ethers include compounds
of the following formulas:
~H2COOR~
.~
"
~W ~ ~ H R5
C=C~ l
~I/ fi-~-CgH29-CH3
Q R6
CH2-(CH2)d-( ~
0~
2S <~_~ lV
C =C~
H~ C~f~CgH29~CH3
Q R~
,~0
-15-
~1`
32 2720-1
,,~
5H~ -CH=CH-COOR
o~\
~ V
W ~C C~
H/ C~f~CgH2g~CH3
Q R6
CH, -CH=CH - ~ Ctl~ )h -COOR .
\~ ~, /H Rs Vl
H \C-C-CgHzg~CH3
Q R6
~H2CH2 -O -~H2 -COOR
O--\~
V I I
~wl~ ~H R5
C=C
H ~ \C-C-CgH29~CH3
Q R~
ÇH2 CH~ -O - ( CH~ ) I, -COOR
0~
<~ Vlll
C=C~
H' ICj-f-CgH29-CH3
Q R8
3o
-16-
ii3~ 2720-1
CH~COOR,
0~ lX
H R5 -( T ) s
Q R~3
CH~ - ~CH~ ),I-COOR .
., ~ _ , ~., A
~ X
H / \ l C_Z ,~ S
Q R~
JH2 -CH-CH-CO(: R
a~
X I
,c=c \ ~ ( r )
ll l
a R8
CH2 -CH=CH - ( CH2 ) h -COOR 1
,0~
J X I I
< ~
W ~ ,H R5
H- \C -C -Z ~( T )s
Q R6
3o
-17 -
2720 - 1
;3;~
CH2CH2 -0 -CHz -COOR
O ~\
Xlll
C=G -\ ~ ( T ) s
Q R~,
CH2CH2 -0 - ( CH2 ) k-COOR
~0~
<'~ XIV
W ~ R5
H / \ C - C Z ~ s
R~
There are also provided cyclic e~hers of the following
f ormu l as:
C, H2 - ( CH2 ) t -CF2 -COOR
O i~
V
w l~ /H R5
~0 H ~ \ C ~ 3H2 g -~H3
Q
,_5H2 - ( CH2 ) t -CF2 -COOR 1
I~\ XVI
w~c=c~ I ~(T)s
3 I n formulas I I I -3( l V, "d" i s an i nteger of one to 5,
-:l8 -
2720-1
66~ ~
inclusive; ~ l is one, 2, or 3; and "k" is one or 2.
CgH~g is alkylene of one ~o 9 carbon atomsl inclusive,
with one to 5 carbon atoms, inclusive, in the chaln between
-CRsRe- and terminal methyl, wherein R5 and R6 are hydrogen,
alkyl o~ one to 4 carbon atoms, inclusive, or fluoro, being
the same or different, with the proviso that one of R5 and R~
is fluoro only when the other is hydrogen or fluoro, and
with the further proviso that, when Z is oxa (-O-) as de-
fined below~ neither Rs nor R~ is fluoro. Q is
R3 OR4 or R3 OR4
wherein R3 is hydrogen or alkyl of one to 4 carbon atoms,
inclusive, and wherein R4 is hydrogen~ tetrahydropyran-2-
yl, tetrahydrofuranyl~ 1-ethoxyethyl or a group of the
formula
H
R8-O-C - f -R
R9 R1o
~0
wherein R8 is alkyl of one to 18 carbon atoms, inclusive,
cycloalkyl o~ 3 to 10 carbon atoms, i nclusive5 aralkyl
o~ 7 to 12 carbon atomsg inclusiveg phenyl~ or phenyl sub-
stituted with one~ 2~ or 3 al kyl of one to 4 carbon atoms3
inclusive, wherein Rg and R1o are the same or differentJ
being hydrogen, alkyl of one to 4 carbon atoms, inclusive,
phenyl or phenyl substituted with one, 23 or 3 alkyl of
one to 4 carbon atoms, 7 nclusi veJ or, when R9 and R1o are
taken together, -(CH2)a- or -(CH2)b-O-(CH2)c- wherein "a"
3 is 3J 4J or 5J b i s oneJ 2J or 3g and c is one, 2, or 3
-lg -
i63~
wi~h the pro~Jiso that b plus c is 2, 3, or 4, and wherein
Rll is hydroyen or phenyl. P~l is hydroqen or alkyl of
one to 8 carbon a-to~s, inclusive. T is alkyl oE one to
4 carbon atoms, inclusive, fluoro, chloro, trifluoromethyl,
or -OR7- wherein R7 is hydrogen or alkyl oE one to 4 carbon
atoms, inclusive, and s is zero, one, 2, or 3, with the
proviso that not more than t~,70 T's are other than alkyl
and when s is 2 or 3 the T's are either the same of dif-
ferent. W is
-C- or -CH2-
RljO H
wherein R4 is as defined above. Z represents an oxa atom
( -o- ) or CjH2j wherein CjH2j i~ a valen~e bond or alkylene
o~ one to 9 carbon atoms, inclusive, substituted with zero,
one, or 2 fluoro, with one to 6 carbon atoms, inclusive
between -CRsR6- and the phenyl ring. The wavy line,
indicates attachment in alpha or beta configuration.
In formulas XV and XVI, t is 2, 3 or 4, and CgH2g~
Q, Rl, Rs, R6, s, T, W, Z, and ~ are as defined above.
The carbon atoms are numbered as for prostanoic acid
(1), except that the carbon atoms in longer or shorter side
chains are named, following the usual convention, as "nor"
or "homo" atoms. Thus, in compound V above, the -CH=CH-
~roup is at the "3,4" position and C-2 is a "nor" atom.
By way of illustrakion, for~ula III represents 9 deoxy-
6~,9~-epoxy-2,3,4--trinor-PGFl, ethyl ester, ~hen CgH2y is
trimethylene, ~ is
- 20 -
32 27~0-
~`~
H OH,
R1 is ethyl~ R5 and R6 are hydrogeng and W is
HO H.
Formula Xl represents 9-deoxy -~J 4^trans-didehydro-6 ~ ga-
epoxy-17-phenyl-2,18, 19J 20-tetr~nor-PGF1, methy1 ester when
Q iS
H OH,
R1 is methyl, R5 and R~ are hydrogenJ s is zero, W is
- C -
HO HJ
and Z is methylene. When W i5 -CH2-~ the compounds are
named as derivatives of 11 -deoxy-PGF1.
For those compounds of formula lll- XVlwherein Q is
R3 OR~,
i,e. wherein the C-15 hydroxyl or ether group is attached
to the side chain in alpha configurationJ the configuration
àt C 15 is identical with that of the naturally occuring
prostaglandins such as PGEl obtained From mammalian ~is-
sues. The 15-epimer compo~nds are represented by ~ormulas
XVI when Q is
R3 OR4
-2~-
3Z
2720-1
and are identified variously as "15-epi" or " lr~
by the appropriate prerix in the name. As is known in the
art, "R" and ~Isl! designations depend on the neighboring
substituents. See R.S. CahnJ J. Chem. Ed. 41, 116 (1964).
Included among the compounds disclosed herein are 9-
deoxy-6,9-epoxy compounds corresponding to ~he compounds of
formu7a III-XVI havin3, at C17 and C~8J cis-CH=CH-, as il-
lustrated by the formula:
,CH2-(cH2)d-COOR
'0~
XVI I
< lc =c .
H' \C-CH2 /Ctl2CH3
R 4b ~ `,c=c~
Also included are 9-deoxy-6,9-epoxy compounds cor-
responding to ~hose of formulas III-XVII except that "W"
in the cyclopentane ring is replaced with
-C- , -C- ~ -C- or -C-
R O / ~H O CH2 H CH20R4
Also included are corresponding compounds wherein the
cyclopentane ring is unsaturated between C10 and C11.
Illustrative are compounds of the following formulas:
~0
-22-
2720 - 1
6~i3;~
f H2 ~ ( CH2 ) d -COOR 1
,0~
~' XVIII
)~~C C ~H I S
R~O H~ \ C--C C9H2g_CH3
Q R6
CH2-(CH2)d_C~)P~1
X I X
~C =C /H I 5
~3 \C--C-cgH29-cH3
Q 1~;
CH2 - ( CH2 )d ~CR 1
;o~
~, ' XX
<`~I~C=C
CH2 /
H 1I F C9H2 g CH3
Q R6
CH~ (CH2 )~I~COOR1
XXI
~ J~'C C/H R5
CH2aR ~./ \
~0 H C--i C9H2g CH3
Q RG
2 2720-1
c~ - ( r~ nn~ ~
~o~
' XXII
, C C
H ICi IC CgH2g-CH~
Q R6
Also included wikhin ~he compounds disclosed herein
are 9-deoxy-699-epoxy compounds corresponding to those of
Formulas III-XXil wherein the Cl3-cl4 ~rans-CH=CH- group
is replaced by cis-CH-CH-, -C-c-J or -CH2CH2-. Merely
illustrative but not limlting are compounds of the fol-
lowing formulas:
~H2-(CH2) d -COOR 1
~ XXlil
/ C-C5H
O~I / \ Q
H H
~ H2-(CH2)d-COOR1
0 ~ XXIV
~ C=C-I-C5H
OH Q
Jo
- 2 1~
2720 - 1
63;~
CH2-(CH2)d-cOoR
0 ~\
~J ~' . XXV
~H CH2CH2-l C5Hll
Still further included within ~he compounds disclosed
herein are 9-deoxy-6J9-epoxy compounds corresponding to
those of formulas III-XXV wherein the C2 carboxylic acid,
ester, or salt group is replaced by
-CH20H
-CHzN ( R 1 a )2
R
-C-N(R 18 )2 or
NH-N
~ I I
N- N
Merely illustrative but not limiting are compounds of the
following formulas:
~H2 - ( CH2 ) 3 -CH20H
2'i ~ XXVI
S--~ C=C /
! H~ ~ C-c5H
OH
3o
2720 -1
~66~
CH~-(CH2)3-CH2NH2
O'~
/~ ~ XXVII
~ / H
/C-C ~
Q
CH2-(CH2)3-~-NH2
~ XXVlli
/~
C =C
OH H' \fi-CsH
Q
~ NH-N
CH2-(CH2 )3-C ~ ll
) `~N--N
~
XXIX
H
C =C '
bH H' c-c5HI1
Included within these formula-IiI through -XXIX com-
pounds are the isomers wherein,~ is in alpha or beta con-
figuration. The nomenclature for these isomers may refer
to "~" or "~" substitution at C-6 org preferably, it may
:30 Follow the "~" and "S" usage, for which see R.S. Cahn~
-26 -
~ 3 ~ 2720 - 1
cited above See Nelson, J. Medic. Chem. 17, 911 (1974) .
Although these formulas represent specific optical
isomers~ it is intended ~hat ~he compounds are claimed not
only in their purified form but also in mixtures, including
racemic mixtures or mixtures of the enantiomeric forms.
With regard to formulas III to XXIX, examples of alkyl
of one to 4 carbon atoms, inclusive, are methyl, ethyl,
propyl, butylg and isomeric forms thereof. Examples oF
aikyl of one to 8 carbon atomsg inclusive, are those given
above and pentyl, hexyl, heptyl, octyl, and isomeric ~orms
thereof. Examples of alkyl of one to 18 carbon atoms,
înclusive,are those given above and nonyl, decyl, undecyl,
dodecy}, tridecyl~ tetradecyl, pentadecyl, hexadecyl,
heptadecyl, octadecyl~ and isomeric forms thereof. Examples
f cycloalkyl of 3 to 10 carbon atoms, inclusive, which in-
cludes alkyl-subs~ituted cycloalkyl, are
cyclopropyl,
2-methylcyclopropyl 9
2,2-dimethylcyclopropylg
2,3-diethylcyclopropyl,
2-butylcyclopropyl,
cyclobutyl,
2-methylcyclobu~yl,
3~propylcyclobutyl,
2~3g4-triethylcyclobutylg
cyclopentyl,
2,2-dimethylcyclopentyl,
2-pentyIcyclopentyl,
3-tert-butylcyclopentyl~
cyclohexyl,
-27-
~ ~ ~ 6 ~ 3 ~ . 2720-1
4-t:ert-b~tylcyclohe)~yl J
3-isopropylcyclohexyl,
2,2-dimethylcyclohexyl,
cycloheptyl J
cyclooctyl,
cyclononyl, and
cyclo,d~-yl. ~............................ .
Examples of aralkyl of 7 to 12 carbon atoms, inclusive,
are
benzyl,
phenethyl,
1-phenyl ethyl,
2 -phenyl propy 1,
4-phenylbutyl,
3-phenyl butyl,
2-(1-naphthylethyl), and
`~ 1-(2-naphthylmethyl).
Exa~ples of phenyl ~l~bsti tuted by al kyl of one to 4 carbon
atoms, ir~~ ve/ are
(o-, m-, or p-)tolyl,
p-ethylphenyl,
p-tert-butylphenyl, 3nd
2,5-dimethyl pheny 1,
Examples of alkylene of one to 9 carbon atoms, inclu-
sive, with one to 5 carbon atomsJ inclusive, in the chain,
wi thi n the scope of CgH29 as def i ned above, are methyleneJ
e~hylene, tri~ethylene, tetramethyle ne9 a nd pentamethylene,
and those alkylene with one or more alkyl substituents on
one or more carbon atoms thereof, e.g. -CH(CH3)-, -C(CH3 )2 ~g
3 -CH(CH2CH~)-, -CH2-CH~CH3)-, -CH(CH3) -CH(CHI3) -,
-28-
i32 2720-1
-CH2-C(CH3)2-, -CHz-CH(CH3~CH~-, -CH2-CH2-CH(CH2CH2CH3)-,
-CH(CH3)-CH(CH3)-CH2-CH2-, -CH2-CH2-CH2-C(CH3)2-CH2, and
-CH2-CH2-CH2-CH2-CH(CH3) -, Examples of al kylene of one
to 9 carbon atoms, inclusive~ substituted with zero, one,
or 2 fluoro, with one to 6 carbon atoms in the chain, with-
in the scope of CjH2j as defined above, are those gi ven
above for CgH2g and hexame~hylene, ;ncluding hexamethylene
with one or more alkyl substituents on one or more carbon
atoms there~F, and including those alkylene groups with
one or 2 fluoro sub~tituents on one or 2 carbon atoms
thereof, e.g~ -CHF-CH2 , -CHF-CHF-, -CH2-CH2-CFz-,
-CH2-CHF-CH2-, -CH2-CH2-CF (CH3 ) -~ -CH2-CHz-CF2-CH2-~
-CH(CH3)-Ctl2-CH2-CHF-5 -CH2-CH2-CH2-CHz-CF
-CHF-CH2-CH2-CH2-CH2-CHF-, -CF2-CH2-CH2-CH2-CH2-CHz-~
-CH2-CH2-CH2-CFz-CH2-CH2-, and -CHz-CH2-CH2-CH2-CH2-CFz.
Examples of ~ (T)s
as defined above are
phenyl,
(o-, m-, or p-)tolyl,
(o-, m-, or p-)ethylphenyl,
(o-, m-, or p-)propylphenyl,
(o-, m-, or p-)butylphenyl,
(o-, m-, or p-)isobutylphenyl,
(~' m-, or p-)ter~-bu~ylphenyl,
2, ~5-xylyl,
2 , 4 -xy 1 y 1 ,
2,5-xyl yl,
2 ,6-~yl yl,
~,4-xylyl,
-29 -
~ 3 ~ 2720 - 1
2J6-diethylphenyl,
2-e~hyl-p-tolyl~
~-ethyl-o-tolyl,
5-ethyl-m-tolyl,
2-propyl-(o-J m-, or p-)tolyl,
4-butyl-m-tolylJ
6-tert-butyl-m-tolylJ
4-isopropyl-2,6-xylyl,
3^propyl-4-ethylphenyl,
(2J3J4-J 2J3~5-J 2J3J6-~ or 2J4J5-)~rimethylphenylg
(o-J m-J or p-)fluorophenylJ
2-fluoro-(o-, m-J or p-)tolyl,
4-fluoro-2,5-xylyl,
(2/4-J 2,5-, 2J6-J 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-chlorophe~yl,
4-chloro-3,5-xylylg
(2J3-J 2,4-, 2,5-, 2,6-, 3,4-J or 3,5-)dichlorophenyl,
4-chloro-3-fluorophenyl,
~-, or 4-)chloro-2-fluorophenylJ
a,a,a-trifluoro-(o-, m-, or p-)tolyl,
(0-3 m-J or p-)methoxyphenylJ
(o-, m-, or p-)ethoxyph.onylJ
(4- or 5-)chloro-2-methoxyphenyl, and
2J4-dichloro(5- or 6 - )me~hoxyphenyl.
Accordingly there is provided a cyclic ether of ~he
3 formula
-~0 -
2720-1
63;2
, O - C H ~ C H2 - D - C OOR ,
,H XXX
H/ C-R2
Q 2
wherein D is (1) a valence bond; (2) -(CH2)d- where d is
one, 2, 3J 4, or 5; (3) -CH=CH-A- where A is a valence bond
or -(CH2)h- where h is one, 2, or 3; or ()1) -CH2-0-CH2-Y-
where Y is a valence bond or -(CH2)k- where k is one or 2;
wherein R1 is hydrogenJ alkyl of one to 8 carbon atoms,
inclusive, or a pharmacologically acceptable cation; and
wherein R2 is
f c gH29-CH3
R6
wherein CgH2g is alkylene of one to g carbon atoms, inclu-
siveJ with one to 5 carbon atoms, inclusive, in the chain
between -CRsR~- and terminal methylj wherein Rs and R~ are
hydl-ogen~ alkyl of one to 4 carbon atoms, inclusive, or
fluoro, being the same or different, with the proviso that
one of Rs and R~ is fluoro only when the other is hydrogen
or a fluoro; or
(2) Rs
2~ 1 z ~ ~(~)s
I
R~
whelein R~ and R~ are as defined above with the proviso
that neither Rs nor R6 is fluoro when Z is oxa (-0-);
~0 wherein 2 represents an oxa atom (-0-) or CjH2j ~7erein
-31-
~6~32 2720-1
.
CjHzj is a valence bond or alkylene of one to 9 cal-bon
atomS, inclusive, with one to 6 carbon atoms, inclusive
. between -CRsR6- and the phenyl ring; wherein T is alkyl
of one to 4 carbon atoms, inclusive, fluoro, chloro, t.ri-
fluoromethyl, or -OR7- wherein R7 is alkyl of
one to 4 carbon atoms, inclusive, and s is zero, one3 2,
or ~J Wi th the proviso that not more than two T's are other
than alkyl and when s is 2 or 3 the T's are either the
same or different; wherein Q2 is
Il A ~" ,'~
O , H H , R3 OR4 , or R3 ~R4
wherein R3 is hydrogen or alkyl of one to 4 carbon atoms
inciusive; wherein R4 is hydrogen., tetrahydropyran-2-yl,
tetrahydrofuranyl~ 1 ethoxyethyl or a group of the formula
R~-O-C f -R
R9 R1o
wherein R~ is alkyl of one to 18 carbon atoms, inclusive,
cycloalkyl o-F 3 to 10 carbon atoms, inclusive, arallcyl of
7 to 12 carbon atoms, inclusiveg phenyl, or phenyl sub-
stituted with one, 2, or 3 alkyl of one to 4 carbon atoms,
inclusive, wherein Rg and R1o are the same or different,
beiny hydrogen~ alkyl of one to 4 carbon atoms, inclusive,
phenyl or pheny1 substituted with one, 2, or 3 alkyl of
one to 4 carbon atoms, inclusive, or, when Rg and Rlo are
taken togetherg -(CH2)a- or -(CH2)b-O-(CH2)c- wherein a
is 3, 4, or 5, b is one3 2, or 3, and c is one, 2, or 3
-32-
2720-1
with the proviso that b plus c is 2, 3, or 4, wher2ir
R~l is hydrogen or phenyl; wherein ~ is
\
~
~R4 OR4 CH2
~ , ~ , or
CH20R4
wherein R~ is as defined above; and wherein ~ indicates
attachment in alpha or beta configuration; including the
lower alkanoates thereoF.
There is also provided a cyclic ether of the for~ula
,O-CH --CH2-D-R31
~C-C~ XXX i
H ~ C-R2
Q2
whel-ein D is (1) a valence bond; (2) -(CH2)d- where d is
one, 2, 3, 4, or 5; (3) -CH=CH-A- where A is a valence
bond or -(CH2)h- where h is one, 2, or 3; or (4) -CH2-O-CH2-Y-
where Y is 3 valence bond or -(CH2)k- where k is one or 2;
wherein R2 is
-C-C9H2~-CH3
RG
-33
2720-1
63Z
wherein C9H2y is alkylene o~ one to 9 carbon atollls,
inclusive, with one to 5 carbon atoms, inclusive,
in the chain between -CR5R6- and terminal rnethyl,
wherein R5 and R6 are hydrogen, alkyl of one to 4
carbon atoms, inclusive, or fluoro, being the same
or different, with the proviso that one of R5 and R6
is fluoro only when the other is hydrogen or a fluoro;
or
(2) R 5
-C-Z ~ (T)s
R
wherein R5 and R6 are as defined above with the pro-
viso that neither R5 nor R6 is fluoro when ~ is oxa (-0-);
wherein Z represents an oxa atom (-O-) or CjH2j wherein
CjH2j is a valence bond or alkylene of one ~.o 9 carbon
a~tomsJ ;nclusive3 with one to 6 carbon~atoms, inclusive
between -CR5R6- and the phenyl ring; wherein T is alkyl
of one to 4 carbon atoms, inclusive, fluoro, chloro,
trifluoromethyl, or -OR7- wherein R7 is alkyl oF one
to 4 carbon atoms, inclusive, and s is zero, one, 2,
or ~, with the proviso that not more than two -r~ S are
other than alkyl and when s is 2 or 3 the T's are
either the same or different;
wherein Q2 is
Il ~ ~" ,'~
O , H H , R3 OR 4 , or R3 OR 4
wherein R~ is hydrogen or alkyl of one to 4 carbon
-34-
6~ii3~ 2720-1
atoms, inclusive; wherein R4 is hydrogen, letrahydro-
pyran-2-ylg tetrahydro-furanyl, 1-ethoxyethyl or a
group of the ~ormula
I H
R8-O-C C-R
R~ R1o
wherein R~ is alkyl o-f one to 18 carbon atomsJ inclu-
sive, cycloalkyl of 3 to 10 carbon atcms, inclusive,
aralkyl of 7 to 12 carbon atoms, incl:usive~ phenylg
or phenyl substi~uted with one, 2, or 3 alkyl of
one to 4 carbon atoms, inclusive, wherein Rg and R1O
are the same or dif~erent, being hydrogeng alkyl of
one to 4 carbon atoms, inclusiveg phenyl or phenyl
substituted with one, 2, or 3 alkyl of one to 4
carbon atoms, inclusive~ or, when Rg and Rlo are
taken together, -(CH2)a- or -(CH2)b-O-(CH2)c- wherein
a is 3, 4, or 5, b is one, 2j or 3, and c is one, 2,
or 3 with the proviso that b plus c is 2, ~, or 4g
wherein Rl~ is hydrogen or phenyl
wherein ~Rp2)is
\
25 , ~
OR 4 OR 4 CH2
or
, , CH20R~
-35-
720-1
wherei n R4 is as defi ned above;
wherei n K31 is
( 1 ) - COOR 32
(2 ) -CH20H, wi th the provi so that R31 is not -CH20H
when D is a valence bond
(3) -CH2N~R~ 8 )2
(4) -C-N(R18)2, or
(5)
NH-N
~N ~IN
wherein R~2 is
(a) cycloalkyl of 3 to 10 carbon atoms, inclusive,
(b) aralkyl of 7 to 12 carbon atoms, inclusive~
~5 (c) phenyl~
(d) phenyl substi tuted wi -th one) 2, or 3 chloro
or alkyl of one to 4 carbon a-toms~ inclusive,
o o
(e ) ~ -NH C ~ -NH-C-CH3?
~f) ~ ~ NH-C ~3
g ) ~NH-C-CH3,
rhj ~ NH-C-N~12 ,
:~0
-36-
2720-1
632
~ CH--N-NII-C-NI~z
(i) ~ ~ , or
(~ ) ~CH-C-R 3~1
n
1' 35
o
wherein R34 is phenyl, p-bromophenyl,
p-biphenylyl, p-nitrophenyl, p-benzamido-
phenyl, or 2-naphthyl, wherein R35 is hydro-
gen or benzoyl, and
wherein R18 is hydrogen~ alkyl of one to 12 carbon ato~sJ
inclusive, benzyl, or phenyl~ being the same or. different;
wherein ^~ indica~es attachment in alpha or beta con-
figuration; including the lower alkanoates thereof.
There is also provided a cyclic ether of the For~ula
~O-CH-~'CH2-D-R~o
22~ 2H XXXII
C =C ~
H' ` C-CH2~ ,CH2CH3
Q2 H ~ H
wherein D, Q2. ~ and,- are as defined above, and
wherein R~o i s
(1) -COOR19
(2 ) -C~120~1
.. .. _ ...
(;~) -CH2N(Rl8 )2
-37-
2 2720-1
(4) -C-N(R1~ )2~ or
NH-N
(5) -C ~ ll
`N -N
wherein R19 is
(a) alkyl of one to 12 carbon atomsj inclusive,
(b) cycloalkyl of 3 to 10 carbon atoms, inclu-
s i veJ
(c) aralkyl oF 7 to 12 carbon atoms, inclusive,
(d) phenyl,
(e) phenyl substituted with one, 2, or ~ chloro
or alkyl of one to 4 carbon atoms, inclusive,
0
(f)< ~ -NH-C ~ NH-C-CH3,
(~ C
(h ) ~ ~ NH-C-CH3,
~j)~ NH-C-NH2 .
~CH--N-NH-C-NH2,
:30
- ~c. -
~3~32 2720-1
(k~
-C-R~
(l) . -CH
wherein R34 is phenyl, p-bromophenyl,
p-biphenylyl, p-nitrophenyl, p-benzamido-
phenylJ or 2-naphthyl, and
~ wherein R3s is hydrogen or benzoyl,
(m) hydrogen; or
(n) a pharmacologically acceptable cation; and
wherein R~8 is hydrogen, alkyl of one to 12 car-
bon atoms, inclusive, benzyl, or phenyl, bein~
the same or different-
There is further provided a cyclic ether of the
formula
~ ,0-CH~-~CH2-D'-R30
(~R 2~ - CH2 XXXIII
C=C~
H~ C-Rz5
Qz
wherein D' is -CH2-CH-CH-A- or -(CH2)t-CF2-
wherein A is a valence bond or -( CH2 )h- where h i 5
one, 23 .or,3; and whereîn t is 2, ~J Or 4;
wherein Q2J ~ ~ R30 and,~ are as defined above, and
wherein R25 includes R23 above, and
-CH2 C_C,~CH2CH3
3~
_ ~,9
j63~
There is st:ill Eurther provided a c~clic ~ther oE the
Eoxmula
,O-CI-I~CH2-L-R 3 o
-CH 2
X'-C-R2s XXXIV
Q2
wherein L is (1) a valence bondl (2) -(CH2)d- wherein
d is one to 5 inclusive, (3) -(CH2)t-CF2- ~7herein t is
2, 3, or 4 (4) -CH2-C~-l=C~I-A- wherein A is a valence bond
or -(CH2)h- wherein h is one, 2, or 3r or (5~ -CH2-0-CH2-Y-
wherein ~ is a valence bond or -(C~2)k- wherein k is one
or 2; wherein X' is cis-CM=CH-, -C-C-, or -CH2CH2-; and
wherein Q2, ~ , R2s, R30, and ~ are as defined above.
Included within the scope o_ ~ in formula III, and
following the above nomenclature, are 11~ compounds, 11-
deoYy--ll-oxo (PGD) compounds, ll-deoxy-ll-methylene com-
pounds, ll-deoxy compound, ll-deox~-10,11-didehydro com-
pounds, and ll-deoxy-ll-hydroxymethyl compounds.
Considering the scope oE R3~ in formula III, there are
included acids, esters, salts, 2-decarboxy-2-hydroxymethyl
compounds, amides, and 2-decarboxv-2-tetrazolyl corlpounds,
Included in this invention are the pharmaco:Lo~ically
acceptable salts when ~1 is hydroqen. Pharmacolo~ically
acceptable salts of these formula III-XXV, XXX, and XXXII-
XXXIV compounds useEul for the pur~oses described above
are those with pharmacoloqically acceptable metal cations,
ammonium, amine cations, or quaternary ammonium cations.
Especially preferred metal cations are those derived
- 40 -
jrc ~ 5
63i~: 2720-1
from the alkali metals, e.g., lithium~ so~ium and potas-
siumg and from the alkaline earth metalsg e.g , magnesium
and calciumJ al~hough 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/ dlmethylamineJ
trimethylamine, e~hylamineJ dibutylamine~ triisopropylamineJ
N-methylhexylamine, decylamine, dodecylamine, allylamine~
crotylamine, cyclopentylamine, dicyclohexylamine, benzyl-
amine, dibenzylamine, a-phenylethylamjne, ~-phenylethyl-
amine, ethylenediamine, diethylenetriamine, and like ali-
phatic, cycloaliphatic, and araliphatic amines containing
up to and including about 18 carbon atoms, as well as
heterocyclic amines, e g,, piperidine, morpholiney pyrrolidine,
pipera~ine~ and lower-alkyl derivatives thereof, e.g.,
1-methylpiperidine, 4-ethylmorpholine, 1-isopropylpyrroli-
dine, 2-methylpyrrolidine, 1,4-dimethylpiperazine, 2-methyl-
piperidine, and the like/ as well as amines containingwater-sol(lbilizing or hydrophilic groups, e.g ) mono-, di-
~and triethanolamine, ethyldiethanolamineJ N-butylethanol-
amine, 2-amino-1-butanol, 2-amino~2-ethyl-1,3-propanediol,
2-amino-2-me~hyl-1-propanol, tris(hydroxyme~hyl)aminomethane,
N-phenylethanolamine, N-(p-tert-amylphenyl)diethanolamine-,
galactami ne, N-methylglycamine, ~-methylglucosamine~
ephedri ne, phenylephrine, epinephrine, procai ne, and the
I i ke .
Examples of suitable pharmacologica1ly acceptable
~u~Lernary ammonium cations are tetramethylammonium, tetra-
-41-
2720-1
;632
ethylammoniumJ benzyltrimethylamrnonium, pheny1triethyl-
ammonium, and the like.
The novel 5~6-dihydro-prostacyclin-type compounds of
forrnula lli-XXXIV have qualitatively the same pharmacologi-
cal properties described above for prostacyclin or prosta-
cyclin-type compounds and can be used for the same purpose~
and in the same manner described abo\/e~ But quite surpris-
ingly, these novel 5,~-dihydro-prostacyclin-type co~pounds
are substantially more specific with regard to potency in
causing prostacyclin-like biological responses. Therefore
each of these novel prostacyclin analogs is more useful
than prostacyclin for at least one of the pharmacological
purposes indicated aboveO Use oF the novel analog for that
purpose results in smaller undesired side effects than when
prostaeyclin is used for the same purpose. Moreover, be-
cause of its prolonged activityJ fewer and smaller doses of
the novel analog can frequently be used to attain the de-
sired result.
These 5,~-dihydro prostacyclin-type compounds are
especially useful for inhibition of platel0t
aggregation in blood for either in vivo or ~n vi~ro appli-
cations described above
To obtain the optimum combination of biological response
specificity, potency, and duration of activity, certain
compounds within the scope of the formulas Ill-XXXiV are
preferred. For example it is preferred -that Q be
R3 OR 4
wherein it is especially preferred that R3 be hydrogen or
-~2~
11~6G32
27~0-1
methylg and that R~ be hydrogen.
Another preference, for the compounds of formulas IIi-
XXV and XXX, i 5 that R1 in -COOR1 be either hydrogen or alkyl
o-f one to 4 carbon atoms, inclusive, especially methyl or
ethyl, for optimum absorption on administration, or a sal~ of
a pharmacologically acceptable ca~ion. Likewise, it is pre-
ferred, for the compounds of formulas XXXII-XXXIV, that R19
when R30 is -COOR19 be either hydrogen or alkyl of one ~o 12
carbon atomsg inclusiveJ especially methyl or ethyl, for opti-
mum absorption on administration, or a salt of a pharmacolo-
gically acceptable cation.
For purposes of stability on long storage, it is pre-
ferred that R32 in -COOR32 for compounds of formulas XXXII-
XXXIV be amido-substi~uted phenyl or substituted phenacyl,
as illustrated herein.
For oral administration i~ is preferred that R31 in com-
pounds of formula XXXI or tha~ R30 in co~pounds of formulas
XXXII-XXXIV be
II
-C-N-(Rls )2
wherein Rl~ is hydrogenJ alkyl of one to 12 carbon atoms, in-
clusive, benzyl, or phenyl, especially hydrogen or alkyl of
one to 4 carbon atoms, and more especially hydrogen or methyl,
both Rl8's being the same or different.
When R2 in the compounds of formulas III-XIV and XXX-
XXXI, or R25 in the compounds of formulas XXXIII XXXIV is
1 5
-C~CgHzg-CH
R6
- 1~ 3 -
2720-1
3~
it is preferred ~hat CgH2g be alkylene of 2, ~, or 4 carbon
atoms, and especially that it be trimethylene. I~ is -further
preferred that R5 and R6 be hydrogen, methylJ ethyl, or fluoro,
being the same or dif-ferent. It is further preferred, when
R5 and R~ are no~ hydrogen, that both R5 and R6 be methyl or
fluoro. It is especially preferred that R2 or R25 be n-
pentyl, 1,1-dimethylpentyl, or 1,1-difluoropentyl.
When Rz in -the compounds of formulas III~XIV and XXX-
XXXI, or R25 in the compounds of formulas XXXIII-XXXIV is
Rs ~ (T)s
R~
it is preferred that "s" be either zero or one. When "s"
is not zero~ it is preferred that T be methyl, chloro, Fluoro,
trifluoromethyl, or methoxy with meta or para attachment to
the phenyl ring. When Z is oxa ~-0-), it is preferred that
R5 and R6 be hydrogen, methyl, or ethyl, being the same or
diFferent. It is further preferred, when R5 and R~ are not
hydrogen, that both Rs and R~ be methyl. When Z is CjH2;, it
is preFerred that CjH2j be a valence bond, methylene, or
ethylene, It is especially preferred that R2 or R25 be
-CH2-0 ~ or
-C2~14 ~
As to variations in ~ in the compounds of Formulas
XXX-XXXIV, it is preferred that ~ be
-4~-
272~-1
~6~
~ ~ ~ , or
dH
As to variations in D in compounds of formulas XXX-XXXII,
and in L in compounds of formula XXXiV, it is preferred that
D or L be -(CH2)3-, -(CH2)4-, or -(CH2)5-, and especially
-(CH2) 3 - -
There are also provided mercury compounds oF ~he formula
~g-G
,0-CH ~ CH-L-R30
(~ ~- C~2 . LXXXI I
~ X-C-Rz 5
~c
wherein G is nitratoJ iodo, chloro, bromo, acetato, tri--
fluoroacetato, or benzoato;
and wherein L, Q2, ~ g R25, R30, X and f~ are as de-
fined`above.
