Note: Descriptions are shown in the official language in which they were submitted.
a~
The present invention relates to 2-oxa-bicyclic
prostaglandins, to a method for their preparation and to pharmaceu-
tical and veterinary compositions containing them.
The compounds of the invention are 2-oxa-bicyclic
prostaglandins of formula (I)
~1
H sCH-(CH2) -R
~CH2
D G
(I)
~10 A ¦
\11 1~ I
~ ~ ~3
Rl Y - ~5- (CH2)n - ~ - X ~ (CH2)n2 R6
R5 R4
wherein R is a member selected from the group consisting of
/OR'
(a) a free or esterified carboxy group; (b) -C-OR' , wherein each
OR'
of the R' groups, which are the same or different, is Cl-C6 alkyl
/ Ra
or phenyl; (c) -CH20H; (d) -CON \ , wherein Ra and Rb are
independently selected from -the group consisting of hydrogen,
CL-C6 alkyl, C2-C6 alkanoyl and phenyl; (e) a radical
N - N
\ ¦~ ; (f) -C-N; Zl is hydrogen or halogen; p is zero or
NH - N
an in-tege:r of 1 to 7; R1 is hydrogen, hydroxy, Cl-C6 alkoxy, ar-
CL-C6-alkoxy, acyloxy; Y is amember seLected from the group con-
g . 2C~12 , C--C-, ~ C=C \ (cis) and / C=C
83193~il
(trans), wherein Z2 is hydrogen or halogen; one oE R2 and R5 is
hydrogen, Cl-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or aryl, and
the other is hydroxy, C~-C6 alkoxy, ar-Cl-C6-alkoxy or R2 and R5,
taken together, form an oxo group; each of R3 and R4, which are
-the same or different, may be hydroyen, Cl-C6 alkyl or fluorine
or R3 and R4, taken together with the carbon atom -to which -they
are linked, form the radical - C - or the :radical / C - ; each
CH2 CH2 - CH
of nl and n2, which are the same or different, is zero or an
integer of 1 to 6; X is a member selected from the group consist-
ing of -O-, -S- and -(CH2)m~, wherein m is zero or 1; R6 is a
member selected from the group consis-ting of
(a') a C3~Cg cycloaliphatic radical, unsubstituted
or substituted by one or more substituents selected from the group
consisting of Cl-C6 alkyl and Cl-C6 alkoxy;
(b') a saturated or unsaturated heterocyclic ring,
unsubstituted or substituted by one or more substituents selected
from the group consisting of halogen, halo-Cl-C6-alkyl, Cl-C6
alkyl and Cl-C6 alkoxy; provided that when X is -O- or -S-, R6
is not cycloalkyl.
Also the pharmaceutically or veterinarily acceptable
salts as well as the optical antipodes, i.e. -the enantiomers, the
racemic mixtures of the optical antipodes, the geometric isomers
and -their mixtures and the m:ix-tures of the dias-tereoisomers of
the compounds of formula (I) are included in the scope oE the
present invention.
:[n -the :Eormulae of -this specifica-tion the broken line
tllll ) ind:ica-tes tha-t a subs-ti-tuen-t bound -to -the cyclopen-tane
- 2 -
`s~
ring is in the ~--configuratiorl, i.e. below the plane of -the ring,
a substituent bound to the 2-oxa-bicyelic system is in the endo-
eonfiguration and a substituent bound to a chain is in the S-
configuration; the heavy solid line (~) indicates that a sub-
stituent bound to the cyclopentane ring is in the ~-configuration,
i.e. above the plane of the ring, a substituent bound to the 2-
oxa-bicyclic system is in the exo-configuration and a substituent
bound to a chain is in the R-configuration; the wavy line attach-
ment (~) indicates that a substituent does not possess a definite
stereochemical identity, i.e. that a substituent bound to the
cyclopentane ring may be both in the ~- and in the ~-configuration,
a substituent bound to the 2-oxa-bicyclic system may be both in
the endo- or in -the exo-configuration and a substituent bound to
a chain may be both in the S- and in the R-configuration.
In the compounds of the above formula (I) the hetero-
eyclie ring B is cis-fused with the cyclopentane ring A and the
two bonds indieated by the dotted lines (....) are both in the
~-eonfiguration with respeet to the ring A.
The side chain ~-linked to the eyclopentane ring A is
in trans-configuration with respect to the ~-fused heterocyelic
ring B and eonsequently it is an exo subs-tituent with respect to
the 2-oxa-bicyclie system.
The earbon a-tom of the heteroeyelie ring B bearing the
~ .'1
side ehain ~ CH-(CH2)p-R bears also an hydrogen atom.
~1
When -the side ehain ~CH-(CH2)p-R is in the endo-
eon~igurat:ion with respeet to the 2-oxa-bieyelie system, then said
~r~
c ~j ~
hydrogen atom is an exo-substituen-t and its absolute configuration
~ 1
is reported as ~ while when the chain ~ CH-(CH2)p-R is in the
exo-configurations, then said hydrogen atom is an endo-substituent
and its absolute configuration is reported as ~.
The compounds of the invention wherein -the chain
~ ; 1
vW~CH-(CH2)p-R i.s in the exo-configuration, the hydrogen atom
linked to the same carbon atom of the ring B having necessarily
the ~-absolute configuration, are reported as 6~H-6,9~-oxide
prostanoic acid derivatives (prostaglandin numbering), while the
~,1
10 compounds wherein the chain ~CH-(CH2)p-R is in the endo-config-
uration, the hydrogen atom linked to the same carbon atom of the
ring B having necessarily the ~-absolute configuration, are
reported as 6~H-6,9~-oxide prostanoic acid derivatives (prostaglan-
din numbering). Alternatively the 6~H-6,9~-oxide prostanoic acid
derivatives are reported as (2'-oxa-bicyclo[3.3.0]octan-3'-exo-
yl)-alkanoic acid derivatives and the 6~H-6,9~-oxide prostanoic
acid derivatives as (2'-oxa-bicyclo[3.3O0]octan-3'-endo-yl~-
alkanoic acid derivatives. The 6~H-6,9~-oxide prostanoic acid
derivatives have a higher chromatographic mobility (i.e. a higher
Rf) and a less positive rotatory power ([~]D) -than the correspond-
ing 6~H-6,9~-oxide derivatives.
All the above notations refer to the natural compounds;
the d,l-compounds are mixtures containing equimolar amounts of
nat-compounds which possess the above repor-ted absolute stereo-
chemistry and o~ ent--compounds which are mirror-like images of
331~
the Eormers; in the en-t-compounds the stereochemical configuration
is the opposite at all the asymmetric centers with respect to the
configuration of the natural compounds and -the prefix ent indicates
just this.
The alkyl, alkenyl, alkynyl, alkoxy, and alkanoyloxy
groups are branched or straight chain groups.
Preferably R is a free, salified or esterified carboxy
group. An ar~C1-C6-alkoxy group :is preferably benzyloxy. An aryl
group is preferably phenyl, ~-naphthyl or ~-naphthyl. A halo-
Cl-C6-alkyl group is preferably trihalo-Cl-C6-alkyl, in particular
trifluoromethyl. A Cl-C6 alkyl group is preferably methyl, ethyl
or propyl. A Cl-C6 alkoxy group is preferably methoxy, ethoxy
or propoxy. A C2-C6 alkenyl radical is preferably vinyl. A
C2-C6 alkynyl radical is preferably ethynyl.
When R is an esterified carboxy group it is preferably
a -COORC group wherein Rc is a Cl-C12 alkyl radical, in particular
methyl, ethyl, propyl or heptyl, or a C2-C12 alkenyl radical, in
particulax allyl.
Preferably Zl is hydrogen.
When Zl is halogen, it is preferably chlorine, bromine
or iodine.
Preferably p is an integer of 1 to 3.
When Rl is acyloxy, it is preferably C2-C12 alkanoyloxy
(in par-ticular C2-C6 alkanoyloxy, e.g., acetoxy, propionyloxy) or
benzoyloxy~
When Z2 is halogen, it is preferably chlorine, bromine
or iodine.
Preferably R3 and R4 are independently selected from
- 5 -
.B~g
the group consisting of hydrogen, Cl-C6 alkyl and Eluorine~
Preferably nl is zero or an integer of 1 to 3; n2 is
preferably an integer of 1 to 3.
When R6 is a C3-Cg cycloaliphatic radical/ it is
preferably a C3-Cg cycloalkyl radical, e.g. cyclopentyl, cyclo-
hexyl or cycloheptyl or a C3-Cg cycloalkenyl radical, e.g. cyclo-
pentenyl, cyclohexenyl or eycloheptenyl.
When R6 is a heterocyclic ring, it may be either a
heteromonocyclic ring or a heterobieyclic ring and contains at
least one heteroatom selected from the group consisting of N, S
and O.
Examples of preferred heteromcnocyclic radicals are
tetrahydrofuryl, tetrahydropyranyl, pyrrolyl, pyrazolyl, oxazolyl,
isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl and 2'-
tetrahydrothienyl.
Exanmples of preferred heterobicyclic radicals are 2-
oxa-bieyelo[3.3.0]oetyl, 2-oxa-bieyelo[3.4.0]nonyl~ 2-thia-bieyelo-
[3.3.0]oetyl, 2-thiabicyelo[3.4.0]nonyl and their aromatie analogs.
Pharmaeeutieally or veterinarily aeeeptable salts of
the eompounds of formula (I) are e.g. those with pharmaeeutieally
and veterinarily aeeeptable bases.
Pharmaeeutieally and veterinarily aeeeptable bases are
either inorganie bases sueh as, for example, alkaline hydroxides
and alkaline-earth hydroxides as well as alurninium and zine
hydroxides or organie bases e.g. organie amines sueh as, for
example, methylamine, dimethylamine, trimethylamine, ethylamine,
dibutylamine, N-methyl-N-hexylamine, deeylamine, dodecylamine,
allyLam:i.ne cyelopentylamine, eyclohexylamine, benzylamine, dibenzyl-
~b
t ~ - 6 -
amine, ~-phenyl-ethylamine, ~-phenyl-ethylamine, ethylenediamine,
diethylenetriamine, morpholine, piperidine, pyrrolidine, piperazine,
as well as the alkyl derivatives of a latter four bases, mono-,
di- and tri-ethanolamine, ethyl-diethanolamine, N-methyl-ethanol-
amine, 2-amino-1-butanol, 2-amino 2--methyl-1-propanol, N-phenyl-
ethanolamine, galactamine, N methyl-glucamine, N-methyl-glucosamine,
ephedrine, procaine,j:dehydroabietilamine, lysine, arginine and
other ~ or ~ amino acid~s;,~:
Preferred salts of the invention are those of the com-
pounds of forrnula (I) wherein R is -COORd wherein Rd is a pharm-
aceutically or veterinarily acceptable cation deriving from one
of the above mentioned bases.
Particularly preferred compounds of -the invention are
6~H-6,9~-oxide compounds of formula (I) wherein R is a free
carboxy group and R6 is C5-C7 cycloalkyl.
The prefixes nor, dinor, trinor, tetranor- etc., are
used to identify the compounds of formula (I) wherein the side
chain bound to the cyclopentane ring A is one, two, three, four,
etc. carbon atoms shorter than the analogous chain in the natural
prostaglandins.
Specific examples of preferred compounds of the invention
are the following:
13t-6~H-6,9~ oxide-11~,15S-dihydroxy-16(S,R)-fluoro-17-cyclohexyl--
20,19,18-trinor-prost-13-enoic acid and the single 16(S)- and
16(R)-fluoro isomer;
13t--6~1--6,9~-ox.ide-11~,15S-dihydroxy-17-cyclohexyl-20,19,18-trinor-
prosk-13-enoic acid;
13-6~-6,9~-oxide-11~,15S-dihydroxy-17-cyclohexyl-20,19,18-trinor-
~1 ''`'
ALJt 7
prost-13-ynoic acid;
13t-6~H-6,9~-oxide-11~,15S-dihydroxy-17-(2'-tetrahydrofuryl)-20,
19,18-trinor-prost-13-enoic acid;
13t-6~H-6,9~-oxide-11~,15S-dihydroxy-17-(2'-tetrahydrothienyl)-
20,19,18 -trinor-prost ~3-enoic acld;
as well as the 5-bromo, thë` 5 1odo, the 5-chloro analogs of all
the 6~H-6,9~-oxide derivatives above listed, as well as the 15R-
epimers, the 15-oxo-derivatives and the 6~H-diastereo-isomers of
all the compounds mentioned above.
The compounds of the inven-tion are prepared by a process
comprising:
(a) halocyclizing a compound of formula (II)
O~ CH2-D-(CH2)p-R
(II)
~ ~ ~ R~2 ~3
R'l Y - C - (CH2)n - ~ - X ~ (CH2)n2 6
'5 R4
wherein p, Y, nl, n2, R3, R4, X and R6 are as defined above, D
is cis- or trans- -CH=CH-, R" is (a") a free or esterified carboxy
/OR'
group; (b") a group -C-OR' , wherein each of the R' groups is
OR'
as defined above (c") the group -CH2-R7, wherein R7 is hydroxy
or a ~nown protecting group bound to the -CH2- group by an
/Ra
ethereal oxygen atom; (d") -CON ~ wherein Ra and Rb are as
- 8 -
't ~
N N
defined above; (e"~ a radicaLi of~f~r.~la -C ¦¦ ; ( f~) -C-N;
NH - N
R'l is hydroyen, hydroxy, C1-C6 alkoxy, ar-C1-C6-alkoxy, acyloxy
or a known protecting group bound to the ring by an ethereal
oxygen atom; one of R'2 and R'5 is hydrogen, Cl-C6 alkyl, C2-C6
alkenyl, C2-C6 alkynyl or aryl and the other is hydroxy, Cl-C6
alkoxy, ar~-Cl-C6-alkoxy or a known protecting group bound -to the
chain by an ethereal oxygen atom, or R'2 and R'5, taken toge-ther,
form an oxo group, so obtaining, after the removal of the known
protecting groups, if present, a compound of formula (I) wherein
Zl is halogen and, if necessary, deetherifying and/or, if desired,
dehalogenating the obtained compound to give a compound of formula
(I) wherein Zl is hydrogen; or
(b) reducing a compound of formula (III)
H ~CH-(CH2)p~R
~,
O CH2
~ B c
r ~t
(III)
~ 3
Rl Y - C ~ (CH2)n ~ C~ - X (CH2)n2 6
R5 R~
wherein Q is halogen or a group ~ Hg( )Z( ), wherein Z( ) is
0~1( ) or the anionic residue o:E an acid, R, p, Rl, Y, R2, R5, R3,
R~l, nL, n2, ~ and R6 are as defined above, so obtaining a compound
_ g_
~$113~
...,. ~ . . ,
of formula (I) wherein Zl is hydrogen; and, if desired, reducing
a compound of formula (I) wherein R2 and R5, taken together, form
an oxo group and Y is -CH=CZ2- wherein Z2 is as defined above,
to give a compound of for~mula.(I) wherein one of R2 and R5 is
hydrogen and the other.is hydro~y and Y is -CH=CZ2-, wherein Z2
is as defined above, or, if desired, converting a compound of
formula (I) wherein R2 and R5, taken together, form an oxo group
and Y is -CH=CZ2- wherein Z2 is as defined above, into a compound
of formula (I) wheréin one of R2 and R5 is hydroxy and the other
is Cl-C6 alkyl, C2-C6 alkenyl, C2~C6 alkynyl or aryl and, if
desired, etherifying a compound of formula (I) wherein one of R2
and R5 is hydroxy and the other is hydrogen, Cl-C6 alkyl, C2-C6
alkenyl, C2-C6 alkynyl or aryl and Y is -CH=CZ2- wherein Z2 is
as defined above, to give a compound of formula (I) wherein one
of R2 and R5 is Cl-C6 alkoxy or ar-Cl-C6-alkoxy and the o-ther is
hydrogen, Cl-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or aryl and
Y is -CH=CZ2- wherein Z2 is as defined above, and/or, if desired,
hydrogenating a compound of formula (I) wherein Y is -CH=CZ2-
wherein Z2 is hydrogen, to give a compound of formula (I) wherein
Y is -CH2CEI2- or, if desired, dehydrohalogenating a compound of
formula (I) wherein Zl is hydrogen and Y is -CH=CZ2- wherein Z2
is halogen,
~,q ~
,~ !i - 1 0
~,~,.8 ~e,~ ,
_ .
to give a compound of formula ~I~ wherein Y is -C~C- and Zl is hydrogen or~
if desired, hydrogenating a compound of formula (I) wherein R2 and R5~ taken
together, form an oxo group and Y is -CH=CZ2- wherein Z2 is hydrogen~ to give
a compound of formula ~I) wherein R2 and R5, taken together, form an oxo
group and Y is -CH2Cll2- or, i desired, dehydrohalogenating a compound of
formula ~I) wherein Zl is hydrogen, R2 and R~, taken together, form an oxo
group, and Y is -CH=CZ2- wherein Z2 is halogen, to give a compound of formula
(I~ wherein Zl is hydrogen, R2 and R5, taken together, form an oxo group and
Y is -C-C- and, if desired, reducing a compound of formula ~I) wherein R2 and
R5, taken together, form an oxo group, to give a compound of formula ~I)
wherein one of R2 and R5 is hydrogen and the other is hydroxy, or, if desired,
converting a compound of formula ~I) wherein R2 and R5, taken toge-ther, form
an oxo group, into a compound of formula ~I) wherein one of R2 and R5 is
hydroxy and ~he other is Cl-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or aryl
and, if desired, etherifying a compound of formula ~I) wherein one of R2 and
R5 is hydroxy and the other is hydrogen, Cl-C6 alkyl, C2-C6 alXenyl, C2-C6
alkynyl or ary~l, to give a compound of formula ~I) wherein one of R2 and R5
is Cl-C6 alkoxy or ar-Cl-C6~alkoxy and the other is hydrogen, Cl-C6 alkyl,
C2-C6 alkenyl, C -C alkynyl or aryl;
and/or, if desired, converting a compound of formula ~I) into another compound
o$ ~ormula (I) and/or, i~ desired, salifying a compound of formula ~I) and/orS
i$ desired, obtaining a $ree compound of formula (I) from a salt thereof
and~or, i$ desired, separating a mixture of isomers into the single isomers.
In the optional steps o$ the above processes when only one or a few
substituents are specifically mentioned for a compound, it is understood that
the other substituents have all the meanings previously indicated for formu-
la ~
r~ ~
3~
The knohn protecting groups, i.e., ether groups, are convertible to
hydroxy groups under mild reaction conditions, e.g., acid hydrolysis.
Examples are acetal ethers, enol ethers and silyl ethers.
The preferred groups are
~CH3)3-SiO- , ~ OAlk
~ O- , O ~ , ~ Si-O-
wherein
W is -O- or -CH~- and Alk is a lower alkyl group.
When in the compound of formula ~III) Q represents a group
~Hg~ )Z~ ), wherein zt ) is the anionic residue of an acid, Z( ) is preferab-
ly selected ~rom the group consisting of Cl( ), Br( ), I( ), Rg-COO~ ),
wherein R8 is an optionally halo-substituted Cl-C12 alkyl group (preferably
Cl-C6 alkyl or trifluoromethyl) and Rg~ COO( ), wherein R9 is e.g.,
hydrogen, Cl-C6 alkyl, halogen, e.g., bromine, or trifluoromethyl.
Preferably Z~ ) is Cl~ ), Br~ ), CH3COO( ), ~F3COO( ) or
~ COO~~),
The halocycli~ation of a compound o~ ~ormula (II) may be performed
by reaction with either a stoichiometric amount or a small excess of a halogen-
ating agent in an inert solvent, in either the presence or in absence o a
base.
PreEer~ed halogenating agents, are, e.g., iodine, bromine~ chlorine,
62
~3 ~
3i3~9`
bromodioxane, bromopyridine, Br2.pyridine.HBr, KI3, pyrrolidone-hydrotribro-
mide, an N-haloamide such as N-chloro-succinimide, N-bromo-succinimide, N-
iodo-succinimide, a cupric halide such as CuC12 or CuBr2, a mixed halide such
as ICI or IBr, as well as a mixture of an alkaline chloride wi~h an alkaline
chlorate, a mixture of an alkaline hromide with an alkaline bromate or a mix-
ture of an alkaline iodide with an alkaline bromate.
Suitable solvents are, for example, halogenated hydrocarbons such as
CHC13, CCl~, CH2C12; aliphatic hydrocarbons such as n-hexane, n-heptane, cyc-
loaliphatic hydrocarbons such as cyclohexane; aromatic hydrocarbons such as
benzene, toluene, pyridine, cyclic or linear ethers, e.g., dioxane, tetrahydro-
furan, diethylether, climethoxyethane; as well as mixtures thereof.
Preferred solvents are halogenated hydrocarbons, e.g. CH2C12, since
both the compound of formula ~II) and the halogenating agent are usually solu-
hle in these solvents.
A stoichiometric amount of a base is necessary when a hydrohalic
acid is formed during the halocyclization reaction.
Such a base may be an inorganic base, e.g., an alkaline or an
alkaline-earth oxide, carbonate or bicarbonate, e.g., CaO, CaCO3 and K2CO3,
NaHCO3, Na2CO3; an organic base such as a tertiary amine, e.g., triethylamine;
or an aromatic base, e.g., pyridine or an alkyl-substituted pyridine; or an
anionic ion-exchange resin.
The halocyclization reaction is preferably carried out at tempera-
tures ranging from about -70C to about 100C; preferably the reaction is
performed at room temperature.
The reaction times range from few minutes to several days, but usu-
ally do not exceed two hours and often a few minutes are sufficient to com-
plete the reaction.
~Yhen other unsaturated bonds are present in the compound of formula
~CI) hesides the double bond contained in the substituent D, those ~msaturatPd
/3
-
bonds may add halogen during the halocyclization reaction.
The added halogen may be easily removed to reobtain
-the original unsaturations, by trea-ting the reaction product with
an alkaline or alkaline-earth iodide in a suitable solvent such
as, eOg., acetone at temperatures ranging from room temperature
to reflux temperature but preferably at room temperature. Reac-tion
time may range from about 2 to 3 hours to about 2 to 3 days.
The removal of the known protecting groups bound to
the ring or to the chain by an ethereal oxygen atom is, whenever
required, performed under conditions of mild acid hydrolysis, for
example with a mono- or poly-carboxylic acid such as formic, acetic,
oxalic, citric and tartaric acid, and in a solvent, which may be
water, acetone, tetrahydrofuran, dimethoxyethane or a lower
aliphatic alcohol, or with a sulphonic acid, e.g., p-toluenesul-
phonic acid in a solvent such as a lower aliphatic alcohol, dry
methanol or dry ethanol, for example, or with a polystyrene-
sulphonic resin.
For example, 0.1 to 0~25 N poly-carboxylic acid (e.g.,
oxalic or citric acid) is used in the presence of a convenient
low-boiling co-solvent which is miscible with water and which can
be easilyremoved ln vacuo at the end of the reaction.
All the cyclization reactions described in this specifi-
cation such as e.g. the hereabove described halocyclization of
a compound of formula (II) -to give a compound of formula (I) where-
in Zl is halogen and the herebelow described cyclization of a com-
pound oE formula (II) to give a compound of formula (III) wherein
Q is .~Hg( )Z( ) a~e i.dentical reactions as to -their mechanism
and the number of the isomers contained in -the reaction mixture
is the same for all the above cyclizations. Thus ~or example the
above halocyclization reaction of a compound of formula (II) can
give to a mixture of four components, i.e. compounds of formula
(I) wherein Zl is halogen, consisting in a couple of diastereo-
isomers having the side chain v~ ~CH-(CH2)p-R in the exo-configura-
tion and differing each other for the S or R configuration of thehalogen Zl and a couple of diastereoisomers having the side chain
V~ H-(CH2)p~R in the endo-configuration and differing each o-ther
for the S or R configuration of the halogen Zl
While the chromatographic mobility (Rf) of the endo-
isomer is clearly different from the chromatographic mobility oE
the exo-isomer, the difference of Rf between two endo- (or exo-)
isomers differing each other only for the S or R configuration
of the Zl substituent, is very small.
The couple of diastereoisomers wherein the chain
CH-(CH2)p-R is in the exo-configuration may be separated from
Zl
the couple of diastereoisomers wherein said chain is in the endo-
configuration by fractional crystallization e.g. from diethylether,
but preferably by thin layer preparative chromatography, by column
chromatography or by high speed liquid chromatography.
The separation by thin layer preparative chromatography
or by column chromatography is preferably carried out on a support
oE silica gel or magnesium silicate with methylene chloride, di-
ethylether, lsopropylether, ethylacetate, benzene, me-thyl acetate,
cyclohexane or their mixtures as elution so]ven-ts.
.~ - 15 -
The reductive dehalogenation of a compound of formula
(I) wherein Zl is halogen, to give a compound of formula (I)
wherein Zl is hydrogen, is performed by reduction, e.g., with
chromous acetate or a hydride such as tri(n-butyl)tin hydricle,
or by catalytic hydrogenation.
When it is desired -to obtain a compound of formula (I)
wherein Y is -C~C- or CH=CZ2- wherein Z2 is as defined above, the
dehalogenation is carried out only by reduction, e.g. with tri(n-
butyl)tin hydride or chromous
- 16 -
.. 1~
acetate.
W~en it is desired to obtain a compound of formula (I) wherein R2
and R5 ta~en together form an oxo group, by the dehalogenation of the compound
of formula (I) wherein Zl is halogen, the :reaction time should not exceed half
an hour.
When the reductive dehalogena-ion is carried out with chromous ace-
tate, this reagent is added, with stirring, to a cooled solution of the com-
pound of formula ~I) wherein Zl is halogen, in a mixture of ethanol and aque-
ous sodium or potassium hydroxide under an atmosphere of nitrogen. The re-
action mixture is then stirred one to three days at room temperature, accord-
ing to the method described in J. Am. Chem. Soc. 76, 5499 (1954).
~hen the dehalogenation is carried out with tri(n-butyl)tin hydride,
about 1.2 equivalents of the reducing agent are used for each equivalent of
t~e compound of formula ~I) wherein Zl is halogen. Suitable solvents for the
reaction are aromatic hydrocarbons such as benzene or toluene and the tempera-
tures preferably are between room temperature and about 70 C.
Preferably the reaction is carried out at about 55C in benzene and
lasts about 12 hours.
The catalytic hydrogenation of a compound of formula ~I) wherein Z
is halogen to give a compound of formula ~I) wherein Zl is hydrogen and Y is
-CH2CH2- may be performed either at room temperature or by heating this com-
pound, e.g., at 30 - 60C either at atmospheric pressure or under pressure,
e.g., at 1.1 - 2 atm. in a solvent such as, e.g., a lower aliphatic alcohol,
tetrahydrofuran, dioxane, benzene, toluene in the presence of a catalyst such
as palladium or platinum on charcoal or CaC03 and optionally in the presence
of an ammonium salt, e g., ammonium acetate or propionate.
The reductive dehalogenation converts a compo~md of formula ~I)
wherein Zl is halogen into a compound of formula ~I) wherein Zl is hydrogen
- ~,87/
`\
and thereore during the dehalogenation the carbon atom carrying the Zl sub-
stituent loses its asymmetry.
The number of the possible diastereoisomers consequently contained
in the dehalogenation reaction mixture is lower than the number of diastereo-
isomers contained in the halocyclization reaction mixture.
When the reductive dehalogenation is carried out directly on the
mixture of four diastereoisomers obtained from the halocyclization process J
a mixture of two only diastereoisomers of formula ~I) wherein Zl is hydrogen
is obtainad, differing each other for the exo- or endo-configuration of the
side chain ~CH2-(CH2)p-R.
~ hen the reductive dehalogenation is carried out on a single couple
of diastereoisomers of formula ~I) having the side chain ~CH-(CH2) -R,
wherein Zl is halogen, in the exo- or in the endo-configuration and differing
each other for the S or R configuration of Zl~ then only one isomer of formu-
la (I) wherein Zl is hydrogen is obtained wherein the side chain
W--CH2-~CH2) -R is in the exo- or in the endo-configuration.
