Note: Descriptions are shown in the official language in which they were submitted.
llS4~1
-- 1 --
DESCRIPTION
"IN~ERMEDIATES FOR PROSTAGLANDIN ANALOGUES''
This invention relates to new chemical compounds
useful as intermediates for the preparation of
trans-~2-prostaglandin El analogues, to processes for
their preparation and to their use in the preparation
of trans-~2-prostaglandin El analogues.
Prostaglandins are derivatives of prostanoic
acid which ha~ the following formula:-
, ~ ~OOH
13 15 17 19
. Various types of prostaglandins are known, the typ~s
depending inter alia on the structure and substituents
on the alicyclic ring. For example, the alicyciic ring
of prostaglandin E(PGE) has the structure:
1l
II
OH
The dotted lines in the foregoing formulae and in other
formulae throughout this specification denote, in
11~;4~1
-- 2 --
accordance with generally accepted rules of nomenclature,
that the attached grouping lies behind the general plane
of the ring system, i.e. that the grouping is in
-configuration, the thickened lines ~ denote that the
grouping lies in front of the general plane of the system.
i.e. that the grouping is in ~-configuration, and the
wavy line ~ indicates that the grouping is in ~-
or ~-configuration.
Such compounds are sub-classified according
to the position of double bond(s) in the side chain~s)
attached to the 8- and 12-positions of the alicyclic
ring. Thus PGl compounds have a trans- double bond
between C -C (trans-~13) and PG compounds have a
13 14~ 2
cls-double bond between C5-C6 and a trans-double bond
between C13-C14 (cis-~5. trans-~ ). For example,
prostaglandin El (PGEl) is characterised by the following
structure III.
7 5 3
- ~ OOH
III
~H ~H
~he structure of PGE2, as a member of the PG2 group,
corre~ponds to that of formula III with a cis-double
bond between the carbon atoms in positions 5 and 6.
Compounds in which the double bond between the carbon
. .
llS44~1
atoms in positions 13 and 14 of members of the PGl group
is replaced by ethylene are known as dihydroprostaglandins,
e.g. dihydro-prostaglandin El (dihydro-PIJEl).
PGE compounds with a trans~double bond between the
carbon atoms in positions 2 and 3 are known as
trans-Q2-PGE compounds and the structure of trans-~ -PGE
corresponds to that of formula III with a trans-double
bond between the carbon atoms in positions 2 and 3.
Moreover, when one or more methylene groups are
added to, or eliminated from, the ~-chain, i.e. the
aliphatic group attached to the 12-position of the alicyclic
ring of the prostaglandins, and/or the ~-chain. i.e. the
aliphatic group attached to the 8-position of the
alicyclic ring of the prostaglandins, the compounds are
known, in accordance with the usual rules of organic
nomenclature, as homo-prostaglandins (methylene group
added) or nor-prostaglandins (methylene group eliminated).
and, when more than one methylene group is added or
eliminated, the number ~s indicated by di-, tri- etc.
before the prefix "homo" or "nor".
Prostaglandins are generally known to possess
pharmacological properties, for example l;hey stimulate
smooth muscle, have hypotensive, diuretic, bronchodilating
and antilipolytic activities, and also i~ihibit blood
platelet aggregation and gastric acid secretion, and are,
accordingly, useful in the treatment of hypertension,
11~44~1
-- 4 --
thrombosis, asthma and gastro-intestinal ulcers, in the
induction of labour and abortion in pregnant ~emale
mammals, in the prevention of arteriosclerosis, and as
diuretic agents. They are fat-soluble substances
obtainable in very small quantities from various tissues
of animals which secrete the prostaglandins in the
living body.
For example, PGE's have an inhibiting effect
on gastric acid secretion and may, accordingly, be used
-in the treatment of gastric ulcers. They also inhibit
the release of free fatty acid induced by epinephrine
and as a result they reduce the concentration of free
fatty acid ln blood, and are, accordingly, useful in the
prevention of arteriosclerosis and hyperlipemia. PGEl
inhibits blood platelet aggregation and also removes the
thrombus and~prevents thrombosis. PG~'s have a
stimulating effect on smooth muscle and increase the
intestinal peristalsis; these actions indicate therapeutic
utility on post-operative ileus and as purgatives. PGE's
may also be used as oxytocics, as abortifacients in the
first and second trimesters; in the post-labour abortion
of the placenta, and as oral contraceptives because they
regulate the sexual cycle of female'mammals. PGE's have
vasodilator and diuretic activities. They are useful for
improvement in patients suffering from cerebral vascular
disease because they increase the cerebral blood flow,
llS44~1
and are also useful in the treatment of asthmatic
conditions in patients because of their bronchodilating
activity.
Two methods for introducing a trans (or E)-
do~ble bond between the carbon atoms in-positions 2 and 3
of prostaglandin compounds are known.
A first method is described in our British
Patent Specification No. 1.416,410, published 3rd December
1975. However, in order to form the double bond between
the carbon atoms in positions 5 and 6 the method requires
the use of a phosphorane co~pound (C6H5)3P=CHCH2COOH~
the carboxy group ~-COOH) of which is~unconjugated.
The resulting instabilit~ of the phosphorane compound makes
it difficult to obtain high yields. In addition, in the
series of reactions described to prepare the trans-~2-
prostaglandins a selective hydrogenation is necessary if
a trans-~2-PGEl analogue is to be obtained. It is
necessary to hydrogenate a double bond between carbon
atoms in positions 5 and 6 whilst leaving a double bond
between carbon atoms in positions 13 and 14 unaffected.
There is a risk of hydrogenation of both double bonds
leading to a lowering of the yield of the desired product.
Finally, the ~-chain is introduced at an early stage in the
series of reactions leading to the desired trans-~2-
prostaglandin, so that a large amount of expensivesubstrate required ~o introduce any desired ~-chain is required.
~he second method is described in our
4~1
British Patent SpecificationsNos. 1,483,240 and 1,540,427,
published 17th August 1977 and 14th February 1979,
respectively. The introduction of the double bond ~etween
the carbon atoms in positions 2 and 3 requires the use
of selenium or sulphur compounds. Trace amounts of such
compounds are harmful to human beings and if the final
trans-~ -prostaglandin products are to be used as
medicines the sulphur or selenium compounds must be
removed. Such removal is diffi~ult and requires
considerable care. In addition, the selenium or sulphur
compounds possess a very unpleasant smell which presents
difficulties in their preparation and use.
As a result of research and experimentation
there have been discovered new chemical compounds which
are useful as intermediates in improved processes for the
preparation of trans-~ -PGEl analogues.
The new chemical compounds of the present
invention, useful for the preparation of trans-~ -
prostaglandin El analogues, are those compounds of the
general formula:-
10 ~ ~ ~ Rl IV
1 ~ _R2_R3
O-~HP
wherein Y represents ~C=O or _C~ (in which R4
represents a hydrogen atom, or a hydroxy-protecting group
.
'` .
