Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
~ 0~'3~;033
This is a divisional of Application No. 275,929,
filed on April 12, 1977.
This invention relates to a novel process for the
preparation of certain prostaglandin analogs and novel inter-
mediate compounds employed in the process.
The prostaglandins are C-20 unsaturated fatty acids
which exhibit diverse physiological effects. The chemistry,
stereochemistry, nomenclature and uses thereof are extensively
discussed in the literature and reviewed in Belgian Patent
10 800,580 granted on December 7, 1973 and also in our copending
~5674) Application Canadian 254,785 filed June 14,1976.
In accordance with the present invention there is
provided a process for preparing an optically acti~e compound of
the general formula:
O~'
~ ' \ ~ Q
.- \~
R- ~ (VIIIA)
and its optical antipode and the racemic mixture thereof which
comprises reacting a compound of the formula:
OR'
Q
.- CHO (VIIA)
its optical antipode or the racemic mixture thereof, wherein
--2--
~,r
0~3
R' is hydrogen or CR";
R" is alkyl of from one to four carbon atom~
naphthyl, phenyl, p~biphenyl or phenylal.kyl of from seven to
nine carbon atoms;
R is hydrogen; tetrahydropyranyl.-2 yloxy or dimethyl-
t-butylsilyl.oxy;
O O o o
.. .. .. ..
Q is tetrazol-5-yl, -CNHCR"', -CNHS02~'l' or -COR wherein
R is hydrogen, alkyl of from one to six carbon atoms, phenyl,
phenalkyl of from seven to nine carbon atoms, ~-naphthyl or p-
biphenyl; and ~`
~" is alkyl of fxom one to four carbon atoms or phenyl,
with the proviso that when R is hydrogen or alkyl R is dimethyl-.
t-butylsilyloxy with the ylide of a compound of the formula:
CH O O O
3 \ " ,i
/ P ~ CH2 ~ C - A
: CH30
~: 15 in a reaction inert solvent at a temperature o~ from 0 to 80~.
until the reaction is substantially complete, wherein A is alkyl
of from four to eight carbon~atoms, 2-indanyl, or a grollp of the
form~la: : .
Ar - (CH2)n- or Ar'-O-CH2~
wherein n i9 l or 2, Ar is ~-naphthyl, ~-naphthylr ~-furyl, ~-
thienyl, ph~nyl or monosubstituted phenyl wherein the substitu-
ent is fluorine, chlorine,: trifluoromethyl, phenyl or alkyl or ~:
.
aIkoxy of from on~ to 9iX oarbon atoms, and Ar' is phenyl or
: monosubstituted phenyl wherein the substituent is 1uorine,
chlo~ine, trifluoromethyl, phenyl, or alkyl or alkoxy of from
one.t~ six carbon atoms.
A preferred embodiment of the process of the inven-
-3-
: -- .,.. " . . . . ~. ~
~0~ 033
tion is that wherein the starting compound has the formula:
H
H-O / N
R . (VIIB~
-
An especially preferred embodiment of the process is
~hat wherein the starting compound has the formula:
O-~-C~3
O
~ ~ NHSO2CH3
.- CHO (VIIC)
R-
wherein R is a~ defined above.
-
The process for preparing a compouna of Formula I isal~o preferred when A is Ar(CH2)- or Ar'-O-CH2- and said proces~
is especially preferred when A i9 C6H5-OCH2-.
The present invention further provides a pxocess for
preparing the optically active intermediate compound of the
general formula:
OR'
~ O ~ Q
.- CHO (VIIA)
its optical antipode or the racemic mixture thereof wherein R'
R and Q are as defined above, which comprises reacting an
optically active compound of the formula:
-4-
Q~33
OR'
y,s)
- (CH2)m (VIA)
its optical antipode or the racemic mixture thereof, wherein
R', R and Q are as defined above and m is 2 or 3, with mercuric
chloride in a reaction-inert solvent at a temperature of from
25 to 80C. until the reaction is substantially complete.
A preferred embodiment of the process is when R' is
hydrogen. The process wherein R' is hydrogen is further pre-
ferred when Q is COOR, wherein R is as defined above. Likewise
the process is preferred when R' is hydrogen and Q is tetrazol-
5-yl. The said process wherein R' is hydrogen is especially pre-
ferred when Q is CONH$O2R"', and most especially preferred when
Q is CONHSO2CH3.
The said process for preparing the compound of Formula
(VIIIA) is also preferxed when R' is COR" and especially when R'
is COCH3. The said process wherein R' is COCH3 is further pre-
ferred when Q is COOR or tetrazol-5-yl, and is especially pre-
ferred when Q is CONHSO2R"', and most especially preferred when
Q is CONHSO2CH3.
The present invention further provides a process for
0 pr~paring an optically active compound of the general formula:
OH
~ ~ ~ Q'
R- ~ ~
~ CH2)m (VI')
its optical antipode or the racemic mixture thereof wherein R
--5--
1.0~3~ ,0?,,13
is hydrogen, tetrahydropyran-2-yloxy, or dimethyl-t-butylsilyl-
oxy; o o O
Il 1l 1l n
Q' is tetrazol-5-yl, -CNHCR"', -CNHSO2R"' or -COH;
R"' is alkyl of from one to four carbon atoms or
phenyl; and
m is 2 or 3;
which comprises reacting an optically active compound of the
formula:
OH
R ~ ~
,~,CH2 ) m
its optical antipode or the racemate thereo~, wherein R and m
are as defined above, with an ylide of a compo~nd of the formula-
Br ~
~ 3 P (CH2)4 - Q-
in a reaction inert solvent at a temperature of from -30 to
80~C. until the reaction is substantially complete. The process
for preparing the compound of Formula III' is preferred when Q'
is COOH, or tetrazol-5-yl, and i~ e pecially preferred when Q'
is CONHS02R"' and most especially preferred when Q' is CONH502CH3.
Some of the intermediate compounds of Formula (VIIA)
are novel and accordingly the present invention also provides an
optically active compound of the formula:
OR'
' ~ Q
. }IO
R- (VIIA)
--6--
~0~0.~3
its optical antipode and the racemic mixture thereof wherein
o
R' is hydrogen or CR";
R" is alkyl of from one to four carbon atoms, ~-
naphthyl, phenyl, ~-biphenyl or phenylalkyl of from seven to
S nine carbon atoms;
R is hydrogen, tetrahydropyran-2-yloxy or dimethyl-t-
butylsilyloxy; and Q is tetrazol-5-yl, -CNHCR"', -~NHSO2R"' or
-COR, wherein R is hydrogen, alkyl of from one to 8iX carbon
atoms, phenyl, phenylalkyl of from seven to nine carbon atoms,
~-naphthyl or ~-biphenyl; and R"' is alkyl of from one to four
carbon atoms or phenyl, with the proviso that when R is hydrogen
or alkyl R is dimethyl-t-butylsilyloxy.
Preferred compounds of Formula ~VIIA) provided by the
invention are the following:
(i) an optically active compound of the formula:
o
OC-CH3
Q , ,~ Q
R.~ CHO
its optical antipode-or a racemic mixture thereof, wherei~ R iQ
as defined above and wherein Q is COOR and R is a3 defined above;
and wherein Q is CONHSO2R"'; especially CONHSO2CH3, or tetrazol-
5-y~ and
~ii) a compound of the formula:
OH
Q ~ Q
. CHO
~O ~ ~30.~ 3
its optical antipode or a racemic mixture thereof, wherein R is
defined above and wherein Q is COOR and R is as defined above,
and wherein Q is tetrazol-5-yl or CONHSO2R"', especially
CONHSO2CH3.