If a mixture of the above diastereoisomers is obtained the single
diastereoisomers may be easily separated by fractional crystalli~ation or by
column chromatography as described above for the separation of the diastereo-
isomers wherein Zl is halogen.
The reduction of the compound of formula ~III) may be carried outby treatment with mixed hydrides such as alkaline, e.g., sodium, potassium or
lithium, borohydrides, with alkaline-earth, e.g., calcium or magnesium, boro-
hydrides in an inert solvent, preferably a solvent miscible ~ith water, such
as tetrahydrofuran, dimethoxyethane or lower aliphatic alcohols, e.g. methanol
or ethanol; or with tri(n-butyl)tin hydride in benzene or toluene, preferably
benzen0; o~ also by treatment with hydrazine hydrate in a lower aliphatic
~:3 ~
alcohol, e.g., methanol or ethanol as solvent, at temperatures
varying from room temperature to the reflux temperature of the
solvent used.
When it is desired to obtain compounds of formula (I)
wherein Zl is hydrogen and R2 and R5 taken together form an oxo
group, the reduction of the compound of formula (III) is preferably
carried out with tri(n-butyl)tin hydride for a short reaction
time, preferably a time varying from about 5 minutes to about half
an hour.
During the above reduction of a compound of formula
(III) the carbon atom carrying the Q substituent loses its
asymmetry and therefore the number of the possible diastereoisomers
contained in the reaction mixture at the end of the reduction pro-
cess is half the number of the diastereoisomers contained in the
starting material, analogously to what above reported with regards
to dehalogenation of a compound of formula (I) wherein Zl is
halogen.
The compound of formula (I) wherein Y is trans-CH=CZ2-
wherein Z2 is as defined above, may be separated from the mixture
by crystallization with a suitable solvent, while the compound
of formula (I) wherein Y is cis-CH=CZ2- wherein Z2 is as defined
above, may be obtained by concentration of the mother liquor and
subsequent chromatographic separation of the residue, either by
column or preparative TLC chromatography using silica gel or mag-
nesium silicate as support and e.g. methylene chloride, diethyl-
ether, isopropylether, ethylacetate, benzene, cyclohexane or their
mixtures as elution solvents.
The removal of the protecting groups, if present, may
- 19 _
1.. ~1
be performed by mild acid hydrolysis as described above for the
compounds obtained by the halocyclization and the reduction pro-
cesses.
~ ither the optional reduction of a compound of formula
(I) wherein R2 and R5, taken together form an oxo group, and Y
is -CH=CZ2-, wherein Z2 is as defined above, to give a compound
of formula (I) wherein Y is -CH=CZ2-, wherein 22 is as defined
above and wherei.n one of R2 and R5 is hydrogen and the other is
hydroxy or the optional conversion of a compound of formula (I)
wherein R2 and R5, taken together, form an oxo group and Y is
-CH=CZ2- wherein Z2 is as defined above, into a compound of
formula (I) wherein Y is
~''''`)
7 - 20 -
-C~=CZ2-, wherein Z2 is as defined above, and wherein one of R2 and R5 is
hydroxy and the other is Cl-C6 alkyl, C2-C6 alkenyl, C2--C6 alkynyl or aryl
must be regarded as different applications of one only reaction which is a
1.2 polar addition to the carbonyl group.
The optional reductlon of an obtained compound of formula ~I) where-
in R2 and R5 taken together form an oxo group, and Y is -CH=CZ2-, wheEein Z2
is as defined above, to give ~ compound of formula (I) wherein Y is -CH=CZ2-,
wherein Z2 is as defined above, and wherein one of R2 and R5 is hydrogen and
the other is hydroxy, is preferably carried ou~ with alkaline or alkaline-
earth metal borohydrides, preferably sodium, lithium, calcium, magnesium or
zinc borohydride, using ~rom 0.5 to 6 moles of the reducing agent for each
mole of the compound of formula (I). The reduction may be performed either
in aqueous or anhydrous inert solvents such as linear or cyclic ethers, e.g.,
ethyl ether, tetrahydrofuran, dimethoxyethane, dioxane or aliphatic or aromatic
hydrocarbons, e.g., n-heptane or benzene, or halogenated hydrocarbons, e.g.
methylene dichloride, or hydroxylated solvents, e.g., ethyl, methyl or iso-
propyl alcohol, or mixturcs of these solvents.
The reac~ion temperature may vary between approximately -40C and
the boiling point of the solvent used, but the preferred temperature ranges
from about ~20C to about 25C.
OH
This reduction leads to a mixture of the two epimeric S ~-C-~ )
~ OH
and R ~-C-" ) alcohols from which the single epimers can be separated,
if desired, by ~ractional cr~rstallization, e.g. with diethylether, n-hexane,
n-heptane, cyclohexane but preferably by chromatography either on silica gel
or magnesium silicate columns or preparative TLC chromatography with, for
example, silica gel, eluting, e.g., ~ith CH2C12, ethyl ether, isopropyl ether,
ethyl acetate, methyl acetate, benzene, cyclohexane or mix-tures of these, or
by high specd liquid chromatography.
The optional conversion of a compound of formula (I) wherein R2 and
R5 taken together form an oxo group and Y is -CH=CZ~-, wherein Z2 is as de-
-fined above, into a compo~ld of formula ~I) wherein one of R2 and R5 is hy-
droxy and the other is Cl-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or aryl and
Y is -CH=CZ2- wherein Z2 is as defined above, may be carried out by treatment
with a Grignard reagent of formula R"'-Mgllal, wherein Hal is halogen, prefer-
ably bromine or iodine and R" ' is Cl-C6 alkyl, C2-C6 alkynyl, C2-C6 alkenyl
or aryl, preferably methyl, vinyl, ethynyl, phenyl.
The Grignard reaction is carried out with 1.05 to 2 moles of the
magnesium derivative for each mole of ketone, operating in anhydrous solvents
which may be linear or cyclic ethers, e.g., ethyl ether, tetrahydrofuran, di-
oxane, dimethoxyathane or aliphatic or aromatic hydrocarbons, e.g., n-heptane,
n-hexane, benzene, toluene, at temperatures varying from approximately -70C
to the boiling point of the solvent used. The preferred temperatures range
between -60 C and 10 C.
The optional etherification of a compound of formula ~I) wherein Y
is -CH=CZ2-, wherein Z2 is as defined above, and one of R2 and R5 is hydroxy
and the other is hydrogen, Cl-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or aryl
to give a compound of formula ~I) wherein Y is -CH=CZ2-, wherein Z2 is as de-
fined above, and one of R2 and R5 is Cl-C6 alkoxy or aralkoxy and the other is
hydrogen, Cl-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or aryl, may be carried
out, for example, by reaction with an optionally aryl-substituted diazoalkane
in the presence of a catalyst such as fluoboric acidor borontri1uoride and in
an organic solvent such as dichloromethane or by reaction of the free or sali-
fied hydroxy group with an a]kyl or aralkyl halide in presence of a base such
as silver oxide and in a solvent such as dlmethylsulphoxide or dimethylform-
amide.
The optional hydrogenation of a compound of formula (I) wherein Y is
-Cl[=CZ2-, wherein Z2 is hydrogen, to give a compound of formula (I) wherein Y
..~
~3~
is -CH2-CH2- is carried out, e.g., catalytically, preferably in an alcoholic
solvent, in the presence of platinum or palladium on charcoal as catalyst at
temperatures varying from about -40C to the reflux temperature of the solvent.
When it is desired to obtain co~pounds of formula (I) wherein Zl is
halogen and Y is CH2-CH2- the hydrogenation is preferably carried out at tem-
peratures ranging from about -40C to about -20C.
The optional dehydrohalogenation of a compound of formula (I) where-
in Zl is hydrogen, and Y is -CH=CZ2-, whercin Z2 is halogen, so as to obtain
the corresponding compounds of formula (I) wherein Zl is hydrogen and Y is
-C-C-J may be carried out using a dehydrohalogenatiilg agent preferably selected
from the group consisting of a dimethylsulfinylcarbanion of formula CH3SOCH2( ),
diazabicycloundecene, diazabicyclononene, the amide or the alkoxide of an
alkaline metal. From 1 to 5, and preferably from 1.5 to 1.8, molar equivalents
of the basic dehydrohalogenating agent may be employed for each mole of the
compound of formula (I) wherein Y is -CH=CZ2-, wherein Z2 is halogen.
This dehydrohalogenation process is preferably carried out in the
absence of atmospheric oxygen, in an inert solvent such as dimethylsulphox~de,
dimethylformamide, hexamethylphosphoramide; a linear or cyclic ether, e.g.,
dimethoxyethane, tetrahydrofuran, dioxane; an aromatic hydrocarbon, e.g.,
benzeneJ toluene; or liquid ammonia or a mixture of these solvents.
The reaction temperature may vary between the liquefaction point of
the ammonia and approximately 100C, but the preferred temperature is room
temperature.
Depending on the solvent, the reaction temperature and the molar
ratio used between the reagent and the compound, the reaction time may vary
from a ew minutes to several hours.
Thc optional reduction of a compound oE formula (I) wherein R2 and
R5 taken together forrn an oxo group and Y is -CH2-CH2- or -C_C- to give a
colllpound Oe formula (I) wherein one of R2 and R5 is hydrogen and the other is
~L8~
hydroxy and Y is -C112-C~12- or -C-C- may be carried out as described above for
the analogous reduction of a compound of formula (I) wherein R2 and R5 taken
~ogether form an oxo group and Y is -CH-CZ2-, wherein Z2 is as defined above.
The optional conversion of a compound of formula (I) wherein R2 and
R5 taken together form an oxo group and Y is -CH2-CH2 or -C-C- into a compound
of formula (I) wherein one of R2 and R5 is hydroxy and the other is Cl-C6
alkyl, C2-C6 alkenyl, C2-C6 alkynyl or aryl may be effected under the same
reaction conditions described above for th~e analogous conversion of the com-
poun~s of formula (I) wherein Y is -CH=CZ2-, wherein Z2 is as defined above.
Also the optional etherification of a compound of formula ~I) where-
in one of R2 and R5 is hydroxy and the other is hydrogen or Cl-C6 alkyl, C2-C6
alkenyl, C2-C6 alkynyl or aryl and Y is -CH2-CH2- or -C_C- may be carried out as
described above for the etherification of a compound of formula (I) wherein one
of R2 and R5 is hydroxy and the other is hydrogen, Cl-C6 alkyl, C2-C6 alkenyl,
Cl-C6 alkynyl or aryl and Y is -CH=CZ2-, wherein Z2 is as defined above.
The optional conversion of a compound of formula (I) into another
compound of formula (I) as well as the salification of a compound of formula
~I) J the preparation of a ree compound from a salt and the separation of ~he
isomers from a mixture may be carried out by known methods.
Thus, for example, a compound of formula (I) wherein one of R2 and
R5 is hydrogen and the other is hydroxy may be converted into a compound of
formula (I) wherein R2 and R5 taken together form an oxo group by oxidation.
The oxidation mc~ be carried out by treatment with an excess of activated
manganese dioxide in an inert solvent preferably a halogenated inert solvent
such as dichloromethane or chloroform at room temperature for a reaction time
varying between several hours and one or more days.
~lternat:iveLy, the oxidation may be carried out by reaction with a
1.1 - 1.2 molar equivalent of dichlorodicyanobenzoquinone (DDQ) in an inert
solvellt such as dioxane, tetrahydrofuran, benzene or a mixture of these at
1,~ o?~
temperatures ranging from about 40C to the boiling point of the solvent.
A compound of formula (I) wherein R i5 a free carboxy group may be converted
into a compound of formula (I) wherein R is an esterified carboxy group, e.g.,
a Cl-C12 carbalkoxy group) by known methods, e.g., by reaction with the appro-
priate alcohol, e.g., a Cl-C12 alipha~ic alcohol, in the presence of an acid
catalyst, e.g., p-toluenesulphonic acid and also by treatment with a diazo-
alkane.
The optional conversion of a compound of formula (I) wherein Rl is
hydroxy into a compound of formula (I) whe-rein Rl is acyloxy~ if desired, may
be performed in a conventional manner, e.g., by treatment with an anhydride or
a halide, such as a chloride of the appropriate carboxylic acid in the pres-
ence of a base.
When one o~ R2 and R5 is hydroxy, this hydroxy group may be protect-
ed before the acylation by one of the known protecting group mentioned above.
The optional conversion of a compound of formula (I) wherein R is an
esteriEied carboxy group into a compound of formula (I) wherein R is a free
carboxy group, if desired, may be carried out by the usual methods of saponi-
fication, e.g., by treatment with an alkaline or alkaline-earth hydroxide in
aqueous or alcoholic aqueous solution followed by acidification.
In a compound of formula (I) wherein R is an esterified carboxy and
Rl is acyloxy, the optional saponification may be carried out selectively with
respect to the esterified carboxy, if desired, by transesterification, i.e., by
reacting it in the same alcohol which esterifies the carboxy groups and in the
presence of a base such as an alkaline or alkaline-earth alkoxide or K2C03.
The optional conversion of a compound of formula (I) wherein Rl is
hydroxy into a compow~d o formula (I) wherein Rl is Cl-C6 alkoxy or aralkoxy,
iE dosired, may be carried out by the usual methods of the etherification, for
cxmnple as described above for the etherification of a compound of formula ~I)
wherein one o R2 and R5 is hydroxy
! .L~
33~
When it is desired to etherify only one of several hydroxyl func-
tions present it is use~ul to protect before the etherification the hydroxy
groups which it is desired to not etheriy, e.g., with the known protecting
groups above mentioned, then removing these at the end of the etherification
by the procedures already described above.
The optional conversion of a compound of formula ~I) wherein R is a
free or esterified carboxygroup into a compound of formula (I) wherein R is
-CH2-OH, if desired, may be carried out, e.g., by reducing the ester with
LiAlH4 in ethyl ether or tetrahydrofuran at reflux temperature.
The optional conversion of a compound of formula (I) wherein R is a
free carboxy group into a compound of formula (I) wherein R is -CO-N ~Ra ,
wherein Ra and Rb are as defined above, may be performed by treatment with an
amine of formula NHRaRb in the presence of a condensing agent, e.g., a carbodi-
imide such as dicyclohexylcarbodiimide, and the optional conversion of a com-
pound of formula (I) wherein R is an esterified carboxy into a compound of
formula (I) wherein R is -CON~ Ra may be effected by treatment with an amine
of formula NHRaRb in a suitable organic solvent at reflux temperature for
- 3 hours.
The optional conversion of a compound of formula (I) wherein R is
a free carboxy group into a compound of formula (I) wherein R is a radical
N - N
-C~ 11 , may be carried out by converting the carboxy group into the cor-
NH_ N
responding halide, preferably chloride, e.g., by reaction with thionyl chlo-
ride or oxaly~l chloride in dioxane or dichloroethane at reflux temperature,
then reacting the halide, e.g., with ammoniaJ to give the amide, dehydrating
the amide to nitrileJ e.g. J with p-toluenesulphonylchloride in pyridine at
~ppro~imately 90C ~ 100CJ and ~inally reacting the nitrile with sodium
o~
azide and ammonium chloride in dimethylformamide at a temperature varying
between the room temperature and 100C. But preferably the hereabove re-
por~ed conversions of the carboxy group into -CN or -C~ ~¦ are performed
~NH -N
on the starting materials i.e. for example on the compounds of formula
and (VI).
The optional salification of a compound of formula ~I) may be per-
formed in a conventional manner.
Also the optional separation of the optically active compounds from
a racemic mixture as well as the optional separation of the diastereoisomers
or of the geometrical isomers from their mixtures may be effected by conven-
tional methods.
The compounds of formula (II) are already known compounds and may
be prepared, e.g., as described by E.J. Corey et al, Ann. of New York Acad.
of Sciences, 180, 24 (1971), by J. Fried et al, J. Med. Chem. 16, 429 (1973),
G.L. Bundy et al, Amer. Chem. Soc. 94, 2124 (1972), by Gandolfi et al, Il Far-
mdoc Ed. Sc. 2 , 1125 (1972), in the United States Patent
Number 3,935,254, Derwent Farmdoc 20717 X, in the German Offenlegungsschrift
Number 26 11 788 (Derwent Farmdoc 61615X), in the German Offenlegungsschrift
Number 26 10 503 ~Derwent Farmdoc 59715X), in the German Offenlegungsschrift
2Q Number 26 27 ~22 (Derwent Farmdoc 85028X), in the United States Patent Number
3,706,789, in the United States Patent Number 3,728,382, in the United States
Patent Number 3,903,131, in the United States Patent Number 3,962,293, in the
llnited States Patent Number 3,969,380, Derwent Farmdoc 73279U, Derwent Farmdoc
31279T, in the Unite~ States Patent Number 3,890,372, in the United States
Number 3,636,120, in the United States Patent Number 3,883,513, in the United
States Patent No. 3,932,389, in the United States Patent Number 3,932,479,
Derwent ~armdoc 195941~, Derwent Farmdoc 54179U and in the British Patent Num-
~er 1,483,880.
~8~
The compound of formula (III) wherein Q is halogen may
be obtained by the same reaction described above for the synthesis
of the compound of formula (I) wherein Zl is halogen.
The compound of formula (III) wherein Q is a group
~ v~Hg( )Z( ) wherein Z( ) is as defined above may be prepared
by cyclizing a compound of formula (II) in the presence of a
source of Hg( ) ions.
Suitable sources of Hg( ) ions may be, e.g., either
compounds of formula Hg(z)2 or compounds of formula Hg(OH)Z.
The above cyclization may be performed, e.g., using
1.01 to 1.5, preferably 1.2, equivalents of the mercuric compound
for each mole of the compound of formula (II), in an organic solvent
miscible with water, e.g., tetrahydrofuran, methanol, ethanol or
in a mixture of the organic solvent and water.
The reaction temperature may vary between ~C and the
boiling point of the reaction mixture and the reaction time ranges
from about 5 minutes to about 2 hours. The cyclization gives a
mixture of four diastereoisomers of formula (III) differing from
each other for the configuration (endo or exo) of the side chain
linked to the heterocyclic ring B or for the configuration (S or
R) of the Q substituent.
The separation of the diastereoisomers from their mix-
ture, which may be carried out according to known methods, e.g.,
those already described above, may be efEected at -this point or,
iE deslred, aEter the reduction of the compound of formula (III).
The compounds of the invention can be used, in general,
Eor the same therapeuticindications as the natural prostaglandins
;n either h~man or veterinary medicine.
- 28 -
In particular, those having an acetylene bond in the
13,14-position instead of an ethylene and those with mono and di-
substituents such as methyl and fluorine groups have the advantages
of superior resistance to degradation by the 15-PG-dehydrogenase
enzymes, which quickly inactivate natural compounds, and, of a
more selective therapeutic action, as indicated below.
In order to obtain a preliminary biological profile,
i.e., to assess whether the compounds of the invention possess
PG-like or thromboxane (TXA2)- like or PGX-like activity, they
were at first tested by a superfusion cascade technique by the
method of Piper and Vane, Nature 2~3, 29 (1969).
In order to increase the sensitivity of the bioassay,
a mixture of antagonists [Gilmore et al. Nature 218, 1135 (1968)]
is added to the Krebs-Henseleit and indomethacin (4 ~g/ml) is also
added to prevent the endogenous biosynthesis of prostaglandins~
..~...~p
l~, - 29 -
Contraction of rat colon (RC), rat stomach strip (RSS) and bovine
coronary artery ~BCA)~ and relaxation of rabbit mesentery artery ~RbMA) are
assumed to represent prostaglandin-like activity. TXA2-like activity is in-
dicated when RbMA is contracted and must be confirmed by in vitro platelet
pro-aggregation activity, since PGF2 -like compounds also contract ~bMA, as
opposed to PGE. Finally, PGX-like activity is indicated by the relaxation of
BCA, and is confirmed by in vitro platelet anti-aggrega~ion activity.
Synthe~ic PGE2 and both the biosynthetic TXA2 ,md PGX are utilized
as standard compolmds.
They are active at a range of concentrations from 1 - 5 ~g/ml.
The compounds of the invention were dissolved in a few drops of
sthanol just before testing; the s~ock solution was prepared in 0.1 M tris-
buffer, pH 9.0, (1 mg/ml) and diluted with Krebs-Henseleit to the required
concentration.
The compound 13-trans-11~,15S-dihydroxy-6~H-6,9~-oxide-prostenoic
acid was taken as the parent compound and is called 6~H-6,9~-oxide; the di-
astereoisomer 13-trans~ ,15S-dihydroxy-6aH-6,9~-oxide-prostenoic acid is
then referred to as 6~H-6,9~-oxide. The chemical names of the other tested
compounds are also referred to those of the parent compounds. The compounds
~ere tested at concentrations up to 100 mg/ml.
The results obtained showed that, in general, the 6~H-diastereo-
isomers, e.g., the compounds 6~H-6,9a-oxide, dl-6~H-5-bromo-6,9~-oxide, 6~H-
6,9~-oxide-16-_-CF3-phenoxy-~-tetranor and 6~H-6,9~-oxide-16-_-chloro-
phenoxy-~-tetranor possess BCA-relaxing activity and therefore have PGX-like
activity.
Among the 6~H-derivatives, only the compound dl-6~11-6,9~-oxide-16-
~,
3~D
methyl-16-butoxy-~-tetranor showed a BCA-contracting activity. The 6~H-
derivatives, e.g. the compound 6~H-6,9~-oxide, dl-6~H-5-~romo-6,9~-oxide,
dl-6~H-6,9~-oxide-16-methyl-16-butoxy-~-tetranor, 6~H-6,9~-oxide-16-m-CF3-
phenoxy-~-tetranor and 6~H-6,9~-oxide-16-_-chloro-phenoxy-~-tetranor also
showed BCA-contracting activity.
In general, the exo-configuration is associated with BCA contrac-
tion.
Furthermore, the compounds of the invention have hypotensive activi-
ty in mammals as does the natural compound PGX. However, as compared to PGX,
they have the great advantage of a higher chemical stability and can be used
in pharmaceutical formulations.
The hypotensive activity was demonstrated ~y the limb perfusion test.
During the perfusion of the rat's left leg, through the left femoral
artery, with a constant perfusion pressure, both the 6~H- and 6~H-6,9~-oxide
compounds caused a lowering of the values of the mean perfusion pressure at
all the doses, over the range from 0.05 - 1 ~g (to -42,5% for 6~H and -32%
for 6~H).
Moreover, the systemic pressure both systolic and diastolic, was
depressed from 0.05 ~g/kg up to 5 ~g/kg ~about -45%).
Because of their hypotensive and vasodilatory activity, the compounds
of the invention are useful for treatment of cases of gangrene of the lower
limbs. For this therapeutic use they have been found to be more active than
PGEl and PGE2. They are also useful in disturbances of the peripheral vas-
culature and, therefore in the prevention and treatment of diseases such as
phlebitis, hepato-renal syndrome, ductus arteriosus, non-obstructive mesenteric
ischemia, arteritis and ischemic ulcerations of the leg.
~3 3~
~3~
Among the compounds of the invention, in particular, the 6~H-deriva-
tives also have a high anti-aggregating activity.
Among the 6~H compounds, the more important ones are, in order of
increasing potency, compounds dl-6~H-5-bromo-6,9c~-oxide, 6~H~6,9c~-oxide-16-m-
CF3-phenoxy-~-tetranor, dl-6~H-6,9c~-oxide, and 6~H-6,9~-oxide.
Using platelet-rich plasma (PRP) from healthy human donors who had
not taken any drugs for at least one week, and monitoring platelet aggregation
by continuous recording of light transmission in a Born aggregometer [Born
G. V. R., Nature (London~ 194, 927 (1962)] there is evidence that the compounds
6~H-6,9a-oxide, dl-6~H-5-bromo-6,9~-oxide, 6~H-6,9c~-oxide-16-_-CF3-phenoxy-~-
tetranor and 6~H-6,9c~-oxide-16-m-chloro-phenoxy-~-tetranor ~imic the biosyn-
thetic PGX in its platelet-antiaggregating properties.
The compounds investigated were incubated for 2-3 minutes at 37C
in the PRP prior to the addition of the aggregating agents, arachidonic acid
(0.4 mM), ADP ~10 ~M), collagen ~38 ~M) or adrenaline (15 ~M). The potency
ratio for the compound is, e.g., 1:10 for arachidonic acid-induced aggregation
and 1:100 for ADP-induced aggregation, as compared with biosynthetic PGX.
A very interesting increase in the an~i-aggregating potency follows
20-methyl su~stitution in both the 6~H- and 6c~H-6,9c~-oxide parent compounds.
2~ Similarly, 6~H-5-bromo-20-methyl~ 6~H-5,14-dibromo, 6~H-13,14-dide-
hydro-20-methyl and inally 6~H-5-bromo-13,14-didehydro compounds and their
6~H 5 iodo (but not 6c~H-5-iodo isomers) are very ac~ive compounds as anti-
aggregating agents.
The compounds of the invention are, therefore, particularly useful
in mammals for inhibiting platelet aggregation, for preventing and inhibiting
thrombus formation and for decreasing the adhesiveness of platelets.
Therefore, they are useful in treatment and prevention of thromboses
~nd myocarclial infarct, in treatment of atherosclerosis, and in general in all
~c~
~3~
syndromes etiologically based on or associated with lipid imbalance or hyper-
lipidemia, as well as in treatment of geriatric patients for prevention of
cerebral ischemic episodes, and in long-term treatment after myocardial in
farct.
When the compounds of the invention are given as anti-aggregating
agents, the routes of administration are the usual ones, oral, intravenous,
subcutaneous, intramuscular. In emergency situations, the preferred route is
intravenous, with doses that can vary from 0.005 to about 10 mg/kg/day. The
exact dose will depend on the condition of the patient, his weight, his age
and the route of administration.
The compounds of the invention were also studied for their uterine
contractile activity, both in vitro and in vivo, against PGF2 as standard.
For example, in vitro, on the uterus of the estrogenized rat, com-
pounds 6~H-6,9~-oxide-16-_-chloro-phenoxy-~-tetranor and 6~H-6,9~-oxide-16-m-
-C~3-phenoxy-~-tetranor, were 1.3 and 3.1 times as active as PGF . In the
2~
in vivo assay, measuring the ntrauterine pressure o~ the ovariectomized rab-
bit, the same compounds were~ and 8.25 times as active as PGF2 (see the
following Table).
; _ in vitro _ v _
_ .
Uterus Ileum
PGF2a _~ . .,_____
6~H-6,9~-oxide-16-m-1.3 0.05 5.9
chloro-phenoxy-~-
tetranor
6~H-6,9~ oxlde-16-m-¦ 3.1 0.1 8.25
C~3-phenoxy-~-tetra- .
~3 ~
33~
Tha ~able shows that the compounds have greater activit~ on the
uterus than on the gastrointestinal tract.
These compounds, which are useful for induction of labor, for ex-
pulsion of dead fetuses from the pregnant female, in either human or veteri-
nary medicine, are without the undesirable side effects of the natural prosta-
glandins, such as vomiting and diarrhea.
For this purpose the compolmds of the invention can be given by in-
~ravenous infusion, at a dose of about 0.01 ~g/kg/minute ~mtil the end of
labor. At ~he same dosage, the compounds of the invention dilate the uterine
cervix, facilitating therapeutic abortion and, in that situation are given
preferably in the form of vaginal tablets or suppositories.
The compounds of the invention, in particular the compound dl-6~H-
6,9~-oxide-16-m-chloro-phenoxy-o-tetranor also have luteolytic activity and
are therefore of use for control of fertility.
The 6~H-6,9~-oxide and their 6~H-isomers were also investigated for
their action on the gastrointestinal tract, in order to know: ~a) cytoprotec-
tive activit~ against lesions induced by non-steroid anti-inflammatory drugs;
~b) ability to prevent the ulcers induced by the method of Togagi-Okabe
~CJapan J. Pharmac. vol. 18, 9 (1968)] and (c) antisecretory activity, accord-
ing to Shay et al Gastroenter. 26, 906 (lg54).
~he cytoprotective ability is a common feature of all the compounds.
For example, given subcutaneously, the 6~H-6,9~-oxide is slightly more active
(1.5 - 2 times) than the standard PGE2 as a gastric antisecretory agent.