11544~1
which is eliminated under basic conditions), Z
represents ~C=O or ~C~HR (in which R5 represents a
hydrogen atom, or a tetrahydropyran-2-yl group),
represents a formyl group, or a grouping of the
formula -CH2oR4 tin which R4 is as hereinbefore defined),
R2 represents a single kond, or an alkylene group
containing from 1 to 5 carbon atoms, R3 represents a
hydrogen atom, an alkyl or alkoxy group containing from
1 to 8 carbon atoms, or a cycloalkyl or cycloalkyloxy
group containing from 4 to 7 carbon atoms unsubstituted
or substituted by at least one alkyl group containing
from 1 to 8 carbon atoms, or represents a phenyl or
phenoxy group unsubstituted or substituted by at least
one halogen atom, trifluoromethyl group or alkyl group
containing from 1 to 4 carbon atoms, with the proviso that
when R2 represents a single bond, R3 d~es not
represent an alkoxy, cycloalkyloxy or phenoxy group,
THP represents a tetrahydropyran-2-yl group, and the
double bond between the carbon atoms in positions 13 and 14
is trans, i.e. E, with the provisos that when Z
represents ~C=O or _C~ OR (in which RS represents a
hydrogen atom), Y represents ~C ~OR (in whlch R4
~1 544~
represents a hydroxy-protecting group which is eliminated
under basic conditions) and Rl represents a grouping of
the formula -CH2oR4 (in which R4 represents a hydroxy-
protecting group which is eliminated under basic conditions),
and (ii) when z represents C ~ OR (in which R5 represents
a tetrahydropyran-2-yl group),
(a) Y represents ~ C~OR (in which R4 represents a hydroxy-
protecting group which is eliminated under basic conditions)
and Rl represents a grouping of the formula -CH2oR4 (in which
R represents a ~ydroxy-protecting group which is eliminated
under basic conditions),
(b) Y represents ~ C~ OR (in which R4 represents a hydrogen
atom) and R represents a grouping of the formula -CH2oR4 (in
which R4 represents a hydrogen atom), or
(c) Y represents ~ C=O and Rl represents a formyl group.
~i
~15~44~
~8
It is to be understood that alkyl and alkylene
groups and alkyl and alkylene moieties of groups ref0rred
to in this specification and the accompanying claims
may be straight- or branched-chain.
The present invention is concerned with all
compounds of general formula IV in the optically active
"natural" form or its enantiomeric form, or mixtures
thereof, more particularly the racemic form, conslsting
of equimolecular mixtures of the optically active "natural"
form and its enantiomeric form.
As will be apparent to those skilled in the art,
the compounds depicted in general formula IV have at least
three centres of chirality at the C-8, C-ll and C-12
carbon atoms. Still further centres of chirality may
occur in branched-chain alkyl or alkylene groups, or when
Ymbol Y represents a group~ C--~oR4 R4
hereinbefore defined, or when the symbol Z represents a
group ~C_~HR , R5 being as hereinbefore defined. The
presence of chirality leads, as is well known, to the
existence of isomerism. However, the compounds of general
formula IV all have such a configuration that the ~ubstituent
groups attached to the cyclopentane ring carbon atoms in
positions identified as 8 and 12 are trans with respect
to each other. Accordingly, all isomers of general
formula IV, and mixtures thereof, which have those
substituent groups attached to the cyclopentane ring carbon
~154~41
t"~ f_
atoms in positions 8 and 12 in the trans-configurat.ion
are to be con~idered w.ithin the scope of gener~.l
formula IV.
Preferably the grouping -R2-R3 represent~,
for example methyl, ethyl, l-methylethyl, propyl,
l-methylpropyl, 2-methylpropyl~ l-ethylpropyl, butyl,
l-methylbutyl, 2 methylbutyl, 3-methylbutyl, l-ethylbutyl,
2-ethylbutyl, pentyl, l-methylpentyl, 2-methylpentyl,
3-methylpentyl, 4-methylpentyl, l,l-dimethylpentyl,
1,2-dimethylpentyl, 1,4-dimethylpentyl, l-ethyl.pentyl,
2-ethylpentyl, 1-propylpentyl, 2-propyIpentyl, hexyl,
l-methylhexyl, 2-methylhexyl, l,l-dimethylhexyl, 1-
ethylhexyl, 2-ethylhexyl, heptyl, 2-ethylheptyl, nonyl,
undecyl, cyclobutyl, l-propylcyclobutyl, l-butylcyclobutyl,
l-pentyl.cyclobutyl, 1-hexylcyclobutyl, 2-methylcyclobutyl,
2-propylcyclobutyl, 3-ethylcyclobutyl, 3-propylcyclobutyl,
2,3,4-triethylcyclobutyl, cyclopentyl, cyclopentylmethyl,
l-cyclopentylethyl, 2-cyclopentylethyl,
2-cyclopentylpropyl, 3-cyclopentylpropyl, 2-pentylcyclopentyl,
2,2-dimethylcyclopentyl, 3-ethylcyclopentyl,
3-propylcyclopentyl, 3-butylcyclopentyl, 3-tert-butyl-
cyclopentyl, (l-methyl-3-propyl)cyclopentyl, (2-methyl-
3-propyl)cyclopentyl, (2-methyl-4-propyl)cyclopentyl,
cyclohexyl, cyclohexylmethyl, l-cyclohexylethyl,
2-cyclohexylethyl, 3-cyclohexylpropyl, (1-methyl-2-
cyclohexyl~ethyl, 2-cyclohexylpropyl, (l-methyl-l-
~ . .
11544~1
.. ' ~ /
o -
cyclohexyl)ethyl, 4-cyclohexylbutyl, 3-ethylcyclohexyl,
3-isopropylcyclohexyl, 4-methylcyclohexyl, 4-ethylcyclohexyl,
4-propylcyclohexyl, 4-tert-butylcyclohexyl, 2,6-
dimethylcyclohexyl, 2,2-dimethylcyclohexyl, (2,6-
dimethyl-4-propyl)cyclohexyl, l-methylcycl.ohexyl.methyl,
cycloheptyl, cycloheptylmethyl, l-cycloheptylethyl,
2-cycloheptylethyl, phenyl, benzyl, l-phenylethyl.,
2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl,
(l-methyl-2-phenyl)ethyl, (1,1-dimethyl-2-phenyl)ethyl,
(l-methyl-l-phenyl)ethyl, l-phenylpentyl, phenoxymethyl,
2-phenoxyethyl, 3-phenoxypropyl, 4-phenoxybutyl.,
5-phenoxypentyl, 3-chlorophenoxymethyl, 4-chlorophenoxymethyl,
4-fluorophenoxymethyl, 3-trifluoromethylphenoxymethyl,
2-methylphenoxymethyl, 3-methylphenoxymethyl,
4-methylphenoxymethyl, 4-ethylphenoxymethyl, 4-tert-
butylphenoxymethyl,4-sec-butylphenoxymethyl, propoxymethyl,
isopropoxymethyl, butoxymethyl, pentyloxymethyl,
hexyloxymethyl, 1-ethoxyethyl, l-propoxyethyl,~
l-isopropoxyethyl, l-neopentyloxyethyl, l-pentyloxyethyl,
(l-methyl-l-ethoxy)ethyl, (l-methyl-l-propoxy)ethyl,
(l-methyl-l-isobutoxy)ethyl, (l-methyl-l-neopentyloxy)
ethyl, (l-methyl-l-butoxy)ethyl, (l-methyl-l-
isopentyloxy)ethyl, (l-methyl-l-pentyloxy)ethyl,
2-ethoxyethyl, 2-propoxyethyl, 2-butoxyethyl, 2-(1-
ethylbutoxy~ethyl, 2-pentyloxyethyl, l-ethoxypropyl,
l-propoxypropyl, l-(2-methylbutoxy)propyl, l-pentyloxypropyl,
115444~L
2-methoxypropyl, 3-methoxypropyl, 3-ethoxypropyl,
3-propoxypropyl, 3-sec-butoxypropyl, 3-isobutoxypropyl,
3-butoxypropyl, (1-methyl-2-methoxy)ethyl, (1-methyl.-2-
ethoxy)ethyl, (l-methyl-2-i~obutoxy)ethyl,
l-pentyloxybutyl, (1-pentyloxy-2-methyl)propyl,
4-methoxybutyl, 4-ethoxybutyl, 4-propoxybutyl,
(l-methyl-3-methoxy)propyl, (1-methyl-3-propoxy)propyl,
(2-methyl-3-methoxy)propyl, (1,1-dimethyl-2-ethoxy]ethyl,
(l,l-dimethyl-2-propoxy)ethyl, (1,1-dimethyl-2-
isobutoxy)ethyl, 5-methoxypentyl, 5-ethoxypentyl,
l-pentyloxypentyl!, ~l-ethyl-3~propoxy)propyl,
cyclobutyloxymethyl, cyclopentyloxymethyl, cyclohexyloxymethyl,
cycloheptyloxymethyl, 2-cyclopentyloxyethyl or
2-cyclohexyloxyethyl. l,l-Dimethylpentyl is particularly
preferred.