The invention still further provides an optically
active compound of the formula:
OR~
Q
S)
O (CH2)m (VIA)
its optical antipode or the racemic mixture thereof wherein R'
is hydrogen or ~R" and R" is alkyl of from one to four carbon
atoms, ~-naphthyl, phenyl, p-biphenyl or phenylalkyl of from
seven to nine carbon atoms;.R is hydrogen, dimethyl-t-butylsilyl-
oxy, or tetrahydropyran-2-yloxy; Q is tetrazol-5-yl;~ CNH~CR"',
-~NHSO2R"' or -~OR; wherein R is hydrogen, alkyl of from one to
six carbon atoms, phenyl, phenylalkyl of from seven to nine
carbon atoms, ~-naphthyl or ~-biphenyl; R"' is alkyl of from one
to four carbon atoms or phenyl and m is 2 or 3.
Preferred compounds of Formula (VIA) above are those
wherein R' is hydrogen and wherein Q is tetrazol-5-yl; COOR,
especially COOH or COOCH3; or CONHSO2R"' especially CONHSO2CH3;
and the optical antipodes and racemic mixtures thereof.
Other preferred compounds of Formula (C) .are those
wherein R' is -COCH3 and wherein Q is CONHSO2R"'; especially
CONHSO2CH3; tetrazol-5-yl; or COOR, especially COOH or COOCH3;
and the optical antipodes or racemic mixtures thereof.
The invention yet further provides an optically active
--8--
~109~033
compound of the formula:
OH
~ 2)m (V~
its optical antipode and the racemic mixture thereof wherein R
is hydrogen, tetrahydropyran-2-yloxy or dimethyl-t-butylsilyl-
oxy; and m is 2 or 3.
The present invention will now be described in more
detail with reference to Reaction Schemes which illustrate the
processes for preparing the novel intermediate compounds of
Formulae (VIIA), ~VA) and (V), as well as the prostaglandin
analogs of Formula (VIIIA) herein. Illustrative of the present
invention is the process for preparing the compounds designated
by the Formulae VIII and XIV in Scheme B hereinafter. These com-
pounds are useful intermediates for the production of prosta-
glandin analogs as will be described hereinafter.
The following Reaction Scheme A illustrates the steps
leading to the preparation of the key intermediate hemithio-
acetal of Formula VI. In this Scheme and the subsequent Schemes
the symbols R, Q and R" have the same meanings as defined above.
~IO~S033
o~
~C)~ - o~`~CHO
o~
'`~
II
0~ _~0,
110 ~J R~
III / IV
OH ~
O ~ H OH
R~ ;~ R.'
V VI
Scheme A
--10--
10~5033
With reference to Reaction Scheme A the intermediate
lactol of Formula V is prepared by reduction of lactone IV with
diisobutyl aluminum hydride. This reduction is most easily
accomplished by contacting lactone IV at a low temperature,
typically -75C., in dry toluene with a 20~ solution of diiso-
butyl aluminum hydride in hexane. Higher reaction temperatures
may be employ~d if over reduction does not occur. The diiso-
butyl aluminum hydride is added to the precooled mixture of
lactone IV in toluene over a period of about 20-30 minutes. The
reaction mixture is then stirred for an additional 30 minutes and
then quenched by the dropwise addition of methanol. The solvents
are evaporated under reduced press~re and the product is isolated.
The product may be purified by column chromatography on silica
gel.
Lactone IV is prepared from lactone III by protection
of its hydroxyl group with a suitable acid labile protecting group.
Such protecting groups are typically te_rahydropyran-2-yloxy or
dimethyl-t-butylsiloxy. Any sufficiently acid-labile group is
satisfactory; however, the most usual one is tetrahydropyranyl,
which can be incorporated in the molecule by treatment with di-
hydropyran and an acid catalyst in an anhydrous medium. Lactone
III is typically contacted with freshly distilled dihydropyran in
dry methylene chloride at a temperature of 0 to 5C. in the
presence of an acid catalyst such as para-toluenesulphonic acid.
Other non-aqueous acid catalysts may likewise be employed. - This
reaction mixture is stirred until reaction is substantially com-
plete, typically after one to two hours at a reaction temperature
of 0C., and the product is then isolated. Lactone III is pre-
pared from parabiphenyl ester II by contacting the said parabi-
phenyl ester with a heterogenous mixture of anhydrous potassium
~0~5033
carbcnate and absolute methanol. This reaction is convenientlyperformed at room temperature for a period of approximately 24
hours. Parabiphenyl ester II is prepared from the known alde-
hyde I by treatment of said aldehyde with 2-mercaptoethanol in
methylene chloride at low temperature, typically 0C., under
nitrogen in the presence of a Lewis acid catalyst such as boron
trifluoride etherate. The reaction time is approximately 10 to
30 minutes. The resulting solution is then warmed to room
temperature and stirred for an additional two hours. The product
is then isolated. Another suitable hemithioacetal protecting
group for the aldehyde function may be generated by substituting
3-mercaptopropanol for 2-mercaptoethanol in the above reaction.
In this case the protecting group is a six membered hemithio-
acetal rather than the 5-membered one illustrated in Formula II.
Reaction Scheme A further illustrates the preparation
of the hemithioacetal of Formula VI which is a key intermediate
compound in the synthetic sequence of the present invention.
In the preparation of the hemithioacetal of Formula
VI the desired ylide reagent is prepared from the appropriate
phosphonium salt dissolved in dimethylsulphoxide by adding to
the solution a solution of sodium methylsulphonylmethylide in
dimethylsulfoxide in a molar ratio of about 2:1 (anion:salt).
The lactol of Formula V is then added (dissolved in methylsulph-
oxide) to the ylide solution prepared above, and the reaction
mixture stirred until reaction is substantially complete. Re-
action times will vary according to the choice of phosphonium
salt and typical reaction times are 1 to 16 hours. The reaction
mixture is then poured into water and the product isolated by
methods familiar to those skilled in the art. This reaction
may be conducted at a temperature of from -30 to 80C. and the
-12-
~0~5033
reaction temperature most frequently employed is room tempera-
ture. The choice of phosphonium salt is dictated by the struc-
ture of the desired final product. When Q is COOH the salt used
is 5-triphenylphosphoniopentanoic acidi when Q is to be COOR the
product obtained from the above reaction wherein Q is COOH is
esterified by for example a diazoalkane or by treatment of the
acid with a mixture of dicyclohexyl carbodiimide and the
appropriate hydroxyl compound. When Q is tetrazol-5-yl the
appropriate phosphonium salt is (4-(tetrazol-5-yl)-_-butyl) tri-
phenylphosphonium bromide. When Q is N-methane sulfonylamino-
carbonyl, (4-methanesulfonylaminocarbonyl-_-butyl)-triphenyl-
phosphonium bromide is used. The proper choice of salt will be
obvious to those skilled in the art, as will the manner of
preparation of the said salt.
