Note: Descriptions are shown in the official language in which they were submitted.
' -~` 10~.~8
This invention relates to new 1,3-benzodioxan-prostanoic
acid derivatives and to a process for producing them.
It is generally known that the numerous actions of pro-
staglandins both in the mammalian organism and in vitro are only
of short duration, because they are rapidly converted into pharm-
acologically inactive products of metabolism. Thus, by the
oxidation of the allylic hydroxy-function at carbon atom 15 by
15-hydroxy-prostaglandin dehydrogenases there is formed a largely
inactive metabolite.
It is therefore desirable to develop prostaglandin ana-
~ logues having a spectrum of action comparable to the natural pro-
; staglandins and to bring about structural alterations by means of
; which the duration and selectivity of the activity is increased.
It has now surprisingly been found that the 1,3-benzo-
dioxan-prostaglandins of the present invention have a longer
duration of action, greater selectivity and a better activity
than the natural prostaglandins.
The present invention accordingly provides 1,3-benzo-
dioxan-prostanoic acid derivatives of the general formula I
?
/ Z~ \B~\/\CORl
R
OH
,i
ri in which Rl represents a hydroxyl group, an aliphatic hydrocarbon-
oxy group containing 1 to 10 carbon atoms, a methyl-sulphamide
group, an unsubstituted or substituted aryloxy group or a group
of the formula -O-CH2-U-V, in which U represents a direct bond
- 1 - ~
. .
" ` '` 10~7178
or a carbonyl or carbonyloxy group and V represents a phenyl
group substituted by one or more substituents selected from
- phenyl groups, aliphatic hydrocarbon-oxy groups containing 1 and
2 carbon atoms and halogen atoms, preferably bromine atoms
A represents a -CH2-CH2- or a trans -CH=CH-group;
B represents a -CH2-CH2- or a cis or trans -CH=CH-group;
Z represents a hydroxymethylene or carbonyl group;
X Y, when Z represents a hydroxymethylene group, represents a
-CH2-CH- or -CH2-C- group and, when Z represents a carbonyl
OH
group, represents a -CH2-CH- or - CH=CH- group;
-- . .
: : .
R2 represents a hydrogen atom and R3 and R4 each represents a
~; hydrogen, fluorine, chlorine, bromine or iodine atom, a tri-fluoromethyl or methyl group or an aliphatic hydrocarbon-oxy
group containing 1 or 2 carbon atoms t and physiologically
; tolerable salts with bases of such compounds in which Rl repre-
s sents a hydroxyl group.
The present invention includes within its scope both
2~ the antipodes and the racemates of the new compounds defined
.!' above.
, The unsubstituted or substituted aryloxy groups
represented by Rl include phenoxy, l-naphthoxy and 2-naphthoxy
groups, each of which may be substituted by 1 to 3 halogen atoms,
one phenyl group, one to three alkyl groups each containing 1
to 4 carbon atoms or one chloromethyl, fluoromethyl, trifluoro-
methyl, carboxyl or hydroxyl group.
The aliphatic hydrocarbon-oxy groups represented by Rl
include straight and branched chained, saturated and unsaturated,
aliphatic hydrocarbon-oxy groups, preferably saturated groups
containing 1 to 10, and especially 1 to 6, carbon atoms. There
may be mentioned, for example, methoxy, ethoxy, propoxy, butoxy,
: 10~71~8
isobutoxy, t-butoxy, pentoxy, hexoxy, heptoxy, octoxy, butenyloxy,
isobutenyloxy and propenyloxy groups.
he symbols R3 and R4 may have the same or different
meanings.
For salt formation, there come into consideration all
those inorganic and organic bases that are known to those skilled
in the art for forming physiologically tolerable salts including
alkali metal hydroxides, for example, sodium or potassium hydro-
xide, alkaline earth metal hydroxides, for example, calcium
hydroxide, ammonia and amines, for example, ethanolamine, diethan-
olamine, triethanolamine, N-methylglucamine, morpholine and
tris-(hydroxymethyl)-methylamine.
The present invention also provides a process for
producing the new 1,3-benzodioxan-prostanoic acid derivatives
of the yeneral formula I and physiologically tolerable salts with
bases of such compounds in which Rl represents a hydroxyl group,
wherein a lactol of the general formula II
-
:, . .
~, OH
0~\ ' '
~ OR5 oR6
,, .
in which R2, R3, R4 and A have the above meanings and R5 and R6
each represents a hydrogen atom or a hydroxyl-protecting group,
, .
_3_
7178
.:
` is reacted with a Wittig reagent of the general formula III
:~ Ph3P CH - (CH2)3 - CORl (III)
in which Ph represents a phenyl group and Rl has the above meaning,
, to form a compound of the general formula
'
,r OH
0~ F~4
. OR5
OR6
in which R2, R3, R4, R5, R6 and A have the above meanings and g
represents a cis of trans -CH=CH- group, and then, if desired,
` after oxidation of the 9-hydroxyl group to form a 9-keto group,
.~ .
` any hydroxyl-protecting groups are split off and, if desired,
.j (depending on the finally desired meanings of Rl, R2, R3, R4,
A, B, X Y and Z in the end product) and in any desired order
. of succession, any free l-carboxyl group is esterified or any
esterified l-carboxyl group is hydrolyzed, and/or any 9-keto
group is reduced, and/or the 5,6-double bond is hydrogenated,
and/or any 13,14-double bond is hydrogenated, and/or any 9-keto-
hydroxy-compound is dehydrated with the elimination of the 11-
hydroxyl group, and/or the 9-hydroxyl group in any 9,11-dihydroxy-
. compound, after intermediate protection of the 11- and 15-hydroxyl
groups if they are not already protected, is oxidized to form a
9-keto group, and/or the ll-hydroxyl group in any 9,11-dihydroxy-
compound, after intermediate protection of the 9-hydroxyl group
and if not already protected also the 15-hydroxyl group, is
. oxidized to form an ll-keto group, and/or any l-carboxyl compound
is converted into a physiologically tolerable salt thereof with
a base and/or any racemate is resolved into its anitpodes.
The reaction of the lactol of the general formula II with
-- 4
:
'~
~7178
the Wittig reagent of the general formula III, which is prepared
from the corresponding phosphonium bromide with sodium methane
sulphinyl-methyl or potassium t-butylate in the usual manner in
dimethyl sulphoxide, is carried out at a temperature of 0 to
100C, preferably 20 to 80C, in an aprotic solvent, preferably
dimethyl sulphoxide or dimethylformamide. The Wittig reagent
.~
may also be formed during the reaction from 4-Rl-CO-triphenyl-
butyl phosphonium bromide with potassium t-butylate.
The oxidation of the 9-hydroxyl group to the ketone,
which may be carried out before splitting off any hydroxyl-
protecting groups, is carried out with the usual oxidizing agents,
for example, Jones reagent (J.Chem.Soc. 1953, 2555). There is
used an excess of the oxidizing agent in a suitable diluent, for
example, acetone, at a temperature between o and -50C, and pre-
ferably at -20C. The reaction has generally terminated after 5
to 30 minutes.
~ .
The oxidation of the 9-hydroxyl group is preferably car-
; ried out after intermediate protection of any free 11- and 15-
hydroxyl groups, for example, by silylation [Chem.Comm. (1972),
1120]. Other suitable oxidizing agents are silver carbonate on
"Celite" ~ or a mixture of chromium trioxide and pyridine (Tetra-
hedron Letters 1968, 3363).
The oxidation of the ll-hydroxyl group is carried out
with the usual oxidizing agents, for example, Jones reagent or
Collins reagent after intermediate protection of the 9- and 15-
hydroxyl groups. There is used a temperature between -40 and
20C, and preferably -20C.
As hydroxyl-protecting groups there are introduced
groups known to those skilled in the art, preferably those of
cyclic ~,~-unsaturated ethers, for example, dihydropyran, di-
hydrofuran and ~-ethoxyethylene, and acyl groups, for example,
aromatic and aliphatic organic acid groups, but preferably the
-- 5 --
, . . .
x "'~~ las7~7s
benzoyl and acetyl groups.
The splitting off of the hydroxyl-protecting groups, for
example, tetrahydropyranyl and tetrahydrofuranyl groups, to form
the compounds of the general formula I is carried out by known
methods in an aqueous solution of an organic acid, for example,
-~ acetic acid or propionic acid, or in an aqueous solution of an
inorganic acid, for example, hydrochloric acid. In order to
improve the solubility, it is of advantage to add an inert organic
solvent miscible with water. Suitable organic salvents include
alcohols, for example, methanol and ethanol, and ethers, for
example, dimethoxyethane, dioxan and tetrahydrofuran. Tetra-
hydrofuran is preferably used. The hydrolysis is preferably
carried out at a temperature between 20 and 80C. In the case
of compounds of the prostaglandin E-type, the hydrolysis is car-
: ried out at below 45C in order to avoid the formation of pro-
staglandin-A compounds as by-products.
The splitting off of acyl groups is carried out with
alkali metal carbonates, for example, potassium carbonate in
methanol at 0 to 50C, and preferably at 25C.
The reduction of the 9-oxo-group to form a mixture of
! the epimeric 9~- and 9~-alcohols is carried out in the usual
manner, preferably in an organic solvent with sodium borohydride
or zinc borohydride. When zinc borohydride is used, there come
into consideration as solvents, for example, dimethoxyethane,
~- diethyl ether, dioxane, benzene and isopropyl ether. When sodium
borohydride is used, suitable solvents include methanol, ethanol,
isopropanol and n-propanol. The resulting epimeric mixture is
split up, for example, in the usual manner by column or layer
chromatography and/or fractional crystallization.
The dehydration of the 9-oxo-compound, by which the 11-
hydroxyl group and a hydrogen atom from the 10-position are split
off to form a prostaglandin-A derivative, may be carried out under
- 6 -
~ 7178
conditions that are generally known to those skilled in the art.
In general, the dehydration is carried out in a solution of an
organic acid, for example, acetic acid, or of an inorganic acid,
for example, hydrochloric acid, at a temperature between 20 and
80C. The reaction has terminated after approximately 2 to 17
hours.
The hydrogenation of the 13,14-and/or 5,6-double bond(s)
is carried out in a known manner in an atmosphere of hydrogen in
the presence of a noble metal catalyst. A suitable catalyst is,
for example, 10% palladium on carbon. When the hydrogenation is
carried out at room temperature, both the 5,6-double bond and
the 13,14-double bond can be saturated. At low temperatures,
preferably at -80 to -10C, the cis-5,6-double bond can be hydro-
genated before the trans-13,14-double bond. A selective reduction
of the cis-5,6-double bond in the presence of a trans-13,14-
double bond is also effected with the catalyst nickel boride
or tris-(triphenylphosphine)-rhodium(I) chloride.
For preparing esters of the general formula I, in which
Rl represents an aliphatic hydrocarbon-oxy group containing 1 to
10 carbon atoms, the l-carboxy-compound is reacted with a diazo-
hydrocarbon in a known manner. The esterification with a diazo-
hydrocarbon is carried out, for example, by mixing a solution of
the diazo-hydrocarbon in an inert solvent, preferably in diethyl
; ether, with the l-carboxy-compound in the same solvent or in
another inert solvent, for example, methylene chloride. After
the reaction has terminated in 1 to 30 minutes, the solvent is
removed and the ester is purified in the usual manner. ~ -
Diazo-alkanes are either known or can be prepared by
known methods [Org.Reactions, Vol. 8, pages 389 - 394 (1954)].
For introducing the ester group of the formula -O-CH2-U-V
represented by Rl, the l-carboxy-compound of the general formula I
is reacted in the presence of an agent capable of splitting off a
-- 7 --
10~7178
hydrogen halide with a halogen compound of the general formula
Hal-CH2.-U-V
in which Hal represents a halogen atom, preferably a bromine atom,
U represents a direct bond or a carbonyl or carbonyloxy group and
V represents a phenyl group substituted by one or more substituents
selected from the phenyl groups, aliphatic hydrocarbon-oxy groups
containing 1 and 2 carbon atoms and halogen atoms, preferably
bromine atoms.
As an agent capable of splitting off a hydrogen halide
there is used, for example, silver oxide, sodium carbonate,
; potassium carbonate, sodium bicarbonate, potassium bicarbonate or
an amine, for example, trimethylamine, triethylamine, tributyl-
amine, trioctylamine or pyridine. The reaction with the halogen
compound is carried out in an inert solvent, preferably in acetone,
acetonitrile, dimethylacetamide, dimethylformamide or dimethyl
sulphoxide at a temperature from -80 to 100C, and preferably at
room temperature.
For preparing esters of the general formula I, in which
Rl represents an unsubstituted or substituted aryloxy group, the
l-carboxy-compound is reacted with the corresponding hydroxy-aryl
compound with dicyclohexyl-carbodiimide in the presence of a suit-
able base, for example, pyridine or triethylamine, in an inert
solvent. Suitable solvents include methylene chloride, ethylene
chloride, chloroform, ethyl acetate and tetrahydrofuran, but pre-
ferably chloroform. The reaction is carried out at a temperature
between -30 and 50C, and preferably at 10C.
The hydrolysis of the prostaglandin esters is carried out
by methods known to those skilled in the art, for example, with
potassium hydroxide in methanol.
The prostaglandin derivatives of the general formula I
in which Rl represents a hydroxyl group can be converted into salts
by neutralization with equivalent quantities of the corresponding
. , ~ ,
10~7~78
inorganic bases. For example, the solid inorganic salt is obtained
by dissolving the corresponding PG-acid in water, which contains
the stoichiometric quantity of the base, after evaporating the
water or after the addition of a solvent miscible with water,
for example, alcohol or acetone.
For preparing an amine salt the PG-acid is dissolved in a
suitable solvent, for example, ethanol, acetone, diethyl ether or
- benzene, and at least the stoichoimetric quantity of the amine
is added to this solution. In such manner, the salt is usually
obtained in the solid form.
:
The lactols of the general formula II used as starting
compounds in the process of the present invention can be prepared
, by reacting a 2-hydroxymethyl-phenol (a saligenin) with a dihalogen-
carboxylic acid to form a 1,3-benzodioxan-2-carboxylic acid of;,
the general formula IV
~ ' .
