Note: Descriptions are shown in the official language in which they were submitted.
The present invention relates to 9-oxo-13,1~-pro-
stadienoic acicl derivatives, includiny the physiologically
-tolerable salts thereof, a process for their preparat:ion and
pharmaceutical compositions containiny them.
German Offenlegungsschrift No. 26 35 985 describes
and claims prostanoic aci.d derivatives of the general
formula
Z
~ ~ ~ B --- W ~ n5
; ~.5
in which Rl represents a -C-R6 or /C-ORg group in which R6
7 8
represents a hydroxyl group, a straigh-t-chain or branched
alkoxy group having frGm 1 to 10 carbon atoms, a substituted
or unsubstituted aryloxy group, a O-CH2-U-V group wherein U
represents a direct bond, a carbonyl group or a carbonyloxy
group and V represents a phenyl ring substituted by one or
rnore phenyl groups, alkoxy groups having 1 or 2 carbon
atoms, or halogen atoms, preferably bromine atoms, or repre-
sents an NHRlo group in which Rlo represents an alkyl oraryl group or an acid radical of an organic carboxylic or
sulphonic acid having from 1 to 15 carbon atoms, R7 and R8
represen-t hydrogen atoms or alkyl groups having from 1 to 4
carbon atoms and Rg either represents an acid radical of an
organic carboxylic or sulphonic acid having from 1 -to 15
carbon atoms or of an inorganic acid or represents a
-ICl-NHRlo group wherein Rlo has -the meaning gi.ven above,
A represents a -CH2-CH2 or a cls- or trans-CEI=CEI- group, .B
represen-ts a -CH2-CE12-, a trans-CI~=CM-, a C-C- group or a
- 2 -
~L2~
-Cll-CII- group wherein the methylene group may be in the D~.or
Cll~
-position, W represents a free or functionally modified
hydroxymethylene group, a free or functionally modified
R11
carbonyl group of a 1~ group wherein Rll represents a
0~1
hydrogen atom or an alkyl group having from 1 to 5 carbon
atoms and the OH group may be in the ~- or ~-position and
may be functionally modified, Z represents a carbonyl or
hydroxymethylene group that may be free or functionally
modified, X Y represents -CH2-CH- or -CEI2-CI- if Z repre-
R12
sents a free or functionally modified hydroxymethylene
group, or represents -CH2-CH- or -Cfl=CH- if Z represents a
12
-- 4 --
free or functionally modified carbonyl group,
wherein the radical R1~ represents a hydroyen atom,
a methyl group, a cyanide group or a free or func-
tionally modified hydroxy group,
R2 represents a hydrogen atom or an alkyl group,
R3 represents a hydrogen atom or an alkyl group,
R4 and R5 are the same and each represents a methyl group or
R4 represents a chlorine atom and R5 represent3 a methyl
group or
R5 represents a chlorine atom and R4 represents a methyl
group,
and if R6 represents a hydroxy group, the physiologically
tolerable salts thereof with base~.
The compoundspossess valuable therapeutic propertie~
and are distinguished especially by the fact that they are
capable of inducing menstruation or terminating a pregnancy
after a single intrauterine administration. They are also
suitable for synchronisingthe sexual cycle in female mammals -
such as apes, cattle, pigs, sheep etc.. The prostaglandin
derivatives described in German Offenlegungsschrift No. 26 35 98.
have a strongly contractive action on the uterus and also a
luteolytic action, that is to say lower dosages are required
to induce abortion than i~ the case with the corresponding
natural prostaglandins. Also, with nakural prostaglandins,
the desired, main actions are usual.ly accompanied by un-
desirable side effects which considerably diminish the
quality of the main action.
- ~20~
We have found that certain of the prostadienoic acids
e~hibit such outstanding properties as an abortifacient that,
when used, the dosage can be reduced by a multiple in comparison
with customary commercial preparations (for example, sulproston)~
as a result of which undesirable ~ide effects are,of course,
even more strongly repressedv When compared with compounds,
- mentioned in German Offenlegungsschift No. 26 35 985, we have
found the compounds of the present invention to possess
greater relative activity of, at least~ in the range o~ from
10 ~ 100.
The present invention provides a (13E)-(8R, llR,12R~-11, 15-
dihydroxy~9-oxo-13, 18-prostadienoic acid which is substituted
at the 16-position by one or two methyl groups and at the
l9-position by one methyl group.
me hydroxy group at the 15-position and the methyl group
at the 16-position may be in any suitable configuration.
Preferably the 15-hydroxy group has an S-configuration when ~he
16-methyl group has an RS-configuration. When the compound is
disubstituted in the 16-position by a methyl group the 15-
hydroxy group preferably has an R-configuration.
The present invention also provides a salt of a compound of
the invention, especial~y a physiologically tolerable salt
thereof.
None of the compounds of the present invention are
speci~ically described in German Offenlegungsschrift No. 26 35 985
Compounds in which A repre~ents a -CH2-CH2- group are not distin-
guished from the other compounds in which A repre~ents a
cis-CH-CH- group in that document.
!. 5~ -
6J5~
Suitable for the salt formation are all inorganic and
organic bases such as those known to the man skilled in the
art for the formation of physiologically tolerable salts. ~here
may be mentioned, by way of example, alkali metal hydroxides t
such as so~ium or potassium hydroxide, alkaline earth metal
hydroxides, such as calcium hydroxide, ammonia, amine3, such as
ethanolamine, diethanolamine, triethanolamine, ~-methylglucamine,
morpholine, tris(hydroxymethyl)-methylamine, etc..
The present invention further provides a proce~s for the
~2~ 6~
--6--
preparation of a compound of the invention, or a salt thereof,
which comprises reacting
(8R,9S,11R,12S) -9-benzoyloxy-13 oxo-11-(tetrahydropyran 2-yloxy)-
14,15,16,17,18,19,20-heptanorprostanoic methyl ester
with eithex
2-(1,4-dimethyl-3-pentenyl~-2-oxoethanephosphonic acid dimethyl
ester
or
2-~1,1,4-trimethyl-3-pentenyl)-2-oxoethanephosphonic acid dimethyl
ester and then whichever of the following steps are necessary or
desired are carried out in any suitable order
a) a free hydroxy group is protected
b) a protected hydroxy group is converted to a free hydroxy group
c) a 15-oxo group is reduced
d) a 9-oxo group is reduced
e) a 9-hydroxy group is oxidised
f) an acid is converted into a salt
g) a salt is converted into an acid
h) a salt is converted into another salt
i~ a mixture of racemates is separated.
The reaction of (8R,9S r 11R,12S)-9-benzoyloxy-13-oxo-11-
(tetrahydropyran-2-yloxy)-14,15,16,17,18,19,20-heptanorprostanoic
acid methyl ester with 2-(1,4-di-or 2-(1,1,4-tri-methyl-3-pentenyl)-
2-oxoethanephosphonic acid dimethyl ester may be carried out in a
~2()$~
manner known per se at a temperature in the range of from
0C to 100C, preEerably from 20C to 80C, in an aprotic
solvent, such as, for example, dimethyl sulphoxide, di-
me-thylformamide, benzene, toluene, xylene, diethyl ether,
tetrahydrofuran, dioxan, chloroform, methylene chloride and
dimethoxyethane.