In general, the cytoprotective activity of the 6~H compounds is
doubled when an acet~lene bond is present in the 13,1~-position; it is quad-
rupled when a 16-alk~l group, usually a methyl, is positioned in the 16(S)-
coniguration.
~s an ulceT~-preventing substance, the parent 6~H-6,9~-oxide analog
3 ~
3 - .37 -
q~8~
.. . . .
is at least equipotent with PGE2 and the following substitutions, 13,14-
acetylene bond; 16S, or R methyl; 16S, or R fluoro, highly increase ~up to
30 times) the potency ratio.
Furthermore, a significant oral antisecretory activity appears when
a methyl group is in the C-15-position of the parent 6~H-6,9~-oxide or in the
16,16-dimethyl compounds, such as the 6~H-6,9~-oxide-16-methyl-16-butoxy-~-
tetranor derivative.
For this purpose the compounds are preferably given by intravenous
in~ection or infusion, subcutaneously or intramuscularly. For intravenous
infusion, the doses vary from about 0.1 ~g to about 500 ~g/kg body weight/
minute. The total daily dose, either by injection or by infusion, is of the
order of 0.1 to 20 mg/kg, the exact dose depending on the age, weight and
condition of the patient or of the animal being treated and on the route of
administration.
In addition, the compounds are also useful for treatment of obstruc-
tive pulmonary diseases such as bronchial asthma, since they have considerable
bronchodilatory activity.
For treatment of the obstructive pulmonary disorders, for example
bronchial asthma, the compounds of the invention can be given by different
~0 routes: orally in the form of tablets, capsules, coated tablets or in liquid
form as drops or syrups; rectally in suppositories3 intravenously, intramuscu-
larly or subcutaneously; by inhalation, as aerosols or solutions for the ne-
bulizer; by insufflation, in powdered form.
Doses of the order of 0.01 - ~ mg/kg can be given from 1 to ~ times
a day, with the exact dose dependlng on the age, weight, and condition of the
patient and on the route of administration.
r:or use ac; an antiasthmatic, the compounds of the invention can be
combined with other antiasthmatic agents, such as sympathicomimetic drugs
3S'-
r
like isoproterenol, ephedrine, etc., xanthine derivatives, such as theophyl-
line and aminophylline, or corticosteroids.
The dosages when used as hypotensive and vasodilatory agents are
about the same as those used for the anti-aggregating effects.
As previously stated, the compounds of the invention can be given,
either to humans or animals in a variety of dosage forms, e.g., orally in the
form of tablets, capsules or liquids; rectally, in the form of suppositories,
parenterally, subcutaneously or intramuscularly, with intravenous administra-
tion being preferred in emergency situations; by inhalation in the form of
aerosols or solutions for nebulizers; in the form of sterila implants for
prolonged action; or intravaginally in the form, e.g., of bougies.
The pharmaceutical or veterinary compositions containing the com-
pounds of the invention may be prepared in conventional ways and contain con-
ventional carriers and/or diluents.
For example, for intraveous injection or infusion, sterile aqueous
isotonic solutions are preferred. For subcutaneous or intramuscular injec-
tion, sterile solutions or suspensions in aqueous or non-aqueous media may be
used; for tissue implants, a sterile tablet or silicone rubber capsule contain-
ing or impregnated with the compound is used.
Conventional carriers or diluents are, for example, water, gelatine,
lactose, dextrose, saccharose, mannitol, sorbitol, cellulose, talc, stearic
acid, calcium or magnesium stearate, glycol, starch, gum arabic, tragacanth
gum, alginic acid or alginates, lecithin, polysorbate, vegetable oils, etc.
For administration by nebulizer, a suspension or a solution of the
compound o~ the invention, preferably in the form of a salt, such as the sodi-
um salt in water, can be usecl. Alternatively, the pharmaceutical preparation
can be in the form of a suspension o~; of a solution of the compound of the
invention in one o t~e usual liquefied propellants, such as dichlorodifluoro-
3~
. ~ ..
` -
.
methane or dichlorotetrafluoroethane, administered from a pressur-
ized container such as an aerosol bomb. When the compound is no-t
soluble in the propellant it may be necessary to add a co-solvent,
such as ethanol, dipropylene glycol and/or a surfactant to the
pharmaceutical formulation.
The invention is illustrated by the following examples,
wherein the abbreviations "THF", "DME", "DMSO", "THP", "Et2O"
refer to tetrahydrofuran, dimethoxyethane, dimethylsulphoxide,
tetrahydropyranyl, and ethyl ether, respectively.
The following examples illustrate the preparation of
compounds of the invention, the preparation ofcompounds which are
the subject of related applications 294,195; 329,309; 366,521 and
394,875 and the preparation of intermediate compounds but do not
limit the present invention.
Example 1
To a solution of 1.0 g of dl-5~-hydroxymethyl-2~,4~-
dihydroxy-cyclopentan-l~-acetic acid--~-lactone-4-p-phenylbenzoate
in 8 ml of benzene/DMSO (75/25) is added wi-th stirring 0.89 g of
dicyclohexylcarbodiimide. At room temperature, 1.42 ml of a solu-
tion of pyridinium trifluoroacetate is added (prepared from 1 mlof trifluoroacetic acid and 2 ml of pyridine brought to 25 ml with
75/25 benzene/DMSO). After 3 hours 19 ml of benzene is added and
the mixture is treated dropwise with an oxalic acid dihydrate
solution, 0.3 g in 3.8 ml of water. After approximately 15 minutes
of stirring, the mixture is fi]tered, and the organic phase is
washed wi-th water until neutral, concentrated to 2 ml, and then
cliluted wi-th 5 ml of isopropyl ether. The product is isola-ted
by filtration and crystallized Erom isopropyl ether to give 0.8 g
- 37 -
of dl-5~-formyl-2~,4~-dihydroxy-cyclopentan-1~-acetic acid-~-
lactone-4-p-phenylbenzoate, m.p. = 129 - 131C. A solution of
800 mg of this in 2.8 ml of anhydrous methanol is treated with
0.62 ml of methyl orthoformate and 18 mg of p-toluenesulfonic acicl
monohydra-te. After 1 hour, 0.01 ml of pyridine is added and the
solution is evaporated to dryness. The residue is dissolved in
ethyl acetate; it is washed with l.On NaOH and then saturated
- 38 -
~, ,q~
NaCl until neutral. The solvent is removed at reduced pressure and the resi-
due is crystallized from methanol to give 800 mg of dl-S~-dimethoxymethyl-2~,
4~-dihydroxy-cyclopentan-1~-acetic acid-y-Lactone-4-_-phenylbenzoate, m. p. =
108 - 110C.
60 mg of K2C03 is added to a solution of this in 5.6 ml of anhydrous
methanol. After 4 hours of stirring at room temperature, the solution is
filtered; it is then reduced to small volume and acidified with a saturated
NaH2PO4 solution. The methanol is removed and the residue taken up in ethyl
acetate. This is washed with saturated NaCl until neutral, is dried over an-
hydrous Na2S04, is filtered, and evaporated under reduced pressure to give
480 mg of dl-5~-dimethoxymethyl-2~,4~-dihydroxy-cyclopentan-1~-acetic acid-y-
lactone.
A solution of this in 4 ml of CH2C12 is treated with 0.32 ml of
2,3-dihydropyran and 4.8 mg of _-toluenesulfonic acid. After 4 hours at room
temperature, pyridine is added and the solution is evaporated at reduced pres-
sure. The crude reaction product is filtered on S g of silica gel, with cyc-
lohexane:ethylether ~50:50) as eluent, to give 380 mg of dl-5~-dimethoxymethyl
2~,4~-dihydroxy-cyclopentan-1~-acetic acid-y-lactone-4-tetrahydropyranyl ether.
Starting from a 4-ester of 5~-dimethoxymethyl-2~,4a-dihydroxy-cyclopentan~
acetic acid-y-lactone ~for example: 4-_-phenylbenzoate, m. p. 128 - 130C,
~]D = -85) or from a 4-ester of 5~-hydroxyme~hyl-2~,4~-dihydroxy-cyclopentan-
l~-acetic-y-lactone ~for example: the 4-~-phenylbenzoate, m. p. = 127 - 129C,
L~] = ~84.5), the same procedure was used to prepare the following compounds:
5~-dimethoxymethyl-2~,4~-dihydroxy-cyclopentan-lr-acetic acid-y-lactone-4-
tetrahydropyranyl ether and 5~-dimethoxymethyl-2~,4~-dihydroxy-cyclopentan-
l~-acetic acid-r-lactone-4-tetrahydropyranyl ether. If 1,4-diox-2-ene is used
lnstead of 2,3-dihydropyran, the corresponding 4-dioxanyl ether derivatives
are obtained.
t ~ ~
Example 2
A solution of 216 mg of 5~-dimethoxymethyl-2~,4~-dihydroxycyclopen-
tan-l~-acetic acid-~-lactone [~]D = -16 [~]365= -48 (C = 1.0 CHC13) in
1.6 ml of dimethylformamide is treated with 0.3 ml of triethylamine followed
by 291 mg of dimethyl-tert-butylchlorosilane. After one hour, the mixture is
diluted with 8.3 ml of water and extracted with hexane. The organic phase is
washed ~ith ~ater and dried over Na2SO4 to give 310 mg of 5~-dimethoxymethyl-
2~,4~-dihydroxycyclopentan-1~-acetic acid-y-lactone-4-dimethyl-tert-butylsilyl
ether.
Example 3
To a solution of dl-5~-hydroxymethyl-2~,4~-dihydroxycyclopentan-1~-
propanoic acid-~-lactone-4-p-phenylbenzoate ~1 g) in 8 ml of benzene:DMSO
C75:25) is added 0.86 g of dicyclohexylcarbodiimide followed by 1.37 ml of a
freshly prepared pyridinium trifluoroacetate ~see example 1). After three
hours, 18 ml of benzene is added; a solution of 0.29 g of oxalic acid dihydrate
in 3.7 ml of ~ater is then added dropwise. After 15 minutes of stirring, the
dicyclohexylurea is removed by filtration and the organic phase is washed with
water until neutral. This is then reduced to volume to approximately 2 ml and
isopropyl ether is added. One obtains 0.793 g of dl-5~-formyl-2~,4~-dihydroxy
cyclopentan-l~-propionic acid-~-lactone-4-~-phenylbenzoate.
A solution of 780 mg of this in 2.7 ml of anhydrous methanol is
treated with 0.59 ml of methylorthoformate and 17.3 mg of p-toluenesulfonic
acid. After approximately one hour, 0.01 ml of pyridine is added and the solu-
tion is evaporated to dryness. The residue is taken up in ethyl acetate; the
organic phase is washed with lN NaOH and then saturated NaCl until neutral.
r:vaporation to dryness gives 769 mg of dl-5~-dimethoxymethyl-2~,4~-dihydroxy-
cyclopentan-l~-propionic acid-~-lactone-4-_-phenylbenzoate. This is then dis-
solved in 5.4 ml of anhydrous methanol and 75 mg of ~2CO3 is added. After
~0
,~ _
four hours of stirring at room temperature and filtra*ion, the solution is
reduced in volume and acidified with a saturated solution of Nal-l2P04. The
methanol is evaporated and the aqueous phase treated with ethyl acetate; the
organic phase is then washed with a saturated NaCl solution until neutral,
dried over Na2S04, and evaporated under vacuum to give crude dl-5~-dimethoxy-
methyl-2~,4~-dihydroxycyclopentan-1~-propanoic acid-~-lactone. A solution of
this in 4 ml of CH2C12 is treated with 0.3 ml of 2,3-dihydropyran and 4.5 mg
of ~-toluenesulfonic acid. After four hours at room temperature, 0.01 ml of
pyridine is added and the solution is evaporated to dryness. The reaction
product is purified on silica gel with cyclohexane: ethyl ether (50:50) as
eluent to give 480 mg of dl-5~-dimethoxymethyl-2~,4~-dihydroxycyclopentan-1~-
propanoic acid-~-lactone-4-tetrahydropyranyl e*her.
From a 4-ester of 5~-hydroxymethyl-2~,4~-dihydroxycyclopentan-1~-
propanoic acid~-lactone and from a 4-ester of 5~-hydroxymethyl-2~,4~-dihy-
droxycyclopentan-l~-propanoic acid-~-lactone ~for example, the 4-p-phenylbenzo-
ate), using the same procedure, the following compounds were obtained:
5~-dimethoxymethyl-2~,4~-dihydroxycyclopentan-1~-propanoic acid-~-lactone-4-
tetrahydropyranyl ether;
5~-dimethoxymethyl-2~94~-dihydroxycyclopentan-l~-propanoic acid-~-lactone-4-
tetrahydropyranyl ether.
If 1,4-diox-2-ene is used instead of 2,3-dihydropyran, the corresponding 4-
dioxanyl ether derivatives are obtained.
Example 4
A solution of 1 g of 5~-formyl-2~-hydroxycyclopentan-1~-acetic
acid-~-lactone in 6.5 ml of anhydrous methanol is treated with 1.74 ml of
methylorthoeormate and 52 mg of p-toluenesulfonic acid. After approximately
one hour, 0.0~ ml of pyridine is added and the solution is evaporated to dry-
ness. The residue is taken up in ethyl acetate,and then washed with lN NaOH
~L~
-- .~5 --
3~
and then saturated NaCl until neutral. Evaporation under ~acuum gives I g of
5~-dimethoxymethyl-2~-hydroxycyclopentan-1~-acetic acid-y-lactone, [~] = -16.
The same procedure gave 5~-dimethoxymethyl-2~-hydroxycyclopentan-
l~-propionic acid-~ lactone and its dl derivatives from 5~-formyl-2~-hydroxy-
cyclopentan-l~-propionic acid-~-lactone.
~xample 5
To a solution of 960 mg of dl-5~-dimethoxymethyl-2~,4~-dihydroxy-
cyclopentan-l~-acetic acid-y-lactone-4-tetrahydropyranyl ether in 16 ml of
toluene, cooled to -70C, is added 8.5 ml of a 0.5N toluene solution of di-
iso-butylaluminum hydride, over a 30 minute period. After a further 30 minutes
of stirring at -70C, 10 ml of a 2M toluene solution of iso-propanol is added
drop~Yise. The solution is warmed to 0C and treated with 3 ml of a 30% solu-
tion of NaH2P04. After 1 hour of stirring, 12 g of anhydrous Na2SO4 is added.
Filtration and evaporation of solvent gives 900 mg of dl-5~-dimethoxymethyl-
2a,4~-dihydroxycyclopentan-1~-ethanal -r -lactol-4-tetrahydropyranyl ether.
~xample 6
Following the procedure o example 5, a solution of 400 mg of 5~-
dimethoxymethyl-2~,4~-dihydroxycyclopentan-1~ acetic acid-y-lactone-4-dimethyl-
tert-butylsilyl ether in 11 ml of toluene, cooled to -70C, is treated drop-
wise with 5~9 ml of a 0.5N toluene solution of di-iso-butylaluminum hydride
to give 0.43 g of 5~-dimethoxymethyl-2~,4~-dihydroxycyclopentan-1~-ethanal-
y- lactol-4-dimethyl-tert-butylsilyl ether.
Example 7
Under a nitrogen atmosphere, a solution of 62~ mg of 5~-dimethoxy-
methyl-2~,4~-dihydroxycyclopentan-1~-propanolc acid-~-lactone-4-tetrahydro-
pyranyl ether in 11 ml of toluene, cooled to -70C, is treated dropwise with
5.9 ml of a 0.5M toluene solution of di-iso-butylaluminum hydride. After 30
minutes at -70C, 10.9 ml of a 2M toluene solution of isopropanol is added
~ _
''1-~
...~
3~
dropwise. The temperature is allowed to rise to 0C and 2 ml of 30% NaH2P04
is added. A$ter one howr of stirring, 8.3 g of anhydrous Na2S0~ is added and
the mixture is filtered. E~aporation of the organic phase under vacuum gives
620 mg of 5~-dimethoxymethyl-2~,4~-dihydroxycyclopentan-1~-propanal-~-lactol-
4-tetrahydropyranyl ether.
Example 8
Using one of the procedures outlined in examples 5, 6 and 7, a 4-
acetal ~4-tetrahydropyranyl ether; ~-dioxanyl ether~ and a 4-dimethylbutyl-
silyl ether of the following compounds are prepared:
5~-dimethoxymethyl-2~ -dihydroxycyclopentan-1~-ethanal-~-lactol, in its
dl and optically active form (or nat-);
5~-dimethoxymethyl-2~,4~-dihydroxycyclopentan-1~-ethanal-~-lactol (or ent-
form);
5~-dimethoxymethyl-2~,4~-dihydroxycyclopentan-1~-propanal-~-lactol, in its dl
and optically active form (or nat-);
5~-dimethoxymethyl-2~,4~-dihydroxycyclopentan-1~-propanal-~-lactol (or ent-
form).
Example 9
0.29 ml of absolute ethanol in 3.5 ml of toluene is added dropwise
to a solution of 5 x 10 3 mol of sodium ~2-methoxyethoxy)aluminum hydride
~1.4 ml of a 70% benzene solution diluted with 5 ml of toluene) cooled to 0 C.
8.2 ml of the alanate solution so prepared is addedJ at -30C, to 0.98 g of
dl-5~-benzyloxymethyl-2~-hydroxycyclopentan-1~-propionic acid-~-lactone in 22
ml of toluene. After 45 minutes, excess reagent is quenched with 6 ml of a
0.5 M toluene solution of isopropanol. The mixture is warmed to 0C, 4 ml of
30% Na~l2P04 is added, and the resulting mixture is stirred for 2 hours. The
inorganic salts are removed by filtration and the solution is evaporated to
dryness to give 0.94 g of dl-5~-benzyloxymethyl-2~-hydroxycyclopentan-lu-
propanal-~-lactol.
~1
.
~3~3~i
Using the procedure reported above, or one of those from examples
4 to 7, the following compounds were prepared from their corresponding y-lac-
tones:
5~-benzyloxymethyl-2~-hydroxycyclopentan~ ethanal-~-lactol;
5~-benzyloxyme~hyl-2~-hydroxycyclopentan-1~-propanal-~-lactol;
5~-dimethoxymethyl-2~-hydroxycyclopentan-1~-ethanal-r-lactol;
5~-dimethoxymethyl-2~-hydroxycyclopentan-1~-propanal-~-lactol.
Example 10
With stirring and external cooling to maintain a reaction tempera-
ture of 20 - 22C, a solution of 1.05 g of potassium tert-butylate in 10 ml
of DMSO is added dropwise to a solution of 1.8 g of 4-carboxybutyl-triphenyl-
phosphonium bromide and 0.38 g of 5~-dimethoxymethyl-2~,4~-dihydroxycyclopen-
tan~ ethanal-y-lac~ol-4-tetrahydropyranyl ether. After the addition, the
mixture is held at room temperature for 1 hour and then diluted with 16 ml of
ice/~ater. The aqueous phase is extracted with ether ~5 x 8 ml) and ether:
benzene (70:30, 5 x 6 ml), the organic layers, after re-extraction with 0.5M
NaOH ~? x lo ml), are discarded. The combined alkaline aqueous phase is acid-
ified to pH 4.8 with 30% NaH2PO4 and then extracted with ethyl ether:pentane
~1:1, 5 x 15 ml); from the combined organic phases, after drying over Na2SO4
and solvent removal, one obtains 0.45 g of 5-_is-7-~2'~,4'~-dihydroxy-5'~-
dimethoxymethylcyclopentan.l'~-yl)-hept-5-enoic acid~4'-tetrahydropyranyl
ether. This in turn is converted to the corresponding methyl ester upon treat-
ment ~Yith diazomethane in ether. An analytic sample is prepared by adsorbing
1~0 mg of the crude product on 1 g of silica gel and eluting with benzene:
ethyl ether ~85:15). N.M.R.: _C=C 5.46 p.p.m. multiplet.
H ~1
Example_
In an anhydrous nitrogen atmosphere, a suspension of 0.39 g of a
75% oil dispersion of NaH in DMS0 ~13.5 ml) is heated to 60 - 65C for 3 1/2
hours; ater coolin~ to room temperature and while maintaining the reaction
mixture at 20 -- 22C, the following are added, in order: 2.6~ g of 3-carboxy-
propyltriphenylphosphonium bromide in 6 ml of DMSO and 0.6 g of 5~-dimethoxy-
methyl-2~,4~-dihydroxycyclopentan-1~-propanal-~-lactol-4-tetrahydropyranyl
ether in 3 ml of DMSO. The mixture is stirred for 3 hours, and then diluted
with 35 ml of water. The aqueous phase is extracted with ethyl ether (5 x 12
ml) and ethyl ether:benzene ~70:30, 7 x 12 ml); the combined organic extract,
after re-extraction with 0.5N NaOH ~2 x 15 ml), is discarded. The combined
alkaline aqueous extract is acidified to pH 4.3 with 30% aqueous Na~l2PO4 and
extracted with ethyl ether:pentane (1:1) to give, after washing until neutral,
drying over Na2SO4, and removal of the solvent, 0.71 g of 4-cis-7-(2'~,4'a-
dihydroxy-5'~-dimethoxymethyl-cyclopent-1'~-yl)-hept-4-enoic acid. Treatment
with diazomethane affords the corresponding methyl ester.
Example 12
The methyl esters of the following acids were prepared from lactols
made according to the procedures in examples 4 to 8 by treatment with a Wittig
reagent (prepared from 4-carboxybutyl-triphenylphosphonium bromide or 3-car-
boxypropyltriphenylphosphonium bromide) and successive esterification with
diazomethane, in their optically active or dl forms:
4-cis-7-(2'~-hydroxy-5'~benzyloxymethylcyclopent-1'~-yl)-hept-4-enoic;
4 -Ci S - 7-(2'~-hydroxy-5'~-dimethoxymethyl-cyclopent-1'~-yl)-hept-4-enoic;
5-cis-7-~2'~-hydroxy-5'~-dimethoxymethyl-cyclopent-1'~-yl)-hept-5-enoic;
5-cis-7-(2'u-hydroxy-5'~-benzyloxymethyl-cyclopent~ -yl)-hept-5-enoic;
5-cis-7-~2'~,4'~-dihydroxy-5'~-dimethoxymethyl-cyclopent-1'~-yl)-hept-5-enoic
and its 4'-dioxanyl, tetrahydropyranil and dimethyl-tert-butylsilyl)-ethers;
4-cls-7-~2'~,4'o~-dihydroxy-5'~-dimethoxymethyl-cyclopent-l'cl-yl)-hept-4-enoic
cmd its 4'-(dioxanyl" tetrahydropyranyl and dimethyl-tert-butylsilyl)-ethers;
~f5
11-'~ f~
.~
3~
4-cis-6-~2'a,4'a-dihydroxy-5'~-dimethoxymethyl-cyclopent-l'a-yl)-hex-4-enoic
and its 4'-~tetrahydropyranylether;
5-cis-8-~2'a,4'a-dihydroxy-5'~-dimethoxymethyl-cyclopent-l'a~yl)oct-5-enoic
and its 4'-tetrahydropyranylether.
Example 13
~ solution of 1.06 g of the methyl ester of 5-cis-7-(2'~,4'a-dihy-
droxy-5'~-dimethoxymethyl-cyclopent-l'a-yl)-hept-5-enoic acid-4'-tetrahydro-
pyranyl ether in 5 ml of methanol is added to 0.84 g of mercuric acetate in
methanol. After 30 minutes at room temperature, a solution of 250 mg of sodi-
um ~orohydride in 2 ml of water is added with stirring and external cooling.
After 20 minutes of stirring, the mixture is acidified to pH 6.5 with aqueous
monosodium phosphate, the methanol is removed under vacuum, and the residue
is taken up in water/ethyl ether. The organic phase, upon removal of the
solvent, affords 1.02 g of 5-~6'-exo-dimethoxymethyl-7'-endo-hydroxy-2'-oxa-
6icyclo[3.3.0]octan-3'~-yl)-pentanoic acid methyl ester-7'-tetrahydropyranyl
ether.
Example 14
A solution of 1.59 g of 4-cls-7-~2'~,4'a-dihydroxy-5'~-dimethoxy-
methyl-cyclopent-l'a-yl)-hept-4-enoic methyl ester-4'-tetrahydropyranyl ether
in 6 ml of THF is added ~o a solution of 1.26 g of mercuric acetate in 4 ml
of water diluted with 4 ml of THF. The mixture is stirred for 1 1/2 hours
until precipitation is complete. 180 mg of sodium borohydride ~in 2.5 ml of
water) is then added and the resulting mixture is stirred for 30 minutes. The
solution is decanted from the precipitate, which is then washed with THF. The
aqueous/organlc decanted solut:i.on is concentrated under reduced pressure and
the ~esidue extracted with ethyl acetate. The combined organic extract, after
washing with water ulltil neutral, affords upon removal of the solvent 0.98 g
of (~-~7~-exo-di.methoxymethyl-8'-endo-'hydroxy-2'_oxa.~bicyclo~3.4.0~nonan-3~-yl)
butanoic acid methyl ester-8'-tetrahydropyranyl ether.
'f~
'1 3 ~
,
~3~
Exam~le 15
~, .
Starting from the esters prepared as described in examples 9 to 11,
by reaction with a mercuric salt and subsequent reductive demercuration as
described in the procedures in examples 13 and 14, the following bicyclic
deriva~ives are obtained:
5-(6'-exo-benzyloxymethyl-2'-oxa-bicyclo[3.3.0]octan-3'~-yl)-pentanoic acid
methyl ester;
5-(6'-exo-dimethoxymethyl-2'-oxa-bicyclo[3.3.0~octan-3'~-yl)-pentanoic acid
methyl ester;
4-(7'-exo-benzyloxymethyl-2'-oxa-bicyclo[3.4.0]nonan-3'~-yl)-butanoic acid
methyl ester;
4-(7'-exo-dimethoxymethyl-2'-oxa-bicyclor3.4.0~nonan-3'~-yl)-butanoic acid
methyl ester;
a 7'-acetal ether (tetrahydropyranyl ether, dioxanyl ether), and a 7'-dimethyl-
tert-butylsilyl ether of 5-~6'-exo-dimethoxymethyl-7'-endo-hydroxy-2'-oxa-
bicyclo~3.3.03Octan-3'~-yl)-pentanoic acid methyl ester;
an 8'-acetal ether (tetrahydropyranyl ether, dioxanyl ether) and
an 8'-dimethyl-tert-butylsilyl ether of 4-~7'-exo-dimethyoxymethyl-8'-endo-
hydroxy-2'-oxa-bicyclo[3.4.0]nonan-3'~-yl)-butanoic acid methyl ester.
4-(6'-exo-dimethoxymethyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'~-yl)-
butanoic acid methyl ester-7'-tetrahydropyranyl ether;
5-(7'-exo-dimethoxymethyl-8'-endo-hydroxy-2'-oxa-bicyclo[3.4.~]nonan-3'~-yl)-
pentanoic acid methyl ester-8'-tetrahydropyranyl ether.
All these compounds are obtained in the d,l-, nat-- and ent-forms.
Example 16
A solution of 0.48 g of bromine in 5 ml of methylene chloride is
added dropwise, with stirring, to a solution of 0.27 g of pyridine and 1.2 g
of S-cis-7-(2'~ dihydroxy-5'~-dimethoxymethyl-cyclopent-1'~-yl)-hept-5-
enoic acid methyl ester-4'-tetrahydropyranyl ether in 6 ml of methylene chlo-
ride, cooled to 0C. Stirring is continued for ten minutes following the ad-
dition. The organic phase is washed with 5 ml of a pH 7 buffer solution 10%
in sodiurn thio sulfate and then with water until neutral. After drying over
Na2S04, removal of the solvent affords 1.38 g of 5-bromo-5-~6'-exo-dimethoxy-
methyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'~-yl)-pentanoic acid
methyl ester-7'-tetrahydropyranyl ether.