The hydroxy-protecting groups which are
eliminated under basi~ conditions represented by R4 as
used in this specification and the accompanying claims
are groups which have no influence on other parts of the
compounds during elimination of the protecting group,
and which are easily eliminated under mild basic conditions.
Preferably, the-hydroxy-protecting group is, for example,
an acyl group such as acetyl, chloroacetyl,
dichloroacetyl, trichloroacetyl, trifluoroacetyl, propionyl,
benzoyl, p-phenylbenzoyl, or naphthyloyl; acetyl is
particularly preferred.
.
.' ~ . ' ~
115~4~1
.~. j,~
According to a feature of the present invention,
the compounds of general formula IV, wherein ~1 represents
a gxouping -CH2oR4, Y represents C _ OR , z repre~ents
C=O, R4 represents a hydroxy-protecting group whlch is
elimina~ed under basic conditions, and the other symbols are
as hereinbefore defined, iOe. compounds of the general
formula:-
OR4a
"~~CH2~R4
2_R3 IVA
~_q~p
(wherein R4a represents a hydroxy-protecting group which
is eliminated under basic conditions, and the other
symbols arç as hereinbefore defined), are prepared by
the Wittig reaction of a compound of the general formula:-
~R4a
~1~, --~CH2oR4
~ V
I HO
o--rHP
(wherein the various symbols are as hereinbefore defined)
with a sodium derivative of a dialkyl phosphonate of
the general formula:-
(R 0)2llcH2lcl-R2-R3 VI
(wherein R6 represents an alkyl group contain;ing from 1 to 4
:~154~41
,
carbon atoms, preferably methyl or ethyl, and the
other symbols are as hereinbefore defined), or with
a phosphorane compound of the general formula:-
(R7)3P=CHc_R2_R3 VII
(wherein R7 represents a phenyl group unsubstituted or
substituted by at least one alkyl group containing from
1 to 4 carbon atoms, preferably phenyl, or represents
an alkyl group containing from 1 to 6 carbon atoms,
preferably butyl or hexyl or represents a cyclohexyl
group, and the other symbols are as hereinbefore defined).
The sodium derivative of the dialkyl phosphonate of
general formula VI may be prepared by the reaction of the
dialkyl phosphonate and sodium hydride.
The Wittig reaction is described in "Organic
Reactions", Volume 14, Chapter 3(1965), John Wiley
& Sons, Inc. (USA). The reaction may be effected in an
inert organic solvent, e.g. an ether such as diethyl
ether, tetrahydrofuran, dioxan or 1,2-dimethoxyethane,
a hydrocarbon such as benzene, toluene, xylene or hexane,
a dialkyl sulphoxide such as dimethyl slllphoxide, a
dialkylformamide such as ~,N-dimethylformamide, a halogenated
hydrocarbon such as methylene chloride or chloroform, or an
alkanol containing from 1 to 4 carbon atoms such as methanol
or ethanol, or a mixture of two or more of them, at a
temperature from -78C to the reflux temperature of the
1154441
r~ xz ~
reaction mixture.
Dialkyl phosphona-tes of general formula VI
and phosphorane compounds of general formula VII are
well known, or may easily be prepared by methods known
~er se. By the term "methods known E~ se" as used in
this specification is meant methods heretofore used or
described in the chemical literature.
The compounds of general formula IV, wherein
R represents a grouping -CH2oR4, Y represents _C G
Z represents ~C _HR , R4 represents a hydroxy-protecting
group which is eliminated under basic conditions, R5
represents a hydrogen atom,-and the other symbols are
as hereinbefore defined, i.e. compounds of the general
formula:-
,OR4a
~" ~ CH2oR4
2_R3 IVB
-~P
(wherein the various symbols are as hereinbefore defined)
are prepared by reduction of compounds of general
formula IVA to convert the 15-oxo group to a 15-hydroxy
group.
The reduction to convert the oxo group to a
hydroxy group may be carried out by using any suitable
reducing reagent such a~ sodium borohydride, potassium
1~5~4~i
.~ ,,,
borohydride, lithium borohydride, zinc borohydride,
lithium tri-tert-butoxyaluminium hydride, lithium
trimethoxyaluminium hydride, sodium cyanoborohydride,
potassium tri-sec-butylborohydride, lithium aluminium
hydride-quinine complex, (-)-isobornyloxymagnesi~m
iodide in an inert organic solvent, e.g. an alkanol
containing from 1 to 4 carbon atoms such as methanol,
ethanol or isopropanol, or an ether-such as tetrahydrofuran,
dioxan or 1,2-dimethoxyethane, or a mixture of two or
more of them, at-a temperature from -78C to ambient.
Preferably, the reduction is effected using diiso-
bornyloxyaluminiumisopropoxide (described in our
Japanese Patent Kokai No. 54-76552), or a
diisobutyl(alkyl-substituted or unsubstituted)
phenoxyaluminium '[d~sa~ibe~ ~n o~r Japanese
Patent Kokai No. 54-154739 and J. Org. Chem., 44,
1363(1979)], or a lithium 1,1'-binaphthyl-2,2'-
dioxyaluminium hydride [described in J. Amer. Chem~
Soc., 101, 5843(1979)]. The product thus obtained i9 a
mixture of isomers in which the 15-hydroxy group is in
a- or ~-configuration and the mixture is separated by
conventional means, ~or example, by thin layer, column
or high-speed liquid chromatography on silica gel to give
the desired isomer of general formula IVB.