The prepara-tion of the compounds 2-(1,~-di- and
2-(1,1,4-tri-methyl-3-pentenyl)-2-oxoe-thanephosphonic acid
dimethyl ester may be carried out according to me-thods known
per se, as have been described in German Offenlegungsschrift
No. 26 35 985.
The oxidation of the 9-hydroxy group may also be
carried out according to methods known per se with the cus-
tomary oxidising agents. For example, the oxidation can be
carried out with the 11- and 15-hydroxy groups being tem~
porarily protected, for example by silylation with Jones
reagent (Chem. Comm. 1972), 1120).
Freeing of functionally modified hydroxy groups is
suitabiy carried out according to known methods. For
example, the splitting off of hydroxy-protec-ting groups,
such as, for example, the tetrahydropyranyl radical, may be
carried out in an aqueous solution of an organic acid, such
as, for example, oxalic acid, ace-tic acid and propionic acid
inter alia, or in an aqueous solution of an inorganic acid,
such as, for example hydrochloric acid. To improve solu-
bility, a water-miscible inert organic solvent is advan-
tageously added. Suitable organic solvents are, Eor example
alcohols such as methanol and ethanol, ethers, such as
di-methoxyethane, dioxan and tetrahydrofuran, and acetone.
Preferably te-trahydropyran is used. The splitting-off
operation is preferably
\
carried out at a temperature in the range of from 20C to 80~C.
Hydrolysis of the acyl groups is carried out, for example
with alkali metal carbonates or hydroxides or with alkaline earth
metal carbonates or hydroxides in an alcohol or in an aqueous
solution of an alcohol. Alcohols that come into consideration are
aliphatic alcohols, such as, for example, methanol, ethanol and
butanol, preferably methanol. As alkali metal carbonates and
hydroxides both potassium and sodium salts are suitable but
potassium salts are preferred. Suitable alkaline earth metal
carbonates and hydroxides are, for example, caicium carbonate,
calcium hydroxi~e and barium carbonate. The reaction is suitably
carried out at a temperature in the range of from -1DC to
+70C, preferably at +25C.
The compounds of the invention may be converted into
salts with suitable amount of the corresponding inorganic bases
with neutralisation taking place. For example, upon dissolving
the prostadienoic acid in water containing the stoichiometric
amount of the base, after evaporating off the water or after
adding a water-miscible solvent, for example alcohol or acetone,
a solid inorganic salt is obtained.
For the preparation of an amine salt, which is
suitably carried out in customary manner, the prostadienoic acid
is, for example, dissolved in a suitable solvent, for example
ethanol, acetone, diethyl ether or benzene, and at least the
stoichiometric amount of the amine is added to that solution. In
so doing, an amine salt is usually obtained in solid form or is
~20S4~;~
isolated in customary manner after evaporation o~ th~ solvent.
Other steps in the process o~ the invention may be
carried out by known methods.
The good dissociation of action of the compounds
according to the invention may be demonstrated in tests on
other non-striated organs, such as, for example, the ileum of
guinea pigs or the isolated trachaea of rabbits, in which
considerably lower stimulation than that produced by the natural
prostaglandins has been observed by us.
Prostadienoic acid derivatives of the present invention
have been found to exhibit a bronchodilative action on the iso
lated trachaea of rabbits in vitro and greatly inhibit gastic
acid secretion and to have a regulatory action in the case of
heart rhythm disorders. The compounds of the invention further-
more reduce blood pressure and have a diuretic action. The
trimethyl substituted compounds of the invention have also been
found to have a cytoprotective action on the stomach.
For medicinal use, the active substance may be converted
into a form suitable for inhalation or for oral or parenteral
administration.
For inhalation, aerosol or spray solutions are advanta-
geously used.
For oral administration, tablets, dragées or capsules
for example, are suitable~
For parenteral administration, sterile, injectable,
aqueous or oily solutions may be used.
~2~
Accordingly, the present invention provides a
pllaralllceutical preparation comprising a compound of the pre-
sent invention, or a physiologlcally tolerable salt thereof,
in admixture of conjunction with a pharmaceutically su:i-table
carrier.
Preferbly the preparation is in unit dosage foxm.
Depending upon the mode oE administration, for example
vaginal, extraamnial, intramuscular or intravenous, the unit
dosage is suitably in the range of from 0.25 g -to 50 mg.
The active substances of the invention may be used
in combina-tion with the auxiliaries ~nown and customary in
galenical pharmacy, for example for the produc-tion of pre-
parations for inducing an abortion, for controlling -the
menstrual cycle or for inducing labour. For this purpose,
sterile aqueous solutions containing in -the range of from
0.0001 to 10 g/ml of the active solution. For the prepara-
tion of aqueous iso~onic solutions, the acid and salts are
especially suitable. To increase solubility, alcohols, such
as ethanol and propylène glycol, may be added. In addition,
suppositories for intravaginal administration can readily be
prepared.
The following 13xamples illustrate the invention.
Unless otherwise indicated, the percentages and proportions
in the Examples are given on a volume basis. The abbrevia-
tions "DIBAH" and "TLC" are used in the J3xamples to indicate
"diisobutylaluminium hydride" and "thin layer chromato-
graphy" respec-tively.
Example 1
-
(13E)-(8R,llR,12R,15S,16RS)~11,15-dihydroxy-16,19-dimethyl-
9-oxo-13,18-prostadienoic acid
~ - 10 -
~2~S'~
.
_~"~,,_~ " C~OH
~ CH3
~ ~ ~H3
0~1 O~
a) 2-ethoxycarbonyl-2,5-dimeth~1-4-hexenoic acid ethyl
ester _ __ _ _
36.1 g of sodium (cut into small pieces) were
placed in a three-necked flask equipped with a reflux
condenser, dropping funnel and stirrer. 800 ml of absolute
ethanol were added dropwise thereto rapidly enough to keep
the solution boiling briskly. 269.6 g of freshly dis-tilled
methylmalonic acid diethyl es-ter were added dropwise to the
hot alcoholate solution, the mixture was stirred for 1/2
hour at 60C and then 241.7 g of dimethylallyl bromide were
added dropwise thereto After stirring for one hour while
heating, the precipitated sodium bromide was fil-ter:ed off,
the precipi-tate was washed and the filtrate concentra-ted.
The residue was taken up in ether, washed neutral with
saturated sodium chloride solution, dried over magnesium
sulphate and concentrated in a rotary evaporator. The
residue remaining after evaporation was fractionated using
an oi] pump~ 266 g of the title compound (b.p.7 = 97-112C)
were obtained.
IR (film): 1735, 1245, 1025, 860/cm.
b) 2-carboxy-2,5-dimethyl-4-hexenoic acid
223.8 g of the diester obtained in a) were heated
under reflux for 4 hours together wi-th 181 g of potassium
hydroxide in 235 ml of water and 450 ml of e-thanol. The
ethanol was subsequently removed in a rotary evapora-tor, the
- residue was dissolved in 235 ml of water and, while cooling
with ice, concentrated hydrochloric acid was added dropwise
until a p~l of 1 was reached. The precipitate (m.p. 162-
-- 11 --
s~
166C) was colleeted, washed with water and used in the next
step without further purification.