Example 17
1.24 g of N-iodosuccinimide is added to a solution of 2 g of 5-cis-
7-(2'~,4'~-dihydroxy-5'~-dimethoxymethyl-cyclopent-1'~-yl)-hept-5-enoic acid
methyl ester-4'-tetrahydropyranyl eth~r in 15 ml of carbon tetrachloride. The
mixture is stirred for 3 hours and 30 ml of eth~l ether is added. The organic
phase is ~ashed with lN Na2S203 and then with water until neutral. Removal of
the solvent affords 2.48 g of 5-iodo-5'-~6'-exo-dimethoxymethyl-7'-endo-hy-
droxy-2'-oxa-bicyclo~3.3.0]octan-3'~-yl)-pentanoic acid methyl ester-7'-tetra-
hydropyranyl ether.
Example 18
422 mg of N-bromosuccinimide is added with stirring to a solution
of 0.78 g of 4-cis-7-(2'~,4'~-dihydroxy-5'~-dimethoxymethyl-cyclopent-1'~-yl)-
hept-4-enoic acid methyl ester-4-tetrahydropyranyl ether in 11 ml of CC14.
After four hours of stirringJ ethyl ether is added; the solution is then
washed with water, lN Na2S203, and water until neutral. Evaporation to dry-
ness gives 0.98 g of 4-bromo-4-(7'-exo-dimethoxymethyl-8'-endo-hydroxy-2'-
oxa-bicyclo[3.4.0]nonan-3'~-yl)-butanoic acid methyl ester-8'-tetrahydropyra-
nyl ether.
Example 19
To a suspen~ion of 0.25 g of dry CaC03 in a solution of 346 mg of
5-cis-7-~2~-hydroxy-5'~-benzyloxymethyl-cyclopent-1'~-yl)-hept-5-enoic acid
i :~L~
methyl ester in 10 ml of CC14 cooled to 0 - 5C is added with stirring a solu-
tion of 75 mg of chlorine in 3 ml of CC14. After stirring for ~ hours, the
inorganic salts are removed by filtration. The solution is washed with a 7%
aqueous solution of KI and Na2S2O3 and then with water until neutral. The
residue upon evaporation to dryness is adsorbed on silica gel and eluted with
cyclohexane:ethyl ether (80:20) to give 0.27 g of 5-chloro-5-(6'-exo-benzyl-
oxymethyl-2'-oxa~bicyclo[3.3.0]octan-3'~-yl)-pentanoic acid methyl ester.
A solution of 0.39 g of 5-cis-7-(2'~,4'~-dihydroxy-5'3-dimethoxy-
methyl-cyclopent-1'~-yl)-hept-5-enoic acid methyl ester-4'-dioxanyl ether and
98 mg of pyridine in 10 ml of dichloromethane is cooled to -40C. A solution
of 81 mg of chlorine in 6 ml of CH2C12 is then added over a period of 30 min-
utes. After 10 minutes of stirring, the mixture is heated to room temperature.
The organic phase is washed with a 7% solution of KI and Na2S2O3 and then with
water until neutral. Removal of the solvent affords 0.39 g of 5-chloro-5-(6'-
exo-dimethoxymethyl-7'-endo-hydroxy-2'-oxa-bicyclo~3.3.0]octan-3 "-yl)-pentan-
oic acid methyl ester-4'-dioxanyl ether.
Example 21
280 mg of iodine in CC14 is added to a solution of 0.39 g of 4-cis-
7-(2'c~,4'~-dihydroxy-5~-dimethoxymethyl-cyclopent-1'~-yl)-hept-4-enoic acid
methyl ester-4'-tetrahydropyranyl ether and 82 mg of pyridine in 10 ml of
CC14. Stirring is continucd until the color disappears; 30 ml of ethyl ether
is then added. The organic phase is washed with water, then a solution 7%
ln KI and Na2S2O3, and then water until neutral. Removal of thc solvent af-
fords 0.48 g of 4-iodo-4-~7'-exo-dimethoxymethyl-8'-endo-hydroxy-2'-oxa-
b~cyclo[3.4.0~nonan-3'Z-yl)-butanoic acid methyl ester-8'-tetrahydropyranyl
ether.
~3 -~_
....
~3~i33~1
Example 22
To a solution of 0.34 g of 5-cis-7-~2'~-hydro~y-5'~-ben~yloxymethyl-
cyclopent-l'~-yl)-hept-5-enoic acid methyl ester in 6 ml of methanol is added
with stirring a solution of 0.325 g of mercuric acetate in water:methanol
(1:9,6 ml). The mixture is stirred for 15 minutes, reduced to 3 ml under
vacuum, and then added to S ml of a saturated solution of NaCl in water. The
precipitate is then extracted with methylene chloride. The organic phase is
~ashed with water and evaporated to dryness to give 0 52 g of crude 5-chloro-
mercurio-5-~6'-exo-benzyloxymethyl-2'-oxa-bicyclo[3.3.0]octan-3'~-yl~-pentanoic
acid methyl ester. A solution of this in methylene chloride ~10 ml) is treat-
ed wi*h 80 mg of pyridine in 2 ml of CH2C12 and then dropwise with stirring
with a solution of 150 mg of Br2 in CH2C12. After 20 minutes of stirring at
room temperature, the organic phase is washed with water, then 7% Ki and
Na2S2O3, and water until neutral. Evaporation to dryness gives 0.34 g of 5-
bromo-5-~6'-exo-benzyloxymethyl-2'-oxa-bicyclo[3.3.0]octan-3')-yl)-pentanoic
acid methyl ester.
Mass spectrum M 424,426 m/e M -HBr 344 m/e M -CHBr ~CH2)3C02~CH3 = 231 m/e.
Example 23
10.5 mg o ~-toluenesulfonic acid monohydrate is added to a solution
of 0.26 g of 5-iodo-5-(6'-exo-dimethoxymethyl-7'-endo-hydroxy-2'-oxa-bicyclo
~3.3.0Joctan-3'~-yl)-pentanoic acid methyl ester-7'-tetrahydropyranyl ether
and the resulting mixture is left at room temperature for 30 minutes. 10 mg
of pyridine is then added and the solution is evaporated to dryness. The
residue is taken up in ethyl ether/water. After drying over Na2S04, the
organic phase gives upon xolvent evaporation 0.23 g of crude 5-iodo-5-~6'-
exo-dimethoxymethyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'~-yl)-pen-
tanoic acicl methyl ester. Separation by chromatography on silica gel with
methylcne chloride: ethyl ether ~75:25) as eluent affords 84 mg of 5-iodo-5-
. ~....
5~1
(6'-exo-dimethoY~ymethyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'-endo-
yl)-pentanoic acid methyl ester and 55 mg of the 3'-exo isomer.
Referring the spectroMetric data, the prostaglandin numbering will be used;
thus the above diastereoisomers can be named as follows: the endo diastereo-
-~^o~o ~ r
isomer: ~ ~H-6,9~-oxide~ -hydroxy-12~-dimethoxy ~ormylacetal-~20 ~ 13)te~-
~f - io C/~
~a~4r-prostanoic acid methyl ester and the exo diastere~ somer1r6~H-6,9~-oxide-
~ e~ ~ r
ll~-hydroxy-12~-dimet]loxy-~ormylace~al-~(20 ~ 13)te~a~e~-prostanoic acid
methyl ester.
Analytical data:
endo diastereoisomer: TLC more polar-or.e spot
Mass spectrum ~m/e; % intensity fragment): 442 0.002 M ; 412 4 M -CH2O,
~ OCH
315/314 3 M -iodine/Hl 283 11 315-CH30H, 75 100 CH oCH3
N.M.R. ~solvent CDC13, TMS internal standard) p.p.m.:
~OCH
3.49 and 3.52 s, 3H/3H, CH ocH3 ; 3.64 s, 3H, CO2CH3;
,,OCH3
4.00 m, 3H ~protons at C5, Cg, Cll); 4-29 d, lH~ -CH OCH
4.60 m, lH, 6~H
C-MR ~at 20MH~ in C6D6 solution TMS int. standard) p.p.m.
172.9, 36.5, 33.1, 25.6, 41.8, 81.0, 38.1, 55.5, 83.1,
41.5, 74.2, 44.6, 108.0, 54.2, 54.1, 51Ø
exo diastereoisomer: TLC less polar-one spot
Mass spectrum: 442 0.01 M , 366 3 M CH2CH~OCH3)2,
31S 4 M -1; 283 10 M -l-C}130H; 75 100 CH~OCH3)2
,,OCH3
N.M.R.: p.p.m. 3.34 and 3.37 3H/3H s CH OCH ; 3-5 and 4-1
m lH and 2}1 protons at C5, C9, Cll uncertain assignment,
~OCH
3.65, s 3~1, CO2CH3; 4.21, dlH, CH OCH ; 4.35 m, 1~1,6
~/
3~
13CMR: p.p.m. 173.0, 37.0, 33.1, 25.5J 40.1, 84.4, 39.7,
57.2, 83.7, 40.5, 75.9, 44.0~ 107.3, 5~.0, 53.8, 51.1.
Example 24
A solution of 980 mg of ~-bromo-4-(7'-exo-dimethoxymethyl-8'-endo-
hydroxy-2'-oxa-~icyclo[3.4.0]nonan-3'~-yl)-butanoic acid methyl ester-8'-
tetrahydropyranyl ether in 6 ml of anhydrous methanol is treated at room
temperature for 30 minutes with 48 mg of _-toluenesulfonic acid. 2% aqueous
NaHCO3 is added and the mixture is extracted with ethyl ether. From the
organic phase, after washing until neutral and evaporation of the solvent,
one obtains 0.68 g of a crude product which after purification on silica gel
with methylene chloride: ethyl ether (80:20) as eluent affords 0.30 g of 4-
bromo-4-~7'-exo-dimethoxymethyl-8'-endo-hydroxy-2'-oxa-bicyclo[3.4.0]nonan-
3'-exo-yl)-butanoic acid methyl ester and 0.29 g of the 3'-endo isomer.
Example 25
Starting from acids prepared according to the procedure of example
11 and performing their halocycli~ation as described in one of the examples
16 to 22, the following haiobicyclic compounds are prepared:
5-chloro-5-(6'-exo-dimethoxymethyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-
3'~-yl)-pentanoic acid methyl ester~7'-tetrahydropyranyl ether ~and 7'-di-
oxanyl ether and 7'-dimethylbutylsilyl ether);
4-chloro-4-~7'-exo-dimethoxymethyl-8'-endo-hydroxy-2'-oxa-bicyclo[3.4.0]nonan-
3'~-yl)-butanoic acid methyl ester-8'-tetrahydropyranyl ether ~and 8'-di-
oxanyl and 8'-dimethylbutylsilyl ethers);
5-chloro-5-~6'-exo-dimethoxymethyl-2'-oxa-bicyclo[3.3.0]octan-3';-yl)-pen-
tanoic acid methyl ester;
S-chloro-5-~6'-exo-benzyloxymethyl-2'-oxa-bicyclo[3.3.0]octan-3'~-yl)-pen-
tanoic acid methyl ester;
4-chloro-4 ~7'-exo-dimethoxymethyl-2'-oxa-bicyclo[3.4.0]nonan-3'~-yl)-
æ
~utano:ic acid methyl es~er;
4-chloro-4-~7'-exo-benzyloxymethyl-2'-oxa-bicyclo[3.4.0]nonan-3'~-yl)-butanoic
acid methyl ester;
5-bromo-5-(6'-exo-dim0thoxymethyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-
3'~-yl)-pentanoic acid methyl ester-7'-tetrahydropyranyl ether ~and 7'-di-
oxanyl and 7'-dimethylbutylsilyl ethers);
4-bromo-4-~7'-exo-dimethoxymethyl-8'-endo-hydroxy-2'-oxa-bicyclo[3.4.0[nonan-
3'~-yl)-butanoic acid methyl ester-8'-tetrahydropyranyl ether (and 8'-dioxanyl
and ~'-dimethylbutylsilyl ethers);
5-bromo-5-~6'-exo-dimethoxymethyl-2'-oxa-bicyclo[3.3.0]octan-3'~-yl)-pentanoic
acid methyl ester;
5-bromo-5-(6'-exo-benzyloxymethyl-21-oxa-bicyclo[3.3.0]octan-3'~-yl)-pentanoic
acid methyl ester;
4-bromo-4-~7'-exo-dimethoxymethyl-2i-oxa-bicyclo[3.4.0]nonan-3'~,-yl)-butanoic
acid methyl ester;
4-bromo-4-~7'-exo-benzyloxymethyl-2'-oxa-bicyclo[3.4.0~nonan-3'~-yl)-butanoic
acid-methyl ester;
5-iodo-5-(6'-exo-dimethoxyme~hyl-7'-endo-hydroxy-2'-oxa-bicyclo~3.3.0]octan-
3'~-yl)-pentanoic acid methyl ester-7'-~etrahydropyranyl ether ~and 7'-di-
oxanyl and 7'-di~ethylbutylsilyl esters);
4-iodo-4-t7'-exo-dimethoxymethyl-8'-endo-hydroxy-2'-oxa-bicyclo~3.4.0]nonan-
3'~-yl)-butanoic acid methyl ester-8'-tetrahydropyranyl ether ~and 8'-di-
oxanyl and 8'-dimethylbutylsilyl ethers);
5-iodo-5-(6'-exo-dimethoxymethyl-2'-oxa-bicyclo[3.3.0]octan-3'~-yl)-pentanoic
acid methyl ester;
5-iodo-5-~6'-exo~benæyloxymethyl-2'-oxa-bicyclo[3.3.0]octan3'~-yl)-pentanoic
acicl methyl ester;
4-ioclo-4-(7'-exo-benzyloxymethyl-2'-oxa-bicyclo[3.4.0]nonan-3'~-yl)-butanoic
53
~31~3~
acid methyl ester;
4-iodo-4-(7'-exo-dimethoxymethyl-2'-oxa-bicyclo[3~4.03nonan-3'~-yl)-butanoic
acid methyl ester~
Example 26
Selective de-acetalization or de-silylization of the ethers de-
scribed in example 25, according to the p-rocedure in examples 23 and 24 af-
fords the 3'~-oxiran-hydroxide-~ormyl acetal derivatives, which give the
following upon separation of isomers:
5-chloro-5-~6'-exo-dimethoxymethyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-
-3'~-yl)-pentanoic acid methyl ester, and its individual 3'-exo and 3'-endo
isomers;
4-chloro-4-~7'-exo-dimethoxymethyl-8'-endo-hydroxy-2'-oxa-bicyclo[3.4.0]nonan-
3'~-yl)-butanoic acid methyl ester, and its individual 3'exo and 3'-endo
isomers;
5-bromo-5-~6'-exo-dimethoxymethyl-7'-endo-hydroxy 2'-oxa-bicyclo~3.3.0]octan-
3'~-yl)-pentaroic acid methyl ester, and its individual 3'-exo and 3'-endo
isomers;
endo isomer: TIC on SiO2 more polar one spot
N.M.R.: (CDC13) p.p.m. 3.4 d,6H, CH oCH3 ; 3.65, s~3H CO2CH3
" OCH3
4.00 m,4H ~protons at C4, C5, Cg, Cll); 4-17 d,l, CH OCH
4.5 m, lH, 6~H
CMR: 173,0, 35.0, 33.3. 23.6, 59.4, 80.6, 36.4, 55.6, ~3.3,
41.6, 74.3, 44.5, 108.0, 54.4, 54~2, 51.1
exo isomer: TLC on SiO2 less polar isomer one spot
N.M.R.: (CDC13) p.p.m.: 3.37 d,6H ~CH oC113 ; 3.66 s,3H,CO2CH3
~ OCH
4.00 m,4H, protons at C4, C5, C9, Cll; 4-2 d,l, -C_ oCH3
4.32 m,lH, 6~H
, ~ 4
: ~ , -- 5~--
8~
CMR: 173.0, 35.5, 33.3, 23.6, 57.7, 84.2, 38.2, 57.9,
83.6, 40.5, 76.0, ~3.9, 107.2, 53.8, 53.8, 51Ø
4-bromo-4-(7'-e~o-dimethoxymethyl-8'-endo-hydroxy-2'-oxa-bicyclo[3.4.0]nonan-
3'~-yl)-butanoic acid methyl ester and its individual isomers, 3'-exo and
3'-endo;
5-iodo-5-(6'-exo-dimethoxymethyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0~octan--
3'~-yl)-pentanoic acid methyl ester and its individual 3'-exo and 3'-endo
isomers;
4-iodo-4-~7'-exo-dimethoxymethyl-8'-endo-hydroxy-2'-oxa-bicyclo[3.4.0]nonan-
3'~-yl)-butanoic acid methyl ester and its individual 3'-exo and 3'-endo
isomers.
Example 27
With stirring under nitrogen, a benzene solution (30 ml) of 2.8 g of
5-iodo-5-(6'-exo-dimethoxymethyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-
3'~-yl)-pentanoic acid methyl ester-7'-tetrahydropyranyl ether is treated with
a solution of 2.~ g of tributyltin hydride in 8 ml o benzene. The mixture
is held at 55C for 8 hours and then overnight at room temperature. The ben-
zene layer is washed with 2 x 10 ml of a 5% NaHC03 solution and then with
water until neutral. The residue upon solvent evaporation is adsorbed on 10 g
of silica gel and eluted with benzene and benzene:ethyl ether ~85:15) to give
1.94 g of 5-(6'-exo-dimethoxymethyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]
octan-3'~-yl)-pentanoic acid methyl ester-7'-te-trahydropyranyl ether.
Example 28
60 mg of ~-toluenesulfonic acid is added to a solution of 1.98 g of
5-~6'-exo-dimethox~nethyl-7'-endo-hydroxy-2'-oxa-bicyclo~3.3.0]octan-3'~-yl)-
pentanoic acid methyl ester-7'-tetrahydropyranyl ether in 10 ml of anhydrous
methanol. ~eter 30 minutes at room temperature, this is added to 20 ml of
20% aqueous Na~lC0~. The mixture is extracted with ethyl ether; the combined
1~L8~3~1
ether extract, after drying over Na2SO4, is evaporated to dryness. The resi-
due is adsorbed on 100 g of silica gel and eluted with methylene chloride:
ethyl ether (94:6) to give 0.64 g of 5-(6'-exo-dimethoxyme~hyl-7'-ando-
hydroxy-2~-oxa-bicyclo[3.3.0]octan-3'-exo-yl)-pentanoic acid methyl ester,
0.52 g of the 3'-endo isomer and 0.12 g o:E the 3' -yl.
N.M.R. (CDC13) endo isomer 4.6 p.p.m. m,lH 6~H, T.L.C. more polar;
exo isomer 4.3 p.p.m. m,l}l 6~H, T.L.C. less polar.
0.32 g of the 3'-endo isomer is dissolved in pyridine (0.8 ml) and
treated for 8 hours at room temperature with 0.3 ml of acetic anhydride. The
mixture is then poured into ice/water, and, af~er acidifying to pH 4.2, is
extracted with ethyl ether. The combined extract, after washing until neutral,
is evaporated to give 0.315 g of 5-(6'-exo-dimethoxymethyl-7'-endo-hydroxy-2'-
oxa-bicyclo[3.3.0]octan-3'-exo-yl)-pentanoic acid methyl ester-7'-acetate.
Example 29
A solution of 1.32 g of 4-(7'-exo-dimethoxymethyl-8'-endo-hydroxy-
2'-oxa-bicyclo[3.4.0Jnonan-3'~-yl)-butanoic acid methyl ester-8'-tert-butyl-
methylsilyl ether in 10 ml of anhydrous methanol is treated with 55 mg of _-
toluenesul~onic acid for 2 hours at room temperature. 0.1 ml of pyridine is
added, the solvent is removed under vacuum, and the residue is taken up in
water/ethyl ether. The organic phase gives, upon removal of the solvent, 1.1
g of the crude 8'-hydroxy-3'~-yl derivative. Chromatography of this on silica
gel with ben~ene:ethyl ether (80:20) as eluent separates this into 4-(7'-exo-
dimethoxymethyl-8'-endo-hydroxy-2'-oxa-bicyclo~3.4.0]nonan-3'-endo-yl)-bu-
tanoic acid methyl ester ~0.42 g) and the 3'-exo-yl isomer (0.34 g).
~:xa]nple 30
Using the p~ocedure in examples 28 and 29, methanolysis of the
~thcrs (acetal or silyl) described in example 15 gives the corresponding free
alcohols.
. .~. -~
-
~1~38~
Example 31
Upon acetylation with pyridine (0.6 ml) and acetic anhydride (0.3 ml)
0.2 g of 5-iodo-5-(6'-exo-dimethoxymethyl-7'-endo-hydroxy-2'-oxa-bicyclo
[3.3.0]octan-3'-endo-yl)-pentanoic acid methyl ester gives 0.21 g of the cor-
responding 7'-acetoxy derivative.
N.M.R. (CDC13) p.p.m.: 2.03 s,3H OCOCH3; 3.36 - 3.40 s,s 3H/3H
/OCH
CH 3; 3.66 s 3H CO CH3 ; 4.00 m 2H protons at
- OCH - -
-3 , " OCII
C5, C9; 4.27 d lH CH ; 4.6 m lH 6~H 5.0 m lH
proton at Cll 3
[The spectrometric data for the 6~H isomer acetate are respectively the fol-
lowing 2.03; 3.34 - 338, 3.66 s+m 4H CO2CH3 and one of C5, Cg protons 4.1 m lH
other of C5, C9 protons 4.2, 4.4 m lH 6~H, 5.1]. A solution of the 5-iodo-3'-
endo-acetate in benzene (5 ml) is treated with 0.4 g of tributyltin hydride for
10 hours at 50 C. After the benzene phase is washed with 5% NaHCO3 and water
evaporation of the solvent and purification on silica gel (10 g) with a ben-
zene:ethyl ether (80:20) eluent afford 0.105 g of 5-(6'-exo-dimethoxymethyl-7'-
endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'-endo-yl)-pentanoic acid methyl ester
-7'-acetate, identical in all respects with a sample prepared by the procedure
in example 28.
Example 32
Using the procedure of examples 27 and 31, the reduction with tri-
butyltin hydride of one of the halo-derivatives synthesized in examples 16-
26 gives the corresponding derivative in whic}l halogen is replaced by hydrogen.
These are identical in every way with the compounds prepared according to the
procedures of examples 15, 28, 29 and 30.
~xample 33
S.~l mg o hydroquinone and a solution of 1.63 g of oxalic acid in
~8 ml o~ ~ater are added to a solution of ~ g of 5-(6'-exo-dimethoxymethyl-
j~
~L8~1!33$1
7'-endo-hydroxy-2'-oxa-bicycloL3.3.0]octan-3'~-yl)-pentanoic acid methyl
ester in 180 ml of acetone. Af~er 12 hours at 40C, the acetone is removed
at reduced pressure and the mixture is extracted with ethyl acetate ~3 x 25
ml). The com~ined organic extract is washed until neutral with a 10% ammonium
sulfate solution and dried over Na2S04. Removal of the solvent affords 3.21 g
of 5-(6'-exo-formyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'~-yl)-pen-
tanoic acid methyl ester. The 6'-exo-formyl-3'-endo and the 6'-exo-formyl-3'-
exo derivatives are prepared from the corresponding individual isomers.
Example 34
10 Using the procedure of example 33) starting from the corresponding
bicyclo[3.3.0]octan-6'-exo-dimethoxymethyl and bicyc lo L 3.4.0]nonan-7'-exo-
dimethoxymethyl derivatives, the following compounds are prepared, either as
individual 3'-exo and 3'-endo or 3'~ isomers:
5-~6'-exo-formyl-2'-oxa-bicyclo[3.3.0]octan-3'-yl)-pentanoic acid methyl
es~er;
4-~7'-exo-formyl-2'-oxa-bicyclo[3.4.0]nonan-3'-yl)-butanoic acid methyl ester;
5-(6'-exo-formyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'-yl)-pelltanoic
acid methyl ester;
4-~7'-exo-formyl-8'-endo-hydroxy-2'-oxa-bicyclo[3.4.0]nonan-3'-yl)-butanoic
2Q acid methyl ester;
5-chloro-5-~6'-exo-formyl-2'-oxa-bicyclo[3.3.0]octan-3'-yl)-pentanoic acid
methyl ester;
4-chloro-4-~7'-exo-formyl-2'-oxa-bicyclo[3.4.0]nonan-3'-yl)-butanoic acid
methyl ester;
5-chloro-5-~6'-exo-ormyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'-yl)-
pentanoic acid methyl ester;
4-chloro-4-~7'-exo-tormyl-8'-endo-hydroxy-2'-oxa-bicyclo[3.4.0]nonan-3'-yl)-
~utanoic acid methyl ester;
~3 ~
-
3~8~
5-bromo-5-(6'-exo-formyl-2'-oxa-bicyclo[3.3.0]octan-3'-yl)-pentanoic acid
methyl ester;
4-bromo-4-(7'-exo-formyl-27-oxa-bicyclo~3.4.0]nonan-3'-yl)-butanoic acid
methyl ester;
5-bromo-5-(6'-exo-formyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.Q]octan-3'-yl)-
pentanoic acid methyl ester;
4-bromo-4-~7'-exo-formyl-8'-endo-hydroxy-2'-oxa-bicyclo[3.4.0]nonan-3'-yl)-
butanoic acid methyl ester;
5-iodo-5-(6'-exo-formyl-2'-oxa-bicyclo[3.3.0]octan-3'-yl)-pentanoic acid
methyl ester;
4-iodo-4-(7'-exo-formyl-2'-oxa-bicyclo[3.4.0]nonan-3'-yl)-butanoic acid
methyl ester;
5-iodo-5-~6'-exo-formyl-7'-endo-hydroxy-2'-oxa-bicyclo~3.3.0]octan-3'-yl)-
pentanoic acid methyl ester;
4-iodo-4-(7'-exo-formyl-8'-endo-hydroxy-2'-oxa-bicyclo[3.4.0]nonan-3'-yl)-
butanoic acid methyl ester;
5-(6'-exo-formyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'-yl)-pentanoic
acid methyl ester-7'-acetate;
5-iodo-5-(6'-exo-formyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'-yl-
2Q pentanoic acid methyl ester-7'-acetate;
5-(7'-exo-formyl-8'-endo-hydroxy-2'-oxa-bicyclo[3.4.0~nonan-3'-yl)-pentanoic
acid methyl ester;
4-(6'-exo-formyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'-yl)-butanoic
acid methy~l ester.
Example 35
To a solutLon of 1.2 g o~ 5-(6'-exo-benzyloxymethyl-2'-oxa-bicyclo
~3.3.0]octan~3~-yl)-pcntanoic acid methyl ester in methanol:methyl acetate
(L0 ml:10 ml) is added 2 ml of a O;lN methanol solution of HCl. After 0.15 g
5~
of PtO2 is added, the mixture is hydrogenated at ambient temperature and pres-
sure until 1 molar equivalent of hydrogen is abosrbed. After the removal of
the gas under vacuum and washing with nitrogen, the suspension is filtered,
neutralized, and evaporated to dryness. The residue is taken up in water/
ethyl acetate, and the organic phase yields 0.84 g of 5-(6'-exo-hydroxymethyl-
2t-oxa-~icyclo[3.3.o]octan-3l~-yl)-pentanoic acid methyl ester. This is then
oxidized to the 6'-exo-formyl derivative by the procedure in example 1, using
dicyclohexylcarbodiimide in DMSO:benzene ~25:75).
Example 36
To a solution of 18.1 g of 5~-tetrahydropyranyloxymethyl-2~,4~-
dihydroxy-cyclopent-lti-acetic acid-y-lactone-4-tetrahydropyranyl ether in 150
ml of toluene cooled to -70C is added in 30 minutes ]28 ml of a 5M solution
of di-iso-butylaluminum hydride (1.2M/M). After 30 minutes at -70 C, 128 ml
of a 2M toluene solution of lsopropanol is added and the solution is brought
to 0C. Then 10 ml of a saturated aqueous solution of NaH2P04 is added and
the mixture is stirred for four hours. Following the addition of 10 g of
anhydrous Na2SO4 and 10 g of fil~ering earth, the solution is filtered and
evaporated to dryness to give 18.1 g of 5~-tetrahydropyranyloxymethyl-2~,4a-
dihydroxy-cyclopent-lt~-ethanal-y-lactol-4-tetrahydropyranyl ether. A solution
o~ this in 24 ml of anhydrous DMS0 is added dropwise to a solution of the
ylide prepared as follows: 9.6 g of 80% sodium hydride in 300 ml of DMSO is
heated for four hours at 60C. Then after the mixture is brought to 18 - 20C,
67 g o 4-car~oxybut~ltriphenyl phosphonium bromide dissolved in 80 ml of an-
hydrous DMSO is added while maintaining a temperature of 20 - 22C to generate
a bright red color. After four hours of stirring, 600 ml of water is added
and the mixture Ls extracted with ethyl ether:benzene ~70:30) to remove the
triphenylphosphine oxide. The benzene organic phase is re-extracted with
~.