, 20 ~ ~ 2 (IV),
'`l
.
in which R2, R3 and R4 have the above meanings. The 1,3-benzo-
~ dioxan-2-carboxylic acid thus obtained, because of the asymmetric
.;,
carbon atom in the 2-position, is in the form of a racemate,
, which can be separated by salt formation with optically active
,.......... .
bases into the optical anitpodes. The subsequent esterification
may be carried out with the racemate or with the enantiomers.
The 1,3-benzodioxan-2-carboxylic acid ester thus obtained is
reacted with triphenyl-phosphine-methylene or a methyl-phosphonic
acid dialkyl ester, and therefrom is subsequently prepared in a
known manner by a Wittig reaction or Wittig-Horner reaction with -
an aldehyde (preferably in the form of the corresponding antipodes)
_ g _
'.:
~7178
; a ketone of the general formula V
.~
O
O~
-- /\~>< 3
<~ \~>I~O/~R4
OR5
. .
in which R2, R3, R4 and R5 have the above meanings. The
optionally resulting mixture of C16-diastereoisomers may be
separated by the usual methods.
-~ In the presence of a noble metal salt catalyst, the
ketone of the general formula V can be hydrogenated in an inert
l~ solvent, if desired, in the 13,14-position (PG-numbering).
,3~ The subsequently effected reduction to the ~-and
C15-alcohols is carried out with sodium borohydride or zinc
borohydride. The mixture of epimers can be resolved by the usual
known methods. After introducing hydroxyl-protecting groups, for
~20 example, with dihydropyran, in the 15-position and, if desired,
- ~:
in the ll-position (PG-numbering), the lactone is reduced with
diisobutyl aluminium hydride or lithium tri-t-butoxy-aluminium
hydride to form the desired lactol of the general formula II.
The reduction to form the lactol of the general formula
II may also be carried out without protecting groups by a simpli-
fied Corey synthesis according to applicants German Patent
Publication No. P 23 28 131 published 2, 1, 1975 with diisobutyl
aluminium hydride or lithium tri-t-butoxy-aluminium hydride.
For introducing the nydroxyl-protecting groups, the
11,15-diol ~PG-numbering) is reacted, for example, with dihydro-
pyran in methylene chloride or chloroform using an acid condensing
agent, for example, para-toluene sulphonic acid. The dihydropyran
is
' ' -10- ,~
. .. : - .- : . .
~ 7178
used in excess, preferably in a quantity 4 to 10 times the theo-
. retical requirement. The reaction has normally terminated at 0
to 30C after 15 to 30 minutes.
One way of preparing the starting compounds acetylated in
, the ll-position is to react the lactol etherified in the 15-
position (PG-numbering) with acetic anhydride in pyridine. By
liberating the lactol-hydroxyl group, a lactol of the general
formula II is obtained.
The new prostanoic acid derivatives of the general
, 10 formula I are valuable pharmaceutical products, because, coupled
with a similar spectrum of action, they have a considerably strong-
er and above all considerably more prolonged action than the
'i~ corresponding natural prostaglandins.
The new prostaglandin analogues of the E-, D- and F-types -
have a very strong luteolytic action, that is to say, to cause
; luteol~sis considerably smaller dosages are required than in the
case of the corresponding natural prostaglandins.
Moreover, for causing abortions considerably smaller
quantities of the new prostaglandin an~logues are required as
compared with those required by the natural prostaglandins.
In the recording of isotonic uterus contraction on the
narcotized rat and on the isolated rat uterus, it is found that
the compounds of the present invention are considerably more
active and their actions last longer than in the case of the
natural prostaglandins, as is shown in the following table with
the compounds numbered 1 to 8 of the present invention as com-
pared with natural PG F2~. The tests were carried out on pregnant
rats by the usual methods. Thus, pregnant rats at the 4th to
7th day of gestation were treated subcutaneously with the com-
pounds of the present invention. On the 9th day the animals werekilled and the uteri examined at the places of implantation.
7178
T a b 1 e
Tested compound Relative action
PG F2~ = 1 on
abortion in the rat
. (5Z,13E)_(8R,9S,llRI12R,15R)-9,11,15-
;, Trihydroxy-15-(~2S)-1,3-benzodioxan-
i 2-yl)-16,17,18,19,20-pentanor-prosta- 300
dienoic acid methyl ester
(5Z,13E)-(8R,9S,llR,12R,15R)-9,11,15- ; :
Trihydroxy-15-((2RS)-1,3-benzodioxan-
l 2-yl)-16,17,18,19,20-pentanor-prosta- 30
dienoic acid methyl ester ~;~
(5Z,13E)-(8R,9S,llR,12R,15R)-9,11,15-
Trihydroxy-15-((2S)-1,3-benzodioxan- 30 ~ .
2-yl)-16,17,18,19,20-pentanor-prosta- :
I dienoic acid (4-phenyl)-phenacyl ester
(5Z,13E)-(8R,9S,llR,12R,15S)-9,11,15-
4 Trihydroxy-15-((2S)-1,3-benzodioxan- 3
2-yl)-16,17,18,19,20-pentanor-prosta-
dienoic acid (4-phenyl)-phenacyl ester
(5Z,13E)-(8R,9S,llR,12R,15R)-9,11,15-
Trihydroxy-15-((2R)-1,3-benzodioxan- 3
2-yl)-16,17,18,19,20-pentanor-prosta-
dienoic acid
(5Z,13E)-(8R,9S,llR,12R,15S)-9,11,15-
6 Trihydroxy-15-((2R)-1,3-benzodioxan- 3
2-yl)-16,17,18,19,20-pentanor-prosta-
dienoic acid methyl ester
.~ (5Z,13E)-(8R,9S,llR,12R,15S)-9,11,15-
7 Trihydroxy-15-(¦2RS)-1,3-benzodioxan- 10
. 2-yl)-16,17,18,19,2o-pentanor-prosta-
- dienoic acid methyl ester
(5Z,13E)-(8R,9S,llR,12R,15S)-9,11,15-
8 Trihydroxy-15-((2R)-1,3-benzodioxan- 10
2-yl)-16,17,18,19,20-pentanor-prosta-
dienoic acid methyl ester
- 12 -
~ ' . '' . ' '
lO~t~8
As shown in the table, the compounds of the present
invention in doses 3 to 300 times smaller have as good an abortive
action as 1 mg per animal of PG F2~.
The new prostanoic acid derivatives are suitable, after
a single intrauterine application, for inducing a menstruation,
interrupting a pregnancy or inducing a birth. They are also
suitable for synchronization of the sexual cycle in female mammals,
for example, cattle, apes, pigs and rabbits.
The present invention accordingly further provides a
method of abortion, wherein there is administered in a suitable -
dose to a pregnant female mammal a compound of the present inven-
tion.
The present invention further provides a method of in-
ducing a birth, wherein there is administered in a suitable dose
to a pregnant female mammal a compound of the present invention.
The good dissociation of action of the compounds of the
present invention is exhibited in the investigation of other
unstriated muscular organs, for example, on the ileum of the
guinea-pig or on the isolated trachea of the rabbit, where a
considerably smaller stimulation is observed than by the natural
prostaglandins.
The active compounds of the PG E-series of the present
invention exhibit on the isolated trachea of the rabbit in vitro
a bronchodilatory action and strongly check the secretion of gas-
tric acid, and have a regulating action in disturbances of cardiac
rhythm. The new compounds of the PG A- and PG E-series also
lower the blood pressure and have a diuretic action.
The active compounds of the F-series of the present
invention hvae a less bronchoconstrictive action than does natural
prostaglandin F2~, which is a great advantage when using it
therapeutically~
For medicinal use, the active substancies can be con-
- 13 -
: ~1371~8
~ . .
verted into a form suitable for inhalation, or for oral or parent-
eral application.
The present invention accordingly further provides a
pharmaceutical preparation which comprises a compound of the
present invention, in admixture or conjunction with a pharmaceuti-
cally suitable carrier. The preparations may contain the usual
carriers and auxiliary substances.
For inhalation, the pharmaceutical preparations are ad-
vantageously in the form of aerosol solutions or spray solutions.
For oral application, tablets, dragées or capsules are
suitable.
For parenteral administration sterile aqueous or oily
solutions suitable for injection are prepared.
~;, ..
s The active compounds of the present invention may be used
in combination with the auxiliary substances known and normally
used in galenical medicine, for example, for making preparations
~`l for causing an abortion, for regulating menstruation or for in- ~ -
; ducing a birth. For such purpose, there may be used sterile aqueous
; solutions containing the active substance in an amount of 0.01 to
10 ~g per ml, in the form of an intravenous infusion solution. The
compounds of the general formula I and the salts of such compounds
in which Rl represents a hydroxyl group are especially suitable for
preparing aqueous isotonic solutions. For increasing their solu-
bility, alcohols, for example ethanol and propylene glycol, may be
added.
The following examples illustrate the invention:
Example 1
(5Z,13E)-(8R,9S,llR,12R,15R)-9 11 15-Trihvdroxy-15((2RS)-1,3-
:
benzodioxan-2-~1)-16,17,18,19,20-pentanor-prostadienolc acid and
the methyl ester.
General formula I: A = trans CH=CH; B = cis CH=CH; X .Y =
."
- 14 -
.
-` 10~717B
.
CH2 CH ; z ~C~\OH ; Rl = OCH3, OH; R2,R3,R4 = H; and OH group
OH ~H
at C 15 is ~-positioned.
(a) 1,3-Benzodioxan-2-carboxylic acid methyl ester.
A solution of 12.4 g of saligenin in 100 ml of dimethyl-
formamide is added dropwise to a suspension of 9.6 g of 50% sodium
hydride in 100 ml of dimethylformamide while cooling with ice-
water. The reaction mixture was stirred overnight at room temp-
erature.
j 10 9 ml of dichloracetic acid were added while cooling with
ice to 50 ml of dimethylformamide. While cooling with ice, a sus-
pension of 5.3 g of 50% sodium hydride in 150 ml of dimethylform-
amide was added. The sodium hydride may also be added without a
solvent.
The resulting solution of sodium dichloracetate was added
dropwise at room temperature to the previously prepared disodium
saligenin solution. The reaction mixture was stirred with the
addition of potassium iodide for a total of 5 hours at 60C.
During the last three hours, the dimethylformamide was distilled
with an oil pump. The semi-solid brown residue was acidified to a
; pH of 3 with a concentrated aqueous solution of citric acid, and
extracted with methylene chloride. The organic phase was dried
over magnesium sulphate, and concentrated in a rotary evaporator,
` and a solution of diazomethane was added at about 10C. After
- stirring for one hour at room temperature, the excess of diazo-
methane and the solvent were removed with a water jet pump. The
residue was added to a saturated solution of sodium chloride, and
extracted with methylene chloride, and the organic phase was dried
with magnesium sulphate, concentrated and purif~ed by column
chromatography over silica gel with hexane/5 - 10% ethyl acetate.
6 g of 1,3-benzodioxan-2-carboyxlic acid methyl ester melting at
28 - 29C were obtained.
- 15 -
~717B
(b) [2-Oxo-2-(1,3-benzodioxan-2-yl)-ethylidene]- triphenyl-
phosphorane.
40 ml of a 2.52 m lithium butyl solution in hexane were
added dropwise to a suspension of 39 g of triphenyl-methyl-phos-
phonium bromide in 250 ml of absolute ether at room temperature
under argon, and the whole was stirred for 15 hours, also under
argon and at room temperature. A solution of 9.78 g of 1,3-benzo-
dioxan-2-carboxylic acid methyl ester in 100 ml of absolute ether,
was added dropwise to the vellow ylene-solution, the mixture was
stirred for one hour at room temperature, and filtered to remove
the white precipitate, which was then dissolved in water and
- extracted with ether. The organic phase was combined with the
filtrate, washed with water, dried over magnesium sulphate and con-
centrated to dryness. The residue was purified by column chroma-
tography over silica gel with hexane/20 - 100% ethyl acetate and
then recrystallized from ethyl acetate.
Yield: 12 g, melting at 95 - 98C.
(c) (lS,5R,6R,7R)-6-l(E)-3-Oxo-3-((2RS)-1,3-benzodioxan-2-yl)-1-
propenyl]-7-benzoyloxy-2-oxabicylco[3,3,0]-octan-3-one.
7 g of 1lS,5R,6R,7R)-6-formyl-7-benzoyloxy-2-oxabicylco-
[3,3,0]octan-3-one [E.J.Corey et al. J.Amer.Chem.Soc. 91, 5675
(1969)] and 11.2 g of [2-oxo-2-(1,3-benzodioxan-2-yl)-ethylidene]-
triphenylphosphorane were stirred for 16 hours in 300 ml of benzene
under argon at room temperature. The mixture was then evaporated
to dryness in vacuo. The residue was purified by column chroma-
tography over silica gel with hexane/20 - 60% ethyl acetate as
eluting agent. 5 g of an oil were obtained.
(d) (lS,5R,6R,7R,3'R)-6-[(E)-3-hydroxy-3-((2RS)-1,3-benzodioxan-
2-yl)-1-propenyl]-7-benzoyloxy-2-oxabicylco~3,3,0]octan-3-one.
140 ml of an etheraeal solution of zinc borohydride (pre-
paration: Nuere Methoden der praparativen organischen Chemie, Vol.
4, page 241, Verlage Chemie), were added to a solution of 2 g of
- 16 -
7~78
. .
the ketone obtained as described under (c) in 140 ml of absolute
dimethoxyethane, and the whole was stirred under argon for 2 hours
,- at room temperature. After dilution with 100 ml of ether, water
, :
was cautiously added to the reaction solution, which was then
extracted by agitation with a saturated solution of sodium chloride,
dried over magnesium sulphate and concentrated to dryness in vacuo.
The reaction products were split up by column chromatography over
silica gel with hexane/30 - 60% ethyl acetate as flow agent. The
first product eluted was the ~-alcohol.
Yield: 0.8 g.
-~ (e) (2RS,3aR,4R,5R,6aS,3'R)-4-[(E~-3-hydroxy-3-((2RS)-1,3-
~ . --
benzodioxan-2-yl)-l-propenyl~-5-hydroxy-perhydrocyclopenta
' [b]-furan-2-ol.
- General formula II: A = trans CH=CH; R2,R3,R4~R5~R6 = H;
the OH-group at C-3' is ~-positioned.
