Note: Descriptions are shown in the official language in which they were submitted.
. ~ ~0~'74~0
:`
This invention relates to novel prostanoic acid derivatives,
and in particular it relates to novel ll-epi-prostanoic acid derivatives
which possess luteolytic activity. The new compounds are therefore advan-
tageous when used as contraceptives or for control of the oestrous cycle in
animals. The compounds may also be useful for the induction of labour, or
as hypotensives, for the relief of bronchospasm, or as inhibitors of gastric
secretion or of blood platelet aggregation.
According to the invention there is provided a process for the
manufacture of ll-epi-prostanoic acid derivatives of the formula:-
R ~
~ ,- CH2.A~CH2)3R
\ ~I)
~ Y.CHR2.XR3
~0
wherein Rl is a carboxy or hydroxymethyl radical or an alkoxycarbonyl radical
of up to 11 carbon atoms, R2 is a hydroxy radical or an alkoxy radical of 1
to 4 carbon atoms, A is an ethylene or cis-vinylene radical, Y is an ethylene
or trans-vinylene radical, X is a direct bond, an alkylideneoxy radical of 1
to 6 carbon atoms wherein the alkylidene is bonded to -CHR and the oxygen
is bonded to R3, or an alkylene radical of 1 to 6 carbon atoms) and R3 is a
phenyl radical which is unsubstituted or which bears one or two substituents
selected from halogen atoms and trifluoromethyl radicals, R4 is a hydroxy
radical and R5 is a hydrogen atom~or R4 and R5 together form an oxo radical,
and, for those compounds wherein Rl is the carboxy radical, the pharmaceut-
ically or veterinarily acceptable salts thereof, which comprises:-
~a) ~ for those compounds where m Rl is a carboxy radical, and X is
other than a direct bond, the hydrolysis of a compound of the formula:-
~ - 2 -
,. ' ' ' . '
.
.
ILQ67490
R8` ~ R5
~ _~ CH2.A~CH2)3R
< (II)
~ ~ Y.CHR7.XR
R6
wherein Rl, R3,R5J A and Y have the meanings defined above, R6 lS a tetra-
hydropyran-2-yloxy or C4 1O-alkoxydialkylmethoxy radical, R is an alkoxy
:~ radical of 1 to 4 carbon atoms or a tetrahydropyran-2-yloxy or C4 10- alkoxy-
: dialkylmethoxy radical and R8 has the meaning defined above for R4, or is a
tetrahydropyran-2-yloxy radical; OT R6 lS a hydroxy radical or an aroyloxy
radical of up to 15 carbon atoms, R7 is a hydroxy radical and R8 is an aroyl-
: oxy radical of up to 15 carbon atoms, whereafter when a salt is required,
the product so obtained is reacted with a base; or
(b) for those compounds wheTein Rl is a carboxy radical, R4 is an
~-hydroxy radical, A is a vinylene radical and X is a direct bond, the re-
action of the lactol of the formula:-
: r~r OH
o~
> (III3
\~--Y . CHR2 . XR3
HO
wherein R2 and R3 have the meanings defined above, with a (4-carboxybutyl)-
triphenylphosphonium salt, in the presence of a strong base, whereafter when`
a salt is required, the product so obtalned is reacted with a base; or
~c) for those compounds wherein Rl is an alkoxycarbonyl radical.,
: the reaction o the corresponding compound of the formula I wherein Rl 15 a
carboxy radical, with a diazoalkane of 1 to 1~ carbon atoms, or of a sal~t
thereof with an alkyl halide; or
.
~ J
-- 3 --
~ ~,o~t749,0
~d) for those compounds wherein Rl is a hydroxymethyl radical,
the reduction of a corresponding compound of the formula I wherein Rl is
an alkoxycarbonyl radical; or
~e) for those compo~mds wherein R is an alkoxy radical, the re-
action of the corresponding compound of the formula I wherein R2 is a hydroxy
radical with an alkyl halide of 1 to 4 carbon atoms in the presence of a
strong base.
A suitable value forRl when it is an alkoxycarbonyl radical is,
for example, a methoxycarbonyl, ethoxycarbonyl, butoxycarbonyl, hexyloxycar-
bonyl or decyloxycarbonyl radical, especially such as an alkoxycarbonyl ra-
dical of up to 6 carbon atoms.
A suitable value for R is in particular a hydroxy radical, but
it may also be for example, a methoxy, ethoxy, propoxy or butoxy radical.
A suitable value for X when it is an alkylideneoxy radical is,
for example, a methyleneoxy, ethylideneoxy ~-CH~CH3).0-), isopropylideneoxy
~-C~CH ) .0-), l-methylpropylideneoxY (-C(CH3)(C2H5).0-) or l-ethylpropyl
ideneoxy (-C~C2H5)2.0-) radical, and a suitable value for X ~hen it is an
alkylene radicai is, for example, a methylene, e~hylidene, isopropylidene,
propylidene, l-methylpropylidene, l-ethylpropylidene, ethylene, l-methylethyl-
ene, l,l-dimethylethylene, 2-methylethylene or trimethylene radical.
A suitable value for a halogen substituent in R3 is, for example,
a chlorine, bromine or fluorine atom.
A suitable pharmaceutically or veterinarily acceptable salt is,
for example, an ammonium, alkylammonium containing 1 to 4 alkyl substituents
each of 1 to 6 carbon atoms, alkanolammonium containing 1 to 3 2-hydroxyethyl
radicals, or alkali metal salt, for example a triethyl ammonium, ethanolam-
monium, diethanolammonium, sodium or potassium salt.
It will be observed that the compounds of the formula I contain
- 4 -
67490
five asymmetric carbon atoms, namely, carbon atoms 8,9,11~12 and 15, thc
relative configuration of the first four of which are ixed, so that it is
clear that the compounds may exist in at least two optically active forms.
It is to be understood that the useful properties of the racemates (comprising
the compound of the formula I and its mirror image) described in this speci-
fication may be present to differing extents in the optical isomers, and that
this invention relates to the racemic form and to any optically active form
which possesses the same useful properties, it being a matter of common ge-
neral knowledge how the optically active forms may be obtained and their re-
spective biological properties determined. It is also to be understood thatthis invention
- 4a -
1(:167490
:
relates to both C-15 epimers, that is, the epimers at
the -CHR2- carbon atom of the;lower side-chain.
A pre~erred group of prostane derivatives of
the invention comprises khose compounds wherein Rl is a
carboxy, hydroxymethyl, methoxycarbonyl or ethoxyoarbonyl
radical, R is a hydroxy radical, A is a cis-vinylene radical,
Y is a trans-vinylene radicalg X is a direct bond or a
methyleneoxy radical wherein the methylene is bonded to
-CHR - and the oxygen is bonded to R3, and R3 is a
chlorophenyl or trifluoromethylphenyl radical.