The compounds of general formula IV, wherein
Rl represents a grouping -CH2oR4, Y represents ~C~HR
? '`:`~
1154~41
.~ f7
.~
Z represents C _ HR , R4 represents a hydro~cy-
protecting group eliminated under basic cond:Ltion~,
R represents a tetrahydropyran-2-yl group, and the
othèr symbols are as hereinbefore defined, i,e.
compounds of the general formula:-
oR4a
~, ~ CH2oR4
_R3 IVC
O--IHP
0-THP
(wherein the various symbols are a~ h`ereinbefore defined),
are prepared by etherification of the 15-hydroxy group
of a compound of general formula IVB with 2,3-
dihydropyran in an inert organic solvent, e.g. methylene
chloride or tetrahydrofuran, in the presence of an
acidic catalyst, e.g. ~-toluenesulphonic acid, sulphuric
acid, trifluoroborane-etherate or phosphorus oxychloride,
at or below ambient temperature.
The compounds of general formula IV, wherein
~l represents a grouping -CH2oR4, Y represents ~ ~ H
Z represents ~C_ HR , R4 represents a hydrogen atom, R5
represents a tetrahydropyran-2-yl group, and the other
symbols are as hereinbefore defined, i.e. compounds of
the general formula:-
llS4441
~" ~
~, ~ /\/cH2o~
2_R3 IVD
O-T~P
O-T~P
(wherein the various symbols are as hereinbefore defined),
are prepared by saponification of compounds of general
formula IVC to convert the groups OR4a to hydroxy groups.
The saponification may be effected by using an aqueous
solution of an alkali metal, e.g. sodium, potassium or
lithium, hyd~oxlde, carbonate or bicarbonate, or of an
alkaline earth metal, e.g. calcium or barium, hydroxide
or carbonate in the absence or presence of a water-
miscible solvent, e.g. an ether such as tetrahydrofuran,
dioxan or 1,2-dimethoxyethane, or an alkanol containing
from 1 to 4 carbon atoms such as methanol or ethanol,
at a temperature from -10C to the reflux temperature of
the reaction mixture, preferably at a temperature from
am~ient to 50C or by using an anhydrous solution of an
alkali metal, e.g. sodium, potassium or lithium, hydroxide
or carbonate in an anhydrous alkanol containing from i to
4 carbon atoms, e.g. absolute methanol or ethanol, at a
temperature from -10C to the reflux temperature of the
reaction mixture, preferably at a temperature from
ambient to 50C.
,,,
' '
1154441
The compounds of general formula IV, where.in
Rl represents a formyl group, Y represents ~C=O, Z
represents~ C _OR , in which R5 represents a
tetrahydropyran-2-yl group, and the other symbols are
as hereinbefore defined, i.e. compounds of the general
formula:-
o
~, ~C~O.
~ 2_R3 IVE
O-THP
O-llffP
(wnerein the various symbols are as hereinbefore defined),
are prepared from compounds of general formula IVD
by oxidation to convert the 9-hydroxy group to a
9-oxo group and simultaneously to convert the
hydroxymethyl group to a formyl group.
The oxidation is carried out by methods known
per se for the conversion of a hydroxy group to an oxo
15 group, for example by methods described in (1) Tetsuji
Rameya, "Synthetic Organic Chemistry III, Organ.ic
Synthesis 1", pp 175-206 (1976), ~ankodo (Japan),
or in (2) "Compendium of Organic Synthetic Methods",
Volume 1 (1971), 2 (1974) and 3 (1977), Section 48,
: 20 John Wiley & Sons, Inc. (USA). Preferably the oxidation
is carried out under mild and neutral conditions, for
example, with dimethyl sulphide-N-chlorosuccinimide complex,
l~S4g~41
g
thioanisole-N-chlorosuccinimide complex, dimethyl
sulphide-chlorine complex or thioanisole-chlorine
complex [cf. J. Amer. Chem. Soc., 94, 7586 (1972)~,
dicyclohexylcarbodiimide-dimethyl sulphoxide complex
[cf. J. Amer. Chem. Soc., 87, 5661 (1965)~, pyridinium
chlorochromate (C5H5NHCrO3Cl) [cf. Tetrahedron Letters,
2647 (1975)], sulphur trioxide-pyridine complex [cf. J.
Amer. Chem. Soc., 89, 5505 (1967~], chromyl chloride
[cf. J. Amer. Chem. Soc., 97, 5929 (1975)], chromium
trioxide-pyridine complex (e.g. Collins' reagent) or
Jones' reagent.
me oxidation using dimethyl sulphide-~-
chlorosuccinimide complex, thioanisole-N-chlorosuccinimide
complex, dimethyl sulphide-chlorine complex or
thioanisole-chlorine complex may be effected by reaction
in a halogenated hydrocarbon such as chloroform, methylene
chloride or carbon tetrachloride, or toluene at -30
to 0C, and then treatment with triethylamine. The
oxidation using the dicyclohexylcarbodiimide-dimethyl
~ulphoxide complex is normally effected by reaction in
excess dimethyl sulphoxide in the presence of an acid,
e.g. phosphoric acid, phosphorous acid, cyanoacetic acid,
pyridine-phosphoric acid salt or trifluoroacetic acid,
as catalyst. The oxidation using pyridinium chlorochromate
may be effected by reaction in a halogenated hydrocarbon
such as chloroform, methylene chloride or carbon
. ~
llS4441
o
tetrachloride in the presence of sodium acetate, normally
at ambient temperature. The oxidation uising the sulphur
trioxide-pyridine complex iA normally effected by
reaction in dimethyl sulphoxide in the presence of
triethylamine at ambient temperature. The oxidation
using chromyl chloride is normally effected by reaction
in a halogenated hydrocarbon such as chloroform, methylene
chloride or carbon tetrachloride in the presence of
tert-butanol and pyridine at a temperature from -30C to
the reflux temperature of the reaction mixturl_. The
oxidation using the chromium tri-oxide-pyridine complex
may be effected by reaction in a halogenated hydrocarbon
such as chlorofo,rm, methylene chloride or carbon
tetrachloride at a temperature from 0C to ambient,
preferably at 0C. m e oxidation using Jones' reagent
is normally effected with acetone and dilute sulphuric
acid at a temperature from 0C to am~ient.
Compounds of general formula V may be prepared
by the series of reactions depicted schematically below
in Scheme A, wherein R represents a benzyl group, or a
hydroxy-protecting group which is eliminated more easily
than a tetrahydropyran-2-yl group under acidic conditions.
the double bond is E or Z, or a mlxture thereof, i.e.
EZ, and the other symbols are as hereinbefore defined. The
(l-methoxy-l-methyl)ethyl,l-methoxycyclohexyl, l-methoxy-l-
phenylethyl and I-ethyoxyethyl tetrahydrofuran-2-yl tri-
methylsilyl groups are suitable hydroxy-protecting groups
removed more easily than the tetrahydropyran-~-yl group.
.
1~544~1
SCHEM_A
_ ~,OH OH
[a~ H=C}~\CH20H
O--THP / O--THP
VIII ~fb~ IX
olR4a o~R4a
Ç~OR8 ~ ~/ON CH20R
O--THP O-~rHP
X / XI
~/[ d]
4a
CH2
CHO
'' ~ ' '
~1544~1
Referring to Scheme A the conversion [a~ may
be carried out by using an ylide of a phosphonium compound
of the general formula:
(R )3PCH2CH2CH20H-X XII
(wherein X represents a halogen atom, and R7 is as
hereinbefore defined) by means heretofore mentioned for
the conversion of compounds of general formula V to
those of general formula IVA.