IR (KBr): 1700, 1230, 840/cm.
c) 2,5-dime-thyl-4-hexenoic acid
The dicarboxylic acid obtained in the preceding
reae-tion step was maintained at 210C for 4 hours at normal
pressure and then for one hour at 75 torr in a distillation
apparatus. The product was then distilled in vacuo. 68 g
of the title compound (b.p.5 - 90-106C; b.p.l = 67-70C)
were obtained.
IR (film): 1705, 1220, 810/cm.
d) 2,5-dimethyl-4-hexenoic acid methyl ester
Ethereal diazomethane was added to the 68 g of
earboxylic acid obtained according to the method descrihed
above, until no rnore nitrogen was evolved upon adding the
reagent and the yellow colour of the reaction solution
remained unchanged. The solvent was then removed ln vaeuo
and -the residue fraetionated. 62.3 g of the ti-tle compond
(b.p.3 5 6 = 32-35C) were obtained.
IR (film): 1735, 1160, 1050, 820/cm.
e) 2,5-dimethyl-4-hexenoie aeid ethyl ester
~35.3 g of 2-e-thoxycarbonyl-2,5-dimethyl-4-hexe-
noie aeid ethyl ester were dissolved in 645 ml of dime-thyl
sulphoxide, and 29.7 g of lithium ehloride and 6.3 ml of
distilled water were added in sueeession. The reaetion
mixture was then heated at 200C for a total of 13 hours and
subsequently, after being left to eool, was poured onto 1
litre of iee-water. The aqueous phase was ex-traeted three
times with 500 ml of methylene ehloride eaeh time. The
eombined organie extraets were then washed twiee with water,
dried over magnesium sulphate, eoneentrated in a rotary
evaporator and distilled ln vaeuo. 53.1 g of the title
eompoulld (b.p.l3 = 75-78C) were isolatedO
~ 12 -
OS~
IR (film): 1735, 1160, 1050/cm.
f) 2-(1,4-di.methyl-3-pentenyl)-2-oxoetharlephosphonic acid
dimethyl ester
. . ~
274.7 ml of a 1.61M butylli.-thium solution in
hexane was added dropwise under argon a-t -60C to a solution
of 59 g of me-thanephosphonic acid dimethyl çster in ~00 ml
of absolute tetrahydrofuxan. After stirring for 15 m.inutes,
a solution of 34.05 g of 2,5-dimethyl-4-hexenoic aci.d ethyl
1~ ester in 100 ml of absolute tetrahydrofuran was added drop-
wise. The reaction mixture was left to warm to room tem-
perature
3SgL~;4
- 14 -
over a period of four houx3 and waa then ~tirred for a
further 3 hours. 26.5 ml of glacial acetic acid were
then added and the mixture was concentxated in vacuoO
The residue was taken up in ether/water, solid ~odium
chloride was added to the aqueous pha~e and extraction
with eth~r waA carried out~ The combined organic pha~e~
were dried over magnesium ~ulphake and concen~rated in a
rotary evaporator. The residue remaining after evapora~ion
wa purified by column chromatography over ~ilica gel
with hexane/50-100% ethyl acetate as eluant. 32 g of ~he
desired compound were obtained.
IR (fil~): 1710t 1260~ 1030/cmr
g) (ls~sR~6s~7R~-6-[(tert~butyldlmethyl~ilyloxy)- -
A solution of 9.9 g of dLmethyl-tert~-butyl~
chlorosilane in 40 ml of absolute dimethylformamide ~nd
9,35 g of imidazole were added to a solution of 13.8 g of
(lS~5R~6R~7R)-6-hydroxy-methyl-7-benzo~loxy-2-oxabicyclo
~3,300]_ octan~3-one in 30 ml of absolute dimethylformamide.
A~ter ~tirring for 2 hours at room temperature and under
an argon a~mo~phere, analytical thin-layer chromatGgraphy
indicated complete reaction. The reaction mixture was
:~Z~S465~
- 15 -
diluted with 850 ml of e~her, washed with approxim~tely
60 ml of saturated qodium bicaxbonate 501ution and
saturated 90dium chloride 501ution and then dried over
magne~ium sulphate. The re~iduè remaining after concen-
tration by evaporation may, if desired, be purified by
column chromatography over ~ilica gel wi~h ether as eluant.
17~8 g of the title compound (m.p. = 74-75C aftex
~rystalli~ation from pentane/ether) were o~ai~ed.
IR: 1775, 1715, 1600, 1580, 1275, 1255, 840, 790, 720~cm.
h) (lS,5R,6S~7R)-6-[(tert,-butyldimet~ylsilyloxy),
methyl l -7-hy~clo r 3 ~ 3 . ol octan~3~one
A ~olution of 17.3 g of the benzoate obtained in
the preceding reaction ~tep in ~00 ml of ab~olute me~hanol
was stirred with 605 g of dry potassium carbonate at room
temperature under argon~ After two hours, analytical
thin-layer ~hromatography indicated complete reaction.Then,
at oC~ 500 ml of O.IN hydrochloric acid were added
dropwise to the reaction mixture~ ~he whole was stirred
for 15 minutes at room temperature, concentrated i~n vacuo
and extracted with ethyl acetate. The organi~ phase was
washed with saturated ~cdium chloride solution and dried
over magnesium sulphate. The residue remaining after
concentration by e~aporation wa~ purified ~y column
chromatography over silica gel with hexane/5~100% ether
as eluant~ 9.1 g of the desired compound (m.p.: ~7-58.5C)
were obtained.
)S4~;~
- 16 -
IR (~ilm)o 1775, 1255, 840, 790/cm.
5~5R~6s~7R)-6-[(tert.~butyldime~hy~ yloxy)-
methylJ-7-(tetrahydrop~ran-2-yloxy)-2-oxabicyclo
-L3~300loctan 3-one
A ~olution of 15.8 g o~ alcohol obtained ac~ording
to ~he method described above in 300 ml of distilled me~hylene
. . .
chloride waQ s~irred with 705 ml of dihydropyran fre~hly
di~tilled u~ing potas~ium hydroxide, and 1D38 g Of
pyridine-~-toluenesulphonate for 14 hour~ at room tem-
perature After con~entxating ~he reactlon solution at
room temperature~ it wa~ diluted with e~her and w~shed ~ith
~emi-~aturated sGdium chloride ~olution. Th2 organic
solu~ion wa~ ~ub~equently dried over magne~ium ~ulphate and
then concentrated to dr~ne~s. The product may8 if desired~
be purified by column chxomatography over ~ilica gel wi~h
hexane/20-5~% ~ther a~ eluant. The yield wa~ 20 g.