,.~
5.5 ml of a solution of 20% strength of diisobutyl-
aluminium hydride (DIBAH) in toluene, were added under argon to
; a solution cooled to -60C of 550 mg of the lacetone-alcohol pre-
pared as described under (d) in 20 ml of absolute toluene, the
whole was stirred for 30 minutes at -60C and the reaction was
terminated by adding dropwise 2 ml of isopropanol. After the
addition of 20 ml of water, the mixture was stirred for 15 min-
utes at 0C, extracted with ethyl acetate and/or methylene chlor-
' ide, agitated with a saturated solution of sodium chloride, dried
s over magnesium sulphate and concentrated to dryness in vacuo.
520 mg of crude product of the above-mentioned lactol were ob-
tained, and the product was used in the next stage without further
purification.
(f) (5Z,13E)-(8R,9S,llR,12R,15R)-9,11,15-Trihydroxy-15-((2RS)-
1,3-benzodioxan-2-yl)-16,17,18,19,20-pentanor-prostadienoic
; acid.
~- General formula I: A = trans CH=CH; B = cis CH=CH; X Y =
.
- 17 -
'
1 ~7178
CH2-CH ; ~ \\~OH ; Rl = OH; R2,R3,R4 = H; the OH group
OH ~ H
at C-15 is ~-positioned.
14.98 ml of a solution of sodium methane-sulphinyl-methyl
in,absolute DMSO (preparation of the solution: 2 g of a suspen- -
sion of 50% strength of sodium hydride were dissolved in 40 ml of
absolute DMSO at 70C) were added to a solution of 3.46 g of 4-
carboxybutyl-triphenyl- phosphonium bromide in 10 ml of absolute
dimethyl sulphoxide (DMSO), and the whole was stirred for 30
minutes at room temperature. The red-brown coloured solution thus
obtained was added dropwise while cooling with water to a solution
of 520 mg of the lactol obtained as described under (e) in 5 ml
of absolute DMSO. The reaction mixutre was then stirred for 2
hours at 50C under argon, then the greater part of the DMSO was
distilled with an oil pump (bath temperature 40 - 50C), 50 ml
of ice-water were added to the residue, and extraction with
ehter was carried out 3 times. The ether extract was discarded.
I The aqueous phase was acidified to a pH of 4 with a solution of
10% strength of citric acid, and extracted by agitation four
times with an ether/hexane mixture (1:1) and three times with
methylene chloride. The organic phases were washed with a sat-
urated solution of sodium chloride, dried over magnesium sul-
phate and concentrated to dryness. The residue was purified by
chroma*ography over silica gel with methylene chloride/l - 10
ethanol as flow agent.
Yield: 310 mg.
(g) The prostaglandin acid obtained as described in (f) was
dissolved in methylene chloride and esterified with an ethereal
solution of diazomethane. The evaporation residue was chromato-
graphed over silica gel with methylene chloride/4% isopropanolas eluting agent. The prostaglandin carboxylic acid methyl ester
identified in the heading of this example was obtained.
- 18 -
.' .: ' . ' ~' ~ :
Yield: 288 mg;
[~]23 = +0.8 tc=o-25; CHC13);
IR: 3400 (wide), 1730, 1590, 1490, 980, 750 cm 1
Example 2
(5Z,13E)-(8R,9S,llR,12R,15S)-9,11,15-Trihydroxy-15-((2RS)-1,3-
_ . . .
benzodioxan-2-yl)-16,17,18,19,20-~Pentanor-prostadienoic acid and
the methyl ester.
General formula I: A = trans CH=CH; B = cis CH=CH; X...Y =
CH2-CH; ~OH ; Rl = OCH3, OH; R2,R3, 4
OH ~H
group at C-15 is ~-positioned.
In the reaction of (lS,5R,6R,7R)-6-[(E)-3-oxo-3-((2RS)-
1,3-benzodioxan-2-yl)-1-propenyl]-7-benoyloxy-2-oxabicyclo[3,3,0]-
octan-3-one described in Example l(d), the ~-alcohol was eluted
from the column as 2nd product:
(a) (lS,5R,6R,7R,3'S)-6-[(E)-3-Hydroxy-3-((2RS)-1,3-benzodioxan-
2-yl)-1-propenyl]-7-benzoyloxy-2-oxabicylco[3,3,0]octan-3-one.
Yield: 0.5 g.
(b) 2RS,3aR,4R,5R,6aS,3'S)-4-~(E)-3-Hydroxy-3-((2RS)-1,3-benzo-
dioxan-2-yl ? - l_propenyl]-5-hydroxy-Perhydrocyclo-penta[b]
; furan-2-ol.
General formula II: ; 2/R3/R4/R5/R6 H;
; the OH group at C-3' is ~-positioned.
410 mg of ~-alcohol obtained as described under (a) were
reacted in a manner analogous to that described in Example l(e)
with diisobutyl-aluminium hydride. 400 mg of crude product were
obtained.
(c) (5Z,13E)-(8R,9S,llR,12R,15S)-9,11,15-Trihydroxy-15-((2RS)-1,3-
benzodioxan-2-yl)-16,17,18,19,20-pentanor-prostadienoic acid.
General formula I: A = trans CH=CH;~ B = cis CH=CH; X Y =
CH2-CH; ~\~OH ; Rl = OH; R2,R3,R4 = H; the OH group
OH ~H
-- 19 --
: , '
',
- ' ~0~7~78
.. ....
at C-15 is ~-positioned.
The 400 mg of lactol obtained as described under (b)
were reacted without further pruification in a manner analogous to
that described in Example l(f) with 2.66 g of 4-carboxybutyl-tri-
phenylphosphonium bromide and 11.52 ml of the sodium methane-
sulphinyl-methyl solution described therein.
Yield: 220 mg.
(d) The prostaglandin acid obtained as described under (c) was
i dissolved in methylene chloride and esterified with an ethereal
solution of diazomethane. The evaporation residue was chromato-
; graphed over silica gel with methylene chloride/4~ isopropanol as -
,~! eluting agent. The prostaglandin carboxylic acid methyl ester
identified in the heading of this example was obtained.
Yield: 198 mg.
[~]D = -0.8 (c=0.25; CHC13);
IR: 3400 (wide), 1730, 1590, 1490, 980, 750 cm
Example 3
.,
(5Z,13E)-(8R,9S,llR,12R,15R)-9,11,15-Trihydroxy-15-((2R)-1,3-
benzodioxan-2-yl)-16,17,18,19,20-pentanor-prostadienoic acid and
the methyl ester.
.,
' General formula I: A = Trans CH=CH; B = cis CH=CH; X Y =
2 CH; z C~OH ; Rl = OCH3, OH; R2,R3,R4 =H; the OH group
OH ~H
,.,
at C-15 is ~-positioned.
(a) (lS,5R,6R,7R)-6-[(E)-3-Oxo-3-((2R)-1,3-benzodioxan-2-yl)-1-
~i propenyl]-7-benzoyloxy-2-oxabicyclol3,3,0]octan-3-one.
~.
x The product was obtained in the form of colourless crystals
by crystallizing the oil described under example l(c) from benzene/
ether.
Melting point: 129 - 130C; [~]D = -147.4C (CHC13).
(b) (lS,5R,6R,7R,3'R)-6-[(E)-3-hydroxy-3-((2R)-1,3-benzodioxan-
. . . .
2-yl)-propenyl]-7-benzoyloxy-2-oxabicyclo[3,3,0loctan-3-one.
- 20 -
., .
.:
:' ' . . :
7178
From 1.5 g of the ketone obtained as described in example
3(a), there was obtained, by the reduction with zinc borohydride
described in example l(d), the ~-alcohol as the first product of
column chromatography.
Yield: 0.61 g;
[~D = -101.3 (CHC13).
(c) (2RS,3aR,4R,5R,6aS,3'R)-4-[(E)-3-hydroxy-3-((2R)-1,3-benzo-
_, _ ,
dioxan-2-yl)-1-propenyl]-5-hydroxy-perhydrocyclo-penta[b]
furan-2-ol.
:
General formula II: A = trans CH=CH; R2,R3,R4,R5,R6 =H;
the OH group at C-3' is ~-positioned.
600 mg of the ~-alcohol obtained as described under (b)
were reacted in a manner analogous to that described in example
l(e) with diisobutyl-aluminium hydride. 450 mg of crude product
were obtained.
(d) (5Z,13E)-(8R,9S,llR,12R,15R)-9,11,15-Trihydroxy-15-((2R)-
(
1,3-benzodio_an-2-yl ? -16,17,18,19,20-~entanor-prostadienoic
j acid.
General formula I: A = Trans CH=CH; B = cis CH=CH; X Y =
CH2-C=H ; ~\OH ; Rl = OH; R2,R3,R4 = H; the OH group at
OH ~H
C-15 is ~-positioned.
The 450 mg of lactol obtained as described under (c) were
reacted without further purification in a manner analogous to that
described in example l(f) with 3.8 g of 4-carboxybutyl-triphenyl- -
phosphonium bromide and 16.5 ml of the sodium methane-sulphinyl-
methyl solution described therein.
Yield: 315 mg. ~-
(e) The prostaglandin acid obtained as described under (d) was
dissolved in methylene chloride and esterified with an ethereal
solution of dizaomethane. The evaporation residue was chromato-
graphed over silica gel with methylene chloride/1-6% isopropanol
- 21 -
: - . -, ............. . - : .
: .
71~78
as flow agent. There was obtained the prostaglandin carboxylic
acid methyl ester identified in the heading of this example.
Yield: 299 mg;
[a]D = -21.2 (c=0.4; CHC13);
IR: 3400 (wide), 1730, 1590, 1490, 980, 750 cm
Example 4
(5Z,13E)-(8R,9S,llR,12R,15S)-9,11,15-Trihydroxy-15-((2R)-1,3-
- , ( ) ,
benzodioxan-2-yl)-16,17,18,19,20-pentanor-prostadienoic acid
and the methyl ester.
General formula I: A = trans CH=CH; B = cis CH=CH; X .Y =
CH2-CH ; ~ \\OH ; Rl = OcH3~ OH; R2~R3,R4 = H; the OH
; OH ~H
group at C-15 is ~-positioned.
~f In the reduction of(ls~5R~6R~7R)-6-[(E)-3-oxo-3-((2R)-l~3-
benzodioxan-2-yl)-1-propenyl]-7-benzoyloxy-2-oxabicyclo[3,3,0]octan-
3-one [the product of example 3(a)] with zinc borohydride des-
cribed under example 3(b), the ~-alcohol was eluted as second
product from the column:
s (a) (lS,5R,6R,7R,3'S)-6-[(E)-3-hydroxy-3-((2R)-1,3-benzodioxan-
x . _
2-yl)-~propenyl]-7-benzoyloxy-2-oxabicyclo[3,3,0]0ctan-3-one.
Yield: 0.41 g;
~'
[a]D = -128 (CHC13).
(b) (2RS,3aR,4R,5R,6aS,3'S)-4-[(E)-3-Hydroxy-((2R)-1,3-benzo-
, . . . .
dioxan-2-yl)-1-propenyl]-5-hydroxy-perhydrocyclo-penta[b]
- furan-2-ol.
General formula II: A = trans CH=CH; 2' 3' 4' 5' 6 H; the
OH group at C-3' is ~-positioned.
410 mg of the ~-alcohol obtained as described under (a)
were reacted in a manner analogous to that described in example
j~
l(e) with diisobutyl-aluminium hydride. 400 mg of crude product
were obtained.
(c) (5Z,13E)-(8R,9S,llR,12R,15S)-9,11,15-Trihydroxy-15-((2R)-1,3-
.
- 22 -
` ` ~0~7~8
benzodioxan-2-yl)-16,17,18,19,20-pentanor-prostadienoic acid.
General formula I: A = trans CH=CH; B = cis CH=CH; X Y =
CH2 CH ; ~C~`OH ; Rl = OH; R2~R3~R4 =H; the OH group at
OH ~H
C-15 is ~-positioned.
The 400 mg of lactol obtained as described under (b) were
reacted without further purification in a manner analogous to that
described in example l(f) with 266 g of 4-carboxybutyl-triphenyl-
phosphonium bromide and 11-52 ml of the sodium methane-sulphinyl-
methyl solution described therein.
Yield: 230 mg.
(d) The prostaglandin acid obtained as described under (c) was
dissolved in methylene chloride and esterified with an ethereal
` solution of diazomethane. The evaporation residue was chromato-
graphed over silica gel with methylene chloride/l - 6% isopropanol
as flow agent. The prostaglandin carboxylic acid methyl ester
identified in the heading of this example was obtained.
Yield: 212 mg;
[~ID = -46.4 (c=0.25; CHC13);
IR: 3400 (wide), 1730, 1590, 1490, 980, 750 cm 1.
~ Example 5
; (5Z,13E)-(8R,9S,llR,12R,15R)-9,11,15-Trihydroxy-15-((2S~-1,3-
benzodioxan-2-~1)-16,17~18~19,20-pentanor-prostadienoic acid
and the methyl ester.
General formula I: A = trans CH=CH; B = cis CH=CH; X Y =
CH2-CH ; ~ ~\OH ; Rl = OCH3, OH; R2~R3~R4 = H; the OH
OH ~H
group at C-15 is ~-positioned.
(a) (lS,5R,6R,7R)-6-[(E)-3-Oxo-3-((2S)-1,3-benzodioxan-2-yl)-1-
propenyl]-7-benzoyloxy-2-oxabicyclo[3,3,0]octan-3-one.
The mother liquor obtained as described in example 3(a)
was chromatographed by column chromatography over silica gel with
-. `
,
7178
hexane/20 - 50% ethyl acetate as eluting agent.
[~]D = -18.8 (CHC13).
(b) (lS,5R,6R,7R,3'R)-6-[(E)-3-Hydroxy-3-((2S)-1,3-benzodioxan-
2-yl)-1-propenyl]-7-benzoyloxy-2-oXabicyclo[3,3,0]octan-3-
one.
From 3 g of the ketone obtained as described in example 5
(a) by the reduction with zinc borohydride described in example 1
(d), the ~-alcohol was obtained as the first product produced by
a column chromatography repeated several times.
Yield: 1.1 g.