There are also provided mercury compounds of the for-
mula
Hg - a
~0-CH ~ CH-L-C=0
~ -CH2 LXXXIil
X-l R2S
wherein L, Q2, ~ , R25~ X, and ~ are as defined above.
~o The novel mercury compounds disclosed herein are use-
_1~5_
2720 -1
;63~
ful -for pharmacological purposes. They have antiprotozoal
and antisyphilitic activity and are consequently effective
in treating streptococci and staphylococci. They have anti-
microbial activity and are useful for topical antiseptic
treatment for animals, including humans, usefu1 domestic
animals, pets, zoological specimens, and laboratory animals.
They are further useful in ophthalmiatrics.
For these purposes, these mercury compounds are pre-
ferably administered topically, for example in alcoholic
solution at 0.002 to 0.01 ~ concentra~ion with a benzal-
konium chloride as a preservative, or as a iotion, cream,
or ointment in 0.5-5.0 ~ concentration in combination with
the usual pharmaceutically acceptable diluents. rhe exact
application and concentration depends on such factors as
the age, weight and condition of the subject.
Certain mercury compounds within the scope of formula
XXXV are preferred for optimum biological response specifi-
city, potency, and duration of activity. For example, it
is preferr-ed that Q2 be
~0 .~\\
~3 OR4
wheIein R4 is hydrogen; it is further preferred that L be
trimethylene. When R3 is alkyl, it is preferred that R3
be methyl. Likewise~ as to R30, when R19 in -COOR19 is
alkyl, it is preferred that R19 be alkyl of one to 4 car-
bon atoms, especially methyl. Another preference is that
G be chloro or acetatoO
The cyclic ethers of formulas XXX-XXXIV, including
~nose of formulas III-XIV, are produced by reactions and
-46-
2720 - 1
i;3
CHART A
,0 -C=O
CH2 XXXV I I
--~C=C/
H / I R2
~.1
, O CH~ OH
(~ - CHz XXX V I I I
H ~C-Re
,0-CII ~ CH2 -COOR 12
( R~- - CH2 XXX I X
--~ C=C ~
tl'~ \ C -R2
Q
, O-CH -~_ CH2 -CO()R
(~-C/2 XL
~C=C
~C-R2
Q
47
2720 - 1
63;~
procedures described and exemplified hereinafter, as shown
schernatically in the charts.
Chart A will make clear the steps by which a cyclic
ether of the formula
, O -CH ~~ CH2 -COOR
~- /
R20 _ _ - CH2 XL
H
C=C
H ~ ~ 11 -R2
is prepared by starting with a lac~one of the formula
, O -C =O
CH2 XXXVI I
--C=C
15H \C-Rz
Q1
and (a) reducing that lactone to a formula-XXXVIII lactol,
(b) reacting that lactol with ~n anion derived from a sub-
stituted acetate of the formula R1200C-CH2-R13 wherein R12
is alkyl of one to 8 carbon atoms, inclusive, and Rl3 is
the group -P(G~H5)3 or -P(O)(OR12)2, to produce a compound
oF formula XXXIX, and (c) transforming the product of step
(b) to the Formula-XL compound by methods known in the art9
including acid hydrolysis oF blocking groups R~o, saponifi-
cation of ester groups R123 and rees-teri-fication as deslred
wi~hin the scope of R1. Separa~ion of XL isomers is achieved
by silica gel chromatography.
In Char~ A, the terms Q, Rl, R2, and r~ have the same
~0 meanings as defined aboveJ namely: Q is
-48-
2720 -1
/ ~ ~' \
R3 OR~ or R~ OR~
wherein R3 is hydrogen or alkyl of one to 4 carbon atoms,
inclusive, and wherein R4 is hydrogen, tetrahydropyran-2-yl,
tetrahydrofuranyl, 1-ethoxyethyl or a group oF the -formula
H
R8-O-C C-R
R9 R1o
wherein R8 is alkyl of one to 18 carbon atoms, inclusive,
cycloalkyl of ~ to 10 carbon atoms, inclusive, aralkyl of
7 to 12 carbon atoms, inclusive, phenyl, or phenyl substi-
tuted with one, 2, or 3 alkyl of one to 4 carbon atoms,
inclusive, wherein Rg and R1o are the same or diFferent,
being hydrogen, alkyl of one to 4 carbon atoms, inclusive~
phenyl or phenyl substituted with one, 2/ or 3 alkyl of one
to 4 carbon atoms, inclusiveJ or, when R9 and R1o are taken
together, (CH2)a- or -(CH2)b-O-(CH2)c- wherein "a" is 3, 4,
or 5, b is one, 2, or ~, and c is one, 2, or 3 with the pro~
~O viso that b plus c is 2, 3, or 4, and wherein R11 is hydrogen
or phenyl. R1 is hydrogen or alkyl of one to 8 carbon atoms,
inclusive. R2 is
(1) Rs
~C~CgH2g-CH3
R6
wherein CgH29 is alkylenP of one to 9 carbon atoms, inclusive,
with one to 5 carbon atoms, inclusive, in the chain between
-CR5R~- and terminal methyl, wherein R5 and R6 are hydrogen,
alkyl of one to 4 carbon atoms3 inclusive, or Fluoro, being
the same or different, with the proviso that one oF R5 and R6
-49-
2720-1
6~
is fluoro only when the other is hydrogen or a ~luoro; or
(2) R, (T)s
Re
wherein R5 and R8 are as defined above with the proviso that
neither R5 nor R6 is fluoro when Z is oxa (-0-);
wherein Z represents an oxa atom (-O-) or CjH2j wherein
CjHzj is a valence bond or alkylene of one to 9 carbon atoms~
inclusive, with one to 6 carbon atoms, inciusive between
-CRsR6- and the phenyl ring; wherein T is alkyl oF one to 4
carbon atoms, inclusive, fluoroJ chloro, trifluoromethyl, or
-OR7- wherein R7 is alkyl of one to 4 carbon atoms, inclu-
sive, and s is zero, one, 2, or 3, with the proviso that
not more ~han two T's are o~her than alkyl and when s is
2 or ~ the T's are ei~her the same or different; ~ indi-
cates attachment in alpha or beta configuration~
Q1 is
D" , \
R3 ~ORgo or R3 OR40
.wherein R3 i s as defined above, and wherein R40 i s the same
as R~ deFined above except that it does not include hydro-
gen, but includes only the blocking groups such as tetra-
hydropyran-2-yl. Rl2 is alkyl of one to 8 carbon atoms
inclusive. ~ is
OR4 o 4 H2
3o
-5
~6~3~ 2720-1
, ~ , or
Ch20R4
wherein R4 is as defined above. ~ is the same as ~
defined above except that R4 therein is replaced with R~o as
defined above, i.e. excluding hydrogen.
The formula-XXXVII lactone reac~ants are known in the
art or are available by processes known in the art. For
example, when ~ is
~ .
THPO
where THP is tetrahydropyran-2-yl and R2 is alkyl, see Corey
et al., J. Am. Chem. Soc. 92, 397 (1970), and U.S. Patent No.
3,931,279 issued to N.A. Nelson; when R2 is phenylrsubstituted3
see U.S. Patent No. ~,987,087 issued to G.L Bundy, and Der-
went Farmdoc Abstracts, Nos. 76383T, 5789U, 73279U, and
64791~W .
` ~0 When ~ j5
~'
OR ~
these 11~ lactones are obtained by iso~erizing a correspond-
ing lactone having the 11~ configuration, with suitable block-
ing at the C-15 posi~ion if desired, b.y methods known in the
art, such as by way of the 11-mesylate or 11-tosylate. For
application of the 11-benzoate for exampleJ see Mitsunobu
et al., J. Am. Chem. Soc. 94~ 679 (1972).
3 When ~ is
-51-
2720-1
~9 ~ ~L~f` ~
and R2 i5 alkyl, see U.S. Patent No. ~gg3lJ279 and Derwent
Farmdoc Abstract No. 10695V; when R2 is phenyl-substituted,
also see U.S. Patent No 3,931,279.
When ~ is
~
a suitable starting material is
OCH3
\ LXXII
` ,
CH0
See E.J. Corey et al., Tetrahedron Lett. 107 (1972). After
~0 introduction of the Rz-containing side chain by known
methods including the Wittig reaction and reduction of the
15-oxo group/ the methyl ether is hydrolyzed to the lactone
in acid,
When ~ ~ is
CH20H
the lactone is available or prepared by processes known in
-52-
~ 6 3 ~ 2720
the art, See Ger. Offen, 2J 4379622 and Derwent Farmdoc
Abs-tract No. 12714W. For exampie a compound of the formula
0 ~ L
~'
,H
C =C
H
Q
is reduced at the -COOH position to the corresp~nding
-CH20H compound using diborane,
When ~ is
~ ,
the hydroxymethyl compound immediately above is converted
first to a tosylate
~HzOH CHzOSOzC~H5CH3
by known methods such as reaction with toluenesulfonyl
"5 chloride in 50~ excess in the presence of pyridine at
about 25 C.; the tosylgroup is then exchanged with
iodide, e~g. sodium iodide in acetone at about 25-40 C,
to form the corresponding iodomethyl compound 9
~0
-53-
2720 - 1
6~32
P~
CHz I
that iodomethyl compound is then dehydroiodinated, for
example with potassium tert-butoxide in ~etrahydrofuran
at -50 C. or below, to yield the methylene compound:
0~
LXXX V
,C=C~
Q
The formula-XXXVIII lactol is obtained on reduction of
~5 lactone XXXVII without reducing the ethylenic group. For
this purpose, diisobutylaluminum hydride is used as known
in the art. The reduction is preferably done at -60 to
-78 C.
The Formula-XXXIX intermediate is obtained from the
~ lactol by reaction with an anion derived from elther a
phosphonoacetate of the formula
R1200C-CH2-P(O)(OR12)2 LXXIV
or a carboxymethylphosphonium compound of the formula
Hal
RlzOOC-CH2-P(C6H5 )3 LXXV
wherein R12 is alkyl of one to 8 carbon atomsJ inclusive
and Hal is chloro, bromo, or iodo. Alternatively, the
phosphonium compound may be referred to by its ylid form,
-5~ -
3;~ 2720-1
RlzOOC-CH~P(C~ ; )3- LXXVa
The reaction is done in the presence of a base, preferably
potassium t-butoxide or sodium hydride for LXXIV, or
potassium t-butoxide, sodium ethoxide, benzyltrimethyl-
ammOnium hydroxide, or, preferably, an alkali metal hydroxide
for LXXV, usually at 0-25 C.
The formula-XL product is obtained on replacement of
the R~o blocking groups with hydrogen, by acid hydrolysis,
for example in dilute acetic acid, aqueous citric acidJ or
aqueous phosphoric acid-tetrahydrofuran. When R1 in the pro-
duct is different than R12I transformation is brough-t about
by methods known in the art, including saponification to yield
the acid, optionally followed by esterification~ Esters are
conveniently prepared by interaction of the acid with an
appropriate diazohydrocarbon. For example, when diazo-
methane is used, the methyl esters are produced. Similar
use of diazoethane, diazobutane, and 1 diazo-2-ethylhexane
for example, gives the ethyl, butyl, and 2-ethylhexyl
esters, respectively. Of these esters~ it is preferred
that R1 be methyl or ethyl.
Esterification with diazohydrocarbons is carried out
by mTxing a solution of the diazohydrocarbon in a suitable
inert solvent, preferably diethyl etherJ with the acid
reactant, advantageously in the same or a different inert
diluent. After the es~erification reaction is complete~
the solvent i5 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
-55~
~663~ 2720-1
-
necessary to effect the desired esterifica~ion, preferably
about one to about ~en minutes, to avoid undesired molecu^
lar changes. Diazohydrocarbons are known in the art or can
be prepared by methods known in the art. See, for example
Organic Reactions, John Wiley & SonsJ IncO, New YorkJ N.Y.g
Vol 8, pp. 389-3g4 (1954).
An alternative method for esterification of the
acid compounds herein comprises transformations 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, and isobutyl iodide. The
silver sal.s are prepared by conven~ional methods, for
exampleJ by dissolving the acid in cold dilute aqueous
ammonia, evaporating the excess ammonia at reduced pres-
sure, and then adding the stoichiometric amount of silver
nitrate.
As for all of the reactions described herein, the
duration oF the reaction is readily determined by monitor-
ing with TLC (thin layer chromatography).
Chart B shows the steps for preparing a cyclic etherof fornlula XLV by starting with a formula-XXXIX inter-
mediate of Chart A, reducing that Formula-XXXIX ester to a
hydroxyethyl compound of formula XLI, oxidizing that
formula-XLI alcohol to an aldehyde of formula XLII, sub-
jecting that formula-XLII aldel-yde to a Wittig alkylation
either (a) with an anion derived from a substituted
acetate of the formula R1200C-CH2-R13 wherein R12 and
R13 are as deFined above to form a compound represented
by the Formula
-56-
~6~3;~ 2720-1
CHART B
, O -/ H ~~ ~ C112 -COOR 1 2
~R21 )- -CH2 XXXIX
~~C=C/
H~ \ C -R2
Q
,0-/ H~ CH2CH2 -OH
--Ctl~ X L I
H~ C-R2
,.O-CH-~_ CH2-CHO
~-CH2,H XLII
,C=C\
H ICl R2
~!l
~, O -CH ~_ CH2 -CH=CH-A -COOR 1
CH2 XL I I I
H ~ ~` C-R2
J
:~0
vi a several steps
-57 -
i6 2720-1
CHART B (conti nued)
,0 -CH ~ ~ ( CH2 ) 3 -A -COOR 14
~' ~ XLIV
R2 1 - -- CH2
.H
"C =C ~
H c-R2
Il
Q
,O-CH--~., (CH2 )3 -A -COOR
R ~ -CH2
~C=C ~ XLV
H ~ ll -R2
-58 -
272 0 - 1
6~3~
,O-CH -~ CH2CH=CH-COOR 12
R~ CH2
~C =C`' X C
H ~ C -R2
Q1
or (2) wlth an anion derived from an ~-carboxyalkyltri-
phenylphosphonium halide of the formula
Hal
( C6Hs ) 3P -CH2 -M-COûtl
wherein M is -(CH2)h wherein h is one, 2, or 3 and Hal is
chloro, bromo~ or iodo to form a compound represented by
the formula
O~CH~ CH2~C-C' M-CooH
~-CH2 H~ ~H LXXV I
C C~'H
H ' C -R2
~0 Q1
thereafter transforming either XLVI or LXXVI, which are bo~h
represented by the formula~XLIII intermediate of Chart B,
~5 to a compound of the formula
,O-CH-~- CH2-CH= CH-A-COOR
~C -C
H~ \FI-R2 LXXVI i
Ql
-~o
-59 -
63~ 2'720-1
That compound LXXVII is then subjected to selective reduction
of the ~,4-ethylenic unsaturation to form a compound of the
formula
,O-CH -~(CH2) 3 -A-COORl 4
~ ~--C~2 XLIV
, C=C'~
H C-R2
Q1
and that compound XLIV is then transformed by known methods
to the desired formula-XLV cyclic ether.
In Chart B and in the following chartsg ~he terms Q,
Q1, R1, R2, R12, ~ , ~ , and~ hav~ the same
meaning as For Chart A. The term "A" represents a valence
bond or -(CH2)h- wherein h is one, 2~ or 3. The term R14
represents hydrogen or an alkali metal cation, e.g. sodium,
potassium, or lithium.
In Chart B, the formula-XXXlX intermediates are pro-
duced by the steps in Chart A above.
A formula- XLI alcohol is obtained from a Formula-
XXXIX ester on reduction, by methods known in the art, forexample using lithium aluminum hydride or lithium trt-
methoxyaluminum hydride in a solvent such as diethyl ether
or tetrahydrofuran.
The formula-XLII aldehyde is obtained by oxidation of
2S the -CHzOH of XLI to -CHO~ avoiding decomposition of the
cyclic ether ring. Useful for this purpose are pyridinium
chlorochromate, Jor-es reagent~ Pfitzner-Moffatt reagent
and especially, Collins' reagen~ (pyridine-CrO3) a-t about
0-15 ~.
3~ The formula XLIII compound is obtained by Wittig alkyla-
-60-
,. 2720 - 1
6~2
tion using an anion derived from an appropriate phosphonate
or phosphonium compound. If "A" is a valence bond, a com-
pound of the formula R1200C-CHz-Rl3 is used, wherein R12 is
alkyl oF one to 8 carbon atoms, inclusive, and R13 is the
group
-P(C~H5 )3
or -P(O)(OR12)2. See for example D.H. Wadsworth et al.g
J. Org. Chem. 30, 680 (1965) as to phosphonatesO See also
Organic Reactions Vol. 14, Chapter 3g John Wiley and Sons,
Inç., N.Y. (1965) as to the Wittig reaction. When A is a
valence bond, the 3,4~ethylenic group of the XLIII compound
is predominately in the trans form When A is ~(CH2)h-
wherein h is one, 2, or ~, the appropriate reagent for the
Wittig alkylation is an anion derived from an ~-carboxy-
alkyltriphenylphosphonium halide of the formula
Hal
(C~H5)3-P-CH2-M-COOH LXXVIII
wherein M is (CHz)h and Hal is chloro, bromo, or iodo. The
resulting ~J4-ethylenic group of compound XLIII is then
predomina~ely in the cis form.
The formula-XLIII compounds are useful intermediates
for preparing the formula-V~ -VI, -XI, and -XII end pro-
ducts, following hydrolysis of the blocking groups and
conversion of R12 to R1 as required. Isomerization of cis
to trans or trans to cis, iF desired, is accomplished, for
example, by ultraviolet radiation as disclosed in U.S.
Patent No. ~g759,978, followed by separation of the product
-61 -
2720 -1
;3;~
as by chromatography.
Continuing with Chart B, the formula-XLlV compounds are
obtained from the formula~XLIII compounds hy selective reduc-
tion of the ~,4-ethylenic unsaturation. For this purpose
several methods are available: for XC above, that of Dennis
et al., Tetrahedron Lett. 1821 (1968 )3 utilizing for the
acids or salts a cyanonickel complex and sodium borohydrideJ
or preferably~ catalytic reduction over 5~ palladium (or
rhodium) on carbon at about 0 C. for the esters.
Finally, the formula-XLV products are obtained by
hydrolysis of the blocking groups and converstion of Rl4 to
R1 as required.
Methods of separating the products similar to those
known in the art are employed, including extraction, chroma-
tographyl crystallization~ and the like.
Chart C shows the steps for preparing a cyclic ether
of formula XLVII by star~ing with a formula-XXXVIII lactol
oF Char~ Ag reacting that lactol w;th a 4-(triphenylphos-
phoranylidene) crotonic acid ester, for example the methyl
ester (Buchta et al., Chem. Ber. 92, 3111 (1959)) obtained
from the corresponding phosphonium compound. The reaction
is done in a temperature range of 70-120 C. and is con-
veniently done in refluxing ben~ene to yield the formula-
XL~I intermediate. The product XLVII is ob-tained on
hydrolysis of the blocking groups and conversion of R1z to
R1 as required.
Chart D shows the steps for preparing a cyclic ether
of formula LII by starting with a formula-XXXlX ester of
Chart A, (a) saponifying that ester to form acid XLVIII,
3~ (b) forming a mixed anhydride oF formula XLIX, (c) forminy
-62 -
~6~3~ 2720-1
CHART C
,O-CH~ OH
~e~- -CH2 XXXVI I I
-~.~, ,1
C=C''
H / C-R2
Ql
(C,~jH5 )3P-CH-CH=CH-COORl2
~_~,O-CH~ CH2CH=CH-COORi2
~R2l J~ Z
~ /H XLVI
H~ \ C ~Rz
Ql
~0 -CH ~ CH2CH=CH -COOR 1
R2-o)~ H2 X L V I I
C=C '
H~ ~ C -R2
Ql
3o
-63
2720 - ~.
CHART D
,0 -CH ~--5H2 -COOR 12
-C ~ X X X I X
H ~ \C -R2
~1
~.,
,O-CH -~- CtJ2-COOH
r~i /
( R2 1 J-- - CH2
\~ /H XLVill
H/ \ I R2
' O O
~ CH3
O-CH~CH2-C-o-C-O-CH2-CH \~H3
(R2 ~ Gtl2
,~ , H X L I X
C=C~
H/ C -R2
Il
Q
( cont i nue d )
3o
-6~-
2720 - 1
66~
CHART D (conti nued)
~ O
,0-CH-~- CH2-C-CHN2
(~\ ,H
H- 6-R2
~1
\J
,0 -CH- --CH2CH2 ~C0011
~C=C L I
H / IC - R 2
Ql
~'
, O -CH ~ CH2CH2 -COOR 1
~/.C=C~ L I I
H ~ C - R2
-65 -
~ 63~ 2720-1
a diazoketone of formula L, (d) forming a compound of
formula LI, and (e) forming the desired formula-Lil product.
The -formula-XXXIX compound is saponified to yield the
acid XLVIII, for example in an aqueous alkaline medium, such
as sodium hydroxide to form an alkaline salt which is then
acidified to yield the Free acid.
The acid XLVIII is conver~ed to anhydride XLIX by
reaction with isobutylchloroformate in the presence of an
organic tertiary amineO The anhydride is formed readily at
temperatures in the range -40 to +60 C., preferably at
-10 to ~10 C. so that the rate is reasonably fast and
yet side reactions are minimized. The isobutylchloroFormate
reagent is preferably used in excess, for example 1~2 molar
equivalents up to 4.0 per mole of the acid XLVIII. The
reaction is preferably done in a solvent and for this pur-
pose acetone is preferred, although other relatively non-
polar solvents are used such as acetonitrile~ dichloro-
methane and chloroform. The reaction is run in the presence
of a tertiary amine~ for example triethylamine3 and the co-
formed amine hydrochloride usually crystallizes out~ butneed not be removed for the next step.
Diazoketone L, obtained by reaction of anhydride XLIX
with diazomethane, yields compound LI on contacting with
water and a catalyst such as colloidal silver, platinum,
2~ or copper. See Bachmann et al., Org. Reactions Vol. lg
page 38 (1942). Thereafter compound LI yields a 6~,9~-
epoxy ether wi-thin the scope of formula IV or X by methods
described hereinO
Chart L~ herein3 shows the steps of an alternate
3 process for preparincg a cyclic ether of formula LII by
-66-
2720-1
CHART L
O-CH-~ CH2CH2-OH
~ I
~, C -C ' X L I
H~ C-R2
Il
a
(a)
0-CH~`J CH2CH2-OTs
~ - CH2 LXXXV I
~ ~H
H,C~
Q 1
~b)
~
~O-CH -~, CH2CH2-OTs
(~ -Cl-12
--~C ~ H
H ~ `h-R2
Q
(c )
J
(cont i nued )
~;0
-67
2720 - 1
~6~
CHAR T L (conL i nu~d )
~ (c)
,0 CH~ CH2CH2-CN
~C~ ~H LXXXV I I I
~I ~ ` C-R2
(~)
,O-CH ~ CH2CH2-COOIl
(~ - /H/H LXXXIX
C=C\
H/ C-R2
Q
(e)
,O-CH~ - C~l~cH2 -cOORl
(~C-C/ Ll I
H ~ I - R2
~0
-68
2720-1
~6~
starting with a formula-XLI hydroxyethyl compo~Ind of Chart
B, (a) transforming that formula-XLI alcohol to tosyla-te
LXXXVI, (b) optionally removing blocking groups such as
THP groups by acid hydrolysis to form compound LXXXVI 1J
(c) exchanging tosylate groups with nitrile groups to form
nitrile LXXXVIII, (d) hydrolyzing that nitrile to acid
LXXXIX, and (e) optionally forming esters within the scope
of formula LII. In Chart L, the terms Q, Q1, R1, R2, ~ ,
~ , and ~ are as used above for Chart A, and Ts repre-
sents the p-toluenesulfonyl ("tosyl") group.
Tosylate LXXXVI is formed by treating the alcohol XLI
wîth p-toluenesuTfonyl chloride in excess tertiary amineg
preferably pyridine, at room temperature. Thereafter block-
ing groups are optionally removed, as by acid hydrolysis,
to form a compound represented by formula LXXXVII.
Nitrile LXXXVIII is obtained on treating the tosylate
with sodium or potassium cyanide in a solvent such as
hexamethylphosphoramide, dimethylformamide, dimethylsulFoxide,
or N-methyl pyrrolidone. The reaction proceeds smoothly
at room temperature.
Acid LXXXIX is formed by alkaline hydrolysis oF the
nitrile~ with subsequent acidification as known in the art.
Finally, esters within the scope of LII are made if
desired by methods known or disclosed herein.
~rj Charts E, F, and G relate to preparation of oxa (-0-)-
type compounds. Char-t E shows the steps for preparing a
cyclic ether or formula LIV by starting with a hydroxyethyl
compound of formula XLlg and (a) subjecting that compound
to a Williamson synthesis to form a compound of formula
LIII, and (b) transforming LIII to the desired formula-LIV
-69-
272 O - 1
6~3~
CHART E
,O-CH~ CH2CH2-OH
(~ - `-CH2 X L I
~C=C~
H IC-R2
~1
,O-CH `-~ CH2CH2-O-cH2-cOORl5
~ /
``_ ~ ,H
C=C
H/ \C-R2
Q
~0
,O~CH ~ CH2CH2 -O -CH2 -COOR
C~12
C-C~ LIV
H C-R2
3~)
-7o
63~ 2720 - 1
CHART F
, O -CH ~ CH2 Cl12 -OH
~P 1 ~ CH2 X L I
,C=~ '
H II R2
~1
:10
,0 CH ~ CH2CH2-O-CH2-CH-CH2
C H2 L V
C C
Q
~/
,0 -CH ,~ CHzCH2 -O - ( C1-12 )2 -CH20H
.~1 )- - C ~12
~.C~C ~ LV I
H ~ C -R2
Q
2~
(conti nued )
~50
-71 -
2720 - 1
6~
CHART F (cont i nued )
,0 -/CH,'~ CH2CH2 -O - ( CH2 )z -COOH
C -C/ L V I I
H ~ C -R2
`'
,0 -CH -~, CH2CH2 -O - ( CH2 )2 -COOR
(R~- - CH2
~.C-C' LVIII
H f ~`C -R2
~0
3o
-72 -
2720-1
3;2
CHART G
,O-CH-~CH2CH2-OH
C=C-' XLI
H' \ Cl-R2
Q
~__~r,O-CH~'--CH2CH2-O-(CH2~3-C(ORl5)3
~R2 ~ ,H LIX
H l-R2
Q
,O-CH '- CH2CH2-O-(CH2)3-COOR
CH2
--'~,C-C/ LX
H ~ \Il-R2
~ Q
,O-~CH ~CH2CH2-O-(CH2)3-CQOR
C H2
,-H
,,C=C ~ L)( I
H l R2
~Q Q
-73-
;2 2720 1
product.
Intermedia~e alcohol XLI of Chart B is transFormed to
compound LIII by the Williamson synthesis employing a halo-
acetate, Hal-CH2-COOR15 or a haloacetic acid sal~ for ex-
ample lithium chloroacetate. See for example U.S. Pat. No~3,920,72~. !n Chart E, R15 represents alkyl oF one to 3
carbon atoms, inclusive. Hal is chloro, bromo, or iodo.
The condensation is done in the presence of a base, for
example n-butyllithium, phenyllithium, ~riphenylmethyl-
lithium, sodium hydride, or potassium t~butoxide. Theacetate is employed in about 100~ excess. The condensation
is conveniently done in a solvent such as dimethyl formamide
tetrahydroFuran, dimethyl sulfoxide, or hexamethylphosphora-
mide. Thereafter, if a salt has been used, the formula-LIlI
compound is obtained by methods known in the art. Product
LIV~ which includes products VII and XIII, is obtained by
the usual steps of hydrolyzing off the blocking groups and
converting R15 to R1 if required.
Chart F shows the steps in preparing a cyclic ether of
formula LVIII by starting with a hydroxyethyl compound of
Formula XLI, and (a) subjecting ~hat hydroxyethyl compound
t~ a Williamson synthesis with an allyl halide to form a
compo-Ind oF formulà LV, (b) Forming an alcohol of -Formula
LVI, (c) oxidizing the terminal hydroxyl group of that
alcohol to yield a carboxylic acid of formula LVII, and
(d) thereafter transforming that acid to the desired
Formula-LVIII product.
Intermedia~e alcohol XLI oF Chart B is transformed ~o
compound lV by a Williamson ether synthesis~ employing allyl
ch)oIide. See for example U.S. Pat. No. 3,920,723. There-
-74 -
i63~ 2 ~20 - l
after, hydrohoration yields alcohol LVI. See, for example~
"Hydroboration", H.C. Brown, W.A. Benjamin, Inc., New York,
1962. The formula-LVII acid is obtained by oxidation, -for
example with -the Jones reagent. Finally, blocking groups
are removed by me-thods described above. The product is
esterified if desired to yield the -Formula-L~III product.
Chart G shows the steps in preparing a cyclic ether of
formula LXI by starting with a hydroxyethyl compound oF
formula XLI, and (a~ condensing that hydroxyethyl compound
with an omega-halo ortho ester of the formula
Hal-(CH2)3-C(OR15)~g wherein Hal and R15 are as defined for
Chart E, to form a compoùnd of formula LIX, (b) trans-
forming compound LiX to a compound of formula LX, and (c)
thereafter transforming compound LX to the desired formula-
LXI product.
Compound LIX is obtained from alcohol XLI by a Williamson
synthesis preferably employing an ortho-4-bromobutyrate
of the formula Hal-(CH2)~-C(OR15)3 wherein Hal is chloro,
bromoJ or iodo and wherein R15 is as defined above. See
ror example U.S. Patent No. 3,921,279. The condensation is
done in the presence of a base and a solvent, for example
po-tassium t-butoxide and te-trahydrofuran, or n-bwtyllithium
and hexamethylphosphoramide. The reaction proceeds smoothly
at -20 to ~50 C. but is preferably done at about 25 C.
for convenience. Following the condensation, ~he formula-
LX compound is obtained by methods known in the art, -For
example by hydrolysis in cold dilute mineral acid. Finallyg
product LXI, which is within the scope of -formulas VIII and
XIV, is obtained by hydrolysis of blocking groups and con-
ver~ion of R15 to R1 as required
75 -
63 2720-l
Included among the compounds of formula XXX are 11-
oxo compounds. For ~heir preparation, the processes of
Charts A-G are employed, but replacing star~ing materials
XXXVII, XXXVIII, XXXIX, and XLI with corresponding com-
pounds wherein ~ is replaced by
i
~X
OSi(CH3 )2 ( t-C~Hg)
Such compounds are available by methods known in the art or
described herein. For this purpose there are prepared lac-
tones of the Formula
O
~Jl
v ~ LXXIX
~
~ H
r r~ /
OR2H `C-R2
Q1
wherein Q1 and R2 are as defined above and R26 is a carboxy-
acyl blocl<ing group:
(1) 0 ~ (R27)g
wherein R27 is a!kyl of one to 4 carbon atoms, inclusive,
phenylalkyl of 7 to 10 carbon atoms, inclusive, phenyl or
ni~ro, and g is zero to 5, inclusive, provided that not more
than two R27's are other than alkylJ and that the total num-
ber of carbon atoms,in the R27ls does not exceed 10 carbon
atoms;
,~0
-76-
2720-1
6~
~d
(2) 0 COOR28
wherein R28 is alkyl of one to 4 carbon atoms~ inclusive; or
(3) 0
~~ ~ (R27)g
(R27)g
wherein R27 and g are as defined above. Starting materials
for these formula-LXXlX lactones are known or readily avail-
able. See for example U.S. Patent No. 3,931,279.
The formula-LXXlX lactone is transformed -to the silylated
starting material by replacing R26 with hydrogen, as wlth
sodium methoxide in methanol, and blocking at the latent
C-11 position with t-bu-tyldimethylsilyl. See E.J. Corey
et al, ~ J. Am. Chem. Soc. 94, 6190 (1972).
Thereafter, the procedures of Charts A-G yield com-
pounds bearing the t-butyldimethylsilyl group at C-ll.
This ~roup is then replaced with hydrogen using -tetrabutyl-
ammonium fluoride. See Corey et al. cited above. Next
the 11-hydroxy group is oxidized to ll-oxo, for example by
~0 ~ Jones oxidation, and finally the R~o groups at C-15 are
replaced, if desired, by acid hydrolysis.
Also included among the compounds of -formula XXX are
11-methylene compounds. Alternate methods for their
preparation, other than those included within Charts A G
above wherein ~ is
?~
utili~e those processes of Charts A-G by replacing starting
3~ matel-ials XXXVII, XXXVIII, XXXIX, and XLI with corr~sponding
-77-
2720-1
632
compounds wherein (R~ is replaced hy
C~2-O-Si(CH3 )2 ( t-C~Hg)
Such compounds are readily pr-epared from the hydroxymethyl
lactones wherein ~ is
~X'
'1.0
CH20H
described herein for the starting materials of Chart A, using
the procedures of Corey e~ al cited above.
Thereafter the procedures of Charts A-G yield compounds
bearing the t-butyldimethylsilyloxymethyl group at C-ll.
lt is preferred that R1 be alkyl. Next ~he silyl groups are
replaced with hydrogen using tetrabutylammonium fluoride,
and the resulting hydroxymethyl groups are converted to
iodomethyl groups by way of tosylation and iodide exchange.
Finally dehydroiod;nation, as with potassium tert-butoxide
in ~etrahydrofuran, yields the 11-methylene compounds.
Also included among the compounds of formula XXX are
15-deoxy compounds. For their preparation, the products of
Charts A-G wherein Q is
~" , ''~
H OH or H OH~
in their free acid form, are used. They are (1) silylated,
e g. with t butyldimethylsilyl chloride and imidazole, (2)
~'~ hydrolyzed to remove silyl ester groups at C-1, e.g. with
-78-
2720-1
~a6~32
aqueous potassium hydroxide, (~) reduced with lithium-
neopentyl alcohol-methyl amine at about -30 C., and (4)
hydroly~ed ~o remove silyl ether groups, thereby yielding
15-deoxy products.