A preferred value for~R', when X is a methyleneoxy
radical, is a 3-chlorophenyl or 3-trifluoromethylphenyl
radical, and a preferred value for R3 when X is a direct
bond, is a 4-trifluoromethyl radical.
Particular ll-ep-i-prostanoic acid derivatives
of the invention are 16-~3-chlorophenoxy)-9~ ,15
trihydrOxy - 17,~18,19,20-tetranor-5-cis,13-trans-prostadienoic~
acid, 16-(3-chlorophenoxy)-9~ ,15~trihydroxy-17,18,19,20-
- :
tetranor-5-cis,13-trans-prostadienoic acid, methyl 16-(3-
chlorophenoxy)-9~ ,15~-trlhydroxy-17,18,19,20-tetranor-5-
cis,l3-trans-prostadienoate, 16-(3-chlorophenoxy)-17,18,19,20-
.
tetranor-5-cis,13-trans-pro~tadien-1,9~ ,15~-tetraol,
16-(3-chlorophenoxy)-11~,15-dihydroxy-9-oxo-17,18,~19,20-~
tetranor~5-cis,13-trans-prostadienoic acid and 9~ ,15~-
trihydroxy-15-(4-trifluoromethylphenylj-16,17,18,19,20-
pentanor-5-cis,13-trans-prostadienoic acid.
~ ;
'' ' " ' ~
. . : ',,
'
~067~9~
In process (a), a suitable C~ 10 alkoxydlalkylmethoxy radical
is, for example, a l-methoxy-l-methylethoxy radical. In process ~b), a suit-
able ~4-carboxybutyl~triphenylphosphonium salt is, for exampleJ the bromide.
In process ~c)~ a suitable salt of a corresponding compound of the formula I
wherein Rl is a carboxy radical is, for exampleJ a sodium or silver salt, and
a suitable alkyl halide is, for examp~Jan!alky-I lodide. In process (d)~ a
suitable complex metal hydride is, for example, lithium aluminium hydride. In
process (e)J a suitable strong base isJ for example, sodium hydride.
The hydrolysis in process (a) may be carrled out with an acîd,
for example, aqueous acetic acid or a sulphonic acid, for example, toluene-~-
sulphonic acid in a Cl 4 alkanol~when R6 or R7 is a tetrahydropyranyloxy ra-
dical, or buffered`citric acid ~e.g. pH 3) when R6 or Rl lS an alkoxydialkyl-
methoxy radical, or it may be carried out with a base, for example, an alkali
metal carbonate such as potassium carbonate, when R6 or R7 is an aroyloxy ra-
dical, and it may be carried out at ambient temperature or at an elevated
temperature of up to 60C.
In process ~b)~, when the strong base used is a sodium base, for
example, methanesulphinylmethyl sodium in dimethyl sulphoxide, or potassium
t-butoxide, the product I obtained is one wherein, substantially completely,
A is c -vinylene, whereas if n-butyl-lithium in sulpholane is used as the
strong base, the product obtained is one which contams a mixture of the com-
pound wherein A is trans-vinylene and the compound wherein A is cis-vinylene.
The starting material of the formula III, used in the process
of the invention, wherein R2 is a hydroxy radical may be obtained by reacting
a lactone IV with an azodicarboxylate ester in the presence of triphenyl-
phosphine and benzoic acid to give the dibenzoate V which is hydrolysed to
:
the diol VI. Reduction of the lactone with di-isobutyl aluminium hydride gives
the required starting material III, ~R = hydroxy3.
Many of the required lactones of the formula IV are known com-
:~ :
-- 6 --
067~90
pounds, and any others which are novel may be prepared by methods completely
analogous to those used in the preparation of the known lactones of the
formula IV.
)~ ~
O I ~O
Y.CH.XR~ ~ Y.CH.XR3
HO OH IV V
~:
O\~
III (R2 =
hydroxy)
Y.CH.XR
HO ~H
VI
The starting material of the formula III wherein R2 is an alkoxy
radical may be obtained by reacting the corresponding compound VI wherein R2
is a hydroxy radical with an alkyl halide, for example, an alkyl bromide or
iodide, in the presence of one equivalent of a strong base, for example, sodium
hydride, followed by the reduction of the product so obtained with di-isobutyl
aluminium hydride, as described above, to give the required starting material
III ~R2 = alkoxy).
The starting material of the formula II, used in the process of
the invention, wherein A is a vinylene radical, R6 and R7 are each a t:tra-
hydropyran-2-yloxy radical, and R8 is a hydroxy radical, may be obtained by
reacting the corresponding compound VI with dihydropyran, to give a bis-~tetra-
hydropyran-2-yl ether), which is reduced with diisobutyl aluminium hydride, as
.. s - 7 -
~06749(~
described above for compound VI, and the resulting lactol is reacted with a
~4-carboxybutyl)triphenylphosphonium saltJ as described above for a lactol
III, to give a starting material II wherein A is c -vinylene, if methanesul-
phlnylmethyl sodium or potassium t-butoxide is used as the strong base, or a
mixture of compounds of the formula II wherein A is tr -vinylene and cis-
vinylene, if n-butyl-lithium in sulpholane is used as the strong base, from
which mixture the starting material II wherein A is c -vinylene may be ob-
tained by chromatography on silica gel impregnated with silver nitrate.
~ Corresponding starting materials of the formula II wherein
R6 and R7 are each an alkoxydialkylmethoxy radical,
.
1~67~9,Q
may be prepared similarly, using an alkoxyalkane,
for example 2-methoxypropene, in place of dihydropyran.
The starting material of the.formula II wherein
R and R7 are ea.ch a tetrahydropyran-2-yloxy radiaal
and R5 and R8 together form an oxo radical, may be obtained
by oxidation of the corresponding compound II wherein R8
is a hydroxy radical, for example with Jones' reagent.