The sequence of steps starting from the intermediate
of Formula VI and leading through the novel aldehyde inter-
mediates of Formulae VII and XIII are illustrated in Reaction
Scheme B which follows:
-13-
~0~033
OH
Q s
O~R" O~J
~ ~ VI
Q R
XII
R.' HO VII
OI~R''
~'' ~~Q
~ ~ OH
R CHO
XIII
J o R.~ ~~
O~R" /
VIII
~ OH
R- ~~
XIV
IX
HO` ~
H ` OH
Scheme B X
--14--
033
The process illustrated in Reaction Scheme B comprises
inter alia reacting a compound of Formula VII or XIII with the
ylide of the appropriate phosphonate of the formula:
CH3 o
O "
~P - CH - C - A
3 2
wherein A is as defined above, in a reaction inert solvent at a
temperature of from 0 to 80C. until reaction is substantially
complete.
The reaction is most conveniently conducted by first
preparing the ylide under nitrogen in a suitable ~olvent such as
dimethoxyethane, ether or tetrahydrofuran by adding a suitable
base, such as sodium hydride or n-butyllithium, slowly to a solu-
tion of the appropriate phosphonate in t~e same solvent at a
reaction temperature of from 0 to 25C., usually 0C. The form-
ation of the ylide is usually compl te within an hour. At this
time the aldehyde of Formula VII or XIII is added, dissolved in
the same solvent, and the reaction mixture is stirred at a
temperature of from 0 to 80C., typically at room temperature,
until reaction is substantially complete, typically for an hour.
Aldehyde VII is used to prepare intermediates for the synthesis
of prostaglandins and their analogs of the F series and aldehyde
XIII is used to prepare intermediates for prostaglandins and
the r analogs of the E series. The reaction mixture is then
brought to pH 6-7 and the product isolated therefrom. Purifica-
tion of the product is achieved typically by chromatography on
silica gel.
The choice of the phosphonate from which the ylide is
prepared is dictated by the structure of the desired final
product. For example, when the final product is desired to have
-15-
~0~5033
a 5-carbon lower side chain at Cl5, (i.e., A is C5Hll) the phos-
phonate used is dîmethyl(2-oxo-heptyl)phosphonate, and if the
methylenephenoxy lower side chain is desired at Cl5, (i.e., A is
0_OCH2) the phosphonate used is dimethyl 2-oxo-3-phenoxypropyl
phosphonate.
According to the present invention the starting mate-
rials for the above reaction, i.e., the compounds of structure
VII and XIII are prepared from compounds of the structure VI or
~II, respectively, as shown in Scheme B by removal of the hemi-
thioacetal protecting group. This is accomplished by reactinga solution of the hemithioacetal in a reaction-inert solveht,
for example, acetonitrile:water (4:1), with mercuric chloride at
a reaction temperature of from about 25 to 80C. until reaction
is substantially complete. Reaction times will vary somewhat
with the substrate but a typical reaction time is from 0.5 to 2.0
hours. Preferably the reaction is conducted when an alkaline
earth metal carbonate is present in the reaction mixture since
the most favorable yields are obtained when this material is
present. The preferred alkaline earth metal carbonate is calcium
carbonate, preferably in a molar ratio of 6:1 (CaCO3:VI or
CaCO3:XII).
The hemithioacetal XII is obtained from Compound VI by
acylation. This is most commonly achieved using the appropriate
acid anhydride in the presence of pyridine although other acyla-
tion systems such as acid chlorides or ketenes may be used.
As indicated in Scheme B, Intermediate VIII may be con-
verted directly to Intermediate XIV by acylation. As indicated
above such an acylation reac~ion is commonly conducted using the
acid anhydride of the desired acyl group in the presence of
pyridine.
-16-
~0~;033
Intermediates XIV and VIII may be converted into
prostaglandin E and F respectively in the following way:
To produce prostaglandins of the F series Compound
VIII is converted into Compound IX by reduction with zinc boro-
hydride. This reduction is usually carried out in dimethoxy-
ethane with a molar ratio of zinc borohydride to Compound VIII
of 1:2. The reaction is usually conducted at room temperature
under nitrogen and a reaction time necessary for complete re-
duction. Other reducing agents such as lithium trialkyl boro-
hydrides may be employed and solvents such as tetrahydrofuranmay be used. The reaction mixture is then cooled in an ice bath,
the cold reaction mixture quenched by the addition of sodium bi-
tartrate and the product isolated. The two epimers produced by
this reaction are separated by column chromatography on silica
gel.
Compound IX then may be converted to the desired PGF
analog by an acidic hydrolysis of the tetrahydropyranyl group.
Any acid which does not cause destruction of the molecule in the
course of the removal of the protecting group may be used. How-
ever, this is accomplished most often by use of 65% aqueousacetic acid, at room temperature for about 18 hours. The product
is purified as above.
E series prostaglandins and their analogs may be ob-
tained from Intermediate XIV as shown in Scheme ~. The reduc-
tion to XV is accomplished in the same manner as the reductionVIII to IX as above. The isomers obtained from this reduction
are separated by column chromatography. Alcohol XV is then pro-
tected as shown in Scheme A Reaction III to IV under the same
conditions as described for that transformation and the result-
ing protected compound XVI is then hydrolyzed by contacting it
-17-
10~5033
in a suitable solvent or mixture of solvents, such as methanol-
tetrahydrofuran (1:1) with lN aqueous sodium h~droxide solution.
This reaction is run at room temperature under nitrogen for
periods usually ranging from 8 to 24 hours, although longer re-
action times are occasionally necessary to effect completehydrolysis. The reaction mixture is then acidified by the addi-
tion of lN hydrochloric acid and the acidified solution is ex-
tracted with ethyl acetate to affo~d the desired product. This
product may be purified, if desired, by column chromatography.
The resulting product XVII is then oxidized to provide
Compound XVIII. This reaction is usually achieved using Jones'
reagent in acetone at reaction temperatures of from -15 to -20C.
After the appropriate amount of Jones' reagent has been added,
the reaction usually stirred for an additional 15 or 20 minutes
and then quenched by the addition of isopropyl alcohol. The
product is then isolated in the usual way.
Ketone XVIII is then converted to the desired prosta-
glandin or its analog by the hydrolysis of the protecting groups
in the same manner and under the same conditions as desc~ibed
for the transformation of Compound IX to Compound X. The result-
ing Compound XIX may be then purified, if desired, by column
chromatography on silica gel.
-18-
10~50;~3
o
OCR "
~ - \ Q
R~
O / XIV
OCR" ~
~"~ ,
"A
¦ XV OH
o
OCR"
'~ Q ~"\~
R ~ ` ~//y HO, ~y,A
XVI H ~.R XIX H '~OH
OH O
Q ~ ~Q
R ~5y ~ , ~--~A
XVII XVIII
Sche~ne C
--19--
10~5033
The various steps illustrated in Schemes B and C start-
ing from compounds VII and XIII and leading to prostaglandin
analogs of Formula XIX are analogous to methods known in the art
but the production of the intermediate compounds VII and XIII
from the key hemithioacetal intermediate of Formula VI is novel
and provldes a surprising and advantageous route for the prepara-
tion of the final prostaglandin products.
Accordingly the invention still further provides in a
process for preparing a prostaglandin from an optically active
aldehyde intermediate of the formula:
OR'
. . .
Q~'
.- CHO (VIIA)
its optical antipode and the racemic mixture thereof, wherein R'
is hydrogen or -~R" and R" is alkyl of from one to four carbon
atoms, ~-naphthyl, phenyl, p-biphenyl or phenylalkyl of from
seven to nine carbon atoms; R is hydrogen, tetrahydropyran-2-yl-
oxy or dimethyl--t-butylsilyloxy; and Q is tetrazol-5-yl,
-~NH~R"~ NHSO2R"' or -~OR, wherein R is hydrogen, alkyl of
one to six carbon atoms, phenyl, phenylalkyl of from 7 to 9
carbon atoms, ~-naphthyl, or p-biphenyl and R"l is alkyl of one
to four carbon atoms or phenyl, by methods known in the art,
the impro~ement which comprises preparing the aldehyde of Formula
(VIIA) by reacting an optically active compound of the formula:
-20-
~10~033
OR'
.