~c) t2RS,3aR,4R,5R,6aS,3'R)-4-[(E)-3-Hydroxy-3-((2S)-1,3-benzo-
dioxan-2-yl)-1-propenyl]-5-hdyroxy-perhydrocyclo-penta[b]
furan-2-ol.
General formula II: A = trans CH=CH; R2,R3,R4,R5,R6 =H;
the OH group at C-3' is ~-positioned.
; 800 mg of the ~-alcohol obtained as described under 5(b)
was reacted in a manner analogous to that described in example
l(e) with diisobutyl-aluminium hydride. 750 mg of crude product
were obtained.
~d) (5Z,13E)-(8R,9S,llR,12R,15R)-9,11,15-Trihydroxy-15-((2S)-
1,3-benzodioxan-2-yl)-16,17,18,19,20-pentanor-prostadienoic
acid
General formula I: A = trans CH=CH; B = cis CH=CH; X Y =
2 - ; z ~C~\OH ; Rl = OH; R2,R3,R4 =H; the OH group at -
OH H
C-15 is ~-positioned.
The 750 mg of lactol obtained as described under (c)
were reacted without further purification in a manner analogous
to that described in example l(f) with 5.1 g of 4-carboxybutyl-
triphenylphosphonium bromide and 22 ml of the sodium methane-
sulphinyl-methyl solution described therein.
Yield: 480 mg.
- 24 -
~, .
10~7178
. .
(e) The prostaglandin acid obtained as described under (d)
was dissolved in methylene chloride and esterified with an ethereal
solution of diazomethane. The evaporation residue was chromato-
graphed over silica gel with hexane/50 - 95% ethyl acetate as
flow agent. The prostaglandin carboxylic acid methyl ester
identified in the heading of this example was obtained.
Yield: 450 mg;
[~]D = +51.2 (c=0.5; CHC13);
IR: 3400 (wide), 1730, 1590, 1490, 980, 750 cm
Example 6
(5Z,13E)-(8R,9S,llR,12R,lSS)-9,11,15-Trihydroxy-15-((2S)-1,3-
,
benzodioxan-2-yl)-16,17,18,19,20-pentanor-prostadienoic acid
and the methyl ester.
- General formula I: A = trans CH=CH; B = cis CH=CH; X Y =
CH2-CH ; \OH ; Rl = OCH3, OH; R ,R ,R = H; the OH
OH ~H
group at C-15 is ~-positioned.
!.i In the reduction of(lS,5R,6R,7R)-6-[(E)-3-oxo-3-((2S)-1,3-
'; benzodioxan-2-yl)-1-propenyl]-7-benzoyloxy-2-oxabicyclo[3,3,0] -
i~ 20 octan-3-one Ethe product of example 5(a)] with zinc borohydride
described under example 5(b), the ~-alcohol was eluted as second
product from the column:
(a) (lS,5R,6R,7R,3'S)-6-[(E)-3-Hydroxy-3-((2S)-1,3-benzodioxan-
2-yl)-1-propenyl]-7-benoyloxy-2-oxabicycloE3,3,0]octan-
3-one.
Yield: 0.7 g.
(b) (2RS,3aR,4R,5R,6aS,3'S)-4-[(E)-3-Hydroxy-3-((2S)-1,3-benzo-
.
dioxan-2-yl)-propenyl]-5-hydroxy-perhYdrocyclo-penta[b]furan-
2-ol.
General formula II: A = trans CH=CH; R2~R3~R4'R5'R6 = H;
the OH group at C-3' is ~-positioned.
600 mg of the ~-alcohol obtained as described under 6(a)
- 25 -
'' .
: ' . .
~0871~8
were reacted in a manner analogous to that described in example
l(e) with diisobutyl-aluminium hydride. 470 mg of crude product
were obtained.
(c) (5Z,13E)-(8R,9S,llR,12R,15S)-9,11,15-Trihydroxy-15-((2S)-
1,3-benzodioxan-2-yl)-16,17,18,19,20-pentanor-prostadienoic
acid.
General formula I: A = trans CH=CH; B = cis CH=CH; X Y =
C 2 CH ; z \\\OH ; Rl = OH; R2,R3,R4 = H; the OH group
OH ~ ~H
at C-15 is ~-positioned.
The 470 mg of lactol obtained as described under (b) were
reacted without further purification in a manner analogous to
; that described in example l(f) with 3.8 g of 4-carboxybutyl-tri-
phenylphosphonium bromide and 16.5 ml of the sodium methane-
sulphinyl-methyl solution described therein.
Yield: 330 mg.
(d) The prostaglandin acid obtained as described under (c) was
converted in a manner analogous to that described in example 5(e)
into the prostaglandin carboxylic acid methyl ester identified in
; 20 the heading of this example.
Yield: 290 mg;
[~]D3 ~ +50 (c=0.5; CHC13);
IR: 3400 (wide), 1730, 1590, 1490, 980, 750 cm
Example 7
(5Z,13E)-(8R,llR,12R,15R)-11,15-Dihydroxy-9-oxo-15-((2RS)-1,3-
)
benzodioxan-2-yl)-16,17,18,19,20-pentanor-prostadienoic acid
and the methyl ester.
General formula I: A = trans CH=CH; B = cis CH=CH; X Y =
CH2-CH ; Z =~ C = O; Rl = OCH3, OH; R2,R3,R4 = H; the OH
OH
group at C-15 is ~-positioned.
(a) (lS,5R,6R,7R,3'R)-6-[(E)-3-Hydroxy-3-((2RS)-1,3-benzodioxan
.
- 26 -
7178
2-yl)-1-propenyl]-7-hydroxy-2-oxabicyclo[3,3,0loctan-3-one.
A mixture of 1.97 g of (lS,5R,6R,7R,3'R)-6-[(E)-3-hydroxy-
3-((2RS)-1,3-benzodioxan-2-yl)-1-propenyll-7-benzoyloxy- 2-oxabi-
cyclo[3,3,0]octan-3-one [prepared according to the procedure
described in example l(d)] and 622 mg of potassium carbonate
(anhydrous) in 91 ml of methanol (absolute) was stirred for 2
hours at room temperature under argon. The mixture was then
poured into 90 ml of 0.lN hydrochloric acid and extracted with
ethyl acetate. The organic phase was washed with brine, dried
with magnesium sulphate and evaporated in vacuo. After chromato-
graphy of the crude product over silica gel (ether/ethyl acetate = - -
7:3), 1.20 g of a colourless oil were obtained.
(b) (lS,5R,6R,7R,3'R)-6-[(E)-3-((2RS)-1,3-benzodioxan-2-yl-1-
propenyl]-3',7-bis-(tetrahydro~r-anyloxy)-2-oxabicYclo-[3,3,0]
octan-3-one.
. _ .
6.1 ml of dihydropyran (freshly distilled) and 15 mg of
::
para-toluene sulphonic acid were added at ice bath temperature
to a solution of 1.85 g of the diol obtained as described under -~
(a) in 50 ml of methylene chloride, and the mixture~-~as stirred
at this temperature fcr 15 minutes, diluted with methylene chlor-
ide and agitated with a solution of sodium carbonate. ~he
organic phase was washed with water, dried with magnesium sul-
phate and evaporated in vacuo. By chromatography over silica gel
(ether), 2.2 g of the bis-tetrahydropyranyl (THP) ether were
obtained.
(c) (2RS,3aR,4R,5R,6aS,3'R)-4-[(E)-3-((2RS)-1,3-benzodioxan-
2-yl)-1-propenyl]-3',5-bis-(tetrahydropyranyloxy)-per-
hydrocyclopenta[b]furan-2-ol.
General formula II: A = trans CH=CH; R2,R3,R4 = H; R5,R6 = THP;
the tetrahydropyranyloxy (OTHP) group at C-3' is ~-positioned.
22 ml of a DIBAH solution of 20% strength in toluene
were added dropwise under argon to a solution cooled to -70C
- 27 -
lOB7~8
,:
of 2.2 g of the lactone obtained as described under (b) in 85 ml
ç of absolute toluene. After 30 minutes, the reaction was termin-, ated by the dropwise addition of isopropanol, and stirred with the
addition of 30 ml of water for 15 minutes at 0C. The mixture
was then extracted with ethyl acetate, washed with brine, dried
,:~ with magnesium sulphate and evaporated ln vacuo. 2.2 g of the
lactol were obtained in the form of a colourless oil.
; (d) (5Z,13E)-(8R,9S,llR,12R,15R)-9-Hydroxy-11,15-bis-(tetra-
hydropyranyloxy)-15-((2RS)-1,3-benzodioxan-2-yl)-16,17,18,
~ .
19,20-pentanor-prostadienoic acid.
34.7 ml of a solution of sodium methane-sulphinyl-
methyl in absolute dimethyl sulphoxide (preparation of the sol-
ution: 2.5 g of a suspension of sodium hydride of 50% strength
in 50 ml of absolute dimethyl sulphoxide were stirred for 1
hour at 70C), were added dropwise to a solution of 9.5 g of
4-carboxybutyl-triphenylphosphonium bromide in 40 ml of absolute
dimethyl sulphoxide, and the whole was stirred for 30 minutes at
room temperature. The ylene-solution thus obtained was then
added dropwise at 15C to a solution of 2.16 g of the lactol
; 20 obtained as described under (c) in 40 ml of absolute dimethyl
sulphoxide in the course of 15 minutes, and the whole was stirred
for 2 hours at 50C. The solvent was then distilled to a great
extend under an oil pump vacuum and at 45C, and the residue
was taken up in 80 ml of water and extracted three times with
ether. The organic extract was discarded. The aqueous phase
. was acidified to a pH of 4-5 with a solution of 10% strength of
citric acid, and extracted several times with a mixture of
hexane/ether 1+1. The ether/hexane extract was washed with
brine, dried with magnesium sulphate and evaporated in vacuo.
After chromatography of the evaporation residue over silica gel
2.48 g of the acid were eluted with ether in the form of a
~: colourless oil.
.,.
- 28 -
- 10~ 8
:.
(e) (5Z,13E)-(8R,llR,12R,15R?-9-Oxo-11,15-bis-(tetrahydro-
pyranyloxy)-15-((2RS)-1,3-benzodioxan-2-yl)-16,17,18,19,20-
, ~
pentanor-prostadienoic acid.
2.46 ml of Jones reagent (J.Chem.Soc. 1953, 2555), were
added at -20C to a solution of 2.35 g of the alcohol obtained
as described under (d) in 30 ml of acetone, and the mixture was
stirred for 30 minutes at -20C. Then 3 ml of isopropyl alcohol
- were added dropwise, and the mixture was stirred for 10 minutes
at -20C, diluted with ether and extracted three times by ~
agitation with water. The organic phase was dried with magnesium ~;
sulphate and evaporated in vacuo. 2.1 g of the ketone were
obtained in the form of a colourless oil. --~
(f) (52,13E)-(8R,llR,12R,15R)-11,15-Dihydroxy-9-oxo-15-((2RS)-
.. . .
1~3-benzodioxan-2-yl)-16~17~18~19~20-pentanor-prostadienoic
acid.
General formula I: A = trans CH=CH; B = cis CH=CH; X Y =
CH2-CH; Z = ~C = O; Rl = OH; R2,R3,R4= H; the OH group at
OH
C-15 is ~-positioned.
2.1 g of the bis-tetrahydropyranyl ether obtained as
described under (e) were stirred for 5 hours at 40C in 42 ml
of a mixture consisting of 65 parts of glacial acetic acid, 35
parts of water and 10 parts of tetrahydrofuran. ~he mixture was
then evaporated to dryness under 0.1 Torr, and the crude product
was purified by column chormatography. With chloroform/ethanol -
95+5, there were eluted 450 mg of the E2-derivative in the form
of a colourless oil.
(g) 7 ml of an ethereal solution of diazomethane were added
- dropwise at ice bath temperature to a solution of 130 mg of the
acid obtained as described under (f) in 4 ml of methylene chloride,
and the mixture was stirred for 2 minutes and then evaporated ln
vacuo. After chromatography of the crude product over silica gel
- 29 -
.
. . : ::. . - .
0871~.Y8
,, :
, (ether/dioxan 95:5), in addition to mixed fractions, 56 mg of the
;,.~.
prostaglandin carboxylic acid methyl ester identified in the
heading of this example were obtained in the form of a thin-
layer chromatographically completely unitary oil.
IR: 3400 (wide), 1740, 1730, 1590, 1490, 980, 750 cm 1
Example 8
(5Z,13E)-(8R,llR,12R,15S)-11,15-dihydroxy-9-oxo-15-(¦2RS3-1,3-
; benzodioxan-2-yl)-16,17,18,19,20-pentanor-prostadienoic acid
and the methyl ester.
General formula I: A = trans CH=CH; B = cis CH=CH; X Y =
. CH2-CH ; Z =, C = O; Rl = OCH3, OH; R2,R3,R4 =H; the OH
-OH
:~ group at C-15 is ~-positioned.
; (a) (lS,5R,6R,7R,3'S)-6-[(E)-3-hydroxy-3-((2RS3-1,3-benzodioxan-
~ 2-yl)-1-propenyl]-7-hydroxy-2-oxabicyclo[3,3,0]-octan-3-one.
'~ 2.16 g of (lS,5R,6R,7R,3'S)-6-[(E) -3-hydroxy-3-((2RS3-
~; 1,3-benzodioxan-2-yl)-1-propenyl]-7-benzoyloxy-2-oxabicyclo[3,3,0]-
~: octan-3-one [prepared as described in example 2(a)] and 687 mg
of anhydrous potassium carbonate were stirred for 2.5 hours in
99 ml of methanol at room temperature. 99 ml of 0.lN-hydro-
chloric acid were then added, the mixture was stirred for 15
minutes and extracted with ethyl acetate, and the organic phase
was agitated with brine, dried and evaporated ln vacuo. The
crude product was chromatographed over silica gel. 1.38 g of
the diol were obtained in the form of a colourless oil.
(b) (lS,5R,6R,7R,3'S)-6-[(E)-3-((2RS3-1,3-benzodioxan-2-yl)-1-
propenyl]-3',7-bis-(tetrahydropyranyloxy)-2-oxabicyclo-
[3,3,0]octan-3-one.