The ylide of a phosphonium compound of general
formula XII may be prepared by reaction of a phosphonium
compound of general formula XII with an appropriate base,
e.g. butyllithium, or a lithium compound of the general
formula:
R9\
NLi XIII
R10~
(wherein R9 and R10, which may be the same or different,
each represent an alkyl group containing from 1 to 6
carbon atoms, or a cycloalkyl group containing from 3
to 6 carbon atoms), e.g. lithium diisopropylamide, in
an inert organic solvent, at a temperature from -78C to
ambient,for example a solvent hereinbefore described as
1154441
~. . .
, ~ J~f
suitable for the Wittig reaction of a compound of
general formula V.
Phosphonium compounds of general formula XII
are well known, or may easily be prepared by methods
known per se.
The conversion [b~ may be carried out, for
example when R~a represents an acyl group, by using an
acyl chloride R4aCl, R4a being as hereinbefore defined,
or an acid anhydride (R4a)20, R4a being as hereinbefore
defined, in an inert organic solvent, eOgO methylene
chloride or pyridine, in the présence of a tertiary amine,
e.g. pyridine or triethylamine, at a temperature below
ambient, preferably at a temperature below 0C.
In the conversion [c], when ~8 represents a
~enzyl group, compounds of general formula XI may be
prepared by reduction of compounds of general formula X
to convert simultaneously the vinylene and benzyloxy
groups to ethylene and hydroxy groups, respectivelyO
The reductioh may be suitably carried out
under an atmosphere of hydrogen in the presence of a
i~ hydrogenation catalyst, e.g. palladium on carbon,
palladium black, platinum dioxide, or Raney ~ickel,
in an inert organic solvent, e.g. an alkanol containing
from 1 to 4 carbon atoms such as methanol or ethanol,
or ethyl acetate, or a mixture of two or more of them,
115444~
f~ - 2~ -
at a temperature from ambient to the reflux temperature
of the reaction mixture at normal or elevated pressure,
e.g. at a hydrogen pressure from atmospheric to 15 kg/cm2.
When R8 is other than a benzyl group, compounds
of general formula X may be converted to compounds
of the general formula:`
OR
~CH-CH /~\CH20R4a XIV
OH
O-THP
(wherein the various symbols are as hereinbefore defined)
by mild hydrolysis under acidic conditions avoiding the
risk of elimination of the tetrahydropyran-2-yl group,
followed by hydrogenation of the compound of general
I formula XIV obtained by means heretofore mentioned for the
conversion of compounds of general formula X wherein R8
represents a benzyl group to those of general formula XI,
to convert the vinylene group in formula XIV to an
ethylene group.
The mild hydrolysis under acidic conditions may
be effected ~1) with an aqueous solution of an organic acid,
e.g. acetic acid, propionic acid, oxalic acid or
~-toluenesulphonic acid, or an inorganic acid, e.g.
1154441
hydrochloric acid, sulphuric acid or phosphoric acid,
advantageously in the presence of a water-miscible organic
solvent, e.g. an alkanol containing from 1 to 4
carbon atoms such as methanol or ethanol, preferably
methanol, or an ether such as 1,2-dimethoxyethane,
dioxan or tetrahydrofuran, preferably tetrahydrofuran, at
or below ambient temperature, preferably at 0C, or
(2) with an anhydrous solution of an organic acid
such as ~-toluenesulphonic acid or trifluoroacetic
acid in an anhydrous alkanol containing from 1 to 4
carbon atoms such as absolute methanol or ethanol, at or
below 0C.
The conversion [d~ may be carried out by means
heretofore mentioned for the conversion of compounds of
general formula IVD to those of general formula IVE.
The starting material of general formula VIII,
wheréin ~ represents a benzyl group, is a known compound
described in J. Org. Chem., 37, 2921 (1972). The
starting materials of general formula VIII, wherein R is
other than a benzyl group, are prepared as described in
our Japanese Patent Kokai ~o. 53-149954.
According to a further feature of the present
invention, the compounds of general formula IV, wherein R
represent`s a formyl group, Y represents ~C=0, Z represents
~C~ HR , R5 represents a tetrahydropyran-2-yl group.
1154441
.
and the other symbols are as hereinbefore defined,
i.e. compounds of general formula IVE are converted to
compounds of the general formula:
O
~1~, ~ COOR
2_R3
0-THP O-THP
(wherein Rll represents an alkyl group containing from 1
to 4 carbon atoms, the double bonds between the carbon
atoms in positions 2 and 3, and positions 13 and 14,
are trans (i.e. E), and the other symbols are as
hereinbefore defined) by the Wittig reaction with a
phosphorane compound of the general formula:
(R7)3P=C~I~OoRll XVI
(wherein R~ and Rll are as hereinbefore defined) by means
heretofore mentioned for the conversion of compounds
of general- formula V to those of general formuLa IVA.
Phosphorane compounds of generalformula XVI
are well known, or may easily be prepared by methods
known E~
Compounds of general formula XV are converted
to tran~ prostaglandin El analogues of the general
formula:
: . :
-
115~
~{ ` ~
,~ ~ OORll XVlI
~r,~R2-R3
OH
OH
(wherein the various symbols are as hereinbefore defi.ned) by
hydrolysis under acidic conditions to convert the
tetrahydropyran-2-yloxy groups to hydroxy groupsO
The hydrolysis to convert the tet:rahydropyran-2-
yloxy groups ir.to hydroxy groups under acidic conditi.ons
is well known. The hydrolysis may be carried out for
example with
(1) an aqueous solution of an organic acid such as acetic
10 acid, propionic acid, oxalic acid, ~-toluenesulphonic acid,
or of an inorganic acid such as hydrochloric acid,
sulphuric acid, phosphoric acid, advantageously in
the presence of an inert organic solvent miscible witn
water, e.g. a lower alkanol such as methanol or ethanol,
15 preferably methanol, or an ether such as 1,2-dimethoxyethane,
dioxan, tetrahydrofuran, preferably tetrahydrofuran, at a
temperature from ambient to 75C, or (2) an anhydrous
solution of an organic acid such as ~-toluenesulphonic
acid or trifluoroacetic acid in a lower alkanol such as
20 methanol or ethanol at a temperature from 0 to 45C, or
1154441
J'~ t~
(3) an anhydrous solution of ~-toluenesulphonic acid-
pyridine complex or trifluoroacetic acid-pyridine complex
in a lower alkanol such as methanol or ethanol at a
temperature from 10 to 60C. Advantageously the
mild hydrolysis under acidic conditions may be carried
out with a mixture of-dilute hydrochloric acid and
tetrahydrofuran, a mixture of dilute hydrochloric acid
and methanol, a mixture of acetic acid, water and
tetrahydrofuran, a mixture of phosphoric acid, water and
tetrahydr~ofura~, a mixture of ~-toluenesulphonic acid
a~d methanol, a mixture of ~-toluenesulphonic acid-pyridine
complex and methanol or a mixture of trifluoroacetic
acid-pyridine complex and methanol.