~ ' '~ ~ Q
. (~S~
R-
o (CH2)m (VIA)
its optical antipode or the racemic mixture thereof, wherein R',
R and Q are as defined above and m is two or three, with
mercuric chloride in a reaction-inert solvent at a temperature
from 25 to 80C. until the reaction is substantially complete.
A pre~erred embodiment of the above process is that
wherein the intermediate of Formula (VIIA) is an aldehyde com-
pound wherein Q is ,~NHS02CH3, R' is -~CH3 and R is tetrahydro-
pyran-2-yloxy and the final prostaglandin product is N-methane-
sulfonyl 9-oxo-11~,15-dihydroxy-16-phenoxy-5-cis-13-trans-
17,18,19,20-tetranorprostadienamide.
For the preparation of ll-desoxy analogs of prosta-
glandins the hemithioacetal intermediate of Formula VI wherein
R is hydrogen is prepared from the known lactone III' by the
same method as that illustrated in Scheme A above by the reac-
tion sequence illustrated in Scheme D which follows:
~0~;033
,o o
,o ~ o~
Qcuo ~:~J
I '
III
OH
O ~H OH
'\~ Q
VI (R = H)
V'
Scheme D
0~)33
As used herein all the structural formulas are meant
to represent either an optically active compound, its antipode
or a racemic mixture of the two.
It will be appreciated by those skilled in the art
that the foregoing synthetic sequences of the present invention
possess the broad flexibility very much to be desired in the
preparation of prostaglandin analogs.
In the se~uences described above, a considerable
latitude exists in the selection of the protecting group used at
a particular ~tage. Thus, in protecting alcohols, dihydropyran-
yloxy groups or dimethyl-t-butyl silyl groups may be employed in
those situations where the protecting group is represented in
the Formulae as R. Similarly the acyl group of Compounds XII
through XVI may he selected f~om a broad range of acyl groups
such as formyl or alkanoyl of from 2 to 4 carbon atoms, ~-naphth-
yl,carbonyl, benzoyl, parabiphenylcarbonyl or phenylalkylcarbonyl
wherein an alkyl group may be of from 7 to 9 carbon atoms.
In numerous in vivo and in vitro tests we have demDn-
strated that the prostaglandin analogs prepared by the process
of the present invention possess physiological activities com-
parable to those exhibited by the natural prostaglandins. These
tests include, among others, a test for effect on isolated
smooth muscle from guinea pig uterus and rat uterus, inhibition
of histamine-induced bronchospasm in the guinea pig, and effect
on dog blood pressure, inhibition of stress-induced ulceration
in the rat, inhibi~ion of gastric acid and pepsin secretion in
rat and dog, inhibition of collagen or ADP-induced blood plate-
let aggregation and abortifacient activity in rats and guinea
pigs by luteolytic and non-luteolytic mechanisms.
The physiological responses observed in these tests
-23-
J~O~S033
are useful in determining the utility of the test substance for
the treatment of various natural and pathological conditions.
Such determined utilities include: antihypertensive activity,
bronchodilator activity, antithrombogenic activity, antiulcer
activity, smooth muscle activity (useful as an anti-fertility
agent, for the induction of labor, and as an abortifacient); and
anti-fertility activity through a mechanism not affecting smooth
muscle, for example, luteolytic mechanisms, and the synchroniza-
tion of the estrous cycle in farm animals.
The prostaglandin analogs prepared by the process of
this inventlon possess more selective activity profiles than
the corresponding naturally occurring prostaglandins, and in
many cases, exhibit a longer duration of action. For example,
N-methanesulfonyl 16-phenoxy-~-tetranorprostaglandin E2 carbox-
amide which exhibits smooth muscle stimulating activity comparabl~-
to PGE2, is inactive in inhibition of histamine-induced broncho-
spasms in guinea pigs. Furthermore, although the threshold dose
of hypotensive response of N-methanesulfonyl 16-phenoxy-~-
tetranor PGE2 carboxamide in dogs is higher than that of PGE2.
Another prime example of the therapeutic importance of these
prostaglandin analogs is the efficacy of 2-descarboxy-2-(tetrazol-
5-yl)-11-desoxy-16-phenyl-~-tetranorprostaglandin E2 and 2-des-
carboxy-2-(tetrazol-5-yl~-11-desoxy-16-(p-fluorophenyl)-~-tetra-
norprostaglandin E2 which exhibits hypotensive activity of great-
ly enhanced potency and duration as compared with PGE2 itself.At the same time, the smooth muscle stimulating activity is
mark~dly depressed in comparison with PGE2.
Particularly useful for fertility control, abortion and
induction of labor are the 16-phenoxy-~-tetranorprostaglandins
3Q 15-indanyl-~-pentanorprostaglandins and 17-aryl-~-trisnorprosta-
-24-
10~0~3
glandins of the E2 and F2~ series based on especially outstand-
ing smooth muscle stimulating activity, and at the same time
reduced diarrheal, bronchodilator or blood pressure effects.
Particularly useful for antiulcex activity are the
16-aryl-~-tetranorprostaglandins of the E2 series based on out-
standing antiulcer and antisecretory activity and at the same
time reduced diarrheal and smooth muscle effects.
Also useful for antihypertensive activity are the
2-descarboxy-2-(tetrazol-5-yl)-11-desoxy-16-aryl-~-tetranor-
prostaglandins of the E2-series based on outstanding oral hypo-
tensive activity and at the same time reduced diarrheal and
smooth muscle effects.
The prostaglandin analogs which have a beta hydroxyl
at C15 have action which is similar to their epimers. In some
cases, however, the selectivity that these compounds diYplay
exceeds that of the epimeric compounds.
For induction of abortion, tablets or an aqueous sus-
pension or alcoholic solution of the 15-substituted ~-pentanor-
prostaglandins of the E and F series would appropriately be
administered at oral doses of about 0.1-20 mg., with 1-7 doses
per day being employed. For intra~aginal administration a suit-
able formulation would be lactose tablets or an impregnated
tampon of the same agent. For such treatments suitable doses
would be from about 0.1-20 mg./dose with 1-7 dosec being employ-
ed. For intra-am~iotic administration a suitable formulation
would be an aqueous solution containing 0.05-10 mg./dose with
1-7 do es being employed. For extra-amniotic administration a
suitable formulation would be an aqueous solution containing
0.005-1 mg./dose with 1-5 doses being employed. Alternatively,
the 15-substituted-~-pentanorprostaglandins of the E and F
-25-
10~50.~3
series of this invention can be infused intravenously for induc-
tion of abortion at doses of 0.05--50 llg./minute for a period of
from about 1-24 hours.
Another use for the 15-substituted-~-pentanorprosta-
glandins of the E and F series is as an inducer of labor. Forthis purpose an ethanol-saline solution is employed as an intra-
venous infusion in the amount of from about 0.1-10 ~g./kg./min.
for from about 1-24 hours.