4.5 ml of dihydropyran (freshly distilled) and 10 mg of
para-toluene sulphonic acid were added at ice bath temperature to
a solution of 1.38 g of the diol obtained as described under (a)
; in 30 ml of methylene chloride, and the mixture was stirred for
- 30 -
., .
0~71~8
15 minutes at approximately 5C, diluted with methylene chloride,
agitated with a sodium bicarbonate solution and with brine, dried
with magnesium sulphate and evaporated in vacuo. After chromato-
graphy of the crude product over silica gel (ether/hexane 8:2),
1.91 g of the bis-tetrahydropyranyl ether were obtained in the
form of a colourless oil.
(c) (2RS,3aR,4R,5R,6aS,3'S)-4-[(E)-3-((2RS)-1,3-benzodioxan-
2-yl)-propenyl]-3~5-bis-(tetrahydropyranyloxy)-perhydr
cyclopenta[b]furan-2-ol.
, .
General formula II: A = trans CH=CH; R2'R3'R4 = H; R5'R6 = THP
the OTHP group at C-3' is ~-positioned.
In a manner analogous to that described in example 7(c),
1.91 g of the lactone obtained, as described under (b), in 75 ml
of absolute toluene were reduced with 19 ml of diisobutyl-aluminium
hydride (DIBAH) solution. By working up in the usual manner,
1.93 g of the lactol were obtained in the form of a colourless
' oil.
(d) (5Z,13E)-(8R,9S,llR,12R,15S)-9-hydroxy-11,15-bis-(tetra-
hydropyranyloxy)-15-((2RS)-1,3-benzodioxan-2-yl)-16,17,18,19,
20-pentanor-prostadienoic acid.
In a manner analogous to that described in example 7(d),
1.93 g of the lactol obtained as described under (c) in 30 ml of
absolute DMSO were reacted with an ylene-solution, which had been
prepared from 8.47 g of 4-carboxybutyl-triphenylphosphonium bromide
and 31 ml of sodium methane-sulphinyl-methyl so~ution. After
working up in the usual manner, the crude product was purified
by column chromatography. 2.1 g of the acid were eluted with
ether in the form of a colourless oil.
(e) (5Z,18E)-(8R,llR,12R,15S)-9-Oxo-11,15-bis-(tetrahydro-
pyranyloxy)-15-((2RS)-1,3-benzodioxan-2-yl)-16,17,18,19,20-
-
pentanor-prostadienoic acid.
In a manner analogous to that described in example 7(e),
^` 1~)~7178
2.05 g of the alcohol obatined as described under (d) in 50 ml
of acetone were oxidized with 2.14 ml of Jones reagent at -20C.
After working up, 1.84 g of the ketone were obtained in the form
of a colourless oil.
(f) (5Z,13E)-(8R,llR,12R,15S)-11,15-dihydroxy-9-oxo-15((2RS)-
1,3-benzodioxan-2-yl)-16,17,18,19,20-pentanor-prostadienoic
acid.
General formula I: A = trans CH=CH; B = cis CH=CH; X...Y =
CH2-CH ; Z =,,C = O ; Rl = OH; R2,R3,R4 = H; the OH group at
OH
C-15 is ~-positioned.
In a manner analogous to that described in example 7(f),
1.84 g of the bis-tetrahydropyranyl ether obtained as described
under (e) were stirred with 18 ml of an acetic acid/tetrahydro-
furan mixture. By working up and chromatography over silica gel
(chloroform/ethanol = 95/5), 528 mg of the E2-derivative were
obtained in the form of a colourless oil.
(g) 98 mg of the prostaglandin acid obtained as described under
(f) were converted in a manner analogous to that described in
example 7(g) into the prostaglandin carboxylic acid methyl ester.
Yield: 76 mg;
IR: 3400 (wide), 1740, 1730, 1590, 1490, 980, 750 cm
Example 9
(5Z,13E)-(8R,llR,12R,15R)-11,15-dihydroxy-9-oxo-15-((2R)-1,3-
benzodioxan-2-yl)-16,17,18,19,20-pentanor-prostadienoic acid
and the methyl ester
General formula I: A = trans CH=CH; B = cis CH=CH; X...Y =
cH2-CH ; Z = ~C = O; Rl = OcH3~ OH; R2~R3~R4 = H; the OH
; OH
group at C-15 is ~-positioned.
The preparation was carried out in a manner analogous to
that described in example 7(a) - (g) from the starting compound
- 32 -
~0i~71~;'8
prepared as described in example 3(b). The yield was 400 mg of
the prostadienoic acid in the form of a colourless oil, and 60 mg
of the prostadienoic acid methyl ester (prepared from 130 mg of
the acid).
IR: 3500 - 3400, 1740, 1730, 1590, 1490, 980, 750 cm 1.
Example 10
(5Z,13E)-(8R,llR,12R,15S)-11,15 Dih~droxy-9-oxo-15-((2R)-1,3-
; benzodioxan-2-yl)-16,17,18,19,20-pentanor-prostadienoic acid and
the methyl ester.
General formula I: A = trans CH=CH; B = cis CH=CH; X Y =
C~l2-C-H ; Z = ,C = O; Rl = OCH3, OH; R2'R3'R4 = H; the OH
OH ;
` group at C-15 is ~-positioned.
The preparation was carried out in a manner analogous to
that described in example 8(a) - (g) from the starting compound -
prepared as described in example 4(a).
Yield: 510 mg of the prostadienoic acid in the form of a colour-
less oil, and
; 70 mg of the prostadienoic acid methyl ester (from 100
mg of the acid);
IR: 3500 - 3400, 1740, 1730, 1590, 1490, 980, 750 cm 1.
Example 11
, (5Z,13E)-(8R,llR,12R,15R)-11,15-Dihydroxy-9-oxo-15-(¦2S)-1,3-
-- ------ .. . .
benzodioxan-2-~1?-16,17,18,19,20-pentanor-prostadienoic acid
and the methyl ester.
General formula I: A = trans CH=CH; B = cis CH=CH; X Y =
CH2-CH ; Z = ~C = O; Rl = OCH3, OH; R2,R3,R4 = H; the OH
OH
group at C-15 is ~-positioned.
The preparation was carried out in a manner analogous
to that described in example 7(a) - (g) from the starting compound
prepared as described in example 5(b).
- 33 -
:
~37178
Yield: 310 mg of the prostadienoic acid in the form of a colour-
less oil, and
50 mg of the prostadienoic acid methyl ester (from 120 mg
of the acid);
IR: 3500 - 3400, 1740, 1730, 1590, 1490, 980, 750 cm
Example 12
(5Z,13E)-(8R,llR,12R,lss)-11,15-Dihydroxy-9-oxo-15-(~2S)-1,3-
benzodioxan-2-yl)-16,17,18,19,20-pentanor-prostadienoic acid
and the methyl ester.
General formula I: A = trans CH=CH; B = cis CH=CH; X Y =
CH2-CH ; Z = ~C = O; Rl = OcH3~ OH; R2'R3'R4 = H; the OH
OH
group at C-15 is ~-positioned.
The preparation was carried out in a manner analogous
to that described in example 8(a) - (g) from the starting compound
prepared as described in example 6(a).
Yield: 410 mg of the prostadienoic acid, and
150 mg of the prostadienoic acid methyl ester (from
210 mg of the acid);
IR: 3500 - 3400, 1740, 1730, 1590, 1490, 980, 750 cm
Example 13
(5Z)-(8R,9S,llR,12R,15R)-9,11,15-Trihydroxy-15-((2RS)-1,3-benzo-
. _ _
dioxan-2-yl)-16,17,18,19,20-pentanor-prostenoic acid and the
methyl ester.
General formula I: A = CH2-CH2; B = cis CH=CH; X Y =
CH2 CH ; ~ ~\H ; Rl = OCH3~ OH; R2,R3,R4 = H; the OH
OH ~ H
group at C-15 is ~-positioned.
(a) (lS,5R,6R,7R,3'R)-6-[3-hydroxy-3-((2RS)-1,3-benzodioxan-2-
yl~-1-prop~1]-7-benzoyloxy-2-oxabicyclo[3,3,0]octan-3-one.
2.3 g of the ~-alcohol obtained as described in example
l(d) and 230 mg of palladium on carbon (10% strength) were agitated
- 34 -
10~78 -
;
for 2 hours in 40 ml of ethyl acetate under an atmosphere of
hydrogen. After filtering and evaporating, 2.3 g of the above-
. mentioned alcohol were obtained in the form of a colourless oil.
IR: 3600, 1775, 1720, 1590, 1490, 770 cm
In the NMR-spectrum no olefinic protons were detected.
(b) (lS,5R,6R,7R,3'R)-6-[3-hydroxy-3-((2RS)-1,3-benzodioxan-2-
yl)-l-propyl]-7-hydroxy-2-oxabicyclo[3~3~o]octan-3-one.
. From 2.20 g of the saturated alcohol obtained as described
under (a), by hydrolysis in accordance with the procedure described
in example 7(a), 1.34 g of the saturated diol were obiained in
` the form of a colourless oil.
..~
IR: 3600 strong, 1775, 1590, 1490, 760 cm 1.
(c) (lS,5R,6R,7R,3'R)-6-[3-((2RS)-1,3-benzodioxan-2-yl)-1-
.,
propyl]-3l~7-bis-(tetrahydropyranyloxy)-2-oxabicycloE3~3~o]
octan-3-one.
From 1.13 g of the diol obtained as described under (b)
with dihydropyran in a manner analogous to that described in
' example 7(b) 1.08 g of the above-mentioned bis-(tetrahydropyranyl)
~ ether were obtained in the form of a colourless oil.
J, 20 IR: 1775, 1590, 1490, 1100, 760 cm
` (d) (2RS,3aR,4R,5R,6aS,3'R)-4-~3-((2RS)-1,3-benzodioxan-2-yl)-
l-propyl]-3,5-bis-(tetrahydropyranyloxy)-perhydrocyclo-
;
,~ penta~b]furan-2-ol.
General formula II: A - CH2-cH2; R2~R31R4 = H; R5'R6 = THP~
the OTHP group at C-3' is ~-positioned.
; In accordance with the procedure described in example
7(c), by the reduction of 1.08 g of the bis-(tetrahydropyranyl)
ether prepared as described under (c) 1.06 g of the above-
; mentioned lactol were obtained in the form of a colourless oil.
IR: 3600, 1590, 1490, 1100, 760 cm
(e) (5Z)-(8R,9S,llR,12R,15R)-9-hydroxy-11,15-bis-(tetrahydro-
pyranyloxy)-15-((2RS)-1,3-benzodioxan-2-yl)-16,17,18,19,20-
,,
- 35 -
-
.
. . . .
1~71~8
pentanor-prostenoic acid.
1.06 g of the lactol obatined as described under (d)
were converted in accordance with the prodedure described in
example 7(d) into 866 mg of the above-mentioned prostenoic acid.
IR: 3600 - 3400, 1710, 1590, 1490, 1100, 760 cm
(f) (5Z)-(8R,9S,llR,12R,15R)-9,11,15-trihydroxy-15-((2RS)-1,3-
benzodioxan-2-yl)-16,17,18,19,20-pentanor-prostenoic acid.
; 310 mg of the compound obtained as described under (e)
were stirred for 3 hours at 50C in 9 ml of a mixture of acetic
acid/water/tetarhydrofuran = 65/35/10. The mixture was evaporated
to dryness ln vacuo, and, by chromatography over 10 g of silica
gel (chloroform/ethanol 4 + 1), 211 mg of the above-mentioned
compound were obtained in the form of a colourless oil.
IR: 3600 - 3300, 1710, 1590, 1490, 760 cm
(g) 7 ml of an ethereal solution of diazomethane were added
dropwise at ice bath temperature to a solution of 130 mg of the
acid obtained as described under (f) in 4 ml of methylene chloride,
and the mixture was stirred for 15 minutes and then evaporated
in vacuo. After chromatography of the crude product over silica
gel (methylene chloride/3% isopropanol), 90 mg of the prostag-
landin carboxylic acid methyl ester identified in the heading of
this example were obtained.
IR: 3600 - 3300, 1730, 1590, 1490, 760 cm
Example 14
(5Z)-(8R,9S,llR,12R,15S)-9,11,15-trihydroxy-15-((2RS)-1,3-benzo-
dioxan-2-yl)-16,17,18,19,20-pentanor-prostenoic acid and the
` methyl ester.
General formula I: A = CH2-CH2; B = cis CH=CH; X Y =
CH2 CH ; z C~OH ; Rl = OCH3~ OH; R2,R3,R4 =H; the OH
; 30 OH ~H
group at C-15 is ~-positioned.
(a) (lS,5R,6R,7R,3'S)-6-[3-hydroxy-3-((2RS)-1,3-benzodioxan-2-
- 36 -
.
37178
yl)-l-propyl]-7-benzoyloxy-2-oxabicylco[3,3,0]octan-3-one.
In a manner analogous to that described in example 13(a),
2.4 g of the ~-alcohol obtained as described in example 2(a)
were hydrogenated to form 2.4 g of the above-mentioned saturated
alcohol. A colourless oil was obtained.
IR: 3600, 1775, 1720, 1590, 1490, 770 cm
(b) (lS,5R,6R,7R,3'S)-6-[3-hydroxy-3-((2RS)-1,3-benzodioxan-
2-yl)-l-propyl]-7-hydroxy-2-oxabicyclo[3~3~o]octan-3-one.
From 2.3 g of the saturated alcohol obtained as described
under (a), by hydrolysis with potassium carbonate in accordance
with the procedure described in example 7(a), 1.39 g of the sat-
urated diol were obtained in the form of a colourless oil.
IR: 3600 (strong), 1775, 1590, 1490, 760 cm 1.
(c) (lS,5R,6R,7R,3'S)-6-[3-((2RS)-1,3-benzodioxan-2-yl)-1-
. . .
propyl]-3',7-bis-(tetrahydropyranyloxy)-2-oxabicyclo[3,3,0]
octan-3-one.
From 1.0 g of the diol prepared as described under (b)
with dihydropyran in a manner analogous to that described in
example 7(b), 0.93 g of the above-mentioned bis-(tetrahydropyranyl)
ether were obtained in the form of a colourless oil.