The trans-Q2-prostaglandin El analogues of
general formula XVII, thus obtained, are useful in human
or veterinary medicines as described in our British
Patent Specification Nos. 1,416,410, 1,483,240 and
1,540,427. mey possess the valuable pharmacological -
properties typical of prostaglandins in a selective
fashion including, in particular, hypotensive activity,
inhibitory activity on blood platelet aggregation,
inhibitory activity on gastric acid secretion and gastric
ulceration and bronchodilator activity and are useful
in the treatment of hypertension, in the treatment of
disorders of the peripheral circulation, in the prevention
and treatment of cerebral throm~osis and myocardial
11544~1
~b - 2~ -
infarction, in the treatment of gastric ulceration and
in the treatment of asthma. The trans-~2-prostaglandin
El analogue of general formula XVII. wherein the group
-R2-R3 represents a l,l-dimethylpentyl group and Rll
represents a methyl group, i.e. (2E,13E)-(11,15R)-9-
oxo-11,15-dihydroxy-16,16-dimethylproqta-2,13-dienoic
acid methyl ester which i8 described and claimed in
Britiqh Patent Specification No. 1,540,427 is u~eful
in the términation of pregnancy and induction of labour
in pregnant female mammals and in the control of oestru~,
contraception and menstrual regulation in female mammals.
It will be appreciated, therefore, that the
new compound~ of the present invention of general
formula IV, i.e. compounds of general formula IVA, IVB,
IVC, IVD and IVE, are useful and important intermediates
for the preparation of therapeutically u~eful trans-~2-
prostaglandin El analogues.
In addition, the new compounds of general
formula V, IX, X, XI and XIV, i.e. compounds of the
general formula:-
fRl2
~ X ~ CH20R 2 XVIII
13
O-~P
1154441
,~,
[wherein X represents an e~hylene or vinylene group,
R12 represents a hydrogen atom, or a hydroxy-protecting
group which is eliminated under basic conditions, R13
represents a formyl group, a hydroxymethyl group (-CH20~),
or a group -CH20R8, in which R8 is as hereinbefore defined,
and the-other symbols are as hereinbefore defined, with the
provisos ~hat,(i)when R repre~ents a formyl group, X
represents an ethylene group and R12 represents a hydroxy-
protecting group which is eliminated under basic conditions,
(ii) when R13 represents a hydroxymethyl group, R12
represents a hydroxy-protecting group which is eliminated
under basic conditions and (iii3 when R13-represents
a group -CH20R8, X represents a.vinylene group~
are also useful and important intermediates for the
preparation of trans-~2-prostaglandin El analoguesO
When X represents a vinylene group the double bond may be
E, Z or a mixture thereof
~The use of the compounds of general formulae
IV and XVIII allows the ~ynthesis of trans- ~ prostaglandin
El analogues by the method~ hereinbefore described which
avoid certain disadvantages of the two known methods
heretofore.~entioned. Use of the p~osphonium compounds
of generali formula XII avoids the need to.use `the unstable
pho~phorane compound required in the method described in
British Specification ~o. 1,416,410 (the compounds of
formula XI~ have the group -CH20H in place of the
unconjugated carboxy group and are therefore more stable,
leading to higher yields); a selective hydrogenation.
. ,
liS~44~
:i' ?
which carries a risk of a reduced yield of the
desired product is not required, and the ~-chain i.9
introduced at a relatively late stage in the method.
Furthermore the use of selenium or sulphur compounds,
and the necessary careful purification steps to remove
traces of such compounds in the final prostaglandin
products, are not required.
:115~4~1
.; ~
The following Examples illustrate the present
invention. In the Examples "TLC", "IR" and "NMR" represent
respectively "Thin layer chromatography", "Infrared
absorption ~pectrum", and "Nuclear magnetic resanance
spectrum". Where solvent ratios are specified in
chromatographic separations, the ratios are by volume: the
solvents in parentheses show the developing solvents used.
Except when specified otherwise, infrared spectra are
recorded by the liquid film method, and nuclear magnetic
resonance spectra are recorded in deuterochloroform
(CDC13) solution.
- EXAMPLE 1
(EZ)-2-15-Hydroxypent-2-enyl)-3~-(1-methoxy-1-methyl)-
ethoxymethyl-4a-(tetrahydropyran-2-yloxy)cyclopentan-lx-ol
Under an atmosphere of nitrogen, 29.1 ml of a
1.5M ~olution of butyllithium in hexane were added to a
suspension of 8.748 g of 3-hydroxypropyltriphenylphosphonium
bromide in 70 ml of tetrahydrofuran, and the mixture was
stirred at room temperature for 10 minutes to give an ylide
solution. To the ylide solution, thus obtained, was added
a solution of 3 g of 2-oxa-6-syn-(1-methoxy-1-
methyl)ethoxymethyl-7-anti-(tetrahydropyran-2-yloxy)-c lS-
bicyclo[3.3.0]octan-3-ol (prepared as described in
Reference Example 2 of our Japanese Patent Kokai ~o.
53-149954) in 10 ml of tetrahydrofuran, and the mixture was
stirred at room temperature for one hour, and then at 40C
llS~441
'` ~'`
.~, ~.,
for 30 minutes. The reaction mixture was poured into a
saturated aqueous solution of ammonium chloride, and
the mixture extracted with ethyl acetate. The extract
was washed with water and a saturated aqueous solution
of sodium chloride, dried over magnesium sulphate, and
concentrated under reduced pressure to give the crude
title compound having the following physical characteristic.
The crude product was used in the next step wlthout
purification.
TLC (ethyl acetate:cyclohexane = 2:1): Rf = 0.23.
(a) Using the procedure described above. but
replacing the 2-oxa-6-syn-(l-methoxy-l-methyl)ethoxymeth
7-anti-(tetrahydropyran-2-yloxy)-cis-bicyclo[3.3.0]octan-
3-ol by 2-oxa-6-syn-benzyloxymethyl-7-anti-(tetrahydropyran-
2-yloxy)-cis-bicyclo~3.3.0]octan-3-ol [prepared as
described in J. Org. Chem., 37, 2921 (1972)], there was
obtained (Ez)-2a-(5-hydroxypent-2-enyl)-3~-
benzyloxymethyl-4a-(tetrahydropyran-2-yloxy~cyclopentan-1-
ol having the following physical characteristic:
TLC (ethyl acetate:cyclohexane = 2:1): Rf = 0.25.
EXAMPLE 2
(Ez)-la-Acetoxy-2a-(5-acetoxypent-2-enyl~-3~ methoxy-l-
methyl)ethoxymethyl-4a-(tetrahydropyran-2-yloxy)cyclopentane
The crude product, prepared as described in
Example 1, was stirred overnight with 14 ml of acetic
anhydride and 33 ml of pyridine at room temperature. The
11S4~41
`^ !" ` _ ,~2~ _
~ ~?-~
reaction mixture was diluted with ethyl acetate, washed
with 0.5N hydrochloric acid, water and a saturated aqueous
solution of sodium chloride, dried over ma~nesium sulphate,
and concentrated under reduced pressure to give the crude
title compound having the following physical characteristic.
The crude product was used in the next step without
purification.
TLC tethyl acetate:cyclohexane = 2:1): Rf = O.79.