Another use for the 15-substituted-~pentanorprosta-
glandins of the E and F series is for fertility control. Forthis purpose a tablet is employed for intravaginal or oral admin-
istration containing 0.1-20 mg. of prostaglandin per dose with
1-7 doses being employed at or following the expected day of
menstruation. For synchronization of the estrous cycle in pigs,
sheep, cows or horses, a solution or suspension containing 0.03-
30 mg./dose of 15-substituted-~-pentanorprostaglandin of the E
and F series is administered subcutaneously from 1-4 days.
15-Substituted-~-pentanorprostaglandins of the E series
are useful gastric antisecretory and antiulcer agents. For
treatment of peptic ulcers these compounds are administered
preferably orally in the form of capsules or tablets at doses of ----
0.001 to 0.1 mg.~kg.~day.
The 15-substituted-~-pen~anorprostaglandin analogs of
the E series of the present invention are useful hypotensive
agents. For treatment of hypertension these drugs could appro-
priately be administered as an intravenous injection at doses
of about ~.5-10 ~g./kg. or preferably in the form of capsules or
tablets at doses of 0.005 to 0.5 mg./kg./day.
To prepare any of the above dosage forms or any of the
numerous other forms possible, various reaction-inert diluents,
-26-
exci~ients or carriers may be employed. Such substances in-
clude, for example, water, ethanol, gelatins, lactose, starches,
magnesium stearate, talc, vegetable oils, benzyl alcohols, gums,
polyalkylene glycols, petroleum jelly, cholesterol and other
known carriers for medicaments. If desired, these pharmaceu-
tical compositions may contain auxiliary substances such as
preserving agents, wetting agents, stabilizing agents, or other
therapeutic agents such as antibiotics.
The following Examples illustrate the preparation of
intermediates and prostaglandin final products according to the
process of the invention. Melting points and boiling points
are given in degrees Centigrade and are uncorrected. Infrared
da~a àre given in microns and NMR data are given in parts per
million and using a TMS standard.
EXAMPLE I
2-~3~-(p-biphenylcarboxy)-5~-hydroxy-2~-(2-thioxalanyl)cyclop~nt-
l~-yl3acetic acid, y-lactone (II)
To a solution of 2~[3a-(p-biphenylcarboxy)-5~-hydroxy
2R-formyl cyclopent-la-yl]acetic acid, ~-lactone (21 g., 0.06
mole) in dry methylene chloride (500 ml.) and 2-mercaptoethanol
(4.68 g., 0.06 mole) cooled to 0C. under nitrogen was added
boron trifluoride etherate (4 ml., 0.03 mole) over a 15 minute
period. The resultant solution was warmed to room temperature
and stirred for two hours. The reaction was diluted to 900 ml.
with more methylene chloride and washed with water (2 x lOQ ml.).
Drying the methylene chloride layer with anhydrous Na2SO4 follow-
ed by filtering and evaporating under reduced pressure yielded
an oil which solidified upon trituration with hexane. Filtra-
tion, washing with hexane and drying under vacuum yielded the
title compound (~3.9 g., 97% yield) m.p. 146.
-27-
~0~350~3~
Substitution of 3-mercapto-1-propanol for 2-mercapto-
ethanol in the above procedure will provide the corresponding
homologous protected aldehyde which may be converted into the
E2- and F~-prostaglandins by the procedures of Examples II-
XVIII.
EXAMPLE Ia
2-[5~-hydroxy-2~-(2-thioxalanyl)cyclopent-1~-yl]acetic acid, y-
lactone (III')
To a solution of 2-[5~-hydroxy-2~-formylcyclopent-1~-
yl]acetic acid, y-lactone (18.5 g., ~.12 mole) in dry methylene
chloride (500 ml.) and 2-mercaptoethanol (9.36 g., 0.12 mole)
cooled to 0C. under nitrogen is added boron trifluoride ether-
ate (8 ml., 0.06 mole) over a 15 minute period. The resultant
solution is warmed to room temperature and stirred for two hours.
The reaction is diluted to 900 ml. with more methylene chloride
and washed with water (2 x 100 ml.). Drying the methylene chlor-
ide layer with anhydrous Na2S04 followed by filtering and evapor-
ating under reduced pressure yields the title compound.
The product of this Example may be converted into 11-
desoxyprostaglandins by the procedures of Examples IV-XVIII.
Treatment of the formyllactone starting matexial with 3-mercapto-
l-propanol under the above described conditions provides the
corresponding protected aldehyde which may be converted into the
ll-desoxyprostaglandins by the procedures of Examples IV-XVIII.
EXAMPT~ II
2-[3,5-dihydroxy-2~-(2-thioxalanyl)cyclopent-1-yl]acetic acid,
y-lactone (III)
A heterogeneous mixture of crude 2-[3-(p-biphenylcarb-
oxy)-5-hydroxy-2~-(2-thioxalanyl)cyclopent-1]-yl acetic acid,
- 30 y-lactone (23.5 g., 0.057 mole) absolute methanol (230 ml.) and
-28-
lo~r~o~33
finely powdered anhydrous potassium carbonate (3.95 g., 0.028
mole) was stirred at room temperature overnight. The precipit-
ated solid was filtered and washed with methanol. The filtrate
was evaporated to approximately 100 ml. and cooled in ice. To
the cooled solution was added O.lN HCl dropwise to bring the
solution to a pH of 3, and the precipitated solids were filter-
ed off. The aqueous layer was saturated with solid sodium
chloride and extracted with ethyl acetate (3 x 50 ml.). Drying
the combined organic layer with anhydrous Na2SO4 followed by
evaporation gave the title compound (12.6 g., 96% yield).
EXAMPLE III
2-[3a-(tetrahydropyran-2-yloxy)-5a-hydroxy-2~-(2-thioxalanyl)-
cyclopent-la-yl]acetic acid, y-lactone (IV)
To a cooled solution (0-5) of crude 2-[3a,5a-dihydroxy-
2~-(2-thioxalanyl)cyclopent-la-yl]acetic acid, y-lactone (2.5 g.,
10.9 mmoles) and freshly distilled dihydropyran (1.47 ml., 16.3
mmoles) in dry methylene chloride (25 ml.) was added ~-toluene-
sulfonic acid monohydrate (250 mg., 1.31 mmoles). The reaction
mixture was stirred for 1.5 hours at 0C., th~n diluted with
ether (60 ml.). The organic solution was washed with saturated
sodium bicarbonate (10 ml.), saturated brine (10 ml.) and dried
over anhydrous sodium sulfate. Concentration under vacuum
afforded the title compound (3.~ g., 100% yield) as an oil.
EXAMPLE IIIa
2-[3a-(dimethyl-t-butylsilyloxy)-5a-hydroxy-2~-(2-thioxalanyl)-
_ __cyclopent-la-yl]acetic acid, y-Lactone (IV)
A mixture of 2-[3a,5a-dihydroxy-2~-(2-thioxalanyl)cyclo-
pent-la-yl]acetic acid, y-lactone ~2.25 g., 10 mmoles), dimethyl-
t-butylsilyl chloride (1.88 g., 12.5 mmoles) and imidazole (1.87
g., 27.5 mmoles) in 5 ml. of dimethylformamide is stirred under
-29-
~0'~0.'33
nitrogen at 37 for 18 hours. The reactlon is concentrated
under reduced pressure and diluted with methylene chloride. The
organic solution is washed with water, dried (anhydrous magnes-
ium sulfate) and concentrated under reduced pressure. Purifi-
cation of the crude product by silica gel chromatography pro-
vides the title compound.