Alternatively, a lactone of the formula
1~
¢~C-C ~ LXXX
OlR2eH \C-R2
H OH
wherein R2 and R2ff are as defined above is (1) transFormed
to ~he 3a-bromo compound, (2) reduced wIth sodium boro-
hydride in dimethylsulfoxide, (3) treated with potassium
carbonate to replace -OR26 with hydroxyl and (4) blocked
at the hydroxyl sites with -OR40 wherein R40 is as defined
above. Thereby a lactone is obtained of the formula
0~
~ LXXXl
/ H' ~ CH2-R2
OR40
which is used to replace lactone XXXVII in Chart A and the
processes of Charts A-G for preparing 15-deoxy products.
An alterna-tive method for preparing the formula iVg
VII, VIiI, X, XIII, XIV, XV, XVI, and XXX-XXXIV cyclic
ethers is by reductive dehalogenation of a compound of ~he
formula
3n
-79-
s
2720-1
~3~63;~
, .
R33
,O-CH~ CH-L-R1G
f ~ / LXIII
~- -C~12
X-C-R25
Q2
wherein L is (1) a valence bond, (2) -(CH2)d-
wherein d is one to 5 inclusive, (3) -(CH2)t-CF2-
wherein t is 2,3, or 4, (4) -CH2-CH=CH-A- wherein A
is a valence bond or -(CH2)h- wherein h is one~ 2g or 3,
or (5) -CH2-O-CH2-Y- wherein Y is a valence bond or
-(CH2)k- wherein k is one or 2;
wherein Q2 is
Il ~ /"~ , "\
O t H H ~ R3 OR4 , or R3 OR4
wherein R3 is hydrogen or alkyl of one to 4 carbon atoms,
inclusive, and wherein R4 is hydrogen, tetrahydropyranyl,
tetrahydrofuranylg 1-ethoxyethyl or a group of the formula
I H
R8-O-C C-R
i R9 R1o
wherein R8 is alkyl of one to 18 carbon atoms, inclusive
cycloalkyl of 3 to 10 carbon atoms, inclusive, aralkyl of
7 to 12 carbon atoms, inclusive, phenyl, or phenyl sub-
stituted with one, 2, or 3 alkyl of one to 4 carbon atoms,
inclusive, wherein Rg and R1o are the same or different,
being hydrogen, alkyl o-f one to 4 carbon atoms, inclusive,
phenyl or phenyl substituted with one, 2, or 3 alkyl of
one to 4 carbon atoms, inclusive, or, when Rg and R1o are
tal<en toyether, -(CH2)a- or -(CH2)b-O-(CH2)c- wherein a
~ is 3, 4, or 5, b is one, 2, or 3, and c is one, 2, or 3
-80-
with -the proviso that b plus c is ~, 3, or 4, and wherein
Rll is hydrogen or phenyl;
wherein Rl 6 iS
(1) -COORl7
~2) -~H20H
(3) -CH 2 N(Rl~)2
o
(4) -C-N(Rl 8) 2 or
~ NH-N
(5) --C
~ N -N
wherein Rl7 is (a) hydrogen, ~b) alkyl of one to 12
carbon atoms, inclusive, (c) cycloalkyl of 3 to 10 car-
bon atoms, .inclusive, (d) aralkyl of 7 to 12 carbon
atoms, inclusi~e, (e) phenyl, (f) phenyl with one, 2, or
3 chloro or alkyl of one -to 4 carbon atoms, inclusive, or
(g) 2-naphthyl;
wherein Rl~ is hydrogen, alkyl of one to 12 carbon atcms,
.inclusive, benzyl, or phenyl, being the same or di~erent;
wherein R2 2 iS
OR .~,, OR 4 CH2
\
or ~
~; , CH2OR4
wherein Rl~ is as defined abcve;
wherein R2s is
- 81 -
jrc~ 9~
2720-1
s
~C-CgH2~-CH3
R6
wherein C9H29 is alkylene of one to 9 carbon atoms, inclu-
sive, with one to 5 carbon atoms, inclusive, in the chainbetween -CR5R6- and terminal me~hyl, wherein R~ and R6 are
hydrogen, alkyl of one to 4 carbon atoms, inclusive, or
fluoro, being the same or different, with the proviso that
one of R5 and R6 is fluoro only when -the other is hydrogen
or fluoro;
( 2 ) . - C - Z -~
R6
wherein R5 and R~ are as defined above with the proviso that
neither R5 nor R~ is fluoro when Z is oxa (-0-); wherein Z
represents an oxa atom (-O-)~or CjH2j wherein CjH2j is a
valence bond or alkylene of one to 9 carbon atoms, inclu-
sive, substituted with zero, one, or 2 fluoro, with one to
t~O 6 carbon atoms~ inclusive between -CR~R~- and the phenyl
ring; wherein T is all<yl of one to 4 carbon atoms, inclu-
sive, fluoro, chloro, trifluoromethyl, or -OR7- wherein
R7 is all<yl of one to ~ carbon atoms, inclusive, and s is
~ero, one) 2, or 3, with the proviso that not more than
two T's are other than alkyl and when s is 2 or 3 the T's
are ei~her the same or differen-~; or
(~i)
-CH2 ~ ,CH2CH3
,C=C,
whereln R33 is i odo or bromo,
-82-
3~
~herein ~ is trans-C~{=CII-, cis-CH=Cfl-, -C~C-, or -CH2C~I2-;
and wherein ~ indicates attachment in alpha or beta con-
figuration.
Chart H shows the steps hy which a PGF2~-kype com-
pound of formula LXII is (a) halogenated and cyclized to
form a compoun~ of formula LX~II, and the compound LXIII is
subjected to reductive dehalogenation to form the formula-
LXIV product. In Char-t H the terms are defined as for com-
pound LXIII above.
The starting materials of formula LXII are prosta-
glandins or prostaglandin-like materials known in the art
or readily avalla~le by processes known in the art. Either
the compounds in which Rl~ of ~ and Q2 is hydrogen or
those in which Rl, is a blockin~ ~roup may be used. For ex-
ample, as to PG~2~ see U.S. Patent No. 3,706,789; as to 15-
methyl- and 15-ethyl-PGF2~, see U.S. Pa-tent No. 3,728,382;
as to 16,16-dime-thyl-PGF2~, see U.S. Patent No. 3,903~131;
as to 16,16-di~luoro-PGF2~, see U.S. Patent No~ 3,969,380;
as to 2-decarboxy-2-hydroxymethyl compounds, see U.S. Pat.
No. 3,636,120; as to 2-decarboxy-2--tetrazolyl derivatives,
see U.S. Patent Nos. 3,883,513, and 3,932,389; as to 2,3-
didehydro-PGF2~ see Derwent Farmdoc No. 46497W and Ger.
O~fen. 2,460,285; as to ll-deoxy-ll-hydroxymethyl-PGF~,
see U.S~ Pa-tent Nos. 3,931,282 and 3,950,363; as to 16-
methylene-PGF2a, see Derwent Farmdoc No. 1959~W and U.S.
Patent No. 3,953,495; as to 17,18-didehydro-PGF2~ compounds,
see U.S. Patent No. 3,920,726; as to 3-(or 4-~oxa-17,18-
didehydro-PGF2~ compounds, see UOS. Patent No. 3,920,723;
as to 15-oxo--PGF2~, see U.S. Patent No. 3,728,382; as to
15-deoxy-PGF2~, see Derwent Farmdoc No. 09239W; as to 11-
~ 3 -
!~-
jrc.i~
32 2720-l
CHART H
(~ H ,.C~ ~H LX I I
X -C -R25
Q2
10 . (a)
R33
. (~-~O - C H-~J CH - L ~R 1 6 LX I I I
X -C -R25
Q2
( b )
0 -CH ^~- Ctl2 ~L ~R 16
R22t- --CH2
~~X -C -R25 LX I V
~s!2
~)o
-84 -
2720-l
i3~
deoxy-15-deoxy-PGF2~ see Derwent Farmdoc No. 05~94U and
U.S. Patent No. 3,853,951; as to ~-homo-PGF2~ compounds,
see Derwent Farmdoc No. 04728W; as to 2-decarboxy-2-amino-
PGF2~ compounds, see Preparation 1 herein;
aS to 16-phenoxy-17,18,19,20-tetranor-PGF2a, see Derwent
Farmdoc No. 7~279U; as to 17-phenyl-18,19,20-trinor-PGF2~,
see U.S.Patent No. ~987,087; as to 13-cis-PGF2~, see U~S.
Pa~ent No. 3,932,479; as to 13,14-didehydro-PGF2~, see
Derwent Farmdoc No. 20717X and 59715X; as to 11-deoxy-PGF2~,
see Derwent Farmdoc No. 10695V; as to PGD2, see U.S. Patent
No. 3~767,813; as to 2a,2b-dihomo-PGF2~, see Derwent Farmdoc
No. 61412S; as -to ~-oxa-PGF~, see U.S. Paten~ No. 3,92~,861;
as to 3-oxa-17-phenyl-18,19,20-trinor-PGF2~ see U.S. Patent
No. 3,9~1,289; as to 2,2-difluoro-PGF2a, see U.S. Patent No.
4,001,~00; as to 11~-PGF2~3 see U.S0 Patent No. 3,890,~71;
and as to 11~-17^phenyl-18,19,20-trinor-PGF2~, see Derwent
~armdoc No. 13090X.
In step "a" of Chart H, the starting material LXII is
subjected -to h~logenation and cyclization to yield the
~0 formula-LXIII halo compounds. For related cyclization
procedures see Staninets and Shilov, Chem. Abs. 64, 12625h
(1966). For iodination there is used ei~her an aqueous
system containiny iodine, potassium iodide, and an alkali
carbonate or bicarbonate, or an organic solvent system such
as dichloromethane containing iodine in the presence of an
alkali metal carbonate. The reaction is carried out at
temperatures below 25 C., preferably about 0-5 C. for 10-20
hr. Therea~ter the reaction is quenched with sodium sul-
fite and sodium carbonate and the formula-LXIII compound
separated from the reaction mixture. For bromination N-
-85-
2 (.!~ L
63;~
bromosuccinimide or N-bromoacetamide are used. See Fieser
et al., Reagents for Organic Synthesis, Vol. I, pp. 7~ and 78,
Vol. IV p. 51, John Wiley and Sons, Inc., New York.
In step "b" of Chart H the halo compound LXIII is sub-
jected to reductive dehalogenation. Useful reagents includetributyltin hydride, triphenyltin hydride, sodium boro-
hydride in dimethyl sulfoxide, and zinc in acetic acid.
Especially preferred is tributyltin hydride freshly pre-
pared From tributyltin chloride and lithium aluminum hydride.
The reaction is run in a solvent such as benzene at about
15-35 C. and monitored by TLC.
Thereafter, any blocking groups are removed by methods
known in the art and the product isolated by methods described
herein or known in the art, for example by chromatography
on silica gel.
A preferred method for preparing amides of formula LXVII
,O-CH ~ CH2-L-C-N(R18)2
~ CH2/ H L.XVII
C=C
H/ -Il-R2 5
Q2
is by the steps shown in Chart I. The halo acid LXV is con-
verced to amide LXVI and thence, by reductive dehalogenation
to the formula-LXVII amide. In Chart I, R18 is hydrogen,
alkyl of one to 12 carbon atoms, inclusive, benzyl, or
phenyl, being the same or different.
Another method -for preparing the formula-lV, VII, VIII,
X, XIII, XIV, XV, XVI, and XXX-XXXIV cyclic ethers is by
~o reductive demercuration of a compound of the formula
-86-
i;3~ 2720-1
CHART I
R33
,O-CH ` CH-L-COOH
~ --CH2 LX V
, C=~'
H ~ ` C -R25
Q2
R33 0
1 1
~y, O-CH-~- CH -L -C -N (R 1~3 )2
R22 ~ -CH2
C=C LXVI
H' ~ 11 -R25
Q2
~0
\~
,O-CH-`- CH2-L-C-N(R 18 )2
$, ~--CH2 LXVI I
H~ ~C-R25
Q2
-87
'~720 - 1
3;~
H g ~
, O -CH r~- CH -L -R~B LX I X
(~ /~z ' ,
~ X -C -R25
. Q2
wherei n L, Q2, (~) , Rz5,, X and ~ ar~ as d~f ined for
~hart H and wherein G is nitrato, ioclo, chloro, bromo,,
acetato, trifluoroacetatcl or benzoato and wherein Rj6 is
(1 ) -COOR37 ,
(2 ) -CH20H
(3 ) -CHzN (R 18 )2
~4) -C-N(R18 )2, or
NH -N
(5 ) -C ll
~N--N
where i n R37 i s
(a) alky,l oF one ~o 12 carbon atoms, inclusive,
(b) cycloalkyl of 3 to 10 carbon atoms, inclusive,
(c) aralkyl of 7 to 12 carbon atoms, inclusive,
(d) phenyl,
(e) phenyl substituted with one, 2, or 3 chloro
or alkyl of one to 4 carbon a~oms, i,nclusive,,
() ~)
( f ) ~ J C ~ C -CH3,
`i (g) ,<~lli-C<~,
(h ) ~NI~-C -Cl-J
-~8 -
NH -C-NH 2 ~
CE~=N-NH-'_-NH 2,
?
R3s
wherein R3 It iS phenyl, p-bromophenyl, p-
biphenylyl, p-nitrophenyl, p-benzamido-
phenyl, or 2-naphthyl, and
wherein R3siS hydrogen or benzoyl, or
(m) hydroge~; and
wherein Rl~ is hydrogen, alkyl of one to 12 car~
bon atoms, inclusive, benzyl, or phenyl, being
the same or different.
Chart J shows the steps by~-hich a PGF2~-type compound
of fo~mula LXVIII is (a) converted to a mercury compound of
~ormula I,XIX and (b) compound LXIX is subjected to reductive
demercuration to form the Eormula-LXX product~ In Chart J
the terms are defined as for compound LXIX above.
Reference to Chart 3 will make clear the steps of this
process. For background on this mercuration~demercuration
0 cyclization see, for example, H.C. Bro~n et al., Organometal.
Chem. Syn. 1, 7 (1970) and Fieser and Fieser, Reagents for
Organic Synthesis, Vol. 3, p. 194, Wiley, N.Y., 1972.
-- 89 -
jrc~
2720-1
3;2
Many of the formula-LXVIII star~ing materials have
been discussed above for Chart H. As to substituted phenyl
esters, see U.S. Patent No. 3,890,~72; and as to substi-
tuted phenacyl esters, see Derwent Farmdoc No. 16828X and
German Offen. 2,5~5,693. In step "a" of Chart J, the
starting material is reacted with an appropriate mercury
(Il) sal~ corresponding to Hg(G )2~ for example mercuric
nitra-te, chloride, or acetate. Preferred is either mercuric
acetate or trifluoroacetate. The reagent is dissolved in
either water or acid, e.g. acetic acid, and combined with a
solution of the formula-LXVIII starting material in a con-
venient solvent such as chloroform or tetrahydrofuran. The
reaction is conveniently done at about 15-35 C.
In step "b" of Chart J the mercurio compound is sub-
jected to reductive demercuration. Useful reagents for
this step include sodium borohydride, sodium amalgam, and
hydrazine. Especially preferred is sodium borohydride in
alkaline solution, e.g. aqueous sodium hydroxide. The
reaction is carried out in a solvent such as tetrahydro-
furan at about 15-35 C. Thereafter the mercury is separated,
blockincJ groups removed if necessary, and the product iso-
lated by methods described herein.
The Formula-LXlX mercurio compouncls are use-ful not only
as intermediates for preparing the formula-LXX p~oducts but
also for their pharmacological applications as set forth
herein. G may be varied, for exampleJ by suitable choice of
reagent Hg(G)2 or by replacement~ for example of aceta-te by
chloro by ion exchange.
Chart K shows the formation of formula-LXXXlV compounds,
iO which are inner salts between hydroxymercurio groups and
-90 -
272 0 - 1
663;~
CHART J
(~- -CH2~ C_C~L-R3e LXVI I I
X IC-R25
Q2
(a)
~,
g-G
~o-CH~ H-L-~36
, ' / LX I X
~R22~ - CH2
X -C -R25
Q2
(b)
, O-CH~ CH2 `L-R 3~3
f--\- !
t R22)- - CH2
\_ LXX
~ X -6 -R25
02
3o
-91 -
2720 - 1
663~
, .
CHART K.
Hg -G
,O-CH-~- CH-L-COOH
/~ I L.XXI
( R2 2 ~ - CH2
. ,
X -IC -R25
Q2
\/
H g O
~ , O -CH ~`~ CH-L -C =O
(R22 - CH2
~, LX)~XIV
X -1: - R2 s
3o
-~2
2720-1
terminal carboxy. They are formed by replacing G with
hydroxy, as in basic solution, followed by treatment with
acid They also have pharmacological utility. In Chart K
the terms are as defined in Chart J.
The intermediates of Charts A-L,including those com-
pounds represented by Formulas XLI, XLII, XLIII, XLIV, XLVI,
XLVIII, XLIX, L, L.I, LIII, LV, LVI, LVII, LIX, LX, LXIII,
LXVI, LXIX, LXXXVI, LXXXVII, and LXXXVIII are frequently not
isolated but used directly for a subsequent process step.
When they are isolated, they are purified by methods known in
the art, for example partition extraction, fractional crys-
talization, and, preferably, silica gel column chromatography.
The compounds of Charts A-L wherein Q, Ql, or Q2 are
in either alpha or beta configuration, for example
H OH or H OH
represent 15-~ and 15-f3 isomers. The transformations
shown herein generally have no effect on the stereo-
~0 chemistry a-t this position and therefore the final products
have the same stero con-figuration at C-15 as in the starting
materi~ls ~-t rhe corresponding carbon atoms Should it be
necessary to separate 15a and 15~ isomers, this can be done
by methods known in the art, for example by chromatography
on neutral silica gel.
When an op-tically active intermediate or starting mate-
rial is employed, subsequent steps yield optically active
intermediates or products. That optical isomer of bicyclo
lactone XXXVII is preferred which will yield product XL, for
~0 example, in the configuration corresponding to that of the
-93-
2720-1
32
na~urally occurring prostaglandins. When the r~cemic form
of the intermediate or startiny material is employed, the
subsequent in~ermediates or products are obtained in their
racemic form. Optîcally active and racemic forms of the
intermediates or starting materials are known or available
by methods known in the art.
Compounds within the scope of formulas XXX-XXXIV, here-
in, occur in -two isomeric forms wherein ~J is in alpha or
beta configuration, i.e endo or exo relative to the hetero-
cyclic ring. These two isomers differ in their mobility onTLG silica gel plates or on a silica gel column. The mem-
bers of each pair of isomers are distinguished herein as
"less polar" or "more polar" isomers, considering that
mobility.
The lower alkanoates of the formula-XX~-to-XXXlV com-
pounds disclosed herein are prepared from those compounds by
replacing any blocking groups (R40) with hydroxy, thereafter
subjecting the hydroxy compound to a carboxyacylating agent,
preferably the anhydride of a lower alkanoic acid, i.e.,
an alkanoic acid oF one to 8 carbon atoms, inclusive. For
example, use oF acetic anhydride gives the corresponding
diacetate. Similar use of propionic anhydride, isobutyric
anhydride~ and hexanoic acid anhydride gives the correspond-
ing carboxyacylates.
The carboxyacylation is advantageously carried out by
mixing the hydroxy compound and the acid anhydride, prefer-
ably in the presence of a tertiary amine such as pyridine
or triethylamine. A substantial excess of the anhydride is
used, preferab`ly about 2 to about 10 moles of anhydride per
~0 mole of the hydroxy compound reactantO The excess anhydride
_91~ _
2720 -1
3~
serves as a reaction diluent and solvent. An inert organic
diluent, for example dioxane, can also be added. It is
preferred to use at least enough of the tertiary amine to
neutrali~e the c~rboxylic acid produced by the reac~ion,
as well as any free carboxyl yroups present in the hydroxy
compound rea~tant.
The carboxyacylation reaction is preferably carried
out in the range about 0 to about 100 C. The necessary
reaction time will depend on such factors as the reaction
temperature, and the nature of the anhydride; with acetic
anhydride, pyridine, and a 25 C. reac~ion temperature, a
12 to 24-hour reaction time is used.
The carboxyacylated product is isolated from the reac-
tion 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 carboxylate is recovered from
the diethyl ether extract by evaporation. The carboxylate
is then purified by conventional methods, advantageously by
chromatography.
~ ompounds within the scope of formulas XXX-XXXIV are
~ransformed from one to another by methods known in the
art Accordingly, a compound wherein ~ is
~ ~
~ .
OH
i!s transformed to another compound wherein ~ is another
ring within the scope of ~ , for example an 11 methylene
-95 -
2720-1
66~3~
compound, by methods known or described herein. A compound
wherein the C13-C1~ group is trans-CH=CH- is transformed
to another compound wherein the C13-CI4 group is cis-CH=CH-,
-C--C-, or -CH2CH~-. For example, -C--C- is obtained by
s~lective br~mination and dehydrobromina-tion. A compound
wherein the C~ substituent is -COOR,e.g. a methyl esterJ
is transformed by kn~wn methods to another compound having
another C2 substituent within the scope of R30, as defined
herein, -for example -CH20H or
. o
-C-N(R18 )2.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The invention is further illustrated by, but not limited
to, the following examples.
All temperatures are in degrees centigrade.
Infrared absorption spectra are recorded on a Perkin-
Elmer model 421 infrared spectrophotometer. Except when
specified otherwise, undiluted ~neat) samples are used.
The NMR spectra are recorded on a Varian A-60, A-60D,
T-60, or XL-100 spectrophotometer in deuterochloroform solu-
tions with ~etramethylsilane as an internal standard.
Mass spectra are recorded on a Varian Model MAT CH7
Mass Spectrometer a CEC Model 110B Double Focusing High
Resolution Mass Spectrometer, or a LKB Modcl 9000 Gas
Chromatograph Mass Spectrometer (ionization voltage 22 or
70 ev.), and are usually run as TMS (trimethylsilyl) deriva-
tives.
"Brine"~ herein, refers to an aqueous saturated sodium
chIoI-ide solution.
-96-
2'~2() - 1
i32
"Skellysolve B", herein, reFers to mixed isomeric
hexanes.
IITLC", hereinJ refers to thin layer chromato~raphy.
Silica gel chromatography, as used 51erein, is under-
stood to include elution, collection of fractions, and com-
bination of those fractions shown by TLC to contain ~he
desired product free of starting material and impurities.
"Concentrating", as used herein, refers to concentra-
tion under reduced pressure, preferably at less than 50 mm.
and a~ temperatures below ~5 C.
"Lower alkanoate", herein, refers to an ester of an
alkanoic acid of one to 8 carbon atoms, inclusive.
Preparation 1 2-Decarboxy-2-amino-PGF Compounds
-
_
~
Chart M shows the steps by which the formula Cl, PGF2~-
or 11-deoxy-PGF2a-type free acid is transformed to the
20 various 2-decarboxy-2-aminomethyl or 2-decarboxy-2-(substi-
tuted amino)methyl-PGFa- or 1l-deoxy~pGFa-type compounds of
formulas CIV, CVI, CVII, CV151, CIX, or CX.
In Chart M,
Y1 is trans-CH=CH-; -C-C-~ or -CH2CH2-;
Ml is
~"
Rss . OH
or
, ~
RSs 011
~a wherein R55 is hydrogen or methyl;
9~
2720-1
CHART M
H0
~CH2-Zl-COOH
<~ Cl
'Y 1 -fi-- C -R57
Ml Ll
O O
H0
,CH2 -Zl -C-0-C-R5 1
<~,~ Cl I
Y 1 - C--Cj - R5 7
Ml Ll
'
H0\ j
2 -Z 1 -C -NH2
Clll
Rlsa Y 1 -fj - -cl-R57
Ml L
H~
,CH2 -Zl -CH2NH2 ~ I V
Y 1 -C~ fi-Rs7
Rss1 L
H0
CH2 -Zl -C -N=N=N
<' ~YI-l --Cl-Rs7 CV
-98 -
63~ 2720-1
CHART 1"1 (conti nued)
Ho
`~ , CH~ - Z 1 -NH -COOR5 1
¢~ `\ CV I
Y 1 -C--C -R7
Rss
~1 L
H0
CH2 -Z 1 -NH2
S ,l~ CVI l
8 L, Ml
H0 CH2-Zl-NHL2
~ ~/ CVIII
Cl ~Rs7
R58 Ll Ml
~J
H0
--1 ' CH~ -Z 1 -NL2 COOR5 1
CIX
Y 1 lCI 6-R57
R58 ~1 L
H0
CH2-Zl-NL2L3
CX
Rs~ Y l -~ -R57
3o
9~
2720-1
32
Ll i s
D `
Rs3 R54,
R5 3 Rs4,
or a mixture of
Rs3 Rs 4
and
" '~
R53 R5~,
wherein Rs3 and Rs4 are hydrogen~ methyl, or fluoro, being
the same or differen~ with ~he proviso that one of R53
and R54 is fluoro only when the other is hydro~en or fluoro;
Zl i s
(1) cis-CH=CH-CH2-(CH2)9-CH2-,
(2) cis-CH=CH-CH2-(~H2)g~CF2~,
whereîn g is one, 2, or 3;
R57 is
(1) -(CH~)m-CHg,
(2 ) -0~(~1 )s
(3 ) -CH2 ~,( T 1 ) s
wherein m is one to 5, inclusive, T1 is chloro~ fluoro~
trifluoromethyl, alkyl of one to 3 carbon atoms, inclu-
sive, or alkoxy of one to 3 carbon atoms, inclusive, and
s is zero~ one~ 2, or 3~ the various T1's being the same
or different, with the proviso that not more than two
T,'s are other than alkyl, with the further proviso that
- 100 -
~ 3~ ~720-1
R5 9 i S
~(T 1 )5
wherein T1 and s are as defined above, only when R53 and R54
are hydrogen or methyl, being ~he same or different;
R58 is hydrogen or hydroxy;
L2 and L3 are hydrogen, alkyl of one to 4 carbon atoms,
inclusive, or -COORs1, wherein R51 is hydrogen, alkyl of one
to 12 carbon atoms, inclusive, cycloalkyl of ~ to 10 carbon
atoms, inclusiv~, aralkyl of 7 to 12 carbon atoms, inclu-
sive, phenyl, or phenyl substituted one, 2, or 3 chloro or
alkyl of one to 3 carbon atoms, inclusive; being.the same
or different, with the proviso that not more than one of
L2 and L3 is -COOR51.
By the procedure of Chart M -the formula Cl compound is
transformed to a formula Cll mixed acid anhydride. These
mixed anhydrides are conveniently prepared from the corres-
ponding alkyl, aralkyl, phenyl, or substituted phenyl
chloroformate in the presence of an organic base (e.g.,
triethylamine). Reaction diluents include water in com-
bination with water miscible organic solvents (e.g.~ tetra-
hydrofuran). This mixed anhydride is then transformed to
eTther the formula Clll PG-type, amide or formula CV PG-
type,azide.
For preparation of the PGF2a-~ype, amide (formula Clll)
the formula Cll mixed acid anhydride is reacted with liquid
ammonia or ammoniurn hydroxide.
Alternatively, the formula Clll compound Is prepared
from the formula Cl free acid by methods known in the art
-101 -
2720-1
3~
for transformation of carboxy acids to corresponding carboxy-
amides. For examp1e, the free acid is transformed to a
corresponding me~hyl ester (employing methods known in the
art; e.g., excess etheral diazomethane)~ and a methyl es~er
thus prepared is transformed to the formula CIII amide.
Thereafter the formula CIV 2-decarboxy-2-aminomethyl-
PGF2a- or 11-deoxy-PGF2~ype compound is prepared from the
formula CIII compound by carbonyl reduction. Methods known
in the art are employed in this ~ransformation. For example,
lithium aluminum hydride is conveniently employed.
The formula CII compound is alternatively used to pre-
pare the formula CV a~ide. This reac~ion is conveniently
carried out employing sodium azide by methods known in the
art. See for example, Fieser and Fieser, Reagents For Or-
rJanic Synthesis Vol. 1, pages 1041 104~, wherein reagents
and reaction condi~ions for the azide formation are discussed.
Finally, the formuia CVI urethane is prepared from the
formula CV azide reaction with an alkanol, aralkanol, phenol,
or substituted phenol. For example, when methanol is em-
'~0 ployed the formula CVI compound is prepared wherein Rl is
methyl. This formula CVI PG-type product is then employed
in the preparation of either the formula CVII or CVIII pro-
duct.
In the preparation of the formula CVIi primary amine
from the formula CVI urethane, methods known in the art
are employed. Thus, for example, treatment of the formula
CVII urethane with strong base at temperatures above 50 C.
are employed. For example, sodium,potassium,or lithium
hydroxide is employed
Alternatively, the form~la CVI compound is employed
-102- .
2'~20 -1
3~
in the preparation o~ the formula CViII compound. Thus,
when L3 is alkyl the formula CVIII compound is prepared
by reduction of ~he formula CVI urethane wherein Rl is
alkyI For this purpose3 lithilIm al umi num hydride is
the conveniently ernployed reducing agent.
~ hereaf~er, the formula C~III product is used to
prepare the corresponding CIX urethane by reaction o~ the
for~ula C~III secondary amine (wherein L2 is alkyl~ with an
alkyl chloroformate. The reaction thus proceeds by methods
known in the art for the preparation of- carbamates ~rom
corresponding secondard amines Finally, the formula CX
product wherein L~ and L3 are both alkyl is prepared by
reduction of the formula CIX carbamide. Accordingly/
methods hereinabove described for the preparation of the
formula CVIII compound from the formula C~I compound are
used.
Preparation lA 2-Decarboxy-2-azidomethyl-PGF~.
(1) A solution of t-butyldimethylsilyl chloride (10 9 ),
imida~ole (9.14 g.)~ and PGF2~ (3 g.) in 12 ml. of dimethyl-
t.~O foI^mamide are magnetically stirred under nitrogen atmospherefor ~4 hours. The resulting mixture is then cooled in an ice
batIl and the reaction quenched by addition of ice water.
The resulI:ir)g mixture is then diluted wi-th 150 ml. of water
and extracted with diethyl ether. The combir7ed ethereal
~5 extracts are then washed with water, saturated ammonium
chloride, a sodium chloride solution, and thereafter dried
over sodium sulfate. Solvent is removed under
-10~ -
~D ~'D ~.'gL~L` ~ 11
v~cuum yielding PGF2~, t^-butyldimet~ylsilyl ~ster,
9,11,15-tris-(~-butyldimethylsil~ her). ~'~R absorptions
are observed at 0.20, 0.30, 0.83, 0.87, 0.89, 1.07-2.50,
3.10-4.21, and 5.38 ~. Characteristic infrared absorptions
are observed at 970, 1000, 1060, 1250, 1355, 1460, 1720,
and 2950 cm. 1.
(2) To a magnetically stirred suspension of lithium
aluminum hydride (7.75 g.) in 18 ml. of diethyl ether is
added dropwise at room temperature over a period of 12 min
8.71 g. oE the reaction product of part (1) above in 40 ml.
of cliethyl ether. After stirring at ambient temperature for
one hr., the resulting product is cooled in an ice water
bath and saturated sodium sulfate is added dropwise until
the appearance of a milky suspension. The resulting pro-
duct is coagulated with sodium sulfaLe, triturated with
diethyl ether, and the solvent is re~oved by suction fil-
tration. Concentration of the dietnyl ether under vacuum
yields 7.014 g. of 2-decarboxy-2-hydroxymethyl-PGF2a,
9,11,15-tris-(t-butyldimethylsilyl ether3. NMR absorp~
tions are observe~ at 0.03, 0.82, 0.37, 1.10-2.60, 3.30-
4.30, and 5.37 ~. Characteristic infrared absorptions are
observed at 775, 840, 970, 1065, 1250, 1460, 2895, 2995,
and 3350 cm. 1.
~3) p-Toluenesulfonyl chloride (3.514 g.), pyridine
t44 ml.), and the reaction product o~ subpart ~), 7.014 g~,
are placed in a freezer at -20 C. for 3 d~ys. ThereaEter,
7.200 g. of 2-decarboxy-2-p-toluenesulfonylo~ymethyl-PGF2a
9,11,15-tris-(t-butyldimethylsilyl ether), is recovered.
NMR absorptions are observed at 0.10, 0.94, 0.97, 1.10,
~0 2.50, 4.03, 3.80-4.80, 5.45, 7.35, and 8.80 ~. In-fra-
- 10'1 -
jrc~
rea absorp-tions are observed at 775, 970, 1180, 1190, 1250,
1360, 1470, 2900, and 2995 cm. 1.
(4) The reaction product of subpart (3) (2.13 g.) is
placed in 42 ml. of acetic acid, tetrahydrofuran, and
water (3:1:1) containing 0.25 ml. o~ 10 percent aqueous hy-
drochloric acid. ~'he reaction mixture becomes homogeneous
after vigorous stirriny for 16 hrs. at room temperature. The
resulting solution is then diluted T~ith 500 ml. of ethyl
acetate; washed with saturated sodium chloride and ethyl
acetate; dried over sodium sulfate; and evaporated under
reduced pressure, yielding 1.301 g. of an oil. Crude pro-
duct is chromatographed on 150 ~. of silica gel packed
with ethyl acetate. Eluting with ethyl acetate yields
0.953 g. of 2-decarbo~y-2-p-toluenesulfonyloxymethyl-PGF2~.
(5) The reaction product of subpart ~4), (0.500 g.~
in 5.0 ml. of dimethylformamide was added to a stirred sus-
pension of sodium azide ~1.5 g.) in 20 ml. of dimethylfor-
mamide. Stirrir~ is continued at ambient temperature for
3 hrs. The reaction mixture is then diluted with water
~75 ml.), extracted with diethyl ether ~500 ml.), and the
etheral extracts washed successively with water, saturated
sodium chloride, and dried over sodium sulfate. Removal
of the diethyl ether under reduced pressure yields 0.364 g. of
2-clecarboxy-2-azidomethyl-PGF2~. A characteristic azido
infrared absorption is observed at 2110 cm. 1
Preparation lB 2-Decarboxy-2-aminomet~yl-PGF~ (Formu-
la CXXXV).
Crude decarboxy-2-azidomethyl-PGF2~ ~Prep. lA, 0.364 g.)
in 12 ml. of diethyl ether is added to a ma~netically s-tir-
red suspension oE lithium aluminum hvdride (0.380 g.) in
105 -
jrc~
6~Z
20 ml. of diethyl ether. Reaction ~emperatur~ is maintainea
at about 0C. and addi-tion of lithi~m aluminum hydride pro-
ceeds dropwise over a 4 min. period. ~fter addition is com-
plete, the resulting mixture is sti--red at ambient tempera-
ture for 1.5 hr. and thereafter placed in an ice bath (0-5C.).