IR ~film): 1775, 1255, 1115, 1080, 1035, 835~ 775/c~.
j) (lS,3R5~SR,6S,7R)-3-hydroxy-6 [~ert.-butyl-
dimethylsilyloxy)-methyl]-7-(tetrahydropyran-2--
yloxY3-2-oxabic clor3 3 6loctane
. ~ ~ Y l _ ~
20 ml of a 20% DIBAH solution in toluene were
added dropwise under argon in the cour~e of 15 minutes to
. . .
~s~
-- 17 --
a ~lution, cooled to -70C, of 5,4 g of th~ lac~one
obtained in ~he preceding reaction ~t~p in 20~ ml of
abQ~lute toluene. After ~tirring for approximately 5
minute~, 102ml of i~opropanol were added at the 3ame
temperature until the formation of foam cea~e~0 The
reaction solution was left to warm to 0C, 16 ml of water
were added, and ~he mixture wa~ ~tirred for 10 minutes
and filtered over a frit. The precipita~e was washed
with e~hyl acetate. The organic phase was washed ~hree
time~ with ~aturated ~odium chloride solution, dried over
magnesium sulphate and concentrated in a rotary evaporatorO
The resulting product (5.41 g) was u~ed in ~he next
reaction ~tep without ~ur~her purification.
k) (5Z)-~8R,9S~llR~12S)-9-hydroxy~ (tetrahydro~ -
pyra~-2-yloxy)-13-(tert.-butyldimethylsilyloxy~-
15,16~17/18/19~20-heptanor-5-pro~tenoic acid_
104.6 ml of a solution of methanesulph~nylme~hyl
sodium in absolute dimethyl sulphoxide (prepared by dissolving
6 g of 5~/0 by weiyht sodium-hydride suspen~ion in 120 ml of
absolute dimethyl sul~hoxide at a maximum of 70~C) were added
dropwise at 15C to a solution of 25.67 g o~ 4-carboxybutyl-
triphenylp~osphonium bromide ~previously dried at 70-80~C
using an oil pump) in 80 ml of ab301ute dim2thyl sulFhoxide,
~his ylene so~ution was stirred for 30 minutes at rowm
temperature and then, while cooling with water, added
dro~wise in the cour~e of 15 minutes to a solutiQn of
. , .
~ ~ll2~)S4~9
5.41 g of the lactol obtained in the precedincJ reaction step
in 50 ml of absolute dimethyl sulphoxide. The reacl:ion
m-ix-ture was -then stirred for four hours at 35-40C under
argon. (50-100 ml of absolute tetrahydrofuran may option-
ally be added to -the reac-tion solution).
For working up, the reaction mix-ture was poured
onto ice-water, extracted three times w:ith e-ther, and the
aqueous phase was acidified to pM 4 with 10% by weiyht
citric acid solution and extracted three times with a 1/1
mixture of ether/hexane. Extraction was then carried out
another three times by shaking with methylene chloride. On
the basis of analytical thin-layer chromatography, the
methylene chloride phase was discarded, but the other two
organic phases were combined, dried over magnesium sul-
phate, filtered and concentrated in a rotary evapora-tor.
The residue was purified by column chromatography over
silica gel wi-th hexane/70-100% ether as eluant.
4.32 g of the carboxylic acid were obtained.
~R (film): 3440 (broad), 3220-2500, 1725, 1700, 1250, 1100,
1020, 830, 770/cm.
1) (5Z)~(8R,9S,llR,12S)-9-hydroxy-11-(tetrahydropyran-
2-yloxy)-13-(tert.-butyldimethylsilyloxy)-14,15,16,17,18,
19,20-heptanor-5-prostenoic acid methyl ester
Preparation wi-th diazomethane:
The 4.32 g of carboxylic acid ob-tained in k) were
~3
s~
- 19 -
diqsolved in 20 ml of methylene chloride, and ethereal
diazomethane solution wa-q added until the evolution of
~as had cea3ed and the yellow colour of th8 ~olution
remained unchanged. After drawing off the excess
diazomethane using a water-jet vacuum, the reaction solution
was concentrated to dryness in a rotary ev~porator.
403 g of the desired carboxylic acid methyl e~ter w~re
ob~ained. ,7:.
~re aration with iodomethane
P . . ~
75 ml of N-ethyldii~opropylamine and 150 ml of
iodomethane in 200 ml of acetonitrile were added dropwise
at room k~mperature in the course of 2 hours to a solutio~
of 32.5 g o~ the carboxylic acid oktained in k) in 450 ml
of acetonitrile. Stirring was carried ou~ for on2 h~ur,
then, after TLC examinakion, the precipitate was suction~
filtered and washed with ethyl acetate, and the organi~
phase was shaken in ~u~cession with sodium bisulphate,
sodium bicarbonate and sodium chloride solutions~ After
drying over magnesium sulphate, the muxture wa~ concenkxated
to drynes~ in a rotary evaporator and the residue w~s
purified by column chromatography over silica gel with
hexane/50-100% ether as eluant~ 32.3 g of the title c~mpound
w~re obtained~
IR (film): 3420 (broad), 1740, 1255, 1120, 1030, 840,
780/cmO
/
i;4~;~
-- 20 --
m) (5Z;)-(8R,9S,llR,12S)-~-benzoyloxy-ll-
~ I:etrahydrop~ran-2~yloxy ) -13 ~ tert . -})utyl
I dimethylsilyloxy~ - 14~15~16J17~18~19~20_
' he~tanor 5-prostenoic acid methyl es er
2.32 ml of distilled benzoyl chloride were added
dropwise while stirring at room temperature to a ~olution
of 4 . 7 g of the 9-hydroxy compound o}:~ained in 1~ in
7Q ml of pyridine. After skirrirag for ~wo hour~ under an
argon a~Mosphere, 1.~ ml of water were added to the
reaction ~olution, the mixture was stirred for a fur~her
hour and then concentrated at 30 & and 1 torr using an oil
pump. The re~idue was taken up in a two-p~ase mixture of
etherfwater~ washed with 50dium bicarbonate and sa~urated
~odium chloride solution, dried over magnesium sulphate
and concen~rated to dryne~s in vacuo. Af~er column
chromatography of ~he evaporation re~idue over silica gel
with hexane/30-50% ethyl acetate a~ eluant~ 5.11 g of ~he
title compound were obtained a a colourle~ oil.
IR (film)~ 1745~ 1720, 1605, 1590, 1280, 1260, 1120, 1030,
~40, 780~ 710/cm~
n) (8R,9S~llR,12S)-9-benzoyloxy~ (tetrahydropyran-2-
yloxy)-13-(tert.-butyldimethylsilyloxy)-14,15,
16,17,18~19,20~heptanorprostanoic acid methyl
ester
1.23 g of lG% by weiyht palladium-on-carbon were
added to
S46~
- 21 -
a solution of 12 . 3 g of the un~atura~ed compound obtained
in m) in 160 ml of ethyl acetate and the mix~ure wa5
hydrog~nated in a shaking apparatus at room temperature
and under a slight hydr~gen overpr~sureO When 640 ml ~f
hydrogen had been ab~orbed~ ~he ~olvent was removed in
acuo, the residue wa~ tak~n up in 40 ml of ether, ~he
organic pha~e was washed with saturated ~odium chlorid~
solution, dried over magnesium sulphate and concentrated
to drynes~ in a rotary evaporatorO 12.1 g o~ the title
compound were ok~ained.