The product of this Example may be converted into the
ll-hydroxyprostaglandins by the procedures of Examples IV-XVII.
EXAMP~E IV
2-[3~-(tetrahydropyran-2-yloxy)-5~-hydroxy-2~-(2-thioxalanyl)-
cyclopent-1~-yl]acetaldehyde, y-hemiacetal (V)
To a solution, cooled to -75 under nitrogen, of crude
2-[3~-(tetrahydropyran-2-yloxy~-Sa-hydroxy-2~-(2-thioxalanyl)-
cyclopent-l~-yl]acetic acid, y-lac~one (3.24 g., 10.3 mmoles)
lS in dry toluene ~50 ml.) was added over a period of 25 minutes a
20% solution of diisobutylaluminum hydride in hexane (14.9 ml.,
12.0 mmoles). After an additional 30 minutes the reaction was
quenched by dropwise addition of methanol and allowed to warm to
room temperature. The toluene was evaporated under reduced
pressure and the residue diluted with ether (200 ml.). The
organic solution was washed with a 50% sodium potassiùm tartrate
solution (3X), saturated brine, then dried with anhydrous Na2SO4
and was concentrated to affoxd the title compound ~3.1 g., 95%
yield) as an oil. The product was purified by column chromato-
graphy on 90 g. of Baker silica gel (60-200 mesh) using benzene~
ethyl acetate as eluents to give the pure title compound (2.9 g.).
The product of this Example may be treated with a phos-
phorane of the structure ~Br~3 wherein Q' is tetrazol-5~yl,
03P~CH2)4Q'
-~NHCR"', -~NHSO2R'I' or ~QH, wherein R"' is alkyl of from one to
-30-
~0~50.~3
four carbon atoms, accordin~ to the procedures of Example V. The
product of this reaction may be converted into the E2- and F2~-
prostaglandins by the procedures of Examples VII-IX and XI-XVIII.
EXAMPLE V
7-[2~-(2-thioxalanyl)-3~-(tetrahydropyran-2-yloxy)-5~-hydroxy-
cyclopent-l~-yl]-cls-5-heptenoic acid (VI)
To a solution of 5-triphenylphosphoniopentanoic acid
t23.045 g., 52.0 mmoles) in dry dimethyl sulfoxide (4~ ml.) was
added dropwise an approximately 2.0N solution of sodium methyl-
sulfinylmethylide (49.3 ml., 98.6 mmoles) in dimethyl sulfoxide.
To the resultant red solution was added over the course of 1.0
hour a solution of 2-[2~-(2-thioxalanyl)-3~-(tetrahydropyran-2-
yloxy)-5~-hydroxycyclopent-1~-yl]acetaldehyde, ~-hemiacetal (6.6
g., 20.8 mmoles) in dry dimethyl sulfoxide (63 ml.). After
being stirred for an additional half hour, the reaction was pour-
ed into ice-water (600 ml.). The basic aqueous solution was ex-
tracted with 2:1 mixture of ethyl acetate:ether (2 x 300 ml.).
The cold aqueous layer was covered with ethyl acetate and acidifi-
ed to pH ~3 with 10~ hydrochloric acid. The aqueous layer was
further extracted with ethyl acetate (2 x 200 ml.) and the com-
bined organic extracts were washed with water followed by brine.
Drying the organic layer over anhydrous sodium sulfate and con-
centrating afford~d a yellow oil weighing 20 g. Addition of
15Q ml. of a mixture of ethyl acetate:ether (2:1) precipitated
a solid which was filtered, washed with ether and the filtrate
evaporated. The yield of crude title compound was 10.2 g. (120%)
which was used directly in the next step.
The product of this Example may be esterified according
to the procedure of ~xample Va with an alkyl diazG compound of
from one to six carbon atoms or phenylalkyl diazo compound of
-31-
~O~iO33
from seven to nine carbon atoms. Alternatively, one equivalent
of the product of this Example may be contacted with ten equiv-
alents of phenol, ~-naphthol or ~-phenylphenol and 1.2 equival-
ents of dicyclohexylcarbodiimide. The resultant esters may be
converted into the E2- and F2a-prostaglandins by the procedures
of Examples VI-IX and XI-XVII.
EXAMPLE Va
Methyl 7-[2~-~2-thioxalanyl)-3a-(tetrahydropyran-2-yloxy)-5~-
hydroxycyclopent-la-yl]-cis-5-heptenoate (VI)
A solution of 7-[2~-(2-thioxalanyl)-3a-(tetrahydropyran-
2-yloxy)-5~-hydroxycyclopent-la-yl]-cis-5-heptenoic acid (520
mg., 1.3 mmoles) in 5 ml. of anhydrous ether is titrated at
room temperature with an ethereal diazomethane solution until
the yellow color persists for 5 minutes. The reaction is then
decolorized by the dropwise addition of glacial acetic acid. The
ethereal solution is then washed with saturated sodium bicarbon-
ate and saturated brine, is dried (anhydrous magnesium sulfate),
and is concentrated under reduced pressure to provide the title
compound.
The product of this Example may be converted into E2-
and F2~-prostaglandins by the procedures of Examples VI-IX and
XI-XVII.
EXAMPLE VI
7-[2~-formyl-3a-(tetrahydropyran-2-yloxy)-5a-hydroxycyclopent-
la yl]-cis-5-heptenoic acid (VII)
=
To a solution of 7-[2~-(2-thioxalanyl)-3a-(tetrahydro-
pyran-2-yloxy)-5a-hydroxycyclopent-la-yl]-c -5-heptenoic acid
(2.0 g., 0.005 mole) 4:1 acetonitrile:water ~85 ml.) was added
sequentially anhydrous calcium ~arbonate (2.87 g., 0.029 mole)
and mercuric chloride (5.4 y., 0.020 mole). The mixture was
-32-
~0~5033
stirred and heated at 50C. under nitrogen for a half hour. The
mixture was filtered through Celite and washed with ether (250
ml.). The combined filtrate was stirred and treated with lN
hydrochloric acid (3 ml.). The ether layer was separated and
washed with brine (3 x 15 ml.). Drying over anhydrous sodium
sulfate and concentration at reduced pressure afforded 1.7 g.
(100%) of the title compound as an oil.
The product of this Example may be treated with a
phosphonate of the formula (MeO)2~CH2~A wherein A is alkyl of
from four to eight carbon atoms, 2-indanyl, or a substituent of
the formula Ar(CH2)n~ or Ar'OCH2- wherein n is one or two and
Ar is a-naphthyl, ~-naphthyl, ~-furyl, a-thienyl, phenyl or mono-
substituted phenyl in which the substituent is fluorine, chlorine,
trifluoromethyl, phenyl or alkyl or alkoxy of from one to six
carbon atoms; and Ar' is phenyl or monosubstituted phenyl in
w~ich the substituent is fluorine, chlorine, trifluoromethyl,
phenyl or alkyl or alkoxy of from one to six carbon atoms accord-
ing to the procedures of Example VII or XIII. The product of
this reaction may be converted into the PGF2a,S by the procedures
of Example ~III and IX.