The starting material of the formula II, used
in the process of the invention, wherein Y is a trans-
lO vinylene radical, R8 is an aroyloxy radical and R6 and R7
are each a hydroxy radical, may be obtained by treating
the known lactone~ 4R-dimethoxymethyl-2,3,3ag,6a~-tetra-
hydro-5~-hydroxy-2-oxocyclopenteno~bJfuran (VII) with an
azodicarboxylic ester in the presence of triphenylphosphine
and benzoic acid, to give the benzoate of the C-5 epimer
of VII (VIII), which is hydrolysed and then protected as
the tetrahydropyranyl ether (IX). The lactone is reduced
; with di-isobutyl aluminium hydride to the lactol X, and
: the lactol is reacted with a phosphonium salt of the formula
Ph3P(CH2)4.COOH.Br in the presence of a strong base, to
give a cyclopentanol derivative XI, wherein A is cis-vinylene
if methanesulphinylmethyl sodium or potassium t-butoxide
is used as the st:rong base, or a mixture of cyclopentanol
derivatives XI wherein A is cis vinylene and trans-vinylene
when n-butyl-lithium in sulpholane is used as the strong
base, from which mixture the cyclopentanol derivative XI
9 ~:
~ ~ 10~;7~
~ ~ ~ o
o~ ~
CHtOCH3)2 ~ ( 3)2 ~ H(OCH3)2
HO B~O THP.O
VII VIII ~O~ IX ;
H ~ 2-A~CH2)3.~co2H
~ > <~ >
THP Or ~H(CH})2~;
3 2
THP,O
HO~ CH2-A(CH2)3CO2CH3 PB.O~ ~ CH2.A~CH2)3c02cH3
CH(OCH~)2 ~
GH2-A~CV2~ C!1~ ~ ~H2A~(CH2)~C02CH3
CH(OCH3)2 ~ ~ HO
HO
XIV ~ ~ ~ XV
PB.O~ ~eH2-A~¢H2~CO2CH3~
> ~ R6 , R7~- OH, R8 = PBO)
HO
XVI ~
`' Bz ~ benzoyl~ THP = tetrahydropyran- ~ 1, PB - 4-phenylbenzoyl
~06'7490
wherein A is the c -vinylene radical may be separated by chromatography
on silica gel impregnated with silver nitrate. Alternatively, the mixture
may be processed through one or more subsequent steps of the synthesis,
and thè corresponding c - intermediate may be separated at any convenient
subsequent stage. A cyclopentanol derivative XI is converted by reaction
with diazomethane to the methyl ester XII. The methyl ester XII is reacted
with an acylating agent derived from an aroic acid, for example, 4-phenyl-
benzoyl chloride~ to give a 4-phenylbenzoate ester XIII, which is select-
ively hydrolysed in two steps, first to remove the tetrahydropyranyl pro-
tecting group ~XIV), and then to hydrolyse the acetal to give thealdehyde (XV). The aldehyde XV is treated with a phosphonate ~CH30)2-
PO.CH2CO.XR or a phosphorane Ph3P:CH.CO.XR3 in the presence of a`strong
base to give the enone XVI, reduction of which with aluminium tri-iso-
propoxide or di-isobornyloxy aluminium isopropoxide gives the required
starting material II wherein A is a cis-vinylene radical, Y is trans-
vinylene, R6 = R7 = hydroxy, and R8 = aroyloxy.
The starting material of the formula II, used in the
process of the invention, wherein A is a cis-vinylene radical, Y is a
trans-vinylene radical, R6 and R8 are each an aroyloxy radical and R7
is a hydroxy radical may be obtained from the methyl ester XII by selective
hydrolysis of the tetrahydropyranyl radical, ~or example, with toluene-p-
~(~6'7~30
: sulphonic acid in tetrahydro~uran, to a diol XVII, which
is reacted with an acylating agent derived from an aroic
acid, for example 4-phenylbenzoyl chloride, to give a bis-
(phenylbenzoate ester) XVIII, which is selectively hydrolysed
with dilute aqueous acid to the corresponding aldehyde XIX.
The aldehyde XIX is reacted wi:th a phosphonate or phosphorane
as described above to give an enone XX, whioh is reduced,
as described above for similar:~enones XVI, to the required
.starting material II (R6 R8~- aroyloxy, R7 ~ hydroxy).
: Starting materials of the formula II wherein Y
is an ethylene radical and either R6 and R7 are each~a
hydroxy.radical and~R8 la an ar~oyloxy radioal, or R7 is
~ ~ a hydroxy radical and R6 and R8 are each an aroyloxy
: radical, may be obtained by reducing respectively an enone
XVI or an enone XX with, for example, sodium borohydride
to give~a mixture of 13,;14-trans and 13,14-dihydro e~nol~s,~
:from:which the~13,14-dihydro~enol~ Y~: èthylene)~may
be separated by oonventional procedures.
Starting materials of the formula II~wherein A :~
is an:ethylene radical may:be obtained by hydrogenation of
~: : a corresponding starting material II wherein A is a cis- ::
:: : ~
vinylene radical, or by hydrogenation of an intermediate
:of the formula XIV or XVIII,~and using the hydrogenated :
~:: intermediate in place of XIV or XVIII in the subsequent :
25: stages of the syntheses described~above.
~: : In an alternative synthesis, bhe intermediate XIV
~ ~ used in the above process may be obtained by treatin~ the
: 3
: - ~~ : ~
~'
:: :
1~36749(:~
HO ~ .
~' '\~----\C2 CH 3
XI I
HO H(OCH3)2
XVII
,
:
PB . O . PB . O~
O~ q 1~
~--\ CH ( cH3 ) 2 ~\ CHO
PB, O Pl3.
XVIII XIX
: PB . O
~Co.XR3 H7 - OH)
PB. O
` XX
,
:
`' '''''''' -
1~674~0
known compound XXI with an azodicarboxylate ester,
as described above, to give a di-ester XXII which is
converted via intermediates analogous to XV and X~I to
the required starting material II (R6 = benzoyloxy,
: 5 R7 - hydroxy, R8 _ 4-phenylbenzoyloxy).
:: PBO PBQ
H~ ~ C2C~l3
CH(OCH3) H~OCH3)2
HO ~ BzO
:: ~ : : `
: XXI : ~: ~ X~I : :
In a further alternative synthesis, a starting
material of the ~ormula II ~R6 -~benzoyloxy, R7 ~ hydroxy,
R8 - 4-phenylbenzoyloxy) may be obtained by treating a
:10~ c~ompound~of the formula~
PBO~
H~ OH
.
with an azodicarboxylate ester as;described above, to
give a starting materia1~of~the ~ormula II (R6 = benzoyloxy,
n
:R7 - hydroxy, R! ~ 4-phenylbenzoyloxy). ;; :: :~
~15 Compounds of the formula XXIII are known for
certain values of -XR3, for example where -XR3 is 3-
:: ~ :
:
: I I
; :
; .
.
7~90
chlorophenoxy, and corresponding compounds for other
values of -XR3 may be manufactured in a completely analo~ous
manner.
Starting materials o~ the ~ormula II wherein Rl
is a carboxy or hydroxymethyl radical may be obtained from
the corresponding compound wherein Rl is an alkoxycarbonyl
radical by, respectively, saponification or complex metal
hydride reduction, for example with lithium aluminium hydride.