IR: 1775, 1590, 1490, 1100, 760 cm
(d) (2RS,3aR,4R,5R,6aS,3'S)-4-[3-((2RS)-1,3-benzodioxan-2-yl)-
.
l-propyl]-3',5-bis-(tetrahydropyranyloxy)-perhydrocyclo-
penta[b]furan-2-ol.
In accordance with the procedure described under example
7(c) by the reduction of 0.74 g of the bis-(tetrahydropyranyl)
ether prepared as described under (c), 0.7 g of the above-mentioned
lactol was obtained in the form of a colourless oil.
IR: 3600, 1590, 1490, 1100, 760 cm
(e) (5Z)-(8R,9S,llR,12R,15S)-9-hydroxy-11,15-bis-(tetrahydro-
pyranyloxy)-15-(¦2RS)-1,3-benzodioxan-2-yl)-16,17,18,19,20-
_entanor-prostenoic acid.
- 37 -
~)87~78
0.7 g of the lactol obtained as described under (d) was
converted in accordance with the procedure described in example
7(d) into 0.51 g of the above-mentioned prostenoic acid.
IR: 3600 - 3400, 1710, 1590, 1490, 1100, 760 cm
(f) (5Z)-(8R,9S,llR,12R,15S)-9,11,15-trihydroxy-15-((2RS)-1,3-
benzodioxan-2-yl)-16,17,18,19,20-pentanor-prostenoic acid.
In a manner analogous to that described in example 13(f),
from 345 mg of the triol obtained as described under (e), 219 mg
of the above-mentioned compound were obtained in the form of
a colourless oil.
IR: 3600 - 3300, 1710, 1590, 1490, 760 cm
(g) By esterification in a manner analogous to that described
in example 13(g), from 120 mg of the acid obtained as described
under (f), 85 mg of the prostaglandin carboxylic acid methyl ester
::,
identified in the heading of this example were obtained.
IR: 3600 - 3300, 1730, 1590, 1490, 755 cm 1.
': :
Example 15
~ (5Z)-(8R,9S,llR,12R,15R)-9,11,15-trihydroxy-15-((2R)-1,3-benzo-
.
dioxan-2-yl)-16,17,18,19,20-pentanor-prostenoic acid and the
methyl ester.
General formula I: A = CH2-CH2; B = cis CH=CH; X Y =
CH2-CH ; ~ ~OH; R1 = OCH3, OH; R2,R3,R4 =H; the OH group
OH ~ ~H
at C-15 is ~-positioned.
Starting from the ~-alcohol obtained as described in
example 3(b), the compounds identified in the heading were ob-
tained by reaction stages analogous to those described in example
~ 13(a) - (g).
- IR: 3500 - 3300, 1730, 1590, 1490, 760 cm . -
Example 16
(5z)-(8R,9S,llR,12R,15S)-9,11,15-trihydroxy-15-((2R)-1,3-benzo-
dioxan-2-yl)-16,17,18,19,20-pentanor-prostenoic acid and the
- 38 -
.
: .
10i~7~78
methyl ester.
':
~, General formula I: A = CH2-CH2; B = cis CH=CH; X Y =
2 _ ; z ~C~OH ; Rl = OCH3, OH; R2,R3,R4 =H; the OH
OH ~H
,~ group at C-15 is ~-positioned.
Starting from the ~-alcohol obtained as described in
' example 4(a), the compounds identified in the heading were ob-
. .
; tained by reaction stages analogous to those described in example
14(a) to (g).
IR: 3400 (wide), 1730, 1590, 1490, 760 cm 1.
Example 17
(5Z)-(8R,9S,llR,12R,15R)-9,11,15-trihydroxy-15-((2S)-1,3-benzo-
; dioxan-2-yl)-16,17,18,19,20-pentanor-prostenoic acid and the
methyl ester.
.~
General formula I: A = CH2-CH2; B = cis CH=CH; X Y =
2 = ; z ~C\,\OH ; Rl= OCH3~ OH; R2,R3,R4 =H; the OH
'~ OH ~ ~ H
group at C-15 is ~-positioned.
Starting from the ~-alcohol obtained as described in
example 5(b), the compounds identified in the heading were obtain-
ed by reaction stages analogous to those described in example 13(a) -
(g).
IR: 3400 (wide), 1735, 1590, 1490, 760 cm 1.
Example 18
,~
(5Z)-(8R,9S,llR,12R,15S)-9,11,15-trihydroxy-15-((2S)-1,3-benzo-
?: ( )
dioxan-2-yl)-16,17,18,19,20-pentanor-prostenoic acid and the
` methyl ester.
General formula I: A =CH2-CH2; B = cis CH=CH; X...Y =
CH -CH ; ~` '`\ ; Rl OCH3~ OH; R2,R3,R4 = H; the OH
,~ _ Z =~C
OH ~ H
group at C-15 is ~-positioned.
Starting from the ~-alcohol obtained as described in
~ 39 -
~0~371'78
example 6(a), the compounds identified in the heading were obtain-
ed by reaction stages analogous to those described in example 14
(a) - (g).
IR: 3400 (wide~, 1735, 1590, 1490, 760 cm
Exam~le 19 ~-
(5Z)-(8R,llR,12R,15R)-11,15-dihydroxy-g-oxo-15-((2RS)-1,3-benzo-
dioxan-2-yl)-16~17~18~19~20-pent n_r-prostenoic acid and the
methyl ester.
General formula I: A = CH2-CH2; B = cis CH=CH; X Y =
:' 10 CH2-CH
OH ~ 1 OcH3, OH; R2,R3,R4 = H; the OH ~
group at C-15 is ~-positioned. ~ -
(a) (5Z)-(8R,llR,12R,15R)-11,15-bis-(tetrahydropyranyloxy)-9-
oxo-15-((2RS)-1,3-benzodioxan-2-yl)-16,17,18,19,20-penta-
, . :
; nor-prostenoic acid.
300 mg of the compound obtained as described in example
13(e) were converted by oxidation in a manner analogous to that
described in example 7(e) into 210 mg of the above-mentioned
compound in the form of a colourless oil. ~-
IR: 3600 - 3300, 1740, 1710, 1590, 1490, 760 cm
(b) (5Z)-(8R,llR,12R,15R)-11,15-dihydroxy-9-oxo-15-((2RS)-1,3-
benzodioxan-2-yl)-16,17,18,19,20-pentanor-prostenoic_acid.
In accordance with the procedure described in example
7(f), from 150 mg of the compound obtained as described under (a),
90 mg of the above-mentioned compound were obtained in the form
of a colourless oil.
IR: 3600 -3400, 1740, 1710, 1590, 1490, 760 cm
(c) In a manner analogous to that described in example 7(g),
from 90 mg of the acid obtained as described under (b), 75 mg of
the prostaglandin carboxylic acid methyl ester identified in the
heading of this example were obtained.
IR: 3600 - 3400, 1740, 1730, 1590, 1490, 750 cm
- 40 -
.
~ 0~7~'78
.:
Example 20
(5Z)-(8R,llR,12R,15S)-11,15-dihydroxy-9-oxo-15-((2RS)-1,3-benzo-
dioxan-2-yl)-16,17,18,19,20-pentanar-prostenoic acid and the
methyl ester.
General formula I: A = CH2-CH2; B = cis CH=CH; X Y =
CH2-CH ; Z =~ C = O ; Rl = OCH3, OH; R2,R3,R4 = H; the OH
OH
group at C-15 is ~-positioned.
(a) (5Z)-(8R,llR,12R,15S)-11,15-Bis-(tetrahydropyranyloxy)-9-
oxo-15-((2RS)-1,3-benzodioxan-2-yl)-16,17,18,19,20-pentanor-
., . . _ _ .
prostenoic acid.
280 mg of the compound obtained as described in example
14(e) were converted by oxidation in a manner analogous to that
described in example 7(e) into 180 mg of the above-mentioned
compound in the form of a colourless oil.
IR: 3600 - 3300, 1740, 1710, 1590, 1490, 760 cm
~, (b) (5Z)-(8R,llR,12R,15S)-11,15-dihydroxy-9-oxo-15-((2RS)-1,3-
.. ..
benzodioxan-2-yl)-16,17,18,19,20-pentanor-prostenoic acid.
, In accordance with the procedure described in example
7(f), 145 mg of the compound obtained as described under (a)
were reacted to form 80 mg of the above-mentioned diol.
IR: 3600 - 3400, 1740, 1710, 1590, 1490, 755 cm 1.
(c) ~ a manner analogous to that described in example 7(g),
from 80 mg of the acid obtained as described under (b), 56 mg
of the prostaglandin carboxylic acid methyl ester identified in
the heading of this example were obtained.
IR: 3600 - 3400, 1740, 1730, 1590, 1490, 755 cm 1.
;~ Example 21
(5Z)-(8R,llR,12R,15R)-11,15-dihydroxy-9-oxo-15-((2R)-1,3-benzo-
. _
dioxan-2-yl)-16,17,18,19,20-pentanor-prostenoic acid and the
methyl ester.
General formula I: A = CH2-CH2; B = cis CH=CH; X Y =
- 41 -
:
,
B717~
CH2-CH ; Z = ~C = O; Rl - OCH3, OH; R2,R3,R4 = H
OH
the OH group at C-15 is ~-positioned.
Starting from the derivative of example 15 corresponding
to the derivative obtained as described in example 13(e), the
compounds identified in the heading were obtained by reaction
stages analogous to those described in example l9(a) - (c).
IR: 3500 - 3400, 1740, 1730, 1590, 1490, 750 cm
Example 22
(5Z)-(8R,llR,12R,15S)-11,15-dihydroxy-9-oxo-15-((2R)-1,3-benzo-
.... ~
dioxan-2-yl)-16,17,18,19,20-pentanor-prostenoic acid and the
methyl ester.
General formula I: A = CH2-CH2; B = cis CH=CH; X...Y =
CH2-CH ; Z = ~C = O ; Rl = OCH3, OH; R2,R3,R4 = E; the OH
OH
group at C-15 is ~-positioned.
Starting from the derivative of example 16 corresponding
to the derivative obtained as described in example 14(e), the
compounds identified in the heading were obtained by reaction
stages analogous to those described in example l9(a) - (c).
IR: 3600 - 3400, 1740, 1730, 1590, 1490, 755 cm 1.
Example 23
(5Z)-(8R,llR,12R,15R)-11,15-dihydroxy-9-oxo-15-((2S)-1,3-benzo-
.. ..
dioxan-2-vl)-16,17,18,19,20-pentanor-~rostenoic acid and the
methyl ester.
General formula I: A = CH2-CH2; B = cis CH=CH; X Y =
CH2-CH ; Z = ~C = O; Rl = OCH3, OH; R2,R3,R4 =H; the OH -
OH
group at C-15 is ~-positioned.
Starting from the derivative of example 17 corresponding
to the derivative obtained as described in example 13(e), the
compounds identified in the heading were prepared by reaction
- 42 -
' ~87~78
stages analogous to those described in example l9(a) - (c).
IR: 3600 - 3400, 1740, 1730, 1590, 1490, 755 cm
Example 24
(5Z)-(8R,llR,12R,15S)-11,15-dihydroxy-9-oxo-15-((2S)-1,3-benzo-
dioscan-2-yl)-16,17,18,19,20-pentanor-prostenoic acid and the
methyl ester.
General formula I: A = CH2-CH2; g = cis CH=CH; X Y =
CH2~CH ; Z =`~C = O; Rl = OCH3~ OH; R2,R3,R4 = OH; the OH
OH
group at C-15 is ~-positioned.
Starting from the derivative of example 18 corresponding
to the derivative obtained as described in example 14(e), the
compounds identified in the heading were prepared by reaction
stages analogous to those described in example l9(a) - (c).
; IR: 3500 - 3400, 1740, 1730, 1590, 1490, 750 cm
Example 25
~0~5~
(5Z~-(8R,12S,15R)-15-hydroxy-9-oxo-15-((2RS)-1,3-benzodioxan-2-
yl)-16~17,18~19~20-pentanor-prostatrienoic acid and the methyl
ester.
General formula I: A = trans CH=CH; B = cis CH=CH; X Y =
/ ; 1 OCH3, OH; R2,R3,R4 =H; the OH group
at C-15 is ~-positioned.
A solution of 88 mg of (5Z,13E)-(8R,llR,12R,15R)-11,15-
dihydroxy 9-oxo-15-((2RS)-1,3-benzodioxan-2-yl)-16,17,18,19,20-
pentanor-prostadienoic acid [obtained as described in example7(f)]
in 6 ml of acetic acid of 90% strength was stirred for 19 hours
at 60C and then evaporated ln vacuo. After chromatography over
silica gel (ether/3% dioxan), the resulting prostatrienoic acid
was esterified with an ethereal solution of diazomethane. 45 mg
of the methyl ester identified in the heading were obtained in
the form of a pale yellow coloured oil.
IR: 3600 - 3300, 1730, 1700, 1590, 1490, 980, 760 cm
- 43 -
;~
7178
Example 26
(5Z,10Z,13E)-(8R~12S,15S)-15-hydroxy-9-oxo-15-((2RS)-1,3-benzo-
. dioxan-2-yl)-16,17,18,19,20-pentanor-prostatrienoic acid and the
;,......................................................................... .
methyl ester.
. .
General formula I: A = trans CH=CH; B = cis CH=CH; X Y =
CH=CH; 2 = \C = O, R1 = OCH3, OH; R2,R3,R4 = H; the OH group
at C-15 is ~-positioned. ;
In a manner analogous to that described in example 25,
- the compounds identified in the heading were prepared from the
compound obtained as described in example 8(f).
IR: 3500 - 3300, 1730, 1705, 1590, 1490, 980, 760 cm
., .
Example 27
(5Z,lOZ,13E)-(8R,12S,15R)-15-hydroxy-9-oxo-15-((2R)-1,3-benzo-
dioxan-2-yl)-16,17,18,19,20-pentanor-prostatrienoic acid and the
methyl ester.
General formula I: A = trans CH=CH; B = cis CH=CH; X Y =
CH=CH; Z =,,C = O; Rl = OCH3~ OH~ R2,R3,R4 = H; the OH
group at C-15 is ~-positioned.
In a manner analogous to that described in example 25,
the compounds identified in the heading were prepared from the
compound obtained as described in example 9(f).