IR (film): 174G, 1720~ 1600, 1580, 1275, 1255~ 1115,
1070~ 1025, 835, 7~0t 710~cm.
) t8R,9S,,llR,12S)-9-benzoyloxy~ (tetrahy ~ opyran-2--
yloxy)-13~hydroxy-14~15,16,17,18,19,20
heptanor~rostanoiC acid methyl_r st~r
16011 ml of a 2M tetrabutylammonium fluoide
solution in tetrahydrofuran were added, while cooling wnth
ice, to a solution of 6.94 g of ~he compound obtained in
the preceding reaction step in 110 ml of absolute
tetrahydrofuranO Af ter ~tirring for 12 hours under an
argon atmosphere, the reaction mixture was diluted with
1. 3 li tres of ether, wa~hed neutral with sat~lrated 3c)dium
chloride solution and the wa~hing solution was subsequently
extracted twice with ether. Ihe combined organic phases
were dried over sodium ~ulphate and concentrated in vacuo.
The residue was purified by column chromatc~graphy over
3L;~0$~;9
- 22 -
silica gel with ethyl acetate as eluant. 5054 g of the
~e~ired compound were obtained as a colourles3 oil.
IR (film): 3460 (broad), 1735, 1715, 1600, 1580, 127~,
1115, 1070, 1025~ 710/cm.
p) (~R,9S,11~,12S)-9-ken20yloxy~13-oxo-ll-
(tetrahydropyran-2-yloxy)~14,15016,17,18019,2~
heptanor~o~tanolc__acid methyl ester _ _ _
A ~olution of 5.54 g of ~he alco~ol ob~aine~
according to the me~hod de~cribed above in 56 ml of
absolute m~thylene chloride was added dropwise at
5 10C in the cour~e of 20 minutes to a ~u~pension of
1807 g of Collins reagent in 170 ml of absolute me~hylene
chlorideO After ~tirring th~ reaction mixture for one
hour in an argon atmosphere, 500 ml of a 1~1 mixture of
e~her and pentane were added and decanting wa~ carried
out. The ~lask wa3 wa~hed two more time~ with 500 ml of
the same mixture a~ mentioned above,each time, The combined
organic phase~ were then shaken three tim~s with 50 ml of
5~ by weight ~odium carbonate ~olu~ion each time and three time~
with 50 ml of 5% sulphuric acid each tim~ and were then
wa~hed neutral With ~aturated sodium chloride solutionO After
drying over magnesium sulphate, the mixture wa~ conc~n-
trated to dryneqs and the re~idue wa~ filtered over a
col~mn of ~ilica gel (50 g; eluant: ethyl acetate/h~xane
= 2~8). 406 g o~ the de~ired aldehyde were ob~ained.
IR (~ilm): 2720, 1735, 1715, 1600, 1580, 1275~ 1115, 1070,
1025, 715/c~.
- 23 -
~1 ) tl3E )--~ 8R~ 9S ~ llR~ 16.RS ~-9-benzoy~ 16~
l9-d~methyl~15-oxo~ (tetrahydropyran-2-yloxy)-
2.48 g of the phosphonate obtained aocording tof), diasolved in 30 ml of absolute dimethoxyethane; were added
dropwise at room temperature under ~rgon to a ~u~pen~ion of
0.48 g of 50/0 by weight sodium hydrid~ (suspende~
in oil) in 60 ml of d~me~ho~ye~hane fre~hly distilled
using lithium aluminium hydxide. After the addition of
0.4~ g of lithium chloride (previously dried in a ~acuum
cupboard ~or 2 hours at 50C)~ the reaction mixture was
stirred ~or 2 hour~ at room temperatureO The ~uspensio~
was subsequently cooled to -20 C and 4r61 g of the aldehyde
ob~ained according to p), dis~olved in 9o ml of ah~olute
dim~thoxye~hane~ wer~ added dropwi~e. The t ~ erature was
then allowed to increa~e from -20C to oC in the course
of 5 hours and to 5C in the course of 105 hours in order
then to stir the reaction ~olution for a fur~her 3 hours
at room ~emperature. At -10 C, ~here were then added
dr~pwi~e 1 ml of glacial acetic acid and approxI~ately
100 ml of wa~er. The pha3es were separated, the aqueous
phase was extracted 5 times with ether, and the organic
by weight
phases were combined and washed with 4%/s~diu~ bicaxbonate
and saturated sodi~um chloride ~olutions. After ~rying
over magnesium sulphate, the mixture was concentrated ~o
drynes~ in a rotary evaporator. The residue ~ subjected
to purification by column chromatography over silica gel
::~2~S~
- 24 -
with ~thyl acetate/hexane - 1/1 as eluant. 5.78 g of the
title compound were obt.ained~
IR ~ 1740,, 1720, 1695, 1670, 16250 1600t 1~80~ 1270,
1105, 1060, 1~25, 705/~mO
r ) (13~ 3 - ( 8R ~, 9S, 11R ,12~ ,15R ,16RS ) -9-benzoyloxy-16 0
l~-d~methyl-15~hydroxy~ e~rahydropyran-2-
ylo~ ~-13 ,18-}~rostadienoic acid methvl e er
2.37 g of sodiurn borohydride were added in
portions to a 50111tiOTI, cooled to ~o&, of !;o78 g of the
ketone ob~ained in the preceding reaction ~tep in 115 ml
of ab~olute methanolO ~fter stirring for one hour at
-40C, S~09 ml of glacial acetic acid were added dropwise
to the reaction solution likewise at -40c. After removing
the ~olvent in a rotary evaporator, methylene chloride/
water were added to the residue, ~olid sodium chloride wa~
added to ~he ~eparated aqueou~ pha~e and the mixture w~s
extracted twice with methylene chl~ride. ~he combined
organic pha~es were washed with ~aturated ~dium chloxlae
~olution, dried over magne~ium ~ulp~ate and concentrated
in vacuo. The isomers were ~eparated by repeated col~mn
chromatography several times over silica gei with hexane~
20-loO~ ethyl acetate as eluant. 2~11 g o~ ~he title
compound w~re isolated a~ the least polar produ~t.
IR (~ilm): 3400 (broad), 1740~ 1720~ 1600~ 1580, 1275,
1120~ 103~, 1020, 710/Gm.
S~
- 25 -
~) ~13E)~(8R,9S,lLX,l~R,15R,16RS~-9-benzoylo~-16~19-
dimeth~l 11,15-bi~(tetrahydropyran-2-yloxy)-13,
18-pro~tadienoic acid methyl e~ter _ _ _
.