;~ Starting materials of the formu1a II wherein
Rl is an alkoxycarbonyl radical may be obtained from an
prostanoic acid derivative of the invention of the
~ormula I wherein Rl is an alkoxycarbonyl radical by
reaction with 2,3-dihydropyran to give a tris(tetrahydro-
pyranyl ether) XXIV which ie reduced with lithium aluminium
~; 15 hydride to a hydroxymethyl~compound XXV which~in turn is :
,
: ~ alkylated to give a starting matéri:al:~II (Rl = alkoxymethyl~
; R6 = R7 = R8 = tetrabydropyran-2-yloT~ O : ~ ~
CH2A(CH2)3R ~:
I(R1=alkoxycarbonyl)
~ Y.CH(o,THP).XR3
THP.O
X~V
:
THP.O
2 ( 2)3CH2H
II (Rl- alkoxymethyl,
: ~ Y.CH(O.THP). ~3 R6=R7=R8=THP-o)
THP.O
X~N
THP = tetrahydropyran-2-yl \S : :
,~ ~
. :
lQ67 ~9~)
As stated above, the compounds of the invention
possess luteolytic properties. For example, 16-(3- ~
chlorophenoxy)-9~ ,15~-trihydroxy-17,18,19,20-tetranor-5-
cis,l3-trans-prostadienoic acid is approximately 50Q times
as active as natural prostaglandin ~2~ in a luteolytic
test in the hamster (or~I dosing), but possesses only 1/12
of the smooth muscle stimulant activity of the natural
compound. The compounds of the invention are therefore
more selective than the natural compound in terms of
luteolytic activity. No indication Or toxicity to small
animals has been noted at the luteolytically effective
doses tested.
The compounds of the invention are;therefore
useful, for example, for the induction of labour in childbirth,
and for this purpose are used in the same way as it is known
;~ to use the naturally-occurring prostaglandins El and E2,
that is to say, by administering a sterile, substantially~
aqueous solution containing from 0.01 to 10 ug./ml., preferably
0.01 to 1 ug./ml. of active compound, by intravenous,
extraovular or intra-amniotic administratlon until labour
commences. Also, for this purpose, the compounds of the
invention may be used in combination, or concurrently~ with
a uterine stimulant, for example oxytocin, in the same way
,
that it is known to use prostaglandin F2~ in combination,
F concurrently, with oxytocin for the induction of labour.
- ~~
1~67~g
When a compound of the invention is to be used ~or the
control of the oestrus cycle in animals, it may be used in combination,
or concurrently, with a gonadotrophin, for example, PMSG ~regnant mare
serum gonado~rophin) or HCG ~human chorionic gonadotrophin) to hasten
the onset of the next cycle.
Thus, the compounds may be formulated as a pharmaceutical
or veterinary composition comprising an ll-epi-prostanoic acid derivative
of the invention, ~ogether with a pharmaceutically or veterinarily accept-
able diluent or carrier.
The compositions may be in a form suitable for oral adminis-
tration, for example, tablets or capsules, in a form suitable for inhala-
tion, for example, an aerosol or a solution suitable for spraylng, in a
form suitable for parenteral administration, for example, sterlle inject-
able aqueous or oily solutions or suspensions, or in the form of a supposi-
tory, suitable for anal or vaginal use.
~: :
; The compositions of the invention may be;prepared by con-
ventional means, and may incorporate conventional excipients.
The invention is lllustrated, but not limited by the follow-
ing Examples.
Example 1
A solution of 16-~3-chlorophenoxy)-9a-hydroxy-11~,15a-blsttetra-
hydropyran-2-yloxy)-17,18,19,20-tetranor-5-cis,13-trans-prostadienoic acid
(108 mg.) in 2 mls. of a
-- - - 17 -
~aG~9~o
2:1 mixture of acetic acid and water, was stirred at 50C.
for 4 hours. The solve~ts were evaporated, the residue
was dissolved in dilute aqueous sodium bicarbonate solution
(2 ml.), the solution was extracted with ethyl aoetate
(3 x 2 ml.) and the extracts were discarded. The aqueous
solution was acidi~ied to pH 3-4 with 2N aqueous oxalic
acid and the acidified solution was extracted with~ethyl
acetate (4 x 5 ml.). The ethyl acetate extracts were
washed with a 1:1 mixture of saturated brine and water,
and were then dried. After evaporation of the ethyl acetate,
the residue consisted ofi16-(3-chlorophenoxy)-9~ ,15~-
trihydroxy-17,18,19,20-tetranor-5-cis,13-trans-prostadienoic
acid. Thin-layer chromatography on silica gel plates,
supplied commercially by Merck of Darmstadt, using a
mixture of 3% acetic acid in ethyl acetate as the developing
solvent, gave the pure compound, RF - 0.2. The n.m.r.-
spectrum in deuteriated acetone showed the following
characteristic bands ( ôvalues):- ~
6.9 - 7.2, broad multiplet, 4 aromatic~protons,
5.2 - 6.1, broad multiplets~ 4 olefinic and 4
exchangeable protons
3.95 - 4.5 broad multiplets, 5H, >CH.0-protons
The mass spectrum of the tetra(trimethylsilyl) derivative
showed (M-CH3)+ = 697.2990, (calculated for C34H61C106Si4-~
697.3Q01). ~ ~
The bis(tetrahydropyranyl ether) used as starting
material may be obtained as follows:- ~
_ _~J _ ~ ~
'' '
7~0
To a solution of 4~-r4-(3-chlorophenoxy)-3R-
hydroxybut-l-trans-enyl]-2~3,3a~,6a~-tetrahydro-5~-hydroxy-
2-oxocyclopenteno~b]furan (838 mg.), triphenylphosphine
(1.63 g.) and benzoic acid (758 mg.) in tetrahydrofuran
- 5 (15 ml.) was added dropwise during 10 minutes diethyl
azodicarboxylate (1.06 g.). After 45 minutes, the solvent
was removed by evaporation, and the residue was extracted
with ethyl acetate (3 x ~0 ml.). The combined extracks
were washed successively with sodium bicarbonate solution
and brine, and dried, and the solvents were evaporated
to give the bis-benzoate ester, 5B-benzoyloxy-4~-~3~-benzoyloxy-4-
(3-chlorophenoxy)but-1-trans-enyl~-2,~,3aB,6a~-tetrahydro-2-
oxocyclopentenorb]furan, RF = 0.6 (5% ethyl acetate in
methylene dichloride).
To a solution of the bis-benzoate ester (1.03 g.)
in-a mixture of methanol and methylene dichloride (2:1)
; was added anhydrous potassium~carbonate (578 mg.). ~The~
mixture was stirred for 6 hours at room temperature,
acidified to pH 5 with lN hydrochloric acid, and dilu~ed
with ethyl acetate (100 ml.). The mixture was washed
successively with saturated sodium bicarbonate solution
and brine, the organic phase was separated and dried, and
the solvents were evaporated under reduced pressure~
The crude product was chromatographed on MFC silica gel,
using ethyl acetate in`methylene dichloride as eluant,
to yield the diol, 4~-r4-(3-chlorophenoxy)-3~hydroxybut-1-
trans-enyl]-2,3,3a~,6a~-tetrahydro-5~-hydroxy-2-oxocyclo-
pentenorb]furan, RF ~ .4 (ethyl acetate). The n.m.r.