(a) Following the procedure described above. but
replacing the crude product of Example 1 used as starting
material by the crude product of Example l(a), the
following compound was prepared. The product was purified by
column chromatography on silica gel using a mixture of ethyl
acetate and cyclohexane (1:2) as eluent to give in 7~%
lS yield based on the starting material of Example l(a):
(EZ)-l-acetoxy-2-(5-acetoxypent-2-enyl)-3~-
benzyloxymethyl-4-(tetrahydropyran-2-yloxy)cyclopentane:
TLC (cyclohèxane:ethyl acetate = 2:1): Rf = O.82
IR: ~= 1740, 1243, 1021 cm
~MR (CC14 solution): ~ = 7.12 (5H, m), 5.40 (2H, m),
5.00 (lH, m), 4.61 (lH, m), 4.36 ~2H, s), 3.97 (2H, t),
3.40 (2H, d), 4.20-3.20 (3H, m), 2.00 (6H, s).
EXAMPLE``3
(-EZ)~l-~-Acetoxy-2a-(5-aceto2ypent-2-enyl)-3~-hydroxymethyl-
4~(tetrahydropyran-2-yloxy)cyclopentane
me crude product, prepared as described in
Example 2, was stirred with 40 ml of tetrahydrofuran and
llS4441
~s~
~ `.`` 3~-
15 ml of 1~ hydrochloric acid at 0C for 30 minutes. The
reaction mixture wa~ neutrali~ed with a saturated aqueou~
solution of sodium bicarbonate, washed with water and a
saturated aqueous solution of sodium chloride, drled over
magnesium sulphate, and concentrated under reduced pressure.
The residue was purified by column chromatography on silica
gel using diethyl ether as eluent to give 2O30 g of the
title compound having the following physical
characteristics:
TLC (ethyl acetate:cyclohexane = 2:1): Rf = 0.42;
IR: ~ = 3460, 1737, 1243, 1023 cm 1;
~MR (CC14 solution): ~ = 5.35 (2H, m), 4.97 (lH, m),
4.56 (lH, m), 3.95 (2H, t), 4.20-3.16 (5H, m), 1.97 (6H, s).
E~MPLE 4
1~-Acetoxy-2a-(5-acetoxypentyl)-3~-hydroxymethyl-4-
(tetrahydropyran-2-yloxy)cyclopentane
Under an atmosphere of hydrogen, a mixture of
10.402 g of the pentenyl compound prepared as described
in Example 3, 120 ml of methanol and 100 mg of platinum
dioxide was stirred at room temperature for 3 hours.
The reaction mixture was filtered, and the filtrate wa~
concentrated under reduced pressure to give 10.264 g of the
title compound having the following physical characteristics:
TLC (ethyl acetate:benzene = 2:1, utilising a silica gel
plate pre-treated with silver nitrate): Rf = 0.47;
IR: ~ = 3460, 1740, 1247, 1020 cm 1,
llS4~1
~6 -
NMR (CC14 solution): ~ = 4.96 (lH, m), 4.52 (lH, m),
3.93 (2H, t), 4.20-3.15 (5H, m), 1.97 (6H, s).
EXAMPLE 5
l~-Acetoxy-2~-(5-aceto~ypentyl)-3~-formyl-4a-
(tetrahydropyran-2-yloxy)cyclopentane
To a suspension of 5.79 g of N-chlorosuccinimide
in 300 ml of toluene were added 3.94 ml of dimethyl
sulphide at 0C, and the mixture was stirred at that
temperature for 40 minutes. To the solution obtained
was added a solution of 11.1 g of the hydroxymethyl
compound, prepared as described in Example 4, in 20 ml
of toluene at -20C. The mixture was stirred at the same
temperature for one hour, and then stirred with 12. 1 ml
of triethylamine at -20C for 30 minutes. ~he reaction
mixture was neutralised with 0.1~ hydrochloric acid, diluted
with diethyl ether, washed with 0.1~ hydrochloric acid,
a saturated aqueous solution of sodium bicarbonate, water
and a æaturated aqueous solution of sodium chloride, dried
over magnesium sulphate, and concentrated under reduced
pressure. The residue was purified by column chromatography
on silica gel using a mixture of ethyl acetate and
cyclohexane (1:1) as eluent to give 10.327 g of the title
compound having the following physical characteristics:
TLC (ethyl acetate:benzene = 2:13: Rf = 0.74;
IR: ~= 1740, 1377, 1247, 1025 cm 1,
NMR: ~ = 9.65 (lH, t), 5.30-4.85 (lH, m), 4.8-3.1 (6H, m).
115~4~i
EXAMPLE 6
l~-Acetoxy-2a-(5-acetoxypentyl)-3~-hydroxymethyl-Lla
(tetrahydropyran-2-yloxy)cyclopentane
Under an atmosphere of hydrogen, a mixture of
4.74 g of the benzyloxymethyl compound, prepared as
described in Example 2(a), 100 ml of ethan~l and 20 g
of Raney nickel (W-7) was heated under reflux for 2 hours.
The reaction mixture was filtered, and the filtrate waq
concentrated under reduced pressure to give 3.48 g of the
title compound having the same physical characteristics
as the product of Example 4.
EXAMPLE 7
(E)-la-Acetoxy-2a-(5-acetoxypentyl)-3~-(3-oxo-4r4
-
dimethyloct-l-enyl)-4~-(tetrahydropyran-2-yloxy)cyclopentane
Under an atmosphere of nitrogen, a solution of
11.154 g of dimethyl 2-oxo-3,3-dimethylheptylphosphonate
in 50 ml of tetrahydrofuran was added dropwise to a
suspension of 1.317 g of sodium hydride (content 63.5%) in
250 ml of tetrahydrofur2n at room temperature, and the
mixture was stirred at ambient temperature for 30 minutes.
To the solution, thus obtained, was added a solution of
10.987 g of the formyl compound, prepared as described
in Example 5 in 100 ml of tetrahydrofuran, and the mixture
was stirred at room temperature for 2.5 hours. The
reaction mixture was acidified with acetic acid, filtered,
and the filtrate was concentrated under reduced pressure.
1154441
`` ```` `~
The residue was purified by column chromatography on
silica gel u~ing a mixture of cyclohexane and ethyl
acetate (3:1) as eluent to give 12.3 g of the title
compound having the following physical characteristics:
TLC (cyclohexane:ethyl acetate = 1:1): Rf = 0.70
IR: ~ = 1740, 1695, l625, 1246, 1025 cm
~MR: ~ = 7.10-6.30 (2H, m), 5.40-5.00 (lH, m), 4.80-4.35
(lH, m), 4.35-3.10 (5H, m).
EXAMPLE 8
(E)-la-Acetoxy-2a-(5-acetoxypentyl)-3~-~3R-hydroxy-4~4
~ .. _ _ .... . _ _ _ _
dimethyloct-l-enyl)-4a-(tetrahydropyran-2-yloxy)cyclopentane
.. _ .. .. . .. _ _
Under an atmo~phere of nitrogen, 100 ml of a 25%
(w/v) solution of diisobutylaluminium hydride in toluene
were added dropwise to a solution of 1.8 ~ of 2,6-di-
tert-butyl-4-methylphenol in 660 ml of toluene at 0
to 5C, and the mixture was stirred at the same temperature
for one hour. To the solution was added a solution of
8.64 g of the 3-oxo compound, prepared as described in
Example 7, in 60 ml of toluene at -78C, and the mixture
wa~ stirred at -30 to -20C for 3 hours. The reaction
mixture was Qtirred with 80 ml of water at 40C for
30 minutes, filtered, and the filtrate was concentrated
under reduced pressure. The residue was purified by column
chromatography on Qilica gel using a mixture of methylene
chloride and ethyl acetate (4:1) as eluent to give 7.5 g of
the title compound having the following physical characteristic~:
1154 4~1
~o
TLC ~benzene:ethyl acetate = 3:1~: Rf = 0.30,
(3S-isomer, Rf = 0.39);
IR:~ = 3740, 1738, 1372, 1243, 1017 cm
~MR (CC14 solution): ~ = 5.42 ~2H, m), 4.96 ~lH, m),4-46 ~lH,m),
3.90 ~2H, t), 4.10-3.15 ~4H, m), 1.97 ~3H, 9),
1.93 ~3H, s`).