Excess reducing agent is then destroyed by addition of
saturated sodium sulfate. ~fter ceasation of gas evolution,
the resulting product is coagulated with sodium sulfate,
triturated with diethyl ether, and solid salts removed
by filtration. The filtrate is then dried with sodium sul-
fate, and evaporated under reduced ?ressure to yield 0.304 g.
of a slightly yellow oil. This oil (100 mg.) is then pur-
ified by preparative thin layer chromatography, yielding
42 g. of title product. NMR absorptions are observed at
0.90, 1.10~2r80, 3.28, 3.65-4.25, and 5.45 ~. Charac-teristic
infrared absorptions are observed at 970, 1060, 1460,
2995, and 3400 cm. ~. The mass spectrum shows parent peak
at 699.4786 and other peaks at 628, 684, 595, 217, and 274.
Example 1 9-Deoxy-6~,9~-epoxy-2,3,4-trinor-PGFI, Ethyl
Ester, Mixed Isomers (Formula II~).
1. Refer to Chart ~. There is first prepared the
ormula-XXXIX 9-deoxy-6~,9~-epoxy-2,3,4-trinor-PGFl, ethyl
ester, bis tetrahydropyranyl ether, mixed isomers. A solu-
tion of triethyl phosphonoacetate (3.58 g.) in 40 ml. of
tetrahydrofuran is treated at 0C~ with a solution of potas-
sium t-butoxide (1.79 g.) in 40 ml. of tetrahydrofuran, fol-
lowed by a solution of the formula-XXXVIII 2~4a-dihydroxy-
5~-(3'a-hydroxy-1'-trans-octenyl)-~-cyclopentylacetaldehyde-
r-lactol, 3'4-bistetrahydropyran-2-~Tl ether (~.J. Corey
jrc~
~ 6 3~
et al., J. AIm Chenl. Soc. 92) 397 (197()),(~6 9)) in 20 ml.
of benzene acldecI over a onc-mlIlu~e p~ri(>cl. Therca~ter t!le
mixture 7s stirred at 0-25 C. for 25 Inin. ~nd ~ilutecl~Iith .
500 ml. of ether-methylene chloride (3:1). The res-lltin~
rnix~-ure is wash~d with water, ~ te potàssiu~n hycll oY~ide
solution, water~ and brirle, dried, ancl concentrate~ to the
~ormula-XXXlX compound in a crucJe procIuct, 8.1 ~.
The above prodlIc~ is subjected to si-lica ~el chronla-
to~raphy, eluting wi~h 40-75~ ethyl acetate in Skellysolve B,
to obt~in the formula-XXXiY~ bis tetrahydropyranyl ether
11.7 9., having NMR peaks at 5.4-5.7, 3.2-4.~, 2.42 ancI
2~56 ~.
II. The above mixed isomers of the formula-XXXlX corn-
p~und (1.0 9~) are hydrolyzed in 15 ml. of acetic a~id ar~d
7.5 ml. of water at 37-39 C. for 3 hr. The mixture ;s
~ooled~ mixed with diethyl ether-methylene chloride (~
and shaken with ice-cold dilute potassium hydroxide solution.
The organic phase is washed with brine, dried, and concentrate~
The residue is subjected to silica gel chromatography, elut-
ing `~ith 0-5~ e~hanol in et~hyl acetate, to obtai n the
f Ol'mU la-lII title compound as mixed less polar and mo~e
polar isomers, 0.55 g., having NMR peaks at 5.27-5.47,
3.3-4.5, 2.4, and 2.52 ~; and mass spectral peaks at 32~,
~04, 2~8, 251, and 235.
Example 2 9-Deoxy-6~,9~-epoxy-2,3,4-trinor-PGF1, Fthyl
Ester, Bis(tetrah~dropyran-~-yl ether),
mixed isomers (Formula XXXIX wh~rein R40 of
Ql and ~ is THP (tetrahydropyran-2-yl)i
and 9-Deoxy-6,9~-epoxy~2,3,4-trinor-PGF1,
Ethyl Ester, less polar isomer and more
polar isomer (Formula 111 wherein ~ o~ Q
and W is hydrocJen).
~ 107 -
i3
In the Drawings
Fiyures l and 2 show the 'H NM~ spectra for
,the-less polar and more polar products, respectively.
1. Refer to Chart A. ~here IS f ~ rs~ prepare~ the
formula-XXXlY. bis(te~rahydro~yranyl et~er). A miY~ture of the
~orn~ula-XXXVIII 2~ 4a-~i hydroxy-5~- [ (~S ) -3-hydroxy- ~rans -1-
octenylJ-1~-cyclopentane acetaldehyde, y-lactol, bis-
(tetrahydropyran-2^yl ether) (10 9, ), e~:hyl (tri~enylphos-
phoranylidine)acetate (10 9.~ and 150 nll. oF ethanol is
sti rred ~or 7~ days under ni trogen. The nlixture is t~len
10 concentrated and the residue is chromatographed on silica
gel, eluti ncg wi th ethyl acetate-Skel lysolve B ~1:1) to
yield the formula-I I I mixed Isomer ti~1e compound, 9.0 9.
The product has Rf 0.34 and 0.39 for the mixture (TLC on
si lica gel in ethyl acetate-hexane (1:3))g and ~ lR peaks
at 5.;J5-5.69, 4.69, ~.98-4.~4, and 2. )18-2~62 ~.
I I . To remove the THP blocki ng groups~ a mi~ture
of the above formula-XXXlX compound ~6.g5 cJ. )J 100 ml. of
aceti c aci d, 50 ml . of water, and 10 ml . o~ tetrahydrofuran
is stirred at l~o C. for 4 hI. The mixt~Ire Is coolecl, di-
20 Iuted wi th 500 ml . of ethyl acetate and washed wi th amixtur~ of 72 9. of socli um hydroxi de i n 500 ml . ol i ce and
water, then wi th bri ne~ dried, and concentrated. The
resi due i s chromatographed on a col umn of 500 g. of f i ne
si lica c~el (40-63 Il, Merck) previously deactivated wi th
acetone-methylene ~hloride (60:40). The column is
eluted with acetone-nlethylelle chlori de mixtures as Follo-~s~
3 liters of 30:70j 0.5 liter o~ 35:65, and 1.5 liter oF
40:60~ ~he ~irst 500 rml. of eluant is discarclecIs ~lnd
thereafter 40 nll ~ Fracttons are col lected. Fractions 110-46
yield the rorn~IIa-~ I I less polar isoIner oF the ti t~e conl-
~j - 108 --
~ 6 3~ 2720-l
pound~ 0.21 g., having Rf 0.39 (TLC on silica gel in
acetone-methylene chloride (40:60)), and NMR peaks at
5.43-5.54, 3.98-4.~3, and 2.57-2.71 ~. See FiGURE 1 for
the 1H NMR spectrum. Fractions 47-62 yield a mixture of
the isomers. Fractions 63-100 yield the formula-lll more
polar isomer of the ti-tle compound, 2.03 g., having Rf 0~32
(TLC on silica gel in acetone-methylene chloride (40:60)),
and NMR peaks at 5.47-5.58, 40~4-4.64, 3.98-4.34, and 2.4~-
2.6~. See FIGURE 2 for the t H NMR spectrum, noting peaks
10 at 4.4-4.6 ~ for -this more polar isomer.
Example ~ 9-Deoxy-6,9a-epoxy-2,3,4-trinor-PGF1, Methyl
Ester, Bi5(tetrahydropyran-2-yl Ether),
mixed isomers (Formula XXXIX);
and 9-Deoxy-6,9a-epoxy-2,3~4-trinor'-P~F
Methyl Ester, less polar isomer and more
polar isomer (Formula lll).
I. Refer to Chart A. A solution of trimethylphos-
phonoacetate (7.11 y.) in 75 ml. of tetrahydrofuran ts
treated at 0 C. with a solution oF potassium t-butoxide
(4.05 g.) in 75 ml. of tetrahydrofuran. The mixture is
stirred at 0-5 for 10 min. and then a solution of 2~4a-
dihydroxy-5~-[(3S)-~-hydroxy-trans-1-octenyl~ -cyclo-
pentane acetaldehyde, ~-lactol, bis(tetrahydropyran-2-yl
ether) (1~.2 g.) in 60 ml. of tetrahydrofuran is added
within one rnin. Thereafter the mixture is stirred at
about 25 C. for 2 hr., ~hen diluted with 600 ml. of diethyl
e-ther-methylene chloride (~:1). The organic phase is
washed with brine, dried, and concentrated. The residue
is chromatographed on silica gel, eluting with ethyl
j~ acetate-Skellysolve B (1:1), to yield the formula-XXXlX
- 109 -
2720-1
~3~
product as mixed C-6 isomers, 12.15 g., having ~r 0 62
(TLC on silica gel in ethyl acetate-hexane (1:~)), and
NMR peaks at 5.33-5.71g 4.71, 3.67g and 2.5-2.61 ~
Il. To prepare -the formula~lll product, a mixture
of ~he above formula-XXXIX bis(tetrahydropyran-2-yl ether)
(12.15 g.) in 200 ml. of acetic acid, 100 ml. of water,
and 10 ml. of tetrahydrofuran is stirred at 40 C. for 4 hr.
The mixture is cooled and diluted with 800 ml. of cold
(-10 C.) ethyl acetate. The organic phase is washed with
a mixture oF sodium hydroxide (150 g.) in 800 ml. of ice
and water, then with brine, dried, and concentrated. The
residue, 11.8 g.) is chromatographed on a column of about
500 g. of fine silica gel (40-63 ~, Merck). The column is
eluted with acetone-methylene chloride mixtures as follows:
8 liters of 40 :60, and 4 liters of 60:40. The first 2
liters oF eluant is discardedJ ~hereafter 17 200 ml.
fractions and 18 300 ml. fractions are collected. Fractions
6-22 yield a mixture of the formula-lll less polar isomer
and more polar isomer, 3.9 g., later separated helow.
'20 ~ractions 23-32 yield the formula-lll more polar isc,mer
of the title compound, 3.55 g.
Rechromatography of the mixed-isomer fraction, ayain
on fine (40-63 ~) silica gel~ followed by fur~her re-
chromatography oF a mixed-isomer Fraction so-obtained,
yields ~he less polar isomer and more polar isomer which,
with the amoun~s aboveJ total: for -the less polar isomer,
1.25 g.,,and for the more polar isomer 5. 44 g.
The formula lli less polar isomer of the title compound
has m.p. 47-48 C. (from die~hyl ether-hexane), Rf 0.41
~0 (TLC on silica gel in acetone-methylene chloride (40:60));
-110 -
2720-1
NMR peaks at 5 50^5.61, 3.86-4.46, 3.72, and 2.51-2.75 6;
and mass spectral peaks at 470.2898, 455, 439, 399, 380,
265, 219, 199, and 173.
The formula-III more polar isomer has Rf 0.35 (TLC on
silica gel in acetone-me-thylene chloride (40:60)); NMR
peaks at 5.50-5.61, 3.88-4.67, 3.72, and 2.52-2.63 ~;
and mass spectral peaks at 470~2903, 455, 399, 380, 309, 199,
and 173.
Example L~ 9-Deoxy-6~,9a-epoxy-2,3,4-trinor-PG~1, Methyl
Ester, Bis(tetrahydropyran-2-yl ester),
Mixed Isomers, by Michael Addition.
I. There is first prepared 2,3,4-trinor-5,6-trans-
didehydro-PGF1~, methyl ester, 11,15-bis(tetrahydropyran-
2-yl ether). A mixture of 2a,4a-dihydroxy-5~-[(3s)-3
hydroxy-trans-1-octenyl]-1~-cyclopentaneacetaldehyde,
~-lactol, bis(tetrahydropyran-2-yl ether) (8.8 9.) methyl-
(triphenylphosphoranylidine)acetate (10.0 g.) and 100 ml.
of tetrahydrofuran is stirred until homogenous and then
left at about 25 C. for 7 days. The mixture is con-
centrated. The residue is chromatographed on silica geldeactivated with ethyl acetate, eluting wi-th ethyl
acetate-SI<ellysolve B (1:1) to yield the above 5,6-trans
compound, 9.6 g., having Rf 0.59 (TLC on silica gel
in ethyl acetate-hexane (1:1)); NMR peaks at 6.80-7.20,
2~, 5.77-6.01, 5.38-5.67~ 4.71, and 3.70 ~; and infrar~d absorp-
tion at 3600, 1730, and 1670 cm~1.
II. To prepare the title compound, a solution of the
above 5~6-trans compound (0.300 9.) in 3 ml. of methanol
and approximately 0.15 ml. of a methanol solution of sodium
.j methoxide is stirred -for 25 min., whereupon the reaction is
~111 -
63Z
~ Iplete as shown hy TLC. ~he mixture is diluted with 35 ml.
of diethyl ethex, ~7ashed wi-th brine, dried over maynesiurn
sulfate, and concentrated. The oil~ xesidue, 0.290 g., con-
sists o~ the mixed isomers of the formula-XXXIX title com-
pound, having identical properties of those reported above
in Example 3.
Example 5 3,3a~,4,5,6,6a~-Hexahydro-5~~hydroxy~2~-
(2'-hydroxyethyl)-4~-(3'~-hydroxy-trans-1-
octenyl)2H-cyclopenla[b~furan~ 3',5'-bis-tetra-
hydropyranyl Ether 'lixed Isomers ~Formula-
XLI: Q~ is
~1 O~HP,
R2 is n-pentyl, ~ is
OTHP
where THP is tetrahydropyranyl, and ~ is
alpha and beta).
Refer to Chart B. A solution of formula-XXXIX, 9-
deoxy-6~,9~-epox~-2,3,4-trinor-PGFl, ethyl ester, bistetra-
hydropyran-2-yl ether (Example l-I, 4.0 ~.) in 40 ml. of
diethyl ether is added to a slurry of lithium aluminum hydride
(0.50 ~.) in 100 ml. oE anhydrous diethyl ether. The mix-
ture is heated at reflux with stirring, for 2 hr. After
coolin~ it is treated successively with 0.70 ml. oE water,
0.70 ml. of 15~ aqueous sodium hydroxide solution and 0.8 ml~
of water. The mixture is filtered and the filtra-te is con-
- 112 ~
jrc:~`
2720-1
6~;2
centrated to yield the formula-xLl titTe compoundsJ3.7 9.,
having NMR peaks at 5.2-5.6, 4.6, and ~.0-4.0 6. An alter-
nate name for ~hese compoundsis ~3aR-[3a,4a(1E,3S*), 5~J6aa ~ -
hexahydro-5-~(tetrahydro-2H-pyran-2-yl)oxy]-4-~ [(tetra-
hydro-2H-pyran-2-yl)oxy]-1-octenyl,--2H-cyoloperlta[a~furan-
2~-ethanol, where ~ indicates unknown configura-tion.
Example 6 ~,~a~,4,5,6,6a~-Hexahydro-5a-hydroxy-2~-
(formylmethyl)4~ -hydroxy-trans-1-octenyl)-
2H-cyclopenta[b]furan~ 3',5-bistetrahydro-
pyran-2-yl Ether Mixed isomersg (Formula
XLII: Q1 is
H OTHP,
R2 is n-pentyl J ~ i S
1~
OTHP
2~
where THP is tetrahydropyranyl, and ~ is
3lpha and beta);
and 9-Deoxy-~,4-~rans-dic~ehydro-6-~,9~-
epoxy-2~nor-P~F1, Ethyl Ester, Bistetra-
hydropyranyl Ether Mixed Isomers (Formula
XLIII: A is a valence bond~ Ql is
H OTHP
~0 R~ is ethyl, ~ is
2720-1
ii6~3~
OTHP
where THP is tetrahydropyranyl, and~ is
alpha and beta).
I. Refer to Chart B. A solution of the formula-XLI
3,3a~,4,5,6,6a~-hexahydro-5a-hydroxy-2~-(2'-hydroxyethyl)-
4~-(3'~-hydroxy-trans-1-octenyl)-2H-cyclopenta[b]furan,
3',5-bistetrahydropyrarl-2-yl ether (Example 5, 2.3 9.) in
15 ml. of dichloromethane is added (in 15 sec.) to a solu-
tion of chromium trioxide (3.8 9.) in 100 ml. o~ dichloro-
methane and 6 ml. of pyridine. The mixture is stirred at
15 C. for 10 mir-., then 25 ml. of benzene is added ~nd the
mixture filtered. The filtrate and washings are concentrated
to about 15 ml. and taken up in 50 ml. of dichloromethane.
The mixture is contacted with CC-4 silica gel (Mallinckrodt
SilicAR ~) and diatomaceous earth and filtered. The filtrate
Is conc~entrated to yield the formula-XLII title aldehyde,
as mlxed isomers.
Il. A solution of the above for~ula-XLII aldehyde in
~0 ml. of benzene is cooled to 10 C. ànd added
to a previously prepared mixture of 1.1 ml. of ~rie~hyl
~5 phosphonoacetate and 0.60 9. of potassium t-butoxide in 30 ml.
of tetrahydrofuran which has been stirred at 0 C~ for 10
min. Thereupon the ice-bath is removed and the mixture
stirred for 30 min. as it gradually warms to about 25 C.
Finally the mixture is diluted with diethyl e~her me~hylene
3o chloride (~:1) and shaken with water. The organic phase is
2720-1
3~
washed with dilu~e aqueous po-tassium hydroxide. water~ and
brine, dried, and concen,rated to a residue~ 3.8 g. The
residue is subjected to silica gel chromatography, elut-
ing with ethyl acetate~Skellysolve B (1:1), to yield the
formula-XLill title compound mixed less polar and more polar
isomers, 2.3 g., having NMR peaks at 5.4-7.2, 4.7, and 3.2-
4.5 ~.
Example 7 9-Deoxy-3,1~-trans-didehydro-6,~-,9a-epoxy-2-
nor-PGF1, Ethyl Ester, Mixed Isomers (Formu-
la V: CgH29 is trimethylene, Q is
H ~H,
R1 is ethyl, R5 and R~ are hydrogen, W is
-C--
, \
H0 Hg
and ~J is alpha and beta)
The formula-XLIII bistetrahydropyranyl ether (Example
6-ll, 0,5 g.) is hydrolyzed in a mixture of 12 ml. of
acetic acid and 6 ml. of water at 37-39 C. for 2,5 hr.
The mixture is cooled and shaken with diethyl ether-di-
chloromethane (3:1) and a mixture of cold brine and
aqueous potassium hydroxide The organic phase is washed
with brine, dried and concentrated. The residue is sub~
jec~ed to silica gel chromatography, eluting with 0-5~
ethanol in ethyl acetate ~o yield the formula-V title com-
pounds,0,29 9., having NMR peaks at 5.71 5.97. 6.68-7 28,
5 32-5 57, and 3.4-4.5 ~; and mass spectral peaks (for the
-115-
2720 -1
3~
TMS derivatives) at 510, 495, 481, 465, 429, 420, 411, ~97,
and ~49.
Example 8 9-Deoxy-6~,9a-epoxy^2-nor-PGF1, MethyI Es-ter,
Mixed Isomers (Formula IV~ CgH29 is tri-
methylene, d is 2, Q is
~"
H OH,
R1 is methy]g R5 and R6 are hydrogen, W is
HO H,
and,~ is alpha and beta).
Refer to Chart B. The acid form of the formula-XLIII
compound is first prepared. A mixture of the formula~XLIII
9-deoxy-3.4-trans-didehydro-6~9~epoxY-2~nor-PGF1~ ~thyl ~stPr, his-
tetrahydroPYran-2-yl ether (Ex~mnle ~ 1.7 g.) an~ 15 ~1. nf methanol
is. treated with a solution of 0.25 ~. oF sodium hvdroxide in 6 ml. ~f
water. The mixture is stirred at about 25 C. fnr S hr. Chi~ed ice is
added and the mixture shaken with diethyl ether-dichloro-
methane (3:1) and cold dilute hydrochloric acid to acidify.
The organic phase Is washed with brine, dried, and concen
trated to yield the formula-XLIII acid, as mixed isomers.
The acid above is dissolved in aqueous sodium hydroxide
(0.2 g. in 25 ml. of water) and the resulting solution ad-
justed to pH 9 Witil dilute hydrochloric acid. Following
the procedure of Denrlis et al., Tetrahedron Lett. 1821
(1968), this solution is treated with a freshly prepared
mixture of nickel chloride hexaIlydrate (0 ~0 g ) and potas-
-116 -
2720-1
ii32
sium cyanide (0.41 9.) in 25 ml. oF water follo~ed by a
fresh solution of sodium borohydrlde (1.0 g.) in 5.0 ml.
of water. The mixture is stirred at about 25 C. for
16 hr. and then cooled in an ice bath while acidifying
with co1d dilute hydrochloric acid to pH 1-2. (Danger:
evolution of hydrogen and hydrogen cyanide). T~e re-
sulting mixture is immediately extracted with diethyl ether-
dichloromethane (3:1) and the organic phase is washed
with dilute acid, water, and brineJ dried, and concentrated
to the acid form of the formula-XLIV bistetrahydropyran-
2-yl ether, as mixed isomers.
The above formula-XLIV acid is converted to the methyl
ester by treatment in diethyl ether solution with diazo-
methaneJ thereafter separating the formula-XLlV methyl
ester, bistetrahydropyran-2-yl ether, having NMR peaks at
5.3-5.6, 4.63, 3 61J and 3.2-4.5 ~.
The above formula-XLIV methyl ester~ bistetrahydropy-
ran-2-yl ether is hydrolyzed to the title compound in 25 ml.
of acetic acid and 12.5 ml. of water at ~7 40 C. for 2.5
hr. Thereafter the product is worked up as for Example 7
and subjected to silica gel chromatography~ eluting with
4~5~, ethanol in ethy~ acetate. There is finally obtained
~he formula-lV title product, as mixed less polar and more
polar isomers, 0.200 g., having NMR peaks at 5.32-5.57,
3.61 and 3.3-4.5 6; and mass spectral peaks a-t 336, 322,
292, and 264.
Example 9 9-Deoxy-3,4-cis-didehydro-6t1,9a-epoxy-PGF1,
Bistetrahydropyran-2-yl Ether, Mixed Isomers
(Formula XLIII: A is methylene, Q1 i5
.
-117-
2720-1
632
H OTHP,
R2 is n-pentyl1 R1 is hydrogen, ~ ~ is
<
OTHP
and , is alpha and beta;
9-Deoxy-6~,9a-epoxy-PGF1g Mixed Isomers
(Formula IV: CgH29 is trimethylene, d is
3, Q is
H OH,
Rl i 5 hydrogen, R5 and R6 are hydrogen, W Ts
~C -
,' ~
HO H,
and ~ is alpha and bèta);
and 9-Deoxy-6~/ga-epoxy-pGFl~ Ethyl Ester,
Mixed Isomers (Formula IV as above except
~hat R1 is ethyl).
1. ReFer to Chart B. Q mixture of the -formula-XLII
aldehyde, namely 3,3a~,4y5,6,6a~-hexahydro-5a-hydroxy-2 -
(formylme~hyl)-4~-(3'a-hydroxy-trans-1-octenyl)2H-cyclopenta-
[b]furan, 3'5-bistetrahydropyran~2-yl ether (Example 6-1,
equivalent of 4 64 g.) and (~-carboxyethyl)triphenylphos-
3~ phonium chloride (see Howard S. Corey, Jr. et al.,J. AmO Chem.
-118-
~ 3~ 2720-1
SocO 86, 1884 (1964), 3.71 9.) in dimethylsulfoxide-tetra-
hydro-furan (1:1 ) i s added under nitrogen, with stirring, to
a slurry oF sodium hydride (0.84 g. o-f 57~) in the same sol-
vent system. The reaction is monitored by TLC and after
about 6 hr. water is added and the mixture ex~racted with
diethyl ether. The aqueous layer is mixed wi~h a suspension
of ammonium chloride (5 9 ) in 25 ml. of brine and the mix-
ture is extracted with ethyl acetate The organic phase is
washed with brine, dried with magnesium sulfate, and con-
centrated. The residue is subjected to silica gel chroma-
tography, eluting with ethyl acetate (25-50~)-hexane to
yield the formula-XLllltitle compound, as mixed isomers.
Ii. The -formula~XL!IIcompound above is reduced in
ethyl acetate solution wi~h hydrogen at sliyhtly above atmos-
pheric pressure in the presence of 5~ palladium-on-carbon
catalyst. The reaction is terminated when one equivalent
o~ hydrogen has been taken Wp. The catalyst is filtered
off and the formula~LlV compound recovered, as mixed isomers.
1ll Following the procedure of Example 7~, the tetra-
hydropyranyl groups~ are nex-t removed by hydrolysis in dilute
acetic acid at about 40 C. and the formula-lV title com-
pound recovered, as mixed isomers.
IV. The ~ormula-lV title ester is obtained by treat-
in~ the above acid in ethanol-diethyl ether solution with
diazoethane at abowt 25 C. for 15 min. and thereaFter
separating the product, as mixed isomers.
Examp!e 10 9-Deoxy-3,4-trans-didehydro-~,9~-epoxy-17-
phenyl-2,18,19,20-tetranor-PGF1, Methyl
Es-ter, Mixed Isomers (Formula Xl: Q is
-119-
2720-1
63~
H OH,
R1 is methyl, Rs and P~6 are hydrogen, s is
zero, ~ is
- C -
H0 H,
and Z i5 methylene).
:lO l~ ReFer to Chart C. A mixture of the formula-XXXVIII
2~,4~-dihydroxy-5~ 'c~-hydroxy~5'-phenyl-1'-trans-hepteny1)-
~-cyclopentylacetaldehyde-y-lactolJ 3~,4-bistetrahydropyran-
2-yl-ether (2.28 g.) and methyl 4-(triphenylphosphoranyli-
dene) crotonate (Buchta et al., Chem. Ber. 92, 3111 (1959),
3.46 g.) in 100 ml. ~f benzene is heated at reflux for 16
hr. The mixture is concentrated to a dark orange semi-solid.
The residue is subjected to silica gel chromatographyJ elut-
ing with acetone (5~)-dichloromethane to yield the bistetra-
hydropyran-2-yl ether of the title compound, a yellow oil,
1.55 g.
The abo~e material is hydrolyzed in acetic acid-
water-tetrahydrofuran (20:10:10) at about 42 C. for 4.5 hr.
Thereupon 50 ml. of water is added, the mixture is -Frozen~
and then freeze-dried. The resulting residual oll is sub
jected to silica gel chromatography, eluting with acetone
(30~)-dichloromethane/ to yield the formula-XI title com-
poundg mixed less polar and more poiar isome~, an oilg
0.444 g., having mass spec~ral peaks at 386, 368, 350, 324,
287, 277) 269, 233, 133, 105, and 91; in~rared absorption
3 peaks at ~390, 1720, 1655, 1600, 1445, 1455~ 1440, 1325g
-120-
2720-1
63;~
1275, 1215~ 1195, 1175, 1060, 975, 750 cm~l; ~nd NMR peaks
at 1.2-~.2, ~.7, 3.8-4.6, 5.4-5.65~ 5.7-6.1, 6 7-7.1, and
7.2 ~.
Example 11 9-Deoxy-6~,9~-epoxy-3-oxa-PGFl, Methyl Ester,
Mixed Isomers (Formula Vll: C9H29 is tri-
me-thylene, Q is
H OH,
R1 is methyl J R5 and R6 are hydrogen, W is
--C--
, ' ~
HO H,
and .~J is alpha and beta).
1. Refer to Chart E. There is first prepared the bis-
tetrahydropyran-2-yl ether of the title compound. A solu-
tion of the Formula-XLI 3,3a~,4,5J6~6a~-hexahydro-5~-
hydrc)xy-2~-(2'-hydroxyethyl-4~-(3~a-hydroxy-trans-1-octenyl)-
2~) '2H-cyclopenta~blfuran, 3',5-bistetrahydropyran-2-yl ether
(Example 5, o.80 g.) in 10 ml. of dime~hyl sulfoxide and
5 rnl. of tetrahydrofuran is treated at about 0-5 C. with
1.1 ml. of 1.6 M n-butyllithium in hexane added dropwise
over a one-minute period. Thereafter the mixture is stir-
red at about 10 C. for 5 min , followed by additions of
8 ml. of dimethylformamide and 0.~5 g. of lithium chloro-
acetate. The mjxture i5 stirred at about 25 C. for 22 hr.
then diluted with 125 ml. of ice and water containing ~ ml.
of concentrated hydrochloric acid The resulting mixture
extracted with dichloromethane and the organic phase is
- 1 2 1 -
27'20 - 1
3~
washed with cold water and brine, and concentra~d. The
residue containing ~he acid form of the formula-LIII bistetra-
hydropyran-2-yl ether, is conver-ted to ~he methyl ester
in diethyl ether by reaction with diazomethane. After 3
min., the excess diazomet,hane is destroyed with acetic
acid and the mixture is w3shed with dilute potassium hydrox-
ide solution and brine, dried, and concentrated ~o yield
the formula-LIII bistetrahydropyran-2-yl ether of the title
compound, as mixed isomers.
Il. The above ether is hydrolyzed in 15 ml. of acetic
acid and 7 5 ml. of water at 37-3~ C. for 2.5 hr. The
mixture is diluted with ice and water and extracted with
diethyl ether-dichloromethane (3:1). The oryanic phase is
washed with dilute aqueous potassium hydroxide and brine,
dried, and concentrated. The residue is subjected to silica
gel chromatography, eluting with 2-5~. methanol in ethyl
acetate, to yield the formula-VII title compound, as mixed
less polar and more polar isomers, 0.400 g., having NMR
peaks at 5.3-5.55, 4.01, 3.69, and 3.4-4.5; and mass spectral
peaks (for the TMS derivative) at 514, 499, 455, 443, 424, and
355.
Example 12 9-~eoxy-6~,9a-epoxy-PGF1 Methyl Ester, Mixed
Isomers, (Formula IV: CgH2g is trimethylene,
d is 3, Q is
/`
H OH,
Rl i5 methyl~ R5 and R6 are hydrogen, W is
HO H~
-122 -
2720-1
;32
and ~_ is alpha or beta);
and 9-Deoxy-6~ga-epoxy-pGFl~ ~ixed Isomers
(Formula IV: CgH2g, d, Q, R5, R~, W, and -~
are as above, and R1 is hydrogen).
I. Refer to Chart H. There is first prepared the
formula LXill halo compound. A solution of PGF2~, 11,15-
bistetrahydropyran-2-yl ether (2.1 9 ) in 10 ml. of
methanol is converted to the methyl ester with 20 ml of
a diethyl ether solution of diazomethane at about 25 C.
for 15 min. Thereafter the mixture is concentrated to an
oil The resulting 11,15-bistetrahydropyran-2-yl-PGF2~,
methyl ester (2.0 g.), suspended in 2~ ml. of water, is
treated with sodium bicarbonate (0.7 9.) and cooled in
an ice bath To the resulting solution is added potassium
iodide (1 93 g ) and iodine (2 28 9 ) and stirring continued
for 16 hr. at about 0 C. Thereafter a solution of sodium
sulfite (1.66 g ) and sodium carbonate (0.76 y.) in 10 ml.
of water is added. After a few minutes the mixture is ex-
tractecl with chloroform. The organic phase is washed with
brine, dried over sodium sulfate, and concentrated to yield
mainly the formula-LXIII iodo compound as the bis(tetra-
hydropyran-2-yl ether), mixed isomers, 2.2 g., an oil, hav-
ing Rf 0.75 (TLC on silica gel in A-IX system).
II. The ahove formula-LXIII 9-deoxy-6~,9~-epoxy-5-
iodo-PGFl, methyl ester, bistetrahydropyranyl ether (2.2 9.)
is dissolved in 15 ml. of benzene and treated with 15 ml.
of an ether solution of tributyltin hydride (freshly pre-
pared from tributyltin chloride and lithium aluminum hy-
dride and containing about 0.145 g. per ml.) added dropwise
over 20 min. after about 30 min an additional 20 ml. of
-123-
2720-1
ii3;2
tributyltin hydride in ether is added and stirring continued
for 1 hr. The reaction mixture is concentrated.
The residue above, largely the biste~rahydropyranyl
ether of the formula-Lxl~ methyl ester, is converted to
the title compound as follows. The oily residue is treated
with 40 ml. oF acetic acid-water-tetrahydrofuran (20:10:3)
for about 16 hr at 25 C. Then 250 ml. of toluene is
added and the mixture is concentratedJ repeating this
procedure again. The residue is again treated in 40 ml.
of acetic acid-water-tetrahydrofuran (20:10:~) at 40-45 c.
for 2 hr. J taken up in 250 ml. of toluene, and concentrated.
The residue is dissolved in 25 ml. of dichloromethane and
subjected to silica gel chromatography, eluting with ethyl
acetate (50-80~)-Skellysolve B. One fraction, 0.77 g., is
again subjected to silica gel chromatography, eluting with
acetone (20-40~)-dichloromethane, to yield the formula-lV
9-deoxy-6~9a-epoxy-PGF1 methyl ester, ~ixed isomers, O.lC) 9~,
having Rf 0.26 (TLC on silica gel in ethyl acetate);
~C~D~27 (chloroform)i NMR peaks at 0.9, 1.15-2.8, 3.3-4.4J
~.8, 4.6~ and 5.65-5.85 ~; and mass spectral peaks (TMS
derivative) at 512, 497) 481, 441, 391, 351~ 325g and 323;
and high-resolution mass spectral peak at 512.~3~.
Ill~ The formula~lV methyl ester above is converted
to the formula-lV acid as follows. A solution of the methyl
es~er (1.0 g.) in 30 mlO of methanol is treated with 20 ml.
of ~N. potassium hydroxide at about 25 C. for 1.5 hr.
Thereafter the mixture is acidified to pH 1 with 45 ml. of
2N. potassium hydrogen sulfate and diluted with 50 ml. of
water. The mixture is saturated with sodium chloride and
ex~racted with ethyl acetate. The organic phase is washed
~124-
2720 - 1
ii3;2
with brine, dried over sodium sulfate, and concentrated to
yield an oil containiny the formula-lV free acid, which
gradually crystallizes The product is subjected to silica
gel chromatography, eluting with ace~:one (30-50~)-dichloro-
methane, to yield the title compound, 9-deoxy-6~,9a-epoxy-
PGF1a, mixed less polar and more polar isomers, oO84 g.
melting 79.2-84.5 C.~ having infrared absorptions at 3340,
3220, 2620, 1715, 1695, 1360, 1320, lZ35, 1210, 1080, 990,
975, and 950 cm 1; [a][~+28 (Chloroform); and mass spectral
peaks (TMS derivative) at 555, 499, 480, 465, 409, and 173;
with high resolution mass spectral peak at 570.3569.
Following the procedures of Example 12, but replaci ng
the PGF~, 11,15-bistetrahydropyran-2-yl ether starting
material with the following formula-LXII compounds or
their C-ll and C-15 ethers, there are obtained the cor-
responding formula-LXIII iodo compounds:
15 Methyl-PGF2a
15-Ethyl-PGF2a
l6~l6-Dimethyl-pGF2a
16,16-Difluoro PGF2~
16-Phenoxy-17, 18J 19~20-tetranOr-PGF2a
17-PheI1Y1-18~ 19J20-trinor-PGF
11-Deoxy-PGF2,~
2a,2b-Dihomo-PGF
3-Oxa-PGF2a
3-oxa-l7-phenyl-l8,l9~2o-trinor-pGF2a.