It~
_ ~ -- :
~1~6~ 0
spectrum (ln deuterated chloroform) showed the following
characteristic bands ( ~values):-
6;8 - 7 6, broad multiplets, 4 aromatic protons,
5.8 - 6.o, 2 olefinic protons,
3.7 - 5.2, broad multiplets, 5H,~ CH.0- protons
To a solution of the diol (215 mg.) in methylene
dichloride (8 ml.) under an atmosphere of nitrogen were
added successively redistilled 2,3-dihydropyran (0.58 ml.)
and a solution of anhydrous toluene-p-sulphonic acid in
tetrahydrofuran (0.6 ml. of a 1% solution). After 10
minutes, pyridine (3 drops) was added, fo]3owed by ethyl
acetate (50 ml.). The solution was washed successively
with saturated sodium bicarbonate solution and sat~urated
brine, and was dried. Evaporation of the solvents gave
a bis(tetrahydropyranyl ether) as a clear oil,
RF = o.6 (ethyl acetate). ~ - ;
To a solution of the~bis(tetrahydropyranyl ether) ~ ;
(320 mg.) in dry toluene (15 ml.~) under an atmosphere of
nitrogen at -78C. was added o.86 ml. of a 1~95M solution
of di-isobutyl aluminium hydride in toluene. After 15
minutes, the reaction was quenched by the dropwise addition
of methanol (3 ml.) and after a further 15 minutes at room
temperature a mixture of 1:1 saturated brine~/water (25 ml.)
was added, and the mixture was extracted with ethyl acetate
(3 x 50 ml.). The extract was washed with saturated brine,
and dried, and the solvents were evaporated to give the
lactol~ 4~-~4-(3-chlorophenoxy)-3~-(tetrahydropyran-2-yloxy)-1-
_ ~ _
1067490
trans-butenyll-2,3,3a~,6a~-tetrahydro-2-hydroxy-5~-
(tetrahydropyran-2-yloxy)cyclopenteno~b]furan, RF ~ 0 3
(25% ethyl acetate in methylene dichloride).
A stirred solution o~ (4-carboxybutyl)triphenyl-
phosphonium bromide (6.21 g.) in dry toluene (125 ml.) was
treated under argon at 90C. with potassium t-butoxide
(3.01 g.) to form a solution of the corresponding ylide.
The ylide solution (22.3 ml.) was then added to a solution
of the lactol (388 mg.) in dry toluene (5 ml.~ at room
temperature. The mixture was stirred for 40 minutes,
then water (1 ml.) was added. The toluene was evaporated,
and the residual gum was partitioned between ether (4 x 10 ml.)
and water (4 ml.). The aqueous layer was separated,
acidified with 2N oxalic acid to pH 4, and extracted with
a 1:1 mixture of ether and pentane (6 x 15 ml ). The
combined extracts were washed with brine, dried over
magnesium sulphate and filtered, and the solvent was
evaporated to give the required bis(tetrahy~ropyranyl ether),
16-(3-chlorophenoxy)9~-hydroxy-llB,15~-bis(tetrahydropyran-2-
yloxy)-17,18,19,20-tetranor-5-cis,13-trans-prostadienoic
acid, RF = 5 (ethyl acetate).
Example 2
The process described in Example 1 was repeated,
using the corresponding 11~,15~ bis(tetrahydropyranyl ether)
as starting material, to give 16-(3-chlorophenoxy)-9~ ,15~-
os~ `e ~o ~G'
trihydroxy-17,18,19,20-tetranor-5-cis jl3-trans-~
.
` 11367'4~0
acid, RF ~ .3 (3% acetic acid in ethyl acetate). The
n.m.r. spectrum ~in deuterated acetone) showed the following
characteristic bands ~ ovalues):-
6~9 - 7.3, broad multiplets, 4 aromatic protons,
5.2 - 6.1, broad multiplets, 4 olefinic and 4
exchangeable protons,
4.0 - 4.6, broad multiplets, 5H, >CH.0- protons
The mass spectrum o~ the tetra(trimethylsilyl) derivative
showed (M-CH3) 697.2970, (calculated for C~4U~61C106Si4 ~
697.3001).
The bis(tetrahydropyranyl etherj used as starting
material may be obtained by the sequence of steps described
in the second part of Example 1, starting from 4B~4-(3-
chlorophenoxy)-3~-(tetrahydropyran-2-yloxy)-1-trans-butenyl]-
2,3,3aB,6aB-tetrahydro-2-oxo-5~-(tetrahydropyran~2-yloxy)-
cyclopenteno~b]furan,~via~the following in~termediates:-
bis-benzoate ester", RF ~ o.6 (5% ethyl acetate in~
methylene dichloride)
; ~ "diol", RF~= 4 (ethyl acetate). The n.m.r. spectrum
in deuterated acetone showed the following
characteristic bands ( ~ values)0-
6.8 - 7.6, broad multiplet, 4 aromatic protons,
5.8 - 6.0, 2 olefinic protons,
3.7 - 5.2, broad multiplet, SH~ ~CH.0- protons
"bis(tetrahydropyranyl ether)", RF = o.6 (25% ethyl
acetate in methylene
dichlorlde)
"lactol", RF = 0.3 (25% ethyl acetate in methylene
dichloride).
- ~67~
Example 3
The process described in Example 1 was repeated,
using 16-(3-chlorophenoxy)-9-oxo-11~,15~-bis(tetrahydropyran-
2-yloxy)-17,18,19,20-tetranor-5-cis,13-trans-prostanoic
acid as starting material, to give 16-(3-chlorophenoxy)-
11~,15a-dihydroxy-9-oxo-17,18,19,20~tetranor-5-cis,13-trans-
prostadienoic acid, RF = 4 (2.5% acetic acid in ethyl
acetate). The n.m.r. spectrum (in deuterated acetone)
showed the following characteristic bands (~values):-
6.9 - 7.2, broad multiplets, 4 aromatic protons,
5.2 - 6.1, broad multiplets, 4 olefinic and 3
exchangeable protons,
3.95 - 4.6, 4H,>-CH.0- protons
The mass spectrum of the tris(trimethylsilyl)derivative
showed M = 667.2936, (calculated for C32H54ClN06Si3= 667.2946).
The bis(tetrahydropyranyl ether) used as starting
material may be obtained as follows:-
A solution of 16-(3-chlorophenoxy)-9~-hydroxy~
15~-bis(tetrahydropyran-2-yloxy)-17,18,19,20-tetranor-5-
cis,13-trans-prostadienoic acid (92 mg.) in acetone (5 ml.)
at 0C. was treated with 8N chromic acid (50.4 ~1.) for
25 minutes. Isopropanol was added, and the solution was
diluted with ethyl acetate (50 ml.), washed with brine and
dried. Evaporation of the solvent gave the required 9-oxo-
bis(tetrahydropyranyl ether), RF = 4 (5% methanol in
methylene dichloride).