0.49 ml of dihydropyran (fre~hly distilled using
potaqsium hydroxide) and 9.7 mg of ~toluenesul~onic acid
were added At ice-bath temperature to a solution of
2,11 g of the alcohol ohtained according to r) i~ 60 ml
of ab~olut~ methylene chloride, ~he mixture wa~ stirred
for 55 minutes at O~C and, having diluted ~he reaction
~olution with methylene chloride, it was extra~ted wi~h
~a~urated ~sodium bicarbonate solution and water. The
organic pha~e wa~ dried over magnesium ~ulpha~e and
concentrate~ in vacuoO The residue wa~ purlfied by column
chrom~tography over ~ilica gel with e~hyl acetate/hexane
- 1/2 as eluant. 2~3 g of the de~ired compound w~re
obkained.
IR (~ilm): 1740, 1720, 1605, 1585, 1275, 1115, 1080, 1025
715/cm.
t) (13E) (8~,9S,llR,12R,15R~16RS)-9-hydroxy-16~
l9-dLmethyl-11,15 bis(tetrahydropyran-2-yloxy)-13,
18- ostadienoic acid
20~6 ml of 2N potassium hydroxide ~olution were
added to a 301ution of 2 o 3 g of the benzoate obtained
ac~ording to ~) in 70 ml of methanol and the mixture wa~
stirred for 31 hours at room temperature. The rea~tion
mixture w~ sub3equently concentrated in a rotary
~ . .
- 26 -
evapoxator, and the residue was taken up in a little
water and extracted twice with 150 r~l of an ether/pentane
mixture each time. The aqueous phase was acidiied to a pH
of 5 with citric acid and exkracted three times with
150 ml of ethyl acetate each time. The combined organic
pha~e3 were washed neutral with ~aturated ~odium chloride
~olutionO dried over magnesium sulphate and concentrated
in vacuo. The residue was purified by column chromato-
graphy over silica gel with hexane/S0-lOG% e~hyl acetate
a~ eluant~ 1~62 g of the title compound were obtainedO
IR (film): 3460~ 2730, 2660, 1730, 1710, 1130, 1110~ 1075,
lO~Oo 81~/~m~
u) (13E)-(8R,llR,12~15R~16R5)-9-oxo-16,19-
dimethyl-11,15- bis (tetrahydropyran-2~yloxy)-13,
0.4~ ~1 of Jone~ reagent was added to a solution~
cooled to -20C, of 360 mg of ~he alcohol obtained
according to t3 in 7 ml of acetone and the mixture wa~
stirred at that temperature for 4~ minukes~ 0~6 ml of
isopropanol was then added, the mixture was stirred for
a fur~her 10 minutes, diluted with cold ether and washed
three time~ w~th cold saturated ~cdium chloride solution~
and ~he organic phase was dried cver magnesiuM sulphate
and concentrated in vacuo. After filtration over a
Sep-Pack prepared column, 327 mg of the title~compound were
obtained.
IR (film): 2730, 2660, 1740, 1710, 1110, 1075, 1025, 810/cm.
. 27 -
v) ~13E)~(8R~llR~12~15R~16RS)-9-oxo~11,15
dîhydroxy-16~19-dimethyl~ 18_pro~tadieno_~ a~i~
The 327 m~ obtained according to the meth2d
described above in u~ were stirred at room temperature~ or 26
hours in 7 ~1 o~ a mixture of glacial acetic acid~water/
tetrahydrofuran (65/35/lO)o The whole wa~ then
concentrated ~everal ti~es with benzene in a~ oil p~mp
vacuum at room kemperature. The re~idue wa~ purified by
col~mn chromatography over silica gel with e~hyl acetate/
0~10% me~hanol as eluant. 68 mg of the title compound
were obtained.
IR (film): 3420, 2730/ 2670d 1735, 1710, 1075, 375/cm.
w) tl3E)-(8~9S,llRtl2R,15S,16RS) 9~enzoyloxy-16,19-
dimethyl-15-~ydroxy 11-~tetrahydropyran-2-
~o~ 13L18-Prostadienoic aci~L~ e~t-r
: In the 30d ium borohydride reduction of the ketone
according to r), in addition to the 2~11 g of ~-alcohol
and 0.27 g of an a/~ mixture, ~67 g of the title co~pound
were eluted from the column as a more polar product.
IR (film): 3400 (broad), 1740, 1720, 1600, 1580~ 1275
1120, 1030, 1020~ 710~cm.
- 28 -
x) (13E3-(8Ro9S,llR,12 ,15S~16RS)-9-benzoyloxy-16,
l9-dimethyl-11,15-bi~(tetrahydropyran-2-
~ nalogou~ly to the method de~crib~d in 5 ) for ~hepreparatio~ of the 15~ omer, 2.96 g of ~he title com-
pound were obtained as a c~olourless oil by reacting
2.67 g of the alcohol obtained in the preced~ng reactio~
Qtep w~th 0.62 ml of dihydropyran and 12.3 mg o~
E~toluenesulphonic acid (reaction time: 75 minute~ and
after column chromatography over ~ilica gel wi~h e~hyl
acetate/hexane = 1/3 ~ eluant.
IR (film): 1740, 1720t 1600, 1585, 1275, lllS9 1075~ 1025,
715/cm.
y) (13E)-¦8R,9S,llR,12R,15S,16RS~-9-hydroxy-16~
l9-dime~hyl-11,15-bisttetrahydropyran~2~yloxy~-13,
18-- ostadienoic acid
~.
Analogously to the method described for ~he
preparation of the 15~-isomer in t),2.22 g of the title
compound were obtained by reacting 2~96 g of ~he compound of x)
with 26.5 ml of 2N pota~sium hydroxide 301~tion and after
column chromatography over silica gel with hexane/50-10~%
ethyl acetate as eluant.
IR (film): 3450, 2730, 2660, 1730, 1710, 1130, lllOt 1075,
1020, ~10/cm.
~s~g
-- 29 --
z) (13E)--(8R~llR,l~R,15S~16Rs)--9--OxC:~--16,1g--
d~methyl-ll t 15-bis (tetrahydropyran-2-
r vloxy )-13 ,18-~rostadienoic acid
360 mg of the alco~ol ok~ained in the preceding
reaction step were reacted analogously to the ~e~hol
described for the preparation of ~he correspondillg
15~-isomer in u). 326 mg of the title co~d ~ere
~btained.
IR (~ilm)- 2730, 2670, 1740, 171~ 5, 1~70, 1020,
810/cm.
- ~13E)-(8R,llR,12R,l~S t 16RS)-9-oxo~ 15~dihydrQxy-16~ ~
19-d~me~h~1-13,18-p~ostadienoic acid
-
Analogou~ly to ~he method described for ~he
synthesis o~ thD 15~-isomer i~ 54 m~ of the .itle
co~npound o~ Example 1 ) were obtained ~y reactiny 326 D~
- of the compound obtained in the preceding reac'cian step.
IR ~film): 3400~ 2730, 2660~ 1740, 1710, 1075~, 97~i~cm.
__ .
~z~s~
-
-- 30 --
Example 2
(13E)-~8R,11R,12R,15R)-11,15-dihydroxy-16,16,19-trimethyl-
9-oxo-13,18-prostadienoic acid_ .
.