Thereafter, following the reductive dehalogenation pro-
cedures of Example 12 and subsequent work-up of the product,
there are obtained the corresponding formula-LXIV pro-
ducts~ as mixtures ot less poiar and more polar isomers:
-12~ -
2'120 -:1
ii3~
9-Deoxy-6~,9a-epoxy-15-methyl-PGF
9-Deoxy-6~,9~ epoxy-15-ethyl-PGF
9-Deoxy-6~,9c~-epoxy 16,16-dimethyl-P(iF
9-Deoxy-6~,9~-epoxy-16,16-difluoro-PGFI
~-Deoxy-6X,9a-epoxy-16-phenoxy-17, 18,19,20-tetranor-
PG F ,
9-Deoxy 6~J9~-epoxy-17-phenyl-18,19,20-trinor-PGF
9-Deoxy-6~,9a-epoxy-11 -deoxy-PGF
9-3eoxy -6~, 9~-epoxy-2aJ2b-di homo-PGF
9-Deoxy-6~J9c~-epoxy-3-oxa-PGF
9-Deoxy-6~J9a-epoxy-~-oxa-17-phenyl-18,19J20-trinor~
PGFl.
Example 13 9-Deoxy-6~,9~-epoxy-PGF1, Methyl Escer,
Mixed Isomers (Formula IV: as in Example
12).
I. Refer to Chart H, and consider R4 on ~ and
Q2 to be hydrogen. There is first prepared the formula-
LXIII halo compound. A solution of PGF2aJ methyl ester
(9.0 g~) in 125 ml. of dichloromethane, cooled in an ice
bathJ is treated with anhydrous sodium carbonate (5.3 g.)
and iodine (6.35 y.) and stirred for one hr. Then it is
allowed to warm up to 25 C. while stirring for 16 hr.
The reaction mixture is diluted with 250 ml. of dichloro-
methane and then 100 ml. of 10~ aqueous sodium sulfite is
added. When the iodine color disappears the oryanic phase
is separated, and the aqueous phase is extracted with di-
chloromethane. The organic phases are combined9 washed
with brine, dried over sodium sulfate~ and concentrated.
The resulting oil, 13.5 g., is subjected to silica gel
chromatography, eluting with acetone (20-50~)-dichloro-
-126-
- 2720-1
32
methane, -to yield the formula~LXIII 9-deoxy-6~9a-epoxy-5-
iodo-PGF1, methyl ester, mixed isomers, 4-.76 g., haviny Rf
0.40 (TLC on silica gel in acetone-dichloromethane (3:7));
[a]D+22 (chloroform); mass spectral peaks (TMS derivative)
at 623, 567, 548g 517, 511, 477, 451J 521, 199, and 17~; high
resolution mass peak at 6~802314; and infrared absorption
peaks at ~380, 2960J 2940, 2860, 1740, 1440J 1365, 1230,
1195, 1175, 1075, 1055, and 1020 cm
ll. NextJ the formula-l~ title compound is prepared.
A solution of the above formula-LX~ 5-iodo compound (0.98 9.)
in 10 ml. of benzene is treated at about 15 C. with 5 mg.
of 2,2,azobis-(2-methylpropionitrile) and a solution Or
o.58 g. of tributyltin hydride in 4 ml. of diethyl ether
added dropwise over about 2 min. The mixture is allowed to
warm to about 25 C. while stirring for 1.25 hr. Another
portion of tributyltin hydride (o.58 g ) is added and
s tirring continued for 0.75 hr. The reaction mixture is
concentrated, then diluted with 25 ml. of Skellysolve B
and 25 ml. o~ water, stirred for 0.5 hr. and ~iltered
~0 thrt)ugh diatomaceous earth. The aqueous phase together
with aqueous washes of the or~anic phase, is mixed with
50 ml. of ethyl acetate, saturated with sodium chloride~
and stirred for 0.5 hr. The organic phase, together with
ethyl acetate washes of the aqueous phase and including
the solution in Skellysolve B, is dried over sodium sulfate
and concentrated. The resulting oil is subjected to silica
; gel chromatography, elutlng with acetone (25-50~)-dichloro-
methane, to yield the formula-lV title compound, mixed
isomers, o.48 g., having the same properties as the pro-
3v duct of Example 12.
-~27 -
2720-1
~ 3~
Example 14 9-Deoxy-6~,9a-epoxy-17-phenyl-18,19,20-trinor-
PGF1, Methyl Ester, Mixed Isomers (Formula
X: d is 3, Q is
~"
H OH,
R1 is methyl, R5 and R6 are hydrogen, s is
zero, W is
H0 H,0,
Z is methylene, and~ is alpha or beta).
I. Refer to Chart H. There is first prepared the
formula-LXIII 5-iodo compound. A solution of 17-phenyl-
18,19J20-trinor-PGF1~, methyl ester (2.3 g.) in 25 ml. of
dichloromethane, cooled in an ice bath, is treated with
anhydrous sodium carbonate (1.06 g.) and iodine (1.27 9.)
and stirred for one hr. Thereafter the mixture. is allowed
to warm to 25 C., with stirring for 16 hrO The reaction
mixture is diluted with 50 ml. of dichloromethane and
treated with '20 ml. of 10~ aqueous sodium sulfite. After
the iodine color has disappearedJ the organic phase,
together with organic extractions of the aqueous phase with
dichloromethane, is dried and concentra~ed to a pale
yellow oil, 2.64 g. The oil is subjected ~o silica gel
chromatography to yield the formula~XIII 9-deoxy-6~,9~-
epoxy-5-iodo-17-phenyl-18,19,20-trinor-PGFl, methyl ester,
mixed isomers, 1.57 g., having Rf 0.24 (TLC on sillca gel
in acetone-dichloromethane (3:7)); NMR peaks at 1.5-2.1,
2.1-2.8, 3.5, 3.66, 3 7-4.2, 4.3-4 69 5.4-5 7, and 7 2 ~;
3~ mass spectral peaks (TMS derivative) a-t 657, 582, 567, 545,
-128-
7, 455, 389, 337, and 259; and infraYed absorp-tion at 3390,
1735, 1600, 1495, 1455, 1435, 1360, 1305, and 975
II~ Next, the formula-X title compound is prepared.
A solution of -the above formula-L`~III 5-iodo compound (1.0 g.)
in 9 ml. of benzene is treated with 3 mg. of 2,2-azobis-
(2-methyl propionitrile) and to th~ cold mixture is added
10 ml. of an ether solution of tributyltin hydride (freshly
prepared and containing about 0.145 g. per ml.) drop-
wise over about 5 min. The mixture is allowed to warm
to 22-25~ C. and stirred for about 45 min. until the
reaction is shown complete by TLC. The mixture is concen-
trated and the residue stirred with 25 ml. of Skellysolve B
and 25 ml. of water for 0.5 hr. The aqueous phase, together
with aqueous washes of thC Skellysolvr- B layer~ ls saturated
with sodium chloride and extracted with ethyl acetate. The
organic phase, together with ethyl acetate extractions of
the aqueous phase, is dried and concentrated to an oil~
0.87 g. The oil is subjec-ted to silica gel chromatography,
eluting with acetone (20-50~) dichloromethane to yield
the ormula-~ title compound, mixed less polar and more
polar isomers, 0.568 g., havin~ Rf 0.17 (TLC on silica ~el
in acetone-dichloromethane 3O7); NMR peaks at 1.2-2.9,
3 . 69 ~ 3 . 7~4 . 6 r 5.4-5.65 r and 7.2 ~; mass spectral peaks at
5~l6, 531r 515r 456, 441, 432, 425, and others; and in-
frared absorption at 3400, 1735, 1495r 1450, 1435r 750
and others cm ~. ~
Example 15 5-~-Iodo-9-deoxy-6~,9~-epoxy-PGEl, Mixed
Isomers, (Formula LXIII: Rl6 is -COO~
A solution of the formula-L~III 5~-iodo-9-deoxy-6~,9~-
epoxy-PGFl, methyl ester, mixed isomers (Example 13,
-129-
jrc~
~6~3~ 2720-1
1.00 g.) in 25 ml. oF methanol is treated at ahout 0 C.
with 20 ml. of 3 N aqueous sodium hydroxide. ~fter 15 min.
the cooling bath is removed and stirring continued for 2 hr.
Crushed ice is added, together with aqueous potassium hydro-
gen sulfate to acidify The mixture is extrac-ted with
ethyi acetate and the organic phase is washed with brine,
dried over magnesium sulfate, and concentrated. The resi-
clue is subjected to silica gel chromatograpny using acid-
washed silica gel, eluting with acetone (40-100~)-methylene
chloride. There is obtained the title compound~ consisting
of mixed isomers~ having [~]D=~20 (C = 0 992 in chloro-
form); infrared absorption at 3360~ 2920, 2860, ~640, 1730,
1710, 1455, 1410~ 1380, 1235, 1185, 1075, 1050, and 970
cm~1; and mass spectral peaks at 696.25~4, 681, 625, 606,
569, 535, 479, and 173.
Example 16 (5S,6S)-5-Iodo-9-deoxy-6,9~-epoxy-PGF1,
Methyl Ester, Less Polar Isomer,
and (5R~6R)-5-Iodo-9-deoxy-6,9a-epoxy-PGFI,
Methyl Ester, More Polar Isomer (Formula
LXIII).
A suspension of PGF2~, methyl ester (3.0 g.) in 60 ml.
of water is treated with sodium carbonate (1.7 gO) and
cooled in an ice bath. To the resulting solu~ion is added
potassium iodide (2.7 9.) and iodine (4~14 g.) and s~irring
~5 continued for 3 hr. at about 0 C. Thereafter sodium
sulfit2 (2.5 g.) and sodium carbonate (0.8 g.) are added
to decolori~e the mixture. After a few mînutes the mixture
is extracted with chloroForm. The organic phase is washed
with hrine. ~rie~ over sodium sulfate, and concentrated to Yield the
nixed isomers of the title comPounds, an oil, which is further
-130-
~ 63~
puri~ied by ~ilica yel ehromato~rdplly, elUtill(J with me~hylelle
chloride (15-50%)-acetone to yield the less polar (55,6S)
title compound, 0.29 Y.J having R~ 0.44 (TLC on silica gel
in ethyl acetate); and the rnore-polar ~5R,6R) ti tle com-
pound, 3.~ y.~ having Rf 0.41 (TLC on silica gel in ethyl
acetate)0
Example 17 9-Deoxy-6,9~-epoxy-PGF1, Methyl Esterg less.
polar isomPr and more-polar isomer. (~ormula-
I V ) .
Refer to Chart H. A solution o-f the less-polar
isomer of the formula-LXIII iodo ether (Example 16~ 0.247 y,)
in ~ ml. of absolute ethanol is trea~ed with tributyl tin
chloride (0,12 g.) and then with a freshly prepared solution
of sodium borohydride (00050 g.) In ~ ml. of absolute
ethanol. After 45 min. the reaction mixture is diluted wi~h
ethyl acetate and wa~er, The organic phase is separated~
washed, dried~ and concentrated to an oil, 0.14 g., havTng
properties identical to those of the title compound, less-
polar isomer, of Example 3~, hel-einafter.
2() Likewise Following the a~ove proceclure but star~ing
with the more-polar formulalXIIIiodo ether, there is
obtained an oil~ 0.14 y., having properties idential to
those of the tltle compound, more-polar isomer, of
Exarnple 38.
Example 18 9-Deoxy-6,9a-epoxy-PGF1~ A~ide, less polar
and more polar isomers (Formula XXVIII).
I. Refer to Chart 1. There is first prepared the
formula-LXVI 5-iodo-9-deoxy-6,9a-epoxy~PGF1~ amide, less
polar and more polar isomers. A solution of the formula-
LXV io~o-ether acid, m;xed isomers (Example 15g 5.0 y,)
-131-
~ 32 2720-
in 50 ml. of acetone is cocled to about -10 C. and
treated wlth 3.0 ml. of triethylamine and 3.0 ml. of
isobutyl chloroformate. After 5 min. there is added 100
ml. of acetonitrile saturated with ammoniaJ and -the
reaction mixture allowed to warm to about 25 C. The mix-
ture is filtered, and the filtrate concentrated. The
residue is taken up in e-thyl acetate and water. The
organic phase is washed with water, dried over magnesium
sulFate and concentrated. The residue is subjected to
silica ~el chromatography, eluting wi-th acetone (25-
100~)-methylene chloride. There are obtained -the formula -
LXVIiodo-ether, amide, less polar isomer, .? 9., having
2f 0.40 (TLC on silica gel in acetone); a fraction of
mixed less and more polar isomers, 2.2 g.; and the more
polar isomer, 1.5 g., having Rf 0.37 (TLC on silica gel
in acetone), infrared absorption at 3250, 315OJ 1660,
1610, 1085, 1065, 1050, and 965 cm~1' and NMR peaks at
6.4, 5.5, 3.5-4.7 and 0.9 ~.
II. A mixture of the formula-LXVI 5-iodo-9-deoxy-
~` ~o 6~9a-epoxy-PG~l, amide,mixed isomers (Example 18-l above,
o.48 y.) in 15 ml. of ethanol is treated at about 25 C.
with about 0.5 ml. of tributyltin chloride and a mix-ture of
s~dium borohydride (0.10 g.) in 5 ml. ~f ethanol. The
reaction is followed by TLC (silica gel in acetone). A-fter
about 30 min. additional 0.75 ml. of tributyltin chloride
is added, and, after further stirring for 45 minO, 0.15 g.
of sodium borohydride is added. After an additional hour
the reaction is complete as shown by Rf = 0.49. The
; reaction mixture is diluted with ice and water and extracted
,o ~ith ethyl acetate. rhe organic phase is washed with brine,
-132-
2720-1
3;~
dried, and concentrated. The residue is subjected to silica
gel chromatogrc~phy, clutiny with ace~one (50-1()0~ llethylerle
chloride. There is obtained a Fraction consis-ting Or a mix-
ture of -~he less and more polar isomers, 0 17 g., and
another frac-tion consisting of the more polar isomer, 0.18 g.
The less polar isomer has Rf o.46 (TLC on silica gel run
twice in acetone). The more polar isomer has ~f 0.43 (TLC
on silica gel run twice in acetone), and infrared absorption
at 3275, 3060, 1680, 1640, 1610, 1300, 1275, 1225, 1160,
I0 1130, 1080, 1045, 970, 910, and 775 cm 1.
Example 19 9-Deoxy-6~,9a-epoxy-PGF1, Methylamide, mixed
isomers (Formula LXVli: one R18 is hydrogen
and the other Rl8 is methyl).
I. Refer to Chart 1. There is first prepared the formu-
la LXVI 5~-iodo-9-deoxy-6~,9a-epoxy-PGF1, methylamide, mixed
isomers. A solution of the formula-LXV 5'7;-iodo-9-deoxy-
6;`~,9a-epoxy-PGF1, mixed isomers (Example 15, 4.66 9.)
, . .
in 50 ml. of acetone is ~reated with 1.42 ml. of triethyl-
amine and cooled to -5 C. Thereupon 1.3 ml. of isobutyl
chloroformate is added, with stirring at 0 C. for 5 min.,
followed by 25 ml. oF 3M rnethylamine in acetonitrile. The
solution is stirred for 20 min. more as it warmed to
about 25 C. The mixture îs filtered and concentrated.
The oily residue is triturated with methylene chloride~
and filtered -~o remove a precipitate. The filtrate is
s~bjected to silica gel chromatography, eluting with
acetone (50-90%)-methylene chloride, to yield the 5~-iodo-
9-deoxy-6~,9~-epoxy-PGF1, methylamide mixed isomers, 3.45 9.,
h aving N~R peaks at 6.3, 5.4-5.7, 3.2-4.7, 2.78, and 0.7-
.65 ~.
-133-
2720-1
i3~
Il. A solution of the above formula-5~-iodo-9-deoxy-
6~,9~-epoxy-PGF1, methylarnide mixed isomers (o.67 g.) in
15 ml~ of me-thanol is treated at about 25 C. with 1.5 ml.
o-f tributyltin chloride and therea-fter with sodium boro-
hydride (0.35 g.) added portionwise within 15 minO Afterone hr. an additional 0.75 ml. of tributyltin chloride is
added and s~irring continued 16 hr. Then another 0.15 g~
of sodium borohydride is added and stirring continued for
15 min. The reaction mixture is diluted with
75 ml. of brine and extracted with ethyl acetate. The
organic phase is separatedg washed with brine, dried over
sodium sulfate, and concentrated. The residue is chroma-
tographed on silica gel,eluting with acetone (25-75~)-
methylene chloride, to yield the title compound as mixed
C-6 isomers, o.46 g., having mass spectral peaks at 511.3520,
and NMR peaks at 6.7, 5.3-5.7, 3.3-4.6, 2.76, and 0.7-2.6 ~.
Example 20 9-~eoxy-6~,9a-epoxy-PGF1, Benzylamide, mixed
isomers (Formula LXVII: one R18 is hydro-
gen and the other R18 is benzyl).
I. Refer to Chart 1. Following the procedures oF
Example 19 there is first prepared the formula-LXVI 5~-iodo-
9-deoxy-6~9a-epoxy-PGF1, benzylamide, mixed isomers. There
is used 4,66 g. of the formula-LXV 5~-iodo-9-deoxy-6~,9a-
epoxy-PGF1~ mixed isomers, and 1.o8 g. of benzylamine
instead of methylamine. The crude product is chromatographed
on silica gelJ eluting with acetone (50-70~)-methylene
chloride, to yield the 5~-iodo-9-deoxy-6~,9a-epoxy-PGF1,
benzylamide mixed isomers~ 4.1 g, having NMR peal<s at
7.3, 6.6/ 5.3-5.7, and 3.5-4.6 ~.
,o 11. Following ~he procedures of Example 19-ll, the
-134-
~'l2~
~36~63;~
above for~nula-LXVIcolllpound is treated with tributyltin
chloride an~ sodium borohydride until the reactiorl is com-
plete as shown by TLC. Silica gel chrornatography yields
the title colnpound as mixed C-6 isorners, 0.22 g., having
mass spectral peal<s at 659.4204, 644, 58~, 569~ 221, and
17~
Example 21 9-Deoxy-6~>9U-epoxy-PGF " Anilide, mixed
isorners (Formula LXVII: one R1~ is hydro-
gen and the other R1~ is phenyl)~
1() I. Refer to Chart 1. Following the procedures of
Exan~ple 19 there is first prepared the formula-LXVI 5~-iodo-
~-deoxy-6~,9~-epoxy-PGF1, anilide, mixed isolners. There
is used 4.vo y. of tne formula-LXV 5~-iodo-9-deoxy-6~,9~-
epoxy-PGFl, mixed isomers, and 0~94 g. of aniline. The
crude produc~ is chromatographed on silica gel3 eluti ng
with acetone (10-50%)-methylene chloride, to yield the
5~-iodo-9-deoxy-6~,9-epoxy-PGFl, anilide mixed isomers,
4.0 9., havi ng NMR peaks at 8. 4, 6,9 7~7, 5.3-5 7, and
,~.11-4.7 ~.
~n ll. Followin~ ~.he procedures of Example 19-ll, the
above formula-LXVI compound is treated with ~ributyltin
cllloride and sodium borohydride until the reaction is com-
plete as sho~n by TLC. Silica gel chromatography yields
the title compound as mixed C-6 isomers, 0.29 g., having
mass spectral peaks at 6450403~, 630, s74, 555, 540~ and
514.
Ex~lnpl~ ~2 5~-Bromo-9-deoxy-6~,9a-epoxy-PGFl, Methyl
Ester, mixed isomers (Formula LXIII)
and 9-Deoxy-6~;,9c~-epoxy-PGF~ lethyl Ester,
,.'~ ` Mi xed i somel-s ( Formu 1 a I V ) .
- 1 35 -
2720-1
63~
I. Re-Fer to Chart H . A solution of PGF~a, methyl
ester (1.00 9.) in 25 ml. o-f methylene chloride is
treated a-t about 0 C. with N-bromosuccinimide (0.50 g.)
added in portions within 3 min. After additional stirring
for 10 min. the reaction is complete as shown by TLC
(on silica gel in ethyl acetate). The solution is washed
with aqueous sodium sulFite and water, dried over magnesium
sulfate, and concen-trated. The colorless oily residue is
chromatographed on silica gel, eluting with acetone (20-
40~)-methylene chloride to yield the mixed isomers of the
formula-LXIII 5-bromo title compound, 1.~8 g., a colorless
oil, having mass spectral peaks at 575 2203, 559, 519, 511g
510~ 500~ 469, 429, 40~, 199, and 173; and having an NMR
spectrum essen~ially identical ~o tha-t of the correspond-
ing 5~.-iodo compound prepared by the method of Example 10,
viz.: 5.5, 4.55, 3.4-4.2, 3.65, and 0.9 ~.
II. Thereafter, Following the procedures of Example
13-II bùt replacing the formula-LXIII 5-iodo compound oF
that example with the formula-lXIII 5-bromo compound above,
theI^e is obtained the formula-lV title compound.
Example 23 9-Deoxy-6~,9a-epoxy-13,14-dihydro-15-deoxy-
PGF1, Methyl Ester (Formula XXXIV: Q2 is
H H
and X' is -GH2CH2--)
and 9-Deoxy-6~ 9a-epoxy-l3~l4-dihydro-pGF
Methyl Ester (Formula XXXIV: Q2 is
H OH
-1~6-
3;~ 2720-1
and X' is -CH2CH2-).
A solution of 9-deoxy-6~9a-epoxy-pGFlJ methyl ester
(Example 13, es-timated 10 mg.) in 3 ml. of m~thanol is
hydrogenated a~ atmospheric pressure in the presence oF
platinum oxide until the starting material is no longer
evident by TLC. There are obtained the title compounds:
the formula-XXXIV 15-deoxy compound having Rf o.60 (TLC on
silica gel in acetone-methylene chloride (~:7) and mass
spectral peaks at 426, 336, 311, and 221; and the formula-
XXXIV 9-deoxy-6~,9a-epoxy-1~,14-dihydro-PGF1, methyl ester
having Rf 0.24 (TLC on silica gel in acetone-methylene
chloride (3:7) and mass spectral peaks at 443, 425, 424J
414, 409, 399, 393, 353~ 334, 309, 267, 219, 199, 177, and
173.
Example 24 9-Deoxy-6~9a-epoxy-l5(s)-l5-methyl-pG
Amide, more polar isomer (Formula XXXI: R
i s O
-G-N(R18)2
wherein R 18 is hydrogen).
A solution of the formula-lV 9-deoxy-6,9a-epoxy-
15(S)-15-methyl-PGF1, more polar isomer (Example 40 ,
0.50 g.) in 10 ml. of acetone is cooled to about -10 C.
and treated with 0.3 ml. of triethylamine and 0.~ ml. of
isobutyl chloroformate. After 5 min. there is added 10
ml. of acetoni-trile saturated with ammonia, and the reaction
mixture allowed to warm to about 25 C. within 10 min.
The mixture is filtered, andlthe filtrate concentrated.
The residue is taken up in ethyl acetate, washed with
3C water, dried over magnesium sulfate, and concentratedO
-1~7-
2720-1
6~3~
The residue is subjected ~o silica gel chromatography,
eluting with acetone (40-100~)-methylene chloride, to
yield the title compoundg a colorless o~il, 0 43 9.,
having Rf 0.14 (TLC on silica gel in methanol-acetic acid-
chloroforrn (5:5:90)), having 4 2, and 0.9 ~, and infrared
absorption at 3360, 3220, 1670, 1620, 1460, 1410, 1380, 1225,
1125, 1075, 1060, and 975 cm~1.
Following the procedure of Example 24 , but starting
with the less polar isomer of 9-deoxy-699~-epoxy-15(S)-15-
methyl-PGF1 (ExampIe 40), there is obtained the less polar
isomer of 9-deoxy-6,9a-epoxy-15(5)-15-methyl-PGF1, amide
Example 25 5-~Chloromercurio)-9-deoxy-6~,9~-epoxy-16,16-
dimethyl-PGF1, Mixed Isomers (Formula LXIX:
G is chloro, L is -(CH2)3-, Q2 is
H OH,
R1 is hydrogen, R2 is
C~13
-C-(CH2)3-CH~,
CH3
is
~5 ~ ,
OH
and~ is alpha or be~a):
and 9-Deoxy-6~ 9a-epoxy-l6~l6-dimeth
-138-
2720-1
~ 6 3~
PGF1, Mixed Isomers (Formula IV. CgH29 is
trimethylene, d i 5 3, Q is
H OH~
R t ~ R5 and R6 are hydrogen; W j5
HO H;
and ~ is alpha or beta)
I Refer to Chart J. A solu-tion of 16,16-dimethyl-
PGF2~) 11315-bistetrahydropyran-2-yl ether (U.S. Patent
No 3,9Q3,131, Example 17J 1.02 9.) in 20 ml. of chloro
form is treated with a solution of mercuric acetate (1.15 9.)
in 40 ml. of acetic acid and left standing with light ex-
c luded for 5 hr Thereupon 70 ml. of toluene is added and
the mixture conce~trated. The residue is taken up in 75
m!. of diethy~ ether contacted with water and brine, dried,
and concentrated. The residue, an oil, which is largely
the bistetrahydropyranyl ether of the formula LXIX chloro-
r~etcllrio title compound, is treated with 50 ml of a mix-
ture of acetic acid-water-tetrahydrofuran (20:10:3) at
43 47 C. for 2.5 hr. Thereupon 40 ml. of toluene is added
and the mixture concentrated to yield the formula- LXIX
chloromercurio compound, an oily residue contatning the
; mixed isomers.
II. The residue from I above is dissolved in 10 ml.
of tetrahydro-furan and diluted with 10 ml. of water. To
3~ the mixture, while stirring, is added 10 ml. of aqueous 3M.
-139-
~ 3~ 2720-1
sodium hydroxide and 10 ml. of aquoues 0.5 M sodium borohy-
dride in ~M. sodium hydroxide. After additional stirring for
one min., the mixture is cooled in an ice bath and diluted
with 100 ml. ol` ethyl acetate and 1() ml of wa~er. There
is then added 12 9 of potassium hydrogen sulfate and solid
sodiùm chloride to saturation The aqueous phase is ex-
tracted ~ith ethyl acetate. ~he ethyl acetate solution is
combined with the organic phase, dried over sodium sulfate,
and concentrated. The residue, an oil, is subjected to
silica gel chromatography, eluting with methanol (1^11~)-
dichloromethane, to yield the formula-IV title compound~
mixed iso~ers, 0.180 9., having Rf 0 24 (TLC on silica gel
in A-IX system); NMR peaks at 0.8-1.1, 1.15-1085, 2.0-2.5,
3 5 3.9, 4.35-4.6, and 5 5-5 7 ~; and mass spectral peaks
(TMS derivative) at 441, 423, 383, 351, 325, 323, 307, 233
and 201.
Example 26 5 -(Acetatomercurio)-9-deoxy-6~,9a-epoxy -PGF
Mixed Isomers (Formula LXIX: G is
CH3C(O)O-, L is -(CH2)3-, Q2 is
H OH,
R25 is n-pentyl, (R22~ is
OH
R30 is -COOH, and,~ is alpha or be~a);
,5ù 5-(Chloromercurio)-9-deoxy~6~?,9a-epoxy-PGFl,
-140-
2720-1
~ ;3~
Mixed Isomers (Formula LXIX: as above except
G is chloro);
and 5 (Hydroxymercurio-9-deoxy-6~,9~-epoxy-
PGF1~ inner saltJ (Formula LX wherein L, Q2,
~ , R25 and ~ are as above).
I. Refer to Chart J. A solution of PGF2~, 11,15 -
bistetrahydropyran-2-yl ether (1.} 9.) in 30 ml. of chloro-
form is treated with a solution of rnercuric acetate (1.59 9.)
in 60 ml. of acetic acid and stirred with light excluded
for 5 hr. To the resulting clear solution is added 75 ml.
of toluene and the mixture is concentrated to yield the bis-
tetrahydropyranyl ether of the formula-Lxlx acetatomercurio
title compound. The residue is treated with 50 ml. of a
mixture of acetic acid-water-tetrahydrofuran (20:10:3) at
about 40 C. for 4 hr. Thereafter 40 ml. of toluene is
added and the mixture is concentrated to yield the formula-
LXIX acetatomercurio title compound, mixed isomers.
Il. The above bistetrahydropyran-2~yl ether of the formula-
LXlX acetatomercurio compound is tat<en up in a mixture
of diethyl ether-water and contacted with 20 ml. of brine.
The organic phase is clried over anhydrous sodium sulfate
and concentrated to yield mainly the bistetrahydropyranyl
ether of the Iformula-LXlX chloromercurio compound. The
residue is treated with 6.6 ml. of a mixture of acetic
acid-water-tetrahydrofuran (20:10:3) at about 40 C~ for
4 hr. Thereupon 20 ml. of toluene is added and the mixture
is concentrated ~o yield the formul3-LXIX chloromercurio
title compound: ~.0 9., an oil, soluble in ethyl aceta~e
or dichloromethane An analytical sample is obtained on
3~ subjecting the material to silica gèl chromatographyJ
-1~1 -
2720-1
i32
eluting wi~h ethyl acetate (50-100~)-hexane. The product~
mixed iso~ers, 0.256 9., an oil, has Cl:Hg atomic ratio 1:1,
and tnfrared absorption spectral peaks at 3360, 2660, 1720,
1705, 1305, 1225, 1185, and 1060 cm 1. An alternate name
for this chloromercurio compound is 14 Carboxy-1-
r~ 3a~,4,5,6,6a~-hexahydro-5~-hydroxy-4~-[( lE~ ~S ) -3-hydroxy-
1-octenyl~-2H-cyclopenta[a]furan-2~-yl¦butyl}chloromercury.
IIi. Refer to Char-t K. The above formula-LXiX chloro-
mercurio product is converted to the formuls-LX hydroxy-
1~ mercurio inner salt by dissolving it in 1 N. potassium hy-
droxide and precipitating with acetic acid. The product, a
waxy solid, is insoluble in water, very slightly soluble in
chloroform or dichloromethane, and soluble in hot methanol.
It is readily soluble in dilute potassium hydroxide thereby
forming the potassium salt of the hydroxymercurio compound.
Following the procedures of Examples 25 and 26~ but
replacing those starting rnaterials with the appropriate
tetrahydropyran-2-yl ether of PGF2~ or a PGF2~ analog, there
are obtained the formula-LXIX mercurio products iden-tified
2t) i n the tabie below as Examples 27-34.
TABLE
, _
Mercurio products of formula LXIX
(all having L equal to trimethylene
and Q2equal to ~0~ wherein
~ R3 OR 4
R4 is hydrogen ; Ex 27-32 having
equal to
\
OH
-142-
2720 -
3;~
TABLE (continued)
Examp l e G Rl R2 R3
27 chloro hydrogen phenethyl hydrogen
28 chloro methyl n-pentyl hydrogen
29 chloro n-octyl n-pen~yl hydrogen
3 chloro methyl 1,1-dimethyl
-pentyl hydrogen
31 ch l oro hydrogen phenoxy- hydrogen
methyl
32 , ~ chloro hydrogen n-pentyl methyl
(Examples 33-34 having ~ ) equal to ~ .)
33 chloro hydrogen n-pentyl hyclrogen
~4 acetatO hydrogen n-pentyl methyl
Exarnple 35 5-(Acetatomercurio)-9-deoxy-6~,9-epoxy-PGF1,
Methyl Ester, Mixed Isomers (Formula LXIX:
G , L, Q2, ~ J , R25, and,-~ are as de-
fined in Example 26, and R 3~ i 5 -COOCH3 ) .
3J ~ solution of the formula-LXlX acetatomercurio com-
-143-
L_ ~ ~ () 1
~66i3;2
pound of Example 26 in methanol-diethyl ether ~1:1) is
treated wi~h a solu~ion of diazomethane in diethyl ether
at about 25 C. for 5 min. The reaction mix-ture is con-
centrated to yield the methyl ester title compound.
Following the procedure of Example 35 but using in
place of the diazomethane, diazoethane, diazobutane,
and 1-diazo-2-ethylhexane, ~here are obtained the cor-
responding ethyl, butyl, and 2-ethylhexyl este~ of 5-
(acetatomercurio)-9-deoxy-6~J9a-epoxy-PGF~. in ~he same
manner, the methyl, ethyl, butyl, and 2-ethylhexyl esters
of 5-(chloromercurio)-9-deoxy-6~,9a-epoxy-PGF1 are pre-
pared. Likewise using each of the acids ;dentified in
Examples 39 and 40, hereafter, there are obtained the cor-
responding methyl, ethyl, butyl, and 2-ethylhexyl esters.
Example 36 5-(Acetatomercurio)-9-deoxy-6~,9~-epoxy-
PGF1, Methyl Ester, Mixed Isomers (Formula-
LXIX: G, L, ~2, ~ , R25, ~36 and ,
are as defined in Example 35)0
Refer to Chart J. A solution of PGF2~, methyl ester
(1.75 ~ ) in 25 ml. of tetrahydrofuran is treated with a
solution of mercuric acetate (3~5 9.) in 25 ml. of water
and 25 ml. of tetrahydroFuran and s~irred at about 25 C.
for 2 hr. The reaction mixture is concentrated and ex-
tracted with ethyl acetate. The organic phase is washed
with water, dried over magnesium sulfate, and concentrated
to the product, mixed isomers, an oil, about 4.0 g., having
NMR peaks at 5.5, 4.7, 3.8-4.6, 3 679 2~0 and 0.9 ~0
Example 37 5-(Chloromercurio~-9-deoxy-6~,9~-epoxy-PGF1,
Methyl Ester, Less Polar Isomer and More Polar
3u Isomer (Formula LXlX of Chart J: G is chloro,
-144-
2720-1
i32
L is -(CH2)~-~ Q2 is
H OH,
~R22~ is
~,~
.
OH g
R25 is n-pentyl,
R3~ is -COOCH3~ and ~ is alpha or beta).
The product is obtained from the acetato compound by
exchange of acetato with chloro. A solu~ion of the acetato-
mercurio compound of Example 36 (2.8 g.) i n 50 ml. methanol
is contacted with 25 ml. of bri ne at about 25 C. for 2 hr.
The mixture is concentrated to half volume and extracted
with ethyl acetate The extract is washed with brine,
dried over magnesi Ulll sulfate and concentrated to a residueJ
2.2 g. ThP residue is subjec~ed to silica gel chromatography,
eluti ng wi~h ethyl acetate (50 -loO~ ) -S kellysolve B to yield
~wo Fractions, one less polar and the other more polar.