_ ~ _
;
lQ67~9,0
Example 4
The process described in Example 3 was repeated,
using the corresponding llB315~-bis(tetrahydropyranyl ether)
as starting material, to give 16-~3-chlorophenoxy)~ ,15B-
dihydroxy-9-oxo-17,18,19,20-tetranor-5-cis,l~-trans-
prostadienoic acid, RF = 5 ~2.5% acetic acid in ethyl
acetate). The n.m.r. sp~ectrum ~in deuterated acetone)
showed the ~ollowing characteristic bands (~ values)~
5.g - 7.2, broad multiplets, 4 aromatic protons,
5.2 - 6.1, broad multiplets, 4 olefinic and 3
~ exchangeable protons,
3.95 - 4.6, 4H~ >CH.0- protons
The mass spectrum of the tris(trimethyIsilyl) derivative
showed M = 667.2928, (calculated ror C32H54ClN06Si~= 667-2946)-
The bis(tetrahydropyranyl ~ther) u~ed as starting~
material may be obtained by oxidation of the corresponding
9a-hydroxy 11~,15~-bis(tetrahydropyranyl ether) dqscribed in
Example 2, by the process described in the second part;of
Example 3, RF = -4 (5% ethyl acetate in methylene dichloride).
` 20 Example 5
The process described in Example 1 was repeated,
using the appropriate bis(tetrahydropyranyl ether) as
~- starting material to give the compounds shown in the table~
below. Mass spectrum data are for the tetra~trimethylsilyl)
derivatives. RF values, for thin layer chromatography
on silica gel3 eluted with ethyl acetate, are alsa given
I
''
:
)6~490
~or the corresponding diol intermediates of the ~ormula VI.
H0
Y.CH(OH).X ~
- Maas sp~ectrum ~ ~ Diol of
R Y XFound Calculated the
` ~ formula VI
~ , ~ . _: : : ~ :
3-trifluoromethyl trans- ~CH20 M =746.3492 746.3458~ RF - 0.4
vi~nylene
hydrogen trans-
vinylene CH2 (M-CH3) 647.3441 Rp - 0.2
= 647.3431
4-chloro trans- ~
vinylene CH20 (M-CH3) ; ~ 697,2999~ RF;-~0.2
~; ~ ~ - 697.2913
3-chIoro ethylene CH20 M = 714.3371 ~ ~
714.3391~ RF ~ 0 3
: _ _. _ :: ' ~
In the manufacture~of the compound wherein;Y
is an ethylene radical, the required starting materlal is
obtained as follows~
:
A mixture of epimers (epimers at C-3 of the~
butenyl side chain) of 4~-~4-(3~-chlorophenoxy)-3-hydroxybut-1-
t~ans-enyl]-2,3,3a~,6a~-tetrahydro-2-~oxo-5~ -phenylbensoyl-
oxy)-oyclopenteno~b]furan (1.83 g.)~was dissolved in ethanol
:
~ ~ ,
- ' ':
~0~7~90
(28 ml.) and the solution was added to nickel boride,
previously prepared from nickel acetate (3.5 g.) and sodium
borohydride-(551 mg.). The mixture was shaken with
hydrogen for 4 hours and was then filtered, and the filtrate
was evaporated to dryness to give a mixture of epimeric
unsaturated alcohols, 4~-~4-(3-chlorophenoxy-3-hydroxybutyl]-
2,3,3a~,6a~-tetrahydro-21-oxo-5~ (p-phenylbenzoyloxy)cyclo-
penteno~b]furan, RF = 0 3 ~50% ethyl acetate in~toluene).
The mixture of epimeric saturated alcohols (1.47 g.3 was
I0 stirred vigorously ~or 2~hours with finely powdered~anhydrous
potassium carbonate (1.02 g.) in methanol~(40 mI.).`~ ~
lN Hydrochloric acid (15 ml.) was added, followed by ethyl
acetate (200 ml.). The organic layer was separated,
washed succe~sively with saturated sodium bicarbonate~solution
and brine, and dried, the solvents were evaporated, and
the residue was chromatographed on "Florisil" (trade mark)
magnesium silicate (50 g.). ~ Elution with ether removed
by-products, and subsequent elution with ethyl acetate gave
~a~mixture of the corresponding sakurated epimeric 11~,15-
diols, R~ = 0.3 (ethyl acetate~
Example 6 ~ `
To a solution of the more polar C-15 epimer of
16-(3-chlorophenoxy)-9a,11~,15~-trihydroxy-17,18,19,20-
tetranor-5-cis,13-trans-prostadienoic acid (59 mg.) in
:
methanol (1 ml.) at 0C. was added~an excess of a solution
of diazomethane in ether~ After~10 minutes, the solvents
were evaporated to give the single C-15 epimer5 methyl
b : :
:
67490
16-(3-chlorophenoxy)-9~ ,15~-trihydroxy-17,18,19,20-tetranor-5-c ,13-
trans-prostadienoate as a clear oil ~ = 0.15 (ethyl acetate) (M~CH3)
639-2754, (calculated for C31H52C106Si3 = 639.2760).
Example 7
A solution of methyl 16-(3-chlorophenoxy)-9a,11~,15~-trihydroxy-
17,18,19,20-tetranor-5-c ,13-trans-prostadlenoate (14 mg.) in a mixture of
ether (1 ml.) and tetrahydro~uran (1 ml.) was added to a suspension of
lithium aluminium hydride (25 mg.) in ether (3 ml.). me mixture was stirred
at room temperature ~or 1 hour, the excess of hydride was destroyed by the
addition of water ~1 ml.) and the mixture was extracted with ethyl acetate.
The extract was dried, and the solvent was evaporated to give 16-~3-chloro-
phenoxy)-17,18,19,20-tetranor-5-cis,13-trans-prostadien-1,9a,11~,15a-tetraol,
= 0.5 (10% methanol in ethyl acetate). The mass spectrum of the tetra
(trimethylsilyl)derivative showed M = 698.3412, (calculated for
C34H63C15si4 = 698-3441)-
Example 8
To a solution o~ methyl 16-(3-chlorophenoxy)-9~ ,15~-trihydroxy-
17,18,19,20-tetranor-5-cis,13-tra s-prostadienoate (22 mg.) in 1,2-dimethoxy-
ethane (2 ml.) were added successively methyl iodide (1 ml.) and sodium
hydrlde (2.25 mg. of` a 60% suspension in oil), and the mixture was stirred
at room temperature for 2 hours. The sol ents wer
-27-
~B
~(~6~490
evaporated under reduced pressure, and the residue was
shaken with a mixture of ethyl acetate (3 x 15 ml.) and
water (3 ml.). The organic phases were separated, combined
and dried, the solvent was evaporated ancl the residue
was puri~ied by thin layer chromatography on silica gel
plates, using ethyl acetate as the developing solvent,
to give methyl 16-(3-chlorophenoxy)-9~,llB-dihydroxy-15~-
methoxy-17,18,19,20-tetranor-5-cis,I3-trans-prostadienoate,
RF = -3 (ekhyl acetate). The mass spectrum of the bis-
(trimethylsilyl)derivative showed (M-CH3) = 581,2490,
~calculated for C29H46C106Si2= 581,2521).