.- ~ COOH
OH ~
a) 2,2,5-trimethyl-4-hexenoic acid ethyl ester
610 ml of a 1.64N butyllithium solution in hexane
were added dropwise under argon at -20C to a solution
of 101.2 g of diisopropylamine in 125 ml of absolute tetra-
hydrofuran.The temperature was allowed to rise for a short
time to approximately 0C,in order then to add 11Ç g of i50-
butyric acid ethyl ester dropwise at from -50 to -60C to the
lithiumdiisopropylamide solution.The reaction solution was
stirred fox one hour at 0C,then cooled to 40C and
subsequently added to a solution,maintained at -20C, of 200 g
of 4-bromo-2-methyl-2-butene (dimethylallyl bromide) in 60 ml
of absolute dimethyl sulphoxide. While allowing the temperature
to rise to room temperature, the reaction mixture was stirred
for 60 hours and subsequently 250 ml of saturated sodium chloride
solution were added. The organic phase was separated off and the
aqueous phase was extracted five times with 200 ml each time of a
1/1 mixture consisting of ekher and hexane. The combined organic
phases were washed neutral wlth 0.5N hydrochloric acid and
saturated sodium chloride solution, dried over magnesium sulphate
and concentrated in a rotary evaporator. The residue was
s~
- 31 -
distilled ln vacuo. 91.5. g of the desired ester were obtained
(b.p.13376-81C).
IR (film): 1735, 1160, 1060, 820/cm.
b) _,2,5-trimeth~-4-hexenoic acid methyl ester
The title compound was prepared according to khe method
described above for the synthesis of the corresponding ethyl
ester using isobutyric acid methyl ester~
b.p.13= 72-74Co
IR (film): 1735, 1160, 1050, 820/cm.
c) 2,2,5-trimethyl-4-hexenoic acid
.
The title compound was prepared according to the method
described in a) above using isobutyric acid as educt and 2 equi-
valents of lithium diisopropylamide. b.p.o 2 o 4 = 94-100C.
IR (film): 1705, 1220, 820/cm.
d) 2-(1,1,4-trimethyl-3-pentenyl)-2-oxoethanephosphonic
acid dimethyl ester
49.5 ml of a 2.02N butyllithium solution in hexane
were added dropwise under argon at -60C to a solution of 13 g of
methanephosphonic acid dimethyl ester in 160 ml of absolute
tetrahydrofuran. After 15 minutes, a solution of 9.2 g of 2/2,5-
trimethyl-4-hexenoic acid ethyl ester in 25 ml of absolute tetra-
hydrofuran was added dropwlse. After 2 hours at -60C, the
reaction mixture was left to warm to room temperature in the cours
of one hour, 5.72 ml of glacial acetic acid were added and the
mixture was then concentrated in vacuo. The residue, a white gel-
1X~0~4~
like mass, was divided in a two--phase mixture consistiny of
35 ml of water and 165 ml of e~her. The organic L~hase was
dried over magnesium sulphate and concentrated in a rotary
evaporator. After the volatile side-products had been dis-
tilled off at 60C and 0.1 torr, the residue was purified bycoluMn chromatography over silica gel with hexane/50-100~
ethyl acetate as eluant. 8.6 g of the title compound were
obtai.ned .
IR (film): 1705, 1260,1030,820/cm.
e) (13E)-(8R,9S,llR,12R)-9-benzoyloxy-16,16,19--trime-thyl-
15-oxo-11-(tetrahydropyran-2-yloxy)-13,18-prostadie-
noic acid methyl ester
4.05 g of the phosphonate obtained according -to d)
dissolved in 45 ml of absolute dimethoxyethane, were added
dropwise at room temperature under aryon to a suspension of
0.74 g of 505 by weight sodium hydride (suspended in oil) in
90 ml of dimethoxyethane freshly distilled using li-thium
aluminium hydride. After the addition of 0.66 g of lithium
chloride (previously dried in a vacuum cupboard for 2 hours
at 50C), the reaction mixtuxe was stirred for 2 hours at
room -temperature. The suspension was subsequently cooled to
-20C and 7.11 g of the aldehyde obtained according to
Example lp) dissolved in 140 ml of absolute dimethoxyehtane,
were added dropwise. The temperature was then allowed to
increase from -20C to 15C in the course of 5 hours in
order then to stir the reaction solution for a further 19
hours at room temperature. At -10C, there were then added
- 32 -
s~
- 33 -
dropwise 1.6 ml of glacial acetic acid and approximately 100 ml
of water. The phases were separated, the aqueous phase was
extracted 5 tlmes with ether, and the organic phases were then
combined and washed with 4% by weight sodlum bicarbonate and
saturated sodium chloride solutions. After drying over magnesium
sulphate, the mixtuxe was concentrated to dryness in a rotary
evaporator. The residue was sub~ected to purification by column
chromatography over silica gel with hexane/150-100~ ethyl acetate
as eluant. 9.19 g of the title compound were obtained.
IR (film): 1740, 1720, 1695, 1670, 1625, 1600, 1580, 1270,
1105, 10S0, 1030, 705/cm.
f) (13E)-(8R,9S;11R,12R,15S)-9-benzoyloxy-16,16,19-tri-
methyl-15-hydroxy-11-(tetrahydropyran~2-yloxy)-13,18-
prostadienoic acid methyl ester
3.68 g of sodium borohydride were added in portions
to a solution, cooled to ~40C, of 9.19 g of the ketone obtainèd
in the preceding reaction step in 180 ml of absolute methanol.
Ater stirring for 3.5 hours at -40C, 7.9 ml of glacial acetic
acid were added dropwise to the reaction solution likewise at
-40C. ~fter removing the solvent in a rotary evaporator,
methylene chloridelwater were added tv the residue~ so~ld
sodium chloride was added to the separated aqueous phase and the
mixture was extracted twice with methylene chloride. ~he combined
organic phases were washed with saturated sodium chloride solution
dried over magnesium sulphate and concentrated in vacuo. The
~2~1S4~
isomers were separated by repeated column cllroma~ography
several times over silica gel with hexane/20-~0% ethyl
acetate as eluant. 2.02 g of the title compoulld were iso-
lated as the more polar product.
IR (film): 3400 (broad), 1740, 1720, 1600, 1580, 1275, 1120,
1030, 1025, 710/cm.
g)(l3E)-(8S,9S,llR,12R,lSS)-9-ben~oyloxy-16,16,19-trilrlethyl-
11,15-bis(tetrahydropyran-2-yloxy)-13,18-prostadienoic
acid methyl ester
0.45 ml of dihydxopyran (freshly distilled using
potassium hydroxide) and 9 mg of p--toluenesulphonic acid
were added a-t ice-bath temperature -to a solution of 2 g of
the alcohol obtained according to f~ in 60 ml of absolute
methylene chloride, the mixture was stirred for 55 minu-tes
at 0C and, having diluted the reaction solution with
methylene chloride, it was extracted with saturated sodium
bicarbonate solution and water. The organic phase was dried
over magnesium sulphate and concentrated ln vacuo. The
residue was purified by column chromatography over silica
gel with ethyl acetate/hexane = 1/2 as eluant. 2.12 g of
the desired compound were obtained.