EXAMPLE VII
9~-hydroxy~ tetrahydropyran-2-yloxy)-15-oxo-cis-5-trans-13-
prostadienoic acid (VIII)
To a solution~ under nitrogen, of dimethyl(2-oxo-heptyl)-
phosphonate t2 g., 0.009 mole) in dimethoxyethane (30 ml.) cooled
to 0~C. was added dropwise 2.2M n-butyl lithium (3.96 ml., 0.0087
mole). A~ter stirring for one hour 7-[2~-formyl-3a-(tetrahydro-
pyran-2-yloxy)-5a-hydroxycyclopent-1~-yl~-cis-5-heptenoic acid
(1.02 g., 0.003 mole) dissolved in dimethoxyethane ~6 ml.) was
added quickly and the mixture stirred at room temperature for a
-33-
~ o~o~
half hour, it was brought to pH -7 with glacial acetic acid.
The neutralized solution was concentrated by rotary evaporation
and the resultant solid was slurried in benzene and filtered.
Concentration o~ the filtrate afforded the crude title compound
which was purified by chrornatography on silica gel using
benzene~ethylacetate as eluant to give the pure title compound
(710 mg.).
The product of this Example may be acylated according
to the procedure of Example XI to form the product of Example
XIII.
EXAMPLE VIII
9~-15}dihydroxy-lla-~tetrahydropyran-2-yloxy)-cis-5-trans-13-
prostadienoic acid (IX)
To a solution of 9~-hydroxy-11~-~tetrahydropyran-2-yl-
oxy)-15-oxo-cls-5-trans-13-prostadienoic acid (0.15 g., 0.343
mmole) in dimethox~ethane (3 ml.) was added a 0.5M solution of
zinc borohydride (1.75 ml., 0.17 mmole) in dimethoxyethane. The
reaction was stirred at room temperature under nitrogen for 2.5
hours then was cooled in ice. ~he cold reaction mixture was
quenched by the addition of a saturated sodium bitartrate solu-
tion dropwise until hydrogen evolution ceased. The mixture was
diluted with ethyl acetate (25 ml.), acidified to about pH 4
with cold lN HCl with rapid stirring. ~h~ ethyl acetate layer
was dried with sodium sulfate and concentrated to afford the
oily epimeric mixture of the title compounds weighing 0.13 g.,
(Rf 0.25 on t.l.c. using 15:5:2 mixture of benzene:dioxan:formic
- acid as eluant), suitable for directly using in the next step.
EXAMPLE IX
PGF2a (X)
A homogeneous solution of-crude 9a,15a-dihydroxy-lla-
-34-
~L0~5033
(tetrahydropyran-2-yloxy)-c -5-trans-13-prostadienoic acid
(0.117 g., 0.267 mmole) in a 65:35 mixture of glacial acetic
acid:water ~5 ml.) was stirred under nitrogen at room tempera-
ture for 16 hours then was concentrated by rotary evaporation
followed by oil pump at 25C. The resultant oil was chromato-
graphed on 5 g. silica gel (CC-7) using chloroform~ethyl acetate
to give 15 mg. 15-epi-PGF2~ followed by 30 mg. of PGF2~, ident-
ical with an authentic sample by IR and NMR.
EXAMPLE X
N-Methanesulfonyl 7-~2~-(1,3-oxathialan-2-yl)-3~-(tetrahydro-
pyran-2-yloxy~-5~-hydroxycyclopent-1~-yl]-cls-5-heptenamide (VI)
To a solution of 27.0 g. (52.0 mmoles) of (4-methane-
sulfonylaminocarbonyl-n-butyl)triphenylphosphonium bromide in
46 ml. of dimethyl sulfoxide is added dropwise 49.3 ml. (98.6
mmoles) of a 2.OM solution of sodium methylsulfonylmethylide in
dimethyl sulfoxide. To the resultant red solution is added over
the course of 15 minutes a solution of 6.6 g. (20.8 mmoles) of
the hemiacetal prepared in Example IV in 63 ml. of dimethyl sulf-
oxide. After being stirred for an additional 2.0 hours, the re-
action is poured onto 600 ml. of ice-water. The cold aqueous
layer is covered with ethyl acetate and acidified to pH ~3 with
10~ hydrochloric acid. The acidified aqueous layer is furtner
extracted with ethyl acetate ~2 x 200 ml.) and the combined
organic ext'racts are washed with water followed by brine. Drying
the organic layer over anhydrous sodium sulfate and concentration
affords the crude product which is triturated with eth~r. Concen-
tration of the ether provides N-methanesl~lfonyl 7-~2~-(1,3-
oxathialan-2-yl)-3~-(tetrahydropyran-2-yloxy)-5~-hydroxycyclo-
pent-lq~yl)]-cls-5-heptenamide (VI).
The product of this Example may be acylated according to
-35-
~0~ Q.~3
the procedure of Example XI employing either ~R"~)2O or R"~Cl
wherein R" is alkyl of from one to four carbon atoms, ~-naphthyl,
phenyl, p-biphenyl or phenylalkyl of from seven to nine carbons.
This product may be converted into the E2-prostaglandins accord-
ing to the procedures of Examples XII-XVIII.
EXAMPLE XI
N-Methanesulfonyl 7-[2~-(1,3-oxathialan-2-yl)-3~-(tetrahydropyran-
2- lox )-5a-acetox c clopent-1~-yl]-cis-5-heptenamide (XII)
Y Y Y Y _ _ _
A mixture of 1.69 g. (3.54 mmoles) of the crude hydroxy
compound VI prepared in Example X, 5.0 ml. of pyridine and 0.368
ml. (3.89 mmoles~ of acetic anhydride is stirred under nitrogen
at 50 overnight. The mixture is then cooled to room tempera-
ture and is diluted with ether ~75 ml.). The ethereal solution
is washed with water ~lx) and with saturated copper sulfate (3x),
is dried (anhydrous magnesium sulfate), and is concentrated to
afford the desired N-methanesulfonyl 7-~2~-(1,3-oxathialan-2-yl)-
3~-(tetrahydropyran-2-yloxy~-5a-acetoxycyclopent-1-yl]-c -5-
heptenamide (XII).
EXAMPLE XII
N-Methanesulfonyl 7-[2~-formyl-3~-(tetrahydropyran-2-yloxy)-5~-
acetox c clo ent-l~- l]-cis-5-he tenamide (XIII)
Y Y P Y , . P
To a solution of 2.9 g. (5.0 mmoles) of the hemithio-
acetal XII prepared in Example XI in 85 ml. of acetonitrile:water
(4:1) is added sequentially 2.87 g. (0.029 mmole) anhydrous
calcium carbonate and 5.4 g. (0.020 mmole) mercuric chloride.
The mixture is stirred and heated at 50 under nitrogen for 0.5
hr. The mixture is filtered through C~lite and washed with 250
ml. ether. The combined filtrate is stirred and treated with 3
ml. of lN hydrochloric acid. The ether layer is sep~rated and
washed with brine (3 x 15 ml.). Drying over anhydrous sodium
-36-
~O~iO.'33
sulfate and concentratlon at reduced pressure afforded the de-
sired N-methanesulfonyl 7-[26-formyl-3~-(tetrahydropyran-2-yl-
oxy)-5~-acetoxycyclopent-1~-yll-cls-5-heptenamide (XIII).
The product of this Example may be treated with a phos-
phonate of the formula (MeO)2~CH2~A wherein A is alkyl of from
four to eight carbon atoms, 2-indanyl, or a substituent of the
formula Ar(CH2)n- or Ar'OCH2- wherein n is one or two and Ar is
~-naphthyl, ~-naphthyl, ~-furyl, ~-th1enyl, phenyl or monosub-
stituted phenyl in which the substituent is fluorine, chlorine,
trifluoromethyl, phenyl or alkyl or alkoxy of from one to six
carbon atoms; and Ar' is phenyl or monosubstituted phenyl in
which the substituent is 1uorine, chlorine, trifluoromethyl,
phenyl or alkyl or alkoxy of from one to six carbon atoms accord-
ing to the procedures of Examples VII or XIII. The product of
this reaction may be converted into the E2-prostaglandins by the
procedures of Examples XIV-XVIII.