. . ~ . .
0.lN NaOH and then with water until neutral; it is then discarded. The
alkaline aqueous phase is acidified to pll 5 - 4.8 and then extracted with
ethyl ether:pentane ~1:1) to give 21.6 g of 5-cis-7-~2'~,4'~-dihydroxy-5'~-
tetrahydropyranyloxymethyl-cyclopent-l~-yl)-hept-S-enoic acid-4'-~etrahydro-
pyranyl ether, which may be converted to its methyl ester by treatment with
diazomethane in ether. 7.72 g of this ester in 28 ml of tetrahydrofuran is
added dropwise to a yellow-brown suspension formed by adding 28 ml of THF to a
solution of 6.13 g of mercuric acetate in 28 ml of water. After the mixture
is stirred ~or 20 minutes at room temperature, it is coo]ed in an ice:water
btath and 810 mg of NaBH4 in 14 ml of water is added drt~ise. Elemental mercury
precipitates out, che suspension is decanted, the tetrahydrofuran is evaporated
at reduced pressure and the residue is extracted with ethyl ether. Removal of
the solvent affords 7.5 g of 5-~6'-exo-tetrahydropyranyloxymethyl-7'-hydroxy-
2'-oxa-bicyclo~3.3.0]octan-3",-yl)-pentanoic acid methyl ester-7'-tetrahydro-
pyranyl ether; 0.42 g of _-toluenesulfonic acid is then added to a solution of
this in 30 ml of methanol. After 2 hours at room temperature, the solution is
concentrated under vacuum and water is added. After extraction with ether and
chromatography on silica gel with ethyl ether as eluent, one obtains 2.4 g of
5-(6'-exo-hydroxymethyl-7'-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'-exo-yl)-
2Q pentanoic acid methyl ester and 2.6 g of the 3'-endo isomer.
Example 37
2.5 g of N-iodosuccinimide is added to a solution of 4.26 g of 5-
cis-7-~2'~,4'u-dihydroxy-5'~-tetrahydropyranyloxymetllyl-cyclopent-1'~-yl)-
hept-5-enoic acid-4'-tetrahydropyranyl ether in CH2C12:CC14 ~10 ml:10 ml) and
the resultlng mixture is stirred for four hours. 30 ml of anhydrous methanol
containing 130 mg of ~-toluenesulfonic acid is added and stirring is continued
eor allother 2 hours. 0.2 ml of pyridine is added, the mixture is reduced to
small volume, and the residue is taken up in water/ethyl acetate. Af~er
washillg with Na2S2O3 and then water until neutral, the organic phase is evap-
~;
orated to dryness to give a residue that is adsorbed on silica gel and eluted
with ethyl ether to give 2.2 g of 5-iodo-5-~6'-exo-hydroxymethyl-7'-hydroxy-
2'-oxa-bicyclo[3.3.0]octan-3'-exo-yl)-pentanoic acid methyl ester and 1.85 g
of the 3'-endo isomer.
~xample _
Following the procedure of example 37, but using the methyl ester
inst0ad of the acid and N-bromoacetamide instead of N-iodosuccinimide, the
5-bromo-5-(6'-exo-hydroxymethyl-7'-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'-yl)-
pentanoic acid methyl ester is prepared. Silica gel chromatography allows
the separation into the 3'-cxo and 3'-endo isomers.
Example 39
A solution of 0.86 g of pyridine and 2.2 g of 5-cis-7-(2'~,4'~-di-
hydroxy~5'~-tetrahydropyranyloxymethyl-cyclopent-1'~-yl)-hept-5-enoic acid
methyl ester-4'-tetrahydropyranyl ether in dichloromethane (20 ml) is cooled
to -30C and 0.38 g of chlorine in 10 ml of CC14:CH2C12 ~1:1) is addedO The
mixture is stirred for 2 hours, warmed to room temperature, and washed with
2N H2S04 and then water until neutral. After evaporation of the solvent, the
residue is dissolved in methanol ~10 ml) and treated with 0.1 g of _-toluene-
sulfonic acid. The solution is then concentrated, diluted with water, and
extracted with ethyl acetate. Removal o the solvent and purification of the
residue on silica gel afford 0.6 g of 5~chloro-5-~6'-exo-hydroxymethyl-7'-
endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'-exo-yl)-pentanoic acid and 0.71 g
of the 3'-endo isomer.
~xample 40
To a solution of 0.356 g o 5-iodo-5-~6'-exo-hydroxymethyl-7'-endo-
hydroxy-2'-oxa bicyclo[3.3.0~octan-3'-exo-yl)-pentanoic acid methyl ester in
4.8 ml oE benzene:~MS0 ~75:25) are added, in order, 0.28 g of dicyclohexyl-
carbodiimide and 0.4 ml of a pyridinium trlfluoroacetate solution ~see example
~ ~
~ ~39~
1). Ater 3 hours of stirring, 8 ml of benzene and then aqueous oxalic acid
~94 mg in 1.2 ml) are added. The precipitate is removed by filtration and
the benzene solution is washed with water until neutral. Removal of the sol-
vent affords 0.32 g of 5-iodo-5-(6'-exo-formyl-7'-endo-hydroxy-2'-oxa-bicyclo
[3.3.0]octan-3'-exo-yl)-pentanoic acid methyl ester.
Example 41
Upon oxidation of the 6'-exo-hydroxymethyl-7'-endo-hydroxy deriva-
tives prepared according to examples 36 - 39, following the procedure of ex-
ample 40, the corresponding 6'-exo-formyl derivatives are prepared.
Example 42
A solution of 3.4 g of (2-oxo-heptyl)dimethoxyphosphonate in 50 ml
of dimethoxyethane i5 added dropwise to a suspension of 0.45 g of 80% NaH
(mineral oil dispersion). After stirring for 1 hour, a solution of 2.7 g of
5-(6'-exo-formyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'~-yl)-pentanoic
acid methyl ester in 40 ml o~ dimethoxyethane is added. In 10 minutes this
is diluted with 50 ml of a 30% aqueous solution of monobasic sodium phosphate.
The organic phase is separated, the aqueous phase is re-extracted, and the
combined organic extract is evaporated. Purification of the crude product on
50 g of silica gel ~cyclohexane:ethyl ether, 50:50) gives l.lg of 5-[6'-exo-
~3"-oxo-oct-1"-trans-en-1"-yl)-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'-
endo-yl~-pentanoic acid methyl ester or 13t-6~H-6(9~)-oxide-11~-hydroxy-15-
oxo-prost-13--enoic acid methyl ester and 0.98 g of 5-[6'-exo-(3"-oxo-oct-1"-
trans-en~ yl)-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'-exo-yl]-pen-
tanoic acid methyl ester or 13t-6~H-6~9~)-oxide-11~-hydroxy-15-oxo-prost-13-
enoic acid methyl ester, plus 0.9 g of a 1:1 mixture of the two isomers ~3'-
exo and 3'-endo~ or 6~H and 6~H). This last mixture is separated into its
t~o isomeric components b~ thin layer chromatography with ethyl ether. They
show the Eollowing absorptions, respectively:
~3
~ Mex~l = 230 m~, = 13,070; ~ MnaXll ~ 228 m~ = 12,~00.
N-M-R- ~CDC13) 0.9 t 3H C20-CH3, 3.68 s 3H CO2CH3, 6.16
d lH vinylic proton at Cl~ (JH14-H15
6.71 q lH vinylic proton at C13 ~ H13 z
B~ the same proced~re, from the corresponding 5-H and 5-halo com-
pounds, the following prostenoic acid derivatives are prepared:
13t-6aH-6(g~)-oxide-15-oxo-prost-13-enoic acid methyl ester;
13t-6aH-6(9a)-oxide-5-chloro-15-oxo-prost-13-enoic acid methyl ester;
13t-6aH-6(9a~-oxide-5-bromo-15-oxo-prost-13-enoic acid methyl ester;
13t-6aH-6(9a)-oxide-5-iodo-15-oxo-prost-13-enoic acid methyl ester;
13t-6aH-6(9a)-oxide-5-chloro-lla-hydroxy-15-oxo-prost-13-enoic acid methyl
ester;
13t-6aH-6(9a)-oxide-5-bromo-lla-hydroxy-15-oxo-pros~-13-enolc acid methyl
ester,
N.M.R. ~ 3.67 s 3H C02CH3, 3.95 m 4H C5, Cg, Cll protons and Hx/Hy proton at
C4; 4.3 m lH 6aH; 6.15 d lH C14 proton; 6.63 q lH C13 proton;
13t-6aH-6(9a)-oxide-5-iodo-11~-hydroxy-15-oxo-prost-13-enoic acid methyl
ester,
N-.M.R. 0.9 s 3H C20CH3, 3.53 m lH pro~on at C5, 3.6 s 3H CO2CH3 3.9 m H
proton at C4, ~.1 m 2H proton at C9, Cll; 4.4.m lH 6aH; 6.2 d lH proton at
Cl~ 6.75 q lH proton at C13;
13t-6~H-6~9a)-oxide-15-oxo-prost-13-enoic acid methyl ester;
13t-6~H-6(9a)-oxide-5-chloro-15-oxo-prost-13-enoic acid methyl ester;
13t-6~H-6(9a)-oxide-5-bromo-15-oxo-prost-13-enoic acid methyl ester;
13t-6~ 6(9a)-oxide-Ci-iodo-15 oxo-prost-13-enoic acid methyl ester;
13t-6~H-6~9a)~oxide-C;-chloro-lla-hydroxy-15-oxo-prost-13-enoic acid methyl
e~ter;
~t~1~3' -~
13t-6~1l-6(9~)-oxide-5-bromo-11~-hydroxy-15-oxo-prost-13-enoic acid methyl
ester,
N.M.R.: 3.65 s 3H C02CH3; 4.00 m 3H proton at C5, C9, Cll, 4.6 m lH 6~H;
6.2 d lH proton at C14; 6.64 q lH proton at C13;
13t-6~H-6~9~)-oxide-5-iodo-lla-hydroxy-15-oxo-prost-13-enoic acid methyl
ester;
N.M.R. 3.66 s 3H C02CH3, 3.96 m 3H protons at Cg, Cll and C5, 4.6 m
lH 6~H, 6.21 d lH proton at C14 6.75 q lH proton at C13.
~ le 43
A solution of 2.16 g of (2-oxo-octyl)dimethylphosphonate in 20 ml
of benzene is added dropwise to a suspension of 292 mg of NaH ~75% mineral
oil dispersion) in 30 ml of benzene. After 30 minutes of stirring, a solu-
tion of 2~6 g of 4-bromo-4-~7'-exo-formyl-8'-endo-hydroxy-2'-oxa-bicyclo[3.4.
O]nonan-3'~-yl)-butanoic acid methyl ester in 20 ml of benzene is added drop
by drop. Stirring is continued for another 30 minutes, and 24 ml of a 30%
aqueous solution of NaH2PO4 is added. The organic phase is separated, and
the aqueous phase is re-extracted tYith benzere. The organic layers are com-
bined and evaporated to dryness. The residue is purified on silica gel (50 g)
Nith CH2C12:ethyl ether ~120:40) as eluent to give 0.52 g of 4-bromo-4-[7'-
exo-~3"-oxo-oct-1"-trans-1"-enyl)-8'-endo-hydroxy-2'-oxa-bicyclo[3.4.0]nonan-
3'-endo-yl]-butanoic acid methyl ester or 13-trans-4-bromo-5~H-5~9~)-oxide-
ll~-hydroxy-15-oxo-prost-13-enoic acid methyl ester and 1.45 g of 4-bromo-4-
~7'-exo-~3"-oxo-oct-1"-trans-1"-enyl)-8'-endo-hydroxy-2'-oxa-bicyclo[3.4.0]
nonan-3'-exo-yl]-butanoic acid methyl ester or 13-trans-4-bromo-5~H-5~9~)-
axide~ -hydroxy-15-oxo-prost-13-enoic acid methyl ester. Methanolic solu-
tions Oe these ttYo compounds absorb in the UV at
A n~ax ~ 230 m~, - 10,640, and A MmaxH = 229 m~, = 11,600, respectively.
`'1-'"~
.. i.~ _~
39
The same procedure, starting from the 4-}l and 4-halo bicyclo deriva-
tives, gives the following prostenoic acids:
13-trans-5~H-5(9a)-oxide 15-oxo-prost-13-enoic acid methyl ester;
13-trans-5~H-5(9a)-oxide-lla-hydroxy-15-oxo-prost-13-enoic acid methyl ester;
13-trans-4-chloro-5~H-5(9a)-oxide-15-oxo-prost-13-enoic acid methyl ester;
13-trans-4-chloro-5~H-5(9a)-oxide-lla-hydroxy-15-oxo-prost-13-enoic acid
methyl ester;
13-trans-4-hromo-5~H-5~9a)-oxide-15-oxo-prost-13-enoic acid methyl ester;
13-trans-4-bromo-5~H-5(9a)-oxide-lla-hydroxy-15-oxo-prost-13-enoic acid
methyl ester;
13-trans-4-iodo-5~H-5(9a)-oxide-15-oxo-prost-13-enoic acid methyl ester;
13-trans-4-iodo-5~H-5(9a)-oxide-lla-hydroxy-15-oxo-prost-13-enoic acid methyl
ester;
13-_rans-5aH-5(9a)-oxide-15-oxo-prost-13-enoic acid methyl ester;
13-trans-5aH-5(9a)-oxide-lla-hydroxy-15-oxo-prost-13-enoic acid methyl ester;
13-trans-4-chloro-5aH-5~9a)-oxide-15-oxo-prost-13-enolc acid methyl ester.
13-trans-4-chloro-5aH-5(9~)-oxide-lla-hydroxy-15-oxo-prost-13-enoic acid
methyl ester;
13-trans-4-bromo-5aH-5(9a)-oxide-15-oxo-prost-13-enoic acid methyl ester;
13-trans-4~bromo-5aH-5(9a)-oxide-lla-hydroxy-15-oxo-pros~-13-enoic acid
methyl ester;
13-trans-4-iodo-5aH-5~9a)-oxide-15-oxo-prost-13-enoic acid methyl ester;
13-trans-4-iodo-5aH-5(9a~-oxide-lla-hydroxy-15-oxo-prost-13-enoic acid methyl
ester.
F.xample 44
By the procedure o example 42~ the reaction o~ 620 mg of (2-oxo-3-
methyl-4-llutox~butyl) phosphonate with 74 mg of NaH (75%) and 0,43 g o~ 5_~
exo-:~ormyl-7'-endo-hydroxy-2'-oxa-bicyclo~3.3.0~octan-3''-yl)-pentanoic acid
1' ~ ~~
3~
methyl ester in dimethoxyethane gives, after chromatography on silica gel
(25 g) with 1:1 ethyl ether:hexane as eluentJ 0.15 g of 13t-6~H-6~9~)-oxide-
ll~-hydroxy-15-oxo-16-methyl-16-butoxy-18~19,20-trinor-prost-13-enoic acid
methyl ester ~ = 238 m~, ~ = 14,500) and 300 mg of the 6~H-isomer
~-~ max = 237 m~, ~ = 12,280)-
Mass spectrum: m/e 410 M , m/e 392 M -H20;
m/e 379 M -OCH3; m/e 295 M -115, m/e 115 ~0-C4H9 -
The two isomers present similar spectra with minimal differences at levelof secondary fragmentation.
Using the same procedure the 5-chloro, 5-bromo and 5-iodo 13t-6~H-
6~9~)-oxide-11~-hydroxy-15-oxo-16-methyl-16-butoxy-18,19,20-trinor-prost-13-
enoic acid methyl ester.
Example 45
By the procedure of example 44, from 4-~7'-exo-formyl-7'-endo-
hydroxy-2'-oxa-bicyclo[3.4.0]nonan-3'~-yl)-butanoic acid methyl ester and the
4-iodo bicyclic derivative the following are obtained:
13t-5~H-5(9~)-oxide-11~-hydroxy-15-oxo-16-methyl-16-butoxy-18,19,20-trinor-
prost-13-enoic acid methyl ester;
13t-4-iodo-5~H-5~9~)-oxide-11~-hydroxy-15-oxo-16-methyl-16-butoxy-18,19,20-
trinor-prost-13-enoic acid methyl ester;
13t-5~1-5~9~)-oxide-11~-hydroxy-15-oxo-16-methyl-16-butoxy-18,19,20-trinor-
prost-13-enoic acid methyl ester;
13t-4-iodo-5~H-5~9~)-oxide~ -hydroxy-15-oxo-16-methyl-16-butoxy-18,19,20-
trinor-prost-13-enoic acid methyl ester.
Example 4~
To a suspension of 45 mg of 80~ Nall in 10 ml of benzene is added a
solution of 375 mg of ~2-oxo-3,3-dimethyl-heptyl)-dimethylphosphonate in 10
ml o~ benzene, followed 30 minutes later by a solution of 0.305 g of 5-iodo-
5-(6'-exo-formyl-21-oxa-bicyclo[3.3.0]octan-3'~-yl)-pentanoic acid methyl
es~er. After stirring for 45 minutes, the mixture is diluted with 10% aqueous
NaH2P04. The organic phase is washed until neutral, dried and concentrated
to small volume. Adsorption on silica gel and elution with cyclohexane:ethyl
ether ~90:10) give 0.12 g of 13t-5-iodo-6~,H-6(9~)-oxide-15-oxo-16,16-dimethyl-
prost-13-enoic acid methyl ester and 0.095 g of 13t-5-iodo-6~H-6(9~)-oxide-15-
oxo-16,16-dimethyl-13-enoic acid methyl ester.
Example 47
By substituting in the procedure of example 46 the formyl derivatives
prepared according to example 34, the following 16,16-dimethyl derivatives are
prepared:
13t-6~H-6(9~)-oxide-15-oxo-16,16-dimethyl-prost-13-enoic acid methyl ester;
13t-6~H-6(9~)-oxide-11~-hydroxy-15-oxo-16,16-dimethyl-prost-13-enoic acid
methyl ester;
13t-5~H-5(9u)-oxide-15-oxo-16,16-dimethyl-prost-13-enoic acid ~nethyl ester;
13t-5~H-5(9~)-oxide-llu-hydroxy-15-oxo-16,16-dimethyl-prost-13-enoic acid
methyl ester;
13t-5-chloro-6~H-6(9u)-oxide-15-oxo-16,16-dimethyl-prost-13-enoic acid methyl
ester;
13t-5-chloro-6~H-6(9c~)-axide-llc~-hydroxy-15-oxo-16,16-dimethyl-prost-13-enoic
acid methyl ester;
13t-4-chloro-5~H-5(9u)-oxide-15-oxo-16/16-dimethyl-prost-13-enoic acid methyl
ester;
13t-4-chloro^5~H-5(9u)-oxide-llu-hydroxy-15-oxo-16,16-dimethyl-prost-13-
enolc acicl methyl est:er;
13t-5-bromo-6~H-6(9~)-oxide-15-oxo-16,16-dimethyl-prost-13 enoic acid methyl
s~
ester;
13t-5-~romo-6~H-6~9~)-oxide-lla-hydroxy-15-oxo-16,16-dimethyl-prost-13-enoic
acid methyl ester;
13t-4-bromo-5~H-5(9~)-oxide-15-oxo-16,16-dimethyl-prost-13-enoic acid methyl
ester;
13t-4-bromo-5~H-5~9~)-oxide-11~-hydroxy-15-oxo-16,16-dimethyl-prost-13-enoic
acid methyl ester;
13t-5-iodo-6~H-6(9a)-oxide-15-oxo-16,16-dimethyl-prost-13-enoic acid methyl
ester;
13t-5-iodo-6~H~6~9a)-oxide-lla-hydroxy-15-oxo-16,16-dimethyl-prost-13-enoic
acid methyl ester;
13t-4-iodo-5~H-5(9a)-oxide-15-oxo-16,16-dimethyl-prost-13-enoic acid methyl
ester;
13t-4-iodo-5~H-5(9a)-oxide-lla-hydroxy-15-oxo-16,16-dimethyl-prost-13-enoic
acid methyl ester;
13t-6aH-6(9a)-oxide-15-oxo-16,16-dimethyl-prost-13-enoic acid methyl ester;
13t-6aH-6~9a)-oxide-lla-hydroxy-15-oxo-16,16-dimethyl-prost-13-enoic acid
methyl ester;
13t-5~H-5(9a)-oxide-15-oxo -16,16-dimethyl-prost-13-enoic acid methyl ester;
13t-5aH-5(9a)-oxide-lla-hydroxy-15-oxo-16,16-dimethyl-prost-13-enoic acid
methyl ester;
13t-5-chloro-6aH-6(9a)-oxide-15-oxo-16,16-dimethyl-prost-13-enoic acid methyl
ester;
13t-5-chloro-6aH-6~9a)-oxide-lla-hydroxy-15-oxo-16,16-dimethyl-prost-13-enoic
acid methyl ester;
13t-4-chloro-5a~l-5(9a)-oxide-15-oxo-16,16-dimethyl-prost-13-enoic acid methyl
ester;
13t~_chlorc)-5all_5(,9a)-Qxide~lla_hydroxy-15-oxo-16,16-dimethyl-prost-13-enoic
acid methyl ester;
13t-5-bromo-6~H-6~9~)-oxide-15-oxo-16,16-dime~hyl-prost-13-enoic acid methyl
ester;
13t-5-bromo-6~H-6(9~)-oxide-11~-hydroxy-15-oxo-16,16-dimethyl-prost-13-enoic
acid methyl ester;
13t-4-bromo-5~H-5(9~)-oxide-15-oxo-16,16-dimethyl-prost-13-enoic acid methyl
ester;
13t-4-~romo-5~H-5(9~)-oxide-11~-hydroxy-15-oxo-16,16-dimethyl-prost-13-enoic
acid methyl ester;
13t-5-iodo-6~H-6(9~)-oxide-15-oxo-16,16-dimethyl-prost-13-enoic acid methyl
ester;
13t-5-iodo-6cLH-6(9~)-oxide-llcL-hydroxy-15-oxo-16,16-dimethrl-prost-13-enoic
acid methyl ester;
13t-4-iodo-5~H-5(9~)-oxide-15-oxo-16,16-dimethyl-prost-13-enoic acid methyl
ester;
13t-4-iodo-5~H-5(9~)-oxide-lla-hydroxy-15-oxo-16,16-dimethyl-prost-13-enoic
acid methyl ester;
Example 48
To a suspension of 178 mg of Nall (75% mineral oil dispersion) in
15 ml of benzene is added dropwise a solution of 1.55 g of [2-oxo-3(S,R)-
fluoro-4-cyclohexyl-butyl]-dimethylphosphonate in 10 ml of anhydrous benzene.
After 30 minutes of stirring, a solution of 1 g of 5-(6'-exo-formyl-7'-endo-
hy~roxy-2'-oxa-bicyclo~3.3.0]octan-3'~-yl)-pentanoic acid methyl ester is
added and stirring is continued for another hour. The mixture is neutralized
with 30% aqueous Na~l2PO~ and the organic phase is separated, concentrated
~md adsorbed on silica gel. Elution with CH2C12:Et20 (90:10) gives, 0.62 g of
13t~6~ 6(9~)-oxide-11~-hydroxy-15-oxo-16(S,R)~Eluoro-17-cyclohexyl-18,19~20-
trinor-~rost~13-enoic acid methyl ester
~-3
~3~33~
MeOH = 238 m~, E = 12~765) and 0.31 g of the 6~H isomer ~ = 238 m~,
~ = 9,~70)-
The N.M.R. data for the former compound are the following (CDC13) p.p.m.
3.64 s 3H C02CH3, 3.8 m lH Cg proton, 4.03 q lH proton at Cll, 4.3 m lH S~H,
5.00 and 5.55 t,t 1/2 H~ 1/2 H proton at C16 3~1P 55 Hz, 6.54 q lH proton at
C14 6. q p 13 H14-H12 ' H13-H12 ' H13-H14
Treating this compound with pyridine and acetic anhydride it is converted into
the ll-acetoxy derivative, for which N.M.R. data are: ~CHC13) p.p.m. 2002
s 3H OCOCH3, 3.64 s 3H C02CH3, 3.8 proton at Cg, 4.25 m lH 6~H; 4.66, 5.22
t-t- 1~2 H, 1/2 H proton at C16; 4.97 q lH pro~on at Cll; 6.51 proton at C14,
6.90 proton at C13;
For the diastereoisomeric hydroxy ketones the mass spectrum shows the follow-
ing masses:
M 424 m/e and then M -H20, M -HF, M -~130H/CH20
M -CH2=CHOH (basis ion) M -115 M -44-59 and M -~CHF-CH2-C~Hll).
In mass spectrum of exo-diastereoisomer the following masses are predominant:
M -CH30H and M -44-28; in that of endo-diastereoisomer the predominant ones
are M -CH30 and M+-44-18.
From the 5-bromo derivative, 13t-5-bromo-6~H-6(9a)-oxide-11~-hydroxy-
15-oxo-16(5,R)-fluoro-17-cyclohexyl-18,1g,20-trinor-prost-13-enoic acid
methyl ester is prepared.
Example 49
Subs,tituting in the procedure of example 48 a phosphonate chosen
from (2-oxo-4-cyclohexyl-butyl)-dimethylphosphonate and (2-oxo-4-phenyl-butyl)-
dimethylphosphonate~ the ~ollowing we~e prepared:
~'
~13~
13t-6~H-6(9~)-oxide-11~-hydrox~-15-oxo-17-c~clohexyl-18,19,20-trinor-prost-
13-enoic acid meth~l ester,
13t-6~H-6(9~)-oxi~e-11~-h~droxy-15-oxo-17-phen~1-18,19,20-trinor-prost-13-
enoic acid methyl ester and their 6~H isomers.
Example 50
To a suspension of 178 mg of NaH (75% mineral oil dispersion) in
anhydrous tetrahydrofuran at 0C is added dropwise ~ith stirring a solution
of 1.63 g of 2-oxo-3-~m-chlorophenoxy)-propyl-dimethylphosphonate in 10 ml
of anhydrousTHF. After 30 minutes of stirring, a solution of 1 g of 5-(6'-
exo-formyl-7'-endo-2'-oxa-blcyclo[3.3.0]octan-3'~-yl)-pentanoic acid methyl
ester is added and stirring is continued for another hour. The mixture is
acidlfied wi~h aqueous NaH2PO4J the organic phase is separated, and the aque-
ous phase is re-extracted with~benzene. From the combined organic ex~ract,
after chromatography on silica gel with CH2C12:Et2O (95:5) as eluent, one
obtains of 0.43 g of 13t-6~H-6~9~)-oxide-11~-hydroxy-15-oxo-16-m-chloro-
phenoxy-17,18,19,20-tetranor-prost-13-enoic acid meth~l ester
~ MeOH = 227 m~, c = i6,800) and 0.11 g of the 6~H isomer (~max = 224 m~,
F = 16,900)-
Both the diastereoisomers show the mass peak m/e 436 according to
C23H29C106. This ion is invoived in the ~ollowing fragmentation:
M -H2O, M -OCH3/CH3OH, M -44~ M -~O-C6H4Cl), M -H2O-(O-C6H4Cl) and
M -~CH2)4-CO2CH3, so furthermore confirming the proposed structure.
The following differences are between the ~wo diastereoisomers: the exo 6~H
isomer shows a peak at hl -32 and a little intense peak at M -44 on the other
hand the endo 6~H isomer shows a peak at M -31 and an intense peak M -44.