E~MPLE 9
~E)-la-Acetoxy-2~-~5-acetoxypentyl)-3~-[3R-
~tetrahydropyran-2-yloxy)-4,4-dimethyloct-1-enyl]-
4a-~tetrahydropyran-2-yloxy)cyclopentane
.... . . .
A mixture of 7.5 g of the 3R-hydroxy compound,
prepared as described in Example 8, 3 ml of 2,3-
dihydropyran, 25 mg of ~-toluenesulphonic acid and 80 ml
of methylene chloride was stirred at room temperature
for 15 minutes. The reaction mixture was neutralised with
a saturated aqueous solution of sodium bicarbonate, and
extracted with ethyl acetate. The extract was washed
with water and a saturated aqueous solution of sodium
chloride, dried over magnesium sulphate, and concentrated
under reduced pressure to give 8.88 g of the title compound
having the following physical characteristic:
TLC ~cyclohexane:ethyl acetate = 2:1): Rf = 0.57.
EXAMPLE 10
(E)-2~-(5-Hydroxypentyl)-3~-~3R-(tetrahydropyran-2-yloxy)-
. . .
4,4-dimethyloct-1-enyl]-~-~tetrahydropyran-2-yloxy)-
cyclopentan-la-ol
llS4441
A mixture of 8.88 g of the acetoxy compound,
prepared as described in Example 9, 4.05 g of potassium
carbonate and 80 ml of methanol was stirred at 50C for
1.5 hours. The reaction mixture was diluted with ethyl
acetate, washed with a saturated aqueous solution of
ammonium chloride, dried over magnesium sulphate, and
concentrated under reduced pressure. The residue was
purified by column chromatography on silica gel using
a mixture of ethyl acetate and cyclohexane (2:1~ as
eluent to give 7.2 g of the title compound having the
following physical characteristics: -
TLC (ethyl acetate:cyclohexane = 2:1): Rf = 0.27,
IR: ~ = 3400, 1137, 1026, 978 cm 1,
~MR: ~ = 5.60-5.23 (2H, m), 4.60 (2H, m), 4.30-3.20 (9H, m).
EXAMPLE 11
(E)-2-(4-Formylbutyl)-3~-[3R-(tetrahydropyran-2-yloxy)-
_,
4,4-dimethyloct-1-enyl]-4a-(tetrahydropyran-2-yloxy)-
cyclopentan-1-one
.
A solution of 0.335 ml of chromyl chloride in
2 ml of carbon tetrachloride was added dropwise to a
solution of 0.786 ml of tert-butanol and 1.01 ml of
pyridine in 13 ml of methylene chloride at -78C. To
the solution was added a solution of 902 mg of the
cyclopentan-la-ol compound, prepared as described in
Example 10, in 5 ml of methylene chloride at room
temperature, and the mixture was stirred at ambient
,,
~5~441
temperature for 2 hour~, then at 34C for 40 minutes.
The reaction mixture wa~ ~tirred with 0.5 ml of dimethyl
sulphide at room temperature for 10 minutes; 60 ml of
diethyl ether and 20 ml of water were added, and the mixture
filtered through a pad of infusorial earth. The ethereal
layer of the filtrate was wa~hed with a saturated aqueous
solution of sodium chloride, dried over magnesium sulphate,
and concentrated under reduced pressure. The residue
was purified by column chromatography on silica gel using
a mixture of cyclohexane and ethyl acetate (3:1) as
eluent to give 675 mg of the title compound having the
following physical characteristics:
TLC (cyclohexane:ethyl acetate = 2:1): Rf = 0.44;
IR:~ = 1745, 1730, 1130, 1078, 1037, 1023 cm
~MR (CC14 solution): ~ = 9.50 (lH, t). 5.70-5.30
(2H, m), 4.71-4.42 (2H, m), 4.31-3.07 t6H, m).
EXAMPLE 12
(2E,13E)-(llx,15R)-9-Oxo-11,15-bis(tetrahydropyran-2-
yloxy)-16,16-dimethylprosta-2,13-dienoic acid methyl ester
Under an atmosphere of nitrogen, a mixture of
184 mg of the cyclopentan-l-one, prepared as described
in Example 11, 231 mg of methoxycarbonylmethylidene-
triphenylphosphorane and 2 ml of chloroform was stirred
at room temperature for 2 hours, and then concentrated
under reduced pressure. The residue was purified by
column chromatography on silica gel using a mixture of
. -
~15444~
C~
cyclohexane and ethyl acetate (3:1) as eluent to
give 192 mg of the title compound having the following
physical characteristics:
TLC (benzene:ethyl acetate = 2:1): Rf = 0.74,
IR:~ = 1745, 1~726, 1654, 1196, 1128, 1030 cm
~MR: ~ = 6.90 (lH, dt), 5.70 (lH, d), 5.80-5,40 (2H, m),
4.60 (2H, m).
The title compound was also prepared by the
procedure described above, replacing the methoxycarbonyl-
methylidenetriphenylphosphorane by a phosphorane compound
(R~)3P=CHCOOCH3, in which R is as indicated in the Table
below, and modifying the reaction temperature, reaction
time and solvent.
R7 reaction reaction solvent yield
temperature time
-C4H9 -20 to 0C 2 hours toluene 100 %
cyclohexyl r.t. ~ 15 hours chloroform 94.1,~
C6H13 r.t. 1.5 hours tetrahydrofuran 98 %
~r.t. is room temperature.
; EXAMPLE 13
(2E,13E)-( lla, 15R)-9-oxo-l1, 15-dihy~roxy-16,16-
d methylprosta-2,13-dienoic acid methyl e~ter
To a solution of 732 mg of (2E,13E)-(lla,15_~-
1154441
,.i, ~
9-oxo-11,15-bis(tetrahydropyran-2-yloxy)-16,16-
dimethylprosta-2,13-dienoic acid methyl ester (which may be
prepared as described in Example 12) in 1~9 ml of
tetrahydrofuran was added 19 ml of a 65% (v/v~
aqueous solution of acetic acid and the solution was
stirred a,t 55 to 60C. for one hour. The reaction mixture
was then extracted with ethyl acetate and the extract
was washed with water and an aqueous solution of sodium
chloride, dried over magnesium sulphate and concentrated
under reduced pressure to give 119 mg of the title
compound having the following physical characteristics:-
TLC (developing solvent, chloroform:tetrahydrofuran:
acetic acid = 10:2:1): Rf = 0.51;
IR:VL3400, 2940, 2850, 1750, 1730, 1660, 1440, 1280 cm 1
NMR: ~=7.10-6.75 (lH, m), 5.95-5.40 (3H, m), 3.71 (3H, s),
4.20-3.60 (2H, m), 2.75 tlH, dd), 1.00-0.75 (9H, m).