Example 9
To a solution of 16-(3-chlorophenoxy)-11~,15~-
dihydroxy-9-oxo-17,18,19,20-tetranor-5-cis,13-trans-prostadienoic
acid (24 mg.) in methanol (3 ml.) was added sodium borohydride
(15 mg.). After 15 minutes~ the reaction was quenched
by the addition of aqueous oxalic acid, and the mixture
was extracted with methy~ene dichloride (2 x 50 ml~
The extrac~s were combined, washed with saturated brine,
.
and dried, and the solvents were evaporated to give a orude
product which was esterified using an excess of diazomethane
in ether (2 ml.). The methyl ester was purified by
chromatography on 1.5 g. of silica gel, using ethyl acetate
as eluenk, to give methyl 16-(3-chlorophenoxy)-9~ ,15~-
trihydroxy-17,18,19,20-tetranor-5--cis,13-trans-prostadienoate,
- ~6'7~90
RF 3 0 30 ~50% acetone~meth~lene dichloride). The mass
spectrum of the tris~trimethylsilyl) derivative showed
~M-CH3) = 639.2798, ~calculated for C31H52C1065i3 = 639.2758).
Example 10
The process descrihed in Example 9 was repeated,
using the corresponding 11~,15~-isomer as starting material,
to give methyl 16-~3-chlorophenoxy)-9~ ,15~-trihydroxy-
17,18,19,20-tetranor-5-cis,13-trans-prostadienoate, RF = 0 33
~50% acetone in methylene chloride~.
Example 11
A solution of 9~-hydroxy-11~,15-bis~l-methoxy-1-
methylethoxy)-15-~4-trifluoromethylphenyl)-16,17,18,19,20-
pentanor-5-cis,13-trans-prostadienoic acid ~123 mg.) in
0.8 ml. of pH 3 citric acid buf~er and 1.8 ml. of acetone
was stirred at room temperature for l8 hours. The solvents
~ere evaporated and the residue was extracted with ethyl
acetate ~3 x 3 ml.). The extracts were combined, washed
with a 1:1 mixture of saturated brine and water, and were
then dried. After evaporation of the ethyl acetate, the
residue consisted of a mixture of the C-15 epimers of 9a,11~,
15-trihydroxy-15-~4-trifluoromethylphenyl)-16,17,18,19,20-
pentanor-5-cis,13-trans-prostadienoic acid. Chromatography
of this residue on CC4 Malinkrodt silica gel ~2 g.), and
elution with acetone/cyclohexane gave the separated C-15
*
epimers of 9a,11~,15-trihydroxy-15-~4-trifluoromethylphenyl)~
16,17,18519,20-pentanor-5-cis,13-trans-prostadienoic acid,
*
i.e. the 15a-OH and 15~-OH epimers
~` - 2g _
:
.
~06~7490
RF = 0.15 and 0.20 (2.5% acetic acid in ethyl acetate).
The n.m.r. spectrum of each epimer (in deuterated acetone)
showed the following characteristic bands (:Svalues):-
7~65, 4 aromatic protons
5.4 - 6.1, 5H, 4 olefinic protons and
PhCH(OH).CH=CH-
4.2 - Ll,9, 6H, C-9, C-ll and 4 exchangeable protons.
The mass spectrum of the tris(trimethylsilyl)
derivative showed M+ = 716.3353, (calculated for
C34H5gF3sSi4 = 716-3394)- ~ ;
~ le bis-ether used as starting material may
be prepared as follows:-
To a solution of 2,3,3a~,6a~tetrahydro-
5~-hydroxy-4~-~3-hydroxy-3-(4-trifluoromethylphenyl)-1-
trans-propenyl]-2-oxocyclopenteno~b]furan (250 mg.)
(prepared by the process described in the second part
of Example 1) in methylene dichloride (4 ml.), under an
atmosphere of nitrogen, were added successlvely redistilled
2-methoxypropene (528 mg.) and a~solution of anhydrous
toluene-p-sulphonic acid in tetrahydrofuran (0.073 ml. of a
1% solution). After 25 minutes, pyridine (2 drops) was
added, followed by ethyl acetate (30 ml.). The so~lution
was washed successively with saturated sodium bicarbonate
and saturated brine and was dried. Evaporation of the
solvents gave a mixture of epimeric l-methoxy-l-methylethyl
ethers as a clear oil, RF = 0.65 (ethyl acetate).
~0
~ 7~9Q
To a solution of the epimeric ether (260 mg.)
in dry toluene ~17 ml.) under an atmosphere of nitrogen
at ~78C., was added 0.75 ml. of a 1.95 m mole/ml. solution
of di-isobutyl aluminium hydride in toluene. After 30 minutes,
the reaction was quenched by the dropwise addition of
methanol (2 ml.), and after a further 15 minutes at room
temperature, a mixture of 1:1 saturated brine/water (15 ml.)
was added, and the mixture was extracted with ethyl acetate
~3 x 25 ml.). The extract was washed with saturated brine
and dried, and the solvents were evaporated to give a
mixture of epimers of the lactol, 2,3,3a~,6aR-tetrahydro-2-
hydroxy-5R-(l-methoxy-l-methylethoxy)-4~-~3-(1-methoxy-1-
methylethoxy)-3-(4-trifluoromethylphenyl)-1-trans-propenyl}-
cyclopenteno~b]furan, RF = 0.15 (40% ethyl acetate~toluene).
A solution of the lactol(260 mg.) in toluene
(7 ml.) was added to a solution of potassium 5-triphenyl-
phosphoranylidene valerate prepared from 1 mole of (4-
carboxybutyl)triphenyl phosphonium bromide with 2 moles
of potassium t-butoxide in toluene. The solution was
stirred for 1 hour, and the solvent was removed by
evaporation under reduced pressure. The residue was shaken
with water (5 ml.) and ether (3 ml.), the aqueous layer
was separated and extracted with ether (4 x 3 ml.) an~ the
extracts were discarded. The aqueous~solution was acidified
2~5 to pH 5.5 with oxalic acid and extracted with a mixture
of equal parts of ether and~petroleum ether (b.p. 40-60C.)
_ ~ _
rla6~ .0
(6 x 4 ml.). The combined extracts were washed with
saturated brine and dried, and evaporation of the solvents
gave 9~-hydroxy~ ,15-bis-(1-methoxy-1-methylethoxy)-
15-(4-trifluoromethylphenyl)-16,17,18,19,20-pentanor-5-
cis,13-trans-prostadienoic acid. RF = 0.38 (10% methanol
in methylene chloride).