Example 51
The substitution of a phosphonate chosen from 2-oxo-3-(m-trlfluoro-
- ~7~
,i , ''
~ ~ ................................................................. ...
methylphenoxy)-propyl-dimethylphosphonate and 2-oxo-3-(~-fluorophenoxy)-
propyl-dimethylphosphonate in the procedure of example 50 leads to the follow-
ing compounds, respectively:
13t-6~H-6~9~)-oxide~ hydroxy-15-oxo-16-m-trifluoromethylphenoxy-17,18,
19,20-tetranor-prost-13-enoic acid methyl ester,
13t-6~H-6~9~)-oxide-11~-hydroxy-15-oxo-16-_-fluorophenoxy-17,18,19,20-
tetranor-prost-13-enoic acid methyl ester, and their 6~H isomers.
The mass spectra of all the compounds agree with the proposed structure for
example showing the mass peak M -115; an interesting difference between the
endo- and exo- trifluoromethyl analogous is that the mass peaks M -CH30H and
M -CF3-C6H4-OH are in the exo-isomer and the mass peak M -CH30 and M -C~3-C6H4-O
are in the endo-isomer.
Example 5?
The substitution of ~2-oxo-3S-methyl-butyl)-dimethylphosphonate for
the phosphonate in the procedure of example 48 gave 13t-6~H-6~9~)-oxide-11~-
hydroxy-15-oxo-16S-methyl-prost-l3-enoic acid methyl ester and its 6~H isomer.
To a solution o-f 2.2 g of the 6~H isomer in 2.6 ml of pyridine, cooled to 0C,
is added 1.05 ml of acetic anhydride. The solution is held at 0C overnight
and then added to an excess of cold 0.05N sulfuric acid. Extraction with
ethyl ether and evaporation to dryness give 2.3 g of 13t-6~H-6~9~)-oxide-11~-
hydroxy-15-oxo-16S-methyl-prost-13-enoic acid methyl ester-ll-acetate
MeOH = 229 m~, = 12,050)-
875 mg of bromine in glacial acetic acid is added dropwise to a
solution of the latter compound in 10 ml of glacial acetic acid, until a
llght orange color appears. 1.52 g of anhydrous potassium carbonate is then
added and the resulting mixture is held at 80C for 4 - 5 hours to comple~e
the precipitation oE potassium bromide. E~cessacetic acid is removed ~mder
73~
~:3 ~
vacuum, water is added, and the pH is brought to pH 6.8 with alkaline hydrate.
This is then extracted with ethyl ether and the organic phase is reduced in
volume. Adsorption on silica gel and elution with methylene chloride:ethyl
ether ~70:30) gives 2.01 g of 13t-6~H-6(9~)-oxide-ll~-hydroxy-14-bromo-15-oxo
15S-methyl-prost-13-enoic acid methyl ester-ll-acetate,
max = 249 m~, = 11,450.
The 6~H isomer is similarly prepared.
Example 53
A solution of 2.06 g of ~2-oxo-3S-methylheptyl)-dimethylphosphonate
in 20 ml of dimethoxyethane is added dropwise to a suspension of 0.265 g of
NaH (80% mineral oil dispersion) in DME (10 ml). After stirring for 30 mi-
nutes, 1.6 g of N-bromosuccinimide is added and vigorous stirring is continued
for 10 minutes. 1.35 g of 5-~6'-exo-formyl-7'-endo-hydroxy-2'-oxa-bicyclo
[3.3.0]octan-3'~-yl)-pentanoic acid methyl ester in 5 ml of dimethoxyethane
is then added. The mixture is stirred for 1 hour and 20 ml of 30% NaH2P04
is added. After the usual work-up, crude 14-bromo-enone is obtained.
Separation on silica gel with methylene chloride:ethyl ether ~85:15) gives
0.9 g of 13t-6~H-6~9~)-oxide-11~-hydroxy-14-bromo-15-oxo-16S-methyl-prost-13-
enoic acid methyl ester and 0.92 g of the 6~H isomer. Upon treatment wi~h
0.4 ml of pyridine and 0.2 ml of acetic anhydride, 0.2 g of the 6~H isomer
gives 0.205 g of the ll-acetoxy derivative~ identical in all respects with
that made by the procedure of example 52.
Example 54
A 501ution o$ 0.43 g of ~2-oxo-octyl)-dimethylphosphonate in 10 ml
of ~enzene is added dropwise to a suspension of 54 mg of NaH ~80% mineral oil
di~persion) in 5 ml of benzene. After 1 hour, when the evolution of H2 has
ccnsed, 0.32 g Oe n-bromosuccinimide is added all at once. To the carbanion
thus prepared, Oe (l-~romo-2-oxo-octyl)-dimethylphosphonate is added a solution
'~3 ,~'
~33~
" ~ .
of 270 mg of 5~6'-exo-formyl-7' endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'~-
yl)-pentanoic acid methyl ester in 8 ml of benzene. After 30 minutes, the
reaction is ~enched by the addition of 20 n~ of a 10% solution of N~12P04.
The organic phase, after being washed until neutral, gives 0.31 g of
13t-6~H-6(9)-oxide-11-hydroxy-14-bromo-15-oxo-20-methyl-prost-13-enoic acid
methyl ester; this is then separated into the 6aH and 6~H isomers.
Example 55
Upon substitution of the ~2-oxo-octyl)-dimethylphosphonate in the
procedure of example 54 with ~2-oxo-4-cyclohexyl-butyl)-dimethylphosphonate
and (2-oxo-4-phenyl-butyl)-dimethylphosphonate, the following compounds were
prepared:
13t-6~H-6(9a)-oxide-11-hydroxy-14-bromo-15-oxo-17-cyclohexyl-18,19,20-
trinor-prost-13-enoic acid methyl ester;
13t-6~H-6(9a~-oxide-lla-hydroxy 14-bromo-15-oxo-17-phenyl-18,19,20-trinor-
prost-13-enoic acid methyl ester.
Example 56
By substituting the formyl derivatives in examples 53, 54 and 55
with 5-iodo-5-(6'-exo-formyl-7'-endo-hydroxy-2'-oxa-bicyclo[3.3.0]octan-3'~-
yl)-pentanoic acid methyl ester, 4-iodo-4-(7'-exo-formyl-8'-endo-hydroxy-2'-
oxa-bicyclo[3.4.0]nonan-3'~-yl)-butanoic acid methyl ester, and the correspond-
ing 4-H derivative, the following compounds were prepared:
13t-s-iodo-6~H-6(9a)-oxide-lla-hydroxy-l4-bromo-l5-oxo-l6s-methyl-prost-l3
enoic acid methyl ester;
13t-4-iodo-5~H-5(9a)-oxide-ll-hydroxy-l4-bromo-l5-oxo-l6s-methyl-prost-l3
enoic acid methyl ester;
13t-5~l~5(9a~oxide-11~-hyd~oxy~14~bromo 15-oxo-16S-methyl-pTost^13-enoic
acid methyl ester;
~ ~ ~ 7~
~ ~3g~
13t-5-iodo-6~H-6(9~)-oxide-11~-hydroxy~14-bromo-15-oxo-20-methyl-pros~-13-
enoic acid methyl ester;
13t-4-iodo-5~H-5(9a)-oxide-11~-hydroxy-14-bromo-15-oxo-20-methyl-prost-13-
enoic acid methyl ester;
13t-5~H-5(9~)-oxide~ -hydroxy-14-bromo 15-oxo-20-methyl~prost-13-enoic acid
methyl ester;
13t-5-iodo-6BH-6~9~)-oxide-11~-hydroxy-14-bromo~15-oxo-17-cyclohexyl-18,19,
20-trinor-prost-13-enoic acid methyl ester;
13t-5~H-5(9~)-oxide-lla-hydroxy-14-bromo-15-oxo-17-cyclohexyl-18,19,20-
trinor-prost-13-enoic acid methyl ester;
13t-5-io~o-6~H-6(9~)-oxide-11~-hydroxy-14-bromo-15-oxo-17-phenyl-18,19,20-
trinor-prost-13-enoic acid methyl ester;
13t-5~H-5(9a)-oxide-lla-hydroxy-14-bromo-15-oxo-17-phenyl-18319,20-trinor-
prost-13-enoic acid methyl ester.
Example 57
A solution of 0.61 g of 2-oxo-octyl-triphenylphosphonium bromide in
6 ml of DMSO is added to a solution of 0.15 g of po~assium t-butylate in 3 ml
of DMSO while keeping the reaction temperature at 16 - 19C. 0.27 g of 5-
~6'-exo-formyl-7'-endo~hydroxy-2'-oxa-bicyclo~3.3.0]octan-3'~-yl)-pentanoic
acid methyl ester in 8 ml of anhydrous tetrahydrofuran is then added. After
30 minutes o~ stirring, an equal volume of water is added and the mixture is
extracted with ethyl e*her. The combined organic extract is washed until
neutral and the solvent is evaporated. Chromatography on silica gel (cyclo-
hexane:ethyl ether, 40:60) gives 0.21 g of 13t-6~H-6~9~)-oxide-ll~-hydroxy-
15-oxo-20-methyl-prost-13-enoic acid methyl ester.
t~
,, ~,
. .,
Subsequent preparative thin layer chromatography (SiO2-Et20) allows separation
of the 6aH and 6~H isomers.
Example 58
A solution of d,l-13t-6aH-6~9a~-oxide-lla-hydroxy-15-oxo-13-enoic
acid methyl ester (exo-isomer at greatest Rf), (0.9 g), in dry ethyl ether
(30 ml) is dripped on to a stirred 0.1 M solution of Zn(BH4)2 in dry ethyl ether
(30 ml), over 15 minutes. After 2 hours, the excess reagent is decomposed by
cautious addition of saturated NaCl solutlon and aqueous 2N sulfuric acid.
The organic layer is separated, washed to neutral and evaporated to dryness
affording a residue which is adsorbed on silica gel, eluted with ethyl ether
to yield 0.38 g of 13t-6aH-6(9a)-oxide-lla,15R-dihydroxy-prostenoic acid
me~hyl ester, as an oil, and 0.42 g of d,l-13t-6aH-6(9a)-oxide-lla,15S-di-
hydroxy-prostenoic acid m0thyl ester, m.p. 69 - 71 C (mass spectrum m/e
350 M -18, 319 M -18 -CH30; 318 M -18-CH3OH~. A solution in methanol (4 ml)
of this ester is treated with 60 mg of li~hium hydroxide and water (0.8 ml)
for 8 hours at room temperature. The methanol is removed in vacuum, ~he
residue is diluted with water and extracted with ethyl ether to remove
neutral impurities. The alkaline phase is treated with aqueous saturated
NaH2PO4 solution until to pH 5 and then extracted with ethyl ether. The
later organic phases are collected to yield after evaporation o the solvents
the free acid d,l-13t-6all-6(9a)-oxide-lla,15S-dihydroxy-prostenoic acid, m.p.
105 - 106C. The 15R-hydroxy compound is a non-crystalli~able oil.
In the same way using nat-keto compound in the reduction reaction
with Zn(BH4)2 we obtained besides the 15-epi alcohol, the nat-13t-6aH-6~9a)-
oxide-lla,15S-dihydroxy-prostenoic acid methyl ester, m.p. 71 - 72C [a]D =
+ 10.2 , [a]365o - * 32.2 (CHC13) and after saponification the free acid
m.p. 101 - 102C [a]l~ = + 6.34, [a]365o = + 33.2 ~CHC13).
B~:
Starting from the endo-diastereoisomers ~more polar compounds),
the following esters were obtained:
13t-6~H-6~9~)-oxide~ ,15R-dihydroxy-prostenoic acid methyl ester ~d,l, nat-,
ent- oils);
13t-6~H-6~9~)-oxide-lla,15S-dihydroxy-prostenoic acid methyl ester ~d, 1, nat-,
[~]D = + 24-5 , [~]365 = ~ 52-9 ~CHC13) oil; ent- [~]D = -22 , oil), and
after saponification the following free acids:
13t-6eH-6~9~)-oxide-11~,15R-dihydroxy-prostenoic acid ~d,l, nat-, ent- oils);
13t-6~H-6~9~)-oxide-11~315S-dihydroxy-prostenoic acid ~d,l oil, nat-, m.p.
78 - 80 C [~]D = + 32-5 ~ [~3365O = + 11-6 ~EtOH), ent- m-p- 78 - 79 C,
[~]D = ~ 31 ~EtOH)).
Example 59
With the temperature of the reaction mixture kept at around -5 to
-8CJ a solutlon of 159 mg of NaBH4 in 7 ml of propan-2-ol, is gradually added
to a solution of 0.332 g of anhydrous CaC12 in propan-2-ol ~ ml); then, under
stirring, a solution of 0.38 g of 13t-6~H-6~9~)-oxide-11~-hydroxy-15-oxo-
16(S,R~-fluoro-17-cyclohexyl-18,19J20-trinor-prost-13-enoic acid methyl ester
in 3 ml of propan-2 ol is added to the above prepared Ca~BH4)2 in a period
of 40 minutes. The reaction mixture is kept under stirring at a temperature
ranging at ~ 5C, then the excess reagent is destroyed by addition of 5 ml of
acetone and 2 ml of water. The solvent is evaporated under vacuum and the
residue is partitioned among water, O.lN H2SO4 and ethyl acetate. The organic
extracts are collected, washed until neutral and after evaporation of solvent
the residue chromatographed on silica gel ~30 g) using CH2Cl2-ethyl ether
70:30 as eluent. The eluate yields 0.21 g of 13t-6~H-6~9~)-oxide-11~,15R-
dihydroxy-16~S,R)~luo~o-17-cyclohexyl -1 8, 1 9, 20-trinor-prost-13-enoic acid
methyl ester, and 0.l4 g oE the 15S-epimer, m.p. 83C - 84C ~from ethyl
ether).
3 ~ ~
In the same way, reductlon of the 6~H-isomer ~220 mg) yields 0.1 g
of 13t-6~H-6~9~)-oxlde-11~,15R-dihydroxy-16(S,R)-fluoro-17-cyclohexyl-18,19,
20-trinor-prost-13-enoic acid methyl ester, m.p. 63 - 6~ C (from isopropylic
ether), and 60 mg of 15S-alcohol.
Example 60
A solution of 0.15 g of 13t-6~H-6(9~)-oxide-11~-hydroxy-15-keto-16-
methyl-16-butoxy-18,19,20-trinor-prostenoic acid methyl ester in methanol
~5 ml) is cooled at -5 . - 10C and reduced by addition of a solution of
NaBH4 ~30 mg) in water (0.5 ml).
The reaction mixture is neutralized by addition of 15% aqueous
NaH2PO~ solution after 15 minutes and then evaporated in vacuum. The aqueous
residue is extracted with ethyl ether to yield a crude mixture of epimeric
15R,15S-alcohols. Chromatographic separation on silica gel ~CH2C12-ethyl
ether 70:30 as eluent) affords respectively 13t-6~H-6~9~)-oxide~ ,15R-di-
hydroxy-16-methyl-16-butoxy-18,19,20-trinor-prostenoic acid methyl ester ~45
mg) and 15S-hydroxy-epimer ~62 mg).
Example 61
By reduction of 13t-5~1-5~9~)-oxide~ -hydroxy-15-keto-16-methyl-
16-butoxy-18J19,20-trinor-prostenoic acid methyl ester, under the same trial
conditions as in the procedure of example 60 followed by chromatographic
separation of the epimeric alcohols ~300 mg) on silica gel ~12 g) with
methylene chloride-ethyl ether 75:25 eluent, we respectively obtained 100 mg
of 13t-5NH-5~9~)-oxide-11~-15R-dihydroxy-15-methyl-16-butoxy-18,19,20-trinor-
prostenoic acid methyl ester, and 110 mg of 15S-epimer. These are then
saponified to yLeld the corresponding free acids.
Exa~nple 62
DrapwisG, ~o a stirred 0.12 M solution o~ zincborohydride in ethyl
cther ~8 ml) a solut:Lon of 0.135 g of 13t-5-bromo-6~H-6~9~)-oxide-11~-hydroxy-
15-oxo-prostenoic acid methyl ester in 2 ml of anhydrous Et2O is added. The
mixture is stirred for 2 hours and th~ excess reagent is decomposed with water-
-2N H2SO4. The organic phase is separated, washed to neutral and evaporated
to dryness. After TLC on silica gel with ethyl ether-ethyl acetate 90:10,
38 mg of 13t-5-bromo-6~H-6~9~)-oxide-11~,15R-dihydroxy-prostenoic acid methyl
ester and 46 mg of 15S-epimer were obtained.
Example 63
Starting from 13t-5,14-dibromo-6~H-6~9~)-oxide-lla-hydroxy-15-oxo-
prostenoic acid methyl ester ~0.2 g) and using a mixture of CH2C12-ethyl
ether 60:40, during the chromatographic separation on silica gel, we obtained
0.056 g of 13t-5~14-dibromo-6~H-6~9~)-oxide-11~,15R-dihydroxy-prostenoic acid
methyl ester and 0.098 g of 15S-isomer.
A solution of this product in methanol is then hydrolized with
aqueous LiOH to yield 72 mg of 13t-5,14-dibromo-6~H-6~9~)-oxide~ ,15S-
dihydroxy-prostenoic acid.
Example 64
Using, in the procedure of example 60, isopropanol as solvent and
NaBH4 ~45 mg), the reduction of 13t-6~H-6~9~)-oxide-11~-hydroxy-15-oxo-16-~m-
trifluoromethyl)-phenoxy-17,18,19,20-tetranor-prost-13-enoic acid methyl ester
~0.47 g) yields 0.20 g of 13t-6~H-6~9~)-oxide-11~,15S-dihydroxy-16-~m-tri-
fluoromethyl)-phenoxy-17,18,19,20-tetranor-prost-13-enoic acid methyl ester,
[~]D = ~ 33.3 ~MeOH) and 0.15 g of 15R-epimer. The 6~H-15S-alcohol epimer
is an oil with [~]D ~ ~ 12 ~MeOH).
Example 65
A solution in dry ethyl ether ~20 ml) of 13t-16S-methyl-6~H-6~9~)-
oxide~ -hydroxy-15-oxo-prost-13-enoic acid methyl ester ~0.002 M, 0.72 g)
ls added to a stirred etheral solution of ~inc borohydride ~0.01 M, 100 ml).
'[`he excess reagent is destroyed, after 30 - 45 minutes, by addition of 2N-
~ &o
~3 513~
sulphuric acid ln NaCl saturated a4ueous solution. The organic phase is
washed until neutral and evaporated to dryness. The residue is chromatog-
raphed on silica gel ~25 g) using methylene-chloride:ethyl ether (80:20)
as eluent affording ~7.5.10 4 M, 0.27 g) of the 15R-hydroxy-isomer and
~l.l.lO 4 M; 0.38 g) of the 15S-alcohol: 13t-16S-methyl-6~1-6~9~)-oxide-11~,
15S-dihydroxy-prost-13-enoic acid methyl ester. ~sing this procedure, the
follo~ing methyl esters ~ere obtained:
13t-6~H-6~9~)-oxide-16S-methyl-11~,15S-dihydroxy-prost-13-enoic acid;
13t-6~H-6(9~)-oxide-16R-methyl-11~,15S-dihydroxy-prost-13-enoic acid;
13t-6~H-6~9~)-oxide-16,16-dimethyl~ ,15S-dihydroxy-prost-13-enoic acid;
13t-6~H-6(9~)-oxide-20-methyl-11~,15S-dihydroxy-prost-13-enoic acid, m.p.
57 - 59 C [~]D = ~14 ~ [~]365 = +47 (CHC13);
13t-6~H-6~9~-oxide-20S-methyl-11~,15S-dihydroxy-prost-13-enoic acid, m.p.
38 - 39 C, [~]D = +21-7 ~ [~]365 = ~77 (CHCl3);
13t-5-bromo-6~H-6(9~)-oxide-16S-methyl-11~,15S-dihydroxy-prost-13-enoic acid;
13t-5-bromo-6~H-6(9~)-oxide-16R-methyl-11~,15S-dihydroxy-prost-13-enoic acid;
13t-5-bromo-6~H-6(9~)-oxide-16,16-dimethyl-11~,15S-dihydroxy-prost-13-enoic
acid;
13t-5-bromo-6~H-6(9~)-oxide-11~,15S-dihydroxy-20-methyl-prost-13-enoic acid,
~]D = + 38 ;
13t-5-iodo-6~H-6(9~)-oxide-16S-methyl-11~,15S-dihydroxy-prost-13-enoic acid;
13t-5-iodo-6~H-6(9~)-oxide-16S-methyl-11~,15S-dihydroxy-prost-13-enoic acid;
13t-5-iodo-6~H 6(9~)-oxide-16R-methyl-11~,15S-dihydroxy-prost-13-enoic acid;
13t-5-iodo-6~H-6(9~)-oxide-16,16-dimethyl-11~,15S-dihydroxy-prost-13-enoic
acid;
13t-5-iodo-6~H-6~9~)-oxide-llN,15S-dihydroxy-20-methyl-prost-13-enoic acid,
[~]D ~ ~ 23 ~ [~]365 = -~ 78 (CHC13);
l3t-5-chloro-6~H-6(9~)-oxide-16S-methyl-11~,15S-dihydroxy-prost-13-enoic acid;
'ID ~
13t-5~ll-5~9~)-oxide-16S-methyl-11~,15s-dihydroxy-prost-13-enoic acid;
13t-5~11-5~9~)-oxide-16,16-dimethyl-11~,15S-dihydroxy-prost-13-enoic acid;
13t-4-bromo-5~1-1-5(9~)-oxide-16S-methyl-11~,15S-dihydroxy-prost-13-enoic
acid;
13t~4-bromo-5~H-5(9~)-oxide-16R-meth~1-11~,15S-dihydroxy-prost-13-enoic
acid;
13t-4-bromo-5~H-5(9~)-oxide-16,16-dimethyl-11~,15S-dihydroxy-prost-13-enoic
acid;
13t-4-iodo-5~H-5(9~)-oxide-16S-methyl-11~,15S-dihydroxy-prost-13-enoic acid;
13t-4-chloro-5~H-5(9~)-oxide-16S-methyl-11~,15S-dihydroxy-prost-13-enoic
acid;
13t-6~H-6(9~)-oxide-16S-me~hyl-11~,15S-dihydroxy-14-bromo-prost-13-enoic
acid;
13t-6~H-6(9~)-oxide-16R-methyl-11~,15S-dihydroxy-14-bromo-prost-13-enoic
acid;
13t-6~H-6~9~)-oxide-20-methyl-ll~,lSS-dihydroxy-14-bromo-prost-13-enoic acid;
13t-6~H-6(9~)-oxide-15~S,R)-20-dimethyl-11~,15S-dihydroxy-14-bromo-prost-13-
enoic acid,
13t-5~H-5(9~)-oxide-16S-methyl-11~,15S-dihydroxy-14-bromo-prost-13-enoic
acid;
13t-5~H-5(9~)-oxide-16R-methyl-11~,15S-dihydroxy-14-bromo-prost-13-enoic
acid;
13t-5~H-5~9a)-oxide-20-methyl~ ,15S-dihydroxy-14-bromo-prost-13-enoic acid;
13t-5~H-5~9c~)-oxide-16(S,R)-20-metllyl-llc~,15S-dihydroxy-14-bromo-prost-13-
enoic acid;
13t-5-bromo-6~l-l-6~9~)-oxide-16S-methyl-11~,15S-dihydroxy-14-bromo-prost-13-
enoic ncicl;
13t-S-bromo-6~ 6(9~)-oxide-16R-methyl-11~,15S-dihydroxy-14-bromo-prost-13-
3:3 ~
enoic acid;13t-5-bromo-6~ 6~9~-oxide-20-methyl-11~,15S-dihydroxy-14-bromo-pros~-13-
enoic acid;
13t-5-bromo-6~H-6~9~)-oxide-16~S,R)-20-dimethyl-11~,15S-dihydroxy-14-bromo-
prost-13-enoic acid;
13t-4-bromo-5~H-5~9~)-oxide-16S-methyl~ ,15S-dihydroxy-14-bromo-prost-13-
enoic acid;
13t-4-bromo-5~H-5~9~)-oxide-16R-methyl-llcY,15S-dihydroxy-l~-bromo-prost-13-
enoic acid;
13t-4-bromo-5~H-5~9~)-oxide-20-methyl-11~,15S-dihydroxy-14-bromo-prost-13-
enoic acid;
13t-4-bromo-5~H- 5~9~)-oxide-16~S,R)-20-dimethyl-llcY,15S-dihydroxy-14-bromo-
prost-13-enoic acid;
together with their 15R-epimeric alcohols, when the corresponding 15-keto
compounds are submitted to reduction followed by chromatographic separation.
Starting from 6aH and 5cYH dias~ereoisomeric 15-keto compounds we prepare the
corresponding 15S- and 15R-alcohols. All these compounds are then saponified
to yield the corresponding free acids.
Example 66
A solution of 13t-5-iodo-6~H-6~9~)-oxide-16R-methyl-15-oxo-prost-
13-enoic acid methyl ester ~0.32 g) in ethyl ether ~8 ml) is added to a stirred
solution of ~inc borohydride in ethyl ether ~25 ml). After 30 minutes, the
excess reagent was destroyed by adclition of a saturated solution of NaCl and
N ~12S04. After the usuaL work up the organic phase is separated and the crude
residue is chromatographed on SiO2 ~eluent ~C112C12-ethyl ether) to yield
0.16 g of 13t-5-iodo-6~1-6~9cY)-oxide-16R-methyl-15S-hydroxy-prost-13-enoic-
ncicl mothyL ester and 0.095 g of 15R-epimer. Using this procedure the follow-
ing methyl esters were obtained:
~3
''I'
. ~. .
13t-6~H-6(9a)-oxide-15S-hydroxy-16S-methyl-prost-13-enoic acid;
13t-6~H-6~9a)-oxide-15S-hydroxy-16R-methyl-prost-13-enoic acid;
13t-6~H-6~9~)-oxide-15S-hydroxy-16,16-dimethyl-prost-13-enoic acid;
13t-5~H-5(9a)-oxide-15S-hydroxy-16S-methyl-prost-13-enoic acid;
13t-5~H-5~9a)-oxide-15S-hydroxy-16R-methyl-prost-13-enoic acid;
13t-5~H-5(9~)-oxide-15S-hydroxy-16,16-dimethyl-pros~-13-enoic acid;
13t-5-bromo-6~H-6~9~)-oxide-15S-hydroxy-16S-methyl-prost-13-enoic acid;
13t-5-bromo-6~H-6~9a)-oxide-15S-hydroxy-16R-methyl-prost-13-enoic acid;
13t-5-bromo-6~H-6(9a)-oxide-15S-hydroxy-16J16-dimethyl-prost-13-enoic acid;
13t-5-bromo-6~H-6~9~)-oxide-15S-hydroxy-20-methyl-prost-13-enoic acid;
13t-5-bromo-6~H-6~9~)-oxide-15S-hydroxy-16S,20-dimethyl-prost-13-enoic acid,
together with their 15R-epimeric alcohols, when the corresponding 15-keto
compounds are submitted to reduction followed by chromatographic separation.
Starting from 6aH and 5aH diastereoisomeric 15-keto compounds we prepare the
corresponding 15S- and 15R-alcohols.