EXAMPLE XIII
N-Methanesulfonyl 9~-acetoxy-11~-(tetrahydropyran-2-yloxy)-lS-
oxo-5-cis-13-trans-16-phenoxy-~-tetranorprostadienamide (XIV)
To a suspension of 220 mg. (5.22 mmoles) of a 57.0%
dispersion of sodium hydride in mineral oil in 20 ml. of tetra-
hydrofuran is added 1.34 g. (5.22 mmoles) of dimethyl 2-oxo-3-
phenoxypropyl phosphonate. The mixture is stirred at room
temperature for 1 hour under nitrogen, then a solution of 1.23
g. (2.37 mmoles) of the crude aldehyde XIII prepared in Example
XII in 4 ml. of tetrahydrofuran is added. The resultant mix-
ture is stirred at room temperature for 2.0 hours under nitrogen.
The reaction i5 then quenched by the addition of glacial acid
~ to pH -6 and is concentrated by rotary evaporation.
The resultant mixture is dissolved in ethyl acetate,
-37-
10~5033
the organic layer is washed with O.lN hydrochloric acid, water
and saturated brine, is dried (anhydrous magnesium sulfate) and
concentrated. Purification of the crude product by column
chromatography affords the desired N-methanesulfonyl 9a-acetoxy-
lla-(tetrahydropyran-2-yloxy)-15-oxo-5-cis-13-trans-16-phenoxy-
~-tetranorprostadienamide (XIV).
EXAMPLE XIV
N-Methanesulfonyl 9a-acetoxy-lla (tetrahydropyran-2-yloxy)-15a-
hydroxy-16-phenoxy-5-cis-13-trans-~-tetranorprostadienamide (XVa)
and
N-Methanesulfonyl 9a-acetoxy-lla-(tetrahydropyran-2-yloxy~-15~-
hydroxy-16-phenoxy-5-cis-13-trans-~-tetranorprostadienamide (XVb)
To a solution, cooled to -78 under nitrogen, of 1.24 g.
(2.1 mmoles) of the lactone XIV prepared in Example XIII in 12
ml. of tetrahydrofuran is added 4.3 ml. of a l.OM solution of
lithium triethylborohydride in tetrahydrofuran. The mixture is
stirred in the cold for 45 minutes then quenched by the addition
of a 9:1 mixture of water:acetic acid. The mixture is let warm
then diluted with ethyl acetate. The organic solution is washed
with water (2x; and saturated brine, is dried (anhydrous magnes-
ium sulfate) and concentrated. Purification of the crude product
by column chromatography provides first N-methanesulfonyl 9a-
acetoxy~ -(tetrahydropyran-2-yloxy)-15~-hydroxy-16-phenoxy-5-
cis-13-trans-~-tetranorprostadienamide (XVb) and further elution
prcvides N-methanesulfonyl 9a-acetoxy-lla-(tetrahydropyran-2-yl-
oxy)-15a-hydroxy-16-phenoxy-5-c -13-trans-~-tetranorprostadien-
amide (XVa).
The 15~-compounds of this Example may be converted into
- the 15-epi-E-prostaglandins by the procedures of Examples XV-
XVIII.
-38-
~o~r;033
~XAMPLE XV
N-Methanesulfonyl 9~-acetoxy~ ,15~-bis-(tetrahydropyran-2-yl-
oxy)-16-phenoxy-5-c1s-13-trans-~-tetranorprostadienamlde (XVI)
A mixture of 0.303 g. (0.510 mmole) of the chromato-
graphed alcohol XVa of Example XIV, 0.14 ml. (1.53 mmoles) of
dihydropyran, 4.2 ml. of methylene chloride, and 1 crystal of
~-toluenesulfonic ac1d monohydrate 1s stirred at room temperature
under nitrogen for 20 m1nutes. The reaction mixture is then
diluted with ether, is washed with water and saturated brine,
is dried (anhydrous magnesium sulfate), and concentrated to
give the desired N-methanesulfonyl 9~-acetoxy-11~,15~-bis-
(tetrahydropyran-2-yloxy)-16-phenoxy-5-c -13-trans-~-tetranor-
prostadienamide (XVI).
- EXAMPLE XVI
N-Methanesulfonyl 9~-hydroxy-11~,15~-bis-(tetrahydropyran-2-yl-
oxy)-16-phenoxy-5-cis-13-trans-~-te ranorprostadienamide (XVII)
A homogenous solution of 0.295 g. (0.436 mmole) of the
crude bis-THP ester XVI prepared in Example XV, 1.3 ml. (1.30
mmoles) of a l.ON aqueous sodium hydroxide solution, 1.3 ml. of
methanol, and 1.3 ml. of tetrahydrofuran is stirred under nitro-
gen overnight. The reaction is then quenched by the addition of
1.30 ml. ~1.3Q mmoles) of a l.ON aqueous hydrochloric acid solu-
tion. The quenched solution is diluted with ethyl acetate. The
organic layer is dried (anhydrous magnesium sulfate) and concen-
trated. The crude product is purified by column chromatography
to afford the desired N-methanesulfonyl 9~-hydroxy-11~,15~-b
(tetrahydropyran-2-yloxy)-16-phenoxy-5-cis-13-trans-~-tetranor-
prostadienamide (XVII).
-39-
~10~033
EXAMPLE XVII
N-Methanesulfonyl 9-oxo-lla,15a-bis-(tetrahydropyran-2-yloxy)-
16 henox -5-cis-13-trans-~-tetranor rostadienamide (XVIII)
_p y P
To a solution, cooled under nitrogen to -15 to -20 of
236 mg. (0.371 mmole) of the chromatographed methanesulfonimide
XVII in Example XVI in 4.0 ml. of acetone is added dropwise
0.163 ml. (0.408 mmole3 of Jones' reagent. The reaction is
stirred in the cold for 15 minutes then is quenched by the addi-
tion of 0.194 ml. of isopropanol. The quenched reaction is
`10 stirred in the cold for 5 minutes then is diluted with ethyl
acetate. The organic solution is washed with water (2x) and
saturated brine (lx), is dried (anhydrous magnesium sulfate),
and is concentrated to afford the desired N-methanesulfonyl
9-oxo-11,15a-bis-(tetrahydropyran-2-yloxy)-16-phenoxy-5-c -13-
15 trans-~-tetranorprostadienamide (XVIII).
EXAMPLE XVIII
N-Methanesulfonyl 9-oxo-lla,15a-dihydroxy-16-phenoxy-5-cis-13-
trans-~-tetranorprostadienamide (XIX~
A homogenous solution of 208 mg. (0.328 mmole~ of the
20 crude THP ether XVIII of Example XVII in 5 ml. of a 65:35 mix-
ture of acetic acid:water is stirred under nitrogen at ambient
temperature for 13 hours. The reaction is concentrated by
rotary evaporation followed by oil pump. The crude, product is
purified by column chromatography on silica gel to provide the
25 desired N-methanesulfonyl 9-oxo-lla,15a-dihydroxy-16-phenoxy-5-
cis-13-trans-~-tetranorprostadienamide (XIX).
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