The less polar consists o-~ the less-pG)lar isomer of the
title compound, waxy crystals, 0.33 g. J recrystallized
from ethyl acetate-hexane as colorless needles m. 60-1 CO
(sof~ening at 56 C. ), having Rf 0.47 (TLC on silica gel
25. in A-IX system); Cl:Hg atomic ratio 1:1; and infrared ab-
sorption bands at 3400, 1735, 1470, 1370, 1245, 1065, g70
and 890 cm . The more-polar isomer is an oil, 1.00 g.,
having Rf 0.41 (TLC on silica gel in A-IX system); Cl:Hg
atomic ratio l:li NMR peaks at 5.5, 308-4.7, 3.65, 3.2)
2 75, and 0.9 ~; ~a~D~14 (C=0.9015 in CHC13); mass sp~ctral
-145-
2720-1
3~
peaks (TMS derivative) at 7l~6, 675.1727, 656, 585, 511, 421,
199, and 173; and infrared absorption bands at 3450, 1740,
1435, 1370, 1240, 1045, 970 and 875 cm l.
Example 38 9-Deoxy-6,9(x-epoxy-PGF1, Methyl Es-ter, less-
polar isomer and more-polar isomer (Formula
I V ) .
Refer to Chart J. A solution of PGF2a, methyl ester
(0.73 g ) in 10 ml. oF tetrahydrofuran is treated with a
suspension prepared by mixing mercuric acetate (0.95 g ) in
:1.0 10 ml. of water wi th 10 ml. of tetrahydrofuran. The mix-
ture is stirred at about 25 C. for 2 hr. to yield the
formula~XlX 5-(acetatomercurio)-9-deoxy-6~,9a-epoxy-PGF1,
methyl es~er. Thereafter a solu-tion of sodium borohydride
(0.200 g.) i n 10 ml. of 1 N potassium hydro>cide is added
in portions within 3 min. Stirring is continued for 20
min. and die-thyl ether and bri ne are added The organic
phase is separated, washed with brine, dried over magnesium
sulfate and concentrated. The oily residue (o.66 g.) is
subjected -~o silica gel chromatography, eluting wi~h e-thyl
acetate (40-100~)-Skellysolve B. There is firs-t obtained
the formula- IV less-polar isomer, 0.070 9., then a
Fraction of mixed isomers., 0.112 g., and finally the
l`ormula-lV more-polar isomer9 0.250 g. The mixed-isomer
fraction is agai n chromatographed to yield approximately
one part of the less-polar isomer for every 2 par-ts of the
more polar isomer. The combined title compound less-polar
isomer is crystallized -from ethyl ace-tate as needles, m.p.
77-7r' C., having [a]D=~13 (C = 0.8245 in chloroform);
NMR peaks at 5.55~ 3.7-4.5, 3.7~ 4.5, 3.1~ 2.1-2.5, and
0.9 ~; and R.F 0.40 (TLC on silica gel in acetone-methylene
-146-
2720-1
3Z
chloride 1:1).
The combined fractions containing -the more-polar isomer
yield the title compound more-polar isomer which is crystal-
lized from diethyl ether-hexane, m.p. approximately 26 C.,
having [alD=-~23 (C = 0.9815 in chloroform); NMR peaks
essentially as for the less-polar isomer above; Rf 0.37
rLc on silica gel in acetone-methylene chloride 1:1); and
mass spectral peaks at 512.3356, 497, 481, 441, 391, and
173.
Example 39 9-Deoxy-6,9a-epoxy-PGF1, less-polar isomer
and more-polar isomer (Formula iV).
Refer to Chart J. A solution of PGF2c~ (2.0 g.) in
40 ml. of tetrahydrofuran is treated wlth a mixture of
mercuricacetate (3.7 g.), 30 ml. water, and 20 ml. of
tetrahydrofuran for 2 hr~, with stirring. Thereafter a
solution of sodium borohydride (0.75 g.) in ~0 ml. of 1 N
sodium hydroxide is added in portions within 3 min. After
15 min. the mixture is cooled and cautiously acidiFied with
dilute hydrochloric acid. Diethyl ether and salt (sodium
o chloride) are added. The organic phase is separated,
washed with brine, dried, and concen-trated to an oil, 2.5 g.
The oil is subjected to high pressure liquid chromatography
on acetic acid-washed silica yel, eluting with acetone
(20-65~)-methylene chloride at approximately 50 pounds
~5 per square inch (350 g./cm2). There are obtained four
main fractions: (1) the less~polar isomer of the title
compound, 0.26 g., (2) mixed isomers, 0.41 cg., (3) the
more-polar isomer, 1.01 g. and (4) recovered unreacted
PGF2~, 0.2 g The pure isomers are crystallized from
~0 e~hyl acetate-hexane The less-polar isomer has Rf 0.50
-1~7-
2720-1
3;~
(TLC on silica gel in A-IX system), m.p. 97-9 ~ , and
1 ~ ID--+13 (C = 1.061 in ethanol). The more-polar isomer
has Rf 0.45 (TLC on silica gel in A-IX system)~ m.p.
78-80 C, and LU ID=~31 (C = 1.031 in ethanol).
From each of the above isomers, by esterification
wi~h dia70methane, -there is obtained the corresponding
methyl ester having the same properties as that of the cor-
responding less-polar or more-polar methyl ester of Example
38.
Example 40 9-Deoxy-6~9cl/-epoxy-l5(s)-l5~methyl-pGF
less polar isomer and more polar isomer
(Formula IV).
~efer to Chart J. A solution of 15(S)-15-methyl-rGF2a (U.S. Pat.
No. 3,728,382) (2.94 9. ) in 50 ml . ~f tetrahydrofuran i s added
in portions within 3 min. to a stirred mixture of mercuric
acetate (52 g.) in 45 ml. of water and 30 ml. of tetra-
hydrofuran. After ~ hr. stirring, a solution of sodium
borohydride (1.1 g.) in 45 ml. of 1 N sodium hydroxide is
added in portions. After 15 min. the mixture i5 cooled
ancl treated with an aqueous solution of potassium hydrogen
sulfate to pH 6. Sodium chloride and diethyl e-ther are
adcIed, with stirring -for 5 min. The organic phase is
separated. The aqueous phase is further acidified to pH 3
and again extracted. The ether extracts are combined,
washed with brine, dried~ and concentrated to an oil, 3.5 9.
The oil is subjected to high pressure liquid chromatography
on acid-washed silica gel, eluting with acetone (40-60~)-
methylene chloride. There are obtainecl three main frac-tions:
(1) the less-polar isomer of the title compound, 0.29 9 ,
~~ (2) mixed isorners, 1.10 9., and (3~ the more-polar isomer,
- 1 11~3 -
u - 1
i32
1.71 g. Further chromatography o-f the mixed-isomer fraction
yields more of ~he less- and more-polar title compound.
There is ob-tained the less-polar isomer o-f the title com-
pound, 0.4~ g., having Rf 0. 43 (TLC on silica gel using
the A-iX system 2 times); [a1D=+9 (C = 1.036 in chloro-form)
NMR peaks at 5.77, 5.53, 4.42, ~.5 4.1, and 0.9 6; infrared
absorption a-t 3380, 2670, 1710, 1455, 1375, 1235, 1080 and
974 cm 1; and mass spectral peaks at 584.3748, 569, 513,
494, 479, 423, 378, 213, 203, and 187.
Likewise, there is obtained the more-polar isomer of
the title compound, 2.35 g., having Rf o.40 (TLC as above);
[a]D=~20 (C = 0.8130 in chloroform); infrared absorptîon
at ~400, 2650, 1710, 1~65, 1220~ 1085, 1055, and 975 cm 1;
with NMR and mass spectral data similar to those of the
less-polar isomer above.
Example 41 9-Deoxy-6,~,9a-epoxy~2,2-dj-fluoro-PGFl,
Methyl Ester, less polar isomer and more
i polar isomer (Formula XV).
Following the procedures of Example 38 but replacing
the PGF2~, me-thyl ester starting material with 2,2-difluoro-
PGF2~, methyl ester, there are obtained the title compounds.
Example 42 9 -Deoxy~6~;-,9a-epoxy-2,2-difluoro -16,16 -
dimethyl-PGF1, Methyl Ester, less-polar
isomer and more-polar isomer (Formula XV).
Following the procedures of Example 38 but replacing
the PGF2~, methyl ester starting material with 2,2-difluoro-
16j16-dimethyl-PGF2a, methyl ester (U.S. Patent No. 4,001,300,
Example 21) ~here are obtained the title compounds.
Example 43 9-Deoxy-6~,9a-epoxy-2,2-di fluoro-17-ph~nyl -
~0 1~,19,20-trinor-PGF1, Methyl Ester, less
-149 -
2720-~
63~
polar isomer and more polar isoIl~ r (ForIllula
XV) .
Following the procedures of Example 38 but replacing
the PGF2~, methyl ester s-tarting material wi-th 2,2-difluoro-
17-phenyl-18,19,20-trinor-PGF2c~, me-~hyl ester (U.S Patent
No. 3,987,o87) there are obtained the title compounds.
Example 44 9-Deoxy-6,9~X-epoxy-PGF1~ THAM Salt.
A solution of the more-polar isomer of ~he formula-
IV 9-deoxy-6~,9a-epoxy-PGF1 (Example ~3q, o.o88 g.) in
10 ml. of warm acetoni trile is treated while stirring,
with a solution of tris(hydroxymethyl)aminomethane (THAM)
(0.027 g. ) in 1 ml. of dimethyl sulfoxide. The mixture is
chilled until a thick gum separates. The supernatant solu-
` tion is decanted to yield the title compound, a gummy
solid, 0.10 9., haviny the same Rf in the A IX system as
the starti ng material.
Example 45 9-Deoxy-6~,9cl-epoxy-2,3;4-trinor-PGF1, Bis-
tetrahydropyranyl Ether, Mixed Isomers
(Formula IV: Q is
~0
Il OTHP,
and W is -Cj ).
THPO H
A solution of the formula - XXXIX 9-deoxy-6~,9a-epoxy-
2,3J4-trinor-PGF1, ethyl ester, biste-trahydropyran-2-yl
ether (Example 1, 3.7 g.) in 30 ml. of methanol is treated
wi-th potassium carbonate (1.0 y.) i n 1? ml. of water for
3') 16 hr. at about 25 C., with stirring. An additional 0.~ y.
- 150 -
'c~
ii63~
of potassium carbonate is added and stirring continued for
4 hr. Ice chips are added and -the mixture shaken with
diethyl e-ther-methylene chloride (3:1) and excess cold
dilute hydrochloric acid. The organic phase is separated,
washed with brine, dried, and concentrated to the lormula-
IV -title compound, 3.5 g.
Example 46 9-Deoxy-6,9~-epoxy-PGF~, Methyl Ester, 11715-
Diacetate, More Polar Isomer.
Acetic anhydride (5 ml.) and pyridine (5 ml.) are mixed
with 9-deoxy-6,9a-epoxy-PGF1, methyl ester, more polar
isomer (Example 38, 20 mg.) and the mixture is allowed
to stand at 25 C for 5-18 hr. The mixture is then cooled
to 0 C., diluted with 50 ml. of water, and acidified
with 5% hydrochloric acid to pH 1. That mixture is ex
tracted with ethyl acetate and the extract is washed suc-
cessively with 5~ hydrochloric acid, 5~ aqueous sodium
bicarbonate solution, water, and brine, dried and concen
trated to give the title compound.
Following the procedure of Example 46 but replacing
the acetic anhydride with propionic anhydride, isobutyric
anhydride, and hexanoic aci~ anhydride, ~here are obtained
the corresponding dieropionate, diisobutyrate and dihexan-
oate der7vatives of 9-deoxy-6,9a-epoxy-PGFl, methyl ester.
Example 47 9-Deoxy-6,9a-epoxy-2,3-dinor-PGF1, Methyl
~5 Ester, less polar isomer (Formula IV)o
1. Refer to Charts B and l. There is first prepared
the Formula-XLI hydroxyethyl compound. The less polar
isomer of 9-deoxy-6,9~-epoxy-2,3,4-trinor-PGF13 methyl
ester, formula XXXIX (Example 3, 0.50 g.) is trea-ted with
3 1.5 ml. of dihydropyran in 5 ml. of methylene chloride
-151-
2'720 -1
3~
together with ~.5 ml. of a saturatecl pyricIine hy~rochloride
solution in methylene chloride at about 25 C. For 16 hr.
There is added ~0 ml. of ethyl aceta~e and the mixture is
washed wi-th water and brine. The organic phase i5 dried
over magnesium sulfate and concentra-ted to yield 9-deoxy-
6,9~-epoxy-2,3,4-trinor-PGF1, me-thyl ester, bis(tetrahydro-
pyran-2-yl)ether, 0 75 g., having Rf o.67 (TLC on silica
gel in ethyl acetate-hexane (1~1)).
~ The above compound, in 8 ml. oF die-thyl ether, is
added to a slurry of lithium aluminum hydride (0.20 g ) in
25 ml. of diethyl ether and the mixture is stirred and
heatecl at reFlux -for 2 hr. It is cooled, treated with 0.~ ml.
of water added cautiously, followed by o.6 ml. of 30~
aqueous~ sodium hydroxide, stirred until gassing StOpSg then
filtered The filtrate is concentrated to yield the
formula-XLI compound, namely ~,3a~,4,5,6,6a~-hexahydro-5~-
(tetrahydropyran-2-yloxy)-2a-(2-hydroxyethyl)-4~-[(3S)-3-
(tetrahydropyran-2-yloxy)-trans-1 octenyl~2~-cyclopenta-
[b~furan, 0.70 g , having RF 0.34 (TLC on silica gel in
methanol-methylene chloride (5:95))
II. Step (a) oF Chart L, to prepare compound LXXXVI.
A mixtIlre of the product of part I (0 70 g.), 5.0 ml. of
pyridine, and p-toluenesulfonyl chloride (0.40 g.) is
stirred at about 25 C. for 5 hr. The mixture is diluted
with 50 mlO of diethyl ether, washed with cold dilute
hydrochloric acid) water, cold dilute potassium carbonate
solution, and brine, dried over magnesium sulfate, and
concentrated. The residue is chromatographed on silica
yel (Merck 40-6~ ~), eluting with ethyl acetate-hexane
JU (4:6) to yield the formula-LXXXVI tosylate, o~84 g. having
-152-
2~0-1
63~
Rf 0.58 and 0.62 corresponding to tetrahydropyranyl epimers
(TLC on silica gel in e-thyl acetate-hexane (4:6)).
Ill. Step (b) of Chart L/ to prepare the tosylate free
of THP blocking groups. A mixture of the product of part
ll (o.84 g. ) in 1~ ml. of acetic acid, 9 ml. of water3 and
2 ml. of -tetrahydrofuran is stirred at 40 C. -for 3.5 hr.
The mixture is cooledJ diluted with 125 ml. of cold (-10 C.)
ethyl acetate and washed with about lO~o sodium hydroxide
in an ice-water mixture, and brine, dried over magnesium
sulfate, and concentrated. The residue is chroMatographed
on silica gel (Merck 40-63 ~), eluting with ethyl acetate,
to yield the formula- LXXX Vll compound, namely
3,3a~,4,5,6J6a~3-hexahydro-4~3-[(~S ) -3-hydroxy-trans-1-octenyl 1-
5~-hydroxy-2a-(2-tosyloxyethyl)2H-cyclopenta~b]furan,
43 9 ~ having Rf 0.37 (TLC on silica gel in ethyl acetate);
NMR peaks at 7.71-7.85, 7.22-7.36, 5.38-5.52~ 3.63-4.23,
and 2.38 ~; and mass spectral peaks at 525.21~8, 596, 581,
506, 435, 409, 390, 173~ 155, and 91.
IV Step (c) of Chart L, to prepare -the formula-
`~0 LXXXVIII nitrile. A mixture of the product of part lll
(0 43 g~) and sodium cyanide (0 100 g~) in 4.3 ml. of
hexamethylphosphoramide is stirred at about 25 C. for
20 hr. The mixture is then diluted with ~0 ml. of ethyl
acetate, washed with water and brine, dried, and con-
centrated. Further washing of the residue redissolved in
ether, with brine, removes traces of hexamethylphosphor-
amide. The ether solution is dried and concentra-ted to
yield the formula-LXXXVIII nitrile, 0.~0 g., having Rf
0.51 (TLC on silica gel in acetone-methylene chloride
(1 1)); NMR peaks at 5.41-5.5~ and j.72-4.~5 ~; and mass
-15~-
2r2~J-1
63;~
Spectral peaI<s at 451.296~, 4~6, 3~0, 3~1, 3~4, ,>~0, ~6
gg~ and 173.
V. Step (d) of Chart L, to prepare the formula-
IXXXIX acid A mixture o-F the product of part IV (0.~0 g.),
3 ml. of 30~ aqueous potassium hydroxide, and 3 nll. o~
methanol is stirred while heating up to 100 C. in 4 hr.,
allowing the methanol to escape, then at 100 C. for addi-
tional ~ hr. The mixture is cooled, acidified wi-th co1d
dilute hydrochloric acid, and ex~racted with 30 ml. of
ethyl acetate. The organic phase is washed with brine,
~ried, and concentrated to yield the formula-LXXXlX acid~
namely 9-deoxy-6,9a-epoxy-2,~-dinor-PGF1, 0.24 9., having
Rf 0.3g (TLC on silica gel in acetone-methylene chloride
(1:1) containing 1~ acetic acid); NMR peaks at 6.48~ 5.42-5.5~,
and 3.63-~.35 ~; and mass spectral pealcs at 542.3244, 52~,
524, 471, 452, ~81, 362, 355, 337, 291, 175, 3nd 173.
Vi. Step (e) of Chart L~ to prepare the formula-LII
(or -IV) methyl ester. The product o~ part V (2.5 mg.) is
treated in ether solution witll excess diazomethane ~or S min.,
thereupon re~!oving the ether and excess diazomethane with
a s~ream of nitrogen. The res;due is chromatographed on
silica gel (~lerck 63-200 ~), eluting with acetone-methylene
chloride (1:1), to yield the title compound~ 1.5 mg.~ having
Rf 0.54 (TLC on silica gel in acetone-methylene chloride
` (1:1)).
Example 48 9-Deoxy-6,9~-epoxy-2,3-dinor-PGF1, Methyl
Esterg more polar isomer (Formula IV).
I. Refer to Charts B and L. Following the procedures
o~ Example 1~7 but replacing the less polar isomer of the
~ formula-XXXIX starting material with the more polar isomer
-15~
~ 6 3 ~ 2720-1
of 9-deoxy-6,9~-epoxy-2,3,4-trinor PGFI, methyl ester
(Example 3, 0.25 g.) and reducing other quantities propor-
tior-ally, there is obtained First the corresponding more
polar bis-THP ether, 0 37 g., having Rf 0.59 (TLC on silica
gel in e~hyl acetate-hexane (1:1)), and then the more polar
formula-XLI hydroxyethyl compound, 0.34 g., having Rf o.38
(TLC on silica gel in ethyl acetate-hexane (3:1)).
II. Tosylate LXXXVI is obtained, 0.43 g., having Rf
0.57 and 0.61 corresponding to tetrahydropyranyl epirners
(TL.C on silica gel in ethyl acetate-hexane (4:6)).
III. Tosylate LXXXVII, free of THP blocking groups,
is obtained, dS the more polar isomer, 0.29 g., having Rf
0.33 (TLC on silica gel in ethyl acetate), NMR peaks at
7.73-7,87, 7.26-7.40~ 5.44-6.57, 3.63-4.54, and 2.42 ~;
and mass spectral data similar to that for the less polar
isomer of Example 47-III.
IV. Nitrile LXXXVIII is obtained~ as -the more polar
isomer) 0,21 g., having Rf 0.50 (TLC on silica gel in
acetone-methylene chloride 1:1)); NMR peaks at 5.44-5.57
~0 and 3.42-~.67 ~; and mass spectral peak at 451.2953,
otheI-wise similar to da-ta For the less polar isomer of
Example 47-IV.
V. Acid LXXXIX, as the more polar isomer, is obtained~
0.18 g., having Rf 0.32 (TLC on silica gel in acetc,ne-
methylene chloride (1:1) containing l~o acetic acid; NMRpeaks at 6.50, 5.45-5.58, and 3.49-4.56 ~; and mass spectral
peak at 542.3292, otherwise similar to data for the less
polar isomer o-f Example 47-V.
VI. Methyl ester LII (or IV) is obtained, namely the
title compound, more polar isomer, 105 mg. from 2.0 mg. of
-155-
2720 - 1
3663~
the acid, having Rf 0.49 (TLC on si lica gel in acetone-
methylene chlori de (1:1 ) ) .
:lO
~0
'~
- 156 -
1~L53663~
SUPPLEMENTAI~Y DISCL(JSURE
The following examples are ~rovided for the
preparation of additional prostacyclin analogs falling
within the invention originally disclosed and claimed
and having pharmacological utility of the same kind as
the products of the examples of the principal disclosure.
Example 49 9-Deoxy-6-9~-epoxy-16,16-dimethyl-PGFI, less
polar and more polar isomer
(Formula IV: d is 3, CgH2y is trimethylene,
~ i s ~
H OH
R is hydrogen, R5 andR6 are methyl, and
W is
, C-
1. Refer to Chart J. The formula-LXIX 5-(acetato-
mercurio)-9-deoxy-6,9~-epoxy-PGFl compounds are first
prepared. A solution of the formula-LXVIII 16,16-dimethyl-
PGF2~, 11,15-bis(tetrahydropyran-2-~1 ether) U.S. Patent
3,954,833, 1.02 g.) in 20 ml. of chloroform is treated
witha solution of mercuric acetate ~1.15 g~) in 40 ml. of
acetic acid. The mixture is left standing in the dark for
5 hr. Then there is added 70 ml. of toluene and the mix-
tuxe concentrated. The residue is dissolved in 75 ml. of
cliethyl ether, washed with water and brine, dried, and con-
~ 157 -
1196632 2 7 20 -1 A
centrated. The resldue is deblocked in ~cet~c acld~
water-tetrahydrofuran (20:10:3) at about 45 C, for
2.5 hr. There ls added 40 ml. of toluene and the mlx-
ture is concentrated. The mlxed isomers have R~ ~.30
and 0.33 ~TLC on s~llca gel ln A-IX system).
II. ~he product of I above is dissolved ~n 70 ml.
of tetrahydrofuran and 10 ml. of water and treated with
- 10 ml. of aqueous 3M sod~um hydroxide and 10 mlO of
aqueous 0.5M sodium borohydride in 3M sodium hydroxide.
The m~xture is stirred at about 25 C. for one minute,
then cooled in an ice bath and treated with 100 ml. of
ethyl acetate, 10 ml. of water, 12 9. of solid potassium
hydrogen sulfate, and finally sodium chloride to satur-
ation. The organic phase is separated, dried, and con-
centrated to an oil. The oll ~ chromatographed on
sil~ca gel to yield the title compounds: less polar
isomer, 0.025 g. havlng Rf 0.28 (TLC on silica gel in
A-IX so~vent system), and more polar isomer, 0.18 9.
hav~ng R~ 0.24 (TLC on s~lica gel in A-IX)l high
resolution mass spectral peak (TMS derlvative 583.3656,
and ~nfrared absorption ~t 3~40, 1740, 1560, 14353 and
1365 cm` 1. The more polar isomer is named ~65)-16916-
d~methyl-PGI.
Example 50 g-Deoxy-699~-epoxy-16916-dimethyl-PGF,,
~ less polar isomer
~Formula IV).
I. Refer to Chart J and to Example 49. There are
first prepared the formul~LXIX 5-(acetatomercur~o)-9-deoxy-
6,9a~epoxy-P6F1 compoundsO A solution of 2.0 9. of
16,16-dimethyl-PGF2~ ln 40 ml. of tetrahydrofuran ls
~ :158 ~
~i'
6~6~2 2 7 2 0 1 A
added to a solution of 3.6 g. of mercur~c acetate ln
30 ml. of water and 20 ml. of tetrahydroPuran and the
mixture is stirred at about 25 C. ~or 2 hr.
II. The product of I above is treated with a
solutibn of 0.75 9. of sod;um borohydride in 30 ml. of
lN sod~um hydroxide and stirred at about 25 C. for
20 min. The mixture ;s acidified with 10% hydrochloric
acid, diluted with 100 ml. of diethyl ether, and saturated
with solid sodium chloride. The organic phase is separated,
washed with brine, dried, and concentrated. The residu~
is chromatographed on silica gel, eluting with acetone
(20-66%)-methylene chloride to yield the title compound>
purified by repeated chromatography, the less polar
isomer, 0.24 9., having Rf 0.55 (TLC on silica gel in
ethyl acetate-cyclohexane-acetic acid (20:30:1)), high
resolution mass spectral peak (TMS derivati~e) 583.3673,
and lnfrared absorption at 3400, 2680, 17109 1465, 1405,
1385, 1365, 1215; 1085, 1020, 1000, and 970 cm 1. The
less polar isomer is named (6R)-16,16-dimethyl-PGI1
There ~s also obtained the more polar isomer9 0.58 9.,
having R~ 0.47 in the same system.
Example 51 9-Deoxy-6,9~-epoxy-16,16-d;methyl-PGF1,
Methyl Ester, less polar isomer
,
(Formula IV).
The correspond~ng acid (Example 50) ls converted
to the title compound by reaction w~th excess ethereal
d~azomethane. The product is named ~6R)-16,16~dimethyl-
PGI~ 9 methyl ester.
Example 52 9-Deoxy-6,9~-epoxy~16,16-dimethyl-P~F1,
Methyl Ester~ more polar isomer
-- 159 --
2720-lA
~ 6 3 ~
(Formula IV: R1 1s methyl).
I. Refer to Chart H. There ~re flrst prepared the
formula-LXIII S-lodo compounds. A mixture o~ 16,16~
dimethyl-PGF2~, ~Pthyl ester (U.S. Patent No. 3,954,833,
1.85 g.) in 35 ml. of methylene dichlor~de and 35 ml. of
. saturated sodium b~carbonate9 cooled in an ice bath, is
treated wlth 1.42 9. of ~odine in 89 ml. of methylene
dtchloride, added over 15 min. The mixture ls stlrred
for one hr. The organic phase is separated, washed with
sodium sulfite and brine ~backwashed with chloroform~,
dried, and concentrated to an oi1, 2.94 g. The product
~s chromatographed on silica gel, eluting with ethyl
acetate (S0-100~)-Skellysolve~B to yield the mixed C-5
.isomers of the 5-iodo compound, 2.40 9. having Rf 0~37
lS (TLC on silica gel in ethyl acetate (60%)-hexane), in-
frared absorption at.342Q, 1735, 1260, 1230, 1195, lt70,
1090, 1075, lOS0, 1020, and 1000 cm 1, and NMR peaks at
3.65, 5.5, 4.5, and O.g~.
II. A solution of the product of I above ~2.40 9.
in 40 ml. of absolute ethanol is treated wlth 2.5 ml.
~f tributyltin chloride and a solution of 0~5 9. of
sodium borohydride in 20 ml. of absolute ethanol. The
mixture is stirred at about 25 C. for 2.5 ~r. There
. is then added, cautiously, dilute aqueous hydrochloric
acld until the m~xture ~s acld~c (pH about 3) and the
mixture i~s concentrated to about one-thtrd volume.
Water is added and the mixture is extracted wi~h ethyl
acetate. the organtc phase is washed with brine, dried~ .
- and concentrated~ The res~due ~s chromatographed on
sltica gel 3 elut~ng wtth ethyl acetate (33-100%)-
~ 160 -
.. . . .
~9~632 2 7 20 -1 A
Skellysolve B, to y~eld the t~tle compound, 1.01 9., hav-
~ng R~ 0.65 (TLC on s;llca gel in ethyl acetate), mass
spectral peaks (TMS derivatiYe) at 5~5.3411~ 509, 45~,
441, 419, 351, and 2019 lnfrared absorption at 3400,
1~40, 15~, 1460, 1435, 13809 ~360, 1240, 1200, 1175,
1055, 1020, and 970 cm~~ and N~R peaks at 5.5, 4.44, 3.65,
and 0.9 ~. This more polar isomer ;s named (6S~-16,16-
dimethyl-PGI1, methyl ester.
Example 53 9-Deoxy-6~,9~-epoxy-16-phenoxy-17,18,19,20-
tetranor-PGF1, Methyl Ester, less polar .
isomer and more polar isomer
(Formula X: d is 3, Q is
~ '
H OH
R1 is methyl, R5 and R6 are hydrog~n, s is
zero, W is
-C
,~
HO
and ~ is oxa (O))
The mixed isomers obtaîned following the paragraphs
followlng Example 12 are separated on s;lica gel ch~oma-
` tography. The less polar isomer is named (6R~-17,18,19,20-
tetranGr-16-phenoxy~PGI19 methyl ester~ The more polar
lsomer is named (6S)-17,18919,20-tetranor-16-phenoxy-
PGI 1 9 methyl ester.
xample 54 9-Deoxy^~,9Q-epoxy~PGF~, n~Butylamide
mixed lsomers
(Formula LXVII: Q2 is
- 161
.
.... .
27 2Or~
3~
~ o ~1 ~
one R1B jS hydrogen and the other ~s n-butyl 9
~ ~5 ~ .
. <~ ' ' ,.
OH
R25 is n-pentyl).
I. Refer to Chart I. There are first prepared the
formula~LX~I 5~iodo-9-deoxy-6~9a-epoxy-pGF~ n-butyl-
am~de, mixed ~somers. ~ solution o~ the formula-LXV 5~-
iodo-9-deoxy-6~,9~-epoxy-PGt,, mixed isomers (Example
15, 5.0 9.) in 50 ml. of acetone is treated with 2.0 ml.
~f triethylamine and cuoled in a methanol-ice bath.
lS There is then added 1.9 ml . of i sobutyl chl oroformate,
wlth stirring continued For 6 min., followed by 15 ml.
of n-butylamine in 20 ml. oF acetone. The mixture is
warmed to about 25 C. and stirred for 3 hr. The mix-
ture is concentrated. The residue is dissolved in ethyl
acetate, washed with water and brlne, dried, and con-
centrated. The residue is chromatographed on silica gel,
elut~ng with acetone (5-100~)-methylene chloride to
yield S.3 g., a dark oilO The product is separated from
~ colored ;mpurity by chromatography, to yield 4.8 9. of
25 the 5-iodo compounds.
II~ A solution of the above formula-LXVI 5~-iodo~
9 deoxy-6~'99~-epoxy-PGF1, n-butylamide mixed i~omer~
(0.~0 ~.3 in 25 ml. of ethanol ~s treated at about 25 G.
w~th about 1.0 ml. of trlbutylt~n chloride and 0.15 9. o~
~0 sod~um borohydride ~n 5 ml. of eth~nol. The react~on ~s
- 1~2 -
272~-~1A
6~
followed by TLC (sillca gel ~n acetone-methylene chlor~de
(1:1)~ After about 1.5 hr. the react~on nl~xture is
diluted with ice and water and extracted with ethyl
acetate. The organ~c phase ls washed with br-lne, dried,
S and concentrated. The residue ls chromatographed on
silica gel, eluting with acetone ~25-55%)-methylene
ch10ride, to yield the t~tle compounds, 0.60 9. having
Rf 0.62 (TLC on silica gel in acetone~, high resolution
mass spectral peak a~ 553.3993, and infrared absorption
peaks at 3300, 3100, 1740, 1715, 1645~ 1555, 1460, 1375,
1330, 1070, 1055, and 965 cm '
Example 55 (5S)-13,14~ ehydro-PGI1
(Formula XXXIV: L is trimethylene, Q2 is
H OH
(~) is
HO
R2~ is n-pentyl, R30 is -COOH, and X'is
-C C ~ and its Methyl Ester.
~P.t~
~, I. Refer to Chart N~ There are first prepared the
formula-XCV 9-deoxy-6(R and S~, 9~-epoxy-14-bromo-PGF1~
methyl esters. Starting with a solutlon of the formula-
XCIII 14-bromo-pGFaa~ methyl ester (Preparation 2, 1.02 9.)
in 10 ml. of tetrahydrofuran, that solution is treated
with a suspension of mercuric aoetate (1.8 g.) in water
114 ml.~ and tetrahydrofuran (8.5 ml.) at about 25 CO
for lS min~ The suspension is cooled ln an.lce-bath and
-- ~63 --
~ 3~ 272~-lh
treated dropwlse with a solut~on of sodium borohydrlde
(0.65 9.) ln lN sodiuln hydrox~de (6.5 ml.), The mlx-
ture is d~luted wlth diethyl ether, decanted from mercury,
washed ~ith water, dried, and concentrated to give the
mixed C-6 isomers. The isomers are separated by silica
gel chromatographyl rluting w~th methylene chloride-
acetone (85:15) to yield fîrst the 6R compounds, 0.183 9.
having Rf 0.3~ (TLC on silica gel in methylene ch1Oride-
acetone ~3:1), infrared absorpt~on at 1040, 1075~ 10~0,
1170, 1195, 1710, 1740, and 3300 cm 1, NMR peaks at 0.90,
1.05-3.1, 3.65, 3.5-4.25, and 5.79 ~, and mass spectral
peaks (TMS derivative) at 590.2450, 575, 551, 519, 511~ 500,
421, 403, 384~ 305, and 173.
An intermediate fraction, 0.20 9., is obtained, fol-
lowed by the 6S compound, 0.452 g. ha~ing Rf 0.31, infr~-
red absorption at 1040, 1095, 11609 1710, 1740, and
330~ cm 19 NMR peaks at 0.89, 1.05-3.1, 3.65, 3.5-4.25,
4.43, and 5.585 ~, and mass spectral peaks at 590.2440
and as found for the 6R compound.
II, The formula-XCVI ¦6S)-13,14-didehydro-PGI1 is
o.btained by treating the formula-XCV 6S ;somer of I
above (0.2~5 9.) in 10 ml. of methanol with 5 ml. of
lN aqueous sodium hydroxide at 25 C. for 20 hr. The
solut~on is cooled and acid~fied with cold, dilute
~5 phosphor;c acid. The m~xture is extracted with diethyl
ether-ethyl acetate ~2 1)o ~he organic phase is washed
~th 5% sodium chloride, dried, and concentrated to give
the a~id of the fnrmula-XCV 14-bromo compound, 0.24 g.,
having Rf 0.36 (TLC on slllca gel in Solvent A, i.e.