Example 67
The following 15S-hydroxy-9~-oxide prostanoic acids methyl esters
together with their 15R-epimeric alcohols are obtained after reduction of the
corresponding 15-keto compounds using one of the procedures described in
examples 58 to 66;
13t-6~H-6~9a)-oxide-11~,15S-dihydroxy-13-prostanoic acid;
13t-14-bromo-6~H-6~9a)-oxide-11~,15S-dihydroxy-13-prostenoic acid;
13t-14-chloro-6~H-6~9a)-oxide-11~,15S-dihydroxy-13-prGstenoic acid;
13t-5,14-dibromo-6~H-6~9a)-oxide-lla,15S-dihydroxy-13-prostenoic acid;
13t-6~1-6~9~)-oxide-11~,15S-dihydroxy-20-methyl-13-prostenoic acid;
13t-14-bromo-6~H-6(9a)-oxide-lla~15S-dihydroxy-20-methyl-13-prostenoic acid;
13t-5,14-dibromo-6~H-6~9a)-oxide-11~,15S-dihydroxy-20-methyl-13-prostenoic
acid;
i3~
il J~ , tj
13t-5-iodo~6~H-6(9)-oxide-lla,15S-dihydroxy~20-methyl-13-prostenoic acid;
13t-5-iodo-14-bro -6~1-6(9~)-oxide-11 ~15S-dihydroxy-20-methyl-13-prostenoic
~cid;
13t-14-bTomo-6~H-6(9c~)-oxide-11~,15S-dihyd.roxy-16(S,R~-fluoro-17-cyclohexyl-
18,19,20-trinor-prost-13-enoic acid;
13t-5,14-dibromo-6~H-6(9a~-oxide~ ,15S-dihydroxy-16(S,R)-1uoro-17-cyclo-
hexyl-18,19,20-trinor-prost-13-enoic acid;
13t-5-bromo-6~H-6(9~)-oxide-11~,15S-dihydToxy-16~S,R)-fluoro-17-cyclohexyl-
18,19,20-trinor-prost-13-enoic acid;
13t-6BH-6(9)-oxide-llc~,15S-dihydroxy-16-difluoro-17-cyclohexyl-18,19,20-
trinor-pr~st-13-enoic acid;
13t-14-bromo-6~H-6(9a)-oxide-lla,15S-dihydroxy-16-difluoro-17-cyclohexyl-
18,19,20-trinor-prost-13-enoic acid;
13t-6~H-6~9a)-oxide-llc~,15S-dihyd~oxy-16(S,R)-fluoro-17-phenyl-18,19,20-
trinor-prost-13-enoic acid;
13t-14-bromo-6~H-6(9~)-oxide-llaglSS-dihydroxy-16(S,R)-fluoro-17-phenyl-18,
19,20-trinor-prostY13-enoic acid;
13t-6BH-6~9~)-oxide-lla,15S-dihydroxy-17-cyclopentyl-18,19,20-trinor-pros~-
13-enoic acid;
13t-6~H-6(9a)~oxide-ll,lSS-dihydroxy-17-cyclohexyl-1~,19,20-trinor-prost-
13-enoic acid;
13t-14-bromo-6~H-6(9a)~oxide-lla,15S-dihydroxy-17-cyclohexyl-18,19,20-trinor-
prost-13-enoic acid;
13t-5,14-dibromo-6~H-6~9a)-oxide-lla,15S~dihydroxy-17-cyclohexyl-18,19,20-
trinor px~st~13~enoic acicl;
~,,
13t-5-bromo-6~_6(9a)-oxide-11~,15S_dihydroxy-17-cyclohexyl-18,19,20-trinor-
prost-13-enoic acid;
13t-5-chloro-6~H-6(9a) -oxide-lla,15S-dihydroxy-17-cyclohexyl-1~,19 ,20-trinor-
prost-13-enoic acid;
13t~5-iodo-6~H~^6(9a)-oxide-lla,15S-dihydroxy-16-methyl-16-butoxy-18,19,20-
trinor-prost-13-enoic acid;
13t-5-iodo-6~H-6(9a)-oxide-lla,15S-dihydroxy-16-methyl-16-propoxy-18,19,20-
trinor~prost-13-enoic acid;
13t-5-iodo-6~H-6(9a)-oxide-lla,15S-dihydroxy-16-methyl-16-amyloxy-18,19,20-
lQ trinor-prost-13-enoic acid;
13t-5-iodo-6~H_6(9a)-oxide-lla,15S-dihydroxy-17-cycloheptyl-18,19~20-trinor-
prost-13-enoic acid;
13t-6~H-6(9a)-oxide-lla,15S-dihydroxy-16~(p-fluoro)-phenoxy-17,18,19,20-
tetranor-13~prostenoic acid;
13t-6BH-6(ga)-oxide-lla~l5s-dihydroxy-l6-phenoxy-l7~ls~l9~2o-tetranor 13-
prostenoic acid;
13t-6~H-6(9a)~oxide-lla,15S-dihydroxy-16-cyclohexyloxy-17,18,19,20-tetranor-
13-prostenoic acid;
13t-6~H-6(9a)-oxide-llaJl5s^dihydroxy-l6-~m-chloro)-phenoxy-l7~l8~l9~2
tetranor-13-prostenoic acid;
13t-6~H-6(9a)-oxide-lla,15S-dihydroxy-16-(m-trifluoromethyl)-phenoxy-17,18,
19,20-tetranor-13-prostenoic acid;
13t-14-bromo-6~H-6(9a)-oxide-lla,15S-dihydroxy-16-(p-fluoro)-phenoxy-17,18,
19,20-tetranor-13-prostenoic acid;
13t 14~br~ 6~1~6C~a~oxide~l].a,15S~dihydToxy~16-phenoxy~17,18,19,20-tetranor-
13-prostenoi.c acid;
13t-14-bromo-6~{~6(9a)-oxide~llaJ15S-dihydroxy-16-(m-chloro)-phenoxy-17,18
19l20~tetranor-13~prostenoic acid;
~7 ~ ~
13t-14-bromo 6~H_~C9a) oxide-lla,15S-dihydroxy-16~(m-trifluoromethyl~-phenoxy-
17,18,19,20-tetranor 13-prostenoic acid;
13t-5-iodo-6~H-6(9a)-oxide-lla,15S-dihydroxy-16-(p-fluoro)-phenoxy-17,18,19,
20-tetranor~13-prostenoic acid;
13t-5-iodo-6~H-6~9a)-oxide-lla,15S-dihydroxy-16-phenoxy-17,18,19,20-tetranor-
13-prostenoic acid;
13t-5-iodo-6~H-6(9a)-oxide-lla,15S-dihydroxy-16-cyclohexyloxy-17,18,19,20-
tetranoT-13-prostenoic acid;
13t-5-iodo-6~H~6(9a)-oxide-lla,15S-dihydroxy-16-(m-chloro)-phenoxy-17,18,19,
2Q-tetranor-13-prostenoic acid;
13t-5-iodo-6~H-6(9a)-oxide-lla,15S-dihydroxy-16-(m-trifluoromethyl)-phenoxy-
17,18,19,20-tetranor-13-prostenoic acid;
13t-5~H-5~9a)-oxide-lla,15S-dihydroxy-13-prostenoic acid;
13t-14-bromo-5~H-5(9a)-oxide-lla,15S-dihydroxy-13-pros*enoic acid;
13t-14-chloro-5~H-5~9a)-oxide-11,15S-dihydroxy-13-prostenoic acid;
13t-4,14-dibromo-5~H-5(9a)-oxide-lla,15S-dihydroxy-13-prostenoic acid;
13t-5RH-5(9a)-oxide-lla,15S-dihydroxy-20-methyl-13-pros~noic acid;
13t-14-bromo-5~H-5(9a)-oxide-lla,155~dihydroxy-20-methyl-13-prostenoic acid;
13t-4,14-dibromo-5~H-5(9a)-oxide-lla,15S-dihydroxy-20-methyl-13-prostenoic acid;
13t-4-iodo-5~H-5(9a3-oxide-lla,15S-dihydroxy-20-methyl-13-prostenoic acid;
13t-4-iodo-14-bromo-5BH-5(9a)-oxide-lla,15S-dihydroxy-20-methyl-13-prostenoic
acid;
13t-14-bromo-5~H-5(9a)-oxide-lla,15S-dihydroxy-16(S,R)-fluoro-17-cyclohexyl-
18,19,20-trinor-pros~-13-enoic acid;
13t~4,14 dibromo~5~H~5~9)-oxide-lla,15S-dihydroxy-16~S,R)-fluoro-17-cyclo-
hexyl~l8,1~,2Q~trino:r~prost~13~enoic acid;
13t-4-bromo-5BH-5(9a)-oxide-lla,15S-dihydroxy-16~S,R)-fluoro-17-cyclohexyl-
18J 19 ~ 20-trinor_prost-13_enoic acid;
13t-SBH 5(9a)-oxide-lla,15S-dihydroxy-16~5,R)-fluoro-17-phenyl-18,19,20-
trinor-pros~-13-enoic acid;
13t-14-bromo-5~H-5~9a)-oxide-lla,15S-dihydroxy-16(S,R)-fluoro~17-phenyl-
18,19,20-trinor-prost 13-enoic acid;
13t-5~H-5~9a)-oxide--lla,15S-dihydroxy-17-cyclopentyl-18,19,20-trinor-prost-
13-enoic acid;
13t-5BH-5~9a)-oxide-lla,15S-dihydroxy-17-cyclohexyl-18,19,20-trinor-prost-
13-enoic acid;
lQ 13t-14-bromo-5~H-5(9a)-oxide-lla,15S-dihydroxy-17-cyclohexyl-18,19,20-
trinor-prost-13-enoic acid;
13t-4,14-dibro -5~H-5(9a)-oxide-lla,15S-dihydroxy-17-cyclohexyl-18,19,20-
trinor-prost-13-enoic acid;
13t-5~1-5(9a)-oxide-11~,15S-dihydroxy-16-phenoxy-17,18,19,20-tetranor-13-
prostenoic acid;
13t-4-iodo-5~H-5(9~)-oxide-11,15S-dihydroxy-16-phenoxy-17,18,19,20-tetranor_
13-prostenoic acid;
13t-4-iodo-5~H-5(9a)-oxide-lla,15S-dihydroxy-16-cyclohexyloxy-17,18,19320-
tetranor-13-prostenoic acid;
13t-4-iodo-5~H-5(9a)-oxide-lla,15S-dihydroxy-16(m-chloro)-phenoxy-17,18,19,
20-tetranor-13~prostenoic acid;
13t-4^iodo-5 ~1-5~9a)-oxide-lla,15S-dihydroxy-16-(m-trifluoromethyl)-phenoxy-
17,18,19,20-tetranor-13-prostenoic acid.
In similar way, we prepare the diastereoisomeric ~I-9a-oxide-lSS-
and o~-9a-oxide-lSR-alcohols when we use aH-9a-oxide-15-keto diastereoisomer
a~ startin~ material~
All these esters are then saponified to obtain the free acids.
, &` ~
~, ~
Example 68
0.46 g o~ 13t-5~H-5(9~)-oxide-16S-methyl-lla-hydroxy-15-oxo-prost-
13-enoic acid methyl ester are treated with pyridine (2 ml) and acetic an-
hydride (1 ml). After 6 hours at room temperature the mixture is diluted with
brine, acidified ~o pH 4.5 - 4.8 and extracted with ethyl ether. The combined
organic phases are then evaporated to dryness yielding 0.48 g of ll-acetoxy-
derivative ~ mex~ = 229 m~, e = 11.058). A solution of this compound in
ethyl ether is then added dropwise to a solution of Zn~BH4)2 in ethyl ether.
After 30 minutes the excess reagent is decom~osed with a N solution of H2SO4
and after the usual work -up, 0.47 g of 13t-5~H-5(9~)-oxide-16S-methyl-ll~,
15~S,R)-dihydroxy-13-prostenoic acid methyl ester ll-acetate are obtained.
A solution of this mixture in CH2C12 ~5 ml) cooled to about -5C, -10C, is
treated with a solution of BF3 etherate ~1.2 x 10 4 M) in CH2C12 and then with
a 5% solution of diazomethane in CH2C12 until a persistent yellow coloration.
The reaction mixture is evaporated to half volume under vacuum, washed with a
5% aqueous Na~lC03 solution and water to neutral, and evaporated *o dryness to
yield 0.47 g of 13t-5~H-5~9~)-oxide-16S-methyl-ll~-hydroxy-15(S~R)-methoxy-
prost-13-enoic acid-ll-acetate which is separated in the individual isomers
by chromatography on SiO2 using benzene-ethyl ether (85:15) as eluent. On the
other hand, 0.21 g of the mixture of 15(S,R)-methoxy-derivatives is dissolved
in dry methanol ~4 ml) and selectively deacetilated by treatment with 20 mg
of K2CO3 for 4 hours at room temperature. After neutralization by dilution
~ith aqueous Nc~12PO4, the methanol evaporated under vacuum and the residue is
extracted ~ith ethyl ether ~2 x 5) ethyl acetate ~2 x 6 ml). The combined
organic phases are evaporated to dryness to yield 180 mg of the crude 13t-
5~ll-5(9~)-oxide-16S-methyl-ll~-hydroxy-15~S,R)-methoxy-prostenoic acid methyl
ester, wh:ich is then readil~ separated by means o~ a silica gel column chroma-
tograph~ using C~12C12-ethyl ether 80:20 as eluent to yield the two pure
~38~
, . .... .
lsomers: 15S-methoxy and 15R-methoxy. Using the same procedure the following
methyl esters were obtained:
13t-6~H-6~9a)-oxide-16S-methyl-lla-hydroxy-15S-methoxy-prost-13-enoic acid;
13t-6~1-6(9a)-oxide-16R-methyl-lla-hydroxy-15S-methoxy-prost-13-enoic acid;
13t-6~H-6~9~)-oxide-20-methyl-lla-hydroxy-15S-methoxy-prost-13-enoic acid;
13t-5-bromo-6~H-6(9~)-oxide-20-methyl-lla-hydroxy-15S-methoxy-prost-13-enoic
acid;
13t-5-bromo-6~l-6(9a)-oxide-11~-hydroxy-15S-methoxy-prost-13-enoic acid;
13t-5-bromo-6~H-6(9a)-oxide-16S-methyl-lla-hydroxy-15S-methoxy-prost-13-enoic
acid,
and their epimeric 15R-methoxy compounds are obtained starting from the cor-
responding ll-acetoxy-15-keto compounds.
Using in this procedure the aH-diastereoisomer instead of the ~H,
the corresponding aH-15-methoxy compounds are also obtained.
The same procedure can be also utilized for any 15-keto compound,
previously described and analogously an other diazo alkane can be used inside
o$ diazomethane.
Example 69
To a solution of 0.26 g of 13t-6~H-6~9a)-oxide-15(S,R)-hydroxy-16S-
methyl-prost-13-enoic acid methyl ester in methylene chloride, treated with
0.3 ml of a solution of BF3 etherate in methylene chloride, cooled at
-10 . -8C, a solution of diazoethane in methylene chloride is added until a
persistent yello~ coloration is formed. The solvent is evaporated under
vacuum and the residue chromatographed on silica gel using ethyl ether-
methylene chloride 10:90 as eluent to yield 0.115 g of 13t-6~H-6(9a)-oxide-
15S~ethoxy-16S-meth~:L-prostenoic acid methylester, and 0.1 g of 15R-ethoxy
:LSOnler .
When a mixture o:F 15S,15R~alcohols, for example 13t-6~H-6(9a)-oxide-
~.
~33~3~
11~,15~S,R)~dihydroxy-16S-methyl-prostenoic acid, containing a free 11-
hydroxy group is submitted to the procedure of the examples 68 and 69, the
simultaneous alkoxylation of the ll-alcoholic function also occurs yielding
with diazomethane for example a~ter chromatographic separation the 13t-6~H-
6~9~)-oxide~ ,15S-dimethoxy-16S-methyl-prostenoic acid methyl ester beside
the 15R-epimeric derivative.
In a similar way the following ]5S-alkox~ prostenoic derivatives
were obtained:
13t-5~H-5(9~)-oxide-11~,15S-dimethoxy-prostenoic acid;
13t-6~H-6(9a)-oxide-11~,15S-dimethoxy-prostenoic acid;
13t-6~H-6(9~)-oxide-5-bromo-11~,15S-dimethoxy-prostenoic acid;
13t-6~H-6(9~)-oxide-5-iodo-11~,15S-dimethoxy-prostenoic acid;
13t-5~H-5(9~)-oxide-15S-methoxy-16S-methyl-prostenoic acid;
13t-6~H-6(9~)-oxide-15S-methoxy-16S-methyl-prostenoic acid;
13t-6~H-6~9~)-oxide-15S-methoxy-16R-methyl-prostenoic acid;
13t-6~H-6(9~)-oxide-15S-methoxy-16-methyl-16-butoxy-18,19,20-trinor-
prostanoic acid,
and their 15R epimers are obtained and when they are saponiied with LiOH in
methanol the free acids are prepared. The same procedure can be used to ob-
tain diastereoisomeric ~H-9~-oxide derivatives.
~xample 70
2 To a stirred solution of 1.33 g of 13t-6~H-6~9~)-oxide-11~-hydroxy-
15-oxo-prost-13-enoic acid meth~l ester-ll-acetate in 6 ml of toluene and 54
ml of benzene, cooled at ~4C, a solution of 1.67 g of methylmagnesium iodide
in eth~l ether is adcled. After 20 minutes, the excess reagent is decomposed
with an iced 20% solution of ammonium chloride in water. After dilution with
one volumc Oe ethyl ether the organic phase is washed with water, sodium bi-
carbonate and water~ dried over magnesium sulphate, treated with 0.1 ml of
q~
~331~
pyridine and evaporated to dryness to yield 1.2 g of 13t-6~1-6(9~)-oxide-11~,
15(S,R)-dihydroxy-15-methyl-prostenoic acid-methylester-ll-acetate, vf which
0.2 g are separated into the pure component by thin layer chromatography on
silica gel, with benzene-ether 60:40 eluent. 1 g of the mixture of th0 two
alcohols is dissolved in anhydrous methanol ~20 ml) and stirred for 4 hours
with 0.25 g of K2C03. The mixture is evaporated to dryness, the residue is
par~itioned between ethyl ether and aqueous 15% NaH2P04. The organic phase
is evaporated in vacuum and the residue is absorbed on silica gel (200 g).
~ Elution with ethyl ether-isopropylic ether 80:20 affords 0.20 g of 13t-6~H ~lC
6~9c~)-oxide~ ,15R-dihydroxy-15-methyl-prost-13-enoic acid methyl esterl
and 0.36 g of 15S-epimer. 0.16 g of this compound are dissolved in 12 ml of
methanol and treated with 0.8 ml of water and 0.2 g of K2C03. After 5 hours
at room temperature the methanol is evaporated under vacuum, the residue is
treated with 20% NaH2P04 and ethyl acetate. The organic phase yields 0.1~ g
of 13t-6ctH-6(9~)-oxide-11~,15S-dihydroxy-15-methyl-prost-13-enoic acid. The
corresponding 6~11-isomers are prepared in the same way.
Example 71
To 1.79 g of 13t-5~H-5(9a)-oxide-11~-hydroxy-15-oxo-prost-13-enoic
acid methyl ester-ll-acetate in 20 ml of anhydrous tetrahydrofurane, 50 ml
of 0.3 M ethynylmagnesium bromide in anhydrous tetrahydrofurane is added.
Keep shaking for one hour, eliminate the excess reagent by treating with a
saturated NH4Cl solution, concentrate the organic phase under vacuum, and
take up with ethyl ether to yield 1.62 g o 13t-5~H-5(9~)-oxide-11~,15(S,R)-
dihydroxy-15-ethynyl-prost-13-enoic acid methyl ester-ll-acetate, which is
d~ssolved in anhydrous methanol and treated with 250 mg of anhydrous potassium
carbonate for 3 hours under shaking. Evaporated under vacuum and dilute with
20~ aclueous Nc~12PO4 and ethyl ether. A$ter evaporating the solvent, the
organic phase yields 1.41 g o~ 13t-5~H-5~9~)-oxide-11~,15(S,R)-dihydroxy-15-
_ ~ ,
ethynyl-prostanoic acid methyl ester, which is separated into the two pure
15S-hydroxy and 15R-hydroxy epimer by silica gel chromatography with benzene-
ethyl ether 1:1 as eluent, and after saponification of the 15S-hydroxy epimer
with K2CO3 in methanol, there is yield of the 13t-5~H-5(9~)-oxide-11~,15S-
dihydroxy-15-ethynyl-prostenoic acid.
Example 72
To a solution in tetrahydrofuran anhydrous (25 ml) of 1.41 g of
13t-5-bromo-6~H-6~9a)-oxide-15-oxo-prost-13-enoic acid methyl ester, a 0.5 M
solution of magnesium vinyl bromide in tetrahydrofurane (25 ml) is added at
0 - 5 C and let stand for 4 hours at room temperature. Decompose the excess
reagent with a saturated solution of ammonium chloride, distil the tetrahydro-
furane under vacuum and take up with ethyl ether. The organic phase is ad-
sorbed on silica gel and eluted with methylene chloride-ethyl ether to yield
0.41 g of 13t-S-bromo-6~H-6~9~)-oxide-15R-hydroxy-15-vinyl-prostenoic acid
methyl ester, and 0.62 g of 15S-isomer, which after saponification with LiOH
in methanol yields 0.49 g of pure 13t-5-bromo-6~H-6~9~)-oxide-15S-hydroxy-15-
vinyl-prostenoic acid.
Example 73
A solution o 0.98 g of 13t-5-bromo-6~H-6~9~)-oxide-11~-hydroxy-15-
oxo-20-methyl-prostenoic acid methyl ester-ll-acetate in 30 ml of benzene-
toluene ~85:15) is cooled at 3 - 4C and to this a solution of 0.92 g of
phenylmagnesium bromide in ethyl ether-benzene 1:1 is added. Let stand for
5 hours at room temperature, then decompose the excess reagent with an iced
solution of 15% NH4Cl, wash the organic phase repeatedly with water to neutral
then evaporate. The crude 15-phenyl-15~S,R)-hydroxy derivative is dissolved
in anhydrous methanol to which 0.25 g. of K2CO3 is added, kept shaking for
2 hours. Evaporate to dryness, dilute with aqueous 20% NaH2PO4 and ethyl
ether, and Erom the organic phase after evaporation of the solvent, there is
93
a yield of 0.81 g o~ 13t-5-bromo-6~H-6~9~)-oxide~ ,15(S,R)-dihydroxy-15-
phenyl-20-methyl-prostenoic acid methyl ester, which after separation on
silica gel with ethyl ether elution y:ields the individual 15S and 15R isomers.
Example 74
-
By reaction of the corresponding 15-oxo-derivative with a reagent
selected from the group of an halogenide of methyl magnesium, vinyl magnesium,
ethynyl magnesium and phenyl magnesium, working to one of the procedures
given in example 70 to 73, the following methylesters were prepared:
13t-6~H-6(9~)-oxide-15S-hydroxy-15-methyl-prostenoic acid;
13t-6~H-6(9a)-oxide-15S-hydroxy-15,20-dimethyl-prostenoic acid;
13t-6~H-6(9u)-oxide-15S-hydroxy-15-ethyl-prostenoic acid;
13t-6~H-6(9~)-oxide-15S-hydroxy-15-ethynyl-prostenoic acid;
13t-6~H-6(9~)-oxide-11~,15S-dihydroxy-15-methyl-prostenoic acid;
13t-6~H-6(9~-oxide-11~,15S-dihydroxy-15-ethyl-prostenoic acid;
13t-6~H-6~9~)-oxide~ 15S-dihydroxy-15-vinyl-prostenoic acid;
13t-6~H-6~9~)-oxide-11~,15S-di.hydroxy-15-ethynyl-prostenoic acid;
13t-6~H-6~9~)-oxide-11~,15S-dihydroxy-15-phenyl-prostenoic acid;
13t-6~H-6~9~)-oxide-11~,15S-dihydroxy-15,20-dimethyl-prostenoic acid;
13t-5-bromo-6~H-6~9~)-oxide-11~,15S-dihydroxy-15-methyl-prostenoic zcid;
13t-5-bromo-6~H-6~9~)-oxide-11~,15S-dihydroxy-15-vinyl-prostenoic acid;
13t-5-bromo-6~H-6 t9G) -oxide-11~,15S-dihydroxy-15-ethynyl-prostenoic acid;
13t-5-bromo-6~H-6~9)-oxide-11~,15S-dihydroxy-15-ethyl-prostenoic acid;
13t-5-bromo-6~H-6~9a)-oxide-11~,15S-dihydroxy-15-phenyl-prostenoic acid;
13t-4-bromo-5~H-5~9~-oxide-11~,15S-dihydroxy-15-methyl-prostenoic acid;
13t-4-bromo-5~H-5~9~)-oxide-11~,15S-dihydroxy-15,20-dimethyl-prostenoic acid;
13t-4-brolno 5~ 5~9~)-oxide-11~,15S-dihydroxy-15-ethynyl-prosteno:ic acid;
13t-5~l-5t9~)-oxide-11~,15S-dihydroxy-15-methyl-prostenoic acid;
13t-5~1-5~9a)-oxide-11~,15S-dihydroxy-15,20-dimethyl-prostenoic acid;
"~`3 ~'
~l~a~
13t-5~1-5(9a)-oxide-lla,15S-dihydroxy-15-phenyl-pros~enoic acid;
13t-5~H-5~9~)-oxide-11~,15S-dihydroxy-15-ethynyl-prostenoic acid;
13t-5~H-5(9~)-oxide-lla,15S-dihydroxy-15-vinyl-prostenoic acid;
13t-5~H-5~9a)-oxide-lla,15S-dihydroxy-15-methyl-prostenoic acid,
and their 15R-hydroxy epimers.
Analogously starting from the a~-(9~)-oxide-15-keto-compounds we
obtained the corresponding ~I-~9a)-oxide-15-substituted alcohols.
Example 75
To a solution of 0.5 g of 13t-6~H-6(9~)-oxide-11~,15S-dihydroxy-
14-bromo-16S-methyl-prostenoic acid-methyl ester-ll-acetate in 2 ml of di-
methylformamide, dimethyl-t-butyl silane chloride (0.21 g) and triethylamine
(0.16 g) are added. Keep shaking for 2 hours, then dilute with 4 volumes of
water and extract with ethyl ether. The organic phase, after the usual
washings, evaporation of the solvent, and filtration through silica gel with
cyclohexane-ethyl ether 90:10 eluent, yields 0.57 g of 13t-6~H-6(9a)-oxide
11~,15S-dihydroxy-14-bromo-16S-methyl-prostenoic acid methyl ester-ll-acetate-
15-dimethyl-t.butylsilylether, from which, by transesterification in anhydrous
methanol and 0.5 molar equivalents of K2CO3, the corresponding ll-hydroxy-
derivative is yielded.
Example 76
To 0.52 g of 13t-5,14-dibromo-6 ~1-6(9a)-oxide-11~,15S-dihydroxy-
prostenoic acid methyl ester in 10 ml of dichloromethane, 2,3-dihydro-pyrane
(0.27 g) and p-toluensulphonic acid (4 mg) are added. Keep at room tempera-
ture for 3 hours, then wash with a 5% solution of KtlC03 and water to neutral,
and evaporate to dryness. Filter through silica gel with cyclohexane-ethyl
othel 90:10 as e~uent, which yields 0.59 g of 13t-5,14-dibromo-6~H-6(9a)-oxide-
lla,15S dihydroxy~prostenoic acid methyl ester-11,15-his-tetrahydropyranyl-
e~her.
~3 ~
~8~
Exam~le 77
The 14-bromo-alcohols yielded by the foregoing examples, when treat-
ed with dimethyl-t.butylchlorosilane in dimethylformamide while, working to
the procedures as in example 75,or with an acetalic ether such as 2,3-dihydro-
pyrane-1,4-diox-2-ene, l-ethoxy-ethylene, and working to the procedure of
example 76, are then converted into ~he co-rresponding silyloxy or the corres-
ponding acetalic ethers.
Exam~le 78
Under an atmosphere of inert gas, to a stirred solution of 0.46 g
of 13t-14-bromo-6~H-6(9~)-oxide-15S-methoxy-16S-methyl-prost-13-enoic acid
methyl ester in anhydrous dimethylsulfoxide ~5 ml), potassium tert-butylate
~0.15 g) is added and the stirring is continued for 30 minutes. The reaction
mixture is diluted with 2 volumes of water and stirred for 15 minutes, then
extracted with ethyl ether. The organic phases are re-extracted with 2 x 5 ml
of 0.2N NaOH and then with water u~til neutral and evaporated to dryness to
give 30 mg of 6~H-6~9~)-oxide-15S-methoxy-16S-methyl-prost-13-ynoic acid methyl
ester. The combined aqueous phase are acidified to pH 5.1 and extracted with
ethyl ether. After evaporation of the solvent, 0.28 g of 6~H-6(9~)-oxide-15S-
methoxy-16S-methyl-prost-13-ynoic acid is obtained.