Example 12
The process described in Example 1 was repeated,
using the corresponding llR,15-bis(tetrahydropyranyl ether)
as starting material, to give the C-15 epimers of 16-(3-
chlorophenoxy)-9~ ,15-trihydroxy-16,16-dimethyl-17,18~19,20-
tetranor-5-cis,13-trans-prostadienoic acid~ RF = 0.15 and
0,20 (2.5% acetic acid in ethyl acetate?-
The mass spectrum of the tetra(trimethylsilyl) derivative
showed M = 725.3224, (calculated for C36H65C106Si4 = 725.3312).
The bis(tetrahydropyranyl ether) used as
starting material may be obtained as follows:-
To a solution of 4~- r4- (3-chlorophenoxy)-3-
;~ hydroxy-4,4-dimethylbut-1-trans-enyl)-2,3,3a~,6a~
tetrahydro-2-oxo-5~-(4-phenylbenzoyloxy)cyclopenteno~bJ-
furan (1.97 g.) in methylene dichloride (36 ml.) were added
successively 2,3-dihydropyran (3~3 ml.) and a solution of
anhydrous toluene-p-sulphonic acid in tetrahydrofuran
(1.8 ml. of a 1% solution). After 10 minutes, pyrldine
(1 ml.) was added, followed by ethyl acetate (200 ml.).
The solution was washed successively with sodium bicarbonate
_~ _
1~6~7~9,0
solution and brine, and was dried. Evaporation of` the
solvents gave the epimeric tetrahydropyranyl ether as a
clear oil, RF = -5 (20% ethyl acetate in methylene dichloride).
To a solution of the epimeric tetrahydropyranyl ether
(2.0 g.) in methanol ~50 ml.) was added finely powdered
anhydrous potassium carbonate (648 mg.). The mixture
was stirred vigorously for 6 hours, then lN hydroahloric
acid (7 ml.) was added, followed by ethyl acetate (200 ml.).
The organic layer was separ~ted, washed successively with
10~ saturated sodium bicarbonate solution and brine and dried,
and the solvents were evaporated. ~ ~he residue was
chromatographed on "Florisil" (trade mark) magnesium
silicate (40 g.). Elution with ether removed the
by-products, subsequent elution with ethyl acetate gave
a mixture of the C-15 epimers of 4~-~4-(3-chlorophenoxy)-4,4-
dimethyl-3-(tetrahydropyran-2-yl)but-1-tranR-enyl~-2,~,3aR,6a~-
; tetrahydro-5~-hydroxy-2-oxo-cyclopenteno[b]furan, RF = 0.25
(40% ethyl acetate in methylene chloride). The process
described in the latter part of Rxample 1 was repeated,
using the above compound in place of the diol.
::
:
~3 : :
_ 3~ --
,~
t7~9~
Example 13
The process described in Example 3 was repeated,
using the appropriate 9-oxo-bis(tetrahydropyranyl ether)
as starting material, to give the derivatives shown in
the following table.
O (CH2)3-cOOH
~\ , ' \e~ . .
~Y.CH(OH).X ~ R
HO
__ _ _ Mass Spectrum
R X Found Calculated
..... : ..
3-trifluoromethyl trans- CH20 M = 701.3202 702.3210 (a)
vinylene
hydrogen ~ ns- CH2 M = 617.3338 617.3388 (a)
4-chloro trans- CH20 (M-CH3~ =
vinylene 623.2438 623.2433 (b)
3-chloro ethylene CH20 M+ = 640.2850 640.2823 ~b)
3-chloro trans- ( 3)2 M = 695.3240 695.3260 (a)
vlnylene
_
(a) - for 9 methoxime-tris(trimethylsilyl) derivative
(b) - for 9-oxo-tris(trimethylsilyl) derivative
_ ~ _
~67~L90
Example 14
A solution of 11~,15-bis(l-methoxy-1-methyl-
ethoxy)-9-oxo-15-(4-trifluoromethylphenyl)-16,17,18,19,20-
pentanor-5-cis,13-trans-prostadîenoic acid (143 ~g.) in
a mixture of 0.7 ml. of pH 3 citric acid buffer and 2.1 ml.
of acetone was stirred a~ room temperature for 18 hours.
The solvents were evaporated, and the residue was extracted
with ethyl acetate ~3 x 20 ml.~. The extracts were
combined, washed with a 1:1 mixture of saturated bri;ne
and water, and then dried. After evaporation of the
ethyl acetate, the residue consisted of a mixture of the
C-15 epimers of 11~,15-dihydroxy-9-oxo-15-(4-trifluoro-
methylphenyl)-16,17,18,19,20-pentanor-5-cis,13-trans-
prostadienoic acid, RF ~ .45 (2~% acetic acid in ethyl
acetate). The n.m.r. spectrum (in deuterated acetone)
showed the following characteristic bands (ôvalues):-
7.67, 4 aromatic protons,
5.3 - 6.3, 4 olefinic protons,
C15 proton and 3 exchangeable protons
The mass spectrum of the bis(trimethylsilyl)-9-methoxime-
methyl ester showed M = 671.3080, (calculated for
C32H52F3No5si3 = 671.3104).
The 9-oxo-bis-ether used as starting material
may be obtained as follows:-
A solution of 9~-hydroxy-1]~,15-bis-(l~methoxy-1-
methylethoxy)-15-(4-trifluoromethylphenyl)-16,17,18,19,20-
~06~74~ ~
The prostadienoic acid derivative may, ofcourse, be replaced by an equivalent amount o~ another
prostadieno;c acid derivative of the invention.
Example 16 % w/v
; 5 15-(4-trifluoromethylphenoxy)-
9~ ,15~-trihydroxy-16,17,18,19,~20-
pentanor-5-cis,13-trans-prostadienoic
acid 0-003
Sodium phosphate ~ ~ 2.90
10 ~ Sodium hydrogen phosphate ~0.30
Water for injection to 100
: ~ :
he sodium phosphate was dissolved in about 80%
of the water, followed by the prostadienoic acid derivative~
and, when dissolved, the sodium hydrogen phosphate. The
~olution was made up to volume with water`for injection,
and the pH was checked t~o be between 6.7;and 7.7. ~The~
solution was filtered to re~ove part1culate matter,~
sterilised by filtration, and filled into pre-sterilised
neutral glass ampoules under~aseptic conditions.~
Immediately before use, the contents of an ampoule~are
~; diluted in sodium chloride B.P. for adm1nistration by
intravenous infusion.
The prostadienoic acid~derivat1ve may, of course,
be replaced by an equivalent amount of another prostanoic
acid derivative of the invention.
:
:
:~ :
:
, ' .;~