IR (film): 1740, 1720, 1605, 1585, 1275, 1115, 1080, 1025,
715/c~l.
h) (13E)-(8R,9S,llR,12R,15S)-9~hydroxy-16,16,19-trime-thyl-
11,15-bis(tetraphydropyran-2-yloxy)-13,18-prostadienoic
acid
-
19 ml of 2N potassium hydroxide solution were
added to a solution of 2.12 g of the benzoate obtained
according to g) in .
- 34 -
~2~S4~;~
60 ml of methanol and the mixture was sklrred for 26 hours at
room temperature. The reaction mixture was subsequently
concentrated in a rotary evaporator, and the residue was taken
up in a little water and extracted twiee with 150 ml of an ether~
pentane mixture each time. The aqueous phase was acidified to a
pH of 5 with eitrie aeid and extracted three times with 150 ml
o~ ethyl acetate each time. The combined organie phases were
washed neutral with saturated sodium chloride solution, dried
o~er magnesium sulphate and concentrated ln vacuo. The residue
was purified by column chromatography over silica gel with hexane/
50-100% ethyl acetate as eluant. 1.43 g of the title compound
were obtained.
IR (film): 3460, 2730, 2660, 1730, 1710, 1130, 1110, 1075,
1025, 810/cm.
i) (13E)-(8R,11R,12R,15S)-9-oxo-16,16,19-trimethyl-
11,15-bis(tetrahydropyran-2-yloxy~-13,18-
prostadienoic acid
-
0.63 ml of Jones reagent was added to a solution,
cooled to -20C, of 500 mg of the alcohol obtained according
to h) in 10 ml of acetone and the mixture was stirred at that
temperature for 45 minutes. 0.8 ml ofisopropanol was then added,
the mixture was stirred for a further 10 minutes, diluted with
cold ether and washed three times with cold saturated sodium
chloride solution, and the organic phase was dried over
magnesium sulphate and concentrated in vacuo. After filtration
oYer a Sep-Pack prepared column, 442 rng of the title compound
~L~OS~
- 36 -
,i
were obtained.
IR (film): 2730, 2660, 1740, 1710, 1105, 1070, 1025, 810/cm.
j) ~13E)-(8R,11R,12R,15S)-11,15-dihydroxy-16,16,19-
trimethyl-9-oxo-13,18-prostadlenoic acid
The 442 mg obtained according to the method descrlbed
above in i) were stirred at room temperature for 24 hours in
9 ml of glacial acetic acid/water/tetrahydrofuran (65/35/10).
The whole was then concentrated several times with benzene in
an oil pump vacuum at room temperature. The residue was purified
by colu~n chromatography over silica gel with ethyl acetate/
0-10% methanol as eluant. 124 mg of the title compotlnd were
obtained.
IR (film): 3420, 2730, 2670,1740, 1710, 1075, 975/cm.
k) t13E)-(8R,9S,11R,12R,15R)-9-benzoyloxy-16,16,19-
trimethyl-15-hydroxy-11-(tetrahydropyran-2-yloxy)-
13,18-prostadienoic acid methyl ester
In the sodium borohydride reduction of the ketone
according to f), in addition to the 2.02 g of a-alcohol and
0.7 g of an a/~ mixture, 4.28 g of the title compound were
eluted from the column as a less polar product.
IR (film): 3400 (broad), 1740, 1720, 1600, 1575, 1275, 1120,
1030, 1020, 710/cm.
~ OS~lL6~
l) (13E)-(8R,9S,11R,12R,15R~-9-benzoyloxy-16,16,19-
trimethyl-11,15-bis(tetrahydropyran-2-yloxy)-13,18-
prostadienoic acid methyl ester _
Analogously to the method described in y) for the
preparation of the 15a-isomer, 4.3 g of the title compound were
obtained as a colourless oil by reacting 4.28 g of the
alcohol obtained in the preceding reaction step with 0.96 ml of
dihydropyran and 11 mg of ~-~oluenesulphonic acid (reaction time:
75 minutes) and after column chromatography over silica gel with
ethyl acetate/hexane=1/3 as eluant.
IR (film): 1740, 1720, 1600, 1585, 1275, 1115, 1075, 1020, 715/cm.
m) (13E~-(8R,9S,11R,12R,15R)-9-hydroxy-16,16,19-
trimethyl-11,15-bisItetrahydropyran-2-yloxy)-13,18-
prostadienoic acid
-
Analogously to the method described for the preparation
of the 15a-isomer in h), 2.8 g of the title compound we.re obtainet
by reacting 4.3 g of the compound obtained in l) with 38.5 ml
of 2N ~otassium hydroxide solution and after column chromatography
over silica gel with hexane/50-100~ ethyl acetate as eluant.
IR (film): 3450, 2730, 2660, 1730, 1710, 1130, 1110, 1075,
1025, 810/cm.
n) (13E)-(8R,11R,12R,15R)-9-oxo-16,16,19-trimethyl-
11,15-bis(tetrahydropyran-2 yloxy)-13,18-
prostadienoic acid
-
500 mg o~ the alcohol ob-tained in the preceding reaction
- 38 _ L2V~
step were reacted analogously to the method described for the
preparation of the corresponding 15a~isomer in i)~ alC) ~ of the
title compound were obtained.
IR (film): 2730, 2670, 1740, 1710, 1110, 1075, 1020, 810/cm.
o) (13E)-t8R,llR, 12R,15R)-11,15-dihydroxy-16,16,19-
trimethyl-9-oxo-13,18-prostadienoii~ acid
Analogously to the method descriked for the synthes~-~s of
the 15~-isomer in j), 110 rrlg of the title compound were obtained
by reacting 410 mg of the compound obtained in the preceding
reaction ~3tep.
IR (film): 3400t 2730, 2660, 1740, 1710, 1075, 975/cm.
Example 3
(I3 )-(8R,llR,12R,15S,16RS~-11,15-dihydroxy-16,19-dimethyl-
9-oxo-13,18-prostadienoic acid. tris(hydroxymethyl)-~ninQmethane
A solution of 32.9 mg of tris(hydroxymethyl)-amin~methane
in 0.1 ml of water was added at 60C to a solution of 94.5 mg
of the compound obtained according to Example 1 in 14 ml of
acetonitrile. The mixture wa3 left to stand at room temperature
for 14 hours. ~e yield was 63.5 mg.
Example 4
(13E)-(8R,llR,l~R,15R)--11,15-dihydroxy-16,16,1~-trimethyl-9-
oxo-13,18-prostadienoic acid. tris(hydroxymethy~ )-alTIinomethane
Analogously to the method described in Example 3, 68~,5 mg
of the title compound were obtained from 98 mg of the co~pound
-, - 38A -
546~
prepared according to Example 2.
For use in parenteral administration t~e following ~olution
was made up and filled into ampoules by conventional techniques~
005 mg of the compound obtained accord.ing to Example 1,
8.9 mg of NaCl~
1.212 mg of trometamol, and
0.01 ml of 96% strength ethanol
m~de up to 1 ml with water for injection.
Ampoules containing the compound obtained according to any one
or Examples 2 to 4 were prepared in a similar manner~
. - - -
~' .