~0 the orJanic phase from ethyl acetate-acetic acid-
cyclohe~ane-water (9:2:5:10)), and lnfrared absorption
- 164 _
~,
6 3Z 2720~1A
950, 1045, 10~0,'1100, 1240, 12~0, 1710, 2650-3100,
and 3400 cm '. .That ac1d ls treated 1.n solut~on ~in
lo ml ~ of dimethylsul~oxide and 1.0 ml. of methanol)
with potassium tert-butoxide ~0.31 9.~ at about 25 C
for 26 hr. The solution 1s diluted wlth cold water,
acidified with 0.2 M potassium hydrogen sulfate and
extracted with diethyl ether ethyl acetate (2 1~o The
organic phase is washed with 5% sodium chloride, dried,
and co.ncentrated to.yield t.he formula-XXXIV title com~
pound, 0.225 g., having Rf 0.43 (TLC on s;lica gel in
solvent A), infrared absorption at 1)55, 1030, 1095,
1710, 2220, 2550-3100, and 3350 cm 19 NMR peaks at 0.90,
1jO5-2.9, 3.96, 4.21, and 6.38 ~, and mass spectral peaks
(TMS derivative) at 568.3420, 533, 497, 478, 463, 407,
395~ 388, 362, 173, and 117.
The above acid is converted to the methyl ester by
reaction with excess ethereal diazomethane. The product,
(6S)-13,l4-didehydro-PGI1, methyl ester, has Rf 0.59 in ~.
ethyl acetate, in~rared absorption at .lOlS, 1045, 1065,
? logo, lliO, 1725, 1740~ 2220, and 3400 cm 1, NMR peaks
at 0.90, 1.1-2.~, 3.45, 3.65, 3.65-4.2, and 4.2-4.65 ~,
and nlass spectral peaks at 510.3209, 495, 479, 439, 4209
395, 337, 330, 323, 313, 3049 225, and 173.
.~ . Example 56 (6R)-13,14-Didehydro-PGI
( Formul a XXXI V
and its Methyl Ester.
. Following the procedures of Example 55 but start;ng
w~th the correspondlng formula-XCV 6R isomer9 na~ely
9-deoxy-(6R), 9a~epoxy-l4-bromo-pGFlN~ methyl ester
(Example 55, 0.76 9.) there ~s obtained the corresponding
- 165 ~
,
, .
~1~663Z 2 7 2 0 - 1 A
ac~d of the 14~bromo compound, 0.14 g. having Rf 0.40
~n solvent A, and subsequently the tltle compound,
0.11 9., having Rf 0.53 in solvent A9 lnfrared absorption
at 1020, 1050, 1075, 1225, 1710, 1725, 2220, 2600-2800,
S and 3350 cm ', and NMR peaks at 0.90, 1.1-2.9, 3.66,
and 4.33 ~,
The above acld ls converted to the methyl ester by
reaction with excess ethereal diazomethane. The product,
(6R)-13,14-d1dehydro-PGI1, methyl ester~ has Rf 0.67 in
ethyl acetate, infrared absorption at 1010, 1050, 1070,
.1080, 1095, 1155, 1170, 1725, 1740, 22~0, and 3400 cm 1,
NMR peaks at 0.90, 1.1-2.9, 3.5-4.0, 3.65, and 4.0-4.55 ~,
and mass spectral peaks at 510.3193, 495, 479, and others
.
found for the 6S compound of EXample 55.
Example 57 (6S,15R~-13,14-Didehydro-PGI
- ~Formula XXXIV: Q2 is
H OH~
and its Methyl Ester.
Following the procedures o~ Example 55 but employlng
the corresponding 14-bromo(15R)-PGF2~, methyl ester
(~ig~)
~Preparation '~ there are obtained the title compounds,
The formula-XCV 9-deoxy-6(R and S), g~-epoxy-14-bromo-
(lSR)-PGF1~, methyl esters are ~;rst prepared and
- separated by chromatography. The 6R isomer ls less polar
and has Rf 0.63 in methylene chlorlde~acetone (7:3~ com-
pared w~th 6S isomer wlth R~ 0055. The 6R ~somer has
NMR peaks at 0.89, 1.05-3.2, 3.6fi, 3.4~4.2, and 5.80 ~
and mass spectral peaks at 59002452, 575~ 559, 5191 and
others. The 6S tsomer has NMR peaks at 0.89, 1.1-3.5,
3.65~ 3.6 4.35~ 4.46, and 5090 ~. The correspondlng
~cids are prepared as in Example 55, us~ng a methanolic
7` 1~6~- .
~,.~ .~ . .
!
2720~1A
6~2
solut~on containlng sod~um hydroxide.
The acld (6S) title co~pound ls obtalned by dehydro-
halogenation w~th potassium tert-butox~de. The formula-
XXXIY acid has R~ 0.32 in methylene chloride-acetone
(7:3~ conta~nlng 0.2% acetic acid, infrared absorpt;on
at 1710, 2220, 2550, and 3400 cm 1, NMR peaks at 0.90,
1.08-2.90, 3.60-4.209 4.20-4.71, and 4.90-5.85 ~, and
mass spectral peaks at 568.34149 553, 497, 478, 4639 395,
388,.381, and 173.
The methyl ester title compound i5 obtained by
reaction of the acid with excess ethereal dia~omethane,
The product has Rf 0.60 in methylene chloride-acetone
(7:3) contain;ng 0.2% acet;c acid, infrared absorption
at 1735, 2220, 2850, 2930, and 3400 cm 1, NMR peaks at
0.90, 1.08-2.75, 3.30-3.62, 3.67, 3.68-4.22, and 4.22-
4.73 ~, and mass spectral peaks at 510.3193, 495~ 479j
43~, 420, 395, 32~, 305, and 173.
Example 58 (6R~l5R)-l3~ Didehydro-pGI
(Formula XXXIV: Q2 is
, ~
H OH
~nd its Methyl Ester.
~ollowing the procedures of Example 55 but employ-
lng t6R,15R)-14-bro~o PGI~ (Exan.ple 57~ and dehalogenating
-25 that compound with potassium tert-butoxide9 the acld (6R)
t~tle co~pound is obta~ned, havlng ~f 0.40 in methylene
chloride~acetone t7:3) containlng 0.2% acetic acld,
~nfrarc.~ absorption at 17109 222( 9 2650, 28509 2930,
and 3400 cm ~9 NMR peaks at 0.90, 1.0~-3,0, 3~45~3.95,
3.95-4.539 and 5.08 ~, and mass spectral peaks at
1 6 7 -
. ~
2 7 2 0 - 1 A
32
568.3419~ 553, 4977 478, 463, 395, 388, 371, 3629 and
173.
The corresponding methyl ester is obtained by re~
ac.tlon of the acid above wlth excess ethereal diazo-
methane and conventional recovery.
Example 59 Trans-~-PGI1, Methyl Ester9 less polar
isomer and more polar isomer
(Formula XXXIiI: . D' is
H~C-C~
Q2 is
H OH
' ~is
H~
R25 is n-pentyl, and R30 is -COOCH3).
(~.18'1),
I. Refer to Chart 0~ The formula-XCVIII phenyl-
selenidyl ethers are prepared by starting with the
formula-XCVII compounds as their 11,15-bis~-butyldi-
mèthylsilyl)ethers. There are prepared from the mixed
PGI1 isomers (Example 17) by reaction with hexamethyl-
d~s~lazane and trimethylchlorosllaneD
A solut~on of these PGI1, methyl esters9 bis(s~lyl
ethers) (1.425 g.) ~n 20 ml. of tetrahydrofuran ~s added -
to a ~ixture of isopropylcyclohexylamine ~1.17 g.),
30 ml. of tetrahydrofuran and n-butyllithium (4.7 ml.
of 106 M ln hexane) prepared at ~78 C. an~ stlrred after
16~ - -
. ~.
2720~1A
32
the add~t~on at -7B C. for 0.5 hr. after which a solu-
t~on of dlphenyl d~selenide (1.76 9. ) ln 15 ml. of
tetrahydrofuran ls addedO The m~xture ~s stlrred further
at -78 C. for one hr., warmed to 0 C. and poured ~nto
150 ml. of saturated aqueous ammonium ch1Orlde and 150 ml.
of d~ethyl ether. The organic phase is separated, washed
' with ice water and brine, dried~ and concentrated. The
re,sidue is separated by high pressure liqu;d column
chromatography~ using 3 Merck "B" columns in series and
eluting with benzene-ethyl acetate (40:1) to yield the
formula-XCVIII phenylselenidyl ethers as mixed C-6
i'somers1 havin~ Rf 0.52 and 0.48 (TLC on silica gel in
benzene-ethyl acetate (2Q;l)), and NMR peaks at 7.S5,
7.30, 5.45, 4.50-3.40, 3.60, 2.50-1.10, 0.90, and 0.03 ~.
. II. ~he formula-XCIX bis(silyl ethers) of the tltle
compounds are next obtained by oxidative el;mination of
phenylselenide from the above compounds. Following the
procedures of Example 60, the product of I above-
(0.964 9.) y~e'lds 0.707 9. of trans-~2-PGI1, methyl
'20 ester, 11,15-b~s(t-butyldimethylsilyl ether), mixed
~somers having Rf 0~41 and 0.39 (TLC on sil;ca gel in
benzene-ethyl acetate (20il~), and NMR peaks at 6.90,
5.90, 5.63, 5.42, 4~50-3.50? 3.64, 2.50-1.10, 0.90, and
0.02 ~.
III. The formula-XXXIII title compounds are ob-
ta~ned'on deblocking the above compounds and separat~ng
the C-6 isomers by chromatography. The product of I I
above (0.707 9.) in 6 ml, of ~el;rahydrofllran is treated
with tetra~n-butylammon~um fluor~de ~3.5 ml. of 1.2 M
solut~on ~n tetrahydrofuran)at about 25 C. for 19 hr.
~ ~'Sg
;", ~.
2720-lA
32
the m~xtur~ 1s dlluted with 250 ml. of ethyl acetate,
washed w~th brine, dr~ed, and concentrated to an o~l.
The o11 is separated by hiyh pressure l~quid column
chromatography using 3 Merck "B" columns in series,
eluting w~th methylene chlor~de-acetone (1:2). There
are obtained the less polar lsomer, 0.125 9., haviny
m.p. 69-71.5 C., and NMR peaks at 7.00, 5.97-5.70,
5.50, 4.35-2.90, 3.68, 2.50-1.10, and 0.90 ~, and the
more polar isomer, 0.09 g., ha~ing NMR peaks at 7.00,
5.97 S.70, 5.50, 4.43, 4.l7-2.90, 3.68, 2.60-1.10, and
0.90 ~.
Example 60 Trans-~2-lÇ,16-dimethyl-P~I1, Methyl Es~er
less polar isomer and more polar isomer
. (Formula XXXIII.: D' is
~C~C~
-CH2~ H 5
Q2 ~s
H OH
~3is
~ '
\~
~0
RaS ls C~CH3)2~(CHa)3~CH3~ and R30 ~5
COOCH 3 .
Io Refer to Chart J. There is first prepare~
the ~ormula-LXVIII 16,16-dimethyl PGF2a9 methyl ester,
11 915-bls(tetrahydropyr~n-2-yl et~er)~ A solution
~f 16,16-d~methyl PG~, 11,15-b~s(tetrahydropyran-2-yl
ether) (7.63 9.~ 1n 180 ml; of aeetonltr~le ~s rn~xed
- 17~ -
. ...
3~ 2720 lA
w~th dlisopropylethylam~ne ~4.47 9.) and treated w~th
methyl lodlde (29.54 9.) at about 25 C. ln the dark
for 25 hr. The reactlsn mixture ls then poured into
500 ml. of brine and extracted with diethyl ether. The
S organic phase ~s ~ashed with ice water, dilute sodium
th~osulfate, and brine, dr~ed, and concentrate~ to
yield the formula-LXVIII methyl ester, 7.61 g. having
~nfrared absorption at 3400, 2900, 1730? 1430, 1350,
1190, 1120, 1070? 10101 975, 900, 865~ 810, ~nd 725 cm 1
and NMR peaks at 5.80-5.02, 4.85-4.47, 4.26 3.179 3.63, 2.78-
l.OS, and 0.88 ~.
II. The formula-LXIX acetatomercurio compounds
are prepared from a solution of the product of I above
(7.0 9.) in 30 ml. of tetrahydrofuran added dropwise to
an ~ce-cooled yellow suspension of mercur~c acetate
(5.92 9.) in 24 ml. of water and 24 ml. of tetrahydro-
furan, followed by stirring at about 25 C. for 2 hr. The
mixture is then poured into an ice-cold solution of
sodium borohydride ~2~83 9.) ir 74.4 ml. of 1 N hydroxide
and stirred for 10 min. The mixture is diluted with
750 ~1. of brine and extracted with diet~yl ether.
The organic phase is drie~, Filtered9 and concentrated
to an oil. The oil is chromatographed on sil;ca gel
eluting with ethyl acetate-Skellysolve B (1:3) to yield
the formula-LXX 16,16-d~methyl-PGI1, methyl ester, 11,15
bis~tetrahydropyran-2-yl ether) mixed isomers, 5.65 9.,
a colorless oil hav~ng Rf 0.44 (TLC on s;l;ca gel in
ethyl acetate-toluene (1:3)), infrared absorption a~
295~9 17309 1430, 13709 1340, 1310, 1250, 1190, 1125,
1070, 1020,~975, 9109 905, 8659 815, 730~ and 705 cm '
~ ~71`~-
~,
~720-lA
32
and NMR peaks at 5.71-5.32~ 4,~5-4.539 4.53~3.04, 3.64,
2.72-1.05~ and 0.87 5.
III. Refer to Chart 0. The formula-XCVlII phenyl-
selerl~dyl ether is prepared by add;ng a solution of the
-5 formula-XCYII compound of II above (5.03 9.) in 50-ml. of.
tetrahydrofuran to a mixture o~ diisopropylamine~ (1.08 g.~
in 125 ml. of tetrahydrofuran and n-butyllith~um (6.54 ml.
o~ 1.5 M solution of hexane~ prepared at -78 C. and
- stirred after the addltion at 78 C. for 1.2 hr. after
which a solution of phenyls21enyl chloride (1.79 ~.) in
30 ml, of tetrahydro~uran is added dropwise over a 7 min.
period. The resultin~ mixture is stirred further ~t
~78.C. for 1.25 hr., then poured into a mixture of
300 ml. of saturated aqueous ammon;um chlor1de and 400
ml. of ice-water and extracted with diethyl ether. The
organic phase is dried and concentrated. The res~due is
chromatographed on silica gel, elu-ting with ethyl acetate-
. toluene (1:8) to yield the formula-XCVIII compounds,
mixed C-6 isomers, as an oil, 3.01 9., havlng Rf 0.53
(TLC on silica gel ~n ethyl acetate-toluene (1:3)), in-
frared absorptlon at 2950, 1730, 1570, 1530, 1360, 1310
1230, 1200, 1130, 1070, ~02~, 975, glO, 905, 870, 815,
740, and 690 cm 1, and NMR peaks at 7.78-7.48, 7.45-7.[69
5.74-5.27, 4.84-4.53, 4.53-3.17, 3.62, 2.66~1.06, and.
~5 0085 ~.
IV. The formula-XGIX bisttet~ahydropyran-~-yl ethers~
of the t~tle compounds are next obtained by oxidative
elimination.of phenylselenlde from the ~ormula-XCVIII
; compounds. The product of III above (3.01 g.~ ln
65 mlc of methylene chloride ~s treated with hydrogen
172 -
. ~; '
2720-lA
,
~6~3~
peroxide (0.99 g. as 10% ~queous solution) at about
25 C. for one hr. The layers are separated and the
organlc phase ls washed with 5% sodium bicarbonate,
saturated a~ueous sodlum bicarbonate7 and brine~ dr~ed,
and concentrated tG an oil, 2.40 9. The o~l is chroma
tograph~d on silica gel, elut1ng with ethyl acetate-
SkellysolYe B (1:3), to yleld the formula-XCIX compounds,
mlxed C ~ isomers, 1.86 g., having infrared absorption
at 2~50, 1730, 1660, 14~0, 1380, 1310, 1260, 1200, 112Q,
1070, 1020, 975, 905, 870, and 830 cm 19 and NMR peaks
a~ 7.38-6.73, 6.06-5.29, 4.85-3.14, 3.72, 2.75-1.06,
and 0.88 ~.
Y. The formula-XXXIII title compounds are obtained
on deblocking the above compounds and separating the C-6
isomers by chromatography. The product of IV above
~1.86 9.) is hydrolyzed in acetic acid-water-tetrahydro-
furan (~0;10:3) at about 40 C. The reaction mixture
is then poured into brine and extracted with ethyl
acetate. The organic phase is washed with ice water,
2~ dried, and concentrated to the mixed isomers of formula-
O and o~l, 1.54 g. The oil is separated by high presure
l~quid column chromatography using the Merck "B" columns
~n series and eluting with acetone-m~thylene chloride
of gradually increasing polarity (from 1:9 to 1:5).
There are obtained the less polar isomer, 0.352 g. 9 and
the more polar isomer, 0.536 g. The less polar compound
showed ~nfrared absorpt~sn at 345~5 2950, 17309 1660~ 1430,
1310~ 12709 121Q9 1170~ 1060, 9709 850, and 720 cm ~9
NMR peaks at 7.42~6.729 6.06 S,35, 4.38~2.84~ 3.70, 2.66
1.069 0.86, and 0.82 ~ 3 and a hlgh resolut~bn mass `
.,
1 7 3 -
2720-lA
i63~
spectral peak at 523.3263 (TMS deriva~ive). The m~re
polar compound showed ~nfrared absorptlon at 3450, 29507
1730, 1560, 1430, 1310, 1270, 12~tO, 1210~ 1180, 1040,
970, 850 and 725 cm 19 NMR peaks at 7.47-6.72, 6.11-
5.35, 4.66~3.0, ~.7n, 2.70-1.08, 0.88, and 0.83 ~, and
a high resolution mass spectral peak at 523.3243.
xample 61 Trans-~2-16,16~dimethyl-PGI1, le5s polar
isomer and more polar isomer
. (Formula XXXIII~.
10 The methyl esters of Example 60 are separately
hydrolyzed in t-butanol with 3N potassium hydroxide
sulfate and extracted with ethyl acetate. The organic
phase is washed with brlne, dried9 and concentrated to -;
the title compound. From the less polar methyl ester
there is obtained the less polar ~cid, haYing infrared .
absorption at 3400, 2900, 17009 1650, 1420, 1250, 1060,
and 970 cm 1, and NMR peaks at 7.38-6.68, 6.137 6.01-
5.33, 4.41-3.52, 2.65-1.05, 0.88, and 0.83 ~. This
less polar acid is named (2E,6R)-16,16-dimethyl-~-
PGI1-
Similarly, the more polar methyl ester yields the
more polar acid, having infrared absorption at 3400,
2900, 1700, 1650, 1420, 1250, 1060, and g70 cm`1, and
NMR peaks at 7~39 6.769 6.25, 6.03-5~399 4072-~o35~ 2~77^
25 1.~6, 0.88, and 0.83 ~. This more polar acld is named
(2E~6S)-15,16-dimethyl-~-PGI1 .
Example 62 9-Deoxy-6,~,9a-epoxy-13~14-dihydro-PGF "
more polar isomer
(Formula XXXIV: L is tr~methyleneg Q2 ~s
? ~- 17 '
-` ' ` ";
2720~1A
;3;~
'~' ~
H OH
~s '
Hd
R25 is n-pentyl, R30 is ~COOH, and
X' is -CH2C~12-).
A solut~on of the formula-IV 9-deoxy-6~,9~-epoxy-PGF1,
more polar isomer (Example 38, 1.00 g.) in 100 m?. o~
ethyl acetate is mixed with 50 mg. o~ palladiu~ ~5%)- . :
on-charcoal and hydrogenated for 7 hr. The mixture is
~iltered and the filtrate is:concentrated to the title
compound, an oil having Rf 0.37 lTLC on silic gel in
A-IX system), and NMR peaks at S.12, 3.3-4~6, and 0.9 ~. !
This more polar acid is named ~6S) 13,14-dihydro-PGI
Example 63 ~-Deoxy-6~,9~-epoxy-2,2-difluoro-16~
phenoxy-17,18,1g,20~tetranor-PGF1, Methyl
Ester, less-polar isomer and morempolar
~somer
(Formula XVI).
Following the pr~cedures of Example 38 but replac1ng
the PGF29 methyl ester startin~ material with 2~Wdi
fluoro-16-phenoxy 17,18,19920 tetranor P~F2~, methyl
ester (U.S. Patent No~ 4~001,300) there are obtained
the t~tle compounds.
Example 64 9~Deoxy-6~,9~-epoxy-16~phenox~-17118919~20
' ~ tetrarior-PGF1 3 Methyl Ester, less polar
and more polar ~somers
-- 17~ ~
2720~1A
~ ~ ~,s~, ~
(Formula X: -d is 39 Q ls
~ OH
- 5 R1 ~s methyl, R5 and R6 are hydrogen, s
~s zero, W is
OH H
and ~ ls oxa ~0-)).
I. Refer to Chart H. There are first prepared
the formula-LXIII 5-lado compounds. A solutlon of 16-
phenoxy-l7~l8~l9~2o-tetranor~pGF2a~ methyl ester 51.0 9.)
in 25 ml. of methylene ch10ride, cooled in an ice bath, ~,
~s treated with 25 ml. of saturated sodium blcarbonate
and a solution of 1.0 g. of lodlne in 50 ml. of methylene
chloride added dropw~se over 20 min. The m~xture is <
st~rred for an add~t~onal l.S hr., then dlluted wl th
50 ml. o~ methylene chlorlde~ washed wlth 5% aqueous
sodium sulfite and brine, drled and concentra~ed. The
residue~ the mixed formula-LXIII 5-iodo isomers, is
chromatographed on sllica ~el, eluting w~th acetone
(20-30~ methylene chl~rlde to yield the separated isomers.
The less polar ~somer~ 0.04 9~ 9 has R~ 0.31 (-TLC on
silica ~el ln acetone t30~)~methylene chlor~de)3 and is
` ~dentif~ed as the 6R isomer. It has mass spectral lines
(~MS derivat~ve3 at 567.1462, 580, 547, 546~ 477, and 243.
The more polar ~somer~ 0.74 ~., has R~ 0.28 in the same
system and ~s ~dentlf~ed as the 6S ~somer.
II. Rext9 the Por~ula X tltle compounds are pre~
- 176
~,~
~663~ 2720-1~
pared, f;rs-t the less polar (6R) compound. Contlnu;ng
w~th the less polar formula-LXIII iodo compound of I above
combined w;th other lots of the same material (0.37 9.)
in 20 ml. of methanol 9 the solution is treated with about
0.8 ml. of tributyltin chloride, stirred for 5 min., and
then with 0.37 grams o~ sodiurn borohydride added
(cautiously) over 10 min. The mixture is stirred at about
25 C. for 1.5 hr., then diluted with 125 ml. of brine
and extracted with ethyl acetate. The organic phase is
washed with brine, dried, and concentrated. The residue
is chromatographed, eluting with acetone ~30%)-methylene
chloride to yield the formula-X less polar title com-
pound, nàmely (6R)-16-phenoxy-17,18919,20-tetranor-PGIl,
methyl ester, 0.24 9. It has Rf 0.20 (TLC on silica gel -,
in acetone (30%)-methylene chlorlde).
The corresponding more polar (6S) formula-X compound
is prepared similarly, following the procedure oF II but
replacing the iodo compound with the more polar formula-
LXIII iodo compound of I above (0.40 9.), There is ob-
tained, after chromatography, the more polar title com-
pound, 0.28 9., having R~ 0.19 (TLC on silica gel in
acetone (30%)-methylene chloride), mass spectral lines
(TMS derivative) at 441.2498, 454, 423, and 351, and
NMR peaks (in CCl4) a~ 6.6a-7.4, 5.6,4.34, 3.7-4O05~ and
3.55 ~. It is named (6S)-16-phenoxy 17,18,19,20-tetranor-
PGI " methyl ester.
Ex~mple G5 9 Deoxy-6~,9~-epoxy-lG-phenoxy-17,18,19,20-
tetranor-PGF1~ less polar and more polar
i somers
tFormula X: R1 is hydrogen;,
~ 177 ~
2720-lA
~ ~ 6 ~ 3 ~
The methyl ei~ers are hydrolyzed to the aclds. The
less polar formula-X compound (Example 64, 0.15 g.) ~n
6 ml. of methanol ~s treated with 3 ml. of water and C.3
gram of sod~um carbonate and the mixture is st~rred at
about 25 C. for about 16 hr. The mixture ~s filtered
through Cellte ~ (a calc~um alum~nosil~cate ~lter
medlum) and concentrated. The resldue 1s ac~dlfled with
lN potassium hydrogen sulfate, d~luted w1th 20 ml. of
br~ne, and extracted wl~h ethyl aceta~e. The organlc
phase ls washed w~th br~ne, dr~ed, and concentrated. The
res~due, an o~l, 0.18 g., ~s chromatographed, elut~ng
with acetone ~25-35X)-methylene chloride, to yield the
less polar formula-X tltle compound, 0.11 9., ha~ng
NMR peaks at 6.73-7.5, 5.67 5.9, 4.38, and 3.5-4.7 ~(in
acetone). The compound ~s named (6R)-16-phenoxy-17,18,19,20-
tetranor PGI 1 ~-
Follow~ng the above procedure but starting w~th
the more polar formula-X methyl ester ~Example 64, 0.52 9.)
and us~ng 0.8 gram of sod~um carbonate, there Is obtalned
the correspond~ng more polar formula-X t~tle compound, , !,''.''
0.38 g., having mass spectral lines at 591 3005, 573,
512, 499, 4091 and 243, and NMR peaks at 6 75-7 5, 5,3_
5.83, 4.17~4.64, and 3.3-4.17 ~ (in CDCl3). The compound
~s named (6S)-16-phenoxy~17,18919920-tetranor-PGI
Example 66 9-Deoxy-6~9~a epoxy-15-epi-16-phenoxy~
17918919,20-tetranor-PGF " Methyl ester,
- less polar and more polar ~somers
~Formula X: ~ ~s
H 0
~ 178 -
.
ii32
Followiny the procedures of Example 64 but
replacing that starting material with 15 epi-16-phenoxy-
17, 18, 19, 20-tetranor-PGF2~, methyl ester, there are
obtained the corresponding 5~iodo compounds which on
reduction yield the title compounds, namely (6R, 15S)-15-
phenoxy-17, 18, 19, 20-tetranor-PGll, methyl ester and
(6S, 15S)-16-phenoxy~17, 18, 19, 20-tetranor-PGll, methyl
ester. `
Example 67 9-Deoxy-6,~-epoxy-15-epi-16-phenoxy-17,
18, 19, 20-tetranor-PGFl, less polar and
more polar isomers.
Following the procedures of Example 65, the
methyl esters of Example 66 are hydrolyzed to the title
compounds, namely (6R,15S)-16-phenoxy-17, 18~ 19, 20-tetranor-
PGll and (6S;15S)-16-phenoxy-17, 18, 19, 20-tetranor-PGll.
Example 68
(6~)-9-Deoxy-6,9~-epoxy-11-deoxy-10,11-didehydro-
PGFl, Methyl Ester, Mixed Isomers (Formula XXll: d is 3,
CgH2 is trimethylene, Q is
H OH ., . !
Rl is methyl, R5 and R6 are hydrogen, and ~ is alpha and beta.)
1. Refer to Chart H. There are first prepared the
corresponding formula-LXlll 5-iodo intermedlates, namely
(5~)-iodo-9, 11-dideoxy-6,9N-epoxy-10, ll-didehydro-PGFl, `~
methyl ester, ~ixed isomers. A mixture of ll-deoxy-10, 11-
didehydro-PGF2~ methyl ester (obtained by reduction of PGA2
methyl ester with 9-borobicyclo-3.3Ol-nonane and separation of
the C-9 isomers, d.45 g.) and 15 ml. of saturated aqueous
so~dium bicarbonate in 10 ml. of methylene chloride is treated
at about 0C. with a solution of iodine (0.35 g.) in 25 ml.
o~ methylene chloride added in portions over 40 min. The
mixture is stirred an additional 10 min., then the organic
phase is wa5hed with aqueous sodium sulfite until colorle~s,
- 179 -
.
~6~32
washed with brine, dried, and concentrated to an oil 0.64 g.,
having Rf 0.48 and 0.52 (TLC on silica gel in ethyl acetate-
cyclohexane (1:1)), and NMR peaks at 5.78, 5.5, 5.2, 4.5,
4005, 3.67, 3.1, and 0.9 5.
11. The iodo compound above (O . 32 g.) together with
O . 3 ml . of tributyl tin chloride in 5 ml of e~hanol is treated
with a solution of 0.10 g. of sodium borohydride in 4 ml. of
ethanol over 15 min. and the mixture stirred an additional
hour. Th~ reaction mixture is acidified with dilute hydro-
chloric acid, diluted with brine, and extracted with ethyl
acetate. The organic phase is washed with hrine, dried, and
concen~rated. The resulting oil is chromatographed, eluting
with ethyl acetate (20-40%)-Skellysolve B to yield the title
compound as mixed C-6 isomers, 0.14 g., having R~ 0.61
(TLC on silica gel in ethyl acetate-cyclohexane (1:1)),
NMR peaks at 5.77, 5.55, 5.18, 3.8-4.25, 3.63, 3.1 and 0.9 ~,
high resolution mass spectral line at 422.2852, and infrared
absorption at 3440, 1740, 1625, 1245, 1200, 1175, 1050, 1025,
and 975 cm
Example 69
(6S)-15-Keto-9-deoxy-6,9a-epoxy-PGFl, Methyl Ester
(Formula XXX: Q2 is
A solution of the more polar isomer of 9-deoxy-6~9N-
epoxy-PGFl (Example 39, 2.00 g.) in 66 ml. of acetone is treated
at -78C. with 3 ml. of 30nes reagent for ~0 min. The reaction
is quenched with isopropanol and the mixture is concentrated,
diluted with brine and extracted with diethyl ether. The
organic phase is washed with brine, dried and concentrated.
The resulting oil is chromatographed~ eluting with acetone
(20 40~-methylene chloride, and rechromatographed to yield
the title compound, 1.39 g.~ having Rf 0.35 (TLC on silica
gel in A-lX system organic phase ~rom ethyl acetate acetic
- 1~0 -
3~
acid-2,2,4-trimethylpentane-water (90:20:50:100), M. Elamberg
et al., J. Biol. Chem. 241, 247 (19Ç6)), NMR peaks at 7.4,
: ~ ~ 6.93, 6.67, 6.31, 6.03, 4.48, 3.9, 2-1-2.8, arld 0.9 ~, mass
spec~ral lines at 4~6.3066, 4B1, 425, 406, 380, 365, and 143,
and infrared absorption at 3420, 3180, ~660, 1730, 1710, 1675,
1630, 1230, 1180, 1080, 1060, 985 and 730 cm 1.
Example 70
(6S) -15-Keto~9-deoxy-6 ,9~-epoxy-13,14-dihydro-PGF
Methyl Ester (Formula XXV: Q is
A solution of the product of Example 69, namely ;~
(6S)-15-keto-9-deoxy-6,9~-epoxy-PGFl, methyl ester (0.75 g.)
in ethyl acetate and 95% ethanol (3:1) is treated with 100
ml. of catalyst (5% palladium on carbon) and hydrogenated
under about one atmosphere for ~ hr. The material is filtered
and concentrated. The resulting oil is chromatographed,
eluting with acetone ~20%)-methylene chloride to yield the
title compound, 0.70 g., having Rf 0.40 (TLC on silica gel
in A-lX), NMR peaks at 7.34, 4.4, 3.96, 3.6, 3.0-2.7, and
0.9 ~, mass spectral lines at 498.3228, 483, 480, 465, 427,,,
408, 393, 325, 318, 235, and 99, and infrarecl absorption at
3420, 2660, 1735, 1755, 1410, and 1380 cm
Example 71
(6S)-9-Deoxy-6,9~-epoxy-(15R)-15-methyl-PGE`l ~Formula
IV: Q is
CH3 ~ OH )O
1. Refer to Chart H. There are first prepared the
corresponding formula LXlll 5 iodo intermediates, namely
(5~)-iodo 9-deoxy-6,9a-epoxy-(15R)-15~methy1-PGFl, methyl
~ster, mixed isomers. A ~olution of (15R)-15-methyl-P~F2~
methyl ester in 100 ml. of methylene chloride is mixed with
150 ml. of saturated aqueous sodium bicarbonate and treated
at about -5 C. with a solution of 3O0 g. of iodine in 200 ml.
of methylene chloride added dropwise over 40 min. The mixture
- 181 -
.~, ,
6~
is stirred for additional 20 min. The organic phase is washed
with aqueous sodium sulite and brine, dried, and concentrated.
The iodo intermediate has R~ 0.42 (TLC on silica gel in ethyl
acetate).
11. A solution o~ the above iodo intermediate (1.00 g )
in 15 ml. of ethanol together with 0O9 ml. of tributyltin
chloride is treated with a solution of 0.3 ~. of sodium boro-
hydride in 12 ml. of eth~nol added portionwise over 15 min.
The mixture is stirred an additional hour, neutralized with
aqueous potassium hydrogen sulfate, diluted with brine and
extracted with ethyl acetate. The organic phase ls washed i~
with brine, dried, and concentrated. The residue is chroma-
tographed, eluting with ethyl acetate (20-60~)-Skellysolve B
to yield the corresponding methyl esters (mixed C-6 isomers)
of the title compounds, 0.60 g.; 'naving Rf 0.36 (TLC on ~,
silica gel in ethyl acetate), and NMR peaks at 5.57, 4.4, ~'J
3.4-4.2, 3.63, 3.2, 1.23, and 0.9 ~.
111. The above mixed methyl esters are transformed to
the free acids by treating in methanol solution with 3 ml. of
3N. sodium hydroxide at about 25C. for 3 hr. The mixture
is concentrated to hal~ volume, diluted with brine, and ice,
acidified with aqueous potassium hydrogen sulfite and
in~ediately extracted with ethyl acetate. The extracts are
washed with brine, dried, and concentrated to the mixed title
compounds, 0.6 g., having R~ 0.24 (TLC on silica gel iR A-lX
system). ~'he product is chromatographed on 230-400'mesh silica
eluting with acetone (20-40%)~methylene chloride to yield the
title compounds, 0.52 gO, having R~ 0.40 in acetone in acetone-
methylene chloride-acetic acid (33:66:2), mass spectral lines
at 584.3753, 569, 513, and 423; and infrared absorption at
3380, 2640, 1710, 1460, 1375, 1230, 1085, 1055, and 975 cm ln
- 1~2 -
3~2
Example 72
(6S)-2,2-Di~luoro-9-deoxy-6,9~-epoxy-13,14-didehydro-
PGFl, Methyl Ester and its (6R) isomer (Formula XXXlV:
L is CH2CH2-CF2-, Q~ is
H OH
~is ~ , '
~ ' ' '''~.OH ~;R2s is n-pentyl, R30 is -COOCH3, and X is -C_C-).