IR: 3600 - 3300, 1730, 1700, 1585, 1490, 980, 760 cm 1. -
Example 28
(5Z,lOZ,13E)-(8R,12S,15S)-15-hydroxy-9-oxo-15-((2R)-1,3-benzo-
-
; dioxan-2-Y1)-16,17~18,19,20-pentanor-prostatrienoic acid_and
the methyl ester.
.:
General formula I: A = trans CH=CH; B = cis CH=CH; X Y =
/ ; 1 OCH3, OH; R2,R3,R4 = H; the OH group
at C-15 is ~-positioned.
In a manner analogous to that described in example 25,
the compounds identified in the heading were prepared from the
compound obtained as described in example 10(f).
- 44 -
' -
,''' ' ' ~
7~8
IR: 3600 - 3300, 1730, 1700, 1590, 1490, 980, 760 cm 1.
Exam~le 29 ~
.~ (5Z,lOZ,13E)-(8R,12S,15R)-15-hydroxy-9-oxo~?¦2S)-1,3-benzodioxan-
2-ylj-16,17,18,19,20-pentanor-prostatrienoic acid and the methyl
ester.
General formula I: A = trans CH=CH; B= cis CH=CH; X Y =
> ; 1 OCH3, OH; R2,R3,R4 = H; the OH group
at C-15 is ~-positioned.
In a manner analogous to that described in example 25,
the compounds identified in the heading were prepared from the
compound obtained as described in example ll(f).
IR: 3500 - 3300, 1730, 1700, 1590, 1485, 980, 760 cm 1.
Example 30
(5Z,lOZ,13E)-(8R,12S,15S)-15-hydroxy-9-oxo-15-((2S)-1,3-benzo-
.
dioxan-2-yl)-16,17,18,19,20-pentanor-prostatrienoic acid and the
methyl ester.
General formula I: A = trans CH=CH; B = cis CH=CH; X Y =
~ ; 1 OCH3, OH; R2,R3,R4 = H; the OH group
at C-15 is ~-positioned.
In a manner analogous to that described in example 25,
the compounds identified in the heading were prepared from the
compound described in example 12(f).
IR: 3600 - 3300, 1730, 1700, 1590, 1490, 980, 760 cm
Example_31
(13E)-(8R,9S,llR,12R,15R)-9,11,15-trihydroxy-15-((2RS)-1,3-benzo-
i
dioxan-2-yl)-16,17,18,19,20-pentanor-prostenoic acid and the
methyl ester.
General formula I: A = trans CH=CH; B = CH2-CH2; X...Y =
CH2-CH ; ~OH ; Rl = OCH3, OH; R ,R ,R = H; the OH
OH ~H
group at C-15 is ~-positioned.
150 mg of the compound obtained as described in example
- ~5 -
'
':
~0i~71~B
l(f) or l(g) were mixed with 15 mg of 10~ strength palladium on
,
carbon, and stirred with 15 ml of ethyl acetate for 2 hours at
-20C under an atmosphere of hydrogen. After filtration, the
mixture was evaporated to dryness in vacuo, and there were
obtained the compounds identified in the heading, 140 mg of the
ester being obtained in the form of a colourless oil.
~, IR: 3600 - 3300, 1730, 1590, 1490, 980, 760 cm
The NMR-spectrum showed only two olefinic protons.
Example 32
: 10 From the corresponding starting compounds obtained as
described in examples 2(d), 3(e), 4(d), 5(e), and 6(d) there can
be prepared in a manner analogous to that described in example 31:
(13E)-(8R,9S,llR,12R,15S)-9,11,15-trihydroxy-15-(¦2RS)-1,3-benzo-
dioxan-2-yl)-16,17,18,19,20-pentanor-prostenoic acid and the methyl
ester,
(13E)-(8R,9S,llR,12R,15R)-9,11,15-trihydroxy-15-((2R)-1,3-benzo-
dioxan-2-yl)-16,17,18,19,20-pentanor-prostenoic acid and the
methyl ester,
(l3E)-(8R~9s~llR~l2R~l5s)-9~ l5-trihydroxy-l5-(l2R)-l~3-benzo-
dioxan-2-yl)-16,17,18,19,20-pentanor-prostenoic acid and the methyl
ester,
(13E)-(8R,9S,llR,12R,15R)-9,11,15-trihydroxy-15-((2S)-1,3-benzo-
dioxan-2-yl)-16,17,18,19,20-pentanor-prostenoic acid and the methyl
ester and
(13E)-(8R,9S,llR,12R,15S)-9,11,15-trihydroxy-15-((2S)-1,3-benzo-
- dioxan-2-yl)-16,17,18,19,20-pentanor-prostenoic acid and the methyl
ester.
Example 33
; By interposing in the sequence of reactions leading to
the compounds of examples 7 to 12, a reduction of the compounds
obtained as described in examples 7(d), 8(d), 9(d), lO(d), ll(d)
and 12(d) analogous to the process described in example 31, the
' '
- 46 -
... .
,i ~0~71~8
..'~
following compounds were obtained:
(13E)-(8R,llR,12R,15R)-11,15-dihydroxy-9-oxo-15-((2RS)-1,3-benzo-
dioxan-2-yl)-16,17,18,19,20-pentanor-prostenoic acid and the
methyl ester,
(13E)-(8R,llR,12R,15S)-11,15-dihydroxy-9-oxo-15-((2RS)-1,3,-benzo-
dioxan-2-yl)-16,17,18,19j20-pentanor-prostenoic acid and the methyl
ester,
(13E)-(8R,llR,12R,15R)-11,15-dihydroxy-9-oxo-15-((2R)-1,3-benzo-
dioxan-2-yl)-16,17,18,19,20-pentanor-prostenoic acid and the
10 methyl ester,
(13E)-(8R,llR,12R,15S)-11,15-dihydroxy-9-oxo-15-((2R)-1,31-benzo-
. dioxan-2-yl)-16,17,18,19,20-pentanor-prostenoic acid and the methyl
ester,
(13E)-(8R,llR,12R,15R)-11,15-dihydroxy-9-oxo-15-((2S)-1,3-benzo-
- dioxan-2-yl)-16,17,18,19,20-pentanor-prostenoic acid and the methyl
ester and
(13E)-(8R,llR,12R,15S)-11,15-dihydroxy-9-oxo-15-((2S)-1,3-benzo-
dioxan-2-yl)-16,17,18,19,20-pentanor-prostenoic acid and the methyl
ester.
Example 34
~ (8R,9S,llR,12R,15R)-9,11,15-trihydroxy-15-((2RS)-1,3-benzodioxan-
2-yl)-16,17,18,19,20-pentanor-prostanoic acid and the methyl ester.
General formula I: 2 CH2; X...Y = CH2-CH ;
OH
~ OH ; Rl = OCH3, OH; R2,R3,R4 = H; the OH group at C-15
~ H
is ~-positioned.
432 mg of the acid or ester thereof obtained as described
in example 1, 45 mg of palladium on carbon (10% strength) and 10
ml of ethyl acetate were agitated at room temperature in an at-
mosphere of hydrogen until 2 mmoles of hydrogen had been absorbed.
After filtration and evaporation, the compounds identified in the
: ::
- 47 -
".
~ 7178
heading were obtained, 420 mg of the ester being obtained in the
form of a colourless oil.
IR: 3600 - 3400, 1730, 1590, 1490, 760 cm 1.
Example 35
In a manner analogous to that described in example 34,
there were obtained with the products obatined as described in
examples 2 to 6 the following derivatives:
(8R,9S,llR,12R,15S)-9,11,15-trihydroxy-15-l(2RS)-1,3-benzodioxan-
2-yl)-16,17,18,19,20-pentanor-prostanoic acid and the methyl ester,
(8R~9s~llR~l2R~l5R)-9~ l5-trihydroxy-l5-((2R)-l~3-benzodioxan
!; 2-yl)-16,17,18,19,20-pentanor-prostanoic acid and the methyl ester, -~
" (8R,9S,llR,12R,15S)-9,11,15-trihydroxy-15-(¦2R)-1,3-benzodioxan- .
2-yl)-16,17,18,19,20-pentanor-prostanoic acid and the methyl ester,
(8R,9S,llR,12R,15R)-9,11,15-trihydroxy-15-((2S)-1,3-benzodioxan-
2-yl)-16,17,18,19,20-pentanor-prostanoic acid and the methyl ester
~; and
(8R,9S,llR,12R,15S)-9,11,15-trihydroxy-15-((2S)-1,3-benzodioxan-
2-yl)-16,17,18,19,20-pentanor-prostanoic acid and the methyl ester.
Example 36
(5Z,13E)-(8R,9S,12R,15R)-9,15-dihydroxy-11-oxo-15-((2RS)-1,3-
benzodioxan-2-yl)-16,17,18,19,20-pentanor-prostadienoic acid and
the methyl ester.
General formula I: A = trans CH=CH; B = cis CH=CH; X Y =
2-C- ; \\OH ; Rl = OCH3, OH; R2,R3,R = H; the OH
O ~H
group at C-15 is a-positioned.
(a) (lS,5R,6R,7R,3'R)-6-[(E)-3-tetrahydropyranyloxy-3-((2RS)-
1,3-benzodioxan-2-yl)-1-propenyl]-7-benzoyloxy-2-oxabicyclo
[3,3,0loctan-3-one.
?
3 ml of dihydropyran (freshly distilled) and 10 mg of
para-toluene sulphonic acid were added at ice bath temperature to
a solution of 2.4 g of the a-alcohol obtained as described in
- 48 -
~ 71~8
;
example l(d) in 50 ml of methylene chloride, and the mixture was
stirred for 15 minutes at that temperature, diluted with methylene
chloride and agitated with a sodium bicarbonate solution. The
organic phase was washed with water, dried with magnesium sul-
phate and evaporated in vacuo. 2.8 g of the above-mentioned
- compound were obtained.
(b) (lS,5R,6R,7R,3'R)-6-[(E)-3-tetrahydropyranyloxy-3-((2RS)-1,3-
.. . .
benzodioxan-2-yl)-1-propenyl]-7-hydroxy-2-oxabicyclo-[3,3,0]
octan-3-one.
. ~
A mixture of the 2.8 g of the product obtained as des-
cribed under (a) and 765 mg of potassium carbonate (anhydrous)
in 110 ml of methanol (absolute) was stirred for 2 hours at room
temperature under argon. The mixture was then diluted with ethyl
acetate and washed until neutral with a saturated solution of
sodium chloride. The organic phase was dried over magnesium
' sulphate and evaporated ln vacuo. 1.85 g of the above-mentioned
compound were obtained.
(c) (2RS,3aR,4R,5R,6aS,3'R)-4-[(E)-3-tetrahydropranyloxy-3-((2RS)-
s 1,3-benzodioxan-2-yl)-1-propeny~-5-hydroxy-perhydrocyclopenta
' [b]furan-2-ol.
; 22 ml of a solution bf DIBAH of 20~ strength in toluene
` were added dropwise under argon to a solution, cooled to -70C,
of 1.85 g of the lactone obtained as described under (b) in 90
ml of absolute toluene. After 30 minutes, the reaction was
terminated by the dropwise addition of isopropanol, and the whole
was stirred at 0C with the addition of 30 ml of water for 15
minutes. Then, extraction with ethyl acetate, washing with brine,
drying with magnesium sulphate and evaporating ln vacuo were carried
; out. 1.8 g of the above-mentioned compound were obtained in the
form of a colourless oil.
. .
(d) (2RS,3aR,4R,5R,6aS,3'R)-4-[(E)-3-tetrahydropyranyloxy-3-
(¦2RS)-1,3-benzodioxan-2-yl)-1-propen~1]-2,5-diacetoxy-
- 49 -
:
- ` ~0~7~78
perhvdrocyclopenta[b]furan-2-ol.
1.8 g of the lactol obtained as described under (c)
were stirred in a mixture of 10 ml of acetic anhydride and 25 ml -
of pyridine for 8 hours at room temperature. After removing the
solvent ln vacuo, 2.0 g of the above-mentioned compound were
obtained.
(e) (2RS,3aR,4R,5R,6aS,3'R)-4-[(E)-3-tetrahydropyranyloxy-3-
.
((2RS)-1,3-benzodioxan-2-yl)-1-propenyl]-5-acetoxy-perhydro-
cyclopenta[b]furan-2-ol.
2.0 g of the diacetate obtained as described in td)
were maintained in a mixture of 5 parts of glacial acetic acid,
5 parts of water and 1 part of tetrahydrofuran for 15 minutes at
25C, and the~mixture was then stirred into a solution of sodium
bicarbonate and washed until neutral. The organic phase was
concentrated, and the residue was purified by column chromatography
over silica gel with ether/pentane = 1/1. 1.5 g of the above-
mentioned compound were obtained.
(f) (5Z,13E)-(8R,9S,llR,12R,15R)-9-hydroxy-11-acetoxy-15-tetra-
,!
hydropyranyloxy-15-((2RS)-1,3-benzodioxan-2-yl)-16,17,18,19,20-
pentanor-prostadienoic acid.
26.3 ml of a solution of sodium methane-sulphinyl-methyl
in absolute DMSO (preparation of the solution: 2.5 g of a sus-
pension of 50% strength of sodium hydride in 50 ml of DMSO were
` stirred for one hour at 70C), were added dropwise to a solution
of 7.2 g of 4~carboxybutyl-triphenylphosphonium bromide in 30 ml
of absolute dimethyl sulphoxide, and the whole was stirred for
30 minutes at room temperature. The resulting ylene-solution was
then added dropwise at 15C to a solution of 1.5 g of the lactol
obtained as described under (e) in 30 ml of absolute DMSO during
the course of 15 minutes, and the whole was stirred for 2 hours
at 50C. The solvent was then distilled to a large exten~ under
an oil pump vacuum at 45C, and the residue was taken up in 70 ml
- 50 -
717B
of water and extracted three times with ether. The organic
extract was discarded. The aqueous phase was acidified with a
solution of 10~ strength of citric acid to a pH of 4 - 5, and
the mixture was extracted four times with a mixture of hexane/
ether = 1/1. The ether/hexane extract was washed with brine,
dried over magnesium sulphate and evaporated 1n vacuo. By chroma-
tography of the residue over silica gel, 1.1 g of the above-
mentioned compound were eluted in the form of a colourless oil.