Example 79
Under an atmosphere of inert gas, with stirring and rigorous ex-
clusion of humidity, 0.84 g of trimethylsilylimidazole is added to an anhydrous
dimethylsul~oxide solution of 0.445 g oE 13t-5~H-5~9~)-oxide-14-bromo-16R-
meth~l-prost-13-enoic acid. Stirring is continued for 30 minutes and then a
solution of 0.19 g of K-tert-butylate is added. After 30 minutes stirring,
the mixture ls diluted with 3 volumes of water and stirred Eor 2 more hours.
Aeter acidl~ication to ptl 5.2, it is extracted wlth ethyl ether:hexane 80:20
nnd t}le organi.c extracts are dried and evaporated to dryness to give 0.31 g
3i~
of 5aH-5(9~)-oxide-16R-methyl-prost-13-ynoic acid.
Example 80
To a solu~ion of sodium methylsulfinylcarbanion, obtained by heating
at 60 C for 3 hours and 30 minutes a suspension of 50 mg of 80% NaH in 8 ml
of anhydrous dimethylsulfoxide, a solution of 13t-6~H-6~9~)-oxide~ ,15S-
dimethoxy-14-bromo-16~S,R)-fluoro-20-methyl-prost-13~enoic acid methyl ester
~0.~6 g~ in 5 ml of dimethyl sulfoxide is added with stirring under an at-
mosphere of inert gas, at a temperature of 18 - 20C. After 40 minutes of
stirring an excess of 25% NaH2P04 is poured in and the mixture extracted with
ethyl ether to give 0.51 g of 6~H-6~9~)-oxide-11~,15S-dimethoxy-16(S,R)-
fluoro-20-methyl-prost-13-ynoic acid methyl ester.
Example 81
To a solution of 80 mg of sodium amide in 10 ml of dimethyl-
sulfoxide a solution of 13t-14-bromo-5~H-5(9~)-oxide-11~,15S-dihydroxy-16-
m-trifluoromethylphenox~-l7~l8~l9~2o-tetranor-prost-l3-enoic acid-11,15-
bis-tetrahydropyran~l-ether (0.65 g) in 5 ml of dimethylsulfoxide is added.
It is stirred for 2 hours and then diluted with water and extracted with
ethyl ether. The ether extracts, after re-extraction with alkali are dis-
carded. The aqueous alkaline extracts are acidified ~o pH 4.5 and extracted
~ith ethyl ether to give 0.54 g of 5~H-5(9~)-oxide-11~,15S-dihydroxy-16-m-
trifluoromethylphenoxy-17,18,19,20-tetranor-prost-13-ynoic acid-11,15-bis-
tetrahydropyranyl ether. A solution of this compound (0.23 g) in anhydrous
ethanol ~5 ml) and 2,2-diethoxypropane (3 ml) is treated with 20 mg of p-
toluenesulfonic acid. After 5~hours at room temperature it is neutralized
with aqueous NaHC03, evaporated under vacuum and the residue partitioned
hetween ~ater and ethyl ether. The org.mic phase is evaporated and after
p~ssing the residue through silica gel 0.1 g oE 5~H-5~9~)-oxide-11~,15S-
clihydroxy~-16-m-trifluoromethylphenoxy-17,18,19,20-tetranor-prost-13-ynoic
~'~ _ ~'
acid ethyl ester is obtained. Deacetalization carried out on another 0.2 g of
product dissolved in 5 ml of acetone and treated with 3.5 ml of 0.2N oxalic
acid for 8 hours at 40C, after e~aporation of the acetone under vacuumJ ex-
traction of the aqueous phase with ethyl ether and chromatography on silica
gel with ethyl ether:ethyl acetate 95:5 the free acid (95 mg) is obtained.
In the same way, starting from 13t-14-chloro-6~H-6(9~ -oxide-lla,
15S-dihydroxy-17-cyclohexyl-18,19,20-trinor-prost-13-enoic acid-11,15-bis-
dioxanylether the 6aH-6(9a)-oxide-lla,15S-dihydroxy-17-cyclohexyl-18,19,20-
trinor-prost-13-ynoic acid is obtained~
Example 8?
To a solution of 0.48 g of~l3t-14-bromo-6~H-6(9a)-oxide-11~,15S-
dihydroxy-16-cyclohexyloxy-17,18,19,20-tetranor-prost-13-enoic acid methyl
ester in 3 ml of anhydrous dimethylsulfoxide is added after 30 minutes a solu-
tion of 1,5-diazabicyclo[5.4.0]undec-5-ene (0.25 g) in 2 ml of anhydrous di-
methylformamide and the reaction mixture maintained for 6 hours at 65 C. It
is diluted with water acidified to pH 4.5, extracted with ethyl ether. From
the organic phase, after evaporation of the solvent and purification on silica
gel ~eluted with benzene-ethyl ether 80:20), 6~H-6(9a)-oxide-lla,15S-dihydroxy-
16-cycloheYyloxy-17,18,19,20-tetranor-prost-13-ynoic acid methyl ester ~0.29
2a g) is obtained~
Example 83
-
Using one of the procedures described in examples 78 to 82 and
starting from ~he corresponding 13t-14-halo-prost-13-enoic acids, the follow-
ing prost-13-ynoic acids are prepared: .
6~ll-6t9a)-oxide-lla,15S-dihydroxy-prost-13-ynoic acid;
6~H-6(9a)-oxide-lla,15R-dihydroxy-prost-13-ynoic acid;
6~}1-6t9a)-oxide-15-methoxy-prost-13-ynoic acid;
6~l-6~9a)-oxide-lla,15S-dihydroxy-l6S-methyl-prost-13-ynoic acid;
~,.
~3i~3~
6~H-6~9a)-oxide-11~,15S-dihydroxy-16S,20-dimethyl-prost-13-ynoic acid;
6~H-6(9a)-oxide-11~,15S-dihydroxy-16R-methyl-prost-13-ynoic acid;
6~H-6~9a)-oxide~ ,15S-dihydroxy-16S-fluoro-prost-13-ynoic acid;
6~H-6(9a)-oxide-11~,15S-dihydroxy-16,16-difluoro-prost-13-ynoic acid;
6~H-6(9a)-oxide-lla,15S-dihydroxy-20-methyl-prost-13-ynoic acid;
6~H-6(9a)-oxide-lla,15S-dihydroxy-17-cyclohexyl-18,19,20-trinor-prost-13-
ynoic acid;
6~H-6(9a)-oxide-lla,155-dihydroxy-16-fluoro-17-cyclohexyl-18,19,20-trinor-
prost-13-ynoic acid;
6~H-6(9a)-oxide-lla,l~S-dihydroxy-16-p-fluorophenoxy-17,18,19,20-tetranor-
prost-13-ynoic acid,
6~H-6~9a)-oxide-11~,15S-dihydroxy-17-phenyl-18,19,20-trinor-prost-13-ynoic
acid;
5~H-5~9a)-oxide-lla,15S-dihydroxy-16S-methyl-prost-13-ynoic acid;
5~H-5~9a)-oxide-lla,15S-dihydroxy-16S,20-dimethyl~prost-13-ynoic acid;
5~H-5~9a)-oxide-lla,15S-dihydroxy-16R-methyl-prost-13-ynoic acid;
5~H-5(9a)-oxide-lla,15S-dihydroxy-16S-fluoro-prost-13-ynoic acid;
5~H-5~9a)-oxide-lla,15S-dihydroxy-prost-13-ynoic acid;
5~H-5~9a)-oxide-lla,15S-dihydroxy-20-methyl-prost-13-ynoic acid.
Starting from aH-~9a)-oxide compounds and using the same procedure,
the epimeric aH-(9a~-oxide-13-ynoic compounds are prepared.
Example 84
A solution of 0.35 g o~ mercuric acetate in mèthanol is added at
room temperature, ~ith stirring, to a solution o~ 0.54 g of 5c,13t--9~ ,15S-
trihydroxy-prostadienoic acid methyl ester-11,15-bis-TIIP-ether (PGF2 -bis-
TilP-ether-methyl ester). After stirring for 15 minutes, 50 mg of sodium
~orohydride is added in small portions, the elemental mercury generated is
removed by filtration and the methanol is evaporated under vacuum. The resi-
due is partitioned between dichloromethane/water; the organic phase, after
Oq
~l8315 3~
washing with sodi~1m bicarbonate and water until neutral, is evaporated to
give 0.51 g of crude 13t~ ,15S-dihydroxy-6~H-6(9~)-oxide-prostenoic acid
methyl ester-11,15-bis-THP-ether. A solution of this in 10 ml of acetone
added to 8 ml of 0.2N oxalic acid is heated to 40 - 45C for 6 hours. After
the removal of the acetone under vacuum, the aqueous suspension is extracted
with ethyl acetate ~3 x 15 ml). The organic phase is washed until neutral
and evaporated to dryness. The residue ~approximately 0.45 g) is adsorbed on
silica gel ~50 g) and eluted with ethyl ether collecting fractions of 20 ml.
From fractions 11 to 50, 13t-11~,15S-dihydroxy-6~H-6(9~)-oxide-prostenoic
acid methyl ester ~0.11 g; m.p. 67 - 6gC) is obtained. I'hen, after a mixture
of diastereoisomers as 5 - 10% of ethyl acetate is added to ethyl ether, 13t-
lla,15S-dihydroxy-6~H-6(9~)-oxide-prostenoic acid methyl ester (0.16 g;
~]D = + 19.62 (CHC13)) is collected.
A sample of the later compound, after crystallization, shows m.p.
40 - ~1 C, [~]D = +25-2 ~ [~]365 = +83.8 ~C~IC13).
The crude free acid has [~]D = +18.3 (EtOH).
A sample is crystallized from pentane-ethyl ether affording pure
crystalline 13t-6~H-6(9~)-oxide-11~,15S-dihydroxy-prost-13-enoic acid, m.p.
80 - 81 C, [~]D = +32.5 ~ [~]365 = +11`1.6 (EtOH). The mass spectrum of the
compound shows the following peaks (m/e, intensity, structure):
336 7% [M-H2O] , 318 3% [M-2H2O] ; 292 100% [M-H2O-~] ;
264 30% [M-H2O-CH2CHCO2H] ; 235 ~% [M-H2O-(C~I2)~CO2H].
The mass spectrum of the 6~H-diastereoisomer is substantially
similar .
Example 85
A solution Oe o.ls g of 5c,13t-9~ ,15S-trihydroxy-15-methyl-
PGF2~methyl cster in 2.5 ml of THF is added to 0.3 g of mercuric acetate in
l.5 ml water/3.0 ml THF. After 30 minutes of stirring, 60 mg of sodium
131~3~
borohydride in 1.2 ml of water is added to the deep yellow suspension~ After
the mercury is separated, the THF is removed under vacuwn and the aqueous sus-
pension is extracted repeatedly with ethyl acetate. The organic phase, when
washed until neutral and evaporated to dryness, yields 0.16 g of product which
is purifiecl by thin layer chromatography to give 0.04 g of 13t~ ,15S-di-
hydroxy-6t~H-6~9~)-oxide-15-methyl-PGF2 -methyl ester, [~]D = ~6.2 (CHC13)
and 0.034 g of the 6~H-6(9~)-oxide-isomer, [~]D = ~19.62 (CHC13).
Example 86
0.43 g of 5c,13t-9~,15S-dihydroxy-16R-methyl-prostadienoic acid
methyl ester-15-dioxanyl ether in methanol (2.5 ml) is reacted with a solution
of 0.38 g of mercuric bromide in methanol. The reaction mixture is held at
room temperature for 15 minutes and overnight at 0C. The crystalline pre-
cipitate which forms is isolated by filtration to give 0.36 g of 13t-15~-
hydroxy-16R-methyl-6~H-6(9~)-oxide-5-bromomercuric prostenoic acid methyl
ester, from which the mercury is removed upon treatment with sodium borohydride
to give 0.12 g of 13t-15S-hydroxy-16R-methyl-6~H-6(9~)-oxide-prostenoic acid
methyl ester. Column chromatography on silica gel affects the separation into
the 6~H-6(9~)-oxide and 6~H-6(9c~)-oxide diastereoisomers.
Example 87
A solution of 0.55 g of 5c-9~,llci,15S-trihydroxy-prostenoic acid
methyl ester in 2.5 ml of DME is added to a solution of 0.5 g of mercuric
acetate in 2 ml of water/ 4 ml of DME. After 15 minutes, the reaction mixture
is treated with a solution of 0.08 g of sodium borohydride in 1.2 ml of water,
the mercury is separated~ the DME is removed under vacuum, and the residue
is extracted several times with dichloromethane. The organic phase is evap-
orated to dryness, aclsorbed on silica gel and eluted with ethyl ether/ethyl
acetate to give 0.21 g of 11~,15S-dihydroxy-6c~H-6(9~)-oxide-prostenoic acid
mcth~l ester and 0.18 g of the 6~EI-6(9~)-oxide isomer.
/d l
3~
Example 88
A solution of 116 mg o~ 5c-9~ ,15S-trihydroxy-17-cyclohexyl-20,
19,18-trinor-prost-5-en-13-ynoic acid methyl ester-11,15-bis-THP-ether in
1.5 ml of methanol is treated with 64 mg of mercuric acetate in 1.5 ml of
methanol. After 10 minutes, 25 mg of sodium borohydride is added. Methanol
is removed under vacuum~ the mercury is separated and the product is dissolved
in water/ethyl acetate. Evaporation of the organic phase to dryness affords
crude llu,15S-dihydroxy-6~H-6(9~)-oxide-17-cyclohexyl-20,19,18-trinor-prost-
13-ynoic acid methyl ester-11,15-bis-THP-ether (100 mg); this is treated in
acetone (4 ml) with 2.5 ml of 0.2N oxalic acid overnight at 40C. After re-
moval of the acetone under vacuum, the mixture is extracted with ethyl acetate.
Evaporation of solvent gives a residue t~hich is puri~ied on silica gel (elu-
ent, ethyl ether) to give 28 mg of 11~,15S-dihydroxy-17-cyclohexyl-20,19,18-
trinor-6~H-6~9~)-oxide-prost-13-ynoic acid methyl ester, [~]D = + 17.2,
[~]365 = +54, and 12.5 mg of the 6~H-6(9~)-oxide-isomer, [~D = + 26.5,
[~]365 = ~ 84 ~EtOH); M 406, M-H2O 388.
Under the same conditions, 5c-9~ ,15S-trihydroxy-16S-methyl-prost-
5-en-13-ynoic acid methyl ester-11,15-bis-THP-ether gives 11~,15S-dihydroxy-
16S-methyl-6~H-6(9~)-oxide-prost-13-ynoic acid methyl ester and its 6~H-6(9~)-
oxide isome-r.
Example 89
0.24 g o~ 13t-11~,15S-dihydroxy-6~H,6(9~)-oxide-16-methyl-16-butoxy-
20,19,18-trinor-prostenoic acid methyl ester and 0.13 g of the 6~H-6(9~)-oxide
isomer are obtained from the reaction of 1.01 molar equivalent of mercuric
acetate (636 mg) in 10 ml of methanol and 1.1 g of 5c,13t-9~ ,15S-trihy-
droxy-16-methyl-16-butoxy-20,19,18-trinor-prostadienoic acid methyl ester-ll,
15-bis-T}IP-etller in 5 ml of methanol. The mercury compound so prepared is
reduced in situ by the cautious addition of 85 mg of sodium borohydride in
3,~ ''' ~
3~3~
small portions. The methanolic solution is then decanted from the solid resi-
due and reduced in volume. 10 ml of 0.2N aqueous oxalic acid and 20 ml o~
acetone are added, and the resulting mixture is held at 50C for 12 hours.
The organic solvents are removed under vacuum, and ~he resulting solution is
saturated with sodium sulfate and extracted with ethyl acetate. The organic
phase is washed with 30% ammonium sulfate (2 x 5 ml) and 2.5 ml of water;
after drying over NaSO4, it is evaporated to give a crude residue which is
purifi.ed on silica gel using an eluent containing an increasing fraction of
benzene-methyl acetate, to give the isomeric 6~H-6(9~)-oxide and 6~H-6(9~)-
oxide.
From the above reaction with 16-_-chloro-phenoxy,16-_-fluoro-
phenoxy, and 16-m-trifluoromethyl-phenoxy-5c,13t-9~ ,15S-trihydroxy-20,
19,18,17-tetranor-prost-5,13-dienoic acid methyl ester-11,15-bis-THP-ether
and the analogous 17-phenyl-18,19,20-trinor-derivative were obtained respec-
tively:
13t-11~,15S-dihydroxy-6~H-6(9~)-oxide-17-phenyl-20,19,18-trinor-prostenoic
acid methyl ester, [~]D = + 28 ;
13t~ ,15S-dihydroxy-6~H-6(9~)-oxide-16-m-chloro phenoxy-20,19,18,17-tetranor-
prostenoic acid methyl ester, [~]D = + 31 ,
13t-11~,15S-dihydroxy-6~H-6(9a)-oxide-16-_-fluoro-phenoxy-20,19,18,17-tetranor-
prostenoic acid methyl ester, [~]D = -~ 30C;
13t-llN,15S-dihydroxy-6~H-6(9c~)-oxide-16-m-trifluoromethyl-phenoxy-20,19,18,
17-tetranor-prostenoic acid methyl ester, [~]D = -~ 33 ;
and thelr 6~H-6~9~)~oxide ison)ers ~hich show [~D ranging between +8 and
12 in CHC13.
Example 90
Using the 15S-fluoro-17-cyclohexyl-Sc,l3t-9~ ,15S-trihydroxy-
2a,1~,18-tr:lnor-prost~-5,13-dienoic acid methyl ester-11,15-bis-THP-ether, in
. ~ j~ -J~
the procedure of example 89, the 13t-lla,15S-dihyclroxy-6aH-G~9a)-oxide-16S-
fluoro-17-cyclohexyl-20~19,18-trinor~prost-13 enoic acid m0thyl ester,
and its 6~ 6(9a)-oxide diastereoisomer are obtained.
Exam~le 91
0,12 g of 13t-lla,15S-dihydroxy-6~1-6(9N~-oxide-prost-13-enoic acid
methyl ester in 6 ml of methanol is reacted with a 0.5 N aqueous solution of
lithium hydrate (2 ml~. After six hours9 the methanol is removed under vacuum.
The residue is diluted with water ~2 ml) and extracted with ethyl ether to
~emove neutral impurities. The alkaline aqueous phase is acidified by treat-
ment with 4 ml of 30% aqueous NaH2P04 and extracted several times with ethyl
ether. The later combined ether extracts are washed with water ~2 x 1 ml~ and
dried; removal of the solvent affords 91 mg of 13t-lla~15S-dihydroxy-6~H-6~9a)-
oxide-prost-13-enoic acid~ m.p. 78 - 80C, [a]D = + 31 ~EtOH). This procedure
is used for saponification of the esters from the preceding examples to the
corresponding free acids.
Example 92
lla,155~dihydroxy-6~H-6(9a)-oxide-16S-methyl-prost-13~ynoic acid
~Q.ll g) in methylene chloride is treated with 1.5 molar equivalent of di-
azomethane in methylene chloride. After 15 minutes, solvent is removed under
~acuum and the residue adsorbed on silica gel. Elution with ethyl ether/
benzene (70:30) gives, in the following order, 12 mg of lla-hydroxy-l5s-
methoxy-6~H-6(9a)-oxide-16S-methyl-prost-13-ynoic acid methyl ester and 78 mg
of lla,15S-dihydroxy-6~H-6(9a)-oxide-16S-methyl-prost 13-ynoic acid methyl
ester. Using in this procedure diazoethane instead of the diazomethane, lla-
hydroxy-15S-ethoxy-6~ 6~9a)-oxide-16S-methyl-prost-13-ynoic acid ethyl ester
is obtained~
839
Example 93
A solution of 12 (0-33 g) in methylene chloride is added to a sus-
pension of finely divided calcium carbonate in 6 ml o~ methylene chloride con-
taining 0.54 g of 5c,13t-9~ ,15S-trihydroxy-prostadienoic acid methyl
ester-11,15-bis-tetrahydropyranyl ether (PGF2~-bis-tetrahydropyranyl ether
methyl es~er). The reaction mixture is cooled in an ice/water bath and kept
in darkness~ After three hours of stirring, inorganic compounds are removed
by filtration and the organic phase is washed with 0.25 N sodium thiosulfate
and water. Removal of the solvent affords 0.66 g of crude 13t-5-iodo-6~H-6
~9a)-oxide~ 9l5S-dihydroxy_prost-13-enoic acid methyl ester-11,15-bis-tetra-
hydropyranyl ether. A solution of this in 10 ml of acetone is added to 8 ml
of O.lN oxalic acid and heated to 45 - 46C for 4 hours. The acetone is then
removed at reduced pressure and the aqueous suspension is extracted with
ethyl acetate (3 x 12 ml); the organic phase is washed until neutral and
evaporated to dryness. The residue (0.42 g) is separated on silica gel with
ethyl ether eluent. Elution of the high Rf fraction with acetone gives 0.14
g of 13t-5-iodo-6aH-6~9~)-oxide-11~,15S-dihydroxy-prost-13-enoic acid methyl
ester, while the low Rf portion is 0.20 g of 13t-5-iodo-6~H-6~9~)-oxide-11~,
15S-dihydroxy-prost-13-enoic acid methyl ester.
The methyl ester of the following acids were prepared analogously:
13t-16S-methyl-5-iodo-6~H-6~9~)-oxide-11~,15S-dihydroxy-prost-13-enoic acid;
13t-20-methyl-5-iodo-6~H-6~9~)-oxide-11~15S-dihydroxy-prost-13-enoic acid,
[~]D = ~ 23 ~ 365 = ~ 78 ~CHC13);
13t-5-iodo-6~H-6~9~)-oxide-11~,15S-dihydroxy-18,19,20-trinor-17-cyclohexyl-
prost-13-enoic acid;
13t-5-iodo-6~H-6~9~)-oxide-11~,15S-dihydroxy-18,19,20-trinor-17-cyclohexyl-
prost-13-enoic acid;
lJ - l~
., .
qs~
13t-5-iodo-6 ~1-6(9~)-oxide-11~,15S-dihydroxy-18,19,20-trinor-17-phenoxy-prost-
13--enoic acid;
13t-5-iodo-6~1-6(9~)-oxide-11~,15S-dihydroxy-18,19,20-trinor-17-yhenoxy-prost-
13-enoic acid;
13t-5-iodo-6~H-6(9~)-oxide-15S-hydroxy-prost-13-enoic acid;
13t-5-iodo-6~1-6(9~)-oxide-15S-hydroxy-prost-13-enoic acid;
13t-5-iodo-6~H-6(9~)-oxide-11~,15S-dihydroxy-prost-13-ynoic acid;
13t-5-iodo-6~1-6(9~)-oxide-11~,15S-dihydroxy-prost-13-ynoic acid;
5-iodo-6~H-6(9~)-oxide-16S-methyl-11~,15S-dihydroxy prost-13-ynoic acid;
5-iodo-6~H-6(9~)-oxide-20-methyl-11~,15S-dihydroxy-prost-13-ynoic acid,
[~]D = ~ 20 (CHC13).
Example 94
To a solution of 0.22 g of 5c,13t-9~ ,15S-trihydroxy-15-methyl-
PGF2~-methyl ester in 10 ml of C1l2C12 and 0.1 ml of pyridine is added drop-
wise to a solution of 180 mg of iodine in methylene chloride. The resulting
mixture is stirred for 1 hour. After dilution with water and washing of the
organic phase l~ith O.lN sodium thiosulfate and water until neutral~ the solu-
tion is evaporated in vacuum to a small volume and adsorbed on a silica gel
plate 0.5 mm in thickness. After development with ethyl ether and elution
with acetone, 0.052 g of 13t-15-methyl-5-iodo-6~H-6(9~)-oxide-11~,15S-di-
hydroxy-prost-13-enoic acid methyl ester and 0.021 g of the isomeric 5-iodo-
6~1-6(9~)-oxide are obtained.
Example 95
0.288 g of 5c-16,16-dimethyl-9~ ,]5S-trihydroxy-prost-5-enoic
acid methyl ester in a solution of 60 mg of pyridine in methylene chloride
(8 ml) is reacted with 115 ml of bromine in methylene chloride. After 30
minutes, starting material has completely disappeared; the organic phase is
washed with water, then 5% aqueous metabisulfite, and then water until neu-
/0~
- 1~
~8~
tral to gi~e, after removal of the'solvent and purification by TLC on silica
gel with ethyl cther as eluent, 0.083 g of 16,16-dimethyl-5-bromo-6~H-6(9~)-
oxide-prostanoic acid methyl ester and 0~04 g of 6oH-diastereoisomer~
The following compounds were prepared analogously:
13t-16,16-dimethyl-5-bromo-6~l-6~9a)-oxide-lla,15S-dihydroxy-prost-13-enoic
acid;
13t-16,16-dimethyl-5-bromo-6~H-6~9a)-~oxide-lla,15S~dihydroxy-prost-13-enoic
acid.
Example 96
To a solution of hydrotribromide pyrrolidone ~1.1 molar equivalents~
in anhydrous tetrahydrofuran ~6 ml) is added a solution of 5c,13t-9a,11a,15S-
trihydroxy-18,19,20-trinor-17-cyclohexyl-prost-5,13-dienoic acid methyl ester-
11,15-bis-tetrahydropyranyl eth~r (0,7 g) in 6 ml of tetrahydrofuran~ The
mixture is stlrred for 12 hours, the precipitatc which forms is removed by
filtration, and the tetrahydrofuran solution is diluted with 2 volumes of
acetone and treated with 4 g of potassium iodide. After 4 hours at room
temperature, the iodine liberated is decomposed with sodium metabisulfate.
1.5 volumes of O.lN aqueous oxalic acid is then added and the mixture heated
to 48 C for 4 hours. The mixture is reduced under vacuum and extracted with
ethyl acetate. Separation on TLC gives 0.1~ g of 13t-5-bromo-6H-6(9a)-oxide-
lla,15S dihydroxy-18~19,20-trinor-17_cyclohexyl-prost_13_enoic acid methyl
ester and 0,11 g of the 5-bromo-6~H-6(9~)-oxide.
Using procedures of the examples 95 and 96, the following 6(9~)-
oxides were obtained:
5-b~olno 6~l~6~9a~oxide 11~,15S~dihydroxy~18,19,20 trinor 17-cyclohexyl
prost-13~ynoic acid methyl ester;
5-bromo-6~l-6t9a)-oxide-11-~,15S dihydroxy-prostanoic acid;
~ /0
-~,
13t-S-bromo-6~H-6C9a~-oxide~ ,15S~dihydroxy-prost-13~enoic acid;
13t-20-methyl-5-bromo 6~H~6~9a)-oxide~ ,15S-dihydroxy prost-13-enoic acid;
13t-15-methyl-5-bromo-6~H-6(9a)-oxide-lla,15S-dihydToxy~prost-13~enoic acid;
13t-15-methyl-5-bromo-6~-6(9a)-oxide-ll~,lSS-dihydroxy-prost-13-enoic acid;
13t-16S-methyl-5-bromo-6~H-6~9~oxide-11~,15S-dihydroxy-prost-13-enoic acid;
13t-5-bromo-6~H-6(9~-oxide-lla,15S-dihydroxy-18,19,20-trinor-17-cyclohexyl-
prost-13-enoic acid;
13t-5-bromo~6~H-6(9~-oxide-lla,15S-dihydroxy-17,18,13,20-tetranor-16-m-tri-
fluoromethyl-phenoxy-prost-13-enoic acid.
Example 97
A solution of 0.1 x 10 3 M of a methyl ester, prepared according to
examples 93 to 96 in 2 ml of methanol is treated with 1 ml of an aqueous
solution of llthium hydrate ~0.2 x 10 3 moles). The mixture is stirred for 3
hours, evaporated nearly to dryness, diluted with 5 ml of water, and extracted
with ethyl ether.
The organic phase is washed with O.lN LiOH ~2N) and water, and is
then discarded. The aqueous phase is acidified to pH 4.8 with 30% aqueous
NaH2PO4 and extracted with ethyl ether to give the free acid.
/0
-~o_