1. There are first prepared the 14-chloro compounds, -
narnely (6S)-2,2-difluoro-9-deoxy-6,9~-epoxy-14-chloro-PGF
and its (6R) isomer. For this purpose the cyclization via
the mercury derivative of the corresponding 2,2-difluoro-14-
chloro-PGF2~, methyl ester is used (following Chart J). A
mixture of mercuric acetate (0.53 g.), water (6 ml.) and , i
tetrahydrofuran (6 ml.) is prepared. To it is added a
solution of 2,2-difluoro-14-chloro-PGF~, methyl ester ;
(U.S. Patent No. 4,029,681, 0.35 g.) in 6 ml. of tetra-
hydrcfuran. The mixture is stirred at about 25C. for 5.5
hr., cooled to 0C~ and treated with 0.12 M sodium boro- j~
hydride in 1 N. NaOH (25 ml.) added dropwise. The resulting
suspension is acidified with 0.2 11 aqueous potassium hydrogen
sulfate and extracted with ethyl acetate. The organic phase
is washed with 5% sodium chlorlde, dried and concentrated to`~
the mixed ~-6 isomers of 2,~-difluoro-9-deoxy-6,g~-epoxy-14-
chloro PGFl, 0~4 g., having R~ 0.17 (TLC on silica gel in the
organic phase from ethyl acetate-acetio acid-cyclohexane-water
(9:2:5:10)).
. llo A solution of the above I4-chloro-acids (0.97 g.)
in 34 ml. of dimethylsulfoxide is treated with potassium t-
butoxide (0.664 g.) for 15 hr. The solution is then neutralized
with cold 0.2 M potassium hydrogen sulfate and extracted with
ethyl acatate. The organic phase is washed with 5~ sodium
\ - 183 -
~,, .
chloride, dried and concentrated. The resulting oil, 0.76 y.,
consisting of the lsomeric acids of the title compound is then
esteri~ied with ethereal diazomethane to yield the mixed
methyl esters, 0.72 y., having Rf 0.43 and 0.52 in ethyl
acetat~-cyclohexane (2:1). The isomers are sep~rated by
chromatography, eluting with hexane-ethyl acetate (3:2), to
yeild the less polar (6R) isomer of the title compounds,
0.202 g., having NMR peaks at 4.23, 3.68, 3.71, 3.23, 1.1~
3.0, and 0.90 ~, 3500, 2240, 1765, 1460, 1440, 1310, 1245, ~ .
1200, 1170, 1135, 1045-1100, 1020, and 965 cm 1, and mass
spectral lines at 546.2998, 531, 475, 456, 430, 359 and 173.
The more polar (6S) isomer, 0.298 g., has NMR peaks at 4O40
3.86, 3.4-4.15, 1.1-3.1, and 0.90 ~, and infrared and mass
spectral data similar to that of the (6R) lsomer.
. .
.
- 184 -
~ !
i
Chart N, herein, shows the ste~,s of a process for
preparing a 13,14-didehydro compoun~ of formula XCVI,
wl-thin the scope of the formula-XX~V compounds above.
The starting materials of formula XC are 15-oxo PCF -type
compounds known in the ar-t or available by methods des-
scribed herein or known in the art. For example see U.S.
Patent No. 3,728,382. It is immate ial whether 5,6-cis
or 5,6-trans compounds are used as either one will ultimately
yield the desired formula-XCVI compound.
In the ~irst step "a" of Chart N the formula-XCI tri-
halo compound is prepared, for example by reaction of the
formu]a~XC compound with pyridinium hydrohromide perbromide
in pyridine. Other halogenating agents are useful, e.g.,
N-bromo- or N-chloro-succinimide. O-ther tertiary amines
are use~ul for the selective monodehydrohalogena-tion.
In step "b", the formula-XCII compound is obtained
as a mixture of alpha and beta hydroxy isomers by reduction
of XCI. For this reduc-tion, use is made of any of the
~nown 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, ~specially sodium, potassium, and zinc boro-
hyclrides, lithium (tri-tert-butoxy) aluminum hydride, metal
tri~l~o~y borohydrides, e.~., sodium trimethoxyborohydride,
litllium borohydride, or diisobutyl aluminum hydride. For
production of the preferred (155) configuration prosta-
cyclin derivatives, the alpha form of the formula-XCII
compound is separated from the beta isomer by silica gel
~0 chromatography using methods known in the art.
In step "c" the C-5 ancl C-6 halogen atoms are removed
by selective dehalogenation for exam?le by contact wi-th
~inc in me-thanolic ammonium chloride, to yield the Eormula-
5 -
jrc~
~66~3~
XCIII monohalo compound. Other monohalo compounds ~7ithin
the scope of XCIII are known in the art. See Eor example
U.S. Patent Mo. 4,029,681. Such transEormations as are
optionally deslred from O,, to Q2 are readily made as known
in the art or described herein.
In steps "d" and "e" the mercuration-demercuration
cyclization described above is employed, See Chart J and
accompanying description.
In step "f" the formula-XCV compounds are treated
with a dehydrohalogenation reagen~ preferably potassium
t-butoxicle, to form the formula-XCVI compounds. The
C-6 isomers are separated either after step "e" or "f".
CHART N
OH
(~ -~CH ~CH-CH-Dt-R36 XC
~ C- C C R
l!
(a)
,OH R3a ~3a
CH2-~H CH- D 1 - R3 6 XC I
--C-C.i
H ~ R 2
~b3
,OH R3a ~3a
CH2- Ctl CH- D 1 - R3~s XC I
\
N I _ R :;
q4
- (c~ tcone~nued~
6~3
CH~Rl ll ( cont ~ nlicd~
. .
l t (C )
2 - C ~I - C ~ R 2 ~
C~C
~' ~e-~,
. Q2
.
(~
~1 9 - G .
,0-~--C~3-L-R3~
2 XCIY
--f~C C <R38
M-- ~C R2
Q2
te~ .
'' '' ,. '.
,O-C ~C~2-L-R36 . '~
~ . \
. ~2~.J -- --CH2 XCY
\~ C iX3~ ' '
il R~.
Q2
~3
. 30 ~ 0O~ H~-L-~
~ ~ o? 1~ X ~ Y ~
~ c~e P~a
t g ~ ~
~ 1~7 ~
t
i
6~3~
Chart 0, herein shows the steps of a process for
a 2 analogs of formula C within the scope of the formula
XXXIII and XXXIV compounds above.
Q5, Q~, ~ , and ~ in Chart 0, as defined
in the TABL~ herein r include silyl blocking groups as
well as the tetrahydropyranyl blocking groups and others
of RLI0. The starting materials of formula XCVII are
therefore available from compounds described above,
optionally silylated by methods described herein or known
in the art.
The formula- X~IIcompounds are obtained on selenenyl~
ation, and are then oxidized, with selenoxide elimination,
to yield the formula-XVIX compounds. See H.J. ~eich et al.,
J. Am. Chem. Soc. 97, 5434 (1975) as to reagents and
conditions for these general reactions.
See also Fieser and Fieser, Reagents for Organic
Synthesis, Vol. 6, pages 235 and 459, John Wiley, N.Y., 1977.
Substituted phenyl and naphthyl esters are prepared by
methods known in the art. See for example U.S. Patent
~0 No. 3,890,372. Phenacyl-type esters are likewise prepared
by methods known in the art. See U.S. Patent No. 3,979,440.
Preparation 2 14-Bromo~PGF2~, Methyl Ester
(Formula XCIII)
and 14-Bromo-(15R)-PGF2~, Methyl Ester
1. Refer to Chart N. The formula-XCI 5~,6~,14-
bromo-15-keto-PGFIa, methyl ester (U.S. Pat. No. 3,728,382,
3.38 g.) in about 25 ml. of pyridine istreated dropwise
with a solution of pyridinium hydrobromide perbromide
t7.08 g.) in 35 ml. of pyridine over 2.25 hr. Thereafter
- 30 the mix~ure is stirred for 27 hr., diluted with e-ther and
filtered. The filtrate is washed with water, cold hydro-
- 188 -
~rc~
.2720-lA
3~
CHART O
,0- CH ~ CH2- ( CH2 ~ 3- COOCH3
- ` C H 2 X C V
X-C-R~5
r~ .
Y5
,O-CH ~ CH2- ( CH2 ) 2-C~i-COOCH3
CH2 se-c6H5 XCYI I I
~X-~-R2~ :
.
' 15
.~
H C O O C I I ,
2 20 ' "O-CH~ CH2-CH2-- ~ H
H 2 X C I X
X- I R25
Qs
~\ ~eoocu3
. C-~ ~
~ 0 - ~ 2 - c t~ a ~ H
~-3 )~ H~
~,
X~ 3
~0
~o
~, ~89 ~-
. . )
663~
bromic acid (5~) a~ueous sodium bicarbonate (5~), then
dried and concentr~ted to yield 3.72 g. product. Similarly
an additional 1.06 g. is prepared and combined. The pro-
duct is subjected ko silica gel chromatography eluting
with hexane-ethyl acetate (65:35) to yield XCI, 2 83 g.,
having NMR peaks at 0.90, 1.1-2.58, 2.58-3.4, 3.4-3.88,
3.67, 3.88-4.61, 6.96, and 7.03~; infrared peaXs at
3400, 1730, 1685, 1610, 1245, 1200, 1170, 1085, and 1050
cm l; and mass spectral peaks (TMS) at 746.0562, 636, 634, 63~,
630, 555, 553, and 551.
There is also obtained as a separate fraction from
the chromatography of the reaction product, 5~-bromo-9-
deoxy-6~,9-epoxy-14-bromo-15-keto-PGF~, methyl ester,
0.93 g., having NMR peaks at 0.90, 1.10-3~03, 3.03-3.46,
3.65, 3.78-5.0, 6.91 and 7.00 ~; infrared peaks at 3480,
2880, 2810, 1735, 1690, 1615, 1245, 1200, 1175, 1150.
and 1080 cm 1; and mass spectral peaks (TMS) at 594.099,
515, and 478.
11. 5~,6~" 14-Tribromo-PGF~, methyl ester (XCII). ;
A solution of XCI (2.38 g.) in 20 ml. of methanol is added
to a solution of sodi~m borohydride ~1~28 g.) in 40 ml~ of
methanol at -35 C. The temperature is held at -25 C.,
for 1 hr. The mixture is diluted with diethyl ether and
quenched with acetic acid. The solution is washed with
~aline solution (5%) and aqueous bicarbonate (S~) solutions,
dried, and concentrated to a mixture of C~15 epimers (XCII~.
Separation is achieved by silica ~el chromatography eluting
with hexane-ethyl ace~ate (3:2 followed by 1:1) to yield,
first, the 15R epimer, 1.57 gO having NMR peaks at
0.9, 1.1-3.35r 3~35-4.65, 366, and
- 190
jrc: ~ ~
;63~
5.75-6.21 ~; inErared peaks at 3380, 1735, 1725, 1250,
n, 1175, 1075, and 1050 crn 1; high resolution mass
spectral peak (TMS derivative) at 749.0362, and ~]D-11
in ethanol; and second, the 15S epimer 0.605 g. having
NMR peaks at 0.9, 1.10-3.35, 3.35-4.6, 3.66, and 5.65-
6.15 ~; infrared peaks at 3380, 1740, 1650, 1435, 1250,
1200, 1175, 1120, 1080, and 1045 cm 1; high resolution
mass spectral peak ~T.~S derivative) at 749.0384; and
[~]D-4~ in ethanol.
III. 14-Bromo-PGF2~, meth~l es-ter. A solution of
the 15S isomer (0.60 g.) in 20 ml. of methanol is
treated with ammonium chloride (O.11 g.) and zinc dus-t
(0.28 g.). The mi~.ture is stirred for 1.5 hr., dilu-ted
with benzene and filtered. The filtrate is washed with
0.2 M. potassium acid sulfate, dried, and concentrated
to yield 0.37 g., having Rf 0.26 (TLC on silver nitrate-
treated silica gel in eth~l acetate); NMR peaks at 0.88,
1.1-2.71, 2.71-3.55, 3.66, 3.80-4.35, 5.23-5.56 and
5.84 ~; and infrared peaks at 3320, 2900, 2820, 1940,
1650, 1430, 1310, 1240, 1215, 1170, 1115, and 1030 cm 1.
Following the ~rocedures of III but empolyin~ the
15R epimer of II, khere is likewise obtained 14-bromo-
(15R)-PGF 2 a r methyl ester.
91 --
j 3~c ~
~9~63~
T~sLE
Defi.nition oE Terms for Formulas
A is
a valence bond or -(CH2 ) h- ~ihere h is one, 2, or 3.
D is
(1) a valence bond; (2) -(CH2)d- where d is
one, 2, 3, 4, or 5; (3) -CH=CH-A- wher~ A is a
valence bond or -(CH2~h- where h is one, 2, or 3;
or (4) -CH2-0-CH2-Y- where Y is a valence bond or
-(CH2)k- where k is one or 2.
-CH2-CH=CH-A- or -(CH2)t-CF2- wherein A is a
valence bond or -(CH2)h- where h is one, 2, or
3; and wherein t is 2, 3, or 4.
alkyl of one to 4 carbon atoms, inclusive, phenyl,
phenyl substituted with one to 2 fluoro, chloro, or
alkyl of one to 4 carbon atoms, inclusive, or aralkyl
of 7 to 12 carbon atoms, inclusive.
G is
nitrato, iodo, chloro, bromo, acetato, tri~
fluoroacetato, or benzoato.
(1) a valence bond, (2) -(C~2)~- wherein d
is one to 5 inclusive, (3) -(CH2)t-CF2- wherein
t is 2, 3, or 4, (4) -CH2-CH=CH-A- wherein A is
a valence bond or ~(CH2~h- wherein h is one~ 2,
or 3, or (5) -CH2-0-CH2-Y- wherein Y is a
valence bond or -(CH2)~- wherein k is one or 2.
Ll is
Rs3 Rsl~ or Rs3 Rsl,
or a mixture o~
- 192 ~
6~:
Rs3 R51, ancl Rs3 Rs~;
wherein Rs 3 and Rsli are hydrogen, methyl, or
fluoro, being the same or different, wi-th the
proviso that one of R5 3 and R51, is fluoro only
when the other is hydrogen or fluoro.
L2 and L3 are
hydrogen, alkyl of one to 4 carbon atoms, inclu-
sive, or -COOR5l~ wherein R5l is hydro~en, alkyl
of one to 12 carbon atoms, inclusive, cycloalkyl
of 3 to 10 carbon atoms, inclusive, aralkyl
of 7 to 12 carbon a-toms, inclusive, phenyl, or
phenyl substituted one, 2, or 3 chloro or alkyl
of one to 3 carbon atoms, inclusive; being the
same or different, with the proviso that not more
than one of L2 and L3 is -COORsl.
M is
-(CH2)h wherein h is one, 2, or 3.
Ml i'
/~ f '\
Rss OH or Rs5 OH
wherein Rs 5 is hydrogen or methyl.
5~ is
R3 OR4 or R3 ORI,
wherein R3 is hydrogen or al~yl of one to 4 car-
bon atoms~ inclusive, and wherein Rli is hydrogen,
tetrahydropyran-2-yl, tetrahydrofuranyl, 1-
ethoxyethyl or a group of the formula
R8-O-C- f-RI ~
R9 Rlo
- 193 -
jrc:~
i3Z
wherein Ra is alkyl of one -to 18 carbon atoms,
inclusive, cycloalkyl of 3 to 10 carbon atoms,
inclusive, aralkyl of 7 -to 12 carbon atoms, in-
clusive, phenyl, or phenyl substituted with one,
2, or 3 alkyl of one to 4 carbon atoms, inclu-
sive, wherein Rg and Rl D are ~he same or dif-
ferent, being hydrogen, alkyl of one -to 4 car-
bon atoms, inclusive, phenyl or phenyl substituted
with one, 2, or 3 alkyl of one -to A carbon atoms,
inclusive, or when Rg and Rlo are taken together,
(CH2)a- or -(CH2)b-O-(CH2)c- wherein "a" is 3,
4, or 5, b is one, 2, or 3, and c is one, 2, or
3 with the proviso that b plus c is 2, 3, or 4,
and wherein Rll is hydrogen or phenyl.
Q1 is
R3 0R40 or R3 0R~io
wherein R3 is as defined above, and wherein R40
is the same as Rli defined above except -that it
does not include hydrogen, but includes only
the blocking groups such as tetrahydropyran-
2-yl.
Q2 is
H H , ORI~ , or R3 OR
wherein R3 and R4 are as defined above ~or Q.
Q3 is
Il ~ /~\ /~
0 , H H , P3 OH , or R3 OH
wllereill R3 is hydrogen or al~yl of one to 4 carbon
atoms, incl~lsive.
Q-, is
/" /~\
~l OH or H OH
Q5 is
~\ ,/~,
R3 OR,~2 or ~3 OR.,~
wherein R4 2 iS (1) tetrahydro?yran-2-yl, (2) te-tra-
hydrofuranyl, (3) l-ethoxyethyl, (4) a ~roup of
the formula
~I
R8~0-C C-R
~9 F~l ~
wherein R6 is al.kyl of one to 18 carbon atoms,
inclusive, cycloalkyl of 3 to 10 carbon a-toms,
inclusive, phenyl, or phenyl substituted with one,
2, or 3 alkyl of one to ~ carbon a-toms, inclus;~e,
wherein Rg and Rlo are the same or different, beiny
hydrogen, alkyl of one to 4 carbon atoms, inclusive,
phenyl or phenyl substi-tuted with one, 2, or 3
alkyl of one to 4 carbon atoms, inclusive, or,
when R9 and Rlo are taken together, -(CH2)a- or
-(CH2)b-O~(CH2)c- wherein a is 3, 4, or 5, b is one,
2, or 3, and c is one, 2 or 3 with the proviso
that b plus c is 2, 3, or 4, and wherein Rll is
hydro~en or phenyl, or (5) a sil.yl ~roup of the
:Eormula -Si(E)3 wherein E is al]cyl of one to 4
carbon atoms, inclusive, phen--l, phenyl substituted
with one or 2 fluoro, chloro, or alkyl of one to
4 carbon atoms, inclusive, or aralkyl of 7 to 12
carbon atoms~ inclusive.
Q6 is
/'~ ,~
R3 OR,,,I or R3 OR""
~0 ~herein Rl,l, ls Rl, 2 as defined for Qs and hydro~en~
- 195 -
-1 r~ -
Rl is
hydrogen or alkyl of one to 8 carbon atoms, in-
clusive, or pharmacologically acceptable cation.
R2 is
(1~ Rs
~-C~CgH2g~CH 3
R6
wherein Cg~l2g is alkylerle of one to 9 carbon atoms,
inclusive, with one to 5 carbon a-toms, inclusive,
:LO in the chain between -CR5Rfi- and -terminal methyl,
wherein Rs and R6 are hydrogen, alkyl of one to 4
carbon atoms, inclusive, o.r ~luoro, being the same
or different, with the proviso that one of Rs and
R6 is fluoro only when -the other is hydrG~-erl or
fluoro; or
(~)
R5
_l_Z ~ _ ~ (T)s
1, '
~ 6
wherein Rs and R6 are as defined above with t~le
~O proviso t~lat neithe~ Rs nor R6 is fl.uoro when 7.
is oxa (-O-); wherein æ represents an o~a atom
~-O-) or Cj~l2j where.in Cjll2~ is a val.ence bo~
or alkylene oE one to 9 carbon atoms inclusive,
with one to 6 carbon atoms, inclusive between
: -CR5R6- and -the phenyl ring; wherein !r is alkyl
of one to 4 carbon atoms inclusive, fluoro, chloro,
trifluoromethyl, or -OR7- wherein R7 is alkyl
of one to 4 carbon a-toms, inclusi.ve, and s is zero,
one, 2, or 3, with -the provi~o tha~ not more than
_ ~9~ _
jrc:
~g~`6~
two T's are other than alkyl and when s is 2 or
3 the T's are either the same or different.
R3 is
hydrogen or alkyl of one to 4 carbon atoms.
R4 is
hydrogen, tetrahydropyran-2-yl, tetrahydrofuranyl,
l~ethoxyethyl or a group of the formula
R8-O-C - C-R
Rg Rlo
~herein R8 is alkyl of one to 18 carbon atoms,
incluslve, cycloalkyl of 3 to lO carbon atoms,
inclusive, aralkyl of 7 to 12 carhon atoms, in-
clusive, phenyl, or phenyl substituted with one,
2, or 3 alkyl of one to 4 carbon atoms, inclu-
sive, wherein Rg and Rlo are the same or dif-
ferent, being hydrogen alkyl of one to 4 car-
bon atoms, inclusive, phenyl or phenyl substituted
with one, 2, or 3 alkyl of one to 4 carbon atoms,
inclusive, or, when Rg and Rlo are taken together,
~) -(CH2)a- or -(C~I2)b-O-(CH2)c- wherein "a" is 3,
4, or 5, b is one, 2, or 3, and c is one, 2, or
3 with the proviso that b plus c is 2, 3, or ~,
i and wherein Rll is hydrogen or phenyl.
Rs and R6 are
hydrogen, alkyl of one to 4 carbon atoms, inclu-
sive, or fluoro, being the same or different,
~ith the proviso tha-t one of Rs and R6 is fluoro
only when the other is hydroc3en of fluoro, and
~ith the fur-ther proviso that~ when Z is o~a
(-O-) as defined below, neither Rs nor R6 is fluoro.
7-
jrc~
63~
R7 is
alkyl of one to 4 carbon atoms, inclusive.
R8 is
alkyl of one to 18 carbon atoms, inclusive,
cycloalkyl of 3 to 10 carbon atoms, inclusive,
aralkyl of 7 to 12 carbon atoms, inclusive,
phenyl, or phenyl substituted ~7ith one, 2 or
3 alkyl of one to 4 carbon ato~s, inclusive.
Rg and Rlo are
:L0 the same or different, being hy~rogen, alkyl of
o~e to 4 carbon a-toms, inclusi~Je, phenyl or
phenyl substituted with one, 2, or 3 alkyl
of one to 4 carbon atoms, inclusive, or, when
Rg an~ Rlo are taken to~ether, -~CH2)a- or
-(CH2)b -0-(CH2)c- wherein a is 3, 4, or 5,
b is one, 2, or 3, and c is one, 2, or 3 with
the proviso that b plus c is 2, 3, or 4.
Rll
hyclrogen or phenyl.
Rl 2 iS
alkyl of one to 8 carbon atoms, inclusive.
3 iS
the group -~tC6Hs)3 or -P(O)(ORI2)2
wherein Rl 2 iS as defined above.
i s
hydrogen or an alkali metal cation.
Rl5 is
alkyl of one to 3 carbon atoms, inclusive.
Rl 6 iS
- 19~ -
~rc:i'``
6~3~
OOR17
~2) -C~120~
(3) -CH2N(R1~)2
(4) 0
~! -C-N-(R1~)2 or
(5) -C li
~N~N
wherein R~7 15 (a) hydrogen, (b) alkyl of one
to 12 carbon atoms, inclusive, (c3 cycloalkyl o~
3 to 10 carbon atoms, ~ncluslve, ~d) aralkyl of
7 to 12 carbon atot~s, ;nclusive, (e) phenyl~
~f) phenyl w;th one, 2, or 3 chloro or alkyl
of one to ~ carbon atorns, inclusive, Dr (9~ ~-
naphthyl; and
~herein Rl~ is hydrogen, alkyl of one to 12
carbon atoms, inclusive, benzyl, or phenyl, be~ng
the same or different.
1 7 ~ S
as defined ~n R16 above.
R1a iS
as d~fined in R1G dbOVe.
R19 is
(d) ~l~yl of one to 12 carbon atoms/ inclusive,
(b) cycloalkyl of 3 to 10 carbon atoms~ inclu-
S i V~? ~
~c) aralkyl of 7 to 12 carbon atolns, inclusiveq
(d) phenyl,
(e) phenyl su~stituted ~th one, 2, or 3 chloro
or alkyl of one to 4 cdrbon dtom5~ jnG1US jV
- 199 -
3~
o o
(-f) - ~ NH-C ~ NH-C-CH3,
o
(g) ~ ~ - NH-C ~ ,
(h) ~ NH-C-CH3,
o
(i) ~ NH-~C-NH2 ~
O
(j) ~ CH=N-NH-C-NH2,
(k)
O
Il I
(1) -CH-C-R
R3s
wherein R3" .is phenyl~ p-bromophenyl,
p-biphenylyl, p-nitrophenyl, p~benzamido-
phenyl, or 2-naphthyl, and
wherein R3s is hydrogen or benzoyl,
(m) hydrogen; or
(n) a pharmacologically acceptable cation
~ is
- 20U -
jrc~
i3;~
OR4 OR4 CH2
`;
, ~ , or
2 4
wherein R4 i.s RS defined abo~e.
(~) iS
the same as ~ defin~d a~ove except that R~
therein is replaced with R~o as defined below,
i.e. e~cluding h~drogen
~ lS
~ >
2 4
wherein R~ is as defined above.
-- ~01 --
~ mab/
ii3;2
,
R25 incl~des
R2, ~s defined above, and
~.C = C ~
~ is
O~U o~
CH2
(~) is
OR~ 4 .
, or
2 4
2 6
a carboxyacyl blocking group:
- 202 -
~mab,~
663~
( 1 )
- C--~/ ( R2 7 ) g
wherein R27 is alkyl of one to 4 carbon atoms,
inclusive, phenylallcyl of 7 to 10 carbon atoms,
- inclus.ive, phenyl or nitro, and g is ~ero to 5,
inclusive, provided that no-t more than two R27's
are other than alkyl, and that the total number
:L0 of carbon atoms in the R27's does no-t exceed 10
carbon ~toms:
(2) -C ~ ~ COOR2~
wherein R2~ is alkyl of one to 4 carbon atoms,
.inclusive; or
c ~3 (R27)g
( 27 g
whereln R27 and g are as defi.ned above.
R~7 i';
as defined in R26 above.
2~
as defined in R26 above.
( 1 ) -COORl g
(2) -CE12OH
(3) -C~12N(Rl~,)2
- 203 -
mab/ ~
(4) -C-N(R1~3)2, or
NE-I-N
(5) -C~ ll
~N--N
wherein Rlg is
(a) alkyl of one to 12 carbon atorns, inclusive,
(b) cycloalkyl of 3 to 10 carbon atoms, in-
clusive,
(c) aralkyl of 7 to 12 carbon atoms, inclusive,
(d) phenyl,
.~0
(e) phenyl substituted with one, 2, or 3 chlofo
or alkyl of one to 4 carbon atoms, inclusive r
(f) - ~ NH C~ ~ NH-C-CH
o
(g) ~ NEI-C
(h)~ ~NEI-C-CH3 ,
( i ) --~NH-C-NE12
~ 11
(i ) ~/ >~CH=N-NH-C-NI-12
(k)
- 20
.mabJ ~
2720-lA
[1) -'~H-C-R 3 4
~35
.wherein R34 ~5 phenyl, p-bromQphenyl 9 p-bi-
phenylyl, p-nltrophenyl, p-benzamidophenyl,
or 2-naphthyl, and whereln R~5 is hydrogen
or ben~oyl,
(m) hydrogen; or
- (n) a pharmacologicdlly acceptable catlon; and
wherein Rl~ ~s hydrogen, alkyl of one to 12 car-
bon atoms 9 inclusive, benzyl, or phenyl, be~ng
J
the same or d~fferent.
R31 iS
~ COOR32
(2) -CH20H, w~th the proviso that R31 ~S not
lS -CH20H when D ~s a valence bond9
(3) ~CH2N(R~s)2,
(4)
~C-N~R1a~2~ or
(5)
~NH-
-~
whereln R~2 is
(a) cycloalkyl of 3 to 10 carbon atom.s, ;nclu-
slve,
(b) aralkyl o~ 7 to 12 carbon atoms9 inclusive,
(c~ phenyl,
~d) phe~yl subst;tuted with one, 2, or 3 chloro
or alkyl of one to 4 canbon atoms, inclusive,
~0
- ~05
. ~
: `:
,i
~66~
NH-C ~
(f) - ~ NH-C ~ ,
(c3) ~ ~ NH-C-CH3,
(h) ~ NH-C-NH2~
{ ~ CH=N-NH-C-NH~ ,
(i) ~ 1 , or
(k) -CEE-C-R
R35
0
wherein R34 is phenyl, p-bromophenyl, p-biphenylyl,
p~-nitropllenyl, p-benæamidophenyl, or 2-napilthyl,
wherein R35 is hydrogen or ber.zoyl, and
wherein R18 is hydrogen, alkyl of one to 12 car-
bon atoms, inclusive, benzyl, or phenyl, being
the same or diErerent; wherein ~ indioates
attachment in alpha or beta configuration;
including the lower alkanoates thereof.
- 20G --
m-lb/~
32
, , ,
32
as define~l in R31 above.
33
iodo or bromo.
34
phenyl, p-bromophenyl, p-biphenylyl, p-ni-tro-
phenyl, p-benzamidophenyl, or 2-naphthyl.
hydrogen or benzoyl.
36
(1) -COOR37
(2) -CH2OH
(3) -CH2N(R18)2
C-N(R18)2, or
NE~-N
(5) -C
\ N -N
wherein R37 is
(a) alkyl of one to 12 carbon atoms, inclusive,
(b) cycloalkyl of 3 to 10 carbon atoms, inclusive,
tc) aralkyl of 7 to 12 carbon atoms, inclusive.
(d) phenyl,
(e) pheIIyl substituted with one, 2, or 3 chloro
or alkyl oE one to 4 carb~n atoms, inclusive,
NEI-C ~
- 207 -
mab~
i3~
(g) ~NH~
(h) ~ NH-C-CH3 ,
(i) ~;9--NH--C-NH2 t
( j ) ~CH=N-NH-C-NH
(k)
O
(1) -CH-C-R
wherein R3~ is phenyl, p-bromophenyl, p-biphenyl-
yl, p-ni-trophenyl, p-benzamidophenyl, or 2-
naphthyl, and wherein R33 is hydro~en or
benzoyl, or
(m) hydrogen; and
whereln R18 is hydrogen, alkyl of one to 12
carbon atoms, inclusive, benzyl, or phenyl,
being the same or different.
37
as defined above in R36.
38
bromo or chloro.
R~o is
~0 the same as R,l defined above excep-t that it does
not include hydro~en, but only the bl~ckin~
. 0 ~3 -
mab/
33Z
groups SUC}l as tetrahydropyran-2-yl.
(~) is
P'. ``' ~X' '
OR42 OR42 CEI2
~ ~ ~ , or
CH20R~,2
wherein R42 includes R40 blocking groups as de-
Eined above, together with silyl groups of the
formula-Si(E)3 wherein E is alkyl of one to 4
carbon atoms, inclusi.ve, phenyl, phenyl sub-
stituted ~.ith one or 2 fluoro, chloro, or alkyl
of one to 4 carbon atoms, inclusive, or aralkyl
of 7 to 12 carbon atoms, inclusive.
R~2 is
as deined in
~ i~
OR44 OR44 Ci~2
, ~ , or
CEI2OR~
20~ -
mab/ ~
663~
wherein R14 includes R~2 blocklng groups and
hydrogen .'
R~4 is
as defined in
R51 is
hydroyen, alkyl of one to 12 carbon atoms, inclu-
sive, cycloalkyl of 3 to 10 carbon atoms, inclusive,
aralkyl of 7 to 12 carbon atoms, inclusive, phenyl,
or phenyl substituted one, 2, or 3 chloro or
. alkyl of one to 3 carbon a-toms, inclusive.
R53 and ~54 are
hydrogen, methyl, or fluoro, being the same or
different, with the proviso that one of R53 and
R54 is fluoro only when the other is hydrogen or
fluoro.
R55 is
hydrogen or methyl.
R57 is
(1) ( 2 m 3'
(2) ~~ ~ ( l)s
(3) -CH2 ~ 1 s
wherein m is one to 5, inclusive, Tl is chloro,
fluoro, trifluoromethyl, alXyl of one to 3 carbon
atoms, inclusive, or alkoxy of one to 3 carbon
atoms, inclusive, and s is ~ero, one, 2, or 3,
the various Tl's being the same or different,
with the proviso -that not more thall two Tl's are
other than al~yl.
R5~ is
hydrogen or hydro~y.
- 2l0 -
mab/
3~
T is
alkyl of one to 4 carbon ato;..s, inclusive, Eluoro,
chloro, trifluoromethyl, or -OR7- wherein R7 is
hydrogen or alkyl of one to f~ carbon atoms, inclu-
sive, and s is zero, one, 2, or 3, with the proviso
that not more than two T's are other than alkyl
and when s is 2 or 3 the T's are either the same
or different.
Tl is
chloro, fluoro, trifluoromethyl, alkyl of one to 3
carbon atoms, inclusive, or alkoxy of one to 3 car-
bon atoms, inclusive, and s i.s zero, one, 2, or 3,
the various Tl's being the same or di.fferent, with
the proviso that not more than ~wo Tl's are oti;er
than alkyl.
W is --C--
~'~ \ or -CH2-
wherein R4 is as defined above.
X is
trans-CH=CH-, c.is-CH=CH-, -C C-, or -CE12C~I2-
X' is
cis-CH=CH-, -C_C-, or -CH2CH2-.
Y is
a valence bond or -tCH2)k- where k is one or 2.
Yl is
trans-CH=CH-, -C-C- or -CH2CH2-.
Z is
an oxa atom (-O-) or CjH2j is a valenre bond or
alkylene of one to 9 carbon atoms, inclusive,
substituted with zero, one, or 2 fl.uoro, with one
to 6 carbon atoms, inclusive ~etween -CR5R6-
and the phenyl. ri.ng.
- 211 -
Mab/l~
3~
i s
2 2 g 2
(2) cis-CH=CH-CE12-(CH2)g-CF2-,
wherein g is one, 2, or 3.
a is
3, 4, or S.
b is
one, 2, or 3.
c is
one, 2, or 3 with the proviso that b plus c is
2, 3, or 4.
d is
an integer of one to S, inclusive.
g (as to (R27)g in carboxyacyl groups) is
~ ero to 5, inclusive.
g (as to ~(CH2)g- in Zl of Preparation 1) is
one, 2, or 3.
h is
one, 2, or 3.
k is
one or 2.
m is
one to S, inclusive.
s is
~ero, one, 2, or 3.
-t is
2, 3, or 4.
EEal is
chloro, bxomo, or iodo.
T~IP is
tetrahydropyran--2-yl.
.~ '
- 2:1.2 -
nab/ i ~
6~
Ts is
p-toluenesulfollyl.
The symbol ~ (wavy line) indicates
attachment in alpha or beta configuration.
C H is
g 2g
alkylene of one to 9 carbon atoms, inclusive,
with one to 5 carbon atoms, inclusive, in the
chain between -CR5R6- and terminal methyl.
Cj~2j is
1~ a valence bond or alkylene G_ one to 9 carbon `
atoms, inclusive, substituted with zero, one,
or 2 fluoro, with one to 6 carbon atoms,
inclusive between -CR5R~- and the phenyl rina.
I
- 213 -
mab/,~.