: (g) (5Z,13E)-(8R,9S,llR,12R,15R)-9,15-bis-(tetra ~dropyranyloxY)-
11-acetoxy-15-((2RS)-1,3-benzodioxan-2-yl)-16,17,18,19,20-
.
pentanor-prostadienoic acid.
2.2 ml of dihydropyran and 6 mg of para-toluene sulphonic
acid were added at ice bath temperature to a methylene chloride
solution of 1.1 g of the compound obtained as described in (f),
and the whole was stirred for 15 minutes at such temperature. The
m~xture was then diluted with methylene chloride, and agitated
with a sodium bicarbonate solution, and the organic phase was
;` washed with water, dried over magnesium sulphate and concentrated.
The residue was treated for 15 minutes at 25C with a mixture of
glacial acetic acid, water and tetrahydrofuran (5/5/1), and the
mixture was then stirred into a solution of sodium bicarbonate
and washed until neutral. After concentrating the organic phase,
1.2 g of colourless oil were obtained.
(h) (5Z,13E)-(8R,9S,llR,12R,15R) -9!15-bis-(tetr_hydropyranyloxy)
ll-hydroxy-15-((2RS)-1,3-benzodioxan-2-yl)-16,17,18,19,20-
.~
pentanor-prostad~eno~-c acid.
The 1.2 g of product obtained in the manner described in
(g) were reacted in a manner analogous to that described in (b)
with potassium carbonate and methanol. 0.8 g of the above-
mentioned compound was obtained.(i) (5Z,13E)-(8R,9S,12R,15R)-9,15-bis-(tetrahydropyranyloxy)-
ll-oxo-15-(¦2RS)-1,3-benzodioxan-2-yl)-16,17,18,19,20-
.
.
~- ~f)B7'17
.
pentanor-prostadienoic acid.
0.84 ml of Jones reagent was added to a solution of 0.8
... . .
g of the alcohol obtained in the manner described in (h) in 10 ml
of acetone, and the mixture was stirred for 30 minutes at -20C.
1 ml of isopropanol was then added dropwise, and the mixture was
; stirred for 10 minutes at -20C, diluted with ether and extracted
byagitation with water three times. The organic phase was dried
~ over magnesium sulphate and evaporated in vacuo. 725 mg of the
x above-metnioned ketone were obtained in the form or a colourless
` 10 oil.
(j) (5Z,13E)-(8R,9S,12R,15R)-9,15-dihydroxy-11-oxo-15-((2RS)-1,3-
... .
s benzodioxan-2-yl)-16,17,18,19,20-pentanor-prostadienoic acid.
~ 650 mg of the bis-tetrahydropyranyl ether prepared in the
,j~ `
manner described in (-i) were stirred for 6 hours at 50C in 15 ml
of a mixture consisting of 65 parts of glacial acetic acid, 35
!:;. parts of water and 10 parts of tetrahydrofuran. The mixture was
then evaporated to dryness under 0.1 Torr, and the resulting crude
product was purified by column chormatography. 280 mg of the
above-mentioned compound were eluted with methylene chloride/5-8%
ethanol.
(k) 7 ml of an ethereal solution of diazomethane were added drop-
wise at ice bath temperature to a solution of 140 mg of the acid
obtained in the manner described in (;) in 10 ml of methylene
chloride, and the mixture was stirred for 10 minutes and then
evaporated in vacuo. After chromatography of the crude product
1,"
over silica gel with ether/dioxan = 95/5 as flow agent, 80 mg of
~ the prostaglandin carboxylic acid methyl ester of the D-type
; identified in the heading of this example were obtained.
IR: 3500 - 3300, 1740, 1730, 1590, 1485, 980, 760 cm 1.
Example 37
In a manner analogous to that described in example 36
starting from the compounds obtained as described in examples 2(a),
- 52 -
,
r 1087~78
3(b), 4(a), 5(b) and 6(a), the following derivatives were obtained:
(SZ,13E)-(8R,9S,12R,15S)-9,15-dihydroxy-11-oxo-15-((~RS)-1,3-
benzodioxan-2-yl)-16,17,18,19,20-pentanor-prostadienoic acid
and the methyl ester,
(5Z,13E)-(8R,9S,12R,15R)-9,15-dihydroxy-11-oxo-15-((2R)-1,3-
benzodioxan-2-yl)-16,17,18,19,20-pentanor-prostadienoic acid and
the methyl ester,
(5Z,13E)-(8R,9S,12R,lSS)-9,15-dihydroxy-11-oxo-15-((2R)-1,3-
benzodioxan-2-yl)-16,17,18,19,20-pentanor-prostadienoic acid
and the methyl ester,
(5Z,13E)-(8R,9S,12R,15R)-9,15-dihydroxy-11-oxo-15-((2S)-1,3-
benzodioxan-2-yl)-16,17,18,19,20-pentanor-prostadienoic acid and
the methyl ester and
(5Z,13E)-(8R,9S,12R,15S)-9,15-dihydroxy-11-oxo-15-((2S)-1,3-
benzodioxan-2-yl)-16,17,18,19,20-pentanor-prostadienoic acid and
the methyl ester.
Example 38
(5Z,13E)-(8R,9S,llR,12R,15R)-9,11,15-trihydroxy-15-((2RS)-1,3-
benzodioxan-6-bromo-2-yl)-16,17,18,19,20-pentanor-prostadienoic
--- :
acid and the methyl ester
General formula I: A = trans CH=CH; B = cis CH=CH; X Y =
CH~-CH ; ~ \\\OH ; Rl = OCH3, OH; R2,R4 = H; R3 = Br
OH ~ ~ H
(in para-position to the phenolic oxygen atom); the OH group
at C-15 is G-positioned.
(a) 5-bromo-2-hydroxy-benzyl alcohol
11.5 ml of bromine in 100 ml of carbon tetrachloride
were added dropwise to a 0 - 5C to a suspension of 24.8 g of
saligenin and 24 g of calcium carbonate in a solvent mixture of
200 ml of carbon tetrachloride and 220 ml of methylene chloride.
The reaction rnixture was stirred for 24 hours at room temperature,
and then filtered, and the precipitate was washed with carbon
-53-
. . . - , ' ' ' '' .
~ 71'78
.
tetrachloride. The CC14/CH2C12 phase was discarded. The solid
matter was taken up in ethyl acetate/water, and the organic phase
was separated, dried over magnesium sulphate and concentrated to
dryness. The residue was recrystallized from methylene chloride.
Lamelliform, colourless crystals (24 g) were obtained.
Melting point: 107 - 109C (methylene chloride).
(b) 1,3-benzodioxan-6-bromo-2-carboxylic acid methyl ester.
A solution of 20.3 g of the 5-bromo-2-hydroxy-benzyl
alcohol obtained in the manner described in (a) in 110 ml of
dimethyl formamide was added dropwise to a suspension of 9.6 g
of sodium hydride of 50% strength in 100 ml of dimethylformamide
while cooling with ice-water. The reaction mixture was stirred
overnight at room temperature. 8.62 ml of dichloracetic acid
were then introduced dropwise while cooling with ice in 100 ml
of dimethylformamide. 5.04 g of sodium hydride of 50% strength
were then added in portions while cooling with ice. The resulting
sodium dichloracetate solution was stirred for 30 minutes at room
temperature, and then introduced dropwise into the bromosaligenin-
disodium solution first prepared. After the addition of 1.5 g
of sodium iodide, the reaction mixture was stirred for 4.5 hours
at 60C, and during the last 2.5 hours the greater part of the
dimethylformamide was distilled ln vacuo. After cooling, the
residue was acidified to a pH of 3 with an aqueous solution of
citric acid, saturated with sodium chloride, and extracted by
agitating several times with methylene chloride. The organic
phase was dried over magnesium sulphate and concentrated in a
, .
rotary evaporator,and an ethereal solution of diazomethane was
added at 0C until the evolution of gas ceased and a yellow
coloration of the reaction solution persisted. The solvent was
removed together with the excess of diazomethane after stirring
for 1/2 hour at room temperature in vacuo. The bright crystalline
magma that remained behind was purified by column chromatography
- 54 -
'
~ 7~78
over silica gel with methylene chloride or hexane/10% ethyl acetate
as flow agent.
Yield: 12.6 g.
Melting point: 120C (matted small needles from methylene chlor-
ide/hexane).
(c) [2-oxo-2-(1,3-benzodioxan-6-bromo-2-yl)-ethylidene]-tri-
phenylphosphorane.
15.63 ml of a 2.15 m solution of lithium butyl in hexane
were added dropwise to a suspension of 13 g of triphenyl-methyl-
phosphonium bromide (dried for 4 hours at 40C under an oil pump)
in 85 ml of absolute ether, while cooling with ice and in an at-
mosphere of argon, and the whole was stirred for 15 hours at room
temperature. 4.59 g of the 1,3-benzodioxan-6-bromo-2-carboxylic
, acid methyl ester obtained as described under (b) in 75 ml of
c absolute benzene were added dropwise to the yellow ylene-solution,
: the mixture was stirred for one hour at room temperature, and the
' white precipitate was filtered, dissolved in water and extracted
, with ether. The organic phase was combined with the filtrate,
washed with water, dried over magnesium sulphate and concentrated
to dryness. The residue was purified by column chromatography
over silica gel with hexane/20 - 100% ethyl acetate.
Yield: 5.6 g.
Melting point: 172 - 174C (ethyl acetate).
The additional reaction stages were carried out in a
manner analogous to that described in example l(c) - (g).
In an analogous manner, all the other prostaglandin
acids and esters thereof described in the present examples can be
converted into the derivatives corresponding to those described
in example 38.
Example 39
(5Z,13E)-(8R,9S,llR,12R,15R)-9,11,15-trihydroxy-15-((2RS)-1,3-
benzodioxan-2-yl)-16,17,18,19,20-pentanor-prostadienoic acid
.
- 55 -
37178
(4-phenyl)-phenacyl ester.
General formula I: A = trans CH=CH; B = CiS CH=CH; X Y =
2 CH ; Z ~ "~OH ; Rl = O-CH2-CO
OH ~ H
R2,R3,R4 = H; the OH group at C-15 is ~-positioned.
75 mg of the prostadienoic acid obtained as described in
example l(f) were stirred with 21 mg of triethylamine and 53 mg
of para-phenyl-phenacyl bromide in 4 ml of acetone for 12 hours
at room temperature under argon. After dilution with water,
extraction with ether was carried out, and the ether extract
B was agitated with a sodium chloride solution~ ~rd over magnesium
sulphate and evaporated in vacuo. The residue was filtered over
.
5 g of silica gel with ether/dioxan mixtures. After recrystal-
lization from meth~lene chloride/hexane, 55 mg of the compound
identified in the heading were obtained in the form of colourless
crystals.
Melting point: 118C.
IR: 3600, 1740, 1695, 1590, 1490, 980, 750 cm .
In a manner analogous to that described in example 39,
all the other prostaglandin acids described in the foregoing
examples can be converted into the corresponding phenacyl esters.
Example 40
The tris-(hydroxYmethvl?-amlnomethane salt of ~5Z,13E)-(8R,9S,llR,
12R,15R)-9,11,15-trihydroxy-15-((2RS)-1,3-benzodioxan-2-yl)-16,17,
.
~ 18~19~20-pentanor-prostadienoic acid.
A solution of 32.9 mg of tris-(hydroxymethyl)-aminomethane
in 0.1 ml of water was added a~ 60C to a solution of 103 mg of
the prostadienoic acid prepared as described in example l(f) in
14 ml of acetonitrile, and the whole was allowed to stand for 14
hours at room temperature. 76 mg of the above-mentioned salt
were obtained in the form of colourless crystals.
In a manner analogous to that described in example 40,
- 56 -
~7178
...
.;
all the other prostaglandin acids described in the foregoing
examples can be converted into the corresponding tris-(hydroxy-
methyl)-aminomethane salts.
Example 41
(5Z,13E)-(8R,9S,llR,12R,15R)-9,11,15-trihydroxy-15-((2S)-1,3-
. )
benzodioxan-2-yl)-16,17,18,19,20-pentanor-prostadienoic acid
(4-phenyl)-phenacyl ester.
General formula I: A = trans CH=CH; B = cis CH=CH; X Y =
2 CH ; z ~ \\\oH ; Rl = O-cH
OH ~H
R2,R3,R4 = H; the OH group at C-15 is ~-positioned.
~ 130 mg of the prostadienoic acid obtained as described
r' in example 5td) were reacted in a manner analogous to that des-
;~ cribed in example 39, and 85 mg of the compound identified in the
heading were obtained in the form of colourless crystals.
Melting point: 79C - 80C.
,. ~
IR: 3430, 1745, 1695, 1585, 1225, 1030, 760, 750, 720 cm 1
Example 42 -
;l (5Z,13E)-(8R,9S,llR,12R,15S)-9,11,15-trihydroxy-15-((2S)-1,3-benzo-
; 20 dioxan-2-x1)-16,17,18,19,20-pentanor-prostadienoic acid (4-phenyl)-
:
phenacyl ester.
General formula I: A = trans CH=CH; B = cis CH=CH; X Y =
2 CH ; z ~ \~\OH ; Rl = O-CH2-CO~
; OH ~H
~: .
R2,R3,R4 = H; the OH group at C-15 is ~-positioned.
. 100 mg of the prostadienoic acid prepared as described
in example 6(c) were reacted in a manner analogous to that describ-
ed in example 39, and 115 mg of the compound identified in the
~,
` heading were obtained in the form of colourless crystals.
Melting point: 60C.
IR: 3440, 1740, 1700, 1590, 1240, 1030, 760, 725 cm 1
- 57 -
.i , .
. ~ . - . ~ ,
-~" 1087178
'i
SUPPLEMENTARY_DISCLOSURE
The title compound of Example 38, namely, (5Z-13E)-
, (8R,9S,llR,12R,15R)-9,11,15-trihydroxy-15-((2RS)-1,3-benzodiozan-
6-bromo-2-yl)-16,17,18,19,20-pentanor-prostadienoic acid has
luteolytic activity with 0.03 mg/d in rats s.c.
, . . .
, .
,~, .
, , .
. 10
,~
$
: l
, . .
;' ...
- 58 -
~ .
.,
